CN115554292A - 医药组成物及降低血糖量和治疗与升糖素相关的病症的方法 - Google Patents
医药组成物及降低血糖量和治疗与升糖素相关的病症的方法 Download PDFInfo
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Abstract
本发明提供了一种医药组成物,包含:一式(I)的活性成分或其药学上可接受的盐类或溶剂合物,以8重量%至30重量%的量存在:
Description
技术领域
本发明涉及包含升糖素受体拮抗剂的医药组成物及用于降低血糖量和治疗与升糖素相关的病症的方法。
背景技术
ALP001E是一种升糖素受体拮抗剂,且用于治疗糖尿病。ALP001E是生物药剂学分类系统(Biopharmaceutical classification system,BCS)中第II类药物,表示水溶性差但膜渗透性佳。它在固态下稳定且对光照射不敏感。然而,ALP001E在水份存在下主要通过水解途径(hydrolytic pathway)降解。它也对酸或碱性环境敏感。
由于ALP001E的这些物理化学和生物药学特性,已经进行了数种尝试以提供稳定的ALP001E组成物,以及提供理想的体外释放及生体可用率(bioavailability)。
因此,期望提供一种包含ALP001E的新颖医药组成物,以使ALP001E可应用于临床。
发明内容
本发明涉及一种新颖医药组成物,包含一升糖素受体拮抗剂ALP001E,其具有良好的稳定性和期望的体外或体内表现。
本发明的一实施例涉及一种医药组成物,包含:一下式(I)的活性成分或其药学上可接受的盐类或溶剂合物,以8重量%至30重量%的量存在:
二或多种赋形剂,以70重量%至92重量%的量存在,其中,该赋形剂至少包含一分散剂和一助溶剂。
除了上述式(I)的活性成分外,当适用时,他们药学上可接受的盐类和溶剂合物也涵盖在本发明中。可以在阴离子与化合物上带正电荷的基团(例如胺基)之间形成盐类。合适的阴离子的例子包含氯、溴、碘、硫酸盐、硝酸盐、磷酸盐、柠檬酸盐(citrate)、甲磺酸盐(methanesulfonate)、三氟醋酸盐(trifluoroacetate)、醋酸盐、苹果酸盐(malate)、甲苯磺酸盐(tosylate)、酒石酸盐(tartrate)、延胡索酸盐(fumurate)、麸胺酸盐(glutamate)、葡萄糖醛酸盐(glucuronate)、乳酸盐(lactate)、戊二酸盐(glutarate)和顺丁烯二酸盐(maleate)。也可以在阳离子与带负电荷的基团之间形成盐类。合适的阳离子的例子包含钠离子、钾离子、镁离子、钙离子和铵阳离子,例如四甲基铵离子。盐类进一步包含那些含有四级氮原子的盐类。溶剂合物是指在活性化合物和药学上可接受的溶剂之间形成的复合物,药学上可接受的溶剂的例子包含水、乙醇、异丙醇、乙酸乙酯、乙酸和乙醇胺(ethanolamine)。
本发明的另一实施例涉及一种用于降低主体血糖量的方法,包含向有需要的主体施用上述医药组成物。
本发明的另一实施例涉及治疗与升糖素相关的病症的方法,包含向有需要的主体施用上述医药组成物。
本发明的医药组成物可以口服、肠胃外(parenterally)、通过吸入式喷雾(inhalation spray)、局部、直肠、鼻、颊、或通过植入贮存器(implanted reservoir)的方式给予主体。本文所用术语“肠胃外”包括皮下(subcutaneous)、皮内(intracutaneous)、静脉内(intravenous)、肌肉内(intramuscular)、关节内(intraarticular)、动脉内(intraarterial)、滑囊(腔)内(intrasynovial)、胸骨内(intrasternal)、鞘内(intrathecal)、疾病部位内(intralesional)和头颅内(intracranial)注射或灌注技术(infusion technique)
在本发明中,医药组成物可以是口服医药组成物,其可以是任何口服可接受剂型,包含胶囊、锭剂、乳剂和水性悬浮液、分散液和溶液。口服固体剂型可以通过喷雾干燥技术、热熔挤出法(hot melt extrusion strategy)、微粉化法(micronization)及奈米研磨法(nano milling technologies)制备。另外,医药组成物可以是鼻喷雾剂或吸入剂组成物,其可依据医药剂型领域已知的技术制备。或者,本发明的医药组成物也可以栓剂的形式用于直肠给药。
在意义上来说,医药组成物中的赋形剂必须是“可接受的”,它与组成物的活性成分是可兼容的(且较佳为可稳定活性成分),且对治疗的主体无害。
