WO2021232836A1 - Cannabinoid compounds and application thereof in treatment of parkinson's disease - Google Patents

Cannabinoid compounds and application thereof in treatment of parkinson's disease Download PDF

Info

Publication number
WO2021232836A1
WO2021232836A1 PCT/CN2021/072758 CN2021072758W WO2021232836A1 WO 2021232836 A1 WO2021232836 A1 WO 2021232836A1 CN 2021072758 W CN2021072758 W CN 2021072758W WO 2021232836 A1 WO2021232836 A1 WO 2021232836A1
Authority
WO
WIPO (PCT)
Prior art keywords
thcv
cbdv
cbg
cbd
full
Prior art date
Application number
PCT/CN2021/072758
Other languages
French (fr)
Chinese (zh)
Inventor
谭昕
王曙宾
金倩
Original Assignee
汉义生物科技（北京）有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 汉义生物科技（北京）有限公司 filed Critical 汉义生物科技（北京）有限公司
Publication of WO2021232836A1 publication Critical patent/WO2021232836A1/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—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
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/60—Moraceae (Mulberry family), e.g. breadfruit or fig
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
    • A61K2236/30—Extraction of the material
    • A61K2236/33—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones
    • A61K2236/333—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones using mixed solvents, e.g. 70% EtOH
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
    • A61K2236/30—Extraction of the material
    • A61K2236/39—Complex extraction schemes, e.g. fractionation or repeated extraction steps
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
    • A61K2236/50—Methods involving additional extraction steps
    • A61K2236/51—Concentration or drying of the extract, e.g. Lyophilisation, freeze-drying or spray-drying
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
    • A61K2236/50—Methods involving additional extraction steps
    • A61K2236/53—Liquid-solid separation, e.g. centrifugation, sedimentation or crystallization
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
    • A61K2236/50—Methods involving additional extraction steps
    • A61K2236/55—Liquid-liquid separation; Phase separation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines

