JPH0249720A - Slightly soluble drug composition - Google Patents
Slightly soluble drug compositionInfo
- Publication number
- JPH0249720A JPH0249720A JP12275989A JP12275989A JPH0249720A JP H0249720 A JPH0249720 A JP H0249720A JP 12275989 A JP12275989 A JP 12275989A JP 12275989 A JP12275989 A JP 12275989A JP H0249720 A JPH0249720 A JP H0249720A
- Authority
- JP
- Japan
- Prior art keywords
- soluble drug
- composition according
- poorly soluble
- solvent
- carrier
- 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
- 239000003814 drug Substances 0.000 title claims abstract description 43
- 229940079593 drug Drugs 0.000 title claims abstract description 42
- 239000000203 mixture Substances 0.000 title claims abstract description 35
- 239000002904 solvent Substances 0.000 claims abstract description 13
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000003960 organic solvent Substances 0.000 claims abstract description 8
- 239000000725 suspension Substances 0.000 claims abstract description 8
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims abstract description 6
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims abstract description 6
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims abstract description 6
- IIUZTXTZRGLYTI-UHFFFAOYSA-N Dihydrogriseofulvin Natural products COC1CC(=O)CC(C)C11C(=O)C(C(OC)=CC(OC)=C2Cl)=C2O1 IIUZTXTZRGLYTI-UHFFFAOYSA-N 0.000 claims abstract description 5
- UXWOXTQWVMFRSE-UHFFFAOYSA-N Griseoviridin Natural products O=C1OC(C)CC=C(C(NCC=CC=CC(O)CC(O)C2)=O)SCC1NC(=O)C1=COC2=N1 UXWOXTQWVMFRSE-UHFFFAOYSA-N 0.000 claims abstract description 5
- DDUHZTYCFQRHIY-UHFFFAOYSA-N Negwer: 6874 Natural products COC1=CC(=O)CC(C)C11C(=O)C(C(OC)=CC(OC)=C2Cl)=C2O1 DDUHZTYCFQRHIY-UHFFFAOYSA-N 0.000 claims abstract description 5
- CXOFVDLJLONNDW-UHFFFAOYSA-N Phenytoin Chemical compound N1C(=O)NC(=O)C1(C=1C=CC=CC=1)C1=CC=CC=C1 CXOFVDLJLONNDW-UHFFFAOYSA-N 0.000 claims abstract description 5
- DDUHZTYCFQRHIY-RBHXEPJQSA-N griseofulvin Chemical compound COC1=CC(=O)C[C@@H](C)[C@@]11C(=O)C(C(OC)=CC(OC)=C2Cl)=C2O1 DDUHZTYCFQRHIY-RBHXEPJQSA-N 0.000 claims abstract description 5
- 229960002867 griseofulvin Drugs 0.000 claims abstract description 5
- 229960000905 indomethacin Drugs 0.000 claims abstract description 5
- 229960002036 phenytoin Drugs 0.000 claims abstract description 5
- IRGJVQIJENCTQF-UHFFFAOYSA-N tritoqualine Chemical compound CN1CCC2=CC=3OCOC=3C(OC)=C2C1C1C2=C(OCC)C(OCC)=C(OCC)C(N)=C2C(=O)O1 IRGJVQIJENCTQF-UHFFFAOYSA-N 0.000 claims description 14
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 6
- 150000001875 compounds Chemical class 0.000 claims description 6
- 235000012239 silicon dioxide Nutrition 0.000 claims description 6
- 239000007921 spray Substances 0.000 claims description 6
- 229920002134 Carboxymethyl cellulose Polymers 0.000 claims description 4
- 235000010948 carboxy methyl cellulose Nutrition 0.000 claims description 4
- 239000008112 carboxymethyl-cellulose Substances 0.000 claims description 4
- 239000010419 fine particle Substances 0.000 claims description 4
- 229920001477 hydrophilic polymer Polymers 0.000 claims description 4
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 3
- 239000001913 cellulose Substances 0.000 claims description 3
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 claims description 3
- 239000000377 silicon dioxide Substances 0.000 claims description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 2
- 229920000881 Modified starch Polymers 0.000 claims description 2
- 239000002202 Polyethylene glycol Substances 0.000 claims description 2
- 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 claims description 2
- WMGSQTMJHBYJMQ-UHFFFAOYSA-N aluminum;magnesium;silicate Chemical compound [Mg+2].[Al+3].[O-][Si]([O-])([O-])[O-] WMGSQTMJHBYJMQ-UHFFFAOYSA-N 0.000 claims description 2
- 239000011575 calcium Substances 0.000 claims description 2
- 229910052791 calcium Inorganic materials 0.000 claims description 2
- 229920002678 cellulose Polymers 0.000 claims description 2
- 229920001223 polyethylene glycol Polymers 0.000 claims description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 2
