CN100594897C - Cannabinoid liquid formulations for mucosal amdinistration - Google Patents

Abstract

The present invention relates to a pharmaceutical preparation, in particular to a preparation containing cannabinoid, which is delivered in the form of spay by the function of a pump. Specifically, the present invention relates to a pharmaceutical preparation which gives a lipophilic drug via the mucosa surface, and the lipophilic drug includes one or manifold cannabinoids. The preparation contains at least one type of lipophilic drug containing one or manifold cannabinoids, solvent and latent solvent, wherein, the total amount of the solvent and the latent solvent is larger than 55 percent wt/ wt of the preparation, the preparation does not contain self-emulsifying agent and / or contains fluorine propellant, and more than 10 mg/ml of cannabinoid exists in the preparation.

Description

The Cannabinoids liquid preparation of mucosa delivery

Invention field

The present invention relates to pharmaceutical preparation, and more particularly, relate to the preparation that contains Cannabinoids through the pumping action spray delivery.

Background of invention

Knownly for a long time medicine is introduced systemic circulation system with effect such as increase active onset and tire by the contact mucosa.

For example, US 3,560, and 625 disclose the aerosol of alkoxy benzamides being introduced systemic circulation system.Two kinds of dissimilar aerosols are disclosed:

A) contain the alkoxy benzamides of 2% weight, the fluorohydrocarbon type of 18% ethanol and 80% propellant; With

B) contain the alkoxy benzamides of 0.5% weight, contain the aerosol apparatus type of the mixed solvent system and 57.8% deionized water of 10.3% ethanol and 31.4% propylene glycol.

US 3,560,625 have found a problem so that produce the arosol spray that is used for sucking EBA seeking the The suitable solvent system, promptly because such fact, though ethanol is undoubtedly best solvent, produce mouthfeel beastly but contain the alcoholic acid mixture that surpasses 18% weight, offset even surpassed the effect of oral route.

WO 01/13866 open delta-9-Tetrahydrocannabinol (Δ ⁹THC) half water (semiaqueous) solution.This solution contains ethanol, the water of 10-30% and pharmaceutically acceptable glycerol.Prepare described solution in order to transmit medicine, and have granularity for this reason less than 10 microns by suction.Water improves dispersion and aerosolization.The example of property has shown the Δ in 50/50 ethanol and propylene glycol mixture as a comparison ⁹The solution of THC.

US 4704406 relates to the sprayable Pharmaceutical composition that contains aryl-alkanoic that is suitable for topical application.

When the applicant planned to produce the spray agent of the plant amedica material (botanical drug substance) that contains one or more Cannabinoidses, they recognized the problem that the highly lipophilic of Cannabinoids may exist when the described active component of preparation.

The applicant at first explores a kind of oromucosal formulation in question of exploitation, and administration is transmitted with the form of pressurised aerosol or spray in preferred Sublingual, as disclosed in the International Patent Application WO of announcing 01/66089 (PCT/GB01/01027).Their initial concerns are the propellant with HFC-123a and HFC-227 system, but these propellant proof and be not suitable for solvent as described Cannabinoids.Described preparation contains the synthetic Δ of the amount of from 0.164 to 0.7% weight ratio ⁹THC and the ethanol that reaches as high as the amount of 20.51% weight as primary solvent.A kind of concrete compositions contains 0.164% synthetic Δ 9-THC, 4.992% ethanol, 4.992% propylene glycol and 89.582%p134a (propellant).

The applicant finds alcoholic acid level even when 20% volume of preparation cumulative volume, they can not dissolve the Δ of enough levels in standard spray dosage ⁹THC is to meet clinical needs, because the dissolubility of described Cannabinoids in described propellant is very poor.They also find to increase alcoholic acid level, because when increasing above critical ratio than low voc solvent, the transmission characteristic of device nozzle changes substantially.HFC-123a and HFC-227 propellant spray delivery maximum are 7mg/ml, yet initial clinical research is advised that described preparation need contain and reached as high as 50mg Cannabinoids/ml.

Therefore, gone through the self-emulsifying drug delivery system that the applicant pays close attention in one piece of survey article of European Journal of Pharmaceutics and Biopharmaceutics 50 (2000) 179-188, its conclusion is that the water solublity of the difference of many chemical entities is real challenges to the appropriate formulations design that is intended to improve oral administration biaavailability.

In the International Application No. WO 02/064109 (PCT/GB02/00620) of pending trial, this application people discloses numerous preparations that contains Cannabinoids at the same time, and described preparation contains at least a self-emulsifier., in said preparation, to comprise at least a self-emulsifier and be considered to necessary so that realize the described preparation of the absorption of enough Cannabinoidses in order obtaining to adhere to mucomembranous surface.A kind of concrete preparation contains the glycerin mono-fatty acid ester of 2% weight, the 5%CBME that obtains the G1 Fructus Cannabis of THC, the CBME that obtains the G5 Fructus Cannabis (cannabis) 5% of CBD, 44% ethanol Bp and 44% propylene glycol.

Astoundingly, the applicant has been found that at the through port transmucosal, thereby particularly the mucosal use of Sublingual and cheek realizes definitely not requiring to exist a kind of self-emulsifier in the liquid preparation of gratifying dosage level.

Really, with US 3,560,625 is opposite with the instruction of European Journal of Pharmaceutics andBiopharmaceutics 50 (2000) 179-188, they can produce a kind of simple and effectively solvent be used for transmitting lipophilic drugs at liquid spray.

Summary of the invention

According to a first aspect of the present invention, a kind of liquid pharmaceutical formulation is provided, be used for comprising the lipophilic drugs of one or more Cannabinoidses through mucomembranous surface, said preparation contains: the lipophilic drugs, solvent and the cosolvent that comprise one or more Cannabinoidses, wherein solvent and the cosolvent total amount in described preparation is greater than 55% weight ratio of described preparation, described preparation does not exist self-emulsifier and/or fluorine-containing propellant, and the amount that is present in the described Cannabinoids in the said preparation is greater than 10mg/ml.

Preferred one or more Cannabinoidses exist with the form from least a extract of at least a Fructus Cannabis (cannabis) plant.Described Cannabis plant optimization comprises at least a Fructus Cannabis (cannabis chemovar (Fructus Cannabis chemovar)).Most preferably described plant extract is a kind of plant amedica material (BDS) of definition in this.

Described preparation can be chosen wantonly and contain flavoring agent in addition, as Oleum menthae.

Except Cannabinoids, described preparation also can contain other active component, is preferably a kind of opiate, as morphine.Therefore, plan provides the preparation that contains one or more Cannabinoidses, ethanol, propylene glycol and opiate (being preferably morphine) basically.

That provide in the mode of embodiment and do not plan to limit in the 1ml volume, can containing of the scope of the invention: THC 25-50mg/ml according to typical liquid pharmaceutical formulation of the present invention, preferred 25mg/ml or 27mg/ml (amount based on Cannabinoids in the plant amedica is calculated), CBD 25-50mg/ml, preferred 25mg/ml (amount based on Cannabinoids in the plant amedica is calculated), propylene glycol 0.5ml/ml, Oleum menthae 0.0005ml/ml and an amount of ethanol (anhydrous) are to 1ml.

Other preferred preparation comprises " high THC " preparation, described preparation contains in the 1ml volume: THC 25mg/ml or 27mg/ml (amount of Cannabinoids is calculated in based on plant amedica), propylene glycol 0.5ml/ml, Oleum menthae 0.0005ml/ml, and an amount of ethanol (anhydrous) is to 1ml; And " high CBD " preparation, it contains in the 1ml volume: CBD 25mg/ml (amount of Cannabinoids is calculated in based on plant amedica), propylene glycol 0.5ml/ml, Oleum menthae 0.0005ml/ml, and an amount of ethanol (anhydrous) is to 1ml.

In these preferred preparations, add the plant amedica material that derives from the Cannabis plant, the amount of the Cannabinoids of proposition is with respect to the total amount (weight) that is present in the Cannabinoids in the final preparation of 1ml.Have the reader of Professional knowledge will understand that the BDS total amount that must add for the Cannabinoids that reaches aequum in final preparation will depend on the concentration of the Cannabinoids that exists in BDS, described concentration will change because of the BDS of different batches.

The simple combination of one or more Cannabinoidses, ethanol and propylene glycol can be used for the spray of pumping action effectively, and this discovery is unexpected.

The applicant has been found that described solvent/co-solvent system is ethanol/propylene glycol and lipophilic medicine comprises the Cannabinoids of one or more plant amedica (BDS) form, and the solvent/co-solvent effectively limit of work is very narrow, is discussed below.

The amount of solvent/co-solvent is preferably greater than 80%, more preferably in 90 to 98% scope.

Described preparation preferred water content is lower than 10%, or is lower than 9%, or is lower than 8%, or is lower than 7%, or is lower than 6%, or is lower than 5%, or is lower than 4%, or is lower than 3%, or is lower than 2%, or is lower than 1%, or is lower than 0.5%.

Described preparation does not preferably contain the propellant of any kind.

Described preparation does not contain any self-emulsifier yet.In this " self-emulsifier " be defined as the reagent that when having the alternately phase (alternate phase) that has desired least energy, forms a kind of emulsion.On the contrary, corresponding with self-emulsifier, emulsifying agent is a kind of reagent that requires extra energy could form emulsion.Usually self-emulsifier is soap, salt or the sulphation alcohol ester of solubility, especially is non-ionic surfactant or tetravalence chemical compound.Exemplary self-emulsifier includes, but are not limited to glycerin mono-fatty acid ester (particularly SE level), glyceryl monostearate (particularly SE level), Polyethylene Glycol (macrogols) and hydrogenant (polyoxyhydrogenated) Oleum Ricini of polyoxygenated such as polyoxyethylene castor oil.

Described preparation can contain flavoring agent in addition.Preferred flavoring agent is an Oleum menthae, preferably exists with the amount that reaches as high as 0.1% volume, is generally 0.05% volume ratio.

Described solvent is preferably selected from C1-C4 alcohol.Preferred solvent is an ethanol.

