尼群地平原位凝胶及可生物降解微球的研究
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摘要
以可生物降解的高分子材料为载体，通过制剂新技术将药物制成微球、微囊、纳米粒、凝胶等剂型，用作缓控释注射剂的研究，是近年来药剂学研究的热点之一。尼群地平是一种有效的抗高血压药，极难溶，本文以其为模型药物，尝试了制备原位凝胶注射剂和可生物降解微球注射剂，以期达到延长药物的作用时间、减少用药次数的目的。
本研究首先采用高效液相色谱法(HPLC法)建立了尼群地平原位凝胶和可生物降解微球中药物的含量和有关物质的测定方法；采用分光光度法(UV法)建立了这两种制剂的体外释放度测定方法。
尼群地平原位凝胶的制备采用了研磨法，建立了原位凝胶的质量评价方法。通过单因素考察试验，以药物含量和体外释放为依据筛选原位凝胶注射剂的处方。原位凝胶注射剂释药机理研究结果表明其释药过程符合药物扩散和骨架溶蚀协同作用的机制。稳定性的影响因素试验结果表明原位凝胶注射剂对高温稳定，对高湿和光照不稳定；加速试验结果表明原位凝胶注射剂经过包装后稳定性良好。安全性试验结果表明，尼群地平原位凝胶注射剂无急性毒性、无溶血性，有轻微刺激性，可以肌内注射给药。
尼群地平可生物降解微球的制各采用了乳化溶剂扩散法，建立了微球的质量评价方法。以微球的载药量、包封率和体外释放行为为质量的评价标准，通过单因素考察试验筛选微球的处方和制备工艺。微球释药机理的研究结果表明其释药过程符合药物扩散机制或药物扩散和骨架溶蚀协同作用的机制。稳定性的影响因素试验结果表明，尼群地平微球对高温、高湿和光照均不稳定；加速试验结果表明微球经过包装后稳定性良好。安全性试验结果表明，尼群地平微球无急性毒性、无溶血性，有轻微刺激性，可以肌内注射给药。
对自制尼群地平原位凝胶注射剂、可生物降解微球注射剂和溶液型注射剂进行了家兔体内药动学研究，其体内分析方法采用HPLC法。结果表明，尼群地平原位凝胶、可生物降解微球和溶液的T_(max)依次为1、3和1h；C_(max)依次为(814.1±97.9)、(168.5±10.8)和(1001±161)ng·ml~(-1)； AUC_(0-t)依次为(618.4±96.5)、(430.0±89.6)和(813.6±71.6)ng·d·ml~(-1)；t_(1/2)依次为(5.664±2.259)、(12.59±7.18)和(2.416±0.639)d；C_(24)、C_(30)、C_(14)依次为2.456、2.846和1.220ng·ml~(-1)。以尼群地平溶液为参比制剂，原位凝胶和可生物降解微球的相对生物利用度分
Recently, the studies on sustained/controlled-release injection have become focuses in pharmaceutical studies. In these studies, the formulations such as microspheres, microcapsules, nanoparticles and gels were made containing drugs, in which macromolecules were used as carriers and new pharmaceutical techniques were introduced. Nitrendipine, which is an effective antihypertension drug and has a very low solubility in vitro, was selected as the model drug to prepare in-situ forming gel and biodegradable microspheres by grinding method and quasi-emulsion solvent diffusion method, respectively. The aim of this paper is to prolong the drug's action time and decrease administration times.
High performance liquid chromatography (HPLC) method was developed for in vitro assay of drug content in NTD in-situ forming gel and microspheres. Ultraviolet-visible spectrophotometry (UV) method was used to study the release of drug from the two formulations. HPLC method was also applied to determine the concentration of the related substance of nitrendipine.
Grinding method was selected to prepare in-situ forming gel of nitrendipine, and the evaluation indexes were found to control the quality of nitrendipine in-situ forming gel. By means of the single factor test, formulation factors on drug content and release from in-situ forming gel were investigated and optimized. The in-situ forming gel of nitrendipine with optimum formulation was prepared and it's release, stability, safety and other physical and chemical property were characterized. The release test disclosed that the release of drug from the formulation was mainly diffusion-controlled and erosion-controlled. Influence parameter studies showed that the formulation of nitrendipine was stable under high temperature, but unstable under high humidity and high light. By accelerating test, the stability of the formulation was strengthened in ampoule. The safety test showed that the formulation had no acute toxicity and hemolysis, but had slight stimulation. The in-situ forming gel of nitrendipine could be used as the muscular injection.
