Pro-drugs as Novel Drug Delivery Systems 9780841202917, 9780841202061, 0-8412-0291-5

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Pro-drugs as Novel Drug Delivery Systems

In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

Pro-drugs as Novel Drug Delivery Systems T . Higuchi and V . Stella, Editors

A symposiu the Division of Medicinal Chemistry at the 168th Meeting of the American Chemical Society, Atlantic City, N . J . , September 10, 1974.

ACS S Y M P O S I U M SERIES

AMERICAN CHEMICAL SOCIETY 1975 WASHINGTON, D. C.

In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

14

Library of Congress

Data

Pro-drugs as novel drug delivery systems. (ACS symposium series; 14) Includes bibliographies and index. 1. Chemistry, Medical and pharmaceutical—Congresses. 2. Drug metabolism—Congresses. I. Higuchi, Takeru, 1918-

II. Stella, V . , 1946-

III. American Chemical Society. Division of Medicinal Chemistry.

IV. American Chemical Society.

V . Title.

VI. Series: American Chemical Society. ACS symposium series; 14. RS421.S92 1974

615'.7

ISBN 0-8412-0291-5

75-11721 ACSMC8 14 1-245

Copyright © 1975 American Chemical Society All Rights Reserved PRINTED I N T H E U N I T E D STATES O F AMERICA

In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

ACS Symposium Series Robert F. Gould, Series Editor

In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

FOREWORD The ACS SYMPOSIU

a medium for publishing symposia quickly in book form. The format of the SERIES parallels that of its predecessor, ADVANCES IN CHEMISTRY SERIES, except that in order to save time the papers are not typeset but are reproduced as they are submitted by the authors in camera-ready form. As a further means of saving time, the papers are not edited or reviewed except by the symposium chairman, who becomes editor of the book. Papers published in the ACS SYMPOSIUM SERIES are original contributions not published elsewhere in whole or major part and include reports of research as well as reviews since symposia may embrace both types of presentation.

In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

PREFACE 'his volume contains the papers presented during the Symposium on Pro-drugs held at Atlantic City, September 10,1974 under the sponsorship of the Division of Medicinal Chemistry. No serious effort was made in organizing the program to provide a comprehensive treatment of the subject matter. Rather it was hoped that the material presented would stimulate greater interest in this chemical approach to the problem of drug delivery. A short review of the subject sets forth some of the basic underlying concepts and approaches array of antibiotics are then discussed. The remainder of the volume details chemical and biological studies on pro-drug candidates developed in our own laboratories. We apologize for the limited coverage of the subject matter contained in this book. This was caused more by necessity than by choice. At the time the program was formulated we were forced to depend largely on projects completed or being carried out in our several facilities or in those of our collaborators. This was in large part due to the sensitive nature of pro-drug research programs in established drug houses and their reluctance to publicize their early efforts in the field. In any case, the examples have been selected to illustrate the real utility of this approach. I would like to take this opportunity to thank all those who took part in the program and Naida Jimenez and her able secretarial assistants for their help in preparing the manuscript. A

University of Kansas

TAKERU HIGUCHI

Lawrence, Kans. March 11, 1975

ix

In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

1 Pro-drugs: An Overview and Definition V. STELLA University of Kansas, Department of Pharmaceutical Chemistry, Lawrence, Kans. 66044

Historically the term pro-drug was first introduced by Albert (1,2) "pro-agent" to describ biotransformation prior to exhibiting their pharmacological effects. Albert suggested that this concept could be used for many different purposes. For example, in his book "Selective Toxicity" (2) he mentions that "as a means of introducing selectivity into toxicity, the principle of latent activity has endless possibilities." Albert himself points out that the pro-drug approach is not new. Methenamine (I) and aspirin (II), both synthesized in the late nineteenth century, are examples of bioreversible derivatives of

(I)

(II) formaldehyde and salicylic acid respectively. Use of salicylic acid as an analgesic and anti-inflammatory agent was somewhat limited by its corrosiveness which was in part overcome with the use of II. Formaldehyde, although a useful topical antiseptic, could not be used orally as a urinary tract antiseptic until i t was converted to I and formulated in an enteric coated tablet. The chemical modification of drugs to overcome pharmaceutical problems has also been termed "drug 1 In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

2

PRO-DRUGS

l a t e n t i a t i o n . " The term was f i r s t used by Harper (3.3!) f o l l o w i n g the suggestion of Dr. L. Golberg. Harper defined drug l a t e n t i a t i o n "as the chemical m o d i f i c a t i o n of a b i o l o g i c a l l y a c t i v e compound to form a new compound which upon i n v i v o enzymatic attack w i l l l i b e r a t e the parent compound. The chemical a l t e r a t i o n s of the parent compound are such that the change i n physicochemical p r o p e r t i e s w i l l a f f e c t the absorption, d i s t r i b u t i o n and enzymatic metabolism." Kupchan et a l . ( 5 . ) , i n attempting to u t i l i z e the prodrug or drug l a t e n t i a t i o n approach f o r s o l v i n g v a r i o u s problems, extended the d e f i n i t i o n of drug l a t e n t i a t i o n to include nonenzymatic r e g e n e r a t i o n of the parent compound. Regeneration takes place as a consequence of h y d r o l y t i c , d i s s o c i a t i v n e c e s s a r i l y enzyme The te^ms pro-drugs, l a t e n t i a t e d drugs and b i o r e v e r s i b l e d e r i v a t i v e s have been used interchangeably. S i n k u l a and Yalkowsky i n t h e i r review (6) s t a t e , "by i n f e r e n c e , l a t e n t i a t i o n i m p l i e s a time l a g element or time component involved i n regenerating the b i o a c t i v e parent molecule i n v i v o . . . . the term pro-drug i s general i n that i t includes l a t e n t i a t e d drug d e r i v a t i v e s as w e l l as those substances which are converted a f t e r a d m i n i s t r a t i o n to the a c t u a l substance which combines with receptors." The term pro-drug i s a catchy, generic term f o r agents which undergo biotransformation p r i o r to exh i b i t i n g t h e i r pharmacological actions and w i l l be used i n t h i s manuscript to describe both s p e c i f i c a l l y designed b i o r e v e r s i b l e d e r i v a t i v e s of a troublesome compound as w e l l as "accidents" or r e t r o s p e c t i v e prodrugs. As A l b e r t (2) s t a t e s , many pro-drugs are the r e s u l t of "accidents" rather than f o r e s i g h t e d attempts to overcome some p h y s i o l o g i c a l , p h y s i c a l or psychol o g i c a l b a r r i e r . For example, anthracene glycosides e x h i b i t t h e i r l a x a t i v e a c t i o n through t h e i r aglycone while codeine may exert i t s a c t i o n due to the format i o n of morphine (2). The u t i l i z a t i o n of the pro-drug approach has been growing since s c i e n t i s t s began to r e a l i z e that problems such as l a c k of s o l u b i l i t y , poor b i o a v a i l a b i l i t y due to p o l a r i t y or " f i r s t pass" e f f e c t , or lack of chemical s t a b i l i t y could be overcome by preparing chemically a l t e r e d temporary transport forms of the drug (see I I I ) . Once the b a r r i e r to the use of the parent compound has been overcome, these temporary transport forms can be converted to the parent compound. This releases the transport moiety "C," which

In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

1.

STELLA

Overview and Definition

DRUG A

3

TEMPORARY TRANSPORT MOIETY C

LINKAGE Β CHI)

obviously has to be n o n t o x i c , so that the parent drug i s f r e e to exert i t s pharmacological a c t i v i t y . Is a s a l t or a complex of a drug a pro-drug? The question of d e f i n i n g drug d e r i v a t i v e s as pro-drugs can be quite c o n t r o v e r s i a l Linkage B i s normally thought of as a covalen a phosphate ester l i n k a g e such products as benzathine p e n i c i l l i n have been viewed as pro-drugs or as examples of drug l a t e n t i a ­ t i o n ( 3 . , 4 . ) , yet the linkage "B between the parent compound, p e n i c i l l i n , and the transport moiety, ben­ z a t h i n e , i s e l e c t r o s t a t i c . The regeneration of p e n i ­ c i l l i n from benzathine p e n i c i l l i n i s simply d i s s o c i a ­ t i o n of t h i s poorly water s o l u b l e s a l t . A complex or a s a l t i s a chemically defined new substance, i . e . , a new thermodynamic e n t i t y , j u s t as a m o d i f i c a t i o n i n ­ v o l v i n g covalent bonding r e s u l t s i n a new chemical substance. I f the p h y s i c a l and chemical p r o p e r t i e s of t h i s new substance give i t unique q u a l i t i e s capable of overcoming some undesirable b a r r i e r to the use of the parent compound and t h i s new substance r e v e r t s to the parent compound a f t e r overcoming t h i s b a r r i e r , then i t i s the b e l i e f of t h i s author that no matter how t r i v ­ i a l the chemical m o d i f i c a t i o n may be, the new sub­ stance i s a pro-drug of the parent compound. A num­ ber of semantic arguments f o r and against t h i s d e f i n i ­ t i o n can be made and r e s e r v a t i o n s about c a l l i n g the s a l t of a compound a pro-drug would be r e a d i l y ad­ m i t t e d . However, procaine and benzathine p e n i c i l l i n (7-11), and mafenide acetate ( s a l t not amide) f o r t o p i c a l a p p l i c a t i o n (12-14) are examples of s p e c i f i c s a l t forms of a parenF~compound which impart unique and important q u a l i t i e s to the s t a b l e , prolonged, and e f f i c i e n t r e l e a s e c h a r a c t e r i s t i c s of the parent com­ pound. S i m i l a r l y , the d i s c u s s i o n l a t e r by Dr. Repta of the water soluble gentisate complex of hexamethylmelamine w i l l demonstrate the uniqueness of t h i s com­ b i n a t i o n over the parent compound, thus q u a l i f y i n g the complex as a pro-drug of hexamethylmelamine. !!

ff

!!

In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

4

PRO-DRUGS

Reviews and overviews of the pro-drug concept are numerous. Apart from the c l a s s i c reviews of Harper (3,1) and A l b e r t (1,2), the reviews of Ariens ( 1 5 - 1 8 ) , Bundgaard ( 1 9 ) , S i n k u l a et a l . ( 6 , 2 0 ) , and S t e l l a Γ21) should be mentioned. Each review o f f e r s a d i f f e r e n t approach to the pro-drug concept, even though obvious overlap does e x i s t . N o t a r i (22) > i n h i s recent t h e s i s on pharmacokinetics and molecular m o d i f i c a t i o n , touches l i g h t l y on the pharmacokinetic i m p l i c a t i o n s of the pro-drug approach, an area of study which de­ serves much more a t t e n t i o n . Rationale f o r the Use of Pro-Drugs The awareness s i r e d pharmacologica a c t i o n has r e c e n t l y been reemphasized by the r e s u r ­ gence and growth of pharmacokinetics which i s the study of the time course of a b s o r p t i o n , d i s t r i b u t i o n , metabolism and e x c r e t i o n of drugs. The c o n c e n t r a t i o n versus time p r o f i l e of a drug, i t s metabolite i n var­ ious t i s s u e s and organs, and the time p r o f i l e of the corresponding pharmacological response has been a par­ t i c u l a r l y e x c i t i n g and f r u i t f u l area i n current phar­ macokinetic research ( 2 3 - 2 5 ) . The awareness that the onset, i n t e n s i t y and d u r a t i o n of drug a c t i o n are g r e a t l y a f f e c t e d by the p h y s i c a l and chemical proper­ t i e s of the drug has promoted the emergence of various t h e o r e t i c a l a'nd p r e d i c t i v e models f o r drug design and evaluation ( 2 6 - 2 8 ) . Ariens et a l . (29) point out that drug a c t i o n i n ­ volves three major phases: the pharmaceutical phase, the pharmacokinetic phase, and the pharmacodynamic phase. The pharmacodynamic phase represents the drugreceptor i n t e r a c t i o n or b i o l o g i c a l a v a i l a b i l i t y of the drug. Scheme I shows a s i m p l i f i e d pharmacokinetic model f o r a t y p i c a l drug e n t i t y and demonstrates that before a drug-receptor i n t e r a c t i o n can occur the drug must reach the t a r g e t organ i n which the drug receptor i s l o c a t e d . A number of b a r r i e r s may l i m i t a drug s a b i l i t y to reach a d e s i r e d t a r g e t organ and the sub­ sequent receptor s i t e and these b a r r i e r s can be of pharmacokinetic o r i g i n . To reach an e f f e c t i v e and de­ s i r e d concentration of drug at the t a r g e t organ r e ­ quires not only the drug to be e f f i c i e n t l y absorbed ( f ^ 1 and.k]_ e i t h e r l a r g e r e l a t i v e to other r a t e con­ stants or c o n t r o l l e d ) but i t a l s o i d e a l l y r e q u i r e s that the amount of drug i n the r e s t of the body be minimized to prevent t o x i c i t y . The pathway shown by the broken l i n e and r a t e constants k i and k 2 would 1

f

T

In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

DRUG

1

DOSAGE FORM

L

41

Scheme I

TISSUE COMPARTMENT

21 w

13

"31

FAT DEPOT OR "DEEP" COMPARTMENT

CENTRAL COMPARTMENT

l4

kV

ELIMINATION PRODUCT

K

+

+

k

2 - ^ e x c r e t i o n ^metabolism other f = f r a c t i o n of dose absorbed

where k. = r a t e constants d e f i n i n g the transport of a drug between various components

k

e

TARGET ORGAN

«a.

g Ο

Ο

3

Ο

6

PRO-DRUGS

be i d e a l . For a comprehensive d i s c u s s i o n of how the p h y s i c a l chemical p r o p e r t i e s of drug molecules a f f e c t various pharmacokinetic parameters, the paper by N o t a r i (22) should be consulted. A p r i o r i , any change i n p h y s i c a l chemical p r o p e r t i e s of a drug molecule due to i t s conversion t o a pro-drug could obviously a f f e c t the time p r o f i l e of the parent drug i n various compartments. For example, on the p o s i t i v e s i d e , a prodrug may be converted t o the parent compound by a spec i f i c enzyme found only i n the target organ. I f the parent compound passes from the target organ i n t o the c e n t r a l compartment and i s immediately e l i m i n a t e d , then the pro-drug w i l l have conferred t o the drug a degree of s p e c i f i c i t y f o r the target organ On the other hand, i f i n attemptin aqueous s o l u b i l i t y g (poo y f i n e d as the primary source of the b i o a v a i l a b i l i t y problem) a w e l l absorbed, water soluble pro-drug der i v a t i v e i s s y n t h e s i z e d , care must be taken to ensure that the pro-drug r e v e r t s t o the parent compound (Scheme I I ) . The r a t e of conversion must insure a buildup i n concentration of the parent drug t o a l e v e l above i t s minimum e f f e c t i v e l e v e l at i t s s i t e of a c t i o n , i . e . , ki| >> (k3 + k2) , the point being that once the p a r t i c u l a r undesirable b a r r i e r has been overcome, r a p i d r e v e r s i o n t o the parent compound i s des i r a b l e t o minimize other complications such as the pro-drug being metabolized t o an i n a c t i v e metabolite or being excreted unchanged from the body. On t h i s

PARENT DRUG

PRO-DRUG

PRO-DRUG METABOLITE (Inactive)

DRUG METABOLITE (Inactive)

Scheme I I

In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

1.

STELLA

Overview and Definition

7

p o i n t , A l b e r t (2) commented that "although a d e t a i l e d knowledge of p e r m e a b i l i t y and enzymes can a s s i s t a s k i l l f u l designer i n f i n d i n g u s e f u l pro-agents, he w i l l have i n mind an organism's normal r e a c t i o n of a f o r e i g n substance i s to burn i t up f o r food." B a r r i e r s of nonpharmacokinetic and nonpharmacodynamic o r i g i n may also play a major r o l e i n preventing a drug from reaching a d e s i r e d target organ. R e f e r r i n g to Scheme I , i t i s obvious that there are other b a r r i e r s (represented by the rate constant k) i n h i b i t i n g the drug's a b i l i t y to reach the dosage form stage. The r e j e c t i o n of a product can be due to pat h o l o g i c a l l i m i t a t i o n s such as t o x i c i t y and high i n cidences of side e f f e c t s t e r a t o g e n i c i t y e t c Phar maceutical l i m i t a t i o n chemical i n s t a b i l i t y of the compound or formulation difficulties. Common p s y c h o l o g i c a l l i m i t a t i o n s can be traced to the unpleasant t a s t e of a drug, pain at an i n j e c t i o n s i t e , or cosmetic damage to the p a t i e n t . Economic b a r r i e r s which are also important are o f t e n overlooked. In the economic s t r u c t u r e of our s o c i e t y , a drug must have the p o t e n t i a l to make economic gains f o r i t s promotor or i t w i l l not reach the market place. Just as pro-drugs can be used to overcome pharmacokinetic b a r r i e r s , pro-drugs have been used to overcome nonpharmacokinetic b a r r i e r s . An unpatented, pharmacologically a c t i v e drug with some physico-chemi c a l p r o p e r t i e s l i m i t i n g i t s usefulness may not be of i n t e r e s t to a large company. I f , however, the b a r r i e r to the drug s use i s s u c c e s s f u l l y removed by b i o r e v e r s i b l e chemical m o d i f i c a t i o n and the m o d i f i c a t i o n i s patentable, the product may then have economic potential. The design of e f f i c i e n t , s t a b l e , s a f e , p a t i e n t acceptable and e s t h e t i c a l l y p l e a s i n g way to d e l i v e r a drug to i t s s i t e of a c t i o n while overcoming v a r i o u s p h y s i c a l , chemical and s o c i a l b a r r i e r s i s c e r t a i n l y an area where the u t i l i z a t i o n of the pro-drug approach holds great p o t e n t i a l . Figure 1 shows the types of b a r r i e r s that have l i m i t e d the s u c c e s s f u l screening and/or f u l l development of suspected pharmacologically a c t i v e agents and f o r which the pro-drug approach has proven to be s u c c e s s f u l i n overcoming. 1

A p p l i c a t i o n s of the Pro-drug Approach I t i s not the o b j e c t i v e of t h i s overview to d i s cuss every p o s s i b l e example where the pro-drug concept was used to overcome a problem. That would be an a r duous task. What w i l l be presented w i l l be a b r i e f

In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

8

PRO-DRUGS

LACK OP SITE SPECIFICITY

TOXICITY IF ABSORBED AS SUCH

UNSTABLE AS " A "

POOR DOCTOR AND NURSE ACCEPTANCE DUE TO PRAGMATIC PROBLEMS POOR PATIENT ACCEPTANCE-TASTE ODOR, PAIN AT INJECTION SITE

NOT ABSORBED FROM GI TRACT BECAUSE OF POLARITY - OR NOT ABSORBED THROUGH BLOOD BRAIN BARRIER OR SKIN

FORMULATION PROBLEMS, E.G., LIQUID-TABLET FORMULATION DESIRED

METABOLIZED AT ABSORPTION SITE

WATER INSOLUBLE NOT ABSORBED NOT CAPABLE OF DIRECT IV INJECTION

ABSORBED TOO QUICKLY SUSTAINED RELEASE DESIRED

Figure 1

l i s t i n g and d i s c u s s i o n of some of the more c l a s s i c examples as w e l l as some recent developments. Hopef u l l y , t h i s approach w i l l encourage a p p l i c a t i o n of the pro-drug concept t o current research and problem s o l v ing by others. The pro-drug approach has apparently l e d t o a great deal of success i n overcoming s p e c i f i c problems associated with c e r t a i n drug molecules. Many of the examples that w i l l be given i n t h i s review are what may be c a l l e d f o r e s i g h t e d pro-drugs, i . e . , cases where the s c i e n t i s t has, through the use of the knowledge of f a c t o r s a f f e c t i n g drug absorption, d i s t r i b u t i o n , metabolism and e x c r e t i o n , designed and synthesized prodrugs with the s p e c i f i c view t o overcome some problem associated w i t h the parent compound. At the same time, there are many examples of " a c c i d e n t a l " prodrugs which, i n r e t r o s p e c t , have been found t o be very u s e f u l and s i g n i f i c a n t l y superior t o the parent com-

In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

1.

