EP3962457A1 - Composition cannabinoïde et procédés de fabrication - Google Patents
Composition cannabinoïde et procédés de fabricationInfo
- Publication number
- EP3962457A1 EP3962457A1 EP19927176.8A EP19927176A EP3962457A1 EP 3962457 A1 EP3962457 A1 EP 3962457A1 EP 19927176 A EP19927176 A EP 19927176A EP 3962457 A1 EP3962457 A1 EP 3962457A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- cannabinoid
- composition
- mesoporous silica
- delta
- surfactant
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000003557 cannabinoid Substances 0.000 title claims abstract description 259
- 229930003827 cannabinoid Natural products 0.000 title claims abstract description 259
- 239000000203 mixture Substances 0.000 title claims abstract description 240
- 238000000034 method Methods 0.000 title claims description 44
- 230000008569 process Effects 0.000 title claims description 21
- 238000004519 manufacturing process Methods 0.000 title claims description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 328
- 239000000377 silicon dioxide Substances 0.000 claims abstract description 160
- 239000004094 surface-active agent Substances 0.000 claims abstract description 67
- 239000000843 powder Substances 0.000 claims abstract description 17
- 239000011148 porous material Substances 0.000 claims description 48
- CYQFCXCEBYINGO-IAGOWNOFSA-N delta1-THC Chemical compound C1=C(C)CC[C@H]2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3[C@@H]21 CYQFCXCEBYINGO-IAGOWNOFSA-N 0.000 claims description 42
- 238000009472 formulation Methods 0.000 claims description 27
- 239000003085 diluting agent Substances 0.000 claims description 26
- 239000003814 drug Substances 0.000 claims description 24
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical group [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 21
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 21
- 235000019333 sodium laurylsulphate Nutrition 0.000 claims description 21
- 238000002156 mixing Methods 0.000 claims description 19
- ZLYNXDIDWUWASO-UHFFFAOYSA-N 6,6,9-trimethyl-3-pentyl-8,10-dihydro-7h-benzo[c]chromene-1,9,10-triol Chemical compound CC1(C)OC2=CC(CCCCC)=CC(O)=C2C2=C1CCC(C)(O)C2O ZLYNXDIDWUWASO-UHFFFAOYSA-N 0.000 claims description 18
- 229960004242 dronabinol Drugs 0.000 claims description 17
- 239000002245 particle Substances 0.000 claims description 16
- AAXZFUQLLRMVOG-UHFFFAOYSA-N 2-methyl-2-(4-methylpent-3-enyl)-7-propylchromen-5-ol Chemical compound C1=CC(C)(CCC=C(C)C)OC2=CC(CCC)=CC(O)=C21 AAXZFUQLLRMVOG-UHFFFAOYSA-N 0.000 claims description 13
- 238000011282 treatment Methods 0.000 claims description 13
- VNGQMWZHHNCMLQ-UHFFFAOYSA-N 6-methyl-3-pentyl-9-propan-2-yldibenzofuran-1-ol Chemical compound C1=CC(C(C)C)=C2C3=C(O)C=C(CCCCC)C=C3OC2=C1C VNGQMWZHHNCMLQ-UHFFFAOYSA-N 0.000 claims description 12
- CYQFCXCEBYINGO-UHFFFAOYSA-N THC Natural products C1=C(C)CCC2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3C21 CYQFCXCEBYINGO-UHFFFAOYSA-N 0.000 claims description 12
- QHMBSVQNZZTUGM-UHFFFAOYSA-N Trans-Cannabidiol Natural products OC1=CC(CCCCC)=CC(O)=C1C1C(C(C)=C)CCC(C)=C1 QHMBSVQNZZTUGM-UHFFFAOYSA-N 0.000 claims description 11
- 229950011318 cannabidiol Drugs 0.000 claims description 11
- QHMBSVQNZZTUGM-ZWKOTPCHSA-N cannabidiol Chemical compound OC1=CC(CCCCC)=CC(O)=C1[C@H]1[C@H](C(C)=C)CCC(C)=C1 QHMBSVQNZZTUGM-ZWKOTPCHSA-N 0.000 claims description 11
- ZTGXAWYVTLUPDT-UHFFFAOYSA-N cannabidiol Natural products OC1=CC(CCCCC)=CC(O)=C1C1C(C(C)=C)CC=C(C)C1 ZTGXAWYVTLUPDT-UHFFFAOYSA-N 0.000 claims description 11
- PCXRACLQFPRCBB-ZWKOTPCHSA-N dihydrocannabidiol Natural products OC1=CC(CCCCC)=CC(O)=C1[C@H]1[C@H](C(C)C)CCC(C)=C1 PCXRACLQFPRCBB-ZWKOTPCHSA-N 0.000 claims description 11
- 201000010099 disease Diseases 0.000 claims description 11
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 11
- 238000010438 heat treatment Methods 0.000 claims description 11
- 239000000419 plant extract Substances 0.000 claims description 11
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 10
- UCONUSSAWGCZMV-HZPDHXFCSA-N Delta(9)-tetrahydrocannabinolic acid Chemical compound C([C@H]1C(C)(C)O2)CC(C)=C[C@H]1C1=C2C=C(CCCCC)C(C(O)=O)=C1O UCONUSSAWGCZMV-HZPDHXFCSA-N 0.000 claims description 9
- 208000008238 Muscle Spasticity Diseases 0.000 claims description 9
- 239000003945 anionic surfactant Substances 0.000 claims description 9
- 206010015037 epilepsy Diseases 0.000 claims description 9
- 208000018198 spasticity Diseases 0.000 claims description 9
- UCONUSSAWGCZMV-UHFFFAOYSA-N Tetrahydro-cannabinol-carbonsaeure Natural products O1C(C)(C)C2CCC(C)=CC2C2=C1C=C(CCCCC)C(C(O)=O)=C2O UCONUSSAWGCZMV-UHFFFAOYSA-N 0.000 claims description 8
- 235000013305 food Nutrition 0.000 claims description 8
- 150000003505 terpenes Chemical class 0.000 claims description 8
- QHCQSGYWGBDSIY-HZPDHXFCSA-N tetrahydrocannabinol-c4 Chemical compound C1=C(C)CC[C@H]2C(C)(C)OC3=CC(CCCC)=CC(O)=C3[C@@H]21 QHCQSGYWGBDSIY-HZPDHXFCSA-N 0.000 claims description 8
- ZROLHBHDLIHEMS-UHFFFAOYSA-N Delta9 tetrahydrocannabivarin Natural products C1=C(C)CCC2C(C)(C)OC3=CC(CCC)=CC(O)=C3C21 ZROLHBHDLIHEMS-UHFFFAOYSA-N 0.000 claims description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 7
- OQCOBNKTUMOOHJ-RSGMMRJUSA-N (5as,6s,9r,9ar)-1,6-dihydroxy-6-methyl-3-pentyl-9-prop-1-en-2-yl-7,8,9,9a-tetrahydro-5ah-dibenzofuran-2-carboxylic acid Chemical compound C1=2C(O)=C(C(O)=O)C(CCCCC)=CC=2O[C@H]2[C@@H]1[C@H](C(C)=C)CC[C@]2(C)O OQCOBNKTUMOOHJ-RSGMMRJUSA-N 0.000 claims description 6
- HJMCQDCJBFTRPX-RSGMMRJUSA-N (5as,6s,9r,9ar)-1,6-dihydroxy-6-methyl-3-pentyl-9-prop-1-en-2-yl-7,8,9,9a-tetrahydro-5ah-dibenzofuran-4-carboxylic acid Chemical compound [C@H]1([C@@H](CC[C@@]2(O)C)C(C)=C)[C@@H]2Oc2c(C(O)=O)c(CCCCC)cc(O)c21 HJMCQDCJBFTRPX-RSGMMRJUSA-N 0.000 claims description 6
- RBEAVAMWZAJWOI-MTOHEIAKSA-N (5as,6s,9r,9ar)-6-methyl-3-pentyl-9-prop-1-en-2-yl-7,8,9,9a-tetrahydro-5ah-dibenzofuran-1,6-diol Chemical compound C1=2C(O)=CC(CCCCC)=CC=2O[C@H]2[C@@H]1[C@H](C(C)=C)CC[C@]2(C)O RBEAVAMWZAJWOI-MTOHEIAKSA-N 0.000 claims description 6
- IQSYWEWTWDEVNO-ZIAGYGMSSA-N (6ar,10ar)-1-hydroxy-6,6,9-trimethyl-3-propyl-6a,7,8,10a-tetrahydrobenzo[c]chromene-2-carboxylic acid Chemical compound C([C@H]1C(C)(C)O2)CC(C)=C[C@H]1C1=C2C=C(CCC)C(C(O)=O)=C1O IQSYWEWTWDEVNO-ZIAGYGMSSA-N 0.000 claims description 6
- ZROLHBHDLIHEMS-HUUCEWRRSA-N (6ar,10ar)-6,6,9-trimethyl-3-propyl-6a,7,8,10a-tetrahydrobenzo[c]chromen-1-ol Chemical compound C1=C(C)CC[C@H]2C(C)(C)OC3=CC(CCC)=CC(O)=C3[C@@H]21 ZROLHBHDLIHEMS-HUUCEWRRSA-N 0.000 claims description 6
- TZGCTXUTNDNTTE-DYZHCLJRSA-N (6ar,9s,10s,10ar)-6,6,9-trimethyl-3-pentyl-7,8,10,10a-tetrahydro-6ah-benzo[c]chromene-1,9,10-triol Chemical compound O[C@@H]1[C@@](C)(O)CC[C@H]2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3[C@@H]21 TZGCTXUTNDNTTE-DYZHCLJRSA-N 0.000 claims description 6
- CYQFCXCEBYINGO-SJORKVTESA-N (6as,10ar)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydrobenzo[c]chromen-1-ol Chemical compound C1=C(C)CC[C@@H]2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3[C@@H]21 CYQFCXCEBYINGO-SJORKVTESA-N 0.000 claims description 6
- UEFGHYCIOXYTOG-UHFFFAOYSA-N 1-hydroxy-6,6,9-trimethyl-3-pentyl-8,9-dihydro-7h-benzo[c]chromen-10-one Chemical compound CC1(C)OC2=CC(CCCCC)=CC(O)=C2C2=C1CCC(C)C2=O UEFGHYCIOXYTOG-UHFFFAOYSA-N 0.000 claims description 6
