TWI445527B - 已抑制變色之安定性醫藥製劑 - Google Patents
已抑制變色之安定性醫藥製劑 Download PDFInfo
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- TWI445527B TWI445527B TW098130635A TW98130635A TWI445527B TW I445527 B TWI445527 B TW I445527B TW 098130635 A TW098130635 A TW 098130635A TW 98130635 A TW98130635 A TW 98130635A TW I445527 B TWI445527 B TW I445527B
- Authority
- TW
- Taiwan
- Prior art keywords
- polyvinyl alcohol
- discoloration
- preparation
- acid
- ascorbic acid
- Prior art date
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- 238000002845 discoloration Methods 0.000 title description 27
- 239000008194 pharmaceutical composition Substances 0.000 title 1
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 64
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 48
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 47
- 238000002360 preparation method Methods 0.000 claims description 43
- 229960000401 tranexamic acid Drugs 0.000 claims description 34
- GYDJEQRTZSCIOI-LJGSYFOKSA-N tranexamic acid Chemical compound NC[C@H]1CC[C@H](C(O)=O)CC1 GYDJEQRTZSCIOI-LJGSYFOKSA-N 0.000 claims description 34
- 239000011668 ascorbic acid Substances 0.000 claims description 31
- 235000010323 ascorbic acid Nutrition 0.000 claims description 31
- 229960005070 ascorbic acid Drugs 0.000 claims description 31
- ZUFQODAHGAHPFQ-UHFFFAOYSA-N pyridoxine hydrochloride Chemical compound Cl.CC1=NC=C(CO)C(CO)=C1O ZUFQODAHGAHPFQ-UHFFFAOYSA-N 0.000 claims description 18
- 239000007787 solid Substances 0.000 claims description 16
- GHOKWGTUZJEAQD-ZETCQYMHSA-N (D)-(+)-Pantothenic acid Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-ZETCQYMHSA-N 0.000 claims description 12
- FAPWYRCQGJNNSJ-UBKPKTQASA-L calcium D-pantothenic acid Chemical compound [Ca+2].OCC(C)(C)[C@@H](O)C(=O)NCCC([O-])=O.OCC(C)(C)[C@@H](O)C(=O)NCCC([O-])=O FAPWYRCQGJNNSJ-UBKPKTQASA-L 0.000 claims description 12
- 229960002079 calcium pantothenate Drugs 0.000 claims description 12
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 claims description 8
- GHOKWGTUZJEAQD-UHFFFAOYSA-N Chick antidermatitis factor Natural products OCC(C)(C)C(O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-UHFFFAOYSA-N 0.000 claims description 6
- LXNHXLLTXMVWPM-UHFFFAOYSA-N Vitamin B6 Natural products CC1=NC=C(CO)C(CO)=C1O LXNHXLLTXMVWPM-UHFFFAOYSA-N 0.000 claims description 6
