JP5359333B2 - Corosolic acid-containing aqueous solution - Google Patents
Corosolic acid-containing aqueous solution Download PDFInfo
- Publication number
- JP5359333B2 JP5359333B2 JP2009024461A JP2009024461A JP5359333B2 JP 5359333 B2 JP5359333 B2 JP 5359333B2 JP 2009024461 A JP2009024461 A JP 2009024461A JP 2009024461 A JP2009024461 A JP 2009024461A JP 5359333 B2 JP5359333 B2 JP 5359333B2
- Authority
- JP
- Japan
- Prior art keywords
- dissolved
- corosolic acid
- solution
- injection
- added
- 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.)
- Active
Links
- FRWNAQDBODEVAL-VMPITWQZSA-N (5e)-5-[(4-nitrophenyl)methylidene]-2-sulfanylidene-1,3-thiazolidin-4-one Chemical compound C1=CC([N+](=O)[O-])=CC=C1\C=C\1C(=O)NC(=S)S/1 FRWNAQDBODEVAL-VMPITWQZSA-N 0.000 title claims description 88
- QNMKGMUGYVWVFQ-UHFFFAOYSA-N 2alpha-Hydroxyursolic acid Natural products CC12CC(O)C(O)C(C)(C)C1CCC1(C)C2CC=C2C3C(C)C(C)(C)CCC3(C(O)=O)CCC21C QNMKGMUGYVWVFQ-UHFFFAOYSA-N 0.000 title claims description 88
- 239000007864 aqueous solution Substances 0.000 title description 20
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 96
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 60
- 239000007788 liquid Substances 0.000 claims description 58
- 238000002347 injection Methods 0.000 claims description 54
- 239000007924 injection Substances 0.000 claims description 54
- 238000002360 preparation method Methods 0.000 claims description 28
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 17
- 150000005846 sugar alcohols Polymers 0.000 claims description 12
- 239000004094 surface-active agent Substances 0.000 claims description 6
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 claims description 5
- SZXQTJUDPRGNJN-UHFFFAOYSA-N dipropylene glycol Chemical compound OCCCOCCCO SZXQTJUDPRGNJN-UHFFFAOYSA-N 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 239000002202 Polyethylene glycol Substances 0.000 claims description 2
- 229920001223 polyethylene glycol Polymers 0.000 claims description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 105
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 53
- 239000000243 solution Substances 0.000 description 39
- 230000000052 comparative effect Effects 0.000 description 34
- 239000003002 pH adjusting agent Substances 0.000 description 34
- 238000003756 stirring Methods 0.000 description 31
- 238000001914 filtration Methods 0.000 description 29
- 239000000203 mixture Substances 0.000 description 28
- 239000008213 purified water Substances 0.000 description 27
- 239000011521 glass Substances 0.000 description 24
- 239000012528 membrane Substances 0.000 description 19
- 239000012153 distilled water Substances 0.000 description 18
- 239000001509 sodium citrate Substances 0.000 description 16
- 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 16
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 15
- 239000011259 mixed solution Substances 0.000 description 15
- -1 triterpene carboxylic acid Chemical class 0.000 description 15
- 238000000034 method Methods 0.000 description 13
- 239000004376 Sucralose Substances 0.000 description 12
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 12
- 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 12
- 235000019408 sucralose Nutrition 0.000 description 12
- 238000001556 precipitation Methods 0.000 description 11
- 238000012360 testing method Methods 0.000 description 11
- 239000004743 Polypropylene Substances 0.000 description 10
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 10
- 229920001155 polypropylene Polymers 0.000 description 10
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 10
- 229940075582 sorbic acid Drugs 0.000 description 10
- 235000010199 sorbic acid Nutrition 0.000 description 10
- 239000004334 sorbic acid Substances 0.000 description 10
- 239000008280 blood Substances 0.000 description 9
- 210000004369 blood Anatomy 0.000 description 9
- 229940100688 oral solution Drugs 0.000 description 9
- 239000004033 plastic Substances 0.000 description 9
- 229920003023 plastic Polymers 0.000 description 9
- 238000003860 storage Methods 0.000 description 9
- JXXCENBLGFBQJM-UHFFFAOYSA-N (3-carboxy-2-hydroxypropyl)-trimethylazanium;chloride Chemical compound [Cl-].C[N+](C)(C)CC(O)CC(O)=O JXXCENBLGFBQJM-UHFFFAOYSA-N 0.000 description 8
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 8
- 229960000678 carnitine chloride Drugs 0.000 description 8
- 229920001971 elastomer Polymers 0.000 description 8
- 239000000806 elastomer Substances 0.000 description 8
- 239000008103 glucose Substances 0.000 description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 7
- 239000003708 ampul Substances 0.000 description 7
- 238000004090 dissolution Methods 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 239000003795 chemical substances by application Substances 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 4
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- 239000000872 buffer Substances 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-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
- 102000004877 Insulin Human genes 0.000 description 2
- 108090001061 Insulin Proteins 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 239000008186 active pharmaceutical agent Substances 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- 235000013361 beverage Nutrition 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- 229940088679 drug related substance Drugs 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
- 235000019414 erythritol Nutrition 0.000 description 2
- 229940009714 erythritol Drugs 0.000 description 2
- 238000011049 filling Methods 0.000 description 2
- 229940125396 insulin Drugs 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 235000021056 liquid food Nutrition 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- XBZYWSMVVKYHQN-MYPRUECHSA-N (4as,6as,6br,8ar,9r,10s,12ar,12br,14bs)-10-hydroxy-2,2,6a,6b,9,12a-hexamethyl-9-[(sulfooxy)methyl]-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-4a-carboxylic acid Chemical compound C1C[C@H](O)[C@@](C)(COS(O)(=O)=O)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(C(O)=O)CCC(C)(C)C[C@H]5C4=CC[C@@H]3[C@]21C XBZYWSMVVKYHQN-MYPRUECHSA-N 0.000 description 1
- 229940058015 1,3-butylene glycol Drugs 0.000 description 1
- TUSDEZXZIZRFGC-UHFFFAOYSA-N 1-O-galloyl-3,6-(R)-HHDP-beta-D-glucose Natural products OC1C(O2)COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC1C(O)C2OC(=O)C1=CC(O)=C(O)C(O)=C1 TUSDEZXZIZRFGC-UHFFFAOYSA-N 0.000 description 1
- 241000254032 Acrididae Species 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 241000254173 Coleoptera Species 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical class OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 244000061508 Eriobotrya japonica Species 0.000 description 1
- 235000009008 Eriobotrya japonica Nutrition 0.000 description 1
- 235000004347 Perilla Nutrition 0.000 description 1
- 244000124853 Perilla frutescens Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 244000269722 Thea sinensis Species 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 102000004139 alpha-Amylases Human genes 0.000 description 1
- 108090000637 alpha-Amylases Proteins 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 239000013011 aqueous formulation Substances 0.000 description 1
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 235000019658 bitter taste Nutrition 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 235000019437 butane-1,3-diol Nutrition 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 229940048820 edetates Drugs 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 238000012812 general test Methods 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 235000013402 health food Nutrition 0.000 description 1
- 241000411851 herbal medicine Species 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000005374 membrane filtration Methods 0.000 description 1
- 231100000957 no side effect Toxicity 0.000 description 1
- 238000010979 pH adjustment Methods 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 238000005192 partition Methods 0.000 description 1
- 150000002966 pentacyclic triterpenoids Chemical class 0.000 description 1
- 229940071643 prefilled syringe Drugs 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- KMUJXIPRPXRPTP-DZBHQSCQSA-N testolic acid Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)(O)[C@@H](CCC(O)=O)[C@@H]3CCC2=C1 KMUJXIPRPXRPTP-DZBHQSCQSA-N 0.000 description 1
- 150000003648 triterpenes Chemical class 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Plant Substances (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
本発明は、コロソリン酸が安定に溶解しており、長期間に渡るも沈澱を生ずることがなく、通常の水性液剤への適用ばかりではなく、注射用液剤としても好適に使用できるコロソリン酸含有水性液剤に関する。 The present invention is a corosolic acid-containing aqueous solution in which corosolic acid is stably dissolved and does not cause precipitation over a long period of time, and can be suitably used not only as a normal aqueous solution but also as an injection solution. It relates to a liquid agent.
コロソリン酸は、バナバやビワ或いはシソなどの植物に多く含まれる血糖値抑制効果を有するトリテルペノイドである。バナバは、インドから東南アジア、オーストラリア北部などの熱帯・亜熱帯地域に広く自生するミソハギ科サルスベリ属の常緑高木で、日本名はオオバナサルスベリ、学名は、Lagerstroemia Speciosa Pers.である。バナバは、フィリピンにおいて1500年以上も前から、その葉や樹皮を煎じて民間療法として利用されてきた。最近では、日本においても、バナバ葉の糖尿病治療効果や血糖値抑制効果が着目され、健康食品(健康茶、各種飲料、顆粒、錠剤)などとして用いられるようになってきた。 Corosolic acid is a triterpenoid having a blood glucose level inhibitory effect that is contained in a large amount in plants such as banaba, loquat or perilla. Banaba is an evergreen tree that belongs to the genus Coleoptera, which grows widely in tropical and subtropical regions from India to Southeast Asia and northern Australia. It is. Banaba has been used as a folk remedy in the Philippines for more than 1500 years, decocting its leaves and bark. Recently, in Japan, attention has been focused on diabetes treatment effect and blood glucose level suppression effect of banaba leaves, and it has come to be used as health food (healthy tea, various beverages, granules, tablets) and the like.
バナバ葉が糖尿病治療効果及び血糖値抑制効果を示すメカニズムについては、インスリン同様、血中グルコースが細胞へ取り込まれるのを促進すること(増強活性)やデンプンの消化酵素であるα−アミラーゼ活性阻害作用が知られており(特許文献1及び2)、その活性成分は、コロソリン酸であることが解明されている。 As for the mechanism that banaba leaves show diabetes treatment effect and blood glucose level suppression effect, like insulin, blood glucose is taken up into cells (enhancement activity) and starch digestive enzyme α-amylase activity inhibition action (Patent Documents 1 and 2), and it has been elucidated that the active ingredient is corosolic acid.
