WO2023207729A1 - 艾司氯胺酮液体制剂及其用途 - Google Patents
艾司氯胺酮液体制剂及其用途 Download PDFInfo
- Publication number
- WO2023207729A1 WO2023207729A1 PCT/CN2023/089327 CN2023089327W WO2023207729A1 WO 2023207729 A1 WO2023207729 A1 WO 2023207729A1 CN 2023089327 W CN2023089327 W CN 2023089327W WO 2023207729 A1 WO2023207729 A1 WO 2023207729A1
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- WO
- WIPO (PCT)
- Prior art keywords
- esketamine
- liquid preparation
- depression
- sodium
- acid
- Prior art date
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- 238000002360 preparation method Methods 0.000 title claims abstract description 135
- 229960000450 esketamine Drugs 0.000 title claims abstract description 128
- 239000007788 liquid Substances 0.000 title claims abstract description 110
- YQEZLKZALYSWHR-ZDUSSCGKSA-N (S)-ketamine Chemical compound C=1C=CC=C(Cl)C=1[C@@]1(NC)CCCCC1=O YQEZLKZALYSWHR-ZDUSSCGKSA-N 0.000 title claims abstract description 108
- BHQCQFFYRZLCQQ-UHFFFAOYSA-N (3alpha,5alpha,7alpha,12alpha)-3,7,12-trihydroxy-cholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 BHQCQFFYRZLCQQ-UHFFFAOYSA-N 0.000 claims abstract description 21
- 239000004380 Cholic acid Substances 0.000 claims abstract description 21
- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 claims abstract description 21
- 235000019416 cholic acid Nutrition 0.000 claims abstract description 21
- 229960002471 cholic acid Drugs 0.000 claims abstract description 21
- KXGVEGMKQFWNSR-UHFFFAOYSA-N deoxycholic acid Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 KXGVEGMKQFWNSR-UHFFFAOYSA-N 0.000 claims abstract description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 21
- 208000020401 Depressive disease Diseases 0.000 claims abstract description 18
- 208000024714 major depressive disease Diseases 0.000 claims abstract description 18
- 208000028552 Treatment-Resistant Depressive disease Diseases 0.000 claims abstract description 17
- 150000003839 salts Chemical class 0.000 claims abstract description 12
- 208000020925 Bipolar disease Diseases 0.000 claims abstract description 10
- 208000028683 bipolar I disease Diseases 0.000 claims abstract description 9
- 208000025307 bipolar depression Diseases 0.000 claims abstract description 9
- 201000003104 endogenous depression Diseases 0.000 claims abstract description 9
- 210000002200 mouth mucosa Anatomy 0.000 claims abstract description 9
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 3
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 36
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 30
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 28
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 28
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid group Chemical group C(CC(O)(C(=O)O)CC(=O)O)(=O)O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 24
- 239000003963 antioxidant agent Substances 0.000 claims description 19
- 235000006708 antioxidants Nutrition 0.000 claims description 19
- 239000000796 flavoring agent Substances 0.000 claims description 19
- 235000013355 food flavoring agent Nutrition 0.000 claims description 19
- 238000000034 method Methods 0.000 claims description 18
- 239000003814 drug Substances 0.000 claims description 16
- 239000000872 buffer Substances 0.000 claims description 15
- 229940079593 drug Drugs 0.000 claims description 15
- 230000003078 antioxidant effect Effects 0.000 claims description 14
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 14
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 14
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 14
- 239000002562 thickening agent Substances 0.000 claims description 14
- 239000012669 liquid formulation Substances 0.000 claims description 13
- 239000012528 membrane Substances 0.000 claims description 13
- 235000002639 sodium chloride Nutrition 0.000 claims description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 11
- 210000004379 membrane Anatomy 0.000 claims description 10
- 239000000230 xanthan gum Substances 0.000 claims description 10
- 235000010493 xanthan gum Nutrition 0.000 claims description 10
- 229920001285 xanthan gum Polymers 0.000 claims description 10
- 229940082509 xanthan gum Drugs 0.000 claims description 10
- 235000015165 citric acid Nutrition 0.000 claims description 8
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical group C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 claims description 8
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 7
- 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 claims description 6
- 229960003964 deoxycholic acid Drugs 0.000 claims description 6
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 6
- 239000000845 maltitol Substances 0.000 claims description 6
- 235000010449 maltitol Nutrition 0.000 claims description 6
- 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 6
- 229940035436 maltitol Drugs 0.000 claims description 6
- 239000003755 preservative agent Substances 0.000 claims description 6
- FHHPUSMSKHSNKW-SMOYURAASA-M sodium deoxycholate Chemical compound [Na+].C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC([O-])=O)C)[C@@]2(C)[C@@H](O)C1 FHHPUSMSKHSNKW-SMOYURAASA-M 0.000 claims description 6
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 6
- 239000006172 buffering agent Substances 0.000 claims description 5
- 239000000463 material Substances 0.000 claims description 5
- 230000003204 osmotic effect Effects 0.000 claims description 5
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 4
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 4
- 241000544066 Stevia Species 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 230000002335 preservative effect Effects 0.000 claims description 4
- HELXLJCILKEWJH-NCGAPWICSA-N rebaudioside A Chemical compound O([C@H]1[C@H](O)[C@@H](CO)O[C@H]([C@@H]1O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)O[C@]12C(=C)C[C@@]3(C1)CC[C@@H]1[C@@](C)(CCC[C@]1([C@@H]3CC2)C)C(=O)O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O HELXLJCILKEWJH-NCGAPWICSA-N 0.000 claims description 4
- 239000011734 sodium Substances 0.000 claims description 4
- 229910052708 sodium Inorganic materials 0.000 claims description 4
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 3
- 235000011054 acetic acid Nutrition 0.000 claims description 3
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims description 3
- 239000004327 boric acid Substances 0.000 claims description 3
- 235000010338 boric acid Nutrition 0.000 claims description 3
- 239000001530 fumaric acid Substances 0.000 claims description 3
- 235000014655 lactic acid Nutrition 0.000 claims description 3
- 239000004310 lactic acid Substances 0.000 claims description 3
- 210000000214 mouth Anatomy 0.000 claims description 3
- 239000003961 penetration enhancing agent Substances 0.000 claims description 3
- 229940104256 sodium taurate Drugs 0.000 claims description 3
- GWLWWNLFFNJPDP-UHFFFAOYSA-M sodium;2-aminoethanesulfonate Chemical compound [Na+].NCCS([O-])(=O)=O GWLWWNLFFNJPDP-UHFFFAOYSA-M 0.000 claims description 3
- 239000011975 tartaric acid Substances 0.000 claims description 3
- 235000002906 tartaric acid Nutrition 0.000 claims description 3
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 claims description 2
- 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 claims description 2
- WBZFUFAFFUEMEI-UHFFFAOYSA-M Acesulfame k Chemical compound [K+].CC1=CC(=O)[N-]S(=O)(=O)O1 WBZFUFAFFUEMEI-UHFFFAOYSA-M 0.000 claims description 2
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- 239000004255 Butylated hydroxyanisole Substances 0.000 claims description 2
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- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical group [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 claims description 2
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- VCMGMSHEPQENPE-ZOWNYOTGSA-N esketamine hydrochloride Chemical compound [Cl-].C=1C=CC=C(Cl)C=1[C@@]1([NH2+]C)CCCCC1=O VCMGMSHEPQENPE-ZOWNYOTGSA-N 0.000 description 22
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- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 1
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- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
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- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
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- 235000019629 palatability Nutrition 0.000 description 1
- LCLHHZYHLXDRQG-ZNKJPWOQSA-N pectic acid Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)O[C@H](C(O)=O)[C@@H]1OC1[C@H](O)[C@@H](O)[C@@H](OC2[C@@H]([C@@H](O)[C@@H](O)[C@H](O2)C(O)=O)O)[C@@H](C(O)=O)O1 LCLHHZYHLXDRQG-ZNKJPWOQSA-N 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 229940075930 picrate Drugs 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-M picrate anion Chemical compound [O-]C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-M 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical compound OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 1
- 229950010765 pivalate Drugs 0.000 description 1
- 239000010318 polygalacturonic acid Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229950008882 polysorbate Drugs 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- 235000011118 potassium hydroxide Nutrition 0.000 description 1
- 235000010333 potassium nitrate Nutrition 0.000 description 1
- 239000004323 potassium nitrate 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
- 238000001556 precipitation Methods 0.000 description 1
- 230000003518 presynaptic effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 229940124811 psychiatric drug Drugs 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 229960001755 resorcinol Drugs 0.000 description 1
- 210000003296 saliva Anatomy 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 description 1
- ZLVSYODPTJZFMK-UHFFFAOYSA-M sodium 4-hydroxybenzoate Chemical compound [Na+].OC1=CC=C(C([O-])=O)C=C1 ZLVSYODPTJZFMK-UHFFFAOYSA-M 0.000 description 1
- 229960003885 sodium benzoate Drugs 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 1
- 229940037001 sodium edetate Drugs 0.000 description 1
- OABYVIYXWMZFFJ-ZUHYDKSRSA-M sodium glycocholate Chemical compound [Na+].C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCC([O-])=O)C)[C@@]2(C)[C@@H](O)C1 OABYVIYXWMZFFJ-ZUHYDKSRSA-M 0.000 description 1
- 239000001540 sodium lactate Substances 0.000 description 1
- 229940005581 sodium lactate Drugs 0.000 description 1
- 235000011088 sodium lactate Nutrition 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 235000010268 sodium methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- LROWVYNUWKVTCU-STWYSWDKSA-M sodium sorbate Chemical compound [Na+].C\C=C\C=C\C([O-])=O LROWVYNUWKVTCU-STWYSWDKSA-M 0.000 description 1
- 235000019250 sodium sorbate Nutrition 0.000 description 1
- OGBHACNFHJJTQT-UHFFFAOYSA-M sodium;4-butoxycarbonylphenolate Chemical compound [Na+].CCCCOC(=O)C1=CC=C([O-])C=C1 OGBHACNFHJJTQT-UHFFFAOYSA-M 0.000 description 1
- PESXGULMKCKJCC-UHFFFAOYSA-M sodium;4-methoxycarbonylphenolate Chemical compound [Na+].COC(=O)C1=CC=C([O-])C=C1 PESXGULMKCKJCC-UHFFFAOYSA-M 0.000 description 1
- IXMINYBUNCWGER-UHFFFAOYSA-M sodium;4-propoxycarbonylphenolate Chemical compound [Na+].CCCOC(=O)C1=CC=C([O-])C=C1 IXMINYBUNCWGER-UHFFFAOYSA-M 0.000 description 1
- QWSZRRAAFHGKCH-UHFFFAOYSA-M sodium;hexane-1-sulfonate Chemical compound [Na+].CCCCCCS([O-])(=O)=O QWSZRRAAFHGKCH-UHFFFAOYSA-M 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 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 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 229910000406 trisodium phosphate Inorganic materials 0.000 description 1
- ASTWEMOBIXQPPV-UHFFFAOYSA-K trisodium;phosphate;dodecahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].[Na+].[O-]P([O-])([O-])=O ASTWEMOBIXQPPV-UHFFFAOYSA-K 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- 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
- A61P25/24—Antidepressants
Definitions
- the present application relates to but is not limited to the technical field of pharmaceutical preparations, and in particular to esketamine liquid preparations and their use as antidepressant drugs.
