阅读说明：本技术 大麻素类化合物及其在治疗帕金森症中的应用 (Cannabinoid compounds and their use in treating parkinson's disease ) 是由 谭昕 王曙宾 金倩 于 2020-05-21 设计创作，主要内容包括：本发明公开了一种大麻全谱系油在治疗帕金森中的应用。所述大麻全谱系油中包含次大麻二酚(CBDV)、大麻萜酚(CBG)、大麻二酚(CBD)和四氢次大麻酚(THCV),不含可致人上瘾的物质四氢大麻酚(THC)。该大麻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大麻二酚(CBDV)、大麻萜酚(CBG)、大麻二酚(CBD)和四氢次大麻酚(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 invention discloses application of cannabis full-spectrum oil in treating Parkinson. The cannabis whole lineage oil contains Cannabidivarin (CBDV), Cannabigerol (CBG), Cannabidiol (CBD) and Tetrahydrocannabidivarin (THCV), and is free of addictive Tetrahydrocannabinol (THC). The cannabis whole-spectrum oil has remarkable (0.01< P <0.05) effect of treating Parkinson, particularly the effect of the composition containing the sub-Cannabidiol (CBDV), the Cannabigerol (CBG), the Cannabidiol (CBD) and the tetrahydrosub-cannabinol (THCV) in the preferable proportion is remarkably superior to the effect of the composition without THCV or without the proportion, and the cannabis whole-spectrum oil has important application value in the preparation of drugs for treating Parkinson, has no toxic or side effect, and can be used for a long time.)

1. Use of a cannabinoid compound comprising CBDV, CBG, CBD, and THCV in the manufacture of a medicament for the treatment of parkinson's disease, the cannabinoid compound being devoid of THC.

2. The use of a cannabinoid according to claim 1 in the manufacture of a medicament for the treatment of parkinson's disease, wherein the cannabinoid comprises CBDV, CBG, CBD and THCV in a mass ratio of 9-12: 1-5: 60-65: 1 to 2.

3. Use of a cannabinoid according to claim 2 in the manufacture of a medicament for the treatment of parkinson's disease, wherein the cannabinoid has a mass ratio of CBDV, CBG, CBD and THCV of 10 "11: 1-3: 62-65: 1.5-2.

4. The use of a cannabinoid according to any of claims 1 to 3, in the manufacture of a medicament for the treatment of parkinson's disease, wherein the treatment of parkinson's disease is the treatment of bradykinesia or akinesia.

5. A pharmaceutical composition for the treatment of parkinson's disease, wherein said pharmaceutical composition comprises CBDV, CBG, CBD and THCV, and is free of THC.

6. The pharmaceutical composition for treating Parkinson's disease 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. The pharmaceutical composition for the treatment of parkinson's disease of any of claims 5 to 6, wherein said CBDV, CBG, CBD or THCV is a chemical synthesis product, a biological synthesis product or a plant extract, preferably wherein the plant extract is obtained from one or more of the stem, flower, leaf, seed and coat of industrial hemp.

8. Use of cannabis whole lineage oil in the manufacture of a medicament for the treatment of parkinson's disease, wherein the cannabis whole lineage oil comprises CBDV, CBG, CBD and THCV, and is free of THC.

9. The use of cannabis whole lineage oil according to claim 8, wherein the mass ratio of CBDV, CBG, CBD and THCV in cannabis whole lineage oil is 9-12: 1-5: 60-65: 1-2; preferably, the mass ratio of CBDV, CBG, CBD and THCV in the cannabis full lineage oil is 10-11: 1-3: 62-65: 1.5-2.

