药学学报, 2022, 57(5): 1486-1494
引用本文:
严梦梦, 吴秀娟, 朱恒清, 刘思远, 袁熙敏, 丁汉成, 衡伟利, 张建军, 钱帅. 基于溶解度参数法和差式扫描量热法优化筛选奥拉帕利固体分散体载体[J]. 药学学报, 2022, 57(5): 1486-1494.
YAN Meng-meng, WU Xiu-juan, ZHU Heng-qing, LIU Si-yuan, YUAN Xi-min, DING Han-cheng, HENG Wei-li, ZHANG Jian-jun, QIAN Shuai. Optimization and screening of carrier for solid dispersion of olaparib based on the solubility parameter and differential scanning calorimetry[J]. Acta Pharmaceutica Sinica, 2022, 57(5): 1486-1494.

基于溶解度参数法和差式扫描量热法优化筛选奥拉帕利固体分散体载体
严梦梦1, 吴秀娟1, 朱恒清1, 刘思远2, 袁熙敏2, 丁汉成1, 衡伟利1, 张建军2, 钱帅1*
1. 中国药科大学中药学院, 江苏 南京 211198;
2. 中国药科大学药学院, 江苏 南京 211198
摘要:
固体分散体是药物高度分散在载体材料中形成的分散体系,常用于改善难溶性药物的溶解度及溶出速率。药物与载体的混溶性是固体分散体溶出性能改善及产品稳定的关键,因此载体种类的选择及载药量的优化至关重要。本研究通过溶解度参数法和Flory-Huggins相互作用理论初步预测奥拉帕利(OLP)与不同载体(VA64、Soluplus、Plasdone S630和Kollidon K29/32)的混溶性,并结合差式扫描量热法(DSC)对药物和载体的混溶性进行实验评估,筛选出具有良好混溶性的载体材料。通过绘制药物与载体的混溶性相图,优选出两者的最佳比例。理论计算和实验评估表明,OLP与VA64的混溶性最佳,当载药量为30%时可同时满足较大载药量和物理稳定性的需求。偏光显微镜、X-射线衍射法、DSC和激光共聚焦拉曼光谱法表明,固体分散体中OLP呈无定形态分散在载体中。粉末溶出试验表明,与OLP晶体相比,其体外溶出度明显提高。本研究采用理论计算和DSC实验评估筛选载体,并得到药物与载体的最佳配比,为固体分散体载体的选择及用量的确定提供更为有效的研究策略。
关键词:    固体分散体      奥拉帕利      载体      理论计算      实验评估     
Optimization and screening of carrier for solid dispersion of olaparib based on the solubility parameter and differential scanning calorimetry
YAN Meng-meng1, WU Xiu-juan1, ZHU Heng-qing1, LIU Si-yuan2, YUAN Xi-min2, DING Han-cheng1, HENG Wei-li1, ZHANG Jian-jun2, QIAN Shuai1*
1. School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, China;
2. School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China
Abstract:
Solid dispersion, a dispersion system in which drug molecules are highly dispersed in carrier materials, has been commonly used to improve the solubility and dissolution rate of poorly soluble drugs. The miscibility between drug and carrier is crucial to improve the dissolution performance and stability of solid dispersion. Therefore, the selection of carrier types and the optimization of drug loading are very important. In the current study, the solubility parameter method and Flory-Huggins theory were used to predict the miscibility between olaparib (OLP) and different carriers (VA64, Soluplus, Plasdone S630 and Kollidon K29/32). Besides, the carrier material with good miscibility was experimentally screened by differential scanning calorimetry (DSC). The optimum of drug-carrier ratio was further performed based on the miscibility phase diagram of drug and carrier. Theoretical calculation and experimental evaluation showed that the miscibility of OLP and VA64 was the best, and the drug loading of 30% could meet the requirements of large drug loading and physical stability. Polarizing light microscope, X-ray powder diffraction, DSC and laser confocal Raman spectroscopy exhibited that OLP was amorphous form in the solid dispersion system. Powder dissolution test demonstrated that the solid dispersion showed significantly enhanced dissolution rate in comparison to crystalline OLP. In this study, theoretical calculation and experimental evaluation were used to screen the types of carriers and optimize the drug loading, which provides an efficient strategy for the selection of carrier and the amount used in solid dispersion.
