JPH035438A - Flurbiprofen clathrate compound and anti-inflammatory and analgesic agent using the same clathrate compound - Google Patents
Flurbiprofen clathrate compound and anti-inflammatory and analgesic agent using the same clathrate compoundInfo
- Publication number
- JPH035438A JPH035438A JP1138096A JP13809689A JPH035438A JP H035438 A JPH035438 A JP H035438A JP 1138096 A JP1138096 A JP 1138096A JP 13809689 A JP13809689 A JP 13809689A JP H035438 A JPH035438 A JP H035438A
- Authority
- JP
- Japan
- Prior art keywords
- cyd
- clathrate compound
- clathrate
- inflammatory
- flurbiprofen
- 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
- SYTBZMRGLBWNTM-UHFFFAOYSA-N flurbiprofen Chemical compound FC1=CC(C(C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-UHFFFAOYSA-N 0.000 title claims abstract description 78
- 229960002390 flurbiprofen Drugs 0.000 title claims abstract description 78
- 150000001875 compounds Chemical class 0.000 title claims abstract description 50
- 230000003110 anti-inflammatory effect Effects 0.000 title claims abstract description 14
- 239000000730 antalgic agent Substances 0.000 title claims abstract description 10
- 239000002260 anti-inflammatory agent Substances 0.000 title abstract description 4
- -1 hydroxypropyl groups Chemical group 0.000 claims abstract description 13
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 claims abstract description 11
- 229920000858 Cyclodextrin Polymers 0.000 claims abstract description 7
- 239000004480 active ingredient Substances 0.000 claims abstract description 7
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 claims abstract description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 13
- 238000010521 absorption reaction Methods 0.000 abstract description 5
- 235000019658 bitter taste Nutrition 0.000 abstract description 4
- GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical compound CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 abstract description 3
- 208000008035 Back Pain Diseases 0.000 abstract description 2
- 208000008930 Low Back Pain Diseases 0.000 abstract description 2
- 201000004328 Pulpitis Diseases 0.000 abstract description 2
- 206010037464 Pulpitis dental Diseases 0.000 abstract description 2
- 239000003513 alkali Substances 0.000 abstract description 2
- 230000001684 chronic effect Effects 0.000 abstract description 2
- 235000019640 taste Nutrition 0.000 abstract description 2
- 230000000202 analgesic effect Effects 0.000 abstract 1
- 239000004615 ingredient Substances 0.000 abstract 1
- 239000003826 tablet Substances 0.000 description 27
- 238000000034 method Methods 0.000 description 17
- 239000000203 mixture Substances 0.000 description 14
- 238000002360 preparation method Methods 0.000 description 12
- 230000007794 irritation Effects 0.000 description 10
- 239000008187 granular material Substances 0.000 description 8
- 238000002347 injection Methods 0.000 description 7
- 239000007924 injection Substances 0.000 description 7
- 230000036470 plasma concentration Effects 0.000 description 7
- 239000002585 base Substances 0.000 description 6
- 238000007922 dissolution test Methods 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 238000000113 differential scanning calorimetry Methods 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 239000000829 suppository Substances 0.000 description 5
- 238000000862 absorption spectrum Methods 0.000 description 4
- 239000000654 additive Substances 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 210000001035 gastrointestinal tract Anatomy 0.000 description 4
- 238000000634 powder X-ray diffraction Methods 0.000 description 4
- 239000003995 emulsifying agent Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000004033 plastic Substances 0.000 description 3
- 229920003023 plastic Polymers 0.000 description 3