- 230000003179 granulation Effects 0.000 claims 1
- 238000005469 granulation Methods 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 abstract description 18
- 238000004090 dissolution Methods 0.000 abstract description 13
- 238000000034 method Methods 0.000 abstract description 10
- 238000004519 manufacturing process Methods 0.000 abstract description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 abstract description 6
- 230000000694 effects Effects 0.000 abstract description 5
- 238000012360 testing method Methods 0.000 description 11
- 238000009472 formulation Methods 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 6
- 238000007922 dissolution test Methods 0.000 description 5
- 230000002459 sustained effect Effects 0.000 description 5
- 241000282472 Canis lupus familiaris Species 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 238000010828 elution Methods 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 229910002016 Aerosil® 200 Inorganic materials 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- 239000008194 pharmaceutical composition Substances 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- WDJUZGPOPHTGOT-OAXVISGBSA-N Digitoxin Natural products O([C@H]1[C@@H](C)O[C@@H](O[C@@H]2C[C@@H]3[C@@](C)([C@@H]4[C@H]([C@]5(O)[C@@](C)([C@H](C6=CC(=O)OC6)CC5)CC4)CC3)CC2)C[C@H]1O)[C@H]1O[C@@H](C)[C@H](O[C@H]2O[C@@H](C)[C@@H](O)[C@@H](O)C2)[C@@H](O)C1 WDJUZGPOPHTGOT-OAXVISGBSA-N 0.000 description 2
- LTMHDMANZUZIPE-AMTYYWEZSA-N Digoxin Natural products O([C@H]1[C@H](C)O[C@H](O[C@@H]2C[C@@H]3[C@@](C)([C@@H]4[C@H]([C@]5(O)[C@](C)([C@H](O)C4)[C@H](C4=CC(=O)OC4)CC5)CC3)CC2)C[C@@H]1O)[C@H]1O[C@H](C)[C@@H](O[C@H]2O[C@@H](C)[C@H](O)[C@@H](O)C2)[C@@H](O)C1 LTMHDMANZUZIPE-AMTYYWEZSA-N 0.000 description 2
- 238000005280 amorphization Methods 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 229960000648 digitoxin Drugs 0.000 description 2
- WDJUZGPOPHTGOT-XUDUSOBPSA-N digitoxin Chemical compound C1[C@H](O)[C@H](O)[C@@H](C)O[C@H]1O[C@@H]1[C@@H](C)O[C@@H](O[C@@H]2[C@H](O[C@@H](O[C@@H]3C[C@@H]4[C@]([C@@H]5[C@H]([C@]6(CC[C@@H]([C@@]6(C)CC5)C=5COC(=O)C=5)O)CC4)(C)CC3)C[C@@H]2O)C)C[C@@H]1O WDJUZGPOPHTGOT-XUDUSOBPSA-N 0.000 description 2
- 229960005156 digoxin Drugs 0.000 description 2
- LTMHDMANZUZIPE-PUGKRICDSA-N digoxin Chemical compound C1[C@H](O)[C@H](O)[C@@H](C)O[C@H]1O[C@@H]1[C@@H](C)O[C@@H](O[C@@H]2[C@H](O[C@@H](O[C@@H]3C[C@@H]4[C@]([C@@H]5[C@H]([C@]6(CC[C@@H]([C@@]6(C)[C@H](O)C5)C=5COC(=O)C=5)O)CC4)(C)CC3)C[C@@H]2O)C)C[C@@H]1O LTMHDMANZUZIPE-PUGKRICDSA-N 0.000 description 2
- LTMHDMANZUZIPE-UHFFFAOYSA-N digoxine Natural products C1C(O)C(O)C(C)OC1OC1C(C)OC(OC2C(OC(OC3CC4C(C5C(C6(CCC(C6(C)C(O)C5)C=5COC(=O)C=5)O)CC4)(C)CC3)CC2O)C)CC1O LTMHDMANZUZIPE-UHFFFAOYSA-N 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 229910002012 Aerosil® Inorganic materials 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 239000000043 antiallergic agent Substances 0.000 description 1
- 238000010241 blood sampling Methods 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 229920006184 cellulose methylcellulose Polymers 0.000 description 1
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 239000004210 ether based solvent Substances 0.000 description 1
- 239000005453 ketone based solvent Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- -1 polyvinylpyrrolidone Chemical class 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 239000008279 sol Substances 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 210000001364 upper extremity Anatomy 0.000 description 1
- 210000003462 vein Anatomy 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】
（産業上の利用分野）
本発明は、水に対する溶解度の小さい難溶性薬剤の医薬
組成物に関する。更に詳しくは、難溶性薬剤の溶解性（
溶解速度と溶出量）を高めた難溶性薬剤含有医薬組成物
に関する。DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) The present invention relates to a pharmaceutical composition of a poorly soluble drug having low solubility in water. More specifically, the solubility of poorly soluble drugs (
The present invention relates to a pharmaceutical composition containing a poorly soluble drug with increased dissolution rate and elution amount.
