JPH107558A - Pharmaceutical preparation capable of improving solubility - Google Patents
Pharmaceutical preparation capable of improving solubilityInfo
- Publication number
- JPH107558A JPH107558A JP15817896A JP15817896A JPH107558A JP H107558 A JPH107558 A JP H107558A JP 15817896 A JP15817896 A JP 15817896A JP 15817896 A JP15817896 A JP 15817896A JP H107558 A JPH107558 A JP H107558A
- Authority
- JP
- Japan
- Prior art keywords
- solvent
- cyanophenyl
- thiazol
- butanol
- difluorophenyl
- 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
- 239000000825 pharmaceutical preparation Substances 0.000 title 1
- 239000002904 solvent Substances 0.000 claims abstract description 31
- 239000000126 substance Substances 0.000 claims abstract description 25
- 239000000203 mixture Substances 0.000 claims abstract description 23
- -1 carboxymethyl ethyl Chemical group 0.000 claims abstract description 19
- BTANRVKWQNVYAZ-UHFFFAOYSA-N 2-butanol Substances CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000002245 particle Substances 0.000 claims abstract description 9
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims abstract description 8
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims abstract description 8
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims abstract description 8
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical group OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims abstract description 5
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims abstract description 5
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims abstract description 5
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims abstract description 5
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims abstract description 5
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims abstract description 5
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 claims abstract description 4
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 claims abstract description 4
- 229920000609 methyl cellulose Polymers 0.000 claims abstract description 3
- 239000001923 methylcellulose Substances 0.000 claims abstract description 3
- 235000010981 methylcellulose Nutrition 0.000 claims abstract description 3
- 229920000642 polymer Polymers 0.000 claims description 17
- 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 claims description 14
- OPAHEYNNJWPQPX-RCDICMHDSA-N ravuconazole Chemical compound C=1SC([C@H](C)[C@](O)(CN2N=CN=C2)C=2C(=CC(F)=CC=2)F)=NC=1C1=CC=C(C#N)C=C1 OPAHEYNNJWPQPX-RCDICMHDSA-N 0.000 claims description 9
- 229920003145 methacrylic acid copolymer Polymers 0.000 claims description 2
- 229920002126 Acrylic acid copolymer Polymers 0.000 claims 1
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 claims 1
- 238000010521 absorption reaction Methods 0.000 abstract description 6
- 150000001875 compounds Chemical class 0.000 abstract description 3
- 241000228212 Aspergillus Species 0.000 abstract description 2
- 208000035473 Communicable disease Diseases 0.000 abstract description 2
- 239000003429 antifungal agent Substances 0.000 abstract description 2
- MUZDXNQOSGWMJJ-UHFFFAOYSA-N 2-methylprop-2-enoic acid;prop-2-enoic acid Chemical compound OC(=O)C=C.CC(=C)C(O)=O MUZDXNQOSGWMJJ-UHFFFAOYSA-N 0.000 abstract 1
- 239000001856 Ethyl cellulose Substances 0.000 abstract 1
- 241000233866 Fungi Species 0.000 abstract 1
- 229940121375 antifungal agent Drugs 0.000 abstract 1
- 229920001577 copolymer Polymers 0.000 abstract 1
- 239000006185 dispersion Substances 0.000 abstract 1
- 229920001249 ethyl cellulose Polymers 0.000 abstract 1
- 235000019325 ethyl cellulose Nutrition 0.000 abstract 1
- 239000004615 ingredient Substances 0.000 abstract 1
- 238000000034 method Methods 0.000 description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 17
- 239000007962 solid dispersion Substances 0.000 description 12
- 239000008186 active pharmaceutical agent Substances 0.000 description 10
- 229940088679 drug related substance Drugs 0.000 description 10
- 230000000694 effects Effects 0.000 description 10
- 239000008187 granular material Substances 0.000 description 10
- 229920002678 cellulose Polymers 0.000 description 8
- 239000001913 cellulose Substances 0.000 description 8
- 239000003814 drug Substances 0.000 description 8
- 229940079593 drug Drugs 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 239000000843 powder Substances 0.000 description 5
- 241000282472 Canis lupus familiaris Species 0.000 description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
- 238000007922 dissolution test Methods 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- 238000010828 elution Methods 0.000 description 3
- 238000005469 granulation Methods 0.000 description 3
