Pharmaceutical formulation

• US 20040034108A1
• Filed: 08/14/2002
• Published: 02/19/2004
• Est. Priority Date: 08/14/2002
• Status: Active Grant

• Current Assignee: GW Research Limited (Jazz Pharmaceuticals Plc)
• Original Assignee: GW Pharmaceuticals Limited (Jazz Pharmaceuticals Plc)
• Inventors: Whittle, Brian
• Granted Patent: US 6,946,150 B2
• Time in Patent Office: Days
• US Class Current: 514/772
• CPC Class Codes: A61K 31/05 Phenols cannabinoids A61K31/658
• CPC Class Codes: A61K 31/352 condensed with carbocyclic rings, e.g. methantheline cannabinoids A61K31/658
• CPC Class Codes: A61K 36/185 Magnoliopsida (dicotyledons)
• CPC Class Codes: A61K 9/006 Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: B65B 31/00 Packaging articles or materials under special atmospheric or gaseous conditions; Adding propellants to aerosol containers
• CPC Class Codes: B65D 65/38 Packaging materials of special type or form

Abstract

The invention relates to pharmaceutical formulations, and more particularly to formulations containing cannabinoids for administration via a pump action spray. In particular, the invention relates to pharmaceutical formulations, for use in administration of lipophilic medicaments via mucosal surfaces, comprising: at least one lipophilic medicament, a solvent and a co-solvent, wherein the total amount of solvent and co-solvent present in the formulation is greater than 55% wt/wt of the formulation and the formulation is absent of a self emulsifying agent and/or a fluorinated propellant.

Claims

1. A liquid pharmaceutical formulation, for use in administration of a lipophilic medicament via a mucosal surface, comprising:

at least one lipophilic medicament, a solvent and a co-solvent, wherein the total amount of solvent and co-solvent present in the formulation is greater than 55% wt/wt of the formulation and the formulation is absent of a self emulsifying agent and/or a fluorinated propellant.

2. A liquid pharmaceutical formulation as claimed in claim 1 with a water content of less than 5%.

3. A liquid pharmaceutical formulation as claimed in claim 1 or 2 wherein the solvent is selected from C1-C4 alcohols.

4. A liquid pharmaceutical formulation as claimed in claim 3 wherein the solvent is ethanol.

5. A liquid pharmaceutical formulation as claimed in any of the preceding claims wherein the co-solvent is selected from glycols, sugar alcohols, carbonate esters and chlorinated hydrocarbons.

6. A liquid pharmaceutical formulation as claimed in claim 5 wherein the glycols are selected from propylene glycol and glycerol, and the carbonate ester is propylene carbonate.

7. A liquid pharmaceutical formulation as claimed in claim 5 wherein the co-solvent is propylene glycol.

8. A liquid pharmaceutical formulation as claimed in claim 1 or 2 wherein the solvent is ethanol and the co-solvent is propylene glycol.

9. A liquid pharmaceutical formulation as claimed in claim 8 wherein ethanol/propylene glycol are present in relative proportions by weight in the range 60/40 to 40/60.

10. A liquid pharmaceutical formulation as claimed in claim 8 wherein ethanol/propylene glycol are present in relative proportions by weight in the range 55/45 to 45/55.

11. A liquid pharmaceutical formulation as claimed in claim 8 wherein ethanol/propylene glycol are present in the relative proportions by weight of about 50/50.

12. A liquid pharmaceutical formulation as claimed in any of the preceding claims further comprising a flavouring.

13. A liquid pharmaceutical formulation as claimed in claim 12 wherein the flavouring is peppermint oil.

14. A liquid pharmaceutical formulation as claimed in claim 12 or claim 13 wherein the flavouring is present in an amount up to 0.1% v/v, preferably 0.05% v/v.

15. A liquid pharmaceutical formulation as claimed in any of the preceding claims wherein the lipophilic medicament comprises one or more cannabinoids.

16. A liquid pharmaceutical formulation as claimed in claim 15 wherein the lipophilic medicament is at least one extract from at least one cannabis plant.

