Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
  • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
  • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
  • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D311/78—Ring systems having three or more relevant rings
  • C07D311/80—Dibenzopyrans; Hydrogenated dibenzopyrans

Definitions

• the present invention relates to a composition
• a composition comprising (-)- ⁇ 9 -trans- tetrahydrocannabinol or related compounds.
• the compound (-)- ⁇ 9 -trans-tetrahydrocannabinol is the active ingredient in marijuana. It is used therapeutically as an inhalant or an oral drug for stimulation of appetite among AIDS and cancer chemotherapy patients.
• Tetrahydrocannabinols can be isolated from marijuana (a mixture of leaves and flowering heads of the plant Cannabis Sativa). Alternatively, THCs can be obtained by synthetic routes, e.g. as described in WO 02/096899.
• Dissolving the (-)- ⁇ 9 -trans-tetrahydrocannabinol in a solvent or carrier improves the stability, but it is still usual to store the solutions under refrigerated conditions, e.g. at 5 0 C, to prevent degradation.
• the present inventors have sought to improve the stability of solutions of (-)- ⁇ 9 -trans-tetrahydrocannabinol and ⁇ 8 -tetrahydrocannabinol.
• WO 2006/063109 discloses a gel capsule comprising a cannabinoid, such as (-)- ⁇ 9 -trans-tetrahydrocannabinol, dispersed in oil that they claim is stable for at least a year.
• a cannabinoid such as (-)- ⁇ 9 -trans-tetrahydrocannabinol
• This application lists a range of different types of compound that might be used as anti-oxidants in the gel capsules.
• the patent application exemplifies a range of suitable anti-oxidants including weak acids and weak bases.
• the stability of the compositions of WO 2006/063109 was assessed using the compendial (USP) HPLC method (see paragraph [0216]), i.e. the compositions were not assessed against pure substances but instead used branded products that would have been less than 100% pure. Accordingly, tne present invention provides a composition comprising:
• side chain alkyl derivatives of either compound we mean compounds with the structure of either of the compounds depicted in the Figure, in which R represents an alkyl side chain.
• R represents an alkyl side chain.
• R is 1,1 dimethylheptyl.
• the Figure shows the chemical structures for alkyl substituted (-)- ⁇ 8 -trans- tetrahydrocannabinol derivatives and (-)- ⁇ 9 -trans-tetrahydrocannabinol derivatives.
• the inventors have found that the addition of the acid improves the stability of the composition, i.e. there is less degradation of the tetrahydrocannabinol compound during prolonged storage of the composition.
• the composition includes a solvent.
• the solvent may be chosen from oils and Ci - C 4 alcohols. Suitable examples of oils include sesame oil, olive oil, canola oil and combinations thereof. Suitable examples of Ci - C 4 alcohols include methanol, ethanol, propanol, iso-propanol and butanol.
• the solvent is sesame oil.
• the sesame oil may be refined or unrefined, but is preferably refined (the US Food and Drug Administration standards require that refined sesame oil is used in pharmaceutical products).
• the composition may further comprise other solvents, but preferably comprises only sesame oil as the solvent.
• the solvent is ethanol.
• the composition comprises an oil and a Ci - C 4 alcohol.
• lne acid used in ttie composition may be an organic acid. W lien an organic acid is used, the organic acid is suitably chosen from citric acid, ascorbic acid, malic acid, oxalic acid, succinic acid and tartaric acid, and is preferably citric acid.
• the acid used in the composition may be a mineral acid.
• the mineral acid is suitably chosen from phosphoric acid, hydrochloric acid, nitric acid and sulphuric acid, and is preferably phosphoric acid.
• the composition comprises a combination of different acids, optionally a combination of at least one organic acid with at least one mineral acid.
• Weak acids have an especially positive stabilizing effect on (-)- ⁇ 9 -trans- tetrahydrocannabinol and its derivatives, forming a stabilized composition. If the amount or concentration of strong acid is too large, the ⁇ 9 -isomer degrades to the ⁇ 8 -isomer.
• the acid may be added to the other constituents either as a separate component, or the acid may be formed in a solution of the other constituents.
• An example of the latter is the use of dissolved CO 2 in ethanol, which also stabilizes the ⁇ 9 -isomer, probably due to formation of carbonic acid.
• the amount of acid is suitably from 0.01-2% as a weight percentage of the composition, preferably from 0.02-1% and most preferably from 0.05-0.5%.
• the amount of (-)- ⁇ 9 -trans-tetrahydrocannabinol in the composition is suitably from 0.1-15% as a weight percentage of the composition, preferably from 1 to 10%.
• the composition may further comprise antimicrobial agents such as methyl paraben or propyl paraben.
• the composition may further comprise preservatives such as alpha-tocopherol or butylated hydroxytoluene (BHT).
• BHT butylated hydroxytoluene
• the composition may further comprise antioxidants. The antimicrobial agents, preservatives and antioxidants may be used alone or in combination.
• trie composition ot trie invention consists essentially of a tetrahydrocannabinol compound, an oil or a Ci -C 4 alcohol, and 0.01-2wt% of an acid chosen from the group consisting of citric acid, ascorbic acid, malic acid, oxalic acid, succinic acid, tartaric acid, phosphoric acid, hydrochloric acid, nitric acid and sulphuric acid. Additional components (e.g. antimicrobial agents, preservatives, antioxidants) may comprise up to lwt% of the solution.
