WO2010100651A2 - Compositions of polymeric myrcene - Google Patents
Compositions of polymeric myrcene Download PDFInfo
- Publication number
- WO2010100651A2 WO2010100651A2 PCT/IL2010/000184 IL2010000184W WO2010100651A2 WO 2010100651 A2 WO2010100651 A2 WO 2010100651A2 IL 2010000184 W IL2010000184 W IL 2010000184W WO 2010100651 A2 WO2010100651 A2 WO 2010100651A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- myrcene
- composition according
- polymeric
- organic solvent
- fraction
- Prior art date
Links
- UAHWPYUMFXYFJY-UHFFFAOYSA-N beta-myrcene Chemical compound CC(C)=CCCC(=C)C=C UAHWPYUMFXYFJY-UHFFFAOYSA-N 0.000 title claims abstract description 590
- VYBREYKSZAROCT-UHFFFAOYSA-N alpha-myrcene Natural products CC(=C)CCCC(=C)C=C VYBREYKSZAROCT-UHFFFAOYSA-N 0.000 title claims abstract description 288
- 239000000203 mixture Substances 0.000 title claims abstract description 225
- 239000012051 hydrophobic carrier Substances 0.000 claims abstract description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 115
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 105
- 238000000034 method Methods 0.000 claims description 91
- 239000003495 polar organic solvent Substances 0.000 claims description 80
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 78
- 240000005428 Pistacia lentiscus Species 0.000 claims description 76
- -1 isopropanbl Chemical compound 0.000 claims description 71
- 208000027418 Wounds and injury Diseases 0.000 claims description 68
- 206010052428 Wound Diseases 0.000 claims description 61
- 229920000175 Pistacia lentiscus Polymers 0.000 claims description 58
- 239000003921 oil Substances 0.000 claims description 53
- 235000019198 oils Nutrition 0.000 claims description 52
- 150000001875 compounds Chemical class 0.000 claims description 46
- 235000007586 terpenes Nutrition 0.000 claims description 42
- 241000196324 Embryophyta Species 0.000 claims description 37
- 238000006116 polymerization reaction Methods 0.000 claims description 37
- 239000002904 solvent Substances 0.000 claims description 35
- 239000008194 pharmaceutical composition Substances 0.000 claims description 33
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 32
- 239000011347 resin Substances 0.000 claims description 31
- 229920005989 resin Polymers 0.000 claims description 31
- 239000000178 monomer Substances 0.000 claims description 29
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 27
- 206010038848 Retinal detachment Diseases 0.000 claims description 26
- 230000008569 process Effects 0.000 claims description 25
- 239000000243 solution Substances 0.000 claims description 25
- 230000001939 inductive effect Effects 0.000 claims description 23
- 239000000463 material Substances 0.000 claims description 23
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 22
- 150000002632 lipids Chemical class 0.000 claims description 20
- 238000002347 injection Methods 0.000 claims description 19
- 239000007924 injection Substances 0.000 claims description 19
- 230000004264 retinal detachment Effects 0.000 claims description 19
- 239000004530 micro-emulsion Substances 0.000 claims description 18
- 239000004006 olive oil Substances 0.000 claims description 18
- 235000008390 olive oil Nutrition 0.000 claims description 18
- 230000001771 impaired effect Effects 0.000 claims description 17
- 230000007658 neurological function Effects 0.000 claims description 17
- 239000000843 powder Substances 0.000 claims description 16
- 208000017520 skin disease Diseases 0.000 claims description 16
- 238000003786 synthesis reaction Methods 0.000 claims description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 claims description 15
- 239000000839 emulsion Substances 0.000 claims description 15
- 201000004810 Vascular dementia Diseases 0.000 claims description 14
- 208000014674 injury Diseases 0.000 claims description 14
- 239000002502 liposome Substances 0.000 claims description 14
- 239000002245 particle Substances 0.000 claims description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 13
- 239000008169 grapeseed oil Substances 0.000 claims description 13
- 239000007908 nanoemulsion Substances 0.000 claims description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- 230000006378 damage Effects 0.000 claims description 12
- 208000015181 infectious disease Diseases 0.000 claims description 12
- XMGQYMWWDOXHJM-UHFFFAOYSA-N limonene Chemical compound CC(=C)C1CCC(C)=CC1 XMGQYMWWDOXHJM-UHFFFAOYSA-N 0.000 claims description 12
- 239000003960 organic solvent Substances 0.000 claims description 12
- 239000007921 spray Substances 0.000 claims description 12
- 230000017423 tissue regeneration Effects 0.000 claims description 12
- 239000002775 capsule Substances 0.000 claims description 11
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 11
- GRWFGVWFFZKLTI-IUCAKERBSA-N (-)-α-pinene Chemical compound CC1=CC[C@@H]2C(C)(C)[C@H]1C2 GRWFGVWFFZKLTI-IUCAKERBSA-N 0.000 claims description 10
- 208000024827 Alzheimer disease Diseases 0.000 claims description 10
- 229920000858 Cyclodextrin Polymers 0.000 claims description 10
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical class CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 10
- 229920001577 copolymer Polymers 0.000 claims description 10
- 229920006395 saturated elastomer Polymers 0.000 claims description 10
- QPRQEDXDYOZYLA-UHFFFAOYSA-N 2-methylbutan-1-ol Chemical compound CCC(C)CO QPRQEDXDYOZYLA-UHFFFAOYSA-N 0.000 claims description 9
- MSXVEPNJUHWQHW-UHFFFAOYSA-N 2-methylbutan-2-ol Chemical compound CCC(C)(C)O MSXVEPNJUHWQHW-UHFFFAOYSA-N 0.000 claims description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 9
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 9
- 208000004210 Pressure Ulcer Diseases 0.000 claims description 9
- 208000006011 Stroke Diseases 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 235000012343 cottonseed oil Nutrition 0.000 claims description 9
- 239000002385 cottonseed oil Substances 0.000 claims description 9
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 claims description 9
- 239000000725 suspension Substances 0.000 claims description 9
- 230000000699 topical effect Effects 0.000 claims description 9
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 8
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 8
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 8
- 239000000194 fatty acid Substances 0.000 claims description 8
- 229930195729 fatty acid Natural products 0.000 claims description 8
- 238000002513 implantation Methods 0.000 claims description 8
- 239000002736 nonionic surfactant Substances 0.000 claims description 8
- 238000001356 surgical procedure Methods 0.000 claims description 8
- 208000002847 Surgical Wound Diseases 0.000 claims description 7
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 7
- 125000004122 cyclic group Chemical group 0.000 claims description 7
- 201000010099 disease Diseases 0.000 claims description 7
- 229920001983 poloxamer Polymers 0.000 claims description 7
- 238000007920 subcutaneous administration Methods 0.000 claims description 7
- MXLMTQWGSQIYOW-UHFFFAOYSA-N 3-methyl-2-butanol Chemical compound CC(C)C(C)O MXLMTQWGSQIYOW-UHFFFAOYSA-N 0.000 claims description 6
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 6
- 201000004384 Alopecia Diseases 0.000 claims description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 6
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 claims description 6
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 6
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 claims description 6
- 208000008589 Obesity Diseases 0.000 claims description 6
- 240000007354 Pistacia atlantica Species 0.000 claims description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 6
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 6
- 231100000360 alopecia Toxicity 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 6
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 claims description 6
- PHTQWCKDNZKARW-UHFFFAOYSA-N isoamylol Chemical compound CC(C)CCO PHTQWCKDNZKARW-UHFFFAOYSA-N 0.000 claims description 6
- 235000001510 limonene Nutrition 0.000 claims description 6
- 229940087305 limonene Drugs 0.000 claims description 6
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical compound COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 claims description 6
- 235000020824 obesity Nutrition 0.000 claims description 6
- 239000002674 ointment Substances 0.000 claims description 6
- JYVLIDXNZAXMDK-UHFFFAOYSA-N pentan-2-ol Chemical compound CCCC(C)O JYVLIDXNZAXMDK-UHFFFAOYSA-N 0.000 claims description 6
- AQIXEPGDORPWBJ-UHFFFAOYSA-N pentan-3-ol Chemical compound CCC(O)CC AQIXEPGDORPWBJ-UHFFFAOYSA-N 0.000 claims description 6
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 claims description 6
- 238000002390 rotary evaporation Methods 0.000 claims description 6
- 241000894007 species Species 0.000 claims description 6
- 239000003826 tablet Substances 0.000 claims description 6
- WTARULDDTDQWMU-RKDXNWHRSA-N (+)-β-pinene Chemical compound C1[C@H]2C(C)(C)[C@@H]1CCC2=C WTARULDDTDQWMU-RKDXNWHRSA-N 0.000 claims description 5
- WTARULDDTDQWMU-IUCAKERBSA-N (-)-Nopinene Natural products C1[C@@H]2C(C)(C)[C@H]1CCC2=C WTARULDDTDQWMU-IUCAKERBSA-N 0.000 claims description 5
- XJPBRODHZKDRCB-NTMALXAHSA-N (z)-3,7-dimethyl-1,3,7-octatriene Chemical compound CC(=C)CC\C=C(\C)C=C XJPBRODHZKDRCB-NTMALXAHSA-N 0.000 claims description 5
- FUDNBFMOXDUIIE-UHFFFAOYSA-N 3,7-dimethylocta-1,6-diene Chemical compound C=CC(C)CCC=C(C)C FUDNBFMOXDUIIE-UHFFFAOYSA-N 0.000 claims description 5
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical class CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims description 5
- WTARULDDTDQWMU-UHFFFAOYSA-N Pseudopinene Natural products C1C2C(C)(C)C1CCC2=C WTARULDDTDQWMU-UHFFFAOYSA-N 0.000 claims description 5
- 125000002015 acyclic group Chemical group 0.000 claims description 5
- 150000001299 aldehydes Chemical class 0.000 claims description 5
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 claims description 5
- XCPQUQHBVVXMRQ-UHFFFAOYSA-N alpha-Fenchene Natural products C1CC2C(=C)CC1C2(C)C XCPQUQHBVVXMRQ-UHFFFAOYSA-N 0.000 claims description 5
- MVNCAPSFBDBCGF-UHFFFAOYSA-N alpha-pinene Natural products CC1=CCC23C1CC2C3(C)C MVNCAPSFBDBCGF-UHFFFAOYSA-N 0.000 claims description 5
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 claims description 5
- 229930006722 beta-pinene Natural products 0.000 claims description 5
- 239000004359 castor oil Substances 0.000 claims description 5
- 239000002537 cosmetic Substances 0.000 claims description 5
- 150000001924 cycloalkanes Chemical class 0.000 claims description 5
- 150000002148 esters Chemical class 0.000 claims description 5
- LCWMKIHBLJLORW-UHFFFAOYSA-N gamma-carene Natural products C1CC(=C)CC2C(C)(C)C21 LCWMKIHBLJLORW-UHFFFAOYSA-N 0.000 claims description 5
- 150000002576 ketones Chemical class 0.000 claims description 5
- 229920000136 polysorbate Polymers 0.000 claims description 5
- 229940068965 polysorbates Drugs 0.000 claims description 5
- GRWFGVWFFZKLTI-UHFFFAOYSA-N rac-alpha-Pinene Natural products CC1=CCC2C(C)(C)C1C2 GRWFGVWFFZKLTI-UHFFFAOYSA-N 0.000 claims description 5
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 claims description 5
- 239000008159 sesame oil Substances 0.000 claims description 5
- 235000011803 sesame oil Nutrition 0.000 claims description 5
- XJPBRODHZKDRCB-UHFFFAOYSA-N trans-alpha-ocimene Natural products CC(=C)CCC=C(C)C=C XJPBRODHZKDRCB-UHFFFAOYSA-N 0.000 claims description 5
- 235000019489 Almond oil Nutrition 0.000 claims description 4
- 208000034656 Contusions Diseases 0.000 claims description 4
- 206010011985 Decubitus ulcer Diseases 0.000 claims description 4
- 208000001034 Frostbite Diseases 0.000 claims description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 4
- 235000019483 Peanut oil Nutrition 0.000 claims description 4
- 244000160949 Pistacia integerrima Species 0.000 claims description 4
- 240000006705 Pistacia terebinthus Species 0.000 claims description 4
- 240000006711 Pistacia vera Species 0.000 claims description 4
- 241000058010 Pistacia x saportae Species 0.000 claims description 4
- 229920002675 Polyoxyl Polymers 0.000 claims description 4
- 229920001214 Polysorbate 60 Polymers 0.000 claims description 4
- 208000000558 Varicose Ulcer Diseases 0.000 claims description 4
- 150000005215 alkyl ethers Chemical class 0.000 claims description 4
- 239000008168 almond oil Substances 0.000 claims description 4
- 235000019438 castor oil Nutrition 0.000 claims description 4
- 239000004568 cement Substances 0.000 claims description 4
- 230000009519 contusion Effects 0.000 claims description 4
- 239000003292 glue Substances 0.000 claims description 4
- 125000005456 glyceride group Chemical group 0.000 claims description 4
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 claims description 4
- 238000001361 intraarterial administration Methods 0.000 claims description 4
- 238000000185 intracerebroventricular administration Methods 0.000 claims description 4
- 238000007918 intramuscular administration Methods 0.000 claims description 4
- 238000007912 intraperitoneal administration Methods 0.000 claims description 4
- 238000007913 intrathecal administration Methods 0.000 claims description 4
- 239000000312 peanut oil Substances 0.000 claims description 4
- 239000000829 suppository Substances 0.000 claims description 4
- 230000000451 tissue damage Effects 0.000 claims description 4
- 231100000827 tissue damage Toxicity 0.000 claims description 4
- 230000008733 trauma Effects 0.000 claims description 4
- 239000008096 xylene Substances 0.000 claims description 4
- NVJUHMXYKCUMQA-UHFFFAOYSA-N 1-ethoxypropane Chemical compound CCCOCC NVJUHMXYKCUMQA-UHFFFAOYSA-N 0.000 claims description 3
- JKTCBAGSMQIFNL-UHFFFAOYSA-N 2,3-dihydrofuran Chemical compound C1CC=CO1 JKTCBAGSMQIFNL-UHFFFAOYSA-N 0.000 claims description 3
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 claims description 3
- MGADZUXDNSDTHW-UHFFFAOYSA-N 2H-pyran Chemical compound C1OC=CC=C1 MGADZUXDNSDTHW-UHFFFAOYSA-N 0.000 claims description 3
- 208000020925 Bipolar disease Diseases 0.000 claims description 3
- 206010006895 Cachexia Diseases 0.000 claims description 3
- 244000124209 Crocus sativus Species 0.000 claims description 3
- 235000015655 Crocus sativus Nutrition 0.000 claims description 3
- 201000004624 Dermatitis Diseases 0.000 claims description 3
- 208000008960 Diabetic foot Diseases 0.000 claims description 3
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 claims description 3
- 206010019909 Hernia Diseases 0.000 claims description 3
- XOBKSJJDNFUZPF-UHFFFAOYSA-N Methoxyethane Chemical compound CCOC XOBKSJJDNFUZPF-UHFFFAOYSA-N 0.000 claims description 3
- RJUFJBKOKNCXHH-UHFFFAOYSA-N Methyl propionate Chemical compound CCC(=O)OC RJUFJBKOKNCXHH-UHFFFAOYSA-N 0.000 claims description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 3
- 208000018737 Parkinson disease Diseases 0.000 claims description 3
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims description 3
- 201000004681 Psoriasis Diseases 0.000 claims description 3
- 208000010378 Pulmonary Embolism Diseases 0.000 claims description 3
- 206010039792 Seborrhoea Diseases 0.000 claims description 3
- 206010039796 Seborrhoeic keratosis Diseases 0.000 claims description 3
- 206010039966 Senile dementia Diseases 0.000 claims description 3
- 206010041648 Splenic infarction Diseases 0.000 claims description 3
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 claims description 3
- IKHGUXGNUITLKF-XPULMUKRSA-N acetaldehyde Chemical compound [14CH]([14CH3])=O IKHGUXGNUITLKF-XPULMUKRSA-N 0.000 claims description 3
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 3
- 239000000443 aerosol Substances 0.000 claims description 3
- 150000001408 amides Chemical class 0.000 claims description 3
- 238000002266 amputation Methods 0.000 claims description 3
- 208000022531 anorexia Diseases 0.000 claims description 3
- 210000001367 artery Anatomy 0.000 claims description 3
- 208000010668 atopic eczema Diseases 0.000 claims description 3
- 239000000828 canola oil Substances 0.000 claims description 3
- 235000019519 canola oil Nutrition 0.000 claims description 3
- 206010008118 cerebral infarction Diseases 0.000 claims description 3
- 208000026106 cerebrovascular disease Diseases 0.000 claims description 3
- 239000003240 coconut oil Substances 0.000 claims description 3
- 235000019864 coconut oil Nutrition 0.000 claims description 3
- 235000005687 corn oil Nutrition 0.000 claims description 3
- 239000002285 corn oil Substances 0.000 claims description 3
- 206010061428 decreased appetite Diseases 0.000 claims description 3
- 229940093476 ethylene glycol Drugs 0.000 claims description 3
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 208000026278 immune system disease Diseases 0.000 claims description 3
- 239000006210 lotion Substances 0.000 claims description 3
- VNKYTQGIUYNRMY-UHFFFAOYSA-N methoxypropane Chemical compound CCCOC VNKYTQGIUYNRMY-UHFFFAOYSA-N 0.000 claims description 3
- 229940017219 methyl propionate Drugs 0.000 claims description 3
- 239000011859 microparticle Substances 0.000 claims description 3
- 201000006417 multiple sclerosis Diseases 0.000 claims description 3
- 208000010125 myocardial infarction Diseases 0.000 claims description 3
- YKYONYBAUNKHLG-UHFFFAOYSA-N n-Propyl acetate Natural products CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 claims description 3
- KPSSIOMAKSHJJG-UHFFFAOYSA-N neopentyl alcohol Chemical compound CC(C)(C)CO KPSSIOMAKSHJJG-UHFFFAOYSA-N 0.000 claims description 3
- 150000002825 nitriles Chemical class 0.000 claims description 3
- 235000014571 nuts Nutrition 0.000 claims description 3
- 230000002093 peripheral effect Effects 0.000 claims description 3
- 229960000502 poloxamer Drugs 0.000 claims description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 3
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 claims description 3
- 229940090181 propyl acetate Drugs 0.000 claims description 3
- 239000004248 saffron Substances 0.000 claims description 3
- 235000013974 saffron Nutrition 0.000 claims description 3
- 201000000980 schizophrenia Diseases 0.000 claims description 3
- 208000008742 seborrheic dermatitis Diseases 0.000 claims description 3
- 201000003385 seborrheic keratosis Diseases 0.000 claims description 3
- 239000003549 soybean oil Substances 0.000 claims description 3
- 235000012424 soybean oil Nutrition 0.000 claims description 3
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 claims description 3
- 150000003712 vitamin E derivatives Chemical class 0.000 claims description 3
- 239000006071 cream Substances 0.000 claims description 2
- 239000000412 dendrimer Substances 0.000 claims description 2
- 229920000736 dendritic polymer Polymers 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 238000007917 intracranial administration Methods 0.000 claims 1
- 230000002685 pulmonary effect Effects 0.000 claims 1
- 229920000642 polymer Polymers 0.000 abstract description 54
- 230000004071 biological effect Effects 0.000 abstract description 21
- 238000009472 formulation Methods 0.000 abstract description 19
- 210000004027 cell Anatomy 0.000 description 111
- 239000013521 mastic Substances 0.000 description 58
- 230000000694 effects Effects 0.000 description 55
- 238000002360 preparation method Methods 0.000 description 41
- 238000011282 treatment Methods 0.000 description 38
- 238000001542 size-exclusion chromatography Methods 0.000 description 33
- 239000003981 vehicle Substances 0.000 description 32
- 239000000047 product Substances 0.000 description 31
- 241001465754 Metazoa Species 0.000 description 29
- 239000007943 implant Substances 0.000 description 29
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 29
- 230000004069 differentiation Effects 0.000 description 28
- 230000024245 cell differentiation Effects 0.000 description 25
- 241000699670 Mus sp. Species 0.000 description 22
- 241000700159 Rattus Species 0.000 description 22
- 239000000284 extract Substances 0.000 description 22
- 238000012360 testing method Methods 0.000 description 20
- 239000002198 insoluble material Substances 0.000 description 19
- 210000001519 tissue Anatomy 0.000 description 18
- 239000002798 polar solvent Substances 0.000 description 17
- 230000001225 therapeutic effect Effects 0.000 description 17
- 238000006243 chemical reaction Methods 0.000 description 16
- 239000012454 non-polar solvent Substances 0.000 description 15
- 238000004519 manufacturing process Methods 0.000 description 14
- 210000001525 retina Anatomy 0.000 description 14
- 210000003491 skin Anatomy 0.000 description 14
- 239000001993 wax Substances 0.000 description 14
- 230000029663 wound healing Effects 0.000 description 14
- 238000011534 incubation Methods 0.000 description 13
- 210000002569 neuron Anatomy 0.000 description 13
- 239000012071 phase Substances 0.000 description 13
- 241000251468 Actinopterygii Species 0.000 description 12
- 230000015572 biosynthetic process Effects 0.000 description 12
- 238000004090 dissolution Methods 0.000 description 12
- 210000003583 retinal pigment epithelium Anatomy 0.000 description 12
- 239000000126 substance Substances 0.000 description 12
- 241000282472 Canis lupus familiaris Species 0.000 description 11
- 206010028980 Neoplasm Diseases 0.000 description 11
- 239000004480 active ingredient Substances 0.000 description 11
- 235000019786 weight gain Nutrition 0.000 description 11
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 10
- XUMBMVFBXHLACL-UHFFFAOYSA-N Melanin Chemical compound O=C1C(=O)C(C2=CNC3=C(C(C(=O)C4=C32)=O)C)=C2C4=CNC2=C1C XUMBMVFBXHLACL-UHFFFAOYSA-N 0.000 description 10
- 235000004768 Pistacia lentiscus Nutrition 0.000 description 10
- 102000013008 Semaphorin-3A Human genes 0.000 description 10
- 108010090319 Semaphorin-3A Proteins 0.000 description 10
- 238000005755 formation reaction Methods 0.000 description 10
- 239000002609 medium Substances 0.000 description 10
- 238000011084 recovery Methods 0.000 description 10
- 150000003505 terpenes Chemical class 0.000 description 10
- 241000543704 Pistacia Species 0.000 description 9
- 230000037396 body weight Effects 0.000 description 9
- 229920001519 homopolymer Polymers 0.000 description 9
- 239000002480 mineral oil Substances 0.000 description 9
- 229930003658 monoterpene Natural products 0.000 description 9
- 235000002577 monoterpenes Nutrition 0.000 description 9
- 230000001737 promoting effect Effects 0.000 description 9
- 210000003994 retinal ganglion cell Anatomy 0.000 description 9
- 239000008158 vegetable oil Substances 0.000 description 9
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 8
- 235000003445 Pistacia Nutrition 0.000 description 8
- 230000009286 beneficial effect Effects 0.000 description 8
- 238000000605 extraction Methods 0.000 description 8
- 235000013305 food Nutrition 0.000 description 8
- 239000007788 liquid Substances 0.000 description 8
- 201000001441 melanoma Diseases 0.000 description 8
- 235000010446 mineral oil Nutrition 0.000 description 8
- 150000002773 monoterpene derivatives Chemical class 0.000 description 8
- 230000001537 neural effect Effects 0.000 description 8
- 210000000056 organ Anatomy 0.000 description 8
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 8
- 235000015112 vegetable and seed oil Nutrition 0.000 description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 7
- 238000010539 anionic addition polymerization reaction Methods 0.000 description 7
- 229910002092 carbon dioxide Inorganic materials 0.000 description 7
- 230000030833 cell death Effects 0.000 description 7
- 239000003153 chemical reaction reagent Substances 0.000 description 7
- 239000006185 dispersion Substances 0.000 description 7
- 239000003814 drug Substances 0.000 description 7
- 238000001704 evaporation Methods 0.000 description 7
- 230000006870 function Effects 0.000 description 7
- 239000011521 glass Substances 0.000 description 7
- 230000006698 induction Effects 0.000 description 7
- 239000003999 initiator Substances 0.000 description 7
- 210000001328 optic nerve Anatomy 0.000 description 7
- 230000002829 reductive effect Effects 0.000 description 7
- 239000000758 substrate Substances 0.000 description 7
- 102000053171 Glial Fibrillary Acidic Human genes 0.000 description 6
- 101710193519 Glial fibrillary acidic protein Proteins 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- RRHGJUQNOFWUDK-UHFFFAOYSA-N Isoprene Chemical compound CC(=C)C=C RRHGJUQNOFWUDK-UHFFFAOYSA-N 0.000 description 6
- 206010029260 Neuroblastoma Diseases 0.000 description 6
- 229920002472 Starch Polymers 0.000 description 6
- 208000025865 Ulcer Diseases 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 6
- 238000004113 cell culture Methods 0.000 description 6
- 230000004663 cell proliferation Effects 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 238000000576 coating method Methods 0.000 description 6
- 238000009826 distribution Methods 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 230000008020 evaporation Effects 0.000 description 6
- 210000005046 glial fibrillary acidic protein Anatomy 0.000 description 6
- 239000004615 ingredient Substances 0.000 description 6
- 238000002156 mixing Methods 0.000 description 6
- 230000004660 morphological change Effects 0.000 description 6
- 238000000926 separation method Methods 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 239000004094 surface-active agent Substances 0.000 description 6
- 238000011200 topical administration Methods 0.000 description 6
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- 241000208223 Anacardiaceae Species 0.000 description 5
- 206010065384 Cerebral hypoperfusion Diseases 0.000 description 5
- 239000012983 Dulbecco’s minimal essential medium Substances 0.000 description 5
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- 102100021878 Neuronal pentraxin-2 Human genes 0.000 description 5
- 101710155147 Neuronal pentraxin-2 Proteins 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 101710202239 Tubulin beta-3 chain Proteins 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 5
- 238000010171 animal model Methods 0.000 description 5
- 201000011510 cancer Diseases 0.000 description 5
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 5
- 230000002500 effect on skin Effects 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 230000001965 increasing effect Effects 0.000 description 5
- 230000003902 lesion Effects 0.000 description 5
- 230000007170 pathology Effects 0.000 description 5
- 239000002953 phosphate buffered saline Substances 0.000 description 5
- 239000008389 polyethoxylated castor oil Substances 0.000 description 5
- 230000008929 regeneration Effects 0.000 description 5
- 238000011069 regeneration method Methods 0.000 description 5
- 239000002195 soluble material Substances 0.000 description 5
- 150000003648 triterpenes Chemical class 0.000 description 5
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 4
- 102100033647 Activity-regulated cytoskeleton-associated protein Human genes 0.000 description 4
- 101710177131 Activity-regulated cytoskeleton-associated protein Proteins 0.000 description 4
- 206010002091 Anaesthesia Diseases 0.000 description 4
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 4
- 102000003952 Caspase 3 Human genes 0.000 description 4
- 108090000397 Caspase 3 Proteins 0.000 description 4
- 206010012289 Dementia Diseases 0.000 description 4
- 108010010803 Gelatin Proteins 0.000 description 4
- 101000979249 Homo sapiens Neuromodulin Proteins 0.000 description 4
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 4
- 102100023206 Neuromodulin Human genes 0.000 description 4
- 229930182555 Penicillin Natural products 0.000 description 4
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 4
- 239000004793 Polystyrene Substances 0.000 description 4
- 230000037005 anaesthesia Effects 0.000 description 4
- 239000003963 antioxidant agent Substances 0.000 description 4
- 235000006708 antioxidants Nutrition 0.000 description 4
- 235000021028 berry Nutrition 0.000 description 4
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 4
- 230000001684 chronic effect Effects 0.000 description 4
- 229940097362 cyclodextrins Drugs 0.000 description 4
- 230000007423 decrease Effects 0.000 description 4
- 208000035475 disorder Diseases 0.000 description 4
- 229930004069 diterpene Natural products 0.000 description 4
- 125000000567 diterpene group Chemical group 0.000 description 4
- 239000002031 ethanolic fraction Substances 0.000 description 4
- 210000000416 exudates and transudate Anatomy 0.000 description 4
- 239000012091 fetal bovine serum Substances 0.000 description 4
- 239000008273 gelatin Substances 0.000 description 4
- 229920000159 gelatin Polymers 0.000 description 4
- 239000007903 gelatin capsule Substances 0.000 description 4
- 235000019322 gelatine Nutrition 0.000 description 4
- 235000011852 gelatine desserts Nutrition 0.000 description 4
- 229920000140 heteropolymer Polymers 0.000 description 4
