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`
`OCULAR
`THERAPEUTICS
`
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`
`'
`
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`
`AND
`DRUG
`DELIVERY
`
`A EWULTI-DISCIPLINARY APPROACH
`
`Edited by
`Indra K. Reddy, Ph.D.
`
`Associate Professor of Pharmaceutics
`College of Pharmacy and Health Sciences
`Northeast Louisiana University
`
`
`
`P ETECHNOMIC:
`
`qgusaurxao co _|NC J
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`I A:’\'CA.‘-3'TER - B.—\_SF.I
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`Innopharma EX1033, Page 1
`Innopharma EX1033, Page 1
`
`
`
`Pharmacy: Library
`University of "-!‘-‘i<‘c.rJn3'!n — Madison
`
`2”I.3..’=
`.‘
`."¥{-L fir‘: Hall
`425 N l.Jl";;».‘:'.'E€,-I” Street
`Madison, WI 53706-1508
`
`Ocular 'I‘I1erapeutics and Drug Delivery
`aTECHNOMIC‘Euh1im:mn
`
`Published’ in the Wesrem Hemrkpkere by
`Technomic Publishing Company, Inc.
`SSI New Holland Avenue. Box 3535
`Lancaster. Pennsylvania 17604 U.S.A.
`
`Distributed in the Rest of the Hbrld by
`Technornic Publishing AG
`Missionsstrasse 42:
`CH-4055 Basel. Swiizerland
`
`Copyright ©1996 by Technomic Publishing Company. Inc.
`All righls reserved
`
`No part of Ibis publicaiion may be reproduced, stored in a
`retrieval system. or transmitted.
`in any four: or by any means.
`electronic. mechanical, photooopyirlg. recording, or olherwise.
`without the prior written permission of the publisher.
`
`Prinlead in the United States of America
`[0 9 8
`1" 6 5 4 3 2E
`
`Main entry under title:
`Ocular Therapeutics and Dmg Delivery: A MLIlti—Discipli1'Iary Approach
`
`A Technomic Publishing Company book
`Bibliography: p.
`Includes index p. 575
`
`"I
`
`Library of Congress Catalog Card No. 95-6(I?09
`
`ISBN No-
`
`I-566%”-~213-8
`
`Innopharma EX1033, Page 2
`Innopharma EX1033, Page 2
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`
`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].
`This is mainly because various compounds have different transcellular
`pathways for penetration. Low molecular weight alcohols and ionized
`forms of drugs such as piloearpine [72], cromolyn sodium [73] and sul-
`fonamides [74] penetrate through less common 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 of hydrolysis of esters ofprodrugs.
`Therefore, enzymatieally susceptible straight chain alkyl esters penetrate
`more easily as compared to less susceptible branched chain alkyl esters of
`same lipophilieity. That is the reason why an esterase inhibitor decreases
`the corneal penetration of 0—butyryltimolol, 1’-methylcyclopro-
`panolytimolol and 0-pivaloyltimolol by 30, 50 and 80% respectively [75].
`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 rnieelle concentra-
`
`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-
`propylene block copolymers, are also gaining a lot of attention due to their
`nontoxic nature. Different drugs behave differently when they are solubi-
`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-
`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 juxtamernbrane 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
`Innopharma EX1033, Page 3
`Innopharma EX1033, Page 3
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`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-
`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
`m0sm-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 conjunctiva] 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-
`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
`m0sm-kg" are irritating to the eye |'89—92]. The original osrnolality 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-
`tion of efficient ocular dosage forms and delivery systems. Many interfacial
`
`Innopharma EX1033, Page 4
`Innopharma EX1033, Page 4
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`_T
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`390
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`FORMULAT1ON AND DRUG DELIVERY CONSIDERATIONS
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`liquid. Viscosity of a liquid can then be determined from the following
`expression:
`
`‘T1/112 = Qifn/Qzfz
`
`where 11., Q1. and :1 are viscosity, density; and the flow time of the solution
`and 11;, 9;, and 1‘; are the viscosity, density, and the flow time of the reference
`liquid.
`
`SUFIFACTANTS
`
`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, phenyl 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, polyoxyl 40 stearate, alkyl aryl polyether alcohol,
`polyoxypropylene-polyoxyethylenediol, and dioctyl sodium sulfosuc-
`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.
`Innopharma EX1033, Page 5
`Innopharma EX1033, Page 5