CN103007288A - 改进的贮库制剂 - Google Patents
改进的贮库制剂 Download PDFInfo
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- CN103007288A CN103007288A CN2012103926224A CN201210392622A CN103007288A CN 103007288 A CN103007288 A CN 103007288A CN 2012103926224 A CN2012103926224 A CN 2012103926224A CN 201210392622 A CN201210392622 A CN 201210392622A CN 103007288 A CN103007288 A CN 103007288A
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Abstract
本发明公开了制剂及相关方法,其包含非聚合、不溶于水、37℃下粘度为至少5,000cP、在环境或生理条件下不均匀结晶的高粘性液体载体材料;包含丙交酯重复单元的特定直链聚合物;以及具有溶解能力的一种或多种溶剂。优选地,所述制剂含有乙酸异丁酸蔗糖酯(SAIB)、丙交酯-乙交酯共聚物(PLGA)以及合适的溶剂,所述溶剂优选NMP。示例性的药物为利司培酮和纳曲酮。
Description
发明背景
发明领域
本发明涉及包含非聚合、不溶于水的高粘性液体载体材料、直链聚合物以及一种或多种溶剂的制剂。更具体地,本发明涉及这样的制剂及其在生物活性物质递送中的用途。
相关领域描述
生物活性化合物的生物可降解的控释体系领域已经进行了广泛的研究。用于药物递送的生物可降解的基质是有用的,因为其无需移除药物耗尽的装置。
最常见的药物递送基质材料是聚合物。自从1966年Kulkarni等人报道了聚乳酸的合成和生物可降解性(“Polylactic acid for surgicalimplants(用于手术植入的聚乳酸),”Arch.Surg.,93:839),生物可降解的聚合物领域已经快速发展。已经报道的用作递送装置基质材料的其它聚合物的实例包括聚酐、诸如聚乙醇酸和丙交酯-乙交酯共聚物的聚酯、诸如聚赖氨酸的聚氨基酸、聚环氧乙烷的聚合物和共聚物、端丙烯酸基的聚环氧乙烷、聚酰胺、聚氨基甲酸酯、聚原酸酯、聚丙烯腈、以及聚磷腈。参见例如Langer的第4,891,225号和第4,906,474号美国专利(聚酐)、Hutchinson的第4,767,628号美国专利(聚丙交酯、丙交酯-乙交酯共聚物)以及Tice等人的第4,530,840号美国专利(聚丙交酯、聚乙醇酸及共聚物)。
生物来源的可降解材料是众所周知的,例如交联明胶。透明质酸已经被交联并用作生物医学应用的可降解溶胀聚合物(Della Valle等人的第4,957,744号美国专利;(1991)“Surface modification of polymericbiomaterials for reduced thrombogenicity (凝血活性降低的聚合生物材料的表面改性),”Polym.Mater.Sci.Eng.,62:731-735)。
还已经开发了生物可降解的水凝胶用于在受控药物递送中用作诸如激素、酶、抗生素、抗肿瘤剂以及细胞悬浮液的生物活性物质的载体。已经实现了被携带的物质的功能属性的短期保存以及该物质进入局部组织或体循环的控释。参见例如Cohen的第5,149,543号美国专利。适当选择水凝胶大分子单体能制备适用于各种外科、医疗诊断及治疗应用的具有一系列渗透性、孔径及降解速率的膜。
目前正使用或正在开发许多用作物质,尤其是生物活性化合物,的载体的分散体系。能够将用于药物制剂和化妆品制剂的分散体系归入悬浮液或乳状液。悬浮液被定义为利用悬浮剂分散于液体介质中的粒径为几纳米至几百微米的固体颗粒。该固体颗粒包括微球体、微胶囊以及纳米球体。乳状液被定义为一种液体在另一种液体中的悬浮液,其通过诸如表面活性剂和脂质的乳化剂的界面膜进行稳定。乳状液制剂包括油包水乳状液和水包油乳状液、多重乳状液、微乳状液、微滴以及脂质体。微滴是由内部具有油相的球形脂质层构成的单层磷脂小泡,如授权给Haynes的第4,622,219号和第4,725,442号美国专利所定义的那样。脂质体是通过将不溶于水的极性脂质与水溶液混合制备的磷脂小泡。将不溶的脂质混合在水中导致的不利的熵产生了含有带入的水溶液的高度有序排列的同心闭合磷脂膜。
Dunn等人的第4,938,763号美国专利公开了通过将非反应性、不溶于水的热塑性聚合物溶于生物相容的水溶性溶剂中以形成液体,将该液体置于体内并使该溶剂消散以产生固体植入物的就地形成植入物的方法。能通过注射器将该聚合物溶液置于体内。该植入物能呈现出其周围空腔的形状。在可选的实施方案中,由反应性液体低聚聚合物形成植入物,该聚合物不含有溶剂并且其通常通过添加固化催化剂在适当位置凝固以形成固体。
Tipton等人的第5,747,058号美国专利公开了用于物质控释的组合物,其包含(i)非聚合、不溶于水、37°C下粘度至少为5,000cP、在环境或生理条件下不均匀结晶的液体载体材料(HVLCM);以及(ii)被递送的物质。
虽然已经评价了许多材料在物质受控递送中的用途,仍然需要提供生物活性物质的受控递送的低毒性制剂和方法。
发明概述
在一方面,本发明涉及制剂,其包含(i)非聚合、不溶于水、37°C下粘度为至少5,000cP、在环境或生理条件下不均匀结晶的高粘性液体载体材料;(ii)包含丙交酯重复单元的直链聚合物,其中所述直链聚合物中丙交酯重复单元与全部重复单元的比率为R;以及(iii)具有溶解能力的一种或多种溶剂;其中所述直链聚合物的重均分子量小于或等于约15,000道尔顿,并且其中(a)R满足如下条件:约0.55≤R≤约0.95;(b)当R满足如下条件:约0.55≤R≤0.85时,所述一种或多种溶剂的溶解能力大于或等于约20%;以及(c)当R满足如下条件:大于约0.85至约0.95时,所述一种或多种溶剂的溶解能力大于或等于约10%。
在另一方面,本发明涉及制剂,其包含(i)非聚合、不溶于水、37°C下粘度为至少5,000cP、在环境或生理条件下不均匀结晶的高粘性液体载体材料;(ii)包含丙交酯重复单元的直链聚合物,其中所述直链聚合物中丙交酯重复单元与全部重复单元的比率为R;以及(iii)具有溶解能力的一种或多种溶剂;其中所述直链聚合物的重均分子量小于或等于约15,000道尔顿,并且其中(a)R满足如下条件:约0.55≤R≤0.85;以及(b)所述一种或多种溶剂的溶解能力大于或等于约20%。
