WO2014180239A1 - Pharmaceutical composition for treating severe altitude sickness - Google Patents
Pharmaceutical composition for treating severe altitude sickness Download PDFInfo
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- WO2014180239A1 WO2014180239A1 PCT/CN2014/075793 CN2014075793W WO2014180239A1 WO 2014180239 A1 WO2014180239 A1 WO 2014180239A1 CN 2014075793 W CN2014075793 W CN 2014075793W WO 2014180239 A1 WO2014180239 A1 WO 2014180239A1
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- acid
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- acceptable salt
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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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
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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
- A61K31/495—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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/10—Antioedematous agents; Diuretics
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- 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
- A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
Definitions
- the present invention relates to the field of pharmaceutical compositions, and in particular to a pharmaceutical composition for the treatment of severe high altitude sickness.
- Severe altitude sickness is a serious acute high altitude disease such as pulmonary edema, brain edema, and shock caused by acute high altitude hypoxia.
- Traditional treatments for severe high altitude sickness are inhalation of hyperbaric oxygen and symptomatic treatment (reducing pulmonary artery pressure, intracranial pressure, etc.), if necessary, endotracheal intubation, continuous positive pressure ventilation and adequate oxygen supply, until the condition is stable, then go to lowland to continue treatment
- painkillers such as aspirin, diuretics such as acetazolamide, furosemide, adrenocortical drugs such as dexamethasone, various vitamins and aminophylline, etc., such as heart failure
- a cardiac glycoside drug such as the scutellaria sinensis or scutellaria.
- the above-mentioned drugs are mainly symptomatic treatments with stable conditions, and the effects are limited, and severe toxic and side effects are caused after a large amount of use, such
- One of the objects of the present invention is to provide a pharmaceutical composition for treating severe high altitude sickness.
- Another object of the present invention is to provide a use of the above composition for the preparation of a pharmaceutical preparation for the treatment of severe high altitude disease such as high altitude pulmonary edema, high altitude cerebral edema and shock.
- trimetazidine or a pharmaceutically acceptable salt thereof and L-carnitine or a derivative thereof or a pharmaceutically acceptable salt thereof for promoting fatty acid oxidation are in a specific weight ratio of 1 in a large number of animal experiments. :200 for combined application or combination into a composition, with anti-hypoxia, improve hemodynamics, improve blood oxygen saturation, protect brain tissue cells and cardiomyocytes under normoxic hypoxia and hypobaric hypoxia It is indicated that the composition can be used for preparing medicine for treating high altitude disease, and is particularly suitable for preparing medicine for treating severe altitude sickness, such as high altitude pulmonary edema, high altitude cerebral edema and shock.
- Severe high altitude disease is a series of severe acute altitude sickness caused by severe acute high altitude hypoxia caused by pulmonary edema, brain edema and shock. Severe acute plateau hypoxia can cause pulmonary venous vasoconstriction, increased resistance, leading to pulmonary hypertension, and increased pulmonary capillary permeability, coupled with lymphatic dysfunction caused by hypoxia, ultimately leading to pulmonary edema; Causes small blood vessels in the brain and increased permeability, resulting in cerebral edema. If the symptoms of high altitude hypoxia disappear, they will eventually lead to high altitude coma, shock, heart, brain and other important organs that die due to insufficient energy supply. Shock is a variety of strong pathogenic factors acting on the body.
- the circulatory function is drastically reduced, the microcirculation perfusion of tissues and organs is seriously insufficient, and the systemic critical pathological process of vital organs and metabolic disorders is important. Shock is an acute syndrome. In this state, the effective blood flow of the whole body is reduced, and the microcirculation is impeded, leading to ischemia and hypoxia of important vital organs.
- the present invention provides a pharmaceutical composition for treating severe high altitude disease, the pharmaceutical composition comprising the active ingredient L-carnitine or a derivative thereof or a pharmaceutically acceptable salt thereof, the active ingredient trimetazidine or a pharmaceutically acceptable drug thereof It is composed of a salt and a pharmaceutically acceptable adjuvant, wherein the weight ratio of L-carnitine or a derivative thereof or a pharmaceutically acceptable salt thereof to trimetazidine or a pharmaceutically acceptable salt thereof is 200:1.
- the L-carnitine or a derivative thereof or a pharmaceutically acceptable salt thereof is selected from the group consisting of L-carnitine, acetyl-L-carnitine, propionyl L-carnitine, and a pharmaceutically acceptable salt thereof;
- the pharmaceutically acceptable salts of trimetazidine and L-carnitine or derivatives thereof include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, maleic acid, and fumaric acid.
- the severe plateau diseases according to the present invention include, but are not limited to, clinical manifestations of severe altitude sickness such as high altitude coma, high altitude pulmonary edema, high altitude cerebral edema and shock.
- the pharmaceutical composition of the present invention can be mixed with a pharmaceutical excipient known in the art and prepared into an oral preparation and an injection preparation by a conventional technique, and the oral preparation includes a pharmaceutical oral preparation such as a tablet or a capsule, and the injection preparation includes an injection solution and lyophilization. Injection of pharmaceutical preparations such as powder injection.
- the pharmaceutical composition of the present invention is: L-carnitine or a derivative thereof or a pharmaceutically acceptable salt thereof 10-500 mg/kg, Trimetazidine or a pharmaceutically acceptable salt thereof 0.1-3 mg /kg.
- a particularly preferred embodiment of the present invention provides an injection capable of rapidly acting and effectively treating severe high altitude disease, including but not limited to high altitude coma, high altitude pulmonary edema, high altitude cerebral edema, and shock.
- the injection comprises the active ingredient L-carnitine or a derivative thereof or a pharmaceutically acceptable salt thereof, the active ingredient trimetazidine or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant, wherein L-carnitine or a derivative thereof or The weight ratio of the pharmaceutically acceptable salt to trimetazidine or a pharmaceutically acceptable salt thereof is 200:1.
- the injection is preferably an injection solution and a lyophilized powder injection; the injection may also be in a combination package.
- L-carnitine or a derivative thereof or a pharmaceutically acceptable salt thereof is selected from the group consisting of L-carnitine, acetyl-L-carnitine, propionyl L-carnitine, and a pharmaceutically acceptable salt thereof;
- Pharmaceutically acceptable salts of oxazine and L-carnitine or derivatives thereof include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, maleic acid, fumaric acid, lyric acid, lemon a salt formed by acid, oxalic acid, succinic acid, tartaric acid, malic acid, mandelic acid, trifluoroacetic acid, pantothenic acid, methanesulfonic acid and p-toluenesulfonic acid; said severe plateau disease includes high altitude coma, high altitude pulmonary edema, high altitude cerebral edema And shock.
- Example 1 Observing the effect of different doses of intravenous injection of L-carnitine and trimetazidine hydrochloride on hypoxia in mice Trimetazidine Hydrochloride: 0.75, 2.25, 4.5 mg/kg, which is equivalent to a daily dose of 5, 15, 30 mg for humans ; L-carnitine: 450 mg/kg, which is equivalent to a daily dose of 3 g for humans.
- mice Forty male mice, weighing 20 ⁇ 2g, were randomly divided into 4 groups according to body weight, 10 rats in each group, 10ml/kg tail vein injection, blank control group was given equal volume of normal saline, 1 time/day, continuous 7 Days, after the last administration of lh, each group of mice was placed in a 160 ml jar with 5 g of sodium lime in advance, one bottle per bottle, and then the cap was smeared with Vaseline to seal, with death as an indicator, record small The survival time of rats is swelled.
