CN116133643A - Liquid composition - Google Patents
Liquid composition Download PDFInfo
- Publication number
- CN116133643A CN116133643A CN202180059438.5A CN202180059438A CN116133643A CN 116133643 A CN116133643 A CN 116133643A CN 202180059438 A CN202180059438 A CN 202180059438A CN 116133643 A CN116133643 A CN 116133643A
- Authority
- CN
- China
- Prior art keywords
- liquid composition
- amount
- active ingredient
- liquid
- hydrate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 139
- 239000007788 liquid Substances 0.000 title claims abstract description 103
- 235000019658 bitter taste Nutrition 0.000 claims abstract description 45
- BRUQQQPBMZOVGD-XFKAJCMBSA-N Oxycodone Chemical compound O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(OC)C2=C5[C@@]13CCN4C BRUQQQPBMZOVGD-XFKAJCMBSA-N 0.000 claims abstract description 42
- 229960002085 oxycodone Drugs 0.000 claims abstract description 42
- 239000004480 active ingredient Substances 0.000 claims abstract description 39
- 239000000654 additive Substances 0.000 claims abstract description 29
- 230000000996 additive effect Effects 0.000 claims abstract description 16
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 36
- 239000012669 liquid formulation Substances 0.000 claims description 35
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims description 32
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 22
- NUVBSKCKDOMJSU-UHFFFAOYSA-N ethylparaben Chemical compound CCOC(=O)C1=CC=C(O)C=C1 NUVBSKCKDOMJSU-UHFFFAOYSA-N 0.000 claims description 20
- 238000000034 method Methods 0.000 claims description 20
- WBZFUFAFFUEMEI-UHFFFAOYSA-M Acesulfame k Chemical compound [K+].CC1=CC(=O)[N-]S(=O)(=O)O1 WBZFUFAFFUEMEI-UHFFFAOYSA-M 0.000 claims description 17
- 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 17
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 claims description 17
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims description 17
- 229960002920 sorbitol Drugs 0.000 claims description 17
- 239000000811 xylitol Substances 0.000 claims description 17
- 235000010447 xylitol Nutrition 0.000 claims description 17
- 229960002675 xylitol Drugs 0.000 claims description 17
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims description 17
- 235000010358 acesulfame potassium Nutrition 0.000 claims description 16
- 229960004998 acesulfame potassium Drugs 0.000 claims description 16
- 239000000619 acesulfame-K Substances 0.000 claims description 16
- 229960002989 glutamic acid Drugs 0.000 claims description 15
- 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 14
- 150000003839 salts Chemical class 0.000 claims description 13
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 claims description 13
- 235000010234 sodium benzoate Nutrition 0.000 claims description 13
- 239000004299 sodium benzoate Substances 0.000 claims description 13
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 11
- 239000011780 sodium chloride Substances 0.000 claims description 11
- 229940127557 pharmaceutical product Drugs 0.000 claims description 10
- 238000013112 stability test Methods 0.000 claims description 9
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 230000006641 stabilisation Effects 0.000 claims description 6
- 238000011105 stabilization Methods 0.000 claims description 6
- 235000010226 sodium ethyl p-hydroxybenzoate Nutrition 0.000 claims description 4
- 239000004402 sodium ethyl p-hydroxybenzoate Substances 0.000 claims description 4
- 230000000087 stabilizing effect Effects 0.000 claims description 2
- YASYEJJMZJALEJ-UHFFFAOYSA-N Citric acid monohydrate Chemical compound O.OC(=O)CC(O)(C(O)=O)CC(O)=O YASYEJJMZJALEJ-UHFFFAOYSA-N 0.000 claims 1
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 10
- 230000000873 masking effect Effects 0.000 abstract description 10
- 235000019596 Masking bitterness Nutrition 0.000 abstract description 4
- 239000003795 chemical substances by application Substances 0.000 abstract description 2
- 238000012360 testing method Methods 0.000 description 43
- 238000009472 formulation Methods 0.000 description 25
- 235000019640 taste Nutrition 0.000 description 24
- BQNSLJQRJAJITR-UHFFFAOYSA-N 1,1,2-trichloro-1,2-difluoroethane Chemical compound FC(Cl)C(F)(Cl)Cl BQNSLJQRJAJITR-UHFFFAOYSA-N 0.000 description 22
- 229960003617 oxycodone hydrochloride Drugs 0.000 description 22
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 14
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 14
- 238000011156 evaluation Methods 0.000 description 13
- 239000000243 solution Substances 0.000 description 9
- 238000003860 storage Methods 0.000 description 9
- 239000012528 membrane Substances 0.000 description 8
- JNJFONBBNLVENC-UHFFFAOYSA-N 1h-imidazole;trifluoromethanesulfonic acid Chemical compound C1=CNC=N1.OS(=O)(=O)C(F)(F)F JNJFONBBNLVENC-UHFFFAOYSA-N 0.000 description 7
- 239000008213 purified water Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 238000011990 functional testing Methods 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- AKYHKWQPZHDOBW-UHFFFAOYSA-N (5-ethenyl-1-azabicyclo[2.2.2]octan-7-yl)-(6-methoxyquinolin-4-yl)methanol Chemical compound OS(O)(=O)=O.C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 AKYHKWQPZHDOBW-UHFFFAOYSA-N 0.000 description 5
- 239000001576 FEMA 2977 Substances 0.000 description 5
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 229960003110 quinine sulfate Drugs 0.000 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 description 4
- 230000008859 change Effects 0.000 description 4
- 235000010228 ethyl p-hydroxybenzoate Nutrition 0.000 description 4
- 239000004403 ethyl p-hydroxybenzoate Substances 0.000 description 4
- 235000003599 food sweetener Nutrition 0.000 description 4
- 210000000214 mouth Anatomy 0.000 description 4
- 239000003002 pH adjusting agent Substances 0.000 description 4
- 239000003765 sweetening agent Substances 0.000 description 4
- 206010058019 Cancer Pain Diseases 0.000 description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 3
- 206010013911 Dysgeusia Diseases 0.000 description 3
- 230000007423 decrease Effects 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000000796 flavoring agent Substances 0.000 description 3
- 235000013355 food flavoring agent Nutrition 0.000 description 3
- -1 inorganic acid salts Chemical class 0.000 description 3
- 230000007774 longterm Effects 0.000 description 3
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 3
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-DUZGATOHSA-N D-araboascorbic acid Natural products OC[C@@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-DUZGATOHSA-N 0.000 description 2
- 239000004386 Erythritol Substances 0.000 description 2
- UNXHWFMMPAWVPI-UHFFFAOYSA-N Erythritol Natural products OCC(O)C(O)CO UNXHWFMMPAWVPI-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- VTAJIXDZFCRWBR-UHFFFAOYSA-N Licoricesaponin B2 Natural products C1C(C2C(C3(CCC4(C)CCC(C)(CC4C3=CC2)C(O)=O)C)(C)CC2)(C)C2C(C)(C)CC1OC1OC(C(O)=O)C(O)C(O)C1OC1OC(C(O)=O)C(O)C(O)C1O VTAJIXDZFCRWBR-UHFFFAOYSA-N 0.000 description 2
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 description 2
- 239000004376 Sucralose Substances 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- NDDAQHROMJDMKS-XFYXLWKMSA-N [(2s,3s,5s,8r,9s,10s,13s,14s)-2-hydroxy-10,13-dimethyl-17-oxo-1,2,3,4,5,6,7,8,9,11,12,14,15,16-tetradecahydrocyclopenta[a]phenanthren-3-yl]azanium;chloride Chemical compound Cl.C1[C@H](N)[C@@H](O)C[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC[C@H]21 NDDAQHROMJDMKS-XFYXLWKMSA-N 0.000 description 2
