Preparation of ophthalmic formulations containing cilostazol as an anti-glaucoma agent and improvement in its permeability through the rabbit cornea.

Abstract

To evaluate the pharmacological properties of cilostazol (CLZ), we examined its intraocular pressure (IOP) -lowering effect. CLZ is an inhibitor of Type III phosphodiesterase that increases intracellular cyclic AMP levels by restraining platelet aggregation, and has a potential protective effect against atherosclerosis. We attempted to apply it for use as an anti-glaucoma agent; however, the application of CLZ in the ophthalmic field is limited due to its poor water solubility. We attempted to enhance CLZ solubility using 2-hydroxypropyl-beta-cyclodextrin (HPbetaCD). The solubility of CLZ increased with increasing HPbetaCD concentrations, and 0.05% CLZ was dissolved in 10% HPbetaCD. Moreover, fine particle suspension of 0.5% CLZ in 5% HPbetaCD (soluble CLZ: ca. 0.027%) were prepared using a Microfluidizer, an impact-type emulsifying comminution device. In an in vitro transcorneal penetration experiment through the rabbit cornea, the CLZ penetration rate was dependent on the CLZ content of the solutions and suspensions. When a 0.05% CLZ ophthalmic solution was instilled into a rabbit eye, the absorption rate constant for CLZ into an aqueous humor was 0.0059+/-0.001 min(-1), and the elimination rate constant was 0.048+/-0.024 min(-1). Also CLZ ophthalmic solutions and fine particle suspension were examined to for their ability to reduce enhanced intraocular pressure (IOP) of rabbits in a darkroom. The instillation of 0.05% CLZ ophthalmic solutions and 0.5% CLZ fine particle suspensions into rabbit eyes reduced the enhanced IOP. These results demonstrate that the instillation of CLZ ophthalmic solutions and fine particle suspensions may represent an effective anti-glaucoma formulation.

• Authors: Norio Okamoto, Yoshimasa Ito, Noriaki Nagai, Takatoshi Murao, Yusuke Takiguchi, Takuji Kurimoto, Osamu Mimura
• Journal: Journal of oleo science (J Oleo Sci) Vol. 59 Issue 8 Pg. 423-30 ( 2010) ISSN: 1347-3352 [Electronic] Japan
• PMID: 20625234 (Publication Type: Journal Article)

Chemical References

• Antihypertensive Agents
• Ophthalmic Solutions
• Tetrazoles
• beta-Cyclodextrins
• 2-Hydroxypropyl-beta-cyclodextrin
• Cilostazol

Topics

• 2-Hydroxypropyl-beta-cyclodextrin
• Absorption (drug effects)
• Animals
• Antihypertensive Agents (administration & dosage, pharmacokinetics, pharmacology)
• Chemistry, Pharmaceutical (methods)
• Cilostazol
• Cornea (drug effects, metabolism)
• Drug Evaluation, Preclinical
• Glaucoma (drug therapy)
• Intraocular Pressure (drug effects)
• Male
• Ophthalmic Solutions (chemical synthesis, chemistry, pharmacokinetics)
• Osmolar Concentration
• Particle Size
• Permeability
• Rabbits
• Solubility (drug effects)
• Tetrazoles (administration & dosage, pharmacokinetics)
• beta-Cyclodextrins (pharmacology)