CN104173356A - 肝适能固态分散物、包括其的药的组成物以及其制备方法 - Google Patents
肝适能固态分散物、包括其的药的组成物以及其制备方法 Download PDFInfo
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- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
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- 229940123527 Nucleotide reverse transcriptase inhibitor Drugs 0.000 description 1
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- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 1
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
- C07D473/32—Nitrogen atom
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
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Abstract
本发明涉及一种具有经改善的稳定性的粒状非晶的固态分散物、一种包括此粒状非晶的固态分散物的药的组成物以及一种制备此粒状非晶的固态分散物的方法。其中，此粒状非晶的固态分散物包括作为核苷酸类似物的9-[2-[[双[(新戊酰氧基)甲基]膦酰基]甲氧基]乙基]腺嘌呤。
Description
本申请为2009年09月16日递交的申请号为200980135777.6，发明名称为肝适能的稳定化固态分散物及其制备方法的分案申请。
技术领域
本发明涉及一种具有经改善的稳定性的非晶的固态分散物，其包括作为核苷酸类似物(nucleotide analogue)的9-[2-[[双[(新戊酰氧基)甲基]膦酰基]甲氧基]乙基]腺嘌呤(9-[2-[[bis[(prvaloyloxy)methyl]phosphono]methoxy]ethyl]adenine，肝适能(adefovir dipivoxil)(分子式1的化合物)，或以下称作″ADE″)，以及一种包括此非晶的固态分散物的药的组成物(pharmaceutical composition)。
[分子式1]
此外，本发明涉及一种制备此具有经改善的稳定性的非晶的固态分散物的方法，其包括下列步骤。将ADE及水溶性聚合物物质(water-soluble polymersubstance)溶解在有机溶剂中，以及藉由使用流体床造粒机(fluidized bedgranulator)或喷雾干燥机(spray dryer)以使结果溶液(resulting solution)被糖醇载体(sugar alcohol carrier)所吸附或分散于糖醇载体中以进行造粒(granulating)。
背景技术
肝适能(ADE)是一种抗病毒药物(antiviral drug)，其为核苷酸反转录酶抑制剂(nucleotide reverse transcriptase inhibitor)且特别是相对于人类免疫缺陷病毒(human immunodeficiency virus，HIV)及B型肝炎病毒(hepatitis type B virus，HBV)显示出显著的活体内抗病毒活性(in vivo antiviral activity)。关于其抗病毒活性，请见″Starret et al.，J.Med.Chem.，37：1857，1994″以及″Samira et al.，J.Med.Chem.，39：4958，1996″。
已知ADE本质上存在两种类型：非晶与结晶。美国专利第6,451,340号及韩国专利第0618663号揭示一种药的组成物以及一种制备此药的组成物的方法，其中此药的组成物包括无水结晶的ADE(anhydrous crystalline ADE)。此外，美国专利第6,635,278号及韩国专利第0624214号揭示一种ADE组成物以及一种制备此ADE组成物的方法，其中此ADE组成物包括碱性赋形剂(alkaline excipient)，以改善稳定性。