Described cosolvent is preferably the solvent of " elementary " solvent that allows to use low amount.In the combination that contains " elementary " solvent, it should dissolve enough lipophilic drugs, promptly dissolves the medically lipophilic drugs of effective dose.Effective dose medically will change because of medicine, but for Cannabinoids, and its effective dose medically will be at least and be preferably greater than the 1.0mg/0.1ml solvent/co-solvent.

Preferred cosolvent is selected from glycol, sugar alcohol, carbonic ester and chlorinated hydrocabon.

Described glycol is preferably selected from propylene glycol and glycerol, most preferably propylene glycol.The preferred propylene carbonate of described carbonic ester.

Most preferred be combined as ethanol as solvent and propylene glycol as cosolvent.

The liquid preparation that the preparation oropharynx transmits Cannabinoids has brought many problems.At first, must in every 0.1ml liquid preparation, transmit 1.0mg at least, or 1.5mg at least, or 2.0mg at least, more preferably 2.5mg at least, even more preferably at least the Cannabinoids of 5mg so that in a unit dose, reach therapeutical effect.The patient may need to take and reaches as high as 120mg Cannabinoids/sky in this, on average is about 40mg/ days, maximum 6 dosage.

Under the situation of Sublingual or cheek transmission,, mean that the amount with amount of formulation transmission active component will be that patient institute is insupportable if through mucous membrane absorbs described active component.

Though can reach described dosage in the ethanol as solvent by dissolving described Cannabinoids, the ethanol of high concentration causes sensation and has exceeded the limit of standing.

Therefore, need to use a kind of cosolvent, can also make the Cannabinoids dissolving of q.s simultaneously so that reduce alcoholic acid amount.

The application has been found that the selection of cosolvent is limited.Preferred cosolvent should have sufficient dissolution, and enough Cannabinoidses are dissolved in the unit dose, just at least and be preferably greater than the 1.0mg/0.1ml preparation, and the amount of the solvent of existence is reduced in the limit that the patient can tolerate.The suitable especially cosolvent that reaches these standards is propylene glycol and glycerol.

In preferred embodiments, be present in 65% weight ratio of the total amount of solvent in the described preparation and cosolvent, more preferably greater than 70% weight ratio, more preferably greater than 75% weight ratio greater than described preparation, more preferably greater than 80% weight ratio, more preferably greater than 85% weight ratio.The total amount that is present in solvent in the described preparation and cosolvent most preferably in 80% weight ratio of described preparation in the scope of 98% weight ratio.

In preferred embodiments, be liquid preparation according to preparation of the present invention, said preparation is by the pumping action spray delivery.Pumping action spraying is characterised in that and requires to adopt outside Pressure stimulation, for example outside manually, the pressure of machinery or power start.This is opposite with compression system, the arosol spray of propellant-driving for example, and wherein activating (actuation) is release by controlled pressure, for example realizes by opening of by-pass valve control.

Find that the pumping action spraying is useful especially when transmitting Cannabinoids.Really, people in the past pay close attention to solvent system always and comprise propellant.

Admit this type systematic defectiveness simultaneously, comprise transmission speed, those skilled in the art attempts by reducing propellant or addressing this problem by changing nozzle always.The applicant finds to use pump to spray in their preparation they can produce spraying, and microgranule wherein has the average aerodynamic granularity between 15 and 45 microns, more particularly between 20 and 40 microns and average about 33 microns.This and the granule that has the dynamic (dynamical) granularity of average air between 5 and 10 microns when adopting compression system to transmit form contrast.

In fact, the contrast experiment that the applicant carries out has shown that the pumping action spraying system has advantage, can transmit described active component in the target region on the bigger surface area.The embodiment 3 that consults is subsequently set forth in this experiment.

The variation of distribution of particles and spraying area confirms by direct experiment.As in the sprayer unit that preparation is filled into as described in the embodiment 4 subsequently pumping action (the Valois vial typeVP7100 of actuating).Same preparation is filled in the pressurizing vessel of using HFA 134a to produce power.

The thin paper 50mm distance of (being positive front) of two containers all meeting at right angles in the direction of propagation that is placed on injection from penetrates.Then light is manifested the spray pattern that penetrates 100ul in both cases and produced.In both cases, the pattern of ejaculation is circular and measures as follows:

	Average diameter (mm)	Average area (mm 2)
			The pumping action spraying	23	425.5
Pressure atomization	16	201.1

The center that is sprayed at the zone of pressurization produces the liquid of concentrating.The pumping action spraying provides more uniform spray pattern and less " bounce-back ".By the pumping action spraying significant bigger area coverage is arranged also.The condition that experimentizes is relevant with the actual device that uses.The spraying of pressure atomization pumping action can reach the larger area oral mucosa relatively.

For the application of pump spraying, described solvent/co-solvent combination must have in preferred solvent/co-solvent makes up viscosity in the defined range of viscosities.Therefore, for the combination of ethanol/propylene glycol, viscosity should be between following: wherein ethanol/propylene glycol is with 60/40 and 40/60, more preferably with 55/45 to 45/55 most preferably the relative volume ratio with about 50/50 exist.

The aerosol transmission that allows to produce when the viscosity of the preparation that (Valois) produces when packing by a mechanical pump such as VP7 activated valve (actuator valve) for the pumping action transmission has the average air kinetics granularity of 20-40 micron, more preferably 25-35 and the particle mean size of 30-35 micron most preferably.Transmit this maximization that contacts feasible and the target mucosa for Sublingual/cheek.

Preferably contain one or more Cannabinoidses as lipophilic drugs according to preparation of the present invention.

Preferred described lipophilic drugs is at least a kind of extract from least a Cannabis plant.Described Cannabis plant optimization comprises at least a Fructus Cannabis (cannabis chemovar).Most preferably described plant extract is a kind of plant amedica material (BDS) of definition in this.

" plant extract " is the extract from plant material, as at Guidance forIndustry Botanical Drug Products Draft Guidance, August 2000, USDepartment of Health and Human Services defines among the Food and Drug AdministrationCentre for Drug Evaluation and Research.

" plant material " is defined as plant or plant part (as bark, trees, leaf, stem, root, flower, really, seed, berry or its part) and exudate.

Term " Cannabis plant " comprises the Fructus Cannabis (Cannabis sativa) and the mutation thereof of wild type, comprise the natural Fructus Cannabis (cannabis chemovars) that contains not commensurability single Cannabinoids, ganja subspecies (Cannabis sativa subspecies indica) comprise mutation ganja mutation (var.Indica) and kafiristanica mutation (var.Kafiristanica), ganja (Cannabis indica) and generation genetic cross (genetic crosses), the plant of selfing (self-crosses) or its hybrid (hybrids).Therefore term " Cannabis plant material " is considered to derive from the plant material of one or more Cannabis plants.Therefore for avoiding query regulation " Cannabis plant material " to comprise exsiccant hemp biological amount (biomass).

Term in the application's context " Fructus Cannabis extract " or the term that is used interchangeably " derive from the extract of Cannabis plant " and comprise " the plant amedica material " that derives from the Cannabis plant material.At Guidance for Industry Botanical Drug Products Draft Guidance, August 2000, US Department of Health and Human Services, definition plant amedica material is among the Food andDrug Administration Centre for Drug Evaluation and Research: " derive from one or more plants, algae, or the drug substance of macroscopic Mycophyta.Be prepared by material of vegetable origin in order to following a kind of or several different methods: pulverize, decoct, squeeze out, water is carried, alcohol extraction or other similar method." the plant amedica material do not comprise the material that derives from natural resources of highly purified or chemical modification.Therefore, under the situation of Fructus Cannabis, " the plant amedica material " that derive from the Cannabis plant do not comprise Cannabinoids highly purified, pharmacopeia level (Pharmacopoeial grade).

According at Guidance for Industry Botanical Drug Products DraftGuidance, August 2000, US Department of Health and Human Services, definition among the Food and Drug Administration Centre for Drug Evaluation and Research, " based on the drug extract (CBMEs) of Fructus Cannabis ", CBMEs as with the described method preparation of embodiment subsequently is classified as " plant amedica material ".

" the plant amedica material " that derives from the Cannabis plant comprises the primary extract with this class methods preparation, described method have dipping for example, diafiltration, with as C1 arrives the alcohol (as ethanol), Norflurane (HFA134a), HFA227 of C5 and in subcritical or postcritical liquid carbon dioxide solvent extraction.Described primary extract can further be carried out purification by supercritical or subcritical solvent extraction, evaporation or chromatography.When using those solvents listed above, the extract that obtains contains nonspecific liposoluble substance.This can remove by the whole bag of tricks, comprises " winterization ", and described winterization comprises sharply and be cooled to-20 ℃ that subsequent filtration goes out waxy precipitation, extracts and distillation with liquid carbon dioxide.

In the embodiment that Cannabinoids provides with BDS, this BDS is preferably by using CO under subcritical or postcritical condition therein ₂Extract, extract once more subsequently,, obtain so that shift out most wax and other precipitation (ballast) as ethanol precipitation.This is because described precipitation is included in selected solvent/co-solvent, can not fine dissolving in the particularly preferred cosolvent propylene glycol and with the wax ester and glyceride, undersaturated fatty acid residue, terpene, carotin and the flavenoids that are precipitated out.Most preferably described BDS is by such method preparation, and this method comprises decarboxylation, extracts with liquid CO 2, further extracts so that remove a large amount of precipitate then.Most preferably fully remove described precipitate by ethanol precipitation.

Best, the temperature that the Cannabis plant material is heated to regulation reaches official hour, so that make Cannabinoids acid (cannabinoid acids) the decarboxylize Cannabinoids that dissociates before extracting BDS.

Preferably " plant amedica material " comprises that those can disclosedly in this prepare the plant amedica material that any method of extract or step obtain from the Cannabis plant material by using.Described extract does not preferably contain wax and other nonspecific liposoluble substance substantially, but preferably fully contains all natural Cannabinoidses that are present in the described plant, most preferably exists with essentially identical ratio in complete Cannabis plant.

Medicinal plants plasmogamy is made as " plant amedica product ", as at Guidance for IndustryBotanical Drug Products Draft Guidance, August 2000, US Department ofHealth and Human Services among the Food and Drug Administration Centre forDrug Evaluation and Research is defined as it: " a kind of plant product that is intended as drug use; A kind of medicine by the preparation of plant amedica material.”

