CN107708667A - 长效利拉鲁肽组合物 - Google Patents
长效利拉鲁肽组合物 Download PDFInfo
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- CN107708667A CN107708667A CN201680035536.4A CN201680035536A CN107708667A CN 107708667 A CN107708667 A CN 107708667A CN 201680035536 A CN201680035536 A CN 201680035536A CN 107708667 A CN107708667 A CN 107708667A
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- composition
- copolymer
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- liraglutide
- peg
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- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
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Abstract
本发明涉及一种长效组合物,包含:治疗有效量的利拉鲁肽,包含亲水性和疏水性部分的嵌段共聚物或接枝共聚物或它们的混合物,至少一种亲水脂分子,和水性载体,其中所述组合物是凝胶的形式,可借助于活塞推动通过针头进行注射。在对有需要的对象单次给药后,本发明的组合物提供约6天至约14天,尤其是约一周的有效血糖控制效果。
Description
技术领域
本发明涉及包含利拉鲁肽的长效组合物,其制备方法以及该组合物在治疗代谢性疾病中的用途。
背景技术
糖尿病是一种代谢失调疾病,最突出的是糖代谢异常,并伴有典型的长期并发症。糖尿病是一种慢性疾病,需要长期的药物治疗。市面上有不同的肠道外抗糖尿病药物,包括人胰岛素和不同的GLP-1激动剂。
天然GLP-1是一种胃肠激素,具有治疗1型与2型糖料病和治疗肥胖的潜力。天然GLP-1的半衰期较短,在体内仅有数分钟,这是因为其被二肽基肽酶-4酶快速降解。同样地,胰岛素的半衰期也较短,因此每日向糖尿病患者给药一次或两次。
通过分别改性天然GLP-1和胰岛素已开发出多种GLP-1激动剂和胰岛素类似物,以克服半衰期短的问题。采用的方法之一是取代这些肽的一个或多个氨基酸并附加亲脂性取代基。这些亲脂性取代的GLP-1激动剂和胰岛素或胰岛素类似物注射后表现出持久的作用。
US5750497公开了亲脂性取代的胰岛素,包括地特胰岛素,其中人胰岛素的B29位赖氨酸被酰化为肉豆蔻酸。每日皮下注射给药一次或两次。
US7615532公开了亲脂性取代的胰岛素类似物。一个具体的例子是德谷胰岛素,其中desB30人胰岛素在B29位通过γ-L-谷氨酰基间隔子与十六烷基二酸连接。每日皮下注射给药一次。
US6268343公开了所述脂肪酸酰化的GLP-1激动剂。一个具体的例子包括利拉鲁肽。利拉鲁肽是每日给药一次的人GLP-1类似物(97%同源)。利拉鲁肽是(Arg34,Lys26(Nε-(γ-Glu(N-十六酰基)))-GLP-1(7-37)。在美国,已批准利拉鲁肽每日一次皮下注射,以改善患有2型糖尿病的成年人的血糖控制。在美国还批准利拉鲁肽用于成年病人的体重管理。
WO06/097537公开了酰化的GLP-1类似物,包括索马鲁肽(semaglutide),其为一种每周给药一次的单酰化的GLP-1激动剂(94%同源)。索马鲁肽在8位具有氨基酸取代基(丙氨酸转变为α-氨基异丁酸,一种合成氨基酸)和在34位具有氨基酸取代基(赖氨酸转变为精氨酸),并且具有酰化的肽骨架,其中,间隔子和C-18脂肪二酸链连接到GLP-1第26位的赖氨酸上。索马鲁肽目前正处于第三期临床开发,用于治疗2型糖尿病。