- 230000001133 acceleration Effects 0.000 description 2
- 239000003125 aqueous solvent Substances 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000004318 erythorbic acid Substances 0.000 description 2
- 235000010350 erythorbic acid Nutrition 0.000 description 2
- 235000019414 erythritol Nutrition 0.000 description 2
- UNXHWFMMPAWVPI-ZXZARUISSA-N erythritol Chemical compound OC[C@H](O)[C@H](O)CO UNXHWFMMPAWVPI-ZXZARUISSA-N 0.000 description 2
- 229940009714 erythritol Drugs 0.000 description 2
- 230000001747 exhibiting effect Effects 0.000 description 2
- 238000002825 functional assay Methods 0.000 description 2
- 229940049906 glutamate Drugs 0.000 description 2
- 229930195712 glutamate Natural products 0.000 description 2
- LPLVUJXQOOQHMX-UHFFFAOYSA-N glycyrrhetinic acid glycoside Natural products C1CC(C2C(C3(CCC4(C)CCC(C)(CC4C3=CC2=O)C(O)=O)C)(C)CC2)(C)C2C(C)(C)C1OC1OC(C(O)=O)C(O)C(O)C1OC1OC(C(O)=O)C(O)C(O)C1O LPLVUJXQOOQHMX-UHFFFAOYSA-N 0.000 description 2
- 239000001685 glycyrrhizic acid Substances 0.000 description 2
- 229960004949 glycyrrhizic acid Drugs 0.000 description 2
- UYRUBYNTXSDKQT-UHFFFAOYSA-N glycyrrhizic acid Natural products CC1(C)C(CCC2(C)C1CCC3(C)C2C(=O)C=C4C5CC(C)(CCC5(C)CCC34C)C(=O)O)OC6OC(C(O)C(O)C6OC7OC(O)C(O)C(O)C7C(=O)O)C(=O)O UYRUBYNTXSDKQT-UHFFFAOYSA-N 0.000 description 2
- 235000019410 glycyrrhizin Nutrition 0.000 description 2
- LPLVUJXQOOQHMX-QWBHMCJMSA-N glycyrrhizinic acid Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@@H]1C([C@H]2[C@]([C@@H]3[C@@]([C@@]4(CC[C@@]5(C)CC[C@@](C)(C[C@H]5C4=CC3=O)C(O)=O)C)(C)CC2)(C)CC1)(C)C)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O LPLVUJXQOOQHMX-QWBHMCJMSA-N 0.000 description 2
- 230000001339 gustatory effect Effects 0.000 description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- GVLGAFRNYJVHBC-UHFFFAOYSA-N hydrate;hydrobromide Chemical compound O.Br GVLGAFRNYJVHBC-UHFFFAOYSA-N 0.000 description 2
- 229940026239 isoascorbic acid Drugs 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000001630 malic acid Substances 0.000 description 2
- 235000011090 malic acid Nutrition 0.000 description 2
- 239000003158 myorelaxant agent Substances 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 229940069328 povidone Drugs 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 230000002335 preservative effect Effects 0.000 description 2
- 239000012488 sample solution Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000013097 stability assessment Methods 0.000 description 2
- 239000012086 standard solution Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 235000019408 sucralose Nutrition 0.000 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 description 2
- 150000005846 sugar alcohols Chemical class 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- UEUXEKPTXMALOB-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEUXEKPTXMALOB-UHFFFAOYSA-J 0.000 description 2
- 239000000892 thaumatin Substances 0.000 description 2
- 235000010436 thaumatin Nutrition 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 1
- 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
- LBLYYCQCTBFVLH-UHFFFAOYSA-M 2-methylbenzenesulfonate Chemical compound CC1=CC=CC=C1S([O-])(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- 108010011485 Aspartame Proteins 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical class F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- BIVBRWYINDPWKA-VLQRKCJKSA-L Glycyrrhizinate dipotassium Chemical compound [K+].[K+].O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@H]1CC[C@]2(C)[C@H]3C(=O)C=C4[C@@H]5C[C@](C)(CC[C@@]5(CC[C@@]4(C)[C@]3(C)CC[C@H]2C1(C)C)C)C(O)=O)C([O-])=O)[C@@H]1O[C@H](C([O-])=O)[C@@H](O)[C@H](O)[C@H]1O BIVBRWYINDPWKA-VLQRKCJKSA-L 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- MKXZASYAUGDDCJ-SZMVWBNQSA-N LSM-2525 Chemical compound C1CCC[C@H]2[C@@]3([H])N(C)CC[C@]21C1=CC(OC)=CC=C1C3 MKXZASYAUGDDCJ-SZMVWBNQSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- ILRKKHJEINIICQ-OOFFSTKBSA-N Monoammonium glycyrrhizinate Chemical compound N.O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@H]1CC[C@]2(C)[C@H]3C(=O)C=C4[C@@H]5C[C@](C)(CC[C@@]5(CC[C@@]4(C)[C@]3(C)CC[C@H]2C1(C)C)C)C(O)=O)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O ILRKKHJEINIICQ-OOFFSTKBSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 235000021314 Palmitic acid Nutrition 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 239000004288 Sodium dehydroacetate Substances 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 230000003444 anaesthetic effect Effects 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000000605 aspartame Substances 0.000 description 1
- 235000010357 aspartame Nutrition 0.000 description 1
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- 229940095574 propionic acid Drugs 0.000 description 1
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- 235000019204 saccharin Nutrition 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
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- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 235000019643 salty taste Nutrition 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000010378 sodium ascorbate Nutrition 0.000 description 1
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 description 1
- 229960005055 sodium ascorbate Drugs 0.000 description 1
- 235000019259 sodium dehydroacetate Nutrition 0.000 description 1
- 229940079839 sodium dehydroacetate Drugs 0.000 description 1
- 229940037001 sodium edetate Drugs 0.000 description 1
- JXKPEJDQGNYQSM-UHFFFAOYSA-M sodium propionate Chemical compound [Na+].CCC([O-])=O JXKPEJDQGNYQSM-UHFFFAOYSA-M 0.000 description 1
- 235000010334 sodium propionate Nutrition 0.000 description 1
- 239000004324 sodium propionate Substances 0.000 description 1
- 229960003212 sodium propionate Drugs 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 description 1
- DSOWAKKSGYUMTF-GZOLSCHFSA-M sodium;(1e)-1-(6-methyl-2,4-dioxopyran-3-ylidene)ethanolate Chemical compound [Na+].C\C([O-])=C1/C(=O)OC(C)=CC1=O DSOWAKKSGYUMTF-GZOLSCHFSA-M 0.000 description 1
- DGPIGKCOQYBCJH-UHFFFAOYSA-M sodium;acetic acid;hydroxide Chemical compound O.[Na+].CC([O-])=O DGPIGKCOQYBCJH-UHFFFAOYSA-M 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000002904 solvent Substances 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
- 238000001179 sorption measurement Methods 0.000 description 1
- 235000019614 sour taste Nutrition 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
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- 238000002560 therapeutic procedure Methods 0.000 description 1
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- 235000010384 tocopherol Nutrition 0.000 description 1
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Classifications
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
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- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
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- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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Abstract
The purpose of the present invention is to provide an oral liquid agent which is easy to take and has high stability by masking the bitter taste of oxycodone which is an active ingredient. The present invention provides a liquid composition containing oxycodone as an active ingredient, which is highly stable, wherein the liquid composition is capable of masking bitterness by an additive and suppressing the formation of an analogue by adjusting the pH to a predetermined range.
