Study Of In Situ Forming Eye Gel Of Timolol Maleate

The poor bioavailability exhibited by conventional ophthalmic formulation due to the physiological constraints imposed by the protective mechanisms of the eye. The conventional ophthalmic formulation has many drawbacks, such as the drainage of drugs results in the reduction of the drug. Due to tear drainage, most of the administered dose passes via naso-lacrimal duct leads to side-effects and systemic effects. Rapid elimination of the eye drops administered often results in a short duration of the therapeutic effect making a frequent dosing regimen necessary. Frequent dosing regimen cause inconvenience to patients. As one of the important fields of controlled release, ophthalmic drug delivery has always received extensive interests. The sensitivity and protection mechanisms of the eye promote more effective drug delivery systems with better compliancy to be developed, however, the applications of numerous pharmaceutical methods are limited simultaneously, which presents great challenge in designing ophthalmic dosage forms. In situ forming eye gels refer to the polymer solutions can be administrated as liquid, which undergo a phase transition to a non-cross linked semisolid gel upon exposure to physiological environments. It showed great potential in ophthalmic application for its convenient administration combined with the favorable of solution and gels. In this thesis, Timolol maleate was selected as the model drug, and a series of relative researches were carried out, including development of in situ forming eye gels with modulated osmolality and pH, drug release, pharmacodynamics after the in situ forming eye gels applied topically, comparison with eye drops and such agents marketed abroad in pharmacodynamics and drug release.The in situ forming eye gels produced sustained drug release, substantially increased the bioavailability of the drug, and showed great potential in ophthalmic application.Objective: Timolol maleate was selected as the model drug, Gelrite was used as the gelling agent, to develop an ion-activated in situ forming eye gels. The formulation was evaluated for stability, in vitro release behavior, irritant, comparing the intraocular pressure reduction.Methods: On the basis of scientific literatures, temperature- dependent, ion-activity and pH-triggered in situ forming eye gels were prepared respectively. Ion-activity in situ forming eye gels was selected for its convenience and compliance.The formulation screening was performed by comparing in vitro release with such agents abroad, in which the best formulation of ion-activity in situ forming eye gels was determined.The in vitro release of timolol maleate in situ forming eye gels was studied with dissolution model. The release medium was simulated tears and samples were obtained at set time. The release data were analyzed with three models: Higuchi equation, Zero Order equation, First Order equation.The content of timolol maleate in the gel was determined by HPLC. The linear range of timolol maleate is 20.0~100.0μg/ml, r=0.9998. The chemical and physical stability of optimal formula was investigated in strong light test, accelerative test and long-term test.Ocular irritation studies were performed according to Draize technique on ten albino rabbits. Multiple dosing eye stimulation were observed, recorded and evaluated. The in situ forming eye gels was topically administered to the left eyes of ten rabbits and the right eyes have no drug administered as the blank group. Evaluation was done as per Draize technique.Pharmacodynamics: Rabbits were selected as laboratory animals. The ocular hypertension model was induced by injecting 0.3% carbopol into anterior chamber of the two eyes of each rabbit. The successful ocular hypertension model eyes were divided randomly into four groups: in situ forming eye gels, in situ forming eye gels marketed aboard, eye drops and blank were administered respectively. Reduction of intraocular pressure was compared within the four groups.Results: From the convenience, compliance and in vitro release considerations, the best formulation of in situ forming gels was 0.5%timolol maleate, 0.5%Gelrite, 4.5%Mannitol, 0.2%Tris, 0.003% Merthiolate sodium and H2O to enough. In this formulation, the accumulative release profile of the drug in vitro could be distributed by First Order equation and provided sustained release of the drug over a 12-hour period in vitro.Study of stability: Result showed that the formulation was stable to heat,unstable to light. Result of accelerative test and long-term test indicate that pH, content and appearance of in situ forming eye gels have not changed obviously.Ocular irritation studies: Multiple dosing had no markedly influences on tested rabbit eyes, both corneas are transparent without turbidness, and iris clarity, no edema and no discharge, but have conjunctival congestion.Pharmacodynamics: The establishment of stable ocular hypertension model was successful by injection of 0.3% carbopol into anterior chamber of rabbit. Experimental glaucoma occurred in twelve of sixteen eyes and ocular hypertension lasted from 21 to 28 days. The levels of intraocular pressure were 23.78~38.80 mmHg. The formulations demonstrated the same therapeutic efficacy when compared with conventional eyedrops and in situ forming eye gels marketed aboard.Conclusion: The formulation underwent gelation in the cul-de-sac upon instillation as drops into the eye. The gel formed in vitro produced sustained drug release over 12-h period. This new formulation was a viable alternative to conventional eye drops by virtue of its ability to enhance bioavailability through its sustained drug release and longer pre-corneal and reduced frequency of administration resulting in better patient acceptance.