CN1309374C - 改进的快速崩解的多颗粒片剂 - Google Patents
改进的快速崩解的多颗粒片剂 Download PDFInfo
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Classifications
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- A61K31/612—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid
- A61K31/616—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid by carboxylic acids, e.g. acetylsalicylic acid
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- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
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Abstract
本发明涉及具有快速崩解性质的改进的多颗粒片剂,它在口腔里的崩解低于40秒,所述的片剂包括被包衣剂包衣的呈微晶形式的活性组分和载体。
Description
技术领域
本发明涉及改进的快速崩解的多颗粒片剂,其在口腔里的崩解低于40秒,一方面包括包衣剂包衣的微晶形式的活性组分,另一方面包括赋形剂。
背景技术
活性组分选自止痛药、退热药、止泻药、解痉药、消化动力调节剂和抗炎药,特别选自扑热息痛、布洛芬、阿司匹林、优洛芬和氯苯哌酰胺。
法国专利FR 9109245揭示了一般令人满意的多颗粒片剂;但是,这些片剂的一些质地在摄入时会导致砂砾和糊状感觉。
从WO 96 02237可知一种多颗粒片剂,其中预先用水分散性粘合剂包衣的活性组分与有高溶胀性粉末的纤维素型试剂、水中易溶的多元醇和一种或数种稀释剂混合;这些片剂与前述的现有技术里揭示的片剂具有相同的缺陷。
发明内容
本发明的目的首先是克服该缺陷,提供具有系统地令人愉快质地的快速崩解的片剂,该片剂也导致活性组分最佳的生物利用度。
申请人公司在广泛的研究后发现,可这样达到本发明的目的:一方面将崩解剂和至少一种颗粒可溶的具有粘合性能的稀释剂并入赋形剂,另一方面通过根据活性组分的理化特征来选择包衣剂。
结果,本发明改进的多颗粒片剂在口腔里的崩解少于40秒,它包括呈包衣的微晶形式的活性组分和赋形剂,该片剂的特征在于:
-赋形剂包括至少一种崩解剂和至少一种可溶的稀释剂,该稀释剂具有粘合性质,由少于13个碳原子的多元醇构成,它是平均粒径为100-500微米的直接压制的产物形式,或平均粒径低于100微米的粉末形式,该多元醇宜选自甘露醇、木糖醇、山梨醇和麦芽酚(maltitol),应当明白,山梨醇不可单独使用,当使用单个具有粘合性质的可溶的稀释剂时,可用直接可压制形式,而当有两个具有粘合性质的可溶的稀释剂时,一个是直接可压制形式,另一个是粉末形式,多元醇可以是相同的,直接可压制多元醇与粉末多元醇的比是99/1到50/50,优选的是80/20到50/50,
-活性组分微晶包衣剂包括至少一个包衣剂,它根据活性组分的理化性质选择,选自聚甲基丙烯酸酯、纤维素聚合物,特别是乙基纤维素、羟丙基-甲基纤维素、羟丙基纤维素和纤维素乙酰基邻苯二甲酸酯和这些聚合物的组合,任选地混入增塑剂或助溶剂,特别是多元醇。
本发明用另外的说明和涉及较佳实施方法的非限定性实施例供更好地理解。
为了制备本发明的多颗粒片剂,该方法如下或为其等价的方法。
首先,活性组分选自止痛药、退热药、止泻药、解痉药、消化动力调节剂和抗炎药,特别选自扑热息痛、布洛芬、阿司匹林、优洛芬和氯苯哌酰胺。
这样制备赋形剂,使至少一种崩解剂与至少一种具有粘合性质的可溶稀释剂混合,所述的可溶稀释剂由少于13个碳原子的多元醇构成,它是平均粒径为100-500微米的直接压制的产物形式,或平均粒径低于100微米的粉末形式,该多元醇宜选自甘露醇、木糖醇、山梨醇和麦芽酚(maltitol),应当明白,山梨醇不可单独使用。