- Example 2 Effects of L-carnitine and trimetazidine hydrochloride (200:1), injection, single-party and compound on acute cerebral hypoxia model in mice
- mice Forty male Kunming mice were randomly divided into 4 groups: normal control group, L-carnitine 600 mg/kg group, trimetazidine hydrochloride 3 mg/kg group, L-carnitine 600+ Trimetazamine hydrochloride 3 mg/ Kg group, 10 in each group. 10 ml/kg was administered by injection, and the normal control group was given an equal volume of physiological saline once a day for 7 days. After the last administration for 1 hour, the mice were quickly decapitated from behind the ear, and the stop time of the mice after the break of the head to the mouth was immediately recorded by the stopwatch. The results are shown in Table 2.
- the homogenate was centrifuged at 2000 r/min for 5 min at 4 ° C, the supernatant was separated, and glutamic acid (Glu), aspartic acid (Asp), and Y-aminobutyric acid (GABA) were detected in the brain tissue of the mouse using an amino acid analyzer. , the content of glycine (Gly).
- Excitatory amino acids (EAA) represented by Glu, Asp, GABA and Gly after brain injury are high in the brain.
- excessive release of Glu is one of the important mechanisms leading to neuronal death in secondary brain injury, especially when Glu activates N-methyl-D-aspartate (NMDA) receptor to induce intracellular calcium overload.
- NMDA N-methyl-D-aspartate
- Trimetazidine 3 18.02 ⁇ 1.19 15.51 ⁇ 2.17 3.65 ⁇ 1.26 3.95 ⁇ 1.05
- L-carnitine 600 + trimetazidine 3 mg / kg group can significantly prolong the gasping time after decapitation in mice (P ⁇ 0.01), and has a synergistic effect, indicating that the composition has significant anti-cerebral hypoxia The role.
- the composition can significantly reduce the EAA content in the brain tissue compared with the single drug, thereby exerting a protective effect on hypoxic brain damage.
- Example 3 Observation of the effects of L-carnitine and trimetazidine hydrochloride (200:1) on hypobaric hypoxia in rats
- the dose of L-carnitine + trimetazidine hydrochloride was set at 600+3 mg/kg.
- mice Twenty Wister rats, weighing 150g ⁇ 190g, were randomly divided into 3 groups: normoxia control group: plain words, materials; acute hypoxia group: animals were placed in hypobaric oxygen chamber, the oxygen partial pressure in the chamber was ll.OlKpa (about equivalent to an oxygen partial pressure of 5000m above sea level) After continuous decompression and oxygen deprivation for 3d, it is placed in a low-pressure oxygen chamber with a partial pressure of oxygen of 13.25Kpa (about the equivalent of 4000m of oxygen). Specimens, Qi Yang. Common animal models and anti-hypoxia drugs for anti-hypoxia research. Chinese Journal of Pharmacy, 2010, 26 (2): 170-173]; Administration group: 10ml/kg injection.
- the number of oxygen partial pressures in the warehouse is 13.25Kpa (about the equivalent of oxygen partial pressure of 4000m above sea level). According to the specimen. All animals are free to eat and drink.
- the administration group can significantly increase the hemodynamic index, indicating that the composition has an increase in hemodynamics. use.
- each of the drug-administered groups significantly increased the oxygen partial pressure and oxygen saturation of the acute hypoxic arteries in rats (P ⁇ 0.01), indicating that the composition was administered with anti-hypoxia.
- Example 5 Compound for injection (L-carnitine + trimetazidine hydrochloride) Sterile lyophilized preparation
- Process Dissolve each of the above ingredients in an appropriate amount of water for injection, aseptically filter, install in ampoules, freeze and seal, and check for leaks.
- Example 5 The L-carnitine in Example 5 was changed to acetyl-L-carnitine or propionyl-L-carnitine, and the other prescriptions and techniques were the same as in Example 5.
- the L-carnitine in Example 5 was changed to L-carnitine with hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, maleic acid, fumaric acid, abietic acid, citric acid,
- the salts formed by oxalic acid, succinic acid, tartaric acid, malic acid, mandelic acid, trifluoroacetic acid, pantothenic acid, methanesulfonic acid and p-toluenesulfonic acid, respectively, are in accordance with the fifth embodiment.
- trimetazidine hydrochloride in the fifth embodiment is changed to trimetazidine with hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, maleic acid, fumaric acid, citric acid, citric acid, oxalic acid
- the salts formed by succinic acid, tartaric acid, malic acid, mandelic acid, trifluoroacetic acid, pantothenic acid, methanesulfonic acid and p-toluenesulfonic acid, respectively, are the same as in the fifth embodiment.
- Example 10 Combination packaging of L-carnitine preparation and trimetazidine hydrochloride preparation
- the L-carnitine formulation and the trimetazidine hydrochloride formulation were prepared or purchased separately, as shown in Table 7.
Abstract
The present invention provides a pharmaceutical composition used for treating severe altitude sickness, characterized by a composition consisting of trimetazidine or pharmaceutically acceptable salt thereof and L-carnitine or derivative thereof or pharmaceutically acceptable salt thereof, and the weight ratio of the above being 1:200.
Description
一种治 ^症高原病的药物组合物 Medicinal composition for treating high altitude sickness
技术领域 Technical field
本发明涉及药物组合物领域， 具体地说， 涉及一种治疗重症高原病的药物组合物。 The present invention relates to the field of pharmaceutical compositions, and in particular to a pharmaceutical composition for the treatment of severe high altitude sickness.
技术背景 technical background
重症高原病是严重的急性高原缺氧引起的肺水肿、 脑水肿、 休克等严重型急性高原病。 重症高原病的传统治疗手段为吸入高压氧和对症治疗（降低肺动脉压、颅压等）， 必要时 采用气管插管， 持续性正压通气并充分给氧， 待病情稳定后转至低地继续治疗及药物治疗， 目前常用的治疗药物有止痛药如阿司匹林， 利尿剂如乙酰唑胺、 呋塞米， 肾上腺皮质激素类 药物如地塞米松， 各种维生素及氨茶碱等， 如出现心力衰竭还要使用强心苷类药物， 如毛旋 花子甙 κ或毛花甙 。 但上述药物主要是病情稳定的对症治疗， 效果有限， 而且大量使用后 会产生严重的毒副作用， 如大量使用利尿剂会使得电解质紊乱。 Severe altitude sickness is a serious acute high altitude disease such as pulmonary edema, brain edema, and shock caused by acute high altitude hypoxia. Traditional treatments for severe high altitude sickness are inhalation of hyperbaric oxygen and symptomatic treatment (reducing pulmonary artery pressure, intracranial pressure, etc.), if necessary, endotracheal intubation, continuous positive pressure ventilation and adequate oxygen supply, until the condition is stable, then go to lowland to continue treatment And drug treatment, currently commonly used treatments are painkillers such as aspirin, diuretics such as acetazolamide, furosemide, adrenocortical drugs such as dexamethasone, various vitamins and aminophylline, etc., such as heart failure Use a cardiac glycoside drug, such as the scutellaria sinensis or scutellaria. However, the above-mentioned drugs are mainly symptomatic treatments with stable conditions, and the effects are limited, and severe toxic and side effects are caused after a large amount of use, such as a large amount of diuretics may cause electrolyte imbalance.
