CN100479819C - 用于口服给药的、含有伊曲康唑的组合物 - Google Patents
用于口服给药的、含有伊曲康唑的组合物 Download PDFInfo
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- CN100479819C CN100479819C CNB2006100651366A CN200610065136A CN100479819C CN 100479819 C CN100479819 C CN 100479819C CN B2006100651366 A CNB2006100651366 A CN B2006100651366A CN 200610065136 A CN200610065136 A CN 200610065136A CN 100479819 C CN100479819 C CN 100479819C
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- itraconazole
- solid dispersion
- orally administered
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Abstract
本发明涉及一种活性组分为伊曲康唑的口服组合物,所述组合物含有40~69.9wt%的固体分散体、0.1~30wt%的渗透诱导剂以及0.1~30wt%的崩解剂,其中,所述固体分散体通过将1重量份的伊曲康唑分散在0.1~10重量份的羟丙基甲基纤维素和0.01~5重量份的吸收促进剂混合物中而以非晶形制备。
Description
相关申请的互相参引
本申请要求于2005年3月17日提交的韩国专利申请No.10-2005-0022312的优先权,所述申请特此通过引用的方式纳入本说明书,以使其如同在本说明书中完整提出一样。
发明领域
本发明涉及一种口服组合物,所述组合物含有40~69.9wt%(重量百分比)的固体分散体、0.1~30wt%的渗透诱导剂以及0.1~30wt%的崩解剂(disintegrant),其中,所述固体分散体通过将1重量份的伊曲康唑分散在0.1~10重量份的羟丙基甲基纤维素和0.01~5重量份的吸收促进剂混合物中以非晶形制备。
背景技术
伊曲康唑,又称为(±)-顺-4-(4-(4-(4-((2-(2,4-二氯苯基)-2-(1H-1,2,4-三唑-1-基甲基)-1,3-二氧戊环-4-基)甲氧基)苯基)-1-哌嗪基)-2,4-二氢-2-(1-甲基丙基)-3H-1,2,4-三唑-3-酮,已熟知它是一种具有杀真菌广谱性的杀真菌药物,特别是一种治疗皮肤真菌病的安全有效的药物。然而,尽管伊曲康唑具有有效的杀真菌活性,但它是一种不溶性药物,其水溶性和pKa值均较低,分别为1μg/ml以下和3.7,故而在很低的pH下即被离子化。因此,伊曲康唑在口服给药时存在其生物利用度非常低的问题。
为提高伊曲康唑的水溶性以改善其生物利用度,WO 85/002767和US4,764,604公开了一种伊曲康唑和环糊精的包合物(includedcomplex),但均未能提高伊曲康唑的水溶性。此外,US 5,504,105公开了一种口服的药用组合物,该药物组合物的特征在于活性组分分散在氢化植物油、中链甘油酯、白巧克力和大豆卵磷脂中,但其生物利用度仅提高了至多1.2~1.8倍,对活性组分功效的影响甚微。
