JP5465867B2 - Stable eguarene sodium solid formulation - Google Patents
Stable eguarene sodium solid formulation Download PDFInfo
- Publication number
- JP5465867B2 JP5465867B2 JP2008289702A JP2008289702A JP5465867B2 JP 5465867 B2 JP5465867 B2 JP 5465867B2 JP 2008289702 A JP2008289702 A JP 2008289702A JP 2008289702 A JP2008289702 A JP 2008289702A JP 5465867 B2 JP5465867 B2 JP 5465867B2
- Authority
- JP
- Japan
- Prior art keywords
- sodium
- weight
- eguarene
- parts
- tablets
- 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
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- 239000011734 sodium Substances 0.000 title claims description 64
- 229910052708 sodium Inorganic materials 0.000 title claims description 64
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 title claims description 63
- 239000007787 solid Substances 0.000 title claims description 23
- 239000000203 mixture Substances 0.000 title description 8
- 238000009472 formulation Methods 0.000 title description 5
- 238000002360 preparation method Methods 0.000 claims description 37
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 33
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 19
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 19
- 229940069328 povidone Drugs 0.000 claims description 17
- 239000000126 substance Substances 0.000 claims description 17
- 229960000913 crospovidone Drugs 0.000 claims description 13
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 13
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 13
- 239000004475 Arginine Substances 0.000 claims description 6
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims description 6
- 239000004472 Lysine Substances 0.000 claims description 6
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- 239000006185 dispersion Substances 0.000 claims description 4
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 claims description 3
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 claims description 3
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 claims description 3
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 claims description 3
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 claims description 3
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 claims description 3
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 claims description 3
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- 239000003826 tablet Substances 0.000 description 27
- 239000000654 additive Substances 0.000 description 22
- 239000008187 granular material Substances 0.000 description 15
- 230000000996 additive effect Effects 0.000 description 13
- 239000007857 degradation product Substances 0.000 description 13
- 239000011261 inert gas Substances 0.000 description 13
- -1 magnesium aluminate Chemical class 0.000 description 13
- 238000000034 method Methods 0.000 description 13
- 229920002261 Corn starch Polymers 0.000 description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
- 239000008120 corn starch Substances 0.000 description 12
- 238000004519 manufacturing process Methods 0.000 description 11
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- 239000000243 solution Substances 0.000 description 11
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 10
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- 230000000052 comparative effect Effects 0.000 description 10
- KXGWXVVNYQOMQZ-UHFFFAOYSA-M egualen sodium Chemical compound [Na+].C1=C(C(C)C)C=CC=C2C(CC)=CC(S([O-])(=O)=O)=C21 KXGWXVVNYQOMQZ-UHFFFAOYSA-M 0.000 description 10
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- 238000004806 packaging method and process Methods 0.000 description 10
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 9
- 229920002678 cellulose Polymers 0.000 description 9
- 239000001913 cellulose Substances 0.000 description 9
- 229950005370 egualen Drugs 0.000 description 9
- 239000000843 powder Substances 0.000 description 8
- 238000003860 storage Methods 0.000 description 8
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 235000011187 glycerol Nutrition 0.000 description 6
- 238000005469 granulation Methods 0.000 description 6
- 230000003179 granulation Effects 0.000 description 6
- 235000017557 sodium bicarbonate Nutrition 0.000 description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 5
- 229920000881 Modified starch Polymers 0.000 description 5
- 238000000354 decomposition reaction Methods 0.000 description 5
- 239000000314 lubricant Substances 0.000 description 5
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 4
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 4
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- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 208000007107 Stomach Ulcer Diseases 0.000 description 4
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 4
- 229930006000 Sucrose Natural products 0.000 description 4
- VJHCJDRQFCCTHL-UHFFFAOYSA-N acetic acid 2,3,4,5,6-pentahydroxyhexanal Chemical compound CC(O)=O.OCC(O)C(O)C(O)C(O)C=O VJHCJDRQFCCTHL-UHFFFAOYSA-N 0.000 description 4
- 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 4
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 4
- 229950008138 carmellose Drugs 0.000 description 4
- 230000003247 decreasing effect Effects 0.000 description 4
- 235000014113 dietary fatty acids Nutrition 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 239000000194 fatty acid Substances 0.000 description 4
- 229930195729 fatty acid Natural products 0.000 description 4
- 201000005917 gastric ulcer Diseases 0.000 description 4
- 239000011521 glass Substances 0.000 description 4
- 150000002484 inorganic compounds Chemical class 0.000 description 4
- 229910010272 inorganic material Inorganic materials 0.000 description 4
- 229960003511 macrogol Drugs 0.000 description 4
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 4
- GEYJUFBPCGDENK-UHFFFAOYSA-M sodium;3,8-dimethyl-5-propan-2-ylazulene-1-sulfonate Chemical compound [Na+].CC(C)C1=CC=C(C)C2=C(S([O-])(=O)=O)C=C(C)C2=C1 GEYJUFBPCGDENK-UHFFFAOYSA-M 0.000 description 4
- 239000005720 sucrose Substances 0.000 description 4
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 3
- 108010010803 Gelatin Proteins 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000011575 calcium Substances 0.000 description 3
- 235000001465 calcium Nutrition 0.000 description 3
- 229910052791 calcium Inorganic materials 0.000 description 3
- 229910000019 calcium carbonate Inorganic materials 0.000 description 3
- 239000004359 castor oil Substances 0.000 description 3
- 235000019438 castor oil Nutrition 0.000 description 3
- 230000015556 catabolic process Effects 0.000 description 3
- 238000006731 degradation reaction Methods 0.000 description 3
- 239000004205 dimethyl polysiloxane Substances 0.000 description 3
- 235000013870 dimethyl polysiloxane Nutrition 0.000 description 3
- 239000007884 disintegrant Substances 0.000 description 3
- 239000008273 gelatin Substances 0.000 description 3
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- 235000011852 gelatine desserts Nutrition 0.000 description 3
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- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
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- 235000019698 starch Nutrition 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 229940012831 stearyl alcohol Drugs 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 229940065721 systemic for obstructive airway disease xanthines Drugs 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 235000010384 tocopherol Nutrition 0.000 description 1
- 229960001295 tocopherol Drugs 0.000 description 1
- 229930003799 tocopherol Natural products 0.000 description 1
- 239000011732 tocopherol Substances 0.000 description 1
- 229940074410 trehalose Drugs 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- UJMBCXLDXJUMFB-UHFFFAOYSA-K trisodium;5-oxo-1-(4-sulfonatophenyl)-4-[(4-sulfonatophenyl)diazenyl]-4h-pyrazole-3-carboxylate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)C1=NN(C=2C=CC(=CC=2)S([O-])(=O)=O)C(=O)C1N=NC1=CC=C(S([O-])(=O)=O)C=C1 UJMBCXLDXJUMFB-UHFFFAOYSA-K 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/095—Sulfur, selenium, or tellurium compounds, e.g. thiols
- A61K31/10—Sulfides; Sulfoxides; Sulfones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
本発明は、エグアレンナトリウムの分解を抑制したエグアレンナトリウム固形製剤に関する。 The present invention relates to a solid preparation of eguarene sodium in which degradation of eguarene sodium is suppressed.
