CN1027133C - 药物的树脂吸附物制备方法 - Google Patents
药物的树脂吸附物制备方法 Download PDFInfo
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- CN1027133C CN1027133C CN89103232A CN89103232A CN1027133C CN 1027133 C CN1027133 C CN 1027133C CN 89103232 A CN89103232 A CN 89103232A CN 89103232 A CN89103232 A CN 89103232A CN 1027133 C CN1027133 C CN 1027133C
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- Prior art keywords
- ranitidine
- resin
- salt
- cation exchange
- exchange resin
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Abstract
通过与一种合成的阴离子交换树脂形成吸附物，可以掩蔽呋喃硝胺(ranitidine)的苦味。该吸附物尤其适用于供口服给药例如可嘴嚼或可吸入的片剂、颗粒剂和水悬浮液或非水悬浮液的药物组合物。
Description
本发明涉及呋喃硝胺（ranitidine）的新衍生物及其制备方法，并涉及在呋喃硝胺改进配制剂，尤其是用于口服给药的制剂中它的用途。
在英国专利说明书号1565966中叙述并提出权利要求的呋喃硝胺，N-〔2〔〔〔5-（二甲氨基）甲基-2-呋喃基〕甲基〕硫代〕乙基〕-N′-甲基-2-硝基-1，1-乙二胺及其生理上可接受的盐，并在英国专利说明书号2084580B中叙述并要求的呋喃硝胺盐酸盐的特定结晶形状。在上述两篇说明书中都涉及到用于口服给药的配制剂，它们可以制成例如片剂、胶囊、颗粒、粉剂、溶液、糖浆、悬浮液或用于颊部给药的片剂或锭剂。在英国专利说明书号2142820A中也叙述了呋喃硝胺口服制剂。
呋喃硝胺是有效的组织胺H-拮抗药，并以其盐酸盐的形式广泛用于治疗下列病症，它能帮助降低胃酸。这类病症包括十二指肠和胃溃疡、反流性食管炎和Zollinger-Ellison综合症。呋喃硝胺还可用于外科技术中的预防剂，并能用于治疗过敏性病症和炎症，在该两种病症中已知组织胺是传递介质。
口服给药成为呋喃硝胺给药的优选途径。然而，呋喃硝胺与许多药物一样具有特有的苦味，因此给某些口服剂型产生了不利因素。另外，众所周知当病人如按医嘱进行口服用药对药味特别不能适应时，他就可能不会完成用药的必要疗程。由呋喃硝胺的苦味所产生的问题在诸如可咀嚼的片剂、颗粒、粉末剂、溶液或悬浮液类的配制剂中尤
为突出。在某种程度上，这种苦味可以通过使用增甜剂和/或调味剂来加以掩蔽，但是这并不能完全令人满意，并且在服用后还可能在口中留下不愉快的感觉。此外，在一些情况中可能不希望或不适合使用增甜剂和/或调味剂。
人们曾报道过多种用于掩蔽与药物有关的苦味的方法，包括使用离子交换树脂，并已经叙述过使用阳离子交换树脂来掩蔽某些含有胺或酰胺基药物的苦味。这类药物的实例包括烟酰胺、盐酸苯海拉明、美沙芬、氯苯吡胺和假麻黄碱。但是在已经叙述过的用作掩蔽与H-受体拮抗药包括呋喃硝胺有关的苦味的方法中，还未曾用过离子交换树脂。