术语“治疗”是指为了治愈、缓和(alleviate)、缓解(relieve)、改变、补救、改善、或影响疾病、症状或倾向(predisposition)的目的而将活性成分投予或施用于一主体。“有效剂量”是指对主体达到期望的效果而需要的活性成分的量。如本领域技术人员所知,有效剂量可根据投药路径、赋形剂使用、及与其他药物治疗(如使用其他活性剂)共同使用的可能性而有所改变。
除非另有说明,否则本文所述术语“重量百分比”(即重量%和”wt%”和”w/w”)是基于医药组成物的总重量计算。
本发明的一个或多个实施例的细节详述如下,通过说明书及权利要求书可显而亦知本发明的其他特征、目的、及优点。
具体实施方式
以下详细发明一种医药组成物,包含:一式(I)的活性成分或其药学上可接受的盐类或溶剂合物,以8重量%至30重量%的量存在:
二或多种赋形剂,以70重量%至92重量%的量存在,其中,该赋形剂至少包含一分散剂和一助溶剂。
本发明提供一种ALP001E的新颖医药组成物,其包含二或多种赋形剂,其中该赋形剂至少包含分散剂和助溶剂。本发明提供的医药组成物是化学和多形态(polymorphically)稳定的。另外,本发明的医药组成物展现出期望的体外和体内表现,且可通过简单、无须繁琐且具成本效益的过程制备,例如喷雾干燥法。此外,本发明提供的医药组成物的干粉通过特定配方比例和制程参数具有可接受的溶解度和增加的口服吸收,这可以实现进入GMP制药业的可能性。
在本发明的医药组成物中,赋形剂可选择性地还包含:黏合剂、稀释剂、崩散剂(disintegrant)、乳化剂、填充剂、助滑剂(glidant)、润滑剂(lubricant)、塑化剂、增稠剂或润湿剂。
黏合剂的例子可包含纤维素(例如乙基纤维素、乙酸纤维素、羧甲基纤维素钙(carboxymethyl cellulose calcium)、羧甲基纤维素钠(sodium carboxymethylcellulose)、甲基纤维素、羟乙基纤维素(HEC)、羟丙基纤维素(HPC)、羟丙基甲基纤维素(HPMC))、交联聚合物(例如聚乙烯基己内酰胺-聚乙烯基醋酸-聚乙二醇接枝共聚物(Soluplus))、明胶、微晶纤维素(microcrystalline cellulose)、天然及合成树胶(gum)(例如阿拉伯胶(acacia)、海藻酸(alginic acid)、海藻酸盐、爱尔兰苔(Irish moss)的萃取物、潘沃胶(panwar gum)、甘地胶(ghatti gum)、伊沙贝果外壳的黏液(mucilageofisabgol husks)、羧甲基纤维素(carboxymethylcellulose)、甲基纤维素、聚乙烯吡咯烷酮(PVP)、维格姆(Veegum)、落叶松阿拉伯半乳聚糖(larch arabogalactan)、粉末状黄蓍(powdered tragacanth)和瓜尔胶(guar gum))、淀粉(例如玉米淀粉、马铃薯淀粉、预糊化淀粉(pre-gelatinized starch)、部分预糊化玉米淀粉(Pre-gelatinized maizestarch))、醣类(例如蔗糖、葡萄糖、右旋糖、糖蜜和乳糖)、或其组合,但本发明并不局限于此。
稀释剂的例子可包含硫酸钙、纤维素、磷酸氢钙(dibasic calcium phosphate)、干淀粉(dry starch)、肌醇(inositol)、高岭土、乳糖、甘露醇(mannitol)、微晶纤维素、糖粉、氯化钠、山梨醇、淀粉(starch)(例如直接压缩淀粉和水解淀粉)、蔗糖、或其组合,但本发明并不局限于此。
崩解剂(disintegrant)的例子可包含洋菜(agar)、海藻酸、海藻酸盐、褐藻胶(aligns)、皂土(bentonite)、碳酸钙、阳离子交换树脂、纤维素(例如甲基纤维素和羧甲基纤维素)、柑橘渣(citrus pulp)、黏土、交联纤维素(例如交联羧甲基纤维(croscarmellose)和交联羧甲基纤维素钠(croscarmellose sodium))、交联聚合物(例如交联聚乙烯吡咯烷酮(crospovidone))、交联淀粉、树胶(例如瓜尔胶(guar gum)和维格姆HV(Veegum HV))、微晶纤维素(例如各种形式的淀粉乙醇酸钠盐(sodium starchglycolate))、天然海棉、波拉克林钾(polacrilin potassium)、淀粉(例如玉米淀粉、马铃薯淀粉、树薯淀粉(tapioca starch)和预糊化淀粉)、木制品(wood products)或其组合,但本发明并不局限于此。
分散剂(dispersant)的例子可包含阿拉伯胶、羟丙基甲基纤维素、羟丙基甲基纤维素醋酸琥珀酸酯(hypromellose acetate succinate,HPMCAS)、果胶、聚乙烯吡咯烷酮(polyvinylpyrolidone))、羧甲基纤维素钠(sodium carbomethylcellulose)、羧甲基纤维素钠(sodium carboxymethylcellulose)、黄蓍胶(tragacanth)、维格姆或其组合,但本发明并不局限于此。