コロソリン酸は、5環性のトリテルペノイドであり、前述のごとく血糖値を調整する機能を有することが知られている。コロソリン酸は、インスリンと大変似通った役割を示し、糖を細胞内に取り込むことを促すと考えられている。しかも、従来の経口血糖降下薬に見られる副作用の肝臓・膵臓・腎臓障害等がなく、また、ブドウ糖移動の賦活作用があること(特許文献2)などが報告されている。コロソリン酸を得るには、乾燥したバナバ葉を熱水若しくはアルコール抽出して濃縮する方法(特許文献3)、またバナバ葉の含水有機溶媒抽出物の不溶性画分をアルカリ性含水有機溶媒を用いて、コロソリン酸を高濃度含有するバナバ葉抽出物を得る方法(特許文献4)、さらにコロソリン酸の工業的な合成方法(特許文献5)が開示されている。 Corosolic acid is a pentacyclic triterpenoid and is known to have a function of adjusting blood glucose level as described above. Corosolic acid plays a very similar role to insulin and is thought to promote the uptake of sugar into cells. In addition, it has been reported that there are no side effects such as liver, pancreas, and kidney damage seen in conventional oral hypoglycemic drugs, and that there is an action to activate glucose movement (Patent Document 2). In order to obtain corosolic acid, a method of concentrating dried banaba leaves by hot water or alcohol extraction (Patent Document 3), and using an alkaline water-containing organic solvent for the insoluble fraction of the water-containing organic solvent extract of banaba leaves, A method for obtaining a banaba leaf extract containing corosolic acid at a high concentration (Patent Document 4) and an industrial synthesis method for corosolic acid (Patent Document 5) are disclosed.
しかしながら、コロソリン酸は水に対し極めて難溶であり、水系に添加した場合は、僅かな量であっても、沈殿又は浮遊物を生じる。このことからバナバ葉抽出物の液状の飲食品や医薬品への添加は困難が伴う。これを解決すべく、バナバ葉抽出物に界面活性剤を添加して可溶化又は分散化を図った技術が報告されている(特許文献6)。しかしこれは、pHが比較的低い範囲に限定されているため製剤上の設計に制約があること、苦味やえぐみを有する界面活性剤を用いることが必須要件となっているため、飲食品の場合、食感に悪影響をもたらすほか、添加された界面活性剤自体若しくはその分解物の沈殿が生じるなどの問題点がある。 However, corosolic acid is extremely poorly soluble in water, and when added to an aqueous system, precipitates or floats are formed even in a small amount. For this reason, it is difficult to add banaba leaf extract to liquid foods and beverages and pharmaceuticals. In order to solve this, a technique has been reported in which a surfactant is added to a banaba leaf extract so as to solubilize or disperse (Patent Document 6). However, since this is limited to a relatively low pH range, there are restrictions on the design of the formulation, and it is essential to use a surfactant with bitterness and puffiness. In addition to adversely affecting the texture, there are problems such as precipitation of the added surfactant itself or a decomposition product thereof.
バナバ葉抽出物を医薬品、特に注射用液剤に適用する場合には、コロソリン酸の溶解技術が必須である。前述の特許文献5では、合成により得たコロソリン酸を注射用液剤へ適用することについて、注射剤以外の多種類の剤形と共に挙げられてはいる。しかしながら、注射用液剤とする具体的な方法、例えばコロソリン酸の溶解や分散方法については全く示されていない。また、高血糖症への対応組成物として、バナバ葉抽出物を精製してガロタニンを有効主成分として取出し、経口的又は注射により投与することで、血糖値の低下に有効なことも知られているが(特許文献7)、コロソリン酸などのトリテルペノイドを実質的に含まない抽出物に関するものであり、水難溶性のコロソリン酸の溶解や分散を検討した発明ではない。 When applying a banaba leaf extract to a pharmaceutical, particularly an injectable solution, a technique for dissolving corosolic acid is essential. In the above-mentioned Patent Document 5, the application of corosolic acid obtained by synthesis to a liquid for injection is mentioned together with various types of dosage forms other than the injection. However, a specific method for preparing an injection solution, for example, a method for dissolving or dispersing corosolic acid is not shown at all. In addition, as a composition for hyperglycemia, it is also known that banaba leaf extract is purified and gallotanin is taken out as an active ingredient and administered orally or by injection, which is effective in lowering blood glucose level. However, it is related to an extract substantially free of triterpenoids such as corosolic acid (Patent Document 7), and is not an invention in which dissolution or dispersion of poorly water-soluble corosolic acid is studied.
以上の従来技術を鑑みても、コロソリン酸を安定に溶解又は分散した注射用液剤等、その水性液剤を製する方法は知られていなかった。 Even in view of the above prior art, a method for producing an aqueous liquid such as a liquid for injection in which corosolic acid is stably dissolved or dispersed has not been known.
本発明は、水に対して極めて難溶であるコロソリン酸を水に安定に溶解又は分散できる技術を提供することを課題とする。 This invention makes it a subject to provide the technique which can melt | dissolve or disperse | distribute corosolic acid which is very hardly soluble in water to water stably.
本発明者らは、前記課題を解決するために鋭意研究を重ねた結果、コロソリン酸に低級アルコールと多価アルコールとを組み合せて配合し、且つpHを10〜14に調整することにより、長期間経過後もコロソリン酸を安定して水溶液中に溶解又は分散させることができることを見出した。また、これは注射剤としても適用できることを見出した。 As a result of intensive studies to solve the above-mentioned problems, the present inventors have formulated long-term results by combining corosolic acid with a combination of a lower alcohol and a polyhydric alcohol and adjusting the pH to 10-14. It has been found that corosolic acid can be stably dissolved or dispersed in an aqueous solution even after the passage. It has also been found that this can be applied as an injection.
すなわち、本発明は、コロソリン酸、低級アルコール及び多価アルコールを含有し、pHが10〜14であるコロソリン酸含有水性液剤を提供するものである。 That is, this invention provides the corosolic acid containing aqueous liquid agent containing corosolic acid, a lower alcohol, and a polyhydric alcohol, and pH is 10-14.
本発明によれば、界面活性剤を必須構成要素とすることなく、安定なコロソリン酸含有水性液剤を提供できる。本発明の水性液剤は、長期間保存しても沈殿等を生じることがないため、医薬用経口液剤としてはもちろん、注射用液剤としても有用である。 According to the present invention, a stable corosolic acid-containing aqueous liquid preparation can be provided without using a surfactant as an essential component. Since the aqueous liquid preparation of the present invention does not cause precipitation or the like even when stored for a long period of time, it is useful not only as a pharmaceutical oral liquid preparation but also as an injection liquid preparation.
本発明に用いられるコロソリン酸は、下記式(1)で表されるトリテルペンカルボン酸である。 Corosolic acid used in the present invention is a triterpene carboxylic acid represented by the following formula (1).
コロソリン酸は、バナバ(学名:Lagerstroemia Speciosa Pers.)(和名:オオバナサルスベリ)の葉から熱水、有機溶媒、含水有機溶媒で抽出することにより得られる。好ましいコロソリン酸の抽出手段としては、バナバ葉からエタノールで抽出し、次いで吸着樹脂を用いて精製する手段が一般的である。本発明においては、バナバ葉抽出物から精製されたコロソリン酸を用いるか若しくは合成したコロソリン酸を使用してもよい。 Corosolic acid is obtained by extracting from leaves of banaba (scientific name: Lagerstroemeria Speciosa Pers.) (Japanese name: giant grasshopper) with hot water, an organic solvent, or a hydrous organic solvent. As a preferable means for extracting corosolic acid, a means for extracting from banaba leaves with ethanol and then purifying using an adsorption resin is general. In the present invention, corosolic acid purified from banaba leaf extract may be used, or synthesized corosolic acid may be used.
本発明の水性液剤中のコロソリン酸含量は、血糖値抑制効果、溶解性及び安定性の観点から、0.00002〜10w/v%、更に0.002〜5w/v%、更に0.1〜5w/v%、特に2〜5w/v%が好ましい。 The corosolic acid content in the aqueous liquid preparation of the present invention is 0.00002 to 10 w / v%, more preferably 0.002 to 5 w / v%, and further 0.1 to 0.1% from the viewpoints of blood glucose level suppressing effect, solubility and stability. 5 w / v%, particularly 2 to 5 w / v% is preferable.
本発明の水性液剤には、低級アルコール(例えばエタノール)及び多価アルコール(例えばプロピレングリコール)の両成分を含有することが、コロソリン酸の溶解性及び安定性を確保する点で必須である。すなわち、低級アルコール単独の投入でも、また多価アルコール単独の投入でも、コロソリン酸の充分な溶解効果をもたらすことは不可能である。
上記に基づき、コロソリン酸の充分な溶解性及び安定性を得るためのそれぞれの成分含有量は、低級アルコールの含有量は、水性液剤の全量に対して、0.1〜30v/v%、更に1〜20v/v%、特に4〜12v/v%が好ましい。また、多価アルコールの含有量は水性液剤の全量に対して、0.01〜80v/v%、更に1〜80v/v%、特に30〜70v/v%が好ましい。
In the aqueous liquid preparation of the present invention, it is essential to contain both components of a lower alcohol (for example, ethanol) and a polyhydric alcohol (for example, propylene glycol) from the viewpoint of securing the solubility and stability of corosolic acid. That is, it is impossible to bring about a sufficient dissolving effect of corosolic acid even if a lower alcohol is added alone or a polyhydric alcohol is added alone.
Based on the above, the content of each component for obtaining sufficient solubility and stability of corosolic acid, the content of the lower alcohol is 0.1-30 v / v% based on the total amount of the aqueous liquid agent, 1-20 v / v%, especially 4-12 v / v% is preferable. The content of the polyhydric alcohol is preferably 0.01 to 80 v / v%, more preferably 1 to 80 v / v%, and particularly preferably 30 to 70 v / v% with respect to the total amount of the aqueous liquid preparation.
本発明で用いる低級アルコールとしては、例えばエタノール、プロピルアルコール、イソプロピルアルコール、ブタノール等の炭素数1〜4のアルコールが挙げられるが、エタノールが安全性及び取扱性の観点から最適である。
本発明に用いる多価アルコールとしては、ジプロピレングリコール、ブチレングリコール、プロピレングリコール、ポリエチレングリコール(例えばマクロゴール400)及びエチレングリコール等の炭素数2〜18の2価のアルコールが挙げられるが、プロピレングリコールが安全性、原料コスト及び取扱性の観点から最適である。
Examples of the lower alcohol used in the present invention include alcohols having 1 to 4 carbon atoms such as ethanol, propyl alcohol, isopropyl alcohol, and butanol. Ethanol is optimal from the viewpoints of safety and handleability.
Examples of the polyhydric alcohol used in the present invention include divalent alcohols having 2 to 18 carbon atoms such as dipropylene glycol, butylene glycol, propylene glycol, polyethylene glycol (for example, Macrogol 400), and ethylene glycol. Is optimal from the viewpoint of safety, raw material cost and handling.
