Food Hydrocolloids as Encapsulating Agents in Delivery Systems [1 ed.] 9781138600140, 9780429470585, 9780429894169, 9780429894152, 9780429894176

Table of contents :



Preface


Editors


Contributors



Chapter 1 Introduction to Food Hydrocolloids


BASHARAT YOUSUF, NISAR AHMAD MIR, MAMTA BHARDWAJ, KHALID GUL, AND ALI ABAS WANI



Chapter 2 Gum-Based Delivery Systems


UMAR SHAH, PRAKHAR CHATUR, HAYDER AL-ALI, MUDASIR AHMAD, ADIL GANI, F. A. MASOODI, AND ASIR GANI



Chapter 3 Starch-Based Delivery System


UMAR SHAH, PRAKHAR CHATUR, HAYDER AL-ALI, MUDASIR AHMAD, ADIL GANI, ASIR GANI, AND F. A. MASOODI



Chapter 4 β-Glucan–Based Delivery System


ASIMA SHAH, F. A. MASOODI, ADIL GANI, AND BILAL AHMAD ASHWAR



Chapter 5 Protein-Based Delivery Systems


SAJAD A. RATHER, F. A. MASOODI, JAHANGIR A. RATHER, REHANA AKHTER, AND TARIQ AHMAD GANAIE



Chapter 6 Nanoscale Encapsulation


ALIREZA MEHREGAN NIKOO, NUSHIN NIKNIA, NEDA RAHMANIAN, AND TOUSEEF AHMED WANI



Index

Citation preview

Food Hydrocolloids as Encapsulating Agents in Delivery Systems

Food Hydrocolloids as Encapsulating Agents in Delivery Systems

Edited by

Adil Gani, F. A. Masoodi, Umar Shah, and ­Asima Shah

CRC Press Taylor & Francis Group 6000 Broken Sound Parkway NW, Suite 300 Boca Raton, FL 33487-2742 © 2019 by Taylor & Francis Group, LLC CRC Press is an imprint of Taylor & Francis Group, an Informa business No claim to original U.S. Government works Printed on acid-free paper International Standard Book Number-13: 978-1-138-60014-0 (Hardback) This book contains information obtained from authentic and highly regarded sources. Reasonable efforts have been made to publish reliable data and information, but the author and publisher cannot assume responsibility for the validity of all materials or the consequences of their use. The authors and publishers have attempted to trace the copyright holders of all material reproduced in this publication and apologize to copyright holders if permission to publish in this form has not been obtained. If any copyright material has not been acknowledged please write and let us know so we may rectify in any future reprint. Except as permitted under U.S. Copyright Law, no part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, and recording, or in any information storage or retrieval system, without written permission from the publishers. For permission to photocopy or use material electronically from this work, please access www.copyright.com (http://www.copyright.com/) or contact the Copyright Clearance Center, Inc. (CCC), 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400. CCC is a notfor-profit organization that provides licenses and registration for a variety of users. For organizations that have been granted a photocopy license by the CCC, a separate system of payment has been arranged. Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe. Visit the Taylor & Francis Web site at http://www.taylorandfrancis.com and the CRC Press Web site at http://www.crcpress.com

Contents P r e fa c e vii E d i t o r s ix

C o n t r i b u t o r s xiii C h a p t e r 1 I n t r o d u c t i o n

to

F o o d H y d r o c o l l o i d s 1

B A S H A R AT YO U S U F, N I S A R A H M A D M I R , M A M TA B H A R DWA J , K H A L I D G U L , A N D A L I A B A S WA N I

C h a p t e r 2 G u m - B a s e d D e l i v e r y S y s t e m s 29 U M A R S H A H , P R A K H A R C H AT U R ,

H AY DE R A L -A L I , M U DA S I R A H M A D, A D I L G A N I ,

F. A . M A S O O D I , A N D A S I R G A N I

C h a p t e r 3 S ta r c h - B a s e d D e l i v e r y S y s t e m 85 U M A R S H A H , P R A K H A R C H AT U R ,

H AY DE R A L -A L I , M U DA S I R A H M A D, A D I L G A N I , A S I R G A N I , A N D F. A . M A S O O D I

C h a p t e r 4 β - G l u c a n – B a s e d D e l i v e r y S y s t e m 129 A S I M A S H A H , F. A . M A S O O D I , A D I L G A N I , A N D B I L A L A H M A D A S H WA R

C h a p t e r 5 P r o t e i n - B a s e d D e l i v e r y S y s t e m s 159 S A J A D A . R AT H E R , F. A . M A S O O D I ,

J A H A N G I R A . R AT H E R , R E H A N A A K H T E R , A N D TA R I Q A H M A D G A N A I E

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C o n t en t s

C h a p t e r 6 N a n o s c a l e E n c a p s u l at i o n 189 A L I R E Z A M E H R E G A N N I KO O, N U S H I N N I K N I A ,

N E DA R A H M A N I A N , A N D T O U S E E F A H M E D WA N I

I n d e x 213

Preface Encapsulation involves packaging of sensitive materials in a s­ uitable carrier material in a guest–host kind of relation that protects it against deleterious reactions before the active compound is released under a suitable set of conditions. This technology of delivering sensitive compounds has made tremendous achievements in the field of food and medicine wherein the main objective behind encapsulation is to protect the bioactive compounds against harsh gastrointestinal conditions, besides other deleterious reactions. Size of the capsules is one of the most important properties of encapsulated products that ­determine their potency. In general, nanocapsules are preferred over microcapsules and larger particulates. Food-grade hydrocolloids form the basis of delivery systems targeted for food and medical ­applications as these are generally recognized as safe and have no safety issues thereof. Different encapsulated products have already been commercialized by various food and pharmaceutical industries of the world. Although fabrication of delivery systems from food-grade materials has fetched greater attention in the last couple of decades, there is great scope for the development of delivery systems for desired ­applications. Food hydrocolloids as wall materials in encapsulation systems have high biocompatibility and can release the payload at the target of interest. The structural attributes of different biopolymers vii

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P refac e

are naturally inspired for encapsulating bioactive compounds. Some of these include cyclodextrins, starches, and β-glucans. This book briefly describes various emerging biomaterials i­ncluding food gums, starches, β-glucans, and proteins for their potential role as wall materials in the development of nutraceutical delivery ­systems. In addition, the book describes different techniques of ­fabrication of nanodelivery systems. This book would be helpful to readers of ­different areas including nanotechnology, polymer ­chemistry, and ­nutraceutical delivery. Finally, we acknowledge the contributors and our fellow researchers for compiling the book. We are also ­thankful to CRC Press/Taylor & Francis Group for their assistance. We wish a great success to this book. Dr. Adil Gani

Editors Dr. Adil Gani is currently a faculty member in the department of food science and technology, University of Kashmir, Srinagar, India. He received his PhD degree in 2008 from SHIST, Allahabad, India. He has been awarded with a Fulbright fellowship for Research and Academic Excellence in the United States (2017–2018) to be availed at Cornell University, Ithaca, New York. His research interests include characterization of major components of food such as proteins, starches, and dietary fibers (mainly β-glucans); encapsulation and targeted delivery of bioactive compounds such as probiotics and phenolics through the gastrointestinal tract; development and characterization of active packaging films; fortification of bakery foods with protein concentrates; development of functional foods with anticancerous and antioxidant activity; and nutraceutical potential of bioactive peptides. He has also been awarded a “Young Scientist Award (Innovations in Research Career)” at ICFP-2018 in the United Arab Emirates. He is president of the Association of Food Scientists  & Technologists (India) (AFSTI), Jammu and Kashmir Chapter (India), lifetime member of the AFSTI, and organizing committee member in “World Congress on Cancer Diagnosis, Treatment and Rehabilitations 2016” for the theme “Food and Its Anticancer Properties.” He has published more than 80 research and review articles in high impact journals of international reputation such as Food ix

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Chemistry, Food Hydrocolloids, Carbohydrate Polymers, Innovative Food Science and Technology, and Royal Society of Chemistry. He has been actively working on the ­targeted delivery of bioactive components using various encapsulating agents. Prof. F. A. Masoodi is currently dean of the School of Applied Sciences & Technology besides heading the department of food science and technology at the University of Kashmir, Jammu and Kashmir, India. After graduating in agricultural sciences, Prof. Masoodi obtained his higher education in food technology from some reputed agricultural institutes of India, which include G. B. Pant University of Agriculture and Technology, Pantnagar, and Punjab Agricultural University, Ludhiana, India. He remained associated with four ­universities of India as a faculty member and played a pioneering role in ­establishing departments of food technology at the University of Kashmir and Chaudhary Charan Singh Haryana Agricultural University, Haryana, India. He has supervised eight PhD scholars so far besides guiding many students for their postgraduate dissertations. He has published around 200 research articles besides four book chapters. His research work has earned him more than 2,100 citations with h-index and i-10 index of 24 and 58, respectively. He has done a pioneering work on the utilization of apple pomace—a by-product of the apple processing industry. He has attended and delivered lectures in numerous conferences and seminars. He also holds memberships in various academic bodies, namely, National Assessment and Accreditation Council (NAAC); Indian Council of Medical Research (ICMR) working group on micronutrients; Research Advisory Committee of National Dairy Research Institute (NDRI), Haryana; and National Agri-Food Biotechnology Institute (NABI), to mention a few. In addition, he has been a member of Expert Panel on Food Additives, Food Safety and Standards Authority of India (FSSAI), Ministry of Health, Govt. of India. Umar Shah is a doctoral fellow of the University Associate School of Molecular and Life Sciences, Curtin University, Bentley and Perth, Australia. He obtained his master’s degree in food technology from Amity University, Noida, India, in 2013. His research interests include the development of active packaging, nanofilms and

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edible coatings, and quantitative and qualitative approaches of using food-processing technologies with knowledge in material properties (animal and plant based) in tailoring the functional and nutritional properties of the system. Dr. Asima Shah is an INSPIRE faculty of the department of food science and technology, University of Kashmir, Jammu and Kashmir, India. She received her PhD degree in 2017 from the University of Kashmir. Her research interests include characterization of polysaccharides such as starches, β-glucans, and pentosans; development of resistant starches; encapsulation and targeted delivery of bioactives; and development of active biodegradable packaging films. She is a lifetime member of the Association of Food Scientists & Technologists (India) (AFSTI), Karnataka, India, and the American Society for Microbiology (ASM).

Contributors Mudasir Ahmad Department of Food Science and Technology University of Kashmir Srinagar, Jammu and Kashmir, India Tariq Ahmad Ganaie Department of Food Science and Technology Islamic University of Science and Technology Awantipora, Jammu and Kashmir, India Rehana Akhter Department of Food Science and Technology University of Kashmir Srinagar, Jammu and Kashmir, India

Hayder Al-Ali School of Molecular and Life Science Curtin University Perth, Australia Bilal Ahmad Ashwar Department of Food Science and Technology University of Kashmir Srinagar, Jammu and Kashmir, India Mamta Bhardwaj Department of Food Engineering and Technology Sant Longowal Institute of Engineering and Technology Sangrur, Punjab, India

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Prakhar Chatur School of Public Health Curtin University Perth, Australia Asir Gani Department of Food Technology Prince of Songkla University Hat Yai, Thailand Khalid Gul Department of Food Science and Technology Gyeongsang National University Jinju, Republic of Korea Nisar Ahmad Mir Department of Food Engineering and Technology Sant Longowal Institute of Engineering and Technology Sangrur, Punjab, India Nushin Niknia Department of Food Chemistry Research Institute of Food Science and Technology Mashhad, Iran Alireza Mehregan Nikoo Department of Food Science and Technology University of Guilan Rasht, Iran

Neda Rahmanian Department of Food Science and Technology University of Jahrom Jahrom, Iran Jahangir A. Rather Department of Food Science and Technology University of Kashmir Srinagar, Jammu and Kashmir, India Sajad A. Rather Department of Food Science and Technology University of Kashmir Srinagar, Jammu and Kashmir, India Ali Abas Wani Process Development for Plant Raw Materials Fraunhofer Institute of Process Engineering and Packaging IVV Freising, Germany Touseef Ahmed Wani Department of Food Science and Technology University of Kashmir Srinagar, Jammu and Kashmir, India

C o n t ribu t o rs

Basharat Yousuf Department of Post-Harvest Engineering and Technology Aligarh Muslim University Aligarh, Uttar Pradesh, India

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1 I ntro ducti on to F o od H yd ro collo ids B A S H A R AT Y O U S U F Aligarh Muslim University

NISAR AHMAD MIR AND M A M TA B H A R D WA J Sant Longowal Institute of Engineering and Technology

K H A LID GUL Gyeongsang National University

A L I A B A S WA N I Fraunhofer Institute of Process Engineering and Packaging IV V

Contents

1.1 Introduction 2 1.1.1 Food Hydrocolloids as Encapsulating Agents 4 1.1.2 Regulatory and Health Aspects of Hydrocolloids 5 1.1.2.1 Regulatory Aspects of Hydrocolloids 5 1.1.2.2 Health-Related Aspects of Hydrocolloids 7 1.1.3 Well-Known and Commonly Used Food Hydrocolloids in Encapsulation Technologies 11 1.1.4 Approaches in Use of Hydrocolloids for Encapsulation 16 1.1.5 Need to Shift Encapsulation Technology from Micro to Nano Level 16 1.1.5.1 Food Hydrocolloids and Their Use as Nanoencapsulating Agents 18 1.1.6 Future Prospects 21 References 21

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1.1 Introduction

The term “hydrocolloid” is derived from the Greek word hydro meaning “water” and kola meaning “glue.” Hydrocolloids are colloidal substances that consist of hydrophilic, long-chain, and high-­molecularweight molecules with a strong affinity for water. Hydrocolloid is a contraction of hydrophilic colloid and is the more scientific name for gums. Hydrocolloids produce highly viscous suspensions or gels when dispersed in water and are termed as hydrophilic colloids or hydrocolloids considering their strong hydrophilic nature and for producing a dispersion, which is intermediate between a true solution and a suspension (Saha and Battacharya, 2010). Hydrocolloids are obtained from botanical sources (starch, cellulose, pectin, gum arabic, karaya, tragacanth, β-glucan, etc.), seaweeds (agar, alginate, and carraggenan), animal sources (gelatin, chitosan, and hyaluronan), and bacterial sources (xanthan, gellan, and dextran). Table 1.1 shows different types of food hydrocolloids and their sources. Hydrocolloids form the basis for much of the energy and nutrients required by the human body and also contribute to the macroscopic structure of foods (Gidley, 2013). They, therefore, play a major role in defining both the sensory and nutritional qualities of human diets. Hydrocolloids are primarily used for thickening and/or gelation, but they often exhibit related secondary functions, such as emulsifying, suspending, whipping, viscosifying, and encapsulating (Janaswamy & Youngren, 2012). They are ubiquitous—no other ingredient contributes more to viscosity, texture, and body in processed foods like they do. Once dispersed in water, hydrocolloids give a thickening or viscosity-producing effect. This property of thickening is common to all hydrocolloids, and the primary reason behind the ample use of hydrocolloids in foods is their ability to modify the rheology of food systems. This includes flow behavior (viscosity) and mechanical solid property (texture), which are the two basic properties of food systems (Milani & Maleki, 2012). The extent of thickening depends on the type and nature of hydrocolloids used. Most of the hydrocolloids result in high viscosities at concentrations below 1%, whereas a few result in low viscosities at a fairly high concentration (Glicksman, 1982). The selection of a hydrocolloid in processed foods is dictated by the functional characteristics required, but the price and security of

Starch Pectin Alginate Agar Cellulose Carrageenan

PLANT EXTRACTS

Guar gum Locust bean gum Tamarind seed gum Tara gum Konjac

SEEDS Gelatin Caseinates

ANIMAL EXTRACTS Gum acacia Gum arabic Tragacanth Karaya gum Gum ghatti

EXUDATES

Table 1.1  Commonly Used Hydrocolloids in Food Industries and Their Sources

Xanthan Dextran Gellan Pullan Gellan Curdlan

MICROBIAL POLYSACCHARIDES

Modified starches Amidated pectins Propylene glycol alginate Cellulose derivatives

MODIFIED POLYSACCHARIDES

Microcrystalline cellulose Methylcellulose Ethylcellulose Hydroxypropylmethylcellulose Hydroxypropylcellulose Carboxymethylcellulose

CELLULOSE-BASED POLYMERS

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supply influence the usage. Starches are, therefore, being widely used in food industries as gelling and thickening agents. Food hydrocolloids being an important additive are finding increasing applications for the encapsulation of nutraceuticals and functional ingredients. They are very convenient as a wall material for nutraceuticals and other food ingredients, since the majority of the hydrocolloids are soluble in aqueous solutions, thus avoiding toxicity problems (Pérez-Masiá et al., 2015). In this chapter, food hydrocolloids as encapsulating agents, their regulatory aspects, and their ­current applications are discussed. 1.1.1 Food Hydrocolloids as Encapsulating Agents

The most important groups of ingredients used in stabilizing and protecting flavors are the hydrocolloids. Hydrocolloids are hydrophilic polymers that are extracted from plants and animals and have been successfully used for the entrapment, protection from the environment, and controlled release of high-valued food products such as antioxidants, antimicrobials, flavors, and probiotics. Hydrocolloids have been successfully demonstrated to protect the encapsulated molecules from external stressors, preserve functionality, and deliver efficiently at the target site (Polowsky & Janaswamy, 2015). Considering incompatibilities to the human digestive system, some hydrocolloids are modified using physicochemical and biochemical methods to improve their encapsulating properties. Starch and its derivatives, maltodextrins, cellulose, agar, carrageenans, gum arabic, alginates, low methoxyl (LM) pectin, chitosan, gellan gum, and gelatin are the natural polymers which are potentially used for encapsulation (King, 1995). Protein-based delivery systems have also been used for the encapsulation recently. The properties that make natural polymers useful for encapsulation–entrapment applications have been reviewed by Reineccius (1989) and Grover (1993) and Whistler (1993). The selection of wall material is very important because it influences the encapsulation efficiency and stability. The ideal wall material should not be reactive with the core, have the ability to seal and maintain the core inside the capsule, be able to provide maximum protection to the core against adverse conditions, lack an unpleasant taste,

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and be economically viable. Food hydrocolloids offer all these benefits and are, therefore, an ideal choice as a wall material for encapsulation. Different techniques have been used to encapsulate functional components using polymeric materials, including extrusion (Li et al., 2011), fluidized bed coating (Zuidam & Shimoni, 2010), nanoemulsions (Silva et al., 2012), coacervation (Tamjidi et al., 2012), spray cooling (Gibbs et al., 1999), and spray drying (Murugesan & Orsat, 2012). The techniques used for the encapsulation strongly influence the stability and delivery of the encapsulated substances, which are beyond the scope of this book. 1.1.2 Regulatory and Health Aspects of Hydrocolloids

1.1.2.1 Regulatory Aspects of Hydrocolloids 1.1.2.1.1  Joint FAO/WHO Expert Committee on Food Additives  There

are no separate laws for regulation of hydrocolloids. They are dealt in the category of food additives or food ingredients. For regulation, a committee called Joint FAO/WHO Expert Committee on Food Additives (JECFA) administered jointly by the Food and Agriculture Organization (FAO) of the United States and the World Health Organization (WHO) was enacted to evaluate the safety of food additives. JECFA provides reports related to specifications, safety, and other aspects of a food additive to the Codex Committee on Food Additives and Contaminants (CCFAC). If the members of the Codex Alimentarius Commission agree, then the specified food additive is assigned with a unique identification number International Numbering System (INS) and included in the Codex General Standard for Food Additives (GSFA). An online database called GSFA is available to check the provisions related to a food additive covered under FAO/WHO Food Standards Codex Alimentarius (Phillips & Williams, 2009). 1.1.2.1.2  European System  Different Commission regulations have

been developed for the list of approved food additives and the specifications of food additives. The food additives that have been approved by the European Union are available in Commission Regulation (EU) No 1129/2011 amending Annex II to Regulation  (EC)

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No 1333/2008. This regulation covers the names and E numbers of different additives, definitions for the group of additives, foods to which they may be added, and the conditions in which they can be used. Another regulation covers the specifications of approved food additives such as criteria of purity, origin, and other relevant information. The specifications are covered in Commission Regulation (EU) No 231/2012. Table 1.2 shows the E numbers assigned to hydrocolloids as food additives and the statuses related to ADI value, quantum satis, and GRAS, which are described as follows: E number is an indicative of the code assigned to a substance which has been permitted to be used as a food additive under the European system. ADI value represents the acceptable daily intake amounts of the food additive in question. GRAS covers those food additives which are “generally recognized as safe” for human consumption. Quantum satis is a term used to indicate that no maximum level has been specified for the food additive. 1.1.2.1.3 Manufacturing Process Changes and, Safety, and Regulatory Status of Hydrocolloids  A book guidance for the industry has been

developed by the Food and Drug Administration (FDA) for determining the influence of manufacturing process changes on different food ingredients and food contact substances, and this covers manufacturing processes of hydrocolloids as well. For example, under 21 CFR 172.620 regulation, carrageenan is defined as “a refined hydrocolloid prepared by aqueous extraction from specific red seaweeds.”

Table 1.2  European Union Specifications of Some Hydrocolloids HYDROCOLLOID

E NUMBER AS PER EUROPEAN FOOD ADDITIVE SYSTEM

ADI

GRAS

QUANTUM SATIS

Alginates Agar Carrageenans Pectins Xanthan gum Pullulans Gum arabic

E 400–405 E 406 E 407 E 440 E 415 E 1204 E 414

Not specified Not specified 75 mg/kg Not specified Not specified Not specified Not specified

✓ ✓ ✓ ✓ ✓ ✓ ✓

– ✓ ✓ ✓ ✓ ✓ ✓

Source: Data adapted from Commission Regulation (EU) No 1129/2011 of 11 November 2011 amending Annex II to Regulation (EC) No 1333/2008 of the European Parliament and of the Council by establishing a Union list of food additives Text with EEA relevance.

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In this regulation, the seaweeds from which carrageenan is extracted are listed. Any change in the manufacturing process is submitted to FDA so as to get the GRAS status. Another example is xanthan gum, which is regulated by 21 CFR 172.695 regulation (FDA, 2012). 1.1.2.2  Health-Related Aspects of Hydrocolloids  Health-related aspects

of hydrocolloids are greatly determined by their amount and the way of their incorporation into the food system. In general, some common properties of hydrocolloids are credited for their positive as well as negative health-related impacts, for example, viscosity and gelforming properties (guar gum, alginates, inulin, pectin, etc.), bulk or water-sequestering properties (cellulose derivatives, hemicellulose, etc.), and the ability to get fermented (pectin, resistant starch, some oligosaccharides, etc.) (Cummings et al., 1992; Dikeman & Fahey, 2006). Various gums such as guar gum, locust bean gum, and xanthan gum exhibit blood cholesterol-lowering properties; polysaccharides such as cellulose and hemicellulose derivatives aid in maintaining the colon health (Gidley, 2013); and others such as inulin show prebiotic effects (Hecker et al., 1998). Thus, in the case of encapsulation, the synchronized effect on health can be observed because of the target and the encapsulating hydrocolloid, depending upon the concentration or amount of hydrocolloid and the nature of target in question. The first and foremost reason behind the usefulness of hydrocolloids in relation to health aspects is their partial or indigestible nature, thus acting as a dietary fiber. Dietary fiber is defined as “the edible parts of plants or analogs of carbohydrates which are resistant to digestion and absorption in small intestine rather are partially or completely fermentable in large intestine” (Arendt & Zannini, 1991). There has been an alarming increase in the incidences of chronic diseases such as diabetes mellitus, colon cancer, and cardiovascular diseases mainly due to heavy consumption of sugars, and high-fat and highcalorie foods. According to a joint report of FAO/WHO, there is a need for increasing the dietary fiber and decreasing the sugar intake (Brennan & Tudorica, 2008). Soluble dietary fibers comprise gums (hydrocolloids), which are one of the important classes of dietary fibers (Dziezak, 1991). Thus, hydrocolloids acting as dietary fiber perform protective functions such as maintaining the colorectal health, decreasing the blood cholesterol (Theuwissen & Mensink, 2008),

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acting as a prebiotic (Hecker et al., 1998), and modifying the blood glycemic response (Christodoulides et al., 2016). Hydrocolloids can portray an inherent role in maintaining colon health because they can possess a large proportion of dietary fiber from 60 to 90% (Viebke et al., 2014). Apart from the inbuilt health benefits of hydrocolloids, these aid in targeted delivery of various drugs, flavoring compounds, and other sensitive bioactive ingredients. Gums are used in colontargeted delivery systems, because they are fermented in the colon and remain indigestible in the stomach and small intestine (Bhosale et al., 2014). In Section 1.1.2.2.1, some of the health implications of hydrocolloids are discussed. 1.1.2.2.1  Colon Health, Prebiotic Role, and Probiotic Delivery  Hydroc

olloids in the colon either function as a prebiotic or add bulk to the stool and may act as both in some cases. In both cases, colon health is promoted. The hydrocolloids that act as prebiotics are fermented in the colon after their transit from the small intestine, resulting in the production of short-chain fatty acids (SCFAs) which are beneficial for colon health, and gases such as hydrogen sulfide are also formed. For instance, inulin acts as a prebiotic and one of its fermented products is butyric acid, which has been found to inhibit the inflammation of colon. In chronic diseases such as chronic vascular disease and colon cancer, inflammation is one of the significant factors (de Souza Oliveira et al., 2011). In addition to this, fermentable hydrocolloids improve bowel movement, competition against pathogenic microorganisms, SCFAs act as energy for colon cells and inhibition of cancerpromoting metabolites, etc. In addition, hydrocolloids carry nutrients to the large intestine via encapsulation (Saura-Calixto, 2010). The disadvantage of these prebiotics is the inevitable formation of gases which may cause flatulence and cramps. In addition, hydrocolloids such as psyllium and gellan show poor fermentation properties, and these exhibit water-holding capacity, resulting in fecal bulking. Due to this, the transit time through the colon is reduced, thus preventing constipation (Passmore et al., 1993). The final call of action of these hydrocolloids depends on the amount and the method by which they are introduced in the body (Brennan et al., 1996). Besides acting as prebiotics, hydrocolloids have the ability to act as carriers for probiotics through microencapsulation. Probiotics aid in

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preventing gastrointestinal diseases. These need to be microencapsulated because of their sensitivity to bile salts, acidity, and oxygen. Shi et al. (2013) explored carrageenan–locust bean gum as an encapsulating agent to encapsulate Lactobacillus bulgaricus in the form of milk microspheres. It was indicated that microencapsulation can improve the viability and stability of probiotic microorganisms. 1.1.2.2.2  Gastric Residence Time and Type 2 Diabetes  Diabetes mel-

litus is associated with the disturbance in glucose metabolism due to the deficiency of insulin hormone, thus resulting in hyperglycemia (American Diabetes Association, 2014). Glycemic Index (GI) is used to define the ability of any carbohydrate food to elevate the blood glucose level after its consumption. The glucose level in the blood after a meal is termed as postprandial response. Postprandial blood glucose is affected by the speed of gastric emptying. It has been indicated that carbohydrate diets that possess lower GI and are unavailable for digestion improve the sensitivity of insulin (Livesey et al., 2008). Hydrocolloids such as gums cause delayed absorption of carbohydrates by increasing the viscosity of the ingredients in the stomach. The gelling property of gums imparts gastric volume and increases fullness compared to the meals which do not gel and dilute homogenously in the stomach (Hoad et al., 2004). Thus, hydrocolloids are found to increase the residence time of food in the stomach, which results in delayed gastric emptying. Thus, decreasing the postprandial glucose response and delay in perceived satiety (Qi et al., 2018) helps in the management of obesity too (Peters et al., 2011). Various hydrocolloids such as guar gum, inulin, gum arabic, and psyllium amongst others have shown evidence of their effect in regulating diabetes, but β-glucan is an exception in this respect (Li & Nie, 2016). In addition to a crucial link between hydrocolloids and diabetes, another subject of interest is the regulation of appetite. Gastric gelation due to hydrocolloids is further responsible behind the prolonged satiety which helps in controlling the total energy intake and thus aids in weight management and provides sustained supply of nutrients (Norton et al., 2006). One such example is micellar casein in milk (Peters et al., 2011). Casein forms the major protein (80%) of milk and is not readily digested compared to whey protein fraction (minor component) (Boirie et al., 1997). This occurs because casein

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shows gelation in the stomach, whereas whey protein does not gel. The difference in absorption is crucial in the case of infant nutrition. This delayed absorption of casein provides sustained delivery of amino acids and calcium, and thus aids in the development of muscles and bones, respectively (Gidley, 2013). 1.1.2.2.3  Hydrocolloids and Coronary Heart Disease  Serum cholesterol

level and low-density lipoproteins are potential markers for elucidating the risk of developing coronary heart disease. Out of various hydrocolloids, glucomannan, β-glucan, and konjac-mannan are the three most effective hydrocolloids that are found to play a key role in maintaining the blood cholesterol levels as per the European Food Safety Authority (Viebke et al., 2014). Psyllium and β-glucan have been approved by FDA for their contribution in reducing the risk of coronary heart diseases (Feinglos et al., 2013). Hydrocolloids act by various probable mechanisms, for instance, increasing the fecal loss of bile acids. This induces the bile production from the liver that accelerates cholesterol oxidation (Stedronsky, 1994); they increase the viscosity and fibers have the ability to reduce bile acid absorption (Anderson et al., 1994). Apart from this, hydrocolloids can be used for microencapsulation of omega-3 fatty acids and phytosterols in order to reduce the risk of cardiovascular diseases. Omega-3 fatty acids act as precursors in forming anti-inflammatory mediators. The role of ω-3 fatty acids in reducing the cardiovascular diseases is pretty much established (von Schacky, 2007). But these fatty acids are prone to oxidation and thus can be delivered via microencapsulation. Phytosterols help in maintaining the membrane integrity and reduce the absorption of intestinal cholesterol. Unstable and water-insoluble behavior of these compounds makes it imperative to go for some targeted delivery techniques such as microencapsulation. Number of studies have been conducted on the microencapsulation of sources of these compounds or the compounds themselves using hydrocolloids such as gelatin and chitosan to encapsulate limonene oil (Prata & Groso, 2015), gum arabic for ω-3 ethyl esters (de Conto et al., 2013), whey protein and gum arabic for tuna oil (Eratte et al., 2015), and gelatin and polyphosphate for fish oil (Barrow et al., 2009). Therefore, hydrocolloids help in reducing cardiovascular diseases via targeted delivery of ω-3 fatty acids and phytosterols by means of microencapsulation.

