CN103429237A - 包含肠能动性调节剂、防止气体滞留的药剂和消化酶的治疗肠易激综合征的口服给药的药物组合物和其制备方法 - Google Patents
包含肠能动性调节剂、防止气体滞留的药剂和消化酶的治疗肠易激综合征的口服给药的药物组合物和其制备方法 Download PDFInfo
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Abstract
本发明涉及用于预防或治疗肠病症,例如肠易激综合征的意图口服给药的片剂、包衣片剂或胶囊剂形式的药物制剂或组合物,其包含肠能动性调节剂、防止气体滞留的药剂、消化酶、粘合剂、稀释剂、吸收剂、崩解剂、润滑剂和助流剂,其有效地使结肠传输正常化,用于提供止痛活性,用于提供解痉活性,以及用于减轻与肠气体相关的症状,例如,膨胀、腹痛和肠胃气胀。
Description
本发明的范围
本发明涉及治疗肠易激综合征(也称为应激性结肠综合征)所使用的药物组合物和它的片剂、包衣片剂或胶囊剂的形式的制剂,其基于∶肠能动性调节剂、防止气体滞留的药剂、消化酶、粘合剂、稀释剂、吸附剂、崩解剂、润滑剂和助流剂。
背景
作为药物的酶具有区别于其它药物类型的两个重要特征。第一,酶通常与它们的底物高亲合性和特异性地结合和起作用;第二,酶是催化分子,这意味着,它们降低确定反应的活化能,由此它们使许多蛋白分子(white
molecules)(底物)转化为目标产物。上述两个特征使得药物酶成为有效和特异性的酶,由此它们在身体内可以进行小分子不能进行的治疗性生物化学活性;因此,科学家致力于开发用作治疗剂的各种酶。在二十世纪六十年代,这种治疗酶学的概念已经存在,作为替代疗法用于遗传缺陷的病例。在1987年,食物与药品管理局批准了第一个含有重组酶的药物:Activase® (阿替普酶,重组人类组织纤溶酶原激活剂),用于治疗阻塞冠状动脉的凝块所引起的心脏病发作。在1990年,批准Adagen®(用聚乙二醇处理的牛腺苷脱氨酶(BAD)形式)用于重度联合免疫缺损(SCID) (其由长期BAD缺乏所引起)类型的患者。在1994年,批准Ceredase®(第一个使用重组酶的酶替代治疗)用于治疗高雪氏病,其与葡糖脑苷脂酶缺乏所引起的溶酶体贮积病有关。沙克罗酶(Sacarosidase)
(从酿酒酵母中获得的β-呋喃果糖苷果糖水解酶(fructohydrolase
β-fructofuranoside))用于治疗先天性的蔗糖酶-异麦芽糖酶缺乏症(CSID),这种病症的患者不能代谢蔗糖。在苯丙酮尿症(由苯丙氨酸羟化酶的活性降低或不存在所引起的遗传疾病,这种酶可以使苯丙氨酸转化为酪氨酸)的情况下,在口服治疗中使用基于苯丙氨酸解氨酶的口服治疗,这种酶源自酵母,其降解胃肠道中的苯丙氨酸。在作为乳糜泻的病例中辅助治疗的口服制剂中使用另一种酶(肽酶),所述乳糜泻是由自身免疫系统对蛋白麸朊的反应所引起的小肠病,所述麸朊可在源自小麦的产品中找到(Vellard,
Michael. The enzyme as a drug: application of enzymes as pharmaceuticals. Current
Opinion in Biotechnology.2003. Vol. 14: 444-450)。用于治疗胃肠道病症的水解酶α-D-半乳糖苷酶,在肠道中转化不能吸收的寡糖,以防止它们被肠细菌群落发酵(气体产生过程);降低肠气体产生,减轻五脏胀,并因此也使膨胀、腹痛和肠胃气胀等症状减轻(http://www.beanogas.com,于2009年4月28日接入)。α-D-半乳糖苷酶水解三种复合糖∶棉子糖、水苏糖和毛蕊糖,以将它们转化为单糖∶葡萄糖、半乳糖和果糖,和转化为二糖∶蔗糖(在正常消化期间,它瞬间水解)。人类通常不产生α-D-半乳糖苷酶,由于这种原因,棉子糖、水苏糖和毛蕊糖能够完好地到达结肠,在结肠中,它们在产生氢气和甲烷(气体)的化学反应中被细菌群落发酵。与食物一起给予酶,可以使这三种寡糖到达结肠之前被分解,防止发酵和气体产生。用作药物的α-D-半乳糖苷酶源于无毒的食品级的真菌黑曲霉(Aspergillusniger)