Description
Technical Field
The present invention relates to an oral liquid composition containing oxycodone (oxycodone), a pharmaceutically acceptable salt thereof, or a hydrate thereof (hereinafter, these may be collectively referred to as "oxycodone") as an active ingredient. More specifically, the present invention relates to an oral liquid composition in which the bitter taste of oxycodone is masked.
Background
Oral preparations containing an active ingredient having a strong bitter taste are rejected by releasing bitter taste in the mouth even in solid preparations such as tablets. When such an active ingredient is developed in the form of an oral liquid, it is a great advantage for the patient from the viewpoint of easy drinking, but conversely, since there is a disadvantage that a bitter taste is perceived more strongly than in the case of a solid preparation, there is a problem that it is difficult to develop a product if a method for masking the bitter taste by some means cannot be found. Therefore, it is said that there is no high possibility of developing a liquid formulation, as a matter of fact, regarding the development of an active ingredient having a strong bitterness of a tablet.
For example, document 1 describes that in a liquid preparation for oral administration containing a bitter component having a strong bitter taste, the bitter component is combined with 3 components of sugar alcohol, an acidic agent and glutamate to form a liquid preparation which can suppress bitter taste and does not leave unpleasant taste in the oral cavity even after oral administration. However, the bitter component of document 1 is not oxycodone. The bitter taste masking technique is completely different from the bitter taste masking technique using 3 or more kinds of additives such as sweeteners in the present invention described later.
On the other hand, in the process of the present invention, if a liquid composition in which the bitter taste of oxycodone is masked with an additive such as a sweetener is formulated, the problem "the pH of the liquid composition becomes low, the oxycodone content decreases due to the reaction of oxycodone with sugar alcohol or the like, and the formation of analogues" occurs. If the pH of the liquid composition is raised to solve the problem that the stability of the preparation cannot be ensured, the problem that the bitterness masking effect cannot be obtained occurs, and the problem of the lawyer (anti) is judged to exist.
As a technique for suppressing the formation of an analogue, for example, in document 2, there is disclosed a method for producing a pharmaceutical composition for injection containing an amino steroid muscle relaxant, wherein a pH adjuster is added to an aqueous solvent in advance before the amino steroid muscle relaxant is added to the aqueous solvent, whereby the formation of an analogue can be suppressed at the time of producing the pharmaceutical composition. However, the active ingredient of the injectable composition of this document 2 is not oxycodone. It is not described whether the method is applicable to a liquid formulation containing oxycodone as an active ingredient, and if applicable, the pH should be specifically adjusted to any range.
Prior art literature
Patent literature
Patent document 1: japanese patent laid-open No. 2000-204036
Patent document 2: japanese patent laid-open publication 2016-121073
Disclosure of Invention
Problems to be solved by the invention
The purpose of the present invention is to provide a liquid composition for oral use, wherein the bitter taste of oxycodone, which is an active ingredient, is masked. Further, the present invention aims to provide a liquid composition in which the formation of an analogue of an active ingredient is suppressed.
Solution for solving the problem
As a result of intensive studies to solve the above problems, the present inventors have found that a liquid composition which suitably masks the bitter taste of oxycodone as an active ingredient can be obtained by adding at least 3 predetermined additives. It has been found that it is effective to adjust the pH of the liquid composition to a predetermined range in order to suppress the formation of an analogue of an active ingredient, thereby obtaining a liquid composition in which bitterness is masked, the formation of an analogue is suppressed, and stability is ensured, and the present invention has been completed.
That is, the present invention relates to the following (1) to (28), but the present invention is not limited to these, and the present invention is also intended to achieve the same object by substantially the same means.
(1) A liquid composition comprising oxycodone, a pharmaceutically acceptable salt thereof, or a hydrate thereof as an active ingredient, wherein the bitterness of the active ingredient is masked.
(2) The liquid formulation according to (1) above, wherein oxycodone, a pharmaceutically acceptable salt thereof, or a hydrate thereof is contained in an amount of 0.01 to 1% by weight relative to 100% by weight of the liquid formulation.
(3) The liquid formulation composition according to the above (1) or (2), which contains at least 3 kinds selected from the group consisting of acesulfame potassium (acesulfame potassium), xylitol, D-sorbitol, and L-glutamic acid as additives.
(4) The liquid composition according to the above (3), wherein the acesulfame potassium is contained in an amount of 0.01 to 0.1% by weight relative to 100% by weight of the liquid composition.
(5) The liquid composition according to the above (3) or (4), wherein the xylitol is contained in an amount of 0.5 to 15% by weight relative to 100% by weight of the liquid composition.
(6) The liquid formulation according to any one of (3) to (5), wherein the liquid formulation contains 1 to 20% by weight of D-sorbitol based on 100% by weight of the liquid formulation.
(7) The liquid composition according to any one of the above (3) to (6), wherein the L-glutamic acid is contained in an amount of 0.01 to 1% by weight relative to 100% by weight of the liquid composition.
(8) The liquid formulation according to any one of (3) to (7), wherein the liquid formulation contains 0.1 to 40% by weight of at least 3 selected from the group consisting of acesulfame potassium, xylitol, D-sorbitol and L-glutamic acid, relative to 100% by weight of the liquid formulation.
(9) The liquid formulation composition according to any one of (3) to (8) above, further comprising citric acid hydrate and/or sodium citrate hydrate as an additive.
(10) The liquid composition according to the above (9), wherein the citric acid hydrate or sodium citrate hydrate is contained in an amount of 0.01 to 1% by weight relative to 100% by weight of the liquid composition.
(11) The liquid formulation according to any one of the above (3) to (10), which further contains sodium benzoate and/or ethyl parahydroxybenzoate as an additive.