乳化剂的例子可包含阿拉伯胶、皂土、明胶(gelatin)、黄蓍胶、三乙醇胺油酸盐(triethanolamine oleate)、吐温20(Tween 20)、吐温80(Tween 80)、或其组合,但本发明并不局限于此。
填充剂的例子可包含碳酸钙、葡聚糖结合剂(dextrates)、高岭土、甘露醇、微晶纤维素、预糊化淀粉、粉状纤维素(powdered cellulose)、硅酸、山梨醇、淀粉、滑石粉、或其组合,但本发明并不局限于此。
助滑剂(glidant)(也称作助流剂(flowing agent))的例子可包含玉米淀粉、滑石粉、二氧化硅、胶体(colloidal)二氧化硅、或其组合,但本发明并不局限于此。
润滑剂(lubricant)的例子可包含洋菜、硬脂酸钙(calcium stearate)、月桂酸乙酯(ethyl laureate)、油酸乙酯(ethyl oleate)、甘油、乙二醇类(例如、甘油山萮酸酯(glycerol behenate)、聚乙二醇(polyethylene glycol,PEG))、氢化植物油(hydrogenated vegetable oil)(例如花生油、棉籽油(cottonseed oil)、葵花油、芝麻油、橄榄油、玉米油、大豆油(soybean oil))、轻级矿物油(light mineral oil)、石松子(lycopodium)、硬脂酸镁、甘露醇、矿物油、二氧化硅或硅胶、硫酸月桂酯钠(sodium laurylsulfate)、硬脂酰反丁烯二酸钠(sodium stearyl fumarate)、山梨醇、硬脂酸(stearicacid)、滑石粉、蜡、硬脂酸锌(zinc stearate)、或其混合,但本发明并不局限于此。
塑化剂(plasticizer)的例子可包含蓖麻油(castor oil)、柠檬酸酯类(citrateesters)(例如柠檬酸三乙酯、柠檬酸三丁酯、乙酰柠檬酸三乙酯(acetyl triethylcitrate)和乙酰柠檬酸三丁酯(acetyl tributyl citrate))、脂肪酸酯类(fatty acidesters)(例如硬脂酸丁酯、单硬脂酸甘油酯(glycerol monostearate)和硬脂醇(stearylalcohol))、乙二醇(glycol)衍生物(例如聚乙二醇和丙二醇)、矿物油、邻苯二甲酸酯类(phthalate esters)(例如磷苯二甲酸二乙酯(diethyl phthalate)、磷苯二甲酸二丁酯和二辛基亚磷酸酯(dioctyl phosphate))、癸二酸酯类(sebacate esters)(例如癸二酸二丁酯(dibutyl sebacate))、三乙酸甘油酯(triacetin)、维生素E TPGS(D-α-生育酚聚乙二醇1000丁二酸酯)(D-α-tocopheryl polyethylene glycol 1000succinate)、或其组合,但本发明并不局限于此。
助溶剂(solubilizer)的例子可包含柠檬酸、酒石酸、苯甲酸、聚乙二醇、乙醇、丙二醇、甘油、n-甲基2-吡咯烷酮、二甲基乙酰胺、蜂蜡、d-α生育酚(d-αtocopherol)、油酸(oleic acid)、单和二甘油酯、cremphor、吐温20、山梨醇酐单油酸酯(sorbitanmonooleate)、薄荷油、聚山梨醇酯、花生油、玉米油、大豆油、芝麻油、橄榄油、棉籽油、α-环状糊精(α-cyclodextrin)、β-环状糊精、γ-环状糊精、磺基丁醚-环状糊精(sulfobutylether-cyclodextrin)、羟丙基-环糊精(hydroxypropyl-cyclodextrin)、甘油、胆碱(choline)、二硬脂酰磷脂丙三醇(distearoyl phosphatidylglycerol,DSPG)、二肉豆蔻酰基磷脂酰胆碱(dimyristoylphosphatidylcholine,DMPC)、二肉豆蔻酰基磷酸酰甘油(dimyristoylphosphatidylglycerol,DMPG)、聚乙二醇15羟基硬脂酸酯(macrogol 15hydroxystearate)、或其组合,但本发明并不局限于此。
增稠剂(thickener)的例子可包含阿拉伯胶、洋菜、铝酸(alamic acid)、藻酸,单硬脂酸铝、镁铝海泡石(attapulgite)、皂土、卡波姆(carbomer)、卡波姆共聚物(copolymer)、卡波姆均聚物、卡波姆互聚物(interpolymer)、羧甲基纤维素钙(carboxymethylcellulose calcium)、羧甲基纤维素钠、鹿角菜胶(carrageenan)、纤维素、糊精、明胶(gelatin)、树胶(gum)(例如结兰胶(gellan gum)、瓜尔胶和黄原胶(xanthangum))、羟乙基纤维素、羟丙基纤维素、羟丙基甲纤维素、硅酸镁铝(magnesium aluminumsilicate)、麦芽糊精(maltodextrin)、甲基纤维素、微晶纤维素、果胶、聚氧化乙烯(polyethylene oxide)、聚乙烯醇、聚乙烯吡咯烷酮(povidone)、丙二醇藻酸(propyleneglycol aliginate)、二氧化硅、胶体二氧化硅、藻酸钠(sodium alginate)、淀粉(包含玉米淀粉、马铃薯淀粉、树薯淀粉和小麦淀粉)、黄蓍胶、或其组合,但本发明并不局限于此。