在另一方面,本发明涉及制剂,其包含(i)非聚合、不溶于水、37°C下粘度为至少5,000cP、在环境或生理条件下不均匀结晶的高粘性液体载体材料;(ii)包含丙交酯重复单元的直链聚合物,其中所述直链聚合物中丙交酯重复单元与全部重复单元的比率为R;以及(iii)具有溶解能力的一种或多种溶剂;其中该直链聚合物的重均分子量小于或等于约15,000道尔顿,并且其中(a)R满足如下条件:大于约0.85至约0.95;以及(b)所述一种或多种溶剂的溶解能力大于或等于约10%。
在另一方面,本发明涉及制剂,其包含(i)非聚合、不溶于水、37°C下粘度为至少5,000cP、在环境或生理条件下不均匀结晶的高粘性液体载体材料;(ii)包含丙交酯重复单元的直链聚合物,其中所述直链聚合物中丙交酯重复单元与全部重复单元的比率为R,其中R满足如下条件:约0.55≤R≤约0.95;以及(iii)基于制剂总重量,约1%重量比至高达约35%重量比的一种或多种溶剂;其中所述直链聚合物的重均分子量小于或等于约15,000道尔顿,并且其中所述一种或多种溶剂包括乙醇、乳酸乙酯、碳酸丙烯酯、四氢呋喃聚乙二醇醚(glycofurol)、N-甲基吡咯烷酮、2-吡咯烷酮、苯甲酸苄酯、miglyol、丙二醇、丙酮、乙酸甲酯、乙酸乙酯、丁酮、苄醇、三乙酸甘油酯、二甲基甲酰胺、二甲亚砜、四氢呋喃、己内酰胺、癸基甲基亚砜、油酸和/或1-十二烷基氮杂环庚烷-2-酮及以上任何溶剂的组合。
发明详述
详细地描述本发明前,应当理解,本发明不受具体的示例性材料或方法参数的限制,因为这些材料或方法参数当然会变化。还应当理解,本文所用的术语仅旨在描述本发明的具体实施方案,而不是限制本发明。
本文引用的所有的出版物、专利和专利申请,不论在上文还是下文中,都在此整体并入本文用于各种目的。
除非上下文明确地另外指明,否则本说明书和所附的权利要求书中所用的单数形式“a”、“an”和“the”包括复数对象。例如,提及的“一聚合物(a polymer)”包括两种或更多种这样的分子的混合物,提及的“一溶剂(a solvent)”包括两种或更多种这样的组合物的混合物,提及的“一粘合剂(an adhesive)”包括两种或更多种这样的材料的混合物等。
A.介绍
本发明人已出人意料地发现,可以通过提供制剂解决本领域的问题,所述制剂包含(i)非聚合、不溶于水、37°C下粘度为至少5,000cP、在环境或生理条件下不均匀结晶的高粘性液体载体材料;(ii)包含丙交酯重复单元的直链聚合物,其中所述直链聚合物中丙交酯重复单元与全部重复单元的比率为R;以及(iii)具有溶解能力的一种或多种溶剂;其中所述直链聚合物的重均分子量小于或等于约15,000道尔顿,并且其中(a)R满足如下条件:约0.55≤R≤约0.95;(b)当R满足如下条件:约0.55≤R≤0.85时,所述一种或多种溶剂的溶解能力大于或等于约20%;以及(c)当R满足如下条件:大于约0.85至约0.95时,所述一种或多种溶剂的溶解能力大于或等于约10%。
本发明人还已出人意料地发现,可以通过提供制剂解决本领域的问题,所述制剂包含(i)非聚合、不溶于水、37°C下粘度为至少5,000cP、在环境或生理条件下不均匀结晶的高粘性液体载体材料;(ii)包含丙交酯重复单元的直链聚合物,其中所述直链聚合物中丙交酯重复单元与全部重复单元的比率为R;以及(iii)具有溶解能力的一种或多种溶剂;其中所述直链聚合物的重均分子量小于或等于约15,000道尔顿,并且其中(a)R满足如下条件:约0.55≤R≤0.85;以及(b)所述一种或多种溶剂的溶解能力大于或等于约20%。
本发明人还已出人意料地发现,可以通过提供制剂解决本领域的问题,所述制剂包含(i)非聚合、不溶于水、37°C下粘度为至少5,000cP、在环境或生理条件下不均匀结晶的高粘性液体载体材料;(ii)包含丙交酯重复单元的直链聚合物,其中所述直链聚合物中丙交酯重复单元与全部重复单元的比率为R;以及(iii)具有溶解能力的一种或多种溶剂;其中所述直链聚合物的重均分子量小于或等于约15,000道尔顿,并且其中(a)R满足如下条件:大于约0.85至约0.95;以及(b)所述一种或多种溶剂的溶解能力大于或等于约10%。
另外,本发明人已出人意料地发现,可以通过提供制剂解决本领域的问题,所述制剂包含(i)非聚合、不溶于水、37°C下粘度为至少5,000cP、在环境或生理条件下不均匀结晶的高粘性液体载体材料;(ii)包含丙交酯重复单元的直链聚合物,其中所述直链聚合物中丙交酯重复单元与全部重复单元的比率为R,其中R满足如下条件:约0.55≤R≤约0.95;以及(iii)基于制剂总重量,以约1%重量比至高达约35%重量比的量存在的一种或多种溶剂;其中所述直链聚合物的重均分子量小于或等于约15,000道尔顿,并且其中所述一种或多种溶剂包括乙醇、乳酸乙酯、碳酸丙烯酯、四氢呋喃聚乙二醇醚、N-甲基吡咯烷酮、2-吡咯烷酮、苯甲酸苄酯、miglyol、丙二醇、丙酮、乙酸甲酯、乙酸乙酯、丁酮、苄醇、三乙酸甘油酯、二甲基甲酰胺、二甲亚砜、四氢呋喃、己内酰胺、癸基甲基亚砜、油酸和/或1-十二烷基氮杂环庚烷-2-酮及以上任何溶剂的组合。
根据本发明的直链聚合物能用于改变待递送的生物活性物质的释放谱,以增加制剂的完整性,或者另外地修饰制剂的性能。根据本发明的这样的直链聚合物包含丙交酯重复单元。这样的聚合物的实例是丙交酯-乙交酯共聚物。直链聚合物中丙交酯重复单元与全部重复单元的比率R示于表1的“R列”中。
本发明制剂的开发中重要的考虑是制剂中的聚合物与HVLCM的混溶性或溶解性。在制剂中的聚合物不与HVLCM混溶或不溶于HVLCM的情况下,可以发生聚合物与HVLCM的相分离。一旦这种情况发生,可能很难将聚合物与HVLCM再混合,特别是在快要使用的时候。如果不适当地将制剂再混合,其可能不会以期望的方式释放药物。另外,可能难以给予该制剂。因此,期望制剂中的聚合物与HVLCM高度混溶或溶于HVLCM。
本发明制剂中的直链聚合物在含有HVLCM的制剂中具有高混溶性或高溶解性。如查阅表1能得知的那样,不是所有含有直链聚合物、HVLCM和溶剂的制剂都得到有用的制剂。作为“对照制剂”列出的制剂是不在本发明的上下文中被认为是有用的制剂的实例。相比之下,诸如表1中示例的那些的本发明实施方案是有用的,并且很少出现相分离。
通过例如测试表现出可接受的溶解行为的制剂6能得知溶解能力的影响。这种制剂包含55wt%的乙酸异丁酸蔗糖酯(SAIB)、25wt%的NMP和20wt%的R为0.65并且Mw为5300的丙交酯-乙交酯共聚物(PLGA)。制剂6的溶解能力为25wt%。作为比较,也提出制剂C11和C 12。制剂C 11包含55wt%的乙酸异丁酸蔗糖酯(SAIB)、20wt%的NMP、5wt%的DMSO和20wt%的R为0.65并且Mw为5300的丙交酯-乙交酯共聚物(PLGA)。同样地,制剂C 12包含55wt%的乙酸异丁酸蔗糖酯(SAIB)、20wt%的NMP、5wt%的苯甲酸苄酯和20wt%的R为0.65并且Mw为5300的丙交酯-乙交酯共聚物(PLGA)。制剂C11和C12包含小于25wt%的NMP并且其溶剂性能方面不够好。因此,制剂C11和C12不满足溶解能力的要求并因此不是本发明的创造性实施方案。
