CN109200046A

CN109200046A - Application of cannabinoids in the treatment of neurodermatitis

Info

Publication number: CN109200046A
Application number: CN201710538732.XA
Authority: CN
Inventors: 张可; 谭昕; 常坦然; 金倩
Original assignee: Hanyi Bio Technology Beijing Co ltd
Current assignee: Hanyi Bio Technology Beijing Co ltd
Priority date: 2017-07-04
Filing date: 2017-07-04
Publication date: 2019-01-15

Abstract

The invention discloses the use of a cannabinoids or a pharmaceutically acceptable salt thereof in the preparation of a pharmaceutical composition for use in the treatment of neurodermatitis, wherein the cannabinoids may be selected from one of tetrahydrocannabinol, cannabidiol, cannabidivarin, tetrahydrocannabidivarin, or the cannabinoids may be selected from: (1) a combination of tetrahydrocannabinol and tetrahydrocannabivarin; (2) a combination of cannabidiol and cannabidivarin; (3) a combination of tetrahydrocannabinol and cannabidivarin; (4) a combination of cannabidiol and tetrahydrocannabivarin; (5) a combination of cannabidiol, cannabidivarin and tetrahydrocannabidivarin; (6) a combination of tetrahydrocannabinol, cannabidivarin and tetrahydrocannabidivarin.

Description

Application of the Cannabinoids compound in treatment neurodermatitis

Technical field

The present invention relates to field of medicaments, in particular to the composition comprising one or more kinds of Cannabinoids compounds exists Treat the application in neurodermatitis.

Background technique

Neurodermatitis is also known as lichen simplex chronicus, is a kind of limitation cutaneous nerve dysfunction dermatoses.It is The chronic dermatosis of feature is turned to paroxysmal pruitus and skin moss.The cause of disease is still not clear, it is considered that with scratch for a long time Grab, rub it is with psychoneural factor and certain external stimulus factors related, wherein mental element, which is presently considered to be, occurs this disease Main inducing, mood swing, spiritual overstretched, anxious, living environment suddenly change etc. can aggravate disease and instead It is multiple.Currently, clinical treatment neurodermatitis mostly uses Histamine agents object, calcium agent etc. antipruritic to the ill, it is aided in vitamin B complex Clothes；Sedative can be selected in itch serious person；The general originator of fash can give procaine intravenous closing or tripterygium wilfordii class medicine is used in combination Object.Although its is quick, only symptomatic treatment, there are palliative and easy to recur deficiencies.

It is some studies have shown that neurodermatitis with psychoneural because being known as apparent correlation, furthermore long-term gastrointestinal tract function Energy obstacle, cryptorrhea and infection focus etc. are likely to become pathogenic factors.Clinically occasionally have using antidepressants and treats The skin diseases such as obstinate pruritus, neurodermatitis, such as trimeprimine and chlorpromazine, facilitating treatment chronic dermatosis often has Itch and sleep disordered, however these antidepressants also have many side effects, it is also possible to which it is mutual to generate drug with dermatologic Effect, and be not that every kind of antidepressants can be used for the treating for skin disease such as neurodermatitis.

Hemp (scientific name: Cannabis sativa L.) Cannabaceae, Cannabis plant, You Mingma, Chinese fiber crops, fire fiber crops, mountain silk Seedling, jute have important agricultural and medical value.It can be made one in hemp containing a kind of toxic component THC (tetrahydrocannabinol) Unreal habituation is caused, drugs can be made, was once forbidden cultivating within suitable long-term.Since the economy of hemp, medical value are high, specialize in industrial The raw material hemp on way is referred to as " industrial hemp ", and tetrahydrocannabinol (THC) content in growth period hemp floral leaf is less than thousand points Three, do not have extract toxic component tetrahydrocannabinol value or sucked directly as drugs, can legal carry out scale Plantation is utilized with industrialized developing.

Cannboid is the active material by extracting, synthesizing in natural plants hemp.Currently, people divide from hemp plant More than 500 substances are separated out, wherein at least 86 kinds of Cannabinoids compound.Cannabinoids compound is peculiar in hemp plant A substance, be main active constituent in cannabis plants, in relation to it research be always hemp research hot spot.Hemp is planted Main Cannabinoids compound has tetrahydrocannabinol (THC), cannabinol (CBN), cannabidiol (CBD), secondary hemp two in strain Phenol (CBDV), tetrahydrocannabinol (THCV) etc., wherein former three accounts for 90% or more of Cannabinoids compound.

