CN102014880A - 治疗性磷酸钙颗粒及其制备和使用方法 - Google Patents
治疗性磷酸钙颗粒及其制备和使用方法 Download PDFInfo
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- CN102014880A CN102014880A CN200980115262XA CN200980115262A CN102014880A CN 102014880 A CN102014880 A CN 102014880A CN 200980115262X A CN200980115262X A CN 200980115262XA CN 200980115262 A CN200980115262 A CN 200980115262A CN 102014880 A CN102014880 A CN 102014880A
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- pharmaceutical composition
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- calcium phosphate
- granule
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- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 title claims abstract description 72
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Abstract
本发明提供了一种适用于高效包封生物活性分子的新型磷酸钙纳米颗粒。本发明进一步提供了包括这些纳米颗粒的药物组合物,以及制备这些纳米颗粒和使用其作为治疗性递送生物活性大分子的载体的方法。
Description
相关申请的参考
本申请要求2008年5月1日提交的美国专利申请序列号61/049,627的优先权,其作为整体引入本文以供参考。
技术领域
本发明主要涉及药物递送领域。更具体地,本发明涉及适用于生物活性分子有效包封(encapsulation)的新型磷酸钙颗粒。本发明还涉及包括这些颗粒的药物组合物,以及制备这些颗粒的方法和使用这些颗粒作为治疗性递送生物活性大分子的载体的方法。
背景技术
大分子药物,包括蛋白质、肽、多糖、核酸、脂质或其组合,是用于治疗各种医疗病症的越来越重要的一类药物。给予大分子药物的主要途径是皮下注射,该方法令人不舒服、较为昂贵并经常造成较差的依从性。口服递送是优选的给予途径,但是,大分子药物经肠道吸收性较差并且易被胃酸、尤其是胃肠道内降解酶所破坏。一种有望克服上述口服大分子递送障碍的方式是使用纳米颗粒,其能防止降解并提高肠道吸收。
已报道载有胰岛素的纳米颗粒可用于向动物递送生物活性胰岛素。例如,Carino等人观察到通过捕获在(乳酸-共-乙交酯)聚合物纳米颗粒中的胰岛素连同富马酸酸酐低聚物及氧化铁添加剂可防止血糖升高(J.Controlled Release 65:261,2000)。Pan等人提供了另一个口服递送胰岛素和壳聚糖纳米颗粒的实例(Intl.J.Pharmaceutics,249:139,2002)。另外,已报道聚烷基氰基丙烯酸酯纳米颗粒也是一种向糖尿病动物口服递送胰岛素的有效载体(Damge et al.,Diabetes,37:246,1988)。已有文献记载通过胃肠道途径吸收微粒材料并涉及淋巴Peyer氏斑(Hussain et al.,Adv.DrugDelivery Rev.50:107,2001)。
颗粒尺寸看起来影响吸收效率的关键因素之一。例如,Jani等人(J.Pharm.Pharmacol.42:821,1990)研究了聚苯乙烯颗粒在大鼠肠道中的吸收并证明其吸收效率和颗粒尺寸的关系。类似地,Desai等人(Pharm.Res.13:1838,1996)也观察到肠道对(乳酸-共-乙交酯)聚合物(poly(lactide-co-glycolide))颗粒的吸收依赖于颗粒尺寸。
已提出将纳米级颗粒用作生物大分子如蛋白质和核酸的载体颗粒。参见美国专利第5,178,882;5,219,577;5,306,508;5,334,394;5,460,830;5,460,831;5,462,750;5,464,634;6,355,271号。
磷酸钙颗粒是生物粘性/生物相容性颗粒并常规用作体外递送核酸至细胞内区室(intracellular compartments)的载体(Chen et al.,Mol.Cell.Biol.7:2745-52,1987)。另外,还已测试磷酸钙可作为用于基因治疗中体内递送大分子核酸的载体(Roy et al.,Intl.J.Pharmaceutics 250:25,2003)。
已有对治疗性磷酸钙颗粒的描述。参见美国专利第6,355,271;6,183,803号;美国专利公开第2005/0234114;2004/0258763;2002/0054914;2002/0068090;2003/0185892;2001/0048925;WO02/064112;WO 03/051394;WO 00/46147;WO 2004/050065号。测试了载有胰岛素的磷酸钙颗粒口服制剂对糖尿病小鼠的效果,并表明能够控制血液葡萄糖(Morcol et al.,Intl.J.Pharmaceutics 277:91,2004)。然而,在该研究中颗粒尺寸的范围为2-4μm,该范围显然不是最佳范围。
为了使磷酸钙颗粒达到期望尺寸,广泛的超声处理是必需的(Cherian et al.,Drug Dev.Ind.Pharmacy,26:459,2000;Roy et al.,Intl.J.Pharmaceutics 250:25,2003),超声处理可能破坏脆弱的包封大分子药物。
此外,将大分子包封于磷酸钙颗粒中的效率常常较低。例如,美国专利第6,355,271号披露了如果在预先形成的磷酸钙颗粒中添加胰岛素,其吸收效率为约40%;如果在颗粒形成过程中混合胰岛素,其吸收效率为约89%。
这些已报道的方法要么造成颗粒尺寸(大小)不够理想,要么需要苛刻的条件,如广泛的超声,其与大分子制剂不相容。因此,仍然需要高效、成本低、易生产的口服大分子递送系统。
发明内容
一方面,本发明提供了一种多(a plurality of)颗粒,包括:a)多个磷酸钙核心纳米颗粒;b)包封在核心纳米颗粒中的GLP-1激动剂;和c)包封在核心纳米颗粒中的共沉淀剂,相对于相应的不含胆汁盐的磷酸钙核心纳米颗粒,该共沉淀剂用于提高GLP-1激动剂在磷酸钙纳米颗粒中的包封效率。在一些实施方式中,所述GLP-1激动剂是依克那肽(exenatide)或其生理上可接受的盐或衍生物。在一些实施方式中,共沉淀剂包括胆汁盐,该胆汁盐选自胆酸盐、脱氧胆酸盐、牛磺胆酸盐、甘胆酸盐、牛磺脱氧胆酸盐、熊脱氧胆酸盐(ursodeocycholate,乌索脱氧胆酸盐)、牛磺熊脱氧胆酸盐、鹅脱氧胆酸盐及其组合构成的组。
