JPWO2014192792A1 - Oral solution - Google Patents
Oral solution Download PDFInfo
- Publication number
- JPWO2014192792A1 JPWO2014192792A1 JP2015519892A JP2015519892A JPWO2014192792A1 JP WO2014192792 A1 JPWO2014192792 A1 JP WO2014192792A1 JP 2015519892 A JP2015519892 A JP 2015519892A JP 2015519892 A JP2015519892 A JP 2015519892A JP WO2014192792 A1 JPWO2014192792 A1 JP WO2014192792A1
- Authority
- JP
- Japan
- Prior art keywords
- vitamin
- salt
- liquid preparation
- riboflavin
- present
- 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.)
- Granted
Links
- 229940100688 oral solution Drugs 0.000 title abstract description 4
- 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 abstract description 48
- AUNGANRZJHBGPY-SCRDCRAPSA-N Riboflavin Chemical compound OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-SCRDCRAPSA-N 0.000 claims abstract description 39
- 239000007788 liquid Substances 0.000 claims abstract description 37
- 238000002360 preparation method Methods 0.000 claims abstract description 31
- 150000003839 salts Chemical class 0.000 claims abstract description 30
- 229930003427 Vitamin E Natural products 0.000 claims abstract description 22
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 claims abstract description 22
- 239000011709 vitamin E Substances 0.000 claims abstract description 22
- 229940046009 vitamin E Drugs 0.000 claims abstract description 22
- 235000019165 vitamin E Nutrition 0.000 claims abstract description 22
- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 claims abstract description 20
- 150000004347 all-trans-retinol derivatives Chemical class 0.000 claims abstract description 11
- 239000000473 propyl gallate Substances 0.000 claims abstract description 10
- 235000010388 propyl gallate Nutrition 0.000 claims abstract description 10
- 229940075579 propyl gallate Drugs 0.000 claims abstract description 10
- AUNGANRZJHBGPY-UHFFFAOYSA-N D-Lyxoflavin Natural products OCC(O)C(O)C(O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229960002477 riboflavin Drugs 0.000 claims abstract description 8
- 229950001574 riboflavin phosphate Drugs 0.000 claims description 13
- -1 flavin adenine nucleotide Chemical class 0.000 claims description 6
- 229930003799 tocopherol Natural products 0.000 claims description 5
- 239000011732 tocopherol Substances 0.000 claims description 5
- FVTCRASFADXXNN-SCRDCRAPSA-N flavin mononucleotide Chemical compound OP(=O)(O)OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O FVTCRASFADXXNN-SCRDCRAPSA-N 0.000 claims description 4
- 235000019192 riboflavin Nutrition 0.000 claims description 4
- 239000002151 riboflavin Substances 0.000 claims description 4
- 235000010384 tocopherol Nutrition 0.000 claims description 4
- 229960001295 tocopherol Drugs 0.000 claims description 4
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 claims description 4
- MJNIWUJSIGSWKK-BBANNHEPSA-N Riboflavin butyrate Chemical compound CCCC(=O)OC[C@@H](OC(=O)CCC)[C@@H](OC(=O)CCC)[C@@H](OC(=O)CCC)CN1C2=CC(C)=C(C)C=C2N=C2C1=NC(=O)NC2=O MJNIWUJSIGSWKK-BBANNHEPSA-N 0.000 claims description 3
- 230000007423 decrease Effects 0.000 abstract description 7
- 229930003471 Vitamin B2 Natural products 0.000 abstract 4
- 235000019164 vitamin B2 Nutrition 0.000 abstract 4
- 239000011716 vitamin B2 Substances 0.000 abstract 4
- 230000015556 catabolic process Effects 0.000 abstract 1
- 238000006731 degradation reaction Methods 0.000 abstract 1
- 230000000052 comparative effect Effects 0.000 description 12
- 229940088594 vitamin Drugs 0.000 description 10
- 229930003231 vitamin Natural products 0.000 description 10
- 235000013343 vitamin Nutrition 0.000 description 10
- 239000011782 vitamin Substances 0.000 description 10
- OHSHFZJLPYLRIP-BMZHGHOISA-M Riboflavin sodium phosphate Chemical compound [Na+].OP(=O)([O-])OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O OHSHFZJLPYLRIP-BMZHGHOISA-M 0.000 description 9
- 239000003814 drug Substances 0.000 description 9
- ZAKOWWREFLAJOT-CEFNRUSXSA-N D-alpha-tocopherylacetate Chemical group CC(=O)OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C ZAKOWWREFLAJOT-CEFNRUSXSA-N 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 235000013305 food Nutrition 0.000 description 5
- 229940042585 tocopherol acetate Drugs 0.000 description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 230000036541 health Effects 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000008213 purified water Substances 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 150000003722 vitamin derivatives Chemical class 0.000 description 3
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- IELOKBJPULMYRW-NJQVLOCASA-N D-alpha-Tocopheryl Acid Succinate Chemical compound OC(=O)CCC(=O)OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C IELOKBJPULMYRW-NJQVLOCASA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 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 description 2