当使用单个具有粘合性质的可溶的稀释剂时,则与山梨醇不同,可用直接可压制形式。
当使用两个具有粘合性质的可溶的稀释剂时,一个是直接可压制形式,另一个是粉末形式,多元醇可以是相同的,其组分平均粒径低于100微米,直接可压制多元醇与粉末多元醇的比是99/1到50/50,优选的是80/20到50/50。
崩解剂宜选自交联的聚乙烯吡咯烷酮(本技术领域称为crospovidone)和交联的羧甲基纤维素钠(本技术领域称为sodium croscarmellose)。
用于赋形剂构成物的崩解剂和粘合剂或可溶稀释剂的各自比例,按片剂总量来计,第一个占3-15%重量,宜为5-10%重量,第二个占40-90%重量,宜为50-70%重量;山梨醇的最大比例为30%重量。
作为本发明片剂组合物组分的活性组分在包衣前以微晶形式存在,其平均直径大致为1-500微米。
对于某些活性组分,宜使用平均直径低于100微米的微晶以增加活性组分和周围环境的交换面积;通过该途径,使溶出的溶解速度和/或体内溶解度最优化。
微晶宜用已知的流化床技术包衣。
对于平均粒径为100-500微米的微晶可直接包衣;对于粒径小于100微米的微晶,这样进行预处理:通过标准湿粒法或干粒法成颗粒,或者当所述的微晶粒径低于约20微米时,微晶预先固定在本身已知的中性的支持物上;用粘合剂,如羟丙基甲基纤维素按照标准的方法将微晶固定在中性支持物上。
从至少一种包衣剂里得到包衣,所述的包衣剂根据活性组分的理化特性,选自聚甲基丙烯酸酯类,特别是某些EUDRAGIT商标下的商品,更具体的是30%聚(丙烯酸乙酯-甲基丙烯酸甲酯)分散液(商品名为EUDRAGIT NE 30 D),E型氨基烷基-甲基丙烯酸酯共聚物(商品名为EUDRAGIT E),纤维素聚合物,特别是乙基纤维素、羟丙基甲基纤维素、羟丙基纤维素和纤维素乙酰邻苯二甲酸酯,这些聚合物的彼此组合,任选地加有增塑剂,例如聚乙二醇6000,或助溶剂,特别是多元醇,例如甘露醇。
作为例举,包衣可由下列起始物构成:
-在一种或多种有机溶剂里的EUDRAGIT NE 30 D,或EUDRAGIT NE 30 D与EUDRAGIT E的混合物,
-任选地有稀醇(hydroalcoholic)溶剂存在下带有增塑剂的乙基纤维素,或乙基纤维素与羟丙基甲基纤维素的混合物,任选地有氢化醇溶剂,
-聚甲基丙烯酸酯,与可溶的纤维素衍生物,特别是与羟丙基-甲基纤维素混合的EUDRAGIT NE 30 D,和增塑剂和/或具有粘合性质的可溶的稀释剂,
-单用EUDRAGIT E 100。
由于对本发明活性组分的微晶的包衣,所述的包衣特别包括可溶的聚合物和不溶的聚合物或它们的组合,定形片剂的特征在于:
-一方面,在pH低于5的酸介质里,片剂崩解后5-20分钟里,从包衣的微晶里溶解出来的活性组分的量等于在相同时间里,从由微晶构成、但所述的微晶未经包衣的活性组分的片剂崩解后即刻释放的活性组分的至少80%,优选的是至少100%,
-另一方面,活性组分在pH相似于唾液的pH,即7.0±0.5的pH条件下的5分钟里不明显溶出,这样保证能令人满意地遮盖其味道。
当片剂崩解后5-20分钟里,从包衣的微晶里溶解出来的活性组分等于在相同时间里,从由微晶构成、但所述的微晶未经包衣的活性组分的片剂崩解后即刻释放的活性组分的至少100%时,活性组分的生物利用度至少等于从所述微晶未经包衣的片剂里得到的相同活性组分的生物利用度。
为了制备片剂,首先制备赋形剂和包衣的微晶的混合物,然后使该混合物在干燥混合器里均质化。
优选的是,向该混合物里掺入甜味剂、调味剂和润滑剂。
甜味剂可选自天冬酰苯丙氨酸甲酯和糖精钠,润滑剂选自硬脂酸镁、硬脂酰基富马酸钠、硬脂酸和聚乙二醇6000。
然后使混合物经压制,该压制力应足以使所得的片剂能被工业化地处理和包装,然后由病人携带和处理,不需要特别小心;作为信息用,满足这些条件的硬度为20-70牛顿。
本发明的片剂对于现有的片剂而言,同时改进了活性组分到达器官的速度和片剂的口味。
具体实施方式
实施例1
剂量为500毫克的多颗粒扑热息痛片剂
上述片剂组合物从下表I得到。
表I
构成 | 百分配方 |
包衣的扑热息痛 | 39.2 |
供直接压制的甘露醇 | 36.7 |