- 229940055726 pantothenic acid Drugs 0.000 claims description 6
- 235000019161 pantothenic acid Nutrition 0.000 claims description 6
- 239000011713 pantothenic acid Substances 0.000 claims description 6
- RADKZDMFGJYCBB-UHFFFAOYSA-N pyridoxal hydrochloride Natural products CC1=NC=C(CO)C(C=O)=C1O RADKZDMFGJYCBB-UHFFFAOYSA-N 0.000 claims description 6
- 239000011726 vitamin B6 Substances 0.000 claims description 6
- 235000019158 vitamin B6 Nutrition 0.000 claims description 6
- 229940011671 vitamin b6 Drugs 0.000 claims description 6
- 235000013878 L-cysteine Nutrition 0.000 claims description 4
- 239000004201 L-cysteine Substances 0.000 claims description 4
- 229920002678 cellulose Polymers 0.000 description 19
- 239000001913 cellulose Substances 0.000 description 19
- 239000007864 aqueous solution Substances 0.000 description 17
- 239000008187 granular material Substances 0.000 description 16
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 16
- 239000002245 particle Substances 0.000 description 16
- 230000000052 comparative effect Effects 0.000 description 11
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 10
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 10
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 10
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 10
- PWKSKIMOESPYIA-UHFFFAOYSA-N 2-acetamido-3-sulfanylpropanoic acid Chemical compound CC(=O)NC(CS)C(O)=O PWKSKIMOESPYIA-UHFFFAOYSA-N 0.000 description 8
- 235000019359 magnesium stearate Nutrition 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- 239000000843 powder Substances 0.000 description 8
- 239000004480 active ingredient Substances 0.000 description 6
- 238000011156 evaluation Methods 0.000 description 6
- 239000003826 tablet Substances 0.000 description 6
- 229920002785 Croscarmellose sodium Polymers 0.000 description 5
- 208000012641 Pigmentation disease Diseases 0.000 description 5
- 239000002202 Polyethylene glycol Substances 0.000 description 5
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 5
- 239000000654 additive Substances 0.000 description 5
- 239000011230 binding agent Substances 0.000 description 5
- 229960001681 croscarmellose sodium Drugs 0.000 description 5
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 5
- 239000011361 granulated particle Substances 0.000 description 5
