CN102552917A - 用于治疗剂的微-粒子脂肪酸盐固体剂量制剂 - Google Patents
用于治疗剂的微-粒子脂肪酸盐固体剂量制剂 Download PDFInfo
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Abstract
本发明涉及用于治疗剂的微-粒子脂肪酸盐固体剂量制剂。特别地，涉及具有其中粒子为约1到约1,000微米直径的粒度分布的脂肪酸盐粒子，粒子在药物组合物中的应用，以及粒子和组合物的制备和使用方法。
Description
本申请为国际申请PCT/US2004/026403于2006年2月13日进入中国国家阶段、申请号为200480023135.4、发明名称为“用于治疗剂的微-粒子脂肪酸盐固体剂量制剂”的分案申请。
优先权声明
本发明要求Opawale等2003年8月13日申请的发明名称为“用于治疗剂的微-粒子脂肪酸固体剂量制剂”的美国临时专利申请No.60/494,821的优先权，其整体内容在此引作参考。
技术领域
本发明涉及微-粒子脂肪酸盐及其在药物制剂中的应用，具体地为用于口服递送多肽药物的药物制剂。
背景技术
与治疗剂诸如多肽的口服相关的问题是制药工业中众所周知的，且正在试图采用各种策略来解决这些问题。
由于在胃和肠中存在大量的多肽降解酶，因此通过胃肠道递送治疗性多肽是困难的。为获得口服递送，治疗性多肽必须耐受胃肠的酶且必须具有通过或环绕肠消化道内胚层输送的能力。
口服递送的方法的实例包含1)利用酶抑制剂来减缓多肽在胃肠道中的降解速率；2)控制pH值来使局部的消化酶失活；3)通过利用渗透作用增强剂增加它们透细胞的和细胞间的运输来提高多肽的吸收；4)利用纳米粒子如微粒载体来促进肠上皮尤其是淋巴集结(Peyer′spatches)的完整吸收，以及来增加对酶降解的抗性；和5)利用液体乳浊液来保护药物免受肠腔内的酶促降解。
用于递送常规小分子药物的口服剂型也被尝试用于改进多肽的口服递送。除了多肽已被化学改性或其中已使用专用的吸收增强剂的情况之外，结果是令人失望的。对本发明人的知识而言，仅仅少量的证明充分的生物利用率和药物动力学的人临床试验来表明使口服递送的多肽商业化是可行的。
本领域需要配制口服递送多肽药物的新的方法，通过使较多量的药物通过胃肠道进入血液来改进目前的技术状态。
发明内容
本发明提供了一种包含具有约1到约1,000微米直径的粒度分布的脂肪酸盐粒子的脂肪酸盐组合物。在某些实施方案中，脂肪酸盐组合物可包括具有至少50％的粒子为约5到约500微米的粒度分布和/或具有至少50％的粒子为约20到约80微米的粒度分布的脂肪酸盐粒子。
本发明也提供了包括具有如在这里描述的粒度分布的脂肪酸盐以及多肽药物的药物组合物。在不同的实施方案中，多肽药物可以是非结合的多肽，PEG化的多肽，潜药和/或与寡聚物结合的多肽。在其它的实施方案中，药物组合物可包括具有在这里描述的粒度分布的脂肪酸盐以及可以是多肽、潜药、纯的或部分的潜药和/或小分子的生物活性剂。生物活性剂可以是非结合的，与寡聚物结合的和/或PEG化的。
附图说明
图1显示鲑鱼降钙素的氨基酸序列以及结构。
图2显示鲑鱼降钙素的化学改型CT-025的氨基酸序列以及结构。
图3显示由式A片剂的CT-025的三个样品释放的癸酸钠的溶解(参见图2)。
图4显示由式A的CT-025片剂的三个样品释放的月桂酸钠的溶解。
图5显示由式B的CT-025片剂的三个样品释放的癸酸钠的溶解。
图6显示由式B的CT-025片剂的三个样品释放的月桂酸钠的溶解。
图7显示由式C的CT-025片剂的三个样品释放的癸酸钠的溶解。
图8显示由式C的CT-025片剂的三个样品释放的月桂酸钠的溶解。
图9显示由六个安慰剂胶囊的样品释放的癸酸钠的溶解。
图10显示由六个CT-025胶囊的样品释放的月桂酸钠的溶解。
图11显示由六个安慰剂胶囊的样品释放的癸酸钠的溶解。
图12显示由六个CT-025胶囊的样品释放的月桂酸钠的溶解。
图13显示禁食猎兔犬(beagle dogs)口服一种含有加工的脂肪酸和430μgCT 025(相当于320μg的鲑鱼降钙素)的片剂之后CT025的血清血浆水平。
图14显示禁食猎兔犬(beagle dogs)口服一种含有加工的脂肪酸与320μg鲑鱼降钙素的片剂之后鲑鱼降钙素的血清血浆水平。
定义
本发明说明书中使用的术语仅用于描述特定实施方案的目的且并非用于对本发明限制。如在说明书和权利要求中使用的，单数形式的“a”，“an”和“the”同样包含复数形式，除非上下文已清楚地表明。
如在这里使用的下列术语具有所示的含义：
“生物活性剂”是指在本发明中可结合的治疗性或药理学的药物。生物活性剂可以是小分子，巨大分子的肽，蛋白或核酸。生物活性剂的实例包含，但不限于，属于下列治疗性类别的那些：ACE-抑制因子；抗-心绞痛药物；抗-心律异常；抗-哮喘的；抗-胆醇血症；抗-惊厥剂；抗-抑郁；抗-腹泻制剂；抗-组胺；抗-高血压药物；抗感染药物；消炎药；抗-脂类剂；抗-躁狂；抗-呕吐剂；抗-中风剂；抗-甲状腺制剂；抗-肿瘤药物；抗-咳嗽；抗-尿酸药物；抗-病毒剂；粉刺药物；生物碱；氨基酸制剂；合成代谢药物；镇痛药；麻醉药；血管生成抑制因子；抗酸药；抗-关节炎药；抗生素；抗凝血剂；镇吐药；抗肥胖药物；抗寄生虫剂；抗精神病药；清热药；解痉药；抗血栓形成药物；抗焦虑药；促进食欲药；食欲抑制剂；β阻滞剂；支气管扩张药；心血管剂；脑扩张药物；螯合剂；缩胆囊肽拮抗剂；化疗剂；认知活化剂；避孕药；冠状动脉扩张药物；咳嗽抑制剂；解充血药去臭剂；皮肤用药；糖尿病药物；利尿剂；润肤剂；酶；红血球生成药物；祛痰药；致育药物；杀菌剂降血糖药；通便剂；偏头痛药物；矿物质填料；溶粘液药；麻醉剂；安定药；神经肌肉药物；NSAIDS；营养添加剂；周围血管扩张药；前列腺素；精神调理药物；肾素抑制因子；呼吸性兴奋药；激素；兴奋药；交感神经阻滞药；甲状腺制剂；镇静剂；子宫松弛药；阴道制剂；血管收缩剂；血管扩张剂；眩晕剂；维生素；和伤口愈合剂。生物制剂的其它非-限制的实例包括香豆素，胰岛素，降钙素，leu-脑啡肽，和met-脑啡肽。
