美洛昔康固体分散体片的制备及其溶出度研究

Preparation of Meloxicam Solid Dispersion Tablets and Study of the Dissolution

关键词:  美洛昔康  固体分散体  溶出  制备工艺  片剂

Key words:  meloxicam  solid dispersion  dissolution  preparation procedure  tablets

摘要:

目的 制备美洛昔康固体分散体片，并考察其体外溶出度。方法 开展抑晶试验初步筛选载体材料，采用X射线衍射仪(X-ray diffraction，XRD)、差示扫描量热仪(differential scanning calorimeter，DCS)对固体分散体进行表征。通过体内药动学测定，评价固体分散体的生物利用度改善情况。考察美洛昔康固体分散体片的最佳制备工艺，并以体外溶出曲线相似因子f₂为主要评价指标，筛选并优化处方中的pH调节剂、填充剂、崩解剂、润滑剂和助流剂用量及混料时间。结果 以Kollidon＠VA64为载体制备的固体分散体有效维持了药物在溶液中的过饱和状态，XRD和DSC结果表明固体分散体中晶体状态的美洛昔康完全转变为非晶态。与原料药相比，固体分散体显著提高了美洛昔康的溶解度，峰值血药浓度(C_max)和相对生物利用度分别提高了208.09%和241.78%。以粉末直接压片法制备的美洛昔康固体分散体片最佳处方及工艺：美洛昔康固体分散体35.2%，乳糖∶微晶纤维素=1∶1.5，枸橼酸钠9.8%，交联聚维酮8%，硬脂酸镁0.75%，二氧化硅0.8%，混料时间5 min。制备的美洛昔康固体分散体片与原研参比制剂在不同pH介质中的溶出相似因子f₂均>50。结论 采用热熔挤出技术与粉末直接压片法制备了美洛昔康固体分散体片，提高了美洛昔康的溶出度和生物利用度，并与原研参比制剂具有相似的溶出行为。

Abstract:

OBJECTIVE To prepare meloxicam solid dispersions tablets, and to investigate their dissolution in vitro. METHODS Crystal inhibition experiments were carried out to screen the carrier materials, and the solid dispersion was characterized by X-ray diffraction(XRD) amd differential scanning calorimeter(DCS). The improved bioavailability of solid dispersions was evaluated through in vivo pharmacokinetic studies. The optimum preparation process of meloxicam solid dispersion tablets was investigated, and the in vitro dissolution curve similarity factor f₂ was used as the main evaluation index to screen and optimize the dosage of pH regulator, filler, disintegrator, lubricant, flow aid and the mixing time in the prescription. RESULTS The solid dispersion prepared with Kollidon@VA64 as carrier effectively maintained the supersaturated state of the drug in solution. The results of XRD and DSC showed that the crystal state of meloxicam in the solid dispersion was completely transformed into amorphous state. Compared with meloxicam, solid dispersions significantly increased the solubility, and its peak blood concentration(C_max) and relative bioavailability were increased by 208.09% and 241.78%, respectively. The optimal formulation and process of meloxicam solid dispersion tablets prepared by direct powder pressing method were meloxicam solid dispersion 35.2%, lactose∶microcrystalline cellulose =1∶1.5, sodium citrate 9.8%, crosslinked povidone 8%, magnesium stearate 0.75%, silica 0.8%, and mixing time 5 min. The dissolution similarity factor f₂ of the prepared meloxicam solid dispersion tablets and the original reference preparation in different pH medium was above 50. CONCLUSION Meloxicam solid dispersible tablets are prepared by hot melt extrusion and powder pressing method. The dissolution and bioavailability of meloxicam are improved, and the dissolution behavior of meloxicam is similar to that of the original reference preparation.