PHARMACEUTICAL COMPOSITIONS FOR THE TREATMENT OF DISEASE AND/OR SYMPTOMS IN ARTHRITIS

Abstract

The invention relates to the use of a combination of cannabinoids for the treatment of pain, inflammation and/or disease modification in arthritis. Preferably the cannabinoids are selected from cannabidiol (CBD) or cannabidivarin (CBDV) and delta-9-tetrahydrocannabinol (THC) or tetrahydrocannabinovarin (THCV). More preferably the cannabinoids are in a predefined ratio by weight of less than or equal to 19:1 of CBD or CBDV to THC or THCV.

Claims

1-42. (canceled)

43. A method for treatment of arthritis comprising administering to a subject in need thereof a pharmaceutical formulation comprising a therapeutically effective amount of a combination of cannabidiol (CBD) and tetrahydrocannabinol (THC), wherein the ratio of CBD:THC by weight is 1.5:1 to 1:1.5, and wherein the amount of the pharmaceutical formulation administered to the subject is effective to modify rheumatoid arthritis disease and treat the symptoms of pain and inflammation caused by the disease.

44. The method of claim 43, wherein the arthritis is osteoarthritis.

45. The method of claim 43, wherein the arthritis is rheumatoid arthritis.

46. The method of claim 43, wherein the treatment of arthritis comprises improvement in quality of sleep in arthritis.

47. The method of claim 43, wherein the ratio of CBD:THC is 0.93:1.

48. The method of claim 43, wherein the pharmaceutical formulation is packaged for delivery sublingually or buccally.

49. The method of claim 43, wherein the pharmaceutical formulation is in the form of a gel or gel spray, a tablet, a liquid, a capsule or for vaporization.

50. The method of claim 43, wherein the pharmaceutical formulation further comprises one or more carrier solvent(s).

51. The method of claim 50, wherein the carrier solvent(s) are ethanol and/or propylene glycol.

52. The method of claim 51, wherein the ratio of ethanol and propylene glycol is between 4:1 and 1:4, optionally wherein the ratio of ethanol and propylene glycol is 1:1.

53. The method of claim 43, wherein the pharmaceutical formulation is in a titratable dosage form.

54. The method of claim 43, wherein the therapeutically effective amount taken by the subject is a dose in the range of 5-25 mg per day of each of CBD and THC.

55. The method of claim 43, wherein CBD is administered separately, simultaneously or sequentially to THC.

56. The method of claim 43, wherein the CBD and THC are present as a Cannabis based medicine extract (CBME), or wherein the CBD and THC are derived from one or more CBME(s).

57. The method of claim 56, wherein the formulation comprises a combination of: a) a Cannabis based medicinal extract which comprises THC at more than 90% of the total cannabinoid content in the extract; and b) a Cannabis based medicinal extract which comprises CBD at more than 90% of the total cannabinoid content in the extract.

58. The method of claim 56, wherein the CBME(s) are produced by extraction with supercritical or subcritical CO.sub.2, or wherein the CBME(s) are produced by contacting plant material with a heated gas at a temperature which is greater than 100 C., sufficient to volatilize one or more of the cannabinoids in the plant material to form a vapor, and condensing the vapor to form an extract.

59. The method of claim 56, wherein the CBME(s) comprise all the naturally occurring cannabinoids in the said plant(s).

60. The method of claim 43, wherein the CBD and THC are substantially pure.

61. The method of claim 43, wherein the CBD and THC are synthetic.

62. The method of claim 56, wherein the CBD-containing CBME is characterized by a chromatographic profile as illustrated in FIG. 4, where the retention time of the CBD is between 5.4 and 6.4 minutes.

63. The method of claim 56, wherein the THC-containing CBME is characterized by a chromatographic profile as illustrated in FIG. 5, where the retention time of the THC is between 9.6 and 10.6 minutes.

64. The method of claim 56, wherein the CBME containing THC and CBD is characterized by a chromatographic profile as illustrated in FIG. 3.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0040] Certain aspects of this invention are further described, by way of example only, with reference to the accompanying drawings in which:

[0041] FIG. 1 shows an HPLC chromatographic profile which characterises a CBD-containing Cannabis based medicine extract;

[0042] FIG. 2 shows an HPLC chromatographic profile which characterises a THC-containing Cannabis based medicine extract; and

[0043] FIG. 3 shows an HPLC chromatographic profile which characterises a Cannabis based medicine extract comprising substantially equal quantities of CBD and THC.