现在，我们发现将呋喃硝胺与离子交换树脂形成复合物可以满意地掩蔽它的苦味，得到的树脂吸附物已实质上没有与呋喃硝胺有关的苦味。
因此，按照上述情况，本发明提供用于口服用药的树脂吸附物，该吸附物包括呋喃硝胺与合成的阳离子交换树脂之间形成的复合物。
按本发明的另一方面，提供用于制备呋喃硝胺树脂吸附物的方法，该方法包括将合成的阳离子交换树脂与呋喃硝胺或其生理上可接受的盐相接触。
按本发明的又一方面，本发明提供了一种掩蔽呋喃硝胺苦味的方法，该方法包括将合成的阳离子交换树脂与呋喃硝胺或其生理上可接受的盐相接触，得到实质上没有与呋喃硝胺有关的苦味的树脂吸附物。
该合成的阳离子交换树脂例如可以是苯乙烯或丙烯酸或甲基丙烯酸与乙烯基芳族化合物如二乙烯基苯的共聚物，并且这类树脂可以从诸如羧酸或磺酸基的弱酸或强酸基团中产生它的交换活性。适宜的树脂的实例为：磺化的苯乙烯和二乙烯基苯的共聚物，或甲基丙烯酸和
二乙烯基苯的共聚物，包括那些可购得的Dowex树脂（从Dow Chemical Company购得）或Amberlite树脂（从Rohm & Haas可购得）。该类树脂可以是酸的形式或与碱金属的盐的形式（如钠或钾）。
这些树脂必须是无毒性的以及可以药用的。
呋喃硝胺可以以其游离碱或生理上可接受的盐的形式来形成按本发明的吸附物后进行使用。这些盐包括与无机酸或有机酸的盐例如盐酸盐、氢溴酸盐、硫酸盐、乙酸盐、马来酸盐、琥珀酸盐、富马酸盐和抗坏血酸盐。按本发明的用途特别优选的盐是盐酸盐。
按本发明的吸附物的实例是那些通过呋喃硝胺盐特别是其盐酸盐与磺化的苯乙烯-二乙烯基苯的盐形式的树脂，特别是其钠盐形式树脂（如Amberlite IRP-69）相接触，或与甲基丙烯酸-二乙烯基苯的盐形式的树脂，特别是其钾盐形式树脂（如Amberlite IRP-88）相接触;或将呋喃硝胺（游离碱）与甲基丙烯酸-二乙烯基苯的游离酸形式树脂（如Amberlite IRP-64）相接触来形成的吸附物。
特别优选的是由甲基丙烯酸-二乙烯基苯的游离酸形式树脂形成的吸附物。这类吸附物可以通过将该树脂与盐形式的呋喃硝胺（特别是其盐酸盐）相接触来形成，或者最好与呋喃硝胺的游离碱相接触来形成。
虽然在该吸附物中相对于树脂来说所有比例的呋喃硝胺均包括在本发明的范围内，但在该吸附物中呋喃硝胺的含量例如可以是在5%至70%（以重量对重量为基础）的范围内，以呋喃硝胺游离碱的重量来表示。吸附物中呋喃硝胺优选含量为15%至55%，更优选为20%至30%。
通过在适宜的溶剂如水中，将合成的阳离子交换树脂与呋喃硝胺游离碱或其盐（特别是呋喃硝胺盐酸盐）溶液相混合，可以制备上述
树脂吸附物。另一种方法，也可以将呋喃硝胺或其盐溶液通过该阳离子交换树脂的柱。
使用一种或多种生理上可接受的载体或赋形剂，可以把该树脂吸附物加到用于口服给药的药物组合物中。
因而，按本发明的最后一个方面，提供了一种供人类或兽类口服的药物组合物，该组合物包括呋喃硝胺与合成的阳离子交换树脂复合的树脂吸附物，该吸附物是通过将合成的离子交换树脂与呋喃硝胺或其可药用的盐相接触形成的。
在口服的配制剂中，呋喃硝胺的优选用量在每单位剂量中为50-600mg范围，更优选的为50-400mg，特别优选的为150-300mg（以游离碱的重量来表示）。可以按单位剂量进行给药，例如每天1至4次，最好每天1次或2次。适当的剂量取决于所治疗症状的特点和严重程度，还应考虑的是根据患者的年龄和体重，在该剂量中可以作必要的例常变化。
