Preparation Of Sustainde-/Controlled-Release Drug Delivery System Using Supercritical Solution Impregnation

Supercritical solution impregnation (SSI) is a process technology to load active compounds onto/into polymer matrices using supercritical carbon dioxide (SCCO2). At present, it is mainly utilized in fabric dyeing, polymer blending, etc., and its application in the preparation of sustained-/controlled-release drug delivery system (SCRDDS) is rarely reported. This work combines the SSI technology with preparation of monodisperse polymer microparticles to develop a process of SCRDDS formulation. The contents of the thesis consist of three main parts:principle of SSI process, preparation of monodisperse polymer microparticles, and loading of drug into microparticles with SSI method.Firstly, the principle of SSI process was studied in detail, in which roxithromycin and poly (l-lactic acid)(PLLA) were selected as model drug and polymer matrix respectively. The interactions among CO2, roxithromycin and PLLA were examined as follows:(1) Solubility of roxithromycin in SCCO2was measured with the static method at temperature range from40to60℃, and pressure from10to30MPa. The minimum of solubility, y2, was determined at1.47×10-5mol/mol, and the maximum was1.84×10-4mol/mol. With the pressure elevating, solubility data increased correspondingly. The effect of temperature on solubility was more complex. Five empirical models and three solubility parameter models were chosen to fit and correlate the obtained solubility data. Among them, correlations of SS model, SP-RM model and SP-3model were better than that of other models, and the average absolute relative deviation (AARD) ranged from6.36%to6.83%.(2) Sorption and diffusion behavior of CO2in PLLA film was examined with the weight variation method at temperature of40-60℃and pressure of10-30MPa. Equilibrium sorption amount, Ms,∞, increased with the elevation of pressure, while increased with the descending of temperature. Desorption diffusion coefficient, Dd, was greatly influenced by Ms,∞. Along with Ms,∞increasing from8.3%to16.9%, Dd expanded approximately10times from0.25x10-11m2/s to2.57x10-11m2/s. Sorption diffusion coefficient, Ds, was in the same order of magnitude as Dd at supercritical conditions. The swelling model and SP-4model were selected to correlate the sorption data. AARD of swelling model was below1%, and AARD of SP-4was only1.94%.(3) Sorption of roxithromycin into PLLA film at SCCO2was determined. The effect of impregnation time (0.5-4.0h), impregnation pressure (8-30MPa), and impregnation temperature (40-70℃) on drug loading capacity(DLC) was investigated. With the time prolonging, DLC approached up to an equilibrium value. At a certain temperature, DLC increased with the elevating of impregnation pressure. The relationship between impregnation temperature and DLC was more complicated. SEM photos showed that no obvious change was observed for the surface and cross-over morphologies of PLLA film. DSC data and XRD spectra implied that roxithromycin could be molecularly dispersed into PLLA film, and headspace gas chromatography data demonstrated that SSI process could remove solvent residual effectively. In vitro release data indicated that drug-loaded PLLA film could slowly release drug for a long period. Besides, partition coefficient (K) of roxithromycin between polymer phase and supercritical phase was calculated.Secondly, an improved orifice method was developed to prepare monodisperse PLLA microparticles. The effects of oil phase flow rate, stirring rate, PLLA concentration, and inner diameter of orifice on average diameter (d) and coefficient of variation (CV) were investigated. Decreasing orifice inner diameter was a valid way to reduce the CV value.Using glass capillary instead of#4.5metal needle, the CV droped greatly from26.13%to17.59%. The microparticles prepared with the improved orifice method presented perfectly spherical shape and narrow size distribution.Finally, roxithromycin was loaded into PLLA microparticles with four different size distributions using SSI method. The effects of impregnation time, microparticles size, impregnation pressure and temperature on total drug loading capacity (TDLC), surface drug loading capacity (SDLC), and interior drug loading capacity (IDLC) were investigated. When impregnation time was above3h, IDLC of microparticles achieved an equilibrium value. With reducing of microparticles size, IDLC decreased while SDLC increased. The smaller micropartciles were prone to adhere to each other. With rising of impregnation pressure, TDLC, SDLC and IDLC increased. The effects of impregnation temperature on TDLC, IDLC and SDLC were more complex. SEM photos indicated that microparticles with diameter below5μm were aggregated badly to form a block. DSC data implied that roxithromycin was dispersed into PLLA microparticles mainly in an amorphous state. In vitro release curves showed that all of drug-loaded microparticles with different size distribution could release slowly for a long period.Furthermore, the application of SSI technology in SCRDDS field was discussed. Three drugs (cholesterol, aspirin and roxithromycin) and three polymers (polyethylene, polystyrene and polyvinyl alcohol) were selected to investigate the effects of solubility parameter difference (△δ) between drug and polymer on DLC. The results demonstrate that SSI process is available for most of drugs using polymers in a wide range. For a certain SCRDDS,△δ between the drug and a polymer could be a criterion to choose a proper polymer matrix.The advantages of SSI method include the high production efficiency, the shape diversity of polymer matrix, and the removal of solvent residual. This work successfully combines SSI technology with monodisperse polymer microparticles preparation to provide a new process to produce SCRDDS formulation.