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  Pharmaceutical Patents  

 

Title:  Compositions comprising cannabinoids for treatment of nausea, vomiting, emesis, motion sickness or like conditions
United States Patent: 
8,034,843
Issued: 
October 11, 2011

Inventors:
 Whittle; Brian (Hornsea, GB), Javid; Farideh Afshin (Yorkshire, GB)
Assignee:
  GW Pharma Limited (Salisbury, Wiltshire, GB)
Appl. No.:
 10/502,822
Filed:
 February 3, 2003
PCT Filed:
 February 03, 2003
PCT No.:
 PCT/GB03/00451
371(c)(1),(2),(4) Date:
 March 02, 2005
PCT Pub. No.:  WO03/063847
PCT Pub. Date:
 August 07, 2003


 

Pharm Bus Intell & Healthcare Studies


Abstract

Cannabinoids, in particular CBD and CBDA and their acid derivatives are provided for use as an active pharmaceutical substance in the treatment of nausea, vomiting, emesis, motion sickness. In particular extracts of cannabis plants are presented which are rich in these substances and suitable for pharmaceutical use.

Description of the Invention

RELATED APPLICATIONS

This application is a national stage filing under 35 U.S.C. .sctn.371 of PCT International application PCT/GB2003/000451, filed Feb. 3, 2003, which was published under PCT Article 21(2) in English.

Functional vomiting is the forceful expulsion of gastric contents produced by involuntary contraction of the abdominal musculature. This occurs when the gastric fundus and lower oesophageal sphincter are relaxed. Functional vomiting may be accompanied by nausea (an unpleasant feeling that vomiting is about to occur). Nausea is associated with altered physiological activity, including gastric hypomotility, and increased parasympathetic tone. Nausea may precede and accompany vomiting. They represent the patient's awareness of afferent stimuli to the medullary vomiting centre.

Physiological vomiting is a functional condition that occurs in response to a number of factors affecting the vomiting centre. It may also be triggered by peripheral factors such as ingestion of toxins, disturbance of the vestibular system, peritoneal inflammation and bowel obstruction. It may also occur in disorders of delayed gastric emptying as, for example, in diabetes and idiopathic gastroparesis.

Psychogenic vomiting may be self-induced or may occur involuntarily in situations that are anxiety inducing, threatening or in some way regarded as distasteful by the subject. It is also possible that psychological factors leading to vomiting are culturally determined (for example, eating exotic food may be considered repulsive in the subject's own cultural group). Vomiting may also express hostility as when children vomit during a temper tantrum or in certain conversion disorders.

Nausea and vomiting may also be induced by cytotoxic chemotherapy and radiotherapy. Post-operatively, patients may also vomit and experience nausea, which may be attributable to the anaesthetic and analgesic agents frequently administered concurrently.

There are therefore peripheral and central mechanisms which are involved in the expression of nausea and frank vomiting. Existing therapies are available for the treatment of these conditions but they have limitations, and there is a need for alternative treatments, particularly where these can exert their effect through a central nervous mechanism.

Investigation of a number of agents in a conscious animal model in which motion sickness is induced has confirmed that extracts of cannabis have an anti-emetic effect. Conventionally, the anti-emetic effect of cannabis has been ascribed to delta.sup.9-tetrahydrocannabinol (.DELTA..sup.9-THC). The use of a whole animal, conscious model to explore this effect, and the availability of cannabis extracts containing predominantly one cannabinoid or another have allowed for more detailed analysis of the contribution of specific cannabinoids.

Surprisingly, it has been found that the anti-emetic effect, in a model of motion sickness in Suncus murinus (the Asian musk (house) shrew), is greatest in high cannabidiol (CBD)(and/or its acid form CBDA) containing extracts rather than in high tetrahydrocannabinol (THC) (and/or its acid form THCA) containing extracts (greater than 50% CBD more preferably greater than 80% most preferably greater than 90% relative to other cannabinoids present).

It is hypothesised that the results will extend to the propyl variant of CBD, namely CBDV and its acid form CBDVA.

More particularly, the results were noted in extracts in which the cannabinoids were predominantly in their acid form since the extracts were prepared by a methanolic extraction and had not been subjected to a decarboxylation step by, for example, heating. It is possible therefore that the therapeutic effects noted are due to the acid form of the cannabinoids. If it is the acid form of the cannabinoid that is responsible for the observed therapeutic effect this is particularly surprising since the acid forms of cannabinoids have not hitherto been known to exhibit therapeutic effects.

According to a first aspect of the present invention there is provided a cannabis extract, rich in CBD and/or CBDA and/or the propyl variants CBDV and/or CBDVA, for use in the manufacture of a medicament for the treatment of nausea, vomiting, emesis, motion sickness or like conditions.

By rich is meant greater than 2% w/w of CBD and/or CBDA and/or the propyl variants CBDV and/or CBDVA, more particularly greater than 5%, more preferably still greater than 7%.

