CN114306234A - TPGS micelle oral liquid containing gabapentin compound and preparation method thereof - Google Patents
TPGS micelle oral liquid containing gabapentin compound and preparation method thereof Download PDFInfo
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- CN114306234A CN114306234A CN202111570945.3A CN202111570945A CN114306234A CN 114306234 A CN114306234 A CN 114306234A CN 202111570945 A CN202111570945 A CN 202111570945A CN 114306234 A CN114306234 A CN 114306234A
- Authority
- CN
- China
- Prior art keywords
- gabapentin
- acid
- vitamin
- succinate
- oral liquid
- Prior art date
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- UGJMXCAKCUNAIE-UHFFFAOYSA-N Gabapentin Natural products OC(=O)CC1(CN)CCCCC1 UGJMXCAKCUNAIE-UHFFFAOYSA-N 0.000 title claims abstract description 146
- 229960002870 gabapentin Drugs 0.000 title claims abstract description 97
- 239000000693 micelle Substances 0.000 title claims abstract description 61
- -1 gabapentin compound Chemical class 0.000 title claims abstract description 56
- 239000007788 liquid Substances 0.000 title claims abstract description 42
- 238000002360 preparation method Methods 0.000 title claims description 27
- 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 title abstract description 12
- 235000014113 dietary fatty acids Nutrition 0.000 claims abstract description 42
- 229930195729 fatty acid Natural products 0.000 claims abstract description 42
- 239000000194 fatty acid Substances 0.000 claims abstract description 42
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 12
- 150000004665 fatty acids Chemical class 0.000 claims abstract description 10
- 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 claims description 36
- 229940099418 d- alpha-tocopherol succinate Drugs 0.000 claims description 36
- 229940113116 polyethylene glycol 1000 Drugs 0.000 claims description 35
- 239000000243 solution Substances 0.000 claims description 28
- 238000000034 method Methods 0.000 claims description 19
- 239000000203 mixture Substances 0.000 claims description 19
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 15
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 239000007864 aqueous solution Substances 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 9
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 claims description 8
- 238000003756 stirring Methods 0.000 claims description 8
- 238000001914 filtration Methods 0.000 claims description 7
- 238000002156 mixing Methods 0.000 claims description 7
- 229920000642 polymer Polymers 0.000 claims description 7
- 239000005639 Lauric acid Substances 0.000 claims description 6
- 229960002446 octanoic acid Drugs 0.000 claims description 6
- 235000015424 sodium Nutrition 0.000 claims description 6
- 239000011734 sodium Substances 0.000 claims description 6
- 229910052708 sodium Inorganic materials 0.000 claims description 6
- 239000005642 Oleic acid Substances 0.000 claims description 5
- 238000000502 dialysis Methods 0.000 claims description 5
- 238000011049 filling Methods 0.000 claims description 5
- 230000036571 hydration Effects 0.000 claims description 5
- 238000006703 hydration reaction Methods 0.000 claims description 5
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 claims description 4
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 claims description 4
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 claims description 4
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 claims description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 4
- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 claims description 4
- UKMSUNONTOPOIO-UHFFFAOYSA-N docosanoic acid Chemical compound CCCCCCCCCCCCCCCCCCCCCC(O)=O UKMSUNONTOPOIO-UHFFFAOYSA-N 0.000 claims description 4
- 235000003599 food sweetener Nutrition 0.000 claims description 4
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 claims description 4
- VKOBVWXKNCXXDE-UHFFFAOYSA-N icosanoic acid Chemical compound CCCCCCCCCCCCCCCCCCCC(O)=O VKOBVWXKNCXXDE-UHFFFAOYSA-N 0.000 claims description 4
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 claims description 4
- 239000003755 preservative agent Substances 0.000 claims description 4
- 230000002335 preservative effect Effects 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 239000003765 sweetening agent Substances 0.000 claims description 4
- 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 claims description 3
- 239000004386 Erythritol Substances 0.000 claims description 3
- UNXHWFMMPAWVPI-UHFFFAOYSA-N Erythritol Natural products OCC(O)C(O)CO UNXHWFMMPAWVPI-UHFFFAOYSA-N 0.000 claims description 3
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 claims description 3
- 235000019414 erythritol Nutrition 0.000 claims description 3