- YEDIZIGYIMTZKP-UHFFFAOYSA-N 1-methoxy-6,6,9-trimethyl-3-pentylbenzo[c]chromene Chemical compound C1=C(C)C=C2C3=C(OC)C=C(CCCCC)C=C3OC(C)(C)C2=C1 YEDIZIGYIMTZKP-UHFFFAOYSA-N 0.000 claims description 6
- CZXWOKHVLNYAHI-LSDHHAIUSA-N 2,4-dihydroxy-3-[(1r,6r)-3-methyl-6-prop-1-en-2-ylcyclohex-2-en-1-yl]-6-propylbenzoic acid Chemical compound OC1=C(C(O)=O)C(CCC)=CC(O)=C1[C@H]1[C@H](C(C)=C)CCC(C)=C1 CZXWOKHVLNYAHI-LSDHHAIUSA-N 0.000 claims description 6
- TWKHUZXSTKISQC-UHFFFAOYSA-N 2-(5-methyl-2-prop-1-en-2-ylphenyl)-5-pentylbenzene-1,3-diol Chemical compound OC1=CC(CCCCC)=CC(O)=C1C1=CC(C)=CC=C1C(C)=C TWKHUZXSTKISQC-UHFFFAOYSA-N 0.000 claims description 6
- COURSARJQZMTEZ-UHFFFAOYSA-N 2-(5-methyl-2-prop-1-en-2-ylphenyl)-5-propylbenzene-1,3-diol Chemical compound OC1=CC(CCC)=CC(O)=C1C1=CC(C)=CC=C1C(C)=C COURSARJQZMTEZ-UHFFFAOYSA-N 0.000 claims description 6
- XWIWWMIPMYDFOV-UHFFFAOYSA-N 3,6,6,9-tetramethylbenzo[c]chromen-1-ol Chemical compound C1=C(C)C=C2OC(C)(C)C3=CC=C(C)C=C3C2=C1O XWIWWMIPMYDFOV-UHFFFAOYSA-N 0.000 claims description 6
- FAVCTJGKHFHFHJ-GXDHUFHOSA-N 3-[(2e)-3,7-dimethylocta-2,6-dienyl]-2,4-dihydroxy-6-propylbenzoic acid Chemical compound CCCC1=CC(O)=C(C\C=C(/C)CCC=C(C)C)C(O)=C1C(O)=O FAVCTJGKHFHFHJ-GXDHUFHOSA-N 0.000 claims description 6
- VAFRUJRAAHLCFZ-GHRIWEEISA-N 3-[(2e)-3,7-dimethylocta-2,6-dienyl]-2-hydroxy-4-methoxy-6-pentylbenzoic acid Chemical compound CCCCCC1=CC(OC)=C(C\C=C(/C)CCC=C(C)C)C(O)=C1C(O)=O VAFRUJRAAHLCFZ-GHRIWEEISA-N 0.000 claims description 6
- GGVVJZIANMUEJO-UHFFFAOYSA-N 3-butyl-6,6,9-trimethylbenzo[c]chromen-1-ol Chemical compound C1=C(C)C=C2C3=C(O)C=C(CCCC)C=C3OC(C)(C)C2=C1 GGVVJZIANMUEJO-UHFFFAOYSA-N 0.000 claims description 6
- QUYCDNSZSMEFBQ-UHFFFAOYSA-N 3-ethyl-6,6,9-trimethylbenzo[c]chromen-1-ol Chemical compound C1=C(C)C=C2C3=C(O)C=C(CC)C=C3OC(C)(C)C2=C1 QUYCDNSZSMEFBQ-UHFFFAOYSA-N 0.000 claims description 6
- IPGGELGANIXRSX-RBUKOAKNSA-N 3-methoxy-2-[(1r,6r)-3-methyl-6-prop-1-en-2-ylcyclohex-2-en-1-yl]-5-pentylphenol Chemical compound COC1=CC(CCCCC)=CC(O)=C1[C@H]1[C@H](C(C)=C)CCC(C)=C1 IPGGELGANIXRSX-RBUKOAKNSA-N 0.000 claims description 6
- NAGBBYZBIQVPIQ-UHFFFAOYSA-N 6-methyl-3-pentyl-9-prop-1-en-2-yldibenzofuran-1-ol Chemical compound C1=CC(C(C)=C)=C2C3=C(O)C=C(CCCCC)C=C3OC2=C1C NAGBBYZBIQVPIQ-UHFFFAOYSA-N 0.000 claims description 6
- IPGGELGANIXRSX-UHFFFAOYSA-N Cannabidiol monomethyl ether Natural products COC1=CC(CCCCC)=CC(O)=C1C1C(C(C)=C)CCC(C)=C1 IPGGELGANIXRSX-UHFFFAOYSA-N 0.000 claims description 6
- KASVLYINZPAMNS-UHFFFAOYSA-N Cannabigerol monomethylether Natural products CCCCCC1=CC(O)=C(CC=C(C)CCC=C(C)C)C(OC)=C1 KASVLYINZPAMNS-UHFFFAOYSA-N 0.000 claims description 6
- XXGMIHXASFDFSM-UHFFFAOYSA-N Delta9-tetrahydrocannabinol Natural products CCCCCc1cc2OC(C)(C)C3CCC(=CC3c2c(O)c1O)C XXGMIHXASFDFSM-UHFFFAOYSA-N 0.000 claims description 6
- 208000010412 Glaucoma Diseases 0.000 claims description 6
- NHZMSIOYBVIOAF-UHFFFAOYSA-N cannabichromanone A Natural products O=C1C(CCC(C)=O)C(C)(C)OC2=CC(CCCCC)=CC(O)=C21 NHZMSIOYBVIOAF-UHFFFAOYSA-N 0.000 claims description 6
- 239000002537 cosmetic Substances 0.000 claims description 6
- HCAWPGARWVBULJ-IAGOWNOFSA-N delta8-THC Chemical compound C1C(C)=CC[C@H]2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3[C@@H]21 HCAWPGARWVBULJ-IAGOWNOFSA-N 0.000 claims description 6
- 208000030507 AIDS Diseases 0.000 claims description 5
- 208000019901 Anxiety disease Diseases 0.000 claims description 5
- SBPMGFIOIRMBJJ-UHFFFAOYSA-N Delta7-cis-iso-tetrahydrocannabivarin Natural products C1C2(C)CCC(C(C)=C)C1C1=C(O)C=C(CCC)C=C1O2 SBPMGFIOIRMBJJ-UHFFFAOYSA-N 0.000 claims description 5
- 206010028813 Nausea Diseases 0.000 claims description 5
- 206010028980 Neoplasm Diseases 0.000 claims description 5
- 208000002193 Pain Diseases 0.000 claims description 5
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 5
- 201000011510 cancer Diseases 0.000 claims description 5
- VAFRUJRAAHLCFZ-UHFFFAOYSA-N cannabigerolic acid monomethyl ether Natural products CCCCCC1=CC(OC)=C(CC=C(C)CCC=C(C)C)C(O)=C1C(O)=O VAFRUJRAAHLCFZ-UHFFFAOYSA-N 0.000 claims description 5
- 235000019359 magnesium stearate Nutrition 0.000 claims description 5
- 201000006417 multiple sclerosis Diseases 0.000 claims description 5
- 230000008693 nausea Effects 0.000 claims description 5
- 208000028173 post-traumatic stress disease Diseases 0.000 claims description 5
- 235000007586 terpenes Nutrition 0.000 claims description 5
- SBPMGFIOIRMBJJ-CTHAPGQVSA-N δ-7-cis-isotetrahydrocannabivarin Chemical compound C1[C@@]2(C)CC[C@@H](C(C)=C)C1C1=C(O)C=C(CCC)C=C1O2 SBPMGFIOIRMBJJ-CTHAPGQVSA-N 0.000 claims description 5
- 206010006895 Cachexia Diseases 0.000 claims description 4
- UVOLYTDXHDXWJU-UHFFFAOYSA-N Cannabichromene Chemical compound C1=CC(C)(CCC=C(C)C)OC2=CC(CCCCC)=CC(O)=C21 UVOLYTDXHDXWJU-UHFFFAOYSA-N 0.000 claims description 4
- 206010012289 Dementia Diseases 0.000 claims description 4
- 206010012335 Dependence Diseases 0.000 claims description 4
- 208000014094 Dystonic disease Diseases 0.000 claims description 4
- 201000004311 Gilles de la Tourette syndrome Diseases 0.000 claims description 4
- 208000023105 Huntington disease Diseases 0.000 claims description 4
- 208000018737 Parkinson disease Diseases 0.000 claims description 4
- 208000000323 Tourette Syndrome Diseases 0.000 claims description 4
- 208000016620 Tourette disease Diseases 0.000 claims description 4
- 208000030886 Traumatic Brain injury Diseases 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 claims description 4
- 208000022531 anorexia Diseases 0.000 claims description 4
- 230000036506 anxiety Effects 0.000 claims description 4
- 235000013361 beverage Nutrition 0.000 claims description 4
- QXACEHWTBCFNSA-SFQUDFHCSA-N cannabigerol Chemical compound CCCCCC1=CC(O)=C(C\C=C(/C)CCC=C(C)C)C(O)=C1 QXACEHWTBCFNSA-SFQUDFHCSA-N 0.000 claims description 4
- 125000002091 cationic group Chemical group 0.000 claims description 4
- 239000003093 cationic surfactant Substances 0.000 claims description 4
- 206010061428 decreased appetite Diseases 0.000 claims description 4
- 230000003412 degenerative effect Effects 0.000 claims description 4
- 208000010118 dystonia Diseases 0.000 claims description 4
- 230000009969 flowable effect Effects 0.000 claims description 4
- 208000002551 irritable bowel syndrome Diseases 0.000 claims description 4
- 230000000926 neurological effect Effects 0.000 claims description 4
- 201000000980 schizophrenia Diseases 0.000 claims description 4
- 208000019116 sleep disease Diseases 0.000 claims description 4
- 238000003756 stirring Methods 0.000 claims description 4
- 230000009529 traumatic brain injury Effects 0.000 claims description 4
- 235000015112 vegetable and seed oil Nutrition 0.000 claims description 4
- 239000008158 vegetable oil Substances 0.000 claims description 4
- 239000003981 vehicle Substances 0.000 claims description 4
- 208000016261 weight loss Diseases 0.000 claims description 4
- 230000004580 weight loss Effects 0.000 claims description 4
- 239000002888 zwitterionic surfactant Substances 0.000 claims description 4