- 238000002991 immunohistochemical analysis Methods 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 238000000569 multi-angle light scattering Methods 0.000 description 4
- 230000000926 neurological effect Effects 0.000 description 4
- 239000007764 o/w emulsion Substances 0.000 description 4
- 239000012188 paraffin wax Substances 0.000 description 4
- 229940049954 penicillin Drugs 0.000 description 4
- 229920001223 polyethylene glycol Polymers 0.000 description 4
- 229920001296 polysiloxane Polymers 0.000 description 4
- 229920002223 polystyrene Polymers 0.000 description 4
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 230000004044 response Effects 0.000 description 4
- 210000000844 retinal pigment epithelial cell Anatomy 0.000 description 4
- 210000004761 scalp Anatomy 0.000 description 4
- 238000000527 sonication Methods 0.000 description 4
- 238000001694 spray drying Methods 0.000 description 4
- 239000003381 stabilizer Substances 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 210000000130 stem cell Anatomy 0.000 description 4
- 229960005322 streptomycin Drugs 0.000 description 4
- 150000003535 tetraterpenes Chemical class 0.000 description 4
- 235000009657 tetraterpenes Nutrition 0.000 description 4
- 238000012549 training Methods 0.000 description 4
- 230000001052 transient effect Effects 0.000 description 4
- 210000004881 tumor cell Anatomy 0.000 description 4
- 239000000341 volatile oil Substances 0.000 description 4
- 230000004584 weight gain Effects 0.000 description 4
- 238000001262 western blot Methods 0.000 description 4
- 241000894006 Bacteria Species 0.000 description 3
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 3
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 3
- XMSXQFUHVRWGNA-UHFFFAOYSA-N Decamethylcyclopentasiloxane Chemical compound C[Si]1(C)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)O1 XMSXQFUHVRWGNA-UHFFFAOYSA-N 0.000 description 3
- 101000713575 Homo sapiens Tubulin beta-3 chain Proteins 0.000 description 3
- 241000721662 Juniperus Species 0.000 description 3
- 241000218652 Larix Species 0.000 description 3
- 238000012347 Morris Water Maze Methods 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- 241000218657 Picea Species 0.000 description 3
- 235000005205 Pinus Nutrition 0.000 description 3
- 241000218602 Pinus <genus> Species 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- 229920002690 Polyoxyl 40 HydrogenatedCastorOil Polymers 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 235000012377 Salvia columbariae var. columbariae Nutrition 0.000 description 3
- 240000005481 Salvia hispanica Species 0.000 description 3
- 235000001498 Salvia hispanica Nutrition 0.000 description 3
- 206010072170 Skin wound Diseases 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 102100036790 Tubulin beta-3 chain Human genes 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 230000032683 aging Effects 0.000 description 3
- 229910052783 alkali metal Inorganic materials 0.000 description 3
- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical compound OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 description 3
- 230000003444 anaesthetic effect Effects 0.000 description 3
- 230000000844 anti-bacterial effect Effects 0.000 description 3
- 230000001093 anti-cancer Effects 0.000 description 3
- 230000004596 appetite loss Effects 0.000 description 3
- 238000000149 argon plasma sintering Methods 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 210000003050 axon Anatomy 0.000 description 3
- 230000006399 behavior Effects 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 210000004556 brain Anatomy 0.000 description 3
- 239000001506 calcium phosphate Substances 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 229920002678 cellulose Polymers 0.000 description 3
- 239000001913 cellulose Substances 0.000 description 3
- 238000012512 characterization method Methods 0.000 description 3
- 238000001311 chemical methods and process Methods 0.000 description 3
- 235000014167 chia Nutrition 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 239000011248 coating agent Substances 0.000 description 3
- 230000003920 cognitive function Effects 0.000 description 3
- 229940086555 cyclomethicone Drugs 0.000 description 3
- 210000001787 dendrite Anatomy 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 239000008298 dragée Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 235000013399 edible fruits Nutrition 0.000 description 3
- 229920001971 elastomer Polymers 0.000 description 3
- 238000004520 electroporation Methods 0.000 description 3
- 238000000105 evaporative light scattering detection Methods 0.000 description 3
- 210000003722 extracellular fluid Anatomy 0.000 description 3
- 239000003925 fat Substances 0.000 description 3
- 235000019197 fats Nutrition 0.000 description 3
- 239000000499 gel Substances 0.000 description 3
- 230000009477 glass transition Effects 0.000 description 3
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 210000004209 hair Anatomy 0.000 description 3
- 210000003780 hair follicle Anatomy 0.000 description 3
- 230000035876 healing Effects 0.000 description 3
- 239000003906 humectant Substances 0.000 description 3
- 229930195733 hydrocarbon Natural products 0.000 description 3
- 230000002209 hydrophobic effect Effects 0.000 description 3
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 3
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 229940059904 light mineral oil Drugs 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 210000004379 membrane Anatomy 0.000 description 3
- 230000006724 microglial activation Effects 0.000 description 3
- 230000002025 microglial effect Effects 0.000 description 3
- 230000000877 morphologic effect Effects 0.000 description 3
- 230000007659 motor function Effects 0.000 description 3
- 230000004112 neuroprotection Effects 0.000 description 3
- 230000007935 neutral effect Effects 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- 230000000399 orthopedic effect Effects 0.000 description 3
- 238000007911 parenteral administration Methods 0.000 description 3
- 230000001575 pathological effect Effects 0.000 description 3
- 235000019271 petrolatum Nutrition 0.000 description 3
- 150000003904 phospholipids Chemical class 0.000 description 3
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000011552 rat model Methods 0.000 description 3
- 230000008439 repair process Effects 0.000 description 3
- 230000002207 retinal effect Effects 0.000 description 3
- 229930004725 sesquiterpene Natural products 0.000 description 3
- 150000004354 sesquiterpene derivatives Chemical class 0.000 description 3
- 239000000600 sorbitol Substances 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 230000000946 synaptic effect Effects 0.000 description 3
- 239000000454 talc Substances 0.000 description 3
- 229910052623 talc Inorganic materials 0.000 description 3
- 235000012222 talc Nutrition 0.000 description 3
- 238000002054 transplantation Methods 0.000 description 3
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical class [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 3
- 231100000397 ulcer Toxicity 0.000 description 3
- 238000000196 viscometry Methods 0.000 description 3
- NCYCYZXNIZJOKI-UHFFFAOYSA-N vitamin A aldehyde Natural products O=CC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C NCYCYZXNIZJOKI-UHFFFAOYSA-N 0.000 description 3
- FMIMFCRXYXVFTA-FUAOEXFOSA-N (4as,6ar,6as,6br,8ar,12ar,14bs)-2,2,6a,6b,9,9,12a-heptamethyl-10-oxo-3,4,5,6,6a,7,8,8a,11,12,13,14b-dodecahydro-1h-picene-4a-carboxylic acid Chemical compound C1CC(=O)C(C)(C)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(C(O)=O)CCC(C)(C)C[C@H]5C4=CC[C@@H]3[C@]21C FMIMFCRXYXVFTA-FUAOEXFOSA-N 0.000 description 2
- FPIPGXGPPPQFEQ-UHFFFAOYSA-N 13-cis retinol Natural products OCC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-UHFFFAOYSA-N 0.000 description 2
- BANXPJUEBPWEOT-UHFFFAOYSA-N 2-methyl-Pentadecane Chemical compound CCCCCCCCCCCCCC(C)C BANXPJUEBPWEOT-UHFFFAOYSA-N 0.000 description 2
- 244000215068 Acacia senegal Species 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- 241000207875 Antirrhinum Species 0.000 description 2
- 235000018062 Boswellia Nutrition 0.000 description 2
- 240000007551 Boswellia serrata Species 0.000 description 2
- 241000252229 Carassius auratus Species 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 206010008089 Cerebral artery occlusion Diseases 0.000 description 2
- 241000207199 Citrus Species 0.000 description 2
- 241000252233 Cyprinus carpio Species 0.000 description 2
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 2
- 206010063560 Excessive granulation tissue Diseases 0.000 description 2
- 206010018341 Gliosis Diseases 0.000 description 2
- 235000010469 Glycine max Nutrition 0.000 description 2
- 229920000084 Gum arabic Polymers 0.000 description 2
- 241001558017 Gynura Species 0.000 description 2
- YQEZLKZALYSWHR-UHFFFAOYSA-N Ketamine Chemical compound C=1C=CC=C(Cl)C=1C1(NC)CCCCC1=O YQEZLKZALYSWHR-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 241001671311 Laurus Species 0.000 description 2
- 208000005230 Leg Ulcer Diseases 0.000 description 2
- 241001529734 Ocimum Species 0.000 description 2
- 235000011205 Ocimum Nutrition 0.000 description 2
- 208000030768 Optic nerve injury Diseases 0.000 description 2
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 2
- 208000002463 Sveinsson chorioretinal atrophy Diseases 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- AOBORMOPSGHCAX-UHFFFAOYSA-N Tocophersolan Chemical compound OCCOC(=O)CCC(=O)OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C AOBORMOPSGHCAX-UHFFFAOYSA-N 0.000 description 2
- KGEKLUUHTZCSIP-HOSYDEDBSA-N [(1s,4s,6r)-1,7,7-trimethyl-6-bicyclo[2.2.1]heptanyl] acetate Chemical compound C1C[C@]2(C)[C@H](OC(=O)C)C[C@H]1C2(C)C KGEKLUUHTZCSIP-HOSYDEDBSA-N 0.000 description 2
- 235000010489 acacia gum Nutrition 0.000 description 2
- 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 description 2
- 239000000061 acid fraction Substances 0.000 description 2
- 229930003651 acyclic monoterpene Natural products 0.000 description 2
- 150000002841 acyclic monoterpene derivatives Chemical class 0.000 description 2
- 239000000853 adhesive Substances 0.000 description 2
- 230000001070 adhesive effect Effects 0.000 description 2
- 238000013019 agitation Methods 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 230000000845 anti-microbial effect Effects 0.000 description 2
- 230000003078 antioxidant effect Effects 0.000 description 2
- 235000019789 appetite Nutrition 0.000 description 2
- 230000036528 appetite Effects 0.000 description 2
- 239000012736 aqueous medium Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000000823 artificial membrane Substances 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 238000001574 biopsy Methods 0.000 description 2
- 210000000481 breast Anatomy 0.000 description 2
- 235000011010 calcium phosphates Nutrition 0.000 description 2
- 150000001720 carbohydrates Chemical class 0.000 description 2
- 239000001569 carbon dioxide Substances 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 230000000747 cardiac effect Effects 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- 210000003710 cerebral cortex Anatomy 0.000 description 2
- 230000002490 cerebral effect Effects 0.000 description 2
- 235000020971 citrus fruits Nutrition 0.000 description 2
- 208000029742 colonic neoplasm Diseases 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 230000007812 deficiency Effects 0.000 description 2
- 230000006735 deficit Effects 0.000 description 2
- 239000004053 dental implant Substances 0.000 description 2
- 229910003460 diamond Inorganic materials 0.000 description 2
- 239000010432 diamond Substances 0.000 description 2
- 238000007865 diluting Methods 0.000 description 2
- 229910001882 dioxygen Inorganic materials 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 208000000718 duodenal ulcer Diseases 0.000 description 2
- 238000002296 dynamic light scattering Methods 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 210000002889 endothelial cell Anatomy 0.000 description 2
- 210000002919 epithelial cell Anatomy 0.000 description 2
- 210000000981 epithelium Anatomy 0.000 description 2
- 239000004744 fabric Substances 0.000 description 2
- 239000010685 fatty oil Substances 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000001030 gas--liquid chromatography Methods 0.000 description 2
- 210000004051 gastric juice Anatomy 0.000 description 2
- 238000005227 gel permeation chromatography Methods 0.000 description 2
- 210000001126 granulation tissue Anatomy 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000008240 homogeneous mixture Substances 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- 239000000017 hydrogel Substances 0.000 description 2
- 238000003384 imaging method Methods 0.000 description 2
- 238000010185 immunofluorescence analysis Methods 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 238000010348 incorporation Methods 0.000 description 2
- 230000000977 initiatory effect Effects 0.000 description 2
- 230000003585 interneuronal effect Effects 0.000 description 2
- 238000007915 intraurethral administration Methods 0.000 description 2
- 208000028867 ischemia Diseases 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 229960003299 ketamine Drugs 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 235000010445 lecithin Nutrition 0.000 description 2
- 239000000787 lecithin Substances 0.000 description 2
- 229940057995 liquid paraffin Drugs 0.000 description 2
- 230000033001 locomotion Effects 0.000 description 2
- 208000019017 loss of appetite Diseases 0.000 description 2
- 235000021266 loss of appetite Nutrition 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 230000003211 malignant effect Effects 0.000 description 2
- 239000003550 marker Substances 0.000 description 2
- 238000004949 mass spectrometry Methods 0.000 description 2
- 238000001840 matrix-assisted laser desorption--ionisation time-of-flight mass spectrometry Methods 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- 210000000274 microglia Anatomy 0.000 description 2
- 201000007309 middle cerebral artery infarction Diseases 0.000 description 2
- 239000012184 mineral wax Substances 0.000 description 2
- 239000004570 mortar (masonry) Substances 0.000 description 2
- 238000010172 mouse model Methods 0.000 description 2
- 150000002786 myrcene derivatives Chemical class 0.000 description 2
- 230000000626 neurodegenerative effect Effects 0.000 description 2
- BKIMMITUMNQMOS-UHFFFAOYSA-N nonane Chemical compound CCCCCCCCC BKIMMITUMNQMOS-UHFFFAOYSA-N 0.000 description 2
- 230000001956 orexigenic effect Effects 0.000 description 2
- 108091008695 photoreceptors Proteins 0.000 description 2
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 2
- 230000000379 polymerizing effect Effects 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 230000010076 replication Effects 0.000 description 2
- 239000013557 residual solvent Substances 0.000 description 2
- 230000002441 reversible effect Effects 0.000 description 2
- 239000005060 rubber Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000004062 sedimentation Methods 0.000 description 2
- 230000037152 sensory function Effects 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 238000004513 sizing Methods 0.000 description 2
- 238000001998 small-angle neutron scattering Methods 0.000 description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 2
- 239000007901 soft capsule Substances 0.000 description 2
- 238000000638 solvent extraction Methods 0.000 description 2
- 230000003238 somatosensory effect Effects 0.000 description 2
- 238000010186 staining Methods 0.000 description 2
- 230000008093 supporting effect Effects 0.000 description 2
- 239000002511 suppository base Substances 0.000 description 2
- 230000008961 swelling Effects 0.000 description 2
- 238000002626 targeted therapy Methods 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 description 2
- 150000003626 triacylglycerols Chemical class 0.000 description 2
- LADGBHLMCUINGV-UHFFFAOYSA-N tricaprin Chemical compound CCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCC)COC(=O)CCCCCCCCC LADGBHLMCUINGV-UHFFFAOYSA-N 0.000 description 2
- 230000036269 ulceration Effects 0.000 description 2
- 230000002792 vascular Effects 0.000 description 2
- 239000012178 vegetable wax Substances 0.000 description 2
- 210000004885 white matter Anatomy 0.000 description 2
- FQTLCLSUCSAZDY-UHFFFAOYSA-N (+) E(S) nerolidol Natural products CC(C)=CCCC(C)=CCCC(C)(O)C=C FQTLCLSUCSAZDY-UHFFFAOYSA-N 0.000 description 1
- MHAVMNJPXLZEIG-CNRMHUMKSA-N (1r,3as,5ar,5br,7ar,11ar,11br,13ar,13br)-5a,5b,8,8,11a-pentamethyl-9-oxo-1-prop-1-en-2-yl-2,3,4,5,6,7,7a,10,11,11b,12,13,13a,13b-tetradecahydro-1h-cyclopenta[a]chrysene-3a-carbaldehyde Chemical compound C1CC(=O)C(C)(C)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(C=O)CC[C@@H](C(=C)C)[C@@H]5[C@H]4CC[C@@H]3[C@]21C MHAVMNJPXLZEIG-CNRMHUMKSA-N 0.000 description 1
- CRDAMVZIKSXKFV-FBXUGWQNSA-N (2-cis,6-cis)-farnesol Chemical compound CC(C)=CCC\C(C)=C/CC\C(C)=C/CO CRDAMVZIKSXKFV-FBXUGWQNSA-N 0.000 description 1
- 239000000260 (2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-ol Substances 0.000 description 1
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- HITROERJXNWVOI-SOFGYWHQSA-N (5e)-octa-1,5-diene Chemical compound CC\C=C\CCC=C HITROERJXNWVOI-SOFGYWHQSA-N 0.000 description 1
- YYGNTYWPHWGJRM-UHFFFAOYSA-N (6E,10E,14E,18E)-2,6,10,15,19,23-hexamethyltetracosa-2,6,10,14,18,22-hexaene Chemical compound CC(C)=CCCC(C)=CCCC(C)=CCCC=C(C)CCC=C(C)CCC=C(C)C YYGNTYWPHWGJRM-UHFFFAOYSA-N 0.000 description 1
- 239000001707 (E,7R,11R)-3,7,11,15-tetramethylhexadec-2-en-1-ol Substances 0.000 description 1
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 description 1
- VOYZLKWKVLYJHD-UZEUFRBSSA-N (z,6s)-2-methyl-6-[(5r,9r,10r,13s,14s,17s)-4,4,10,13,14-pentamethyl-3-oxo-1,2,5,6,9,11,12,15,16,17-decahydrocyclopenta[a]phenanthren-17-yl]hept-2-enoic acid Chemical compound CC1(C)C(=O)CC[C@]2(C)[C@@H](CC[C@]3([C@H]([C@H](CC\C=C(\C)C(O)=O)C)CC[C@@]33C)C)C3=CC[C@H]21 VOYZLKWKVLYJHD-UZEUFRBSSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- NCYCYZXNIZJOKI-IOUUIBBYSA-N 11-cis-retinal Chemical compound O=C/C=C(\C)/C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C NCYCYZXNIZJOKI-IOUUIBBYSA-N 0.000 description 1
- WAYINTBTZWQNSN-UHFFFAOYSA-N 11-methyldodecyl 3,5,5-trimethylhexanoate Chemical compound CC(C)CCCCCCCCCCOC(=O)CC(C)CC(C)(C)C WAYINTBTZWQNSN-UHFFFAOYSA-N 0.000 description 1
- NCYCYZXNIZJOKI-HPNHMNAASA-N 11Z-retinal Natural products CC(=C/C=O)C=C/C=C(C)/C=C/C1=C(C)CCCC1(C)C NCYCYZXNIZJOKI-HPNHMNAASA-N 0.000 description 1
- VRACDWUCKIDHCO-UHFFFAOYSA-N 16-methylheptadecyl 10-[5,6-dihexyl-2-[8-(16-methylheptadecoxy)-8-oxooctyl]cyclohex-3-en-1-yl]dec-9-enoate Chemical compound CCCCCCC1C=CC(CCCCCCCC(=O)OCCCCCCCCCCCCCCCC(C)C)C(C=CCCCCCCCC(=O)OCCCCCCCCCCCCCCCC(C)C)C1CCCCCC VRACDWUCKIDHCO-UHFFFAOYSA-N 0.000 description 1
- BDEHGQOUMOLWCN-UHFFFAOYSA-N 16-methylheptadecyl benzoate Chemical compound CC(C)CCCCCCCCCCCCCCCOC(=O)C1=CC=CC=C1 BDEHGQOUMOLWCN-UHFFFAOYSA-N 0.000 description 1
- 229940043268 2,2,4,4,6,8,8-heptamethylnonane Drugs 0.000 description 1
- CKQNDABUGIXFCL-UHFFFAOYSA-N 2-(2-octanoyloxyethoxy)ethyl octanoate Chemical compound CCCCCCCC(=O)OCCOCCOC(=O)CCCCCCC CKQNDABUGIXFCL-UHFFFAOYSA-N 0.000 description 1
- UADWUILHKRXHMM-UHFFFAOYSA-N 2-ethylhexyl benzoate Chemical compound CCCCC(CC)COC(=O)C1=CC=CC=C1 UADWUILHKRXHMM-UHFFFAOYSA-N 0.000 description 1
- 229940106004 2-ethylhexyl benzoate Drugs 0.000 description 1
- HZLCGUXUOFWCCN-UHFFFAOYSA-N 2-hydroxynonadecane-1,2,3-tricarboxylic acid Chemical compound CCCCCCCCCCCCCCCCC(C(O)=O)C(O)(C(O)=O)CC(O)=O HZLCGUXUOFWCCN-UHFFFAOYSA-N 0.000 description 1
- LNRUVXAPKCPQGX-UHFFFAOYSA-N 2-octyldodecyl benzoate Chemical compound CCCCCCCCCCC(CCCCCCCC)COC(=O)C1=CC=CC=C1 LNRUVXAPKCPQGX-UHFFFAOYSA-N 0.000 description 1
- VOYZLKWKVLYJHD-UHFFFAOYSA-N 24Z-masticadienonic acid Natural products CC1(C)C(=O)CCC2(C)C(CCC3(C(C(CCC=C(C)C(O)=O)C)CCC33C)C)C3=CCC21 VOYZLKWKVLYJHD-UHFFFAOYSA-N 0.000 description 1
- UIVPNOBLHXUKDX-UHFFFAOYSA-N 3,5,5-trimethylhexyl 3,5,5-trimethylhexanoate Chemical compound CC(C)(C)CC(C)CCOC(=O)CC(C)CC(C)(C)C UIVPNOBLHXUKDX-UHFFFAOYSA-N 0.000 description 1
- FMIMFCRXYXVFTA-UHFFFAOYSA-N 3-Oxo-12-oleanen-28-oic acid Natural products C1CC(=O)C(C)(C)C2CCC3(C)C4(C)CCC5(C(O)=O)CCC(C)(C)CC5C4=CCC3C21C FMIMFCRXYXVFTA-UHFFFAOYSA-N 0.000 description 1
- MIJYXULNPSFWEK-GTOFXWBISA-N 3beta-hydroxyolean-12-en-28-oic acid Chemical compound C1C[C@H](O)C(C)(C)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(C(O)=O)CCC(C)(C)C[C@H]5C4=CC[C@@H]3[C@]21C MIJYXULNPSFWEK-GTOFXWBISA-N 0.000 description 1
- FWBHETKCLVMNFS-UHFFFAOYSA-N 4',6-Diamino-2-phenylindol Chemical compound C1=CC(C(=N)N)=CC=C1C1=CC2=CC=C(C(N)=N)C=C2N1 FWBHETKCLVMNFS-UHFFFAOYSA-N 0.000 description 1
- KEIDIOZOTSZXPK-UHFFFAOYSA-N 4-methylpentyl decanoate Chemical compound CCCCCCCCCC(=O)OCCCC(C)C KEIDIOZOTSZXPK-UHFFFAOYSA-N 0.000 description 1
- UILQHUKSFUOOLH-NHSHZOTLSA-N 6-[(5S,9S,10R,13S,14S,17R)-3-hydroxy-4,4,10,13,14-pentamethyl-2,3,5,6,9,11,12,15,16,17-decahydro-1H-cyclopenta[a]phenanthren-17-yl]-2-methylhept-2-enoic acid Chemical compound CC(CCC=C(C)C(O)=O)[C@H]1CC[C@]2(C)C3=CC[C@@H]4C(C)(C)C(O)CC[C@]4(C)[C@@H]3CC[C@@]12C UILQHUKSFUOOLH-NHSHZOTLSA-N 0.000 description 1
- BRORPGSJXSLXKN-UHFFFAOYSA-N 6-methylheptyl 3,5,5-trimethylhexanoate Chemical compound CC(C)CCCCCOC(=O)CC(C)CC(C)(C)C BRORPGSJXSLXKN-UHFFFAOYSA-N 0.000 description 1
- LSIDHXSWCFFFGE-UHFFFAOYSA-N 7-Methyloctyl octanoate Chemical compound CCCCCCCC(=O)OCCCCCCC(C)C LSIDHXSWCFFFGE-UHFFFAOYSA-N 0.000 description 1
- 206010000087 Abdominal pain upper Diseases 0.000 description 1
- 235000006491 Acacia senegal Nutrition 0.000 description 1
- 102000007469 Actins Human genes 0.000 description 1
- 108010085238 Actins Proteins 0.000 description 1
- 208000036762 Acute promyelocytic leukaemia Diseases 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 101100248253 Arabidopsis thaliana RH40 gene Proteins 0.000 description 1
- 208000031104 Arterial Occlusive disease Diseases 0.000 description 1
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Natural products OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 241000271566 Aves Species 0.000 description 1
- 208000034309 Bacterial disease carrier Diseases 0.000 description 1
- DNJVYWXIDISQRD-UHFFFAOYSA-N Cafestol Natural products C1CC2(CC3(CO)O)CC3CCC2C2(C)C1C(C=CO1)=C1CC2 DNJVYWXIDISQRD-UHFFFAOYSA-N 0.000 description 1
- 240000007857 Castanea sativa Species 0.000 description 1
- 229920002101 Chitin Polymers 0.000 description 1
- 229920001661 Chitosan Polymers 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 244000180278 Copernicia prunifera Species 0.000 description 1
- 235000010919 Copernicia prunifera Nutrition 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 229920000742 Cotton Polymers 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- IELOKBJPULMYRW-NJQVLOCASA-N D-alpha-Tocopheryl Acid Succinate Chemical compound OC(=O)CCC(=O)OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C IELOKBJPULMYRW-NJQVLOCASA-N 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 229920005682 EO-PO block copolymer Polymers 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- JKLISIRFYWXLQG-UHFFFAOYSA-N Epioleonolsaeure Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C)CCC5(C(O)=O)CCC(C)(C)CC5C4CCC3C21C JKLISIRFYWXLQG-UHFFFAOYSA-N 0.000 description 1
- 241001553290 Euphorbia antisyphilitica Species 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 1
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 1
- 230000005526 G1 to G0 transition Effects 0.000 description 1
- 208000018522 Gastrointestinal disease Diseases 0.000 description 1
- 206010061431 Glial scar Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 229920002907 Guar gum Polymers 0.000 description 1
- 229920000569 Gum karaya Polymers 0.000 description 1
- 241000590002 Helicobacter pylori Species 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 108700002232 Immediate-Early Genes Proteins 0.000 description 1
- KDCSSVADTHDYGI-KEBDBYFISA-N Isomasticadienonic acid Chemical compound CC12CCC(=O)C(C)(C)C1CCC1=C2CCC2(C)C(C(CC\C=C(/C)C(O)=O)C)CCC21C KDCSSVADTHDYGI-KEBDBYFISA-N 0.000 description 1
- 229930182816 L-glutamine Natural products 0.000 description 1
- 244000147568 Laurus nobilis Species 0.000 description 1
- 235000017858 Laurus nobilis Nutrition 0.000 description 1
- 208000020358 Learning disease Diseases 0.000 description 1
- 108010092277 Leptin Proteins 0.000 description 1
- 206010024264 Lethargy Diseases 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- VTAJIXDZFCRWBR-UHFFFAOYSA-N Licoricesaponin B2 Natural products C1C(C2C(C3(CCC4(C)CCC(C)(CC4C3=CC2)C(O)=O)C)(C)CC2)(C)C2C(C)(C)CC1OC1OC(C(O)=O)C(O)C(O)C1OC1OC(C(O)=O)C(O)C(O)C1O VTAJIXDZFCRWBR-UHFFFAOYSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 229920000161 Locust bean gum Polymers 0.000 description 1
- 244000182264 Lucuma nervosa Species 0.000 description 1
- UPYKUZBSLRQECL-UKMVMLAPSA-N Lycopene Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1C(=C)CCCC1(C)C)C=CC=C(/C)C=CC2C(=C)CCCC2(C)C UPYKUZBSLRQECL-UKMVMLAPSA-N 0.000 description 1
- 235000019759 Maize starch Nutrition 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 238000006957 Michael reaction Methods 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- 206010029113 Neovascularisation Diseases 0.000 description 1
- CAHGCLMLTWQZNJ-UHFFFAOYSA-N Nerifoliol Natural products CC12CCC(O)C(C)(C)C1CCC1=C2CCC2(C)C(C(CCC=C(C)C)C)CCC21C CAHGCLMLTWQZNJ-UHFFFAOYSA-N 0.000 description 1
- FQTLCLSUCSAZDY-ATGUSINASA-N Nerolidol Chemical compound CC(C)=CCC\C(C)=C\CC[C@](C)(O)C=C FQTLCLSUCSAZDY-ATGUSINASA-N 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- YBRJHZPWOMJYKQ-UHFFFAOYSA-N Oleanolic acid Natural products CC1(C)CC2C3=CCC4C5(C)CCC(O)C(C)(C)C5CCC4(C)C3(C)CCC2(C1)C(=O)O YBRJHZPWOMJYKQ-UHFFFAOYSA-N 0.000 description 1
- MIJYXULNPSFWEK-UHFFFAOYSA-N Oleanolinsaeure Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C)CCC5(C(O)=O)CCC(C)(C)CC5C4=CCC3C21C MIJYXULNPSFWEK-UHFFFAOYSA-N 0.000 description 1
- 235000019482 Palm oil Nutrition 0.000 description 1
- 239000005662 Paraffin oil Substances 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 208000008469 Peptic Ulcer Diseases 0.000 description 1
- 239000004264 Petrolatum Substances 0.000 description 1
- 206010057249 Phagocytosis Diseases 0.000 description 1
- BLUHKGOSFDHHGX-UHFFFAOYSA-N Phytol Natural products CC(C)CCCC(C)CCCC(C)CCCC(C)C=CO BLUHKGOSFDHHGX-UHFFFAOYSA-N 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 1
- 229920002685 Polyoxyl 35CastorOil Polymers 0.000 description 1
- 208000033826 Promyelocytic Acute Leukemia Diseases 0.000 description 1
- 241000186429 Propionibacterium Species 0.000 description 1
- 241000589516 Pseudomonas Species 0.000 description 1
- 240000000111 Saccharum officinarum Species 0.000 description 1
- 235000007201 Saccharum officinarum Nutrition 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- 208000034189 Sclerosis Diseases 0.000 description 1
- 206010040943 Skin Ulcer Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- HNZBNQYXWOLKBA-UHFFFAOYSA-N Tetrahydrofarnesol Natural products CC(C)CCCC(C)CCCC(C)=CCO HNZBNQYXWOLKBA-UHFFFAOYSA-N 0.000 description 1
- BHEOSNUKNHRBNM-UHFFFAOYSA-N Tetramethylsqualene Natural products CC(=C)C(C)CCC(=C)C(C)CCC(C)=CCCC=C(C)CCC(C)C(=C)CCC(C)C(C)=C BHEOSNUKNHRBNM-UHFFFAOYSA-N 0.000 description 1
- 241000278713 Theora Species 0.000 description 1
- CAHGCLMLTWQZNJ-HGKXYCPESA-N Tirucallol Chemical compound C([C@@]12C)C[C@H](O)C(C)(C)[C@@H]1CCC1=C2CC[C@@]2(C)[C@H]([C@H](CCC=C(C)C)C)CC[C@@]21C CAHGCLMLTWQZNJ-HGKXYCPESA-N 0.000 description 1
- 101710101607 Toxic shock syndrome toxin-1 Proteins 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- BGDKAVGWHJFAGW-UHFFFAOYSA-N Tropicamide Chemical compound C=1C=CC=CC=1C(CO)C(=O)N(CC)CC1=CC=NC=C1 BGDKAVGWHJFAGW-UHFFFAOYSA-N 0.000 description 1
- FPIPGXGPPPQFEQ-BOOMUCAASA-N Vitamin A Natural products OC/C=C(/C)\C=C\C=C(\C)/C=C/C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-BOOMUCAASA-N 0.000 description 1
- 206010072731 White matter lesion Diseases 0.000 description 1
- 238000000333 X-ray scattering Methods 0.000 description 1
- SMEGJBVQLJJKKX-HOTMZDKISA-N [(2R,3S,4S,5R,6R)-5-acetyloxy-3,4,6-trihydroxyoxan-2-yl]methyl acetate Chemical compound CC(=O)OC[C@@H]1[C@H]([C@@H]([C@H]([C@@H](O1)O)OC(=O)C)O)O SMEGJBVQLJJKKX-HOTMZDKISA-N 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 229940081735 acetylcellulose Drugs 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid group Chemical group C(C=C)(=O)O NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 230000003044 adaptive effect Effects 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 238000005273 aeration Methods 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 229940040563 agaric acid Drugs 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- BOTWFXYSPFMFNR-OALUTQOASA-N all-rac-phytol Natural products CC(C)CCC[C@H](C)CCC[C@H](C)CCCC(C)=CCO BOTWFXYSPFMFNR-OALUTQOASA-N 0.000 description 1
