12 667 561 use of tetrahydrocannabinol a

8/4/2019 12 667 561 Use of Tetrahydrocannabinol A

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1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1us 20100286098Al(19) United States(12) Patent Application PublicationRobson et al. (10) Pub. No.: US 2010/0286098 Al(43) Pub. Date: Nov. 11,2010(54) (30) Foreign Application Priority DataSE OF TETRAHYDROCANNABINOL

AND/OR CANNABIDIOL FOR THETREATMENT OF INFLAMMATORY BOWELDISEASE

(75) Inventors: Philip Robson, Wiltshire (GB);Geoffrey Guy, Salisbury (GB);Roger Pertwee, Aberdeen (GB);Joanna Jamontt, Hatfield (GB)

Correspondence Address:WOLF GREENFIELD & SACKS, P.C.600 ATLANTIC AVENUEBOSTON, MA 02210-2206 (US)

(73) Assignee: GW Pharma Limited, Salisbury,Wiltshire (GB)

(21) Appl. No.: 12/667,561(22) PCTFiled: Jun. 25, 2008(86) PCTNo.: PCT/GB2008/002183

371 (c)(I),(2), (4) Date: Jul. 21, 2010

luI. 5, 2007 (GB) 0713083.4Publication Classification

(51) Int. CI.A61K 311606 (2006.01)A61K 311352 (2006.01)A61P 1100 (2006.01)A61K 31156 (2006.01)A61P 37106 (2006.01)A61P 1104 (2006.01)

(52) U.S. CI. 514/161; 514/454; 514/171(57) ABSTRACTThe present invention relates to the use of a substantially puretetrahydrocannabinol (THC) or a THC containing extract inwhich THC is a primary cannabinoid, in the manufacture of amedicament for use in the treatment of an inflammatorybowel disease. A further embodiment of the invention relatestothe use of a substantially pure cannabidiol (CBD) or a CBDcontaining extract inwhich CBD is a primary cannabinoid, inthe manufacture of a medicament for use in the treatment ofan inflammatory bowel disease. Additionally the substan-t ially pure cannabidiol (CBD) or a CBD containing extract inwhich CBD is a primary cannabinoid are used in the manu-facture of a medicament for use as an adjunct therapy in thetreatment of an inflannnatory bowel disease.


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USE OF TETRAHYDROCANNABINOLAND/OR CANNABIDIOL FOR THE

TREATMENT OF INFLAMMATORY BOWELDISEASE

FIELD OF THE INVENTION[0001] The present invention relates to the use of a substan-tially pure tetrahydrocannabinol (THC) or a THC containingextract in which THC is a primary cannabinoid, in the manu-facture of a medicament for use in the treatment of an inflam-matory bowel disease.[0002] A further embodiment of the invention relates to theuse of a substantially pure cannabidiol (CBD) or a CBDcontaining extract in which CBD is a primary cannabinoid, inthe manufacture of a medicament for use in the treatment ofan inflannnatory bowel disease.[0003] Additionally the substantially pure cannabidiol(CBD) or a CBD containing extract in which CBD is a pri-mary cannabinoid are used in the manufacture of a medica-ment for use as an adjunct therapy in the treatment of aninflammatory bowel disease.

BACKGROUND DESCRIPTION[0004] Inflammatory bowel disease is the term used todescribe chronic diseases that cause inflannnation of theintestines. Diseases such as ulcerative colitis and Crohn'sdisease are examples of inflammatory bowel conditions.[0005] Ulcerative colit is is an inflammatory disease of thecolon. In ulcerative colitis, the lining of the intestinal wallreddens and swells and develops ulcers.[0006] The condit ion is often most severe in the rectal area,which can cause frequent diarrhoea. Addit ionally mucus andblood may appear in the stool if the lining of the colon isdamaged.[0007] Crohu's disease may affect any part of the digestivesystem, from the mouth to the anus, but it is most common inthe lower part of the small bowel or the first part of the largebowel. Itoften affects more than one part of the bowel leavingnormal, unaffected areas in between.[0008] Crohu's disease is a chronic relapsing inflannnatorydisorder of the gastrointest inal (GI) tract occurring world-wide, most notably in North America and Europe with anincidence of 2-6 per 100,000 per year and a prevalence of60-80 per 100,000. The onset of disease can occur in any agegroup but is more common in young adults. Crohu's diseaseis characterised by mucosal membrane inflammation affect-ing any part of the GI tract, with the terminal ileum (35%),ileocaecal region (40%) and colon (20%) generally being themost affected areas.[0009] Crohu's disease patients have an increased bloodflow in the wall of the bowel; this causes inflannnation andulceration, which extends to the deepest layers of the bowel.[0010] The exact cause of 'Crohn's disease is not known, butit is thought that the body's immune system overreacts to avirus or bacterium, causing ongoing inflammation in thebowel. The disease often tends to run in families.[0011] Crohu's disease is usually a life-long condition,with alternating flare-ups of symptoms and periods of remis-sion. The symptoms include: diarrhoea, up to 10 or 20 timesa day; pain, anywhere in the abdomen, and is often describedas cramping or colicky. The abdomen may be sore to the touchand swollen; loss of appetite; weight loss; fever; rectal bleed-ing; anaemia; fissures and abscesses in the anal area.