然而，经发现，当ADE与水分(moisture)接触时，ADE容易地且快速地被水解，且因此水解的副产物还加速ADE的衰变(degradation)(请见″Yuan etal.，Pharm.Res.17：1098，2000″)。
商标(trade designation)为Hepsera(GSK)的结晶的ADE的药的组成物已经在市场上贩售。然而，由于制备ADE药物的组成物的制程需要水来配制(formulate)小粒(granule)，所以还需进行干燥步骤使小粒的水分含量降低1.5％或更低。因此，由于在高温下长时间与水分接触，所以不可能满足稳定性的需求。
此外，通过使用聚合物物质与有机溶剂结合所制备的ADE固态分散物已经被报导，所述的聚合物物质例如是羟丙甲基纤维素(hydroxypropylmethylcellulose，HPMC)与聚乙烯吡咯烷酮(polyvinylpyrrolidone，PVP)。然而，聚合物物质吸收周围的水分，导致ADE的衰变加速。另外，由于长期暴露在高温下，因此有招致固态分散物的型态改变(morphological change)的风险，所以稳定性改善的程度不足以满足。
发明内容
因此，本发明的目的在于提供固态分散物类型的肝适能，其相较于传统的肝适能制备，具有对热及水分的经改善的稳定性。
本发明是关于一种具有经改善的稳定性的粒状非晶的固态分散物，其包括分子式1的ADE、水溶性聚合物物质及糖醇，以及关于一种为了人类免疫缺陷病毒感染(human immunodeficiency virus(HIV)infection)或B型肝炎(hepatitis B)的治疗的药的组成物，其包括所述粒状非晶的固态分散物。
并且，本发明关于一种制备具有可溶性及经改善的稳定性的粒状非晶的固态分散物的方法，其包括下列步骤。将水溶性聚合物物质及肝适能溶解于有机溶剂中，有机溶剂例如是丙酮(acetone)或丙酮与药学上可接受的有机溶剂的混合溶液；以及藉由使结果溶液被糖醇载体所吸收或分散于糖醇载体中以进行造粒。
根据本发明的较佳的水溶性聚合物为选自由聚乙二醇(polyethyleneglycol，PEG)、聚乙烯醇(polyvinylalcohol，PVA)、羟丙甲基纤维素(HPMC)及聚乙烯吡咯烷酮(PVP)所组成的族群中的一个或多个。更佳的水溶性聚合物为乙烯吡咯烷酮-醋酸乙烯(vinylacetate)共聚物(Kollidone VA64)。美国专利第4,301,146号揭示一种药物的稳定的固态分散物，其只由聚合物物质所制造。既然这样，聚合物物质可防止药物分子与水分子接触，因此改善其稳定性。然而，这样的聚合物物质有容易吸收水分的倾向，因此降低大部分药物的稳定性。
在根据本发明的固态分散物中，ADE与水溶性聚合物的重量比(weightratio)较佳为1∶0.1至1∶10，更佳为1∶0.5至1∶5。相对于1重量份(part byweight)的ADE，若水溶性聚合物的重量比低于0.1，其难以制备非晶的固态分散物，而若此重量比超过10时，其不适合配制成锭(tablet)。
此外，ADE与糖醇的重量比较佳为1∶0.5至1∶10，更佳为1∶3至1∶6。相对于1重量份的ADE，若糖醇的重量比低于0.5，固态分散物的稳定性会降低，而若此重量比超过10时，其难以配制。
根据本发明的糖醇为选自由乳糖(lactose)、葡萄糖(glucose)、甘露醇(mannitol)、山梨醇(sorbitol)及异麦芽酮糖醇(isomalt)所组成的族群中的一个或多个，其中较佳的是乳糖或异麦芽酮糖醇。
经报导，如果某些药物与具有粘合活性(binding activity)的糖醇压缩在一起，可改善压缩药物配制的医药用途(pharmaceutical use)。由于大部分糖醇为吸湿性(hydroscopic)，通过粉碎(pulverization)而成的表面积越大，此配制吸收周围的水分就越多，因而降低稳定性。然而，当糖醇被粉碎且充分地分散于各自的颗粒(particle)之间时，压缩配制可维持其在粉碎强度(pulverizingstrength)与水分吸收的稳定性。此糖醇代表性的例子可包括山梨醇、异麦芽酮糖醇及同类物。