- 239000008188 pellet Substances 0.000 description 5
- 229920001223 polyethylene glycol Polymers 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- XUMBMVFBXHLACL-UHFFFAOYSA-N Melanin Chemical compound O=C1C(=O)C(C2=CNC3=C(C(C(=O)C4=C32)=O)C)=C2C4=CNC2=C1C XUMBMVFBXHLACL-UHFFFAOYSA-N 0.000 description 4
- 229920001577 copolymer Polymers 0.000 description 4
- 238000005469 granulation Methods 0.000 description 4
- 230000003179 granulation Effects 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 239000000178 monomer Substances 0.000 description 4
- 230000019612 pigmentation Effects 0.000 description 4
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 4
- 229920002554 vinyl polymer Polymers 0.000 description 4
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 3
- 230000000996 additive effect Effects 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 239000007888 film coating Substances 0.000 description 3
- 238000009501 film coating Methods 0.000 description 3
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 3
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 3
- 239000000825 pharmaceutical preparation Substances 0.000 description 3
- 238000010998 test method Methods 0.000 description 3
- 229920002261 Corn starch Polymers 0.000 description 2
- ZAKOWWREFLAJOT-CEFNRUSXSA-N D-alpha-tocopherylacetate Chemical compound 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 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 208000018756 Variant Creutzfeldt-Jakob disease Diseases 0.000 description 2
- 208000005881 bovine spongiform encephalopathy Diseases 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000007937 lozenge Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 229940127557 pharmaceutical product Drugs 0.000 description 2
- 239000000049 pigment Substances 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 238000006116 polymerization reaction Methods 0.000 description 2
- 229920002689 polyvinyl acetate Polymers 0.000 description 2
- 239000011118 polyvinyl acetate Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000007127 saponification reaction Methods 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 238000009495 sugar coating Methods 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 2
