CA2472561C - Process for the production of dronabinol - Google Patents
Process for the production of dronabinol Download PDFInfo
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- CA2472561C CA2472561C CA2472561A CA2472561A CA2472561C CA 2472561 C CA2472561 C CA 2472561C CA 2472561 A CA2472561 A CA 2472561A CA 2472561 A CA2472561 A CA 2472561A CA 2472561 C CA2472561 C CA 2472561C
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- dronabinol
- cannabidiol
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
- A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrane Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Medicines Containing Plant Substances (AREA)
Abstract
A method for the production of dronabinol is disclosed, whereby: a) cannabidiol is isolated from fibrous hemp as cannabidiol acid, b) the cannabidiol, optionally obtained by decarboxylation, is cyclised in the presence of Lewis acids in a non-polar solvent to give dronabinol, c) the above is isolated by a chromatographic method and d) the residue obtained from the eluant after distilling off the solvent is purified by vacuum distillation. The dronabinol can be used for dispensing purposes in a syringe filled therewith and as inhalation solution for thermal nebulisation with hot air.
Description
PROCESS FOR THE PRODUCTION OF DRONABINOL
The object of the invention is a process for the production of dronabinol from fibrous hemp.
Dronabinol is a cannabinoid with the chemical description (6aR-trans)-6a,7,8,10a-tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-1-ol. Dronabinol A9-tetrahydrocannabinol) is a natural constituent of various cannabis plants, from which it can be obtained by extraction. Dronabinol can also be chemically synthesised and is a pale-yellow, resinous oil, which is sticky at room temperature and hardens in cool storage. It is insoluble in water, but can be dissolved in oils such as sesame oil.
US patent 4 025 516 already discloses a process for the production of A9-tetrahydrocannabinol by condensation of the (+)-p-mentha-2,8-dien-1-ol with olivetol in the presence of BF3 etherate. US Patent 5 342 971 also describes synthesis of dronabinol from cannabidiol acid esters in the presence of Lewis acids and subsequent hydrolysis. In addition, synthesis of dronabinol from hydroxy-cannabidiol with Lewis acids is also already known in US Patent 5 227 537. The production of dronabinol from tetrahydrocarbinol-rich cannabis with subsequent distillation and/or chromatography is described in international patent application WO 00/25127.
The abovementioned synthetic processes were developed because isolation of A9-tetra hydroca nnabi nol from cannabis indica is legally prohibited, e.g. by the conditions of German narcotics legislation. Since synthetic processes are very expensive, dronabinol on the other hand is gaining increasing medicinal importance, due to its immunosuppressive and cytostatic properties, but especially for alleviating the side effects occurring in cancer therapy, and the problem arose of creating a simple process for producing dronabinol from plant materials, which would comply with legal requirements. Obtaining O9-tetrahydrocannabinol from fibrous hemp (cannabis sativa) is considered permissible.
The object of the invention is therefore a process for the production of dronabinol, wherein a) cannabidiol or cannabidiol acid is isolated from fibrous hemp,
The object of the invention is a process for the production of dronabinol from fibrous hemp.
Dronabinol is a cannabinoid with the chemical description (6aR-trans)-6a,7,8,10a-tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-1-ol. Dronabinol A9-tetrahydrocannabinol) is a natural constituent of various cannabis plants, from which it can be obtained by extraction. Dronabinol can also be chemically synthesised and is a pale-yellow, resinous oil, which is sticky at room temperature and hardens in cool storage. It is insoluble in water, but can be dissolved in oils such as sesame oil.
US patent 4 025 516 already discloses a process for the production of A9-tetrahydrocannabinol by condensation of the (+)-p-mentha-2,8-dien-1-ol with olivetol in the presence of BF3 etherate. US Patent 5 342 971 also describes synthesis of dronabinol from cannabidiol acid esters in the presence of Lewis acids and subsequent hydrolysis. In addition, synthesis of dronabinol from hydroxy-cannabidiol with Lewis acids is also already known in US Patent 5 227 537. The production of dronabinol from tetrahydrocarbinol-rich cannabis with subsequent distillation and/or chromatography is described in international patent application WO 00/25127.