(12) The liquid composition according to the above (11), wherein the sodium benzoate is contained in an amount of 0.005 to 0.5% by weight based on 100% by weight of the liquid composition.
(13) The composition according to the above (11) or (12), wherein the ethyl parahydroxybenzoate is contained in an amount of 0.0005 to 0.05% by weight based on 100% by weight of the liquid composition.
(14) The liquid formulation according to any one of the above (3) to (13), which further contains sodium chloride as an additive.
(15) The liquid composition according to the above (14), wherein the sodium chloride is contained in an amount of 0.005 to 1% by weight based on 100% by weight of the liquid composition.
(16) The liquid formulation according to any one of the above (3) to (15), which further contains propylene glycol as an additive.
(17) The liquid formulation according to (16), wherein the propylene glycol is contained in an amount of 0.005 to 1% by weight based on 100% by weight of the liquid formulation.
(18) The liquid formulation according to any one of (1) to (17), wherein the pH is 3.3 to 4.8.
(19) The liquid composition according to any one of (1) to (18), wherein the analogue formed from the active ingredient over time is suppressed to a level below an allowable standard when a stability test of a pharmaceutical product formulated in the Ministry of labor of Japanese Kokai is carried out.
(20) The liquid composition according to (19), wherein the ratio of the amount of each of the analogues to the amount of the active ingredient is 0.2% or less, respectively, when the stability test of the pharmaceutical product formulated in the Ministry of the Japanese Kokai is carried out.
(21) The liquid composition according to (19), wherein the ratio of the amount of each of the analogues to the amount of the active ingredient is 0.15% or less, respectively, when the stability test of the pharmaceutical product formulated in the Ministry of the Japanese Kokai is carried out.
(22) The liquid composition according to (19), wherein the ratio of the amount of each of the analogues to the amount of the active ingredient is 0.1% or less, respectively, when the stability test of the pharmaceutical product formulated in the Ministry of the Japanese Kokai is carried out.
(23) The liquid composition according to any one of (19) to (22), wherein the ratio of the total amount of the analogues to the amount of the active ingredient is 0.6% or less when a stability test of a pharmaceutical product formulated in the Ministry of the Japanese Kokai is carried out.
(24) A method for stabilizing a liquid composition, characterized in that the production of an analogue in the liquid composition is suppressed by adjusting the pH of the liquid composition containing oxycodone, a pharmaceutically acceptable salt thereof, or a hydrate thereof as an active ingredient to 3.3 to 4.8.
(25) The stabilization method according to the above (24), wherein the ratio of the amount of each of the analogues to the amount of the aforementioned active ingredient is 0.2% or less, respectively.
(26) The stabilization method according to the above (24), wherein the ratio of the amount of each of the analogues to the amount of the aforementioned active ingredient is 0.15% or less, respectively.
(27) The stabilization method according to the above (24), wherein the ratio of the amount of each of the analogues to the amount of the aforementioned active ingredient is 0.1% or less, respectively.
(28) The stabilization method according to any one of the above (24) to (27), wherein the ratio of the total amount of the analogues to the amount of the above-mentioned active ingredient is 0.6% or less.
ADVANTAGEOUS EFFECTS OF INVENTION
The liquid composition of the present invention is an oral liquid which is easy to take and has reduced bitterness of oxycodone as an active ingredient for patients with cancer pain, and has extremely high usefulness. In addition, since the formation of the analogue is suppressed with the lapse of time and the stability is high, the conditions as a medicine requiring quality assurance in years are also satisfied sufficiently.
Detailed Description
The present invention provides a liquid composition containing oxycodone, a pharmaceutically acceptable salt thereof, or a hydrate thereof as an active ingredient, wherein the bitter taste of the active ingredient is masked. The masking is performed by containing at least 3 additives selected from the group consisting of acesulfame potassium, xylitol, D-sorbitol, and L-glutamic acid. The liquid composition of the present invention can be a liquid composition having high stability in which the formation of an analogue is suppressed by adjusting the pH to 3.3 to 4.8.
The liquid composition of the present invention contains oxycodone, a pharmaceutically acceptable salt thereof, or a hydrate thereof as an active ingredient. Oxycodone is one of the strong opioids used in stage 3 of stage 3 in WHO mode cancer pain therapies in 1996, and is of medical usefulness in terms of drugs. The oxycodone may be used in the form of pharmaceutically acceptable salts other than the free form, and examples thereof include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, hydrofluoric acid salt, and hydrobromide; organic acid salts such as acetic acid, tartrate, lactate, citrate, fumarate, maleate, succinate, methanesulfonate, benzenesulfonate, toluenesulfonate, naphthalenesulfonate, camphorsulfonate, and the like; amino acid salts such as alginate, aspartate, glutamate, etc.; metal salts such as sodium salt, potassium salt and cesium salt. Particularly preferred is oxycodone hydrochloride which is commercially available and widely used clinically as an analgesic for cancer pain. In addition, stereoisomers, hydrates, and solvates of oxycodone are also included as an active ingredient of the liquid formulation composition of the present invention.
The content of oxycodone, a pharmaceutically acceptable salt thereof, or a hydrate thereof in the liquid composition of the present invention is not particularly limited, and may be appropriately selected. For example, in the case of oxycodone hydrochloride or oxycodone hydrochloride hydrate, the content of oxycodone hydrochloride or oxycodone hydrochloride hydrate may be 0.01 to 1 wt%, preferably 0.03 to 0.8 wt%, and more preferably 0.05 to 0.6 wt% relative to 100 wt% of the present liquid composition.
The liquid composition of the present invention is characterized by masking the bitter taste of oxycodone, a pharmaceutically acceptable salt thereof, or a hydrate thereof as an active ingredient. For this purpose, at least 3 additives selected from the group consisting of acesulfame potassium, xylitol, D-sorbitol, and L-glutamic acid are added as one method. Further, in the liquid composition of the present invention, additives such as pH adjusting agents such as citric acid hydrate and sodium citrate hydrate may be contained in combination. Thus, the liquid composition of the present invention has the advantage of reduced bitterness and stability. The additives and the amounts thereof added to the liquid formulation of the present invention are described in detail below, however, the present invention is not limited thereto.
