CN1251039A - 镇咳组合物 - Google Patents
镇咳组合物 Download PDFInfo
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- CN1251039A CN1251039A CN98803693A CN98803693A CN1251039A CN 1251039 A CN1251039 A CN 1251039A CN 98803693 A CN98803693 A CN 98803693A CN 98803693 A CN98803693 A CN 98803693A CN 1251039 A CN1251039 A CN 1251039A
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- theobromine
- complex
- salt
- composition
- pharmaceutical composition
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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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
- A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/14—Antitussive agents
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- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pulmonology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Saccharide Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Plant Substances (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Detergent Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明涉及任选地与其它已知活性成分和惰性固体或液体载体、添加剂和辅剂混合的可可碱和/或其盐和/或其复合物在生产适于缓解咳嗽症状的药物组合物中的用途。本发明的另一个目的是对需要缓解咳嗽的人或动物进行治疗的方法,该方法包括施用有效量的任选地与其它已知活性成分和惰性固体或液体载体、添加剂和辅剂混合的可可碱和/或其盐和/或其复合物。
Description
本发明涉及含有式(III)的可可碱[3,7-二氢-3,7-二甲基-1H-嘌呤-2,6-二酮]或其盐或其复合物(complex)作为镇咳剂的镇咳制剂。
已知在茶叶(Thea sinensis)、可可豆(Theobroma cacao)和咖啡豆(Coffea arabica)中存在着三种天然的甲基黄嘌呤生物碱,即式(I)的茶碱、式(II)的咖啡因和式(III)的可可碱。这些植物与人类的饮食密切相关,因为它们是多种被广泛消费的商品和饮料的原料。
在茶叶中,除茶碱和可可碱外,咖啡因是主要的生物碱。在咖啡中,咖啡因是最主要的生物碱,而在可可粉和生产巧克力的基本原料巧克力液体中,可可碱是主要的生物碱,但同时也含有一些咖啡因。
这三种天然的甲基黄嘌呤(I、II、III)具有复杂的生物学作用,但尽管在化学结构上非常相似,它们在效力的强度以及作用谱上均有明显差异。
在文献中普遍接受的观点是,甲基黄嘌呤化合物的广谱药理学作用可以从两种主要的分子机理推导出。一种是环状核苷酸磷酸二酯酶(PDE)的非特异性抑制作用,第二种是腺苷受体的拮抗作用。已对多种烷基黄嘌呤化合物进行了实验并且证实,作为一般的原则,如果在黄嘌呤部分的N1原子上没有取代基或者如果N7原子含有取代基,则上述两种作用均比相应的1,3-二烷基黄嘌呤要弱。
可可碱的N1原子没有被取代而N7原子被取代,因此,按照一般原则,可可碱的活性应当比咖啡因或茶碱都弱。的确,就PDE抑制作用和腺苷拮抗作用而言,三种天然甲基黄嘌呤化合物的活性顺序为:茶碱>咖啡因>可可碱。
甲基黄嘌呤化合物、特别是茶碱的一个非常重要并且与临床密切相关的特点是,它们在体内和体外均可以松弛不同种类的平滑肌。茶碱的支气管平滑肌松弛作用以及其它优良的治疗特性被广泛用于治疗哮喘。可可碱和咖啡因的类似作用要比茶碱弱得多。