实施例7和8示出了理解溶解能力的另一种方式。这些实施方案示出如何能够测定本发明制剂的溶解能力。除了基线NMP溶剂体系,在两种另外的溶剂体系和本发明制剂的两种不同实施方案中进行这种测定。
实施例9和10示出包含生物活性物质的本发明制剂的实施方案。
现在将更详细地描述本发明。
定义
除非另外指出,所有的百分比是重量百分比。
本文引用的所有参考文献被全文并入本文作为参考,并以相同程度用于所有目的,如同指明将每一单独的出版物或专利或专利申请具体且单独地通过引用整体并入本文,以用于所有目的和/或在本文中完全地再现。本文参考文献的讨论仅旨在概括这些作者的主张,并非承认任何参考文献构成现有技术。申请人保留质疑所引用的参考文献的准确性和相关性的权利。
通过参考本文提供的如下定义、附图和示例性公开内容最好地理解本发明。
“给予(administering)”或“给予(administration)”意指以药学有用的方式向个体提供药物。
“生物活性物质”意指包括以下的分子:药物、肽、蛋白、碳水化合物(包括单糖、低聚糖和多糖)、核蛋白、粘蛋白、脂蛋白、合成的多肽或蛋白或与蛋白连接的小分子、糖蛋白、类固醇、核酸(任何形式的DNA,包括cDNA或RNA或其片段)、核苷酸、核苷、寡核苷酸(包括反义寡核苷酸)、基因、脂质、激素、矿物质补充剂、包括维生素C和维生素E在内的维生素,或以上的任意组合,当在体内给予动物时,其产生生物学作用,所述动物包括但不限于鸟类和包括人在内的哺乳动物。
药物意指作为处理、治疗或预防疾病或病症的药物在内部或外部使用的任何物质,并包括但不限于免疫抑制剂、抗氧化剂、麻醉剂、化疗剂、类固醇(包括类视黄醇)、激素、抗生素、抗病毒剂、抗真菌剂、抗增殖剂(antiproliferative)、抗组胺剂、抗凝剂、抗光老化剂、向黑素肽(melanotropic peptide)、非类固醇和类固醇抗炎化合物、抗精神病药以及包括UV吸收剂在内的辐射吸收剂。
术语生物活性物质还包括诸如杀虫剂、农药、杀真菌剂、杀鼠剂以及植物营养物和生长促进剂的试剂。
在一实施方案中,制剂是疫苗并且待递送的物质是抗原。所述抗原能得自细胞、细菌或病毒颗粒或其部分。如本文定义的那样,抗原可以是蛋白、肽、多糖、糖蛋白、糖脂、核酸或其组合,所述抗原在诸如哺乳动物、鸟或鱼的动物内引起免疫源应答。如本文定义的那样,所述免疫源应答能够是体液介导或细胞介导的。在免疫源应答所针对的材料的抗原性不好的情况下,可以利用诸如几种可商购的试剂盒中的一种的标准共价结合技术,将该材料与诸如白蛋白的载体或半抗原轭合。
优选抗原的实例包括诸如流感蛋白、人免疫缺陷病毒(HIV)蛋白和甲、乙或丙型肝炎蛋白的病毒蛋白和细菌蛋白、诸如革兰氏阴性菌细胞壁的脂多糖和淋病双球菌(Neisseria gonorrhea)蛋白和细小病毒。
药学物质的非限制性实例包括诸如呋喃西林、丙酸钠的抗感染剂,包括青霉素、四环素、土霉素、金霉素、杆菌肽、制霉菌素、链霉素、新霉素、多粘菌素、短杆菌肽、氯霉素、红霉素和阿奇霉素在内的抗生素,包括乙酰磺胺、磺胺甲噻二唑、磺胺二甲嘧啶、磺胺嘧啶、磺胺甲嘧啶和磺胺异噁唑在内的磺胺,以及包括碘苷在内的抗病毒剂,诸如安他唑啉、噻吡二胺(methapyritene)、氯苯那敏、吡拉明、非尼拉敏、氢化可的松、可的松、乙酸氢化可的松、地塞米松、21-磷酸地塞米松、氟新诺龙、去炎松、甲羟孕酮、泼尼松龙、泼尼松龙21-琥珀酸钠和乙酸泼尼松龙的抗过敏症药,诸如豚草花粉抗原、花粉症花粉抗原、灰尘抗原和乳汁抗原的脱敏剂,诸如天花、黄热病、瘟热、猪瘟、水痘、抗蛇毒素、猩红热、白喉类毒素(dyptheria toxoid)、破伤风类毒素、鸽痘、百日咳、流行性感冒、狂犬病、流行性腮腺炎、麻疹、脊髓灰质炎和新城病的疫苗,诸如苯肾上腺素、萘唑啉和四氢唑啉(tetrahydrazoline)的减充血剂,诸如匹鲁卡品、水杨酸望菌素(esperine salicylate)、卡巴胆碱、氟磷酸二异丙酯、依可碘酯和溴化德美卡灵的缩瞳剂和抗胆碱酯酶剂,诸如硫酸阿托品、环喷托酯、后马托品、东莨菪碱、托吡卡胺、优加托品和羟化苯丙胺的副交感神经阻滞药,诸如肾上腺素的拟交感神经药,诸如戊巴比妥钠、苯巴比妥、司可巴比妥钠、可待因、α-溴代异戊酰脲、卡溴脲的镇静剂和催眠药,诸如3-(2-氨基丙基)吲哚乙酸和3-(2-氨基丁基)吲哚乙酸的抗抑郁剂,诸如利血平、氯丙嗪(chlorpromayline)和乙酰哌啡钠嗪的安定药,诸如甲睾酮和氟甲睾酮(fluorymesterone)的雄性类固醇,诸如雌酮、17-β-雌二醇、乙炔基雌二醇和二乙基己烯雌酚的雌激素,诸如孕酮、甲地孕酮、美仑孕酮、氯地孕酮、炔孕酮、羟炔诺酮、19-去甲孕酮、炔诺酮、甲羟孕酮和17-β-羟孕酮的孕前剂,例如诸如PGE.sub.1、PGE.sub.2和PGF.sub.2的前列腺素的体液试剂(humoral agent),诸如阿司匹林、水杨酸钠和水杨酰胺的退热剂,诸如阿托品、乙胺太林、罂粟碱和溴化甲基东莨菪碱的解痉剂,诸如4-氨基喹啉、8-氨基喹啉、氯喹和息疟定的抗疟剂,诸如苯海拉明、晕海宁、去敏灵、奋乃静和氯苯那敏(chlorphenazine)的抗组胺剂,诸如二苯氢氟噻嗪(dibenzhydroflumethiazide)、三氟甲噻、氯噻嗪和三硝酸三乙醇胺酯的心脏药剂;抗精神病药,其包括典型和非典型抗精神病药,其中非典型抗精神病药包括利司培酮、帕潘立酮或奥氮平;诸如维生素、天然和合成的生物活性肽和蛋白的营养剂,其包括生长因子、细胞粘附因子、细胞因子和生物反应调节物;以及以上试剂的药物可接受的盐和多晶型物。
包含于组合物中的生物活性物质的量足以向宿主动物或植物递送实现期望效果的有效量。包含于组合物中的生物活性物质的量取决于期望的释放谱、生物学效果所需的生物活性物质的浓度和生物学活性物质释放的期望周期。
组合物中生物活性物质的浓度还将取决于生物活性物质的吸收、失活和排泄速率以及本领域技术人员已知的其它因素。应当指出,剂量值还将随待改善的疾病状态的严重性而变化。还应当理解,对于任何具体的个体,应根据个体的需要和管理或监督给予本发明制剂的人的专业判断,随时间调整具体的剂量方案,并且本文所述的浓度范围仅是示例性的,并不意图限制要求保护的发明的范围或实施。可以以单剂量给予制剂,或者可以将制剂分成以变化的时间间隔给药的许多较小剂量。
存在于制剂中的生物活性物质通常为制剂总重量的约0.5%至约30%重量比,并且更通常为约1%至约20%重量比。另一优选范围是约2%至约10%重量比。对于诸如生长因子的非常有活性的生物活性物质,优选范围是小于1%重量比,并且小于0.0001%。
“制剂”意指用于实施本发明的药物组合物。
“直链”意指聚合物中的分子形成基本没有支链或交联结构的长链。