- 230000003179 granulation Effects 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 238000010298 pulverizing process Methods 0.000 description 3
- 125000003626 1,2,4-triazol-1-yl group Chemical group [*]N1N=C([H])N=C1[H] 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- UOCLXMDMGBRAIB-UHFFFAOYSA-N 1,1,1-trichloroethane Chemical compound CC(Cl)(Cl)Cl UOCLXMDMGBRAIB-UHFFFAOYSA-N 0.000 description 1
- QQJIRQMOCFESJB-UHFFFAOYSA-N 1-(1,2,4-triazol-1-yl)butan-2-ol Chemical compound CCC(O)CN1C=NC=N1 QQJIRQMOCFESJB-UHFFFAOYSA-N 0.000 description 1
- VYBBTMLUOQMSTJ-UHFFFAOYSA-N 2-(2,4-difluorophenyl)-1-(1,2,4-triazol-1-yl)butan-2-ol Chemical compound C=1C=C(F)C=C(F)C=1C(O)(CC)CN1C=NC=N1 VYBBTMLUOQMSTJ-UHFFFAOYSA-N 0.000 description 1
- 241000222120 Candida <Saccharomycetales> Species 0.000 description 1
- 241001337994 Cryptococcus <scale insect> Species 0.000 description 1
- NHTMVDHEPJAVLT-UHFFFAOYSA-N Isooctane Chemical compound CC(C)CC(C)(C)C NHTMVDHEPJAVLT-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- 241000593312 Selfia Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 239000000378 calcium silicate Substances 0.000 description 1
- 229910052918 calcium silicate Inorganic materials 0.000 description 1
- OYACROKNLOSFPA-UHFFFAOYSA-N calcium;dioxido(oxo)silane Chemical compound [Ca+2].[O-][Si]([O-])=O OYACROKNLOSFPA-UHFFFAOYSA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- JVSWJIKNEAIKJW-UHFFFAOYSA-N dimethyl-hexane Natural products CCCCCC(C)C JVSWJIKNEAIKJW-UHFFFAOYSA-N 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229940117841 methacrylic acid copolymer Drugs 0.000 description 1
- HYIMSNHJOBLJNT-UHFFFAOYSA-N nifedipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1[N+]([O-])=O HYIMSNHJOBLJNT-UHFFFAOYSA-N 0.000 description 1
- 229960001597 nifedipine Drugs 0.000 description 1
- MCSAJNNLRCFZED-UHFFFAOYSA-N nitroethane Chemical compound CC[N+]([O-])=O MCSAJNNLRCFZED-UHFFFAOYSA-N 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
Landscapes
- Plural Heterocyclic Compounds (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【０００１】[0001]
【産業上の利用分野】本発明は、(2R,3R)-3-(4-(4-シア
ノフェニル)チアゾール-2-イル)-2-(2,4-ジフルオロフ
ェニル)-1-(1H-1,2,4-トリアゾール-1-イル)-2-ブタノ
ール及び高分子物質からなる薬剤組成物に関するもので
ある。The present invention relates to (2R, 3R) -3- (4- (4-cyanophenyl) thiazol-2-yl) -2- (2,4-difluorophenyl) -1- (1H The present invention relates to a pharmaceutical composition comprising (-1,2,4-triazol-1-yl) -2-butanol and a polymer substance.
【０００２】[0002]
【従来技術】(2R,3R)-3-(4-(4-シアノフェニル)チアゾ
ール-2-イル)-2-(2,4-ジフルオロフェニル)-1-(1H-1,2,
4-トリアゾール-1-イル)-2-ブタノールは、水にきわめ
て難溶性の薬物である。一般に、水難溶性の薬物の溶解
性を改善する方法として、薬物を微粉化する方法、界面
活性剤を添加する方法、固体分散体を調製する方法等が
知られている。例えば、特公昭５９ー１４４４６号公報
には難溶性薬物であるニフェジピンを微粉化して比表面
積を増大することにより溶解性を改善する方法が開示さ
れ、また、特開昭５８ー１８３６１５号公報には難溶性
薬物を溶媒に溶解し噴霧乾燥することにより、薬物を非
晶質化し溶解性を改善する方法が開示されている。PRIOR ART (2R, 3R) -3- (4- (4-cyanophenyl) thiazol-2-yl) -2- (2,4-difluorophenyl) -1- (1H-1,2,
4-Triazol-1-yl) -2-butanol is a very poorly soluble drug in water. Generally, as a method for improving the solubility of a poorly water-soluble drug, a method of pulverizing the drug, a method of adding a surfactant, a method of preparing a solid dispersion, and the like are known. For example, Japanese Patent Publication No. 59-14446 discloses a method of improving the solubility by pulverizing nifedipine, which is a poorly soluble drug, to increase the specific surface area, and JP-A-58-183615 discloses the method. A method is disclosed in which a poorly soluble drug is dissolved in a solvent and spray-dried to make the drug amorphous to improve solubility.
【０００３】[0003]
【発明が解決しようとする課題】(2R,3R)-3-(4-(4-シア
ノフェニル)チアゾール-2-イル)-2-(2,4-ジフルオロフ
ェニル)-1-(1H-1,2,4-トリアゾール-1-イル)-2-ブタノ
ールは、通常の製剤化によっては実質上水に溶解しない
ため生体に投与した場合の吸収が低く、吸収のバラツキ
も大きい。このことは臨床上大きな問題になる可能性が
ある。しかし、溶解性を増大する技術のうち、微粉化に
よる方法は溶解性の改善効果に限界があり、界面活性剤
の使用は安全性の点から問題がある。本発明者は、固体
分散体の調製により上記課題を解決すべく鋭意検討した
結果、意外にも以下の構成により課題を解決できること
を見いだし本発明を完成した。[Problems to be Solved by the Invention] (2R, 3R) -3- (4- (4-cyanophenyl) thiazol-2-yl) -2- (2,4-difluorophenyl) -1- (1H-1 Because 2,2,4-triazol-1-yl) -2-butanol is practically insoluble in water by ordinary formulation, its absorption when administered to a living body is low, and the absorption varies greatly. This can be a major clinical problem. However, among the techniques for increasing the solubility, the method based on pulverization has a limited effect of improving the solubility, and the use of a surfactant has a problem in terms of safety. The present inventors have conducted intensive studies to solve the above problems by preparing a solid dispersion, and as a result, have surprisingly found that the following structure can solve the problems, and have completed the present invention.