此外， 常用含红景天的中药制剂进行缺氧的预防和治疗， 这类中药能够辅助提高机体对 缺氧的适应性， 降低应激反应， 但该类中药起效缓慢， 效果有限， 不能满足重症高原病的治 疗需要。 In addition, traditional Chinese medicine preparations containing Rhodiola are commonly used for prevention and treatment of hypoxia. Such Chinese medicines can help improve the body's adaptability to hypoxia and reduce stress response. However, these Chinese medicines have slow onset and limited effect and cannot be satisfied. The need for treatment of severe altitude sickness.
中国专利申请号 200310104871.X公开了左卡尼汀具有预防和治疗高原病的作用，但未见 应用于临床的报道。 Chinese Patent Application No. 200310104871.X discloses that L-carnitine has a preventive and therapeutic effect on high altitude disease, but no clinical application has been reported.
显然， 目前市场上缺乏一种安全、 有效用于治疗和急救重症高原病的药物。 本发明的目的之一是提供一种治疗重症高原病的药物组合物。 Obviously, there is currently no drug on the market that is safe and effective for the treatment and emergency treatment of severe high altitude sickness. One of the objects of the present invention is to provide a pharmaceutical composition for treating severe high altitude sickness.
本发明的目的之二是提供一种上述组合物在制备治疗重症高原病例如高原肺水肿、 高原 脑水肿和休克的药物制剂中的用途。 Another object of the present invention is to provide a use of the above composition for the preparation of a pharmaceutical preparation for the treatment of severe high altitude disease such as high altitude pulmonary edema, high altitude cerebral edema and shock.
本发明的研究者经过大量的动物实验， 意外地发现将曲美他嗪或其可药用盐与促进脂肪 酸氧化的左卡尼汀或其衍生物或其可药用盐按照特定的重量比例 1:200进行联合应用或组合 成组合物应用， 具有抗缺氧、 提高血液动力学指标， 提高血氧饱和度， 对常压缺氧和低压缺 氧条件下的脑组织细胞和心肌细胞具有保护作用， 说明该组合物是能够用于制备治疗高原病 的药物， 特别适于制备治疗重症高原病， 例如高原肺水肿、 高原脑水肿和休克的药物。 The researchers of the present invention have unexpectedly discovered that trimetazidine or a pharmaceutically acceptable salt thereof and L-carnitine or a derivative thereof or a pharmaceutically acceptable salt thereof for promoting fatty acid oxidation are in a specific weight ratio of 1 in a large number of animal experiments. :200 for combined application or combination into a composition, with anti-hypoxia, improve hemodynamics, improve blood oxygen saturation, protect brain tissue cells and cardiomyocytes under normoxic hypoxia and hypobaric hypoxia It is indicated that the composition can be used for preparing medicine for treating high altitude disease, and is particularly suitable for preparing medicine for treating severe altitude sickness, such as high altitude pulmonary edema, high altitude cerebral edema and shock.
重症高原病是严重的急性高原缺氧引起的肺水肿、 脑水肿、 休克等一系列严重型急性高 原病。 严重的急性高原缺氧可引起肺小静脉血管收缩， 阻力增加， 导致肺动脉高压， 又可使 肺毛细血管通透性增高， 加上缺氧引起的淋巴循环障碍， 最终促发肺水肿； 还可引起脑部小 血管痉挛和通透性增加， 产生脑水肿。 高原缺氧症状如不能自行消失， 最终导致高原昏迷， 休克， 心、 脑等重要脏器由于能量供应不足而死亡。 休克系各种强烈致病因素作用于机体，
使循环功能急剧减退， 组织器官微循环灌流严重不足， 以至重要生命器官机能、 代谢严重障 碍的全身危重病理过程。 休克是一急性的综合征。 在这种状态下， 全身有效血流量减少， 微 循环出现障碍， 导致重要的生命器官缺血缺氧。 Severe high altitude disease is a series of severe acute altitude sickness caused by severe acute high altitude hypoxia caused by pulmonary edema, brain edema and shock. Severe acute plateau hypoxia can cause pulmonary venous vasoconstriction, increased resistance, leading to pulmonary hypertension, and increased pulmonary capillary permeability, coupled with lymphatic dysfunction caused by hypoxia, ultimately leading to pulmonary edema; Causes small blood vessels in the brain and increased permeability, resulting in cerebral edema. If the symptoms of high altitude hypoxia disappear, they will eventually lead to high altitude coma, shock, heart, brain and other important organs that die due to insufficient energy supply. Shock is a variety of strong pathogenic factors acting on the body. The circulatory function is drastically reduced, the microcirculation perfusion of tissues and organs is seriously insufficient, and the systemic critical pathological process of vital organs and metabolic disorders is important. Shock is an acute syndrome. In this state, the effective blood flow of the whole body is reduced, and the microcirculation is impeded, leading to ischemia and hypoxia of important vital organs.
本发明提供了一种用于治疗重症高原病的药物组合物， 所述药物组合物由活性成分左卡 尼汀或其衍生物或其可药用盐， 活性成分曲美他嗪或其可药用盐和可药用辅料组成， 其中左 卡尼汀或其衍生物或其可药用盐与曲美他嗪或其可药用盐的重量比为 200: 1。 The present invention provides a pharmaceutical composition for treating severe high altitude disease, the pharmaceutical composition comprising the active ingredient L-carnitine or a derivative thereof or a pharmaceutically acceptable salt thereof, the active ingredient trimetazidine or a pharmaceutically acceptable drug thereof It is composed of a salt and a pharmaceutically acceptable adjuvant, wherein the weight ratio of L-carnitine or a derivative thereof or a pharmaceutically acceptable salt thereof to trimetazidine or a pharmaceutically acceptable salt thereof is 200:1.
本发明药物组合物中， 所述的左卡尼汀或其衍生物或其可药用盐选自左卡尼汀、 乙酰左 卡尼汀、 丙酰左卡尼汀及其可药用盐； 所述的曲美他嗪和左卡尼汀或其衍生物的可药用的盐 包括它们与盐酸、 溴氢酸、 碘氢酸、 硫酸、 硝酸、 磷酸、 乙酸、 马来酸、 富马酸、 枸缘酸、 柠檬酸、 草酸、 琥珀酸、 酒石酸、 苹果酸、 扁桃酸、 三氟乙酸、 泛酸、 甲磺酸和对甲苯磺酸 形成的盐。 In the pharmaceutical composition of the present invention, the L-carnitine or a derivative thereof or a pharmaceutically acceptable salt thereof is selected from the group consisting of L-carnitine, acetyl-L-carnitine, propionyl L-carnitine, and a pharmaceutically acceptable salt thereof; The pharmaceutically acceptable salts of trimetazidine and L-carnitine or derivatives thereof include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, maleic acid, and fumaric acid. a salt formed by sulphuric acid, citric acid, oxalic acid, succinic acid, tartaric acid, malic acid, mandelic acid, trifluoroacetic acid, pantothenic acid, methanesulfonic acid and p-toluenesulfonic acid.
本发明所述的重症高原病包括但不限于高原昏迷、 高原肺水肿、 高原脑水肿和休克等重 症高原病临床表现。 The severe plateau diseases according to the present invention include, but are not limited to, clinical manifestations of severe altitude sickness such as high altitude coma, high altitude pulmonary edema, high altitude cerebral edema and shock.
本发明的药物组合物可与本领域公知的药用辅料混合， 用常规的技术制备成口服制剂和 注射制剂使用， 口服制剂包括片剂， 胶囊等药物口服制剂， 注射制剂包括注射液和冻干粉针 剂等注射药物制剂。 The pharmaceutical composition of the present invention can be mixed with a pharmaceutical excipient known in the art and prepared into an oral preparation and an injection preparation by a conventional technique, and the oral preparation includes a pharmaceutical oral preparation such as a tablet or a capsule, and the injection preparation includes an injection solution and lyophilization. Injection of pharmaceutical preparations such as powder injection.
