[go: up one dir, main page]

CN1143320A - 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

Info

Publication number
CN1143320A
CN1143320A CN95191906A CN95191906A CN1143320A CN 1143320 A CN1143320 A CN 1143320A CN 95191906 A CN95191906 A CN 95191906A CN 95191906 A CN95191906 A CN 95191906A CN 1143320 A CN1143320 A CN 1143320A
Authority
CN
China
Prior art keywords
pharmaceutical composition
sublingual
oxepino
dibenzo
chloro
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN95191906A
Other languages
English (en)
Other versions
CN1079670C (zh
Inventor
L·P·C·蒂尔雷斯
J·H·韦宁加
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck Sharp and Dohme BV
Original Assignee
Akzo Nobel NV
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=8216678&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=CN1143320(A) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Akzo Nobel NV filed Critical Akzo Nobel NV
Publication of CN1143320A publication Critical patent/CN1143320A/zh
Application granted granted Critical
Publication of CN1079670C publication Critical patent/CN1079670C/zh
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Physiology (AREA)
  • Nutrition Science (AREA)
  • Psychiatry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

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]oxepino[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-2，3，3a，12b-四氢-1H-二苯并[2，3：6，7]oxepino[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]oxepino[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 theFuture 1993，18(12)，1117-1123)。已明确Org 5222[5-氯-2-甲基-2，3，3a，12b-四氢-1H-二苯并[2，3：6，7]oxepino[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]oxepino[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]oxepino[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]oxepino[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]oxepino[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]oxepino[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，pp 1640-1641；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]oxepino[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′sPharmaceutical 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]oxepino[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]oxepino[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]oxepino [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]oxepino[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0.2g Org5222[5-氯-2-甲基-2，3，3a，12b-四氢-1H-二苯并[2，3：6，7]oxepino[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]oxepino[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：0.2g 5-氯-2-甲基-2，3，3a，12b-四氢-1H-二苯并[2，3：6，7]oxepino[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3
以实施例1b所述方式制备含有下述组分的药物组合物：2g 5-氯-2-甲基-2，3，3a，12b-四氢-1H-二苯并[2，3：6，7]oxepino [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：0.2g 5-氯-2-甲基-2，3，3a，12b-四氢-1H-二苯并[2，3：6，7 ]oxepino [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：0.4g 5-氯-2-甲基-2，3，3a，12b-四氢-1H-二苯并[2，3：6，7]oxepino[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]oxepino[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 Org 5222的冻干球。以相似的方式分别将60或6mg Org 5222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：0.094g 5-氯-2-甲基-2，3，3a，12b-四氢-1H-二苯并[2，3：6，7 ]oxepino[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10ugOrg5222.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Org 5222(或安慰剂)。
在Org 5222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Org 5222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]oxepino[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-2，3，3a，12b-四氢-1H-二苯并[2，3：6，7]oxepino[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-2，3，3a，12b-四氢-1H-二苯并[2，3：6，7]oxepino[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)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP94200521.6 1994-03-02
EP94200521 1994-03-02

Publications (2)

Publication Number Publication Date
CN1143320A true CN1143320A (zh) 1997-02-19
CN1079670C CN1079670C (zh) 2002-02-27

Family

ID=8216678

Family Applications (1)

Application Number Title Priority Date Filing Date
CN95191906A Expired - Lifetime CN1079670C (zh) 1994-03-02 1995-03-01 舌下或颊给药的药物组合物

Country Status (23)

