WO2022183480A1 - Pharmaceutical composition containing ginkgolide-type compound and cannabidiol and application thereof in medicine - Google Patents

Pharmaceutical composition containing ginkgolide-type compound and cannabidiol and application thereof in medicine Download PDF

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WO2022183480A1
WO2022183480A1 PCT/CN2021/079279 CN2021079279W WO2022183480A1 WO 2022183480 A1 WO2022183480 A1 WO 2022183480A1 CN 2021079279 W CN2021079279 W CN 2021079279W WO 2022183480 A1 WO2022183480 A1 WO 2022183480A1
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ginkgolide
cannabidiol
pharmaceutical composition
acid
pharmaceutically acceptable
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PCT/CN2021/079279
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French (fr)
Chinese (zh)
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孙毅
楚洪柱
苏桂转
王美微
许学珍
张靖
魏用刚
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成都百裕制药股份有限公司
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Priority to PCT/CN2021/079279 priority Critical patent/WO2022183480A1/en
Priority to CN202180076840.4A priority patent/CN116437911A/en
Publication of WO2022183480A1 publication Critical patent/WO2022183480A1/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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants

Definitions

  • the invention relates to a pharmaceutical composition containing a ginkgolide compound and cannabidiol, and its use in preparing medicines.
  • Ginkgo biloba is an important traditional Chinese medicine in my country.
  • the use of ginkgo biloba as medicine began in the Ming Dynasty.
  • the medical value of ginkgo has attracted widespread attention at home and abroad.
  • Scholars at home and abroad have conducted extensive research on the chemistry, pharmacology and preparation of ginkgo biloba.
  • a range of drugs have been developed.
  • Imported Ginkgo biloba extract for injection, the trade name is Ginado, mainly used for various brain and peripheral blood circulation disorders, mainly for acute and chronic cerebral insufficiency and its sequelae, ear blood flow and nerve disorders, eye blood flow and nerve disorders, peripheral circulatory disorders, etc.
  • Ginkgolide is a terpenoid lactone extract made from Ginkgo biloba leaves. Ginkgolide is also the main active ingredient of Ginkgo biloba, including Ginkgolide A, Ginkgolide B, Ginkgolide C, Ginkgolide D, Ginkgolide J, Ginkgolide M, Ginkgolide K, Ginkgolide L, ginkgolide N, ginkgolide P, ginkgolide Q, bilobalide, etc.
  • ginkgolide is a specific and potent inhibitor of platelet activating factor (PAF) receptor, which can selectively antagonize platelet aggregation induced by PAF, and can effectively prevent platelet aggregation and thrombus formation.
  • PAF platelet activating factor
  • the main effect of ginkgolide on the central nervous system is that it can reduce cerebral vascular resistance, increase cerebral blood flow, and promote cerebral blood circulation; it can prevent the damage caused by cerebral ischemia, significantly improve the state of cerebral ischemia, and significantly inhibit the cerebral ischemia caused by ischemia. Edema, electrolyte imbalance, inflammatory cell infiltration.
  • the main effect of ginkgolide on the blood circulation system is that it can inhibit platelet aggregation, reduce blood viscosity, improve microcirculation in patients with ischemia, and reduce thrombosis.
  • Cannabis (Cannabis sativa L.) is an annual herb of the Moraceae Cannabis genus, originating in Central and East Asia and widely distributed in the United States, India, Brazil and other places. Cannabis has a long history of medicinal use, but its addictive and hallucinogenic effects limit its clinical application. Cannabis contains hundreds of different chemicals, and about 70 components are called cannabinoids, mainly including cannabidiol (CBD), cannabidiol (CBN), and tetrahydrocannabinol (THC). and its homologues, among which cannabidiol (CBD) has the highest content.
  • CBD cannabidiol
  • CBD cannabidiol
  • THC tetrahydrocannabinol
  • CBD has a wide range of pharmacological activities, and in recent years, cannabinoid-related drugs have been developed one after another, such as; GW Pharmaceuticals' cannabinoid oral mucosal spray (Sative) for the treatment of multiple sclerosis spasticity, another cannabinoid oral solution (Epidiolex) ) for the treatment of childhood-onset epilepsy.
  • cannabinoid-related drugs have been developed one after another, such as; GW Pharmaceuticals' cannabinoid oral mucosal spray (Sative) for the treatment of multiple sclerosis spasticity, another cannabinoid oral solution (Epidiolex) ) for the treatment of childhood-onset epilepsy.
  • the present invention provides a pharmaceutical composition of ginkgolide and cannabidiol, and its use in preparing medicine.
  • the present invention relates to a pharmaceutical composition, which is characterized in that the pharmaceutical composition comprises the following components: (1) ginkgolide, (2) cannabidiol, wherein the ginkgolide is ginkgolide A, Ginkgolide B, Ginkgolide C, Ginkgolide D, Ginkgolide J, Ginkgolide M, Ginkgolide K, Ginkgolide L, Ginkgolide N, Ginkgolide P, Ginkgolide Q, One or any two or more combinations of bilobalide in any proportion; the ginkgolide or cannabidiol includes its stereoisomers, hydrates, metabolites, solvates, and pharmaceutically acceptable salts or eutectic.
  • the ginkgolide or cannabidiol includes its stereoisomers, hydrates, metabolites, solvates, and pharmaceutically acceptable salts or eutectic.
  • An embodiment of the present invention is characterized in that the pharmaceutical composition involved comprises (1) ginkgolide, (2) cannabidiol, wherein the ginkgolide is ginkgolide A and ginkgolide B , ginkgolide C, ginkgolide J, bilobalide one or any two or more combinations in any proportion; described ginkgolide or cannabidiol includes its stereoisomers, hydrates, metabolites Product, solvate, pharmaceutically acceptable salt or co-crystal.
