Studies On Poly(Methacrylic Acid-co-Poloxamer) Hydrogels

Llydrogels have been widely used in controlled drug delivery systems for their good biological compatibility and easy manipulation of swelling level and solute permeability. Recent advances in the development of neutral and ionic hydrogels have concentrated on synthesis of materials that respond to a number of physiological stimuli, such as p11, ionic strength and temperature. In this paper, a new pH-sensitive swellable poly(methacrylic acid-co-poloxainer) hydrogels were synthesized. And cross-linked poloxamer gel spheres were prepared with a novel suspension polymerization method in an aqueous two-phase system. The properties of drug permeation and drug release were studied to evaluate the applications of such hydrogels in pharmaceutical field. Poloxamer was modified with methacryloyl chloride to obtain the polymerizable derivative (macromer). Copolymers of poloxamer and methacrylic acid were prepared by free radical polymerization at the presence of (NH4)2S208 and Na2HSO3 as redox initiators in a water-ethanol mixture solution. The aqueous-two phase system for the preparation of cross-linked poloxamer gel spheres was composed of the macromer aqueous solution and dextranlmagnesium sulfate aqueous solution. The resulted macromer and hydrogels were characterized by UV-Vis, FuR, 111 NMR., SEM and DSC method. The acute toxicity of such polymer was also evaluated. The equilibrium swelling studies of the hydrogels were performed in various pH medium, and permeation experiments of model drugs, dextromethorphan hydrobromide (DMP), vitamin B12 (YB12) and bovine serum albumin (BSA) were conducted with equilibrated swollen hydrogel membranes in solutions of pH 4.0 and pH 7.0. A soaking method was used to load drug into the hydrogels. The kinetics gel swelling and drug release was studied, and the experimental dates was fitted by various mathematical models to determine the mechanisms of gel swelling and drug release. Insulin was loaded by swelling the P(MAA-co-poloxamer) hydrogels in an ethanol-HC1 solution, and insulin content was measured by HPLC method. Insulin-containing polymer was orally administrated with different insulin doses to male, alloxan-diabetic rats. At different time intervals, blood glucose values were determined by glucose enzyme method. Area over the curve (AOC) of blood glucose level versus time profile was used to assess the relative pharmacological bioavailability. -3- R拁 ~-*~9~ The conversion of methacrylate per poloxamer molecule was estimated from integral values of proton signals in 慔 NMR spectrum. The efficiency of methacrylation of poloxamer is 93 %, which indicates that one poloxamer molecule carries two polymerizable function groups. According to monomer composition and polymerization conditions, non-porous or porous (micro-syneresis) hydrogels could be synthesized. P(MAA-co-poloxamer) copolymer had low toxicity, LD50>12 g/kg (mouse, oral administration), no organ abnormities were observed. Amphiphilic poloxamer spheres with different particle sizes and swelling ratios could be prepared in completely aqueous emulsion system without the use of organic solvent and surfactant. Depending on the starting composition of the reaction mixture, the viscosity of the two phases was different, thus the resulting spheres had various mean diameters and various equilibrium water contents. At low pH environment, the gels shrink and the diffusion coef...