JPS5916820A - Solid pharmaceutical containing amorphous malotilate - Google Patents
Solid pharmaceutical containing amorphous malotilateInfo
- Publication number
- JPS5916820A JPS5916820A JP12481782A JP12481782A JPS5916820A JP S5916820 A JPS5916820 A JP S5916820A JP 12481782 A JP12481782 A JP 12481782A JP 12481782 A JP12481782 A JP 12481782A JP S5916820 A JPS5916820 A JP S5916820A
- Authority
- JP
- Japan
- Prior art keywords
- malotylate
- porous material
- malotilate
- organic solvent
- stirring
- 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.)
- Pending
Links
- 239000007787 solid Substances 0.000 title claims abstract description 4
- YPIQVCUJEKAZCP-UHFFFAOYSA-N Malotilate Chemical compound CC(C)OC(=O)C(C(=O)OC(C)C)=C1SC=CS1 YPIQVCUJEKAZCP-UHFFFAOYSA-N 0.000 title abstract description 8
- 229950000470 malotilate Drugs 0.000 title abstract 6
- 239000000203 mixture Substances 0.000 claims abstract description 24
- 239000013078 crystal Substances 0.000 claims abstract description 21
- 239000011148 porous material Substances 0.000 claims abstract description 15
- 239000003960 organic solvent Substances 0.000 claims abstract description 14
- 238000003756 stirring Methods 0.000 claims abstract description 14
- 238000010438 heat treatment Methods 0.000 claims abstract description 6
- -1 magnesium metasilicate aluminate Chemical class 0.000 claims abstract description 6
- 238000009736 wetting Methods 0.000 claims abstract description 5
- 238000002156 mixing Methods 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 7
- YKTSYUJCYHOUJP-UHFFFAOYSA-N [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] Chemical compound [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] YKTSYUJCYHOUJP-UHFFFAOYSA-N 0.000 claims description 3
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 claims description 2
- ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 2,3-dimethylbutane Chemical group CC(C)C(C)C ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 0.000 claims 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 claims 1
- GDVKFRBCXAPAQJ-UHFFFAOYSA-A dialuminum;hexamagnesium;carbonate;hexadecahydroxide Chemical compound [OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Al+3].[Al+3].[O-]C([O-])=O GDVKFRBCXAPAQJ-UHFFFAOYSA-A 0.000 claims 1
- 229960001545 hydrotalcite Drugs 0.000 claims 1
- 229910001701 hydrotalcite Inorganic materials 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 239000000843 powder Substances 0.000 abstract description 8
- 238000004090 dissolution Methods 0.000 abstract description 5
- 210000001035 gastrointestinal tract Anatomy 0.000 abstract description 3
- 230000001154 acute effect Effects 0.000 abstract description 2
- 230000001684 chronic effect Effects 0.000 abstract description 2
- 208000019423 liver disease Diseases 0.000 abstract description 2
- 238000010298 pulverizing process Methods 0.000 abstract description 2
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 abstract description 2
- 235000012239 silicon dioxide Nutrition 0.000 abstract description 2
- 230000001747 exhibiting effect Effects 0.000 abstract 1
- 230000000246 remedial effect Effects 0.000 abstract 1
- 238000000034 method Methods 0.000 description 9
- 239000003814 drug Substances 0.000 description 8
- 150000001875 compounds Chemical class 0.000 description 7
- 229940079593 drug Drugs 0.000 description 6
- 239000008187 granular material Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 239000007902 hard capsule Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 241000282472 Canis lupus familiaris Species 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 150000004645 aluminates Chemical class 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000005469 granulation Methods 0.000 description 2
