CN1655789A - 新型含氟班色林多晶型物a的药物组合物 - Google Patents
新型含氟班色林多晶型物a的药物组合物 Download PDFInfo
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- CN1655789A CN1655789A CNA038117029A CN03811702A CN1655789A CN 1655789 A CN1655789 A CN 1655789A CN A038117029 A CNA038117029 A CN A038117029A CN 03811702 A CN03811702 A CN 03811702A CN 1655789 A CN1655789 A CN 1655789A
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- flibanserin polymorph
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- PPRRDFIXUUSXRA-UHFFFAOYSA-N flibanserin Chemical compound FC(F)(F)C1=CC=CC(N2CCN(CCN3C(NC4=CC=CC=C43)=O)CC2)=C1 PPRRDFIXUUSXRA-UHFFFAOYSA-N 0.000 title claims abstract description 53
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Classifications
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Abstract
本发明涉及包含氟班色林多晶型物A的口服药物组合物、其制备方法以及其作为药剂的用途。
Description
本发明涉及口服含氟班色林(flibanserin)的药物组合物、其制备方法以及作为药剂的应用。
背景技术
化合物1-[2-(4-(3-三氟甲基-苯基)哌嗪-1-基)乙基]-2,3-二氢-1H-苯并咪唑-2-酮(氟班色林)的氢氯化物公开于欧洲专利申请EP-A-526434中,并且具有以下的化学结构式:
氟班色林具有5-HT1A和5-HT2-受体亲和力。因此它是有可能治疗一系列疾病的治疗剂,例如,抑郁、精神分裂症、帕金森症、焦虑、睡眠失调、性和精神紊乱与年龄性记忆力减退。
在一种药物活性物质在批准上市作为药物之前,具有某种药物活性是其当然需要满足的先决条件。然而,有许多附加要求需要药物活性剂必须满足。这些要求是基于活性物质其本身具有的各种各样的参数。不用很严格地说,这些参数例子例如活性剂在不同环境中的稳定性,其在生产成为药物的过程中和活性物质在其最后药剂组合物中的稳定性。用于制备药物组合物的药物活性物质应尽可能地纯净,其在不同环境条件下长时间保存的过程中的稳定性必须被保证。防止应用的药物组合物中除含有实际的活性物质以外,例如还含有其降解产物,这一点是绝对必要的。在这种情况下药剂中活性物质的含量将少于规定含量。
在药物制剂中活性物质的均匀分布是一个关键性因素,特别是当药剂以低剂量给药时。为确保均匀分布,活性物质的粒子大小,例如通过碾磨,可以被减小到合适的程度。由于需要尽可能地避免碾磨(或微粉化)产生的副反应使药物活性物质降解或无定形化,尽管在过程中需要猛烈的条件,活性物质在整个碾磨过程保持高度稳定性,这一点是十分必要的。只有当活性物质在碾磨过程中足够稳定时,才有可能以可重现方式生产通常含有特定数量活性物质的均一的药物组成。
最后,药物组合物的特性无疑有助于活性物质的生物利用度以及药剂在预期医疗应用中的功效。
本发明的目的在于提供一种含有氟班色林的口服给药的新型制剂,所述的药物组合物符合上述苛刻的要求。
发明内容
现已惊讶地发现,特定多晶型形式的氟班色林游离碱满足本发明的制剂要求。可以通过特定的反应条件得到这种特定的多晶型形式(多晶型物A),此条件将在下面作详细的介绍。在其他特征中,该多晶型形式其特征在于在应用DSC(差示扫描热量法)热量分析时在161℃时有吸热最大值。
本发明的药物组合物为一种口服给药的片剂,包含含氟班色林多晶型物A的片芯,至少一种药物可接受赋形剂的混合物,并包括在所述核外的膜包衣,所述的氟班色林多晶型物A特征在于用DSC检测在161℃有吸热最大值。
根据本发明膜包衣片剂中片芯的总质量,氟班色林多晶型物A占1到50重量%,优选5到45重量%,特别优选10到40重量%。根据片芯的总质量,特别优选地氟班色林多晶型物A的比例为15到35重量%之间,更加优选地在17到32重量%之间。
根据本发明的药物制剂的片芯包含,除氟班色林多晶型物A之外,至少一种作为填充剂/干燥粘合剂的赋形剂。在本发明的范围内,典型的填充剂为例如,乳糖一水合物、经良好研磨的物质或改性乳糖如喷雾干燥乳糖和聚附乳糖(Tablettose)、无水乳糖、微晶纤维素、磷酸氢钙、玉蜀黍淀粉、糖醇如甘露醇和山梨醇以及其混合物。在本发明的制剂中优选的填充剂选自乳糖类、微晶纤维素、玉蜀黍淀粉、糖醇以及其混合物。在本发明的制剂中更优选的填充剂选自乳糖类、微晶纤维素以及其混合物。如若应用乳糖作为填充剂,优选采用乳糖一水合物的良好研磨物(例如200目级)。
根据本发明的膜包衣的片芯还包含干燥和/或湿粘合剂,例如聚乙烯吡咯酮(例如Kollidon K 25)、交联聚乙烯吡咯酮(例如Kollidon VA 64)、羟丙基甲基纤维素、羟丙基纤维素、玉蜀黍淀粉以及其混合物。优选的粘合剂选自聚乙烯吡咯酮、羟丙基甲基纤维素、羟丙基乙基纤维素、羟丙基纤维素以及其混合物。最优选羟丙基甲基纤维素作为粘合剂。如若应用羟丙基甲基纤维素(HPMC),优选HPMC聚合物HPMC USP2910和USP2208例如由Dow Chemical Company提供的例如像Methocel E5、E4M、E15M、(K15M和K100M)。在上述提及的缩写中指定″E″代表USP2910,″K″代表USP2208。数字指定代表在2%水溶液中的粘度(例如,5代表粘度为5厘泊;15M代表粘度为15000厘泊)。