本发明关于一种药的组成物，除肝适能的粒状非晶的固态分散物之外，其还包括药学上可接受的载体(pharmaceutically acceptable carrier)。此药学上可接受的载体可为选自由稀释剂(diluent)、破碎剂(disintegrating agent)、粘合剂(binding agent)及润滑剂(lubricant)所组成的族群中的一个或多个。此载体可使得控制固态分散物的溶解率及分解时间(disintegration time)成为可能，致使控制生物可用性(bioavailability)及改善固态分散物的稳定性。适当的赋形剂可包括淀粉(starch)、蔗糖(sucrose)、微晶纤维素(microcrystalline cellulose)、磷酸氢二钠(dibasic sodium phosphate)、磷酸二氢钾(monobasic potassiumphosphate)、麦芽糊精(maltodextrin)、糊精、环糊精(cyclodextrin)、半乳糖(galactose)及同类物。
本发明提供一种固态分散物及一种包括此固态分散物的药的组成物，此固态分散物对热及水分的敏感度较低，且因此相较于传统的固态分散物在热力学(thermodynamically)上更为稳定。
附图说明
图1为结晶的ADE的XRD图样，其显示在约7.4、7.9、10.2、12.4、15.1、16.4、17.3、18.0、20.2、21.4及22.3.时由2θ所表示的特征峰(characteristic peak)。
图2为比较范例1的非晶的固态分散物的XRD图样。
图3为用以作为糖醇的异麦芽酮糖醇的XRD图样。
图4为范例6的非晶的固态分散物的XRD图样，其中未观察到ADE的特征峰，且只有异麦芽酮糖醇的XRD图样，暗示ADE以非晶的类型存在。
具体实施方式
以下，将利用下列范例详细描述本发明。然而，本发明的范例仅用于说明的用途，并不解释为限制本发明的范围。
[范例1]
将10g的肝适能及30g的Kollidone VA64完全溶解于100g的丙酮中。此溶液通过使用流体床造粒机(Glatt GPCG-1，德国)以60g的乳糖作为载体来进行喷雾干燥(spray dried)，而获得粒状非晶的肝适能固态分散物。在此，流体床干燥的流入温度(inflow temperature)为65℃，且其排出温度(dischargetemperature)在35℃至45℃的范围内。
[范例2]
除了使用30g的乳糖之外，根据如范例1中所描述的相同方法制备非晶的肝适能固态分散物。
[范例3]
除了使用90g的乳糖之外，根据如范例1中所描述的相同方法制备非晶的肝适能固态分散物。
[范例4]
除了使用15g的Kollidone VA64之外，根据如范例1中所描述的相同方法制备非晶的肝适能固态分散物。
[范例5]
除了使用20g的Kollidone VA64之外，根据如范例1中所描述的相同方法制备非晶的肝适能固态分散物。
[范例6]
除了使用60g的异麦芽酮糖醇作为代替乳糖的载体之外，根据如范例1中所描述的相同方法制备非晶的肝适能固态分散物。
[范例7]
除了使用30g的异麦芽酮糖醇作为代替乳糖的载体之外，根据如范例1中所描述的相同方法制备非晶的肝适能固态分散物。
[范例8]
除了使用200ml的乙醇(ethanol)作为代替100ml的丙酮的有机溶剂之外，根据如范例1中所描述的相同方法制备非晶的肝适能固态分散物。
[范例9]
除了使用200ml的甲醇(methanol)作为代替100ml的丙酮的有机溶剂之外，根据如范例1中所描述的相同方法制备非晶的肝适能固态分散物。
[范例10]
除了使用二氯甲烷(methylene chloride)/甲醇(50ml/50ml)作为代替100m1的丙酮的有机溶剂之外，根据如范例1中所描述的相同方法制备非晶的肝适能固态分散物。
[比较范例1]包括肝适能及Kollidone VA64的固态分散物的制备
将10g的肝适能及30g的Kollidone VA64完全溶解于100g的丙酮中。此溶液通过使用喷雾干燥机(Büchi Mini Spray Dryer，B-191，瑞士)来进行喷雾干燥，而获得非晶的肝适能固态分散物。在此，喷雾干燥在与范例1中所描述的相同条件下进行。
[比较范例2]