按本发明的组合物例如可以是制成片剂、胶囊、颗粒、粉末或用于颊部给药的片剂和咀嚼剂形式，或液体制剂如悬浮液。颗粒剂和粉末剂可以直接吞服，或在给药前分散于水或其它适宜的赋形剂中。胶囊可以是明胶型硬胶囊或软胶囊，包括可以咀嚼的明胶软胶囊。
具体的剂量形式有可咀嚼的或可吸入的片剂（包括浇注的可咀嚼片剂），可咀嚼的明胶软胶囊，颗粒和水悬浮液或非水悬浮液，在这些剂量形式中特别优选的是可咀嚼的或可吸入的片剂，颗粒，和水悬浮液或非水悬浮液。
该组合物可以按适宜的常规技术，使用常规的载体或赋形剂进行配制。
因此，例如用于直接吞服或用于给药前复制的颗粒可以通过将上述的树脂吸附物与粘结剂（如聚乙烯吡咯烷酮或羟丙基甲基纤维素）
和其它合适的赋形剂例如填料（如糖类例如：乳糖、蔗糖、葡萄糖、果糖和甘露糖，或糖醇类如山梨醇、木糖醇和甘露糖醇）一起进行造粒来制备。通过用适当的制片辅剂如润滑剂（如硬脂酸镁）和辅助的粘结剂一起进行压制可以得到该树脂吸附物的片剂。浇注成形的可咀嚼片剂能通过将树脂吸附物与一种或多种低熔点脂肪基质（如甘油三酯基质）混合来制备。胶囊可以通过将该树脂吸附物分散于合适的赋形剂如分馏的椰子油中并使用明胶软胶囊和硬胶囊的标准装填设备来制备。
将上述树脂吸附物分散于合适的含水赋形剂如水或含水的醇（如乙醇）里，并任选与合适的粘性增强剂（如纤维素衍生物或 吨胶）一起进行混合可以得到水悬浮液。将该树脂吸附液分散于合适的非水性基质赋形剂里，并任选与合适的粘性增强剂（如胶态二氧化硅、氢化的食用脂肪或硬脂酸铝）一起混合可以得到非水悬浮液。合适的非水赋形剂包括如杏仁油，花生油，豆油或分馏的植物油如分馏的椰子油。还可适当地包括防腐剂（如羟基苯甲酸的甲酯、乙酯、丙酯或丁酯，苯甲酸钠或山梨酸）。
如需要时，可以将该树脂加到呋喃硝胺的溶液或其生理上可接受的盐在适当的水赋形剂里在原处形成树脂吸附物的水基质悬浮液，或最好是将水加至粉末状或颗粒状的该树脂和呋喃硝胺或呋喃硝胺盐的干燥混合物中来形成。
在适当的情况下，制备的各种剂型可以任选含有适量和/或浓郁的增甜剂、调味剂和/或着色剂。
按本发明的药物组合物可供单剂量形式或多剂量形式使用。单剂量可以例如以干燥产物的形式存在，该产物包括装于一个小囊或其他单剂量包装物中的树脂吸附物或树脂和呋喃硝胺或其盐（与合适的赋形剂一起混合）的混合物。然后在使用前将该组分加至水或其它合适
的赋形剂中。非水悬浮液的单剂量可以是在一个恰当设计的单位容器内的简便形成的悬浮液形式存在。
下列实施例A至E将说明按本发明的树脂吸附物的制备。
实施例A
用水洗涤10g Amberlite IRP-69（钠盐型的磺酸树脂），将雷尼替丁盐酸盐溶液（20g溶于100ml水中）加至该湿的树脂里，混合物在室温搅拌3小时。滤出树脂物并先后以水和丙酮洗涤，然后，在室温条件下将其暴露于干燥空气中进行干燥。该干燥的树脂吸附物含有37%雷尼替丁（按重量）并实质上已无苦味。
实施例B
将呋喃硝胺游离碱（15g）在蒸馏水（100ml）中的溶液加至Amberlite IRP-64（游离酸形式的羧酸树脂）（35g）在蒸馏水（150ml）中的搅拌悬浮液里。该混合物于室温搅拌3小时，然后收集固体，并先后用水和丙酮洗涤。产物在真空和室温条件下干燥，该干燥的树脂吸附物含有27%呋喃硝胺（按重量）并已实质上无苦味。
实施例C
