CN114599388A - 一种包含特立帕肽的口服药物组合物及其制备方法 - Google Patents
一种包含特立帕肽的口服药物组合物及其制备方法 Download PDFInfo
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- CN114599388A CN114599388A CN202080073936.0A CN202080073936A CN114599388A CN 114599388 A CN114599388 A CN 114599388A CN 202080073936 A CN202080073936 A CN 202080073936A CN 114599388 A CN114599388 A CN 114599388A
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- teriparatide
- pharmaceutical composition
- deoxycholic acid
- polyethylene glycol
- surfactant
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Abstract
本发明涉及一种口服药物组合物及其制备方法,该口服药物组合物包含由特立帕肽(teriparatide)、脱氧胆酸(deoxycholic acid)、Nα‑脱氧胆酰基‑L‑赖氨酰甲基酯(Nα‑deoxycholyl‑L‑lysyl‑methylester,DCK)和D‑α‑生育酚聚乙二醇1000琥珀酸酯(D‑α‑tocopherol polyethylene glycol 1000succinate)组成的离子键复合物,本发明的口服药物组合物能够提高特立帕肽的肠道粘膜渗透率和口服给药生物利用度、改善患者依从度,可用于治疗骨质疏松症。
Description
技术领域
本发明涉及一种包含特立帕肽(teriparatide)的口服药物组合物及其制备方法,上述口服药物组合物包含由特立帕肽(teriparatide)、脱氧胆酸(deoxycholic acid)、Nα-脱氧胆酰基-L-赖氨酰甲基酯(Nα-deoxycholyl-L-lysyl-methylester,DCK)和D-α-生育酚聚乙二醇1000琥珀酸酯(D-α-tocopherol polyethylene glycol 1000succinate)组成的离子键复合物。
背景技术
甲状旁腺激素(parathyroid hormone;PTH)是由甲状旁腺分泌的由84个氨基酸组成的多肽,是调节血液中钙离子浓度的主要激素之一。其在骨骼中发挥合成代谢(骨形成)和分解代谢的功能,这些代谢随着暴露于PTH的时间和模式而有所不同。此外,间歇性地暴露PTH可促进合成代谢,引起成骨细胞的分化与增殖或者细胞凋亡的减少。持续性地暴露PTH可促进分解代谢,其与核因子κB受体活化因子配体(receptor activator of nuclearfactor-κB ligand,RANKL)的表达增加和骨保护素(osteoprotegerin)的表达减少有关。
从PTH的N-末端开始的34个氨基酸残基,即特立帕肽(PTH(1-34);teriparadite)对于激活1型PTH受体是必需的,该受体多表达于骨骼和肾脏中。PTH(1-34)与1型PTH受体结合能够激活包括G蛋白依赖性cAMP/蛋白激酶A途径(G protein-dependent cAMP/proteinkinase Apathway)在内的一系列信号转导体系、调节血浆钙浓度。特立帕肽是一种基因重组PTH(1-34)(rhPTH(1-34);作为人基因重组PTH(1-34)(recombinant human PTH(1-34))),临床用于治疗绝经后女性的骨质疏松症和性腺抑制性男性的骨质疏松症。特立帕肽的间歇性给药通过使成骨细胞的活性优于破骨细胞来刺激新骨形成,降低骨质疏松症中骨折的风险。其他的多数骨质疏松症治疗法不具有分解代谢特性,是仅抑制破骨细胞活性的预防性治疗方法。这样的骨吸收抑制剂(antiresorptives)包括双膦酸盐(bisphosphonate)、雌激素受体调节剂(estrogen recept modulator)和降钙素(calcitonin)。另一方面,特立帕肽可在有骨折风险、且对其他骨吸收抑制剂无反应的患者的骨质疏松症治疗中使用。
目前,特立帕肽以皮下注射的方式在大腿或腹部给药,一天一次,持续两年。然而,这种皮下注射方式会带给患者疼痛,患者必须要学习正确的注射方法,存在不便。因此,为了提高患者的服药依从性,人们尝试开发PTH肽的口服给药、经皮给药及鼻腔给药等替代药物递送系统。口服给药的优点包括患者便利性以及特立帕肽浓度达到Tmax所经历的时间增加。然而,PTH口服递送的最大问题之一是肽本身的口服生物利用度低。导致这一问题的原因在于肽的半衰期短、被胃酸和消化道的蛋白酶降解、以及由于其大分子量(约4117.72Da)而导致的胃肠道细胞膜渗透率低。因此,迫切需要开发一种新型特立帕肽给药递送系统,以提高患者的服药依从性。
在PCT/DK2004/000482中公开了一种用于改善上述问题的技术。在PCT/DK2004/000482中,尝试采用常规的肠溶衣等,使PTH在口服给药两个小时后释放,以尽量减少药物在胃肠中的降解,提高吸收率。然而,PTH的口服生物利用度低的主要原因不仅在于药物在胃肠道内的降解,还与药物分子的脂质亲和力低、分子量大而导致的肠道粘膜渗透率低有关。因此,以通常的肠溶性口服给药剂型所表现出的口服生物利用度不足以充分发挥PTH的治疗效果。此外,在PCT/CZ2012/000025中,还尝试将特立帕肽与β-葡聚糖、海藻酸、壳聚糖这样的水溶性多糖基于非共价键来制备复合物,以尽量减少药物的酶降解、提高其口服生物利用度,但是未给出用于提高药物本身的肠道粘膜渗透率的方案。
另一方面,在PCT/IL2017/050920中公开了包含如NAC(8-N-(2-羟基苯甲酰基)氨基辛酸酯)、NAD(10-N-(2-羟基苯甲酰基)氨基癸酸)、5-CNAC(8-N-(5-氯水杨酰基)氨基辛酸)、4-MOAC(8-N-(2-羟基-4-甲氧基苯甲酰基)氨基辛酸)、4-CNAB(4-N-(2-羟基-4-氯苯甲酰基)氨基丁酸)及这些的盐这样的吸收促进剂的PTH(1-34)的口服剂型。上述发明中使用的吸收促进剂作为一种合成表面活性剂,会非特异性地提高药物在胃肠道内的吸收率。因此,在小动物的情况下,即使使用少量的吸收促进剂也能够充分显现出促进药物吸收效果,但在灵长类动物和人这样的胃肠道液体积大的情况下,则存在如下缺点:单位剂型中所含的吸收促进剂被肠内存在的消化液和水稀释,难以发挥充分的吸收促进效果。此外,还存在如下缺点:为了显现出与小动物相同水平的胃肠道促进吸收作用,必须服用过量的吸收促进剂,由此会因新型合成表面活性剂而导致胃肠道内不明原因的副作用。
对此,本发明人等为了克服上述现有技术中存在的问题而进行了深入研究,结果发现,在使用脱氧胆酸和脱氧胆酸衍生物作为吸收促进剂且使用TPGS作为增溶剂的情况下,口服药物的吸收效率有所提高,上述脱氧胆酸和脱氧胆酸衍生物在分子水平上通过如离子键这样的非共价键与药物形成复合物,并且与存在于肠道细胞膜中的胆汁酸输送体特异性地、选择性地结合,能够提高药物吸收效率,从而完成了本发明。
发明内容
发明要解决的问题
因此,本发明的主要目的在于提供一种包含特立帕肽的口服药物组合物,其能够提高特立帕肽的肠道粘膜渗透率和口服给药生物利用度、改善患者依从度。
本发明的另一目的在于提供一种用于制备上述包含特立帕肽的口服药物组合物的制备方法。
[支持本发明的韩国国家研发项目]
[课题编号]10215797
[部门名称]韩国中小企业部
[研究管理专门机构](财团)韩国碳融合技术研究所
[研究项目名称]创业飞跃团体项目(Start-up Leap Package)
[研究课题名称]使用口服节拍式抗癌剂的免疫抑制剂活性促进药物的开发
[主管单位]株式会社艾跨BNP(ICURE BNP Co.,Ltd.)