- 230000009471 action Effects 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 230000003078 antioxidant effect Effects 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 2
- 238000013329 compounding Methods 0.000 description 2
- 229940099418 d- alpha-tocopherol succinate Drugs 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- LNTHITQWFMADLM-UHFFFAOYSA-N gallic acid Chemical compound OC(=O)C1=CC(O)=C(O)C(O)=C1 LNTHITQWFMADLM-UHFFFAOYSA-N 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 239000003002 pH adjusting agent Substances 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 208000003265 stomatitis Diseases 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- 235000019156 vitamin B Nutrition 0.000 description 2
- 239000011720 vitamin B Substances 0.000 description 2
- 150000003712 vitamin E derivatives Chemical class 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 239000004278 EU approved seasoning Substances 0.000 description 1
- LPHGQDQBBGAPDZ-UHFFFAOYSA-N Isocaffeine Natural products CN1C(=O)N(C)C(=O)C2=C1N(C)C=N2 LPHGQDQBBGAPDZ-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 229930003270 Vitamin B Natural products 0.000 description 1
- GFFGJBXGBJISGV-UHFFFAOYSA-N adenyl group Chemical class N1=CN=C2N=CNC2=C1N GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 235000013361 beverage Nutrition 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229960001948 caffeine Drugs 0.000 description 1
- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 235000018823 dietary intake Nutrition 0.000 description 1
- 230000002049 effect on nutrition Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 235000011194 food seasoning agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 235000013376 functional food Nutrition 0.000 description 1
- 235000004515 gallic acid Nutrition 0.000 description 1
- 229940074391 gallic acid Drugs 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 239000012676 herbal extract Substances 0.000 description 1
- 241000411851 herbal medicine Species 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 230000007721 medicinal effect Effects 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 235000019629 palatability Nutrition 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- YXJHJCDOUFKMBG-BMZHGHOISA-M riboflavin sodium Chemical compound [Na+].OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)[N-]C2=O YXJHJCDOUFKMBG-BMZHGHOISA-M 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000005728 strengthening Methods 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 235000011044 succinic acid Nutrition 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 125000002640 tocopherol group Chemical class 0.000 description 1
- 235000019149 tocopherols Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 235000021122 unsaturated fatty acids Nutrition 0.000 description 1
- 150000004670 unsaturated fatty acids Chemical class 0.000 description 1
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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/525—Isoalloxazines, e.g. riboflavins, vitamin B2
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23K—FODDER
- A23K20/00—Accessory food factors for animal feeding-stuffs
- A23K20/10—Organic substances
- A23K20/174—Vitamins
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/15—Vitamins
-
- 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
- A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
- A61K31/355—Tocopherols, e.g. vitamin E
-
- 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
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
-
- 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
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/02—Nutrients, e.g. vitamins, minerals
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Polymers & Plastics (AREA)
- Engineering & Computer Science (AREA)
- Food Science & Technology (AREA)
- Nutrition Science (AREA)
- General Chemical & Material Sciences (AREA)
- Animal Husbandry (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Emergency Medicine (AREA)
- Obesity (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Zoology (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Mycology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
ビタミンＢ２又はその塩と、ビタミンＥ又はその誘導体とを含有する内服液剤において生じる、ビタミンＢ２又はその塩の光安定性の低下、すなわちビタミンＢ２やその塩の光による分解を抑制する手段を提供することを目的とし、ビタミンＢ２又はその塩類、ビタミンＥ又はその誘導体及び没食子酸プロピルを配合したことを特徴とする内服液剤。Provided is a means for suppressing a decrease in photostability of vitamin B2 or a salt thereof, that is, degradation of vitamin B2 or a salt thereof caused by light, which occurs in an oral solution containing vitamin B2 or a salt thereof and vitamin E or a derivative thereof. For this purpose, an oral liquid preparation comprising vitamin B2 or a salt thereof, vitamin E or a derivative thereof and propyl gallate.