- 230000003179 granulation Effects 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 239000004570 mortar (masonry) Substances 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 230000036470 plasma concentration Effects 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 230000007704 transition Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- JYUXDXWXTPSAEL-UHFFFAOYSA-N 1,4-dioxane;oxolane Chemical compound C1CCOC1.C1COCCO1 JYUXDXWXTPSAEL-UHFFFAOYSA-N 0.000 description 1
- YLZOPXRUQYQQID-UHFFFAOYSA-N 3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-1-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]propan-1-one Chemical compound N1N=NC=2CN(CCC=21)CCC(=O)N1CCN(CC1)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F YLZOPXRUQYQQID-UHFFFAOYSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 241000286819 Malo Species 0.000 description 1
- 240000009253 Morus australis Species 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 238000002083 X-ray spectrum Methods 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- WMGSQTMJHBYJMQ-UHFFFAOYSA-N aluminum;magnesium;silicate Chemical compound [Mg+2].[Al+3].[O-][Si]([O-])([O-])[O-] WMGSQTMJHBYJMQ-UHFFFAOYSA-N 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- DALDUXIBIKGWTK-UHFFFAOYSA-N benzene;toluene Chemical compound C1=CC=CC=C1.CC1=CC=CC=C1 DALDUXIBIKGWTK-UHFFFAOYSA-N 0.000 description 1
- JGVDBODXXHHCJH-UHFFFAOYSA-N butyl acetate;ethyl acetate Chemical compound CCOC(C)=O.CCCCOC(C)=O JGVDBODXXHHCJH-UHFFFAOYSA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 239000000571 coke Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- POLCUAVZOMRGSN-UHFFFAOYSA-N dipropyl ether Chemical compound CCCOCCC POLCUAVZOMRGSN-UHFFFAOYSA-N 0.000 description 1
- 238000007922 dissolution test Methods 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- ZYBWTEQKHIADDQ-UHFFFAOYSA-N ethanol;methanol Chemical compound OC.CCO ZYBWTEQKHIADDQ-UHFFFAOYSA-N 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 238000001125 extrusion Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 238000011899 heat drying method Methods 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 229910001234 light alloy Inorganic materials 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 238000003801 milling Methods 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 102000054765 polymorphisms of proteins Human genes 0.000 description 1
- 238000000634 powder X-ray diffraction Methods 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
本発明はマロチラート（一般名：ジイソプロピル１．３
−ジチオール−２−イリデンマロネート）を含する固形
製剤′ｆ＠組成物に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention provides malotylate (common name: diisopropyl 1.3
- dithiol-2-ylidenemalonate).
マロチラートは、次式］：
（）
の構造式で示される化合物であり、急性、慢性の肝障害
に対し慶れた治療効果を有し−さらＣご長期間使用して
も何ら毒性を示さない隈れた医薬品として期待され、開
発中のものである。Malotylate is a compound represented by the following structural formula: (), and has excellent therapeutic effects on acute and chronic liver disorders. It is expected to be a rare drug and is currently under development.
このマロチラートは、互変性の結晶多形を有し、低温安
定形（Ａ形結晶：融点５０〜５３℃）および高温安定形
（Ｂ形結晶：融点６０〜６３℃）をもち、通常は人形結
晶さして存在する化合物である。このような結晶多形を
有する物質は、品質管理上の問題を生ずるおそれがある
。This malochilate has a tautomeric crystal polymorphism, and has a low-temperature stable form (type A crystal: melting point 50-53°C) and a high-temperature stable form (type B crystal: melting point 60-63°C), and is usually a doll crystal. It is a very common compound. Substances having such crystal polymorphisms may cause quality control problems.
さらに、マロチラー１−は水に溶は番こくい難溶性医薬
品であり、難溶性薬物の生体内における吸収速度は、そ
れらを含有する製剤からの該薬物の溶出速度に律速され
るといわれているように、−・歩ヒトの吸収性向上のた
めには簡単な操作で溶出性の優れた製剤を作ることが望
１れている。Furthermore, Marothiller 1- is a poorly soluble drug that is poorly soluble in water, and it is said that the rate of absorption of poorly soluble drugs in the body is determined by the rate of dissolution of the drug from the formulation containing them. As such, in order to improve absorption in humans, it is desired to produce preparations with excellent dissolution properties through simple operations.