根据本发明膜包衣片剂中片芯的总质量,填充剂优选为50到99重量%,更优选55到95重量%,特别优选约为60到90重量%。根据片芯的总重量,特别优选地,填充剂总重量的比例在65到85重量%之间,更优选在68到80重量%之间。
本发明片剂制剂的片芯优选包含氟班色林多晶型物A和作为药物可接受赋形剂的乳糖一水合物。更优选地,根据本发明片剂制剂的片芯包含氟班色林多晶型物A和作为药物可接受赋形剂的乳糖一水合物和微晶纤维素。在本发明制剂中包含的作为充填成分(或药物可接受赋形剂)的乳糖一水合物与微晶纤维素的混合物中,乳糖一水合物与微晶纤维素的比例为例如在约为15∶1到约为1∶5之间,优选在约为10∶1到约为1∶3之间,更优选约为6∶1到约为1∶1。
在另一个优选的实施方案中,本发明片剂制剂包含氟班色林多晶型物A和作为药物可接受赋形剂的乳糖一水合物、微晶纤维素和HPMC。本发明特别优选的制剂包含作为填充剂/粘合剂成分(或药物可接受赋形剂)的乳糖一水合物、微晶纤维素和HPMC的混合物,根据作为制备片芯的填充剂/粘合剂的总重量,乳糖一水合物的重量为例如在50到95重量%之间,优选60到90重量%,更优选约为65到85重量%。在一个优选实施方案中,根据作为制备片芯的填充剂/粘合剂的总重量,这些片剂的制剂包含乳糖一水合物约为70到80重量%。在特别优选实施方案中,本发明包含作为填充剂/粘合剂成分(或药物可接受赋形剂)的乳糖一水合物、微晶纤维素和HPMC的混合物,根据作为制备片芯的填充剂/粘合剂的总重量,微晶纤维素的重量为例如在5到45重量%之间,优选15到35重量%,更优选约为20到30重量%。在特别优选实施方案中,根据作为制备片芯的填充剂/粘合剂的总重量,这些片剂的制剂包含的微晶纤维素约为22到28重量%。在特别优选实施方案中,本发明包含作为填充剂/粘合剂成分(或药物可接受赋形剂)的乳糖一水合物、微晶纤维素和HPMC的混合物,根据作为制备片芯的填充剂/粘合剂的总重量,HPMC的重量为例如在0.5到5重量%之间,优选1.0到4.5重量%。在特别优选实施方案中,根据作为制备片芯的填充剂/粘合剂的总重量,这些片剂的制剂包含HPMC约为1到3重量%。
根据本发明片剂制剂的片芯除包含上述成分外,还可以包含崩解剂。在本发明的范围中,这些崩解剂也可以被称为分解剂。本发明的这些崩解剂优选地选自淀粉乙醇酸钠、交联聚乙烯吡咯烷酮、交联甲羧纤维素钠、钠-羧基甲基纤维素、干玉蜀黍淀粉以及其混合物。在本发明的范围中,特别优选淀粉乙醇酸钠、交联聚乙烯吡咯烷酮、钠-羧基甲基纤维素和交联甲羧纤维素钠,优选应用交联甲羧纤维素钠。如果应用上述崩解剂,其重量根据本发明膜包衣片剂的片芯的总重量而定,例如在0.1-10重量%之间,优选约为0.5-5重量%,更优选约为1-3重量%。
本发明膜包衣片剂的片芯还可以包含助流剂作为其他成分。在本发明的范围中,助流剂包括例如,二氧化硅、滑石粉、硬脂酸镁以及其混合物。基于本发明优选应用二氧化硅,特别优选胶体、高度分散的形式。如果应用上述助流剂,其重量根据本发明膜包衣片剂的片芯的总重量而定,例如在0.1-5重量%之间,优选约为0.3-2重量%,更优选约为0.4-1.5重量%。
本发明膜包衣片剂的片芯还可以包含流动剂、润滑剂和脱膜剂或抗粘合剂作为其他成分。在本发明的范围中,这些包括例如,硬脂酸、硬脂酸镁、硬脂酸钙、硬脂酰延胡索酸钠、三山嵛酸甘油酯、滑石粉以及其混合物。基于本发明优选应用硬脂酸和硬脂酸镁。如果应用上述一种或几种成分,其重量根据本发明膜包衣片剂的片芯的总重量而定,例如在0.01-5重量%之间,优选约为0.05-3重量%,更优选约为0.1-2重量%。特别是如果应用硬脂酸镁的情况下,其重量约占本发明膜包衣片剂的片芯的总重量0.2-1.5重量%。
本发明包裹膜包衣片剂片芯的包衣包含至少一种或多种成膜剂,其选自羟丙基甲基纤维素、羟丙基纤维素、甲基纤维素、羟甲基纤维素、羟乙基纤维素和聚(乙基丙烯酸酯)甲基异丁烯酸,例如后者以丙烯酸树脂NE 30 D的形式。可选地,例如可应用丙烯酸树脂(Eudragit)RL 30 D或丙烯酸树脂E12.5。上面提及的成分可选择应用其混合物。优选的成膜剂是羟丙基甲基纤维素、羟丙基纤维素、羟甲基纤维素和羟乙基纤维素,其中基于本发明特别优选羟丙基甲基纤维素和羟丙基纤维素。上面提及的成膜剂可单独或混和使用。如果应用上述提及的成膜剂,在本发明的范围中羟丙基甲基纤维素特别重要。成膜剂重量约占本发明膜包衣片剂的膜包衣的总重量20-95重量%,优选30-90重量%。
包裹片芯的膜包衣可含有乳化剂和/或可塑剂,例如,聚乙二醇、甘油和丙二醇,也可以为其混和的形式。优选应用聚乙二醇作为可塑剂。对本发明为非限制性地,聚乙二醇400和聚乙二醇6000为特别优选的聚乙二醇。在本发明的介绍中,词语聚乙二醇(Macrogol)可以理解为词语聚乙二醇(polyethyleneglyco)。上述提及的数值400和6000是指所用聚乙二醇的平均分子量。可塑剂重量约占本发明膜包衣片剂的膜包衣的总重量1-50重量%,优选5-40重量%,特别优选10-30重量%。特别优选的可塑剂约占膜包衣片剂的膜包衣的总重量的10-25重量%,更优选约为12-18重量%。
本发明膜包衣片剂的膜包衣还可以含有色素和着色辅料。将在例子中提及铁氧化物、二氧化钛、滑石粉以及其混合物。如应用滑石粉,其重量应约占膜包衣片剂的膜包衣的总重量5-50重量%,优选10-40重量%,特别优选15-30重量%。优选的滑石粉的重量应约占膜包衣片剂的膜包衣的总重量15-20重量%。如应用二氧化钛,其重量应约占膜包衣片剂的膜包衣的总重量5-55重量%,优选10-40重量%,特别优选15-35重量%。优选的二氧化钛的重量应约占膜包衣片剂的膜包衣的总重量20-30重量%。如应用铁氧化物,其重量应约占膜包衣片剂的膜包衣的总重量0.1-5重量%,优选0.25-3重量%,特别优选0.5-1.5重量%。
在特别优选实施方案中,本发明片剂片芯的膜包衣包含羟丙基甲基纤维素、聚乙二醇和二氧化钛。在另一个特别优选实施方案中,本发明片剂片芯的膜包衣包含羟丙基甲基纤维素、聚乙二醇、二氧化钛和滑石粉。在另一个特别优选实施方案中,本发明片剂片芯膜包衣包含羟丙基甲基纤维素、聚乙二醇、二氧化钛和滑石粉和铁氧化物,优选氧化红铁(三氧化二铁)。
本发明药物组合物可按照本专利申请中试验部分的步骤提纲进行制备。