【０００４】[0004]
【課題を解決するための手段】本発明は、(2R,3R)-3-(4
-(4-シアノフェニル)チアゾール-2-イル)-2-(2,4-ジフ
ルオロフェニル)-1-(1H-1,2,4-トリアゾール-1-イル)-2
-ブタノール及び高分子物質を溶媒に溶解若しくは懸濁
後、溶媒を留去してなる(2R,3R)-3-(4-(4-シアノフェニ
ル)チアゾール-2-イル)-2-(2,4-ジフルオロフェニル)-1
-(1H-1,2,4-トリアゾール-1-イル)-2-ブタノール及び高
分子物質からなる組成物である。本発明はまた、(2R,3
R)-3-(4-(4-シアノフェニル)チアゾール-2-イル)-2-(2,
4-ジフルオロフェニル)-1-(1H-1,2,4-トリアゾール-1-
イル)-2-ブタノール及び高分子物質を溶媒に溶解若しく
は懸濁し、さらに該溶媒に不溶性の粒子を添加後、溶媒
を留去してなる(2R,3R)-3-(4-(4-シアノフェニル)チア
ゾール-2-イル)-2-(2,4-ジフルオロフェニル)-1-(1H-1,
2,4-トリアゾール-1-イル)-2-ブタノール含有組成物で
ある。According to the present invention, there is provided (2R, 3R) -3- (4
-(4-cyanophenyl) thiazol-2-yl) -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) -2
After dissolving or suspending butanol and a polymer substance in a solvent, the solvent is distilled off to obtain (2R, 3R) -3- (4- (4-cyanophenyl) thiazol-2-yl) -2- (2 , 4-difluorophenyl) -1
-(1H-1,2,4-triazol-1-yl) -2-butanol and a polymer substance. The present invention also relates to (2R, 3
R) -3- (4- (4-cyanophenyl) thiazol-2-yl) -2- (2,
4-difluorophenyl) -1- (1H-1,2,4-triazole-1-
(Il) -2-butanol and a high-molecular substance are dissolved or suspended in a solvent, and after adding insoluble particles to the solvent, the solvent is distilled off to obtain (2R, 3R) -3- (4- (4- (Cyanophenyl) thiazol-2-yl) -2- (2,4-difluorophenyl) -1- (1H-1,
It is a 2,4-triazol-1-yl) -2-butanol-containing composition.
【０００５】本発明における(2R,3R)-3-(4-(4-シアノフ
ェニル)チアゾール-2-イル)-2-(2,4-ジフルオロフェニ
ル)-1-(1H-1,2,4-トリアゾール-1-イル)-2-ブタノール
は、アスペルギルス属、カンジダ属、クリプトコッカス
属等による感染症に有効な抗真菌薬である。その構造式
を化１に示す。In the present invention, (2R, 3R) -3- (4- (4-cyanophenyl) thiazol-2-yl) -2- (2,4-difluorophenyl) -1- (1H-1,2, 4-Triazol-1-yl) -2-butanol is an effective antifungal drug against infectious diseases caused by Aspergillus, Candida, Cryptococcus and the like. Its structural formula is shown in Chemical Formula 1.
【０００６】[0006]
【化１】 Embedded image
【０００７】本発明における高分子物質とは、ヒドロキ
シプロピルメチルセルロース、カルボキシメチルエチル
セルロース（ＣＭＥＣ）、ヒドロキシプロピルセルロー
ス、メチルセルロース、ポリビニルピロリドン、ヒドロ
キシプロピルメチルセルロースフタレート及び/又はメ
タアクリル酸コポリマーであり、これら高分子単独で
も、２種以上組み合わせて用いてもよい。The polymer substance in the present invention is hydroxypropylmethylcellulose, carboxymethylethylcellulose (CMEC), hydroxypropylcellulose, methylcellulose, polyvinylpyrrolidone, hydroxypropylmethylcellulose phthalate and / or methacrylic acid copolymer. However, two or more kinds may be used in combination.
【０００８】本発明における、溶媒とは(2R,3R)-3-(4-
(4-シアノフェニル)チアゾール-2-イル)-2-(2,4-ジフル
オロフェニル)-1-(1H-1,2,4-トリアゾール-1-イル)-2-
ブタノール及び/又は高分子物質を溶解若しくは懸濁し
得る液体を意味し、具体的には水、エタノール、メタノ
ール、イソプロピルアルコール、アセトン、イソオクタ
ン、トルエン、メチルエチルケトン、酢酸イソプロピ
ル、トリクレイン、トリクロロエタン、クロルベンゼ
ン、ニトロメタン、ニトロエタン、アセトニトリル、ジ
メチルホルムアミド、ジメチルアセトアミド、エチレン
グリコールを挙げることができ、これらを混合して用い
ることもできる。In the present invention, the solvent is (2R, 3R) -3- (4-
(4-cyanophenyl) thiazol-2-yl) -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) -2-
Butanol and / or a liquid capable of dissolving or suspending a polymer substance, specifically, water, ethanol, methanol, isopropyl alcohol, acetone, isooctane, toluene, methyl ethyl ketone, isopropyl acetate, tricrein, trichloroethane, chlorobenzene, Examples thereof include nitromethane, nitroethane, acetonitrile, dimethylformamide, dimethylacetamide, and ethylene glycol, and these can be used in combination.