- WIDIPARNVYRVNW-CHWSQXEVSA-N (6ar,10ar)-3,6,6,9-tetramethyl-6a,7,8,10a-tetrahydrobenzo[c]chromen-1-ol Chemical compound CC1=CC(O)=C2[C@@H]3C=C(C)CC[C@H]3C(C)(C)OC2=C1 WIDIPARNVYRVNW-CHWSQXEVSA-N 0.000 claims description 3
- TZFPIQSSTVIJTQ-HUUCEWRRSA-N (6ar,10ar)-3-butyl-1-hydroxy-6,6,9-trimethyl-6a,7,8,10a-tetrahydrobenzo[c]chromene-2-carboxylic acid Chemical compound C([C@H]1C(C)(C)O2)CC(C)=C[C@H]1C1=C2C=C(CCCC)C(C(O)=O)=C1O TZFPIQSSTVIJTQ-HUUCEWRRSA-N 0.000 claims description 3
- IXJXRDCCQRZSDV-GCKMJXCFSA-N (6ar,9r,10as)-6,6,9-trimethyl-3-pentyl-6a,7,8,9,10,10a-hexahydro-6h-1,9-epoxybenzo[c]chromene Chemical compound C1C[C@@H](C(O2)(C)C)[C@@H]3C[C@]1(C)OC1=C3C2=CC(CCCCC)=C1 IXJXRDCCQRZSDV-GCKMJXCFSA-N 0.000 claims description 3
- KXKOBIRSQLNUPS-UHFFFAOYSA-N 1-hydroxy-6,6,9-trimethyl-3-pentylbenzo[c]chromene-2-carboxylic acid Chemical compound O1C(C)(C)C2=CC=C(C)C=C2C2=C1C=C(CCCCC)C(C(O)=O)=C2O KXKOBIRSQLNUPS-UHFFFAOYSA-N 0.000 claims description 3
- JSCNOJMNXGDROK-UHFFFAOYSA-N 2-[(3,4-dichlorophenyl)methylamino]-3,7-dihydropurin-6-one Chemical compound C1=C(Cl)C(Cl)=CC=C1CNC(N1)=NC(=O)C2=C1N=CN2 JSCNOJMNXGDROK-UHFFFAOYSA-N 0.000 claims description 3
- WBRXESQKGXYDOL-DLBZAZTESA-N 5-butyl-2-[(1r,6r)-3-methyl-6-prop-1-en-2-ylcyclohex-2-en-1-yl]benzene-1,3-diol Chemical compound OC1=CC(CCCC)=CC(O)=C1[C@H]1[C@H](C(C)=C)CCC(C)=C1 WBRXESQKGXYDOL-DLBZAZTESA-N 0.000 claims description 3
- GKVOVXWEBSQJPA-UONOGXRCSA-N 5-methyl-2-[(1r,6r)-3-methyl-6-prop-1-en-2-ylcyclohex-2-en-1-yl]benzene-1,3-diol Chemical compound CC(=C)[C@@H]1CCC(C)=C[C@H]1C1=C(O)C=C(C)C=C1O GKVOVXWEBSQJPA-UONOGXRCSA-N 0.000 claims description 3
- JVOHLEIRDMVLHS-UHFFFAOYSA-N Cannabicycloic Acid Natural products C1=2C(O)=C(C(O)=O)C(CCCCC)=CC=2OC2(C)CCC3C(C)(C)C1C23 JVOHLEIRDMVLHS-UHFFFAOYSA-N 0.000 claims description 3
- REOZWEGFPHTFEI-JKSUJKDBSA-N Cannabidivarin Chemical compound OC1=CC(CCC)=CC(O)=C1[C@H]1[C@H](C(C)=C)CCC(C)=C1 REOZWEGFPHTFEI-JKSUJKDBSA-N 0.000 claims description 3
- VBGLYOIFKLUMQG-UHFFFAOYSA-N Cannabinol Chemical compound C1=C(C)C=C2C3=C(O)C=C(CCCCC)C=C3OC(C)(C)C2=C1 VBGLYOIFKLUMQG-UHFFFAOYSA-N 0.000 claims description 3
- YOVRGSHRZRJTLZ-UHFFFAOYSA-N Delta9-THCA Natural products C1=C(C(O)=O)CCC2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3C21 YOVRGSHRZRJTLZ-UHFFFAOYSA-N 0.000 claims description 3
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 3
- IGHTZQUIFGUJTG-QSMXQIJUSA-N O1C2=CC(CCCCC)=CC(O)=C2[C@H]2C(C)(C)[C@@H]3[C@H]2[C@@]1(C)CC3 Chemical compound O1C2=CC(CCCCC)=CC(O)=C2[C@H]2C(C)(C)[C@@H]3[C@H]2[C@@]1(C)CC3 IGHTZQUIFGUJTG-QSMXQIJUSA-N 0.000 claims description 3
- IQSYWEWTWDEVNO-UHFFFAOYSA-N THCVA Natural products O1C(C)(C)C2CCC(C)=CC2C2=C1C=C(CCC)C(C(O)=O)=C2O IQSYWEWTWDEVNO-UHFFFAOYSA-N 0.000 claims description 3
- 125000000129 anionic group Chemical group 0.000 claims description 3
- HRHJHXJQMNWQTF-UHFFFAOYSA-N cannabichromenic acid Chemical compound O1C(C)(CCC=C(C)C)C=CC2=C1C=C(CCCCC)C(C(O)=O)=C2O HRHJHXJQMNWQTF-UHFFFAOYSA-N 0.000 claims description 3
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- RTVVXRKGQRRXFJ-UHFFFAOYSA-N sodium;2-sulfobutanedioic acid Chemical compound [Na].OC(=O)CC(C(O)=O)S(O)(=O)=O RTVVXRKGQRRXFJ-UHFFFAOYSA-N 0.000 description 1
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- 235000011069 sorbitan monooleate Nutrition 0.000 description 1
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- 235000014347 soups Nutrition 0.000 description 1
- 239000008347 soybean phospholipid Substances 0.000 description 1
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- SFVFIFLLYFPGHH-UHFFFAOYSA-M stearalkonium chloride Chemical compound [Cl-].CCCCCCCCCCCCCCCCCC[N+](C)(C)CC1=CC=CC=C1 SFVFIFLLYFPGHH-UHFFFAOYSA-M 0.000 description 1
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- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid group Chemical class S(O)(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
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- MDKGKXOCJGEUJW-UHFFFAOYSA-N suprofen Chemical compound C1=CC(C(C(O)=O)C)=CC=C1C(=O)C1=CC=CS1 MDKGKXOCJGEUJW-UHFFFAOYSA-N 0.000 description 1
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- WBWWGRHZICKQGZ-GIHLXUJPSA-N taurocholic acid Chemical compound C([C@@H]1C[C@H]2O)[C@@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@@H]([C@@H](CCC(=O)NCCS(O)(=O)=O)C)[C@@]2(C)[C@H](O)C1 WBWWGRHZICKQGZ-GIHLXUJPSA-N 0.000 description 1
- 229960005333 tetrabenazine Drugs 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- 229960002372 tetracaine Drugs 0.000 description 1
- GKCBAIGFKIBETG-UHFFFAOYSA-N tetracaine Chemical compound CCCCNC1=CC=C(C(=O)OCCN(C)C)C=C1 GKCBAIGFKIBETG-UHFFFAOYSA-N 0.000 description 1
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- YUKARLAABCGMCN-PKLMIRHRSA-N tiagabine hydrochloride Chemical compound Cl.C1=CSC(C(=CCCN2C[C@@H](CCC2)C(O)=O)C2=C(C=CS2)C)=C1C YUKARLAABCGMCN-PKLMIRHRSA-N 0.000 description 1
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- XFYDIVBRZNQMJC-UHFFFAOYSA-N tizanidine Chemical compound ClC=1C=CC2=NSN=C2C=1NC1=NCCN1 XFYDIVBRZNQMJC-UHFFFAOYSA-N 0.000 description 1
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- XJPBRODHZKDRCB-UHFFFAOYSA-N trans-alpha-ocimene Natural products CC(=C)CCC=C(C)C=C XJPBRODHZKDRCB-UHFFFAOYSA-N 0.000 description 1
- 125000005208 trialkylammonium group Chemical group 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 229940029614 triethanolamine stearate Drugs 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- FAGMGMRSURYROS-UHFFFAOYSA-M trihexadecyl(methyl)azanium;chloride Chemical compound [Cl-].CCCCCCCCCCCCCCCC[N+](C)(CCCCCCCCCCCCCCCC)CCCCCCCCCCCCCCCC FAGMGMRSURYROS-UHFFFAOYSA-M 0.000 description 1
- CBEQULMOCCWAQT-WOJGMQOQSA-N triprolidine Chemical compound C1=CC(C)=CC=C1C(\C=1N=CC=CC=1)=C/CN1CCCC1 CBEQULMOCCWAQT-WOJGMQOQSA-N 0.000 description 1
- 229960001128 triprolidine Drugs 0.000 description 1
- 229960004418 trolamine Drugs 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- MSRILKIQRXUYCT-UHFFFAOYSA-M valproate semisodium Chemical compound [Na+].CCCC(C(O)=O)CCC.CCCC(C([O-])=O)CCC MSRILKIQRXUYCT-UHFFFAOYSA-M 0.000 description 1
- 229960000604 valproic acid Drugs 0.000 description 1
- 239000012178 vegetable wax Substances 0.000 description 1
- PJDFLNIOAUIZSL-UHFFFAOYSA-N vigabatrin Chemical compound C=CC(N)CCC(O)=O PJDFLNIOAUIZSL-UHFFFAOYSA-N 0.000 description 1
- 229960005318 vigabatrin Drugs 0.000 description 1
- 239000011719 vitamin A Substances 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
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- 229940045997 vitamin a Drugs 0.000 description 1
- 229940063674 voltaren Drugs 0.000 description 1
- 235000020234 walnut Nutrition 0.000 description 1
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- 238000005303 weighing Methods 0.000 description 1
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- UBQNRHZMVUUOMG-UHFFFAOYSA-N zonisamide Chemical compound C1=CC=C2C(CS(=O)(=O)N)=NOC2=C1 UBQNRHZMVUUOMG-UHFFFAOYSA-N 0.000 description 1
Classifications
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Definitions
- compositions comprising a cannabinoid or a cannabinoid mixture adsorbed onto at least one mesoporous silica wherein the cannabinoid mixture comprises a cannabinoid and a surfactant.