  • the related pharmaceutical composition is characterized in that the ginkgolide or its stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt or co-crystal is in The mass percentage in the pharmaceutical composition is 0.1-99%, preferably 10-30%.
  • the related pharmaceutical composition is characterized in that the cannabidiol or its stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt or co-crystal is in
  • the mass percentage in the pharmaceutical composition is 0.1-99%, preferably 70-90%.
  • One embodiment of the present invention relates to a pharmaceutical composition, characterized in that the ginkgolide or its stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt or co-crystal
  • the content is 1mg-1500mg.
  • One embodiment of the present invention relates to a pharmaceutical composition, characterized in that the ginkgolide or its stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt or co-crystal
  • the content is 1mg-1500mg.
  • the related pharmaceutical composition is characterized in that the cannabidiol and ginkgolide are administered separately, sequentially or simultaneously with each other; Ginkgolide 1-100mg/kg; further preferably, the dosages are: cannabidiol 1-200mg/kg, ginkgolide 1-50mg/kg; the drug administration objects include humans and animals.
  • an embodiment of the present invention is characterized in that, the pharmaceutical composition is used in the preparation of drugs for post-traumatic stress disorder, anxiety, autism, generalized anxiety disorder, social anxiety disorder, and depression. use.
  • One or more embodiments of the present application provide the pharmaceutical compositions of the present application for use as a medicament.
  • One or more embodiments of the present application provide a pharmaceutical composition of the present application for use in a method of treating/suppressing post-traumatic stress disorder, anxiety, autism, generalized anxiety disorder, social anxiety disorder, depression.
  • One or more embodiments of the present application provide methods of treating/suppressing post-traumatic stress disorder, anxiety, autism, generalized anxiety disorder, social anxiety disorder, depression, comprising administering a composition of the present application to a patient having The object required for this.
  • “Pharmaceutically acceptable salt” or “a pharmaceutically acceptable salt thereof” means that a compound of the present invention retains the biological effectiveness and properties of a free acid or free base that is treated with a non-toxic inorganic base or Organic bases, said free bases are salts obtained by reacting with non-toxic inorganic or organic acids.
  • Co-crystal refers to a crystal formed by the combination of an active pharmaceutical ingredient and a co-crystal former under the action of hydrogen bonds or other non-covalent bonds, wherein the pure state of API and CCF are solid at room temperature, and each component There is a fixed stoichiometric ratio between them.
  • a co-crystal is a multi-component crystal that includes both binary co-crystals formed between two neutral solids and multi-component co-crystals formed between neutral solids and/or solvates.
  • Non-limiting examples of such "co-crystal formers” include alanine, valine, leucine, isoleucine, proline, phenylalanine, tryptophan, methionine, glycine, serine, Threonine, cysteine, tyrosine, asparagine, glutamine, lysine, arginine, histidine, aspartic acid, aspartic acid, glutamic acid, pyroglutamine Acid, sulfuric acid, phosphoric acid, nitric acid, hydrobromic acid, acid, formic acid, acetic acid, propionic acid, benzenesulfonic acid, benzoic acid, phenylacetic acid, salicylic acid, alginic acid, anthranilic acid, camphoric acid, citric acid, vinylsulfonic acid acid, formic acid, fumaric acid, furoic acid, gluconic acid, glucuronic acid, glutamic acid, glycolic acid, isethionic
  • Steps refer to isomers resulting from different arrangements of atoms in a molecule in space, including cis-trans isomers, enantiomers and conformational isomers.
  • FIG. 1 is the percentage of freezing time calculated from the recorded data in the fear memory test of Example 3.
  • FIG. 1 is the percentage of freezing time calculated from the recorded data in the fear memory test of Example 3.
  • the rats were randomly divided into 3 large groups, and each large group was randomly divided into 3 experimental groups and 1 blank group, with 6 rats in each group, all experimental groups were subjected to a single prolonged stress (single prolonged stress, SPS). Three large groups of rats were used to conduct the experiments of the three examples.
  • SPS-induced post-traumatic stress disorder in rats The limbs of the rats were tied with surgical tape, their head movements were restricted, and they were fixed on a metal plate for 2 h, followed by forced swimming for 20 min, followed by a 15-min rest period, and then exposed to ether vapor until they were Anesthetized and unresponsive. All rats were kept in rearing cages, 2 per cage, and were kept in undisturbed state for 14 days, during which the drug was administered continuously every day.
  • the single-administration group was intraperitoneally injected with cannabidiol (200 mg/kg), the combined medication group was intraperitoneally injected with ginkgolide (50 mg/kg) and cannabidiol (200 mg/kg) successively, and the blank group was intraperitoneally injected with normal saline.
  • the rats were placed in the middle grid of the open field box, and then their hands were quickly withdrawn and kept away from the open field box to avoid disturbing the animals.
  • Video recording was started, and the following parameters were recorded within 5 minutes: the number of crossings, the number of standing times, and the total movement distance.
  • the rats were taken out, the rat feces and urine in the open field box were cleaned up, and the inside of the open field box was wiped with a rag dipped in 70% alcohol to avoid leaving odors that would affect the behavior of the next rat.
  • the elevated plus maze consists of two opposite open arms (30cm ⁇ 5cm) and two opposite closed arms (30cm ⁇ 5cm) and a central area (5cm ⁇ 5cm), 50cm from the ground. Place the rat in the central area and make it face an open arm. After releasing, start video recording and observe and record the activity data of the rat within 5 minutes: the number of open arm entry, the time of open arm entry, the number of closed arm entry, and the time of closed arm entry. After 5 minutes, the rats were taken out, the rat feces and urine in the maze were cleaned, and the maze was wiped with a rag dipped in 70% alcohol to avoid leaving odors that would affect the behavior of the next rat. This data was deleted if the rat fell during the experiment.