- UNXHWFMMPAWVPI-ZXZARUISSA-N erythritol Chemical compound OC[C@H](O)[C@H](O)CO UNXHWFMMPAWVPI-ZXZARUISSA-N 0.000 claims description 3
- 229940009714 erythritol Drugs 0.000 claims description 3
- 238000002347 injection Methods 0.000 claims description 3
- 239000007924 injection Substances 0.000 claims description 3
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims description 3
- 239000002994 raw material Substances 0.000 claims description 3
- 239000000600 sorbitol Substances 0.000 claims description 3
- 235000010356 sorbitol Nutrition 0.000 claims description 3
- 239000000811 xylitol Substances 0.000 claims description 3
- 235000010447 xylitol Nutrition 0.000 claims description 3
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims description 3
- 229960002675 xylitol Drugs 0.000 claims description 3
- FTLYMKDSHNWQKD-UHFFFAOYSA-N (2,4,5-trichlorophenyl)boronic acid Chemical compound OB(O)C1=CC(Cl)=C(Cl)C=C1Cl FTLYMKDSHNWQKD-UHFFFAOYSA-N 0.000 claims description 2
- OYHQOLUKZRVURQ-NTGFUMLPSA-N (9Z,12Z)-9,10,12,13-tetratritiooctadeca-9,12-dienoic acid Chemical compound C(CCCCCCC\C(=C(/C\C(=C(/CCCCC)\[3H])\[3H])\[3H])\[3H])(=O)O OYHQOLUKZRVURQ-NTGFUMLPSA-N 0.000 claims description 2
- 108010011485 Aspartame Proteins 0.000 claims description 2
- 235000021357 Behenic acid Nutrition 0.000 claims description 2
- 239000005711 Benzoic acid Substances 0.000 claims description 2
- 239000005632 Capric acid (CAS 334-48-5) Substances 0.000 claims description 2
- 239000005635 Caprylic acid (CAS 124-07-2) Substances 0.000 claims description 2
- 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 claims description 2
- 235000021314 Palmitic acid Nutrition 0.000 claims description 2
- 235000021355 Stearic acid Nutrition 0.000 claims description 2
- 239000004376 Sucralose Substances 0.000 claims description 2
- 239000000605 aspartame Substances 0.000 claims description 2
- 235000010357 aspartame Nutrition 0.000 claims description 2
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 claims description 2
- 229960003438 aspartame Drugs 0.000 claims description 2
- 229940116226 behenic acid Drugs 0.000 claims description 2
- 235000010233 benzoic acid Nutrition 0.000 claims description 2
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 claims description 2
- 239000000845 maltitol Substances 0.000 claims description 2
- 235000010449 maltitol Nutrition 0.000 claims description 2
- VQHSOMBJVWLPSR-WUJBLJFYSA-N maltitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-WUJBLJFYSA-N 0.000 claims description 2
- 229940035436 maltitol Drugs 0.000 claims description 2
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 claims description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 2
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 claims description 2
- 239000002244 precipitate Substances 0.000 claims description 2
- 229940085605 saccharin sodium Drugs 0.000 claims description 2
- 235000010199 sorbic acid Nutrition 0.000 claims description 2
- 239000004334 sorbic acid Substances 0.000 claims description 2
- 229940075582 sorbic acid Drugs 0.000 claims description 2
- 229960002920 sorbitol Drugs 0.000 claims description 2
- 239000008117 stearic acid Substances 0.000 claims description 2
- 235000019408 sucralose Nutrition 0.000 claims description 2
- BAQAVOSOZGMPRM-QBMZZYIRSA-N sucralose Chemical compound O[C@@H]1[C@@H](O)[C@@H](Cl)[C@@H](CO)O[C@@H]1O[C@@]1(CCl)[C@@H](O)[C@H](O)[C@@H](CCl)O1 BAQAVOSOZGMPRM-QBMZZYIRSA-N 0.000 claims description 2
- TUNFSRHWOTWDNC-HKGQFRNVSA-N tetradecanoic acid Chemical compound CCCCCCCCCCCCC[14C](O)=O TUNFSRHWOTWDNC-HKGQFRNVSA-N 0.000 claims description 2
- 239000010409 thin film Substances 0.000 claims description 2
- 239000003814 drug Substances 0.000 abstract description 21
- 150000003951 lactams Chemical class 0.000 abstract description 17
- 150000001875 compounds Chemical class 0.000 abstract description 14
- 235000019658 bitter taste Nutrition 0.000 abstract description 6
- 238000009833 condensation Methods 0.000 abstract description 4
- 230000005494 condensation Effects 0.000 abstract description 4
- 229940079593 drug Drugs 0.000 description 13
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 11
- 239000012535 impurity Substances 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 239000003960 organic solvent Substances 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 229930003427 Vitamin E Natural products 0.000 description 5
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 5
- 229940046009 vitamin E Drugs 0.000 description 5
- 235000019165 vitamin E Nutrition 0.000 description 5
- 239000011709 vitamin E Substances 0.000 description 5
- 238000010521 absorption reaction Methods 0.000 description 4
- OBETXYAYXDNJHR-UHFFFAOYSA-N alpha-ethylcaproic acid Natural products CCCCC(CC)C(O)=O OBETXYAYXDNJHR-UHFFFAOYSA-N 0.000 description 4
