CN1341022A - 含有质子泵抑制剂的药物组合物 - Google Patents

含有质子泵抑制剂的药物组合物 Download PDF

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CN1341022A
CN1341022A CN00804029A CN00804029A CN1341022A CN 1341022 A CN1341022 A CN 1341022A CN 00804029 A CN00804029 A CN 00804029A CN 00804029 A CN00804029 A CN 00804029A CN 1341022 A CN1341022 A CN 1341022A
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K·弗雷豪夫
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Abstract

本发明涉及一种含有适用于治疗人类和动物与胃酸有关的疾病的质子泵抑制剂(PPI)的口服药物制剂。更具体地说,该组合物为一种糊剂,并且特别适用于为马输送质子泵抑制剂。

Description

含有质子泵抑制剂的药物组合物
本发明概要
本发明涉及一种改进的奥美拉唑口服糊剂。
本发明背景
奥美拉唑是一种通过抑制H+K+-ATP酶(壁细胞中产生氢离子的最终步骤所涉及的酶)起作用的胃酸分泌的潜在抑制剂，并已应用于与胃酸相关的疾病(如人类的胃溃疡和十二指肠溃疡)的治疗。消化性溃疡在一些动物(特别是马)中也是常见疾病。虽然至今仍未弄清马出现胃十二指肠溃疡的病因，但在某些情况下似乎紧张在其中起着重要的作用。
由于奥美拉唑是高度酸不稳定的，因而其口服制剂包有肠溶衣。生产包有肠溶衣的制剂既昂贵又耗时，并需要复杂的技术及设备。包有肠溶衣制剂的另一个缺点是其湿度敏感性。
WO94/25070公开了含有包有肠溶衣的干颗粒与干的胶凝剂混合形式的质子泵抑制剂的口服组合物，服用前将所述干颗粒与胶凝剂的混合物做成糊状凝胶。因此所述组合物需要进行肠溶包衣，带来了上述与这种制剂相关的各种缺点。此外，由于这种湿凝胶在室温下长期储存是不稳定的，因而无法以现成制剂的形式进行生产和销售，而必须在服用时临时制备，使得使用时不方便。
美国专利5,708,017描述了包含质子泵抑制剂、增稠剂、碱化剂和疏水油性液体赋形剂的质子泵抑制剂的糊剂。
本发明详述
本发明提供一种改进的奥美拉唑的糊剂，它包括：
(a)约1％-约60％(重量)的奥美拉唑；
(b)约0.1％-约2％(重量)的两种至四种碱化剂；
(c)约1％-约3％(重量)的增稠剂；和
(d)约30％-约95％(重量)的疏水油性液体赋形剂，它包括：
(i)植物油，和
(ii)中链脂肪酸的甘油三酯或中链脂肪酸的丙二醇二酯。
奥美拉唑公开于美国专利4,255,432。本发明中奥美拉唑的量不是特别的重要，只要药品能保持半固体制剂形式即可；通常奥美拉唑的量可高达约60％(重量)。优选奥美拉唑的量不超过约50％(重量)，更优选为约30％-约40％(重量)。
适宜的碱化剂为，例如各种药学可接受的胺碱，如单乙醇胺、二乙醇胺、三乙醇胺，或各种羧酸盐，如乙酸钠、柠檬酸钠、山梨酸钾、硬脂酸钠等。优选一种碱化剂为山梨酸钾，另一种或另两种碱化剂可选自胺碱(如单乙醇胺)和羧酸盐(如硬脂酸钠)。碱化剂的存在量应足以为酸不稳定的奥美拉唑提供一个非酸性的环境；碱化剂的总量一般为约0.1％-约2％(重量)，优选为约1％-约1.5％(重量)。
增稠剂可以是任何药学可接受的不溶于或实际上不溶于水的增稠剂；其实例包括二氧化硅、各种蜡如蓖麻蜡(castor wax)或氢化蓖麻油、石蜡、十六醇十八醇混合物等。优选的疏水性增稠剂为氢化蓖麻油。增稠剂的量约为最终组合物的0.5％-10％(重量)；优选约为1％-2％(重量)。