  • total arm entry times open arm entry times + closed arm entry times
  • ratio of open arm entry times (%) open arm entry times/(open arm entry times + closed arm entry times) ⁇ 100 %
  • open arm entry time ratio (%) open arm entry time/(open arm entry time+closed arm entry time) ⁇ 100%.
  • the rats were placed in the observation box to adapt for 5 minutes, and then a prompt tone (30s, 5kHz, 75dB) was given, and then electric shocks (2s, 2mA) were randomly applied to the bottom of the observation box for 10 times within 5 minutes.
  • a prompt tone (30s, 5kHz, 75dB) was given, and then electric shocks (2s, 2mA) were randomly applied to the bottom of the observation box for 10 times within 5 minutes.
  • the rats were placed in the same observation box, and the above-mentioned prompt tone before the application of electric shock was given, but no electric shock was applied, and the rat's rigidity response within 5 minutes was recorded and recorded (except for breathing, without any other movement) time. Likewise, after the experiment, clean the observation box.
  • Percent freeze time (freeze time/total time) x 100% was calculated from the recorded data.
  • the percentage of freezing time can reflect the strength of fear memory in rats.
  • the experimental data confirmed that the freezing response caused by SPS stimulation was similar to that of post-traumatic stress disorder. It can be inferred that SPS stimulation caused a similar fear response to trauma.
  • the ginkgolide and cannabidiol composition of the present invention is more effective in reducing the fear memory behavior related to post-traumatic stress disorder.

Abstract

A pharmaceutical composition containing a ginkgolide-type compound and cannabidiol and an application thereof in medicine.

Description

含有银杏内酯类化合物和大麻二酚的药物组合物及其在医药上的应用Pharmaceutical composition containing ginkgolide and cannabidiol and its application in medicine 技术领域technical field
本发明涉及一种含有银杏内酯类化合物和大麻二酚的药物组合物，以及其在制备药物的用途。The invention relates to a pharmaceutical composition containing a ginkgolide compound and cannabidiol, and its use in preparing medicines.
背景技术Background technique
银杏是我国重要的中药，银杏叶入药始于明代，银杏的医用价值已引起国内外的广泛关注，国内外学者对银杏叶的化学、药理、制剂等进行了广泛的研究，并在此基础上开发了一系列药物。进口注射用银杏叶提取物，商品名为金纳多，主要用于各种脑部、周边等血液循环障碍，主治急慢性脑机能不全及其后遗症、耳部血流及神经障碍、眼部血流及神经障碍、末梢循环障碍等。国产金阁莱(银杏叶提取物注射液)，主要用于活血化瘀，通经活络，用于瘀血阻络所致的缺血性中风病中经络等。银杏内酯为银杏叶经提取加工制成的萜类内酯提取物。银杏内酯也是银杏叶的主要有效成分，包括银杏内酯A、银杏内酯B、银杏内酯C、银杏内酯D、银杏内酯J、银杏内酯M、银杏内酯K、银杏内酯L、银杏内酯N、银杏内酯P、银杏内酯Q、白果内酯等。药理和临床研究表明，银杏内酯是血小板活化因子(PAF)受体特异高效的强抑制剂，可以选择性的拮抗由PAF诱导的血小板聚集，可有效的防止血小板聚集和血栓的形成。银杏内酯对中枢神经系统作用主要表现为能降低脑血管阻力，增加脑血流量，促进脑血循环；能阻止脑缺血后引起的损伤，明显改善脑缺血状态，显著抑制缺血引起的脑水肿、电解质紊乱、炎性细胞浸润。银杏内酯对血液循环系统的作用主要表现为可以抑制血小板聚集，降低血液粘度，改善缺血病人的微循环，减少血栓形成。Ginkgo biloba is an important traditional Chinese medicine in my country. The use of ginkgo biloba as medicine began in the Ming Dynasty. The medical value of ginkgo has attracted widespread attention at home and abroad. Scholars at home and abroad have conducted extensive research on the chemistry, pharmacology and preparation of ginkgo biloba. A range of drugs have been developed. Imported Ginkgo biloba extract for injection, the trade name is Ginado, mainly used for various brain and peripheral blood circulation disorders, mainly for acute and chronic cerebral insufficiency and its sequelae, ear blood flow and nerve disorders, eye blood flow and nerve disorders, peripheral circulatory disorders, etc. Domestic Jin Ge Lai (Ginkgo biloba extract injection) is mainly used for promoting blood circulation and removing blood stasis, clearing meridians and collaterals, and for ischemic stroke caused by blood stasis and blocking collaterals. Ginkgolide is a terpenoid lactone extract made from Ginkgo biloba leaves. Ginkgolide is also the main active ingredient of Ginkgo biloba, including Ginkgolide A, Ginkgolide B, Ginkgolide C, Ginkgolide D, Ginkgolide J, Ginkgolide M, Ginkgolide K, Ginkgolide L, ginkgolide N, ginkgolide P, ginkgolide Q, bilobalide, etc. Pharmacological and clinical studies have shown that ginkgolide is a specific and potent inhibitor of platelet activating factor (PAF) receptor, which can selectively antagonize platelet aggregation induced by PAF, and can effectively prevent platelet aggregation and thrombus formation. The main effect of ginkgolide on the central nervous system is that it can reduce cerebral vascular resistance, increase cerebral blood flow, and promote cerebral blood circulation; it can prevent the damage caused by cerebral ischemia, significantly improve the state of cerebral ischemia, and significantly inhibit the cerebral ischemia caused by ischemia. Edema, electrolyte imbalance, inflammatory cell infiltration. The main effect of ginkgolide on the blood circulation system is that it can inhibit platelet aggregation, reduce blood viscosity, improve microcirculation in patients with ischemia, and reduce thrombosis.