" Cannabis plant " comprises wild type Fructus Cannabis (Cannabis sativa) and mutation thereof, comprises the natural Fructus Cannabis (cannabis chemovars) that contains each not commensurability single Cannabinoids.

Term " Cannabinoids " also comprises material that can be by purifying natural source or the material of highly purified, the pharmaceutical grade that obtains through synthesizing mean.Therefore, can be used for transmitting Cannabis plant extract and single Cannabinoids according to preparation of the present invention, or its synthetic analog, no matter whether derive from the Cannabis plant, and the combination of Cannabinoids.

Preferred Cannabinoids includes, but not limited to the tetrahydrochysene Cannabinoids, their precursor, alkyl (particularly propyl group) analog, cannabidiol, their precursor, alkyl (particularly propyl group) analog and cannabinol.In preferred embodiments, described preparation can comprise any following Cannabinoids that is selected from: tetrahydrocannabinol, Δ ⁹-tetrahydrocannabinol (THC or Δ ⁹-THC), Δ ⁸-tetrahydrocannabinol, Δ ⁹-tetrahydrocannabinol propyl group analog (THCV), cannabidiol (CBD), cannabidiol propyl group analog (CBDV), cannabinol (CBN), cannabichromene (CBC), cannabichromene propyl group analog and cannabigerol (CBG), or two or more any combination in these Cannabinoidses.Well-known THCV and CBDV (being respectively the propyl group analog of THC and CBD) are prevailing Cannabinoids in special Cannabis plant variety and find that THCV has more good characteristic in nature than THC and CBD.The patient of picked-up THCV reports that THCV causes, and the excited situation excitement that causes than THC is little.Its also less serious sequela (hangover) that causes.

Most preferably contain THC and/or CBD according to preparation of the present invention.

In preferred embodiments, described preparation can contain predetermined weight ratios concrete, different Cannabinoidses, as concrete ratio or the tetrahydrocannabinovarin (tetrahydrocannabinovarin of CBD to THC, THCV) to cannabidivarin CBDV Cannabidivarol (cannabidivarin, CBDV), or THCV to the ratio of THC.Some the concrete ratio that has been found that Cannabinoids is used for the treatment of clinically or handles special disease or medical science situation.In detail, have been found that some this type of preparation can be used in particular for the field that eases the pain and stimulate appetite.

The applicant's special survey is more useful than any single Cannabinoids to the combination of special Cannabinoids.Embodiment preferred be those wherein the weight of CBD greater than the preparation of the weight of THC.It is new for uncommon that this type of preparation is called as " inverse proportion " preparation and this type of preparation, because in worldwide obtainable many medical treatment and (recreational) amusement Cannabis plant, the relative THC of CBD is accessory composition.THC and CBD or THCV and CBDV exist with almost equal amount in other embodiments, or THC or THCV are 95.5% of main component and the total Cannabinoids that can reach existence.

Preferred preparation contains the THC and the CBD of definite weight ratio.Most preferred preparation contains THC: THC and the CBD of CBD in 0.9: 1.1 to 1.1: 0.9 weight ratio scope, even more preferably the ratio of THC: CBD is essentially 1: 1.Other preferred preparation contains the THC and the CBD of following weight ratio: more than or equal to 19: 1 THC: CBD, more than or equal to the THC of 19: 1 CBD: THC, 4.5: 1 THC: CBD, 1: 4 THC: CBD and 1: 2.7: CBD.For THC wherein: the CBD ratio is essentially for 1: 1 the preparation, and preferred described preparation contains THC and the CBD of about 25mg/ml respectively.

Medically use Fructus Cannabis for many years always, and be a kind of widely used prescription drugs composition at the Victorian era (Victoriantimes).Use it as hypnosis tranquilizer treatment " hysteria, mental disorder, epilepsy, nerve insomnia, migraine, pain and dysmenorrhea ".The use of Fructus Cannabis lasts till the twentieth century middle period, and its effectiveness as prescription drugs is reappraised at present.The discovery of specificity Cannabinoids receptor and new medication expands the use based on the medicine of Fructus Cannabis to traditional indication becomes possibility with new indication.

The recreational use of Fructus Cannabis is impelled legislation, thereby causes forbidding its use.Many in history doctors think that the neuropathic pain in spinal cord injury and other form comprises under the situation of the pain of multiple sclerosis and spasm, and Fructus Cannabis is the unique ability of elimination to the drug-fast pain of opioid analgesic that have.

In the U.S. and the Caribbean, the Fructus Cannabis of planting because of recreational use is selectively so that it contains high-load tetrahydrocannabinol (THC) always, is cost with the loss of other Cannabinoids.In Merck Index (1996), other is known to be present in the material that Cannabinoids in the Fructus Cannabis such as cannabidiol and cannabinol are considered to non-activity.Though cannabidiol is considered to a kind of composition of non-activity in the past, evidence suggests that it has the pharmacological activity that is different from THC aspect several.Only use a kind of or other " activity " composition can not be explained the therapeutical effect of Fructus Cannabis satisfactorily.

Shown that independent use tetrahydrocannabinol (THC) produces pain relief than low degree than the Fructus Cannabis extract of the THC that provides same amount.Studied the pharmacological basis under this phenomenon.In some cases, in identical preclinical test, THC and cannabidiol (CBD) have the pharmacological property of adverse effect, and have the pharmacological property of same function in other test.For example, in some clinical research and in the anecdote report, there is a kind of CBD of sensation to improve THC to remarkable effect that nerve play.The spectrum activity of these two kinds of Cannabinoidses can help to explain some treatment benefits of the Fructus Cannabis that is grown in zones of different in the world.It also points out the beneficial effect by THC and CBD combination results.The applicant is studying these aspects always.Following table 1 shows the difference of the pharmacological properties of these two kinds of Cannabinoidses.

Table 1

Effect T HC THCV CBD CBDV document

CB ₁(brain receptor) ++ ± Pertwee etc., 1998

CB ₂(peripheral acceptor)+-

The CNS effect

Convulsion

--++ Carlini etc., 1973

Anti-cardiazol--the GW data

(Antimetrazol)

Anti-galvanic shock-++ the GW data

Of flaccid muscles--++ Petro, 1980

Antinociceptive activity +++GW data

Stiff disease ++ ++ the GW data

Nerve is played remarkable effect ++-GW data

Psychosis-++ Zuardi etc., 1991

The neuroprotective antioxidant+++ Hampson A J etc.,

Behavior * ++-1998

Emesis++

Calm (minimizing spontaneous behaviour) ++ Zuardi etc., 1991

Stimulate appetite ++

Appetite-suppressing-++

Anxiety GW data

The cardiovascular effect

The bradycardia-+Smiley etc., 1976

Tachycardia+-

Hypertension §+-

Hypopiesia §-+Adams etc., 1977

Antiinflammatory action ± ±

Immunomodulating/anti-inflammatory activity

Scratch (Raw) paw edema assay-++ the GW data

Cox 1 GW data

Cox 2 GW data

The TNFa antagonism++ ++ ++

Glaucoma +++

* effect does not rely on the CB1 receptor.

THC is former convulsant (pro convulsant).

§ THC has two-way function to blood pressure; It causes hypotensive situation and also reports for the life-time service person and causes hypertension in (naive) patient who tests first.GWInternal Report No 002/000159。

The direct experiment that these pharmacology features and the application carry out has shown unexpectedly that the THC of different proportion and being combined in some treatment of conditions of CBD are useful especially.The toxicity of further finding THC and CBD mixture clinically is less than the toxicity of using THC separately.

Therefore, the invention provides pharmaceutical preparation with the above basic feature, its contain have special ratios as the Cannabinoids of active medicine and described Cannabinoids CBD than THC, have been found that described preparation is used for the treatment of clinically or handles special disease or medical conditions.

On the other hand, the present invention also relates to have the pharmaceutical preparation of all above basic features that define, and it contains the tetrahydrocannabinovarin (THCV) or the cannabidivarin CBDV Cannabidivarol (CBDV) of special ratios.THCV and CBDV (being respectively the propyl group analog of THC and CBD) are known Cannabinoids, the main THCV characteristic that has fine qualities when expressing (expressed) and having been found that respectively with THC and CBD relatively in special Cannabis plant variety.The patient of picked-up THCV reports that THCV causes excited than THC cause little.It is also less to cause serious sequela.

The present invention also further relates to and has the pharmaceutical preparation of all basic features as defined above, and the THCV that contains special ratios is than THC, has been found that this type of preparation is at alleviating pain with particularly useful aspect stimulateing appetite.

The applicant's special survey has more advantage to the combination of special Cannabinoids than the single Cannabinoids of any independent use.Embodiment preferred be those wherein the weight of CBD greater than the preparation of the weight of THC.This type of preparation is called as " inverse proportion " preparation and is new for uncommon, because in the Cannabis plant worldwide obtainable various medical science and amusement, THC CBD is accessory Cannabinoids composition relatively.In other embodiments, THC and CBD or THCV and CBDV exist to be close to the amount that equates, perhaps THC or THCV are 95.5% of major ingredients and the total Cannabinoids that can reach existence.

The ratio of particularly preferred Cannabinoids and their suitable target medical conditions are shown in following table 2.

The target treatment group of the Cannabinoids of the different ratios of table 2.

Group of products THC: CBD ratio target treatment field

High THC＞95: 5 cancer pains, migraine stimulates appetite

50: 50 multiple sclerosiss of average ratio, spinal cord injury, peripheral nervous

Disease, other neuropathic pain.

Inverse proportion/key ratio CBD＜25: 75 rheumatic arthritis, inflammatory bowel disease

High CBD＜5: 95 psychosiss (schizophrenia), epilepsy and fortune

Moving obstacle, shock, head injury, Disease

Modification in RA and other inflammatory disease

Disease, appetite inhibiting

The preparation that contains Cannabinoids concrete, requirement ratio can be prepared with pharmaceutical carrier well-known to those skilled in the art and excipient with pure Cannabinoids.Also can buy the Cannabinoids of pharmaceutical grade " pure " from suppliers, for example CBD and THC can be from Sigma-AldrichCompany Ltd, Fancy Road, and Poole Dorset, BH12 4QH buys or can be through chemosynthesis.Perhaps, Cannabinoids can adopt technology well-known to those skilled in the art to extract from the Cannabis plant.