润湿剂(wetting agent)的例子可包含月桂酸二甘单酯(diethylene glycolmonolaurate)、单硬脂酸丙二酯(propylene glycol monostearate)、聚氧乙烯月桂醚(polyoxyethylene lauryl ether)、山梨醇酐单油酸酯、硫酸月桂酯钠(SLS)、硬脂酰反丁烯二酸钠(SSF)、吐温20(Tween 20)、吐温80(Tween 80)、或其组合,但本发明并不局限于此。
于本发明中,医药组成物包含分散剂和增溶剂的两赋形剂。
于本发明中,式(I)的活性成分或其药学上可接受的盐类或溶剂合物可以8重量%至30重量%、9重量%至30重量%、9重量%至29重量%、9重量%至28重量%、10重量%至28重量%、11重量%至28重量%、12重量%至28重量%、13重量%至28重量%、13重量%至27重量%、14重量%至27重量%、14.5重量%至27重量%、14.5重量%至26重量%、14.5重量%至25重量%、14.5重量%至24重量%、14.5重量%至23重量%、14.5重量%至22重量%、14.5重量%至21重量%、14.5重量%至20重量%、14.5重量%至19重量%、15重量%至19重量%、15重量%至18.5重量%、或15.5重量%至18.5重量%的量存在。
于本发明中,分散剂可以40重量%至88重量%、45重量%至88重量%、50重量%至88重量%、55重量%至88重量%、60重量%至88重量%、60重量%至87重量%、60重量%至86重量%、60重量%至85重量%、60重量%至84重量%、60重量%至83重量%、60重量%至82重量%、60重量%至81重量%、60重量%至80重量%、61重量%至80重量%、62重量%至80重量%、63重量%至80重量%、64重量%至80重量%、65重量%至80重量%、66重量%至80重量%、67重量%至80重量%、68重量%至80重量%、69重量%至80重量%、70重量%至80重量%、71重量%至80重量%、71重量%至79重量%、72重量%至79重量%、72重量%至78重量%、73重量%至78重量%、或73重量%至77重量%的量存在。
于本发明中,助溶剂可以2重量%至20重量%、2重量%至19重量%、2重量%至18重量%、2重量%至17重量%、2重量%至16重量%、2重量%至15重量%、3重量%至15重量%、3重量%至14重量%、4重量%至14重量%、4重量%至13重量%、5重量%至13重量%、5重量%至12重量%、5重量%至11重量%、5重量%至10重量%、6重量%至10重量%、6重量%至9重量%、或7重量%至9重量%的量存在。
于本发明中,分散剂与助溶剂的重量比可以在3.0至20.0、3.5至20.0、4.0至20.0、4.5至20.0、4.5至19.5、4.5至19.0、4.5至18.5、4.5至18.0、4.5至17.5、4.5至17.0、4.5至16.5、4.5至16.0、4.5至15.5、4.5至15.0、4.5至14.5、4.5至14.0、4.5至13.5、4.5至13.0、4.5至12.5、5.0至12.5、5.0至12.0、5.5至12.0、5.5至11.5、6.0至11.5、6.0至11.0、6.5至11.0、7.0至11.0、7.5至11.0、8.0至11.0、8.5至11.0、或8.5至10.5的范围。当重量比在上述范围时,本发明的医药组成物具有改善体内溶解度或口服生体可用率的增强效果。
在本发明的一实施例中,分散剂可包含羟丙基甲基纤维素醋酸琥珀酸酯(hypromellose acetate succinate)。然而,本发明并不局限于此,根据需要,本发明的医药组成物中可以使用上述任何其他分散剂。
在本发明的一实施例中,助溶剂可包含聚乙二醇15羟基硬脂酸酯(macrogol 15hydroxystearate)。然而,本发明并不局限于此,根据需要,本发明的医药组成物中可以使用上述任何其他助溶剂。
在本发明的第一实施例中,式(I)的活性成分或其药学上可接受的盐类或溶剂合物可以8重量%至30重量%的量存在;该分散剂可以40重量%至88重量%的量存在;且该助溶剂可以2重量%至20重量%的量存在。