【０００９】本発明における溶媒に不溶性の粒子とは、
上記溶媒に溶解せずに、溶媒を留去したときにその表面
に(2R,3R)-3-(4-(4-シアノフェニル)チアゾール-2-イ
ル)-2-(2,4-ジフルオロフェニル)-1-(1H-1,2,4-トリア
ゾール-1-イル)-2-ブタノール及び高分子物質からなる
組成物が吸着若しくは付着できる粒子を意味し、具体的
には、種々の粒子径の結晶セルロース、無水ケイ酸、ケ
イ酸カルシウム等を挙げることができ、好ましくは粒子
径２００から３００μｍを有する結晶セルロースであ
る。The solvent-insoluble particles in the present invention are:
Without dissolving in the above solvent, when the solvent is distilled off, the surface thereof has (2R, 3R) -3- (4- (4-cyanophenyl) thiazol-2-yl) -2- (2,4-difluoro Phenyl) -1- (1H-1,2,4-triazol-1-yl) -2-butanol means particles to which a composition comprising a polymer substance can be adsorbed or adhered, specifically, various particles Examples thereof include crystalline cellulose having a diameter, silicic anhydride, and calcium silicate, and are preferably crystalline cellulose having a particle diameter of 200 to 300 μm.
【００１０】本発明における組成物中の(2R,3R)-3-(4-
(4-シアノフェニル)チアゾール-2-イル)-2-(2,4-ジフル
オロフェニル)-1-(1H-1,2,4-トリアゾール-1-イル)-2-
ブタノールの少なくとも一部は、非晶質若しくは結晶構
造がルーズになっていると考えられる。非晶質とは結晶
構造を失った状態を意味し、より詳しくは、分子が規則
正しい空間配置をつくらずに集合して生ずる固体物質の
状態であり、一定の融点、凝固点を有さない。In the composition of the present invention, (2R, 3R) -3- (4-
(4-cyanophenyl) thiazol-2-yl) -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) -2-
It is believed that at least a portion of the butanol has a loose amorphous or crystalline structure. Amorphous means a state in which the crystal structure has been lost, and more specifically, a state of a solid substance formed by assembling molecules without forming a regular spatial arrangement, and does not have a fixed melting point and freezing point.
【００１１】本発明かかる(2R,3R)-3-(4-(4-シアノフェ
ニル)チアゾール-2-イル)-2-(2,4-ジフルオロフェニル)
-1-(1H-1,2,4-トリアゾール-1-イル)-2-ブタノール及び
高分子物質との組成物は、これら物質を前記溶媒に溶解
若しくは懸濁後溶媒を留去して得ることができる。溶媒
を留去するには、加温する方法、減圧にする方法、減圧
加温する方法等を任意に選ぶことができる。また、溶解
液若しくは懸濁液を乳糖、結晶セルロース、無水ケイ酸
等の賦形剤に吸着後、溶媒を留去する方法も用いること
ができる。The (2R, 3R) -3- (4- (4-cyanophenyl) thiazol-2-yl) -2- (2,4-difluorophenyl) according to the present invention
Compositions with -1- (1H-1,2,4-triazol-1-yl) -2-butanol and polymeric substances are obtained by dissolving or suspending these substances in the solvent and then distilling off the solvent. be able to. To remove the solvent, a method of heating, a method of reducing the pressure, a method of heating under reduced pressure, or the like can be arbitrarily selected. Further, a method of adsorbing the solution or suspension to an excipient such as lactose, crystalline cellulose, or silicic acid anhydride and then distilling off the solvent can also be used.