取约200g Amberlite IRP-69悬浮于蒸馏水（2升）中并搅拌30分钟，然后停止搅拌并将悬浮液静止30分钟，倾出液体层，该固体再另外悬浮于2升蒸馏水中，将上述搅拌和静止操作再重复进行四次。然后将该树脂填装于9cm直径的色谱柱中，在重力作用条件下，将呋喃硝胺盐酸盐的蒸馏水溶液（10%W/V）通过色谱柱，直至加入柱内的呋喃硝胺盐酸盐浓度约等于流出液中的浓度为止。
从柱中取出药物树脂盐，先后用水（3×200ml），无水乙醇（3×200ml）洗涤，并在真空条件下干燥得到含有相当于51%W/W呋喃硝胺碱的药物树脂盐，同呋喃硝胺盐酸盐相比较该药物的味道有了显著的改进。
实施例D
呋喃硝胺盐酸盐（300g）溶于蒸馏水（1升），加至Amberlite IRP-88（钾盐形式的羧酸树脂）（200g），产生的悬浮液在室温搅拌3小时。然后停止搅拌，使固体静止2小时。倾出液体，该固体物悬浮于蒸馏水（1升），搅拌2小时，静止后倾出液体。
该固体物悬浮于含有呋喃硝胺盐酸盐（300g）蒸馏水（1升）中。搅拌3小时后，过滤分离固体，先后用蒸馏水（3×300ml），无水乙醇（3×300ml）洗涤并在真空条件下干燥，产生的药物树脂盐含有相当于17%W/W的呋喃硝胺碱并实质上没有苦味。
实施例E
呋喃硝胺盐酸盐（5.6g）溶于氢氧化钠（0.64g）在蒸馏水（100ml）的溶液里，向其中加入Amberlite IRP-64（10g），产生的悬浮液在室温搅拌3小时。发现该树脂从溶液中吸收了80%呋喃硝胺盐酸盐，得到含有相当于28%W/W呋喃硝胺碱的药物树脂盐。过滤分离该药物树脂盐，先后用水（3×30ml）和无水乙醇（3×30ml）洗涤，在真空条件下干燥，得到实质上无苦味的产物。
下列实施例1至15将说明按本发明的药物组合物，其中该药物树脂盐就是在上述实施例中叙述的树脂吸附物，较主要的是呋喃硝胺-Amberlite IRP-64树脂盐。其它的药物树脂盐可以按类似方法，通过将另外的合成阳离子交换树脂与呋喃硝胺或其可药用的盐相接触而配制形成。
实施例1 干燥颗粒
药物树脂盐＊ 50g
木糖醇 144g
薄荷香料 1g
羟丙基甲基纤维素 5g
＊ 含有相当于25%W/W的呋喃硝胺碱。
将药物树脂盐、木糖醇和薄荷香料一起混合，用羟丙基甲基纤维素在含水乙醇中的溶液制成颗粒，然后干燥。
实施例2 可咀嚼的或可吸入的片剂
使用配备有适宜冲头的合适压片机，将上述（a）制备的颗粒物压制成片。
实施例3 可咀嚼的片剂
药物树脂盐＊ 6.72g
甘露醇 16.2g
Aspartame 0.5g
薄荷香料 0.25g
聚乙烯吡咯烷酮 1.25g
硬脂酸镁 0.063g
＊ 含有相当于22.3%W/W的呋喃硝胺碱。
除硬脂酸镁外，将所有粉末一起混合成均匀的混合物，然后加入硬脂酸镁，在短时间内混合该粉末。再将该混合物压制成总重量为约2.5g的片子，每片含有相当于150mg呋喃硝胺的碱。
实施例4 水悬浮液
药物树脂盐 100g
羟丙基甲基纤维素 5g
薄荷香料 5g
糖精 0.3g
山梨醇溶液B.P.C. 100g
羟基苯甲酸丙酯 0.15g
羟基苯甲酸丁酯 0.075g
纯化水 加至1000ml
将羟丙基甲基纤维素溶于含有该配方的其它成分的纯化水中，然后将药物树脂盐分散于该溶液，产生的悬浮液调节至所需体积并充分混合。
实施例5 水悬浮液
药物树脂盐＊ 12g
吨胶 0.2g
Avicel RC591＊＊ 1.5g
糖精钠 0.1g
羟基苯甲酸丙酯 0.15g
羟基苯甲酸丁酯 0.075g
薄荷香料 0.5g
二氧化钛 0.2g
乙醇 7.5ml