エグアレンナトリウム[化学名：３−エチル−７−イソプロピル−１−アズレンスルホン酸ナトリウム・１／３ 水和物]は、経口投与で優れた胃粘膜保護作用を有し、胃潰瘍などの治療薬として優れた薬物である（特許文献１）。従来から、エグアレンナトリウムと同じ母核構造をもつアズレンスルホン酸ナトリウムが、種々の炎症性疾患、胃炎・胃潰瘍等の治療に用いられているが、その不安定さから、安定性を確保すべく、製剤化に際しては工夫を必要とし、様々な方法が提案されている。アズレンスルホン酸ナトリウム又はアズレン誘導体を、製剤化に際し安定化する方法について、例えば、シクロデキストリンで包接する方法（特許文献２）、単独あるいは高分子化合物とともに噴霧乾燥又は凍結乾燥する方法（特許文献３）、脱酸素剤とともに密封包装する方法（特許文献４）、エデト酸及びその塩類を配合する方法（特許文献５）、プロピレングリコールなどの多価アルコールを配合する方法（特許文献６）、界面活性剤を配合する方法（特許文献７）、キサンチン類を配合する方法（特許文献８）などが提案されている。 Egualen sodium [Chemical name: Sodium 3-ethyl-7-isopropyl-1-azulenesulfonate 1/3 hydrate] has excellent gastric mucosal protective action by oral administration, and is used as a therapeutic agent for gastric ulcer and the like It is an excellent drug (Patent Document 1). Conventionally, sodium azulenesulfonate having the same mother nucleus structure as eguarene sodium has been used for the treatment of various inflammatory diseases, gastritis and gastric ulcer, etc. However, various methods have been proposed for making a formulation. Regarding a method for stabilizing sodium azulenesulfonate or an azulene derivative during formulation, for example, a method of inclusion with cyclodextrin (Patent Document 2), a method of spray drying or freeze-drying alone or with a polymer compound (Patent Document 3) , A method of hermetically packaging with an oxygen scavenger (Patent Document 4), a method of blending edetic acid and its salts (Patent Document 5), a method of blending a polyhydric alcohol such as propylene glycol (Patent Document 6), a surfactant A method of blending (Patent Document 7), a method of blending xanthines (Patent Document 8), and the like have been proposed.
エグアレンナトリウムは、アズレンスルホン酸ナトリウムと同じアズレン環を母核構造として持ちながら、アズレンスルホン酸ナトリウムに比べ遥かに安定な化合物である。しかしながら、そうであっても、高温、高湿度又は曝光下においては、わずかながらエグアレンナトリウム由来の分解物の生成が認められ、製剤化において、保管時に分解物の生成を抑える手法を施すことが要請されている。
本発明は，エグアレンナトリウムの分解物の生成を抑えた、エグアレンナトリウム固形製剤、すなわち安定なエグアレンナトリウム固形製剤を提供することを目的とする。 An object of the present invention is to provide an eguarene sodium solid preparation, that is, a stable eguarene sodium solid preparation, in which the production of a degradation product of eguarene sodium is suppressed.
本発明者らは、上記目的を達成するため鋭意検討を重ねた結果、意外にも、ポビドン又はその誘導体を配合することによって、エグアレンナトリウム由来の分解物の生成を抑えることができることを見出した。また、塩基性を有する添加物を配合することによりエグアレンナトリウム由来の分解物の生成を抑えることができることを見出した。また、エグアレンナトリウムを含有する製剤を、容器中の空気を不活性ガスで置換した容器に封入すること、すなわち、いわゆる不活性ガス置換包装によって、エグアレンナトリウム由来の分解物の生成を抑えることができることを見出した。本発明は、これらの知見に基づいてなされた発明である。 As a result of intensive studies to achieve the above object, the present inventors have surprisingly found that the formation of a degradation product derived from eguarene sodium can be suppressed by blending povidone or a derivative thereof. . Moreover, it discovered that the production | generation of the degradation product derived from egalene sodium could be suppressed by mix | blending the additive which has basicity. In addition, the preparation containing eguarene sodium is sealed in a container in which the air in the container is replaced with an inert gas, that is, so-called inert gas replacement packaging is used to suppress the formation of degradation products derived from eguarene sodium. I found out that I can. The present invention has been made based on these findings.
