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CN1079670C - 舌下或颊给药的药物组合物 - Google Patents

舌下或颊给药的药物组合物 Download PDF

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CN1079670C
CN1079670C CN95191906A CN95191906A CN1079670C CN 1079670 C CN1079670 C CN 1079670C CN 95191906 A CN95191906 A CN 95191906A CN 95191906 A CN95191906 A CN 95191906A CN 1079670 C CN1079670 C CN 1079670C
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L·P·C·蒂尔雷斯
J·H·韦宁加
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Abstract

本发明涉及舌下或颊给药的药物组合物，它含有反-5-氯-2-甲基-2，3，3a，12b-四氢-1H-二苯并[2，3：6，7]氧杂环庚三烯并[4，5-c]吡咯或其可药用盐，和适用于舌下或颊给药组合物的可药用辅助剂；还涉及该化合物用于制备治疗精神性疾病，例如精神病和精神分裂症的舌下或颊给药的药物组合物的应用。

Description

舌下或颊给药的药物组合物
本发明涉及舌下或颊给药的药物组合物，更具体地说是涉及用于治疗各类精神性疾病的舌下或颊给药的组合物。
美国专利4,145,434公开了化合物反-5-氯-2-甲基一2，3，3a，12b-四氢-1H-二苯并[2，3：6，7]氧杂环庚三烯并[4，5-c]吡咯及其制备方法。公开的该化合物具有CNS抑制活性、抗组胺和抗5-羟色胺活性。
De Boer等综述了反-5-氯-2-甲基-2，3，3a，12b-四氢-1H-二苯并[2，3：6，7]氧杂环庚三烯并[4，5-c]吡咯的药理学活性、其动力学和代谢，以及对人类志愿者和精神分裂症患者进行的基本安全性和功效研究。(Drugs of the Future1993，18(12)，1117-1123)。已明确Org5222[5-氯-2-甲基-2，3，3a，12b-四氢-1H-二苯并[2，3：6，7]氧杂环庚三烯并[4，5-c]吡咯马来酸盐(1∶1)]是一种很有效的多巴胺和5-羟色胺拮抗剂，具有较强的抗精神病活性。
然而，反-5-氯-2-甲基-2，3，3a，12b-四氢-1H-二苯并[2，3：6，7]氧杂环庚三烯并[4，5-c]吡咯的口服疗效的第一阶段临床研究表明它产生严重的心脏中毒作用，例如体位性低血压和/或压力感受器功能的损害。
令人意外的是，反-5-氯-2-甲基-2，3，3a，12b-四氢-1H-二苯并[2，3：6，7]氧杂环庚三烯并[4，5-c]吡咯经舌下或颊给药基本上不产生心血管副作用。
因此，本发明涉及舌下或颊给药的药物组合物，它含有反-5-氯-2-甲基-2，3，3a，12b-四氢-1H-二苯并[2，3：6，7]氧杂环庚三烯并[4，5-c]吡咯或其可药用盐，和适用于舌下或颊给药组合物的可药用辅助剂。
本发明的组合物用于治疗患有可被反-5-氯-2-甲基-2，3，3a，12b-四氢-1H-二苯并[2，3：6，7]氧杂环庚三烯并[4，5-c]吡咯治疗的疾病的哺乳动物(包括人类)。这类疾病包括精神性疾病，例如紧张、兴奋、焦虑、精神病和精神分裂症。该组合物还用于与抗组胺和抗5-羟色胺有关的疾病。
本发明药物组合物的最简单形式由水溶液组成，例如，水溶液含有0.9％氯化钠和5-氯-2-甲基-2，3，3a，12b-四氢-1H-二苯并[2，3：6，7]氧杂环庚三烯并[4，5-c]吡咯，或其可药用盐。马来酸盐(Org 5222)是优选的盐。当将水性药物组合物保留于患者舌下或口中时，活性化合物被快速吸收。