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1.1.3 Well-Known and Commonly Used Food Hydrocolloids in Encapsulation Technologies

Different materials are used to encapsulate food or any other biological materials. However, not all materials are certified for food applications. The majority of materials used for microencapsulation in the food sector are biomolecules which mostly involve carbohydrate polymers/polysaccharides. A number of hydrocolloids are being used as encapsulating agents for encapsulation of different bioactive or other sensitive compounds, either for their protection from the external environment or for the sustained/controlled release of such components in any system. In this section, we present the commonly used food hydrocolloids for encapsulation. Hydrocolloids are used extensively in encapsulation of food ingredients as the encapsulating agent/ wall material. A number of carbohydrates and proteins have already been investigated and are being used as encapsulating agents in both the food and pharmaceutical industries (Table 1.3). Maintaining the protein integrity during encapsulation and release has been a major challenge, and therefore, novel methodologies to overcome this obstacle are of much importance (Castellanos et al., 2003). Nonetheless, hydrocolloids are being extensively used for encapsulation and formation of capsules that encase the core material. Generally, capsules can be categorized into various groups depending upon their size such as macrocapsules (>5,000 μm), microcapsules (0.2–5,000 μm), and nanocapsules (40%), gum arabia forms a highly viscous, gel-like mass and shows pseudoplastic behavior, whereas at low concentrations it exhibits Newtonian behavior (Karamalla, Siddig & Osman, 1998).

Table 2.2  Specifications of Gum Arabic S. NO. 1 2 3 4 5 6 7 8

COMPOUND

MINIMUM QUANTITY

Arsenic (AS) Ash (total) Ash (acid insoluble) Heavy metals (as Pb) Lead Insoluble matter Loss on drying Starch, dextrin

>3 ppm >4% >0.5% >40 ppm >10 ppm >1% >15% >0.1%

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37

Table 2.3  Chemical Composition of Gum Arabic S. NO.

COMPOSITION

RANGE (% AGE)

1 2 3 4 5 6 7

Galactose Arabinose Rhamnose Glucuronic acid Protein Nitrogen Moisture

39–42 24–27 12–16 15–16 1.5–2.6 0.22–0.39 12.5–16.0

2.3.1.2  Gum Arabic as an Micro- and Nanoencapsulating Agents  Al-Assaf

et al. (2007) suggested gum arabic as a useful prebiotic with beneficial physiological effects. The gum arabic is highly when used in combination with other gums, proteins and carbohydrates. It is widely used for encapsulation of bioactives due to its high ­emulsifying properties, high solubility, low viscosity, biocompatibility, e­ cofriendly, and biodegradability (Devi et al., 2017; Priftis et al., 2012). Zhang and Liu (2011) encapsulated cardamom oleoresin in combination with gum arabic, maltodextrin, or modified starch by spray drying. The gum arabic and maltodextrin were used as encapsulated agents for encapsulation of salmon oil in microgels to increase the level of polyunsaturated fatty acids in the yoghurt from 1.76% to 7.50% ­without affecting pH, syneresis, and color of yoghurt. Spray-drying technique was used to encapsulate Bifidobacterium infantis (CCRC 14633), B. infantis (CCRC 14661), B. longum (ATCC 15708), and B. longum (CCRC 14634) in gum acacia, gelatin, and soluble starch. The size of the capsule was 10–20 μm with fair encapsulation efficiency. The spray-drying technique was used to encapsulate Lactobacillus acidophilus (BCRC 1407) and B. longum (BCRC 14605) in 20% gum a­ rabic and 30% maltodextrin with an overall size of 10 μm of capsule, and inlet and outlet temperatures of 100°C and 50°C, respectively. The gum acacia was also used as an encapsulated agent for ­delivery of Lactobacillus paracasei (NFBC 338) (Desmond et al., 2002). Curcumin was encapsulated in highly water-soluble polysaccharide gum arabic for its enhanced delivery to hepatocarcinoma cells. An increased curcumin collection of HepG2 cells due to the targeted efficiency of the galactose groups was present in this gum. Miniemulsion technique was used for the preparation and identification of gelatin-gum arabic aldehyde nanogels. The in vitro cytotoxicity of the gel was characterized and found

38

UM A R SH A H E T A L .

to be nontoxic to cells, thus making it a potential candidate for drug and gene delivery (Sarika & James, 2015). Ilyasoglu and Nehir (2014) nanoencapsulated fish oil with gum arabic and sodium caseinate with multilayered interfacial membranes using electrostatic attraction between sodium caseinate and gum arabic. The encapsulation efficiency and particle size were 78 and 232 nm, respectively, with good bioaccessibility upon in vitro digestion. Jasmine oil was nanoencapsulated in gum arabic and gellan gum by complex coacervation. The nanocapsule showed good flavor control of jasmine essential oil up to 5 h of storage (Lv et al., 2014). An encapsulation efficiency of 90% was achieved when curcumin-loaded with biopolymeric nanodispersion containing sodium caseinate and gum arabic was prepared and characterized. The salvianolic acid B (Sal B) was encapsulated in starch nanoparticles (StNPs) and acacia nanocomposite by self-assembly and embedded in suit. Various blends of gums were prepared and characterized. The in vitro release profile of Sal B from StNPs and gum nanocomposite was prolonged for over 12 h, indicating that StNPs and gum nanocomposites are proficient candidates for the controlled release of Sal B (Li et al., 2017). An anticancerous, hydrophobic, and polyphenolic agent (curcumin) was nanoencapsulated in gum arabic aldehyde-gelatin nanogel to improve its bioavailability and therapeutic efficiency toward cancer cells. The in vitro drug release showed an encapsulation efficiency of 65% and induced toxicity in MCF-7 cells, and consequently suggested as a good carrier for anticancerous drugs (Sarika and Nirmala, 2016). 2.3.2 Gum Tragacanth

2.3.2.1 Introduction  This complex heterogeneous polysaccharide

occurs naturally as slightly acidic, calcium, magnesium, or potassium salt with a molar mass of approximately 8.4 × 105 g/mol and is obtained from the stems and branches of Astragalus gummifer Labillardiere and other Asiatic species of Astragalus (FAO, 1992; Stauffer, 1980). They are mostly grown in Turkey, Iran, Iran, Iraq, Syria, Lebabon, Afghanistan, Pakistan, and some parts of Russia (FAO, 1992). The two main components of tragacanth are water-swellable and watersoluble components. This gum mostly contains a small amount of uronic acid (3%). The tragacanthic acid fraction possesses a higher

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39

molar mass and rodlike molecular shape. The main chain is formed by (1→4)-linked d-galactose residues with side chains of d-xylose units attached to main chain by (1→3) linkages. The water-soluble tragacanthin is a neutral, highly branched arabinogalactan with a spherical molecular shape and is composed of (1→6)- and (1→3)-linked d-galactose with attached chains of (1→2)-, (1→3)-, and (1→5)-linked l-arabinose (Verbeken et al., 2003; FAO, 1995). Gum tragacanth is acid resistant, resistant to degradation at low pH, and a bifunctional emulsifier. At lower concentration, it exhibits pseudoplastic behavior. Tragacanth as an encapsulating agent showed an excellent formulation with an average size of 22 nm and a microbial reduction of 100% after 12 h stirring (Ghayempour, Montazer & Mahmoudi, 2015). 2.3.2.2  Tragacanth as Micro- and Nanoencapsulating Agents  Tragacanth

is used as an encapsulating agent to produce antimicrobial nanocapsules containing plant extract. In the first study conducted in 2015, tragacanth was used as a nanoencapsulation agent for plant extract, and high-efficient nanocapsules were prepared with spherical shapes and smooth surface with an average size of 22 nm (Ghayempour, Montazer & Mahmoudi, 2015). The pH-sensitive nanohydrogel was prepared based on gum tragacanth biopolymer using 3-aminopropyltriethoxysilane (APTES) modifier and glyceroldiglycidylether (GDE), polyvinyl alcohol (PVA), and glutaraldehyde (GA) as crosslinking agents for loading and release of indomethacin. An overall release of up to 70% was observed at pH 9 after 24 h (Hosseini, Hemmati & Ghaemy, 2016). The pH- and temperature-sensitive graft copolymer, tragacanth, and amphiphilic-alkyne-­terminated terpolymer were prepared and investigated for controlled release of quercetin. The results showed the release profile of quercetin as the first-order model (Hemmati & Ghaemy 2016). The combination of gum tragacanth and poly(methyl methacrylate-co-maleic anhydride)g-poly(caprolactone) microgel was prepared and investigated. The in vitro release of quercetin as a model drug was 40%–80% after 7 h at pH 7 (Hemmati, Masoumi & Ghaemy, 2015). Water-soluble tragacanth and oligochitosan nanoparticles were prepared and studied for gene delivery. All the properties including nanoparticles size, polydispersity index, surface change, spherical morphology, and transfection efficiency of nanocomplexes revealed OCH-WST nanoparticles as

40

UM A R SH A H E T A L .

an effective gene carrier for active gene delivery into cells containing sugar receptors (Fattahi et al., 2013). The electrospun nanofibers containing gum tragacanth/PCL were used as wall material for nanodelivery of curcumin. The in vitro release kinetics showed a sustained release of curcumin with strong antibacterial activity against MRSA (99.9%) and ESBL (85.14%) bacteria. The faster and efficient wound healing in mice treated with enhanced granulation tissues formation, epithelial regeneration, angiogenesis, and collagen fibers in mice group treatment with CUR-loaded nanofibers (Ranjbar-Mohammadi et al., 2016). 2.3.3 Pectin

2.3.3.1 Introduction  Pectin is a very complex, nonrandom structural

heteropolysaccharide comprising homogalacturonan, rhamnogalacturonan-I, and ­rhamnogalacturonan-II (Naqash et al., 2017). Its average MW is in the range of 50,000–180,000 Da. The esterification of the carboxyl group with methanol classifies pectin into two groups: high methoxyl pectin (HM) which has 50%–80% esterified carboxyl group and low methoxyl pectin (LM) which has 25%–50% esterified carboxyl group (Sinha & Kumaria, 2001; Masoodi et al., 2002; Masoodi & Chauhan, 1998). Pectin was first reported in 1825 by Henri Braconnot. The esterification degree, MW, and extraction condition determine the properties of pectin (gelling, textural properties, and stability) and find its ample use in food formulation (Naqash et al., 2017; Liu, Fishman & Hicks, 2003). The type of pectin, concentration of ­pectin, modification of hydroxyl methoxy pectin, and temperature determine the gel process and consequently the gelling activity (Semde et al., 2000; Sinha & Kumaria, 2001). Pectin is soluble in water and insoluble in most of the organic solvents. Pectin exhibits newtonian behaviour at lower concentration and pseudoplastic behavior at higher concentration (Pedersen, 1980). 2.3.3.2  Pectin as Micro- and Nanoencapsulating Agents  Pectin is used as

an excipient or carrier for oral and colon-specific delivery in different formulations as it remains unaffected in the upper digestive tract, but it gets easily degraded by microflora in colon (Chourasia & Jain, 2004; Fathi, Martin & McClements, 2014; Liu et al., 2003; Sriamornsak,

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2011). Pectin is proven to be useful in the construction of drug delivery systems for targeted action. It is also found to treat gastrointestinal disorders and reduce the level of cholesterol in blood, besides its suspending and thickening properties. A number of studies have been conducted on pectin and its combination with other hydrocolloids to act as nanoencapsulating agent for target delivery of bioactive ingredients. Fathi et al. (2014) produced nanospheres of pectin in combination with calcium and carbonate ion or glutaraldehyde. The permeable structure and low molecular compounds of calcium pectinate has a downside, as it causes low entrapment efficiency and fast release of encapsulate (Sonia & Sharma, 2012). Ultrasonic rays were used to increase encapsulation load of pectin nanoparticles as it causes depolymerization and size reduction and consequently increases the rate of dissolution of encapsulate (Dutta & Sahu, 2012). When pectin is used in combination with other hydrocolloids, it forms smaller particles as compared to sole biopolymer (Fathi & Varshosaz, 2013; Perera et al., 2010; Tsai et al. 2014; Pliszczak et al., 2011). Takei et al. (2010) used oxidized pectin to encapsulate ­doxorubicin for enhanced biological and anticancer effect. The anionic pectin in combination with β-lactoglobulin for encapsulation of ergocalciferol resulted in increased shelf-life stability of bioactive as compared to uncomplexed β-lactoglobulin. An increased protection against thermal degradation was achieved, when pectin in combination with whey protein was used to encapsulate anthocyanins (Arroyo-Maya & McClements, 2015). A combination of pectin and chitosan were used for the preparation of stable nanoparticles for the period of 14 days in aqueous solution (Birch & Schiffman, 2014). Lycopence was nanoencapsulated in pectin/gelatin combination by the complex coacervation technique, and an encapsulation efficiency of 93.2% was achieved (Silva, Hamerski & Scheer 2012). The high methoxyl pectin in combination with whey protein isolate was used as encapsulating agents for loading of lactoferrin through acidification (Raei et al., 2017). The microbeads of doxorubicin conjugated with thiolated pectin via reducible disulfide bonds were prepared and fabricated by ionotropic gelation. The particle size of the microbeads was in the range of ­0.87–1.14 mm. The results of the study suggested microbeads of pectin and doxorubicin conjugate as a good promising platform for anticancerous delivery (Cheewatanakornkool et al., 2017). Esfanjani et al. (2015)

42

UM A R SH A H E T A L .

nanoencapsulated saffron extract in multiple emulsions of pectin and whey protein concentrate by the spray-drying technique. It was seen that W/O/W multiple emulsion stabilized by sequential adsorption of pectin/WPC was the most effective technique resulting in better encapsulated efficiency of encapsulate. The phenolic extracts of olive leaves were nanoencapsulated in whey protein concentrate and pectin complexes (Mohammadi et al., 2016). 2.3.4 Guar Gum

2.3.4.1 Introduction  Guar gum is a galactomannan, also known as

locust bean gum, tara gum, and carob bean gum (Gidley & Reid, 2006). It is a nonionic, biodegradable, water-soluble, and low-cost natural polysaccharide obtained from the seeds of Cyamopsis tetragonoloba (carob tree). It is composed of linear chains of β-d-(1→4) mannopyranosyl units and short-side branched alpha-d-galactopyranosyl units attached by (1–6) linkages (Sharma et al., 2015; Bemiller & Whistler, 1993). Locust beam gum is one of the most widely used gums for controlled and targeted delivery in colon and is used in medicinal industry as a binder, a disintegrator, a hydrophilic matrix, and an encapsulating agent. Guar gum is soluble in cold water and remains stable in the pH range of 5–7, but forms a gel-like structure in hot water. The solution of this gum exhibits pseudoplastic behavior and finds its use as a thickener, an emulsifier, and a retardant agent in food industry (Barbucci et al., 2008; Kostyra & Barylko-Pikielna, 2007). Guar gum is used as an encapsulating agent in various formulations as it remains unaffected in the upper digestive tract, but it gets easily degraded by microflora in colon. The highly viscous nature of guar gum limits its use in encapsulation and hence various modifications can be employed, which include physical, chemical, enzymatic, or combination of hydrocolloids (Prabaharan, 2011). Guar gum can be modified by derivatization, grafting, network formation, use of acids and enzymes, hydrothermal degradation, microwave-mediated free radical degradation, and irradiation in particular ultrasonication to improve its ­properties for diverse biomedical applications (Mudgil, Barak, & Khatkar, 2012; Sarkar et al., 2012; Karaman et al., 2014; Prabaharan, 2011). Guar gum nanoparticles have been prepared by nanoprecipitation and cross-linking methods (Soumya et al., 2010). Different factors

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responsible for the nanoparticle formation are the molecular mass of the galactomannan, solvent surfactant, cross-linker, and agitation. 2.3.4.2  Guar Gum as Micro- and Nanoencapsulating Agents  Guar gum and its derivatives can be used in controlled release formulations in various forms such as coatings, matrix tables, hydrogels, microspheres, and nanoparticles for targeted drug delivery (Aminabhavi et al., 2014). Guar gum and its derivatives are used in various controlled release f­ ormulation as a carrier for different drugs such as trimetazidine dihydrochloride (Krishnaiah et al., 2002c), metoprolol tartrate (Krishnaiah et al., 2002a), celecoxib (Krishnaiah et al., 2002e), metronidazole (Krishnaiah et al., 2002a), tinidazole (Krishnaiah et al., 2003c), 5-­fluorouracil (Krishnaiah et al., 2002a), ornidazole (Krishnaiah et al., 2003b), and methotrexate (Chourasia & Jain, 2004). Guar gum was chemically modified (α-galactosidase modified o-acetyl-­galactoglucomannan) for encapsulation of bovine serum albumin, which resulted in a decrease in burst release (Roos et al., 2014). The mesoporous silica nanoparticle-based enzyme responsive materials were encapsulated in guar gum for colon-specific drug delivery. The study further showed that 5FU from guar gum was specifically triggered via enzymatic biodegradation of guar gum by colonic enzymes in simulated conditions and the release drug showed anticancerous activity in colon cancer cell lines in vitro confirmed by flow cytometry and biochemical assay. A further study suggests an intermediate step to apply guar gum-based silica nanoparticles for a detailed in vivo investigation (Kumar et al., 2017). The design of nanoparticles based on locus bean gum and chitosan for vaccination purposes was prepared by polyelectrolyte complexation and synthesized LBG sulfate derivative. Two model antigens, Salmonella enterica serovar Entertidis and ovalbumin with encapsulation efficiencies of around 26% and 32%, were associated with the wall material (Braz et al., 2017). Jana and Sen (2017) encapsulated aleclofenac in locust bean gum and chitosan gum using glutaraldehyde as a cross-­ linking agent. The study revealed that aceclofenac drug delivery from nanocomposites occurred via anomalous transport mechanism in vitro and showed minimized gastrointestinal side effects to drug by providing medication in a slow sustained fashion. The ibuprofen drug was incorporated in montmorillonite guar gum and cationic guar gum and studied for its in vitro release behavior (Dziadkowiec et al., 2017).

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2.3.5 Gum Karaya

2.3.5.1 Introduction  Gum karaya also known as gum sterculia is a

complex polysaccharide containing calcium and magnesium salt with a molecular mass of up to 1.6 × 107 g/mol obtained from the stems and branches of Sterculia urens Roxb. and its other species or from the species of Cochlospermum (Le Cerf, Irinei & Muller 1990). It is mainly grown in Asia continent, particularly in India. The backbone of the ­ -d-galacturonic acid and a-l-rhamnose resigum karaya consists of α dues, and the side chains are attached by (1→2) or (1→3) linkage of β-d-galactose to the main chain (Weiping, 2000). The color of this gum is white to grayish white and has a 10% solubility in room temperature water and 30% soluble in hot water (Verbeken et al., 2003).

2.2.5.2  Gum Karaya as Nano- and Microencapsulating Agents  Like other

plant gums, gum karaya is compatible with other hydrocolloids such as protein and carbohydrates. Less information is available concerning its use as an encapsulating agent. Alange, Birajdar, and Kulkarni (2017) encapsulated anticancerous drug capecitabine in gum karaya. They found that this gum reduced early drug release in the upper part of gastrointestinal (GI) tract and guaranteed maximum drug release in the colonic region and a rapid enhancement in drug release in rat caecal content medium due to the action of colonic bacteria on PAAm-g-gum karaya copolymers. Gum karaya was synthesized and characterized to evaluate effect of pH on its mucoadhesive properties and sustained release profile. The gum showed no cytotoxicity regulating using HepG2 cell line and consequently seemed to be a promising excipient for development of mucoadhesive drug delivery systems (Bahulkar, Munot & Surwase, 2015). 2.3.6 Mesquite Gum

2.3.6.1  Mesquite Gum as an Encapsulating Agent  Mesquite gum is a complex acidic polysaccharide which is formed by (1→3)-linked β-dgalactose residues with (1→6)-linked branches having 1-arabinose, 1-rhamnose, β-d-glucuronate, and 4-0-methyl β-d-glucuronate as single sugar or oligosaccharide side chains (Orozco-Villafuerte et al., 2003; Anderson & Farquhar, 1982; Anderson & Weiping 1989;

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Vernon-Carter et al., 2000). This gum is largely grown in the southern part of the United States and Mexico. Mesquite gum has a chemical nature similar to gum arabic. Its color in the solution is brown, and it has a high level of solubility compared to gum arabic (Lopez-Franco et al., 2012). The mesquite gum matrix is used for encapsulation of carotenoids. The results showed that this gum provides best stability and protection to carotenoids against degradation (Garcia-Marquez et al., 2015). Although the properties of this gum suggest its possible use as a nanoencapsulating agent for targeted and controlled release, only few studies have suggested this to be an effective tool as a wall material. 2.3.7 Persian Gum

2.3.7.1 Persian Gum as an Encapsulating Agent  Persian gum, also

known as mountain almond, is a natural polysaccharide which is obtained from wild almond trees native to Iran. It belongs to family Rosacea and genus Prunus which includes the peach, plum, apricot, cherry, and almond trees (Abbasi, 2017). The gum is a transparent, semi-cloudy, odorless, and can be found in d ­ ifferent shapes such as large granules, sugar crystals, and powder with diverse colors varying from white to brownish red (Dabestani et al., 2017). The major monosaccharides of Persian gum comprise rhamnose, galactose, and arabinose. In 2006, initial attempt on characterization of this gum established in the Food Colloids and Rheology laboratory of Tarbiat Modares University, after which various studies have be masterminded throught out the world (Abbasi, 2017). The chemical composition of Persian gum is 82%–90% w/w carbohydrate (of which 98% is sugar), 0.19% w/w fat, 0.20–1.02% w/w protein, 0.60% w/w tannins, and about 1.66%–3.63% w/w ash content. and with major monovalent (Na, K) and divalent (Zn, Fe, Mg, Ca) elements largely vary (Abbasi 2017; Abbasi & Rahimi, 2015; Jooyandeh et al., 2017). The chemical composition of insoluble and soluble fraction of Persian gum is described in Table 2.4. The watersoluble fraction (30%W/W) of persian gum makes a clear solution, whereas its water-insoluble fraction (70% W/W) absorbs water and swells. The water-soluble fraction contains a higher amount of protein compared to the  water-insoluble fraction. At concentration

46

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Table 2.4  Chemical Composition of Insoluble and Soluble Fractions of Persian Gum S. NO. 1 2 3 4 5 6

PROPERTY

PERSIAN GUM (INSOLUBLE)

PERSIAN GUM (SOLUBLE)

pH Dry matter (%) Total ash (%) Fat (%) N (%) Protein (%)

4.76 69.92 1.82 0.17 0.010 0.062

4.93 29.15 0.77 0.20 0.023 0.146

>11%–12%, it forms a true gel network (Dabestani et al., 2017). It shows acidic nature when dispersed in water (pH 4.30–4.62 at 1% w/w). This gum is merchandized in various shapes, sizes, and colors ranging from white, light yellow, dark yellow, light brown, and red, and its pH is inversely proportional to the color of the gum, i.e., the lighter the color, the higher is the pH and vice versa (Abbas et al., 2015). 2.3.8 Angum Gum

2.3.8.1  Angum Gum as an Encapsulating Agent  Angum gum is a bio-

polymer which is obtained from the natural exudate of Amygdalus scoparia Spach. It is grown mainly in the southern and western rangeland of Iran. The gum is widely consumed in Iran as a functional ingredient for nutritional and medicinal purposes (Jafari, Beheshti & Assadpour, 2013). Gum arabic, angum gum, and whey protein are used as a wall material for crocin loading by microemulsion. The angum gum has shown high viscosity (ten times higher) and high gel behavior. The droplet size of W1/O microemulsions was found to be 10 nm on average compared to gum arabic (Mehrnia et al., 2017).

2.4 Microbial Gums

Microbial gums are obtained by biotechnological interventions. Most of microbial gums satisfy all the important requirements to be used as encapsulating agents for target delivery. Table 2.5 displays recent examples of microbial gums as nanoencapsulating agents.

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2.4.1 Carrageenan Gum

2.4.1.1 Introduction  Carrageenan is the generic name for high-

MW-­sulfated polysaccharide bearing d-galactose and 3,6-anhydrod-­galactose. It has a linear structure consisting of d-galactose units alternatively linked by α-(1→3) and β-(1→4) bonds. Carrageenan can be

Table 2.5  Recent Examples of Microbial Gums as Nanoencapsulating Agents ENCAPSULANT

ENCAPSULATE

Cashew gum Modified cashew gum

Larvicide Indomethacin

Cashew gum + chitosan Cashew gum and alginates

Lippia sidoides oil LSEO

HPMCP

Letein

Xanthan gum + guar gum

Lysozyme

Gellan gum

Ondansetron

Sodium alginate + gellan gum + skimed milk

Lactobacillus kefiranofaciens M1

Curcumin alginate

Collagen

Alginate + MPEG-PGL

Curcumin

Alginate

Dexorubicin

Alginated + TMC

Curcumin

EFFECT

REFERENCE

Increased release profile Good colloidal stability and increased release profile of drug Increased encapsulation efficiency up to 70% Increased efficiency and release profile under in vitro conditions Improved stability of bioactive upon encapsulation Increased stability and higher drug total mass output Promising mucoadhesive properties Improved controlled release of probiotics under simulated conditions In vitro release kinetics and enhanced granule tissue formation Increased encapsulation stability and increased antioxidant activity Sixtyfold higher cytotoxicity of drug against MDA-MB-231 Significant increased loading content and improved thermal stability

Paula et al. (2012) Pitombeira et al. (2015) Slomes et al. (2017) Ribeiro et al. (2016)

Blanch et al. (2007)

Ding et al. (2015)

Kubo, Miyazaki & Attwod (2003) Wang et al. (2015)

Jiang et al. (2013)

Li et al. (2012)

Lee & Mooney (2012)

Martins et al. (2013)

(Continued )

48

UM A R SH A H E T A L .