(http://www.beanogas.com,于2009年4月28日接入)。在医学上用于消化病症的各种其它酶当中、存在有淀粉酶、β-D-半乳糖苷酶、纤维素酶、半纤维素酶、脂肪酶、木瓜酶、胃蛋白酶、芦丁、糜蛋白酶和胰蛋白酶。
肠易激综合征(IBS),以前称为应激性结肠综合征,是肠的功能性障碍,其特征为:与肠排便习惯的变化相关的腹部不适或疼痛的症状。目前认为IBS是促进症状发作的许多因素之间相互作用的结果,而不是单一疾病。还没有可以解释它的单一生理病理学机理,但存在至少三个相关的因素,这些因素以在人与人之间存在差异的方式发挥作用。
这些因素是∶
i)改变的肠反应性,ii)响应于导致腹泻或便秘的症状的内腔激惹性刺激(食物、膨胀、炎症、细菌因素)或环境刺激(心理-社会应激)的能动性或分泌iii)内脏感觉和疼痛提高的肠超敏反应。
“脑-肠”轴的调节的变化。
IBS的诊断基于阳性症状的鉴别,这称为罗马III诊断标准(Longstreth,G.F. 2006. Functional bowel disorders. Gastroenterology.
Vol. 130,No. 5:1480-91),和基于排除具有类似表现形式的其它肠道疾病。这些标准是∶
在过去三个月内,每月至少三天出现复发性腹部不适或腹痛,同时伴随有下列情况中的两种或更多种:a)排便改善,b)与排便频率的变化有关的发作,和c)与粪便外观的变化有关的发作。
其中不适是指未被描述成疼痛的不愉快的感觉。
在过去三个月中必须已经满足该标准,同时在诊断之前至少六个月有症状的发作。
IBS是世界上最常见的医学病症之一,更常在年龄30至50岁的女性中出现,在拉丁美洲的患病率为9%至18%之间(Schmulson, Max J. 2008. Limited diagnostic screening can
decrease the direct economic impact of irritable bowel syndrome (IBS). Rev Med
Chile. Vol. 136: 1398-1405)。
在墨西哥,症状模式是具有便秘的IBS;腹胀是这种模式的疾病的常见症状。据报道,在墨西哥人群当中,腹胀和气体是高频率出现的症状。肠易激综合征是实际的病理性病症,就医疗护理费用和丧失工作而言,除对社会和国家构成显著的经济负担之外,还对患者具有显著的影响(症状严重、功能受损、生活质量下降) (American Gastroenterological
Association; 2002; American Gastroenterological Association position statement;
“irritable bowel syndrome.
Gastroenterology”. Vol. 123, No.
6:2105-7)。
对这种疾病还没有理想或标准疗法。自1969年以来,马来酸曲美布汀(Trimebutine)
(通常被称为曲美布汀)已经用作功能性肠病症(包括肠易激综合征)的治疗。它的主要作用是调节肠能动性,并且提高由五脏胀所引起的疼阈(Roman
F. J.等人,1999. Pharmacological properties of
trimebutine and N-monodesmethyltrimebutine. J Pharmacol Exp Ther. Vol. 289, No.