艾塞那肽,一种含有39个氨基酸的肽,是一种改性的GLP-1激动剂,可用于每日两次注射以治疗2型糖尿病。2012年,美国批准了一种用于每周给药一次的艾塞那肽的缓释制剂。这种每周给药一次的制剂由包封在微球内的艾塞那肽组成。US20140220134公开了每月给药一次的艾塞那肽制剂,其利用在中链甘油三酯中包含聚(丙交酯-共-乙交酯)聚合物的缓释微球悬浮液。
然而,仍需要降低病人的注射频率,提供一种用于每周给药一次,优选每月给药一次的长效组合物。
发明内容
发明人已发现GLP-1激动剂的亲脂性衍生物,如利拉鲁肽的长效组合物。具体地,本发明提供一种长效组合物,包含:
a)治疗有效量的利拉鲁肽,
b)包含亲水性和疏水性部分的嵌段共聚物或接枝共聚物,或它们的混合物,
c)至少一种亲水脂分子,和
d)水性载体,
其中,所述组合物是凝胶的形式,可借助于活塞推动通过针头进行注射。更具体地,本发明的所述组合物提供一种利拉鲁肽的长效组合物,用于每周给药一次。
附图说明
图1(a)、(b)、(c)、(d)、(e)示出了利拉鲁肽和艾塞那肽与泊洛沙姆的相互作用。图1(a)示出了在玻璃小瓶中,在注射用水(WFI)中利拉鲁肽与氨丁三醇形成溶液。1(b)示出了泊洛沙姆188在WFI中形成溶液,1(c)示出了利拉鲁肽与氨丁三醇和聚山梨酯80在WFI中形成溶液。1(d)示出了利拉鲁肽与氨丁三醇和泊洛沙姆188在WFI中形成凝胶。1(e)示出了艾塞那肽与泊洛沙姆188在WFI中保留溶液状态而不形成凝胶。
图2(a)、(b)、(c)、(d)、(e)示出了利拉鲁肽和艾塞那肽与的相互作用,图2(a)示出了在玻璃小瓶中,利拉鲁肽与氨丁三醇在WFI中形成溶液,2(b)示出了在WFI中形成溶液,2(c)示出了与氨丁三醇在WFI中形成溶液,2(d)示出了利拉鲁肽与氨丁三醇和在WFI中形成凝胶,2(e)示出了艾塞那肽与在WFI中形成保留溶液状态而不形成凝胶。
图3示出了实施例4的组合物依据实施例6进行分析时的低温透射电子显微镜图像。
图4示出了实施例5的组合物依据实施例6进行分析时的低温透射电子显微镜图像。
图5提供了比较实施例1和实施例4的db/db小鼠的临床前药效数据。
图6至图9提供了db/db小鼠的临床前药效数据,该数据为在28天内每周给药一次实施例4和实施例7的组合物,与每日给药一次的对比,并依据实施例11进行测定。
具体实施方式
本发明提供利拉鲁肽的长效组合物,利用该组合物的治疗方法,以及制备该组合物的方法。本发明的组合物可用于治疗代谢性疾病,例如糖尿病和肥胖。
发明人有利地发现了利拉鲁肽的长效凝胶组合物。该组合物优于诺和力()的优点在于,其以较低的频率给药,从而为患者提供方便并提高患者的依从性,并且进一步地,在一段更长的时间内提供有效的血糖控制效果。本发明的组合物提供一种利拉鲁肽的长效组合物,用于每周给药一次。进一步地,发明人发现本发明的凝胶组合物尽管有很高的稠度,但在通过针头进行注射时仍具有充分的流动特性。进一步地,该组合物在注射位点处恢复其稠度,从而提供对血糖水平的长期控制。
在一方面,本发明提供一种长效组合物,包含:
a)治疗有效量的利拉鲁肽,
b)包含亲水性和疏水性部分的嵌段共聚物或接枝共聚物,或它们的混合物,
c)至少一种亲水脂分子,和
d)水性载体,
其中,上述组合物是凝胶的形式,可借助于活塞推动通过针头进行注射。
在此使用的术语“长效”指的是在此公开和要求保护的利拉鲁肽组合物的作用持续时间。更具体地,指的是给药一剂本发明的利拉鲁肽组合物后,血糖水平被控制的一段时间。在对有需要的对象单次给药后,本发明的组合物提供约6天至约14天的有效血糖控制效果。在一个更优选的实施例中,本发明的组合物在单次给药后提供约一周的有效血糖控制效果,从而该组合物可以每周一次注射给药。