The biodegradable microspheres of nitrendipine were prepared by quasi-emulsion solvent diffusion method, and the evaluation indexes were found to control the quality of the microspheres. Applying drug loading, incorporation efficiency and release profiles as main indexes, formulation factors and technology factors were investigated and optimized by the single factor test. The
本研究首先采用高效液相色谱法(HPLC法)建立了尼群地平原位凝胶和可生物降解微球中药物的含量和有关物质的测定方法；采用分光光度法(UV法)建立了这两种制剂的体外释放度测定方法。
尼群地平原位凝胶的制备采用了研磨法，建立了原位凝胶的质量评价方法。通过单因素考察试验，以药物含量和体外释放为依据筛选原位凝胶注射剂的处方。原位凝胶注射剂释药机理研究结果表明其释药过程符合药物扩散和骨架溶蚀协同作用的机制。稳定性的影响因素试验结果表明原位凝胶注射剂对高温稳定，对高湿和光照不稳定；加速试验结果表明原位凝胶注射剂经过包装后稳定性良好。安全性试验结果表明，尼群地平原位凝胶注射剂无急性毒性、无溶血性，有轻微刺激性，可以肌内注射给药。
尼群地平可生物降解微球的制各采用了乳化溶剂扩散法，建立了微球的质量评价方法。以微球的载药量、包封率和体外释放行为为质量的评价标准，通过单因素考察试验筛选微球的处方和制备工艺。微球释药机理的研究结果表明其释药过程符合药物扩散机制或药物扩散和骨架溶蚀协同作用的机制。稳定性的影响因素试验结果表明，尼群地平微球对高温、高湿和光照均不稳定；加速试验结果表明微球经过包装后稳定性良好。安全性试验结果表明，尼群地平微球无急性毒性、无溶血性，有轻微刺激性，可以肌内注射给药。
对自制尼群地平原位凝胶注射剂、可生物降解微球注射剂和溶液型注射剂进行了家兔体内药动学研究，其体内分析方法采用HPLC法。结果表明，尼群地平原位凝胶、可生物降解微球和溶液的T_(max)依次为1、3和1h；C_(max)依次为(814.1±97.9)、(168.5±10.8)和(1001±161)ng·ml~(-1)； AUC_(0-t)依次为(618.4±96.5)、(430.0±89.6)和(813.6±71.6)ng·d·ml~(-1)；t_(1/2)依次为(5.664±2.259)、(12.59±7.18)和(2.416±0.639)d；C_(24)、C_(30)、C_(14)依次为2.456、2.846和1.220ng·ml~(-1)。以尼群地平溶液为参比制剂，原位凝胶和可生物降解微球的相对生物利用度分
Recently, the studies on sustained/controlled-release injection have become focuses in pharmaceutical studies. In these studies, the formulations such as microspheres, microcapsules, nanoparticles and gels were made containing drugs, in which macromolecules were used as carriers and new pharmaceutical techniques were introduced. Nitrendipine, which is an effective antihypertension drug and has a very low solubility in vitro, was selected as the model drug to prepare in-situ forming gel and biodegradable microspheres by grinding method and quasi-emulsion solvent diffusion method, respectively. The aim of this paper is to prolong the drug's action time and decrease administration times.
High performance liquid chromatography (HPLC) method was developed for in vitro assay of drug content in NTD in-situ forming gel and microspheres. Ultraviolet-visible spectrophotometry (UV) method was used to study the release of drug from the two formulations. HPLC method was also applied to determine the concentration of the related substance of nitrendipine.
Grinding method was selected to prepare in-situ forming gel of nitrendipine, and the evaluation indexes were found to control the quality of nitrendipine in-situ forming gel. By means of the single factor test, formulation factors on drug content and release from in-situ forming gel were investigated and optimized. The in-situ forming gel of nitrendipine with optimum formulation was prepared and it's release, stability, safety and other physical and chemical property were characterized. The release test disclosed that the release of drug from the formulation was mainly diffusion-controlled and erosion-controlled. Influence parameter studies showed that the formulation of nitrendipine was stable under high temperature, but unstable under high humidity and high light. By accelerating test, the stability of the formulation was strengthened in ampoule. The safety test showed that the formulation had no acute toxicity and hemolysis, but had slight stimulation. The in-situ forming gel of nitrendipine could be used as the muscular injection.
The biodegradable microspheres of nitrendipine were prepared by quasi-emulsion solvent diffusion method, and the evaluation indexes were found to control the quality of the microspheres. Applying drug loading, incorporation efficiency and release profiles as main indexes, formulation factors and technology factors were investigated and optimized by the single factor test. The
引文
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