[支持本发明的韩国国家研发项目]
[课题编号]P0010215
[部门名称]韩国产业通商资源部
[研究管理机构]韩国产业技术振兴院
[研究项目名称]基础研究再发现支持项目
[研究课题名称]通过改变口服剂型的抗癌剂技术平台开发
[主管单位]株式会社艾跨BNP(ICURE BNP Co.,Ltd.)
用于解决问题的方案
根据本发明的一个实施方式,本发明提供一种包含离子键复合物的口服药物组合物,上述离子键复合物由特立帕肽(teriparatide)、脱氧胆酸(deoxycholic acid)、Nα-脱氧胆酰基-L-赖氨酰甲基酯(Nα-deoxycholyl-L-lysylmethylester,DCK)和D-α-生育酚聚乙二醇1000琥珀酸酯(D-α-tocopherol polyethylene glycol 1000succinate)组成。
作为用于治疗骨质疏松症的药物,特立帕肽通常以皮下注射的方式在大腿或腹部给药,一天一次,持续两年。然而,这种皮下注射方式会带给患者疼痛,患者必须要学习正确的注射方法,存在不便。对此,本发明人发现,在使用包含由特立帕肽、脱氧胆酸、作为脱氧胆酸衍生物的Nα-脱氧胆酰基-L-赖氨酰甲基酯(Nα-deoxycholyl-L-lysylmethylester,DCK)、和D-α-生育酚聚乙二醇1000琥珀酸酯组成的离子键复合物的口服药物组合物的情况下,能够提高药物的肠道粘膜渗透率和口服给药生物利用度、改善患者服药依从性,从而完成了本发明。
在本发明的口服药物组合物中,上述特立帕肽(teriparatide)作为甲状旁腺激素的片段(PTH(1-34)),除包含上述PTH(1-34)之外,还能够包含选自PTH(1-28)、PTH(1-31)、PTH(1-38)和PTH(1-41)中的一种以上的特立帕肽。
在组成特立帕肽的肽的氨基酸序列中,能够与作为带正电荷的脱氧胆酸衍生物的Nα-脱氧胆酰基-L-赖氨酰甲基酯(Nα-deoxycholyl-L-lysylmethylester,DCK)结合的氨基酸共有4个,如天冬氨酸(Aspartic acid,Asp)和谷氨酸(Glutamic acid,Glu),能够与带负电荷的脱氧胆酸结合的带正电荷的氨基酸共有8个,如精氨酸(Arginine,Arg)、组氨酸(Histidine,His)及赖氨酸(Lysine),因此,一分子的特立帕肽最多能与12个脱氧胆酸和脱氧胆酸衍生物生成离子键。
即,由于能够利用特立帕肽分子中所有能够用于结合脱氧胆酸分子的位点,所以与特立帕肽结合的脱氧胆酸和脱氧胆酸衍生物分子增多,由此导致脱氧胆酸和脱氧胆酸衍生物与存在于肠道粘膜细胞中的胆汁酸输送体结合的可能性增加。结果,如本发明那样,在将包含脱氧胆酸和脱氧胆酸衍生物的离子键复合物用作口服药物组合物的情况下,能够显著提高特立帕肽的肠道粘膜渗透率和生物利用度。
本发明的口服药物组合物的特征在于,相对于1摩尔的特立帕肽,能够含有0.1至10摩尔的作为上述脱氧胆酸衍生物的Nα-脱氧胆酰基-L-赖氨酰甲基酯(Nα-deoxycholyl-L-lysylmethylester,DCK),优选含有2至8摩尔。当上述脱氧胆酸衍生物大于10摩尔时,促进药物吸收的效果不会随着脱氧胆酸衍生物的添加量的增加而急剧增加,大量未结合的脱氧胆酸衍生物会起到表面活性剂的作用,反而会引起刺激肠粘膜等的副作用。
本发明的口服药物组合物的特征在于,相对于1摩尔的特立帕肽,能够含有1至20摩尔的上述脱氧胆酸,优选含有4至16摩尔。当上述脱氧胆酸大于20摩尔时,促进药物吸收的效果不会随着脱氧胆酸的添加量的增加而大幅增加,大量未结合的脱氧胆酸会起到表面活性剂的作用,反而会引起刺激肠粘膜等的副作用。
根据本发明的一个实施例,确认了由本发明的特立帕肽、脱氧胆酸、作为脱氧胆酸衍生物的Nα-脱氧胆酰基-L-赖氨酰甲基酯(Nα-deoxycholyl-L-lysylmethylester,DCK)和D-α-生育酚聚乙二醇1000琥珀酸酯组成的离子键复合物(实施例1)的肠道粘膜渗透率,其结果显示,与不包含增溶剂的比较例1和比较例2相比,实施例1显示了显著的肠道粘膜渗透率,此外,与不使用TPGS而使用泊洛沙姆、辛酸癸酸聚乙二醇甘油酯(Labrasol)或聚氧乙烯氢化蓖麻油作为增溶剂的比较例3、5及6相比,实施例1也显示了显著的肠道粘膜渗透率。此外,还确认出,与同时使用TPGS和泊洛沙姆作为增溶剂的比较例4相比,单独使用TPGS的实施例的肠道粘膜渗透率进一步得到提高。进而还确认出,与仅包含作为肠道粘膜渗透促进剂的脱氧胆酸衍生物Nα-脱氧胆酰基-L-赖氨酰甲基酯(Nα-deoxycholyl-L-lysylmethylester,DCK)的情况(比较例7)相比,同时包含Nα-脱氧胆酰基-L-赖氨酰甲基酯(Nα-deoxycholyl-L-lysylmethylester,DCK)和脱氧胆酸的本申请发明的实施例的肠道粘膜渗透率进一步得到提高。
从这些结果来看,本发明的离子键复合物在使用TPGS的情况下,比使用其他增溶剂更能显著地提高肠道粘膜渗透率,在包含脱氧胆酸衍生物且包含脱氧胆酸的情况下,会与特立帕肽形成更多的离子键,因此能够显著地提高肠道粘膜渗透率,这表示为了提高特立帕肽的肠道粘膜渗透率,在包含特立帕肽的口服药物组合物中,优选同时包含脱氧胆酸和作为脱氧胆酸衍生物的Nα-脱氧胆酰基-L-赖氨酰甲基酯(Nα-deoxycholyl-L-lysyl-methylester,DCK),最优选将TPGS用作增溶剂。