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[0012] During a flare-up of symptoms problems in otherareas of the body may also occur, such as mouth ulcers, jointpain, eye inflammation, rashes and ulcers on the skin.[0013] With chronic Crohu's disease, severe inflannnationmay cause complications to develop. This includes a fistula,which is an abnormal connection between the bowel and aneighbouring part of the body, such as the bladder, vagina, oranother loop of bowel. Fistulas may lead to recurrent infec-tions of the urinary or genital tracts. Other complicationsinclude an abscess (collection of pus) inside the abdomen ora stricture, a narrowing of the bowel caused by scar t issue thatcan obstruct the passage of material through the bowel. Itisalso known that patients who have had Crohn's disease for 8to 10 years are at an increased risk of bowel cancer.[0014] There isno cure for Crohu's disease. Symptoms canbe improved with dietary changes, drugs or surgery, or acombination of these.[0015] Medicines to reduce inflannnation such as corticos-teroids are often used in Crohri's disease along with medi-cines that suppress the immune system. Anti -diarrhoea medi-cines, antibiotics and painkillers may also be used duringflare-ups.[0016] Existing therapies currently available for use in thetreatment of acute active Crohu's disease, particularly cort i-costeroids' are not universally effective or well tolerated byall patients and/or may not be cost-effective in the long-term.In addition, approximately 45% of patients cannot discon-tinue corticosteroid treatment without an exacerbation oftheir disease and consequently, many patients can becometolerant to such drugs although, this is more evident in mod-erate-severe disease.[0017] Many people with Crohu's disease require surgicaltreatment at some time to treat complications such as analabscesses, or fistulae, to remove areas of narrowed, non-functioning bowel, or when drugs are not controlling thedisease.[0018] About 15-20% of patients have frequent flare-ups,whereas a few have only one or two bouts of Crohri's diseaseduring their lifetime. Most people are somewhere in betweenand are able to continue with normal life activities onceCrohn's disease has been diagnosed and treatment has started.Unfortnnately these are unpredictable.[0019] The use of cannabis as a medicine has long beenknown and during the 19 th Century, preparations of cannabiswere recommended as a hypnotic sedative which were usefulfor the treatment of hysteria , delirium, epilepsy, nervousinsomnia, migraine, pain and dysmenorrhoea.[0020] Until recent times the administration of cannabis toa patient could only be achieved by preparation of cannabisby decoction which could then be swallowed, or by the patientinhaling the vapours of cannabis by smoking the dried plantmaterial. Recent methods have sought to find new ways todeliver cannabinoids to a patient including those whichbypass the stomach and the associated first pass effect of theliver which can remove up to 90% of the active ingested doseand avoid the patient having to inhale unhealthy tars andassociated carcinogens into their lungs.[0021] Formulations containing specific, defined ratios ofcannabinoids may be formulated from pure, synthetic can-nabinoids or from extracts derived from the cannabis plant incombination with pharmaceutical carriers and excipients orcombinations thereof.[0022] Cannabinoids are a group of chemicals known toactivate cannabinoid receptors in cells. These chemicals,