17. A liquid pharmaceutical formulation as claimed in claim 16 wherein the extract from at least one cannabis plant is a botanical drug substance.

18. A liquid pharmaceutical formulation as claimed in claim 17 wherein the botanical drug substance has undergone an extraction step to remove a substantial proportion of waxes and other solvent insoluble materials present in plant material.

19. A liquid pharmaceutical formulation as claimed in claim 17 or 18 wherein the botanical drug substance is a CO₂ extract of one or more cannibis plants.

20. A liquid pharmaceutical formulation as claimed in any of one the preceding claims consisting essentially of one or more cannabinoids, ethanol and propylene glycol, and optionally a flavouring and/or an opiate.

22. A liquid pharmaceutical formulation as claimed in any one of claims 15 to 21 wherein the cannabinoids include THC and/or CBD.

23. A liquid pharmaceutical formulation as claimed in claim 22 wherein THC and CBD are present in a ratio (w/w) of from 0.9:

1.1 to 1.1;

0.9.

24. A liquid pharmaceutical formulation as claimed in claim 22 wherein THC and CBD are present in a ratio (w/w) of about 1:

1.

25. A liquid pharmaceutical formulation according to claim 24 which formulation includes 2.5 g/ml of each of THC and CBD.

26. A liquid pharmaceutical formulation as claimed in any one of claims 15 to 21 which comprises both the cannabinoids cannabidiol (CBD) and tetrahydrocannabinol (THC), or the cannabinoids tetrahydrocannabinovarin (THCV) and cannabidivarin (CBDV), in a pre-defined ratio by weight.

27. A liquid pharmaceutical formulation according to claim 26 which comprises both the cannabinoids cannabidiol (CBD) and tetrahydrocannabinol (THC), wherein the CBD is present in an amount by weight which is greater than the amount by weight of THC.

28. A liquid pharmaceutical formulation according to claim 27 wherein the ratio by weight of CBD to THC is greater than 2.5:

1.

29. A liquid pharmaceutical formulation according to claim 27 or claim 28 wherein the ratio by weight of CBD to THC is between 99:

1 and 2.5;

1, preferably between about 20;

1 and about 2.5;

1.

30. A liquid pharmaceutical formulation according to any one of claims 27 to 29 wherein the ratio by weight of CBD to THC is about 19:

1.

31. A liquid pharmaceutical formulation according to any one of claims 27 to 29 wherein the ratio by weight of CBD to THC is in the range from about 5:

1 to about 3;

1.

32. A liquid pharmaceutical formulation according to any one of claims 27 to 31 which is substantially free of cannabinoids other than CBD and THC.

33. A liquid pharmaceutical formulation according to claim 32 which is substantially free of other cannabinoids found in Cannabis sp.

34. A liquid pharmaceutical formulation according to any one of claims 27 to 33 wherein the CBD and THC are in substantially pure form.

35. A liquid pharmaceutical formulation according to any one of claims 27 to 31 which further comprises one or more other cannabinoids.

36. A liquid pharmaceutical formulation according to claim 35 wherein the one or more other cannabinoids are tetrahydrocannabinovarin (THCV) and/or cannabidivarin (CBDV).

37. A liquid pharmaceutical formulation according to any one of claims 27 to 31, 35 or 36 wherein the CBD and THC form part of least one extract from at least one Cannabis plant, said at least one extract comprising all the naturally occurring cannabinoids in said plant.

38. A liquid pharmaceutical formulation according to claim 37 wherein the Cannabis plant is selected from Cannabis sativa, Cannabis indica, a genetic cross between them, a self-cross or a hybrid thereof.

39. A liquid pharmaceutical formulation according to claim 38 wherein the Cannabis plant is Cannabis sativa, subspecies indica and is selected from var. indica and var. kafiristanica.

40. A liquid pharmaceutical formulation as claimed in any one of claims 37 to 39 which comprises extracts from two or more different Cannabis varieties wherein in the final formulation the amount of CBD is greater than the amount of THC by weight.