本发明所述的药物组合物， 成人给药的日剂量为： 左卡尼汀或其衍生物或其可药用盐 10-500mg/kg, 曲美他嗪或其可药用盐 0.1-3mg/kg。 The pharmaceutical composition of the present invention, the daily dose for administration to an adult is: L-carnitine or a derivative thereof or a pharmaceutically acceptable salt thereof 10-500 mg/kg, Trimetazidine or a pharmaceutically acceptable salt thereof 0.1-3 mg /kg.
本发明一个特别优选的实例是提供了一种能够快速发挥作用和有效治疗重症高原病的注 射剂， 所述的重症高原病包括但不限于高原昏迷、 高原肺水肿、 高原脑水肿和休克， 所述注 射剂由活性成分左卡尼汀或其衍生物或其可药用盐， 活性成分曲美他嗪或其可药用盐和可药 用辅料组成， 其中左卡尼汀或其衍生物或其可药用盐与曲美他嗪或其可药用盐的重量比为 200: 1。 所述的注射剂优选注射液和冻干粉针剂； 所述的注射剂也可以是组合包装型式。 其中 所述的左卡尼汀或其衍生物或其可药用盐选自左卡尼汀、 乙酰左卡尼汀、 丙酰左卡尼汀及其 可药用盐； 所述的曲美他嗪和左卡尼汀或其衍生物的可药用的盐包括它们与盐酸、 溴氢酸、 碘氢酸、 硫酸、 硝酸、 磷酸、 乙酸、 马来酸、 富马酸、 枸缘酸、 柠檬酸、 草酸、 琥珀酸、 酒 石酸、 苹果酸、 扁桃酸、 三氟乙酸、 泛酸、 甲磺酸和对甲苯磺酸形成的盐； 所述的重症高原 病包括高原昏迷、 高原肺水肿、 高原脑水肿和休克。 A particularly preferred embodiment of the present invention provides an injection capable of rapidly acting and effectively treating severe high altitude disease, including but not limited to high altitude coma, high altitude pulmonary edema, high altitude cerebral edema, and shock. The injection comprises the active ingredient L-carnitine or a derivative thereof or a pharmaceutically acceptable salt thereof, the active ingredient trimetazidine or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant, wherein L-carnitine or a derivative thereof or The weight ratio of the pharmaceutically acceptable salt to trimetazidine or a pharmaceutically acceptable salt thereof is 200:1. The injection is preferably an injection solution and a lyophilized powder injection; the injection may also be in a combination package. Wherein the L-carnitine or a derivative thereof or a pharmaceutically acceptable salt thereof is selected from the group consisting of L-carnitine, acetyl-L-carnitine, propionyl L-carnitine, and a pharmaceutically acceptable salt thereof; Pharmaceutically acceptable salts of oxazine and L-carnitine or derivatives thereof include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, maleic acid, fumaric acid, lyric acid, lemon a salt formed by acid, oxalic acid, succinic acid, tartaric acid, malic acid, mandelic acid, trifluoroacetic acid, pantothenic acid, methanesulfonic acid and p-toluenesulfonic acid; said severe plateau disease includes high altitude coma, high altitude pulmonary edema, high altitude cerebral edema And shock.
具体实施方式 detailed description
下面的实施例仅仅用于进一步解释本发明， 而不是对本发明范围的限制。 The following examples are merely illustrative of the invention and are not intended to limit the scope of the invention.
实施例一：观察左卡尼汀和盐酸曲美他嗪组合不同剂量配比静脉注射对小鼠常压缺氧的影响
盐酸曲美他嗪： 0.75、 2.25、 4.5mg/kg, 约相当于人用日剂量 5、 15、 30mg; 左卡尼汀： 450mg/kg， 约相当于人用日剂量 3g Example 1: Observing the effect of different doses of intravenous injection of L-carnitine and trimetazidine hydrochloride on hypoxia in mice Trimetazidine Hydrochloride: 0.75, 2.25, 4.5 mg/kg, which is equivalent to a daily dose of 5, 15, 30 mg for humans ; L-carnitine: 450 mg/kg, which is equivalent to a daily dose of 3 g for humans.
选用雄性小鼠 40只， 体重 20±2g， 按体重随机分为 4组， 每组 10只， 10ml/kg尾静脉 注射给药， 空白对照组给予等体积生理盐水， 1次 /天， 连续 7天， 末次给药 lh后， 将各组小 鼠放入预先加有 5g钠石灰的 160ml广口瓶中， 每瓶 1只， 然后将瓶盖用凡士林涂抹封紧， 以 死亡为指标， 记录小鼠存活时间 嵇扬.抗缺氧研究常用动物模型及抗缺氧药物.解放军 药学学报， 2010, 26 (2) ： 170-173], 结果见表 1。 Forty male mice, weighing 20±2g, were randomly divided into 4 groups according to body weight, 10 rats in each group, 10ml/kg tail vein injection, blank control group was given equal volume of normal saline, 1 time/day, continuous 7 Days, after the last administration of lh, each group of mice was placed in a 160 ml jar with 5 g of sodium lime in advance, one bottle per bottle, and then the cap was smeared with Vaseline to seal, with death as an indicator, record small The survival time of rats is swelled. Common animal models and anti-hypoxia drugs for anti-hypoxia research. Chinese Journal of Pharmacy, 2010, 26 (2): 170-173], the results are shown in Table 1.
表 1 常压耐缺氧存活时间比较 （n=10， x±S) Table 1 Comparison of normal pressure and hypoxia survival time (n=10, x±S)
组别 /剂量 （mg/kg) 存活时间 (min) 延长存活时间 (％) Group / dose (mg / kg) survival time (min) prolong survival time (%)
正常对照组 22.1 ±4.4 - 左卡尼汀 450+盐酸曲美他嗪 0.75 30.4±5.8** 37.6 Normal control group 22.1 ± 4.4 - L-carnitine 450 + trimetazidine hydrochloride 0.75 30.4 ± 5.8** 37.6
左卡尼汀 450+盐酸曲美他嗪 2.25 32.8±4.6** 48.4 L-carnitine 450 + trimetazidine hydrochloride 2.25 32.8 ± 4.6** 48.4
左卡尼汀 450+盐酸曲美他嗪 4.5 32.5±3.2** 47.0 L-carnitine 450 + trimetazidine hydrochloride 4.5 32.5 ± 3.2** 47.0
注： 与正常对照组比较， **P<0.01。 Note: **P<0.01 compared with the normal control group.
结果表明： 各给药组均能显著延长小鼠耐缺氧存活时间， 说明左卡尼汀与盐酸曲美他嗪 组合成的组合物具有抗缺氧的作用， 可以用于治疗重症高原病， 左卡尼汀用量不变， 以左卡 尼汀和盐酸曲美他嗪重量比 200:1效果明显好于 600:1， 与 100:1效果差别相似， 所以优选最 佳比 200:1。 The results showed that each of the drug-administered groups significantly prolonged the hypoxia-tolerant survival time of mice, indicating that the combination of L-carnitine and trimetazidine hydrochloride has anti-hypoxia effect and can be used for the treatment of severe high altitude disease. The amount of L-carnitine was unchanged, and the effect of L-carnitine and trimetazidine hydrochloride at 200:1 was significantly better than 600:1, which was similar to the effect of 100:1, so the optimal ratio of 200:1 was preferred.