Table 2.5 (Continued )  Recent Examples of Microbial Gums as Nanoencapsulating Agents ENCAPSULANT

ENCAPSULATE

EFFECT

Alginates + gellan gum Alginates + starch

Bifidobacterium bifidum Illex para guariensis

Improved protection of probiotic Improved bacterial tolerance

Alginates + starch

L. acidophiles and B. lactis Carvacrol L. casei and B. lactis

Increased viability of probiotics Enhanced activity of drug Improved availability of pro­biotics at beneficial site Better survival of probiotics under simulated conditions Improved encapsulation efficiency Increased loading content

Alginates + whey Alginate

Carrageenen + sodium alginates

L. acidophilus La-5, B. bifidum Bb-12

Alginate/βlactoglobulin Maltodextrin/whey protein Cyclodextrin

Curcumin Flaxseed oil Catechin

REFERENCE Chan et al. (2005) Lopez Cordoba, Deladino & Martino (2013) Kailasapathy & Masondole (2005) Zhang et al. (2014) Shewan & Stokes (2013) Ozer, Suzun & Kirmaci (2008) Hosseini et al. (2015) Abreu et al. (2012)

Controlled drug delivery at Krishnaswamy, Orsat & targeted sites Thangavel. (2012)

isolated from red weeds belonging to the class Rhodophyceae, especially Chondrus crispus, Euchema spp., Gigartina stellata, and Iridaea spp. The polymer chains comprise alternating (1→3)-linked β-d-galactopyranosyl and (1→4)-linked α-d-galactopyranosyl units. Some of the (1→3)-linked units occur as 2- and 4-sulfates, whereas the (1→4)-linked units occur as 2and 6-sulfates, 2,6-disufates, 3,6-anhydride, and 3,6-­andydride-2-sulfate (Percival, 1972). Carrageenan is divided into three types based on the difference in the number of sulfate groups: kappa (κ), iota (ι) and lambda (λ). The carrageenan safety in terms of use in food systems has been approved jointly by FAO/WHO. The carrageenan and its derivatives are used in various pharmaceutical formulations as a mucoadhesive material, e.g., pravastatin was encapsulated using carrageenan as a wall material. Various properties such as in vitro mucoadhesive strength, in vitro drug release, swelling index, and in vitro residence time have been studied in detail (Mansouri et al., 2015). 2.4.1.2 Carrageenan as Nano- and Microencapsulating Agents  It is important to note here that probiotics are adjoined to polysaccharide like carrageenan solution at 40°C–45°C and gelation occursby

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cooling to 20°C, even if used at higher concentrations such as 2%–5% (Kraseakoopt, Bhandaru & Deeth, 2003). A strong gel for encapsulation was reported when carrageenan in combination with locust gum in the ratio of 1:2 was used (Miles, Morris & Carroll, 1984). It has a capacity to form gels and consequently entrap cells. In most of the cases, for encapsulation purposes carrageenan is used at concentrations of 2%–5%, but gels formed are fragile and cannot withstand stresses (Chen et al., 2007). The carrageenans show a wide spectrum of rheological behavior because of their varying chemical nature (Mangione et al., 2003). The ι-type forms elastic gel, the κ-type results in brittle gel, and the λ-type forms viscous solution. The 3% κ-carrageenan and locust bean gums have been used as encapsulating agents for Streptococcus thermophilus with 0.5–2 mm size of microsphere. Carrageenan is used as thickening, stabilizing, and gelling agents in various food and show a synergistic effect when used in combination with other plant gums. Carrageenan forms complex coacervates with most of the protein for encapsulation (Gowraraju et al., 2017). Ding and Shah (2009) microencapsulated cells in carrageenan/alginate/xanthan gum and found better survival after 2 h of incubation at pH 2 than in free cells. L. reuteri in κ-carrageenan/locus bean gum was encapsulated by extrusion process and found the survival of probiotic active during simulated conditions. The blend of carrageenan and sodium alginate was used to successfully encapsulate L. acidophilus La-5 and B. bifidum Bb-12 by extrusion/emulsion process (Ozer & Kimaci 2009). 2.4.2 Alginate Gum

2.4.2.1 Introduction  Alginate gum is a nontoxic, linear heteropoly-

saccharide that consists of anionic copolymer comprising 1→4-linked β-d-mannuronic acid (M residue) and α-l-guluronic acids (G residue) obtained from brown sea algae and some bacteria (Rehm, 2009; Moe et al., 1995; Cottrell & Kovacs, 1980). The versatility and positive cellular response of this unbranched binary copolymer polysaccharide makes it a promising candidate for development of hydrogel particles and scaffolds. It exists in three forms as homopolymeric M-blocks (M–M–M). Ionbinding sites in alginates are controlled by the cavities formed by diaxially linked G residues providing junction zone in the gel network. This binding zone between the G-block is described as

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egg-box model. Therefore, the length of d-manuronic acid polymer is a major structure contributing factor to gel formation and subsequent instantaneous entrapment of probiotic cells in three-dimensional lattice of alginate (Gacesa, 1992). Other factors known to affect gel formation of alginates include concentration of the alginate and CaCl 2 and gel-hardening time (Chandramouli et al., 2004). These anionic copolymers vary widely in composition and sequence and are arranged in a pattern of blocks along the chain. The average MW of alginate is in the range of 200,000–300,000 Da; however, MW and polymerization degree depend on the enzymatic activity at the time of extraction/ production, isolation process, and biotechnological procedure. The average weight of the alginate is in the range 4 × 104 to 5 × 105 g/mol (Draget & Taylor 2011; Draget et al., 2000). At lower pH concentration and in presence of divalent cations (calcium and zinc), alginates form strong heat stable of high viscosity and exhibit Newtonian behavior, whereas at higher concentration alginates exhibit pseudoplastic behavior. In external gelation method, alginate microparticles are fabricated by the process of water-in-oil emulsion and maintained by surfactants like Tween® 80 and usually calcium chloride in a solution form is added to the emulsion. The internal gelation is very rarely used for microencapsulation purposes in which calcium carbonate is used and fabricated by the process of water-in-oil emulsion followed by addition of organic acid-like acetic acid. Calcium and carbonic acid are formed, when these penetrate into water phase (Cook et al., 2014). The major drawbacks associated with alginates are leaching of encapsulating agent during preparation and rapid dissolution in intestinal pH or in the presence of sodium ions, and in most of the cases, the concentration range of 0.5%–4% is used and recommended for nanodelivery. In addition, there are various drawbacks associated with alginate microparticles such as, susceptible to split and lose their mechanical stability in acidic conditions, sensitive to monovalent ions or chelating agents, permeable texture results in fast diffusion of moisture and other fluids through breads. To overcome the problem associated with mechanical stability of alginate microsphere, alginate in combination with other natural and artificial hydrocolloids is used and also ionically cross-linked by addition of divalent cations in aqueous solution (Matricardi et al., 2008). The properties such as mild gel setting conditions, biocompatibility, biodegradability, pH

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sensitiveness, low cost, and mucoadhesiveness of alginates satisfy its need for use as effective matrices for the entrapment and/or delivery of variety of biological agents (Corbo et al., 2013; Shafiei et al., 2012). 2.4.2.2  Alginates as Nano- and Microencapsulating Agents  Various studies

have broadly reported the encapsulation of probiotics by calcium alginate, usually at a concentration of 0.5%–5% (Jankowski et al., 1997; Khalil & Mansour 1998; Huq et al., 2017; Mokhtari et al., 2017; Demitri et al., 2017; Li et al., 2017; Simo et al., 2017; Perdo et al., 2016; Sathyabama et al., 2017). The reciprocal action of alginate with mucus related to improvement of adhesiveness satisfies its need for sustained therapeutic action in the GI tract (Fangueriro et al., 2012; Liew et al., 2006). Alginate in combination with cornstarch, glycerol, and chitosan was used to improve its properties such as easily cryogenic effect, physical, and chemical stability (Martins et al., 2013; Anal & Singh, 2007; Vivek, 2013; Sultana et al., 2000; Krasaekoopt, Bhandari et al., 2006). Muthukumarasamy & Holley (2006) found ­alginate in combination with starch as better encapsulating agents in simulated gastric juice using extrusion. Alginate in combination with guar gum and glutaraldehyde was used to overcome leaching of encapsulants (George & Abraham, 2007). The alginate and chitosan nanoparticles were used in combination to prevent rapid dissolution in intestinal pH (George & Abraham 2006; George & Abraham, 2007; McClements, 2011). The emulsion gelation was used to encapsulate Lactobacillus casei and Bifidobacterium lactis using alginate microgels as an encapsulant to ensure the availability at a beneficial level at the time of consumption (Shewan & Stokes, 2013; Zanjani et al., 2014). Various drugs (indomethacin, prednisolone, metoclopramide hydrochloride, antiemetic drug, diclofenac, resveratrol, and risperidone) have been studied in alginate matrix for target delivery by various technologies (Nayak et al., 2011; Mooranian et al., 2015; Kassem et al., 2015; Bera et al., 2015). The techniques such as emulsification/internal gelation were used to produce hydrogel nanoparticles. The insoluble nature of alginate calcium particles at low pH satisfies its need for use as a nanoencapsulating agent for targeted and prolonged release of acid-sensitive bioactives in the intestine (George & Abraham, 2006). Zhang et al. (2014) reported that alginate in combination with whey protein can be used as a targeted delivery carrier to enhance the activity of carvacrol. They suggested that alginate concentration has a large effect on the gastric resistance of microparticles, and

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whey protein is the dominant parameter in controlling intestinal release. Kailasapathy & Masondole (2005) reported that alginate in combination with starch is used to enhance the life of L. acidophilus up to 2 log cell number and B. lactis up to 1 log cell number. Thus, they suggested microencapsulation as an effective tool for the viability of probiotic. Lactococcus lactis ssp. were used as an encapsulating agent in 1.875% alginate and 2% alginate. In both cases, an increase in encapsulation efficiency was seen with higher concentration of encapsulating agents (Solanki et al., 2013). In lipid nanoparticles, lipase and turmeric oil was also encapsulated in alginates (Strasdat & Bunjes, 2012; Liu et al., 2012; Lertsutthiwong & Rojsitthisak, 2011). The Ca–alginate c­ ombination (ion-induced gelification) was used to encapsulate i­soniazid, pyrazinamide, and rifampicin with the encapsulation efficiencies in the nanoparticles of 70%–90% for isoniazid and pyrazinamide, and 90% for rifampicin, which was significantly higher than oral free drug (Zahoor et al., 2005). The chitosan and alginate in combination was used as an encapsulating agent and formed hydrogel beads with a diameter between 25.3 ± 0.1 and 31.7 ± 0.1 μm (McClements, 2011). The improved viability was seen when L. acidophilus and L. casei were nanoencapsulated in alginate and chitosan microbeads with galactooligosaccharides and inulin as prebiotics. Alginate was used as a nanoencapsulating agent for the encapsulation of B. longum to improve bacteria tolerance during freezing in cheddar cheese. The liquid extract of yerba mate (llex paraguariensis) was encapsulated in alginate/starch matrix by the formation of calcium-alginate hydrogel beads in solution with starch as filler (Lopez Cordoba, Deladino & Martino, 2013). The author reveals that by addition of starch, there is an increase in encapsulation efficiency ranging from 55% to 65%. The polyphenolic was released mainly in simulated gastric fluid due to erosion and diffusion in calcium-alginate hydrogels without starch, while in combination was due to diffusion only. An improved thermo tolerance was established, when B. bifidum was encapsulated using 2% alginate and 1% gellan gum. During heat treatment, encapsulating agents provided improved protection for probiotic as the cell counts of B. bifidum remained at 105–106 CFU/g for microcapsules stored for 60 days (Chan et al., 2005). Encapsulating L. acidophilus in sodium alginate and Tween® 80 by ultrasound has lead to creates successful matrix to protect probiotic cells in simulated gastric and intestinal conditions. Alginate in combination with cashew gum was used to encapsulate larvicide. The size of the particle was 223–339 nm, and up

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to 45%–95% of oil was released within 30–50 h. The calcium alginate/ resistant starch was used as encapsulating agents for controlled release of probiotics (B. animalis ssp. lactis Bb12, and L. rhamnosus LBRE-LSAS) in yogurt. The results indicated i­mprovement in survival of probiotic under simulated gastrointestinal condition. The alginates in combination with TMC were used an encapsulating agent for encapsulation of curcumin. The major outcome of the work was significant increase in loading contents of curcumin, improved thermal stability with controlled, and sustained release profile (Martins et al., 2013). Alginates are widely used for delivery of various low-­molecular bioactives (Lee & Mooney, 2012). The microparticles with d ­ oxorubicin-conjugated aginate core were used for targeting of folate receptor and nanofibers exhibited a 60-fold higher cytotoxicity against MDA-MB-231 breast cancer. Alginates are also used to encapsulate lectins (anticancer agent) for controlled release in hepatocellular carcinoma, and the release behavior of anticancer drug was thoroughly investigated (El-Aassar et al., 2014). The oxidized alginate and MPEG-PGL copolymer was used as wall material to nanoencapsulate curcumin by evaporation method. The nanocurcumin showed a significant encapsulation stability and a slight increase in antioxidant activity was observed. The enhanced granulation tissue formation, re-epithelization, and collagen deposition with significantly faster wound healing with complete wound closure at day 14 was seen upon nanoencapsulation (Li et al., 2012). The nanohybrid scaffold was prepared by encapsulating curcumin in alginate and collagen and then studied for in vitro release kinetics and diabetic wound healing (Karri et al., 2016). The major outcomes of the study were biphasic release characterized by swift release for 24h that followed by sustained release. In addition, there was no sign of cytotoxicity to 372-L1 fibroblast, greater percentage of wound contraction achieved in animal treated with CURencapsulated nanohybrid scaffolds. Which is lead to increase: granulation tissue formation, reepithelization, anglogenesis, anti-inflammatory and antioxidant activity significantly (Jiang et al., 2013). 2.4.3 Gellan Gum

2.4.3.1 Introduction  Gellan gum is a high-MW anionic linear polysac-

charide produced by fermentation from Sphingomonas paucimobilis. This polymer is a tetrasaccharide repeating unit of d-glucose, l-rhamnose,

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and d-­glucuronate with a molar ratio of 2:1:1 and molar mass in the range of 5 × 105 g/mol (Fialho et al., 2008). The 3-linked glucose unit is substituted with glyceryl at O(2) and with acetyl at O(6). It can, therefore, be designated as →4)-l-rhamnopyranosyl-α-(1→3)-d-glucopyranosylβ-(1→4)-d-glucuronopyranosyl-β-(1→4)-d-glucopyranosyl-β-(1→ (Chaplin, 2009). The gellan gum chemically is composed of 60% glucose, 20% glucuronic acid, and 20% rhamnose, and is divided into three types based on the amount of acetyl group: native gellan gum, deacetylated gellan gum, and clarified gellan gum. The gellan has been accepted for use as a food additive by the United States in 1992 preceded by EU approval as E 418 and followed by Canada, Australia, and South Africa. 2.4.3.2 Gellan Gum as Nano- and Microencapsulating Agents  On the

basis of esterification degree, gellan is divided into high and low acyl types. High acyl gellan gums produce soft, elastic, transparent, and flexible gels, whereas low acyl gums form hard and nonelastic brittle gels. Gellan gum is conventionally used in the food industry due to its distinct gelling, thickening, stabilizing, and texturizing properties and has been widely used for formulation of new drug delivery systems for oral, ocular, nasal, buccal, gastric, and colonic drug ­delivery system (Arrigo et al., 2013). Chemical hydrogels of gellan are prepared using chemical cross-linking of networks to increase their mechanical properties and enable slower drug release profiles. In view of its unique structure and beneficial properties, gellan is currently being used for the development of hydrogels for controlled release in various pharmaceutical formulations. High acyl gellan gums produce soft, elastic, transparent, and flexible gels, and low acyl gums form hard, non-elastic brittle gels. The blend of skim milk, sodium alginate, and gellan gum was used as wall material for encapsulation of L. kefiranofaciens M1 by freeze drying technique (Wang et al., 2015). In the presence of salts and acids, it forms gel and the gelation occurs in two steps: formation of double helices during cooling followed by cation-mediated aggregation of the double helices leading to gelation (Fasolin, Picone & Santana, 2013). It has been reported that this gum also has the capacity to form polyelectrolyte complexes with oppositely charged polymers such as chitosan (Ohkawa, Kitagawa & Yamamoto, 2004). One of the important properties of the gellan is that it is produced in easy-to-swallow solid dosage forms (gels and coatings) and can refashion rate of release

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of active ingredients from tablets and capsules (Prajapati et al., 2013; Kubo, Miyazaki  & Attwood, 2003). The in situ gelling ophthalmic and oral controlled release formulations has been formulated by gellan gum and recommended as a promising mucoadhesive and gelling polymer in nasal formulations as they shown residence time of 4–5 h in nasal cavity without any harmful property. Gellan gum was used as wall material for ondansetron hydrochloride in treatment of nausea and vomiting. 2.4.4 Xanthan Gum

2.4.4.1 Introduction  Xanthan gum is a fermentation-derived natural, high molar mass anionic polyelectrolyte obtained from Xanthomonas campestris. It consists of 1→4-linked β-d-glucose units having a trisaccharide side chain attached to alternate d-glucosyl residues. The MW of this gum varies from 1.5 × 105 g/mol to several million. The solution of gum exhibits pseudoplastic behavior. Xanthan gum is widely used in targeted and controlled drug delivery in the form of nanoparticles, liposomes, niosomes, microspheres, hydrogels, dendrimers, and nanofibers (Benny et al., 2014). The slow dissolution and substantial swelling are the main problems associated with unmodified form of xanthan gum and hence various modifications are required for combat these disadvantage for improved target release. The carboxymethylation and grafting (free radical, microwave irradiation, chemoenzyme) are the main chemical modifications done to improve physicochemical properties. Xanthan gum shows various positive physicochemical changes when it is used in combination with other hydrocolloids particularly with gum guar. Sworn (2002) reported that a synergistic interaction of xanthan gum with guar gum enhances viscosity. 2.4.4.2  Xanthan as an Encapsulating Agent  Xanthan gum was utilized

to reorganize thoroughly vigorous zeolite NaA particles suspension and upon heating double helical xanthan gum chain got split to interact with zeolite NaA particles. Xanthan gum was also used to encapsulate lysozyme for targeted and sustained release (Ding et al., 2015). A viscoelastic gel was produced when xanthan in combination with guar gum was used. Xanthan has productively increased the stability

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of liposomes and has shown a higher drug total mass output and drug deposition for pulmonary delivery of rifampicin. The xanthan gum was also used as wall material for encapsulation of human chondrocytes as cell-based therapies with high stability for cartilage regeneration. The xanthan gum was also used for preparation of niosomes and has shown good spreadability and better physical stability in comparison with xanthan free formulation. This gum can also be applied as a gelling agent in preparation of serratiopetidase noisome gel. The xanthan microsphers were used to decelerate drug release and extending drug time in microspheres of calcium alginate and suggested that drug entrapment capability increase with increase in xanthan gum concentration. Xanthan gum has also been used as a binder and disintegrator in tables. The comparative analysis of xanthan with ethyl cellulose for colonic delivery of metronidazole has shown xanthan containing formulation sustained drug release more than its counterpart. 2.4.5 Dextrin Gum

2.4.5.1 Introduction  Dextrin gum is a bacterial, linear, water-­

soluble, biodegradable polysaccharide of glucan composed mostly of varying glucose units linked by α(1→6) glucosidic bonds and small percentage of α(1→3) linkages. The nature of the attached group in modified dextrin (15%–100%) or degree of substitution determines its properties in terms of ­solubility and can form self-organized nanoscale particles (Broaders, Grandhe  & Frechet, 2011). The mucoadhesive emulsion of cyclodextrin was prepared to load antibacterial, antiviral, contraceptive, and antifungal agents, and was also used as a drug s­ olubility enhancer.

2.4.5.2  Dextrin as an Encapsulating Agent  Dextrin and its derivatives

have a potential application as encapsulating agents (Tiyaboonchai & Limpeanchob, 2007). They were used as nanoencapsulating agents to enhance the effectiveness and therapeutic property of chemotherapeutic agents within the target site. The antimicrobial, antioxidants, fish oil, essential oils, and drug-like ketorolac, etodolac, budesonide, and flufenamic were encapsulated in dextrin derivatives (Piercey et al., 2012; Krishnaswamy, Orsat & Thangavel, 2012; Vyas, Trivedi & Chaturvedi, 2007, 2009; Varshosaz et al., 2009). Lycopence and lutein

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were encapsulated in dextrin-hypromellose phthalate (HPMCP) by supercritical fluid method for improved stability (Blanch et al., 2007; Tapia et al., 2007). 2.4.6 Cashew Gum

2.4.6.1 Introduction  Cashew gum is a hydrophilic, branched polysac-

charide extracted from Anacardium occidentale with a high molecular mass consisting of 72% d-galactopyranose, 14% d-­glucopyranose, 4.6% 1-arabinofuranose, 3.2% 1-rhamnopy-ranose, and 4.5% d-­glucuronic acid (Pitombeira et al., 2015; Ribeiro et al., 2016). The chemistry of cashew gum has not been fully understood till date. It is supposed that solubility, pH, and chemical structure of cashew gum broadly depend on the nature of solution, stage of maturity, and integration with other hydrocolloids (Porto et al., 2015). This gum is partially soluble in water and exhibits Newtonian behavior.

2.4.6.2  Cashew Gum as Nano- and Microencapsulating Agents  Andrade, Carvalho, and Takeiti (2013) reported that similar to the technofunctional properties of gum arabic and due to high cost and low supply of gum arabic, cashew gum can be used as a substitute of arabia gum. Various studies have been performed on cashew gum and compared it with other gum arabic (Gyedu-Akoto et al., 2008). Asante et al. (2001) suggested that the quality of the gum can be checked in terms of viscosity, i.e., the higher the viscosity of the gum, the better its quality. Like all other gums, cashew gum when used in combination or in modified form can improve its techno-functional properties (Oliverira, Paula & Paula, 2014). Several studies have suggested that modification of cashew gum, such as sulfation, caboxylmethylation, and acetylation, can effectively be utilized to ease formulation of micro- and nanoparticles as controlled and targeted delivery systems (Ribeiro et al., 2016). LSEO was nanoencapsulated in combination with cashew gum and alginate by spray drying. The encapsulation efficiency was around 55% and in vitro release profile of oil was in between 45% and 95% within 2 days (Oliverira et al., 2014). Indomethacin was nanoencapsulated in hydrophobically modified cashew gum by dialysis technique. The spherical nanoparticles presented a unimodal distribution with a mean size of 179 nm and decreased upon entrapment.

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The encapsulating agents showed good stability of their particle size and size distribution upon 12-month evaluation. In addition, in vitro release profile revealed an initial burst in first 2 h followed by an indomethacin controlled release up to 72 h (Pitombeira et al., 2015). The cashew/chitosan gum is used as an encapsulating agent for encapsulation of Lippia sidoides oil by spray drying with a nanoparticle size of 405 nm and an encapsulation efficiency of 70% (Simoes et  al., 2017). Pilocarpine hydrochloride was encapsulated in combination with cashew gum and acetylated chitosan for controlled release. The in vitro release profile of pilocarpine hydrochloride was 60% up to 100 min and then slowed down. Paula et al. (2012) encapsulated larvicide in cashew gum for controlled release. The size of the particle was 288–357 nm, and the in vitro release profile was 39%–61%. Diclofenac diethylamine was nanoencapsulated in acetylated cashew gum by nanoprecipitation and dialysis method. The release profile of the diclofencac diethylamine showed more controlled release compared to free drug. The transdermal permeation reached 90% penetration of the drug. 2.5 Animal Origin

Table 2.6 displays recent examples of animal gum used as nanoencapsulating agents. Table 2.6  Recent Examples of Animal Gums as Nanoencapsulating Agents ENCAPSULANT

ENCAPSULATE

EFFECT

Hsian-tsao + chitosan

Paclitaxel

Improved controlled release

Chitosan+ polethylene glycol CM chitosan + ZnO

Paclitaxel

Improve antipolerative activity and cell cycle inhibition Improved encapsulation efficiency at targeted sites

CM chitosan + additives CM Chitosan + PEA

E. coli, P. aeruginosa, S. aureus Ornidazole Ketrofen

Colon-specific drug delivery with excellent pH sensitivity Higher drug delivery in acidic solution and much potential for controlled drug delivery of hydrophobic drugs

REFERENCE You, Liu & Zhoa (2017) Prabaharan (2015) Zhong, Huilin & Zivanovic (2009) Vaghani, Patel & Satish (2012) Prabaharan, Reis & Mano (2007) (Continued )

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Table 2.6 (Continued )  Recent Examples of Animal Gums as Nanoencapsulating Agents ENCAPSULANT

ENCAPSULATE

Linoleic acid + modified Adriamycin chitosan OCM-chitosan

Campotothecin

Chitosan + additives

Hyaluonic acid

Chitosan + additives Chitosan derivatives Chitosan triphosphate

Chitosan

Chitosan

Excellent loading capacity and efficiency under in vitro simulated conditions Enhanced solubility and significant release of anticancer drug under simulated GI conditions Improved physicochemical and mechanical properties Accelerated in vitro

REFERENCE Tan and Liu (2009) Salerno and Pascual (2015)

Correia et al., 2011 TGF 1 Zhang et al. (2009) Green tea Antitumor activity against Liang et al. polyphenols HePG2 cells (2017) Epigallocatechin- Improved oral delivery and Dube, Nicolazzo & 3-gallate favorable therapeutic effect of Larson (2011) drug Propionic acid Effective carrier for controlled Rivero et al. release of antimicrobial (2013) compounds Retinol Increased solubility by Kim et al. (2006) 1,500-fold as compared to unencapsulated L. acidophilus and Greater probiotic viability Krasaekoopt & L. casei Watcharapoka (2014)

Alginates + chitosan + galactooligosaccharides + insulin Chitosan + CM cellulose L. acidophilus

Chitosan/ poly(γ-glutamic acid) Chitosan/ poly(γ-glutamic acid) Chitosan/poly(butyl) cyano acrylate Chitosan/Tween 20

EFFECT

Curcumin

Higher survival of probiotics under simulated gastric and intestinal conditions for 120 min Improved drug delivery under simulated conditions Excellent encapsulation efficiency Enhanced drug delivery

Curcumin

Controlled release of bioactive

Curcumin and doxorubicin Catechin

Priya, Vijayalakshmi & Raichur (2011) Duan et al. (2012) Tang et al. (2013) Duan et al. (2011) O’Toole et al. (2012)

2.5.1 Chitosan

2.5.1.1 Introduction  The chitosan is the second most abundant natu-

ral polymer after cellulose. It is obtained from chitin and is found in shrimp, carp, and lobster shells. An interesting polysaccharide chitosan

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is linear, cationic, biocompatible, nontoxic, and biodegradable polymer consisting of randomly distributed β(1→4)-linked d-glucosamine and N-acetyl-d-glucosamine. Chitosan is obtained by alkaline deacetylation of chitin and is an introductory polysaccharide containing a considerable percentage of nitrogen (Shukla et al., 2013; Mazzarino et al., 2012; Bhattarai, Gunn & Zhang, 2010). It is a cationic polymer studied as an excipient in mucoadhesive dosage forms and controlled delivery formulations, which is attributed to its gelling and adhesive properties. Chitosan has been recommended safe by various regulatory agencies of Japan, the United States, Italy, Portugal, and England for its use as a dietary accessory and food additive. Chitosan as a polymer has special status due to the presence of nitrogen, cationicity, and its capacity to form polyelectrolyte complexes, pH sensitivity, bioadhesive ability, solubility, absorbability, controllable biodegradability, and mucoadhesive properties, thus allowing polymer to become water soluble after formation of carboxylate salts such as formate, acetate, lactate, malate, citrate, glyoxylate, pyruvate, glycolate, and ascorbate (Liu et al., 2017; Bhattarai et al., 2010). All the above properties satisfy its need for use in sustained and controlled release including nonviral vector for DNA gene and drug delivery (Kumar, 2000). Native chitosan was replaced by some chemical and biological modifications to enhance susceptibility to degradation by nucleases of their cargo and to improve cellular membrane permeability and solubility at physiological pH, thus increasing colloidal stability and specificity, and enable the formation of polyelectrolyte complexes in gene delivery (Rinaudo, 2006; Tiera et al., 2006). The chemical modifications have been a strong tool to control interaction of chitosan with drugs for enhanced load capability, upgrade bulk properties, and to outfitter release profile of nanoparticles. The esterification degree, acetyl-glucosamine, source, and isolation technique determine the composition and molar mass. Chitosan is insoluble at higher pH and soluble at easily acidic pH. It has been used as an antioxidant, antimicrobial agent in various formulations (Shahidi, Arachchi & Jeon, 1999) and for target delivery of ­bioactives. This positively charged gum has miscellaneous biotic activities, such as antitumor activity, immune-­enhancing effect, antibacterial, and antifungal properties, and is used for the delivery of anticancer drugs, antibacterial drugs, antifungal drugs, anti-­inflammatory drugs, and protein/peptides, and for DNA/gene delivery. Chitosan capsules are not very often used, as they do not increase the viability of probiotic