- 229940100609 all-trans-retinol Drugs 0.000 description 1
- 239000011717 all-trans-retinol Substances 0.000 description 1
- 235000019169 all-trans-retinol Nutrition 0.000 description 1
- 229920005603 alternating copolymer Polymers 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 238000012436 analytical size exclusion chromatography Methods 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000003579 anti-obesity Effects 0.000 description 1
- 239000000883 anti-obesity agent Substances 0.000 description 1
- 230000001741 anti-phlogistic effect Effects 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 229940125710 antiobesity agent Drugs 0.000 description 1
- 230000001640 apoptogenic effect Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 239000002948 appetite stimulant Substances 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 229940070312 arachidyl propionate Drugs 0.000 description 1
- 208000021328 arterial occlusion Diseases 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000002238 attenuated effect Effects 0.000 description 1
- 230000003376 axonal effect Effects 0.000 description 1
- 235000013871 bee wax Nutrition 0.000 description 1
- 239000012166 beeswax Substances 0.000 description 1
- 238000009227 behaviour therapy Methods 0.000 description 1
- 229940005787 behenyl benzoate Drugs 0.000 description 1
- UADWUILHKRXHMM-ZDUSSCGKSA-N benzoflex 181 Natural products CCCC[C@H](CC)COC(=O)C1=CC=CC=C1 UADWUILHKRXHMM-ZDUSSCGKSA-N 0.000 description 1
- VVKREWPWSWPBGC-UHFFFAOYSA-N benzoic acid;2-(2-hydroxypropoxy)propan-1-ol Chemical compound CC(O)COC(C)CO.OC(=O)C1=CC=CC=C1 VVKREWPWSWPBGC-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 229930003642 bicyclic monoterpene Natural products 0.000 description 1
- 150000001604 bicyclic monoterpene derivatives Chemical class 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 229920001400 block copolymer Polymers 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 229940115397 bornyl acetate Drugs 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- DNJVYWXIDISQRD-JTSSGKSMSA-N cafestol Chemical compound C([C@H]1C[C@]2(C[C@@]1(CO)O)CC1)C[C@H]2[C@@]2(C)[C@H]1C(C=CO1)=C1CC2 DNJVYWXIDISQRD-JTSSGKSMSA-N 0.000 description 1
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 238000011088 calibration curve Methods 0.000 description 1
- 230000005907 cancer growth Effects 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- 150000001746 carotenes Chemical class 0.000 description 1
- 235000005473 carotenes Nutrition 0.000 description 1
- 210000001168 carotid artery common Anatomy 0.000 description 1
- 235000010418 carrageenan Nutrition 0.000 description 1
- 239000000679 carrageenan Substances 0.000 description 1
- 229920001525 carrageenan Polymers 0.000 description 1
- 229940113118 carrageenan Drugs 0.000 description 1
- 210000000845 cartilage Anatomy 0.000 description 1
- 210000005056 cell body Anatomy 0.000 description 1
- 230000011712 cell development Effects 0.000 description 1
- 230000006727 cell loss Effects 0.000 description 1
- 230000011748 cell maturation Effects 0.000 description 1
- 210000003855 cell nucleus Anatomy 0.000 description 1
- 238000003570 cell viability assay Methods 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000036755 cellular response Effects 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- 239000013043 chemical agent Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 210000003161 choroid Anatomy 0.000 description 1
- RRGUKTPIGVIEKM-UHFFFAOYSA-N cilostazol Chemical compound C=1C=C2NC(=O)CCC2=CC=1OCCCCC1=NN=NN1C1CCCCC1 RRGUKTPIGVIEKM-UHFFFAOYSA-N 0.000 description 1
- 229960004588 cilostazol Drugs 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 230000007278 cognition impairment Effects 0.000 description 1
- 230000006999 cognitive decline Effects 0.000 description 1
- 208000010877 cognitive disease Diseases 0.000 description 1
- 230000001149 cognitive effect Effects 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 238000004891 communication Methods 0.000 description 1
- 238000010668 complexation reaction Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 239000000824 cytostatic agent Substances 0.000 description 1
- 229940099418 d- alpha-tocopherol succinate Drugs 0.000 description 1
- DIOQZVSQGTUSAI-NJFSPNSNSA-N decane Chemical compound CCCCCCCCC[14CH3] DIOQZVSQGTUSAI-NJFSPNSNSA-N 0.000 description 1
- 238000010908 decantation Methods 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 208000002925 dental caries Diseases 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 230000035614 depigmentation Effects 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 210000004207 dermis Anatomy 0.000 description 1
- 235000019700 dicalcium phosphate Nutrition 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- TVWTZAGVNBPXHU-FOCLMDBBSA-N dioctyl (e)-but-2-enedioate Chemical compound CCCCCCCCOC(=O)\C=C\C(=O)OCCCCCCCC TVWTZAGVNBPXHU-FOCLMDBBSA-N 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- IACXYDVFQDGXJF-UHFFFAOYSA-N docosyl benzoate Chemical compound CCCCCCCCCCCCCCCCCCCCCCOC(=O)C1=CC=CC=C1 IACXYDVFQDGXJF-UHFFFAOYSA-N 0.000 description 1
- PRAKJMSDJKAYCZ-UHFFFAOYSA-N dodecahydrosqualene Natural products CC(C)CCCC(C)CCCC(C)CCCCC(C)CCCC(C)CCCC(C)C PRAKJMSDJKAYCZ-UHFFFAOYSA-N 0.000 description 1
- DLAHAXOYRFRPFQ-UHFFFAOYSA-N dodecyl benzoate Chemical compound CCCCCCCCCCCCOC(=O)C1=CC=CC=C1 DLAHAXOYRFRPFQ-UHFFFAOYSA-N 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000013583 drug formulation Substances 0.000 description 1
- 201000006549 dyspepsia Diseases 0.000 description 1
- 239000000806 elastomer Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 230000013020 embryo development Effects 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 210000003038 endothelium Anatomy 0.000 description 1
- FFDHYUFECJTEAY-UHFFFAOYSA-N epimacherinic acid Natural products CC1(C)CCC2(CCC3(C)C(CCC4C5(C)CCCC(C)(C)C5CCC34C)C2C1)C(=O)O FFDHYUFECJTEAY-UHFFFAOYSA-N 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 230000002964 excitative effect Effects 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 229930002886 farnesol Natural products 0.000 description 1
- 229940043259 farnesol Drugs 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 210000003608 fece Anatomy 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 238000005194 fractionation Methods 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 230000002538 fungal effect Effects 0.000 description 1
- 210000002592 gangliocyte Anatomy 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 230000007387 gliosis Effects 0.000 description 1
- LPLVUJXQOOQHMX-UHFFFAOYSA-N glycyrrhetinic acid glycoside Natural products C1CC(C2C(C3(CCC4(C)CCC(C)(CC4C3=CC2=O)C(O)=O)C)(C)CC2)(C)C2C(C)(C)C1OC1OC(C(O)=O)C(O)C(O)C1OC1OC(C(O)=O)C(O)C(O)C1O LPLVUJXQOOQHMX-UHFFFAOYSA-N 0.000 description 1
- 239000001685 glycyrrhizic acid Substances 0.000 description 1
- 229960004949 glycyrrhizic acid Drugs 0.000 description 1
- UYRUBYNTXSDKQT-UHFFFAOYSA-N glycyrrhizic acid Natural products CC1(C)C(CCC2(C)C1CCC3(C)C2C(=O)C=C4C5CC(C)(CCC5(C)CCC34C)C(=O)O)OC6OC(C(O)C(O)C6OC7OC(O)C(O)C(O)C7C(=O)O)C(=O)O UYRUBYNTXSDKQT-UHFFFAOYSA-N 0.000 description 1
- 235000019410 glycyrrhizin Nutrition 0.000 description 1
- LPLVUJXQOOQHMX-QWBHMCJMSA-N glycyrrhizinic acid Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@@H]1C([C@H]2[C@]([C@@H]3[C@@]([C@@]4(CC[C@@]5(C)CC[C@@](C)(C[C@H]5C4=CC3=O)C(O)=O)C)(C)CC2)(C)CC1)(C)C)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O LPLVUJXQOOQHMX-QWBHMCJMSA-N 0.000 description 1
- 210000000020 growth cone Anatomy 0.000 description 1
- 239000003966 growth inhibitor Substances 0.000 description 1
- 230000007773 growth pattern Effects 0.000 description 1
- 235000010417 guar gum Nutrition 0.000 description 1
- 239000000665 guar gum Substances 0.000 description 1
- 229960002154 guar gum Drugs 0.000 description 1
- 229940037467 helicobacter pylori Drugs 0.000 description 1
- 230000000971 hippocampal effect Effects 0.000 description 1
- 230000008801 hippocampal function Effects 0.000 description 1
- 210000001320 hippocampus Anatomy 0.000 description 1
- 238000000265 homogenisation Methods 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- OPEHDFRKFVXKNP-UHFFFAOYSA-N icosyl propanoate Chemical compound CCCCCCCCCCCCCCCCCCCCOC(=O)CC OPEHDFRKFVXKNP-UHFFFAOYSA-N 0.000 description 1
- 230000001976 improved effect Effects 0.000 description 1
- 238000012606 in vitro cell culture Methods 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 230000005865 ionizing radiation Effects 0.000 description 1
- 229940100554 isononyl isononanoate Drugs 0.000 description 1
- KUVMKLCGXIYSNH-UHFFFAOYSA-N isopentadecane Natural products CCCCCCCCCCCCC(C)C KUVMKLCGXIYSNH-UHFFFAOYSA-N 0.000 description 1
- 229940119170 jojoba wax Drugs 0.000 description 1
- 235000010494 karaya gum Nutrition 0.000 description 1
- TYQCGQRIZGCHNB-JLAZNSOCSA-N l-ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(O)=C(O)C1=O TYQCGQRIZGCHNB-JLAZNSOCSA-N 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 239000004922 lacquer Substances 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 201000003723 learning disability Diseases 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 239000003077 lignite Substances 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 239000004973 liquid crystal related substance Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 description 1
- 235000010420 locust bean gum Nutrition 0.000 description 1
- 239000000711 locust bean gum Substances 0.000 description 1
- 238000000464 low-speed centrifugation Methods 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- VOYZLKWKVLYJHD-FTORBOHPSA-N masticadienonic acid Natural products C[C@@H](CCC=C(C)C(=O)O)[C@@H]1CC[C@]2(C)C3=CC[C@H]4C(C)(C)C(=O)CC[C@]4(C)[C@H]3CC[C@@]12C VOYZLKWKVLYJHD-FTORBOHPSA-N 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 206010027175 memory impairment Diseases 0.000 description 1
- 230000003340 mental effect Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- BSUHUYNJLGMEPD-UHFFFAOYSA-N methanol;propan-1-ol Chemical compound OC.CCCO BSUHUYNJLGMEPD-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- SNVLJLYUUXKWOJ-UHFFFAOYSA-N methylidenecarbene Chemical compound C=[C] SNVLJLYUUXKWOJ-UHFFFAOYSA-N 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 239000000693 micelle Substances 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 239000004200 microcrystalline wax Substances 0.000 description 1
- 235000019808 microcrystalline wax Nutrition 0.000 description 1
- 238000007392 microtiter assay Methods 0.000 description 1
- 229930003647 monocyclic monoterpene Natural products 0.000 description 1
- 150000002767 monocyclic monoterpene derivatives Chemical class 0.000 description 1
- 239000012120 mounting media Substances 0.000 description 1
- 210000002200 mouth mucosa Anatomy 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 210000000107 myocyte Anatomy 0.000 description 1
- DIOQZVSQGTUSAI-UHFFFAOYSA-N n-butylhexane Natural products CCCCCCCCCC DIOQZVSQGTUSAI-UHFFFAOYSA-N 0.000 description 1
- WASNIKZYIWZQIP-AWEZNQCLSA-N nerolidol Natural products CC(=CCCC(=CCC[C@@H](O)C=C)C)C WASNIKZYIWZQIP-AWEZNQCLSA-N 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 210000003061 neural cell Anatomy 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 210000004498 neuroglial cell Anatomy 0.000 description 1
- 238000002610 neuroimaging Methods 0.000 description 1
- 230000007971 neurological deficit Effects 0.000 description 1
- 230000002232 neuromuscular Effects 0.000 description 1
- 230000003961 neuronal insult Effects 0.000 description 1
- 230000035771 neuroregeneration Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000004745 nonwoven fabric Substances 0.000 description 1
- 238000013116 obese mouse model Methods 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- KPWVFNOPNOTYNJ-UHFFFAOYSA-N octadecyl benzoate Chemical compound CCCCCCCCCCCCCCCCCCOC(=O)C1=CC=CC=C1 KPWVFNOPNOTYNJ-UHFFFAOYSA-N 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- YPMOZWCBANATQH-UHFFFAOYSA-N octyl 7-methyloctanoate Chemical compound CCCCCCCCOC(=O)CCCCCC(C)C YPMOZWCBANATQH-UHFFFAOYSA-N 0.000 description 1
- 230000009965 odorless effect Effects 0.000 description 1
- 229940100243 oleanolic acid Drugs 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- 239000008601 oleoresin Substances 0.000 description 1
- 230000033667 organ regeneration Effects 0.000 description 1
- 210000003463 organelle Anatomy 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000003791 organic solvent mixture Substances 0.000 description 1
- 208000013371 ovarian adenocarcinoma Diseases 0.000 description 1
- 201000006588 ovary adenocarcinoma Diseases 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 150000002926 oxygen Chemical class 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000005022 packaging material Substances 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 239000002540 palm oil Substances 0.000 description 1
- 230000003071 parasitic effect Effects 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 208000011906 peptic ulcer disease Diseases 0.000 description 1
- 238000009527 percussion Methods 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 208000028169 periodontal disease Diseases 0.000 description 1
- 229940066842 petrolatum Drugs 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000008782 phagocytosis Effects 0.000 description 1
- 239000008180 pharmaceutical surfactant Substances 0.000 description 1
- 150000008105 phosphatidylcholines Chemical class 0.000 description 1
- 210000000608 photoreceptor cell Anatomy 0.000 description 1
- 230000037081 physical activity Effects 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- BOTWFXYSPFMFNR-PYDDKJGSSA-N phytol Chemical compound CC(C)CCC[C@@H](C)CCC[C@@H](C)CCC\C(C)=C\CO BOTWFXYSPFMFNR-PYDDKJGSSA-N 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 210000001127 pigmented epithelial cell Anatomy 0.000 description 1
- 239000000419 plant extract Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229940068918 polyethylene glycol 400 Drugs 0.000 description 1
- 210000001316 polygonal cell Anatomy 0.000 description 1
- 239000002952 polymeric resin Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 150000003097 polyterpenes Chemical class 0.000 description 1
- 229920003225 polyurethane elastomer Polymers 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- HZLWUYJLOIAQFC-UHFFFAOYSA-N prosapogenin PS-A Natural products C12CC(C)(C)CCC2(C(O)=O)CCC(C2(CCC3C4(C)C)C)(C)C1=CCC2C3(C)CCC4OC1OCC(O)C(O)C1O HZLWUYJLOIAQFC-UHFFFAOYSA-N 0.000 description 1
- 230000004224 protection Effects 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 210000001747 pupil Anatomy 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 229920005604 random copolymer Polymers 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000007115 recruitment Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000003716 rejuvenation Effects 0.000 description 1
- 230000008263 repair mechanism Effects 0.000 description 1
- 230000004043 responsiveness Effects 0.000 description 1
- 229940100486 rice starch Drugs 0.000 description 1
- 231100000241 scar Toxicity 0.000 description 1
- 239000000565 sealant Substances 0.000 description 1
- 230000000276 sedentary effect Effects 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000002356 single layer Substances 0.000 description 1
- 238000005549 size reduction Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 238000000235 small-angle X-ray scattering Methods 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000012439 solid excipient Substances 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 238000002798 spectrophotometry method Methods 0.000 description 1
- 229940031439 squalene Drugs 0.000 description 1
- TUHBEKDERLKLEC-UHFFFAOYSA-N squalene Natural products CC(=CCCC(=CCCC(=CCCC=C(/C)CCC=C(/C)CC=C(C)C)C)C)C TUHBEKDERLKLEC-UHFFFAOYSA-N 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 229920006301 statistical copolymer Polymers 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000011146 sterile filtration Methods 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 230000035882 stress Effects 0.000 description 1
- 208000023516 stroke disease Diseases 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 230000009182 swimming Effects 0.000 description 1
- 210000000225 synapse Anatomy 0.000 description 1
- 230000003956 synaptic plasticity Effects 0.000 description 1
- 229920003002 synthetic resin Polymers 0.000 description 1
- 230000009967 tasteless effect Effects 0.000 description 1
- 210000002435 tendon Anatomy 0.000 description 1
- 229920001169 thermoplastic Polymers 0.000 description 1
- 239000004416 thermosoftening plastic Substances 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 239000000606 toothpaste Substances 0.000 description 1
- 229940034610 toothpaste Drugs 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- 239000012745 toughening agent Substances 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- CRDAMVZIKSXKFV-UHFFFAOYSA-N trans-Farnesol Natural products CC(C)=CCCC(C)=CCCC(C)=CCO CRDAMVZIKSXKFV-UHFFFAOYSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000011277 treatment modality Methods 0.000 description 1
- 229940078499 tricalcium phosphate Drugs 0.000 description 1
- 235000019731 tricalcium phosphate Nutrition 0.000 description 1
- 229910000391 tricalcium phosphate Inorganic materials 0.000 description 1
- 229940093633 tricaprin Drugs 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- 229960004791 tropicamide Drugs 0.000 description 1
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 1
- 238000009489 vacuum treatment Methods 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 235000019155 vitamin A Nutrition 0.000 description 1
- 239000011719 vitamin A Substances 0.000 description 1
- 229940045997 vitamin a Drugs 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 238000004260 weight control Methods 0.000 description 1
- 208000016261 weight loss Diseases 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
- 229940100445 wheat starch Drugs 0.000 description 1
- 239000003871 white petrolatum Substances 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 230000037314 wound repair Effects 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- BPICBUSOMSTKRF-UHFFFAOYSA-N xylazine Chemical compound CC1=CC=CC(C)=C1NC1=NCCCS1 BPICBUSOMSTKRF-UHFFFAOYSA-N 0.000 description 1
- 229960001600 xylazine Drugs 0.000 description 1
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/22—Anacardiaceae (Sumac family), e.g. smoketree, sumac or poison oak
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
Definitions
- the invention relates to compositions isolated from mastic gum, and their therapeutic use. More particularly, the invention relates to compositions comprising an isolated fraction of polymeric myrcene and formulations which maintain the biological activity of the active polymer.
- mastic also known as gum mastic or mastic gum, which is a tree resin obtained as an exudate from Pistacia lentiscus L., a member of the family Anacardiaceae. Mastic was used in the ancient Mediterranean world for gastrointestinal disorders such as gastralgia, dyspepsia and peptic ulcer.
- Greek Patent No. GR 1,003,541 discloses antimicrobial and antifungal action of the chios mastic oil extracted from the leaves, branches and fruit of Pistacia lentiscus var Chia.
- Greek Patent No. GR 1,003,868 discloses use of a product derived from Pistacia lentiscus var. Chia as an antioxidant, as a wound healing inductor and as a cytostatic agent.
- U.S. Patent Application Publication No 2005/0238740 discloses that certain fractions extracted from mastic resin exhibit anti-microbial and anti-cell proliferative activities.
- a first extract (termed “total fraction” or “whole extract”) contains all the compounds of the mastic gum except the polymer resin;
- a second extract is an acid fraction containing all the triterpenic acids of the total fraction, and
- a third extract is a neutral fraction containing all the other terpenes of the total fraction.
- an essential oil obtained by distillation which contains monoterpenes, inter alia, ⁇ -myrcene.
- the application discloses pharmaceutical formulations comprising any of the aforementioned total, acid or neutral fractions optionally combined with the essential oil, or synthetic equivalents thereof, or comprising isolated component products or synthetic equivalents thereof, as well as the use thereof in methods for treating microbial infections including H. pylori, Propionibacterium, Staphlococcus, Pseudomonas, and cell hyperproliferation.
- TMEWP total mastic extract without polymer
- TMEWP was prepared since the high percentage of poly- ⁇ -myrcene in crude mastic preparations, as used in previous studies, was speculated to hinder potential in vivo activity during oral administration.
- the authors further disclose that removal of the poly- ⁇ - myrcene can produce an enhanced therapeutic moiety with anti-H. pylori activity.
- EP Patent Application No. 1520585 discloses use of a product obtained from a plant of the genus Pistacia for the manufacture of a medicament for treating or preventing cancer.
- essential oils distilled from leaves, twigs, fruits, nuts and flowers of different Pistacia species contain a large number of monomelic terpene compounds in varying proportions inter alia ⁇ -myrcene.
- the application further discloses that the oils have activity against certain tumor cells lines such as colon and ovary adenocarcinomas, and that bornyl acetate was the only single component found to have anti-cancer activity.
- WO 2005/112967 discloses the purification from mastic of an anti-cancer compound having antiproliferative effects, which is found in a soluble fraction obtained by suspending mastic in a solvent selected from a non-acidic, aliphatic hydrocarbon, an aqueous solution containing at least 25% of a water-soluble, non-acidic, aliphatic hydrocarbon, or a combination thereof, and removing the insoluble fraction.
- the application further discloses a method for treating cancer cells comprising administering a pharmaceutically effective amount of a fraction of mastic gum resin that inhibits growth of cancer cells.
- the anti-cancer compound is effective against various types of cancer cells, including human colon cancer cells.
- Van der Berg et al disclose isolation and purification of the polymer fraction of mastic using extraction and size exclusion chromatography (Van der Berg et al (1998) Tetrahedron Lett 3:2645-2648).
- the polymer has a broad molecular weight distribution i.e. 20,000 to 100,000 Da, is formed from monomer units of 136 Da, and has the structure of 1,4-poly- ⁇ -myrcene, with cis- and trans- configurations at a ratio of 3:1.
- U.S. Patent No. 5,506,406 discloses mastic oil produced by dissolving mastic in an oil or fat, and filled in a soft capsule which optionally further contains an amphipathic substance such as chitin or chitosan. According to the disclosure, the capsule is effective for eliminating and inhibiting H. pylori, and for reducing the smell of feces.
- U.S. Patent No. 5,637,290 discloses an oral hygiene product comprising the combination of a toothpaste and an ingredient selected from natural mastic, extracted mastic oil and synthetic mastic oil agents. Also disclosed is use of mastic for incorporation into suntan lotion, hair products and cosmetics.
- U.S. Patent No. 6,623,728 discloses cosmetic skin care emulsion compositions comprising from about 0.001 wt% to about 10 wt% solubilized gum mastic; a volatile water miscible solvent; and a cosmetically acceptable vehicle.
- the emulsion is preferably an oil-in-water emulsion, and preferred solvents include ethanol, methanol propanol, isopropyl alcohol and mixtures thereof. According to the disclosure, the same types of solvents are used to obtain the solubilized gum mastic.
- U.S. Patent No. 6,811,769 discloses an oral composition comprising an oil extract of mastic, such as that prepared with olive oil or palm oil; and an antiphlogistic, such as glycyrrhizic acid. According to the disclosure, the composition has antibacterial action against periodontal disease-related bacteria and against tooth decay-related bacteria.
- U.S. Patent No. 7,294,651 discloses use of isoprenoid compounds, inter alia, terpene compounds for inhibiting the production of exoproteins of Gram positive bacteria, such as Toxic Shock Syndrome Toxin- 1 produced by S. aureus.
- suitable terpenes may be cyclic or acyclic, saturated or unsaturated, and also include polyterpenes.
- U.S. Patent No. 4,564,718 discloses preparation of functionally terminated polymers, referred to as "liquid rubbers" having glass transition temperatures substantially less than room temperature, by polymerization of a terpene or oxygen derivative thereof having a double bond or conjugated double bond available for polymerization, with an initiator which provides the desired functional termination.
- the polymers preferably have a molecular weight of 500 to 20,000, and preferred acyclic monoterpenes for preparation thereof are inter alia ⁇ -myrcene.
- the patent discloses preparation of polymeric myrcene of molecular weight of about 2000 and of about 4000.
- the patent further discloses that the polymers of the invention may be further reacted with other reagents to provide elastomers, sealants or adhesives, or they may be used as rubber toughening agents. Further disclosed is preparation of hydroxy-terminated polymyrcene from myrcene, and use thereof to prepare a polyurethane elastomer.
- Newmark et al J. Polymer Sci. 26, 71-77 (1988) discloses synthesis of polymyrcene having an observed molecular weight of 87,000 and a calculated molecular weight of 46,000.
- U.S. Patent No. 4,374,957 discloses a tacky thermoplastic elastomeric linear triblock polymer corresponding to the formula A-B-A, wherein A is a nonelastic linear homopolymer block of a monovinyl aromatic hydrocarbon having an average molecular weight between 10,000 and 60,000 and a glass transition temperature above 70 °C, and wherein B is an elastomeric homopolymeric block of myrcene having an average molecular weight between 50,000 and 200,000 and a glass transition temperature below about -40 °C.
- U.S. Patent No. 5,759,569 discloses biodegradable compostable articles that at least partially comprise certain trans-polymers, wherein the polymers have a weight average molecular weight of at least about 20,000 and are made by polymerizing a monomer component that comprises: (1) from about 70 to 100 mole % 1,3-dienes inter alia ⁇ - myrcene; and (2) up to about 30 mole % other compatible co monomers.
- the articles include inter alia packaging materials; disposable absorbent articles (e.g., diapers, sanitary napkins); garment articles such as protective clothing, surgical drapes, surgical gowns, surgical sheets; woven, knitted and non-woven fabrics; surgical sponges, tampon applicators, disposable syringes and containers.
- disposable absorbent articles e.g., diapers, sanitary napkins
- garment articles such as protective clothing, surgical drapes, surgical gowns, surgical sheets; woven, knitted and non-woven fabrics; surgical sponges, tampon applicators, disposable syringes and containers.
- U.S. Patent Nos. 7,232,872 and 7,214,750 disclose a polymerization process comprising contacting one or more monomer(s) inter alia myrcene, one or more Lewis acid(s), one or more initiator(s), and a diluent comprising one or more hydrofluorocarbon(s) in a reactor.
- U.S. Patent Application Publication No 2007/0179260 and U.S. Patent No. 7,417,103 disclose 3,4-isoprene-based polymers with high regioregularity and a method for producing same.
- the number average molecular weight of the polymer is 5000 to 6,000,000, and the polymer may also include units of 1,4- isoprenes such as myrcene.
- the polymer is suitable for use as a plastic material due to its mechanical and thermal durability.
- the prior art does not contain any teaching or suggestion of the use of an isolated fraction of polymeric myrcene, whether that derived from mastic, or that chemically synthesized, as an active ingredient in a pharmaceutical composition or in a therapeutic application.
- the prior art does not teach or suggest use of an isolated fraction of polymeric myrcene in a composition for treating neurological conditions or skin disorders.
- compositions comprising polymeric forms of the monoterpene compound known as myrcene, which exhibit a variety of beneficial biological activities which may be exploited for therapeutic applications. More specifically, compositions comprising isolated fractions of polymeric myrcene, including that chemically synthesized and that derived from plant sources such as mastic gum, are now disclosed to have activity in neuroprotection, tissue regeneration and wound and tissue repair.