在本发明的口服药物组合物中,上述口服药物组合物除包含TPGS之外,还能够进一步包含泊洛沙姆(poloxamer)作为增溶剂,而且,除包含泊洛沙姆之外,还能够进一步包含辛酸癸酸聚乙二醇-8甘油酯(caprylocaproyl macrogol-8glycerides;商品名:Labrasol)或聚氧乙烯氢化蓖麻油(Cremophor)。
作为本发明的另一实施方式,本发明提供一种口服药物组合物的制备方法,其包括:通过向包含特立帕肽(teriparatide)和D-α-生育酚聚乙二醇1000琥珀酸酯(D-α-tocopherol polyethylene glycol 1000succinate)的溶液中加入脱氧胆酸(deoxycholicacid)和Nα-脱氧胆酰基-L-赖氨酰甲基酯(Nα-deoxycholyl-L-lysyl-methylester,DCK)水溶液而形成离子键复合物的第一步骤、通过在上述第一步骤制备的离子键复合物中混合粘结剂、崩解剂、稀释剂和润滑剂而制备颗粒的第二步骤,以及将上述第二步骤中制备的颗粒压制成片剂形状的第三步骤。
在本发明的口服药物组合物的制备方法中,为了将上述离子键复合物制成片剂,如第二步骤那样,还能够包含粘结剂、崩解剂、稀释剂及润滑剂。作为上述粘结剂,能够采用现有的用于制备片剂的任何粘结剂,例如可包含但不限于选自聚乙烯吡咯烷酮(polyvinylpyrrolidone)、明胶(gelatin)、淀粉(starch)、蔗糖(sucrose)、甲基纤维素(methylcellulose)、乙基纤维素(ethyl cellulose)、羟丙基纤维素(hydroxypropylcellulose)、羟丙基烷基纤维素(hydroxypropylalkylcellulose)中的一种以上。此外,作为上述崩解剂,能够使用现有的用于制备片剂的任何崩解剂,例如可包含但不限于选自交联聚乙烯吡咯烷酮(Polyvinyl pyrrolidone)、交联羧甲基纤维素钠(sodium carboxymethylcellulose)、交联羧甲基纤维素钙(calcium carboxymethyl cellulose)、交联羧甲基纤维素(carboxymethyl cellulose)、淀粉乙醇酸钠(sodium starch glycolate)、羧甲基淀粉(carboxymethyl starch)、羧甲基淀粉钠(sodium carboxymethyl starch)、甲基丙烯酸钾-二乙烯基苯共聚物(potassium methacrylatedivinyl benene copolymer)、直链淀粉、交联直链淀粉(amylose)、淀粉衍生物(starch derivative)、微晶纤维素(microcrystalline cellulose)、纤维素衍生物(cellulose derivative)、环糊精(cyclodextrin)及环糊精衍生物(cyclodextrin derivative)中的一种以上。作为上述稀释剂,能够使用现有的用于制备片剂的任何稀释剂,例如可包含但不限于选自乳糖(lactose)、糊精(dextrin)、淀粉(starch)、微晶纤维素(microcrystalline cellulose)、磷酸氢钙(calcium Hydrogen Phosphate)、无水磷酸氢钙、碳酸钙(calcium carbonate)、糖类(saccharide)中的一种以上。上述润滑剂能够使用现有的用于制备片剂的任何润滑剂,例如可包含但不限于选自硬脂酸(stearic acid)、硬脂酸锌(stearic acid zinc)、硬脂酸镁(stearic acid magnesium)、硬脂酸钙(stearic acid calcium)、滑石(talc)中的一种以上。
本发明的口服药物组合物的制造方法的特征在于,还包括用肠溶性物质给上述第三步骤中制备的片剂进行包衣的步骤。通过在第三步骤中制备的片剂表面形成包衣层,能够抑制口服时药物在胃的酸性条件下释放,由此尽量减少药物降解。
在本发明的口服药物组合物中,上述肠溶性物质能够使用通常用于制备肠溶性制剂的任何物质,例如可包含但不限于选自尤特奇(Eudragit,甲基丙烯酸-丙烯酸乙酯共聚物)、羟丙基甲基纤维素邻苯二甲酸酯(hydroxypropyl methylcellulose phthalate)、乙酰琥珀酸羟丙基甲基纤维素(acetylsuccinate hydroxyl propyl methylcellulose)、醋酸邻苯二甲酸纤维素(cellulose acetate phthalates)、聚醋酸乙烯邻苯二甲酸酯(polyvinyl acetate phthalates)、羧甲基乙基纤维素(carboxy methyl ethylcellulose)及虫胶(shellac)中的一种以上。
上述肠溶包衣层还能够包含增塑剂,除此之外,还能够包含色素、抗氧化剂、滑石、二氧化钛、调味剂等。作为上述增塑剂,能够使用选自蓖麻油、脂肪酸、被取代的甘油三酯(triglycerides)和甘油酯(glycerides),分子量为300至50000的聚乙二醇(polyethyleneglycol)及其衍生物中的一种以上的组分。作为用于制备上述肠溶包衣层的包衣液的溶剂,能够使用水或有机溶剂,作为上述有机溶剂优选使用乙醇(ethanol)、异丙醇(isopropanol)、丙酮(acetone)、氯仿(chloroform)、二氯甲烷(dichloromethane)或这些的混合物。