STELLA

Overview and Definition

9

pound. When the r a t i o n a l e f o r the design or use of a p a r t i c u l a r pro-drug i s d i s c u s s e d , i t should be stated that the current a p p l i c a t i o n of the pro-drug may not have been the reason f o r s y n t h e s i z i n g the pro-drug i n the f i r s t p l a c e . Use of Pro-Drugs i n Overcoming Absorption Problems To s t a t e that the pro-drug approach has been used to overcome absorption problems i s r a t h e r meaningless unless the p a r t i c u l a r absorption b a r r i e r i s d e f i n e d . For example, a drug may be poorly absorbed from the g a s t r o i n t e s t i n a l (GI) t r a c t , i n t o the c e n t r a l nervous system (CNS), i n t o th through th s k i n e t c . because the drug i compounds and other h i g h l y p o l a r chemicals are not w e l l absorbed through these b a r r i e r s because the barr i e r s are l i p o i d a l i n nature. The q u a l i f y i n g s t a t e ment should be made that some h i g h l y p o l a r molecules such as v i t a m i n s , amino acids and carbohydrates are absorbed through these b a r r i e r s but are absorbed by a c t i v e t r a n s p o r t . A drug may be poorly absorbed from the GI t r a c t because of the very water i n s o l u b l e chara c t e r i s t i c s of the drug. The r a t e determining step to absorption may become the d i s s o l u t i o n r a t e of the drug. A l s o , a drug may apparently be poorly absorbed i n t o general c i r c u l a t i o n as a r e s u l t of the s o - c a l l e d " f i r s t pass" e f f e c t (30-31). The " f i r s t pass" e f f e c t r e s u l t s from the l o s s of the drug due to metabolism of the drug i n the GI mucosa or l i v e r i n i t s i n i t i a l passage through these organs. Understanding the problem drugs would be an easy task i f they could be p a r t i t i o n e d i n t o neat categor i e s . I n v a r i a b l y , poor absorption of a drug cannot be a t t r i b u t e d to any s i n g l e f a c t o r . To F a c i l i t a t e Passage Through L i p i d Membranes of Drugs w i t h Poor L i p i d S o l u b i l i t y . Catecholamines. Chemical m o d i f i c a t i o n to i n crease l i p i d s o l u b i l i t y and to f a c i l i t a t e the absorpt i o n of pharmacologically a c t i v e catecholamines from the GI t r a c t and through the blood b r a i n b a r r i e r (BBB) has l e d to a great deal of study. Moderate success has been achieved to date. D e f i c i e n c i e s of b r a i n dopamine (IV) r e s u l t i n g from degeneration of the s u b s t a n t i a n i g r a seem to be associated w i t h a number of symptoms of Parkinson's disease (35-40). Therefore, attempts have been made to r a i s e the b r a i n l e v e l s of dopamine i n p a t i e n t s

In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

10

PRO-DRUGS

HO (IV) s u f f e r i n g from Parkinson's disease. I t has been stated that dopamine i t s e l f cannot be used because i t i s incapable of bein absorbed th BBB fact primarily attribute h i g h l y i o n i z e d s t a t e at p h y s i o l o g i c a l pH. A precursor or a pro-drug of dopamine, L-Dopa (V) or L-3,4-dihydroxyphenylalanine, has repeatedly been found to be e f f e c t i v e i n the treatment of Parkinson's disease (41-50). L-Dopa i s absorbed from the GI t r a c t and

l

DOPA DECARBOXYLASE

DOPAMINE i n t o the CNS through the a c t i v e transport mechanism f o r amino acids (51-52). I n the CNS, Dopa decarboxylase can convert L-Dopa to the d e s i r e d dopamine. I t has been assumed that the poor absorption of dopamine i s due t o i t s p o l a r i t y and h i g h l y i o n i z e d s t a t e . However, r a p i d enzymatic metabolism of c a t e c h o l molecules v i a conjugation mechanisms such as s u l f a t i o n , g l u c u r o n i d a t i o n and O-methylation c o n t r i b u t e h e a v i l y t o the r a p i d l o s s of dopamine i f dopamine i s administered o r a l l y , i . e . , dopamine given o r a l l y probably never reaches the BBB. Even w i t h L-Dopa, approximately only 20% of an o r a l l y administered dose reaches general c i r c u l a t i o n as L-Dopa since i t can be r a p i d l y conjugated, decarboxylated, O-methylated and o x i d i z e d i n the GI t r a c t and mucosa (53-60). The degree of t h i s so c a l l e d " f i r s t pass" e f f e c t i n any given i n d i v i d u a l

In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

1.

STELLA

Overview and Definition

11

p a t i e n t i s a f u n c t i o n of the age, genetic s t r u c t u r e , d i e t , e t c , of the i n d i v i d u a l . I t has been suggested that part of t h i s " f i r s t pass" e f f e c t might be circumvented by the use of L-Dopa esters (VI) which can be transformed to the

(VI):

R = a l k y l substituent

a c t i v e drug, L-Dopa, f o l l o w i n g absorptio (§1) . t i a l l y t h i s may seem incongruous because i t appears that the e s t e r should have the same absorption prob­ lems as dopamine i t s e l f , i . e . , VI i s a primary amine and the catechol groups have not been protected from metabolism. The i o n i z a t i o n of phenolic amines i n ­ c l u d i n g L-Dopa has r e c e n t l y been discussed by M a r t i n (62) and others (63-66). The i o n i z a t i o n c h a r a c t e r i s ­ t i c s of molecules s i m i l a r to dopamine can be depicted schematically by Schemes I I I and IV. In these schemes K]_ and K2 represent the normal macroscopic or observed i o n i z a t i o n constants and k^, k 2 , 12> 21 ~ croscopic i o n i z a t i o n constants. I f i t i s assumed that only N~—OH or (00) i s absorbed through l i p o i d a l memk

e

a n d

k

a r e

e

ΗΝ——0

(00) Scheme I I I

In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

m i

12

PRO-DRUGS

Θ Φ

ΗΝ ψ^^^ΟΕ

Κ

1

*

θ Κ

+

2

θ

* Ν ******* ο

^| *mmimmmfi\ OH

Scheme IV branes, then the percentage of t o t a l drug present at p h y s i o l o g i c a l pH of 7 Λ (00) w i l l b functio f the various microscopi cussion of the i n t e r r e l a t i o n s h i p s of the microscopic and macroscopic constants see references 6 2 - 6 6 ) . The f o l l o w i n g drugs were subjected to a n a l y s i s of 35(00.) present at p h y s i o l o g i c a l pH; tyramine ( V I I ) , t y r o s i n e e t h y l e s t e r ( V I I I ) , epinephrine ( I X ) , dopamine ( I V ) , and morphine ( X ) . An estimate of ρΚχ, pK2, pk]_, and pk2 f o r a t y p i c a l L-Dopa e s t e r (VI) was made and ap­ proximate $(00) c a l c u l a t e d at p h y s i o l o g i c a l pH. Table I gives the pK]_, pK2, pk]_, pk2, R(where R i s the r a ­ t i o (+-)/(00) and equals k]_/k2) and $(00) at physio­ l o g i c a l pH f o r these compounds. As i s r e a d i l y appar­ ent from t h i s t a b l e l i t t l e passive absorption from the

(VII)

(VIII)

(X)

In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

1.

STELLA

Overview and Definition

13

Table I Compound

pK

PK

1

8.87

IV

2

10.63

*

pk

1

8.90

pk

10.06

7.21

9.44

VII

9.61

10.65

VIII

7.33

9.80

9.42

7.33

IX

8.66

X

8.31

9.51

8.87

8.45

8.76* 9.70

7.22 10.32

0.21

15

*

*

VI

$(00)

R

2

0.03

* 60.2

4.2 0.008

0.12 53.1

0.38

7.98

Roughly estimated from the data of M a r t i n ( 6 2 ) based on the e f f e c t on p K i , pK2, p k i , pk2 of est e r i f i c a t i o n of the carboxyl group of t y r o s i n e to give t y r o s i n e e t h y l e s t e r . GI t r a c t or through the BBB would be expected f o r IV, V I I or IX unless some compensation f o r the small f r a c t i o n of ( 0 0 ) present i s made i n terms of increased l i p o p h i l i c i t y and/or reduced " f i r s t pass" metabolism. The r a t h e r high f r a c t i o n of ( 0 0 ) present at physiol o g i c a l pH f o r V I , V I I I and X suggests that these compounds should have l i t t l e problem penetrating l i p o i d a l membranes, assuming they possess s u f f i c i e n t l i p o p h i l i c i t y . Any reduced b i o a v a i l a b i l i t y of these compounds can probably be a t t r i b u t e d to a " f i r s t pass" e f f e c t . L a i et a l . (6l) have synthesized esters of L-Dopa i n an attempt to overcome the " f i r s t pass" metabolism of L-Dopa while Anden et^ a l . (67.) have prepared the methyl e s t e r of t y r o s i n e to help absorption and prevent decarboxylation. Pinder suggested 0 , 0 - d i a c e t y l - ( X I ) , 0 , 0 - d i ( t r i methylsilyl)dopamine (XII) as u s e f u l pro-drugs of dopamine capable of penetrating the BBB (68). If i t i s assumed that pk2> the microscopic i o n i z a t i o n constant f o r the amino group of dopamine, i s unaffected by a c y l a t i o n or s i l y a t i o n of the hydroxy groups, $ ( 0 0 ) i s c a l c u l a t e d to be 0 . 2 2 , i . e . , a c y l a t i o n of the hydroxy groups does l i t t l e to improve the f r a c t i o n of n e u t r a l species present at p h y s i o l o g i c a l pH. What a c y l a t i o n may do i s protect the hydroxy groups from being conjugated and increase the l i p o p h i l i c i t y of the molecule. Pinder based h i s suggestions on the r e s u l t s

In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

14

PRO-DRUGS

CH C0 o

(XIII) of C r e v e l i n g et a l . ( £ 9 , 7 0 ) who had shown that 3 , 4 , β-triacetyl (XIIÏT, and 3 , 4 , 3 - t r i ( t r i m e t h y l s i l y l ) (XIV) d e r i v a t i v e s of norepinephrine caused prolonged release of the parent catecholamine i n mice b r a i n s . However, as pointed out by C r e v e l i n g et_ a l . ( 6 9 , 7 0 ) even though both X I I I and XIV r e a d i l y entered the CNS, the d e r i v a t i v e s survived as noncatechol e n t i t i e s f o r long periods i n the b r a i n . For example, when H 3 tagged X I I I was given I.V. to mice approximately 20$ of t o t a l b r a i n r a d i o a c t i v i t y could be a t t r i b u t e d to catechol species while the remaining 80$ was noncatechol s p e c i e s . In the hearts of the same animals the reverse was the case, i . e . , the d e r i v a t i v e appeared to be q u i c k l y converted to c a t e c h o l species. This tends to suggest that enzymatic regeneration of the n o r e p i nephrine from X I I I may not be f a c i l e i n the CNS. Borgman et a l . (Jl) have r e c e n t l y synthesized a s e r i e s of 0 , 0 - d i a c e t y l d e r i v a t i v e s of v a r i o u s dopaminergic catecholamines i n c l u d i n g dopamine. The i n a b i l i t y of XI to antagonize oxotremorine-induced tremor i n mice ( 7 1 ) , reserpine-induced depression ( 7 1 ) or to cause hypothermia ( 7 1 ) i n mice suggests that P i n d e r s proposal that XI should penetrate the CNS may be e r r o neous. The use of I.V. dopamine i n the treatment of shock ( 7 2 , 7 3 ) suggests that dopamine pro-drugs such as XI and other 0 , 0 - d i a c y l ( 1 1 , 7 4 ) and amino a c i d amides d e r i v a t i v e s of dopamine (75.) might provide u s e f u l , f

In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

1.

STELLA

Overview and Definition

15

o r a l l y b l o a v a i l a b l e forms of dopamine f o r the t r e a t ­ ment of shock. In the treatment of shock, p e r i p h e r a l and not CNS l e v e l s of dopamine are d e s i r e d . Other examples of attempted chemical m o d i f i c a t i o n intended to promote CNS absorption of amines include the studies of V e r b i s c a r et a l . (76.) w i t h amphetamine, B j u r u l f et a l . (77.) w i t h chlorphentermine and Kupchan et a l . (75") w i t h normeperidine. Each study attempted carbamoylation of the amine i n an e f f o r t to (a) i n ­ crease the l i p o p h i l i c i t y of the amine by preventing the i o n i z a t i o n r e a c t i o n . P e n e t r a t i o n i n t o the CNS from blood has been c o r r e l a t e d to l i p o p h i l i c i t y and the c o n c e n t r a t i o n of u n d i s s o c i a t e d molecules i n the blood ( 7 9 - 8 1 ) : and/o (b) t th metaboli a c t i o of monoamine oxidas r e s u l t s w i t h amphetamine and normeperidine were mar g i n a l . The carbamates of amphetamine d i d appear to provide a prolonged r e l e a s e e f f e c t . The r e s u l t s of B j u r u l f ert a l . ( 7 7 ) w i t h N-carbethoxychlorphentermine (XV) or Oberex® TSraco), a pro-drug of the anorectic agent chlorphentermine, showed that the pro-drug had a " r e l a t i v e l y prolonged e f f e c t which makes one dose i n the morning apparently s u f f i c i e n t . "

CH 3 (XV) Water soluble v i t a m i n s . Many of the water s o l u ­ ble Β vitamins such as thiamine (vitamin Βχ, XVI), r i b o f l a v i n (vitamin B 2 , XVII) and p y r i d o x i n e (vitamin B6, XVIII) are h i g h l y polar and a c t i v e l y absorbed agents. Thiamine, being a water soluble compound w i t h a quaternary n i t r o g e n , i s poorly absorbed i n t o the CNS (83) and poorly absorbed from the GI t r a c t ( 8 4 - 8 7 ) . Thiamine passes through these b a r r i e r s because both i n CNS and o r a l a b s o r p t i o n , i t i s a c t i v e l y absorbed. However, a c t i v e absorption processes are saturable and/or e a s i l y i n h i b i t e d . I n h i b i t i o n of the o r a l ab­ s o r p t i o n of thiamine by chronic a l c o h o l consumption has been i m p l i c a t e d i n Wernicke's encephalopathy ( 8 8 ) and i n h i b i t e d CNS absorption of thiamine has been im­ p l i c a t e d i n the Leigh's disease (89.,£0) · Thomson

In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

16

PRO-DRUGS

0 (XVII) et a l . (88) have shown that chronic a l c o h o l consumpt i o n and long d i e t a r y d e f i c i e n c y may reduce the i n t e s t i n a l absorption of thiamine. Thiamine undergoes a r a t h e r unusual second i o n i z a t i o n (Scheme V) t o a t h i o l a t e i o n (XIX), i n v o l v i n g the consumption of two moles of hydroxide i o n f o r each mole of thiamine. D e r i v a t i z a t i o n of XIX leads t o many l i p i d s o l u b l e prodrugs o f (a) the d i s u l f i d e type, such as thiamine prop y l d i s u l f i d e (TPD, XX), thiamine t e t r a f u r f u r y l d i s u l f i d e (TTPD, XXI) and 0,0 -dibenzoylthiamine d i s u l f i d e ( X X I I ) ; (b) d i a c y l type, such as 0,S-diacetylthiamine (DAT, X X I I I ) ; and (c) 0,S- and S-carbonate e s t e r s of thiamine, such as 0,S-diethoxycarbonylthiamine (DECT, XXIV). These and many other d e r i v a t i v e s have been synthesized i n Japan since the e a r l y 1950 s (91)· The synthesis of these d e r i v a t i v e s was not n e c e s s a r i l y aimed at p r e f e r e n t i a l GI or CNS absorption of thiamine but was geared mainly t o the p o s s i b l e use of these l i p i d s o l u b l e thiamine d e r i v a t i v e s as s t a b l e food add i t i v e s . The p o l i s h i n g of r i c e had l e d t o some t h i a mine d e f i c i e n c y i n Japan. Thiamine i t s e l f could not be used as a food a d d i t i v e f o r r i c e because i t i s too water s o l u b l e , thus e a s i l y washed from r i c e . I t i s a l s o chemically unstable (92) and very poorly absorbed. f

f

In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

1.

STELLA

Overview and Definition

17

(XIX) Scheme V Compounds l i k e (XX-XXIV) and t h e i r homologues do not possess a quaternized n i t r o g e n so a l l o w i n g them to be p a s s i v e l y absorbed from the GI t r a c t . Each are q u a n t i t a t i v e l y converted t o thiamine once i n the body (93). XXIII and XXIV and t h e i r homologues are converted t o thiamine by t h i o e s t e r a s e s and esterases (93). The d i s u l f i d e compounds (XX-XXII) and t h e i r homologues are converted to thiamine by a d i s u l f i d e exchange mechanism i m p l i c a t i n g g l u t a t h i o n e and g l u t a thione reductase ( 9 4 - 9 7 ) . Grode et a l . (9.8) r e c e n t l y speculated that d i s u l f i d e thiamine pro-drugs might be s u s c e p t i b l e to i n t e r a c t i o n with serum p r o t e i n s v i a a d i s u l f i d e exchange r e a c t i o n and p r e c i p i t a t e antibody formation. Their r e s u l t s show that long term dosing of XXI i n r a b b i t s d i d not e l i c i t antibody formation. Thomson et a l . (8J3) have presented some e x c e l l e n t data on thiamine blood and CNS l e v e l s i n Wernicke's encephalopathy as w e l l as lowered blood and CNS l e v e l s of thiamine i n a l c o h o l i c s having symptoms s i m i l a r to but not n e c e s s a r i l y s u f f e r i n g from Wernicke's disease. Their r e s u l t s show that XX on s i n g l e o r a l dosing r e s u l t e d i n increased, and i n some cases normal, red blood c e l l (RBC) t r a n s k e t o l a s e a c t i v i t y i n a l c o h o l i c , thiamine d e f i c i e n t p a t i e n t s while thiamine i t s e l f had

In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

CH ^NH »

C-CH CH OH S-SR 2

2

(XX) : R

C H 3

2

7

(XXI) : R = -CH 2

J3H

CÏÏ

V

„CH-

0

I CH NH $

C-CH CH 0CR o

I

2

o

2

i

s

2

R

0 (XXIII) : R = -CH. (XXIV) : R = -OC H 2

N

^

V

C H

2

^ ^

5

^CH.

τ CH ^N3

CH

CH I

I N,

S

0 II C-CH CH 0C I S 0 i C-CH CH oB 2~ 2 :

2

o

A

0

2 o

0

S

CH.

CK (XXII)

In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

1.

STELLA

Overview and Definition

19

only a small e f f e c t on RBC transketolase a c t i v i t y . Six hours a f t e r o r a l a d m i n i s t r a t i o n of XX, 5 of 6 a l ­ c o h o l i c p a t i e n t s with Wernicke's disease and the ac­ companying b i l a t e r a l rectus palsy showed complete r e -

0

I

2

3

4

s

* 24

TIME (hours) Annals of Internal Medicine

Figure 2. Thiamine blood levels in malnourished alco­ holic patients with fatty livers (Δ) and in normal subjects (0)> given 50 mg of XX (open symbols) or 50 mg of thia­ mine hydrochloride (closed symbols) (88)

mission showing thiamine dose of

of the occular p a l s y , with the s i x t h p a t i e n t an improved c o n d i t i o n . Figure 2 gives the blood l e v e l versus time p r o f i l e f o r a 50 mg XX compared t o an i d e n t i c a l dose of thiamine

In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

20

PRO-DRUGS

given to malnourished a l c o h o l i c p a t i e n t s with f a t t y l i v e r and normal s u b j e c t s . Figure 3 i s a comparison of blood l e v e l and c e r e b r o s p i n a l f l u i d concentration versus time p r o f i l e and the accompanying c l i n i c a l r e sponse f o r a group of thiamine d e f i c i e n t a l c o h o l i c s t r e a t e d w i t h thiamine f o r 25 hours and then t r e a t e d with an equivalent dose of XX.