更に、本発明の水性液剤のpHは、コロソリン酸の溶解性を良好にして、安定性を保つ観点から10〜14にするのが良い。pHを調整するには、塩基性物質又は緩衝剤を添加すればよく、ここに用いられる塩基性物質又は緩衝剤は、pH調整後にヒトに対して安全なものであれば特に制限されない。好ましい塩基性物質としては、水酸化ナトリウム、水酸化カリウム等の水酸化アルカリ金属類、炭酸水素ナトリウム、炭酸ナトリウム等の炭酸アルカリ金属類又は炭酸水素アルカリ金属類、更にはモノエタノールアミン、トリエタノールアミン等の有機アミン類、クエン酸ナトリウムのような有機酸アルカリ金属塩類の中から選ばれる1種又は2種以上の混合物を用いることができる。これらの塩基性物質又は緩衝剤の含有量は、pHを10〜14とする量であればよく、特に限定はされない。本発明の水性液剤のpHは、更に11〜13、特に11.5〜12.5であることが好ましい。 Furthermore, the pH of the aqueous liquid preparation of the present invention is preferably 10 to 14 from the viewpoint of improving the solubility of corosolic acid and maintaining stability. In order to adjust the pH, a basic substance or buffer may be added, and the basic substance or buffer used here is not particularly limited as long as it is safe for humans after pH adjustment. Preferred basic substances include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal carbonates such as sodium hydrogen carbonate and sodium carbonate, or alkali metal hydrogen carbonates, and also monoethanolamine and triethanolamine. One kind or a mixture of two or more kinds selected from organic amines such as organic acid alkali metal salts such as sodium citrate can be used. The content of these basic substances or buffers is not particularly limited as long as the pH is 10 to 14. The pH of the aqueous liquid preparation of the present invention is preferably 11 to 13, particularly 11.5 to 12.5.
本発明の水性液剤には、液剤の性質改善や付加価値を増やすために、その他の薬剤をコロソリン酸の溶解性を妨げない成分である限りにおいて、配合することができる。このような成分としては、例えば、安息香酸塩、パラオキシ安息香酸エステル類、エデト酸塩などの保存剤、安定化剤などの他、経口用水性液剤とする場合は、ビタミン類、生薬類、香料、矯味剤などを配合することができる。 In the aqueous liquid preparation of the present invention, in order to improve the properties of the liquid preparation and increase the added value, other drugs can be blended as long as they are components that do not hinder the solubility of corosolic acid. Examples of such components include preservatives and stabilizers such as benzoates, paraoxybenzoates, and edetates, as well as vitamins, herbal medicines, and fragrances when used as oral aqueous solutions. A flavoring agent can be blended.
上述のごとく、本発明の水性液剤は、コロソリン酸を主成分とし、エタノール等の低級アルコール、プロピレングリコール等の多価アルコール及びpHを10〜14に調整するために、塩基性物質又は緩衝剤を添加することにより製造することができる。 As described above, the aqueous liquid preparation of the present invention contains corosolic acid as a main component, a lower alcohol such as ethanol, a polyhydric alcohol such as propylene glycol, and a basic substance or buffering agent in order to adjust pH to 10-14. It can manufacture by adding.
本発明のコロソリン酸含有水性液剤は、長期間保存してもコロソリン酸の沈殿が生ずることがなく、安定であることから、医薬品としては経口液剤として、更に注射用液剤として好適である。また液状の食品用としても好適である。 The corosolic acid-containing aqueous liquid preparation of the present invention is suitable as an oral liquid preparation and further as an injectable liquid preparation as a pharmaceutical because it does not cause precipitation of corosolic acid even when stored for a long period of time and is stable. It is also suitable for liquid foods.
本発明においてバナバ葉抽出物から精製したコロソリン酸を注射用水性液剤に使用する場合、原薬のコロソリン酸の純度は、血糖値抑制効果及び安全性の観点から、少なくとも50%以上、更には80%以上、特に好ましくは90%以上であることが望ましい。このコロソリン酸を原薬とした注射用水性液剤は、皮下、筋肉、或いは静脈投与として用いられるが、特に静脈投与が最適である。これらの注射用水性液剤の場合も、薬理学的に許容される範囲で、前述した水性液剤に用いられる製剤添加物と同様のものを使用することができる。すなわち、コロソリン酸、低級アルコール及び多価アルコールを併せ配合する。ここに、低級アルコールはエタノール、また、多価アルコールはプロピレングリコールが最適である。この他の添加物としては、pH調整剤として、水酸化ナトリウム、モノエタノールアミン、トリエタノールアミン、或いはクエン酸ナトリウムなどが用いられる。ここにpH調整剤は水酸化ナトリウムが最適であり、コロソリン酸の溶解性を良好にして、且つ安定に保つためには、pHを10〜14、好ましくはpHを11〜13、特に好ましくはpH11.5〜12.5の範囲に調整することがよく、更に等張化剤として塩化ナトリウム、グリセリンなどが用いられる。この様にして調製された注射用水性液剤は、必要に応じてメンブランフィルターを使用して濾過し、ガラス製アンプルやガラス製バイアル瓶などの容器に充填して使用する。また、プラスチック製のプレフィルドシリンジを用いてもよい。更に容器充填の後、加熱滅菌を施すことが望ましい。以上の工程により得られた注射用水性液剤は、微黄色〜無色の澄明で、やや粘性のある液体である。 In the present invention, when corosolic acid purified from banaba leaf extract is used in an aqueous solution for injection, the purity of corosolic acid as the drug substance is at least 50% or more, more preferably 80 from the viewpoint of blood sugar level suppressing effect and safety. % Or more, particularly preferably 90% or more. This aqueous solution for injection using corosolic acid as a drug substance is used for subcutaneous, intramuscular or intravenous administration, and intravenous administration is particularly optimal. In the case of these aqueous solutions for injection, the same additives as those used for the aqueous solution described above can be used within the pharmacologically acceptable range. That is, corosolic acid, a lower alcohol and a polyhydric alcohol are combined. Here, ethanol is most suitable as the lower alcohol, and propylene glycol is most suitable as the polyhydric alcohol. As other additives, sodium hydroxide, monoethanolamine, triethanolamine, sodium citrate, or the like is used as a pH adjuster. Here, sodium hydroxide is optimal as the pH adjusting agent, and in order to improve the solubility of corosolic acid and keep it stable, the pH is 10 to 14, preferably 11 to 13, particularly preferably pH 11. It is preferable to adjust to the range of 5 to 12.5, and sodium chloride, glycerin and the like are used as an isotonic agent. The aqueous liquid preparation for injection thus prepared is filtered using a membrane filter as necessary, and filled into a container such as a glass ampoule or a glass vial. Also, a plastic prefilled syringe may be used. Furthermore, it is desirable to perform heat sterilization after filling the container. The aqueous liquid preparation for injection obtained by the above steps is a slightly yellow to colorless clear, slightly viscous liquid.
本発明の水性液剤をビーグル犬に投与したところ、コロソリン酸血中濃度移行が確認された。 When the aqueous liquid of the present invention was administered to beagle dogs, it was confirmed that corosolic acid blood concentration shifts.
次に実施例及び試験例を挙げて本発明を詳細に説明するが、本発明はこれらにより制限されるものではない。 EXAMPLES Next, although an Example and a test example are given and this invention is demonstrated in detail, this invention is not restrict | limited by these.
[実施例1〜7及び比較例1〜7]
表1に示した組成の水性液剤(実施例1〜7及び比較例1〜7)を調製した。実施例1の調製方法を下記に示した。尚、実施例2〜7及び比較例1〜7は、実施例1に準じた方法で調製した。
[Examples 1-7 and Comparative Examples 1-7]
Aqueous liquid agents (Examples 1 to 7 and Comparative Examples 1 to 7) having the compositions shown in Table 1 were prepared. The preparation method of Example 1 was shown below. In addition, Examples 2-7 and Comparative Examples 1-7 were prepared by a method according to Example 1.
〔水性製剤の調製例(実施例1)〕
コロソリン酸(バナバ葉抽出物 純度96.5%)125mgを試験管に取り、無水エタノール0.8mL、プロピレングリコール3mL及び1N水酸化ナトリウム液0.25mLを加えて、80℃の温浴中で加温させた後、卓上型超音波洗浄器(ヤマト科学社製:BRANSONIC 220型)中で2〜3分間振り混ぜた。次いで精製水を適量加えて全量5mLの水性液剤を得た。
[Preparation Example of Aqueous Formulation (Example 1)]
Take 125 mg of corosolic acid (banaba leaf extract purity 96.5%) in a test tube, add 0.8 mL of absolute ethanol, 3 mL of propylene glycol and 0.25 mL of 1N sodium hydroxide solution, and warm in a warm bath at 80 ° C. Then, the mixture was shaken and mixed for 2 to 3 minutes in a tabletop ultrasonic cleaner (manufactured by Yamato Kagaku Co., Ltd .: BRANSONIC 220 type). Next, an appropriate amount of purified water was added to obtain a total amount of 5 mL of an aqueous solution.
表1は、実施例1〜7及び比較例1〜7の組成を示した表である。 Table 1 is a table showing the compositions of Examples 1 to 7 and Comparative Examples 1 to 7.
[実施例8]
コロソリン酸(バナバ葉抽出物 純度96.5%)2500mgを無水エタノール8mL及びプロピレングリコール60mLの混液に約80℃の温浴上で攪拌溶解した。次に、予めpH調整剤として水酸化ナトリウム適量を溶解させた注射用蒸留水を加えて全量を100mLとし、0.22μmメンブランフィルターで濾過した。この液2mLをガラス製アンプルに充填し、熔閉した後、121℃で20分間滅菌し、pH12.0の注射用水性液剤を得た。
[Example 8]
2500 mg of corosolic acid (banaba leaf extract purity 96.5%) was dissolved in a mixture of 8 mL of absolute ethanol and 60 mL of propylene glycol with stirring on a warm bath at about 80 ° C. Next, distilled water for injection in which an appropriate amount of sodium hydroxide was dissolved in advance as a pH adjuster was added to make a total volume of 100 mL, followed by filtration through a 0.22 μm membrane filter. 2 mL of this solution was filled in a glass ampoule and melted, and then sterilized at 121 ° C. for 20 minutes to obtain an aqueous solution for injection having a pH of 12.0.