- Depression is a form of manic-depressive disorder, characterized by low mood, slowed thinking, reduced speech and movement, and slowness as typical symptoms. Depression seriously disrupts the lives and work of patients and places a heavy burden on families and society. About 15% of patients with depression die of suicide. A joint study by the World Health Organization, the World Bank and Harvard University shows that depression has become the second largest disease burden in China.
- ketamine has attracted much attention as a psychiatric drug for the treatment of depression, and a large number of reports have proven its antidepressant effect.
- the mechanism of ketamine may be by increasing monoamine release or inhibiting presynaptic monoamine reuptake, thereby increasing the levels of monoamine compounds in the brain to achieve antidepressant effects.
- Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist.
- NMDA N-methyl-D-aspartate
- Most of the ketamine currently used clinically is the racemate, which contains two enantiomers, namely dexketamine and levoketamine.
- the affinity of dexketamine, that is, Esketamine, to NMDA, opioid receptors, and M-choline receptors is about 2 to 4 times higher than that of dexketamine, while its inhibitory effect on 5-HT is only 50 times that of dexketamine. %.
- side effects such as hallucinations and dreams during the use of ketamine are mainly caused by the L-isomer. Therefore, esketamine has better efficacy and fewer side effects such as hallucinations and addiction.
- a new mechanism of antidepressant drug developed by Johnson & Johnson in the United States is a nasal spray containing esketamine hydrochloride as the main drug.
- This product has quick-acting and long-lasting effects on patients with refractory depression and suicidal tendencies. It has strong curative effect and was approved for marketing in the United States for the first time in March 2019.
- this product was granted Breakthrough Drug Designation (BTD) by the FDA for the treatment of treatment-resistant depression and severe depression associated with imminent risk of suicide in 2013 and 2016, respectively.
- BTD Breakthrough Drug Designation
- esketamine has achieved good antidepressant effects when administered through the nasal cavity, nasal administration cannot meet the medicinal needs of patients with nasal inflammation or poor nasal mucosal tolerance; in addition, for the nasal spray preparation of esketamine hydrochloride that has been marketed, the volume for nasal administration is small. In order to achieve a therapeutic dose, the concentration of esketamine hydrochloride in this preparation is relatively high, close to the water solubility saturation of esketamine.
- This application provides an esketamine liquid preparation, which is administered through the oral mucosa.
- the preparation of this application has high stability, fast absorption, high bioavailability, simple administration method and good compliance.
- this application provides an esketamine liquid preparation, which is administered through the oral mucosa; it includes Includes esketamine or a pharmaceutically acceptable salt thereof, cholic acid or a derivative thereof, and water.
- this application provides the use of the above-mentioned esketamine liquid preparation in preparing drugs for preventing, alleviating or treating depression.
- the drugs can be used to treat major depression, unipolar depression, refractory depression, Resistant depression, anxious depression, bipolar depression.
- the present application provides a method for preventing, alleviating or treating depression in a patient using the above-mentioned esketamine liquid preparation, which method includes administering a therapeutically effective amount of the above-mentioned esketamine liquid preparation to the patient.
- this application provides the above-mentioned esketamine liquid preparation for preventing, alleviating or treating depression in patients, and the depression is major depression, unipolar depression, treatment-resistant depression, and refractory depression. Depression, anxious depression, bipolar depression.
- the present application provides a method for preparing the aforementioned esketamine liquid preparation.
- Figure 1 is a diagram showing the relationship between administration routes and pharmacokinetics of different esketamine preparations proposed in this application;
- Figure 2 is a diagram showing the relationship between different administration routes and AUC of different esketamine preparations proposed in this application.
- the first aspect of this application provides an esketamine liquid preparation, which is administered through the oral mucosa; it includes esketamine or a pharmaceutically acceptable salt thereof, bile acid or a derivative thereof, and water.
- esketamine used herein is also known as S-ketamine, esketamine, (S)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone hydrochloride, etc. Refers to the (S)-enantiomer of ketamine.
- the content of esketamine in the liquid preparation is 0.5% w/v to 8.5% w/v.
- the esketamine liquid preparation described in this application has high bioavailability. Therefore, the liquid preparation can be prepared as a product with a lower substance concentration, which can not only meet the prevention or treatment needs of clinical patients, but also avoid the complications caused by high-concentration administration. risks of abuse. At the same time, esketamine liquid preparation has good compatibility with saliva, reducing irritation to mucous membranes and reducing drug side effects.
- the concentration of esketamine in the liquid preparation is 0.7% w/v to 8.4% w/v; in another embodiment, the concentration of esketamine in the liquid preparation is 1.4% w /v ⁇ 6.3% w/v; in another embodiment, the concentration of esketamine in the liquid preparation is 1.4% w/v ⁇ 5.6% w/v.
- the concentration of esketamine in the liquid formulation is 0.7% w/v, 0.8% w/v, 0.9% w/v, 1.0% w/v, 1.1% w/v, 1.2% w/v, 1.3% w/v, 1.4% w/v, 1.5% w/v, 1.6% w/v, 1.7% w/v, 1.8% w/v, 1.9% w/v, 2.0% w/ v, 2.1% w/v, 2.2% w/v, 2.3% w/v, 2.4% w/v, 2.5% w/v, 2.6% w/v, 2.7% w/v, 2.8% w/v, 2.9% w/v, 3.0% w/v, 3.1% w/v, 3.2% w/v, 3.3% w/v, 3.4% w/v, 3.5% w/v, 3.6% w/v, 3.7% w/v, 3.8% w/v, 3.9% w/v, 4.0% w/v, 3.1%
- acids that can form pharmaceutically acceptable salts with esketamine include hydrochloric acid, sulfuric acid, phosphoric acid, maleic acid, acetic acid, adipic acid, alginic acid, citric acid, aspartic acid, benzoic acid , benzenesulfonic acid, hydrogen sulfate, butyric acid, camphoric acid, camphorsulfonic acid, digluconic acid, fumaric acid, glyceryl phosphate, stearic acid, heptanoic acid, caproic acid, hydrobromic acid (i.e.
- hydroiodic acid Namely HI
- lactic acid methanesulfonic acid, nicotinic acid, oxalic acid, dihydroxynaphthoic acid, pectic acid, persulfate, 3-phenylpropionic acid, picric acid, pivalic acid, propionic acid, succinic acid, tartaric acid, sulfur Cyanic acid, glutamic acid, p-toluenesulfonic acid, undecanoic acid and mandelic acid.
- pharmaceutically acceptable salts of esketamine include hydrochloride, sulfate, phosphate, maleate, acetate, adipate, alginate, citrate, Aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, fumarate, glycerophosphate, stearate , Enanthate, caproate, hydrobromide (HBr) salt, hydroiodic acid (HI) salt, lactate, methanesulfonate, nicotinate, oxalate, dihydroxynaphthoate, Pectate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, glutamate, bicarbonate , p-toluenesulfonate, undecanoate and mandelate.
- the concentration of cholic acid or its derivatives in the liquid preparation is 0.001% w/v to 0.015% w/v; in another embodiment, the concentration of cholic acid or its derivatives in the liquid preparation is The concentration of cholic acid or its derivatives in the liquid preparation is 0.001% w/v ⁇ 0.013% w/v; in another embodiment, the concentration of cholic acid or its derivatives in the liquid preparation is 0.001% w/v ⁇ 0.012% w/v; further In one embodiment, the concentration of cholic acid or its derivatives in the liquid preparation is 0.001% w/v, 0.002% w/v, 0.003% w/v, 0.004% w/v, 0.005% w/v, 0.006 % w/v, 0.007% w/v, 0.008% w/v, 0.009% w/v or 0.010% w/v.
- the cholic acid or its derivative is one of sodium taurate, sodium taurodeoxycholate, sodium deoxycholate, sodium cholate, sodium glycodeoxycholate, or a combination thereof .
- the pH of the liquid preparation is 2.5-5.7; in another embodiment, the pH range of the liquid preparation is 3.0-5.7; in yet another embodiment, the esketamine liquid preparation The pH range is 4.0-5.7; in another embodiment, the pH of the liquid preparation is 5.0-5.5; in yet another embodiment, the pH of the liquid preparation is 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6 or 5.7.