（従来の技術および発明が解決しようとする問題点）
インドメタシン、グリセオフルビン、フェニトイン、ト
リトクアリン、ジゴキシン、ジギトキシン等の生理活性
を有する薬剤は、いずれも水に対する溶解度が小さく、
固形製剤とした場合、その溶出性が悪く、バイオアベイ
ラビリティ−が低いという欠点がある。(Prior art and problems to be solved by the invention) All physiologically active drugs such as indomethacin, griseofulvin, phenytoin, tritoqualin, digoxin, and digitoxin have low solubility in water.
When made into a solid preparation, it has the drawbacks of poor dissolution and low bioavailability.
例えば、下記構造式（１）で示されるトリトクアリンは
抗アレルギー剤として、また最近では肝疾患の治療薬と
して有効であることが見出された薬剤である。For example, tritoqualin shown by the following structural formula (1) is a drug that has been found to be effective as an antiallergic agent and recently as a therapeutic agent for liver diseases.
従来、このトリトクアリンと担体とを有機溶媒に溶解さ
せた溶液または懸濁させた懸濁液から溶媒を除去するこ
とにより、溶出性の改善と持続的な過飽和現象がみられ
る薬剤組成物が得られることが知られているが、常温も
しくは加熱した状態で、必要に応じ真空下で該溶媒を徐
々に除去しているため、８〜１０時間もの時間を要し、
効率上の問題があった。Conventionally, by removing the solvent from a solution or suspension in which tritoqualin and a carrier are dissolved in an organic solvent, a pharmaceutical composition that exhibits improved dissolution properties and a sustained supersaturation phenomenon can be obtained. However, since the solvent is gradually removed at room temperature or in a heated state under vacuum if necessary, it takes 8 to 10 hours.
There were efficiency issues.
また、別の方法として、有機溶媒を使用せずに、トリト
クアリンと担体とを混合粉砕する方法もあるが、この方
法では十分な溶出性を確保するためにトリトクアリンの
数倍量の担体を必要とし、担体分のコスト高となるのみ
ならず、固形製剤とする際に、大スケールの機器を必要
とする、バッチ数が増える、時間がかかる等の製造効率
の問題があった。Another method is to mix and grind tritoqualin and carrier without using an organic solvent, but this method requires several times the amount of carrier than tritoqualin to ensure sufficient dissolution. This not only increases the cost of the carrier, but also poses problems in manufacturing efficiency, such as requiring large-scale equipment, increasing the number of batches, and taking time when preparing solid preparations.
（問題点を解決するための手段）
本発明者らはかかる問題点を解決することを目的とし、
検討を重ねた結果、トリトクアリンを始めとする難溶性
薬剤の溶出性が著しく改善されて、持続的な過飽和現象
を持つ難溶性薬剤組成物を効率よく短時間に製造できる
ことを見出し、本発明を完成するに至った。(Means for solving the problem) The present inventors aimed to solve the problem,
As a result of repeated studies, it was discovered that the dissolution of poorly soluble drugs such as tritoqualin was significantly improved, and a poorly soluble drug composition with a sustained supersaturation phenomenon could be efficiently produced in a short time, and the present invention was completed. I ended up doing it.
本発明は、難溶性の薬剤と担体とを有機溶媒に溶解させ
た溶液または懸濁させた懸濁液から急激に溶媒を除去す
ることにより得られる難溶性薬剤組成物である。The present invention is a poorly soluble drug composition obtained by rapidly removing the solvent from a solution or suspension in which a poorly soluble drug and a carrier are dissolved in an organic solvent.
以下本発明につき、詳細に説明する。The present invention will be explained in detail below.
本発明における難溶性の薬剤とは、インドメタシン、グ
リセオフルビン、フェニトイン、トリトクアリン、ジゴ
キシン、ジギトキシン等の局方医薬品各条の性状の項に
おいて溶解性が「はとんど溶けない」とされている薬剤
であればいずれのものでもよく、特に水に対する溶解度
が１００μｇ／ｒｎ１以下の薬剤を用いると、溶解性（
溶解速度と溶解量）の改善効果が顕著に現われる。In the present invention, poorly soluble drugs are drugs whose solubility is "hardly soluble" in the description section of the pharmacopoeial drug monograph, such as indomethacin, griseofulvin, phenytoin, tritoqualin, digoxin, and digitoxin. Any drug may be used as long as it has a water solubility of 100 μg/rn1 or less.