Definitions

  • the invention relates to the field of biomedicine, in particular to the application of a cannabis full-spectrum oil in the treatment of Parkinson's.
  • Parkinson's disease is a degenerative disorder of the central nervous system and is the second most common neurodegenerative disease after Alzheimer's disease.
  • PD is usually classified as a movement disorder. Its main characteristics are rest tremor, stiffness, bradykinesia, and postural instability. Among them, rest tremor is the most common and usually the earliest symptom, and dementia usually occurs in the late stages of the disease. .
  • the motor symptoms of PD originate from the death of dopamine-producing cells in the substantia nigra (a region of the midbrain), and the cause of this cell death is unknown. Although dopamine can effectively treat the motor symptoms in the early stage of the disease, the effectiveness of dopamine is lost in the late stage of the disease, and its long-term use can cause motor complications.
  • Cannabis belongs to the Cannabis family and the genus Cannabis, and has important agricultural and medicinal values.
  • Cannabinoids are a class of chemical substances that are known to activate cannabinoid receptors in cells. Pharmacological studies have shown that the main active ingredients in cannabis are cannabinoids.
  • Phytocannabinoids are cannabinoids extracted from the cannabis plant and can also be artificially synthesized. At least 85 different cannabinoids can be isolated from the cannabis plant, and their structure differs depending on where the precursor cannabinoids (CBG) are cyclized.
  • CBD cannabinoids
  • the main cannabinoid compounds in cannabis plants are tetrahydrocannabinol (THC), cannabidiol (CBN), cannabidiol (CBD), cannabidiol (CBDV), tetrahydrocannabinol (THCV), and cannabidiol Phenols (CBG), among which the first three account for more than 90% of cannabinoid compounds.
  • CBDV is a non-addictive component in marijuana, which can hinder the effect of THC, the main addictive substance in marijuana, on the human nervous system, and has pharmacological activities in the treatment of epilepsy, neuropathic pain, arthritis, influenza and other pharmacological activities. Therefore, it should be recognized that although cannabis compounds are produced in different strains of the cannabis plant, it cannot be assumed that they all have the same characteristics. It is precisely because of this that research on the many extracts in cannabis is always going on, and new breakthroughs are constantly being made.
  • European patent EP2726069 discloses cannabinoids for the prevention or treatment of neurodegenerative diseases or diseases, wherein, preferably, the cannabinoid is cannabinene (CBC), cannabidiol (CBDV) and/or cannabinoid acid (CBDVA), the neurodegenerative disease or disorder to be prevented or treated is Alzheimer's disease.
  • CBC cannabinene
  • CBDV cannabidiol
  • CBDVA cannabinoid acid
  • cannabinoids an extract of cannabis plants, are more effective than purified compounds in preventing neurodegeneration, especially cannabinoid extracts tetrahydrocannabinoid (THC) or cannabinoid (CBD).
  • THC tetrahydrocannabinoid
  • CBD cannabinoid
  • the present invention provides an application of cannabinoid compounds in the treatment of Parkinson's.
  • the cannabinoid compounds include cannabidiol (CBDV) and cannabidiol (CBG). ), cannabidiol (CBD) and tetrahydrocannabinol (THCV), does not contain the addictive substance tetrahydrocannabinol (THC), has no toxic side effects, and can safely and effectively treat Parkinson’s disease, especially paraben Kinsen disease exercise complications.
  • the cannabinoid compound of the present invention contains CBDV, CBG, CBD and THCV, but does not contain THC.
  • the mass ratio of CBDV, CBG, CBD and THCV in the cannabinoid compound is 9-12:1-5:60-65:1-2.
  • the mass ratio of CBDV, CBG, CBD and THCV in the cannabinoid compound is 10-11:1-3:62-65:1.5-2.
  • the present invention provides a pharmaceutical composition for treating Parkinson's, the pharmaceutical composition contains CBDV, CBG, CBD and THCV without THC.
  • the mass ratio of CBDV, CBG, CBD and THCV in the pharmaceutical composition is 9-12:1-5:60-65:1-2.
  • the mass ratio of CBDV, CBG, CBD and THCV in the pharmaceutical composition is 10-11:1-3:62-65:1.5-2.
  • the pharmaceutical composition of the present invention can be made into specific dosage forms.
  • These dosage forms include tablets, sugar-coated tablets, film-coated tablets, enteric-coated tablets, capsules, hard capsules, soft capsules, oral liquids, oral liquids, etc.
  • the pharmaceutical excipient may be an inert diluent or filler (for example, sucrose, microcrystalline cellulose, starch, calcium carbonate, sodium chloride, calcium phosphate, Calcium sulfate or sodium phosphate); disintegrants, including starch/starch derivatives, croscarmellose sodium, alginate, alginic acid, polyvinylpyrrolidone or sodium starch glycolate; suitable lubricants, such as hard Magnesium fatty acid; binders (e.g.
  • gum arabic alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, sodium carboxymethyl cellulose, methyl cellulose, hypromellose Cellulose, ethyl cellulose, polyvinylpyrrolidone or polyethylene glycol); and lubricants, glidants, and anti-sticking agents (such as stearic acid, silicate, or talc).
  • Other pharmaceutical excipients such as coloring agents, flavoring agents, plasticizers, humectants, buffers, and humectants, may also be included.
  • the tablets can be coated.
  • the coating may be adapted to release the active drug substance in a predetermined pattern (for example, to achieve a controlled release formulation) or it may be adapted to not release the active drug substance until after passing through the stomach (enteric coating).
  • the coating can be sugar coating, film coating (e.g.
  • enteric coatings such as cellulose acetate phthalate, hypromellose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, insect Gum and/or ethyl cellulose.
  • the preparation for oral use can also be used as a chewable tablet or as a hard gelatin capsule in which the active ingredient is mixed with an inert solid diluent (such as potato starch, microcrystalline cellulose, calcium carbonate, calcium phosphate or kaolin), or as a hard gelatin capsule in which the active ingredient is mixed.
  • an inert solid diluent such as potato starch, microcrystalline cellulose, calcium carbonate, calcium phosphate or kaolin
  • the ingredients are presented in soft gelatin capsules in which the ingredients are mixed with a water-live oil medium, such as liquid paraffin or olive oil.
  • the preparation for oral use can also be a liquid for oral administration, which is suitable for powders, dispersible powders or granules for preparing aqueous suspensions by adding water.
  • the pharmaceutical composition of the present invention is formed by mixing various active ingredients of the present invention with a pharmaceutically acceptable carrier, and then can be conveniently administered in various dosage forms suitable for the disclosed administration route. Administration can be once to multiple times a day, for several days to several years, or it can even last the patient's life.
  • the carrier includes an inert solid diluent or filler, a sterile aqueous solution and various organic solvents.
  • Pharmaceutical preparations can be conveniently made into unit dosage forms according to standard procedures for pharmaceutical formulations. Each unit dose contains a therapeutically effective amount of active compound.
  • the therapeutically effective amount of the drug in the combination of the present invention includes an amount effective for reducing the symptoms of Parkinson's disease, stopping or slowing down the progression of the disease (once it is clinically obvious), or preventing or reducing the risk of developing the disease, specifically It may vary depending on the nature of the active compound and the expected dosage regimen. Generally, it is in the range of 0.1 mg to 5000 mg per unit dose. It should be pointed out that the dosage and method of use of the active ingredient depend on many factors, including the general condition and age of the patient to be treated, the nature of the disease to be treated, the specific active ingredient or the selected active ingredient, and the subjective judgment of the physician.
  • CBDV cannabidiol
  • CBD cannabidiol
  • THCV tetrahydrocannabinol
  • CBDV cannabidiol
  • CBDV cannabidiol
  • CBD cannabidiol
  • CBD cannabidiol
  • THCV tetrahydrocannabinol
  • the pharmaceutical composition can be obtained; the CBDV, CBG, CBD, and THCV can also be present in the same product at the same time, for example, a plant extract containing the CBDV, CBG, CBD, and THCV at the same time, such as a full spectrum of industrial hemp oil .
  • the plant extraction part of the plant extract may be one or more of the stalk core, flower, leaf, seed and seed shell of industrial hemp, especially the flower and/or leaf.
  • the present invention also provides an application of a cannabis full spectrum oil in the preparation of a medicine for treating Parkinson's.
  • the cannabis full spectrum oil contains CBDV, CBG, CBD and THCV, and does not contain THC.
  • the mass ratio of CBDV, CBG, CBD and THCV in the cannabis full spectrum oil is 9-12:1-5:60-65:1-2.
  • the mass ratio of CBDV, CBG, CBD and THCV in the cannabis full spectrum oil is 10-11:1-3:62-65:1.5-2.
  • the THC-free mentioned in the present invention means that the THC content (mass percentage) in the cannabinoid compound or cannabis full-spectrum oil is less than 0.3%, preferably, less than 0.1%, more preferably, less than 0.01 %, especially preferred, THC is not detected according to conventional methods in the art.
  • the treatment of Parkinson's in the present invention refers to the treatment and prevention including the treatment, prevention, prevention, delay and reduction of the symptoms triggered by the etiology of Parkinson's syndrome, preferably Parkinson's disease or its symptoms.
  • the treatment subjects include but are not limited to (1) protection against toxicity caused by ⁇ -synuclein, or reduction or delay of the toxicity, and (2) protection against abnormal glutamate accumulation, oxidative stress, Protection of toxic dopaminergic neurons caused by mitochondrial dysfunction or neuroinflammation, or reduction or delay of said toxicity.
  • the present invention is suitable for the treatment of any mammalian subjects at any stage of the disease, especially Parkinson's syndrome in human subjects, especially for the treatment of bradykinesia or dyskinesia.
  • the present invention also provides a preparation method of the cannabis full-spectrum oil, the preparation method comprising the following steps:
  • the cannabinoid compounds, pharmaceutical compositions and cannabis full-spectrum oils provided by the present invention have significantly different (0.01 ⁇ P ⁇ 0.05) effects in treating Parkinson's, especially containing the preferred ratio of cannabidiol (CBDV),
  • CBDV cannabidiol
  • the composition of cannabidiol (CBG), cannabidiol (CBD) and tetrahydrocannabinol (THCV) is very significantly different than the effect when administered without THCV or when administered without the ratio of the present invention, which It has important application value in the preparation of drugs for treating Parkinson's, has no toxic side effects, and can be used for a long time.
  • compositions, step, method, product, or device containing the listed elements is not necessarily limited to those elements, but may include other elements not explicitly listed or inherent in such a composition, step, method, product, or device Elements.
  • the pharmaceutical excipient when the oral dosage form of the present invention is a tablet, may be an inert diluent or filler (for example, sucrose, microcrystalline cellulose, starch, including potato starch, calcium carbonate, Sodium chloride, calcium phosphate, calcium sulfate, or sodium phosphate); disintegrants, including starch/starch derivatives, croscarmellose sodium, alginate, alginic acid, polyvinylpyrrolidone or sodium starch glycolate ; Suitable lubricants, such as magnesium stearate; binders (such as gum arabic, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, sodium carboxymethyl cellulose, methyl Base cellulose, hypromellose, ethyl cellulose, polyvinylpyrrolidone or polyethylene glycol); and lubricants, glidants, and anti-adherents (such as stearic), stea
  • the tablets can be coated.
  • the coating may be adapted to release the active drug substance in a predetermined pattern (for example, to achieve a controlled release formulation) or it may be adapted to not release the active drug substance until after passing through the stomach (enteric coating).
  • the coating can be sugar coating, film coating (e.g.
  • hypromellose methylcellulose, methylhydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, acrylate copolymer, Polyethylene glycol and/or polyvinylpyrrolidone), or enteric coatings (such as cellulose acetate phthalate, hypromellose phthalate, hydroxypropyl methyl cellulose acetate succinate, polyvinyl acetate Phthalates, shellac and/or ethyl cellulose).
  • enteric coatings such as cellulose acetate phthalate, hypromellose phthalate, hydroxypropyl methyl cellulose acetate succinate, polyvinyl acetate Phthalates, shellac and/or ethyl cellulose.
  • the preparation for oral use can also be used as a chewable tablet or as a hard gelatin capsule in which the active ingredient is mixed with an inert solid diluent (such as potato starch, microcrystalline cellulose, calcium carbonate, calcium phosphate or kaolin), or as a hard gelatin capsule in which the active ingredient is mixed.
  • an inert solid diluent such as potato starch, microcrystalline cellulose, calcium carbonate, calcium phosphate or kaolin
  • the ingredients are presented in soft gelatin capsules in which the ingredients are mixed with a water-live oil medium, such as liquid paraffin or olive oil.
  • the preparation for oral use may also be a liquid for oral administration, which is suitable for preparing powders, dispersible powders or granules of aqueous suspensions by adding water.
  • Suitable suspending agents such as sodium carboxymethyl cellulose, methyl cellulose or/and sodium alginate, and the like.
  • the total cannabinoid content in the obtained full-spectrum oil reached 78.41%, of which CBDV 10.52%, CBG 1.57%, CBD 64.80%, THCV 1.52%, THC was not detected.
  • test drug Prepare the full spectrum oil according to the method of Example 1.
  • pure oil according to the mass ratios of CBDV, CBG, CBD and THCV of 9:1:60:1 and 12:5:65:2.
  • Cannabinoid compounds were mixed to prepare test groups numbered 1-3.
  • mass ratio of 10.5:1.5:65 take CBDV, CBG, and CBD to make the test group numbered as 4 groups; according to the mass ratio of 10.5:1.5:65:4 to take the combination of CBDV, CBG, CBD and THCV to make the number as 5 experimental groups.
  • Model preparation and behavioral determination 60 successful PD models were randomly divided into 6 groups.
  • the experimental groups of groups 1 to 5 were fed with the prepared 5 groups of test drugs, all administered at 8.5 mg/kg for 4 weeks; the 6th group was the PD control group, and the PD model rats were treated as follows: intraperitoneal injection of levorotatory Dopa methyl ester + benserazide (50mg/kg levodopa methyl ester and 25mg/kg benserazide, dissolved in 0.2% vitamin C sterilized saline), 2 times/day (10 am and 6 pm Point) for 4 weeks.
  • AIM evaluation AIM is divided into 4 components (upper limb AIM, orofacial AIM, axial AIM and rotation AIM) for evaluation, and each part is divided into 5 levels (0-4) according to its presence and severity, namely: 0 None; 1: duration is less than 30s; 2: duration is 30s to 60s; 3: if duration is greater than 60s, external stimuli can stop it; 4: duration is greater than 60s, external stimuli cannot stop it. Evaluation is performed every 20 minutes after medication, and observation is made for 1 minute each time. The total AIM scores are calculated according to the average of the total scores during the observation period. Theoretically, the maximum AIM score of each component after a single administration of a rat is 4 points, and the total AIM score is 16 points.
  • Orofacial AIM scores showed that the orofacial scores of the test groups in groups 1-3 were equivalent, and the difference in the mean between groups 1-3 and 4-6 was statistically significant (P ⁇ 0.05). Compared with group 4, the orofacial AIM score of the second group was lower, and the difference was statistically significant (P ⁇ 0.05); compared with the fifth group, the orofacial AIM score of the second group was lower, and the difference was statistically significant (P ⁇ 0.01).
  • the upper limb AIM score showed that the upper limb scores of the test groups in groups 1-3 were equivalent, and the difference in the mean between groups 1-3 and 4-6 was statistically significant (P ⁇ 0.01). Among them, the upper limb AIM scores of groups 1-3 were lower than those of groups 4-5, and the difference was statistically significant (P ⁇ 0.01).
  • the axial AIM scores showed that the axial scores of the test groups in groups 1-3 were equivalent, and the difference in the mean between groups 1-3 and 4-6 was statistically significant (P ⁇ 0.01).
  • the axial AIM value of the 1-3 group was lower than that of the PD group (group 6) until the 22nd and 29th days, the difference was statistically significant (P ⁇ 0.05), and the 1-3 group was compared with the 4-5 group The difference between the 22nd and 29th day was statistically significant (P ⁇ 0.01), and the axial AIM score was significantly reduced.
  • the rotating AIM score shows that the quality of CBDV, CBG, CBD, and THCV of Examples 2-4 of the present invention is comparable to the rotating scores of the 1-3 test groups prepared according to the present invention, and the comparison of the average values of the 1-3 groups and the 4-6 groups is different There is statistical significance (P ⁇ 0.01).
  • the Rotational AIM score value of the 1-3 group was lower than that of the PD group on the 22nd and 29th day, the difference was statistically significant (P ⁇ 0.01), and the 1-3 group was compared with the 4-5th group on the 22nd and 29th day The difference was statistically significant (P ⁇ 0.01), which significantly reduced the rotating AIM score.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Natural Medicines & Medicinal Plants (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Neurosurgery (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Alternative & Traditional Medicine (AREA)
  • Botany (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Psychology (AREA)
  • Biotechnology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medical Informatics (AREA)
  • Microbiology (AREA)
  • Mycology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines Containing Plant Substances (AREA)

Abstract

Disclosed in the present invention is application of a full-spectrum cannabis oil in the treatment of Parkinson's disease. The full-spectrum cannabis oil contains cannabidivarine (CBDV), cannabigerol (CBG), cannabidiol (CBD), and tetrahydrocannabivarin (THCV), and does not contain the addictive substance, tetrahydrocannabinol (THC). The full-spectrum cannabis oil has a significantly different (0.01<P<0.05) effect in treating Parkinson's disease, in particular, a composition containing CBDV, CBG, CBD, and THCV in a preferred ratio of the present invention has a significantly different effect better than those administered without THCV or administered in ratios different from that in the present invention, has a high application value in preparation of drugs for treating Parkinson's disease, has no toxic side effects, and allows a long term use.

