DRUG ENTRAPMENT IN POLYMERIC MATRICES I. DRUG INCLUSION IN POLYMERS CROSSLINKED BY ESTERIFICATION
Abstract
In recent years the subject of controlled and sustained drug release has become one of the major considerations in the design of pharmaceuticals. The main objective of this alteration is to control and/or prolong the release of the drug in order to reduce toxicity or side effects, to increase therapeutic effectiveness or to prolong the duration of action over that of the drug given in the free state. The approach to controlled drug release pursued in this study employed a non-coating, highly reproducible, quantitative physico-chemical entrapment of drug in esterified polymeric crosslinked systems. The esterification reactions were conducted between polycarboxyl or polyanhydride polymers and selected diols in the presence of the drug. The result was a drug-polymer combination in which the drug was entrapped in a molecular or in a gross particulate state of dispersion and from which various rates of prolonged drug release can be controlled. The initial phase of the research was involved with the screening and selection of polycarboxyl and polyanhydride polymers and selected diols as crosslinking agents. The polymer esters produced were evaluated as to their potential suitability as matrices for the entrapment of drugs based on their physical form, melting and softening points, degree of crosslinking, and solubility properties. Ethylene maleic acid and polyethylene glycols 1000, 1540, and 4000 produced the most promising esters. In vitro release studies were performed on several drug-polymer systems containing the hydrochloride, oxalate and maleate salts of chlorpromazine. The drug-polymer systems were designed to show the effects of variables, such as the degree of crosslinking, molecular weight of the crosslinking moiety, drug solubility, particle size of the system and compression on the release of the drug from the polymer matrix. In vivo studies on a selected drug-polymer system showed that drug-polymer system produced significantly longer duration of drug action as reflected by depressed central motor activity in comparison to the equivalent dose of the free drug. The duration of action of the drug-polymer system was 8 hours compared to 4 hours for the free drug. A physical mixture of the drug with the same polymer ester produced no pharmacodynamic alteration of drug action compared to the drug alone. . . . (Author's abstract exceeds stipulated maximum length. Discontinued here with permission of school.) UMI
Degree
Ph.D.
Subject Area
Pharmaceuticals
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