Description
本発明は、内服液剤に関し、更に詳細には、医薬品、指定医薬部外品、保健機能食品および食品の分野に利用しうる、ビタミンＢ２又はその塩とビタミンＥ又はその誘導体を配合した内服液剤に関する。 TECHNICAL FIELD The present invention relates to an internal liquid preparation, and more specifically, an internal liquid preparation containing vitamin B 2 or a salt thereof and vitamin E or a derivative thereof, which can be used in the fields of pharmaceuticals, designated quasi drugs, health functional foods and foods. About.
ビタミンＢ２又はその塩は、口角炎、口内炎等の諸症状の緩和に有効であるなど様々な薬効が知られており、重要な水溶性ビタミンであるため、医薬品、指定医薬部外品、食品などに広く配合されている。Vitamin B 2 or a salt thereof is known to have various medicinal properties, such as effective in alleviating various symptoms such as stomatitis and stomatitis, and is an important water-soluble vitamin. It is widely blended.
また、ビタミンＥ又はその誘導体は、脂質、特に不飽和脂肪酸に対する抗酸化作用により、過酸化脂質の生成を防ぐなど重要な脂溶性ビタミンであるため、医薬品、指定医薬部外品、食品などに広く配合されている。 Vitamin E or its derivatives are important fat-soluble vitamins, such as preventing the formation of lipid peroxides by antioxidant action on lipids, especially unsaturated fatty acids, so they are widely used in medicines, designated quasi drugs, foods, etc. It is blended.
これらビタミンＢ２などの水溶性ビタミンと、ビタミンＥなどの脂溶性ビタミンを併せて摂取することで、肉体疲労時の栄養補給や滋養強壮に優れた効果を示すことが期待される。例えば、特許文献１にはビタミンＢ２などの水溶性ビタミンとビタミンＥなどの脂溶性ビタミンに加えてアミノ酸やミネラルを配合した錠剤が開示されている。And water-soluble vitamins such as these vitamins B 2, by ingestion together fat-soluble vitamins such as vitamin E, is expected to exhibit an excellent effect on nutrition and nutritional fortification during physical fatigue. For example, a tablet is disclosed formulated with amino acids and minerals in addition to the fat-soluble vitamins such as water-soluble vitamins and vitamin E such as vitamin B 2 in Patent Document 1.
ところで近年、ビタミンを含有する製剤として、服用が容易で嗜好性の高い内服液剤が求められている。そこで、本発明者らは、ビタミンＢ２あるいはその塩と、ビタミンＥあるいはその誘導体を配合した内服液剤を製剤設計していたところ、脂溶性であるビタミンＥ等の存在下では、水溶性であるビタミンＢ２やその塩の光に対する安定性が低下するという新たな事実を見出した。In recent years, there has been a demand for a liquid preparation containing vitamins that is easy to take and has high palatability. Therefore, the present inventors have designed an internal liquid preparation containing vitamin B 2 or a salt thereof and vitamin E or a derivative thereof, and are water-soluble in the presence of fat-soluble vitamin E or the like. stability to light of vitamin B 2 and its salts have found a new fact that reduced.
本発明は、上記のビタミンＥ又はその誘導体と、ビタミンＢ２又はその塩を含有する内服液剤において生じる、ビタミンＢ２又はその塩の光安定性の低下、すなわちビタミンＢ２やその塩の光による分解を抑制する手段を提供することを課題とするものである。The present invention includes a vitamin E or a derivative thereof described above, occurs in oral liquid preparation containing vitamin B 2 or a salt thereof, reduction in light stability of vitamin B 2 or a salt thereof, i.e. with light of vitamin B 2 and its salts It is an object of the present invention to provide means for suppressing decomposition.