10. The preparation method of the hemp full-spectrum oil is characterized by comprising the following steps:

(1) crushing an industrial hemp flower and leaf medicinal material, sieving, baking at 90-110 ℃ for 150-250 min, adding 65-75% ethanol into a certain amount of baked hemp flower and leaf medicinal material according to the material-liquid ratio of 1: 6-12, stirring and extracting, centrifuging and filtering, concentrating filtrate under reduced pressure until no alcohol smell exists, adding purified water until the weight of the solution is 6-10 times of that of the medicinal material, and uniformly stirring to obtain a supernatant;

(2) measuring a sample loading solution, purifying the sample loading solution by a macroporous resin column at a flow rate of 2-4 BV/h, standing for 55-65 min after sample loading, eluting the sample loading solution by purified water, 45-55% ethanol and 75-85% ethanol sequentially at a flow rate of 7-10 BV/h, determining an eluting end point of water, eluting 2.5-3 BV by 45-55% ethanol and 4.5-5.5 BV by 75-85% ethanol, collecting ethanol eluent, and concentrating the ethanol eluent under reduced pressure until the water content is lower than 5% to obtain a crude oil product of the whole pedigree;

(3) taking a crude product of the full spectrum oil, adding 65-75% ethanol, stirring and dissolving, filtering, purifying the obtained filtrate by a chromatographic packing column at a flow rate of 1.5-2.5 BV/h, eluting by 65-75% ethanol for 4.5-5.5 BV after sample loading, and concentrating the 65-75% ethanol eluent under reduced pressure until the water content is lower than 5% to obtain the hemp full spectrum oil, wherein the total content of cannabinoids in the hemp full spectrum oil is more than 75%, CBDV 9-12%, CBG 1-5%, CBD 60-65%, THCV 1-2%, and THC is not detected.

Technical Field

The invention relates to the field of biological medicines, and in particular relates to application of cannabis whole-lineage oil in treatment of Parkinson.

Background

Parkinson's Disease (PD) is a degenerative disorder of the central nervous system, the second most common neurodegenerative disease after alzheimer's disease. PD is generally classified as a movement disorder, primarily characterized by resting tremor, stiffness, bradykinesia, and postural instability, with resting tremor being the most common and often the earliest developing symptom, with dementia usually occurring in the later stages of the disease. Motor symptoms of PD arise from the death of dopamine-producing cells in the substantia nigra (a region of the midbrain), the cause of which is unknown. Although dopamine is effective in treating motor symptoms in the early stages of the disease, dopamine's efficacy is lost in the later stages of the disease and its long-term use can lead to motor complications.

Cannabis is belonging to Cannabis family and genus Cannabis, and has important agricultural and medicinal value. Cannabinoids are a class of chemical substances known to activate cannabinoid receptors in cells, and pharmacological studies have shown that the main active ingredient in cannabis is a cannabinoid (cannabinoids). The phyto-cannabinoid is a cannabinoid extracted from cannabis sativa plant, and can also be synthesized artificially. At least 85 different cannabinoids can be isolated from the cannabis plant, differing in their structure depending on where the precursor Cannabinoid (CBG) is cyclized. The main cannabinoids in the hemp plant include Tetrahydrocannabinol (THC), Cannabinol (CBN), Cannabidiol (CBD), Cannabidivarin (CBDV), Tetrahydrocannabidivarin (THCV) and Cannabigerol (CBG), wherein the three components account for more than 90% of the cannabinoids.

It is well known that different cannabinoids have different properties. For example, CBDV is a non-addictive component in marijuana, can block the influence of the main addictive substance THC in marijuana on the human nervous system, and has pharmacological activity of treating epilepsy, neuropathic pain, arthritis, influenza and the like. Thus, it should be appreciated that while cannabinoids are all produced in different lines of the cannabis plant, it cannot be assumed that they all have the same properties. Because of this, research is constantly ongoing on numerous extracts in cannabis, and new breakthroughs are continuing. For example, european patent EP2726069 discloses cannabinoids for use in the prevention or treatment of neurodegenerative diseases or disorders, wherein preferably the cannabinoids are cannabichromene (CBC), Cannabinoxide (CBDV) and/or cannabinoid acid (CBDVA) and the neurodegenerative disease or disorder to be prevented or treated is alzheimer's disease. British patent GB2432312 discloses that cannabis plant extract cannabinoids are more effective in preventing neurodegeneration than purified compounds, in particular the extract cannabinoids Tetrahydrocannabinoids (THC) or Cannabinoids (CBD). However, there are few reports of THCV and less reports of its use in treating parkinson's disease in the currently disclosed series of cannabinoid pharmaceutical applications.