利拉鲁肽在组合物中可以以碱的形式、以其盐的形式或者以它们的混合物存在。盐的典型例子包括与合适的无机酸,诸如盐酸、氢溴酸等形成的盐。盐的典型例子还包括与有机酸,诸如甲酸、乙酸、丙酸、乳酸、酒石酸、抗坏血酸等形成的盐。盐的典型例子还包括与碱,诸如三乙醇胺、二乙胺、葡甲胺、赖氨酸、精氨酸、丙氨酸、亮氨酸、二乙基乙醇胺、乙醇胺、三乙胺、氨丁三醇、胆碱、三甲胺、牛磺酸、苯扎明、甲胺、二甲胺、三甲胺、甲基乙醇胺、丙胺、异丙胺等形成的盐。在一个优选实施例中,可以采用利拉鲁肽乙酸盐的形式。进一步地,术语“利拉鲁肽”还包括利拉鲁肽碱和少量乙酸的混合物,例如,乙酸可以少于利拉鲁肽重量的3%,并且本发明包括这种形式的利拉鲁肽。这些形式的利拉鲁肽已商品化。
本发明组合物中的利拉鲁肽浓度可占组合物总重量的约3%至约20%。优选地,组合物包含利拉鲁肽的浓度为组合物总重量的约3%至约15%。更优选地,利拉鲁肽的浓度为约7%至约10%。值得注意的是,利拉鲁肽本身是由32个氨基酸组成的以亲脂性链衍生化的聚合物,因此其在本发明组合物的粘度特性中起到辅助作用。
可在本发明中使用的嵌段共聚物可以选自聚氧乙烯-聚氧丙烯嵌段共聚物、聚乙烯醇和聚乙二醇共聚物、聚甲基丙烯酸甲酯和聚乙二醇共聚物、聚甲基丙烯酸甲酯和聚甲基丙烯酸共聚物、聚乳酸和聚乙二醇共聚物、聚氧化乙烯-聚丁二烯共聚物、聚氧化乙烯-聚(乙烯乙烯)共聚物、2-甲基丙烯酰氧乙基磷酸胆碱(MPCTM)和甲基丙烯酸正丁酯(BMA)、聚(2-(二甲氨基)甲基丙烯酸乙酯)(PDMAEMA)和聚甲基丙烯酸甲酯(PMMA)、葡聚糖-嵌段-聚(ε-己内酯)(DEX-b-PCL)(两亲性二嵌段共聚物)、PolyVivo mPEG-PLGA二嵌段共聚物、PolyVivo mPEG-PCL二嵌段共聚物、PLGA-嵌段-PEG-嵌段-PLGA(聚乳酸羟基乙酸共聚物-嵌段-聚乙二醇-嵌段-聚乳酸羟基乙酸共聚物)三嵌段共聚物、mPEG-PLLA(甲氧基聚乙二醇-b-聚(L-丙交酯))二嵌段共聚物、mPEG-PDLLA(甲氧基聚乙二醇-b-聚(D,L-丙交酯))二嵌段共聚物、mPEG-PS(甲氧基聚乙二醇-b-聚苯乙烯)二嵌段共聚物、mPEG-P(5BZTMC)(甲氧基聚乙二醇-聚(5-苄氧基-三亚甲基碳酸酯))共聚物、mPEG-PTMC(甲氧基聚乙二醇-聚三亚甲基碳酸酯)共聚物、PCL-PEG-PCL(聚己内酯-b-聚乙二醇-b-聚己内酯)共聚物、PLA-PCL-PEG-PCL-PLA(聚(D,L)丙交酯-b-聚己内酯-b-聚乙二醇-b-聚己内酯-b-聚(D,L)丙交酯)共聚物、PLA-PEG-PLA(聚(D,L-丙交酯)-b-聚乙二醇-b-聚(D,L-丙交酯))共聚物、PDLLA-PEG-PDLLA(聚(D,L-丙交酯)-b-聚乙二醇-b-聚(D,L-丙交酯))共聚物、PEG-PDLLA-Decyl(聚乙二醇-b-聚(D,L-乳酸)-癸基)共聚物、Kollidon VA64聚乙烯吡咯烷酮-乙酸乙烯酯共聚物、聚(N-乙烯基-2-吡咯烷酮)-聚(D,L-丙交酯)、聚(2-乙基-2-恶唑啉)-嵌段-聚(ε-己内酯)共聚物、聚氧化乙烯-聚氧化丁烯二嵌段和三嵌段共聚物、聚苯乙烯-聚氧化乙烯二嵌段和三嵌段共聚物、聚(2-甲基-2-恶唑啉)-b-聚(2-烷基-2-恶唑啉)、聚甲基丙烯酸甲酯-聚氧化乙烯二嵌段共聚物、聚(N-异丙基丙烯酰胺)-聚(γ-苄基-L-谷氨酸酯)、聚氧化乙烯-聚亚甲基丙二酸、聚氧化乙烯-聚丙烯酸、聚氧化乙烯-聚甲基丙烯酸、聚氧化乙烯-聚苯甲酸乙烯酯、聚氧化乙烯-聚(N-异丙基丙烯酰胺)、聚氧化乙烯-聚(2-乙烯基吡啶)、聚乙烯基苯甲醇-聚(低聚(乙二醇)甲基丙烯酸酯)、聚苯乙烯-聚丙烯酸、聚苯乙烯-聚甲基丙烯酸和聚(2-乙氧基乙基乙烯基醚)-聚(2-甲氧基乙基乙烯基醚)或它们的混合物。
在一个优选实施例中,可在本发明组合物中使用的嵌段共聚物可以是聚氧乙烯-聚氧丙烯嵌段共聚物。这种共聚物已商品化为不同品级的泊洛沙姆,如泊洛沙姆105、泊洛沙姆108、泊洛沙姆122、泊洛沙姆123、泊洛沙姆181、泊洛沙姆188、泊洛沙姆212、泊洛沙姆217、泊洛沙姆235、泊洛沙姆237、泊洛沙姆282、泊洛沙姆331、泊洛沙姆338、泊洛沙姆401、泊洛沙姆403和泊洛沙姆407或它们的混合物。在一个优选实施例中,上述嵌段共聚物可以是泊洛沙姆188。