3:1391-1397)。
在功能性的肠病症(包括肠易激综合征)中,腹痛、腹胀和肠胃气胀代表非常常见的症状,但它们的生理病理和治疗还没有被完全阐明。患者经常将这些症状与肠中的过度气体生成相关联,并且对于肠易激综合征(对此已经使用了二甲基硅油)的症状改善来说,减少气体产生可以代表有效策略。二甲基硅油是直接作用于胃肠粘液的表面张力的惰性硅,由此影响消化道中的气泡形成,破坏它们,并促使小气泡融合到更大的气泡中,其转化成防止气体滞留和伴随的不适。重要的是,应当注意,在肠易激综合征患者中,不但通过气体产生的增加、而且通过消化道中气体的“正常”存在加上内脏敏感性提高,可以产生这些症状或使这些症状恶化。目前存在治疗这种问题的策略,例如,使用活性炭、限制饮食和益生菌(probiotic)消耗;然而,这些策略中没有一个是理想的,并且在每种情况下获得的结果互相矛盾。在这方面,在非吸收性的寡糖(存在于豆类、果实和蔬菜中)到达结肠(在结肠中,它们被细菌群落发酵,并产生气体)之前使它们分解,可以代表有吸引力的替代性方法。给予α-D-半乳糖苷酶可以获得这种效果(Di Stefano M.等人,2007;
“The effect of oral alpha-galactosidase
on intestinal gas production and gas-related symptoms”. Dig Dis Sci. January. Vol. 52, No. 1:78-83)。
存在用于肠病症的调节肠能动性的药物产品,例如∶
曲美布汀(Trimebutine)和其盐,
非诺维林,
美贝维林,
双环维林,
匹维溴铵,
阿洛司琼,
替加色罗,
洛哌丁胺,
间苯三酚(Floroglucinol),
三甲基间苯三酚(Trimetilfloroglucinol),
丁基莨菪胺(Butylscopolamine),
帕吉维林(Pargeverine)。
所有这些可以与二甲基硅油联用,获得肠病症所使用的口服给药的药物制剂,如同肠易激综合征的具体情况那样。
还存在用于治疗肠病症的具有生理活性的多种酶,例如,α-D-半乳糖苷酶、淀粉酶、纤维素酶、半纤维素酶、脂肪酶、木瓜酶、芦丁、糜蛋白酶和胰蛋白酶。
所有上述酶可以与二甲基硅油和肠能动性调节剂联用,以获得肠病症所使用的口服给药的药物制剂,如同肠易激综合征的具体情况那样。
曲美布汀和其盐、具有止痛性质的肠能动性调节剂、二甲基硅油、防止气体滞留的药剂和酶或酶组合的联用,对于肠易激综合征患者的复合症状减轻产生有效治疗。
人们认为曲美布汀作用于奥尔巴赫神经丛(肌肉)和迈斯纳神经丛(粘膜下层),具体地说,它作用于负责调控蠕动的脑啡肽能受体。曲美布汀对于运动过度的作用与对于运动不足的作用差不多,其抑制或增加蠕动,并且导致小肠传输的正常化。曲美布汀也具有止痛(调节内脏敏感性)、解痉和止吐性质(Delvaux M.