Description

***素类化合物及其在治疗帕金森症中的应用Cannabinoid compounds and their application in the treatment of Parkinson's disease 技术领域Technical field
本发明涉及生物医药领域，具体是涉及一种***全谱系油在治疗帕金森中的应用。The invention relates to the field of biomedicine, in particular to the application of a cannabis full-spectrum oil in the treatment of Parkinson's.
背景技术Background technique
帕金森病(PD)是中枢神经***的变性障碍，是阿尔茨海默病之后的第二最常见神经退行性疾病。PD通常被归类为运动障碍，其主要特征是休息时震颤、僵硬、运动徐缓和姿势不稳，其中，休息性震颤是最常见且通常是最早发展的症状，通常在该疾病的晚期发生痴呆。PD的运动症状源自黑质(中脑的一个区域)中多巴胺产生细胞的死亡，该细胞死亡的原因不明。尽管多巴胺能够有效地治疗该疾病早期阶段的运动症状，但是，多巴胺的效力在该疾病的晚期阶段会发生损耗，并且它的长期使用会导致运动并发症。Parkinson's disease (PD) is a degenerative disorder of the central nervous system and is the second most common neurodegenerative disease after Alzheimer's disease. PD is usually classified as a movement disorder. Its main characteristics are rest tremor, stiffness, bradykinesia, and postural instability. Among them, rest tremor is the most common and usually the earliest symptom, and dementia usually occurs in the late stages of the disease. . The motor symptoms of PD originate from the death of dopamine-producing cells in the substantia nigra (a region of the midbrain), and the cause of this cell death is unknown. Although dopamine can effectively treat the motor symptoms in the early stage of the disease, the effectiveness of dopamine is lost in the late stage of the disease, and its long-term use can cause motor complications.
***隶属于***科、***属植物，具有重要的农用及药用价值。***素是一类已知的能激活细胞中***素受体的化学物质，药理研究表明，***中的主要活性成分为***素类化合物(cannabinoids)。植物***素是从***植物中提取的***素，也可以人工合成。从***植物中可分离出至少85种不同的***素，它们的结构因前体***素(CBG)在哪里发生环化而不同。***植株中主要的***素类化合物有四氢***酚(THC)、***酚(CBN)、***二酚(CBD)、次***二酚(CBDV)、四氢次***酚(THCV)、***萜酚(CBG)等，其中前三者占***素类化合物的90％以上。Cannabis belongs to the Cannabis family and the genus Cannabis, and has important agricultural and medicinal values. Cannabinoids are a class of chemical substances that are known to activate cannabinoid receptors in cells. Pharmacological studies have shown that the main active ingredients in cannabis are cannabinoids. Phytocannabinoids are cannabinoids extracted from the cannabis plant and can also be artificially synthesized. At least 85 different cannabinoids can be isolated from the cannabis plant, and their structure differs depending on where the precursor cannabinoids (CBG) are cyclized. The main cannabinoid compounds in cannabis plants are tetrahydrocannabinol (THC), cannabidiol (CBN), cannabidiol (CBD), cannabidiol (CBDV), tetrahydrocannabinol (THCV), and cannabidiol Phenols (CBG), among which the first three account for more than 90% of cannabinoid compounds.
众所周知，不同的***素具有不同的性质。例如，CBDV是***中的 非成瘾性成分，能阻碍***中主要的致人上瘾物质THC对人体神经***的影响，并具有治疗癫痫、神经性疼痛、关节炎、流感等药理活性。因此，应当认识到，虽然***类化合物都是在***植物的不同品系中生产的，但不能假定它们都具有相同的特性。正是因为这一点，针对***中的众多提取物的研究始终在进行，并且不断有新的突破。例如，欧洲专利EP2726069公开了用于预防或治疗神经退行性疾病或疾病的***素，其中，优选地，***素是***色烯(CBC)、次***二酚(CBDV)和/或***素酸(CBDVA)，要预防或治疗的神经退行性疾病或紊乱是阿尔茨海默病。英国专利GB2432312公开了***植物提取物***素在预防神经变性方面比纯化化合物更有效，特别***素的提取物四氢***素(THC)或***素(CBD)。然而，目前公开的一系列***素的药物应用中，THCV很少有报道，更少有报道将其用于治疗帕金森。As we all know, different cannabinoids have different properties. For example, CBDV is a non-addictive component in marijuana, which can hinder the effect of THC, the main addictive substance in marijuana, on the human nervous system, and has pharmacological activities in the treatment of epilepsy, neuropathic pain, arthritis, influenza and other pharmacological activities. Therefore, it should be recognized that although cannabis compounds are produced in different strains of the cannabis plant, it cannot be assumed that they all have the same characteristics. It is precisely because of this that research on the many extracts in cannabis is always going on, and new breakthroughs are constantly being made. For example, European patent EP2726069 discloses cannabinoids for the prevention or treatment of neurodegenerative diseases or diseases, wherein, preferably, the cannabinoid is cannabinene (CBC), cannabidiol (CBDV) and/or cannabinoid acid (CBDVA), the neurodegenerative disease or disorder to be prevented or treated is Alzheimer's disease. British Patent GB2432312 discloses that cannabinoids, an extract of cannabis plants, are more effective than purified compounds in preventing neurodegeneration, especially cannabinoid extracts tetrahydrocannabinoid (THC) or cannabinoid (CBD). However, there are few reports about THCV in the medical applications of a series of cannabinoids that have been disclosed, and there are even fewer reports about its use in the treatment of Parkinson's.
发明内容Summary of the invention
本发明针对上述背景技术中的研究的空白和不足，提供了一种***素类化合物治疗帕金森中的应用，所述***素类化合物中包含次***二酚(CBDV)、***萜酚(CBG)、***二酚(CBD)和四氢次***酚(THCV)，不含可致人上瘾的物质四氢***酚(THC)，无毒副作用，可安全有效的治疗帕金森病，尤其是帕金森病运动并发症。In view of the gaps and deficiencies in the above-mentioned background technology, the present invention provides an application of cannabinoid compounds in the treatment of Parkinson's. The cannabinoid compounds include cannabidiol (CBDV) and cannabidiol (CBG). ), cannabidiol (CBD) and tetrahydrocannabinol (THCV), does not contain the addictive substance tetrahydrocannabinol (THC), has no toxic side effects, and can safely and effectively treat Parkinson’s disease, especially paraben Kinsen disease exercise complications.
为达到本发明的目的，本发明所述***素类化合物中包含CBDV、CBG、CBD和THCV，不含THC。In order to achieve the purpose of the present invention, the cannabinoid compound of the present invention contains CBDV, CBG, CBD and THCV, but does not contain THC.
优选地，在本发明的一些实施例中，所述***素类化合物中CBDV、CBG、CBD和THCV的质量比为9～12：1～5：60～65：1～2。Preferably, in some embodiments of the present invention, the mass ratio of CBDV, CBG, CBD and THCV in the cannabinoid compound is 9-12:1-5:60-65:1-2.
更优选地，在本发明的一些实施例中，所述***素类化合物中CBDV、CBG、CBD和THCV的质量比为10-11：1-3：62-65：1.5-2。More preferably, in some embodiments of the present invention, the mass ratio of CBDV, CBG, CBD and THCV in the cannabinoid compound is 10-11:1-3:62-65:1.5-2.
另一方面，本发明提供了一种治疗帕金森的药物组合物，所述药物组 合物中包含CBDV、CBG、CBD和THCV，不含THC。In another aspect, the present invention provides a pharmaceutical composition for treating Parkinson's, the pharmaceutical composition contains CBDV, CBG, CBD and THCV without THC.
优选地，在本发明的具体示例中，所述药物组合物中CBDV、CBG、CBD和THCV的质量比为9～12：1～5：60～65：1～2。Preferably, in a specific example of the present invention, the mass ratio of CBDV, CBG, CBD and THCV in the pharmaceutical composition is 9-12:1-5:60-65:1-2.
更优选地，在本发明的一些实施例中，所述药物组合物中CBDV、CBG、CBD和THCV的质量比为10-11：1-3：62-65：1.5-2。More preferably, in some embodiments of the present invention, the mass ratio of CBDV, CBG, CBD and THCV in the pharmaceutical composition is 10-11:1-3:62-65:1.5-2.
本发明所述药物组合物可制成具体的剂型，这些剂型包括片剂、糖衣片剂、薄膜衣片剂、肠溶衣片剂、胶囊剂、硬胶囊剂、软胶囊剂、口服液、***剂、颗粒剂、冲剂、丸剂、散剂、膏剂、丹剂、混悬剂、粉剂、溶液剂、注射剂、栓剂、软膏剂、硬膏剂、霜剂、喷雾剂、滴剂和贴剂等，优选为口服剂型。The pharmaceutical composition of the present invention can be made into specific dosage forms. These dosage forms include tablets, sugar-coated tablets, film-coated tablets, enteric-coated tablets, capsules, hard capsules, soft capsules, oral liquids, oral liquids, etc. Supplements, granules, granules, pills, powders, ointments, pills, suspensions, powders, solutions, injections, suppositories, ointments, plasters, creams, sprays, drops and patches, etc., preferably It is an oral dosage form.
进一步优选地，当本发明所述的口服剂型为片剂时，药用赋形剂可以是惰性稀释剂或填料(例如蔗糖、微晶纤维素、淀粉、碳酸钙、氯化钠、磷酸钙、硫酸钙或磷酸钠)；崩解剂，包括淀粉/淀粉衍生物、交联羧甲基纤维素钠、海藻酸盐、藻酸、聚乙烯吡咯烷酮或羟基乙酸淀粉钠；适宜的润滑剂，例如硬脂酸镁；粘合剂(例如***树胶、褐藻酸、褐藻酸钠、明胶、淀粉、预凝胶化淀粉、微晶纤维素、羧甲基纤维素钠、甲基纤维素、羟丙甲纤维素、乙基纤维素、聚乙烯吡咯烷酮或聚乙二醇)；和润滑剂、助流剂，以及抗粘剂(例如硬脂酸、硅酸盐或滑石)。还可以包含其他药用赋形剂，例如着色剂、调味剂、增塑剂、保湿剂、缓冲剂和湿润剂等。Further preferably, when the oral dosage form of the present invention is a tablet, the pharmaceutical excipient may be an inert diluent or filler (for example, sucrose, microcrystalline cellulose, starch, calcium carbonate, sodium chloride, calcium phosphate, Calcium sulfate or sodium phosphate); disintegrants, including starch/starch derivatives, croscarmellose sodium, alginate, alginic acid, polyvinylpyrrolidone or sodium starch glycolate; suitable lubricants, such as hard Magnesium fatty acid; binders (e.g. gum arabic, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, sodium carboxymethyl cellulose, methyl cellulose, hypromellose Cellulose, ethyl cellulose, polyvinylpyrrolidone or polyethylene glycol); and lubricants, glidants, and anti-sticking agents (such as stearic acid, silicate, or talc). Other pharmaceutical excipients, such as coloring agents, flavoring agents, plasticizers, humectants, buffers, and humectants, may also be included.
必要时可对片剂进行包衣。包衣可以适于以预定模式释放活性药物物质(例如，为了实现受控释放制剂)或者它可以适于直到通过胃后才释放活性药物物质(肠溶衣)。包衣可以是糖包衣、薄膜包衣(例如甲基纤维素、甲基羟乙基纤维素、羟丙基纤维素、羧甲基纤维素、丙烯酸酯共聚物、聚乙二醇和/或聚乙烯吡咯烷酮)，或肠溶衣(例如邻苯二甲酸乙酸纤维素、邻苯二甲酸羟丙甲纤维素、琥珀酸乙酸羟丙基甲基纤维素、聚乙酸乙烯邻苯二甲酸酯、虫胶和/或乙基纤维素)。If necessary, the tablets can be coated. The coating may be adapted to release the active drug substance in a predetermined pattern (for example, to achieve a controlled release formulation) or it may be adapted to not release the active drug substance until after passing through the stomach (enteric coating). The coating can be sugar coating, film coating (e.g. methyl cellulose, methyl hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, acrylate copolymer, polyethylene glycol and/or poly Vinylpyrrolidone), or enteric coatings (such as cellulose acetate phthalate, hypromellose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, insect Gum and/or ethyl cellulose).