另一方面,本发明提供一种多颗粒,包括:a)多个磷酸钙核心纳米颗粒;b)包封在核心纳米颗粒中的生物活性大分子;和c)包封在核心纳米颗粒中的共沉淀剂,相对于相应的不含脂肪酸盐的磷酸钙核心纳米颗粒,该共沉淀剂用于提高生物活性大分子在纳米颗粒中的包封效率。在一些实施方式中,共沉淀剂包括脂肪酸盐,该脂肪酸盐选自己酸盐、辛酸盐、壬酸盐、癸酸盐、月桂酸盐、豆蔻酸盐及其组合构成的组。
又一方面,本发明提供一种制备磷酸钙颗粒的方法,该方法包括:a)在共沉淀剂存在下用磷酸盐水溶液接触钙盐水溶液;b)混合步骤a)中产生的溶液直到磷酸钙颗粒达到期望尺寸;以及c)回收磷酸钙颗粒。在一些实施方式中,该方法包括在共沉淀剂存在下用磷酸盐水溶液接触钙盐水溶液之前,向磷酸盐水溶液或钙盐水溶液中添加生物活性大分子的另一步骤,由此磷酸钙颗粒与生物活性大分子共结晶。在一些实施方式中,共沉淀剂包括脂肪酸盐,该脂肪酸盐选自己酸盐、辛酸盐、壬酸盐、癸酸盐、月桂酸盐、豆蔻酸盐及其组合构成的组。
另一方面,本发明提供包括本发明的磷酸钙颗粒和药用载体的药物组合物。在一些实施方式中,该药物组合物为胶囊、片剂、丸剂(球粒,spheres)或粉剂形式。在一些实施方式中,药物组合物进一步包括肠溶衣和/或吸收促进剂。
又一方面,本发明提供一种用于治疗需要生物活性大分子治疗的对象的方法,该方法包括给予该对象治疗有效量的包括本发明的磷酸钙颗粒的药物组合物。在一些实施方式中,药物组合物通过口服途径给予。在一些实施方式中,生物活性大分子是GLP-1激动剂,例如,依克那肽或其生理上可接受的盐或衍生物。
具体实施方式
除非另有限定,本文所使用的所有技术术语、注释和其它科学术语或词汇旨在具有本发明所述领域技术人员通常所理解的含义。在一些情况中,在本文中限定具有通常所理解的含义的术语是为了清楚和/或方便参考,并且本文将这些限定包含在内,不必理解为其相对于本领域中的普遍理解而表现实质性差别。本领域技术任意案件完全理解本文描述或参考的多项技术与程序,并且常常采用常规方法加以利用。如果合适,除非另外注明,涉及使用商购试剂盒与试剂的程序通常是按照制造商限定的方案和/或参数加以实施。
本文给出对一般性方法的讨论,仅是出于解释说明的目的。本领域技术人员在阅读本披露内容后能够明了其他可替换方法和实施方式。
本文所使用的“一个/种(a or an)”表示“至少一个/种(at leastone)”或“一个/种或多个/种(one or more)”。
用连词“或”联接的一组术语,除非另有明确解释,否则不应解读要求该组之间相互排斥,而应解读为“和/或”。
本文所使用的术语“治疗”是指改善或在其他方面有利改变病症、失调或疾病的症状的任何方式。在治疗血液恶性肿瘤的情况中,血液恶性肿瘤可能会发作、复发或难以治愈。不必完全根除病症、失调和疾病。特定失调症状的改善是指症状的任何减轻,无论是长久性减轻或是暂时性减轻,该症状减轻可归因于或是相关于本发明治疗组合物的给予或相应方法和组合疗法的给予。治疗也包括按照本文披露方法对该组合物的药物利用。
本文所使用的术语“对象”不限于特定物种或样品类型。例如,术语“对象”可以指患者,且往往是人类患者。但是,该术语不限于人类,而是包括各种哺乳动物物种。
本文所使用的术语“给予”是指提供本发明组合物给某对象的任何合适的方法。并不是要将本发明局限于任何特定的给予模式。在一些实施方式中,本发明所述药物组合物通过口服途径给予。在其它实施方式中,本发明所述化合物和药物组合物通过肠道外途径给予,例如,通过肌肉、腹膜内、静脉内、脑池内或皮下注射或输注。药物组合物可配制成适合的剂量单位制剂以适用于每种给予途径。
本文所使用的术语,化合物的“有效量”或“治疗有效量”是指可提供多数患者和个体所需治疗或预防效果的无毒但足够量的化合物。在治疗血液恶性肿瘤(恶性血癌)的情况中,所述无毒量不一定意味着不使用有毒试剂,而是意味着给予可耐受而又足够的量以提供患者和个体所需的治疗或预防效果。药物活性化合物的有效量可根据给予途径、以及给予药物或药理活性试剂的个体的年龄、体重和性别而变化。受益于本披露内容的本领域技术人员,通过考虑单位剂量范围内给予之后的新陈代谢、生物利用率和影响化合物血浆水平的其它因素,能够容易地确定适合的有效量,针对不同的给予途径本文将进一步描述上述单位剂量范围。
本文所使用的术语“包封”、“嵌入”或“合并”表示被一种物质复合、包装、粘结、联结、涂层、分层或封闭。因此,所述物质包封在一种颗粒中是指该物质合并到该颗粒结构中,或涂覆或附着到颗粒的表面,或两者皆有。
本文所使用的术语“组合物”是指包含特定量的特定成分的产物,以及由所述特定量的特定成分的组合直接或间接而产生的任何产蝴。
在本披露内容中,本发明的多个方面以范围形式出现。应当理解,范围形式的描述仅仅是为了方便和简洁,不应理解为是对本发明范围的固定限制。因此,范围的描述应当被认为具有所述范围内具体披露的所有可能的子范围以及单个数值。例如,如1至6的范围描述应当被认为具有如1至3、1至4、1至5、2至4、2至6、3至6等具体披露的子范围,以及在该范围内的单个数字,如1、2、3、4、5和6。不管范围的宽度如何,这都适用。
如前如述,本发明提供一种多颗粒,包括:a)多个磷酸钙核心纳米颗粒;b)包封在核心纳米颗粒中的GLP-1激动剂;和c)包封在核心纳米颗粒中的共沉淀剂,相对于相应的不含胆汁盐的磷酸钙核心纳米颗粒,该共沉淀剂能提高GLP-1激动剂在磷酸钙纳米颗粒中的包封效率。
本文所使用的术语“GLP-1激动剂”是指完全或部分激活人类GLP-1受体的化合物。胰高血糖素样肽1(GLP-1)由肠中的L-细胞释放的并负责提高口服摄入葡萄糖或脂肪后的胰岛素响应。该术语包括GLP-1肽及其变型体、类似物和衍生物。例如,GLP-1肽包括野生型胰高血糖素样肽、其截断体、延长体、突变体或其它变型体。该术语包括类似物如ZP10A或BIM-51077,GLP-1或其结合到聚乙二醇的类似物,GLP-1或其与白蛋白融合(如白蛋白胰高血糖素样肽1(albugon))或与白蛋白化学结合(如利拉鲁肽或CJC-1131)的类似物。类似地,extendin-4,也称为依克那肽,是一种GLP-1激动剂,并且和其类似物及衍生物一起包括在术语“GLP-1激动剂”中。依克那肽在美国专利第5,424,286号中公开并以商标出售。因此,如那些在美国专利第7,329,646号中公开的依克那肽,依克那肽类似物,以及长效结合物如CJC-1134,都在本发明的考虑之内。
GLP-1激动剂用于治疗糖尿病、刺激胰岛素释放、治疗高血糖症、治疗血脂障碍(dyslipisemia)、治疗和防止心血管疾病、减少中风后的发病和死亡、增加尿流、降低血液胰高血糖素、降低胃动力和/或延迟胃排空、治疗肥胖、II型糖尿病、饮食失调和胰岛素抵抗综合征。该方法也可用于降低血液葡萄糖水平、降低血脂水平、减少心脏病风险、减小食欲和减轻对象体重。当降低血液胰高血糖素时,该方法可用于治疗高血糖素血症(hyperglucagonemia),如患有坏死松解性游走性红斑的患者、患有高血糖素瘤的患者、患有糖尿病相关性失调的患者,例如但不限于II型糖尿病。关于治疗心血管疾病,GLP-1激动剂用于治疗心肌梗塞、急性冠状动脉综合征(ACS)、不稳定心绞痛(UA)、非Q波心肌坏死(NQCN)、左心室肥厚、冠状动脉疾病、原发性高血压、急性高血压急症、心肌病、心功能不全、运动耐量、慢性心脏衰竭、心率失常、心脏节律紊乱、高山脑水肿(syncopy)、动脉粥样硬化、轻度慢性心脏衰竭、心绞痛、心脏搭桥闭塞、间歇性跛行(动脉粥样硬化oblitterens)、舒张功能障碍和收缩功能障碍。