- the liquid preparation includes esketamine or a pharmaceutically acceptable salt thereof at a concentration of 0.5% w/v to 8.5% w/v, and a concentration of 0.001% w/v to 0.015% w/v.
- Cholic acid or its derivatives and water, the pH value of the liquid preparation ranges from 2.5 to 5.7.
- the esketamine liquid formulation may further include a viscosifier.
- the tackifier is xanthan gum, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, polyvinyl alcohol , carbomer or polyvinylpyrrolidone, or combinations thereof.
- the tackifier sodium carboxymethylcellulose is selected from sodium carboxymethylcellulose 800, sodium carboxymethylcellulose 4000, sodium carboxymethylcellulose 8000, sodium carboxymethylcellulose One or more of 12,000.
- the combination of tackifiers includes, without limitation: carboxymethylcellulose sodium 4000 and carboxymethylcellulose sodium 12000, carboxymethylcellulose sodium 800 and carboxymethylcellulose sodium 12000 , carboxymethylcellulose sodium 4000 and xanthan gum, carboxymethylcellulose sodium 4000 and hypromellose, carboxymethylcellulose sodium 4000 and xanthan gum composition,
- carboxymethylcellulose sodium 4000 and hypromellose carboxymethylcellulose sodium 4000 and xanthan gum composition
- the ratio (w/w) of the two thickener combinations ranges from 1:5 to 5:1.
- the concentration of the tackifier is 0.01% w/v ⁇ 3.5% w/v; in another embodiment, the concentration of the tackifier is 0.05 ⁇ 3.0% w/v; In yet another embodiment, the concentration of the tackifier is 0.05-2.0% w/v; in yet another embodiment, the concentration of the tackifier is 0.01% w/v, 0.05% w/v, 0.1% w/v, 0.15% w/v, 0.2% w/v, 0.25% w/v, 0.30% w/v, 0.35% w/v, 0.40% w/v, 0.45% w/v, 0.50% w/v, 0.55% w/v, 0.60% w/v, 0.65% w/v, 0.70% w/v, 0.75% w/v, 0.80% w/v, 0.85% w/v, 0.90% w/ v, 0.95% w/v or 1.00% w/v.
- the esketamine liquid formulation further includes one or more of the following auxiliary materials: buffering agents, flavoring agents, antioxidants, osmotic pressure regulators and preservatives.
- the esketamine liquid formulation further includes one or more of the following auxiliary materials: buffers, flavoring agents, antioxidants, osmotic pressure regulators, preservatives and penetration enhancers.
- the buffer can be citric acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, acetic acid, boric acid, sodium borate, succinic acid, tartaric acid, lactic acid, Fumaric acid, trisodium phosphate (trisodium phosphate dodecahydrate or TSP), sodium benzoate, benzoic acid, sodium hydroxide, potassium hydroxide, alkali metal carbonates, sodium carbonate, imidazole, pyrophosphate, glucose Sodium acid, sodium lactate, phosphoric acid, borate, bicarbonate, Tris-HCl, citrate, or combinations thereof.
- the buffer described in this application can maintain the pH of the liquid preparation within a stable range, which is beneficial to improving the stability of the solution preparation.
- the concentration of the buffer is 0.1-0.3% w/v; in one embodiment, the concentration of the buffer is 0.1-0.2% w/v; in another embodiment, the concentration of the buffer is 0.1 ⁇ 0.15% w/v; in another embodiment, the concentration of the buffer is 0.1% w/v, 0.11% w/v, 0.12% w/v, 0.13% w/v, 0.14% w/ v, 0.15% w/v, 0.16% w/v, 0.17% w/v, 0.18% w/v, 0.19% w/v, 0.2% w/v, 0.21% w/v, 0.22% w/v, 0.23% w/v, 0.24% w/v, 0.25% w/v, 0.26% w/v, 0.27% w/v, 0.28% w/v, 0.29% w/
- the present application provides a liquid formulation of esketamine, which formulation further includes a flavoring agent.
- Flavoring agents can mask the possible peculiar smell of the pharmaceutical composition and improve its palatability, which is beneficial to improving patient compliance.
- the flavoring agent of the liquid preparation is sodium saccharin, fructose, sucralose, stevia, menthol, maltitol, xylitol, aspartame, cyclamate, saccharin, orange peel glycosides, thaumatin, stevia or acesulfame potassium, or combinations thereof.
- the application provides an esketamine liquid preparation, and the concentration of the flavoring agent is 0.01 to 0.05% w/v; in another embodiment, the concentration of the flavoring agent is 0.01 ⁇ 0.03% w/v; in another embodiment, the concentration of the flavoring agent is 0.01% w/v, 0.02% w/v, 0.03% w/v, 0.04% w/v, 0.05% w/ v.
- the present application provides a liquid formulation of esketamine, the formulation further comprising an antioxidant.
- Antioxidants can effectively prevent or delay the oxidation of preparations, prevent oxidative deterioration of drugs and their preparations, as well as discoloration, precipitation and other problems caused by oxidation, and increase drug stability.
- the antioxidant of the liquid preparation is ethylenediaminetetraacetic acid (EDTA, edetic acid) or its sodium or calcium salt, vitamin E, gallate, sodium bisulfite, ascorbic acid or its salt , butylated hydroxyanisole or tocopherol, or combinations thereof.
- the application provides an esketamine liquid preparation
- the concentration of the antioxidant is 0.010-0.020% w/v; in another embodiment, the concentration of the antioxidant is 0.010-0.015 % w/v; in another embodiment, the concentration of the antioxidant in the liquid preparation is 0.010% w/v, 0.011% w/v, 0.012% w/v, 0.013% w/v, 0.014% w/ v, 0.015% w/v, 0.016% w/v, 0.017% w/v, 0.018% w/v, 0.019% w/v, 0.02% w/v.
- the esketamine liquid formulation further includes a preservative.
- the preservative is selected from the group consisting of methyl paraben, ethyl paraben, propyl paraben, butyl paraben, sodium methyl paraben, sodium paraben, Sodium ethyl benzoate, sodium propylparaben, sodium butylparaben, sorbic acid, potassium sorbate, sodium sorbate, benzoic acid, sodium benzoate, benzyl alcohol, benzalkonium bromide, benzalkonium chloride One or more of ammonium, chlorobutanol, resorcinol and sodium edetate.
- the esketamine liquid formulation further comprises an osmotic pressure regulator.
- the visco-osmotic pressure regulator is selected from one or more of sodium chloride, potassium nitrate, boric acid and glucose; preferably, it is sodium chloride.
- the esketamine liquid formulation further includes a penetration enhancer.
- the penetration enhancer is selected from the group consisting of sodium deoxycholate, Tween 80, hypromellose, sodium lauryl sulfate, sodium docusate, polysorbate, myristyl maltose One or more of glycosides, sodium glycocholate, tauroursodeoxycholic acid (TUDCA), lecithin, hydroxypropyl- ⁇ -cyclodextrin, sodium sulfobutyl- ⁇ -cyclodextrin or PEG400 .
- the second aspect of this application specifically provides an esketamine liquid preparation, which includes esketamine hydrochloride, cholic acid or its derivatives, a thickener and water; the pH range of the liquid preparation is 4.5 to 5.5, and the The content of esketamine in the liquid preparation is 0.7% w/v to 8.4% w/v.
- the types of viscosifiers and their content with cholic acid or derivatives thereof are as described above.
- the tackifier is one of sodium carboxymethylcellulose 4000, sodium carboxymethylcellulose 8000, sodium carboxymethylcellulose 12000, xanthan gum and hypromellose , or a combination thereof.
- the simultaneous use of cholic acid or its derivatives and a thickening agent can make the API in the prescription more fully released in vitro, and can better promote the permeability of esketamine through the oral mucosa, Synergistically improves the bioavailability of esketamine solution formulations.
- the thickening agent is sodium carboxymethylcellulose 4000, sodium carboxymethylcellulose 8000, sodium carboxymethylcellulose 12000, xanthan gum and One of hypromellose, or a combination thereof.
- the tackifier is xanthan gum; in another embodiment, the tackifier is hypromellose; in another embodiment, the tackifier is carboxymethyl Sodium cellulose 4000 and sodium carboxymethylcellulose 12000; in another embodiment, the tackifier is sodium carboxymethylcellulose 4000 and hypromellose.
- the third aspect of this application specifically provides an esketamine liquid preparation, which includes esketamine hydrochloride, cholic acid or its derivatives, a thickening agent, a buffer and water; the pH range of the liquid preparation is 4.5 to 5.5 , the content of esketamine in the liquid preparation is 0.7% w/v to 8.4% w/v.
- the types of viscosifiers and buffers and their contents with cholic acid or derivatives thereof are as described above.
- the application provides a liquid preparation of esketamine, and the buffering agent is citric acid.
- the fourth aspect of this application specifically provides an esketamine liquid preparation, which includes esketamine hydrochloride, cholic acid or its derivatives, a thickener, an antioxidant, a flavoring agent, a buffer and water; the liquid preparation
- the pH range is 4.5 to 5.5, and the content of esketamine in the liquid preparation is 0.7% w/v to 8.4% w/v.
- the types of viscosifiers, antioxidants, flavoring agents and buffers and their contents with cholic acid or derivatives thereof are as described above.
- the tackifier is one of sodium carboxymethylcellulose 4000, sodium carboxymethylcellulose 8000, sodium carboxymethylcellulose 12000, xanthan gum and hypromellose , or a combination thereof.
- the antioxidant is disodium edetate
- the flavoring agent is sodium saccharin or maltitol
- the thickening agent is carboxymethylcellulose.