- compositions disclosed herein may be prepared by solvent extraction of certain plant material, such as mastic gum, in so as to obtain isolated fractions which are soluble in both, polar and non-polar solvents, and are depleted of various monomelic terpene compounds which interfere with the desired biological activity.
- plant material such as mastic gum
- the teachings of the present invention have been exemplified with mastic gum extracts prepared by a two-step extraction procedure, so as to obtain a fraction that is soluble in both a polar solvent and a non-polar solvent, and wherein material from the mastic gum that is soluble in the polar solvent but remains insoluble in the non-polar solvent is eliminated.
- the present invention has also been exemplified both with polymeric myrcene isolated from a natural source i.e. tree resin mastic, and with chemically synthesized polymeric myrcene having the molecular weight in the same range and chemical structure as that of the corresponding polymer isolated from mastic.
- teachings of the present invention are particularly surprising and unexpected over teachings which disclose the use of mastic gum extract fractions from which polymeric myrcene has been removed.
- the prior art asserts that polymeric fractions derived from mastic are not therapeutically useful, and that the presence of polymeric myrcene in therapeutic compositions actually inhibits the beneficial biological activities and bioavailability of the active compounds.
- the prior art teaches that the active compounds in mastic gum correspond to various low molecular weight terpene- type molecules, inter alia monomelic myrcene.
- the activity of polymeric myrcene for induction of neuronal cell differentiation renders the present invention useful for reformation of inter-neuronal junctions and overcoming defective inter-neuronal communication in brain and neural tissue affected by pathologies associated with inadequate synaptic formation.
- This pathology underlies many nervous system pathologies, including for example Alzheimer's disease.
- the invention is further useful for promoting wound healing and rejuvenation of a large number of cells and tissues.
- polymeric myrcene encompasses polymeric forms of myrcene having a degree of polymerization of at least 6.
- Polymeric myrcene includes without limitation, polymeric ⁇ -myrcene (poly- ⁇ -myrcene), polymeric ⁇ -myrcene (poly- ⁇ - myrcene), homopolymers thereof and heteropolymers (also known as copolymers) which contain myrcene subunits. Also included are geometric isomers, optical isomers and diastereoisomers of polymeric myrcene compounds.
- myrcene in its monomelic form such as ⁇ -myrcene and ⁇ -myrcene, as active ingredients of the fractions and compositions disclosed herein.
- ⁇ -myrcene refers to 7-methyl-3 -methylene- 1,6-octadiene and ⁇ - myrcene refers to the structural isomer 2-methyl-6-methylene-l,7-octadiene.
- the present invention provides a composition comprising an effective amount of an isolated fraction of mastic gum, wherein the fraction is characterized in that it is soluble in at least one polar organic solvent and in at least one non-polar organic solvent, and wherein said fraction is substantially devoid of compounds which are soluble in said polar organic solvent but insoluble in said non-polar organic solvent.
- composition is obtained by a process comprising the steps of:
- step (c) optionally removing said polar organic solvent; (d) treating the soluble fraction obtained in step (b) or (c) with a non-polar organic solvent, (e) isolating a fraction soluble in said nonpolar organic solvent; and
- steps (d) to (f) may precede steps (a) to (c).
- steps (a) to (c) are carried out prior to steps (d) to (f); or steps (d) to (f) are carried out prior to steps (a) to (c).
- steps (a) to (c) and/or steps (d) to (f) are repeated for a multiplicity of cycles.
- steps (c) and (f) comprise removing the solvent by a means selected from the group consisting of rotary evaporation, application of high vacuum and a combination thereof.
- the process further comprises the step of size fractionating the fraction obtained by said process.
- Polar organic solvents suitable for use in the invention may be selected from an alcohol, an ether, an ester, an amide, an aldehyde, a ketone, a nitrile, and combinations thereof.
- Suitable polar organic solvents include methanol, ethanol, propanol, isopropanol, 1-butanol, 2-butanol, sec-butanol, t-butanol, 1-pentanol, 2- pentanol, 3-pentanol, neopentanol, 3 -methyl- 1-butanol, 2-methyl- 1-butanol, 3-methyl-2- butanol, 2-methyl-2-butanol, ethyleneglycol, ethyleneglycol monomethyl ether, diethyl ether, methylethyl ether, ethylpropyl ether, methylpropyl ether, 1,2-dimethoxyethane, tetrahydrofuran, dihydrofuran, furan, pyran, dihydropyran, tetrahydropyran, methyl acetate, ethyl acetate, propyl acetate, acetaldehyde, methylformat
- the polar organic solvent is ethanol.
- Non-polar organic solvents suitable for use in the invention may be selected from acyclic or cyclic, saturated or unsaturated aliphatic hydrocarbons and aromatic hydrocarbons, each of which is optionally substituted by one or more halogens, and combinations thereof.
- the non-polar organic solvent is selected from C5-C10 alkanes, C5-C10 cycloalkanes, C6-C14 aromatic hydrocarbons and C7-C14 perfluoroalkanes, and combinations thereof.
- the non-polar organic solvent is selected from pentanes, hexanes, heptanes, octanes, nonanes, decanes, cyclopentane, cyclohexane, cycloheptane, benzene, toluene, xylene, and isomers and mixtures thereof.
- the C5-C10 alkane is selected from the group consisting of pentane, hexane, heptane, octane, nonane, decane, cyclohexane, and isomers and mixtures thereof.
- the non-polar organic solvent is hexane.
- the polar organic solvent comprises ethanol and the non- polar organic solvent comprises hexane.
- the composition is substantially devoid of terpene compounds which are soluble in said polar organic solvent and insoluble in said non-polar organic solvent.
- the terpene compounds are monomelic terpene compounds.
- the terpene compounds are selected from ⁇ -myrcene, ⁇ -myrcene, cis- ⁇ -ocimene, dihydromyrcene, limonene, ⁇ -pinene, ⁇ -pinene and combinations thereof.
- the composition comprises from about 0.01 to about 25% (w/w) of the isolated fraction of mastic gum, based on the total weight of the composition. In a particular embodiment, the composition comprises from about 0.01 to about 12% (w/w) of the isolated fraction of mastic gum, based on the total weight of the composition.
- the isolated fraction of gum mastic comprises polymeric myrcene.
- the invention provides a pharmaceutical composition
- a pharmaceutical composition comprising a therapeutically effective amount of an isolated fraction of polymeric myrcene, and a pharmaceutically acceptable carrier.
- the composition comprises from about 0.01 to about 12% (w/w) polymeric myrcene, based on the total weight of the composition.
- the polymeric myrcene is selected from the group consisting of polymeric ⁇ -myrcene (poly- ⁇ -myrcene), polymeric ⁇ -myrcene (poly- ⁇ - myrcene), myrcene copolymers and combinations thereof.
- the poly- ⁇ -myrcene is selected from the group consisting of 1,4-poly- ⁇ -myrcene, 3,4-poly- ⁇ - myrcene, 1,2-poly- ⁇ -myrcene and combinations thereof.
- the polymeric myrcene comprises a myrcene isomer selected from the group consisting of a cis isomer, a trans isomer and combinations thereof.
- the 1,4- poly- ⁇ -myrcene is selected from the group consisting of cis-l,4-poly- ⁇ -myrcene, trans- 1,4-poly- ⁇ -myrcene and combinations thereof.
- the polymeric myrcene comprises cis-l,4-poly- ⁇ -myrcene.
- the polymeric myrcene has a cyclic conformation.
- the polymeric myrcene has a branched conformation.
- the polymeric myrcene has a degree of polymerization in the range of at least about 6 to about 1800. In a particular embodiment, the degree of polymerization is at least about 10. In a particular embodiment, the degree of polymerization is at least about 15. In a particular embodiment, the degree of polymerization is at least about 25. In a particular embodiment, the degree of polymerization is at least about 35. hi a particular embodiment, the degree of polymerization is in the range of about 6 to about 30. In a particular embodiment, the degree of polymerization is in the range of about 30 to about 500, for example, in the range of about 33 to about 150.
- the polymeric myrcene has a number average molecular weight of at least about 800. hi a particular embodiment, the number average molecular weight is at least about 1,000. hi a particular embodiment, the number average molecular weight is at least about 2000. In a particular embodiment, the number average molecular weight is at least about 3000. hi a particular embodiment, the number average molecular weight is at least about 5000. hi a particular embodiment, the polymeric myrcene has a number average molecular weight in the range from at least about 800 to about 100,000.
- the number average molecular weight is in a range selected from the group consisting of: at least about 800 to about 80,000; at least about 800 to about 50,000; at least about 800 to about 20,000; at least about 800 to about 10,000; at least about 800 to about 5000; at least about 1,000 to at least about 50,000; at least about 1,000 to about 10,000; at least about 1,000 to about 5000; about 5000 to about 10,000; about 10,000 to about 15,000; about 5000 to about 20,000; about 15,000 to about 30,000; about 25,000 to about 40,000; about 35,000 to about 50,000; about 45,000 to about 60,000; about 55,000 to about 70,000; about 65,000 to about 80,000; about 75,000 to about 90,000; about 85,000 to about 100,000; or any combinations and sub-ranges thereof.
- the polymeric myrcene has a number average molecular weight in the range from about 5,000 to about 20,000.
- composition may comprise different molecular weight fractions of polymeric myrcene, for example in the range from at least about 800 to about 100,000, or various combinations thereof.
- polymeric myrcene has a polydispersity index less than 5.
- the polymeric myrcene is the product of a chemical synthesis.
- the chemical synthesis comprises use of monomelic myrcene as a substrate.
- the substrate is ⁇ -myrcene.
- the ⁇ -myrcene substrate is derived from a plant.
- the product of the chemical synthesis comprises cis-1,4- poly- ⁇ -myrcene.
- the chemical synthesis comprises an anionic polymerization reaction.
- the chemical synthesis further comprises dissolving the polymeric myrcene obtained therefrom in a hydrophobic carrier, such as at least one vegetable oil.
- the isolated fraction of polymeric myrcene is derived from a natural source.
- Natural sources include plants classified in the family Anacardiaceae.
- gum mastic is from a plant classified in the family Anacardiaceae.
- Suitable plants include those classified in a genus selected from the group consisting of Pistacia, Pinus, Picea, Juniperus, Alsies, Larix, Antirrhinum, Boswellia, Citrus and Gynura.
- the species of Pistacia is selected from the group consisting of P. lentiscus, P. atlantica, P. palestina, P. saportae, P. terebinthus, P. vera and P.
- the species of Pistacia is Pistacia lentiscus L.
- the natural source is a plant material selected from the group consisting of resin, leaves, twigs, roots, flowers, seeds, buds, bark, nuts and roots.
- the natural source is a plant classified in a genus selected from the group consisting of Ocimum, Laurus and Lavendula.
- the isolated fraction of polymeric myrcene is obtained by a process comprising the steps of:
- step (d) treating the soluble fraction obtained in step (b) or (c) with at least one non- polar organic solvent;
- steps (d) to (f) may precede steps (a) to (c), and wherein steps (a) to (c) and steps (d) to (f) are each independently carried out for a number of cycles; so as to obtain an isolated fraction of polymeric myrcene.
- the isolated fraction of polymeric myrcene has a degree of purity of at least about 80% (w/w).
- the isolated fraction of polymeric myrcene may have a degree of purity of at least about 85% (w/w).
- the isolated fraction of polymeric myrcene has a degree of purity of at least about 90% (w/w), or at least about 93%, or at least about 95%, or at least about 97%, or at least about 98% or at least about 99%.
- the isolated fraction of polymeric myrcene has a degree of purity of at least 80%, and the polymeric myrcene has a degree of polymerization of at least 6.
- the isolated fraction of polymeric myrcene has a degree of purity of at least 90%, and the polymeric myrcene has a degree of polymerization of at least 10.
- the isolated fraction of polymeric myrcene comprises at least 90% (w/w) of cis-l,4-poly- ⁇ -myrcene.
- the isolated fraction of polymeric myrcene comprises a mixture of cis-l,4-poly- ⁇ -myrcene and trans- 1 ,4-poly- ⁇ -myrcene, wherein the mixture comprises at least 50% (w/w) of cis-l,4-poly- ⁇ - myrcene.
- the isolated fraction of polymeric myrcene comprises at least 90% (w/w) of cis-l,4-poly- ⁇ -myrcene having a number average molecular weight of at least 800, or at least 1,000, or at least 5,000 or at least 10,000. In a particular embodiment, the isolated fraction of polymeric myrcene comprises at least 80% (w/w) of cis-l,4-poly- ⁇ -myrcene having a number average molecular weight in the range from about 800 to about 5,000.
- the isolated fraction of polymeric myrcene comprises at least 90% (w/w) of cis-l,4-poly- ⁇ -myrcene having a number average molecular weight in the range from about 1,000 to about 10,000. In a particular embodiment, the isolated fraction of polymeric myrcene comprises at least 90% (w/w) of cis-l,4-poly- ⁇ -myrcene having a number average molecular weight in the range from about 5,000 to about 20,000.
- the isolated fraction of polymeric myrcene comprises at least 90% (w/w) of cis-l,4-poly- ⁇ -myrcene having a number average molecular weight in the range from about 10,000 to about 20,000 . In a particular embodiment, the isolated fraction of polymeric myrcene comprises at least 90% (w/w) of cis-l,4-poly- ⁇ -myrcene having a number average molecular weight in the range from about 20,000 to about 30,000 .
- the isolated fraction of polymeric myrcene comprises at least 90% (w/w) of cis-l,4-poly- ⁇ -myrcene having a number average molecular weight in the range from about 30,000 to about 50,000 In a particular embodiment, the isolated fraction of polymeric myrcene comprises at least 90% (w/w) of cis-l,4-poly- ⁇ -myrcene having a number average molecular weight in the range from about 50,000 to about 80,000.
- the composition comprises less than about 10% (w/w), and more preferably, less than about 5% (w/w), of terpene compounds which are soluble in a polar organic solvent and insoluble in a non-polar organic solvent, hi particular embodiments, the composition is substantially devoid of terpene compounds which are soluble in a polar organic solvent and insoluble in a non-polar organic solvent.
- the composition comprises less than about 10% (w/w), and more preferably, less than about 5% (w/w), of monomelic terpene compounds, hi a particular embodiment, the composition is substantially devoid of myrcene monomers.
- terpene compounds include monomelic and oligomeric forms of terpene compounds, including those variously classified as monoterpenes, diterpenes, sequiterpenes, triterpenes and tetraterpenes, including their acid, aldehyde and alcohol forms.
- the composition comprises less than about 10% (w/w), and more preferably, less than about 5% (w/w), of a terpene compound selected from the group consisting of: ⁇ -myrcene, ⁇ -myrcene, cis- ⁇ -ocimene, dihydromyrcene, limonene, ⁇ -pinene, ⁇ -pinene and combinations thereof.
- a terpene compound selected from the group consisting of: ⁇ -myrcene, ⁇ -myrcene, cis- ⁇ -ocimene, dihydromyrcene, limonene, ⁇ -pinene, ⁇ -pinene and combinations thereof.
- the isolated fraction of polymeric myrcene is derived from a plant and the composition is substantially devoid of myrcene monomers and myrcene oligomeric forms having a degree of polymerization less than about 6.
- the isolated fraction of polymeric myrcene is derived from a plant and the composition is substantially devoid of terpene compounds which are soluble in at least one polar organic solvent and insoluble in at least one non-polar organic solvent.
- the isolated fraction of polymeric myrcene is the product of a chemical synthesis and the composition is substantially devoid of myrcene monomers and myrcene oligomeric forms having a degree of polymerization less than about 6.
- the isolated fraction of polymeric myrcene is the product of a chemical synthesis and the composition is substantially devoid of terpene compounds which are soluble in a polar organic solvent and insoluble in a non-polar solvent.
- the present invention discloses a pharmaceutical composition
- a pharmaceutical composition comprising a synthetic polymeric myrcene wherein the polymeric myrcene has a number average molecular weight in the range of at least about 800 up to about 50,000, and wherein the isolated fraction of polymeric myrcene has a degree of purity of at least 80%.
- the pharmaceutically acceptable carrier comprises a hydrophobic carrier.
- the hydrophobic carrier comprises at least one oil.
- the oil is selected from the group consisting of a mineral oil, a vegetable oil and combinations thereof.
- the vegetable oil is selected from the group consisting of almond oil, canola oil, coconut oil, corn oil, cottonseed oil, grape seed oil, olive oil peanut oil, saffron oil, sesame oil, soybean oil, and combinations thereof.
- the mineral oil is light mineral oil.
- the hydrophobic carrier comprises at least one wax.
- the hydrophobic carrier comprises a combination of at least one oil and at least one wax.
- a composition according to the invention is in a form suitable for administration by a route selected from the group consisting of oral, topical, parenteral and transdermal.
- the composition is in a form suitable for administration by injection.
- the composition is a parenteral formulation for administration by a route selected from the group consisting of intravenous, intramuscular, subcutaneous, intradermal, intraperitoneal, intraarterial, intracerebral, intracerebro ventricular, intraosseus and intrathecal.
- the composition is a topical formulation for administration by a route selected from the group consisting of dermal, vaginal, rectal, inhalation, intranasal, ocular, auricular and buccal.
- the composition is in a form suitable for cosmetic or dermatologic administration.
- the pharmaceutical composition is in a form selected from the group consisting of a capsule, a tablet, a liposome, a suppository, a suspension, an ointment, a cream, a lotion, a solution, an emulsion, a film, a cement, a powder, a glue, an aerosol and a spray.
- the capsule is selected from the group consisting of a hard gelatin capsule and a soft gelatin capsule.
- the emulsion is a nanoemulsion or a microemulsion.
- the formulation comprises at least one of an inclusion complex, a nanoemulsion, a microemulsion, a powder, a lipid raft, a lipid microparticle, a dendrimer and a liposome.
- the inclusion complex comprises at least one cyclodextrin.
- the at least one cyclodextrin comprises hydroxypropyl- ⁇ -cyclodextrin.
- the nanoemulsion comprises droplets having average particle size of less than 800 run. In a particular embodiment, the droplets have average particle size of less than 500 run. In a particular embodiment, the droplets have average particle size of less than 200 nm.
- the powder is a spray dried powder.
- the liposome comprises a multilamellar vesicle.
- the microemulsion comprises a non- ionic surfactant.
- the non-ionic surfactant is selected from the group consisting of a polyoxyl castor oil, a polyoxyethylene sorbitan fatty acid ester (polysorbates), a poloxamer, a vitamin E derivative, a polyoxyethylene alkyl ether, a polyoxyethylene sterate, or saturated polyglycolyzed glyceride or combinations thereof.
- the composition is disposed on the article of manufacture in the form of a coating.
- the article of manufacture comprises a vessel, wherein the composition is disposed within the vessel.
- the article of manufacture is selected from the group consisting of a fabric article, a diaper, a wound dressing, a medical device, a needle or plurality of needles, a microneedle or plurality of microneedles, an injection device and a spray dispenser.
- the article of manufacture comprises a plurality of microneedles.
- the medical device is selected from the group consisting of a prosthetic, an artificial organ or component thereof, a valve, a catheter, a tube, a stent, an artificial membrane, a pacemaker, a sensor, an endoscope, an imaging device, a pump, a wire and an implant.
- the implant is selected from the group consisting of a cardiac implant, a cochlear implant, a corneal implant, a cranial implant, a dental implant, a maxillofacial implant, an organ implant, an orthopedic implant, a vascular implant, an intraarticular implant and a breast implant.
- the composition is suitable for administration by a means selected from the group consisting of electroporation, sonication, radio frequency, pressurized spray and combinations thereof.
- the composition is for treating impaired neurological function.
- the impaired neurological function comprises a decrease in a function selected from the group consisting of cognitive function, sensory function, motor function and combinations thereof.
- the impaired neurological function is associated with a condition or disease, including for example, impaired neurological function is associated with a condition or disease, including for example, trauma, vascular dementia, senile dementia, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis, Parkinson's disease, stroke, schizophrenia, bipolar disorder, depression, obesity, anorexia, cachexia an infection, and an immunological disorder.
- the impaired neurological function is due to exposure to a drug, such as an anesthetic.
- the composition is for treating a skin or scalp disorder selected from the group consisting of alopecia, eczema, psoriasis, seborrheic keratosis and seborrhea.
- Skin and scalp disclosers include disorders of skin, scalp and hair appendages, including for example, nails and hair follicles.
- the skin disorder is a skin wound, including for example, a venous leg ulcer, a pressure ulcer, a diabetic foot ulcer, a burn, an amputation wound, a decubitus ulcer (bed sore), a split-skin donor graft, a skin graft donor site, a medical device implantation site, a bite wound, a frostbite wound, a puncture wound, a shrapnel wound, a dermabrasion, a contusion, an infection, a wound and a surgical wound.
- a skin wound including for example, a venous leg ulcer, a pressure ulcer, a diabetic foot ulcer, a burn, an amputation wound, a decubitus ulcer (bed sore), a split-skin donor graft, a skin graft donor site, a medical device implantation site, a bite wound, a frostbite wound, a puncture wound, a shrapnel wound, a dermabrasion, a contusion
- the composition is for inducing or promoting tissue tissue repair.
- tissue repair encompasses induction and promotion of tissue regeneration, including of neural tissues.
- the composition is for inducing or promoting tissue tissue repair following an injury or insult.
- the injury or insult is selected from the group consisting of a myocardial infarction, a pulmonary embolism, a cerebral infarction, peripheral artery occlusive disease, a hernia, a splenic infarction, a venous ulcer, an axotomy, a retinal detachment, an infection and a surgical procedure.
- the scope of the present invention encompasses shorter and longer forms of polymeric myrcene, including synthetic and semi-synthetic forms, including myrcene copolymers, and derivatives substituted with various functionalities, and conjugates with additional molecules, as are known in the art, with the stipulation that these variants and modifications preserve the therapeutic capacity of the polymeric myrcene in the context of the methods of the present invention.
- Figure 1 shows size exclusion chromatography of a mastic resin extract using SEDEX and PDA detectors.
- Figure 2 show low (Fig. 2A) and heavy (Fig. 2B) molecular weight fractions of a mastic resin extract obtained by preparative size exclusion chromatography.
- Figure 3 shows the 1 H-NMR spectrum of the heavy MW fraction obtained by preparative SEC of a mastic resin extract.
- Figure 4 shows the 13 C-NMR spectrum of the heavy MW fraction obtained by preparative size exclusion chromatography of a mastic resin extract.
- Figure 5 shows analytical size exclusion chromatography of high (Fig. 5A) and low (Fig. 5B) products obtained in a chemical synthetic process for polymeric myrcene.
- Figure 6 shows the 1 H-NMR spectrum of the synthesized 1,4-poly- ⁇ -myrcene.
- Figure 7 shows the 13 C-NMR spectrum of the synthesized 1,4-poly- ⁇ -myrcene.
- Figure 8 shows the effects of RPh-I on ARPE- 19 cells.
- Fig. 8 A control cultures treated with oil vehicle
- Fig 8B test cultures 48 hours after RPh-I (0.1%; lmg/ml) administration and incubation
- Fig 8C test cultures 4872 hours after RPh-I (0.25%; 2.5 mg/ml) administration and incubation
- Fig.8D test cultures 72 hours after RPh-I (0.25%; 2.5 mg/ml) administration and incubation .
- Figure 9 shows immunofluorescence analysis of differentiated ARPE- 19 cells before (left panels) and after (right) 72 hours of incubation with RPh-I, indicating expression of tubulin, beta 3 (TUBB3), activity-regulated cytoskeleton-associated protein (Arc/Arg3.1) and neuronal pentraxin II (NPTX2) following the treatment.
- Figure 10 shows the effect of RPh-I on ARPE- 19 cell proliferation as monitored by an assay to assess total protein content.
- Figure 11 shows ARPE- 19 cells of various grades of differentiation.
- Fig. HA differentiation grade 3
- Fig. 1 IB differentiation grade 4
- Fig. 11C differentiation grade 5.
- Figure 12 shows the effect of RPh-I on human melanoma cells.
- Fig. 12 A oil vehicle treated control cells
- Fig. 12B cells treated with RPh-I (5 ⁇ L) after 48 hours incubation
- Fig. 12C cells treated with RPh-I (2 ⁇ L) after 48 hours incubation
- Fig. 12D cells treated with RPh-I (5 ⁇ L) after 72 hours incubation.
- Figure 13 shows the effects of chemically synthesized polymeric myrcene on RPh-I cells.
- Fig. 13 A differentiation induced with Fraction 18.1;
- Fig. 13B differentiation induced with Fraction 18.2.
- Figure 14 shows regeneration of fur in an aging Golden Retriever male dog afflicted with a dermal lesion associated with alopecia following treatment with RPh-I.
- Fig. 14 A prior to treatment;
- Fig. 14B following 2 weeks of treatment.
- Figure 15 shows the effect of RPh-I on wound healing of inflicted wounds in experimental mice as indicated by the wound size (mm 2 ) at various time points after wound infliction in mice treated with RPh-I by SC injection (Group A, grey bars), topically (Group B, black bars) and in mice treated with vehicle alone (Group C, open bars).
- Figure 16 shows the effect of RPh-I on recovery from cerebral hypoperfusion in a vascular dementia rat model, as assessed by the Morris water maze test.
- Performance of RPh-I -treated animals (Group A; cross-hatched bars), vehicle treated animals (Group B; horizontally striped bars) and in sham control animals (filled bars) were tested for frequency in platform location (Fig. 16A); the time spent in platform area (Fig. 16B); the latency to find the platform (Fig. 16C); the frequency in zone 1 location (Fig. 16D); the time spent in light part (Fig. 16E); the latency to find the platform (Fig. 16F); and the velocity (Fig. 16G).
- Figure 17 shows the effect of RPh-I on weight gain.
- Figure 17A shows weight gain in animals after cerebral hypoperfusion in a vascular dementia rat model.
- Weight of Group B animals (RPh-I treated; triangle symbols) is recovering significantly faster then Group A animals (vehicle treated; square symbols).
- Figure 18 shows the effect of RPh-I on recovery from transient middle cerebral artery occlusion (tMCAO) in a rat stroke model.
- Fig. 18A shows neuro-muscular score (Neuroscore) at various time points in days (d) as indicated, following MCAO in rats treated with RPh-I (Group A) or with vehicle (Group B). Significant differences were seen only in Group A, between day 8 and day 14, and between day 8 and day 28.
- Neuro-muscular score Neuro-muscular score
- Fig. 18B shows the results of stepping test at various time points following MCAO in rats treated with RPh-I (Group A; black bars) or with vehicle (Group B; open bars) treatment. Significant differences were found between the two groups only on day 28.
- Fig. 18C shows the results of adhesive removal test at various time points in days (d) as indicated, following MCAO in rats treated with RPh-I (Group A) or with vehicle (Group B). Significant differences were seen only in Group A, between day 2 and the other days.
- Figure 19 shows the average number of surviving Retinal Ganglion Cells (RGC) following axotomy of the optic nerve in RPh-I treated and control-treated rats.
- Figure 20 shows Western blot analysis of expression of SEMA3 (Fig. 20A) and caspase-3 (Fig. 20B) in detached retinas (RD) and non-injured retinas (control) from animals treated with RPh-I or vehicle following retinal detachment.
- the inventor of the present invention has surprisingly found that isolated fractions of mastic gum have activity in ameliorating impaired neurological function, healing of skin and scalp disorders and wounds, and in promoting tissue repair. Such fractions are known to contain polymeric myrcene. Furthermore, it has also been surprisingly found that purified fractions of polymeric myrcene exhibit the same biological activities as that observed with isolated fractions of mastic gum. The aforementioned biological activities of polymeric myrcene have been demonstrated both with that derived from a plant source and that chemically synthesized. Moreover, the molecular weight range of the polymer, and the degree of purity of the preparation are important factors influencing the biological activity of the polymeric myrcene. These findings are highly unexpected in light of prior art which teaches that the polymeric fraction obtained from mastic, has no therapeutic benefit, and in fact hinders certain biological activities attributed to crude mastic preparations and mastic extracts.
- the isolated fraction of mastic gum as described herein may be employed as an active ingredient in a pharmaceutical composition for a number of therapeutic indications
- compositions of the invention may be used in methods of treating impaired neurological function and skin and scalp conditions.
- the composition Upon contact with cells of both human and non-human subjects, the composition induces cell differentiation in a wide array of tissues, cell compartments and cell lineages, including skin, endothelium, mucous membranes, bones, tendons and cartilage.
- the cell differentiation activity of the pharmaceutical composition may be exploited for promoting in vivo incorporation of medical devices, implants and organ transplants. Definitions
- the terms “mastic”, “mastic resin”, “gum mastic” and “mastic gum”, are used interchangeably to refer to a tree resin (also known as an oleoresin) obtained as an exudate from any tree classified in the family Anacardiaceae. Trees in the genus Pistacia, most notably Pistacia lentiscus L., and in particular the cultivar P. lentiscus L. cv. Chia (cultivated on the Greek island of Chios), are known for their high yield of mastic. Other varieties include P. lentiscus L. var. emarginata Engl., and P. lentiscus L. var. latifolia Coss. Additional species of Pistacia include for example, P. atlantica, P. palestina, P. saportae, P. terebinthus, P. vera and P. integerrima.
- polymer refers to a compound or a mixture of compounds, comprising repeating subunits (also referred to as monomers) of the same chemical structure, wherein the monomers are in covalent connection.