如前所述,相对于不含共沉淀剂的磷酸钙纳米颗粒,本文描述的组合物用以提高生物活性大分子的包封效率。共沉淀剂存在下包封效率可大于或等于25%、30%、35%、40%、45%、50%、55%、60%、65%、70%、75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%。
本发明颗粒的小尺寸是显著影响颗粒作为药物递送媒介物(vehicle)的有效性的重要因素。因此,在一些实施方式中,核心纳米颗粒的平均直径小于约1000nm,优选小于约300nm,小于约200nm,小于约100nm或小于约50nm。
在一些实施方式中,共沉淀剂可包含化学品,在该化学品中钙盐具有低水溶解度,并且该化学品可大量吸收生物活性大分子。在一些实施方式中,共沉淀剂可包括胆汁盐(bile salt);其包括共轭或非共轭的胆酸,实例包括但不限于,胆酸盐、脱氧胆酸盐、牛磺胆酸盐、甘胆酸盐、牛磺脱氧胆酸盐、熊脱氧胆酸盐、牛磺熊脱氧胆酸盐、鹅脱氧胆酸盐及其衍生物和组合。在其它实施方式中,共沉淀剂可包括脂肪酸盐。实例包括但不限于,己酸盐、辛酸盐、壬酸盐、癸酸盐、月桂酸盐、豆蔻酸盐、棕榈酸盐、硬脂酸盐、花生酸盐(arachidate)及其衍生物和组合。
在一些实施方式中,所述颗粒适于递送生物活性大分子到粘膜表面。在一些实施方式中,所述颗粒适于通过口服途径递送生物活性大分子到需要其的对象。
在一些实施方式中,所述颗粒可进一步包括生物粘性涂层,其增强颗粒粘附到粘膜表面。所述生物粘性涂层可包括这样的物质,如卡波姆、聚卡波非、壳聚糖、藻酸盐、硫柳汞(thiomer)、明胶、羟丙甲基纤维素、羧甲基纤维素、聚乙烯醇、聚乙二醇、聚乙烯吡咯烷酮、富马酸酸酐低聚物、聚酯、聚丙烯酸酯、多糖、改性葡聚糖、果胶、黄原胶及其盐、衍生物和组合。
在一些实施方式中,所述颗粒可进一步包括肠溶衣,其含有容许颗粒选择性地粘附到胃肠道某些区域的pH敏感性聚合物。所述肠溶衣材料包括但不限于邻苯二甲酸醋酸纤维素、邻苯二甲酸羟丙基甲基纤维素、邻苯二甲酸聚醋酸乙烯酯、各种丙烯酸树脂聚合物、及其盐和衍生物。
在一些实施方式中,所述颗粒可进一步包括位置选择性涂层,其包含容许颗粒选择性地粘附到胃肠道某些区域的聚合物。例如,所述涂层可施加至用于结肠特异性递送的颗粒,并且涂层材料包括但不限于偶氮聚合物、结肠可降解多糖如果胶、直链淀粉、瓜尔豆胶、木聚糖、环糊精、葡聚糖、它们的盐、衍生物及其组合。
本发明进一步包括一种多颗粒,包括:a)多个磷酸钙核心纳米颗粒;b)包封在核心纳米颗粒中的生物活性大分子;和c)包封在核心纳米颗粒中的共沉淀剂,该共沉淀剂相对于不含脂肪酸盐的磷酸钙核心纳米颗粒,提高生物活性大分子在核心纳米颗粒中的包封效率。
在一些实施方式中,所述生物活性大分子选自蛋白质、肽、多糖、核酸、脂质、碳水化合物及其组合所构成的组。
在一些实施方式中,所述蛋白质选自抗凝血酶、白蛋白、α-1-蛋白酶抑制剂、抗血友病因子、凝血因子、抗体、抗CD20抗体、抗CD52抗体、抗CD33免疫毒素、DNA酶、促红细胞生成素、IX因子、VII因子、VIII因子、卵泡刺激素、粒细胞集落刺激因子(G-CSF)、聚乙二醇G-CSF、半乳糖苷酶α或β、胰高血糖素、葡萄糖脑苷脂酶、粒细胞巨噬细胞集落刺激因子(GM-CSF)、绒毛膜促性腺激素、乙肝抗原、乙肝表面抗原、乙肝核心抗原、乙肝包络抗原(envelopment antigen)、丙肝抗原、水蛭素、抗HER-2抗体、抗IgE抗体、抗IL-2受体抗体、胰岛素、甘精胰岛素、门冬胰岛素、赖脯胰岛素、干扰素、聚乙二醇干扰素、干扰素α或α2a或α2b或α2b或类似物(concensus)、干扰素β或β-1a或β-1b或β丝氨酸(betaser)、干扰素γ、白细胞介素-2、白细胞介素-11、白细胞介素-12、促黄体激素、奈西立肽、成骨蛋白-1、成骨蛋白-2、莱姆疫苗、血小板衍生生长因子、抗血小板抗体、抗RSV抗体、生长激素、抗肿瘤坏死因子(TNF)抗体、TNF受体-Fc融合蛋白、组织纤溶酶原活化剂(tPA)、TNK-tPA、促甲状腺激素(TSH)、纤维蛋白溶解酶、溶栓酶、腺苷脱氨酶、聚乙二醇化腺苷脱氨酶、复合纤溶酶链激酶、天冬酰胺酶、胶原酶、链激酶、蔗糖酶、尿激酶、抑肽酶、肉毒杆菌毒素、成纤维细胞生长因子、血管内皮生长因子和毒液构成的组。所述蛋白质可通过重组技术、化学合成而生产或者从生物来源提取。所述蛋白质还包括突变体和经修饰的类似物或衍生物。蛋白质来源可以来自人类或其它物种。
在一些实施方式中,所述肽选自ACTH、抗血管生成肽、血小板反应素(adamtsostatin)、脂联素、脂肪动员激素、deiponutrin、脂肪甘油三酯脂肪酶(adipose desnutrin)、肾上腺髓质素、刺鼠相关蛋白、alarin、抑因侧体神经肽、釉原蛋白、降钙素、糊精、淀粉、血管生成素、血管紧张素、食欲肽(anorexigenic peptide)、抗炎肽、抗利尿因子、抗微生物肽、APJ受体内源性配体(apelin)、蜜蜂抗菌肽、RGD肽、心房利钠肽、心房肽、心耳肽、自分泌运动因子(autotaxin)、蛙皮素、铃蟾激肽、缓激肽、脑利钠肽、脑源性神经营养因子、brevinin、C肽、半胱天冬酶抑制剂、胰肽、颊肽、囊素、C型利钠肽、降钙素相关肽、降钙素受体、刺激肽、钙调蛋白、CART、软骨抑制素(cartilostatin)、casomokinin、酪啡肽、儿茶酚胺释放抑制肽、组织蛋白酶、抗菌肽、小脑肽、脂肪细胞因子(chemerin)、chelocystokinin、嗜铬粒蛋白、睫状神经营养因子、芋螺睡眠肽、芋螺加压素、芋螺毒素、肽素、皮质激素刺激素、促肾上腺皮质激素释放因子、皮质醇稳定蛋白、耦合因子、防御素、三角洲睡眠诱导肽、皮啡肽、加压素、脱氨-加压素、利尿激素、强啡肽、内激肽、吗啡肽、内啡肽、内皮抑素、内皮素、脑啡肽、肠抑素、重组促胰岛素分泌肽、重组促胰岛素分泌肽-4、红血球生成素(erythropoieticpeptide)、上皮生长因子、脂肪靶向肽、甘丙肽、抑胃肽、胃泌素、胃泌素释放肽、生长素、胰高血糖素、胰高血糖素样肽、谷胱甘肽衍生物、面筋外啡肽、生长激素释放因子、GM-CSF抑制肽、生长激素肽、鸟苷、HIV肽、helodemine、血细胞激肽、HCV肽、HBV肽、HSV、疱疹病毒肽、水蛭素、水螅肽、胰岛素样生长因子、海德林、促黑激素、肛褶蛙肽、角质细胞生长因子、运动升压素、激肽原、亲吻肽(kisspeptin)、京都啡肽、层粘连蛋白肽、瘦素肽、白细胞激肽、白细胞焦激肽、亮抑酶肽、促黄体激素释放激素(LHRH)、淋巴因子、黑色素浓集激素及其抑制剂、黑素细胞刺激素释放抑制剂、促黑细胞激素-增效因子、吗啡调节神经肽、MSH、神经降压素、厌食肽、神经激肽、神经调节肽、神经肽Y、神经降压素、神经营养因子、孤菲肽、肥胖抑制素、阿片受体拮抗剂、增食欲素、骨钙素、催产素、胰抑素、肽YY、气拉明样肽、分泌素、生长抑素、精子激活肽、P物质、脑啡肽类镇痛剂(syndyphalin)、血小板反应素、胸腺五肽、胸腺肽、促甲状腺激素释放激素、转化生长因子、促吞噬肽、肿瘤坏死因子拮抗剂或相关肽、usrechistachykinin、尿皮素、加压素拮抗剂、阿片样物质片段(valorphin)、催产加压素、VIP、爪蟾肽或相关肽构成的组。所述肽可以通过重组技术、化学合成或从生物资源中提取来生产。所述肽包括突变体或经修饰的类似物或衍生物。肽的来源可以是人类或其它物种。
