• 中国中文核心期刊
  • 中国科学引文数据库核心期刊
  • 中国科技核心期刊
  • 中国高校百佳科技期刊
高级检索

共无定形体系改善低水溶性药物达比加群酯甲磺酸盐和他达拉非的溶出行为及稳定性

鲍兴嘉, 陈鑫, 王世茹, 凌运妮, 张建军, 高缘

鲍兴嘉, 陈鑫, 王世茹, 凌运妮, 张建军, 高缘. 共无定形体系改善低水溶性药物达比加群酯甲磺酸盐和他达拉非的溶出行为及稳定性[J]. 中国药科大学学报, 2019, 50(5): 549-559. DOI: 10.11665/j.issn.1000-5048.20190507
引用本文: 鲍兴嘉, 陈鑫, 王世茹, 凌运妮, 张建军, 高缘. 共无定形体系改善低水溶性药物达比加群酯甲磺酸盐和他达拉非的溶出行为及稳定性[J]. 中国药科大学学报, 2019, 50(5): 549-559. DOI: 10.11665/j.issn.1000-5048.20190507
BAO Xingjia, CHEN Xin, WANG Shiru, LING Yunni, ZHANG Jianjun, GAO Yuan. Coamorphous combinations of poorly water-soluble drugs dabigatran etexilate mesylate and tadalafil for improving dissolution and physical stability[J]. Journal of China Pharmaceutical University, 2019, 50(5): 549-559. DOI: 10.11665/j.issn.1000-5048.20190507
Citation: BAO Xingjia, CHEN Xin, WANG Shiru, LING Yunni, ZHANG Jianjun, GAO Yuan. Coamorphous combinations of poorly water-soluble drugs dabigatran etexilate mesylate and tadalafil for improving dissolution and physical stability[J]. Journal of China Pharmaceutical University, 2019, 50(5): 549-559. DOI: 10.11665/j.issn.1000-5048.20190507

共无定形体系改善低水溶性药物达比加群酯甲磺酸盐和他达拉非的溶出行为及稳定性

基金项目: 国家自然科学基金资助项目(No.81773675,No.81873012);中国药科大学“双一流”建设资助项目(No.CPU2018GY11,No.CPU2018GY27)

Coamorphous combinations of poorly water-soluble drugs dabigatran etexilate mesylate and tadalafil for improving dissolution and physical stability