已知并且受到广大消费茶和含咖啡因饮料的人群支持的是,咖啡因和茶碱均有很强的中枢神经***(CNS)刺激作用。可可碱对CNS的作用比咖啡因或茶碱都弱(Mumford,G.K.等,精神药理学(Psychopharmacology),1994,115:1)。
咖啡因和茶碱对心肌和心血管***都有很强并且复杂的作用。已知这些化合物具有显著的外周血管扩张作用,但在较高剂量下,它们会造成心动过速。可可碱的心血管作用要弱得多。
利尿作用是这些甲基黄嘌呤化合物(I、II、III)、特别是茶碱的非常典型的特征。与茶碱或咖啡因相比,可可碱仅有很弱的利尿作用。
这些天然甲基黄嘌呤化合物除了在治疗作用上存在差别外,在其毒副作用上也有不同。由于茶碱的治疗剂量范围窄,因此给药过量的危险性较高,而咖啡因则相对较弱。与茶碱或咖啡因相比,由可可碱引起的危险副作用的可能性可以忽略不计(Stavric,B.,Fd.Chem.Toxic.1988,26:725)。
涉及天然甲基黄嘌呤化合物、特别是茶碱和咖啡因的科学文献的范围非常广泛。可以在涉及该论题的成千上万篇科技文章、专利说明书、综述和书籍中寻找到资料。这些研究认为,由于可可碱生理学活性很弱,该化合物没有治疗意义。上述观点受到了最为著名的药理学书籍之一的支持:
“茶碱、咖啡因和可可碱具有一些共同的有治疗意义的药理学作用。它们可以松弛平滑肌、特别是支气管肌肉,刺激中枢神经***(CNS)、刺激心肌、作用于肾产生利尿作用。由于可可碱在这些药理学作用中显示出的强度很低,在治疗中几乎不使用该化合物。”(Rall,T.V.,Goodman and Gliman’s,治疗的药理学基础(ThePharmacological Basis of Therapeutics),第8版,620页,PergamonPress,New York,1990)。没有发现关于可可碱镇咳作用的文献。
在以上事实的基础上,我们非常出人意料地发现了可可碱(III)具有很强并且长效的镇咳作用。可可碱的镇咳作用与最常用作镇咳剂的***衍生物之一可待因相当。
可可碱的这种出人意料并且优良的镇咳作用可以在治疗中得到很好的应用,因为可可碱的毒性低并且没有危险的副作用。需要强调的是,与***结构的镇咳化合物相反,可可碱没有任何呼吸抑制作用,此外,除了其镇咳作用外,可可碱还有某些有利的对支气管肺的作用:根据我们现有的资料,可可碱可以明显地刺激粘液纤毛清除功能,该功能与溴己新(一种已知的祛痰药)相似。
据文献记载,茶碱对于柠檬酸喷雾引起的豚鼠咳嗽具有弱的镇咳活性。这种弱的镇咳活性不能通过增加茶碱的剂量得到改善,因为会出现有害的副作用(Forsberg,K等,呼吸(Respiration),1992,59:72)。在同样的试验模型中,氨茶碱(茶碱乙二胺)在所有的试验剂量下均无效(Franzone,J.S.等,II Farmaco,Ed.Sc.1981,36:201)。
未通过咖啡因或可可碱证实同样的镇咳作用。我们用盐酸可待因作为参照化合物,在柠檬酸喷雾引起的咳嗽模型中对其镇咳活性进行了实验。
急性镇咳活性实验在雌雄均有、体重250-300g的Hartley白化豚鼠(Charles River)中进行。对Tardos的方法进行微小改变(Tardos,L.,Erdély,I.,药物研究(Arzneim.Forsch.)(Drug Res.)1966,16:617)。通过与透明的室(体积为6.7升)连接的喷雾器产生喷雾。用流量为0.16升/秒、压力为0.5巴的压缩空气产生喷雾。通过恒定的气流驱动的短管将蒸气通入室中。将动物单独放在透明室中并接触柠檬酸(溶于蒸馏水的15w/v%柠檬酸溶液)气溶胶3分钟。由经过训练的观察者计数从接触喷雾开始直至结束时的咳嗽次数。动物的咳嗽被定义为腹部的强烈收缩,随后通过动物张开的嘴强迫呼气。为了对物质进行测试,仅使用在第一次试验的3分钟时间内咳嗽的次数等于或大于6次的动物。将所选动物用所研究的黄嘌呤化合物或参照物可待因以在0.1%甲基纤维素中的混悬液的形式(处理组)或用0.1%甲基纤维素本身(对照组)口服给药一次。载体的体积为0.1ml/100g体重。用试验物质处理1小时后,进行第二次柠檬酸刺激。镇咳活性用第二次和第一次刺激之间咳嗽次数减少的百分比表示。将药物处理组与载体处理的对照组进行比较。
如图1所示,在单次口服给药后,可可碱和参照物可待因剂量依赖性地减少咳嗽的次数。
图1
可可碱、咖啡因和参照物盐酸可待因
对15%柠檬酸喷雾引起的豚鼠咳嗽模型的镇咳作用
为了进行统计学分析,使用Mann-Whithney U试验;将处理组与对照组进行比较。n.s.=无显著性;**p<0.01;***p<0.001
在第二次咳嗽刺激前1小时对动物口服给药。
载体为0.1%甲基纤维素。
可可碱的镇咳作用强度与可待因相当。可可碱和可待因的镇咳作用分别在4和8mg/kg的剂量下就已经很明显。当可可碱的剂量为64mg/kg时,咳嗽次数大大减少(69.0±1.9%)。同样剂量的可待因减少咳嗽次数的程度略低(54.2±5.7%)。计算出的可可碱和可待因的ED50分别为37mg/kg和49mg/kg。