接枝共聚物可以选自聚乙烯己内酰胺-聚乙酸乙烯酯-聚乙二醇接枝共聚物,即市售商品、PUREBRIGHT mb-37-50T和PUREBRIGHT mb-37-100T(2-甲基丙烯酰氧乙基磷酸胆碱(MPCTM)和甲基丙烯酸正丁酯(BMA))共聚物、Kollicoat(PVA-PEG接枝共聚物)、聚(苯乙烯-共-甲基丙烯酸甲酯-共-马来酸酐)和聚(氧化乙烯)甲醚接枝共聚物、聚乙烯醇-聚乙二醇接枝共聚物和聚(N-异丙基丙烯酰胺)-b-[聚丙烯酸乙酯-g-聚(2-乙烯基吡啶)]或它们的混合物。在一个优选实施例中,上述接枝共聚物可以是基于聚乙烯己内酰胺-聚乙酸乙烯酯和聚乙二醇的接枝共聚物。
所用的嵌段共聚物或接枝共聚物的浓度应足以使本发明的组合物具有类似粘性凝胶的稠度,优选半固态的稠度。发明人发现本发明的凝胶组合物尽管有很高的稠度,但在通过针头进行注射时仍具有充分的流动特性。在注射位点处,组合物恢复其稠度,并提供长期的血糖水平控制效果。上述嵌段共聚物或接枝共聚物的浓度为组合物重量的1%至5%。更优选地,聚氧乙烯-聚氧丙烯嵌段共聚物的浓度为组合物重量的1.5%至3%。
在此使用的术语“亲水脂分子”指的是同时含有亲水性基团和疏水性(亲脂性)基团的化合物。适合用于本发明组合物中的亲水脂分子包括但不限于,甘油单酯和甘油二酯、聚甘油化脂肪酸、聚乙氧基化脂肪酸、PEG脂肪酸单酯和二酯及它们的混合物、PEG甘油脂肪酸酯、醇油酯交换产品、丙二醇脂肪酸酯、丙二醇酯和甘油酯的混合物、PEG失水山梨醇脂肪酸酯、PEG烷基醚、PEG烷基酚、和失水山梨醇脂肪酸酯。
在本发明组合物中作为亲水脂分子使用的甘油单酯、甘油二酯和甘油三酯的例子是甘油单油酸酯、甘油单月桂酸酯、甘油单棕榈酸酯、单硬脂酸甘油酯、乙酸甘油酯、月桂酸甘油酯、甘油辛酸酯、癸酸甘油酯、单硬脂酸甘油酯、甘油二油酸酯、辛酸单甘油酯、辛酸二甘油酯、二癸酸甘油酯、豆莞酸二甘油酯、甘油二棕榈酸酯、甘油二月桂酸酯、甘油三油酸酯、三硬脂酸甘油酯和脂肪酸的甘油酯类。
在本发明组合物中作为亲水脂分子使用的聚甘油化脂肪酸的例子是聚甘油-2,4,10硬脂酸酯、聚甘油-2,3,4,6,10油酸酯、聚甘油-2异硬脂酸酯、聚甘油-10月桂酸酯、聚甘油-6蓖麻油酸酯、聚甘油-10亚油酸酯、聚甘油-2,3二油酸酯、聚甘油-3二硬脂酸酯和聚甘油-10三油酸酯。
在本发明组合物中作为亲水脂分子使用的聚乙氧基化脂肪酸的例子是PEG 1-10硬脂酸酯、PEG 2油酸酯、PEG 4月桂酸酯、PEG 4-100单油酸酯、PEG 4单硬脂酸酯。
在本发明组合物中作为亲水脂分子使用的PEG-脂肪酸二酯及其与单酯的混合物的例子是月桂酸、油酸、硬脂酸、棕榈酸与不同品级PEG的二酯,例如PEG-4二月桂酸酯、PEG-4-二油酸酯、PEG-4二硬脂酸酯、PEG-10二棕榈酸酯、PEG-6二月桂酸酯、PEG-6二油酸酯、PEG-6二硬脂酸酯、PEG-8二月桂酸酯、PEG-8二油酸酯、PEG-8二硬脂酸酯、PEG-12二月桂酸酯、PEG-12二油酸酯、PEG-12二硬脂酸酯、PEG-32二月桂酸酯、PEG-32二油酸酯、PEG-32二硬脂酸酯。
在本发明组合物中作为亲水脂分子使用的PEG甘油脂肪酸酯的例子是月桂酸、油酸、硬脂酸与不同品级的PEG形成的酯,例如PEG-15甘油月桂酸酯、PEG-20甘油月桂酸酯、PEG-20甘油硬脂酸酯、PEG-20甘油油酸酯和PEG-15甘油油酸酯。
在本发明组合物中作为亲水脂分子使用的醇油酯交换产品的例子是PEG-5-10蓖麻油、PEG-5,7,10氢化蓖麻油、PEG-6花生油、PEG-6核油、PEG-6玉米油、PEG-20玉米油甘油酯、PEG-8和6辛酸/癸酸甘油酯、季戊四醇四异硬脂酸酯、季戊四醇二硬脂酸酯、季戊四醇四油酸酯、季戊四醇四硬脂酸酯、季戊四醇四辛酸酯/四癸酸酯。
在本发明组合物中作为亲水脂分子使用的丙二醇脂肪酸酯的例子是丙二醇单辛酸酯、丙二醇单月桂酸酯、丙二醇油酸酯、丙二醇豆蔻酸酯、丙二醇蓖麻油酸酯、丙二醇二辛酸酯/二癸酸酯、丙二醇二辛酸酯、丙二醇二月桂酸酯、丙二醇二硬脂酸酯和丙二醇二辛酸酯。
在本发明组合物中作为亲水脂分子使用的丙二醇酯和甘油酯混合物的例子是油酸和硬脂酸的酯类。