用于经口使用的制剂也可以作为咀嚼片或作为其中活性成分与惰性固体稀释剂(例如马铃薯淀粉、微晶纤维素、碳酸钙、磷酸钙或高岭土)混合的硬明胶胶囊，或作为其中活性成分与水活油介质，例如液体石蜡或橄榄油混合的软明胶胶囊呈现。The preparation for oral use can also be used as a chewable tablet or as a hard gelatin capsule in which the active ingredient is mixed with an inert solid diluent (such as potato starch, microcrystalline cellulose, calcium carbonate, calcium phosphate or kaolin), or as a hard gelatin capsule in which the active ingredient is mixed. The ingredients are presented in soft gelatin capsules in which the ingredients are mixed with a water-live oil medium, such as liquid paraffin or olive oil.
用于经口使用的制剂还可以经口施用的液体，适用于通过加入水制备含水混悬剂的粉剂、可分散粉剂或颗粒剂。The preparation for oral use can also be a liquid for oral administration, which is suitable for powders, dispersible powders or granules for preparing aqueous suspensions by adding water.
通过将多种本发明的活性成分与药物可接受的载体混合而形成本发明所述药物组合物，然后可以以适合公开给药途径的各种剂型方便地给予。施用可以是每天一次至多次，持续若干天至若干年，或者可以甚至持续患者一生。所述的载体包括惰性固体稀释剂或填充剂、无菌水溶液和各种有机溶剂。药物制剂可根据药物配方的标准程序方便地制成单位剂型。每单位剂量包含治疗有效量的活性化合物。The pharmaceutical composition of the present invention is formed by mixing various active ingredients of the present invention with a pharmaceutically acceptable carrier, and then can be conveniently administered in various dosage forms suitable for the disclosed administration route. Administration can be once to multiple times a day, for several days to several years, or it can even last the patient's life. The carrier includes an inert solid diluent or filler, a sterile aqueous solution and various organic solvents. Pharmaceutical preparations can be conveniently made into unit dosage forms according to standard procedures for pharmaceutical formulations. Each unit dose contains a therapeutically effective amount of active compound.
本发明组合中药物的治疗有效量包括对于减少帕金森病症状、终止或减慢疾病的进展(一旦其已是临床明显的)、或防止或减少形成该疾病的风险是有效的量，具体的可能会根据活性化合物的性质和预期的剂量方案而改变。一般来说，在每单位剂量0.1mg～5000mg的范围内。需要指出的是，活性成分的使用剂量和使用方法取决于诸多因素，包括待治疗患者的一般情况和年龄、待治疗疾病的性质和具体活性成分或所选择的活性成分以及诊治医师的主观判断。The therapeutically effective amount of the drug in the combination of the present invention includes an amount effective for reducing the symptoms of Parkinson's disease, stopping or slowing down the progression of the disease (once it is clinically obvious), or preventing or reducing the risk of developing the disease, specifically It may vary depending on the nature of the active compound and the expected dosage regimen. Generally, it is in the range of 0.1 mg to 5000 mg per unit dose. It should be pointed out that the dosage and method of use of the active ingredient depend on many factors, including the general condition and age of the patient to be treated, the nature of the disease to be treated, the specific active ingredient or the selected active ingredient, and the subjective judgment of the physician.
本发明中，所述次***二酚(CBDV)、***萜酚(CBG)、***二酚(CBD)和四氢次***酚(THCV)可以是化学合成产物、生物合成产物、植物提取物或采用其它方式制备得到。In the present invention, the cannabidiol (CBDV), cannabidiol (CBG), cannabidiol (CBD) and tetrahydrocannabinol (THCV) may be chemical synthesis products, biosynthesis products, plant extracts or Prepared by other methods.
进一步地，所述次***二酚(CBDV)、***萜酚(CBG)、***二酚(CBD)和四氢次***酚(THCV)可以分别为各组分的纯净物产品，将其混合即可得到所述药物组合物；所述CBDV、CBG、CBD和THCV也可以同时存在于同一种产品中，例如同时包含所述CBDV、CBG、CBD和THCV 的植物提取物，如工业***全谱系油。Further, the cannabidiol (CBDV), cannabidiol (CBG), cannabidiol (CBD) and tetrahydrocannabinol (THCV) can be the pure products of the respective components, which can be mixed. The pharmaceutical composition can be obtained; the CBDV, CBG, CBD, and THCV can also be present in the same product at the same time, for example, a plant extract containing the CBDV, CBG, CBD, and THCV at the same time, such as a full spectrum of industrial hemp oil .
优选的，所述植物提取物的植物提取部位可以为工业***的秆芯、花、叶、籽和籽的外壳中的一种或多种，特别是花和/或叶。Preferably, the plant extraction part of the plant extract may be one or more of the stalk core, flower, leaf, seed and seed shell of industrial hemp, especially the flower and/or leaf.
再一方面，本发明还提供了一种***全谱系油在制备治疗帕金森药物中的应用，所述***全谱系油中包含CBDV、CBG、CBD和THCV，不含THC。In another aspect, the present invention also provides an application of a cannabis full spectrum oil in the preparation of a medicine for treating Parkinson's. The cannabis full spectrum oil contains CBDV, CBG, CBD and THCV, and does not contain THC.
优选地，在本发明的具体示例中，所述***全谱系油中CBDV、CBG、CBD和THCV的质量比为9～12：1～5：60～65：1～2。Preferably, in a specific example of the present invention, the mass ratio of CBDV, CBG, CBD and THCV in the cannabis full spectrum oil is 9-12:1-5:60-65:1-2.
更优选地，所述***全谱系油中CBDV、CBG、CBD和THCV的质量比为10-11：1-3：62-65：1.5-2。More preferably, the mass ratio of CBDV, CBG, CBD and THCV in the cannabis full spectrum oil is 10-11:1-3:62-65:1.5-2.
本发明所述的不含THC是指所述的***素类化合物或***全谱系油中THC的含量(质量百分比)低于0.3％，优选的，低于0.1％，更优选的，低于0.01％，特别优选的，按照本领域常规方法未检出THC。The THC-free mentioned in the present invention means that the THC content (mass percentage) in the cannabinoid compound or cannabis full-spectrum oil is less than 0.3%, preferably, less than 0.1%, more preferably, less than 0.01 %, especially preferred, THC is not detected according to conventional methods in the art.
本发明中所述治疗帕金森指的是治疗和预防包括由帕金森综合征，优选帕金森病的病因触发的症状或其症状的治疗、防止、预防、延缓和减少。在治疗对象包括但不限于(1)针对由α-突触核蛋白引起的毒性的保护，或所述毒性的减少或延缓，和(2)针对由异常谷氨酸积累、氧化性应激、线粒体功能障碍或神经炎症所致的毒性的多巴胺能神经元的保护，或所述毒性的减少或延缓。The treatment of Parkinson's in the present invention refers to the treatment and prevention including the treatment, prevention, prevention, delay and reduction of the symptoms triggered by the etiology of Parkinson's syndrome, preferably Parkinson's disease or its symptoms. The treatment subjects include but are not limited to (1) protection against toxicity caused by α-synuclein, or reduction or delay of the toxicity, and (2) protection against abnormal glutamate accumulation, oxidative stress, Protection of toxic dopaminergic neurons caused by mitochondrial dysfunction or neuroinflammation, or reduction or delay of said toxicity.
本发明适用于治疗处于疾病的任何阶段的任何哺乳动物对象，特别是人对象中的帕金森综合征，尤其是用于治疗运动徐缓或运动不能。The present invention is suitable for the treatment of any mammalian subjects at any stage of the disease, especially Parkinson's syndrome in human subjects, especially for the treatment of bradykinesia or dyskinesia.
又一方面，本发明还提供了一种所述***全谱系油的制备方法，所述制备方法包括以下步骤：In another aspect, the present invention also provides a preparation method of the cannabis full-spectrum oil, the preparation method comprising the following steps:
(1)取工业***花叶药材进行粉碎，过筛，90～110℃烘烤150～250min，取一定量烘烤后的***花叶药材，按料液比1:6～12(w/v)加入65～75％的乙醇，搅拌提取，离心过滤，滤液减压浓缩至无醇味，补加纯化水至溶液 重量为药材重量的6～10倍，搅拌均匀，即得上样液；(1) Take industrial hemp mosaic medicinal materials, sieving, and baking at 90～110℃ for 150～250min, take a certain amount of hemp mosaic medicinal materials after baking, according to the material-to-liquid ratio 1:6～12(w/v ) Add 65-75% ethanol, stir extraction, centrifugal filtration, and concentrate the filtrate under reduced pressure until there is no alcohol, add purified water until the weight of the solution is 6-10 times the weight of the medicinal material, and stir evenly to obtain the sample solution;
(2)量取上样液，以2～4BV/h的流速经大孔树脂柱纯化，上样毕静置55～65min，再以7～10BV/h的流速依次用纯化水、45～55％乙醇、75～85％乙醇洗脱，确定水洗脱终点后，45～55％乙醇洗脱2.5～3BV，75～85％乙醇洗脱4.5～5.5BV，收集乙醇洗脱液，减压浓缩至水分低于5％，即得全谱系油粗品；(2) Measure the sample solution and purify it through a macroporous resin column at a flow rate of 2 to 4 BV/h. After the sample is loaded, let it stand for 55 to 65 minutes, and then use purified water and 45 to 55 at a flow rate of 7 to 10 BV/h. Elute with 75% ethanol and 75-85% ethanol. After confirming the end point of water elution, 45-55% ethanol elutes 2.5-3BV, 75-85% ethanol elutes 4.5-5.5BV, collect ethanol eluate, and concentrate under reduced pressure. When the moisture content is less than 5%, the crude oil of the whole spectrum is obtained;
(3)取全谱系油粗品，加入65～75％乙醇搅拌溶解，过滤，所得滤液以1.5～2.5BV/h的流速经色谱填料柱纯化，上样毕，再以1.5～2.5BV/h的流速用65～75％乙醇洗脱4.5～5.5BV，65～75％乙醇洗脱液减压浓缩至水分低于5％，即得***全谱系油，所述全谱系油中总***素含量达75％以上，其中CBDV 9～12％、CBG 1～5％、CBD 60～65％、THCV 1～2％，THC未检出。(3) Take the crude oil of the whole spectrum, add 65 to 75% ethanol, stir to dissolve, filter, the filtrate obtained is purified by the chromatographic packing column at a flow rate of 1.5 to 2.5 BV/h, after loading the sample, and then at 1.5 to 2.5 BV/h The flow rate is eluted with 65-75% ethanol for 4.5-5.5 BV, and the 65-75% ethanol eluate is concentrated under reduced pressure to a water content of less than 5% to obtain a cannabis full-spectrum oil. The total cannabinoid content in the full-spectrum oil is up to Above 75%, of which CBDV 9-12%, CBG 1-5%, CBD 60-65%, THCV 1-2%, THC is not detected.