0

2

4

6

46 2 4 TIME (HOURS) 9

J

Annals of Internal Medicine

Figure 3. Comparison of clinical and laboratory abnormalities response to 50 mg of thiamine hydrochloride followed by XX in thiamine deficient ahoholics (88) In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

1.

STELLA

21

Overview and Definition

Subacute n e c r o t i s i n g encephalomyleopathy (SNE) o r Leigh's d i s e a s e , a t e r m i n a l disease a f f l i c t i n g c h i l dren, has been suspected to be due to thiamine CNS d e f i c i e n c y p o s s i b l y caused by malabsorption of t h i a mine i n t o the CNS. I f thiamine CNS absorption i s i n h i b i t e d , the use of a p a s s i v e l y absorbed l i p i d s o l uble thiamine pro-drug may prove u s e f u l . Pincus ( 8 9 ) attempted to use XX i n a number of Leigh's disease cases with some degree of success. Temporary remissions have been noted ( 8 9 ) . Iwasaki ( 9 9 ) has s t u d i e d

Blood

0

13

0 13

0 13

TIME (hours) Vitamins (Kyoto)

Figure 4. Thiamine levels in milk and blood after parenteral administration of 200 mg of modified thiamine compounds given S.C. to goats (99)

the absorption of XXIII and XX i n t o a l i p i d depot (goat milk) a f t e r subcutaneous (S.C.) i n j e c t i o n of these d e r i v a t i v e s to goats. Iwasaki's r e s u l t s are shown i n Figure 4. On the b a s i s of t h i s experiment,

In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

22

PRO-DRUGS

XXIII would be expected to produce higher CNS l e v e l s of thiamine than XX or thiamine i t s e l f , e s p e c i a l l y i n the presence of an i n h i b i t e d thiamine CNS uptake mech­ anism. A p r e l i m i n a r y c l i n i c a l i n v e s t i g a t i o n using X X I I I , at Loyola Medical Center, Maywood, I l l i n o i s , on a p o s s i b l e Leigh's disease case produced encouraging r e s u l t s (100). For a complete review of thiamine pro-drugs, the paper of Kawasaki (93.) should be consulted. For a summary of various s y n t h e t i c procedures f o r preparing various thiamine pro-drugs, the reader i s d i r e c t e d to the paper by Matsukawa et a l . (£1). The improved o r a l b i o a v a i l a b i l i t y of thiamine through dosing with v a r i ­ ous thiamine pro-drug i w e l l documented i th Jap anese l i t e r a t u r e (91*93,99,102-113) Chronic a l c o h o l i n g e s t i o n has a l s o been shown to i n h i b i t the a c t i v e absorption of r i b o f l a v i n , other a c t i v e l y absorbed water soluble vitamins (114,115)> amino acids (116-118) and carbohydrates (116). F a t t y a c i d esters of r i b o f l a v i n have been synthe­ s i z e d by Yagi et a l . ( l u , 1 2 0 ) "to widen the a p p l i ­ c a t i o n of r i b o f l a v i n to pharmaceutical and n u t r i t i o n a l f i e l d s . " Their r e s u l t s show that 2 ,3 ,4 ,5 -tetrap a l m i t a t e , - t e t r a c a p r a t e , - t e t r a b u t y r a t e and - t e t r a propionate esters of r i b o f l a v i n could be hydrolyzed to r i b o f l a v i n and the corresponding f a t t y a c i d by pancreatic l i p a s e . S h i n t a n i et_ a l . (121) have shown that the d i - and t r i p a l m i t a t e e s t e r s of pyridoxine given o r a l l y to mice had vitamin B5 a c t i v i t y . However, i f the esters were given i n t r a p e r i t o n e a l l y ( I . P . ) , the v i t a m i n Bg a c t i v ­ i t y was diminished. Results i n r a t s confirmed the e a r l i e r f i n d i n g s i n mice (122). I t seemed that the palmitate esters required cleavage to pyridoxine be­ fore absorption and that i n j e c t i o n of the esters r e ­ s u l t e d i n t h e i r incomplete conversion to the pyridox­ ine. The triaminobenzoate e s t e r of pyridoxine has a l s o been prepared (123) as a p o s s i b l e pro-drug form of pyridoxine. L i p o p h i l i c d e r i v a t i v e s of ascorbic a c i d , such as β-palmitoylascorbic a c i d (124,125) and 6-stearoylasc o r b i c a c i d (126,127), have been synthesized as l i p o ­ p h i l i c a n t i o x i d a n t s f o r nonaqueous formulations. Various mono- and p o l y a c y l d e r i v a t i v e s of ascorbic f

f

f

f

In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

1.

STELLA

23

Overview and Definition

a c i d have been synthesized with the view to increase the aqueous s t a b i l i t y of ascorbic a c i d . The weak v i t a m i n C a c t i v i t y of the 2 , 3 5 6 - t e t r a c e t y l d e r i v a ­ t i v e administered o r a l l y has been noted (128) while 6-benzoyl (129-132), β-stearoyl ( 1 2 6 1 2 7 ) 7 ^ - l a u r y l (126,127) and some d i a c e t y l d e r i v a t i v e s have v i t a m i n C a c t i v i t y e q u i v a l e n t , but not s u p e r i o r , to ascorbic a c i d . However, as w i l l be discussed l a t e r , the 2and/or 3-acyl d e r i v a t i v e s are more chemically s t a b l e than ascorbic a c i d i t s e l f . The l i p o p h i l i c 6-palmit o y l d e r i v a t i v e i s used as a l i p o p h i l i c a n t i o x i d a n t . 5

5

3

Nucleosides and n u c l e o t i d e s . Another group of h i g h l y p o l a r , poorly l i p o p h i l i c molecules with r e s u l t i n g poor p e r m e a b i l i t analogs of the n a t u r a purin pyrimidin sides (133). These compounds can i n t e r f e r e with nu­ c l e i c a c i d synthesis and the synthesis of p r o t e i n s and carbohydrates. The r o u t i n e use of the nucleoside analog, 6-azauridine (XXV), i n the treatment of neo­ p l a s t i c diseases and p s o r i a s i s was i m p r a c t i c a l be­ cause of i t s poor o r a l b i o a v a i l a b i l i t y . The poor b i o a v a i l a b i l i t y can be a t t r i b u t e d to the poor perme­ a b i l i t y c h a r a c t e r i s t i c s of XXV and/or metabolism of 0

(XXV): R = -H (XXVI): R = - C O C H 3 (XXVII): R = -COC^H

In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

24

PRO-DRUGS

XXV during the absorption process. The synthesis of various e s t e r s of XXV such as 2 , 3 , 5 ' - t r i a c e t y l (XXVI), and 2 , 3 , 5 - t r i b e n z o y l - 6 - a z a u r i d i n e (XXVII) as w e l l as other mono- and p o l y a c y l d e r i v a t i v e s was carr i e d out i n an e f f o r t to obtain an o r a l l y b i o a v a i l a b l e form of XXV (134-139). XXVI on i n j e c t i o n i n p a t i e n t s s u f f e r i n g from various n e o p l a s t i c diseases (140) was found to be excreted i n the u r i n e as 6-azauridine (2911%) and monoacetyl-6-azauridine (4-19?). The t r e a t ment of p s o r i a s i s with o r a l doses of XXVI of 250 mg/Kg/day proved s u c c e s s f u l ( l 4 l ) . XXVI given o r a l l y to r a t s showed a n t i f e r t i l i t y p r o p e r t i e s s i m i l a r to XXV w i t h the added advantage that XXVI was o r a l l y absorbed !

f

f

f

1

(142).

Welch (134) ha o r a l l y every 8 hours and s completely absorbed. O o r a l dosing, XXVI i s excreted 80$ as XXV and 11% as i t s 5 - a c e t y l d e r i v a t i v e w i t h only traces of XXVI excreted. O r a l l y administered XXVI caused the same c l i n i c a l e f f e c t s as a molar equivalent dose of XXV given I.V. The poor o r a l b i o a v a i l a b i l i t y of the n u c l e o s i d e , p s i c o f u r a n i n e , (XXVIII), has been a t t r i b u t e d to the b a s i c i t y of i t s 6-amino group, and i t s n o n l i p o p h i l i c character (143). Various acetate esters of XXVIII were prepared i n c l u d i n g t h ^ t e t r a a c e t a t e e s t e r (XXIX). Oral CD50 studies with S. hemolyticus i n f e c t e d mice showed XXIX to be twice as e f f e c t i v e as the parent compound XXVIII. Figure 5 gives human serum l e v e l s of XXVIII as f

OR

OR

(XXVIII) : (XXIX) :

R = -H R = -COCH

In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

1.

STELLA

Overview and Definition

25

a f u n c t i o n of time a f t e r o r a l dosing w i t h XXVIII and XXIX. The poor b i o a v a i l a b i l i t y of XXVIII from an o r a l dose of XXVIII was confirmed and the s u p e r i o r i t y of XXIX as an o r a l l y a v a i l a b l e form of XXVIII demonstra­ t e d . Hoeksema et a l . (143.) s t a t e that the higher s o l ­ u b i l i t y of XXIX r e l a t i v e to XXVIII i n chloroform (>150

> χ χ

J. -L

12 3 4 5 TIME (hours)

6

7

8

Biochemical and Biophysical Research Communications

Figure 5. Serum levels in humans of XXVIII as a function of time after 1.5 g oral dosing of XXVIII (φ) or XXIX (O) (143)

mg/ml compared to 0.007 mg/ml), while m a i n t a i n i n g a reasonable aqueous s o l u b i l i t y (3 mg/ml compared t o 13 mg/ml), s t r o n g l y suggested that the s u p e r i o r o r a l a v a i l a b i l i t y of XXVIII from XXIX can be a t t r i b u t e d to the increased l i p o p h i l i c character of XXIX. C y c l i c 3 ,5'-adenosine monophosphate (XXX), a po­ l a r n u c l e o t i d e r e g u l a t o r of g l y c o g e n o l y s i s , has been a c y l a t e d by Pasternak et a l . (144). The d i b u t a n o y l d e r i v a t i v e , N°-2 -0-dibutanoyladenosine-3 ,5 -mono­ phosphate (XXXI), given I.V. to dogs showed a greater hyperglycemic a c t i v i t y than XXX i t s e l f . Two^other de­ r i v a t i v e s , the N - b u t a n o y l (XXXII) and the N - o c t a n o y l (XXXIII) d e r i v a t i v e s , a l s o showed s u p e r i o r and pro1

f

f

1

b

In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

26

PRO-DRUGS

NHR-

?— (XXX): (XXXI): (XXXII): (XXXIII):

R R R R

OR 1

1

= R = -COC H =~COC H , R2 = -H = -COC^H^, R = -H 3

1

3

1

7

7

2

longed hyperglycemic a c t i v i t y compared t o XXX. Posternak et a l . (144) a t t r i b u t e d t h i s g r e a t e r a c t i v i t y to increased entrance i n t o c e l l s and/or the r e s i s t a n c e of the d e r i v a t i v e s t o i n a c t i v a t i o n by phosphodiester­ ases . The a c e t a t e , formate and propionate e s t e r s o f 9(β-D-arabinofuranosyl)adenine have been synthesized as o r a l l y a v a i l a b l e forms of the parent drug (145) . Adamantoyl e s t e r s of v a r i o u s deoxyribonucleosides ( s p e c i ­ f i c a l l y the 5 e s t e r s ) have been prepared by Gerzon et a l . (146). Although the authors a t t r i b u t e the a c t i v ­ i t y of the 5 -adamantoyl e s t e r s t o the i n t a c t e s t e r , the p o s s i b i l i t y that the esters were a c t i n g as pro­ drugs of the parent nucleoside was not excluded. f

!

Other p o l a r compounds. The large d i f f e r e n c e be­ tween e f f e c t i v e o r a l and I.V. doses of many quaternary ammonium drugs has been a t t r i b u t e d to the incomplete o r a l absorption of quaternary compounds (147>148). The o r a l absorption of quaternary ammonium compounds from the GI t r a c t has always presented a problem. At l e a s t one quaternary compound, thiamine, has been shown t o be a c t i v e l y absorbed (84).

In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

1.

STELLA

Overview and Definition

27

Levine et_ a l . (149) were able to show that i n t r a ­ molecular c y c l i z a t i o n s could be used to overcome t h i s problem. Table I I shows four compounds. Compound XXXV under p h y s i o l o g i c a l conditions found i n the p l a s ­ ma and i n t e s t i n a l t r a c t i s converted to XXXIV, the quaternary compound, v i a an i n t r a m o l e c u l a r nucleop h i l i c r e a c t i o n . S i m i l a r l y , XXXVII i s converted to XXXVI. The absorption f i g u r e s quoted i n Table I I were from i n s i t u i n t e s t i n a l loop experiments and do not r e f l e c t the concentration of quaternary compounds ac­ t u a l l y appearing i n the blood stream. As can be seen TABLE I I Compoun Hours

V

CH.

CH

Λ

J

"(CH )

© Ν

2

3

Ik

Ν ©

5

V

(XXXIV) CH„

CH_ I ( C H2'5) - N

3

Br — ( C H ) - N 0

C

0

C

( C H ^ — Br

56

(XXXV) CH,

CH,

Λ ® Ν

(CH ) 2

16.8

5

V

(XXVI) CH CH. I 3, I 3 C I — ( CH ) ^ - N — ( CH ) — N — ( CH ) - C l 0

2

2

5

2

ή

21

(XXXVII)

In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

28

PRO-DRUGS

seen from the Table I I , the quaternary compounds were poorly absorbed because of t h e i r low l i p i d s o l u b i l i t y while the t e r t i a r y amine d e r i v a t i v e s were b e t t e r ab­ sorbed. Studies (149) of the u r i n a r y e l i m i n a t i o n pro­ ducts a f t e r dosing with the t e r t i a r y amine precursors showed that metabolic pathways other than conversion to the quaternary compounds were o c c u r r i n g . As a r e ­ s u l t , the superior absorption c h a r a c t e r i s t i c s of the t e r t i a r y amine precursors d i d not n e c e s s a r i l y r e f l e c t increased blood l e v e l s of quaternary compounds. The mechanisms d e s c r i b i n g the i n t r a m o l e c u l a r cyc l i z a t i o n s of ω-haloalkylamines to t h e i r quaternary analogues have been discussed by S t r e i t w i e s e r (150) and Kusnetsov et a l (151) Whil Levin t a l pio neered the p o s s i b l of the ω-haloalkylamines to t h e i r quaternary analogues, Ross and coworkers (152-157)» i n a s e r i e s of s t u d i e s , have attempted to u t i l i z e t h i s concept more f u l l y . Ross and Proden (152) studied the absorption and f o r ­ mation of XXXVIII~Trom XXXIX i n mouse b r a i n a f t e r I.P. a d m i n i s t r a t i o n of XXXIX. The I.P. i n j e c t i o n of XXXVIII i t s e l f d i d not give any detectable amounts of XXXVIII i n the b r a i n , whereas I.P. a d m i n i s t r a t i o n of XXXIX r e ­ s u l t e d i n s u b s t a n t i a l b r a i n l e v e l s of XXXVIII. The q u a n t i t a t i v e conversion of XXXIX to XXXVIII i n mouse b r a i n homogenates was a l s o observed. The purpose of the study was t o e f f e c t CNS absorption o f a quaternary CH

CH

3

(XXXIX)

l

CH

3

(XXXVIII)

In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

1.

STELLA

Overview and Definition

29

compound by the a d m i n i s t r a t i o n of i t s t e r t i a r y ω-haloalkylamine precursor. The study of the e l i m i n a t i o n of quaternary compounds from the CNS has been l i m i t e d by absorption, i . e . , the study of e l i m i n a t i o n i s d i f f i ­ c u l t i f i t has never been e s t a b l i s h e d that the quater­ nary compound was e f f e c t i v e l y absorbed i n the f i r s t place. The very long e l i m i n a t i o n h a l f - l i f e o f XXXVIII from the brains of mice, approximately 30 hours, dem­ onstrates the poor e l i m i n a t i o n of i n s i t u formed p o l a r m a t e r i a l s from the CNS. These r e s u l t s are consistent with the f i n d i n g s of a long e l i m i n a t i o n h a l f l i f e f o r the polar and charged i n s i t u formed acetate anion e l i m i n a t i o n from the CNS (545). Ross and coworker (155) hav subsequentl stud ied the various parameter of ω-haloalkylamines t o t h e i r quaternary d e r i v a t i v e s .

(XL)

(XLI) Scheme VI Scheme VI was the general r e a c t i o n studied. The dura­ t i o n and i n t e n s i t y of l o c a l anesthesia using i n vivo and i n v i t r o t e s t s , f o r both XL and XLI, were studied. Chemical studies of the e f f e c t of η and -x on the con­ v e r s i o n of XL t o XLI and the l o c a l anesthetic a c t i v i t y of both the t e r t i a r y analog i t s e l f and the formed qua­ ternary compound suggested that the formed quaternary compounds c o n t r i b u t e t o the d u r a t i o n of the anesthesia (155*157). The l o c a l anesthetic e f f e c t s of XL and XLI on the s c i a t i c nerve of guinea p i g s , i n v i v o , and f r o g , i n v i t r o , showed that sustained l o c a l anesthetic a c t i v i t y occurred f o r compounds where η = 5 and χ =

In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

30

PRO-DRUGS

- C l or -Br. Apparently the prolonged a c t i v i t y was w e l l c o r r e l a t e d with the extremely slow e l i m i n a t i o n of i H s i t u formed quaternary compound from the s c i a t i c nerve ( 1 5 7 ) and the concentration of the quaternary compound i n the nerve. S i m i l a r studies with b r e t y l i u m r e l a t e d d e r i v a t i v e s (153)> x y l o c h o l i n e r e l a t e d d e r i v a t i v e s ( 1 5 4 ) and troxonium r e l a t e d d e r i v a t i v e s ( 1 5 6 ) have a l s o r e c e n t l y been published. The poor o r a l b i o a v a i l a b i l i t y of many a n t i b i o t i c s , such as a m p i c i l l i n ( 1 5 8 - 1 6 4 ) , erythromycin ( 1 6 5 - 1 6 7 ) *

oleandomycin (-168) and lincomycin (169*170) has been a t t r i b u t e d t o both t h e i r p o l a r character as w e l l as metabolism i n the GI t r a c t , GI mucosa or l i v e r during absorption. The poo b i o a v a i l a b i l i t f ampicilli compared to a numbe w i l l be discussed by Dr. S i n k u l a . The a n t i b i o t i c , oleandomycin ( X L I I ) was found t o have a f a i r l y broad a n i t b a c t e r i a l spectrum and t o be OR 0 C H — 0 I II CH CHCHCHCHC 0

v

3 0

1

2

1

CH^ ^^"2 (CH ) N 3

2

(XLII): (XLIII):

R = -H R = -COCH,

e f f e c t i v e both o r a l l y and p a r e n t e r a l l y ( 1 7 1 ) . I t was subsequently shown that i t s t r i a c e t y l d e r i v a t i v e , t r i acetyloleandomycin ( X L I I I ) was more e f f e c t i v e o r a l l y than the parent compound ( 1 6 8 , 1 7 2 - 1 7 5 ) · This i n creased e f f e c t i v e n e s s was a t t r i b u t e d t o the greater b i o a v a i l a b i l i t y of XLII from X L I I I than from XLII i t s e l f (See Figure 6 ) . Clemer et a l . have shown that X L I I I has some a n t i b a c t e r i a l a c t i v i t y of i t s own against S. aureus and S. l u t e a but that the a c t i v i t y was only 2 5 $ that of oleandomycin free base ( 1 7 2 ) . A f t e r i n g e s t i o n of X L I I I , XLII i s detected i n urine

In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

1.

STELLA

Overview and Definition

31

along with 3-acetyloleandomycin, (major m e t a b o l i t e ) , 1-acetyloleandomycin and 1,3-diacetyloleandomycin ( i n termediate metabolites) and 2,3-diacetyloleandomycin (minor m e t a b o l i t e s ) .

