Patent Abstract:
the present invention is directed to the novel use of complexes of cyclodextrin . in particular the invention is directed to a complex of a cyclodextrin selected from the group consisting of α - cd , β - cd and γ - cd and a cannabinoid selected from the classical cannabinoid - group consisting of canabinol , tetrahydrocanabinol and canabidiol .

Detailed Description:
the present invention describes the use of natural cds to improve the dissolution rate , absorption rate and bioavailability of classical cannabinoids when administered sublingually or buccally . sublingual and buccal drug administration routes are potential alternatives for cannabinoid therapy due to the circumvention of the first - pass metabolism resulting in increased bioavailability of the cannabinoids . the absorption of the cannabinoids across the oral mucosa may also increase the onset of action compared to absorption of cannabinoids from the gi - tract ( traditional oral formulations ). one of the major requirements of sublingual / buccal drug administration is a fast dissolution of the drug at the site of absorption ( sublingual area in the mouth ). this is due to the fact that only the dissolved drug is able to absorb into the systemic circulation and that in sublingual drug administration the patient may swallow ( due to increased salvation ) the dosage form before the release of the drug . the present innovation is based on the finding that insoluble cannabinoid / natural cyclodextrin complexes can be used to significantly increase the dissolution rate of cannabinoids which can be used in sublingual cannabinoid formulations . the increased dissolution rate of the cannabinoids is due to the better solubility / dissolution properties of the solid cannabinoid / natural cyclodextrin inclusion complexes compared to pure cannabinoid , whereas the dissolution rate of pure cannabinoids is too slow for sublingual drug formulations . the solid cannabinoid / natural cd complexes can be prepared by simply stirring cannabinoids and natural cds in an aqueous solution which leads to the precipitation of solid complexes ( i . e ., the cannabinoid molecules are inside of the cd cavity and form inclusion complexes ). the complexation of cannabinoids with natural cds produce low solubility complexes that leads to the precipitation of solid “ true ” cannabinoid / natural - cd complexes . the “ true ” cannabinoid / natural - cd complexes significantly improve the dissolution , solubility and bioavailability properties of cannabinoids , and thus improves the pharmaceutical usefulness of cds in cannabinoid formulations . as discussed above , the bioavailability of thc is 6 - 20 % after oral administration . thc is commercially available as a capsule containing 5 - 10 mg of thc ( marinol ). in sublingual and buccal formulations a smaller dose of cannabinoids can be administered due to by - pass of the first - pass metabolism . jarho et al . showed that with a 40 % solution of hp - β - cd , a 1 mg / ml solution of thc can be obtained . thus , it can be calculated that ( after freeze - drying ) 400 mg of hp - β - cd would be needed to complex 1 mg of thc . the same formulation can be prepared theoretically with 3 . 6 mg of natural β - cd ( assuming 1 : 1 stochiometry for the complex ) which increases the usefulness of cd technology in sublingual and buccal drug formulations . the novel inclusion complexes of the invention can be prepared in conventional manner , known to a person skilled in art . such complexes are typically made by dissolving a selected cannabinoid in a selected cd , and the product , which precipitates , is the cannabinoid / cd - complex . the amounts of cannabinoids and cd are selected to give desired complexation efficiency which also depends on the complexation constant between cannabinoid and cd . the complexation constant ( k ) between cannabinoids and cds are usually in a range of 1 m − 1 to 100 000 m − 1 . typically cannabinoid and cd are used in a weight ratio ( dry weight to dry weight ) ranging between 1 : 3 and 1 : 1000 . the formation of inclusion complex can be facilitated by using solvents , such as organic solvents , for example methanol or ethanol . the temperature can vary to some degree , but it is typically for convenience the ambient temperature . the cannabinoid / cd - solution can also be freeze - dried or spray - dried , to form a powder to be included in a pharmaceutical preparation . the cannabinoid cd inclusion complexes can also be prepared under heterogenous conditions ( suspension ) and in solid phase . these methods include methods such as kneading , grinding , and the so - called