Country Link
US (1) US5763476A (zh)
EP (1) EP0746317B1 (zh)
JP (2) JP4099224B2 (zh)
KR (1) KR100330942B1 (zh)
CN (1) CN1079670C (zh)
AT (1) ATE167057T1 (zh)
AU (1) AU692530B2 (zh)
BR (2) BR9506924A (zh)
CA (1) CA2182981C (zh)
CZ (1) CZ284633B6 (zh)
DE (2) DE69502939T2 (zh)
DK (1) DK0746317T3 (zh)
ES (1) ES2118584T3 (zh)
FI (1) FI117923B (zh)
FR (1) FR10C0056I2 (zh)
HK (1) HK1008417A1 (zh)
HU (1) HU225051B1 (zh)
LU (1) LU91751I2 (zh)
NO (2) NO308772B1 (zh)
NZ (1) NZ282394A (zh)
PL (1) PL180465B1 (zh)
RU (1) RU2139051C1 (zh)
WO (1) WO1995023600A1 (zh)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103120688A (zh) * 2013-01-11 2013-05-29 盛世泰科生物医药技术(苏州)有限公司 一种闪释制剂的药物组合
CN103893139A (zh) * 2012-12-28 2014-07-02 石药集团中奇制药技术（石家庄）有限公司 一种阿塞那平组合物及其制备方法