41. A liquid pharmaceutical formulation according to any one of claims 37 to 39 wherein said extract is prepared by supercritical or sub-critical fluid extraction of dried Cannabis plant.

42. A liquid pharmaceutical formulation according to claim 26 which comprises both the cannabinoids cannabidiol (CBD) and tetrahydrocannabinol (THC), wherein the THC is present in an amount by weight which is greater than the amount by weight of CBD.

43. A liquid pharmaceutical formulation according to claim 42 wherein the pre-defined ratio by weight of CBD to THC is between 1:

99 and 1;

1.5.

44. A liquid pharmaceutical formulation according to claim 43 wherein said pre-defined ratio by weight of CBD to THC is about 1:

39.

45. A liquid pharmaceutical formulation according to claim 43 wherein said pre-defined ratio by weight of CBD to THC is about 1:

2.

46. A liquid pharmaceutical formulation according to claim 26 which comprises both the cannabinoids tetrahydrocannabinovarin (THCV) and cannabidivarin (CBDV) wherein the CBDV is present in an amount by weight which is greater than the amount by weight of THCV.

47. A liquid pharmaceutical formulation according to claim 46 which further comprises CBD and/or THC.

48. A liquid pharmaceutical formulation according to claim 46 or 47 wherein the ratio by weight of CBDV to THCV is greater than 1.5:

1.

49. A liquid pharmaceutical formulation according to any one of claims 46 to 48 wherein the ratio by weight of CBDV to THCV is in the range from about 99:

1 to about 1.5;

1, preferably from about 20;

1 to about 2.5;

1.

50. A liquid pharmaceutical formulation according to any one of claims 46 to 49 wherein the ratio by weight of CBDV to THCV is about 9:

1.

51. A liquid pharmaceutical formulation according to any one of claims 46 to 49 wherein the ratio of CBDV to THCV by weight is from about 5:

1 to 3;

1.

52. A liquid pharmaceutical formulation according to claim 46 or any one of claims 48 to 51 which is substantially free from other cannabinoids found in Cannabis sp.

53. A liquid pharmaceutical formulation according to any one of claims 46 to 52 wherein the CBDV and THCV form part of an extract from a Cannabis plant, said extract comprising all of the naturally occurring cannabinoids in said plant.

54. A liquid pharmaceutical formulation according to claim 53 wherein the Cannabis plant is selected from Cannabis sativa, Cannabis indica or a genetic cross between them, a self-cross or a hybrid thereof.

55. A liquid pharmaceutical formulation as claimed in any one of claims 15 to 21 which comprises both the cannabinoids THC and THCV wherein the THCV is present in an amount by weight which is approximately equal to or greater than the amount by weight of THC.

56. A liquid pharmaceutical formulation according to claim 55 wherein the ratio by weight of THCV to THC is between 99:

1 and 1.5;

1.

57. A liquid pharmaceutical formulation according to claim 55 or 56 wherein the ratio by weight of THCV to THC is approximately 17:

3.

58. A liquid pharmaceutical formulation according to any one of claims 55 to 57 which also comprises CBD and/or CBDV at an amount by weight which is less than the amount by weight of THCV.

59. A liquid pharmaceutical formulation according to any one of claims 55 to 58 wherein the THCV and THC form part of an extract from a Cannabis plant, said extract comprising all the naturally occurring cannabinoids in said plant.

60. A liquid pharmaceutical formulation according to claim 59 wherein said Cannabis plant is selected from Cannabis sativa, Cannabis indica or the result of a genetic cross between them, a self-cross or a hybrid thereof.

61. A liquid pharmaceutical formulation according to any one of claims 26 to 42, 46 to 59 for use in the treatment of inflammatory disease or any disease or condition during the course of which oxidative stress plays a part.

62. A liquid pharmaceutical formulation according to claim 32 or 51 for use in the treatment of rheumatoid arthritis, or inflammatory bowel disease or Crohn'"'"'s disease.