在一些实施方式中,所述生物活性大分子是一种疫苗,该疫苗选自腺病毒、炭疽热、BCG、肉毒杆菌、霍乱、白喉类毒素、白喉和破伤风类毒素、白喉破伤风和百日咳、嗜血杆菌B、甲肝、乙肝、流感、脑炎、麻疹、腮腺炎、风疹、脑膜炎、鼠疫、百日咳、肺炎球菌、脊髓灰质炎、狂犬病、轮状病毒、德国麻疹、天花、破伤风类毒素、伤寒、水痘、黄热病、细菌抗原及其任何组合构成的组。
在一些实施方式中,所述生物活性大分子是一种过敏原(变应原),该过敏原选自家尘螨、动物皮屑、霉菌、花粉、豚草、乳胶、胡蜂毒液和昆虫源性过敏原和其组合构成的组。
在一些实施方式中,所述生物活性大分子选自GLP-1激动剂、胰岛素、促红细胞生成素、干扰素、生长激素、PTH、降钙素、亮丙瑞林(leuprolide,一种促性腺激素释放激素类似物)及其衍生物构成的组。在一些实施方式中,GLP-1激动剂是依克那肽或其生理上可接受的盐及衍生物。
在一些实施方式中,上面列出的所述生物活性大分子可包括相关分子家族,包括具有原始结构的野生型分子、具有修饰结构或序列的类似物、以及化学或生物修饰的类似物。
本发明进一步包括药物组合物,该药物组合物包含本发明的磷酸钙颗粒和药用载体。
合适的载体及其制剂在本领域中是已知的并且已在Remington,The Science and Practice of Pharmacy 20th Ed.Mack Publishing,2000中描述。所述药物组合物可被制成溶液、胶囊、片剂、粉剂和气溶胶形式;并可被制成适合于口服递送、粘膜递送或递送至眼表的形式。所述组合物可包括其它组分,例如缓冲液、防腐剂、非离子表面活性剂、增溶剂、吸收促进剂、稳定剂、缓和剂、润滑剂和张度剂。可将所述组合物制成以获得大分子的受控释放。
在一些实施方式中,所述颗粒在药用载体中被制成胶囊、片剂、微粒、液体、凝胶、软膏和/或霜剂形式。所述药物组合物可通过任何适合的方式给予,例如口服,如以片剂、胶囊、颗粒或粉剂形式;舌下;口腔含服;肠外,如通过皮下、静脉、肌内、皮内(或透皮)、或脑池内注射或输注技术(如,作为无菌可注射水溶液或非水溶液或悬浮液);经鼻,如通过吸入喷雾或喷洒;局部,如以溶液或悬浮液形式的眼用(ocularly)霜剂或软膏的形式;阴道,以阴道栓剂、棉球或药膏形式;或直肠,如以栓剂形式;包含无毒、药用媒介物或稀释剂的剂量单位制剂。例如,纳米颗粒可以以适于立即释放或延迟释放的形式给予。立即释放或延迟释放可通过使用包括本发明化合物的合适药物组合物或通过使用仪器(特别是在延迟释放情况下)如皮下移植物或渗透泵而实现。
用于给予本发明化合物的药物组合物可方便地以剂量单位形式出现并可通过制药领域中熟知的任何方法制备。这些方法主要包括使非颗粒与载体结合的步骤,该载体构成一种或多种助剂(accessory ingredients)。一般来说,通过将纳米颗粒均匀而紧密地结合到固体载体中或精细划分的固体载体(固体载体粉末,finelydivided solid carrier)或这两者来准备所述药物组合物,然后,如果需要,将产物成形为所需的制剂。在药物组合物中,含有足够量的所述活性目标化合物以对疾病进程或病症产生期望的效果。
含有纳米颗粒的药物组合物可以是适合于口服的形式,例如,片剂、锭剂、糖锭、水性或油性悬浮液、分散粉末或颗粒、乳剂、硬或软胶囊、或糖浆或酏剂。用于口服的组合物可以根据制造药物组合物的领域中任何已知的方法来准备,这些组合物可以包含一种或多种试剂,如甜味剂、调味剂、着色剂和防腐剂,例如用以提供药用稳定和可口的制备品。片剂包含纳米颗粒,该纳米颗粒与适用于片剂制备的无毒药用赋形剂混合。这些赋形剂例如可以是惰性稀释剂,如碳酸钙、碳酸钠、乳糖、磷酸钙或磷酸钠;成粒剂和崩解剂,如玉米淀粉或褐藻酸;结合剂,如淀粉、明胶或阿拉伯树胶;润滑剂,如硬脂酸镁、硬脂酸或滑石;以及扰动脂质双层膜并协助药物跨肠道吸收的吸收促进剂,如清洁剂或表面调节剂,包括EDTA、胆汁盐和中链脂肪酸盐(如己酸盐、辛酸盐、壬酸盐、癸酸盐、月桂酸盐和豆蔻酸盐)。所述片剂可不涂层或通过已知技术涂层用以延迟在胃肠道中的分解和吸收并因此提供长时间的持续作用。例如,可使用时间延迟物质,如单硬脂酸甘油酯或双硬脂酸甘油酯等。这些物质可涂层以形成用于控制释放的渗透性治疗片剂。
水悬浮液包括纳米颗粒,该纳米颗粒与适用于制备水悬浮液的赋形剂混合。这样的赋形剂是悬浮剂,例如羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、海藻酸钠、聚乙烯醇吡咯烷酮、黄芪胶和阿拉伯胶;分散剂或润湿剂可以是天然产生的磷脂(如卵磷脂),或环氧烷与脂肪酸的缩聚产物(condensation products)(如聚氧乙烯硬脂酸酯),或环氧乙烷与长链脂肪醇的缩聚产物(如十七乙烯氧鲸蜡醇(heptadecaethyleneoxycetanol)),或环氧乙烷与衍生自脂肪酸和己糖醇的偏酯的缩聚产物(如聚氧乙烯失水山梨糖醇单油酸酯polyoxyethylene sorbitol monooleate),或环氧乙烷与衍生自脂肪酸和己糖醇酐的偏酯的缩聚产物(如聚乙烯失水山梨糖醇单油酸酯)。所述水性悬浮液还可包含一种或多种防腐剂,例如乙基、或n-丙基、对羟基苯甲酸酯、一或多种着色剂、一或多种调味剂、以及一或多种甜味剂如蔗糖或糖精。
油性悬浮液可以通过在植物油如花生油、橄榄油、香油或椰子油中或矿物油如液体石蜡中悬浮纳米颗粒而制成。油性悬浮液可包括增稠剂,如蜂蜡、固体石蜡或十六醇。可以添加如上文所述那些的甜味剂和调味剂来提供可口的口服制备品。这些组合物可通过添加抗氧化剂如抗坏血酸来保存。
可分散粉末和颗粒适用于通过加水以制备液体悬浮液,该分散粉末和颗粒提供纳米颗粒与分散剂或润湿剂、悬浮剂和一种或多种防腐剂的混合。合适的分散剂或润湿剂通过上述已提到的那些加以例示。其他赋形剂,例如甜味剂、调味剂和着色剂,也可以存在。
本发明所述药物组合物也可以是水包油的乳液形式。油性相可以是植物油(如橄榄油或花生油),或矿物油(如液体石蜡)或其混合物。适合的乳化剂可以是天然产生的胶,例如阿拉伯胶或黄芪胶;天然产生的磷脂,例如大豆,卵磷脂;和来自脂肪酸和己糖醇酐的酯或偏酯,例如,失水山梨糖醇单油酸酯;和上述偏酯和环氧乙烷的缩聚产物,例如,聚氧乙烯失水山梨糖醇单油酸酯。所述乳液也可包括甜味剂和调味剂。
糖浆和酏剂可与甜味剂一起配制,例如甘油、丙二醇、山梨糖醇或蔗糖。这样制剂也可包括缓和剂、防腐剂、调味剂和着色剂。
所述药物组合物可以是注射用无菌水或油质悬浮液形式。该悬浮液可以根据已知技术制成,该技术使用上述那些适合的分散剂或润湿剂以及悬浮剂。所述注射用无菌制剂也可以是在无毒的肠外可接受的稀释剂或溶剂中的一种注射用无菌溶液或悬浮液,例如为1,3-丁二醇(1,3-butane diol)溶液。可采用的可接受媒介物和溶剂是水、林格氏液和等渗氯化钠溶液。另外,无菌的固定油常规地用作溶剂或悬浮介质。为了这个目的,可使用任何温和的固定油,包括合成的甘油单酯或甘油二酯。另外,发现脂肪酸如油酸可用于注射制剂的配制。
对于呼吸道给予,包括鼻内给予,所述活性化合物可通过本领域中用于向呼吸道给予的任何方法和制剂进行给予。
因此一般地纳米颗粒可以以溶液和悬浮液形式或以干粉进行给予。
溶液和悬浮液一般是水性的,例如仅由水制备(如无菌水或无热原水)或由水和生理上可接受的共溶剂(如乙醇、乙二醇或聚乙二醇如PEG 400)制备。