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cells, but they are always used as a coating or shell. Various modification techniques (physical and chemical) or combination of chitosan with other hydrocolloids have been employed to extend biopolymer functional properties. The covalent cross-linking has been widely used for the preparation of chitosan nanoparticles for a long time (Liu et al., 2009). The intermolecular cross-linking of chitosan nanoparticles was done by the use of water-soluble condensation agents of c­ arbodiimide, natural dicarboxylic acid, and tricarboxylic acids (­succinic acid, mailic acid, tartaric acid, and citric acid) (Liu et al., 2009). In this case, production of chitosan nanoparticles was due to ­reaction between carboxylic group of natural acids and amino groups of chitosan. The nanoparticles produced by reaction between carboxylic group of natural acids and pendant amino groups of chitosan group were stable in aqueous media at low pH, neutral, and mild alkaline conditions. The toxicity of glutaraldehyde on cell viability limits its use as a cross-linking agent in the field of drug delivery. Tripolyphosphate (TPP) has been widely used as a polyanion cross-linker in various studies and was first used for the synthesis of chitosan nanoparticles. The combination of chitosan and tripolyphosphate (TPP) forms a gel by ionic interaction between positively charged amino groups of chitosan and negatively charged counter ions of TPP and has widely be used for targeted and controlled release of bioactives and drugs. The chitosan and its derivatives have been widely used as ion removal, fiber formation, cosmetics, gene delivery, and drug delivery. The production of nanoparticle chitosan reveals biological effects like higher antitumor activity, and it is because of membrane disruption and apoptosis-­inducing activity for cancer cells (Qi et al., 2008). 2.5.1.2 Chitosan as Nano- and Microencapsulating Agents  Chitosan

gels eliminated in colon, as enteric coating materials, are used for target delivery in colon. Drugs, such as sodium diclofenac and anti-­ inflammatory drugs, are entrapped inside core of the chitosan microsphere. These microspheres are then coated with enteric coating, which is then used for drug delivery. In this study, drug release was found to be released over period of 12 h. Buschmann et  al. (2013) suggested grafting a neutral polymer to this gum, so as to reduce surface charge and develop increased stability. The ionically crosslinked water-soluble chitosan derivative nanoparticles can easily be dissolved in neutral aqueous media, avoiding potential toxicity of

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acids and consequently protecting bioactivity of loaded biomacromolecules. N(2-hydroxyl)propyl-3-trimethyl ammonium chitosan chloride nanoparticles (110–180 nm) were synthesized by a reaction between glycidyl-trimethyl-ammonium chloride and chitosan, and bovine serum albumin was nanoencapsulated in it with an encapsulation efficiency of up to 90%. The ovalbumin was nanoencapsulated in N-trimethyl chitosan nanoparticles by ionic cross-linking of N-trimethyl chitosan with TPP. Nanoparticles of an average size of  350 nm with positive zeta potential and an efficiency up to 95% were synthesized (Amidi et al., 2010). Lin et al. (2007) also used chitosan and poly glutamic acid nanoparticles (particle size of 196) for encapsulation of insulin with an encapsulation efficiency of >72%. In  another study, pH-dependent efficiency of insulin was reported when chitosan in colloidal form was used and insulin. Further, it was seen to resist harsh gastric condition for 2 h, which was necessary for the drug to exert its function within body. Konecsni, Low, and Nickerson (2012) reported that chitosan tripolyphosphate nanoparticles were able to retard the release of rutin in simulated conditions. An improved encapsulation efficiency and release behavior were seen, when catechins were encapsulated in chitosan nanoparticles. Chitosans in combination with alginates were used to improve functional properties (mucoadhesiveness and resistance to acids) (Nagarwal, Kumar & Pandit, 2012; Sanna et al., 2012). The blends of chitosan and carboxymethyl cellulose were used to encapsulate L. acidophilus and showed high survival of probiotic under simulated gastric and intestinal condition for 120 min (Priya, Vijayalakshmi & Raichur, 2011). The chitosan–PEO semi-IPN hydrogel was used to encapsulate drugs such as amoxicillin and metronidazole antibiotics and a selective release mechanism in vivo was seen. The chitosan was used for targeted delivery by various scientists in stomach and colon and were considered to be important for the treatment of local maladies such as Crohn’s disease, inflammation, ulcerative colitis, infection, and carcinomas. They were prepared in such a way that they can bypass acidic environment of stomach and release loaded drug into the intestine. 5-Fluorouracil, insulin, and nitrofurantoin were effective in selective drug release in an intestinal medium compared to a gastric medium (George & Abraham, 2006). It has been reported that chitosan/alginate encapsulating agents has been use successfully

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to encapsulate bovine serum albumin and insulin (Sarmento et al., 2007). L. acidophilus and L. casei were encapsulated in combination of alginate and chitosan with galactooligosaccharides and inulin as prebiotic agents. In this study, the author concluded that alginate and chitosan with galactooligosaccharides had great effect in probiotic viability (Krasaekoopt & Watcharapoka, 2014). The improved thermal stability and antioxidant activity of curcumin was retained, when chitosan/zein was used as encapsulating agents. The ionic cross-linked water-soluble chitosan nanoparticles can easily be dissolved in neutral aqueous media, avoiding the toxicity of acids and consequently protecting bioactivity of encapsulate in contrast to its native form. The reaction between glycidyl trimethyl-ammonium chloride and chitosan resulted in synthesis of N-(2-hydroxyl)propyl3-trimethyl ammonium. In this case, glycidyl-trimethyl-ammonium chloride was used as ionic cross-linking agent, which resulted in the synthesis of water-soluble chitosan derivative. For the oral delivery of genes like β Gal in intestine by oral administration, chitosan (DDA 100%, MW 9.5 × 105) and N-acetylated chitosan was used and gene expression at duodenum, jejunum, ileum, and colon after 5 days post administration. An efficient gene transduction in the intestinal epithelium, stomach, and gastric and upper intestinal mucosa despite the harsh environment condition in the GI tract was reported when chitosan nanoparticles were used. Further, it has been reported that these nanoparticles were effectively used to protect the complexed NA against nuclease degradation. The gene proclamation also caused a particular action after mortification of the chitosanbased nanocomplexes in acidic pH conditions and in microflora of colon (Buschmann et al., 2013). The interaction of calcium ion with chitosan (ionic gelification) was used for preparation carboxymethyl chitosan nanoparticles. The encapsulation of doxorubicin in carboxymethyl chitosan nanoparticles resulted in increased anti-cancerous activity. The chitosan nanoparticles as an encapsulating agent for targeted delivery of retinol increased its solubility by 1,600-fold (Kim et al., 2006). The propionic acid was encapsulated in chitosan matrix and was found to be an effective carrier for controlled release of antimicrobial compounds (Rivero et al., 2013). An improved release behavior of β-carotenoids was seen without interfering negatively with organoleptic properties during storage in chitosan/CMC

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encapsulation system. The encapsulated larvicide in chitosan/cashew gum and studied it for slow and sustained release profile. The size of the particle was 789 μm, and the in vitro release profile was 83%. The increased mucoadhesive property of the GI tract leads to improved active absorption in curcumin-loaded chitosan particles. Chitosantriphosphate nanoparticles were used as an encapsulating agent for encapsulation of epigallocatechin-3-gallate and found to be a beneficial approach for improved oral delivery and consequently reaching favorable therapeutic effects of the drug such as antioxidant, neuroprotective, and anticancer activities (Dube, Nicolazzo & Larson, 2011). Furthermore, it was highlighted that using encapsulation has improve the delivery of antioxidant to the targeted area. Green tea polyphenols were encapsulated in chitosan derivatives and were noticed to have an important antitumor activity against HePG2 cells as they were released from encapsulants at the targeted site and consequently interfere with HePG2 cell apoptosis cascades (Liang et al., 2017). Green tea polyphenols can be used as an anti-dose for human colon cancer cell line HT-29. Chitosan nanoparticles are also used as encapsulating agents for brain-specific delivery of neurotransmitter dopamine and morphogenic protein for enhancing bone regeneration and have created a new horizon as these are found to be the most investigated biopolymers for cell encapsulation. The sustained release of TGF 1 accelerated in vitro chondrocytes when chitosan porous scaffolds were used as an encapsulating agent for delivery of TGF 1 by freeze drying process (Zhang et al., 2009). The effectively prepared nanoparticles of size between 265 and 387 nm were seen to have a significant encapsulation efficiency of insulin near about 85%. Higher encapsulation efficiency of insulin (90%) was reported when nanoparticles for polyethylene glycol and trimethyl chitosan were used as encapsulating agents; it is important to note that the particle size was almost the same in 200–400 nm range. Chitosan nanoparticles were used to encapsulate hyaluronic acid by freeze drying and showed an overall improvement in physicochemical properties and increased mechanical properties (Correia et al., 2011; Peter et al., 2010). Further, chitosan in combination with collagen was formed with the freeze drying technique and was found to be effective in lowering scaffold degradation with an increase in the chitosan amount. There was a threefold increase in the survival time of

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L. rhamnosus (40–120 min) in acid conditions and less reduction of cell number, when chitosan coating of microbeads was used. Salerno and Pascual (2015) reported wound healing and ­antibacterial properties of chitosan hydrogel. The anticancer drug camptothecin was encapsulated in O-carboxymethyl (OCM)-chitosan, and the results revealed an enhanced solubility and significant release. The nanoformulation of chitosan loaded with curcumin was found to be toxic to cancer cells and nontoxic to beneficial cells and enhanced solubility of curcumin in water. Tan and Liu (2009) encapsulated adriamycin in linoleic acidmodified chitosan and studied its in vitro release profile. Further, the anticancerous activity of encapsulated drug against HeLa cells was found to be comparable to the activity of free adriamycin. A sustainable in vitro release profile with excellent loading capacity and efficiency was seen, when carboxymethyl (CM) chitosan hydrogel nanoparticles were used as encapsulating agents for encapsulation of doxorubicin. The ketoprofen was encapsulated in CM chitosan-containing phosphatidylethanolamine (PEA), and the results revealed that the amount of drug release was much higher in the acidic solution than in the alkaline solution because of swelling properties of matrix at acidic pH, and the amphiphilic matrix has much potential for controlled drug delivery of hydrophobic drugs (Prabaharan, Reis & Mano, 2007). The excellent pH sensitivity (higher pH-dependent swelling and drug release at pH 6.8 and 7.4) was seen, when CM chitosan was used to encapsulate ornidazole and was found as a promising carrier for administration of colon-specific drug delivery (Vaghani, Patel & Satish, 2012). The higher encapsulation efficiency at the targeted site was seen by CM chitosan in with ZnO binanocomposite for encapsulation of Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Sarcina (Zhong, Huilin & Zivanovic, 2009). The optimized nanoparticles of chitosan and polyethylene glycol were used to nanoencapsute paclitaxel for tumor targeted drug delivery. It was seen that chitosan and poltethylene glycol NP had substantially increased in blood circulation and also reduced macrophase uptake and only a few NPs concealed in the liver with a superior anti-proliferative effect and cell cycle inhibition was seen (Prabaharan, 2015). Chitosan is prone to form poly electrolyte complex with hyaluronic acid, chondroitin sulfate, genipin, epichlorhydrin, diethyl squarate, hexamethylene, and dialdehydes. Various physical and functional properties of chitosan suggested that it could bind

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dietary fats and consequently prevent absorption. Novel encapsulation agents, hsian-tsao gum and chitosan, were prepared by coacervation and investigated. Further, You, Liu & Zhao (2017) suggested the use of HG-CS as promising agents to be used in the food industry. 2.6 Outlook and Research Question

Although the era of nanoencapsulation is in the embryonic stage, this has been progressing fast and is suggested to be one of the fastest growing branches of modern science. Further, recent advances in gum-based delivery systems have added to our knowledge. Gums as a controlled and targeted delivery vehicle are economically viable, and hence, various combinations of gums are suggested to become an important tool to overcome the existing challenges that are associated therewith. These modified or blended gums have resulted in enhanced safety and security of encapsulate. Various blends have been developed to provide wall material with improved encapsulation efficiency consequently giving them an increased application in both industrial and academic research. Currently, nanoencapsulation for targeted and controlled delivery research mainly focuses on physicochemical properties, drug loading ability, in vitro toxicity. However, there is a lack of information about important issues such as specific integration of encapsulating agents with human organs, tissues, cells, or biomolecules, the effect on human metabolism by encapsulating agents and multiple modifications to obtain tailored encapsulation agents with desired functional properties.

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3 S tarch -B ased D eli v ery System U M A R S H A H , P R A K H A R C H AT U R , A N D H AY D E R A L -A L I Curtin University

M U DA S I R A H M A D A N D A D I L G A N I University of Kashmir

A S I R G A N I A N D F. A . M A S O O D I Prince of Songkla University

Contents

3.1 3.2 3.3 3.4

Introduction 86 Classification, Isolation, and Purification of Starch 88 Chemical Structure 91 Modification of Starch 92 3.4.1 Chemical Modifications 92 3.4.1.1 Cross-Linked Starch 93 3.4.1.2 Oxidized Starch 97 3.4.1.3 Acid Hydrolysis of Starch 99 3.4.1.4 Substituted Starch 101 3.4.1.5 High Amylose Starch 104 3.4.2 Physical Modifications 105 3.4.2.1 Modification by Ultrasound Waves 105 3.4.2.2 Modification by γ-Irradiation 108 3.4.2.3 Modification by Osmotic Pressure Treatment 110 3.4.2.4 Modification by Heat-Moisture Treatment 110 3.4.2.5 Modification by Pulsed Electric Field 111 3.4.2.6 Spray Drying 112 3.4.2.7 Microwave Treatment 113

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3.4.2.8 Use of Electrospinning in Modified Starch for Controlled Delivery 115 3.5 Regulatory Status 117 3.6 Outlook and Research Question 117 References 118 3.1 Introduction

As the world population is growing, ongoing challenges such as nonsustainable production, lack of recyclability, health concern, and preservation have prompted food and pharmaceutical industries to employ micro- and nanodelivery systems for controlled and targeted release of bioactive, genes, drugs, and probiotics (Shah et al., 2016a; Neethirajan & Jayas, 2011; Ahmad et al., 2019; Ahmad et al., 2018; Ahmad et al., 2017; Gani et al., 2017b). Although this science is in the embryonic stage, it has brought new hopes and expectations to the food and pharma sector. Over the last decade, researchers have mainly focused on the selection and combination of wall materials to obtain suitable drug release speed, surface modification of the nanoparticles to improve targeting ability, optimization of the methodology of nanoparticles to increase their drug delivery capabilities, and investigation of in vivo dynamic processes to disclose the interaction of nanoparticles with blood and targeting tissues and organs. These encapsulating systems (micro and nano) overcome existing flaws and provide new solutions and opportunities (Esfanjani and Jafari, 2016; Simoes et al., 2017). Food hydrocolloid particles at the micro (10 −6 m) and nano (10 −9 m) scales exhibit different physical, chemical, and biological properties or even exhibit novel material functionalities and applications compared to macro scale. Nowadays, much emphasis has been put on food hydrocolloid nanoparticles as they increase oral bioavailability of drugs due to their specialized uptake mechanisms (absorptive endocytosis) and are able to remain in blood circulation for a long time, thus releasing incorporated drug in a controlled fashion which leads to less plasma fluctuations and minimum side effects (Kim, Park & Lim, 2015). Among other polymers, starch has gained heights as it satisfies all principal aspects, such as free radical scavenging capacity, antioxidant, anti-immunomodulatory activity, inhibition of tumor cell

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proliferation, radio protective effect, low cost, non-toxicity, hydrophilicity, biocompatibility, biodegradability, and ease of modification, thus making it a promising wall material for micro- and nanoencapsulation of bioactive, genes, drugs, and probiotics (Shah et al., 2016b; Zhu et al., 2018). Starch is the major dietary source of carbohydrates, is non-allergenic, and low in cost with generally recognized as safe (GRAS) certification, and naturally occurs as granules in the chloroplast of green leaves and the amyloplast of seeds, pulses, and tubers (Rodrigues & Emeje, 2012). Chemically, this polysaccharide consists of large units of monosaccharides or sugar (glucose) units linked by glycosidic bonds. The two major types of biopolymers in starch are amylose (linear in nature) and amylopectin (branched in nature) and are assembled in the form of granules with the size ranging from 1 to 100 μm (Zhu et al., 2018). The starches from various sources (rice, potato, maize, barley, sorghum, Indian horse chestnut, etc.) have been extracted for use in encapsulation technologies (Gani et al., 2017a; Ashwar et al., 2018; Shah et al., 2015). On the basis of amylose content, the starch has been classified as low (less than 20% amylose), medium (21%–25%), and high (more than 26%). The starch with high amylose content is known to have high resistance to digestion and to have high-resistant starch content to survive into the large intestine (Oh, Bae & Lee, 2018). Starch has a long tradition for use in encapsulation technologies such as nasal delivery of drugs and delivery of vaccines administered orally and intramuscularly (Rodrigues & Emeje, 2012). However, native starch-based delivery systems have some drawbacks associated with it such as poor controlled rate of hydration, thickness, a decrease in viscosity upon storage, and microbial contamination susceptibility (Ashwar et al., 2018). In order to overcome these flaws and to improve starch encapsulation efficiencies, various modification techniques have been employed to native starch, which include chemical (cross-linking starch, substituted starches, oxidized starch, acid hydrolyzed starch), physical (ultrasonic waves, microwave radiation, osmotic-pressure treatment, pulsed electric fields, moist heat treatment, γ-irradiation), and/or enzymatic method or the combination of these for various applications including encapsulation and controlled delivery (Shah et al., 2016b). These starch-based delivery systems are scientifically proven to have better encapsulation

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efficiency and provided better protection than lipid and proteinbased delivery systems (Fathi et al., 2014). Thus, food scientists are more focused on developing wall materials based on modified starch to encapsulate various food ingredients as evident by the increasing number of publications in this area during the last decade (Ashwar et al., 2018; Hasanvand et al., 2015; Zhu et al., 2018; Nielsen et al., 2016; Wang & Copeland, 2013). The objective of this chapter is to summon all the valid physical, chemical, and dual methods including recent advances in modified starch encapsulation technologies for further research. The following sections discuss various techniques applied to modify starch and their subsequent use as wall material for targeted and controlled release of drugs, bioactive, genes, and probiotics. 3.2 Classification, Isolation, and Purification of Starch

Starch is a homopolysaccharide formed by units of glucose and is synthesized by most part of vegetable cells. It is stored especially in seeds (cereals and legumes), tubers (potatoes), roots (carrots), and some fruits (banana). The starch exists as water-insoluble granules generally of size between 3 and 60μm. Starch can be classified on the basis of the rate and extent of its digestibility or different velocities and degrees of hydrolysis by alpha-amylase as rapidly digestible starch, slowly digestible starch, and resistant starch. Thus, total starch is the sum of starch that is not accessible to digestive enzymes (slowly digestible starch), starch that is accessible to digestive enzymes (rapidly digestible starch), and resistant starch (because it opposes the hydrolytic action of alpha-amylase and is not absorbed in the intestine; nevertheless, it may then be fermented by colonic microflora, thus acting as dietary fiber) (Cummings & Englyst, 1987). The resistant starch was later defined as the sum of starch and the degradation products of starch that on average, reach the large intestines of humans. There are three types of resistant starches: RS 1, RS 2, and RS 3 (Perera, Meda & Tyler, 2010). RS 1 is defined as the enzyme-inaccessible starch resulting from structural rigidity and is calculated as the difference between enzyme extractable glucose contents of food determined with and without homogenization treatment prior to analysis. RS 2 is defined as the starch present in the raw food that is resistant to digestion and is measured as the difference in the amount

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of glucose liberated by pancreatin and amyloglucosidase after 120 min of hydrolysis from two samples of the same food. RS 3 is defined as retrograded starch formed during cooling of gelatinized starch. For the extraction of starch, the raw material should be clean and devoid of contaminants (stones, soil, bad seeds, tubers, roots, yams, and foreign plant residues). The air aspiration systems should be used to remove most of the contaminants and soil particles adhering to plant material should be removed by scouring and water washing followed by drying. It is important to note here that drying should be done at lower temperatures as higher temperatures may lead to alteration in physicochemical properties of native starch. Various researchers have suggested different methods for isolation and purification of starch, and the principle of selecting the isolation method of the polysaccharide is keeping the intrinsic properties of starch unchanged during the process of isolation and purification. The first step of extraction is to crush materials, so as to expose more surface area such that intracellular polysaccharides release easily. Various crushing methods and instruments have been designed, and one of the newest approaches is ultrasonic gas flow crushing technology to rupture the cell wall, thus increasing the efficiency of extraction. The lipids and other materials are removed by ethanol reflux for 6–8 h using Soxhlet extractor. Broadly speaking, in the case of pulses, there are two main types of starch extraction: wet milling and dry milling. Wet milling isolation generally yields high impurity, whereas dry milling is carried out by hammer mills, pin mills, and air classification, and requires a very high degree of particle size reduction in order to separate starch granules from the protein matrix (Hoover et al., 2010). The low-protein-starch fraction gets separated by air classification followed by water washing step to remove the remainder of the attached protein. Starch extraction could be assessed by determining starch separation efficiency (SSE) as follows:

SSE = ( % starch in the starch fraction ) ( % yield of the fraction ) /

( % starch in the flour )



The rate of purity of pulse starches by wet milling is higher than that by dry milling. The method is also called isoelectric focusing, and the pH used for extraction is between 8.5 and 10 (Hoover et al., 2010).

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The most commonly used methods for extraction of starch are extraction by dilute alkali-water solution, enzymolysis method, extraction by hot water, and other methods such as DMSO (dimethyl sulfoxide), the organic solvent of alkali metal salt like 2-­methoxyethanol-LiCL, or acidic aqueous solution. The hot water extraction is the most commonly used extraction which works on the principle that starches have bigger solubility in hot water. Starch is stable in hot water and consequently receives minimal damage by this treatment. The common practice is to extract for 2–6 h by hot water; if the extract is low in viscosity, then the residue in the extract can be easily filtered, and if the extract is viscous, then the residue can be removed using centrifugation (Bao et al., 2001). Another method is extraction by dilute alkali-water solution, which works on the principle that the solubility of starch is generally higher in dilute alkali solution than in hot water. In this method, NaOH solution or Na 2CO3 solution of 5%–15% is used to extract at a temperature below 10°C. Usually, hot water is first used to extract starch, followed by a dilute alkali solution to extract remaining starch in the residue (Bao et al., 2001). In the enzymolysis method, the crushed raw materials are suspended in water and optimal reaction conditions of composite enzymes, optimal temperature, and pH are set. Then a certain amount of composite enzymes is added in suspension and allowed to react for a period of time. The filtrate is the extract solution of polysaccharide after filtering the residue (Chaplin & Kennedy, 1994). In various studies, the combination of hot water extraction followed by the use of enzymes to extract (enzymolysis) starch increases the yield (Shi et al., 2016). The extract obtained may contain some residual impurities (inorganic salts, monosaccharides, protein, fats, and others) and can be removed by dialysis method. The period for dialysis is less than 36 h. The dialysis bags have different specifications of molecular weight (MW) cutoff (MWCO) for dialysis and need to be pretreated before use. The pretreatment involves boiling at around 0.5 h to remove impurities before use. Various methods have been developed to purify starch after extraction such as grading precipitation method, salting out method, metal coordination method, and quaternary ammonium salt precipitation method.

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3.3 Chemical Structure

Starch is the primary source of energy stored in cereal grains, and the amount of starch contained in grains varies from 60% to 75% of the weight of grain and produces a considerable amount (70%–80%) of calories consumed by humans worldwide. Starch occurs as granules in the chloroplast of green leaves and the amyloplast of seeds, pulses, and tubers (Rodrigues & Emeje, 2012). It is a polymer of six-carbon sugar d-glucose and the structure of monosaccharide d-glucose can be depicted in either an open-chain or a ring form. The ring configuration is referred to as a pyranose, i.e., d-glucopyranose, and is thermodynamically stable. The highly reactive aldehyde group at carbon number 1 (C1) on d-glucose makes it a reducing sugar, and in biological systems, d-glucopyranose is usually present in relatively small amounts compared with the level of various disaccharides and polysaccharides that are present. Starch consists of a d-glucopyranose polymer linked together by α-1,4 and α-1,6 glycosidic bonds; during bond formation, carbon number 1 (C1) on a d-glucopyranose molecule reacts with carbon number 4 (C4) or carbon number 6 (C6) from an adjacent d-­glucopyranose molecule as the aldehyde group on one end of starch polymer is always free. The starch polymers always have one reducing end and one non-reducing end. The glycosidic linkages in starch are in the α-configuration and formation of α-linkage is determined by the orientation of hydroxyl (–OH) group on CI of the pyranose ring and this linkage allows starch polymers to form helical structures. Glucose polymerization in starch results in two types of polymers: amylose and amylopectin. The amylose is essentially a linear polymer or slightly branched in which glucose residues are α-d-(1–4)-linked typically consisting 15%–20% of starch with the degree of polymerization up to 6,000 and molecular mass of 105–106 g/mol. The amylopectin is a large branched molecule with α-d-(1–4) and α-d-(1–4) linkages and has a molecular mass of 107–109 g/mol and an average degree of polymerization is 2 million which makes it one of the largest molecules in nature (Sajilata et al., 2006). The structural differences between amylose and amylopectin contribute to significant differences in starch properties and functionality but both contain D-glucopyranose molecule.

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The internal architecture of native starch granules is characterized by concentric growth rings originating from the helium of granule, and each ring (ranging from 120 to 500 nm length) is composed of blockelets ­(20–50 nm). Each blocklet consists of semi-crystalline lamellae (9 nm length) consisting of amylopectin and amylose chain (0.1–1 nm) (Naguleswaran et al., 2014). In these lamellae, the crystalline region is mostly formed by amylopectin chains packed into a crystalline lattice and amorphous region contains amylopectin branched points with amylose and amylopectin molecules in a disordered conformation (Naguleswaran et al., 2014). 3.4 Modification of Starch

In order to overcome the existing flaws such as poor solubility, poor mechanical properties, and encapsulation efficiencies, various modification techniques such as physical and chemical methods have been employed (Shah et al., 2016a). Section 3.4.1 describes these modification techniques in detail. 3.4.1 Chemical Modifications

In the past few years, there has been a great focus on chemical modifications of starches. Broadly speaking, monofunctional and difunctional reagents can be used in modification of starch for encapsulation technologies (Masina et al., 2017). Monofunctional reagents such as hydroxylpropylation (esterification) provide nonionic, cationic, hydrophobic, or covalently reactive substituted groups, which in turn alter the gelatinization and pasting properties of starch, thus resulting in a more stabilized starch derivatives in which the association between amylose and amylopectin is blocked (Sui & BeMiller, 2013). Bifunctional reagents (trimetaphosphate) can react with more than one hydroxyl group and consequently reinforce starch granules, which in turn can stabilize starch by modifying its swellability, solubility, and mobility (Xiao, 2012). The chemical modifications such as crosslinking, substituted, oxidized, and acid hydrolyzed can be employed to starch for use as a wall material in micro- and nanodelivery systems; however, there is dearth of new methods as they lead to issues concerning consumers and environment.