従来、医薬重さして使用されるある神の結晶性化合物が
、特定の手段を用いるお無晶化するこ吉は知られている
。It is known that certain crystalline compounds, which have been traditionally used in medicine, can be made amorphous using specific means.
例えば、特開昭５／、−１３３２１７号公報においては
、特定の医薬用化合物にカルシビン）をホールミル粉砕
することによる無晶化方法が、又、特開昭５６−４９３
１４号公報においては、固型薬物に特定の添加剤（例え
は、ヒトロキノプロビルメチルセルロースーボリビニル
ヒロリドン、クエン酸等）を添加し、有板溶媒に溶解後
膣溶媒を除去することにより無晶化する方法が開示され
ているが、医薬品として使用される結晶性化合物がそれ
自体或はいかなる条件で無晶化するかは、その物質のも
つ特有の性質に起因し、上記無晶化方法があ壕ね〈全て
の物質に適用できるとも限らない。For example, in Japanese Patent Application Laid-Open No. 56-493, a method for amorphizing calcibin by whole-milling a specific pharmaceutical compound is disclosed.
In Publication No. 14, by adding specific additives (for example, human quinoprobyl methylcellulose-borivinylhyloridone, citric acid, etc.) to a solid drug, dissolving it in a plated solvent, and removing the vaginal solvent. Although a method for amorphousization has been disclosed, whether a crystalline compound used as a pharmaceutical becomes amorphous by itself or under what conditions is due to the unique properties of the substance, The method is complicated (it may not be applicable to all substances).
なお、無晶形は結晶学的に不安定なことが多く、経時的
により安定な結晶状態へ転移し７易いといわれている。Note that amorphous forms are often crystallographically unstable and are said to be likely to transition to a more stable crystalline state over time.
そこで本発明渚は、前記マロチラートの欠点を改善すべ
く、通常の結晶形マロチラートの無晶化によるより安定
な製剤検討さ、それらの溶出性および消化管からの吸収
性を鋭意検討した結果、意外にもマロチラートを通常の
医薬品添加物として利用し得る多孔質物質と、室温ない
し加温下に混合攪拌するか一有機溶媒に溶解させたマロ
チラート溶液で多孔質物質を充分に湿潤させた後溶媒を
除去するか、あらかじめマロチラートを溶解する有機溶
媒で多孔質物質を湿潤した後マロチラートを添加し、混
合攪拌して有機溶媒を除去すれば無晶形に変化し、かく
して得られた無晶形マロチラートは極めて安定性に優れ
、より速い溶出性および消化管からの優れた吸収性を呈
することを見出し、本発明を完成した、
本発明において使用される担体としては、比表面１責が
大きなものがよく特に約２５Ｏｎ？、’Ｆｌ 以上のも
のが好せしい。これ等の例としては、メタ）７−イ酸ア
ルミン酸マグ不ノウム、軽貿漁［水ゲイ酸−合成硅酸ア
ルミニウム、酸化マグ洋／τツノ・、合ｈｙヒドロタル
サイト、酸化アルミニウム等が挙げられる。Therefore, in order to improve the above-mentioned drawbacks of malotylate, the present inventor, Nagisa, has investigated a more stable formulation by making the usual crystalline form of malotylate amorphous, and after intensively studying their dissolution properties and absorbability from the gastrointestinal tract, we have unexpectedly discovered that Malotylate can also be used as an ordinary pharmaceutical additive by mixing and stirring at room temperature or under heating with a porous material, or by thoroughly moistening the porous material with a solution of malotylate dissolved in an organic solvent, and then removing the solvent. If the organic solvent is removed, or the porous material is wetted with an organic solvent that dissolves malothyrate in advance, malotylate is added, mixed and stirred, and the organic solvent is removed, it changes to an amorphous form, and the amorphous malotylate thus obtained is extremely stable. The present invention has been completed based on the discovery that the carrier has excellent properties, faster dissolution properties, and excellent absorbability from the gastrointestinal tract.The carrier used in the present invention preferably has a large specific surface area, especially about 25 On? , 'Fl or higher is preferable. Examples of these include magunium meta)7-ioic acid aluminate, light trading [water silicate-synthetic aluminum silicate, magnanium oxide/τtsuno., synthetic hyhydrotalcite, aluminum oxide, etc.] Can be mentioned.