除了使用10g的Kollidone VA64之外，根据如比较范例1中所描述的相同方法制备非晶的肝适能固态分散物。
[比较范例3]
除了使用50g的Kollidone VA64之外，根据如比较范例1中所描述的相同方法制备非晶的肝适能固态分散物。
[测试范例1]非晶的肝适能的X光粉末绕射分析(X-ray powder diffractionanalysis)
在60℃及75％的相对湿度(relative humidity)的条件下，结晶的肝适能、比较范例1的非晶的固态分散物、作为糖醇的异麦芽酮糖醇及范例6的非晶的固态分散物分别被封装至可诱导的封闭型高密度聚乙烯容器(inducibleclosed type high-density polyethylene container)中。四周后，每一样本通过使用X光绕射仪(X-ray diffractometer，型号：X′pert-pro)进行X光粉末绕射分析，结果如图1至图4所示。
[测试范例2]非晶的肝适能的热力学的稳定性测试
在40℃及75％的相对湿度的条件下，粒状非晶的固态分散物连同3g的硅胶(silica gel)被封装至可诱导的封闭型高密度聚乙烯容器中。在不同时间根据面积归一化法(area normalization method)测量残留的ADE含量。表1所示为视糖醇的添加而定的ADE衰变的程度。
表1
[制备范例1]锭的制备
100g的范例1的粒状非晶的肝适能固态分散物(10g的肝适能)、23g的乳糖、7.5g的预凝胶淀粉(pre-gelated starch)、12g的交联羧甲基纤维素钠(croscarmellose sodium)、9g的滑石(talc)及1.5g的硬脂酸镁(magnesiumstearate)被均质混合(homogeneously mixed)及配制成锭，每锭包含10mg的肝适能。
[制备范例2]锭的制备
除了使用范例6的非晶的肝适能固态分散物之外，根据如制备范例1中所描述的相同方法制备锭。
Claims (9)
1.一种粒状非晶的肝适能固态分散物，包括：
肝适能；
水溶性聚合物物质；以及
糖醇。
2.如权利要求1所述的粒状非晶的肝适能固态分散物，其中所述肝适能与所述水溶性聚合物物质的重量比为1∶0.1至1∶10。
3.如权利要求1所述的粒状非晶的肝适能固态分散物，其中所述肝适能与所述糖醇的重量比为1∶0.5至1∶10。
4.如权利要求1所述的粒状非晶的肝适能固态分散物，其中所述水溶性聚合物物质为选自由羟甲基纤维素、聚乙烯吡咯烷酮、羟丙基纤维素、聚乙二醇、聚乙烯醇及乙烯吡咯烷酮/醋酸乙烯共聚物所组成的族群中的一个或多个。
5.如权利要求1-4中任一项所述的粒状非晶的肝适能固态分散物，其中所述糖醇为选自由乳糖、葡萄糖、甘露醇、山梨醇及异麦芽酮糖醇所组成的族群中的一个或多个。
6.一种药的组成物，用于治疗人类免疫缺陷病毒感染或B型肝炎，包括：
如权利要求5所述的粒状非晶的肝适能固态分散物；以及
药学上可接受的载体。
7.一种制备粒状非晶的肝适能固态分散物的方法，所述粒状非晶的肝适能固态分散物如权利要求1-4中任一项所述，所述方法包括下列步骤：
将水溶性聚合物物质及肝适能溶解在有机溶剂中，以形成结果溶液；以及
藉由使所述结果溶液被糖醇所吸附或分散于所述糖醇中以进行造粒。
8.如权利要求7所述的制备粒状非晶的肝适能固态分散物的方法，其中所述水溶性聚合物物质为选自由羟甲基纤维素、聚乙烯吡咯烷酮、羟丙基纤维素、聚乙二醇、聚乙烯醇及乙烯吡咯烷酮/醋酸乙烯共聚物所组成的族群中的一个或多个。
9.如权利要求7或8所述的制备粒状非晶的肝适能固态分散物的方法，其中所述糖醇为选自由乳糖、葡萄糖、甘露醇、山梨醇及异麦芽酮糖醇所组成的族群中的一个或多个。
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| WO2013029198A1 (zh) * | 2011-08-29 | 2013-03-07 | 天津泰普药品科技发展有限公司 | 阿德福韦酯固体制剂及其制备方法 |
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| KR100983322B1 (ko) | 2010-09-20 |
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