The abovementioned synthetic processes were developed because isolation of A9-tetra hydroca nnabi nol from cannabis indica is legally prohibited, e.g. by the conditions of German narcotics legislation. Since synthetic processes are very expensive, dronabinol on the other hand is gaining increasing medicinal importance, due to its immunosuppressive and cytostatic properties, but especially for alleviating the side effects occurring in cancer therapy, and the problem arose of creating a simple process for producing dronabinol from plant materials, which would comply with legal requirements. Obtaining O9-tetrahydrocannabinol from fibrous hemp (cannabis sativa) is considered permissible.
The object of the invention is therefore a process for the production of dronabinol, wherein a) cannabidiol or cannabidiol acid is isolated from fibrous hemp,
2 b) the cannabidiol optionally obtained by decarboxylation is cyclised in the presence of Lewis acids in a non-polar solvent to give dronabinol, c) this is isolated by a chromatographic process and d) the residue obtained from the eluant after distilling off the solvent is purified by vacuum distillation.
In order to produce dronabinol according to the present invention the blossoms or also the leaves of fibrous hemp derived from certified seed are advantageously separated out from other plant material and sifted after drying. But it is also possible to use the plant material freed and cut from the stalks without preliminary sifting for extraction of active ingredients. Because cannabidiol acid and cannabidiol are concentrated especially in the resinous glands found on the leaf or blossom surface, and these glands can be separated mechanically by sifting from the remaining plant material, this method is successful in obtaining a material containing cannabidiol acid and cannabidiol which are required as starting materials for dronabinol synthesis in sufficiently high concentrations.
The active ingredients are isolated by extraction with a non-polar solvent, e.g. benzine, from the blossom constituents or the cut plant material obtained by sifting as per the present invention. The extraction of active ingredients is effectively carried out in such a way that fresh blossoms or fresh plant material are treated with a solvent, which has been concentrated with already active ingredients via an earlier extraction procedure.
In this way the active ingredient concentration increases continuously in the solvent, without distillation of the solvent being necessary. Since the solvent treatment of the plant material can be undertaken at room temperature, thermal decarboxylation of the cannabidiol acid isolated from the blossom constituents is largely avoided.
In the resulting solvent extract cannabidiol and cannabidiol acid are frequently present according to age and preliminary treatment of the plant material. Whereas cannabidiol acid is obtained predominantly from fresh plant material, cannabidiol predominates in older plant material.
The further steps for obtaining the cannabidiol now depend on whether it is predominantly cannabidiol acid or cannabidiol present in the blossom extract.
In order to produce dronabinol according to the present invention the blossoms or also the leaves of fibrous hemp derived from certified seed are advantageously separated out from other plant material and sifted after drying. But it is also possible to use the plant material freed and cut from the stalks without preliminary sifting for extraction of active ingredients. Because cannabidiol acid and cannabidiol are concentrated especially in the resinous glands found on the leaf or blossom surface, and these glands can be separated mechanically by sifting from the remaining plant material, this method is successful in obtaining a material containing cannabidiol acid and cannabidiol which are required as starting materials for dronabinol synthesis in sufficiently high concentrations.
The active ingredients are isolated by extraction with a non-polar solvent, e.g. benzine, from the blossom constituents or the cut plant material obtained by sifting as per the present invention. The extraction of active ingredients is effectively carried out in such a way that fresh blossoms or fresh plant material are treated with a solvent, which has been concentrated with already active ingredients via an earlier extraction procedure.
In this way the active ingredient concentration increases continuously in the solvent, without distillation of the solvent being necessary. Since the solvent treatment of the plant material can be undertaken at room temperature, thermal decarboxylation of the cannabidiol acid isolated from the blossom constituents is largely avoided.
In the resulting solvent extract cannabidiol and cannabidiol acid are frequently present according to age and preliminary treatment of the plant material. Whereas cannabidiol acid is obtained predominantly from fresh plant material, cannabidiol predominates in older plant material.
The further steps for obtaining the cannabidiol now depend on whether it is predominantly cannabidiol acid or cannabidiol present in the blossom extract.
3 To obtain cannabidiol acid from the solvent extract the latter is treated with an aqueous lye, preferably in counter-current extraction in the presence of a reducing agent, whereby the cannabidiol acid is dissolved with salification in the aqueous phase. The acid is precipitated from this ensuing acidification.