根据氟班色林的药效,本发明还涉及包含氟班色林多晶型物A的药剂制剂作为药物的应用。
本发明的另一方面是涉及包含氟班色林多晶型物A的本发明制剂在治疗疾病上的应用,其中应用化合物显示出的与5-HT1A和5-HT2-受体的亲和性具有治疗作用。
本发明的另一方面是涉及包含氟班色林多晶型物A的本发明制剂在治疗疾病,如抑郁、精神分裂症、帕金森症、焦虑、睡眠失调、性和精神紊乱和年龄性记忆力减退上的应用。
特别地,本发明涉及对于包含氟班色林多晶型物A的本发明制剂在治疗性欲紊乱上的应用。
在一种优选的实施方案中,本发明涉及包含氟班色林多晶型物A的本发明制剂在治疗以下疾病中应用,如机能减退的性欲障碍、性欲缺失(loss ofsexual desire)、性欲缺乏(lack of sexual desire)、性欲减退(decreased sexualdesire)、性欲抑制(inhibited sexual desire)、性功能缺失(loss of libido)、性功能失调(libido disturbance)和性冷淡。
特别优选地本发明涉及包含氟班色林多晶型物A的本发明制剂在治疗紊乱,如机能减退的性欲障碍、性欲缺失、性欲缺乏、性欲减退、性欲抑制中应用。在一种特别优选的实施方案中,本发明涉及包含氟班色林多晶型物A的本发明制剂,在治疗紊乱,如机能减退的性欲障碍和性欲缺失中应用。
本发明的另一方面涉及一种治疗疾病的方法,其中利用显示的对5-HT1A和5-HT2-受体的亲和性的化合物具有治疗作用,所述方法包括施用本发明含有氟班色林多晶型物A的制剂。
本发明的另一方面涉及一种治疗抑郁、精神分裂症、帕金森症、焦虑、睡眠失调、性和精神紊乱和年龄性记忆力减退的方法,所述方法包括施用本发明含有氟班色林多晶型物A的制剂。
特别地,本发明涉及一种治疗性欲紊乱的方法,所述方法包括施用本发明含有氟班色林多晶型物A的制剂。
在优选实施方案中,本发明涉及一种治疗紊乱,如机能减退的性欲障碍、性欲缺失、性欲缺乏、性欲减退、性欲抑制、性功能缺失、性功能失调和性冷淡的方法,所述方法包括施用本发明含有氟班色林多晶型物A的制剂。
本发明特别优选是一种治疗紊乱,如机能减退的性欲障碍、性欲缺失、性欲缺乏、性欲减退、性欲抑制的方法,所述方法包括施用本发明含有氟班色林多晶型物A的制剂。
在一种特别优选实施方案中,本发明涉及一种治疗紊乱,如机能减退的性欲障碍和性欲缺失的方法,所述方法包括施用本发明含有氟班色林多晶型物A的制剂。
本发明含有氟班色林多晶型物A制剂的上述提及的治疗作用,可以在男性和女性身上实现。然而,根据本发明的另一方面,本发明含有氟班色林多晶型物A的制剂优选应用于治疗女性性功能障碍。
本发明含有氟班色林多晶型物A制剂的有益影响,无论是否失调是天生的,或是后天的,以及病原起源独立的[器质性的(由生理和药物诱导的),心理发生性的,由器质性的(由生理和药物诱导的)和心理发生性的组合的,或不明]都可以被观察到。
本发明将通过下面的例子进一步描述。这些例子公开了本发明的某种优选实施方案。相应的,本发明不受下面这些明确的公开例子所约束是显而易见的。
氟班色林多晶型物A的合成:
向反应器中加入375kg的1-[(3-三氟甲基)苯基]-4-(2-氯乙基)哌嗪、2500kg水和200kg的45%氢氧化钠水溶液。搅拌中加入169.2kg的1-(2-丙烯基)-1,3-二氢-苯并咪唑-2H-酮、780kg异丙醇、2000kg水和220kg的45%氢氧化钠水溶液。将反应混合物加热到75-85℃,并加入160kg浓盐酸和200kg水。在恒定的温度下搅拌反应混合物约45分钟。蒸馏水和异丙醇的混合物(约3000kg)后,冷却残留物至65-75℃,加入125kg的45%氢氧化钠水溶液调节pH值至6.5-7.5。冷却至45-50℃时,加入约4kg的45%氢氧化钠水溶液调节pH值至8-9。随后冷却混合物至30-35℃,离心。得到的残留物用340l水和126l异丙醇洗,然后再用水洗,直到氯化物全部消失。这种湿产物在约为45-55℃下真空干燥,得到358kg粗制氟班色林多晶型物A。向另一个反应器中加入得到的粗制产物和1750kg丙酮,搅拌中加热反应混合物直到回流。过滤得到的溶液,并蒸馏浓缩滤液。使温度在0-5℃维持1小时,然后过滤分离沉淀物,于55℃至少干燥12小时。得到最终产量为280kg的纯氟班色林多晶型物A。
氟班色林多晶型物A的表征:
氟班色林多晶型物A应用DSC(差示扫描热量法)鉴定。检测多晶型物A的峰温度约为161℃。利用DSC鉴定的时候,应用一种带有TC 10-A处理装置的Mettler TA 3000系统和DSC 20单元。加热率为10K/分钟。
氟班色林多晶型物A还可以通过粉末X射线衍射计鉴定。多晶型物A的X射线粉状衍射图谱可以按照以下条件得到:
装置: 带数码microvax 2000的飞利浦PW 1800/10衍射计
参数设定:
X射线
管类型: Cu(长精细焦点)
波长(λ): Kα1=1.54060
Kα2=1.54439
强度比例(α2/α1): 0.500
起始角[°2Θ]: 2.000
终止角[°2Θ]: 60.000
步进[°2Θ]: 0.020
最大强度[s]: 7310.250
扫描类型: 持续
最小峰尖宽: 0.00
最大峰尖宽: 1.00
峰底宽: 2.00
最小显著性: 0.75
峰数: 69
发生器: 高电压: 50KV
管电流: 30mA
多晶型物A的粉末X射线衍生图谱如图1所。适当的数值收集在表1中。
表1:
角度 d-值 d-值 峰宽 峰强度 背景 相对 显著性
[°2Θ] α1[] α2[] [°2Θ] [counts] 强度 强度
[counts] [%]
5.195 16.9967 17.0390 0.960 8 69 0.1 1.05
9.045 9.7689 9.7931 0.100 92 96 1.3 0.97
9.335 9.4660 9.4896 0.080 114 98 1.6 0.88
10.025 8.8160 8.8379 0.140 400 100 5.5 7.18
10.595 8.3430 8.3637 0.140 204 102 2.8 3.46
11.290 7.8309 7.8503 0.140 467 104 6.4 6.91
13.225 6.6891 6.7058 0.180 548 112 7.5 13.10