The effect of improving the dissolution rate and amount of dissolution is noticeable.
本発明において使用される担体としては、ポリビニルピ
ロリドン、結晶セルロース、架橋カルボキシメチルセル
ロースナトリウム、ポリエチレングリコール、カルボキ
シメチルセルロースナトリウム、カルボキシメチルセル
ロースカルシウム、カルボキシメチルセルロース、部分
アルファ化デンプン等の親水性高分子化合物および・／
または軽質無水ケイ酸、含水二酸化ケイ素、メタケイ酸
アルミン酸マグネシウム等の親水性の無機微粒子が好ま
しく、特に、親水性高分子化合物としてはポリビニルピ
ロリドン、結晶セルロース、架橋カルボキシメチルセル
ロースが、親水性の無機微粒子としては軽質無水ケイ酸
、含水二酸化ケイ素がとりわけ好ましい。The carriers used in the present invention include hydrophilic polymer compounds such as polyvinylpyrrolidone, crystalline cellulose, crosslinked sodium carboxymethylcellulose, polyethylene glycol, sodium carboxymethylcellulose, calcium carboxymethylcellulose, carboxymethylcellulose, partially pregelatinized starch, etc.
Alternatively, hydrophilic inorganic fine particles such as light anhydrous silicic acid, hydrated silicon dioxide, and magnesium aluminate metasilicate are preferable. In particular, as hydrophilic polymer compounds, polyvinylpyrrolidone, crystalline cellulose, and crosslinked carboxymethyl cellulose are preferable. Particularly preferred are light anhydrous silicic acid and hydrated silicon dioxide.
なおこれらの担体は、単独で用いても、２種以上を組み
合わせて使用してもよい。Note that these carriers may be used alone or in combination of two or more.
本発明における担体の量は、難溶性の薬剤１重量部に対
し、０．１〜３重遺部が好ましく、特に０．１〜１重川
部用好ましい。The amount of carrier in the present invention is preferably 0.1 to 3 parts by weight, particularly preferably 0.1 to 1 part by weight, per 1 part by weight of the poorly soluble drug.
また、本発明で用いられる有機溶媒は、アルコール系、
ケトン系、エーテル系等の溶媒中で難溶性薬剤を溶解す
るものであればいずれのものでもよく、必要に応じて担
体をも溶解する溶媒が望ましく、特に塩化メチレン、メ
タノール、エタノール、イソプロピルアルコール、アセ
トン、酢酸エチル、クロロホルムが好ましい。In addition, the organic solvent used in the present invention includes alcohol-based,
Any solvent may be used as long as it dissolves the poorly soluble drug in a ketone-based or ether-based solvent, and if necessary, a solvent that also dissolves the carrier is preferable, particularly methylene chloride, methanol, ethanol, isopropyl alcohol, Acetone, ethyl acetate and chloroform are preferred.
本発明の難溶性薬剤組成物を得るに際し、急激に有機溶
媒を除去する際には、スプレードライヤーまたは流動層
乾燥機を用いるのが好ましく、特にスプレードライヤー
により適当な送気温度で溶液または懸濁液を噴霧乾燥す
ることが望ましい。When rapidly removing the organic solvent in order to obtain the poorly soluble drug composition of the present invention, it is preferable to use a spray dryer or a fluidized bed dryer. It is desirable to spray dry the liquid.
本発明においては、このように急激に溶媒を除去するこ
とにより、難溶性薬剤の非晶化が促進される。すなわち
、従来の技術では非晶化度が２０〜３０％であったのに
対し、本発明により、担体を選択すれば、非晶化度が５
０％以上に向」ニする。これにより、難溶性薬剤の溶出
性が更に著しく改善され、高濃度での持続的過飽和現象
がもたらされる。In the present invention, by rapidly removing the solvent in this manner, amorphization of the poorly soluble drug is promoted. In other words, the degree of amorphism was 20 to 30% in the conventional technology, but with the present invention, if the carrier is selected, the degree of amorphism can be reduced to 5%.
Towards 0% or higher. This further significantly improves the dissolution of the poorly soluble drug, resulting in a sustained supersaturation phenomenon at high concentrations.
なお、本発明でいう「持続的な過飽和現象」とは、第１
図に示すように該製剤の溶出試験で過飽和状態が５０分
程度持続することをいう。In addition, the "sustained supersaturation phenomenon" as used in the present invention refers to the first
As shown in the figure, this means that the supersaturated state lasts about 50 minutes in the dissolution test of the preparation.