“非聚合、不溶于水、37°C下粘度为至少5,000cP、在环境或生理条件下不均匀结晶的高粘性液体载体材料”意指高粘性液体载体材料(“HVLCM”),其是非聚合、不溶于水的,并且其37°C下的粘度为至少5,000cP,优选至少10,000cP、15,000cP、20,000cP、25,000cP或甚至50,000cP,其在环境或生理条件下不均匀结晶。术语不溶于水是指材料于环境条件下在水中溶解的程度不到1%重量比。
在优选实施方案中,当HVLCM与溶剂混合以形成能与用于受控递送的基质混合的低粘性液体载体材料(“LVLCM”)时,HVLCM的粘性显著降低。LVLCM/基质组合物通常比HVLCM/基质组合物更容易置于体内,因为其更容易流入和流出注射器或其它植入装置,并且能容易地制备成乳状液。LVLCM能够具有任何期望的粘性。已经发现,粘度范围小于约2000cP并更具体地小于1000cP的LVLCM通常用于体内应用。
在优选实施方案中,将乙酸异丁酸蔗糖酯(“SAIB”)用作HVLCM,所述乙酸异丁酸蔗糖酯名义上是优选地被2个乙酸和6个异丁酸部分酯化的蔗糖分子。
SAIB无口服毒性并且目前在食品工业中用于稳定乳状液。其为非常粘的液体并具有不寻常的属性,即稍微加热或添加溶剂时,其粘性发生明显的变化。其可溶于许多生物相容的溶剂。当在溶液或乳状液中时,能通过注射或气雾剂喷雾应用SAIB。SAIB与纤维素酯和其它能影响物质递送速率的聚合物相容。
在其它实施方案中,HVLCM能是硬脂酸酯,例如丙二醇、甘油基、二乙基氨基乙基和乙二醇的那些硬脂酸酯;硬脂酸酰胺和其它长链脂肪酸酰胺,例如N,N’-亚乙基双硬脂酰胺、硬脂酰胺MEA和DEA、亚乙基双硬脂酰胺、椰油胺氧化物;长链脂肪醇,例如十六烷醇和十八烷醇;长链酯,例如肉豆蔻酸肉豆蔻酯、二十二烷醇芥酸酯(behenyerucate)和甘油磷酸酯。在一具体的实施方案中,HVLCM是乙酰化的蔗糖二硬脂酸酯(Crodesta A-10)。Gibson等人的美国专利申请公开US2004/0101557公开了适合用作HVLCM的其它材料。
制剂中HVLCM的量将取决于制剂的期望属性和所选溶剂的溶解能力。如果所选溶剂的溶解能力性能差,则溶剂的实际量可以很大,而制剂中HVLCM的量则相应地减少。相对于组合物的总重量,HVLCM在受控递送组合物中的量通常为约99.5%至约10%重量比,更通常95%至25%,并且最通常85%至45%。
“聚合物”意指由连接的一系列重复单元组成的天然存在或合成的化合物。聚合物包括但不限于热塑性聚合物和热固性聚合物。聚合物可以包括直链聚合物和/或支链聚合物。聚合物可以由单一种类的单体合成或者可以是由超过一种单体合成的共聚物。在实施方案中,根据本发明的聚合物包括包含丙交酯重复单元的聚合物。根据本发明的聚合物还可以包含其它合适材料的重复单元,其包括但不限于乙交酯重复单元、聚乙二醇重复单元、己内酯重复单元、戊内酯重复单元等。这些聚合物的引发剂包括但不限于包括1,6-己二醇、1,2-丙二醇、1,3-丙二醇、1,4-丁二醇等的二醇引发剂,包括双官能团的聚(乙二醇)(PEG)的二醇引发剂,包括1-十二烷醇、乳酸甲酯、乳酸乙酯等的单官能团的醇引发剂,包括甲氧基(聚乙二醇)(mPEG)的单官能团的PEG,以及包括水、乙醇酸、乳酸、柠檬酸等的其它引发剂。在优选实施方案中,聚合物包括生物可降解的聚合物。在另外的优选实施方案中,聚合物包括生物相容的聚合物。在实施方案中,聚合物的量为约1wt%至约45wt%,聚合物的量更优选为约5wt%至约35wt%,聚合物的量更优选为约5wt%至约25wt%,所有的重量比均基于制剂的总重量。在其它实施方案中,聚合物的量可以为约15wt%至约45wt%,聚合物的量优选为约15wt%至约35wt%,所有的重量比基于制剂的总重量。
“重复单元”意指共价连接入聚合物的单体残基。在实施方案中,丙交酯重复单元包括丙交酯残基。在某些实施方案中,乙交酯重复单元包括乙交酯残基。在实施方案中,直链聚合物可以具有丙交酯重复单元与直链聚合物中全部重复单元的比率R,其中R可以为约0.55至约0.95。特别关注的R的范围为约0.55至0.85,以及大于0.85至约0.95。可以通过质子NMR或类似技术经由试验或分析确定R。
“溶剂”意指能溶解其它材料的物质。优选地,用于实施本发明的溶剂是生物相容、与水混溶和/或溶于水和/或无毒的。在实施方案中,生物活性物质可溶于溶剂中。用于向哺乳动物注射本发明制剂的溶剂不应在植入位点产生明显的组织刺激或坏死,除非刺激或坏死是期望的效果。
溶剂优选与水混溶和/或溶于水,使得该溶剂将扩散至体液或其它水性环境,从而使得制剂呈现出更粘的形式。某些不与水混溶和/或不溶于水的溶剂可以用于实施本发明。合适的溶剂的实例包括但不限于乙醇、乳酸乙酯、碳酸丙烯酯、四氢呋喃聚乙二醇醚、N-甲基吡咯烷酮、2-吡咯烷酮、苯甲酸苄酯、miglyol、丙二醇、丙酮、乙酸甲酯、乙酸乙酯、丁酮、苄醇、三乙酸甘油酯、二甲基甲酰胺、二甲亚砜、四氢呋喃、己内酰胺、癸基甲基亚砜、油酸和/或1-十二烷基氮杂环庚烷-2-酮及以上任何溶剂的组合;其条件为如果放弃保护以上列出的溶剂中的一种或多种溶剂,则可以将其特定地排除在本发明的范围之外。
当将SAIB用作HVLCM时,优选的溶剂包括乙醇、二甲亚砜、乳酸乙酯、乙酸乙酯、苄醇、三乙酸甘油酯、N-甲基吡咯烷酮、碳酸丙烯酯和四氢呋喃聚乙二醇醚。SAIB不与甘油、玉米油、花生油、1,2-丙二醇、聚乙二醇(PEG200)、超精制芝麻油和超精制花生油混溶。因此,不优选将后一组溶剂与SAIB一起使用。
“溶解能力”意指一种或多种溶剂的量,其将制剂中的HVLCM和直链聚合物溶解的程度与制剂中假定量N-甲基吡咯烷酮将制剂中的HVLCM和直链聚合物溶解的程度相同。溶解能力表示为基于含有N-甲基吡咯烷酮的假定制剂的总重量,制剂中N-甲基吡咯烷酮的假定重量百分比。
因此,在一实施方案中,溶解能力为约20%的制剂将具有足量的一种或多种溶剂以溶解HVLCM和直链聚合物,达到与向制剂中添加约20%重量比的NMP而非该一种或多种溶剂相同的程度。如果在这种实施方案中,NMP作为该一种或多种溶剂存在,其将以基于制剂总重量约20%重量比的量存在。如果该一种或多种溶剂是对于HVLCM和直链聚合物来说更差的溶剂,则所述一种或多种溶剂将以基于制剂总重量大于约20%重量比的量存在。这在实施例10和11中进行进一步说明。
在某些实施方案中,当R(直链聚合物中丙交酯重复单元与全部重复单元的比率)为约0.55至0.85时,一种或多种溶剂的溶解能力大于或等于约35%,更优选大于或等于约25%,并且还更优选大于或等于约20%。同样地,在某些实施方案中,当R为大于0.85至约0.95时,一种或多种溶剂的溶解能力大于或等于约25%,更优选大于或等于约15%,并且还更优选大于或等于约10%。溶解能力下限的降低表示要求保护的制剂的范围的缩小。这是由于对所列举的溶解能力的全部范围表现出满意的溶解行为的制剂的数目随着溶解能力下限的降低而减少。