63. A liquid pharmaceutical formulation according to claim 31 or 50 for use in the treatment of psychotic disorders, epilepsy, movement disorders, stroke, head injury, or diseases which require appetite suppression.

64. A liquid pharmaceutical formulation according to any one of claims 15 to 21 which comprises approximately equal amounts of CBD and THC or THCV and CBDV for the treatment of multiple sclerosis, spinal cord injury, peripheral neuropathy or other neurogenic pain.

65. A liquid pharmaceutical formulation according to any one of claims 15 to 21 which comprises a ratio by weight of THC to CBD or THCV to CBDV of from about 39:

1 to about 99;

1 for use in the treatment of cancer pain or migraine or for stimulation of appetite.

66. A liquid pharmaceutical formulation for use according to claim 65 wherein the ratio by weight of THC to CBD or THCV to CBDV is approximately 39:

1.

67. A liquid pharmaceutical formulation for use according to claim 65 or 66 wherein in the formulation the THC and CBD and/or THCV and CBDV form part of an extract from a Cannabis plant, said extract comprising all the naturally occurring cannabinoids in said plant.

71. A liquid pharmaceutical formulation as claimed in any of claims 1 to 14 wherein the lipophilic medicament is selected from:

morphine, pethidine, codeine, methadone, diamorphine, fentanyl, alfentanil, temazepam, buprenorphine, lipophilic analgesics and drugs of abuse.

72. A liquid pharmaceutical formulation as claimed in any of the preceding claims which is packaged for delivery as a spray having a mean aerodynamic particle size, when delivered, of from 20-40 microns, more preferably 25-35 and most preferably 30-35 microns.

73. A liquid pharmaceutical formulations as claimed in claim 72 which is packaged for delivery as a pump-action spray.

74. A liquid pharmaceutical formulation as claimed in claim 73 wherein the formulation is dispensed through a mechanical pump.

75. A liquid pharmaceutical formulation as claimed in claim 74 wherein the mechanical pump comprises a VP7 actuator valve.

76. A liquid pharmaceutical formulation as claimed in any of the preceding claim wherein the formulation is packaged in a container coloured to omit UV light and light from the blue region of the spectrum, preferably at wavelengths in the range of 200-500 nm.

77. A liquid pharmaceutical formulation as claimed in claim 76 wherein the container is coloured amber.

78. A liquid pharmaceutical formulation as claimed in any of the preceding claims wherein the lipophilic medicament is packaged in an inert atmosphere.

79. A liquid pharmaceutical formulation as claimed in claim 78 wherein the lipophilic medicament is packaged under nitrogen.

21. A liquid pharmaceutical formulation wherein the lipophilic medicament comprises tetrahydrocannabinol, Δ

9-tetrahydrocannabinol, Δ

⁸-tetrahydrocannabinol, Δ

⁹-tetrahydrocannabinol propyl analogue, cannabidiol, cannabidiol propyl analogue, cannabinol, cannabichromene, cannabichromene propyl analogue, cannabigerol or any mixture thereof.

68. A liquid pharmaceutical formulation comprising in a 1 ml vol:

THC 25 mg/ml (based on amount of cannabinoid in a botanical drug substance), CBD 25 mg/ml (based on amount of cannabinoid in a botanical drug substance), propylene glycol 0.5 ml/ml, peppermint oil 0.0005 ml/ml, and ethanol (anhydrous) qs to 1 ml.

69. A liquid pharmaceutical formulation comprising in a 1 ml vol:

THC 25 mg/ml (based on amount of cannabinoid in a botanical drug substance), propylene glycol 0.5 ml/ml, peppermint oil 0.0005 ml/ml, and ethanol (anhydrous) qs to 1 ml.

70. A liquid pharmaceutical formulation comprising in a 1 ml vol:

CBD 25 mg/ml (based on amount of cannabinoid in a botanical drug substance), propylene glycol 0.5 ml/ml, peppermint oil 0.0005 ml/ml, and ethanol (anhydrous) qs to 1 ml.