Methods for removing contaminants from plant-derived pharmaceuticals

Abstract

Methods of removing contaminants such as pesticides, herbicides, and fungicides from plant-derived pharmaceuticals, such as Cannabis-derived pharmaceuticals, are disclosed. Plant-derived pharmaceuticals, such as Cannabis-derived pharmaceuticals, and methods of using the plant-derived pharmaceuticals are also disclosed.

Claims

1. A method of removing contaminants from a Cannabis plant-derived pharmaceutical, said method comprising: reacting one or more contaminants within a Cannabis plant-derived extract with an alkali metal hydroxide in a polar solvent to form one or more contaminant by-products in a reaction mixture, wherein said reacting step comprises: adding the Cannabis plant-derived extract to the alkali metal hydroxide in the polar solvent to form the reaction mixture; agitating the reaction mixture with mixing; and adding a neutralizing acid to the reaction mixture, wherein the neutralizing acid comprises glacial acetic acid, or a dilute mineral acid comprising hydrochloric acid, sulfuric acid, or nitric acid; and separating the one or more contaminant by-products from the Cannabis plant-derived extract so as to obtain a contaminant-reduced Cannabis plant-derived extract, wherein said separating step comprises: adding a first alkane to the reaction mixture so as to form a non-aqueous liquid phase within the reaction mixture, wherein the first alkane comprises butane, pentane, cyclopentane, hexane, cyclohexane, heptane, octane, isooctane, or any combination thereof; and separating an upper non-aqueous liquid phase from a lower aqueous liquid phase, the upper non-aqueous liquid phase comprising the first alkane and the contaminant-reduced Cannabis plant-derived extract, wherein the contaminant-reduced Cannabis plant-derived extract comprises one or more cannabinoids.

2. The method of claim 1, wherein the one or more contaminants comprise one or more pesticides, one or more herbicides, one or more fungicides, or any combination thereof.

3. The method of claim 1, wherein the one or more contaminants comprise one or more hydrolyzable pesticides.

4. The method of claim 1, wherein the alkali metal hydroxide comprises lithium hydroxide, sodium hydroxide, potassium hydroxide, or calcium hydroxide.

5. The method of claim 1, wherein the polar solvent comprises methanol; the neutralizing acid comprises hydrochloric acid; and the first alkane comprises hexane, heptane, or any combination thereof.

6. The method of claim 1, further comprising: passing the upper non-aqueous liquid phase through one or more columns with each column comprising one or more adsorbents; and collecting an effluent exiting the one or more columns.

7. The method of claim 6, wherein the one or more adsorbents comprise magnesium silicate, activated alumina, magnesium salt of activated alumina, sodium sulfate, silica, bonded phase silica, polymeric non-ionic reversed phase resins, or any combination thereof.

8. The method of claim 7, wherein the one or more adsorbents comprise (i) silica gel in a first column, and (ii) magnesium silicate in a second column.

9. The method of claim 6, further comprising: passing one or more column volumes of a rinse mixture through the one or more columns, the rinse mixture comprising heptane and ethyl acetate at a heptane:ethyl acetate ratio of about 80:20 by volume; and collecting the rinse mixture exiting the one or more columns.

10. The method of claim 9, further comprising: evaporating the rinse mixture under reduced pressure so as to (1) remove one or more of: (i) the first alkane, (ii) heptane, (iii) ethyl acetate, and (iv) any residual neutralizing acid, and (2) result in the contaminant-reduced Cannabis plant-derived extract.

11. A method of removing contaminants from a plant-derived pharmaceutical, said method comprising: reacting one or more contaminants within a plant-derived extract with an alkali metal hydroxide in a polar solvent to form one or more contaminant by-products in a reaction mixture; and separating the one or more contaminant by-products from the reaction mixture so as to obtain a contaminant-reduced plant-derived extract, wherein said reacting step comprises: adding the plant-derived extract to the alkali metal hydroxide in the polar solvent to form the reaction mixture; agitating the reaction mixture with mixing; and adding a neutralizing acid to the reaction mixture, wherein the neutralizing acid comprises hydrochloric acid; and wherein said separating step comprises: adding a first alkane to the reaction mixture so as to form a non-aqueous liquid phase within the reaction mixture; separating an aqueous liquid phase of the reaction mixture from the non-aqueous liquid phase; passing the non-aqueous liquid phase through one or more columns with each column comprising one or more adsorbents; passing one or more column volumes of a rinse mixture through the one or more columns, the rinse mixture comprising a second alkane and ethyl acetate; and evaporating the rinse mixture under reduced pressure so as to (1) remove one or more of: (i) the first alkane, (ii) the second alkane, (iii) ethyl acetate, and (iv) any residual neutralizing acid, and (2) result in the contaminant-reduced plant-derived extract.

12. The method of claim 11, wherein (a) the second alkane comprises heptane, and (b) the rinse mixture comprises (i) the heptane, and (ii) up to about 20 weight percent (wt %) of the ethyl acetate.

13. The method of claim 11, wherein the one or more contaminants comprise one or more pesticides, one or more herbicides, one or more fungicides, or any combination thereof.

