Elucidation of the mechanism of incorporation of insulin in controlled release systems based on complexation polymers.

The objective of this study was to investigate the insulin incorporation and release properties of poly(methacrylic acid-g-ethylene glycol) P(MAA-g-EG) microparticles as a function of copolymer composition. These microparticles exhibited unique pH-responsive characteristics in which interpolymer complexes were formed in acidic media and dissociated in neutral/basic environments. The microparticles containing equimolar amounts of MAA and PEG were capable of efficient insulin loading using equilibrium partitioning (>90%). Additionally, insulin release from the gel was significantly retarded in acidic media while rapid release occurred under neutral/basic conditions. In contrast, as the amount of MAA of the polymer was increased, the entrapment efficiency of insulin within the gel greatly reduced and the insulin was readily released from the polymer network in the acidic and neutral/basic media. In addition, in order to evaluate the potential application of the microparticles to other drugs, theophylline, vancomycin, fluorescein-isothiocyanate-labeled dextrans (FITC-Ds) with average molecular weights of 4400 (FITC-D-4), 12,000 (FITC-D-10) and 19,500 (FITC-D-20) were utilized as model hydrophilic drugs. The incorporation profiles showed that the uptake of theophylline and vancomycin to the microparticles was lower than that of insulin. Additionally, polymer microparticles loaded with theophylline and vancomycin exhibited pH-sensitive release behavior, however, the oscillatory behavior is less pronounced than those of insulin. The values of drug incorporation ratio showed that the microparticles were capable of incorporating almost 90% of insulin and 15% of vancomycin from solution. On the other hand, the other hydrophilic drugs showed very low incorporation efficiency to the microparticles. These data suggest that gels containing equimolar amounts of MAA:EG have the potential to be used as an oral carrier of peptide drugs, especially for insulin.

[1]  N. Peppas,et al.  Complexation graft copolymer networks: swelling properties, calcium binding and proteolytic enzyme inhibition. , 1999, Biomaterials.

[2]  J. Luksa,et al.  Rapid high-performance liquid chromatographic determination of vancomycin in human plasma. , 1995, Journal of chromatography. B, Biomedical applications.

[3]  N. Yui,et al.  Hyaluronic acid grafted with poly(ethylene glycol) as a novel peptide formulation. , 1999, Journal of controlled release : official journal of the Controlled Release Society.

[4]  O. Güven,et al.  Controlled release of terbinafine hydrochloride from pH sensitive poly(acrylamide/maleic acid) hydrogels. , 2000, International journal of pharmaceutics.

[5]  M. Sefton,et al.  Adsorption Isotherms of Insulin onto Various Materials , 1984, Diabetes.

[6]  D. Williams,et al.  Structural and mode of action studies on the antibiotic vancomycin. Evidence from 270-MHz proton magnetic resonance. , 1977, Journal of the American Chemical Society.

[7]  H. Nakazawa,et al.  Reversed-Phase High-Performance Liquid Chromatography of Peptides , 1986 .

[8]  T. Ishizaki,et al.  The effect of assay methods on plasma levels and pharmacokinetics of theophylline: HPLC and EIA. , 1979, British journal of clinical pharmacology.

[9]  H. Klostermeyer,et al.  The chemistry and biochemistry of insulin. , 1966, Angewandte Chemie.

[10]  Gerrit Borchard,et al.  Mucoadhesive Polymers in Peroral Peptide Drug Delivery. II. Carbomer and Polycarbophil Are Potent Inhibitors of the Intestinal Proteolytic Enzyme Trypsin , 1995, Pharmaceutical Research.

[11]  N. Peppas,et al.  Oral delivery of insulin using pH-responsive complexation gels. , 1999, Journal of pharmaceutical sciences.

[12]  Conclusions , 1989 .

[13]  E. Crandall,et al.  Size-dependent dextran transport across rat alveolar epithelial cell monolayers. , 1997, Journal of pharmaceutical sciences.

[14]  Y. Cohen,et al.  Characterization of glucose-sensitive insulin release systems in simulated in vivo conditions. , 2000, Biomaterials.

[15]  A. Mitra,et al.  Lipid emulsions as vehicles for enhanced nasal delivery of insulin. , 2000, International journal of pharmaceutics.

[16]  N. Peppas,et al.  Solute transport analysis in pH-responsive, complexing hydrogels of poly(methacrylic acid-g-ethylene glycol). , 1999, Journal of biomaterials science. Polymer edition.

[17]  N. Peppas,et al.  Analysis of the Complexation/Decomplexation Phenomena in Graft Copolymer Networks , 1997 .

[18]  J P Bai,et al.  Effects of polyacrylic polymers on the lumenal proteolysis of peptide drugs in the colon. , 1995, Journal of pharmaceutical sciences.