作为本发明的另一实施方式,本发明提供一种口服药物组合物的制备方法,其特征在于包括:通过向包含特立帕肽(teriparatide)和D-α-生育酚聚乙二醇1000琥珀酸酯(D-α-tocopherol polyethylene glycol 1000succinate)的溶液中加入脱氧胆酸(deoxycholic acid)和Nα-脱氧胆酰基-L-赖氨酰甲基酯(Nα-deoxycholyl-L-lysylmethylester,DCK)水溶液而形成离子键复合物的第一步骤、向上述离子键复合物溶液中加入作为第一表面活性剂的辛酸癸酸聚乙二醇-8甘油酯(caprylocaproyl macrogol-8glycerides;Labrasol)和作为第一助表面活性剂的吐温80而制备混合物的第二步骤、将上述第二步骤的混合物分散在第一油相中而制备油包水型(water-in-oil,w/o)第一纳米乳液的第三步骤、以及在上述第三步骤的第一油包水型纳米乳液中加入作为第二表面活性剂的聚氧乙烯氢化蓖麻油(Cremophor)或吐温80与作为第二助表面活性剂的聚乙二醇(polyethylene glycol)400的混合物而制备水包油包水型(water-in-oil-in-water,w/o/w)第二纳米乳液的第四步骤。
本发明的口服药物组合物的制备方法的特征在于,上述第一油相为选自硅油(silicone oil)、酯类油(ester oil)、烃类油(hydrocarbon oil)、丙二醇单辛酸酯(propylene glycol mono caprylate)、丙二醇二辛酸酯(propylene glycol dicaprylocaprate)、油酸聚乙二醇-6甘油酯(oleoyl macrogol-6glyceride)、月桂酸聚乙二醇-6甘油酯(lauroyl macrogol-6glyceride)、亚油酸聚乙二醇-6甘油酯(linoleicoilmacrogol-6glyceride)、中链甘油三酯(medium chain tri-glyceride)、油酸(oleicacid)、硬脂酸(stearic acid)、山嵛酸甘油酯(glyceryl behenate)、单硬酯酸甘油酯(glycerol mono stearate)和蓖麻油(castor oil)中的一种以上。
本发明的口服药物组合物的制备方法的特征在于,相对于组合物的总重量,上述w/o/w第二纳米乳液内能够包含0.1至40重量%的第一油相,优选包含1至20重量%的第一油相。当上述油小于0.1重量%时,难以使离子键复合物的水溶液分散在油相中,当上述油大于40重量%时,会出现不分散在第二外部水相中而产生相分离的问题。
本发明的口服药物组合物的制备方法的特征在于,相对于组合物的总重量,包含0.1至40重量%的上述第一表面活性剂与第一助表面活性剂的混合物以及第二表面活性剂与第二助表面活性剂的混合物。当上述表面活性剂与助表面活性剂的混合物小于0.1重量%时,第一内部水相难以分散在第一油相中,当大于40重量%时,表面活性剂及油、内部水相等的重量相对减小,可能会出现相分离的问题。
本发明中使用的第一表面活性剂和第二表面活性剂能够使分散有特立帕肽复合物的水相分散在油相中,进而使w/o纳米乳液在口服后很好地分散在胃肠道内的胃液及肠液中。
制备纳米乳液时使用的表面活性剂能够是选自泊洛沙姆(poloxamer)、辛酸癸酸聚乙二醇-8甘油酯(Labrasol)、聚氧乙烯氢化蓖麻油(Cremophor)、甘油单辛酰基癸酸酯(Capmul MCM)、月桂酰聚乙二醇-32甘油酯(Gelucire 44/14)、Solutrol(聚乙二醇-15羟基硬脂酸酯)、聚山梨醇酯(Tween)、山梨糖醇单月桂酸酯(司盘)及它们的混合物中的一种以上。
本发明的口服药物组合物的制备方法的特征在于,相对于1重量份的特立帕肽,含有0.1至100重量份的D-α-生育酚聚乙二醇1000琥珀酸酯。
本发明中能使用的第一助表面活性剂和第二助表面活性剂有助于降低表面能,使分散有作为活性物质的特立帕肽复合物的内部水相能够通过该表面活性剂分散在油相中,并且有助于使油包水型(w/o)纳米乳液在口服后很好地分散于胃肠道内的胃液和肠液中。
制备纳米乳液时使用的助表面活性剂能够是选自二乙二醇单乙基醚(transcutolHP)、聚山梨醇酯(polysorbate)、聚乙二醇(polyethylene glycol)、丁二醇(butyleneglycol)、丙二醇(propylene glycol)、乙醇(ethanol)、异丙醇(isopropanol)及这些的混合物中的一种以上。此时,上述助表面活性剂与表面活性剂混合使用,助表面活性剂与表面活性剂的混合比例按重量比计能够为1∶0.1至1∶10、优选以1∶0.5至1∶2进行混合。此外,基于组合物的总重量,能够包含0.1至40重量%、优选为1至20重量%的上述助表面活性剂与表面活性剂的混合物。
按照上述制备方法制备的水包油包水型(w/o/w)纳米乳液能够以填充在软胶囊或硬胶囊中的形式制备,并且能够通过进一步包括使用含有肠溶包衣剂的包衣溶液给得到的胶囊进行包衣的步骤来形成。
发明效果
如上所述,本发明的包含特立帕肽的口服药物组合物是通过使用脱氧胆酸、Nα-脱氧胆酰基-L-赖氨酰甲基酯(Nα-deoxycholyl-L-lysylmethylester,DCK)和TPGS将作为骨质疏松症治疗药的特立帕肽制成离子键复合物,再将其制成片剂形状或担载于水包油包水型纳米乳液中得到的,上述口服药物组合物能够提高肠道粘膜渗透率和生物利用度,并改善患者依从度。
