US20090298929A1 - Novel natural cyclodextrin complexes - Google Patents
Novel natural cyclodextrin complexes Download PDFInfo
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- US20090298929A1 US20090298929A1 US12/541,397 US54139709A US2009298929A1 US 20090298929 A1 US20090298929 A1 US 20090298929A1 US 54139709 A US54139709 A US 54139709A US 2009298929 A1 US2009298929 A1 US 2009298929A1
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- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
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- 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
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- 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
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- 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
- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6949—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
- A61K47/6951—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
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- 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
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- 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
- A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
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- A—HUMAN NECESSITIES
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- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- the present invention describes the use of natural cyclodextrins ( ⁇ -CD, ⁇ -CD and ⁇ -CD) in sublingual and buccal formulations in order to improve the dissolution rate and bioavailability of selected cannabinoids, especially classical cannabinoids such as cannabidiol (CBD), cannabinol (CBN) and ⁇ 9 -tetrahydrocannabinol (THC).
- CBD cannabidiol
- CBN cannabinol
- THC ⁇ 9 -tetrahydrocannabinol
- Cannabinoids are a group of compounds which are ligands to cannabinoid receptors (CB 1 , CB 2 ) found in the human body (Pertwee, 1997). Cannabinoids were originally found from Cannabis sativa L., the origin of marijuana and hashish. Over the last few years, marijuana or its components have been reported in the 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.
- CBD 1 , CB 2 cannabinoid receptors
- cannabinoids as an oxytoxic, anxiolytic, anti-convulsive, anti-depressant and anti-psychotic agent (Williamson and Evans, 2000), or anti-cancer agent, as well as an appetite stimulant.
- cannabinoids are chemically related compounds, collectively classified as cannabinoids, and many chemically related compounds, collectively classified as cannabinoids.
- THC tetrahydrocannabinol
- CBD cannabidiol
- CBN cannabinol
- various synthetic ligands for cannabinoid receptors have been developed during the last few 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.
- THC tetrahydrocannabinol
- THC tetrahydrofuran
- Dronabinol is a synthetic analog of THC which is marketed in USA as 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 are cyclic oligosaccharides consisting of ( ⁇ -1,4)-linked ⁇ -D-glucopyranose units, with a lipophilic central cavity and a hydrophilic outer surface (Fromming 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 ⁇ -cyclodextrin ( ⁇ -CD), ⁇ -cyclodextrin ( ⁇ -CD) and ⁇ -cyclodextrin ( ⁇ -CD), containing six, seven, and eight glucopyranose units, respectively.
- ⁇ -CD appears to be the most useful pharmaceutical complexing agent because of its cavity size, availability, low cost and other properties.
- CD derivatives available, such as hydroxypropyl- ⁇ -CD and methylated CDs.
- natural CDs have been shown to form low solubility complexes with various drugs, as opposed to water-soluble CDs derivatives.
- Water-soluble CD derivatives form only water-soluble complexes with lipophilic drugs.
- 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).
- 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.
- HP- ⁇ -CD increases the aqueous solubility of THC and that co-administration of small amounts of a water-soluble polymer, hydroxypropyl methylcellulose (HPMC) enhances the complexation between HP- ⁇ -CD and THC.
- HPMC hydroxypropyl methylcellulose
- the present invention is directed to a novel use of a complex between a specific group of cyclodextrins and cannabinoids.
- the invention relates to a complex of a cyclodextrin selected from the group consisting of ⁇ -CD, ⁇ -CD and ⁇ -CD, and a cannabinoid selected from the classical cannabinoid-group consisting of cannabinol, tetrahydrocannabinol and cannabidiol.
- the present invention is also directed to a process for the preparation of a complex of a cyclodextrin selected from the group consisting of ⁇ -CD, ⁇ -CD and ⁇ -CD, and a cannabinoid selected from the classical cannabinoid-group consisting of cannabinol, tetrahydrocannabinol and cannabidiol, the process comprising combining the selected cyclodextrin with the selected cannabinoid in solution, in a heterogenous state or in the solid state, including using methods such as precipitation, freeze-drying, spray-drying, kneading, grinding, slurry-method, co-precipitation, and neutralization, and optionally separating said complex.