实施例二： 左卡尼汀和盐酸曲美他嗪 （200:1)， 注射给药， 单方和复方对小鼠急性脑缺氧模 型的作用 Example 2: Effects of L-carnitine and trimetazidine hydrochloride (200:1), injection, single-party and compound on acute cerebral hypoxia model in mice
将 40只雄性昆明小鼠随机分为 4组： 正常对照组、 左卡尼汀 600mg/kg组、 盐酸曲美他 嗪 3 mg/kg组、 左卡尼汀 600+盐酸曲美他嗪 3mg/kg组， 每组 10只。 10ml/kg注射给药， 正 常对照组给予等体积的生理盐水， 1次 /天， 连续给药 7天。 末次给药 lh后， 将小鼠从耳后迅 速断头， 立即按秒表记录小鼠断头后至张口喘气停止时间， 结果见表 2。 Forty male Kunming mice were randomly divided into 4 groups: normal control group, L-carnitine 600 mg/kg group, trimetazidine hydrochloride 3 mg/kg group, L-carnitine 600+ Trimetazamine hydrochloride 3 mg/ Kg group, 10 in each group. 10 ml/kg was administered by injection, and the normal control group was given an equal volume of physiological saline once a day for 7 days. After the last administration for 1 hour, the mice were quickly decapitated from behind the ear, and the stop time of the mice after the break of the head to the mouth was immediately recorded by the stopwatch. The results are shown in Table 2.
表 2 单、 复方对小鼠急性脑缺氧模型的作用 （n=10， ±S) Table 2 Effect of single and compound on acute cerebral hypoxia model in mice ( n = 10, ±S)
组别 /剂量 （mg/kg) 断头后喘气时间 （s) Group/dose (mg/kg) Gasping time after decapitation (s)
正常对照组 17.4+1.8 Normal control group 17.4+1.8
左卡尼汀 600 19.8 ±1.5 L-carnitine 600 19.8 ±1.5
曲美他嗪 3 17.8±2.1 Trimetazidine 3 17.8±2.1
左卡尼汀 600+曲美他嗪 3 24.8±1.3** L-carnitine 600+ trimetazidine 3 24.8±1.3**
注： 与正常对照组比较， **P<0.01。
脑组织生化指标测定： 小鼠死亡后， 立即冰浴条件下取脑组织， 以冰生理盐水冲洗， 除 去残血， 按 1:9比例加入冰冷的无水乙醇， 冰浴条件下用高速匀浆机 （10s/次， 间隔 15s， 共 4次）将脑组织制成 10%脑组织匀浆。 将匀浆液于 4°C以 2000r/min离心 5min， 分离上清， 采 用氨基酸分析仪检测小鼠脑组织中谷氨酸（Glu)、天冬氨酸（Asp)、 Y-氨基丁酸（GABA)、 甘氨酸（Gly)的含量。脑损伤后以 Glu、 Asp, GABA和 Gly等为代表的兴奋性氨基酸（EAA) 在脑内含量较高。 尤其是 Glu的过度释放是导致继发性脑损伤神经元死亡的重要机制之一， 特别是 Glu激活 N-甲基 -D-天门冬氨酸 （NMDA) 受体引起神经元内钙超载而激发的级联损 伤效应是导致迟发性神经元死亡的重要原因， 线粒体功能的损伤程度决定了神经元的死亡方 式 [Clemens J A, Stephenson D T， Smalsting E B. Global ischemia activate nuclear. Storke， 1997， 28:1073-1076.] 0 结果见表 3。 Note: **P<0.01 compared with the normal control group. Determination of biochemical indicators of brain tissue: After the death of the mouse, the brain tissue was taken immediately under ice bath conditions, washed with ice physiological saline, and the residual blood was removed. Ice-cold absolute ethanol was added in a ratio of 1:9, and high-speed homogenization was carried out under ice bath conditions. The brain tissue was made into 10% brain tissue homogenate (10s/time, interval 15s, 4 times in total). The homogenate was centrifuged at 2000 r/min for 5 min at 4 ° C, the supernatant was separated, and glutamic acid (Glu), aspartic acid (Asp), and Y-aminobutyric acid (GABA) were detected in the brain tissue of the mouse using an amino acid analyzer. , the content of glycine (Gly). Excitatory amino acids (EAA) represented by Glu, Asp, GABA and Gly after brain injury are high in the brain. In particular, excessive release of Glu is one of the important mechanisms leading to neuronal death in secondary brain injury, especially when Glu activates N-methyl-D-aspartate (NMDA) receptor to induce intracellular calcium overload. The cascade damage effect is an important cause of delayed neuronal death, and the degree of damage of mitochondrial function determines the way neurons die [Clemens JA, Stephenson DT, Smalsting E B. Global ischemia activate nuclear. Storke, 1997, 28 :1073-1076.] 0 results are shown in Table 3.
表 3 对脑组织中兴奋性氨基酸 （EAA) 含量的影响 （x±S， n=10) Table 3 Effect on the content of excitatory amino acids (EAA) in brain tissue (x±S, n=10)
组别 /剂量 （mg/kg) Glu Asp GABA Gly Group / Dose (mg/kg) Glu Asp GABA Gly
( μ mol/L) ( μ mol/L) ( μ mol/L) ( μ mol/L) ( μ mol / L) ( μ mol / L ) ( μ mol / L ) ( μ mol / L )
正常对照组 21.15±1.06 16.03±2.11 4.11±0.78 4.96 ±2.25 Normal control group 21.15±1.06 16.03±2.11 4.11±0.78 4.96 ±2.25
左卡尼汀 600 17.22±1.12 15.24±4.15 3.12±0.91 3.45 ±1.24 L-carnitine 600 17.22±1.12 15.24±4.15 3.12±0.91 3.45 ±1.24
曲美他嗪 3 18.02±1.19 15.51±2.17 3.65±1.26 3.95 ±1.05 Trimetazidine 3 18.02±1.19 15.51±2.17 3.65±1.26 3.95 ±1.05
左卡尼汀 600+曲美他嗪 3 12.15±1.29** 15.13±1.58 3.02±0.56* 3.24±2.14 L-carnitine 600+ trimetazidine 3 12.15±1.29** 15.13±1.58 3.02±0.56* 3.24±2.14
注： 与正常对照组比较， *P<0.05， **P<0.01。 Note: *P<0.05, **P<0.01 compared with the normal control group.
结果表明： the result shows:
由表 2， 左卡尼汀 600+曲美他嗪 3mg/kg组能显著延长小鼠断头后喘气时间 （P<0.01)， 并具 有协同作用， 说明本组合物具有显著的抗脑缺氧的作用。 From Table 2, L-carnitine 600 + trimetazidine 3 mg / kg group can significantly prolong the gasping time after decapitation in mice (P <0.01), and has a synergistic effect, indicating that the composition has significant anti-cerebral hypoxia The role.
由表 3， 组合物与单方药物相比， 可显著降低脑组织中 EAA含量， 从而发挥对缺氧脑损伤的 保护作用。 From Table 3, the composition can significantly reduce the EAA content in the brain tissue compared with the single drug, thereby exerting a protective effect on hypoxic brain damage.
实施例三： 观察左卡尼汀和盐酸曲美他嗪 （200:1) 对大鼠低压缺氧的影响 Example 3: Observation of the effects of L-carnitine and trimetazidine hydrochloride (200:1) on hypobaric hypoxia in rats
设置左卡尼汀 +盐酸曲美他嗪剂量为 600+3mg/kg。 The dose of L-carnitine + trimetazidine hydrochloride was set at 600+3 mg/kg.