相反,咖啡因在2-16mg/kg的剂量下没有镇咳作用。在更高的剂量(32和64mg/kg)下,咖啡因明显减少咳嗽的次数(分别为17.5±3.7%和48.4±3.1%),但这些剂量接近该化合物的毒性剂量,因此咖啡因的镇咳作用不适用于治疗。
这三种化合物在大鼠中的急性口服毒性为(LD50mg/kg):咖啡因:192;可可碱:1265;可待因:427(Sigma-Aldrich化学安全数据库(TheSigma-Aldrich Library of Chemical Safety Data),ed.Lenga R.E.,第II版,Sigma-Aldrich Corporation,USA,1988)。
从给出的ED50和LD50值计算出可可碱的镇咳治疗指数(LD50/ED50)为34,可待因的为8.7。可可碱的镇咳治疗指数比可待因高约4倍。
进一步的实验表明,可可碱的镇咳作用可以持续数小时。按照1小时急性实验中的描述,测定对Hartley豚鼠口服给药32mg/kg可可碱的镇咳作用的时间依赖性。
图2
对豚鼠口服给药32mg/kg可可碱后
镇咳结果调整至对照值。
如图2所示,可可碱具有长效镇咳活性。
口服给药32mg/kg可可碱引起的镇咳作用的时间过程大体与在口服给药32mg/kg的豚鼠中测得的可可碱血浆浓度的时间过程相对应(参见图2)。证实这两种时间过程之间的密切对应关系是非常重要的,并且对于本发明的主题是非常有利的。口服给药后能在短时间内达到预期的治疗效果是一个非常重要的特点。最近进行的人类实验的结果表明,与含纯的可可碱的胶囊相比,基于巧克力的可可碱制剂可以明显改善可可碱的小肠吸收速率和血浆浓度(在两种制剂中使用相同剂量的可可碱)。胶囊给药后3小时达到可可碱的最大血浆浓度,而当使用基于巧克力的制剂时,吸收要快得多,在给药后2小时达到最大血浆浓度(Mumford,G.K.等,欧洲临床药理学杂志(Eur.J.Clin.Pharmacol.)1996,51:319)。必需强调的是,在豚鼠中,处理4小时后可可碱血浆浓度的降低相对较陡,而在人中,可可碱的血浆半衰期延长(t1/2=6.1-10小时,Shively,C.A.等,临床药理学治疗(Clin.Pharmacol.Ther.)1985,37:415)。可待因在人血浆中的半衰期更短:2-4小时(Raisine T.,Pasternak G.,Goodman and Gliman’s,治疗的药理学基础,第9版,Mc Graw-Hill,New York,1996,534页)。
同样值得一提的是,可可碱在人血浆中浓度的降低比茶碱或咖啡因慢(Birkett,D.J.,甲基黄嘌呤在人体内的代谢。抗哮喘黄嘌呤化合物和腺苷,235页,Andersson K.E.and Persson C.G.A.编,ExcerptaMedica,Amsterdam,1985)。
在豚鼠中可可碱的血浆浓度和其镇咳作用之间的密切联系清楚地表明了在人类中的长效镇咳作用。
考虑到可可碱在豚鼠中的剂量-效应曲线、其优良的毒理学特性和极小的副作用,可可碱的推荐成人镇咳剂量在200-500mg之间,每天2或3次。
如前所述,与胶囊制剂相比,基于巧克力的可可碱制剂有助于在人体内达到更高的血浆浓度(Mumford,G.K.等,欧洲临床药理学杂志1996,51:319),于是我们实验了是否可以通过食用普通的巧克力来达到所需的镇咳效果。
已知不同类型的普通巧克力,从牛奶巧克力到黑巧克力,含有不同含量的可可碱。黑巧克力的可可碱含量约为牛奶巧克力的3倍以上。一种特制的黑巧克力条(41g)(Hershey’s Special Dark,New andImproved)含有185mg可可碱和36mg咖啡因(Mumford,G.K.等,欧洲临床药理学杂志1996,51:319)。这意味着为了达到所需的镇咳作用,必需食用至少1-3条这种特制的黑巧克力(41-123g),每天2-3次。当然,对于可可碱含量较少的巧克力,则需要食用更多条。由于健康的原因,长时间(慢性给药)食用如此多的巧克力显然是不允许的。巧克力中的咖啡因成分由于能引起特征性的CNS刺激和其它药理学作用,会产生更重要的问题(Mumford,G.K.等,精神药理学,1994,115:1)。
基于可可碱和咖啡因在不同可可制品中的含量,如果想要通过普通的可可制品(可可饮料和含可可的食品)来施用镇咳剂量的可可碱,其情况与巧克力类似(Zoumas,B.L.,甲基黄嘌呤组合物和可可及巧克力制品的消费模式,咖啡因(CAFFEINE),Spiller,G.编,CRCPress,USA,1997)。
可可碱的强镇咳作用(比咖啡因和茶碱的镇咳作用都强)的分子机理尚不清楚。如前所述,该作用确实是令人惊奇的,因为可可碱的所有其它作用均比另外两种天然的黄嘌呤衍生物弱。