Families Citing this family (65)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999032108A1 (en) * 1997-12-19 1999-07-01 Akzo Nobel N.V. Org-5222 in the treatment of depression
CA2476250C (en) * 2002-02-13 2010-08-03 Michael K. Weibel Drug dose-form and method of manufacture
US7306812B2 (en) 2003-05-09 2007-12-11 Cephalon, Inc. Dissolvable backing layer for use with a transmucosal delivery device
US7276246B2 (en) * 2003-05-09 2007-10-02 Cephalon, Inc. Dissolvable backing layer for use with a transmucosal delivery device
MXPA05012317A (es) * 2003-05-16 2006-01-30 Pfizer Prod Inc Combinaciones terapeuticas de agentes antipsicoticos atipicos con agentes moduladores del gaba anticonvulsivos o benzodiazepinas.
TWI327915B (en) * 2003-06-12 2010-08-01 Organon Nv Pharmaceutical composition comprising antipsychotic agent and use of the antipsychotic agent for treating patients with overweight
EP1753460A2 (en) * 2004-05-11 2007-02-21 Pfizer Products Inc. Combination of atypical antipsychotics and 5-ht1b receptor antagonists
GB0416861D0 (en) * 2004-07-29 2004-09-01 Quadrant Drug Delivery Ltd Composition
RU2403039C2 (ru) * 2004-10-15 2010-11-10 H.B.Opганон Лечение биполярных расстройств и сопутствующих симптомов
KR101422843B1 (ko) * 2005-04-07 2014-07-24 머크 샤프 앤 도메 비.브이. 아세나핀 말레에이트의 결정형
US7872147B2 (en) 2005-04-07 2011-01-18 N. V. Organon Intermediate compounds for the preparation of trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole
DE602006010132D1 (de) 2005-04-07 2009-12-17 Organon Nv Zwischenprodukte für die Herstellung von Trans-5-Chlor-2-Methyl-2,3,3a,12b-Tetrahydro-1h-DibenzÄ2,3:6,7ÜOxepinoÄ4,5-cÜPyrrol
US7741358B2 (en) * 2005-04-14 2010-06-22 N.V. Organon Crystal form of asenapine maleate
US7750167B2 (en) 2006-07-05 2010-07-06 N.V. Organon Process for the preparation of asenapine and intermediate products used in said process
US7875729B2 (en) 2007-01-05 2011-01-25 Synthon Bv Process for making asenapine
PE20091156A1 (es) * 2007-12-17 2009-09-03 Astrazeneca Ab Sales de (3-{[[3-(6-amino-2-butoxi-8-oxo-7,8-dihidro-9h-purin-9-il)propil](3-morfolin-4-ilpropil)amino]metil}fenil)acetato de metilo
CA2727573A1 (en) * 2008-06-25 2009-12-30 Pfizer Inc. Diaryl compounds and uses thereof
WO2010127674A1 (en) * 2009-05-06 2010-11-11 Sunin K/S Transdermal compositions of asenapine for the treatment of psychiatric disorders
BRPI1011453A2 (pt) 2009-06-24 2016-03-15 Msd Oss Bv formulacao, forma de dosagem de um medicamento, e, sal de hemipamoato de asenapina
AR077429A1 (es) 2009-07-29 2011-08-24 Organon Nv Compuestos hidroxiasenapina sus derivados y composiciones farmaceuticas que comprenden los mismos
CA2802990A1 (en) 2010-06-18 2011-12-22 Dr. Reddy's Laboratories Ltd. Asenapine maleate
JP5815702B2 (ja) 2010-07-29 2015-11-17 ラボラトリオス レスヴィ，エス．エル． アセナピンの新規な製造方法
WO2012038975A2 (en) * 2010-09-22 2012-03-29 Msn Laboratories Limited Process for the preparation of (3ars,12brs)-5-chloro-2-methyl-2,3,3a12b-tetrahydro-1hdibenzo[2,3:6,7] oxepino [4,5-c]pyrrole maleate and it's pharmaceutical composition thereof
NO3034079T3 (zh) 2010-11-15 2018-06-09
WO2012066565A2 (en) 2010-11-16 2012-05-24 Cadila Healthcare Limited Asenapine maleate amorphous and crystalline form and process for preparation thereof
EP2468750A1 (en) 2010-12-13 2012-06-27 Chemo Ibérica, S.A. Polymorphic forms of asenapine maleate and processes for their preparation
WO2012123325A1 (en) 2011-03-11 2012-09-20 Medichem S.A. NEW CRYSTAL FORMS OF THE SALT OF TRANS-5-CHLORO-2-METHYL-2,3,3A,12b-TETRAHYDRO-1H-DIBENZO[2,3:6,7]OXEPINO[4,5-c]PYRROLE WITH MALEIC ACID
EP2524919A1 (en) 2011-05-17 2012-11-21 Sandoz AG Novel crystalline salts of Asenapine with organic Di-acids and Tri-acids
EP2709615A1 (en) 2011-05-18 2014-03-26 Laboratorios Lesvi, S.L. Monoclinic crystalline form of asenapine maleate with a specific particle size distribution
US9505771B2 (en) * 2011-05-18 2016-11-29 Laboratories Lesvi S.L. Stable micronised monoclin form of asenapine maleate and its synthesis
WO2013041604A1 (en) 2011-09-21 2013-03-28 Sandoz Ag Crystal form of asenapine maleate
EP2572703A1 (en) 2011-09-21 2013-03-27 Hexal AG Compressed oral dosage form for asenapine maleate
CN102657635B (zh) * 2012-05-04 2013-08-07 上海现代药物制剂工程研究中心有限公司 具有微孔的海绵状的阿塞那平舌下膜剂及其制备方法
ITMI20121810A1 (it) 2012-10-24 2014-04-25 Chemo Iberica Sa Poliformi di maleato di asenapina e processo per la loro preparazione
WO2014078568A1 (en) 2012-11-14 2014-05-22 The Johns Hopkins University Methods and compositions for treating schizophrenia
US9597291B2 (en) 2012-12-11 2017-03-21 Alfred E. Tiefenbacher (Gmbh & Co. Kg) Orally disintegrating tablet containing asenapine
CA3053189A1 (en) 2012-12-20 2014-06-26 Kashiv Biosciences, Llc Orally disintegrating tablet formulation for enhanced bioavailability
WO2014116770A1 (en) * 2013-01-23 2014-07-31 Arx, Llc Production of unit dose constructs
WO2014127786A1 (en) 2013-02-22 2014-08-28 Zentiva, K.S. Orally disintegrating pharmaceutical composition comprising asenapine
IN2013MU02206A (zh) * 2013-06-28 2015-06-12 Alembic Pharmaceuticals Ltd
AU2014368961B2 (en) 2013-12-20 2019-10-17 Agenebio, Inc. Benzodiazepine derivatives, compositions, and methods for treating cognitive impairment
WO2015125152A2 (en) * 2014-02-18 2015-08-27 Hetero Research Foundation Pharmaceutical compositions of asenapine
HUE065482T2 (hu) 2014-04-04 2024-05-28 Intra Cellular Therapies Inc Deuterált heterociklus-fúzionált gamma-karbolinok mint 5-HT2A receptorok antagonistái
TR201509009A1 (en) * 2014-12-11 2017-02-21 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi THIN FILM STRIP OF ASENAPINE
WO2016198113A1 (en) 2015-06-11 2016-12-15 Alrise Biosystems Gmbh Process for the preparation of drug loaded microparticles
WO2016205739A1 (en) 2015-06-19 2016-12-22 Belew Mekonnen Benzodiazepine derivatives, compositions, and methods for treating cognitive impairment
PT3407888T (pt) 2016-01-26 2021-03-19 Intra Cellular Therapies Inc Compostos de piridopirroloquinoxalina, suas composições e utilizações
EP3407889B1 (en) 2016-03-25 2021-05-19 Intra-Cellular Therapies, Inc. Organic compounds and their use in treating or preventing central nervous system disorders
US10085971B2 (en) 2016-08-22 2018-10-02 Navinta Iii Inc Pharmaceutical solution of asenapine for sublingual or buccal use
US20180170941A1 (en) 2016-12-19 2018-06-21 Agenebio, Inc. Benzodiazepine derivatives, compositions, and methods for treating cognitive impairment
US11505555B2 (en) 2016-12-19 2022-11-22 Agenebio, Inc. Benzodiazepine derivatives, compositions, and methods for treating cognitive impairment
ES2769286T3 (es) 2016-12-20 2020-06-25 Lts Lohmann Therapie Systeme Ag Sistema terapéutico transdérmico que contiene asenapina
US11337932B2 (en) 2016-12-20 2022-05-24 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine and polysiloxane or polyisobutylene
US10961245B2 (en) 2016-12-29 2021-03-30 Intra-Cellular Therapies, Inc. Substituted heterocycle fused gamma-carbolines for treatment of central nervous system disorders
WO2018126143A1 (en) 2016-12-29 2018-07-05 Intra-Cellular Therapies, Inc. Organic compounds
MX2019011329A (es) 2017-03-24 2019-12-02 Intra Celular Therapies Inc Composiciones novedosas y metodos.
ES2881783T3 (es) 2017-06-26 2021-11-30 Lts Lohmann Therapie Systeme Ag Sistema terapéutico transdérmico que contiene asenapina y polímero de acrílico y silicona
CA3094204A1 (en) 2018-03-16 2019-09-19 Intra-Cellular Therapies, Inc. Novel methods
WO2019246300A1 (en) 2018-06-19 2019-12-26 Agenebio, Inc. Benzodiazepine derivatives, compositions, and methods for treating cognitive impairment
MX2020014286A (es) 2018-06-20 2021-03-25 Lts Lohmann Therapie Systeme Ag Sistema terapeutico transdermico que contiene asenapina.
WO2020047241A1 (en) 2018-08-29 2020-03-05 Intra-Cellular Therapies, Inc. Novel compositions and methods
US11957791B2 (en) 2018-08-31 2024-04-16 Intra-Cellular Therapies, Inc. Methods
CN118873536A (zh) 2018-08-31 2024-11-01 细胞内治疗公司 新方法
EP3993798A4 (en) 2019-07-07 2023-04-26 Intra-Cellular Therapies, Inc. NOVEL PROCESSES
US20240132513A1 (en) 2022-08-19 2024-04-25 Agenebio, Inc. Benzazepine derivatives, compositions, and methods for treating cognitive impairment