- 238000004090 dissolution Methods 0.000 description 4
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 239000008213 purified water Substances 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 210000001035 gastrointestinal tract Anatomy 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 235000019640 taste Nutrition 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- OGNSCSPNOLGXSM-UHFFFAOYSA-N (+/-)-DABA Natural products NCCC(N)C(O)=O OGNSCSPNOLGXSM-UHFFFAOYSA-N 0.000 description 2
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000010408 film Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 2
- 238000011835 investigation Methods 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 239000012528 membrane Substances 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
- 229940100688 oral solution Drugs 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- CHHHXKFHOYLYRE-UHFFFAOYSA-M 2,4-Hexadienoic acid, potassium salt (1:1), (2E,4E)- Chemical compound [K+].CC=CC=CC([O-])=O CHHHXKFHOYLYRE-UHFFFAOYSA-M 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 206010010904 Convulsion Diseases 0.000 description 1
- 235000016623 Fragaria vesca Nutrition 0.000 description 1
- 240000009088 Fragaria x ananassa Species 0.000 description 1
- 235000011363 Fragaria x ananassa Nutrition 0.000 description 1
- 206010025476 Malabsorption Diseases 0.000 description 1
- 208000004155 Malabsorption Syndromes Diseases 0.000 description 1
- 240000008790 Musa x paradisiaca Species 0.000 description 1
- 235000018290 Musa x paradisiaca Nutrition 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 206010061334 Partial seizures Diseases 0.000 description 1
- 206010036376 Postherpetic Neuralgia Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- BCKXLBQYZLBQEK-KVVVOXFISA-M Sodium oleate Chemical compound [Na+].CCCCCCCC\C=C/CCCCCCCC([O-])=O BCKXLBQYZLBQEK-KVVVOXFISA-M 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 238000009098 adjuvant therapy Methods 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
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- 239000000022 bacteriostatic agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 239000011258 core-shell material Substances 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 235000015872 dietary supplement Nutrition 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 230000005611 electricity Effects 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000000887 hydrating effect Effects 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 description 1
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- 230000002045 lasting effect Effects 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 238000003760 magnetic stirring Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
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- 239000011259 mixed solution Substances 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 210000000214 mouth Anatomy 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
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- 230000002093 peripheral effect Effects 0.000 description 1
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- 239000008363 phosphate buffer Substances 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 235000010241 potassium sorbate Nutrition 0.000 description 1
- 239000004302 potassium sorbate Substances 0.000 description 1
- 229940069338 potassium sorbate Drugs 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
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- 238000003908 quality control method Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
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- 238000005070 sampling Methods 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
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- 229930003799 tocopherol Natural products 0.000 description 1
- 229960001295 tocopherol Drugs 0.000 description 1
- 239000011732 tocopherol Substances 0.000 description 1
- 235000010384 tocopherol Nutrition 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 229910021642 ultra pure water Inorganic materials 0.000 description 1
- 239000012498 ultrapure water Substances 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention relates to TPGS micelle oral liquid containing a gabapentin compound, wherein the gabapentin compound is prepared from gabapentin and fatty acid or gabapentin, fatty acid salt and hydrochloric acid. The prepared TPGS micelle oral liquid containing the gabapentin compound can effectively reduce the generation of lactam of a condensation compound in gabapentin molecules, improve the stability of the medicine, cover the bitter taste of gabapentin and improve the compliance of patients.