& Wingate D. 1997. Trimebutine: “Mechanism
of action, effects on gastrointestinal function and clinical results”. J Int Med Res. Vol. 25, No. 5:225-46)。
在推荐用于治疗IBS复合症状的溶液剂之中,文件WO2001/047515报道了单独的曲美布汀开发成治疗躯体痛和腹部炎症的有用药物的用途;然而,它只是集中于这种疾病的症状缓解方面。
类似地,存在许多关注与IBS相关的炎症、腹痛和疾病的治疗的文件;然而,在任何下列引文中所示的所述文件中没有解决对于IBS的根源的治疗∶
文件MXPA02006376涉及单独的曲美布汀在预防或治疗躯体痛和与胃疾病相关的炎症中的用途;然而,当看待减轻症状时,作为致病原因的函数(function),疼痛未能消除。
文件US 2003/0119903报道了单独的曲美布汀在制备治疗躯体炎症性疼痛以及与胃疾病有关的慢性疼痛的药物中的用途。
文件US 2004/0009234报道了预防胃肠道病症的药物组合物和相关治疗,其使用单独的曲美布汀,但没有获得抵御这些疾病的根源的期望的最终结果。
文件MX00PA05010821A报道了曲美布汀治疗便秘的用途,但没有获得抵御这些疾病的根源的期望的最终结果。
文件WO1995001803报道了曲美布汀治疗胃肠疼痛和病症的用途,所述病症例如由过量摄入食物所引起的消化不良、胃-食管回流、胃弱和便秘,但没有获得抵御这些疾病的根源的期望的最终结果。
文件WO95001784报道了使用法莫替丁、硫糖铝、二甲基硅油和α-D-半乳糖苷酶的治疗和减轻消化不良、胃灼热及其它胃肠道病症的药物组合物的用途;然而,具体公开的组合物缺少有效促进快速胃排空的药剂,而由于不能快速排便的患者将没有症状减轻的感觉,这使得治疗IBS的效率很低。
文件US 2008/0038240报道了使用酶来增加人对碳水化合物的吸收,同时避免形成肠气体。
文件US 4447412报道了治疗消化功能障碍的酶组合物,其由胰酶和蛋白水解酶组成。
文件US 4079125报道了能够经受住几个小时的胃液暴露的延长释放的酶组合物,其保护酶的生物活性,并且在暴露于肠液5-30分钟之后释放它们。
文件US 5460812和US
324514报道了酶在治疗消化病症中的用途。
本发明的一个目标是提供应用于肠病症的口服给药的药物组合物,其基于肠能动性调节剂、防止气体滞留的药剂、消化酶、粘合剂、稀释剂、吸附剂、崩解剂、润滑剂和助流剂。
本发明的另一个目标是提供有效地正常化小肠传输的、应用于肠病症的口服给药的药物制剂,其基于肠能动性调节剂、防止气体滞留的药剂、消化酶、粘合剂、稀释剂、吸附剂、崩解剂、润滑剂和助流剂。
本发明的另一个目标是提供在治疗胃肠疾病中有效地实现止痛活性的、应用于肠病症的口服给药的药物制剂,其基于肠能动性调节剂、防止气体滞留的药剂、消化酶、粘合剂、稀释剂、吸附剂、崩解剂、润滑剂和助流剂。
本发明的另一个目标是提供有效地实现解痉活性的、应用于肠病症的口服给药的药物制剂,其基于肠能动性调节剂、防止气体滞留的药剂、消化酶、粘合剂、稀释剂、吸附剂、崩解剂、润滑剂和助流剂。
本发明的最后目标是提供有效地减轻与肠气体有关的症状(例如膨胀、疼痛和肠胃气胀)的、应用于肠病症的口服给药的药物组合物或制剂,其基于肠能动性调节剂、防止气体滞留的药剂、消化酶、粘合剂、稀释剂、吸附剂、崩解剂、润滑剂和助流剂。
本发明的详细说明
基于肠能动性调节剂、防止气体滞留的药剂和消化酶,将药物制剂制备成片剂、包衣片剂或胶囊剂形式,用于肠易激综合征,亦称应激性结肠综合征。
将肠能动性调节剂、防止气体滞留的药剂、消化酶、粘合剂、稀释剂、崩解剂、润滑剂和助流剂混合。