晶体粉末甘露醇 | 12.3 |
交联的聚乙烯吡咯烷酮 | 8.6 |
天冬酰苯丙氨酸甲酯 | 2.7 |
红醋栗调味剂 | 0.4 |
硬脂酸镁 | 0.1 |
总计 | 100.0% |
如下所述制备片剂。
将扑热息痛微晶引入流化床装置,使EUDRAGIT E 100、EUDRAGIT NE 30 D和胶体二氧化硅在乙醇中的分散液喷雾于微晶上,以得到被10%聚合物包衣的微晶。
所有的赋形剂过筛,在干燥的混合器里使含包衣的扑热息痛和赋形剂均质化。在装有17mm直径的冲模的压片机上将混合物分配入模。
压制力调节到使片剂硬度达40±10牛顿的力。
这样制得的片剂在口腔里的崩解时间低于40秒。
这个时间相应于这样的时间:它分开了片剂与口腔里唾液接触的时刻,和另一方面的由于片剂与唾液接触崩解得到的悬浮液溶胀的时刻。
上述的崩解时间低于40秒是健康对象代表组得到的平均值。
对上述片剂的药代动力学研究显示,活性组分,即扑热息痛的生物利用度与市售的扑热息痛片剂给予后观察到的生物利用度没有明显的不同。通过对本发明片剂上存在的包衣而掩盖扑热息痛的味道不会延误吸收,它甚至稍快,在平均0.5小时达最大,而市售的参照片剂平均0.88小时达最大。
下表II显示了对于本发明片剂和市售的有即刻释放活性组分并未包衣的扑热息痛片剂的性质进行记录的值。
表II
参数 | 含500毫克扑热息痛的本发明片剂 | 含500毫克扑热息痛的市售片剂 |
滞后时间(小时) | 0.17 | 0.17 |
T最大(小时) | 0.50 | 0.88 |
C最大(微克/ml) | 6.28±1.61 | 6.26±2.37 |
AUC0-t(微克小时/ml) | 18.59±3.44 | 18.10±3.40 |
AUCinf(微克小时/ml) | 19.68±3.85 | 19.24±3.79 |
该表中,
-滞后时间表示给药和检测对象血中活性成分之间经过的时间(小时),
-T最大指活性组分血清浓度达到最大值所需的时间(小时),
-C最大(微克/ml)指活性组分在T最大时的最大浓度,它表达为每毫升血清中的活性组分微克,
-AUC0-t指直至最后取样定量时活性组分的血清浓度对时间的函数曲线下的面积,和
-AUCinf指活性组分的血清浓度对外推到无限的时间的函数曲线下的面积。
表II结果显示,用来遮盖活性组分味道的包衣不会导致活性组分生物利用度的改变或延误吸收,这在给予某些需要速效的活性组分,特别是止痛剂时是至关重要的。
实施例2
剂量2毫克的多颗粒氯苯哌酰胺片剂
从下表III得到上述片剂组合物。
表III
组成 | 百分数配方 |
包衣的氯苯哌酰胺 | 15.1 |
供直接压制的甘露醇 | 56.6 |
晶体粉末甘露醇 | 18.8 |
交联的聚乙烯吡咯烷酮 | 5.0 |
天冬酰苯丙氨酸甲酯 | 3.0 |
薄荷调味剂 | 0.7 |
硬脂酸镁 | 0.8 |
总计 | 100.0% |
如实施例1所述的方法制备该片剂。
活性组分为微晶形平均粒径小于20微米;结果,使这些微晶固定在由多元醇构成的、平均粒径为60微米的中性支持物上,所述的固定用羟丙基-甲基纤维素溶液进行。
然后用20%的EUDRAGIT NE 30 D和EUDRAGIT E 100的混合物时包含氯苯哌酰胺的中性支持物进行包衣。
该片剂的硬度为30±5牛顿。
它在口腔里20秒内崩解。
实施例3
剂量12.5毫克的优洛芬片剂
从下表IV得到上述片剂组合物。
表IV
组成 | 百分数配方 |
包衣的优洛芬 | 6.7 |
供直接压制的甘露醇 | 63.3 |
晶体粉末甘露醇 | 22.2 |
交联的聚乙烯吡咯烷酮 | 5.0 |
天冬酰苯丙氨酸甲酯 | 1.3 |
薄荷调味剂 | 0.7 |
硬脂酸镁 | 0.8 |
总计 | 100.0% |
如实施例2所述的方法制备该片剂。
活性组分为微晶形式其平均粒径小于20微米;结果,使这些微晶固定在由多元醇构成的、平均粒径为60微米的中性支持物上,所述的固定用羟丙基-甲基纤维素溶液进行。
然后用20%的EUDRAGIT NE 30 D、羟丙基甲基纤维素和聚乙二醇6000的混合物将包含优洛芬的中性支持物包衣。
该片剂的硬度为35±5牛顿。
它在口腔里20秒内崩解。
实施例4