【００１２】また、非晶質の(2R,3R)-3-(4-(4-シアノフ
ェニル)チアゾール-2-イル)-2-(2,4-ジフルオロフェニ
ル)-1-(1H-1,2,4-トリアゾール-1-イル)-2-ブタノール
を得る他の方法は、(2R,3R)-3-(4-(4-シアノフェニル)
チアゾール-2-イル)-2-(2,4-ジフルオロフェニル)-1-(1
H-1,2,4-トリアゾール-1-イル)-2-ブタノール及び高分
子物質を溶媒に溶解若しくは懸濁後、瞬間真空造粒する
方法である。瞬間真空造粒とは、溶解若しくは懸濁した
(2R,3R)-3-(4-(4-シアノフェニル)チアゾール-2-イル)-
2-(2,4-ジフルオロフェニル)-1-(1H-1,2,4-トリアゾー
ル-1-イル)-2-ブタノール及び高分子物質を１５０℃以
上の高温に加熱した加熱管に送り、つづいて減圧状態に
保った捕集室に送り粉末を得る方法である。瞬間真空造
粒には、例えば商品名ＣＲＵＸとして発売されている装
置を用いることができる。Also, amorphous (2R, 3R) -3- (4- (4-cyanophenyl) thiazol-2-yl) -2- (2,4-difluorophenyl) -1- (1H-1 Another method of obtaining 2,2,4-triazol-1-yl) -2-butanol is (2R, 3R) -3- (4- (4-cyanophenyl)
Thiazol-2-yl) -2- (2,4-difluorophenyl) -1- (1
This is a method in which H-1,2,4-triazol-1-yl) -2-butanol and a polymer substance are dissolved or suspended in a solvent and then subjected to instantaneous vacuum granulation. Instant vacuum granulation refers to dissolved or suspended
(2R, 3R) -3- (4- (4-cyanophenyl) thiazol-2-yl)-
Send 2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) -2-butanol and a polymer substance to a heating tube heated to a high temperature of 150 ° C. or higher, Subsequently, the powder is sent to a collection chamber kept under reduced pressure to obtain powder. For the instantaneous vacuum granulation, for example, an apparatus sold under the trade name CRUX can be used.
【００１３】さらに、非晶質の(2R,3R)-3-(4-(4-シアノ
フェニル)チアゾール-2-イル)-2-(2,4-ジフルオロフェ
ニル)-1-(1H-1,2,4-トリアゾール-1-イル)-2-ブタノー
ルを得る別途の手段は、(2R,3R)-3-(4-(4-シアノフェニ
ル)チアゾール-2-イル)-2-(2,4-ジフルオロフェニル)-1
-(1H-1,2,4-トリアゾール-1-イル)-2-ブタノール及び高
分子物質を溶媒に溶解若しくは懸濁後、噴霧乾燥する方
法、または、両物質を混合後、加熱溶融、高圧溶融若し
くは高圧加温溶融する方法がある。噴霧乾燥とは、溶解
液若しくは懸濁液を、温風中に噴霧して短時間に乾燥す
ることにより粒子を得る方法であり、後者の方法は、例
えば、エクストルーダーという装置により実施すること
ができる。Further, amorphous (2R, 3R) -3- (4- (4-cyanophenyl) thiazol-2-yl) -2- (2,4-difluorophenyl) -1- (1H-1 Another means of obtaining 2,2,4-triazol-1-yl) -2-butanol is (2R, 3R) -3- (4- (4-cyanophenyl) thiazol-2-yl) -2- (2 , 4-difluorophenyl) -1
-(1H-1,2,4-triazol-1-yl) -2-butanol and a polymer substance are dissolved or suspended in a solvent and then spray-dried, or after mixing both substances, heat melting, high pressure There is a method of melting or high-temperature heating and melting. Spray drying is a method of obtaining particles by spraying a solution or suspension in hot air and drying it in a short time, and the latter method can be carried out by, for example, an apparatus called an extruder. it can.
【００１４】本発明における(2R,3R)-3-(4-(4-シアノフ
ェニル)チアゾール-2-イル)-2-(2,4-ジフルオロフェニ
ル)-1-(1H-1,2,4-トリアゾール-1-イル)-2-ブタノール
の製造方法は、特に限定されないが、例えば特開平８ー
２０５７８号公報に開示される方法により得ることがで
きる。In the present invention, (2R, 3R) -3- (4- (4-cyanophenyl) thiazol-2-yl) -2- (2,4-difluorophenyl) -1- (1H-1,2, The method for producing 4-triazol-1-yl) -2-butanol is not particularly limited, but it can be obtained, for example, by the method disclosed in JP-A-8-20578.
【００１５】本発明における(2R,3R)-3-(4-(4-シアノフ
ェニル)チアゾール-2-イル)-2-(2,4-ジフルオロフェニ
ル)-1-(1H-1,2,4-トリアゾール-1-イル)-2-ブタノール
と高分子の比率は、一般に化合物１重量部に対し高分子
物質0.1〜50重量部であり、好ましくは0.5〜10重量部、
より好ましくは1〜5重量部である。In the present invention, (2R, 3R) -3- (4- (4-cyanophenyl) thiazol-2-yl) -2- (2,4-difluorophenyl) -1- (1H-1,2, The ratio of 4-triazol-1-yl) -2-butanol to the polymer is generally 0.1 to 50 parts by weight, preferably 0.5 to 10 parts by weight of the polymer substance per 1 part by weight of the compound.
More preferably, it is 1 to 5 parts by weight.
【００１６】本発明にかかる溶媒は１種又は２種以上を
混合して使用することができるが、混合する場合の配合
比は特に限定されず、使用する高分子物質の種類と量に
より適宜選ぶことができる。例えば、高分子物質として
カルボキシメチルエチルセルロースを使用し、溶媒とし
て水及びエタノールを使用する場合は、水：エタノール
＝５：９５〜３０：７０が好ましく、より好ましくは１
０：９０〜２５：７５である。また、溶媒の使用量は特
に限定されないが、化合物及び/又は高分子物質を溶解
若しくは懸濁させうる量を使用することが好ましい。The solvent according to the present invention can be used alone or as a mixture of two or more, but the mixing ratio in the case of mixing is not particularly limited, and is appropriately selected depending on the type and amount of the polymer substance used. be able to. For example, when carboxymethylethylcellulose is used as the polymer substance and water and ethanol are used as the solvent, water: ethanol = 5: 95 to 30:70 is preferable, and 1: 1 is more preferable.