“个体(subject)”可与“个体(individual)”互换使用,并意指期望用于实施本发明的任何人或动物。术语“个体”不指定具体年龄,因此本体系适合用于任何年龄的个体,例如婴儿、青少年、成人和老年个体。在某些实施方案中,个体可以包括患者。
“重均分子量”或“Mw”表示感兴趣的聚合物的重量平均分子量。其能够表示为每一分子重量范围中聚合物的重量对分子重量的图的一次矩。在某些实施方案中,可以通过凝胶渗透色谱法(GPC)测量重均分子量、数均分子量(Mn)和分子量分布(MWD=Mw/Mn)。GPC是柱分级方法,其中基于尺寸分离溶液中的聚合物分子。通过检测器观察分离的聚合物分子以生成GPC色谱图,其为洗脱体积或时间(与分子大小相关)对丰度的图。可以对GPC色谱求积分以测定Mw、Mn和MWD。
进样至装置前,将含有约50mg感兴趣的聚合物的GPC样品的10ml溶剂通过0.2μm Teflon滤器过滤。进样50-200μl以生成色谱图。可以使用各种体系生成色谱图。在一实施方案中,体系包括使用Chemstation软件的Agilent LC 1100。在另一实施方案中,体系包括Waters 510泵、Shimadzu CTO-10A柱温箱和Waters 410示差折射仪。可以通过使用软件的Polymer Labs数据获取单元直接将数据记录至PC。可以使用聚苯乙烯标准品生成校准曲线。计算相对于聚苯乙烯的Mw、Mn和MWD。用于GPC的优选溶剂包括氯仿、二氯甲烷(亚甲基氯)和四氢呋喃(THF)。优选的不同色谱柱组合包括:(1)串联的两个Polymer Labs Mixed C柱,(2)串联的两个Polymer LabsMixed D柱,或(3)串联的两个Polymer Labs Mesopore色谱柱。优选的聚苯乙烯校准品包括:Polymer Labs Easical PS1试剂盒、PolymerLabs Easical PS2试剂盒、Polymer Labs S-L-10试剂盒。
在实施方案中,用于实施本发明的聚合物的重均分子量小于或等于约15,000道尔顿,另外更优选小于或等于约12,500道尔顿,并且还更优选小于或等于约10,000道尔顿。
制剂
如上文指出的那样,本发明制剂的开发中的重要考虑是聚合物在制剂中与HVLCM的混溶性或溶解性。在制剂中的聚合物不与HVLCM混溶或不溶于HVLCM的情况下,可以发生制剂中聚合物与HVLCM的相分离。一旦这种情况发生,可能很难将聚合物与HVLCM再混合,特别是在快要使用的时候。如果不适当地再混合,可能导致释放性能的不期望的大幅度变化。因此,期望聚合物在制剂中与HVLCM具有高度溶混性或溶解性。
本发明的制剂具有制剂中聚合物与HVLCM的高度溶混性或溶解性。用于根据配制策略考虑的其它要点可以包括如下文所述的要点。使制剂的总溶剂含量最小化通常是生物学期望的,例如在一实施方案中,溶剂含量基于制剂的总重量为约1wt%至高达约35wt%溶剂,优选基于制剂的总重量为约1wt%至高达约30wt%溶剂,并且还更优选基于制剂的总重量为约1wt%至高达约25wt%溶剂。相比之下,增加溶剂含量能将HVLCM/直链聚合物组合物从相分离向单一相行为移动。一种或多种溶剂应该是生物相容的,其可以排除某些溶剂在本发明中的使用。在一实施方案中,一种或多种溶剂应该是对聚合物和HVLCM两者都好的溶剂。在可选的实施方案中,制剂可以包含HVLCM、直链聚合物、一种或多种对直链聚合物好的溶剂和一种或多种对HVLCM好的溶剂,所得制剂是单相的。
可以通过本领域技术人员熟知的视觉技术研究各种HVLVM/直链聚合物/溶剂制剂的溶解性和相分离。对于明显不稳定或倾向于相分离的制剂,直链聚合物可以吸收溶剂但仍作为分离的、非常粘的层或相保留在制剂中。可以通过充分加热和混合使其它制剂成为均匀的澄清溶液。然而,当冷却至室温时,可以形成两种澄清的液体相。有时,不容易检测这两种澄清的层,因此需要强光和对制剂的完整检查以分辨两相间的边界。在许多情况下,制剂可以在初始冷却至室温时表现为澄清和均匀,但是在室温下静置几天或更长的时间后,所述制剂可以分成两相。对于在相分离边缘的制剂,制剂可以变得浑浊并且有时候缓慢地分成两相。
本发明的制剂能任选地包含各种添加剂以改善制剂的期望属性。添加剂能以任何足以赋予制剂期望属性的量存在。所用添加剂的量一般是添加剂性质和要获得的效果的函数,并且本领域技术人员能够容易地确定。
当存在添加剂时,添加剂通常以相对于制剂总重量约0.1%至约20%重量比的量存在于制剂中,并且更通常以相对于制剂总重量约1%、2%或5%至约10%重量比的量存在于组合物中。诸如缓冲剂的某些添加剂可以仅以相对于制剂总重量的少量存在。
本发明组合物使用的另一种添加剂是非生物可降解的聚合物。能作为添加剂使用的不易蚀的聚合物的非限制性实例包括聚丙烯酸脂、乙烯-乙酸乙烯酯聚合物、纤维素和纤维素衍生物、酰基取代的乙酸纤维素及其衍生物、不易蚀的聚氨基甲酸酯、聚苯乙烯、聚氯乙烯、聚氟乙烯、聚(乙烯基咪唑)、氯磺化聚烯烃以及聚环氧乙烷。
优选的非生物降解的聚合物包括聚乙烯、聚乙烯吡咯烷酮、乙烯乙酸乙烯酯、聚乙二醇、乙酸丁酸纤维素(“CAB”)以及乙酸丙酸纤维素(“CAP”)。
能用于本发明制剂的另一类添加剂是天然和合成的油和脂肪。来自动物或来自植物坚果种子的油通常包括主要是油酸、棕榈酸、硬脂酸和亚麻酸的脂肪酸的甘油酯。通常,分子含有的氢越多,油变得越稠。
合适的天然和合成的油的非限制性实例包括粗制或精制的植物油、花生油、中链甘油三酯、豆油、杏仁油、橄榄油、芝麻油、花生油、茴香油、山茶油、玉米油、蓖麻油、棉籽油和豆油,以及中链脂肪酸甘油三酯。
脂肪通常是诸如硬脂酸和棕榈酸的高级脂肪酸的甘油酯。这些酯及其混合物在室温下是固体并且表现出晶体结构。猪油和牛脂是实例。一般地,油和脂肪增加了制剂的疏水性并延缓了降解和水的吸收。
能用于本发明的制剂的另一类添加剂包括碳水化合物和碳水化合物衍生物。这些化合物的非限制性实例包括单糖(诸如果糖及其异构体葡萄糖(右旋糖)的简单糖),诸如蔗糖、麦芽糖、纤维二糖和乳糖的二糖以及多糖。
可以按需要添加其它添加剂,例如防腐剂、稳定剂、抗氧化剂、着色剂、等渗剂、湿润剂、络合剂、维生素和维生素前体、表面活性剂等。防腐剂的优选实例为对羟基苯甲酸酯(paraben)衍生物,并且对羟基苯甲酸甲酯和对羟基苯甲酸丙酯是最优选的防腐剂。抗氧化剂的优选实例为丁基羟基茴香醚、丁基羟甲苯、没食子酸丙酯、乙酸维生素E和纯化的氢醌,并且乙酸维生素E和丁基羟甲苯是最优选的抗氧化剂。湿润剂的优选实例为山梨醇。络合剂的优选实例为柠檬酸。