But if the active ingredient is predominantly present as free cannabidiol, the solvent is distilled off and the residue is dissolved in a polar organic solvent, whereby unwanted lipophilic constituents precipitate and are filtered off. The active ingredient is then obtained by evaporating the filtrate.
If the solvent extract contains a mixture of cannabidiol acid and cannabidiol, it is recommended to first treat the solvent extract with an aqueous alkali solution and subsequent extraction of the cannabidiol remaining in the organic solvent by means of a polar organic solvent.
The cannabidiol acid contained in the resulting extracts is then decarboxylated by heating, and the resulting cannabidiol is distilled off in a vacuum and crystallised.
Decarboxylation is carried out with the exclusion of oxygen, thus either in a vacuum or with an inert gas such as nitrogen. Crystallisation of the cannabidiol is facilitated by trituration of the distillate e.g. with petrol ether.
The resulting cannabidiol is cyclised according to the inventive process advantageously by means of Lewis catalysts, optionally with the addition of basic drying agents to give dronabinol. Anhydrous salts of silver, tin, zinc or magnesium, e.g. zinc chloride, zinc bromide, zinc iodide, zinc trifluormethansulfonate, tin chloride, tin bromide, tin iodide, tin trifluormethansulfonate, magnesium chloride, magnesium bromide, magnesium iodide, magnesium trifluormethansulfonate, silver chloride, silver bromide, silver iodide, silver trifluormethansulfonate are used in an organic solvent as suitable Lewis acids.
The resulting raw dronabinol is then purified chromatographically. To this is added a solution of the raw dronabinol in an organic solvent e.g. via a silica gel column. After the solvent is removed from the eluant the residue then undergoes high-vacuum distillation, whereby flash distillation or distillation in a bulb tube, preferably with the addition of bases, have proven particularly effective.
But if the active ingredient is predominantly present as free cannabidiol, the solvent is distilled off and the residue is dissolved in a polar organic solvent, whereby unwanted lipophilic constituents precipitate and are filtered off. The active ingredient is then obtained by evaporating the filtrate.
If the solvent extract contains a mixture of cannabidiol acid and cannabidiol, it is recommended to first treat the solvent extract with an aqueous alkali solution and subsequent extraction of the cannabidiol remaining in the organic solvent by means of a polar organic solvent.
The cannabidiol acid contained in the resulting extracts is then decarboxylated by heating, and the resulting cannabidiol is distilled off in a vacuum and crystallised.
Decarboxylation is carried out with the exclusion of oxygen, thus either in a vacuum or with an inert gas such as nitrogen. Crystallisation of the cannabidiol is facilitated by trituration of the distillate e.g. with petrol ether.
The resulting cannabidiol is cyclised according to the inventive process advantageously by means of Lewis catalysts, optionally with the addition of basic drying agents to give dronabinol. Anhydrous salts of silver, tin, zinc or magnesium, e.g. zinc chloride, zinc bromide, zinc iodide, zinc trifluormethansulfonate, tin chloride, tin bromide, tin iodide, tin trifluormethansulfonate, magnesium chloride, magnesium bromide, magnesium iodide, magnesium trifluormethansulfonate, silver chloride, silver bromide, silver iodide, silver trifluormethansulfonate are used in an organic solvent as suitable Lewis acids.
The resulting raw dronabinol is then purified chromatographically. To this is added a solution of the raw dronabinol in an organic solvent e.g. via a silica gel column. After the solvent is removed from the eluant the residue then undergoes high-vacuum distillation, whereby flash distillation or distillation in a bulb tube, preferably with the addition of bases, have proven particularly effective.
4 The resulting end product is very pure dronabinol, which at room temperature is a viscous fluid, but liquefies at higher temperatures and e.g. at a temperature of 60 to 80 C can be easily filled into a calibrated, gas-tight glass syringe. This dronabinol-filled glass syringe is delivered to pharmacies, where the liquefied contents are precisely metered after the glass syringe has been gently heated, from which various pharmaceuticals can be produced, such as e.g. liquid drugs by adding precisely measured quantities of dronabinol e.g. to sesame oil or other edible oils, and gelatine capsules filled with dronabinol, in which the dronabinol is taken up by oleum cacao and fixed in the capsules, and also inhalation solutions, in which the dronabinol is dissolved in alcohol.
