CN114555124A - 药物共晶盐制剂 - Google Patents
药物共晶盐制剂 Download PDFInfo
- Publication number
- CN114555124A CN114555124A CN202080073340.0A CN202080073340A CN114555124A CN 114555124 A CN114555124 A CN 114555124A CN 202080073340 A CN202080073340 A CN 202080073340A CN 114555124 A CN114555124 A CN 114555124A
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- Prior art keywords
- api
- salt
- pharmaceutically acceptable
- acid
- mixture
- Prior art date
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- 239000000374 eutectic mixture Substances 0.000 claims abstract description 28
- 239000002904 solvent Substances 0.000 claims abstract description 21
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 18
- 230000005496 eutectics Effects 0.000 claims abstract description 17
- 238000001556 precipitation Methods 0.000 claims abstract description 16
- 239000003112 inhibitor Substances 0.000 claims abstract description 15
- 239000007788 liquid Substances 0.000 claims abstract description 12
- 238000000034 method Methods 0.000 claims description 25
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- 239000002253 acid Substances 0.000 claims description 16
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- HPFDGTFXAVIVTH-UHFFFAOYSA-N 1-((1-((1-Methoxypropan-2-yl)oxy)propan-2-yl)oxy)propan-2-ol Chemical compound COCC(C)OCC(C)OCC(C)O HPFDGTFXAVIVTH-UHFFFAOYSA-N 0.000 claims description 2
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- JFMGYULNQJPJCY-UHFFFAOYSA-N 4-(hydroxymethyl)-1,3-dioxolan-2-one Chemical compound OCC1COC(=O)O1 JFMGYULNQJPJCY-UHFFFAOYSA-N 0.000 claims description 2
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- UYUXSRADSPPKRZ-UHFFFAOYSA-N D-glucuronic acid gamma-lactone Natural products O=CC(O)C1OC(=O)C(O)C1O UYUXSRADSPPKRZ-UHFFFAOYSA-N 0.000 claims description 2
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- DKMROQRQHGEIOW-UHFFFAOYSA-N Diethyl succinate Chemical compound CCOC(=O)CCC(=O)OCC DKMROQRQHGEIOW-UHFFFAOYSA-N 0.000 claims description 2
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- 229920005682 EO-PO block copolymer Polymers 0.000 claims description 2
- KMTRUDSVKNLOMY-UHFFFAOYSA-N Ethylene carbonate Chemical compound O=C1OCCO1 KMTRUDSVKNLOMY-UHFFFAOYSA-N 0.000 claims description 2
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- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 claims description 2
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- VKNUORWMCINMRB-UHFFFAOYSA-N diethyl malate Chemical compound CCOC(=O)CC(O)C(=O)OCC VKNUORWMCINMRB-UHFFFAOYSA-N 0.000 claims description 2
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- XTDYIOOONNVFMA-UHFFFAOYSA-N dimethyl pentanedioate Chemical compound COC(=O)CCCC(=O)OC XTDYIOOONNVFMA-UHFFFAOYSA-N 0.000 claims description 2
