Patent Application: US-50512204-A

Abstract:
the present invention is directed to novel complexes of cyclodextrin . in particular the invention is directed to a complex of a cyclodextrin selected from the group consisting of rm - β - cyclodextrin , dm - β - cyclodextrin and tm - β - cyclodextrin , and a cannabinoid selected from the classical cannabinoid - group consisting of cannabinol , tetrhydrocannabinol and cannabidiol .

Description:
the present invention describes the use of methylated cds to improve the aqueous solubility , dissolution rate , absorption rate and bioavailability of classical cannabinoids . the present invention is based on the finding that methylated β - cds increase the aqueous solubility of cannabinoids significantly more compared to other cds . thus , high concentrations of cannabinoids in aqueous solution can achieved by the said methylated cds . by freeze - drying a solution containing the said methylated β - cd and cannabinoid , the cannabinoids can be transformed to a homogenous powder with good dissolution properties . in this powder the cannabinoids are complexed by the cd - molecules ( i . e ., the cannabinoid molecules are inside of the cd cavity , forming inclusion complexes ) the dissolution rate of the cannabinoids increasing due to the excellent solubility / dissolution properties of the cd . this novel finding can be utilized in a novel type of cannabinoid formulations . cannabinoids are highly lipophilic compounds with poor dissolution properties . in oral drug delivery the major problem of cannabinoids is a high first - pass metabolism and poor dissolution properties . thus , sublingual and buccal dosage forms are potential alternatives for cannabinoid therapy due to circumvention of the first - pass metabolism in this manner of administration . the major problem in sublingual and buccal dosage forms is the low aqueous dissolution rate of cannabinoids . in the present innovation the poor dissolution properties have been overcome by means of complex formation with methylated β - cds that significantly increases the dissolution rate of cannabinoids and allows the use of sublingual and buccal dosage forms of cannabinoids . the cannabinoid / methylated β - cd complexes can also be utilized in other oral formulations , such as in tablets or capsules , in order to improve the dissolution rate and bioavailability of cannabinoids . in addition , the improved dissolution properties of cannabinoids in cd containing formulations can also be utilized in other drug administration routes of cannabinoids , such as in pulmonary and nasal administration . compared to earlier findings , methylated β - cd improves the aqueous solubility of cannabinoids more efficiently , imparting promising dissolution properties for cannabinoids . jarho et . al . ( 1998 ) showed that the aqueous solubility of thc can be increased with hp - β - cd . however , the complexation of cannabinoids with methylated β - cd is more efficient compared to hp - β - cd . this improves the pharmaceutical usefulness of cds significantly . 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 ). 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 2 g of hp - β - cd is needed to establish a dosage form containing 5 mg of complexed thc . this is an amount that is too much for tablet formulations . according to the invention it has now been shown that the same amount of thc can be complexed with 200 mg of rm - β - cd . in sublingual and buccal formulations a smaller dose of cannabinoids can be administered due to by - pass of the first pass metabolism . however , also in these applications methylated β - cds offer superior characteristics compared to , for example , hp - β - cd . as indicated above , for example , 400 mg of hp - β - cd would be needed to complex 1 mg of thc . the same formulation can be prepared with 25 . 7 mg of rm - β - cd which increases the usefulness of cd technology also 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 . the product is usually a mixture of cannabinoid / cd - complex , uncomplexed cannabinoid and uncomplexed cd . 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 1 : 1 , k 1 : 2 ) 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 : 4 and 1 : 1000 , such as 1 : 4 to 1 : 250 . when the methylated cds are used as a solution such a solution can contain 0 . 1 to 50 % by weight of cd . the formation of inclusion complex can be facilitated by using solvents , such as organic solvents , for example ethanol . the temperature can vary to some degree , but it is typically for convenience the ambient temperature . small amounts of water - soluble polymers , such as hydroxypropylmethylcellulose at elevated temperatures can also be used to improve the complexation of cannabinoid with cds . after mixing , typically for 1 - 3 days , the solution obtained is allowed to come to an equilibrium , and can thereafter , if desired , 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 oral , including sublingual and buccal , administration , or , for example , for nasal and / or pulmonary administration , but can also be a pharmaceutical preparation for e . g . parenteral , topical or rectal use . 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 manufacture of such pharmaceutical formulations is well known in the art . thus the pharmaceutical composition may be in a dosage form suitable for oral use , such as tablets , capsules , liquid dosage forms , such as suspensions , emulsions , syrups etc , or e . g . a powder for pulmonary use . all such formulations are made using per se known formulation techniques and carriers , adjuvants and / or additives . suitable vehicles for making oral administration forms such as tablets or capsules are for example starch , lactose , sucrose , sorbitol , talc , stearates , etc . the complex according to the invention may also be administered parenterally , for example using aqueous or oily suspensions , emulsions , or dispersions containing the active agent in combination with conventional pharmaceutically acceptable excipients . formulations for rectal use are e . g . suppositories containing the said complex in combination with carrier substances suitable for rectal use . also contemplated within the invention is the topical administration of the complex , for which administration form creams , ointments , jellies , solutions , suspensions or the like are useful which contain a pharmacologically active amount of the said complex together with a per se known pharmaceutically acceptable carrier or vehicle . 