“有效量”是指足以产生可以是治疗性作用的预期效果的化合物或组合物的量。有效量随年龄、受试者的基本状况、待治疗病症的严重性变化、施用的特定生物活性剂、药物的持续时间、任意共同作用药物的特性、使用的药用载体以及本领域技术人员知识和专门技术等因素而变化。适当的，任意个体情况的“有效量”可由本领域的普通技术人员参考相关教科书以及文献和/或通过利用常规实验来确定。(参见，例如，Remington，Tlte Science Arzd Practice of Pharmacy(20th ed.2000)，全部内容在这里引入作为参考)。
“可水解的”是指键在生理条件下易受水解。
“亲水性的”是指显示出水溶性的特性，且术语“亲水性部分”是指一个部分其是亲水性的和/或其当连接于另一化学个体时，增加这种化学个体的亲水性。实例包括，但不限于，糖和聚烯烃基部分诸如聚乙二醇。“亲脂性的”是指显示出脂溶性的特性，诸如在脂肪和脂肪组织中累积，溶于脂类的能力和/或渗透，与生物膜相互作用和/或交叉的能力，且术语“亲脂性部分”是指一个部分其是亲脂性的和/或其，当连接于另一化学个体时，增加这种化学个体的亲油性。“两性的”是指显示出亲水性和亲脂性的特性，且术语“两性的部分”是指一个部分其是两性的和/或其，当连接于多肽或非-多肽药物时，增加所产生的结合物的两亲性，例如，PEG-脂肪酸改性的部分，糖-脂肪酸改性的部分。
“低级烷基”是指具有一到六个碳原子例如，C1，C2，C3，C4，C5或C6的取代的或未取代的、线性或支链烷基部分。“高级烷基”是指具有六个或更多碳原子的取代或未取代的、线性或支链烷基部分，例如，C7，C8，C9，C10，C11，C12，C13，C14，C15，C16，C17，C18，C19，C20等等。
“单分散的”描述化合物的混合物其中混合物中的约100％的化合物具有相同的分子量。″基本上单分散的”描述化合物的混合物其中混合物中至少约95％的化合物具有相同的分子量。“纯单分散的”描述化合物的混合物，其中混合物中约100％的化合物具有相同的分子量且具有相同的分子结构。因此，纯单分散的混合物是单分散的混合物，但单分散的混合物未必是纯单分散的混合物。“基本上纯的单分散的”描述一种化合物的混合物，其中混合物中至少约95％的化合物具有相同的分子量且具有相同的分子结构。因此，基本上纯单分散的混合物是基本上单分散的混合物，但基本上单分散的混合物未必是基本上纯单分散的混合物。本发明制剂中使用的结合多肽优选是单分散的，基本上单分散的，纯单分散的或基本上纯单分散的，但也可以是多分散。”多分散的”是指具有不是单分散的，基本上单分散的，纯单分散的或基本上纯单分散的分散性。
“聚二醇”或PAG是指取代或未取代的，线性或分支的聚二醇聚合物诸如聚乙二醇(PEG)，聚丙二醇(PPG)，和聚丁烯乙二醇(PBG)，及其组合(例如，包括两种或多种不同PAG亚基，诸如选自PEG、PPG、PPG和PBG亚基的两种或多种不同PAG单位的组合的线性或分支聚合物)，且包括聚二醇的单烷基醚。术语PAG亚基是指单独的PAG单位，例如，，“PEG亚基”是指单独的聚乙二醇单位，例如，-(CH2CH2O)-，“PPG亚基′是指单独的聚丙二醇单位，例如，-(CH2CH2CH2O)-，且“PBGs亚基”是指单独的聚丙二醇单位，例如，-(CH2CH2CH2CH2O)-。PAGs和/或PAG亚基也包括取代的PAGs或PAG亚基，例如，包括烷基侧链，诸如甲基、乙基或丙基侧链或羰基侧链的PAGs，以及包括一或多个分枝形式的PAG亚基，诸如异-PPG或异-PBG的PAGs。
“药用的”是指，本发明的组合物相对于元件诸如盐，载体，赋形剂或稀释液为(i)可以与本发明组合物结合而不致使组合物不适宜预定目的的其它组分相容的元件，和(ii)适用于在这里提供的受试者而没有不适当的不良副作用(诸如毒性，刺激和过敏反应)。当组合物的益处大于它们的危险时，副作用是“不适当的”。
“多肽药物”是指一种多肽，当其施用于受试者时具有治疗性活性或产生具有治疗活性的代谢产物，和衍生物或这种多肽的结合物。
“多肽”是指肽或蛋白。
“潜药”或“纯的潜药”是指生物活性剂已被化学改性使得，(i)其保持某些，全部或没有其亲本药物化合物的生物活性，和(ii)其在受试者中被代谢来产生亲本药物化合物。在上下文中，寡聚的多肽潜药或纯的潜药，在体内除去全部的寡聚物来产生生物学活性的非结合多肽。
“治疗”或“处理”是指产生调节作用的任意类型的治疗，其，例如，对患病症、疾病或病的受试者可以是有益的作用，包含改善受试者的病症(例如，一或多种症状)，延缓病症的发展，预防或延缓病症的发作，和/或改变本领域众所周知的临床参数，疾病或病等等，和/或增强正常的生理功能。