- the composition is in the form of a free flowing powder.
- Cannabinoids are compounds derived from Cannabis sativa, an annual plant in the Cannabaceae family. The plant contains over 100 cannabinoids.
- the most active naturally occurring cannabinoid is tetrahydrocannabinol (THC), which is used for the treatment of a wide range of medical conditions, including glaucoma, AIDS wasting, neuropathic pain, treatment of spasticity associated with multiple sclerosis, fibromyalgia and chemotherapy- induced nausea.
- THC has been reported to exhibit a therapeutic effect in the treatment of allergies, inflammation, infection, epilepsy, depression, migraine, bipolar disorders, anxiety disorder, and drug dependency and withdrawal syndromes.
- THC is particularly effective as an anti-emetic drug and is administered to curb emesis, a common side effect accompanying the use of opioid analgesics and anaesthetics, highly active anti retroviral therapy and cancer chemotherapy.
- cannabinoids are poorly absorbed systemically from oral dosage forms in the aqueous environment of the gastrointestinal tract, and simple oral formulations of cannabinoids, therefore, tend to exhibit low bioavailability.
- cannabinoids such as high lipophilicity, low aqueous solubility, high viscosity, and sensitivity to light and oxygen, present unique product formulation challenges.
- these materials can be solids or viscous liquids, with the resinous or crystalline behavior depending on the particular cannabinoid, its purity, and extraction and isolation methods. Oily, viscous liquids can be particularly troublesome to formulate, process, and handle.
- the primary solubility-enhancing technologies currently applied in the cannabis industry are self nano-emulsifying drug delivery technologies (SNEDDS), cyclodextrins, and liposomes.
- SNEDDS self nano-emulsifying drug delivery technologies
- cyclodextrins cyclodextrins
- liposomes suffer from the disadvantage that novel or high amount of excipients are needed for solubilization and stabilization of a cannabinoid.
- compositions that exists as a free-flowing powder at room temperature.
- the compositions may improve ease of processing and flexibility for further formulation and process development.
- a further advantage of the composition is that they may increase the aqueous dissolution rate of the cannabinoid.
- the cannabinoid compositions may also enable the dissolution rate of the cannabinoid to be controlled by varying the amount or proportion of one or more of the constituents in the composition.
- a powder composition comprising a cannabinoid or a cannabinoid mixture adsorbed onto at least one mesoporous silica wherein the cannabinoid mixture comprises a cannabinoid and a surfactant.
- the cannabinoid may be selected from the group consisting of a plant extract, cannabigerolic acid (CBGA); cannabigerolic acid monomethylether (CBGAM), cannabigerol (CBG), cannabigerol monomethylether (CBGM), cannabigerovarinic acid (CBGVA), cannabichromevarin (CBCV), cannabichromenic acid (CBCA) cannabichromene (CBC), cannabidiolic acid (CBDA), cannabidiol (CBD), cannabidiol monomethyl ether (CBDM), cannabidiol-C4 (CBD-D4), cannabidivarinic acid (CBDVA), cannabidivarin (CBDV), cannabidiorcol (CBD-D1), delta-9-tetrahydrocannabinolic acid A (THCA-A), delta-9- tetrahydrocannabinolic acid B (THCA-B),
- the surfactant may be an anionic, cationic, or zwitterionic surfactant.
- the surfactant is an anionic surfactant.
- the anionic surfactant may be sodium lauryl sulfate.
- the concentration of the surfactant in the composition is from about 0.1 % to about 35% (w/w).
- composition may further comprise a terpene or terpenoid.
- the cannabinoid or cannabinoid mixture may comprise a diluent.
- the ratio of diluent:cannabinoid may be about 50:1 to about 1 :50.
- the diluent may be a plant-based oil such as a vegetable oil.
- the mesoporous silica may be ordered mesoporous silica or disordered
- the mesoporous silica has an average pore volume of about 0.50 cm 3 /g to about 10 cm 3 /g.
- the mesoporous silica may have an average pore size of about 2nm to about 50nm.
- the mesoporous silica may be a mesoporous silica particle.
- the mesoporous silica particles have an average particle size diameter of between about 2 pm to at least about 250 pm, for example the average diameter may be about 2 pm, about 10 pm, about 25 pm, about 50 pm, about 75 pm, about 100 pm, about 125 pm, about 150 pm, about 175 pm, about 200 pm, about 225 pm, or at least about 250 pm.
- the ratio of surfactant: mesoporous silica may be from about 1 :5 to about 1 :50. In one embodiment the ratio of surfactant: mesoporous silica may be from about 1 :25 to about 1 :35, for example about 1 :29.
- the composition is a flowable powder.
- the composition comprises a blend of two or more mesoporous silica.
- a formulation comprising an effective amount of the composition of the first aspect and at least one carrier, diluent or excipient.
- the excipient may be one or more of microcrystalline cellulose, croscarmellose sodium, and magnesium stearate.
- the formulation is a pharmaceutically acceptable formulation.
- step b) further comprises mixing the cannabinoid with the surfactant wherein the cannabinoid and the surfactant form a cannabinoid mixture that adsorbs to the mesoporous silica.
- the cannabinoid or cannabinoid mixture is heated to a temperature that increases fluidity or decreases viscosity.
- the cannabinoid or cannabinoid mixture may be heated to a temperature up to about 100°C.
- the cannabinoid is crystalline at room temperature, it is heated above its melting temperature. For example the cannabinoid may be heated to about 20°C above its melting temperature.
- the cannabinoid is resinous at room temperature, it is heated above its glass transition temperature. For example the cannabinoid may be heated to about 20°C above its glass transition temperature.
- the process may further comprise the step of stirring the cannabinoid or
- a food, beverage or cosmetic product comprising the composition of the first aspect.
- an eighth aspect there is provided a method of treatment of a disease or condition responsive to a cannabinoid, the method comprising administering to the subject an effective amount of a composition of the first aspect or a formulation of the second aspect.
- composition of the first aspect for the manufacture of a medicament for treatment of a disease or condition responsive to a cannabinoid.
- composition of the first aspect for use in treatment of a disease or condition responsive to a cannabinoid.
- the disease or condition may be selected from the group comprising pain, spasticity associated with multiple sclerosis, nausea, posttraumatic stress disorder, cancer, epilepsy, cachexia, glaucoma, HIV/AIDS, degenerative neurological conditions, anorexia and weight loss associated with HIV, irritable bowel syndrome, epilepsy, spasticity, Tourette syndrome, amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease, dystonia, dementia, glaucoma, traumatic brain injury, addiction, anxiety, depression, sleep disorders, posttraumatic stress disorder, and schizophrenia.
- 'a' and 'an' are used to refer to one or more than one (i.e. , at least one) of the grammatical object of the article.
- 'an element' means one element, or more than one element.
- the term 'about' means that reference to a figure or value is not to be taken as an absolute figure or value, but includes margins of variation above or below the figure or value in line with what a skilled person would understand according to the art, including within typical margins of error or instrument limitation.
- use of the term 'about' is understood to refer to a range or approximation that a person or skilled in the art would consider to be equivalent to a recited value in the context of achieving the same function or result.
- the term 'effective amount' refers to an amount of a cannabinoid sufficient to produce a desired therapeutic, pharmacological, or physiological effect in the subject being treated.
- the term is intended to qualify the amount of the cannabinoid that will achieve the goal of improvement in disease severity and/or the frequency of incidence over treatment of each agent by itself while preferably avoiding or minimizing adverse side effects.
- Those skilled in the art can determine an effective dose using information and routine methods known in the art.
- adsorption may comprise the cannabinoid mixture being adsorbed into the volume or bulk of the
- adsorption of the cannabinoid mixture to the surface of the mesoporous silica may be by way of intermolecular forces between the cannabinoid mixture and the mesoporous silica.
- a 'carrier, diluent or excipient' includes, but is not limited to, any medium comprising a suitable water soluble organic carrier, conventional solvents, oil, hydrophobic diluent, dispersion media, fillers, solid carriers, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents.
- suitable water-soluble organic carriers include, but are not limited to, saline, dextrose, corn oil, dimethylsulfoxide, and gelatin or
- hydroxypropylmethylcellulose capsules Other conventional additives include lactose, mannitol, corn starch, potato starch, binders such as microcrystalline cellulose, cellulose derivatives such as hydroxypropylmethylcellulose, acacia, gelatins, disintegrators such as sodium carboxymethylcellulose, and lubricants such as talc or magnesium stearate.
- 'Subject' includes any human or non-human mammal.
- the compounds of the present invention may also be useful for veterinary treatment of mammals, including companion animals and farm animals, such as, but not limited to dogs, cats, horses, cows, sheep, and pigs.
- the subject is a human.
- the term 'administering' and variations of that term including 'administer' and 'administration' includes contacting, applying, delivering or providing a compound or composition of the invention to a subject by any appropriate means.
- compositions disclosed herein comprise a mixture of a cannabinoid (either purified or as part of a plant extract) and a surfactant which is adsorbed onto a mesoporous silica.
- compositions disclosed herein comprise a cannabinoid (either purified or as part of a plant extract) which is adsorbed onto a mesoporous silica.
- the technology described herein can provide any one or more of a number of advantages.
- the technology is capable of achieving a higher cannabinoid load compared to other solubility enhancing technologies, due to the high specific surface area ( ⁇ 700 m 2 /g) and large pore volume ( ⁇ 1 cm 3 /g) of the
- mesoporous silica In some embodiments described herein, the interaction between the mesoporous silica and the cannabinoid mixture is not critical for loading and stability, making the technology suitable for a wide range of cannabinoids and plant extracts containing cannabinoids.