The preferred therapeutic use of the ratio of other preferred THC: CBD, THCV: CBDV and THC: TCHV and this type of preparation is set forth in claim subsequently.Specifically, the present invention's plan includes, but not limited to following embodiment:

(A) liquid pharmaceutical formulation according to a first aspect of the present invention comprises cannabidiol (CBD) and two kinds of Cannabinoidses of tetrahydrocannabinol (THC), and wherein the weight ratio of the CBD of Cun Zaiing is greater than the weight of THC.In detail, the present invention includes CBD wherein to the weight ratio of THC preparation greater than 2.5: 1, or wherein CBD to the weight ratio of THC between 99: 1 and 2.5: 1, the preferred preparation between about 20: 1 and about 2.5: 1, or wherein CBD is about 19: 1 preparation to the weight ratio of THC, or wherein CBD to the weight ratio of the THC preparation in about 5: 1 to about 3: 1 scopes.

Embodiment preferred comprises, but be not limited to, be substantially free of the preparation of the Cannabinoids that is different from CBD and THC, be substantially free of the preparation of other Cannabinoids of in Fructus Cannabis (Cannabis sp), finding, wherein CBD and THC are the preparation of pure substantially form, the preparation that further comprises one or more other Cannabinoidses, particularly wherein one or more other Cannabinoidses are the preparation of tetrahydrocannabinovarin (THCV) and/or cannabidivarin CBDV Cannabidivarol (CBDV), wherein CBD and THC constitute the part from least a extract of at least a Cannabis plant, described at least a extract contains all naturally occurring Cannabinoidses in the described plant, and contain preparation from the extract of two or more different Fructus Cannabis kinds, wherein in the end in the preparation weight of CBD greater than the weight of THC.

(B) liquid pharmaceutical formulation according to a first aspect of the present invention comprises cannabidiol (CBD) and two kinds of Cannabinoidses of tetrahydrocannabinol (THC), and wherein the weight of the THC of Cun Zaiing is greater than the weight of CBD.

Embodiment preferred comprises, but be not limited to, wherein Yu Ding CBD is to preparation between 1: 99 and 1: 1.5 of the weight ratio of THC, wherein predetermined CBD is about 1: 39 preparation to the weight ratio of THC and the CBD that wherein is scheduled to is about 1: 2 preparation to the weight ratio of THC.

(C) liquid preparation according to a first aspect of the present invention comprises tetrahydrocannabinovarin (THCV) and/or two kinds of Cannabinoidses of cannabidivarin CBDV Cannabidivarol (CBDV), and wherein the weight of the CBDV of Cun Zaiing is greater than the weight of THCV.

Embodiment preferred comprises, but be not limited to, the preparation that further contains CBD and/or THC, wherein CBDV is to the weight ratio of the THCV preparation greater than 1.5: 1, wherein CBDV to the weight ratio of THCV in about 99: 1 to about 1.5: 1 scopes, the preferred preparation in about 20: 1 to 2.5: 1 scopes, wherein CBDV is about 9: 1 preparation to the weight ratio of THCV, wherein CBDV is to the preparation of weight ratio between about 5: 1 to 3: 1 of THCV, be substantially free of the preparation of other Cannabinoids (except CBDV and the THCV) that is found in the Fructus Cannabis (Cannabis sp), and wherein CBDV and THCV constitute preparation from the part of the extract of Cannabis plant, and described extract contains all naturally occurring Cannabinoidses in the described plant.

(D) liquid pharmaceutical formulation according to a first aspect of the present invention comprises tetrahydrocannabinovarin (THCV) and two kinds of Cannabinoidses of tetrahydrocannabinol (THC), wherein THCV to the weight ratio of THC between 99: 1 and 1.5: 1.

Embodiment preferred comprises, but be not limited to, wherein THCV to the weight ratio of THC be about 17: 3 preparation, the weight that also contains CBD and/or CBDV is less than the preparation of the weight of THCV, wherein THCV and THC constitute the preparation from the part of the extract of Cannabis plant, described extract contains all naturally occurring Cannabinoidses in the described plant.

In a preferred embodiment of the invention, described preparation comprises the extract, particularly Fructus Cannabis (Cannabis sativa) of one or more kinds in whole Cannabis plants, plant ganja or genetic cross, selfing or its hybrid.In any special Fructus Cannabis kind accurately Cannabinoids content can with method well-known to those skilled in the art such as TLC or HPLC be qualitative and quantitative measurement.Therefore, people can select the Fructus Cannabis kind in case therefrom preparation will produce CBD to THC or CBDV to THCV or THCV extract to the required ratio of THC.Perhaps, can mix or be blended together, so that produce material, to be formulated as pharmaceutical preparation with preferred Cannabinoids ratio from the extract of two or more different cultivars.

By planting the medicine that special Fructus Cannabis (chemovars of cannabis) preparation contains satisfied THC-and CBD-ratio is possible.Can plant these chemovars (differentiate by the Cannabinoids that produces, rather than differentiate this plant) by the various plants planting technology that those skilled in the art were familiar with by the morphological characteristic of this plant.Breeding described plant by montage cutting (cuttings) production material guarantees that genotype is fixed and guarantees that the plant of each results contains the Cannabinoids of substantially the same ratio.

In addition, find also can obtain other chemovars, be expressed as its Cannabinoids content and be mainly tetrahydrocannabinovarin (THCV) or cannabidivarin CBDV Cannabidivarol (CBDV) by the method for gardening selection.

On the gardening, plantation is very easily by the chemovars that the montage cutting produces THC, THCV, CBD and the main Cannabinoids of CBDV conduct.This guarantees that in each results genotype is identical and qualitative preparation (ratio of the Biomass of every kind of Cannabinoids) is identical.By these chemovars, can prepare extract by similar extracting method.The method easily of preparation primary extract comprises dipping, diafiltration, uses the solvent extraction to alcohol (ethanol), Norflurane (HFA134a), HFA227 and the liquid carbon dioxide under pressure of C5 such as C1.Described primary extract can further be carried out purification by supercritical or subcritical extraction, evaporation or chromatography.When using those solvents listed above, the extract that obtains contains nonspecific liposoluble substance or " precipitate ".Can remove by the whole bag of tricks, comprise sharply being cooled to-20 ℃, subsequent filtration is removed waxy precipitation, is extracted and distillation with liquid carbon dioxide.Preferred plant culture and preparation method of extract show in an embodiment.The extract that obtains is suitable to be incorporated in the pharmaceutical preparation.

Have many can be effectively with the medical diseases of Fructus Cannabis treatment, for example comprise cancer pain, migraine, stimulate appetite, multiple sclerosis, spinal cord injury, peripheral neurophaty, other neuropathic pain, rheumatoid arthritis, inflammatory bowel disease, psychosis (schizophrenia), epilepsy and the dyskinesia, shock, head injury, appetite inhibiting.The ratio of different Cannabinoidses has determined the disease that special curative effect is arranged (described in general introduction and appending claims in the table 2) of the suitableeest treatment in given preparation.

In detail, the present invention's plan includes, but not limited to following embodiment:

(A) according to the pharmaceutical preparation of a first aspect of the present invention, described preparation contains the cannabidiol (CBD) and the tetrahydrocannabinol (THC) of predetermined weight ratio, or Cannabinoids tetrahydrocannabinovarin (THCV) and cannabidivarin CBDV Cannabidivarol (CBDV), be used for the treatment of inflammatory diseases or any disease that oxidative stress works in its pathogenic process or disease.

(B) according to the pharmaceutical preparation of a first aspect of the present invention, described preparation comprises cannabidiol (CBD) and two kinds of Cannabinoidses of tetrahydrocannabinol (THC) and does not contain Cannabinoids except CBD and THC substantially, or described preparation comprises Cannabinoids tetrahydrocannabinovarin (THCV) and cannabidivarin CBDV Cannabidivarol (CBDV), wherein CBDV to the weight ratio of THCV from about 5: 1 to 3: 1, be used for the treatment of rheumatoid arthritis, or inflammatory bowel disease or Crohn ' s disease.

(C) according to the pharmaceutical preparation of a first aspect of the present invention, described preparation comprises cannabidiol (CBD) and two kinds of Cannabinoidses of tetrahydrocannabinol (THC), wherein CBD arrives in about 3: 1 scope at about 5: 1 the weight ratio of THC, or described preparation comprises Cannabinoids tetrahydrocannabinovarin (THCV) and cannabidivarin CBDV Cannabidivarol (CBDV), wherein CBDV is about 9: 1 to the weight ratio of THCV, is used for the treatment of psychotic disorder, epilepsy, the dyskinesia, shock, head injury or needs the disease of appetite-suppressing.

(D) according to the pharmaceutical preparation of a first aspect of the present invention, described preparation comprises almost CBD and THC or the THCV and the CBDV of equivalent, is used for the treatment of multiple sclerosis, spinal cord injury, peripheral neurophaty or other neuropathic pain.

(E) according to the pharmaceutical preparation of a first aspect of the present invention, the THC that described preparation contains to CBD or THCV to the weight ratio of CBDV for from about 39: 1 to about 99: 1, be used for the treatment of cancer pain or migraine or be used to stimulate appetite.Specific embodiment be included in the described preparation adopt weight ratio be about 39: 1 THC to CBD or THCV to CBDV, THC that adopts in described preparation and CBD and/or THCV and CBDV form the part from the extract of Cannabis plant, and this extract contains all the naturally occurring Cannabinoidses in described plant.

The present invention also further relates to the form according to liquid preparation of the present invention, wherein said preparation, or its lipophilic drugs composition is packaged in the container of tinting at least, and to avoid the light of ultraviolet light and spectrographic blue region, optimal wavelength is at the light of 200-500nm scope.In a preferred embodiment, described container is painted amber.

On the other hand, the present invention also relates to form according to liquid preparation of the present invention, wherein said preparation, or its lipophilic drugs composition is packaged under inert atmosphere at least.In preferred embodiments, described preparation, or its lipophilic drugs composition is packaged under nitrogen at least.