发明详述
本发明提供了微-粒子脂肪酸盐和包括这种盐的组合物，以及制备和使用这种盐和组合物的方法。微-粒子脂肪酸盐在用于口服递送药物尤其是多肽药物诸如多肽结合物的固体剂量制剂的制备中是尤其有用的。本发明的微-粒子脂肪酸盐制剂令人惊讶地能促进递送药学上有效量的多肽通过胃肠道进入体循环中。没有受特定理论的约束，本发明人相信微-粒子脂肪酸盐快速地溶于内脏来产生保护多肽不受酶攻击的微环境并参与输送多肽通过内脏上皮。
微-粒子脂肪酸盐
本发明提供了在配制治疗性化合物中有用的微-粒子脂肪酸盐。发明人令人惊讶地发现增加脂肪酸盐的比表面积，即，通过减少盐粒子的大小，显著地增加它们促进递送多肽药物跨越肠粘膜的能力。优选地，溶解速度高于稀释速度。
本发明有用的脂肪酸盐的实例包含，但不限于，短链的、中链的和长链的脂肪酸。优选脂肪酸盐的某些实例为中链脂肪酸盐，诸如丁酸(四烷酸)，己酸(六烷酸)，辛酸(八烷酸)，癸酸(十烷酸)，月桂酸(十二烷酸)，肉豆蔻酸(十四酸)，棕榈酸(十六烷酸)，棕榈酸(9-十六碳烯酸)，硬脂酸(十八烷酸)，油酸(9-十八碳烯酸)，亚油酸(9，12-十八碳二烯酸)，α-亚麻酸(ALA)(9，12，15-十八碳三烯酸)，γ-亚麻酸(GLA)(6，9，12-十八碳三烯酸)，花生酸(二十烷酸)，顺9-二十碳烯酸(9-二十烯酸)，花生四烯酸(AA)(5，8，11，14-二十碳四烯酸)，EPA(5，8，11，14，17-二十碳五烯酸)，山芋酸(二十二碳烷酸)，芥子酸(13-二十二烯酸)，DHA(4，7，10，13，16，19-二十二碳六烯酸)，木蜡酸(二十四酸)。
为提供适当的溶解-稀释的比率，盐以下述目前所用的粒子大小拉提供。脂肪酸盐可以提供在组合物中，其中至少约10％，20％，30％，40％，50％，60％，70％，80％，90％，95％，96％，97％，98％，99％或约100％的粒子为约1到约1,000微米的直径。脂肪酸盐可以提供在组合物中，其中至少约10％，20％，30％，40％，50％，60％，70％，80％，90％，95％，96％，97％，98％，99％或约100％的粒子为约5到约500微米的直径。脂肪酸盐可以提供在组合物中，其中至少约10％，20％，30％，40％，50％，60％，70％，80％，90％，95％，96％，97％，98％，99％或约100％的粒子为约10到约100微米的直径。脂肪酸盐可以提供在组合物中，其中至少约10％，20％，30％，40％，50％，60％，70％，80％，90％，95％，96％，97％，98％，99％或约100％的粒子为约20到约80微米的直径。此外，脂肪酸盐可以提供在组合物中，其中脂肪酸盐粒子的平均粒度为约1到约1,000微米直径，优选地约5到约500微米的直径，更优选地约10到约100微米的直径，理想地约20到约80微米的直径。
制剂
本发明的微-粒子脂肪酸盐用于固体内服剂量形式的制剂中，诸如用于口服递送药物的片剂和胶囊。当目前的工作集中于递送多肽药物的新制剂的应用时，可以理解制剂同样在小分子药物制剂中是有用的。制剂通常包含本发明的微-粒子脂肪酸盐和药物诸如多肽药物和/或小分子药物。然而，其它各种各样的赋形剂也可被包含在本发明的制剂中，只要这种赋形剂不消除通过利用微-粒子脂肪酸盐提供的有益作用。本发明的制剂在多肽药物且尤其是化学改性的多肽药物诸如结合多肽的递送中是尤其有用的。
在某些实施方案中，本发明的制剂可包括胆汁盐，其在特定的实施方案中可以是非结合的胆汁盐其中初级侧链在末端位置具有单独的羧基且其是未取代的(例如，胆酸盐，熊脱氧胆酸盐，鹅去氧胆酸盐和脱氧胆酸盐)。在其它实施方案中的，本发明的制剂可包括结合的胆汁盐，其是初级侧链具有用例如通过其氮原子连接于羧基的氨基酸衍生物取代的羧基的胆汁盐(例如，牛磺胆酸盐，甘胆酸盐，牛黄脱氧胆酸盐和甘氨脱氧胆酸盐)。也可以使用不同的非结合的和/或结合的胆盐的混合物。
在其它实施方案中，本发明的组合物和/或制剂特定地不包含任何胆汁盐或不包含特定的胆盐。例如，本发明的组合物和制剂可包括任意一或多种任意组合的胆盐以及也排除一或多种其它任意组合的胆汁。本发明的制剂可包含牛磺胆酸盐和/或排除胆酸盐。任意特定的胆盐可包含，和任意特定的胆汁盐可被特异性排除，因此，任意包含和排除胆盐的组合在本发明的范围之内。
本领域药物制剂中使用的各种任选的已知组分也可以被包含在本发明的实施方案中。实例包含，但不限于，本领域公知的表面活性剂，缓冲液组分，包被剂，崩解剂，填充剂，润滑剂组分，乳化剂，片剂粘合剂，填料和润湿剂。
而任选的，可对本发明制剂有用的表面活性剂来增加脂肪酸可溶性，其可改进溶解和稀释的比例。有用的表面活性剂的实例包括，但不限于，阿拉伯树胶，卵磷脂，十二烷基硫酸钠，单硬脂酸甘油(glyceralmonostearate)，单和二-甘油酯，油酸，poloxomer，聚山梨酸酯，山梨聚糖酯和三乙醇胺。当存在时，表面活性剂可以＞0％到约20％重量比的量包含在药物组合物中。更优选地，表面活性剂可以＞0％到约5％重量比的量包含在药物组合物中。理想地，表面活性剂可以＞0％到约2％重量比的量包含在药物组合物中。