Description
Technical Field
The invention relates to a composition containing gabapentin and a preparation method thereof, in particular to TPGS micelle oral liquid containing a gabapentin compound and a preparation method thereof, belonging to the field of pharmaceutical preparations.
Background
Gabapentin, an agonist of gamma-aminobutyric acid (GABA) receptors, was first successfully developed and marketed by the company picrorhizae, and is used clinically mainly for the treatment of peripheral neuralgia and adjuvant treatment of focal partial seizures, and also for the treatment of pain (such as postherpetic neuralgia) and anxiety. The molecular structural formula of gabapentin is shown below:
gabapentin is currently marketed in several countries and regions, where dosage forms are mainly tablets and oral solutions. Gabapentin is readily soluble in water, but the preparation of oral gabapentin formulations presents the following difficulties: (1) gabapentin is very bitter in taste; (2) the gabapentin has primary amino and carboxyl in molecules, so that the intramolecular condensation is easy to generate lactam, and the damp-heat action can accelerate the intramolecular cyclization of the gabapentin to generate lactam impurities. The molecular structural formula of lactam is shown as follows:
during the preparation and storage of gabapentin, the lactam formed by degradation is toxic and requires strict quality control. The gabapentin oral liquid sold in the market of the pfizer company needs to be refrigerated for storage (2-8 ℃), and is inconvenient to store, transport and carry. The oral liquid is mostly taken by old people and children who have difficulty in swallowing and inconvenience in taking, and the preparation on the market is heavy and lasting in bitter taste, so that the compliance of patients is greatly reduced. Based on the above, the development of the gabapentin oral liquid which is stable, convenient to store, transport and carry and good in taste is of great significance.
Patent CN1303991C provides a method for preparing a stable pharmaceutical formulation of 4-amino-3-substituted butyric acid derivatives, by incorporating an amino acid as a stabilizer, to obtain a stable solid or liquid pharmaceutical formulation of 4-amino-3-substituted butyric acid derivatives including gabapentin. The results of the stability experiments for the disclosed gabapentin formulation after addition of the amino acid show that: the lactam impurity has increased to 0.3 percent in 12 months at normal temperature, which indicates that the effective period is still short.
The polymer micelles (polymeric micelles) are generally composed of a large number of amphiphilic block copolymer molecular chains in an oriented arrangement mode, the hydrophobic chain segments wrap the drugs in cores through weak interaction with drug molecules, and hydrophilic chains outwards stabilize the micelles, so that a typical core-shell structure is presented, and the size of the micelle is in the range of tens to hundreds of nanometers. The polymer micelle oral administration system is used for improving the solubility of insoluble drugs, is beneficial to reducing the irritation of the drugs to gastrointestinal tracts, increasing the drug concentration of absorption parts, improving the stability of the drugs in the gastrointestinal tracts and improving the bioavailability.
Polyethylene glycol 1000 vitamin E succinate (TPGS) is a water-soluble derivative of natural vitamin E, is obtained by esterification reaction of hydrophilic polyethylene glycol and lipophilic vitamin E succinate, has physiological activities of polyethylene glycol and vitamin E, is a self-colored or light yellow waxy solid at normal temperature, has a melting point of 37-41 ℃, and can stably exist in the air. TPGS was first developed and marketed by Eastman corporation of America in 1950, has surfactant properties due to its lipophilic group of tocopherol and hydrophilic group of long chain of polyethylene glycol, and can be used as solubilizer, absorption enhancer, emulsifier, plasticizer, and carrier of liposoluble drug delivery system, such as liposome, micelle, etc. Studies show that TPGS as a high-efficiency emulsifier prepared nanoparticles has high encapsulation efficiency and strong cell uptake capacity on medicaments. TPGS also has the effects of increasing the stability of the medicine, promoting the penetration and absorption of the medicine, and the like. In addition, TPGS, as a water-soluble vitamin E, has a different absorption mechanism in the intestinal tract from that of fat-soluble vitamin E, and can be used as a nutritional supplement for people with malabsorption of fat-soluble vitamin E.