  • 摘要: 达比加群酯甲磺酸盐(DE)和他达拉非(TD)为低水溶性BCS Ⅱ类药物,本研究通过减压旋蒸法制备DE-TD共无定形,以提高两者溶出度,改善生物利用度。利用X射线粉末衍射法、差量扫描量热分析、傅里叶变换红外光谱、热重分析等手段进行表征,并考察共无定形的溶出行为和稳定性。结果表明,制备获得的DE-TD共无定形物的Tg为119 ℃,红外光谱表明在DE的N-H基团与TD的C==O基团之间可能形成氢键。特性溶出和粉末饱和溶出实验表明,共无定形样品相较于晶体药物可显著改善两种药物的溶出度。DE无定形样品在25 ℃/75%RH恒温恒湿条件下放置10 d即发生转晶,而共无定形样品在25 ℃/60%RH和40℃/75%RH条件下90 d均无转晶现象。
    Abstract: 〓 Dabigatran etexilate mesylate(DE)and tadalafil(TD)are BCS class II drugs with poor water solubility. 〓 In this study coamorphization technique was used to improve their solubilities/dissolutions and hence to enhance their oral absorptions. The coamorphous DE-TD were prepared by solvent-evaporation method and characterized by PXRD, DSC, FTIR and TGA. In addition, dissolution behavior and physical stability were also investigated. Only halo pattern and a single Tg of 119 °C was observed on the PXRD and DSC of the co-evaporated product, respectively, indicating the formation of coamorphous DE-TD. FTIR result suggested that a hydrogen bond was probably formed between N-H group of DE and C==O group of TD. In comparison to crystalline counterparts, coamorphous DE-TD showed a significantly improved intrinsic dissolution rate and prolonged supersaturation time in intrinsic dissolution and supersaturation dissolution studies, respectively. No crystallization was observed under affecting factors testing(30 days)as well as long-term and accelerated stability testing(90 days)for the prepared coamorphous DE-TD under 25°C/60%RH or 40°C/75%RH, while amorphous DE crystalized at 10 days under 25 ℃/75% RH.
  • [1] Guo HH,Miao NN,Li TF,et al.Pharmaceutical coamorphous:a newly defined single-phase amorphous binary system[J].Prog Chem(化学进展),2014,26(2/3):478-486.
    [2] Qian S,Heng WL,Wei YF,et al.Coamorphous lurasidone hydrochloride-saccharin with charge-assisted hydrogen bonding interaction shows improved physical stability and enhanced dissolution with pH-independent solubility behavior[J].Cryst Growth Des,2015,15(6):2920-2928.
    [3] Gao Y,Liao J,Qi X,et al.Coamorphous repaglinide-saccharin with enhanced dissolution[J].Int J Pharm,2013,450(1/2):290-295.
    [4] Loebmann K,Strachan C,Grohganz H,et al.Co-amorphous simvastatin and glipizide combinations show improved physical stability without evidence of intermolecular interactions[J].Eur J Pharm Biopharm,2012,81(1):159-169.
    [5] Qian S, Li Z, Heng WL, et al. Charge-assisted intermolecular hydrogen bond formed in coamorphous system is important to relieve the pH-dependent solubility behavior of lurasidone hydrochloride[J].RSC Adv, 2016,6(108):106396-106412.
    [6] Chavan RB,Thipparaboina R,Kumar D,et al.Coamorphous systems:a product development perspective[J].Int J Pharm,2016,515(1/2):403-415.
    [7] Chen J,Guo HH,Zhang JJ,et al.Physicochemical characteristics of coamorphous simvastatin-gliclazide[J].J China Pharm Univ(中国药科大学学报),2015,46(3):301-308.
    [8] Hernandez I,Baik SH,Pinera A,et al.Risk of bleeding with dabigatran in atrial fibrillation[J].JAMA Intern Med,2015,175(1):18-25.
    [9] Schulman S,Kearon C,Kakkar AK,et al.Extended use of dabigatran,warfarin,or placebo in venous thromboembolism[J].N Engl J Med,2013,368(8):709-718.
    [10] Daugan A,Grondin P,Ruault C,et al.The discovery of tadalafil:a novel and highly selective PDE5 inhibitor.2:2,3,6,7,12,12a-hexahydropyrazino [1′,2′:1,6] pyrido [3,4-b] indole-1,4-dione analogues[J].J Med Chem,2003,46(21):4533-4542.
    [11] Humbert M,Lau EM,Montani D,et al.Advances in therapeutic interventions for patients with pulmonary arterial hypertension[J].Circulation,2014,130(24):2189-2208.
    [12] Bendayan D,Shitrit D,Kramer MR.Combination therapy with prostacyclin and tadalafil for severe pulmonary arterial hypertension:a pilot study[J].Respirology,2008,13(6):916-918.