- 229940042585 tocopherol acetate Drugs 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- KKDYHBLPJDARJP-UHFFFAOYSA-N C(CCCCCCCCC)N.C(C1=CN=CC=C1)(=O)O Chemical compound C(CCCCCCCCC)N.C(C1=CN=CC=C1)(=O)O KKDYHBLPJDARJP-UHFFFAOYSA-N 0.000 description 1
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 description 1
- 206010014970 Ephelides Diseases 0.000 description 1
- IMROMDMJAWUWLK-UHFFFAOYSA-N Ethenol Chemical compound OC=C IMROMDMJAWUWLK-UHFFFAOYSA-N 0.000 description 1
- 208000010201 Exanthema Diseases 0.000 description 1
- 208000003351 Melanosis Diseases 0.000 description 1
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 1
- 101100043636 Oryza sativa subsp. japonica SSIIIA gene Proteins 0.000 description 1
- 101100066911 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) FLO5 gene Proteins 0.000 description 1
- 206010064127 Solar lentigo Diseases 0.000 description 1
- 206010052568 Urticaria chronic Diseases 0.000 description 1
- XTXRWKRVRITETP-UHFFFAOYSA-N Vinyl acetate Chemical compound CC(=O)OC=C XTXRWKRVRITETP-UHFFFAOYSA-N 0.000 description 1
- 229930003268 Vitamin C Natural products 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 230000003266 anti-allergic effect Effects 0.000 description 1
- 230000002364 anti-haemorrhagic effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 238000005266 casting Methods 0.000 description 1
- 208000024376 chronic urticaria Diseases 0.000 description 1
- 238000007334 copolymerization reaction Methods 0.000 description 1
- 229960002433 cysteine Drugs 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 201000005884 exanthem Diseases 0.000 description 1
- 239000003527 fibrinolytic agent Substances 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- -1 hydroxypropyl group Chemical group 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000000820 nonprescription drug Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 230000000379 polymerizing effect Effects 0.000 description 1
- 229940068984 polyvinyl alcohol Drugs 0.000 description 1
- 206010037844 rash Diseases 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
- 230000002087 whitening effect Effects 0.000 description 1
Classifications
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- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4415—Pyridoxine, i.e. Vitamin B6
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- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