Contain being preferably packaged in the vial of one or more Cannabinoidses according to preparation of the present invention.This bottle is preferably in and is filled to superpressure a little under inert atmosphere such as the nitrogen, preventing/to slow down the oxidation Decomposition of Cannabinoids, and stoping light to enter, thereby the form that prevents the photochemical degradating of Cannabinoids is packed.Adopt amber vial can reach this purpose most effectively, because the applicant has determined the light of ultraviolet light and blue color spectrum, particularly the light in the 200-500nm wave-length coverage can cause light degradation.Because Cannabinoids is to oxidation Decomposition and photochemical degradating sensitivity, at the inert atmosphere intermediate package and/or be packaged in the container of tinting (as amber container) to avoid the light of ultraviolet light and spectrographic blue region, optimal wavelength is equally applicable to comprise the packing of the lipophilic drugs of one or more Cannabinoidses in the advantage of the light of 200-500nm scope, described Cannabinoids is not mixed with according to preparation of the present invention (the plant amedica material that for example contains Cannabinoids is as described in embodiment subsequently).

Be applicable to that the preparation principle that gives Fructus Cannabis extract and Cannabinoids also is applicable to other medicines such as alkaloid, alkali and acid.Necessary condition is if described medicine is insoluble to saliva, then should make its solubilising and/or make it become (unionised) form of suitable unionization by adding buffer salt solution and regulating pH.

Other lipophilic drugs that can be included in the ordinary preparation of the present invention can comprise, but be not limited to, morphine, pethidine, codeine, methadone, heroin, sweet smell be slave, alfentanil, buprenorphine, temazepam, lipotropy analgesic and addictive drug too.Term " addictive drug " comprises can make patient produce dependent chemical compound, particularly can be used as the chemical compound of analgesic, is generally opiate or its synthesis of derivatives.

Therefore, according to another aspect of the present invention, a kind of liquid preparation is provided, be used for the through mucous membrane surface and give at least a lipophilic drugs, said preparation comprises: a kind ofly be selected from following lipophilic drugs: morphine, pethidine, codeine, methadone, heroin, sweet smell be slave, alfentanil, temazepam, buprenorphine, lipotropy analgesic and addictive drug too, solvent and cosolvent, wherein be present in the 55%wt/wt of the total amount of solvent in the described preparation and cosolvent greater than preparation, described preparation does not contain self-emulsifier and/or fluorine-containing propellant.

The mode by embodiment only with following experimental data and demonstrative preparation, adds that accompanying drawing further sets forth the present invention, wherein:

Fig. 1 a and 1b be presented at high CBD (Fig. 1 a) and the Fructus Cannabis extract of high THC (Fig. 1 b) give the mean plasma concentration of Cannabinoids CBD, THC and 11-hydroxyl THC behind the patient.

Fig. 2 is presented at the mean plasma concentration that the Fructus Cannabis extract that will contain the THC of 1: 1 ratio: CBD gives Cannabinoids CBD, THC and 11-hydroxyl THC behind the patient.

Fig. 3 shows the aerosol spray area coverage with respect to the propylene glycol % in propylene glycol/ethanol liquid spray.

Fig. 4 shows the relation of the function of the content of propylene glycol in viscosity and the propylene glycol/ethanol liquid spray.

Fig. 5 shows the aerosol spray area coverage of gas phase for the viscosity of propylene glycol/ethanol liquid spray.

Fig. 6 and 6a show solution example from the THC that stores, be exposed to light before charcoal treatment and after the HPLC analysis result.

Fig. 7 and 7a show solution example from the CBD that stores, be exposed to light before charcoal treatment and after the HPLC analysis result.

The exploitation of the spray of pumping action

When initial the applicant was conceived to adopt hypogloeeis drops (BDS is dissolved in the mixture of glycerin/propylene glycol and ethanol) THC 5mg/ml, CBD 5mg/ml and THC/CBD 5mg/ml to add 5 mg/ml, the patient was to the absorption of Cannabinoids.

The results are shown in the following table 3:

Table 3

Initial absorption 20 minutes
	T is about 2 hours most
The maximum 6ng/ml THC of C, 2ng/ml CBD
	The about 16ng.h/ml THC of AUC 0-12 after every kind of Cannabinoids of about 20mg, 8ng.h/ml CBD
Blood plasma level is approximately 1ng/ml THC and 0.5ng/ml CBD after 6 hours

11 hydroxy tetrahydro cannabinols are approximately 1.9 to the ratio of THC (AUC 0-12), show a large amount of orally ingestibles has occured.

When transferring to pumping action undertongue spraying agent (problem subsequently is with hydroflurocabon propellant system solubilising Cannabinoids), the applicant obtains to be shown in the result of table 4. This solvent system contains 50: 50 ethanol: propane diols (v/v ratio) and contain respectively THC 25mg/ml; CBD 50mg/ml and THC/CBD 25mg/ml add 50mg/ml.

Table 4

Initial absorption 60 minutes
	T is about 3 hours most
The maximum 6ng/mlTHC of C, 8ng/ml CBD
	The about 16ng.h/ml THC of AUC 0-12 after about 21mg THC and 35mg CBD, 22ng.h/ml CBD
Blood plasma level is approximately 1ng/ml THC and 1ng/ml CBD after 6 hours

11 hydroxy tetrahydro cannabinols are approximately 1.6 to the ratio of THC (AUC 0-12). The distributional class of every kind of Cannabinoids seemingly has nothing to do (THC, CBD, THC add CBD) with preparation.

After considering different dosage, although the degree that absorbs can compare with drops, infiltration rate relatively slowly and the ratio of metabolism reduce.

Although the speed that absorbs is slower, described pump spray system and ethanol/propylene glycol carrier system provides and has accurately given the chance that enough Cannabinoidses also reduce metabolism effectively in the dosage form flexibly.

The data that obtain are shown in Fig. 1 a, 1b and 2, and described figure has shown the mean plasma concentration of the preparation consistent with reference table 3 and 4.

The effective communication of Cannabinoids can be realized with the solvent that contains ethanol and propane diols, set forth by the blood plasma level that is shown in Fig. 1 a, 1b and 2. In Fig. 1 a and 1b, show respectively the preparation that contains high THC and high CBD. Similarly, the preparation (THC: CBD 1: 1) of determining ratio is set forth among Fig. 2.

Notably be to find that described ethanol/propane diols system only works in quite narrow limit with the pumping action spray.

To cause the discovery of pump spray exploitation to be described below, as in following preparation 1-4 illustrated:

The importance of embodiment 1-granularity

The applicant observes the shortcoming that propellant aerosol that they are developing has " rebounding ", and this is the effect of transmission speed and granularity seemingly.

They determine opposite with the propellant drive system, and the pump spraying can be transmitted the aerosol spray of controllable granularity, so that be created in the granularity (thereby medicine hits the amount of sublingual/buccal mucosa and the amount maximum of absorbable Cannabinoids) between 20 and 40 microns.Need control the viscosity of described preparation carefully for the microgranule that produces suitable granularity.If described preparation is thickness too, then the overslaugh droplet forms, and forms to spray and the obstruction valve; If the not enough thickness of described preparation, then their excessive atomizings form the aerosol of coverage rate widely and this aerosol no longer individually directly to the sublingual/buccal mucosa.This may cause described preparation to be concentrated and some preparations are swallowed.In both cases, the result is unsatisfactory.

In fact, prove that following confirmation working range is quite narrow for preferred etoh solvent and preferred cosolvent propylene glycol:

Studied ethanol/propylene glycol various combination viscosity and compare spraying with vp7/100 valve (Valois).The result is made form to be listed in the table below in 5:

Table 5

Propylene glycol/ethanol	Relative viscosity (running time is in second)	Spray
			100/0	442	Form and spray
80/20	160	Form and spray
			60/40	80	Some injections
50/50	62	Good aerosol spray
			40/60	44	Good aerosol spray
20/80	26	Good aerosol spray
			0/100	16	Good aerosol spray

From described data, be presented at greater than 60/40 o'clock and will do not accept extra propylene glycol.When reading US 3,560 in the lump, 625 o'clock, these the possibility of result hinted that described solvent/co-solvent combination is bad., the applicant finds that the patient can stand this predetermined alcoholic acid level when having given preparation.

The effect to the aerosol spray quantizes to viscosity on the paper of the exposure of the gauged distance by different preparations being sprayed to 0.5cm.This is apart from the nozzle of representative pumping action spraying unit when normally using and the common distance between the chamber, Sublingual.Described paper is that the image of autotype paper and described spray is sheared and weighs so that obtain relative area coverage.Then by being worth divided by every cm with this ²The weight of autotype paper (weight of the paper by the weighing known area is determined) is converted to real area coverage with this relative value.In following table 6, provide the result.

Propylene glycol/ethanol	The area coverage of aerosol stream
		100/0	3.5cm 2
80/20	14.2cm 2
		60/40	17.9cm 2
50/50	20.7cm 2
		40/60	29.4cm 2
20/80	54.4cm 2
		0/100	93.8cm 2

Described data show is in Fig. 3.

Provide the graph of a relation (Fig. 4) of ethanol and content of propylene glycol and viscosity in the mixture in addition and as the figure (Fig. 5) of the spray area coverage of the function of viscosity.

Described figure emphasizes that very big and unwelcome qualitative change, this variation appear at outside the narrow range of ethanol/propylene glycol weight ratio of 60/40 to 40/60, and more especially in 55/45 to 45/55 scope, most preferably weight ratio is about 50/50.

For guaranteeing to use described combination in narrow scope, other factors also is important.Increase ethanol horizontal exceeding 60% volume and will cause and stimulate and the propylene glycol level reaches 60% and be low to moderate at 55% o'clock that the nonpolar derivant that is present among the BDS begins to be precipitated out at the environment lay up period that prolongs under the BDS situation.

Expect that other spendable cosolvent has similar restriction.Cosolvent is got over thickness, and the problem that produces the spray that forms spraying is just big more, and polarity is big more, and the danger that precipitation increases is just big more.

; because can dissolving, the combination of ethanol/propylene glycol can reach 50mg/ml (i.e. needed Cannabinoids level is gone up in treatment) at most; be nonirritating, pharmaceutically acceptable; and the effect that propylene glycol is also brought into play penetration enhancer makes the bioavailability maximization of Cannabinoids, so is particularly advantageous.