- Mesoporous Silica Mesoporous Silica
- Mesoporous silica is a solid, highly porous material. The nanometer-scale pores result in extremely high specific surface areas. As described herein, adsorption of a mixture of a cannabinoid or cannabis extract and a surfactant on mesoporous silica converts a viscous liquid into a free-flowing powder due to the extremely high specific surface area of the silica structure. This improves the flow properties when compared to that of the cannabinoid or cannabis extract alone and is advantageous due to ease of processing for downstream development. In addition to its process improvement capabilities, mesoporous silica can enhance the aqueous solubility of cannabinoids, especially for cannabinoids that are crystalline at room temperature. In particular, the crystal structure is disrupted and the amorphous form of the drug is confined in the pore structure. This results in a higher apparent solubility and dissolution rate when compared to the crystalline form.
- solubility of resinous cannabinoids is enhanced due to the distribution of the drug across the large specific surface area of the mesoporous silica
- the incorporation of solubility enhancing excipients may further enhance the dissolution rate and solubility of the cannabinoid.
- a further advantage of embodiments of the technology is that may be used to control and modify the release rate of cannabinoid compounds, which is a key attribute for obtaining desired drug release properties.
- release rate may be controlled or modified based on pore size.
- the choice of surfactant can be used to modify release rate.
- mesoporous silica exhibits excellent thermostability properties, making it an excellent material to preserve the physicochemical stability of the cannabis extract during processing and storage, which is especially beneficial for cannabis extracts comprising volatile terpenes and terpenoids.
- adsorption of the cannabinoid mixture onto mesoporous silica reduces the volatility of the terpenes and terpenoids, thereby reducing evaporative losses of these compounds.
- mesoporous silica is biologically inert and biocompatible. This is in contrast to alternative technologies that use cyclodextrins, novel excipients or large amounts of excipients to solubilise and stabilise an active (e.g. SNEDDS, solid dispersions).
- compositions of the invention are typically prepared by a sol-gel process, producing either a disordered mesoporous structure (DMS) or ordered mesoporous structure (OMS) pore structure. Both are available in a wide range of particle sizes, specific surface areas, and pore volumes, making them applicable for a variety of cannabinoids and drug delivery approaches.
- DMS is commercially available and used in the pharmaceutical, cosmetic, food, and beverage industries for a wide variety of applications. [056] DMS is commercially available and is comprised of a coherent and rigid network of continuous pores. DMS may be manufactured by any known means. In some embodiments, DMS may be synthesized via sol-gel chemistry where the particle characteristics are produced into this highly porous material.
- Ordered Mesoporous Silicas were first synthesized as molecular sieves and are now applied to a variety of fields such as adsorption, chromatography, catalysis, and optics.
- the mesopore structure is synthesized via sol-gel synthesis but utilizes a template such as surfactant or polymeric micelles to control pore structure.
- the template is removed, leading to its porosity and narrow pore size distribution. It should be noted that they are referred to as“ordered” despite their
- OMS material types are MCM-41 and SBA-15, which form a hexagonal porous structure.
- silica is“Generally Recognized As Safe” by the United States Food and Drug Administration (FDA). Recently, silica nanoparticles in the form of Cornell dots (C dots) received FDA approval for a Phase I human clinical trial for targeted molecular imaging. It was reported that mesoporous silica exhibited a three-stage degradation behavior in simulated body fluid, suggesting that MSNs might degrade after administration, which is favorable for cargo release. Several in vivo biodistribution studies of MSNs have been reported. One study evaluated the systematic toxicity of MSNs after intravenous injection of single and repeated dose to mice. The results of clinical features, pathological
- MSNs were mainly excreted through feces and urine following different administration routes.
- pore sizes in mesoporous silica are in the range of 2-50 nm and an ordered arrangement of pores.
- the pore size of the mesoporous silica can be controlled during production.
- the pore volume may be about 0.5 cm 3 /g, 1 cm 3 /g, 2 cm 3 /g, 3 cm 3 /g, 4 cm 3 /g, 5 cm 3 /g, 6 cm 3 /g, 7 cm 3 /g, 8 cm 3 /g, 9 cm 3 /g, or about 10 cm 3 /g.
- the pore volume is around 2 cm 3 /g when the pore size is less than 15 nm and surface area is about 1000 m 2 /g.
- the interaction of cannabinoid with mesopores is a surface phenomenon.
- the amount of cannabinoid mixture adsorbed can be determined by changes in pore volume.
- many consecutive loadings of the cannabinoid mixture can result in almost complete filling of mesopores, indicating that the amount of cannabinoid is directly proportional to pore volume. That is, while a greater pore volume will enable a greater cannabinoid loading, the remaining pore volume will decrease with the amount of drug loaded.
- the surface area of the mesoporous silica is a determining factor for the quantity of adsorbed cannabinoids, although it is believed that surface chemistry may also be influential.
- two different approaches are used, namely modifying (increasing or decreasing) the surface area and modifying the affinity of the surface for the cannabinoid.
- the amount of cannabinoid mixture (or other drug) adsorbed is directly proportional to specific surface area.
- MCM-41 is synthesized by specific surface area (SBET value) 1157 m 2 g _1 and SBA-15 with specific surface area value of 719 m 2 g 1 .
- the mesoporous silica is a particle having an average diameter from 2 - 250 pm.
- the mesoporous silica particles may have an average diameter of between about 2 pm to at least about 250 pm, for example the average diameter may be about 2 pm, about 10 pm, about 25 pm, about 50 pm, about 75 pm, about 100 pm, about 125 pm, about 150 pm, about 175 pm, about 200 pm, about 225 pm, or at least about 250 pm.
- mesoporous silicas may be used in the compositions and formulations of the invention, including for example FSM-16, which has folded sheets of mesoporous materials.
- FSM-16 which has folded sheets of mesoporous materials.
- Various other commercially available mesoporous silica products can be used including those developed by Technical Delft University (TUD-1), Hiroshima Mesoporous Material-33 (HMM-33), Centrum voor Oppervlaktechemie en Katalyse/Centre for Research Chemistry and Catalysis (COK-12), all of which vary in their pore symmetry and shape.
- SYLOID® 63FP/AL-1 SYLOID® 72FP SYLOID® 244FP, SYLOID® XDP 3050, SYLOID® XDP 3150, may also be used.
- the mesoporous silica is SYLOID® 3050 XDP.
- mesoporous silicas are presented in Table 2.
- fumed silica such as Aeropearl® by evonik
- magnesium aluminium silica for example Neuselin®
- the cannabinoid can be synthetic or a naturally occurring cannabinoid derived from a plant.
- the plant is of the genus Cannabis.
- Cannabinoids that occur in other plant genera can also be used in the formulations.
- cannabinoids derived from plants of the genera Echinacea, Acmella, Helichrysum, and Radula can be used in the compositions.
- the lipophilic alkamides (alkylamides) from Echinacea species including the cis/trans isomers dodeca-2E,4E,8Z,10E/Z-tetraenoic-acid-isobutylamide can be used.
- Other suitable cannabinoids include beta-caryophyllene and anandamide.
- Cannabinoid compounds suitable for use in the invention include, but are not limited to, tetrahydrocannabinoids, their precursors, alkyl (particularly propyl) analogues, cannabidiols, their precursors, alkyl (particularly propyl) analogues, [070]
- the cannabinoid may be selected from the group consisting of: cannabigerolic acid (CBGA); cannabigerolic acid monomethyl ether (CBGAM), cannabigerol (CBG),
- CBDGM cannabigerol monomethyl ether
- CBGVA cannabigerovarinic acid
- cannabichromevarin cannabichromenic acid (CBCA) cannabichromene (CBC), cannabidiolic acid (CBDA), cannabidiol (CBD), cannabidiol monomethyl ether (CBDM), cannabidiol-C4 (CBD-D4), cannabidivarinic acid (CBDVA), cannabidivarin (CBDV), cannabidiorcol (CBD-D1)
- delta-9-tetrahydrocannabinolic acid A THCA-A
- delta-9- tetrahydrocannabinolic acid B THCA-B
- delta-9-tetrahydrocannabinol D9-THC
- delta-9- tetrahydrocannabinolic acid C4 THCA-C4
- delta-9-tetrahydrocannabinol-C4 delta-9-tetrahydrocannabivarinic acid (THCVA)
- cannabichromene propyl analogue cannabinor, and any combination of two or more of these cannabinoids.
- the cannabinoid may be present in an extract of a plant.
- 'cannabinoid mixtures' as used herein includes mixtures containing two or more cannabinoids, including plant extracts comprising a mixture of two or more cannabinoids.
- the silicas may be two different types of silica(e.g. Syloid 244 and Syloid 3050) or two or more portions of the same type of silica each with a different particle size distribution.
- Plant extracts containing cannabinoids may also contain one or more terpenes and/or terpenoids.
- the plant extracts may contain a terpene selected from the group comprising t-carophyllene, myrcene, a-humulene, a-pinene, a-bisabolol, b-pinene, limonene, ocimene and/or terpinolene, guaiol, a-terpineol, and terpinolene, linalool, fenchol, guaiene, and 3-careen.
- 'cannabinoid mixtures' as used herein may contain one or more terpenes.
- the cannabinoid or cannabinoid mixture may be present in any amount suitable for a desired application.
- the cannabinoid or plant extract containing the cannabinoid may be present in an amount ranging from less than about 1 % to about 90 weight %, relative to the weight of the composition.
- a higher or lower concentration of the cannabinoid mixture may be used, and the concentration may vary within the
- the cannabinoid may be present in an amount ranging from about 0.01 % to about 50%, about 1 % to about 50%, about 2 to about 5%, about 5% to about 10%, about 10 % to about 20%, about 20 % to about 30%, about 30 % to about 40%, or about 40 % to about 50% by weight of the formulation.
- the cannabinoid may be present in an amount ranging from about 25% to about 30%, about 30% to about 35%, or about 35% to about 40% by weight of the formulation.
- a desired amount of cannabinoid or cannabinoid mixture may be achieved by repeatedly loading the mesoporous silica with the cannabinoid or the cannabinoid mixture.