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Abstract
本发明涉及一种在37℃和1atm下为液体的药物组合物,所述药物组合物包含至少一种活性药物成分(API)盐、亲水性药学上可接受的共晶组分和聚合物增溶剂的共晶混合物,并且还包含沉淀抑制剂(PI)。在另一个方面,本发明涉及用于制备该组合物的方法。
Description
本发明涉及药物制剂领域。具体而言,本发明涉及一种基于共晶混合物制备药物制剂的方法以及通过该方法可获得的制剂。
过去十年里,人们对提高药物溶解度和生物利用度的配方技术越来越感兴趣。由于溶解度差、大规模固有成本高、漫长的时间延迟,药物研发中约40%的药物无法上市。因此,显然需要开发使药物更易溶解的方法。已经尝试了几种方法来解决这个问题,例如用聚合物配制药物、在给药前使药物溶解在脂质中、使药物颗粒微粉化和结晶工程(例如盐)。
口服途径是最优选的活性成分给药途径,因为其有几个好处,例如更好的患者依从性、安全性和多功能性。因此,大量的活性成分以口服药物剂型配制,主要用作固体药物制备,例如片剂、咀嚼片、胶囊。然而,在开发用于口服给药的固体形式时存在一些障碍和困难,因为许多活性药物成分在水性溶液中的溶解度较低,导致溶解速率降低,治疗效果有限。活性成分的水溶性是最重要的物理化学性质之一,因为低水溶性和低溶解速率会降低活性成分在胃肠道的吸收。活性成分溶解度低也会导致生物利用度降低、食物效应几率增加、剂型不完全释放更频繁、患者间变化性更大。
水溶性差的活性药物成分是通常在水中溶解度低于0.1mg/ml的化合物,占药物活性成分的绝大多数,因此限制了其潜在用途,增加了配制生物可利用药物产品的难度。在该类中,示例活性成分包括伊曲康唑(Itraconazole)、环孢素A(Cyclosporine A)、卡维地洛(Carvedilol)和灰黄霉素(Griseofulvin)。溶解不良的活性成分已经刺激了活性成分递送技术的发展,通过活性成分分子周围环境的化学或机械改变,或物理改变聚集的活性成分颗粒的大分子特性,克服了其溶解的障碍。这些技术包括增强溶解度的传统方法,如粒径减小、在环糊精活性成分复合物中添加表面活性剂和包含物,也包括使用更新颖的机制,如自乳化体系、通过纳米颗粒微粉化、pH调节和盐溶过程。
已知多种方法可用于口服给药剂型的工业制备,所述口服给药剂型包含具有低溶解度的活性药物成分。然而,在本领域中,由于所述活性成分的溶解度非常差,在生产具有理想生物利用度的口服固体制剂时遇到了实质性困难。
水溶性差的API需要专门的配置技术,从而在口服时在胃肠(GI)道有效吸收。在API在全身pH范围内不溶于水溶液的情况下,API的吸收将非常多变且较差,这会影响API的安全性并限制其治疗效果。
本领域建议的特定配置技术涉及API在深共晶溶剂(DES)中的配方或溶解。然而,这种方法仍然受限于可用于使DES以足够高浓度溶解API的组分类型。例如,碱性API可能需要酸性DES才能达到200mg/ml的高浓度,但酸性DES中的酸可能会随着时间的推移使API降解,使其不适合实际使用。
其他方法同样基于共晶体系的原理,涉及形成至少基于API本身的共晶混合物(参见US2007224261和Aroso等人《国际药物学杂志》(International Journal ofPharmaceutics)492(2015)73–79)。然而,这些方法仍受不理想的生物利用度之苦,这是因为当共晶混合物与水环境(例如胃肠液)混合时,活性药物成分会从混合物中分离,从而限制患者身体的吸收。
本发明的目的是改善水溶性差的活性成分的溶解度和生物利用度特性。
本发明人已发现,通过提供与沉淀抑制剂(PI)结合的基于至少一种盐形式的API的共晶混合物可以实现该目标。发现盐和沉淀抑制剂的特定组合可导致良好的溶解度和生物利用度。
此外,有利的是,发明人发现,通过使用亲水性药学上可接受的共晶组分(本文进一步简称为共晶组分)作为第二组分来形成共晶混合物(第一组分为API盐),该组合物通常在给药后立即释放API,而不是缓释。这也被认为归因于本组合物的良好生物利用度性质。
此外,发明人发现,可以通过以液体(在生理条件下,即37℃和1atm)提供药物组合物来改善生物利用度,这是优选的。
因此,本发明涉及一种药物组合物,所述药物组合在37℃C和1atm下为液体并且基于至少一种活性药物成分(API)盐、亲水性药学上可接受的共晶组分和聚合物增溶剂的共晶混合物,并且其还包含沉淀抑制剂(PI)。
在另一方面中,本发明涉及一种制备药物组合物的方法,所述药物组合在37℃和1atm下为液体,所述方法包括:提供至少一种活性药物成分(API)盐、亲水性的药学上可接受的共晶组分和聚合物增溶剂的共晶混合物;并且使得所述共晶混合与沉淀抑制剂(PI)混合以形成所述药物组合物。
有利的是,由于共晶混合物是基于API本身的,因此可以获得非常高的API浓度,例如甚至高达580mg/ml。然而,在典型的组合物中,由于伴随生物利用度的阻碍,如此高的浓度不是优选的。因此,API优选以至少50mg/ml、优选至少100mg/ml、更优选至少150mg/ml的浓度存在于组合物中。然而,低于50mg/ml的浓度,例如,1至25mg/ml,也是很有可能的。
如本文所述,共晶混合物是组分的均匀混合物,其熔点低于该混合物中各组分的熔点。本发明的组合物优选在1atm下具有等于或低于37℃的熔点,即,其在生理条件下为液体。因此,该组合物在20℃和1atm下可以是固体,且仅在给药至身体后才液化。在优选实施方式中,共晶混合物本身在生理条件下也是液体,并且在1atm下具有等于或低于37℃的熔点。
根据本发明的组合物的液态可与具有凝胶状态的已知组合物(例如在WO 2011/014850中公开)区分。本组合物是液体,因此是流体,不像凝胶在稳态时不发生流动。事实上,根据本发明的聚合物增溶剂的作用是防止凝胶形成。