これ等担体の使用量は〜マロチラートの結晶１重量部当
り約半量ないし２倍旧あればよく、従来法における担体
の使用量に比べはるかに少損ですみ、その他の添加剤及
び剤型の小型化等を考慮すると、本願発明は、工業的製
剤技術上非常に優れたものである。The amount of these carriers used is approximately half to twice as much per 1 part by weight of malotylate crystals, which results in much less loss than the amount of carriers used in conventional methods, and allows for other additives and smaller dosage forms. Considering the above, the present invention is extremely superior in terms of industrial formulation technology.
マロチラート結晶と製剤学的に許容しうる担体とを混合
攪拌するに際しては、先つマロ千う−ド結晶ヲホールミ
ル、フィソノミル、／エツトミル等医薬品の粉砕機とし
て通常使用される粉砕機で粉砕後、無晶化用担体をこｆ
ｌこ添加し混合攪拌するがよい。両者の混合には、Ｖ型
混合機や、リボン型混合機、ナウターミキ→）−一、ス
ーパーミキサー等の通常の医薬用混合機が使用できるが
、前述の粉砕機で同時Ｃ（行うことも可能である。マロ
チラートと無晶化和体との混合攪拌時の加温は、特に限
定されないが、特に４５〜ら５℃で行うのが効率的であ
るｎ また本発明の組成物は、マロチラートを有機溶
媒に溶解し、この溶液で多孔質物質を完全に湿部させた
後、溶媒を除去するか、また、あらかじめマロチラート
を溶解する有機溶媒で多孔′ｈ物質を湿潤した後マロチ
ラートを添加し、よく攪拌後有機溶媒を除去して得られ
る。When mixing and stirring malotylate crystals and a pharmaceutically acceptable carrier, first grind the malotylate crystals with a grinder commonly used as a grinder for pharmaceuticals, such as Whole Mill, Physonomyl, and Ethomil. Remove the crystallization carrier.
It is best to add 1 liter and mix and stir. For mixing the two, a normal pharmaceutical mixer such as a V-type mixer, a ribbon-type mixer, Nauta Miki →)-1, or a super mixer can be used, but it is also possible to use the above-mentioned pulverizer to mix the two at the same time. Heating during mixing and stirring of malochilate and the amorphous compound is not particularly limited, but it is particularly efficient to heat it at a temperature of 45 to 5°C. After dissolving in an organic solvent and completely wetting the porous material with this solution, the solvent is removed, or malotylate is added after wetting the porous material with an organic solvent in which malotylate is previously dissolved; It is obtained by stirring well and removing the organic solvent.
使用し得る有機溶媒としては、マロチラートを溶解する
溶媒であればよく〜ジクロルメタン、クロロホルム、四
塩化炭素等の・・ロゲン化化合物、メタノール−エタノ
ール、プロノくノール等の脂訪族アルコール、ｎ−ヘキ
サン、ノクロｌ＼キサン、ペンタン、ヘプタン等の低級
炭化水素、エチルエーテル、プロピルエーテル、テトラ
ヒドロフラン−ジオキサン等のエーテル類、アセトン、
メチルエチルケトン等のケトン類、酢酸エチル−酢酸ブ
チル等のエステル類さらには、ベンゼン−トルエン、キ
シレン等の芳香族炭化水素などがあけられる。使用量は
、特に限定されないが、打着しくは、多孔質物質１重量
部に対して５〜５０容重匍部である。Organic solvents that can be used include any solvent that dissolves malothyrate, such as dichloromethane, chloroform, carbon tetrachloride, etc., rogogenated compounds, methanol-ethanol, aliphatic alcohols such as pronocentol, n-hexane, etc. , lower hydrocarbons such as xane, pentane, and heptane, ethers such as ethyl ether, propyl ether, and tetrahydrofuran-dioxane, acetone,
Examples include ketones such as methyl ethyl ketone, esters such as ethyl acetate-butyl acetate, and aromatic hydrocarbons such as benzene-toluene and xylene. The amount used is not particularly limited, but it is preferably 5 to 50 parts by weight per 1 part by weight of the porous material.