14. The method of claim 11, wherein the one or more contaminants comprise one or more hydrolyzable pesticides.

15. The method of claim 11, wherein the contaminant-reduced plant-derived extract comprises one or more cannabinoids.

16. The method of claim 14, wherein the contaminant-reduced plant-derived extract comprises one or more cannabinoids.

17. A method of removing contaminants from a plant-derived pharmaceutical, said method comprising: reacting one or more contaminants within a plant-derived extract with an alkali metal hydroxide in a polar solvent to form one or more contaminant by-products in a reaction mixture, the one or more contaminants comprising one or more pesticides, one or more herbicides, one or more fungicides, or any combination thereof; and separating (i) the one or more contaminant by-products, and (ii) a contaminant-reduced plant-derived extract from the reaction mixture, wherein said separating step comprises: adding a first alkane to the reaction mixture so as to form a non-aqueous liquid phase within the reaction mixture; separating an aqueous liquid phase of the reaction mixture from the non-aqueous liquid phase; passing the non-aqueous liquid phase through one or more columns with each column comprising one or more adsorbents; passing one or more column volumes of a rinse mixture through the one or more columns, the rinse mixture comprising a second alkane and ethyl acetate; and evaporating the rinse mixture under reduced pressure so as to (1) remove one or more of: (i) the first alkane, (ii) the second alkane, (iii) ethyl acetate, and (2) result in the contaminant-reduced plant-derived extract.

18. The method of claim 17, wherein said reacting step comprises: adding the plant-derived extract to the alkali metal hydroxide in the polar solvent to form the reaction mixture; agitating the reaction mixture with mixing; and adding a neutralizing acid to the reaction mixture, wherein the neutralizing acid comprises hydrochloric acid.

19. The method of claim 18, wherein the one or more contaminants comprise one or more hydrolyzable pesticides.

20. The method of claim 17, wherein the contaminant-reduced plant-derived extract comprises one or more cannabinoids.

Description

BRIEF DESCRIPTION OF THE FIGURES

(1) The present invention is further described with reference to the appended figure, wherein:

(2) FIGS. 1A-1B depict an exemplary process flowchart showing steps for the removal of contaminants from plant-derived pharmaceuticals.

DETAILED DESCRIPTION OF THE INVENTION

(3) The present invention is directed towards methods of removing contaminants from plant-derived pharmaceuticals. The present invention is further directed towards plant-derived pharmaceuticals obtained using the herein-described methods, and methods of using the plant-derived pharmaceuticals.

(4) I. Methods of Removing Contaminants from Plant-Derived Pharmaceuticals

(5) The present invention is directed towards methods of removing contaminants from plant-derived pharmaceuticals.

(6) The functional groups of the cannabinoids are: (1) alkanes, (2) alkenes, (3) aromatic rings, (4) phenolic hydroxyls, (5) carboxylic acids, and (6) aryl alkyl ethers. Neutral cannabinoids (i.e., without a carboxylic acid functional group) are insoluble in water.

(7) Without special conditions, the functional groups of the cannabinoids are not subject to attack by most nucleophiles.

(8) The most common alkali metal hydroxides (e.g., alkaline earth hydroxides) are lithium hydroxide, sodium hydroxide, potassium hydroxide, and calcium hydroxide. All of these substances are: (1) inexpensive, (2) readily soluble both in water and the lower molecular weight alcohols (methanol, ethanol, isopropyl alcohol, and n-propanol), and (3) strong nucleophiles and agents of hydrolysis.

(9) Pesticides contain a wide range of functional groups. Most pesticides contain at least one functional group that can be attacked by nucleophiles such as an alkali metal hydroxide in alcoholic solution. Of the 59 pesticides, fungicides, and synergists with levels in Cannabis regulated by the State of Oregon, 45 are subject to nucleophilic attack under these conditions, 6 might be, and 8 are not. Once a functional group has been transformed by such a reaction, the biological activity is usually lost.

(10) None of the cannabinoids contain any functional groups that can be attacked by strong nucleophiles such as an alkali metal hydroxide in alcoholic solution.

(11) The present invention provides what is believed to be the best solution to eliminate all hydrolyzable pesticides, which is nearly all pesticides, from Cannabis extracts. The method of entirely removing all hydrolyzable pesticides from a given Cannabis extract comprises a reaction step, wherein one or more contaminants are reacted with an alkali metal hydroxide solution, followed by an adsorbent based clean-up step to eliminate any pesticide fragments and any remaining pesticides. This desired method is described below, as well as shown in FIGS. 1A-1B.

(12) As shown in FIG. 1A, exemplary method 100 of the present invention starts at step 10, wherein an alcoholic solution of alkali metal hydroxide, such as potassium hydroxide, is formed. From step 10, exemplary method 100 proceeds to step 15, wherein a given Cannabis extract is added to the alcoholic solution of alkali metal hydroxide. From step 15, exemplary method 100 proceeds to step 20, wherein the resulting reaction solution is agitated with heating (e.g., heating to boil for about an hour) and/or ultrasonic vibration with sufficient molar excess of alkali metal hydroxide for a sufficient time to insure complete reaction, typically for up to an hour or more.