在本发明的第二实施例中,式(I)的活性成分或其药学上可接受的盐类或溶剂合物可以9重量%至28重量%的量存在;该分散剂可以60重量%至87重量%的量存在;且该助溶剂可以3重量%至15重量%的量存在。
在本发明的第三实施例中,式(I)的活性成分或其药学上可接受的盐类或溶剂合物可以10重量%至28重量%的量存在;该分散剂可以60重量%至85重量%的量存在;且该助溶剂可以5重量%至13重量%的量存在。
在本发明的第四实施例中,式(I)的活性成分或其药学上可接受的盐类或溶剂合物可以14.5重量%至20重量%的量存在;该分散剂可以70重量%至80重量%的量存在;且该助溶剂可以5重量%至10重量%的量存在。
在上述第一至第四实施例的任何一个中,分散剂可包含羟丙基甲基纤维素醋酸琥珀酸酯。
在上述第一至第四实施例的任何一个中,助溶剂可包含聚乙二醇15羟基硬脂酸酯。
在上述实施例中,医药组成物包含有效剂量的活性成分。有效剂量可为例如有需要的主体每公斤在0.01至10毫克(mg)、0.1至10毫克、1至10毫克、1至8毫克、2至8毫克、或2至7毫克的范围内。然而,本发明并不局限于此,有效剂量可以根据主体、给药途径、赋形剂的使用、以及与其他治疗方法(例如使用其他活性剂)共同使用的可能性进行调整。
在上述实施例中,可以将医药组成物制备成粉剂。在此,制备医药组成物的粉末的方法可以是喷雾干燥法,但本发明并不局限于此。
当通过喷雾干燥法制备医药组成物的粉末时,入口温度可以在69℃至101℃或70℃至85℃的范围内。出口温度可以在42℃至52℃的范围内。雾化(atomization)压力可以在0.15MPa至0.22MPa的范围内。鼓风机(blower)可以是5级至7级的范围。空气量可以设定在0.20m3/min至0.60m3/min的范围内,例如0.40m3/min。氧气量可以设定为小于3%(<3%)。然而,本发明并不局限于此。喷雾干燥法的参数可以根据所期望的粉末直径或医药组成物的组成而变化。
在本发明中,当将活性成分配制成本发明的医药组成物时,水溶性差的活性成分(ALP001E)可借由溶剂喷雾干燥法制备。本发明的医药组成物的粉剂显示出改善的溶解度或增加的生体可用率。此外,本发明的医药组成物的特定配方和工艺参数可以实现具有工艺和操作优势的制药技术。例如,入口温度在69℃至101℃的温和范围内,可以快速产生喷雾干燥粉末且易于操作。
在上述实施例中,可以将医药组成物的粉末置于胶囊内。胶囊的材料可以是,例如,明胶。
在上述实施例中,医药组成物的粉末可以被压缩成片剂、颗粒(granule)或粒子(particle)。当医药组成物被配制成片剂、颗粒或粒子时,医药组成物可以进一步包含一涂层,其中,活性成分和赋形剂是包含于涂层中。
在上述实施例中,医药组成物可以是口服医药组成物,其可以被配制成粉剂、胶囊、片剂或颗粒。
在上述实施例中,医药组成物可以用于降低主体的血糖量。
在上述实施例中,医药组成物可以用于治疗与与升糖素(glucagon)相关的病症。
本发明也包含一种用于降低主体的血糖量的方法,包含向有需要的主体施用本发明的上述医药组成物。
本发明进一步涵盖一种治疗与升糖素相关的病症的方法,包含向有需要的主体施用本发明的上述医药组成物。
在本发明中,上述主体可以是哺乳动物,例如人、猪、马、牛、狗、猫、小鼠或大鼠。
在本发明中,与升糖素相关的疾病、状态或病症可以是例如高血糖症(hyperglycemia)、第II型糖尿病(Type II diabetes)、代谢症候群(metabolicsyndrome)、葡萄糖耐受不良(impaired glucose tolerance)、葡萄糖尿症(glucosuria)、糖尿病肾病变(diabetic nephropathy)、糖尿病神经病变(diabetic neuropathy)、糖尿病视网膜病变(diabetic retinopathy)、高胰岛素血症(hyperinsulinemia)、胰岛素抗性症候群(insulin resistance syndrome)、白内障(cataracts)、肥胖症(obesity)、血脂异常(dyslididemia)、高血压(hypertension)、和心肌梗塞(myocardial infarction)。但本发明并不局限于此,且本发明的医药组成物可以应用于与升糖素信号传导途径相关的任何其他疾病、状态、或病症。在本发明的一实施例中,与升糖素相关的疾病、状态或病症可以是高血糖症、第II型糖尿病、葡萄糖耐受不良、胰岛素抗性症候群、或肥胖症。于本发明的另一实施例中,与升糖素相关的疾病、状态或病症可以是第II型糖尿病。
以下实施例可清楚地展现出本发明的上述和其他技术内容、特征和/或效果。通过具体实施例的说明,人们将更进一步了解本发明所采用的技术手段和效果,以达到上述目的。此外,本领域技术人员应能理解且可实施此发明的内容,因此在不背离本发明的概念的所有等同的变化或修饰应被所附申请范围包含。