TV Zanelati etc. (Antidepressant-like effects of cannabidiol in mice: possible involvement of 5-HT_1A receptors,British journal of pharmacology,2010) It was found that cannabidiol can be by activating 5-HT_1AReceptor-inducible antidepression sample effect, it is believed that cannabidiol has the anti-suppression in mouse Strongly fragrant activity.THC or cannabidiol are disclosed in patent US2014302086 and at least one selected from citric acid, ascorbic acid, mandarin orange The small molecule compositions of tangerine essential oil etc. refer to that above-mentioned composition can treat neurodermatitis.Patent WO0206999A2 is disclosed Containing the cannboid total weight at least drug of 80wt%, wherein the weight ratio of THC/CBD is 75:25-20:80, and is referred to above-mentioned Composition can be used for treating neurodermatitis.However the above-mentioned prior art has only carried out the therapeutical uses of the composition simply Enumerate, specification does not act on THC or cannabidiol in neurodermatitis and specifically being verified, and Composition in US2014302086 can also alleviate the ingredient of neurodermatitis containing other, be difficult clear THC or hemp two The effect of phenol can not clearly show that CBD or THC can treat the conclusion of neurodermatitis from above-mentioned in the prior art.

Present inventor takes a large amount of research, refreshing in treatment to the Cannabinoids compound of natural botanical source It is verified through the effect in terms of property dermatitis, is screened in a variety of Cannabinoids compounds, and largely face Bed test successfully specifies that several Cannabinoids compounds and combinations thereof have apparent curative effect to neurodermatitis finally.

Summary of the invention

After having read the detailed description of preferred embodiment and appended claims, the purpose of the present invention, advantage and use Way will show those skilled in the art.The present invention is directed to for insufficient, hair present on the treatment of existing neurodermatitis Existing Cannabinoids compound can treat neurodermatitis, can be used for preparing the drug for the treatment of neurodermatitis.

And the present invention provides the methods and composition preparation that use these compositions treatment neurodermatitis Treat the application in the drug of neurodermatitis.

The present invention is intended to provide one or more Cannabinoids compounds or its pharmaceutical salt are in preparation for treating mind Purposes in pharmaceutical composition through property dermatitis.

Preferably, the present invention provides be selected from tetrahydrocannabinol (THC), cannabidiol (CBD), cannabidivarin (CBDV), one of tetrahydrocannabinol (THCV) Cannabinoids compound or its pharmaceutical salt are being prepared separately for controlling Treat the purposes in the pharmaceutical composition of neurodermatitis.

Preferably, the present invention provides Cannabinoids compounds or its pharmaceutical salt to prepare for treating nerve skin Purposes in scorching pharmaceutical composition, the Cannabinoids compound are selected from:

(1) combination of tetrahydrocannabinol (THC) and tetrahydrocannabinol (THCV)；

(2) combination of cannabidiol (CBD) and cannabidivarin (CBDV)；

(3) combination of tetrahydrocannabinol (THC) and cannabidivarin (CBDV)；

(4) combination of cannabidiol (CBD) and tetrahydrocannabinol (THCV)；

(5) combination of cannabidiol (CBD), cannabidivarin (CBDV) and tetrahydrocannabinol (THCV)；

(6) combination of tetrahydrocannabinol (THC), cannabidivarin (CBDV) and tetrahydrocannabinol (THCV).

The present invention also provides a kind of for treating the composition of neurodermatitis, including 1) Cannabinoids compound or its Pharmaceutical salt, 2) one or more pharmaceutically acceptable carriers or excipient.

Preferably, the Cannabinoids compound is selected from tetrahydrocannabinol (THC), cannabidiol (CBD), secondary hemp two One of phenol (CBDV), tetrahydrocannabinol (THCV).

Preferably, the Cannabinoids compound is selected from:

(2) combination of cannabidiol (CBD) and cannabidivarin (CBDV)；

(3) combination of tetrahydrocannabinol (THC) and cannabidivarin (CBDV)；

(4) combination of cannabidiol (CBD) and tetrahydrocannabinol (THCV)；

It is furthermore preferred that the Cannabinoids compound is selected from:

(1) combination of tetrahydrocannabinol (THC) and tetrahydrocannabinol (THCV) by weight tetrahydrocannabinol (THC) and Tetrahydrocannabinol (THCV) is 100:5-20；

(2) combination of cannabidiol (CBD) and cannabidivarin (CBDV) is by weight cannabidiol (CBD) and time hemp Diphenol (CBDV) is 100:20-50；

(3) combination of tetrahydrocannabinol (THC) and cannabidivarin (CBDV) by weight tetrahydrocannabinol (THC) and time Cannabidiol (CBDV) is 100:40-100；