- a cyclodextrin selected from the group consisting of ⁇ -CD, ⁇ -CD and ⁇ -CD
- a cannabinoid selected from the classical cannabinoid-group consisting of cannabinol, te
- FIG. 1 shows the dissolution profile of CBD from gelatin capsule.
- FIG. 2 shows the dissolution profile of a natural ⁇ -CD/CBD complex form a gelatin capsule.
- FIG. 3 shows the dissolution profile of a natural ⁇ -CD/CBD complex from a gelatin capsule.
- 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.
- THC is commercially available as a capsule containing 5-10 mg of THC (Marinol).
- 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 .
- cannabinoid and CD are used in a weight ratio (dry weight to dry weight) ranging between 1:3 and 1:1000.
- inclusion complex can be facilitated by using solvents, such as organic solvents, for example methanol or ethanol.
- 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.
- a powder containing a CBD/ ⁇ -CD inclusion complex was prepared by the precipitation method.
- a methanol solution of CBD was added dropwise to an aqueous ⁇ -CD solution and after equilibration the white precipitate (CBD/ ⁇ -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- ⁇ -CD dissolution medias (pH 6.6) to ensure the free solubility of CBD.
- FIGS. 1 and 2 show that the complexation of CBD with natural ⁇ -CD significantly increases the dissolution rate of CBD.
- CBD is fully dissolved in 30 minutes.
- the dissolution rate is much slower and CBD is not fully dissolved in 3 hours.
- a powder containing a CBD/ ⁇ -CD inclusion complex was prepared by the precipitation method.
- a methanol solution of CBD was added dropwise to an aqueous ⁇ -CD solution and after equilibration the white precipitate (CBD/ ⁇ -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- ⁇ -CD dissolution medias (pH 6.6) to ensure the free solubility of CBD.
- FIGS. 1 and 3 show that the complexation of CBD with natural ⁇ -CD significantly increases the dissolution rate of CBD.
- CBD is fully dissolved in 30 minutes.
- the dissolution rate is much slower and CBD is not fully dissolved in 3 hours.
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.
Description
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- This application is a Continuation of U.S. application Ser. No. 10/505,136, filed Sep. 16, 2004 (now allowed); which is a 371 of PCT/FI03/00126, filed Feb. 20, 2003; the disclosure of each of which is incorporated herein by reference.
- The present invention describes the use of natural cyclodextrins (α-CD, β-CD and γ-CD) in sublingual and buccal formulations in order to improve the dissolution rate and bioavailability of selected cannabinoids, especially classical cannabinoids such as cannabidiol (CBD), cannabinol (CBN) and Δ9-tetrahydrocannabinol (THC).
- 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., the origin of marijuana and hashish. Over the last few years, marijuana or its components have been reported in the 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), or 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 few 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 under the name Dronabinol) which in 1985 was approved by the 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)-linked α-D-glucopyranose units, with a lipophilic central cavity and a hydrophilic outer surface (Fromming 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. There are also a number of CD derivatives available, such as hydroxypropyl-β-CD and methylated CDs. One of the major differences between natural CDs and the CD derivatives above is that natural CDs have been shown to form low solubility complexes with various drugs, as opposed to water-soluble CDs derivatives. Water-soluble CD derivatives form only water-soluble complexes with lipophilic drugs.
- 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 a methanol/water solution and hypothesised that CDs (in general) may also be used to improve the aqueous solubility, membrane permeability and bioavailability of THC. Jarho et al. (1998) have reported that HP-β-CD increases the aqueous solubility of THC and that co-administration of small amounts of a water-soluble polymer, hydroxypropyl methylcellulose (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.
- The present invention is directed to a novel use of a complex between a specific group of cyclodextrins and cannabinoids. Specifically, the invention relates 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 cannabinol, tetrahydrocannabinol and cannabidiol.
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- Specifically, the present invention is directed to the use of the complex for the preparation of a pharmaceutical composition for sublingual or buccal administration. The invention is also directed to pharmaceutical compositions containing such a complex which are intended for sublingual or buccal administration, for example in the form of a tablet, capsule, chewing gum, lozenge or pill.
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- Furthermore, the invention is directed to a method for treating an individual, such as a human, for a condition responsive to treatment with a cannabinoid, the method comprising administering sublingually or buccally to said individual a sufficient amount of 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 cannabinol, tetrahydrocannabinol and cannabidiol.