有機溶媒の除去に際しては、室温、好着しくは結晶転移
点以上の温度で常圧捷たは減圧下でおこなう。具体的に
は、通常の加熱乾燥法、ノブレードライ法さらには凍結
乾燥法等がもちいられる。The organic solvent is removed at room temperature, preferably at a temperature above the crystal transition point, under normal pressure or reduced pressure. Specifically, a conventional heat drying method, a blade drying method, a freeze drying method, etc. can be used.
本発明における無晶状とは、Ｘ腓回仇スペクトルにおい
て結晶形マロチラート特有の結晶ピークを示さない状態
をいう。即ち、低温安定形結晶では、２θ＝ １０．２
ｃ、 ２０．５ｃおよび２６９ｅに、また、高温安定形
結晶では、２θ＝ ７．６°。In the present invention, the term "amorphous" refers to a state in which a crystal peak peculiar to crystalline malotylate is not shown in the X-ray spectrum. That is, in a low temperature stable crystal, 2θ = 10.2
c, 20.5c and 269e, and 2θ = 7.6° for the high temperature stable crystal.
１８．８°および２２７゛にそれぞれ特徴的な結晶ピー
クを有しているが一本発明の組成物のＸ線回折スペクト
ルでは、前記結晶ピークはいずれも認められない。Although it has characteristic crystalline peaks at 18.8° and 227°, none of the above crystalline peaks are observed in the X-ray diffraction spectrum of the composition of the present invention.
本発明の方法で得られた無晶形マロ千ら一ト組成物は−
その１−＋経口剤として用いるこさもできるが、他の適
当な添加剤を加えるこ吉に上り適当な剤型、例えば、細
粒剤、顆粒剤、錠剤、坐剤智とすることもできる。The amorphous Malo 1,000 composition obtained by the method of the present invention is -
Although it can be used as an oral preparation, it can also be made into a suitable dosage form by adding other suitable additives, such as fine granules, granules, tablets, and suppositories.
実施例１
マロチラートの結晶１ｇを乳鉢で粉砕した後、メタケイ
酸アルミン酸マグネシウム（比表ｉＩＪ＋ 積２５０
ｒｒ？／９ ’） １５ 、ｆＪ を加え均一に混合
する。混合物を約５０℃で約３０分間加温攪拌した後、
室温で放冷し無晶形マロチラートを得る。この物は粉末
Ｘ−線回１７？スペクトルで測定した結果、前記マロチ
ラートの結晶に特上のピークが全く消失していた。Example 1 After pulverizing 1 g of crystals of malochilate in a mortar, magnesium aluminate metasilicate (specific table iIJ+ product 250
rr? /9') 15 and fJ are added and mixed uniformly. After heating and stirring the mixture at about 50°C for about 30 minutes,
Allow to cool at room temperature to obtain amorphous malotylate. Is this thing powder X-ray cycle 17? As a result of spectral measurement, it was found that the particular peak in the malotylate crystals had completely disappeared.
かくして得られた無晶形マロチラート組成物を５℃、５
０℃及び４０℃７５％相対温度で１ケ・日本薬局方溶出
試験法第２法（・τドル法）試験液；日本桑局方第−液
９００１１１’パドル回転数；１００回転／分
実施例３
マロチラートの結晶（Ａ形）１０ｇとメタケイ酸アルミ
ン酸マグネノウム（比表面積３００ｒｒ？／９）１５９
とを均一に混合し、次いて５０℃で３０分間加温攪拌し
た後室温で放冷し無み一形マロチラードを得る。（粉末
Ｘ純回折スペクトルでＲ認）
−Ｆ述製法で製した無晶形マロチラート（メタケイ酸ア
ルミン酸マク坏ノウム吉の混合物）０．２５ＩＩ（マロ
チラートとしてｏｌｙ）を０号の硬カプセルに充填しカ
プセル剤とする。The thus obtained amorphous malotylate composition was heated at 5°C for 50 minutes.
