Delay in ICR/f Rat Lens Opacification by the Instillation of Eye Drops Containing Disulfiram and Hydroxypropyl-.BETA.-cyclodextrin Inclusion Complex

2014

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Tranilast (TL), an antiallergic agent, has been clinically used in the treatment of bronchial asthma, although its clinical use has been limited by its poor solubility in water, photodegradation and systemic side effects. In this study, we prepared a gel ointment containing TL nanoparticles (TL nano gel ointment), and investigated its usefulness. In addition, we demonstrated the preventive effects of the TL nano gel ointment on inflammation in adjuvant-induced arthritis (AA) rats. The TL nano gel ointment was prepared using Bead Smash 12 (a bead mill) and additives including sodium docusate, 2-hydroxypropyl-β-cyclodextrin, methylcellulose and Carbopol 934; the mean particle diameter of the TL nanoparticles was 71.0 25.4 nm. In in vitro skin penetration experiments, the amount of penetrated TL, the penetration rate (J c ) and the penetration coefficient through the skin (K p ) of the TL nano gel ointment were significantly higher than those of a gel ointment containing TL microparticles (TL micro gel ointment; particle diameter 50.5 26.3 µm). The TL concentrations in the skin tissue and plasma of rats receiving the TL nano gel ointment were also higher than in rats receiving the TL micro gel ointment. In addition, the application of the TL nano gel ointment attenuated the increase in paw edema of the hind feet of AA rats in comparison with AA rats treated with the TL micro gel ointment. These results suggest that TL nanoparticles can be applied to the formulation of a transdermal system, and that a transdermal formulation using TL nanoparticles might be a delivery option for the clinical treatment of RA.

Section: Discussionmentioning

confidence: 99%

Therapeutic Effects of Gel Ointments Containing Tranilast Nanoparticles on Paw Edema in Adjuvant-Induced Arthritis Rats

2014

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“…17) On the other hand, we also showed that a development of the DSF eye dropscontaininghigherthan0.5%wasimportantforstrongly inhibition of the lens opacification. However, high concentration of 2-hydroxypropyl-β-cyclodextrin need to prepare the solution containing high DSF amount (12% HPβCD need to preparethe1.4%DSFsolution),andthehighconcentrationof HPβCDcausetheirritationtocornea.…”

Section: Ddc Pharmacokinetics In Lens Following the Instillation Of Omentioning

confidence: 51%

“…We preciously prepared a 2-hydroxypropyl-β-cyclodextrin (HPβCD) solutioncontainingDSF(DSFsolution),andfoundthatitsinstillationdelayedlensopacificationinarecessive-typehereditary cataractous strain of rats (ICR/f and UPL rats). [17][18][19][20] In addition, we reported that the induction of inducible nitric oxide synthase (iNOS) via nuclear factor-kappa B (NF-κB) produces excessive nitric oxide (NO), and that this excessive NO causes enhanced lipid peroxidation and a decrease in cytochrome c oxidase in the lenses of hereditary cataractous strains of rats during cataract development. 18,19) The enhanced lipid peroxidation and decrease in cytochrome c oxidase lead to a decrease in Ca 2+ -ATPase function, resulting in lens opacification via the enhancement of Ca 2+ content in the lens.…”

Section: -5)mentioning

confidence: 99%

“…18,19) The ophthalmic formulation containing DSF has the ability to attenuate the expression of iNOS, resulting in a delay in cataract development. [17][18][19][20] Furthermore, we designed a high quality suspension containing DSF nanoparticles (nano-DSF suspension), and showed that the corneal penetration and corneal residence time of DSF from this nano-DSF suspension were significantly higher than from a regular DSF solution (conventional eye drops). 15) In this study, we investigate the changes in drug contents in the lenses of rats instilled with the DSF solution andnano-DSFsuspension.…”

Section: +mentioning

confidence: 99%

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An Ophthalmic Formulation of Disulfiram Nanoparticles Prolongs Drug Residence Time in Lens