14.595 6.0642 6.0793 0.180 404 121 5.5 9.17
15.460 5.7268 5.7410 0.140 4186 125 57.3 23.20
16.655 5.3185 5.3317 0.200 515 130 7.0 12.38
17.085 5.1856 5.1985 0.100 1347 132 18.4 2.78
17.285 5.1260 5.1388 0.060 1399 135 19.1 2.26
17.420 5.0866 5.0992 0.100 1204 135 16.5 4.71
18.140 4.8863 4.8984 0.180 1043 139 14.3 13.14
18.650 4.7538 4.7656 0.120 1063 142 14.5 0.91
19.140 4.6332 4.6447 0.140 7310 144 100.0 32.77
19.820 4.4757 4.4869 0.160 3624 146 49.6 9.02
20.080 4.4184 4.4294 0.140 5402 149 73.9 21.06
20.385 4.3530 4.3638 0.160 2652 149 36.3 23.25
21.215 4.1845 4.1949 0.160 369 154 5.0 5.78
21.890 4.0570 4.0670 0.200 773 156 10.6 3.09
22.630 3.9259 3.9357 0.280 4277 161 58.5 74.66
23.210 3.8291 3.8386 0.120 484 164 6.6 3.33
24.355 3.6516 3.6607 0.060 2725 169 37.3 1.16
24.610 3.6144 3.6234 0.140 3540 172 48.4 17.08
24.995 3.5596 3.5684 0.100 529 174 7.2 1.01
25.260 3.5228 3.5316 0.120 557 174 7.6 3.02
26.575 3.3514 3.3597 0.240 2421 182 33.1 42.58
27.155 3.2811 3.2893 0.140 676 185 9.2 1.32
27.310 3.2629 3.2710 0.100 767 185 10.5 2.75
27.865 3.1991 3.2071 0.120 420 188 5.7 1.08
28.210 3.1608 3.1686 0.100 1467 190 20.1 0.79
28.325 3.1482 3.1560 0.140 1789 190 24.5 4.41
28.650 3.1132 3.1210 0.180 1204 190 16.5 11.65
29.520 3.0234 3.0309 0.220 1011 196 13.8 15.74
30.250 2.9521 2.9594 0.120 159 199 2.2 1.22
31.105 2.8729 2.8800 0.360 282 204 3.9 8.14
31.905 2.8026 2.8096 0.100 339 207 4.6 0.96
32.350 2.7651 2.7720 0.120 237 210 3.2 3.01
33.300 2.6884 2.6950 0.180 1347 216 18.4 14.06
33.640 2.6620 2.6686 0.100 404 216 5.5 1.45
34.880 2.5701 2.5765 0.200 202 222 2.8 1.04
35.275 2.5422 2.5486 0.240 299 225 4.1 4.84
36.055 2.4890 2.4952 0.280 202 228 2.8 3.78
36.910 2.4333 2.4393 0.320 169 234 2.3 0.90
37.160 2.4175 2.4235 0.120 216 234 3.0 2.14
37.680 2.3853 2.3912 0.240 240 237 3.3 1.58
39.435 2.2831 2.2888 0.280 449 246 6.1 2.67
39.675 2.2698 2.2755 0.080 396 246 5.4 0.82
40.325 2.2347 2.2403 0.160 520 250 7.1 0.95
40.930 2.2031 2.2086 0.120 480 253 6.6 2.66
41.445 2.1769 2.1823 0.240 372 256 5.1 2.65
41.990 2.1499 2.1552 0.120 538 259 7.4 1.31
42.670 2.1172 2.1225 0.160 428 262 5.9 1.45
43.145 2.0950 2.1002 0.120 433 266 5.9 1.50
44.190 2.0478 2.0529 0.160 376 269 5.1 0.89
46.095 1.9675 1.9724 0.160 279 279 3.8 0.86
46.510 1.9509 1.9558 0.240 310 282 4.2 0.87
48.305 1.8826 1.8872 0.200 506 292 6.9 2.06
48.900 1.8610 1.8657 0.240 615 296 8.4 1.67
50.330 1.8115 1.8160 0.160 437 303 6.0 1.73
51.035 1.7881 1.7925 0.080 416 306 5.7 0.93
53.550 1.7099 1.7141 0.480 177 317 2.4 2.84
54.500 1.6823 1.6865 0.400 130 324 1.8 1.37
55.420 1.6565 1.6606 0.320 130 328 1.8 1.72
56.220 1.6348 1.6389 0.320 121 331 1.7 0.87
56.770 1.6203 1.6243 0.240 142 335 1.9 1.59