[0044] FIG. 4 shows an HPLC chromatographic profile of a CBD-containing Cannabis based medicine extract (CBME).

[0045] FIG. 5 shows an HPLC chromatographic profile of a THC-containing Cannabis based medicine extract (CBME).

SPECIFIC DESCRIPTION

[0046] A Cannabis based medicine extract (CBME) was prepared as outlined in Example 1 and contained approximately equal amounts of the cannabinoids THC and CBD and this was administered to patients with chronic rheumatoid arthritis with pain as a secondary condition. The administration of this combination of cannabinoids could possibly reduce the pain and inflammation caused by the rheumatoid arthritis but unexpectedly the Cannabis based medicine extract containing approximately equal quantities of THC and CBD also produced a disease modifying effect in the patients with rheumatoid arthritis.

[0047] The features of the invention are illustrated further by reference to the following examples, together with the accompanying Figures in which:

[0048] FIG. 1 shows an HPLC chromatographic profile of a CBD-containing Cannabis based medicine extract (CBME).

[0049] FIG. 2 shows an HPLC chromatographic profile of a THC-containing Cannabis based medicine extract (CBME).

[0050] FIG. 3 shows an HPLC chromatographic profile of a Cannabis based medicine extract (CBME) containing substantially equal quantities of CBD and THC.

[0051] FIG. 4 shows an HPLC chromatographic profile of a CBD-containing Cannabis based medicine extract (CBME).

[0052] FIG. 5 shows an HPLC chromatographic profile of a THC-containing Cannabis based medicine extract (CBME).

EXAMPLE 1

Preparation of Cannabis Based Medicine Extracts (CBME)

[0053] Medicinal Cannabis was produced and prepared with reference to the method disclosed in WO 02/064109 (Example 15). The resulting plant material was processed as described in the steps below. The process of manufacture of a High THC or High CBD Cannabis based medicine extract is described below: [0054] Medicinal Cannabis (High THC or High CBD) is obtained; followed by [0055] Chopping to predominantly 2-3 mm; followed by [0056] Heating at 100-150 C. for sufficient time to decarboxylate the acid form of cannabinoids to produce neutral cannabinoids; followed by [0057] Extraction with a specific volume of liquid carbon dioxide over 6 to 8 hours; followed by [0058] Removal of CO.sub.2 by depressurisation to recover crude extract; followed by [0059] Winterisation followed by chilling (20 c./48 h) to precipitate unwanted waxes; followed by [0060] Removal of unwanted waxy material by cold filtration; followed by [0061] Removal of ethanol from the filtrate by thin film evaporation under reduced pressure.

[0062] The resulting extract is referred to as a Cannabis based medicinal drug extract and is also classified as a Botanical Drug Substance according to the US Food and Drug Administration Guidance for Industry Botanical Drug Products.

[0063] The quantity of cannabinoid in the CBME can be accurately assessed by way of measurement by HPLC with reference to the method disclosed in WO 02/064109 (Example 16).

[0064] An example of an HPLC chromatogram of a CBD-containing CBME produced using a high CBD medicinal Cannabis plant extracted with CO.sub.2 is shown in FIG. 1. An example of an HPLC chromatogram of a THC-containing CBME produced using a high THC medicinal Cannabis plant extracted with CO.sub.2 is shown in FIG. 2. An example of an HPLC chromatogram containing the relevant ratios of THC and CBD CBMEs is shown in FIG. 3.

[0065] The invention has been exemplified with reference to THC and CBD yet it is clear to a man skilled in the art that the pharmacological similarities between THC and THCV and CBD and CBDV are such that similar results could be produced using the cannabinoids THCV and CBDV in place of or in addition to THC and CBD.