附图说明
图1示出了本发明的实施例1和实施例4中特立帕肽的生物利用度的确认结果。
具体实施方式
下面通过实施例进一步对本发明进行详细说明。这些实施例仅用于示例本发明,不得解释为本发明的范围被这些实施例所限定。
制备例:脱氧胆酸衍生物的制备
脱氧胆酸(deoxycholic acid)衍生物通过使带正电荷的赖氨酸与脱氧胆酸进行化学性结合来制备。首先,在800mL的四氢呋喃(tetrahydrofuran)中溶解26g的脱氧胆酸。另外在7.4mL的N-甲基吗啉(N-methyl morpholine)和6.4mL的氯甲酸乙酯(ethylchloroformate)的混合溶剂中溶解20g的H-Lys(Boc)-OMe·HCl。在上述脱氧胆酸溶液中加入H-Lys(Boc)-OMe·HCl溶液后,搅拌30分钟,然后回流2小时。在常温下搅拌过夜,将得到的反应沉淀物过滤后蒸除残留溶剂。干燥后的沉淀物利用氯仿(chloroform)和甲醇(methanol)通过柱层析纯化后,在冷水浴(ich batch)下溶解在乙酰氯(acetyl chloride)和甲醇(methanol)的混合溶剂中。除去溶剂后,将残留物重新溶解在水中,用氯仿(chloroform)清洗3次后,取水相进行冷冻干燥来制备作为脱氧胆酸衍生物的Nα-脱氧胆酰基-L-赖氨酰甲基酯(Nα-deoxycholyl-L-lysyl-methylester,DCK)。
实施例1和比较例:特立帕肽、脱氧胆酸、脱氧胆酸衍生物和增溶剂的离子键复合
物的制备
在纯水中溶解特立帕肽和作为增溶剂的D-α-生育酚聚乙二醇1000琥珀酸酯(D-α-tocopherol polyethylene glycol 1000succinate;TPGS),然后一边搅拌一边缓慢加入另外制备的脱氧胆酸衍生物的水溶液来制备离子键复合物。此时,缓慢加入脱氧胆酸衍生物的水溶液,使特立帕肽与作为脱氧胆酸衍生物的Nα-脱氧胆酰基-L-赖氨酰甲基酯(Nα-deoxycholyl-L-lysyl-methylester,DCK)的摩尔比为1∶2或1∶4。然后一边搅拌上述复合物溶液一边缓慢加入另外制备的脱氧胆酸钠水溶液来制备离子键复合物。此时,缓慢加入脱氧胆酸水溶液,使特立帕肽与脱氧胆酸的摩尔比为1∶4或1∶8。最终,将混合液离心分离后冷冻干燥来制备以下表1组成的粉末状态的复合物,它们是特立帕肽和脱氧胆酸衍生物的复合物、或者是特立帕肽与脱氧胆酸的复合物、又或者是特立帕肽与两者混合物的复合物。
此外,在比较例中,作为增溶剂,使用泊洛沙姆(poloxamer)、辛酸癸酸聚乙二醇-8甘油酯(caprylocaproyl macrogol-8glycerides;商品名:Labrasol)以及聚氧乙烯氢化蓖麻油(Cremophor)制备了复合物,在不包含脱氧胆酸的情况下制备了复合物。
[表1]
实验例1:由特立帕肽、脱氧胆酸、脱氧胆酸衍生物和增溶剂组成的复合物的人造
肠道粘膜渗透率的确认
利用人造肠道粘膜渗透率评价系统(parallel artificial membranepermeability assay,PAMPA)来评价上述制备的实施例1、比较例1至7通过人造肠道粘膜的有效渗透率(effective permeability,Pe)。首先,用磷酸盐缓冲液(PBS,pH6.8)溶解上述实施例1、比较例1至7的试样至以特立帕肽的浓度为200μg/mL,然后分别取200μL加入到PAMPA系统的供给部,PAMPA系统的接收部分别以300μL的磷酸盐缓冲液(PBS,pH6.8)填充,然后将供给部与接收部结合,在常温下放置5小时。然后取出接收部和供给部的各孔中的溶液,用孔径为0.45μm的膜过滤器过滤后,利用HPLC系统在下述条件下对通过人造肠道粘膜的特立帕肽的浓度进行了分析。
每个试样取50μL注入到HPLC系统中,在下述条件下进行分离:流动相为0.1%(w/v)三氟乙酸(trifluoroacetic acid;TFA)水溶液(A)和含有0.1%(w/v)TFA的乙腈(acetonitrile)(B),流速为1.0mL/min,流动相B的组成在25分钟内以51%至76%呈线性变化。在220nm处测定特立帕肽,按下式1计算通过人造肠道粘膜的有效渗透率(Pe)。
[式1]
Pe=-ln[1-CR(t)/Cequilibrium]/[S×(1/VD+1/VR)×t]
其中,Pe为有效渗透率(cm/s),S为有效渗透面积(0.288cm2),VD为供给部的孔的溶液体积(0.2mL),VR为接收部的孔的溶液体积(0.3mL),t为采样时间(s),CR(t)为在t时间点接收部的药物浓度,Cequilibrium是指[CD(t)×VD+CR(t)×VR]/(VD+VR),CD(t)是指在t时间点供给部的药物浓度。
将利用上式计算得出的实施例1、比较例1至7通过人造肠道粘膜的有效渗透率结果示于下述表2。
[表2]
有效渗透率(P<sub>e</sub>,x10<sup>-6</sup>cm/s) | |
实施例1 | 14.9±4.79 |
比较例1 | 0.582±0.132 |
比较例2 | 2.36±0.646 |
比较例3 | 7.57±2.09 |
比较例4 | 11.9±3.38 |
比较例5 | 8.27±2.47 |