此外,在本说明书中,除非另有说明,否则一数值(value)可以解释为涵盖该数值的±10%以内的范围,且更具体地,指涵盖该数值的±5%以内的范围;除非另有说明,否则范围(range)可以解释为由较小的端点、较小的四分位数(quartile)、中位数(median)、较大的四分位数和较大的端点定义的复数的子范围(subranges)所组成。
实施例
无需进一步详细阐述,相信本领域技术人员可以基于以上描述,以最大程度利用本发明。因此,以下具体实施例应被解释为仅仅是说明性的,而不以任何方式限制本发明的其余部分。本文引用的所有出版物其整体均被引用而并入本案。
借由以下实施例解释本发明,所述实施例不用于限制本发明的范围。除非另有说明,否则在以下实施例中,本文使用的“%”,用来表示内容(contents)或物质(object)的量,为重量百分比。
化学药品
ALP001E:ALP001E的制备可参考US 20190345118。
丙酮:作为溶剂。
乙醇(200Proof):作为溶剂。
羟丙基甲基纤维素醋酸琥珀酸酯(Hypromellose Acetate Succinate):在ALP001E的固体分散体(solid dispersion)中作为分散剂或载体。
聚乙二醇15羟基硬脂酸酯(Macrogol 15 Hydroxystearate):它不仅改善药物溶解度和吸收度,也涉及产物的稳定性。它主要为12-羟硬脂酸(12-hydroxystearic acid)的单酯和二酯以及由12-羟硬脂酸的乙氧基化获得的聚乙烯二醇(macrogol)的混合物。也被称为具有α-氢-ω-羟基聚(氧-1,2-乙烷二基)(α-hydro-ω-hydroxypoly(oxy-1,2-ethanediyl))的12-羟基十八烷酸(12-hydroxyoctadecanoic acid)聚合物;12-羟硬脂酸聚乙二醇共聚物(12-hydroxystearic acid polyethylene glycol copolymer);聚乙二醇15羟基硬脂酸酯;聚乙二醇-15-羟基硬脂酸酯(polyethylene glycol-15-hydroxystearate);以及聚乙二醇66012-羟基硬脂酸酯(polyethylene glycol 660 12-hydroxystearate)。
<配方A至H的制备>
下表1列出配方A至H的成分。下表2列出配方A至H的喷雾干燥的制程参数。
以下简要地描述制备配方A至H的喷雾干燥末的步骤。
步骤1:将羟丙基甲基纤维素醋酸琥珀酸酯(hypromellose acetate succinate)溶解在丙酮中,并搅拌溶液直到羟丙基甲基纤维素醋酸琥珀酸酯完全溶解为澄清或混浊的黏性溶液。表1中列出羟丙基甲基纤维素醋酸琥珀酸酯和丙酮的含量。
步骤2:将聚乙二醇15羟基硬脂酸酯(Macrogol 15 Hydroxystearate)溶解在乙醇(200Proof)中,在聚乙二醇15羟基硬脂酸酯完全溶解于乙醇中时,制得溶液B。表1也列出了溶液B的配方。
步骤3:将ALP001E快速溶解在步骤1制备的澄清或混浊的黏性溶液中,并搅拌ALP001E和溶液直到呈现澄清或混浊的黏性溶液(溶液A)。
步骤4:在烧杯中混合溶液A和溶液B,且在搅拌器(blender)中保持搅拌。
步骤5:将混合溶液注入喷雾干燥机(spray dryer)中。喷雾干燥机的参数如表2所描述,进料气体为氮气。将入口温度调整在70℃至85℃的范围内,直到出口温度在42℃至52℃的范围内。
步骤6:将收集的喷雾干燥粉末放入干燥箱至隔夜(18至24小时),此过程用于将残余溶剂移除至小于5000ppm。将最终产物储存于玻璃瓶中,并在-30℃的冰箱中保存。ALP001E和最终产物在高湿度条件下可能不稳定,因此,该程序应在湿度控制环境中进行。
表1
*在干燥过程中被蒸发
表2
<性质测量>
测量获得的配方A至H的粉末的性质,并将结果列于下表3。以下简要地描述测量方法。
在本实施例中,借由使用电子天平(M Mettler-Toledo Basic MoistureAnalyzer)测量配方的所有成分,并通过计算转换成产率。通过目视检查(visualinspection)检查配方的外观。
为了测量来自配方的降解产物(degradation product),使用HPLC系统。使用Agilent 1100HPLC系统来执行HPLC分析,该系统包含四元帮浦(quaternary pump)、在线除气机(in-line degasser)、自动进样器和光电二极管数组侦测器。管柱采用ThermoScientific Hypersil BDS C18反相管柱(reverse phase column),250mm x 4.6mm,5μm。