1 at 0°C and 40°C 75% relative temperature Japanese Pharmacopoeia Dissolution Test Method 2 (τ dollar method) Test solution: Japanese Mulberry Pharmacopoeia No. 900111' Paddle rotation speed: 100 revolutions/min Example 3 10 g of malotylate crystals (type A) and magnenoum metasilicate aluminate (specific surface area 300rr?/9) 159
The mixture was then mixed uniformly with the mixture, heated and stirred at 50° C. for 30 minutes, and then allowed to cool at room temperature to obtain one-form malotirade. (Recognized as R based on powder X pure diffraction spectrum) - Fill amorphous malotylate (mixture of aluminometasilic acid makkonnoumikichi) 0.25II (oly as malotylate) into a No. 0 hard capsule and capsule as a drug.
上記カフセル剤を被験体（雄性ピークル犬、６匹、体ｇ
ｉ’ １０．５〜１３．０ｋｆ’）に２１１６１タＩ九
投局し、マロチラートの主代謝物であるイン７０ビルノ
・イドロゲン１．６−シチオールー２−イリテンマロ不
一ト（以下Ｍ−１と略称ず）の血漿中濃度を測定した。The above cuff cell preparation was administered to subjects (male Peakle dogs, 6 dogs, body g).
i' 10.5 to 13.0kf'), the main metabolite of malotylate, in-70virnohydrogen 1,6-sithio-2-yritemalohydrogen (hereinafter abbreviated as M-1), was released. The plasma concentration of 1) was measured.
対照としてマロチラートの結晶性粉末（Ａ形）ｏ２ｙを
充填し７１こカフセル−稈ｊをイソ２用しＭ、−１の血
漿中濃度を測定した。その結果は表−３に示す辿り本発
明の無晶３Ｙ、マロイーラードは潰れた吸収効果を呈し
た・
表−３Ａ発明物資の吸収効果
）？−ＡＵ（’；血漿中＃度曲線下面積※※Ｎ１−１の
定附；尚速液体クロマ１〜クラ７法実施例４
マロチラートの結晶粉末（Ｂ形）５ｏｇと４１質無水ケ
イ酸（比表面積３８０ｄｌｌ ）４８ ｇ とを混合し
、約５０℃で約２時間混合攪拌する０次いで室温で放冷
し無晶形マロチラートをイ灯る。（粉床Ｘ脚註ＪＪｉス
ペクトルで１１伍認）流動層造粒ａ（フローコーク−ミ
ニ）を７４−ＩＩい、上記操作で得た無晶形マロチラー
ト（混合物）８０９４こ、ヒドロキノプロピルセルロー
ス（１１ＰＬ−Ｃ； ８ 本曹達■製）の工／ｌノール
Ｎ 液（２９→１００ ｍ ） ８２ ｒｔｌ を噴
霧し流動造粒１−、、引き続き流動乾燥する。乾燥後３
２メツツユのふるいで１８ ：ｉｔ！Ａ Ｉ、て細粒剤
を得たＣ実施例
マロチラート１に９をエタノール５／に浴解し７、この
溶液ｌこメタケイ酸アールミン酸−７り坏ノウム（比表
面積３８０ ｒｒ？／Ｅ／ ） １ ｋｖを力１１え
撹拌練合した。練合物ノを８０℃でスフレ−ドライ を
おこない本発明の組ＩＪｙ物を得た。As a control, the plasma concentration of M, -1 was measured using 71 capsule-culm j filled with malotylate crystalline powder (form A) o2y. The results are shown in Table 3. The amorphous 3Y of the present invention and Malloy lard exhibited a collapsed absorption effect (Table 3A Absorption effect of the invented material)? -AU('; Area under the #degree curve in plasma ※※ Determination of N1-1; Fast Liquid Chroma 1-Cl 7 Method Example 4 5 og of crystalline powder of malochilate (Type B) and Mix 48 g of surface area (380 dll) and mix and stir at about 50°C for about 2 hours.Then, let it cool at room temperature and light up the amorphous malochilate.(Powder bed Granules A (Flow Coke Mini) were mixed with 74-II, amorphous malotylate (mixture) 8094 obtained by the above procedure, and hydroquinopropyl cellulose (11PL-C; manufactured by Honsoda ■)/lNol N solution. (29→100 m) 82 rtl was sprayed and fluidized granulation 1-, followed by fluidized drying. After drying 3
2 Metsutsuyu no Sieve 18: it! Example C malotylates 1 and 9 were dissolved in ethanol 5/7 to obtain fine granules. 1 kv was stirred and kneaded with a force of 11. The kneaded material was soufflé-dried at 80°C to obtain a composition of the present invention.
