Molecular Design for Enhancement of Ocular Penetration

Shirasaki, Yoshihisa

doi:10.1002/jps.21200

Cited by 88 publications

(68 citation statements)

References 141 publications

(152 reference statements)

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“…But inadequate accessibility of targeted ocular tissues after oral administration often requires high drug doses that cause unwanted systemic side effects. Examples are acetazolamide and ethoxzolamide, carbonic anhydrase inhibitors, and antiglaucoma drugs that have been discontinued due to their systemic toxicity (Kaur et al, 2002;Shirasaki, 2008).…”

Section: Discussionmentioning

confidence: 99%

Expansion of First-in-Class Drug Candidates That Sequester Toxic All-Trans-Retinal and Prevent Light-Induced Retinal Degeneration

et al. 2014

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All-trans-retinal, a retinoid metabolite naturally produced upon photoreceptor light activation, is cytotoxic when present at elevated levels in the retina. To lower its toxicity, two experimentally validated methods have been developed involving inhibition of the retinoid cycle and sequestration of excess of all-trans-retinal by drugs containing a primary amine group. We identified the first-in-class drug candidates that transiently sequester this metabolite or slow down its production by inhibiting regeneration of the visual chromophore, 11-cis-retinal. Two enzymes are critical for retinoid recycling in the eye. Lecithin:retinol acyltransferase (LRAT) is the enzyme that traps vitamin A (all-trans-retinol) from the circulation and photoreceptor cells to produce the esterified substrate for retinoid isomerase (RPE65), which converts all-trans-retinyl ester into 11-cis-retinol. Here we investigated retinylamine and its derivatives to assess their inhibitor/substrate specificities for RPE65 and LRAT, mechanisms of action, potency, retention in the eye, and protection against acute light-induced retinal degeneration in mice. We correlated levels of visual cycle inhibition with retinal protective effects and outlined chemical boundaries for LRAT substrates and RPE65 inhibitors to obtain critical insights into therapeutic properties needed for retinal preservation.

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Section: Discussionmentioning

confidence: 99%

Expansion of First-in-Class Drug Candidates That Sequester Toxic All-Trans-Retinal and Prevent Light-Induced Retinal Degeneration

et al. 2014

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“…When it comes to molecular design of ophthalmic drug, the focus should be on the specificity and capacity of these non-P450 enzymes. One of the examples is the prodrug approach that successfully exploits esterases in ocular drug design (Shirasaki, 2007).…”

Section: P450 Mrna Expression In Human Ocularmentioning

confidence: 99%

Drug Transporter and Cytochrome P450 mRNA Expression in Human Ocular Barriers: Implications for Ocular Drug Disposition

Zhang

Xiang²,

Gale³

et al. 2008

Drug Metab Dispos

133

125

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ABSTRACT:Studies were designed to quantitatively assess the mRNA expression of 1) 10 cytochrome P450 (P450) enzymes in human cornea, iris-ciliary body (ICB), and retina/choroid relative to their levels in the liver, and of 2) 21 drug transporters in these tissues relative to their levels in human small intestine, liver, or kidney. Potential species differences in mRNA expression of PEPT1, PEPT2, and MDR1 were also assessed in these ocular tissues from rabbit, dog, monkey, and human. P450 expression was either absent or marginal in human cornea, ICB, and retina/choroid, suggesting a limited role for P450-mediated metabolism in ocular drug disposition. In contrast, among 21 key drug efflux and uptake transporters, many exhibited relative expression levels in ocular tissues comparable with those observed in small intestine, liver, or kidney. This robust ocular transporter presence strongly suggests a significant role that transporters may play in ocular barrier function and ocular pharmacokinetics. The highly expressed efflux transporter MRP1 and uptake transporters PEPT2, OCT1, OCTN1, and OCTN2 may be particularly important in absorption, distribution, and clearance of their drug substrates in the eye. Evidence of cross-species ocular transporter expression differences noted in these studies supports the conclusion that transporter expression variability, along with anatomic and physiological differences, should be taken into consideration to better understand animal ocular pharmacokinetic and pharmacodynamic data and the scalability to human for ocular drugs.

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“…3,4 Furthermore, the eye possesses specific defense mechanisms, such as lacrimation, tear dilution, and tear turnover, which can reduce the residential time of a drug solution to 5-6 minutes in the precorneal space after topical administration, with only 1%-3% of the solution ultimately penetrating into the cornea and reaching the intraocular tissues. 5,6 This low penetration after topical application is primarily because drug entry into the ocular globe is restricted predominantly by corneal barrier functions, which serve to protect the anterior ocular segment, and by the conjunctival-scleral barrier, which 6028 li et al serves to protect the intermediate and posterior segments.…”

Section: Introductionmentioning

confidence: 99%

Positively charged micelles based on a triblock copolymer demonstrate enhanced corneal penetration

Li¹,

Li²,

Zhou³

et al. 2015

IJN

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Purpose The cornea is a main barrier to drug penetration after topical application. The aim of this study was to evaluate the abilities of micelles generated from a positively charged triblock copolymer to penetrate the cornea after topical application. Methods The triblock copolymer poly(ethylene glycol)-poly(ε-caprolactone)- g -polyethyleneimine was synthesized, and the physicochemical properties of the self-assembled polymeric micelles were investigated, including hydrodynamic size, zeta potential, morphology, drug-loading content, drug-loading efficiency, and in vitro drug release. Using fluorescein diacetate as a model drug, the penetration capabilities of the polymeric micelles were monitored in vivo using a two-photon scanning fluorescence microscopy on murine corneas after topical application. Results The polymer was successfully synthesized and confirmed using nuclear magnetic resonance and Fourier transform infrared. The polymeric micelles had an average particle size of 28 nm, a zeta potential of approximately +12 mV, and a spherical morphology. The drug-loading efficiency and drug-loading content were 75.37% and 3.47%, respectively, which indicates that the polymeric micelles possess a high drug-loading capacity. The polymeric micelles also exhibited controlled-release behavior in vitro. Compared to the control, the positively charged polymeric micelles significantly penetrated through the cornea. Conclusion Positively charged micelles generated from a triblock copolymer are a promising vehicle for the topical delivery of hydrophobic agents in ocular applications.

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Molecular Design for Enhancement of Ocular Penetration

Cited by 88 publications

References 141 publications

Expansion of First-in-Class Drug Candidates That Sequester Toxic All-Trans-Retinal and Prevent Light-Induced Retinal Degeneration

Expansion of First-in-Class Drug Candidates That Sequester Toxic All-Trans-Retinal and Prevent Light-Induced Retinal Degeneration

Drug Transporter and Cytochrome P450 mRNA Expression in Human Ocular Barriers: Implications for Ocular Drug Disposition

Positively charged micelles based on a triblock copolymer demonstrate enhanced corneal penetration

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