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which are found in cannabis plants, are also produced endog-enously in humans and other animals, these are termedendocannabinoids. Synthetic cannabinoids are chemicalswith similar structures to plant cannabinoids or endocannab-inoids.[0023] To date there has been no clinical research to assessthe use of cannabinoids in the treatment of inflammatorybowel disease. Anecdotal reports suggest that patients suffer-ing from Crohu's disease using whole cannabis either as adecoction or by smoking can obtain relief of symptoms.[0024] The applicant's co-pending patent applications (EP1361864 and EP1542657) suggests that the use of a broadratio CBD product might be useful in the treatment of inflam-matory bowel disease, although it fails to provide any data tothe potential usefulness of such a product.[0025] Furthermore the European patent EPI071417(Feldmann et al.) describes the use of pure cannabidiol. Thepure CBD is thought to be useful as an anti-inflammatoryagent and much data is provided for its use as a treatment forrheumatoid arthrit is. However, there is no data to support itsuse in the treatment of inflammatory bowel disease.[0026] In addition there are many published reports (Frideetal. (2005) and Di Carlo and Izzo (2003)) which describe theusefulness of CBD as an anti -inflammatory and as such mak-ing CBD a useful treatment in inflammatory bowel disease.[0027] Also Massa and Monory in 2006 describes the useof the bodies natural cannabinoids, endocannabinoids asnatural protectants in inflammatory and gastrointestinal dis-orders.[0028] Although there is data relating to the use of canna-bidiol in inflammatory bowel disease there has been noprogress in production of a medicament that can be used by apatient suffering from inflammatory bowel disease. This maybe due to the data generated in in vitro and in vivo animalmodels not transpiring an effect in clinical patients actuallysuffering from the disease.[0029] As is clear from the above there is an umnet require-ment for an efficacious treatment for inflammatory boweldisease and it is thought that the administration of cannab-inoids alone and in combination with each other or as anadjunct medicament may be efficacious in the treatment ofpatients suffering from inflammatory bowel disease.[0030] The present invention describes how both the can-nabinoids cannabidiol (CBD) and tetrahydrocannabinol(THC) are useful in the treatment of inflammatory boweldisease, either alone or more particularly when used in com-bination.[0031] Additionally it was found that the use of CBD wasparticularly useful as an adjunct therapy with other medica-tions used inthe treatment of inflammatory bowel disease. Inparticular the other medicaments may include one or more ofthe following: aminosalicylates; corticosteroids; and immu-nosupressants. This data has been generated in patients actu-ally suffering from inflammatory bowel disease and as suchgives credence to the data.

SUMMARY OF THE INVENTION[0032] According to the first aspect of the present inventionthere is provided the use of a substantially pure tetrahydro-cannabinol (THC) or a THC containing extract in which THCis a primary cannabinoid, inthe manufacture of a medicamentfor use in the treatment of an inflammatory bowel disease.

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[0033] Preferably the THC is in a unit dose form suitablefor delivering a daily dose of THC in the range of frombetween 2.5 to 100 mg.[0034] Preferably the medicament further comprises sub-stantially pure cannabidiol (CBD) or a CBD containingextract in which CBD is the primary cannabinoid.[0035] Preferably the CBD is in a unit dose form suitablefor delivering a daily dose of CBD in the dose range of frombetween 5 to 200 mg.[0036] Each cannabinoid is provided in a therapeuticallyeffective amount. Dose ranges for the THC and CBD may bedetermined by reference to the cannabinoid content which ispreferably in the range of between 2.5 and 200 mg of the totalcannabinoids.[0037] More preferably the THC and CBD are in a ratio ofbetween 5:1 to 1:5 (THC:CBD) based on the weight of can-nabinoids.[0038] More preferably stil l the THC and CBD are in a ratioof between 2: 1 to 1:2 (THC:CBD) based on the weight ofcannabinoids.[0039] More preferably still the THC and CBD may beadministered separately, sequentially or simultaneously toone another.[0040] According to the second aspect of the present inven-tion there is provided the use of a substantially pure canna-bidiol (CBD) or a CBD containing extract in which CBD is aprimary cannabinoid, in the manufacture of a medicament foruse as an adjunct therapy in the treatment of an inflammatorybowel disease.[0041] Preferably the medicament is used an adjuncttherapy in combination with a primary medicament takenfrom the group comprising: aminosalicylates; corticoster-oids; and immunosupressants.[0042] More preferably the medicament and the primarymedicament may be administered separately, sequentially orsimultaneously to one another.[0043] A plant extract is defined as an extract from a plantmaterial as described by the Guidance for Industry 1.0Botanical Drug Products Draft Guidance, August 2000, USDepartment of Health and Human Services, Food and DrugAdministration Centre for Drug Evaluation and Research.[0044] Plant material is defined as a plant or plant part (e.g.bark, wood, leaves, stems, roots, flowers, fruits, seeds, berriesor parts thereof) as well as exudates.[0045] Botanical drug substances which are derived fromcannabis plants include primary extracts prepared by suchprocesses as for example, maceration, percolation, extractionwith solvents such as Cl to C5 alcohols (e.g. ethanol), Nor-flurane (HFA134a), HFA227, liquid carbon dioxide underpressure and extraction using a hot gas.[0046] A primary extract may be further purified by super-critical or subcritical extraction, vaporisation and chromatog-raphy. When solvents such as those listed above are used theresultant extract may contain non-specific lipid-soluble mate-rial. This can be removed by a variety of processes includingwinterisation, which involves chilling to _200 C. followed byfiltration to remove waxy ballast, extraction with liquid car-bon dioxide and by distillation.[0047] Botanical drug substances are formulated intoBotanical Drug Products which are defined in the Guidancefor Industry Botanical Drug Products Draft Guidance, August2000, US Department of Health and Human Services, Foodand Drug Administration Centre for Drug Evaluation and


