Pharmaceutical formulations

• US 20040192760A1
• Filed: 04/22/2004
• Published: 09/30/2004
• Est. Priority Date: 02/14/2001
• Status: Active Grant

• Current Assignee: GW Research Limited (Jazz Pharmaceuticals Plc)
• Original Assignee: GW Pharmaceuticals Limited (Jazz Pharmaceuticals Plc)
• Inventors: Guy, Geoffrey, Whittle, Brian
• Granted Patent: US 10,004,684 B2
• Time in Patent Office: Days
• US Class Current: 514/454
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• 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 47/14 Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• CPC Class Codes: A61K 9/0031 Rectum, anus
• CPC Class Codes: A61K 9/0056 Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
• CPC Class Codes: A61K 9/006 Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
• CPC Class Codes: A61K 9/0073 Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy; nasal sprays A61K9/0043; inhalation of vapours of volatile or heated drugs, e.g. essential oils or nicotine, A61K9/007; devices A61M
• CPC Class Codes: A61K 9/107 Emulsions ; Emulsion preconcentrates; Micelles composition of emulsions A61K47/00
• CPC Class Codes: A61K 9/1075 Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers A61K9/0026 takes precedence
• CPC Class Codes: A61K 9/122 Foams; Dry foams edible foams A61K9/0056
• CPC Class Codes: A61K 9/2018 Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• CPC Class Codes: A61K 9/2063 Proteins, e.g. gelatin
• CPC Class Codes: A61K 9/209 containing drug in at least two layers or in the core and in at least one outer layer
• CPC Class Codes: A61K 9/4858 Organic compounds
• CPC Class Codes: A61K 9/7007 Drug-containing films, membranes or sheets A61K9/0041, A61K9/0043, A61K9/006, A61K9/0063 take precedence
• CPC Class Codes: B01D 11/0288 Applications, solvents

Abstract

The invention relates to pharmaceutical formulations for use in the administration of lipophilic medicaments via mucosal surfaces. In particular the invention provides pharmaceutical formulations for use in administration of a lipophilic medicament via a mucosal surface which upon hydration form an emulsion containing the lipophilic medicament which is capable of adhering to a mucosal surface and allowing controlled release of the medicament The invention further provides pharmaceutical formulations which contain, as active ingredients, specific combinations of cannabinoids in pre-defined ratios.

Claims

1. A cannabis-based pharmaceutical formulation 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.

2. A pharmaceutical formulation according to claim 1 which comprises both the cannabinoids cannabidiol (CBD) and tetrahydrocannabinol (THC) in approximately equal amounts by weight.

3. A pharmaceutical formulation according to claim 1 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.

4. A pharmaceutical formulation according to claim 1 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.

5. A pharmaceutical formulation according to claim 1 wherein the formulation is in a liquid dosage form producing particles having a mean aerodynamic particle size between 15 and 45 microns.

6. A pharmaceutical formulation according to claim 5 wherein the particle size is between 20 and 40 microns.

7. A pharmaceutical formulation according to claim 5 wherein the average particle size is about 33 microns.

8. A formulation according to claim 4 wherein the ratio by weight of CBD to THC is in the range from about 5:

1 to about 3;

1.

9. A formulation according to claim 1 which is substantially free of cannabinoids other than CBD and THC.

10. A formulation according to claim 1 which is substantially free of other cannabinoids found in Cannabis sp.

11. A formulation according to claim 1 wherein said CBD and THC are in substantially pure form.

12. A formulation according to claim 1 which further comprises one or more other cannabinoids.

13. A formulation according to claim 12 wherein the one or more other cannabinoids are tetrahydrocannabinovarin (THCV) and/or cannabidivarin (CBDV).

14. A formulation according to claim 1 wherein the CBD and THC are derived from at least one extract from at least one Cannabis plant, said at least one extract comprising all the naturally occurring cannabinoids in said plant.

15. A formulation according to claim 14 wherein the Cannabis plant is selected from Cannabis sativa, Cannabis indica, a genetic cross between them, a self-cross or a hybrid thereof.

16. A formulation according to claim 15 wherein the Cannabis plant is Cannabis sativa, subspecies indica and is selected from vary indica and var. kafiristanica.