- the antioxidant is disodium edetate, the flavoring agent is sodium saccharin or maltitol, and the thickening agent is xanthan gum; in another embodiment, the antioxidant It is disodium edetate, the flavoring agent is sodium saccharin or maltitol, and the thickening agent hypromellose; in another embodiment, the thickening agent is sodium carboxymethylcellulose 4000 and sodium carboxymethylcellulose 12000; in another embodiment, the antioxidant is disodium edetate, the flavoring agent is sodium saccharin or maltitol, and the thickening agent is carboxymethylcellulose Sodium 4000 and hypromellose.
- the application provides a liquid preparation of esketamine, and the buffering agent is citric acid.
- the fifth aspect of this application provides the use of an esketamine liquid preparation in the preparation of drugs to prevent, alleviate or treat depression.
- the drugs can be used to treat major depression, unipolar depression, refractory depression, Resistant depression, anxious depression, bipolar depression.
- the application provides the use of an esketamine liquid preparation in the preparation of a drug for preventing, alleviating or treating depression, and the liquid preparation is applied to the oral buccal membrane of a patient.
- the sixth aspect of the present application provides a method of using an esketamine liquid preparation to prevent, alleviate or treat depression in a patient, including administering a therapeutically effective amount of the esketamine liquid preparation to the patient.
- the present application provides a method of using esketamine liquid formulation to prevent, alleviate or treat depression in a patient, the depression being major depression, unipolar depression, treatment-resistant depression, refractory depression Sexual depression, anxious depression, bipolar depression.
- the application provides a method of preventing, alleviating or treating depression in a patient using an esketamine liquid formulation, which is applied to the buccal membrane of the patient's oral cavity.
- the seventh aspect of this application provides an esketamine liquid preparation for preventing, alleviating or treating depression in patients, where the depression is major depression, unipolar depression, treatment-resistant depression, and refractory depression disorders, anxiety depression, and bipolar depression.
- a liquid formulation of esketamine for preventing, alleviating, or treating depression in a patient is administered to the buccal membrane of the oral cavity of a mammal.
- this application provides a preparation method for the aforementioned esketamine liquid preparation, including the following preparation steps:
- the solution passes through a 0.45 ⁇ m filter membrane, and the filtrate is filled into a prefilled syringe to obtain the finished product.
- the esketamine liquid preparation provided in this application is rapidly absorbed and takes effect quickly within 4 to 7 minutes, and its AUC0-240min can be greater than 7000ng/mL.
- the esketamine liquid preparation has high bioavailability, no crystallization phenomenon, and high stability. It can not only meet the needs of large-scale processing and production, but also reduce the risk of medication for patients.
- the esketamine liquid preparation provided in this application can effectively improve the bioavailability of the active substance by using cholic acid or its derivatives; by further adding a thickening agent to increase the retention time of the liquid preparation in the oral mucosa, it can further Increase the absorption of esketamine and synergistically improve the bioavailability of esketamine liquid preparations.
- the esketamine liquid preparation provided in this article is simple and easy to administer, which greatly increases patient compliance. Due to the small dosage and small volume, it can greatly reduce irritation to the mucous membrane and reduce the risk of abuse.
- concentrations of all ingredients are in percent weight/volume (%w/v). As is generally understood, the % w/v value refers to the amount of a particular component or ingredient in the formulation. It is known that equivalent concentrations can be expressed in different units. For example, a concentration of 0.1% w/v can also be expressed as a 1 mg/ml solution.
- the preparation method includes the following preparation steps:
- the solution passes through a 0.45 ⁇ m filter membrane, and the filtrate is filled into a 1 ml prefilled syringe (purchased from Shandong Zibo Minkang Pharmaceutical Packaging Co., Ltd.), 1 ml/tube to obtain the finished preparation.
- Esketamine Hydrochloride Buccal Solution is prone to produce the following two impurities during the preparation and storage process:
