WO2012045285A1 - Pharmaceutical composition and application thereof - Google Patents

Pharmaceutical composition and application thereof Download PDF

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Publication number
WO2012045285A1
WO2012045285A1 PCT/CN2011/080569 CN2011080569W WO2012045285A1 WO 2012045285 A1 WO2012045285 A1 WO 2012045285A1 CN 2011080569 W CN2011080569 W CN 2011080569W WO 2012045285 A1 WO2012045285 A1 WO 2012045285A1
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Prior art keywords
pharmaceutical composition
mass ratio
anisodamine
scopolamine
neostigmine
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PCT/CN2011/080569
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French (fr)
Chinese (zh)
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苏定冯
刘冲
孙利
沈甫明
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中国人民解放军第二军医大学
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Publication of WO2012045285A1 publication Critical patent/WO2012045285A1/en

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    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4425—Pyridinium derivatives, e.g. pralidoxime, pyridostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the invention belongs to the field of pharmaceutical compositions, and in particular relates to a pharmaceutical composition and application thereof. Background technique
  • Septic shock can be seen in sepsis caused by various microorganisms (also known as septic shock), especially infection with Gram-negative bacteria, and shock caused by endotoxin (endotoxic shock).
  • Endotoxin is a complex of a lipopolysaccharide (Lipoply Saccharide) and a microprotein (Protein) on the cell wall of Gram-negative bacteria.
  • Endotoxin shock refers to a large amount of endotoxin acting on the body's immune system and coagulation system, which exceeds the body's ability to clear the system and produce a large number of biologically active substances such as tumor necrosis factor alpha, interleukin 1, histamine and kinin. Etc., leading to disorder of the body's microcirculation and coagulopathy, a series of clinical symptoms.
  • endotoxic shock there are numerous drugs for treating septic shock (endotoxic shock).
  • Muscarinic receptor blockers are used clinically for the treatment of circulatory shock, especially septic shock, such as the treatment of explosive epidemic cerebrospinal meningitis and toxic bacterial dysentery with anisodamine (Wang ST, Chin. Med. J. 1978, 6: 497-500), the conventional dose for the treatment of endotoxin shock is: early infection 1 mg / kg, mid-term l-2 mg / Kg, late 2-3 mg/kg, intravenous drip, every 10-15 minutes interval; its side effects are mainly dry mouth, flushing, mild dilatation, blurred near-neighbor, etc., individual patients There is an increase in heart rate and difficulty in urinating.
  • Cholinesterase inhibitors are commonly used to treat intestinal perforation-induced acute peritonitis models, but cause acetylcholine accumulation leading to side effects in the cardiovascular system and digestive system (Hofer S., Eisenbach C., Lukic I. K” Schneider L” Bode K " Brueckmann M” Mautner S” Wente M. N” Encke J., Werner J., Dalpke AH, Stremmel W” Nawroth PP, Martin E., Krammer PH, Bierhaus A., Weigand MA, Pharmacologic cholinesterase Inhibition improves survival in experimental sepsis. Crit. Care. Med. 2008, 36(2):404-408
  • the technical problem to be solved by the present invention is to overcome the existing muscarinic receptor blocker in treating endotoxin shock, the drug is used in a large amount and has many side effects, or the cholinesterase inhibitor causes acetylcholine accumulation to cause cardiovascular disease. Defects such as adverse reactions of the system and the digestive system, etc., provide a pharmaceutical composition having more significant anti-infective shock, especially endotoxin shock, and anti-squeeze or anti-burn scald, small toxic and side effects and application thereof .
  • the pharmaceutical composition of the present invention comprises a muscarinic receptor blocker and a cholinesterase inhibitor.
  • the invention has been found to have a significant effect on the treatment of endotoxin shock, crush injury or burn burn in combination with a muscarinic receptor blocker and a choline lipase inhibitor, and the dosage of the drug used is small, and the therapeutic effect is greatly Strengthens, and overcomes the side effects of muscarinic receptor blockers such as dry mouth, flushing, mild dilatation, blurred near-neighbour, and the use of cholinesterase inhibitors to induce M receptor excitability on cardiovascular Adverse reactions to the system and the digestive system.
  • the mass ratio of the muscarinic receptor blocker to the cholinesterase inhibitor is preferably 10-1.6 X 10 4 , more preferably 2.5 X 10 2 -4.0 X 10
  • the muscarinic receptor blocker is a muscarinic receptor blocker conventionally used in the art, preferably selected from the group consisting of anisodamine, an anisodamine-containing plant extract, atropine, scopolamine, and scopolamine One or more of the plant extracts.
  • the anisodamine has the structural formula shown in Formula 1, which is an ester formed from tropic acid and an organic base, and has a structure similar to that of atropine and scopolamine, and has an asymmetric relationship at the 6-position carbon atom of the tropyl group. Hydroxyl.
  • the anisodamine and scopolamine can also be extracted from plants.
  • the anisodamine can be extracted from the plant hawthorn, and the extraction method can be referred to the literature "Simultaneous analysis of hyoscyamine, scopolamine, 6-hydroxyhyoscyamine and apoatropine in Solanaceous hairy roots by reversed-phase high-performance liquid chromatography” (Journal of Chromatography A, 2005, 1091 (1 - 2): 32-39).
  • Scopolamine can be extracted from Solanaceae, and the extraction method can be found in "Analysis of tropane and related alkaloids" (Journal of Chromatography A, 2002, 978(l-2): l-35).
  • the muscarinic receptor blocker is anisodamine
  • the alkaline lipase inhibitor is neostigmine.