优选的药物组合物是固体药物组合物，将其插入颊囊或放入舌下后，在被施用者口中快速崩解。快速崩解意指按照Remington’sPharmaceutical Sciences，18th Edition[(Ed.A.R.Genaro)，1990，pp1640-1641；还参见US Pharmacopeia，Chapter<701>]中所述的方法测定，药物组合物在37℃的水中在30秒内崩解，优选在10秒内崩解。
在优选的实施方案中，本发明的药物组合物是片剂或锭剂，它含有可药用的水溶性或水可分散性载体物质的快速崩解组分。例如，正象美国专利4,371,516中公开的那样，含有可药用的水溶性或水可分散性载体物质的快速崩解组分的片剂和锭剂是本领域已知的。此类片剂可通过冻干水溶液来制备，所述水溶液含有5-氯-2-甲基-2，3，3a，12b-四氢-1H-二苯并[2，3：6，7]氧杂环庚三烯并[4，5-c]吡咯，水溶性或水可分散性载体物质，还可选择性地含有可药用赋形剂。这类赋形剂是本领域已知的，例如参见Remington’s Pharmaceutical Sciences，18th Edition(Ed.A.R.Genaro)，1990，第1635-1638页，它们常用于药物组合物，例如表面活性剂、着色剂、芳香剂、防腐剂等。
水溶性或水可分散性载体物质优选是水溶性的。适宜的水溶性载体是(多)糖，如水解的葡聚糖、糊精、甘露醇，和藻酸盐，或者它们的混合物，或者它们与其他载体物质如聚乙烯醇、聚乙烯吡咯烷酮和水溶性纤维素衍生物，像羟丙基纤维素的混合物。
优选的载体物质是明胶，尤其是部分水解的明胶。例如，可在高压釜中、120℃下将明胶水溶液加热2小时制备部分水解的明胶。使用的水解明胶的浓度约为1-6％(w/v)，优选约为2-4％(w/v)。
本发明组合物的优选剂型，即片剂或锭剂可通过本领域已知的方法制备。例如，按照英国专利2,111,423中所述的方法，将含有预定量的5-氯-2-甲基-2，3，3a，12b-四氢-1H-二苯并[2，3：6，7]氧杂环庚三烯并[4，5-c]吡咯、药用水溶性或水可分散性载体物质，还可选择性地含有可药用辅助剂和赋形剂的水性组合物转移到模具中，之后冷冻该组合物，并优选通过冻干使溶剂升华。该组合物优选含有表面活性剂，例如吐温80(聚氧乙烯(20)山梨醇单油酸酯)，它有助于防止冻干产物粘在模具上。
模具包括一系列圆柱状或其他形状的凹槽，每种槽的尺寸都相应于所需剂型的大小。另外，模具的尺寸也可以大于所需剂型的大小，在冻干内容物后再将产品切割成所需大小。剂型优选以冻干球(lyosphere)形式冻干，它是含活性成分的冻干的球状小滴。
例如，像美国专利4,305,502和5,046,618中公开的那样，优选的模具对应于薄膜材料中的凹槽。薄膜材料类似于常规凸泡包装中所用的材料。
本发明药物组合物的每份剂型含有一个剂量单位的5-氯-2-甲基-2，3，3a，12b-四氢-1H-二苯并[2，3：6，7]氧杂环庚三烯并[4，5-c]吡咯为活性成分。一个剂量单位可包含0.005mg-15mg的活性成分。一个剂量单位优选含有0.03-0.50mg的5-氯-2-甲基-2，3，3a，12b-四氢-1H-二苯并[2，3：6，7]氧杂环庚三烯并[4，5-c]吡咯。
本发明还涉及反-5-氯-2-甲基-2，3，3a，12b-四氢-1H-二苯并[2，3：6，7]氧杂环庚三烯并[4，5-c]吡咯用于制备治疗精神性疾病，例如精神病和精神分裂症的舌下或颊给药的药物组合物的应用。
应用本发明的药物组合物提供治疗的方法包括将依照本发明的剂型插入被治疗者，例如人的颊囊或舌下。使患者症状减缓所需提供的极限剂量不依赖于个体特征，而是取决于患者的体重、健康状况和年龄。通常，每天施用1-4剂量单位的本发明的药物组合物就足以获得疗效。治疗可持续必要或所需长的时间。