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Silva et al. (2017) classified starch on the basis of rate of digestion and location at which it is metabolized as rapidly digestible starch (RDS), slow digestible starch (SDS), and resistant starch (RS). RDS is the fraction that is hydrolyzed to glucose within 20 min. SDS gets converted between 20 and 120 min and resistant starch is not hydrolyzed even after 120 min (Englyst et al., 1996; BeMiller & Huber, 2015). Chemical modification of starch by various reagents adds chemical moieties on the linear chains of the α-D-glucopyranosyl units of starch chain by molecular scission, oxidation, or molecular arrangements, etc., thus enhancing starch functionality. The hydroxypropyl, hydroxyethyl, methyl, and acetyl groups are commonly employed substituents used in starch modification and oxidized starches largely form depolymerized group of modified starch (Shah et al., 2016a). The mechanism of action in chemical modification of starch largely depends on two factors: intrinsic and extrinsic. The intrinsic factors include inherent properties of starch such as granule composition and structure and extrinsic factor related to the conditions imposed by the reaction system such as reagent parameters and reagent medium conditions. The delivery systems developed by biopolymers are more preferable over metallic and synthetic polymers and have been widely studied in both in vivo and in vitro studies. Various studies have shown that nanodelivery systems can load a high amount of drugs, accumulate in tumors and other targeted organs, and provide efficient delivery of payloads. These nano-starch crystals have a reactive surface covered with hydroxyl group, which consequently provide the possibility of modification via a chemical reaction strategy. The purpose of chemical modifications is to contribute to specific functions and to expand applications of starch nanocrystals. 3.4.1.1 Cross-Linked Starch  Cross-linking of starch is the formation

of chemical linkage between molecular chains in order to create a three-dimensional structure of connected molecules, i.e., hydroxyl group (–OH) reacts with the multifunctional reagents resulting in chemical bonds that are responsible for granule integrity and consequently enhances the resistance to viscosity breakdown as a result of mechanical shear, acid conditions, or high temperature. This occurs by heating native starch in H 2O above gelatinization temperature

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which leads to weakening of hydrogen bonds and tangential swelling of starch granules. Initially, this causes birefringence of granule and increase in viscosity. On continuous heating, the swollen granules collapse and fragment, releasing molecules, aggregates and fragments leading to viscosity drop and development of a cohesive rubbery texture (Huber & Bemiller, 2009). This technique is commonly used in various technologies of scientific and industrial interest to improve the properties of the resulting starch. The cross-linking can be achieved by radical polymerization, chemical reaction of complementary groups, condensation reactions, high energy irradiation, enzymes, ionic interactions, crystallization (homopolymer systems, stereocomplex formation), and hydrogen bonding and is mainly employed to achieve an improved stability and mechanical properties of starch (Hennink and Nostrum, 2012; Wang et al., 2016). The phosphoryl chloride (POCl3), glutaraldehyde, epichlorohydrin, citric acid, hexamethoxymethylmelamine, formaldehyde, boric acid, borax, sodium trimetaphosphate (STMP), trisodium trimetaphosphate, and the mixture of STMP and tripolyphosphates are the reagents approved by FDA for cross-linking purposes (Li et al., 2015; Wang et al., 2016). They induce intra- and inter-molecular bonds in starch granules to stabilize and strengthen granules and to exhibit low swelling, improved water absorption capacity to maintain constant viscosity, and decreased enthalpy of gelatinization and optimum water stability (Shah et al., 2016a). However, their effectiveness largely depends on the degree of modification, botanical source of starch, and cross-linking agents (Park et al., 2018). The controlled degradation of starch particles (3–340 mm) was achieved by modulating sodium metaphosphate and epichlorohydrin. Various studies in the last decade prepared microcapsules by cross-linked starch which involved the phase separation of one or more hydrocolloids from the initial solution and subsequently deposition of newly formed coacervate phase around the active ingredient suspended or emulsified in the same reaction media. Then the wall of the microcapsules forms a cross-linked structure and consequently results in good thermal and moisture-resistant properties, which can be used for controlled or targeted release application. In order to modify starch, grafting is the most commonly used technique to alter physicochemical properties of the starch and is widely used for controlled drug delivery applications in recent times. Since the

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grafted starch forms a rigid gel as it comes in contact with biological fluids, it behaves like non-Fickian. This suggested that the release was controlled by a combination of tablet erosion and the diffusion of the drug from the swollen matrix (Singh & Nath, 2012). STMP and POCL3 were used as cross-linking agents for the sustained delivery. The main reason for this modification is the change in amylopectin chain entanglement and porosity (Onofre, Mendez-Montealvo & Wang, 2010). The microgel was produced by oxidized potato starch (OPS) polymers which are obtained by the chemical cross-linking process by STMP for targeted delivery of β-carotene to human intestine as this natural antioxidant is beneficial for human health and is well known for its aqueous insolubility and its sensitivity to environmental stimuli. The in vitro analysis of the encapsulate was performed and showed that positively charged β-carotene nanoemulsion droplets were absorbed by the negatively charged starch microgel particles, which prevented the early release of β-carotene in the stomach and further in intestinal conditions. β-Carotene will be released from microgel as both the encapsulate and the encapsulant carry negative charge. Hence, in vitro release experiment suggested that oxidized starch could be used to prevent the early release of encapsulate as understimulated gastrointestinal fluids suggested that encapsulate remained stable at the gastric condition and the majority was released under intestinal conditions (Wang et al., 2015). The starch was cross-linked by glutaraldehyde, genipin, and citric acid, and then coated with iron magnetic nanoparticles loaded with curcumin and synthesized via coprecipitation technique. The characterization of nanoparticles and the effect of cross-linking on different properties of nanoparticles were evaluated. The zeta analysis showed that the cross-linking-imparted stability to system enhances drug loading and encapsulation efficiency of the system and release of the drug was dependent on time, cross-linker nature, cross-linker concentration, and pH of the medium (Saikia et al., 2016). Anirudhan and Parvathy (2014) encapsulated theophylline in cross-linked carboxymethyl starch (CL-CMS) and monotmorillonite (MMT) (during reaction carboymethylation occurs as a result of the reaction between native starch and monochloacetic acid in water/isopropanol medium at 60°C) and studied drug release behavior. The in vitro

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analysis of the drug revealed that encapsulation of 74% was achieved and matrix releases drug at much faster rate in the basic medium than in acidic medium, thereby holding the promise of developing semiIPN system as a potential candidate for release of theophylline. The cross-linked anionic starch microspheres were prepared with STMP through emulsification-cross-linking reactions at 50°C and studied for drug release and micro level characterization. The microspheres prepared have good sphericity and fine dispersibility and drug loading and releasing properties were investigated using methylene blue as model drug on single factor study. The author revealed that the loading ratio of methylene blue was significantly influenced by dissolution medium, loading temperature, and methylene concentration. The increase of loading time or drug concentration could lead to increase of drug loading amount of microspheres (Fang et al., 2008). β-Carotene was encapsulated in cross-linked potato starch in combination with maize oil by double emulsion method. The author further revealed that β-carotene was uniformly distributed in the inner oil phase of starch microsphere and microspheres were stable at stomach conditions and were broken to release β-carotene at intestinal conditions. The cross-linked starch improved thermal as well as storage stability of β-carotene (Wang et al., 2015). The soluble starch from potato was cross-linked to encapsulate methylene blue by emulsion cross-linking. The prepared spherical microparticles were smooth surfaced with high loading capacity. The starch was acetylated to enhance hydrophobicity, reduce swelling ability, and enhance resistance to enzymatic hydrolysis, which are useful attributes for development of delivery systems for pharmaceutical agents and food ingredients (Fathi et al., 2014). More recently, synthesis of starch nanoparticles by emulsion cross-linking technique was reported, which involved dispersion of aqueous phase containing hydrophilic natural materials such as starch and crosslinkers in oil phase with the presence of emulsifiers. The emulsion can generate small particles through cross-linking reaction as reported by Fang et al. (2008) and Franssen and Hennink (1998). Both Fang et al. (2008) and Franssen and Hennik (1998) observed that starch microspheres with an average diameter of 19 μm and 25 μm were produced and to reduce the size of these particles, emulsion should contain nanoscale droplets (miniemulsions, submicron emulsion, and nanoemulsions) as these emulsion droplets maintain their shape and size

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within dispersion phase. Zhou et al. (2014) also attempted to reduce the particle size using ionic liquid-in-oil emulsion approach, by substituting water phase using a 1-octyl-3-methylimidazolium acetate. 3.4.1.2  Oxidized Starch  In various studies, the oxidized starch has

been used for targeted and controlled release of bioactives, drugs, and probiotics. The most commonly used oxidizing agents for use in starch-based drug delivery include hypochlorite, permanganate, ceric ammonium, nitrate, hydrogen peroxide, per sulfate periodate, and dichromate (Yaacob, 2011). Oxidized starches are the group of converted starches in which β-alkoxycarbonyl system is established when a carbonyl unit is introduced at C-2, C-3, or C-4 of a substituted d-glucopyranosyl unit, thus leading to chain cleavage in an alkaline system. Broadly speaking, there are two types of starches treated with oxidizing agents: bleached starches and chlorinated starches. Bleached starches are prepared by treating starch with certain specified oxidizing agents such as peracetic acid (0.45%), sodium hypochlorite (0.82%), sodium chlorite (0.5%), potassium permanganate, and ammonium persulfate (0.075%) at a very low level. The chlorinated starches are prepared by treating starch with sodium hypochlorite. The treatment involves slow addition of solution of sodium hypochlorite to a suspension of granular starch in water up to a maximum of 5.5% available chlorine (the amount varied to suit the desired degree of conversion) followed by adjustment to neutral or slightly acidic and excess hypochlorite is destroyed by addition of a reducing agent such as bisulfite after which the starch granules can be washed, dehydrated, and dried. Proper care must be taken to avoid excess temperature increase as the reaction is exothermic and requires a temperature in the range of 30°–35°C by adjusting the rate at which the reagents are added. The excess temperature may lead to partially solubilized and swollen starch, consequently resulting in excessive loss of solubles and problems in washing and dewatering the starch granules. The oxidation reaction is normally carried out under mild to moderate alkalinity as the pH at which starch oxidizes is an important factor controlling the course of oxidation. Besides pH, the concentration of the oxidizing agents and the temperature are sensitive parameters and need proper adjustment. These oxidizing agents target hydroxyl groups of starch for oxidation under controlled temperature and pH. It involves the

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oxidation of hydroxyl group to carbonyl groups, which is followed by depolarization of chains by cleaving the α-(1→4) linkages between the glucopyranose units (Masina et al., 2017). Their mechanism of action (varies according to the nature of oxidative method and reagents utilized) results in various alteration to molecular structure of starch that functionalizes copolymer to required properties (reduced viscosity, high clarity, low temperature, stability, and increase in tensile strength) and consequently have greater implications and functionalization potential in drug delivery applications (Fonseca et al., 2015; Singh et al., 2007). This modification can also alter surface morphology, which in turn has a significant effect on matrix functionalization, hence resulting in controlled biodegradation of starch matrix. Thus, surface morphology is of great importance in starch drug delivery system in which release of active agents is controlled or sustained over a specified period with predictable release kinetics (Masina et al., 2017). Sangseethong et al. (2010) produced carboxyl starch (anionic starch) by oxidation of starch with hypochlorite which largely functionalizes copolymer and consequently enables chemical reactions with other macromolecules. The enzyme (Nattokinase) was microencapsulated in oxidized starch and studied for a targeted release in thrombolytic disease treatment. The high encapsulation efficiency was reported at a targeted site during simulated condition (Huang et al., 2013). The oxidized starch was cross-linked with chitosan via reductive alkylation studies. The key analysis from this hydrogel stated that the increase in starch ratio was directly proportional to swellability and inversely proportional to tensile strength (Baran, Mano and Reis, 2004; Sangseethong et al., 2010). OPS and glycerol-1,3-diglycidyl were used as wall materials for controlled uptake and release of lysozyme. It was found that both swelling capacity and lysozyme uptake at saturation increased with increasing degree of oxidation. Further, the lysozyme release was promoted at low pH and high ionic strength, which were considered to be the most suitable conditions for triggering the release of encapsulate, thus suggesting the oxidized starch as an effective agent for controlled uptake and release of proteins lysozyme (Zhao et al., 2015). OPS and oxidized wheat starch (OWS) were used as wall materials for encapsulation of indomethacin and characterized for controlled release. The in vitro release of indomethacin was low in the simulated

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gastric fluid at pH 1.3 and consistent in the simulated intestinal fluid (SIF) at pH 7.4 (Loghin et al., 2017). In another study, a combination of oxidized corn starch (OCS) and gelatin (G) was explored as a new microcapsule composite by spray drying as the blend G/OCS of showed longer gel time, higher transparency, lower viscosity, and faster dissolution rate than that G/CS under same conditions. This was attributed to the formation of Schiff base between the aldehyde group of OCS and the amino group of gelatin, which improved the compatibility between gelatin and oxidized starch (Chen et al., 2017). The antibacterial wound dressings were prepared with oxidized amylose as an effective way to introduce linalool into collagen matrix as the result showed that the content of linalool in composite dressings was efficiently increased due to the solubilization effect of oxidized amyloses and had abilities to keep the wound in the moist environment, thus preventing excess accumulation of exudates with excellent antibacterial activities, enhanced blood compatibility, and good cell biocompatibility (Lyu et al., 2017). The OPS was used as a wall material to encapsulate blueberry anthocyanins by binding and adsorption method. The resulting microspheres with a high degree of oxidation were seen to adsorb more anthocyanins (62 mg per gram of modified starch at pH 3 and ionic strength 0.05 M). The starch hydrogel protected the degradation of anthocynin in the GI condition while delivering them to intestines. 3.4.1.3  Acid Hydrolysis of Starch  The hydrolysis of starch by mineral acid was discovered in 1811 by a chemist- G.S.C. Kirchoff working in Europe. Starch hydrolysates are widely available with various compositions ranging from high-molecular-weight products which are virtually tasteless to crystalline dextrose (d-glucose). This method has widely been used for the preparation of nanoparticles. This chemical treatment involves depolymerization of starch to a desired extent by treating native starch with mineral acid such as hydrochloric and sulfuric acid at high temperature. It consists of the continuous flow pressurized reactors in which the acidified starch is maintained at a temperature of 135°C–150°C for 5–8 min and in this process hydrochloric acid is commonly used at a concentration of 0.02–0.03 M in a starch slurry of about 23° Baume (40% dry substance). The crystalline region in starch granules are more resistant to acid hydrolysis than the

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amorphous region, and crystalline moieties can be isolated by mild acid hydrolysis as the mild acid hydrolysis may selectively erode the amorphous region, thus resulting in high crystalline starch nanoparticles (Kim et al., 2015). Mostly acid-hydrolyzed starch is observed in two ways: recovery of soluble sugar in solution and recovery of insoluble starch residues. This modification serves the partially dibranching amylopectin portion of starch located with the amorphous region of granules, conferring more amylose-like behavior to treated starch due to an increase in the linear component. Thus, acid hydrolysis of starch is a two-step process which involves hydrolysis of amorphous parts within starch followed by erosion of crystalline region in starch granules (Mussulman & Wagoner, 1968). The decrease in swelling power, loss of pasting properties, increase in solubility, broader range for gelatinization temperature, and tendency to retrogradation are caused by acid hydrolysis to starch (Shah et al., 2016a). The degree of hydrolysis largely depends on the type of solvent used, reaction temperature, and reaction time. Due to its selective hydrolysis, the recovery yield is low and requires long period and hence hinders the use of oxidized starch at industrial level. For this reason, researches have suggested to use dual modification in particular physical treatment with acid hydrolysis (Ma et al., 2008; Tan et al., 2008). The comparative analysis of starch-hydrolyzed nanoparticles by H 2SO4 and HCl revealed that H 2SO4 hydrolysis shortened the preparation time and increased the yield of starch nanoparticles. The possible explanation is that during hydrolysis, the formation of sulfate–ester linkages on the surface of nanoparticles limits the flocculation of nanoparticles and consequently produces nanosuspension with increased stability (Kim et al., 2015). For hydrophobic food, ingredients such as vitamins and lipids are encapsulated by hydrolyzed starch in combination with maltodextrins because of high water solubility, low cost, and bland flavor. The hydrolyzed starches from pinhao (Araucaria angustifolia) in combination with gelatin were used as a wall material for encapsulation of β-carotene by freeze drying. The capsules from starch hydrolysates had 93% carotene content and presence of the gelatin greatly reduced surface carotene content because of formation of film surrounding the capsules. The shape of the microcapsules was irregular with smooth surface and the average size of the microcapsules was 21–24 μm and thus suggested to be suitable for preparation and encapsulation

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(Spada et al., 2012). Lactobacillus plantarum was microencapsulated in partially hydrolyzed starch and studied. The cavities and channels in native maize starch were enlarged by enzymatic hydrolysis, thus allowing them to act as a wall material with significantly higher total probiotic numbers (Li et al., 2016). The insulin was nanoencapsulated in PEGylated starch nanoparticles and resulted in higher encapsulation efficiency than starch acetate nanoparticles (Minimol, Paul & Sharma, 2013). The acid-hydrolyzed starch produces starch nanocrystals with good solubility property. The drawbacks associated with acid hydrolysis to produce starch nanoparticles with inherent crystallinity are extended period and low yield, and thus, scientists focus more on alternative techniques such as extrusion, ohmic heating, ultrasound, and γ-irradiation as they shorten periods with higher yield than acid hydrolysis. 3.4.1.4 Substituted Starch  Monofunctional reagents are used to

react with hydroxyl groups of starch molecules to introduce substitutional groups in order to stabilize amylose against retrogradation, consequently enhance the shelf life through tolerance to temperature fluctuation such as freeze-thaw cycles, and are usually used in conjunction with cross-linking (Shah et al., 2016a). The degree of substitution is largely dependent on the replacement of hydroxyl group of starch molecules into larger ester or ether groups, in which interchain associations can be blocked, thus resulting in more stable pastes and gels with a lower tendency to retrograde and the nature of substituent used for modification affects the effectiveness of stabilization. Hydrocolloid starch can be covalently substituted with different functional groups using succinic anhydride, acetic anhydride, and propylene oxide to improve the encapsulation efficiency in delivery systems. In acetylated starch, some of the hydroxyl groups of starch are replaced by ester (acetyl) group and the first starch acetates were reported in 1865 by Schuetzenberger. This replacement of hydroxyl groups by ester group causes various physicochemical changes such as low GT, good cooking, storage stability, stability of product texture and appearence, reinforced hydrophobicity and thermal stability, film-forming ability, and improved thermoplasticity. The chemically hydrophobic substituted starch acetate with small cracks after dissolution, which is responsible for its sustained release activity, was

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produced by treating native starch with acetic anhydride in the presence of aqueous/organic solvent. Caldwell and Wurzburg (1953) synthesized ocetenyl succinic anhydride (OSA) which is a lightly substituted half ester of sodium ocetenyl succinate prepared by reacting OSA to a suspension of granular starch at a neutral pH under agitation. The pH of the medium determines the existence of starch octenyl succinate half-ester as either sodium salt or the acid. OSA starch contains both the hydrophilic (carboxylic or sodium carboxylate group) and hydrophobic (ocetenyl) groups with a stable ratio of 1:1. This modification shows low GT, an increase in freeze-thaw stability, thickening power, viscosity stability, paste clarity, the ability to swell in cold water, and stability in acid and salt, thus reducing the tendency of retrogradation and modifying texture of starch. The partial etherifications of starch with propylene oxide (10%) in alkaline conditions resulted in the formation of hydroxypropylated starch and the preparation involves a reaction between concentrated aqueous suspension of starch granules and propylene oxide with high agitation in alkaline solution and mostly sodium sulfate is added to reaction mixture to minimize starch gelatinization. This treatment results in reduced bond strength between starch molecules that facilitate gelatinization, lowers molecular association or retrogradation, increases water holding, possesses gelling property, improves freeze-thaw and cold stability, improves textural the property of products, and enhances the shelf-life of the food products. This substitution is more stable than acetylated and phosphorylated starches. Cheuk et al. (2015) prepared nanoencapsulated coenzyme Q10 in octenyl succinic anhydride (OSA)-modified starch and rice bran oil. The author revealed that encapsulating agents were able to entrap encapsulate (coQ10) within nanoscale particles and nanoencapsulation was very successful as displayed by the inability of CO2 supercritical fluid extraction to extract CoQ10 without lengthy enzymatic catabolism of the modified starch carrier. The 98% encapsulation efficiency was achieved when OSA starch was used as a wall material to encapsulate photosensitive molecules (resveratrol) (Matos et al., 2017). The in vitro analysis (colon targeted delivery) of granular and crystalline structures of resistant OSA-modified starch was performed. The enhancement in succinylation of starch consequently increases the enzyme and acid resistibility to digestion, indicating the improvement of the colon-targeting

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property of starch as the substitution (DS) increases. As is evident from the in vitro study, the resistant OSA starch-based matrix was effective in delivering a bioactive component to the colon, when resistant starch content and hydrophobicity were suitable (Li et al., 2012). Wang et al. (2011) prepared and characterized OSA-modified corn starch as delivery carrier material. The result showed an increase in the resistant starch content with an increase in the degree of substitution, indicating the improvement of the colon-targeting property. The swelling ratio of modified starch in the simulated condition was greater than that of native starch, and its hydrophilicity decreased with an increase in the degree of substitution. For the first 8 h, the release of bioactive was less than 7% and close to 100% over a period of 36 h when the degree of substitution was 0.60. This suggests OSA as a potential carrier for colon-targeted delivery of bioactive food components (Wang et al., 2011). The hydrophobicity of the OSA was introduced and the hydrophilicity of starch backbone was retained, when starch was modified by OSA (Li et al., 2012). Caldwell and Wurzburg (1953) patented OSA-modified starch. Billmers and Mackewicz (1997) suggested the use of OSA-modified starch as a cheap encapsulating agent which also has been certified by GRAS. When ocetenyl succinate is used to modify starch polymer, it confers the ability to form a stable oil-in-water emulsion. The use of this modified starch with its (1→4) glucosyl backbone is perfect for gut absorption of any encapsulated material through the small intestine. The octenyl side chains have the ability to reduce the activity of alpha-amylase and modify the release of material due to starch hydrolysis after consumption (Cheuk et al., 2015). Qi and Xu (1999) used OSA to modify starch for encapsulation of various food ingredients. The study further revealed an increase in the long-term stability of encapsulate. Jeon et al. (2003) modified starch by succinylated and octenyl succinylated starches to encapsulate benzaldehyde dimethyl trisulfide and 2-mercaptopropionic acid and benzothiazole gallic acid that resulted in amphiphilic starch and consequently increased encapsulation efficiency. Further, an increase in hydrophobicity of starch was achieved by encapsulation gallic acid in acetylated starch (Robert et al., 2012). The propyl starch-based nanoparticles were used to encapsulate various drugs for their transdermal delivery, and the authors concluded that encapsulation efficiency was found

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to be much better for hydrophobic drugs with a null burst effect (Santander-Ortega et al., 2010). Cortes et al. (2014) encapsulated probiotics in OSA-modified starch and reported higher encapsulation efficiency under simulated gastrointestinal conditions in comparison with encapsulation in phosphorylated and acetylated starches, which is mainly because of more hydrophobic nature of the OSA starch than others, consequently retarding water penetration and enzyme access. Another scientist also used OSA as a wall material for encapsulation of isoeugenol and tested the impact of encapsulation on its antibacterial properties in model food systems (growing media, carrot juice, and milk). The results of this study revealed that emulsion encapsulation enhances antibacterial activity of isoeugenol against Gram-negative (Escherichia coli K 12) and Gram-positive (Listeria monocytogenes) bacteria in carrot juice and growth media and the increase in growth could be attributed to its enhanced solubility in emulsions, promoting physical contacts between compounds and cells (Nielsen et al., 2016). Yu and Huang (2010) encapsulated curcumin in OSA starch-based emulsion, resulting in enhanced in vitro anticancer activity than the pure curcumin dissolved in DMSO, which is due to increased interactions of curcumin with cancer cells. 3.4.1.5 High Amylose Starch  Starch is a hydroxy-functional polymer

and most processes for chemical modification of starch depend on the intrinsic reactivity of the hydroxyl group. Hence, the high amylose starches can be utilized for the encapsulation of bioactive. The high amylose starch by inclusion complexes can encapsulate a range of bioactive components such as polyphenols and unsaturated fatty acids. The generally used techniques for encapsulation by high amylose are coprecipitation, acidification, and electrospinning. In coprecipitation, high amylose starches are dissolved in water at high temperature (145°C) and are kept at relatively high temperature (90°C). Then the food ingredients are added followed by cooling at room temperature to form inclusion complexes. In acidification, high amylose starches are dissolved in an alkaline solution at 90°C and dissolved ingredients are added and mixed followed by adjustment of pH (5–6) by H3PO4 to facilitate the formation of inclusion complexes. In various studies, high amylose starch has been used as an encapsulation agent (Cohen et al., 2008; Kong & Ziegler, 2014; Kong & Ziegler, 2014).

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The high amylose maize starch (Hylon VII) starch was used as a wall material to encapsulate Genistein by acidification of an alkaline solution. The results revealed that V6 III type amylose inclusion complexes were formed and the loading of genistein was higher. In vivo analysis showed that the inclusion complexes increased the bioavailability of genistein (Cohen et al., 2008). Gokmen et al. (2011) encapsulated flaxseed oil in high amylose maize starch (Hylon VII) by acidification of an alkaline solution and found that encapsulation decreased lipid oxidation and formation of hydroxymethylfurfural and acrylamide. Palmitic acid, ascorbyl palmitate, and acetyl trimethylammonium bromide were encapsulated in high amylose maize starch by electrospinning. The use of electrospinning facilitated the formation of inclusion complexes with guest molecules and the native lipids in maize starch had no effect on amylose inclusion complex formation (Kong & Ziegler 2014). In another study, amylose (starch) inclusion complex with amphiphilic material as an effective encapsulation platform technology was used to encapsulate β-carotene. X-ray diffraction showed that β-carotene molecules did not crystallize into separated phase but homogeneously immobilize within the amylose inclusion complexes with improving stability upon storage. Amylose inclusion complexes may be useful as a delivery composition for bioactive molecules such as genistein, linoleic acid, fatty acid esters of vitamins, and long-chain unsaturated fatty acids as the crystalline inclusion complex structure is expected to protect these active ingredients against the acidic environment of stomach, and their bioavailability will be improved in lower gastrointestinal tract. 3.4.2 Physical Modifications

Numerous shortcomings of the chemical modifications such as environmental pollution, regent overdose, and time-consuming have given rise of the emerging and novel technologies to use in encapsulation technologies. 3.4.2.1  Modification by Ultrasound Waves  This green technology is a

sound wave with a frequency range of 2 × 104 to 109 kHz and is generated with either piezoelectric or magnetostrictive transducers that create high energy vibrations. This treatment is one of the physical

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methods of modification of starch which causes depolymerization of starch and the process is considered to be environmentally friendly as it reduces usage of chemicals, waste production, and energy consumption such as it shortened the time of octenyl-­succinylation of carboxymethylated potato starch from 24 h conventionally spent to a few minutes without the use of p-­toluenesulphonic acid (Sujka, 2017). The mechanism of action is it causes physical degradation of granules with visible fissures and pores on the surface but no alterations of granules shape and size and the extent of damage to granule are related to the phenomenon of cavitation. Starch granules are bombarded by bubbles of gases in the suspension medium before the collapse and the rapidly collapsing bubbles cause arising of shear forces and microjets close to the surface of a granule which in turn result in its break-up or the solvent molecules may dissociate to form radicals which may induce polymer degradation. The gas type of atmosphere, the temperature of the system, frequency, time of treatment, and properties of starch dispersion (solid concentration and botanical origin) will determine the effectiveness of ultrasound on treated starch (Shah et al., 2016b). The sonication causes cracks and pores to starch granules. This cavitation is a series of dynamic processes of bubbles in liquid when exposed to an ultrasonic field (Kim et al., 2015). The ultrasound technique was used to disintegrate starch granule into nanosized particles and further studied in terms of size, morphology, and structural properties and the proposition of a possible mechanism. The characterization of the disintegrated starch suggested ultrasound as an effective tool for targeted delivery (Boufi et al., 2018). Chang et al. (2017) treated different solutions of aqueous amylose (1, 2, and 5 wt%) with 100 W ultrasound for preparation of nanoparticles. The results revealed that ultrasonic treatments led to a decrease in viscosity of amylose solutions, scission of amylose chains, and narrowing of size distribution of amylose molecules, thus giving rise to smaller amylose nanoparticles with more uniform size and this treatment was suggested to be effective for preparation of smaller starch nanoparticles through nanoprecipitation with higher efficiency and lower cost. The ultrasound treatment in combination with acid hydrolysis was used for the preparation of starch nanoparticles from waxy starches. About 50%–70% of amorphous region in starch was removed by acid hydrolysis after 2 days and subsequently ultrasonic treatment (60%

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vibration amplitude, 3 min) was applied to re-disperse suspension of large microparticles of starch hydrolyzates, which was recovered by mild centrifugation (Kim et al., 2015). It is important to note here that proper care must be taken to minimize the chances of crystalline structure disruption in starch. One of the procedures to reduce disruption by ultrasound is the use of low temperature (4°C) to facilitate the association of starch chains, minimizing crystallinity disruption and formation of new crystalline structure in starch nanoparticles by chain association. During the abovementioned study, starch hydrolyzates obtained after 6 days of acid hydrolysis were more resistant to subsequent ultrasonication than those obtained after 2 or 4 days regardless of hydrolysis temperature and the combination of acid hydrolysis and ultrasound increased recovery yield of starch nanoparticles. The hydrolyzed starch was treated with ultrasound at different vibration amplitudes (20% and 40%) and durations (30 and 60 min/day). The results suggested that ultrasound effectively prevented aggregation of nanoparticles and helped to the re-disperse suspension of large microparticles of starch hydrolyzates (Kim et al., 2013). The effects of sonication (ultrasonic power, time, and same temperature but different ultrasonic frequency) on corn starch and its cavitation were studied. The results showed that the peak viscosity of starch without ultrasound was 1076 BU and decreased by 18.87% and 17.66% with 25 and 20 kHz, respectively. Ultrasonic waves significantly changed thermal stability, retrogradation, and gel properties of starch and caused depression on the surface of starch granules. High-frequency ultrasonic waves produced more cavitation yield and caused a faster collapse of bubbles than low-frequency treatment (Hu et al., 2015). The ultrasound treatment in combination with enzymatic method was used to produce microporous wheat starch with increased adsorption capacity. In enzymatic treatment, starch slurry was treated with different concentrations of α-amylase with enzyme activity of at least 10,000 units/g for 24 h at 45°C. In the ultrasound method, slurry (20% w/v) was sonicated at 240 W and 35 kHz for 20, 40, and 60 min. It was observed under SEM analyses that sonication caused cracks and fissures and enzyme treatment produced some pores on the granules. Further, it was observed that oil adsorption capacity, hydration capacity, and adsorption capacity of the starch increased in a dosedependent manner (Majzoobi et al., 2015).