本発明者らは、上記課題を解決すべく内服液剤の配合成分について鋭意検討した結果、ビタミンＢ２又はその塩とビタミンＥ又はその誘導体とを含有した内服液剤中に、没食子酸プロピルを配合することにより、ビタミンＢ２又はその塩の光安定性の低下を抑制できることを見出し、本発明を完成するに至った。The present inventors have made extensive studies for a blending component in oral liquid preparation to solve the above problems, the oral liquid preparation containing a vitamin B 2, or a salt thereof and vitamin E or a derivative thereof, formulated propyl gallate As a result, it was found that a decrease in photostability of vitamin B 2 or a salt thereof can be suppressed, and the present invention has been completed.
即ち本発明は、
（１）ビタミンＢ２又はその塩、ビタミンＥ又はその誘導体及び没食子酸プロピルを配合したことを特徴とする内服液剤、
（２）ビタミンＢ２又はその塩が、リボフラビン、リン酸リボフラビン、酪酸リボフラビン、フラビンアデニンヌクレオチド又はそれらの塩から選ばれる（１）に記載の内服液剤、
（３）ビタミンＥ又はその誘導体が、α型、β型、γ型のトコフェロール又はそれらの誘導体から選ばれる（１）または（２）に記載の内服液剤、
（４）ビタミンＥの誘導体が、酢酸トコフェロール又はコハク酸トコフェロールである（１）ないし（３）の何れかの項記載の内服液剤、
（５）没食子酸プロピルを、ビタミンＢ２又はその塩１質量部に対し、０.０１〜２質量部配合した（１）ないし（４）の何れかの項記載の内服液剤、
である。That is, the present invention
(1) An internal liquid preparation comprising vitamin B 2 or a salt thereof, vitamin E or a derivative thereof and propyl gallate,
(2) The internal liquid preparation according to (1), wherein vitamin B 2 or a salt thereof is selected from riboflavin, riboflavin phosphate, riboflavin butyrate, flavin adenine nucleotide, or a salt thereof,
(3) The internal liquid preparation according to (1) or (2), wherein vitamin E or a derivative thereof is selected from α-type, β-type, γ-type tocopherol or derivatives thereof,
(4) The internal liquid preparation according to any one of (1) to (3), wherein the vitamin E derivative is tocopherol acetate or tocopherol succinate,
(5) An oral solution according to any one of (1) to (4), wherein 0.01 to 2 parts by mass of propyl gallate is blended with 1 part by mass of vitamin B 2 or a salt thereof.
It is.
本発明により、ビタミンＢ２又はその塩と、ビタミンＥ又はその誘導体とを配合した内服液剤中で生じる、ビタミンＢ２又はその塩の光安定性の低下、すなわち光によるビタミンＢ２やその塩の含量の低下を有効に抑制することができる。The present invention, vitamin B 2 or a salt thereof, occurs in oral liquid preparation containing a combination of vitamin E or its derivatives, vitamin B 2 or a salt reduction in light stability, i.e., vitamin B 2 or a salt thereof with light The decrease in content can be effectively suppressed.
本発明の内服液剤は、必須成分としてビタミンＢ２又はその塩（以下、「ビタミンＢ２類」と略称する）、ビタミンＥ又はその誘導体（以下、「ビタミンＥ類」と略称する）および没食子酸プロピルの３成分を含有するものである。The internal use liquid preparation of the present invention comprises vitamin B 2 or a salt thereof (hereinafter abbreviated as “vitamin B 2 ”), vitamin E or a derivative thereof (hereinafter abbreviated as “vitamin E”) and gallic acid as essential components. It contains three components of propyl.