根据本发明的共晶混合物所基于的组分之一是API盐。API的盐形成通常为本领域所熟知,也可提高溶解度和溶解速率。盐的抗衡离子可以改变扩散层中盐颗粒溶解表面处的pH值,导致与相应游离形式的溶解速率相比,盐的溶解速率更高。根据汉德森-海森巴赫方程(Henderson-Hasselbalch equations),pH值的变化对可电离药物的水溶性有高度影响。理论上,弱碱性药物的溶解度在其pKa与pH最大(pH溶解度曲线中最大溶解度的pH值)之间的pH值范围内随pH值的降低呈指数增加。
API盐可通过API与成盐物质反应生成活性药物成分的盐。对于本发明,优选地,对于碱性API,例如弱碱性药物,例如普萘洛尔(propranolol)、西替利嗪(cetirizine)或苯海拉明(diphenhydramine),根据本发明的API盐由所述API和pKa值比碱性AP的共轭酸的pKa低3以下的酸形成。合适的酸优选选自下组:盐酸、硫酸、磷酸、马来酸、L-酒石酸、富马酸、柠檬酸、乙醇酸、苹果酸、马尿酸、乳酸、琥珀酸、己二酸、癸二酸、乙酸、对甲苯磺酸、甲烷磺酸、苯磺酸、草酸、丙二酸、龙胆酸、苯甲酸和烟酸。在特别优选的实施方式中,酸包括盐酸。
在本发明的一些实施方式中,API盐基于酸性API(例如,弱酸性药物,例如,如布洛芬(ibuprofen)或苯妥英(phenytoin))以及碱,优选使用其共轭酸的pKa值大于7或更高的碱。合适的碱优选选自:氢氧化钠、氢氧化钾、碳酸钠、碳酸钾、甘氨酸钠、赖氨酸钠、一水合甘氨酸钠、N-甲基葡糖胺、甘氨酸钾以及磷酸三钠和磷酸钾。在特别优选的实施方式中,碱包括氢氧化钠或氢氧化钾。
API盐的组合物、尤其是抗衡离子的结构,可能影响API盐的性质以及盐形成共晶混合物的适宜性。共晶混合物的形成通常基于与API盐和共晶组分相关的氢键供体和受体相互作用的存在。因此,优选存在与共晶混合物相关的稳定络合物的构型,其涉及两种组分A或B之一内的电子供体基团(例如羰基氧、酰胺基氮或醚氧)与烷基质子、羟基质子、胺质子或σ-受体基团(例如氯)之间的强相互作用。在不囿于任意特定理论的情况下,认为小的(例如原子型)抗衡离子——例如HCl或氯化胆碱中的Cl——可以促进降低API盐和共晶组分熔点所需的强分子间作用力,从而在37℃下形成液体。为此原因,优选API盐具有能够形成强分子间键的小的抗衡离子,或者共晶组分具有这样的部分。
因此,在一些实施方式中,API盐基于碱性API和酸,形成API盐所用的酸优选包含原子型阴离子(例如,卤素阴离子),同时所述药学上可接受的共晶组分包含一个或多个能够形成氢键的官能团。或者,在实施方式中,形成API盐所用的酸包含分子型阴离子,并且所述药学上可接受的共晶组分包含能够形成强分子间键的原子型阴离子或者小的(例如原子型)部分。
US 2007/224261和WO 2014/145156中也描述了API盐共晶混合物的形成以及该概念背后的原理,所述文献全文纳入本文。
如本文所用,术语“药物”、“活性成分”、和“活性药物成分”可互换使用。
如上文所述,本发明旨在处理水溶性差的API。例如,当API为弱碱性化合物时,其在pH=6.8下的水溶性不超过1mg/mL;当API为弱酸性化合物时,其在pH=1.2下的水溶性不超过1mg/mL;对于中性或不可电离化合物,其在pH=1.0-8.0的生理pH下任意pH值的水溶性不超过1mg/mL。API的溶解度可通过在250mL pH值范围为1至7.4(覆盖GI生理条件)的水性溶液中添加最高剂量强度来确定。如果最高剂量强度的API未溶解在250mL pH值为1-7.4的溶液中,则认为API水溶性差。
如本文所用,术语“弱碱性化合物”以及对任何特定新型化学实体、药物或活性药物成分的引用包括碱、药学上可接受的盐、多晶型物、立体异构体、溶剂化物、酯及其混合物,其是在水性介质中质子化不完全的化学碱。在一个实施方式中,本发明组合物的弱碱性化合物可指在具有至少一个pKa小于14的化合物,其中,pKa可通过测量或计算得到。在另一实施方式中,本发明组合物的弱碱性化合物可指具有至少一个小于14的pKa的化合物,其在生理pH之间具有pH依赖性溶解度,在更高pH下具有较低溶解度。在另一实施方式中,本发明组合物的弱碱性药物可指具有至少一个0.0-10.0的pKa的化合物,其在1.0-8.0的生理pH之间具有pH依赖性溶解度,在约6.0-8.0的pH下具有最低的溶解度。在另一实施方式中,弱碱性化合物在pH 6.8下的溶解度不超过约1mg/mL。在另一实施方式中,弱碱性化合物包括至少一个碱性氮原子。在另一实施方式中,弱碱性化合物的pKa小于14,pH 6.8下的溶解度不超过约1mg/mL。在另一实施方式中,弱碱性化合物的pKa小于14,并且包括至少一个碱性氮原子。在另一实施方式中,弱碱性化合物的pKa小于14,pH 6.8下的溶解度不超过约1mg/mL,并且包括至少一个碱性氮原子。
如本文所用,术语“弱酸性化合物”以及对任何特定新型化学实体、药物或活性药物成分的引用包括酸、药学上可接受的盐、多晶型物、立体异构体、溶剂化物、酯及其混合物,其是在水性介质中去质子化不完全的化学碱。在一个实施方式中,本发明组合物的弱酸性药物可指具有至少一个小于14的pKa的化合物,其中,pKa可通过测量或计算得到。在另一实施方式中,本发明组合物的弱酸性化合物可指具有至少一个小于14的pKa的化合物,其在生理pH之间具有pH依赖性溶解度,在更低pH下具有较低溶解度。在另一实施方式中,本发明组合物的弱酸性药物可指具有至少一个0.0-10.0的pKa的化合物,其在1.0-8.0的生理pH之间具有pH依赖性溶解度,在约1.0-2.0的pH下具有较低溶解度。在另一实施方式中,弱酸性化合物在pH 1.0-2.0下的溶解度不超过约1mg/mL。在另一实施方式中,弱酸性化合物包括至少一个酸官能团。在另一实施方式中,弱酸性化合物的至少一个pKa小于14,pH 1.2下的溶解度不超过约1mg/mL。在另一实施方式中,弱酸性化合物的pKa小于14,并且包括至少一个酸性官能团。在另一实施方式中,弱酸性化合物的pKa小于14,pH 1.2下的溶解度不超过约1mg/mL,并且包括至少一个酸性官能团。