The resulting dronabinol can also be applied from an alcohol solution by means of a special inhaler (e.g. Inhalator Vulcano marketed by Vapormed), such that the active ingredient is evaporated by means of a hot air current in a closed pouch, from which it can then be inhaled as aerosol. This form of application ensures particularly high bioavailability. Bioavailability can be further improved by adding other substances such as cannabidiol and/or essential oils and/or local anaesthetic, as irritation of airways is decreased during inhalation and a longer dwell time of the aerosol in the lungs is thus possible.
The process according to the present invention is distinguished by a series of considerable advantages. First it should be emphasised that the fibrous hemp used as starting material can be added in without problem, as it is not subject to any legal restrictions.
In procedural terms it is a particular advantage that the use of an organic solvent containing already active ingredients for extracting the plant materials leads to an overall desired increase in the active ingredient concentration, without the consequence of loading via thermal concentration when obtaining the extract.
This extensively prevents decarboxylation of cannabidiol acid. At the same time extraction of cannabidiol acid from the solvent extract by means of aqueous alkali, which effectively leads to selective concentration of the active ingredients via counter-current extraction, also considerably reduces the content of any possible pesticides.
An added advantage is that thermal decarboxylation of the extract residue obtained from plant material prevents problems which might arise during distillative treatment of the raw product through ensuing generation of gas.
A further procedural advantage can be achieved by the dronabinol obtained via cyclising of cannabidiol first being cleaned via distillation and crystallisation, thus facilitating subsequent chromatographic treatment.
With all synthesis of O9-tetrahydrocannabinol it must be taken into consideration that the thermodynamically more stable A8-tetrahydrocannabinol, although not of interest for medical applications, does not occur. There is also the danger of developing tetrahydrocannabinol basically during cyclising according to the present invention with BF3 etherate, though this unwanted reaction can be prevented if a basic drying agent is employed during cyclising.
Even more beneficial is the use of weak Lewis acids, since the formation of A8-tetrahydrocannabinol is then clearly reduced.
A particularly significant embodiment of the present invention is in filling highly purified dronabinol into syringes, from which smaller quantities of dronabinol can easily be taken for dispensing purposes, without the remaining quantities of the oxygen-sensitive substance coming into contact with air.
The process according to the present invention thus opens up novel and simple access to dronabinol which is becoming more and more important for medical purposes.
Example I
Production of dronabinol
The resulting dronabinol can also be applied from an alcohol solution by means of a special inhaler (e.g. Inhalator Vulcano marketed by Vapormed), such that the active ingredient is evaporated by means of a hot air current in a closed pouch, from which it can then be inhaled as aerosol. This form of application ensures particularly high bioavailability. Bioavailability can be further improved by adding other substances such as cannabidiol and/or essential oils and/or local anaesthetic, as irritation of airways is decreased during inhalation and a longer dwell time of the aerosol in the lungs is thus possible.
The process according to the present invention is distinguished by a series of considerable advantages. First it should be emphasised that the fibrous hemp used as starting material can be added in without problem, as it is not subject to any legal restrictions.
In procedural terms it is a particular advantage that the use of an organic solvent containing already active ingredients for extracting the plant materials leads to an overall desired increase in the active ingredient concentration, without the consequence of loading via thermal concentration when obtaining the extract.
This extensively prevents decarboxylation of cannabidiol acid. At the same time extraction of cannabidiol acid from the solvent extract by means of aqueous alkali, which effectively leads to selective concentration of the active ingredients via counter-current extraction, also considerably reduces the content of any possible pesticides.
An added advantage is that thermal decarboxylation of the extract residue obtained from plant material prevents problems which might arise during distillative treatment of the raw product through ensuing generation of gas.
A further procedural advantage can be achieved by the dronabinol obtained via cyclising of cannabidiol first being cleaned via distillation and crystallisation, thus facilitating subsequent chromatographic treatment.