可以按照许多方法制备发明的制剂。在某些实施方案中,首先将室温下的溶剂、室温下的直链聚合物以及加热至80°C的HVLCM混合。然后,在60-80°C下混合数小时至过夜(8-16小时)的时间,直至制剂充分混合。在其它实施方案中,将直链聚合物溶于所有的溶剂中。添加热HVLCM(在高达80°C下加热)。然后,在室温至80°C的温度下混合达1小时至过夜(8-16小时)的时间,直至制剂充分混合。在其它实施方案中,将直链聚合物溶于溶剂中的某些溶剂中。将剩余的溶剂与HVLCM混合。向直链聚合物/溶剂混合物中添加热HVLCM/溶剂混合物(在高达80°C下加热)。然后在室温至80°C的温度下混合达1小时至过夜(8-16小时),直至制剂充分混合。
优选在高于室温的温度下制备本发明的制剂。一旦混合,可以将制剂冷却回室温并初次观察浑浊(初期相分离的标志)、两个液体层(通常具有低至中等的粘性)的存在或在较低粘性层下方的粘性层的存在。然后可以将制剂置于室温达相当的时间(通常为一周或更长)并再次观察浑浊、分成中等粘性的两层或粘性层的存在。
可以使用诸如注射的常规给药途径给予个体本发明的制剂。可以向本发明的制剂添加有效量的生物活性物质从而获得期望的药理学效果。
虽然已经描述并指出了本发明的特征和优势,如应用于本实施方案的那样,医疗领域的技术人员将理解,能对本说明书所述的方法进行各种修改、变化、增加和删节而不偏离本发明的精神。
本发明不受按照本申请所述的具体实施方案的限制,该具体实施方案旨在作为本发明各个方面的单独示例。对于本领域技术人员显而易见的是,能对本发明进行许多修改和变更,而不偏离本发明的精神和范围。除了本文列举的那些,前述描述的本发明范围内的功能上相当的方法对本领域技术人员是显而易见的。这些修改和变更旨在落入所附的权利要求书的范围内。本发明仅受所附的权利要求书以及这些授予的权利要求书的全部等同范围的限制。
如下实施例的意图是示例,并且不以任何方式限制要求保护的发明。
实施例
实施例1:制剂实施例
制备了根据本发明的各种制剂实施例,以及各种对照制剂实施例。与这些实施例相关的信息如表1所示。下文列出了若干代表性实施例的聚合物合成和制剂技术。使用这些代表性的技术以及这些代表性技术可常规获得的修改制备剩下的非代表性实施例。
实施例2:
在100°C的玻璃器皿烘箱中干燥500mL三口圆底烧瓶、玻璃搅拌器轴承、气体接头和玻璃搅拌轴以除去所有痕量水分。向烧瓶中加入如下材料:179.00g DL-丙交酯、71.00g乙交酯和13.75g 1,6-己二醇。烧瓶装有具有Teflon浆的搅拌轴、搅拌器轴承和与真空歧管和氮气供应相连的气体接头。用橡皮气囊密封搅拌器轴/轴承,抽空反应混合物达几分钟并用氮气回填烧瓶。将烧瓶浸入保持在150°C下的油浴中并使用与轴/桨组件相连的顶置式搅拌器进行搅拌。一旦所有单体都熔化,向熔化物中添加含有0.075g 2-乙基己酸亚锡的甲苯溶液(浓度为0.13416g/mL的559mL溶液)。继续搅拌4小时。然后将油浴温度降至115°C,停止搅拌并用橡皮气囊密封搅拌器轴/轴承,并将反应混合物在完全真空中抽空1小时。然后将聚合物倒入玻璃碟中的Teflon薄膜上并将其冷却。将完成的聚合物保存于真空烘箱和/或塑料袋中以隔离环境水分。所得的聚合物通过GPC测定的Mw为约5300Da,并且R比率为0.65。
实施例3:制剂6
从低温保存中取出根据实施例2制备的PLGA聚合物,并将其升温至室温。将SAIB(在玻璃广口瓶中)加热至80°C,持续数小时。将5.69克热SAIB倒入玻璃广口瓶中。然后将2.59克NMP加入该玻璃广口瓶中。然后,将2.05克65/35PLGA聚合物加入该玻璃广口瓶中。将该广口瓶密封并固定至旋转混合轮(rotating mixing wheel)。将该混合轮放入80°C的烘箱中并打开,从而使该广口瓶在圆周轨迹的外部以足以实现混合的速率转动。在80°C下混合2小时后,从混合轮中取出该广口瓶并将其冷却至室温。制剂组成为55%SAIB、25%NMP和20%PLGA。放置时,制剂保持澄清并且不表现出任何相分离的迹象。
实施例4:
在100°C的玻璃器皿烘箱中干燥1L三口圆底烧瓶、玻璃搅拌器轴承、气体接头和搅拌轴以除去所有痕量水分。向烧瓶中加入如下材料:179.00g DL-丙交酯、71.00g乙交酯和2.1g水。烧瓶装有搅拌轴、Teflon浆、搅拌器轴承和与真空歧管和氮气供应相连的气体接头。密封搅拌器轴/轴承,抽空反应混合物数分钟并用氮气回填烧瓶。将此过程再重复4次。将烧瓶浸入保持在159°C下的油浴中并使用与轴/桨组件相连的顶置式搅拌器进行搅拌。一旦所有单体都熔化,向熔化物添加含有0.1125g 2-乙基己酸亚锡的甲苯溶液。持续搅拌15小时。然后将油浴温度降至115°C,停止搅拌并密封搅拌器轴/轴承,并将反应混合物在完全真空中抽空1小时。然后将聚合物倒入玻璃碟中的Teflon薄膜上并将其冷却。将完成的聚合物保存在真空烘箱和/或塑料袋中以隔离环境水分。所得聚合物通过GPC测定的Mw为约7200Da,并且R比率为0.65。
实施例5:对照制剂C3
将根据实施例4制备的3.28克PLGA溶于1.55克DMSO和1.55克乙醇的混合物中。添加24.98克热SAIB,得到含10.5%PLGA、4.9%DMSO、4.9%乙醇和79.7%SAIB的题述制剂。该制剂在室温下分成两相。添加另外的DMSO(3.90克)和另外的乙醇(2.25克)以得到含8.8%PLGA、14.5%DMSO、10.1%乙醇和66.6%SAIB的题述制剂。该制剂保持分为两层。
实施例6:制剂6(可选的制剂方法学)
从低温保存中取出根据实施例2制备的PLGA聚合物,并将其升温至室温。将20.36克65/35PLGA聚合物加入玻璃广口瓶中。向该广口瓶中添加25.45克NMP,并将该广口瓶密封。将该广口瓶固定至旋转混合轮(Glas CoI,Terre Haute,IN)。打开该混合轮从而使该广口瓶在圆周轨迹的外部转动,并且在约80°C下加热直至聚合物溶于NMP中。向聚合物/NMP溶液中添加55.49克SAIB(加热的)。密封该广口瓶并将其固定至旋转混合轮(Glas CoI,Terre Haute,IN)。打开混合轮从而使该广口瓶在圆周轨迹的外部以足以实现混合的速度转动。混合溶液直至实现均匀的制备。制剂组成为55%SAIB、25%NMP和20%PLGA,所有百分比均表示为基于制剂总重量的wt%。放置时,该介质保持澄清并且不表现出任何相分离的迹象。
实施例7:溶解能力试验
将分子量为4700Da、丙交酯/乙交酯比率为65/35并且用己二醇引发的约2.5g PLGA和6.855g SAIB添加至小瓶中(即聚合物与SAIB的重量关系固定)。缓慢添加如下文表2所示的溶剂并于60°C下在Emprotech烘箱中混合制剂,直至形成单一相溶液。然后从烘箱中取出该溶液,并将其在约室温下置于实验桌上约1周。如果溶液相分离,则添加更多的溶剂并在60°C下混合制剂直至形成单一相的溶液,并且其在约室温下置于实验桌上1周仍保持单一相。最终的组成如下文表2的表所示。这种介质的溶解能力为25.61wt%。需要26.44wt%的BA或者42.64wt%的DMSO以实现该溶解能力。
表2(数字为总最终重量的重量百分比)
材料 | 试验A | 试验B | 试验C |