制备本发明组合物的合适药物包括但不限于:治疗类的成员:镇痛药、抗炎药、驱虫药、抗心律失常药、抗菌药、抗病毒药、抗凝药、抗抑郁药、抗糖尿病药、抗癫痫药、抗真菌药、抗痛风药、抗高血压药、抗疟疾药、抗偏头痛药、抗毒蕈碱药、抗肿瘤药、勃起功能障碍改善药、免疫抑制剂、抗原生动物药、抗甲状腺药、抗焦虑药、镇静药、催眠药、精神安定药、β受体阻滞药、心脏变力药(cardiac inotropic agent)、皮质类固醇、利尿药、抗帕金森病药、胃肠药、组胺受体拮抗剂、角膜剥脱剂、调血脂药(lipid regulating agent)、抗心绞痛药、cox-2抑制剂、白细胞三烯抑制剂、大环内酯类、肌肉松弛剂、营养剂、阿片类镇痛药(opioidanalgesics)、蛋白酶抑制剂、性激素、兴奋剂、抗骨质疏松药、抗肥胖药、认知增强剂(cognition enhancer)、抗尿失禁药、营养油、抗良性前列腺肥大药、必需的脂肪酸、非必需的脂肪酸以及它们当中两种或更多种的任何组合。
合适的活性药物成分的具体示例包括但不限于:阿比特龙(abiraterone,)、阿曲霉素(acutretin)、阿苯达唑(albendazole)、沙丁胺醇(albuterol)、氨鲁米特(aminogluthemide)、胺碘酮(amiodarone)、氨氯地平(amlodipine)、安非他明(amphetamine)、两性霉素B((amphotericin B))、阿托伐他汀(atorvastatin)、阿托伐醌(atovaquone)、阿奇霉素(azithromycin)、巴氯芬(baclofen)、倍氯米松(beclomethsone)、苯扎普利(benezepril)、苯甲酸酯(benzonatate)、倍他米松(betamethasone)、比卡鲁坦(bicalutanide)、博赛泼维(boceprevir)、布地奈德(budesonide)、安非他酮(bupropion)、白消安(busulphan)、布替萘芬(butenafine)、骨化二醇(calcifediol)、钙泊三醇(calciprotiene)、骨化三醇(calcitriol)、喜树碱(camptothecan)、坎地沙坦(candesartan)、辣椒素(capsaicin)、卡马西平(carbamezepine)、胡萝卜素(carotenes)、塞来昔布(celecoxib)、西力伐他汀(cerivistatin)、塞替利嗪(cetrizine)、氯苯吡胺(chlorpheniramine)、胆钙化醇(cholecalciferol)、西洛他唑(cilostazol)、西咪替丁(cimetidine)、桂利嗪(cinnarizine)、环丙沙星(ciprofloxacin)、西沙必利(cisapride)、克拉霉素(clarithromycin)、氯马斯汀(clemastine)、克罗米芬(clomiphene)、氯米帕明(clomipramine)、氯吡格雷(clopidrogel)、可待因(codeine)、辅酶Q10(coenzyme Q10)、环苯扎林(cyclobenzaprine)、环孢霉素(cyclosporine)、达那唑(danazol)、丹曲洛林(dantrolene)、右氯苯那敏(dexchlopheniramine)、双氯芬酸(diclofenac)、双香豆素(dicoumarol)、地高辛(digoxin)、二氢表雄酮(dihydroepiandrosterone)、二氢麦角胺(dihydroergotamine)、二氢二氢速留醇(dihydrotachysterol)、地红霉素(dirithromycin)、多奈哌齐(donepezil)、依法韦伦(efavirenz)、依普沙坦(eposartan)、麦角钙化醇(ergocalciferol)、麦角胺(ergotamine)、必需脂肪酸源(essential fattyacid sources)、右佐匹克隆(eszopiclone)、依托度酸(etodolac)、依托泊苷(etoposide)、法莫替丁(famotidine)、非诺贝特(fenofibrate)、芬太尼(fentanyl)、非索非那定(fexofenadine)、非那雄胺(finasteride)、氟康唑(flucanazole)、氟比洛芬(flurbiprofen)、氟伐他汀(fluvastatin)、磷苯妥钠(fosphenytion)、夫罗曲坦(frovatriptan)、呋喃唑酮(furazolidone)、加巴喷丁(gabapentin)、吉非罗齐(gemfibrozil)、格列本脲(glibenclamide)、格列吡嗪(glipizide)、优降糖(glyburide)、格列美脲(glymepride)、灰黄霉素(griseofulvin)、卤泛群(halofantrine)、布洛芬(ibuprofen)、厄贝沙坦(irbesartan)、伊立替康(irinotecan)、异山梨醇(isosorbide)、异维甲酸(isotreinoin)、伊曲康唑(itraconazole)、伊维菌素(ivermectin)、酮康唑(ketoconazole)、酮咯酸(ketorolac)、拉莫三嗪(lamotrigine)、兰索拉唑(lanosprazole)、来氟米特(leflunomide)、赖诺普利(lisinopril)、洛哌丁胺(loperamide)、氯雷他定(loratadine)、洛伐他汀(lovastatin)、L-甲状腺素(L-thryroxine)、叶黄素(lutein)、番茄红素(lycopene)、甲羟孕酮(medroxyprogesterone)、米非司酮(mefepristone)、甲氟喹(mefloquine)、甲地孕酮(megesterol)、美他沙酮(metaxalone)、美沙酮(methadone)、甲氧沙林(methoxsalen)、灭滴灵(metronidazole)、甲硝唑(metronidazole)、咪康唑(miconazole)、咪达唑仑(midazolam)、米格列醇(miglitol)、米诺地尔(minoxidil)、米托蒽醌(mitoxantrone)、孟鲁司特(montelukast)、萘丁美酮(nabumetone)、奈非那韦(nelfinavir)、硝苯地平(nifedipine)、纳布啡(nalbuphine)、那拉曲坦(naratiptan)、尼索地平(nilsolidipine)、尼鲁米特(nilutanide)、呋喃妥因(nitrofurantoin)、尼扎替丁(nizatidine)、奥美拉唑(omeprazole)、奥普瑞白介素(oprevelkin)、雌二醇(osteradiol)、奥沙普秦(oxaprozin)、紫杉醇(paclitaxel