betadex and Glaucoma

Acetazolamide (ACZ), a carbonic anhydrase inhibitor (CAI), and other oral CAIs have been an integral part of antiglaucoma therapy for > 40 years. ACZ is used orally for the reduction of intraocular pressure in patients suffering from glaucoma. However, this treatment leads to unpleasant systemic side effects. The answer to the undesirable effects of ACZ is the topical delivery of this drug into the eye, where it could elicit its physiological action. However, the development of a topical formulation of ACZ is limited by its poor ocular bioavailability, which can be largely attributed to its poor penetration coefficient and poor biphasic solubility.. This review offers an overview of different approaches to delivering ACZ to the eye, highlighting the potential of the ternary system ACZ:HP-beta-CD:TEA as a tool for formulating aqueous ACZ eye drop solutions.. A critical analysis is provided to highlight the key issues to design formulations containing hydrophilic cyclodextrins.. The ACZ:HP-beta-CD:TEA complex is an important new approach to improve the ocular bioavailability of this drug. This approach may be applied to other CAIs in the future.

Topics: Acetazolamide; Administration, Topical; beta-Cyclodextrins; Carbonic Anhydrase Inhibitors; Cornea; Drug Design; Ethanolamines; Female; Glaucoma; Humans; Intraocular Pressure; Male

Preparation and evaluation of topical ophthalmic formulations containing nimodipine-CD complexes prepared using HP-β-CD, SBE-β-CD and M-β-CD for the management of glaucoma.. Nimodipine-CD complexes were prepared using a freeze-drying method. Two different molar ratios (NMD:CD) were used for each cyclodextrin. The inclusion complexes were characterized using DSC, FTIR, yield (%), drug content and in vitro release characteristics. NMD-CD complexes incorporated into chitosan eye drops and a temperature-triggered in situ gelling system were evaluated for their pH, viscosity and in vitro release characteristics. We determined the intraocular pressure (IOP) lowering effect of NMD-hydroxypropylmethylcellulose (HPMC) eye drops through a single dose response design using C57BL/6J mice. The minimum effective concentration (MEC) of nimodipine was further applied to mice that vary in the parental allele of Cacna1s, the drug target of nimodipine. Cytotoxicity was also evaluated.. Our ophthalmic formulations possessed pH and viscosity values that are compatible with the eye. In vitro release of nimodipine was significantly increased from chitosan eye drops containing NMD-CD complexes compared to uncomplexed drug. Administration of nimodipine can lower IOP significantly after a single drop of drug HPMC suspension. The IOP-lowering response of the MEC (0.6%) was significantly influenced by the parental allele of Cacna1s.. Nimodipine can be used as a promising topical drug for management of glaucoma through ocular delivery.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Administration, Ophthalmic; Animals; beta-Cyclodextrins; Chemistry, Pharmaceutical; Chitosan; Drug Liberation; Freeze Drying; Glaucoma; Hypromellose Derivatives; Intraocular Pressure; Mice, Inbred C57BL; Nimodipine; Ophthalmic Solutions

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.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Absorption; Animals; Antihypertensive Agents; beta-Cyclodextrins; Chemistry, Pharmaceutical; Cilostazol; Cornea; Drug Evaluation, Preclinical; Glaucoma; Intraocular Pressure; Male; Ophthalmic Solutions; Osmolar Concentration; Particle Size; Permeability; Rabbits; Solubility; Tetrazoles

Tenon's fibroblast (TF) bleb encapsulation is a common cause of filtering surgery failure. Various pharmacologic agents have been used in an attempt to inhibit this response. The effects of three angiogenesis inhibitors were studied. AGM-1470, a fumagillin analog and hydrocortisone 21-phosphate (HC21P) complexed with heparin or with the heparin analog beta-cyclodextrin tetradecasulfate (BCD-TDS) in modulating human tenon's fibroblasts in cell culture. It has been clinically demonstrated that well vascularized blebs are associated with a poorer prognosis. In addition to reducing bleb neovascularization, angiogenesis inhibitors may have an additional therapeutic role in decreasing fibroblast activity. Drug effects were assessed by studying cell growth rates by cell Coulter counting and rate of wound closure. TF's were grown in DMEM with 10% FBS and 1% PCN-strep with fungizone. Angiogenesis inhibitors were added to growth medium in varying concentrations: AGM-1470 alone, HC21P complexed with heparin and HC21P complexed with BCD-TDS. Controls were grown in control medium alone, medium with added ethanol, or with added BCD-TDS, heparin or HC21P. We found a dose related inhibition of cell growth with all of the angiogenesis inhibitor combinations, which was not seen in the control groups. Tenon's fibroblast proliferation was significantly inhibited by AGM-1470 as seen in the four higher concentrations (P < 0.05) with insignificant inhibition at the lowest concentration of AGM-1470 (P = 0.38). The heparin:HC21P and heparin:BCD-TDS combinations demonstrated significant inhibition at all concentrations (P < 0.05). Wound closure was significantly inhibited by all the added agents, except AGM-1470 and the controls. The rate of wound closure was significantly reduced by the highest concentrations of the heparin:HC21P and heparin:BCD-TDS combinations (P < 0.05), although it was not significantly affected by lower concentrations (P > 0.05). Rank order of potencies of these agents for inhibition of TF proliferation was AGM-1470, BCD-TDS:HC21P, heparin:HC21P, HC21P, while the rank order of potencies for these agents for inhibition of wound closure was HC21P, heparin:HC21P, BCD-TDS:HC21P, AGM-1470. These selected angiogenesis inhibitors appear to have marked inhibitory effects on TF proliferation and migration, which may have a potential clinical role in modulating wound healing associated with glaucoma filtering surgery.

Topics: beta-Cyclodextrins; Cell Division; Cells, Cultured; Cyclodextrins; Cyclohexanes; Dose-Response Relationship, Drug; Eye; Fibroblasts; Glaucoma; Humans; Hydrocortisone; Neovascularization, Pathologic; O-(Chloroacetylcarbamoyl)fumagillol; Sesquiterpenes; Time Factors; Wound Healing