- An example of a monomer from which a polymer may be formed is a terpene, for example a monoterpene such as myrcene.
- Polymers may have various degrees of polymerization and thus encompass polymeric forms of various chain length. Polymers include homopolymers and heteropolymers (also known as copolymers), and may have various isomeric and diastereoisomeric configurations.
- polymeric myrcene and “polymyrcene” interchangeably refer to a polymer formed from myrcene monomers.
- Polymeric myrcene encompasses polymeric forms having various degrees of polymerization and preferably myrcene polymers having a degree of polymerization of at least 6.
- the invention encompasses without limitation, polymeric ⁇ -myrcene (poly- ⁇ -myrcene), polymeric ⁇ -myrcene (poly- ⁇ -myrcene), homopolymers thereof, heteropolymers (also known as copolymers) comprising myrcene monomers in direct or indirect covalent connection with heterologous monomers, trans- and cis- isomers thereof, D- and L-enantiomers thereof, or combinations thereof.
- Polymeric myrcene may be obtained in isolated form from a plant source, in particular from mastic, or may be the product of a chemical synthesis reaction.
- an isolated fraction of mastic gum refers to a fraction obtained following extraction of gum mastic in at least one polar or non-polar organic solvent, or combinations thereof.
- the isolated fraction of the invention is generally soluble in either or both of polar and non-polar organic solvents.
- an isolated fraction of polymeric myrcene refers to a preparation of polymeric myrcene having a defined molecular weight or molecular weight range, which is separated away from other chemical components present in the source from which the polymeric myrcene was isolated, in particular a chemical reaction mixture or a plant extract.
- degree of purity refers to the content of a specified chemical compound in a preparation, expressed as a percentage on a weight per weight basis of the specified chemical compound relative to other chemical compounds in the preparation.
- homopolymer refers to a polymer that is produced from a single type of monomer.
- polymeric myrcene is a homopolymer when it is produced only from myrcene monomers, for example ⁇ -myrcene.
- a homopolymer may also be a mixture of polymers produced from the same monomer, but having a varying degree of polymerization i.e. chain length. Accordingly, polymeric myrcene may encompass a range of compounds of different chain lengths and accordingly different molecular weights. Further, a homopolymer may contain monomers having different isomeric configurations, for example, ⁇ -myrcene and ⁇ -myrcene.
- heteropolymer and “copolymer” refer to a polymer produced from more than one type of monomer.
- a myrcene copolymer is produced from myrcene monomers, in addition to a heterologous type of monomer that is not myrcene.
- Copolymers include alternating copolymers, periodic copolymers, random copolymers, block copolymers and statistical copolymers, as is known in the art.
- degree of polymerization refers to the number of monomers or monomelic units which are covalently associated together to form a polymer, for example, the number of myrcene monomers in a polymeric myrcene compound.
- weight average molecular weight refers to the average molecular weight of a polymer having molecules of different chain lengths, as expressed by the equation:
- N t is the number of molecules of molecular weight M 1 .
- the weight average molecular weight can be determined for example, by light scattering, small angle neutron scattering, X-ray scattering, and sedimentation velocity.
- number average molecular weight refers to the average molecular weight of a polymer having molecules of different chain lengths, as expressed by the equation: where N t is the number of molecules of molecular weight M t .
- the number average molecular weight can be determined for example, by gel permeation chromatography (also known as size exclusion chromatography) or viscometry.
- polydispersity index and “molecular distribution” are herein used interchangeably to refer to the ratio of the weight average molecular weight to the number average molecular weight.
- Terpene compounds refers to isoprene-containing hydrocarbons and related oxygen-containing compounds such as alcohols, aldehydes or ketones (terpenoids).
- Terpene hydrocarbons in general, have the molecular formula (C 5 Hs) n , and include monoterpenes, sesquiterpenes, diterpenes, triterpenes, and tetraterpenes which respectively have 2, 3, 4, 6 and 8 isoprene units.
- Terpenes may be further classified as acyclic or cyclic.
- Examples of monoterpenes include myrcene, limonene and pinene, which are respectively examples of acyclic, monocyclic and bicyclic monoterpenes.
- Examples of sesquiterpenes include nerolidol and farnesol.
- Examples of diterpenes include cafestol and phytol.
- Examples of a triterpene and a tetraterpene are squalene and carotene, respectively.
- substantially devoid means that a preparation or pharmaceutical composition according to the invention that generally contains less than 3% of the stated substance, preferable less than 1% and most preferably less than 0.5%.
- terapéuticaally effective amount refers to that amount of a pharmaceutical ingredient which substantially induces, promotes or results in a desired therapeutic effect.
- pharmaceutically acceptable carrier refers to a diluent or vehicle which is used to enhance the delivery and/or pharmacokinetic properties of a pharmaceutical ingredient with which it is formulated, but has no therapeutic effect of its own, nor does it induce or cause any undesirable or untoward effect or adverse reaction in the subject.
- pharmaceutically acceptable hydrophobic carrier refers to a hydrophobic non-polar diluent or vehicle in which the polymeric myrcene is dissolved or suspended.
- cell differentiation refers to the process in which a less specialized cell becomes a more specialized cell.
- Cell differentiation may be established on the basis of changes in any of a number of cellular characteristics, including but not limited to size, shape, organelle appearance, membrane potential, metabolic activity, and responsiveness to signals.
- a particular "grade” may be given to a cell type to describe the extent of differentiation.
- pair neurological function refers to a decline or decrease in at least one of sensory, cognitive or motor function, as compared to a previous level of function or activity, and/or as compared to non-impaired individuals matched according to accepted criteria.
- the present invention employs isolated fractions comprising polymeric myrcene.
- the fraction may be from a plant source, in particular mastic gum, or it may be the product of a chemical synthesis.
- Polymeric myrcene for use in the invention is a polymer compound, or a mixture of polymers of different molecular weights, which are formed from myrcene subunits.
- Suitable plant sources of polymeric myrcene includes those classified either in the family Anacardiaceae or a different plant family. Plant species useful for obtaining the compositions of the invention include without limitation, those of the genera Pistacia, Pinus, Picea, Juniperus, Alsies, Larix, Ocimum, Laurus and Lavendula.
- Pistacia include without limitation, P. lentiscus, P. atlantica, P. palestina, P. saportae, P. terebinthus, P. vera and P. integerrima.
- the polymeric myrcene may be obtained from any plant part, including for example, resin, leaves, branches, berries and seeds.
- An isolated fraction of polymeric myrcene may be most conveniently obtained from mastic gum, although other plant parts and products may be used.
- Various methods for obtaining and characterizing an isolated fraction comprising polymeric myrcene from mastic gum are exemplified in Examples 1 and 2 herein.
- Commercial preparations of mastic are available for example, from the Chios Gum Mastic Growers Association, or from G. Baldwin & Co., U.K.
- polymeric myrcene may be chemically produced as a synthetic equivalent of a naturally occurring polymer, such as cis-l,4-poly- ⁇ -myrcene, or it may be a myrcene polymer not known to occur in nature, such as polymeric ⁇ -myrcene.
- the invention is not limited to the process by which the polymeric myrcene is produced or whether it is natural, synthetic or semi-synthetic.
- the polymeric myrcene may be a synthetic product, produced by a chemical process using as a substrate a monomelic form of the monoterpene myrcene.
- the monomelic myrcene substrate may be isolated from a plant, or may be chemically or enzymatically converted from a precursor terpene, as is known in the art.
- monomelic ⁇ -myrcene isolated from a plant source may be subsequently polymerized to polymeric ⁇ -myrcene by a chemical process.
- the myrcene substrate is derived from a natural source, the resultant product may be referred to as a semi-synthetic product.
- a suitable chemical synthetic process employs an anionic polymerization reaction, for example that which comprises use of at least one alkane or cycloalkane solvent and at least one alkyl alkali metal.
- the alkyl alkali metal may be butyl lithium
- the alkane solvent may be hexane
- the cycloalkane solvent may be cyclohexane.
- the alkane solvent and the alkyl alkali metal initiator may be present in the reaction mixture at a ratio of at least 20:1.
- the anionic polymerization reaction may be terminated by a compound such as water, an alcohol, molecular oxygen and carbon dioxide.
- the synthetic process for 1,4-poly- ⁇ -myrcene disclosed herein is particularly suitable for maintaining the various biological activities of the polymer, such as promoting cell differentiation.
- Monomelic ⁇ -myrcene is known to occur in a variety of plants, including trees in the genera Pinus, Picea, Juniperus, Alsies and Larix, and flowers in the genera Antirrhinum, Boswellia, Citrus and Gynura.
- polymeric myrcene may be obtained as the purified product of a chemical synthesis reaction, as exemplified in Example 3 herein.
- Chemically synthesized polymeric myrcene may be isolated from unreacted substrate and other reagents, analyzed and further fractionated according to molecular weight using analytical and separation methods as are known in the art. Such methods include those which separate molecules on the basis of size, charge or hydrophobicity, including for example, size exclusion chromatography (SEC), high pressure liquid chromatography (HPLC), gas liquid chromatography (GLC) and combinations thereof.
- SEC size exclusion chromatography
- HPLC high pressure liquid chromatography
- GLC gas liquid chromatography
- Analytical methods for determining the precise chemical structure of the obtained polymer include nuclear magnetic resonance (for example 1 HNMR and 13 CNMR) ⁇ viscometry, various mass spectrometry methods (for example MALDI-TOF), combination methods such as Liquid Chromatography-Mass spectrometry (LC-MS)), light-scattering techniques such as for example Multi Angle Laser Light Scattering (MALLS), total carbon analysis, UV-VIS spectrophotometry, IR and FT-IR spectrophotometry and other methods as are known in the art..
- the same methods and approaches may be used for purifying and characterizing polymeric myrcene from plants, as shown herein in Example 2.
- a fraction of polymeric myrcene which is a product of a chemical synthesis should be substantially devoid of myrcene monomers and myrcene oligomeric forms having a degree of polymerization less than about 5. It is also preferred that the isolated product be substantially devoid of monomelic terpene compounds which are soluble in polar organic solvents.
- Similar methods may be used for obtaining isolated fractions of mastic gum and isolated fractions of polymeric myrcene, when the polymeric myrcene is to be derived from a plant source, such as mastic gum.
- collected plant material for example mastic gum
- a suitable solvent usually a polar solvent.
- suitable polar solvents include for example, alcohols, ethers, esters, amides, aldehydes, ketones, nitriles and combinations thereof.
- polar organic solvents are methanol, ethanol, propanol, isopropanol, 1-butanol, 2- butanol, sec-butanol, t-butanol, 1-pentanol, 2-pentanol, 3-pentanol, neopentanol, 3-methyl- 1-butanol, 2-methyl- 1-butanol, 3-methyl-2-butanol, 2-methyl-2-butanol, ethyleneglycol, ethyleneglycol monomethyl ether, diethyl ether, methylethyl ether, ethylpropyl ether, methylpropyl ether, 1,2-dimethoxyethane, tetrahydrofuran, dihydrofuran, furan, pyran, dihydropyran, tetrahydropyran, methyl acetate, ethyl acetate, propyl acetate, acetaldehyde, methylformate,
- the mastic gum and the solvent are preferably combined such that the solvent is in large excess, for example 10:1 or 20:1.
- the mixture may be periodically or continuously agitated over a period ranging from a few minutes to a number of hours.
- the solvent may be decanted without any treatment, or optionally the mixture may be first subjected to low speed centrifugation, for example at 100 to 2000 rpm, as is known in the art.
- the insoluble material is recovered from the extract and a fresh aliquot of solvent is added to the insoluble material, such that the extraction and dissolution process is repeated for a number of cycles, in order to obtain as much as possible of the polar solvent soluble compounds.
- the extracts containing polar solvent soluble material are combined and the polar solvent is evaporated (for example by using a rotary evaporation as is known in the art), so as to yield polar solvent soluble material, which may be referred to as a crude, or "first step" extract.
- the first step extract material is combined with a non-polar organic solvent and extracted by shaking over a period of 1 hour.
- Suitable non-polar solvents include acyclic or cyclic, saturated or unsaturated aliphatic hydrocarbons and aromatic hydrocarbons, for example, C5-C10 alkanes, C5-C10 cycloalkanes, C6-C14 aromatic hydrocarbons, and combinations thereof. Each of the foregoing may be optionally substituted by one or more halogens, for example, C7-C14 perfluoroalkanes.
- non-polar organic solvents are pentanes, hexanes, heptanes, octanes, nonanes, decanes, cyclopentane, cyclohexane, cycloheptane, benzene, toluene, xylene, and isomers and mixtures thereof. Material remaining insoluble or precipitating in the presence of the non-polar solvent is removed and discarded. The non-polar solvent-soluble fraction is then obtained by evaporating the non-polar solvent (for example by rotary evaporation).
- This fraction may be referred to as purified or "two step" extract, corresponding to an isolated fraction of mastic gum which is characterized by the fact that it is soluble in both a polar solvent and a non-polar solvent, while materials which are soluble in the polar solvent but insoluble in the non-polar solvent, have been removed.
- This feature distinguishes the isolated fractions of the invention over prior art extracts of mastic gum, the latter of which generally include a wide variety of compounds which are soluble only in polar solvents. According to the teachings of the present invention, such compounds interfere with the beneficial biological activities of the isolated fractions disclosed herein.
- the two step extract may be dried further, for example by high vacuum treatment (for example ⁇ 0.01 mbar for up to several days) to remove residual solvent and other volatile material, weighed and combined with a suitable non-polar organic solvent or other carrier to effect its dissolution.
- high vacuum treatment for example ⁇ 0.01 mbar for up to several days
- such isolated fractions contain polymeric myrcene.
- the obtained fractions containing polymeric myrcene may be used directly, or further purified, characterized and/or fractionated using means known in the art, as enumerated above.
- the isolated fractions of the invention may be obtained by a process comprising the steps of:
- step (d) treating the soluble fraction obtained in step (b) or (c) with a non-polar organic solvent, (e) isolating a fraction soluble in said nonpolar organic solvent;
- steps (d) to (f) may precede steps (a) to (c).
- the process may further comprise size fractionating the soluble fraction obtained following step (c) or step (f), for example by size exclusion chromatography, or any other method known in the art.
- the process may further comprise removing the solvent after either or both of steps (c) or (f).
- Solvent removal may be carried out by any means known in the art, for example rotary evaporation, application of high vacuum and a combination thereof.
- steps (a) to (c) are carried out prior to steps (d) to (f) or vice versa.
- the polar organic solvent comprises ethanol and the non-polar organic solvent comprises hexane.
- steps (a) to (c) and steps (d) to (f) may each be independently carried out for a number of cycles to optimize the extraction process and degree of purification of the product.
- suitable carriers such as hydrophobic carriers including pharmaceutically acceptable oils, optionally in combination with waxes, as described herein.
- compositions comprising the fractions isolated from mastic gum as herein described should comprise less than about 20% (w/w) of monomelic and oligomeric terpene compounds which are soluble in the polar organic solvent and are substantially insoluble in the non-polar organic solvent, wherein the aforementioned solvents refer to those used in the preparation of the fraction. More preferably, the isolated fractions comprise less than about 5% (w/w) of such terpene compounds. Even more preferably, the isolated fractions are substantially devoid of such terpene compounds. .
- the inhibitory effects of fractions comprising such low molecular weight compounds on the biological activity of polymeric myrcene are exemplified herein in Example 8.
- an isolated fraction comprising polymeric myrcene is derived from a plant and is substantially devoid of myrcene monomers and myrcene oligomeric forms having a degree of polymerization less than 6.
- an isolated fraction comprising polymeric myrcene is derived from a plant and is substantially devoid of terpene compounds which are soluble in a polar organic solvent but are substantially insoluble in a non-polar organic solvent.
- polymeric myrcene may not have a single molecular weight, but rather, a distribution of molecular weights, representing a population of polymeric myrcene molecules of different chain length i.e. degree of polymerization.
- the degree of polymerization is at least about 6. In a particular embodiment, the degree of polymerization is at least about 10. In a particular embodiment, the degree of polymerization is at least about 25. . In a particular embodiment, the degree of polymerization is at least about 35. In a particular embodiment, the polymeric myrcene has a degree of polymerization in the range of at least about 6 to about 1800. Suitable exemplary ranges include about 30 to about 500, or about 35 to about 150. The number average molecular weight of the polymeric myrcene is preferably at least about 800.
- the number average molecular weight is at least about 1 ,000, such as at least 2000 or at least 3000, and even more preferably, the number average molecular weight is at least about 5000.
- the polymeric myrcene has a number average molecular weight in the range from about 5000 to about 20,000. In a particular embodiment, the polymeric myrcene has a number average molecular weight in the range from at least about 800 to about 100,000.
- the number average molecular weight is in a range selected from the group consisting of: at least about 800 to about 5000; at least about 800 to about 15,000; about 5000 to about 15,000; about 5000 to about 20,000; about 15,000 to about 30,000; about 25,000 to about 40,000; about 35,000 to about 50,000; about 45,000 to about 60,000; about 55,000 to about 70,000; about 65,000 to about 80,000; about 75,000 to about 90,000; about 85,000 to about 100,000; and combinations thereof, hi a particular embodiment, the number average molecular weight is at least about 5000.
- composition may comprise different molecular weight fractions of polymeric myrcene, for example in the range from at least about 5000 to about 20,000, as well as in the range from about 25,000 to about 40,000.
- polymeric myrcene has a molecular distribution of less than 5.
- the isolated fraction consists essentially of polymeric myrcene that has a number average molecular weight in the range from about 5000 to about 20,000.
- the molecular weight of the polymeric product may be expressed in a number of ways, for example, weight average molecular weight or number average molecular weight, as is known in the art.
- Molecular weight may be determined by any of a number of means, such as light scattering, multi angle laser light scattering (MALLS), small angle neutron scattering, X-ray scattering, sedimentation velocity, viscometry (Mark-Houwink equation), mass spectrometry (e.g. MALDI-TOF) and gel permeation chromatography.
- the polymeric myrcene may exist as different geometric isomers, resulting from the arrangement of substituents around the carbon-carbon double bond.
- Such isomers are designated as the cis- or trans- configuration (also referred to respectively as the Z or E configuration), wherein cis- (or Z) represents substituents on the same side of the carbon- carbon double bond, and trans- (or E) represents substituents on opposite sides of the carbon-carbon double bond.
- the various geometric isomers and mixtures thereof are included within the scope of the invention.
- the polymeric myrcene product may contain one or more asymmetric carbon atoms and may therefore exhibit optical isomerism and/or diastereoisomerism. All stereoisomers and diastereoisomers are included within the scope of the invention, either as a single isomer or as a mixture of sterochemical isomeric forms.
- the various stereoisomers and diastereoisomers may be separated using conventional techniques, for example chromatography or fractional crystallisation.
- desired optical isomers may be made by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation or epimerisation, or by derivatisation, for example with a homochiral acid followed by separation of the diastereomeric derivatives by conventional means.
- polymeric myrcene examples include polymeric ⁇ -myrcene (poly- ⁇ - myrcene), including 1,4-poly- ⁇ -myrcene, 3,4-poly- ⁇ -myrcene, 1,2-poly- ⁇ -myrcene, cis- 1,4-poly- ⁇ -myrcene, trans- 1,4-poly- ⁇ -myrcene, polymeric ⁇ -myrcene (poly- ⁇ -myrcene) or combinations thereof.
- the isolation and characterization of 1,4-poly- ⁇ -myrcene from mastic is disclosed for example in Van der Berg et al (1998) Tetrahedron Lett 3:2645- 2648.
- the polymeric myrcene has a linear conformation, a branched conformation or a cyclic conformation.
- the isolated fraction of polymeric myrcene according to the invention has a degree of purity of at least 90%, such as at least 93%, or at least 95%, or at least 97%, or at least 98% or at least 99%.
- a degree of purity as possible is desirable inter alia to ensure compliance with health regulatory agency requirements.
- the fraction of polymeric myrcene may contain myrcene polymeric species having various molecular weights, such as within a defined narrow or wide range, without reducing the specified degree of purity.
- the isolated fraction of polymeric myrcene may contain different structural isomers as described above of polymeric myrcene without reducing the specified degree of purity.
- the isolated fraction of polymeric myrcene comprises at least 90% (w/w) of cis-l,4-poly- ⁇ -myrcene.
- the isolated fraction of polymeric myrcene comprises a mixture of cis-l,4-poly- ⁇ -myrcene and trans- 1,4-poly- ⁇ -myrcene, wherein the mixture comprises at least 80% (w/w) of cis-l,4-poly- ⁇ -myrcene.
- the isolated fraction of polymeric myrcene comprises at least 90% (w/w) of cis-l,4-poly- ⁇ -myrcene having a number average molecular weight of at least 800.
- the number average molecular weight may be at least 1,000.
- the average molecular weight may be at least 2000.
- the number average molecular weight may be at least 3,000.
- the number average molecular weight may be at least 5000.
- the number average molecular weight may be at least 10,000.
- the isolated fraction of polymeric myrcene comprises at least 90% (w/w) of cis-l,4-poly- ⁇ -myrcene having a number average molecular weight in the range from about 800 to about 5000.
- the isolated fraction of polymeric myrcene comprises at least 90% (w/w) of cis-l,4-poly- ⁇ -myrcene having a number average molecular weight in the range from about 1,000 to about 10,000. In a particular embodiment, the isolated fraction of polymeric myrcene comprises at least 90% (w/w) of cis-l,4-poly- ⁇ -myrcene having a number average molecular weight in the range from about 10,000 to about 20,000.
- the isolated fraction of polymeric myrcene comprises at least 90% (w/w) of cis-l,4-poly- ⁇ -myrcene having a number average molecular weight in the range from about 5000 to about 20,000.
- the isolated fraction of polymeric myrcene consists essentially of cis-l,4-poly- ⁇ -myrcene that has a number average molecular weight in the range from about 5000 to about 20,000.
- the isolated fraction of polymeric myrcene has a degree of purity of at least 90%, and the polymeric myrcene has a degree of polymerization of at least 10.
- the isolated fraction of polymeric myrcene comprises at least 90% (w/w) of cis-l,4-poly- ⁇ -myrcene having a number average molecular weight in the range from about 20,000 to about 30,000. In a particular embodiment, the isolated fraction of polymeric myrcene comprises at least 90% (w/w) of cis-l,4-poly- ⁇ -myrcene having a number average molecular weight in the range from about 30,000 to about 50,000.
- the isolated fraction of polymeric myrcene comprises at least 90% (w/w) of cis-l,4-poly- ⁇ -myrcene having a number average molecular weight in the range from about 50,000 to about 80,000.
- the isolated fraction of polymeric myrcene is substantially purified of terpene compounds which are soluble in a polar organic solvent but substantially insoluble in a non-polar organic solvent.
- the composition should comprise less than about 10% (w/w), and more preferably, less than about 5% (w/w), and most preferably, less than about 3% (w/w), of terpene compounds which are soluble in a polar organic solvent but substantially insoluble in a non-polar organic solvent, hi particular embodiments, the composition is substantially devoid of terpene compounds which are soluble in a polar organic solvent but insoluble in a non-polar organic solvent. In particular embodiments, the composition comprises less than about 10% (w/w), and more preferably less than about 5% (w/w), and most preferably, less than about 3% (w/w), of monomelic terpene compounds.
- the composition is substantially devoid of myrcene monomers and myrcene oligomeric forms having a degree of polymerization less than about 5.
- the composition comprises less than about 10% (w/w), and more preferably, less than about 5% (w/w), and most preferably, less than about 3% (w/w), of a terpene compound selected from the group consisting of: ⁇ -myrcene, ⁇ -myrcene, cis- ⁇ -ocimene, dihydromyrcene, limonene, ⁇ -pinene, ⁇ -pinene, and combinations thereof.
- composition for use in the invention comprises a therapeutically effective amount of an isolated fraction of polymeric myrcene, and a pharmaceutically acceptable hydrophobic carrier.
- a suitable hydrophobic carrier comprises at least one oil, such as for example a mineral oil, a vegetable oil or combinations thereof.
- mineral oil refers to a clear colorless nearly odorless and tasteless liquid obtained from the distillation of petroleum. It may also be referred to as white oil, white mineral oil, liquid petrolatum, liquid paraffin or white paraffin oil.
- the mineral oil is light mineral oil, a commercially available product which may be obtained either as a NF (National Formulary) grade product or as a USP (US Pharmacopoeia) grade product.
- the mineral oil is preferably free of aromatics and unsaturated compounds.
- Suitable vegetable oils include, but are not limited to almond oil, canola oil, coconut oil, corn oil, cottonseed oil, grape seed oil, olive oil peanut oil, saffron oil, sesame oil, soybean oil, or combinations thereof.
- the mineral oil is light mineral oil.
- the pharmaceutically acceptable carrier may alternately or in addition comprise a suitable oil replacement.
- Oil replacements include alkanes having at least 10 carbon (e.g., isohexadecane), benzoate esters, aliphatic esters, noncomodogenic esters, volatile silicone compounds (e.g., cyclomethicone), and volatile silicone substitutes.
- benzoate esters include Ci 2 C 15 alkyl benzoate, isostearyl benzoate, 2-ethyl hexyl benzoate, dipropylene glycol benzoate, octyldodecyl benzoate, stearyl benzoate, and behenyl benzoate.
- Examples of aliphatic esters include C 12 Ci 5 alkyl octonoate and dioctyl maleate.
- Examples of noncomodogenic esters include isononyl isononanoate, isodecyl isononanoate, diisostearyl dimer dilinoleate, arachidyl propionate, and isotridecyl isononanoate.
- Examples of volatile silicone substitutes include isohexyl decanoate, octyl isononanoate, isononyl octanoate, and diethylene glycol dioctanoate.
- Cyclomethicone is an evaporative silicone which may be included in the carrier to assist in making the composition amenable to ejection from a spray dispenser. Furthermore, due to its evaporative property, cyclomethicone may assist in retaining and fixing the formulation on the surface to which it is sprayed e.g. a wound site.
- the hydrophobic carrier may further comprise at least one wax.
- Waxes include for example, beeswax; vegetable waxes, sugar cane waxes, mineral waxes, and synthetic waxes.
- Vegetable waxes include for example, carnauba, candelilla, ouricury and jojoba wax.
- Mineral waxes include for example, paraffin wax, lignite wax, microcrystalline waxes and ozokerites.
- Synthetic waxes include for example, polyethylene waxes.
- the pharmaceutical composition may be formulated in any of a number of forms such as for example, a capsule (including a softgel capsule), a tablet, a gel, a liposome, a suppository, a suspension, an ointment, a solution, an emulsion or microemulsion, a film, a cement, a powder, a glue, an aerosol, a spray and a gel.
- a capsule including a softgel capsule
- a tablet including a softgel capsule
- a gel a liposome, a suppository, a suspension, an ointment, a solution, an emulsion or microemulsion, a film, a cement, a powder, a glue, an aerosol, a spray and a gel.
- the polymeric myrcene may be suitably formulated as inclusion complexes, nanoemulsions, microemulsions, powders and liposomes.
- an inclusion complex comprises at least one cyclodextrin.
- cyclodextrins comprise hydroxypropyl- ⁇ - cyclodextrin.
- nanoemulsions comprise droplets having average particle size of less than 800 nm.
- the droplets have average particle size of less than 500 nm.
- the droplets have average particle size of less than 200 nm.
- powders are spray dried powders.
- liposomes comprise multilamellar vesicles.
- a microemulsion comprises a non-ionic surfactant.
- Non-ionic surfactants include, without limitation, polyoxyl castor oils, polyoxyethylene sorbitan fatty acid esters (polysorbates), a poloxamer, a vitamin E derivative, polyoxyethylene alkyl ethers, polyoxyethylene sterates, saturated polyglycolyzed glycerides or combinations thereof.
- compositions of the invention may be administered by any means that achieve their intended purpose.
- administration may be by oral, parenteral, topical or transdermal routes.
- Parenteral administration includes intravenous, intramuscular, subcutaneous, intradermal, intraperitoneal, intraarterial, intrauterine, intraurethral, intracardial, intracerebral, intracerebroventricular, intrarenal, intrahepatic, intratendon, intraosseus and intrathecal routes of administration.
- Topical administration includes application via a route selected from dermal, vaginal, rectal, inhalation, intranasal, ocular, auricular and buccal.
- the administering may in addition comprise a technique or means such as electroporation, or sonication in order to assist in their delivery, for example transdermally.
- Other techniques which may be employed include for example, radio frequency or pressurized spray application.
- the dosage administered will be dependent upon the age, health, and weight of the subject, the use of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired.
- the amount of the polymeric myrcene of the present invention in any unit dosage form comprises a therapeutically effective amount which may vary depending on the recipient subject, route and frequency of administration.
- the amount of polymeric myrcene or isolated mastic gum fraction present in the pharmaceutical composition may conveniently be in the range from about 0.01% to about 25%, such as 0.01% to about 12%, on a weight per weight basis, based on the total weight of the composition.
- the percentage of polymeric myrcene or isolated mastic gum fraction in the composition may be in the range from about 0.05% to about 2.5%.
- the percentage of polymeric myrcene or isolated mastic gum fraction in the composition may be conveniently in the range from about 0.1% to about 7%.
- the percentage of polymeric myrcene or isolated mastic gum fraction in the composition may be in the range from about 0.005% to about 7%.
- compositions of the invention may be manufactured in a manner which is itself known to one skilled in the art, for example, by means of conventional mixing, granulating, dragee-making, softgel encapsulation, dissolving, extracting, or lyophilizing processes.
- the formulations are non-aqueous and/or do not comprise polar solvents which directly contact the polymeric myrcene active ingredient, so as to avoid loss of biological activity of the active ingredient.