17. A formulation as claimed in claim 14 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.

18. A formulation according to claim 12 wherein said extract is prepared by supercritical or sub-critical fluid extraction of dried Cannabis plant.

27. A formulation according to claim 1 which allows delivery of at least 1.0 mg of cannabinoids per 0.1 ml of liquid formulation.

28. A formulation according to claim 14 which is a botanical drug product prepared from a botanical drug substance.

29. A formulation according to claim 14 wherein each extract is derived from a specific chemovar.

30. A formulation according to claim 28 wherein the botanical drug substance has an HPLC profile with THC, CBD and CBN having retention times of 9.6-10.6 minutes, 5.4-5.9 minutes and 7.9-8.7 minutes respectively.

31. A formulation according to claim 30 wherein the extract comprises a CBD herbal drug extract having a chromatographic profile as shown in FIG. 5.

32. A formulation according to claim 30 wherein the extract comprises a THC herbal drug extract having a chromatographic profile as shown in FIG. 6.

40. A pharmaceutical formulation according to claim 1 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.

41. A formulation according to claim 40 which further comprises CBD and/or THC.

42. A formulation according to claim 40 or 41 wherein the ratio by weight of CBDV to THCV is greater than 1.5:

1.

43. A formulation according to any one of claims 40 to 42 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

44. A formulation according to any one of claims 40 to 43 wherein the ratio by weight of CBDV to THCV is about 9:

1.

45. A formulation according to any one of claims 40 to 43 wherein the ratio of CBDV to THCV by weight is from about 5:

1 to 3;

1.

46. A formulation according to claim 40 or any one of claims 42 to 45 which is substantially free from other cannabinoids found in Cannabis sp.

47. A formulation according to any one of claims 40 to 46 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.

48. A formulation according to claim 47 wherein the Cannabis plant is selected from Cannabis sativa, Cannabis indica or a genetic cross between them, a self-cross or a hybrid thereof.

49. A formulation according to claim 40 which allows delivery of at least 1.0 mg of cannabinoids per 0.1 ml of liquid formulation.

50. A formulation according to claim 47 which is a botanical drug product prepared from a botanical drug substance.

51. A formulation according to claim 47 wherein each extract is derived from a specific chemovar.

64. A pharmaceutical formulation according to any one of claims 1 to 18, 39 to 48, 52 to 56 or 63 for use in the treatment of inflammatory disease or any disease or condition during the course of which oxidative stress plays a part.

65. A pharmaceutical formulation according to claim 8 or 45 for use in the treatment of rheumatoid arthritis, or inflammatory bowel disease or Crohn'"'"'s disease.

66. A pharmaceutical formulation according to claim 44 for use in the treatment of psychotic disorders, epilepsy, movement disorders, stroke, head injury, or diseases which require appetite suppression.

70. A pump-action spray comprising a pharmaceutical formulation according to any one of claims 1 to 18, 39 to 48, 52 to 57, 63, or 74 to 118.

71. A pump-action spray according to claim 70 wherein the formulation is delivered through a nozzle such that the mean aerodynamic diameter of the particles produced is between 15 and 45 microns.

72. A pump action spray according to claim 70 or 71 which allows delivery of at least 1.0 mg of cannabinoids per 0.1 ml of liquid formulation.

73. A formulation according to claim 1 which is not in the form of a propellant-driven aerosol or a propellant-driven liquid spray.

74. A pharmaceutical formulation according to claim 1, which further comprises at least one self emulsifying agent, wherein upon hydration the formulation forms an emulsion containing the lipophilic medicament which is capable of adhering to a mucosal surface and allowing controlled release of the medicament.

75. A formulation according to claim 74 which is not in the form of a propellant-driven aerosol or a propellant-driven liquid spray.

76. A formulation according to claim 74 or claim 75 which further comprises one or more viscolising agents.

77. A formulation according to claim 76 wherein the viscolising agent(s) is/are not block copolymers of oxyethylene and oxypropylene.