比较例6 | 6.52±1.27 |
比较例7 | 9.07±3.39 |
*各个值的含义为平均±标准偏差(n=4)。
结果如上述表2所确认的,与比较例1相比,在将脱氧胆酸衍生物与特立帕肽以1∶4的摩尔比形成复合物的比较例2中,特立帕肽通过人造肠道粘膜的渗透率提高了4.05倍。其原因可判断为,脱氧胆酸衍生物本身使特立帕肽的脂溶性增强,提高了对肠道粘膜的脂质渗透率。
然而,在形成特立帕肽和脱氧胆酸衍生物的复合物时加入了如TPGS、泊洛沙姆、辛酸癸酸聚乙二醇-8甘油酯(Labrasol)和聚氧乙烯氢化蓖麻油的增溶剂的情况下,与特立帕肽与脱氧胆酸衍生物的摩尔比为1∶4的复合物相比,前者的渗透率分别提高了3.84倍、3.21倍、3.50倍、2.76倍,尤其是如实施例1使用TPGS作为增溶剂的复合物,与特立帕肽(比较例1)、特立帕肽与脱氧胆酸衍生物的摩尔比为1∶4的复合物(比较例2)相比,其人造肠道粘膜渗透率分别提高了25.6倍和6.31倍。
此外,与使用泊洛沙姆、辛酸癸酸聚乙二醇-8甘油酯(Labrasol)和聚氧乙烯氢化蓖麻油作为增溶剂的比较例3、比较例5及比较例6相比,如实施例1使用TPGS作为增溶剂的复合物的人造肠道粘膜渗透率也有所提高。
而且,与使用TPGS和泊洛沙姆共同作为增溶剂的比较例4相比,单独使用TPGS的本申请发明的实施例1的人造肠道粘膜渗透率也有所提高。
不仅如此,与不包含脱氧胆酸而包含作为脱氧胆酸衍生物的Nα-脱氧胆酰基-L-赖氨酰甲基酯(Nα-deoxycholyl-L-lysyl-methylester,DCK)和TPGS的比较例7相比,同时包含脱氧胆酸和脱氧胆酸衍生物的本申请发明的实施例1的人造肠道粘膜渗透率有所提高。
这些结果可判断为是起因于脱氧胆酸衍生物本身对药物的脂质亲和性的增强效果以及增溶剂对肠道脂质膜的增溶作用,尤其是伴随肠道脂质膜增溶作用而产生的特立帕肽的脂质亲和性的增强效果看起来是起因于脱氧胆酸和脱氧胆酸衍生物的组合以及TPGS。
实验例2:由特立帕肽、脱氧胆酸、脱氧胆酸衍生物和增溶剂组成的复合物的透过
肠道细胞膜的渗透率的确认
以作为肠道细胞膜的Caco-2细胞膜为对象,对如实施例1、比较例1至7中制备的复合物的表观渗透率进行了如下评价。在24孔转移小室(Transwell)中将Caco-2细胞分别处理至浓度为1×105细胞/mL后,将细胞培养14-16天,然后将跨过Caco-2细胞膜的电阻(跨膜电阻,TEER)值为>350Ω·cm2的细胞单层膜(cell monolayer)用于实验。首先,除去转移小室中的培养基,然后以HBSS填充供给部和接收部,在37℃培养20分钟后,再测定TEER值,然后除去HBSS。之后在HBSS中溶解以特立帕肽计为200μM的实施例1、比较例1至7的试样得到药物溶液,在每个转移小室的供给部中涂布各0.1mL该药物溶液,接收部以0.6mL的HBSS填充,然后在37℃下培养,并在0.5、1、2、3、4、5小时的时间点从各个接收部取100μL试样,用膜过滤器(孔隙0.45μm,PVDF)过滤后,利用HPLC在上述实验例1所述条件下对透过肠道细胞膜的特立帕肽的浓度进行了分析。利用下式2计算肠道细胞膜表观渗透率(Papp),将其结果示于表3。
[式2]
Papp=dQ/dt×1/(S×Ci)
其中,dQ/dt是指药物向供给部渗透的渗透速率(μmoL/h),S是指渗透面积(cm2)。Ci是指药物在供给部的初始浓度(μM)。
[表3]
表观渗透率(P<sub>app</sub>,x10<sup>-6</sup>cm/s) | |
实施例1 | 4.70±0.589 |
比较例1 | 0.362±0.045 |
比较例2 | 1.04±0.241 |
比较例3 | 2.01±0.517 |
比较例4 | 3.56±0.610 |
比较例5 | 1.90±0.486 |
比较例6 | 1.68±0.408 |
比较例7 | 3.13±0.467 |
*各个值的含义为平均±标准偏差(n=4)。
如上述表3所示,其结果显示,与特立帕肽(比较例1)的渗透率相比,将特立帕肽和脱氧胆酸衍生物以1∶4的摩尔比配合形成的复合物(比较例2)的透过肠道细胞膜的渗透率提高了2.87倍。该脱氧胆酸衍生物对药物的肠道粘膜渗透率提高效果不仅起因于药物的脂质亲和力的提高,而且还起因于脱氧胆酸与存在于肠道细胞膜表面的胆汁酸转运蛋白的选择性地、特异性地结合所导致的药物的细胞膜渗透率的增强。
然而,由于与亲水性的特立帕肽的一分子肽相结合的脱氧胆酸衍生物分子是疏水性的,所以复合物分子自身会形成自组装胶束,造成脱氧胆酸衍生物分子无法暴露在分子外部而位于胶束内核,导致其与存在于肠道细胞膜的胆汁酸转运蛋白之间的特异性相互作用降低。因此,为了抑制这种复合物的自组装胶束的形成,实施例1与比较例3至7同样在特立帕肽-脱氧胆酸衍生物的离子键复合物的制备过程中加入了如TPGS、泊洛沙姆、辛酸癸酸聚乙二醇-8甘油酯(Labrasol)及聚氧乙烯氢化蓖麻油等增溶剂,在该情况下,由于脱氧胆酸衍生物与胆汁酸转运蛋白的特异性相互作用提高及增溶剂本身在肠道细胞脂质膜的溶解度提高作用的协同作用,它们的肠道细胞膜渗透率与特立帕肽-脱氧胆酸衍生物(比较例2)的复合物相比分别提高了3.01倍、1.93倍、1.83倍、1.62倍。尤其是如实施例1使用TPGS作为增溶剂的复合物的情况下,其人造肠道粘膜渗透率与特立帕肽(比较例1)和特立帕肽和脱氧胆酸衍生物的摩尔比为1∶4的复合物(比较例2)相比分别提高了13.0倍和4.52倍。