本发明的制剂还可以包括缓冲液。优选的缓冲液是药学上可接受的。本发明制剂中使用的缓冲液优选地具有约5到约10的pH，更优选地大于7.0到约10.0，更加优选地大于7.0到约9.0，且理想地约7.6到约8.0。在这里描述的高pH具有可瞬间中和胃中低pH且因此使胃酶诸如胃蛋白酶失活的益处。此外，在这里描述的高pH缓冲系统使溶液中的脂肪酸维持良好的pH。本发明制剂的使用在胃肠道中产生一个环境，其有助于保护结合或非结合的多肽药物且当同本发明的微-粒子脂肪酸盐结合时增强那些多肽药物的渗透性。
适于本发明药物组合物的缓冲液组分的实例包括，但不限于乙酸，碳酸铵，磷酸铵，硼酸，柠檬酸，乳酸，柠檬酸钾，偏磷酸钾，磷酸二氢钾，乙酸钠，柠檬酸钠，磷酸氢二钠和磷酸二氢钠。
在某些实施方案中，本发明的制剂以诸如片剂剂型提供，其是非肠道(enterically)涂层的且在某些实施方案中，剂型是肠道涂层的。在其它实施方案中，本发明的制剂不包括粘合剂且在某些实施方案中，包括粘合剂。可以或可以不包括一或多种崩解剂，润滑剂，填充剂，填料。
本发明制剂中使用的活性成分可以密封在纳米粒子中。
纳米粒度范围的粒子被肠上皮完全的吸收，尤其是，通过派伊尔氏淋巴集结(Peyer′s patches)，且到达位点诸如肝脏脾及其它组织。密封在纳米粒子中的多肽药物和/或小分子药物可较少地被酶降解。一旦在血流中，可提供粒子来连续释放药物。
活性成分
优选的活性成分为多肽药物。优选的多肽药物为降钙素，寡聚物-结合的降钙素，PEG化的降钙素，脑钠尿肽，寡聚物-结合的脑钠尿肽，PEG化的脑钠尿肽，胰岛素，寡聚物-结合的胰岛素，PEG化的胰岛素，GLP-1，寡聚物-结合的GLP-1，和/或PEG化的GLP-1。优选的药物类型为主要通过透细胞途径的那些。
本发明有用的其它多肽药物包括，但不限于，腺苷脱氨酶，促肾上腺皮质激素，精氨酸酶，精氨酸脱氨酶，天冬酰胺酶，糜蛋白酶，内啡肽，脑啡肽，红细胞生成素，胰高血糖素，胰高血糖素样肽-1，生长激素，下丘脑释放因子，胰岛素，干扰素，利钠肽(例如脑钠尿肽和心房钠尿肽)，非-天然存在的鸦片样物质，催产素，木瓜酶，甲状旁腺激素，催乳激素，核糖核酸酶，促生长因子，抑生长素，生长激素，过氧化物歧化酶，甲状腺刺激激素，胰蛋白酶，抗利尿激素，以及化学改性的和/或结合形式的此种多肽。
本发明优选的多肽可具有约300到约10,000,000道尔顿范围内的大小，更优选地在约1,000到约50,000道尔顿范围内且理想地在约1,000到约10,000道尔顿的范围内。
在一个优选的实施方案中，多肽药物为与具有下列结构的改性部分结合的多肽：
任一上述部分可以，例如，与人胰岛素结合在亲核残基例如，Al，B1或B29，或任意上述的组合。
在另一实施方案中，多肽药物与具有下列通式：
-X-R1-Y-PAG-Z-R2
的改性部分结合
其中，
X，Y和Z为独立选择的连接基团且各自任选地存在，且当存在时，X通过共价键与胰岛素相结合。
至少存在R1和R2中的一个，且为低级烷基并可以任选地包括羰基，
R2为封端基团，和
PAG为插入一或多个链烯乙二醇部分的线性或支链碳链，且任选地插入一或多个其它选自-S-，-O-，-N-，和-C(O)-的其它部分，和
其中改性部分具有最大3，4，5，6，7，8，9，10，11，12，13，14，15，16，17，18，19，20，21，22，23，24，或25个数目的重原子。
在本发明的实施方案中，任意一个或多个X，Y和Z不存在。此外，当存在时，X，Y和/或Z可独立地选自-C(O)-，-O-，-S-和-N-。在一个实施方案中，Z为-C(O)-。
在某些实施方案中，R1为低级烷基，且R2为0。在其它实施方案中，R2为低级烷基，且R1为0。
改性部分可以，例如，在亲核残基例如，Al，B1或B29，或任意上述的组合处与人胰岛素结合。
在另一实施方案中，改性部分可以包括线性或分支的，取代的具有选自-C，-C-，-O-，＝O，-S-，-N-，-Si-的3-25个原子的主链的碳链部分。重原子通常包括一或多个碳原子和一或多个选自选自-O-，-S-，-N-和＝O，优选-O-，-N-和＝O，更优选-O-和＝O的非-碳重原子。碳原子和非-碳重原子通常以每个非-碳重原子至少1个碳原子的比例存在，优选地每个非-碳重原子至少2个碳原子，更优选地每个非-碳重原子至少3个碳原子。碳原子和氧原子通常以每个氧原子至少1个碳原子的比例存在，优选地每个氧原子至少2个碳原子，更优选地每个氧原子至少3个碳原子。改性部分可以包括一或多个封端基团，诸如分支的或线性的C1-6，分支的或线性的，或羰基。改性部分通常包括氢，一或多个氢可用氟(其是重原子但不应视为上述通式中的重原子)取代。改性部分可以与人胰岛素结合在，例如，亲核残基例如，Al，B1或B29，或任意上述的组合。
在本发明的其它实施方案中，多肽药物可以是天然的胰岛素，非结合的，生物活性的胰岛素类似物和/或结合的胰岛素。在特定的实施方案中，多肽药物可以是下列的：
胰岛素B29Lys-(NH-CO(CH2)5(OCH2CH2)7OCH3)
其中-NH-基团是Lys的ε-氮。
在本发明特定的实施方案中，多肽药物可以是天然的降钙素，非结合的，生物活性的降钙素类似物和/或结合的降钙素。在特定的实施方案中，多肽药物可以是下列的：
Cys Ser Asn Leu Ser Thr Cys Val Leu GlyLys(NH-CO(CH2)7(OCH2CH2)7OCH3)
Leu Ser Gly Glu Leu His Lys(NH-CO(CH2)7(OCH2CH2)7OCH3)LeuGln Thr Tyr
Pro Arg Thr Asn Thr Gly Ser Gly Thr Pro
