| AB is an immunosuppressant with a 31-membered triene macrolide lactam structure. It blocks signaling transduction from multiple cytokines receptor, inhibits the progression of T cells and other cells through G1 phase to S phase, exerts its immunosuppressive effect. Currently it is the world most new and effective immunosuppressive agent, possesses immunosuppressive activity 100-fold greater than cyclosporine which is widely used in the clinic and low toxicity. It is indicated for the prophylaxis and treatment of organ rejection after receiving organ transplant and autoimmune diseases such as rheumatoid arthritis, lupus erythematosus, dry eye syndrome. From the current clinical application, it has very good anti-rejection effect, and it has a better clinical therapeutic effect if AB be used in a combination therapy with other immunosuppressants such as cyclosporine A. It is a kind of high efficiency, low toxicity, no renal toxicity and specificity of anti-oncology of novel immunosuppressive inhibitors.AB is poorly water-soluble drugs. Following oral administration, AB is rarely absorbed in the human body, with low bioavailability and large individual differences. At present in domestic and abroad market, two dosage forms for AB were developed and marketed, namely oral solution and tablet. Absolute bioavailability of AB oral solution is only about 14%. Imported AB tablet by using nanocrystalline technology, show a 27% increased bioavailability compared to the oral solution. AB tablet has entered into the Chinese market, but it can not be copied because of patent protection. AB is instable under stress conditions, such as high temperature, high humidity, light and other factors. the related substances are difficult to control and content significantly decrease in such conditions, product quality is difficult to qualified. So the long-term research was conducted in many aspects to improve its stability and bioavailability.Objective:Solid dispersion technology can significantly improve the solubility and bioavailabity of poorly soluble drugs, so AB solid dispersions were developed by this technology to achieve the purpose of solubilization. Formulation screening and process optimization were conducted by dissolution test and accelerating stability test at 60℃ for 10 days. The analytical methods were established to carry out stability study and pharmacokinetic experiments were used to determinate the bioavailability of AB capsule.Method:The development of AB capsule: AB solid dispersions were prepared by solvent coprecipitation method with water-soluble carriers: hydroxypropyl methyl cellulose of low viscosity(HPMC 3cps), polyvinylpyrrolidone(PVP k30), hydroxypropyl beta cyclodextrin(HP-β-CD), the surfactant Poloxamer 188, 40 hydrogenated castor oil polyoxyethylene(RH40), 35 castor oil polyoxyethylene(EL-35). The carrier materials and dosage were screened. Suitable amount of excipients and disintegrating agents were added. To increase the solubilization, the water-insoluble hydrophilic colloidal silica materials with good stability and larger specific surface area were added for further dispersion. AB solid dispersions were prepared by mixing, drying, crushing and sieving process. Then AB solid dispersions were prepared to AB capsule mixed with suitable amount of fillers. Dissolution test and accelerated stability test at 60℃ for 10 days were carried out to screen the formulation and process. Identification of AB solid dispersions were through differential thermal analysis and X-ray diffraction analysis.Quality research of AB capsule: The analytical methods of content, content uniformity, dissolution tests for AB capsule were established and the corresponding methodological studies were conducted. AB capsule was prepared according to the optimal formulation and process. One batch of trial samples were carried out stress testing, including the effect of the strong light, high temperature, high humidity factors. Three batches of trial samples were investigated the accelerated stability at 40℃and long-term stability at 25℃, the measuring items included character, dissolution, content, and related substances.Pharmacokinetic study of AB capsule: Three pharmacokinetic studies were performed separately in the male rhesus monkeys by single-dose crossover experiments design: the bioequivalence study of AB capsule, AB oral solution and AB microemulsion oral solution; the pharmacokinetic study of AB capsule after following high, medium and low three different dosage of administration; pharmacokinetic study of AB capsule under fed conditions and fasting conditions. The relative bioavailability, the correlation of drug dosage and bioavailability, and the food effects on AB capsule were Investigated.Result:AB solid dispersions of water-soluble carrier were prepared by solvent coprecipitation method. The solid dispersions carriers and dosage were screened based on the feasibility study of preparation process, dissolution test, and accelerated stability at 60℃ high temperature for 10 days. HP-β-CD were determined for the optimizing formulation preliminarily. Then colloidal silica materials were added for further dispersion to increase the solubilization, the optimal formulation was determined through screening the usage amounts of colloidal silica, excipients, disintegrating agents and filling agents. Solvent coprecipitation production process was determined through the simple and good reproducibility of process between wet granulation process technique and solvent coprecipitation production process. Process parameters were further optimized by orthogonal design. By differential thermal analysis and X-ray diffraction analysis, AB crystal state were observed disappear in the AB solid dispersions and exist in amorphous state, thus achieving the purpose of solubilization。The analytical methods of content, content uniformity, dissolution tests for AB capsule were established and proved be reliable, accurate and sensitive by the corresponding methodological studies. Stress testing results indicated that AB capsule was sensitive to humidity. The preparation should use moisture proof package to ensure the stability. The stability study results of accelerated stability study at 40℃for 6 months and long-term stability study at 25℃for 12 months proved that AB capsule not only had achieved expected solubilization effect, but also showed good stability, feasible technology and good repeatability.The pharmacokinetic study of different formulations in animals showed the bioavailability of AB capsule was significantly higher than the commercial AB oral solution,the relative bioavailability of AB capsule was 181.36% compared to the AB oral solution. The pharmacokinetic studies of different administered dose showed that Cmax and AUC(0-t) increased with the increase of the administered dose, and had a linear correlation with dose. The pharmacokinetic study under fed and fasted condition showed that bioavailability of AB capsule decreased due to food.Conclusion : AB is poorly water-soluble drugs. Following oral administration, AB is rarely absorbed in the human body, with low bioavailability and large individual differences. AB capsule was prepared by solid dispersion technology to realize the significant solubilization purpose. The pharmaceutical and quality studies had showed that the formulation was stable, production process was simple and repeatability was good. In-vivo pharmacokinetic study in animals further demonstrated that AB capsule had higher bioavailability comparing with commercial AB oral solution.The bioavailability had a linear correlation with administered dose and decreased due to food-effect. Compared to commercial AB oral solution, AB capsule that we developed not only had higher bioavailability, but also as a solid preparation was more convenient to use and store under the normal temperature. So it is potential to be developed. |
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