EXAMPLE 2

Assessment of the Efficacy of a Cannabis Based Medicine Extract by Way of a Clinical Trial in Human Rheumatoid Arthritis Patients

[0066] A seven week, multi-centre, double blind, randomised, parallel group study was undertaken in order to evaluate the efficacy a Cannabis based medicine extract on pain in rheumatoid arthritis. The Cannabis based medicine extract contained delta-9-tetrahydrocannabinol (THC) at a concentration of 27 mg/ml and cannabidiol (CBD) at a concentration of 25 mg/ml in ethanol:propylene glycol (50:50) excipient. The Cannabis based medicine extract was presented in a pump action spray where each activation delivers 100 l of spray, containing THC (2.7 mg) and CBD (2.5 mg).

[0067] The subjects in the study were randomised equally to either the Cannabis based medicine extract or a placebo. The placebo matched the appearance, smell and taste of the active formulation, but containing no active components, in ethanol:propylene glycol (50:50) excipient. Again the placebo was presented in a pump action spray where each activation delivers 100 l of spray.

[0068] Patients were screened to determine eligibility at visit 1 and baseline assessments were taken at this time. The patients returned 2 weeks later for visit 2 at which point they were randomised into one of the two groups. The study medication was administered as an evening dose only and patients were asked to titrate their dose until they obtained optimum efficiency.

[0069] After 2 weeks titration on the medication the patients returned for visit 3, at this point the patient confirmed the dose that they were to take for the remaining 3 weeks of the study.

[0070] The dose of medication that each patient took varied but was in the range of 5-25 mg each of THC and CBD, with the majority of patients receiving between 10 and 20 mg each of THC and CBD. The average dose that each patient titrated to was 13.5 mg THC and 12.5 mg CBD.

[0071] After 5 weeks on the study medication the patients returned to make visit 4. All baseline assessments were repeated at this stage.

[0072] Efficacy assessments were considered as part of the study. Diary card self-assessments were recorded by each patient on a daily basis for morning pain at rest and on movement, morning stiffness and quality of sleep. Short form McGill Questionnaires were completed at visits 1 and 4 in order to compare changes in intensity of pain, intensity of pain at present, pain at present and global impression of change.

[0073] A Disease Activity Score was calculated at visits 1 and 4 from a 28 joint count, erythrocyte sedimentation rate and global disease activity score.

[0074] Assessments of the use of rescue analgesia, adverse events, blood chemistry and vital signs were all recorded at visits 1 and 4 in order to consider any changes.

Results:

[0075] Some of the data collated from this study is described below.

Comparison of Morning Pain at Rest in Patients with Rheumatoid Arthritis when Administered at a Cannabis Based Medicine Extract Containing THC at a Concentration of 27 mg/ml and CBD at a Concentration of 25 mg/ml

[0076] The efficacy of a Cannabis based medicine extract was assessed as described above and the degree of morning pain at rest was recorded by self assessment on a daily basis. The data was collated and statistical analysis was undertaken. Patients assessed morning pain at rest on a scale of 0 (no pain) to 10 (extremely bad pain). Tables 1 and 2 illustrate the results.

TABLE-US-00002 TABLE 1 THC:CBD (27 mg/ml:25 mg/ml) Placebo (N = 31) (N = 27) Baseline Mean 5.5 5.6 Std Dev 1.8 1.6 Minimum 2 3 Median 5.3 5.3 Maximum 10 9 Week 1 Mean 4.6 5.2 Std Dev 1.6 1.6 Minimum 1 3 Median 4.6 4.9 Maximum 9 9 Week 1- Mean 0.9 0.4 change from Std Dev 1.1 1.0 baseline Minimum 5 3 Median 0.6 0.4 Maximum 1 2 Week 2 Mean 3.7 4.3 Std Dev 1.9 1.9 Minimum 1 1 Median 3.7 4.2 Maximum 9 10 Week 2- Mean 1.7 1.1 change from Std Dev 1.8 1.6 baseline Minimum 6 5 Median 1.3 0.8 Maximum 1 2 Week 3 Mean 3.7 4.4 Std Dev 1.8 1.7 Minimum 0 0 Median 3.6 4.3 Maximum 8 8 Week 3- Mean 1.8 1.1 change from Std Dev 1.8 1.7 baseline Minimum 7 5 Median 1.3 0.8 Maximum 0 2 Week 4 Mean 3.5 4.4 Std Dev 1.8 1.9 Minimum 0 1 Median 3.3 4.4 Maximum 9 8 Week 4- Mean 2.0 1.0 change from Std Dev 1.9 1.7 baseline Minimum 7 5 Median 1.6 0.8 Maximum 1 3 Week 5 Mean 3.4 4.3 Std Dev 1.8 1.9 Minimum 0 0 Median 3.1 4.3 Maximum 8 8 Week 5- Mean 2.0 1.1 change from Std Dev 2.0 1.9 baseline Minimum 7 5 Median 1.8 1.0 Maximum 1 2 Week 6 Mean 3.6 4.6 Std Dev 1.7 0.5 Minimum 2 4 Median 3.0 4.9 Maximum 6 5 Week 6- Mean 2.3 0.2 change from Std Dev 0.9 1.3 baseline Minimum 3 2 Median 2.0 0.5 Maximum 2 1 End Point Mean 3.5 4.7 Std Dev 1.7 2.1 Minimum 0 0 Median 3.1 4.1 Maximum 8 9 End Point- Mean 2.0 0.9 change from Std Dev 1.9 1.7 baseline Minimum 7 5 Median 1.5 0.7 Maximum 1 2