大麻(Cannabis sativa L.)为桑科大麻属一年生草本植物，起源于中亚和东亚，广泛分布于美国、印度、巴西等地。大麻的药用历史悠久，但成瘾性和精神致幻作用，使其临床应用受到极大限制。大麻含有数百种不同的化学物质，大约有70多种成分被称为大麻素，主要包括大麻二酚(cannabidiol，CBD)、大麻酚(cannabinol，CBN)、四氢大麻酚(Tetrahydrocannabinol，THC)及其同系物等，其中大麻二酚(CBD)含量最高。CBD具有广泛的药理活性，近年来，大麻素相关药品被陆续开发，例如；GW Pharmaceuticals的大麻素口腔黏膜喷雾剂(Sative)，用于治疗多发性硬化症痉挛，另一个大麻素口服溶液(Epidiolex)用于治疗儿童发作性癫痫。Cannabis (Cannabis sativa L.) is an annual herb of the Moraceae Cannabis genus, originating in Central and East Asia and widely distributed in the United States, India, Brazil and other places. Cannabis has a long history of medicinal use, but its addictive and hallucinogenic effects limit its clinical application. Cannabis contains hundreds of different chemicals, and about 70 components are called cannabinoids, mainly including cannabidiol (CBD), cannabidiol (CBN), and tetrahydrocannabinol (THC). and its homologues, among which cannabidiol (CBD) has the highest content. CBD has a wide range of pharmacological activities, and in recent years, cannabinoid-related drugs have been developed one after another, such as; GW Pharmaceuticals' cannabinoid oral mucosal spray (Sative) for the treatment of multiple sclerosis spasticity, another cannabinoid oral solution (Epidiolex) ) for the treatment of childhood-onset epilepsy.
目前，人们对银杏内酯和大麻二酚都是采用其各自的药效，将银杏内酯与大麻二酚制备成组合物的技术尚未见报道。At present, people use their respective medicinal effects for ginkgolide and cannabidiol, and the technology for preparing a composition from ginkgolide and cannabidiol has not yet been reported.
发明内容SUMMARY OF THE INVENTION
为了满足临床需要，本发明提供一种银杏内酯与大麻二酚的药物组合物，以及其在制 备药物的用途。In order to meet clinical needs, the present invention provides a pharmaceutical composition of ginkgolide and cannabidiol, and its use in preparing medicine.
本发明涉及一种药物组合物，其特征在于，所述的药物组合物包含以下成分：(1)银杏内酯,(2)大麻二酚，其中，所述银杏内酯为银杏内酯A、银杏内酯B、银杏内酯C、银杏内酯D、银杏内酯J、银杏内酯M、银杏内酯K、银杏内酯L、银杏内酯N、银杏内酯P、银杏内酯Q、白果内酯的一种或任意两种及以上以任意比例的组合；所述的银杏内酯或大麻二酚包括其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐或者共晶。The present invention relates to a pharmaceutical composition, which is characterized in that the pharmaceutical composition comprises the following components: (1) ginkgolide, (2) cannabidiol, wherein the ginkgolide is ginkgolide A, Ginkgolide B, Ginkgolide C, Ginkgolide D, Ginkgolide J, Ginkgolide M, Ginkgolide K, Ginkgolide L, Ginkgolide N, Ginkgolide P, Ginkgolide Q, One or any two or more combinations of bilobalide in any proportion; the ginkgolide or cannabidiol includes its stereoisomers, hydrates, metabolites, solvates, and pharmaceutically acceptable salts or eutectic.
本发明的一个实施方案，其特征在于，所涉及的药物组合物包括(1)银杏内酯,(2)大麻二酚，其中，所述的银杏内酯为银杏内酯A、银杏内酯B、银杏内酯C、银杏内酯J、白果内酯的一种或任意两种及以上以任意比例的组合；所述的银杏内酯或大麻二酚包括其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐或者共晶。An embodiment of the present invention is characterized in that the pharmaceutical composition involved comprises (1) ginkgolide, (2) cannabidiol, wherein the ginkgolide is ginkgolide A and ginkgolide B , ginkgolide C, ginkgolide J, bilobalide one or any two or more combinations in any proportion; described ginkgolide or cannabidiol includes its stereoisomers, hydrates, metabolites Product, solvate, pharmaceutically acceptable salt or co-crystal.
本发明的一个实施方案，所涉及的药物组合物，其特征在于，所述的银杏内酯或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐或者共晶在所述药物组合物中的质量百分比为0.1-99％，优选10-30％。One embodiment of the present invention, the related pharmaceutical composition, is characterized in that the ginkgolide or its stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt or co-crystal is in The mass percentage in the pharmaceutical composition is 0.1-99%, preferably 10-30%.
本发明的一个实施方案，所涉及的药物组合物，其特征在于，所述的大麻二酚或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐或者共晶在所述药物组合物中的质量百分比为0.1-99％，优选70-90％。One embodiment of the present invention, the related pharmaceutical composition, is characterized in that the cannabidiol or its stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt or co-crystal is in The mass percentage in the pharmaceutical composition is 0.1-99%, preferably 70-90%.