此外,如实施例1使用TPGS作为增溶剂的复合物的情况下,其肠道细胞膜渗透率与使用泊洛沙姆、辛酸癸酸聚乙二醇-8甘油酯(Labrasol)及聚氧乙烯氢化蓖麻油作为增溶剂的比较例3、比较例5及比较例6相比有所提高。
而且,与使用TPGS和泊洛沙姆共同作为增溶剂使用的比较例4相比,单独使用TPGS的本申请发明的实施例1的肠道细胞膜渗透率也有所提高。
不仅如此,与不包含脱氧胆酸而包含作为脱氧胆酸衍生物的Nα-脱氧胆酰基-L-赖氨酰甲基酯(Nα-deoxycholyl-L-lysylmethylester,DCK)和TPGS的比较例7相比,同时包含脱氧胆酸和脱氧胆酸衍生物的本申请发明的实施例1的肠道细胞膜渗透率有所提高。
这些结果可判断为是起因于脱氧胆酸衍生物本身的药物的脂质亲和力增强效果和增溶剂对肠道脂质膜的增溶作用,尤其是伴随肠道脂质膜增溶作用而产生的特立帕肽的脂质亲和力的增强效果看起来是起因于脱氧胆酸和脱氧胆酸衍生物的组合以及TPGS。
实施例2:包含由特立帕肽、脱氧胆酸、脱氧胆酸衍生物和增溶剂组成的复合物的
口服固体制剂的制备
经历了如下湿法制粒工艺:即在上述实施例1中制备的由特立帕肽、脱氧胆酸、脱氧胆酸衍生物及TPGS组成的复合物中混合如表4所示其它添加剂。将制备的颗粒干燥,加入硬脂酸镁进行混合后,压制成合适形状,由此制备片剂或填充至硬胶囊中。得到的骨架片剂和胶囊内容物组成如下表4所示。
[表4]
成分(mg) | 实施例2 |
特立帕肽 | 0.1 |
脱氧胆酸衍生物 | 0.056 |
脱氧胆酸 | 0.08 |
TPGS | 7.52 |
聚乙烯吡咯烷酮 | 12.48 |
交联羧甲基纤维素钠 | 10 |
微晶纤维素 | 34.382 |
乳糖 | 34.382 |
硬脂酸镁 | 1 |
水分* | 适量 |
总量 | 100 |
*在制备过程中去除。
实施例3:包含特立帕肽复合物的骨架片剂(matrix tablets)的包衣
用羟丙基甲基纤维素2910对上述实施例2中制备的骨架片剂进行第一层包衣后,直接用作为含有色素的肠溶包衣剂的羟丙基甲基纤维素邻苯二甲酸酯进行第二层包衣,由此制备实施例3的片剂。此时,包衣液的组成如表5所示,包衣用包衣锅进行喷液包衣。
[表5]
*包衣与未包衣的芯部骨架片剂的比以重量%表示。
实施例4:包含由特立帕肽、脱氧胆酸、脱氧胆酸衍生物和增溶剂组成的复合物的
口服水包油包水型(water-in-oil-in-water type,w/o/w)纳米乳液的制备
将17.76mg(相当于0.1mg的特立帕肽)的实施例1中制备的特立帕肽、脱氧胆酸、脱氧胆酸衍生物和TPGS的复合物重新分散在38mg的纯水中,然后加入112mg的第一表面活性剂和第一助表面活性剂的1∶1混合物(辛酸癸酸聚乙二醇-8甘油酯∶吐温80=1∶1,w/w)进行混合后,加入并混合50mg的油酸聚乙二醇甘油酯(Labrafil M1944)作为油相而制备w/o纳米乳液。向其中加入630mg的第二表面活性剂和第二助表面活性剂的混合物(吐温80∶聚氧乙烯氢化蓖麻油EL∶PEG 400=1∶2∶2,w/w/w),制备液态的口服纳米乳液。
实验例3:口服制剂的大鼠生物利用度确认
向雌性SD大鼠(Sprague-Dawley rat,200-250g,6-7周龄)腹腔内注射氯胺酮(ketamine,45mg/kg)和赛拉嗪(xylazine,5mg/kg)进行麻醉后,剖开大鼠的腹部取出小肠后,在其近端空肠(proximal jejunum)注射上述制备的将实施例1和实施例4以及比较例1和比较例2分散在纯水中的药液,注射量为各400μL,以特立帕肽计相当于100μg/kg。此外,为了评价相对生物利用度,另外在皮下注射了溶解于生理盐水的特立帕肽溶液,注射量为150μL,以特立帕肽计相当于20μg/kg。
药物给药后间隔一段时间采集血液样本各150μL,与50μL的3.8%柠檬酸钠水溶液进行混合。之后将血液试样在2500×g、4℃条件下离心分离15分钟后,取血浆在-70℃保存。使用人PTH(1-34)ELISA试剂盒(ALPCO Diagnostics,USA),在620nm波长下血浆中特立帕肽的浓度。使用WinNonlin软件(ver.5.3;Pharsight Corporation,USA),通过非隔室分析法(non-compartment method)来推算药动力学参数等,将结果示于表6和图1。
[表6]
aTmax:达到Cmax的时间
bCmax:最大血浆浓度
CAUClast:从0到最后一次血浆浓度测定时间点的血浆浓度-时间曲线下的时间曲线下面积
dAUCinf:从0到无穷大的血浆浓度-时间曲线下面积
e生物利用度:(AUClast,空肠内给药/特立帕肽给药量,空肠内给药)/(AUClast,皮下注射/特立帕肽给药量,皮下注射)×100
*各个值的含义为平均±标准偏差(n=4)。