（発明の効果）
本発明の方法により製造された難溶性薬剤組成物は、そ
の製造工程において、担体を難溶性薬剤と同等量または
同等量程度使用し、急激に溶媒を除去することにより、
製造効率向上と製造コストダウンを図ることえ出来、ま
た、従来の方法力」二に、著しい溶出改善効果及び持続
的過飽和現象をもたらすことができる。(Effects of the Invention) The poorly soluble drug composition produced by the method of the present invention can be produced by using the same amount or about the same amount of the carrier as the poorly soluble drug and rapidly removing the solvent in the manufacturing process.
It is possible to improve production efficiency and reduce production costs, and it can also bring about a remarkable elution improvement effect and a sustained supersaturation phenomenon compared to conventional methods.
（実施例）
次にこの発明の実施例及び試験例を示して、この発明を
更に具体的に説明する。(Examples) Next, the present invention will be explained in more detail by showing examples and test examples of the present invention.
実施例１
塩化メチレン１５００ｇにトリトクアリン（三菱化成社
製） ５０ｇを溶解させ、更にポリビニルピロリドンに
−３０５０ｇを溶解させた。同溶液をスプレードライヤ
ーに口・アトマイザ−社製、モービルマイナー型）にて
ディスク型アトマイザ−の回転数２４００Ｏｒｐｍ０、
排気温度３０℃、試料供給量４０ｇ／分で噴霧乾燥し、
難溶性薬剤組成物（製剤１）を得た。Example 1 50 g of tritoqualin (manufactured by Mitsubishi Kasei Corporation) was dissolved in 1500 g of methylene chloride, and -3050 g was further dissolved in polyvinylpyrrolidone. Apply the same solution to a spray dryer using an atomizer (manufactured by Mobil Minor) using a disk type atomizer at a rotation speed of 2400 rpm.
Spray drying was carried out at an exhaust temperature of 30°C and a sample supply rate of 40 g/min.
A poorly soluble drug composition (Formulation 1) was obtained.
実施例２
塩化メチレン１５００ｇにトリトクアリン５０ｇを溶解
させ、更にアエロジル２００（日本アエロジル社製）５
０ｇを懸濁させた。同懸濁液を実施例１と同じスプレー
ドライヤーにて噴霧乾燥し、組成物（調剤２）を得た。Example 2 50 g of tritoqualin was dissolved in 1500 g of methylene chloride, and further 50 g of Aerosil 200 (manufactured by Nippon Aerosil Co., Ltd.) was dissolved.
0g was suspended. The suspension was spray-dried using the same spray dryer as in Example 1 to obtain a composition (Preparation 2).
実施例３
塩化メチレン２１００ｇ、 トリトクアリン７０ｇ、
アビセルＲＣ−５９１ＮＦ （旭化成社製）３０ｇ、ポ
リビニルピロリドンに一３０５ｇを使用し、前記実施例
２に準じて組成物（調剤３）を得た。Example 3 2100 g of methylene chloride, 70 g of tritoqualin,
A composition (preparation 3) was obtained according to Example 2 using 30 g of Avicel RC-591NF (manufactured by Asahi Kasei Corporation) and 305 g of polyvinylpyrrolidone.
実施例４
塩化メチレン２０００ｇ、メタノール１５００ ｇの混
合溶媒にそれぞれインドメタシン、グリセオフルビン、
フェニトイン３０ｇを溶解させた。更にそれぞれの溶液
にアエロジル２００ ３０ｇ、アク・チ・ゾル（旭化成
社製） １２ｇを懸濁させた。Example 4 Indomethacin, griseofulvin, and
30 g of phenytoin was dissolved. Furthermore, 30 g of Aerosil 200 and 12 g of Aku Chi Sol (manufactured by Asahi Kasei Corporation) were suspended in each solution.
同懸濁液を実施例１と同じスプレードライヤーにて噴霧
乾燥し、組成物（ｍ剤４．５．６）を得た。The same suspension was spray-dried using the same spray dryer as in Example 1 to obtain a composition (M formulation 4.5.6).
比較例
塩化メチレン１３０ｇにトリトクアリン１ｏｇを溶解さ
せ、更にアエロジル２００ １０ｇを懸濁させて得られ
た懸濁液から、真空乾燥機を用い６０℃、Δ７０ｃｍＨ
ｇで２時間にわたって徐々に溶媒を除去して得られた組
成物を対照剤とした。木製法は、従来の製法に属する。Comparative Example A suspension obtained by dissolving 1 og of tritoqualin in 130 g of methylene chloride and further suspending 10 g of Aerosil 200 was dried at 60°C and Δ70 cmH using a vacuum dryer.