本発明の内服液剤に使用するビタミンＢ２とは、通常可食性のものを指し、具体的にはリボフラビン、リン酸リボフラビン、酪酸リボフラビン、フラビンアデニンヌクレオチドナトリウム及びそれらの塩などを挙げることができる。また、その塩としては、ナトリウム塩、カリウム塩などの医薬品、食品として利用可能な塩が挙げられる。The vitamin B 2 to be used in oral liquid preparation of the present invention, refers to those usually edible, it can be specifically mentioned riboflavin, riboflavin phosphate, riboflavin butyrate, and flavin adenine nucleotide sodium and salts thereof. In addition, examples of the salt include salts that can be used as pharmaceuticals and foods such as sodium salt and potassium salt.
本発明の内服液剤に配合されるビタミンＢ２類の量は、栄養摂取量の面から、リボフラビンに換算して１日当たり０.０１〜１００ｍｇであり、０.５〜５０ｍｇであることが好ましく、１ｍｇ〜２０ｍｇであることが最も好ましい。また、この配合量は、例えば容量１００ｍＬの内服液剤の濃度に換算すると、内服液剤全体の０.００００１〜０.１質量％（Ｗ／Ｖ％）であり，０.０００５〜０.０５質量％であることが好ましく、０.００１〜０.０２質量％が最も好ましい。The amount of vitamin B 2 compounded in the internal liquid preparation of the present invention is 0.01 to 100 mg per day in terms of nutritional intake, and preferably 0.5 to 50 mg in terms of riboflavin. Most preferably, it is 1 mg to 20 mg. Moreover, this compounding quantity is 0.0001-0.1 mass% (W / V%) of the whole internal use liquid, for example when converted into the density | concentration of the internal use liquid with a capacity | capacitance of 100 mL, and 0.0005-0.05 mass%. And 0.001 to 0.02% by mass is most preferable.
一方、本発明の内服液剤に使用するビタミンＥとは、通常可食性のものを指し、具体的にはα型、β型、γ型のトコフェロールなどを挙げることができる。また、その誘導体としては、公知のビタミンＥ誘導体、例えば、酢酸トコフェロール、コハク酸トコフェロールなどが挙げられる。 On the other hand, the vitamin E used in the internal liquid preparation of the present invention is usually edible, and specifically includes α-type, β-type, γ-type tocopherol and the like. Examples of the derivatives include known vitamin E derivatives such as tocopherol acetate and tocopherol succinate.
本発明において配合することができるビタミンＥ類の配合量は、１日当たり０.０１〜２００ｍｇであり、０.５〜１５０ｍｇであることが好ましく、１ｍｇ〜１００ｍｇであることが最も好ましい。また、この配合量は、例えば容量１００ｍＬの内服液剤の濃度に換算すると、内服液剤全体の０.００００１〜０.２質量％（Ｗ／Ｖ％）であり，０.０００５〜０.１５質量％であることが好ましく、０.００１〜０.１質量％が最も好ましい。 The amount of vitamin E that can be blended in the present invention is 0.01 to 200 mg per day, preferably 0.5 to 150 mg, and most preferably 1 to 100 mg. Moreover, this compounding quantity is 0.0001-0.2 mass% (W / V%) of the whole internal use liquid agent, when converted into the density | concentration of the internal use liquid agent of a capacity | capacitance of 100 mL, for example, 0.0005-0.15 mass% It is preferable that 0.001 to 0.1% by mass is most preferable.
更に、本発明の内服液剤に使用する没食子酸プロピルの配合量は、ビタミンＥ類を内服液剤に配合した際に生じるビタミンＢ２類の光安定性低下を抑制する効果を有する範囲であれば特に制限はされないが、好ましくは内服液剤中に含まれるビタミンＢ２類１質量部に対して０.０１〜２質量部であり、さらに好ましくは０.１〜１質量部である。Furthermore, the amount of propyl gallate for use in oral liquid preparation of the present invention, particularly as long as it has the effect of suppressing the photostability reduction of vitamin B 2 such that occurs when blended with vitamin E in oral liquid preparation restrictions are not limited to, preferably from 0.01 to 2 parts by weight with respect to class 2 1 part by weight vitamin B contained in oral liquid preparation, more preferably 0.1 to 1 parts by weight.