Disclosure of Invention
Through a great deal of research, the water-soluble gabapentin and fatty acid form an oil-soluble gabapentin fatty acid compound, and the compound and TPGS are prepared into a micellar solution to produce the following unexpected effects:
firstly, gabapentin fatty acid complex significantly improves the stability of gabapentin oral liquid. The gabapentin amino and the fatty acid carboxylic acid group are combined through static electricity, so that the condition that primary amino and carboxyl exist in gabapentin molecules and intramolecular condensation is carried out to generate lactam is reduced. The concrete points are as follows: (1) can obviously reduce the generation of lactam impurities and improve the safety of the medicine; (2) the storage can be carried out at normal temperature, so that the storage and transportation cost is obviously reduced; (3) the storage and carrying of the patient are convenient; (4) the effective period can be obviously prolonged.
Secondly, the gabapentin fatty acid compound can be prepared into micelles together with polyethylene glycol 1000 vitamin E succinate (TPGS), and then the micelles are mixed with a flavoring agent and a bacteriostatic agent to prepare the oral liquid. The polymer micelle can prevent the direct contact of the medicine and the oral cavity, cover the bitter taste of gabapentin, improve the taste of the oral liquid and improve the compliance of patients.
The specific technical scheme is as follows:
the invention provides a polyethylene glycol 1000 vitamin E succinate micelle oral liquid containing a gabapentin compound, which is characterized in that: the oral liquid consists of gabapentin fatty acid compound and polyethylene glycol 1000 vitamin E succinate, wherein the weight ratio of the gabapentin fatty acid compound to the polyethylene glycol 1000 vitamin E succinate is 1: 1-1: 5, preferably 1: 2-1: 3.
The gabapentin fatty acid compound provided by the invention is characterized in that: the preparation method comprises the steps of taking gabapentin and fatty acid as raw materials, dissolving the fatty acid and the gabapentin in a solvent to form a solution, standing to form a compound, and removing the solvent to obtain the gabapentin compound.
The invention provides a preparation method of the gabapentin fatty acid compound, which is characterized by comprising the following steps: the molar ratio of gabapentin to fatty acid is 1: 1-1: 5; wherein the fatty acid includes one or more of caprylic acid, capric acid, oleic acid, lauric acid, palmitic acid, linoleic acid, stearic acid, myristic acid, arachidic acid and behenic acid; wherein the organic solvent includes but is not limited to one or a mixture of more than two of ethanol, methanol, acetonitrile and acetone; the standing temperature is 10-40 ℃, and preferably 20-25 ℃; the standing time is 1-7 days, preferably 2-3 days.
The invention provides a preparation method of the gabapentin fatty acid compound, which is characterized by comprising the following steps: the method comprises the following steps of taking gabapentin, sodium fatty acid and hydrochloric acid as raw materials, adding an aqueous solution of the sodium fatty acid into the aqueous solution of the gabapentin under stirring, adjusting the pH value of the solution to 2-6 with the hydrochloric acid, stirring to separate out a precipitate, standing, and filtering to obtain the gabapentin aqueous solution; wherein the molar ratio of gabapentin to sodium fatty acid is 1: 1-1: 5.
The invention also provides a preparation method of the polyethylene glycol 1000 vitamin E succinate micelle of the gabapentin fatty acid compound, which is characterized by comprising the following steps: the preparation method of the polyethylene glycol 1000 vitamin E succinate micelle comprises but is not limited to one of a solvent injection method, a film hydration method, a one-step preparation method and a dialysis method.