其中NH-基团是赖氨酸的ε-氮。
对本发明制剂有用的其它结合多肽在下列专利中，其全部内容在这里引入作为参考：Enzon，Inc.的美国专利No.6,303,569，2001年10月16日授权，名称为″Trialkyl-lock-facilitated polymeric prodrugs ofamino-containing bioactive agents″；Enzon，Inc.的美国专利No.6,214,330，2001年04月10日授权，名称为″Coumarin and relatedaromatic-based polymeric prodrugs″；Enzon，Inc.的美国专利No.6,113,906，2000年09月05日授权，名称为″Water-solublenon-antigenic polymer linkable to biologically active material″：美国专利No.5,985,263，1999年11月16日授权，名称为″Substantially purehistidine-linked protein polymer conjugates″；Enzon，Inc.的美国专利No.5,900,402，1999年05月04日授权，名称为″Method of reducing sideeffects associated with administration of oxygen-carrying proteins″：Protein Delivery，Inc.的美国专利No.5,681,811，1997年10月28日授权，名称为″Conjugation-stabilized therapeutic agent compositions，deliveryand diagnostic formulations comprising same，and method of making andusing the same″：Enzon，Inc.的美国专利No.5,637,749，1997年06月10日授权，名称为″Aryl imidate activated polyalkyleneoxides″：Enzon，Inc.的美国专利No.5,612,460，1997年03月18日授权，名称为″Activecarbonates of polyalkylene oxides for modification of polypeptides″：Enzon，Inc.的美国专利No.5,567,422，1996年10月22日授权，名称为″Azlactone activated polyalkylene oxides conjugated to biologicallyactivenucleophiles″：Enzon，Inc.的美国专利No.5,405,877，1995年04月11日授权，名称为″Cyclic imide thione activated polyalkyleneoxides″：以及Protein Delivery，Inc.的美国专利No.5,359,030，1994年10月25日授权，名称为″Conjugation-stabilized polypeptide compositions，therapeutic delivery and diagnostic formulations comprising same，andmethod of making and using the same，″以及国际专利授权No.WO/2004/047871，名称为″Modified naturetic compounds，conjugates，and uses thereof″。对本发明制剂有用的结合多肽的其它实例在下列美国专利申请中，其全部内容在这里引入作为参考：美国专利申请No.09/134,803，1998年8月14日申请；美国专利申请No.10/018,879，2001年12月19日申请；美国专利申请No.10/235,381，2002年9月5日申请；美国专利申请No.10/235,284，2002年9月5日申请；以及美国专利申请No.09/873,797，2001年6月4日申请。本发明特定地考虑包括上述专利以及专利申请中描述的各属和种类的治疗性化合物的制剂。
制剂的制备
设计本发明的制剂来在吸收位点使脂肪酸快速溶解。遵循此目标，本发明制剂的制备方法通常包括提供具有在这里所述减小的粒子大小的脂肪酸盐的步骤。
本发明的制剂可加工成包括本发明的微-粒子脂肪酸盐与缓冲液组分的冷冻干燥粉末。
本发明的制剂可加工成包括本发明的微-粒子脂肪酸盐以及有或没有缓冲液组分及其它制剂组分的喷雾干粉。
本发明的制剂可加工成包括本发明的微-粒子脂肪酸盐以及有或没有缓冲液组分及其它制剂组分的混合或润湿颗粒化的干颗粒或干粉末。
本发明的具有粒度范围的脂肪酸盐可通过使用任意适当的减少粒度的设备碾磨来提供。细粉状的脂肪酸可形成固体内服剂量形式诸如胶囊或片剂的基体。
活性成分及其它组分可通过本领域已知的方法与上述组合物结合。
测定
本发明的制剂优选地具有高溶解速率。可如下测定溶解速率：使用具有500mL pH7.4磷酸盐缓冲液的50rpm的USP溶解装置2(叶片)。
USP 26，<711>溶解试验描述：