制备粘合剂溶液。
将肠能动性调节剂、酶α-D-半乳糖苷酶、粘合剂、稀释剂、崩解剂、润滑剂和助流剂过筛,以使任何团块破碎。
将前述步骤中提到的所有物质混合,而后用粘合剂溶液湿润。
将前述步骤得到的产品研磨、干燥和过筛。
如果最终组合物是固体,则压缩该混合物,以形成片剂或包衣片剂;否则制备胶囊剂。
将片剂或胶囊剂包装在包装材料中。
为了实施具体制作过程,将使用制造具有指定特征的药物制剂所通常所使用的设备。使用的所有原料是药物级的原料。下面详细说明了一些如何制备制剂的实践实施例,这只是为了举例说明,而不是为了限制性的目的。
实施例
通过湿法制粒获得的马来酸曲美布汀/α-D-半乳糖苷酶/二甲基硅油的片剂制剂的实施例。
组份 | 数量 |
马来酸曲美布汀 | 200.000 mg |
二甲基硅油 | 75.000 mg |
α-D-半乳糖苷酶 | 90.000 mg* |
预胶凝淀粉 | 75.000 mg |
含水乳糖 | 105.000 mg |
交联羧甲纤维素钠 | 30.000 mg |
微晶纤维素 | 115.000 mg |
磷酸氢钙 | 300.000 mg |
硬脂酸镁 | 10.000 mg |
*90 mg相当于450 U/gal。U/Gal考量的是每克具有5,000 U/gal的酶活性的α-D-半乳糖苷酶原料。
通过湿法造粒制备马来酸曲美布汀/α-D-半乳糖苷酶/二甲基硅油的片剂的方法。
1. 通过将20%的预胶凝淀粉分散在足够数量的水中,制备粘合剂溶液。
2. 使下列原料通过420至2,000微米筛目尺寸的筛网∶
-余下的预胶凝淀粉(80%)
-α-D-半乳糖苷酶
-马来酸曲美布汀
-含水乳糖
-交联羧甲纤维素钠
-磷酸氢钙。
3. 将磷酸氢钙和预胶凝淀粉(80%)加入到混合器/造粒机中,在50至200 rpm下混合5至20分钟。
4. 在混合的最后,且在不停止搅拌的情况下,手动加入“串”形式的二甲基硅油,加入时间不超过15分钟。
5. 将马来酸曲美布汀、α-D-半乳糖苷酶、含水乳糖和交联羧甲纤维素钠加入到混合器中,在50至200 rpm下混合5至20分钟。
6. 用得自步骤1的粘合剂溶液湿润。
7. 使从步骤6中的研磨机获得的产品通过孔口为3,000至5,000微米的筛网。
8. 将产品在30至60℃的温度下干燥,直到它达到1.0-3.0%的残余湿度为止。
9. 将步骤8中获得的产品研磨通过带有0.033至0.094英寸筛网的研磨机,速度为500至1,500 rpm。
10. 使微晶纤维素和硬脂酸镁通过筛目尺寸为420至2,000微米的筛网。
11. 将下列产品加到混合器中∶
步骤9中获得的颗粒;
步骤10中获得的微晶纤维素,并在15至30 rpm下混合10至30分钟。
12. 将步骤9中获得的硬脂酸镁加入到混合器中,并在15至30 rpm下混合5至10分钟。
13. 将步骤12中获得的产品压缩。
通过直接压片法获得的马来酸曲美布汀/α-D-半乳糖苷酶/二甲基硅油的制剂的实施例。
组份 | 数量 |
马来酸曲美布汀 | 200,000 mg |
二甲基硅油 | 75,000 mg |
α-D-半乳糖苷酶 | 90,000 mg* |
交联羧甲纤维素钠 | 30,000 mg |
微晶纤维素 | 210,000 mg |
硅酸铝镁 | 310,000 mg |
硬脂酸镁 | 10,000 mg |
*90 mg相当于450 U/gal。U/Gal考量的是每克具有5,000 U/gal的酶活性的α-D-半乳糖苷酶原料。
通过直接压片法制备马来酸曲美布汀/α-D-半乳糖苷酶/二甲基硅油片剂的实施例方法。
1. 使下列原料通过420至2,000微米筛目尺寸的筛网∶
-α-D-半乳糖苷酶
-马来酸曲美布汀
-微晶纤维素
-交联羧甲纤维素钠
-磷酸氢钙。