选用 Wister大鼠 30只， 体重 150g〜190g， 随机分为 3组： 常氧对照组： 平原地区词养、 取材； 急性缺氧组： 将动物置于低压氧舱内， 仓内氧分压为 ll.OlKpa (约相当于海拔 5000m 的氧分压） 连续减压缺氧 3d后， 再置于仓内氧分压为 13.25Kpa (约相当于海拔 4000m的氧 分压） 的低压氧舱内采取标本 ， 嵇扬.抗缺氧研究常用动物模型及抗缺氧药物.解放军药 学学报， 2010, 26 (2)： 170-173]； 给药组： 10ml/kg注射给药。 于进低压氧舱前 4d开始， 持续 7d， 在仓内氧分压为 13.25Kpa (约相当于海拔 4000m的氧分压） 的低压氧舱内采取数
据及标本。 所有动物自由进食及饮水。 Twenty Wister rats, weighing 150g~190g, were randomly divided into 3 groups: normoxia control group: plain words, materials; acute hypoxia group: animals were placed in hypobaric oxygen chamber, the oxygen partial pressure in the chamber was ll.OlKpa (about equivalent to an oxygen partial pressure of 5000m above sea level) After continuous decompression and oxygen deprivation for 3d, it is placed in a low-pressure oxygen chamber with a partial pressure of oxygen of 13.25Kpa (about the equivalent of 4000m of oxygen). Specimens, Qi Yang. Common animal models and anti-hypoxia drugs for anti-hypoxia research. Chinese Journal of Pharmacy, 2010, 26 (2): 170-173]; Administration group: 10ml/kg injection. Starting from 4 days before entering the low-pressure oxygen chamber, lasting for 7 days, the number of oxygen partial pressures in the warehouse is 13.25Kpa (about the equivalent of oxygen partial pressure of 4000m above sea level). According to the specimen. All animals are free to eat and drink.
血液动力学测定： 各组动物在相应时间点内分别经右颈外静脉插至心导管、 肺动脉、 经 左颈总动脉插入心导管至主动脉、 左心室； 用四道生理记录仪检测记录心率 （HR)、 肺动脉 压 （PAP)、 主动脉收缩压 （SAP)、 主动脉舒张压 （DAP)、 左室收缩压 （LVSP)、 左室舒张 压 （LVEDP)、 左心室压力最大上升速率 （+dp/dtmax)， 结果见表 4 Hemodynamic measurement: Each group of animals was inserted into the cardiac catheter, pulmonary artery, and the left common carotid artery into the aorta and left ventricle through the right external jugular vein at the corresponding time points. The heart rate was detected by four physiological recorders. (HR), pulmonary arterial pressure (PAP), aortic systolic pressure (SAP), aortic diastolic pressure (DAP), left ventricular systolic pressure (LVSP), left ventricular diastolic pressure (LVEDP), maximal rate of left ventricular pressure (+ Dp/dt max ), the results are shown in Table 4
复方对模拟高原缺氧条件下大鼠血液学指标的影响 （n=10 Effect of compound prescription on hematological parameters of rats under simulated plateau hypoxia (n=10)
组别 /剂量 PAP SAP DAP LVSP +dp/dt HRGroup / dose PAP SAP DAP LVSP +dp/dt HR
(mg/kg) (kPa) (kPa) (kPa) (kPa) (kPa) (heat/min) 常氧对照组 3.5 ±0.6 15.8 ± 1.6 10.5 ±2.8 16.9± 1.6 664 ± 83 360 ±40 急性缺氧组 5.3 ±0.7 22.9 ±3.7 15.6±3.2 25.5 ±3.0 695 ±72 377 ±50 左卡尼汀 600+盐酸曲美 4.1 士 18.0 士 12.3 士 19.8 士 555 士 370 ±50 他嗪 3 0.8** 2.2** 2.1** 2.2** 45** (mg/kg) (kPa) (kPa) (kPa) (kPa) (kPa) (heat/min) Normal oxygen control group 3.5 ± 0.6 15.8 ± 1.6 10.5 ± 2.8 16.9 ± 1.6 664 ± 83 360 ± 40 Acute hypoxia Group 5.3 ±0.7 22.9 ±3.7 15.6±3.2 25.5 ±3.0 695 ±72 377 ±50 L-Carnitine 600+ Trimetsulfate 4.1 Stereo 18.0 ± 12.3 ± 19.8 ± 555 ± 370 ± 50 Oxazine 3 0.8** 2.2** 2.1** 2.2** 45**
注： 与急性缺氧组比较， **P<0.01 Note: Compared with acute hypoxia group, **P<0.01
血气分析：主动脉采血 lml，肝素抗凝，测定血氧分压 Pa02、氧饱和度 Sa02等血气指标， 结果见表 5 Blood gas analysis: blood sampling of aorta lml, heparin anticoagulation, determination of blood oxygen partial pressure Pa0 2 , oxygen saturation Sa0 2 and other blood gas indicators, the results are shown in Table 5
表 5复方对模拟高原缺氧条件下大鼠血气分析的影响 （n=10 ±S)Table 5 Effect of compound on blood gas analysis in rats under simulated plateau hypoxia ( n = 10 ± S)
3\ Pa02(kPa) Sa02(%) 3\ Pa0 2 (kPa) Sa0 2 (%)
常氧对照组 12.2 + 2.4 ~~ 91.4 + 6.3 Normal oxygen control group 12.2 + 2.4 ~~ 91.4 + 6.3
急性缺氧组 5.5 ± 1.5 63.7 ± 13.8 Acute hypoxia group 5.5 ± 1.5 63.7 ± 13.8
左卡尼汀 600+盐酸曲美他嗪 3 7.5 ± 1.7** 76.3 ± 15.2** L-carnitine 600 + trimetazidine hydrochloride 3 7.5 ± 1.7** 76.3 ± 15.2**
注： 与急性缺氧组比较， **P<0.01 Note: Compared with acute hypoxia group, **P<0.01
心肌损伤标志物测定：主动脉采血 2ml，测定乳酸脱氢酶（LDH)活性及血浆内皮素（ET-1 )、 心钠素 （ANP) 含量， 结果见表 6 Determination of myocardial injury markers: 2ml of aortic blood collection, determination of lactate dehydrogenase (LDH) activity and plasma endothelin (ET-1), atrial natriuretic peptide (ANP) content, the results are shown in Table 6.
表 6复方对模拟高原缺氧条件下大鼠心肌损伤的保护 （n=10 ±S) Table 6 Protection of myocardial injury in rats under simulated plateau hypoxia ( n = 10 ± S)
组别 LDH (U/L) ET-1 (pg/ml) ANP (pg/ml) 常氧对照组 3469.17 + 236.15 188.52 + 30.05 172.13 + 52.17 ~ 急性缺氧组 4575.25 ±391.05 861.25 ±58.13 431.21 ±74.24 左卡尼汀 600+盐酸曲美他嗪 3 3813.11 ±324.06** 321.06±54.06** 270.56±48.08** 注： 与急性缺氧组比较， **P<0.01 Group LDH (U/L) ET-1 (pg/ml) ANP (pg/ml) Normal oxygen control group 3469.17 + 236.15 188.52 + 30.05 172.13 + 52.17 ~ Acute anoxic group 4575.25 ±391.05 861.25 ±58.13 431.21 ±74.24 Left Carnitine 600 + trimetazidine hydrochloride 3 3813.11 ±324.06** 321.06±54.06** 270.56±48.08** Note: Compared with acute hypoxia group, **P<0.01
结果表明： the result shows:
由表 4， 给药组均能显著增加血液动力学指标， 说明本组合物具有增加血液动力学的作
用。 From Table 4, the administration group can significantly increase the hemodynamic index, indicating that the composition has an increase in hemodynamics. use.