The composition obtained by gradually removing the solvent at 100 g for 2 hours was used as a control agent. The wooden method belongs to the traditional manufacturing method.
試験例１
前記実施例１〜３でそれぞれ調製した製剤１〜３と対照
剤とについて、ｐＨ４，０の緩衝液９０〇−１３７℃、
１１００ｒｐ、パドル法での溶出試験を行い、トリトク
アリンの溶出性を調べた。また、Ｘ線回折法によりそれ
ぞれの非晶化度を測定した。その結果は第１図に示す通
りで、従来の技術と比較して、非晶化率が向上したこと
により溶出性も改善されていることが明らかになった。Test Example 1 For the preparations 1 to 3 prepared in Examples 1 to 3 and the control agent, a buffer solution of pH 4.0 at 900-137°C,
An elution test was conducted using the paddle method at 1100 rpm to examine the elution properties of tritoqualin. Further, the degree of amorphism of each was measured by X-ray diffraction method. The results are shown in FIG. 1, and it was revealed that the dissolution property was also improved due to the improved amorphization rate compared to the conventional technique.
試験例２
前記実施例１で調製した製剤１と対照剤とをそれぞれカ
プセル充填し、カプセル剤の形でのピーグル犬経口投与
試験を行い、バイオアベイラビリティ−を比較した。そ
の結果は第２図に示す通りで、従来の技術により得られ
た組成物と比較して、本発明組成物ははるかに高い血中
濃度を示し、バイオアベイラビリティ−が改善されてい
ることが明らかになった。なお、第２図は、試験に用い
たピーグル犬の測定時ごとの平均値をプロットしたもの
である。Test Example 2 Formulation 1 prepared in Example 1 and the control agent were each filled into capsules, and an oral administration test was conducted on Peagle dogs in the form of capsules to compare bioavailability. The results are shown in Figure 2, and it is clear that the composition of the present invention has a much higher blood concentration and improved bioavailability compared to compositions obtained by conventional techniques. Became. In addition, FIG. 2 is a plot of the average value for each measurement time of the pegle dogs used in the test.
試験内容の詳細について下記に示した。Details of the test contents are shown below.
被験動物：雄性ピーグル犬（体重１３〜１５ｋｇ）１群
６頭のクロスオーバー法
被験薬 ：製剤１、対照剤とも、それぞれ、トリトクア
リンｌｏＯｍｇを含有する
カプセル剤
投 与 ：２４時間絶食後、摂食（２００ｇ）３０分後
にそれぞれの製剤を水３０ｍ１と共に強制経口投与、投
与後６時
間絶食、摂水自由
採 血 ：投与直前及び投与後０，２５．０．５、■、
２．３．４．６．８．２４時間
の計ｌＯ点
上肢静脈より１回２ｍｆｌ！をヘパリンナ） ＩＪウム
を含んだ注射筒を用い
て採取し、１５０００ｒｐｍ、 １分間の遠心分離によ
り血漿を得た。Test animals: Crossover method with 6 male peagle dogs (body weight 13-15 kg) in 1 group Test drug: Administration of capsules containing tritoqualin loOmg for both Formulation 1 and the control drug: After fasting for 24 hours, feeding ( 200g) 30 minutes later, each formulation was forcibly administered with 30ml of water, fasted for 6 hours after administration, and had free access to water.Blood sampling: Immediately before administration and after administration 0.25.0.5,■,
2.3.4.6.8. 2 mfl once from the upper limb vein at 1O point for 24 hours! Plasma was collected using a syringe containing IJum (heparinina) and centrifuged at 15,000 rpm for 1 minute to obtain plasma.
定 量 ： ＩＩＰＬｃ法、蛍光検出器使用また、個々
のピーグル犬における最高血中濃度および試験後２４時
間の血中濃度下面積のバラツキを示すと次の表のとおり
である。Quantification: IIPLc method, fluorescence detector used The table below shows the maximum blood concentration in individual pegle dogs and the variation in the area under blood concentration 24 hours after the test.
成物及びそれぞれの服薬の溶出試験の結果を示す図であ
る。FIG. 2 is a diagram showing the results of a dissolution test of the composition and each medication.
試験例３
前記実施例４で調製した製剤４．５．６とそれぞれの服
薬とについて、精製水９００ｍｆ、３７℃、１１００ｒ
ｐ、パドル法での溶出試験を行い、薬剤の溶出性を調べ
た。その結果は第３図に示す通りで、服薬と比較して、
製剤の方が溶出性が改善されていることが明らかになっ
た。Test Example 3 Regarding the formulation 4.5.6 prepared in Example 4 and each dose, purified water 900mf, 37°C, 1100r
p. A dissolution test using the paddle method was conducted to examine the dissolution properties of the drug. The results are shown in Figure 3, and compared to taking medication,
It became clear that the formulation had improved dissolution properties.