- In addition, the present invention is also directed to a process for the preparation of 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 cannabinol, tetrahydrocannabinol and cannabidiol, the process comprising combining the selected cyclodextrin with the selected cannabinoid in solution, in a heterogenous state or in the solid state, including using methods such as precipitation, freeze-drying, spray-drying, kneading, grinding, slurry-method, co-precipitation, and neutralization, and optionally separating said complex.
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FIG. 1 shows the dissolution profile of CBD from gelatin capsule. -
FIG. 2 shows the dissolution profile of a natural β-CD/CBD complex form a gelatin capsule. -
FIG. 3 shows the dissolution profile of a natural γ-CD/CBD complex from a gelatin capsule. - 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.
-
FIG. 1 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).FIG. 2 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). -
FIGS. 1 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.
-
FIG. 1 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).FIG. 3 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). -
FIGS. 1 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 Δ9-tetrahydrocannabinol-β-cyclodextrin inclusion complex. J. Nat. Prod. 46:633-637, 1983.
- Song Z-H, Slowey C-A: Involvement of cannabinoid receptors in the intraocular pressure lowering effects of WIN55212-2. J. Pharm. Exp. Ther. 292:136-139, 2000.
- Williamson E M, Evans F J: Cannabinoids in clinical practise. Drugs 60:1303-1314, 2000.
- Zhang M-Q, Rees D C: A review of recent application of cyclodextrins for drug discovery. Exp. Opin. Ther. Patents. 9:1697-1717, 1999.
Claims (10)
1. A complex comprising:
(a) β-cyclodextrin
(b) a cannabinoid
wherein said complex is an insoluble powder form.
2. A complex comprising:
(a) γ-cyclodextrin
(b) a cannabinoid
wherein said complex is an insoluble powder form.
3. The complex of claim 1 wherein the cannabinoid is Δ9-tetrahydrocannabinol.
4. The complex of claim 1 or claim 2 wherein the cannabinoid and cyclodextrin are present in the complex in a weight ratio, based on dry weight, of 1:3 to 1:1000.
5. A pharmaceutical composition comprising the complex of claim 1 or claim 2 and at least one pharmaceutical acceptable carrier, adjuvant or additive.
6. The pharmaceutical composition of claim 5 wherein said composition is in a form suitable for sublingual or buccal administration.
7. A pharmaceutical composition of claim 5 which is a tablet, a capsule, a chewing gum, a lozenge, a pill or a pastille.
8. A method of treatment of a subject comprising administering to the subject afflicted with or suffering from nausea, muscular spasms, multiple sclerosis, uterine cramps; bowel cramps, pain, migraine headache, glaucoma, asthma, inflammation, insomnia, high blood pressure, anxiety, convulsions, depression or psychosis, an effective amount of the complex of claim 1 or claim 2 .
9. The method of claim 8 wherein said composition is administered such that 0.1 to 50 mg of cannabinoid are administered per day.
10. A method of claim 8 wherein the composition is administered to the subject in need thereof by a buccal or a sublingual route.
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US10/505,136 US7592328B2 (en) | 2002-02-20 | 2003-02-20 | Natural cyclodextrin complexes |
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US12/541,397 US20090298929A1 (en) | 2002-02-20 | 2009-08-14 | Novel natural cyclodextrin complexes |
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EP (1) | EP1476473B1 (en) |
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- 2003-02-20 US US10/505,136 patent/US7592328B2/en not_active Expired - Lifetime
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US7592328B2 (en) | 2009-09-22 |
EP1476473A1 (en) | 2004-11-17 |
US20050153931A1 (en) | 2005-07-14 |
AU2003205808C1 (en) | 2008-10-09 |
NZ535154A (en) | 2007-01-26 |
FI113340B (en) | 2004-04-15 |
CA2476834C (en) | 2015-12-01 |
EP1476473B1 (en) | 2014-06-18 |
AU2003205808A1 (en) | 2003-09-09 |
AU2003205808B2 (en) | 2008-04-24 |
FI20020334A (en) | 2003-08-21 |
FI20020334A0 (en) | 2002-02-20 |
WO2003070775A1 (en) | 2003-08-28 |
CA2476834A1 (en) | 2003-08-28 |
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