(13) Following complete reaction in step 20, exemplary method 100 proceeds to step 25, wherein the reaction solution is allowed to cool down (e.g., to room temperature). From step 25, exemplary method 100 proceeds to step 30, wherein a neutralizing acid such as a mineral acid (e.g., hydrochloric acid, sulfuric acid, and the like) or a carboxylic acid (e.g., glacial acetic acid and the like) is added to the reaction solution to neutralize the alkaline metal hydroxide and solubilize water-soluble neutralization products such as potassium acetate. The neutralizing acid is added to water and the resulting diluted acid is then added to the mixture. The water serves to absorb the heat of acid-base neutralization. In any case, the neutralizing acid is added in excess to protonate the Cannabinoid acids and the phenolic groups.

(14) From step 30, exemplary method 100 can proceed to step 35A, wherein the alcoholic solvent (i.e., an alcohol solvent other than methanol) is removed by evaporation under reduced pressure, and may be recovered for possible reuse in step 10. If the starting neutralizing acid is concentrated hydrochloric acid diluted with water, then once the alcoholic solvent is removed, an amount of sodium chloride is formed, and a small amount of hydrochloric acid, and the Cannabinoid oil should be present in the resulting reaction mixture. If the starting neutralizing acid is glacial acetic acid diluted with water, then once the alcoholic solvent is removed, an amount of white crystalline potassium acetate is formed, and a small amount of liquid glacial acetic acid, and the Cannabinoid oil should be present in the resulting reaction mixture.

(15) From step 35A, exemplary method 100 proceeds to step 40A, wherein an alkane, such as heptane, is added to the reaction mixture to solubilize cannabinoids within the reaction mixture. From step 40A, exemplary method 100 proceeds to step 45A shown in FIG. 1B, wherein water is separated from the alkane/oil of the reaction mixture via a separatory funnel or any other type of biphasic separation device.

(16) Returning to step 30, if the alcoholic solvent used is methanol, exemplary method 100 can proceed to step 35B, where an alkane solvent (such as pentane, hexane, heptane and the like) is added directly to the reaction mixture since both methanol and water are immiscible with an alkane and the substances of interest are very soluble in the alkane. From step 35B, exemplary method 100 proceeds to step 40B, wherein the water/alcohol is separated from the alkane/oil by a separatory funnel or any other type of biphasic separation devices. From step 40B, exemplary method 100 proceeds to step 45B shown in FIG. 1B, wherein the methanol is removed from the water/methanol mixture by evaporation under reduced pressure for possible reuse in future contaminant-removal cycles (i.e., in step 10). Other alcohols, such as ethanol, isopropanol, n-propanol and so on, are miscible with alkanes so this only works with methanol.

(17) From step 45A or 45B, exemplary method 100 proceeds to step 50, wherein, the recovered alkane/oil layer is put into contact with a drying agent, such as sodium sulfate, magnesium sulfate, and the like, to eliminate all water content. In this step, the powdered drying agent can be added to the recovered alkane/oil layer, agitated, and then filtered off. Alternatively, the drying agent can be added to a chromatographic column and the recovered alkane/oil layer pumped through the filled column.

(18) From step 50, exemplary method 100 proceeds to step 55, wherein the dried alkane/oil layer is passed through a silica gel column. From step 55, exemplary method 100 proceeds to step 60, wherein one or more, typically several, column volumes of a mixture of heptane and ethyl acetate (80:20 v/v) is passed through the silica gel column. The silica gel column (i) allows the non-polar Cannabinoids to pass through unretained, (ii) absorbs any water, (iii) retains fragments of the hydrolyzed pesticides, and (iv) retains unhydrolyzable polar pesticides.

(19) If Piperonyl Butoxide, a non-toxic (i.e., to humans) ingredient commonly added to commercially available insecticides, is believed to be present, exemplary method 100 proceeds from step 60 to step 65, wherein the resulting mixture is passed through a FLORISIL® (magnesium silicate) column to absorb the Piperonyl Butoxide.

(20) It should be noted that the vast majority of commercially available pesticides contain Piperonyl Butoxide because it increases the toxicity of the pesticides to insects. Piperonyl Butoxide is not affected by the above-described hydrolysis step and it elutes from the silica gel column at the same time as the Cannabinoids. Piperonyl Butoxide has a polyether like side chain. FLORISIL® is a tradename for micron sized heat activated (675° C.) magnesium silicate.

(21) From step 65, exemplary method 100 proceeds to step 70, wherein the heptane and ethyl acetate are removed by evaporation under reduced pressure to obtain a pesticide-free Cannabinoid product. If it is known that no Piperonyl Butoxide is present in a given sample, exemplary method 100 may proceed directly to step 70 (i.e., without step 65 shown in FIG. 1B).

(22) The above-described exemplary method 100 has been found to effectively remove many contaminants including, but not limited to, many of the pesticides listed in Table 1 below.

