| Poly (N-isopropylacrylamide) (PNIPA) is a thermosensitive polymer, which exhibits a lower critical solution temperature (LCST) at about 32℃ in aqueous solutions. It is soluble in water and adopts a hydrated conformation at temperatures below its LCST. On the other hand, temperature induced phase separation occur and polymer aqueous solution precipitate due to PNIPA exhibit a dehydrated globule state at temperatures above its LCST. β-cyclodextrin (β-CD) is cyclic oligosaccharide that has the ability to accommodate water insoluble drugs in its cavity to form inclusion complexes. The formed inclusion complex will increase the solubility, stability and pharmacological activity of hydrophobic drugs, which leads to widespread applications in pharmaceutical field. In this study, PNIPA was introduced to β-CD to synthesize a novel thermosensitive drug carrier PNIPA/β-CD, which not only has the characteristic thermosensitivity of PNIPAm but also has the drug-inclusion ability of β-CD. Since the drug-loaded carrier PNIPA-β-CD can be dissolved in aqueous solutions directly to obtain an injecTablele liquid at ambient temperature, while it can deposit in situ at body temperature with minimal syneresis, it may be potential drug carrier for parenteral drug delivery consequently.PNIPA having carboxyl end group was synthesized by a radical polymerization using β -mercaptopropionic acid as a chain transfer agent, and the molecular weights of the PNIPA could be controlled by ratios between the chain transfer agent and the monomer. The LCST of the PNIPA can be controlled by copolymerization with other monomers. The addition of hydrophilic monomers typically increases the LCST whereas the incorporation of more hydrophobic units has the opposite effect. PNIPA oligmers with molecular weights at 1813, 3995 and 8306 g/mol were synthesized by different β -mercaptopropionic ratio, and v/e also synthesized PNIPA copolymer with LCST at 25.7 ℃ and 37.9 ℃ with butyl methacrylate (BMA) and N,N-dimethylacrylamide (DMAA). PNIPA-β-CD was synthesized by introducing carboxyl terminated PNIPA into the primary OH groups of β-CD . The obtained polymer was characterized by FTIR, ~1H-NMR and the temperature sensitivity wascharacterized by UV, TEM and laser light scattering .The LCST of PNIPA-B-CD in 0.05 M, 0.1 M, 0.2 M buffer solution is 23.9°C > 22.4°C > 20.0°C and in pH 2.2,4.0,6.0 buffer solution is 27.5°C, 29.7T\ 31.5°C.Solvent volatizing method, grinding method and dialysis method were used to prepare three kind of drug(indomethacin, diflunisal , medroxyprogesterone) PNIPA-B-CD inclusion complex .Among three methods, the solvent volatizing method is a better method to all the drug. To indomethacin, the load amount of the complex prepared by the dialysis method which ethanol as the solvent is to 4.06mg/100mg ,and the output efficiency gets 92.4 % .So, PNIPA-B-CD can accommodate water insoluble drugs in their cavities to form inclusion complexes.In vitro release profile of indomethacin from indomethacin/PNIPA-B-CD complex was examined in different ion- intensity buffer solution and different pH buffer solution at 25°C and 37°C. When the LCST of PNIPA-B-CD in the buffer is higher than 25 "C . Much more indomethacin was released from the indomethacin/PNIPA-B-CD complex at 25°C than at 37°C . When the LCST of PNIPA-B-CD in the buffer is lower than 25 °C, there is no obvious different indomethacin release between 25°C and 37°C. So the release profile of indomethacin from the complex is of thermosensitive.In vivo study was carried out using healthy rat. The samples were administrated at high, middle, low dose by subcutaneous injection. The blood samples were withdrawn periodically and analyzed for its drug content by HPLC method. The time-blood concentration data were disposed by DAS pharmacokinetics computer program and the pharmacokinetics parameters were statistics analyzed. Mobile phase: acetonitrile-6mM H3PO4 (55: 45, v/v);flow rate: 2 ml/min;UV absorption wavelength: 260nm;column temperature : 40 °C, injection volume: 20 jul. The data of mean recovery and precision indicated that the HPLC analysis method was accurate and feasible. From DAS program, various pharmacokinetics parameters were calculated. The AUC and Cmax of indomethacin/PNIPA-B-CD complex has no significantly difference as compared to indomethacin/B-CD complex in the same dose,but the ti/2 (a> and Tmax of the former was increased than the latter. The AUC and Cmax of Indomethacin/PNIPA-6-CD complex significantly increases as compared to indomethacin PBS solution in the same dose, and the ti/2 and Tmax of the former were also increased than the latter. The more dose of indomethacin/PNIPA-8-CD, the more ti/2 ca> and Tmax. |
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