Family Cites Families (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NL7605526A (nl) * 1976-05-24 1977-11-28 Akzo Nv Nieuwe tetracyclische derivaten.
GB1548022A (en) * 1976-10-06 1979-07-04 Wyeth John & Brother Ltd Pharmaceutial dosage forms
IE45770B1 (en) * 1976-10-06 1982-11-17 Wyeth John & Brother Ltd Pharmaceutical dosage forms
FR2480283A1 (fr) * 1980-04-10 1981-10-16 Science Union & Cie Nouveaux derives tricycliques, leurs procedes de preparation et leur utilisation comme medicament
JPS5967218A (ja) * 1982-10-07 1984-04-16 Grelan Pharmaceut Co Ltd 軟質な口腔製剤
GB8613688D0 (en) * 1986-06-05 1986-07-09 Euro Celtique Sa Pharmaceutical composition
CA2027243A1 (en) * 1989-10-17 1991-04-18 Everett H. Ellinwood, Jr. Intraoral formulated trifluorobenzodiazepines and the use thereof
US5496559A (en) * 1991-04-08 1996-03-05 Sumitomo Pharmaceuticals Company, Limited Porous solid formulations containing proteinaceous physiologically active substances
CA2095499A1 (en) * 1992-05-08 1993-11-09 Petrus J. M. Van Den Oetelaar Depot preparation
EP0569096A1 (en) * 1992-05-08 1993-11-10 Akzo Nobel N.V. Depot preparation