As the sweetener which can be used as an additive for the liquid composition of the present invention, refined white sugar, aspartame, saccharin Na hydrate, D-mannitol, D-sorbitol, dextrin, erythritol, sucralose (sucralose), xylitol, powder reduced maltose syrup, thaumatin (thaumatin), acesulfame potassium, or a combination thereof, and the like can be mentioned. Among them, a combination of potassium acesulfame, xylitol and D-sorbitol is preferable. The content of acesulfame potassium may be 0.01 to 0.1% by weight, preferably 0.03 to 0.09% by weight, more preferably 0.04 to 0.08% by weight, and even more preferably 0.05 to 0.07% by weight, relative to 100% by weight of the liquid composition. The xylitol content may be set to 0.5 to 15% by weight, preferably 1 to 10% by weight, more preferably 2 to 8% by weight, and still more preferably 3 to 6% by weight, relative to 100% by weight of the liquid composition. The content of D-sorbitol may be 1 to 20% by weight, preferably 2 to 15% by weight, more preferably 4 to 12% by weight, and still more preferably 6 to 10% by weight, relative to 100% by weight of the liquid composition. In addition to these sweeteners, L-glutamic acid as a taste-modifying agent may be added, and the content of L-glutamic acid may be set to 0.01 to 1% by weight, preferably 0.03 to 0.3% by weight, more preferably 0.05 to 0.2% by weight, and even more preferably 0.07 to 0.15% by weight, relative to 100% by weight of the liquid composition. The total content of 3 additives selected from acesulfame potassium, xylitol, D-sorbitol, or L-glutamic acid may be set to 0.1 to 40% by weight, preferably 0.5 to 30% by weight, more preferably 1 to 25% by weight, and even more preferably 1 to 20% by weight, relative to 100% by weight of the liquid composition.
Examples of the preservative which can be used as an additive for the liquid composition of the present invention include benzoic acid, sodium benzoate, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, sorbic acid, potassium sorbate, erythorbic acid (erythorbic acid), sodium dehydroacetate, sodium edetate (edetate sodium), ascorbic acid, sodium ascorbate, palmitic acid anti-spoilage ester, propionic acid, sodium propionate, propyl gallate, tocopherol, and combinations thereof, and examples of the preservative include sodium benzoate and/or ethyl parahydroxybenzoate. The content of sodium benzoate may be set to 0.005 to 0.5 wt%, preferably 0.008 to 0.1 wt%, more preferably 0.01 to 0.08 wt%, and still more preferably 0.02 to 0.06 wt% relative to 100 wt% of the liquid composition. The content of ethyl parahydroxybenzoate may be set to 0.0005 to 0.05% by weight, preferably 0.0008 to 0.01% by weight, more preferably 0.001 to 0.005% by weight, and even more preferably 0.0015 to 0.005% by weight, relative to 100% by weight of the liquid composition. The total content of sodium benzoate and ethyl parahydroxybenzoate may be set to 0.005 to 0.5% by weight, preferably 0.008 to 0.1% by weight, more preferably 0.01 to 0.08% by weight, and even more preferably 0.02 to 0.06% by weight, relative to 100% by weight of the liquid composition.
Examples of the flavoring agent which can be used as an additive of the liquid composition of the present invention include DL-malic acid, sodium chloride, citric acid hydrate, sodium citrate hydrate, glycyrrhizic acid (glycyrrhizic acid), dipotassium glycyrrhizinate, monoammonium glycyrrhizinate, L-glutamic acid, sodium L-glutamate, glycine, and combinations thereof, and examples of the flavoring agent include sodium chloride. The content of sodium chloride may be set to 0.005 to 1% by weight, preferably 0.01 to 0.5% by weight, more preferably 0.03 to 0.3% by weight, and even more preferably 0.05 to 0.2% by weight, relative to 100% by weight of the liquid composition.
The pH adjuster that can be used as an additive of the liquid composition of the present invention includes dilute hydrochloric acid, phosphoric acid, sodium hydrogen phosphate hydrate, acetic acid, sodium acetate hydrate, lactic acid, tartaric acid, malic acid, citric acid hydrate, sodium citrate hydrate, or a combination thereof, and the like, and the preferred examples include tartaric acid, malic acid, citric acid hydrate, and sodium citrate hydrate, and the further preferred examples include citric acid hydrate and/or sodium citrate hydrate. The content of the citric acid hydrate or the sodium citrate hydrate may be set to 0.01 to 1 wt%, preferably 0.05 to 0.8 wt%, more preferably 0.1 to 0.6 wt%, and still more preferably 0.2 to 0.4 wt%, respectively, relative to 100 wt% of the liquid composition. Since citric acid hydrate or sodium citrate hydrate has both functions as a flavoring agent, the liquid composition of the present invention can be used for both these purposes.
As the cosolvent which can be used as an additive of the liquid composition of the present invention, polyethylene glycol (Macrogol), glycerin, povidone (Povidone), cyclodextrin, propylene glycol, or a combination thereof can be used, and propylene glycol is exemplified as a preferable example. The propylene glycol content may be set to 0.005 to 1% by weight, preferably 0.01 to 0.5% by weight, more preferably 0.03 to 0.3% by weight, and even more preferably 0.05 to 0.2% by weight, relative to 100% by weight of the liquid composition.
The pH of the liquid composition of the present invention can be adjusted by the kind and content of the additive, and is preferably 3.3 to 4.8, more preferably 3.5 to 4.5, and even more preferably 3.8 to 4.2. By adjusting the pH to this range, the bitterness masking and stability of the liquid composition of the present invention can be ensured.
The liquid composition of the present invention may contain various additives used for the production of general pharmaceutical preparations, as long as the effects of the present invention are not impaired. Examples of such additives include stabilizers, surfactants, solubilizers, thickeners, suspending agents, fragrances, colorants, and the like, in addition to the above examples, and may be appropriately selected and added according to the purpose.
Examples
The present invention will be described in detail with reference to examples, but the present invention is not limited to these examples.
Example 1
Table 1 shows an example of the formulation of the liquid composition of the present invention. Liquid compositions containing oxycodone hydrochloride hydrate having the compositions shown in table 1 were prepared according to the following production methods.
TABLE 1
| Composition and portion (mg) | Formulation 1 | Formulation 2 | Formulation 3 | Formulation 4 |
| Oxycodone hydrochloride hydrate | 2.88 | 5.77 | 11.54 | 23.07 |
| Citric acid hydrate | 7.75 | 7.75 | 15.50 | 15.50 |
| Sodium citrate hydrate | 6.146 | 6.146 | 12.292 | 12.292 |
| D-sorbitol solution (70%) | 310.75 | 310.75 | 621.50 | 621.50 |
| Xylitol | 125.00 | 125.00 | 250.00 | 250.00 |
| Acesulfame potassium | 1.625 | 1.625 | 3.25 | 3.25 |
| Sodium chloride | 2.50 | 2.50 | 5.00 | 5.00 |
| Sodium benzoate | 1.00 | 1.00 | 2.00 | 2.00 |
| P-hydroxybenzoic acid ethyl ester | 0.075 | 0.075 | 0.15 | 0.15 |
| Propylene glycol | 2.50 | 2.50 | 5.00 | 5.00 |
| Purified water | Proper amount of | Proper amount of | Proper amount of | Proper amount of |
| Total amount of | 2.5mL | 2.5mL | 5mL | 5mL |
| pH | 4.0 | 4.0 | 4.0 | 4.0 |
An example of the method for producing the liquid composition of the present invention according to the formula 4 is shown in the following table 1.