山梨醇溶液BPC 10g
纯化水 加至100ml
＊ 含有相当于25%W/W的呋喃硝胺碱。
＊＊89%W/W微晶纤维素和11%W/W羧甲基纤维素钠的混合物。
将糖精钠溶于大部分水中，在剧烈搅拌下加入吨胶和Avicel RC591。另将羟基苯甲酸酯和香料溶于乙醇并加至上述混合物中，再加入山梨醇溶液、二氧化钛和药物树脂盐。产生的悬浮液用水配制至所需体积，用高剪切混合器进行混合得到均匀的悬浮液。
实施例6 水悬浮液（其中药物树脂盐是在原处形成）
呋喃硝胺盐酸盐 33.6g
Amberlite IRP-69树脂 200g
羟丙基甲基纤维素 5g
薄荷香料 5g
糖精 0.3g
山梨醇溶液B.P.C. 100g
羟基苯甲酸丙酯 0.15g
羟基苯甲酸丁酯 0.075g
纯化水 加至1000ml
将羟丙基甲基纤维素溶于含有该配方其它成分的纯化水中，再将雷尼替丁盐酸盐溶于该溶液中，加入树脂，将产生的悬浮液调节至所需体积并充分混合。
实施例7 能复制的水悬浮液
药物树脂盐＊ 12.0g
吨胶 0.2g
Avicel RC591＊＊ 1.5g
糖精钠 0.3g
山梨酸 0.2g
甲羟基苯甲酸钠 0.12g
丙羟基苯甲酸钠 0.08g
薄荷香料 0.5g
二氧化钛 0.2g
山梨醇粉 20g
＊ 含有相当于25%W/W的呋喃硝胺碱
＊＊89%W/W微晶纤维素和11%W/W羧甲基纤维素钠的混合物
用适当的混合器将所有粉末一起混合，然后装入一个150ml的瓶内。临到给药时，加入80ml饮用水，然后摇动该混合物，得到相当于每5ml溶液中含有150mg呋喃硝胺碱的100ml悬浮液。
实施例8 可复制的水悬浮液（其中该药物树脂盐是在原处形成的）
呋喃硝胺游离碱 3g
Amberlite IRP-64 4g
吨胶 0.2g
Avicel RC591＊ 1.5g
糖精钠 0.3g
山梨酸 0.2g
甲羟基苯甲酸钠 0.12g
丙羟基苯甲酸钠 0.08g
薄荷香料 0.5g
二氧化钛 0.2g
山梨醇粉 20g
＊ 89%W/W微晶纤维素和11%W/W羧甲基纤维素钠的混合物
按实施例7的方法配制。
实施例9 可复制的水悬浮液（其中药物树脂盐在原处形成）
呋喃硝胺盐酸盐 3.36g
Amberlite IRP-64 4.0g
碳酸氢钠 0.8g
吨胶 0.2g
Avicel RC591＊ 1.5g
糖精钠 0.3g
山梨酸 0.2g
甲羟基苯甲酸钠 0.12g
丙羟基苯甲酸钠 0.08g
薄荷香料 0.5g
二氧化钛 0.2g
山梨醇粉末 20g
＊89%W/W微晶纤维素和11%W/W羧甲基纤维素钠的混合物
按实施例7的方法配制。
实施例10 可复制的单位剂量水悬浮液
药物树脂盐＊ 0.6g
吨胶 20mg
薄荷香料 10mg
Aspartame 20mg
木糖醇 2g
＊含有相当于25%W/W的呋喃硝胺碱
用合适的混合器将上述粉末进行混合，然后装入单位剂量容器。一次服用剂可以将该粉末放进约20ml的饮用水中并搅拌30秒钟来制备。
可以用另外的糖类例如山梨醇、甘露醇、葡萄糖或蔗糖代替木糖醇。还可用其它浓郁的增甜剂如糖精钠、环己基氨基磺酸盐、thaumatin和acesulfam K代替aspartame。
实施例11 可复制的单位剂量水悬浮液（其中的药物树脂盐是在原处形成的）
呋喃硝胺碱 0.15g
Amberlite IRP-64 0.2g
吨胶 20mg
薄荷香料 10mg
Aspartame 20mg
木糖醇 2g