前記組成物６００ｇ、アビセルＰ）４１ｏ１１ｏ。600 g of said composition, Avicel P) 41o11o.
〃、白糖１８０．９、カルボ”キシメチルセルロース力
ルノウム１００７を混合しこれをヒドロギ／グロヒルメ
チルセルロース２０ ｇ（ｈ ５９ｂ−γルコール溶液
と練合し、押出し造粒後を用いて造粒後、乾かｉして顆
粒酌とした。〃, white sugar 180.9, carboxymethylcellulose 1007% were mixed, and this was kneaded with 20 g of hydrogy/glohil methylcellulose (h 59b-γ alcohol solution, granulated using extrusion granulation, and then dried. It was made into granules.
実施例６
軽質合１ｊ又ケイ酸アルミニウム（比表世＋ ｌ１５０
（１ｒｒ？／ｇ） １ ｋｑをクロロホルム５１で湿
潤した後−マロチラート１ ｋｙを加えて攪拌練合しま
た。練合物を８０℃で送風乾燥して本発明の絹ｌｊｙ物
を得たｅ
前記組成物２００ｇ、カルボキノメチル（ニルロース１
ｏ９を混合後ヒドロキノプロビルセルロース２９の１０
％アルコール熔液下線合造粒した０
乾燥後ステアリン酸マグ不ノウム４ｇ、軽質無水硅ｒＷ
５＆を混合し硬カプセルに充填し硬カプセル剤としたｅ
参考例１
マロチラートの結晶２９を乳鉢で粉砕した後、メタ）７
−イ酸アルεン酸マグネ／ウム（比表面積１１０ｉ／ｇ
）４．［］５＋を加え均一番こ混合する０混合物を約５
０℃で約１時間加温攪拌した後、室温で放冷する。Example 6 Light alloy 1j or aluminum silicate (specification + l150
(1rr?/g) 1 kq was moistened with 51 chloroform, then 1 ky of malotylate was added and kneaded with stirring. The kneaded product was air-dried at 80° C. to obtain the silk product of the present invention. 200 g of the above composition, carboquinomethyl (nilulose 1
After mixing o9, hydroquinoprobyl cellulose 29 part 10
% alcohol solution underlined and granulated 0 After drying, magnonium stearate 4g, light anhydrous silica rW
5 & was mixed and filled into hard capsules to make a hard capsule.Reference Example 1 After crushing malochilate crystals 29 in a mortar, meta) 7
- Magnesium/aluminum ester (specific surface area 110i/g
)4. []Add 5+ and mix evenly until the 0 mixture is about 5
After heating and stirring at 0° C. for about 1 hour, the mixture is allowed to cool at room temperature.
上記処理物を粉末Ｘ線回折スペクトルで測定した結果、
マロチラート結晶のヒータが確認された。As a result of measuring the above treated product using powder X-ray diffraction spectrum,
A malochilate crystal heater was confirmed.