When with Malvern Marsteriser test, the particle mean size of described preferred composition has been shown as 33 μ m.Described droplet is more much bigger than 5 μ m, therefore reduces the danger of inhalation aerosol.

The effect of water when embodiment 2-Cannabinoids is present among the BDS

As be described in as described in the research of following table 7, the existence of water demonstration above 5% will cause the precipitation of BDS in described preparation:

Table 7-adds entry continuously with preparation 5ml 25mg/mlTHC and 5ml 25mg/ml CBD in ethanol/propylene glycol (50/50)

The volume ml that adds entry	Final volume ml	Final ratio of solvent % volume, water/propylene glycol/ethanol	Observe
				0	5	0/50/50	Solution
0.05	5.05	1/49.5/49.5	Ppt forms when still mixing and dissolves
				0.21	5.26	5/47.5/47.5	Ppt forms.Solution is still muddy after mixing

Certainly preferably use dehydrated alcohol according to described observation.

As follows according to exemplary formulation of the present invention (unrestricted):

Compositions 1 (common)

Composition	The amount of per unit (1ml)	Effect
			Active component THC (BDS) CBD (BDS)	25-50mg/ml 25-50mg/ml	Active
Excipient propylene glycol Oleum menthae ethanol (anhydrous)	0.5ml/ml 0.0005ml/ml is in right amount to 1ml	Cosolvent flavoring agent solvent

Compositions 2 (high THC)

Composition	The amount of per unit (1ml)	Effect
			Active component THC (BDS)	25mg/ml	Active
Excipient propylene glycol Oleum menthae ethanol (anhydrous)	0.5ml/ml 0.0005ml/ml is in right amount to 1ml	Cosolvent flavoring agent solvent

Compositions 3 (high CBD)

Composition	The amount of per unit (1ml)	Effect
			Active component CBD (BDS)	25mg/ml	Active
Excipient propylene glycol Oleum menthae ethanol (anhydrous)	0.5ml/ml 0.0005ml/ml is in right amount to 1ml	Cosolvent flavoring agent solvent

Compositions 4 (THC/CBD is essentially 1: 1)

Composition	The amount of per unit (1ml)	Effect
			Active component THC (BDS) CBD (BDS)	25mg/ml 25mg/ml	Active
Excipient propylene glycol Oleum menthae ethanol (anhydrous)	0.5ml/ml 0.0005ml/ml is in right amount to 1ml	Cosolvent flavoring agent solvent

Embodiment 3

The utilization of following examples elaboration the application's oral mucosa liquid spray and the blood levels of comparing and producing by buccal absorption with sublingual administration.

The liquid preparation that below is suitable for oral administration contains self-emulsifier, therefore can not be within the scope of the present invention.Yet the general rule of setting forth by the purposes of these compositionss is equally applicable to transmit according to preparation of the present invention.Prepare solution by dissolving (being no more than under 50 ℃ the temperature) following composition (quantitative particulars is represented according to weight portion):

A B C D E

Glyceryl monostearate (self-emulsifier) 2-2-2

Glycerin mono-fatty acid ester (self-emulsifier)-2-2-

Cremophor RH40 20 30 30 20 30

CBME-G1 provide THC 5 10---

CBME-G5 provide CBD--5 10-

CBME-G1 and G5 provide THC﹠amp; CBD----each is 10 years old

Alpha-tocopherol 0.1 0.1 0.1 0.1 0.1

Ascorbyl palmitate 0.1 0.1 0.1 0.1 0.1

Ethanol BP is to obtain 100 100 100 100 100

Drug extract (CBME) based on Fructus Cannabis is a Fructus Cannabis extract, and it can be by for example with liquid carbon dioxide dipping, and the alcoholic solution by rapid cooling concentration shifts out precipitate and by filtering or centrifugally shifting out sedimentary inertia plant component and prepare to-20 ℃.

Will be by mixing product that these compositions form to in the amount packing vial of 6ml and close with the pumping action aerosol apparatus.In use, by disperseing (break-up) button or conventional design to discharge dosage.Be applicable to the VP7 type of the Patent equipment (Proprietary devices) of this purpose, but can obtain similarly device from other manufacturer for Valois production.Described bottle can be packed in the secondary package (secondary packaging) so that allow directly to be sprayed to the special area of oral mucosa.Perhaps, can use patent button so that directly be sprayed to the preferred region of oral mucosa with extension.

Every 1ml product contains the 50-100mg Δ ⁹-tetrahydrocannabinol (THC) and/or cannabidiol (CBD).Whenever once spray by a pump transmission, can be directly to and reach oral mucosa.In above-mentioned preparation, use the Cannabinoids of concentration known.CBME-G1 is the extract from the Fructus Cannabis strain of THC high yield, and CBME-G5 is the extract from the Fructus Cannabis kind of CBD high yield.Those skilled in the art understands that the Cannabinoids of purification and the extract that contains Cannabinoids can prepare as mentioned above by quantitative adjusting.

Though the alcoholic solution of CBME can be used alone as spray, owing to limited the amount of transferable Cannabinoids as the strong and stimulating (aggressive nature) of the high concentration straight alcohol of solvent.This has limited and can use on mucosa and do not make the patient produce the amount of uncomfortable feeling.When one group of patient is received in THC or CBD in the above-mentioned type solution, when Sublingual or oral mucosa were directly sprayed, the patient reported that the Sublingual uses and have excitement, but felt slightly during to oral mucosa or do not have a sticky feeling when same solution spray.The preparation of a spot of the type is sprayed on the oral mucosa to stimulating swallowing reflex significantly.This provides the more time of staying for preparation contacts with oral surfaces.

Give one group of patient 13 people with preparation, make them accept 4mg THC, 4mg CBD or placebo (only containing solvent) by sublingual tablet, the spraying of Sublingual pumping action or oral cavity route.

Be determined at the absorption [area under absorption curve (AUC)] and the primary metabolite of Cannabinoids in the blood sample that extracts after the administration.In following table 8, provided standardized meansigma methods.

Table 8

These results show that the Cannabinoids total amount that Sublingual and oral cavity (oropharynx) approach absorb is similarly, but the amount of 11-hydroxyl (11-OH) metabolite that measures after oropharynx (oral cavity) administration has substantive reduce (about 25%).This is found and reduces the gulping down because of (with reducing liver subsequently) metabolism contradiction not of oral preparation.

The 11-hydroxy metabolite thing (11-OH THC) of well-known THC may have more significant effect to nerve than parent compound.Therefore the amount that as far as possible reduces this metabolite during administration suits the requirements, and the preparation that this can be by using the application and method reduce the amount of oral cavity and Sublingual swallowing and realize.Described pumping action spray obviously provides the straightforward procedure of the amount that reduces the metabolite of swallowing and being produced by the intestinal absorption under the oropharynx level.

The plantation of the medicinal Cannabis of embodiment 4-

From seeds germinated, planting 3 weeks of plant, 24 hours sun exposures as the clone under 25 ± 1.5 ℃ the temperature, under glass; Keep plant to be in growth conditions.Long (day length) 8-9 week cause blooming by exposing daytime of 12 hours.

Use inartificial Insecticides (tech) ﹠ Herbicides (tech), pesticide or fumigant.Organically plant plant, with controlling the insecticide nuisance biology.

Planting dried drug from seed aborning is summarized as follows with the basic step of Fructus Cannabis:

Seed plantation (accession)

↓

G-Pharm (UK) germination

↓

Selection to Cannabinoids content and vigor (vigour)

↓

Maternal plant

↓

The montage rooting of cuttings

On the peat earth pillar 25 ℃, long 14-21 days 24 hour daytime

↓

The montage cutting thing that to take root is potted plant in 5 liters of basins that predetermined compost is housed

↓

Settle the clone plant seedling

In 3 weeks, 24 hour daytime is long, 25 ℃

↓

Remove lower branch at 3 weekends

Be usually used in producing the montage cutting thing of a new generation

↓

Induced flowering

Plant is long so that induced flowering through 12 hour daytime again

↓

Flower forms and is ripe

25 ℃ of following 8-9 weeks

↓

Results

90% flower and leaf fall into decay

↓

Dry

Under the lucifuge condition

↓

Medicinal Fructus Cannabis

Embodiment 5-measures the content of Cannabinoids in plant and the extract

Differentiate by TLC

A) raw material and method

It is 1 μ l capillary tube or little that equipment adopts the equipment that can transmit the liquor capacity of accurately controlling

Rise syringe;

TLC developing tank with a lid;

Hot-air blower;

Silica gel G thin layer chromatography (TCL) plate (SIL N-HR/UV254), 200um is thick, contains fluorescence indicator on polyester support;

The maceration tank of developer (visualisation reagent);

60: 80/20% ether of mobile phase 80% petroleum ether;

Developer 0.1%w/v fast blue B aqueous solution (100mg is in the 100ml deionized water).Selectable method is for to scan under UV254 and 365nm.

B) sample preparation

I) herbal raw material

Take by weighing meticulous ground, the exsiccant Fructus Cannabis of about 200mg and put into the volumetric flask of 10ml.Use methanol: the extraction solvent of chloroform (9: 1) is supplied volume.

Supersound extraction 15 minutes.Incline gently and supernatant and be directly used in chromatography.

Ii) herb extracts

Take by weighing about 50mg extract, put into the volumetric flask of 25ml.Supply volume with methanol.Violent jolting is directly used in chromatography then to dissolving.

C) standard substance

0.1mg/ml the methanol solution of δ-9-THC

0.1mg/ml the methanol solution of CBD.

During use with this standard solution in refrigerated storage below-20 ℃ and after initial preparation, can use and reach 12 months.

D) testing liquid and method

Be applied to the point that respectively separates with minimum 10mm.

I) extract solution of 5 μ l herb extracts or 1 μ l medical herbs is suitable

The ii) methanol standard solution of 10 μ l 0.1mg/ml δ-9-THC

The iii) methanol standard solution of 10 μ l 0.1mg/ml CBD

The TLC plate of eluting 8cm distance is removed this plate then.Solvent is evaporated from this plate, repeat eluting (two expansion) then for the second time.

Characteristic color/orange beginning that described plate is immersed in the fast blue B reagent simply up to Cannabinoids occurs.Remove this plate and drying under the environmental condition of dark.