78. A formulation according to claim 76 wherein the viscolising agent(s) is/are not nonionic surfactants.

79. A formulation according to claim 78 which comprises at least one viscolising agent that when hydrated forms a gel having positive surface electrical charge and at least one viscolising agent that when hydrated forms a gel having negative surface electrical charge.

80. A formulation according to claim 79 which comprises at least one viscolising agent that when hydrated forms a gel having positive surface electrical charge which is gelatin or glycogelatin and at least one viscolising agent that when hydrated forms a gel having negative surface electrical charge which is starch, pre-gelatinised starch, acacia or polydextrose.

81. A formulation according to any one of claims 76 to 80 wherein at least one of the viscolising agents is solubilised by the action of an enzyme present in saliva.

82. A formulation according to any one of the preceding claims which is a solid dosage form, preferably a gel, compressed tablet or capsule.

83. A formulation according to claim 82 which is in the form of a gel for administration of a lipophilic medicament via the sublingual and/or buccal mucosae, wherein on contact with saliva the gel or gel-spray forms an emulsion containing the lipophilic medicament that adheres to the sublingual and/or buccal mucosae.

84. A formulation according to claim 82 which is in the form of a compressed tablet for administration of a lipophilic medicament via the sublingual and/or buccal mucosae, wherein on contact with saliva the tablet disintegrates completely and forms an emulsion containing the lipophilic medicament that adheres reversibly to the sublingual and/or buccal mucosae.

85. A formulation according to any one of claims 82 to 84 wherein the total amount of viscolising agent(s) included in the formulation is greater than 60% w/w of the formulation.

86. A formulation according to any one of claims 82 to 84 wherein the self-emulsifying agent(s) is/are present in an amount at least 5% w/w, preferably at least 10% w/w of the formulation.

87. A formulation according to claim 74 or claim 75 which further contains at least one solvent.

88. A formulation according to claim 74 or claim 75 which further contains at least one co-solvent.

89. A formulation according to claim 88 wherein the co-solvent is a solubilising agent.

90. A formulation according to claim 89 wherein the solubilising agent is a polyoxyethylene castor oil derivative.

91. A formulation according to claim 90 wherein the polyoxyethylene castor oil derivative is cremophor, preferably cremophor RH40.

92. A formulation according to any one of claims 87 to 90 which is a gel-spray.

93. A formulation according to claim 92 which is in the form of a gel-spray for administration of a lipophilic medicament via the sublingual and/or buccal mucosae, wherein on contact with saliva the gel or gel-spray forms an emulsion containing the lipophilic medicament that adheres to the sublingual and/or buccal mucosae.

94. A formulation according to any one of claims 87 to 93 which further contains one or more viscolising agents, wherein the total amount of viscolising agent(s) included in the formulation is at least 1% w/w of the formulation.

95. A formulation according to any one of claims 87 to 94 wherein the self-emulsifying agent(s) is/are present in an amount at least 2% w/w, preferably at least 5% w/w of the formulation.

96. A formulation according to any one of claims 74 to 95 which includes at least one self-emulsifying agent selected from glyceryl mono-oleate, glyceryl monostearate and self-emulsifying grade glyceryl monostearate.

97. A formulation according to any one of claims 74 to 96 wherein the lipophilic medicament is at least one cannabis extract.

98. A formulation according to any one of claims 74 to 96 wherein the lipophilic medicament comprises one or more natural or synthetic cannabinoids.

99. A formulation according to claim 98 wherein the lipophilic medicament comprises tetrahydrocannabinol, Δ

⁹-tetrahydrocannabinol, Δ

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

100. A pharmaceutical formulation according to claim 74 for use in administration of a lipophilic medicament via a mucosal surface, wherein the lipophilic medicament is at least one extract from at least one cannabis plant.

101. A pharmaceutical formulation according to claim 74 for use in administration of a lipophilic medicament via a mucosal surface, wherein the lipophilic medicament comprises a combination of two or more natural or synthetic cannabinoids.

102. A formulation according to claim 101 wherein the lipophilic medicament comprises any combination of two or more cannabinoids selected from tetrahydrocannabinol, Δ

⁹-tetrahydrocannabinol, Δ

⁹-tetrahydrocannabinol propyl analogue, cannabidiol, cannabidiol propyl analogue, cannabinol, cannabichromene, cannabichromene propyl analogue and cannabigerol.