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The synergistic impact of glucoamylase and ultrasound on starch hydrolysis was studied. The hydrolysis extent increased with reaction time and reached maximum value under the ultrasonic intensity of 7.20 W/mL at 10 min. The ultrasound did not alter optimum enzymatic kinetics, and starch degradation kinetics indicated a promotion of the reaction rate and enzyme substrate affinity. The measurement of molecular weight, solubility, thermal properties, and structure of the substrates revealed that sonoenzmolysis reaction generated greater impact on starch properties and molecular weight and radii of gyration decreased by 80% and 90%, respectively, while the starch solubility improved by 136.50% (Wang et al., 2017). The small starch particles (500 nm) were prepared by hydrolyzed waxy rice starch using enzymatic treatment (α-amylase), followed by ultrasonication. Due to the hydrolysis of α-(1→4) glycosidic linkages in amylose and amylopectin by α-amylase, some cracks and pores were observed on the surface of hydrolyzed starch granules causing fragmentation of granules. The sonication-induced aggregation of the starch hydrolyzates by increasing the mean diameter of these hydrolyzates. The increase in the diameter was dependent on the degree of enzymatic hydrolysis. Also, the hydrolyzed starch was more susceptible to sonication treatment and caused a change in the X-ray diffraction pattern of starch. The ultrasonic treatment was used for starch nanoparticles to nanoencapsulate peppermint oil. The starch nanoparticles showed good uniformity and an almost perfect spherical shape with a diameter of 150–200 nm, a loading capacity of 25.5%, encapsulation efficiency of 87.7%, and a yield of encapsulate of 93.2% with enhanced stability against thermal treatment (Liu et al., 2017). The above results suggest ultrasonication as rapid, high yield, and nontoxic and have great potential in encapsulation and sustained release. 3.4.2.2  Modification by γ-Irradiation  The γ-irradiation to food hydrocolloids will cause emergence of reactive intermediates or radicals and cause rearrangement and/or formation of new bonds which consequently oxidize products, grafts, and scission of main chains, i.e., degradation or cross-linking or in simple terms γ-irradiation caused fragmentation of large molecules by cleaving glycosidic linkages and generated free radicals which are capable of hydrolyzing chemical bonds, thereby producing smaller fragments of starch called dextrin.

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Broadly speaking, two types of ionizing radiations are used for radiation sterilization and cross-linking: γ rays emitted from artificial radioactive isotopes 60Co and 137Cs and beams of energetic electrons from electron accelerators and absorption of radiation in both cases occurs on a subatomic level. The irradiation of starch and other hydrocolloids leads to two main processes: chain scission and cross-linking. The effectiveness of irradiation depends on the structure of the starch polymer, irradiation condition, the presence of air, and additives. The rate of drug release or release kinetics in irradiated starches depends on many factors such as solubility of drug in polymeric membrane/ matrix material, drug solubility in environmental solution, drug diffusivity in polymeric membrane/matrix material and environmental solution, thickness of membrane, diffusion coefficient of solvent in polymer, and thickness of hydrodynamic boundary diffusion layer. The effect of radiation on release kinetics would be determined by the complex interplay of relevant factors before and after irradiation. Various studies have been reported regarding the use of this rapid, convenient, and green technology in encapsulation technologies. It fragments large molecules by cleaving glycosidic linkages and involves chemical changes such as degradation of macromolecules, leading to the formation of carbonyl and carboxyl derivatives (Ciesla et al., 2014). The increase in gel consistency and a decrease in melting point and melting enthalpy were achieved by γ-irradiation which has a positive effect on the eating quality of starch (Wu et al., 2002). The irradiation of food hydrocolloids leads to chain scission and cross-linking. Both chain scission and cross-linking are favorable for the efficient encapsulation and structure of the starch. The presence of air and irradiation conditions determines the efficiency of the modification. In various studies, cross-linking of starch was performed by irradiation. Cross-linking by irradiation randomly introduces cross-links in space within hydrogels, whereas chemically cross-link hydrogels exhibit a more inhomogeneous distribution of cross-linking point. Thus, crosslinking by irradiation is of special interest as it not only produces a three-dimensional network with chemicals but also reduce microbial load at the same time. Starch nanoparticles with the size of 20 and 30 nm were obtained by γ-irradiation at a dose of 20 kGy from cassava and waxy maize starches, respectively, and studied. A large number of hydroxyl groups on the surface of irradiated starch suggest its more

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susceptibility to thermal degradation than non-irradiated starches (Kim, Park & Lim, 2015). Lamanna et al. (2013) used γ-irradiation for production starch nanoparticles. The study revealed that irradiated starch nanoparticles were more susceptible to thermal degradation than parent native starch, thus suggesting that these nanoparticles have a large number of hydroxyl groups on their surface where the thermal degradation starts. The nanoparticles obtained displayed amorphous XRD pattern but the transformation to the amorphous structure was not related to γ-irradiation and was because of heat treatment prior to γ-irradiation. 3.4.2.3 Modification by Osmotic Pressure Treatment  It involves treating starch in the presence of high salt solution. No other chemical is involved and thus there is no concern for the effect on environment and safety. To obtain a uniform starch suspension, the starch solution is suspended in sodium sulfate and heated distribution (Kaur et al., 2012). The higher yield of modified starch was achieved by osmotic pressure treatment (OPT) in comparison with heat-moisture treatment. The most commonly used salts in osmotic pressure starch modification are sodium sulfate and sodium chloride. They showed increased cross-linking efficiency, increased the percentage of crystallinity, and gelatinization with no effect on X-ray diffraction patterns. Although very less work has been performed on OPT starch as encapsulating agents till date, the above properties satisfy its use as encapsulating agents. 3.4.2.4  Modification by Heat-Moisture Treatment  This method is one

of the easiest, cheapest, and environmentally friendly treatments used to modify starch without destroying its granular structure. This method involves low moisture level (18%–27%) and high-­ temperature heating, i.e., above the glass transition temperature (Tg) but below gelatinization temperature (90°C–120°C) for a time of 15–16 h (Shah et al., 2016a). This modification changes structure and physicochemical properties of starch, such as granule swelling, amylose leaching, pasting properties, gelatinization parameters, tensile strength, thermal stability acid, and enzyme hydrolysis (Arns et al., 2015; Shah et al., 2016a). It is important to note here that heat-moisture treatment affects differently the thermal and pasting

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properties of starch, and these effects are intensified by treatment time which leads to a reduced extraction yield of starch by the alkaline method and with increasing time of exposure to high temperatures, suggesting an alteration in structure. Oh, Bae and Lee (2018) reported the effect of heat-moisture treatment on digestibility and physical properties of amylose starch. The results revealed an increase in gel strength and pasting properties above 130°C and a decrease in gelatinization temperature and enthalpy, thus changing the semicrystalline region. The in vitro starch digestibility of moisture heat treatment was rapid and the predicted GI was low. The low GI, high gel strength, and pasting properties suggested the ­negative correlation of heating temperature with in vitro starch digestibility, thus suggesting moisture heat treatment as a useful tool for enhancing physical and nutritional properties of starch. The high amylose starch was modified by dry heat treatment and studied for digestibility and other physical properties. The in vitro digestibility and physicochemical properties of heat-moisture-treated starch blended with galactomannan were investigated. The results revealed that resistant starch contents in heat-moisture-treated native starch blended with galactomannan were related to the ratio of galactose/mannose residues in galactomannan. The degree of attachment of galactomannan to starch was also positively correlated with g­ alactose/mannose residue ratio of galactomannan and the phenomena became more obvious with an increase in addition amount of gums. Further, a combination of non-starch hydrocolloid with heat-moisture-treated starch had no effect on a crystal-type pattern of starch (Chen, Xiong & Gao, 2017). 3.4.2.5  Modification by Pulsed Electric Field  Pulsed electric field (PEF)

is a nonthermal, green technology that works on the principle of the electric field that causes disruption in starch granules, i.e., it could significantly alter the microstructure and macromolecular interactions of biomacromolecules (Giteru et al., 2018). PEF involves the application of short pulses (μs-ms) of a high-voltage electric field to materials placed between two electrodes, and the energy dissipated can cause the ionization of functional groups in biomacromolecules and/or can also break electrostatic interactions in macromolecules chains resulting in cleavage or coalescence of monomeric units.

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For example, the surface morphology of native starch is smooth, oval, and irregular; after subjecting to PEF, roughness or surface damage emerges, and in further treatment, some pits emerge and small starch particles are aggregated to form bigger ones. Besides the change in surface structure, PEF-modified starch is prone to cause rearrangements, destruction of starch molecules, and reduction in gelatinization, viscosity, crystallinity, solubility, gel consistency, and gel clarity (Shah et al., 2016a). This treatment to starch can also cause dipole chemical reactions and resulting conformational changes, thus giving an opportunity for incorporation and blending of several food hydrocolloids (Giteru et al., 2018). The effectiveness of this modification on starch depends on the ability of electric field to increase the fluctuation of a system internal energy or electric field strength (E), total specific energy (Q), and temperature (T), characteristic of pulse (pulse waveform, pulse width/tp, pulse number/n, pulse repetition rate/f ), time of exposure, and electric properties of product such as resistivity (R)/conductivity, temperature, and pH (Hu et al., 2014; Yan et al., 2014; Aguiló-Aguayo, Soliva-Foruny & Martin-Belloso, 2010b; Morales-de la Peña et al., 2011). The waxy rice starch was subjected to PEF treatment, and an improvement in granule morphology, molecular weight, semicrystalline structure, thermal properties, and digestibility was seen. The author suggested the pulsed electric treatment as an effective tool for micro- and nanoencapsulation technologies (Zeng et al., 2016). 3.4.2.6  Spray Drying  This is one of the most commonly used physical

modification techniques in starch as a delivery vehicle because of its fast, relatively cheaper, and reproducible nature, and produces particles of good quality for encapsulation of food ingredients. During spray drying, the pregelatinized starch is produced, which changes the insoluble form into a high viscosity gel and consequently controls the drug release behavior and mechanism which is dominated by polymer erosion. The less amylose and high amylopectin proportion would be a better option as it seems to be responsible for the cohesive character of the gel, while amylose provides hardness to dosage form (Herman, Remon & Vilder 1989; Peerapattana et al., 2010). Compared to freeze drying, spray drying is a more economical, faster, single-step drying method and yields uniformly spherical particles as

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there is a possibility to control particle size and morphology by varying process parameters and formulations. During encapsulation of active ingredients, its work is based on dissolving or dispersing the active ingredients in a solution of biopolymer and followed by atomization in the heated air chamber, which rapidly removes the solvent and produces a dried particle consisting of active ingredient embedded in a porous wall material. The size and efficiency of the encapsulation depend on the following factors: the properties of the materials used such as core and wall properties, solution viscosity, particle size, and spray dryer features such as atomizer type, flow rates, inlet/outlet temperatures, and humidity (Jafari, Assadpoor, Bhandari & He, 2008). The β-carotene was encapsulated in modified starch by spray drying technique with nanoemulsion mean droplet size of 114–160 nm. These nanoemulsions were converted to micro-sized powders after spray drying and powder showed good dissolution in water and reconstituted emulsions had a similar particle size, suggesting that spray drying process did not affect the properties of nanoemulsion (Liang et al., 2013). 3.4.2.7 Microwave Treatment  This minimal processing technology

offers advantages such as low cost, eco-friendly, high productivity, reduced reaction times, straightforward, simple handling and processing, and conforms to all accepted norms of green chemistry (Shah et al., 2015). This physical modification is used to prepare starch graft copolymers and is a useful tool for a wide range of chemical reactions, which is due to its precisely controlled temperature and pressure environment. Thus, it produces the end product that is purer and if all other factors (Wattage of radiation, polysaccharide concentration, and monomer concentration) are kept constant, then the percentage grafting can be precisely controlled in terms of net irradiation time, which were regulated electronically (Setty et al., 2014). The use of microwave irradiation in organic synthesis and polymerization reactions has become a popular technique, and its utilization as a drug delivery system based on polymeric materials improves the efficiency, reduces toxicity, reduces side effect, and improves recovery of encapsulate in particular drug. The simple hydrogel of polyacrylamide-grafted starch was used for controlled delivery of cefriaxone sodium. The amide functional groups of grafted polyacrylamide chains acquire a polyelectrolyte

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character and it greatly enhances functionality of copolymer during alkaline hydrolysis and upon hydrolysis reaction, a –CoNH2 group of polyacrylamide chains could be converted to a –COOH group resulting in the incorporation of ionic property, which shows a rapid response to the changing environment such as pH and ionic strength (Al-Karawi & AL-Daraji, 2010). In various studies, controlled release drug delivery systems were found to increase the therapeutic activity of drug, reduce side effects, and enable the drug to be targeted only to desired organs or tissues (George & Abraham 2006; Kenawy et al., 2001; Kenawy et al., 2008; Van den Mooter et al., 2006). During the last decade, polymer-drug conjugates were used to develop highly advanced controlled release drug delivery systems, which could, to a great extent, optimize the therapeutic properties of drugs, safety, and affectivity. This technology has been used more and more in polymer synthesis in the last decade (Kempe, Becer & Schubert, 2011; Singh, Kumar & Sanghi, 2012). Alfaifi et al. (2014) showed that two amino acids were graft copolymerized using the microwave-assisted grafting technique onto starch for delivery of model drug atenolol. The loading was confirmed by ATR-FTIR, TGA, and NMR. The study showed that drug release takes place in the alkaline medium than in acidic medium indicating that these polymers can be used as carriers for drugs whose target is a colon. The graft copolymers of waxy maize starch and poly-γglutamic acid were produced in an aqueous solution using microwave treatment and the reaction conditions were optimized with regard to temperature and pH. The temperature of 180°C and pH 7.0 were the best reaction conditions resulting in a poly-glutamic acid graft of 0.45% based on nitrogen analysis, and the average graft content and graft efficiency were 4.20% and 2.73%, respectively. The grafted copolymer at 180°C and pH 7.0 absorbed more than 20 times its own weight amount of water and form gel and rheology study revealed that the gel formed exhibited viscoelastic solid behavior (Xu et al., 2016). The copolymeric material (Sago starch) was used as wall material for controlled release tablet formulations (lamivudine). The acrylamide grafting was performed on the backbone of sago starch and modified starch was tested for acute toxicity and drug excipient compatibility studies. The in vitro release study showed that the optimized formulation exhibits the highest correlation value in the case of Higuchi

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model, and the release mechanism of optimized formulation predominantly exhibited the combination of diffusion and erosion process with a significant difference in pharmacokinetic parameters such as Tmax, Cmax, AUC, Vd, T1/2, and MDT compared to marketed conventional tablet Lamivir. 3.4.2.8 Use of Electrospinning in Modified Starch for Controlled Delivery  In the 1930s, Soviet scientists invented electrospinning

with commercialization attempts being recorded throughout the last century. The resulting modified starch has potential as vehicles for drug delivery, nanoencapsulation for bioactive molecules, and biomolecular sensors and ultrafiltration media. This is one of the emerging technology in encapsulation science due to its ease of use, wide applicability, and possibility of obtaining structures that possess high surface-to-­volume ratio (nanostructures), thus enhancing the stability and bioavailability of encapsulate (Tampau et al., 2017; Pérez-Masiá et al., 2014). This is an effective technique that uses electrostatic forces to create polymer fibers with submicron or nanometer scale diameters and with controlled surface morphology. The three main parts of electrospun are electrically conductive needle tip or spinneret, ground collector, and a power supply, responsible for generating a high voltage (5–50 kV). The process involves loading starch solution into electrically conductive needle tip and held by its surface tension at the end of the capillary tip. As the intensity of electrostatic force increases, the tube elongates to form a cone-shaped structure called as Taylor cone. Once the applied electric field reaches a critical value, the repulsive electrical forces exceed the surface tension forces. The charged jet of the polymer solution is ejected from the tip of the Taylor cone, which becomes very long and thin. During the same time, the solvent evaporates leaving behind a charged polymer fiber which accelerates toward the collector of opposite polarity (Tampau et al., 2017). It is important to note here that the absence of high temperatures during the process makes it very useful for encapsulation volatile or organic active agents that would otherwise lose their desirable properties (Wen et al., 2017; Ghorani & Tucker, 2015). The properties of electrospinning include no use of heat, ability to mask undesirable flavors and odors, ease of operation, cheaper, easy incorporation of bioactive compounds, and decreased size requirement for

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bioactive compounds, thus resulting in high load capacity and high encapsulation efficiency (Hu et al., 2014). The delivery of drugs is one of the most potential applications of electrospinning as it results in high encapsulation efficiency, simultaneous delivery of diverse therapies, ease to the operation, suitable porosity, and cost-effectiveness (Mendes et al., 2016). The electrospun was first used for the controlled release of tetracycline hydrochloride by poly(lactic acid) and poly(ethylene-co-vinyl acetate) (Kenawy et al., 2002) and then various drugs ranging from antibiotics (Lu et al., 2012; Xie, Tan, Wang et al., 2008) and anticancer agents (Gilchrist et al., 2013; Hong et al., 2008) to proteins (Chew et al., 2005; Li et al., 2010), aptamer, DNA (De Laporte & Shea, 2007; Luu et al., 2003), and RNA (Rujitanaroj et al., 2011) have been incorporated into electrospun fibers. Carvacrol was encapsulated in starch and poly-ε-caprolactone (PCL), matrices by electrospinning. The geometry of nanostructures obtained was nanofibrillar with some beads, whereas it is particles that are mainly deposited for the starch system. The encapsulation efficiency of carvacrol was better in PCL than starch, where greater variability was observed (Tampau et al., 2017). The electrospun web was prepared from starch in acetic anhydride in mini reactor followed by addition of aqueous sodium hydroxide solution followed by loading of drug in starch acetate with a degree of substitution of 1.1 and 2.3 and studied for drug release efficiency. The encapsulated drug showed slow release in starch acetate with a degree of substitution of 2.3 due to hydrophobicity and high affinity between drug and starch acetate fibers (Xu, Yang & Yang, 2009). As native starch lacks desired physical properties and is difficult to electrospin, hydroxypropyl starch was blended with polyethylene oxide (PEO) in different ratios by dissolving in boiling water. It was reported that hydroxypropyl starch/PEO nanofibers were non-cytotoxic and promoted cell growth and adhesion, and this porous architecture makes it suitable for tissue engineering applications (Hemamalini & Giri Dev, 2018). The blend of thermal modification between soluble starch (2.5%) and polyethylene-maleic anhydride (10%) was prepared in water and DMSO, respectively, and the blend was heated to prepare esterified starch, followed by electrospun. Due to thermally induced esterification, the resulting starch was highly porous and insoluble in water, and possessed high thermal stability than pure starch; hence,

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it has a wide range of applications ranging from tissue engineering to filtration applications (Hemamalini and Giri Dev, 2018). 3.5 Regulatory Status

Balancing the desired functionality of encapsulating ingredients in the final product with increased complexity of regulations, food laws, and consumer preference is among the main challenges food scientists are facing. As per regulatory standpoint, it is important to note that selection of an encapsulating ingredient solely on function may not be ideal and the major consideration should be given to the source of the ingredient as each source potentially creates repercussions in the labeling or safe use of an ingredient. Potentially, the largest responsibility of food scientists and the regulatory department is to ensure that the encapsulant selected for ingredient meets and complies with all food safety and standards. While encapsulating starch, some points should be taken into consideration which includes a source of the sample, allergens, types of modification done, natural claims, and nutritional content. 3.6 Outlook and Research Question

Nowadays, scientists are more focused on the behavior of dispersed systems within human digestive systems and this problem will necessarily have to involve collaboration with scientists from various other disciplines such as biochemistry, microbiology, and medicine. Over the last decade, some basic progress has already been made but is somehow incoherent and immature. In the near future, the food hydrocolloid researchers will mainly focus on emulsion stability under extreme conditions (pH, ionic strength, enzymes, etc.); breakdown of particles, aggregates, gels, etc., under different hydrodynamic conditions; structure of multicomponent layers at oil–water and air-water interfaces; and properties of colloidal systems composed of mixtures of biopolymers and nanoparticles (including protein aggregates). Although the era of starch nanoencapsulation is in embryonic stage, this is progressing fast and is suggested to be one of the fastest growing branches of modern science. These starch-based delivery systems are economically viable, and hence, the combination of hydrocolloids is suggested to become an important tool to overcome the existing

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challenges that are associated therewith. In the last decade, most of the researches in nanoencapsulation for targeted and controlled delivery mainly focused on physicochemical properties, drug loading ability, in vitro toxicity, and in the near future important issues such as specific integration of encapsulating agents with human organs, tissues, cells, or biomolecules. The effect on human metabolism by encapsulating agents will deeply be focused and studied. Multiple modifications to obtain tailored encapsulation agents with desired functional properties will be predicted in the near future.

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4 β - G lucan – B ased D eli v ery System A S I M A S H A H , F. A . M A S O O D I , A N D A DIL GA N I University of Kashmir

B I L A L A H M A D A S H WA R University of Kashmir

Contents

4.1 G  eneral Overview and Sources 129 4.2 Isolation and Purification of β-Glucan 131 4.3 Chemical Structure and Properties of β-Glucan 135 4.3.1 Hydration Properties of β-Glucan 137 4.3.2 Solution Properties of β-Glucan 138 4.3.3 Viscosity of β-Glucan 139 4.4 Modifications of β-Glucan 140 4.5 β-Glucan as a Delivery Vehicle in Micro- and Nanoencapsulation Technologies 142  egulatory Status 144 4.6 R References 144 4.1 General Overview and Sources

β-Glucan is a dietary fiber and a non-starch polysaccharide consisting of repeating β-d-glucopyranose units connected through glycosidic linkages. It is arranged in either linear chains or branched ­structures depending upon the source (Lam & Cheung, 2013). In cereals, ­glucopyranose units are linked through β-(1→4) and β-(1→3) glycosidic bonds, whereas in fungal, bacterial, and algal sources, they are linked through β-(1→3) and β-(1→6) glycosidic bonds (Maheshwari et  al., 2017). β-Glucan has drawn much attention over the years because of its physical and chemical properties. The physical and 12 9

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physiological properties of β-glucan are of commercial, nutritional, and nutraceutical importance. β-Glucan has various functional properties such as thickening, emulsification, stabilizing, and gelation. It is also used as a fat mimetic in the development of calorie-reduced foods (Biliaderis & Izydorczyk, 2007). It exhibits a wide spectrum of biological activities including anticancer, immune-enhancing, antiaging, and anti-inflammatory and antioxidant properties (Ahmad et al., 2012; Zhu et al., 2016). The synthesis of β-glucan molecules occurs through catalyzation reactions involving polymerization of α-laminaribiosyl fluoride via the formation of (1→4)-β-linkages to yield a new linear crystalline (1→3) (1→4)-β-d-glucan with a repeating 4 and 3 glucose unit. The enzyme involved in the synthesis of β-glucan molecules is endoglycosynthase (Magda et al., 2004). After synthesis, the length and molecular weight of β-glucan are controlled by endo-β-(1→3) (1→4)-glucanase, which is a thermostable enzyme developed during the germination of cereal crops (Hrmova et al., 1997). The mechanism of β-glucan synthesis varies from species to species. In microorganisms like Saccharomyces cerevisiae, two genes, KRE6 and SKN1, are found to be involved in (1→6)-β-glucan biosynthesis (Roemer & Bussey, 1991). β-Glucan is quite diversified and can be found in a variety of natural sources such as cereals, mushrooms, yeast, and some bacteria. Cereal β-glucan is present in the endosperm and subaleurone layer of the grain cell wall (Cui & Wang, 2009). Among cereals, oat and barley are considered to be the richest sources of β-glucan ranging from 4% to 7% (Lazaridou & Biliaderis, 2007; Bhatty, 1992). β-Glucans were extracted from rye (Tosh et al., 2004), rice (Inglett et al., 2004), wheat (Hollmann & Lindhauer, 2005), and corn and millets (Demirbas, 2005). The levels of β-glucans in wheat, rye, sorghum, and rice were found to be in the range of 0.4%–1.4%, 1.2%–2.9%, 0.1%–1.0%, and 0.04%, respectively (Biliaderis & Izydorczyk, 2007). In cereal grains, the β-glucan content is affected by both genotype and e­ nvironmental factors. MacGregor and Fincher (1993) reported that six-row barleys have slightly less β-glucan levels than two-row varieties, whereas Fastnaught et al. (1996) reported that there was no ­difference in β-glucan levels of two- and six-row barleys. In addition, mushrooms and yeasts are good sources of β-glucan. The different types of β-glucan includes pleuran obtained from Pleurotus ostreatus (Carbonero

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et al., 2006; Bergendiova et al., 2011; Synytsya et al., 2009), lentinan from Lentinula edodes (Ooi & Liu, 2000; Zhang et al., 2011), ­zymosan from S. cerevisiae (Di-Carlo & Fiore, 1958; Miura et al., 1999), grifolan from Grifola frondosa (Mao et al., 2007; Tada et al., 2009), and betafectin from S. cerevisiae (Kernodle et al., 1998). Some other commercially important sources are ­curdlan—an exopolysaccharide produced from Alcaligenes faecalis ­(a Gram-negative bacteria) (Zhao & Cheung, 2011; Zhan et al., 2012), laminarin from Laminaria ­species (a ­seaweed) (Kuda et al., 1992; Zhao & Cheung, 2011), and schizophyllan from Schizophyllum commune (a fungus) (Zhang et al., 2013). There are also various reports on the extraction of β-glucan from other sources such as paramylon and its amorphous isomer (Watanabe et al., 2013), Laminaria digitata (Vetvicka et al., 2007), corn pericarp (Yoshida et al., 2014), Makgeolli—an alcoholic beverage of Korea (Min et al.,  2012), and Japanese cedar bark (Adachi et al., 2013). Some sources of β-glucan from plants, fungi, bacteria, and algae are summarized in Table 4.1. 4.2 Isolation and Purification of β-Glucan