2. 将硅酸铝镁加入到混合器中,并在40至100
rpm之间的速度下开始搅拌。在不停止搅拌的情况下,手动地非常逐渐地加入“串”形式的二甲基硅油,加入时间不超过30分钟(混合物A)。
3. 将下列产品加到混合器中∶
一半得自步骤2的混合物A
一半微晶纤维素
一半马来酸曲美布汀
α-D-半乳糖苷酶
交联羧甲纤维素钠
余下的马来酸曲美布汀
余下的微晶纤维素
余下的混合物A
并在15至30
rpm下混合10至30分钟(混合物B)。
4. 使硬脂酸镁通过420至2,000微米筛目尺寸的筛网。
5. 将步骤4中获得的硬脂酸镁加入到混合物B中,并在15至30 rpm下混合5至10分钟。
6. 将步骤5中获得的产品压缩。
通过干法制粒获得的马来酸曲美布汀/α-D-半乳糖苷酶/二甲基硅油的片剂的制备实施例。
组份 | 数量 |
马来酸曲美布汀 | 200.000 mg |
二甲基硅油 | 75.000 mg |
α-D-半乳糖苷酶 | 90.000 mg* |
羟丙基纤维素 | 50.000 mg |
含水乳糖 | 110.000 mg |
交聚维酮 | 30.000 mg |
微晶纤维素 | 125.000 mg |
磷酸氢钙 | 310.000 mg |
硬脂酸镁 | 10.000 mg |
*90 mg相当于450 U/gal。U/Gal考量的是每克具有5,000 U/gal的酶活性的α-D-半乳糖苷酶原料。
通过干法制粒制备马来酸曲美布汀/α-D-半乳糖苷酶/二甲基硅油片剂的实施例方法。
1. 使下列原料通过420至2,000微米筛目尺寸的筛网∶
-羟丙基纤维素
-α-D-半乳糖苷酶
-马来酸曲美布汀
-含水乳糖
- 50%交聚维酮
- 磷酸氢钙。
2. 将磷酸氢钙和羟丙基纤维素掺入到制粒混合设备中,并在50至200
rpm下混合5至20分钟。
3. 混合之后,在不停止搅拌的情况下,手动加入“串”形式的二甲基硅油,加入时间不超过30分钟。
4. 将马来酸曲美布汀、α-D-半乳糖苷酶、微晶纤维素、50%的交聚维酮加入到混合器中,并在50至200 rpm下混合5至20分钟。
5. 将步骤4中获得的产品压缩。
6. 利用具有1,180至2,000微米筛目尺寸的制粒设备,将步骤5中获得的产品研磨。
7. 将步骤6中获得的颗粒再次压缩。
8. 利用具有1,400至1,700微米筛目尺寸的制粒设备,将步骤7中获得的产品研磨。
9. 使50%的交聚维酮、微晶纤维素和硬脂酸镁通过筛目尺寸为420至2,000微米的筛网。
10. 将下列产品加到混合器中∶
步骤8中获得的颗粒;
得自步骤9的50%的交联羧甲纤维素钠
步骤9中获得的微晶纤维素
并在15至30
rpm下混合10至30分钟。
11. 将步骤9中获得的硬脂酸镁加入到混合器中,并在15至30 rpm下混合5至10分钟。
12. 将步骤11中获得的产品压缩。下面是可以充分发挥指定功能的赋形剂∶
功能 | 赋形剂 |
粘合剂 | 羟丙基纤维素、玉米淀粉、丙基纤维素、甲基纤维素 |
稀释剂 | 乳糖、微晶纤维素、甘露醇、蔗糖 |
吸收剂 | 磷酸氢钙、硅酸镁铝、胶体二氧化硅、微晶纤维素 |
崩解剂 | 交联羧甲纤维素钠、玉米淀粉、交聚维酮 |
润滑剂 | 硬脂酸镁、滑石、硬脂酸 |
助流剂 | 胶体二氧化硅 |
-稀释剂选自具有提高的粉末表观体积的功能,并因此增加丸剂或胶囊剂的重量的赋形剂。
-吸收剂选自能够在明显干燥的条件下吸收某些量的液体的赋形剂。
-崩解剂选自能够在丸剂和颗粒剂接触液体时使它们破碎(崩解)的赋形剂。
-润滑剂选自能够在压缩过程或装填胶囊剂期间降低颗粒和床(matrix)壁之间摩擦的赋形剂。
-助流剂选自能够通过降低粒间摩擦而使进料斗中的颗粒流向床腔的赋形剂。
-粘合剂选自能够使粉末形式的物料粘结形成颗粒的赋形剂。
Claims (49)