TIME (hours) Antibiotics Annual

Figure 6. Antibiotic activity vs. time curve in human beings given 500 mg XLII (O), 500 mg XLIII (·), and 250 mg XLIII (•). Activity expressed in terms of XLII base (168).

The o r a l b i o a v a i l a b i l i t y problems of erythromycin (XLIV) are w e l l e s t a b l i s h e d (165-167)- E s t e r i f i c a t i o n of XLIV at the 2 p o s i t i o n , ( i . e . , Hp = -COR- where R 3 = a l k y l , a r y l , alkoxy or -(CH ) COOR4 where R4 = a l k y l group) to give various e s t e r s was done w i t h the expressed purpose of lowering the aqueous s o l u b i l i t y of the erythromycin i n an attempt to decrease i t s b i t t e r t a s t e . Many of these esters on o r a l dosing gave s u p e r i o r or equivalent blood l e v e l s to e r y t h r o mycin base (176-181). The propionate e s t e r i n p a r t i c u l a r was considered to give superior l e v e l s of erythromycin when compared to erythromycin. There i s some d i s c u s s i o n as to whether the conversion of the 2 -propionate ester to erythromycin i s complete i n T

2

n

1

In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

32

PRO-DRUGS

(XLIV): erythromycin erythromycin

A, ÏC FT B, R* R

= = = =

-OH, -H -H, -H

v i v o . E s t e r i f i c a t i o n of erythromycin at the 2 , 4 " , and 1 1 p o s i t i o n s r e s u l t e d i n s i g n i f i c a n t increases i n the l i p o p h i l i c i t y of the molecules. Whether these esters r e v e r t t o the parent compound, maintain a c t i v i t y of t h e i r own, or impart any r e a l advantage over erythromycin i t s e l f i s a c u r r e n t l y c o n t r o v e r s i a l t o p i c ( 1 8 0 , 1 8 2 ) . The a b i l i t y of a number of erythromycin esters and s a l t s to mask the b i t t e r t a s t e of e r y t h r o mycin w i l l be discussed l a t e r . The p o l a r a n t i b i o t i c , lincomycin (XLV) has been e s t e r i f i e d at the 2 and 7 p o s i t i o n (XLVI) i n an attempt to produce a t a s t e l e s s form of XLV s u i t a b l e f o r p e d i a t r i c dosing ( 1 8 3 - 1 8 5 ) . Obviously the b i o l o g i c a l p r o p e r t i e s of XLVI, such as absorption charact e r i s t i c s and regeneration of the parent compound, a l s o need to be optimized. Good a c t i v i t y f o r 2 - a c y l and 2-alkoxycarbonyl d e r i v a t i v e s were noted i n S. aureus i n f e c t e d mice. The maximum a c t i v i t y was noted for through C^g e s t e r s with median chain length e s t e r s having the b e t t e r a c t i v i t y ( 1 8 4 ) . The F

In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

1.

STELLA

Overview and Definition I 3

Ν.

CH H

1

33

3

2

(XLV) : R = R = -H ? (XLVI) : 1 R and/or R = a c y l or alkoxycarbonyl s u b s t i t u e n t 2,7-dicarbonate e s t e r s were found to be i n a c t i v e i n v i t r o but had i n v i v o a c t i v i t y a f t e r S.C. i n j e c t i o n and o r a l dosing i n S. aureus i n f e c t e d mice. A number of the d e r i v a t i v e s (both a c y l and carbonate e s t e r s ) were shown to achieve the o r i g i n a l o b j e c t i v e of the authors, i . e . , a t a s t e l e s s lincomycin d e r i v a t i v e with i n v i v o a c t i v i t y comparable to lincomycin base (185)« Mâlek et a l . (l86) have attempted to increase del i v e r y of p o l a r a n t i b i o t i c s such as p e n i c i l l i n to p u l monary t i s s u e and lymph nodes by d e r i v a t i v e formation. The authors argue that d e l i v e r y to the lymphatic system might be achieved i f drugs such as streptomycin, neomycin and viomycin were a s s o c i a t e d as macromolecular s a l t s with c a r b o x y l , s u l f o n y l or phosphoryl high molec u l a r weight polymers. They conclude that these macromolecules, w i t h t h e i r c o l l o i d a l p r o p e r t i e s , have a high a f f i n i t y f o r the lymphatic system. The authors prepared a number of macromolecular s a l t s of the various a n t i b i o t i c s (the authors termed the r e s u l t a n t s a l t s "antibiolymphins") i n c l u d i n g (a) p o l y a c r y l a t e s a l t s , (b) s a l t s w i t h s u l f o n y l and phosphorylated polysacchar i d e s , and (c) s a l t s w i t h n a t u r a l p o l y c a r b o x y l i c acids of the polyuronic and polysaccharide s e r i e s . A f t e r I.M., I.P., I.V., and i n t r a p l u r a l a d m i n i s t r a t i o n of the macromolecular s a l t s of streptomycin, neomycin and v i o mycin, l e v e l s of the various drugs i n the lymphatic system appeared to be higher than l e v e l s obtained from a d m i n i s t r a t i o n of an equivalent dose of the nonderiva-

In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

34

PRO-DRUGS

t i z e d drug. The o r a l absorption of heavy metal c h e l a t i n g agents such as ethylenediaminetetraacetic a c i d (EDTA, XLVII) and diethylenetriaminepentaacetic a c i d (DTPA, XLVIII) had been shown to be l e s s than k% of the t o t a l dosage (187). The r e l a t i v e l y poor e f f e c t i v e n e s s of a number of c h e l a t i n g agents t o promote r a d i o a c t i v e metal m o b i l i z a t i o n has been a t t r i b u t e d t o t h e i r poor permeability characteristics. The chelating agents (2-hydroxyethylenediamine-N,N,N-triacetic acid (HEDTA, LXIX) and N,N'-bis(2-hyHOOCCH

^CH COOH

2

2

\cH CH N HOOCCH (XLIX) .0 Hr-COOCCH

\

NCH„CH„N

/

H C OOCCH 5

2

/

\

2

2

Ù

\

/

0

2

(LI)

CH^COOH CH C00H o

(LII)

In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

1.

STELLA

35

Overview and Definition f

droxycyclohexyl)-ethylenediamine-N,N -diacetic a c i d (DOC L) have been d e r i v a t i z e d to the l e s s polar compounds LI and L I I r e s p e c t i v e l y . A f t e r I.V. administrat i o n of L I , m o b i l i z a t i o n of various radiometals from the l i v e r of Ce ^^ dosed cats was f a r s u p e r i o r to an equivalent dose of XLIX. LI administered o r a l l y was as e f f i c i e n t at radiometal m o b i l i z a t i o n as an equivalent I.V. dose of L I . The increased o r a l b i o a v a i l a b i l i t y and increased p e r m e a b i l i t y to various organs of LI and LII were a t t r i b u t e d to the l e s s polar nature of the der i v a t i v e s and t h e i r ready conversion to the parent compound . The increased m o b i l i z a t i o n of radiometals by LI was a t t r i b u t e d to the formed XLIX because LI was shown to have no heav i o c h e l a t i n capacit (188) 5

1

Opthalmic absorptio o epinephrine. e highly p o l a r adrenergic agent, epinephrine ( I X ) , i s u s e f u l i n the treatment of glaucoma. As demonstrated e a r l i e r , l e s s than 1% of IX i s present i n i t s n e u t r a l form at p h y s i o l o g i c a l pH. A c y l a t i o n of the phenolic hydroxy groups to give the d i p i v a l y l d e r i v a t i v e ( L I I I ) was found to increase the therapeutic e f f e c t i v e n e s s of IX by a f a c t o r of approximately 100 (to be discussed f u r ther by Dr. McClure). Even though the f r a c t i o n of

•CHCH NH(CH )

(CH ) CC0 Q

2

Q

3

(LIII) n e u t r a l molecule present at p h y s i o l o g i c a l pH should not be g r e a t l y a f f e c t e d by the a c y l a t i o n , the l i p i d s o l u b i l i t y of L I I I i s f a r superior to i t s parent compound, IX. Since corneal absorption i n v o l v e s transport through a l i p o i d a l b a r r i e r , the greater l i p o p h i l i c i t y of L I I I may account f o r i t s superior therapeutic e f f e c t i v e n e s s . The use of the d i p i v a l y l e s t e r was necessary not only to increase the l i p o p h i l i c i t y of the compound but a l s o to help guarantee adequate aqueous s t a b i l i t y . Percutaneous absorption of p o l a r drug e n t i t i e s . The absorption of drugs i n t o and through the s k i n i s an area of study which has achieved wide coverage but which i s not, as y e t , f u l l y understood. I t i s generall y accepted that only n e u t r a l , r e l a t i v e l y l i p o i d a l drug

In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

36

PRO-DRUGS

molecules can be absorbed percutaneously (19*0 · The work of Imai et_ a l . ( 1 8 9 ) on the percutaneous absorpt i o n of the p o l a r v i t a m i n , a s c o r b i c a c i d (LIV) and i t s h i g h l y p o l a r 3-phosphoryl e s t e r (LV) tends to contrad i c t t h i s g e n e r a l i z a t i o n . The relevancy of t h i s work

1>=0

H-

-OH

H-

-OH H

(LIV); (LV):

R = -H R = -P0 H 3

2

and the true e f f e c t i v e n e s s of percutaneous absorption of LIV from LV i s not known at t h i s time. The s u l f a drug mafenide (LVI) used i n burn therapy was r e l a t i v e l y i n e f f e c t i v e when a p p l i e d percutaneously as i t s hydrochloride s a l t ( L V I I ) . However, a p p l i c a t i o n of the acetate s a l t of mafenide ( L V I I I ) was found to be very e f f e c t i v e i n burn treatment (12-14). Mafenide i s marketed as Sulfamylon® ( L V I I I i n a watermiscible cream formulation) and Sulfamylon® hydrochloride s o l u t i o n (LVII as a 5% aqueous s o l u t i o n ) . The i n e f f e c t i v e ness of the 5% aqueous s o l u t i o n of LVII i n the t r e a t ment of burns has been discussed (190). The d i f f e r e n c e i n a c t i v i t y between LVII and L V I I I i s an i n t e r e s t i n g problem. The pKa of mafenide i s 8.52 at 21°C (191). A 5% aqueous s o l u t i o n of LVII would be expected to have a pH of approximately 4.5. The pH of an aqueous f i l m of L V I I I , regardless of c o n c e n t r a t i o n , would be expected t o have a pH of approximately 6.6. Therefore, the f r a c t i o n of mafenide present i n i t s n e u t r a l and presumably absorbable form, i n a 5% s o l u t i o n of LVII i s approximately 0.01$ whereas t h e / f r a c t i o n present i n an aqueous s o l u t i o n of L V I I I i s approximately 1%. A model f o r the absorption of mafenide i n t o the s k i n i s shown x

In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

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37

Overview and Definition

( L V I I ) ; X ® = CI © (LVIII); X © =

CH3COO©

i n Scheme V I . Whethe depend on whether Χ i s a weak or strong base or wheth er LVII or L V I I I i s i n buffered s o l u t i o n s . Since the acetate anion i s a much stronger base than the c h l o r i d e anion, the e q u i l i b r i u m i s forced t o the r i g h t f a v o r i n g the formation of LVI. L V I I I i s considered a pro-drug of LVI, yet i t i s simply a s a l t of LVI and regeneration of LVI from L V I I I i n v o l v e s simple d i s s o c i a t i o n . S t e r o i d s are an area where the pro-drug approach has been apparently s u c c e s s f u l l y u t i l i z e d i n attempts to promote t o p i c a l or percutaneous absorption. Ste­ r o i d s such as triamcinolone ( L I X ) , f l u o c i n o l o n e (LX) and f l u c l o r o l o n e have been d e r i v a t i z e d t o t h e i r acetonide d e r i v a t i v e s (192), triamcinolone acetonide

Scheme VI

In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

38

PRO-DRUGS

(LXa), f l u o c i n o l o n e acetonide (LXb), f l u o c i n o l o n e acetonide-21-acetate (LXc), f l u c l o r o l o n e acetonide and desonide. Ester d e r i v a t i v e s of various other s t e r o i d s such as the v a l e r a t e ester of betamethasone, the p r o p i onate ester of c l o b e t a s o l , the p i v a l a t e and hexanoate esters of f l u c o c o r t o l o n e , the acetate ester of hydroc o r t i s o n e , the p i v a l a t e e s t e r of flumethasone, the d i propionate ester of beclomethasone, and the acetate ester of methylprenisolene are examples of a few of the c o r t i c o s t e r o i d esters i n use (192,193)· T o p i c a l c o r t i c o s t e r o i d s are used i n the treatment of inflammatory, a l l e r g i c and p r u r i t i c s k i n c o n d i t i o n s . Whether any of the pro-drug d e r i v a t i v e s exert any a n t i inflammatory a c t i v i t f thei whethe the quire conversion t i t y can probably be argued. Poulsen (194) has r e c e n t l y discussed formulation f a c t o r s a f f e c t i n g the percutaneous d e l i v e r y of drugs. As pointed out by Poulsen, there are many f a c t o r s a f f e c t i n g the dermal d e l i v e r y of a drug. I t appears that f o r s o l u t i o n s , g e l s , creams, e t c . , the d i f f u s i o n of drug across the s k i n b a r r i e r i s rate l i m i t i n g . I n such cases, the p h y s i c a l and chemical properties of the drugto be d e l i v e r e d and the v e h i c l e which contains the drug are of paramount importance. I n p a r t i c u l a r , the a c t i v i t y of the drug i n the v e h i c l e or the e f f e c t i v e concent r a t i o n of the drug i n the v e h i c l e determines, "the d r i v i n g force f o r d i f f u s i o n from the v e h i c l e (194). The d i f f u s i o n c o e f f i c i e n t , the a c t i v i t y of a drug i n a v e h i c l e , and the p a r t i t i o n c o e f f i c i e n t of a drug between the stratum corneum and the v e h i c l e are a l l a f fected by the p h y s i c a l properties of a drug. Acetonide formation of the dihydroxy groups i n some s t e r o i d s (Scheme VII) or e s t e r i f i c a t i o n of hydroxy groups i n other s t e r o i d s generally r e s u l t s i n an a p r i o r i i n crease i n p a r t i t i o n c o e f f i c i e n t between the stratum corneum and a h y d r o p h i l i c v e h i c l e . This causes an i n crease i n the d i f f u s i o n constant across human stratum corneum and lowers the s o l u b i l i t y of the s t e r o i d i n the hydrophilic vehicle. Poulsen points out that the q u a n t i t a t i v e d i f f e r ences i n anti-inflammatory a c t i v i t y between various der i v a t i v e s of an agent i s d i f f i c u l t t o judge because of v e h i c l e e f f e c t s (194). For example, i n the comparison of the anti-inflammatory a c t i v i t y of LXb t o LXc (administered as a carboxypolymethylene g e l containing various r a t i o s of propylene glycol/water as the s o l v e n t ) , LXb was found t o be more a c t i v e than LXc (human v a s o c o n s t r i c t o r assay) when the percentage of propylene g l y c o l i n the g e l was 55$· These d i f f e r e n c e s were a t t r i b u t e d t o d i f f e r e n c e s i n s o l u b i l i t i e s of LXb and LXc i n the ve­ h i c l e as a f u n c t i o n of propylene g l y c o l concentration. LXb (0.025$) was completely soluble i n the v e h i c l e when the percentage of propylene g l y c o l was >20-40$ while LXc (0.025$) d i d not d i s s o l v e completely i n the v e h i c l e u n t i l the percentage of propylene g l y c o l reached ap­ proximately 80$. The importance of v e h i c l e composi­ t i o n , see Poulsen (194) f o r a complete d i s c u s s i o n of t h i s problem, i n the anti-inflammatory a c t i v i t y of s t e ­ r o i d s and t h e i r d e r i v a t i v e s was r e c e n t l y re-emphasized by the study of Barry and Woodford (192). M a i s t r e l l o et a l . ( 1 9 5 ) have r e c e n t l y attempted t o quantitate the t o p i c a l anti-inflammatory e f f e c t s of various s t e r o i d a l agents administered as s o l u t i o n s i n 2-(2-ethoxyethoxy)ethanol. The greater a c t i v i t y of LXa r e l a t i v e to LIX was r e a d i l y apparent. The pro-drug approach has been s u c c e s s f u l i n im­ proving the anti-inflammatory c l i n i c a l e f f i c a c y of per­ cutaneously administered s t e r o i d s as can be seen by the large number of s t e r o i d s c u r r e n t l y a v a i l a b l e as e i t h e r esters or acetonide d e r i v a t i v e s ( r e l a t i v e to nonderivat i z e d s t e r o i d s ) . However, the r o l e of the v e h i c l e i n the success of these products has only r e c e n t l y begun to be understood and f u l l y appreciated (194) .

In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

40

PRO-DRUGS

To Increase the Aqueous S o l u b i l i t y of Drugs to Help F a c i l i t a t e Oral Absorption. Rather s u r p r i s i n g l y , there are few examples of the pro-drug approach being used to increase the aqueous s o l u b i l i t y of poorly water s o l u b l e drugs i n an e f f o r t to increase the o r a l absorp­ t i v i t y of the drugs. The c l a s s i c a l examples of im­ proved water s o l u b i l i t y of poorly water s o l u b l e drugs are those f o r which an I.V. i n j e c t a b l e form of the drug was d e s i r e d . The apparent l a c k of examples may be due to the f a c t that improvement i n the o r a l absorption of a drug can o f t e n be e f f e c t e d by formulation techniques. The o r a l b i o a v a i l a b i l i t y of 5,5-diphenylhydantoin, n i t r o f u r a n t o i n , g r i s e o f u l v i n , d i g o x i n , prednisolone, etc., has been s u c c e s s f u l l y improved by formulation techniques. The poor and e r r a t i c o r a b i o a v a i l a b i l i t y o d i goxin due t o i t s low water s o l u b i l i t y and formulation v a r i a b l e s has been w e l l e s t a b l i s h e d (196-200). Higuchi and Ikeda (201) have r e c e n t l y demonstrated that the complex between hydroquinone and d i g o x i n (2 d i g o x i n : 3 hydroquinone) had a much higher d i s s o l u t i o n r a t e than digoxin i t s e l f . Any c r y s t a l l i n e m a t e r i a l such as d i g o x i n w i l l have a d i s s o l u t i o n r a t e h i g h l y dependent on i t s aqueous s o l u b i l i t y as w e l l as other v a r i a b l e s defined i n the Noyes-Whitney equation (202). The energetics of the d i s s o l u t i o n process are determined by the breakdown of i n t e r m o l e c u l a r forces i n the c r y s t a l l a t t i c e and the s o l v e n t , both r e q u i r i n g energy, r e l a t i v e to the r e l e a s e of s o l v a t i o n energy due to s o l u t e - s o l v e n t i n t e r a c t i o n s . The high m e l t i n g point ( 2 6 5 ° with decomposition) of d i g o x i n s t r o n g l y suggested that c r y s t a l l a t t i c e energy played an important r o l e i n the poor aqueous s o l u b i l i t y of d i g o x i n . The complexation of d i g o x i n w i t h a polyhydroxy compound such as hydroquinone might d i s r u p t t h i s t i g h t c r y s t a l l a t t i c e to form a complex with a s u p e r i o r aqueous s o l u b i l i t y . On d i s s o l u t i o n , d i s s o c i a ­ t i o n of the complex would r a p i d l y release d i g o x i n . " I n t r i n s i c a l l y more r a p i d l y d i s s o l v i n g forms of d i g o x i n would provide greater assurance of more reproducible and more b i o a v a i l a b l e d i g o x i n products" (201). Use of d i g o x i n d e r i v a t i v e s such as i t s 4 ' - m e t h y l d e r i v a t i v e (203-205) and a c y l a t e d d e r i v a t i v e s such as acetyldigoxin-α Γ2Ό6,207), a c e t y l d i g o x i n - 3 (203*208211) have been promoted. The acylated d e r i v a t i v e s of g i t o x i n (212-214), as w e l l as c y c l i c a c e t a l s and acet a l s of d i g i t o x i n , d i g o x i n , and quabain have been of i n t e r e s t (215). Although 4 ' - a c e t y l d i g o x i n ( L X I I ) has been shown to regenerate d i g o x i n ( L X I ) , 4 ' ' m e t h y l d i goxin ( L X I I I ) was not thought to r e v e r t to d i g o x i n . ft

f

1

1

In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

1.