57.405 1.6039 1.6079 0.240 112 339 1.5 1.19
58.500 1.5764 1.5804 0.240 67 342 0.9 1.57
含氟班色林的膜包衣片剂的制备:
A)使用仪器:
在制备本发明的药物组合物的方法中应用下面设备:
制备制粒液和膜包衣混悬液的带有Ekato搅拌器和Ultra Turrax的混合容器;
高度剪切混合机/颗粒机(例如Diosna P 400);
湿法过筛机(例如Alexanderwerk);
流化床干燥器(例如Glatt WSG 15);
干法过筛机(例如Quadro Comil AS 197);
自由降落混料机(例如Servolift 120l或容器混合器);
旋转式压片机(例如Fette P 1200);
膜包衣机(例如Glatt GC 1250);
B)方法说明:
第一步准备湿法制粒的制粒液。将纯净水装在合适的混和容器中并加热至约80℃。然后搅拌加入羟丙甲纤维素(Methocel E5 Prem)和/或湿粘合成分,将此分散液冷却至室温。如若必要,液体放置过夜(溶解完全/减少起泡),在使用前搅拌均匀。如若必要,任何的重量缺失可以由纯净水补偿。此制粒液的干燥物质(固体成分)优选在范围4-6%。
在制粒过程中,依次加入经过精细磨过并且过筛的乳糖一水合物,所需量的微粉化的氟班色林多晶型物A(根据剂量强度),和微晶纤维素(AvicelPH101),以叶轮和斩波器片叶搅拌4分钟直至均匀。其次向制粒液中应用手动或喷雾尖嘴加入制粒液,再次应用叶轮和斩波器片叶湿块制粒2-3分钟。从高度剪切混合机/制粒机中卸出后,湿块应用通过一种3.0mm筛目的筛网湿法过筛以除去大的团块。将湿法过筛的物质移动至常规的流化床干燥器(或至托盘干燥器),并且以入口空气温度约为100℃出口空气温度(或产品温度)约为50℃的条件下干燥。从干燥过程中的质量损失而言,颗粒的残留湿度为0.5-1.5%。干燥的颗粒应用2mm的粗筛应用Comil筛以干法过筛。最后,将过筛的颗粒填充至一种合适的自由降落混料机(free-ballblender)中,例如容器混合机,加入交联的羧基甲基纤维素钠(交联甲羧纤维素钠,商标名:Ac-Di-Sol)和硬脂酸镁,混和各成分10-20分钟,优选15分钟,以10rpm的混和速度直至均匀。
最后的制片混合物应用合适的压片机(例如旋转式压片机),应用合适的工具(例如在50mg的片剂情况下:9mm圆形,双面凸起的,含有倾斜角度边缘的;或在100mg的片剂的情况下:14×6.8mm椭圆形),压制成含有不同目标重量的含有所需剂量强度的氟班色林片剂。对于不同工具尺寸的预定硬度标准需根据期望得到的预期药物溶出度和产品特性而定。
由于药物物质氟班色林味苦并且具有轻度过敏性,需要在片剂片芯上应用保护膜包衣,以得到稳定的和消费者满意的产品。为满足该目标,将纯净水填充至一个合适的混和容器中,借助高强度搅拌器先溶解聚乙二醇6000然后溶解羟丙基甲基纤维素,制得包衣混悬液。在下一步中,向成膜聚合体溶液中倾倒二氧化钛的含水浆液、滑石粉和氧化红铁(在着色膜片剂的情况下)。这种包衣混悬液的干燥物质为10-15%之间,优选约为12~13%。
将上述制备的片剂片芯填充进合适的膜包衣机(例如,含有36″盘的Accela Cota,或带有多孔盘以及上部喷雾系统的Glatt GC 1250包衣机),预加热至温度约为50℃。当产品温度达到后,借助喷压约为2巴、喷速约为4kg/小时(在Accela Cota的情况下)、进气孔温度约为60-85℃的一个或多个喷嘴,向片芯上喷洒包衣混悬液。为得到高质量的膜包衣,在喷洒过程中将产品的温度控制和维持为48-52℃尤为重要。在喷洒过后,在从设备中卸出之前,膜包衣片剂冷却至约30℃。整个膜包衣过程的时间为2-3小时。
在进行了全部的程序和质量监控后,大量的膜包衣片剂现在准备初步包装至各自市场包装规格中(例如PVC/PVDC泡包装或HDPE瓶)。
与以上说明的准备方法相类似,可得到下面的膜包衣片剂。
实施例1-组分
片芯
成分 | mg/片 |
氟班色林多晶型物A | 25.000 |
乳糖一水合物 | 71.720 |
微晶纤维素 | 23.905 |
HPMC(Methocel E5) | 1.250 |
羧基甲基纤维素钠 | 2.500 |
硬脂酸镁 | 0.625 |
包衣
成分 | mg/片 |
HPMC(Methocel E5) | 1.440 |
聚乙二醇6000 | 0.420 |
二氧化钛 | 0.600 |
滑石粉 | 0.514 |
红氧化铁 | 0.026 |
总膜包衣片剂 | 128.000 |
实施例2-组分
片芯
成分 | mg/片 |
氟班色林多晶型物A | 50.000 |
乳糖一水合物 | 143.440 |
微晶纤维素 | 47.810 |
HPMC(例如Pharmacoat 606) | 2.500 |
羧基甲基纤维素钠 | 5.000 |
硬脂酸镁 | 1.250 |
包衣
成分 | mg/片 |
HPMC(例如Pharmacoat 606) | 2.400 |
聚乙二醇6000 | 0.700 |
二氧化钛 | 1.000 |
滑石粉 | 0.857 |
红氧化铁 | 0.043 |
总膜包衣片剂 | 255.000 |
实施例3-组分
片芯
成分 | mg/片 |
氟班色林多晶型物A | 100.000 |
乳糖一水合物 | 171.080 |
微晶纤维素 | 57.020 |
HPMC(例如Methocel E5) | 3.400 |
羧基甲基纤维素钠 | 6.800 |
硬脂酸镁 | 1.700 |
包衣
成分 | mg/片 |
HPMC(例如Methocel E5) | 3.360 |
聚乙二醇6000 | 0.980 |
二氧化钛 | 1.400 |
滑石粉 | 1.200 |
红氧化铁 | 0.060 |
总膜包衣片剂 | 347.000 |
实施例4-组分
片芯
成分 | mg/片 |
氟班色林多晶型物A | 2.000 |
无水二碱基磷酸钙 | 61.010 |
微晶纤维素 | 61.010 |
HPMC(Methocel E5) | 1.950 |
羧基甲基纤维素钠 | 2.600 |
胶体二氧化硅 | 0.650 |