(4) combination of cannabidiol (CBD) and tetrahydrocannabinol (THCV) is by weight cannabidiol (CBD) and tetrahydro Secondary cannabinol (THCV) is 100:2.5-10；

(5) combination of cannabidiol (CBD), cannabidivarin (CBDV) and tetrahydrocannabinol (THCV) is by weight big Numb diphenol (CBD), cannabidivarin (CBDV) and tetrahydrocannabinol (THCV) are 100:20-50:2.5-10；

(6) combination of tetrahydrocannabinol (THC), cannabidivarin (CBDV) and tetrahydrocannabinol (THCV) is by weight Tetrahydrocannabinol (THC), cannabidivarin (CBDV) and tetrahydrocannabinol (THCV) are 100:40-100:5-20.

Pharmaceutical salt of the present invention includes the acid-addition salts formed with inorganic acid or organic acid, the inorganic acid example Such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid；The organic acids for example acetic acid, propionic acid, caproic acid, enanthic acid, pyruvic acid, lactic acid, Malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, o- (4- hydroxy benzoyl) benzene Formic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, trimethylacetic acid, butylacetic acid, dodecyl sulphate, gluconic acid, paddy ammonia Acid, naphthoic acid, salicylic acid, stearic acid etc..

Composition of the present invention can be made into specific dosage form, for example oral by any approach appropriate, rectum, Nose, lung, part (including oral cavity and sublingual), in transdermal, brain pond, intraperitoneal, vagina and parenteral (including subcutaneous, intramuscular, sheath It is interior, intravenous and intradermal) approach administration, preferably oral route.It should be understood that optimization approach depends on the general of patient to be treated Situation and age, the property of disease to be treated and concrete activity ingredient or selected active constituent.

The composition of oral administration includes solid dosage forms, such as capsule, tablet, sugar coated tablet, pill, pastille, powder agent And granule.

The composition of oral administration further includes liquid dosage form, such as solution, emulsion, suspension, syrup and elixir.

The composition of parenteral includes sterile aqueous and non-aqueous injection solutions, dispersion liquid, suspension or lotion, with And the aseptic powdery of sterile injectable solution or dispersion liquid is redissolved in front of use.

The suitable form of administration of others includes suppository, spray, cream, gelling agent, inhalant, patch, implants etc..

Composition of the invention or composition produced by the invention can be given by any approach appropriate, such as with The forms such as tablet, capsule, powder agent, syrup are oral, or parental injection as a solution.In order to prepare this combination Methods known in the art can be used in object, and in the art usually used any pharmaceutically acceptable carrier, dilute can be used Release agent, excipient or other additives.

For parenteral, can be used the aseptic aqueous solutions of one or more active constituents, aqueous propylene glycol solution, Aqueous vitamin e solution or sesame oil or peanut oil solution.If it is necessary, this aqueous solution should be buffered appropriately, and liquid Body diluent is made of enough salt or glucose isotonic first.Aqueous solution be particularly suitable for it is intravenous, intramuscular, subcutaneous and Intraperitoneal administration.Sterile aqueous media used by being made is easy by standard technique well known by persons skilled in the art.

It is (preferably sterile by the way that one or more active constituents and possible additive are dissolved in a part of solvent for injection Water), solution is adjusted to required volume, and sterile solution is simultaneously filled into ampoule or bottle appropriate, and it is molten can to prepare injection Liquid.Common any appropriate additive, such as tonicity agents, preservative, antioxidant in the art etc. can be added.

Appropriate pharmaceutical carrier includes inert solid diluent or filler, aseptic aqueous solution and various organic solvents.

The example of solid carrier has lactose, carclazyte, sucrose, cyclodextrin, talcum powder, agar, pectin, Arabic gum, tristearin Acid, the lower alkyl ether of cellulose, cornstarch, potato starch, talcum powder, magnesium stearate, gelatin etc..

The auxiliary material or additive of any other the purpose of being commonly used in coloring, flavoring, anti-corrosion can be used, as long as them and work Property ingredient or used ingredient are compatible.

The example of liquid-carrier has syrup, peanut oil, olive oil, phosphatide, fatty acid, fatty acid amine, polyoxyethylene and water. Similar, carrier or diluent may include any slow-release material known in the art, such as mix individually or with wax Glycerin monostearate or distearin.

The composition formed and mixing one or more active constituents of the invention with pharmaceutically acceptable carrier, It then can be to be suitble to the various dosage forms of open administration route easily to give.It can be facilitated by method known in pharmaceutical field Ground has preparation with unit dosage forms.