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Overview and Definition

41

0 II

OH H However, the studies of Rietbock e_t a l . (204) confirm that demethylation of L X I I I does occur. Whether any of these d e r i v a t i v e s , monoalkyl ( 2 0 3 - 2 0 5 ) monoacyl ( 2 0 6 214), or p o l y a c y l ( 2 1 6 ) , have any r e a l advantage over d i g o x i n i t s e l f i s debatable. White and G r i s v o l d ( 2 1 7 ) claim good o r a l absorption p r o p e r t i e s f o r LXII i n cats and LXII i s marketed as Acylanid® (Sandoz) i n the United S t a t e s . Recently, Hussain and R y t t i n g ( 2 1 8 ) argued that a l l o p u r i n o l (LXIV) owed i t s low water s o l u b i l i t y of 0 . 7 8 mg/ml to strong i n t e r m o l e c u l a r hydrogen bonding i n i t s c r y s t a l l a t t i c e . A melting point of 3 6 5 f o r LXIV seemed to confirm t h i s assumption. D i s r u p t i o n of the c r y s t a l l a t t i c e by t r a n s i e n t pro-drug formation was suggested as a means of i n c r e a s i n g the aqueous s o l u b i l i t y of a l l o p u r i n o l . The authors synthesized 1e t h o x y e t h y l - 4 - a l l o p u r i n y l ether (LXV) and 2 - t e t r a h y d r o p y r a n y l - 4 - a l l o p u r i n y l ether (LXVI) and demonstrated the improved d i s s o l u t i o n r a t e from a constant surface area p e l l e t of LXV and LXVI when compared to LXIV. LXV and LXVI were shown to regenerate LXIV under a c i d i c 0

In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

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PRO-DRUGS

c o n d i t i o n s . Unfortunately the authors d i d not attempt to confirm the p r e d i c t e d improved b i o a v a i l a b i l i t y of LXIV from i t s pro-drug d e r i v a t i v e s by i n v i v o s t u d i e s . However, a u s e f u l conclusion from the work i s that improved aqueous s o l u b i l i t y of an agent need not necess a r i l y r e q u i r e d e r i v a t i z a t i o n to a water soluble s a l t

(LXIV):

R = -H

(LXV):

R = -CH (CH )-OC H 2

3

2

5

(LXVI): form of the drug. I f the determining f a c t o r t o poor aqueous s o l u b i l i t y i s the strength of the c r y s t a l l a t t i c e of the drug, and t h i s c r y s t a l energy i s not s u f f i c i e n t l y r e l i e v e d by s o l v a t i o n energy on d i s s o l u t i o n , then d i s r u p t i o n of the c r y s t a l l a t t i c e by pro-drug f o r mation may provide a s i g n i f i c a n t increase i n aqueous as w e l l as l i p i d s o l u b i l i t y . The strong c r y s t a l l a t t i c e energies of the hydant o i n s , 5*5-diphenylhydantoin and n i t r o f u r a n t o i n , and various pro-drug forms of these drugs w i l l be discussed l a t e r by S t e l l a et a l . The a n t i f u n g a l agent, g r i s e o f u l v i n (LXVII), has been shown to be poorly absorbed a f t e r o r a l administrat i o n t o man as w e l l as animals (219-225)» The study by Bates et a l . (226) has shown that the absorption of g r i s e o f u l v i n can be g r e a t l y enhanced by the concomital a d m i n i s t r a t i o n of f a t s . I t appears that the incomplete b i o a v a i l a b i l i t y of LXVII i s a f u n c t i o n of i t s low water s o l u b i l i t y . This can be traced t o i t s high l i p o p h i l i c i t y , a contrast to the c r y s t a l l a t t i c e s t r u c t u r e problems associated with the e a r l i e r examples. F i s c h e r and Riegelman (227) attempted t o increase the aqueous s o l u b i l i t y of LXVII by pro-drug formation. The d e r i v a t i v e s

In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

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43

studied were g r i s e o f u l v i n - 4 ' - a l c o h o l ( L X V I I I ) , g r i s e o f u l v i n - ^ -oxime (LXIX), griseofulvin-4'-carboxymethoxime (LXX) and griseofulvin-4'-hemisuccinate (LXXI). In a l l d i s c u s s i o n s thus f a r , most of the d e r i v a t i v e s were e s t e r s of the parent compound where regeneration of the parent compound was p o s s i b l e by the known presence and abundance of esterases i n the body. The s a l t and complex pro-drugs reverted to the parent compounds by d i s s o c i a t i o n (a nonenzymatic process). In the case of g r i s e o f u l v i n pro-drugs, the conversion of LXVIII to

CI

(LXVII): (LXVIII): (LXIX): (LXX): (LXXI):

CH

R R R R R

= = = = =

=0 -OH =N0H =N0CH C00H -OCOCHpCHpCOOH p

LXVII r e q u i r e s an o x i d a t i v e metabolism. On I.V. dosing to a r a b b i t , the disappearance of LXVIII from the p l a s ma of the r a b b i t had a h a l f - l i f e of 28 minutes whereas the formed g r i s e o f u l v i n had a h a l f - l i f e of 70 minutes. LXXI i s converted to LXVII by esterase h y d r o l y s i s of the e s t e r f u n c t i o n followed by o x i d a t i o n of the formed LXVIII. Oximes have a l s o been shown to be enzymaticall y converted to the corresponding ketone (228). Although each of the LXVII pro-drugs had s u p e r i o r aqueous s o l u b i l i t i e s when compared to LXVII (227)* none of the d e r i v a t i v e s on o r a l dosing showed any sup e r i o r i t y over LXVII i t s e l f . This was p o s t u l a t e d to be due to e i t h e r incomplete conversion of the d e r i v a t i v e s to LXVII, concurrent metabolism to i n a c t i v e metabol i t e s , or e l i m i n a t i o n from the body before conversion to LXVII was complete. To Help S t a b i l i z e Drugs Against Metabolism and/or H y d r o l y s i s During Oral Absorption. Many drugs are extremely a c t i v e i f administered p a r e n t e r a l l y but s u f f e r from the problem of incomplete absorption on o r a l

In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

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dosing. This incomplete absorption, as has already been noted, can r e s u l t from the drug being too p o l a r or poorly water s o l u b l e . A t h i r d p o s s i b l e reason f o r i n complete absorption i s that the drug, i f administered o r a l l y , may be r a p i d l y metabolized by enzymes secreted i n t o the GI t r a c t , by b a c t e r i a i n the GI t r a c t , by enzymes encountered while passing through the GI mucosa, and/or by the l i v e r i n i t s i n i t i a l t r a n s i t through the l i v e r before ever reaching the general c i r c u l a t i o n . Examples of drugs poorly absorbed due to one or a comb i n a t i o n of these processes have already been d i s cussed, e.g., L-Dopa. This o v e r a l l process of incomp l e t e systematic a v a i l a b i l i t y on o r a l absorption due to metabolism during the absorption process has been termed the " f i r s t pass " f i r s t pass" e f f e c t originally g only l i v e r e x t r a c t i o n (30). I t has become l e s s w e l l defined and i s used g e n e r i c a l l y to describe dose dependent b i o a v a i l a b i l i t y due to metabolism of o r a l l y adm i n i s t e r e d drugs during the absorption process. Magee et a l . (229) have r e c e n t l y studied the i n s i t u absorption of various prostaglandins from the small i n t e s t i n e of r a t s . Although disappearance from the r a t lumen was f a i r l y r a p i d f o r a l l the p r o s t a g l a n d i n s , very l i t t l e of the dose a c t u a l l y appeared i n the blood stream and only a small f r a c t i o n of t h i s " e f f e c t i v e l y " absorbed dose was i n t a c t p r o s t a g l a n d i n . The p r o s t a g l a n d i n , 15-methyl P a (LXXII) and i t s methyl e s t e r (LXXIII) were s t u d i e d . LXXII had an apparent absorpt i o n h a l f - l i f e of 60-70 minutes w i t h approximately 2$ of the dose reaching general c i r c u l a t i o n but of that only 0.8$ was i n t a c t LXXII. When LXXIII was administered up to 7$ of the dose reached general c i r c u l a t i o n , and 1.8$ of the dose was present i n serum as i n 2

OH

(LXXII): R = -H (LXIII):

R =

-CH

In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

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Overview and Definition

45

t a c t LXXII w i t h l i t t l e or no detectable LXXIII. This i s a c l e a r example of an agent, n o t o r i o u s l y suscept i b l e to metabolism, that was chemically modified to p a r t i a l l y overcome the " f i r s t pass" e f f e c t . That e s t e r i f i c a t i o n of prostaglandins i n h i b i t s the metabolism of prostaglandins was c l e a r l y demons t r a t e d by the greater a c t i v i t y of the methyl e s t e r of p r o s t a g l a n d i n 15-methyl over the parent non-methyl e s t e r p r o s t a g l a n d i n . The greater potency i s a t t r i buted to a lengthening of the metabolic h a l f - l i f e (230) of the e s t e r form r e l a t i v e to the parent a c i d p r o s t a glandin. Another group of compounds which undergoes considerable metabolism during o r a l absorption are s t e r o i d s The b i o a v a i l a b i l i t unknown because of a n a l y t i c a i t y and i n t e r f e r e n c e from n a t u r a l s t e r o i d a l hormones i n analyzing f o r absorbed i n t a c t s t e r o i d . Another c o n t r i b u t i o n to t h i s unknown b i o a v a i l a b i l i t y i s that many of the s t e r o i d s are probably metabolized to act i v e agents. Schedl et a l . (231) showed that the r a t e of abs o r p t i o n of various s t e r o i d s using the i n s i t u r a t i n t e s t i n a l loop experiment was r a p i d and i n v e r s e l y prop o r t i o n a l to the number of hydroxy or p o l a r groups present i n the molecule. This observation was confirmed when many of the s t e r o i d s were a c e t y l a t e d and the absorption r a t e of the a c e t y l a t e d versus the nona c e t y l a t e d s t e r o i d s compared. Although many of the s t e r o i d s were found to be r a p i d l y absorbed, the weak o r a l potency of a number of the agents, e.g., t e s t o s terone, progesterone and desoxycorticosterone, which were apparently w e l l absorbed, the authors s t a t e that the "pharmacologic a c t i v i t y of a s t e r o i d by the o r a l route i s independent of i t s absorption r a t e . Blood l e v e l s of s t e r o i d s f o l l o w i n g o r a l a d m i n i s t r a t i o n are more a f u n c t i o n of metabolic d i s p o s i t i o n than of abs o r p t i o n r a t e " (231). A c e t y l a t i o n may not only help increase the absorption r a t e of these s t e r o i d s but may a l s o provide a degree of metabolic p r o t e c t i o n . Tanabe et a l . (232) and P r i e d et a l . (233) have shown that 17ot,21-acetonides of various c o r t i c o s t e r o i d s have higher o r a l a c t i v i t y than t h e i r parent s t e r o i d s on o r a l dosing. The study of P r i e d et a l . (233) demonstrated the higher a c t i v i t y of l6a,17a-acetonide of triamcinolone (LXXIV) over the parent s t e r o i d (LXXV). Gardi et a l . (234) a l s o observed that p r e d n i solone acetonide (LXXVI) when administered o r a l l y and prednisolone cyclopentylidenedioxy (LXXVII) when app l i e d l o c a l l y had greater a c t i v i t y than the parent

In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

46

PRO-DRUGS

CH 0H I c=o o 2

In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

ilu 1.

STELLA

Overview and Definition

ary

a m i c a l Society

47

prednisolone. The a n t i f e r t i l i t y , anti-inflammatory compound 9ct,ll$ , 2 1 - t r i c h l o r o - l 6 a , 1 7 a - ( i s o p r o p y l i d e n e d i o x y ) - l , 4 , 6 - p r e g n a t r i e n e - 3 5 2 0 - d i o n e , an acetonide der i v a t i v e , was a l s o shown to be o r a l l y a c t i v e (235). The s t e r o i d desoxycorticosterone (LXXVIII) i s very unstable and d i f f i c u l t to handle but i t s acetate e s t e r has been used p a r e n t e r a l l y i n the treatment of Addison's disease. LXXVIII as i t s acetate e s t e r has been found to be destroyed a f t e r o r a l a d m i n i s t r a t i o n but when given s u b l i n g u a l l y was found to be u s e f u l i n the treatment of Addison's disease (236). Gardi et a l . (237) have r e c e n t l y demonstrated the high o r a l a c t i v i t y of l , 3 , 5 ( 1 0 ) - e s t r a t r i e n - 1 7 6 - y l enol ethers and a c e t a l s a classe f orall d t e r a l l y a c t i v e estrogeni i s a t t r i b u t e d to th regenerate Moreover the authors s t a t e that "the ether linkage should be s t a b l e enough to survive the a c i d i c g a s t r i c medium and s u i t a b l y delay the hepatic i n a c t i v a t i o n after oral administration." That catecholamines show poor absorption through l i p o i d a l membranes was e s t a b l i s h e d e a r l i e r i n t h i s manuscript. " F i r s t pass" metabolism, p r i m a r i l y due to conjugation ( g l u c u r o n i d a t i o n and/or s u l f a t i o n ) , was also mentioned as a primary means of l i m i t i n g the systemic a v a i l a b i l i t y of catecholamines and other phenol i c compounds. The n a r c o t i c antagonist naloxone (LXXIX) has been shown to have low potency after oral administration (238-241). The short duration of action of LXXIX a f t e r p a r e n t e r a l dosing due to r a p i d metabolism suggests that naloxone might be r a p i d l y metabolized by the l i v e r and/or g a s t r i c mucosa on o r a l dosing, i . e . , the poor o r a l a c t i v i t y r e s u l t s from a " f i r s t pass" e f f e c t . Linder and Fishman (240) synthesized a s e r i e s of s u l f a t e and acetate e s t e r s of LXXIX and t e s t e d t h e i r n a r c o t i c antagonist a c t i v i t y a f t e r o r a l and pare n t e r a l dosing i n r a t s . The 3-acetyl d e r i v a t i v e (LXXX), 14-acetyl d e r i v a t i v e (LXXXI) and 3,14-diacetyl d e r i v a t i v e (LXXXII) a l l showed good o r a l a c t i v i t y i n the morphine challenge t e s t whereas LXXIX administered o r a l l y was r e l a t i v e l y i n e f f e c t i v e . A f t e r I.V. adminis t r a t i o n , both LXXX and LXXXI were more potent than LXXIX whereas LXXXII was s l i g h t l y l e s s potent than LXXIX. These r e s u l t s suggest that the a c e t y l a t i o n of the 3 and/or 14 hydroxy groups of LXXIX blocked (or p a r t i a l l y blocked) the " f i r s t pass" metabolism of LXXIX (probably s u l f a t i o n and/or g l u c u r o n i d a t i o n ) by p r o t e c t i n g the hydroxy groups.

In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

48

PRO-DRUGS

(LXXIX): (LXXX); (LXXXI) (LXXXII)

Rt K: = -COCHo, R^ = -H R^ = -H, R = -COCH. R = R = -COCH^ 2

2

:

Way and Adler (242), i n t h e i r review of morphine (LXXXIII), morphine m e t a b o l i t e s , and other n a r c o t i c a n a l g e t i c s , s t a t e that the poor o r a l a c t i v i t y of morphine r e l a t i v e t o i t s p a r e n t e r a l a c t i v i t y may be due to the poor o r a l absorption of morphine. The e s s e n t i a l l y negative pharmacological a c t i v i t y o f o r a l l y adm i n i s t e r e d morphine i n man can be i n t e r p r e t e d as e i t h e r poor i n t r i n s i c absorption and/or " f i r s t pass" metabol i s m . Heroin or 3 6-diacetylmorphine (LXXXIV) e x h i b i t s 3

CH

0

N-

(LXXXIII): (LXXXIV):

R = -H R = -COCH

In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

1.

STELLA

Overview and Definition

49

considerable i f not somewhat i r r e g u l a r a c t i v i t y i n man a f t e r o r a l dosing which i s again c o n s i s t e n t with the b l o c k i n g (or p a r t i a l blocking) of " f i r s t pass" metabo­ l i s m . The r a p i d d e a c e t y l a t i o n of LXXXIV i n a l l b i o l o g ­ i c a l t i s s u e s , i n c l u d i n g the CNS, to LXXXIII and i t s mo­ noesters i s w e l l e s t a b l i s h e d (242). Kupchan et^ a l . (243) synthesized l a b i l e ether d e r i v a t i v e s of morphine and phenazocine and showed t h e i r a c t i v i t y to be l e s s than those of the parent compounds. Papers by Y o s h i mura et a l . (244), Oguri et a l . (245) and Mori et a l . (246) have confirmed the presence of glucuronide and s u l f a t e metabolites of morphine. Their r e s u l t s sur­ p r i s i n g l y show that the 6-glucuronide and 6 - s u l f a t e me­ t a b o l i t e s when i n j e c t e d S.C i mic (246) giv highe potency and l a r g e r d u r a t i o pared to a comparabl morphine pointe by the authors, both the 6-glucuronide and 6 - s u l f a t e are minor metabolites of morphine. In a s e r i e s of papers by F i e l d s et a l . (247-250), various l a t e n t i a t e d forms of t h i o l s , amino-thiols and 2-acetamidoethanethiol were attempted to help reduce the t o x i c i t y and/or improve a c t i v i t y , i . e . , increase a v a i l a b i l i t y , but w i t h marginal success. Similarly, H a r t l e s et a l . (251) and Siuda et a l . (252) synthesized and t e s t e d f o r a c t i v i t y a number of a c y l and carbamate d e r i v a t i v e s of mafenide (LVI). Their o b j e c t i v e was to f i n d o r a l l y a c t i v e forms of LVI. LVI was shown to un­ dergo rapid^metabolism on o r a l absorption and i t was f e l t that Ν - a c y l and N^-alkoxycarbonyl d e r i v a t i v e s might prevent the r a p i d metabolism so r e s u l t i n g i n ade­ quate blood l e v e l s . Regeneration of LVI from i t s N^a c y l and N^-alkoxycarbonyl d e r i v a t i v e s was f e l t to be too slow and inadequate to produce reasonable blood l e v e l s of LVI. Recently the t u b e r c u l o s t a t i c agent, p-aminosalic y l i c a c i d (LXXXV), has been shown to undergo " f i r s t pass" metabolism due to N - a c e t y l a t i o n (253) . In e f ­ f o r t s to o b t a i n t a s t e l e s s forms of LXXXV, various chem­ i c a l and formulation m o d i f i c a t i o n s of LXXXV have been attempted. Most of these m o d i f i c a t i o n s r e s u l t i n a slower release form of LXXXV which i s then more r e a d i l y and e f f i c i e n t l y metabolized. However, an i n t e r e s t i n g pro-drug of LXXXV, the calcium 4-benzamidosalicylate (LXXXVI), which i s q u i t e water i n s o l u b l e has been shown to be as c l i n i c a l l y e f f e c t i v e on a molar basis as LXXXV and yet t a s t e l e s s (254,255). This appears p a r a d o x i a l i n that most slow release forms of LXXXV provide incom­ p l e t e b i o a v a i l a b i l i t y due to the " f i r s t pass" e f f e c t . I t appears that LXXXVI may provide a poorly s o l u b l e , t a s t e l e s s form of LXXXV while circumventing " f i r s t

In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

50

PRO-DRUGS

pass" a c e t y l a t i o n (the aromatic group already being acylated) and once i n the body regenerates LXXXV. The r a t e of d e a c y l a t i o n of N-acyl d e r i v a t i v e s of drugs other than formyl d e r i v a t i v e s and benzoyl d e r i v a t i v e s i s poor. Chiou ( 2 5 6 ) has shown that deformylation o f 4,4 -diformamidodiphenylsulfone (DFD, LXXXVII) t o the a n t i m a l a r i a l agent, 4,4-diaminodiphenylsulfone (DDS, LXXXVIII) by kynurenine formamidase of mammalian l i v e r s does occur (see scheme V I I I ) . f

Θ

Ca(H 0)

J 2

(LXXXVI)

Lj yu \ (LXXXVII) KYNURENINE FORMAMIDASE

(LXXXVIII)

Scheme V I I I

In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

Θ

1.