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- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
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- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
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- A61K9/1629—Organic macromolecular compounds
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- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Immunology (AREA)
- Molecular Biology (AREA)
- Biophysics (AREA)
- Transplantation (AREA)
- Rheumatology (AREA)
- Pain & Pain Management (AREA)
- Dermatology (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Description
本發明為有關含有凝血酸(tranexamic acid)和抗壞血酸也不易發生製劑變色之內服用醫藥固形製劑。
凝血酸作為抗血纖維蛋白溶酶劑具有抗出血、抗過敏、抗炎症效果等,而泛用為醫療用醫藥品,也配合於OTC醫藥品。於1979年對慢性蕁麻疹患者投與凝血酸之結果,竟然併發之肝斑消退之報告,藉此,對肝斑治療凝血酸開始成為處方(以上參照例如非專利文獻1)。
抗壞血酸自古已知不僅抑制黑色素色素之產生,並由將已蓄積之黑色素色素分解作用而抑制色素沈著,於OTC醫藥品,維生素C主藥製劑之承認效能上許可用於由老人斑、雀斑、曬傷‧斑疹之色素沈著(參照非專利文獻2)。
又有掲示含有凝血酸和抗壞血酸之色素沈著症治療用製劑,較凝血酸單劑或抗壞血酸單劑投與之場合其色素沈著症之改善度為佳(參照專利文獻1)。
更且含有凝血酸、抗壞血酸及L-半胱胺酸之美白用組成物由本發明者等掲示,得知比併用凝血酸和抗壞血酸更抑制色素沈著(參照專利文獻2)。於同文獻之製劑例,掲示除有效成分之上述3成分,作為添加劑含有結晶纖維素、玉米澱粉、低取代度羥丙基纖維素、羥丙基纖維素、硬脂酸鎂、羥丙基甲基纖維素、聚乙二醇、滑石及氧化鈦之錠劑。
又於專利文獻3之製劑例,掲示含有除作為有效成分之凝血酸、抗壞血酸、L-半胱胺酸、維生素B6鹽酸鹽及泛酸鈣之外,含有結晶纖維素、玉米澱粉、低取代度羥丙基纖維素、羥丙基纖維素、硬脂酸鎂、羥丙基甲基纖維素、聚乙二醇、滑石及氧化鈦作為製劑添加劑之錠劑(參照專利文獻3)。
他方面,聚乙烯醇共聚物(PVA共聚物)為聚乙烯醇與聚合性乙烯基單體共聚合者,但以牛海綿狀腦症(BSE)問題為契機,使用脫明膠膠囊素材(參照例如專利文獻4)。作為PVA共聚物之膠囊以外之醫藥用途,掲示錠劑或顆粒劑之被覆劑(專利文獻5)或製劑之結合劑(專利文獻6)之利用。
又聚乙烯醇部分皂化物為將聚乙酸乙烯酯皂化而得之聚合物,皂化度為78~96mol%。作為醫藥用途,利用為錠劑或顆粒劑之被覆劑或製劑之結合劑等(例如參照非專利文獻3)。
但至今作為有效成分含有凝血酸及抗壞血酸等者,作為添加劑當然聚乙烯醇之外,含有聚乙烯醇共聚物及/或聚乙烯醇部分皂化物之製劑完全未知。
專利文獻1:特開平4-243825號公報
專利文獻2:特開2004-217655號公報
專利文獻3:特開2005-314403號公報
專利文獻4:特開2007-091670號公報
專利文獻5:特開2007-022938號公報
專利文獻6:國際申請第2005/019286號小冊
非專利文獻1:Pharmacia Vol.44 No.5 2008 p.437-442
非專利文獻2:一般用醫藥品製造(輸入)承認基準時報2008年版
非專利文獻3:醫藥品添加物辭典2005藥事日報社2005
本發明者等將專利文獻1之實施例1掲示之含有凝血酸和抗壞血酸之顆粒劑實際試作時,發現於長期保存(溫度40℃、相對濕度75%之加速試驗)有漸次變色(紅變)之問題。
也即本發明之課題為提供於含有凝血酸和抗壞血酸之製劑中,無變色等之安定性優異之內服用固形製劑。
本發明者等為解決上述課題,長年反復試行錯誤探索於以凝血酸和抗壞血酸為有效成分含有之製劑,如何添加物始最有助製劑安定性。
結果發現於含有凝血酸和抗壞血酸之製劑,添加聚乙烯醇共聚物及/或聚乙烯醇部分皂化物,則顯著抑制製劑之變色之驚奇事實。
更於本發明之製劑中,將聚乙烯醇共聚物及/或聚乙烯醇部分皂化物作為造粒用結合劑使用時,發現顯著抑制製劑之變色,終於完成本發明。
也即本發明為
(1)於含有凝血酸和抗壞血酸之製劑中,添加聚乙烯醇共聚物及/或部分皂化聚乙烯醇而成為特徵之內服用醫藥固形製劑,本發明之適宜之對應可為如下者。
(2)以更含有L-半胱胺酸為特徵之(1)記載之內服用醫藥固形製劑。
(3)以更含有泛酸及/或維生素B6為特徵之(1)或(2)記載之內服用醫藥固形製劑。
(4)維生素B6為維生素B6鹽酸鹽之(3)記載之內服用醫藥固形製劑。
(5)泛酸為泛酸鈣之(3)或(4)記載之內服用醫藥固形製劑。