WO 97/44014公开了一种伊曲康唑的固体分散体,该固体分散体具有较高的生物利用度并且不受食物的影响,其制备是通过采用熔融-挤出法将伊曲康唑和诸如羟丙基甲基纤维素等水溶性聚合物的混合物加热至245~265℃,以将熔融的伊曲康唑分散在未熔化的水溶性聚合物中。然而,其中存在几个问题:熔融法应在高达245~265℃的温度下进行,并且熔融的伊曲康唑难以均匀地分散在聚合物中。此外,未熔化的伊曲康唑残留在体内,从而对在体内的溶出或吸收产生副作用。
韩国专利公报No.2001-0098419公开了一种实现固体分散的方法,即将不溶性的伊曲康唑分散在聚乙烯吡咯烷酮和一种吸收促进剂的混合物中,从而将晶形药物制成为非晶形药物,以显著提高水溶性。然而,其问题在于固体分散体的崩解并不长时间发生,并且伊曲康唑的溶出度(dissolution rate)低,这是因为使用了过量的聚乙烯吡咯烷酮,即使是在模拟的胃液中对固体制剂进行溶出试验时,亦是如此。
因此,需要开发一种不溶性药物即伊曲康唑的生物利用度较高的口服组合物。
发明内容
本发明的发明人发现,将渗透诱导剂,例如氯化钾、碳酸镁等,以及崩解剂添加至其中伊曲康唑分散于羟丙基甲基纤维素和吸收促进剂的混合物中的固体分散体中时,不溶性伊曲康唑的溶出性能可适当控制并有显著改善,从而实现本发明。
因此,本发明的目的在于提供一种口服组合物,所述口服组合物含有固体分散体、渗透诱导剂和崩解剂,其中所述固体分散体通过将伊曲康唑分散在羟丙基甲基纤维素和吸收促进剂的混合物中以非晶形制备。
本发明的另一个目的在于提供一种制备含有伊曲康唑的口服组合物的方法,该组合物的伊曲康唑具有较高的生物利用度,所述方法包括:将伊曲康唑分散在羟丙基甲基纤维素和吸收促进剂的混合物中以制备非晶形的固体分散体,然后将所述固体分散体与渗透诱导剂和崩解剂相混合。
本发明的另一个目的在于提供一种固体分散体,该固体分散体通过将伊曲康唑分散在羟丙基甲基纤维素和吸收促进剂的混合物中而以非晶形制备。
附图说明
图1示出了由本发明实施例和对比例制得的组合物在pH为1.2时的溶出试验的结果。
●:实施例2,
○:实施例3,
▲:对比例1,
△:对比例2。
图2示出了由本发明实施例2制得的组合物和市售制剂的溶出试验的结果。
●:实施例2,
□:市售制剂(Janssen Korea Ltd.的SporanoxTM胶囊)。
图3示出了由本发明实施例2和对比例2制得的组合物在pH4.0和pH6.8时的溶出试验的结果。
▲:pH4.0+1%聚山梨醇酯80(Polysorbate 80),实施例2的组合物,
■:pH4.0+1%聚山梨醇酯80,对比例2的组合物,
△:pH6.8+1%聚山梨醇酯80,实施例2的组合物,
□:pH6.8+1%聚山梨醇酯80,对比例2的组合物。
图4示出了含有聚乙烯吡咯烷酮的固体分散体(SDP)和含有羟丙基甲基纤维素的固体分散体(SDH)在pH1.2和pH4.0时的溶出试验的结果。
▲:SPD-pH1.2,
△:SDH-pH1.2,
■:SDP-pH4.0,
□:SDH-pH4.0。
具体实施方式
结合以下详细描述,对本发明更完整的评价及其附带优点将随着理解的加深而更明显。
本发明涉及一种口服组合物,所述组合物含有40~69.9wt%的固体分散体、0.1~30wt%的渗透诱导剂以及0.1~30wt%的崩解剂,其中,所述固体分散体通过将1重量份的伊曲康唑分散在0.1~10重量份的羟丙基甲基纤维素和0.01~5重量份的吸收促进剂混合物中以非晶形制备。