提供试验来测定片剂或胶囊剂型在个体中的溶解要求。在其中描述的装置类型中，使用装置2。对于不遵照溶解规范的硬或软的胶囊和凝胶-糖衣片剂，重复试验如下。其中在个体专论中的培养基如说明的具有小于6.8pH的水或基质，也可以使用添加每1000mL产生750,000或更少单位活性的纯化胃蛋白酶的相同基质。对于具有6.8或更大pH的介质而言，可添加胰酶来产生每1000mL不超过1750USP单位的蛋白酶活性。USP参考标准<11>(溶解校准，分解)。(溶解校准，非分解)用于校准设备。
装置2：装置包括下列：玻璃或其它惰性透明材料制成的带盖容器；马达；金属驱动轴；和搅拌元件。容器部分浸于任意适当大小的水浴中或放入加热套中。水浴或加热套允许试验过程中容器内部温度在37±0.5℃并且保持水浴液恒定、平稳的运动。装置的任何部分，包括其中放置有助于搅拌的装置的环境，没有除取决于平稳转动搅拌元件之外的振动。允许试验过程中观察样品和搅拌元件的装置是优选的。容器是圆柱形的，具有半球形底部和具有下列尺寸和容量：对于1升的额定容量而言，高为160mm到210mm且内径为98mm到106mm。顶部的侧面是凸边的。合适的盖子可用来阻止蒸发。
轴和搅拌元件由不锈钢，316型或等价物制成。放置轴使得其轴在任一点距离容器的纵轴不超过2mm且平稳地转动和没有显著的摆动。使用速度-调节装置来允许选择轴转速以及维持在特定的搅拌速度。叶片由桨叶形成且轴用作搅拌元件。
此处所述的术语“高溶解速率”是指当如在这里描述的试验时，本发明脂肪酸在pH 7.4缓冲液中的溶解速率足够的快，其在10分钟内释放至少约25％的脂肪酸到溶液中。在其它实施方案中，溶解速率可为十分钟内至少约30％，35％，40％，45％，50％，55％，60％，65％，70％，75％，80％，85％，90％，95％，96％，97％，98％，99％或约100％的脂肪酸溶解到溶液中。
治疗方法
本发明提供了通过将有效量的包括生物活性剂诸如多肽药物、潜药和/或小分子的制剂施用于受试者来治疗需要治疗的受试者的方法。制剂可存在于药用载体中。
在特定的实施方案中，本发明提供了通过将有效量的包括天然的降钙素、非结合的、生物活性剂降钙素类似物、结合的降钙素和/或下列物质的制剂口服施用于受试者来治疗骨质疏松症或疼痛(例如，骨质疏松疼痛或末梢疼痛)的方法：
Cys Ser Asn Leu Ser Thr Cys Val Leu GlyLys(NH-CO(CH2)7(OCH2CH2)7OCH3)Leu Ser Gly Glu Leu HisLys(NH-CO(CH2)7(OCH2CH2)7OCH3)Leu Gln Thr Tyr Pro Arg Thr AsnThr Gly Ser Gly Thr Pro。
其中-NH-基团是赖氨酸的ε-氮。
在其它实施方案中，本发明提供了通过将有效量的包括天然胰岛素、非结合的、生物活性剂胰岛素类似物、结合的胰岛素和/或下列物质的制剂口服施用于受试者来治疗糖尿病和/或高血糖症的方法：
胰岛素B29 Lys-(NH-CO(CH2)5(OCH2CH2)7OCH3)
其中-NH-基团是赖氨酸的ε-氮：或
与具有选自下列结构的改性部分结合的胰岛素：
任何一个上述部分可以，例如，在亲核残基例如在，Al，B1或B29，或任意上述的组合处与人胰岛素结合。
具体实施方式
实施例
这些技术已经应用于各种天然的多肽以及化学改性的多肽。
制备降钙素以及CT-025(改性的降钙素)制剂
碾磨癸酸钠和月桂酸钠
鲑鱼降钙素和CT-025(参见图2)制剂制备如下：
| 赋形剂 | ％w/w |
| 癸酸钠 | 53.4％ |
| 月桂酸钠 | 46.6％ |
1.混合癸酸钠和月桂酸钠(优选1∶1的摩尔比)。
2.通过喷射碾磨磨粉机来获得精细粒度。精细粒度为小于或50-100微米范围内的粒度。
3.预混合生成的物质用于下一处理
制剂A
制剂的制备
1.由冰箱中移取CT-025(参见图2)并允许在环境条件下解冻1小时，然后在开口容器中平衡另外2小时。
2.制备1％乙酸溶液：吸取2mL的冰醋酸至200mL QS中，用净化水充满并摇匀。
3.称取CT-025并转入100mL Pyrex玻璃瓶中。添加45mL的1％乙酸溶液并涡动来溶解。这些为粒化溶液。
4.混合癸酸钠/月桂酸钠；在具有5L滚筒的关键造粒机中与所有的甘露糖醇，山梨糖醇和交联羧甲纤维素钠预混合。
5.启动造粒机并将叶轮和断续器设置在适当的速度来获得充分的混合。
6.添加步骤2中的粒化溶液。用在10mL增加总计60-65mL的粒化液体中的1％乙酸溶液冲洗溶液容器。
7.粒化约20分钟。
8.转移粒子至加衬铝箔的托盘中。
9.在37℃恒温箱中干燥粒子16-24小时。目的湿度＜3％。
10.使干燥粒子流经#12滤网。
11.将硬脂酰延胡索酸钠和粒子添加到8夸脱V-搅拌器中。混合2分钟；然后出料。
12.使用适当的压片机来制备900mg锭形片剂，压缩颗粒成片剂。
制剂B
如上所述实现制剂的制备。
制剂C
如上所述实现制剂的制备。
制剂D
由冰箱中移取鲑鱼降钙素并允许在环境条件下解冻1小时，然后在开口容器中平衡另外2小时，且如上所述制备制剂。
制剂E(胶囊)
| 赋形剂 | ％w/w | mg/片剂 |
| CT-025(参见图2) | 0 | 0 |
| 癸酸钠 | 23.1 | 155.07 |
| 月桂酸钠 | 26.5 | 3.95 |
| 甘露糖醇 | 34.8 | 5.18 |
| 山梨糖醇 | 10.1 | 1.50 |