)、帕立骨化醇(paricalcitol)、帕罗西汀(paroxetine)、镇痛新(pentazocine)、吡格列酮(pioglitazone)、皮左非汀(pizofetin)、普伐他汀(pravastatin)、强的松龙(prednisolone)、普罗布考(probucol)、黄体酮(progesterone)、伪麻黄碱(pseudoephedrine)、吡啶斯的明(pyridostigmine)、雷贝拉唑(rabeprazole)、雷洛昔芬(raloxifene)、罗非考昔(refocoxib)、瑞格列奈(repaglinide)、利福布汀(rifabutine)、利福喷丁(rifapentine)、利福昔明(rifaximine)、利美索龙(rimexolone)、利托那韦(ritanovir)、利扎曲坦(rizatriptan)、罗格列酮(rosiglitazone)、沙奎那韦(saquinavir)、舍曲林(sertraline)、西布曲明(sibutramine)、西地那非(sildenafil)、辛伐他汀(simvastatin)、西罗莫司(sirolimus)、安体舒通(spironolactone)、舒马曲普坦(sumatriptan)、他克林(tacrine)、他克莫司(tacrolimus)、它莫昔芬(tamoxifen)、坦索罗辛(tamsulosin)、蓓萨罗丁(targretin)、他扎罗汀(tazarotene)、特拉匹韦(telaprevir)、替米沙坦(telmisartan)、替尼泊苷(teniposide)、特比萘芬(terbinafine)、特拉唑嗪(terzosin)、四氢大麻酚(tetrahydrocannabinol)、噻加宾(tiagabine)、噻氯匹定(ticlidopine)、替罗非班(tirofibran)、替扎尼定(tizanidine)、托吡酯(topiramate)、拓扑替康(topotecan)、托瑞米芬(toremifene)、曲马多(tramadol)、维甲酸(tretinoin)、曲格列酮(troglitazone)、曲伐沙星(trovafloxacin)、泛癸利酮(ubidecarenone)、缬沙坦(valsartan)、文拉法辛(venlafaxine)、氨己烯酸(vigabatrin)、维替泊芬(vertoporfin)、维生素A(vitamin A)、维生素D(vitamin D)、维生素E(vitamin E)、维生素K(vitamin K)、扎鲁司特(zafirlukast)、齐留通(zileuton)、齐拉西酮(ziprasidone)、佐米曲坦(zolmitriptan)、唑吡坦(Zolpidem)和佐匹克隆(zopiclone)。以上罗列并非详尽无遗,因为可以使用许多其他药物物质。此外,还可以任何多晶型形式使用任何药学上可接受的盐、酯、溶剂化物、水合物和其他可递送任何药物的衍生物,并且可以使用任何两种或更多种活性成分的组合来制备制剂。尽管许多药物通常使用其药学上可接受的衍生物(如盐和酯)配制,但为简洁起见,仅列出了基础药物。
进一步用于与API盐形成共晶混合物的共晶组分是亲水性的。因此,该组合物可在水性环境中快速溶解。本文所用的“水性环境”通常指胃肠液(对于体内的情况)和水性测试介质(对于体外的情况)。更具体地说,“水性环境”包括:胃(如果水性环境是体内的、并且pH值为1.0至2.0);以及肠道(如果水性环境是体内的,并且pH值为5.0至8.0)。所述共晶组分优选亲水至其在水中的溶解度至少为5mg/ml、优选至少25mg/ml、更优选至少50mg/ml的程度。如果该组合物很好地溶于水,API通常可在给药后立即释放。在优选实施方式中,该组合物为立即释放制剂,给药后立即释放其内容物,并且6小时内释放>95%的内容物。
当通过氢键与API盐结合时,共晶组分通常使混合物的熔点降低。在一些典型的实施方式中,共晶组分是选自以下类别的一种或多种:有机酸、酚类化合物、萜类、有机碱、糖或甜味剂、二醇、氨基酸、季铵化合物、以及这些种类的衍生物。
在一个可以优选的实施方式中,共晶组分可包括一种或多种有机酸,其可以是但不限于如下中的一种:苹果酸、柠檬酸、乳酸、富马酸、酒石酸、抗坏血酸、庚二酸、葡萄糖酸、乙酸和/或其衍生物(例如烟酰胺)。
作为附加或者替代方式,共晶组分可包括一种或多种酚类化合物,其可以是但不限于盐酸酪胺和香草醛中的一种。
作为附加或者替代方式,共晶组分可包括一种或多种萜,其可以是但不限于松油醇和紫苏醇(perillyl alcohol)中的一种。
在另一实施方式中,共晶组分可包括一种或多种有机碱,其可以是但不限于脲和鸟嘌呤中的一种。
此外,共晶组分可包括一种或多种糖或甜味剂,所述一种或多种糖或甜味剂选自但不限于:蔗糖、葡萄糖、果糖、乳糖、麦芽糖、木糖、蔗糖、肌醇、木糖醇、糖精、三氯蔗糖、阿斯巴甜、安赛蜜和核糖醇以及它们的磷酸盐。
另外,共晶组分可以包含一种或多种氨基酸。合适的氨基酸可选自但不限于:例如,丙氨酸、谷氨酸、谷氨酸盐、天冬酰胺、天冬氨酸、赖氨酸、精氨酸、脯氨酸和苏氨酸。。
在另一实施方式中,共晶组分可包括一种或多种季铵化合物,其可以是但不限于氯化胆碱、单硝酸硫胺和肉毒碱中的一种。
聚合物增溶剂通常有助于共晶混合物的形成和稳定性,甚至在使该混合物与沉淀抑制剂混合之前亦是如此。此外,聚合物增溶剂有助于沉淀抑制剂(PI)在组合物中的溶解。聚合物增溶剂可包含一种或多种增塑剂。
在本发明的典型组合物中,聚合物增溶剂与亲水性共晶组分的摩尔比为20:1至1:10,优选15:1至1:2。
聚合物增溶剂也称为增塑剂,在本领域中经常用作药物赋形剂。例如,参见Sheskey等人《药用辅料手册》(Handbook of Pharmaceutical Excipients)第8修订版,伦敦医药出版社(Pharmaceutical Press London)。本发明中聚合物增溶剂的作用是降低共晶混合物和组合物的粘度,并防止凝胶形成。