Mano

2016

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Disulfiram (DSF) is a dimer of diethyldithiocarbamate (DDC) that we previously added to a solution of 2-hydroxypropyl-β-cyclodextrin (DSF solution). We found that the instillation of this DSF solution delayed lens opacification in a hereditary cataractous ICR/f rat. In this study, we attempted to design an ophthalmic formulation containing DSF nanoparticles for use as a lens targeted drug delivery system (nano-DSF suspension), and investigated the changes in drug content in the lens after the instillation of DSF solution or nano-DSF suspension. The nano-DSF suspension was prepared by a bead mill method to yield a mean particle size of nano-DSF of 181 nm. Following the instillation of 1.4% DSF solution or the nano-DSF suspension, DDC was detected only in the aqueous humor and lens; in both, the area under the curve (AUC) and mean residence time (MRT) for the nano-DSF suspension were higher than for the DSF solution. In addition, we found that the DDC residence time in the cortex and nucleus of the lens was higher than in the capsule-epithelium. Although DDC was not detected in the cortex and nucleus of lenses following the instillation of the 1.4% DSF solution, the instillation of a 1.4% nano-DSF suspension led to the accumulation of DDC in both areas. In conclusion, it is possible that the instillation of a nano-DSF suspension can supply more DDC into the aqueous humor and lens than a conventional formulation, and these findings provide information significant for the prevention of cataracts and the design of a lens targeted drug delivery system. Key words nanoparticle;lens;disulfiram;drugdeliverysystem;cataractCataracts are the leading cause of treatable blindness worldwide, and cataract surgery and intraocular drugs have been used as therapy. However, the availability of cataract surgery andintraoculardrugsisnotsufficientindevelopingcountries, and WHO has reported cataracts as the main cause of low vision in the many developing countries.1) Based on this background, the design and improvement of anti-cataract eye drops is very important.Eye drops comprise the major ophthalmic preparation, and their use is both convenient and safe. However, a high level of transcorneal penetration following the instillation of eye drops is necessary for drug delivery into the lens. Furthermore, the concentration of drugs administered as eye drops is dilutedtoapproximately20%bylacrimalfluids.2) In addition, the drops are lost from the tear film within 0.5-2min, with eye drop components excreted through the nasolacrimal duct into the mouth, 2) with a small amount remaining associated with the conjunctival tissue.2) Therefore, with traditional eye drops, only small amounts of the administered drug actually penetrate the cornea to reach the desired lens tissue due to corneal barriers and dilution caused by lacrimal fluids. 3-5)In an attempt to overcome these problems, several strategies have been devised using microparticles, viscous solutions and hydrogels. 3,[6][7][8][9][10] Recently, it has been reported that drug penetration ac...

“…17) In a previous study, we prepared a HPβCD solution containing DSF and HPMC (DSF eye drops), and found that the instillation of these DSF eye drops delayed lens opacification in ICR/f rats, a recessive-type hereditary cataractous strain. 18,19) Therefore, it is possible that the antioxidant effect of DSF eye drops may provide a means to prevent or delay the formation of cataracts, and so it is very important to increase the efficacy of DSF eye drops. In this study, we attempted to enhance the delay effect of cataract development of DSF eye drops using low-substituted methylcellulose (MC, METOLOSE SM-4).…”

mentioning

confidence: 99%

Pharmacokinetic and Pharmacodynamic Evaluation of the Anti-cataract Effect of Eye Drops Containing Disulfiram and Low-Substituted Methylcellulose Using ICR/f Rats as a Hereditary Cataract Model

Takeuchi

2012

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We attempted to develop anti-cataract eye drops using disulfiram (DSF) and low-substituted methylcellulose (MC), and evaluated their anti-cataract effect in terms of the lens opacification vs. age-profile curves using a one-exponential equation. The eye drops were prepared using 0.5% DSF and 2% MC (DSF eye drops), and ICR/f rats, a recessive-type hereditary cataractous strain, were used as the experimental model. Gelation of DSF eye drops containing MC was first observed at about 35°C, close to body temperature. In in vivo transcorneal penetration experiments using rabbit corneas, only diethyldithiocarbamate (DDC) was detected in the aqueous humor, while DSF was not detected. The DDC penetration level of DSF eye drops containing MC was approximately 1.3-fold higher than that of DSF eye drops. The opacification rate constant (k) of ICR/f rat instilled with DSF eye drops with or without MC was lower, and the initial time of opacification (τ) was longer than those of ICR/f rats instilled with saline. Furthermore, the k of ICR/f rats instilled with DSF eye drops with MC was lower than that of ICR/f rats instilled with DSF eye drops without MC. In conclusion, the analysis of kinetic parameters including k and τ using a one-exponential equation provided useful information for clarifying the anti-cataract effect of eye drops. ICR/f rats instilled with DSF eye drops using a low-substituted MC-based drug delivery system demonstrated a delay in cataract development, probably resulting from an increase in the retention of DSF eye drops on the cornea. Key words cataract; disulfiram; methylcellulose; 2-hydroxypropyl-β-cyclodextrin; ICR/f rat A cataract is defined as any alteration in the optical homogeneity of the lens or decrease in its transparency, 1,2) and numerous factors have been implicated in the etiology of cataracts including genetic factors, diabetes, smoking, nutrition, the cumulative effect of X-rays, UV irradiation, and alterations in both endocrine and enzymatic equilibria.2-7) In human senile cataracts, an ionic imbalance in the lens with increased levels of Ca 2+ is related to cataract development. ; however, no potent anti-cataract drugs have yet to be introduced due to uncertainties regarding efficacy and safety.Disulfiram (DSF), a dimer of diethyldithiocarbamate (DDC), has long been used to treat alcoholic syndrome without severe side effects.11) DSF is a powerful antioxidant that scavenges reactive oxygen species including hydroxyl radicals, superoxide, and peroxynitrite, and chelates metal ions in rats.12,13) However, its application in the ophthalmic field is limited due to its poor water solubility. One problem with lipophilic drugs, such as DSF, administered as aqueous eye drops is obtaining the desired drug concentration in any drug delivery system. Cyclodextrins are cyclic oligosaccharides comprising R-D-glucose linked by R-(1-4) glucosidic bonds. The potential use of natural cyclodextrins and their synthetic derivatives has been studied extensively to improve certain properties such as their solub...