  • the mass ratio of the anisodamine to neostigmine is preferably in the present invention, and the pharmaceutical composition is preferably one of the following:
  • an anti-infectious shock drug one of the following is preferred in the preparation of an anti-infectious shock drug:
  • Neostigmine the mass ratio of anisodamine or scopolamine is 1:250-1:1000;
  • Neostigmine The mass ratio of atropine is 1:30-1:50, preferably 1:40;
  • the physostigmine the mass ratio of anisodamine or scopolamine is 1:800-1:1200, preferably 1:1000;
  • the physostigmine: atropine has a mass ratio of 1:30 to 1:50, preferably 1:40.
  • Neostigmine the mass ratio of anisodamine or scopolamine is 1:500-1:4000, preferably 1:500-1:1000;
  • Xinsi Mingming The mass ratio of atropine is 1:2000-1:4000;
  • the mass ratio of atropine is 1:450-1:550, preferably 1:500;
  • Neostigmine the mass ratio of anisodamine or scopolamine is 1:2000-1:4000;
  • Xinsi Mingming The mass ratio of atropine is 1:250-1:500;
  • the pharmaceutical composition of the present invention may be prepared by mixing the above-mentioned commercially available compounds or extracts containing the above-mentioned compounds extracted from plants by a conventional method in the art.
  • the pharmaceutical composition of the present invention may further comprise other active pharmaceutical ingredients for treating shock, treating crush injury or treating burns and burns, such as dopamine or phentolamine, as long as it does not significantly affect the present.
  • active pharmaceutical ingredients for treating shock, treating crush injury or treating burns and burns such as dopamine or phentolamine, as long as it does not significantly affect the present.
  • dopamine or phentolamine such as dopamine or phentolamine
  • the pharmaceutical composition of the present invention may further comprise a pharmaceutically acceptable carrier, as needed.
  • the pharmaceutically acceptable carrier refers to a conventional pharmaceutical carrier in the pharmaceutical field, wherein a diluent such as starch, powdered sugar, dextrin, microcrystalline cellulose, mannitol, lactose, soybean oil, etc.; a vinylpyrrolidone or hydroxypropylcellulose; a disintegrating agent such as sodium carboxymethylcellulose or a low-substituted hydroxypropylcellulose; a lubricant such as magnesium stearate or talc; a stabilizer such as carboxymethylcellulose Sodium or cyclodextrin; preservatives such as ethyl p-hydroxybenzoate or sodium benzoate.
  • a diluent such as starch, powdered sugar, dextrin, microcrystalline cellulose, mannitol, lactose, soybean oil, etc.
  • the active ingredient of the pharmaceutical composition is a therapeutically effective amount of a pharmaceutical composition of a muscarinic receptor blocker and a cholinesterase inhibitor of the invention.
  • the pharmaceutical composition can be prepared into various dosage forms by using a conventional method in the medical field and the pharmaceutically acceptable carrier. When used orally, it can be prepared into conventional solid preparations such as tablets, capsules, soft capsules, liquid preparations, granules, ointments, pills, pills, suspensions, dispersing agents, syrups or suppositories, etc. For injection, it can be prepared as an injection.
  • Each of the pharmaceutical compositions of the present invention can be administered to a patient in need of such treatment by intravenous injection, subcutaneous injection or oral administration in a dosage form.
  • the general dose administered to a patient in need of treatment is 1-100 mg/kg for muscarinic receptor blockers and 6.25-100 ug/kg for cholinesterase inhibitors ; preferred doses of muscarinic receptor blockade
  • the agent is 12.5-50 mg/kg
  • the cholinesterase inhibitor is 12.5-50 ug/kg
  • the optimal dose is anisodamine 12.5 mg/kg, neostigmine 50 ug/kg. In the specific use process, it may also be changed according to the age, condition and the like of the patient.
  • the present invention also relates to the use of a pharmaceutical composition as described above for the preparation of an anti-infective shock drug, an anti-squeeze drug or an anti-scald drug.
  • the anti-infective shock drug is preferably an anti-endotoxic shock drug.
  • the reagents and starting materials used in the present invention are commercially available.
  • a positive progressive effect of the present invention resides in:
  • the present invention provides a pharmaceutical composition and uses thereof.
  • the pharmaceutical composition is used for treating anti-infective shock, especially anti-endotoxic shock, and anti-squeezing or anti-burning scald, anti-shock, anti-squeeze or anti-burn scald effect, the effect is remarkable, and the poison
  • the side effects are small, overcoming the side effects often caused by existing drugs. detailed description
  • Table 1 shows the formulations of the pharmaceutical compositions of Examples 1 to 7 of the present invention, which were simply mixed uniformly according to the components listed in Table 1 and their ratios, to prepare each of the pharmaceutical compositions.
  • anisodamine plant extract can be referred to the literature "Simultaneous analysis of hyoscyamine, scopolamine, 6P-hydroxyhyoscyamine and apoatropine in Solanaceous hairy roots by reversed-phase high-performance liquid chromatography” (Journal of Chromatography A, 2005, 1091(1-2): 32-39);
  • the extraction method of the scopolamine plant extract can be referred to the literature "Analysis of tropane and related alkaloids” (Journal of Chromatography A, 2002, 978(l-2): l- 35 ) o
  • the pharmaceutical composition of the present invention was examined using a time window for treating endotoxin shock, and was administered at 0 hours, 3 hours, and 6 hours in shock, and the results are shown in the following table.
  • the present invention investigates the time window of pharmaceutical compositions for the treatment of endotoxin shock, as shown in the above table, and the results indicate that the pharmaceutical compositions of the present invention have anti-shock effects at 3 hours and 6 hours after the onset of shock.