- pharmaceutical compositions for oral use may be obtained by combining the active compounds with solid and semi-solid excipients and suitable preservatives, and/or antioxidants.
- the resulting mixture may be ground and processed.
- the resulting mixture of granules may be used, after adding suitable auxiliaries, if necessary, to obtain tablets, softgels, capsules, or dragee cores.
- Suitable excipients are, in particular, fillers such as saccharides, e.g., lactose or sucrose, mannitol or sorbitol; cellulose preparations and/or calcium phosphates, e.g., tricalcium phosphate or calcium hydrogen phosphate; as well as binders, such as starch paste, using, e.g., maize starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/or polyvinyl pyrrolidone.
- fillers such as saccharides, e.g., lactose or sucrose, mannitol or sorbitol; cellulose preparations and/or calcium phosphates, e.g., tricalcium phosphate or calcium hydrogen phosphate; as well as binders, such as starch paste, using, e.g., maize starch, wheat starch
- disintegrating agents may be added such as the above- mentioned starches and also carboxymethyl-starch, cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate.
- Auxiliaries are flow- regulating agents and lubricants, e.g., silica, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and/or polyethylene glycol.
- Dragee cores are provided with suitable coatings which, if desired, are resistant to gastric juices.
- concentrated saccharide solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures.
- suitable cellulose preparations such as acetylcellulose phthalate or hydroxypropymethyl-cellulose phthalate, are used.
- Dye stuffs or pigments may be added to the tablets or dragee coatings, e.g., for identification or in order to characterize combinations of active compound doses.
- compositions for oral use include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
- the push-fit capsules can contain the active compounds in the form of granules, which may be mixed with fillers, such as lactose; binders, such as starches; and/or lubricants, such as talc or magnesium stearate and, optionally, stabilizers.
- the active compounds are preferably dissolved or suspended in suitable liquids, such as fatty oils, or liquid paraffin.
- suitable liquids such as fatty oils, or liquid paraffin.
- stabilizers may be added.
- compositions for oral use include a film designed to adhere to the oral mucosa, as disclosed for example in U.S. Patent Nos. 4,713,243; 5,948,430; 6,177,096; 6,284,264; 6,592,887, and 6,709,671.
- compositions in the form of suppositories consist of a combination of the active compound(s) with a suppository base.
- Suitable suppository bases include for example, natural or synthetic triglycerides, polyethylene glycols, or paraffin hydrocarbons.
- Formulations for parenteral administration include suspensions and microparticle dispersions of the active compounds as appropriate.
- oily injection suspensions may be administered.
- Suitable lipophilic solvents or vehicles include fatty oils, e.g., sesame oil, or synthetic fatty acid esters, e.g., ethyl oleate, triglycerides, polyethylene glycol-400, cremophor, or cyclodextrins.
- Injection suspensions may contain substances which increase the viscosity of the suspension include, e.g., sodium carboxymethyl cellulose, sorbitol, and/or dextran.
- the suspension may also contain stabilizers.
- compositions can also be prepared using liposomes comprising the active ingredient.
- liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals which are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolisable lipid capable of forming liposomes can be used. In general, the preferred lipids are phospholipids and the phosphatidyl cholines (lecithins), both natural and synthetic. Methods to form liposomes are known in the art, as disclosed for example, in Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N. Y. (1976) and in U.S. Patent No. 7,048,943.
- Formulations for topical administration include ointments.
- Suitable carriers include vegetable or mineral oils, white petrolatum, branched chain fats or oils, animal fats and waxes.
- the preferred carriers are those in which the active ingredient is soluble.
- Stabilizers, humectants and antioxidants may also be included, as well as agents imparting color or fragrance, if desired.
- Ointments may be formulated for example, by mixing a solution of the active ingredient in a vegetable oil such as almond oil with warm soft paraffin, and allowing the mixture to cool.
- the pharmaceutical composition may comprise an oil-in-water emulsion or microemulsion in order to facilitate its formulation for oral, parenteral or topical use
- emulsions/microemulsions generally include lipids, surfactants, optionally humectants, and water.
- Suitable lipids include those generally know to be useful for creating oil-in- water emulsions/microemulsions, for example fatty acid glyceride esters.
- Suitable surfactants include those generally known to be useful for creating oil-in-water emulsions/microemulsions wherein lipids are used as the oil component in the emulsion.
- Non-ionic surfactants may be preferred, such as for example, ethoxylated castor oil, phospholipids, and block copolymers of ethylene oxide and propylene oxide.
- Suitable humectants, if used, include for example propylene glycol or polyethylene glycol.
- the pharmaceutical composition may be formulated in the form of a gel, such as a hydrogel formed from a gel-forming polymer such as carrageenan, xanthan gum, gum karaya, gum acacia, locust bean gum, guar gum.
- a hydrogel may be combined with an oil- in-water emulsion comprising the active ingredient.
- the pharmaceutical composition may be formulated in the form of a cement such as those comprising polymethylmetacrylate (PMMA) or calcium phosphate, as are used in orthopedic surgery.
- PMMA polymethylmetacrylate
- Ca phosphate calcium phosphate
- the pharmaceutical composition may be formulated in the form of a powder, in particular such as those used for transdermal applications using radio frequency, as described for example, in U.S. Patent Nos. 6,074,688 and 6,319,541 and WO 2006/003659.
- the pharmaceutical composition may be formulated in the form of a glue, such as those comprising octocyanoacrylate used for wound closure applications.
- the pharmaceutical composition is substantially devoid of monomelic and low molecular weight terpene compounds, including for example, those classified as monoterpenes, diterpenes, sesquiterpenes, triterpenes, tetraterpenes.
- terpene compounds include ⁇ -myrcene, ⁇ -myrcene, cis- ⁇ -ocimene, dihydromyrcene, limonene, ⁇ -pinene, ⁇ -pinene, tirucallol, betulonal, masticadienonic acid, masticadienolic acid, isomasticadienonic acid, isomasticadienolic acid, oleanolic acid, and oleanonic acid.
- the present invention provides therapeutic uses and methods of treating impaired neurological function, treating skin and scalp disorders, inducing tissue repair and wounds in a subject in need thereof.
- the methods comprise administering to the subject a therapeutically effective amount of a composition comprising an isolated fraction of mastic gum, or an isolated fraction of polymeric myrcene, as described herein.
- the step of administering the compositions may comprise any acceptable route including oral, topical, parenteral, and transdermal.
- Parenteral administration includes intravenous, intramuscular, subcutaneous, intradermal, intraperitoneal, intraarterial, intrauterine, intraurethral, intracardial, intracerebral, intracerebroventricular, intrarenal, intrahepatic, intratendon, intraosseus and intrathecal routes of administration.
- Topical administration includes application via a route selected from dermal, vaginal, rectal, inhalation, intranasal, ocular, auricular and buccal.
- the step of administering comprises contacting cells of a particular type, of a particular lineage or at a particular stage of differentiation, with the composition.
- the cells may be any of a wide variety of cell types, including in particular, neural cells, neuronal cells, endothelial cells, epithelial cells and stem cells of said lineages. Further, the cells may be of any lineage for example, ectodermal, mesodermal, entodermal lineages and stem cells of said lineages.
- the step of contacting cells is carried out in vivo, ex vivo or in vitro.
- the method disclosed herein for treating impaired neurological function is particularly advantageous for subjects afflicted with neurodegenerative conditions and diseases, including in particular, trauma, vascular dementia, senile dementia, Alzheimer's disease, amyotrophic laterial sclerosis (ALS), multiple sclerosis), stroke and Parkinson's disease.
- the method may be advantageously applied in subjects suffering from impaired neurological function due to an infection (e.g. viral, bacterial, fungal, parasitic) or an immunological disorder.
- the impaired neurological function is due to exposure to a drug, such as an anesthetic.
- Impaired neurological function may also be associated with a condition selected from the group consisting of schizophrenia, bipolar disorder, depression, obesity, anorexia and cachexia.
- Skin and scalp disorders include all disorders of skin, scalp and hair appendages, including for example, nails and hair follicles. Particular conditions that may benefit from the invention include alopecia, eczema, psoriasis, seborrheic keratosis, seborrhea and skin wounds.
- Skin wounds include venous leg ulcers, pressure ulcers, diabetic foot ulcers, burns, amputation wounds, decubitus ulcers (bed sore), split-skin donor grafts, skin graft donor sites, medical device implantation sites, bite wounds, frostbite wounds, puncture wounds, shrapnel wounds, dermabrasions, contusions, an infection wounds and surgical wounds. Wounds may be the result of infection; exposure to ionizing radiation; exposure to laser, or exposure to a chemical agent.
- the invention may be particularly effective for scar-less repair of wounds.
- the invention may be particularly effective and economical for treatment of chronic non-healing wounds.
- the efficacy of a particular treatment in promoting wound healing may be assessed by various criteria, including the rate of closure measured by length, width and depth of the wound over time, epithelization rate, formation of granulation tissue and tissue tensile strength.
- the methods disclosed herein for inducing or promoting tissue regeneration are particularly advantageous for subjects who have tissue damage, which for example, may be associated with, or the result of an injury or insult.
- the methods for inducing or promoting tissue regeneration may be used in subjects who have suffered an injury or insult selected from the group consisting of a myocardial infarction, a pulmonary embolism, a cerebral infarction, peripheral artery occlusive disease, a hernia, a splenic infarction, a venous ulcer, an axotomy, a retinal detachment, a wound (for example, a burn wound, bite wound, a frostbite wound, a puncture wound, a shrapnel wound, a contusion, an infection wound or a surgical wound), an infection and a surgical procedure.
- Example 4 discloses that an isolated fraction of polymeric myrcene (derived from mastic of Pistaci ⁇ ) induces differentiation of retinal pigment epithelium cells.
- Example 5 discloses that polymeric myrcene shortens the recovery time from anesthesia in experimental animals.
- Example 6 discloses that the same fraction has activity in inducing differentiation in melanoma and neuroblastoma tumor cell lines.
- Example 7 discloses that chemically synthesized polymeric myrcene of various molecular weight ranges induces differentiation in retinal pigment epithelium cells.
- Example 8 discloses that small molecular weight compounds from mastic which are separated from polymeric myrcene during preparation thereof on the basis of their being soluble only in a polar solvent in accordance with the invention, interfere with, reduce and hinder the cell differentiation inducing activity exerted by polymeric myrcene.
- Examples 9, 10 and 11 disclose that the invention may be applied to wound healing in mammals and non-mammalian subjects.
- Example 12 discloses that compositions comprising polymeric myrcene according to the invention have ameliorating effects in an animal model of vascular dementia.
- Example 13 discloses that the invention may be used to stimulate appetite in subjects affected by various disorders that result in appetite loss or pathological weight gain result in obesity.
- Example 14 discloses that compositions comprising polymeric myrcene according to the invention have ameliorating effects in an animal model of stroke.
- Example 15 discloses that compositions comprising polymeric myrcene according to the invention have ameliorating effects in an animal model of optic nerve injury/trauma.
- Example 16 discloses that compositions comprising polymeric myrcene according to the invention have ameliorating effects in an animal model of retinal detachment and provides evidence of scar-less repair of wounds.
- the step of contacting cells may be carried out in vitro or ex vivo.
- cells, or an organ or tissue derived therefrom which is intended for implantation or transplantation into the subject may be treated according to the invention.
- cell explants or cells or tissues grown and maintained in culture may be contacted with the composition.
- the cells may originate for example, from stem cells of an autologous or homologous donor, and be intended for organ regeneration and/or implantation into a recipient.
- the cells are from a heterologous donor and are intended for implantation or transplantation into a recipient.
- the cells are those of an organ or tissue from a heterologous donor intended for implantation or transplantation into a recipient.
- the cells are those which secrete soluble factors.
- Medical devices include, but are not limited to a prosthetic, an artificial organ or component thereof, a valve, a catheter, a tube, a stent, an artificial membrane, a pacemaker, a sensor, an endoscope, an imaging device, a pump, a wire and an implant.
- Implants include, but are not limited to a cardiac implant, a cochlear implant, a corneal implant, a cranial implant, a dental implant, a maxillofacial implant, an organ implant, an orthopedic implant, a vascular implant, an intraarticular implant and a breast implant.
- the medical device is an organ implant, which may in certain cases comprise autologous cells of the subject.
- the step of contacting comprises a means selected from the group consisting of electroporation, sonication, radio frequency, pressurized spray and combinations thereof.
- the step of contacting comprises establishing contact between interstitial fluid and the composition.
- This may be particularly advantageous for wounds which are surrounded by interstitial fluid.
- Contact between interstitial fluid and the composition may be accomplished by piercing and/or teasing the dermis with a needle, a microneedle, or an apparatus comprising a plurality of needles or microneedles.
- needles or microneedles are preferably non-hollow and may be fashioned in a plurality for example, on a comb or brush-like apparatus.
- the method of the invention is suitable for application in humans, non-human mammals, fish and birds.
- the method of the invention may encompass use of an article of manufacture which incorporates the composition comprising polymeric myrcene described herein.
- the pharmaceutical composition may be in the form of a coating on the article of manufacture, or may be contained within a vessel which is integral to the article of manufacture.
- the pharmaceutical composition is advantageously present as a coating on devices which are inserted to the body and are intended for integration therein, for example an implant.
- the pharmaceutical composition can thus promote tissue closure over the implant due to the activity of polymeric myrcene in inducing cell differentiation.
- the pharmaceutical composition may be advantageously incorporated onto or into articles used in wound healing or tissue repair, for example, a dressing or bandage.
- the pharmaceutical composition can thus promote wound healing due to the activity of polymeric myrcene in inducing cell differentiation.
- the pharmaceutical composition may be incorporated to a delivery device such as a needle, an injection device or a spray dispenser from which the composition is delivered to a body site requiring therapy, for example a wound site.
- a delivery device such as a needle, an injection device or a spray dispenser from which the composition is delivered to a body site requiring therapy, for example a wound site.
- Articles of manufacture include, but are not limited to a fabric article, a diaper, a wound dressing, a medical device, a needle, a microneedle, an injection device and a spray dispenser.
- the article of manufacture comprises a plurality of microneedles. Medical devices and implants are as hereinbefore described.
- Method 1 Mastic resin (10 g) was combined with absolute ethanol (200 ml) and the mixture was allowed to stand overnight. The mixture was shaken, larger insoluble particles were allowed to settle over 20 minutes, and the ethanol was transferred into a new flask. The remainder was shaken with a fresh portion of absolute ethanol (150 ml) for 10 minutes. This ethanol fraction was combined with the first fraction. The procedure was repeated with another 150 ml portion of absolute ethanol which was combined with first two ethanol fractions. Subsequently, the ethanol was removed in vacuo using a rotary evaporator (water-bath temperature 30 0 C). Hexane (300 ml) was added to the remaining residue and the mixture was shaken repeatedly over a period of two hours.
- the clear hexane solution was transferred into a clean pre-weighed flask and the hexane was removed using a rotary evaporator. To the obtained isolated fraction was added immediately the desired amount of oil and the mixture was shaken until a homogeneous mixture was obtained.
- Method 2 Mastic resin (10 g) was combined with absolute methanol (300 ml) and the mixture was allowed to stand overnight. The mixture was shaken, larger insoluble particles were allowed to settle over 20 minutes, and the methanol soluble fraction was transferred into a new flask. The remaining insoluble material was shaken with a fresh portion of absolute methanol (200 ml) for 10 minutes. This second methanol soluble fraction was combined with the first methanol soluble fraction. The procedure was repeated with another 200 ml portion of absolute methanol, and a third methanol soluble fraction was combined with first two methanol soluble fractions. Subsequently, the methanol was removed in vacuo using a rotary evaporator (water-bath temperature 30 0 C).
- Hexane (300 ml) was added to the remaining residue and the mixture was shaken repeatedly over a period of two hours. After standing overnight in the closed flask in order to complete dissolution of soluble material and precipitation of any insoluble material, the clear hexane solution was transferred into a clean pre-weighed flask and the hexane was removed using a rotary evaporator. To the obtained isolated fraction was added immediately the desired amount of oil and the mixture was shaken in the closed flask until a homogeneous mixture was obtained.
- Method 3 Mastic resin (5 g) was pulverized with pestle and mortar and combined with hexane (200 ml). The mixture was shaken every 30 minutes during an eight hour period and subsequently left to stand overnight. The hexane soluble fraction was removed from insoluble material and transferred to a clean flask. The hexane was removed from the hexane soluble fraction using a rotary evaporator. The remaining residue was then subjected to a high-vacuum system ( ⁇ 0.01 mbar) for at least 24 hours in order to remove additional volatile materials. Absolute ethanol (100 ml) was then added to the remaining residue and the mixture was shaken repeatedly over a period of 1 hour.
- the ethanol soluble fraction was transferred to clean flask and the extraction was repeated with two additional 100 ml portions of absolute ethanol. The ethanol soluble fractions were combined and any remaining insoluble material was allowed to settle overnight. The clear ethanol solution was transferred into a clean, pre-weighed flask and the ethanol was removed under vacuum. To the remainder was added immediately the desired quantity of oil and the mixture was shaken until a homogeneous formulation was obtained.
- Method 4 Leaves, soft twigs, fruits and berries of Pistacia lentiscus L., P. atlantica or P. palestina trees were collected, cleaned and pulverized. Dissolution with ethanol or methanol was initially carried out essentially as described in Methods 1 and 2, and subsequent dissolutions were carried out using combinations of ethanol or methanol with a vegetable oil for a number of cycles.
- Method 5 Leaves (30 g) of Pistacia lentiscus L. were collected, cleaned and cut to small pieces with a knife and placed in a food processor. Olive oil (100ml) was added and processed. The whole mixture was removed and placed in a glass beaker. Two hundred ml of ethanol (96%) was added and the mixture heated to 65° C for 20 min. The whole mixture was placed in gauze and the liquid was pressed out. The upper ethanol phase was removed by pipetting and discarded. Residual ethanol may be removed from the oil phase by evaporation.
- Method 7 For each preparation, approximately ten grams of resin exudate collected from Pistacia lentiscus L., P. atlantica or P. palestina trees in the area of Zikhron Yaakov, Israel was used. The resin was combined with 30 ml methanol in a suitable glass vessel and the mixture was vigorously shaken repeatedly during a time period of 30 minutes to 2 hours-. A portion of the resin dissolved, while insoluble material settled at the bottom of the vessel. The upper liquid was decanted, and additional aliquots of methanol were added as above, and the shaking and decantation process was repeated. The insoluble material remaining was then immersed in distilled water for 30 seconds to 1 minute, resulting in a white milky liquid with insoluble material remaining.
- the insoluble material remaining after the final cycle (typically corresponding to 20 to 35% by weight of the commercial starting material, or 10 to 25% of the collected resin starting material) was solubilized in one of olive oil, peanut oil, grape seed oil, sesame oil, cotton oil or soy oil to give a final concentration of 8 to 10% (w/w).
- Pulverized mastic ( ⁇ 10 g) was combined with 100 ml methanol. After shaking for few minutes, the methanol was decanted, leaving a reduced mass of non- soluble white material due to the removal of solubilized material. An additional amount of methanol was added, and the steps of shaking, decanting and solvent addition were rapidly repeated for a number of cycles. The insoluble material remaining after the final cycle (typically corresponding to 20 to 30% by weight of the starting material) was solubilized in olive oil. The dissolution process typically involves olive oil warmed to 45 0 C and gentle agitation in the beaker.
- Pulverized mastic ( ⁇ 10 g) was combined with 25 ml soy oil and 100 ml methanol in a glass beaker. Stirring using a magnetic stirrer was carried out for 2 hours. The solvent was decanted off and fresh methanol was added, followed by stirring for one hour. The solvent was decanted off, followed by evaporation under vacuum to remove residual solvent.
- Pulverized mastic ( ⁇ 10 g) was combined with 100 ml ethanol (96%) in a glass beaker. Stirring using a magnetic stirrer was carried out for 10 minutes. The solvent was decanted off and an additional amount of ethanol was added, followed by stirring for 5 minutes and decanting off the solvent. The steps of solvent addition, stirring and decanting were repeated for 4 cycles. Then n-hexane (100 ml) was added to the insoluble white material, followed by repeated shaking until the material dissolved. A small sample was desiccated and weighed in order to determine the concentration. The bulk of the hexane solution was applied to a calibrated size exclusion column and the fraction having molecular weight up to 1500 was discarded. The fraction having molecular weight greater than 1500 was mixed with 20 grams of heavy paraffin ointment. The mixture is homogenized by repeated mixing, and the hexane was removed by evaporation under vacuum.
- This procedure may also be performed by mixing paraffins and waxes having increasing molecular weight in order to obtain a more solid product.
- Rh-I is used herein to refer to an isolated fraction prepared as in any of the above Methods, and following dissolution in a suitable oil, wax or combination thereof.
- RPh-I was used directly for in vitro cell culture experiments or for treatment of test animals, typically at final concentrations ranging from 0.025 to 5% in a particular oil or mixture of oils, as specified herein. Furthermore, as shown in Example 2, the major component of RPh-I was determined to be 1,4-poly- ⁇ -myrcene of molecular weight in the range from 5000 to 20,000.
- Mastic resin from Pistacia lentiscus L. was extracted according to method 1 or 2 in order to obtain the desired fraction (termed RPh-I) which was analyzed by Size Exclusion Chromatography (SEC) in order to define the molecular weight distribution.
- SEC Size Exclusion Chromatography
- the chemical structure of RPh-I was analyzed by nuclear magnetic resonance (NMR) following preparative SEC fractionation.
- the RPh-I contains a "light" fraction with molecular weights below 1,000 and a "heavy” polymer fraction with molecular weight in the range 5000 to 20,000. Based on NMR analysis ( 1 H-NMR and 13 C-NMR) the predominant compound in the "heavy" fraction has a structure consistent with that of 1,4-poly- ⁇ -myrcene.
- Preparative separations were carried out using ethyl acetate and tetrahydrofuran (THF) as eluents.
- THF tetrahydrofuran
- the "heavy" polymer fraction was observed to exhibit various beneficial biological activities, including that of inducing cell differentiation, as described in Examples 4 and 6.
- the "light” fraction demonstrated toxicity in in vitro efficacy experiments using pigmented retinal epithelial cells. It was found that in order to preserve the activity of the polymer fraction, it is highly important to protect it from oxidation or cross-linking reactions by diluting it in a hydrophobic solvent, preferably oil, optionally in combination with a wax.
- Mastic resin (10 g) was combined with absolute ethanol (200 ml) and the mixture was allowed to stand overnight. The mixture was shaken, larger insoluble particles were allowed to settle over 20 minutes, and the ethanol was transferred into a new flask. The remainder was shaken with a fresh portion of absolute ethanol (150 ml) for 10 minutes. This ethanol fraction was combined with the first fraction. The procedure was repeated with another 150 ml portion of absolute ethanol which was combined with first two ethanol fraction. Subsequently, the ethanol was removed in vacuo on a rotary evaporator (water bath temperature 30 0 C). To the remainder was added hexane (300 ml) and the mixture was shaken repeatedly over a period of two hours. After standing overnight in the closed flask in order to complete precipitation of any insoluble material, the clear hexane solution was transferred into a clean flask and used for analytical and preparative separations.
- SEC Size Exclusion Chromatography
- a PLgel (7.5*300 mm 5 ⁇ 10 3 A 0 ) column was used and calibrated with polystyrene standards of molecular weights 1,000, 2000, 5000, 10,000, 30000 and 70000.
- Solvents used hexane, ethyl acetate, tetrahydrofuran (THF), dichloromethane (DCM) and acetone
- THF tetrahydrofuran
- DCM dichloromethane
- acetone acetone
- THF was found to be optimal.
- the chromatography instrument used was a ThermoPhinnigan TSP fitted with either a diode array detector or an ELSD detector, using a flow rate of lml/min, run time of 15 min and 100% THF for the mobile phase.
- the column was calibrated with polystyrene standards of molecular weights 1,000, 2000, 5000, 10,000, 30000 and 70000.
- the collected fractions from these two different mobile phases were divided into two, one half was evaporated to dryness using an evaporator and 3ml oil was added. To the second half 3 ml oil was added and then the organic solvent was evaporated. The obtained samples were analyzed for biological activity.
- the heavy MW material from the THF elution was analyzed by 1 H-NMR and 13 C-NMR at 300 MHz and 75 MHZ respectively.
- Figure 1 shows the SEC analytical chromatogram obtained_using a PDA detector (faint line) and an ELSD-SEDEX detector (bold line). A fraction corresponding to molecular weight in the range of about 60,000 to about 5000 (eluting at 5-7 minutes) was detected only with the ELSD detector. Both detectors indicated the presence of a fraction of molecular weight in the range ⁇ 1,000.
- Figure 2 shows the heavy (Fig. 2B) and low molecular weight (Fig. 2A) fractions obtained by preparative SEC.
- the heavy fraction was obtained by SEC run in DCM/hexane, while the light fraction was obtained by SEC run in THF/hexane.
- Table 1 summarizes the fractions obtained using preparative SEC and various solvent systems.
- Figure 3 shows the 1 H-NMR spectrum obtained for the heavy MW material from preparative SEC run in hexane 60% /THF 40%.
- Figure 4 shows the 13 C-NMR spectrum obtained for the heavy MW material from preparative SEC run in hexane 50% /THF 50%.
- Synthetic 1 ,4-polymeric ⁇ -myrcene preparations of various molecular weights was prepared, using methods generally based on procedures disclosed in Newmark et al (1988) J. Polym Sci.26:71-77.
- lithium was removed following the reaction by diluting the final mixture with an excess of hexane and washing twice with water. The organic phase was separated and dried with sodium sulfate.
- a 10% solution of the synthesized polymer in olive oil was prepared by adding olive oil to a final concentration of 10% (without hexane) and the hexane solvent evaporated.
- Apparent molecular weight was determined using SEC and calculation from a calibration curve prepared using polystyrene standards of molecular weight 2000, 5000, 10,000, 30000 and 70000. The conditions used for SEC were as follows:
- polymeric myrcene having calculated molecular weights in the range from about 3000 to about 46,000.
- the products may be designated as being in the range of "high” molecular weight polymeric myrcene i.e. ⁇ 20,000 to about 50,000, and "low” molecular weight polymeric myrcene i.e. ⁇ 3000 to -11,000.
- Representative analytical SEC profiles for "high” and “low” molecular weight polymeric ⁇ -myrcene are shown in Figures 5A and 5B, respectively.
- Figure 6 shows a representative 1 H-NMR spectrum of the ⁇ -myrcene polymerization product.
- Figure 7 shows a representative 13 C-NMR spectrum of the ⁇ -myrcene polymerization product.
- the synthetic reaction used for producing polymeric ⁇ -myrcene involves a mechanism of anionic polymerization (known as the "Michael reaction”).
- a typical anionic reaction is the polymerization of styrene using butyllithium, C 4 HgLi, in an inert solvent such as n-hexane.
- termination reactions do not occur in anionic polymerization.
- Anionic polymerization gives rise to very sharp molecular mass distributions because transfer processes are absent. If the solvent is extremely pure, the polymer chains will still be active after all the monomer has been consumed.
- the degree of polymerization is expressed as:
- Example 4 RPh-I induces neuronal-like differentiation in retinal pigment epithelial cell cultures.
- the present invention is directed to induction of differentiation and cell maturation, and has direct application to regeneration of functional tissue, in particular neuronal tissue.
- RPh-I induces differentiation of retinal pigment epithelial cells, an epithelial tissue of neuronal origin, to morphological neuronal cells producing axons, dendrites and junctions between cells known as synapses.
- the morphological differentiation in RPh-I treated cells is accompanied by de novo expression of the neuron-specific differentiation antigen ⁇ 3 tubulin.
- the induction of neuronal cell differentiation strongly suggests that RPh-I affects neuronal stem cell differentiation into functional neurons.
- the experiments described herein support use of an isolated fraction of mastic as described in Example 1, as well as of polymeric myrcene, an active molecule in RPh-I, as a therapeutic modality to elicit neuro-regeneration in neurodegenerative diseases such as dementia and Alzheimer's disease.
- Synthetic polymeric myrcene is also within the scope of the invention and is useful in the therapeutic methods of the invention.
- Retinal pigment epithelium (RPE) cells are also within the scope of the invention and is useful in the therapeutic methods of the invention.
- the retinal pigment epithelium is a single layer of hexagonal pigmented epithelial cells of neuronal origin, which forms the outermost cell layer of the eye retina and is attached to the underlying choroid.
- RPE functions include support, nourishment and protection of the underlying photoreceptors of the neuro-retina.
- RPE cells are involved in the phagocytosis of the outer segment of photoreceptor cells, in the vitamin A cycle where they isomerize all-trans retinol to 11-cis retinal and in supplying the photoreceptors with D-glucose, amino acids and ascorbic acid.
- ARPE- 19 cells do not form melanin and are not pigmented. In culture the cells grow as spindle shaped and as polygonal cells.
- ARPE- 19 cells obtained from the American Type Culture Collection, ATCC were plated in flat bottom 96 well tissue culture microplates (Costar) at a concentration of 2 - 5xlO 3 cells per well (1 - 2.5xlO 4 cells/mL) in a growth medium consisting of DMEM.Ham F-12, 1:1, supplemented with 10% Fetal Bovine Serum, 200 mM glutamine, 100 units/mL penicillin and 100 ⁇ g/mL streptomycin. The cells were allowed to adhere to the plate surfaces overnight prior to treatment with RPh-I .