Disclosure of Invention

In view of the blank and deficiency of the research in the background technology, the invention provides an application of a cannabinoids compound in treating Parkinson, wherein the cannabinoids compound comprises Cannabidivarin (CBDV), Cannabigerol (CBG), Cannabidiol (CBD) and Tetrahydrocannabidivarin (THCV), does not contain substance Tetrahydrocannabinol (THC) capable of causing addiction to people, has no toxic or side effect, and can safely and effectively treat Parkinson's disease, especially motor complications of Parkinson's disease.

For the purpose of the invention, the cannabinoids comprise CBDV, CBG, CBD and THCV and do not contain THC.

Preferably, in some embodiments of the present invention, the mass ratio of CBDV, CBG, CBD and THCV in the cannabinoid is 9-12: 1-5: 60-65: 1 to 2.

More preferably, in some embodiments of the invention, the mass ratio of CBDV, CBG, CBD and THCV in the cannabinoid is 10-11: 1-3: 62-65: 1.5-2.

In another aspect, the invention provides a pharmaceutical composition for treating parkinson comprising CBDV, CBG, CBD and THCV, without THC.

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 to 2.

More preferably, in some embodiments of the invention, 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 can be prepared into specific dosage forms, which comprise tablets, sugar-coated tablets, film-coated tablets, enteric-coated tablets, capsules, hard capsules, soft capsules, oral liquid, buccal agents, granules, medicinal granules, pills, powder, ointment, pellets, suspensions, powder, solutions, injections, suppositories, ointments, plasters, creams, sprays, drops, patches and the like, and preferably oral dosage forms.

Further preferably, when the oral dosage form of the present invention is a tablet, the pharmaceutically acceptable excipient may be an inert diluent or filler (e.g., sucrose, microcrystalline cellulose, starch, calcium carbonate, sodium chloride, calcium phosphate, calcium sulfate, or sodium phosphate); disintegrating agents including starch/starch derivatives, croscarmellose sodium, alginates, alginic acid, polyvinylpyrrolidone or sodium starch glycolate; suitable lubricants, such as magnesium stearate; a binder (e.g., gum arabic, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, sodium carboxymethyl cellulose, methyl cellulose, hypromellose, ethyl cellulose, polyvinylpyrrolidone, or polyethylene glycol); and lubricants, glidants, and anti-adherents (e.g., stearic acid, silicates, or talc). Other pharmaceutically acceptable excipients may also be included, such as coloring agents, flavoring agents, plasticizers, humectants, buffering agents, and wetting agents, and the like.

The tablets may be coated if necessary. The coating may be adapted to release the active drug substance in a predetermined pattern (e.g. to achieve a controlled release formulation) or it may be adapted not to release the active drug substance until after passage through the stomach (enteric coating). The coating may be a sugar coating, a film coating (e.g., methylcellulose, methylhydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, acrylate copolymers, polyethylene glycol, and/or polyvinylpyrrolidone), or an enteric coating (e.g., cellulose acetate phthalate, hypromellose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, shellac, and/or ethylcellulose).

Formulations for oral use may also be presented as chewable tablets or as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example potato starch, microcrystalline cellulose, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with a water-miscible oil medium, for example liquid paraffin or olive oil.

Formulations for oral use may also be liquids for oral administration, suitable for the preparation of powders, dispersible powders or granules of aqueous suspensions by the addition of water.