图1表示向大鼠进行药物给药后血浆中特立帕肽的浓度随时间的变化。将比较例1的特立帕肽以0.1mg/kg空肠内(intrajejunal)给药后,血浆中最大药物浓度(Cmax)为0.041±0.010ng/mL,时间-浓度曲线下面积(AUClast)为0.030±0.007ng·h/mL,且相对于皮下注射的相对生物利用度被评价为0.810±0.191%。另一方面,将特立帕肽-脱氧胆酸衍生物的1∶4摩尔复合物(比较例2)以特立帕肽计0.1mg/kg的量空肠内给药后,与单独将特立帕肽空肠内给药的情况进行对比,此时,Cmax提高了11倍、AUClast提高了17.6倍、与皮下注射相比,相对生物利用度提高了17.8倍。另一方面,与用比较例1(仅为特立帕肽)或比较例2(特立帕肽和脱氧胆酸衍生物的1∶4摩尔复合物)进行给药的情况相比,在用实施例1的特立帕肽、脱氧胆酸、脱氧胆酸衍生物和TPGS的复合物进行给药的情况下,Cmax分别提高了14.2倍和1.30倍、AUClast分别提高了24.4倍和1.39倍、与皮下注射相比相对生物利用度分别提高了24.7倍和1.39倍。包含实施例1的特立帕肽、脱氧胆酸、脱氧胆酸衍生物和TPGS的复合物的实施例4的口服纳米乳液的情况下,与比较例1(特立帕肽单独)相比,Cmax和AUClast分别提高了17.3倍和29.8倍,与皮下注射相比相对生物利用度被评价为24.3±5.66%,提高了30倍。
Claims (13)
1.一种口服药物组合物,其包含离子键复合物,所述离子键复合物由特立帕肽(teriparatide)、脱氧胆酸(deoxycholic acid)、Nα-脱氧胆酰基-L-赖氨酰甲基酯(Nα-deoxycholyl-L-lysyl-methylester,DCK)和D-α-生育酚聚乙二醇1000琥珀酸酯(D-α-tocopherol polyethylene glycol 1000succinate)组成。
2.根据权利要求1所述的口服药物组合物,其特征在于,相对于1摩尔的特立帕肽,含有0.1至10摩尔的所述Nα-脱氧胆酰基-L-赖氨酰甲基酯(Nα-deoxycholyl-L-lysyl-methylester,DCK)。
3.根据权利要求1所述的口服药物组合物,其特征在于,相对于1摩尔的特立帕肽,含有1至20摩尔的所述脱氧胆酸。
4.根据权利要求1所述的口服药物组合物,其特征在于,所述口服药物组合物还包含泊洛沙姆。
5.一种口服药物组合物的制备方法,其包括如下步骤:
第一步骤,在包含特立帕肽(teriparatide)和D-α-生育酚聚乙二醇1000琥珀酸酯(D-α-tocopherol polyethylene glycol 1000succinate)的溶液中加入脱氧胆酸(deoxycholic acid)和Nα-脱氧胆酰基-L-赖氨酰甲基酯(Nα-deoxycholyl-L-lysyl-methylester,DCK)水溶液而形成离子键复合物;
第二步骤,在所述第一步骤中制备的离子键复合物中混合粘结剂、崩解剂、稀释剂及润滑剂而制备颗粒;以及
第三步骤,将所述第二步骤中制备的颗粒压制成片剂形状。
6.根据权利要求5所述的口服药物组合物的制备方法,其特征在于,还包括将所述第三步骤中制备的片剂用肠溶性物质进行包衣的步骤。
7.根据权利要求6所述的口服药物组合物的制备方法,其特征在于,所述肠溶性物质选自尤特奇(Eudragit,甲基丙烯酸-丙烯酸乙酯共聚物)、羟丙基甲基纤维素邻苯二甲酸酯、乙酰琥珀酸羟丙基甲基纤维素、醋酸邻苯二甲酸纤维素、聚醋酸乙烯邻苯二甲酸酯、羧甲基乙基纤维素和虫胶中的一种以上。
8.一种口服药物组合物的制备方法,其特征在于,包括如下步骤:
第一步骤,在包含特立帕肽(teriparatide)和D-α-生育酚聚乙二醇1000琥珀酸酯(D-α-tocopherol polyethylene glycol 1000succinate)的溶液中加入脱氧胆酸(deoxycholic acid)和Nα-脱氧胆酰基-L-赖氨酰甲基酯(Nα-deoxycholyl-L-lysylmethylester,DCK)水溶液而形成离子键复合物;
第二步骤,在所述离子键复合物溶液中加入作为第一表面活性剂的辛酸癸酸聚乙二醇-8甘油酯和作为第一助表面活性剂的吐温80而制备混合物;
第三步骤,将所述第二步骤的混合物分散在第一油相中而制备油包水型(water-in-oil,w/o)第一纳米乳液;以及
第四步骤,在所述第三步骤的第一油包水型纳米乳液中加入作为第二表面活性剂的聚氧乙烯氢化蓖麻油或吐温80和作为第二助表面活性剂的聚乙二醇400的混合物而制备水包油包水型(water-in-oil-in-water,w/o/w)第二纳米乳液。
9.根据权利要求8所述的口服药物组合物的制备方法,其特征在于,所述第一油相选自硅油、酯类油、烃类油、丙二醇单辛酸酯、丙二醇二辛酸酯、油酸聚乙二醇-6甘油酯(Oleoylmacrogol-6glycerides)、月桂酸聚乙二醇-6甘油酯、亚油酸聚乙二醇-6甘油酯、中链甘油三酯、油酸、硬脂酸、山嵛酸甘油酯、单硬酯酸甘油酯和蓖麻油中的一种以上。
10.根据权利要求8所述的口服药物组合物的制备方法,其特征在于,相对于组合物总重量,所述w/o/w第二纳米乳液内包含0.1至40重量%的第一油相。
11.根据权利要求8所述的口服药物组合物的制备方法,其特征在于,相对于组合物的总重量,包含0.1至40重量%的所述第一表面活性剂与第一助表面活性剂的混合物以及所述第二表面活性剂与第二助表面活性剂的混合物。
12.根据权利要求8所述的口服药物组合物的制备方法,其特征在于,所述第一助表面活性剂与第一表面活性剂、所述第二助表面活性剂与第二表面活性剂各自独立地以1∶0.1至1∶10重量比混合。
13.根据权利要求8所述的口服药物组合物的制备方法,在所述口服药物组合物中,相对于1重量份的特立帕肽,含有0.1至100重量份的所述D-α-生育酚聚乙二醇1000琥珀酸酯。
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