在本发明组合物中作为亲水脂分子使用的PEG失水山梨醇脂肪酸酯的例子是PEG-4,6,10失水山梨醇单月桂酸酯、PEG-10失水山梨醇单棕榈酸酯、PEG-4,6,8,10失水山梨醇单硬脂酸酯、PEG-5,6,10失水山梨醇单油酸酯、PEG-6失水山梨醇四油酸酯、PEG-6失水山梨醇四硬脂酸酯、PEG失水山梨醇六油酸酯、PEG失水山梨醇六硬脂酸酯。
在本发明组合物中作为亲水脂分子使用的PEG烷基醚的例子是PEG油基醚、PEG月桂基醚、PEG十六烷基醚和PEG十八烷基醚。
在本发明组合物中作为亲水脂分子使用的PEG烷基酚的例子是PEG-10壬基苯酚和PEG-15辛基酚醚。
在本发明组合物中作为亲水脂分子使用的失水山梨醇脂肪酸酯的例子是失水山梨醇单棕榈酸酯、失水山梨醇单油酸酯、失水山梨醇单硬脂酸酯、失水山梨醇单月桂酸酯、失水山梨醇三油酸酯、失水山梨醇三硬脂酸酯、失水山梨醇倍半硬脂酸酯和失水山梨醇倍半油酸酯。
适合用于本发明组合物中的亲水脂分子还可以包括磷脂。本发明中使用的磷脂从植物源、动物源或合成源获得。天然磷脂可以从蔬菜源,如大豆、油菜(油菜籽)种子、小麦胚芽,和动物原料,如蛋黄、牛奶等获得。天然磷脂的例子是大豆卵磷脂、蛋卵磷脂、酶改性的天然磷脂如单酰基-磷脂酰胆碱(lyso PC)、大豆PE、大豆PG、蛋PG、和饱和类似物。合成磷脂的例子是PEG(聚乙二醇)化的磷脂和阳离子磷脂1,2-二酰基-P-O-乙基磷脂酰胆碱或它们的混合物。半合成磷脂的例子包括二棕榈酰磷脂酰胆碱(DPPC)、1-棕榈酰-2-油酰磷脂酰胆碱(POPC)、二油酰磷脂酰胆碱(DOPC)、二亚油酰基磷脂酰胆碱(DLiPC)、溶血磷脂酰胆碱(LPC)、1-棕榈酰-LPC(PaLAC)、1-油酰-LPC(OiLPC)、磷脂酰乙醇胺(PE)、缩醛磷脂酰乙醇胺(PlaE)、缩醛磷脂酰乙醇胺的甘油缩醛(GAPlaE)、双十二烷基磷脂酰乙醇胺(DDPE)、二反油酰基磷脂酰乙醇胺(DEPE)、二油酰磷脂酰乙醇胺(DOPE)、二亚麻油酰磷脂酰乙醇胺(DLiPE)、二油酰磷脂酰-N-单甲基乙醇胺(DOPE-Me)、二磷脂酰甘油(DPG)、磷脂酰甘油(PG)、磷脂酰丝氨酸(PS)、磷脂酰肌醇(PI),优选的磷脂包括磷脂酰胆碱。优选的磷脂酰胆碱是大豆磷脂酰胆碱(SPC)或它们的混合物。
适合用于本发明组合物中的亲水脂分子可以包括非离子和两性离子表面活性剂、甘油单酯和鞘脂类和磷脂,正如Fontell等人(Colloidal&Polymer Science,268:264-285(1990))公开的。
本发明组合物可以皮下给药,并且优选地包含亲水脂分子,该亲水脂分子是甘油单油酸酯、甘油二油酸酯、甘油三油酸酯和磷脂酰胆碱的混合物。更优选地,使用药典级市售的商品名为的亲水脂分子。通过源自植物的甘油与植物源的脂肪酸的酯化反应制备948,其包含40%理论含量的甘油单酯,比例为甘油单酯(32.0-52.0%)、甘油二酯(30.0-50.0%)和甘油三酯(5.0-20.0%)。
依据以下理论含量的甘油单酯,可以有不同比例的甘油单酯、甘油二酯和甘油三酯混合物,可提供为不同品级的
通常,在本发明组合物中,磷脂与甘油单酯、甘油二酯和甘油三酯混合物的重量比为50:50。另一方面,在本发明组合物中,磷脂与甘油二酯例如甘油二油酸酯的重量比的范围为20:60至30:70。
在本发明中,上述亲水脂分子的浓度为组合物重量的50%至80%,优选地,为组合物重量的60%至70%。
本发明组合物包含水性载体。水性载体包括用于溶解水溶性或水混溶性成分的水,和至少一种用于溶解亲水脂分子尤其是不溶于水的亲水脂分子的水混溶性溶剂。上述水性载体是水和水混溶性溶剂的混合物。适合用于本发明组合物中的水性载体包括但不限于水、醇类、醚类、酯类和酮类或它们的混合物。醇类可以包括一类载体,且包括单醇、二元醇和多元醇,例如乙醇、甘油或丙二醇。合适的醚类可以包括二***、三缩四乙二醇、二乙二醇和聚乙二醇。优选地,水性载体选自水、乙醇、丙二醇、三缩四乙二醇和它们的混合物。与常规液体和半固态组合物不同,本发明组合物含有的液体载体浓度低于本发明其他成分的总浓度。水性载体的浓度为组合物重量的20%至40%,优选地,为组合物重量的25%至35%。本发明组合物可以含有水,其浓度为组合物重量的10%至25%,优选地,为组合物重量的14%至21%。上述这些含有低浓度的水性载体或水、可用作长效组合物的利拉鲁肽药学组合物在本领域中不为人所知。