- Both of the above two impurities can be purchased through commercial channels.
- the inventor conducted long-term stability experiments on the samples prepared in Examples 1-10 in an environment of 25°C ⁇ 2°C and RH 60% ⁇ 5%.
- the mobile phase is uniform; the detection wavelength is 215nm; the flow rate is 1.0ml per minute; the column temperature is 30°C; the injection volume is 20 ⁇ l.
- Chromatographic conditions Use octadecylsilane bonded silica gel as filler (Agela MP C18 4.6 ⁇ 150mm, 5 ⁇ m or equivalent column efficiency); use 25mM phosphate buffer (take 3.4g of potassium dihydrogen phosphate, add 1000ml of water to dissolve, Use phosphoric acid Adjust the pH value to 2.5) as mobile phase A, and use acetonitrile as mobile phase B. Carry out gradient elution according to the table, the detection wavelength is 215nm; the column temperature is 30°C; the flow rate is 1.0ml per minute; the injection volume is 20 ⁇ l.
- the Franz diffusion cell method was used and a phospholipid biomimetic barrier was used.
- Bionic membrane simulates oral mucosa, and the diffusion medium uses PBS buffer; after the diffusion pool reaches 37°C, first add 0.5ml of artificial saliva above the bionic membrane, and then add 0.2ml of prescription solution.
- the sampling time points are 10min, 20min, and 30min. , 45min, 60min, 180min, 240min, 300min, 360min, using waste mode, take 1ml sample at each time point, and detect the content with liquid phase.
- the preparation method includes the following preparation steps:
- the preparation method includes the following preparation steps:
- the preparation method is as in Comparative Example 2, using sodium deoxycholate to replace carbomer 974P and hydroxypropylmethyl- ⁇ -cyclodextrin.
- Comparative Example 1 uses unilateral nasal administration, and the dosage is 0.05ml/animal (1 spray);
- Example 1 uses unilateral buccal fluid administration, and the dosage is 0.125ml/animal;
- Comparative Example 2 In Example 3, unilateral buccal membrane administration was used, and the dosage was 1 tablet/animal (7 mg); in Comparative Examples 2 and 3, sublingual administration was used, and the dosage was 1 tablet/animal (7 mg).
- the blood collection method is ear vein blood collection.
- the blood collection time points are: 0min (before administration), 2min, 5min, 10min, 15min, 30min, 60min, 120min, and 240min.
- the in vivo drug absorption of esketamine hydrochloride administered with buccal liquid and buccal film is significantly higher than that of nasal administration and oral dissolving film administration, which is about 1 times higher, and the onset time of these two routes is similar. It takes about 4 to 7 minutes and takes effect faster than oral dissolving film administration.
- the technical solution of this application can also be used for buccal liquid and buccal film delivery systems of R-ketamine, ketamine or pharmaceutically acceptable salts, by adjusting or changing the content of active ingredients, the types and dosage of pharmaceutical excipients, etc. to achieve this goal. Purpose of invention.
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Abstract
一种艾司氯胺酮液体制剂,为水性溶液剂,包含艾司氯胺酮或其药学上可接受的盐、胆酸或其衍生物和水,pH值为2.5-5.7。艾司氯胺酮液体制剂经口腔黏膜给药,制剂稳定性高、吸收快、生物利用度高,施用方式简单、依从性好。可用于重性抑郁症、单相抑郁症、难治性抑郁症、顽固性抑郁症、焦虑性抑郁症、双相抑郁症的预防、缓解或治疗。
Description
本申请要求于2022年4月26日提交中国专利局、申请号为202210450509.0、发明名称为“艾司氯胺酮液体制剂及其用途”的中国专利申请的优先权,其内容应理解为通过引用的方式并入本申请中。
本申请涉及但不限于药物制剂技术领域,特别涉及艾司氯胺酮液体制剂及其作为抗抑郁药物的用途。
抑郁症是躁狂抑郁症的一种发作形式,以情感低落、思维迟缓、以及言语动作减少,迟缓为典型症状。抑郁症严重困扰患者的生活和工作,给家庭和社会带来沉重的负担,约15%的抑郁症患者死于自杀。世界卫生组织、世界银行和哈佛大学的一项联合研究表明,抑郁症已经成为中国疾病负担的第二大病。
近年来,氯胺酮作为精神科药物治疗抑郁症颇受关注,已有大量报道证明其抗抑郁作用。氯胺酮作为一个快速起效的抗抑郁药物,其机制可能是通过增加单胺释放或抑制突触前单胺再摄取,从而升高大脑单胺化合物水平来达到抗抑郁的作用。
氯胺酮为N-甲基-D-天门冬氨酸(NMDA)受体拮抗剂,目前临床使用的氯胺酮多为消旋体,含有两个对映体,即右旋氯胺酮和左旋氯胺酮。研究表明,右旋氯胺酮,即艾司氯胺酮(Esketamine)对NMDA、阿片受体、M胆碱受体的亲和力比左旋高约2~4倍,而对5-HT的抑制作用仅为左旋的50%。此外,氯胺酮在应用中出现幻觉、梦境等副作用主要由左旋型异构体产生。因此,艾司氯胺酮疗效更佳,致幻、成瘾等副作用更小。
美国强生(Johnson&Johnson)研制的一种新机制的抗抑郁药物,就是以盐酸艾司氯胺酮为主药的鼻喷雾剂,该品对难治性抑郁症和已有自杀倾向的患者具有速效、持久的强大疗效,并于2019年3月获批在美国首次上市。此外,该品分别于2013年和2016年获得FDA授予的治疗难治性抑郁症的突破性药物资格和治疗伴有紧迫自杀风险的重度抑郁症的突破性药物资格(BTD)。
虽然艾司氯胺酮通过鼻腔给药的形式已到达很好的抗抑郁效果,但是针对鼻腔有炎症或者鼻粘膜耐受性较差的患者,经鼻给药无法满足该类患者的药用需求;此外,对于已上市的盐酸艾司氯胺酮的鼻喷制剂,其经鼻给药的体积较小,为达到治疗剂量,该制剂中盐酸艾司氯胺酮浓度较高,接近艾司氯胺酮水溶饱和度。这种高浓度的盐酸艾司氯胺酮溶液在一定程度上会增加氯胺酮滥用的风险;再者,通过药代动力学研究发现,艾司氯胺酮经鼻喷给药,药物吸收速度快,但是鼻喷给药,体内药物吸收不好,生物利用度不高。因此,为了更好的扩展氯胺酮在抗抑郁的临床应用范围,满足更多抑郁症患者的需求,降低治疗成本,减轻患者家庭负担,亟需考虑其他有效的给药途径。
发明内容
本申请提供了一种艾司氯胺酮液体制剂,其经口腔黏膜给药,本申请的制剂稳定性高、吸收快、生物利用度高,施用方式简单、依从性好。
一方面,本申请提供了一种艾司氯胺酮液体制剂,该液体制剂经口腔黏膜给药;其包
括艾司氯胺酮或其药学上可接受的盐,胆酸或其衍生物,和水。
另一方面,本申请提供了上述艾司氯胺酮液体制剂在制备预防、缓解或治疗抑郁症药物中的用途,所述药物可用于治疗重性抑郁症、单相抑郁症、难治性抑郁症、顽固性抑郁症、焦虑性抑郁症、双相抑郁症。
