Preparation And Properties Of Paa-HPMC Nanogels And Insulin Drug Loaded Nanogels

Protein drugs have the bad bioavailability due to high molecular weight, poorpermeability of biomembrane, absorption difficulties with oral administration,and they are vulnerable to the impact of gastrointestinal pH, enzymes, bacterialcatabolism and hepatic first-pass effect. The biological half-life of protein drugsare usually short, so, the patient need frequently being given medicine whosecompliance is poor. Sustained and controlled release technology has beenconsidered an effective way to improve the efficacy of these drugs. This subject,starting from the basic research on the influence of acrylic acid （AA） on the lowercritical solution temperature （LCST） behavior of hydroxypropyl methycellulose（HPMC） solution, designed and synthesized a kind oftemperature-and pH-sensitive nanogel （PAA/HPMC compound gel）. We expect thesmaller size and environmental sensitivity make it become a good deliverysystem for protein drugs.HPMC is a peculiar thermo-sensitive polymer which exhibits a lower criticalsolution temperature （LCST） at higher than60℃in aqueous solutions, undergo athermo-reversible sol：gel phase transition on heating. The LCST of HPMC solutionunder mixing with AA monomer was drastically reduced from60C to38C withthe increase of the concetration of AA while the HPMC is kept the same at0.5wt%.The decrease of the phase transition temperature is attributed to strong hydrogenbonding between the HPMC and AA. The concentration of HPMC, external pHand the presence of small molecule salt affect the degree of influence. Similarly,some small molecular weak acids whose structure are similar to AA, suchas methacrylic acid （MAA）, chloroacetic acid （CA）, propionic acid （PA）, aceticacid （HOAc）, make the LCST of HPMC shifted to much lower temperature thanthat of the pure HPMC, but differ widely in their effects. When HPMC and weakacids were mixed, the weak acids as a proton donor interacting with a protonacceptor （HPMC） give a complex in which decreasing the LCST of the hydrophilicHPMC resulted in the phase transition at a lower temperature. The effect ofdifferent weak acids was proposed to depend on the ability of forming complexesbased on hydrogen bond to induce the hydrophobicity of HPMC chains. The effect on LCST correlated strongly with molecular parameters as molecular area andvolume, the O-electronegativity from–OH group of the weak acids and log P valuewhich may facilitate hydrophobic interactions of HPMC chains.Then surfactant-free PAA/HPMC nanogels have been synthesized via thepolymerization of AA monomer with the collapsed HPMC as a template or core attheir LCST, using KPS and TEMED as redox initiator in the presence of BIS ascross-linked agent. These techniques do not apply any organic solvents orsurfactants. We obtained PAA/HPMC nanogels who have50-150nm diameterswhen the reaction take place4-5h at their LCST using the cross-linked agent andinitiator whose dosage are4wt%-5wt%（based on AA）. And the obtainedPAA/HPMC nanogels have excellent temperature-and pH-sensitivity.Invitro release of prepared nanogels was studied using insulin as a model drug.Insulin loaded nanogels have100-200nm diameters characterized by transmissionelectron microscope. They can enter the human body organs wherea lot of large particles are difficult to enter and reach the lesion siteacross many biological barriers due to the small size of the nanogels. HPMC/PAAnanogels demonstrated significant sustained release of insulin in vitro. The in vitrodrug released process complied with diffusion-dissolution kinetics model(Q=k₁t^1/2+k₂t+k₃t²+k₄t³), effecting by diffusion, the relaxation and dissolutionof the carrier material itself. The same time, drug release in pH7.4partial neutral environment much faster than that in pH1.2gastric juice. Andthe drug release rate was a mutation near the LCST of the carrier. These all showthat the obtained nanogel achieve the controlled release of protein drugs.