这样的溶液或悬浮液可另外包括其它赋形剂如防腐剂(如苯扎氯)、增溶剂/表面活性剂例如聚山梨醇酯(如吐温80、Span 80、苯扎氯)、缓冲剂、等渗调节剂(如氯化钠)、吸收增强剂和粘度增强剂。悬浮液可另外包括悬浮剂(如微晶纤维素和羧甲基纤维素钠)。
溶液或悬浮液可直接通过传统方式用于鼻腔,例如用滴管、吸管或喷雾。这些剂型可以单剂量或多剂量形式提供。在多剂量形式下,需提供剂量测定的方式。在使用滴管或吸管的情况下,剂量测定可通过对象给予合适的预定量的溶液或悬浮液来实现。在喷雾的情况下,剂量测定可以通过例如剂量雾化喷射泵的方式来实现。
呼吸道给予也可通过制备气溶胶制剂的方式实现,在该气溶胶制剂中化合物通过装有适合压缩气体的压力包提供,压缩气体例如为含氯氟烃(CFC)(如二氯二氟甲烷、三氯四氟甲烷或二氯氟乙烷),二氧化碳或其它合适的气体。气溶胶也可适合地包含表面活性剂如卵磷脂。活性化合物的剂量可通过提供测量值加以控制。
可替换地,活性化合物可以以干粉的形式提供,例如纳米颗粒在合适的粉末基质,如乳糖、淀粉、淀粉衍生物(如羟丙基甲基纤维素和聚乙烯吡咯烷酮(PVP))中的粉末混合。方便地,粉末载体会在鼻腔内形成凝胶。粉末组合物可以以单元剂量形式存在,例如以明胶的胶囊或药筒(cartridge)形式,或可通过吸入器方式给予粉末的吸塑包装(blister pack)形式。
在用于呼吸道给予的剂型中,包括鼻内剂型,所述纳米颗粒一般具有小颗粒尺寸,例如5微米或更小量级的颗粒尺寸。如果必要,这种颗粒尺寸可通过本领域中已知的方法获得,如通过微粉化方式。
当需要的时候,可使用适于使活性化合物持续释放的剂型。
本发明的纳米颗粒也可以以用于直肠给予药物的栓剂形式给予。这些组合物可通过将纳米颗粒与适合的无刺激性赋形剂混合来制备,该赋形剂常温下为固体而在直肠温度下是液体,因此会在直肠中溶化以释放药物。这样的物质是可可脂和聚乙二醇。
适合于阴道给予的组合物可以以阴道栓剂、棉球、霜剂、凝胶、软膏、泡沫或喷雾形式存在,上述剂型除了活性组分之外还包含本领域中已知合适的载体。
使用霜剂、药膏、凝胶剂、溶液或悬浮液等,包括本发明中的纳米颗粒,进行局部给予(出于本申请的目的,局部使用包括漱口水和含漱剂)。
所述纳米颗粒也可以以用于兽用组合物(兽药组合物)的形式存在,该兽用组合物例如可通过本领域中的常规方法制备。这些兽用组合物的实例包括适合于以下的那些:(a)口服给予、外用,如兽用顿服药(例如,水或非水溶液或悬浮液等);片剂或大丸药;用于与饲料混合的粉末、颗粒或球粒;施用于舌头上的糊剂(paste);(b)肠外给予例如通过皮下、肌内或静脉注射,如为无菌溶液或悬浮液;或(当合适的时候)通过乳房内注射,其中悬浮液或溶液可以通过乳头导入乳房;(c)局部施用,如为霜剂、软膏或喷雾,其施用于皮肤上;或(d)通过直肠或阴道内给予,如为阴道栓剂、霜剂或泡沫。
本发明进一步涵盖制备磷酸钙颗粒的方法,所述方法包括:a)在共沉淀剂存在下用磷酸盐水溶液接触钙盐水溶液;b)混合步骤a)中产生的溶液直到获得期望尺寸的磷酸钙颗粒;以及c)回收磷酸钙颗粒。
在一些实施方式中,钙盐水溶液的浓度范围从约5mM到约200mM。在一些实施方式中,磷酸盐水溶液的浓度范围从约5mM到约200mM。
在一些实施方式中,所述方法进一步包括在共沉淀剂存在下用磷酸盐水溶液接触钙盐水溶液之前添加生物活性大分子至磷酸盐水溶液或钙盐水溶液中的步骤,由此磷酸钙颗粒与生物活性大分子共结晶。
如本文所描述的,所述共沉淀剂可包括胆汁盐、脂肪酸盐或其组合。在一些实施方式中,胆汁盐可选自胆酸盐、脱氧胆酸盐、牛磺胆酸盐、甘胆酸盐、牛磺脱氧胆酸盐、熊脱氧胆酸盐、牛磺熊脱氧胆酸盐、鹅脱氧胆酸盐及其组合构成的组。在一些实施方式中,脂肪酸盐可选自己酸盐、辛酸盐、壬酸盐、癸酸盐、月桂酸盐、豆蔻酸盐及其组合构成的组。
在一些实施方式中,所述共沉淀剂的浓度范围从约0.01%到约5%,从约0.2%到约3%,或从约0.5%到约1.5%。
本发明的颗粒可进一步用表面改性剂涂层或浸渍、或涂层并浸渍。适用于本发明的这些表面改性剂包括方便生物活性大分子结合或包封至颗粒中但不会使大分子变性的物质。适合的表面改性剂的实例在美国专利5,460,830、5,462,751、5,460,831和5,219,577中已描述。其它适合的表面改性剂的实例可包括基础或修饰糖,如纤维二糖或美国专利5,219,577所描述的寡核苷酸。例如,如美国专利5,460,830所描述的,适合的表面改性剂也包括碳水化合物、碳水化合物衍生物、以及含碳水化合物样组分的、特征为富含--OH侧基的其它大分子。聚乙二醇(PEG)是特别适合的表面改性剂。
磷酸钙颗粒的涂层可通过将表面改性剂母液如纤维二糖或PEG(例如,292mM左右),添加到磷酸钙核心颗粒的悬浮液中来制备,其以约1ml母液添加到约20ml颗粒悬浮液中的比例进行添加。旋涡搅拌该混合物并放置过夜以形成至少部分涂覆的核心颗粒。通常,该过程会使颗粒基本上完全涂覆,尽管可能存在一些局部涂覆或未涂覆的颗粒。
在又一方面,本发明提供了一种治疗需要生物活性大分子治疗的对象的方法,该方法包括向对象给予治疗有效量的本发明的包含磷酸钙颗粒的药物组合物。在优选的实施方式中,生物活性大分子是一种GLP-1激动剂,如依克那肽,或其生理上可接受的盐或衍生物。
本发明组合物的给予可通过本领域中任何已知的方式进行,包括:口服、静脉、皮下、通过吸入、动脉、肌内、心内、脑室内、肠外、鞘内和腹膜内。给予可以是全身给予(如静脉),或局部给予。在一些实施方式中,将所述药物组合物给予到粘膜表面。在一些实施方式中,所述药物组合物通过口服途径给予。
以下所包括的实例用于解释说明的目的,并不是要限制本发明范围。
实施例
实施例1.熊脱氧胆酸盐对于将依克那肽包封至磷酸钙纳米颗
粒中的包封效率的影响
为了评价胆汁盐对依克那肽在磷酸钙纳米颗粒中包封效率的影响,取两支50ml离心管并加入以下表格中所列组分。加入200毫克聚乙二醇(PEG,MW6000)、0或70毫克脱氧胆酸盐(溶解在乙醇中并用等摩尔的NaOH中和)、20mM HEPES缓冲液pH 6.9、0.4ml 2.5M Na2HPO4,并用蒸馏水将终体积调节到10ml。这些溶液标注为A1和A2,其组成总结在表1中。
表1
A1 | A2 | |
PEG(%) | 1 | 1 |
UDCA(%) | 0 | 0.7 |
磷酸盐(mM) | 20 | 20 |
体积(ml) | 10 | 10 |
在两个单独的50ml离心管中,加入60mM CaCl2和1.5mg/ml依克那肽制成10ml溶液并标注为B1和B2。在280nm处测量两个B溶液的吸光度值(optic density,光密度)。通过缓慢混合相应的A和B溶液来制备磷酸钙纳米颗粒。沉淀立即可见并在室温下持续轻柔混合5分钟。以8000rpm旋降(spin down)混合物10min。在280nm处测量上清液的吸光度值并用以下方程计算包封效率:
效率(%)=[1-(上清液的OD280×20)/(溶液B的OD280×10)]×100%
产生的纳米颗粒的包封效率总结在表2中。
表2
1 | 2 |
UDCA(%) | 0 | 0.35 |
效率(%) | 9.3 | 92.9 |
该结果表明无UDCA时,依克那肽很差地包封至磷酸钙纳米颗粒中,而UDCA的存在可明显提高(十倍)依克那肽的包封效率。
实施例2.癸酸盐对于将依克那肽包封至磷酸钙纳米颗粒中包