[実施例9]
コロソリン酸(バナバ葉抽出物 純度96.5%)1000mgを無水エタノール3mL及びプロピレングリコール30mLの混液に約80℃の温浴上で攪拌溶解した。次に、予めpH調整剤として水酸化ナトリウム適量を溶解させた注射用蒸留水を加えて全量を100mLとし、0.22μmメンブランフィルターで濾過した。この液5mLをガラス製バイアル瓶に充填し、施栓した後、121℃で20分間滅菌し、pH11.5の注射用水性液剤を得た。
[Example 9]
1000 mg of corosolic acid (banaba leaf extract purity 96.5%) was dissolved in a mixture of 3 mL of absolute ethanol and 30 mL of propylene glycol with stirring on a warm bath at about 80 ° C. Next, distilled water for injection in which an appropriate amount of sodium hydroxide was dissolved in advance as a pH adjuster was added to make a total volume of 100 mL, followed by filtration through a 0.22 μm membrane filter. 5 mL of this solution was filled into a glass vial, plugged, and then sterilized at 121 ° C. for 20 minutes to obtain an aqueous liquid for injection with pH 11.5.
[実施例10]
コロソリン酸(バナバ葉抽出物 純度96.5%)500mgを無水エタノール2mL及びプロピレングリコール30mLの混液に約80℃の温浴上で攪拌溶解した。次に、予めpH調整剤として水酸化ナトリウム適量を溶解させた注射用蒸留水を加えて全量を100mLとし、0.22μmメンブランフィルターで濾過した。この液5mLをポリプロピレン製外筒とエラストマー製ガスケットを有するプラスチック製シリンジに充填した後、121℃で15分間滅菌し、pH11.0の注射用水性液剤を得た。
[Example 10]
500 mg of corosolic acid (banaba leaf extract purity 96.5%) was dissolved in a mixture of 2 mL of absolute ethanol and 30 mL of propylene glycol with stirring on a warm bath at about 80 ° C. Next, distilled water for injection in which an appropriate amount of sodium hydroxide was dissolved in advance as a pH adjuster was added to make a total volume of 100 mL, followed by filtration through a 0.22 μm membrane filter. After 5 mL of this solution was filled in a plastic syringe having a polypropylene outer cylinder and an elastomer gasket, it was sterilized at 121 ° C. for 15 minutes to obtain an aqueous liquid for injection having a pH of 11.0.
[実施例11]
コロソリン酸(バナバ葉抽出物 純度96.5%)4500mgを無水エタノール15mL、プロピレングリコール65mL及びpH調整剤トリエタノールアミン5mLの混液に約80℃の温浴上で攪拌溶解した。次に、予めpH調整剤として水酸化ナトリウム適量を溶解させた注射用蒸留水を加えて全量を100mLとし、0.22μmメンブランフィルターで濾過した。この液3mLをガラス製アンプルに充填し、熔閉した後、121℃で20分間滅菌し、pH13.7の注射用水性液剤を得た。
[Example 11]
4500 mg of corosolic acid (banaba leaf extract purity 96.5%) was dissolved in a mixed solution of 15 mL of absolute ethanol, 65 mL of propylene glycol and 5 mL of pH adjuster triethanolamine on a warm bath at about 80 ° C. Next, distilled water for injection in which an appropriate amount of sodium hydroxide was dissolved in advance as a pH adjuster was added to make a total volume of 100 mL, followed by filtration through a 0.22 μm membrane filter. 3 mL of this solution was filled in a glass ampoule and melted, and then sterilized at 121 ° C. for 20 minutes to obtain an aqueous solution for injection having a pH of 13.7.
[実施例12]
コロソリン酸(バナバ葉抽出物 純度96.5%)2500mgを無水エタノール8mL及びジプロピレングリコール55mLの混液に約80℃の温浴上で攪拌溶解した。次に、予めpH調整剤として水酸化ナトリウム適量を溶解させた注射用蒸留水を加えて全量を100mLとし、0.22μmメンブランフィルターで濾過した。この液5mLをガラス製バイアル瓶に充填し、施栓した後、121℃で20分間滅菌し、pH12.0の注射用水性液剤を得た。
[Example 12]
2500 mg of corosolic acid (banaba leaf extract purity 96.5%) was dissolved in a mixed solution of 8 mL of absolute ethanol and 55 mL of dipropylene glycol on a warm bath at about 80 ° C. Next, distilled water for injection in which an appropriate amount of sodium hydroxide was dissolved in advance as a pH adjuster was added to make a total volume of 100 mL, followed by filtration through a 0.22 μm membrane filter. 5 mL of this solution was filled in a glass vial, plugged, and then sterilized at 121 ° C. for 20 minutes to obtain an aqueous solution for injection having a pH of 12.0.
[実施例13]
コロソリン酸(バナバ葉抽出物 純度96.5%)3000mgを無水エタノール10mL及び1,3−ブチレングリコール40mLの混液に約80℃の温浴上で攪拌溶解した。次に、予めpH調整剤として水酸化ナトリウム適量を溶解させた注射用蒸留水を加えて全量を100mLとし、0.22μmメンブランフィルターで濾過した。この液3mLをポリプロピレン製外筒とエラストマー製ガスケットを有するプラスチック製シリンジに充填した後、121℃で15分間滅菌し、pH11.8の注射用水性液剤を得た。
[Example 13]
3000 mg of corosolic acid (banaba leaf extract purity 96.5%) was dissolved in a mixed solution of 10 mL of absolute ethanol and 40 mL of 1,3-butylene glycol on a warm bath at about 80 ° C. Next, distilled water for injection in which an appropriate amount of sodium hydroxide was dissolved in advance as a pH adjuster was added to make a total volume of 100 mL, followed by filtration through a 0.22 μm membrane filter. After 3 mL of this solution was filled in a plastic syringe having a polypropylene outer cylinder and an elastomer gasket, it was sterilized at 121 ° C. for 15 minutes to obtain an aqueous injection solution having a pH of 11.8.
[実施例14]
コロソリン酸(バナバ葉抽出物 純度96.5%)1500mgを無水エタノール16mL、プロピレングリコール20mL及びマクロゴール400 20mLの混液に約80℃の温浴上で攪拌溶解した。次に、予めpH調整剤として水酸化ナトリウム適量を溶解させた注射用蒸留水を加えて全量を100mLとし、0.22μmメンブランフィルターで濾過した。この液1mLをガラス製アンプルに充填し、熔閉した後、121℃で20分間滅菌し、pH12.5の注射用水性液剤を得た。
[Example 14]
1500 mg of corosolic acid (banaba leaf extract purity 96.5%) was dissolved in a mixed solution of 16 mL of absolute ethanol, 20 mL of propylene glycol and 20 mL of Macrogol 400 on a warm bath at about 80 ° C. Next, distilled water for injection in which an appropriate amount of sodium hydroxide was dissolved in advance as a pH adjuster was added to make a total volume of 100 mL, followed by filtration through a 0.22 μm membrane filter. 1 mL of this solution was filled in a glass ampoule and melted, and then sterilized at 121 ° C. for 20 minutes to obtain an aqueous liquid for injection having a pH of 12.5.
[実施例15]
コロソリン酸(バナバ葉抽出物 純度96.5%)500mgを無水エタノール6mL及びエチレングリコール30mLの混液に約80℃の温浴上で攪拌溶解した。次に、予めpH調整剤として炭酸ナトリウム500mg及び水酸化ナトリウム適量を溶解させた注射用蒸留水を加えて全量を100mLとし、0.22μmメンブランフィルターで濾過した。この液5mLをポリプロピレン製外筒とエラストマー製ガスケットを有するプラスチック製シリンジに充填した後、121℃で15分間滅菌し、pH10.5の注射用水性液剤を得た。
[Example 15]
500 mg of corosolic acid (banaba leaf extract purity 96.5%) was dissolved in a mixture of 6 mL of absolute ethanol and 30 mL of ethylene glycol with stirring on a warm bath at about 80 ° C. Next, 500 mg of sodium carbonate and distilled water for injection in which appropriate amounts of sodium hydroxide were dissolved in advance were added as a pH adjuster to make a total volume of 100 mL, followed by filtration through a 0.22 μm membrane filter. After 5 mL of this solution was filled in a plastic syringe having a polypropylene outer cylinder and an elastomer gasket, it was sterilized at 121 ° C. for 15 minutes to obtain an aqueous liquid for injection having a pH of 10.5.
[実施例16]
コロソリン酸(バナバ葉抽出物 純度96.5%)2500mgをイソプロパノール4mL及びプロピレングリコール50mLの混液に約80℃の温浴上で攪拌溶解した。次に、予めpH調整剤として水酸化ナトリウム適量を溶解させた注射用蒸留水を加えて全量を100mLとし、0.22μmメンブランフィルターで濾過した。この液5mLをポリプロピレン製外筒とエラストマー製ガスケットを有するプラスチック製シリンジに充填した後、121℃で15分間滅菌し、pH11.8の注射用水性液剤を得た。
[Example 16]
2500 mg of corosolic acid (banaba leaf extract purity 96.5%) was dissolved in a mixed solution of 4 mL of isopropanol and 50 mL of propylene glycol with stirring on a hot bath at about 80 ° C. Next, distilled water for injection in which an appropriate amount of sodium hydroxide was dissolved in advance as a pH adjuster was added to make a total volume of 100 mL, followed by filtration through a 0.22 μm membrane filter. After 5 mL of this solution was filled into a plastic syringe having a polypropylene outer cylinder and an elastomer gasket, it was sterilized at 121 ° C. for 15 minutes to obtain an aqueous injection solution having a pH of 11.8.
[実施例17]
コロソリン酸(バナバ葉抽出物 純度14.3%)700mgを無水エタノール3mL及びプロピレングリコール40mLの混液に約80℃の温浴上で攪拌溶解した。次に、予めpH調整剤としてクエン酸ナトリウム400mg及び水酸化カリウム適量を溶解させた精製水を加えた後、パラオキシ安息香酸エチル10mg及びスクラロース45mgを加えて攪拌溶解し、更に精製水を加えて全量を100mLとして濾紙濾過した。この液30mLをガラス製ドリンク瓶に充填し、施栓した後、90℃で10分間殺菌し、pH10.5の内服液剤を得た。
[Example 17]
700 mg of corosolic acid (banaba leaf extract purity 14.3%) was dissolved in a mixed solution of 3 mL of absolute ethanol and 40 mL of propylene glycol with stirring on a warm bath at about 80 ° C. Next, after adding purified water in which 400 mg of sodium citrate and an appropriate amount of potassium hydroxide were dissolved in advance as a pH adjuster, 10 mg of ethyl paraoxybenzoate and 45 mg of sucralose were added and dissolved by stirring. Was filtered through filter paper. 30 mL of this solution was filled into a glass drink bottle, plugged, and then sterilized at 90 ° C. for 10 minutes to obtain an internal solution having a pH of 10.5.
