The Study On Compound Methyl-sulphate Neostigmine In Situ Ophthalmic Gel

According to the latest theory of trigger mechanism of myopia, preventing and curing of myopia, we can relieve and eliminate the eye's regulatory tension and eye fatigue, and lower the eye pressure even cure the myopia by taking proper medicament and functional nutrition for eyes. The compound preparation containing methyl-sulphate neostigmine, vitamin B₆, chlorphenamine maleate and taurine is one of these medicaments. But some usual preparation such as eye drop, eye paste, and so on, are difficult in drug absorption, lower in bioavailability and patients compliance, and in poor curative effect, because of the special physiological environment of eyes and their high sensitivity. This limited the usage of many pharmaceutical methods for eyes, and made the designation of ophthalmic preparations difficult. In situ gel, also environmental sensitive gel, is a kind of polymer solutions can be administrated as liquid, which undergo a pgase transition to a non-chemic crosslinked semisolid gel while exposing to physiological environments. This delivery system has both the advantages of solutions and gels, and is a good carrier for ophthalmic preparation. It can release the medicaments slowly and sustainedly, and increase the bioavailability, reduce doses, increase the patients' compliance, at last, increase the curative effect effectively. In this dissertation, a series of researches related to the temperature-sensitive ophthalmic gel of compound methyl-sulphate neostigmine (containing methyl-sulphate neostigmine, vitamin B₆, chlorphenamine maleate and taurine) were carried out, including the research of the base material of ophthalmic in situ gel and its formulation filtration, the preparation techniques, quality researches of the temperature-sensitive ophthalmic gel of compound methyl-sulphate neostigmine. And its drug release in vitro, stability and irritancy also be inspected.There are three kinds of in situ gels: thermo-setting, pH-setting and ion-setting. According to the requirements of special physiological environment of the eyes (pH7.2-7.4, the surface temperature is 34-35℃, abundant cation such as Na⁺, K⁺,Ca²⁺ in the tears ), we have researched the base material of in situ ophthalmic gel and filtrated the formulation of proper base material. Carbopol P-934 and P940 has been selected and researched as the base material of in situ pH-setting gel and its co-effect of combination with hydroxyl-propyl-methyl-cellulose (HPMC, K₄M), a kind of bio-adhesive material. The formulation of base material of in situ pH-setting ophthalmic gel is 0.02% carbopol P934, 0.02% carbopol P940 and 0.5% HPMC. The formulation of base material of in situ ion-setting ophthalmic gel is 0.45% Gelrite. And the chief base material of in situ thermo-setting gel is poloxamer P407 and P188. The latter can increase the gelation temperature to meet the temperature of eyes. The formulation of base material of in situ thermo-setting ophthalmic gel is 24% poloxamer P407 and 10% poloxamer P188.According to experimental results of the interaction of the ingredients of compound methyl-sulphate neostigmine with the base material, Vitamin B₆ can cause the base material of ion-setting gel—Gelrite—gelated; and some deposition formed while mixing the solution of vitamin B₆, chlorphenamine maleate and the base material fo the pH-setting gel. So we have accepted the thermo-setting mechanism as the formulation mechanism of Compound Methyl-sulphate Neostigmine Ophthalmic Gel. And the final formulation of Compound Methyl-sulphate Neostigmine Ophthalmic Gel is 0.001% methyl-sulphate neostigmine, 0.1% vitamin B₆, 0.01% chlorphenamine maleate, 0.1% taurine, 0.05% benzalkonium chloride, 24% poloxamer P407 and 10% poloxamer P188.The quality criteria of Compound Methyl-sulphate Neostigmine Ophthalmic Gel has been researched, including quality characters, cheching items such as pH, gelation temperature, related substances, identification, and so on. And the method of quantitative determination is established. The character of its appearance, pH, gelation temperature, and so on, all have met the law of ophthalmic preparation. The HPLC chromatographic parameters of all 4 ingredients of this preparation are established. And we also established the parameters of solid-phase extraction during the sample disposal of the related substances checking of chlorphenamine maleate.According to the in vivo characteristic of ocular administration, improved edition of the 3rd solubility determination method of US Pharmacopoeia was used to study the drug release of vitamin B₆ and taurine. A self-made vitreous tube of no bottom, and covered with a dialytic bag as the semi-permeable membrane (mounted with the oar and the semi-permeable membrane just in the release medium, the diameter is 3.5cm, the area of drug release is 9.62cm²) was used. It was taken 3-4 hours to release 80% of effective composition. It's shown that this preparation can effectively delay the drug release and be a good sustained-release preparation.The irritancy and stability of Compound Methyl-sulphate Neostigmine in situ Ophthalmic Gel has been researched. The results show that this preparation is stable in low temperature and unstable in high temperature and strong light exposure (the concentration of some ingredients of this preparation has been changed and some impurity has been produced.). So this preparation must be stored in a dark and low temperature environment. There is no apparent irritancy to rabbit eyes having been observed, and this preparation is complied with the law of ophthalmic preparations.It's a meaningful work for our research of having established a new sustained-release preparation and a new technique which could effectively improve the patient's obedience and fit to using in eyes. It has gotten rid of those defects of eye drops and pastes. So this new preparation is fit to cure such a kind of eye disease as myopia which need be treated in a long term.