封效率的影响
为了评价癸酸盐对依克那肽在磷酸钙颗粒中包封效率的影响,取三支50ml离心管并加入以下表格中所列的组分。加入200毫克聚乙二醇(PEG,MW 6000)、0、50或100毫克溶解在乙醇中的癸酸钠、20mM HEPES缓冲液pH 6.9和20mM Na2HPO4,并用蒸馏水将终体积调节到10ml。将这些溶液标注为A1-A3,其组成总结在表3中。
表3
A1 | A2 | A3 | |
PEG(%) | 1 | 1 | 1 |
癸酸盐(%) | 0 | 0.5 | 1.0 |
磷酸盐(mM) | 20 | 20 | 20 |
体积(ml) | 10 | 10 | 10 |
在三个分开的50ml离心管中,加入60mM CaCl2和1.5mg/ml依克那肽制成10ml溶液并标注为B1-B3。在280nm处测量两个B溶液的吸光度值。通过缓慢混合相应的A和B溶液来制备磷酸钙纳米颗粒。沉淀立即可见并在室温下持续轻柔混合5分钟。以8000rpm旋降混合物10min。在280nm处测量上清液的吸光度值并如实施例1计算包封效率。产生的纳米颗粒的包封效率总结在表4中。
表4
1 | 2 | 3 | |
癸酸盐(%) | 0 | 0.25 | 0.5 |
效率(%) | 9.3 | 40.7 | 61.1 |
该结果表明无癸酸盐时,依克那肽较差地包封至磷酸钙纳米颗粒中,而癸酸盐的存在可以以剂量依赖性方式明显提高依克那的包封效率。
实施例3.癸酸盐对于将胰岛素包封至磷酸钙纳米颗粒中包封
效率的影响
为了评价癸酸盐对胰岛素在磷酸钙纳米颗粒中包封效率的影响,取三支50ml离心管并加入以下表格中所列组分。加入200毫克聚乙二醇(PEG,MW6000)、0、39或117毫克癸酸纳,20mMHEPES缓冲液pH 6.9和20mM Na2HPO4,并用蒸馏水将终体积调节到10ml。这些溶液标注为A1-A3,其组成总结在表5中。
表5
A1 | A2 | A3 | |
PEG(%) | 1 | 1 | 1 |
癸酸盐(%) | 0 | 0.39 | 1.17 |
磷酸盐(mM) | 10 | 10 | 10 |
体积(ml) | 10 | 10 | 10 |
在三个分开的50ml离心管中,加入60mM CaCl2和1mg/ml胰岛素制成10ml溶液并标注为B1-B3。在280nm处测量两个B溶液的吸光度值。通过缓慢混合相应的A和B溶液来制备磷酸钙纳米颗粒。沉淀立即可见并在室温下持续轻柔混合5分钟。以8000rpm旋降混合物10分钟。在280nm处测量上清液的吸光度值并如实施例1计算包封效率。产生的纳米颗粒的包封效率总结在表6中。
表6
1 | 2 | 3 | |
癸酸盐(%) | 0 | 0.2 | 0.6 |
效率(%) | 0.2 | 73.8 | 85.3 |
该结果表明,在癸酸盐存在下,胰岛素在磷酸钙纳米颗粒中的包封效率以剂量依赖方式得到明显提高
实施例4.包封依克那肽的磷酸钙纳米颗粒的体内活性
评价包封在磷酸钙纳米颗粒中的依克那肽在ob/ob糖尿病小鼠模型中的活性。
动物:32只8-10周大的ob/ob小鼠(Jackson实验室)笼养(cage)在通风室中。食物和水随意(ad librium)提供。光周期设定为每12小时一次。
处理。小鼠禁食2小时,测定空腹血糖,再将小鼠随机分为4组,每组8只小鼠。
a.空白,用一空胶囊处理,
c.PO1,口服依克那肽,每只小鼠一个胶囊或1μg根据实施例1制备的依克那肽,以及
d.PO5,口服依克那肽,每只小鼠一个胶囊或5μg根据实施例1制备的依克那肽。
胶囊通过灌胃针(gavage needle)给予,接着皮下给予血样在0、0.5、1、2、4、6、8和10小时采自尾静脉,并用血糖仪(ReliOn Ultima)测定血糖水平。两只小鼠在给予胶囊后死亡并从分析中排除。
口服依克那肽对空腹血糖的影响如表7中所示。口服1μg依克那肽,血糖水平相对于空白对照下降但并未达到统计学上的显著性。口服5μg依克那肽,血糖水平的降低在大多数时间点达到了统计学上的显著性。
表7依克那肽处理对小鼠血糖水平的影响
组别 | 数量 | 0.5hr | 1hr | 2hr | 4hr | 6hr | 8hr | 10hr |
空白 | 7 | 153±40 | 141±26 | 138±32 | 91±31 | 100±22 | 103±33 | 124±34 |
SC | 8 | 80±23^ | 53±13^ | 37±9^ | 37±11^ | 46±17^ | 54±24^ | 65±20^ |
PO1 | 7 | 134±24 | 124±44 | 106±33 | 86±17 | 107±59 | 107±39 | 117±44 |
PO5 | 8 | 104±32* | 107±56 | 65±28* | 53±20* | 69±24* | 82±26 | 89±20* |
^p<0.005;*p<0.05
该结果表明口服递送的依克那肽以剂量依赖方式显著降低空腹血糖水平。
实施例5.通过口服依克那肽降低糖尿患者的空腹血糖
评价糖尿患者口服包封在磷酸钙纳米颗粒中的依克那肽的可行性。19位II型糖尿病患志愿参加本研究。本研究设计是开放标记、随机和交叉的。每位患者实施了三个循环的评价。
在第一个循环中,每位患者禁食超过12小时。在第二天早上监测血糖水平。用ReliOn Ultima测定手指刺点取样的血糖水平。该循环不进行处理以建立基线。
在第二个循环中,每位患者禁食超过12小时。在第二天早上监测血糖水平。每位患者在0时间点通过皮下注射而给予5μg并在处理后6小时监测空腹血糖水平。
在第三个循环中,每位患者禁食超过12小时。在第二天早上监测血糖水平。每位患者给予按照实施例1所述配制的口服依克那肽制剂25、50、75或100μg,并在处理后6小时监测空腹血糖水平。每位患者给予口服依克那肽一次。
每位患者的检测顺序是任意的且在每次循环后都有2天的清除期(wash out period)。研究后,在基线循环中有18位患者数据,在注射循环中有18位患者数据,在25和50μg口服依克那肽处理中有5位患者数据,以及在75和100μg口服依克那肽处理中有4位患者数据。
与每个循环处理前相比,血糖变化百分比示于表8中。与基线循环相比,皮下注射造成血糖的明显降低。每个口服依克那肽处理在处理后2小时表现出血糖的缓慢降低,而与皮下注射相比,在处理后6小时表现出相似水平的血糖降低。
表8依克那肽处理对糖尿病患者血糖的影响
循环 | n | 1hr | 2hr | 4hr | 6hr |
空白 | 18 | 9±11 | 6±10 | -6±18 | -13±16 |
SC | 18 | 0±14 | -20±18 | -24±17 | -26±13 |
PO25 | 5 | 3±5 | 1±13 | -20±2 | -22±6 |
PO50 | 5 | 5±12 | -6±13 | -18±14 | -21±9 |
PO75 | 4 | 2±6 | -8±11 | -19±8 | -22±4 |
PO100 | 4 | 7±8 | 5±6 | -13±8 | -24±9 |
本研究表明口服给予包封在磷酸钙纳米颗粒中的依克那肽可以使糖尿病患者的血糖水平明显降低。
实施例6.UDCA存在下胰岛素浓度对包封效率的影响