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Research as: "A botanical product that is intended for use asa drug; a drug product that is prepared from a botanical drugsubstance."[0048] The term "inflammatory bowel disease" is used todescribe diseases associated with inflammation of the bowel.These include but are not limited to: Crohn's disease andulcerative colitis.[0049] Preferably the inflammatory bowel disease ISCrohn's disease.[0050] Alternatively the inflammatory bowel disease ISulcerative colitis.[0051] According to the third aspect of the present inven-tion there is provided a method of treating an inflammatorybowel disease comprising administering a therapeuticallyeffective amount of substantially pure tetrahydrocannabinol(THC) or a THC containing extract in which THC isa primarycannabinoid to a patient in need thereof.[0052] According to the fourth aspect of the present inven-tion there is provided method of treating an inflammatorybowel disease comprising administering a therapeuticallyeffective amount of an adjunct medicament comprising sub-stantially pure cannabidiol (CBD) or a CBD containingextract in which CBD is a primary cannabinoid to a patient inneed thereof.[0053] According to the fifth aspect ofthe present inventionthere is provided method of treating an inflammatory boweldisease comprising administering a therapeutically effectiveamount of a substantially pure tetrahydrocannabinol (THC)or a THC containing extract in combination with a substan-tially pure cannabidiol (CBD) or a CBD containing extract toa patient in need thereof, wherein the ratio ofTHC to CBD isbetween 5:1 to 1:5 (THC:CBD).[0054] The preferred embodiments of the first and secondaspects of the current invention as described above applymutatis mutandis to the third, fourth and fifth aspects.[0055] Certain aspects of this invention are furtherdescribed, by way of example only.

SPECIFIC DESCRIPTION[0056] Recently, clinical trials have been performed oncannabinoids, in order to test the mainly anecdotal evidenceof their analgesic and other medicinal properties.[0057] One study has found that the combination of tet-rahydrocannabinol (THC) and cannabidiol (CBD) in anapproximately equal ratio was an effective analgesic inpatients with central neuropathic pain (Berman et aI. , 2004).The cannabinoid-containing plant extracts of CannabisSativa L.containing either THC or CBD were mixed in a 1:1ratio and compared against placebo.[0058] Ithas been suggested that there may be an interac-tion between the cannabinoid components in a cannabis plantextract with other non-cannabinoid components in the plantextract.[0059] The components ofthe THC and CBD plant extractsused in the following examples are described in Table 1below.

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TABLE 1componen ts of the THC and CBD plant extracts

THC-rich extract(%w/wofextract)

CBD-rich extract(%w/wofextract)

Primary/SecondaryCannabinoid:THCContentCBDContentOther Cannabinoids:

63.0-78.00.1-1.5

2.0-6.557.0-72.0

CannabigerolCannabichromeneTetrahyrocannabidivarinTetrahydrocannabinolicacidCannabidivarinCannabidiolic acidTerpenes:

1.0-2.00.8-2.20.4-1.0


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non-cannabinoid containing fraction have been identifiedusing supercritical CO2 extraction, ethanol and hexaneextraction techniques. These include: chlorophyll, flavinoids,glycosides and alkaloids.[0067] Another cannabis plant extraction technique isextraction with hot gas as described in the applicants grantedUnited Kingdom patent GB2376464.