The pharmaceutical compositions of the present invention are formed by admixing a plurality of active ingredients of the present invention with a pharmaceutically acceptable carrier and then may be conveniently administered in a variety of dosage forms suitable for the disclosed routes of administration. Administration may be once to many times per day for several days to several years, or may even last for the life of the patient. The carrier includes inert solid diluents or fillers, sterile aqueous solutions and various organic solvents. The pharmaceutical preparations may conveniently be presented in unit dosage form according to standard procedures for pharmaceutical formulations. Each unit dose containing a therapeutically effective amount of the active compound.

Therapeutically effective amounts of drugs in the combinations of the invention include amounts effective to reduce symptoms of Parkinson's disease, to stop or slow the progression of the disease (once it has become clinically significant), or to prevent or reduce the risk of developing the disease, which may vary depending on the nature of the active compounds and the intended dosage regimen. Generally, it is in the range of 0.1mg to 5000mg per unit dose. It is to be noted that the dosage and method of application of the active ingredients will depend upon a variety of factors including the general condition and age of the patient to be treated, the nature of the condition to be treated and the particular active ingredient or ingredients selected and the subjective judgment of the treating physician.

In the present invention, the Cannabidivarin (CBDV), Cannabigerol (CBG), Cannabidiol (CBD) and Tetrahydrocannabidivarin (THCV) may be chemically synthesized products, biologically synthesized products, plant extracts or prepared in other ways.

Further, the Cannabidiol (CBDV), Cannabigerol (CBG), Cannabidiol (CBD) and Tetrahydrocannabinol (THCV) can be pure products of each component respectively, and the medicinal composition can be obtained by mixing the components; the CBDV, CBG, CBD and THCV may also be present in the same product at the same time, for example a plant extract comprising the CBDV, CBG, CBD and THCV at the same time, such as industrial cannabis whole lineage oil.

Preferably, the plant extract fraction of the plant extract may be one or more of the stem core, flowers, leaves, seeds and hulls of seeds of industrial hemp, in particular flowers and/or leaves.

In yet another aspect, the invention provides the use of a cannabis whole lineage oil comprising CBDV, CBG, CBD and THCV in the manufacture of a medicament for the treatment of parkinson's disease, in the absence of THC.

Preferably, in a specific example of the present invention, the mass ratio of CBDV, CBG, CBD and THCV in the cannabis full lineage oil is 9-12: 1-5: 60-65: 1 to 2.

More preferably, the mass ratio of CBDV, CBG, CBD and THCV in the cannabis full lineage oil is 10-11: 1-3: 62-65: 1.5-2.

The THC-free component of the cannabinoids or the cannabis whole-spectrum oil is less than 0.3% of THC (mass percentage), preferably less than 0.1%, more preferably less than 0.01%, and particularly preferably no THC is detected according to a conventional method in the field.

The treatment of parkinson in the present invention refers to the treatment and prevention of the symptoms or their symptoms, including those triggered by the etiology of parkinsonism, preferably parkinson's disease, treatment, prevention, delay and reduction. Including but not limited to (1) protection against, or reduction or delay in, toxicity caused by alpha-synuclein, and (2) protection against, or reduction or delay in, toxic dopaminergic neurons resulting from abnormal glutamate accumulation, oxidative stress, mitochondrial dysfunction, or neuroinflammation.

The invention is suitable for treating parkinsonism in any mammalian subject, particularly a human subject, at any stage of the disease, especially for treating bradykinesia or akinesia.

In yet another aspect, the present invention also provides a method for preparing the hemp full spectrum oil, the method comprising the steps of:

(1) crushing an industrial hemp flower and leaf medicinal material, sieving, baking at 90-110 ℃ for 150-250 min, adding 65-75% ethanol into a certain amount of baked hemp flower and leaf medicinal material according to a material-liquid ratio of 1: 6-12 (w/v), stirring and extracting, centrifuging and filtering, concentrating filtrate under reduced pressure until no alcohol smell exists, adding purified water until the weight of the solution is 6-10 times of the weight of the medicinal material, and uniformly stirring to obtain a sample solution;