STELLA

51

Overview and Definition

The Use of Pro-Drugs to E f f e c t Sustained or Release

Prolonged

Sustained r e l e a s e has u s u a l l y been e f f e c t e d i n pharmacy by the use of various dosage form changes such as coated slow r e l e a s e beads and granules, m u l t i p l e l a y e r t a b l e t s , and other formulation techniques (257)« Many of the examples of pro-drugs causing sustained r e lease incorporate a formulation technique combined w i t h chemical m o d i f i c a t i o n ideas. Stempel (257) has described the advantages of prolonged or sustained r e l e a s e products: (a) reduces the number and frequency of doses needed to be administ e r e d ; (b) e l i m i n a t e th "peak" d "valley" effect noted w i t h conventiona o f t e n reduces the t o t a g the d e s i r e d pharmacological a c t i v i t y ; (d) e l i m i n a t e s the problem of nighttime a d m i n i s t r a t i o n of drugs; (e) helps minimize the problem of p a t i e n t noncompliance by decreasing the number of times a p a t i e n t must remember to take t h e i r medication; ( f ) reduces the incidence of peak blood l e v e l s r i s i n g above the t o x i c blood l e v e l s ; (g) reduces the incidence of GI side e f f e c t s . To maint a i n an e f f e c t i v e blood l e v e l of the very short h a l f l i v e d drug cytosine arabinoside (LXXXIX), long term I.V. i n f u s i o n s of considerable inconvenience to the p a t i e n t and nursing s t a f f are needed. 5 - A c y l d e r i v a t i v e s of LXXXIX (an immunosuppressive, a n t i v i r a l and c y t o t o x i c agent) as w e l l as 2 and 3 esters have been synthesized and t e s t e d (258-262). When the s l i g h t l y water s o l u b l e 5 - a c y l d e r i v a t i v e s (XC) were administered I.P. to mice as suspensions the pro-drugs d i s solved s l o w l y , g r a d u a l l y r e l e a s i n g XC to the c i r c u l a t i o n where the d e r i v a t i v e s were enzymatically cleaved to LXXXIX a l l o w i n g i t to exert i t s pharmacological act i v i t y . Gray et a l . (258) demonstrated a q u a l i t a t i v e c o r r e l a t i o n between a c t i v i t y of the XC d e r i v a t i v e s and decreasing aqueous s o l u b i l i t y suggesting that the slow d i s s o l u t i o n of the suspension of the 5 - e s t e r s was important. The s l i g h t l y s o l u b l e e s t e r s such as the 5 p a l m i t a t e , 5'-stéarate, 5 -benzoate and 5 -adamantoate were p a r t i c u l a r l y impressive. The s l i g h t l y water s o l uble but s t e r i c a l l y hindered e s t e r , 2,4,6-trimethylbenzoate and the sulfonate e s t e r , 2 , 4 , 6 - t r i i s o p r o p y l benzene sulfonate were l e s s e f f e c t i v e than the parent compound, presumably because of t h e i r slower enzymatic cleavage to the parent compound. Probably the area i n which the greatest e f f o r t has been made to e f f e c t sustained or prolonged r e l e a s e act i v i t y v i a the pro-drug approach has been i n the area 1

f

f

f

f

f

f

1

In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

52

PRO-DRUGS

OH

H

(LXXXIX): (XC);

R = -H R = a c y l substituent

of s t e r o i d therapy. Recently Tanaka et a l . ( 2 6 3 ) have attempted to q u a n t i t a t e f a c t o r s which a f f e c t the prol o n g a t i o n of a c t i v i t y of drug i n j e c t e d I.M. i n o i l y s o l u t i o n s . James et a l . ( 2 6 4 ) showed that f o r a s e r i e s of testosterone (XCI) esters the b i o l o g i c a l h a l f l i f e f o r the r e l e a s e of testosterone and i t s esters from an I.M. o i l i n j e c t i o n was c l o s e l y r e l a t e d to the o i l / w a t e r d i s t r i b u t i o n c o e f f i c i e n t of the d e r i v a t i v e s . The o i l used by James ejb a l . ( 2 6 4 ) was e t h y l o l e a t e . I t was i n t e r e s t i n g to note that the homologous s e r i e s of f o r myl through v a l e r y l esters of testosterone had approximately equal s o l u b i l i t y i n the e t h y l oleate showing that the d i s t r i b u t i o n c o e f f i c i e n t was l a r g e l y determined by the decrease i n water s o l u b i l i t y . Apart from these i n t e r e s t i n g b a s i c s t u d i e s , the r e s u l t s of many workers have shown that longer duration of a c t i o n of testosterone from an I.M. i n j e c t i o n could be e f f e c t e d by a c y l a t i o n of the 173-hydroxy group ( 2 6 5 - 2 8 8 ) . Increasing chain length of the a c y l group e f f e c t i v e l y i n creased the d u r a t i o n of a c t i o n , i . e . , the testosterone esters are thought to gradually leach out of the I.M. i n j e c t i o n s i t e ( o i l based I.M. i n j e c t i o n ) , regenerate testosterone i n the general c i r c u l a t i o n which then exerts i t s androgenic a c t i v i t y ( 2 6 4 ) .

In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

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Overview and Definition

53

Miescher ert a l . ( 2 6 5 ) were the f i r s t t o promote the use of long chain esters o f testosterone as depot forms of testosterone. Ott et^ a l . ( 2 7 6 ) have suggest­ ed that the β-cyclopentylpropionate ester of t e s t o s ­ terone (XCII) i n j e c t e d I.M. i n cottonseed o i l was a superior ester form of testosterone when compared i n a s e r i e s of saturated and nonsaturated e s t e r s . This conclusion was based on the r e l a t i v e growth of seminal v e s i c l e s i n castrated r a t s a f t e r I.M. dosing of the various e s t e r s . S i m i l a r l y , Meier and Tschopp ( 2 8 4 ) using the growth of the capon c r e s t as an i n d i c a t o r , showed that the undecylenate e s t e r of testosterone (XCIII) was f a r superior i n d u r a t i o n of a c t i o n t o the propionate, i s o b u t y r a t e and η-valerate e s t e r s Voss (277) and Haack et OR

0· (XCI)

R

-H

(XCIII)

R

-COC H

(XCIV)

R

-C0CH C0C H

R

-C0C H

(XCVIII)

R

~

(XCIX)

R

(C)

R

(XCII) 10

o

21

n

(XCV) (XCVI)

o

1

(XCVII) C

O

C

6 i3 H

In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

54

PRO-DRUGS

ketonic esters of t e s t o s t e r o n e , e s p e c i a l l y t e s t o s t e r one decanoylacetate (XCIV). Dekanski and Chapman ( 2 7 3 ) f e l t that testosterone phenyl propionate (XCV) was as e f f e c t i v e as XCIÏ but was f a r superior t o the e a r l i e r promoted testosterone propionate (XCVI). D i c z f a l u s y et a l . ( 2 7 1 ) demonstrated the s u p e r i o r i t y of a s e r i e s of alkoxyhydrocinnamic a c i d esters of testosterone t o both XCV and XCVI. Para-heptyloxyhydrocinnamyltestosterone (XCVII), showing considerable a c t i v i t y over 90 days, appeared superior t o XCV and XCVI. The study of Junkmann and W i t z e l ( 2 6 7 ) i s the most comprehensive review of depot forms of t e s t o s t e r one and other s t e r o i d s . The enanthate (XCVIII), undecanoate ( X C I I I ) , and palmitat (XCIX) f terone a l l showed e x c e l l e n E v a l u a t i o n of various other esters of testosterone as depot forms of testosterone can be found ( 2 6 5 - 2 8 8 ) . I t i s i n t e r e s t i n g t o note that Kishimoto ( 2 8 9 ) has r e c e n t l y noted the presence of enzymes i n the CNS that are capable of s y n t h e s i z i n g f a t t y a c i d esters of t e s tosterone. McEwen et. a l . ( 2 9 0 ) have suggested that d i hydrotestosterone i s the a c t i v e form of testosterone. I t does appear that testosterone esters are l e g i t i m a t e pro-drugs of testosterone. However, because the major e v a l u a t i o n of t h e i r release c h a r a c t e r i s t i c s i s based on some pharmacological e f f e c t , some minor doubt does e x i s t as t o whether the esters are t r u l y pro-drugs. Junkmann and W i t z e l ( 2 6 7 ) document the various testosterone esters a v a i l a b l e commercially i n Europe. In the United S t a t e s , XCII, XCVI, XCVIII and t e s t o s terone phenylacetate (C) are a l l commercially a v a i l a b l e as depot forms of testosterone. Nandrolone (nortestosterone, CI) and various nandrolone d e r i v a t i v e s have a l s o been e s t e r i f i e d f o r the purpose of prolonging the a c t i o n of these anabolic agents a f t e r t h e i r S.C. or I.M. i n j e c t i o n i n an o i l v e h i c l e ( 2 9 1 - 2 9 5 * 2 6 7 * 2 7 1 ) « Nandrolone phenylpropionate (CII) and nandrolone decanoate (CIII) are both commerc i a l l y a v a i l a b l e . C I I I i s longer a c t i n g than C I I and i s administered monthly whereas C I I I i s administered weekly ( 2 9 6 ) . The longer a c t i v i t y of C I I I (myotrophic e f f e c t s as measured by seminal v e s i c l e growth i n r a t s ) with a s i n g l e 4 mg I.M. dose i n sesame o i l r e l a t i v e t o CII ( s i m i l a r l y administered) was demonstrated by de V i s s e r and Overbeek ( 2 9 5 ) . The a c t i o n of CII and the mechanisms of anabolic androgenic a c t i v i t y were l a t t e r discussed by van der Vies ( 2 9 5 ) · A q u a n t i t a t i v e s t r u c ture anabolic a c t i v i t y a n a l y s i s of a s e r i e s of nandrolone esters has r e c e n t l y been presented by Chaudry and James ( 2 9 4 ) while Pala et a l . ( 2 9 1 ) t e s t e d terpenoates

In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

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Overview and Definition

55

of nandrolone f o r anabolic a c t i v i t y . Depot forms (I.M. i n j e c t i o n i n an o i l v e h i c l e ) of other s t e r o i d s are a l s o quite common. The weekly use of dromostanolone propionate i n the treatment of breast carcinoma was discussed by Seay e_t a l . (297) · Long a c t i n g estrogenic s t e r o i d s u s e f u l i n the t r e a t ment of estrogen d e f i c i e n c y i n women has been a goal of many workers. D e r i v a t i v e s of e s t r a d i o l (CIV), such as the oligemeric d e r i v a t i v e s (CV longest a c t i n g der i v a t i v e ) of Kuhl ert a l . (298), p o l y e s t r a d i o l phosphate (CVI) of D i c z f a l u s y et a l . (299), e s t r a d i o l 3benzoate-17-cyclooctenyl ether (CVII) of P a l c o n i et a l . (300), 3- and/or 17-acyl d e r i v a t i v e s of e s t r a d i o l of F e r r i n (301), and others (302-310) were a l l shown to have prolonged estrogeni t r a t i o n . CVI was a l s treatment of p r o s t a t i c carcinoma. Prolonged release forms of dihydroxy progesterone f o r b i r t h c o n t r o l (acetophenide d e r i v a t i v e s ) have been found u s e f u l (311-313) while the caproate e s t e r of hydroxyprogesterone (Delalutin®) i s used as a long a c t i n g s t e r o i d i n amonorrhea (314). The use of desoxycorticosterone acetate and t r i methylacetate i n adrenal i n s u f f i c i e n c y (Addison's d i s ease) has proven s u c c e s s f u l (315) · Desoxycorticosterone t r i m e t h y l a c e t a t e (CIX, Percorten® p i v a l a t e ) has a very prolonged a c t i o n and should not be administered more than once a month (316). Long a c t i n g , pro-drug r e p o s i t o r y i n j e c t a b l e forms of c o r t i c o s t e r o i d s u s e f u l i n the treatment of i n f l a m mation are betamethasone acetate, methylprednisolone acetate (Depo-Medrol®), f l u o r o c o r t i s o n e acetate ( F l o r inef® a c e t a t e ) , hydrocortisone cypionate (Cortef®) and triamcinolone hexacetonide (Aristocort®), to name a few

(316).

Winter et a l . (317) found that the r e l e a s e of the parent s t e r o i d i n t o general c i r c u l a t i o n was a f u n c t i o n not only of the p h y s i c a l p r o p e r t i e s of the pro-drug ( a f f e c t i n g the r e l e a s e from the i n j e c t i o n s i t e ) but a l s o the chemical p r o p e r t i e s of the pro-drug ( a f f e c t ing the regeneration r a t e of s t e r o i d once released from the i n j e c t i o n s i t e ) . Fluphenazine (CX) d i h y d r o c h l o r i d e i s a drug usef u l i n the c o n t r o l of psychotic behavior and i s administered o r a l l y or by I.M. i n j e c t i o n (318.). Patient compliance with a n t i p s y c h o t i c drugs i s a r e a l problem (319). Fluphenazine enanthate (CXI) and fluphenazine decanoate (CXII) are fluphenazine esters given by I.M. i n j e c t i o n ( i n sesame o i l v e h i c l e ) which have prolonged a c t i v i t y f o r up to two and four weeks (318,320-324).

In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

(CVI): R = e s t r a d i o l molecule

In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

1.

STELLA

Overview and Definition

57

Depot forms of other n e u r o l e p t i c drugs e f f e c t e d by es­ t e r i f i c a t i o n (325-331) and I.M. dosing i n an o i l v e h i ­ c l e are α-fluphenthixol ( C X I I I ) , as i t s decanoate e s t e r (CXIV), and p i p o t h i a z i n e (CXV) as i t s palmitate (CXVI) and undecanoate esters (CXVII). The prolongation of n e u r o l e p t i c a c t i v i t y of CXIV i n Viscoleo® administered I.M. compared to CXIII dihyd r o c h l o r i d e was demonstrated by Nymark et^ a l . (325)· Figure 7 compares the i n h i b i t i o n of a c o n d i t i o n a l

TIME, (DAYS) Acta Pharmacologica et Toxicologica

Figure 7. Days after drug administration—single I.M. dose of CXIV in oil (Q) or CXIII oral daily ( · ) (325)

avoidance response a f t e r o r a l CXIII d i h y d r o c h l o r i d e administered once d a i l y (5 mg/Kg) to CXIV (10 mg/Kg) a f t e r a s i n g l e I.M. i n j e c t i o n i n o i l . Dreyfus et a l . (323) i n the case of CX e s t e r s , V i l l e n e u v e et a l . 1*327) i n the case of CXV e s t e r s , and Jorgensen et a l . (326) i n the case of CXIII esters were able to show that the metabolic p a t t e r n of the esters was i d e n t i c a l to those

In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

PRO-DRUGS

58

(CX):

R = -H

(CXI) (CXII): R = - C O C H n

(CXIII): R = -H (CXIV):

R = -COC H Q

C H CH C H / 2

2

\ c H CH 0 R

2

g

2

S0 N(CH ) 2

(CXV):

3

2

R = -H

(CXVI): R = - C O C (CXVII):

1 5

R = -C0C

H

i n

3 1

H

o l

In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

1.

59

Overview and Definition

STELLA

(CXIX) (CXX):

R = -COC H 15

31

of the parent compounds and that the a c t i v i t y of the e s t e r s appeared to be r e l a t e d to the formation of the parent n e u r o l e p t i c . Another p a r e n t e r a l r e p o s i t o r y pro-drug e f f e c t e d through e s t e r formation was O-palmitoylamodiaquine (CXX), a moderately s u c c e s s f u l depot form of amodiaquine (CXIX) (332). E l s l a g e r (333), i n h i s review of chemotherapy i n the treatment of m a l a r i a and i n p a r t i c ­ u l a r r e p o s i t o r y forms of a n t i m a l a r i a l drugs, discussed at great lengths v a r i o u s means by which the d u r a t i o n of a c t i o n of v a r i o u s a n t i m a l a r i a l agents could be extend­ ed. The two most i n t e r e s t i n g examples given were v a r i ­ ous a c y l a t e d and S c h i f f base forms of 4,4'-diaminodiphenylsulfone (LXXXVIII) and the use of s p a r i n g l y water s o l u b l e s a l t s of c y c l o g u a n i l (CXXI) and chloroguanide (CXXII). 4,4 -Diacetoamidodiphenylsulfone (CXXIII) was found to give a r e p o s i t o r y a n t i m a l a r i a l e f f e c t when i n ­ j e c t e d I.M. to P. berghei i n f e c t e d mice. However, CXXIII had poor a c t i v i t y i n r a t s . The poor a c t i v i t y i n r a t s was a t t r i b u t e d by Thompson (334) to the i n a b i l ­ i t y of r a t s to metabolize CXXIII to LXXXVIII whereas f

0 CH CHN-^/ 3

ν

(CXXIII)

In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

60

PRO-DRUGS

mice were able t o convert CXXIII t o LXXXVIII. CXXIII was found to be u s e f u l i n the treatment of P. f a l i c i ρarum i n humans f o r 42 days a f t e r a s i n g l e 3-25 mg/Kg I.M. i n j e c t i o n (333). As noted i n the s t e r o i d examples, the a b i l i t y of a drug t o leave an I.M. i n j e c t i o n s i t e i s h i g h l y depen­ dent on the s o l u b i l i t y of the drug i n p h y s i o l o g i c a l f l u i d s and i n the i n j e c t i o n v e h i c l e . I f the drug i s water i n s o l u b l e , an I.M. i n j e c t i o n of a suspension of the drug w i l l deposit i n the muscle and over a period of time gradually d i s s o l v e s , r e l e a s i n g the drug i n t o general c i r c u l a t i o n . The aqueous s o l u b i l i t y of any amine s a l t i s dependent on the counter anion with the s o l u b i l i t y equal t o the square root of the s o l u b i l i t y product of the s a l t the s a l t i s h i g h l y p dependent

Cl

(CXXII)

Ç1

(CXXI)

The poor i n v i t r o a c t i v i t y of chloroguanide (CXXII) compared to i t s good i n v i v o a c t i v i t y suggested that CXXII was metabolized i n the body t o an a c t i v e metabolite (335-340). This a c t i v e metabolite was found to be c y c l o g u a n i l (CXXI) which has a short d u r a t i o n of a c t i o n because of r a p i d e x c r e t i o n (333)> Various spari n g l y water soluble s a l t s of CXXII were found t o be poor r e p o s i t o r y forms of CXXII but the pamoate s a l t of CXXI (CXXIV) with an aqueous s o l u b i l i t y of 0.03 mg/ml at pH 7 was found t o be e f f e c t i v e against P. berghei i n i n f e c t e d mice f o r up t o 8 1/2 weeks when given S.C.

In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

1.

Overview and Definition

STELLA

61

(333). Figure 8 shows a p l o t of the logarithm PMW, the estimated weeks 50% of the mice were protected from challenge w i t h P. b e r g h e i against logarithm S, the s o l u b i l i t y of various s a l t s of CXXI. The s o l i d l i n e i s s

ο oc a

tu H ϋ LU I-

Ο- S Ui Ο

£ .

2 ω ο

χ ce Lu

g * X

Lu LU

LU

8"

|i CO Lu

Figure 8. Plot of log PMW vs. log (solubility) for a series of CXXI salts. Plotted from the data of ElsUger (333). In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

62

PRO-DRUGS

(CXXIV) the l e a s t squares l i n e described by equation 1. l o g PMW

= -0.71

+ 0.11

l o g S + 0.077

The (eq.