[実施例18]
コロソリン酸(バナバ葉抽出物 純度14.3%)100mgを無水エタノール2mL、プロピレングリコール30mL及びマクロゴール400 10mLの混液に約80℃の温浴上で攪拌溶解した。次に、予めpH調整剤として炭酸ナトリウム150mg、クエン酸ナトリウム300mg及び水酸化カリウム適量を溶解させた精製水を加えた後、リン酸リボフラビンナトリウム5mg、塩酸ピリドキシン10mg、パラオキシ安息香酸エチル10mg及びスクラロース35mgを加えて攪拌溶解し、更に精製水を加えて全量を100mLとして濾紙濾過した。この液10mLを内面コートがポリプロピレン製のアルミスティック分包に充填し、シールした後、85℃で20分間殺菌し、pH10.5の内服液剤を得た。
[Example 18]
100 mg of corosolic acid (banaba leaf extract purity 14.3%) was stirred and dissolved in a mixed solution of 2 mL of absolute ethanol, 30 mL of propylene glycol and 10 mL of Macrogol 400 on a warm bath at about 80 ° C. Next, 150 mg of sodium carbonate, 300 mg of sodium citrate, and purified water in which an appropriate amount of potassium hydroxide was dissolved in advance were added as pH adjusters. The solution was stirred and dissolved, and further purified water was added to make a total volume of 100 mL, followed by filtration with filter paper. 10 ml of this solution was filled in an aluminum stick sachet whose inner surface coat was made of polypropylene, sealed, and then sterilized at 85 ° C. for 20 minutes to obtain an internal solution having a pH of 10.5.
[実施例19]
コロソリン酸(バナバ葉抽出物 純度14.3%)20mgを無水エタノール0.5mL及びプロピレングリコール2mLの混液に攪拌溶解した。次に、予めpH調整剤としてクエン酸ナトリウム350mg及び水酸化ナトリウム適量を溶解させた精製水を加えた後、パラオキシ安息香酸エチル10mg、ソルビン酸200mg、スクラロース20mg及びエリスリトール4500mgを加えて攪拌溶解し、更に精製水を加えて全量を100mLとして濾紙濾過した。この液50mLをガラス製ドリンク瓶に充填し、施栓した後、90℃で10分間殺菌し、pH10の内服液剤を得た。
[Example 19]
20 mg of corosolic acid (banaba leaf extract purity 14.3%) was dissolved by stirring in a mixed solution of 0.5 mL of absolute ethanol and 2 mL of propylene glycol. Next, after adding purified water in which 350 mg of sodium citrate and an appropriate amount of sodium hydroxide were dissolved in advance as a pH adjuster, ethyl paraoxybenzoate 10 mg, sorbic acid 200 mg, sucralose 20 mg and erythritol 4500 mg were stirred and dissolved, Further, purified water was added to make a total volume of 100 mL, and filtered through filter paper. 50 mL of this solution was filled into a glass drink bottle, plugged, and then sterilized at 90 ° C. for 10 minutes to obtain a pH 10 oral solution.
[実施例20]
コロソリン酸(バナバ葉抽出物 純度14.3%)5mgを無水エタノール0.1mL及びプロピレングリコール0.04mLの混液に攪拌溶解した。次に、予めpH調整剤としてクエン酸ナトリウム250mg及び水酸化ナトリウム適量を溶解させた精製水を加えた後、塩化カルニチン50mg、パラオキシ安息香酸エチル5mg、ソルビン酸100mg及びスクラロース20mgを加えて攪拌溶解し、更に精製水を加えて全量を100mLとして濾紙濾過した。この液全量をガラス製ドリンク瓶に充填し、施栓した後、90℃で10分間殺菌し、pH10の内服液剤を得た。
[Example 20]
5 mg of corosolic acid (banaba leaf extract purity 14.3%) was stirred and dissolved in a mixed solution of 0.1 mL of absolute ethanol and 0.04 mL of propylene glycol. Next, after adding purified water in which sodium citrate 250 mg and appropriate amount of sodium hydroxide were dissolved in advance as a pH adjuster, carnitine chloride 50 mg, ethyl paraoxybenzoate 5 mg, sorbic acid 100 mg and sucralose 20 mg were added and dissolved by stirring. Further, purified water was added to make a total volume of 100 mL, followed by filtration with filter paper. The total amount of this liquid was filled in a glass drink bottle, plugged, and then sterilized at 90 ° C. for 10 minutes to obtain a pH 10 oral solution.
[実施例21]
コロソリン酸(バナバ葉抽出物 純度14.3%)5mgを無水エタノール0.04mL及びプロピレングリコール0.04mLの混液に攪拌溶解した。次に、予めpH調整剤としてクエン酸ナトリウム250mg及び水酸化ナトリウム適量を溶解させた精製水を加えた後、塩化カルニチン50mg、パラオキシ安息香酸エチル5mg、ソルビン酸100mg及びスクラロース20mgを加えて攪拌溶解し、更に精製水を加えて全量を100mLとして濾紙濾過した。この液全量をガラス製ドリンク瓶に充填し、施栓した後、90℃で10分間殺菌し、pH10の内服液剤を得た。
[Example 21]
5 mg of corosolic acid (banaba leaf extract purity 14.3%) was stirred and dissolved in a mixed solution of 0.04 mL of absolute ethanol and 0.04 mL of propylene glycol. Next, after adding purified water in which sodium citrate 250 mg and appropriate amount of sodium hydroxide were dissolved in advance as a pH adjuster, carnitine chloride 50 mg, ethyl paraoxybenzoate 5 mg, sorbic acid 100 mg and sucralose 20 mg were added and dissolved by stirring. Further, purified water was added to make a total volume of 100 mL, followed by filtration with filter paper. The total amount of this liquid was filled in a glass drink bottle, plugged, and then sterilized at 90 ° C. for 10 minutes to obtain a pH 10 oral solution.
[実施例22]
コロソリン酸(バナバ葉抽出物 純度14.3%)5mgを無水エタノール0.1mL及びプロピレングリコール0.01mLの混液に攪拌溶解した。次に、予めpH調整剤としてクエン酸ナトリウム250mg及び水酸化ナトリウム適量を溶解させた精製水を加えた後、塩化カルニチン50mg、パラオキシ安息香酸エチル5mg、ソルビン酸100mg及びスクラロース20mgを加えて攪拌溶解し、更に精製水を加えて全量を100mLとして濾紙濾過した。この液全量をガラス製ドリンク瓶に充填し、施栓した後、90℃で10分間殺菌し、pH10の内服液剤を得た。
[Example 22]
5 mg of corosolic acid (banaba leaf extract purity 14.3%) was stirred and dissolved in a mixed solution of 0.1 mL of absolute ethanol and 0.01 mL of propylene glycol. Next, after adding purified water in which sodium citrate 250 mg and appropriate amount of sodium hydroxide were dissolved in advance as a pH adjuster, carnitine chloride 50 mg, ethyl paraoxybenzoate 5 mg, sorbic acid 100 mg and sucralose 20 mg were added and dissolved by stirring. Further, purified water was added to make a total volume of 100 mL, followed by filtration with filter paper. The total amount of this liquid was filled in a glass drink bottle, plugged, and then sterilized at 90 ° C. for 10 minutes to obtain a pH 10 oral solution.
[実施例23]
コロソリン酸(バナバ葉抽出物 純度14.3%)5mgを無水エタノール0.1mL及びプロピレングリコール0.04mLの混液に攪拌溶解した。次に、予めpH調整剤としてクエン酸ナトリウム250mg及び水酸化ナトリウム適量を溶解させた精製水を加えた後、塩化カルニチン50mg、パラオキシ安息香酸エチル5mg、ソルビン酸100mg及びスクラロース20mgを加えて攪拌溶解し、更に精製水を加えて全量を100mLとして濾紙濾過した。この液全量をガラス製ドリンク瓶に充填し、施栓した後、90℃で10分間殺菌し、pH10の内服液剤を得た。
[Example 23]
5 mg of corosolic acid (banaba leaf extract purity 14.3%) was stirred and dissolved in a mixed solution of 0.1 mL of absolute ethanol and 0.04 mL of propylene glycol. Next, after adding purified water in which sodium citrate 250 mg and appropriate amount of sodium hydroxide were dissolved in advance as a pH adjuster, carnitine chloride 50 mg, ethyl paraoxybenzoate 5 mg, sorbic acid 100 mg and sucralose 20 mg were added and dissolved by stirring. Further, purified water was added to make a total volume of 100 mL, followed by filtration with filter paper. The total amount of this liquid was filled in a glass drink bottle, plugged, and then sterilized at 90 ° C. for 10 minutes to obtain a pH 10 oral solution.
[比較例8]
コロソリン酸(バナバ葉抽出物 純度96.5%)2500mgをプロピレングリコール60mLに約80℃の温浴上で攪拌溶解した。次に、予めpH調整剤として水酸化ナトリウム適量を溶解させた注射用蒸留水を加えて全量を100mLとし、0.22μmメンブランフィルターで濾過した。この液2mLをガラス製アンプルに充填し、熔閉した後、121℃で20分間滅菌し、pH12.0の注射用水性液剤を得た(実施例8より無水エタノールを除いた組成)。
[Comparative Example 8]
2500 mg of corosolic acid (banaba leaf extract purity 96.5%) was dissolved in 60 mL of propylene glycol with stirring on a warm bath at about 80 ° C. Next, distilled water for injection in which an appropriate amount of sodium hydroxide was dissolved in advance as a pH adjuster was added to make a total volume of 100 mL, followed by filtration through a 0.22 μm membrane filter. 2 mL of this solution was filled in a glass ampoule and melted, and then sterilized at 121 ° C. for 20 minutes to obtain an aqueous liquid for injection having a pH of 12.0 (composition obtained by removing anhydrous ethanol from Example 8).