0:90 to 25:75. The amount of the solvent used is not particularly limited, but it is preferable to use an amount capable of dissolving or suspending the compound and / or the polymer.
【００１７】本発明により得られた組成物は、粉砕、篩
過してそのまま若しくは通常用いられる製剤化助剤を添
加して散剤、顆粒剤等の剤形とすることができる。ま
た、さらに通常用いられる手段により錠剤、カプセル剤
等とすることもできる。The composition obtained by the present invention can be pulverized and sieved to give a dosage form such as a powder or granule as it is or by adding a commonly used formulation aid. In addition, tablets, capsules and the like can be further prepared by commonly used means.
【００１８】次に本発明の効果について説明する。な
お、以下の効果例及び実施例においては、(2R,3R)-3-(4
-(4-シアノフェニル)チアゾール-2-イル)-2-(2,4-ジフ
ルオロフェニル)-1-(1H-1,2,4-トリアゾール-1-イル)-2
-ブタノールを単に原薬と称する。Next, the effects of the present invention will be described. In the following effects and examples, (2R, 3R) -3- (4
-(4-cyanophenyl) thiazol-2-yl) -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) -2
-Butanol is simply referred to as the drug substance.
【００１９】効果例１ 実施例１又は２で得た固体分散
体を原薬として２５ｍｇ相当を秤りとり、溶出試験（Ｊ
Ｐ１液及びＪＰ２液、１００ｒｐｍ、パドル法、３７
℃、９００ｍｌ）を行った。対照として乳糖４倍散を用
いた。結果を図１、２に示した。本発明にかかる組成物
は、原薬の溶出改善が認められた。改善効果は、特にヒ
ドロキシプロピルメチルセルロース、ヒドロキシプロピ
ルセルロース及びポリビニルピロリドンにおいて著しか
った。Effect Example 1 The solid dispersion obtained in Example 1 or 2 was weighed in an amount of 25 mg as a drug substance and subjected to an elution test (J
P1 solution and JP2 solution, 100 rpm, paddle method, 37
° C, 900 ml). Lactose 4-fold powder was used as a control. The results are shown in FIGS. In the composition according to the present invention, the elution of the drug substance was improved. The improvement effect was particularly remarkable in hydroxypropylmethylcellulose, hydroxypropylcellulose and polyvinylpyrrolidone.
【００２０】効果例２ 実施例１で得た顆粒をビーグル
犬に原薬として4mg/kg経口投与し、吸収実験を行った。
なお、用いたビーグル犬は絶食状態で実験を行った。対
照として乳糖４倍散を用いた。結果を図３に示した。本
発明にかかる組成物は原薬の吸収改善が認められた。Effect Example 2 The granules obtained in Example 1 were orally administered to a beagle dog as a drug substance at 4 mg / kg, and an absorption experiment was conducted.
The experiment was performed in a fasted state with the used beagle dog. Lactose 4-fold powder was used as a control. The results are shown in FIG. The composition according to the present invention was found to have improved absorption of the drug substance.
【００２１】効果例３ 実施例３で得た顆粒を用いて効
果例１と同様の試験を行った。結果を図４、５に示し
た。本発明にかかる原薬とヒドロキシプロピルメチルセ
ルロースの固体分散体を結晶セルロースに吸着させた顆
粒は、溶出の改善が認められた。Effect Example 3 The same test as in Effect Example 1 was performed using the granules obtained in Example 3. The results are shown in FIGS. The granules obtained by adsorbing the solid dispersion of the drug substance according to the present invention and hydroxypropylmethylcellulose on crystalline cellulose showed improved elution.
【００２２】効果例４ 実施例３で得た顆粒を用いて効
果例２と同様の試験を行った。結果を図６に示した。本
発明にかかる原薬とヒドロキシプロピルメチルセルロー
スの固体分散体を結晶セルロースに吸着させた顆粒は、
吸収の改善が認められた。Effect Example 4 The same test as in Effect Example 2 was performed using the granules obtained in Example 3. The results are shown in FIG. Granules obtained by adsorbing a solid dispersion of the drug substance and hydroxypropylmethylcellulose according to the present invention on crystalline cellulose,
Improved absorption was observed.
【００２３】[0023]
【実施例】次に、本発明を実施例を挙げて具体的に説明
するが、本発明が実施例に限定されるものではない。EXAMPLES Next, the present invention will be described specifically with reference to examples, but the present invention is not limited to the examples.