1)

c o r r e l a t i o n c o e f f i c i e n t was 0 . 9 0 6 . As i s r e a d i l y apparent, the l e s s water s o l u b l e s a l t s gave the greater r e p o s i t o r y e f f e c t s confirming that the r a t e determining step i n the r e l e a s e of CXXI from the S.C. i n j e c t i o n of 400 mg/Kg equivalent of CXXI was the d i s s o l u t i o n of the sparingly soluble s a l t s . For a comprehensive review of r e p o s i t o r y s a l t , est e r and amide forms of various other a n t i m a l a r i a l s , the reader i s d i r e c t e d to the review by E l s l a g e r (333)> a s e r i e s of papers by E l s l a g e r et a l . ( 3 3 2 , 3 4 1 - 3 4 4 ) , and the references t h e r e i n . Recently naloxone (CXXV), used as a n a r c o t i c ant a g o n i s t , was found to be very potent but e f f e c t i v e f o r only three to four hours i f administered p a r e n t e r a l l y (238-241). Levine et a l . (346) found that by g i v i n g I.M. i n j e c t i o n s of a.suspension of naloxone pamoate (CXXVI) a sustained r e l e a s e a c t i o n was seen which blocked the e f f e c t of opiates without harmful side e f f e c t s f o r up to 72 hours. Use of s p a r i n g l y s o l u b l e a c i d s a l t s to e f f e c t sustained r e l e a s e a f t e r I.M. pare n t e r a l a d m i n i s t r a t i o n w i t h a number of other amines such as streptomycin (347*348) dihydrostreptomycin (347)s naltrexone (349TT~eyelazocine ( 3 5 0 ) , and others (351) have proven to be r a t h e r s u c c e s s f u l . Thompson and Hecht (352) prepared and demonstrated the sustained

In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

1.

STELLA

Overview and Definition

63 r

r e l e a s e of cyanocobalamine (CXXVII) or v i t a m i n B^2 ? om cyanocobolamine zinc tannate (CXXVIII). Figure 9 shows the serum l e v e l s of CXXVII a f t e r I.M. i n j e c t i o n of 500 \ig of CXXVII i n normal s a l i n e compared to serum l e v e l s of CXXVII from a molar equivalent amount of CXXVIII.

ol

0

»

3

«

»

ι

I

I

I

I

I

Li

6

9

12

15

18

21

24

27

30

DAY

AFTER INJECTION American Journal of Clinical Nutrition

Figure 9. CXXVII serum levels in humans after I.M in­ jection of 500 mg of CXXVII ( · ) and a molar equivalent amount of CXXVIII (Q) (352)

P a r e n t e r a l l y sustained r e l e a s e of a c i d substances such as p e n i c i l l i n has s i m i l a r l y been e f f e c t e d by the use of s p a r i n g l y soluble s a l t s of p e n i c i l l i n such as benzathine and procaine p e n i c i l l i n (7-11). The spar-

In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

64

PRO-DRUGS

i n g l y soluble protamine z i n c i n s u l i n might a l s o be considered as a chemical m o d i f i c a t i o n u s e f u l i n e f f e c t i n g sustained r e l e a s e (353) of i n s u l i n . Attempts to produce sustained r e l e a s e or prolonged a c t i o n medication f o r o r a l a d m i n i s t r a t i o n by the use of s p a r i n g l y water s o l u b l e s a l t s have been m a r g i n a l l y succ e s s f u l . Quinidine polygalacturonate does produce a prolonged r e l e a s e q u i n i d i n e on o r a l a d m i n i s t r a t i o n (345). The marginal success of these types of products stems from the f a c t that the minimum s o l u b i l i t y (or maximum s t a b i l i t y ) of the s a l t s occurs around n e u t r a l i t y . Because the GI t r a c t has a wide spectrum of pH (from the strong a c i d of the stomach to the s l i g h t l y a l k a l i n e lower i n t e s t i n e ) f th comple s a l t ( i n c l u d i n g r e s i n s ) ten r a p i d l y than the e q u i l i b r i u y (or r e s i n s ) might i n d i c a t e . Marginal prolonged r e l e a s e e f f e c t s were noted with codeine r e s i n a t e ( 3 5 4 ) and amphetamine r e s i n a t e (355)» M i l l e r et a l . ( 3 5 6 ) i n a c l i n i c a l study appeared to confirm that a" s i n g l e 75 nig dose of imipramine pamoate was t h e r a p e u t i c a l l y equival e n t to d i v i d e d doses of 25 mg three times a day of imipramine hydrochloride. Other examples are amphetamine tannate ( 3 5 7 ) * p y r a n t e l pamoate ( 3 5 8 , 3 5 9 ) * pamoates ( 3 6 0 ) , tannâtes (351) and résinâtes ( 3 6 1 , 3 6 2 ) of various amine drugs. An i n t e r e s t i n g study by Loucas and Haddad (363) demonstrated that p i l o c a r p i n e a l g i n a t e , a s p a r i n g l y water s o l u b l e s a l t of p i l o c a r p i n e , when a p p l i e d as s o l i d f l a k e s to the cul-de-sac of the eye could e f f e c t the prolonged release of p i l o c a r p i n e . Another i n t e r e s t i n g prolonged r e l e a s e pro-drug i s t r i a c e t i n (CXXIX), a dermal d e l i v e r y form of the f u n g i s t a t i c agent a c e t i c a c i d ( 3 6 4 ) . The d i r e c t percutaneous a p p l i c a t i o n of a c e t i c acid i s too c o r r o s i v e and short a c t i n g while CXXIX g r a d u a l l y releases a c e t i c a c i d i n noncorrosive q u a n t i t i e s . Dimethylol urea (CXXX) and 3 - m e t h y l o l - 5 , 5 - d i methylhydantoin (CXXXI) are two prolonged r e l e a s e forms of the s k i n d i s i n f e c t a n t formaldehyde (CXXXII). Both drugs, when a p p l i e d dermally, g r a d u a l l y release CXXXII (364,365).

The use of polyethylene g l y c o l d e r i v a t i v e s (CXXXIII) of procaine (CXXXIV) by Weiner and Z i l k h a ( 3 6 6 ) to prolong the l o c a l anesthetic a c t i o n of dermall y a p p l i e d procaine was s u c c e s s f u l . CXXXIII and the equivalent d e r i v a t i v e with PEG 400 showed a slower onset of a c t i o n but an increase i n d u r a t i o n of a c t i o n . The r e s u l t s were c o n s i s t e n t with CXXXIV being the act i v e agent r a t h e r than the i n t a c t CXXXIII.

In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

1.

STELLA

65

Overview and Definition

CH 0C0CH I CH-OCOCEL CH OCOCH o

o

2

3

2

-> CH COOH (FUNGISTATIC AGENT) 3

3

(CXXIX)

HOCH NHCNHCH OH 2

2

(CXXX)

H(?H

i n vivo

H 3

CH π—c I ΗΝ

(CXXXII)

3

C= 0 1 N—CH OH 2

Τ Ο (CXXXI)

RCO(CH CH 0) CR 2

2

i|

R = —NH—ν

(CXXXIII)

Ο (H C ) NCH CH OC 5

2

2

2

2

('

ν

M

COCH CH N(C H ) 2

2

NH

2

(CXXXIV)

In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

2

5

2

66

PRO-DRUGS

E s t e r i f i c a t i o n of i n s e c t r e p e l l e n t dihydroxyacetone increased the d u r a t i o n a c t i o n of t h i s dermally app l i e d product ( 3 6 7 ) * Garner et a l . ( 3 6 7 ) suggested that the i n t a c t e s t e r s may have some a c t i v i t y of t h e i r own and may not be a c t i n g as pro-drugs. The Use of Pro-Drugs to Increase the Aqueous S o l u b i l i t y of a Drug to Allow f o r E i t h e r D i r e c t Aqueous I.V. or I.M. I n j e c t i o n , or Opthalmic D e l i v e r y As we have already seen, many drugs possess very poor aqueous s o l u b i l i t y which o f t e n leads to l i m i t e d o r a l b i o a v a i l a b i l i t y . S i m i l a r l y , many drugs on o r a l dosing undergo " f i r s t " metabolism P a r e n t e r a l ad m i n i s t r a t i o n of drug travenously or i n t r a m u s c u l a r l y y advantages (a) allows r a p i d blood l e v e l s of the drug to be obt a i n e d . This i s e s p e c i a l l y u s e f u l i n emergency t r e a t ments; (b) e f f i c i e n t d e l i v e r y of the drug, e s p e c i a l l y f o r drug t e s t i n g ; and (c) allows d e l i v e r y of a drug when o r a l therapy i s not f e a s i b l e . A number of s p a r i n g l y water s o l u b l e drugs are adm i n i s t e r e d i n mixed organic/aqueous v e h i c l e s . I.M. i n j e c t i o n s of chlordiazepoxide ( 3 6 8 ) , diazepam ( 3 6 9 - 3 7 0 ) * and sodium diphenylhydantoin ( 3 7 1 - 3 7 5 ) administered i n propylene glycol/water v e h i c l e s have shown delayed abs o r p t i o n due to p r e c i p i t a t i o n of the administered drug at the i n j e c t i o n s i t e . The delayed absorption w i t h sodium diphenylhydantoin (I.M. dosing) l e d to increased seizure r a t e s i n t r e a t e d p a t i e n t s ( 3 7 ^ ) · As discussed e a r l i e r , s t e r o i d s are a group of compounds w i t h poor aqueous s o l u b i l i t y . Adrenal c o r t i c o s t e r o i d s such as betamethasone, dexamethasone, hydroc o r t i s o n e , methylprednisolone and prednisolone are a l l a v a i l a b l e commercially as water s o l u b l e sodium phosphate esters or sodium hemisuccinate e s t e r s . These soluble c o r t i c o s t e r o i d s are used i n emergency treatment of b r o n c h i a l asthma ( s t a t u s asthmaticus), acute adrenal c o r t i c a l i n s u f f i c i e n c y , a l l e r g i c drug r e a c t i o n s and are given i n t r a a r t i c u l a r l y or i n t r a s y n o v i a l l y i n the t r e a t ment of j o i n t inflammation. The water s o l u b l e prodrugs (CXXXV as sodium phosphate, or CXXXVI as sodium succinate) regenerate the parent s t e r o i d i n v i v o ( 3 7 9 ) » CXXXV regenerates the parent s t e r o i d v i a a c i d and a l k a l i n e phosphatase enzymes while CXXXVI regenerates the parent s t e r o i d v i a esterase enzymes. Lange and S t e i n ( 3 7 6 ) synthesized other water s o l uble d e r i v a t i v e s of s t e r o i d s such as amino a c i d carbamates (CXXXVII). However, these d e r i v a t i v e s were found to be e i t h e r i n a c t i v e or poorly a c t i v e .

In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

1.

STELLA

67

Overview and Definition

R-P-OH (β

Na®

(CXXXV)

i n vivo

R

v

Na ( CXXXVI

where R = c o r t i c o s t e r o i d molecule Although prednisolone hemisuccinate sodium s a l t (CXXXIX) i s the current commercially a v a i l a b l e water s o l u b l e form of prednisolone (CXXXVIII), other water s o l u b l e d e r i v a t i v e s such as prednisolone-21-m-sulfobenzoate sodium s a l t (XCLI) and prednisolone-21-disodium phosphate (XCL) have a l s o been synthesized and t e s t e d (377-379). S i m i l a r l y , methylprednisolone sodium s u c c i ­ nate (316,380), hydrocortisone-21-phosphate (379,381), -21-succinate (316,379*381-382), -21-aminoalkylcarboxyl a t e s (383), -21-m-sulfobenzoates (384) , and -21-sulf a t e s (384), dexamethasone sodium phosphate (316,379)* betamethasone disodium phosphate (316) have been syn­ t h e s i z e d and found to be water s o l u b l e , p a r e n t e r a l l y b i o a v a i l a b l e forms of the parent s t e r o i d s . The succinate e s t e r s of the various s t e r o i d s are u s e f u l but s u f f e r somewhat from s t a b i l i t y problems, i . e . , the drug must be s u p p l i e d as a l y o p h i l i z e d powder f o r r e c o n s t i t u t i o n (316). Flynn et. a l . (385)> i n d i s ­ cussing the s o l v o l y s i s and f a c t o r s a f f e c t i n g the s t a ­ b i l i t y of corticosteroid-21-phosphate e s t e r s , s t a t e s that " a d d i t i o n a l l y , some types of phosphate e s t e r s are s u f f i c i e n t l y s t a b l e to allow the f o r m u l a t i o n of s o l u ­ t i o n s with p r a c t i c a l s h e l f - l i v e s . " Another added ad­ vantage of phosphate e s t e r s as opposed to the succinate esters i s t h e i r very r a p i d conversion to the parent s t e r o i d . Melby et a l . (379) i n a very i n t e r e s t i n g study showed that I.M. administered hydrocortisone-21phosphate ( X C L I I ) , (XCL), dexamethasone-21-phosphate (XCLIII) and I.V. administered XCLII a l l produced higher plasma l e v e l s of the parent s t e r o i d than the corresponding 21-succinate e s t e r s , (see Figure 10).

In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

68

PRO-DRUGS

ο 0 RCNHCH CCP

Κ®

(CXXXVII):

R = various s t e r o i d molecules

2

CH 0R C=0 -OH o

(CXXXVIII): R (CXXXIX): R (XCL): R

-COCH CH COO° 2

-PO ®

Na®

2

χ

2Na®

(XCLI): R = so

u

3

v

Na

I t was suggested by Melby ejb a l . (379) that the 21-suc­ cinate esters underwent metabolism at other points i n the molecule before d e - e s t e r i f i c a t i o n . This could oc­ cur i f d e - e s t e r i f i c a t i o n was slow r e l a t i v e to other metabolic processes. The 21-phosphates, on the other hand, undergo r a p i d dephosphorylation r e l e a s i n g the parent s t e r o i d . Although Melby elb a l . s (379) data does not suggest i t , another p o s s i b l e mechanism i s that the 21-succinate might be excreted unchanged. The ac­ t i v e e l i m i n a t i o n of a c i d i c drugs such as p e n i c i l l i n and p r o b e n i c i d have been shown to occur (386) . Sandman et a l . (387»388) i n studying the aqueous s t a b i l i t y of chloramphenicol succinate (XCLIV), a water soluble pro-drug of chloramphenicol (XCLV) s u i t a b l e f o r I.V., I.M. and opthalmic d e l i v e r y of chloramphenicol, noted an unusual p a r t i a l a c y l t r a n s f e r r e a c t i o n (see scheme IX) of the s u c c i n y l group to give a c y c l i c hemiortho ester (XCLVI). A s i m i l a r r e a c t i o n may a l s o po­ t e n t i a l l y occur f o r hydrocortisone (see Scheme X). f

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1.

STELLA

Overview and Definition

69

XCLIX, i f formed, would be more s t a b l e , i . e . , would not be subjected to esterase a c t i v i t y , and might be e l i m i nated or metabolized v i a other pathways.

250

TIME (minutes) Metabolism

Figure 10. Mean 17,21 -dihydroxy-20-oxosteroids in plasma following I.M. injection of XCLII ( · ), LV. injection of XCLII (•), I.M. injection of hydrocortisone-21 succinate (0)> &nd LV. injection of hydrocortisone-21succinate (•), in a dose of lmg/kg of body weight in humans (379)

The estrogenic s t e r o i d , d i e t h y l s t i l b e s t e r o l (CL), may be given I.V. as i t s diphosphate e s t e r (CLI) d i s o dium s a l t i n the treatment of p r o s t a t i c carcinoma. However, the o r i g i n a l synthesis of CLI was not done with the i n t e n t i o n of obtaining a water s o l u b l e form of CL but to help l o c a l i z e CL i n the carcinoma c e l l s by u t i l i z i n g the high a c i d and a l k a l i n e phosphatase l e v e l s (389-397) i n carcinoma c e l l s to e f f e c t p r e f e r e n t i a l uptake of CL. Water soluble g l y c i n e esters of CL have

In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

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PRO-DRUGS

0 Il

0 Ν·A

I I 2 ΟΗΝΗ i C=0 I CHC1

2

ο

HΘ Φ 2 2

0

(XCLIV)

i n vivo

CH CH COO* Na 2

2

6

CHCHCH 0H I I 2 OHNH I c=o I CHC1 o

^CH I

NH I

0

(XCLV)

CHC1 (XCLVI)

Scheme IX

(XCLVIII)

(XCLIX)

Scheme X

In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

0

1.

STELLA

71

Overview and Definition

a l s o been synthesized (398.). Hydroxydione (CLII) i s a water i n s o l u b l e b a s a l anesthetic that may be given I.V. (398) as i t s sodium succinate d e r i v a t i v e ( C L I I I ) . 0

(CLII) : R = -H ( C L I I I ) : R = -COCH CH COO Na 0

2

2

As stated e a r l i e r , chloramphenicol (XCLV), a s l i g h t l y water s o l u b l e a n t i b i o t i c , cannot be used d i ­ r e c t l y f o r I.V., or I.M. i n j e c t i o n or f o r l o c a l s o l u ­ t i o n a p p l i c a t i o n as eye/ear drops. Glazko ejt a l . (399) overcame t h i s problem by s y n t h e s i z i n g the sodium s a l t of chloramphenicol monosuccinate (XCLIV). XCLIV can be given I.V./I.M. as a r e c o n s t i t u t e d i n j e c t a b l e and i s reasonably q u a n t i t a v e l y converted to XCLV and s u c c i n i c a c i d (399) by esterase a c t i v i t y present i n plasma (400-402). Adenine arabinoside (CLIV), an an­ t i v i r a l , c y t o t o x i c agent whose low aqueous s o l u b i l i t y prevented i t s use i n small volume I.V. p r e p a r a t i o n s , was s o l u b i l i z e d by p r e p a r a t i o n of the 5'-formate e s t e r (CLV) (see paper by Dr. Repta). LePage et a l . (403.) prepared the 5 -phosphate (CLVI) of CLIV. However, CLVI may undergo deamination before regenerating CLIV which may l i m i t i t s usefulness (4θ3»4θ4). Oxazepam (CLVII), a minor t r a n q u i l i z e r and a c t u a l ­ l y a metabolite of diazepam (405-408), has been s o l u ­ b i l i z e d as oxazepam sodium succinate ( C L V I I I ) . CLVIII i s a pro-drug of CLVII with favorable p h y s i c a l proper­ t i e s f o r I.V. or I.M. a d m i n i s t r a t i o n (409-413). An i n t e r e s t i n g side l i n e to t h i s work i s that the number 3 carbon of CLVII i s an o p t i c a l l y a c t i v e center and the two p o s s i b l e isomers of CLVIII have been shown t o regenerate CLVII at d i f f e r i n g r a t e s (410). The d i f f

In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

72

PRO-DRUGS

(CLIV) (CLV): R = -COH 9

(CLVI) : R = -P0 H Na' o

(CLVII): R = -H 8

(CLVIII): R = -COCHgCHgCOoSla

f e r i n g r a t e s were also found t o be a f u n c t i o n of the p a r t i c u l a r animal species i n which the regeneration was studied (410). Recently S t e l l a and Higuchi (4l4) synthesized and demonstrated the p o s s i b l e usefulness of 3 N ,N -diethylaminoethyl-5-methyl-2,2-ethylphenylhydantoate (CLIX) as a water s o l u b l e pro-drug of mephenytoin (CLX). CLIX i s converted to CLX under p h y s i o l o g i c a l c o n d i t i o n s without enzyme mediation. C u r r e n t l y the only i n j e c t able anticonvulsant hydantoin a v a i l a b l e i s sodium d i phenylhydantoin which, due to i t s a l k a l i n i t y , has many unwanted side e f f e c t s (415). A d e r i v a t i v e of 5,5-diphenylhydantoin s i m i l a r to CLIX w i l l be reported by S t e l l a et a l . l a t e r . t

i

3

In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

1.

