A NEW APPROACH TO THE MODIFICATION OF THE THERAPEUTIC ACTIVITY OF A DRUG: POLYMER-DRUG SALT FORMATION (POLYACRYLIMIDE)
Abstract
An investigation was undertaken to study the feasibility of interacting polymer and drug entities by chemical means as a new and improved method of preparing a prolonged action product. A polymeric moiety was initially sought which could be chemically readily modified to provide a range of chemical reactivity with basic amine medicinal agents and a range of prolonged release drug characteristics. One macromolecule, a copolymer of acrylamide and acrylic acid (PAAM) available commercially as Cyanamer P-26, appeared to fulfill the desired criteria. Because of its chemical nature polyacrylimide (PAIM), prepared by imidization of PAAM, was found to exhibit satisfactory solubility characteristics and was also promising for prolonged drug release applications. Solubility studies were conducted to determine the ability of PAIM to interact and solubilize excess quantities of free base drugs. Considerable solubilization of the free bases methapyrilene and phenylpropanolamine by PAIM was obtained. Interacted products of methapyrilene and PAIM were subsequently prepared by reacting the two water-immiscible compounds in water. A 2:1 drug-polymer ratio was found to produce a polymer-drug system in which approximately 85% of the original drug was associated with PAIM by what is believed to be salt formation. Dialysis studies in artificial gastrointestinal fluids have demonstrated that the drug released from the interacted compound crosses the semipermeable membrane at a similar rate to that of the free drug. In vitro release rate studies were determined for the polymer-drug interacted product compressed in a tablet form. The rotating bottle procedure was used with a gradual pH change of the fluid media over an eight hour period. The in vitro release pattern indicates that the interacted product imparts prolonged release characteristics to the drug. It is believed that as a result of the slow dissolution of the polymer at the tablet surface, a protective sheath forms around the tablet which has the effect of reducing the rate of release of the drug. The characterization of PAIM was elucidated by subjecting the polymer to physical and chemical techniques including solubility studies, potentiometric titrations, nitrogen and viscosity determinations, and infrared analyses. The results indicate that the conditions for the imidization reaction considerably influence the chemical nature of PAIM and consequently the extent of polymer-drug interaction. . . . (Author's abstract exceeds stipulated maximum length. Discontinued here with permission of school.) UMI
Degree
Ph.D.
Subject Area
Pharmaceuticals
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