| 交联羧甲纤维素钠 | 5.0 | 0.74 |
| 硬脂酰延胡索酸钠，NF | 0.5 | 0.07 |
| 总计 | 100 | 671.3 |
制剂的制备
1.混合癸酸钠和月桂酸钠。流经喷射碾磨磨粉机。
2.添加来自步骤1的预混合物和所有的甘露糖醇，山梨糖醇，交联羧甲纤维素钠和硬脂酰延胡索酸钠；然后混合。
3.将671.3mg的混合物填充到000号硬度胶囊中。
未碾磨的制剂F(胶囊)
| 赋形剂 | ％w/w | mg/片剂 |
| CT-025(参见图2) | 0 | 0 |
| 癸酸钠 | 23.1 | 155.07 |
| 月桂酸钠预混合物 | 26.5 | 3.95 |
| 甘露糖醇 | 34.8 | 5.18 |
| 山梨糖醇 | 10.1 | 1.50 |
| 交联羧甲纤维素钠 | 5.0 | 0.74 |
| 硬脂酰延胡索酸钠，NF | 0.5 | 0.07 |
| 总计 | 100 | 671.3 |
制剂的制备
1.混合癸酸钠和月桂酸钠。(不研磨)。
2.添加来自步骤1的预混合物，和所有的甘露糖醇，山梨糖醇，交联羧甲纤维素钠和硬脂酰延胡索酸钠；然后混合。
3.将671.3mg的混合物填充到000号硬度胶囊中。
8.2.测定降钙素制剂
使用如上所述的配方和处理步骤制备片剂和胶囊制剂。图3-8显示了证明癸酸钠盐和月桂酸钠盐容易由各种其中脂肪酸已被碾磨到最佳粒度的片剂制剂中释放的溶解结果。
图3显示由CT-025的三个样品释放的癸酸钠的溶解(图2)式A的片剂。
图4显示式由A的CT-025片剂的三个样品释放的月桂酸钠的溶解。
图5显示由式B的CT-025片剂的三个样品释放的癸酸钠的溶解。
图6显示由式B的CT-025片剂的三个样品释放的月桂酸钠的溶解。
图7显示由式C的CT-025片剂的三个样品释放的癸酸钠的溶解。
图8显示由式C的CT-025片剂的三个样品释放的月桂酸钠的溶解。
用碾磨的脂肪酸(式E，图9和10)和未碾磨的脂肪酸(式F，图11和12)制备胶囊制剂。当脂肪酸未碾磨时溶解结果显著地减慢。图9显示由六个安慰剂胶囊的样品释放的癸酸钠的溶解，其中的脂肪酸是已碾磨的。图10显示由三个CT-025胶囊的样品释放的月桂酸钠的溶解，其中的脂肪酸是未碾磨的。
图11显示由三个安慰剂胶囊的样品释放的癸酸钠的溶解。
图12显示由三个CT-025胶囊的样品释放的月桂酸钠的溶解。
一种含有CT-025(每片剂320μg降钙素等价物)(图13，371＝式B；372＝式C)或鲑鱼降钙素(每片剂320μg降钙素等价物)(图14；373＝式D)与碾磨的脂肪酸的片剂被给药于禁食的猎兔犬。狗禁食过夜且在早上给药。在15，30，60，90和120分钟颈静脉抽取血液样品。分析血样来计算CT-025或鲑鱼降钙素等价物中鲑鱼降钙素的血浆浓度
图13显示禁食猎兔犬(beagle dogs)口服一种含有加工的脂肪酸和430μg CT-025(相当于320μg的鲑鱼降钙素)的片剂之后CT-025的血清血浆水平。
图14显示禁食猎兔犬(beagle dogs)口服一种含有加工的脂肪酸与320μg鲑鱼降钙素的片剂之后鲑鱼降钙素的血清血浆水平。
本发明在这里描述了优选的实施方案。本发明可体现为不同的形式且不应该被理解为局限于在这里阐述的特定实施方案。更合适地，提供的这些实施方案使得公开彻底和完全，且本领域技术人员而言将充分地表达本发明的范围。
除非另有定义，在这里使用的所有技术和科学术语具有与本领域普通技术人员通常对本发明所理解的相同的含义。本发明说明书中使用的术语仅用于描述特定实施方案的目的且并非用于对本发明进行限制。
在这里引用的所有出版物，专利申请，专利及其它参考文献整体引入作为参考，用于说明参考文献中存在的句子和/或短语的含义。
参考文献
下列参考文献的全部内容在这里引作参考：
A.T.Florence.The oral absorption of micro-and nanoparticulates：neither exceptional nor unusual.Phare.Res.14(1997)259-266
Ermak等，Uptake and transport of copolymer biodegradablemicrospheres by rabbit Peyer′s patch M cells.Cell Tissue Res.279(1995)433-436
Sakuma等，Designof nanoparticles composed of graft copolymersfor oral polypeptide delivery.Adv Drug Del Rev.47(2001)21-37
Claims (17)
1.一种包含具有50到100微米直径的粒度分布的脂肪酸盐粒子的组合物，其中脂肪酸盐包括大约相等量的癸酸钠盐和月桂酸钠盐的组合，其中所述组合物还包括多肽药物作为生物活性剂，且所述多肽药物为鲑鱼降钙素，并且其中所述组合物为固体口服剂型且所述固体口服剂型为片剂。
2.权利要求1的组合物，进一步包括缓冲剂。
3.权利要求1的组合物，进一步包括具有从5到10的pH的缓冲剂。
4.权利要求1的组合物，进一步包括具有从大于7.0到约9.0的pH的缓冲剂。
5.权利要求1的组合物，其中脂肪酸盐在10分钟内在pH 7.4缓冲剂中具有大于50％的溶解速率。
6.权利要求1的组合物，其中脂肪酸盐在10分钟内在pH 7.4缓冲剂中具有大于75％的溶解速率。
