Drug release behavior and preparation of microspheres composed of hydrophilic/hydrophobic blends of ethylcellulose and hydroxypropylcellulose

• Main Authors: Guo-Ming Yang, 楊國明
• Other Authors: Eamor M. Woo
• Format: Others
• Language: zh-TW
• Published: 2006
• Online Access: http://ndltd.ncl.edu.tw/handle/65485277761312816580

博士 === 國立成功大學 === 化學工程學系碩博士班 === 94 === 　In this work, the technology of microencapsulation is adopted to prepare the microspheres to obtain the controlled drug release. The study adopts the novel system of oil in oil suspention evaporation method to obtain various matrixes of microspheres successfully by hydrophobic ethylcellulose (EC) and hydrophilic hydroxypropylcellulose (HPC), and to approach various mechanisms from water-soluble drug captopril (CAP) and poorly soluble drug isosorbide dinitrate (ISDN). 　First, the microcapsules were prepared using the oil in oil suspention evaporation method for sustained release of water-soluble drug CAP from microcapsules composed of EC and HPC. Factors affecting the size and size distribution of microcapsules were investigated. The optimum conditions on the maximum products of 250-425μm of EC/HPC/CAP microspheres particle size were fined as well. The 250-425μm microcapsules were characterized using an x-ray diffractometer, static contact angle instrument and UV/visible spectrophotograph. The microcapsules for the sustained release were studied on the various EC/HPC compositions. The cumulative releases of CAP from the microcapsules at various times were measured. The results could be well described by a first order release kinetics for the first 0.7 hours and zero order release kinetics for the release time from 2 to 10 hours. The rate coefficients of first and zero-order stages linearly depended upon the EC/HPC composition. 　Therefore, microcapsules for sustained release of poorly soluble isosorbide dinitrate (ISDN) were prepared based on EC and/or HPC as matrix materials using the oil in oil suspention evaporation method. The release behaviors of microspheres were studied by four EC/HPC compositions (1, 0.833, 0.67 and 0.5 weight fraction EC) and three-mode sizes (100-150, 250-300, and 400-450 μm). The result of the static contact angle of EC/HPC composition was obtained with further respective discussion by dividing the lines of demarcation into two parts as EC/HPC = 3/3. Above all, the part of non-obvious swelling EC: HPC= 6:0, 5:1, 4:2, 3:3 was analyzed. The cumulative amounts of ISDN releasing from the microspheres as functions of mode fractions size and polymer compositions were measured in vitro. It was observed that the microspheres’ size influenced the release behavior of drug more obviously than the polymer composition. The higher hydrophilic HPC content and the smaller size reveal that the faster release rate of drug and the smaller amount of drug residue. The microspheres of 400～450 μm exhibit a slow drug release rate and larger fraction of drug residues. The kinetics of drug release depends on the size and polymer composition. The microspheres with 100-150 μm, of all polymer compositions, present one-stage diffusion kinetic with a lag period for drug release. On the other hand, the microspheres with the other 250-300μm and 400-450μm sizes exhibit two-stage diffusion kinetic with a lag period. 　The novel system of microencapsulation for sustained release of poorly soluble isosorbide dinitrate (ISDN) was prepared by using the oil/oil suspension evaporation method. More content Hydroxypropyl cellulose (HPC) and poorer content ethylcellulose (EC) were used as a rate-controlled matrix. The aim of this study was to investigate the effect of the more content HPC (EC: HPC= 2:4, 1:5, 0:6) of microspheres matrix on the release rate of an incorporated ISDN drug and drug release kinetics. In vitro drug release models, the preparation methods of microspheres and films were measured. The ISDN microspheres of the more content HPC of microspheres matrix present one-stage diffusion kinetic with no clear lag period for drug release. On the other hand, the films with oil/oil suspension evaporation method exhibit two-stage diffusion kinetic for drug release. The former release stage exhibits zero-order dissolution model while the latter release stage exhibits Higuchi square time diffusion model. According to SEM picture and the kinetic model, the outer layer with a large amount of drug is obtained. Therefore, the former mechanism of EC/HPC/ISDN is zero order kinetics. Nevertheless, the gradient concentrations are occurred in the inner part, thus the latter release part is Higuchi square time diffusion model. The microspheres obtained are still surmised to have a core-shell morphology but the skin of the microsphere is a very thin wall allowing high release rates to present one-stage release model. However, when the high ratio EC/HPC matrix of microsphere water uptake too fast, the erosion rate of drug release and matrix water uptake to swell and reach the equilibrium. The outer skin is so thin that the release rate is too fast, so there is only a zero-order release model while the microsphere is too small and the outer layer is too thin. The water immediately uptakes the whole glassy state, so the inner part concentration of microspheres is homogeneous. Because the concentration is larger than the outer part, the ISDN release from the microspheres belongs to zero order mechanism. Also the skin layer of microsphere is comparatively much thinner than the film, so the water immediately attacked the whole glassy state to form the homogeneous inner concentration of the microsphere, which is far larger than the outer concentration. So the ISDN release kinetics of the microsphere is one stage of zero-order kinetics. However, the film presents larger thickness than microsphere that it needs more time for the penetration of water and the swelling of matrix, so the kinetics is two stages controlled release.