Example I[0068] Cannabidiol (CBD) has been shown to interact withtetrahydrocannabinol (THC) in behavioural studies, but it isnot known if these cannabinoids interact in vivo in inflam-matory disorders.[0069] In this example, the TNBS (trinitrobenzenesulfonicacid) model of colitis was used to characterize the effects ofCBD alone, THC alone and a combination of CBD and THC(in two different ratios) on inflammation and in vitro motilityand secretory parameters.[0070] Colitis was evoked in male Wistar rats by intra-colonic administration of 6.7 mg TNBS in 0.2S ml 2S%ethanol. The degree of inflammation was quantified using amacroscopic damage score (MDS, 0-13 scale) and myelop-eroxidase (MPO) activity.[0071] Using the Ussing chamber technique, secretoryresponses evoked by veratridine (a nerve stimulant, IxIO-sM) were assessed and expressed as % response to carbachol(lxIO-SM).[0072] Longitudinal muscle strips were used for the motil-ity studies and contractile responses to carbachol (lxI0-8-3xI0-SM) were evaluated.[0073] CBD was used at doses of S, 10, IS and 20 mg/kg.THC was used at doses of S, 10 and 20 mg/kg. In additionTHC at doses of S and 10 mg/kg was administered in combi-nation with CBD at a dose of 10 mg/kg.[0074] Doses were administered i.p. , once daily starting O. Shour before TNBS administration and animals (n=6-11 pergroup) were sacrificed 72 hours after colitis induction.[0075] Results:[0076] The use of a TNBS model results in the untreated(control) animals showing a significantly depressed contrac-ti le and secretory response, whereas their macroscopic dam-age score (MDS) andmyeloperoxidase (MPO) activity scoresare increased.[0077] CBD Alone Treatments[0078] Table 2 shows that CBD treatment at 10 mg/kgproduced a clear reduction in MDS, but this failed to bestatistically significant.

TABLE 2Effects of cannabidiol on macrosco12ic damage

Vehicle CBD5 CBD 10 CBD 15 CBD20MDS Mean 5.46 6.75 2.83 5.60 4.60

SEM 0.85 1.65 1.01 0.68 1.40

[0079] Table 3 shows that CBD also reduced MPO in a dosedependent manner, but the effect was not significant.

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TABLE 3Effects of cannabidiol on myeloperoxidase

activiVehicle CBD 5 CBD 10 CBD 15 CBD20

MPO Mean 6.030.75

5.381.15

4.650.99

4.001.51

2.680.38ngHRP/mg SEM

protein]

[0080] THC Alone Treatments[0081] Table 4 shows that the MDS was lowered by THC at10mg/kg, the dose-response relationship of this cannabinoidshowing a bell-shaped pattern.

TABLE 4Effects of tetrahydrocannabinol on macroscopic

darna eTHC THC

Vehicle THC5 10 20MDS Mean 6.00 6.50 2.67 4.67

SEM 0.50 0.76 1.02 0.71

[0082] Table S shows that THC at 10 and 20 mg/kg reducedTNBS-induced neutrophil infiltration.

TABLESEffects oftetrahydrocannabinol on myeloperoxidase

activiTHC THC

Vehicle THC5 10 20MPO Mean 3.35 4.29 1.77 2.13[ngHRP/mg SEM 0.38 0.44 0.12 0.23protein]

[0083] However THC alone did not affect secretoryresponses to nerve stimulation, in addit ion responses to car-bachol were not significantly increased by THC (data notshown).[0084] THC and CBD Combination Treatments[0085] Tables 6 and 7 show that the combined treatment ofTHC at S mg/kg and CBD at 10 mg/kg resulted in reductionofMDS and MPO (4.20.S, 2.40.3, respectively, P


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TABLE 7Effects of tetrahydrocannabinol in combination witb

CBD on ill elo ercwidase activiTHC THC

(5 mg/kg) + (10 mg/kg) +CBD CBD

Vehicle (10 mg/kg) (10 mg/kg)MPO Mean 3.35 2.44 2.62[ngHRP/mg SEM 0.38 0.32 0.58protein]

[0086] Table 8 shows that the secretory responses to nervestimulation when treated with THC at 10 mg/kg and CBD at10 mg/kg were significantly enhanced (62.88.8, P


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[0100] Harvey Bradshaw Index;[0101] C-Reactive Protein (CRP);[0102] Erythrocyte Sedimentation Rate (ESR);[0103] Platelet count;[0104] Circulating interleukin (IL)-2 receptors;[0105] IL-6 Inflammatory Bowel Disease Question-

naire (IBDQ); and[0106] Neutrophil count.

