Pharmaceutical formulations

• US 10,004,684 B2
• Filed: 02/14/2002
• Issued: 06/26/2018
• 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: Whittle, Brian, Guy, Geoffrey
• Primary Examiner(s): Ricci, Craig D
• Assistant Examiner(s): Stone, Christopher R
• Application Number:
  US10/468,041
• Publication Number:
  US 20040192760A1
• Time in Patent Office: 5,976 Days
• 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 liquid pharmaceutical formulation for oro-pharangeal delivery comprising cannabidiol (CBD) and tetrahydrocannabinol (THC), formulated as a pump-action spray in a pre-defined ratio by weight, a solvent and a co-solvent, wherein the CBD and THC are provided as carbon dioxide extracts obtained from two or more different Cannabis chemovars from which non-specific lipid-soluble material has been removed, and in which the Cannabis chemovars include a first chemovar in which THC is more than 95% of the total cannabinoid and a second chemovar in which CBD is more than 90% of the total cannabinoid, and wherein the CBD and THC are present in the formulation in an amount of at least 1.0 mg per 0.1 ml, and wherein the solvent is ethanol, and the co-solvent is a polyoxyethylene castor oil derivative, propylene glycol or glycerol.

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 pharmaceutical formulation according to claim 4 wherein the ratio by weight of CBD to THC is in the range from 5:

1 to 3;

1.

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

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

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

12. A pharmaceutical formulation according to claim 11 wherein the one or more other cannabinoids are tetrahydrocannabivarin (THCV) and/or cannabidivarin (CBDV).

13. A pharmaceutical formulation according to claim 1 wherein the CBD and THC are derived from the extracts from two or more Cannabis chemovars, said extracts from two or more Cannabis chemovars comprising all the naturally occurring cannabinoids in said Cannabis chemovars.

14. A pharmaceutical formulation according to claim 13 wherein the Cannabis chemovars are selected from Cannabis sativa, Cannabis indica, a genetic cross between them, a self-cross or a hybrid thereof.

15. A pharmaceutical formulation according to claim 14 wherein the Cannabis chemovars are Cannabis sativa, subspecies indica and is selected from var. indica and var. kafiristanica.

16. A pharmaceutical formulation as claimed in claim 13, wherein in the final formulation the amount of CBD is greater than the amount of THC by weight.

17. A pharmaceutical formulation according to claim 11 wherein said extract is prepared by supercritical or sub-critical fluid extraction of dried Cannabis plant.

26. A pharmaceutical formulation according to claim 13 which is a botanical drug product prepared from a botanical drug substance.

27. A pharmaceutical formulation according to claim 13 wherein each extract is derived from a specific chemovar.

28. A pharmaceutical formulation according to claim 26 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.

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

a) providing two or more different Cannabis plant chemovars for which the amount of CBD and THC by weight is known, and wherein THC is more than 95% of the total cannabinoid in the first chemovar and CBD is more than 90% of the total cannabinoid in the second chemovar;

b) preparing a carbon dioxide extract of said two or more Cannabis chemovars;

c) removing non-specific lipid-soluble material from the extract;

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

e) further formulating the product of step (d) into a liquid pharmaceutical formulation for oropharangeal delivery with a pharmaceutically acceptable carrier or diluent, a solvent and a co-solvent;

wherein the CBD and THC are present in the formulation in an amount of at least 1.0 mg per 0.1 ml;

wherein the solvent is ethanol, and the co-solvent is a polyoxyethylene castor oil derivative, propylene glycol or glycerol; and

wherein the liquid pharmaceutical formulation is formulated as a pump-action spray.

19. A method according to claim 18 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.

20. A method according to claim 19 wherein the particle size is between 20 and 40 microns.

21. A method according to claim 19 wherein the average particle size is about 33 microns.

22. A method according to claim 18 wherein the extract of step (b) is prepared using extraction with liquid carbon dioxide under pressure.

23. A method according to claim 18 wherein prior to extraction said dried Cannabis is heated to a temperature of from about 60°

C. to about 225°

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

24. A method according to claim 18 which comprises extracting said two or more Cannabis chemovars with supercritical or subcritical CO2.

25. A method according to claim 24 wherein after extraction with said supercritical or subcritical CO2 said extract is subjected to “

winterisation”

to remove waxes from the extract in step (c).

29. The method according to claim 18 wherein the formulation comprises approximately equal amounts of CBD and THC by weight.

30. The method according to claim 18 wherein the amount by weight of THC in said formulation is greater than the amount by weight of CBD.

31. A method according to claim 18 wherein the pharmaceutical formulation 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.

32. A method according to claim 18 wherein said pre-defined ratio by weight of CBD to THC is in the range from about 5:

1 to 3;

1.

33. A method according to claim 18 wherein said formulation is formulated for delivery sub-lingually, buccally, or orally.

34. A method according to claim 18 wherein said formulation is formulated to deliver CBD prior to delivery of THC and/or to provide a controlled release formulation.