疏水油性液体赋形剂包括：(i)植物油，和(ii)中链脂肪酸的甘油三酯或中链脂肪酸的丙二醇二酯。植物油的实例包括杏仁油、棉子油、橄榄油、花生油、红花油、芝麻油和大豆油。优选的植物油为芝麻油。中链脂肪酸为碳链长度为8-12的脂肪酸，优选的脂肪酸为饱和脂肪酸。优选的甘油三酯和丙二醇二酯为甘油癸/辛三酯和丙二醇癸酸酯/辛酸酯(也称为丙二醇辛酸酯癸酸酯)。甘油癸/辛三酯和丙二醇癸酸酯/辛酸酯为市售产品，如商标为Miglyol的商品(HulsAmerica，Inc.，新泽西)。更优选的疏水油性液体赋形剂包括芝麻油和丙二醇癸酸酯/辛酸酯(如Miglyol840)。根据糊剂中其他赋形剂的量，所述疏水性赋形剂的存在量约为30-95％(重量)。优选所述疏水性赋形剂的存在量为约50-约80％(重量)。植物油与甘油三酯在疏水性赋形剂中的比例为约1∶3-约5∶1；优选为约1∶1-约2∶1。
本发明组合物可以包括通常用于人类制剂及兽药中的其他成分。例如可加入：各种调味剂(如焦糖、胡萝卜、苹果、肉桂和香肠调料)、着色剂(如氧化铁、二氧化钛、铝色淀)、增甜剂(如糖、糖精钠)、防腐剂(如对羟基苯甲酸酯)、抗氧化剂(如BHT、BHA)、分散剂(如硬脂酸钙)和粘度调节剂(如白蜡或合成蜡如三山俞酸(tribehenate)甘油酯、三肉豆蔻酸甘油酯、氢化的椰油-甘油酯)。
可通过将粉末形式的奥美拉唑分散于含有除增稠剂之外的任何其他赋形剂的疏水性液体赋形剂中来制备本发明的组合物。然后混合物中再加入增稠剂并进行混合以得到所需的稠度。也可通过下法制备本发明的组合物：将赋形剂分散于疏水油性液体赋形剂中，然后加入增稠剂，如需要再加入其他的植物油来获得所需的稠度；将粉末形式的奥美拉唑加入到所得混合物中，充分混合整个混合物以便分散奥美拉唑。如此得到的糊剂可灌入计量注射器，直接将此活性药物为需要治疗的动物给药。
本发明的奥美拉唑糊剂较前述的奥美拉唑糊剂具有改进的性能。本发明的制剂具有较好的化学和物理稳定性外形，并提供更高的药物生物利用度。
本发明的组合物可用于治疗人类或动物的消化性溃疡疾病。可通过口服此组合物为动物输送奥美拉唑以提高其系统活性。所述组合物也可用于通过困难地吞咽固体剂型(如肠溶片剂和肠溶胶囊)的方式为人类输送奥美拉唑。可直接将本发明组合物送入需要治疗溃疡的动物(如马)的口中；优选使用糊剂给药注射器以便利于药物服用。糊剂的稠度应使得一旦其附着于动物舌头的背部便不容易滴出或排出。所述糊剂在实际应用中没有空气泡，因此增强了给药的准确性。本发明制剂的另一优点是可以适应个别需要的剂量给药。
本发明组合物的服用量根据以下各种因素的不同而异：需治疗动物的具体种类、疾病的严重程度、得病动物的身体状况以及其他因素。治疗溃疡领域的医生或专职兽医能很容易地确定需治疗的具体宿主的合适剂量。一般而言，可使用约0.2毫克/千克-约20毫克/千克范围的剂量。
我们提供以下的实施例以便更充分地说明本发明，但绝不能将其视为对本发明范围的限制。
                            实施例1
    组分     重量百分数
    奥美拉唑基料     37.0
    山梨酸钾     0.20
    硬脂酸钠     0.10
    硬脂酸钙     1.0
    单乙醇胺     0.10
    氧化铁黄     0.20
    肉桂油     0.30
    氢化蓖麻油     1.25
    丙二醇辛酸酯癸酸酯     25.0
    芝麻油     适量
将山梨酸钾(0.50千克)、硬脂酸钙(2.50千克)、硬脂酸钠(0.25千克)和氧化铁黄(0.50千克)加入到双锥掺合机并混合成分散粉末。使所得粉末通过60目筛并以高速研磨。将该研磨粉末的预掺合物收集到聚乙烯袋中以便在糊剂生产中使用。
将丙二醇辛酸酯癸酸酯(62.5千克)和芝麻油(37.5千克)加入到大小合适的坚式螺杆半固体糊剂混合机中。调节液体混合物的温度至低于约25℃，如需要，可开启混合螺杆。在碎块机(1umpbreaker)开启的情况下将研磨粉末预掺合物、单乙醇胺(0.25千克)和肉桂油(0.75千克)加入到混合机中。接着，往所述混合机中加入氢化蓖麻油(3.13kg)。混合至产品的温度达到50±5℃为止。关闭混合螺杆和碎块机，并使容器中的批料(batch)保持30±5分钟以确保完成凝胶过程。
在开启冷却水的情况下将剩余的芝麻油(49.6千克)加入到混合机中。开动混合螺杆和碎块机约2分钟以分散各种物料，然后关闭。将奥美拉唑粉末(92.5千克)分成8-10份加入到混合机中，每加一份开启混合机直至足以将大部分粉末润湿，随后关机以再加入下一份粉末。当加入所有的奥美拉唑后再继续混合10分钟以便充分分散奥美拉唑；然后开启碎块机再继续混合10分钟以确保完全均匀。将所得糊剂装入注射器。