The invention also provides a method for preparing polyethylene glycol 1000 vitamin E succinate micelle of gabapentin fatty acid compound by the solvent injection method, which is characterized by comprising the following steps: uniformly mixing the gabapentin fatty acid compound and the polyethylene glycol 1000 vitamin E succinate in an organic solvent to form an organic phase, then adding the organic phase into an aqueous solution to obtain a mixed solution, and removing or not removing the organic solvent to obtain the drug micelle solution.
The invention also provides a method for preparing polyethylene glycol 1000 vitamin E succinate micelle of gabapentin fatty acid compound by the thin film hydration method, which is characterized by comprising the following steps: uniformly mixing gabapentin fatty acid compound and polyethylene glycol 1000 vitamin E succinate in an organic solvent, removing the organic solvent to obtain a drug-loaded membrane, adding an aqueous solution to hydrate the drug-loaded membrane, and completely and uniformly hydrating to obtain a drug micelle solution.
The invention also provides a method for preparing polyethylene glycol 1000 vitamin E succinate micelles of gabapentin fatty acid compound by the one-step method, which is characterized by comprising the following steps: the gabapentin fatty acid compound and the polyethylene glycol 1000 vitamin E succinate are melted and then added into water for dissolution, so as to obtain the drug micelle solution.
The invention also provides a method for preparing polyethylene glycol 1000 vitamin E succinate micelles of gabapentin fatty acid compound by the dialysis method, which is characterized by comprising the following steps: the gabapentin fatty acid compound and the polyethylene glycol 1000 vitamin E succinate are dissolved and mixed uniformly in an organic solvent, and the organic solvent is removed by a dialysis device to obtain a drug micelle solution.
In the above method for preparing polyethylene glycol 1000 vitamin E succinate micelle of gabapentin fatty acid compound of the present invention, the organic solvent used includes but is not limited to one or a mixture of two or more of ethanol, methanol, acetonitrile, acetone, dimethyl sulfoxide, glycerol, and 1, 2-propylene glycol.
The invention also provides a preparation method of the polyethylene glycol 1000 vitamin E succinate micelle oral liquid of the gabapentin fatty acid compound, which is characterized by comprising the following steps: mixing the prepared polyethylene glycol 1000 vitamin E succinate micelle solution of the gabapentin compound with the aqueous solution in which the sweetening agent, the preservative and the essence are dissolved uniformly, fixing the volume, filtering and filling to obtain the gabapentin compound. The sweetener includes but is not limited to one or a mixture of more than two of sorbitol, xylitol, aspartame, saccharin sodium, sucralose, maltitol and erythritol; the preservative used in the method comprises one or a mixture of more than two of benzoic acid and salts thereof, sorbic acid and salts thereof and parabens.
The polyethylene glycol 1000 vitamin E succinate micelle oral liquid containing the gabapentin fatty acid compound, which is prepared by the invention, is stored for 24 months at 25 ℃, and the content of lactam impurities is 0.15 percent, which is obviously superior to the stability of the oral liquid of the gabapentin and amino acid composition provided by the existing preparation oral liquid (stored for 24 months at 5 ℃ and the content of lactam impurities is about 0.23 percent) and the comparison patent CN1303991C (stored for 12 months at 25 ℃ and the content of lactam impurities is about 0.3 percent). The polymer micelle oral liquid containing the gabapentin compound prepared by the invention is tasted by volunteers and basically has no bitter taste.
In conclusion, the polyethylene glycol 1000 vitamin E succinate micelle oral liquid containing the gabapentin fatty acid compound and the preparation method thereof provided by the invention utilize the combination of amino groups in gabapentin molecules and carboxyl groups in fatty acid molecules to form the compound, thereby reducing the generation of lactam of an intramolecular condensation compound of gabapentin and improving the stability of the medicine. The polyethylene glycol 1000 vitamin E succinate micelle has a wrapping effect on the medicine, so that the bitter taste can be covered, and the compliance of a patient is improved.
Detailed Description
The following exemplary embodiments are provided to illustrate the present invention, and simple replacement or improvement of the present invention by those skilled in the art is within the technical scheme of the present invention.