With all synthesis of O9-tetrahydrocannabinol it must be taken into consideration that the thermodynamically more stable A8-tetrahydrocannabinol, although not of interest for medical applications, does not occur. There is also the danger of developing tetrahydrocannabinol basically during cyclising according to the present invention with BF3 etherate, though this unwanted reaction can be prevented if a basic drying agent is employed during cyclising.
Even more beneficial is the use of weak Lewis acids, since the formation of A8-tetrahydrocannabinol is then clearly reduced.
A particularly significant embodiment of the present invention is in filling highly purified dronabinol into syringes, from which smaller quantities of dronabinol can easily be taken for dispensing purposes, without the remaining quantities of the oxygen-sensitive substance coming into contact with air.
The process according to the present invention thus opens up novel and simple access to dronabinol which is becoming more and more important for medical purposes.
Example I
Production of dronabinol
5 ml of boron trifluoride etherate is added to a solution of 5 g of cannabidiol in 1600 ml of methylene chloride with stirring and the solution is left to stand at room temperature.
On completion of reaction the procedure is stopped with the addition of 500 ml water.
The residue obtained after distillation of the solvent contains A8-tetrahydrocannabinol 5.59%
On completion of reaction the procedure is stopped with the addition of 500 ml water.
The residue obtained after distillation of the solvent contains A8-tetrahydrocannabinol 5.59%
6 dronabinol 74.60%
The mixture is separated into its constituents by means of preparative HPLC
and the purified dronabinol undergoes vacuum distillation.
Example 2 ml of boron trifluoride etherate is added to a solution of 5 g of cannabidiol in 1600 ml of methylene chloride and 5 g of potassium carbonate with stirring and the solution is left to stand at room temperature. On completion of reaction the procedure is stopped with the addition of 500 ml water. The residue obtained after distillation of the solvent contains A8-tetrahydrocannabinol 1.59%
dronabinol 82.40%
The treatment is the same as for Example 1 Example 3 A solution of 5 g cannabidiol in 1600 ml dichloro ethane with 10 g zinc chloride is cooked for 24 hours on reflux. On completion of reaction the procedure is stopped with the addition of 500 ml water. The residue obtained after distillation of the solvent contains A8-tetrahydrocannabinol 5.01%
dronabinol 86.37%
The treatment is the same as for Example 1
The mixture is separated into its constituents by means of preparative HPLC
and the purified dronabinol undergoes vacuum distillation.
Example 2 ml of boron trifluoride etherate is added to a solution of 5 g of cannabidiol in 1600 ml of methylene chloride and 5 g of potassium carbonate with stirring and the solution is left to stand at room temperature. On completion of reaction the procedure is stopped with the addition of 500 ml water. The residue obtained after distillation of the solvent contains A8-tetrahydrocannabinol 1.59%
dronabinol 82.40%
The treatment is the same as for Example 1 Example 3 A solution of 5 g cannabidiol in 1600 ml dichloro ethane with 10 g zinc chloride is cooked for 24 hours on reflux. On completion of reaction the procedure is stopped with the addition of 500 ml water. The residue obtained after distillation of the solvent contains A8-tetrahydrocannabinol 5.01%
dronabinol 86.37%
The treatment is the same as for Example 1
Claims (20)
1. A process for synthesizing dronabinol from a starting material comprising active ingredients in a solvent, characterized in that A) the starting material used for the synthesis of dronabinol is cannabidiolic acid, cannabidiol or a mixture thereof, and B) the cannabidiol, which is optionally obtained by decarboxylation of cannabidiolic acid, is cyclized with the aid of a Lewis catalyst into the dronabinol.
2. The process of claim 1, characterized in that the starting material is fibrous hemp.
3. The process of claim 1 or 2, further characterized in that the dronabinol is purified by a chromatographic process.
4. The process of any one of claims 1 to 3, further characterized in that a residue obtained from an eluate after distilling off the solvent is purified by vacuum distillation
5. A process for preparing dronabinol, characterized in that a) cannabidiol or cannabidiolic acid is isolated from fibrous hemp, b) the cannabidiol, which is optionally obtained by decarboxylation of cannabidiolic acid, is cyclized in the presence of a Lewis catalyst in a non-polar solvent to give dronabinol, and either c) the dronabinol is isolated by a chromatographic process, or d) a residue obtained from an eluate from step b) after the solvent has been distilled off is purified by vacuum distillation.