Active constituent of the invention can be formulated as similar or dissimilar pharmaceutical composition and its unit dosage forms.

It preferably, is 2.5-400mg Cannabinoids compound containing unit dose in pharmaceutical composition of the present invention Or its pharmaceutical salt, it is furthermore preferred that containing unit dose in the pharmaceutical composition is 25-300mg Cannabinoids chemical combination Object or its pharmaceutical salt, most preferably, in the pharmaceutical composition containing unit dose is 50-200mg Cannabinoids Close object or its pharmaceutical salt, in embodiments of the present invention, in the pharmaceutical composition containing unit dose be 25mg, 30mg、40mg、50mg、60mg、70mg、80mg、90mg、100mg、110mg、120mg、130mg、140mg、150mg、160mg、 170mg, 180mg, 190mg or 200mg Cannabinoids compound or its pharmaceutical salt.

The present invention also provides a kind of prevention and/or the method for the treatment of neurodermatitis, the method includes applying daily It is 1-500mg Cannabinoids compound or its pharmaceutical salt with drug dose, it is furthermore preferred that daily administration drug dose is 25-300mg Cannabinoids compound or its pharmaceutical salt, most preferably, daily administration drug dose are 50-200mg hemp Chlorins compound or its pharmaceutical salt, in embodiments of the present invention, daily administration drug dose can also for 25mg, 30mg、40mg、50mg、60mg、70mg、80mg、90mg、100mg、110mg、120mg、130mg、140mg、150mg、160mg、 170mg, 180mg, 190mg or 200mg Cannabinoids compound or its pharmaceutical salt.

Cannabinoids compound of the present invention or its pharmaceutical salt can be chemosynthesis product, biosynthesis produces Object, plant extracts are prepared using other modes.Preferably, Cannabinoids compound of the present invention is that plant mentions Object is taken, the plant can be the shell of the stalk core of hemp Cannabis sativa L., flower, leaf, root and/or seed.

When Cannabinoids compound of the present invention is plant extracts, Extraction solvent can be low mass molecule alcohol (such as first Alcohol, ethyl alcohol, butanol or propyl alcohol)；Acetic acid esters (such as methyl acetate or ethyl acetate)；Ketone (such as acetone)；Ether (such as methyl ether or Ether)；Low-boiling aliphatic hydrocarbon or aromatic hydrocarbon or chlorinated hydrocabon.The method of extraction includes:

(1) using or mixtures thereof said extracted solvent of about 3-10 times weight to hemp Cannabis sativa L.'s Stalk core, flower, leaf, root and/or seed shell be heated to reflux, preferably at least handle about 1 hour, be then filtered to remove residue, with After remove solvent, preferably vacuum condition remove solvent, by the medicinal extract of acquisition about 110-135 DEG C of temperature heat about 40 minutes, Chromatographic isolation is then carried out, is preferred for chromatographic flowing phase mixture by methanol/water and acetic acid or ethanol/water and acetic acid Composition.

(2) using or mixtures thereof said extracted solvent of about 3-10 times weight to the stalk core of hemp, flower, leaf, root and/or The shell of seed is heated to reflux, and is preferably at least handled about 1 hour, then filtering is at least extracted with the sodium hydrate aqueous solution of 1-10% Take twice, the sodium hydrate aqueous solution preferably comprises from about the ethyl alcohol of 20wt%, extract liquor is mixed with 5% sulfuric acid solution with Make pH value about 2-4, then uses low boiling point solvent (such as low boiling point aliphatic hydrocarbon, aromatic hydrocarbon, chlorohydrocarbon, methyl acetate, acetic acid second Ester or its mixture) it extracts at least twice, solvent is removed under cryogenic vacuum, is then carried out chromatographic isolation, is preferred for chromatography The flowing phase mixture of method is made of methanol/water and acetic acid or ethanol/water and acetic acid.

Patient of the present invention is mammal, such as people, mouse, rat, cavy, dog, cat, horse, ox, pig or non- People primate, such as monkey, chimpanzee or baboon.Preferably, the patient behaves.

Unless otherwise stated, term " pharmaceutically acceptable carrier or excipient " is meant that the ingredient without biology Activity or other bad active impurity, such as the ingredient can be included in disclosed pharmaceutical preparation and give patient, but not cause Significant bad biological effect generates interaction with the other compositions for including in said preparation in harmful manner.

Unless otherwise stated, term " treatment " includes inhibition, delay, mitigation, decrease, limitation, mitigation or recession disease Disease, obstacle, illness or state, generation and/or process and/or its symptom.