本發明因配合凝血酸和抗壞血酸也抑制變色之安定性製劑而有用。本發明即使更於製劑中以L-半胱胺酸、維生素B6鹽酸鹽、泛酸鈣等為有效成分含有也可得抑制變色之安定性製劑而有用。
本發明中「維生素B6」乃指維生素B6及其鹽,但宜為維生素B6鹽酸鹽。
本發明中「泛酸」乃指泛酸及其鹽,但宜為泛酸鈣。
本發明中凝血酸、抗壞血酸、泛酸鈣、維生素B6鹽酸鹽各收載於第15改正日本藥典。
本發明中L-半胱胺酸及聚乙烯醇部分皂化物收載於例如醫藥品添加物規格2003。
本發明中「聚乙烯醇部分皂化物」為將乙酸乙烯酯聚合而得之聚乙酸乙烯酯聚合體之部分皂化物,通常皂化度為78~96mol%,黏度以2~100mm2
/s較佳。
本發明使用之聚乙烯醇部分皂化物為以商品名Gohsenol(日本合成化學工業)市售,容易購入。
又含有聚乙烯醇部分皂化物之膜被覆用基劑乃以商品名Opadry II(日本Colorcon)市售,容易購入。
本發明中「聚乙烯醇共聚物」可依WO2005/19286和WO2002/17848記載之方法製造,係將平均聚合度100~2000之部分皂化聚乙烯醇與至少1種以上之聚合性乙烯基單體按重量比6:4~9:1之比例共聚合而得之共聚物,該共聚物之20℃中2重量%溶液之黏度為10~300mPa‧s之聚乙烯醇共聚物。
宜為將平均聚合度150~1000之部分皂化聚乙烯醇與至少1種以上之聚合性乙烯基單體以重量比6:4~9:1之比例共聚合而得之共聚物,該共聚物於20℃中2重量%溶液之黏度為10~250mPa‧s之聚乙烯醇共聚物。
所用聚合性乙烯基單體以丙烯酸、甲基丙烯酸、聚乙二醇等較佳。
又聚乙烯醇與聚乙二醇(聚乙二醇)之共聚物也以本發明所用聚乙烯醇共聚物較佳。
本發明所用聚乙烯醇共聚物為例如以商品名POVACOAT(日新化成)、商品名Kollicoat IR(BASF)市售而容易購入。
本發明之製劑中,凝血酸、抗壞血酸、及聚乙烯醇共聚物或聚乙烯醇部分皂化物之含量比為凝血酸每1重量份各為0.01~10重量,及0.001~1重量,宜為0.1~2重量,及0.01~0.5重量。
本發明之製劑為含有凝血酸和抗壞血酸,彼等可以互相混雜存在,也可以互相不接觸而隔著境界來存在,但以凝血酸和抗壞血酸各別顆粒於製劑中存在較佳。
其次記載本發明之醫藥製劑組成物之製法如下。
本發明中固形製劑乃指第15改正日本藥典記載之顆粒劑、丸劑、散劑、錠劑(包括多層錠)、膠囊劑等。
本發明中劑形以顆粒劑或錠劑較佳,也可施加糖衣或膜被覆。
本發明之醫藥固形製劑可用公知技術製造。
若本發明之醫藥固形製劑之劑形為顆粒劑或錠劑之場合,可用公知技術製造,更將這些顆粒劑或錠劑依公知之方法施加糖衣或膜被覆。
為更詳細說明本發明,以下記載實施例及比較例。
1.1於鑄膜(casting film)之比較試驗
以僅羥丙基甲基纖維素(別名羥丙基甲基纖維素)之8%水溶液為對照。
將凝血酸0.5g和抗壞血酸0.2g分散‧溶解於羥丙基甲基纖維素之8%水溶液57.5g。
將凝血酸0.5g和抗壞血酸0.2g分散‧溶解於聚乙烯醇共聚物(日新化成製,商品名POVACOAT,以下省略)之8%水溶液57.5g。
將凝血酸0.5g和抗壞血酸0.2g分散‧溶解於聚乙烯醇共聚物之50%乙醇水溶液57.5g。
將凝血酸0.5g和抗壞血酸0.2g分散‧溶解於含有聚乙烯醇部分皂化物之膜被覆用基劑(商品名Opadry Ⅱ)之8%水溶液57.5g。
將凝血酸0.5g和抗壞血酸0.2g分散‧溶解於聚乙烯醇部分皂化物之8%水溶液57.5g。
1.2試驗方法
將實施例1~4、比較例1~2之試料適量取出,而塗布於白色板上,於50℃放置一晝夜,作成鑄膜。將各鑄膜之變色以目視觀察。變色之評價乃用如下基準。
1.3評價基準
A:無變色
B:稍變色
C:有變色
D:顯著變色
1.4試驗結果
試驗結果如表1。由同表之結果,得知若用聚乙烯醇共聚物及聚乙烯醇部分皂化物來造粒之場合,可抑制變色。
2.1作為造粒黏著劑之比較試驗
於流動層造粒機(Flowcoater FLO5,弗氏產業)將凝血酸2403.8g、泛酸鈣118.6g、結晶纖維素適量投入‧混合,將羥丙基甲基纖維素水溶液噴霧來調製造粒粉末而作成a顆粒。
又於流動層造粒機將抗壞血酸961.5g、L-半胱胺酸769.2g、維生素B6鹽酸鹽19.2g、結晶纖維素適量投入‧混合,將羥丙基甲基纖維素水溶液噴霧來調製造粒粉末而作成b顆粒。
混合該a、b顆粒而造粒顆粒。於該造粒顆粒3651.3g混合結晶纖維素205.1g、交聯羧甲醚纖維素鈉102.6g、硬脂酸鎂41.0g,打錠而得成為中心核之裸錠。
於流動層造粒將凝血酸2403.8g、L-半胱胺酸769.2g、泛酸鈣118.6g、維生素B6鹽酸鹽19.2g、結晶纖維素適量投入混合,將聚乙烯醇共聚物(POVACOAT)水溶液噴霧來調製造粒粉末而作成a顆粒。
又於流動層造粒機將抗壞血酸961.5g、結晶纖維素適量投入混合,作為結合劑將聚乙烯醇共聚物(POVACOAT)水溶液噴霧來調製造粒粉末而作成b顆粒。
混合該a、b顆粒而造粒顆粒。於該造粒顆粒3651.3g混合結晶纖維素205.1g、交聯羧甲醚纖維素鈉102.6g、硬脂酸鎂41.0g,打錠而得成為中心核之裸錠。
於該流動層造粒機將凝血酸2403.8g、泛酸鈣118.6g、結晶纖維素適量投入‧混合,將聚乙烯醇共聚物(POVACOAT)水溶液噴霧來調製造粒粉末而作成a顆粒。又將抗壞血酸961.5g、L-半胱胺酸769.2g、維生素B6鹽酸鹽19.2g、結晶纖維素適量投入混合,作為結合劑將聚乙烯醇共聚物(POVACOAT)水溶液噴霧來調製造粒粉末而作成b顆粒。