(2) measuring a sample loading solution, purifying the sample loading solution by a macroporous resin column at a flow rate of 2-4 BV/h, standing for 55-65 min after sample loading, eluting the sample loading solution by purified water, 45-55% ethanol and 75-85% ethanol sequentially at a flow rate of 7-10 BV/h, determining an eluting end point of water, eluting 2.5-3 BV by 45-55% ethanol and 4.5-5.5 BV by 75-85% ethanol, collecting ethanol eluent, and concentrating the ethanol eluent under reduced pressure until the water content is lower than 5% to obtain a crude oil product of the whole pedigree;

(3) taking a crude product of the full spectrum oil, adding 65-75% ethanol, stirring and dissolving, filtering, purifying the obtained filtrate by a chromatographic packing column at a flow rate of 1.5-2.5 BV/h, eluting by 65-75% ethanol for 4.5-5.5 BV after sample loading, and concentrating the 65-75% ethanol eluent under reduced pressure until the water content is lower than 5% to obtain the hemp full spectrum oil, wherein the total content of cannabinoids in the hemp full spectrum oil is more than 75%, CBDV 9-12%, CBG 1-5%, CBD 60-65%, THCV 1-2%, and THC is not detected.

The cannabinoids compound, the pharmaceutical composition and the cannabis whole-spectrum oil provided by the invention have remarkable (0.01< P <0.05) effect of treating Parkinson, particularly, the composition comprising the sub-Cannabidiol (CBDV), the Cannabigerol (CBG), the Cannabidiol (CBD) and the tetrahydrosub-cannabinol (THCV) in the preferable proportion is remarkably superior to the effect of the composition without THCV or the composition without the proportion, and the composition has important application value in the preparation of the medicament for treating Parkinson, has no toxic or side effect, and can be used for a long time.

Detailed Description

In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. Additional aspects and advantages of the invention will be set forth in part in the description which follows and, in part, will be obvious from the description, or may be learned by practice of the invention. It is to be understood that the following description is only illustrative of the present invention and is not to be construed as limiting the present invention.

The terms "comprises," "comprising," "includes," "including," "has," "having," "contains," "containing," or any other variation thereof, as used herein, are intended to cover a non-exclusive inclusion. For example, a composition, process, method, article, or apparatus that comprises a list of elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such composition, process, method, article, or apparatus.

Furthermore, the description below of the terms "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., means that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily for the same embodiment or example.

In some embodiments, when the oral dosage form of the invention is a tablet, the pharmaceutically acceptable excipient may be an inert diluent or filler (e.g., sucrose, microcrystalline cellulose, starch, including potato starch, calcium carbonate, sodium chloride, calcium phosphate, calcium sulfate, or sodium phosphate); disintegrating agents including starch/starch derivatives, croscarmellose sodium, alginates, alginic acid, polyvinylpyrrolidone or sodium starch glycolate; suitable lubricants, such as magnesium stearate; a binder (e.g., gum arabic, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, sodium carboxymethyl cellulose, methyl cellulose, hypromellose, ethyl cellulose, polyvinylpyrrolidone, or polyethylene glycol); and lubricants, glidants, and anti-adherents (e.g., stearic acid, silicates, or talc). Other pharmaceutically acceptable excipients, such as coloring agents, flavoring agents, plasticizers, humectants, buffering agents, and wetting agents, and the like, may also be present.

The tablets may be coated if necessary. The coating may be adapted to release the active drug substance in a predetermined pattern (e.g. to achieve a controlled release formulation) or it may be adapted not to release the active drug substance until after passage through the stomach (enteric coating). The coating may be a sugar coating, a film coating (e.g., based on hypromellose, methylcellulose, methylhydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, acrylate copolymers, polyethylene glycol, and/or polyvinylpyrrolidone), or an enteric coating (e.g., cellulose acetate phthalate, hypromellose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, shellac, and/or ethylcellulose).

Formulations for oral use may also be presented as chewable tablets or as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example potato starch, microcrystalline cellulose, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with a water-miscible oil medium, for example liquid paraffin or olive oil.