Unless otherwise stated, term "comprising" indicates " opening " or " inclusive " term, so that they include enumerating Element, but also allow to include additional, unmentioned element.

Unless otherwise stated, term " about " generally means that +/- the 5% of described value, more generally refer to the +/- of described value 4%, more generally refer to +/- the 3% of described value, more generally refer to +/- the 2% of described value, more generally refers to +/- the 1% of described value, it is more logical Often refer to +/- the 0.5% of described value.

The present invention demonstrates Cannabinoids compound or its pharmaceutical salt to treatment nerve skin by largely research Inflammation has positive effect, and individual Cannabinoids compound and said combination all have the various diseases for improving neurodermatitis Shape can be used to prepare the drug for the treatment of neurodermatitis.

Specific embodiment

It should be noted that in the absence of conflict, the features in the embodiments and the embodiments of the present application can phase Mutually combination.Below in conjunction with embodiment, the present invention will be described in detail.

1 capsule unit dosage form of embodiment

Formulation ingredients: cannabidiol 200mg

Microcrystalline cellulose 90mg

Pregelatinized starch 100mg

Cross-linked carboxymethyl cellulose 7mg

Magnesium stearate 0.5mg

Preparation method: the active constituent is sieved, and is mixed with auxiliary material, is filled this blend into hard gelatin capsule.

2 capsule unit dosage form of embodiment

Formulation ingredients: cannabidiol 400mg

Microcrystalline cellulose 100mg

Pregelatinized starch 150mg

Cross-linked carboxymethyl cellulose 10mg

Magnesium stearate 0.2mg

The preparation method is the same as that of Example 1.

3 tablet unit dosage form of embodiment

Formulation ingredients: tetrahydrocannabinol 100mg

Dextrin 100mg

Microcrystalline cellulose 25mg

Polyvinylpyrrolidone 10mg

Sodium carboxymethyl starch 15mg

Magnesium stearate 1mg

Preparation method: the active constituent is sieved, and with dextrin, microcrystalline cellulose, polyvinylpyrrolidone, carboxymethyl Sodium starch mixing is until form uniform mixture, sieving obtains mixture, and mixes with magnesium stearate.Then by resulting powder Type mixture is pressed into the tablet for needing shapes and sizes.

4 tablet unit dosage form of embodiment

Formulation ingredients: tetrahydrocannabinol 40mg

Pregelatinized starch 150mg

Microcrystalline cellulose 25mg

Sodium carboxymethyl starch 15mg

Magnesium stearate 1mg

Preparation method: the active constituent is sieved, and mixed with pregelatinized starch, microcrystalline cellulose, sodium carboxymethyl starch It closes until forming uniform mixture, sieving obtains mixture, and mixes with magnesium stearate.Then by resulting powdered mixture It is pressed into the tablet for needing shapes and sizes.

5 tablet unit dosage form of embodiment

Formulation ingredients: cannabidiol 200mg

Cannabidivarin 40mg

Dextrin 150mg

Sodium carboxymethyl starch 15mg

Magnesium stearate 1mg

Preparation method: the active constituent is sieved, and is mixed with dextrin, sodium carboxymethyl starch until being formed uniform mixed Object is closed, sieving obtains mixture, and mixes with magnesium stearate.Then resulting powdered mixture is pressed into and needs shape and big Small tablet.

6 tablet unit dosage form of embodiment

Formulation ingredients: tetrahydrocannabinol 100mg

Cannabidivarin 40mg

Pregelatinized starch 150mg

Microcrystalline cellulose 25mg

Sodium carboxymethyl starch 15mg

Magnesium stearate 1mg

7 tablet unit dosage form of embodiment

Formulation ingredients: cannabidiol 200mg

Tetrahydrocannabinol 10mg

Pregelatinized starch 150mg

Microcrystalline cellulose 25mg

Polyvinylpyrrolidone 10mg

Sodium carboxymethyl starch 15mg

Magnesium stearate 1mg

Preparation method: the active constituent is sieved, and with pregelatinized starch, microcrystalline cellulose, polyvinylpyrrolidone, Sodium carboxymethyl starch mixing is until form uniform mixture, sieving obtains mixture, and mixes with magnesium stearate.Then by institute The powdered mixture obtained is pressed into the tablet for needing shapes and sizes.