【００２４】実施例１ 500mlナス型フラスコに、原薬
２ｇを秤りとり、エタノールに溶解させた。これにポリ
ビニルピロリドン６ｇを加え溶解後、溶媒を留去した。
残渣を捕集し、解砕機で粉砕後３２メッシュ篩過品を採
取して本発明にかかる顆粒を得た。 実施例２ 500mlナス型フラスコに、原薬２ｇを秤りと
り、エタノールに溶解させた。これに水を加えて、８５
％エタノール溶液とし、ヒドロキシプロピルメチルセル
ロース、ヒドロキシプロピルメチルセルロースフタレー
ト又はヒドロキシプロピルセルロースをそれぞれ別に６
ｇを加えて溶解後、溶媒を留去した。残渣を捕集し、解
砕機で粉砕後３２メッシュ篩過品を採取して本発明にか
かる顆粒を得た。Example 1 In a 500 ml eggplant-shaped flask, 2 g of the drug substance was weighed and dissolved in ethanol. After adding and dissolving 6 g of polyvinylpyrrolidone, the solvent was distilled off.
The residue was collected, pulverized by a crusher, and then a 32 mesh sieved product was collected to obtain a granule according to the present invention. Example 2 In a 500 ml eggplant-shaped flask, 2 g of the drug substance was weighed and dissolved in ethanol. Add water to this and add 85
% Ethanol solution, and hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate or hydroxypropylcellulose was separately added to 6% each.
After adding and dissolving g, the solvent was distilled off. The residue was collected, pulverized by a crusher, and then a 32 mesh sieved product was collected to obtain a granule according to the present invention.
【００２５】実施例３ 1000mlナス型フラスコに、原薬
５ｇを秤りとり、エタノールに溶解させた。水を加えて
８５％エタノール溶液とし、ヒドロキシプロピルメチル
セルロース１５ｇ及び結晶セルロース（商品名セルフィ
ア、旭化成工業株式会社製、粒子径２００〜３００μ
ｍ）１００ｇを加えて懸濁後、溶媒を留去した。残渣を
捕集し、解砕機で粉砕後３２メッシュを篩過し、４８メ
ッシュを篩過しない顆粒を採取して本発明にかかる顆粒
を得た。Example 3 In a 1000 ml eggplant-shaped flask, 5 g of the drug substance was weighed and dissolved in ethanol. Water was added to make an 85% ethanol solution, and 15 g of hydroxypropylmethylcellulose and crystalline cellulose (trade name: SELFIA, manufactured by Asahi Chemical Industry Co., Ltd., particle diameter: 200 to 300 μm)
m) 100 g was added and suspended, and then the solvent was distilled off. The residue was collected, crushed by a crusher, sieved through 32 mesh, and granules not sieved through 48 mesh were collected to obtain granules according to the present invention.
【図１】図１は本発明にかかる組成物（固体分散体）及
び対照のＪＰ１液による溶出試験を示す図であるFIG. 1 is a diagram showing a dissolution test using a composition (solid dispersion) according to the present invention and a JP1 liquid as a control.
【図２】図２は本発明にかかる組成物（固体分散体）及
び対照のＪＰ２液による溶出試験を示す図である。FIG. 2 is a view showing a dissolution test using a composition (solid dispersion) according to the present invention and a JP2 liquid as a control.
【図３】図３は本発明にかかる組成物（固体分散体）及
び対照をビーグル犬に経口投与した場合の血漿中薬物濃
度を示す図である。FIG. 3 is a graph showing the drug concentration in plasma when a composition (solid dispersion) according to the present invention and a control are orally administered to a beagle dog.
【図４】図４は本発明にかかる組成物（固体分散体）を
結晶セルロースに吸着させたもの及び対照のＪＰ１液に
よる溶出試験を示す図である。FIG. 4 is a diagram showing a composition obtained by adsorbing a composition (solid dispersion) according to the present invention on crystalline cellulose and a dissolution test using a control JP1 solution.
【図５】図５は本発明にかかる組成物（固体分散体）を
結晶セルロースに吸着させたもの及び対照のＪＰ２液に
よる溶出試験を示す図である。FIG. 5 is a diagram showing a composition obtained by adsorbing the composition (solid dispersion) according to the present invention on crystalline cellulose and a dissolution test using a control JP2 solution.
【図６】図６は本発明にかかる組成物（固体分散体）を
固体分散体に吸着させたのも及び対照をビーグル犬に経
口投与した場合の血漿中薬物濃度を示す図である。FIG. 6 is a graph showing the drug concentration in plasma when the composition (solid dispersion) according to the present invention is adsorbed on a solid dispersion and when a control is orally administered to a beagle dog.
Claims (3)
ール-2-イル)-2-(2,4-ジフルオロフェニル)-1-(1H-1,2,
4-トリアゾール-1-イル)-2-ブタノール及び高分子物質
を溶媒に溶解若しくは懸濁後、溶媒を留去してなる(2R,
3R)-3-(4-(4-シアノフェニル)チアゾール-2-イル)-2-
(2,4-ジフルオロフェニル)-1-(1H-1,2,4-トリアゾール-
1-イル)-2-ブタノール及び高分子物質からなる組成物。(1) (2R, 3R) -3- (4- (4-cyanophenyl) thiazol-2-yl) -2- (2,4-difluorophenyl) -1- (1H-1,2,
After dissolving or suspending 4-triazol-1-yl) -2-butanol and a polymer substance in a solvent, the solvent is distilled off (2R,
3R) -3- (4- (4-cyanophenyl) thiazol-2-yl) -2-
(2,4-difluorophenyl) -1- (1H-1,2,4-triazole-
A composition comprising 1-yl) -2-butanol and a polymer substance.