7.权利要求1的组合物，其中多肽药物包括聚乙二醇化多肽。
8.权利要求1的组合物，其中多肽药物与寡聚物相结合。
9.权利要求1的组合物，其中多肽药物包括结合的降钙素，其中降钙素与寡聚物相结合。
10.权利要求1的组合物，其中多肽药物包括：
其中R＝(O)C-(CH2)7(OCH2CH2)7OCH3。
11.权利要求1的组合物，以片剂形式提供，其中片剂具有高达10分钟内30％的脂肪酸溶入溶液的溶解速率。
12.权利要求1的组合物，以片剂形式提供，其中片剂具有高达10分钟内50％的脂肪酸溶入溶液的溶解速率。
13.权利要求1的组合物，以片剂形式提供，其中片剂具有高达10分钟内70％的脂肪酸溶入溶液的溶解速率。
14.权利要求1的组合物，以片剂形式提供，其中片剂具有高达10分钟内90％的脂肪酸溶入溶液的溶解速率。
15.权利要求1的组合物，以片剂形式提供，其中片剂具有高达10分钟内95％的脂肪酸溶入溶液的溶解速率。
16.权利要求1的组合物，以片剂形式提供，其中片剂具有高达10分钟内100％的脂肪酸溶入溶液的溶解速率。
17.前述权利要求任一项的组合物在制备用于治疗受试者的骨质疏松症或骨质疏松疼痛的药物中的应用。
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-
2004
- 2004-08-13 CN CN2012100034615A patent/CN102552917A/zh active Pending
- 2004-08-13 JP JP2006523417A patent/JP4880461B2/ja not_active Expired - Fee Related
- 2004-08-13 PT PT47811393T patent/PT1660047E/pt unknown
- 2004-08-13 PL PL04781139T patent/PL1660047T3/pl unknown
- 2004-08-13 CA CA2535013A patent/CA2535013C/en not_active Expired - Fee Related
- 2004-08-13 KR KR1020067002974A patent/KR101152470B1/ko not_active Expired - Fee Related
- 2004-08-13 AU AU2004264958A patent/AU2004264958B2/en not_active Ceased
- 2004-08-13 US US10/918,264 patent/US7635675B2/en active Active
- 2004-08-13 CN CNA2004800231354A patent/CN1863510A/zh active Pending
- 2004-08-13 WO PCT/US2004/026403 patent/WO2005016312A1/en not_active Ceased
- 2004-08-13 EP EP04781139.3A patent/EP1660047B1/en not_active Expired - Lifetime
- 2004-08-13 DK DK04781139.3T patent/DK1660047T3/en active
- 2004-08-13 ES ES04781139.3T patent/ES2445947T3/es not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| CN1863510A (zh) | 2006-11-15 |
| US7635675B2 (en) | 2009-12-22 |
| CA2535013C (en) | 2013-02-12 |
| JP4880461B2 (ja) | 2012-02-22 |
| US20050095216A1 (en) | 2005-05-05 |
| DK1660047T3 (en) | 2014-03-10 |
| PL1660047T3 (pl) | 2014-05-30 |
| AU2004264958B2 (en) | 2010-04-15 |
| EP1660047B1 (en) | 2013-11-27 |
| EP1660047A1 (en) | 2006-05-31 |
| KR20060082851A (ko) | 2006-07-19 |
| WO2005016312A1 (en) | 2005-02-24 |
| AU2004264958A1 (en) | 2005-02-24 |
| JP2007502303A (ja) | 2007-02-08 |
| CA2535013A1 (en) | 2005-02-24 |
| ES2445947T3 (es) | 2014-03-06 |
| PT1660047E (pt) | 2014-02-27 |
| KR101152470B1 (ko) | 2012-06-01 |
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Application publication date: 20120711 |