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Abstract

Disclosed is a pharmaceutical composition containing a muscarinic receptor blocker and a cholinesterase inhibitor. The present pharmaceutical composition is used against septic shock, especially against endotoxin shock, and against crush wounds, burns, and scalding injuries. Also disclosed is the application of the pharmaceutical composition in preparing a pharmaceutical.

Description

一种药物组合物及其应用 技术领域  Pharmaceutical composition and application thereof
本发明属于药物组合物领域， 特别涉及一种药物组合物及其应用。 背景技术  The invention belongs to the field of pharmaceutical compositions, and in particular relates to a pharmaceutical composition and application thereof. Background technique
感染性休克可见于各种微生物引起的败血症 （故又称败血症休克）， 特 别是革兰氏阴性细菌的感染， 由内毒素引起的休克 （内毒素性休克）。 内毒 素是革兰氏阴性菌细胞壁上的一种脂多糖 （Lipoply Saccharide ) 和微量蛋白 (Protein) 的复合物。 内毒素休克， 是指大量内毒素作用于机体的免疫系统 和凝血系统， 超过机体各自卫系统的清除能力， 产生大量生物活性物质， 如 肿瘤坏死因子 α、 白细胞介素 1、 组胺和激肽等， 导致机体微循环紊乱和凝 血功能障碍， 出现一系列临床症状。 现有技术中， 治疗感染性休克 （内毒素 休克） 的药物众多。  Septic shock can be seen in sepsis caused by various microorganisms (also known as septic shock), especially infection with Gram-negative bacteria, and shock caused by endotoxin (endotoxic shock). Endotoxin is a complex of a lipopolysaccharide (Lipoply Saccharide) and a microprotein (Protein) on the cell wall of Gram-negative bacteria. Endotoxin shock refers to a large amount of endotoxin acting on the body's immune system and coagulation system, which exceeds the body's ability to clear the system and produce a large number of biologically active substances such as tumor necrosis factor alpha, interleukin 1, histamine and kinin. Etc., leading to disorder of the body's microcirculation and coagulopathy, a series of clinical symptoms. In the prior art, there are numerous drugs for treating septic shock (endotoxic shock).
毒蕈碱受体阻断剂在临床上被用于治疗循环性休克， 特别是感染性休 克， 如用山莨菪碱治疗爆发型流行性脑脊髓膜炎和中毒性细菌性痢疾等 (Wang S.T., Kuo N. L., Experience in emergency treatment of shock due to infection. Chin. Med. J. 1978 , 6:497-500)， 其治疗内毒素休克的常规剂量为： 感染早期 lmg/kg， 中期 l-2 mg/kg， 晚期 2-3 mg/kg， 静脉点滴小壶入， 每间 隔 10-15分钟给药一次； 其副作用主要表现为口干、 面红、 轻度扩瞳、 视近 物模糊等， 个别患者有心率加快及排尿困难。  Muscarinic receptor blockers are used clinically for the treatment of circulatory shock, especially septic shock, such as the treatment of explosive epidemic cerebrospinal meningitis and toxic bacterial dysentery with anisodamine (Wang ST, Chin. Med. J. 1978, 6: 497-500), the conventional dose for the treatment of endotoxin shock is: early infection 1 mg / kg, mid-term l-2 mg / Kg, late 2-3 mg/kg, intravenous drip, every 10-15 minutes interval; its side effects are mainly dry mouth, flushing, mild dilatation, blurred near-neighbor, etc., individual patients There is an increase in heart rate and difficulty in urinating.
胆碱脂酶抑制剂常用来治疗肠穿孔诱导的急性腹膜炎模型，但会引起乙 酰胆碱蓄积导致心血管系统和消化系统的副作用 （Hofer S.， Eisenbach C.， Lukic I. K" Schneider L" Bode K" Brueckmann M" Mautner S" Wente M. N" Encke J., Werner J., Dalpke A. H., Stremmel W" Nawroth P. P., Martin E., Krammer P. H., Bierhaus A., Weigand M. A., Pharmacologic cholinesterase inhibition improves survival in experimental sepsis. Crit. Care. Med. 2008, 36(2):404-408 Cholinesterase inhibitors are commonly used to treat intestinal perforation-induced acute peritonitis models, but cause acetylcholine accumulation leading to side effects in the cardiovascular system and digestive system (Hofer S., Eisenbach C., Lukic I. K" Schneider L" Bode K " Brueckmann M" Mautner S" Wente M. N" Encke J., Werner J., Dalpke AH, Stremmel W" Nawroth PP, Martin E., Krammer PH, Bierhaus A., Weigand MA, Pharmacologic cholinesterase Inhibition improves survival in experimental sepsis. Crit. Care. Med. 2008, 36(2):404-408
但是， 毒蕈碱受体阻断剂和胆碱脂酶抑制剂联合使用的药物组合物尚未 见报道。 发明内容  However, pharmaceutical compositions in combination with muscarinic receptor blockers and cholinesterase inhibitors have not been reported. Summary of the invention
本发明所要解决的技术问题是克服了现有的毒蕈碱受体阻断剂治疗内 毒素休克时， 药物的用药剂量大且副作用多， 或者胆碱脂酶抑制剂会引起乙 酰胆碱蓄积导致心血管系统和消化系统的不良反应等的缺陷，提供了一种具 有较显著的抗感染性休克、特别是内毒素休克，以及抗挤压伤或抗烧伤烫伤， 毒副作用小的药物组合物及其应用。  The technical problem to be solved by the present invention is to overcome the existing muscarinic receptor blocker in treating endotoxin shock, the drug is used in a large amount and has many side effects, or the cholinesterase inhibitor causes acetylcholine accumulation to cause cardiovascular disease. Defects such as adverse reactions of the system and the digestive system, etc., provide a pharmaceutical composition having more significant anti-infective shock, especially endotoxin shock, and anti-squeeze or anti-burn scald, small toxic and side effects and application thereof .
