betadex and Ocular-Hypertension

L-Pyroglutamic acid (PGA) is an endogenous molecule derived from l-glutamate. We demonstrate the effects of PGA on intraocular pressure (IOP) in experimentally induced ocular hypertension in rabbits. In the in vitro and in vivo transcorneal penetration studies, the PGA solution (PGA in saline) did not penetrate the rabbit cornea. On the other hand, the penetration of PGA was improved by the addition of zinc chloride and 2-hydroxypropyl-β-cyclodextrin (HPCD), and PGA penetration was enhanced with increasing HPCD concentration. Therefore, PGA solutions containing 0.5% zinc chloride and 5% or 10% HPCD (PGA/HPCD(5% or 10%) eye drops) were used to investigate the effects for IOP in this study. An elevation in IOP was induced by the rapid infusion of 5% glucose solution (15 mL/kg of body weight) through the marginal ear vein or maintaining under dark phase for 5 h. In the both models, the induced elevation in IOP was prevented by the instillation of PGA/HPCD eye drops, and the IOP-reducing effect enhanced with increasing HPCD concentration in the drops. Nitric oxide (NO) levels elevated in the aqueous humor following the infusion of 5% glucose solution, and this increase was also suppressed by the instillation of PGA/HPCD eye drops. In conclusion, the present study demonstrates that the instillation of PGA/HPCD eye drops has an IOP-reducing effect in rabbits with experimentally induced ocular hypertension, probably as a result of the suppression of NO production.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Animals; Aqueous Humor; beta-Cyclodextrins; Cornea; In Vitro Techniques; Intraocular Pressure; Male; Nitric Oxide; Ocular Hypertension; Ophthalmic Solutions; Pyrrolidonecarboxylic Acid; Rabbits

We have studied the effect of disulfiram (DSF) solution containing 2-hydroxypropyl-beta-cyclodextrin and hydroxypropylmethylcellulose (DSF eye drops) on intraocular pressure (IOP) in experimentally induced ocular hypertension in rabbits. In both in vitro and in vivo transcorneal penetration experiments using rabbit corneas, only diethyldithiocarbamate (DDC) was detected in the aqueous humor, while DSF was not detected. The amount of DDC penetration for 0.25% DSF eye drops was about 4-fold that for 0.1% DSF eye drops in in vivo transcorneal penetration experiments. The elevation in IOP was induced by the rapid infusion of 5% glucose solution (15 ml/kg of body weight) through the marginal ear vein, and IOP was measured with an electronic tonometer. The induced elevation in IOP was reduced by the instillation of 0.1-0.5% DSF eye drops, and the IOP-reducing effect increased with the increase in DSF concentration in the drops. Nitric oxide (NO) levels increased in the aqueous humor following the infusion of the 5% glucose solution, and this increase was also suppressed by the instillation of DSF eye drops. In conclusion, the present study demonstrates that the instillation of DSF eye drops has an IOP-reducing effect in rabbits with experimentally induced ocular hypertension, probably caused by the suppression of NO production.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Animals; Aqueous Humor; beta-Cyclodextrins; Disulfiram; Intraocular Pressure; Male; Ocular Hypertension; Ophthalmic Solutions; Rabbits

Forskolin, a diterpene which displays a potent IOP-lowering activity in several animal species, is very poorly water soluble. This characteristic imposes the ocular administration of the drug as a suspension, a type of formulation which may present several preparative and biological disadvantages, such as e.g. difficulty of sterilization and poor bioavailability. The present report is concerned with an investigation on the solubilization of forskolin by some eye-compatible polymeric agents. While beta- and gamma-cyclodextrin were not particularly effective solubilizers, one polyoxyethylene-polyoxypropylene block copolymer (PluronicR F-127) increased 40 times the drug solubility in water (c. 120 mg/100 ml vs. c. 3 mg/100 ml). When tested on rabbits with artificially increased IOP, the Pluronic vehicle prolonged significantly the duration of the hypotensive activity of forskolin with respect to a standard 1.0% suspension of the drug. The potential of these alternative formulations for increasing the ocular bioavailability of forskolin is discussed.

Topics: Administration, Topical; Animals; beta-Cyclodextrins; Colforsin; Cyclodextrins; gamma-Cyclodextrins; Intraocular Pressure; Male; Ocular Hypertension; Poloxalene; Rabbits; Solubility; Solutions