Studies On Injectable PH-and Temperature Sensitive Sustained Release Hydrogels

A new kind of biodegradable pH- and temperature sensitive block copolymer OSM₁-PCLA-PEG-PCLA-OSM₁ was synthesized in this paper. Firstly, temperature-responsive block copolymers PLGA-PEG-PLGA were synthesized by ring-opening polymerizations. Secondly, we chose sulfonamide as raw material to synthesis pH sensitive fragment sulfamerazine oligomers by conventional free radical polymerizations. Based on PLGA-PEG-PLGA and sulfamerazine oligomers, OSM₁-PCLA-PEG-PCLA-OSM₁ was synthesized under room temperature using condensation reaction. The chemical structure of OSM₁-PCLA-PEG-PCLA-OSM₁ block copolymers was characterized by UV, FTIR, ¹H-NMR, ¹³C-NMR, GPC and so on.The biodegradable pH- and temperature sensitive block copolymers which we synthesized are a kind of novel smart polymer carriers. To verify the pH- and temperature sensitive properties, the pKa of SM₁, SM₁M and OSM₁ was determined by potentiometric titration method. The pKa of SM₁, SM₁M and OSM₁ was 6.35, 6.75 and 7.25 respectively, that showed certain pH sensitive properity. They are soluble in water at low temperature（<10℃） or high pH （pH8.0） and form free flowing liquid, but respond to small change in pH and temperature stimuli and form physically crosslinked hydrogels by sol-gel phase transition. At low pH （pH7.4）, the non-ionized OSM₁ acts as a hydrophobic block in OSM₁-PCLA-PEG-PCLA-OSM₁, so the copolymer solution forms a gel with temperature increasing（37℃）. To verify the sol-gel phase transition of copolymer solution at high concentrations, the micelle size was determined by increasing the temperature at pH7.4 and 8.0. The micelle sizes at both pH7.4 and pH8.0, which were approximately 135 and 86 nm at room temperature, respectively. But the micelle sizes were observed to decrease slightly with increasing temperature to 37℃. This micelle size results provide strong evidence to support the sol-gel transition of the block copolymer at low pH and high temperature. The CMC of PCLA-PEG-PCL and OSM₁-PCLA-PEG-PCLA-OSM₁ was 1×10^-5 g/ml and 3×10^-6 g/ml, determined by surface tension method and pyrene as Fluorescent Probe. The properties of pH- and temperature sensitive block copolymers show that the block copolymers solution possesses both pH and temperature sensitive properties, hold high potential as injectable sustained release carriers of drug delivery systems.The 5-fluorouracil （5-FU） and docetaxel （DTX） were selected as model drug to investigate the drug release behavior and the parameters influencing the drug release. The 5-FU （a model hydrophilic drug） was released from the copolymer hydrogel over 9 days and DTX （a model hydrophobic drug） was released over 16 days with diffusion and erosion release profile, respectively. The concentration of block copolymer and drug loading have less effect on drug release, the release rate of 5-FU and DTX both increase with decreasing copolymer solution concentration and increasing drug loading. But significantly affected drug release dominated by hydrogel erosion and model drug properties. The in vitro erosion period of the copolymer hydrogel was about 25 days. The erosion rate was increased at low pH（pH6.6） and high pH（pH8.0）, compared with pH7.4.Last, we investigated the biocompatibility and pharmcokinetics in vivo. Subcutaneous injection of the copolymer solutions had a mild inflammatory reaction and the inflammation was relieved as time prolonged, indicating that the copolymer had a good compatibility. The C_max, T_Max t_1/2, AUC and MRT of the subcutaneous injection the 5-FU sustained formulation （10/20mg individual） was 29.2/36.7μg/ml, 0.5/0.5h, 29.2/33.2h, 342.4/485.9mg·h/mL and 27.2/26.9h respectively, while the common 5-FU solution pharmacokinetic parameters C_max, T_Max, t_1/2, AUC and MRT with the subcutaneous injection were 72.7μg/ml, 0.25h, 0.29h, 44.5mg·h/mL and 0.57h. The pharmacokinetics research show that the block copolymer solution has good sustained release effect after formed a gel in vivo by subcutaneous injection, compared with common 5-FU solution. But the low and high doses sustained formulation showed no significant difference after subcutaneous injection.