我们认为,甲基黄嘌呤化合物的多种复杂的作用在镇咳作用中起作用。可可碱极佳的镇咳活性可能是由于在复杂和多级的作用中,腺苷受体(主要是A1)的拮抗作用明显弱于茶碱或咖啡因。
已进行了一些实验了来研究成瘾性。
这些实验的目的是检查在重复(慢性)给药后,可可碱的镇咳活性是否能保持恒定。按照以上的描述对同样的方法进行修改。将选定的Hartley白化豚鼠用32mg/kg可可碱以在0.1%甲基纤维素中的混悬液形式(处理组)或用0.1%甲基纤维素本身(对照组)每日给药一次,共进行14天。在第1天-第7天-第14天测试镇咳作用。在指定的天数,在临给药前和给药1小时后计数咳嗽的次数。对照组(n=12)进行与可可碱处理组(n=13)相同的实验方案。
将镇咳作用调整至对照值,在第1天、第7天和第14天,分别为46.1±2.3%、54.1±3.4%和49.0±4.9%。在用高(32mg/kg)口服剂量连续处理14天后,可可碱的镇咳活性没有因成瘾性的形成而降低。
注意,在人中,以黑巧克力的形式施用相对高的每日剂量(6mg/kg/天)一周,既不会改变可可碱的代谢,也不会改变其清除率(Shively,C.A.等,临床药理学治疗,1985,37:415)。
关于可可碱的代谢还应当注意的是,根据我们的实验,可可碱的主要代谢物3-甲基黄嘌呤在窄的剂量范围内具有一定的镇咳作用。但是,在更高的剂量下,剂量-活性曲线变形。
粘液纤毛清除,呼吸气管的主要防御机制,会被慢性支气管炎明显损伤(Dirksen,H.等,欧洲呼吸疾病杂志(Eur.J.Respir.Dis.)1987,71(153补编(Suppl.153)):145)。患有支气管炎的患者是最经常使用镇咳药物的人群。传统的类阿片镇咳剂如可待因,不仅破坏呼吸参数,而且还对粘液纤毛清除有抑制作用(Melville,G.N.,Iravani,J.,加拿大生理药理学杂志(Can.J.Physiol.Pharmacol.)1975,53:1122)。注意,在人和体外动物实验中,茶碱具有明显的粘液纤毛清除改善活性(Wanner,A.,美国药物杂志(Am.J.Med.)1985,79(6A补编):16;Wagner,U.等,欧洲药理学杂志,1996,298:265)。我们研究的目的是研究可可碱(其与茶碱的不同之处是具有强的镇咳活性,其强度与可待因相当)是否会影响兔子呼吸气道的粘液纤毛清除。为了研究可可碱对粘液纤毛清除活性的影响,采用Achterrath-Tuckerman的方法(Achterrath-Tuckerman,U.等,肺(Lung),1992,170:201)。使用盐酸溴己新(一种已知的祛痰剂)作为参照物。
该模型涉及通过吸入给药99m锝标记的同源红细胞悬浮液。在吸入标记的红细胞前30分钟静脉内给药可可碱和参照物溴己新。在最后吸入雾化的细胞悬浮液后,用γ-照相机在封闭的胸腔上方测定放射性60分钟。绘制时间-活性曲线并与测定的点拟合。粘液纤毛清除的数值表示为单位时间(小时)内放射性标记物的量消除的百分数。粘液纤毛清除数值的增加定量地表明了以前的药物处理增强了粘液纤毛活性。为了进行统计学评估,将药物处理组与载体处理组用Student’s t试验进行比较。以2、4和8mg/kg的剂量静脉内给药可可碱剂量依赖性地增加粘液纤毛清除。最高的可可碱注射剂量(8mg/kg)使清除增加60%(p<0.05)。20mg/kg的溴己新可以产生相同的清除率。
在上述研究中所确定的镇咳剂量范围内,可可碱可明显增强兔子的粘液纤毛清除功能。
镇咳剂通常用来阻断有害的刺激性咳嗽,这种咳嗽可导致咳嗽-刺激-咳嗽的恶性循环。
必需强调的是,完全或者太强地抑制咳嗽是不利的,因为这会抑制排痰性咳嗽。
理想的镇咳药应能减少咳嗽的频率并减少痛苦,但不会使咳嗽反射受到损害,也就是说,理想的镇咳药能够抑制有害的咳嗽但不会损害有益的咳嗽。此外,理想的镇咳剂还具有支气管扩张活性,刺激粘液纤毛清除功能,并且没有毒副作用。
可可碱似乎能够满足以上的所有要求。
根据本发明,可可碱可作为镇咳药用于治疗各种疾病。考虑到其祛痰的作用,可可碱特别适于单独或与其它药物联用来治疗导气管疾病(支气管炎、流感等)。
因此,本发明涉及适于缓解咳嗽症状的药物组合物,该组合物含有治疗有效量的式(III)的可可碱和/或其盐和/或其复合物,其任选地与其它已知活性成分和惰性固体或液体载体、添加剂和辅剂混合。
另一方面,本发明涉及任选地与其它已知活性成分和惰性固体或液体载体、添加剂和辅剂混合的可可碱和/或其盐和/或其复合物在生产用于缓解咳嗽症状的药物组合物中的用途。
本发明的另一目的是对需要缓解咳嗽的人或动物进行治疗的方法,该方法包括,施用有效量的任选地与其它已知活性成分和适宜的惰性固体或液体载体、添加剂和辅剂混合的可可碱和/或其盐和/或其复合物的步骤。