本发明的药物组合物， 其含有毒蕈碱受体阻断剂和胆碱脂酶抑制剂。 本发明经过研究发现毒蕈碱受体阻断剂和胆碱脂酶抑制剂的联合使用 治疗内毒素休克、 挤压伤或烧伤烫伤时， 作用效果显著， 并且使用的药物剂 量小， 治疗作用大大加强， 且克服了毒蕈碱受体阻断剂的口干、 面红、 轻度 扩瞳、 视近物模糊等副作用， 以及使用胆碱脂酶抑制剂会引起的 M受体兴 奋对心血管系统和消化系统的不良反应。  The pharmaceutical composition of the present invention comprises a muscarinic receptor blocker and a cholinesterase inhibitor. The invention has been found to have a significant effect on the treatment of endotoxin shock, crush injury or burn burn in combination with a muscarinic receptor blocker and a choline lipase inhibitor, and the dosage of the drug used is small, and the therapeutic effect is greatly Strengthens, and overcomes the side effects of muscarinic receptor blockers such as dry mouth, flushing, mild dilatation, blurred near-neighbour, and the use of cholinesterase inhibitors to induce M receptor excitability on cardiovascular Adverse reactions to the system and the digestive system.
其中，所述的毒蕈碱受体阻断剂与胆碱脂酶抑制剂的质量比值较佳的为 10-1.6 X 104, 更佳的为 2.5 X 102-4.0 X 10 Wherein, the mass ratio of the muscarinic receptor blocker to the cholinesterase inhibitor is preferably 10-1.6 X 10 4 , more preferably 2.5 X 10 2 -4.0 X 10
其中， 所述的毒蕈碱受体阻断剂为本领域常规使用毒蕈碱受体阻断剂， 较佳的选自山莨菪碱、 含山莨菪碱的植物提取物、 阿托品、 东莨菪碱、 含东 莨菪碱的植物提取物中的一种或多种。  Wherein, the muscarinic receptor blocker is a muscarinic receptor blocker conventionally used in the art, preferably selected from the group consisting of anisodamine, an anisodamine-containing plant extract, atropine, scopolamine, and scopolamine One or more of the plant extracts.
所述的山莨菪碱的结构式如式 1所示， 它是由托品酸和有机碱形成的酯 类， 结构与阿托品和东莨菪碱相类似， 在托品基的 6位碳原子上有不对称的 羟基。 The anisodamine has the structural formula shown in Formula 1, which is an ester formed from tropic acid and an organic base, and has a structure similar to that of atropine and scopolamine, and has an asymmetric relationship at the 6-position carbon atom of the tropyl group. Hydroxyl.
Figure imgf000004_0001
Figure imgf000004_0001
Figure imgf000005_0001
所述的毒扁豆碱的结构式如式 5所示。
Figure imgf000005_0001
The structural formula of the physostigmine is as shown in Formula 5.
Figure imgf000005_0002
Figure imgf000005_0002
所述的溴吡斯的明的结 6所;  Said knot of bromide;
Figure imgf000005_0003
Figure imgf000005_0003
式 6 本发明中， 所述的山莨菪碱和东莨菪碱还可以从植物中提取。所述的山 莨菪碱可从植物山莨菪中提取， 提取方法可参考文献《 Simultaneous analysis of hyoscyamine, scopolamine, 6 -hydroxyhyoscyamine and apoatropine in Solanaceous hairy roots by reversed-phase high-performance liquid chromatography》 ( Journal of Chromatography A, 2005， 1091(1 -2):32-39 )。 东 莨菪碱可从茄科植物中提取， 提取方法可参考文献 《Analysis of tropane and related alkaloids》 （Journal of Chromatography A, 2002, 978(l-2): l-35 )。  In the present invention, the anisodamine and scopolamine can also be extracted from plants. The anisodamine can be extracted from the plant hawthorn, and the extraction method can be referred to the literature "Simultaneous analysis of hyoscyamine, scopolamine, 6-hydroxyhyoscyamine and apoatropine in Solanaceous hairy roots by reversed-phase high-performance liquid chromatography" (Journal of Chromatography A, 2005, 1091 (1 - 2): 32-39). Scopolamine can be extracted from Solanaceae, and the extraction method can be found in "Analysis of tropane and related alkaloids" (Journal of Chromatography A, 2002, 978(l-2): l-35).
本发明中一较佳实例， 所述的毒蕈碱受体阻断剂为山莨菪碱， 所述的胆 碱脂酶抑制剂为新斯的明。所述的山莨菪碱与新斯的明的质量比值较佳的为 本发明中， 所述的药物组合物较佳的为下述之一： In a preferred embodiment of the present invention, the muscarinic receptor blocker is anisodamine, the biliary The alkaline lipase inhibitor is neostigmine. The mass ratio of the anisodamine to neostigmine is preferably in the present invention, and the pharmaceutical composition is preferably one of the following:
其中， 在制备抗感染性休克药物优选下述之一：  Among them, one of the following is preferred in the preparation of an anti-infectious shock drug:
新斯的明： 山莨菪碱或东莨菪碱的质量比为 1:250-1:1000;  Neostigmine: the mass ratio of anisodamine or scopolamine is 1:250-1:1000;
新斯的明： 阿托品的质量比为 1:30-1:50， 较佳的为 1:40;  Neostigmine: The mass ratio of atropine is 1:30-1:50, preferably 1:40;
毒扁豆碱： 山莨菪碱或东莨菪碱的质量比为 1:800-1:1200， 较佳的为 1:1000；  The physostigmine: the mass ratio of anisodamine or scopolamine is 1:800-1:1200, preferably 1:1000;
毒扁豆碱： 阿托品的质量比为 1:30-1:50， 较佳的为 1:40。  The physostigmine: atropine has a mass ratio of 1:30 to 1:50, preferably 1:40.