本发明的一个实施方案，所涉及的药物组合物，其特征在于，其中所述的银杏内酯或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐或者共晶含量为1mg-1500mg。One embodiment of the present invention relates to a pharmaceutical composition, characterized in that the ginkgolide or its stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt or co-crystal The content is 1mg-1500mg.
本发明的一个实施方案，所涉及的药物组合物，其特征在于，其中所述的银杏内酯或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐或者共晶含量为1mg-1500mg。One embodiment of the present invention relates to a pharmaceutical composition, characterized in that the ginkgolide or its stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt or co-crystal The content is 1mg-1500mg.
本发明的一个实施方案，所涉及的药物组合物，其特征在于，其中大麻二酚和银杏内酯彼此分别、顺序或同时给药；给药剂量分别为：大麻二酚1-300mg/kg，银杏内酯1-100mg/kg；进一步优选，给药剂量分别为：大麻二酚1-200mg/kg，银杏内酯1-50mg/kg；药物给与对象包括人及动物。According to an embodiment of the present invention, the related pharmaceutical composition is characterized in that the cannabidiol and ginkgolide are administered separately, sequentially or simultaneously with each other; Ginkgolide 1-100mg/kg; further preferably, the dosages are: cannabidiol 1-200mg/kg, ginkgolide 1-50mg/kg; the drug administration objects include humans and animals.
本发明的一个实施方案，所涉及的药物组合物，其特征在于，所述的药物组合物在制备创伤后应激障碍、焦虑、自闭症、广泛性焦虑症、社交焦虑症、抑郁药物的用途。An embodiment of the present invention, the related pharmaceutical composition, is characterized in that, the pharmaceutical composition is used in the preparation of drugs for post-traumatic stress disorder, anxiety, autism, generalized anxiety disorder, social anxiety disorder, and depression. use.
本申请的一个或多个实施方式提供了本申请的药物组合物，其用作药物。One or more embodiments of the present application provide the pharmaceutical compositions of the present application for use as a medicament.
本申请的一个或多个实施方式提供了本申请的药物组合物，其用于治疗/抑制创伤后应激障碍、焦虑、自闭症、广泛性焦虑症、社交焦虑症、抑郁的方法。One or more embodiments of the present application provide a pharmaceutical composition of the present application for use in a method of treating/suppressing post-traumatic stress disorder, anxiety, autism, generalized anxiety disorder, social anxiety disorder, depression.
本申请的一个或多个实施方式提供了治疗/抑制创伤后应激障碍、焦虑、自闭症、广泛性焦虑症、社交焦虑症、抑郁的方法，其包括将本申请的组合物施用于有此需要的对象。One or more embodiments of the present application provide methods of treating/suppressing post-traumatic stress disorder, anxiety, autism, generalized anxiety disorder, social anxiety disorder, depression, comprising administering a composition of the present application to a patient having The object required for this.
发明详述Detailed description of the invention
除非有相反的陈述，在说明书和权利要求书中使用的术语具有下述含义。Unless stated to the contrary, terms used in the specification and claims have the following meanings.
“药学上可接受的盐”或者“其药学上可接受的盐”是指本发明化合物保持游离酸或者游离碱的生物有效性和特性，且所述的游离酸通过与无毒的无机碱或者有机碱，所述的游离碱通过与无毒的无机酸或者有机酸反应获得的盐。"Pharmaceutically acceptable salt" or "a pharmaceutically acceptable salt thereof" means that a compound of the present invention retains the biological effectiveness and properties of a free acid or free base that is treated with a non-toxic inorganic base or Organic bases, said free bases are salts obtained by reacting with non-toxic inorganic or organic acids.
“共晶”是指活性药物成分和共晶形成物在氢键或其他非共价键的作用下结合而成的晶体，其中API和CCF的纯态在室温下均为固体，并且各组分间存在固定的化学计量比。共晶是一种多组分晶体，既包含两种中性固体之间形成的二元共晶，也包含中性固体与或溶剂化物形成的多元共晶。所述“共晶形成物”的非限定性实例包括丙氨酸、缬氨酸、亮氨酸、异亮氨酸、脯氨酸、苯丙氨酸、色氨酸、蛋氨酸、甘氨酸、丝氨酸、苏氨酸、半胱氨酸、酪氨酸、天冬酰胺、谷氨酰胺、赖氨酸、精氨酸、组氨酸、天冬氨酸、门冬氨酸、谷氨酸、焦谷氨酸、硫酸、磷酸、硝酸、氢溴酸、酸、甲酸、乙酸、丙酸、苯磺酸、苯甲酸、苯乙酸、水杨酸、褐藻酸、氨茴酸、樟脑酸、柠檬酸、乙烯磺酸、蚁酸、富马酸、糠酸、葡萄糖酸、葡萄糖醛酸、谷氨酸、乙醇酸、羟乙磺酸、乳酸、马来酸、苹果酸、扁桃酸、粘液酸、双羟萘酸、泛酸、硬脂酸、琥珀酸、磺胺酸、酒石酸、对甲苯磺酸、丙二酸、2-羟基丙酸、草酸、羟乙酸、葡萄糖醛酸、半乳糖醛酸、枸橼酸、肉桂酸、对甲苯磺酸、甲磺酸、乙磺酸或三氟甲磺酸、氨、异丙基胺、三甲基胺、二乙胺、三乙胺、三丙基胺、二乙醇胺、乙醇胺、二甲基乙醇胺、2-二甲基氨基乙醇、2-二乙基氨基乙醇、二环己基胺、咖啡碱、普鲁卡因、胆碱、甜菜碱、苯明青霉素、乙二胺、葡萄糖胺、甲基葡糖胺、可可碱、三乙醇胺、氨丁三醇、嘌呤、哌嗪、哌啶和N-乙基哌啶。"