β-Glucan is found in the endosperm cell walls of cereal grains along with other starch and non-starch polysaccharides (Ahmad et al., 2012). Thus, its recovery is not easy and involves various steps. A typical extraction process involves three basic steps: (i) inactivation of endogenous enzymes, (ii) extraction of β-glucan with a suitable solvent, and (iii) β-glucan precipitation (Brennan & Cleary, 2005). The different extraction methods for isolation of β-glucan are hot water extraction, solvent extraction, alkali extraction, acidic extraction, and enzymatic extraction (Wei et al., 2006; Bhatty, 1993; Irakli et al., 2004; Ahmad et al., 2010). Lazaridou et al. (2004) reported refluxing (treatment with hot aqueous ethanol) as a first step to extract β-glucan from whole oat and barley flour. This step is carried out to deactivate the endogenous enzymes, particularly β-glucanases since they are responsible for β-glucan degradation. This is followed by ­aqueous extraction at low temperature, enzymatic digestion, and dialysis for removal of starch and protein contaminants and hydrolysates. After precipitation, the polysaccharide is dried by a solvent exchange method. Ahmad et al. (2012) reported the use of other several enzymes,

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Table 4.1  Some Sources of β-Glucan from Plants, Fungi, Bacteria, and Algae SOURCE Plants

Fungi

Bacteria

Algae

SPECIES Hordeum vulgare Avena sativa Secale cereale Triticum spp. Phoenix dactylifera Gossypium hirsutum Ganoderma lucidum Coriolus versicolor Lentinus edodes Schizophyllum commune Pleurotus ostreatus Agaricus bisporus Agaricus blazei Angelica sinensis Pleurotus florida Pleurotus eryngii Saccharomyces cerevisiae Cordyceps sinensis Astraeus hygrometricus Pleurotus ostreatoroseus Schizosaccharomyces pombe Amillariella mellea Alcaligenes faecalis Lactobacillus paracasei Agrobacterium sp. Aureobasidium pullulans Acetobacter xylinum Ulva lactuca Thuret Laminaria digitata

REFERENCES Shah et al. (2015a) Shah et al. (2015b) Wood (2010) Maheshwari et al. (2017) Ishurd et al. (2002) Maltby et al. (1979) Nie et al. (2013) Khan et al. (2017) Mizuno (1999) Khan et al. (2017) Karacsonyi and Kuniak (1994) Khan et al. (2015) Angeli et al. (2009) Cao et al. (2006) Rout et al. (2005) Carbonero et al. (2006) Khan et al. (2016) Yalin et al. (2005) Chakraborty et al. (2004) Elaine et al. (2006) Sugawara et al. (2004) Yan et al. (2018) Sasaki et al. (1978) Stack et al. (2010) Kalyanasundaram et al. (2012) Sato et al. (2012) Li et al. (2004) Lahaye et al. (1994) Kadam et al. (2015)

such as ­x yloacetylesterase, endo-xylanases, feruloyl esterase, and ­arabinofuranosidase, for extraction of β-glucan from various sources. Agbenorhevi et al. (2011) reported the use of hot water extraction in combination with termamyl (starch hydrolyzing enzyme) for extraction of β-glucan from oat flour. After centrifugation at 4,000 rpm for 15 min, the supernatant was dialyzed for 3 days followed by concentration, precipitation, and freeze drying of ­polysaccharide. Tosh et al. (2004) reported extraction of β-glucan from rye flour by refluxing in ethanol for 3 h. Starch was removed by use of thermostable α-amylase

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and β-glucan was obtained by centrifugation. Cold and hot aqueous extraction method was used for extraction of β-glucan from Agaricus bisporus and A. brasiliensis (Khan et al., 2015; Smiderle et al., 2013). Hot water extraction method has been reported for ­isolation of β-glucan polysaccharide from Ganoderma lucidum, G. resinaceum, and G. atrum (Ye et al., 2010; Liu et al., 2010; Amaral et al., 2008; Chen et al., 2008; Zhang et al., 2012). Nguyen et al. (1998) reported the treatment of yeast cells with 1 M potassium hydroxide for 20 h at 4°C under mild agitation. The supernatant obtained after centrifugation was treated with saturated ammonium sulfate and kept overnight. The precipitated β-glucan was recovered by centrifugation. Also, the extractability of β-glucan is found to be dependent on various physical parameters such as pH, t­ emperature, ionic strength of solvent, duration of extraction and presence of enzymes (endogenous or microbial), and method of milling (Wood, 1993). Temelli (1997) reported ­maximum β-glucan yield at pH 7.0 and temperature 55°C from whole condor barley flour. Burkus and Temelli (1998) reported highest β-glucan purity at pH 7 in condor barley and at pH 8 in waxy barley with a maximum yield of 81.3% and 79.3% in condor and waxy barley when treated with α-amylase, respectively. Other methods reported for extraction of polysaccharide from Ganoderma are ­microwave (Huang et al., 2007; Xu et al., 2007), ultrasonic (Zhao et al., 2010), DEAE-cellulose and gel-­filtration chromatography (Bao et al., 2002), and ultra-filtration (Ye et al., 2009). Pressurized water extraction (PWE) is an emerging technique in which the extraction solvent provides the medium for β-glucanase inactivation together with an efficient solvent extraction. In the PWE process, the high temperature of the fluid increases its solubility and diffusion rate, whereas the high pressure keeps the fluid below its boiling point (Villares et al., 2012). PHW is used in both batch and semi-­continuous modes to extract β-glucans from barley with extraction yields of 53.7% and 52.4% and molecular weights of 200 and 100–500 kDa, respectively (Benito-Román et al., 2013a, 2013b). Benito-Román et al. (2015) reported 51% β-glucan extraction yield with a molecular weight of 500–600 kDa using pressurized aqueous ethanol extraction (PHAE) at 135°C–175°C and extraction times up to 55 min. The optimal extraction condition reported for A. bisporus L., Lentinus edodes S., and P. ostreatus is 200°C, and 5 cycles of 5 min

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each at 10.3 MPa (Palanisamy et al., 2014). Lo et al. (2007) found the maximum recovery for extraction of α-(1,4)-glucans and β-(1,6)glucans at a pressure of 10.1 MPa for 70 min at 28°C. Another advanced technique that has been used for extraction of polysaccharides is ultrasound-assisted extraction (UAE). In the UAE technique, the raw material that is placed in the extraction solvent is subjected to ultrasound waves using a probe or a sonicator (Chemat et  al., 2011). At high intensities, the sound waves generated travel into the liquid creating alternating high–low pressure (compression–­ rarefaction) cycles. These continuous high–low pressure cycles create small bubbles in the liquid that collapse violently producing intense local heating. This phenomenon is called “cavitation.” Cavitation produces intense shear forces that permit the extracting solvent to penetrate deep into the solid, thereby increasing the diffusion rate of the desired molecule to the solvent (Wang et al., 2008). Chen et al. (2010a,b) reported that the optimum UAE conditions required for the polysaccharide extraction from G. lucidum (Fr.) Karst. are a ultrasonic frequency of 8 kHz, an extraction temperature of 95°C for 3 h, and a water-to-raw material ratio of 12:1. Sourki et al. (2017) reported that the best results for extraction of β-d-glucan from hull-less barley were obtained at the sonication time of 4.8 min, amplitude 50%, and pH 9. For maximum extraction of polysaccharide from A. bisporus, the optimum conditions required are an ultrasonic power of 230 W, an extraction temperature of 70°C for 62 min, and a water-to-material ratio of 30:1 (mL:g) (Tian et al., 2012). For large-scale production of β-glucan concentrates and isolates, two processing techniques that are most commonly employed are dry processing and wet processing. Dry processing involves the use of pin/ roller/ impact mills and air classification to obtain β-glucan-rich ­fractions. Dry milled β-glucan is produced from different ­starting materials such as dehulled oat, dehulled barley, wheat, and rye (Wood et al., 1989; Knuckles & Chiu, 1995; Dexter & Wood, 1996; Glitso & Bach Knudsen, 1999). Wet milling process involves extraction of dry milled fractions using aqueous, mild alkaline, or acidic conditions, followed by centrifugation/ultrafiltration/precipitation with ethanol for recovery of β-glucan. Wet milling process is used for extraction of β-glucan from oat flour (Knuckles et al., 1997), pearled barley (Morgan, 2002), wheat flour (Cui et al., 1999), and barley flour (Cavallero et al., 2002).

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For further purification of the polysaccharide ion-exchange chromatography through DEAE-cellulose columns, gel filtration and affinity chromatography are used (Wasser, 2002). Lazaridou et al. (2004) reported the use of β-d-xylanase enzyme from Trichoderma viride (EC 3.2.1.8) for removal of arabinoxylans. The derived oligosaccharides were further removed by dialysis followed by precipitation with ethanol. Polysaccharide with a wide polydispersity can be fractionated by preparative gel permeation chromatography (Zhang et al., 2007). The most common gels for the separation of polysaccharides on the basis of molecular weight are Sephadex, Sephacryl, and Sepherose. 4.3 Chemical Structure and Properties of β-Glucan

β-Glucans obtained from different sources vary in their molecular structure, chain conformation, solubility, and nature of linkage, and thus have different biological activities (Descroix et al., 2006). Generally, cereal β-glucans are linear polysaccharides consisting of (1→3) (1→4) glycosidic bonds in which (1→4)-β-linkages occur mostly in groups of two or three and are interrupted by a single (1→3)-linkage (Wood, 1993; Wood et al., 1994b). Therefore, the β-glucan structure constitutes predominantly β-(1→3)-linked cellotriosyl and cellotetraosyl units (~90%) and lesser amount of long cellulosic oligosaccharides (~5%–10), with a degree of polymerization (DP) between 5 and 20 (Ebringerova et al., 2005; Woodward et al., 1983). The β-(1→4)-linkage is capable of interchain aggregation ­giving close packing to crystalline structures, whereas the β-(1→3) linkages interrupt the β-(1→4) linkage sequence and gives rise to kinks in the chain, making it soluble (Liu et al., 2015; Woodward et al., 1983; Shah et al., 2017b). Aman and Graham (1987) reported 20% and 46% of β-glucan to be insoluble in oat and barley, respectively. For structural elucidation of β-glucan, its hydrolysis is carried by enzyme lichenase which specifically cleaves the (1→4)-linkage next to the (1→3)-linkage at its r­ educing end yielding oligosaccharides with different DPs (Lazaridou & Biliaderis, 2007). The main products of cereal β-glucan hydrolysis are DP3 (3-O-β-cellobiosyl-d-glucose) and DP4 (3-O-β-cellotriosyl-d-glucose) which constitutes about 90% of the total β-glucan content. Also, a small amount of cellodextrin-like oligosaccharides containing more than three consecutive (1→4)-linked glucose residues terminated by

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a (1→3)-linkage at the reducing end is released. These constitute only 5%–10% of the total β-glucan content with DPs in the range of 5–20, DP9 being the most abundant (Wood et al., 1994b; Izydorczyk et al., 1998; Wood et al., 1994a). The relative amount of DP3 in the β-glucan is found in the range of 67%–72% in wheat, 52%–69% in barley, and 53%–61% in oat, whereas DP4 is found in the range of 25%–33% in barley, 34%–41% in oat, and 21%–24% in wheat. An often used indicator of structural difference among β-glucans is the ratio of cellotriose to cellotetraose units, i.e., DP3:DP4 (Wood et al., 1991; Izydorczyk et al., 1998). DP3/DP4 is considered as a fingerprint of the structure of cereal β-glucans. Wood (2011) reported the values of DP3:DP4 ratio in the range of 2.1–2.4 for oat β-glucan, 3.0–3.8 for wheat β-glucan, and 2.8–3.4 for barley β-glucans. For rye β-glucan, the values of DP3:DP4 ratiohave been reported in the range of 2.31–1.94 (Roubroeks et al., 2000) and 3.0–3.2 (Wood et al., 1994b). The ratio of DP3 to DP4 also varies among the species of same genera which may be attributed to genotypic and environmental factors. Miller et al. (1993) reported that the DP3:DP4 ratio for β-glucans in domestic cultivars of Avena sativa varies in the range of 2.05–2.11, whereas in other cultivars of Avena, it varies from 1.81 to 2.33. Wood et al. (2003) reported that the DP3/ DP4 ratios for β-glucans from waxy and -nonwaxy cultivars were 3.0 and 2.7–2.8, respectively. β-Glucan in oat differs from other β-glucans due to its molecular-structural features which includes DP3:DP4 ratio, amount of cellulose oligomers, ratio of β-(1→3) or β-(1→6) linkages, and molecular mass (Cui et al., 2000). In yeast and mushroom, glucose monomers are joined by (1→3) (1→6) glycosidic linkages. Zhang et al. (2013) reported a triple helical structure in schizophyllan consisting of β-(1→3)-D-glucan with β-(1→6) branching at every third backbone residue. In pleuran, the backbone consists of β-(1→3)-linked d-glucopyranosyl units with every fourth unit being replaced with single d-glucopyranosyl groups (Carbonero et al., 2006; Bergendiova et al., 2011; Synytsya et al., 2009). In laminarin, the backbone consists of β-(1→3)-d-glucose units with β-(1→6) branching at the 3:1 ratio on approximately every tenth backbone residue (Kuda et al., 1992; Zhao & Cheung, 2011). Grifolan contains β-(1→3)-linkages and forms a triple helix structure (Mao et al., 2007; Tada et al., 2009), whereas curdlan is an unbranched β-(1→3)-d-glucan (Zhao & Cheung, 2011; Zhan et al., 2012).

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4.3.1 Hydration Properties of β-Glucan

The hydration properties of fiber are usually described by measuring the water binding and swelling capacity. Hydration properties of fiber depend on the chemical structure, hydrophobic/hydrophilic properties, surface area, and particle size (Thibault & Ralet, 2001). The water-binding capacity (WBC) measures the amount of water retained by the fiber when subjected to external stresses such as centrifugal force or compression forces or under gravity. Ahmad et al. (2008) reported WBC of β-glucan extracted from barley flour using four different types of extraction methods in the range of 2.91–3.79 g/g. Huang et al. (2011) reported WBCs of 5.88, 3.52, and 0.08 mL/g for wheat, oat, and inulin fiber, respectively. The WBC of okara—an insoluble fiber from soybean by-products—was reported as 8.87 g/g (Espinosa-Martos & Ruperez, 2009). Dreher (1987) reported the WBCs of sugar beet fiber, wheat bran, soybean bran, and corn bran as 4.56, 2.6, 2.4, and 2.5 g/g, respectively. Mora et al. (2013) reported water-holding capacity (g/g) of 5.2 for wheat bran, 2.05 for corn, 9.84 for green beans, 7.03 for green prickly pear husk, and 7.48 for red prickly pear husk. Drzikova et al. (2005) reported 4.6 g/g as the average water-holding capacity of oat meal extrudates. The water-holding capacities were reported in the range of 2.46–13.94 g/g for oat β-glucan samples (Liu et al., 2015) and 6.14–6.74 g/g for native barley β-glucan samples (Lee et al., 2016). Swelling power (SP) is defined as the volume occupied by a known weight of fiber when hydrated with water without any external stress except gravity. The SP was 3.45 (g/g) for β-glucan obtained from A. bisporus (Khan et al., 2015) and 14.05 (g/g) for native oat β-glucan (Moura et al., 2011). Dalgetty and Baik (2006) reported the swelling capacities of 3.61, 1.88, and 2.38 (g/g) for chickpea, pea, and lentil hulls, respectively. Mora et al. (2013) reported the swelling capacities of 2.92, 0.79, 8.09, 4.58, and 3.99 mL/g for wheat bran, corn, green beans, green prickly pear husk, and red prickly pear husk, respectively. Mei et al. (2010) reported the swelling capacity of dietary fiber extracted from ten varieties of sweet potato in the range of 8.11–12.56 g/g. Al-Sheraji et al. (2011) reported the SP of 16 g/g for dietary fiber from Mangifera pajang Kort. fruit pulp.

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4.3.2 Solution Properties of β-Glucan

In spite of the good water solubility of β-glucan, this polysaccharide under suboptimal solvent quality favors polymer–polymer rather than polymer–solvent interactions. β-Glucan contains celluloselike segments linked through (1→3) glycosidic bonds, which allows β-glucan to form a viscous solution upon solublization (Burkus & Temelli, 2005). The solution properties of β-glucan are influenced by the ratio of (1→4)/(1→3) linkages and the arrangement of the cellotriosyl and cellotetraosyl units in the polymer. The insolubility of glucan molecule is attributed to β-(1→4) linkages, while β-(1→3) linkages break the stiffness and linearity of the β-(1→4)-linked segments and impart solubility and flexibility to these polymers. Also, the presence of at least three consecutive cellotriosyl residues provides conformational regularity in the β-glucan chain, and hence more stability. Therefore, the higher the content of cellotriosyl units in the β-glucan chain, the lower is its solubility. Two possible mechanisms have been suggested for its aggregation. The first mechanism is that long ­segments of β-(1→4)-linked d-glucopyranosyl units behave like cellulose. Hydrogen bonds are formed between these cellulose-like regions on two or more polymer chains and form stable junction zones that lead to the formation of aggregates (Woodward et al., 1988; Varum & Smidsrod, 1988; Doublier & Wood, 1995). These bonds can be ­interrupted by increased temperature, high pH, or several solvents (Novak & Vetvicka, 2008). The second mechanism is that hydrogen bonds are formed between consecutive cellotriosyl units, which form stable junction zones (Tosh et al., 2004). Rheologically, cereal β-glucan solutions exhibit a viscoelastic behavior, typical of well-characterized disordered coil-type polysaccharides. At low shear rate and concentration below 0.3%, β-glucan solutions behave like Newtonian fluids, whereas above this concentration and at high shear rate, the solutions are non-Newtonian and show shearthinning behavior (Doublier & Wood, 1995). At lower frequencies, β-glucan solutions show liquid-like behavior (i.e., the loss modulus, G″, is greater than the storage modulus, G′, and both ­moduli increase with increasing frequency), whereas at higher frequencies, β-glucan solutions show solid-like behavior (i.e., G′ is greater than G″, and both moduli become largely independent of frequency). Tan (δ) is the ratio

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of the viscous modulus (G″) to the elastic modulus (G′) and is a useful parameter to determine the extent of elasticity in a fluid. The tan (δ) values of β-glucan samples isolated from oat (10%) and barley (8%) are reported in the range of 0.047–0.258 and 0.07–0.289, respectively (Lazaridou et al., 2003; Lazaridou et al., 2004; Vaikousi et al., 2004). Ryu et al. (2012) reported shear-­thinning behavior for 3% b ­ arley β-glucan gels with flow behavior index (n) and consistency index (K) (Pa s) in the range of 0.73–0.92 and 0.06–1.14 using a power-law model, respectively. Liu et al. (2015) reported that β-glucans extracted from untreated and ultrafine grinding-treated oat bran exhibited a Newtonian behavior at a concentration of 0.5%, whereas it exhibited pseusoplastic behavior at a concentration of 0.75%. The flow behavior index (n) of oat β-glucan samples was reported in the range of 0.99–1.02 (at 0.5%) and 0.92–0.97 (at 0.75%) and the consistency index (K) (Pa s) in the range of 0.03–0.07 (at 0.5%) and 0.07–0.18 (at 0.75%). Xu et al. (2013) reported shear-thinning behavior for C-trim samples having oat β-glucan in the range of 20%–95%. The flow behavior index of C-trim samples varied from 0.24 to 0.62, and the consistency index varied from 39.06 to 671.44 (Pa s). The linear dynamic rheological properties for C-trim dispersions indicated that the C-trim with higher β-glucan content exhibited stronger viscoelastic properties. It was reported that the phase shifts of C-trim samples with β-glucan contents of 20%, 30%, 50%, and 95% were 31.5°–61.0°, 24.3°–57.7°, 19.2°–23.9°, and 1.8°–7.0°, which were measured over the frequency range of 0.1–500 rad/s, respectively. Burkus and Temelli (2005) reported that the flow behavior index (n) of barley β-glucan gums extracted from laboratory and pilot plants was in the range of 0.689–0.965 and 0.986–0.997, and the consistency coefficient was in the range of 0.110–2.950 and 0.0039–0.043, respectively, over the temperature range of 0.1°C–75°C. 4.3.3 Viscosity of β-Glucan

Viscosity is one of the most important properties of β-glucan that has been studied to determine its application in food systems. β-Glucan has a capacity to form highly viscous solutions that are responsible for its physiological effects. It has been postulated that β-glucans decrease the absorption of cholesterol, reabsorption of bile acids, and delay

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gastric emptying by increasing the viscosity of the gastrointestinal tract contents, and hence decrease the postprandial serum glucose levels in humans and animals (Brennan & Cleary, 2005). High viscosity of β-glucan reflects its use as a thickening, stabilizing, and fat-­replacing agent in different food applications, e.g., ice creams, sauces, and salad dressings (Ahmad et al., 2012). Ahmad et al. (2010) reported that the viscosity of oat β-glucan obtained by different extraction ­procedures varied from 35.6 to 56.16 cP. Lee et al. (2015) reported that the viscosity of β-glucan obtained from raw waxy and nonwaxy barleys varied from 12.8 to 32.8 cP. The apparent and complex viscosity (Pas) of β-glucan obtained from oat products was reported to be 16.27 and 2.3 for extruded oat meal, 0.09 and 0.12 for autoclaved oat meal, and 41.08 and 4.8 for oat bran at a concentration of 2% (Dongowski et al., 2005). The intrinsic viscosity of oat β-glucan was reported to be in the range of 1.7–7.2 dL/g (Agbenorhevi et al., 2011), 4.9–6.4 dL/g (Skendi et al., 2003), and 0.67–3.83 dL/g (Lazaridou et al., 2003). Liu et al. (2016) reported that the intrinsic viscosities of β-D-glucan obtained from Ganoderma lucidum and scleroglucan were 1,248.05 and 1,210 mL/g (Moresi et al., 2001). Ahmad et al. (2009) reported that the viscosity of barley β-glucans obtained by different extraction procedures varied from 34.30 to 52.82 (cP). Ghotra et al. (2009) reported that the viscosities (mPa s) of barley β-glucan, sodium alginate, xanthan, and guar gum dispersions were in the range of 87–287, 16–78, 60–2,317, and 108–1,193, respectively, at a concentration of 0.5% and shear rates of 1.29–129 s−1. 4.4 Modifications of β-Glucan

β-Glucan is a type of dietary fiber with many food and non-food applications such as a thickener, emulsifier, an adhesive and binder, an encapsulating agent, a film former, a gelling agent, a water binder, and a fat-sparing agent (Ahmad et al., 2012). Also, β-glucan exhibits biological activities including immune-enhancing, antitumor, and antiaging and anti-inflammatory properties (Zhu et al., 2016). However, native β-glucan possesses certain limitations to be used as food or an ingredient in foods, due to high viscosity, less solubility, low paste clarity, less stability at low temperatures, and low p ­ ermeability into cell (Byun et al., 2008; Shah et al., 2015a,b; Moura et al., 2011).

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Therefore, in order to acquire the enhanced physiochemical and nutraceutical properties, various physical, chemical, and ­enzymatic methods have been used to modify glucan molecule. Physical modification of starch involves ultrasound treatment, ultrafine grinding, and irradiation. γ-Irradiation of β-glucan has been shown to decrease the SP and viscosity with an increase in solubility, foaming, and emulsifying properties in baker’s yeast (Saccharomyces cereviseae) (Khan et al., 2016), black yeast (Aureobasidium sp.) (Byun et al., 2008), and button mushroom (Agaricus bisporus) (Khan et al., 2015). Shah et al. (2015a,b) reported that the treatment of barley β-glucan at different irradiation doses of 2, 4, and 8 kGy resulted in decreased molecular weight with increased antioxidant and anticancer activities. In another study, germination and microwave processing of barley resulted in the degradation of β-glucan with enhanced antioxidant activity and lower viscosity (Ahmad et al., 2016). Shin and Lee (2003) reported the use of ultrasonication to improve the immuneenhancing property of β-glucan. Ultrafine grinding of oat bran at the revolution speed of 2,500–2,800 rpm for 6 h resulted in β-glucan extracted with lower molecular weight and increased solubility and water-holding capacity (Liu et al., 2015). Chemical modification is the most common type of modification, which includes oxidation, carboxymethylation, and sulfation. In the oxidative treatment, the formations of carbonyl and carboxyl groups are promoted which substitute for hydroxyl groups of the molecule. Moura et al. (2011) reported the use of hydrogen peroxide (H 2O2) at different concentration levels (0.3%, 0.6%, and 0.9%) and reaction times (30 and 60 min) for oxidation of β-glucan. The oxidized β-glucan gels showed decreased viscosity, hardness, adhesiveness, and gumminess. Oat β-glucans were treated with 2, 2, 6, 6-tetramethyl1-piperidine oxoammonium ion, in which C6 primary –OH groups were oxidized into carboxyl groups. The results showed that the oxidation increased water solubility of oat β-glucans with enhanced ­cholesterol-lowering potential (Park et al., 2009). Carboxymethylation of β-glucan is a two-step process-alkalization with aqueous alkaline hydroxide, mostly sodium hydroxide and etherification with monochloroacetic acid (Ding et al., 2013). Carboxymethylation ­modification results in water-soluble glucan due to the introduction of carboxymethyl substituents. In sulfation, the β-glucans are sulfated

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using a chlorosulfonic acid-pyridine method. Briefly, a chlorosulfonic acid-pyridine complex is prepared in an ice bath, and then polysaccharide is added with continuous stirring at a heating temperature to complete the phosphorylation modification reaction. After treating with NaOH solution, the sulfated polysaccharide is obtained by precipitation in ethanol. Furthermore, dialysis and lyophilization can also be used. In the sulfation modification, the C-6 position of the glucan is fully substituted, whereas the C-2, C-3, and C-4 positions are partially substituted. Sulfated mycelia of Grifola frondosa inhibited tumor growth and enhanced the peritoneal macrophage phagocytosis in sarcoma 180-bearing mice (Nie et al., 2006). Also, Shi et al. (2007) reported that sulfated β-glucan inhibited the growth of human gastric carcinoma SGC-7901 cells in a dose-dependent manner, and induced apoptosis of the cancer cell line. In another chemical modification, an aminated β-glucan was prepared, which showed improved wound healing in an animal model with diabetes mellitus (Berdal et al., 2007). The enzymatic modification is done by exposing the β-glucan to enzymes particularly hydrolyzing enzymes that tend to break the molecule into low molecular weight functional derivatives. The most commonly used enzymes to break the linkages are cellulase and lichenase (Tosh et al., 2004). 4.5  β-Glucan as a Delivery Vehicle in Micro- and Nanoencapsulation Technologies

Encapsulation is a process of enclosing a core material inside a matrix for the purpose of protection, immobilization, and controlled or targeted release of the core material. The encapsulating material must be biodegradable, food grade, and stable in food systems during processing, storage, and consumption. The most suitable and commonly used carrier materials for food applications are carbohydrate, protein, and lipid-based. Among different types of wall materials, β-glucan is one such unique polysaccharide that could be efficiently used as a wall material. The uniqueness of β-glucan is because of its honeycomb structure that can accommodate bioactive ingredient easily. Honey comb structure confers its ability to withstand mechanical strength and protect the incorporated ingredient against harsh environment

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conditions, i.e., pH, light, and oxidation. It acts as a thermoprotectant and disintegrates at the postal region of the colon, and when administrated orally, its bioavailability is low (Shah et al., 2016; Gani et al., 2018). In addition, it has a prebiotic quality promoting the growth of beneficial microflora in the intestines, in particular lactobacilli and bifidobacteria (Ohimain & Ruth, 2012). β-Glucan gels have been widely studied for encapsulating various molecules such as anthocyanin (Xiong et al., 2006), protein (Lazaridou et al., 2015), and fish oil (Kurek et al., 2018). Ahmad et al. (2018) reported the use of barley β-glucan to encapsulate saffron bioactives in order to improve its stability during their passage through the GI tract using the spray drying technique. β-Glucans from S. cerevisiae are porous and hollow (2–4 μm), and therefore provide an efficient system for targeted delivery of various molecules such as DNA, siRNA, and proteins using either a polyplex or a layer-by-layer (LbL) synthesis method (Soto & Ostroff, 2012). A biopolymer consisting of chitosan and sulfated oat β-glucan has been used as a material to create a prebiotic coating for targeted delivery of probiotics to the gastrointestinal system, using the LbL technology (Yucel et al., 2017). Barley and yeast β-glucan aerogels were used for acetylsalicylic acid impregnation by supercritical CO2. Polysaccharide aerogels have resulted in high-loading capacity of the active compounds in matrices (Salgado et al., 2017). However, the limiting property of β-glucan is its size which allows the slow release of the material encapsulated in its matrix. It has been reported that larger particles release encapsulated compounds more slowly and takes longer time, whereas by reducing the particle size the adhesive force increases, leading to a higher bioavailability of the encapsulated compound (Chen et al., 2006). The particle size of the wall material directly affects the bioavailability of the bioactive compound at various sites within the body. Therefore, by decreasing the matrix size from micrometers to nanometers, highly controllable delivery system can be obtained which also allows their incorporation into food products without affecting sensory qualities (Lopez-Rubio & Lagaron, 2012). Nanoparticles have been referred to as sphere-like substrates with dimensions ranging from 1 to 100 nm (Fathia et al., 2014). Nanomaterials hold great promise regarding their application in nutrition due to their size-dependent qualities, high surface/volume ratio, unique optical properties, easy absorption, and high retention

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time in the blood for enhanced activity (Rangan et al., 2016). Also the role of nanoparticles have been extended for the development of nanodelivery systems for many bioactive compounds such as antioxidants, bioactive peptides, and essential fatty acids, which can ­protect and have sustainable release of the encapsulated compounds (He & Hwang, 2016). Many biopolymer-based nanoparticle delivery systems such as whey protein, casein protein, starch, prolamins, gelatin, and chitosan, in combination or alone, have been developed extensively for the biomedical and functional food sectors. Nasrollahi et al. (2015) prepared β-1,3-glucan nanoparticles as a carrier for doxorubicin and trastuzumab for their controlled release against HER2+ breast cancer. The nanoparticles consisted of ­doxorubicin – [glucan– doxorubicin–] with succinic anhydride as linker and had spherical morphology with positive zeta potential. β-Glucan nanoparticles were also prepared by breaking the chain into low molecular weight using various concentrations of trifluoroacetic acid, which showed a minimum size of 250 nm. Such nanoparticles were later used as a carrier for single-stranded DNA (Hwang et al., 2018). Using supercritical fluid CO2 extraction techniques followed by ultrasonication, β-glucan from oyster mushroom (P. autrateus) can be e­ fficiently extracted in nanosize and further used for targeted delivery of bioactive food component (Mahmoud et al., 2015). 4.6 Regulatory Status

As recommended by Food and Drug Administration (FDA), β-glucans extracted from barley and oat at a 3 g/day dosage would reduce cardiovascular disease risk including reduction in blood glucose and has satiety effect as well.