其中， 在制备抗挤压伤药物优选下述之一：  Among them, one of the following is preferred in the preparation of an anti-squeeze drug:
新斯的明： 山莨菪碱或东莨菪碱的质量比为 1:500-1:4000， 较佳的为 1:500-1:1000；  Neostigmine: the mass ratio of anisodamine or scopolamine is 1:500-1:4000, preferably 1:500-1:1000;
新斯的明： 阿托品的质量比为 1:2000-1:4000;  Xinsi Mingming: The mass ratio of atropine is 1:2000-1:4000;
溴吡斯的明： 山莨菪碱或东莨菪碱的质量比为 1:250-1:500;  Bromide: the mass ratio of anisodamine or scopolamine is 1:250-1:500;
溴吡斯的明： 阿托品的质量比为 1:450-1:550， 较佳的为 1:500;  Bromide: The mass ratio of atropine is 1:450-1:550, preferably 1:500;
其中， 在制备抗烧伤烫伤药物优选下述之一：  Among them, one of the following is preferred in the preparation of an anti-burn scald drug:
新斯的明： 山莨菪碱或东莨菪碱的质量比为 1:2000-1:4000;  Neostigmine: the mass ratio of anisodamine or scopolamine is 1:2000-1:4000;
新斯的明： 阿托品的质量比为 1:250-1:500;  Xinsi Mingming: The mass ratio of atropine is 1:250-1:500;
溴吡斯的明： 山莨菪碱或东莨菪碱的质量比为 1:250-1:500;  Bromide: the mass ratio of anisodamine or scopolamine is 1:250-1:500;
溴吡斯的明： 阿托品的质量比为 1:500-1:2000。  Bromide: The mass ratio of atropine is 1:500-1:2000.
本发明中述及的各原料或试剂均市售可得。  Each of the starting materials or reagents described in the present invention is commercially available.
本发明药物组合物的制备方法可以是将现有的市售可得的上述化合物， 或从植物中提取的含上述化合物的提取物， 按配比， 采用本领域的常规方法 混合， 即可。  The pharmaceutical composition of the present invention may be prepared by mixing the above-mentioned commercially available compounds or extracts containing the above-mentioned compounds extracted from plants by a conventional method in the art.
本发明的药物组合物还可包含现有其他的治疗休克、治疗挤压伤或治疗 烧伤烫伤的药物活性成分， 如多巴胺或者酚妥拉明等， 只要其不显著影响本 发明药物组合物效果即可。 The pharmaceutical composition of the present invention may further comprise other active pharmaceutical ingredients for treating shock, treating crush injury or treating burns and burns, such as dopamine or phentolamine, as long as it does not significantly affect the present. The effect of the pharmaceutical composition of the invention is sufficient.
根据需要， 本发明的药物组合物还可包括药学上可接受的载体。 所述的 药学上可接受的载体是指药学领域常规的药物载体， 其中， 稀释剂如淀粉、 糖粉、 糊精、 微晶纤维素、 甘露醇、 乳糖和大豆油等； 粘合剂如聚乙烯吡咯 垸酮或羟丙基纤维素等； 崩解剂如羧甲基纤维素钠或低取代羟丙纤维素等； 润滑剂如硬脂酸镁或滑石粉等； 稳定剂如羧甲基纤维素钠或环糊精等； 防腐 剂如对羟基苯甲酸乙酯或苯甲酸钠等。 另外， 还可以在该药物组合物中加入 其他辅助剂如香味剂和 /或甜味剂如蔗糖、果糖和天冬甜素等。该药物组合物 的活性成分是治疗有效量的本发明的毒蕈碱受体阻断剂和胆碱脂酶抑制剂 的药物组合物。 该药物组合物可采用医学领域常规的方法， 将所述的活性成 分与药学上可接受的载体制成各种剂型。 当用于口服时， 可将其制备成常规 的固体制剂如片剂、 胶囊、 软胶囊、 液体制剂、 颗粒剂、 煎膏剂、 丸剂、 滴 丸剂、 悬浮剂、 分散剂、 糖桨剂或栓剂等； 用于注射时， 可将其制备成注射 液。 本发明的各药物组合物可以按剂型通过静脉注射、 皮下注射或口服的形 式施加于需要这种治疗的患者。施加给需要治疗的患者的一般的剂量为毒蕈 碱受体阻断剂为 l-100mg/kg，胆碱脂酶抑制剂为 6.25-100ug/kg;较佳的剂量 毒蕈碱受体阻断剂为 12.5-50 mg/kg, 胆碱脂酶抑制剂为 12.5-50ug/kg; 最佳 的剂量为山莨菪碱 12.5mg/kg， 新斯的明 50ug/kg。 在具体使用过程中， 还可 根据患者的年龄、 病情等酌情变化。 The pharmaceutical composition of the present invention may further comprise a pharmaceutically acceptable carrier, as needed. The pharmaceutically acceptable carrier refers to a conventional pharmaceutical carrier in the pharmaceutical field, wherein a diluent such as starch, powdered sugar, dextrin, microcrystalline cellulose, mannitol, lactose, soybean oil, etc.; a vinylpyrrolidone or hydroxypropylcellulose; a disintegrating agent such as sodium carboxymethylcellulose or a low-substituted hydroxypropylcellulose; a lubricant such as magnesium stearate or talc; a stabilizer such as carboxymethylcellulose Sodium or cyclodextrin; preservatives such as ethyl p-hydroxybenzoate or sodium benzoate. In addition, other adjuvants such as flavoring agents and/or sweeteners such as sucrose, fructose and aspartame may also be added to the pharmaceutical composition. The active ingredient of the pharmaceutical composition is a therapeutically effective amount of a pharmaceutical composition of a muscarinic receptor blocker and a cholinesterase inhibitor of the invention. The pharmaceutical composition can be prepared into various dosage forms by using a conventional method in the medical field and the pharmaceutically acceptable carrier. When used orally, it can be prepared into conventional solid preparations such as tablets, capsules, soft capsules, liquid preparations, granules, ointments, pills, pills, suspensions, dispersing agents, syrups or suppositories, etc. For injection, it can be prepared as an injection. Each of the pharmaceutical compositions of the present invention can be administered to a patient in need of such treatment by intravenous injection, subcutaneous injection or oral administration in a dosage form. The general dose administered to a patient in need of treatment is 1-100 mg/kg for muscarinic receptor blockers and 6.25-100 ug/kg for cholinesterase inhibitors ; preferred doses of muscarinic receptor blockade The agent is 12.5-50 mg/kg, and the cholinesterase inhibitor is 12.5-50 ug/kg ; the optimal dose is anisodamine 12.5 mg/kg, neostigmine 50 ug/kg. In the specific use process, it may also be changed according to the age, condition and the like of the patient.