使用具有Compact oven SC 885自动进样器的万通库仑计模块917(MetrohmCoulometer model 917)进行分析。以三重复(triplicate)测试50mg的粉末样品,并将烤箱温度设定为105℃。用于分析的试剂为hydranal Coulomat AG Oven。也使用AND MX-50湿度天平(moisture balance)分析含水量。将大约1g的材料放置于金属锅上,并加热至105℃直到重量变化小于0.01%。
使用具有自动进样器和冷藏(refrigerated)冷却系统(cooling accessory)的TAInstruments Q20 MDSC进行DSC分析。使用TZero锅压机(pan press)将大约1至5mg的样品密封至TZero铝锅中。
使用粉末颗粒尺寸分布仪(distribution instrument)(Syepatec HELOS粒径分析仪(particle size analyzer))测量平均粒径(mean particle size)。
表3
1:将配方A至H的粉末在60℃下放置7天,这些数据指出配方A至H的热稳定性。
通过将配方A至H的干燥粉末放置在60℃下7天(Day 7),并与配方A至H的新鲜干燥粉末(Day 0)比较,来测量配方A至H的干燥粉末的外观、杂质和热稳定性。根据表3所示的结果,第7天的配方A、B和E至G的干燥粉末与第0天的配方A、B和E至G的干燥粉末相比,没有观察到明显的外观变化。此外,HPLC的数据指出,在第7天的配方A至H的干燥粉末中,没有观察到大于0.1%的杂质。
此外,在与第0天(Day 0)的配方A至C和E至G的干燥粉末相比,第7天(Day 7)的配方A至C和E至G的干燥粉末的DSC数据显示没有明显的变化,但与第0天的配方D和H的干燥粉末相比,在第7天的配方D和H的干燥粉末中观察到ALP001E峰(Tm范围:从120℃至125℃)的Tm峰介于115℃和130℃之间。这些结果表示配方A至C和E至G的干燥粉末具有良好的稳定性。
此外,如表3所示,配方A至C和E的干燥粉末的粒径分布(particledistributions)范围是不相同的。在配方A的干燥粉末中,D10(Dv 0.1)为1~3μm,D50(Dv0.5)为4~10μm,且D90(Dv 0.9)为11~20μm。在配方B的干燥粉末中,D10(Dv 0.1)为1~3μm,D50(Dv 0.5)为5~15μm,且D90(Dv 0.9)为25~50μm。在配方C的干燥粉末中,D10(Dv0.1)为3~6μm,D50(Dv 0.5)为20~35μm,且D90(Dv 0.9)为50~70μm。在配方E的干燥粉末中,D10(Dv 0.1)为1~3μm,D50(Dv 0.5)为4~10μm,且D90(Dv 0.9)为11~20μm。在此,D50(Dv 0.5)是指体积分布的中值的粒径(particle size);且D10(Dv 0.1)和D90(Dv 0.9)分别指10%和90%的颗粒的体积在该粒径之下。
<体外溶离测试(dissolution testing)>
使用美国药典(USP)溶离试验仪第2型(Dissolution Apparatus Type 2(桨形(paddles))),以75rpm(无限大(infinity)时为250rpm),在37±0.5℃下,使用pH为6.8具有0.25%w/v十二基硫酸钠(SDS)的磷酸盐缓冲溶液(900mL)作为溶离介质(dissolutionmedium)进行体外溶离测试(dissolution testing)。体外溶离测试的参数列于下表4,且结果列于下表5中。
表4
表5
由表5结果可知,与APL001E的溶解度相比,配方A至C和E至G的干燥粉末的溶解度明显增加,特别是配方A至C和E至G的干燥粉末的溶解度更显著的增加。这些数据表示配方A至C和E至G的干燥粉末具有改善的溶解度。
<溶解度>
简要描述测量配方的溶解度的方法。
将测试配方加到指定的缓冲溶液或溶液(ddH2O或0.9%盐水,pH 7.4)中至最终浓度为3mg/mL,接着超声处理(sonicating)30分钟。下一步,将混合物放入37℃的水浴中24小时。以vortex将混合物充分混合,并转移1mL的混合物至1.5mL的离心管(eppendorf tube)中,接着以20817xg离心30分钟。收集10μL的上清液,并以LC-MS/MS测定收集的上清液的浓度。结果列于下表6中。
表6
根据表6所示的结果,与APL001E的溶解度相比,配方A至C和E至G的干燥粉末的溶解度明显增加。这些数据表示配方A至C和E至G的干燥粉末具有改善的溶解度。
<口服生体可用率(Oral bioavailability)>
简单地说,使用三只健康的、研究用的米格鲁犬(Beagle dog),年龄为4-10年,体重为9-12公斤。药物动力学实验有静脉速注(intravenous bolus,IV bolus)组和口服组。