1.用于预防或治疗肠病症的适合于口服给药的片剂、包衣片剂或胶囊剂形式的药物组合物或制剂,该制剂由下列组成∶肠能动性调节剂、防止气体滞留的药剂、消化酶、粘合剂、稀释剂、吸收剂、崩解剂、润滑剂和助流剂。
2.根据权利要求1的药物制剂,其中肠能动性调节剂选自∶曲美布汀、非诺维林、美贝维林、双环维林、乙基溴、阿洛司琼、替加色罗、洛哌丁胺、间苯三酚、三甲基间苯三酚、丁基莨菪胺和帕吉维林。
3.根据权利要求2的药物制剂,其中肠能动性调节剂是曲美布汀和其可接受的药用盐。
4.根据权利要求2的药物制剂,其中肠能动性调节剂是非诺维林和其可接受的药用盐。
5.根据权利要求2的药物制剂,其中肠能动性调节剂是美贝维林和其可接受的药用盐。
6.根据权利要求2的药物制剂,其中肠能动性调节剂是双环维林和其药学上可接受的盐。
7.根据权利要求2的药物制剂,其中肠能动性调节剂是乙基溴和其药学上可接受的盐。
8.根据权利要求2的药物制剂,其中肠能动性调节剂是阿洛司琼和其药学上可接受的盐。
9.根据权利要求2的药物制剂,其中肠能动性调节剂是替加色罗和其药学上可接受的盐。
10.根据权利要求2的药物制剂,其中肠能动性调节剂可以是洛哌丁胺和其药学上可接受的盐。
11.根据权利要求2的药物制剂,其中肠能动性调节剂是间苯三酚和其药学上可接受的盐。
12.根据权利要求2的药物制剂,其中肠能动性调节剂是三甲基间苯三酚和其药学上可接受的盐。
13.根据权利要求2的药物制剂,其中肠能动性调节剂是丁基莨菪胺和其药学上可接受的盐。
14.根据权利要求2的药物制剂,其中肠能动性调节剂是帕吉维林和其药学上可接受的盐。
15.根据权利要求1的药物制剂,其中粘合剂可以是羟丙基纤维素、玉米淀粉、丙基纤维素、甲基纤维素。
16.根据权利要求1的药物制剂,其中稀释剂选自乳糖、微晶纤维素、磷酸氢钙和甘露醇。
17.根据权利要求1的药物制剂,其中吸收剂选自磷酸氢钙、硅酸镁铝、胶体二氧化硅和微晶纤维素。
18.根据权利要求1的药物制剂,其中崩解剂选自交联羧甲纤维素钠、玉米淀粉和交聚维酮。
19.根据权利要求1的药物制剂,其中润滑剂选自硬脂酸镁、滑石和硬脂酸。
20.根据权利要求1的药物制剂,其中助流剂是胶体二氧化硅。
21.根据权利要求1的药物制剂,其中防止气体的药剂是二甲基硅油。
22.根据权利要求1的药物制剂,其中所述酶是α-D-半乳糖苷酶。
23.根据权利要求1的药物制剂,其中所述酶是淀粉酶。
24.根据权利要求1的药物制剂,其中所述酶是β-D-半乳糖苷酶。
25.根据权利要求1的药物制剂,其中所述酶是纤维素酶。
26.根据权利要求1的药物制剂,其中所述酶是半纤维素酶。
27.根据权利要求1的药物制剂,其中所述酶是脂肪酶。
28.根据权利要求1的药物制剂,其中所述酶是木瓜酶。
29.根据权利要求1的药物制剂,其中所述酶是胃蛋白酶。
30.根据权利要求1的药物制剂,其中所述酶是糜蛋白酶。
31.根据权利要求1的药物制剂,其中所述酶是芦丁。
32.根据权利要求1的药物制剂,其中所述酶是胰蛋白酶。
33.根据权利要求22的药物制剂,其中所述消化酶是具有450 Ugal的酶能量的α-D-半乳糖苷酶。
34.制备用于肠病症的口服给药的片剂、包衣片剂或胶囊剂形式的药物组合物的方法,该药物组合物基于肠能动性调节剂、防止气体滞留的药剂和消化酶,该方法包括:将肠能动性调节剂、防止气体滞留的药剂和消化酶混合并过筛;将该混合物立即研磨、干燥和过筛;获得适合于口服给药的药物制剂。
35.根据权利要求34的方法,其中用粘合溶液进行湿化。
36.根据权利要求34的方法,其中基于粘合剂和水来制备粘合溶液。
37.根据权利要求34的方法,其中将组份混合。
38.根据权利要求34的方法,其中在50至200 rpm下将配方组份混合大约5至30分钟。
39.根据权利要求34的方法,其中用粘合溶液进行肠能动性调节剂和消化酶的湿化。