- RPh-I was prepared essentially as described in Example 1, Method 1 to provide a 10% solution in a carrier composed of grape seed oil, olive oil, cottonseed oil, Mygliol ® 810 or Mygliol ® 812.
- the preparations were added to the cultures at volumes of 0.5 ⁇ l, 2 ⁇ l, 5 ⁇ l and 20 ⁇ l. These volumes, introduced into an overall sample medium volume of 200 ⁇ l, correspond to final RPh-I concentrations of 0.025%, 0.1%, 0.25% and 1%, respectively.
- the oil carrier served as a vehicle control and was applied to control cultures at the same volumes.
- the cultures were incubated in a 37 0 C, 5% CO 2 incubator for 72 hrs. The medium was then removed, the cultures washed twice with phosphate buffered saline (PBS), fixed with absolute methanol for 10 min and stained with Hemacolor ® reagents (Boehringer Mannheim), which stain cells in a manner similar to Giemsa, and may beused in a quantitative cell viability assay (see Keisari, Y. A colorimetric microtiter assay for the quantitation of cytokine activity on adherent cells in tissue culture. J Immunol. Methods 146, 155-161, 1992).
- the dye was eluted with 20% SDS, and quantified in an ELISA reader at 630 nm (triplicate samples evaluated).
- DMEM Dulbecco's minimal essential medium
- Ham F12 medium consisting of 1:1 mixture of Dulbecco's minimal essential medium (DMEM) and Ham F12 medium, supplemented with 10 fetal bovine serum and penicillin (100 units/ml), streptomycin (100 ⁇ g/ml) and glutamine (2mM).
- the cells were allowed to adhere overnight to the coverslips and 7% RPh-I in olive oil (or olive oil alone for control preparations) was administered to the cultures at a volume of 25 ⁇ l/ml medium and incubated at 37 0 C, 5% CO 2 for 72 hrs. The cells were then washed 2X with PBS and fixed with 4% para-formaldehyde. To determine beta-3 tubulin protein expression in the cells, the glass coverslips were stained with a mouse monoclonal primary antibody directed against human beta-3 tubulin followed by a secondary FITC-labelled anti- mouse IgG. The cell nuclei were counter stained with DAPI. Test and control preparations were then evaluated in a confocal microscope.
- Control oil-treated cultures displayed the typical spindle shaped and polygonal growth pattern characteristic of ARPE- 19 RPE cells (Fig. 8A). After 48 hours of incubation in culture, treated cells treated with RPh-I (0.1%; 1 mg/ml) were altered in shape, and developed thick, densely staining very long single protrusions reminiscent of neuronal cell axons (Fig. 8B). After 48 hour of incubation, cells treated with RPh-I (0.25%; 2.5 mg/ml) displayed a larger number of thinner long protrusions reminiscent of dendrites (Fig.
- ARPE- 19 cells Using inactive preparations of RPh-I which did not induce differentiation as described above, ARPE- 19 cells began to produce large amounts of melanin granules and these cultures continued to proliferate and cell density increased to confluence.
- ARPE- 19 cells with RPh-I Treatment of ARPE- 19 cells with RPh-I (5% in cottonseed oil) was shown to result in expression of the neuronal and synaptogenesis markers ⁇ 3 tubulin (TUBB3), a neuronal-type differentiation marker; Arc/Arg3.1, associated with synaptic plasticity; and neuronal pentraxin II (NPTX2), a neuronal immediate early gene that functions in excitatory synaptogenesis.
- Immunofluorescence analysis of differentiated ARPE- 19 cells showed that after 72 hours of incubation with RPh-I, the cells stained positively for ⁇ 3TUB, Arc/Arg3.1 and NPTX2 (Fig. 9, right panels), whereas little or no expression of these markers was seen prior to treatment (Fig. 9, left panels).
- RPh-I treatment of ARPE- 19 cells leads to cessation in cell replication.
- Cells were treated with RPh-I for 72 hours and the total protein content (related to the total number of cells present in the culture) was compared to untreated control ARPE- 19 cells.
- the RPh-I treated cultures contained significantly lower protein content as compared to control cultures, confirming that cell proliferation was substantially terminated.
- mice C57B1/6 mice, 8 per group were injected with RPh-I via the sub-cutaneous route three times over 7 days (every other day) with 0.05 ml of a 3% solution in grape seed oil for a dose of 30 mg/kg. The mice were then subjected to A sub-lethal dose (120 mg/kg) of ketamine was then administered to the mice. A control group was treated with 0.05 ml of the grape seed oil vehicle.
- Cells were plated at 2x10 3 cells per well in 96 well flat bottom microplates (Costar) and cultured in 200 ml of medium DMEM (Dulbecco's medium) supplemented with 10 fetal bovine serum, 200 mM L-glutamine, 100 units/ml penicillin and 100 microgram/ml streptomycin (all reagents from Gibco-BRL). Following overnight attachment, RPh-I (from a 10% solution in grape seed oil) was added to the cell cultures to provide final concentrations of 0.025%, 0.1%, 0.25% and 0.5%, and incubation was continued for 48 and 72 hours. The grape seed oil vehicle was used as control. After 72 hours, cells were fixed with methanol and stained with Hemacolor® reagents (Boehringer Mannheim).
- DMEM Dulbecco's medium
- RPh-I from a 10% solution in grape seed oil
- melanoma cells with RPh-I Treatment of melanoma cells with RPh-I was found to induce formation of melanin after 24-48 hrs, as shown by Fig. 12B and Fig 12C, as compared to the control treated cells in Fig. 12 A.
- the RPh-I treatment further caused arrest of replication, as shown by the decreased cell density, for example in Fig. 12D.
- cell death was seen in cultures incubated with each of the four RPH-I concentrations tested.
- Polymeric myrcene an active component in RPh-I, is associated with the induction of differentiation of various cell lines derived from the malignant cancers melanoma and neuroblastoma.
- a block in terminal differentiation is recognized as a major avenue in the perpetuation of cell proliferation in cancer. Overcoming this block has already proven to be an effective treatment modality of several forms of cancer (e.g. retinoids in treatment of acute promyelocytic leukemia) and is now known as "targeted therapy".
- Targeted therapy does not kill cancerous cells but modifies their behavior, primarily by inducing differentiation. Accordingly, the aggressiveness of many cancers can be reduced.
- polymeric myrcene an active ingredient of RPh-I has been found to overcome the block in tumor cell differentiation, as indicated by formation of neuronal cell dendrites in neuroblastoma cell lines, and induction of melanin formation in melanoma cell lines. In both cases these changes were associated with cessation in cell proliferation and cell death.
- Example 7 Chemically synthesized polymeric myrcene induces cell differentiation in retinal pigment epithelial cell cultures.
- ARPE- 19 cells were plated in flat bottom 96 well tissue culture microplates (BIOFIL) at a concentrations of 5xlO 3 cells per well (2.5xlO 4 cells/mL) in a growth medium consisting of DMEM.Ham F-12, 1:1, supplemented with 10% Fetal Bovine Serum, 200 mM glutamine, 100 units/mL penicillin and 100 ⁇ g/mL streptomycin. The cells were allowed to adhere to the plate surfaces overnight prior to treatment with the chemically synthesized polymeric myrcene fractions.
- BIOFIL tissue culture microplates
- Fraction 18-1 molecular weight in the range of about 50,000 daltons
- fraction 18-2 molecular weight in the range of about 20,000 daltons
- Fractions 18-1 and 18-2, and RPh-I were each prepared at a concentration of 10% in olive oil.
- Each preparation was added to the ARPE- 19 cell cultures using volumes of 0.5 ⁇ l, 2 ⁇ l, 5 ⁇ l and 20 ⁇ l, corresponding to final concentrations of 0.025%, 0.1%, 0.25% and 1%, respectively.
- Olive oil served as vehicle control and was applied to control cultures at the same volumes.
- the cultures were incubated in a 37 0 C, 5% CO 2 incubator for 72 hrs. The medium was then removed, the cultures washed twice with phosphate buffered saline (PBS), fixed with absolute methanol for 10 min and stained with Hemacolor® reagents.
- PBS phosphate buffered saline
- Fractions 18-1 and 18-2 were shown to have activity in inducing neuro- differentiation in ARPE- 19 cells (Fig. 13 and Table 4). Optimal activity was observed with Fraction 18-1 at 0.25% (as shown in Fig. 13A), while 0.1% was somewhat effective and 0.025% had no effect (Table 4). The effect of fraction 18-2 is shown in Fig. 13B.
- RPh-I a formulation of an isolated fraction of mastic gum, has activity in inducing differentiation of neuronal cells.
- Example 8 The effect of RPh-I in inducing cell differentiation is blocked by the polar solvent-soluble fraction present in mastic resin.
- RPh-I is a fraction which has been isolated from mastic resin on the basis of its being soluble in both polar organic solvents and non-polar organic solvents, while compounds that are soluble only in polar organic solvents but not in non-polar organic solvents are .discarded (the latter herein designated Fraction SP).
- Fraction SP A major component in RPh-I is polymeric myrcene, as shown in Example 2.
- Fraction SP corresponds to prior art mastic fractions which have been attributed to have various beneficial biological activities.
- the aim of the present study was to assess the effect of SP on the cell differentiation effect exerted by RPh-I. It is now disclosed that compounds present in SP interfere with and block the cell differentiation effects induced by RPh-I.
- preparation TC whole mastic dissolved in oil (warmed to 60° C) was prepared to obtain preparation TC.
- An aging Golden Retriever male dog had an open chronic leg wound for more than 6 months.
- the dermal lesion was associated with alopecia (loss of fur) and depigmentation of the surrounding fur.
- the dog was treated by several cycles of topical treatment with RPh-I. Following the initial application, transient edema with swelling occurred for 16-20 hrs. This was followed by de novo formation of functional epithelial tissue (epithelization) and neoangiogenesis (novel formation of microvasculature) with normal tissue contours, resulting from rapid and vigorous formations of granulation tissue. Wound healing contracted inwards towards the center of the wound, suggesting the presence of fibro- myocytes (of mesodermal origin).
- Figure 14 shows the afflicted area before (Fig. 14A) and after (Fig. 14B) treatment with RPh-I.
- a different dog had a jaw tumor (non-induced), portions of which protruded into the buccal cavity.
- the protruding portions were surgically excised, while the sections of the tumor that were embedded within the jaw could not be removed.
- the tumor was diagnosed as a sarcoma.
- RPh-I formulated in grape seed oil was applied to the affected jaw area. The treatment brought about complete cure of the gums covering the surgical incision site to the extent that no scar was left and the surgical incision site was no longer discernable. Even the expected recurrence of the tumor from portions embedded in the jaw was prevented for an extended interval of several weeks.
- the treatment with RPh-I induced an extraordinarily rapid healing of the surgical incision site and complete regeneration of the gums.
- wound healing was accompanied by a general increase in vitality, mental awareness and physical activity in the treated dogs.
- the above results support the use of polymeric myrcene, the active component of RPh-I, for wound healing, regeneration of hair follicles and reversal of neurological degeneration.
- Example 10 Treatment of wounds in fish.
- Gold fish as well as koi fish are prone to integument ulcers caused by bacteria, in particular Aeuromonas hydrophila.
- Gold fish weighing approximately 100 gram each, which had developed bacterial ulcerations were divided into two groups in separate tanks, each group containing four fish. Each tank was filled with a volume of 100 liters of water and maintained under aeration with an air pump. The groups were randomized by weight and wound size (in the range of 1-1.5 cm by 1-1.5 cm). Each fish was injected intramuscularly through intact integument at a site approximately 5 mm from an ulcer with 20 microliters of either grape seed oil alone (control group), or a 1% solution of RPh-I in grape seed oil (treatment group).
- Example 11 Effect of RPh-I in wound healing using B6.V-Lepob/Olahsd mice model
- B6.V-Lepob/OlaHsd mice (express obesity at age 4 weeks) were used to evaluate the effect of RPh-I in wound healing.
- Full thickness skin puncture was performed using a disposable biopsy puncher (Uni-Punch® Disposable Biopsy Punch, Premier) in the distal zone of each mouse back.
- the puncture has an ellipse shape.
- Average long axis length of punctures ranged between 5.1 to 5.3 mm.
- the average width axis length of punctures ranged between 4.8 to 5.1 mm.
- the rate of wound healing during the period from Day 0 to Day 11 following wound infliction was significantly more rapid in mice treated with RPh-I as compared to those treated with vehicle alone (p-0.034) ⁇
- Example 12 Effect of RPh-I in reversing the neurodegenerative effects of chronic cerebral hypoperfusion (vascular dementia) in a rat model.
- Vascular dementia is a subtype of dementia with a prevalence that is second only to that of Alzheimer's disease in westernized societies. VD causes many neuropsychiatric and physical problems, and represents a significant economic burden.
- Brain imaging has revealed obvious changes in the cerebral cortex and white matter, and these lesions are thought to be the core pathology for cognitive declines in patients with vascular dementia (see for example, Farkas et al., Experimental cerebral hypoperfusion induces white matter injury and microglial activation in the rat brain. Acta Neuropathol. 2004;108:57-64; Stenset et al., White matter lesion subtypes and cognitive deficits in patients with memory impairment. Dement Geriatr Cogn Disord. 2008 26: 424-431).
- Cerebral lesions can be experimentally induced in rat brains by permanent occlusion of both common carotid arteries which can affect cognitive function.
- This model is similar to vascular dementia and the experimental technique can decrease the blood flow in the cerebral cortex and hippocampus by up to 40-80% for several months, inducing certain learning disorders.
- this model was used to study the effects of RPh-I treatment in reversing the deficiencies caused by vascular dementia lesions.
- a total of 40 animals were randomized into 3 groups i.e. an untreated sham control group, a vehicle control group and an RPh-I treated group (10-15 animals per group). They were randomized into 3 groups, an untreated sham control group, a vehicle control and an RPh-I treated group.
- Ten ⁇ l of RPh-I (5% in cottonseed oil) or vehicle was administered subcutaneously 2x/wk, with the first dose administered 14 days after induction of vascular dementia.
- the Morris water maze (MWM) test is sensitive to hippocampal function.
- the water maze task is performed to evaluate two CCA-related learning deficits using the method described previously (Watanabe et al., Cilostazol Stroke. 2006;37(6):1539-1545).
- a circular transparent acrylic platform is prepared, the top surface of which is 3 cm below the water. Rats are released facing the wall, and the time taken to escape to the platform is recorded as the escape latency. Tests are performed on day 3 before CCA occlusion and on days 14, 35, 56, 84 and 112 after CCA occlusion.
- Example 9 The dogs with various wounds described in Example 9 additionally suffered from loss of appetite and would not eat food placed in front of them. Following after approximately 10 days of treatment with RPh-I as described, dogs gradually re-gained interest in food and started to eat. Within a month, the dogs showed strong interest in food and appetite was similar to that of normal healthy dogs.
- Example 10 The fish with ulcerations described in Example 10 additionally suffered from loss of appetite.
- the control group continued to ignore food applied into the water, whereas the fish treated with RPh-I responded eagerly with rapid movement in response to administration of food.
- Rats described in Example 12 additionally suffered from weight loss after chronic cerebral hypoperfusion. After 35 days of treatment (day 56 of study) rats treated with RPh- 1 as described, recovered their weight significantly faster than animals treated with vehicle (Fig. 17A).
- mice of group B and C gained 10.2% and 9.1% respectively.
- RPh-I is regulator of pathological weight disorder and can serve as an orexigenic (appetite stimulant) or anti- obesity agent.
- Example 14 Effect of RPh-I in Transient Middle Cerebral Artery Occlusion (tMCAO) stroke model in rats.
- RPh-I transient middle cerebral arterial occlusion model
- Axotomy of the optic nerve was performed on the right eye of deeply anesthetized rats (19 rats per group).
- the test group received a sub-dermal injection in the posterior neck area of RPh-I (5% in cottonseed oil); 0.025ml/i ⁇ jection), and the control group was similarly injected with the same volume of vehicle.
- the first injection was given to all the animals directly after surgery.
- Subsequent injections (same dosage and method of administration) were administered twice a week, every 3 to 4 days.
- a fluorescent retrograde neurotracer (Di-Asp) was inserted into the axotomized optic nerve in order to stain surviving Retinal Ganglion Cells (RGC), and 24 hours later, the rats were sacrificed in a CO 2 saturated chamber and the injured right eye was enucleated. The retinas were isolated, flattened on a slide and fixed with xylene based mounting medium.
- Retinal detachment was performed on the right eye of deeply anesthetized animals (xylazine 50mg/kg and ketamine 35mg/kg) following dilatation of the pupil with Tropicamide drops 0.5%.
- RD was induced through the generation of a small opening in the retina at the ora serata followed by a sub-retinal injection of 5 ⁇ l saline with a 3OG syringe needle. Approximately half of the retinal area was detached by this procedure.
- Rats with RD were divided into two experimental groups, with the test group receiving a sub-dermal injection in the posterior neck area of RPh-I (5% in cottonseed oil; 0.025ml/injection), and the control group injected with the same volume of vehicle.
- the first injection was given to all the animals directly after surgery.
- the second injection (same dosage and method of administration) was administered 48 hours after surgery.
- the operated rats were euthanized in a CO 2 saturated chamber.
- the injured right eye and the untreated left eye were enucleated.
- the retinas were isolated, frozen on dry ice and processed for Western blot analysis or immunohistochemical analysis.
- the left eye retinas served as non-operated controls.
- Semaphorin3 A Semaphorin3 A
- NPl Neuropilinl
- GAP43 GAP43
- Sema3A is an axonal growth inhibitor that has been shown to be involved in retinal ganglion cell loss following injury to the optic nerve.
- High levels of Sema3A were detected in retinas after RD as shown by Western blot analysis (Fig. 20A).
- Samples were normalized to beta-actin expression (lower band, Fig.20A).
- Sema3A expression was clearly higher in detached retinas as compared to the controls. Sema3A expression was observed mainly around the retinal ganglion cells. Similar to the results observed in Western blot analysis, Sema3A expression was reduced in RD animals treated with RPh-I.
- NPl is a functional Sema3A receptor.
- TUNEL-positive cells indicating apoptotic processes, were evident 24 hours post retinal detachment and increased after 7 days.
- Caspase-3 was activated in response to RD. However, caspase-3 was elevation was significantly attenuated in RD animals treated with RPh-I (Fig. 20B).
- GAP43 is an intracellular protein that is tightly connected to the membrane of the growth cones. It is normally expressed during the process of synaptogenesis. In the retina, GAP43 is expressed in the neurons at an early stage of embryogenesis, while the optic nerve is still elongating. In the rat optic nerve, GAP43 is found both in axons and cell bodies of RGCs, but the expression disappears at the age of 8 to 16 weeks, and is found again following ischemia or injury to the optic nerve.
- GFAP glial fibrillary acidic protein
- Microglial invasion and activation are regarded as harmful or beneficial to neurons.
- Microglial activation after acute CNS injury is primarily a reactive and adaptive glial cell response, which is triggered by injured neurons and which is designed to ameliorate primary tissue damage and to promote subsequent repair and gliosis (glial scar) as a result.
- Microglia become activated in the retina usually after injury stimulate and recruit endothelial cells and fibroblasts.
- Immunohistochemical analysis of sections of detached and non-injured retinas labeled with IB4 and stained with the nuclear dye PI showed evidence of activated microglial cells in detached retinas only. However, in detached retinas from animals treated with RPh-I, less microglial activation was evident as compared to detached retinas from animals that were treated with vehicle.
- the results showed reduced recruitment of active microglia around an injury region and support a scar-less repair mechanism of wounds.
- Example 17 Preparation of complexes of cyclodextrin with polymeric myrcene.
- Cyclodextrins by virtue of their ability to form inclusion complexes with many drugs, can substantially increase the aqueous solubility of biopharmaceuticals, in particular those that are defined as water-insoluble such as polymeric myrcene. Cyclodextrins are water-soluble compounds, which can form reversible complexes with poorly water-soluble molecules resulting in a soluble molecular inclusion complex. When the inclusion complex of the drug-cyclodextrin combination is diluted in a sufficiently large volume of water or blood, it dissociates rapidly, releasing the sequestered pharmacologically active agent.
- Complexation of polymeric myrcene with ⁇ -HPCD will be performed as follows: a. Dissolution of pre weighed polymeric myrcene in a minimum amount of non-polar solvent such as hexane, heptane, or the like. b. Drop wise addition of the non-polar solvent to the ⁇ -HPCD powder. c. Drying at 50-80 ° C until non-polar solvent evaporates. d. Mixing with necessary amount of water. e. Dissolution with sonication and heating. f. Filtration through 0.2-0.45 ⁇ m filter.
- Example 18 Preparation of nanoemulsions of polymeric myrcene.
- Liquid oil-in-water nanoemulsion formulations are to be prepared by high pressure emulsif ⁇ cation techniques of all lipid ingredients and the active component polymeric myrcene dissolved in the lipid oil phase and emulsified with an aqueous phase, projected to result in the formation of stable, spheric and uniformly dispersed drug-containing lipid nanodroplets.
- the emulsion droplet size reduction is essential to generate drug formulations with high stability.
- Preferred nanoemulsion droplets have a mean droplet size of less than one micron (generally in the range of 0.1-0.2 ⁇ m) uniformly dispersed in an aqueous phase.
- the uniqueness of the large internal hydrophobic oil core of the nanoemulsion droplets provides high solubilization capacity for water insoluble compounds such as polymeric myrcenes.
- the oil phase is composed of 13% lipoid E-75, 0.026% ⁇ TP-succinate, propylparaben as antioxidant and 86.9% Miglyol ® 810.
- Polymeric myrcene prepared as in Example 1 is dissolved in the oil phase. The components are mixed with mild heating until a homogenous completely solubilized solution is obtained.
- the aqueous phase is composed of 0.1% EDTA, 0.5% Tween-80, 2.3% glycerol, methylparaben as preservative and 97.1% water. pH was adjusted to 7.4 by NaOH IN. 3. Mixing of oil and aqueous phases
- Oil phase (3.7g) is heated and added to 70 ml of the aqueous phase (preheated). The mixture is gently stirred for 10-15 min at room temperature.
- An oil-in-water emulsion is prepared using the medium size dispenser and high shear homogenizing unit Polytron ® , at 20,000rpm for 5 min.
- the droplet size of the emulsion obtained after step 4 is reduced to the submicron (nanosize) range by submitting the emulsion to high shear homogenization using the Gaulin ® Microlab 70 high pressure homogenizer at 800 bar pressure. A total of 5-6 cycles should be performed to obtain homogenous nanoemulsion droplets having average particle size of less than 200nm.
- Particle size is to be determined by photon correlation spectroscopy (PCS) using a N4MD particle size analyzer (Coulter ® Electronics, UK). When most of the particles (> 90%) are smaller than 200nm, the sizing process is determined to be complete.
- a convenient process for manufacturing the polymeric myrcene-lipid mixture product is by direct spray-drying of the formulation from a mixture of non-polar solvent dispersion containing all the lipid ingredients and water containing the hydrophilic components, taking into account cost effectiveness and upscaling considerations.
- the selected spray-drying method is optimized in order to get a fine, free-flowing powder.
- Polymeric myrcene is dissolved in the lipid phase containing the lipid ingredients lecithin, tricaprin (capric acid triglyceride), tocopherol succinate and warmed ( ⁇ 40 0 C) in a nonpolar solvent until a good dispersion is obtained.
- a dispersion of fumed silicon dioxide (Cab-O-Sil ® ) in water (5%) was prepared by swelling the powder in purified water.
- the resultant slurry (prewarmed to 40 0 C) is then poured slowly into the nonpolar solvent lipid dispersion and the mixture is agitated at 40 0 C for about 1 hr until a homogenous dispersion is obtained.
- the mixture is then spray-dried using the Yamato Pulvis ® GA32 spray-dryer.
- the spray-drying conditions are: flow rate 7ml/min, inlet temperature 130 0 C, outlet temperature 70 0 C, and drying air flow 0.5 mVmin.
- a homogeneous dry powder containing the polymeric myrcene-lipid mixture is expected to be obtained.
- the polymeric myrcene-lipid mixture formulation prepared by the direct spray drying process is expected to show good water dispersibility, thus being suitable for the preparation of solid-dosage forms such as hard gelatin capsules or tablets for the enhanced oral delivery of polymeric myrcene with potential good oral bioavailability.
- Example 20 Preparation of liposomal preparations containing polymeric myrcene.
- Lipids containing dissolved polymeric myrcenes were dissolved in 100 ml dichloromethane in a round bottom flask, and stirred for 30 min at room temperature until a clear transparent solution was obtained. Solvent will be evaporated using a rotary evaporation unit at 39 °C. First, the flask will be rotated at 4.5 rpm, 5 min under atmospheric pressure, followed by 10-30 min (until full evaporation of the solvent) under weak vacuum, and finally 15 min under full vacuum. At the end of the evaporation process a uniform lipid film will be created. The lipid film will be dissolved in 15 ml isotonic buffer.
- Liposomes are prepared by vigorous shaking for 10-30 min using multi-wrist shaker, until a uniform and milky dispersion of multilamellar vehicle (MLV) will be formed and no remaining lipid film will be apparent, hi order to obtain an equilibrated and homogenous liposome preparation the flask will be further shaken at 37 °C for 30-90 min. at 270 rpm.
- MLV multilamellar vehicle
- Example 21 Preparation of microemulsions containing polymeric myrcenes.
- surfactants commonly used in parenterals may be utilized to develop water- in-oil and oil-in-water-microemulsions acceptable for injectable, oral and topical use.
- the pharmaceutically acceptable surfactants suitable for the formation of microemulsion formulations are non-ionic surfactants including polyoxyl 40 hydrogenated castor oil (sold under the trade name Cremophor RH40 ® ), polyoxyl 35 castor oil (sold under the trade name Cremophor ® EL), p ⁇ lyoxyethylene sorbitan fatty acid esters (polysorbates), poloxamers (Pluronics ® ), vitamin E-TPGS 1,000 (VE-TPGS 1,000), polyoxyethylene alkyl ethers, Solutol ® HS-15, Tagat ® TO, Peglicol 6-oleate, polyoxyethylene sterates, or saturated polyglycolyzed glycerides, all of which are commercially available.
- the preferred surfactants include polyoxyl 40 hydrogenated castor oil (Cremophor ® RH40 ® ), polyoxyl 35 hydrogenated castor oil (Cremophor ® EL), polyoxyethylene sorbitan fatty acid esters (polysorbates), poloxamers (Pluronics ® ), and vitamin E-TPGS 1,000.
- the total amount of the surfactant present in the composition will be generally from about 100 to about 700 mg/g, and preferably from about 300 to about 500 mg/g.
- Preparation of microemulsions containing polymeric myrcene may be performed by dissolving the polymeric myrcenes in an appropriate amount of oil such as medium chain tryglycerides (Miglyol) in a suitable vial. The vial is then capped. The vial is put into a water bath of about 50-60 °C and shaken gently until all of the drug material is completely dissolved. After the vial is cooled to room temperature, an appropriate amount of surfactant (such as Cremophor ® EL or VE-TPGS) is added and followed by the mixture of mono- and di-glycerides of fatty acids, if any. The vial is then capped and placed into the water bath of about 50-60 0 C.
- an appropriate amount of surfactant such as Cremophor ® EL or VE-TPGS
- the vial is shaken gently to obtain a clear, uniform solution.
- This solution can be filled into HPMC capsules and stored at room temperature before oral dosing.
- the substituted polymer powders such as HPMC
- the resulting composition can then be filled into either soft gelatin or hard gelatin capsules and stored at room temperature before oral dosing.
- the microemulsion formulation can be used as a topically or filtered through 0.2um membranes to be administered parenterally.