According to another aspect of the present invention there is provided the use of CBD and/or CBDV in the manufacture of a medicament for the treatment of nausea, vomiting, emesis, motion sickness or like conditions.

According to another aspect of the present invention there is provided a cannabinoid acid for use as an active pharmaceutical substance.

According to yet another aspect of the present invention there is provided CBDA or CBDVA for use as an active pharmaceutical substance.

Preferably the active pharmaceutical substance is present as a medicament for the treatment of nausea, vomiting, emesis, motion sickness or like conditions.

In one embodiment the CBD and/or CBDA and/or CBDV and/or CBDVA are present with other cannabinoids as a mixture derived from a plant extract (CMBE, cannabis based medicinal extract).

Plant extracts are preferred as, in addition to one or more cannabinoids, they will contain other chemical entities that may provide a beneficial effect either in their own right or in combination with the one or more cannabinoids. Such other chemicals include, for example, volatile oils e.g. terpene or carotene rich volatiles. Known terpenes present in the CMBE include C.sub.10 terpenes, e.g. mycerene, and pinenes and C.sub.15 terpenes e.g. caryophyllene.

Preferably the CBD or CBDV and/or the acids thereof are present with THC or THCV and/or the acids thereof.

Alternatively the CBD or CBDV and/or the acids thereof are substantially free (less than 10%, more prferably less than 5% and most preferably less than 2% relative to other cannabinoids present) from other cannabinoids.

In another embodiment the CBD or CBDV and/or the acids thereof are synthetic.

The invention also extends to methods of treating nausea, vomiting, emesis, motion sickness or like conditions with CBD or CBDV and/or the acids thereof, either as the sole active ingredient or in mixtures as plant extracts.

Whilst the observation has been made on an extract administered intraperitoneally, the skilled man will appreciate that a medicament can be prepared for administration by any suitable means. These include, but are not limited to, solids, semi solids, e.g. gels, liquids, sprays, aerosols, inhalers, vapourisers, enemas, rectal suppositories and the like. The route of administration need not be intraperitoneally but could be oral, buccal, sublingual, or by any other suitable route e.g. the respiratory tract, nasal tract and distal rectum.

A "plant extract" is an extract from a plant material as defined in the Guidance for Industry Botanical Drug Products Draft Guidance, August 2000, US Department of Health and Human Services, Food and Drug Administration Centre for Drug Evaluation and Research.

"Plant material" is defined as a plant or plant part (e.g. bark, wood, leaves, stems, roots, flowers, fruits, seeds, berries or parts thereof) as well as exudates.

The term "Cannabis plant(s)" encompasses wild type Cannabis sativa and also variants thereof, including cannabis chemovars which naturally contain different amounts of the individual cannabinoids, Cannabis sativa subspecies indica including the variants var. indica and var. kafiristanica, Cannabis indica and also plants which are the result of genetic crosses, self-crosses or hybrids thereof. The term "Cannabis plant material" is to be interpreted accordingly as encompassing plant material derived from one or more cannabis plants. For the avoidance of doubt it is hereby stated that "cannabis plant material" includes dried cannabis biomass.

In the context of this application the terms "cannabis extract" or "extract from a cannabis plant", which are used interchangeably encompass "Botanical Drug Substances (BDS)" derived from cannabis plant material. A Botanical Drug Substance is defined in the Guidance for Industry Botanical Drug Products Draft Guidance, August 2000, US Department of Health and Human Services, Food and Drug Administration Centre for Drug Evaluation and Research as: "A drug substance derived from one or more plants, algae, or macroscopic fungi. It is prepared from botanical raw materials by one or more of the following processes: pulverisation, decoction, expression, aqueous extraction, ethanolic extraction, or other similar processes." A botanical drug substance does not include a highly purified or chemically modified substance derived from natural sources. Thus, in the case of cannabis, "botanical drug substances" derived from cannabis plants do not include highly purified, Pharmacopoeial grade cannabinoids.

"Botanical drug substances" derived from cannabis plants include primary extracts prepared by such processes as, for example, maceration, percolation, extraction with solvents such as C1 to C5 alcohols (e.g. ethanol), Norflurane (HFA134a), HFA227 and liquid carbon dioxide under pressure. The primary extract may be further purified for example by supercritical or subcritical extraction, vaporisation and chromatography. When solvents such as those listed above are used, the resultant extract contains non-specific lipid-soluble material. This can be removed by a variety of processes including "winterisation", which involves chilling to -20.degree. C. followed by filtration to remove waxy ballast, extraction with liquid carbon dioxide and by distillation.

Preferred "cannabis extracts" include those which are obtainable by using any of the methods or processes specifically disclosed herein for preparing extracts from cannabis plant material. The extracts are preferably substantially free of waxes and other non-specific lipid soluble material but preferably contain substantially all of the cannabinoids naturally present in the plant, most preferably in substantially the same ratios in which they occur in the intact cannabis plant.

