te:. ·.-
`
`O CULAR
`T HERAPEUTICS
`AND
`DRUG
`DELIVERY
`A i\tlULTI-DISCIPLliVARY APPROACH
`
`Edited by
`I nd ra K. Reddy, Ph. D.
`Associate Professor of Pharmaceutics
`College of Pharmacy and Health Sciences
`Northeast Louisiana University
`
`--(cid:173)
`
`TECHNOMIC
`PUBLISHING CO.. INC
`I ,ANCASTER. BASEL
`
`LUPIN EX1021, Page 1
`
`

`
`Ph2rmacy Library
`University o,f 't'i"t:ons!n - Madison
`21 3: • <> .- . ··lcr!ln Hall
`425 N. i...;112rter Street
`Madison, WI 53706-1508
`
`Ocular Therapeutics and Drug Delivery
`a TECHNOMI CY,ublicat10n
`
`Published in the Western Hemisphere by
`Technomic Publishing Company, Inc.
`851 New Holland Avenue, Box 3535
`Lancaster, Pennsylvania 17604 U.S.A.
`
`Distributed in the Rest of the World by
`Technomic Publishing AG
`Missionsstrasse 44
`CH-4055 Basel, Switzerland
`
`Copyright © 1996 by Technornic Publishing Company, Inc.
`All rights reserved
`
`No part of this publication may be reproduced, stored in a
`retrieval system. or trnnsmitted, in any form or by any means,
`electronic, mechanical, photocopying, recording, or otherwise,
`without the prior written permission of the publisher.
`
`Printed in the United States of America
`m 9 s 7 6 5 4 3 2 1
`
`Main entry under title:
`Ocular Thernpeutics and Drug Delivery : A Multi-Disciplinary Approach
`
`A Technomic Publishing Company book
`Bibliography: p.
`Includes index p. 575
`
`Library of Congress Catalog Card No. 95-60709
`ISBN No. 1-56676-213-8
`
`LUPIN EX1021, Page 2
`
`

`
`42
`
`OVERVIEW, BASIC PRINCIPLES AND METHODOLOGY
`
`anilines [71]. There are some deviations from the parabolic relationship
`when drugs are of varied chemical structure and molecular weight [51] 0
`This is mainly because various compounds have different transcellular
`pathways for penetration. Low molecular weight alcohols and ionized
`forms of drugs such as pilocarpine [72], cromolyn sodium [73] and sul(cid:173)
`fonamides [74] penetrate through less co'mmon paracellular pathways.
`Enzymatic lability also influences the extent of penetration of prodrugs
`into the cornea. The penetration of aliphatic timolol esters across the cornea
`of rabbits shows enzymatic lability [70,75]. The rate of diffusion in the
`cornea increases with increase in the rate ofhydrolysis of esters of prodrugs.
`Therefore, enzymatically susceptible straight chain alkyl esters penetrate
`more easily as compared to less susceptible branched chain alkyl esters of
`same lipophilicity. That is the reason why an esterase inhibitor decreases
`the corneal penetration of 0-butyryltimolol, 1 '-methylcyclopro(cid:173)
`panolytimolol and 0-pivaloyltimolol by 30, 50 and 80% respectively [75] 0
`When prodrug of pilocarpine is administered to the tear film, it is envisioned
`that the controlling factor for corneal penetration is the formation of
`pilocarpine in the epithelium instead of its absorption into the epithelium or
`its diffusion across the stroma to the endothelium.
`
`MICELLAR SOLUBILIZATION
`
`Solubilization in surfactant solutions above the critical micelle concentra(cid:173)
`tion (CMC) offers a very good method to formulate dosage forms of poorly
`soluble drugs in water. Because of their relatively nontoxic nature, nonionic
`surfactants have been used most frequently for drug solubilization. A new
`class of nonionic surface active polymers, polyoxy-ethylene-polyoxy(cid:173)
`propylene block copolymers, are also gaining a lot of attention due to their
`nontoxic nature. Different drugs behave differently when they are solubi(cid:173)
`lized in a surfactant system. Some drugs get inactivated, whereas others
`show higher activity.
`The properties such as solubility, diffusion coefficient, and lipid-water
`partitioning coefficient of drug-penetration enhancer complexes may differ
`significantly from the properties of individual components, i.e., the proper(cid:173)
`ties of the free drug or penetration enhancer. This is mainly due to the
`formation of mixed micelles. Mixed micelles of bile salt and insulin provide
`a high juxtamembrane concentration of soluble insulin which results in high
`flow rate of insulin monomers from the nares (nostrils) into the nasal
`membranes [76]. The effects of various lipid-bile salt mixed micelles on
`intestinal absorption of streptomycin were reported using in situ closed-loop
`method in rats [77]. While mixed micelles composed of monoolein or
`unsaturated fatty acids markedly enhanced the absorption of streptomycin,
`saturated fatty acids caused only a small enhancement of absorption, and
`
`LUPIN EX1021, Page 3
`
`