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103893139A (zh) * 2012-12-28 2014-07-02 石药集团中奇制药技术（石家庄）有限公司 一种阿塞那平组合物及其制备方法
CN103893139B (zh) * 2012-12-28 2018-06-08 石药集团中奇制药技术（石家庄）有限公司 一种阿塞那平组合物及其制备方法
CN103120688A (zh) * 2013-01-11 2013-05-29 盛世泰科生物医药技术(苏州)有限公司 一种闪释制剂的药物组合

Also Published As

Publication number Publication date
FR10C0056I2 (zh) 2011-11-25
NO308772B1 (no) 2000-10-30
DE69502939T2 (de) 1998-10-22
DE122010000050I2 (de) 2011-07-21
HK1008417A1 (en) 1999-05-07
KR100330942B1 (ko) 2002-11-16
CZ284633B6 (cs) 1999-01-13
JP4616810B2 (ja) 2011-01-19
PL180465B1 (pl) 2001-02-28
BR1100625A (pt) 1999-12-28
EP0746317B1 (en) 1998-06-10
CN1079670C (zh) 2002-02-27
NO2010024I2 (no) 2012-04-10
NZ282394A (en) 1997-12-19
ES2118584T3 (es) 1998-09-16
AU1947895A (en) 1995-09-18
RU2139051C1 (ru) 1999-10-10
LU91751I2 (fr) 2011-01-04
FI963398L (fi) 1996-08-30
NO963639D0 (no) 1996-08-30
FI117923B (fi) 2007-04-30
JP4099224B2 (ja) 2008-06-11
CA2182981C (en) 2006-10-17
DK0746317T3 (da) 1999-03-22
DE69502939D1 (de) 1998-07-16
DE122010000050I1 (de) 2011-05-05
JP2006342178A (ja) 2006-12-21
NO963639L (no) 1996-10-30
MX9603713A (es) 1997-12-31
HU9602383D0 (en) 1996-10-28
ATE167057T1 (de) 1998-06-15
BR9506924A (pt) 1997-09-30
US5763476A (en) 1998-06-09
FR10C0056I1 (zh) 2011-01-28
CA2182981A1 (en) 1995-09-08
JPH09509674A (ja) 1997-09-30
FI963398A0 (fi) 1996-08-30
EP0746317A1 (en) 1996-12-11
CZ254196A3 (en) 1997-10-15
NO2010024I1 (no) 2011-01-03
PL316080A1 (en) 1996-12-23
HU225051B1 (en) 2006-05-29
AU692530B2 (en) 1998-06-11
WO1995023600A1 (en) 1995-09-08
HUT76319A (en) 1997-08-28