15.50mg of citric acid hydrate, 12.292mg of sodium citrate hydrate, 3.25mg of acesulfame potassium, 5.00mg of sodium chloride, 2.00mg of sodium benzoate, 0.15mg of ethyl p-hydroxybenzoate, 5.00mg of propylene glycol, 250.00mg of xylitol and 621.50mg of D-sorbitol solution (70% solution) were added in this order to warm purified water according to the 17 th revision project of Japanese pharmacopoeia and oral liquid, and dissolved and cooled to room temperature.
23.07mg of oxycodone hydrochloride hydrate in an amount corresponding to 20mg of anhydrate was added and stirred at room temperature while being completely dissolved. Purified water was added thereto to adjust the total amount to 5.25g (corresponding to 5 mL). If necessary, a pH adjuster is added to adjust the pH to a predetermined pH.
Because oxycodone hydrochloride is an anesthetic, its use is limited, and in a formulation containing this component, it is not easy to perform a taste function test. Thus, regarding the formulations a to F used in test examples (1) and (2), oxycodone hydrochloride hydrate was replaced with right Sha Meifen (dextromethorphan) hydrobromide hydrate or quinine sulfate dihydrate in an amount exhibiting the same bitterness, and the formulations were produced in the same manner as in example 1, and taste functional tests in test examples (1) and (2) below were performed.
Test example (1): gustatory functional assay
Taste functional tests were performed with randomly selected male and female 21 as panelists. The liquid compositions of formulations A, B and C shown in table 2 were classified into "at the time of application" and "after taste", and the evaluation of "bitterness", "sweetness" and "sourness" was performed based on the evaluation criteria of table 3. The term "when applied" means "when contained in the mouth". Test sequence: (1) Each test specimen was rinsed 3 times with water (20-30 mL). (2) A predetermined amount (5 mL) of the test specimen was placed in the mouth for about 5 seconds (within 10 seconds), and the taste was evaluated and immediately discharged. (3) rinsing again with water (20-30 mL) 3 times. (4) evaluating aftertaste. (5) Finally, from among the 3, a preferred liquid formulation was selected in terms of the taste of the drug. The bitter taste of 2mg of right Sha Meifen hydrobromide hydrate was estimated to correspond to the bitter taste of 23.07mg of oxycodone hydrochloride hydrate (20 mg in terms of anhydrate) by the prior test using a taste sensor and taste function test. An example of the evaluation results is shown in table 4.
TABLE 2
| Composition and portion (mg) | Formula C | Formulation A | Formulation B |
| Right Sha Meifen hydrobromic acid salt solutionComposition | 2.00 | 2.00 | 2.00 |
| Citric acid hydrate | 6.00 | 14.50 | 15.50 |
| Sodium citrate hydrate | - | 13.50 | 12.00 |
| L-glutamic acid | 5.00 | 5.00 | - |
| D-sorbitol solution (70%) | 621.50 | - | 621.50 |
| Xylitol | 500.00 | 500.00 | 250.00 |
| Acesulfame potassium | 2.00 | 3.30 | 3.25 |
| Sodium chloride | 5.00 | 5.00 | 5.00 |
| Sodium benzoate | 2.00 | 2.00 | 2.00 |
| P-hydroxybenzoic acid ethyl ester | 0.15 | 0.15 | 0.15 |
| Propylene glycol | 5.00 | 5.00 | 5.00 |
| Dilute hydrochloric acid | Proper amount of | - | - |
| Purified water | Proper amount of | Proper amount of | Proper amount of |
| Total amount of | 5mL | 5mL | 5mL |
| pH | 3.0 | 4.0 | 4.0 |
TABLE 3
TABLE 4
As is apparent from Table 4, the compositions of the present invention (formulas A and B) are preferred liquids in which bitterness was masked in taste-functional tests.
Test example (2): gustatory functional assay
Taste functional tests were performed with randomly selected male and female 21 as panelists. The liquid compositions of formulations D, E and F shown in table 5 were prepared in the same manner as the test procedure and evaluation standard of test example (1). By the prior test using a taste sensor and taste function test, it was estimated that the bitter taste of 0.75mg quinine sulfate dihydrate corresponds to the bitter taste of 23.07mg oxycodone hydrochloride hydrate (20 mg in terms of anhydrate). An example of the evaluation results is shown in table 6.
TABLE 5
| Composition and portion (mg) | Formula D | Formula E | Formula F |
| Quinine sulfate dihydrate | 0.75 | 0.75 | 0.75 |
| Citric acid hydrate | 6.00 | 14.50 | 15.50 |
| Sodium citrate hydrate | - | 13.50 | 12.00 |
| L-glutamic acid | 5.00 | 5.00 | - |
| D-sorbitol solution (70%) | 621.50 | - | 621.50 |
| Xylitol | 500.00 | 500.00 | 250.00 |
| Acesulfame potassium | 2.00 | 3.30 | 3.25 |
| Sodium chloride | 5.00 | 5.00 | 5.00 |
| Sodium benzoate | 2.00 | 2.00 | 2.00 |
| P-hydroxybenzoic acid ethyl ester | 0.15 | 0.15 | 0.15 |
| Propylene glycol | 5.00 | 5.00 | 5.00 |
| Dilute hydrochloric acid | Proper amount of | - | - |
| Purified water | Proper amount of | Proper amount of | Proper amount of |
| Total amount of | 5mL | 5mL | 5mL |
| pH | 3.0 | 4.0 | 4.0 |
TABLE 6
As is apparent from Table 6, the compositions of the present invention (formulas E and F) are preferred liquids in which bitterness was masked in taste-functional tests.
The composition of the present invention has been developed as a pharmaceutical product in japan, and it is necessary to satisfy the allowable standards of the same level as those of other oxycodone immediate release formulations, in accordance with the storage stability of the pharmaceutical product formulated by the ministry of labour of the japanese thick living. Accordingly, various tests on the storage stability of the composition of the present invention were conducted, and the results thereof are shown below.
Test example (3): stability assessment test
Liquid compositions (oxycodone hydrochloride concentration 4.0 mg/mL) of the formulations G, H and I shown in Table 7 were prepared in the same manner as in example 1. The liquid compositions of the respective formulations were subjected to stability evaluation tests under the condition of storage at 80℃for 6 days (corresponding to storage at 25℃for 5.5 years). Regarding the evaluation items, the content of oxycodone hydrochloride hydrate, pH, total number of analogues and total amount of analogues were measured by the following test methods.
[ method for measuring oxycodone hydrochloride content ]
Measured by high performance liquid chromatography (internal standard method, isocratic) conditions. The oxycodone hydrochloride content is expressed as a ratio (%) of oxycodone hydrochloride after the stability test in the liquid composition of each formulation to oxycodone hydrochloride at the beginning.