すなわち、本発明は、ポビドン及びその誘導体並びに塩基性を有する添加物から選択される一種以上の添加物を配合してなるエグアレンナトリウム固形製剤である。ポビドン誘導体は、クロスポビドンが好ましい。また、塩基性を有する添加物としては、例えば、塩基性無機化合物、塩基性有機化合物が用いられる。そして、塩基性無機化合物としては、炭酸マグネシウム、炭酸カルシウム、水酸化マグネシウム、酸化マグネシウム、炭酸ナトリウム、炭酸水素ナトリウム及び水酸化ナトリウムから選ばれた一種又は二種以上が好ましく用いられる。また、塩基性を有する添加物としては、アルギニン、リジン、ヒスチジン及びオルニチンから選ばれた一種叉は二種以上が好ましく用いられる。また、本発明は、固形製剤を水に１Ｗ／Ｖ％濃度に分散させたときの水分散液のｐＨが６．５以上になるに十分な量の上記の塩基性を有する添加物を配合してなるエグアレンナトリウム固形製剤である。また、本発明は、不活性ガス置換包装されてなるエグアレンナトリウム固形製剤である。 That is, the present invention is an eguarene sodium solid preparation comprising one or more additives selected from povidone and derivatives thereof and basic additives. The povidone derivative is preferably crospovidone. Moreover, as an additive which has basicity, a basic inorganic compound and a basic organic compound are used, for example. And as a basic inorganic compound, the 1 type (s) or 2 or more types chosen from magnesium carbonate, calcium carbonate, magnesium hydroxide, magnesium oxide, sodium carbonate, sodium hydrogencarbonate, and sodium hydroxide are used preferably. In addition, as the additive having basicity, one or more selected from arginine, lysine, histidine and ornithine are preferably used. In addition, the present invention includes a sufficient amount of the above-mentioned basic additive so that the pH of the aqueous dispersion when the solid preparation is dispersed in water at a concentration of 1 W / V% is 6.5 or more. This is a solid preparation of eguarene sodium. Moreover, this invention is an eguarene sodium solid formulation by which inert gas substitution packaging is carried out.
ポビドン及びその誘導体並びに塩基性を有する添加物から選択される一種以上の添加物を配合することにより、エグアレンナトリウム由来の分解物の生成を抑え、安定なエグアレンナトリウム固形製剤を得ることができる。さらに、ポビドン及びその誘導体と塩基性を有する添加物とを併用して配合することにより、エグアレンナトリウム固形製剤の安定性をより向上させることができる。また、エグアレンナトリウム固形製剤を、容器中の空気を不活性ガスで置換した容器に封入することによって、エグアレンナトリウム由来の分解物の生成を抑え、安定なエグアレンナトリウム固形製剤を得ることができる。 By adding one or more additives selected from povidone and its derivatives and basic additives, it is possible to suppress the production of degradation products derived from eguarene sodium and obtain a stable egarenic sodium solid preparation. . Furthermore, the stability of the eguarene sodium solid preparation can be further improved by blending povidone and its derivatives in combination with an additive having basicity. In addition, by sealing the egalene sodium solid preparation in a container in which the air in the container is replaced with an inert gas, it is possible to suppress the production of degradation products derived from eguarene sodium and obtain a stable eguarene sodium solid preparation. it can.
本発明におけるエグアレンナトリウムは、例えば、特許文献１に開示される公知の方法により製造することが出来る。本発明で用いるポビドンは、Ｎ−ビニルー２−ピロリドンの重合体、すなわちポリビニルピロリドンである。また、ポビドン誘導体としては、クロスポビドンが挙げられる。クロスポビドンは、ポリビニルピロリドンの架橋物である。本発明で用いる塩基性を有する添加物としては塩基性無機化合物及び塩基性有機化合物が挙げられる。塩基性無機化合物としては、具体的には炭酸マグネシウム、炭酸カルシウム、水酸化マグネシウム、酸化マグネシウム、炭酸ナトリウム、炭酸水素ナトリウム、水酸化ナトリウムなどが挙げられ、好ましくは炭酸水素ナトリウムが用いられる。また、塩基性有機化合物としては、具体的には塩基性アミノ酸であるアルギニン、リジン、ヒスチジン、オルニチン等の医薬品、食品で汎用されるものが挙げられ、好ましくはアルギニン、リジンが用いられる。これらは、一種叉は２種以上用いることができる。 The eguarene sodium in this invention can be manufactured by the well-known method disclosed by patent document 1, for example. The povidone used in the present invention is a polymer of N-vinyl-2-pyrrolidone, that is, polyvinylpyrrolidone. Moreover, a crospovidone is mentioned as a povidone derivative. Crospovidone is a crosslinked product of polyvinylpyrrolidone. Examples of basic additives used in the present invention include basic inorganic compounds and basic organic compounds. Specific examples of the basic inorganic compound include magnesium carbonate, calcium carbonate, magnesium hydroxide, magnesium oxide, sodium carbonate, sodium bicarbonate, sodium hydroxide and the like, and preferably sodium bicarbonate is used. Specific examples of basic organic compounds include basic amino acids such as arginine, lysine, histidine, ornithine, and those commonly used in foods, and arginine and lysine are preferably used. These can be used alone or in combination of two or more.
ポビドン、その誘導体又は塩基性を有する添加物の配合量は、製剤中のエグアレンナトリウムの含有量に応じて適宜選択する。配合量の一例を挙げるとすれば、製剤中のエグアレンナトリウム１重量部に対し、クロスポビドンは０．１〜３重量部、好ましくは０．２〜０．５重量部、ポビドンは０．１〜３重量部、好ましくは０．２〜０．５重量部、塩基性を有する添加物は０．００５〜１重量部、好ましくは、０．０５〜０．１重量部程度である。塩基性を有する添加物を配合する場合は、製剤した固形製剤を水に１Ｗ／Ｖ％濃度に分散させたときの水分散液のｐＨが６．５以上になるに十分な量の塩基性を有する添加物を配合するのが好ましい。ｐＨが７以上になるに十分な量の塩基性を有する添加物を配合するのがさらに好ましい。また、本発明において、ポビドン又はその誘導体と塩基性を有する添加物とを、併用して配合することにより、エグアレンナトリウム固形製剤の安定性をより向上させることができる。 The amount of povidone, its derivative or basic additive is appropriately selected according to the content of eguarene sodium in the preparation. As an example of the blending amount, crospovidone is 0.1 to 3 parts by weight, preferably 0.2 to 0.5 parts by weight, and povidone is 0.1 parts by weight with respect to 1 part by weight of egualen sodium in the preparation. -3 parts by weight, preferably 0.2-0.5 parts by weight, and the additive having basicity is 0.005 to 1 parts by weight, preferably about 0.05 to 0.1 parts by weight. When adding an additive having basicity, a sufficient amount of basicity is required so that the pH of the aqueous dispersion becomes 6.5 or more when the prepared solid preparation is dispersed in water at a concentration of 1 W / V%. It is preferable to add the additive which has. It is more preferable to add a sufficient amount of an additive having basicity so that the pH becomes 7 or more. Moreover, in this invention, the stability of an eguarene sodium solid formulation can be improved more by mix | blending povidone or its derivative (s), and the additive which has basicity together.