8 tablet unit dosage form of embodiment

Formulation ingredients: tetrahydrocannabinol 100mg

Tetrahydrocannabinol 10mg

Pregelatinized starch 150mg

Microcrystalline cellulose 25mg

Polyvinylpyrrolidone 10mg

Sodium carboxymethyl starch 15mg

Magnesium stearate 1mg

9 tablet unit dosage form of embodiment

Formulation ingredients: tetrahydrocannabinol 100mg

Cannabidivarin 40mg

Tetrahydrocannabinol 10mg

Dextrin 150mg

Sodium carboxymethyl starch 15mg

Magnesium stearate 1mg

Preparation method: the active constituent is sieved, and is mixed with dextrin and sodium carboxymethyl starch until being formed uniform Mixture, sieving obtains mixture, and mixes with magnesium stearate.Then resulting powdered mixture is pressed into need shape and The tablet of size.

10 tablet unit dosage form of embodiment

Formulation ingredients: cannabidiol 200mg

Cannabidivarin 40mg

Tetrahydrocannabinol 10mg

Dextrin 150mg

Sodium carboxymethyl starch 15mg

Magnesium stearate 1mg

11 injection unit dosage forms of embodiment (10mL liquid drugs injection)

Formulation ingredients: tetrahydrocannabinol 500mg

Appropriate hydroxypropyl-β-cyclodextrin

0.1mol/L HCl is appropriate

Appropriate sodium chloride

Water for injection adds to 1000mL

Preparation method: water for injection about 800ml is taken, appropriate hydroxypropyl-β-cyclodextrin is added, adds tetrahydrocannabinol Ingredient is allowed to dissolve, and adjusting pH value with 0.1mol/L HCl is 6.2-6.5, adds to the full amount of water for injection, stirs evenly, and sodium chloride is added To isotonic, it is filling to be passed through steam 121 DEG C of sterilizings 15min, 10ml in ampoule for filtration, encapsulating for allotment.

12 injection unit dosage forms of embodiment (10mL powder-injection)

Formulation ingredients: cannabidivarin 4000mg

Mannitol 50g

0.1mol/L HCl is appropriate

Appropriate hydroxypropyl-β-cyclodextrin

Appropriate sodium chloride

Water for injection adds to 1000mL

Preparation method: taking water for injection about 800ml, be added recipe quantity mannitol and appropriate hydroxypropyl-β-cyclodextrin, then Each cannboid active constituent is added to be allowed to dissolve, stirring is lower to add appropriate 0.1mol/L HCl to adjust pH value for 6.2-6.5, so After add to the full amount of water for injection, sodium chloride is added and deploys to isotonic, filtration is freeze-dried according to freeze drying powder injection technique, Powder-injection is made, 10ml is filling.

Embodiment 13 is administered alone Cannabinoids compound and causes the influence of effect of itching to histamine phosphate

Experimental principle:

Feel itch by central regulation, the adjusting is by being located at the excitement of neuron in spinal cord and inhibiting circuit and opium sample system What system was realized, therefore psychological factor can cause nerve immunity to change, and make central nervous excitation and inhibit functional disturbance, lead to feel of itching Adjustment mechanism, which gets muddled, causes maincenter to be itched feel.Cannabinoids compound can then pass through cannabinoid CB 1 and/or CB2 receptor tune Nervous centralis is saved, improvement itch is reached.

Implementation method:

Take cavy 70, be divided at random blank control group (distilled water 100mg/ days), cannabidiol group (50mg/ days, 100mg/ days, 200mg/ days), tetrahydrocannabinol group (40mg/ days, 80mg/ days, 100mg/ days), cannabidivarin group (40mg/ It, 80mg/ days, 100mg/ days), tetrahydrocannabinol group (5mg/ days, 10mg/ days, 20mg/ days), control group (chlorpheniramine 10mg/ days), every group 5.Dorsal portion shaving 2cm × 2cm after each group cavy is right is administered orally according to above-mentioned dosage respectively, Successive administration 3 days.It is administered the 3rd day, is abraded at shaving respectively with coarse sandpaper, to injure epidermis, have slight oozing of blood for degree, 10 minutes Afterwards, 0.01% histamine phosphate solution of 0.05ml is dripped at every cavy surface of a wound respectively, hereafter every 3min phosphoric acid group incremented by successively Concentration (such as 0.02%/0.03%/0.04%/0.05%/0.06% etc.) the histamine phosphate solution of amine is until cavy returns When head licks sufficient, the total amount of the given histamine of every cavy is recorded, using this total amount as itch-threshold.

Experimental result:

From this experiment as can be seen that cannabidiol and tetrahydrocannabinol, which is administered alone, can be relieved histamine phosphate and cause Itch effect.