`
`triolein, diolein, oleyl alcohol and methyl oleate had no enhancement effect
`on the absorption [77]. The difference in the enhancing effects of
`monoolein, unsaturated fatty acids and saturated fatty acids was not at(cid:173)
`tributed to the interaction or the absorbability of lipids, but rather, to the
`alteration of the mucosal membrane permeability. No observation has been
`reported in literature relating mixed micelles of ocular drug and drug
`enhancer to the drug permeability. However, the mixed micelles of base and
`salt form of tetracaine (a local anesthetic agent) have been shown to be
`transported across mouse skin most effectively [78,79].
`
`OSMOLALITY
`
`The osmolality of the lacrimal fluid is dependent on the number of
`dissolved ions and crystalloids. Proteins make a very small contribution to
`the total osmotic pressure of tears because of their molecular weight and
`low concentration [80]. The osmolality varies from 302 mOsm·kg- • to 318
`mOsm·kg-• in normal eye [81-83]. The osmolality of tears in the night
`during sleep varies from 280 to 293 mOsm· kg- • [84]. The osmolality varies
`across the ocular surface. The osmolality in the fluid of the tear strip is less
`than the osmolality in the conjunctival sac [85]. The osmolality of tear films
`is increased in the case of ocular surface diseases like dry-eye and in contact
`lens wearers after forty years of age [83, 86].
`When hypertonic solution is applied to the eye, water flow passes from
`the aqueous layer through the cornea to the eye surface [87]; whereas, in
`the case of hypotonic solution, the permeability of the epithelium is in(cid:173)
`creased considerably and water flows into the cornea [88].
`The osmotic pressure of the mixture of tears and instilled solution depends
`upon the osmolality of the instilled solution. Ophthalmic solutions which
`produce osmolality lower than 266 mOsm · kg-• or higher than 640
`mOsm·kg-• are irritating to the eye [89 - 92]. The original osmolality is
`achieved within 1 or 2 minutes after instillation of the nonisotonic solution
`depending on the drop size [93].
`
`CONCLUSION
`
`Although significant progress has been made in our understanding of
`ocular drug absorption and disposition over the last few years, ocular drug
`delivery by topical route is still considered to be primitive. This is because
`the physiological protective mechanisms of the eye in concert with the
`anatomical barrier, the cornea, prevent the free access of foreign substances
`including drugs to the inner eye.
`The surface chemical considerations are very important in the formula(cid:173)
`tion of efficient ocular dosage forms and delivery systems. Many interfacial
`
`LUPIN EX1021, Page 4
`
`

`
`390
`
`FORMULATION AND DRUG DELIVERY CONSIDERATIONS
`
`liquid. Viscosity of a liquid can then be determined from the following
`expression:
`
`where 7J1, Qt , and t1 are viscosity, density; and the flow time of the solution
`and 'f/2 , Q2 , and t2 are the viscosity, density, and the flow time of the reference
`liquid.
`
`SURF ACT ANTS
`
`Surfactants may be added to an ophthalmic preparation to solubilize or
`disperse the drug effectively. Nonionic surfactants are the most commonly
`used in ophthalmic preparations because of their lower incidence of toxic
`effects. However, their interaction with other adjuvants and packaging
`components must be carefully evaluated. Surfactants have also been shown
`to improve corneal permeability. Nonionic surfactants have been shown to
`cause an appreciable increase in the penetration of fluorescein into the
`aqueous humor in man [74]. The presence of surfactants may affect the
`efficacy of preservatives used. For example, the preservative activity of
`methyl paraben is considerably reduced by the presence of polysorbate 80
`[54]. Other preservatives such as chlorobutanol, pheny 1 ethanol and benzyl
`alcohol also interact with polysorbate 80, but to a considerably lesser extent
`than the parabens. The presence of an interaction between surfactants and
`preservatives does not necessarily mean that they cannot be used together.
`However, a knowledge of the extent and nature of such an interaction, and
`sufficient testing is necessary to develop an effective formulation. For
`potential toxicity reasons, the minimum possible quantity of surfactants
`must be used in ophthalmic formulations.
`One of the most commonly used surface-active agents in ophthalmic
`formulations is benzalkonium chloride. It is the surfactant of choice because
`of its anti-microbial activity. Other surfactants used are benzethonium
`chloride, polysorbate 20, polyoxyl40 stearate, alkyl aryl poly ether alcohol,
`polyoxypropylene-polyoxyethylenediol, and dioctyl sodium sulfosuc(cid:173)
`cinate.
`
`STABILIZING AGENTS
`
`If the drug molecule is susceptible to degradation by oxidation, stabilizers
`such as chelating agents or anti-oxidants are included in an ophthalmic
`formulation to improve the shelf-life of the product.
`
`LUPIN EX1021, Page 5