SAIB | 53.86 | 41.99 | 54.55 |
PLGA | 19.70 | 15.37 | 19.84 |
NMP | 25.61 | ||
BA | 26.44 | ||
DMSO | 42.64 |
实施例8:溶解能力试验
将分子量为6600Da、丙交酯/乙交酯比率为65/35并且用十二烷醇引发的约2.5g PLGA和6.855g SAIB添加至小瓶中。缓慢添加如下文表3所示的溶剂并于60°C下在Emprotech烘箱中混合制剂,直至形成单一相溶液。然后从烘箱中取出该溶液,并将其在约室温下置于实验桌上约1周。如果溶液相分离,则添加更多的溶剂并在60°C下混合制剂直至形成单一相的溶液,并且其在约室温下置于实验桌上1周时仍保持单一相。最终组成示于下文表3中。这种介质的溶解能力为17.36wt%。需要19.70wt%的BA或者31.22wt%的DMSO以实现该溶解能力。
表3(数字为总最终重量的重量百分比)
材料 | 试验D | 试验E | 试验F |
SAIB | 58.83 | 50.37 | 60.58 |
PLGA | 21.47 | 18.41 | 22.06 |
NMP | 17.36 | ||
BA | 19.70 | ||
DMSO | 31.22 |
实施例9:纳曲酮制剂
在60°C的Lindberg/Blue M烘箱中,通过在密封瓶中轻轻倒转35分钟,将0.555克PLGA(65/35L/G,用1-十二烷醇引发,通过GPC测得的MW为6400道尔顿,来自Birmingham)与3.620克苄醇(来自J.T.Baker)混合,得到均质的溶液。向该混合物中添加6.094克热SAIB(来自Eastman Chemicals)。通过在室温下轻轻倒转约65小时混合介质。获得了均匀的介质(SAIB/苄醇/PLGA 59.34/35.25/5.40)。向另一瓶中添加0.118克纳曲酮碱(Mallinckrodt)。向该瓶中添加4.205克该介质。通过轻轻倒转约3小时,将纳曲酮溶于该介质中,得到均匀、澄清、浅黄色的溶液。纳曲酮制剂的组成(以基于全部制剂重量的wt%表示)为:
实施例10:利司培酮制剂
将非典型抗精神病药利司培酮按如下方法添加至实施例3的制剂(制剂26)中:
向7.33克制剂26中添加1.095克利司培酮(来自Kemprotec)。将小瓶置于设为30%的Glas-Col旋转轮上约2小时,直至获得均质的悬浮液。所得制剂的组成为48%SAIB、22%NMP、17%PLGA和13%利司培酮,所有百分比均表示为基于制剂总重量的重量百分比。所得介质为稳定的均质悬浮液。
表1:
以下是本发明的其它方面:
1.制剂,其包含:
(i)非聚合、不溶于水、37°C下粘度为至少5,000cP、在环境或生理条件下不均匀结晶的高粘性液体载体材料;
(ii)包含丙交酯重复单元的直链聚合物,其中所述直链聚合物中丙交酯重复单元与全部重复单元的比率为R;以及
(iii)具有溶解能力的一种或多种溶剂;
其中所述直链聚合物的重均分子量小于或等于约15,000道尔顿,并且
其中
(a)R满足如下条件:约0.55≤R≤约0.95;
(b)当R满足如下条件:约0.55≤R≤0.85时,所述一种或多种溶剂的溶解能力大于或等于约20%;以及
(c)当R满足如下条件:大于约0.85至约0.95时,所述一种或多种溶剂的溶解能力大于或等于约10%。
2.项1所述的制剂,其中当R满足如下条件:约0.55≤R≤0.85时,所述一种或多种溶剂的溶解能力大于或等于约25%;并且当R满足如下条件:大于约0.85至约0.95时,所述一种或多种溶剂的溶解能力大于或等于约15%。
3.项2所述的制剂,其中当R满足如下条件:约0.55≤R≤0.85时,所述一种或多种溶剂的溶解能力大于或等于约35%;并且当R满足如下条件:大于约0.85至约0.95时,所述一种或多种溶剂的溶解能力大于或等于约25%。
4.项1所述的制剂,其中所述非聚合、不溶于水、37°C下粘度为至少5,000cP、在环境或生理条件下不均匀结晶的高粘性液体载体材料包括乙酸异丁酸蔗糖酯。
5.项1所述的制剂,其还包含生物活性物质。
6.项5所述的制剂,其中所述生物活性物质包括非典型抗精神病药。
7.项6所述的制剂,其中所述非典型抗精神病药包括利司培酮或其药物可接受的盐或多晶型物。
8.项1所述的制剂,其中所述直链聚合物包括丙交酯-乙交酯共聚物。
9.项1所述的制剂,其中基于所述制剂的总重量,所述直链聚合物以约1wt%至约45wt%的量存在。
10.项9所述的制剂,其中基于所述制剂的总重量,所述直链聚合物以约15wt%至约45wt%的量存在。
11.制剂,其包含:
(i)非聚合、不溶于水、37°C下粘度为至少5,000cP、在环境或生理条件下不均匀结晶的高粘性液体载体材料;
(ii)包含丙交酯重复单元的直链聚合物,其中所述直链聚合物中丙交酯重复单元与全部重复单元的比率为R;以及
(iii)具有溶解能力的一种或多种溶剂;
其中所述直链聚合物的重均分子量小于或等于约15,000道尔顿,并且
其中
(a)R满足如下条件:约0.55≤R≤0.85;以及
(b)所述一种或多种溶剂的溶解能力大于或等于约20%。
12.项11所述的制剂,所述一种或多种溶剂的溶解能力大于或等于约25%。
13.项12所述的制剂,所述一种或多种溶剂的溶解能力大于或等于约35%。
14.项11所述的制剂,其中所述非聚合、不溶于水、37°C下粘度为至少5,000cP、在环境或生理条件下不均匀结晶的高粘性液体载体材料包括乙酸异丁酸蔗糖酯。
15.项11所述的制剂,其还包含生物活性物质。
16.项15所述的制剂,其中所述生物活性物质包括非典型抗精神病药。
17.项16所述的制剂,其中所述非典型抗精神病药包括利司培酮或其药物可接受的盐或多晶型物。
18.项11所述的制剂,其中所述直链聚合物包括丙交酯-乙交酯共聚物。
19.项11所述的制剂,其中基于所述制剂的总重量,所述直链聚合物以约1wt%至约45wt%的量存在。
20.项19所述的制剂,其中基于所述制剂的总重量,所述直链聚合物以约15wt%至约45wt%的量存在。
21.制剂,其包含:
(i)非聚合、不溶于水、37°C下粘度为至少5,000cP、在环境或生理条件下不均匀结晶的高粘性液体载体材料;
(ii)包含丙交酯重复单元的直链聚合物,其中所述直链聚合物中丙交酯重复单元与全部重复单元的比率为R;以及
(iii)具有溶解能力的一种或多种溶剂;
其中所述直链聚合物的重均分子量小于或等于约15,000道尔顿,并且
其中
(a)R满足如下条件:大于约0.85至约0.95;以及
(b)所述一种或多种溶剂的溶解能力大于或等于约10%。
22.项21所述的制剂,其中所述一种或多种溶剂的溶解能力大于或等于约15%。
23.项22所述的制剂,其中所述一种或多种溶剂的溶解能力大于或等于约25%。