[比較例9]
コロソリン酸(バナバ葉抽出物 純度96.5%)1000mgを無水エタノール3mLに約80℃の温浴上で攪拌溶解した。次に、予めpH調整剤として水酸化ナトリウム適量を溶解させた注射用蒸留水を加えて全量を100mLとし、0.22μmメンブランフィルターで濾過した。この液5mLをガラス製バイアル瓶に充填し、施栓した後、121℃で20分間滅菌し、pH11.5の注射用水性液剤を得た(実施例9よりプロピレングリコールを除いた組成)。
[Comparative Example 9]
1000 mg of corosolic acid (banaba leaf extract purity 96.5%) was dissolved in 3 mL of absolute ethanol with stirring on a warm bath at about 80 ° C. Next, distilled water for injection in which an appropriate amount of sodium hydroxide was dissolved in advance as a pH adjuster was added to make a total volume of 100 mL, followed by filtration through a 0.22 μm membrane filter. 5 mL of this solution was filled into a glass vial, plugged, and then sterilized at 121 ° C. for 20 minutes to obtain an aqueous liquid for injection having a pH of 11.5 (composition excluding propylene glycol from Example 9).
[比較例10]
コロソリン酸(バナバ葉抽出物 純度96.5%)500mgを無水エタノール2mL及びプロピレングリコール30mLの混液に約80℃の温浴上で攪拌溶解した。次に、予めpH調整剤として水酸化ナトリウム適量を溶解させた注射用蒸留水を加えて全量を100mLとし、0.22μmメンブランフィルターで濾過した。この液5mLをポリプロピレン製外筒とエラストマー製ガスケットを有するプラスチック製シリンジに充填した後、121℃で15分間滅菌し、pH9.5の注射用水性液剤を得た(実施例10の水酸化ナトリウムを減量してpH9.5とした組成)。
[Comparative Example 10]
500 mg of corosolic acid (banaba leaf extract purity 96.5%) was dissolved in a mixture of 2 mL of absolute ethanol and 30 mL of propylene glycol with stirring on a warm bath at about 80 ° C. Next, distilled water for injection in which an appropriate amount of sodium hydroxide was dissolved in advance as a pH adjuster was added to make a total volume of 100 mL, followed by filtration through a 0.22 μm membrane filter. After 5 mL of this solution was filled into a plastic syringe having a polypropylene outer cylinder and an elastomer gasket, it was sterilized at 121 ° C. for 15 minutes to obtain an aqueous solution for injection having a pH of 9.5 (sodium hydroxide of Example 10 was added). The composition was reduced to pH 9.5).
[比較例11]
コロソリン酸(バナバ葉抽出物 純度96.5%)4500mgをプロピレングリコール65mL及びpH調整剤トリエタノールアミン5mLの混液に約80℃の温浴上で攪拌溶解した。次に、予めpH調整剤として水酸化ナトリウム適量を溶解させた注射用蒸留水を加えて全量を100mLとし、0.22μmメンブランフィルターで濾過した。この液3mLをガラス製アンプルに充填し、熔閉した後、121℃で20分間滅菌し、pH13.7の注射用水性液剤を得た(実施例11より無水エタノールを除いた組成)。
[Comparative Example 11]
4500 mg of corosolic acid (banaba leaf extract purity 96.5%) was dissolved in a mixture of propylene glycol 65 mL and pH adjuster triethanolamine 5 mL with stirring on a hot bath at about 80 ° C. Next, distilled water for injection in which an appropriate amount of sodium hydroxide was dissolved in advance as a pH adjuster was added to make a total volume of 100 mL, followed by filtration through a 0.22 μm membrane filter. 3 mL of this solution was filled in a glass ampoule and melted, and then sterilized at 121 ° C. for 20 minutes to obtain an aqueous liquid for injection having a pH of 13.7 (composition obtained by removing anhydrous ethanol from Example 11).
[比較例12]
コロソリン酸(バナバ葉抽出物 純度96.5%)2500mgを無水エタノール8mLに約80℃の温浴上で攪拌溶解した。次に、予めpH調整剤として水酸化ナトリウム適量を溶解させた注射用蒸留水を加えて全量を100mLとし、0.22μmメンブランフィルターで濾過した。この液5mLをガラス製バイアル瓶に充填し、施栓した後、121℃で20分間滅菌し、pH12.0の注射用水性液剤を得た(実施例12よりジプロピレングリコールを除いた組成)。
[Comparative Example 12]
2500 mg of corosolic acid (banaba leaf extract purity 96.5%) was dissolved in 8 mL of absolute ethanol with stirring in a hot bath at about 80 ° C. Next, distilled water for injection in which an appropriate amount of sodium hydroxide was dissolved in advance as a pH adjuster was added to make a total volume of 100 mL, followed by filtration through a 0.22 μm membrane filter. 5 mL of this solution was filled in a glass vial, plugged, and then sterilized at 121 ° C. for 20 minutes to obtain an aqueous liquid for injection having a pH of 12.0 (composition excluding dipropylene glycol from Example 12).
[比較例13]
コロソリン酸(バナバ葉抽出物 純度96.5%)3000mgを無水エタノール10mLに約80℃の温浴上で攪拌溶解した。次に、予めpH調整剤として水酸化ナトリウム適量を溶解させた注射用蒸留水を加えて全量を100mLとし、0.22μmメンブランフィルターで濾過した。この液3mLをポリプロピレン製外筒とエラストマー製ガスケットを有するプラスチック製シリンジに充填した後、121℃で15分間滅菌し、pH11.8の注射用水性液剤を得た(実施例13より1,3−ブチレングリコールを除いた組成)。
[Comparative Example 13]
3000 mg of corosolic acid (banaba leaf extract purity 96.5%) was dissolved in 10 mL of absolute ethanol with stirring on a warm bath at about 80 ° C. Next, distilled water for injection in which an appropriate amount of sodium hydroxide was dissolved in advance as a pH adjuster was added to make a total volume of 100 mL, followed by filtration through a 0.22 μm membrane filter. 3 mL of this solution was filled into a plastic syringe having a polypropylene outer cylinder and an elastomer gasket, and then sterilized at 121 ° C. for 15 minutes to obtain an aqueous liquid for injection having a pH of 11.8 (from Example 13, 1,3- Composition excluding butylene glycol).
[比較例14]
コロソリン酸(バナバ葉抽出物 純度96.5%)1500mgを無水エタノール16mL、プロピレングリコール20mL及びマクロゴール400 20mLの混液に約80℃の温浴上で攪拌溶解した。次に、予めpH調整剤として水酸化ナトリウム適量を溶解させた注射用蒸留水を加えて全量を100mLとし、0.22μmメンブランフィルターで濾過した。この液1mLをガラス製アンプルに充填し、熔閉した後、121℃で20分間滅菌し、pH9の注射用水性液剤を得た(実施例14の水酸化ナトリウムを減量してpH9とした組成)。
[Comparative Example 14]
1500 mg of corosolic acid (banaba leaf extract purity 96.5%) was dissolved in a mixed solution of 16 mL of absolute ethanol, 20 mL of propylene glycol and 20 mL of Macrogol 400 on a warm bath at about 80 ° C. Next, distilled water for injection in which an appropriate amount of sodium hydroxide was dissolved in advance as a pH adjuster was added to make a total volume of 100 mL, followed by filtration through a 0.22 μm membrane filter. 1 mL of this solution was filled into a glass ampoule and melted, and then sterilized at 121 ° C. for 20 minutes to obtain an aqueous solution for injection of pH 9 (composition of pH 14 by reducing the amount of sodium hydroxide in Example 14). .
[比較例15]
コロソリン酸(バナバ葉抽出物 純度96.5%)500mgを無水エタノール6mLに約80℃の温浴上で攪拌溶解した。次に、予めpH調整剤として炭酸ナトリウム500mg及び水酸化ナトリウム適量を溶解させた注射用蒸留水を加えて全量を100mLとし、0.22μmメンブランフィルターで濾過した。この液5mLをポリプロピレン製外筒とエラストマー製ガスケットを有するプラスチック製シリンジに充填した後、121℃で15分間滅菌し、pH10.5の注射用水性液剤を得た(実施例15よりエチレングリコールを除いた組成)。
[Comparative Example 15]
500 mg of corosolic acid (banaba leaf extract purity 96.5%) was dissolved in 6 mL of absolute ethanol with stirring in a hot bath at about 80 ° C. Next, 500 mg of sodium carbonate and distilled water for injection in which appropriate amounts of sodium hydroxide were dissolved in advance were added as a pH adjuster to make a total volume of 100 mL, followed by filtration through a 0.22 μm membrane filter. After 5 mL of this solution was filled into a plastic syringe having a polypropylene outer cylinder and an elastomer gasket, it was sterilized at 121 ° C. for 15 minutes to obtain an aqueous liquid for injection having a pH of 10.5 (excluding ethylene glycol from Example 15). Composition).
[比較例16]
コロソリン酸(バナバ葉抽出物 純度96.5%)2500mgをプロピレングリコール50mLに約80℃の温浴上で攪拌溶解した。次に、予めpH調整剤として水酸化ナトリウム適量を溶解させた注射用蒸留水を加えて全量を100mLとし、0.22μmメンブランフィルターで濾過した。この液5mLをポリプロピレン製外筒とエラストマー製ガスケットを有するプラスチック製シリンジに充填した後、121℃で15分間滅菌し、pH11.8の注射用水性液剤を得た(実施例16よりイソプロパノールを除いた組成)。
[Comparative Example 16]
2500 mg of corosolic acid (banaba leaf extract purity 96.5%) was dissolved in 50 mL of propylene glycol with stirring in a warm bath at about 80 ° C. Next, distilled water for injection in which an appropriate amount of sodium hydroxide was dissolved in advance as a pH adjuster was added to make a total volume of 100 mL, followed by filtration through a 0.22 μm membrane filter. After 5 mL of this solution was filled in a plastic syringe having a polypropylene outer cylinder and an elastomer gasket, it was sterilized at 121 ° C. for 15 minutes to obtain an aqueous liquid for injection having a pH of 11.8 (isopropanol was removed from Example 16). composition).
[比較例17]
コロソリン酸(バナバ葉抽出物 純度14.3%)700mgを無水エタノール3mLに約80℃の温浴上で攪拌溶解した。次に、予めpH調整剤としてクエン酸ナトリウム400mg及び水酸化カリウム適量を溶解させた精製水を加えた後、パラオキシ安息香酸エチル10mg及びスクラロース45mgを加えて攪拌溶解し、更に精製水を加えて全量を100mLとして濾紙濾過した。この液30mLをガラス製ドリンク瓶に充填し、施栓した後、90℃で10分間殺菌し、pH10.5の内服液剤を得た(実施例17よりプロピレングリコールを除いた組成)。
[Comparative Example 17]
700 mg of corosolic acid (banaba leaf extract purity 14.3%) was dissolved in 3 mL of absolute ethanol with stirring in a hot bath at about 80 ° C. Next, after adding purified water in which 400 mg of sodium citrate and an appropriate amount of potassium hydroxide were dissolved in advance as a pH adjuster, 10 mg of ethyl paraoxybenzoate and 45 mg of sucralose were added and dissolved by stirring. Was filtered through filter paper. 30 mL of this solution was filled in a glass drink bottle, plugged, and then sterilized at 90 ° C. for 10 minutes to obtain a pH 10.5 oral solution (composition excluding propylene glycol from Example 17).