硬脂酸镁 | 0.780 |
包衣
成分 | mg/片 |
HPMC(Methocel E5) | 1.440 |
聚乙二醇6000 | 0.420 |
二氧化钛 | 0.600 |
滑石粉 | 0.514 |
红氧化铁 | 0.026 |
总膜包衣片剂 | 133.000 |
实施例5-组分
片芯
成分 | mg/片 |
氟班色林多晶型物A | 100.000 |
无水二碱基磷酸钙 | 69.750 |
微晶纤维素 | 69.750 |
HPMC(例如Methocel E5) | 2.750 |
羧基甲基纤维素钠 | 5.000 |
胶体二氧化硅 | 1.250 |
硬脂酸镁 | 1.500 |
包衣
成分 | mg/片 |
HPMC(例如Methocel E5) | 2.400 |
聚乙二醇6000 | 0.700 |
二氧化钛 | 1.043 |
滑石粉 | 0.857 |
总膜包衣片剂 | 255.000 |
实施例6-组分
片芯
成分 | mg/片 |
氟班色林多晶型物A | 20.000 |
乳糖一水合物 | 130.000 |
微晶纤维素 | 43.100 |
羟丙基纤维素(例如Klucel LF) | 1.900 |
淀粉乙醇酸钠 | 4.000 |
硬脂酸镁 | 1.000 |
包衣
成分 | mg/片 |
HPMC(例如Methocel E5) | 2.400 |
聚乙二醇6000 | 0.700 |
二氧化钛 | 1.043 |
滑石粉 | 0.857 |
总膜包衣片剂 | 205.000 |
Claims (10)
1.一种口服给药的药物组合物,所述的组合物包括含有氟班色林多晶型物A的片剂片芯,以及至少一种药物可接受赋形剂,并还包括包裹所述片剂片芯的膜包衣,所述的氟班色林多晶型物A通过DSC检测时在161℃有吸热最大值。
2.权利要求1中所述的药物组合物,其特征在于,药物可接受赋形剂为一种填充剂,选自乳糖一水合物、精细研磨物或改性乳糖如喷雾干燥乳糖与聚附乳糖(Tablettose)、无水乳糖、微晶纤维素、磷酸氢钙、玉蜀黍淀粉、糖醇以及其混合物。
3.权利要求1或2所述的药物组合物,其特征在于,氟班色林多晶型物A占片芯总重量的1到50重量%。
4.权利要求1、2或3所述的药物组合物,其特征在于,片芯含有的填充剂占片芯总重量的50到99重量%。
5.权利要求1、2、3或4所述的药物组合物,其特征在于,片芯还含有粘合剂,选自聚乙烯吡咯酮、交联聚乙烯吡咯酮、羟丙基甲基纤维素、羟丙基纤维素、玉蜀黍淀粉以及其混合物。
6.权利要求1至5中任一项所述的药物组合物,其特征在于,片芯还含有崩解剂,选自淀粉乙醇酸钠、交联聚乙烯吡咯烷酮、交联甲羧纤维素钠、钠-羧基甲基纤维素、干玉蜀黍淀粉以及其混合物。
7.权利要求1至6中任一项所述的药物组合物,其特征在于,片芯还含有助流剂、润滑剂和脱膜剂或抗粘合剂,选自二氧化硅、滑石粉、硬脂酸镁以及其混合物。
8.权利要求1至7中任一项所述的药物组合物,其特征在于,包裹片芯的膜包衣包含至少一种成膜剂,选自羟丙基甲基纤维素、羟丙基纤维素、甲基纤维素、羟甲基纤维素、羟乙基纤维素和聚(乙基丙烯酸酯)甲基异丁烯酸酯。
9.权利要求1至8中任一项的包含氟班色林多晶型物A的制剂在治疗疾病上的用途,其中应用对5-HT1A和5-HT2-受体显示出亲和性的化合物可能具有治疗作用。
10.权利要求9中的用途,其特征在于,疾病选自抑郁、精神分裂症、帕金森症、焦虑、睡眠失调、性和精神紊乱以及年龄性记忆力减退。
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CN201110122058XA Division CN102240289A (zh) | 2002-05-22 | 2003-05-19 | 含氟班色林多晶型物a的药物组合物 |
CNA2007100014771A Division CN101002780A (zh) | 2002-05-22 | 2003-05-19 | 新型含氟班色林多晶型物a的药物组合物 |
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CN201110122058XA Pending CN102240289A (zh) | 2002-05-22 | 2003-05-19 | 含氟班色林多晶型物a的药物组合物 |
CNA2007100014771A Pending CN101002780A (zh) | 2002-05-22 | 2003-05-19 | 新型含氟班色林多晶型物a的药物组合物 |
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CNA2007100014771A Pending CN101002780A (zh) | 2002-05-22 | 2003-05-19 | 新型含氟班色林多晶型物a的药物组合物 |
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EP (1) | EP1511489B1 (zh) |
JP (1) | JP3919788B2 (zh) |
KR (1) | KR101054237B1 (zh) |
CN (3) | CN1655789A (zh) |
AT (1) | ATE499939T1 (zh) |
BR (1) | BRPI0311189B8 (zh) |
CA (1) | CA2483597C (zh) |
CY (1) | CY1111470T1 (zh) |
DE (1) | DE60336225D1 (zh) |
DK (1) | DK1511489T3 (zh) |
EA (1) | EA007185B1 (zh) |
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NO (1) | NO329414B1 (zh) |
NZ (1) | NZ537253A (zh) |
PL (1) | PL211062B1 (zh) |
RS (1) | RS51718B (zh) |
SI (1) | SI1511489T1 (zh) |
UA (1) | UA80135C2 (zh) |