本发明还涉及如前所述的药物组合物在制备抗感染性休克药物、抗挤压 伤药物或抗烫伤药物中的应用。  The present invention also relates to the use of a pharmaceutical composition as described above for the preparation of an anti-infective shock drug, an anti-squeeze drug or an anti-scald drug.
其中， 所述的抗感染性休克药物较佳的为抗内毒素性休克药物。  Wherein, the anti-infective shock drug is preferably an anti-endotoxic shock drug.
本发明所用试剂和原料均市售可得。  The reagents and starting materials used in the present invention are commercially available.
本发明的积极进步效果在于： 本发明提供了一种药物组合物及其应用。 该药物组合物用于治疗抗感染性休克、 特别是抗内毒素休克， 以及抗挤压伤 或抗烧伤烫伤， 抗休克、 抗挤压伤或抗烧伤烫伤作用增强， 效果显著， 且毒 副作用小， 克服了现有的药物常造成的副作用。 具体实施方式 A positive progressive effect of the present invention resides in: The present invention provides a pharmaceutical composition and uses thereof. The pharmaceutical composition is used for treating anti-infective shock, especially anti-endotoxic shock, and anti-squeezing or anti-burning scald, anti-shock, anti-squeeze or anti-burn scald effect, the effect is remarkable, and the poison The side effects are small, overcoming the side effects often caused by existing drugs. detailed description
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在 所述的实施例范围之中。  The invention is further illustrated by the following examples, which are not intended to limit the invention.
实施例 1-7  Example 1-7
表 1给出了本发明的药物组合物实施例 1~7的配方，按表 1中所列组分 及其配比， 简单混合均匀， 即制得各药物组合物。  Table 1 shows the formulations of the pharmaceutical compositions of Examples 1 to 7 of the present invention, which were simply mixed uniformly according to the components listed in Table 1 and their ratios, to prepare each of the pharmaceutical compositions.
表 1 本发明药物组合物的配方  Table 1 Formulation of the pharmaceutical composition of the present invention
Figure imgf000008_0001
Figure imgf000008_0001
注： 上述的山莨菪碱植物提取物提取方法可参考文献 《 Simultaneous analysis of hyoscyamine, scopolamine, 6P-hydroxyhyoscyamine and apoatropine in Solanaceous hairy roots by reversed-phase high-performance liquid chromatography 》 ( Journal of Chromatography A, 2005， 1091(1-2):32-39)； 所述的东莨菪碱植物提取物的提取方法可参 考文献 《 Analysis of tropane and related alkaloids》 (Journal of Chromatography A, 2002, 978(l-2): l-35 ) o Note: The above extraction method of anisodamine plant extract can be referred to the literature "Simultaneous analysis of hyoscyamine, scopolamine, 6P-hydroxyhyoscyamine and apoatropine in Solanaceous hairy roots by reversed-phase high-performance liquid chromatography" (Journal of Chromatography A, 2005, 1091(1-2): 32-39); The extraction method of the scopolamine plant extract can be referred to the literature "Analysis of tropane and related alkaloids" (Journal of Chromatography A, 2002, 978(l-2): l- 35 ) o
效果实施例 1 Effect embodiment 1
考察本发明的药物组合物使用治疗内毒素休克的治疗效果， 为便于计 算，均使用剂量计算。采用对小鼠腹腔注射内毒素 (25mg/kg:>来诱导内毒素休 克的模型 ( Borovikova L. V" Ivanova S., Zhang Μ·, et al: Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature, 2000, 405:458-462)，接着分别单独给予不同剂量的毒蕈碱受体阻断剂或者胆 碱脂酶抑制剂 （对比例）， 或者按照不同比例， 给予毒蕈碱受体阻断剂后接 着给予胆碱脂酶抑制剂联合治疗， 给药方式均为腹腔注射。 然后每隔 3小时 观察一次， 共观察 72小时， 记录动物的生存情况。 The therapeutic effect of the pharmaceutical composition of the present invention for treating endotoxin shock was examined, and for calculation, a dose calculation was used. A model for inducing endotoxin shock by intraperitoneal injection of endotoxin (25 mg/kg:>) in mice (Borovikova L. V" Ivanova S., Zhang Μ·, et al: Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature , 2000, 405: 458-462), followed by separate administration of different doses of muscarinic receptor blockers or cholinesterase inhibitors (comparative), or muscarinic receptor blockers in different ratios This is followed by administration of a combination of cholinesterase inhibitors, all of which are administered intraperitoneally. Then observe every 3 hours for a total of 72 hours to record the survival of the animals.