    [13] Kruger S,Haage P,Breuer C,et al.Diagnosis of pulmonary arterial hypertension and pulmonary embolism with magnetic resonance angiography[J].Chest,2001,120(5):1556-1561.
    [14] Chai FJ,Sun LL,Ding YF,et al.A solid self-nanoemulsifying system of the BCS class IIb drug dabigatran etexilate to improve oral bioavailability[J].Nanomedicine,2016,11(14):1801-1816.
    [15] U.S.Food and Drug Administration.Center for drug evaluation and research application number 22-5.12[EB].(2010-12-15)[2019-02-10] .http:// www.accessdata.fda.gov/ drugsatfda_ docs/ nda/ 2010/ 022512Orig1s000TOC.cfm.
    [16] Wlodarski K,Sawicki W,Haber K,et al.Physicochemical properties of tadalafil solid dispersions - Impact of polymer on the apparent solubility and dissolution rate of tadalafil[J].Eur J Pharm Biopharm,2015,94:106-115.
    [17] Wei YF,Ling YN,Su ML,et al.Characterization and stability of amorphous tadalafil and four crystalline polymorphs[J].Chem Pharm Bull,2018,66(12):1114-1121.
    [18] Hildebrand JH,Scott RL.The solubility of non electrolytes[M].3rd ed.New York:Reinhold Publishing Corporation,1950:153-173.
    [19] Greenhalgh DJ,Williams AC,Timmins P,et al.Solubility parameters as predictors of miscibility in solid dispersions[J].J Pharm Sci,1999,88(11):1182-1190.
    [20] Fedors RF. A method for estimating both the solubility parameters and molar volumes of liquids[J].Polym Eng Sci,1974,14(2):147-154.
    [21] Mohammad MA, Alhalaweh A, Velaga SP. Hansen solubility parameter as a tool to predict cocrystal formation[J].Int J Pharm,2011,407(1/2):63-71.
    [22] Barton AFM.CRC handbook of solubility parameters and other cohesion parameters [M].2nd ed.Florida:CRC Press,1991:160-185.
    [23] Wood J,Syarto J,Letterman H.Improved holder for intrinsic dissolution rate studies[J].J Pharm Sci,1965,54(7):1068.
    [24] Wang FY,Zhang Q,Zhang ZY,et al.Solid-state characterization and solubility enhancement of apremilast drug-drug cocrystals[J].CrystEngComm,2018,20(39):5945-5948.
    [25] Lobmann K,Grohganz H,Laitinen R,et al.Amino acids as co-amorphous stabilizers for poorly water soluble drugs-part 1:preparation,stability and dissolution enhancement[J].Eur J Pharm Biopharm,2013,85(3):873-881.
    [26] Ceric H,Dogan J,Leksic E,et al.Solid state forms of dabigatran etexilate,dabigatran etexilate mysylate and processes for preparation thereof: WO,2012027543A1[P].2012-03-01 [2019-02-16] .
    [27] Wizel S,Vant A,Diller D,et al.Tadalafil crystal forms and processes for preparing them:WO,2006050458A2[P].2006-11-11 [2019-02-16] .
    [28] Yu L.Amorphous pharmaceutical solids:preparation,characterization and stabilization[J].Adv Drug Deliv Rev,2001,48(1):27-42.
    [29] Wlodarski K,Sawicki W,Paluch KJ,et al.The influence of amorphization methods on the apparent solubility and dissolution rate of tadalafil[J].Eur J Pharm Sci,2014,62:132-140.
    [30] Vyas V,Sancheti P,Karekar P,et al.Physicochemical characterization of solid dispersion systems of tadalafil with poloxamer 407[J].Acta Pharm,2009,59(4):453-461.
    [31] Qian S,Wang SS,Li Z,et al.Charge-assisted bond N+-H mediates the gelation of amorphous lurasidone hydrochloride during dissolution[J].Int J Pharm,2017,518(1/2):335-341.
    [32] Guzman HR,Tawa M,Zhang Z,et al.Combined use of crystalline salt forms and precipitation inhibitors to improve oral absorption of celecoxib from solid oral formulations[J].J Pharm Sci,2007,96(10):2686-2702.
    [33] Raina SA,Zhang GGZ,Alonzo DE,et al.Enhancements and limits in drug membrane transport using supersaturated solutions of poorly water soluble drugs[J].J Pharm Sci,2014,103(9):2736-2748.
计量
  • 文章访问数:  711
  • HTML全文浏览量:  0
  • PDF下载量:  1363
  • 被引次数: 0
出版历程
  • 刊出日期:  2019-10-24

目录

    /

    返回文章
    返回
    x 关闭 永久关闭