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US7923449B2 (en) | 2005-10-29 | 2011-04-12 | Boehringer Ingelheim International Gmbh | Benzimidazolone derivatives for the treatment of premenstrual and other female sexual disorders |
US8227471B2 (en) | 2001-10-20 | 2012-07-24 | Sprout Pharmaceuticals, Inc. | Treating sexual desire disorders with flibanserin |
US8227476B2 (en) | 2005-08-03 | 2012-07-24 | Sprout Pharmaceuticals, Inc. | Use of flibanserin in the treatment of obesity |
US8512748B2 (en) | 2006-08-25 | 2013-08-20 | Boehringer Ingelheim International Gmbh | Controlled release system and method for manufacturing the same |
CN103251598A (zh) * | 2005-11-08 | 2013-08-21 | 贝林格尔.英格海姆国际有限公司 | 氟班色林在治疗绝经前性欲障碍中的用途 |
US8545886B2 (en) | 2006-08-14 | 2013-10-01 | Boehringer Ingelheim International Gmbh | Extended release tablet formulations of flibanserin and method for manufacturing the same |
US8658207B2 (en) | 2006-08-14 | 2014-02-25 | Boehringer Ingelheim International Gmbh | Extended release tablet formulations of flibanserin and method for manufacturing the same |
WO2017128932A1 (zh) * | 2016-01-31 | 2017-08-03 | 孟晓明 | 氟班色林的新晶型及其制备方法及其用途 |
US9763936B2 (en) | 2006-06-30 | 2017-09-19 | Sprout Pharmaceuticals, Inc. | Flibanserin for the treatment of urinary incontinence and related diseases |
US10166230B2 (en) | 2007-09-12 | 2019-01-01 | Sprout Pharmaceuticals Inc. | Treatment of vasomotor symptoms |
US10675280B2 (en) | 2001-10-20 | 2020-06-09 | Sprout Pharmaceuticals, Inc. | Treating sexual desire disorders with flibanserin |
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US20050239798A1 (en) * | 2004-04-22 | 2005-10-27 | Boehringer Ingelheim Pharmaceuticals, Inc. | Method for the treatment of premenstrual and other female sexual disorders |
WO2006096439A2 (en) * | 2005-03-04 | 2006-09-14 | Boehringer Ingelheim International Gmbh | Pharmaceutical compositions for the treatment and/or prevention of schizophrenia and related diseases |
EP1888071A1 (en) * | 2005-05-19 | 2008-02-20 | Boehringer Ingelheim International GmbH | Method for the treatment of drug-induced sexual dysfunction |
WO2006125041A1 (en) * | 2005-05-19 | 2006-11-23 | Boehringer Ingelheim International Gmbh | Method for the treatment of sexual dysfunctions due to medical conditions |
CA2672957C (en) | 2006-12-20 | 2015-04-14 | Boehringer Ingelheim International Gmbh | Sulfated benzimidazolone derivatives having mixed serotonine receptor affinity |
EP1955699A1 (en) * | 2007-02-08 | 2008-08-13 | Boehringer Ingelheim Pharma GmbH & Co. KG | Use of flibanserin for the treatment of insomnia |
EP2090297A1 (en) * | 2008-02-13 | 2009-08-19 | Boehringer Ingelheim International GmbH | Formulations of flibanserin |