In some embodiments of the invention, formulations for oral use may also be liquids for oral administration, suitable for the preparation of powders, dispersible powders or granules of aqueous suspensions by the addition of water. Suitable suspending agents are, for example, sodium carboxymethylcellulose, methylcellulose or/and sodium alginate, etc.

The technical features of the embodiments of the present invention may be combined with each other as long as they do not conflict with each other.

Example 1

Crushing industrial hemp flower and leaf medicinal materials, sieving the medicinal materials by a No. 1 sieve, baking the medicinal materials at 100 ℃ for 200min, adding 70% ethanol into a certain amount of baked hemp flower and leaf medicinal materials according to the material-liquid ratio of 1:8(w/v), stirring and extracting the mixture twice at room temperature for 1 hour each time, filtering the mixture, merging extracting solutions, centrifugally filtering the mixture, concentrating the centrifugal filtrate under reduced pressure (65 ℃ and-0.08 to-0.09 Mpa) until no alcohol smell exists, ensuring the density of the centrifugal filtrate to be 1.070(60 ℃), supplementing purified water until the weight of the solution is 8 times of the weight of the medicinal materials, and uniformly stirring the solution to obtain a sample loading solution.

Measuring a sample loading solution, purifying by a treated macroporous resin column (the diameter-height ratio is 1: 5) at the flow rate of 4BV/h, standing for 60min after sample loading, eluting by purified water, 50% ethanol and 80% ethanol sequentially at the flow rate of 9BV/h, determining the end point of water elution by a molish reaction, eluting by 50% ethanol for 3BV and 80% ethanol for 5BV, collecting 80% ethanol eluent, and concentrating under reduced pressure (65 ℃, minus 0.08-minus 0.09Mpa) to the water content of less than 5% to obtain the crude oil of the whole lineage.

Taking the crude oil of the whole spectrum system, adding 70% ethanol, stirring and dissolving, filtering, purifying the obtained filtrate by a processed polymeric chromatographic packed column UniPSN 30 (the diameter-height ratio is 1: 6) at the flow rate of 2BV/h, eluting by 70% ethanol for 5BV at the flow rate of 2BV/h, and concentrating the 70% ethanol eluent under reduced pressure (65 ℃, minus 0.08-minus 0.09Mpa) to the water content of less than 5%, thus obtaining the oil of the whole spectrum system.

The total cannabinoid content in the obtained whole-lineage oil was 78.41%, wherein CBDV 10.52%, CBG 1.57%, CBD 64.80%, THCV 1.52%, and THC were not detected.

Example 2 animal testing

1. Preparation of test drugs, whole lineage oil was prepared as in example 1, and 9: 1: 60: 1 and 12: 5: 65: 2 CBDV, CBG, CBD and THCV, pure cannabinoids were prepared and mixed to prepare test groups numbered 1-3, respectively. In addition, the weight ratio of 10.5: 1.5: 65 mixing CBDV, CBG and CBD to prepare a test group with the number of 4 groups; according to the mass ratio of 10.5: 1.5: 65: and 4, mixing CBDV, CBG, CBD and THCV to prepare a test group with the number of 5.

PD rat model preparation: taking 100 rats to enter an experiment, wherein 10 rats are a sham operation group, injecting physiological saline into the medial forebrain tract, injecting 3% sodium pentobarbital into the abdominal cavity to anaesthetize the rats, strictly horizontally fixing the head of the rat on a brain stereotaxic apparatus, and determining the right lateral forebrain and medial tract (the method refers to a rat brain map compiled by the New Youngi): 3.7mm behind bregma, 1.7mm on the right side of sagittal suture, 7.8mm under skull periosteum and 2.4mm of incisal line; ② 4.4mm behind bregma, 1.2mm on the right side of sagittal suture, 7.8mm under skull periosteum and 2.4mm of incisal line. The injection site was drilled as described above, and 6-OHDA 6. mu.l (prepared with 0.2% vitamin C in physiological saline, concentration: 4. mu.g/. mu.l) was extracted with a 10. mu.l microinjector, 3. mu.l was injected at each site, the needle was withdrawn after 10min, and the wound was sutured. After 3 weeks, rats were injected intraperitoneally with apomorphine (0.5mg/kg), with a mean rotational frequency >7 times/min as a successful PD model.