また更に、本発明にかかる内服液剤のｐＨは、一般には２.０〜７.０の範囲であり、好ましくは２.５〜５.５であり、最も好ましくは２.５〜４.０である。ｐＨが２.０未満であると酸味が強すぎて服用性の点で好ましくなく、ｐＨが７.０を超える領域では服用性の点で好ましくないからである。なお、本発明の内服液剤では、そのｐＨを上記範囲に保つために、必要に応じてｐＨ調整剤が配合される。ｐＨ調整剤としては、クエン酸、リンゴ酸、フマル酸、酒石酸、乳酸、コハク酸などの有機酸及びそれらの塩、塩酸などの無機酸、水酸化ナトリウムなどの無機塩基などが挙げられる。 Furthermore, the pH of the internal solution according to the present invention is generally in the range of 2.0 to 7.0, preferably 2.5 to 5.5, and most preferably 2.5 to 4.0. is there. This is because if the pH is less than 2.0, the acidity is so strong that it is not preferable in terms of dosing properties, and if the pH exceeds 7.0, it is not preferable in terms of dosing properties. In addition, in the internal use liquid preparation of this invention, in order to maintain the pH in the said range, a pH adjuster is mix | blended as needed. Examples of the pH adjuster include organic acids such as citric acid, malic acid, fumaric acid, tartaric acid, lactic acid, and succinic acid and salts thereof, inorganic acids such as hydrochloric acid, and inorganic bases such as sodium hydroxide.
また、本発明の内服液剤にはその他の成分として、他のビタミン類、ミネラル類、アミノ酸及びその塩、他の生薬や生薬抽出物、カフェインなどを本発明の効果を損なわない範囲で適宜に配合することができる。 In addition, in the oral liquid of the present invention, other vitamins, minerals, amino acids and salts thereof, other herbal medicines and herbal extracts, caffeine, and the like are appropriately added as long as the effects of the present invention are not impaired. Can be blended.
さらに必要に応じて、甘味料、酸味料、増粘安定剤、酸化防止剤、着色剤、香料、矯味剤、保存料、調味料、苦味料、強化剤、可溶化剤、乳化剤など、内服液剤で使用される添加物を本発明の効果を損なわない範囲で適宜に配合することができる。これらの添加物等は、単独で配合しても、２種以上を適宜組み合わせて配合してもよい。 Furthermore, as needed, oral liquids such as sweeteners, acidulants, thickening stabilizers, antioxidants, coloring agents, flavorings, flavoring agents, preservatives, seasonings, bittering agents, strengthening agents, solubilizers, emulsifiers, etc. Additives used in the above can be appropriately blended within a range not impairing the effects of the present invention. These additives may be blended singly or in combination of two or more.
本発明の内服液剤は、常法により調製することができ、その方法は特に限定されるものではない。通常、各成分を適量の精製水で溶解した後、ｐＨを調整し、残りの精製水を加えて容量調整し、必要に応じてろ過、殺菌処理することにより得られる。 The internal liquid preparation of the present invention can be prepared by a conventional method, and the method is not particularly limited. Usually, it is obtained by dissolving each component with an appropriate amount of purified water, adjusting the pH, adjusting the volume by adding the remaining purified water, and performing filtration and sterilization treatment as necessary.
このようにして得られる本発明の内服液剤は、例えばシロップ剤、ドリンク剤などの医薬品や指定医薬部外品などの各種製剤、健康飲料などの各種飲料に適用することができる。 The internal liquid preparation of the present invention thus obtained can be applied to various preparations such as pharmaceuticals such as syrups and drinks, designated quasi-drugs, and various beverages such as health drinks.
以下に実施例及び試験例を挙げ、本発明をさらに詳細に説明するが、本発明はこれらの実施例等に何ら限定されるものではない。 EXAMPLES The present invention will be described in more detail below with reference to examples and test examples, but the present invention is not limited to these examples.
実 施 例 １〜３ および 比 較 例 １〜４
内服液剤の調製：
表１に記載の処方の各成分を秤量して、精製水に溶解させ、そのｐＨが所定の値（３.２）になるよう、かつ、全量が１００ｍＬとなるように調整した。続いて濾紙ろ過を行い、その後にガラス瓶に充填し、キャップを施して本発明の実施例１〜３及び比較例１〜４の内服液剤を得た。Examples 1-3 and Comparative Examples 1-4
Preparation of oral solution:
Each component of the formulation described in Table 1 was weighed and dissolved in purified water, and the pH was adjusted to a predetermined value (3.2) and the total amount was adjusted to 100 mL. Subsequently, filtration with a filter paper was performed, and then a glass bottle was filled, and a cap was applied to obtain internal liquid preparations of Examples 1-3 and Comparative Examples 1-4 of the present invention.