本発明の製剤において、その他の配合成分として、通常の経口投与製剤に用いられる添加剤を使用することができる。医薬品に添加することができる成分であれば特に限定されないが、例えば賦形剤、崩壊剤、結合剤、滑沢剤、界面活性剤、安定化剤、可塑剤、矯味剤、コーティング剤、着色剤等を配合することができる。 In the preparation of the present invention, as other compounding ingredients, additives used in usual oral preparations can be used. Although it will not specifically limit if it is a component which can be added to a pharmaceutical, For example, an excipient | filler, a disintegrating agent, a binder, a lubricant agent, surfactant, a stabilizer, a plasticizer, a corrigent, a coating agent, a coloring agent Etc. can be blended.
賦形剤としては、アルファー化デンプン、部分アルファー化デンプン、二酸化ケイ素、クエン酸カルシウム、ケイ酸アルミン酸マグネシウム、ケイ酸カルシウム、ケイ酸マグネシウム、軽質無水ケイ酸、結晶セルロース、結晶セルロース・カルメロースナトリウム、合成ケイ酸アルミニウム、合成ヒドロタルサイト、コムギデンプン、コメデンプン、ゼラチン、炭酸カルシウム、トウモロコシデンプン、トレハロース、白糖、バレイショデンプン、ブドウ糖、乳糖水和物、D-マンニトール、無水乳糖、無水リン酸水素カルシウム、メタケイ酸アルミン酸マグネシウム、メチルセルロース、リン酸水素カルシウム、リン酸水素ナトリウム等が挙げられる。崩壊剤としては、アルファー化デンプン、カルボキシメチルスターチナトリウム、カルメロース、カルメロースカルシウム、カルメロースナトリウム、カンテン末、クロスカルメロースナトリウム、結晶セルロース、結晶セルロース・カルメロースナトリウム、低置換度ヒドロキシプロピルセルロース、デキストリン、トウモロコシデンプン、部分アルファー化デンプン、メタケイ酸アルミン酸マグネシウム等が挙げられる。 Excipients include pregelatinized starch, partially pregelatinized starch, silicon dioxide, calcium citrate, magnesium aluminate, calcium silicate, magnesium silicate, light anhydrous silicic acid, crystalline cellulose, crystalline cellulose and carmellose sodium , Synthetic aluminum silicate, synthetic hydrotalcite, wheat starch, rice starch, gelatin, calcium carbonate, corn starch, trehalose, sucrose, potato starch, glucose, lactose hydrate, D-mannitol, anhydrous lactose, anhydrous hydrogen phosphate Examples include calcium, magnesium aluminate metasilicate, methyl cellulose, calcium hydrogen phosphate, sodium hydrogen phosphate, and the like. Disintegrants include pregelatinized starch, sodium carboxymethyl starch, carmellose, carmellose calcium, carmellose sodium, agar powder, croscarmellose sodium, crystalline cellulose, crystalline cellulose / carmellose sodium, low-substituted hydroxypropylcellulose, dextrin Corn starch, partially pregelatinized starch, magnesium aluminate metasilicate and the like.
結合剤としては、エチルセルロース、カラメル、カルメロース、グァーガム、コムギデンプン、コメデンプン、ゼラチン、低置換度ヒドロキシプロピルセルロース、トウモロコシデンプン、バレイショデンプン、パラフィン、ヒドロキシエチルセルロース、ヒドロキシエチルメチルセルロース、ヒドロキシプロピルスターチ、ヒドロキシプロピルセルロース、ヒプロメロース、部分アルファー化デンプン、ポリビニルアルコール、マクロゴール、メチルセルロース、ワックス等が挙げられる。滑沢剤としてはカルナウバロウ、グリセリン、ケイ酸マグネシウム、軽質無水ケイ酸、軽質流動パラフィン、ジメチルポリシロキサン、ステアリルアルコール、ステアリン酸、ステアリン酸マグネシウム、ステアリン酸カルシウム、タルク、流動パラフィン等が挙げられる。滑沢剤は、錠剤化する成形材料の流動性を改善するためや、製造される錠剤に、スティッキング、ラミネーション、キャッピング等の打錠障害や、打錠工程における杵や臼のギシツキを防止するために、通常、成形材料中に添加される成分であるが、錠剤の濡れ性の改善のために、錠剤表面に塗布してもよい。 As binders, ethyl cellulose, caramel, carmellose, guar gum, wheat starch, rice starch, gelatin, low substituted hydroxypropyl cellulose, corn starch, potato starch, paraffin, hydroxyethyl cellulose, hydroxyethyl methylcellulose, hydroxypropyl starch, hydroxypropylcellulose , Hypromellose, partially pregelatinized starch, polyvinyl alcohol, macrogol, methylcellulose, wax and the like. Examples of the lubricant include carnauba wax, glycerin, magnesium silicate, light anhydrous silicic acid, light liquid paraffin, dimethylpolysiloxane, stearyl alcohol, stearic acid, magnesium stearate, calcium stearate, talc, and liquid paraffin. Lubricants are used to improve the flowability of molding materials to be tableted, to prevent tableting failures such as sticking, lamination, and capping on the manufactured tablets, and to prevent wrinkles in the tableting process from wrinkles and mortars. In addition, it is a component that is usually added to the molding material, but may be applied to the tablet surface in order to improve the wettability of the tablet.