STELLA

73

Overview and Definition

B i o r e v e r s i b l e chemical m o d i f i c a t i o n of drug mole­ cules t o increase the aqueous s o l u b i l i t y o f a compound has a l s o been u t i l i z e d i n s o l u b i l i z i n g menadione, e i t h e r as i t s b i s u l f i t e adduct, i t s disodium diphos­ phate e s t e r , or i t s carboxymethoxime d e r i v a t i v e ( 4 l 6 4 l 8 ) , tetrahydrocannabinol as a s e r i e s of b i f u n c t i o n a l esters (419-421), and α-methydopa as i t s e t h y l ester (422) .

HN\

H

5

(CLIX) in vivo/in vitro

-c=o

HC5

2

ΗΝ

Ν—CH^ II

0 (CLX)

The Use of Pro-Drugs t o Lower the T o x i c i t y of a Drug A drug may e x h i b i t t o x i c i t y i f i t accumulates s e l e c t i v e l y i n some t i s s u e or organ and i n t e r a c t s with some receptor i n the organ thus e l i c i t i n g a r e a c t i o n which i s not n e c e s s a r i l y the desired pharmacological r e a c t i o n . Any drug-receptor i n t e r a c t i o n w i l l be depen­ dent on the amount of drug reaching the receptor and i t s time p r o f i l e i n contact with the receptor. As stated e a r l i e r , "peak" and " v a l l e y " e f f e c t s of m u l t i p l e dosing might r a i s e the concentration of a drug i n the plasma above i t s t o x i c l e v e l o r , at the end of i t s

In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

74

PRO-DRUGS

c y c l e (before the next dose i s g i v e n ) , the plasma l e v e l may drop below the therapeutic l e v e l . For these r e a sons, a sustained r e l e a s e or prolonged release form of a drug may be d e s i r a b l e to narrow the d i f f e r e n c e seen between the "peaks" and " v a l l e y s . " I f a pro-drug w i t h i n t r i n s i c a l l y lower t o x i c i t y i s designed to regenerate the parent compound slowly (the equivalent to slow absorption) the t o x i c i t y of the parent compound might be lowered. A few i n t e r e s t i n g , although c o n t r o v e r s i a l , and perhaps marginal examples of t h i s phenomena do e x i s t . The agent 5,5-ethylphenylhydantoin (CLXI), was used as an a n t i c o n v u l s a n t . I t was removed from the market because of t o x i c i t y and i n i t s place mephenytoin (CLX) was promoted (423) i s N-demethylated t althoug out t o x i c i t y i t i s s t i l l used i n the treatment of p e t i t mal s e i z u r e s (423)» The known a c t i v i t y of CLX, which does not i n v o l v e any l a g time, i s c o n s i s t e n t with CLX maintaining some anticonvulsant a c t i v i t y of i t s own. S i m i l a r l y primacolone (primidone, CLXII) was promoted as a nontoxic anticonvulsant u s e f u l i n the t r e a t ment of grand mal s e i z u r e s (424). S p e c i f i c a l l y , i t was f e l t that i t might replace phenobarbitone ( C L X I I I ) . I t has since been found that CLXII i s m e t a b o l i c a l l y o x i d i z e d to CLXIII both i n humans and animals (426-428). Kutt (425) i n a recent review of pharmacodynamic and

y

•NH .NH (CLXII)

(CLXIII)

In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

OH

1.

STELLA

Overview and Definition

75

pharmacokinetic measurements of a n t i e p i l e p t i c drugs states that CLXIII plasma l e v e l s a f t e r chronic admini s t r a t i o n of CLXII are 1.5-3 times higher than the CLXII l e v e l s . This i s c o n s i s t e n t with the slow e l i m i n a t i o n of CLXIII. Even though the long term a n t i e p i l e p t i c e f f e c t s of CLXII might be a t t r i b u t e d to i t s m e t a b o l i t e , CLXIII, i t does appear that CLXII and another metabolite phenylethylmalonamide have a n i t e p i l e p t i c a c t i v i t y of t h e i r own (425)* Another drug whose t o x i c i t y appears r e l a t e d to i t s t i s s u e d i s t r i b u t i o n i s the c y t o t o x i c agent adriamycin (CLXIV). The c a r d i o t o x i c i t y of CLXIV has been w e l l est a b l i s h e d . Arcamone et a l . (429) synthesized and showed the change i d i s t r i b u t i o i mic hear t i s s u e a f t e r the a d m i n i s t r a t i o tanoate (CLXV). CLXV was shown to have comparable c y t o x i c a c t i v i t y to CLXIV. A f t e r CLXV dosing of t r i tium l a b e l l e d compound, CLXV showed greater amounts of r a d i o l a b e l l e d m a t e r i a l i n lungs, l i v e r , and spleen r e l a t i v e to CLXIV dosed animals, but lower amounts of r a d i o l a b e l l e d m a t e r i a l s were seen i n the heart and kidney. Probably the area of drug t o x i c i t y which has been given the greatest a t t e n t i o n and f o r which the pro-drug approach has o f t e n been used i s g a s t r i c i r r i t a t i o n . Drug induced g a s t r i c u l c e r a t i o n has been a recognized

OCH.

'3

0

OH 0

H

NH (CLXIV): R (CLXV): R

2

H

-H -COC^H

7"15

In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

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PRO-DRUGS

problem e s p e c i a l l y i n p a t i e n t s t r e a t e d f o r inflammatory diseases. S a l i c y l a t e s i n c l u d i n g a c e t y l s a l i c y l i c a c i d or a s p i r i n , as w e l l as s a l i c y l i c a c i d i t s e l f , have been known to induce g a s t r i c bleeding, u l c e r a t i o n and genera l GI i r r i t a t i o n (430-441). Attempts to modify s a l i c y l i c and a c e t y l s a l i c y l i c a c i d i r r i t a t i o n by the prodrug approach has a long h i s t o r y . None of the products studied appears to hold any great advantage over acet y l s a l i c y l i c a c i d e i t h e r i n a c t i v i t y or decreased gast r i c i r r i t a n t properties. However, p o t e n t i a l decreased g a s t r i c i r r i t a n t properties with the use of some of the pro-drugs have been claimed by some of t h e i r promoters (442-445).

Other s a l i c y l i benzoi a c i d e r i v a t i v e whic have shown g a s t r i c i r r i t a n c a l l y modified i n attempts to decrease t h e i r i r r i t a n t properties. The g l y c e r y l ester of N - a r y l a n t h r a n i l i c a c i d apparently has lower g a s t r i c i r r i t a n t p r o p e r t i e s than the parent compound (446), while various b i o r e v e r s i b l e d e r i v a t i v e s of n i c o t i n i c a c i d showed no advantage or showed marginal advantages over n i c o t i n i c a c i d (447-448).

A l l potent n o n s t e r o i d a l anti-inflammatory agents appear to e x h i b i t GI i r r i t a n t p r o p e r t i e s . Indomethicin (CLXVI) has been p a r t i c u l a r l y notorious. The a c i d i c p r o p e r t i e s of the anti-inflammatory agents and GI i r r i tants i n general suggest that the b i o r e v e r s i b l e b l o c k ing of the a c i d f u n c t i o n may lead to a decrease i n GI i r r i t a t i o n . This i s not to say that t h e i r i r r i t a n t mechanism of a c t i o n i s l o c a l because i t has been shown that p a r e n t e r a l a d m i n i s t r a t i o n of many of these agents does promote u l c e r a t i o n * However, i t also stands to reason that high l o c a l i z a t i o n i n the GI mucosa of these^ agents on o r a l a d m i n i s t r a t i o n can only help promote rapid ulceration. Glamkowski et_ al_. (449), although not s t a t i n g that t h e i r i n t e n t i o n was to bypass the g a s t r i c i r r i t a n t p r o p e r t i e s of CLXVI, tested the a c t i v i t y of the aldehyde analog of CLXVI. Using the canageenan-induced foot odema t e s t i n the r a t , the aldehyde analog (CXVII) was 0.6-0.7 times as a c t i v e as CLXVI. Subsequent a n a l y s i s of plasma showed that CLXVII gave s u b s t a n t i a l plasma l e v e l s of CLXVI presumably as a r e s u l t of oxidat i v e metabolism (see F i g u r e 11). Whether the lower CLXVI l e v e l s a f t e r CLXVII dosing i s due to incomplete absorption or incomplete metabolism i s u n c e r t a i n . The authors d i d not state whether any d i f f e r e n c e s i n GI i r r i t a n t p r o p e r t i e s between the two compounds e x i s t e d .

In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

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STELLA

Overview and Definition

77

Figure 11. CLXVI plasma level-time profile after administration of CLXVI (O) d CLXVII (·) at a dose of 10 mg/kg orally to rats. Plotted from the data of Glamkowski et al. (449) an

(CLXVI): R = -COOH (CLXVII): R =

-COH

In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

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PRO-DRUGS

Phenylbutazone (CLXVIII), another a c i d (carbon acid) n o n s t e r o i d a l agent, has been shown to be a GI i r r i t a n t . I t has yet to be e s t a b l i s h e d whether the 0trimethoxybenzoyl enol e s t e r of CLXVIII (CLXIX), which supposedly i s b e t t e r t o l e r a t e d and l e s s t o x i c than CLXVIII (450), or an a c y c l i c form of CLXVIII (CLXX), which i s p a r t i a l l y metabolized to CLXVIII (451-454), hold any great advantage over CLXVIII. C l o f i b r a t e or p-chlorophenoxyisobutyric a c i d e t h y l e s t e r (CLXXI) synthesized by Jones ejb a l . (455) was found to be u s e f u l as an antihypercholesteremic agent. I t i s g e n e r a l l y accepted that the corresponding a c i d , p-chlorophenoxyisobutyric a c i d (CLXXII), i s the pharmac o l o g i c a l l y a c t i v e specie (456) Th f th e t h y l e s t e r as opposed to pears r e l a t e d to the b e t t e r tolerance of CLXXI on pro longed a d m i n i s t r a t i o n (457). Oleandrin, a potent d i u r e t i c u s e f u l i n the t r e a t ment of cardiac i n s u f f i c i e n c y , was e s t e r i f i e d to i t s

0 II

(CLXIX)

Ca ++

2 (CLXX)

In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

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STELLA

Overview and Definition

79

acetate ester i n an attempt to lower i t s GI d i s t u r bance tendencies (458-459). Pain due to I.M. i n j e c t i o n i s a t o x i c i t y problem that has been associated with a number of compounds. Intramuscular i n j e c t i o n s of the a n t i b i o t i c , clindamycin, were found to be p a i n f u l but a phosphate ester prodrug of clindamycin on I.M. dosing (460-461) was p a i n l e s s . S i m i l a r l y chloramphenicol sodium succinate (399) and b i o r e v e r s i b l e oleandomycin d e r i v a t i v e s (168,172173) were l e s s i r r i t a t i n g on I.M. i n j e c t i o n than the parent compounds. Subcutaneous and I.M. i n j e c t i o n of i o n i c i r o n and c o l l o i d a l i r o n were found to be e i t h e r t o x i c or very p a i n f u l . Martin et a l (462) and others (463-466) found that i r o n administere (Imferon®) was w e l l low t o x i c i t y and i r r i t a t i o n , and was a s a t i s f a c t o r y hematinic agent. Complexes of i r o n with s o r b i t a l (467) have also proven s u c c e s s f u l . Terrato et a l . (468-470) have studied o r a l i r o n absorption from complexes with low molecular weight noncarbohydrate polymers and shown that the absorption i s enhanced i n the presence of these c h e l a t i n g agents. In the body, i r o n i s stored as the complex f e r r i t i n and i s transported i n combination with the p r o t e i n B - g l o b u l i n . The use of polysaccharide molecules such as dextran, e t c . , was an attempt to simulate the n a t u r a l l y occurring macromolecules as a transport medium f o r i r o n . Two general examples where the pro-drug approach has l e d to a reduction i n t o x i c i t y but where the mechanisms are not understood are amphotericin methyl est e r (CLXXIII) and the e t h y l ester of p r o s t a g l a n d i n . Bonner et a l . (471) tested both the a c t i v i t y and t o x i c i t y of a s e r i e s of polyene a n t i b i o t i c esters and found that the t o x i c i t y of the esters was much lower than the t o x i c i t y of the parent compounds. Amphotericin (CLXXIV) i s administered as a large volume I.V. c o l l o i d suspension. The z w i t t e r i o n i c nature of CLXXIV i s a t t e s t e d to by i t s low water s o l u b i l i t y at n e u t r a l pH and i n c r e a s i n g s o l u b i l i t y below pH 2 and above pH 11 (472) . CLXXIII i s water soluble at n e u t r a l pH a l l o w i n g i t to be administered as true s o l u t i o n . The t o x i c i t y of the o r i g i n a l c o l l o i d a l CLXXIV may have been due to the I.V. a d m i n i s t r a t i o n of p a r t i c u l a t e matter. The a c t i v i t y of CLXXIII versus CLXXIV, against C. a l b i c a n s i n f e c t e d mice was e s s e n t i a l l y i d e n t i c a l . The e t h y l est e r s of prostaglandins are claimed by Anderson et a l . (473) to lead to a decrease i n diarrhea associated with prostaglandin a d m i n i s t r a t i o n .

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The Use of Pro-Drugs to Overcome Problems of Poor Patient Acceptance of a Product The commercial p o t e n t i a l of a product might be judged i n terms of a) i t s a b i l i t y to cure or suppress some diseased s t a t e more s u c c e s s f u l l y than agents curr e n t l y a v a i l a b l e , and b) the p o t e n t i a l market produced by that disease. However, a c r i t i c a l c o n s i d e r a t i o n often overlooked i s a p a t i e n t acceptance f a c t o r . P a i n f u l i n j e c t i o n s might be a deterrent to the use of a drug, e s p e c i a l l y i f m u l t i p l e dosing i s r e q u i r e d . An a n t i b i o t i c might be extremely b i t t e r t a s t i n g making i t s u i t able f o r dosing i n a capsule or coated t a b l e t but uns u i t a b l e f o r a p e d i a t r i suspensio chewabl t a b l e dosage form. Poor p a t i e n p e c i a l l y with p e d i a t r i c and p o s s i b l y g e r i a t r i c prod u c t s , can often be a deterrent f a c t o r f o r commercializ a t i o n of a product f o r that segment of the population. Chloramphenicol (XCLV) i s an example of a u s e f u l drug which, although s p a r i n g l y water s o l u b l e , had an unpleasant b i t t e r t a s t e . Various d e r i v a t i v e s of XCLV such as i t s palmitate e s t e r (CLXXV) were synthesized and t e s t e d f o r t a s t e acceptance and t h e i r a b i l i t y to d e l i v e r XCLV (474-476) on o r a l dosing. Other s p a r i n g l y soluble XCLV d e r i v a t i v e s have been synthesized i n an e f f o r t to overcome the t a s t e problem (477-479). Because of the s p a r i n g l y water soluble nature of CLXXV, i t presented a number of o r a l b i o a v a i l a b i l i t y problems that were overcome by the use of a metastable polymorph of CLXXV and the c a r e f u l screening of p a r t i c l e s i z e e f f e c t s (480). Glazko et a l . (475,481) i n t h e i r studies of the b i o a v a i l a b i l i t y of XCLV from CLXXV noted some unusual r e s u l t s . I t might seem that CLXXV should be p a r t i a l l y absorbed as such and be converted to XCLV both i n the GI t r a c t and plasma but no CLXXV was found i n plasma. Recently Andersgaard et_ a l . (482) noted that the d i s s o l u t i o n of CLXXV from p a r t i c l e s was c a t a lyzed by pancreatic l i p a s e and that on d i s s o l u t i o n XCLV was r e l e a s e d . S u r p r i s i n g l y the pancreatic l i p a s e d i d not catalyze the conversion of CLXXV to XCLV i n the bulk phase s o l u t i o n . The authors postulate that the pancreatic l i p a s e i s a c t u a l l y adsorbed onto the CLXXV p a r t i c l e and a c t u a l l y catalyzes a s o l i d s t a t e hydrolys i s of the ester to i t s corresponding a c i d and a l c o h o l fractions. A question that probably should be asked i s why does a drug t a s t e b i t t e r ? B i t t e r n e s s r e s u l t s from a compound d i s s o l v i n g i n the s a l i v a of the mouth and i n t e r a c t i n g with a b i t t e r t a s t e receptor. Molecular t h e o r i e s on the cause of sweet and b i t t e r t a s t e have

In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

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appeared i n the l i t e r a t u r e and w i l l not be discussed here (483-485). The general method of overcoming a bitter taste i n a pharmaceutical has i n v o l v e d e i t h e r a f o r m u l a t i o n technique, i . e . coated t a b l e t , use of capsules, or prep a r a t i o n of a b i o r e v e r s i b l e , l e s s water s o l u b l e d e r i v a t i v e of the drug. CLXXV was one example of the l a t t e r technique. The lowering of the water s o l u b i l i t y does not block the drug-receptor i n t e r a c t i o n but simply prevents the drug from ever reaching the r e c e p t o r . I f the molecular theory of sweet and b i t t e r receptors i s accepted, simply b l o c k i n g the e l e c t r o p h i l i c or nucleop h i l i c s i t e of i n t e r a c t i o n should s u f f i c e . Other examples of pro-drugs used to overcome t a s t e problems are the p a l m i t a t discussed f u r t h e r b s a l t of erythromycin (486), the e t h y l s u c c i n a t e and e t h y l carbonate e s t e r s of erythromycin ( 1 7 8 , 1 7 9 ) , phosphate and carbonate e s t e r s of lincomycin ( 4 8 7 - 4 8 9 ) , a c y l e s t e r N-oxide oleandomycin ( 4 9 0 ) , and the t r i a c e t y l e s t e r of oleandomycin which was l e s s s o l u b l e and therefore l e s s b i t t e r than oleandomycin ( 1 6 8 , 1 7 2 - 1 7 3 ) . N - A c e t y l s u l f i s o x a z o l e (Lipogantrisin®) and N - a c e t y l sulfamethoxypyridazine (Kynex®) were two t a s t e l e s s der i v a t i v e s of s u l f i s o x a z o l e and sulfamethoxypyridazine s u i t a b l e as p e d i a t r i c suspensions ( 4 9 1 ) . The 3 , 4 , 5 trimethoxybenzoate s a l t of t e t r a c y c l i n e was a l s o found f

f

to be t a s t e l e s s

(492).

The unpleasant t a s t e of acetaminophen (CLXXVI) has prevented i t s use i n a chewable t a b l e t f o r m u l a t i o n f o r p e d i a t r i c p a t i e n t s . Repta and Hack ( 4 9 3 ) prepared 2 (p-acetaminophenoxy)tetrahydropyran (CLXXVII), a prodrug of CLXXVI, which was shown to have a lower water s o l u b i l i t y than CLXXVI and i s r e a d i l y converted to CLXXVI under a c i d i c c o n d i t i o n s . A s e r i e s of 0 - a c y l and O-carbonate e s t e r s of CLXXVI as pro-drugs of CLXXVI were evaluated by D i t t e r t et a l . ( 4 9 4 - 4 9 8 ) . Their obj e c t i v e d i d not appear to be the blockage of CLXXVI's t a s t e problem. C h l o r a l hydrate (CLXXVIII), a hypnotic, was l i m i t e d i n i t s use by an unpleasant, b i t t e r t a s t e and odor as w e l l as f o r m u l a t i o n problems (to be d i s cussed f u r t h e r i n the next s e c t i o n ) . Various d e r i v a t i v e s of CLXXVIII have been attempted to overcome the t a s t e and odor problems. One example was d i c h l o r a l phenazone (CLXXIX), a molecular complex between CLXXVIII and phenazone ( 4 9 9 ) . A l t e r n a t i v e l y CLXXVIII i s considered to be a precursor (a pro-drug) of t r i chloroethanol (CLXXX), a high b o i l i n g point c o r r o s i v e l i q u i d ( 5 0 0 ) . S o l i d pro-drugs of CLXXX have been promoted ( 4 9 7 , 4 9 8 , 5 0 1 , 5 0 2 ) , i n c l u d i n g t r i c l o r p h o s (CLXXXI),

In Pro-drugs as Novel Drug Delivery Systems; Higuchi, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

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