| This study selected a model drug nimodipine (Nimodipine, NMD), which is a dihydropyridine calcium channel blocker. Because NMD could pass through the blood-brain barrier, increase the tolerance to hypoxia of brain cells, it can be used for the treatment of cerebral dysfunction such as ischemic cerebrovascular disease, migraine, cerebral infarction, cerebral hemorrhage, also mild to moderate hypertension, senile dementia, vertebrobasilar insufficiency etc. It is safe and effective in clinical use.NMD is a poorly water-soluble drug, its solubility in water is about 4μg·mL-1; but it belonged to the second category of drugs in Biopharmaceutical Classification System because of its larger partition coefficient (LogP=4.144). For such kind of drugs, dissolution is the rate-limiting step in absorption, thus for enhancing its bioavailability in vivo, the key point is in vitro dissolution is increased effectively.In this study, firstly, per-processed the micronize NMD into solid dispersion with high dissolution, and then, post-processed the solid dispersion into semi-solid matrix capsules. By combining the two technologies, through increasing dissolution, the ultimate goal is to enhance in vivo absorption of NMD, further to achieve higher bioavailability.In this research, NMD solid dispersion was prepared by hot-melt extrusion technology. The principle as follows:the active ingredient and adjuvant which was mixed uniformly was transported into temperature controlled conveying system under the promotion and high-intensity extrusion of twin-screw, by softening, melting, shearing, dispersion, mixing again, together with the barrel-watt thermal heating and mechanical energy of twin-screw extrusion, material was changed from aggregation state to molecular state, refinement of the same materials and homogenization among dissimilar materials were achieved, and ultimately to achieve uniform mixing of molecular states. Based on solubility parameter theory, through prescription screening, accorded to "NMD-EudragitE100-PlasdoneS630 5:4:1 (w/w)" prepared solid dispersion, after added 2.0% silica, it is difficult to gather and crystallize for the powder, each solid dispersion particle which were coated by silica and formed a independent individual unit, the hydrophilic silica powder dispersed the units into dissolution media, then NMD entered media from the unit without any interference, the individual acts converged general behavior. It appeared as:containing by the mixed carrier EudragitE100 and PlasdoneS630, NMD could reach a higher dissolution in O.1mol·L-1 HCl (about 70% at 5 min and maintenance of 80% between 10-30min). Combined of differential scanning calorimetry, X-ray powder diffraction and infrared spectroscopy to identify, crystal of NMD disappeared and it existence with amorphous state in solid dispersion. Through the analysis of influencing factors, the chemical properties of solid dispersion powder was stable; but physical stability was affected mainly by heat, namely under high temperature, NMD crystallized and dissolution decreased significantly. Therefore, besides shading and sealing, the NMD solid dispersion powder need preserved under lower temperature.To achieve a higher dissolution and prepare more stable agent, semi-solid matrix was utilized in this study, for post-processing the NMD solid dispersion. The basic idea is:at high temperature, disperse the NMD solid dispersion powder into molten matrix, which was composed of high melting point material and low melting point material, and then fill into a hard capsule quantitatively. Achieve Nimodpine Semi-Solid Matrix Capsule (NMD-SSMC), with meliceris content at room temperature. In this study, Plasdone-S630 was used as high melting point matrix; PEG400 was used as low melting point matrix. The capsules obtained could achieve 95% dissolution in O.lmol·L-1 HCl. In addition, in pH4.5 acetate buffer, pH6.8,7.2 phosphate buffer and water, NMD dissolution all could reach more than 90% within 20min. And what is more, dissolution of NMD-SSMC was significantly higher than domestic and imported tablets in market. According to the researches of viscosity and cooling rate, in large-scale production, the material could be filled into hard capsules at 60℃, R.S.D. of weight variation could be controlled at 2%. And no liquid leakage was found. Influencing factors test, accelerated test and long-term stability test indicated, NMD-SSMC with package can be stored at room temperature. Simulated commercial packaging, after stored 6 months under 40±2℃, RH75±5%, and 12 months under 25±2℃, RH60±10% separately, there was no reduction in content, although speed of NMD dissolution became much slow down, but still be able to reach 90% until 30min.As a non-clinical pharmacokinetic evaluation, two formulations, two-cycle, randomized, crossover, own control study was applied, with administration of oral single dose. HPLC method was applied to determine plasma concentration of test (NMD-SSMC) and reference (Nimotop) in beagle dogs. Analysesed by DAS 2.1.1, Cmax of NMD-SSMC was 375.30ng·mL-1, appeared at 1.58hr; while Cmax of Nimotop was 319.08ng·mL-1, appeared at 3.17hr. Both AUC(0-t) and AUC(0-∞), NMD-SSMC were approximately 1.5 times compared with Nimotop, The dosage form characteristics of semi-solid matrix capsules speed up the dissolution of drugs, and PEG400 in the gastrointestinal tract can increase the permeability of epithelial cells to promote the absorption of water insoluble drugs, therefore, compared with the tablet, drugs with first-pass effect dispersed from semi-solid matrix capsules, could saturate metabolizing enzymes more rapidly, with a larger amount entered blood, its oral bioavailability was improved. |
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