Similar Documents

Publication Publication Date Title
CN1079670C (zh) 舌下或颊给药的药物组合物
KR100296954B1 (ko) 신규의항알러지항염증조성물
CN1080118C (zh) 冻干的奥丹亚龙制剂
EP1246668B1 (en) An rapid acting freeze dired oral pharmaceutical composition for treating migraine
KR100292124B1 (ko) 온단세트론을포함하는경구조성물
RU2572692C2 (ru) Сублингвальные композиции дексмедетомидина и способы их применения
JP4948691B2 (ja) 舌下又は頬投与によって送達される薬物の徐放
CA3145388A1 (en) Non-sedating dexmedetomidine treatment regimens
JP2852608B2 (ja) 口腔乾燥症治療剤
WO2022183029A1 (en) Methods and compositions for treating agitation
JP2023545372A (ja) デクスメデトミジン塩酸塩を用いた双極性障害及び精神病の治療
WO2007010501A2 (en) A pharmaceutical composition comprising a combination of beta blocker and an ace inhibitor
JP2007509031A (ja) ガランタミンの口腔用製剤およびその使用
MXPA96003713A (en) Sublingual pharmaceutical composition or bu
JPH05139964A (ja) 塩酸メキシレチン腸溶性製剤
JPH10511637A (ja) ヒスタミンｈ▲下２▼−アンタゴニストの吸収を増強するためのグルコースのようなパラセルラー吸収エンハンサーの使用
JP3428465B2 (ja) 新規な抗アレルギー抗炎症組成物
US20210052608A1 (en) Methods of treating bacterial infections with minocycline
CA2205600C (en) Freeze-dried ondansetron compositions
Pravin Formulation and evaluation of oral dispersible tablets of antihypertensive drug atenolol
JPH10502331A (ja) 酸分泌過多による軽胃腸障害を治療する低投与量ラニチジン組成物

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
ASS Succession or assignment of patent right

Owner name: ORGANON IRELAND LTD.

Free format text: FORMER OWNER: AKZO NOVEL N.V. CORP.

Effective date: 20040114

C41 Transfer of patent application or patent right or utility model
TR01 Transfer of patent right

Effective date of registration: 20040114

Address after: Swiss hole

Patentee after: Organon Ireland Ltd.

Address before: Holland Arnhem

Patentee before: AKZO NOBEL N.V.

ASS Succession or assignment of patent right

Owner name: ORGANON NV

Free format text: FORMER OWNER: ORGANON IRELAND LTD.

Effective date: 20061229

C41 Transfer of patent application or patent right or utility model
TR01 Transfer of patent right

Effective date of registration: 20061229

Address after: Holland

Patentee after: N.V. ORGANON

Address before: Swiss hole

Patentee before: Organon Ireland Ltd.

C56 Change in the name or address of the patentee

Owner name: MSD OUSI CO., LTD.

Free format text: FORMER NAME: ORGANON NV

CP01 Change in the name or title of a patent holder

Address after: Holland

Patentee after: N.V. Organon

Address before: Holland

Patentee before: N.V. ORGANON

ASS Succession or assignment of patent right

Owner name: MERCK SHARP + DOHME CORP.

Free format text: FORMER OWNER: ORGANON BIOLOGICAL NETHERLANDS CO., LTD.

Effective date: 20131014

Owner name: ORGANON BIOLOGICAL NETHERLANDS CO., LTD.

Free format text: FORMER OWNER: MSD OUSI CO., LTD.

Effective date: 20131014

C41 Transfer of patent application or patent right or utility model
TR01 Transfer of patent right

Effective date of registration: 20131014

Address after: Haarlem

Patentee after: MERCK SHARP & DOHME B.V.

Address before: Haarlem

Patentee before: Organon biological science Holland Co.,Ltd.

Effective date of registration: 20131014

Address after: Haarlem

Patentee after: Organon biological science Holland Co.,Ltd.

Address before: Holland

Patentee before: N.V. Organon

C17 Cessation of patent right
CX01 Expiry of patent term

Expiration termination date: 20150301

Granted publication date: 20020227