[0077] Statistical analysis of this data is shown in Table 2.

TABLE-US-00003 TABLE 2 THC:CBD (27 mg/ml:25 mg/ml) Placebo LS LS Differ- p- Mean s.e. Mean s.e. ence 95% CI value 2.01 0.30 0.87 0.32 1.13 [2.02, 0.25] 0.013

[0078] The LS Mean figure is the mean change from the baseline adjusted score, a negative difference indicates a benefit.

[0079] Tables 1 and 2 demonstrate that the administration of THC:CBD (27 mg/ml:25 mg/ml) to patients suffering pain in rheumatoid arthritis results in a statistically significant reduction in morning pain at rest when compared to the placebo.

Comparison of Quality of Sleep in Patients with Rheumatoid Arthritis when Administered a Cannabis Based Medicine Extract Containing THC at a Concentration of 27 mg/ml and a CBD at a Concentration of 25 mg/ml

[0080] The efficacy of a Cannabis based medicine extract was assessed as described above and the quality of sleep experienced by the patient was recorded by self assessment on a daily basis. The data was collated and statistical analysis was undertaken. Patients assessed quality of sleep on a scale of 0 (very good) to 10 (very bad). Tables 3 and 4 illustrate the results.

TABLE-US-00004 TABLE 3 THC:CBD (27 mg/ml:25 mg/ml Placebo (N = 31) (N = 27) Baseline Mean 5.7 5.8 Std Dev 1.9 1.8 Minimum 2 3 Median 5.5 6.0 Maximum 10 10 Week 1 Mean 4.7 5.3 Std Dev 1.8 1.8 Minimum 2 2 Median 4.9 5.4 Maximum 8 10 Week 1- Mean 1.0 0.5 change from Std Dev 1.7 1.1 baseline Minimum 6 3 Median 0.9 0.3 Maximum 2 2 Week 2 Mean 3.6 4.6 Std Dev 2.1 1.7 Minimum 0 2 Median 3.5 4.4 Maximum 10 9 Week 2- Mean 2.1 1.1 change from Std Dev 2.0 1.9 baseline Minimum 8 7 Median 1.7 0.8 Maximum 1 2 Week 3 Mean 3.8 4.4 Std Dev 2.2 1.9 Minimum 0 0 Median 3.6 4.4 Maximum 9 8 Week 3- Mean 2.0 1.4 change from Std Dev 2.0 1.8 baseline Minimum 7 6 Median 1.6 1.1 Maximum 1 1 Week 4 Mean 3.5 4.5 Std Dev 2.2 2.1 Minimum 0 1 Median 3.4 4.0 Maximum 9 9 Week 4- Mean 2.3 1.4 change from Std Dev 2.2 2.1 baseline Minimum 9 6 Median 1.9 0.9 Maximum 2 2 Week 5 Mean 3.3 4.5 Std Dev 2.2 2.2 Minimum 0 0 Median 3.0 4.3 Maximum 8 9 Week 5- Mean 2.5 1.3 change from Std Dev 2.2 2.1 baseline Minimum 9 6 Median 2.1 1.2 Maximum 1 2 Week 6 Mean 2.6 5.1 Std Dev 1.8 1.6 Minimum 1 4 Median 2.2 4.9 Maximum 5 7 Week 6- Mean 2.2 0.2 change from Std Dev 1.1 1.7 baseline Minimum 3 3 Median 2.3 0.3 Maximum 1 1 End Point Mean 3.4 4.6 Std Dev 2.2 2.2 Minimum 0 1 Median 3.5 4.0 Maximum 8 10 End Point- Mean 2.3 1.1 change from Std Dev 2.2 2.0 baseline Minimum 9 5 Median 1.8 0.9 Maximum 1 2