表 2本发明的药物组合物治疗内毒素休克的治疗效果  Table 2 Therapeutic effect of the pharmaceutical composition of the present invention for treating endotoxic shock
Figure imgf000009_0001
结论：效果实施例研究了本发明的药物组合物治疗内毒素休克，观察小 鼠 72小时生存率，结果上表所示。举例说明，比较效果例 6和对比例 3及 6， 发现 25mg/kg,ip的山莨菪碱与 25ug/kg,ip的新斯的明的联合使用， 小鼠的生 存率远远大于单独使用 25mg/kg,ip的山莨菪碱或者 25ug/kg,ip的新斯的明时 的生存率。 由此表明， 两药合用对内毒素休克小鼠 72小时存活率大大高于 两药分别单独应用， 两种药物的协同抗休克作用大大加强。 并且， 上述效果 实施例同对比例相比发现， 两类药物小剂量合用还明显降低这两类药单独应 用时的副作用等不良反应。
Figure imgf000009_0001
Conclusion: Effect Examples The pharmaceutical composition of the present invention was studied for the treatment of endotoxin shock, and the 72-hour survival rate of the mice was observed. The results are shown in the above table. For example, comparing effect example 6 and comparative examples 3 and 6, it was found that 25 mg/kg, ip anisodamine combined with 25 ug/kg, ip neostigmine, the survival rate of mice is much greater than 25 mg alone. /kg, ip anisodamine or 25ug/kg, ip's neostigler's survival rate. This indicates that the 72-hour survival rate of endotoxin-shock mice is significantly higher than that of the two drugs alone, and the synergistic anti-shock effect of the two drugs is greatly enhanced. Moreover, the above-mentioned effect examples showed that compared with the comparative examples, the small-dose combination of the two types of drugs also significantly reduced adverse reactions such as side effects when the two drugs were used alone.
效果实施例 2  Effect Example 2
考察本发明的药物组合物使用治疗内毒素休克的时间窗，在休克发生 0 小时， 3小时， 6小时分别用药， 结果如下表。  The pharmaceutical composition of the present invention was examined using a time window for treating endotoxin shock, and was administered at 0 hours, 3 hours, and 6 hours in shock, and the results are shown in the following table.
表 3本发明的药物组合物在不同时间给药治疗内毒素休克的治疗效果  Table 3 Therapeutic effects of the pharmaceutical composition of the present invention for treating endotoxin shock at different times
Figure imgf000010_0001
Figure imgf000010_0001
结论：本发明考察了药物组合物治疗内毒素休克的时间窗，如上表所示， 结果表明在休克发生以后 3小时， 6小时适用本发明的药物组合物均有抗休 克的作用。  Conclusion: The present invention investigates the time window of pharmaceutical compositions for the treatment of endotoxin shock, as shown in the above table, and the results indicate that the pharmaceutical compositions of the present invention have anti-shock effects at 3 hours and 6 hours after the onset of shock.
效果实施例 3  Effect Example 3
挤压伤模型的制备： 大鼠称重编号， 然后用氯胺酮 100mg/kg和地西泮 10mg/kg腹腔注射麻醉， 麻醉后下肢置于 20kg的铁块下挤压 6小时， 在撤 离重物前 30分钟各组分别给予药物治疗具体见下表用药量， 同时给予 5ml 生理盐水腹腔注射。 表 4本发明的药物组合物治疗挤压伤的治疗效果 Preparation of the crush injury model: Rats were weighed, then anesthetized with ketamine 100 mg/kg and diazepam 10 mg/kg intraperitoneally. After anesthesia, the lower extremities were placed under a 20 kg iron block for 6 hours, before evacuating the weight. For each of the 30 minutes, the drug treatment was given as shown in the following table, and 5 ml of normal saline was administered intraperitoneally. Table 4 The therapeutic effect of the pharmaceutical composition of the present invention in treating crush injury
Figure imgf000011_0001
Figure imgf000011_0001
效果实施例 4 Effect Example 4
烧伤模型的制备： 大鼠称重编号， 然后用氯胺酮 100mg/kg和地西泮 10mg/kg腹腔注射麻醉， 麻醉后背部向下放入自制的模具中在开水中烫 10 秒。 烫伤 6小时后腹腔注射内毒素 （LPS ) 2mg/kg造模， 造模成功后给药， 具体见下表用药量， 观察大鼠 48小时的生存情况。 Preparation of a burn model: Rat weighing number, then ketamine 100 mg/kg and diazepam 10 mg/kg was anesthetized by intraperitoneal injection. After anesthesia, the back was placed in a homemade mold and blanched in boiling water for 10 seconds. After 6 hours of scald, endotoxin (LPS) was injected intraperitoneally with 2 mg/kg. After successful modeling, the drug dosage was observed. The survival of the rats was observed for 48 hours.
表 5本发明的药物组合物治疗烧伤的治疗效果  Table 5 Therapeutic effect of the pharmaceutical composition of the present invention for treating burns
Figure imgf000012_0001
Figure imgf000012_0001

Claims

权利要求 Rights request
1、 一种药物组合物， 其含有毒蕈碱受体阻断剂和胆碱脂酶抑制剂。A pharmaceutical composition comprising a muscarinic receptor blocker and a cholinesterase inhibitor.
