Preparation And Applications Of Drug-Loaded Porous Polvmer Matrices Using Supercritical Solution Impregnation

Supercritical solution impregnation (SSI) is a technology to load small molecular substances into matrices using supercritical carbon dioxide (SCCO2). So far, SSI has been widely used in dyeing and wood impregnation, etc., but its application in the preparation of sustained-/controlled-release drug delivery system is rarely reported, and the investigations on SSI process are still in progress. In this work, we performed the SSI process on several porous polymer matrices, and developed an approach to prepare sustained-/controlled-release drug delivery systems. Two aspects are included in this thesis, i.e., the principles of SSI and its application in preparing drug-loaded porous polymer matrices for sustained-/controlled-release drug delivery.Firstly, dexamethasone and poly (l-lactic acid) (PLLA) were selected as model drug and polymer matrix respectively to study the principles of SSI process. The interactions among CO2, dexamethasone and PLLA were examined as follows:(1) The interactions between dexamethasone and CO2:A static method was used to measure the solubility of dexamethasone in SCCO2 with/without a cosolvent at temperature range from 313.2 to 323.2 K, and pressure from 10.0 to 25.0 MPa. Four semi-empirical models were chosen to fit the obtained dexamethasone solubility data, and then diffusion coefficients of dexamethasone in SCCO2 were calculated. The minimum solubility of dexamethasone in SCCO2 was 1.21×10-6 mol/mol, and the maximum was 1.52×10-6 mol/mol. With the pressure elevating, solubility data increased correspondingly. The effect of temperature on solubility was more complex. With 3% ethanol as the cosolvent, the solubility of dexamethasone in SCCO2 was enhanced to the range from 1.97×10-6 to 2.98×10-6 mol/mol. All of four semi-empirical models were able to correlate the obtained dexamethasone solubility data. The diffusion coefficients of dexamethasone in SCCO2 were determined in the range of 0.50×10-8-2.04×10-8 m2/s at temperature range from 313.2 to 333.2 K, and pressure from 10.0 to 25.0 MPa.(2) The interactions between PLLA and CO2:Swelling and diffusion behavior between PLLA and SCCO2 was examined at temperature of 313.2-333.2 K, and pressure of 10.0-25.0 MPa. The equilibrium swelling ratio of PLLA in SCCO2 was determined using image acquisition method and was observed in the range of 15.8-24.9%. Based upon that, the equilibrium sorption amount were calculated in the range of 3.75-17.74%, which increased with the elevation of pressure and the descending of temperature. Under the same conditions, the diffusion coefficients of CO2 in PLLA were from 1.12×10-10 to 2.27×10-10 m2/s.(3) The interactions among CO2, dexamethasone and PLLA:The sorption and diffusion behavior of dexamethasone into PLLA porous microparticles in SCCO2 was investigated at temperature of 313.2-333.2 K, and pressure of 10.0-25.0 MPa. The diffusion coefficients of dexamethasone in PLLA were from 0.72×10-13 to 2.22×10-13 m2/s, and elevated with the increase of temperature and pressure. Drug loading capacity (DLC) approached up to an equilibrium value after 2 h. DLC was in the range of 0.88-1.73 mg/g, and increased with the elevating of pressure, while decreased with the further elevating of pressure. The effect of temperature on DLC was more complex. After the SSI process, the pores at the surface of the porous PLLA microparticles were closed with shrinked particle size, and the mass median aerodynamic diameters (MMAD) of drug-loaded porous PLLA microparticles were in the range of 4.08-4.81 μm suitable for pulmonary delivery. Moreover, SSI process could remove solvent residual effectively. In vitro release data indicated that, compared with drug-loaded porous particles prepared using conventional method, drug-loaded porous PLLA microparticles prepared using SSI process could eliminate the burst release effectively, and lead to sustained drug release for a long period. Besides, partition coefficients (K) of dexamethasone between polymer phase and supercritical phase were calculated in the range of 0.09-0.28.Secondly, SSI process was used to load drugs to several porous polymer materials for sustained-/controlled-release drug delivery. Then the characterizations of the drug-loaded porous polymer materials were carried out according to their specific applications.(1) SSI process was used to load ibuprofen to porous chitosan film for oral mucosal drug delivery. The water-uptake, erosion and in vitro mucoadhesion properties of the porous chitosan film were determined, and the effects of SSI process parameters on the DLC, in vitro drug release, ex vivo drug release and antibacterial activity were also studied. The results showed that the DLC was in the range of 7.85% to 130.44%. Ibuprofen loaded to the porous chitosan film in different crystal forms like microparticles, flake, rod-like and needle-like, and the crystal forms could affect the release behavior. The ex vivo release profile indicated that the drug released from the porous film could permeate through the buccal mucosa of the rabbit without burst release. The results of antibacterial study indicated that the drug-loaded porous film could inhibit the proliferation of the bacteria.(2) SSI process was used to load silver sulfadiazine (AgSD) to asymmetric chitosan film for wound dressing. The effect of SSI process parameters on the DLC was studied, and the water-uptake, water vapor transmission rate (WVTR), in vitro release, antibacterial activity as well as in vivo wound healing process of the drug-loaded asymmetric chitosan film was investigated. The maximum DLC was 5.02 mg/g at 323.2 K,20.0 MPa, and DLC increased with the elevating of pressure, and decreased with the further elevating of pressure; the effect of temperature on DLC was more complex. The water-uptake and WVTR could be adjusted with tailoring the thickness of the dense layer of the asymmetric film. Drug-loaded asymmetric chitosan film could lead to a sustained drug release, and also could inhibit the growth of both gram-positive and gram-negative bacteria. The results of in vivo wound healing indicated that the drug-loaded asymmetric chitosan film could promote the healing of the wound.This work combines the SSI technology with preparation of carrier matrices to develop a novel process to obtain drug-loaded material for sustained-/controlled-release drug delivery, which has a wide application. The SSI method could remove the solvent residual, and the drug-loading process was independent of the preparation of carrier matrices and could be controlled individually. SSI process was used to prepare several drug-loaded porous polymer matrices and revealed the potential in the application of the preparation of sustained-/controlled-release drug delivery systems.