Key words:    solid dispersion    olaparib    carrier    theoretical calculation    experimental evaluation   
收稿日期: 2021-08-31
DOI: 10.16438/j.0513-4870.2021-1261
基金项目: 国家自然科学基金资助项目(82074029,82104401);中国博士后基金资助项目(2020M671665,2021M693517);国家药品监督管理局药品监管创新与评价基金项目(3342100010);中央高校基金资助项目(2632021ZD15).
通讯作者: 钱帅,Tel:13915957175,E-mail:silence_qs@163.com
Email: silence_qs@163.com
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参考文献:
[1] Di L, Kerns EH, Carter GT. Drug-like property concepts in pharmaceutical design[J]. Curr Pharm Des, 2009, 15:2184-2194.
[2] Guo H, Miao N, Li T, et al. Pharmceutical coamorphous-a newly defined single-phase amorphous binary system[J]. Prog Chem (化学进展), 2014, 26:478-486.
[3] Verheyen S, Blaton N, Kinget R, et al. Mechanism of increased dissolution of diazepam and temazepam from polyethylene glycol 6000 solid dispersions[J]. Int J Pharm, 2002, 249:45-58.
[4] Pandi P, Bulusub R, Komminenic N, et al. Amorphous solid dispersions:an update for preparation, characterization, mechanism on bioavailability, stability, regulatory considerations and marketed products[J]. Int J Pharm, 2020, 586:119560.
[5] Jiang T, Zheng L, Yuan M, et al. Preparation and quality evaluation of azelnidipine enteric solid dispersion[J]. China Pharm (中国药房), 2021, 32:1862-1867.
[6] Chaudhary S, Nair AB, Shah J, et al. Enhanced solubility and bioavailability of dolutegravir by solid dispersion method:in vitro and in vivo evaluation-a potential approach for HIV therapy[J]. Pharm Sci Tech, 2021, 22:127.
[7] Trasi NS, Purohit HS, Taylor LS. Evaluation of the crystallization tendency of commercially available amorphous tacrolimus formulations exposed to different stress conditions[J]. Pharm Res, 2017, 34:2142-2155.
[8] Yan H, Huang Y, Shen Y, et al. A review on carriers and preparation techniques of amorphous solid dispersion[J]. Chin J New Drugs (中国新药杂志), 2017, 26:427-432.
[9] Cai P, Ou L, Zhao G, et al. Research progress in the influence of carrier materials on the dissolution behavior of solid dispersion and its mechanism[J]. Chin J New Drugs (中国新药杂志), 2021, 30:1600-1604.
[10] Paudel A, Worku ZA, Guns JMS, et al. Manufacturing of solid dispersions of poorly water soluble drugs by spray drying:formulation and process considerations[J]. Int J Pharm, 2013, 453:253-284.
[11] Ponnammal P, Kanaujia P, Yani Y, et al. Orally disintegrating tablets containing melt extruded amorphous solid dispersion of tacrolimus for dissolution enhancement[J]. Pharmaceutics, 2018, 10:35.
[12] Zhao X, Du L, Zhang X, et al. Compatibility and phase separation of polymer blends[J]. Chin Polym Bull (高分子通报), 2001, 4:75-81.
[13] Gao Q, Kong B, Yin R. The PARP inhibitors for the treatment of recurrent ovarian cancer[J]. Prog Obstet Gynecol (现代妇产科进展), 2018, 27:721-725.
[14] Mohammad MA, Alhalaweh A, Velaga SP. Hansen solubility parameter as a tool to predict cocrystal formation[J]. Int J Pharm, 2011, 407:63-71.
[15] Karger BL, Snyder LR, Eon C. An expanded solubility parameter treatment for classification and use of chromatographic solvents and adsorbents[J]. J Chromatogr A, 1976, 125:71-88.
[16] Van Krevelen DW. Cohesive Properties and Solubility[M]. Amsterdam:Elsevier, 1997:189-225.
[17] Fedors RF. A method for estimating both the solubility parameters and molar volumes of liquids[J]. Polym Eng Sci, 1974, 14:8.
[18] Forster A, Hempenstall J, Tucker I, et al. Selection of excipients for melt extrusion with two poorly water-soluble drugs by solubility parameter calculation and thermal analysis[J]. Int J Pharm, 2001, 226:147-161.