[ method for measuring the amount of the analogue and the number of the analogue ]
The amount of analog was determined by high performance liquid chromatography (absolute standard curve method, gradient conditions). The amount of each analogue was calculated by comparing the peak area of the chromatogram of the sample solution with the peak area of oxycodone of the standard solution. The standard solution used was a 125-fold diluted sample solution. The sum of the amounts of each analogue expressed as a ratio (%) of the amount of each analogue to the amount of oxycodone hydrochloride in the liquid formulation composition is calculated, and the total amount of the analogue is expressed as a ratio (%) of the amount of all the analogues to the amount of oxycodone hydrochloride in the liquid formulation composition. In test examples (4) to (7) described below, the calculated content of each of the analogues was also represented by the ratio (%) of the amount of each of the analogues to the amount of oxycodone hydrochloride in the liquid formulation composition. Further, the number of peaks of the analogues detected in the chromatogram of each sample solution was measured as the total number of analogues.
TABLE 7
| Composition and portion (mg) | Formulation G | Formula H | Formula I |
| Oxycodone hydrochloride hydrate | 23.07 | 23.07 | 23.07 |
| Citric acid hydrate | 6.00 | 14.50 | 15.50 |
| Sodium citrate hydrate | - | 13.50 | 12.00 |
| L-glutamic acid | 5.00 | 5.00 | - |
| D-sorbitol solution (70%) | 621.50 | - | 621.50 |
| Xylitol | 500.00 | 500.00 | 250.00 |
| Acesulfame potassium | 2.00 | 3.30 | 3.25 |
| Sodium chloride | 5.00 | 5.00 | 5.00 |
| Sodium benzoate | 2.00 | 2.00 | 2.00 |
| P-hydroxybenzoic acid ethyl ester | 0.15 | 0.15 | 0.15 |
| Propylene glycol | 5.00 | 5.00 | 5.00 |
| Dilute hydrochloric acid | Proper amount of | - | - |
| Purified water | Proper amount of | Proper amount of | Proper amount of |
| Total amount of | 5mL | 5mL | 5mL |
| pH | 3.0 | 4.0 | 4.0 |
TABLE 8
(n=1 each)
The oxycodone hydrochloride concentration in brackets
For one example of the results, the oxycodone hydrochloride hydrate content and pH are shown in table 8, and the total number of analogs and the total amount of analogs are shown in table 9.
TABLE 9
Average value (n=3)
The total number and amount of analogues do not include the analogues contained in the original drug.
As is apparent from tables 8 and 9, the liquid compositions of the present invention (formulations H and I) showed a stable pH in the stability evaluation test, a decrease in oxycodone hydrochloride hydrate content, and an increase in the total number of analogues and the total amount of analogues both suppressed.
Test example (4): rigorous test
With respect to the liquid compositions of formulas 1, 2, 3 and 4 shown in Table 1, a severe test was conducted under conditions of 60℃for 2 months (1 month of 60℃is equivalent to 4.2 years of 25 ℃) to determine the content of each analogue and the total amount of the analogue in the same manner as in test example (3). An example of the results is shown in table 10. In table 10, a plurality of values are recorded in 1 field of each analog content column, which indicates that a plurality of other kinds of analogs can be detected, for example, a case in which 3 analog contents are recorded in 1 field indicates that 3 analogs can be detected. The same applies to tables 11 and 12 described below.
TABLE 10
From table 10, it is apparent that the liquid compositions of formulas 1, 2, 3 and 4 were inhibited from producing the analogues in the above-mentioned severe test, and as a result, it was revealed that any of the number of analogues, the content of each analogue and the total amount of the analogues was inhibited.
Test example (5): acceleration test
The liquid compositions of formulas 1, 2, 3 and 4 shown in Table 1 were subjected to accelerated tests at 40℃and 75% RH for 10 months, and the content and total amount of each analogue were measured in the same manner as in test example (3). An example of the results is shown in Table 11.
TABLE 11
As apparent from table 11, the liquid compositions of formulas 1, 2, 3 and 4 were inhibited from producing the analogues in the above-mentioned acceleration test, and as a result, it was revealed that any of the number of analogues, the content of each analogue and the total amount of the analogues was inhibited.
Test example (6): long-term storage test
The liquid compositions of formulas 1, 2, 3 and 4 shown in Table 1 were subjected to long-term storage test at 25℃and 60% RH for 36 months, and the content and total amount of each analogue were measured in the same manner as in test example (3). An example of the results is shown in table 12.
TABLE 12
From table 12, it is apparent that the liquid compositions of formulas 1, 2, 3 and 4 were inhibited from producing the analogues in the above long-term storage test, and the results showed that any of the number of analogues, the content of each analogue and the total amount of the analogues was inhibited.
Test example (7): stability assessment test
Liquid formulations of formulas 5 to 16 (oxycodone hydrochloride concentration 4.0 mg/mL) shown in Table 13 were prepared in the same manner as in example 1. The liquid composition of each formulation was subjected to a stability evaluation test under the condition of storage at 80℃for 6 days (corresponding to storage at 25℃for 5.5 years), and the total number of analogues and the total amount of analogues were measured in the same manner as in test example (3). An example of the results is shown in table 14.
TABLE 13
TABLE 14
As is apparent from table 14, in the above-described stability evaluation test, the generation of the analogues was inhibited depending on the rise in pH of the liquid formulation composition in a predetermined range, and as a result, it was shown that any of the number of analogues, the content of each analogue and the total amount of the analogues was inhibited.
Test example (8): evaluation of bitterness masking by taste recognition device
The effect of pH on the bitter masking effect was evaluated according to the CPA (Change of membrane Potential causedby Adsorption) assay using a taste sensor of taste recognition device (TS-5000Z, manufactured by Smart sensor technology (Intelligent Sensor Technology), inc.).
The taste sensor detects, as a sensor output, a change in membrane potential of the lipid membrane due to electrostatic interaction or hydrophobic interaction with the taste substance. An example of a method for measuring bitterness using a taste sensor is shown below. First, the taste sensor is immersed in a solution called a reference solution to obtain a membrane potential Vr. Next, the test liquid is immersed in the taste sensor to obtain a membrane potential Vs. The resulting change in membrane potential (Vs-Vr) is referred to as the "relative value" of the 1 st sensor output, and corresponds to the front taste such as sour taste or salty taste. Then, after washing the taste sensor with the reference liquid, the taste sensor is immersed in the reference liquid again to obtain the membrane potential Vr'. The resulting change in the membrane potential (Vr' -Vr) is referred to as "CPA value" of the 2 nd sensor output, and corresponds to aftertaste such as bitterness or astringency.
However, the CPA value of oxycodone hydrochloride is difficult to measure, and thus the CPA value of a liquid composition containing oxycodone hydrochloride is estimated using a bitter taste standard substance (quinine sulfate) that can be used for measuring the CPA value. That is, the relative values of oxycodone hydrochloride and quinine sulfate were measured first, and the concentrations of both estimated to exhibit the same bitter taste were determined from the relative values of both. As a result, the CPA value was measured for a formulation containing quinine sulfate at a concentration estimated to exhibit a bitter taste equivalent to the oxycodone hydrochloride at the desired concentration, and the estimated value of the bitter taste was calculated.