由表 5， 各给药组均能显著提高大鼠急性缺氧动脉血氧分压和氧饱和度 （P<0.01 )， 说明 本组合物注射给药具有抗缺氧的作用。 From Table 5, each of the drug-administered groups significantly increased the oxygen partial pressure and oxygen saturation of the acute hypoxic arteries in rats (P < 0.01), indicating that the composition was administered with anti-hypoxia.
由表 6， 与常氧对照组相比， 急性缺氧组大鼠血浆 LDH活性明显升高 （P<0.01 )， ET-1 和 ANP含量明显增加 （P<0.01 )。 与急性缺氧组比较， 各给药组 LDH活性明显降低， ET-1 和 ANP含量均显著下降 （P<0.01 )。 可见， 本组合物注射给药可明显减轻低压缺氧下的心肌 组织损伤程度， 对心肌组织具有一定的保护作用。 From Table 6, compared with the normoxic control group, plasma LDH activity was significantly increased in the acute hypoxia group (P<0.01), and ET-1 and ANP levels were significantly increased (P<0.01). Compared with the acute hypoxia group, the LDH activity was significantly decreased in each administration group, and the levels of ET-1 and ANP were significantly decreased (P<0.01). It can be seen that the injection of the composition can significantly alleviate the degree of myocardial tissue damage under hypobaric hypoxia, and has a certain protective effect on myocardial tissue.
实施例四： 复方 （左卡尼汀 +盐酸曲美他嗪） 输液 Example 4: Compound (Luocarnitine + Trimetazamine Hydrochloride) Infusion
处方： 左卡尼汀 600g Prescription: L-carnitine 600g
盐酸曲美他嗪 3g Trimetazamine Hydrochloride 3g
依地酸二钠 5g Disodium edetate 5g
盐酸 200g Hydrochloric acid 200g
注射用水 加至 10000ml Water for injection added to 10000ml
工艺： 取约 8000ml热注射用水， 按处方量投入左卡尼汀、盐酸曲美他嗪， 搅拌使全溶， 加抗氧剂， 并用 10%盐酸调 PH至 6.0左右， 加注射用水适量， 在加入 0.15%活性炭脱色， 过 滤至澄明， 灌封于 100ml输液瓶内， 充氮气， 加塞， 轧盖， 于 10CTC灭菌 30min即可。 Process: Take about 8000ml of hot water for injection, add L-carnitine and trimetazidine hydrochloride according to the dosage, stir to dissolve, add antioxidant, and adjust the pH to 6.0 with 10% hydrochloric acid, add appropriate amount of water for injection. Add 0.15% activated carbon to decolorize, filter to clear, potting in 100ml infusion bottle, fill with nitrogen, add stopper, cap, and sterilize at 10CTC for 30min.
实施例五： 注射用复方 （左卡尼汀 +盐酸曲美他嗪） 无菌冻干制剂 Example 5: Compound for injection (L-carnitine + trimetazidine hydrochloride) Sterile lyophilized preparation
处方： 左卡尼汀 3000g Prescription: L-carnitine 3000g
盐酸曲美他嗪 15g Trimetazidine Hydrochloride 15g
水解明胶 （填充剂） 5000ml Hydrolyzed gelatin (filler) 5000ml
甘露醇 （填充剂） 100g Mannitol (filler) 100g
葡萄糖酸钙 （填充剂） 10g Calcium gluconate (filler) 10g
半胱氨酸 （稳定剂） 0.50g Cysteine (stabilizer) 0.50g
工艺： 将上述各成分用适量注射用水溶解后， 无菌过滤， 安装于安瓿中， 冷冻干燥后封 口， 漏气检查即得。 Process: Dissolve each of the above ingredients in an appropriate amount of water for injection, aseptically filter, install in ampoules, freeze and seal, and check for leaks.
实施例六： 复方 （左卡尼汀 +盐酸曲美他嗪） 注射液 Example 6: Compound (L-carnitine + trimetazidine hydrochloride) injection
处方： 左卡尼汀 2000g Prescription: L-carnitine 2000g
盐酸曲美他嗪 10g Trimetazamine Hydrochloride 10g
盐酸 200g Hydrochloric acid 200g
注射用水 加至 10000ml Water for injection added to 10000ml
工艺： 取约 8000ml热注射用水， 按处方量投入左卡尼汀、盐酸曲美他嗪， 搅拌使全溶，
加抗氧剂， 并用 10%盐酸调 PH至 6.0左右， 加注射用水适量， 在加入 0.2%活性炭脱色， 过 滤至澄明， 灌封于 5ml安瓿瓶内， 充氮灌封， 湿热灭菌， 121 °C灭菌 30min即可。 Process: Take about 8000ml of hot water for injection, and add L-carnitine and trimetazidine hydrochloride according to the dosage. Stir to dissolve. Add antioxidant, and adjust the pH to 6.0 with 10% hydrochloric acid, add appropriate amount of water for injection, decolorize with 0.2% activated carbon, filter to clear, potting in 5ml ampoule, nitrogen filling and potting, moist heat sterilization, 121 ° C can be sterilized for 30 minutes.
实施例七： 复方注射液 Example 7: Compound injection
将实施例五中的左卡尼汀改为乙酰左卡尼汀或丙酰左卡尼汀， 其他处方和工艺与实施例五一 致。 The L-carnitine in Example 5 was changed to acetyl-L-carnitine or propionyl-L-carnitine, and the other prescriptions and techniques were the same as in Example 5.
实施例八： 复方注射液 Example 8: Compound injection
将实施例五中的左卡尼汀改为左卡尼汀与盐酸、溴氢酸、碘氢酸、硫酸、硝酸、磷酸、 乙酸、 马来酸、 富马酸、 枸缘酸、 柠檬酸、 草酸、 琥珀酸、 酒石酸、 苹果酸、 扁桃酸、 三氟乙酸、 泛酸、 甲磺酸和对甲苯磺酸分别形成的盐， 其他处方和工艺与实施例五一致。 The L-carnitine in Example 5 was changed to L-carnitine with hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, maleic acid, fumaric acid, abietic acid, citric acid, The salts formed by oxalic acid, succinic acid, tartaric acid, malic acid, mandelic acid, trifluoroacetic acid, pantothenic acid, methanesulfonic acid and p-toluenesulfonic acid, respectively, are in accordance with the fifth embodiment.
实施例九： 复方注射液 Example 9: Compound injection
将实施例五中的盐酸曲美他嗪改为曲美他嗪与溴氢酸、 碘氢酸、 硫酸、 硝酸、 磷酸、 乙酸、 马来酸、 富马酸、 枸缘酸、 柠檬酸、 草酸、 琥珀酸、 酒石酸、 苹果酸、 扁桃酸、 三氟乙酸、 泛酸、 甲磺酸和对甲苯磺酸分别形成的盐， 其他处方和工艺与实施例五一致。 The trimetazidine hydrochloride in the fifth embodiment is changed to trimetazidine with hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, maleic acid, fumaric acid, citric acid, citric acid, oxalic acid The salts formed by succinic acid, tartaric acid, malic acid, mandelic acid, trifluoroacetic acid, pantothenic acid, methanesulfonic acid and p-toluenesulfonic acid, respectively, are the same as in the fifth embodiment.