Embodiment 14 applies Cannabinoids compound composition and causes the influence of effect of itching to histamine phosphate

Although be administered alone cannabidiol and tetrahydrocannabinol show it is certain histamine phosphate is caused to itch the alleviation of effect, But it prefers to it can be found that having the active constituent of more preferably effect.Therefore, this experiment compares different group Cannabinoids chemical combination Compositions cause the influence of effect of itching to histamine phosphate.

Implementation method:

Cavy 90 are taken, it is random to divide equally are as follows:

Tetrahydrocannabinol (THC) and tetrahydrocannabinol (THCV) drug combination group；

Cannabidiol (CBD) and cannabidivarin (CBDV) drug combination group；

Tetrahydrocannabinol (THC) and cannabidivarin (CBDV) drug combination group；

Cannabidiol (CBD) and tetrahydrocannabinol (THCV) drug combination group；

Cannabidiol (CBD), cannabidivarin (CBDV) and tetrahydrocannabinol (THCV) drug combination group；

Tetrahydrocannabinol (THC), cannabidivarin (CBDV) and tetrahydrocannabinol (THCV) drug combination group:

Every group 5, experimental procedure is the same as embodiment 13.

Experimental result:

From this experiment as can be seen that compared with cannabidiol and tetrahydrocannabinol is administered alone, two or more cannboids The combination of class compound has more preferably effect, this may be from the receptor binding site difference phase of different Cannabinoids compound effects It closes.

The clinical research of 15 Cannabinoids compounds on nerve dermatitis of embodiment

Select the generalized neurodermatitis patient of Dermatology Outpatient Department and inpatient department.

Diagnostic criteria: meet the diagnosis in " clinical dermatology " in relation to neurodermatitis.Its clinical manifestation mainly with Skin lichenification and violent itch are characterized.It mostly occurs in nape or its two sides, the fossa cubitalis, rouge nest, forearm, thigh, shank And lumbosacral region etc..Subjective symptoms is often the violent itch of paroxysmal, night be very, most of patients have dizziness, insomnia, irritable, The neurasthenic symptom such as anxious.

Exclusion criteria: 1. skin lesion merges bacterium or fungal infections；2. gestation or breast feeding women；3. in first 1 week selected The used glucocorticoid medicine in part, or took Loratadine person；4. system applied glucocorticoids in 1 month Drug person；5. known to research medicine and its matrix components allergy sufferers；6. having Chronic Liver, kidney diaseases or other severe illness person；⑦ There are diabetes or serious immunologic hypofunction person.

90 clinical observations of neurodermatitis patient made a definite diagnosis are selected, patient is randomly divided into nine groups, wherein Cannabinoids Eight groups of He Wu treatment group, totally 80 people, women 24, the age 30~61 years old, uses embodiment 1/3/5/6/7/8/9/ by male 56 The preparation of 10 preparations, every group of 10 men and women random selection.10 people of control group doxepin hydrochloride group, wherein male 5, women 5, Age 30~61 years old.

Treatment method: preparation prepared by the oral embodiment 1/3/5/6/7/8/9/10 of Cannabinoids compound treatment group, 1 Secondary/d takes before sleeping, and even served 2 weeks；Control group uses doxepin hydrochloride 25mg/ times, takes orally, 1 time/d, takes before sleeping, even served 2 Week.

Observation index includes itch degree, degree of inflammation, scales of skin that peel off plumpness degree and target skin lesion face, selects the skin lesion of most serious Position is as target cutaneous lesion, and area, clinical symptoms and the sign of record target skin lesion change when each follow-up, does not have to during treatment Other any drugs.Carry out observation, the assessment of skin lesion part in treating first 1 week, treating in 2 weeks and drug withdrawal 1 month weekly.Skin lesion Methods of marking is as follows:

Curative effect determinate standard: standards of grading are that each index scores by 4 grades of point systems in each assessment, i.e., 0 is Nothing, 1 be it is slight, 2 be moderate, and 3 be severe.The rotten to the corn scoring < 1 of all patients is required to divide when entering group, skin lesion area is then remembered without exception It is 3 points, and records the aggregate value of each index scoring.Efficacy determination: sentenced using the percentage of integrated value reduction as therapeutic index Disconnected curative effect, the calculation formula of therapeutic index are as follows: integrated when (integral when integrating total-each follow-up when first visit is total)/first visit Total × 100%.Therapeutic index > 90%, for recovery from illness, 61%~89%, to be effective, 20%~60% is effective, < 20%, It is invalid.

Clinical test results are as follows:

From this experiment as can be seen that cannabidiol, tetrahydrocannabinol is administered alone and two or more hemps are administered in combination The combination of chlorins compound all has clinical efficacy to neurodermatitis, and the group of two or more Cannabinoids compounds is administered simultaneously Closing has more preferably effect.