Duplicate this image or for good and all write down this result by digital scanning instrument (preferred option) by position and the color of in trace paper, indicating speckle.

Analyze THC, THCA, CBD, CBDA and CBN by HPLC

A) material and method

Equipment: HP 1100 HPLC of band diode array detector and automatic sampler.This equipment (SOPlab037) is assembled and operated to S.O.P. according to inside

The HPLC post: Discovery C8 5 μ m, 15x0.46cm add Kingsorb ODS2 pre-column 5 μ m 3x0.46cm.

Mobile phase: acetonitrile (acetonotrile): methanol: 0.25% acetic acid aqueous solution (16: 7: 6 volume ratios)

Column operation temperature: 25 ℃

Flow velocity: 1.0ml/ minute

Volume injected: 10 μ l

Running time: 25 minutes

Detect: neutral and acid Cannabinoids 220nm (bandwidth 16nm)

Reference wavelength: 400nm./bandwidth 16nm

Slit: 4nm

(bandwidth 16nm) monitors acid Cannabinoids routinely at the 310nm place, just to qualitative confirmation and authentication purposes.

Data capture: the HP Chemistation of band A7.01 version software

B) sample preparation

40mg is dissolved in based on the drug extract of Fructus Cannabis in the methanol of 25ml and and dilutes this solution to 1-10 with methanol.

This diluent is used for chromatography.

Draw 0.5ml with the glass pipette and fill solution as sample, it is included in the sublingual spraying unit of pumping action.This solution dilution is supplied scale in the 25ml flask and with methanol.

Dilute the described solution of 200 μ l with 800 μ l methanol.

By getting the 100mg sample and with 5 or 10ml methanol/chloroform (9: 1w/v) Processing of Preparation medical herbs or resin sample.This dispersion liquid of supersound process is 10 minutes in the test tube of a sealing, allows its cooling, will wait duplicate samples centrifugal and carry out suitable dilution with methanol before chromatography.

C) standard

This method adopts external standard method.Preparation THC, CBD and CBN stock the diluent of titer in methanol or ethanol, obtain the roughly final working standard liquid of accurate 0.1mg/ml.This working standard liquid is stored in-20 ℃ and can use and reach 12 months after initial preparation.

Before any test solution of injection, press every kind of titer of triplicate injection.Interval duplicate injection titer to suit during handling test solution.When lacking reliable CBDA and THCA standard substance, adopt CBD and these chemical compounds of THC normal response factorial analysis respectively.

Determined that eluting order is CBD, CBDA, CBN, THC and THCA.Adopt described method can detect other Cannabinoids and also can differentiate and measure other Cannabinoids as required.

D) test solution

Should contain analyte in linear working range 0.02-0.2mg/ml with the test solution of methanol preparation dilution and its.

E) the acceptable standard of chromatography method

Below acceptable standard be applicable to the result of every kind of program can cause the sufficient fractionation (comprising two kinds) of all analytes because find these standards near the analyte CBD and the CBDN of eluting.

I) the retention time window of every kind of analyte

CBD 5.4-5.9 minute

CBN 7.9-8.7 minute

THC 9.6-10.6 minute

Ii) peak type (according to the symmetry factor of BP method)

CBD＜1.30

CBN＜1.25

THC＜1.35

Iii) developed the amending method of many standard methods, contained those samples of the impurity peaks of back eluting such as method CBD2A with processing and prolong elution time to 50 minute.All solution should clarify it by centrifugal before transferring to the bottle of automatic sampler, and described bottle seals with the barrier film strip of paper used for sealing and the lid of special teflon face.

Iv) for the quality of chromatography method, pre-column is important, and when back-pressure rise in 71 Palestine and Israels and/or about retention time and split that acceptable standard drops on them specifiedly should change pre-column off limits the time.

F) date processing

Cannabinoids can be subdivided into, and neutral and tart-available DAD dual wavelength pattern is carried out qualitative identification.Acid Cannabinoids has strong absorption in the 220-310nm zone.Neutral Cannabinoids only has strong absorption in the 220nm zone.

Usually only adopt in the data of 220nm place record and carry out quantitative analysis.

Also can adopt DAD to carry out the UV spectral scan at each peak, can be stored in the library of spectra then and be used for differentiating.

On Hewlett Packard Chemstation, utilize batch processing software to carry out quantitative date processing.

G) sample tomographic map

The HPLC sample tomographic map of THC and CBD herb extracts provides in accompanying drawing subsequently.

The preparation of embodiment 6-herb extracts

Below provide demonstration and produce the flow chart of the process of extract from the chemovars of high THC and high CBD:

Medicinal Fructus Cannabis (high THC or high CBD)

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Be cut into the size that is mainly 2-3mm

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Heat time enough so that make the sour form decarboxylation of Cannabinoids at 100 to 150 ℃,

To produce neutral Cannabinoids

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With designated volume liquid CO 2 extracted 6 to 8 hours

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Remove carbon dioxide by decompression and obtain crude extract

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" winterization processing "-crude extract is dissolved among the ethanol Ph.Eur., sharply cool off this solution (20 ℃/48 hours) subsequently to being settled out unwanted wax

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Remove by filter unwanted wax by cold

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From filtrate, remove ethanol by thin film evaporation under reduced pressure

Resulting extract is called as the medical extract based on Fructus Cannabis, and also is categorized as the plant amedica material according to USFood and Drug Administration Guidance for Industry Botanical DrugProducts.

Embodiment 7

Under mean temperature 21+2 ℃, RH 50-60%, the high THC Fructus Cannabis of plantation in vial.In the dark, the RH of room temperature and 40-50% gathers in the crops down and dry medical herbs.When drying, peel off the exsiccant Biomass of leaf and head inflorescence and this from stem and be called as " medicinal Fructus Cannabis ".

Medicinal Fructus Cannabis is pulverized in the chamber for the coarse powder (can by the granule of 3mm mesh sieve) and the supercritical extraction device of packing into.The density of packing into is 0.3 and makes the liquid carbon dioxide under 600 bar pressures pass through this material under 35 ℃ the temperature.Carried out supercritical extraction 4 hours and extract is recovered in the collection container by progressively reducing pressure.Be further purified the buttery resin-like extract of the brown-green that is produced.In being dissolved in ethanol BP (2 parts) and make temperature of-20 ℃ of its experience in the time of 24 hours, precipitate (containing fat-soluble, waxy substance) occurs in solution and by removing by filter.Under low pressure in rotary evaporator, remove and desolvate.The extract that is produced is a pilular extract, and it contains about 60% THC and other Cannabinoids of about 6%, and wherein cannabidiol accounts for 1-2% and all the other comprise cannabinol for accessory Cannabinoids.Based on the weight meter of exsiccant medicinal Fructus Cannabis, quantitative yield is 9%w/w.

Chemovar to high CBD similarly handles, obtain containing about 60% CBD and reach as high as 4% tetrahydrocannabinol, the total amount of other Cannabinoids 6% with interior extract.Adopt above-mentioned universal method to prepare extract with THCV and CBDV chemovar.

But it should be appreciated by those skilled in the art that other combination at serviceability temperature and pressure under supercritical and the subcritical condition (for example in+10 ℃ to 35 ℃ and 60-600 crust scope) preparation extract.

Embodiment 8-light is to the influence of the stability of the alcoholic solution of THC, CBD or THCV

Following examples comprise the data that are supported in the packing of liquid dosage form in the amber glass bottle, and this packing can provide some protections to prevent the degraded influence of light to Cannabinoids.

Selection for the minimum possible storage temperature of the solution that contains the cannabinoid 1 activity composition also provides further proof.

Background and general introduction:

Known light is many materials, comprises the initiator of the degradation reaction of Cannabinoids.This knowledge has been used to select the packing of liquid preparation, uses the amber glass bottle as the lucifuge barrier widely in medicine is showed.

Set up experiment so that follow the tracks of the influence of white light to the methanol solution stability of THC, CBD or THCV.Can have the rudimental knowledge of Different Effects (the viz. tretinoin is only stable in HONGGUANG or dark) according to the light of different wave length to the stability of chemical compound, with sample packaging in colored cellulose acetate membrane or in the paper tinsel of lucifuge.Parallel (concurrent) test is adopted charcoal treatment CBME so that the influence of plant pigment to degradation process removed in research.

Material and method

Cannabinoids: the CBME solution of preparation 1mg/ml in AR methanol.(Biotage Flash 12AC 7.5cmCartridges b/no.273012S), is diluted to 1mg/ml to the methanol solution (100mg/ml) that makes CBME then by activated-charcoal column.Solution is stored in the soda glass bottle, tightens the lid of this vial tightly and use in the above and twine film phonograph seal.With tube package in following colored cellulose acetate membrane:

Red, yellow, green and aeruginous.

Also solution is filled in the amber glass U-save bottle; With diaphragm seal and above the sealing.A pipe of each series of samples is packaged in the aluminium foil tightly so that reach the purpose of complete lucifuge.This as " dark " control in case the monitoring of environmental temperature to the effect of degradation behavior.All above-mentioned pipes are placed in the box with 40 watts of incandescences of 2x (white Osram) fluorescent tube.On the wall of this box, serve as a contrast and monitor with frequent interval with the paper tinsel and the temperature inside that can produce reflection.

Another pipe of each series is stored in below-20 ℃, as a kind of reference sample of vacation; In addition, a pipe is directly exposed under the light and not protection.Chromatographic analysis is carried out to regain sample up to the interval that reaches 112 days in the back beginning one's study.This research is called as AS01201/AX282.

Extract the sample of test solution, and dilute according to the requirement that is suitable for PLC and TLC analyze.Carry out HPLC according to TM GE.004.V1 (SOPam058).On silica gel (MNSilG/UV) plate, carry out TLC according to TM GE.002.V1 (SOPam056).

In order to separate degradation products, utilize other TLC system:

A) SilG/UV, immobile phase, hexane/acetone 8/2v/v mobile phase

B) RPC18 immobile phase, acetonitrile/methanol/0.25% acetic acid aqueous solution, 16/7/6 volume ratio use fast blue B salt as the Cannabinoids developer.