6. The process of any one of claims 1 to 5, characterized in that the active ingredients are extracted from the flowers or leaves of fibrous hemp.
7. The process of any one of claims 1 to 6, characterized in that the active ingredients are isolated from constituents obtained by extraction of the starting material using a non-polar solvent.
8. The process of any one of claims 1 to 7, characterized in that the active ingredients of the starting material are accumulated in the solvent by extracting fresh plant material with a solvent which already comprises active ingredients without distilling off the solvent.
9. The process of any one of claims 5 to 8, characterized in that the active ingredients obtained by extraction are purified by a) treating the extract with aqueous alkali, from which the free carboxylic acids are precipitated after the acidification; and/or b) distilling off the solvent and dissolving the residue in a polar organic solvent to precipitate out undesired lipophilic constituents which are filtered off and obtaining the active ingredient present in the filtrate by evaporative concentration;
c) decarboxylating the residue obtained in a) and/or b) by heating;
d) distilling the product of step c) under reduced pressure; and e) crystallizing the cannabidiol formed.
c) decarboxylating the residue obtained in a) and/or b) by heating;
d) distilling the product of step c) under reduced pressure; and e) crystallizing the cannabidiol formed.
10. The process of any one of claims 1 to 9 characterized in that the Lewis catalyst used is an anhydrous salt of silver, tin, zinc or magnesium in an organic solvent.
11. The process of claim 10 characterized in that the Lewis catalyst is selected from the group consisting of zinc chloride, zinc bromide, zinc iodide, zinc trifluoromethanesulphonate, tin chloride, tin bromide, tin iodide, tin trifluoromethanesulphonate, magnesium chloride, magnesium bromide, magnesium iodide, magnesium trifluoromethanesulphonate, silver chloride, silverbromide, silveriodide, and silvertrifluoromethanesulphonate.
12. The process of any one of claims 1 to 9, characterized in that the cannabidiol is cyclized to dronabinol by adding BF3 etherate, optionally in the presence of an alkaline desiccant in an organic solvent.
13. The process of claim 12, characterized in that the alkaline desiccant used is potassium carbonate.
14. The process of any one of claims 1 to 9, characterized in that the cannabidiol is cyclized to dronabinol by adding a weak Lewis acid in an organic solvent.
15. The process of claims 13 and 14, characterized in that the solution comprising dronabinol is chromatographed on a silica gel column.
16. The process of any one of claims 9 to 15, characterized in that the residue of dronabinol obtained from the eluate is purified by a vacuum distillation.
17. The process of claim 16 wherein the vacuum distillation is a high-vacuum distillation.
18. An inhalation solution for thermal nebulization with hot air, characterized in that it comprises dronabinol prepared according to one of claims 1 to 16.
19. The inhalation solution of claim 18, characterized in that it additionally comprises cannabidiol, a local anaesthetic and/or etherical oils.
20. A process for producing a medicament comprising dronabinol which is obtained by the process of any one of claims 1-17, characterized in that, in a first step, the dronabinol is introduced into a calibrated gas-tight glass syringe and, in a second step, the liquefied contents are delivered in a controlled dosage, the ingredients being delivered without the remaining amount of dronabinol introduced coming into contact with air.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE10106024.6 | 2001-02-05 | ||
| DE10106024A DE10106024B4 (en) | 2001-02-09 | 2001-02-09 | Process for the preparation of dronabinol |