合适的聚合物增溶剂的示例包括有机酸的酯和内酯、二羧酸及其酯、二醇和三醇的酯、醚和碳酸盐、以及二醇。一种或多种有机酸酯和/或内酯可以选自苹果酸二乙酯、柠檬酸三乙酯、柠檬酸三丁酯、乳酸乙酯、琥珀酸二甲酯、琥珀酸二乙酯、葡萄糖醛酸内酯和D-(+)-葡萄糖醛酸γ-内酯。作为附加或者替代方式,聚合物增容剂可以包括一种或多种二羧酸和/或二羧酸酯,其选自己二酸单甲酯、戊二酸二甲酯和戊二酸单甲酯。作为附加或者替代方式,聚合物增容剂可以包括一种或多种二醇和/或三醇的酯、醚和碳酸盐,其选自碳酸甘油酯、碳酸丙烯酯、碳酸乙烯酯、碳酸1,2-丁烯酯、甘油缩甲醛(glycerol formal)、DL-1,2-异亚丙基甘油、1-丁氧基丙烷-2-醇、三(丙二醇)甲醚、二丙二醇甲醚乙酸酯、丙二醇甲醚乙酸酯、二丙二醇甲醚、1-甲氧基-2-丙醇、二乙二醇单乙醚、3-甲氧基-3-甲基-1-丁醇、异山梨醇二甲醚和二酐-d-葡萄糖醇(dianhydro-d-glucitol)。作为附加或者替代方式,聚合物增容剂可以是二醇,其选自但不限于:丙二醇、二丙二醇、丁二醇、甘油、四甘醇、1,2-己二醇、1,2-丁二醇、PEG 400和聚甘油。
该组合物中的沉淀抑制剂提高了API的生物利用度。在其他应用中,聚合物沉淀抑制剂(PPI)是特定的PI,已被证明有助于改善胃肠(GI)道中水溶性差的API的药物溶解度和生物利用度。在这方面,请参考Vasconceles等人,《今日药物发现》2007第12卷第1068-1075页(Drug Discovery Today,2007,Vol 12,pages 1068-1075)的出版物,PPI在此处和/或其中的参考文献中进行了描述,其作用是减少API沉淀,从而产生过饱和状态,导致提高能够渗透GI道的分子的药物生物利用度。聚合PI也公开于Warren等人的《药物靶向杂志》(Journal of Drug Targeting),2010年,第18(10)期,第704-731页和Xu和Dai的《国际药剂学杂志》(International Journal of Pharmaceutics)第453(2013)36-43页。
在本发明的优选实施方式中,PI是亲水的。PI优选是亲水性的,以达到其在水中的溶解度为至少为0.1mg/ml的程度。因此,PI的亲水性可能小于共晶组分的亲水性。
水溶性良好的PI包括环糊精,其是本发明中使用的优选PI。本发明中可用的环糊精是指在pH范围低于14的水性介质中可溶的环糊精。合适的环糊精可包括但不限于:α-环糊精、β-环糊精和γ-环糊精。有利的是,环糊精可以在共晶体系中提供双重功能,第一功能是作为使得共晶混合物稳定化的共晶组分,第二功能是作为提高活性成分溶解度的赋形剂。
作为附加或者替代方式,PI包括一种或多种PPI。本发明中可用的PPI是指在pH范围低于14(一般而言,优选在PI的上述范围内)的水性介质中可溶的聚合物。这些聚合物可以是带有极性或带电荷官能团的离子或中性聚合物。优选地,PPI是水溶性聚合物。合适的PPI可以选自下组:N-乙烯基内酰胺的均聚物和共聚物,尤其是N-乙烯基吡咯烷酮的均聚物和共聚物,例如,聚乙烯基吡咯烷酮(PVP),N-乙烯基吡咯烷酮和乙酸乙烯酯或丙酸乙烯酯的共聚物,聚乙烯基己内酰胺-聚乙烯基乙酸酯-聚乙二醇接枝共聚物,例如以商品名销售的那些,环氧乙烷和环氧丙烷的嵌段共聚物,也称为聚氧乙烯/聚氧丙烯嵌段共聚物,或聚氧乙烯聚丙二醇,如以商品名泊洛沙姆销售的那些,月桂酰聚氧化甘油酯纤维素酯和纤维素醚;特别是,甲基纤维素、羟基烷基纤维素,特别是羟丙基纤维素、羟基烷基烷基纤维素,特别是羟丙基甲基纤维素,高分子聚环氧烷,如聚环氧乙烷和聚环氧丙烷以及环氧乙烷和环氧丙烷的共聚物,乙酸乙烯酯聚合物,如乙酸乙烯酯和巴豆酸的共聚物,部分水解的聚乙酸乙烯酯(也称为部分皂化的“聚乙烯醇”),聚乙烯醇,低聚糖和多糖,如卡拉胶、半乳甘露聚糖和黄原胶,以及其中一种或多种的混合物。
在组合物中,PI可以在共晶混合物中均匀混合,因此与共晶混合物存在于同一相中。换句话说,PI可以溶解在共晶混合物中,从而形成单一液相,例如37℃下为液体。发现,因此可以特别有效地抑制API盐沉淀。因此,共晶混合物也可被视为PI的共晶溶剂。
在一个具体实施方式中,组合物由基于API盐、共晶组分和聚合物增溶剂的共晶混合物以及PI组成。不需要其它赋形剂。
根据本发明的药物组合物中的PI相对于API盐的重量比优选0.2:1至40:1,优选0.35:1至20:1,更优选0.5:1至10:1。该比率还适用于包括多种PI和/或API的组合物,在该情况下,该比率涉及存在于组合物中的所有PI和/或API。最合适的比例取决于组合物所需的物理化学性质,如粘度和组合物中API盐的所需浓度。
当混合物暴露于水性环境中时,可通过在组合物中以不同浓度(类似于API浓度)加入PI,然后在溶解设备中对制剂进行测试,来选择合适或最有效地提高活性成分溶液中游离药物浓度的特别合适的或最佳的PI。可以分析随时间的API浓度变化,并且可以确定随时间具有有效浓度甚至最高浓度的PI是优选的。各PI可在不同浓度(例如50mg/ml和100mg/ml)下与自身进行比较,并在类似浓度下与其他PI进行比较。为此,术语“溶解度”指1999年马里兰州罗克维尔美国药典公约第24号《美国药典》(以下简称“USP”)中的试验711“溶解度”(United States Pharmacopeia 24,United States Pharmacopeial Convention,Inc.,Rockville,Maryland,1999)。各种液体可以用作溶解介质,包括酸、缓冲液、模拟消化道液体等,并且其中许多在USP的各种专著中定义。步骤的示例是使用“设备2”,所述设备具有包含介质的容器,所述介质用旋转桨搅拌。通常,将剂量单位浸入介质中,并每隔一段时间提取介质样品进行药物含量分析,通常使用高效液相色谱(HPLC)技术进行。
与传统配方技术相比,本发明及其优选实施方式提供了若干显著优点。首先,通过在共晶混合物形成时加入活性成分,而不是使其溶解在赋形剂中,可以获得明显高得多的浓度。这种高浓度允许在单个胶囊(约0.91ml)中给予高有效加载量(payload),例如200mg,与必须给予20ml才能达到相同有效加载量的低浓度(例如10mg/ml)相比,这是非常有益的。考虑到患者的依从性、物流成本和生产成本,本行业高度推荐单胶囊全剂量给药。因此,本发明的药物组合物可适合用于包括肠内给药的医疗治疗中,即,通过人体胃肠道给药,例如包含该组合物的胶囊的口服和/或直肠给药。与固体分散体等标准固体制剂技术相比,液体制剂具有显著优势,例如剂量灵活、开发速度提高和简化放大生产(scale up process)。
