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`OVERVIEW, BASIC PRINCIPLES AND METHODOLOGY
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`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.
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`MICELLAR SOLUBILIZATION
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`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
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`Innopharma EX1021, Page 3
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