Result and discussion:

The HPLC quantitative analysis:

To take from the HPLC analysis result of sample storage, that be exposed to the solution under the light and draw, see Fig. 6,6a (before the charcoal treatment and after THC) and 7,7a (before the charcoal treatment with after CBD).

The stability that can be observed THC all solution from Fig. 6 and 6a all is significantly improved, except those (at ambient temperature) of storing in the dark with the sample (not being under the photochemistry stress therefore) of-20 ℃ of storages.When untreated extract is compared with the extract of charcoal treatment, be stored in and also shown improvement in the amber vial.This may obtain reflection in the improvement of the heat stability of the extract of charcoal treatment.

There are similar data in Fig. 7 and 7a demonstration to the extract that contains CBD, and it is obviously more responsive to the influence of light than THC therefrom to can be observed this Cannabinoids.Do not having under the situation of active carbon, all exposures, except in the amber glass bottle, lucifuge (paper tinsel) and storage under-20 ℃ all were degraded to undetectable CBD level before 40 days.After charcoal treatment, the figure between 42 and 62 days improves.The amber glass bottle of protection CBD shows a kind of improvement, and never activated carbon decolorizing is in 112 days 38% residual compounds at one time about 64% residual compounds after the charcoal treatment.Also shown the improvement of CBD stability in the lucifuge solution after charcoal treatment.This may only reflect and has reduced thermal oxidative degradation, or the photochemical degradating of the remnants that caused by light (and/or air) during CBME and formulations prepared from solutions.

The thin layer chromatography qualitative analysis:

Assess photodegradative solution with thin layer chromatography, adopt existing positive phase system (be silica stationary mutually and hexane/ether as mobile phase) and two kinds of other systems, can be dissolved in the more high polarity that forms in the degradation process or polymerized product.

Therefore, through 112 days, the intensity of THC and accessory CBD speckle reduced (not video data) in the light filter of all colours for THC in the chromatography demonstration of employing hexane/ether system.Simultaneously, flow or increase near the intensity of the painted thing of fast blue B of initial point.The solution of paper tinsel protection shows that these influences are not arranged.

Conclusion and suggestion:

Known Cannabinoids is because many natural challenges, i.e. light, heat, oxygen, enzyme etc. and degrade.In the extraction through the herbal plants raw material of cleaning procedure widely not, some in these processes may can also continue probably.Doubtly be, shift out Cannabinoids in any protective agent that also may exist from plant tissue, this makes the special degradation pathway of extract experience probably.

Be packaged in the amber glass bottle, in amber light filter, carry out preparation production, and be stored in plant extract and pharmaceutical preparation low as far as possible and have both produce and distribute require and the temperature of patient's compliance under, eliminate or reduce the influence of light at least the Cannabinoids degraded.These effects have greatly improved the bin stability of plant extract and finished product.

What is interesting is, notice as if CBD is more unstable than THC when experience photochemistry stress.This discovery with the stability of relative thermal oxide is opposite, and wherein THC is more unstable.As if though this shows that polymeric catabolite may be the common result of photochemistry and thermal oxidative degradation, for these two kinds of processes, definite detailed mechanism is different.

Can draw as drawing a conclusion:

1) selects amber glass bottle packing liquid medicine that the stability of improving is provided, and can carry out accessory improvement by other lucifuge measure.

2) preparation of dry run and extraction subsequently and Fructus Cannabis extract should be carried out under low-light level, amber filter light.

3) should consider extract is covered under the inert atmosphere (as nitrogen).

4) after winterization by simple activated carbon filtration clean hemp extract, can obtain basic improvement to the storage life of product.

Claims (29)

1. one kind is used for the liquid pharmaceutical formulation that the through mucous membrane surface gives lipophilic drugs, it comprises: one or more Cannabinoidses, ethanol and propylene glycol, wherein be present in the 55%wt/wt of the total amount of ethanol in the described preparation and propylene glycol greater than said preparation, water content in this liquid pharmaceutical formulation is lower than 5% volume, and described preparation does not contain self-emulsifier and not fluorine-containing propellant, and described liquid pharmaceutical formulation is packaged into spray and transmits, and described spray has the average air kinetics granularity of 20-40 micron when transmitting.

2. the liquid pharmaceutical formulation that requires of a claim 1, the described particle mean size when wherein transmitting is in the scope of 25-35 micron.

3. the liquid pharmaceutical formulation that requires of a claim 1, the described particle mean size when wherein transmitting is in the scope of 30-35 micron.

4. the liquid pharmaceutical formulation that requires of a claim 1, wherein ethanol/propylene glycol exists with the relative weight ratio in 60/40 to 40/60 scope.

5. the liquid pharmaceutical formulation of each requirement in the claim 1～3, wherein said Cannabinoids is at least a extract from least a Cannabis plant.

6. the liquid pharmaceutical formulation that requires of a claim 5, wherein said extract from least a Cannabis plant is the plant amedica material.

7. the liquid preparation that requires of a claim 6, wherein said plant amedica material experience extraction step is so that remove most of wax and the insoluble raw material of other solvent that is present in the plant material.

8. the liquid pharmaceutical formulation of each requirement in the claim 1～3, said preparation is made up of one or more Cannabinoidses, ethanol and propylene glycol substantially, perhaps also contains flavoring agent and/or opiate.

9. the liquid pharmaceutical formulation of each requirement in the claim 1～3, wherein said Cannabinoids comprises tetrahydrocannabinol, Δ ⁹-tetrahydrocannabinol, Δ ⁸-tetrahydrocannabinol, Δ ⁹-tetrahydrocannabinovarin, cannabidiol, cannabidivarin CBDV Cannabidivarol, cannabinol, cannabichromene, cannabigerol or its any mixture.

10. the liquid pharmaceutical formulation that requires of a claim 9, wherein said Cannabinoids comprises tetrahydrocannabinol and/or cannabidiol.

11. the liquid pharmaceutical formulation that a claim 10 requires, wherein tetrahydrocannabinol and cannabidiol exist with 0.9: 1.1 to 1.1: 0.9 ratio (w/w).

12. the liquid pharmaceutical formulation that claim 9 requires, described preparation comprises cannabidiol and two kinds of Cannabinoidses of tetrahydrocannabinol, or tetrahydrocannabinovarin and two kinds of Cannabinoidses of cannabidivarin CBDV Cannabidivarol.

13. the pharmaceutical preparation according to claim 12, described preparation comprise cannabidiol and two kinds of Cannabinoidses of tetrahydrocannabinol, wherein the weight of cannabidiol existence is greater than the weight of tetrahydrocannabinol.

14. the preparation according to claim 13, wherein cannabidiol to the weight ratio of tetrahydrocannabinol greater than 2.5: 1.

15. the preparation according to claim 13 or 14, wherein cannabidiol to the weight ratio of tetrahydrocannabinol in 5: 1 to 3: 1 scope.

16. the preparation according to claim 13 or 14, described preparation does not contain the Cannabinoids except cannabidiol and tetrahydrocannabinol.

17. the liquid pharmaceutical formulation according to claim 12, described preparation contain cannabidiol and two kinds of Cannabinoidses of tetrahydrocannabinol, wherein the weight of tetrahydrocannabinol existence is greater than the weight of cannabidiol.

18. the preparation according to claim 17, wherein cannabidiol to the weight ratio of tetrahydrocannabinol between 1: 99 and 1: 1.5.

19. the pharmaceutical preparation according to claim 12, described preparation contain tetrahydrocannabinovarin and two kinds of Cannabinoidses of cannabidivarin CBDV Cannabidivarol, wherein the weight of cannabidivarin CBDV Cannabidivarol existence is greater than the weight of tetrahydrocannabinovarin.

20. the preparation according to claim 19, wherein cannabidivarin CBDV Cannabidivarol to the weight ratio of tetrahydrocannabinovarin greater than 1.5: 1.

21. cannabidiol and tetrahydrocannabinol or tetrahydrocannabinovarin and the cannabidivarin CBDV Cannabidivarol purposes in preparation claim 12 described liquid pharmaceutical formulation, wherein said liquid pharmaceutical formulation are used for the treatment of any disease or disease that inflammatory diseases or oxidative stress participate in its pathogenic process.

22. cannabidiol and the tetrahydrocannabinol purposes in the described liquid pharmaceutical formulation of preparation claim 16, wherein said liquid pharmaceutical formulation is used for the treatment of rheumatoid arthritis or inflammatory bowel disease or Crohn disease.

23. weight ratio is 51 to 31 cannabidiol and the purposes of tetrahydrocannabinol in the described liquid pharmaceutical formulation of preparation claim 15, wherein said liquid pharmaceutical formulation is used for the treatment of psychosis, epilepsy, the dyskinesia, apoplexy, head injury or needs the disease of appetite-suppressing.

24. cannabidiol and the tetrahydrocannabinol purposes in the described liquid pharmaceutical formulation of preparation claim 11, wherein said liquid pharmaceutical formulation is used for the treatment of multiple sclerosis, spinal cord injury, peripheral neurophaty or other neuropathic pain.

25. weight ratio is 39.1 to 99.1 cannabidiol and tetrahydrocannabinol or tetrahydrocannabinovarin and the purposes of cannabidivarin CBDV Cannabidivarol in the described liquid pharmaceutical formulation of preparation claim 12, wherein said liquid pharmaceutical formulation is used for the treatment of cancer pain or migraine or is used to stimulate appetite.

26. containing following composition: tetrahydrocannabinol 27mg/ml, cannabidiol 25mg/ml, propylene glycol 0 5ml/ml, Oleum menthae 0 0005ml/ml and dehydrated alcohol in the 1ml volume, a liquid pharmaceutical formulation, said preparation complement to 1ml in right amount.

27. containing following composition: tetrahydrocannabinol 27mg/ml, propylene glycol 0.5ml/ml, Oleum menthae 0 0005ml/ml and dehydrated alcohol in the 1ml volume, a liquid pharmaceutical formulation, said preparation complement to 1ml in right amount.

28. a liquid pharmaceutical formulation, said preparation contain following composition in the 1ml volume: cannabidiol 25mg/ml, propylene glycol 0.5ml/ml, Oleum menthae 0.0005ml/ml and dehydrated alcohol complement to 1ml in right amount.

29. the liquid preparation of each requirement in the claim 1～3, wherein said Cannabinoids is packaged in inert atmosphere.

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