Claims

1. A cannabinoid compound or a pharmaceutically acceptable salt thereof selected from tetrahydrocannabinol (THC), cannabidiol (CBD), hypocannabinol (CBDV), tetrahydrocannabinol (THCV) Use in the separate preparation of a pharmaceutical composition for the treatment of neurodermatitis.

2. Use of a cannabinoid compound or a pharmaceutically acceptable salt thereof in the preparation of a pharmaceutical composition for the treatment of neurodermatitis, the cannabinoid compound being selected from:

(1) a combination of tetrahydrocannabinol (THC) and tetrahydrocannabinol (THCV);

(2) a combination of cannabidiol (CBD) and sub-cannabidiol (CBDV);

(3) a combination of tetrahydrocannabinol (THC) and cannabidiol (CBDV);

(4) a combination of cannabidiol (CBD) and tetrahydrocannabinol (THCV);

(5) a combination of cannabidiol (CBD), hypocannabinol (CBDV) and tetrahydrocannabinol (THCV);

(6) A combination of tetrahydrocannabinol (THC), hypocannabinol (CBDV) and tetrahydrocannabinol (THCV).

3. The purposes of the cannabinoid compound of claim 2 or a pharmaceutically acceptable salt thereof in the preparation of a pharmaceutical composition for the treatment of neurodermatitis, wherein:

(1) The combination of tetrahydrocannabinol (THC) and tetrahydrocannabinol (THCV) by weight ratio of tetrahydrocannabinol (THC) and tetrahydrocannabinol (THCV) is 100:5-20;

(2) The combination of cannabidiol (CBD) and sub-cannabidiol (CBDV) is 100:20-50 by weight of cannabidiol (CBD) and sub-cannabidiol (CBDV);

(3) The combination of tetrahydrocannabinol (THC) and secondary cannabidiol (CBDV) is 100:40-100 by weight of tetrahydrocannabinol (THC) and secondary cannabidiol (CBDV);

(4) The combination of cannabidiol (CBD) and tetrahydrocannabinol (THCV) is 100:2.5-10 by weight of cannabidiol (CBD) and tetrahydrocannabinol (THCV);

(5) Combination of cannabidiol (CBD), sub-cannabidiol (CBDV) and tetrahydrocannabinol (THCV) by weight of cannabidiol (CBD), sub-cannabidiol (CBDV) and THC Phenol (THCV) is 100:20-50:2.5-10;

(6) Combination of tetrahydrocannabinol (THC), sub-cannabidiol (CBDV) and tetrahydrocannabinol (THCV) by weight THC, sub-cannabidiol (CBDV) and tetrahydrocannabinol (THC) Secondary cannabinol (THCV) was 100:40-100:5-20.

4. a pharmaceutical composition for the treatment of neurodermatitis, characterized in that, the pharmaceutical composition is made up of the following components:

1) Cannabinoid compounds or their pharmaceutically acceptable salts;

2) one or more pharmaceutically acceptable carriers or excipients;

The cannabinoid compound is selected from one of tetrahydrocannabinol (THC), cannabidiol (CBD), sub-cannabinol (CBDV), and tetrahydrocannabinol (THCV).

5. a pharmaceutical composition for the treatment of neurodermatitis, characterized in that, the pharmaceutical composition is made up of the following components:

1) Cannabinoid compounds or their pharmaceutically acceptable salts;

2) one or more pharmaceutically acceptable carriers or excipients;

The cannabinoid compounds are selected from:

(2) a combination of cannabidiol (CBD) and sub-cannabidiol (CBDV);

(3) a combination of tetrahydrocannabinol (THC) and cannabidiol (CBDV);

(4) a combination of cannabidiol (CBD) and tetrahydrocannabinol (THCV);

6. The pharmaceutical composition of claim 5, wherein the cannabinoid compound is selected from the group consisting of:

(1) The combination of tetrahydrocannabinol (THC) and tetrahydrocannabinol (THCV) is 100:5-20 by weight of tetrahydrocannabinol (THC) and tetrahydrocannabinol (THCV);

7. The composition according to any one of claims 4-6, wherein the pharmaceutical composition is selected from capsules, tablets, pills, lozenges, granules, solutions, emulsions, suspensions , syrups, sterile injectables, sterile powders, suppositories, sprays, ointments, creams, gels, inhalants, skin patches or implants.

8. The method for preparing the composition of any one of claims 4-6, characterized in that, comprising the steps of: mixing one or more of the cannabinoid compounds or their pharmaceutically acceptable salts in proportion to obtain the composition.