又一方面,本申请提供了一种使用上述艾司氯胺酮液体制剂预防、缓解或治疗患者抑郁症的方法,所述方法包括向患者施用治疗有效量的上述艾司氯胺酮液体制剂。
再一方面,本申请提供了上述艾司氯胺酮液体制剂,用于预防、缓解或治疗患者的抑郁症,所述抑郁症为重性抑郁症、单相抑郁症、难治性抑郁症、顽固性抑郁症、焦虑性抑郁症、双相抑郁症。
又一方面,本申请提供了前述艾司氯胺酮液体制剂的制备方法。
附图概述
附图用来提供对本申请技术方案的理解,并且构成说明书的一部分,与本申请的实施例一起用于解释本申请的技术方案,并不构成对本申请技术方案的限制。
图1为本申请提出不同艾司氯胺酮制剂给药途径与药代的关系图;
图2为本申请提出不同艾司氯胺酮制剂不同给药途径与AUC的关系图。
详述
本申请第一方面提供了一种艾司氯胺酮液体制剂,该液体制剂经口腔黏膜给药;其包括艾司氯胺酮或其药学上可接受的盐,胆酸或其衍生物,和水。
除非另外说明,本文所用的艾司氯胺酮,也被称为S-氯胺酮、艾氯胺酮、(S)-2-(2-氯苯基)-2-(甲基氨基)盐酸环己酮等,其指的是氯胺酮的(S)-对映体。
在本发明的液体制剂中,无论使用的是艾司氯胺酮,还是艾司氯胺酮药学上可接受的盐,在计算活性物质含量时,均以艾司氯胺酮的含量来进行计算。
在本申请所述艾司氯胺酮液体制剂的一实施方案中,所述液体制剂中艾司氯胺酮的含量为0.5%w/v~8.5%w/v。
本申请所述艾司氯胺酮液体制剂生物利用度高,因此,该液体制剂可以被制备为较低物质浓度的产品,既能满足临床患者的预防或治疗需求,又可以避免因高浓度给药带来的滥用风险。同时,艾司氯胺酮液体制剂与唾液相容性良好,减少对粘膜的刺激性,降低药物副作用。
在一实施方案中,所述液体制剂中艾司氯胺酮的浓度为0.7%w/v~8.4%w/v;在另一实施方案中,所述液体制剂中艾司氯胺酮的浓度为1.4%w/v~6.3%w/v;在又一实施方案中,所述液体制剂中艾司氯胺酮的浓度为1.4%w/v~5.6%w/v。还在一实施方案中,所述液体制剂中艾司氯胺酮的浓度为0.7%w/v、0.8%w/v、0.9%w/v、1.0%w/v、1.1%w/v、1.2%w/v、1.3%w/v、1.4%w/v、1.5%w/v、1.6%w/v、1.7%w/v、1.8%w/v、1.9%w/v、2.0%w/v、2.1%w/v、2.2%w/v、2.3%w/v、2.4%w/v、2.5%w/v、2.6%w/v、2.7%w/v、2.8%w/v、2.9%w/v、3.0%w/v、3.1%w/v、3.2%w/v、3.3%w/v、3.4%w/v、3.5%w/v、3.6%w/v、3.7%w/v、3.8%w/v、3.9%w/v、4.0%w/v、4.1%w/v、4.2%w/v、4.3%w/v、4.4%w/v、4.5%w/v、4.6%w/v、4.7%w/v、4.8%w/v、4.9%w/v、5.0%w/v、5.1%w/v、5.2%w/v、5.3%w/v、5.4%w/v、5.5%w/v、5.6%w/v、5.7%w/v、5.8%w/v、5.9%w/v、
6.0%w/v、6.1%w/v、6.2%w/v、6.3%w/v、6.4%w/v、6.5%w/v、6.6%w/v、6.7%w/v、6.8%w/v、6.9%w/v、7.0%w/v、7.1%w/v、7.2%w/v、7.3%w/v、7.4%w/v、7.5%w/v、7.6%w/v、7.7%w/v、7.8%w/v、7.9%w/v、8.0%w/v、8.1%w/v、8.2%w/v、8.3%w/v或8.4%w/v。
在一实施方案中,可以与艾司氯胺酮形成药学上可接受盐的酸包括盐酸、硫酸、磷酸、马来酸、乙酸、己二酸、藻酸、枸橼酸、天冬氨酸、苯甲酸、苯磺酸、硫酸氢、丁酸、樟脑酸、樟脑磺酸、双葡糖酸、延胡索酸、甘油磷酸、硬脂酸、庚酸、己酸、氢溴酸(即HBr)、氢碘酸(即HI)、乳酸、甲磺酸、烟酸、草酸、双羟基萘酸、果胶酸、过硫酸、3-苯基丙酸、苦味酸、新戊酸、丙酸、琥珀酸、酒石酸、硫氰酸、谷氨酸、对甲苯磺酸、十一酸和扁桃酸。
在一实施方案中,艾司氯胺酮药学上可接受的盐,包括盐酸盐、硫酸盐、磷酸盐、马来酸盐、乙酸盐、己二酸盐、藻酸盐、枸橼酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、双葡糖酸盐、延胡索酸盐、甘油磷酸盐、硬脂酸盐、庚酸盐、己酸盐、氢溴酸(即HBr)盐、氢碘酸(即HI)盐、乳酸盐、甲磺酸盐、烟酸盐、草酸盐、双羟基萘酸盐、果胶酸盐、过硫酸盐、3-苯基丙酸盐、苦味酸盐、新戊酸盐、丙酸盐、琥珀酸盐、酒石酸盐、硫氰酸盐、谷氨酸盐、碳酸氢盐、对甲苯磺酸盐、十一酸盐和扁桃酸盐。
在一实施方案中,所述液体制剂中胆酸或其衍生物的浓度为0.001%w/v~0.015%w/v;在另一实施方案中,所述液体制剂中胆酸或其衍生物的浓度为0.001%w/v~0.013%w/v;在又一实施方案中,所述液体制剂中胆酸或其衍生物的浓度为0.001%w/v~0.012%w/v;还在一实施例中,所述液体制剂中胆酸或其衍生物的浓度为0.001%w/v、0.002%w/v、0.003%w/v、0.004%w/v、0.005%w/v、0.006%w/v、0.007%w/v、0.008%w/v、0.009%w/v或0.010%w/v。
在一实施方案中,所述胆酸或其衍生物为牛磺酸钠、牛磺脱氧胆酸钠、脱氧胆酸钠、胆酸钠、甘氨脱氧胆酸钠中的一种,或其组合。
在一实施方案中,所述液体制剂的pH为2.5~5.7;在另一实施方案中,所述液体制剂的pH范围为3.0~5.7;在又一实施方案中,所述艾司氯胺酮液体制剂的pH范围为4.0~5.7;在又一实施方案中,所述液体制剂的pH为5.0~5.5;还在一实施方案中,所述液体制剂的pH为2.5、2.6、2.7、2.8、2.9、3.0、3.1、3.2、3.3、3.4、3.5、3.6、3.7、3.8、3.9、4.0、4.1、4.2、4.3、4.4、4.5、4.6、4.7、4.8、4.9、5.0、5.1、5.2、5.3、5.4、5.5、5.6或5.7。
在一实施方案中,所述液体制剂包括浓度为0.5%w/v~8.5%w/v的艾司氯胺酮或其药学上可接受的盐、浓度为0.001%w/v~0.015%w/v胆酸或其衍生物和水,所述液体制剂的pH值范围为2.5~5.7。
在本申请的某一些实施方案中,所述艾司氯胺酮液体制剂还可以包含增粘剂。
在一实施方案中,所述增粘剂为黄原胶、羧甲基纤维素钠、羟丙基甲基纤维素、甲基纤维素、乙基纤维素、羟乙基纤维素、聚乙烯醇、卡波姆或聚乙烯吡咯烷酮,或其组合。
在某一实施方案中,所述增粘剂羧甲基纤维素钠选自羧甲基纤维素钠800、羧甲基纤维素钠4000、羧甲基纤维素钠8000、羧甲基纤维素钠12000中的一种或多种。
在一实施方案中,所述增粘剂的组合非限制性地包括:羧甲基纤维素钠4000与羧甲基纤维素钠12000、羧甲基纤维素钠800与羧甲基纤维素钠12000、羧甲基纤维素钠4000与黄原胶、羧甲基纤维素钠4000与羟丙甲纤维素、羧甲基纤维素钠4000与黄原胶组合物、
羧甲基纤维素钠4000与羟丙甲纤维素组合物,两种增粘剂组合的配比(w/w)范围为1∶5~5∶1。
在另一实施方案中,所述增粘剂的浓度为0.01%w/v~3.5%w/v;在另一实施方案中,所述增粘剂的浓度为0.05~3.0%w/v;在又一实施方案中,所述增粘剂的浓度为0.05~2.0%w/v;还在一实施方案中,所述增粘剂的浓度为0.01%w/v、0.05%w/v、0.1%w/v、0.15%w/v、0.2%w/v、0.25%w/v、0.30%w/v、0.35%w/v、0.40%w/v、0.45%w/v、0.50%w/v、0.55%w/v、0.60%w/v、0.65%w/v、0.70%w/v、0.75%w/v、0.80%w/v、0.85%w/v、0.90%w/v、0.95%w/v或1.00%w/v。
在另一实施方案中,所述艾司氯胺酮液体制剂还包含下列辅料中一种或多种:缓冲剂、矫味剂、抗氧化剂、渗透压调节剂和防腐剂。在另一实施方案中,所述艾司氯胺酮液体制剂还包含下列辅料中一种或多种:缓冲剂、矫味剂、抗氧化剂、渗透压调节剂、防腐剂和促渗剂。
在本申请所述艾司氯胺酮液体制剂的一实施方案中,所述缓冲剂可以为枸橼酸、磷酸二氢钠、磷酸氢二钠、乙酸、硼酸、硼酸钠、琥珀酸、酒石酸、乳酸、富马酸、磷酸三钠(磷酸三钠十二水合物或TSP)、苯甲酸钠、苯甲酸、氢氧化钠、氢氧化钾、碱金属碳酸盐、碳酸钠、咪唑、焦磷酸盐、葡糖酸钠、乳酸钠、磷酸、硼酸盐、碳酸氢盐、Tris-HCl、枸橼酸盐,或其组合。
本申请所述缓冲剂能够维持液体制剂pH在一个稳定的范围内,有利于提高溶液制剂的稳定性。所述缓冲剂的浓度为0.1~0.3%w/v;在一实施方案中,所述缓冲剂的浓度为0.1~0.2%w/v;在另一实施方案中,所述缓冲剂的浓度为0.1~0.15%w/v;在另一实施方案中,所述缓冲剂的浓度为0.1%w/v、0.11%w/v、0.12%w/v、0.13%w/v、0.14%w/v、0.15%w/v、0.16%w/v、0.17%w/v、0.18%w/v、0.19%w/v、0.2%w/v、0.21%w/v、0.22%w/v、0.23%w/v、0.24%w/v、0.25%w/v、0.26%w/v、0.27%w/v、0.28%w/v、0.29%w/v、0.3%w/v。
在另一实施方案中,本申请提供一种艾司氯胺酮液体制剂,该制剂还包括矫味剂。矫味剂能够掩蔽药物组合物可能具有的异味而改善其适口性,有利于提高患者的依从性。在一实施方案中,所述液体制剂的矫味剂为糖精钠、果糖、三氯蔗糖、甜菊素、薄荷脑、麦芽糖醇、木糖醇、阿斯巴甜、甜蜜素、糖精、新橙皮苷、奇异果甜蛋白、甜叶菊或安赛蜜,或其组合。
在一实施方案中,本申请提供的一种艾司氯胺酮液体制剂,所述矫味剂的浓度为0.01~0.05%w/v;在另一实施方案中,所述矫味剂的浓度为0.01~0.03%w/v;在另一实施方案中,所述矫味剂的浓度为0.01%w/v、0.02%w/v、0.03%w/v、0.04%w/v、0.05%w/v。
在另一实施方案中,本申请提供一种艾司氯胺酮液体制剂,该制剂还包括抗氧化剂。抗氧化剂能够有效阻止或延缓制剂的氧化,可以防止药物及其制剂的氧化变质,以及由氧化所导致的变色、产生沉淀等问题,增加药物稳定性。在一实施方案中,所述液体制剂的抗氧化剂为乙二胺四乙酸(EDTA,依地酸)或其钠盐或钙盐、维生素E、没食子酸盐、亚硫酸氢钠、抗坏血酸或其盐、丁羟茴醚或生育酚,或其组合。
在一实施方案中,本申请提供的一种艾司氯胺酮液体制剂,所述抗氧化剂的浓度为0.010~0.020%w/v;在另一实施方案中,所述抗氧化剂的浓度为0.010~0.015%w/v;在另一实施例中,所述液体制剂的抗氧化剂的浓度为0.010%w/v、0.011%w/v、0.012%w/v、0.013%w/v、0.014%w/v、0.015%w/v、0.016%w/v、0.017%w/v、0.018%w/v、0.019%w/v、0.02%w/v。
