Cannabinoids are a group of compounds which are ligands to cannabinoid receptors (CB1, CB2) found in the human body (Pertwee, 1997). Cannabinoids were originally found from Cannabis Sativa L., an origin of marijuana and hashish. Over the last few years, marijuana or its components have been reported in scientific literature to counter the symptoms of a broad range of conditions including multiple sclerosis and other forms of muscular spasm, including uterine and bowel cramps; movement disorders; pain, including migraine headache; glaucoma, asthma, inflammation, insomnia, and high blood pressure. There may also be utility for cannabinoids as an oxytoxic, anxiolytic, anti-convulsive, anti-depressant and anti-psychotic agent (Williamson and Evans, 2000), anti-cancer agent, as well as an appetite stimulant.
Nowadays over 60 chemically related compounds, collectively classified as cannabinoids, have been isolated from Cannabis Sativa L., including tetrahydrocannabinol (THC), cannabidiol (CBD) and cannabinol (CBN). In addition, various synthetic ligands for cannabinoid receptors have been developed during the last years. The cannabinoids are usually divided in the groups of classical cannabinoids, non-classical cannabinoids, aminoalkylindol-derivatives and eicosanoids (Pertwee, 1997). Classical cannabinoids are isolated from Cannabis Sativa L. or they can comprise synthetic analogs of these compounds. Non-classical cannabinoids are bi-or tricyclic analogs of tetrahydrocannabinol (THC) (without the pyran ring); aminoalkylindols form a group which differs structurally substantially from classical and non-classical cannabinoids.
The pharmacological and toxicological studies of cannabinoids have been focused mainly on THC (commercially available by the name Dronabinol) which in 1985 was approved by FDA for the treatment of chemotherapy associated nausea and vomiting, and later for AIDS-associated wasting and anorexia. Dronabinol is a synthetic analog of THC which is marketed in USA as Marinol. In Marinol, THC is dissolved in sesame oil and it is administered orally as a capsule containing 5 or 10 mg of THC. The major problem of THC in oral administration is its low bioavailability due to its poor dissolution properties and high first pass metabolism. The bioavailability of orally ingested THC ranges from only 6% to approximately 20% depending on the drug vehicle employed.
Cyclodextrins (CDs) are cyclic oligosaccharides consisting of (α-1,4)-inked α-D-glucopyranose units, with a lipophilic central cavity and a hydrophilic outer surface (Frömming and Szejtli, 1994). CDs are able to form inclusion complexes with many drugs by taking up the whole drug, or more commonly, the lipophilic moiety of the molecule, into the cavity. The most abundant natural CDs are α-cyclodextrin (α-CD), β-cyclodextrin (β-CD) and γ-cyclodextrin (γ-CD), containing six, seven, and eight glucopyranose units, respectively. Of these three CDs, β-CD appears to be the most useful pharmaceutical complexing agent because of its cavity size, availability, low cost and other properties. Since β-CD has limited aqueous solubility, numerous water-soluble β-CD derivatives have been synthesized, including hydroxypropyl-β-cyclodextrin (HP-β-CD), sulfobutylether-β-cyclodextrin (SBE-β-CD), maltosyl-β-cyclodextrin (ML-β-CD) and methylated CDs, including dimethyl-β-cyclodextrin (DM-β-CD), trimethyl-β-cyclodextrin (TM-β-CD) and randomly methylated β-cyclodextrin (RM-β-CD).
In drug formulations, CDs have been used mainly to increase the aqueous solubility, stability and bioavailability of various drugs, food additives and cosmetic ingredients (Frömming and Szejtli, 1994). In addition, CDs can also be used to convert liquid compounds into microcrystalline powders, prevent drug-drug or drug-additive interactions, reduce gastro-intestinal or ocular irritation, and reduce or eliminate unpleasant taste and smell.
Studies dealing with the use of CDs with cannabinoids (classical, non-classical and aminoalkylindol derivatives) are referred to in the following publications. Shoyama et al. (1983) have reported that THC forms an inclusion complex with natural β-CD with increasing chemical stability of THC. Shoyama et al. (1983) prepared the solid THC/β-CD inclusion complex by mixing THC and β-CD in methanol/water solution and hypothesised that CDs may also be used to improve the aqueous solubility and membrane permeability of THC. Jarho et al. (1998) have reported that HP-β-CD increases the aqueous solubility of THC and co-administration of small amounts of water-soluble polymer (HPMC) enhances the complexation between HP-β-CD and THC. In addition, Song et al. (2000) and Porcella et al. (2001) have recently used HP-β-CD to solubilize the aminoalkylindol derivative WIN-55212 in topical ophthalmic formulations.