本发明提供的***素类化合物、药物组合物及***全谱系油具有差异显著的(0.01<P<0.05)治疗帕金森的作用，特别是包含本发明优选比例的次***二酚(CBDV)、***萜酚(CBG)、***二酚(CBD)和四氢次***酚(THCV)的组合物差异性极显著的优于不含THCV施用时或不按本发明配比施用时的效果，其在治疗帕金森药物制备中具有重要的应用价值，且无毒副作用，可以长期使用。The cannabinoid compounds, pharmaceutical compositions and cannabis full-spectrum oils provided by the present invention have significantly different (0.01<P<0.05) effects in treating Parkinson's, especially containing the preferred ratio of cannabidiol (CBDV), The composition of cannabidiol (CBG), cannabidiol (CBD) and tetrahydrocannabinol (THCV) is very significantly different than the effect when administered without THCV or when administered without the ratio of the present invention, which It has important application value in the preparation of drugs for treating Parkinson's, has no toxic side effects, and can be used for a long time.
具体实施方式Detailed ways
为了使本发明的目的、技术方案及优点更加清楚明白，以下结合实施例，对本发明进行进一步详细说明。本发明的附加方面和优点将在下面的描述中部分给出，部分将从下面的描述中变得明显，或通过本发明的实践了解到。应当理解，以下描述仅仅用以解释本发明，并不用于限定本发明。In order to make the objectives, technical solutions, and advantages of the present invention clearer, the present invention will be further described in detail below in conjunction with embodiments. The additional aspects and advantages of the present invention will be partly given in the following description, and partly will become obvious from the following description, or be understood through the practice of the present invention. It should be understood that the following description is only used to explain the present invention, but not to limit the present invention.
本文中所用的术语“包含”、“包括”、“具有”、“含有”或其任何其它变形，意在覆盖非排它性的包括。例如，包含所列要素的组合物、 步骤、方法、制品或装置不必仅限于那些要素，而是可以包括未明确列出的其它要素或此种组合物、步骤、方法、制品或装置所固有的要素。The terms "comprising", "including", "having", "containing" or any other variations as used herein are intended to cover non-exclusive inclusion. For example, a composition, step, method, product, or device containing the listed elements is not necessarily limited to those elements, but may include other elements not explicitly listed or inherent in such a composition, step, method, product, or device Elements.
此外，下面所描述的术语“一个实施例”、“一些实施例”、“示例”、“具体示例”、或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中，对上述术语的示意性表述不是必须针对相同的实施例或示例。In addition, the description of the terms "one embodiment", "some embodiments", "examples", "specific examples", or "some examples" described below means specific features and structures described in conjunction with the embodiment or example. , Materials or features are included in at least one embodiment or example of the present invention. In this specification, the schematic representation of the above-mentioned terms does not necessarily refer to the same embodiment or example.
在一些实施例中，当本发明所述的口服剂型为片剂时，药用赋形剂可以是惰性稀释剂或填料(例如，蔗糖，微晶纤维素，淀粉，包括马铃薯淀粉，碳酸钙，氯化钠，磷酸钙，硫酸钙，或磷酸钠)；崩解剂，包括淀粉/淀粉衍生物、交联羧甲基纤维素钠、海藻酸盐、藻酸、聚乙烯吡咯烷酮或羟基乙酸淀粉钠；适宜的润滑剂，例如硬脂酸镁；粘合剂(例如***树胶、褐藻酸、褐藻酸钠、明胶、淀粉、预凝胶化淀粉、微晶纤维素、羧甲基纤维素钠、甲基纤维素、羟丙甲纤维素、乙基纤维素、聚乙烯吡咯烷酮或聚乙二醇)；和润滑剂、助流剂，以及抗粘剂(例如硬脂酸、硅酸盐或滑石)。还可以是其他药用赋形剂，例如着色剂、调味剂、增塑剂、保湿剂、缓冲剂和湿润剂等。In some embodiments, when the oral dosage form of the present invention is a tablet, the pharmaceutical excipient may be an inert diluent or filler (for example, sucrose, microcrystalline cellulose, starch, including potato starch, calcium carbonate, Sodium chloride, calcium phosphate, calcium sulfate, or sodium phosphate); disintegrants, including starch/starch derivatives, croscarmellose sodium, alginate, alginic acid, polyvinylpyrrolidone or sodium starch glycolate ; Suitable lubricants, such as magnesium stearate; binders (such as gum arabic, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, sodium carboxymethyl cellulose, methyl Base cellulose, hypromellose, ethyl cellulose, polyvinylpyrrolidone or polyethylene glycol); and lubricants, glidants, and anti-adherents (such as stearic acid, silicate, or talc). It can also be other pharmaceutical excipients, such as colorants, flavoring agents, plasticizers, humectants, buffers, and humectants.
必要时可对片剂进行包衣。包衣可以适于以预定模式释放活性药物物质(例如，为了实现受控释放制剂)或者它可以适于直到通过胃后才释放活性药物物质(肠溶衣)。包衣可以是糖包衣、薄膜包衣(例如基于羟丙甲纤维素、甲基纤维素、甲基羟乙基纤维素、羟丙基纤维素、羧甲基纤维素、丙烯酸酯共聚物、聚乙二醇和/或聚乙烯吡咯烷酮)，或肠溶衣(例如邻苯二甲酸乙酸纤维素、邻苯二甲酸羟丙甲纤维素、琥珀酸乙酸羟丙基甲基纤维素、聚乙酸乙烯邻苯二甲酸酯、虫胶和/或乙基纤维素)。If necessary, the tablets can be coated. The coating may be adapted to release the active drug substance in a predetermined pattern (for example, to achieve a controlled release formulation) or it may be adapted to not release the active drug substance until after passing through the stomach (enteric coating). The coating can be sugar coating, film coating (e.g. based on hypromellose, methylcellulose, methylhydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, acrylate copolymer, Polyethylene glycol and/or polyvinylpyrrolidone), or enteric coatings (such as cellulose acetate phthalate, hypromellose phthalate, hydroxypropyl methyl cellulose acetate succinate, polyvinyl acetate Phthalates, shellac and/or ethyl cellulose).
用于经口使用的制剂也可以作为咀嚼片或作为其中活性成分与惰性固体稀释剂(例如马铃薯淀粉、微晶纤维素、碳酸钙、磷酸钙或高岭土)混 合的硬明胶胶囊，或作为其中活性成分与水活油介质，例如液体石蜡或橄榄油混合的软明胶胶囊呈现。The preparation for oral use can also be used as a chewable tablet or as a hard gelatin capsule in which the active ingredient is mixed with an inert solid diluent (such as potato starch, microcrystalline cellulose, calcium carbonate, calcium phosphate or kaolin), or as a hard gelatin capsule in which the active ingredient is mixed. The ingredients are presented in soft gelatin capsules in which the ingredients are mixed with a water-live oil medium, such as liquid paraffin or olive oil.
在本发明的一些实施方式中，用于经口使用的制剂还可以经口施用的液体，适用于通过加入水制备含水混悬剂的粉剂、可分散粉剂或颗粒剂。合适的悬浮剂，例如羧甲基纤维素钠、甲基纤维素或/和海藻酸钠等。In some embodiments of the present invention, the preparation for oral use may also be a liquid for oral administration, which is suitable for preparing powders, dispersible powders or granules of aqueous suspensions by adding water. Suitable suspending agents, such as sodium carboxymethyl cellulose, methyl cellulose or/and sodium alginate, and the like.
本发明各个实施方式中所涉及到的技术特征只要彼此之间未构成冲突就可以相互组合。The technical features involved in the various embodiments of the present invention can be combined with each other as long as they do not conflict with each other.
实施例1Example 1
取工业***花叶药材进行粉碎，过1号筛，100℃烘烤200min，取一定量烘烤后的***花叶药材，按料液比1:8(w/v)加入70％乙醇，室温搅拌提取两次，每次1小时，过滤，合并提取液，离心过滤，离心过滤液减压浓缩(65℃，-0.08～-0.09Mpa)至无醇味，密度为1.070(60℃)，补加纯化水至溶液重量为药材重量的8倍，搅拌均匀即得上样液。Take the industrial hemp flower leaf medicinal material and crush it, pass through a No. 1 sieve, and bake at 100°C for 200 minutes, take a certain amount of the roasted hemp flower leaf medicinal material, add 70% ethanol according to the material-to-liquid ratio 1:8 (w/v), at room temperature Stir and extract twice, 1 hour each time, filter, combine the extracts, centrifuge and filter, and concentrate the centrifugal filtrate under reduced pressure (65°C, -0.08～-0.09Mpa) until it has no alcohol taste, and the density is 1.070 (60°C). Add purified water until the weight of the solution is 8 times the weight of the medicinal material, and stir evenly to obtain the sample solution.
量取上样液，以4BV/h的流速经已处理好的大孔树脂柱(径高比为1：5)纯化，上样毕，静置60min，再以9BV/h的流速依次用纯化水、50％乙醇、80％乙醇洗脱，用molish反应确定水洗脱终点，50％乙醇洗脱3BV，80％乙醇洗脱5BV，收集80％乙醇洗脱液，减压浓缩(65℃，-0.08～-0.09Mpa)至水分至5％以下，即得全谱系油粗品。Measure the sample solution and purify it on a processed macroporous resin column (diameter-to-height ratio of 1:5) at a flow rate of 4BV/h. After loading the sample, let it stand for 60min, and then use it for purification at a flow rate of 9BV/h. Elute with water, 50% ethanol, 80% ethanol, determine the end of water elution with Molish reaction, 50% ethanol eluate 3BV, 80% ethanol eluate 5BV, collect 80% ethanol eluate, and concentrate under reduced pressure (65℃, -0.08～-0.09Mpa) to the moisture content below 5%, the crude oil of the whole spectrum is obtained.
取全谱系油粗品，加入70％乙醇搅拌溶解，过滤，所得滤液以2BV/h的流速经已处理好的聚合色谱填料柱UniPSN 30(径高比为1：6)纯化，上样毕，再以2BV/h的流速用70％乙醇洗脱5BV，70％乙醇洗脱液减压浓缩(65℃，-0.08～-0.09Mpa)至水分至5％以下，即得全谱系油。Take the crude oil of the whole spectrum, add 70% ethanol and stir to dissolve, filter, and the filtrate obtained is purified by the processed polymer chromatography packing column UniPSN 30 (diameter-to-height ratio 1:6) at a flow rate of 2BV/h. After loading the sample, 5BV was eluted with 70% ethanol at a flow rate of 2BV/h, and the 70% ethanol eluate was concentrated under reduced pressure (65°C, -0.08～-0.09Mpa) until the water content was below 5% to obtain the full spectrum oil.
所得全谱系油中总***素含量达78.41％，其中CBDV 10.52％、CBG 1.57％、CBD 64.80％、THCV 1.52％，THC未检出。The total cannabinoid content in the obtained full-spectrum oil reached 78.41%, of which CBDV 10.52%, CBG 1.57%, CBD 64.80%, THCV 1.52%, THC was not detected.
实施例2动物试验Example 2 Animal Test
1.试验药物的准备，按实施例1的方法制备得到全谱系油，另按9：1：60：1和12：5：65：2的CBDV、CBG、CBD和THCV质量比，准备纯净的***素类化合物，分别混合制备成编号为1-3组的试验组。此外，按质量比10.5：1.5：65取CBDV、CBG和CBD混合制成编号为4组的试验组；按质量比10.5：1.5：65：4取CBDV、CBG、CBD和THCV混合制成编号为5组的试验组。1. Preparation of the test drug. Prepare the full spectrum oil according to the method of Example 1. In addition, prepare pure oil according to the mass ratios of CBDV, CBG, CBD and THCV of 9:1:60:1 and 12:5:65:2. Cannabinoid compounds were mixed to prepare test groups numbered 1-3. In addition, according to the mass ratio of 10.5:1.5:65, take CBDV, CBG, and CBD to make the test group numbered as 4 groups; according to the mass ratio of 10.5:1.5:65:4 to take the combination of CBDV, CBG, CBD and THCV to make the number as 5 experimental groups.