为了生产含有可可碱的药物或辅助药物(paramedicine),可以采用各种制剂,例如,注射液、糖浆、糖衣丸、片剂、锭剂、栓剂、胶囊和其各种缓释形式如脂质体。基于人体的吸收资料,巧克力形式的锭剂和糖衣丸制剂、特别是富含可可碱的巧克力制品和脂质体也可以使用。优选将可可碱和/或其盐和/或其复合物部分或完全作为可可粉、速溶可可粉或巧克力的成分来生产适于缓解咳嗽症状的药物组合物。下列本发明的制剂是采用常规的制药和食品技术制备的。本发明药物制剂中的可可碱含量为0.1-99.9w/w%,优选1-30w/w%。根据患者的年龄和给药途径,每日剂量为10-3000mg。
本发明由如下制剂实施例支持,但可可碱作为镇咳剂的用途并不仅限于这些实施例。
实施例1片剂:
可可碱 500g
玉米淀粉 130g
磷酸钙 209g
硬脂酸镁 1.0g
840g
将混合的化合物通过已知方法造粒,压制成1000片840mg的片剂,每片含有500mg活性成分。
实施例2长效糖衣丸:
可可碱 450g
羧甲基纤维素 300g
硬脂酸 20g
乙酸邻苯二甲酸纤维素 30g
800g
将活性成分、羧甲基纤维素和硬脂酸混合并用乙酸邻苯二甲酸纤维素的200cm3乙酸乙酯-乙醇溶液造粒,压制成800mg的片剂并用含糖的5%聚乙烯吡咯烷酮的水溶液通过已知方法包衣。所有的糖衣丸均含有450mg活性成分。
实施例3胶囊:
可可碱 350g
聚乙烯吡咯烷酮 200g
滑 60g
硬脂酸镁 60g
淀粉乙醇酸钠 100g
770g
将所有成分混合并通过已知方法造粒。用该颗粒填充1000粒胶囊得到含有350mg活性成分的胶囊。
实施例4栓剂:
可可碱 50g
固体豚脂(Adeps solidus) 150g
200g
将固体豚脂熔化并搅拌加入活性成分。将该混悬液倒入100粒冷的栓剂模具中得到含有500mg活性成分的栓剂。
实施例5糖浆:
可可碱 25g
羧甲基纤维素 1g
蔗糖 30g
香料 0.1g
着色剂 0.01g
防腐剂 0.01g
蒸馏水 加至100g
将40g蒸馏水和蔗糖煮沸。冷却,混入香料、着色剂和悬浮在溶胀的羧甲基纤维素(10cm3蒸馏水+1g羧甲基纤维素)中的可可碱并用蒸馏水将糖浆调至100g。1g该糖浆含有250mg活性成分。
实施例6巧克力锭剂:
可可碱 约50g
可可粉 20g
蔗糖 20g
奶粉 5g
乙基香草醛 0.01g
可可脂 加至250g
称取活性成分,考虑可可粉中的可可碱含量,使每250g巧克力组合物含有50g可可碱。将150g可可脂熔融至刚好在熔点以上并混入可可粉、蔗糖、奶粉、乙基香草醛和活性成分。将该悬浮液用熔融的可可脂加至250g。将该混合物倒入冷的模具中。得到100粒巧克力锭剂,每粒含500mg可可碱。
实施例7脂质体:
可可碱水杨酸盐 15g
磷脂(Phospholipon)90H 30g
乙醇 22.5g
纯净水,USP 82.5g
将成分按照配方的顺序混合。将液相的温度升至磷脂的转变温度并加入相同温度的水。将该混合物以约50RPM在45℃搅拌20分钟,停止加热并继续搅拌至制剂达到25℃。
Claims (13)
1.适于缓解咳嗽症状的药物组合物,该组合物含有治疗有效量的任选地与其它已知活性成分和惰性固体或液体载体、添加剂和辅剂混合的式(III)的可可碱和/或其盐和/或其复合物。
2.权利要求1的组合物,含有可可碱作为活性成分。
3.权利要求1的组合物,含有可可碱的盐或复合物作为活性成分。
4.权利要求1的组合物,含有部分或完全作为可可粉、速溶可可粉和/或巧克力的成分的可可碱和/或其盐和/或其复合物。
5.权利要求1-4中任意一项所述的组合物,为注射液、糖浆、糖衣丸、片剂、锭剂、栓剂、胶囊和它们的缓释形式,优选脂质体的形式。
6.任选地与其它已知活性成分和惰性固体或液体载体、添加剂和辅剂混合的可可碱和/或其盐和/或其复合物在生产用于缓解咳嗽症状的药物组合物中的用途。
7.权利要求6所述的可可碱的用途,用于生产适于缓解咳嗽症状的药物组合物。
8.权利要求6所述的可可碱的盐和/或复合物的用途,用于生产适于缓解咳嗽症状的药物组合物。
9.权利要求6所述的、任选地与其它已知活性成分和惰性固体或液体载体、添加剂和辅剂混合的可可碱和/或其盐和/或其复合物的用途,部分或完全作为可可粉、速溶可可粉和/或巧克力的成分用于生产缓解咳嗽症状的药物组合物。
10.权利要求6-9中任意一项所述的、任选地与其它已知活性成分和惰性固体或液体载体、添加剂和辅剂混合的可可碱和/或其盐和/或其复合物的用途,用于生产适于缓解咳嗽症状的药物组合物,所述药物组合物为注射液、糖浆、糖衣丸、片剂、锭剂、栓剂、胶囊和它们的缓释形式,优选脂质体的形式。
11.对需要缓解咳嗽的人或动物进行治疗的方法,该方法包括,施用有效量的任选地与其它已知活性成分和适宜的惰性固体或液体载体、添加剂和辅剂混合的可可碱和/或其盐和/或其复合物的步骤。