ール-2-イル)-2-(2,4-ジフルオロフェニル)-1-(1H-1,2,
4-トリアゾール-1-イル)-2-ブタノール及び高分子物質
を溶媒に溶解若しくは懸濁し、さらに該溶媒に不溶性の
粒子を添加後、溶媒を留去してなる(2R,3R)-3-(4-(4-シ
アノフェニル)チアゾール-2-イル)-2-(2,4-ジフルオロ
フェニル)-1-(1H-1,2,4-トリアゾール-1-イル)-2-ブタ
ノール含有組成物。(2) (2R, 3R) -3- (4- (4-cyanophenyl) thiazol-2-yl) -2- (2,4-difluorophenyl) -1- (1H-1,2,
4-Triazol-1-yl) -2-butanol and a high-molecular substance are dissolved or suspended in a solvent, and after adding particles insoluble in the solvent, the solvent is distilled off to obtain (2R, 3R) -3- (4- (4-cyanophenyl) thiazol-2-yl) -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) -2-butanol-containing composition Stuff.
セルロース、カルボキシメチルエチルセルロース、ヒド
ロキシプロピルセルロース、メチルセルロース、ポリビ
ニルピロリドン、ヒドロキシプロピルメチルセルロース
フタレート又はメタアクリル酸・アクリル酸コポリマー
である請求項１又は２記載の組成物。3. The composition according to claim 1, wherein the polymer substance is hydroxypropylmethylcellulose, carboxymethylethylcellulose, hydroxypropylcellulose, methylcellulose, polyvinylpyrrolidone, hydroxypropylmethylcellulose phthalate or methacrylic acid / acrylic acid copolymer. .
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP15817896A JPH107558A (en) | 1996-06-19 | 1996-06-19 | Pharmaceutical preparation capable of improving solubility |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP15817896A JPH107558A (en) | 1996-06-19 | 1996-06-19 | Pharmaceutical preparation capable of improving solubility |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH107558A true JPH107558A (en) | 1998-01-13 |
Family
ID=15665982
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP15817896A Pending JPH107558A (en) | 1996-06-19 | 1996-06-19 | Pharmaceutical preparation capable of improving solubility |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH107558A (en) |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH11302157A (en) * | 1998-04-17 | 1999-11-02 | Eisai Co Ltd | Tablet quickly disintegrating in oral cavity |
| WO2001095941A1 (en) * | 2000-06-14 | 2001-12-20 | Nippon Shinyaku Co., Ltd. | Solid dispersions and medicines |
| WO2002100379A1 (en) * | 2001-06-07 | 2002-12-19 | Takeda Chemical Industries, Ltd. | Method for preparing solid dispersion |
| WO2003042248A1 (en) * | 2001-11-15 | 2003-05-22 | Samsung Fine Chemicals Co., Ltd. | Preparation method of solvent-free water-dispersible hydroxypropyl methyl cellulose phthalate nanoparticle |
| KR100520589B1 (en) * | 1998-04-09 | 2005-10-10 | 로쉐 디아그노스틱스 게엠베하 | Carvedilol-galenics |
| JP2006500349A (en) * | 2002-08-12 | 2006-01-05 | ファイザー・プロダクツ・インク | Semi-order pharmaceutical and polymeric pharmaceutical compositions |
| JP2008501802A (en) * | 2004-06-08 | 2008-01-24 | バーテックス ファーマシューティカルズ インコーポレイテッド | Pharmaceutical composition |
| WO2008114859A1 (en) * | 2007-03-22 | 2008-09-25 | Astellas Pharma Inc. | Pharmaceutical composition containing pyrazole derivative |
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-
1996
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| JP4806885B2 (en) * | 2000-06-14 | 2011-11-02 | 日本新薬株式会社 | Solid dispersions and drugs |
| WO2002100379A1 (en) * | 2001-06-07 | 2002-12-19 | Takeda Chemical Industries, Ltd. | Method for preparing solid dispersion |
| WO2003042248A1 (en) * | 2001-11-15 | 2003-05-22 | Samsung Fine Chemicals Co., Ltd. | Preparation method of solvent-free water-dispersible hydroxypropyl methyl cellulose phthalate nanoparticle |
| US6893493B2 (en) | 2001-11-15 | 2005-05-17 | Samsung Fine Chemicals Co., Ltd. | Preparation method of solvent-free water-dispersible hydroxypropyl methyl cellulose phthalate nanoparticle |
| JP2006500349A (en) * | 2002-08-12 | 2006-01-05 | ファイザー・プロダクツ・インク | Semi-order pharmaceutical and polymeric pharmaceutical compositions |
| JP2008501802A (en) * | 2004-06-08 | 2008-01-24 | バーテックス ファーマシューティカルズ インコーポレイテッド | Pharmaceutical composition |
| JP2009539804A (en) * | 2006-06-06 | 2009-11-19 | テイボテク・フアーマシユーチカルズ・リミテツド | Method for preparing a spray-dried preparation of TMC125 |
| WO2008114859A1 (en) * | 2007-03-22 | 2008-09-25 | Astellas Pharma Inc. | Pharmaceutical composition containing pyrazole derivative |
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