Co-crystal" refers to a crystal formed by the combination of an active pharmaceutical ingredient and a co-crystal former under the action of hydrogen bonds or other non-covalent bonds, wherein the pure state of API and CCF are solid at room temperature, and each component There is a fixed stoichiometric ratio between them. A co-crystal is a multi-component crystal that includes both binary co-crystals formed between two neutral solids and multi-component co-crystals formed between neutral solids and/or solvates. Non-limiting examples of such "co-crystal formers" include alanine, valine, leucine, isoleucine, proline, phenylalanine, tryptophan, methionine, glycine, serine, Threonine, cysteine, tyrosine, asparagine, glutamine, lysine, arginine, histidine, aspartic acid, aspartic acid, glutamic acid, pyroglutamine Acid, sulfuric acid, phosphoric acid, nitric acid, hydrobromic acid, acid, formic acid, acetic acid, propionic acid, benzenesulfonic acid, benzoic acid, phenylacetic acid, salicylic acid, alginic acid, anthranilic acid, camphoric acid, citric acid, vinylsulfonic acid acid, formic acid, fumaric acid, furoic acid, gluconic acid, glucuronic acid, glutamic acid, glycolic acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, mucus acid, pamoic acid , pantothenic acid, stearic acid, succinic acid, sulfanilic acid, tartaric acid, p-toluenesulfonic acid, malonic acid, 2-hydroxypropionic acid, oxalic acid, glycolic acid, glucuronic acid, galacturonic acid, citric acid, cinnamic acid , p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid or trifluoromethanesulfonic acid, ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, Dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, caffeine, procaine, choline, betaine, benzyl penicillin, ethylenediamine, glucosamine, Methylglucamine, theobromine, triethanolamine, tromethamine, purine, piperazine, piperidine, and N-ethylpiperidine.
“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体，包括顺反异构体、对映异构体和构象异构体。"Stereoisomers" refer to isomers resulting from different arrangements of atoms in a molecule in space, including cis-trans isomers, enantiomers and conformational isomers.
附图说明Description of drawings
图1为在实施例3恐惧记忆测试中由记录数据计算的僵直时间百分比。FIG. 1 is the percentage of freezing time calculated from the recorded data in the fear memory test of Example 3. FIG.
具体实施方式Detailed ways
本发明说明书对具体实施方案进行了详细描述，本领域技术人员应认识到，上述实施方案是示例性的，不能理解为对本发明的限制，对于本领域技术人员来说，在不脱离本发明原理的前提下，通过对本发明进行若干改进和修饰，这些改进和修饰获得技术方案也落在本发明的权利要求书的保护范围内。以下通过实施例具体说明本发明的有益效果。The specification of the present invention describes the specific embodiments in detail. Those skilled in the art should realize that the above-mentioned embodiments are exemplary and should not be construed as limiting the present invention. For those skilled in the art, without departing from the principles of the present invention Under the premise, by carrying out several improvements and modifications to the present invention, the technical solutions obtained by these improvements and modifications also fall within the protection scope of the claims of the present invention. The beneficial effects of the present invention will be specifically described below through examples.
银杏内酯和大麻二酚药物组合物对创伤后应激障碍的作用Effects of a pharmaceutical composition of ginkgolide and cannabidiol on post-traumatic stress disorder
1实验材料1 Experimental material
1.1实验动物1.1 Experimental animals
6周龄健康雄性Wistar大鼠72只(由中国科学院上海实验动物中心提供)，体重为180～210g。72 6-week-old healthy male Wistar rats (provided by Shanghai Experimental Animal Center, Chinese Academy of Sciences), weighing 180-210 g.
1.2实验试剂1.2 Experimental reagents
银杏内酯注射液(成都百裕制药股份有限公司市售的银杏内酯注射剂，其中，银杏内酯A：B：C＝20：30：10，银杏内酯A、B、C总量与白果内酯的重量比为52：48，银杏总内酯含量为5mg/ml)；Ginkgolide injection (a commercially available ginkgolide injection by Chengdu Baiyu Pharmaceutical Co., Ltd., wherein, ginkgolide A:B:C=20:30:10, the total amount of ginkgolide A, B, C and ginkgo The weight ratio of lactone is 52:48, and the total lactone content of ginkgo is 5mg/ml);
大麻二酚(购于Ryss Lab,Inc.，HPLC检测纯度为99.26％，溶于乙醇：聚氧乙烯蓖麻油：生理盐水＝1：1：18的混合溶液，制备成20.0mg/ml大麻二酚溶液)。Cannabidiol (purchased from Ryss Lab, Inc., 99.26% purity by HPLC, soluble in ethanol: polyoxyethylene castor oil: physiological saline = 1: 1: 18 mixed solution, prepared as 20.0 mg/ml cannabidiol solution).
2实验方法2 Experimental methods
将大鼠随机分为3个大组，每个大组又随机分为3个试验组和1个空白组，每组6只大鼠，所有试验组进行单次延长应激(single prolonged stress,SPS)。3个大组的大鼠分别用于进行3个实施例的实验。The rats were randomly divided into 3 large groups, and each large group was randomly divided into 3 experimental groups and 1 blank group, with 6 rats in each group, all experimental groups were subjected to a single prolonged stress (single prolonged stress, SPS). Three large groups of rats were used to conduct the experiments of the three examples.