12.权利要求11所述的方法,使用部分或完全作为可可粉、速溶可可粉或巧克力的成分的可可碱和/或其盐和/或其复合物。
13.权利要求11或12所述的治疗方法,以注射液、糖浆、糖衣丸、片剂、锭剂、栓剂、胶囊和它们的缓释形式、优选脂质体的形式使用可可碱和/或其盐和/或其复合物。
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HU9700654A HUP9700654A2 (hu) | 1997-03-26 | 1997-03-26 | Teobromin tartalmú köhögéscsillapító készítmények |
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CN (1) | CN1251039A (zh) |
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BG (1) | BG103780A (zh) |
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DK (1) | DK0969843T3 (zh) |
EA (1) | EA001971B1 (zh) |
EE (1) | EE9900428A (zh) |
ES (1) | ES2178188T3 (zh) |
HU (1) | HUP9700654A2 (zh) |
IL (2) | IL131811A0 (zh) |
NO (1) | NO994640L (zh) |
PL (1) | PL190899B1 (zh) |
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN100571540C (zh) * | 2001-10-18 | 2009-12-23 | Lotte制果株式会社 | 具有抗癌活性的可可碱 |
CN101112383B (zh) * | 2006-07-25 | 2010-05-26 | 安国药品株式会社 | 用于治疗咳嗽的组合物 |
CN102740853A (zh) * | 2009-11-13 | 2012-10-17 | 比蔻匹亚有限公司 | 可可碱的药物组合及其在治疗中的用途 |
Families Citing this family (18)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2004018512A (ja) * | 2002-06-20 | 2004-01-22 | Morinaga & Co Ltd | 冷え性改善用組成物および冷え性改善用組成物の製造のためのカカオ豆加工物の使用 |
US20080003280A1 (en) * | 2006-06-26 | 2008-01-03 | Levine Brian M | Combination cough treatment compounds and method of treating common coughs |
US7914828B2 (en) * | 2008-10-17 | 2011-03-29 | Levine Brian M | Combination herbal product to benefit respiratory tract |
GB0921803D0 (en) | 2009-12-14 | 2010-01-27 | Biocopea Ltd | Drug composition and its use in therapy |
GB0910375D0 (en) | 2009-06-16 | 2009-07-29 | Biocopea Ltd | Drug composition and its use in therapy |
US20150216869A1 (en) * | 2009-06-16 | 2015-08-06 | Biocopea Limited | Drug Combinations and Uses in Treating a Coughing Condition |
US9314465B2 (en) | 2009-06-16 | 2016-04-19 | Infirst Healthcare Limited | Drug combinations and uses in treating a coughing condition |
US20150005325A1 (en) * | 2009-06-16 | 2015-01-01 | Biocopea Limited | Drug Combinations and Uses in Treating a Coughing Condition |