混合該a、b顆粒而造粒顆粒。於該造粒顆粒3651.3g混合結晶纖維素205.1g、交聯羧甲醚纖維素鈉102.6g、硬脂酸鎂41.0g,打錠而得成為中心核之裸錠。
於流動層造粒機將凝血酸2403.8g、泛酸鈣118.6g、結晶纖維素適量投入混合,將聚乙烯醇部分皂化物水溶液噴霧來調製造粒粉末而作成a顆粒。
又於流動層造粒機將抗壞血酸961.5g、L-半胱胺酸769.2g、維生素B6鹽酸鹽19.2g、結晶纖維素適量投入‧混合,將聚乙烯醇部分皂化物水溶液噴霧來調製造粒粉末而作成b顆粒。
混合該a、b顆粒而造粒顆粒。於該造粒顆粒3651.3g將結晶纖維素205.1g、交聯羧甲醚纖維素鈉102.6g、硬脂酸鎂41.0g混合,打錠而得成為中心核之裸錠。
於流動層造粒機將凝血酸386.6g、泛酸鈣19.1g、菸鹼醯胺20.6g、生育酚乙酸酯(乙酸生育酚)50%倍散末30.9g、結晶纖維素適量投入混合,將聚乙烯醇共聚物(POVACOAT)水溶液噴霧來調製造粒粉末而作成a顆粒。
又於流動層造粒機將抗壞血酸255.5g、L-半胱胺酸204.4g、維生素B6鹽酸鹽10.2g、結晶纖維素適量投入混合,將聚乙烯醇共聚物(POVACOAT)水溶液噴霧來調製造粒粉末而作成b顆粒。
混合該a、b顆粒而造粒顆粒。於該造粒顆粒741.4g混合結晶纖維素30.5g、交聯羧甲醚纖維素鈉20.0g、硬脂酸鎂8.1g,打錠而得成為中心核之裸錠。
2.2試驗方法
將實施例5~8及比較例3之試料60錠充填於玻璃瓶(6K規格瓶),於25℃、75%RH保存4週後,以目視觀察變色。變色之評價使用如下基準。
2.3評價之基準
與1.3同樣,以A:無變色、B:稍變色、C:有變色、D:顯著變色之4階段評價。
2.4試驗結果
試驗結果如表2及3。由同表之結果,使用聚乙烯醇共聚物及聚乙烯醇部分皂化物來造粒之場合,判明可抑制變色。
3.1於公知製劑之比較試驗
使用專利文獻3之製劑例3.2掲示之錠劑。也即每6錠混合凝血酸750mg、抗壞血酸300mg、L-半胱胺酸240mg、泛酸鈣24mg、維生素B6鹽酸鹽6mg、結晶纖維素適量、低取代度羥丙基甲基纖維素適量,使用羥丙基甲基纖維素水溶液來造粒後,混合適量硬脂酸鎂,打錠而得成為中心核之裸錠。
粉碎該裸錠,將適量分散‧溶解於羥丙基甲基纖維素水溶液。
粉碎該裸錠,將適量分散‧溶解於羥丙基甲基纖維素溶液(水:乙醇=8:2)。
粉碎該裸錠,將適量分散‧溶解於聚乙烯醇共聚物溶液(水:乙醇=8:2)。
3.2試驗方法
實施例9、比較例4及5之試料適量取出,而塗布於白色板上,於50℃放置一晝夜,作成鑄膜。將各鑄膜之變色以目視觀察。變色之評價乃用如下基準。
3.3評價之基準
與1.3同樣,以A:無變色、B:稍變色、C:有變色、D:顯著變色之4階段評價。
3.4試驗結果
試驗結果如表4。由同表之結果,判明使用聚乙烯醇共聚物則可抑制變色。
Claims (6)
- 一種內服用醫藥固形製劑,其特徵為於含有凝血酸(tranexamic acid)和抗壞血酸之製劑中,添加聚乙烯醇共聚物及/或部分皂化聚乙烯醇而成。
- 如申請專利範圍第1項之內服用醫藥固形製劑,其進一步含有L-半胱胺酸。
- 如申請專利範圍第1項之內服用醫藥固形製劑,其進一步含有泛酸及/或維生素B6。
- 如申請專利範圍第3項之內服用醫藥固形製劑,其中維生素B6為維生素B6鹽酸鹽。
- 如申請專利範圍第3項之內服用醫藥固形製劑,其中泛酸為泛酸鈣。
- 如申請專利範圍第1至5項之內服用醫藥固形製劑,其中凝血酸和抗壞血酸係互相混雜存在。
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CN (1) | CN102137663B (zh) |
BR (1) | BRPI0918539A2 (zh) |
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MX (1) | MX340436B (zh) |
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WO2011049093A1 (ja) * | 2009-10-20 | 2011-04-28 | 第一三共ヘルスケア | 変色及び臭いが抑制されたフィルムコーティング錠 |
JP2013049671A (ja) * | 2011-08-04 | 2013-03-14 | Fancl Corp | アスコルビン酸製剤 |
JP6245786B2 (ja) * | 2011-10-17 | 2017-12-13 | 大同化成工業株式会社 | 医薬用結合剤及び該結合剤を用いた製剤 |
CN103054861A (zh) * | 2012-12-29 | 2013-04-24 | 北京阜康仁生物制药科技有限公司 | 一种含氨甲环酸的复方固体制剂 |
EP3173101B1 (en) * | 2014-07-25 | 2020-10-21 | Mitsubishi Chemical Corporation | Polyvinyl alcohol particles, pharmaceutical binder using same, pharmaceutical tablet, sustained-release pharmaceutical tablet, and method for producing polyvinyl alcohol particles |