此外,本发明还涉及一种制备含有伊曲康唑的口服组合物的方法,该组合物的伊曲康唑具有较高的生物利用度,所述方法包括如下步骤:
将1重量份的伊曲康唑分散在0.1~10重量份的羟丙基甲基纤维素和0.01~5重量份的吸收促进剂混合物中以制备非晶形的固体分散体,
将40~69.9wt%的所述固体分散体与0.1~30wt%的渗透诱导剂和0.1~30wt%的崩解剂相混合。
并且,本发明还涉及一种固体分散体,该固体分散体通过将1重量份的伊曲康唑分散在0.1~10重量份的羟丙基甲基纤维素和0.01~5重量份的吸收促进剂混合物中以非晶形制备。
韩国专利公报No.2001-0098419公开了一种伊曲康唑制剂,其中该伊曲康唑制剂的生物利用度通过将伊曲康唑制成为非晶形而得到提高。然而,这样存在一个问题,当伊曲康唑制剂以固体分散体形式口服给药时,活性组分,即伊曲康唑在模拟胃液中的溶出会延时,这是因为在制备固体分散体时使用了过量的水溶性聚合物聚乙烯吡咯烷酮。
为解决上述伊曲康唑在胃环境中溶出延时的问题,在本发明中,伊曲康唑固体分散体的制备采用水溶性聚合物,即羟丙基甲基纤维素,以及吸收促进剂,例如柠檬酸,从而在pH1.2和pH4.0的含有模拟胃液和1%(w/w)聚山梨醇酯80的溶液中,将溶出度显著提高了20%以上。并且,在本发明中,还向伊曲康唑的固体分散体添加渗透诱导剂,如氯化钾、碳酸镁等,以及崩解剂,如微晶纤维素、羟基乙酸淀粉钠等,以使不溶性的伊曲康唑在胃环境中有效溶出。
在本发明中,伊曲康唑固体分散体可通过将1重量份的伊曲康唑分散在0.1~10重量份的羟丙基甲基纤维素和0.01~5重量份的吸收促进剂混合物中而以非晶形制得。伊曲康唑固体分散体的含量优选为40~69.9wt%,以口服组合物的总重量计。如果伊曲康唑固体分散体的含量小于40wt%,将不足以获得所需的药效;而如果伊曲康唑固体分散体的含量大于69.9wt%,将对伊曲康唑的有效溶出产生副作用。
在本发明中,吸收促进剂可选自柠檬酸、抗坏血酸、胆汁酸、胆酸、甘露醇、水杨酸、葡萄糖、右旋糖、蔗糖、山梨醇和麦芽糖中的一种或多种。
在本发明中,渗透诱导剂可选自氯化钠、氯化钾、氯化镁、硫酸钾、硫酸钠、硫酸镁、碳酸镁、碳酸氢钙、甘露醇、葡萄糖、乳糖和蔗糖中的一种或多种。渗透诱导剂的含量优选为0.1~30wt%,以口服组合物的总重量计。如果渗透诱导剂的含量小于0.1wt%,则伊曲康唑将延时溶出;如果渗透诱导剂的含量大于30wt%,则伊曲康唑的溶出快速提高,导致副作用,例如皮肤过敏等。
在本发明中,崩解剂可选自微晶纤维素、低取代的羟丙基纤维素、交联羧甲基纤维素钠(croscamellose sodium)、羟基乙酸淀粉钠、羧甲基纤维素钠、羧甲基纤维素和交联聚乙烯吡咯烷酮(crospovidone)中的一种或多种。崩解剂的含量优选为0.1~30wt%,以口服组合物的总重量计。如果崩解剂的含量小于0.1wt%,崩解将延时;如果崩解剂的含量大于30wt%,固体制剂将由于颗粒具有流动性及可压缩性差等原因而难以制备。
此外,本发明的口服组合物还可包括选自可药用赋形剂、粘合剂和润滑剂中的一种或多种。
在本发明中,赋形剂可选自乳糖、白糖、葡萄糖、果糖、甘露醇、玉米淀粉、马铃薯淀粉、小麦淀粉、预糊化淀粉、微晶纤维素或纤维素衍生物、糊精、磷酸氢钙、磷酸二氢钙、碳酸钙、波拉克林钾、乙酸、碳酸铵、磷酸铵、硼酸、乳酸、柠檬酸、磷酸钾、磷酸钠、乙酸钠、柠檬酸钠、乳酸钠、抗坏血酸和棕榈酸抗坏血酸酯中的一种或多种。赋形剂的含量优选为2~90wt%,以口服组合物的总重量计。