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 . 01 % to 5 % of active agent , cannabinoid , in a suitable carrier would be sufficient for topical use , whereas a dosage form for oral use of 0 . 1 mg to 5 g , typically 0 . 1 mg to 500 mg cannabinoid , 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 aqueous solubility studies of thc and cbd with rm - β - cd and hp - β - cd has been shown ( fig1 . shows the effect of rm - β - cd and (▴) hp - β - cd (▪) concentration on aqueous solubility of thc ; fig2 . shows the effect of rm - β - cd (▴) and hp - β - cd (▪) concentration on aqueous solubility of cbd ). solubility studies show that rm - β - cd increases the aqueous solubility of both cannabinoids significantly more compared to hp - β - cd . au the phase - solubility diagrams ( cannabinoid concentration as a function of cd concentration ) are ap - type ( higuchi and connors 1965 ) and calculated complexation constants for 1 : 1 and 1 : 2 inclusion complexes has been shown in table 1 . the powder containing thc / rm - β - cd inclusion complex was prepared by dissolving cbd in an aqueous rm - β - cd solution which was freeze - dried after equilibration ( 2 days ). the hplc analysis of powder above showed that 12 . 4 mg of the powder contained 1 . 0 mg of thc . all the experiments were performed in 2 % rm - β - cd dissolution medias ( ph 6 . 6 ) to ensure the free dissolution of thc . fig3 shows the dissolution profile ( dissolved thc as a function of time ) of thc from the gelatine capsule containing 1 . 0 mg of pure cbd and 99 mg of lactose ( mean ± sd , n = 4 ). fig4 shows the same data with capsule containing 25 . 7 mg of rm - β - cd / thc - complex ( equivalent to 1 mg of thc ) and 74 . 3 mg of lactose ( mean ± sd , n = 4 ). fig3 and 4 show that the complexation of thc with rm - β - cd increases significantly the dissolution rate of thc ( observe the different time scale in the figures ). with rm - β - cd / thc formulation cbdis fully dissolved in 5 minutes and the dissolution of thc is controlled by the dissolution rate of the capsule ( fig8 ). without rm - β - cd the dissolution rate is much slower and thc is fully dissolved after 1 hour . in order to study the effect of inclusion complex formation on dissolution of thc the dissolution studies were also performed with the gelatine capsule containing a physical mixture of thc ( 1 . 0 mg ), rm - β - cd ( 25 . 7 mg ) and lactose ( 74 . 3 mg ). the results ( fig5 , mean ± sd , n = 3 ) show that the physical mixture - formulation did not have an effect on the dissolution rate of thc . thus , the inclusion complex formation between thc and rm - β - cd is crucial for fast dissolution of thc . the dissolution studies were also carried out with the tablet prepared from freeze - dried rm - β - cd / thc - complex . tablets contained 25 . 7 mg of rm - β - cd / thc - complex ( equivalent to 1 . 0 mg of thc ) power and 74 . 3 mg of lactose . the results ( fig6 , mean ± sd , n = 6 )) show that thc is fully dissolved in 15 minutes , which is significantly faster compared to the gelatine capsule containing pure thc ( fig3 ). in conclusion , the present results show that the complexation of thc with rm - β - cd increases significantly the dissolution rate of thc . in this example the effect of rm - β - cd on dissolution characteristics of cbd have been shown also with four different cbd formulations . the powder containing cbd / rm - β - cd inclusion complex was prepared by dissolving cbd in the aqueous rm - β - cd solution which was freeze - dried after equilibration ( 2 days ). the hplc analysis of the powder above showed that 12 . 4 mg of the powder contained 1 . 0 mg of cbd . all the experiments were performed in 2 % rm - β - cd dissolution medias ( ph 6 . 6 ) to ensure the free dissolution of cbd . fig7 shows the dissolution profile ( dissolved cbd as a function of time ) cbd from the gelatine capsule containing 1 . 0 mg of pure cbd and 99 mg of lactose ( mean ± sd , n = 6 ). fig8 shows the same data with capsule containing 12 . 4 mg of rm - β - cd / cbd - complex ( equivalent to 1 mg of cbd ) and 86 . 6 mg of lactose ( mean ± sd , n = 6 ). fig7 and 8 show that the complexation of cbd with rm - β - cd increases significantly the dissolution rate of cbd ( observe the different time scale in the figures ). with rm - β - cd / cbd formulation cbd is fully dissolved in 5 minutes and the dissolution of cbd is controlled by the dissolution rate of the capsule ( fig8 ). without rm - β - cd the dissolution rate is much slower and cbd is fully dissolved after 3 hours . in order to study the effect of the inclusion complex formation on the fast dissolution of cbd the dissolution studies were also performed with the gelatine capsule containing physical mixture of cbd ( 1 . 0 mg ), rm - β - cd ( 12 . 4 mg ) and lactose ( 86 . 6 mg ). the results ( fig9 ; mean ± sd , n = 6 ) show that physical mixture - formulation did not have an effect on dissolution rate of cbd . thus , the inclusion complex formation between cbd and rm - β - cd is crucial for the fast dissolution of cbd . the dissolution studies were also carried out with the tablet prepared from freeze - dried rm - β - cd / cbd - complex . the tablets contained 12 . 4 mg of rm - β - cd / cbd - complex ( equivalent to 1 . 0 mg of pure cbd ) powder and 86 . 6 mg of lactose . the results ( fig1 , mean ± sd , n = 6 ) show that cbd is fully dissolved in 15 minutes , which is significantly faster compared to the gelatine capsule containing pure cbd ( fig7 ). in conclusion the present results show that the complexation of cbd with rm - β - cd increases significantly the dissolution rate of cbd . frömming 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 : 409412 , 2001 . pertwee , r g : pharmacology of cannabinoid cb1 and cb2 receptors . pharmacol . ther . 74 : 129 - 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