(1) Determination of the relative values of oxycodone hydrochloride and quinine sulfate
The relative values (mV) of oxycodone hydrochloride and quinine sulfate were measured using a bitter taste sensor (BT 0 sensor) of a taste recognition device (TS-5000Z, manufactured by Smart sensor technologies Co., ltd.). From the results of the relative values of the two, as shown in Table 15, it was confirmed that the concentrations of quinine sulfate dihydrate which exhibited bitter taste equivalent to oxycodone hydrochloride of 1.0mg/mL, 2.0mg/mL and 4.0mg/mL were 0.037mg/mL, 0.058mg/mL and 0.094mg/mL, respectively.
TABLE 15
(2) Determination of CPA value for each formulation
From the results of the above (1), the CPA value (mV) of each liquid composition was measured using a bitterness sensor (BT 0 sensor) of a taste recognition apparatus (TS-5000Z, manufactured by Smart sensor technologies Co., ltd.) for each of the formulations X to Z of Table 16 containing quinine sulfate dihydrate 0.094mg/mL exhibiting a bitterness equivalent to 4.0mg/mL oxycodone hydrochloride, and the estimated value of bitterness (CPA value. Times.0.3) was calculated. An example of the results is shown in table 17.
TABLE 16
| Composition and portion (mg) | Formula X | Formula Y | Formulation Z |
| Quinine sulfate dihydrate | 9.4 | 9.4 | 9.4 |
| L-glutamic acid | 250 | 250 | 250 |
| D-sorbitol | 5000 | 5000 | 5000 |
| Xylitol | 10000 | 10000 | 10000 |
| Erythritol | 7500 | 7500 | 7500 |
| Sodium benzoate | 40 | 40 | 40 |
| P-hydroxybenzoic acid ethyl ester | 3 | 3 | 3 |
| Propylene glycol | 100 | 100 | 100 |
| Dilute hydrochloric acid | Proper amount of | Proper amount of | Proper amount of |
| Purified water | Proper amount of | Proper amount of | Proper amount of |
| Total amount of | 100mL | 100mL | 100mL |
| pH | 2.5 | 3.0 | 3.5 |
TABLE 17
| Subject fluid | Estimated value of bitterness (mV) |
| Formulation x | 2.64 |
| Formula Y | 7.97 |
| Formulation Z | 14.00 |
| Quinine sulfate dihydrate (0.094 mg/mL) | 19.33 |
As is apparent from table 17, in the masking evaluation test by the above-mentioned bitterness sensor, it was revealed that the masking effect of bitterness was improved depending on the decrease in pH of the liquid formulation. The results of the masking evaluation test using the bitter taste sensor were confirmed to correlate with the results of the functional test performed by other methods.
Industrial applicability
As described above, the liquid formulation composition of the present invention containing oxycodone, a pharmaceutically acceptable salt thereof, or a hydrate thereof as an active ingredient can appropriately mask bitter taste by containing at least 3 additives selected from the group consisting of acesulfame potassium, xylitol, D-sorbitol, and L-glutamic acid as additives. In addition, by adjusting the pH of the liquid composition of the present invention to a range of 3.3 to 4.8, the formation of an analogue can be suppressed and stability can be ensured. The liquid composition of the present invention is highly useful as a therapeutic agent for pain in various cancer patients.
Claims (13)
1. A liquid composition comprising oxycodone, a pharmaceutically acceptable salt thereof, or a hydrate thereof as an active ingredient, wherein the bitterness of the active ingredient is masked.
2. The liquid formulation composition according to claim 1, which contains at least 3 selected from the group consisting of acesulfame potassium, xylitol, D-sorbitol, or L-glutamic acid as an additive.
3. The liquid formulation composition of claim 2, further comprising citric acid hydrate and/or sodium citrate hydrate as an additive.
4. A liquid formulation composition according to claim 2 or 3, further comprising sodium benzoate and/or ethyl parahydroxybenzoate as additives.
5. The liquid formulation of any one of claims 2-4, further comprising sodium chloride as an additive.
6. The liquid formulation of any one of claims 2-5, further comprising propylene glycol as an additive.
7. The liquid formulation according to any one of claims 1 to 6, having a pH of 3.3 to 4.8.
8. The liquid formulation according to any one of claims 1 to 7, wherein an analogue produced from the active ingredient over time is suppressed to a level below an allowable standard when a stability test of a pharmaceutical product formulated in the ministry of labour of japan is carried out.
9. The liquid composition according to claim 8, wherein the ratio of the amount of each of the analogues to the amount of the active ingredient is 0.2% or less, respectively, when the stability test of the pharmaceutical product by the Ministry of the Japanese Kokai is carried out.
10. The liquid composition according to claim 8 or 9, wherein the ratio of the total amount of the analogues to the amount of the active ingredient is 0.6% or less when a stability test of a pharmaceutical product formulated in the ministry of labour of thick living in japan is performed.
11. A method for stabilizing a liquid composition, characterized in that the production of an analogue in the liquid composition is suppressed by adjusting the pH of the liquid composition containing oxycodone, a pharmaceutically acceptable salt thereof, or a hydrate thereof as an active ingredient to 3.3 to 4.8.
12. The stabilization method according to claim 11, wherein the ratio of the amount of each of the analogues to the amount of the active ingredient is 0.2% or less, respectively.
13. The stabilization method according to claim 11 or 12, wherein a ratio of a total amount of analogues to an amount of the active ingredient is 0.6% or less.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2020129390 | 2020-07-30 | ||
| JP2020-129390 | 2020-07-30 | ||
| PCT/JP2021/028088 WO2022025176A1 (en) | 2020-07-30 | 2021-07-29 | Liquid medicine composition |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN116133643A true CN116133643A (en) | 2023-05-16 |
Family
ID=80036302
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202180059438.5A Withdrawn CN116133643A (en) | 2020-07-30 | 2021-07-29 | Liquid composition |
Country Status (5)
| Country | Link |
|---|---|
| JP (1) | JPWO2022025176A1 (en) |
| KR (1) | KR20230044359A (en) |
| CN (1) | CN116133643A (en) |
| TW (1) | TW202220657A (en) |
| WO (1) | WO2022025176A1 (en) |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP4959864B2 (en) | 1998-11-11 | 2012-06-27 | 大日本住友製薬株式会社 | Glutamate-containing solution |
| JP2016121073A (en) | 2014-12-24 | 2016-07-07 | ニプロ株式会社 | Method for producing pharmaceutical composition for an injection |
-
2021
- 2021-07-29 JP JP2022539558A patent/JPWO2022025176A1/ja active Pending
- 2021-07-29 CN CN202180059438.5A patent/CN116133643A/en not_active Withdrawn
- 2021-07-29 WO PCT/JP2021/028088 patent/WO2022025176A1/en active Application Filing
- 2021-07-29 KR KR1020227042258A patent/KR20230044359A/en active Pending
- 2021-07-30 TW TW110128144A patent/TW202220657A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| TW202220657A (en) | 2022-06-01 |
| JPWO2022025176A1 (en) | 2022-02-03 |
| KR20230044359A (en) | 2023-04-04 |
| WO2022025176A1 (en) | 2022-02-03 |
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