2.PD大鼠模型制备：取100只大鼠进入实验，其中10只为假手术组，于内侧前脑束注射生理盐水，腹腔注射3％戊巴比妥钠麻醉大鼠，严格将大鼠头颅水平固定于脑立体定向仪上，确定右侧前脑内侧束(方法参照包新民编著的大鼠脑图谱)：①前囟后3.7mm，矢状缝右侧1.7mm，颅骨骨膜下7.8mm，门齿线2.4mm；②前囟后4.4mm，矢状缝右侧1.2mm，颅骨骨膜下7.8mm，门齿线2.4mm。按上述确定的注射位点钻孔，用10μl的微量注射器抽取6-OHDA6μl(含0.2％维生素C的生理盐水配置，浓度4μg/μl)，每点注射3μl，留针10min后退针，缝合创面。3周后，大鼠腹腔注射阿朴***(0.5mg/kg)，平均旋转频率>7次/min为成功PD模型。2. Preparation of PD rat model: 100 rats were taken into the experiment, 10 of them were sham operation group, and the rats were anesthetized with 3% pentobarbital sodium and 3% sodium pentobarbital injected into the medial forebrain tract. Fix the skull horizontally on a stereotaxic instrument to determine the right medial tract of the forebrain (refer to the rat brain atlas compiled by Bao Xinmin): ① 3.7mm posterior to bregma, 1.7mm to the right of sagittal suture, 7.8mm below skull periosteum , The incisor line 2.4mm; ②The posterior bregma is 4.4mm, the sagittal suture is 1.2mm on the right side, the skull is 7.8mm under the periosteum, and the incisor line is 2.4mm. Drill holes according to the injection site determined above, and draw 6 μl of 6-OHDA (with 0.2% vitamin C in physiological saline configuration, concentration 4 μg/μl) with a 10 μl micro-syringe, inject 3 μl at each point, leave the needle for 10 minutes, then retract the needle, and suture the wound. After 3 weeks, the rats were intraperitoneally injected with apomorphine (0.5mg/kg), and the average rotation frequency>7 times/min was a successful PD model.
3.模型制备与行为学测定：将60只成功的PD模型随机分为6大组。3. Model preparation and behavioral determination: 60 successful PD models were randomly divided into 6 groups.
第1-5组实验组，分别喂服准备的5组试验药物，均按8.5mg/kg给药，持续4周；第6组为PD对照组，PD模型大鼠处理方式为：腹腔注射左旋多巴甲酯+苄丝肼(50mg/kg左旋多巴甲酯和25mg/kg苄丝肼，溶于含0.2％维生素C的消毒生理盐水中)，2次/天(上午10点和下午6点)，持续4周。The experimental groups of groups 1 to 5 were fed with the prepared 5 groups of test drugs, all administered at 8.5 mg/kg for 4 weeks; the 6th group was the PD control group, and the PD model rats were treated as follows: intraperitoneal injection of levorotatory Dopa methyl ester + benserazide (50mg/kg levodopa methyl ester and 25mg/kg benserazide, dissolved in 0.2% vitamin C sterilized saline), 2 times/day (10 am and 6 pm Point) for 4 weeks.
在治疗过程中于第8、15、22、29天上午用药后进行大鼠行为学观察和评分。In the course of treatment, rats were observed and scored in behavioral observations after taking the medicine in the morning on the 8, 15, 22, and 29 days.
AIM评定：AIM分成4个组分(上肢AIM、口面部AIM、轴性AIM和旋转AIM)进行评定，每部分又根据其有无和严重程度分为5个等级(0-4)，即：0无；1：持续时间小于30s；2：持续时间为30s到60s；3： 持续时间大于60s，外界刺激可使之停止；4：持续时间大于60s，外界刺激不能使之停止。用药后每20min评估一次，每次观察1min。AIM总分按观察时间内总积分的平均值进行统计，理论上1只大鼠一次用药后各组分AIM最大评分为4分，总AIM评分为16分。AIM evaluation: AIM is divided into 4 components (upper limb AIM, orofacial AIM, axial AIM and rotation AIM) for evaluation, and each part is divided into 5 levels (0-4) according to its presence and severity, namely: 0 None; 1: duration is less than 30s; 2: duration is 30s to 60s; 3: if duration is greater than 60s, external stimuli can stop it; 4: duration is greater than 60s, external stimuli cannot stop it. Evaluation is performed every 20 minutes after medication, and observation is made for 1 minute each time. The total AIM scores are calculated according to the average of the total scores during the observation period. Theoretically, the maximum AIM score of each component after a single administration of a rat is 4 points, and the total AIM score is 16 points.
4.统计分析方法，实验数据采用SPSS 13.0统计软件进行分析。所得计量资料以均数±标准差表示，多个样本均数的比较采用单因素方差分析，结果如表1所示。4. Statistical analysis method, the experimental data is analyzed using SPSS 13.0 statistical software. The measurement data obtained are expressed as mean±standard deviation, and the comparison of the mean of multiple samples adopts one-way analysis of variance. The results are shown in Table 1.
表1动物试验结果Table 1 Animal test results
组别Group 口面部Mouth and face 上肢Upper limb 轴向Axial 旋转Spin 时间/天Time/day
11 1.46±0.231.46±0.23 1.61±0.201.61±0.20 2.49±0.242.49±0.24 2.67±0.152.67±0.15 88
22 1.42±0.191.42±0.19 1.59±0.211.59±0.21 2.45±0.222.45±0.22 2.63±0.132.63±0.13 88
33 1.48±0.221.48±0.22 1.63±0.231.63±0.23 2.48±0.222.48±0.22 2.69±0.122.69±0.12 88
44 2.17±0.192.17±0.19 2.54±0.232.54±0.23 3.23±0.313.23±0.31 3.78±0.163.78±0.16 88
55 1.99±0.211.99±0.21 2.27±0.202.27±0.20 3.01±0.273.01±0.27 3.45±0.213.45±0.21 88
66 1.87±0.151.87±0.15 2.03±0.232.03±0.23 2.87±0.312.87±0.31 3.33±0.223.33±0.22 88
11 1.45±0.151.45±0.15 1.59±0.211.59±0.21 2.43±0.202.43±0.20 2.65±0.152.65±0.15 1515
22 1.39±0.161.39±0.16 1.54±0.211.54±0.21 2.37±0.182.37±0.18 2.61±0.152.61±0.15 1515
33 1.42±0.151.42±0.15 1.57±0.211.57±0.21 2.40±0.212.40±0.21 2.63±0.122.63±0.12 1515
44 2.41±0.192.41±0.19 2.58±0.172.58±0.17 3.23±0.293.23±0.29 3.56±0.233.56±0.23 1515
55 2.08±0.152.08±0.15 2.39±0.202.39±0.20 3.01±0.203.01±0.20 3.36±0.183.36±0.18 1515
66 2.20±0.182.20±0.18 2.31±0.152.31±0.15 2.99±0.272.99±0.27 3.41±0.253.41±0.25 1515
11 1.26±0.141.26±0.14 1.53±0.211.53±0.21 2.26±0.222.26±0.22 2.58±0.182.58±0.18 22twenty two
22 1.21±0.131.21±0.13 1.47±0.201.47±0.20 2.22±0.192.22±0.19 2.52±0.182.52±0.18 22twenty two
33 1.25±0.131.25±0.13 1.51±0.211.51±0.21 2.25±0.212.25±0.21 2.55±0.192.55±0.19 22twenty two
44 2.74±0.252.74±0.25 2.95±0.182.95±0.18 3.55±0.223.55±0.22 3.62±0.213.62±0.21 22twenty two
55 2.56±0.172.56±0.17 2.68±0.212.68±0.21 3.38±0.173.38±0.17 3.49±0.253.49±0.25 22twenty two
66 2.45±0.262.45±0.26 2.62±0.192.62±0.19 3.27±0.153.27±0.15 3.43±0.243.43±0.24 22twenty two
11 1.27±0.121.27±0.12 1.58±0.201.58±0.20 2.19±0.252.19±0.25 2.33±0.352.33±0.35 2929
22 1.21±0.121.21±0.12 1.52±0.211.52±0.21 2.12±0.252.12±0.25 2.28±0.342.28±0.34 2929
33 1.25±0.111.25±0.11 1.55±0.201.55±0.20 2.15±0.262.15±0.26 2.31±0.352.31±0.35 2929
44 2.90±0.172.90±0.17 3.25±0.233.25±0.23 3.73±0.253.73±0.25 3.78±0.233.78±0.23 2929
55 2.57±0.212.57±0.21 2.88±0.172.88±0.17 3.38±0.203.38±0.20 3.58±0.163.58±0.16 2929
66 2.43±0.312.43±0.31 2.64±0.182.64±0.18 3.30±0.193.30±0.19 3.54±0.213.54±0.21 2929
5.结果分析5. Result analysis
口面部AIM评分表明，第1-3组试验组口面部评分相当，第1-3组和第4-6组比较均值差异有统计学意义(P<0.05)。与第4组比较，第2组口面部AIM评分较低，差异有统计学意义(P<0.05)；与第5组比较，第2组口面部AIM评分较低，差异有统计学意义(P<0.01)。Orofacial AIM scores showed that the orofacial scores of the test groups in groups 1-3 were equivalent, and the difference in the mean between groups 1-3 and 4-6 was statistically significant (P<0.05). Compared with group 4, the orofacial AIM score of the second group was lower, and the difference was statistically significant (P<0.05); compared with the fifth group, the orofacial AIM score of the second group was lower, and the difference was statistically significant (P <0.01).
上肢AIM评分表明，第1-3组试验组上肢评分相当，第1-3组和第4-6组比较均值差异有统计学意义(P<0.01)。其中第1-3组上肢AIM评分低于第4-5组，差异有统计学意义(P<0.01)。The upper limb AIM score showed that the upper limb scores of the test groups in groups 1-3 were equivalent, and the difference in the mean between groups 1-3 and 4-6 was statistically significant (P<0.01). Among them, the upper limb AIM scores of groups 1-3 were lower than those of groups 4-5, and the difference was statistically significant (P<0.01).
轴向AIM评分表明，第1-3组试验组轴向评分相当，第1-3组和第4-6组比较均值差异有统计学意义(P<0.01)。第1-3组用药至第22、29天轴向AIM值比PD组(第6组)降低，差异有统计学意义(P<0.05)，且第1-3组与第4-5组比较第22、29天差异有统计学意义(P<0.01)，明显降低了轴向AIM评分。The axial AIM scores showed that the axial scores of the test groups in groups 1-3 were equivalent, and the difference in the mean between groups 1-3 and 4-6 was statistically significant (P<0.01). The axial AIM value of the 1-3 group was lower than that of the PD group (group 6) until the 22nd and 29th days, the difference was statistically significant (P<0.05), and the 1-3 group was compared with the 4-5 group The difference between the 22nd and 29th day was statistically significant (P<0.01), and the axial AIM score was significantly reduced.
旋转AIM评分表明，根据本发明实施例2-4的CBDV、CBG、CBD和THCV质量比制备的第1-3组试验组旋转评分相当，第1-3组和第4-6组比较均值差异有统计学意义(P<0.01)。第1-3组用药至第22、29天旋转AIM评分值比PD组降低，差异有统计学意义(P<0.01)，且第1-3组与第4-5组比较第22、29天差异有统计学意义(P<0.01)，明显降低了旋转AIM评分。The rotating AIM score shows that the quality of CBDV, CBG, CBD, and THCV of Examples 2-4 of the present invention is comparable to the rotating scores of the 1-3 test groups prepared according to the present invention, and the comparison of the average values of the 1-3 groups and the 4-6 groups is different There is statistical significance (P<0.01). The Rotational AIM score value of the 1-3 group was lower than that of the PD group on the 22nd and 29th day, the difference was statistically significant (P<0.01), and the 1-3 group was compared with the 4-5th group on the 22nd and 29th day The difference was statistically significant (P<0.01), which significantly reduced the rotating AIM score.
本领域的技术人员容易理解，以上所述仅为本发明的实施例而已，并 不用以限制本发明，凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等，均应包含在本发明的保护范围之内。Those skilled in the art can easily understand that the above descriptions are only the embodiments of the present invention and are not intended to limit the present invention. Any modification, equivalent replacement and improvement, etc. made within the spirit and principle of the present invention shall be applicable. It is included in the protection scope of the present invention.