(23) TABLE-US-00001 TABLE 1 Pesticides in Cannabis Regulated by the State of Oregon Chemical Group Abstract Subject To Pesticide Services Action Nucleophilic Common (CAS) Level Attack No. Name Registry (ppm) Chemical Structure Present? 1 Abamectin 71751-41-2 0.5 Yes 2 Acephate 30560-19-1 0.4 Yes 3 Acequinocyl 57960-19-7 2 Yes 4 Acetamiprid 135410-20-7 0.2 Yes 5 Aldicarb 116-06-3 0.4 Yes 6 Azoxystrobin 131860-33-8 0.2 Yes 7 Bifenazate 149877-41-8 0.2 Yes 8 Bifenthrin 82657-04-3 0.2 Yes 9 Boscalid 188425-85-6 0.4 No 10 Carbaryl 63-25-2 0.2 0 Yes 11 Carbofuran 1563-66-2 0.2 Yes 12 Chlorantraniliprole 500008-45-7 0.2 Yes 13 Chlorfenapyr 122453-73-0 1 No 14 Chlorpyrifos 2921-88-2 0.2 Yes 15 Clofentezine 74115-24-5 0.2 Maybe 16 Cyfluthrin 68359-37-5 1 Yes 17 Cypermethrin 52315-07-8 1 Yes 18 Daminozide 1596-84-5 1 Yes 19 DDVP (Dichlorvos) 62-73-7 0.1 Yes 20 Diazinon 333-41-5 0.2 0 Yes 21 Dimethoate 60-51-5 0.2 Yes 22 Ethoprophos 13194-48-4 0.2 Yes 23 Etofenprox 80844-07-1 0.4 No 24 Etoxazole 153233-91-1 0.2 No 25 Fenoxycarb 72490-01-8 0.2 Yes 26 Fenpyroximate 134098-61-6 0.4 Yes 27 Fipronil 120068-37-3 0.4 Yes 28 Flonicamid 158062-67-0 1 May-be 29 Fludioxonil 131341-86-1 0.4 No 30 Hexythiazox 78587-05-0 1 0 Yes 31 Imazalil 35554-44-0 0.2 May-be 32 Imidacloprid 138261-41-3 0.4 Yes 33 Kresoxim- methyl 143390-89-0 0.4 Yes 34 Malathion 121-75-5 0.2 Yes 35 Metalaxyl 57837-19-1 0.2 Yes 36 Methiocarb 2032-65-7 0.2 Yes 37 Methomyl 16752-77-5 0.4 Yes 38 Methyl parathion 298-00-0 0.2 Yes 39 MGK-264 113-48-4 0.2 May-be 40 Myclobutanil 88671-89-0 0.2 0 Yes 41 Naled 300-76-5 0.5 Yes 42 Oxamyl 23135-22-0 1 Yes 43 Paclobutrazol 76738-62-0 0.4 Maybe 44 Permethrins 52645-53-1 0.2 Yes 45 Phosmet 732-11-6 0.2 Yes 46 Piperonyl butoxide 51-03-6 2 No 47 Prallethrin 23031-36-9 0.2 Yes 48 Propiconazole 60207-90-1 0.4 No 49 Propoxur 114-26-1 0.2 Yes 50 Pyrethrins 8003-34-7 1 0 Yes 51 Pyridaben 96489-71-3 0.2 Yes 52 Spinosad 168316-95-8 0.2 Yes 53 Spiromesifen 283594-90-1 0.2 Yes 54 Spirotetramat 203313-25-1 0.2 Yes 55 Spiroxamine 118134-30-8 0.4 No 56 Tebuconazole 80443-41-0 0.4 May-be 57 Thiacloprid 111988-49-9 0.2 Yes 58 Thiamethoxam 153719-23-4 0.2 Yes 59 Trifloxystrobin 141517-21-7 0.2 Yes

(24) Further, the above-described exemplary method 100 has been found to effectively produce essentially pesticide-free cannabinoids including, but not limited to, many of the cannabinoids listed in Tables 2 and 3 below.