| PCT/EP2002/001172 WO2002062782A1 (en) | 2001-02-09 | 2002-02-05 | Method for the production of dronabinol |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2472561A1 CA2472561A1 (en) | 2002-08-15 |
| CA2472561C true CA2472561C (en) | 2010-11-02 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2472561A Expired - Lifetime CA2472561C (en) | 2001-02-09 | 2002-02-05 | Process for the production of dronabinol |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP1409474B1 (en) |
| AT (1) | ATE388144T1 (en) |
| CA (1) | CA2472561C (en) |
| DE (2) | DE10106024B4 (en) |
| ES (1) | ES2303547T3 (en) |
| WO (1) | WO2002062782A1 (en) |
Families Citing this family (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH697767B1 (en) * | 2002-01-16 | 2009-02-13 | Giuliano Silvestri | Method and apparatus for the separation of toxic levels of plant parts and for the extraction of THC. |
| GB2393182B (en) * | 2002-09-23 | 2007-03-14 | Gw Pharma Ltd | Method of preparing cannabidiol from plant material |
| DE102005028937B4 (en) | 2005-06-22 | 2009-07-23 | Bionorica Ag | Process for the preparation of dronabinol |
| EP1928853A4 (en) | 2005-09-29 | 2011-02-16 | Amr Technology Inc | Process for production of delta-9-tetrahydrocannabinol |
| US9376367B2 (en) | 2011-09-29 | 2016-06-28 | The Health Concept Gmbh | Cannabinoid carboxylic acids, salts of cannabinoid carboxylic acids, and the production and uses of same |
| AU2014330891B2 (en) | 2013-10-04 | 2018-11-01 | Natural Extraction Systems, LLC | Method and apparatus for extracting botanical oils |
| WO2015070167A1 (en) * | 2013-11-11 | 2015-05-14 | The Werc Shop, LLC | Solvent-free processing, system and methods |
| US10647691B2 (en) | 2016-05-13 | 2020-05-12 | Symrise Ag | Method for purifying cannabinoid compounds |
| US10239808B1 (en) | 2016-12-07 | 2019-03-26 | Canopy Holdings, LLC | Cannabis extracts |
| CN107669744A (en) * | 2017-11-30 | 2018-02-09 | 云南汉木森生物科技有限责任公司 | Pack containing industrial hemp |
| EP3745884A1 (en) | 2018-01-31 | 2020-12-09 | Canopy Holdings, Llc | Hemp powder |
| US10822320B2 (en) | 2018-08-10 | 2020-11-03 | Natural Extraction Systems, LLC | Methods to purify cannabinoids |
| US10669248B2 (en) * | 2018-08-10 | 2020-06-02 | Natural Extraction Systems, LLC | Methods to chemically modify cannabinoids |
| CA3119729A1 (en) | 2018-10-10 | 2020-04-16 | Treehouse Biotech, Inc. | Synthesis of cannabigerol |
| US11767306B2 (en) * | 2020-01-17 | 2023-09-26 | Cannacraft, Inc | Methods for converting CBD to tetrahydrocannabinols |
| US11786838B2 (en) | 2020-03-23 | 2023-10-17 | Cannacraft, Inc. | Methods for removing pesticides from Cannabis products |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE4100441A1 (en) * | 1991-01-09 | 1992-07-16 | Mack Chem Pharm | PROCESS FOR PREPARING 6,12-DIHYDRO-6-HYDROXY-CANNABIDIOL AND USE THEREOF FOR THE PREPARATION OF TRANS-DELTA-9-TETRAHYDROCANNABINOL |
| US5342971A (en) * | 1992-12-29 | 1994-08-30 | The Australian National University | Process for the preparation of dibenzo[b,d]pyrans |
-
2001
- 2001-02-09 DE DE10106024A patent/DE10106024B4/en not_active Expired - Fee Related
-
2002
- 2002-02-05 CA CA2472561A patent/CA2472561C/en not_active Expired - Lifetime
- 2002-02-05 EP EP02719764A patent/EP1409474B1/en not_active Expired - Lifetime
- 2002-02-05 ES ES02719764T patent/ES2303547T3/en not_active Expired - Lifetime
- 2002-02-05 AT AT02719764T patent/ATE388144T1/en not_active IP Right Cessation
- 2002-02-05 WO PCT/EP2002/001172 patent/WO2002062782A1/en active IP Right Grant
- 2002-02-05 DE DE50211842T patent/DE50211842D1/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| ES2303547T3 (en) | 2008-08-16 |
| CA2472561A1 (en) | 2002-08-15 |
| DE10106024A1 (en) | 2002-08-22 |
| ATE388144T1 (en) | 2008-03-15 |
| DE10106024B4 (en) | 2004-10-14 |
| WO2002062782A1 (en) | 2002-08-15 |
| EP1409474B1 (en) | 2008-03-05 |
| DE50211842D1 (en) | 2008-04-17 |
| EP1409474A1 (en) | 2004-04-21 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKEX | Expiry |
Effective date: 20220207 |