- microemulsions containing polymeric myrcenes have good water-dispersibility properties and self-emulsify when diluted in aqueous media to form small nanometric micelles that with enhanced bioavailability.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Natural Medicines & Medicinal Plants (AREA)
- Alternative & Traditional Medicine (AREA)
- Biotechnology (AREA)
- Botany (AREA)
- Medical Informatics (AREA)
- Microbiology (AREA)
- Mycology (AREA)
- Epidemiology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Dermatology (AREA)
- Heart & Thoracic Surgery (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Immunology (AREA)
- Vascular Medicine (AREA)
- Cardiology (AREA)
- Hospice & Palliative Care (AREA)
- Urology & Nephrology (AREA)
- Pulmonology (AREA)
- Obesity (AREA)
- Child & Adolescent Psychology (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
Abstract
Description
Claims
Priority Applications (16)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
ES10710912T ES2739033T3 (en) | 2009-03-04 | 2010-03-04 | Polymeric Myrcene Compositions |
AU2010220057A AU2010220057C1 (en) | 2009-03-04 | 2010-03-04 | Compositions of polymeric myrcene |
EP10710912.6A EP2403512B1 (en) | 2009-03-04 | 2010-03-04 | Compositions of polymeric myrcene |
PL10710912T PL2403512T3 (en) | 2009-03-04 | 2010-03-04 | Compositions of polymeric myrcene |
CA2754565A CA2754565C (en) | 2009-03-04 | 2010-03-04 | Compositions of polymeric myrcene |
EP19158751.8A EP3578191A1 (en) | 2009-03-04 | 2010-03-04 | Compositions of polymeric myrcene |
EA201190170A EA021833B1 (en) | 2009-03-04 | 2010-03-04 | Compositions of polymeric myrcene |
US13/254,380 US8722105B2 (en) | 2009-03-04 | 2010-03-04 | Compositions of polymeric myrcene |
BRPI1013222A BRPI1013222B8 (en) | 2009-03-04 | 2010-03-04 | composition consisting of an isolated fraction of gum mastic obtained from pistacia lentiscus l. |
CN201080018570.3A CN102413834B (en) | 2009-03-04 | 2010-03-04 | The composition of polymeric myrcene |
DK10710912.6T DK2403512T3 (en) | 2009-03-04 | 2010-03-04 | COMPOSITIONS OF POLYMER MYRC |
IL214923A IL214923A (en) | 2009-03-04 | 2011-09-01 | Compositions comprising isolated fractions of mastic gum |
US14/226,293 US9655938B2 (en) | 2009-03-04 | 2014-03-26 | Compositions of polymeric myrcene |
IL248056A IL248056B (en) | 2009-03-04 | 2016-09-26 | Compositions of polymeric myrcene |
US15/486,964 US10307449B2 (en) | 2009-03-04 | 2017-04-13 | Compositions of polymeric myrcene |
US16/391,881 US10806763B2 (en) | 2009-03-04 | 2019-04-23 | Compositions of polymeric myrcene |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US15721609P | 2009-03-04 | 2009-03-04 | |
US61/157,216 | 2009-03-04 |
Related Child Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP19158751.8A Previously-Filed-Application EP3578191A1 (en) | 2009-03-04 | 2010-03-04 | Compositions of polymeric myrcene |
US13/254,380 A-371-Of-International US8722105B2 (en) | 2009-03-04 | 2010-03-04 | Compositions of polymeric myrcene |
US14/226,293 Continuation US9655938B2 (en) | 2009-03-04 | 2014-03-26 | Compositions of polymeric myrcene |
Publications (3)
Publication Number | Publication Date |
---|---|
WO2010100651A2 true WO2010100651A2 (en) | 2010-09-10 |
WO2010100651A3 WO2010100651A3 (en) | 2010-10-28 |
WO2010100651A4 WO2010100651A4 (en) | 2010-12-23 |
Family
ID=42536397
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/IL2010/000184 WO2010100651A2 (en) | 2009-03-04 | 2010-03-04 | Compositions of polymeric myrcene |
Country Status (15)
Country | Link |
---|---|
US (4) | US8722105B2 (en) |
EP (2) | EP3578191A1 (en) |
CN (2) | CN105147759A (en) |
AU (1) | AU2010220057C1 (en) |
BR (1) | BRPI1013222B8 (en) |
CA (1) | CA2754565C (en) |
DK (1) | DK2403512T3 (en) |
EA (2) | EA021833B1 (en) |
ES (1) | ES2739033T3 (en) |
HK (1) | HK1218710A1 (en) |
HU (1) | HUE045444T2 (en) |
IL (2) | IL214923A (en) |
PL (1) | PL2403512T3 (en) |
TR (1) | TR201911270T4 (en) |
WO (1) | WO2010100651A2 (en) |
Cited By (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2012032523A2 (en) | 2010-09-07 | 2012-03-15 | Regenera Pharma Ltd. | Compositions comprising acidic extracts of mastic gum |
CN102526163A (en) * | 2011-12-27 | 2012-07-04 | 浙江景岳堂药业有限公司 | Method for extracting Olibanum and Myrrha in Fengtongling medicament |
EP2493461A1 (en) * | 2009-10-28 | 2012-09-05 | Regenera Pharma Ltd. | Therapeutic uses of oligomeric and polymeric monoterpenes |
WO2013186766A1 (en) * | 2012-06-11 | 2013-12-19 | Regenera Pharma Ltd. | Extracts and therapeutic uses thereof |
WO2016142936A1 (en) * | 2015-03-08 | 2016-09-15 | Regenera Pharma Ltd. | Use of isolated fractions of mastic gum for treating optic neuropathy |
US9458362B2 (en) | 2014-04-02 | 2016-10-04 | Kraton Polymers U.S. Llc | Adhesive compositions containing a block copolymer with polymyrcene |
WO2017051423A1 (en) | 2015-09-24 | 2017-03-30 | Regenera Pharma Ltd. | Compositions comprising triterpenoids |
WO2018047175A1 (en) | 2016-09-08 | 2018-03-15 | Regenera Pharma Ltd. | Compositions comprising triterpenoids and uses thereof for treating optic neuropathy |
WO2018047176A1 (en) * | 2016-09-08 | 2018-03-15 | Regenera Pharma Ltd. | Compositions comprising acidic extracts of mastic gum and uses thereof for treating optic neuropathy |
US10053603B2 (en) | 2014-04-02 | 2018-08-21 | Kraton Polymers U.S. Llc | Block copolymers containing a copolymer myrcene block |
EP3363448A1 (en) | 2017-02-15 | 2018-08-22 | Phytoitalia SRL | Terpene enriched fractions free from polyterpenes extracted from chios mastic gum and cosmetic, nutraceutical, medical devices and pharmaceutical compositions containing them |
US10307292B2 (en) | 2011-07-18 | 2019-06-04 | Mor Research Applications Ltd | Device for adjusting the intraocular pressure |
WO2019170239A1 (en) | 2018-03-08 | 2019-09-12 | Phytoitalia Srl | Terpene enriched fractions free from polyterpenes extracted from chios mastic gum and cosmetic, nutraceutical, medical devices and pharmaceutical compositions containing them |
WO2020091703A1 (en) * | 2018-11-01 | 2020-05-07 | Yeditepe Universitesi | A medicine for treatment of psoriasis and production method thereof |
US11083736B2 (en) | 2015-09-24 | 2021-08-10 | Regenera Pharma Ltd. | Compositions comprising triterpenoids |
RU2785038C2 (en) * | 2018-11-01 | 2022-12-02 | Едитепе Университеси | Drug for treatment of psoriasis and its production method |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2754564C (en) | 2009-03-04 | 2017-09-12 | Regenera Pharma Ltd. | Therapeutic uses of mastic gum fractions |
CN105147759A (en) | 2009-03-04 | 2015-12-16 | 瑞吉纳拉制药公司 | Compositions of polymeric myrcene |
US8979797B2 (en) * | 2010-12-16 | 2015-03-17 | Ams Research Corporation | High pressure delivery system and method for treating pelvic disorder using large molecule therapeutics |
US10548917B2 (en) * | 2016-05-23 | 2020-02-04 | Kaeco Group Inc. | Supplement for the prevention and treatment of gastrointestinal distress in horses and other species |
US11439676B2 (en) | 2018-10-16 | 2022-09-13 | Kaeco Group, Inc. | Method for prevention or treating gastrointestinal distress in humans using mastic gum compositions |
Citations (20)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4374957A (en) | 1981-10-29 | 1983-02-22 | Michigan Molecular Institute | Triblock polymers of a monovinyl aromatic compound and myrcene |
US4564718A (en) | 1984-08-14 | 1986-01-14 | The University Of Manchester Institute Of Science And Technology | Functionally terminated polymers from terpene monomers and their applications |
US4713243A (en) | 1986-06-16 | 1987-12-15 | Johnson & Johnson Products, Inc. | Bioadhesive extruded film for intra-oral drug delivery and process |
US5506406A (en) | 1993-05-17 | 1996-04-09 | Atomic Energy Corporation Of South Africa Ltd. | Method and apparatus for determining the concentration of a heavy element in a rock face |
US5637290A (en) | 1995-06-28 | 1997-06-10 | Leather Line Imports, Inc. | Oral hygiene product including chios mastic oil |
US5759569A (en) | 1995-01-10 | 1998-06-02 | The Procter & Gamble Company | Biodegradable articles made from certain trans-polymers and blends thereof with other biodegradable components |
US5948430A (en) | 1996-11-11 | 1999-09-07 | Lts Lohmann Therapie-Systeme Gmbh | Water soluble film for oral administration with instant wettability |
US6074688A (en) | 1995-06-06 | 2000-06-13 | Delsys Pharmaceautical Corporation | Method for electrostatically depositing a medicament powder upon predefined regions of a substrate |
GR1003541B (en) | 1999-05-11 | 2001-03-07 | Chios mastic oil used for cosmetic & pharmaceutical purposes as well as for the production of toothpicks, chewing gums, and dental flosses | |
US6623728B2 (en) | 2000-06-30 | 2003-09-23 | Unilever Home & Personal Care Usa Division Of Conopco, Inc. | Cosmetic skin care compositions and containing gum mastic |
US6811769B2 (en) | 2002-08-23 | 2004-11-02 | Shuji Watanabe | Oral composition, method of making the oral composition and oral hygiene method in japanese and chinese herbal remedy |
EP1520585A1 (en) | 2003-10-02 | 2005-04-06 | Data Medica Padova S.p.A. | Cancer treatment using natural plant products or essential oils or components from some pistacia species |
US20050238740A1 (en) | 2002-05-01 | 2005-10-27 | Spiros Fotinos | Use of mastic and its components for the control of microbial infections |
WO2005112967A2 (en) | 2004-05-19 | 2005-12-01 | Balfour Marketing Corp. | Anticancer activity of chios mastic gum |
WO2006003659A2 (en) | 2004-07-06 | 2006-01-12 | Transpharma Medical Ltd. | Delivery system for transdermal immunization |
US7048943B2 (en) | 2001-02-13 | 2006-05-23 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | Carotenoid-loaded liposomes |
US7214750B2 (en) | 2002-12-20 | 2007-05-08 | Exxonmobil Chemical Patents Inc. | Polymerization processes |
US7232872B2 (en) | 2002-12-20 | 2007-06-19 | Exxonmobil Chemical Patents Inc. | Polymerization processes |
US20070179260A1 (en) | 2004-03-04 | 2007-08-02 | Riken | Isotactic 3, 4-isoprene-based polymer |
US7294651B2 (en) | 2001-10-02 | 2007-11-13 | Kimberly-Clark Worldwide, Inc. | Inhibition of exoprotein production using isoprenoid compositions |
Family Cites Families (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS63179908A (en) * | 1987-01-22 | 1988-07-23 | Japan Synthetic Rubber Co Ltd | Myrcene polymer and production thereof |
DE3820218A1 (en) | 1988-06-14 | 1989-12-28 | Osama L M Dr Med Dr Rer N Omer | PHYTOTHERAPEUTIC FOR THE TREATMENT OF DEPRESSIVE SYNDROME |
US8178516B2 (en) | 1992-06-30 | 2012-05-15 | Sylvan Labs, LLC | Compositions and method for treatment of chronic inflammatory diseases |
JPH10130254A (en) * | 1996-11-01 | 1998-05-19 | Jumoku Seiri Kinousei Butsushitsu Gijutsu Kenkyu Kumiai | Dihydrocoumarin-based compound and estrogenic agent |
GR1003550B (en) | 1999-09-22 | 2001-03-13 | Stable concoction of isohexylonafthazarines with penta-and tetra cyclic triterpenes, components of natural oil resins and gums | |
US7056491B2 (en) | 2000-11-08 | 2006-06-06 | Wisconsin Alumni Research Foundation | Monoterpenes and sesquiterpenes as chemotherapeutic and radiation sensitizers and immunomodulators |
GR1003868B (en) * | 2001-02-06 | 2002-04-19 | Lavipharm S.A. | Evaluation of the wound healing, antioxidant and cytostatic properties of mastic and its element and relative applications |
US20070219141A1 (en) | 2003-12-08 | 2007-09-20 | David Jones | Plant Materials Extraction Method |
WO2006020246A1 (en) | 2004-07-23 | 2006-02-23 | Tsung-Chung Lin | Anti-hypersensitive inflammation and anti-allergy activities of zingiber zerumbet (l.) smith |
EP1817941A4 (en) | 2004-11-13 | 2009-11-11 | Metaproteomics Llc | Compositions exhibiting inhibition of cyclooxygenase-2 |
US20070036873A1 (en) | 2005-07-27 | 2007-02-15 | Shibnath Ghosal | Method of treatment or management of stress |
US20070148187A1 (en) | 2005-12-27 | 2007-06-28 | Intact Enterprises, Inc. | Mastic gum composition for use as a dietary supplement in humans and animals |
AR060847A1 (en) | 2007-05-03 | 2008-07-16 | Spannagel Lucia Antonia | FORMULATION BASED ON CALENDULA, ALOE AND CENTELLA. |
CA2754564C (en) * | 2009-03-04 | 2017-09-12 | Regenera Pharma Ltd. | Therapeutic uses of mastic gum fractions |
CN105147759A (en) | 2009-03-04 | 2015-12-16 | 瑞吉纳拉制药公司 | Compositions of polymeric myrcene |
-
2010
- 2010-03-04 CN CN201510616984.0A patent/CN105147759A/en active Pending
- 2010-03-04 EA EA201190170A patent/EA021833B1/en not_active IP Right Cessation
- 2010-03-04 EA EA201492273A patent/EA201492273A1/en unknown
- 2010-03-04 BR BRPI1013222A patent/BRPI1013222B8/en not_active IP Right Cessation
- 2010-03-04 ES ES10710912T patent/ES2739033T3/en active Active
- 2010-03-04 CA CA2754565A patent/CA2754565C/en active Active
- 2010-03-04 DK DK10710912.6T patent/DK2403512T3/en active
- 2010-03-04 PL PL10710912T patent/PL2403512T3/en unknown
- 2010-03-04 EP EP19158751.8A patent/EP3578191A1/en active Pending
- 2010-03-04 HU HUE10710912A patent/HUE045444T2/en unknown
- 2010-03-04 TR TR2019/11270T patent/TR201911270T4/en unknown
- 2010-03-04 AU AU2010220057A patent/AU2010220057C1/en not_active Ceased
- 2010-03-04 EP EP10710912.6A patent/EP2403512B1/en active Active
- 2010-03-04 WO PCT/IL2010/000184 patent/WO2010100651A2/en active Application Filing
- 2010-03-04 US US13/254,380 patent/US8722105B2/en active Active
- 2010-03-04 CN CN201080018570.3A patent/CN102413834B/en not_active Expired - Fee Related
-
2011
- 2011-09-01 IL IL214923A patent/IL214923A/en active IP Right Grant
-
2014
- 2014-03-26 US US14/226,293 patent/US9655938B2/en active Active
-
2016
- 2016-06-10 HK HK16106667.1A patent/HK1218710A1/en unknown
- 2016-09-26 IL IL248056A patent/IL248056B/en active IP Right Grant
-
2017
- 2017-04-13 US US15/486,964 patent/US10307449B2/en active Active
-
2019
- 2019-04-23 US US16/391,881 patent/US10806763B2/en active Active
Patent Citations (26)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4374957A (en) | 1981-10-29 | 1983-02-22 | Michigan Molecular Institute | Triblock polymers of a monovinyl aromatic compound and myrcene |
US4564718A (en) | 1984-08-14 | 1986-01-14 | The University Of Manchester Institute Of Science And Technology | Functionally terminated polymers from terpene monomers and their applications |
US4713243A (en) | 1986-06-16 | 1987-12-15 | Johnson & Johnson Products, Inc. | Bioadhesive extruded film for intra-oral drug delivery and process |
US5506406A (en) | 1993-05-17 | 1996-04-09 | Atomic Energy Corporation Of South Africa Ltd. | Method and apparatus for determining the concentration of a heavy element in a rock face |
US5759569A (en) | 1995-01-10 | 1998-06-02 | The Procter & Gamble Company | Biodegradable articles made from certain trans-polymers and blends thereof with other biodegradable components |
US6319541B1 (en) | 1995-06-06 | 2001-11-20 | Delsys Pharmaceutical Corporation | Method and apparatus for electrostatically depositing a medicament powder upon predefined regions of a substrate |
US6074688A (en) | 1995-06-06 | 2000-06-13 | Delsys Pharmaceautical Corporation | Method for electrostatically depositing a medicament powder upon predefined regions of a substrate |
US5637290A (en) | 1995-06-28 | 1997-06-10 | Leather Line Imports, Inc. | Oral hygiene product including chios mastic oil |
US6592887B2 (en) | 1996-11-11 | 2003-07-15 | Lts Lohmann Therapie-Systeme Ag | Water soluble film for oral administration with instant wettability |
US6284264B1 (en) | 1996-11-11 | 2001-09-04 | Lts Lohmann Therapie-Systeme Gmbh | Water soluble film for oral administration with instant wettability |
US6177096B1 (en) | 1996-11-11 | 2001-01-23 | Lts Lohmann Therapie-Systeme Gmbh | Water soluble film for oral administration with instant wettability |
US5948430A (en) | 1996-11-11 | 1999-09-07 | Lts Lohmann Therapie-Systeme Gmbh | Water soluble film for oral administration with instant wettability |
US6709671B2 (en) | 1996-11-11 | 2004-03-23 | Lts Lohmann Therapie-Systeme Ag | Water soluble film for oral administration with instant wettability |
GR1003541B (en) | 1999-05-11 | 2001-03-07 | Chios mastic oil used for cosmetic & pharmaceutical purposes as well as for the production of toothpicks, chewing gums, and dental flosses | |
US6623728B2 (en) | 2000-06-30 | 2003-09-23 | Unilever Home & Personal Care Usa Division Of Conopco, Inc. | Cosmetic skin care compositions and containing gum mastic |
US7048943B2 (en) | 2001-02-13 | 2006-05-23 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | Carotenoid-loaded liposomes |
US7294651B2 (en) | 2001-10-02 | 2007-11-13 | Kimberly-Clark Worldwide, Inc. | Inhibition of exoprotein production using isoprenoid compositions |
US20050238740A1 (en) | 2002-05-01 | 2005-10-27 | Spiros Fotinos | Use of mastic and its components for the control of microbial infections |
US6811769B2 (en) | 2002-08-23 | 2004-11-02 | Shuji Watanabe | Oral composition, method of making the oral composition and oral hygiene method in japanese and chinese herbal remedy |
US7214750B2 (en) | 2002-12-20 | 2007-05-08 | Exxonmobil Chemical Patents Inc. | Polymerization processes |
US7232872B2 (en) | 2002-12-20 | 2007-06-19 | Exxonmobil Chemical Patents Inc. | Polymerization processes |
EP1520585A1 (en) | 2003-10-02 | 2005-04-06 | Data Medica Padova S.p.A. | Cancer treatment using natural plant products or essential oils or components from some pistacia species |
US20070179260A1 (en) | 2004-03-04 | 2007-08-02 | Riken | Isotactic 3, 4-isoprene-based polymer |
US7417103B2 (en) | 2004-03-04 | 2008-08-26 | Riken | Isotactic 3,4-isoprene-based polymer |
WO2005112967A2 (en) | 2004-05-19 | 2005-12-01 | Balfour Marketing Corp. | Anticancer activity of chios mastic gum |
WO2006003659A2 (en) | 2004-07-06 | 2006-01-12 | Transpharma Medical Ltd. | Delivery system for transdermal immunization |
Non-Patent Citations (18)
Title |
---|
"Methods in Cell Biology", vol. XIV, 1976, ACADEMIC PRESS |
AL-HABBAL ET AL., CLIN EXP PHARMACOP PHYSIO, vol. 11, no. 5, 1984, pages 541 - 4 |
BARRA ET AL., J AGRIC FOOD CHEM, vol. 55, no. 17, 2007, pages 7093 - 7098 |
BEBB ET AL., J ANTIMICROB CHEMOTHER, vol. 52, 2003, pages 522 - 23 |
CAWSE ET AL., JOURNAL OF APPLIED POLYMER SCIENCE, vol. 31, 1986, pages 1963 - 1975 |
FARKAS ET AL.: "Experimental cerebral hypoperfusion induces white matter injury and microglial activation in the rat brain", ACTA NEUROPATHOL., vol. 108, 2004, pages 57 - 64 |
KEISARI, Y: "A colorimetric microtiter assay for the quantitation of cytokine activity on adherent cells in tissue culture", J. IMMUNOL., vol. 146, 1992, pages 155 - 161, XP023657784, DOI: doi:10.1016/0022-1759(92)90224-H |
KIMURA R; OHNO M: "Impairments in remote memory stabilization precede hippocampal synaptic and cognitive failures in SXFAD Alzheimer mouse model", NEUROBIOL DIS., 5 November 2008 (2008-11-05) |
LOUGHLIN ET AL., J ANTIMICROB CHEMOTHER, vol. 51, 2003, pages 367 - 371 |
MARNER ET AL., PHYTOCHEMISTRY, vol. 30, 1991, pages 3709 - 3712 |
MARONE ET AL., J CHEMOTHER, vol. 13, 2001, pages 611 - 614 |
NEWMARK ET AL., J. POLYM SCI., vol. 26, 1988, pages 71 - 77 |
NEWMARK ET AL., J. POLYMER SCI., vol. 26, 1988, pages 71 - 77 |
PARASCHOS ET AL., ANTIMICROB AGENTS CHEMOTHER, vol. 51, no. 2, 2007, pages 551 - 559 |
SAID ET AL., J ETHNOPHARMACOL, vol. 15, no. 3, 1986, pages 271 - 8 |
STENSET ET AL.: "White matter lesion subtypes and cognitive deficits in patients with memory impairment", DEMENT GERIATR COGN DISORD., vol. 26, 2008, pages 424 - 431 |
VAN DER BERG ET AL., TETRAHEDRON LETT, vol. 3, 1998, pages 2645 - 2648 |
WATANABE ET AL., CILOSTAZOL STROKE., vol. 37, no. 6, 2006, pages 1539 - 1545 |
Cited By (41)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2493461A1 (en) * | 2009-10-28 | 2012-09-05 | Regenera Pharma Ltd. | Therapeutic uses of oligomeric and polymeric monoterpenes |
EP2493461A4 (en) * | 2009-10-28 | 2013-04-03 | Regenera Pharma Ltd | Therapeutic uses of oligomeric and polymeric monoterpenes |
US9271949B2 (en) | 2010-09-07 | 2016-03-01 | Regenera Pharma Ltd. | Compositions comprising acidic extracts of mastic gum |
US10159680B2 (en) | 2010-09-07 | 2018-12-25 | Regenera Pharma Ltd. | Compositions comprising acidic extracts of mastic gum |
EP2613777A4 (en) * | 2010-09-07 | 2015-08-12 | Regenera Pharma Ltd | Compositions comprising acidic extracts of mastic gum |
EP3581177A2 (en) | 2010-09-07 | 2019-12-18 | Regenera Pharma Ltd. | Compositions comprising acidic extracts of mastic gum |
KR101910781B1 (en) * | 2010-09-07 | 2018-10-22 | 레제네라 파마 리미티드 | Compositions Comprising Acidic Extracts Of Mastic Gum |
WO2012032523A2 (en) | 2010-09-07 | 2012-03-15 | Regenera Pharma Ltd. | Compositions comprising acidic extracts of mastic gum |
US9770456B2 (en) | 2010-09-07 | 2017-09-26 | Regenera Pharma Ltd. | Compositions comprising acidic extracts of mastic gum |
EP3581177A3 (en) * | 2010-09-07 | 2020-02-26 | Regenera Pharma Ltd. | Compositions comprising acidic extracts of mastic gum |
US10561670B2 (en) | 2010-09-07 | 2020-02-18 | Regenera Pharma Ltd. | Compositions comprising acidic extracts of mastic gum |
US10307292B2 (en) | 2011-07-18 | 2019-06-04 | Mor Research Applications Ltd | Device for adjusting the intraocular pressure |
CN102526163A (en) * | 2011-12-27 | 2012-07-04 | 浙江景岳堂药业有限公司 | Method for extracting Olibanum and Myrrha in Fengtongling medicament |
WO2013186766A1 (en) * | 2012-06-11 | 2013-12-19 | Regenera Pharma Ltd. | Extracts and therapeutic uses thereof |
US10053603B2 (en) | 2014-04-02 | 2018-08-21 | Kraton Polymers U.S. Llc | Block copolymers containing a copolymer myrcene block |
US9458362B2 (en) | 2014-04-02 | 2016-10-04 | Kraton Polymers U.S. Llc | Adhesive compositions containing a block copolymer with polymyrcene |
JP2018507873A (en) * | 2015-03-08 | 2018-03-22 | レジネラ ファーマ リミテッド | Use of an isolated fraction of mastic gum to treat optic neuropathy |
US11000562B2 (en) | 2015-03-08 | 2021-05-11 | Regenera Pharma Ltd. | Use of isolated fractions of mastic gum for treating optic neuropathy |
WO2016142936A1 (en) * | 2015-03-08 | 2016-09-15 | Regenera Pharma Ltd. | Use of isolated fractions of mastic gum for treating optic neuropathy |
US10285996B2 (en) | 2015-09-24 | 2019-05-14 | Regenera Pharma Ltd. | Compositions comprising triterpenoids |
US10588911B2 (en) | 2015-09-24 | 2020-03-17 | Regenera Pharma Ltd. | Compositions comprising triterpenoids |
EP3352742A4 (en) * | 2015-09-24 | 2019-05-15 | Regenera Pharma Ltd. | Compositions comprising triterpenoids |
US11173164B2 (en) | 2015-09-24 | 2021-11-16 | Regenera Pharma Ltd. | Compositions comprising triterpenoids |
US11083736B2 (en) | 2015-09-24 | 2021-08-10 | Regenera Pharma Ltd. | Compositions comprising triterpenoids |
WO2017051423A1 (en) | 2015-09-24 | 2017-03-30 | Regenera Pharma Ltd. | Compositions comprising triterpenoids |
JP2018528973A (en) * | 2015-09-24 | 2018-10-04 | レジネラ ファーマ リミテッド | Composition comprising triterpenoids |
CN108289863A (en) * | 2015-09-24 | 2018-07-17 | 瑞吉纳拉制药公司 | Include the composition of triterpenes |
CN108289863B (en) * | 2015-09-24 | 2021-03-16 | 瑞吉纳拉制药公司 | Composition comprising triterpenes |
JP2019529363A (en) * | 2016-09-08 | 2019-10-17 | レジネラ ファーマ リミテッド | Composition comprising an acidic extract of mastic gum for the treatment of optic neuropathy and use thereof |
WO2018047175A1 (en) | 2016-09-08 | 2018-03-15 | Regenera Pharma Ltd. | Compositions comprising triterpenoids and uses thereof for treating optic neuropathy |
EP3509577A4 (en) * | 2016-09-08 | 2020-04-08 | Regenera Pharma Ltd. | Compositions comprising acidic extracts of mastic gum and uses thereof for treating optic neuropathy |
US10751347B2 (en) | 2016-09-08 | 2020-08-25 | Regenera Pharma Ltd. | Compositions comprising acidic extracts of mastic gum and uses thereof for treating optic neuropathy |
WO2018047176A1 (en) * | 2016-09-08 | 2018-03-15 | Regenera Pharma Ltd. | Compositions comprising acidic extracts of mastic gum and uses thereof for treating optic neuropathy |
JP2019526590A (en) * | 2016-09-08 | 2019-09-19 | レジネラ ファーマ リミテッド | Compositions containing triterpenoids and their use for the treatment of optic neuropathy |
US11207333B2 (en) | 2016-09-08 | 2021-12-28 | Regenera Pharma Ltd. | Compositions comprising triterpenoids and uses thereof for treating optic neuropathy |
JP7012379B2 (en) | 2016-09-08 | 2022-01-28 | レジネラ ファーマ リミテッド | Compositions Containing Triterpenoids for Treating Optic Neuropathies and Their Use |
EP3363448A1 (en) | 2017-02-15 | 2018-08-22 | Phytoitalia SRL | Terpene enriched fractions free from polyterpenes extracted from chios mastic gum and cosmetic, nutraceutical, medical devices and pharmaceutical compositions containing them |
WO2019170239A1 (en) | 2018-03-08 | 2019-09-12 | Phytoitalia Srl | Terpene enriched fractions free from polyterpenes extracted from chios mastic gum and cosmetic, nutraceutical, medical devices and pharmaceutical compositions containing them |
WO2020091703A1 (en) * | 2018-11-01 | 2020-05-07 | Yeditepe Universitesi | A medicine for treatment of psoriasis and production method thereof |
US20210393724A1 (en) * | 2018-11-01 | 2021-12-23 | Yeditepe Universitesi | Medicine for treatment of psoriasis and production method thereof |
RU2785038C2 (en) * | 2018-11-01 | 2022-12-02 | Едитепе Университеси | Drug for treatment of psoriasis and its production method |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US10806763B2 (en) | Compositions of polymeric myrcene | |
US10251923B2 (en) | Therapeutic uses of mastic gum fractions | |
US9770456B2 (en) | Compositions comprising acidic extracts of mastic gum | |
AU2015203595B2 (en) | Therapeutic uses of mastic gum fractions | |
AU2015203604A1 (en) | Insecticidal Composition and Method |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
WWE | Wipo information: entry into national phase |
Ref document number: 201080018570.3 Country of ref document: CN |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 10710912 Country of ref document: EP Kind code of ref document: A2 |
|
WWE | Wipo information: entry into national phase |
Ref document number: 13254380 Country of ref document: US |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2754565 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2010710912 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 201190170 Country of ref document: EA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 7117/DELNP/2011 Country of ref document: IN Ref document number: 2010220057 Country of ref document: AU |
|
ENP | Entry into the national phase |
Ref document number: 2010220057 Country of ref document: AU Date of ref document: 20100304 Kind code of ref document: A |
|
REG | Reference to national code |
Ref country code: BR Ref legal event code: B01A Ref document number: PI1013222 Country of ref document: BR |
|
WWE | Wipo information: entry into national phase |
Ref document number: 248056 Country of ref document: IL |
|
REG | Reference to national code |
Ref country code: BR Ref legal event code: B01E Ref document number: PI1013222 Country of ref document: BR |
|
ENP | Entry into the national phase |
Ref document number: PI1013222 Country of ref document: BR Kind code of ref document: A2 Effective date: 20110905 |