Claims (10)

  1. 一种***素类化合物在制备治疗帕金森的药物中的应用，其特征在于，所述***素类化合物中包含CBDV、CBG、CBD和THCV，不含THC。An application of a cannabinoid compound in the preparation of a medicine for treating Parkinson's, characterized in that the cannabinoid compound contains CBDV, CBG, CBD and THCV, and does not contain THC.
  2. 根据权利要求1所述的***素类化合物在制备治疗帕金森的药物中的应用，其特征在于，所述***素类化合物中CBDV、CBG、CBD和THCV的质量比为9～12：1～5：60～65：1～2。The use of the cannabinoid compound in the preparation of a medicine for treating Parkinson's according to claim 1, wherein the mass ratio of CBDV, CBG, CBD and THCV in the cannabinoid compound is 9-12:1. 5:60～65:1～2.
  3. 根据权利要求2所述的***素类化合物在制备治疗帕金森的药物中的应用，其特征在于，所述***素类化合物中CBDV、CBG、CBD和THCV的质量比为10-11：1-3：62-65：1.5-2。The application of the cannabinoid compound in the preparation of a medicine for treating Parkinson's according to claim 2, wherein the mass ratio of CBDV, CBG, CBD and THCV in the cannabinoid compound is 10-11:1 3: 62-65: 1.5-2.
  4. 根据权利要求1-3任一项所述的***素类化合物在制备治疗帕金森的药物中的应用，其特征在于，所述治疗帕金森为治疗运动徐缓或运动不能。The use of the cannabinoid compound according to any one of claims 1 to 3 in the preparation of a medicament for the treatment of Parkinson's, characterized in that the treatment of Parkinson's is for the treatment of bradykinesia or dyskinesia.
  5. 一种治疗帕金森的药物组合物，其特征在于，所述药物组合物中包含CBDV、CBG、CBD和THCV，不含THC。A pharmaceutical composition for treating Parkinson's, characterized in that the pharmaceutical composition contains CBDV, CBG, CBD and THCV, and does not contain THC.
  6. 根据权利要求5所述的治疗帕金森的药物组合物，其特征在于，所述药物组合物中CBDV、CBG、CBD和THCV的质量比为9～12：1～5：60～65：1～2；优选地，所述药物组合物中CBDV、CBG、CBD和THCV的质量比为10-11：1-3：62-65：1.5-2。The pharmaceutical composition for treating Parkinson's according to claim 5, wherein the mass ratio of CBDV, CBG, CBD and THCV in the pharmaceutical composition is 9-12:1-5:60-65:1~ 2; Preferably, the mass ratio of CBDV, CBG, CBD and THCV in the pharmaceutical composition is 10-11:1-3:62-65:1.5-2.
  7. 根据权利要求5-6任一项所述的治疗帕金森的药物组合物，其特征在于，所述CBDV、CBG、CBD或THCV是化学合成产物、生物合成产物或植物提取物，优选地，所述植物提取物的植物提取部位为工业***的秆芯、花、叶、籽和籽的外壳中的一种或多种。The pharmaceutical composition for treating Parkinson's according to any one of claims 5-6, wherein the CBDV, CBG, CBD or THCV is a chemical synthesis product, a biosynthesis product or a plant extract, preferably The plant extract part of the plant extract is one or more of the stalk core, flower, leaf, seed and seed shell of industrial hemp.
  8. 一种***全谱系油在制备治疗帕金森的药物中的应用，其特征在于，所述***全谱系油中包含CBDV、CBG、CBD和THCV，不含THC。An application of a cannabis full-spectrum oil in preparing a medicine for treating Parkinson's, characterized in that the cannabis full-spectrum oil contains CBDV, CBG, CBD and THCV, and does not contain THC.
  9. 根据权利要求8所述***全谱系油在制备治疗帕金森的药物中的应用，其特征在于，所述***全谱系油中CBDV、CBG、CBD和THCV的质 量比为9～12：1～5：60～65：1～2；优选地，所述***全谱系油中CBDV、CBG、CBD和THCV的质量比为10-11：1-3：62-65：1.5-2。The use of the cannabis full spectrum oil in the preparation of a medicine for treating Parkinson's according to claim 8, wherein the mass ratio of CBDV, CBG, CBD and THCV in the cannabis full spectrum oil is 9-12:1-5 : 60～65:1～2; Preferably, the mass ratio of CBDV, CBG, CBD and THCV in the cannabis full spectrum oil is 10-11:1-3:62-65:1.5-2.
  10. 一种所述***全谱系油的制备方法，其特征在于，所述制备方法包括以下步骤：A preparation method of the cannabis full-spectrum oil, characterized in that, the preparation method comprises the following steps:
    (1)取工业***花叶药材进行粉碎，过筛，90～110℃烘烤150～250min，取一定量烘烤后的***花叶药材，按料液比1:6～12加入65～75％的乙醇，搅拌提取，离心过滤，滤液减压浓缩至无醇味，补加纯化水至溶液重量为药材重量的6～10倍，搅拌均匀，即得上样液；(1) Take industrial hemp mosaic medicinal materials, smash them, sieving, and bake at 90～110℃ for 150～250min, take a certain amount of roasted hemp mosaic medicinal materials, add 65～75 according to the material-to-liquid ratio 1:6～12 % Ethanol, stirring and extracting, centrifugal filtration, the filtrate is concentrated under reduced pressure until there is no alcohol taste, supplemented with purified water until the weight of the solution is 6-10 times the weight of the medicinal material, stir evenly, and then the sample solution is obtained;
    (2)量取上样液，以2～4BV/h的流速经大孔树脂柱纯化，上样毕静置55～65min，再以7～10BV/h的流速依次用纯化水、45～55％乙醇、75～85％乙醇洗脱，确定水洗脱终点后，45～55％乙醇洗脱2.5～3BV，75～85％乙醇洗脱4.5～5.5BV，收集乙醇洗脱液，减压浓缩至水分低于5％，即得全谱系油粗品；(2) Measure the sample solution and purify it through a macroporous resin column at a flow rate of 2 to 4 BV/h. After the sample is loaded, let it stand for 55 to 65 minutes, and then use purified water and 45 to 55 at a flow rate of 7 to 10 BV/h. Elute with 75% ethanol and 75-85% ethanol. After confirming the end point of water elution, 45-55% ethanol elutes 2.5-3BV, 75-85% ethanol elutes 4.5-5.5BV, collect ethanol eluate, and concentrate under reduced pressure. When the moisture content is less than 5%, the crude oil of the whole spectrum is obtained;
    (3)取全谱系油粗品，加入65～75％乙醇搅拌溶解，过滤，所得滤液以1.5～2.5BV/h的流速经色谱填料柱纯化，上样毕，再以1.5～2.5BV/h的流速用65～75％乙醇洗脱4.5～5.5BV，65～75％乙醇洗脱液减压浓缩至水分低于5％，即得***全谱系油，所述全谱系油中总***素含量达75％以上，其中CBDV 9～12％、CBG 1～5％、CBD 60～65％、THCV 1～2％，THC未检出。(3) Take the crude oil of the whole spectrum, add 65 to 75% ethanol, stir to dissolve, filter, the filtrate obtained is purified by the chromatographic packing column at a flow rate of 1.5 to 2.5 BV/h, after loading the sample, and then at 1.5 to 2.5 BV/h The flow rate is eluted with 65-75% ethanol for 4.5-5.5 BV, and the 65-75% ethanol eluate is concentrated under reduced pressure to a water content of less than 5% to obtain a cannabis full-spectrum oil. The total cannabinoid content in the full-spectrum oil is up to Above 75%, of which CBDV 9-12%, CBG 1-5%, CBD 60-65%, THCV 1-2%, THC is not detected.
PCT/CN2021/072758 2020-05-21 2021-01-19 Cannabinoid compounds and application thereof in treatment of parkinson's disease WO2021232836A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202010434010.1A CN113694049B (en) 2020-05-21 2020-05-21 Cannabinoid compounds and their use in treating parkinson's disease
CN202010434010.1 2020-05-21

