高载药量恩杂鲁胺固体分散体的制备及体外评价
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摘要
通过喷雾干燥方法制备载药量高达60%的恩杂鲁胺二元和三元固体分散体,以提高其溶出度。通过表观溶解度试验考察了4种辅料[聚乙烯己内酰胺-聚乙酸乙烯酯-聚乙二醇接枝共聚物(Soluplus)、聚丙烯酸树脂(Eudragit L100)、乙烯吡咯烷酮-乙酸乙烯酯共聚物(Kollidon VA64)和聚乙烯吡咯烷酮(PVP K30)]的增溶作用和抑晶效果,从中筛选合适的辅料;又加入表面活性剂(十二烷基二苯醚二磺酸钠盐和十二烷基硫酸钠)制备了三元固体分散体,并进行体外溶出度试验。采用X射线粉末衍射(XRPD)、扫描电镜(SEM)和差示扫描量热(DSC)分析对制备的固体分散体进行物相鉴别。结果表明,以Soluplus为辅料制备的二元无定形恩杂鲁胺固体分散体能显著提高药物的溶出速率和溶解度。三元固体分散体相较于二元固体分散体能进一步改善恩杂鲁胺的溶解性能,且对过饱和状态下的药物具有良好的抑晶作用。
Enzalutamide solid dispersions with a drug loading up to 60% were prepared by spray drying, in order to enhance the dissolution extent and rate of the poorly soluble drug, enzalutamide. The solubilization and crystallization inhibition effects of four polymers [polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer(Soluplus), methacrylic acid copolymers(Eudragit L100), vinylpyrrolidone-vinyl acetate copolymers(Kollidon VA64), polyvinylpyrrolidone(PVP K30)] were investigated by apparent solubility test. Based on the screening results, a surfactant [sodium lauryl diphenyl ether disulfonate(Dowfax 2 A1) or sodium dodecyl sulfate(SDS)] was added to prepare ternary solid dispersions. Then, the in vitro dissolution of binary solid dispersions with different carriers and the above ternary solid dispersions were investigated in phosphate buffer containing 0.1% Tween-80. The physicochemical properties of the products were characterized by X-ray powder diffraction(XRPD) analysis, scanning electron microscopy(SEM) and differential scanning calorimetry(DSC). The results showed that enzalutamide existed in an amorphous state form in both binary and ternary solid dispersions prepared with Soluplus. It indicated that Soluplus could significantly improve the dissolution rate and extent of enzalutamide. Compared with the binary solid dispersions, the ternary solid dispersions could further improve the solubility of enzalutamide, and could maintain good crystallization inhibition effect in the supersaturated solution.
Enzalutamide solid dispersions with a drug loading up to 60% were prepared by spray drying, in order to enhance the dissolution extent and rate of the poorly soluble drug, enzalutamide. The solubilization and crystallization inhibition effects of four polymers [polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer(Soluplus), methacrylic acid copolymers(Eudragit L100), vinylpyrrolidone-vinyl acetate copolymers(Kollidon VA64), polyvinylpyrrolidone(PVP K30)] were investigated by apparent solubility test. Based on the screening results, a surfactant [sodium lauryl diphenyl ether disulfonate(Dowfax 2 A1) or sodium dodecyl sulfate(SDS)] was added to prepare ternary solid dispersions. Then, the in vitro dissolution of binary solid dispersions with different carriers and the above ternary solid dispersions were investigated in phosphate buffer containing 0.1% Tween-80. The physicochemical properties of the products were characterized by X-ray powder diffraction(XRPD) analysis, scanning electron microscopy(SEM) and differential scanning calorimetry(DSC). The results showed that enzalutamide existed in an amorphous state form in both binary and ternary solid dispersions prepared with Soluplus. It indicated that Soluplus could significantly improve the dissolution rate and extent of enzalutamide. Compared with the binary solid dispersions, the ternary solid dispersions could further improve the solubility of enzalutamide, and could maintain good crystallization inhibition effect in the supersaturated solution.
引文
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[8] JANSSENS S,HUMBEECK J V,VAN DEN MOOTER G. Evaluation of the formulation of solid dispersions by co-spray drying itraconazole with Inutec SP1, a polymeric surfactant, in combination with PVPVA 64[J]. Eur J Pharm Biopharm, 2008, 70(2):500-505
[9] AL-OBAIDI H, KE P, BROCCHINI S, et al.Characterization and stability of ternary solid dispersions with PVP and PHPMA[J]. Int J Pharm, 2011, 419(1/2):20-27.
[10] KUMAR S, SHEN J, BURGESS D J. Nano-amorphous spray dried powder to improve oral bioavailability of itraconazole[J]. J Controlled Release, 2014,192:95-102.
[11] WLODARSKI K, SAWICKI W, HABER K, et al.Physicochemical properties of tadalafil solid dispersionsImpact of polymer on the apparent solubility and dissolution rate of tadalafil[J]. Eur JPharm Biopharm, 2015, 94:106-115.
[2] DOUGLAS A L, SANJAY K, RANDY J W, et al.Formulations of enzalutamide:US, 20140100256[P].2014-04-10.
[3] ALAM M A, ALI R, AL-JENOOBI F I, et al. Solid dispersions:a strategy for poorly aqueous soluble drugs and technology updates[J]. Expert Opin Drug Del, 2012,9(11):1419-1440.
[4] VASCONCELOS T, MARQUES S, DAS NEVES J, et al. Amorphous solid dispersions:Rational selection of a manufacturing process[J]. Adv Drug Deliv Rev, 2016,100:85-101.
[5] LEUNER C, DRESSMAN J. Improving drug solubility for oral delivery using solid dispersions[J]. Eur J Pharm Biopharm, 2000, 50(1):47-60.
[6] ALBADARIN A B, POTTER C B, DAVIS M T, et al.Development of stability-enhanced ternary solid dispersions via combinations of HPMCP and Soluplus(?)processed by hot melt extrusion[J]. Int J Pharm,2017, 532(1):603-61.
[7] MARKS J A, WEGIEL L A, TAYLOR L S, et al. Pairwise polymer blends for oral drug delivery[J]. J Pharm Sci,2014,103(9):2871-2883.
[8] JANSSENS S,HUMBEECK J V,VAN DEN MOOTER G. Evaluation of the formulation of solid dispersions by co-spray drying itraconazole with Inutec SP1, a polymeric surfactant, in combination with PVPVA 64[J]. Eur J Pharm Biopharm, 2008, 70(2):500-505
[9] AL-OBAIDI H, KE P, BROCCHINI S, et al.Characterization and stability of ternary solid dispersions with PVP and PHPMA[J]. Int J Pharm, 2011, 419(1/2):20-27.
[10] KUMAR S, SHEN J, BURGESS D J. Nano-amorphous spray dried powder to improve oral bioavailability of itraconazole[J]. J Controlled Release, 2014,192:95-102.
[11] WLODARSKI K, SAWICKI W, HABER K, et al.Physicochemical properties of tadalafil solid dispersionsImpact of polymer on the apparent solubility and dissolution rate of tadalafil[J]. Eur JPharm Biopharm, 2015, 94:106-115.