在本发明中,粘合剂可选自羟丙基纤维素、羟丙基甲基纤维素、羟基纤维素、甲基纤维素、乙基纤维素、羟乙基纤维素、聚乙烯吡咯烷酮、聚乙烯醇、明胶、糊精和微晶纤维素中的一种或多种。粘合剂的含量优选为2~40wt%,以口服组合物的总重量计。
在本发明中,润滑剂可选自硬脂酸镁、十八烷基富马酸钠、硬脂酸、滑石、二氧化硅和胶态二氧化硅中的一种或多种。润滑剂的含量优选为0.1~20wt%,以口服组合物的总重量计。
本发明的口服组合物可优选制成用于口服给药的固体,例如片剂、胶囊、颗粒剂、粉剂、丸剂、干糖浆等等,优选片剂或胶囊。
本发明的口服组合物可制成含有100~400mg,优选150~300mg伊曲康唑固体分散体的单位剂型。剂量单位优选为片剂或胶囊的形式。以给药一周计,本发明的口服组合物优选每天给药两次,每次200mg伊曲康唑。
如图4所示,使用水溶性聚合物羟丙基甲基纤维素和吸收促进剂柠檬酸制备的伊曲康唑固体分散体在含有模拟胃液和1%(w/w)聚山梨醇酯80的pH1.2和pH4.0的溶液中表现出较高的溶出度,该速度比根据韩国专利公报No.2001-0098419公开的、采用水溶性聚合物聚乙烯吡咯烷酮制备的伊曲康唑固体分散体的溶出度高至少20%。并且,本发明的口服组合物除含有伊曲康唑固体分散体外以外,还含有渗透诱导剂,例如氯化钾、碳酸镁等,和崩解剂,例如微晶纤维素、羟基乙酸淀粉钠等,从而表现出不溶性伊曲康唑在胃环境中的有效溶出。
结合下述实施例进一步对本发明进行更详细的说明。这些实施例仅旨在示例性地说明本发明,而不应解释为以任何方式对本发明范围作限制。
实施例1
将一百克原料伊曲康唑制剂(Sigma Chemical)溶解于1,000g二氯甲烷中。然后,将22.2g作为吸收促进剂的柠檬酸和100g羟丙基甲基纤维素(Dow Chemical,重均分子量为10,000~1,500,000)充分溶解于2,000g二氯甲烷/乙醇(1:1,v/v)混合溶剂中。采用喷雾干燥器(B-191微型喷雾干燥器,Buchi Co.,瑞士)对伊曲康唑溶液以及羟丙基甲基纤维素和柠檬酸的混合物溶液进行喷雾,以形成伊曲康唑分散于羟丙基甲基纤维素和柠檬酸中的固体分散体,生成白色非晶粉末。伊曲康唑:羟丙基甲基纤维素:柠檬酸的重量比为45:45:10。
实施例2
将实施例1制得的伊曲康唑固体分散体与胶态二氧化硅通过30目的网筛筛分并充分混合。然后,向其中加入下列表1中除硬脂酸镁和滑石以外的其它组分,混合,干燥并造粒,过25目网筛得到尺寸均匀的颗粒。随后,向其中加入硬脂酸镁和滑石并充分混合,将混合物制成片剂。将120g欧巴代AMB(Opadry AMB)(Colorcon)加至546g纯水中,充分混合以制备包衣液。采用片剂包衣机(SFC-30FN型自动包衣机,Sejong Pharmatech,韩国),保持入口温度为60~70℃,出口温度为40~43℃,将包衣液涂膜在制得的片剂上,其中每粒片剂涂有20mg的包衣液。
[表1]
伊曲康唑固体分散体 | 222.2mg |
微晶纤维素 | 58.0mg |
脱水乳糖 | 143.0mg |
交联羧甲基纤维素钠 | 120.0mg |
碳酸镁 | 20.0mg |
胶态二氧化硅 | 8.0mg |
滑石 | 7.0mg |
硬脂酸镁 | 6.0mg |
实施例3