(25) TABLE-US-00002 TABLE 2 Cannabinoids Common Water Class Substance Abbreviation Soluble? Cannabichromene Cannabichromene CBC No Cannabichromene Cannabichromenic acid CBCA Yes Cannabichromene Cannabichromevarin CBCV No Cannabichromene Cannabichromevarinic acid CBCVA No Cannabichromene Cannabicyclols No Cannabichromene Cannabicyclol CBL No Cannabichromene Cannabicyclolic acid CBLA Yes Cannabichromene Cannabicyclovarin CBLV No Cannabidiols Cannabidiol CBD No Cannabidiols Cannabidiol monomethylether CBDM No Cannabidiols Cannabidiolic acid CBDA No Cannabidiols Cannabidiorcol CBD-C1 No Cannabidiols Cannabidivarin CBDV No Cannabidiols Cannabidivarinic acid CBDVA Yes Cannabielsoins Cannabielsoic acid B CBEA-B No Cannabielsoins Cannabielsoin CBE No Cannabielsoins Cannabielsoin acid A CBEA-A No Cannabigerols Cannabigerol CBG No Cannabigerols Cannabigerol monomethylether CBGM No Cannabigerols Cannabigerolic acid CBGA Yes Cannabigerols Cannabigerolic acid CBGAM Yes monomethylether Cannabigerols Cannabigerovarin CBGV No Cannabigerols Cannabigerovarinic acid CBGVA Yes Cannabinols and Cannabinodiol CBND No cannabinodiols Cannabinols and Cannabinodivarin CBVD No cannabinodiols Cannabinols and Cannabinol CBN No cannabinodiols Cannabinols and Cannabinol methylether CBNM No cannabinodiols Cannabinols and Cannabinol-C2 CBN-C2 No cannabinodiols Cannabinols and Cannabinol-C4 CBN-C4 No cannabinodiols Cannabinols and Cannabinolic acid CBNA Yes cannabinodiols Cannabinols and Cannabiorcool CBN-C1 No cannabinodiols Cannabinols and Cannabivarin CBV No cannabinodiols Cannabitriols 10-Ethoxy-9-hydroxy- No delta-6a-tetrahydrocannabinol Cannabitriols 8,9-Dihydroxy-delta-6a- No tetrahydrocannabinol Cannabitriols Cannabitriol CBT No Cannabitriols Cannabitriolvarin CBTV No Delta-8- Delta-8- Δ8-THC No tetrahydrocannabinols tetrahydrocannabinol Delta-8- Delta-8- Δ8-THCA Yes tetrahydrocannabinols tetrahydrocannabinolic acid Delta-9- Delta-9- THC No tetrahydrocannabinols tetrahydrocannabinol Delta-9- Delta-9- THC-C4 No tetrahydrocannabinols tetrahydrocannabinol-C4 Delta-9- Delta-9- THCA-A Yes tetrahydrocannabinols tetrahydrocannabinolic acid A Delta-9- Delta-9- THCA-B Yes tetrahydrocannabinols tetrahydrocannabinolic acid B Delta-9- Delta-9- THCA-C4 Yes tetrahydrocannabinols tetrahydrocannabinolic acid-C4 Delta-9- Delta-9- THC-C1 No tetrahydrocannabinols tetrahydrocannabiorcol Delta-9- Delta-9- THCA-C1 Yes tetrahydrocannabinols tetrahydrocannabiorcolic acid Delta-9- Delta-9- THCV No tetrahydrocannabinols tetrahydrocannabivarin Delta-9- Delta-9- THCVA Yes tetrahydrocannabinols tetrahydrocannabivarinic acid Miscellaneous 10-Oxo-delta-6a- OTHC No cannabinoids tetrahydrocannabinol Miscellaneous Cannabichromanon CBCF No cannabinoids Miscellaneous Cannabifuran CBF No cannabinoids Miscellaneous Cannabiglendol No cannabinoids Miscellaneous Cannabiripsol CBR No cannabinoids Miscellaneous Cannbicitran CBT No cannabinoids Miscellaneous Dehydrocannabifuran DCBF No cannabinoids Miscellaneous Delta-9-cis- cis-THC No cannabinoids tetrahydrocannabinol Miscellaneous Tryhydroxy-delta-9- triOH-THC No cannabinoids tetrahydrocannabinol

(26) TABLE-US-00003 TABLE 3 Cannabinoids with Carboxylic Acids and Corresponding Decarboxylated Products Cannabigerolic acid CBGA Cannabigerol CBG Δ9-tetrahydrocannabinolic acid THCA Δ9-tetrahydrocannabinol THC Cannabidiolic acid CBDA Cannabidiol CBD Cannabichromenenic acid CBCA Cannabichromene CBC Cannabigerovarinic acid CBGVA Cannabigerivarin CBGV Tetrahydrocanabivarinic acid THCVA Tetrahydrocannabivarin THCV Cannabidivarinic acid CBDVA Cannabidivarin CBDV Cannabichromevarinic acid CBCVA Cannabichromevarin CBCV
II. Plant-Derived Pharmaceuticals

(27) The present invention is also directed to plant-derived pharmaceuticals formed via the herein-described contaminant removal methods. The plant-derived pharmaceuticals include, but are not limited to, the cannabinoids listed in Tables 2 and 3 above.

(28) III. Methods of Using Plant-Derived Pharmaceuticals

(29) The present invention is also directed towards methods of using plant-derived pharmaceuticals formed via the herein-described contaminant removal methods. Methods of using the plant-derived pharmaceuticals formed via the herein-described contaminant removal methods include, but are not limited to, methods of treating a patient with a disease or disorder, wherein the treatment comprises administering an effective amount of one or more of the plant-derived pharmaceuticals to the patient.

(30) In one exemplary embodiment, the method of treated a patient with a disease or disorder comprises administering an effective amount of one or more pesticide-free cannabinoids, such as one or more of the cannabinoids shown in Tables 2 and 3, to the patient. A number of diseases and/or disorders may be treated using Cannabinoids including, but not limited to, (1) anxiety (i.e., to reduce anxiety), (2) inflammation (i.e., to reduce inflammation), (3) pain (i.e., to relief pain), (4) nausea and vomiting caused by chemotherapy (i.e., to reduce nausea and vomiting), (5) cancer (i.e., to kill cancer cells and slow tumor growth), (6) multiple sclerosis (i.e., to relax tight muscles in people with multiple sclerosis), and (7) appetite and weight gain (i.e., to stimulate appetite and improve weight gain in people with cancer and AIDS).

(31) The present invention will be further described in the following additional embodiments, examples, and claims.