为了允许肠内给药,亲水性药学上可接受的共晶组分、聚合物增溶剂和沉淀抑制剂(PI)分别以药学上可接受的量存在于组合物中。美国食品和药物管理局(FDA)编制了非活性成分数据库,其提供了存在于FDA批准的药品中的非活性成分的信息。此外,该组合物通过胃肠(GI)道的生物利用度允许肠内给药。
除非上下文另外清楚地说明,否则,本文中所使用的单数形式的“一个”、“一种”和“该”也包括复数形式。术语“和/或”包括一个或多个相关列表项的任何和所有组合。应理解,术语“包括”和/或“包含”限定了所述特征的存在,但不排除存在或添加一个或多个其他特征。
为了清楚并简洁的描述,本文将特征描述为相同或单独实施方式的一部分,然而,应理解本发明的范围可以包括具有所描述的全部或部分特征的组合的实施方式。
可以通过以下非限制性实施例对本发明进行说明。
实施例1
制备伊曲康唑(itraconazole)的氯化氢(HCl)盐,并使之与氯化胆碱和二丙二醇以0.25:0.5:2的摩尔比混合。将该混合物加热至50℃并搅拌30分钟,直至形成无色透明的溶液。该混合物在室温下在一个月内都是稳定的。伊曲康唑HCl和氯化胆碱的熔点均显著降低,分别从170℃和302℃降至低于室温(20℃)。
实施例2
制备伊曲康唑(itraconazole)的氯化氢(HCl)盐,并使之与木糖醇和二丙二醇以0.25:0.5:2的摩尔比混合。将该混合物加热至50℃,加热30分钟,直至形成无色透明的溶液。该混合物在室温下在一个月内都是稳定的。伊曲康唑HCl和氯化胆碱的熔点均显著降低,分别从170℃和302℃降至低于室温(20℃)。
实施例3
盐酸1-金刚烷胺的氯化氢(HCl)盐购自TCI Chemicals(A0588)。API HCl与木糖醇和二丙二醇以0.25:0.5:2的摩尔比混合。将该混合物加热至50℃,加热60分钟,直至形成无色透明的溶液。该混合物在室温下在一个月内都是稳定的。API HCl和氯化胆碱的熔点均显著降低,分别从280℃和302℃降至低于室温(20℃)。
实施例4
盐酸1-金刚烷胺的氯化氢(HCl)盐购自TCI Chemicals(A0588)。API HCl与氯化胆碱和二丙二醇以0.25:0.5:2的摩尔比混合。将该混合物加热至50℃,加热60分钟,直至形成无色透明的溶液。该混合物在室温下在一个月内都是稳定的。API HCl和氯化胆碱的熔点均显著降低,分别从280℃和302℃降至低于室温(20℃)。
实施例5
盐酸氨基胍的氯化氢(HCl)盐购自TCI Chemicals(A0588)。API HCl与氯化胆碱和二丙二醇以0.25:0.5:2的摩尔比混合。将该混合物加热至50℃,加热60分钟,直至形成无色透明的溶液。该混合物在室温下在一个月内都是稳定的。API HCl和氯化胆碱的熔点均显著降低,分别从280℃和302℃降至低于室温(20℃)。
实施例6
盐酸氨基胍的氯化氢(HCl)盐购自TCI Chemicals(A0588)。API HCl与木糖醇和二丙二醇以0.25:0.5:2的摩尔比混合。将该混合物加热至50℃,加热60分钟,直至形成无色透明的溶液。该混合物在室温下在一个月内都是稳定的。API HCl和氯化胆碱的熔点均显著降低,分别从280℃和302℃降至低于室温(20℃)。
实施例7
盐酸普萘洛尔(propanolol hydrochloride)的氯化氢(HCl)盐购自TCIChemicals(A0588)。API HCl与氯化胆碱和二丙二醇以0.25:0.5:2的摩尔比混合。将该混合物加热至50℃,加热60分钟,直至形成无色透明的溶液。该混合物在室温下在一个月内都是稳定的。API HCl和氯化胆碱的熔点均显著降低,分别从280℃和302℃降至低于室温(20℃)。
实施例8
盐酸普萘洛尔(propanolol hydrochloride)的氯化氢(HCl)盐购自TCIChemicals(A0588)。API HCl与氯化胆碱和二丙二醇以0.25:0.5:2的摩尔比混合。将该混合物加热至50℃,加热60分钟,直至形成无色透明的溶液。该混合物在室温下在一个月内都是稳定的。API HCl和氯化胆碱的熔点均显著降低,分别从280℃和302℃降至低于室温(20℃)。
实施例9
头孢唑啉(Cefazolin)的钠(Na)盐购自TCI Chemicals(A0588)。API HCl与木糖醇和三丙二醇以1:0.5:4的摩尔比混合。将该混合物加热至50℃,加热60分钟,直至形成无色透明的溶液。该混合物在室温下在一个月内都是稳定的。头孢唑啉钠和木糖醇的熔点均显著降低至低于室温(20℃)。
实施例10
磷霉素(Fosfomycin)的二钠(2Na)盐购自TCI Chemicals(A0588)。API 2Na与木糖醇和三丙二醇以1:1:4的摩尔比混合。将该混合物加热至50℃,加热60分钟,直至形成无色透明的溶液。该混合物在室温下在一个月内都是稳定的。磷霉素2Na和木糖醇的熔点均显著降低至低于室温(20℃)。
实施例11
氯沙坦(Lorsartan)的钾(K)盐购自TCI Chemicals(A0588)。API K与尼泊金丙酯钠(sodium propyl paraben)和三丙二醇以1:0.5:4的摩尔比混合。将该混合物加热至50℃,加热60分钟,直至形成无色透明的溶液。该混合物在室温下在一个月内都是稳定的。氯沙坦K和尼泊金丙酯钠的熔点均显著降低至低于室温(20℃)。
实施例12
磺胺甲嘧啶(Sulfamethazine)的钠(Na)盐购自TCI Chemicals(A0588)。API Na与尼泊金丙酯钠和三丙二醇以1:0.7:4的摩尔比混合。将该混合物加热至50℃,进行60分钟,直至形成无色透明的溶液。该混合物在室温下在一个月内都是稳定的。磺胺甲嘧啶Na和尼泊金丙酯钠的熔点均显著降低至低于室温(20℃)。
实施例13
生产盐酸普萘洛尔(propanolol hydrochloride)的氯化氢(HCl)盐,并使之与木糖醇、山梨醇和三丙二醇(triporpylene glycol)以0.5:0.375:0.375:10的摩尔比混合。将该混合物加热到约50℃并搅拌60小时,直到形成无色且清澈的溶液。该混合物在室温下在一个月内都是稳定的。伊曲康唑HCl、木糖醇和山梨醇的熔点均显著降低,分别从170℃、92℃和95℃降至低于室温(20℃)。
