| Gels are extensively used as carriers in drug delivery and drugs are expected to get sustained release from these gels. Owning some preferred properties, such as biodegradable, biocompatible, and gentle physical and chemical profiles, gels are widely studied in drug delivery field. Multiple functional gels were developed to carry drug for different objects. Thermo-sensitive hydrogel is a kind of intelligent material that can response the temperature change and get a phase transition. Most thermo-sensitive hydrogels display as liquid and turned into semi-solid gel as temperature increased to the lower clinical solution temperature(LCST). A lot of thermo-sensitive hydrogels possess a LCST near the body temperature, which leads these materials to be used as in situ gels by biomedical researchers.In this project, thermo-sensitive gels poloxamer 407 and chitosan-glycerol system were chosen for study. The thermo-sensitive properties and the formation mechanism were investigated. Both gels were utilized to prepare sustained drug delivery system, and moreover, the in vivo character of gels in controlling drug release was investigated. In this study, an application method was established using thermo-sensitive hydrogels as drug carriers, and two kinds of multi-phase drug delivery systems were developed, which may supply some new ideas in controlling and modulating drug delivery.Poloxamer 407 (P407) is a kind of reversible thermo-sensitive hydrogel. In the present study, we at first observed the phase transition phenomenon and detected the rheological character of this material. The results showed that P407 liquid could turn into a viscoelastic gel as temperature increased from 4℃ to the LCST. Gel strength was influenced by the concentration of P407 and the stress. The LCST decreased as P407 concentration increasing. And different additives contribute variously to gel formation process. Cellulose and PEG showed slight influence in LCST while saltsshowed strong influence in gel formation. Anion components Cl~, SO42", PO43"could decrease the LCST. In contrast, cations such as Ca2+ did not show this property. The theory that the gel formation is induced by hydrophilic chain entanglement was supported by the results.Furthermore, a membraneless diffusion model was used to investigate the effect of P407 on drug release. The released of BSA from this gel was following the erosion of P407 gel, and the release rate was controlled by gel erosion. Temperature, concentration of P407 and additives viscosity were relative with the cumulative release, and a multiple linear regress equation was obtained to describe this relation.PLGA is a kind of ploy-ester material which is widely used in drug delivery. It is a useful coploymer with high quality of biocompatibility and biodegradablity. Conjugated by lactic acid and glycolic acid, PLGA presents various degrade velocity correlate to conjugated ratio. In PLGA microparticles, initial burst is always a puzzling problem. In this study, PLGA mirospheres was prepared and mixed with P407, then in vitro release experiment was carried out. The result showed that no burst release was appeared using this delivery system and the release quality was reformed by these two preparations mixed. The burst release of BSA in PLGA microspheres is 16.81 + 2.12%, while it is only 0.82% + 0.17% in the release system which poloxamer 407 mixed in.Besides the hydrophobic microparticles, hydrophilic alginate-calcium microspheres were prepared and also mixed with P407. P407 gel effectively controlled the burst release of insulin, which used as model agent, in the alginate-calcium microspheres. The above effect was detected both in vitro and in vivo. In vitro release demonstrated that in the alginate-calcium microspheres, insulin released to 95.68 + 17.72% at 7h. In P407 gels, at 24h, the amount of insulin release is 25.70+5.94% and 16.17+1.85% insulin and insulin microspheres controlled by P407 seperately. The results of in vivo hypoglycemic effect on diabetic rats displayed a well correlation with in vitro releasepatterns, suggesting that Poloxamer 407 could result in sustain release of insulin through subcutaneous injection. In vitro study also demonstrated that poloxamer 407 could protect the activity of insulin to some extent.Chitosan is the deacetylated derivative of chitin. It is a cationic polysaccharide which is easily obtained from natural products. Chitosan is often used as sustained drug release carriers. As a basic polysaccharide, chitosan will precipitate when pH increased to 6.2. In this project, the chitosan-glycerol thermo-sensitive, pH dependent hydrogel was prepared using highly deacetylated chitosan and glycerol, and basic phosphate solution as pH modulator. Glycerol ratio and pH showed strong relation to gel formation in a certain range.Then, the change of pH and conductivity of chitosan-glycerol mixture with the change of temperature was determined. The gel formation mechanism was explored in the study by calculating the ionize degree of gel components. The results showed that the ID (ionize degree) decreased as temperature increased, suggesting that the electrostatic force is not the main driving force for the gel formation, while hydrophobic effect seems contributed to gel formation, for the gel conductivity increased sharply at 25 °C,which means the increasing of hydrophobic effect.In vitro release investigation showed that chitosan-glycerol gel could induce sustained release of drugs, 5-FU maintained the release to 240h in this gel, the main release mechanism is passive diffusion and the release model comply to Higuchi equation.After investigating the thermo-sensitive, pH dependent property of the chitosan-glycerol gel mixtrue, and its sustained release effect on drugs in vitro, meloxicam was selected as model drugs to evaluate the sustained release effect in vivo. Meloxicam-loaded chitosan-glycerol gel was injected subcutaneously in rats. The pharmacokinetic parameters showed that to some extent, gel sustained meloxicamrelease in vivo. Cmax is 8h and lh in gel group and solution group, respectively. AUC was increased in gel group (900.13 + 327.80) compared to that in solution group (597.42 + 283.35) .Based on the chitosan-glycerol gel, emulsion was introduced to this system and a new multiple drug delivery system was developed. Adding of emulsion influenced the gel formation. The high ratio of oil phase in the emulsion makes it difficult to form the gel. In this novel drug delivery system, the release rate could be modulated by the change of emulsion components, indicating a new idea for modulating the drug delivery in sustained carriers.In this project, two kinds of thermo-sensitive hydrogels were investigated. Poloxamer 407 and chitosan-glycerol gel were tested as sustained drug carriers for in situ gelling injection. The gel formation mechanism and influence factors were studied. Both the in vitro and in vivo experimental methods were operated. The results indicated that these two kinds of thermo-sensitive gels displayed well profile in controlling drug delivery. Furthermore, two kinds of multiple phase drug delivery system based on the thermo-sensitive gels and microparticles were developed. The systems well reformed the release character, and were potentially applied in modulating the drug release. |
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