SPS诱发大鼠创伤后应激障碍：用手术胶带绑住大鼠四肢，限制其头部活动，固定在金属板上2h，紧接着强迫游泳20min，随后休养15min，接着暴露于乙醚蒸气中直到被麻醉并失去反应。将所有大鼠关在饲养笼内，每笼2只，在不受干扰的状态下圈养14天，期间连续每天给药。单一给药组腹腔注射大麻二酚(200mg/kg)，组合用药组先后腹腔注射银杏内酯(50mg/kg)和大麻二酚(200mg/kg)，空白组腹腔注射生理盐水。SPS-induced post-traumatic stress disorder in rats: The limbs of the rats were tied with surgical tape, their head movements were restricted, and they were fixed on a metal plate for 2 h, followed by forced swimming for 20 min, followed by a 15-min rest period, and then exposed to ether vapor until they were Anesthetized and unresponsive. All rats were kept in rearing cages, 2 per cage, and were kept in undisturbed state for 14 days, during which the drug was administered continuously every day. The single-administration group was intraperitoneally injected with cannabidiol (200 mg/kg), the combined medication group was intraperitoneally injected with ginkgolide (50 mg/kg) and cannabidiol (200 mg/kg) successively, and the blank group was intraperitoneally injected with normal saline.
实施例1：旷场实验Example 1: Open Field Experiment
将大鼠置于旷场箱正中格，随后迅速将手撤出并远离旷场箱以免对动物造成干扰，开始录像，记录5min内以下参数：跨格次数、站立次数、运动总距离。每次测试结束后取出大鼠，清理旷场箱内大鼠粪便和尿液，并用蘸有70％酒精抹布擦拭旷场箱内部，避免留下气味对下一只大鼠的行为测试造成影响。The rats were placed in the middle grid of the open field box, and then their hands were quickly withdrawn and kept away from the open field box to avoid disturbing the animals. Video recording was started, and the following parameters were recorded within 5 minutes: the number of crossings, the number of standing times, and the total movement distance. After each test, the rats were taken out, the rat feces and urine in the open field box were cleaned up, and the inside of the open field box was wiped with a rag dipped in 70% alcohol to avoid leaving odors that would affect the behavior of the next rat.
Figure PCTCN2021079279-appb-000001
Figure PCTCN2021079279-appb-000001
实验结果：给予大鼠银杏内酯和大麻二酚组合物后，大鼠跨格次数、站立次数、运动总距离明显提高，表明本发明组合物可以改善大鼠的焦虑状态。Experimental results: after the rat ginkgolide and cannabidiol composition was administered, the rat's crossing times, standing times, and total exercise distance were significantly increased, indicating that the composition of the present invention can improve the rat's anxiety state.
实施例2：高架十字迷宫实验Example 2: Elevated Plus Maze Experiment
高架十字迷宫由两条相对开放臂(30cm×5cm)和两条相对闭合臂(30cm×5cm)及中央区(5cm×5cm)组成，距离地面50cm。将大鼠置于中央区并使其面向一条开放臂，释放 后开始录像并观察记录5min内大鼠的活动数据：开放臂进入次数、开放臂进入时间、闭合臂进入次数、闭合臂进入时间。5min后取出大鼠，清理迷宫内大鼠粪便和尿液，并用蘸有70％酒精抹布擦拭迷宫，避免留下气味对下一只大鼠的行为测试造成影响。如果在实验过程中大鼠跌落，则删除该数据。The elevated plus maze consists of two opposite open arms (30cm×5cm) and two opposite closed arms (30cm×5cm) and a central area (5cm×5cm), 50cm from the ground. Place the rat in the central area and make it face an open arm. After releasing, start video recording and observe and record the activity data of the rat within 5 minutes: the number of open arm entry, the time of open arm entry, the number of closed arm entry, and the time of closed arm entry. After 5 minutes, the rats were taken out, the rat feces and urine in the maze were cleaned, and the maze was wiped with a rag dipped in 70% alcohol to avoid leaving odors that would affect the behavior of the next rat. This data was deleted if the rat fell during the experiment.
由记录的活动数据计算出：进臂总次数＝开放臂进入次数+闭合臂进入次数；开放臂进入次数比(％)＝开放臂进入次数/(开放臂进入次数+闭合臂进入次数)×100％；开放臂进入时间比(％)＝开放臂进入时间/(开放臂进入时间+闭合臂进入时间)×100％。Calculated from the recorded activity data: total arm entry times = open arm entry times + closed arm entry times; ratio of open arm entry times (%) = open arm entry times/(open arm entry times + closed arm entry times) × 100 %; open arm entry time ratio (%)=open arm entry time/(open arm entry time+closed arm entry time)×100%.
Figure PCTCN2021079279-appb-000002
Figure PCTCN2021079279-appb-000002
实验结果：相比于空白组，SPS刺激导致大鼠趋向于逃离到闭合臂中，且在开放臂停留时间短暂，反映出对外界的探索欲望、好奇心理减弱，且焦虑反应、警觉度增强，与创伤后应激障碍表现相似，而给予大鼠银杏内酯和大麻二酚组合物后可以明显改善创伤后应激障碍的症状。Experimental results: Compared with the blank group, the SPS stimulation caused the rats to tend to escape into the closed arm, and stayed in the open arm for a short time, reflecting the weakened desire to explore the outside world, the weakened curiosity, and the enhanced anxiety response and alertness. Similar to post-traumatic stress disorder, administration of a combination of ginkgolide and cannabidiol to rats can significantly improve the symptoms of post-traumatic stress disorder.