Additional Embodiments

(32) Methods of Removing Contaminants From Plant-Derived Pharmaceuticals

(33) 1. A method of removing contaminants from a plant-derived pharmaceutical, said method comprising: reacting one or more contaminants within a plant-derived extract with an alkali metal hydroxide in polar solvent to form one or more contaminant by-products in a reaction mixture; and separating the one or more contaminant by-products from the plant-derived extract so as to obtain a contaminant-reduced, plant-derived extract.
2. The method of embodiment 1, wherein the one or more contaminants comprise one or more pesticides, one or more herbicides, one or more fungicides, or any combination thereof.
3. The method of embodiment 1 or 2, wherein the one or more contaminants comprise one or more hydrolyzable pesticides.
4. The method of any one of embodiments 1 to 3, wherein the alkali metal hydroxide comprises lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, or ionic liquids such as 1-ethyl-3-methylimidazolium hydroxide.
5. The method of any one of embodiments 1 to 4, wherein the alkali metal hydroxide comprises potassium hydroxide.
6. The method of any one of embodiments 1 to 5, wherein the polar solvent comprises methanol, ethanol, n-propanol, isopropanol, butanol, dimethyl sulfoxide, dimethylformamide, or any combination thereof.
7. The method of any one of embodiments 1 to 6, wherein the polar solvent comprises methanol.
8. The method of any one of embodiments 1 to 7, further comprising: forming a polar solvent solution comprising the alkali metal hydroxide in the polar solvent, wherein the alkali metal hydroxide is present in the polar solvent at a concentration of from about 0.125 grams (g) to 0.5 g of alkali metal hydroxide per milliliter (ml) of polar solvent.
9. The method of any one of embodiments 1 to 8, wherein said reacting step comprises: adding the plant-derived extract to the alkali metal hydroxide in the polar solvent to form the reaction mixture; and agitating the reaction mixture with mixing while (i) heating the reaction mixture to boiling for a period of time up to about one hour, (ii) ultrasonically vibrating the reaction mixture for a period of time up to about one hour, or (iii) both (i) and (ii).
10. The method of embodiment 9, wherein said method further comprises, following said agitating step: allowing the reaction mixture to cool down to below about 40° C.
11. The method of any one of embodiments 1 to 10, wherein said reacting step further comprises: following a cooling down step, adding a neutralizing acid to the reaction mixture, wherein the neutralizing acid comprises organic carboxylic acids such as glacial acetic acid, or a dilute mineral acid such as hydrochloric acid, sulfuric acid, nitric acid, and the like.
12. The method of embodiment 11, wherein the neutralizing acid comprises glacial acetic acid.
13. The method of embodiment 11 or 12, wherein the neutralizing acid is added in an amount of from about 6.0 ml to about 18.0 ml.
14. The method of any one of embodiments 11 to 13, wherein the neutralizing acid is added in an amount of about 8.0 ml (e.g., 130 mM of glacial acetic acid).
15. The method of any one of embodiments 1 to 14, wherein said separating step comprises: evaporating the polar solvent from the reaction mixture under reduced pressure so as to result in a polar solvent-free reaction mixture comprising (i) crystalline alkali metal acetate, (ii) neutralizing acid, and (iii) the plant-derived extract.
16. The method of embodiment 15, wherein said separating step further comprises: adding a first alkane to the polar solvent-free reaction mixture so as to form a non-aqueous liquid phase.
17. The method of embodiment 16, wherein from about 30 ml to about 120 ml of water is added to the polar solvent-free reaction mixture.
18. The method of embodiment 16 or 17, wherein about 40 ml of water is added to the polar solvent-free reaction mixture.
19. The method of any one of embodiments 16 to 18, wherein from about 30 ml to about 120 ml of the first alkane is added to the polar solvent-free reaction mixture.
20. The method of any one of embodiments 16 to 19, wherein about 40 ml of the first alkane is added to the polar solvent-free reaction mixture.
21. The method of any one of embodiments 16 to 20, wherein the first alkane is butane, pentane, cyclopentane, hexane, cyclohexane, heptane, octane, isooctane, or any combination thereof.
22. The method of any one of embodiments 16 to 21, wherein the first alkane is heptane.
23. The method of any one of embodiments 16 to 22, further comprising: agitating the aqueous liquid phase and the non-aqueous liquid phase so as to dissolve (1)(i) the crystalline alkali metal acetate, and (ii) the neutralizing acid in the aqueous liquid phase, and (2) the plant-derived extract in the non-aqueous liquid phase.
24. The method of any one of embodiments 16 to 23, further comprising: introducing the aqueous liquid phase and the non-aqueous liquid phase into a separatory funnel so as to form an upper non-aqueous liquid phase and a lower aqueous liquid phase; and separating the lower aqueous liquid phase from the upper non-aqueous liquid phase.
25. The method of embodiment 24, further comprising: passing the upper non-aqueous liquid phase through one or more columns with each column comprising one or more adsorbents; and collecting an effluent exiting the one or more columns.
26. The method of embodiment 25, wherein the one or more adsorbents comprise magnesium silicate (e.g., FLORISIL® adsorbent), activated alumina, magnesium salt of activated alumina, silica, bonded phase silica, polymeric non-ionic reversed phase resins, or any combination thereof.
27. The method of embodiment 25 or 26, wherein the one or more adsorbents comprise silica gel in a first column.
28. The method of any one of embodiments 25 to 27, wherein the one or more adsorbents comprise magnesium silicate (e.g., FLORISIL® adsorbent) in a second column.
29. The method of any one of embodiments 24 to 28, wherein each of the one or more columns comprises from about 25 g to about 60 g of the one or more adsorbents.
30. The method of any one of embodiments 24 to 29, wherein each of the one or more columns comprises about 40 g of the one or more adsorbents.
31. The method of any one of embodiments 24 to 30, further comprising: passing one or more column volumes of a rinse mixture through the one or more columns (e.g., an initial weak solvent (e.g., one or more second alkanes such as heptane) with or without some small percentage (e.g., 1-20 wt %) of a stronger solvent (e.g., methanol, ethanol, isopropanol, n-propanol, ethyl acetate, acetone, dichloromethane, chloroform, toluene, and the like) to reduce collection volume but without eluting any residual undesirable non-Cannabinoid substances); and collecting the effluent exiting the one or more columns.
32. The method of embodiment 31, wherein the one or more column volumes comprises from about 40 ml to about 180 ml of the rinse mixture.
33. The method of embodiment 31 or 32, wherein the one or more column volumes comprises about 120 ml of the rinse mixture.
34. The method of any one of embodiments 31 to 33, wherein the second alkane and the ethyl acetate are present, by volume, at a ratio of 80:20 v/v.
35. The method of any one of embodiments 31 to 34, wherein the second alkane comprises heptane.
36. The method of any one of embodiments 25 to 35, further comprising: evaporating the effluent under reduced pressure so as to (1) remove one or more of: (i) the first alkane, (ii) the weak solvent (e.g., second alkane), and (iii) the stronger solvent (e.g., ethyl acetate), and (2) result in the contaminant-reduced plant-derived extract.
37. The method of any one of embodiments 1 to 36, further comprising: testing the contaminant-reduced plant-derived extract for possible detectable levels of one or more contaminants.
38. The method of any one of embodiments 1 to 37, wherein from about 5 g to about 25 g of the plant-derived extract is reacted with the alkali metal hydroxide in the alcohol.
39. The method of any one of embodiments 1 to 38, wherein about 10 g of the plant-derived extract is reacted with the alkali metal hydroxide in the alcohol.
40. The method of any one of embodiments 1 to 39, wherein the plant-derived extract is a Cannabis-derived extract.
41. The method of any one of embodiments 1 to 40, wherein the contaminant-reduced plant-derived extract comprises one or more cannabinoids.