[19] Gupta J, Nunes C, Vyas S, et al. Prediction of solubility parameters and miscibility of pharmaceutical compounds by molecular dynamics simulations[J]. J Phys Chem, 2011, 115:2014-2023.
[20] Hansen CM.Hansen Solubility Parameters:A User's Handbook[M]. 2nd. Hoboken:CRC Press, 2007.
[21] Just S, Sievert F, Thommes M, et al. Improved group contribution parameter set for the application of solubility parameters to melt extrusion[J]. Eur J Pharm Biopharm, 2013, 85:1191-1199.
[22] Tian Y, Qian K, Jacobs E, et al. The investigation of Flory-Huggins interaction parameters for amorphous solid dispersionacross the entire temperature and composition range[J]. Pharmaceutics, 2019, 11:420.
[23] Hildebrand JH, Scott RL. The Solubility of Non-Electrolytes[M]. New York:Reinhold, 1950.
[24] Marsac PJ, Li T, Taylo LS. Estimation of drug-polymer miscibility and solubility in amorphous solid dispersions using experimentally determined interaction parameters[J]. Pharm Res, 2009, 26:139-151.
[25] Tian Y, Booth J, Meehan E, et al. Construction of drug-polymer thermodynamic phase diagrams using Flory-Huggins interaction theory:identifying the relevance of temperature and drug weight fraction to phase separation within solid dispersions[J]. Mol Pharm, 2013, 10:236-248.
[26] Potter CB, Davis MT, Albadarin AB, et al. Investigation of the dependence of the Flory-Huggins interaction parameter on temperature and composition in a drug-polymer system[J]. Mol Pharmaceut, 2018, 15:5327-5335.
[27] Lin D, Huang Y. A thermal analysis method to predict the complete phase diagram of drug-polymer solid dispersions[J]. Int J Pharm, 2010, 399:109-115.
[28] Thakore SD, Akhtar J, Jain R, et al. Analytical and computational methods for the determination of drug-polymer solubility and miscibility[J]. Mol Pharm, 2021, 18:2835-2866.
[29] Guo Z, Lu M, Li Y, et al. The utilization of drug-polymer interactions for improving the chemical stability of hot-melt extruded solid dispersions[J]. J Pharm Pharmacol, 2014, 66:285-296.
[30] Li D, Guo G, Deng X, et al. PLA/PEG-PPG-PEG/dexamethasone implant prepared by hot-melt extrusion for controlled release of immunosuppressive drug to implantable medical devices, part 2:in vivo evaluation[J]. Drug Deliv, 2013, 20:134-142.
[31] Qian F, Huang J, Hussain MA. Drug-polymer solubility and miscibility:stability consideration and practical challenges in amorphous solid dispersion development[J]. J Pharm Sci, 2010, 99:2941-2947.
[32] Wang X, Zhao J, Song Y. Preparation of rivaroxaban solid dispersion by hot melt extrusion[J]. Chin J New Drugs (中国新药杂志), 2018, 27:714-719.
[33] Zhao Y, Inbar P, Chokshi HP, et al. Prediction of the thermal phase diagram of amorphous solid dispersions by Flory-Huggins theory[J]. J Pharm Sci, 2011, 100:3196-3207.
[34] Menear KA, Ottridge AP, Londesbrough DJ, et al. Polymorphic form of 4-[3-(4-cyclopropanecarbonyl-piperazine-‍1-carbonyl)-4-fluoro-benzyl] ‍-2H-phyhalazin-1-one:EP, 2064189[P].2008-04-24.
[35] Gokce H, Bahceli S. A study of molecular structure and vibrational spectra of copper(II) halide complex of 2-(2'-thienyl)pyridine[J]. Spectrochim Acta A Mol Biomol Spectrosc, 2012, 96:139-147.
[36] Hurley D, Carter D, Ng LYF, et al. An investigation of the inter-molecular interaction, solid-state properties and dissolution properties of mixed copovidone hot-melt extruded solid dispersions[J]. J Drug Deliv Sci Tec, 2019, 53:101132.
[37] Song H, Gao L, Fu Q. Improcement of in vitro dissolution and physical stability for spironolactone solid dispersion formulated with Soluplus[J]. Acta Pharm Sin (药学学报), 2019, 54:14-21.
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