試 験 例 １
（１）試験方法
実施例１及び比較例１から４の各試料を、Ｄ６５光安定性試験機にて３０００ｌｘで６時間曝光させた。また、実施例１から３及び比較例１、２の各試料を、Ｄ６５光安定性試験機にて３０００ｌｘで２時間２０分曝光させた。Test example 1
(1) Test method Each sample of Example 1 and Comparative Examples 1 to 4 was exposed at 3000 lx for 6 hours with a D65 light stability tester. Moreover, each sample of Examples 1 to 3 and Comparative Examples 1 and 2 was exposed at 3000 lx for 2 hours and 20 minutes using a D65 light stability tester.
曝光後、各試験液中のリン酸リボフラビンナトリウム残存率を液体クロマトグラフ法（カラム：ＯＤＳ-８０ＴＳ（東ソー）、移動相：水：アセトニトリル：リン酸＝８８０：１２０：１、流速：１ｍＬ/ｍｉｎ、検出：蛍光検出器（励起波長３７０ｎｍ、蛍光波長５２５ｎｍ））により定量し、暗所保存品に対する曝光品のリン酸リボフラビンナトリウム残存率（％）を算出した。 After exposure, the residual rate of riboflavin sodium phosphate in each test solution was determined by liquid chromatography (column: ODS-80TS (Tosoh), mobile phase: water: acetonitrile: phosphoric acid = 880: 120: 1, flow rate: 1 mL / min. , Detection: Quantification was performed with a fluorescence detector (excitation wavelength: 370 nm, fluorescence wavelength: 525 nm), and the residual rate (%) of riboflavin sodium phosphate in the exposed product relative to the stored product in the dark was calculated.
（２）結果
暗所保存品に対する３０００ｌｘで６時間曝光後のリン酸リボフラビンナトリウム残存率（％）を表２に、暗所保存品に対する３０００ｌｘで２時間２０分曝光後のリン酸リボフラビンナトリウム残存率（％）を表３に示す。(2) Results The residual rate of riboflavin sodium phosphate (%) after exposure to 3000 lx for 6 hours in the dark storage product is shown in Table 2, and the residual rate of riboflavin sodium phosphate after 2 hours and 20 minutes exposure to 3000 lx for the dark storage product (%) Is shown in Table 3.
表２での比較例１と比較例２の結果から、トコフェロール類である酢酸トコフェロールを配合したリン酸リボフラビンナトリウム配合液剤は、トコフェロール類を含有しない場合に比べ、３０００ｌｘで６時間曝光後、リン酸リボフラビンナトリウムの残存率が低くなることが分かった。これに対し、没食子酸プロピルを配合した実施例１では、酢酸トコフェロールを配合しているにも関わらず、リン酸リボフラビンナトリウムのみを含有する内服製剤（比較例１）に比べても、リン酸リボフラビンナトリウムの残存率の低下が抑制されることが分かった。 From the results of Comparative Example 1 and Comparative Example 2 in Table 2, the riboflavin sodium phosphate mixture containing tocopherol acetate, which is a tocopherol, is phosphoric acid after exposure at 3000 lx for 6 hours compared to the case where it does not contain tocopherols. It was found that the residual rate of riboflavin sodium was low. On the other hand, in Example 1 in which propyl gallate was blended, riboflavin phosphate was also compared with the oral preparation containing only riboflavin sodium phosphate (Comparative Example 1) despite the blending of tocopherol acetate. It was found that the decrease in the residual rate of sodium was suppressed.