实施例3：恐惧记忆测试Example 3: Fear Memory Test
第1天将大鼠置于观察箱中适应5min，随后给予一声提示音(30s,5kHz,75dB)，接着5min内在观察箱底板上随机施加电击(2s,2mA)10次。结束后，清理观察箱内大鼠粪便和尿液，并用蘸有70％酒精抹布擦拭观察箱，避免留下气味对下一只大鼠的行为测试造成影响。第2天将大鼠置于相同的观察箱中，并给予上述施加电击前的提示音，但不施加电击，录像并观察记录大鼠5min内的僵直反应(除呼吸外，无任何其他运动)时间。同样地，实验结束后，清理观察箱。On the 1st day, the rats were placed in the observation box to adapt for 5 minutes, and then a prompt tone (30s, 5kHz, 75dB) was given, and then electric shocks (2s, 2mA) were randomly applied to the bottom of the observation box for 10 times within 5 minutes. After the end, clean the rat feces and urine in the observation box, and wipe the observation box with a rag dipped in 70% alcohol, so as to avoid leaving the smell and affecting the behavior test of the next rat. On the second day, the rats were placed in the same observation box, and the above-mentioned prompt tone before the application of electric shock was given, but no electric shock was applied, and the rat's rigidity response within 5 minutes was recorded and recorded (except for breathing, without any other movement) time. Likewise, after the experiment, clean the observation box.
由记录的数据计算出僵直时间百分比＝(僵直时间/总时间)×100％。Percent freeze time = (freeze time/total time) x 100% was calculated from the recorded data.
实验结果在表1中表示。The experimental results are shown in Table 1.
实验结果：僵直时间百分比可以反映大鼠恐惧记忆强弱情况，实验数据证实，SPS刺激引起的僵直反应与创伤后应激障碍相似，可以推断SPS刺激导致类似创伤的恐惧反应。与空白组和大麻二酚组相比，本发明的银杏内酯和大麻二酚组合物更有效减轻了与创伤后应激障碍相关的恐惧记忆行为。Experimental results: The percentage of freezing time can reflect the strength of fear memory in rats. The experimental data confirmed that the freezing response caused by SPS stimulation was similar to that of post-traumatic stress disorder. It can be inferred that SPS stimulation caused a similar fear response to trauma. Compared with the blank group and the cannabidiol group, the ginkgolide and cannabidiol composition of the present invention is more effective in reducing the fear memory behavior related to post-traumatic stress disorder.

Claims (5)

  1. 一种药物组合物，其特征在于，包括(1)银杏内酯,(2)大麻二酚，其中，所述银杏内酯为银杏内酯A、银杏内酯B、银杏内酯C、银杏内酯D、银杏内酯J、银杏内酯M、银杏内酯K、银杏内酯L、银杏内酯N、银杏内酯P、银杏内酯Q、白果内酯的一种或任意两种及以上以任意比例的组合；所述的银杏内酯或大麻二酚包括其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐或者共晶。A pharmaceutical composition, comprising (1) ginkgolide and (2) cannabidiol, wherein the ginkgolide is ginkgolide A, ginkgolide B, ginkgolide C, ginkgolide One or any two or more of ginkgolide D, ginkgolide J, ginkgolide M, ginkgolide K, ginkgolide L, ginkgolide N, ginkgolide P, ginkgolide Q, and ginkgolide Combination in any ratio; the ginkgolide or cannabidiol includes its stereoisomers, hydrates, metabolites, solvates, pharmaceutically acceptable salts or co-crystals.
  2. 根据权利要求1所述的药物组合物，其特征在于，包括(1)银杏内酯,(2)大麻二酚，其中，所述的银杏内酯为银杏内酯A、银杏内酯B、银杏内酯C、银杏内酯J、白果内酯的一种或任意两种及以上以任意比例的组合；所述的银杏内酯或大麻二酚包括其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐或者共晶。The pharmaceutical composition according to claim 1, characterized in that, comprising (1) ginkgolide, (2) cannabidiol, wherein the ginkgolide is ginkgolide A, ginkgolide B, ginkgolide Lactone C, ginkgolide J, bilobalide one or any two or more combinations in any ratio; described ginkgolide or cannabidiol includes its stereoisomer, hydrate, metabolite, Solvates, pharmaceutically acceptable salts or co-crystals.
  3. 根据权利要求1、2任一项所述的药物组合物，其特征在于，所述的银杏内酯或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐或者共晶在所述药物组合物中的质量百分比为10-30％；所述的大麻二酚或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐或者共晶在所述药物组合物中的质量百分比为70-90％。The pharmaceutical composition according to any one of claims 1 and 2, wherein the ginkgolide or its stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt or co- The mass percentage of the cannabidiol in the pharmaceutical composition is 10-30%; the cannabidiol or its stereoisomers, hydrates, metabolites, solvates, pharmaceutically acceptable salts or co-crystals are in the The mass percentage in the pharmaceutical composition is 70-90%.
  4. 如权利要求1-3任一项所述的药物组合物，其特征在于，其中大麻二酚和银杏内酯彼此分别、顺序或同时给药，给药剂量分别为：大麻二酚1-300mg/kg，银杏内酯1-100mg/kg。The pharmaceutical composition according to any one of claims 1-3, wherein the cannabidiol and ginkgolide are administered separately, sequentially or simultaneously, and the dosages are: 1-300 mg of cannabidiol/ kg, ginkgolide 1-100mg/kg.
  5. 如权利要求1-4任一项所述的药物组合物，所述的药物组合物在制备创伤后应激障碍、焦虑、自闭症、广泛性焦虑症、社交焦虑症、抑郁药物的用途。The pharmaceutical composition according to any one of claims 1-4, wherein the pharmaceutical composition is used in the preparation of drugs for post-traumatic stress disorder, anxiety, autism, generalized anxiety disorder, social anxiety disorder, and depression.
PCT/CN2021/079279 2021-03-05 2021-03-05 Pharmaceutical composition containing ginkgolide-type compound and cannabidiol and application thereof in medicine WO2022183480A1 (en)

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