在一实施方案中,所述艾司氯胺酮液体制剂还包含防腐剂。在一些实施方案中,所述防腐剂选自对羟基苯甲酸甲酯、对羟基苯甲酸乙酯、对羟基苯甲酸丙酯、对羟基苯甲酸丁酯、对羟基苯甲酸甲酯钠、对羟基苯甲酸乙酯钠、对羟基苯甲酸丙酯钠、对羟基苯甲酸丁酯钠、山梨酸、山梨酸钾、山梨酸钠、苯甲酸、苯甲酸钠、苯甲醇、苯扎溴铵、苯扎氯铵、三氯叔丁醇、间苯二酚和乙二胺四乙酸钠(依地酸钠)中的一种或者多种。
在一实施方案中,所述艾司氯胺酮液体制剂还包含渗透压调节剂。在一些实施方案中,所述粘渗透压调节剂选自氯化钠、硝酸钾、硼酸和葡萄糖中的一种或者多种;优选地,为氯化钠。
在一实施方案中,所述艾司氯胺酮液体制剂还包含促渗剂。在一些实施方案中,所述促渗剂选自脱氧胆酸钠、吐温80、羟丙甲纤维素、十二烷基硫酸钠、多库酯钠、聚山梨醇酯、十四烷基麦芽糖苷、甘胆酸钠、牛磺熊去氧胆酸(TUDCA)、卵磷脂、羟丙基-β-环糊精、磺丁基-β-环糊基钠或PEG400中的一种或多种。
本申请第二方面具体提供了一种艾司氯胺酮液体制剂,其包括盐酸艾司氯胺酮,胆酸或其衍生物,增粘剂和水;所述液体制剂的pH范围为4.5~5.5,所述液体制剂中艾司氯胺酮的含量为0.7%w/v~8.4%w/v。
在一实施方案中,所述增粘剂的种类以及它们与胆酸或其衍生物的含量如前所述。
在另一实施方案中,所述增粘剂为羧甲基纤维素钠4000、羧甲基纤维素钠8000、羧甲基纤维素钠12000、黄原胶和羟丙甲纤维素中的一种,或其组合。
在本申请所提供的艾司氯胺酮液体制剂中,同时使用胆酸或其衍生物和增粘剂可以使处方中API体外释放更充分,能够更好的促进艾司氯胺酮通过口腔粘膜的渗透性,协同提高艾司氯胺酮溶液制剂的生物利用度。
在本申请所述艾司氯胺酮液体制剂的一实施方案中,所述增粘剂为羧甲基纤维素钠4000、羧甲基纤维素钠8000、羧甲基纤维素钠12000、黄原胶和羟丙甲纤维素中的一种,或其组合。在一实施方案中,所述增粘剂为黄原胶;在另一实施方案中,所述增粘剂羟丙甲纤维素;在另一实施方案中,所述增粘剂为羧甲基纤维素钠4000和羧甲基纤维素钠12000;在另一实施方案中,所述增粘剂为羧甲基纤维素钠4000及羟丙甲纤维素。
本申请第三方面具体提供了一种艾司氯胺酮液体制剂,其包括盐酸艾司氯胺酮,胆酸或其衍生物,增粘剂,缓冲剂和水;所述液体制剂的pH范围为4.5~5.5,所述液体制剂中艾司氯胺酮的含量为0.7%w/v~8.4%w/v。
在一实施方案中,所述增粘剂和缓冲剂的种类以及它们与胆酸或其衍生物的含量如前所述。
在一实施方案中,本申请提供的一种艾司氯胺酮液体制剂,所述缓冲剂为枸橼酸。
本申请第四方面具体提供了一种艾司氯胺酮液体制剂,其包括盐酸艾司氯胺酮,胆酸或其衍生物,增粘剂,抗氧化剂,矫味剂,缓冲剂和水;所述液体制剂的pH范围为4.5~5.5,所述液体制剂中艾司氯胺酮的含量为0.7%w/v~8.4%w/v。
在一实施方案中,所述增粘剂、抗氧化剂、矫味剂和缓冲剂的种类以及它们与胆酸或其衍生物的含量如前所述。
在另一实施方案中,所述增粘剂为羧甲基纤维素钠4000、羧甲基纤维素钠8000、羧甲基纤维素钠12000、黄原胶和羟丙甲纤维素中的一种,或其组合。
在本申请所述艾司氯胺酮液体制剂的一实施方案中,所述抗氧化剂为依地酸二钠,所述矫味剂为糖精钠或麦芽糖醇,所述增粘剂为羧甲基纤维素钠4000、羧甲基纤维素钠8000、
羧甲基纤维素钠12000、黄原胶和羟丙甲纤维素中的一种,或其组合。在一实施方案中,所述抗氧化剂为依地酸二钠,所述矫味剂为糖精钠或麦芽糖醇,所述增粘剂为黄原胶;在另一实施方案中,所述抗氧化剂为依地酸二钠,所述矫味剂为糖精钠或麦芽糖醇,所述增粘剂羟丙甲纤维素;在另一实施方案中,所述增粘剂为羧甲基纤维素钠4000和羧甲基纤维素钠12000;在另一实施方案中,所述抗氧化剂为依地酸二钠,所述矫味剂为糖精钠或麦芽糖醇,所述增粘剂为羧甲基纤维素钠4000及羟丙甲纤维素。
在一实施方案中,本申请提供的一种艾司氯胺酮液体制剂,所述缓冲剂为枸橼酸。
本申请第五方面提供了一种艾司氯胺酮液体制剂在制备预防、缓解或治疗抑郁症药物中的用途,所述药物可用于治疗重性抑郁症、单相抑郁症、难治性抑郁症、顽固性抑郁症、焦虑性抑郁症、双相抑郁症。
在一实施方案中,本申请提供的一种艾司氯胺酮液体制剂在制备预防、缓解或治疗抑郁症药物中的用途,所述液体制剂被施用于患者的口腔颊膜。
本申请第六方面提供了一种使用艾司氯胺酮液体制剂预防、缓解或治疗患者抑郁症的方法,包括向患者施用治疗有效量的艾司氯胺酮液体制剂。
在一实施方案中,本申请提供一种使用艾司氯胺酮液体制剂预防、缓解或治疗患者抑郁症的方法,所述抑郁症为重性抑郁症、单相抑郁症、难治性抑郁症、顽固性抑郁症、焦虑性抑郁症、双相抑郁症。
在一实施方案中,本申请提供的一种使用艾司氯胺酮液体制剂预防、缓解或治疗患者抑郁症的方法,所述液体制剂被施用于患者的口腔颊膜。
本申请第七方面提供了一种艾司氯胺酮液体制剂用于预防、缓解或治疗患者的抑郁症,所述抑郁症为重性抑郁症、单相抑郁症、难治性抑郁症、顽固性抑郁症、焦虑性抑郁症、双相抑郁症。
在一实施方案中,一种艾司氯胺酮液体制剂用于预防、缓解或治疗患者的抑郁症,所述液体制剂被施用于哺乳动物的口腔颊膜。
第八方面,本申请提供了前述艾司氯胺酮液体制剂的制备方法,包括以下制备步骤:
a)称取处方量盐酸艾司氯胺酮、加入纯化水,充分搅拌溶解后,再依次加入处方量的任选的抗氧化剂如依地酸二钠、任选的缓冲剂如枸橼酸、任选的调味剂如糖精钠充分搅拌溶解;
b)加入处方中胆酸或其衍生物、任选的增粘剂,充分搅拌溶解
c)用氢氧化钠调节pH至相应值;
d)将溶液转移至特定的容量瓶中,补水定容至刻度;
e)定容后溶液过0.45μm的滤膜,滤液灌装至预灌封注射器内,即得制剂成品。
本申请的有益效果如下:
(1)本申请所提供的艾司氯胺酮液体制剂吸收迅速,在4~7min内快速起效,其AUC0-240min可大于7000ng/mL。该艾司氯胺酮液体制剂的生物利用度高,同时不会出现析晶现象,稳定性高,既能满足规模化加工生产的需要,又降低了患者的用药风险。
(2)本申请所提供艾司氯胺酮液体制剂通过使用胆酸或其衍生物,可有效提高活性物质的生物利用度;通过进一步加入增粘剂,增加液体制剂在口腔黏膜的滞留时间,可进一步提高艾司氯胺酮吸收量,协同提高艾司氯胺酮液体制剂的生物利用度。
(3)本中请所提供的艾司氯胺酮液体制剂给药方式简便易行,患者依从性大大增加,由于给药剂量小、体积小,可大大减少对粘膜的刺激,同时降低滥用风险。
除非另有说明,否则所有成分的浓度均以重量/体积%(%w/v)为单位。如通常所理解的,%w/v值是指配制品中特定组分或成分的量。众所周知,能以不同单位表示等效浓度。例如,0.1%w/v的浓度也可以表示为1mg/ml溶液。
本申请公开了经口腔黏膜给药的艾司氯胺酮液体制剂及其用途,本领域技术人员可以借鉴本文内容,适当改进工艺参数实现。特别需要指出的是,所有类似的替换和改动对本领域技术人员来说是显而易见的,它们都被视为包括在本申请。本申请的方法及应用已经通过较佳实施例进行了描述,相关人员明显能在不脱离本申请内容、精神和范围内对本文所述的方法和应用进行改动或适当变更与组合,来实现和应用本申请技术。本申请中所用试剂或仪器均可由市场购得。
仪器:
S220-KpH计、SHJ-6AB磁力搅拌水浴锅、ME204T/02电子天平、ME3002T/02电子天平、DSC-800T全自动透皮扩散仪、戴安U300高效液相色谱仪。
实施例1
处方:
制备方法,包括以下制备步骤:
a)称取处方量盐酸艾司氯胺酮、加入总重量之80%的纯化水,充分搅拌溶解后,再依次加入处方量的依地酸二钠、枸橼酸、糖精钠充分搅拌溶解;
b)加入不同处方中相对应的脱氧胆酸钠、羧甲基纤维素钠4000,充分搅拌溶解;
c)用氢氧化钠调节pH至4.5~5.5;
d)将溶液转移至特定的容量瓶中,补水定容至刻度10ml;
e)定容后溶液过0.45μm的滤膜,滤液灌装至1ml预灌封注射器内(购于山东淄博民康药业包装有限公司),1ml/支即得制剂成品。
实施例2
处方:
制备方法参照实施例1。
实施例3
处方:
制备方法参照实施例1。
实施例4
处方:
制备方法参照实施例1。
实施例5
处方:
制备方法参照实施例1
实施例6
处方
制备方法参照实施例1。
实施例7
处方
制备方法参照实施例1。
实施例8
处方
制备方法参照实施例1。
实施例9
处方
制备方法参照实施例1。
实施例10
处方
制备方法参照实施例1。
实施例11本申请的盐酸艾司氯胺酮口颊液的稳定性测试
盐酸艾司氯胺酮口颊液在制备和储存过程中易产生如下2个杂质:
上述2个杂质均可通过商业渠道购买获得。
本发明人对实施例1-10,制备得到的样品在25℃±2℃和RH60%±5%的环境中进行了长期稳定性实验。
1.氯胺酮含量检测的方法:
照高效液相色谱法(通则0512)测定
色谱条件:用十八烷基硅烷键合硅胶为填充剂;取0.95g己烷磺酸钠溶于1L的乙腈和水的混合溶液(乙腈∶水=25∶75),再加4ml冰醋酸混匀为流动相;检测波长为215nm;流速为每分钟1.0ml;柱温为30℃;进样体积20μl。
2.氯胺酮有关物质检测的方法:
照高效液相色谱法(通则0512)测定。
色谱条件:用十八烷基硅烷键合硅胶为填充剂(Agela MP C18 4.6×150mm,5μm或柱效相当);以25mM磷酸盐缓冲液(取磷酸二氢钾3.4g,加水1000ml使溶解,用磷酸
调pH值至2.5)为流动相A,以乙腈为流动相B。按下表进行梯度洗脱,检测波长为215nm;柱温为30℃;流速为每分钟1.0ml;进样体积20μl。
表4:实施例1-10的长期试验结果
通过表4长期试验的结果可见,本申请所得的药物制剂在室温下放置长达6个月,盐酸艾司氯胺酮口颊液的总杂均不超过0.5%,最大单杂也均不超过0.2%,其质量仍符合质量标准,质量稳定。
实施例12本申请的盐酸艾司氯胺酮口颊液的体外渗透试验
本研究采用Franz扩散池法,选用磷脂仿生屏障(仿生膜)模拟口腔黏膜,扩散介质采用PBS缓冲液;待扩散池达37℃后,在仿生膜上方先加入0.5ml人工唾液,然后加入0.2ml处方溶液,取样时间点为10min、20min、30min、45min、60min、180min、240min、300min、360min,采用waste模式,每个时间点取1ml样品,液相检测含量。
表5:实施例1-10的体外渗透结果
对比例1盐酸艾司氯胺酮鼻喷雾剂(参照专利CN 111297803 A制备)
处方组分
产品规格:每喷含艾司氯胺酮7mg
制备方法,包括以下制备步骤:
a)称取处方量盐酸右氯胺酮、加入一定量的纯化水,充分搅拌溶解后,再依次加入处方量的依地酸二钠、枸橼酸充分搅拌溶解;
b)用氢氧化钠调节pH至4.5;
c)将溶液转移至特定的容量瓶中,补水定容至刻度;
d)定容后溶液过0.45μm的滤膜,滤液按需求灌装。
对比例2盐酸艾司氯胺酮口溶膜1(参照专利CN 111447920 A制备)
处方组分
制备方法,包括以下制备步骤:
a)称取处方量盐酸艾司氯胺酮、加入一定量的纯化水,充分搅拌溶解后,再依次加入处方量的羟丙甲纤维素、羟丙基纤维、PEG400素充分搅拌溶解;