界面活性剤としては、アルキルアリルポリエーテルアルコール、コレステロール、モノステアリン酸グリセリン、ショ糖脂肪酸エステル、スクワラン、ステアリルアルコール、セタノール、ソルビタン脂肪酸エステル、ソルビタンセスキオレイン酸エステル、ポリオキシエチレン硬化ヒマシ油、ポリオキシエチレンステアリルエーテル、ポリオキシエチレンソルビタンモノラウレート、ポリソルベート、マクロゴール、モノオレイン酸ソルビタン、モノステアリン酸ソルビタン、ラウリル硫酸ナトリウム、ラウロマクロゴール等が挙げられる。安定化剤としては、アスコルビン酸、アルブミン、エデト酸ナトリウム、トコフェロール等が挙げられる。可塑剤としては、アジピン酸ジオクチル、クエン酸トリエチル、グリセリン脂肪酸エステル、グリセリン、ジメチルポリシロキサン、中鎖脂肪酸トリグリセリド、濃グリセリン、ヒマシ油、フタル酸ジオクチル、プロピレングリコール、マクロゴール、流動パラフィン等が挙げられる。 Surfactants include alkyl allyl polyether alcohol, cholesterol, glyceryl monostearate, sucrose fatty acid ester, squalane, stearyl alcohol, cetanol, sorbitan fatty acid ester, sorbitan sesquioleate, polyoxyethylene hydrogenated castor oil, polyoxy Examples include ethylene stearyl ether, polyoxyethylene sorbitan monolaurate, polysorbate, macrogol, sorbitan monooleate, sorbitan monostearate, sodium lauryl sulfate, lauromacrogol and the like. Examples of the stabilizer include ascorbic acid, albumin, sodium edetate, tocopherol and the like. Examples of the plasticizer include dioctyl adipate, triethyl citrate, glycerin fatty acid ester, glycerin, dimethylpolysiloxane, medium chain fatty acid triglyceride, concentrated glycerin, castor oil, dioctyl phthalate, propylene glycol, macrogol, and liquid paraffin. .
矯味剤としては、アスパルテーム、アマチャ末、アミノアルキルメタクリレートコポリマー、エリスリトール、オレンジ、カカオ末、果糖、還元麦芽糖水アメ、カンゾウ末、キシリトール、クエン酸カルシウム、クエン酸水和物、L-グルタミン、L-グルタミン酸、グレープフルーツエキス、サッカリン、シクロデキストリン、酒石酸、ステビア抽出精製物、精製白糖、精製ハチミツ、D-ソルビトール、トレハロース、白糖、ブドウ糖、マルチトール、D-マンニトール、メントール、緑茶末、レモン油等の医薬品、食品で汎用されるものを用いることが出来る。着色剤としては、黄酸化鉄、黄色三二酸化鉄、褐色酸化鉄、カーボンブラック、黒酸化鉄、酸化チタン、食用青色1号、食用黄色4号、食用黄色5号、食用赤色2号、食用赤色3号、食用赤色102号、銅クロロフィル、フェノールレッド、メチルロザニリン、マラカイトグリーン、メチレンブルー等が挙げられる。 As a corrigent, aspartame, amateur powder, aminoalkyl methacrylate copolymer, erythritol, orange, cacao powder, fructose, reduced maltose water candy, licorice powder, xylitol, calcium citrate, citric acid hydrate, L-glutamine, L- Pharmaceuticals such as glutamic acid, grapefruit extract, saccharin, cyclodextrin, tartaric acid, stevia extract, purified sucrose, purified honey, D-sorbitol, trehalose, sucrose, glucose, maltitol, D-mannitol, menthol, green tea powder, lemon oil Any of those commonly used in foods can be used. Coloring agents include yellow iron oxide, yellow ferric oxide, brown iron oxide, carbon black, black iron oxide, titanium oxide, edible blue No. 1, edible yellow No. 4, edible yellow No. 5, edible red No. 2, edible red No. 3, Edible Red No. 102, copper chlorophyll, phenol red, methyl rosaniline, malachite green, methylene blue and the like.
本発明の製剤の剤型としては、散剤、顆粒剤（コーティング顆粒等を含む）、細粒剤、錠剤（素錠、コーティング錠、糖衣錠、チュアブル錠、口腔内崩壊錠など）、丸剤、トローチ剤等として知られている種々の固形剤型を採用することができる。 The dosage form of the preparation of the present invention includes powders, granules (including coated granules, etc.), fine granules, tablets (plain tablets, coated tablets, dragees, chewable tablets, orally disintegrating tablets, etc.), pills, troches Various solid dosage forms known as agents and the like can be employed.
散剤、顆粒剤、細粒剤、錠剤、カプセル剤については、例えば第１５改正日本薬局方の製剤総則に記載された粉砕、分級、混合、練合、造粒、乾燥、整粒、打錠等の方法など、この技術分野における常法により製造することが出来る。すなわち、錠剤の場合には、賦形剤、結合剤、崩壊剤、矯味剤などに、クロスポビドン、ポビドン又は塩基性を有する添加物を加え混合し、エグアレンナトリウムの溶液を加えて顆粒とし、これに滑沢剤等を加えて打錠して錠剤とするか、あるいは、単にエグアレンナトリウムとクロスポビドン、ポビドン又は塩基性添加物及びその他の添加物を混合し、打錠するといった乾式法等によっても製することができる。造粒方法としては、特に制限は無いが、例えば流動層造粒、攪拌造粒、高速攪拌造粒、押出し造粒等の湿式造粒、乾式造粒が挙げられる。錠剤の製造方法は特に制限は無く、例えばロータリー式打錠機を用いて行うことができる。打錠機としては杵及び臼に滑沢剤を塗布する装置を備えたものを用いることも出来る。 For powders, granules, fine granules, tablets, capsules, for example, pulverization, classification, mixing, kneading, granulation, drying, granulating, tableting, etc., described in the 15th revised Japanese Pharmacopoeia It can be produced by a conventional method in this technical field such as That is, in the case of tablets, crospovidone, povidone or basic additives are added to and mixed with excipients, binders, disintegrants, flavoring agents, etc., and a solution of eguarene sodium is added to form granules, Add a lubricant, etc. to this to make tablets into tablets, or simply mix egalen sodium with crospovidone, povidone or basic additives and other additives, and tablet, etc. Can also be manufactured. The granulation method is not particularly limited, and examples thereof include wet granulation such as fluidized bed granulation, stirring granulation, high speed stirring granulation, extrusion granulation, and dry granulation. There is no restriction | limiting in particular in the manufacturing method of a tablet, For example, it can carry out using a rotary type tableting machine. As the tableting machine, a machine equipped with a device for applying a lubricant to the punch and die can be used.