Botanical drug substances are formulated into "Botanical Drug Products" which are defined in the Guidance for Industry Botanical Drug Products Draft Guidance, August 2000, US Department of Health and Human Services, Food and Drug Administration Centre for Drug Evaluation and Research as: "A botanical product that is intended for use as a drug; a drug product that is prepared from a botanical drug substance."

"Cannabinoids" may be highly purified, Pharmacopoeial Grade substances and may be obtained by purification from a natural source or via synthetic means. The cannabinoids will include, but are not limited to, tetrahydrocannabinoids, their precursors, alkyl (particularly propyl) analogues, cannabidiols, their precursors, alkyl (particularly propyl) analogues, and cannabinol.

In preferred embodiments of the invention the formulations comprise extracts of one or more varieties of whole Cannabis plants, particularly Cannabis sativa, Cannabis indica or plants which are the result of genetic crosses, self-crosses or hybrids thereof. The precise cannabinoid content of any particular cannabis variety may be qualitatively and quantitatively determined using methods well known to those skilled in the art, such as TLC or HPLC. Thus, one may chose a Cannabis variety from which to prepare an extract which will produce the desired ratio of CBD or CBDV to THC or THCV. Alternatively, extracts from two of more different varieties may be mixed or blended to produce a material with the preferred cannabinoid ratio for formulating into a pharmaceutical formulation.

The preparation of convenient ratios of CBD, CBDV, CBDA and CBDVA-containing medicines is made possible by the cultivation of specific chemovars of cannabis. These chemovars (plants distinguished by the cannabinoids produced, rather than the morphological characteristics of the plant) can be bred by a variety of plant breeding techniques which will be familiar to a person skilled in the art. Suitable methods are given in Example 3. Propagation of the plants by cuttings for production material ensures that the genotype is fixed and that each crop of plants contains the cannabinoids in substantially the same ratio.

Horticulturally, it is convenient to grow chemovars producing e.g. CBD and CBDV as the predominant cannabinoid from cuttings. This ensures that the genotype in each crop is identical and the qualitative formulation (the proportion of each cannabinoid in the biomass) is the same. From these chemovars, extracts can be prepared by the similar method of extraction. Convenient methods of preparing primary extracts include maceration, percolation, extraction with solvents such as C1 to C5 alcohols (ethanol), Norflurane (HFA134a), HFA227 and liquid carbon dioxide under pressure. The primary extract may be further purified for example by supercritical or subcritical extraction, vaporisation and chromatography. When solvents such as those listed above are used, the resultant extract contains non-specific lipid-soluble material. This can be removed by a variety of processes including chilling to -20.degree. C. followed by filtration to remove waxy ballast, extraction with liquid carbon dioxide and by distillation. Preferred plant cultivation and extract preparation methods are shown in the Examples. The resulting extract is suitable for incorporation into pharmaceutical preparations.

A detailed examination of the pharmacological differences between CBD and THC has revealed significant differences in these compounds and consequently the finding that CBD and/or its acid CBDA appear to be responsible for the therapeutic effects noted was surprising. THC is bound with high avidity to CB1 and CB2 receptors in cerebral cortex and other sites; CBD is relatively inactive against CB1 receptors and appears to have non-cannabinoid receptor pharmacological actions in the central nervous system. Without prejudice to the teaching of the invention, it is possible that the anti-emetic effect of CBD and/or its acid CBDA is mediated via a non-cannabinergic mechanism.

Table 1 (see Original Patent) illustrates some of the differences between these cannabinoids.

Whilst it is known that THC can be used to control nausea and vomiting pre-operatively the effect of other cannabinoids or combinations or the effect of the acid forms present in, for example, plant extracts was not hitherto known.

The applicants studied the effect of other cannabinoids as cannabis extracts, and particularly extracts containing predominantly CBD or its acid form CBDA in Suncus murinus and in which an emetic response can be induced by a motion stimulus. Compounds which are effective in this test have therapeutic benefit in the treatment of motion-induced nausea and vomiting, and also these conditions when induced by other pathways in the peripheral and central nervous systems.

The applicant has determined that, for example, extracts in which the content of CBD and/or CBDA is 2-20% w/w, and the content of THC and or THCA is 0.1-2% w/w are particularly beneficial.
 

Claim 1 of 16 Claims

1. A method of treating motion sickness in a mammal comprising administering a pharmaceutically acceptable amount of, or an extract consisting essentially of a pharmaceutically acceptable amount of, CBD and/or CBDA and/or the propyl variants CBDV and/or CBDVA, wherein the amount of CBD and/or CBDA and/or the propyl variants CBDV and/or CBDVA is greater than 50% of the total cannabinoid content, wherein the CBDA, and/or CBDVA and/or CBD and/or CBDV is/are present as a cannabis extract, and wherein the cannabis extract contains less than 10% (w/w) of other cannabinoids.
 

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