なお、表２の比較例３に示したとおり、汎用される抗酸化剤であるアスコルビン酸を配合した場合、リン酸リボフラビンナトリウムの残存率は比較例２と比較して低いことから光安定性はむしろ低下することが分かった。また、比較例４の亜硫酸ナトリウム配合時のリン酸リボフラビンナトリウムの残存率は比較例２よりもわずかに高いものの、酢酸トコフェロールを配合していない比較例１よりも低いことから十分な光安定性は得られないことが分かった。よって、没食子酸プロピルは、ビタミンＢ２またはその塩を配合する内服液剤において、光安定性の低下防止に顕著な効果を有するものということができる。In addition, as shown in Comparative Example 3 in Table 2, when ascorbic acid, which is a commonly used antioxidant, is blended, the residual ratio of riboflavin sodium phosphate is lower than that of Comparative Example 2, so that the light stability is Rather it was found to decline. Moreover, although the residual rate of the riboflavin sodium phosphate at the time of mixing sodium sulfite of Comparative Example 4 is slightly higher than that of Comparative Example 2, it is lower than that of Comparative Example 1 in which tocopherol acetate is not mixed. I found out that I couldn't Therefore, it can be said that propyl gallate has a remarkable effect in preventing the deterioration of light stability in an internal liquid preparation containing vitamin B 2 or a salt thereof.
また、表３に示される実施例１から３では、内服液剤中に含まれる没食子酸プロピルの量に依存して内服液剤中のリン酸リボフラビンナトリウムの残存率の低下が抑制されることから、この作用が没食子酸プロピルの作用によることが確認できた。 Further, in Examples 1 to 3 shown in Table 3, since the decrease in the residual rate of riboflavin sodium phosphate in the internal liquid is suppressed depending on the amount of propyl gallate contained in the internal liquid, this It was confirmed that the action was due to the action of propyl gallate.
本発明により、水溶性ビタミンであるビタミンＢ２類と、脂溶性ビタミンであるビタミンＥ類を含有する、滋養強壮に優れた効果を有し、かつ光安定性の低下を防止した内服液剤を得ることができる。INDUSTRIAL APPLICABILITY According to the present invention, an oral liquid preparation containing a vitamin B 2 that is a water-soluble vitamin and a vitamin E that is a fat-soluble vitamin, having an excellent effect of nourishing toughness and preventing a decrease in photostability is obtained. be able to.
そしてこの内服液剤は、上記のようにビタミンＢ２類とビタミンＥ類とを安定に含有するものであるため、商品性の高い医薬品、指定医薬部外品、食品、健康飲料、特定保健用食品としての利用が期待されるものである。
And this oral liquid formulation, since those containing vitamin B 2 such as vitamin E and stably as described above, product highly pharmaceuticals, designated quasi-drugs, foods, health drinks, food for specified health use Is expected to be used.
Claims (3)
The oral liquid according to claim 1 or 2, wherein vitamin E or a derivative thereof is selected from α-type, β-type, γ-type tocopherol or derivatives thereof.
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| JPH10175855A (en) * | 1996-10-16 | 1998-06-30 | Taisho Pharmaceut Co Ltd | Physical fatigue relieving agent |
| JP2005104960A (en) * | 2003-09-12 | 2005-04-21 | Eisai Co Ltd | Internal liquid agent and taste quality change-preventing liquid agent for glucuronolactone-containing solution |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BR9105986A (en) * | 1990-02-05 | 1992-11-10 | Univ Texas | TIME-RELEASE FORMULATION OF VITAMINS, MINERALS AND OTHER BENEFICIAL SUPPLEMENTS |
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2014
- 2014-05-28 JP JP2015519892A patent/JP6323453B2/en active Active
- 2014-05-28 WO PCT/JP2014/064073 patent/WO2014192792A1/en active Application Filing
- 2014-05-30 TW TW103119032A patent/TW201534350A/en unknown
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH10175855A (en) * | 1996-10-16 | 1998-06-30 | Taisho Pharmaceut Co Ltd | Physical fatigue relieving agent |
| JP2005104960A (en) * | 2003-09-12 | 2005-04-21 | Eisai Co Ltd | Internal liquid agent and taste quality change-preventing liquid agent for glucuronolactone-containing solution |
Also Published As
| Publication number | Publication date |
|---|---|
| TW201534350A (en) | 2015-09-16 |
| WO2014192792A1 (en) | 2014-12-04 |
| JP6323453B2 (en) | 2018-05-16 |
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