• the composition of the invention consists essentially of (-)- ⁇ 9 -trans-tetrahydrocannabinol, sesame oil and 0.05-0.5wt% citric acid or phosphoric acid, wherein additional components may comprise up to lwt% of the solution.
• compositions according to the invention may be prepared by adding the acid to a solution of a tetrahydrocannabinol compound in sesame oil or a C1-C4 alcohol and mixing.
• Solutions of (-)- ⁇ 9 -trans-tetrahydrocannabinol in sesame oil may be prepared by dissolving pure (-)- ⁇ 9 -trans-tetrahydrocannabinol in sesame oil, or by mixing sesame oil with a solution of (-)- ⁇ 9 -trans-tetrahydrocannabinol in ethanol, and then distilling off the ethanol.
• Sesame oil was degassed under vacuum distillation and blanketed with nitrogen.
• the sesame oil was refined sesame oil from Jeen International (Compositions 1-2, 7-17) or Dipasa (Compositions 3-6).
• a solution of (-)- ⁇ 9 -trans- tetrahydrocannabinol in ethanol was added to the sesame oil and the acid was also added. The solution was mixed and the ethanol was removed using a rotary evaporator.
• compositions contained 6.65wt% (-)- ⁇ 9 -trans-tetrahydrocannabinol based on the weight of the composition.
• additional components in each composition were as shown in Table 1 below:
• Citric acid was added to 2ml samples of a solution of (-)- ⁇ 9 -trans- tetrahydrocannabinol in ethanol (the concentration of the (-)- ⁇ 9 -trans- tetrahydrocannabinol was 66.6mg/ml). The solutions were mixed. The amount of citric acid in each solution is shown in Table 2 below:
• compositions 1-18 The stability of the sesame oil compositions (compositions 1-18) was assessed at three different conditions: 5 0 C or Normal Storage (Refrigerated) Conditions; 25°C/60% Relative Humidity or Accelerated Conditions; and 40°C/75% Relative Humidity or High Temperature/High Humidity Conditions.
• the degradation of the (-)- ⁇ 9 -trans-tetrahydrocannabinol was monitored using a High Performance Liquid Chromatography (HPLC) method with ultraviolet detection at 228nm. Each detected impurity peak was measured using percent peak area (% PA) with respect to the peak area counts for (-)- ⁇ 9 -trans-tetrahydrocannabinol for each chromatogram, i.e.
• the degradation of the composition was assessed against (-)- ⁇ 9 -trans-tetrahydrocannabinol not against a branded product containing (-)- ⁇ 9 -trans-tetrahydrocannabinol.
• Each impurity peak was identified with a relative retention time (RRT) relative to the (-)- ⁇ 9 -trans-tetrahydrocannabinol peak elution time from each chromatogram. Impurity peaks measuring above 0.05% PA were recorded.
• l able ⁇ snows trie results ot trie stability tests tor compositions 1-ib. me period of time after which the degradation of the composition was assessed is indicated beside each table.
• composition 13 Composition 13, 4 weeks composition 14, 4 weeKs
• compositions 1, 3, 5 and 7 did not contain any organic acid, and the tables show that considerable degradation occurred during the observation period. By contrast, the degradation observed for compositions 2, 4 and 6 (which all contained 0.1 wt% citric acid) was considerably less. Compositions 5 and 6 both contained antimicrobial agents and preservatives, yet composition 6 (containing 0.1 wt% citric acid) was more stable than composition 5.
• Compositions 8-18 contained a variety of acids.
• Compositions 8, 10, 11, 12, 13, 14, 15, 17 and 18 (containing 0.1 wt% ascorbic acid, 0.1 wt% citric acid, 0.1 wt% lactic acid, ⁇ . iwt% tumaric acid, U.iwt% malic acid, U. iwt% oxalic acid, U.iwt% succinic acid, 0.1 wt% tartaric acid and 0.1 wt% phosphoric acid respectively) all showed improved stability compared to composition 7 (containing no organic acid).
• compositions 9 and 16 (containing 0.1 wt% acetic acid and 0.1 wt% salicylic acid) did not show an appreciable improvement compared to composition 7 and it would seem that these acids are less effective at improving stability (although the inventors believe that these acid may provide an improvement if used at another concentration).
• compositions 19-23 The stability of the ethanol compositions (compositions 19-23) was assessed in substantially the same manner as for the sesame oil compositions except that they were only assessed at only one set of conditions (4O 0 C) and the compositions were analysed after 60 hours and 1 month.
• composition 19 the composition that did not contain citric acid (composition 19) showed the greatest degradation and there seems to be a slight correlation between increasing citric acid content and increased stability.

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• 2006
  • 2006-11-10 US US11/595,682 patent/US8039509B2/en active Active
• 2007
  • 2007-11-09 CN CNA2007800495962A patent/CN101578276A/zh active Pending
  • 2007-11-09 EP EP07822462.3A patent/EP2086954B1/en active Active
  • 2007-11-09 JP JP2009535748A patent/JP5453096B2/ja active Active
  • 2007-11-09 CA CA002669021A patent/CA2669021A1/en not_active Abandoned
  • 2007-11-09 MX MX2009005003A patent/MX2009005003A/es active IP Right Grant
  • 2007-11-09 AU AU2007316584A patent/AU2007316584B2/en not_active Ceased
  • 2007-11-09 WO PCT/EP2007/062174 patent/WO2008055992A1/en not_active Ceased
• 2009
  • 2009-05-07 IL IL198651A patent/IL198651A/en active IP Right Grant
• 2011
  • 2011-09-20 US US13/237,388 patent/US20120010279A1/en not_active Abandoned
• 2012
  • 2012-08-28 US US13/596,716 patent/US8476312B2/en active Active
• 2013
  • 2013-06-07 US US13/912,823 patent/US8906956B2/en active Active

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