选择本发明的伊曲康唑HCl制剂,以评估与市售伊曲康唑制剂(意大利杨森制药(ex Janssen-Cilag SpA;Italy))相比,API的体内生物利用度。该研究的目的是展示与最佳可获得市售制剂相比,本发明技术在显著增加制剂浓度(增加13倍)和增加剂量(增加2.2倍)时的令人印象深刻的性能。下面的数据显示出,即使对较高给药剂量进行校正,生物利用度增加。
为此,禁食的雄性Sprague-Dawley大鼠(n=6)的质量约为300g,使用10mg/ml口服溶液通过口填喂给药1.5mg伊曲康唑(itrazonacole)。为了进行比较,另一组禁食的雄性Sprague-Dawley大鼠(n=6)通过130.9mg/ml按照本发明的F4制剂以尺寸9HPMC胶囊给药来给予3.25mg伊曲康唑HCl。
给药后,确定随时间变化的API血浆水平。制剂给药后0、1、2、3、5、7、9、12、24和48小时提取样品。通过液相色谱质谱(LC-MS)确定API水平。
Claims (14)
1.一种制备用于肠内给药的药物组合物的方法,所述药物组合物在37℃和1atm下为液体,所述方法包括:提供至少一种活性药物成分(API)盐、亲水性药学上可接受的共晶组分和药学上可接受量的聚合物增溶剂的共晶混合物,并且使得所述共晶混合物与药学上可接受量的沉淀抑制剂(PI)混合以形成所述药物组合物。
2.如前述权利要求所述的方法,其中,API盐基于碱性API和酸,所述酸包含原子型阴离子,并且所述亲水性药学上可接受的共晶组分包含一种或多种能够形成氢键的官能团,或者
API盐基于碱性API和酸,所述酸包含分子型阴离子,并且所述亲水性药学上可接受的共晶组分包含能够形成强分子间键的小的部分。
3.如权利要求1所述的方法,其中,API盐基于酸性API和碱,所述碱包含原子型阴离子,并且所述亲水性药学上可接受的共晶组分包含一种或多种能够形成氢键的官能团。
4.如前述权利要求中任一项所述的方法,其中,药学上可接受的共晶组分包含一种或多种有机酸、酚类化合物、萜类、有机碱、糖或甜味剂、二醇、氨基酸、季铵盐化合物、此类的衍生物及它们的组合。
5.如前述权利要求中任一项所述的方法,其中,所述聚合物增溶剂包括一种或多种有机酸酯和/或有机酸内酯、一种或多种二羧酸和/或二羧酸酯、一种或多种二醇和/或三醇的酯、醚和碳酸酯/盐、一种或多种二醇或它们的组合,优选地,所述聚合物增溶剂包括一种或多种有机酸酯和/或有机酸内酯,其选自苹果酸二乙酯、柠檬酸三乙酯、柠檬酸三丁酯、乳酸乙酯、琥珀酸二甲酯、琥珀酸二乙酯、葡萄糖醛酸内酯和D-(+)-葡萄糖醛酸γ-内酯;一种或多种二羧酸和/或二羧酸酯,其选自己二酸单甲酯、戊二酸二甲酯和戊二酸单甲酯;一种或多种二醇和/或三醇的酯、醚和碳酸酯/盐,其选自碳酸甘油酯、碳酸丙烯酯、碳酸乙烯酯、碳酸1,2-丁烯酯、甘油缩甲醛、DL-1,2-异亚丙基甘油、1-丁氧基丙烷-2-醇、三(丙二醇)甲醚、二丙二醇甲醚乙酸酯、丙二醇甲醚乙酸酯、二丙二醇甲醚、1-甲氧基-2-丙醇、二乙二醇单乙醚、3-甲氧基-3-甲基-1-丁醇、异山梨醇二甲醚和二酐-d-葡萄糖醇;一种或多种二醇,其选自丙二醇、二丙二醇、丁二醇、甘油、四甘醇、1,2-己二醇、1,2-丁二醇、PEG 400和聚甘油;或它们的组合。
6.如前述权利要求中任一项所述的方法,其中,所述PI是聚合物沉淀抑制剂(PPI),其包含pH值1至8时在水性介质、优选在水中的溶解浓度大于0.1mg/ml的聚合物,更优选地选自:N-乙烯基内酰胺的均聚物和共聚物,尤其是N-乙烯基吡咯烷酮的均聚物和共聚物,例如,聚乙烯吡咯烷酮(PVP),N-乙烯基吡咯烷酮和乙酸乙烯酯或丙酸乙烯酯的共聚物,聚乙烯基己内酰胺-聚乙烯基乙酸酯-聚乙二醇接枝共聚物,如环氧乙烷和环氧丙烷的嵌段共聚物,也称为聚氧乙烯/聚氧丙烯嵌段共聚物,或聚氧乙烯聚丙二醇,如月桂酰聚氧化甘油酯纤维素酯和纤维素醚;特别是,甲基纤维素、羟基烷基纤维素,特别是羟丙基纤维素、羟基烷基烷基纤维素,特别是羟丙基甲基纤维素,高分子聚环氧烷,如聚环氧乙烷和聚环氧丙烷以及环氧乙烷和环氧丙烷的共聚物,乙酸乙烯酯聚合物,如乙酸乙烯酯和巴豆酸的共聚物,部分水解的聚乙酸乙烯酯(也称为部分皂化的“聚乙烯醇”),聚乙烯醇,低聚糖和多糖,如卡拉胶、半乳甘露聚糖和黄原胶,以及它们中一种或多种的混合物。
7.如前述权利要求中任一项所述的方法,其中,所述PI包含一个或多个环糊精,优选在pH值1至8的水性介质——优选水——中溶解浓度大于0.1mg/ml的环糊精,更优选选自α-环糊精、β-环糊精和γ-环糊精的一种或多种环糊精。
8.一种药物组合物,所述药物组合物优选在37℃和1atm下为液体,所述药物组合物通过如前述权利要求中任一项所述的方法获得,所述组合物基于至少一种活性药物成分(API)盐、亲水性药学上可接受的共晶组分和聚合物增溶剂的共晶混合物,并且还包含沉淀抑制剂(PI)。
9.如权利要求8所述的药物组合物,其中,沉淀抑制剂在共晶混合物中溶解并均匀混合。
10.如权利要求8-9中任一项所述的药物组合物,其中,基于总组合物,API的浓度为至少50mg/ml,优选至少100mg/ml,更优选至少150mg/ml。
11.如权利要求8-10中任一项所述的药物组合物,其中,PI与API的重量比为0.2:1至40:1,优选0.35:1至20:1,或更优选0.5:1至10:1。
12.如权利要求8-11中任一项所述的药物组合物,其中,聚合物增溶剂与共晶组分的摩尔比为20:1至1:10,优选10:1至1:2。
13.如权利要求8-12中任一权利要求所述的药物组合物用于医疗治疗的用途,所述医疗治疗包括肠内给药,优选口服给药,更优选包含所述药物组合物的胶囊的口服给药。
14.沉淀抑制剂(PI)和至少一种活性药物成分(API)盐、亲水性的药学上可接受的共晶组分和药学上可接受量的聚合物增溶剂的共晶混合物的组合提高活性药物成分(API)盐的生物利用度的用途。
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NL2028762B1 (en) | 2021-07-16 | 2023-01-23 | Seranovo Holding B V | Micelle-generating formulations for enhanced bioavailability |
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