2、 如权利要求 1所述的药物组合物， 其特征在于： 所述的毒蕈碱受体 阻断剂选自山莨菪碱、 含山莨菪碱的植物提取物、 阿托品、 东莨菪碱、 以及 含东莨菪碱的植物提取物中的一种或多种。 2. The pharmaceutical composition according to claim 1, wherein: the muscarinic receptor blocker is selected from the group consisting of anisodamine, an anisodamine-containing plant extract, atropine, scopolamine, and scopolamine-containing One or more of the plant extracts.
3、 如权利要求 1所述的药物组合物， 其特征在于： 所述的胆碱脂酶抑 制剂为新斯的明、 溴吡斯的明和毒扁豆碱中的一种或多种。  The pharmaceutical composition according to claim 1, wherein the cholinesterase inhibitor is one or more selected from the group consisting of neostigmine, bromide and physostigmine.
4、 如权利要求 1所述的药物组合物， 其特征在于： 所述的毒蕈碱受体 阻断剂与胆碱脂酶抑制剂的质量比值为 10-1.6X 104。 4. The pharmaceutical composition according to claim 1, wherein the mass ratio of the muscarinic receptor blocker to the cholinesterase inhibitor is 10-1.6 X 10 4 .
5、 如权利要求 4所述的药物组合物， 其特征在于： 所述的毒蕈碱受体 阻断剂与胆碱脂酶抑制剂的质量比值为 2.5X 102-4.0X 103。 The pharmaceutical composition according to claim 4, wherein the mass ratio of the muscarinic receptor blocker to the cholinesterase inhibitor is 2.5X 10 2 -4.0X 10 3 .
6、 如权利要求 1所述的药物组合物， 其特征在于： 所述的毒蕈碱受体 阻断剂为山莨菪碱； 所述的胆碱脂酶抑制剂为新斯的明。  The pharmaceutical composition according to claim 1, wherein the muscarinic receptor blocker is anisodamine; and the cholinesterase inhibitor is neostigmine.
7、 如权利要求 6所述的药物组合物， 其特征在于： 所述的山莨菪碱与 新斯的明的质量比值为 250。  The pharmaceutical composition according to claim 6, wherein the mass ratio of the anisodamine to neostigmine is 250.
8、 如权利要求 1所述的药物组合物， 其特征在于： 所述的药物组合物 为下述之一：  The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is one of the following:
新斯的明： 山莨菪碱或东莨菪碱的质量比为 1:250-1:1000;  Neostigmine: the mass ratio of anisodamine or scopolamine is 1:250-1:1000;
新斯的明： 阿托品的质量比为 1:30-1:50， 较佳的为 1:40;  Neostigmine: The mass ratio of atropine is 1:30-1:50, preferably 1:40;
毒扁豆碱： 山莨菪碱或东莨菪碱的质量比为 1:800-1:1200， 较佳的为 1:1000；  The physostigmine: the mass ratio of anisodamine or scopolamine is 1:800-1:1200, preferably 1:1000;
毒扁豆碱： 阿托品的质量比为 1:30-1:50， 较佳的为 1:40;  The physostigmine: the mass ratio of atropine is 1:30-1:50, preferably 1:40;
新斯的明： 山莨菪碱或东莨菪碱的质量比为 1:500-1:4000， 较佳的为 1:500-1:1000；  Neostigmine: the mass ratio of anisodamine or scopolamine is 1:500-1:4000, preferably 1:500-1:1000;
新斯的明： 阿托品的质量比为 1:2000-1:4000; 溴吡斯的明： 山莨菪碱或东莨菪碱的质量比为 1:250-1:500; Xinsi Mingming: The mass ratio of atropine is 1:2000-1:4000; Bromide: the mass ratio of anisodamine or scopolamine is 1:250-1:500;
溴吡斯的明： 阿托品的质量比为 1:450-1:550， 较佳的为 1:500;  Bromide: The mass ratio of atropine is 1:450-1:550, preferably 1:500;
新斯的明： 山莨菪碱或东莨菪碱的质量比为 1:2000-1:4000;  Neostigmine: the mass ratio of anisodamine or scopolamine is 1:2000-1:4000;
新斯的明： 阿托品的质量比为 1:250-1:500;  Xinsi Mingming: The mass ratio of atropine is 1:250-1:500;
溴吡斯的明： 山莨菪碱或东莨菪碱的质量比为 1:250-1:500;  Bromide: the mass ratio of anisodamine or scopolamine is 1:250-1:500;
溴吡斯的明： 阿托品的质量比为 1:500-1:2000。  Bromide: The mass ratio of atropine is 1:500-1:2000.
9、 如权利要求 1所述的药物组合物， 其特征在于： 所述的药物组合 ί 还包括药学上可接受的载体。  9. The pharmaceutical composition according to claim 1, wherein: said pharmaceutical combination ί further comprises a pharmaceutically acceptable carrier.
10、如权利要求 1~9任一项所述的药物组合物在制备抗感染性休克药 抗挤压伤药物或抗烧伤烫伤药物中的应用。  The use of the pharmaceutical composition according to any one of claims 1 to 9 for the preparation of an anti-infective shock medicine for anti-crushing drugs or anti-burn and scald drugs.
11、 如权利要求 10所述的应用， 其特征在于所述的抗感染性休克药  11. The use according to claim 10, characterized in that said anti-infective shock medicine
PCT/CN2011/080569 2010-10-09 2011-10-09 Pharmaceutical composition and application thereof WO2012045285A1 (en)

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