Publications (1)

Publication Number Publication Date
WO2021232836A1 true WO2021232836A1 (en) 2021-11-25

Family

ID=78645738

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2021/072758 WO2021232836A1 (en) 2020-05-21 2021-01-19 Cannabinoid compounds and application thereof in treatment of parkinson's disease

Country Status (2)

Country Link
CN (1) CN113694049B (en)
WO (1) WO2021232836A1 (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115010690A (en) * 2022-06-06 2022-09-06 云南翰谷生物科技有限公司 Preparation method of high-purity cannabinol crystal
WO2024033539A1 (en) * 2022-08-11 2024-02-15 GW Research Limited Cannabidiol compositions for use in the treatment of neurodegenerative and neurological disorders

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113712943A (en) * 2020-05-25 2021-11-30 汉义生物科技（北京）有限公司 Application of hemp full-spectrum oil in treating epilepsy

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109568389A (en) * 2017-09-29 2019-04-05 汉义生物科技（北京）有限公司 A kind of preparation method of high-purity cannabinoids extract
CN109963595A (en) * 2016-10-11 2019-07-02 Gbs全球生物制药公司 For treating the compound mixture containing cannboid of neurodegenerative disease
CN110330409A (en) * 2019-07-24 2019-10-15 汉义生物科技（北京）有限公司 A kind of preparation method of industrial hemp extract

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BR102015024165A2 (en) * 2015-09-18 2017-03-28 Prati Donaduzzi & Cia Ltda oral pharmaceutical composition comprising cannabinoid, process for its preparation and use

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109963595A (en) * 2016-10-11 2019-07-02 Gbs全球生物制药公司 For treating the compound mixture containing cannboid of neurodegenerative disease
CN109568389A (en) * 2017-09-29 2019-04-05 汉义生物科技（北京）有限公司 A kind of preparation method of high-purity cannabinoids extract
CN110330409A (en) * 2019-07-24 2019-10-15 汉义生物科技（北京）有限公司 A kind of preparation method of industrial hemp extract

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115010690A (en) * 2022-06-06 2022-09-06 云南翰谷生物科技有限公司 Preparation method of high-purity cannabinol crystal
CN115010690B (en) * 2022-06-06 2023-03-21 云南翰谷生物科技有限公司 Preparation method of high-purity cannabinol crystal
WO2024033539A1 (en) * 2022-08-11 2024-02-15 GW Research Limited Cannabidiol compositions for use in the treatment of neurodegenerative and neurological disorders

Also Published As

Publication number Publication date
CN113694049B (en) 2022-11-22
CN113694049A (en) 2021-11-26

Similar Documents

Publication Publication Date Title
WO2021232836A1 (en) Cannabinoid compounds and application thereof in treatment of parkinson&#39;s disease
EP2044935B1 (en) A composition containing non-psychotropic cannabinoids for the treatment of inflammatory diseases
US9987320B2 (en) Traditional chinese medicine composition, and preparation and application thereof
EP3485885A1 (en) Compound and method for treatment of diseases and disorders
USRE49035E1 (en) Traditional Chinese medicine composition, and preparation and application thereof
US20200384049A1 (en) Compound and method for treatment of movement disorders
JPH1059846A (en) Preventive or remedy for cararacta
RU2668135C1 (en) Pharmaceutical composition for the treatment and prevention of degenerative neurological disorders which comprises, as an active ingredient, a mixed root extract of the tree peony root, the root of dahuric angelica and the root of thorowax or its fraction
CN108699020B (en) Novel dapagliflozin crystal form and preparation method and application thereof
CN105287614B (en) A kind of Dengyin naotong pharmaceutical composition and preparation method thereof, preparation and application
CN106573029B (en) Composition of valerian root extract and lavender oil for the treatment of sleep disorders
EP2172206A1 (en) The method for a sequoyitol-containing extract obtaining from the genus of trifolium, sobyean and ginkgo biloba and use thereof
AU2021257523B2 (en) Ginsenoside composition having alcoholic fatty liver-preventing and -treating function
JP4863875B2 (en) Treatment for depression comprising prickly pear plant parts and / or extracts therefrom
EP2286819B1 (en) Pharmaceutical composition for treating cardio-cerebro vascular diseases and preparative method and kit thereof
CN101429184B (en) Two-crystal type of substance of luteolin, production method, medicament composition and uses thereof
CN112043700B (en) Application of demethylenetetrahydroberberine hydrochloride in preparation of medicines for preventing or treating neurodegenerative diseases
CN111212637A (en) Use of benzoate-containing compositions for treating glycine encephalopathy
TWI720511B (en) Use of composition containing labisia pumila var. alata extracts in alleviating depression related symptoms
WO2009062374A1 (en) The pharmaceutical use of liquiritigenin for preparing medicine for treating neurodegenerative diseases
CN103012345A (en) Luteolin alpha crystal form substance, preparation method thereof as well as pharmaceutical composition and application thereof
CN112691102A (en) Application of baicalein in preventing and treating Parkinson&#39;s disease/Parkinson&#39;s syndrome depression symptoms
CN110433168B (en) Application of cornuside in preparation of medicine for treating Alzheimer&#39;s disease
WO2021238242A1 (en) Use of full-spectrum hemp oil in treatment of epilepsy
CN113116867A (en) Composition for preventing and/or treating influenza

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21808952

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 21808952

Country of ref document: EP

Kind code of ref document: A1