3. Model preparation and behavioral determination: the 60 successful PD models were randomly divided into 6 large groups.

In the experimental groups 1-5, 5 groups of prepared experimental drugs are respectively fed and administrated according to 8.5mg/kg for 4 weeks; group 6 was the PD control group, and the PD model rats were treated in the following manner: levodopa methyl ester + benserazide (50mg/kg levodopa methyl ester and 25mg/kg benserazide in sterile saline containing 0.2% vitamin C) was injected intraperitoneally for 4 weeks 2 times/day (10 am and 6 pm).

Behavioral observations and scoring of rats were performed on days 8, 15, 22, and 29 morning after drug administration during the course of treatment.

AIM evaluation: AIM was rated in 4 fractions (upper arm AIM, orofacial AIM, axial AIM and rotational AIM), each fraction being further rated on a 5-scale (0-4) by its presence and severity, namely: 0 is absent; 1: the duration is less than 30 s; 2: a duration of 30s to 60 s; 3: the duration is longer than 60s, and the external stimulation can stop the operation; 4: the duration is longer than 60s, and the external stimulus can not stop the operation. The evaluation was performed every 20min after administration, and each observation was performed for 1 min. The total AIM score is counted according to the average value of the total score in the observation time, and theoretically, the maximum AIM score of each component of 1 rat after once administration is 4 scores, and the total AIM score is 16 scores.

4. Statistical analysis method, the experimental data is analyzed by SPSS 13.0 statistical software. The obtained measurement data are expressed as means ± standard deviation, and the results are shown in table 1 by comparing the means of a plurality of samples by using one-way anova.

TABLE 1 results of animal experiments

5. Analysis of results

The oral-facial AIM scores showed comparable oral-facial scores in test groups 1-3, with statistical differences between the mean values in groups 1-3 and 4-6 (P < 0.05). Group 2 had a lower oral facial AIM score than group 4, with statistically significant differences (P < 0.05); group 2 had a lower oral facial AIM score than group 5, with statistically significant differences (P < 0.01).

Upper limb AIM scores showed comparable upper limb scores in groups 1-3, with statistical significance in comparing mean differences between groups 1-3 and groups 4-6 (P < 0.01). Where groups 1-3 had lower upper limb AIM scores than groups 4-5, the differences were statistically significant (P < 0.01).

The axial AIM scores showed comparable axial scores in the test groups 1-3, with statistical significance (P <0.01) for the mean differences between groups 1-3 and 4-6. The axial AIM values were reduced by day 22 and day 29 with the groups 1-3 compared to the PD group (group 6), with the differences being statistically significant (P <0.05), and the axial AIM scores were significantly reduced in the groups 1-3 compared to the groups 4-5 with the differences on day 22 and day 29 being statistically significant (P < 0.01).

The rotating AIM scores showed that the mass ratios of CBDV, CBG, CBD and THCV prepared according to examples 2-4 of the invention were comparable with the rotating scores of test groups 1-3, and the comparative mean differences between groups 1-3 and 4-6 were statistically significant (P < 0.01). Groups 1-3 were administered until day 22, 29 with a statistically significant difference (P <0.01) compared to the PD group, and groups 1-3 had a statistically significant difference (P <0.01) compared to groups 4-5 with day 22, 29, with a significantly reduced rolling AIM score.

It will be understood by those skilled in the art that the foregoing is only exemplary of the present invention, and is not intended to limit the invention, which is intended to cover any variations, equivalents, or improvements therein, which fall within the spirit and scope of the invention.