CA3060366A1 (en) | 2017-04-28 | 2018-11-01 | Astellas Pharma Inc. | Pharmaceutical composition for oral administration comprising enzalutamide |
JP2019081757A (ja) * | 2017-10-31 | 2019-05-30 | 武田コンシューマーヘルスケア株式会社 | 固形製剤の製造方法 |
CN112822995B (zh) * | 2018-10-09 | 2023-06-02 | 帝斯曼知识产权资产管理有限公司 | 局部组合物 |
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JPH04243825A (ja) * | 1991-01-25 | 1992-08-31 | Ss Pharmaceut Co Ltd | 色素沈着症治療剤 |
JPH093348A (ja) * | 1995-06-20 | 1997-01-07 | Lion Corp | 色素の変色抑制方法及び色素配合組成物 |
KR100829474B1 (ko) | 2000-08-29 | 2008-05-16 | 닛신 가세이 가부시키가이샤 | 경질 캡슐 |
JP2004217655A (ja) | 2002-12-27 | 2004-08-05 | Dai Ichi Seiyaku Co Ltd | 美白用組成物 |
JP2004250376A (ja) * | 2003-02-20 | 2004-09-09 | Lion Corp | 医薬組成物用色素、医薬組成物用色素の製造方法、医薬組成物及び医薬組成物の変色・退色防止方法 |
EP1657265B1 (en) * | 2003-08-20 | 2012-10-17 | Shionogi & Co., Ltd. | Novel coating composition |
JP2005068115A (ja) * | 2003-08-28 | 2005-03-17 | Pola Chem Ind Inc | 安定な皮膚外用剤 |
JP2005314403A (ja) * | 2004-03-31 | 2005-11-10 | Dai Ichi Seiyaku Co Ltd | 新規美白用組成物 |
WO2006003965A1 (ja) * | 2004-06-30 | 2006-01-12 | Daiichi Sankyo Healthcare Co., Ltd. | 美白組成物 |
JP5614826B2 (ja) | 2005-07-13 | 2014-10-29 | 塩野義製薬株式会社 | 退色を抑制した製剤 |
JP2007091670A (ja) | 2005-09-29 | 2007-04-12 | Shionogi & Co Ltd | 退色が抑制された着色カプセル |
JP2007197410A (ja) * | 2006-01-30 | 2007-08-09 | Lion Corp | フィルムコーティング錠 |
JP2008201711A (ja) * | 2007-02-20 | 2008-09-04 | Ss Pharmaceut Co Ltd | システイン臭が低減された固形製剤 |
MX2011001071A (es) * | 2008-08-06 | 2011-04-26 | Daiichi Sankyo Healthcare Co | Composicion farmaceutica estable que contiene acido tranexamico y acido ascorbico. |
MX2011002400A (es) * | 2008-09-05 | 2011-04-07 | Daiichi Sankyo Healthcare Co | Preparacion farmaceutica solida que tiene ingredientes activos separados por limites en la misma. |
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EP2335697A1 (en) | 2011-06-22 |
EP2335697B1 (en) | 2014-03-12 |
MX340436B (es) | 2016-07-08 |
TW201016212A (en) | 2010-05-01 |
WO2010029930A1 (ja) | 2010-03-18 |
BRPI0918539A2 (pt) | 2015-12-08 |
HK1152651A1 (en) | 2012-03-09 |
JP5498387B2 (ja) | 2014-05-21 |
EP2335697A4 (en) | 2011-08-17 |
JPWO2010029930A1 (ja) | 2012-02-02 |
MX2011002364A (es) | 2011-04-04 |
KR20110057151A (ko) | 2011-05-31 |
CN102137663B (zh) | 2016-09-28 |
KR101623608B1 (ko) | 2016-05-23 |
CN102137663A (zh) | 2011-07-27 |
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