US9308211B2 (en) | 2009-06-16 | 2016-04-12 | Infirst Healthcare Limited | Drug combinations and uses in treating a coughing condition |
GB201014391D0 (en) * | 2010-08-27 | 2010-10-13 | Biocopea Ltd | Drug composition and its use in therapy |
GB0919889D0 (en) * | 2009-11-13 | 2009-12-30 | Biocopea Ltd | Drug composition and its use in therapy |
US10016437B2 (en) | 2009-06-16 | 2018-07-10 | Infirst Healthcare Limited | Drug combinations and uses in treating a coughing condition |
GB0921805D0 (en) | 2009-12-14 | 2010-01-27 | Biocopea Ltd | Drug composition and its use in therapy |
AU2015201845B2 (en) * | 2009-11-13 | 2015-11-05 | Infirst Healthcare Limited | Drug combination with theobromine and its use in therapy |
US8361519B2 (en) | 2010-11-18 | 2013-01-29 | Aadvantics Pharmaceuticals, Inc. | Combination herbal product to benefit respiratory tract in people exposed to smoke |
NL1040474C2 (en) | 2013-10-31 | 2015-05-04 | Veramed B V | Nasal compositions stimulating ciliary activity. |
ES2552706B1 (es) * | 2014-05-29 | 2016-09-13 | Universitat De Les Illes Balears | La teobromina y sus derivados para el tratamiento o prevenciónde la litiasis renal |
KR20160126217A (ko) | 2015-04-23 | 2016-11-02 | 주식회사 진명 에프 엠 씨 | 용기 투입장치 |
Family Cites Families (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IT1113122B (it) * | 1978-04-06 | 1986-01-20 | Abc Ist Biolog Chem Spa | Composizione farmaceutica ad attivita' antibrocospastica e antitosse |
FR2531339A1 (fr) * | 1982-08-04 | 1984-02-10 | Dietlin Francois | Nouveau procede d'obtention de formes pharmaceutiques a liberation programmee |
HU197574B (en) | 1986-10-09 | 1989-04-28 | Chinoin Gyogyszer Es Vegyeszet | Process for production of derivatives of 3,7-dihydro-3-methil-7-//1,2,4-oxadiasole/-3-il/alkylenil/-1h-purin-2,6-dion and medical compositions containing these substances |
GB2201591B (en) * | 1987-03-02 | 1990-11-14 | Ricerfarma Srl | Analgesic antipyretic and anti-inflammatory compositions. |
US5009819A (en) * | 1987-11-12 | 1991-04-23 | The Liposome Company, Inc. | Taste moderating composition |