本发明组合物还可以包含pH调节剂。在此使用的术语“pH调节剂”指的是可以改变溶液pH值的化合物。pH调节剂的例子包括但不限于:NaOH、KOH、Na2CO3、NaHCO3、K2CO3、KHCO3、NaH2PO4、Na2HPO4、葡甲胺、Ca(OH)2、Mg(OH)2、吡哆醇、三乙醇胺、氢氧化铵、胞嘧啶、二乙胺、葡甲胺、鸟氨酸、甘氨酸、赖氨酸、精氨酸、天冬氨酸、丙氨酸、亮氨酸、二乙基乙醇胺、鸟嘌呤、烟酰胺、哌嗪、胍、乙醇胺、哌啶、三乙胺、氨丁三醇、苯乍生、苯乍生、腺嘌呤、它们的混合物;和酸,包括盐酸等矿物酸和乙酸等有机酸。用于本发明组合物中的优选的pH调节剂包括氨丁三醇或乙酸。
在另一个实施例中,本发明提供一种组合物的制备方法,包括:
a)制备第一相,包括在水中溶解治疗有效量的利拉鲁肽和嵌段共聚物或接枝共聚物或它们的混合物,该第一相形成凝胶;
b)制备第二相,包括在水混溶性溶剂或其混合物中溶解亲水脂分子或其混合物;和
c)将步骤b)的第二相添加到步骤a)的第一相中形成凝胶组合物。
制备本发明组合物的步骤a)包括在注射用水中溶解治疗有效量的利拉鲁肽和嵌段共聚物或接枝共聚物或它们的混合物,以制备水相。利用制药工业中的常规技术制备上述水相,包括视情况溶解和混合适宜成分以获得期望的最终产品。上述水相形成凝胶。
制备本发明组合物的方法中的步骤b)包括在水混溶性溶剂或其混合物中溶解亲水脂分子或其混合物,以制备第二相。在60-70℃的温度下,于搅拌条件下在水混溶性溶剂中溶解亲水脂分子。这个过程包括使用搅拌器的常规混合方法。通常,将需要量的溶剂装入配备有搅拌器的容器中。在搅拌的同时缓慢加入亲水脂分子,同时维持混合物的温度为60-70℃。可选地,可以通过无菌过滤,优选通过0.2μ的膜滤器过滤,以消毒上述第二相。
上述方法中的步骤c)包括通过搅拌,将步骤b)的包含亲水脂分子的第二相添加到步骤a)的水相中,以形成凝胶。
在一个优选实施例中,本发明组合物可以通过以下方法制备:在注射用水中溶解治疗有效量的利拉鲁肽、氨丁三醇和泊洛沙姆-观察到上述利拉鲁肽组合物当与水接触时形成凝胶相。例如,当利拉鲁肽与氨丁三醇和泊洛沙姆-188或混合时,在水中形成凝胶。上述利拉鲁肽溶液的凝胶相分别示于图1(d)和图2(d)。
在另一个优选实施例中,本发明组合物可以通过以下方法制备:
a)制备第一相,包括在注射用水中溶解治疗有效量的利拉鲁肽、氨丁三醇和泊洛沙姆-
b)制备第二相,包括将甘油单油酸酯或甘油单油酸酯的混合物、甘油二油酸酯、甘油三油酸酯和磷脂酰胆碱,与乙醇和丙二醇混合;
c)将第二相添加到第一相中。
本发明的组合物在以下方面非常有利,可以使治疗有效水平的利拉鲁肽维持超过6天至14天。特别的实施例是每周一次给药。给予治疗有效量的上述组合物使血糖水平从基线水平明显下降。进一步地,平均血糖下降与相当或优于
进一步地,本发明的组合物还有效地降低HblAc水平和增加β细胞群。另外,本发明的组合物还有效地降低体重。因此,本发明的组合物可用于预防或治疗2型糖尿病、高血糖症或葡萄糖耐量降低以及用于治疗肥胖等代谢性疾病。
本发明组合物可以注射给药。在另一个实施例中,本发明组合物可以皮下注射或肌肉注射给药。
实施例
下文将详细说明本发明组合物的实施例。然而,需要注意的是本发明不限于这些说明性例子,还可以以多种其他方式实现。
比较例1
组合物制备方法:
(A)第I相:在注射用水(20mg)中溶解利拉鲁肽(5mg)、氨丁三醇(0.5mg)和聚山梨酯-80(2.5mg),并保存于20-25℃。
(B)第II相:大豆磷脂酰胆碱(SPC)(42.5mg)、甘油油酸酯(单油酸酯、二油酸酯和三油酸酯以及游离脂肪酸的混合物)(甘油单油酸酯(GMO):甘油二油酸酯(GDO):甘油三油酸酯(GTO)=44:42:9)(42.5mg)、丙二醇(5mg)和乙醇(10mg),在60-70℃的温度下于搅拌条件下混合和溶解15-20分钟。