錠剤、顆粒剤については、公知の方法でコーティングを施しても良い。コーティング剤としては、アミノアルキルメタクリレートコポリマー、エチルセルロース、オパドライ、カルナウバロウ、カルボキシビニルポリマー、カルメロースカルシウム、クエン酸トリエチル、グリセリン、グリセリン脂肪酸エステル、酸化チタン、ジメチルポリシロキサン、白糖、ゼラチン、タルク、パラフィン、ヒプロメロース、ヒプロメロースフタル酸エステル、フタル酸ジブチル、プロピレングリコール、ポリオキシエチレン硬化ヒマシ油、ポリソルベート、マクロゴール、ポリビニルアセタールジエチルアミノアセテート、メタクリル酸コポリマー、メチルセルロース、ラウロマクロゴール等が挙げられる。さらに、錠剤の場合には、種々の崩壊剤等を配合することにより、口腔内崩壊錠、チュアブル錠などとすることもできる。 Tablets and granules may be coated by a known method. Coating agents include aminoalkyl methacrylate copolymer, ethylcellulose, opadry, carnauba wax, carboxyvinyl polymer, carmellose calcium, triethyl citrate, glycerin, glycerin fatty acid ester, titanium oxide, dimethylpolysiloxane, sucrose, gelatin, talc, paraffin, hypromellose , Hypromellose phthalate, dibutyl phthalate, propylene glycol, polyoxyethylene hydrogenated castor oil, polysorbate, macrogol, polyvinyl acetal diethylaminoacetate, methacrylic acid copolymer, methylcellulose, lauromacrogol and the like. Furthermore, in the case of a tablet, an orally disintegrating tablet, a chewable tablet and the like can be prepared by blending various disintegrants and the like.
エグアレンナトリウム固形製剤は、不活性ガス雰囲気下において、エグアレンナトリウム由来の分解物の生成が抑えられる。本発明は、不活性ガス置換包装されてなるエグアレンナトリウム固形製剤にかかわる。エグアレンナトリウム固形製剤の不活性ガス置換包装は、エグアレンナトリウム固形製剤を、外気と遮断が可能な容器中に収納し、該容器内の空気を不活性ガスで置換することにより行える。容器としては、アルミラミネート分包容器、瓶、缶、ＰＴＰ、カプセルなどの一般の医薬品に用いられる容器が使用できる。また、不活性ガスとしては、窒素、ヘリウム、アルゴンなどが用いられる。不活性ガスの充填は通常使用される一般的な装置を使用することができる。ここで、不活性ガス置換包装とは、不活性ガスが大部分の雰囲気であって、酸素濃度が１０％以下、好ましくは３％以下に減少している雰囲気の容器内に、エグアレンナトリウム固形製剤が封入された包装形態をいう。 The production of egualene sodium solid preparation suppresses the production of degradation products derived from eguarene sodium in an inert gas atmosphere. The present invention relates to a solid preparation of eguarene sodium which is packaged with an inert gas. The inert gas replacement packaging of the eguarene sodium solid preparation can be performed by storing the eguarene sodium solid preparation in a container that can be shut off from the outside air and replacing the air in the container with an inert gas. As a container, the container used for common pharmaceuticals, such as an aluminum laminate packaging container, a bottle, a can, PTP, a capsule, can be used. As the inert gas, nitrogen, helium, argon or the like is used. For filling with the inert gas, a commonly used general apparatus can be used. Here, the inert gas replacement packaging refers to a solid solution of eguarene sodium in an atmosphere where the inert gas is mostly in an atmosphere and the oxygen concentration is reduced to 10% or less, preferably 3% or less. A packaging form in which a preparation is enclosed.
本発明のエグアレンナトリウム固形製剤は、優れた胃粘膜損傷形成抑制作用、潰瘍治癒促進作用などを示し、胃潰瘍の治療に用いることができる。本発明のエグアレンナトリウム固形製剤を胃潰瘍などの治療に用いる場合には、上記のように種々の剤型にして、経口投与することができる。その投与量は、エグアレンナトリウムとして、約１５〜６０ｍｇ／日、好ましくは、３０ｍｇ／日である。
以下、本発明について実施例及び比較例により更に詳細に説明するが、本発明の範囲はこれら実施例及び比較例に何ら限定されるものではない。
The eguarene sodium solid preparation of the present invention exhibits excellent gastric mucosal damage formation inhibiting action, ulcer healing promoting action, etc., and can be used for the treatment of gastric ulcer. When the eguarene sodium solid preparation of the present invention is used for treatment of gastric ulcer and the like, it can be orally administered in various dosage forms as described above. The dosage is about 15 to 60 mg / day, preferably 30 mg / day, as egualen sodium.
EXAMPLES Hereinafter, although an Example and a comparative example demonstrate this invention further in detail, the scope of the present invention is not limited to these Examples and comparative examples.
エグアレンナトリウムを５０％エタノールに加え、攪拌して溶解し、エグアレンナトリウム溶液（０．３３ｇ/ｍＬ）を調製した。トウモロコシデンプン（１３３重量部）、ヒドロキシプロピルセルロース（２重量部）、クロスポビドン（１０重量部）を混合し、上記エグアレンナトリウム溶液（エグアレンナトリウムとして１５重量部を含有する）を加え、造粒した。得られた顆粒を乾燥、整粒した後、打錠機で圧縮成型して錠剤とした。 Egualen sodium was added to 50% ethanol and dissolved by stirring to prepare an egualen sodium solution (0.33 g / mL). Corn starch (133 parts by weight), hydroxypropylcellulose (2 parts by weight), crospovidone (10 parts by weight) are mixed, and the above eguarene sodium solution (containing 15 parts by weight as eguarene sodium) is added, and granulated. did. The obtained granules were dried and sized, and then compressed into tablets using a tableting machine.
トウモロコシデンプン（１３３重量部）、ヒドロキシプロピルセルロース（２重量部）、ポビドン（１０重量部）を混合し、実施例1で調製したエグアレンナトリウム溶液（エグアレンナトリウムとして１５重量部を含有する）を加え、造粒した。得られた顆粒を乾燥、整粒した後、打錠機で圧縮成型して錠剤とした。 Corn starch (133 parts by weight), hydroxypropyl cellulose (2 parts by weight), povidone (10 parts by weight) were mixed, and the eguarene sodium solution prepared in Example 1 (containing 15 parts by weight as egalen sodium) was used. In addition, granulated. The obtained granules were dried and sized, and then compressed into tablets using a tableting machine.