采用实施例1制得的伊曲康唑固体分散体和下列表2中的组分制备片剂。采用如实施例2中相同的方法制备片剂并对其进行包衣。
[表2]
伊曲康唑固体分散体 | 222.2mg |
微晶纤维素 | 58.0mg |
脱水乳糖 | 153.0mg |
交联羧甲基纤维素钠 | 120.0mg |
碳酸镁 | 10.0mg |
胶态二氧化硅 | 8.0mg |
滑石 | 7.0mg |
硬脂酸镁 | 6.0mg |
实施例4
采用实施例1制得的伊曲康唑固体分散体和下列表3中的组分制备片剂。采用如实施例2中相同的方法制备片剂并对其进行包衣。
[表3]
伊曲康唑固体分散体 | 222.2mg |
微晶纤维素 | 83.0mg |
脱水乳糖 | 123.0mg |
交联羧甲基纤维素钠 | 115.0mg |
氯化镁 | 20.0mg |
胶态二氧化硅 | 8.0mg |
滑石 | 7.0mg |
硬脂酸镁 | 6.0mg |
实施例5
将实施例1制得的伊曲康唑固体分散体和胶态二氧化硅通过30目网筛筛分,并充分混合。然后,向其中加入下列表4中除硬脂酸镁以外的其它组分,混合,干燥并造粒,过25目网筛得到尺寸均匀的颗粒。随后,向其中加入硬脂酸镁并充分混合以制备片剂。片剂形成后,通过如实施例2中相同的方法对片剂进行包衣。
[表4]
伊曲康唑固体分散体 | 222.2mg |
微晶纤维素 | 80.0mg |
脱水乳糖 | 173.0mg |
交联羧甲基纤维素钠 | 75.0mg |
氯化钾 | 20.0mg |
胶态二氧化硅 | 8.0mg |
硬脂酸镁 | 6.0mg |
实施例6
采用实施例1制得的伊曲康唑固体分散体和下列表5中的组分制备片剂。采用如实施例2中相同的方法制备片剂并对其进行包衣。
[表5]
伊曲康唑固体分散体 | 222.2mg |
微晶纤维素 | 70.0mg |
脱水乳糖 | 133.0mg |
交联羧甲基纤维素钠 | 135.0mg |
碳酸氢钙 | 10.0mg |
胶态二氧化硅 | 8.0mg |
硬脂酸镁 | 6.0mg |
对比例1
采用实施例1制得的伊曲康唑固体分散体和下列表6中的组分制备片剂。采用如实施例2中相同的方法制备片剂并对其进行包衣。
[表6]
伊曲康唑固体分散体 | 222.2mg |
微晶纤维素 | 93.0mg |
脱水乳糖 | 158.0mg |
交联羧甲基纤维素钠 | 90.0mg |
胶态二氧化硅 | 8.0mg |
滑石 | 7.0mg |
硬脂酸镁 | 6.0mg |
对比例2
采用实施例1制得的伊曲康唑固体分散体和下列表7中的组分制备片剂。采用如实施例2中相同的方法制备片剂并对其进行包衣。
[表7]
伊曲康唑固体分散体 | 222.2mg |
微晶纤维素 | 78.0mg |
脱水乳糖 | 143.0mg |
交联羧甲基纤维素钠 | 120.0mg |
胶态二氧化硅 | 8.0mg |
滑石 | 7.0mg |
硬脂酸镁 | 6.0mg |
对比例3
将一百克原料伊曲康唑制剂(Sigma Chemical)溶解于1,000g二氯甲烷中。然后,将22.2g作为吸收促进剂的柠檬酸和200g聚乙烯吡咯烷酮(BASF,重均分子量为2,500~3,000,000)充分溶解于2,000g二氯甲烷/乙醇(1:1,v/v)混合溶剂中。采用喷雾干燥器(B-191微型喷雾干燥器,Buchi Co.,瑞士)对伊曲康唑溶液以及聚乙烯吡咯烷酮和柠檬酸的混合物溶液进行喷雾,以形成伊曲康唑分散于聚乙烯吡咯烷酮和柠檬酸中的固体分散体,生成白色非晶粉末。伊曲康唑:聚乙烯吡咯烷酮:柠檬酸的重量比为45:45:10。