[比較例18]
コロソリン酸(バナバ葉抽出物 純度14.3%)100mgをプロピレングリコール30mL及びマクロゴール400 10mLの混液に約80℃の温浴上で攪拌溶解した。次に、予めpH調整剤として炭酸ナトリウム150mg、クエン酸ナトリウム300mg及び水酸化カリウム適量を溶解させた精製水を加えた後、リン酸リボフラビンナトリウム5mg、塩酸ピリドキシン10mg、パラオキシ安息香酸エチル10mg及びスクラロース35mgを加えて攪拌溶解し、更に精製水を加えて全量を100mLとして濾紙濾過した。この液10mLを内面コートがポリプロピレン製のアルミスティック分包に充填し、シールした後、85℃で20分間殺菌し、pH10.5の内服液剤を得た(実施例18より無水エタノールを除いた組成)。
[Comparative Example 18]
100 mg of corosolic acid (banaba leaf extract purity 14.3%) was dissolved in a mixed solution of 30 mL of propylene glycol and 10 mL of Macrogol 400 with stirring on a hot bath at about 80 ° C. Next, 150 mg of sodium carbonate, 300 mg of sodium citrate, and purified water in which an appropriate amount of potassium hydroxide was dissolved in advance were added as pH adjusters. The solution was stirred and dissolved, and further purified water was added to make a total volume of 100 mL, followed by filtration with filter paper. 10 ml of this solution was filled into an aluminum stick sachet whose inner surface coat was made of polypropylene, sealed, and then sterilized at 85 ° C. for 20 minutes to obtain an internal solution having a pH of 10.5 (composition excluding absolute ethanol from Example 18). ).
[比較例19]
コロソリン酸(バナバ葉抽出物 純度14.3%)20mgを無水エタノール0.5mLに攪拌溶解した。次に、予めpH調整剤としてクエン酸ナトリウム350mg及び水酸化ナトリウム適量を溶解させた精製水を加えた後、パラオキシ安息香酸エチル10mg、ソルビン酸200mg、スクラロース20mg及びエリスリトール4500mgを加えて攪拌溶解し、更に精製水を加えて全量を100mLとして濾紙濾過した。この液50mLをガラス製ドリンク瓶に充填し、施栓した後、90℃で10分間殺菌し、pH10の内服液剤を得た(実施例19よりプロピレングリコールを除いた組成)。
[Comparative Example 19]
20 mg of corosolic acid (banaba leaf extract purity 14.3%) was dissolved by stirring in 0.5 mL of absolute ethanol. Next, after adding purified water in which 350 mg of sodium citrate and an appropriate amount of sodium hydroxide were dissolved in advance as a pH adjuster, ethyl paraoxybenzoate 10 mg, sorbic acid 200 mg, sucralose 20 mg and erythritol 4500 mg were stirred and dissolved, Further, purified water was added to make a total volume of 100 mL, and filtered through filter paper. After filling 50 mL of this liquid into a glass drink bottle and plugging it, it was sterilized at 90 ° C. for 10 minutes to obtain a pH 10 oral solution (composition excluding propylene glycol from Example 19).
[比較例20]
コロソリン酸(バナバ葉抽出物 純度14.3%)5mgをプロピレングリコール0.04mLに攪拌溶解した。次に、予めpH調整剤としてクエン酸ナトリウム250mg及び水酸化ナトリウム適量を溶解させた精製水を加えた後、塩化カルニチン50mg、パラオキシ安息香酸エチル5mg、ソルビン酸100mg及びスクラロース20mgを加えて攪拌溶解し、更に精製水を加えて全量を100mLとして濾紙濾過した。この液全量をガラス製ドリンク瓶に充填し、施栓した後、90℃で10分間殺菌し、pH10の内服液剤を得た(実施例20より無水エタノールを除いた組成)。
[Comparative Example 20]
5 mg of corosolic acid (banaba leaf extract purity 14.3%) was dissolved in 0.04 mL of propylene glycol with stirring. Next, after adding purified water in which sodium citrate 250 mg and appropriate amount of sodium hydroxide were dissolved in advance as a pH adjuster, carnitine chloride 50 mg, ethyl paraoxybenzoate 5 mg, sorbic acid 100 mg and sucralose 20 mg were added and dissolved by stirring. Further, purified water was added to make a total volume of 100 mL, followed by filtration with filter paper. The total amount of this liquid was filled into a glass drink bottle, plugged, and then sterilized at 90 ° C. for 10 minutes to obtain a pH 10 oral solution (composition excluding absolute ethanol from Example 20).
[比較例21]
コロソリン酸(バナバ葉抽出物 純度14.3%)5mgを無水エタノール0.04mLに攪拌溶解した。次に、予めpH調整剤としてクエン酸ナトリウム250mg及び水酸化ナトリウム適量を溶解させた精製水を加えた後、塩化カルニチン50mg、パラオキシ安息香酸エチル5mg、ソルビン酸100mg及びスクラロース20mgを加えて攪拌溶解し、更に精製水を加えて全量を100mLとして濾紙濾過した。この液全量をガラス製ドリンク瓶に充填し、施栓した後、90℃で10分間殺菌し、pH10の内服液剤を得た(実施例21よりプロピレングリコールを除いた組成)。
[Comparative Example 21]
5 mg of corosolic acid (banaba leaf extract purity 14.3%) was dissolved by stirring in 0.04 mL of absolute ethanol. Next, after adding purified water in which sodium citrate 250 mg and appropriate amount of sodium hydroxide were dissolved in advance as a pH adjuster, carnitine chloride 50 mg, ethyl paraoxybenzoate 5 mg, sorbic acid 100 mg and sucralose 20 mg were added and dissolved by stirring. Further, purified water was added to make a total volume of 100 mL, followed by filtration with filter paper. The total amount of this solution was filled in a glass drink bottle, plugged, and then sterilized at 90 ° C. for 10 minutes to obtain a pH 10 internal use solution (composition excluding propylene glycol from Example 21).
[比較例22]
コロソリン酸(バナバ葉抽出物 純度14.3%)5mgを無水エタノール0.1mLに攪拌溶解した。次に、予めpH調整剤としてクエン酸ナトリウム250mg及び水酸化ナトリウム適量を溶解させた精製水を加えた後、塩化カルニチン50mg、パラオキシ安息香酸エチル5mg、ソルビン酸100mg及びスクラロース20mgを加えて攪拌溶解し、更に精製水を加えて全量を100mLとして濾紙濾過した。この液全量をガラス製ドリンク瓶に充填し、施栓した後、90℃で10分間殺菌し、pH10の内服液剤を得た(実施例22よりプロピレングリコールを除いた組成)。
[Comparative Example 22]
5 mg of corosolic acid (banaba leaf extract purity 14.3%) was dissolved by stirring in 0.1 mL of absolute ethanol. Next, after adding purified water in which sodium citrate 250 mg and appropriate amount of sodium hydroxide were dissolved in advance as a pH adjuster, carnitine chloride 50 mg, ethyl paraoxybenzoate 5 mg, sorbic acid 100 mg and sucralose 20 mg were added and dissolved by stirring. Further, purified water was added to make a total volume of 100 mL, followed by filtration with filter paper. The total amount of this liquid was filled in a glass drink bottle, plugged, and then sterilized at 90 ° C. for 10 minutes to obtain a pH 10 oral solution (composition excluding propylene glycol from Example 22).
[比較例23]
コロソリン酸(バナバ葉抽出物 純度14.3%)5mgを無水エタノール0.1mL及びプロピレングリコール0.04mLの混液に攪拌溶解した。次に、予めpH調整剤としてクエン酸ナトリウム250mg及び水酸化ナトリウム適量を溶解させた精製水を加えた後、塩化カルニチン50mg、パラオキシ安息香酸エチル5mg、ソルビン酸100mg及びスクラロース20mgを加えて攪拌溶解し、更に精製水を加えて全量を100mLとして濾紙濾過した。この液全量をガラス製ドリンク瓶に充填し、施栓した後、90℃で10分間殺菌し、pH8.5の内服液剤を得た(実施例23の水酸化ナトリウムを減量してpH8.5とした組成)。
[Comparative Example 23]
5 mg of corosolic acid (banaba leaf extract purity 14.3%) was stirred and dissolved in a mixed solution of 0.1 mL of absolute ethanol and 0.04 mL of propylene glycol. Next, after adding purified water in which sodium citrate 250 mg and appropriate amount of sodium hydroxide were dissolved in advance as a pH adjuster, carnitine chloride 50 mg, ethyl paraoxybenzoate 5 mg, sorbic acid 100 mg and sucralose 20 mg were added and dissolved by stirring. Further, purified water was added to make a total volume of 100 mL, followed by filtration with filter paper. The total amount of this solution was filled in a glass drink bottle, plugged, and then sterilized at 90 ° C. for 10 minutes to obtain an internal solution of pH 8.5 (the sodium hydroxide in Example 23 was reduced to pH 8.5). composition).
〔試験例1〕
実施例1〜7及び比較例1〜7の水性液剤の性状を観察し、溶解判定を実施した。尚、溶解判定は下記の評価基準に従い−及び±を適合とし、+及び++を不適とした。試験結果は表2の溶解判定の欄に記載した。
[Test Example 1]
The properties of the aqueous liquid preparations of Examples 1 to 7 and Comparative Examples 1 to 7 were observed, and dissolution determination was performed. In the dissolution determination, − and ± were considered appropriate and + and ++ were considered inappropriate according to the following evaluation criteria. The test results are listed in the column of dissolution determination in Table 2.
・溶解判定基準
− :沈殿、懸濁又は浮遊物などが認められない(適合)。
± :沈殿、懸濁又は浮遊物など極僅かに認められる(適合)。
+ :沈殿、懸濁又は浮遊物などが認められる(不適)。
++:沈殿、懸濁又は浮遊物などが顕著に認められる(不適)。
・ Dissolution criteria
−: No precipitation, suspension or suspended matter is observed (conformity).
±: Slight precipitation, suspension or suspended matter is recognized (conformity).
+: Precipitation, suspension or suspended matter is observed (unsuitable).