- compositions of the invention comprise a surfactant to improve loading of the cannabinoid onto the mesoporous silica.
- the surfactant also facilitates improved desorption of the cannabinoid from the mesoporous silica into aqueous solution and/or desorption of the cannabinoid.
- the cannabinoid and the surfactant are mixed to form a cannabinoid mixture prior to adsorption (loading) on to a mesoporous silica.
- the cannabinoid, surfactant and the mesoporous silica are mixed together and the cannabinoid mixture forms concomitantly with loading.
- Surfactants play important roles in the compositions. First, a surfactant lowers the surface tension of a liquid. This facilitates loading solution-based drugs into nano-sized pores. Second, through reduction of surface tension, surfactants facilitate (in vivo) wetting of the finished dosage form. This is an important step in dissolution of the drug and helps increase the delivery of the drug from the dosage form.
- the surfactant is an anionic surfactant.
- Suitable anionic surfactants include alkyl sulfonates, aryl sulfonates, alkyl phosphates, alkyl phosphonates, potassium laurate, sodium lauryl sulfate, sodium dodecylsulfate, alkyl polyoxyethylene sulfates, sodium alginate, dioctyl sodium sulfosuccinate, phosphatidic acid and their salts, sodium carboxymethylcellulose, bile acids and their salts, cholic acid, deoxycholic acid, glycocholic acid, taurocholic acid, and glycodeoxycholic acid, and calcium carboxymethylcellulose, stearic acid and its salts, (e.g., calcium stearate), phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, dioctylsulfosuccinate, dialkylesters of sodium
- the surfactant is a cationic surfactant.
- Suitable cationic surfactants include quaternary ammonium compounds, benzalkonium chloride, cetyltrimethylammonium bromide, chitosans, lauryldimethylbenzylammonium chloride, acyl carnitine hydrochlorides, alkyl pyridinium halides, cetyl pyridinium chloride, cationic lipids, polymethylmethacrylate trimethylanmonium bromide, sulfonium compounds, polyvinylpyrrolidone-2-dimethylaminoethyl methacrylate dimethyl sulfate, hexadecyltri methyl ammonium bromide, phosphonium compounds, quaternary ammonium compounds, benzyl- di(2-chloroethyl)ethylammonium bromide, coconut trimethyl ammonium chloride, coconut trimethyl ammonium bromine bromine,
- the surfactant is a nonionic surfactant.
- Suitable nonionic surfactants include polyoxyethylene fatty alcohol ethers, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene fatty acid esters, sorbitan esters, glyceryl esters, glycerol monostearate, polyethylene glycols, polypropylene glycols, polypropylene glycol esters, cetyl alcohol, cetostearyl alcohol, stearyl alcohol, aryl alkyl polyether alcohols, polyoxyethylene- polyoxypropylene copolymers, poloxamers, poloxamines, methylcellulose, hydroxycellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylinethylcellulose, noncrystalline cellulose, polysaccharides, starch, starch derivatives, hydroxyethylstarch, polyvinyl alcohol, polyvinylpyrrolidone, triethanolamine stearate, amine oxides, dextran,
- the surfactant is a zwitterionic surfactant.
- Suitable zwitterionic surfactants include zwitterionic phospholipids, for example phosphatidylcholine, phosphatidylethanolamine, diacyl-glycero-phosphoethanolamine (such as dimyristoyl- glycero-phosphoethanolamine (DMPE), dipalmitoyl-glycero-phosphoethanolamine (DPPE), distearoyl-glycero-phosphoethanolamine (DSPE), and dioleolyl-glycero- phosphoethanolamine (DOPE)).
- DMPE dimyristoyl- glycero-phosphoethanolamine
- DPPE dipalmitoyl-glycero-phosphoethanolamine
- DSPE distearoyl-glycero-phosphoethanolamine
- DOPE dioleolyl-glycero- phosphoethanolamine
- Mixtures of phospholipids that include anionic and zwitterionic phospholipids
- the surfactant is sodium lauryl sulfate.
- the ratio of surfactant: mesoporous silica can be used to modulate adsorption of the cannabinoid onto the mesoporous silica.
- the ratio of surfactant: mesoporous silica can be used to modulate desorption of the cannabinoid.
- the ratio of surfactantcannabinoid is between about 1:1 to about 1:50.
- the ratio may be about 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, 1:20, 1:21, 1:22, 1:23, 1:24, 1:25, 1:26, 1:27, 1:28, 1:29, 1:30, 1:31, 1:32, 1:33, 1:34, 1:35, 1:36, 1:37, 1:38, 1:39, 1:40, 1:41, 1:42, 1:43, 1:44, 1:45, 1:46, 1:47, 1:48, 1:49, or about 1:50.
- the mass ratio of surfactant: mesoporous silica is from about 1 :25 to about 1 :35, for example 1 :29 which in an exemplary formulation corresponds to about 1.5% w/w surfactant and about 43% (w/w) mesoporous silica.
- the mass ratio of surfactant: mesoporous silica is about 1:29.
- the cannabinoid may be diluted with a suitable diluent. Dilution may be desired for example to achieve a desired dosage of the cannabinoid in the composition or to facilitate ease of handling of the cannabinoid prior to incorporation into the composition. Alternatively or in addition, dilution may be used to impart other desirable characteristics such as flavour or aroma to the composition. Alternatively or in addition dilution may be used to mask undesirable taste or smell.
- the ratio of diluent:cannabinoid is between about 1:1 to about 1:50.
- the ratio may be about 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10,
- the ratio of diluent:cannabinoid is between about 50:1 to about 1:1.
- the ratio may be about 50:1, 1:49, 1:48, 1:47, 1:46, 1:45, 1:44, 1:43, 1:42, 1:41, 1:40, 1:39, 1:38, 1:37, 1:36, 1:35, 1:34, 1:33, 1:32, 1:31, 1:30, 1:29, 1:28, 1:27, 1:26, 1:25, 1:24, 1:23, 1:22, 1:21, 1:20, 1:19, 1:18, 1:17, 1:16, 1:15, 1:14, 1:13, 1:12, 1:11, 1:10, 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 1:2, or about 1:1.
- Suitable diluents include oils and waxes that are known to be safe for administration to a subject.
- suitable diluents may be mineral oils, vegetable oils, fluorinated or perfluorinated oils, natural or synthetic waxes, silicones, cationic polymers, proteins and hydrolyzed proteins, ceramide type compounds, fatty amines, fatty acids and their derivatives, as well as mixtures of these different compounds.
- the synthetic oils include polyolefins, e.g., poly-a-olefins such as polybutenes, polyisobutenes and polydecenes.
- the mineral oils suitable for use in the compositions of the invention include hexadecane and oil of paraffin.
- Animal and vegetable oils may be used as diluents including oil from olive, sunflower, safflower, canola, corn, soy, avocado, jojoba, squash, raisin seed, sesame seed, nuts (for example peanut, walnut, hazelnut, etc.), fish, eucalyptus, lavender, vetiver, litsea cubeba, lemon, sandalwood, rosemary, chamomile, savory, nutmeg, cinnamon, hyssop, caraway, orange, geranium, cade, bergamot, glycerol tricaprocaprylate, purcellin oil, mint oil (e.g. peppermint, spearmint) and blends thereof.
- Natural or synthetic waxes may also be used as diluents, these include carnauba wax, candelila wax, alfa wax, paraffin wax, ozokerite wax, vegetable waxes such as olive wax, rice wax, hydrogenated jojoba wax, absolute flower waxes such as black currant flower wax, animal waxes such as bees wax, modified bees wax (cerabellina), marine waxes and polyolefin waxes such as polyethylene wax, and blends thereof.
- Preparation of the cannabinoid mixture involves the addition of the surfactant to the purified cannabinoid or plant extract.
- the cannabinoid is added to surfactant. In one embodiment this may occur as a separate step prior to loading the mesoporous silica with the mixture.
- the surfactant, purified cannabinoid or plant extract and the mesoporous silica are combined in a single step and the cannabinoid mixture is formed concomitantly with loading.
- the surfactant concentration may be in excess of the CMC so that at least a portion of the cannabinoid is contained in micelles of the surfactant.
- the ratio of surfactantcannabinoid is between about 1 : 1000 to about 1 :5.
- the ratio may be about 1 : 1000, 1 :950, 1 :900, 1 :850, 1 :800, 1 :750, 1 :700, 1 :650, 1 :600, 1 :550, 1 :500, 1 :450, 1 :400, 1 :350, 1 :300, 1 :250, 1 :200, 1 : 150, 1 : 100, 1 :50, 1 :25, 1 : 10, or about 1 :5.
- compositions disclosed herein are prepared by heating the cannabinoid, particularly if it is not already a liquid at room temperature, in order to increase its fluidity and/or reduce its viscosity.
- the surfactant is mixed with the cannabinoid and the mesoporous silica.
- the cannabinoid and the surfactant form a cannabinoid mixture that adsorbs to the mesoporous silica, that is the cannabinoid mixture is loaded into the mesoporous silica.
- the cannabinoid is heated as above and mixed with the surfactant to form a cannabinoid mixture.
- the cannabinoid mixture is then mixed with the mesoporous silica, wherein the cannabinoid mixture adsorbs to the mesoporous silica.
- the heating step may not be required.
- typically cannabinoids exist as viscous oils, or in crystalline form at room temperature. In these cases the cannabinoid is heated to a temperature that increases the fluidity and/or decreases the viscosity of the cannabinoid in order to facilitate ease of handling.
- the cannabinoid can be heated to about 25°C, about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 55°C, about 60°C, about 65°C, about 70°C, about 75°C, about 80°C, about 85°C, about 90°C, about 95°C, or about 100°C.
- the cannabinoid is crystalline at room temperature, it is heated above its melting temperature.
- the cannabinoid may be heated to about 20°C above its melting temperature.
- the cannabinoid may be heated to 5°C, 10°C, 15°C or 20°C above its melting temperature.
- the melting temperature of cannabinoids that are crystalline at room temperature are known in the art or can readily be determined by a skilled person.
- the cannabinoid is resinous at room temperature, it is heated above its glass transition temperature.
- the cannabinoid may be heated to about 20°C above its glass transition temperature.