- 239000000375 suspending agent Substances 0.000 description 3
- 239000006188 syrup Substances 0.000 description 3
- 235000020357 syrup Nutrition 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 230000001760 anti-analgesic effect Effects 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 238000000748 compression moulding Methods 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 230000002949 hemolytic effect Effects 0.000 description 2
- 230000000622 irritating effect Effects 0.000 description 2
- 238000004898 kneading Methods 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 229920001450 Alpha-Cyclodextrin Polymers 0.000 description 1
- 239000001116 FEMA 4028 Substances 0.000 description 1
- 208000012895 Gastric disease Diseases 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 239000003522 acrylic cement Substances 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 238000005273 aeration Methods 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- HFHDHCJBZVLPGP-RWMJIURBSA-N alpha-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO HFHDHCJBZVLPGP-RWMJIURBSA-N 0.000 description 1
- 229940043377 alpha-cyclodextrin Drugs 0.000 description 1
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 1
- 235000011175 beta-cyclodextrine Nutrition 0.000 description 1
- 229960004853 betadex Drugs 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- GDSRMADSINPKSL-HSEONFRVSA-N gamma-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO GDSRMADSINPKSL-HSEONFRVSA-N 0.000 description 1
- 229940080345 gamma-cyclodextrin Drugs 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 210000002200 mouth mucosa Anatomy 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- 239000004745 nonwoven fabric Substances 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 239000006069 physical mixture Substances 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920006254 polymer film Polymers 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 231100000820 toxicity test Toxicity 0.000 description 1
- 210000000689 upper leg Anatomy 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
【発明の詳細な説明】
［産業上の利用分野］
本発明は、フルルビプロフェン包接化合物およびこの包
接化合物を用いる消炎鎮痛剤に関する。DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a flurbiprofen clathrate compound and an anti-inflammatory analgesic agent using this clathrate compound.
［従来の技術］
フルルビプロフェン（以下、ＦＰと称す）は強い消炎鎮
痛作用を有し、慢性関節リウマチ、腰痛症、歯髄炎等の
消炎鎮痛剤成分として広く用いられている。しかしなが
ら、このＦＰは特異な苦みと味を有する水難溶性の物質
であり、かつ粘膜刺激性を有するため、薬剤としてその
まま服用した場合には、服用しづらいとともに消化管か
らの吸収性に乏しく、また胃障害等の副作用を惹起しや
すいという難点がある。[Prior Art] Flurbiprofen (hereinafter referred to as FP) has a strong anti-inflammatory and analgesic effect, and is widely used as an anti-inflammatory and analgesic component for chronic rheumatoid arthritis, low back pain, pulpitis, and the like. However, this FP is a poorly water-soluble substance with a unique bitterness and taste, and also has mucous membrane irritating properties, so when taken as a drug, it is difficult to take and is poorly absorbed from the gastrointestinal tract. It has the disadvantage that it tends to cause side effects such as gastric disorders.
これらの欠点を解消し副作用を軽減することは、製剤技
術的に非常に重要な意義を持つものであり、過去にいく
つかの方法が提案されている。Eliminating these drawbacks and reducing side effects is of great significance in terms of formulation technology, and several methods have been proposed in the past.
その一つに、ＦＰをα−シクロデキストリン（以下、α
−ＣｙＤと称す）、β−シクロデキストリン（以下、β
−ＣｙＤと称す）あるいはγ−シクロデキストリン（以
下、γ−ＣｙＤと称す）と接触させることにより包接化
合物を形成し、これを用いて製剤化する方法（特開昭５
６−３４６１８号公報、特開昭５６−４６８３８号公報
）がある。One of them is to convert FP to α-cyclodextrin (hereinafter referred to as α
-CyD), β-cyclodextrin (hereinafter referred to as β
-CyD) or γ-cyclodextrin (hereinafter referred to as γ-CyD) to form an clathrate compound, and use this to form a formulation (JP-A-5
6-34618 and Japanese Patent Application Laid-open No. 56-46838).