第１図は実施例１〜３及び比較例で調製した組成物の溶
出試験の結果を示す図、第２図は実施例１及び比較例で
調製した組成物のピーグル犬投与試験における測定時間
毎の血中濃度の平均値を示す図、第３図は実施例４で調
製した組特許出願人 三菱化成株式会社Figure 1 is a diagram showing the results of dissolution tests for the compositions prepared in Examples 1 to 3 and Comparative Examples, and Figure 2 is a diagram showing the results of the dissolution test for the compositions prepared in Examples 1 to 3 and Comparative Examples. Figure 3 shows the average blood concentration of the compound prepared in Example 4, patent applicant Mitsubishi Kasei Corporation
Claims (1)
または懸濁させた懸濁液から急激に溶媒を除去すること
により得られる難溶性薬剤組成物。 ２、難溶性薬剤の水に対する溶解度が１００μｇ／ｍｌ
以下であることを特徴とする請求項１記載の組成物。 ３、担体が親水性高分子化合物および／または親水性無
機微粒子であることを特徴とする請求項１または２記載
の組成物。 ４、親水性高分子化合物が、ポリビニルピロリドン、結
晶セルロース、架橋カルボキシメチルセルロース、ポリ
エチレングリコール、カルボキシメチルセルロースナト
リウム、カルボキシメチルセルロースカルシウム、カル
ボキシメチルセルロースおよび部分アルファ化デンプン
よりなる群から選択される少なくとも１種の化合物であ
ることを特徴とする請求項３記載の組成物。 ５、親水性無機微粒子が、軽質無水ケイ酸、含水二酸化
ケイ素およびメタケイ酸アルミン酸マグネシウムよりな
る群から選択される少なくとも１種の微粒子であること
を特徴とする請求項３記載の組成物。 ６、担体の使用量が、難溶性薬剤１重量部に対して０．
１〜３重量部であることを特徴とする請求項１〜５の何
れか１項に記載の組成物。 ７、担体の使用量が、難溶性薬剤１重量部に対して０．
１〜１重量部であることを特徴とする請求項６記載の組
成物。 ８、急激に溶媒を除去する際に、スプレードライヤーま
たは流動層造粒乾燥機を用いることを特徴とする請求項
１〜７の何れか１項に記載の組成物。 ９、難溶性薬剤がトリトクアリンであることを特徴とす
る請求項１〜８の何れか１項に記載の組成物。 １０、難溶性薬剤がインドメタシンであることを特徴と
する請求項１〜８の何れか１項に記載の組成物。 １１、難溶性薬剤がグリセオフルビンであることを特徴
とする請求項の１〜８の何れか１項に記載の組成物。 １２、難溶性薬剤がフェニトインであることを特徴とす
る請求項１〜８の何れか１項に記載の組成物。[Scope of Claims] 1. A poorly soluble drug composition obtained by rapidly removing the solvent from a solution or suspension in which a poorly soluble drug and a carrier are dissolved in an organic solvent. 2. Solubility of poorly soluble drug in water is 100μg/ml
The composition according to claim 1, characterized in that: 3. The composition according to claim 1 or 2, wherein the carrier is a hydrophilic polymer compound and/or a hydrophilic inorganic fine particle. 4. The hydrophilic polymer compound is at least one compound selected from the group consisting of polyvinylpyrrolidone, crystalline cellulose, crosslinked carboxymethylcellulose, polyethylene glycol, sodium carboxymethylcellulose, calcium carboxymethylcellulose, carboxymethylcellulose, and partially pregelatinized starch. 4. A composition according to claim 3, characterized in that: 5. The composition according to claim 3, wherein the hydrophilic inorganic fine particles are at least one type of fine particles selected from the group consisting of light anhydrous silicic acid, hydrated silicon dioxide, and magnesium aluminate metasilicate. 6. The amount of carrier used is 0.00 parts by weight of the poorly soluble drug.
A composition according to any one of claims 1 to 5, characterized in that the amount is 1 to 3 parts by weight. 7. The amount of carrier used is 0.00 parts by weight of the poorly soluble drug.