按实施例10的方法进行配制。
实施例12 可复制的单位剂量水悬浮液（其中的药物树脂盐在原处形成）
呋喃硝胺盐酸盐 0.168g
Amberlite IRP-88 0.2g
吨胶 20mg
薄荷香料 10mg
Aspartame 20mg
木糖醇 2g
按实施例10的方法进行配制。
实施例13 非水悬浮液
药物树脂盐＊ 12g
Aspartame 1g
薄荷香料 0.5g
木糖醇 15g
胶态二氧化硅 0.2g
分馏的椰子油 加至100ml
＊含相当于25%W/W的呋喃硝胺碱
通过高剪切混合将药物树脂盐和木糖醇分散于一定量的分馏椰子油中，再加入剩余组分，使用合适的混合器进行混合。该悬浮液用分馏的椰子油配制至所需体积并进行充分混合。每5ml该悬浮液含相当于150mg的呋喃硝胺碱。
可以用另外的糖类如甘露醇、山梨醇、蔗糖或葡萄糖代替木糖醇。还可以用其它合速的油类如花生油或豆油代替分馏的椰子油。
实施例14 可咀嚼的明胶软胶囊
每粒胶囊含有：
药物树脂盐＊ 0.6g
Aspastame 20mg
香料 适量
分馏的椰子油 0.8g
＊ 含有相当于25%W/W呋喃硝胺碱
使用合适的高剪切混合器，将药物树脂盐和其它粉末分散于分馏的椰子油内，将产生的悬浮液装入可咀嚼的明胶软胶囊。每粒胶囊含有相当于150mg的呋喃硝胺碱。
实施例15 浇注成形的可咀嚼片剂
每片含有：
药物树脂盐＊ 0.6g
Aspartame 0.01g
香料 0.005g
可口油 0.36g
Witepsol HI 5＊＊ 1.8g
＊含有相当于25%W/W的呋喃硝胺碱
＊＊由Dynamit Nobel制造的甘油三酯塞药基料
将Witepsol HI 5和可口油一起熔融并加热至36℃。加入各固体料并将熔融的混合物一起浇注入片子成形的模具内，固化后取出片子，每片含有相当于150mg的呋喃硝胺碱。
Claims (8)
1、一种制备呋喃硝胺(ranitidine)与合成的阳离子交换树脂复合的树脂吸附物的方法，
所述合成的阳离子交换树脂是磺化的苯乙烯和二乙烯基苯的共聚物，或是甲基丙烯酸和二乙烯基苯的共聚物，该方法包括将该合成的阳离子交换树脂与呋喃硝胺或其可药用的盐相接触。
2、按权利要求1所述的方法，其中该树脂可以由弱酸或强酸基团来产生它的交换活性。
3、按权利要求2的方法，其中该合成的阳离子交换树脂是酸的形式或与碱金属的盐的形式。
4、按权利要求1的方法，其中该合成的阳离子交换树脂是游离酸形式的甲基丙烯酸-二乙烯基苯树脂。
5、按权利要求1至4中任一项所述的方法，其中所形成的该吸附物含5%至70%的呋喃硝胺，它是用基于树脂吸附物重量中呋喃硝胺游离碱的重量来表示的。
6、按权利要求5所述方法，其中所形成的该吸附物含20%至30%的呋喃硝胺。
7、按权利要求1至4中任一项所述的方法，其中该合成的阳离子交换树脂是与呋喃硝胺或呋喃硝胺盐酸盐相接触。
8、按权利要求1至4中任一项所述的方法，其中包括由呋喃硝胺游离碱与游离酸形式的甲基丙烯酸二乙烯基苯树脂进行接触。
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100450548C (zh) * | 2006-12-22 | 2009-01-14 | 江苏奥赛康药业有限公司 | 一种波拉克林树脂组合物的口腔贴片及其制备方法 |
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