Add time:07/24/2019         Source:sciencedirect.com

Some lower aliphatic esters of timolol have previously been developed as prodrugs to potentially diminish the systemic absorption and hence side-effects of topically applied timolol through increased corneal absorption. Although these esters are promising timolol prodrugs for ocular delivery, they suffer from instability in aqueous solution. In this study a large number of other alkyl, cycloalkyl and aromatic esters of timolol were prepared and their hydrolysis studied in aqueous solution and human plasma with the aim of developing chemically more stable yet enzymatically labile timolol prodrug esters. The stability of the esters varied widely and was increased greatly with increasing steric effects within the ester acyl groups. The most stable derivatives were found to be pivaloyl, 2-ethyl-butyryl, 3,3-dimethylbutyryl, cyclopropanoyl and substituted benzoate esters such as 4-methoxybenzoate and 2-amino-benzoate. Maximum stability of all esters occurred at pH 3–4. From a study of the influence of temperature on the stability it was shown that it is feasible to obtain shelf-lives greater than 5 years for solutions of the most stable esters at pH 3–4.5 and 5 °C.

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