7. A composition according to claim 6, characterized in that the amount is 1 to 1 part by weight. 8. The composition according to any one of claims 1 to 7, wherein a spray dryer or a fluidized bed granulation dryer is used to rapidly remove the solvent. 9. The composition according to any one of claims 1 to 8, wherein the poorly soluble drug is tritoqualin. 10. The composition according to any one of claims 1 to 8, wherein the poorly soluble drug is indomethacin. 11. The composition according to any one of claims 1 to 8, wherein the poorly soluble drug is griseofulvin. 12. The composition according to any one of claims 1 to 8, wherein the poorly soluble drug is phenytoin.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63-119191 | 1988-05-18 | ||
| JP11919188 | 1988-05-18 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH0249720A true JPH0249720A (en) | 1990-02-20 |
Family
ID=14755171
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP12275989A Pending JPH0249720A (en) | 1988-05-18 | 1989-05-18 | Slightly soluble drug composition |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0249720A (en) |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1992001453A1 (en) * | 1990-07-19 | 1992-02-06 | Otsuka Pharmaceutical Co., Ltd. | Solid preparation |
| JPH0648937A (en) * | 1992-04-07 | 1994-02-22 | Seitai Kagaku Kenkyusho:Kk | Medical agent suitable for oral administration and its production |
| WO1997034601A1 (en) * | 1996-03-18 | 1997-09-25 | Eisai Co., Ltd. | Drug compositions improved in solubility |
| US5780062A (en) * | 1994-11-09 | 1998-07-14 | The Ohio State University Research Foundation | Small particle formation |
| JP2007145856A (en) * | 1998-04-09 | 2007-06-14 | Roche Diagnostics Gmbh | Carvedilol preparation |
| WO2009113522A1 (en) * | 2008-03-11 | 2009-09-17 | あすか製薬株式会社 | Solid dispersion, pharmaceutical compositions containing the same, and processes for the production of both |
| WO2010092925A1 (en) * | 2009-02-12 | 2010-08-19 | あすか製薬株式会社 | Solid dispersion, pharmaceutical composition comprising the solid dispersion, and processes for producing the solid dispersion and the pharmaceutical composition |
| WO2010117035A1 (en) * | 2009-04-09 | 2010-10-14 | ライオン株式会社 | Complex and process for production thereof, and granules and tablets |
| JP2013028636A (en) * | 2000-10-24 | 2013-02-07 | Ajinomoto Co Inc | Nateglinide-containing preparation |
-
1989
- 1989-05-18 JP JP12275989A patent/JPH0249720A/en active Pending
Cited By (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1992001453A1 (en) * | 1990-07-19 | 1992-02-06 | Otsuka Pharmaceutical Co., Ltd. | Solid preparation |
| US5316773A (en) * | 1990-07-19 | 1994-05-31 | Otsuka Pharmaceutical Co., Ltd. | Particulate preparation containing a flourracil derivative and hydroxypropylmethyl-cellulose |
| JPH07112975B1 (en) * | 1990-07-19 | 1995-12-06 | Otsuka Pharma Co Ltd | |
| JPH0648937A (en) * | 1992-04-07 | 1994-02-22 | Seitai Kagaku Kenkyusho:Kk | Medical agent suitable for oral administration and its production |
| US5780062A (en) * | 1994-11-09 | 1998-07-14 | The Ohio State University Research Foundation | Small particle formation |
| WO1997034601A1 (en) * | 1996-03-18 | 1997-09-25 | Eisai Co., Ltd. | Drug compositions improved in solubility |
| JP2007145856A (en) * | 1998-04-09 | 2007-06-14 | Roche Diagnostics Gmbh | Carvedilol preparation |
| JP2013028636A (en) * | 2000-10-24 | 2013-02-07 | Ajinomoto Co Inc | Nateglinide-containing preparation |
| WO2009113522A1 (en) * | 2008-03-11 | 2009-09-17 | あすか製薬株式会社 | Solid dispersion, pharmaceutical compositions containing the same, and processes for the production of both |
| CN102083467A (en) * | 2008-03-11 | 2011-06-01 | Aska制药株式会社 | Solid dispersion, pharmaceutical compositions containing the same, and processes for the production of both |
| US8722094B2 (en) | 2008-03-11 | 2014-05-13 | Aska Pharmaceutical Co., Ltd. | Solid dispersion and pharmaceutical composition of the same, and production processes thereof |
| WO2010092925A1 (en) * | 2009-02-12 | 2010-08-19 | あすか製薬株式会社 | Solid dispersion, pharmaceutical composition comprising the solid dispersion, and processes for producing the solid dispersion and the pharmaceutical composition |
| WO2010117035A1 (en) * | 2009-04-09 | 2010-10-14 | ライオン株式会社 | Complex and process for production thereof, and granules and tablets |
| JPWO2010117035A1 (en) * | 2009-04-09 | 2012-10-18 | ライオン株式会社 | Composite, production method thereof, granule and tablet |
| JP5578171B2 (en) * | 2009-04-09 | 2014-08-27 | ライオン株式会社 | Composite, production method thereof, granule and tablet |
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