slurry method . in solution , methods such as co - precipitation and neutralization can be used to prepare the solid inclusion complexes . the pharmaceutical preparation can be any suitable pharmaceutical preparation for sublingual and buccal administration . the pharmaceutical preparation according to the invention contains the said complex in pharmaceutically acceptable amounts together with pharmaceutically acceptable carriers , adjuvants or vehicles known in the art . the pharmaceutical composition may be in a dosage form suitable for sublingual or buccal use , such as tablets , capsules , lozenges , pills , pastilles , chewing gum etc . suitable vehicles for making such administration forms are for example starch , lactose , sucrose , sorbitol , talc , stearates , and gums etc . all such formulations are made using per se known formulation techniques . the therapeutic dose to be given to a patient in need of treatment will vary depending i . a . on the body weight and age of the patient , the particular condition being treated as well as the manner of administration and are easily determined by a person skilled in the art . generally a concentration of 0 . 1 mg to 500 mg cannabinoid , typically 0 . 1 mg to 50 mg per unit dose , to be given for example 1 to 4 times a day , would be suitable for most purposes . the following examples illustrate the invention without limiting the same in any way . in this example the effect of natural β - cd on the dissolution characteristics of cbd have been described . a powder containing a cbd / β - cd inclusion complex was prepared by the precipitation method . in this method a methanol solution of cbd was added dropwise to an aqueous β - cd solution and after equilibration the white precipitate ( cbd / β - cd inclusion complex ) was isolated and dried . the hplc analysis of the powder showed that 9 . 1 mg of the powder contained 1 . 0 mg of cbd . all the following dissolution experiments were made in 2 % rm - β - cd dissolution medias ( ph 6 . 6 ) to ensure the free solubility of cbd . fig1 shows the dissolution profile ( dissolved cbd as a function of time ) of cbd from a gelatine capsule containing 1 . 0 mg of pure cbd and 99 mg of lactose ( mean ± sd , n = 6 ). fig2 shows the same data with a capsule containing 9 . 1 mg of natural β - cd / cbd - complex ( equivalent to 1 mg of thc ) and 90 . 9 mg of lactose ( mean ± sd , n = 4 ). fig1 and 2 show that the complexation of cbd with natural β - cd significantly increases the dissolution rate of cbd . with a β - cd / cbd formulation , cbd is fully dissolved in 30 minutes . without β - cd , the dissolution rate is much slower and cbd is not fully dissolved in 3 hours . in this example the effect of natural γ - cd on the dissolution characteristics of cbd have been described . a powder containing a cbd / γ - cd inclusion complex was prepared by the precipitation method . in this method a methanol solution of cbd was added dropwise to an aqueous γ - cd solution and after equilibration the white precipitate ( cbd / γ - cd inclusion complex ) was isolated and dried . the hplc analysis of the powders showed that 7 . 7 mg of the powder above contained 1 . 0 mg of cbd . all the following dissolution experiments were made in 2 % rm - β - cd dissolution medias ( ph 6 . 6 ) to ensure the free solubility of cbd . fig1 shows the dissolution profile ( dissolved cbd as a function of time ) of cbd from a gelatine capsule containing 1 . 0 mg of pure cbd and 99 mg of lactose ( mean ± sd , n = 6 ). fig3 shows the same data with a capsule containing 7 . 7 mg of a natural γ - cd / cbd - complex ( equivalent to 1 mg of thc ) and 92 . 3 mg of lactose ( mean ± sd , n = 4 ). fig1 and 3 show that the complexation of cbd with natural γ - cd significantly increases the dissolution rate of cbd . with a γ - cd / cbd formulation , cbd is fully dissolved in 30 minutes . without γ - cd , the dissolution rate is much slower and cbd is not fully dissolved in 3 hours . fröomming k - h , szejtli j : cyclodextrins in pharmacy . kluwer academic publishers , dortrecht , 1994 . higuchi t , connors k a : phase - solubility techniques . adv . anal . chem . instr . 4 : 117 - 212 , 1965 . porcella a , maxia c , gessa g l , pani l : the synthetic cannabinoid win55212 - 2 decreases the intraocular pressure in human glaucoma resistant to conventional therapies . eur . j . neurosci . 13 : 409 - 412 , 2001 . pertwee , r g : pharmacology of cannabinoid cb1 and cb2 receptors . pharmacol . ther . 74 : 129 - 180 , 1997 . shoyama y , morimoto s , nishioka i : cannabis xv : preparation and stability δ 9 - 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