- the cannabinoid may be heated to 5°C, 10°C, 15°C or 20°C above its glass transition temperature.
- the glass transition temperature of cannabinoids that are resinous at room temperature are known in the art, or can readily be determined by a skilled person.
- the cannabinoid may be heated in the absence or in the presence of the surfactant.
- the process may further comprise the step of stirring the cannabinoid mixture and the mesoporous silica.
- the cannabinoid mixture is primarily located in the pores of the mesoporous silica, with little or no mixture outside the pores. In other embodiments, the cannabinoid mixture is located outside the pores of the mesoporous silica. Both embodiments require the cannabinoid mixture to be loaded or adsorbed onto the mesoporous silica.
- the composition is formulated into a dosage form, it is advantageous to minimize the size of the dosage form, and it is typically advantageous to maximize the drug loading.
- the loading techniques require the cannabinoid mixture to be fluidized, either as a liquid solution or through heating (e.g. melt) as described above. Loading the mixture as a melt provides an advantage in that no subsequent evaporation step is necessary to remove the solvent medium.
- one or more diluents may be incorporated (e.g. , Medium Chain Triglyceride) when loading resinous cannabinoids with the melt method.
- the inventors have observed that viscosity of the cannabinoid or cannabinoid mixture has an influence on the desorption process. In many cases, melts of cannabinoids can still have high viscosities that hinder both drug loading and desorption.
- a diluent can be used to‘thin’ the cannabinoid, making it easier to handle during formulation and can facilitate loading (i.e. , flow) into the pores of the mesoporous silica.
- the diluent can also provide a competitive interaction between the silica surface and the cannabinoid or cannabinoid mixture during loading. Upon contact with the aqueous media, this diluent facilitates desorption and improves the extent of cannabinoid release, especially when combined with a solubilizer or emulsifier.
- Solvent-based approaches may be used. These require a subsequent drying step to evaporate the solvent(s), which can be accomplished using many different available drying techniques that are well known to those skilled in art, including for example, use of a Rotavap (rotary evaporator). For example, this method can involve soaking mesoporous silica in a solution of cannabinoid mixture in a solvent, typically with stirring while preventing solvent evaporation. The solvent is then typically removed with a rotary evaporator.
- a Rotavap rotary evaporator
- the cannabinoid mixture and the mesoporous silica are heated to allow the mixture to become a liquid or to reduce the viscosity of the liquid. This is followed by mixing to load the cannabinoid mixture into the pores (i.e. , allowing adsorption to occur). In some cases, a portion of cannabinoid mixture may also be loaded onto the external surface of the mesoporous silica.
- heating is not required.
- the cannabinoid mixture and mesoporous silica are combined at room temperature and the mixture is adsorbed to the mesoporous silica at room temperature.
- An alternative method to load the cannabinoid mixture onto the mesoporous silica involves dissolving the cannabinoid or cannabinoid mixture in a liquid solvent medium before combining it with the mesoporous silica.
- the solvent can then be evaporated using any method known in the art such as evaporation or filtration.
- a concentrated solution of dissolved cannabinoid is mixed with mesoporous silica and the liquid is taken up through capillary forces.
- the cannabinoid mixture is loaded in multiple stages into the mesopores until the target theoretical load is achieved. This is a preferred method for crystalline cannabinoids because the majority of the solvent can be removed before the next loading cycle. In comparison, when this approach is used with resinous cannabinoids much of the solvent can remain in the pores making multiple loading cycles less effective.
- Spray-drying can also be used to load the mesoporous silica and provide a composition of the invention.
- This process can be divided into four subprocesses: (1) feedstock preparation, (2) atomization, (3) drying, and (4) collection.
- the liquid feedstock consists of a suspension of mesoporous silica in a concentrated cannabinoid solution (see above).
- the resulting particle size and morphology can be fine tuned according to the excipients and process parameters used.
- Another loading method utilizes the fluidized bed approach in mixing, granulation (if required), and drying are all carried out in the same equipment.
- a suspension of a given cannabinoid-to-silica ratio is formulated and thoroughly mixed.
- the solvent in this suspension is then evaporated by spraying the suspension with the fluidized bed equipment.
- Co-milling may also be used.
- this solvent-free mechanical shearing process is reportedly disrupts the crystalline structure of a cannabinoid without causing significant chemical degradation through use of a low-energy jar-milling configuration.
- Physical mixtures of crystalline compounds (such as cannabinoids) and a mesoporous silica at suitable proportions are coground at room temperature. This leads to what is known as spontaneous amorphization in which the cannabinoid or cannabinoid mixture are adsorbed onto the mesoporous silica.
- cryogenic milling is a suitable method for adsorption onto mesoporous silica.
- the invention provides compositions that have enhanced or controlled release of the cannabinoid.
- the release rate is influenced by a combination of the properties of the loaded cannabinoid mixture and the mesoporous silica, including pore diameter and pore morphology.
- the pore diameter of the mesoporous silica is an important factor affecting the release rate of the cannabinoid, with the release rate tending to increase as pore diameter increases.
- the pore morphology can also be modified in order to control the release rate of the cannabinoid.
- the particle size and shape affect the length of the pathway that a cannabinoid needs to diffuse in order to be released. For example, spherical SBA-15 particles have a larger number of pore openings compared to fiber-like particles.
- Pore length also influences the release rate and, in general, compositions that have delayed cannabinoid release comprise mesoporous silica having pores with a more tortuous diffusion route. This makes the deeper parts of the particle less accessible to a solvent and hence the selection of mesoporous silica is important for controlling the release profile of a cannabinoid. Accordingly, the release rate of the cannabinoid can be controlled by choice of mesoporous silica, in particular the pore size and pore geometry.
- compositions have enhanced cannabinoid release.
- the rate of dissolution of the cannabinoid from the mesoporous silica is related to the confined space inside the pores that prevents long range ordering, thus preventing the crystallization of the loaded substances. This stabilized amorphous form of the cannabinoid can improve its dissolution rate.
- aqueous release medium such as a bodily fluid, stomach or intestinal contents
- water penetrates the pores and the adsorbed hydrophobic cannabinoid mixture is displaced from the hydrophilic silica surface and transported by way of Fickian diffusion.
- the release rate depends on factors such as porosity, the
- cannabinoid solubility in the release medium, the initial load, and the diffusion coefficient of the cannabinoid molecules in the medium.
- compositions disclosed herein may be formulated into any known dosage form.
- the formulations described herein may comprise one or more pharmaceutically acceptable excipients including carriers, vehicles and diluents.
- excipient herein means any substance, not itself an active agent, used as a diluent, adjuvant, or vehicle added to a formulation to improve its handling or storage properties or to permit or facilitate formation of a solid dosage form such as a tablet, capsule, or a solution or suspension suitable for oral, parenteral, intradermal, subcutaneous, or topical application.
- Excipients can include, by way of illustration and not limitation, diluents, disintegrants, binding agents, adhesives, wetting agents, polymers, lubricants, glidants, stabilizers, and substances added to mask or counteract a disagreeable taste or odor, flavors, dyes, fragrances, and substances added to improve appearance of the composition.
- Acceptable excipients include (but are not limited to) stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, magnesium carbonate, talc, gelatin, acacia gum, sodium alginate, pectin, dextrin, mannitol, sorbitol, lactose, sucrose, starches, gelatin, cellulosic materials, such as cellulose esters of alkanoic acids and cellulose alkyl esters, low melting wax, cocoa butter or powder, polymers such as polyvinyl-pyrrolidone, polyvinyl alcohol, and polyethylene glycols, and other pharmaceutically acceptable materials.
- excipients examples include Remington's Pharmaceutical Sciences, 20th Edition (Lippincott Williams & Wilkins, 2000). The choice of excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.
- the formulations of the invention are suitable for oral, rectal, vaginal, or topical delivery.
- Non-limiting examples of particular formulation types include tablets, troches, capsules, caplets, powders, granules, ready-to-use solutions or suspensions, lyophilized materials, gels, creams, lotions, ointments, drops, and suppositories.
- Solid formulations such as the tablets or capsules may contain any number of suitable pharmaceutically acceptable excipients or carriers described above.
- Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example, magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example, potato starch; or acceptable wetting agents such as sodium lauryl sulphate.
- the tablets may be coated according to methods well known in pharmaceutical practice.
- Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
- Such liquid preparations may contain conventional additives, such as suspending agents, for example, sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example, lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example, almond oil, oily esters such as glycerin, propylene glycol, or ethyl alcohol; preservatives, for example, methyl or propyl p-hydroxybenzoate or sorbic acid; and, if desired, conventional flavouring or colouring agents.
- suspending agents for example, sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example, lecithin, sorbitan
- the effective amount of the cannabinoid in the formulation that is administered and the dosage regimen with the compositions and/or formulations of the present invention depends on a variety of factors, including the age, weight, sex, and medical condition of the subject, the severity of the disease, the route and frequency of administration, the particular compound employed, as well as the pharmacokinetic properties (e.g., adsorption, distribution, metabolism, excretion) of the individual treated, and thus may vary widely. Such treatments may be administered as often as necessary and for the period of time judged necessary by the treating physician or other medical professional.
- the dosage regimen or therapeutically effective amount of the compound to be administrated may need to be optimized for each individual.
- compositions may contain active ingredient in the range of about 0.1 mg to 2000 mg, typically in the range of about 0.5 mg to 500 mg and more typically between about 1 mg and 200 mg.
- the formulations are consumed orally.
- a single dose is at from 0.1 mg but may be up to about 250 mg.
- a single dose may be 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50mg, 55mg,
- a subject may consume one or multiple doses per day.
- a subject may take 1 , 2, 3, 4 or 5 doses per day.
- the dosing interval is selected from the group consisting of once per week dosing, twice per week dosing, three times per week dosing, four times per week dosing, five times per week dosing, six times per week dosing, weekly dosing, and twice-monthly dosing.
- dosing may be as needed or as desired by the user.
- compositions and formulations described herein contain cannabinoids and the invention also relates to a method of treating a condition or disease responsive to a cannabinoids such as pain (including chronic pain), spasticity associated with multiple sclerosis, nausea (chemotherapy-induced nausea and vomiting), posttraumatic stress disorder, cancer, epilepsy, cachexia, glaucoma, HIV/AIDS, degenerative neurological conditions, anorexia and weight loss associated with HIV, irritable bowel syndrome, epilepsy, spasticity, Tourette syndrome, amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease, dystonia, dementia, traumatic brain injury, addiction, anxiety, depression, sleep disorders, and schizophrenia and other psychoses.