Example 1: gabapentin-lauric acid compound micelle oral liquid
Step 1 preparation of a compound: 20.0g (0.1mol) of lauric acid and 5g (0.03mol) of gabapentin are fully dissolved in 50ml of dimethyl sulfoxide, and the mixture is kept still for 3 days at room temperature, thus obtaining the gabapentin lauric acid compound solution.
Step 2, preparation of compound micelle: adding 50.0g of polyethylene glycol 1000 vitamin E succinate into the gabapentin lauric acid compound solution obtained in the step 1 for dissolution, and removing dimethyl sulfoxide by using a dialysis device to obtain a drug micelle solution.
Step 3, preparing the compound micelle oral liquid: weighing 25g of xylitol, 0.05g of orange essence and 0.1g of potassium sorbate, adding the mixture into 150ml of purified water to dissolve the mixture into a solution, slowly and uniformly mixing the solution with the medicinal micelle solution prepared in the step (2) under a stirring state, fixing the volume to 200ml, filtering and filling the mixture to obtain the polyethylene glycol 1000 vitamin E succinate micelle oral liquid containing the gabapentin compound.
Example 2: gabapentin octanoic acid compound micelle oral liquid
Step 1 preparation of a compound: 4.5g (0.03mol) of octanoic acid and 5g (0.03mol) of gabapentin were dissolved in 100ml of acetone, and the mixture was allowed to stand at about 40 ℃ for 1 day to obtain a gabapentin octanoic acid complex solution.
Step 2, preparation of compound micelle: adding 50.0g of polyethylene glycol 1000 vitamin E succinate into the gabapentin octanoic acid compound solution obtained in the step 1 for dissolving, performing reduced pressure rotary evaporation on the solution in a solanaceous bottle to remove acetone to obtain a uniform film, adding 100ml of purified water, and performing rotary hydration in a water bath kettle at 37 ℃ to obtain a medicinal micelle solution.
Step 3, preparing the compound micelle oral liquid: weighing 20g of sorbitol, 0.01g of banana essence and 0.1g of methyl paraben, adding into 50ml of purified water to be dissolved to prepare a solution, slowly adding into the medicinal micelle solution prepared in the step 2 under the stirring state, uniformly mixing, fixing the volume to 200ml, filtering, and filling to obtain the micelle oral liquid of the gabapentin compound.
Example 3: gabapentin-oleic acid compound micelle oral liquid
Step 1 preparation of a compound: adding 45.7g (0.15mol) of sodium oleate and 5g (0.03mol) of gabapentin into 100ml of water for full dissolution, adjusting the pH of the solution to 3-6 by hydrochloric acid under magnetic stirring at about 20 ℃, stirring for 1 hour, and centrifuging to obtain gabapentin oleic acid compound solid.
Step 2, preparation of compound micelle: heating and melting the gabapentin oleic acid compound obtained in the step 1 and 50.0g of polyethylene glycol 1000 vitamin E succinate, adding 100ml of water, and performing ultrasonic hydration dissolution at 37 ℃ to obtain a mixture micelle solution.
Step 3, preparing the compound micelle oral liquid: weighing 10g of erythritol, 0.01g of strawberry essence and 0.1g of sodium benzoate, adding into 50ml of purified water, dissolving to prepare a solution, slowly adding into the mixture micelle solution obtained in the step 2 under a stirring state, uniformly mixing, fixing the volume to 200ml, filtering, and filling to obtain the micelle oral liquid of the gabapentin compound.
Example 4:
and placing the obtained sample in stabilizing boxes with different temperatures, and sampling at regular time to carry out stability investigation.
And (4) investigation indexes are as follows: content of lactam impurity in the sample.