[0107] To compare for CBD-containing cannabis plantextract with placebo in the percentage of responders andsubjects in remission at the end of treatment;

[0108] To evaluate the patient's global impression ofchange (PGIC) with for CBD-containing cannabis plantextract compared with placebo; and

[0109] To evaluate safety and tolerability of for CBD-containing cannabis plant extract compared with pla-cebo.

[0110] Method:[0111] Eligible subjects had Crohn's disease with activeinflammation of the colon and/or terminal ileum and scoredbetween 175 and 450 inclusive on the CDAI. Subjects whohad symptoms of intestinal obstruction believed by the inves-tigator to be due to a fibrous stricture or findings suggestive ofintestinal perforation were excluded. Subjects who hadreceived TNFa-modifying agents within two months beforeadministration of study drug were also excluded.[0112] The investigational medicinal product (IMP) waspresented in a solid dosage format. Each pastille contained 20mg CBD and no more than 1.3 mg THC. The maximumpermitted dose of IMP was 10 pastilles taken orally withinany 24-hour period (200 mg CBD). Up to five pastilles weretaken in the morning and evening before food with an intervalof approximately 12hours between doses. Subjects followeda stepwise titration to their optimal dose based on efficacy,tolerabil ity and the maximum permitted dose.[0113] Placebo, produced to match the taste, smell andappearance of the active formulation but containing no activecomponents, were presented as 1000 mg pastil les. Five pas-ti lles were administered orally twice daily prior to food.[0114] Throughout the study, the investigator could pre-scribe any concomitant medications or treatments deemednecessary to provide adequate supportive care.[0115] The CBD-containing plant extract could be pre-scribed as an adjunct therapy to existing amino salicylate,corticosteroid (including inhaled and topical preparations) orimmunosuppressive therapies.[0116] Withdrawing existing medication for treatment ofCrohn's disease was not considered ethically acceptable,however, any such medication must have remained stable fortwo weeks (aminosalicylates and corticosteroids) and for fourweeks (immunosupressants) prior to IMP administration andfor the duration of the study. Subjects could not commencetreatment with these medications or nutritional formulas dur-ing the study but were allowed to use orinit iate treatment withcreams, ointments and inhalers containing corticosteroids.[0117] Crohn's Disease Activity Index (CDAI)[0118] Crohn's disease activity was assessed at Visits 2, 3,4, 5/withdrawal and 6 using the CDAI. This index comprisedeight items providing a global rating score of disease activitycalculated from the information recorded in the subject dia-ries for the seven days prior to each visi t and following clini-cal examination by the investigator at each visi t. The numberof complications presumed related to Crohn's disease wasalso scored if present during examination or from symptoms