- pain including chronic pain
- spasticity associated with multiple sclerosis nausea (chemotherapy-induced nausea and vomiting), posttraumatic stress disorder
- cancer epilepsy
- cachexia glaucoma
- HIV/AIDS degenerative neurological conditions
- anorexia and weight loss associated with HIV irritable bowel syndrome
- a further embodiment relates to the use of the compositions disclosed herein for the manufacture of a medicament for treating a disease or condition responsive to a
- cannabinoid such as those listed above.
- compositions of the present invention may be administered along with a pharmaceutical carrier, diluent or excipient as described above.
- the compounds may be administered in combination with other agents, for example, other therapeutic agents.
- the composition may be formulated or administered in combination with one or more other therapeutic agents.
- a composition may be included in combination treatment regimens with known treatments or therapeutic agents, and/or adjuvant or prophylactic agents.
- Combination regimens may involve the active agents being administered together, sequentially, or spaced apart as appropriate in each case. Combinations of active agents including compounds of the invention may be synergistic.
- composition may further comprise pharmacologically active agents that are poorly soluble in water.
- suitable agents include:
- anesthetics such as bupivacaine, lidocaine, proparacaine, and tetracaine
- analgesics such as acetaminophen, ibuprofen, fluriprofen, ketoprofen, voltaren, phenacetin, and salicylamide;
- anti-inflammatories selected from the group consisting of naproxen and
- antihistamines such as chlorpheniramine maleate, phenindamine tartrate
- diphenhydramine hydrochloride promethazine, brompheniramine maleate, dexbrompheniramine maleate, clemastine fumarate and triprolidine;
- antimicrobial agents such as erythromycin, penicillin and cephalosporins and their derivatives
- Skeletal muscle relaxants (dantrolene sodium, baclofen), benzodiazepines
- alpha2-adrenergic agonists clonidine, tizanidine
- botulinum toxins onabotulinumtoxinA, abobotulinumtoxinA, incobotulinumtoxinA,
- 5-H ⁇ 3 inhibitors such as dolasteron (Anzemet), granisetron (Kytril, Sancuso), and ondansetron (Zofran) palonosetron (Aloxi));
- NK1 inhibitors e.g. substance P inhibitor aprepitant (Emend), Netupitant, Rolapitant;
- Dopamine D2 receptor antagonist e.g. Metoclopramide
- Histamine blockers such as diphenhydramine or meclozine
- Progestagens such as megestrol acetate and medroxyprogesterone acetate, • Omega-3 fatty acids (e.g. EPA)
- the co-administration of compounds of the invention may be effected by the compounds being in the same unit dose as another active agent, or the compounds and one or more other active agent(s) may be present in individual and discrete unit doses administered at the same, or at a similar time, or at different times according to a dosing regimen or schedule.
- Sequential administration may be in any order as required, and may require an ongoing physiological effect of the first or initial compound to be current when the second or later compound is administered, especially where a cumulative or synergistic effect is desired.
- compositions may be included in consumer products such as food products, cosmetics, and sunscreen.
- the food product may be a baked good (for example a bread, cake, biscuit or cookie, beverage (e.g., tea, soda or flavored milk), breakfast food (e.g., cereal), muesli bar, tinned food, snack food (e.g., chips, crisps, corn snacks, nuts, seeds), confection, condiment, marinade, dairy product, dips, spreads or soups.
- a baked good for example a bread, cake, biscuit or cookie
- beverage e.g., tea, soda or flavored milk
- breakfast food e.g., cereal
- muesli bar e.g., tinned food
- snack food e.g., chips, crisps, corn snacks, nuts, seeds
- confection condiment, marinade, dairy product, dips, spreads or soups.
- the cosmetic may be a be liquid, lotion, cream, powder (pressed or loose), a dispersion, an anhydrous cream or stick.
- the cosmetic may be a spray, perfume, foundation, mascara, lipstick, lip gloss, lip liner, lip plumper, lip balm, lip stain, lip conditioner, lip primer, lip booster, lip butter, deodorant, bath oils, bubble baths, bath salts, body butter, nail polish, hand sanitizer, shampoo, conditioner, hair colors, hair sprays, hair gels, primer, concealer, highlighter, bronzer, mascara, eye shadow, eyebrow pencils, eyebrow cream, eyebrow wax, eyebrow gel, eyebrow powder, moisturizer, or toner.
- the consumer product may contain less than about 1 % (w/w) of the composition or about 1 % (w/w), or about 2% (w/w), or about 3% (w/w), or about 4% (w/w), or about 5% (w/w), or about 6% (w/w), or about 7% (w/w), or about 10% (w/w), or about 11 % (w/w), or about 12% (w/w), or about 13% (w/w), or about 14% (w/w), or about 15% (w/w), or about 16% (w/w), or about 17% (w/w), or about 18% (w/w), or about 19% (w/w), or about 20% (w/w), or about 25% (w/w), or about 30% (w/w), or about 35% (w/w), or about 40% (w/w), or about 45% (w/w), or about 50% (w/w) of the composition.
- Example 1 Delta-9-THC mesoporous silica composition
- Syloid 3050 XDP (50 pm median particle size) was selected as the mesoporous silica carrier and sodium lauryl sulfate (SLS) as the anionic surfactant.
- SLS sodium lauryl sulfate
- the tablet blend was prepared (see example below) using an optimized blending procedure and analyzed using HPLC for potency and homogeneity with acceptance criteria of ⁇ 5% for both. Following this, tablets were prepared by direct compression using standard tableting excipients. Tablets were also analyzed for potency and batch homogeneity using HPLC. Finally, the tablet weight, thickness, and hardness were also assessed and compared against the batch release specifications prior to sale.
- Example 3 CBD mesoporous silica tablets
- the tablet blend was prepared in accordance with table 4 and tablets were prepared by direct compression Table 4: CBD ingredients
- Example 4 CBD mesoporous silica tablets
- the tablet blend was prepared in accordance with table 5 and tablets were prepared by direct compression
- Example 5 Incipient wetness loading of resinous distillate onto mesoporous silica
- Resinous distillate was dissolved in 99% isopropanol (iso-propyl alcohol) to a concentration of 147.25 mg/ l. A portion of this solution was added to the mesoporous silica (either Syloid 3050 XDP or Syloid 244). The portion of the solution added to the silica is equal or slightly less than the pore volume of the silica. After the cannabinoid is adsorbed onto the silica the isopropanol is removed by evaporation and another portion of the solution is added to silica. This process is repeated until the desired amount of distillate (30% by weight of silica) was added.
- isopropanol iso-propyl alcohol
- Example 6 Incipient wetness loading of Delta-9-THC onto mesoporous silica
- a solution of 113.9 mg/ml Delta-9-THC in 99% isopropanol was prepared.
- a mixture of Syloid 244 and Syloid 3050 XDP was prepared in a 1 :3 ratio., specifically 157mg of Syloid 244 was mixed with 471 mg of Syloid 3050 XDP (total weight of 628mg).
- 0.2 ml of the Delta-9-THC solution was added incrementally to the silica mixture until a total of 6 ml of the solution was added, for a total of 683.4 mg Delta-9-THC.
- the weight of the silica had increased to 131 1.4mg indicating that all of the Delta-9-THC was loaded onto the silica and the total load of Delta-9- THC was 52%.
- the loaded silica was a flowable powder.
- Example 7 Scale-up incipient wetness loading of resinous distillate onto mesoporous silica
- a solution of 60.36 mg/ml resinous distillate in isopropanol was prepared by first softening the distillate by hearting then adding the isopropanol.
- silica mixture was separated into three portions and the volume of the resinous distillate solution required to achieve 25%, 37.5% and 50% loading of the silica was calculated.
- silica mixture was loaded by incrementally adding the aliquots of the solution of resinous distillate to the silica. Solvent was removed using a rotary evaporator (Rotovap®) before the addition of more solution.
- the tablet blend was prepared in accordance with table 6 and tablets were prepared by direct compression
- the tablet blend was prepared in accordance with table 7 and tablets were prepared by direct compression
- a 1 :4 mixture of Syloid 244:Syloid 3050 was loaded with delta-9-THC as described in Example 6. Once loaded the dried silica mixture contained 40% delta-9-THC by weight. This loaded silica was used to prepare the tablet blend in accordance with table 8. Following this, tablets were prepared by direct compression.
- Example 11 HPLC method to quantitate cannabinoids
- Cannabinoids were eluted from the column and identified by reference to known controls eluted from the column under the same conditions. Cannabinoids were quantitated by reference to a calibration curve of peak area vs concentration of the known controls.
- Example 12 Cannabinoid release from loaded silica
- a silica blend loaded with 37.5% delta-9-THC was prepared as per Example 7.
- Example 13 Inclusion of surfactant increases cannabinoid release from loaded silica
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US11596606B2 (en) | 2019-05-30 | 2023-03-07 | Metta Medical Inc | Activated cannabinoid controlled release compound tablet and method of forming the same |
MX2023000870A (es) | 2020-07-21 | 2023-05-19 | Chembeau LLC | Formulaciones cosmeticas de diester y usos de las mismas. |
CZ310004B6 (cs) * | 2021-09-22 | 2024-05-01 | CB21 Pharma, s.r.o | Formulace kanabinoidů pro perorální podání |
WO2023250274A1 (fr) * | 2022-06-22 | 2023-12-28 | Ilera Therapeutics Llc | Matrice de capture et de dissolution améliorée pour cannabinoïdes et leurs procédés de fabrication |
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MX2010011670A (es) * | 2008-04-28 | 2011-05-02 | Formac Pharmaceuticals N V | Material de silice mesoporoso ordenado. |
US20120231083A1 (en) * | 2010-11-18 | 2012-09-13 | The Board Of Trustees Of The University Of Illinois | Sustained release cannabinoid medicaments |
US20180263953A1 (en) * | 2016-09-27 | 2018-09-20 | CannTab Therapeutics, Limited | Sustained Release Cannabinoid Formulations |
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