(34) Contaminant-Reduced Plant-Derived Pharmaceuticals

(35) 42. A contaminant-reduced plant-derived extract formed by the method of any one of embodiments 1 to 41.

(36) Methods of Using Contaminant-Reduced Plant-Derived Pharmaceuticals

(37) 43. A method of using the contaminant-reduced plant-derived extract formed by the method of any one of embodiments 1 to 41, said method comprising: treating a patient suffering from a disease or disorder by administering an effective amount of the contaminant-reduced plant-derived extract to the patient.
44. The method of embodiment 43, wherein the effective amount of the contaminant-reduced plant-derived extract is orally provided to the patient.
45. The method of embodiment 43 or 44, wherein the effective amount of the contaminant-reduced plant-derived extract is intravenously provided to the patient.
46. The method of any one of embodiments 43 to 45, wherein the disease or disorders comprises (1) anxiety (i.e., to reduce anxiety), (2) inflammation (i.e., to reduce inflammation), (3) pain (i.e., to relief pain), (4) nausea and vomiting caused by chemotherapy (i.e., to reduce nausea and vomiting), (5) cancer (i.e., to kill cancer cells and slow tumor growth), (6) multiple sclerosis (i.e., to relax tight muscles in people with multiple sclerosis), (7) appetite and weight gain (i.e., to stimulate appetite and improve weight gain in people with cancer and AIDS), or any combination thereof.

(38) The present invention is further illustrated by the following example, which is not to be construed in any way as imposing limitations upon the scope thereof. On the contrary, it is to be clearly understood that resort may be had to various other embodiments, modifications, and equivalents thereof which, after reading the description herein, may suggest themselves to those skilled in the art without departing from the spirit of the present invention and/or the scope of the appended claims.

Example 1

(39) Methods of removing contaminants from Cannabis-derived extracts were conducted as follows:

(40) 1) Add 5.0 g of KOH (90 mM) pellets to 40 ml of methanol and dissolve;

(41) 2) Add 10 g of Cannabis extract to the KOH/methanol mixture and agitate until the Cannabis extract dissolves;

(42) 3) With agitation, either (i) heat to boiling for 1 hour, or (ii) add ultrasonic vibrations for 1 hour;

(43) 4) Cool down;

(44) 5) Add 8 ml Glacial Acetic Acid (130 mM);

(45) 6) Evaporate methanol under reduced pressure and recover the methanol so as to produce (i) a relatively large amount of white crystalline potassium acetate, (ii) a relatively small amount of liquid glacial acetic acid, and (iii) the cannabinoid oil;

(46) 7) Add 40 ml of water to the mixture of (i) white crystalline potassium acetate, (ii) liquid glacial acetic acid, and (iii) the cannabinoid oil;

(47) 8) Add 40 ml of heptane to the mixture and agitate until the potassium acetate and the glacial acetic acid are dissolved in the aqueous lower layer and the cannabinoid oil in the heptane upper layer;

(48) 9) Use a separatory funnel to recover the upper heptane layer; 10) Pass the recovered upper heptane layer through a column of 40 g of silica gel;

(49) 11) Pass 120 ml of heptane:ethyl acetate mixture (80:20, v/v) through the silica gel column;

(50) 12) Evaporate under reduced pressure the heptane/ethyl acetate from the mixture until only the Cannabis extract is left; and

(51) 13) Test the Cannabis extract for pesticide levels.