103. A pharmaceutical formulation according to claim 74 for use in administration of a lipophilic medicament via a mucosal surface, which further comprises at least one solvent, at least one co-solvent and at least one self emulsifying agent, wherein upon hydration the formulation forms an emulsion containing the lipophilic medicament which is capable of adhering to a mucosal surface and allowing controlled release of the medicament, characterised in that the total amount of solvent and co-solvent present in the formulation is greater than 55% w/w of the formulation.

104. A formulation according to claim 103 wherein the total amount of solvent plus co-solvent present in the formulation is greater than 65% w/w, preferably greater than 70% w/w, more preferably greater than 75% w/w, more preferably greater than 80% w/w, more preferably greater than 85% w/w of the formulation.

105. A formulation according to claim 104 which comprises between 80% w/w and 95% w/w of solvent plus co-solvent.

106. A formulation according to any one of claims 103 to 105 wherein the solvent is a lower alkyl (C₁-C₄) alcohol and the co-solvent is propylene glycol, glycerol, a macrogol or a polyoxy hydrogenated castor oil.

107. A formulation according to claim 106 wherein the solvent is ethanol and the co-solvent is propylene glycol.

108. A formulation according to claim 107 wherein the ratio of ethanol to propylene glycol present in the formulation is between 4:

1 and 1;

4.

109. A formulation according to claim 108 wherein the ratio of ethanol to propylene glycol present in the formulation is about 1:

1.

110. A formulation according to claim 106 wherein the solvent is ethanol and the co-solvent is a polyoxy hydrogenated castor oil, preferably cremophor RH40^IM.

111. A formulation according to claim 110 wherein the amount of polyoxy hydrogenated castor oil present in the formulation is between 5 and 55% w/w of the total amount of polyoxy hydrogenated castor oil plus ethanol present in the formulation.

112. A formulation according to claim 111 wherein the amount of polyoxy hydrogenated castor oil present in the formulation is between 20 and 40% w/w of the total amount of polyoxy hydrogenated castor oil plus ethanol present in the formulation.

113. A formulation according to claim 112 wherein the amount of polyoxy hydrogenated castor oil present in the formulation is approximately 30% w/w of the total amount of polyoxy hydrogenated castor oil plus ethanol present in the formulation.

114. A formulation according to any one of claims 103 to 113 wherein the self-emulsifying agent s) is/are present in an amount greater than 1% w/w of the formulation.

115. A formulation according to any one of claims 103 to 114 which comprises glyceryl mono-oleate as a self-emulsifying agent.

116. A formulation according to any one of claims 103 to 115 wherein the lipophilic medicament comprises at least one cannabis extract.

117. A formulation according to any one of claims 103 to 115 wherein the lipophilic medicament comprises one or more natural or synthetic cannabinoids.

118. A formulation according to claim 117 wherein the lipophilic medicament comprises tetrahydrocannabinol, Δ

⁹-tetrahydrocannabinol, Δ

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

19. A method of preparing a Cannabis-based pharmaceutical formulation which comprises CBD and THC in a pre-defined ratio by weight or CBDV and THCV in a pre-defined ratio by weight which method comprises the steps of:

a) providing at least one dried Cannabis plant for which the amount of CBD and THC or CBDV and THCV by weight is known;

b) preparing an extract of said at least one Cannabis plant

c) formulating a material from said extract or extracts prepared in step (b) which exhibits said pre-defined ratio of CBD to THC or CBDV to THCV; and

d) further formulating the product of step (c) into a pharmaceutical formulation with a pharmaceutically acceptable carrier or diluent.

20. A method according to claim 19 wherein the pharmaceutically acceptable carrier or diluent is a liquid and the formulation produces particles having a mean aerodynamic particle size between 15 and 45 microns.

21. A method according to claim 20 wherein the particle size is between 20 and 40 microns.

22. A method according to claim 20 wherein the avarage particle size is about 33 microns.

23. A method according to claim 19 wherein the extract of step (b) is prepared using at least one of the following procedures:

i) maceration

(ii) percolation

(iii) extraction with solvent such as C₁-C₅ alcohols, norflurane or HFA227

(iv) subcritical or supercritical fluid extraction.