(C)第III相:浓缩凝胶相(第I相与第II相的混合物):在60-70℃的温度下于搅拌条件下将第II相添加到第I相中,形成浓缩凝胶相。
实施例2
研究酰化和非酰化GLP-1激动剂与聚氧乙烯-聚氧丙烯嵌段共聚物的相互作用,酰化GLP-1激动剂如利拉鲁肽在水性载体中与聚氧乙烯-聚氧丙烯嵌段共聚物形成凝胶。然而,非酰化GLP-1激动剂如艾塞那肽在水性载体中则不形成凝胶,仍保留为溶液相,如图1(a)-1(e)所示。
实施例3
研究酰化和非酰化GLP-1激动剂与聚乙烯聚乙烯己内酰胺-聚乙酸乙烯酯-聚乙二醇接枝共聚物,的相互作用,酰化GLP-1激动剂如利拉鲁肽在水性载体中与形成凝胶。然而,非酰化GLP-1激动剂如艾塞那肽在水性载体中则不形成凝胶,仍保留为溶液相,如图2(a)-2(e)所示。
实施例4
组合物制备方法:
(A)第I相:在注射用水(20mg)中溶解利拉鲁肽(5mg)、氨丁三醇(0.5mg)和泊洛沙姆-188(2.5mg),并保存于20-25℃。
(B)第II相:大豆磷脂酰胆碱(90G)(42.5mg)、甘油油酸酯(单油酸酯、二油酸酯和三油酸酯以及游离脂肪酸的混合物)(甘油单油酸酯(GMO):甘油二油酸酯(GDO):甘油三油酸酯(GTO)=44:42:9)(948)(42.5mg)、丙二醇(5mg)和乙醇(10mg),在60-70℃的温度下于搅拌条件下混合和溶解15-20分钟。
(C)第III相:浓缩凝胶相(第I相与第II相的混合物):在50-70℃的温度下于搅拌条件下将第II相添加到第I相中,形成浓缩凝胶相。该脂质凝胶呈黄色,粘性为半固态稠度。
实施例5
组合物制备方法:
(A)第I相:在注射用水(20mg)中溶解利拉鲁肽(5mg)、氨丁三醇(0.5mg)和泊洛沙姆-188(2.5mg),并保存于20-25℃。
(B)第II相:甘油单油酸酯(85mg)、丙二醇(5mg)和乙醇(10mg),在60-70℃的温度下于搅拌条件下混合和溶解15-20分钟。
(C)第III相:浓缩凝胶相(第I相与第II相的混合物):在50-70℃的温度下于搅拌条件下将第II相添加到第I相中,形成浓缩凝胶相。
实施例6
利用透射电子显微镜(TEM)技术检查实施例4和实施例5的凝胶组合物当分散于WFI中时的形态。
利用FEI’s Tecnai(TM)Spirit低温透射电子显微镜进行形态学研究。将凝胶分散剂样品滴落在标准碳包铜网格(网状物)上并空气干燥。在120kV的加速电压下运行的透射电子显微镜下观察TEM图像,并进行分析。
实施例4和实施例5的凝胶组合物显示当凝胶分散于注射用水时形成立方结构(示于图3和图4)。
实施例7
根据与实施例4相同的方法制备凝胶组合物。该凝胶呈黄色,粘性为半固态稠度。
实施例8
根据与实施例4相同的方法制备凝胶组合物。该凝胶呈黄色,粘性为半固态稠度。
实施例9
根据与实施例4相同的方法制备凝胶组合物。当根据实施例10进行测试时,该组合物在多达8.5天的持续时间内提供对血糖水平的控制。
实施例10
对患有2型糖尿病的db/db小鼠模型进行临床前药效研究。这些动物经过5天适应。第0天称重每只动物。从后眼窝丛采集约100μL血液以测定基线值,利用血糖试纸血糖仪(One TouchTM UltraTM;美国强生集团理康公司)测量血液中的葡萄糖浓度。动物随机分入处理组,每组包括4只雄性动物和4只雌性动物。根据动物各自的体重计算用于每只动物的剂量体积。在动物颈部皮下注射单剂/多剂比较例1和实施例4的组合物。在注射后以特定的时间间隔采集血液。血糖水平测定如下。利用PRISM软件进行统计分析。据观察,与比较例1相比,实施例4提供显著更好的血糖降低效果7天,如图5所示。
实施例11