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reported by the subject. The determination of the final CDAIscore involved the measurement of haematocrit and bodyweight and the multiplication of each score for the eight i temsby individual weighting factors. A subject was defined clini-cally as a 'responder' if they had dropped 70 or more on theCDAI and defined as being in 'clinical remission' ifthere wasa reduction to less than 150 in the CDAI.[0119] Harvey Bradshaw Index[0120] Disease activity was assessed at Visits 2, 3, 4,5/withdrawal and 6 using the Harvey Bradshaw Index wheresubjects rated their general wellbeing, abdominal pain and thenumber ofl iquid stools per day for the previous 24hours. Thisinformation was obtained from the subject diary cards.[0121] During each visit, the investigator examined thesubject for the presence of an abdominal mass, which wasrated on a four-point scale. The complications of Crohn'sdisease were scored (one per item) if present during exami-nation. Components of the Harvey Bradshaw Index wererecorded.[0122] The Selective Reminding Test (SRT)[0123] The SRT was completed by the subject at baseline(Visit 2) and on completion or withdrawal from the study(Visit 5) as a measure of memory impairment.[0124] C Reactive Protein (CRP), Erythrocyte Sedimenta-t ion Rate (ESR) and Platelet Count[0125] Laboratory markers of inflammation CRP, ESR andplatelet count were determined from plasma samplesobtained atVisits 2, 3, 4, 5/withdrawal and 6 and analysed byPivotal (CRP and platelet count only). ESR was analysed bysite staff or by a local laboratory, as appropriate.[0126] Plasma IL-2 Receptor and IL-6 Levels[0127] Plasma samples were collected from subjects atVis-its 2, 4, 5/withdrawal and 6 and sent frozen to Pivotal foranalysis of circulating soluble IL-2 receptor and IL-6 levels.[0128] Inflammatory Bowel Disease Questionnaire(IBDQ)[0129] At Visits 2, 5/withdrawal and 6, subjects completedthe IBDQ, a disease specific health-related quality of lifequestionnaire comprising 32 questions divided into fourdimensions as follows: bowel function (10 questions), sys-temic symptoms (5 questions), social function (5 questions)and emotional function (12 questions).[0130] Each question was graded on a seven-point scalewhere 1represents worst function and 7 represents best func-tion. Therefore, the minimum (worst) score was 32 and themaximum (best) score was 224 (70 for the bowel functiondimension; 35 for the systemic symptoms dimension; 35 forthe social function dimension; 84 for the emotional functiondimension). Thus, the higher the score, the better the subject' sfunctional status. The IBDQ has been shown to correlate wellwith disease activity.[0131] Patient's Global Impression of Change (PGIC)[0132] The subject gave their impression of the overallchange in their condition during the study at Visits 5/with-drawal and 6 using the following scale; 1=very muchimproved, 2=much improved, 3=minimally improved, 4=nochange, 5=minimally worse, 6=much worse, 7=very muchworse.[0133] Daily Symptom Diary[0134] Subjects were issued with a daily diary to completethroughout the study for assessment of general wellbeing(scored as O=generally well, 1=slightly below par, 2=poor,3=very poor, 4=terrible), number of bowel actions per dayand the proportion ofliquid or very soft stools, anti-diarrhoeal


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use, abdominal pain/cramps (rated as O=none, 1=mild,2=moderate, 3=severe) and oral temperature. The diary wascompleted at the same time each day.[0135] At Visits 2, 3, 4, 5/withdrawal and 6, the diary infor-mation for the previous seven days (if available at with-drawal) was used to calculate the CDAI score.[0136] Subject IMP dosing was recorded in the daily diary.[0137] The following clinical laboratory parameters werealso tested:

[0138] Haematology-red blood cells (RBC), haemo-globin, haematocrit, mean cell volume (MCV), plateletsand white blood cells (WBC) with automated differen-tial. In the event of a grossly abnormal blood count, ablood film was to be examined.

[0139] Biochemistry-sodium, potassium, urea, creati-nine, total bilirubin, alkaline phosphatase, aspartatetransferase (AST), alanine aminotransferase (ALT),gamma glutamyl transferase (GGT), albumin, total pro-tein and calcium.

[0140] Urinalysis-the investigator performed routinelab-stix analysis ofthe following parameters: pH, blood,protein, glucose and nitrites. Pivotal Laboratories per-formed microscopy on urine samples with abnormallab-stix results.

[0141] Results:[0142] Of the eight subjects who completed the study, allbut one (receiving placebo) reported an improvement inCrohu's disease as determined by the decrease in CDAI scorefrom baseline as shown in Table 11 below.

TABLE 11pSurnm of Individual CDAbResults

Total ChangeCDAI Total CDAI score - in CDAIscore - final t reatment! score

Subject IMP baseline withdrawal (and %)102 CBD-CPE* 197 166 -31 (-16)107 CBD-CPE 244.6 46 -198.6 (-81)117 CBD-CPE 321.5 213.54 -107.96 (-34)118 CBD-CPE 356 297.8 -58.2 (-16)105 Placebo 246.1 180.1 -66 (-27)106 Placebo 203 160.9 -42.1 ( -21)122 Placebo 252 239.1 -12.9 ( -5)125 Placebo 238 330.7 92.7 (39)

*CBD-CPE-CBD-containing plant extract

[0143] The average reduction in CDAI score from baselinein the four completers taking CBD-containing plant extractwas 98.94 points or 36.8%, whereas that for placebo was only28.3 or 3.5%.[0144] This demonstrates a very clear pattern of improve-ment in the subjects receiving CBD-containing plant extractover those taking placebo.