24. A method according to claim 19 wherein prior to extraction said dried Cannabis is heated to a temperature of from about 60°

C. to about 225°

C., preferably about 100°

C. to about 150°

C., to decarboxylate the acid form of any cannabinoids present in the extract.

25. A method according to claim 19 which comprises extracting said at least one Cannabis plant with supercritical or subcritical CO₂.

26. A method according to claim 25 wherein after extraction with said supercritical or subcritical fluid said extract is subjected to “

winterisation”

to remove waxes from the extract.

33. The method according to any of claims 19 to 26 wherein the formulation comprises approximately equal amounts of CBD and THC by weight.

34. The method according to any of claims 19 to 26 wherein the amount by weight of THC in said formulation is greater than the amount by weight of CBD.

35. A pharmaceutical formulation according to any of claims 19 to 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.

36. A method according to any of claims 19 to 26 wherein said pre-defined ratio by weight of CBD to THC is in the range from about 5:

1 to 3;

1.

37. A method according to any one of claims 19 to 36 wherein said formulation is formulated for delivery nasally, sub-lingually, buccally, topically, orally, rectally, intravenously, intra-peritoneally, intra-muscularly, sub-cutaneously, transdermally, intra-vaginally, intra-urethrally, by nebulizer, as inhaled vapour or by installation directly into the bladder.

38. A method according to any one of claims 19 to 36 wherein said formulation is formulated to deliver CBD prior to delivery of THC and/or to provide a controlled release formulation.

39. A Cannabis-based pharmaceutical formulation which is obtainable by the method of any one of claims 19 to 38.

67. A pharmaceutical formulation obtainable by the method of claim 19 which comprises approximately equal amounts of CBD and THC or THCV and CBDV for the treatment of multiple sclerosis, spinal cord is injury, peripheral neuropathy or other neurogenic pain.

52. A pharmaceutical formulation 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.

53. A pharmaceutical formulation according to claim 52 wherein the ratio by weight of THCV to THC is between 99:

1 and 1.5;

1

54. A formulation according to claim 52 or 53 wherein the ratio by weight of THCV to THC is approximately 17:

3.

55. A formulation according to any of claims 52 to 54 which also comprises CBD and/or CBDV at an amount by weight which is less than the amount by weight of THCV.

56. A formulation according to any of claims 52 to 55 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.

57. A formulation according to claim 56 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.

69. The pharmaceutical formulation of any of claims 52 to 56 for use in the treatment of cancer pain or migraine or for stimulation of the appetite.

58. A method of preparing a Cannabis-based pharmaceutical formulation which comprises a pre-determined ratio by weight of THCV to THC which method comprises the steps of:

a) providing at least one dried Cannabis plant for which the amount of THCV and THC by weight is known,

b) preparing an extract of said at least one Cannabis plant;

c) formulating a material from said extract or extracts prepared in step (c) which exhibits said pre-defined ratio of THCV to THC; and

d) further formulating the product of step (c) into a pharmaceutical formulation with a pharmaceutically acceptable carrier or diluent.

59. A method according to claim 58 wherein the extract of step (b) is prepared using at least one of the following procedures:

i) maceration

(ii) percolation

(iii) extraction with solvent such as C₁-C₅ alcohols, norflurane or HFA227

(iv) subcritical or supercritical fluid extraction.

60. A method according to claim 58 wherein prior to extraction said dried Cannabis is heated to a temperature of from about 60°

C. to about 225°

C., preferably about 100°

C. to about 150°

C., to decarboxylate the acid form of any cannabinoids present in the extract.

61. A method according to claim 58 which comprises extracting said at least one Cannabis plant with supercritical or subcritical CO₂.

62. A method according to claim 58 wherein after extraction with said supercritical or subcritical fluid said extract is subjected to “

winterisation”

to remove waxes from the extract.

63. A Cannabis-based pharmaceutical formulation which is obtainable by the method of claim 58.

68. A pharmaceutical formulation 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.