根据实施例10说明的过程进行临床前药效研究。实施例4和实施例7的组合物与相对比。在28天内每日注射其人体等效剂量为0.3mg/kg(1.8mg是的最大允许剂量)。在注射后以0天(0、2、6、12小时)、1天、2天、4天、6天、7天、10天、14天(0、2、6、12小时)、15天、17天、21天、24天、28天(0、2、6、12小时)和29天的时间间隔采集血液,并测量血糖水平。在第0、7、14和21天时(即每周)注射10mg/kg利拉鲁肽(5倍人体等效剂量)剂量的实施例4和实施例7的组合物。在注射后以0天(l小时、4小时、8小时、1天、2天、4天、7天预剂量)、7天(l小时、4小时、8小时、8天、9天、12天、14天预剂量)、14天(l小时、4小时、8小时、15天、17天、19天、21天预剂量)和21天(l小时、4小时、8小时、22天、23天、25天、28天的时间间隔采集血液,并测量血糖水平。在不同的时间间隔测量体重。利用试剂盒(血红蛋白ACl试剂盒,BioSystem公司,西班牙)在研究开始时和结束时(28天)测量HbAlc。在最后的时间点后,通过二氧化碳窒息处死所有的动物。采集所有动物的胰腺并称重。然后将组织放入一个装有10%缓冲***和转移切片的试管中。然后用醛复红染色技术染色组织切片,以染色β细胞。利用光学显微镜进行β细胞计数,并计算每毫克胰腺的β细胞群(每毫克胰腺组织的β细胞总数)。
实施例4和实施例7的组合物和溶液()显示在多达4周内显著降低血糖水平百分比。Vicotza降低的平均血糖百分比为25%,而本发明组合物降低约31%,如图6和下表所示。
实施例7和实施例4的组合物和溶液()显示,在进行4周处理后,与安慰剂相比,体重分别减少5.8gm、3.8gm和2.83gm。因此,与日用溶液()相比,本发明组合物更有效地减少体重,如图7所示。
HbAlc结果示于图8,也证明本发明组合物降低HbAlc值的功效。与安慰剂相比,实施例7、实施例4和分别降低HbAlc 2.72%、1.83%和1.59%。
在开始时和结束时(28天)测量β细胞群的增加。实施例7和实施例4的组合物和溶液()分别显示,在进行4周处理后,与安慰剂相比,每毫克胰腺的β细胞总数分别增加7、6和1.9,如图9所示。
Claims (13)
1.一种长效组合物,包含:
a)治疗有效量的利拉鲁肽,
b)包含亲水性和疏水性部分的嵌段共聚物或接枝共聚物,或它们的混合物,
c)至少一种亲水脂分子,和
d)水性载体,
其中,所述组合物是凝胶的形式,借助于活塞推动通过针头进行注射。
2.根据权利要求1所述的组合物,其特征在于,利拉鲁肽的浓度为所述组合物重量的3%至15%。
3.根据权利要求2所述的组合物,其特征在于,所述嵌段共聚物选自聚氧乙烯-聚氧丙烯嵌段共聚物、聚乙烯醇和聚乙二醇共聚物、聚乳酸和聚乙二醇共聚物、聚氧化乙烯-聚丁二烯共聚物、聚氧化乙烯-聚(乙烯乙烯)共聚物、葡聚糖-嵌段-聚(ε-己内酯)共聚物。
4.根据权利要求3所述的组合物,其特征在于,所述嵌段共聚物是聚氧乙烯-聚氧丙烯嵌段共聚物。
5.根据权利要求4所述的组合物,其特征在于,所述嵌段共聚物是泊洛沙姆188。
6.根据权利要求4所述的组合物,其特征在于,所述聚氧乙烯-聚氧丙烯嵌段共聚物的浓度为所述组合物重量的1.5%至3%。
7.根据权利要求2所述的组合物,其特征在于,所述接枝共聚物是聚乙烯聚乙烯己内酰胺-聚乙酸乙烯酯-聚乙二醇接枝共聚物。
8.根据权利要求2所述的组合物,其特征在于,所述亲水脂分子的浓度为所述组合物重量的50%至80%。
9.根据权利要求2所述的组合物,其特征在于,所述亲水脂分子选自甘油单油酸酯、甘油二油酸酯、甘油三油酸酯、聚甘油-3-二油酸酯、磷脂酰胆碱和它们的混合物。
10.根据权利要求9所述的组合物,其特征在于,所述亲水脂分子是甘油单油酸酯、甘油二油酸酯、甘油三油酸酯和磷脂酰胆碱的混合物。
11.根据权利要求2所述的组合物,其特征在于,所述水性载体的浓度为所述组合物重量的20%至40%。
12.根据权利要求11所述的组合物,其特征在于,所述水性载体是水和水混溶性溶剂的混合物。
13.根据权利要求12所述的组合物,其特征在于,水的浓度为所述组合物重量的10%至25%。
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