下列实施例将进一步说明本发明。实施例1a：水解明胶(3％w/v)的制备
在加热和持续搅拌下，将明胶(30g)溶于1升蒸馏水中。于121℃(105巴)在高压釜中将所得溶液加热1小时，之后使该溶液冷至室温，得到水解明胶(3％w/v)。b：固体药物剂型的制备
用固态二氧化碳冷却带有凹槽的聚乙烯氯薄膜。搅拌下，将o.2gOrg5222[5-氯-2-甲基-2，3，3a，12b-四氢-1H-二苯并[2，3：6，7]氧杂环庚三烯并[4，5-c]吡咯马来酸盐(1∶1)]溶于1升水解明胶中。在继续搅拌的同时将0.5ml该溶液加到每个凹槽中。在冷冻凹槽的内容物时，将PVC膜放入冻干系统中。最后，将铝箔封在膜上以封闭包含冻干药剂的凹槽。每个凹槽包含一个药物单位剂量，含有0.10mg 5-氯-2-甲基-2，3，3a，12b-四氢-1H-二苯并[2，3：6，7]氧杂环庚三烯并[4，5-c]吡咯马来酸盐(1∶1)。实施例2
以实施例1b所述方式制备含有下述组分的药物组合物：0.2g5-氯-2-甲基-2，3，3a，12b-四氢-1H-二苯并[2，3：6，7]氧杂环庚三烯并[4，5-c]吡咯马来酸盐(1∶1)(0rg5222)，0.50g吐温80(聚氧乙烯(20)山梨醇单油酸酯，30g蔗糖和1升水解明胶(3％w/v)。实施例3
以实施例1b所述方式制备含有下述组分的药物组合物：2g5-氯-2-甲基-2，3，3a，12b-四氢-1H-二苯并[2，3：6，7]氧杂环庚三烯并[4，5-c]吡咯马来酸盐(1∶1)(Org 5222)，0.50g吐温80(聚氧乙烯(20)山梨醇单油酸酯，30g蔗糖和1升水解明胶(3％w/v)。  实施例4
制备含有下述组分的药物组合物：0.2g5-氯-2-甲基-2，3，3a，12b-四氢-1H-二苯并[2，3：6，7]氧杂环庚三烯并[4，5-c]吡咯马来酸盐(1∶1)(Org 5222)，17g藻酸钠，35g葡聚糖(分子量约为40.000)，17.5g葡萄糖和蒸馏水至1升体积，将该组合物冻干成单位剂型。实施例5
制备含有下述组分的药物组合物：0.4g5-氯-2-甲基-2，3，3a，12b-四氢-1H-二苯并[2，3：6，7]氧杂环庚三烯并[4，5-c]吡咯马来酸盐(1∶1)(Org 5222)，50g葡聚糖，0.20g吐温80(聚氧乙烯(20)山梨醇单油酸酯)，30g聚乙烯吡咯烷酮和水至1升的体积，将该组合物冻干成单位剂型。实施例6
按下述制备冻干球：将138.9g蔗糖，40.8g柠檬酸钠，和111mg聚山梨醇酯20溶于300ml蒸馏水中，用1N盐酸和1N氢氧化钠将PH调至7，并加水至500ml。经搅拌使该溶液均匀化，并使其滤过一无菌的0.22um过滤器，之后将该溶液冷冻为0.1ml的小滴，将该小滴在冷冻状态下转移到冷冻干燥仪中，然后冻干取出球状冻干的剂型(冻干球)。
将120mg 5-氯-2-甲基-2，3，3a，12b-四氢-1H-二苯并[2，3：6，7]氧杂环庚三烯并[4，5-c]吡咯马来酸盐(1∶1)(Org 5222)溶于1ml乙醇，将83ul该溶液加至一个冻干球，之后经微热除去乙醇得到含10mg Org5222的冻干球。以相似的方式分别将60或6mg Org5222溶于1ml乙醇，之后将16.6ul该溶液加至一个冻干球来制备分别含1和0.1mg Org 5222的冻干球。实施例7
制备含有下述组分的药物组合物：0.094g5-氯-2-甲基-2，3，3a，12b-四氢-1H-二苯并[2，3：6，7]氧杂环庚三烯并[4，5-c]吡咯马来酸盐(1∶1)(Org 5222)，30甘露醇，40g明胶和蒸馏水至1升体积，按照实施例1b的方法将该组合物冻干成单位剂型，每单位剂型含10ugOrg 5222。实施例8
如下测定体位性低血压(倾斜要求)及直接的血液动力学和电生理学作用：方法