The content determination method comprises the following steps: HPLC
Chromatographic conditions are as follows: a chromatographic column: agilent ZORBAX Eclipse C18 (4.6X 150mm,3.5 μm)
Column temperature: 40 deg.C
Flow rate: 0.8mL/min
Wavelength: 210nm
Sample introduction amount: 10 μ L
Mobile phase A: 10mM potassium dihydrogen phosphate buffer (pH6.9)
Mobile phase B: acetonitrile
Gradient program:
| Time | phase A (acetonitrile) | Phase B (ultrapure water) |
| 0 | 90 | 10 |
| 3 | 90 | 10 |
| 10 | 45 | 55 |
| 13 | 45 | 55 |
| 14 | 90 | 10 |
| 20 | 90 | 10 |
The results of the examination are shown in the following table:
stability experiment lactam impurity detection result
Experimental results and conclusions:
compared with the oral liquid in the patent CN1303991C, the lactam impurity is increased to 0.3 percent when the oral liquid is placed at normal temperature for 12 months. The lactam impurity of the oral solution of the preparation on the market is increased to 0.23 percent when the oral solution is placed at the temperature of 2-8 ℃ for 24 months.
The experimental results show that: compared with the common gabapentin oral liquid on the market and the preparation described in the patent CN1303991C, the polymer micelle oral liquid containing the gabapentin compound provided by the invention has the advantages that the content of lactam impurities is obviously reduced, and the stability is improved.
The oral liquid prepared from the polymer micelle prepared in example 2 is tasted by 20 volunteers, and is sweet and palatable, almost has no bitter taste, and is acceptable.
Claims (7)
1. The polyethylene glycol 1000 vitamin E succinate micelle oral liquid containing gabapentin compound is characterized by comprising gabapentin fatty acid compound and polyethylene glycol 1000 vitamin E succinate, wherein the weight ratio of the gabapentin fatty acid compound to the polyethylene glycol 1000 vitamin E succinate is 1: 1-1: 5, preferably 1: 2-1: 3.
2. The polyethylene glycol 1000 vitamin E succinate micelle oral liquid containing gabapentin complex as claimed in claim 1, wherein the gabapentin fatty acid complex is prepared by dissolving gabapentin and fatty acid in a solvent to form a solution, standing to form the complex, and removing the solvent.
3. The polyethylene glycol 1000 vitamin E succinate micelle oral liquid containing gabapentin complex according to claims 1 and 2, wherein the molar ratio of gabapentin to fatty acid is 1:1 to 1: 5; fatty acids include, but are not limited to, one or a mixture of two or more of caprylic acid, capric acid, oleic acid, lauric acid, palmitic acid, linoleic acid, stearic acid, myristic acid, arachidic acid, and behenic acid; the solvent includes but is not limited to one or a mixture of more than two of ethanol, methanol, acetonitrile and acetone; the standing temperature is 10-40 ℃, preferably 20-25 ℃; the standing time is 1-7 days, preferably 2-3 days.
4. The polyethylene glycol 1000 vitamin E succinate micelle oral liquid containing gabapentin complex as claimed in claim 1, wherein the gabapentin fatty acid complex is prepared by using gabapentin, sodium fatty acid and hydrochloric acid as raw materials, adding an aqueous solution of sodium fatty acid into the gabapentin aqueous solution under stirring, adjusting the pH value of the solution to 2-6 with hydrochloric acid, stirring to separate out a precipitate, standing, and filtering.
5. The polyethylene glycol 1000 vitamin E succinate micelle oral liquid containing gabapentin complex according to claims 1 and 4, wherein the molar ratio of gabapentin to sodium fatty acid is 1:1 to 1: 5.
6. The polyethylene glycol 1000 vitamin E succinate micelle oral liquid containing gabapentin complex as claimed in claims 1-5, wherein the preparation method of the polymer micelle comprises but is not limited to one of solvent injection method, thin film hydration method, one-step preparation method and dialysis method.
7. The polyethylene glycol 1000 vitamin E succinate micelle oral liquid containing the gabapentin complex as claimed in claims 1-6, wherein the preparation method of the oral liquid comprises the steps of uniformly mixing the prepared polyethylene glycol 1000 vitamin E succinate micelle solution of the gabapentin complex with an aqueous solution in which a sweetening agent, a preservative and essence are dissolved, fixing the volume, filtering and filling; wherein the sweetener includes but is not limited to one or a mixture of more than two of sorbitol, xylitol, aspartame, saccharin sodium, sucralose, maltitol and erythritol; the preservative includes but is not limited to one or a mixture of more than two of benzoic acid and salts thereof, sorbic acid and salts thereof and parabens.
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