为了评价胰岛素浓度对其包封进磷酸钙纳米颗粒中的包封效率的影响,制备含有20mg/ml聚乙二醇(PEG,MW 10000,Fluka)、20mM HEPES Ph 6.964、7.5mg/ml熊脱氧胆酸钠、10mM Na2HPO4的溶液。并制备含有60mM CaCl2和1或4mg/ml胰岛素的第二溶液。将两个溶液的终体积调到20ml并从含胰岛素的样品中取出等份以测定280nm处的吸光度值。搅拌下,使两溶液混合,立即可见沉淀。在室温下继续搅拌5分钟然后以10000rpm离心溶液15分钟。如实施例1测量上清液在280nm处的吸光度值以评价包封效率。每个组分的终浓度和获得的包封效率在表9中列出。
表9
组分 | A | B |
PEG(%) | 1 | 1 |
UDCA(%) | 0.375 | 0.375 |
HEPES(mM) | 10 | 10 |
钙(mM) | 30 | 30 |
磷酸盐(mM) | 5 | 5 |
胰岛素(mg/ml) | 0.5 | 2 |
效率(%) | 93.8 | 93.3 |
结果清楚地证明熊脱氧胆酸盐(UDCA)存在下胰岛素包封入磷酸钙纳米颗粒中的包封效率很高,与胰岛素浓度无关。
实施例7.癸酸钠存在下胰岛素浓度对包封效率的影响
为了评价胰岛素浓度对其在磷酸钙纳米颗粒中的包封效率的影响,制备含有20mg/ml聚乙二醇(PEG,MW 10000,Fluka)、20mM HEPES pH 6.964、11.7mg/ml癸酸钠、10mM Na2HPO4的溶液。准备五种含有60mM CaCl2和0.2、0.5、1、2或4mg/ml的胰岛素的CaCl2溶液。将每种溶液的终体积调到20ml并从每种包含胰岛素的样品中取出等份以测定280nm处的吸光度值。搅拌下,使两溶液混合并立即可见沉淀。在室温下继续搅拌5分钟然后在10000rpm下离心溶液15分钟。如实施例1测量上清液在280nm处的吸光度值并评价包封效率。每个组分的终浓度和相应的包封效率总结在表10中。
表10
样品 | 1 | 2 | 3 | 4 | 5 |
PEG(%) | 1 | 1 | 1 | 1 | 1 |
癸酸钠(%) | 0.585 | 0.585 | 0.585 | 0.585 | 0.585 |
HEPES(mM) | 10 | 10 | 10 | 10 | 10 |
钙(mM) | 30 | 30 | 30 | 30 | 30 |
磷酸盐(mM) | 5 | 5 | 5 | 5 | 5 |
胰岛素(mg/ml) | 0.1 | 0.25 | 0.5 | 1 | 2 |
效率(%) | 77.8 | 88.9 | 87.6 | 73.2 | 58.5 |
本结果表明当最佳胰岛素浓度降至0.25和0.5mg/ml之间时,胰岛素通过癸酸钠在磷酸钙纳米颗粒中的包封与胰岛素浓度相关。在胰岛素浓度较低或较高时(分别为0.1或≥1.0mg/ml)得到的包封效率比0.25或0.5mg/ml胰岛素时获得的要低。鉴于在实施例6中发现的在熊脱氧胆酸盐(UDCA)存在时包封效率与胰岛素浓度无关,该发现是令人惊讶的。
实施例8.癸酸钠存在时依克那肽浓度对包封效率的影响
为了评价依克那肽浓度对其向磷酸钙纳米颗粒中包封效率的影响,制备含有20mg/ml聚乙二醇(PEG,MW 10000,Fluka)、20mM HEPES pH值6.964、11.7mg/ml癸酸钠、10mM Na2HPO4的溶液。制备五种含有60mM CaCl2和0.2、0.5、1、2或4mg/ml依克那肽的CaCl2溶液。将每种溶液的终体积调到20ml并从每种包含依克那肽的样品中取出等份以测定280nm处的吸光度值。搅拌下,使两溶液混合并立即可见沉淀。在室温下继续搅拌5分钟然后以10000rpm离心溶液15分钟。每个组分的终浓度在下表中列出。如实施例1测量上清液在280nm处的吸光度值并评价包封效率。每个组分的终浓度和相应的包封效率在表11中列出。
表11
样品 | 1 | 2 | 3 | 4 | 5 |
PEG(%) | 1 | 1 | 1 | 1 | 1 |
癸酸钠(%) | 0.585 | 0.585 | 0.585 | 0.585 | 0.585 |
HEPES(mM) | 10 | 10 | 10 | 10 | 10 |
钙(mM) | 30 | 30 | 30 | 30 | 30 |
磷酸盐(mM) | 5 | 5 | 5 | 5 | 5 |
依克那肽(mg/ml) | 0.1 | 0.25 | 0.5 | 1 | 2 |
效率(%) | 79.7 | 85.8 | 77.4 | 50.2 | 33.3 |
与实施例7中的结果类似,该试验表明癸酸钠存在下依克那肽在磷酸钙纳米颗粒中的包封效率的提高与依克那肽浓度相关。在较高浓度依克那肽(≥1.0mg/ml)时,包封效率明显较低,而最佳依克那肽浓度需降至0.1至0.5mg/ml之间。同样,因为依克那肽在熊脱氧胆酸盐(UDCA)存在时其包封效率与依克那肽浓度无关(数据未显示),所以这是一个令人惊讶的发现。
因此,尽管生物活性大分子如胰岛素或依克那肽向磷酸钙纳米颗粒中的包封效率可以被胆汁盐(如UDCA)和中链脂肪酸(如癸酸盐)提高到类似程度,本发明人出乎意料地发现这些化合物对包封的提高曲线(profiles)很大不同。UDCA诱导的提高与药物浓度无关,但癸酸盐诱导的提高则表现出显著的浓度相关性。基于目前获得的结果,癸酸盐诱导的包封效率提高的最佳大分子浓度应在0.2至1.0mg/ml之间。
实施例9.包含UDCA纳米颗粒的胰岛素释放
为了评价实施例6中制备的磷酸钙纳米颗粒的胰岛素释放,将纳米颗粒悬浮在0.2M磷酸钠缓冲液中pH 9.1,或悬浮在0.01N的HCl溶液中,pH 2.0。纳米颗粒浓度为1.5mg/ml并将混合物在37℃振荡60分钟。然后以10000rpm旋降样品10分钟以去除纳米颗粒。使上清液经过0.45μm滤膜(filter)并用HPLC测定胰岛素含量。从包含UDCA的磷酸钙纳米颗粒中释放的胰岛素含量示于表12中。
表12
样品 | 1 | 2 |
释放缓冲液 | 0.2M磷酸钠,pH 9.1 | 0.01N HCl,pH 2.0 |
胰岛素含量(μg/mg) | 3.34 | 2.65 |
外观 | 清澈 | 浑浊 |
含有UDCA的纳米颗粒在0.2M磷酸钠缓冲液中基本被清除,胰岛素的释放看起来已基本上完全。但在0.01N HCl溶液中,颗粒并没有完全溶解,胰岛素的释放也不完全。
实施例10.包含癸酸盐纳米颗粒的胰岛素释放
为了评价实施例7中制备的磷酸钙纳米颗粒的胰岛素释放,将纳米颗粒悬浮在0.2M磷酸钠缓冲液中,pH 9.1,或悬浮在0.01N的HCl溶液中,pH 2.0。纳米颗粒浓度为1.5mg/ml并将混合物在37℃振荡60分钟。然后以10000rpm旋降样品10分钟以去除颗粒。使用0.45μm滤膜使上清液澄清(clear)并用HPLC测定胰岛素含量。从包含癸酸盐的磷酸钙颗粒中释放的胰岛素含量示于表13中。
表13
样品 | 1 | 2 |
释放缓冲液 | 0.2M磷酸钠,pH 9.1 | 0.01N HCl,pH 2.0 |
胰岛素含量(μg/mg) | 2.59 | 2.65 |
外观 | 浑浊 | 清澈 |
包含癸酸盐的纳米颗粒在0.01N HCl溶液中基本被清除,胰岛素的释放看起来已完全。但在0.2M磷酸钠缓冲液中,颗粒并未完全溶解,而胰岛素的含量与包含癸酸盐的纳米颗粒在0.01N HCl溶液中的释放接近。