References

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Ahmad, A., Anjum F. M., Zahoor, T., & Nawaz, H. (2008). Effect of barley ß-glucan on sensory characteristics of bread. Pakistan Journal of Agricultural Sciences, 45, 88–94. Ahmad, A., Anjum, F. M., Zahoor, T., Nawaz, H., & Ahmed, Z. (2010). Extraction and characterization of β-d-glucan from oat for industrial utilization. International Journal of Biological Macromolecules, 46, 304–309. Ahmad, A., Anjum, F. M., Zahoor, T., Nawaz, H., & Din, A. (2009). Physicochemical and functional properties of barley β-glucan as affected by different extraction procedures. International Journal of Food Science and Technology, 44, 181–187. Ahmad, A., Muhammad, F., Zahoor, A. T., Nawaz, H., & Dilshad, S. M. R. (2012). Beta glucan: A valuable functional ingredient in foods. Critical Reviews in Food Science and Nutrition, 52, 201–212. Ahmad, M., Ashrafa, B., Gani, A., Gani, A. (2018). Microencapsulation of saffron anthocyanins using glucan and cyclodextrin: Microcapsule characterization, release behaviour & antioxidant potential during invitro digestion. International Journal of Biological Macromolecules, 109, 435–442. Ahmad, M., Gani, A., Shah, A., Gani, A., & Masoodi, F. A. (2016). Germination and microwave processing of barley (Hordeum vulgare L) changes the structural and physicochemical properties of β-d-glucan & enhances its antioxidant potential. Carbohydrate Polymers, 153, 696–702. Al-Sheraji, S. H., Ismail, A., Manap, M. Y., Mustafa, S., Yusof, R. M., & Hassan, F. A. (2011) Functional properties and characterization of dietary fiber from Mangifera pajang Kort. fruit pulp. Journal of Agricultural Food Chemistry, 59, 3980–3985. Aman, P., & Graham, H. (1987). Analysis of total and insoluble mixed-linked (1→3), (1→4)-β-D-glucans in barley and oats. Journal of Agricultural and Food Chemistry, 35, 704–709. Amaral, A. E., Carbonero, E. R., Simao, C. G., Kadowaki, M. K., Sassaki, G. L. Osaku, C. A., Gorina, A. J. P., & Iacomini, M. (2008). An unusual water-soluble β-glucan from the basidiocarp of the fungus Ganoderma resinaceum. CarbohydratePolymers, 72, 473–478. Angeli, J. P. F., Ribeiro, L. R., Bellini, M. F., & Mantovani, M. S. (2009). β-Glucan extracted from the medicinal mushroom Agaricus blazei prevents the genotoxic effects of benzo [a] pyrene in the human hepatoma cell line HepG2. Archives of Toxicology, 83, 81–86. Bao, X. F., Wang, X. S., Dong, Q., Fang, J. N., & Li, X. Y. (2002). Structural features of immunologically active polysaccharides from Ganoderma lucidum. Phytochemistry, 59, 175–181. Benito-Román, O., Alonso, E., & Cocero, M. J. (2013a). Pressurized hotwater extraction of β-glucan from waxy barley. Journal of Supercritical Fluids, 73, 120–125. Benito-Román, O., Alonso, E., Gairola, K., & Cocero, M. J. (2013b). Fixed bed extraction of β-glucan from cereals by means of pressurized hot water. Journal of Supercritical Fluids, 82, 122–128.

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5 P rotein -B ased D eli v ery Systems S A J A D A . R AT H E R , F.   A .   M A S O O D I , J A H A N G I R A . R AT H E R , R EH A NA AK HTER, A ND TA R I Q A H M A D G A N A I E University of Kashmir

Contents

5.1 Introduction 159 5.1.1 Plant-Based Proteins as Encapsulating Agents 162 5.1.1.1 Vegetable Proteins 162 5.1.1.2 Cereal Proteins 167 5.1.2 Animal-Based Proteins as Encapsulating Agents 169 5.1.2.1 Casein 169 5.1.2.2 Whey Proteins 173 5.1.2.3 Gelatin 174 5.1.3 Conclusion and Future Prospects 175 References 176 5.1 Introduction

A multitude of materials are used to entrap, coat, or encapsulate active compounds of different types, origins, and properties. However, a limited number of materials thereof have been certified for food and pharmaceutical applications as “generally recognized as safe” (GRAS). Encapsulation has been widely used by the food and pharmaceutical industry for decades for coating several ingredients such as flavors, antioxidants, colors, acidulants, probiotics, polyunsaturated fatty acids (PUFAs), enzymes, vitamins, and drugs (Can Karaca et al., 2015; Pegg & Shahidi, 2007). It is defined as a mechanical, chemical, or physicochemical process that isolates and protects the active ingredients potentially sensitive core material to environmental factors such as temperature, oxygen, light, moisture, pH, and other characteristics 15 9

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that affect the activity of the compound (Quintero et al., 2018). The material that is encapsulated can be a liquid, a solid, or a gas and is called a core material, active agent, internal phase, or payload phase. The substance or material that is encapsulating the core is called a wall material, coating material, membrane, shell, carrier material, external phase, or matrix (Jeyakumari et al., 2016; Jain et al., 2015). In the encapsulation process, unlike the immobilization process, the coating material covers completely the active ingredient, whereas in the immobilization process, some degree of exposure to the environment might occur (Kent & Doherty, 2014). The application of an encapsulating agent (e.g., proteins) allows for protection of a sensitive core material from harsh environmental conditions, controlled release of the ingredient under specific conditions, masking unpleasant odors and tastes, dilution and uniform dispersion of the active ingredient, and easier handling (Can Karaca et al., 2015; Desai & Park, 2005; Lia et al., 2015; Zhang et al., 2015). Microcapsules can be classified into different groups according to their size (>100 nm to several microns) and morphologies (Augustin & Hemar, 2009; Kailasapathy, 2009). Microcapsules tend to be either mono- or multinuclear in nature depending on the preparation method/conditions and the wall materials involved (Figure 5.1). In mononuclear microcapsules, the core ingredient is concentrated at the center and surrounded by the wall material(s), whereas

Figure 5.1  Morphology of microcapsules.

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in multinuclear microcapsules, the core material is dispersed as small droplets throughout the wall material resembling that of an aggregated cluster of mononuclear microcapsules (Dong et al., 2007; Gouin, 2004). Mono-and multinuclear microcapsules tend to display rapid burst or prolonged release of their core ingredient, respectively (Dong et al., 2007; Gouin, 2004). Coatings can also be added for improved protection, more tailor release profiles or release of multiple core materials; however, payloads tend to be lowered than uncoated microcapsules (Gouin, 2004). An ideal microcapsule wall should be entirely food grade, be able to emulsify the active core ingredient to form a stable oil-in-water emulsion, provide protection against oxidation and mechanical stress, have characteristic of controllable release of core material, and possess a high load capacity and low surface oil content (Desai & Park, 2005; McClements et al., 2007; Pegg & Shahidi, 2007). Microcapsules should be miscible in the food product, be able to withstand processing, have controlled release profiles, and retain the bioavailability of its core ingredient (Desai & Park, 2005; McClements et al., 2007; Pegg & Shahidi, 2007). Microcapsules are prepared by physical and chemical methods. Physical methods include spray drying, spray chilling, rotary disk atomization, fluid bed coating, coextrusion, and pan coating. Chemical methods include simple and complex coacervation, interfacial polymerization, and phase separation (Zuidam & Heinrich, 2010; Gibbs et al., 1999). During the recent past, researchers have turned their attention towards polymers of natural origin. Thus, polysaccharides, such as starch, maltodextrin (Semyonov et al., 2010), gums (Gharsallaoui et al., 2012), pectin (Gharsallaoui et al., 2010), and chitosan (Gharsallaoui et al., 2012), among others (Avramenko et al., 2016), have been used as encapsulation agents. Regardless of the source (e.g., plant or animal), proteins are versatile macromolecules due to their ability to self-associate, their dynamic structure, biocompatibility, amphiphilic properties, and biodegradability, awarding it technical-functional properties such as emulsifying, foaming, and gelling agents (Li & Tang, 2013; Zhang et al., 2014; Wan et al., 2015; Avramenko et al., 2016; Chang et al., 2016). The chemical, functional, and structural versatility of proteins makes them suitable candidates for the encapsulation of bioactive ingredients (Wan et al., 2015). The aim of this

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chapter is to present and update the existing knowledge about proteins either already in use or of potential use in the microencapsulation of various ingredients or additives used by the food industry. 5.1.1 Plant-Based Proteins as Encapsulating Agents

Proteins obtained from plant sources are macromolecules of industrial interest due to its high availability, biodegradability, renewable character, and functional properties. Proteins obtained from soy, pulses (e.g., pea, chickpea, and lentil), and cereals (e.g., wheat, barley, and zein), etc. (Table 5.1) as encapsulating agents have increased in recent years due to their amphiphilic nature, ability to stabilize oil-in-water emulsions and film-forming abilities, and excellent physicochemical properties, and are considered as biodegradable, renewable, highly available, and good coating materials. Their production entails less consumption of natural resources, and they are considered as “environmentally economic” (Li & Tang, 2013; Quintero et al., 2018). Proteins obtained from soy, beans, peas, chickpeas, oats, corn, rice, and sunflower seeds are included among the most studied proteins obtained from plant sources as encapsulating agents (Pierucci et al., 2006; Li & Tang, 2013; Liu et al., 2014; O’Neill et al., 2015; Wan et al., 2015; Piornos et al., 2017). In this scenario, these macromolecules have a potential use as a wall-forming material for the encapsulation processes of active ingredients. 5.1.1.1 Vegetable Proteins  Vegetable proteins, which are relatively

cheap, biocompatible, and biodegradable biopolymers, are actually becoming a realistic alternative to synthetic polymers for some specific applications ­(Chel-Guerrero et al., 2002; Mateos-Aparicio et al., 2008; Vliet et al., 2002). Their use as wall material for active components microencapsulation reflects this actual tendency, particularly in food, pharmaceutical, and cosmetic fields (Gharsallaoui et al., 2010; Nori et al., 2010; Patel et al., 2012; Rascón et al., 2011; Wang et al., 2011a). Their properties such as water solubility and amphiphilic properties, the ability to self-associate and interact with a variety of substances, high molecular weight, and molecular chain flexibility give them excellent surfactant properties for emulsification.  These  proteins are thus very suitable for microencapsulation

VEGETABLE PROTEINS Soy protein isolate Soy glycinin Soy glycinin/sodium dodecylsulfate Mixture of proteins and polysaccharides SPI/glucose syrup SPI/maltodextrin Soy protein isolate Soy protein isolate Soy protein isolate/gelatin Soy protein isolate Soy protein isolate Soy protein isolate/gum arabic Soy protein isolate/pectin Soy protein isolate Soy protein isolate Soy protein isolate/lactose Soy protein isolate/lactose blends Soy protein isolate Soy protein isolate/sunflower protein Soy protein Soy lecithin and lentil protein isolate

WALL MATERIAL

Orange oil Hexadecane Hexadecane Fish oil Stearin, palme oil Phospholipide Fish oil Casein hydrolysate Casein hydrolysate Paprika oleoresin Pepperoni oleoresin Orange oil Propolis α-Tocopherol Orange oil Orange oil and flavors Fish oil Ascorbic acid/α-tocopherol/vitamins α-Tocopherol Linseed oil Canola oil

CORE MATERIAL

Table 5.1  Examples of Plant Proteins as a Wall Material for Microencapsulation

Spray drying Simple coacervation Complex coacervation Spray drying Spray drying Spray drying Simple coacervation Spray drying Spray drying Spray drying Spray drying Complex coacervation Complex coacervation Spray drying Spray drying Spray drying Gelation Spray drying Spray drying Spraydrying/freezedrying Spray drying

ENCAPSULATION TECHNIQUE

Kim et al. (1996) Lazko et al. (2004a) Lazko et al. (2004b) Augustin et al. (2006) Rusli et al. (2006) Yu et al. (2007) Gan et al. (2008) Molina Ortiz et al. (2009) Favaro et al. (2010) Rascón et al. (2011) Rascón et al. (2011) Jun-xia et al. (2011) Nori et al. (2011) Nesterenko et al. (2012) Tang and Li (2013a) Tang and Li (2013b) Li and Tang (2013) Nesterenko et al. (2014) Nesterenko et al. (2014) González et al. (2016) Chang et al. (2016) (Continued)

REFERENCE

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Complex coacervation Spray drying Spray drying Spray drying Spray drying Spray drying Spray drying Spray drying Freeze drying Freeze drying Spray drying Spray drying Simple coacervation Simple coacervation Complex coacervation Solvent evaporation Solvent evaporation Phase separation Supercritical anti-solvent process Homogenization at 2,500 rpm followed by spray drying Anti-solvent precipitation method

Ascorbic acid a- Tocopherol Ascorbic acid Triglyceride Iron Linoleic acid Linseed oil Flaxseed oil Flaxseed oil

Linoleic acid Fish oil Pyrrolnitrin Hexadecane Vaselin oil Retinoic acid Diltiazemhydrochloride Essential oils Lysozyme Flaxseed oil

Quercetin

Corn zein

ENCAPSULATION TECHNIQUE

Triglyceride

CORE MATERIAL

Pea globulins and gum arabic carboxymethylcellulose Pea proteins and maltodextrin Pea proteins and maltodextrin Pea proteins and maltodextrin Pea proteins and pectin Pea protein Pea protein Proteins isolated from lentils and chickpeas Chickpea protein isolate/maltodextrin Lentil protein isolate/maltodextrin CEREAL PROTEINS Wheat gliadin, corn zeine Barley protein Gluten/casein Gliadin α-Gliadin/gum arabic Gliadin Gluten/poly(ethylene oxide) Corn zein Corn zein Zein

WALL MATERIAL

Table 5.1 (Continued )  Examples of Plant Proteins as a Wall Material for Microencapsulation

Patel et al. (2012)

Iwami et al. (1987) Wang et al. (2011b,c) Yu & Lee (1997) Mauguet et al. (2002) Ducel et al. (2004,2005) Ezpeleta et al., 1996 Andreani et al. (2009) Parris et al. (2005) Zhong et al. (2009) Quispe-Condori et al. (2011)

Pierucci et al. (2006) Pierucci et al. (2007) Pereira et al. (2009) Gharsallaoui et al. (2010) de Azevedo et al. (2013) Costa et al. (2015) Can Karaca et al. (2013a) Can Karaca et al. (2013b) Can Karaca et al. (2013b)

Ducel et al. (2004)

REFERENCE

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techniques requiring preliminary emulsions such as spraydrying, coacervation, and solvent evaporation. Finally, due to their facility for adhesion and good film formation, their resistance toward oils or organic solvents, and gas barrier properties (De Graaf et al., 2001), proteins are really good wall forming product. The use of soy proteins obtained from plant sources as an encapsulating material is most prevalent, in part due to their widespread use as an ingredient. The major fractions of soy proteins are known as 2S, 7S, 11S, and 15S (Klupšaitė & Juodeikienė, 2015; Berk, 1992). Among the total soy protein fractions, about 70% are 11S and 7S, and the 11S/7S ratio is a varietal characteristic. The 2S fraction consists of ­low-molecular-weight polypeptides (in the range of 8–20 kDa) and comprises the soy trypsin inhibitors. The 7S fraction is highly heterogeneous and its principal component is β-conglycinin, which is a sugar-containing globulin with a molecular weight on the order of 70 kDa. The fraction also comprises enzymes (β-amylase and lipoxygenase) and hemagglutinins. The 11S globulin fraction consists of glycinin, which is the principal protein of soybeans. Glycinin has a molecular weight of 350 kDa and is composed of 12 subunits that are associated through hydrogen bonding and disulfide bonds. The ability of soy proteins to undergo association–dissociation reactions under known conditions is related to their functional properties. The 15S protein fraction is a dimer of glycinin. Conglycinin and glycinin are storage proteins. They are found in the protein bodies within the cells of the cotyledons. Soy protein has been used alone or in combination with anionic polysaccharides depending on the application. However, allergen concerns are causing industry to consider alternative materials. Rascón et al. (2011) investigated the performance of soy protein isolate (SPI) on the microencapsulation. The isolated and purified soy proteins show interesting physicochemical and functional attributes, in particular gel-forming, emulsifying, and surfactant properties (Gu et al., 2009). These protein characteristics and their solubility are strongly dependent on pH, heat treatment, and the presence and concentration of salts or other ingredients (oil, carbohydrate, and surfactant). The use of SPI as an encapsulating material has been studied by various researchers. SPI is used as an individual coating material, or it can also be mixed with polysaccharides (Augustin et al., 2006;

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Rusli et al., 2006; Yu et al., 2007). The combination of proteins with polysaccharides as a wall material favors better protection, oxidative stability, and drying properties (Augustin et al., 2006). Due to SPI hydrosolubility, microparticles are mainly produced using the spraydrying technique (Augustin et al., 2006; Charve & Reineccius, 2009; Favaro-Trindade et al., 2010; Kim et al., 1996; Ortiz et al., 2009; Rascón et al., 2010; Rusli et al., 2006; Yu et al., 2007). Coacervation and gelation have also been investigated (Chen and Subirade, 2009; Gan et al., 2008; Lazko et al., 2004a; Lazko et al., 2004b; Mendanha et al., 2009; Nori et al., 2010). Can Karaca et al. (2015) investigated the use of chickpea and lentil proteins plus maltodextrin for the entrapment of flaxseed oil by spray drying (Can Karaca et al., 2013a) and freeze drying (Can Karaca et al., 2013b). Lentil protein- and chickpea protein-based maltodextrin capsules produced by spray drying resulted in high entrapment efficiencies of 88% and 86%, respectively, and released 37% of the entrapped flaxseed oil after 2 h under simulated gastric fluid conditions, followed by an additional 47% after 3 h under simulated intestinal fluid (SIF) conditions. The same authors (Can Karaca et al., 2013a) using freeze drying investigated similar materials, at different oil concentrations (5.3%–21.0%), with different maltodextrin types (dextrose equivalents of 9 and 18) and concentrations (25%–41%) on capsule properties using surface response methodologies. An optimal wall formulation of 35.5% maltodextrin-DE 9 and 10.5% oil resulted in the best entrapment efficiency (83%), lowest surface oil (3%), and acceptable mean droplet diameter (3 mm). The authors also found that as the emulsion oil content increased, the oil droplet diameter and surface oil content decreased, and observed a decrease in entrapment efficiency. Pulse proteins represent an attractive alternative to soy due to their non-genetically modified status and low risk for allergen (Can Karaca et al., 2015). Pea proteins are extracted from pea seeds where they represent a 20%–30% fraction including mainly globulins (65%–80%) and two minority fractions, albumins, and glutelins. Globulins comprise three different proteins: legumin, vicilin, and convicilin (Koyoro & Powers, 1987). Pea legumin represents the 11S globulin fraction with a molar mass between 350 and 400 kDa, while vicilin and convicilin represent the 7S globulin fraction with a molar mass of about 150 kDa. Pea proteins extracted

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from grains possess interesting gel-forming (Akintayo et al., 1999) and emulsifying (Raymundo et al., 2005) properties. However, in the literature for microencapsulation uses, these proteins are generally associated with polysaccharides (Gharsallaoui et al., 2010; Pereira et al., 2009; Pierucci et al., 2007). Indeed, polysaccharide/ protein interactions give new functions to pea proteins without chemical or enzymatic modification, particularly solubility, foaming, and surfactant properties (Liu et al., 2010). These interactions can also create stable ­emulsions and thus give better particle size distribution and improve the efficiency of the microencapsulation process. Ducel et al. (2004) studied the potential of pea globulin as wall materials in the microencapsulation of a model oil (Miglyol 812 N) using a complex coacervation process involving a range of anionic polysaccharides (gum arabic, sodium alginate, and carboxymethylcellulose). The authors observed that mixtures of pea globulin and gum arabic (protein: polysaccharide mixing ratio of 50:50; pH 3.00) were best suited for encapsulation. Gharsallaoui et al. (2010) also developed pea protein microcapsules containing Miglyol 812 N as a model oil. Oil-in-water emulsions containing 5% Miglyol 812 N, 0.25% pea protein, and 11% maltodextrin (pH 2.4) were subjected to spray drying and reconstitution at pH 2.4. It was reported that employment of an additional pectin coating improved the stability to droplet aggregation after drying. The stabilizing effect of pectin was attributed to increased steric repulsion between the oil droplets. 5.1.1.2 Cereal Proteins  Cereal proteins have limited their use as

encapsulating agents, unless modified in some capacity to improve their performance. Among cereal proteins, wheat gluten is the most studied in the microencapsulation field (Ducel et al., 2005; Ducel et  al., 2004; Ezpeleta et al., 1996; Iwami et al., 1987; Mauguet et al., 2002; Yu & Lee, 1997). Gluten is composed of gliadins with molar masses in the range of 3 × 104 –8 × 104 g/mol (MacRitchie et  al., 1990) and glutenins with molar masses in the range of 8  × 104 g/mol to several million (Kasarda, 1989). Gliadins and glutenins comprise about 80% of the wheat proteins and have unusually high levels of proline and glutamine amino acids thus designated as “prolamins” (Shewry et al., 1986). Gliadins represent a mixture of three

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S A JA D A . R AT HER E T A L .

monomeric gluten proteins α-, γ-, and ω-types (Shewry et al., 1986). The α- and γ-types are classified as sulfur-rich prolamins, whereas the ω-type gliandins are classified as sulfur-poor prolamins. Glutenin is a mixture of disulfide-stabilized polymers of high-molar-mass glutenin subunits (HMM-GS) and low-molar-mass glutenin subunits (LMM-GS) (Veraverbeke & Delcour, 2002). The low water solubility and viscoelasticity provide gluten proteins with various interesting physicochemical characteristics, such as gel- and film-forming properties (Sun et al., 2009). Glutens proteins alone or in combination with polysaccharides are good for encapsulating active core materials using various techniques. Some studies have also been made with other cereal proteins as a wall material: barley protein or corn zein (Parris et al., 2005; Wang et al., 2011b; Wang et al., 2011c; Zhong et al., 2009; Patel et al., 2012). Barley proteins, studied by Wang et al. (2011c), are composed of two protein fractions: glutelin and hordein. Both these fractions show excellent film-forming and emulsifying properties (Wang et al., 2011b). Corn-extracted prolamin zein is a protein fraction soluble in hydro-alcoholic solutions and is well known for its good film-forming properties (Beck, 1996). Zein is the most important protein in corn. It is a prolamin protein and therefore dissolves in 70%–80% ethanol (Dickey & Parris, 2001, 2002). It is hydrophobic and thermoplastic material. Hydrophobic nature is related to its high content of nonpolar amino acids (Shukla & Cheryan, 2001). Zein has excellent film-forming properties and can be used for fabrication of biodegradable films. Its films are formed through the development of hydrophobic, hydrogen, and limited disulfide bonds between zein chains. Zein films are relatively good water vapor barriers compared to other edible films (Guilbert, 1986). Water vapor barrier properties can be improved by adding fatty acids or by using a cross-linking reagent. Zein coating has shown to reduce moisture, oxygen, and carbon dioxide transmission loss in fresh tomatoes (Park et al., 1994). Xue et al. (2013) used zein protein extracted from a corn gluten meal using an ultrasonic treatment to encapsulate tomato oleoresin by spray drying. The authors observed an increase in entrapment efficiencies 74% to 89% as the zein concentration increased from 1% to 10% (w/v), with no further increases in efficiencies as zein levels were raised further to 14%.

P r o t ein - Ba sed D eli v ery Sys t em s

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5.1.2 Animal-Based Proteins as Encapsulating Agents

Animal proteins tend to be advantages as wall materials, in part since they are much easier to work with. Animal proteins are more soluble than plant-derived proteins over a wider pH range. They tend to be smaller nature (e.g., soy glycinin has a molecular mass ~350 kDa, whereas casein proteins have a molecular mass of ~20 kDa) and more flexible, thus allowing them to diffuse more rapidly to the interface to stabilize the oil droplets within a coarse emulsion (Can Karaca et al., 2015). Among animal-based proteins, casein, whey protein, and gelatin are the most commonly used wall materials for microencapsulation (Table 5.2). 5.1.2.1 Casein  Casein is the collective name for a family of milk

proteins. In contrast to the whey proteins (second milk protein fraction), caseins are insoluble and account for 80% of total bovine milk proteins, which are translated to 2.75% of total milk components (Pereira, 2014). In bovine milk, casein comprises four peptides: αS1, αS2, β, and ƙ, differing in their amino acid, phosphorus, and carbohydrate content but similar in their amphiphilic character. Hydrophilic and hydrophobic regions of casein show block distribution in the protein chain. Casein peptides carry a negative charge on their surface as a result of phosphorylation and tend to bind nanoclusters of amorphous calcium phosphate. Due to these properties, in suitable conditions, casein molecules agglomerate into spherical micelles (Glab & Boratynski, 2017). Caseins are extremely heat-stable proteins and do not coagulate by heat. Caseins are insoluble at their isoelectric point (~pH 4.6). However, the solubility behavior varies for casein fractions isolated from milk. Solutions of 10–15 wt% having high viscosity can be prepared at pH 6–7. Caseins are also soluble at pH