1-15. (canceled)16. A method of treating tissue injury in a patient with

colitis compnsmg administering tetrahydrocannabinol(THC) or THC and cannabidiol (CBD) in an effectiveamount.

17. A method of treating an inflammatory bowel diseasecomprising administering cannabidiol (CBD) together withtetrahydrocannabinol (THC), wherein the CBD is adminis-tered in an amount which potentiates the effect of the THC.

18. A method of treating an inflammatory bowel disease,comprising administering a therapeutically effective amount

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of a substantially pure tetrahydrocannabinol (THC) or a THCcontaining extract in combination with a substantially purecannabidiol (CBD) or a CBD containing extract to a patient inneed thereof, wherein the ratio ofTHC to CBD is between 2:1to 1:2 (THC:CBD).

19. A method of treating colitis as claimed in claim 16,wherein the THC is in a unit dose form suitable for deliveringa daily dose ofTHC in the range off rom between 2.5 to 100mg.

20. A method of treating an inflammatory bowel disease asclaimed in claim 17, wherein the THC is in a unit dose formsuitable for delivering a daily dose of THC in the range offrom between 2.5 to 100 mg.

21. A method of treating an inflammatory bowel disease asclaimed in claim 18, wherein the THC is in a unit dose formsuitable for delivering a daily dose of THC in the range offrom between 2.5 to 100 mg.

22. A method of treating colitis as claimed in claim 16,wherein the CBD is in a unit dose form suitable for deliveringa daily dose of CBD in the dose range of from between 5 to200 mg.

23. A method of treating an inflammatory bowel disease asclaimed in claim 17, wherein the CBD is in a unit dose formsuitable for delivering a daily dose of CBD in the dose rangeof from between 5 to 200 mg.

24. A method of treating an inflammatory bowel disease asclaimed in claim 18, wherein the CBD is in a unit dose formsuitable for delivering a daily dose of CBD in the dose rangeof from between 5 to 200 mg.

25. A method of treating an inflammatory bowel disease asclaimed in claim 18, wherein the THC and CBD are in a ratioof 1:1.

26. A method of treating colitis as claimed in claim 16,wherein the THC and CBD may be administered separately,sequentially or simultaneously to one another.

27. A method of treating an inflammatory bowel disease asclaimed in claim 17, wherein the THC and CBD may beadministered separately, sequentially or simultaneously toone another.

28. A method of treating an inflammatory bowel disease asclaimed in claim 18, wherein the THC and CBD may beadministered separately, sequentially or simultaneously toone another.

29. A method of treating colitis as claimed in claim 16,wherein the THC and CBD are used an adjunct therapy incombination with a primary medicament taken from thegroup comprising: aminosalicylates; corticosteroids; andimmunosupressants.30. A method of treating an inflammatory bowel disease asclaimed in claim 17, wherein the THC and CBD are used anadjunct therapy in combination with a primary medicamenttaken from the group comprising: aminosalicylates; corticos-teroids; and immunosupressants.

31. A method of treating an inflammatory bowel disease asclaimed in claim 18, wherein the THC and CBD are used anadjunct therapy in combination with a primary medicamenttaken from the group comprising: aminosalicylates; corticos-teroids; and immunosupressants.

32. A method of treating colitis as claimed in claim 29,wherein the primary medicament may be administered sepa-rately, sequentially or simultaneously to the THC and CBD.


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33. A method of treating an inflammatory bowel disease asclaimed in claim 30, wherein the primary medicament may beadministered separately, sequentially or simultaneously tothe THC and CBD.

34. A method of treating an inflammatory bowel disease asclaimed in claim 31, wherein the primary medicament may beadministered separately, sequentially or simultaneously tothe THC and CBD.

35. A method of treating an inflammatory bowel disease asclaimed in claim 17, wherein the inflammatory bowel diseaseis Crohu's disease.

Nov. 11,20108

36. A method of treating an inflammatory bowel disease asclaimed in claim 18, wherein the inflammatory bowel diseaseis Crohu's disease.

37. A method of treating an inflammatory bowel disease asclaimed in claim 17, wherein the inflammatory bowel diseaseis ulcerative colitis.

38. A method of treating an inflammatory bowel disease asclaimed in claim 18, wherein the inflammatory bowel diseaseis ulcerative colitis.

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12 667 561 use of tetrahydrocannabinol a

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