++: Precipitation, suspension, or suspended matter is noticeable (unsuitable).
表2は、実施例1〜7及び比較例1〜7の溶解判定結果を示した表である。 Table 2 is a table showing dissolution determination results of Examples 1 to 7 and Comparative Examples 1 to 7.
実施例1〜7は、溶解判定が適合したことが確認された。一方、「多価アルコール抜き」、「アルカリ抜き」又は「低級アルコール抜き」の比較例1〜3及び界面活性剤を添加した比較例4〜7は、沈殿、懸濁又は浮遊物が発生し、特に沈殿及び白濁が顕著であった。従って、比較例1〜7はコロソリン酸の溶解性が低いことが確認された。 In Examples 1 to 7, it was confirmed that the dissolution determination was suitable. On the other hand, Comparative Examples 1 to 3 of “without polyhydric alcohol”, “without alkali” or “without lower alcohol” and Comparative Examples 4 to 7 with the addition of a surfactant generate precipitates, suspensions or suspended matters, In particular, precipitation and cloudiness were remarkable. Therefore, it was confirmed that Comparative Examples 1-7 had low solubility of corosolic acid.
〔試験例2〕
製造直後及び40℃相対湿度75%−6箇月間保存後の実施例8〜23及び比較例8〜23の水性液剤について、コロソリン酸の含量を測定した。尚、定量は逆相分配高速液体クロマトグラフ法により実施した。
[Test Example 2]
The content of corosolic acid was measured for the aqueous solutions of Examples 8 to 23 and Comparative Examples 8 to 23 immediately after production and after storage at 40 ° C relative humidity 75% -6 months. The quantification was performed by the reverse phase partition high performance liquid chromatograph method.
表3は実施例8〜23及び比較例8〜23の水性液剤中のコロソリン酸含量測定結果を示した表である。 Table 3 is the table | surface which showed the corosolic acid content measurement result in the aqueous liquid agent of Examples 8-23 and Comparative Examples 8-23.
実施例8〜23の各水性液剤中のコロソリン酸含量実測値は仕込み理論値と良く相関していた。また、40℃相対湿度75%−6箇月間保存後においてコロソリン酸含量の変化はほとんどなかった。一方、比較例8〜23のコロソリン酸含量実測値は、調製工程中のメンブランフィルター又は濾紙による濾過工程により損失し、仕込み理論値より低値を示した。また、40℃相対湿度75%−6箇月間保存後において更に含量が低下する傾向が認められた。 The actual measured value of corosolic acid content in each of the aqueous liquid preparations of Examples 8 to 23 correlated well with the charged theoretical value. Moreover, there was almost no change in corosolic acid content after storage at 40 ° C. relative humidity 75% -6 months. On the other hand, the corosolic acid content actual measurement values of Comparative Examples 8 to 23 were lost by the membrane filtration process or the filter paper filtration process during the preparation process, and were lower than the charged theoretical values. Moreover, the tendency for a content to fall was recognized after 40 degreeC relative humidity 75% -6 months storage.
〔試験例3〕
製造直後及び40℃相対湿度75%−6箇月間保存後の実施例8〜16及び比較例8〜16の注射用水性液剤について、日本薬局方 一般試験法 注射剤の不溶性異物試験を実施した。
表4は実施例8〜16及び比較例8〜16の注射用水性液剤の不溶性異物試験の結果を示した表である。
[Test Example 3]
For the injectable aqueous solutions of Examples 8 to 16 and Comparative Examples 8 to 16 immediately after production and after storage at 40 ° C. and relative humidity of 75% for 6 months, an insoluble foreign matter test for injections was conducted.
Table 4 is a table showing the results of insoluble foreign matter tests of the aqueous solutions for injection of Examples 8 to 16 and Comparative Examples 8 to 16.
実施例8〜16の各注射用水性液剤は、日本薬局方一般試験法の不溶性異物試験に適合した。また、40℃相対湿度75%−6箇月間保存後においても変化は認められなかった。一方、比較例8〜16の注射用水性液剤は試験に不適であり、コロソリン酸の溶解が充分でなく析出したものと考えられた。 Each of the aqueous solutions for injection of Examples 8 to 16 was compatible with the insoluble foreign matter test of the Japanese Pharmacopoeia General Test Method. Further, no change was observed even after storage at 40 ° C. relative humidity 75% -6 months. On the other hand, it was considered that the aqueous solutions for injection of Comparative Examples 8 to 16 were unsuitable for the test, and corosolic acid was not sufficiently dissolved and precipitated.
〔試験例4〕
製造直後及び40℃相対湿度75%−6箇月間保存後の実施例17〜23及び比較例17〜23の内服液剤について、第15改正日本薬局方通則27に記載されている液状の医薬品の観察方法に準じた方法により性状を評価した。
表5は実施例17〜23及び比較例17〜23の内服液剤の性状を評価した結果を示した表である。
[Test Example 4]
Observation of liquid pharmaceuticals described in Fifteenth Amendment Japanese Pharmacopoeia General Rules 27 for internal use liquids of Examples 17 to 23 and Comparative Examples 17 to 23 immediately after production and after storage at 40 ° C. relative humidity 75% -6 months Properties were evaluated by a method according to the method.
Table 5 is the table | surface which showed the result of having evaluated the property of the internal use liquid agent of Examples 17-23 and Comparative Examples 17-23.
実施例17〜23の各内服液剤は、「澄明な液」であった。また、40℃相対湿度75%−6箇月間保存後においてもほとんど変化は認められなかった。pHが若干低い実施例23は、40℃相対湿度75%−6箇月間保存後において僅かに懸濁が発生した。一方、比較例17〜23の内服液剤は製造直後より懸濁が認められ、更に40℃相対湿度75%−6箇月間保存後においては沈殿も認められた。 Each internal solution of Examples 17 to 23 was a “clear solution”. In addition, almost no change was observed even after storage at 40 ° C. relative humidity 75% -6 months. In Example 23, which had a slightly lower pH, a slight suspension occurred after storage at 40 ° C. relative humidity 75% -6 months. On the other hand, the internal liquid preparations of Comparative Examples 17 to 23 were observed to be suspended from immediately after production, and further to precipitation after storage at 40 ° C. relative humidity 75% -6 months.
本発明によるコロソリン酸含有水性液剤は、水に対して極めて難溶であるコロソリン酸を水に安定に溶解し、長期間保存しても沈殿等を生じることがなく、注射用液剤や内服液剤として有用であることが示された。 The corosolic acid-containing aqueous liquid preparation according to the present invention stably dissolves corosolic acid, which is extremely insoluble in water, and does not cause precipitation or the like even when stored for a long period of time. It has been shown to be useful.
Claims (4)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2009024461A JP5359333B2 (en) | 2009-02-05 | 2009-02-05 | Corosolic acid-containing aqueous solution |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2009024461A JP5359333B2 (en) | 2009-02-05 | 2009-02-05 | Corosolic acid-containing aqueous solution |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2010180152A JP2010180152A (en) | 2010-08-19 |
JP5359333B2 true JP5359333B2 (en) | 2013-12-04 |
Family
ID=42761969
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2009024461A Active JP5359333B2 (en) | 2009-02-05 | 2009-02-05 | Corosolic acid-containing aqueous solution |
Country Status (1)
Country | Link |
---|---|
JP (1) | JP5359333B2 (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2024004951A1 (en) * | 2022-06-27 | 2024-01-04 | サントリーホールディングス株式会社 | Beverage, and method for reducing inherent sourness originating from citric acid and/or salt thereof in beverage |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3437232A1 (en) * | 1984-10-10 | 1986-04-17 | Mack Chem Pharm | STABILIZED INJECTION SOLUTIONS FROM PIROXICAM |
EP1014953B1 (en) * | 1997-03-05 | 2012-04-25 | Sugen, Inc. | Formulations for hydrophobic pharmaceutical agents |
JP3213283B2 (en) * | 1997-10-16 | 2001-10-02 | 山之内製薬株式会社 | Injection |
JP2005328839A (en) * | 2004-04-19 | 2005-12-02 | Microcel:Kk | Solubilized liquid of hardly-soluble component and method for producing the same |
JP2006169236A (en) * | 2004-11-16 | 2006-06-29 | Yuusu Techno Corporation:Kk | Glycogenesis inhibitor |
-
2009
- 2009-02-05 JP JP2009024461A patent/JP5359333B2/en active Active
Also Published As
Publication number | Publication date |
---|---|
JP2010180152A (en) | 2010-08-19 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP2009256216A (en) | Liquid amlodipine besylate formulation for internal administration stable in solution state | |
WO2014010656A1 (en) | Superior blood alcohol concentration reduction accelerating agent | |
JP2010514706A (en) | Forsythiaside injection and preparation method thereof | |
JP2010514706A5 (en) | ||
JP5766021B2 (en) | Stable aqueous solution | |
RU2498801C1 (en) | Stabilised dihydroquercetin solution | |
EP2745839B1 (en) | Pharmaceutical composition in the form of an oral suspension including a flavonoid fraction and xanthan gum | |
JP5359333B2 (en) | Corosolic acid-containing aqueous solution | |
CN104414963A (en) | Levosimendan-containing medicine composition | |
CN102688189B (en) | Lurasidone medicine composition and preparation method thereof | |
JP6308210B2 (en) | Aqueous liquid composition containing L-histidine in high concentration | |
KR101297354B1 (en) | Stable and taste masking syrup composition of transparent solution comprising Dexibuprofen | |
JP5823131B2 (en) | A composition containing windproof tsushosan | |
CN107510650A (en) | A kind of Pidotimod oral administration solution and preparation method thereof | |
KR101244284B1 (en) | Lquid composition powder freezing dried male silk pupa with an increased stability | |
JP2019517574A (en) | Preparation of curcuminoid in water (liquid) and its process | |
CN1857414A (en) | Volatile clove oil and its process for producing medicine composition | |
JP4574742B1 (en) | Propolis composition | |
JPWO2017130576A1 (en) | Pharmaceutical composition | |
JP5672880B2 (en) | Ipriflavone solubilized composition | |
CN1415292A (en) | Formula for improving water-solubility of armillarisin and its preparation | |
EP3946407A1 (en) | Formulation to enhance the bioavailibity and stability of curcuminoids and/or its derivatives thereof | |
JP6024371B2 (en) | Herbal extract-containing liquid composition | |
JP5412708B2 (en) | Liquid composition for internal use | |
JP2015020982A (en) | Lycium fruit extract-containing oral solution, solubilizer and solubilization method |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20111025 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20130521 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20130717 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20130806 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20130819 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 5359333 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |