(19) TZZ_¥__T (11) EP 1 361 864 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 9/08 (2006.01) A61K 9/107 (2006.01) 04.12.2013 Bulletin 2013/49 A61K 36/185 (2006.01) (21) Application number: 02712063.3 (86) International application number: PCT/GB2002/000620 (22) Date of filing: 14.02.2002 (87) International publication number: WO 2002/064109 (22.08.2002 Gazette 2002/34) (54) LIQUID SPRAY FORMULATIONS FOR BUCCAL DELIVERY OF CANNABINOIDS FLÜSSIGE SPRAY FORMULIERUNGEN ZUR BUCCALEN VERABREICHUNG VON CANNABINOIDEN PREPARATIONS DE SPRAY LIQUIDE POUR L’ADMINISTRATION BUCCALE DE CANNABINOIDES (84) Designated Contracting States: (74) Representative: Schiller, Dominic Christopher et AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU al MC NL PT SE TR Harrison Goddard Foote LLP Designated Extension States: 4th Floor, Merchant Exchange RO SI 17-19 Whitworth Street West Manchester M1 5WG (GB) (30) Priority: 14.02.2001 GB 0103638 30.03.2001 US 280044 P (56) References cited: 05.04.2001 US 827158 WO-A-00/25127 WO-A-01/66089 11.05.2001 GB 0111597 WO-A-95/25504 WO-A1-02/32420 07.09.2001 GB 0121715 WO-A1-02/069993 US-A- 3 560 625 12.09.2001 US 951022 • EITAN ALHANATY; ET AL.: "Osmotic fragility of (43) Date of publication of application: liposomes as affected by antihemolytic 19.11.2003 Bulletin 2003/47 compounds" BIOCHIMICA ET BIOPHYSICA ACTA, vol. 339, no. 1, 1974, pages 146-155, (60) Divisional application: XP008008726 10180611.5 / 2 286 793 • PATRICIA S. FETTERMAN ET AL.: 10180628.9 / 2 292 211 "CONSTITUENTS OF CANNABIS SATIVA L. I: 10180638.8 / 2 298 283 PROPYLHOMOLOGS OFCANNABINOIDS FROM 10180665.1 / 2 298 284 AN INDIAN VARIANT" JOURNAL OF PHARMACEUTICAL SCIENCES., vol. 61, no. 9, (73) Proprietor: GW Pharma Limited September 1972 (1972-09), pages 1476-1477, Salisbury, XP002217537 AMERICAN PHARMACEUTICAL Wiltshire SP4 0JQ (GB) ASSOCIATION. WASHINGTON., US ISSN: 0022-3549 (72) Inventors: • KARNIOL I. G. ET AL.: "Cannabidiol interferes • WHITTLE, BRIAN with the effects of delta-9-tetrahydrocannabinol Hornsea, in man", EUROPEAN JOURNAL OF Yorkshire HU18 1QS (GB) PHARMACOLOGY, vol. 28, 1974, pages 172-177, • GUY, GEOFFREY • ZUARDI A. W. ET AL.: "Action of cannabidiol on Dorchester, the anxiety and other effects produced by delta- Dorset DT2 7QP (GB) 9-THC in normal subjects", PSYCHOPHARMACOLOGY, vol. 76, 1982, pages 245-250, Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 1 361 864 B1 Printed by Jouve, 75001 PARIS (FR) (Cont. next page) EP 1 361 864 B1 • HOLLISTER L. E. AND GILLESPIE H.: • FRISCHKNECHT H.-R. ET AL.: "Behavioral "Interactions in man of delta-9- effects of hashish in mice", tetrahydrocannabinol. II. Cannabinol and PSYCHOPHARMACOLOGY, vol. 70, 1980, pages cannabidiol", CLINICAL PHARMACOLOGY AND 155-161, THERAPEUTICS, vol. 18, no. 1, 1975, pages 80-83, • WILLIAMSON E. M. AND EVANS F. J.: • HEALTH AND SAFETY EXECUTIVE: "Pilot study: "Cannbinoids in clinical practice", DRUGS, vol. the effects of cannabis based medicine on 60, no. 6, 2000, pages 1303-1314, cognitive performance", 2000, CONTRACT • GORTER R. W.: "Cancer cachexia and RESEARCH REPORT 300/2000 cannabinoids", RESEARCH IN COMPLEMENTARY MEDICINE, vol. 6, no. supp3, 1999, pages 21-22, 2 EP 1 361 864 B1 Description [0001] The invention relates to liquid spray formulations for use in the administration of medicaments, in particular lipophilic medicaments, via mucosal surfaces. 5 [0002] Medicaments taken by mouth and swallowed are absorbed first into the blood perfusing the gastrointestinal tract. The venous drainage from the GI tract is into the blood perfusing the liver. This means that medicaments absorbed from the lumen of gastrointestinal tract are immediately presented to the liver - the major detoxifying organ of the body. In addition to protecting the organism from ingested toxins, the liver also metabolises medicaments which are treated in the same way. Blood from the liver then returns to the left side of the heart via the hepatic portal vein and reaches 10 the rest of the systemic circulation. This first pass through the liver may result in the removal of a substantial proportion of an ingested medicament. The first pass effect is more pronounced for some drugs than others; in the case of can- nabinoids more than 90% of an ingested dose is removed during the first pass. [0003] Certain areas of the alimentary canal have a venous drainage which does not involve a first pass through the liver. These areas (the mucous membrane of the buccal cavity, under the tongue and the nasopharynx,, and also the 15 distal rectum) drain directly into the left side of the heart. The avoidance of the first pass effect is the rationale for the use of buccal, nasal and sublingual formations, and also suppositories. Each of these types of formulation has advantages and disadvantages, as follows: [0004] Suppositories are subject to hygiene and patient compliance restrictions. [0005] Formulations intended for administration to the nasal mucosae may cause pain or reflex sneezing, and in 20 extreme cases cause irritation and damage to the nasal mucosae. [0006] Sublingual formulations may stimulate the flow of saliva and it is difficult for patients to avoid swallowing when substantial amounts of saliva are produced. Buccal formulations may be subject to the same limitations. [0007] Both sublingual and buccal formulations depend on the efficient transfer of medicament from a hydrophilic vehicle to the mucous membrane of the sublingual or buccal mucosae. Transfer of medicament through the interstices 25 between or through epithelial cells is governed principally by the lipid solubility of the medicament. Where a drug is water insoluble this is a further barrier to absorption from the sublingual area. There are therefore physical and biological limitations on the therapeutic usefulness of lipophilic medicaments, such as for example cannabis and cannabinoids, given by mouth and swallowed. [0008] The present invention relates to liquid spray formulations which are particularly suitable for use for administration 30 of lipophilic medicaments via a mucosal surface such as, for example, the sublingual mucosa or the buccal mucosa. [0009] Prior art liquid cannabinoid formulations include: [0010] Pilot study: the effect of cannabis based medicine on cognitive performance, which teaches administration an sublingual drops; [0011] A phase one study of sublingual cannabis- based medicine extract, J. Pharm. Pharmacol based medicine extract, 35 J. Pharm. Pharmacol 2000, 52 (supplement) 294, which teacher administration via a standard dose sublingual aerosol; and WO 99/32107 which teacher nasal delivery of a cannabinoid in a biphasic delivery system. [0012] By direct experiment it has been shown that lipophilic medicaments can be effectively brought into intimate contact with the absorptive mucous membrane when they are formulated into a self-emulsifying formulation. [0013] In the context of the present invention the following terms will be understood to have the following meanings: 40 [0014] A "self-emulsifying agent" is an agent which will form an emulsion when presented with an alternate phase with a minimum energy requirement. In contrast, an emulsifying agent, as opposed to a self- emulsifying agent, is one requiring additional energy to form an emulsion. In the case of the spray formulations disclosed herein, self- emulsification occurs on contact with the alternative phase (saliva). [0015] A "primary" (self) emulsifier is one whose primary function is as a (self) emulsifier. 45 [0016] A secondary (self) emulsifier is one whose secondary function is as a (self) emulsifier. The secondary (self) emulsifier may have another function, e.g. as a solubiliser or viscosifying agent. [0017] Generally a self-emulsifying agent will be a soluble soap, a salt or a sulphated alcohol, especially a non- ionic surfactant or a quaternary compound. These are often known as self-emulsifying grades (SE grade), e.g. SE grade glyceryl mono oleate, and SE grade glyceryl monostearate. 50 [0018] The "Hydrophilic Lipophilic Balance" (HLB) system, the balance between the hydrophilic and lipophilic moieties of a surface-active molecule, is used as a basis for rational means of selecting and classifying emulsifying agents. In the HLB system each emulsifying agent is assigned a number between 1 and 20 (see Pharmaceutical Codex). Emulsifying agents with HLB values of between 3 and 6 are lipophilic and form water- in-oil emulsions, while values of 8 to 18 indicate predominantly hydrophilic characteristics and the formation of oil- in-water emulsions. The preferred emulsifying agents 55 for use in the present invention generally exhibit HLB values of between 8 and 18. [0019] Surprisingly, formulations according to the invention do not produce reflex salivation. pump-action liquid spray formulation which is not a propellant-driven aerosol formulation, comprising solutions or emulisfiable formulations con- taining at least 1.0 mg of cannabinoids per 0.1 ml of liquid spray formulation for buccal delivery, wherein the liquid spray 3 EP 1 361 864 B1 formulation comprises: • tetrahydrocannabinol (THC) and cannabidiol (CBD) in a pre- defined ratio by weight, • a solvent and, 5 • a co-solvent, wherein the solvent is ethanol and the co-solvent is either: (i) a co-solvent which acts as a solubility enhancer which is a polyoxyethylene castor oil derivative, or 10 (ii) a co-solvent which is propylene glycol or glycerol, and in which the liquid spray formulation is discharged through a break- up button and delivered through a nozzle such that the mean aerodynamic diameter of the particles produced is between 15 and 45 microns.