于IV bolus组中,通过静脉速注将ALP001(由下式(II)表示的ALP001E的活性代谢产物,其溶解于一载剂(0.1M NaHCO3,pH7.4))施用于狗,依据实验设计中狗的体重,剂量由40mg至50mg。基于无隔室分析(non-compartmental analysis)获得药物动力学参数,IVbolus的AUC(曲线下面积)为2.18μg.h/mL。它将用于生体可用率估算。
于口服组中,将包含配方的干燥粉末的胶囊口服施用于狗。在施用胶囊前,替狗秤重并取狗的血液。将含有喷雾干燥粉末的胶囊塞入狗的嘴巴(其中,依据实验设计中动物的体重,活性成分ALP001E的剂量由35mg至50mg),并在将胶囊塞入狗的嘴巴后立即给予3ml的水。
对于IV bolus组和口服组,在狗禁食4小时后才接受药物治疗,并在给药前采集狗的血液样本。在给药后于预定时间(10分钟、1小时、2小时、4小时、5小时、7小时及24小时)收集血液样本。用经验证的高效液相层析法(high performance liquid chromatography)测定血浆中的药物浓度。
借由无隔室法(non-compartmental method)对血浆浓度数据进行分析和建模(modelled),以获得药物动力学参数。此外,借由比较口服组的数据和IV bolus组的数据来获得生体可用率。结果列于下表7中。
表7
表7中显示的结果表示,配方A至C、E和G的口服干燥粉末,尤其是配方B和E的口服干燥粉末,具有良好的生体可用率。此外,当羟丙基甲基纤维素醋酸琥珀酸酯和聚乙二醇15羟基硬脂酸酯的比例在期望范围内时,干燥粉末的口服生体可用率增加。特别地,配方B和E的干燥粉末的口服生体可用率分别为58.4%和54.6%。
根据以上显示的结果,本发明提供一种新颖的医药组成物,其具有改善的稳定性、可接受的溶解度或增加的口服吸收率。因此,本发明的医药组成物可通过口服施用,用于降低主体血糖量或治疗与升糖素相关的病症。
其他实施例
本说明书中发明的所有特征可以以任何组合来结合。本说明书中发明的每个特征可以由具有相同、等同或相似目的的替代特征代替。因此,除非另有明确说明,否则所发明的每个特征仅是一系列等同或相似特征的示例。
此外,根据以上描述,本领域技术人员可以容易地确定本发明的本质特征,并在不脱离本发明的精神和范围下,可以对本发明进行各种改变和修饰以使其适应各种用途和条件。因此,其他实施例也在权利要求的内。
Claims (20)
2.根据权利要求1所述的医药组成物,其特征在于,该分散剂与该助溶剂的重量比为3.0至20.0。
3.根据权利要求1所述的医药组成物,其特征在于,该式(I)的活性成分或其药学上可接受的盐类或溶剂合物以9重量%至28重量%的量存在。
4.根据权利要求3所述的医药组成物,其特征在于,该式(I)的活性成分或其药学上可接受的盐类或溶剂合物以10重量%至28重量%的量存在。
5.根据权利要求4所述的医药组成物,其特征在于,该式(I)的活性成分或其药学上可接受的盐类或溶剂合物以14.5重量%至20重量%的量存在。
6.根据权利要求1所述的医药组成物,其特征在于,该分散剂以40重量%至88重量%的量存在。
7.根据权利要求6所述的医药组成物,其特征在于,该分散剂以60重量%至85重量%的量存在。
8.根据权利要求7所述的医药组成物,其特征在于,该分散剂以70重量%至80重量%的量存在。
9.根据权利要求1所述的医药组成物,其特征在于,该助溶剂以2重量%至20重量%的量存在。
10.根据权利要求9所述的医药组成物,其特征在于,该助溶剂以5重量%至13重量%的量存在。
11.根据权利要求10所述的医药组成物,其特征在于,该助溶剂以5重量%至10重量%的量存在。
12.根据权利要求1所述的医药组成物,其为一口服医药组成物。
13.根据权利要求1所述的医药组成物,其特征在于,该分散剂包含羟丙基甲基纤维素醋酸琥珀酸酯。
14.根据权利要求1所述的医药组成物,其特征在于,该助溶剂包含聚乙二醇15羟基硬脂酸酯。
15.根据权利要求1所述的医药组成物,其特征在于,该式(I)的活性成分或其药学上可接受的盐类或溶剂合物以10重量%至28重量%的量存在;该分散剂以60重量%至85重量%的量存在;且该助溶剂以5重量%至13重量%的量存在。
16.根据权利要求15所述的医药组成物,其特征在于,该分散剂包含羟丙基甲基纤维素醋酸琥珀酸酯,且该助溶剂包含聚乙二醇15羟基硬脂酸酯。
17.根据权利要求1所述的医药组成物,其特征在于,该式(I)的活性成分或其药学上可接受的盐类或溶剂合物以14.5重量%至20重量%的量存在;该分散剂以70重量%至80重量%的量存在;且该助溶剂以5重量%至10重量%的量存在。
18.根据权利要求17所述的医药组成物,其特征在于,该分散剂包含羟丙基甲基纤维素醋酸琥珀酸酯,且该助溶剂包含聚乙二醇15羟基硬脂酸酯。
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