b)加入不同处方中相对应的卡波姆974P、羟丙甲-β-环糊精,充分搅拌溶解;
c)静置消泡后,涂布,烘干,用模具敲成所需的规格;
对比例3盐酸艾司氯胺酮口溶膜2(参照专利CN 111447920 A制备)
处方组分
制备方法参照对比例2,使用脱氧胆酸钠替换卡波姆974P和羟丙甲-β-环糊精。
试验例1体内药代实验
1、实验分组
表6:动物分组情况
2、实验方案
本实验采用新西兰白兔,2.5kg~3.0kg,每组6只,雌雄各半。对比例1采用单侧经鼻给药,给药量为0.05ml/只(1喷);实施例1采用单侧口颊液给药,给药量为0.125ml/只;对比例2、对比例3采用单侧口颊膜给药,给药量为1片/只(7mg);对比例2、对比例3采用舌下给药,给药量为1片/只(7mg)。采血前将家兔置于兔固定盒中,采血方式为耳缘静脉采血,采集血液时间点为:0min(给药前),2min、5min、10min、15min、30min、60min、120min、240min。每个时间点取约1mL全血至含肝素钠的采血管中,4000rpm离心10min,离心得血浆样品,取上清液分装3份至0.5ml EP管中(前2份装1501l,多余血浆装于第3个冻存管中作为备份样),血浆样品分装处理后置于≤-80℃保存样本。
3、实验结果
表7:六组样品不同给药途径兔子药代实验结果
由表7和图1可知,在盐酸艾司氯胺酮兔子的不同给药途径组中,与经鼻给药组(对比例1)相比,口颊液的口颊给药组(实施例1)的Tmax与其相近,大约在4~7min内,而口溶膜组(对比例2、对比例3)的Tmax在20~60min的范围内,说明本申请的盐酸艾司氯胺口颊液的颊膜给药与其鼻喷的经鼻给药的起效时间类似,而口溶膜的起效时间慢。
由平均Cmax的数据可知,与经鼻给药组(对比例1)相比,口颊液的口颊给药组(实施例1)的Cmax明显增大,提高约1倍;而口溶膜组(对比例2、对比例3)的Cmax低于经鼻给药组,降低了约1~2倍,说明了本申请盐酸艾司氯胺酮口颊液颊膜给药的药物吸收较经鼻给药更高。
由表7和图2可知,与经鼻给药组(对比例1)相比,口颊液的口颊给药组(实施例1)的AUC0-240min明显增大(p<0.05),提高约1倍;而口溶膜组(对比例2、对比例3)的AUC0-240min与经鼻给药组相差不大(p>0.05),这个结果与Cmax的结果一致,进一步说明了本申请的盐酸艾司氯胺酮口颊液颊膜给药的体内药物吸收高于经鼻给药、口溶膜给药。
综上所述,盐酸艾司氯胺酮口颊液颊膜给药的体内药物吸收显著高于经鼻给药、口溶膜给药,提高约1倍,且这两种途径的起效时间相近,约4~7min,起效速度快于口溶膜给药。
本申请技术方案也可用于R-氯胺酮、氯胺酮或药学上可接受的盐的口颊液颊膜给药系统,通过调整或改变活性成分含量、可用于药学上的辅料种类、用量等手段达到本发明目的。
虽然本申请所揭露的实施方式如上,但所述的内容仅为便于理解本申请而采用的实施方式,并非用以限定本申请。任何本申请所属领域内的技术人员,在不脱离本申请所揭露的精神和范围的前提下,可以在实施的形式及细节上进行任何的修改与变化,但本申请的保护范围,仍须以所附的权利要求书所界定的范围为准。
Claims (23)
- 一种艾司氯胺酮液体制剂,该液体制剂经口腔黏膜给药;其含有浓度为0.5%w/v~8.5%w/v的艾司氯胺酮或其药学上可接受的盐,胆酸或其衍生物,和水;所述液体制剂的pH值范围为2.5~5.7。
- 根据权利要求1所述的艾司氯胺酮液体制剂,其中,所述液体制剂包括浓度为0.5%w/v~8.5%w/v的艾司氯胺酮或其药学上可接受的盐,浓度为0.001%w/v~0.015%w/v胆酸或其衍生物,和水;所述液体制剂的pH值范围为2.5~5.7。
- 根据权利要求2所述的艾司氯胺酮液体制剂,其中,在所述液体制剂中艾司氯胺酮的浓度为0.7%w/v~8.4%w/v;优选地,为1.4%w/v~6.3%w/v;更优选地,为1.4%w/v~5.6%w/v。
- 根据权利要求2所述的艾司氯胺酮液体制剂,其中,在所述液体制剂中胆酸或其衍生物选自牛磺酸钠、牛磺脱氧胆酸钠、脱氧胆酸钠、胆酸钠、甘氨脱氧胆酸钠中一种,或其组合,优选脱氧胆酸钠或牛磺酸钠。
- 根据权利要求2所述的艾司氯胺酮液体制剂,其中,在所述液体制剂中胆酸或其衍生物的浓度为0.001%w/v~0.012%w/v,优选地,为0.001%w/v~0.010%w/v;更优选地,为0.003%w/v~0.010w/v。
- 根据权利要求2所述的艾司氯胺酮液体制剂,其中,所述液体制剂的pH范围为3.0~5.7;优选地,为4.0~5.7;更优选地,为4.5~5.5;特别优选地,为5.0~5.5。
- 根据权利要求1至6中任一项所述的艾司氯胺酮液体制剂,所述的液体制剂还包含增粘剂。
- 根据权利要求7所述的艾司氯胺酮液体制剂,其中,所述增粘剂为黄原胶、羧甲基纤维素钠、羟丙基甲基纤维素、甲基纤维素、乙基纤维素、羟乙基纤维素、聚乙烯醇、卡波姆和聚乙烯吡咯烷酮中一种,或其组合。
- 根据权利要求8所述的艾司氯胺酮液体制剂,其中,所述羧甲基纤维素钠为羧甲基纤维素钠800、羧甲基纤维素钠4000、羧甲基纤维素钠8000或羧甲基纤维素钠12000,或其组合。
- 根据权利要求7所述的艾司氯胺酮液体制剂,其中,所述增粘剂的浓度为0.01%w/v~3.5%w/v。
- 根据权利要求1至10中任一项所述的艾司氯胺酮液体制剂,所述的液体制剂还包含下列辅料中一种或多种:缓冲剂、矫味剂、抗氧化剂、渗透压调节剂和防腐剂;或者所述的液体制剂还包含下列辅料中一种或多种:缓冲剂、矫味剂、抗氧化剂、渗透压调节剂、防腐剂和促渗剂。
- 根据权利要求11所述的艾司氯胺酮液体制剂,其中,所述的液体制剂还包含缓冲剂、矫味剂和抗氧化剂。
- 根据权利要求11或12所述的艾司氯胺酮液体制剂,其中,所述的缓冲剂为枸橼酸、枸橼酸钠、乙酸、乙酸钠、乳酸、磷酸二氢钠、磷酸氢二钠、琥珀酸、硼酸、硼酸钠、酒石酸和富马酸中的一种,或其组合。
- 根据权利要求11或12所述的艾司氯胺酮液体制剂,其中,所述的矫味剂为糖精钠、果糖、三氯蔗糖、甜菊素、薄荷脑、麦芽糖醇、木糖醇、阿斯巴甜、甜蜜素、糖精、新橙皮苷、奇异果甜蛋白、甜叶菊和安赛蜜中一种,或其组合。
- 根据权利要求11或12所述的艾司氯胺酮液体制剂,其中,所述的抗氧化剂为依地酸二钠、维生素E、没食子酸盐、亚硫酸氢钠、抗坏血酸或其盐、丁羟茴醚和生育酚中一种,或其组合物。
- 权利要求1~15中任一项所述艾司氯胺酮液体制剂在制备预防、缓解或治疗抑郁症药物中的用途。
- 根据权利要求16所述的用途,其中,所述抑郁症为重性抑郁症、单相抑郁症、难治性抑郁症、顽固性抑郁症、焦虑性抑郁症、或双相抑郁症。
- 根据权利要求16或17所述的用途,其中,所述液体制剂被施用于患者的口腔颊膜。
- 一种使用权利要求1~15中任一项所述艾司氯胺酮液体制剂预防、缓解或治疗抑郁症患者的方法,包括向患者口腔颊膜施用治疗有效量的所述艾司氯胺酮液体制剂。
- 根据权利要求19所述的方法,其中,所述抑郁症为重性抑郁症、单相抑郁症、难治性抑郁症、顽固性抑郁症、焦虑性抑郁症或双相抑郁症。
- 根据权利要求1~15中任一项所述艾司氯胺酮液体制剂用于预防、缓解或治疗患者的抑郁症。
- 根据权利要求21所述艾司氯胺酮液体制剂用于预防、缓解或治疗患者的抑郁症,其中,所述抑郁症为重性抑郁症、单相抑郁症、难治性抑郁症、顽固性抑郁症、焦虑性抑郁症或双相抑郁症。
- 根据权利要求21或22所述艾司氯胺酮液体制剂用于预防、缓解或治疗患者的抑郁症,其中,所述液体制剂被施用于患者的口腔颊膜。
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Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1996025925A1 (en) * | 1995-02-24 | 1996-08-29 | Weg Stuart L | Nasal and ocular administration of ketamine to manage pain and for detoxification |
US20140079740A1 (en) * | 2012-08-02 | 2014-03-20 | ClinPharm Support GmbH | Oral transmucosal adminstration forms of s-ketamine |
CN105073096A (zh) * | 2013-03-15 | 2015-11-18 | 詹森药业有限公司 | S-盐酸氯胺酮的药物组合物 |
CN106963941A (zh) * | 2017-03-14 | 2017-07-21 | 沈阳大学 | 一种具有肠道粘液穿透能力的胰岛素口服剂及其制备方法 |
EP3932393A1 (en) * | 2020-07-03 | 2022-01-05 | Alkaloid AD Skopje | Pharmaceutical formulation |
-
2023
- 2023-04-19 WO PCT/CN2023/089327 patent/WO2023207729A1/zh unknown
- 2023-04-19 CN CN202310427065.3A patent/CN116942648A/zh active Pending
- 2023-04-25 TW TW112115317A patent/TW202341964A/zh unknown
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1996025925A1 (en) * | 1995-02-24 | 1996-08-29 | Weg Stuart L | Nasal and ocular administration of ketamine to manage pain and for detoxification |
US20140079740A1 (en) * | 2012-08-02 | 2014-03-20 | ClinPharm Support GmbH | Oral transmucosal adminstration forms of s-ketamine |
CN105073096A (zh) * | 2013-03-15 | 2015-11-18 | 詹森药业有限公司 | S-盐酸氯胺酮的药物组合物 |
CN106963941A (zh) * | 2017-03-14 | 2017-07-21 | 沈阳大学 | 一种具有肠道粘液穿透能力的胰岛素口服剂及其制备方法 |
EP3932393A1 (en) * | 2020-07-03 | 2022-01-05 | Alkaloid AD Skopje | Pharmaceutical formulation |
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