トウモロコシデンプン（１４３重量部）、ヒドロキシプロピルセルロース（２重量部）、結晶セルロース（１０重量部）、クロスポビドン（５重量部）、ポビドン（５重量部）を混合し、実施例1で調製したエグアレンナトリウム溶液（エグアレンナトリウムとして１５重量部を含有する）を加え、造粒した。得られた顆粒を乾燥、整粒した後、打錠機で圧縮成型して錠剤とした。 Corn starch (143 parts by weight), hydroxypropylcellulose (2 parts by weight), crystalline cellulose (10 parts by weight), crospovidone (5 parts by weight), povidone (5 parts by weight) were mixed and the egg prepared in Example 1 was mixed. Allen sodium solution (containing 15 parts by weight as egalen sodium) was added and granulated. The obtained granules were dried and sized, and then compressed into tablets using a tableting machine.
トウモロコシデンプン（１３２重量部）、ヒドロキシプロピルセルロース（２重量部）、炭酸水素ナトリウム（１重量部）を混合し、実施例1で調製したエグアレンナトリウム溶液（エグアレンナトリウムとして１５重量部を含有する）を加え、造粒した。得られた顆粒を乾燥、整粒した後、打錠機で圧縮成型して錠剤とした。 Corn starch (132 parts by weight), hydroxypropylcellulose (2 parts by weight), sodium hydrogen carbonate (1 part by weight) are mixed, and the eguarene sodium solution prepared in Example 1 (containing 15 parts by weight as egalen sodium) ) And granulated. The obtained granules were dried and sized, and then compressed into tablets using a tableting machine.
トウモロコシデンプン（１３２重量部）、ヒドロキシプロピルセルロース（２重量部）、炭酸水素ナトリウム（５重量部）を混合し、実施例1で調製したエグアレンナトリウム溶液（エグアレンナトリウムとして１５重量部を含有する）を加え、造粒した。得られた顆粒を乾燥、整粒した後、打錠機で圧縮成型して錠剤とした。 Corn starch (132 parts by weight), hydroxypropylcellulose (2 parts by weight), sodium hydrogen carbonate (5 parts by weight) are mixed, and the eguarene sodium solution prepared in Example 1 (containing 15 parts by weight as egalen sodium) ) And granulated. The obtained granules were dried and sized, and then compressed into tablets using a tableting machine.
トウモロコシデンプン（１４０重量部）、ヒドロキシプロピルセルロース（２重量部）、結晶セルロース（１０重量部）、クロスポビドン（５重量部）、ポビドン（５重量部）及び炭酸水素ナトリウム（１重量部）を混合し、実施例1で調製したエグアレンナトリウム溶液を加え、造粒した。得られた顆粒を乾燥、整粒した後、打錠機で圧縮成型して錠剤とした。 Corn starch (140 parts by weight), hydroxypropylcellulose (2 parts by weight), crystalline cellulose (10 parts by weight), crospovidone (5 parts by weight), povidone (5 parts by weight) and sodium bicarbonate (1 part by weight) are mixed Then, the eguarene sodium solution prepared in Example 1 was added and granulated. The obtained granules were dried and sized, and then compressed into tablets using a tableting machine.
トウモロコシデンプン（１４０重量部）、ヒドロキシプロピルセルロース（２重量部）、結晶セルロース（１０重量部）及びリジン（１重量部）を混合し、実施例1で調製したエグアレンナトリウム溶液（エグアレンナトリウムとして１５重量部を含有する）を加え、造粒した。得られた顆粒を乾燥、整粒した後、打錠機で圧縮成型して錠剤とした。 Corn starch (140 parts by weight), hydroxypropylcellulose (2 parts by weight), crystalline cellulose (10 parts by weight) and lysine (1 part by weight) were mixed, and the eguarene sodium solution prepared in Example 1 (as egalen sodium) Containing 15 parts by weight) and granulated. The obtained granules were dried and sized, and then compressed into tablets using a tableting machine.
トウモロコシデンプン（１４０重量部）、ヒドロキシプロピルセルロース（２重量部）、結晶セルロース（１０重量部）及びアルギニン（１重量部）を混合し、実施例1で調製したエグアレンナトリウム溶液（エグアレンナトリウムとして１５重量部を含有する）を加え、造粒した。得られた顆粒を乾燥、整粒した後、打錠機で圧縮成型して錠剤とした。 Corn starch (140 parts by weight), hydroxypropyl cellulose (2 parts by weight), crystalline cellulose (10 parts by weight) and arginine (1 part by weight) were mixed, and the egualen sodium solution prepared as Example 1 (as egualen sodium) Containing 15 parts by weight) and granulated. The obtained granules were dried and sized, and then compressed into tablets using a tableting machine.
〔比較例１〕
トウモロコシデンプン（１３３重量部）、ヒドロキシプロピルセルロース（２重量部）、結晶セルロース（１０重量部）を混合し、実施例1で調製したエグアレンナトリウム溶液（エグアレンナトリウムとして１５重量部を含有する）を加え、造粒した。得られた顆粒を乾燥、整粒した後、打錠機で圧縮成型して錠剤とした。
[Comparative Example 1]
Corn starch (133 parts by weight), hydroxypropyl cellulose (2 parts by weight), crystalline cellulose (10 parts by weight) are mixed and the eguarene sodium solution prepared in Example 1 (containing 15 parts by weight as egalen sodium) And granulated. The obtained granules were dried and sized, and then compressed into tablets using a tableting machine.