DK339289D0 (da) | 1989-07-07 | 1989-07-07 | Dak Lab As | Farmaceutisk praeparat |
CA2170488A1 (en) | 1993-09-07 | 1995-03-16 | Sekhar Mitra | Compositions containing an amino acid salt of propionic acid non-steroidal anti-inflammatory agent and at least one of a decongestant, an expectorant, an antihistamine and an antitussive |
US5560913A (en) * | 1995-01-27 | 1996-10-01 | The Procter & Gamble Company | Pharmaceutical compositions |
US5641512A (en) | 1995-03-29 | 1997-06-24 | The Procter & Gamble Company | Soft gelatin capsule compositions |
EP0841947A1 (en) * | 1995-07-28 | 1998-05-20 | The Procter & Gamble Company | Compositions containing analgesics and antihistamines and methods for treating respiratory disorders |
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1997
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- 1998-03-20 CN CN98803693A patent/CN1251039A/zh active Pending
- 1998-03-20 EP EP98912636A patent/EP0969843B1/en not_active Expired - Lifetime
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- 1998-03-20 IL IL13181198A patent/IL131811A0/xx active IP Right Grant
- 1998-03-20 PT PT98912636T patent/PT969843E/pt unknown
- 1998-03-20 DE DE69805983T patent/DE69805983T2/de not_active Expired - Lifetime
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- 1998-03-20 WO PCT/HU1998/000027 patent/WO1998042322A2/en active IP Right Grant
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- 1998-03-20 EA EA199900876A patent/EA001971B1/ru not_active IP Right Cessation
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Cited By (4)
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---|---|---|---|---|
CN100571540C (zh) * | 2001-10-18 | 2009-12-23 | Lotte制果株式会社 | 具有抗癌活性的可可碱 |
CN101112383B (zh) * | 2006-07-25 | 2010-05-26 | 安国药品株式会社 | 用于治疗咳嗽的组合物 |
CN102740853A (zh) * | 2009-11-13 | 2012-10-17 | 比蔻匹亚有限公司 | 可可碱的药物组合及其在治疗中的用途 |
CN102740853B (zh) * | 2009-11-13 | 2015-04-08 | 第一医疗保健有限公司 | 可可碱的药物组合及其在治疗中的用途 |
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