在实施例9和10中示出的结果表明含UDCA和癸酸盐的磷酸钙纳米颗粒表现出不同的胰岛素释放行为。包含UDCA的纳米颗粒在高PH值时(0.2M磷酸钠,pH 9.1)表现出更高效的颗粒溶解和更完全的胰岛素释放,而包含癸酸盐的纳米颗粒在低PH值时(0.01N HCl,pH 2.0)表现出更高效的颗粒溶解。令人惊讶的是,在本研究中,包含癸酸盐的纳米颗粒所释放的胰岛素含量与pH值无关。
Claims (36)
1.一种多颗粒,包括:
a)多个磷酸钙核心纳米颗粒;
b)包封在所述核心纳米颗粒中的GLP-1激动剂;和
c)包封在所述核心纳米颗粒中的包括胆汁盐的共沉淀剂;
其中,相对于不含所述胆汁盐的磷酸钙核心纳米颗粒,所述胆汁盐的存在提高GLP-1激动剂包封到核心纳米颗粒中的包封效率。
2.根据权利要求1所述的颗粒,其中,所述GLP-1激动剂是依克那肽或其生理上可接受的盐或衍生物。
3.根据权利要求1所述的颗粒,其中,所述核心纳米颗粒的平均直径小于300nm。
4.根据权利要求1所述的颗粒,其中,所述胆汁盐选自胆酸盐、脱氧胆酸盐、牛磺胆酸盐、甘胆酸盐、牛磺脱氧胆酸盐、熊脱氧胆酸盐、牛磺熊脱氧胆酸盐、鹅脱氧胆酸盐及其组合构成的组。
5.一种药物组合物,包括权利要求1所述的颗粒和药用载体。
6.根据权利要求5所述的药物组合物,其中,所述组合物为胶囊、片剂、丸剂或粉末形式。
7.根据权利要求6所述的药物组合物,其中,所述组合物还包括肠溶衣。
8.根据权利要求5所述的药物组合物,还包括吸收促进剂。
9.根据权利要求8所述的药物组合物,其中,所述吸收促进剂是中链脂肪酸盐。
10.根据权利要求9所述的药物组合物,其中,所述中链脂肪酸盐选自己酸盐、辛酸盐、壬酸盐、癸酸盐、月桂酸盐、豆蔻酸盐及其组合构成的组。
11.一种用于治疗需要GLP-1激动剂治疗的对象的方法,所述方法包括给予所述对象治疗有效量的根据权利要求5-10中任一项所述的药物组合物。
12.根据权利要求11所述的方法,其中,所述药物组合物通过口服途径给予。
13.根据权利要求11所述的方法,其中,所述药物组合物给予至粘膜表面。
14.一种多颗粒,包括:
a)多个磷酸钙核心纳米颗粒;
b)包封在所述核心纳米颗粒中的生物活性大分子;以及
c)包封在所述核心纳米颗粒中的包括脂肪酸盐的共沉淀剂;
其中,相对于不含所述脂肪酸盐的磷酸钙核心纳米颗粒,所述脂肪酸盐的存在提高所述生物活性大分子包封到所述核心纳米颗粒中的包封效率。
15.根据权利要求14所述的颗粒,其中,所述核心纳米颗粒的平均直径小于300nm。
16.根据权利要求14所述的颗粒,其中,所述脂肪酸盐选自己酸盐、辛酸盐、壬酸盐、癸酸盐、月桂酸盐、豆蔻酸盐及其组合构成的组。
17.根据权利要求14所述的颗粒,其中,所述生物活性大分子选自蛋白质、肽、多糖、核酸、脂质和碳水化合物构成的组。
18.根据权利要求17所述的颗粒,其中,所述生物活性大分子选自GLP-1激动剂、胰岛素、促红细胞生成素、干扰素、生长激素、PTH、降血钙素、亮丙瑞林及其衍生物构成的组。
19.根据权利要求18所述的颗粒,其中,所述GLP激动剂是依克那肽或其生理上可接受的盐或衍生物。
20.一种药物组合物,包括权利要求14所述的颗粒和药用载体。
21.根据权利要求20所述的药物组合物,其中,所述组合物为胶囊、片剂、丸剂或粉末形式。
22.根据权利要求21所述的药物组合物,其中,所述组合物还包括肠溶衣。
23.根据权利要求20所述的药物组合物,还包括吸收促进剂。
24.根据权利要求23所述的药物组合物,其中,所述吸收促进剂是中链脂肪酸盐。
25.根据权利要求24所述的药物组合物,其中,所述中链脂肪酸盐选自己酸盐、辛酸盐、壬酸盐、癸酸盐、月桂酸盐、豆蔻酸盐及其组合构成的组。
26.一种用于治疗需要生物活性大分子治疗的对象的方法,所述方法包括给予所述对象治疗有效量的根据权利要求20-25中任一项所述的药物组合物。
27.根据权利要求26所述的方法,其中,所述药物组合物通过口服途径给予。
28.根据权利要求26所述的方法,其中,所述药物组合物给予至粘膜表面。
29.制备一种多磷酸钙颗粒的方法,所述方法包括:
a)在包括脂肪酸盐的共沉淀剂存在下,用磷酸盐水溶液接触钙盐水溶液;
b)混合步骤a)中产生的溶液,直到获得具有期望尺寸的磷酸钙颗粒;以及
c)回收所述磷酸钙颗粒。
30.根据权利要求29所述的方法,其中,所述脂肪酸盐选自己酸盐、辛酸盐、壬酸盐、癸酸盐、月桂酸盐、豆蔻酸盐及其组合构成的组。
31.根据权利要求29所述的方法,其中,所述钙盐的浓度范围为约5mM至约200mM。
32.根据权利要求29所述的方法,其中,所述磷酸盐的浓度范围为约5mM到约200mM。
33.根据权利要求29所述的方法,进一步包括,在包括脂肪酸盐的共沉淀剂存在下用所述磷酸盐水溶液接触所述钙盐水溶液之前,向所述磷酸盐水溶液或所述钙盐水溶液中添加生物活性大分子,由此所述磷酸钙颗粒与所述生物活性大分子共结晶。
34.根据权利要求33所述的方法,其中,所述生物活性大分子选自蛋白质、肽、多糖、核酸、脂质和碳水化合物构成的组。
35.根据权利要求34所述的方法,其中,所述生物活性大分子选自GLP-1激动剂、胰岛素、促红细胞生成素、干扰素、生长激素、PTH、降血钙素、亮丙瑞林及其衍生物构成的组。
36.根据权利要求35所述的方法,其中,所述GLP激动剂是依克那肽或其生理上可接受的盐或衍生物。
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CN103073645A (zh) * | 2012-12-31 | 2013-05-01 | 浙江大学 | 一种生物矿化的胰岛素蛋白纳米颗粒及其制备方法和应用 |
CN105722504A (zh) * | 2013-11-05 | 2016-06-29 | 医学研究理事会 | 无定形的镁取代磷酸钙组合物及其用途 |
CN106999624A (zh) * | 2014-11-17 | 2017-08-01 | 海洋纳米技术有限公司 | 治疗用具有形态发生活性的含视黄醇的非晶形聚磷酸钙纳米颗粒 |
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US5219577A (en) | 1990-06-22 | 1993-06-15 | The Regents Of The University Of California | Biologically active composition having a nanocrystalline core |
US5460830A (en) | 1990-06-22 | 1995-10-24 | The Regents Of The University Of California | Biochemically active agents for chemical catalysis and cell receptor activation |
US5460831A (en) | 1990-06-22 | 1995-10-24 | The Regents Of The University Of California | Targeted transfection nanoparticles |
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