实施例十： 左卡尼汀制剂、 盐酸曲美他嗪制剂的组合包装 Example 10: Combination packaging of L-carnitine preparation and trimetazidine hydrochloride preparation
分别制备或购买左卡尼汀制剂和盐酸曲美他嗪制剂， 如表 7所示。 The L-carnitine formulation and the trimetazidine hydrochloride formulation were prepared or purchased separately, as shown in Table 7.
表 7 不同规格的左卡尼汀制剂和盐酸曲美他嗪制剂 Table 7 Different specifications of L-carnitine preparation and trimetazidine hydrochloride preparation
得上述 2种制剂进行组合， 每种组合制剂的数量可以按照临床需要进行确定
The above two preparations are combined, and the amount of each combination preparation can be determined according to clinical needs.
Claims
1、 一种治疗重症高原病的药物组合物， 其特征在于该药物组合物包括活性成分 左卡尼汀或其衍生物或其可药用盐， 活性成分曲美他嗪或其可药用盐和可药用 辅料，其中左卡尼汀或其衍生物或其可药用盐与曲美他嗪或其可药用盐的重量比 为 200: 1。 A pharmaceutical composition for treating severe high altitude disease, characterized in that the pharmaceutical composition comprises the active ingredient L-carnitine or a derivative thereof or a pharmaceutically acceptable salt thereof, and the active ingredient trimetazidine or a pharmaceutically acceptable salt thereof And a pharmaceutically acceptable adjuvant, wherein the weight ratio of L-carnitine or a derivative thereof or a pharmaceutically acceptable salt thereof to trimetazidine or a pharmaceutically acceptable salt thereof is 200:1.
2、 权利要求 1所述的药物组合物， 其特征在于其中所述的左卡尼汀或其衍生物 或其可药用盐选自左卡尼汀、 乙酰左卡尼汀、 丙酰左卡尼汀及其可药用盐。 The pharmaceutical composition according to claim 1, wherein the L-carnitine or a derivative thereof or a pharmaceutically acceptable salt thereof is selected from the group consisting of L-carnitine, Acetyl L-carnitine, Propionyl Zuka Nitin and its pharmaceutically acceptable salts.
3、 权利要求 1所述的药物组合物， 其特征在于其中所述的曲美他嗪和左卡尼汀 或其衍生物的可药用的盐包括它们与盐酸、溴氢酸、碘氢酸、硫酸、硝酸、磷酸、 乙酸、 马来酸、 富马酸、 枸缘酸、 柠檬酸、 草酸、 琥珀酸、 酒石酸、 苹果酸、 扁 桃酸、 三氟乙酸、 泛酸、 甲磺酸、 对甲苯磺酸形成的盐。 3. The pharmaceutical composition according to claim 1, wherein said pharmaceutically acceptable salts of trimetazidine and L-carnitine or derivatives thereof include hydrochloric acid, hydrobromic acid, and hydroiodic acid. , sulfuric acid, nitric acid, phosphoric acid, acetic acid, maleic acid, fumaric acid, sulphuric acid, citric acid, oxalic acid, succinic acid, tartaric acid, malic acid, mandelic acid, trifluoroacetic acid, pantothenic acid, methanesulfonic acid, p-toluene a salt formed by an acid.
4、 权利要求 1-3任一权利要求所述的药物组合物， 其特征在于其中所述的药物 组合物是口服剂和注射剂。 The pharmaceutical composition according to any one of claims 1 to 3, wherein the pharmaceutical composition is an oral preparation and an injection.
5、 权利要求 4所述的药物组合物， 其特征在于其中所述的注射剂是注射液或冻 干粉针剂。 The pharmaceutical composition according to claim 4, wherein the injection is an injection or a freeze-dried powder.
6、 权利要求 5所述的药物组合物， 其特征在于其中所述的注射剂是组合包装注 射剂。 The pharmaceutical composition according to claim 5, wherein the injection is a combination package injection.
7、 左卡尼汀或其衍生物或其可药用盐和曲美他嗪或其可药用盐在制备治疗重症 高原病的药物中的用途，其特征在于： 左卡尼汀或其衍生物或其可药用盐与曲美 他嗪或其可药用盐的重量比为 200: 1。 7. Use of L-carnitine or a derivative thereof or a pharmaceutically acceptable salt thereof and trimetazidine or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of severe high altitude disease, characterized in that: L-carnitine or its derivative The weight ratio of the substance or a pharmaceutically acceptable salt thereof to trimetazidine or a pharmaceutically acceptable salt thereof is 200:1.
8、 权利要求 7所述的用途， 其特征在于其中所述的左卡尼汀或其衍生物或其可 药用盐选自左卡尼汀、 乙酰左卡尼汀、 丙酰左卡尼汀及其可药用盐。 The use according to claim 7, wherein the L-carnitine or a derivative thereof or a pharmaceutically acceptable salt thereof is selected from the group consisting of L-carnitine, acetyl-L-carnitine, and propionyl L-carnitine And pharmaceutically acceptable salts thereof.
9、 权利要求 7所述的用途， 其特征在于所述的曲美他嗪和左卡尼汀或其衍生物 的可药用的盐包括它们与盐酸、 溴氢酸、 碘氢酸、 硫酸、 硝酸、 磷酸、 乙酸、 马 来酸、 富马酸、 枸缘酸、 柠檬酸、 草酸、 琥珀酸、 酒石酸、 苹果酸、 扁桃酸、 三 氟乙酸、 泛酸、 甲磺酸和对甲苯磺酸形成的盐。 9. The use according to claim 7, characterized in that the pharmaceutically acceptable salts of trimetazidine and L-carnitine or derivatives thereof include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, Nitric acid, phosphoric acid, acetic acid, maleic acid, fumaric acid, sulphuric acid, citric acid, oxalic acid, succinic acid, tartaric acid, malic acid, mandelic acid, trifluoroacetic acid, pantothenic acid, methanesulfonic acid and p-toluenesulfonic acid salt.
10、权利要求 6-9任一权利要求所述的用途， 其特征在于其中所述的药物是注射 液或冻干粉针剂。 10. Use according to any of claims 6-9, characterized in that the medicament is an injection or a lyophilized powder injection.
11、 权利要求 10所述的用途， 其特征在于所述的药物是组合包装注射剂。 11. Use according to claim 10, characterized in that the medicament is a combined package injection.
12、权利要求 7所述的用途， 其特征在于成人给药的日剂量为： 左卡尼汀或其衍 生物或其可药用盐 10-500mg/kg， 曲美他嗪或其可药用盐 0.1-3mg/kg。
The use according to claim 7, characterized in that the daily dose for administration to an adult is: L-carnitine or a derivative thereof or a pharmaceutically acceptable salt thereof, 10-500 mg/kg, trimetazidine or a pharmaceutically acceptable drug thereof Salt 0.1-3mg/kg.
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| USD903097S1 (en) | 2018-05-18 | 2020-11-24 | Trudell Medical International | Mask |
| US11439869B2 (en) | 2017-05-19 | 2022-09-13 | Trudell Medical International | Positive expiratory pressure device |
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| CN110105307B (en) * | 2019-05-14 | 2021-06-01 | 中南民族大学 | Trimetazidine oxalate and preparation method and application thereof |
| CN110054599B (en) * | 2019-05-14 | 2021-05-07 | 中南民族大学 | Trimetazidine oxalate and preparation method and application thereof |
| CN113491687A (en) * | 2020-04-02 | 2021-10-12 | 常州高新技术产业开发区三维工业技术研究所有限公司 | Detoxifying medicine composition and application thereof |
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