(52) For one exemplary lot, eight pesticides within the original Cannabis extract were removed to undetectable levels as shown in Table 4 below.

(53) TABLE-US-00004 TABLE 4 Select Pesticide Content In A Cannabis Extract Prior to and After Processing Using the Method of Example 1 Pesticide Level In Organic Extract Level In Treated Extract Bifenazate 41.0 ppm Not Detectable Bifenthrin 1.04 ppm Not Detectable Boscalid 1.96 ppm Not Detectable Fenpyroximate 2.86 ppm Not Detectable Myclobutanil 0.39 ppm Not Detectable Pyrethrins 5.36 ppm Not Detectable Spiromesifen 11.9 ppm Not Detectable Trifloxystrobin 3.38 ppm Not Detectable

(54) In addition, it should be understood that although the above-described methods of removing contaminants from plant-derived pharmaceuticals, plant-derived pharmaceuticals and methods of using plant-derived pharmaceuticals are described as “comprising” one or more components or steps, the above-described methods of removing contaminants from plant-derived pharmaceuticals, plant-derived pharmaceuticals and methods of using plant-derived pharmaceuticals may “comprise,” “consists of,” or “consist essentially of” the above-described method steps and components of the methods of removing contaminants from plant-derived pharmaceuticals, plant-derived pharmaceuticals and methods of using plant-derived pharmaceuticals. Consequently, where the present invention, or a portion thereof, has been described with an open-ended term such as “comprising,” it should be readily understood that (unless otherwise stated) the description of the present invention, or the portion thereof, should also be interpreted to describe the present invention, or a portion thereof, using the terms “consisting essentially of” or “consisting of” or variations thereof as discussed below.

(55) As used herein, the terms “comprises,” “comprising,” “includes,” “including,” “has,” “having,” “contains”, “containing,” “characterized by” or any other variation thereof, are intended to encompass a non-exclusive inclusion, subject to any limitation explicitly indicated otherwise, of the recited components. For example, a method of removing contaminants from plant-derived pharmaceuticals, plant-derived pharmaceutical, and/or method of using plant-derived pharmaceuticals that “comprises” a list of elements (e.g., components or steps) is not necessarily limited to only those elements (or components or steps), but may include other elements (or components or steps) not expressly listed or inherent to the method of removing contaminants from plant-derived pharmaceuticals, plant-derived pharmaceutical, and/or method of using plant-derived pharmaceuticals.

(56) As used herein, the transitional phrases “consists of” and “consisting of” exclude any element, step, or component not specified. For example, “consists of” or “consisting of” used in a claim would limit the claim to the components, materials or method steps specifically recited in the claim except for impurities ordinarily associated therewith (i.e., impurities within a given component). When the phrase “consists of” or “consisting of” appears in a clause of the body of a claim, rather than immediately following the preamble, the phrase “consists of” or “consisting of” limits only the elements (or components or steps) set forth in that clause; other elements (or components) are not excluded from the claim as a whole.

(57) As used herein, the transitional phrases “consists essentially of” and “consisting essentially of” are used to define a method of removing contaminants from plant-derived pharmaceuticals, plant-derived pharmaceutical, and/or method of using plant-derived pharmaceuticals that includes materials, steps, features, components, or elements, in addition to those literally disclosed, provided that these additional materials, steps, features, components, or elements do not materially affect the basic and novel characteristic(s) of the claimed invention. The term “consisting essentially of” occupies a middle ground between “comprising” and “consisting of”.

(58) Further, it should be understood that the herein-described methods of removing contaminants from plant-derived pharmaceuticals, plant-derived pharmaceuticals, and/or methods of using plant-derived pharmaceuticals may comprise, consist essentially of, or consist of any of the herein-described components, method steps, and/or features, as shown in the figures with or without any feature(s) not shown in the figures. In other words, in some embodiments, the methods of removing contaminants from plant-derived pharmaceuticals, plant-derived pharmaceuticals, and/or methods of using plant-derived pharmaceuticals of the present invention do not have any additional features other than those shown in the figures, and such additional features, not shown in the figures, are specifically excluded from the methods of removing contaminants from plant-derived pharmaceuticals, plant-derived pharmaceuticals, and/or methods of using plant-derived pharmaceuticals. In other embodiments, the methods of removing contaminants from plant-derived pharmaceuticals, plant-derived pharmaceuticals, and/or methods of using plant-derived pharmaceuticals of the present invention do have one or more additional features that are not shown in the figures.

(59) The present invention is described above and further illustrated below by way of claims, which are not to be construed in any way as imposing limitations upon the scope of the invention. On the contrary, it is to be clearly understood that resort may be had to various other embodiments, modifications, and equivalents thereof which, after reading the description herein, may suggest themselves to those skilled in the art without departing from the spirit of the present invention and/or the scope of the appended claims.