剂量325毫克的乙酰水杨酸多颗粒片剂
从下表V得到上述片剂组合物。
表V
组成 | 百分数配方 |
包衣的乙酰水杨酸 | 37.4 |
供直接压制的甘露醇 | 38.0 |
晶体粉末甘露醇 | 12.6 |
交联的聚乙烯吡咯烷酮 | 8.6 |
天冬酰苯丙氨酸甲酯 | 2.9 |
硬脂酰富马酸钠 | 0.5 |
总计 | 100.0% |
如实施例1所述的方法制备该片剂。
构成上述片剂的乙酰水杨酸微晶被4.5%乙基纤维素N7和聚乙二醇6000包衣。
该片剂的硬度为50±15牛顿。
它在口腔里20秒内崩解。
实施例5
剂量100毫克的布洛芬多颗粒片剂
从下表VI得到上述片剂组合物。
表VI
组成 | 百分数配方 |
包衣的布洛芬 | 14.4 |
供直接压制的甘露醇 | 52.5 |
晶体粉末甘露醇 | 17.5 |
交联的聚乙烯吡咯烷酮 | 10.0 |
天冬酰苯丙氨酸甲酯 | 3.7 |
樱桃调味剂 | 0.9 |
硬脂酸镁 | 1.0 |
总计 | 100.0% |
如实施例1所述的方法制备该片剂。
平均粒径30微米范围里的布洛芬微晶用标准湿粒方法制粒。所得的颗粒然后用20%乙基纤维素N7和聚乙二醇6000的混合物包衣。
所得的经包衣的布洛芬晶体与赋形剂混合,然后压制。
所得片剂的硬度为40±10牛顿。
它在口腔里30秒内崩解。
Claims (9)
1.一种多颗粒片剂,它在口腔里的崩解少于40秒,它包括呈包衣的微晶形式的活性组分和赋形剂,该片剂的特征在于:
-赋形剂包括,按片剂总量来计,3-15%重量的至少一种崩解剂和40-90%重量的至少一种可溶的稀释剂,该稀释剂由少于13个碳原子的多元醇构成,所述的多元醇是平均粒径为100-500微米的直接压制的产物形式,或平均粒径低于100微米的粉末形式,所述的多元醇选自甘露醇、木糖醇、山梨醇和麦芽酚,条件是,当使用单个可溶的稀释剂时,可使用除了山梨醇外的其它多元醇的直接可压制形式,而当使用至少两个可溶的稀释剂时,一个是直接可压制形式,其它的是相同的多元醇或另一种多元醇的粉末形式,直接可压制多元醇与粉末多元醇的比是99/1到50/50,
-活性组分微晶包衣包括至少一个包衣剂,选自聚甲基丙烯酸酯、纤维素聚合物,和这些聚合物的组合。
2.根据权利要求1所述的多颗粒片剂,其特征在于崩解剂和可溶稀释剂用量比分别为5-10%重量和50-70%重量。
3.根据权利要求1或2所述的多颗粒片剂,其特征在于,山梨醇的最大用量为30%重量。
4.根据权利要求1或2所述的多颗粒片剂,其特征在于直接可压制多元醇与粉末多元醇的比为80/20-50/50。
5.根据权利要求1所述的多颗粒片剂,其特征在于包衣剂选自乙基纤维素、羟丙基甲基纤维素、羟丙基纤维素和纤维素乙酰基邻苯二甲酸酯。
6.根据权利要求1所述的多颗粒片剂,其特征在于,所述的包衣剂中还混入增塑剂或助溶剂。
7.根据权利要求6所述的多颗粒片剂,其特征在于,所述的助溶剂是多元醇。
8.根据权利要求1所述的多颗粒片剂,其特征在于所述的活性组分选自止痛药、退热药、止泻药、解痉药、消化动力调节剂和抗炎药。
9.根据权利要求1所述的多颗粒片剂,其特征在于所述的活性组分选自扑热息痛、布洛芬、阿司匹林、优洛芬和氯苯哌酰胺。
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- 1998-07-21 CN CNB988073218A patent/CN1309374C/zh not_active Expired - Lifetime
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- 1998-07-21 WO PCT/FR1998/001601 patent/WO1999004763A1/fr active IP Right Grant
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- 1998-07-21 TR TR2000/00139T patent/TR200000139T2/xx unknown
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