24.项21所述的制剂,其中所述非聚合、不溶于水、37°C下粘度为至少5,000cP、在环境或生理条件下不均匀结晶的高粘性液体载体材料包括乙酸异丁酸蔗糖酯。
25.项21所述的制剂,其还包含生物活性物质。
26.项21所述的制剂,其中所述生物活性物质包括非典型抗精神病药。
27.项26所述的制剂,其中所述非典型抗精神病药包括利司培酮或其药物可接受的盐或多晶型物。
28.项21所述的制剂,其中所述直链聚合物包括丙交酯-乙交酯共聚物。
29.项21所述的制剂,其中基于所述制剂的总重量,所述直链聚合物以约1wt%至约45wt%的量存在。
30.项29所述的制剂,其中基于所述制剂的总重量,所述直链聚合物以约15wt%至约45wt%的量存在。
31.制剂,其包含
(i)非聚合、不溶于水、37°C下粘度为至少5,000cP、在环境或生理条件下不均匀结晶的高粘性液体载体材料;
(ii)包含丙交酯重复单元的直链聚合物,其中所述直链聚合物中丙交酯重复单元与全部重复单元的比率为R,其中R满足如下条件:约0.55≤R≤约0.95;以及
(iii)基于所述制剂的总重量,以约1%重量比至高达约35%重量比的量存在的一种或多种溶剂;
其中所述直链聚合物的重均分子量小于或等于约15,000道尔顿,并且
其中所述一种或多种溶剂包括乙醇、乳酸乙酯、碳酸丙烯酯、四氢呋喃聚乙二醇醚、N-甲基吡咯烷酮、2-吡咯烷酮、苯甲酸苄酯、miglyol、丙二醇、丙酮、乙酸甲酯、乙酸乙酯、丁酮、苄醇、三乙酸甘油酯、二甲基甲酰胺、二甲亚砜、四氢呋喃、己内酰胺、癸基甲基亚砜、油酸和/或1-十二烷基氮杂环庚烷-2-酮及以上任何溶剂的组合。
32.项31所述的制剂,其中所述非聚合、不溶于水、37°C下粘度为至少5,000cP、在环境或生理条件下不均匀结晶的高粘性液体载体材料包括乙酸异丁酸蔗糖酯。
33.项31所述的制剂,其还包含生物活性物质。
34.项33所述的制剂,其中所述生物活性物质包括非典型抗精神病药。
35.项34所述的制剂,其中所述非典型抗精神病药包括利司培酮或其药物可接受的盐或多晶型物。
36.项31所述的制剂,其中所述直链聚合物包括丙交酯-乙交酯共聚物。
37.项31所述的制剂,其中基于所述制剂的总重量,所述一种或多种溶剂以约1%重量比至高达30%重量比的量存在。
38.项37所述的制剂,其中基于所述制剂的总重量,所述一种或多种溶剂以约1%重量比至高达约25%重量比的量存在。
39.项31所述的制剂,其中基于所述制剂的总重量,所述直链聚合物以约1wt%至约45wt%的量存在。
40.项39所述的制剂,其中基于所述制剂的总重量,所述直链聚合物以约15wt%至约45wt%的量存在。
Claims (18)
1.制剂,其包含:
(i)非聚合、不溶于水、37°C下粘度为至少5,000cP、在环境或生理条件下不均匀结晶的高粘性液体载体材料;
(ii)包含丙交酯重复单元的直链聚合物,其中所述直链聚合物中丙交酯重复单元与全部重复单元的比率为R;以及
(iii)具有溶解能力的一种或多种溶剂;
其中所述直链聚合物的重均分子量小于或等于15,000道尔顿,并且
其中
(a)R满足如下条件:0.55<R≤0.95;
(b)当R满足如下条件:0.55<R≤0.85时,所述一种或多种溶剂的溶解能力大于或等于20%;以及
(c)当R满足如下条件:大于0.85至0.95时,所述一种或多种溶剂的溶解能力大于或等于10%。
2.如权利要求1所述的制剂,其中当R满足如下条件:0.55<R≤0.85时,所述一种或多种溶剂的溶解能力大于或等于25%;并且当R满足如下条件:大于0.85至0.95时,所述一种或多种溶剂的溶解能力大于或等于15%。
3.如权利要求2所述的制剂,其中当R满足如下条件:0.55≤R<0.85时,所述一种或多种溶剂的溶解能力大于或等于35%;并且当R满足如下条件:大于0.85至0.95时,所述一种或多种溶剂的溶解能力大于或等于25%。
4.如权利要求1所述的制剂,其中R满足如下条件:0.55<R<0.85。
5.如权利要求1至4中任一权利要求所述的制剂,其中所述一种或多种溶剂包括乙醇、乳酸乙酯、碳酸丙烯酯、四氢呋喃聚乙二醇醚、N-甲基吡咯烷酮、2-吡咯烷酮、苯甲酸苄酯、miglyol、丙二醇、丙酮、乙酸甲酯、乙酸乙酯、丁酮、苄醇、三乙酸甘油酯、二甲基甲酰胺、二甲亚砜、四氢呋喃、己内酰胺、癸基甲基亚砜、油酸和/或1-十二烷基氮杂环庚烷-2-酮及以上任何溶剂的组合。
6.制剂,其包含
(i)非聚合、不溶于水、37°C下粘度为至少5,000cP、在环境或生理条件下不均匀结晶的高粘性液体载体材料;
(ii)包含丙交酯重复单元的直链聚合物,其中所述直链聚合物中丙交酯重复单元与全部重复单元的比率为R,其中R满足如下条件:0.55<R≤0.95;以及
(iii)基于所述制剂的总重量,以1%重量比至高达35%重量比的量存在的一种或多种溶剂;
其中所述直链聚合物的重均分子量小于或等于15,000道尔顿,并且
其中所述一种或多种溶剂包括乙醇、乳酸乙酯、碳酸丙烯酯、四氢呋喃聚乙二醇醚、N-甲基吡咯烷酮、2-吡咯烷酮、苯甲酸苄酯、miglyol、丙二醇、丙酮、乙酸甲酯、乙酸乙酯、丁酮、苄醇、三乙酸甘油酯、二甲基甲酰胺、二甲亚砜、四氢呋喃、己内酰胺、癸基甲基亚砜、油酸和/或1-十二烷基氮杂环庚烷-2-酮及以上任何溶剂的组合。
7.如权利要求6所述的制剂,其中基于所述制剂的总重量,所述一种或多种溶剂以1%重量比至高达30%重量比的量存在。
8.如权利要求7所述的制剂,其中基于所述制剂的总重量,所述一种或多种溶剂以1%重量比至高达25%重量比的量存在。
9.如权利要求1或6所述的制剂,其中所述非聚合、不溶于水、37°C下粘度为至少5,000cP、在环境或生理条件下不均匀结晶的高粘性液体载体材料包括乙酸异丁酸蔗糖酯。
10.如权利要求1或6所述的制剂,其还包含生物活性物质。
11.如权利要求10所述的制剂,其中所述生物活性物质包括非典型抗精神病药。
12.如权利要求11所述的制剂,其中所述非典型抗精神病药包括利司培酮或其药物可接受的盐或多晶型物。
13.如权利要求1或6所述的制剂,其中所述直链聚合物包括丙交酯-乙交酯共聚物。
14.如权利要求1或6所述的制剂,其中基于所述制剂的总重量,所述直链聚合物以1wt%至45wt%的量存在。
15.如权利要求14所述的制剂,其中基于所述制剂的总重量,所述直链聚合物以15wt%至45wt%的量存在。
16.如权利要求1或6所述的制剂,其中基于所述制剂的总重量,所述一种或多种溶剂以20%重量比至高达30%重量比的量存在。
17.如权利要求1或6所述的制剂,其中基于所述制剂的总重量,所述直链聚合物以15wt%至35wt%的量存在。
18.如权利要求1或6所述的制剂,其中当在25°C下保持一周时,所述非聚合、不溶于水的高粘性液体载体材料、所述直链聚合物和所述一种或多种溶剂仍为单相。
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