DE102008047910A1 (de) | 2008-09-19 | 2010-03-25 | Molkerei Meggle Wasserburg Gmbh & Co. Kg | Tablettierhilfsstoff auf Laktose- und Cellulosebasis |
US20120010216A1 (en) * | 2010-07-06 | 2012-01-12 | Brown Arthur M | Pharmaceutical compositions containing vanoxerine |
CN104926734B (zh) * | 2015-07-07 | 2017-04-05 | 苏州立新制药有限公司 | 氟班色林的制备方法 |
Family Cites Families (3)
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IT1251144B (it) * | 1991-07-30 | 1995-05-04 | Boehringer Ingelheim Italia | Derivati del benzimidazolone |
PT1414816E (pt) * | 2001-08-02 | 2005-04-29 | Bidachem Spa | Polimorfo estavel da flibanserina, processo tecnico para a sua preparacao e sua utilizacao na preparacao de medicamentos |
DE10138273A1 (de) * | 2001-08-10 | 2003-02-27 | Boehringer Ingelheim Pharma | Arzneimittel mit neuroprotektiver Wirkung |
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2003
- 2003-05-19 DK DK03730069.6T patent/DK1511489T3/da active
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- 2003-05-19 CN CNA038117029A patent/CN1655789A/zh active Pending
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- 2003-05-19 PL PL372457A patent/PL211062B1/pl unknown
- 2003-05-19 UA UA20041210555A patent/UA80135C2/uk unknown
- 2003-05-19 EP EP03730069A patent/EP1511489B1/en not_active Expired - Lifetime
- 2003-05-19 CN CN201110122058XA patent/CN102240289A/zh active Pending
- 2003-05-19 CN CNA2007100014771A patent/CN101002780A/zh active Pending
- 2003-05-19 DE DE60336225T patent/DE60336225D1/de not_active Expired - Lifetime
- 2003-05-19 JP JP2004505057A patent/JP3919788B2/ja not_active Expired - Fee Related
- 2003-05-19 ES ES03730069T patent/ES2361994T3/es not_active Expired - Lifetime
- 2003-05-19 SI SI200331994T patent/SI1511489T1/sl unknown
- 2003-05-19 RS YU98704A patent/RS51718B/en unknown
- 2003-05-19 WO PCT/EP2003/005226 patent/WO2003097058A1/en active Application Filing
- 2003-05-19 BR BRPI0311189A patent/BRPI0311189B8/pt not_active IP Right Cessation
- 2003-05-19 MX MXPA04011487A patent/MXPA04011487A/es active IP Right Grant
- 2003-05-19 NZ NZ537253A patent/NZ537253A/en not_active IP Right Cessation
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2004
- 2004-10-05 IL IL16444004A patent/IL164440A0/xx unknown
- 2004-10-08 ZA ZA200408151A patent/ZA200408151B/en unknown
- 2004-10-22 NO NO20044547A patent/NO329414B1/no not_active IP Right Cessation
- 2004-11-19 HR HRP20041092AA patent/HRP20041092B1/hr not_active IP Right Cessation
- 2004-12-13 EC EC2004005493A patent/ECSP045493A/es unknown
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2011
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