Claims (11)

1.一种用于口服给药的药物制剂，包括：
(a)约1％-约60％重量的奥美拉唑；
(b)约0.1％-约2％重量的两种至四种碱化剂；
(c)约1％-约3％重量的增稠剂；和
(d)疏水油性液体赋形剂，包括：
(i)植物油，和
(ii)中链脂肪酸的甘油三酯或中链脂肪酸的丙二醇二酯。
2.权利要求1的组合物，其中所述增稠剂为氢化蓖麻油。
3.权利要求1的组合物，其中所述疏水液体赋形剂包括丙二醇癸酸酯/辛酸酯和植物油。
4.权利要求1的组合物，其中所述疏水液体赋形剂包括芝麻油和中链脂肪酸的甘油三酯或中链脂肪酸的丙二醇二酯。
5.权利要求1的组合物，其中所述疏水液体赋形剂包括丙二醇癸酸酯/辛酸酯和芝麻油。
6.权利要求1的组合物，其中一种碱化剂为山梨酸钾。
7.权利要求1的组合物，其中所述碱化剂为山梨酸钾、硬脂酸钠和单乙醇胺。
8.权利要求1的组合物，其中所述奥美拉唑的量为约30％-约40％重量。
9.权利要求1的组合物，其中所述碱化剂的总量为约1％-约1.5％重量。
10.权利要求1的组合物，其中所述疏水油性液体赋形剂的量为约30％-约90％重量。
11.权利要求1的组合物，其中所述疏水油性液体赋形剂的量为约50％-约80％重量。
CNB00804029XA 1999-02-23 2000-02-18 含有质子泵抑制剂的药物组合物 Expired - Lifetime CN1227009C (zh)

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CN112972481A (zh) * 2021-03-18 2021-06-18 华农（肇庆）生物产业技术研究院有限公司 药物组合物及其制备方法和应用

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CN112972481A (zh) * 2021-03-18 2021-06-18 华农（肇庆）生物产业技术研究院有限公司 药物组合物及其制备方法和应用

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