40.根据权利要求39的方法,其中将组份干燥。
41.根据权利要求40的方法,其中将组份的干燥在30至60℃的温度下进行。
42.根据权利要求41的方法,其中组合物达到不大于5%的最终残余湿度。
43.根据权利要求42的方法,其中将产品研磨。
44.根据权利要求43的方法,其中在500至1500 rpm下用420至2,000微米的筛目尺寸进行产品的研磨。
45.根据权利要求44的方法,其中将组合物过筛。
46.根据权利要求45的方法,其中通过420至2,000微米的筛目尺寸进行过筛。
47.根据权利要求1的方法,其中使润滑剂与肠能动性调节剂和消化酶混合。
48.根据权利要求47的方法,其中使润滑剂与肠能动性调节剂和消化酶在15至30 rpm下混合5至10分钟。
49.适合于口服给药的片剂、包衣片剂或胶囊剂形式的组合物或药物制剂在预防或治疗肠病症或与肠易激病症相关的不适中的用途。
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PCT/MX2011/000138 WO2012067481A2 (es) | 2010-11-16 | 2011-11-15 | Composición farmacéutica de administración oral para el tratamiento del síndrome de intestino irritable, a base de un modificador de la motilidad intestinal, un agente que previene la retención de gases y enzimas digestivas y proceso para su preparación |
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CN106163544A (zh) * | 2013-08-09 | 2016-11-23 | 阿勒根制药国际有限公司 | 适于经肠施用的消化酶组合物 |
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JP6385642B2 (ja) * | 2013-02-28 | 2018-09-05 | 小林製薬株式会社 | 内服用組成物 |
US9402885B2 (en) * | 2013-07-15 | 2016-08-02 | Alfa Wassermann S.P.A. | Method of treating GERD with alpha and beta galactosidases |
WO2016114734A1 (en) * | 2015-01-16 | 2016-07-21 | Biofarma Ilaç Sanayi Ve Ticaret A. Ş. | Pharmaceutical formulation of trimebutine maleate and simethicone comprising acidifying agent |
IT201700006355A1 (it) * | 2017-01-20 | 2018-07-20 | Neilos S R L | Composizione per il trattamento dei disturbi gastrointestinali |
CN109200278A (zh) * | 2018-10-08 | 2019-01-15 | 毛玉坤 | 腔镜去粘液消泡剂及其制备方法 |
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