参考例２
マロチラートの結晶２ｇと軽質無水ケイ酸（比表面積２
００Ｒ／ｇ）を使用し、参考例１と同様の操作を行なっ
たが無晶形マロチラートは得られなかった（粉末Ｘｉ回
折ヌペクトルで確認）。Reference example 2 2 g of crystals of malochilate and light anhydrous silicic acid (specific surface area 2
00R/g) and the same operation as in Reference Example 1 was performed, but amorphous malotylate was not obtained (confirmed by powder Xi diffraction nupector).
参考例ろ
マロチラートの結晶２ｇとメタ／１イ酸了ルミン酸マグ
坏ゾウム（比表面積２［〕ｏｎｒ、Ｑ）２１を用い実施
例５と同様の操作を行なったが、無晶形マロチラートは
得られなかった（粉末Ｘ線回Ｖ［スペクトルで確認）。Reference Example The same operation as in Example 5 was carried out using 2 g of malotylate crystals and 21 meta/1-isoic acid magzoum (specific surface area 2[]onr, Q), but amorphous malotylate was not obtained. (Confirmed by powder X-ray cycle V [spectrum]).
（１才か１名）(1 year old or 1 person)
Claims (3)
イリデンマロネート （以下、マロチラートいう。）を
多孔質物質と室温ないし加温下に混合攪拌するか、結晶
形マロチラートを有機溶媒に溶解し、該溶液で多孔質物
質を充分に湿潤させた後、溶媒を除去するか、あらかじ
めマロチラートを溶解する有機溶媒で多孔質物質を湿潤
した後、マロチラートを添加し、混合攪拌後、溶媒を除
去して得られる無晶形マロチラートを含有する固形製剤
組成物。(1) Crystal form diisopropyl 1. Ro-dithiol-2-
After mixing and stirring ylidene malonate (hereinafter referred to as malotylate) with a porous material at room temperature or under heating, or dissolving crystalline malotylate in an organic solvent and sufficiently moistening the porous material with the solution. A solid pharmaceutical composition containing amorphous malotylate obtained by removing the solvent or wetting a porous material with an organic solvent in which malotylate is dissolved in advance, adding malotylate, mixing and stirring, and then removing the solvent.
合成硅酸アルミニウム、メタ硅酸アルミン酸マグネシウ
ム、合成ヒドロタルサイト及び酸化アルミニウムよりな
る群から選ばれた１または２以上からなる特許１ｉＷｉ
猛囲第１項記載の組成物。(2) Does the porous material have a specific surface area of 250 n? /F! Patent 1iWi consisting of one or more selected from the group consisting of the above synthetic aluminum silicate, magnesium metasilicate aluminate, synthetic hydrotalcite, and aluminum oxide.
The composition according to item 1.
１：０．５〜２．０である特許謂罫駆囲第１項記載の組
成物。(3) The composition according to paragraph 1 of the patent, wherein the mixing ratio of crystalline malotylate and porous material is 1:0.5 to 2.0.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP12481782A JPS5916820A (en) | 1982-07-17 | 1982-07-17 | Solid pharmaceutical containing amorphous malotilate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP12481782A JPS5916820A (en) | 1982-07-17 | 1982-07-17 | Solid pharmaceutical containing amorphous malotilate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPS5916820A true JPS5916820A (en) | 1984-01-28 |
Family
ID=14894842
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP12481782A Pending JPS5916820A (en) | 1982-07-17 | 1982-07-17 | Solid pharmaceutical containing amorphous malotilate |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS5916820A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU644978B2 (en) * | 1992-01-17 | 1993-12-23 | Nihon Nohyaku Co., Ltd. | Topical composition for accelerating wound healing |
-
1982
- 1982-07-17 JP JP12481782A patent/JPS5916820A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU644978B2 (en) * | 1992-01-17 | 1993-12-23 | Nihon Nohyaku Co., Ltd. | Topical composition for accelerating wound healing |
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