実験例１
実施例及び比較例で得られた錠剤につき、その安定性を試験した。この試験は、実施例及び比較例で得られた錠剤を、以下の条件１〜３の保存条件にて５日間保存した。エグアレンナトリウムの分解によって種々の類縁物質が生成するが、５日間保存後に、エグアレンナトリウムの分解によって生成する類縁物質類の合計含量（総類縁物質の含量：質量％）を、高速液体クロマトグラフィーにて測定した。その測定結果を表１に示す。また、打錠用粉末１錠分を秤取し、水を加えて１Ｗ／Ｖ％の水分散液を調製し、そのｐＨを測定した。その結果も表１に示す。
Experimental example 1
The stability of the tablets obtained in Examples and Comparative Examples was tested. In this test, the tablets obtained in Examples and Comparative Examples were stored for 5 days under the following storage conditions 1 to 3. Degradation of egualen sodium produces various related substances. After storage for 5 days, the total content of related substances produced by the degradation of eguarene sodium (total related substance content: mass%) was analyzed by high performance liquid chromatography. Measured at The measurement results are shown in Table 1. Further, 1 tablet powder for tableting was weighed, water was added to prepare a 1 W / V% aqueous dispersion, and the pH was measured. The results are also shown in Table 1.
［保存条件］
条件１
保存条件：室温、暗所
包装形態：ガラス瓶密栓
条件２
保存条件：５０℃、暗所
包装形態：ガラス瓶密栓
条件３
保存条件：５０℃、７５％ＲＨ、暗所
包装形態：ガラス瓶開放
[Storage conditions]
Condition 1
Storage conditions: Room temperature, dark packaging: Glass bottle cap
Condition 2
Storage conditions: 50 ° C, dark packaging: Glass bottle cap
Condition 3
Storage conditions: 50 ° C., 75% RH, dark packaging: Glass bottle open
クロスポビドン、ポビドンを配合した実施例１〜３の製剤においては、比較例の製剤に比べ、いずれの条件においても、エグアレンナトリウムの分解によって生じる総類縁物質量が少なく、クロスポビドン、ポビドンの配合により、製剤中のエグアレンナトリウム由来の分解物の生成量が減少したことが分かる。また、塩基性を有する添加物である炭酸水素ナトリウムを配合した実施例４、５の製剤においても、いずれの条件においても、比較例に比べ、エグアレンナトリウムの分解によって生じる総類縁物質量が少なく、製剤中のエグアレンナトリウム由来の分解物の生成量が減少したことが分かる。さらに、クロスポビドン、ポビドン及び炭酸水素ナトリウムを配合した実施例６の製剤においては、各々を単独で配合した実施例１〜５の製剤に比較して、エグアレンナトリウムの分解によって生じる総類縁物質量が少なく、製剤中のエグアレンナトリウム由来の分解物の生成量が減少したことが分かる。また、塩基性を有する添加物であるリジン又はアルギニンを添加した実施例７，８は、いずれも、いずれの条件においても、比較例に比べ、エグアレンナトリウムの分解によって生じる総類縁物質量が少なく、製剤中のエグアレンナトリウム由来の分解物の生成量が減少したことが分かる。 In the preparations of Examples 1 to 3 containing crospovidone and povidone, compared to the preparation of the comparative example, the amount of total related substances generated by the decomposition of eguarene sodium is small in any condition, and the combination of crospovidone and povidone Thus, it can be seen that the production amount of the degradation product derived from eguarene sodium in the preparation decreased. In addition, in the preparations of Examples 4 and 5 in which sodium hydrogen carbonate, which is a basic additive, was blended, the amount of total related substances generated by the decomposition of eguarene sodium was smaller in all conditions than in the comparative example. It can be seen that the production amount of the degradation product derived from eguarene sodium in the preparation decreased. Furthermore, in the preparation of Example 6 containing crospovidone, povidone and sodium bicarbonate, the amount of total related substances produced by the decomposition of eguarene sodium as compared with the preparations of Examples 1 to 5 containing each of them alone It can be seen that the amount of degradation product derived from eguarene sodium in the preparation decreased. In addition, in Examples 7 and 8 to which lysine or arginine, which is a basic additive, was added, the amount of total related substances generated by the decomposition of eguarene sodium was smaller than that of the comparative example under any conditions. It can be seen that the production amount of the degradation product derived from eguarene sodium in the preparation decreased.
比較例１で得られたエグアレンナトリウム錠剤を、ガラス瓶に入れ、窒素ガスで置換した状態でキャップをし、密栓状態で保管した。
密栓状態での保管において、実験例１の条件１及び条件２の保存条件下で、実験１と同様にして、エグアレンナトリウムの分解によって生成する類縁物質類の合計含量（総類縁物質の含量：質量％）を測定して、その安定性を試験した。その結果、条件１（室温、暗所）では、総類縁物質の含量は０．１５質量％であり、条件２（５０℃、暗所）では、総類縁物質の含量は０．１６質量％であった。なお、不活性ガス置換しない場合（比較例１）については、条件１（室温、暗所）では総類縁物質の含量は０．３０質量％であり、条件２（５０℃、暗所）では、総類縁物質の含量は０．４３質量％であった。窒素置換した場合は、窒素置換しない場合に比べ、総類縁物質量の生成量が少なく、製剤中のエグアレンナトリウム由来の分解物の生成量が減少したことが分かる。
The eguarene sodium tablet obtained in Comparative Example 1 was put in a glass bottle, capped with nitrogen gas, and stored in a sealed state.
In storage in a sealed state, the total content of related substances (total related substance content: produced by decomposition of eguarene sodium) in the same manner as in Experiment 1 under the storage conditions of Conditions 1 and 2 of Experimental Example 1. Mass%) and measured its stability. As a result, in condition 1 (room temperature, dark place), the content of total related substances is 0.15% by mass, and in condition 2 (50 ° C., dark place), the content of total related substances is 0.16% by mass. there were. In the case where the inert gas is not replaced (Comparative Example 1), the content of the total related substances is 0.30% by mass in Condition 1 (room temperature, dark place), and in Condition 2 (50 ° C., dark place), The content of all related substances was 0.43% by mass. It can be seen that when nitrogen substitution was performed, the amount of total related substances produced was smaller than when nitrogen substitution was not carried out, and the production amount of degradation products derived from eguarene sodium in the preparation was reduced.
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| CN2009102260483A CN101732290B (en) | 2008-11-12 | 2009-11-12 | Stable solid formulation of egualen sodium |
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| JP6133702B2 (en) * | 2013-06-18 | 2017-05-24 | 紀州技研工業株式会社 | Ink jet ink, method for producing the same, and method for using the same |
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