实验例1:溶出试验
对实施例2~6和对比例1~2制得的组合物以及市售制剂(Janssen Korea Ltd.SporanoxTM胶囊)进行溶出试验。结果示于下列表8及图1和2中。将pH1.2的溶液(Korean Pharmacopeia)用作溶出液,并通过由高效液相色谱分析(HPLC)测得的伊曲康唑的溶出量确定溶出度。在本说明书中,溶出度均按照上述相同的方式测定。
[表8]
如表8和图1所示,在对比例1和2含有崩解剂但不含渗透诱导剂的组合物中,溶出度显著较低,并且难以控制,因为各组分含量的细微变化将导致溶出度的显著改变。而在实施例2~6含有渗透诱导剂及崩解剂的组合物中,溶出度显著提高,并可在宽范围内(参见图1)控制溶出度。
此外,如表8和图2所示,本发明实施例2的组合物也表现出与市售制剂相当或更高的溶出度。
并且,以下进行的实验将表明本发明含有渗透诱导剂的组合物在pH4.0和pH6.8以及pH1.2下均具有较高的溶出度。分别在pH4.0的含有1%聚山梨醇酯80的溶液中和pH6.8的含有1%聚山梨醇酯80的溶液中测定实施例2(含有渗透诱导剂和崩解剂)和对比例2(不含渗透诱导剂)含有伊曲康唑的组合物的溶出度。结果示于图3。如图3所示,本发明含有渗透诱导剂和崩解剂的组合物,其溶出度在pH4.0和pH6.8下均高于对比例的组合物。
此外,为检验水溶性聚合物的种类对溶出度的影响,分别对实施例1含有羟丙基甲基纤维素作为水溶性聚合物的固体分散体和对比例3含有聚乙烯吡咯烷酮作为水溶性聚合物的固体分散体进行溶出试验。用222.2mg各种固体分散体(对应于100g伊曲康唑)填充0号胶囊,并分别在pH1.2和pH4.0的含有1%(w/w)聚山梨醇酯80的溶液中对各固体分散体进行溶出试验。结果示于下表9和图4。
[表9]
如表9和图4所示,与对比例3含有聚乙烯吡咯烷酮的固体分散体中的溶出度相比,在实施例1含有羟丙基甲基纤维素的固体分散体中,溶出度在pH1.2的溶液中提高至少20%,而在pH4.0的溶液中提高至少60%。
如前所述,在本发明的口服组合物中,可有效控制并显著提高在胃环境中的溶出度,从而解决由伊曲康唑的不溶性引起的生物利用度低的问题。并且,本发明的口服组合物还具有经济效益,因为可由其通过干法制粒直接制备片剂。
Claims (4)
1.一种口服组合物,含有:
40~69.9wt%的固体分散体,其中将1重量份的伊曲康唑分散在0.1~10重量份的羟丙基甲基纤维素和0.01~5重量份的吸收促进剂中;
1~30wt%的渗透诱导剂;以及
1~30wt%的崩解剂,
其中所述渗透诱导剂选自氯化钠、氯化钾、氯化镁、硫酸钾、硫酸钠、硫酸镁、碳酸镁和碳酸氢钙中的一种或多种,并且所述吸收促进剂选自柠檬酸、抗坏血酸、胆汁酸、甘露醇、水杨酸、葡萄糖、右旋糖、蔗糖、山梨醇和麦芽糖。
2.权利要求1的口服组合物,其中所述吸收促进剂为胆酸。
3.权利要求1的口服组合物,其中所述崩解剂选自微晶纤维素、低取代的羟丙基纤维素、交联羧甲基纤维素钠、羟基乙酸淀粉钠、羧甲基纤维素钠、羧甲基纤维素钙和交联聚乙烯吡咯烷酮中的一种或多种。
4.权利要求1的口服组合物,进一步包括粘合剂和润滑剂中的一种或多种。
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