将麻醉小猎兔犬(10-20kg，Harlan，France)安放在仪器上。将一个微量测压计安置在近主动脉弓的动脉上，另一个安置在左心室。以彼此相距约1cm的距离将一对节段长的压电晶体(Triton Technology)缝合到心内左心室壁。所有连线均经皮下掘道并在颈背处外置。手术后两周将狗置于与八孔道记录仪(Gould ES3000)相连的Pavlov-stand和转换器上。也采用常规的二极肢导联记录心电图(标准二极导联)。
给神志清醒的狗口服(1，2.5，5，10，或50mg/kg)或皮下(0.01，0.1，或1mg/kg)施用Org5222(或安慰剂)。
在Org5222施用后的5小时观察期间内连续记录主动脉的收缩、舒张和平均血压(mmHg)，心率(搏/分)，心室收缩段的缩短(mm)和QT间隔，并且每隔15分钟进行自动分析。按照Bazett’s式计算QTc(它反映心脏的极化恢复时间)。
提起狗的前肢将狗倾斜至90°竖直位置30秒。倾斜反应是指在观察的30秒期间内观察到的主动脉血压和心率的最大变化，并且在Org5222施用前30分钟和临施用前及施用后15，30，60，90，120，180，240和300分钟进行测评。
倾斜要求后的每种情形下，在药物临施用前及施用后15，30，60，90，120，240，300，360分钟和21小时采血样。从血样分离血清，加入内标顺-5-氯-2-甲基-2，3，3a，12b-四氢-1H-二苯并[2，3：6，7]氧杂环庚三烯并[4，5-c]吡咯马来酸盐(1∶1)(Org 5033)，用正己烷提取碱化的血浆将Org 5222和内标分离。采用NDP-测定法通过毛细管气相色谱(cGC)测定Org 5222的浓度。结果
对倾斜的低血压反应是中度的并且是随Org 5222的剂量依赖性增长的，而与施用的途径无关。但是，对于相同的Org 5222血浆水平而言，口服施用Org 5222后伴随的心动过速总是比舌下施用后更明显(表1)。表1：计算每个浓度范围(ng/ml)和每种施用途径，即口服(po)和舌下(sl)下，由于倾斜的平均心率变化(作安慰剂作用的校正)。
  Org 5222血浆浓度(ng/ml)    每个浓度范围的平均心率变化
    po     sl
      0-3     5.7     4.6
      3-10     21.3     0.6
      10-30     21.1     18.3
      30-100     47.8     14.9
      100-300     52.8     8.9
  结论：
Org 5222口服施用后伴随体位性低血压的心动过速较舌下施用后更为明显。舌下施用后的直接血液动力学和电生理学作用也不如口服施用后明显，并且与减弱收缩力和QTc的延长无关。
另外，经口服处理的狗表现出明显的副作用，例如长期兴奋；而经舌下处理的狗仅表现出短时的兴奋，之后持续长时间的镇静。

Claims (4)

1.一种舌下或颊给药的药物组合物，其特征在于该组合物含有反-5-氯-2-甲基一2，3，3a，12b-四氢-1H-二苯并[2，3：6，7]氧杂环庚三烯并[4，5-c]吡咯或其可药用盐，和适用于舌下或颊给药组合物的可药用辅助剂。
2.权利要求1的药物组合物，其中该组合物还含有可药用的水溶性或水可分散性载体物质。
3.权利要求2的药物组合物，其中的载体物质是部分水解的明胶。
4.反-5-氯-2-甲基一2，3，3a，12b一四氢-1H-二苯并[2，3：6，7]氧杂环庚三烯并[4，5-c]吡咯用于制备治疗精神性疾病的舌下或颊给药的药物组合物的应用。
CN95191906A 1994-03-02 1995-03-01 舌下或颊给药的药物组合物 Expired - Lifetime CN1079670C (zh)

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