[0081] Statistical analysis of this data is shown in Table 4.

TABLE-US-00005 TABLE 4 THC:CBD (27 mg/ml:25 mg/ml) Placebo LS LS Differ- p- Mean s.e. Mean s.e. ence 95% CI value 2.31 0.35 1.14 0.38 1.17 [2.00, 0.14] 0.027

[0082] The LS Mean figure is the mean change from the baseline adjusted score, a negative difference indicates a benefit.

[0083] Tables 3 and 4 demonstrate that the administration of THC:CBD (27 mg/ml:25 mg/ml) to patients suffering pain in rheumatoid arthritis results in an improved quality of sleep when compared to the placebo.

Comparison of Disease Activity Score in Patients with Rheumatoid Arthritis when Administered a Cannabis Based Medicine Extract Containing THC at a Concentration of 27 mg/ml and CBD at a Concentration of 25 mg/ml

[0084] The efficacy of a Cannabis based medicine extract was assessed as described above and the Disease Activity Score for each patient was determined at visits 1 and 4. The data was collated and statistical analysis was undertaken. Tables 5 and 6 illustrate the results.

TABLE-US-00006 TABLE 5 THC:CBD (27 mg/ml:25 mg/ml) Placebo (N = 31) (N = 27) Visit 1 Mean 5.88 6.00 Std Dev 0.95 1.03 Minimum 4.6 3.8 Median 5.70 6.00 Maximum 7.8 7.8 Visit 4 Mean 5.00 5.90 Std Dev 1.09 1.10 Minimum 3.0 4.0 Median 4.90 5.80 Maximum 7.1 8.2 Change from Mean 0.85 0.16 Visit 1 Std Dev 0.81 0.98 Minimum 2.7 3.0 Median 0.70 0.05 Maximum 0.5 1.3

[0085] Statistical analysis of this data is shown in Table 6.

TABLE-US-00007 TABLE 6 THC:CBD (27 mg/ml:25 mg/ml) Placebo LS LS Differ- p- Mean s.e. Mean s.e. ence 95% CI value 0.88 0.16 0.03 0.17 0.76 [1.23, 0.28] 0.002

[0086] The LS Mean figure is the mean change from the baseline adjusted score, a negative difference indicates a benefit.

[0087] Tables 5 and 6 demonstrate that the administration of THC:CBD (27 mg/ml:25 mg/ml) to patients suffering pain in rheumatoid arthritis results in an improved Disease Activity Score when compared to the placebo.

[0088] The use of a mixture of THC and CBD, where the cannabinoids are in approximately equal quantities when provided to patients with pain associated with rheumatoid arthritis resulted in a decrease in morning pain at rest. The quality of sleep that was experienced by the patients provided with the mixture of equal quantities of THC and CBD was also shown to improve. The patients who were provided with the medication also experienced a decrease in their pain at present as recorded from a questionnaire. Most significantly of all was the effect the medication had on the patients Disease Activity Score.

[0089] The Disease Activity Score is a method used to measure the degree of rheumatoid arthritis experienced by a patient. It involves determination of how swollen and tender 28 different joints are. A blood test is also used as part of the Disease Activity Score to measure the erythrocyte sedimentation rate. This rate is a lab method for determining an acute phase response to inflammation. A global disease activity score based on how the patient is feeling also contributes to an overall figure that is calculated. A composite score of greater than 3.7 is considered to be high.

[0090] The significance of the findings of the present invention that the use of an approximately 1:1 combination of THC and CBD are able to decrease the Disease Activity Score in patients with rheumatoid arthritis is great.

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