これらの方法により得られる、ＦＰとシクロデキストリ
ンの包接化合物（以下、ＦＰ−ＣＶＤ包接化合物と称す
）は、ＦＰに比べて溶解性が向上しているが、未だ不十
分であり、その改善が望まれていた。さらに、これらの
ＦＰ−ＣＶＤ包接化合物をラットに経口投与した場合の
ＦＰの血清中濃度は、ＦＰを単独で投与した場合と比較
して高く、血清中濃度−時間曲線上面積（ＡＵＧ）も、
ＦＰ−ＣＶＤ包接化合物を投与した場合の方がＦＰを単
独で投与、した場合より大きいことから、ＦＰ−ＣＶＤ
包接化合物は、ＦＰ単独よりも消化管における吸収性が
向上しているが、未だ不十分であり、その改善が望まれ
ていた。Although the clathrate compound of FP and cyclodextrin obtained by these methods (hereinafter referred to as FP-CVD clathrate compound) has improved solubility compared to FP, it is still insufficient and needs improvement. was desired. Furthermore, when these FP-CVD clathrate compounds were orally administered to rats, the serum concentration of FP was higher than when FP was administered alone, and the area under the serum concentration-time curve (AUG) was also higher. ,
FP-CVD was larger when the FP-CVD clathrate compound was administered than when FP was administered alone.
Although clathrate compounds have better absorbability in the gastrointestinal tract than FP alone, it is still insufficient, and improvements have been desired.
そこで、上述のＦＰ−ＣＶＤ包接化合物の溶解性や消化
管における吸収性等を更に向上させたものとして、ＦＰ
とへブタキス（２，３，６−トリー０−メチル）−β−
シクロデキストリン（以下、ＴＭ−β−ＣＶＤと称す）
との包接化合物を用いた製剤（特開昭５９−４６２２８
号公報）や、ＦＰとへブタキス（２，６−ジー０−メチ
ル）−β−シクロデキストリン（以下、ＤＭ−β−ＣＶ
Ｄと称す）との包接化合物を用いた製剤（Ｊ 、 Ｐｈ
ａｒｍ。Therefore, as a product that further improves the solubility and absorbability in the gastrointestinal tract of the above-mentioned FP-CVD clathrate compound,
tohebutakis(2,3,6-tri-0-methyl)-β-
Cyclodextrin (hereinafter referred to as TM-β-CVD)
Preparation using clathrate compound with (JP-A-59-46228
Publication), FP and hebutakis(2,6-di-0-methyl)-β-cyclodextrin (hereinafter referred to as DM-β-CV
Formulation using a clathrate compound with D (referred to as J, Ph
arm.
Ｓｃ１．７４（８）：８４１（１９８５））がある。Sc1.74(8):841 (1985)).
［発明が解決しようとする課題］
しかしながら、ＴＭ−β−Ｃ３／Ｄ、ＤＭ−β−ＣＶＤ
等のメチル化−β−ＣＶＤの、刺激性等の安全性の指標
となる赤血球に対する溶血活性は、天然のＣｙＤである
α−ＣＹＤ、β−ＣＶＤおよびγ−ＣｙＤに比べて高い
。さらに、家兎大腿外側広筋内注射による局所組織障害
性については、比較的低濃度の天然ＣｙＤは障害性を示
さないのに対して、メチル化−β−ＣＶＤでは障害が認
められている（今井輝子他、薬物動態、 ２（６）ニア
３−８０（１９８７））。[Problem to be solved by the invention] However, TM-β-C3/D, DM-β-CVD
The hemolytic activity of methylated-β-CVD against red blood cells, which is an indicator of safety such as stimulation, is higher than that of natural CyDs α-CYD, β-CVD, and γ-CyD. Furthermore, regarding local tissue damage caused by intravasus lateralis thigh muscle injection in rabbits, relatively low concentrations of natural CyD do not show any damage, whereas methylated-β-CVD does ( Teruko Imai et al., Pharmacokinetics, 2(6) Near 3-80 (1987)).
したがって本発明の目的は、溶解性および吸収性に優れ
、かつ刺激性のより少ないＦＰ包接化合物およびこのＦ
Ｐ包接化合物を有効成分とする消炎鎮痛剤を提供するこ
とにある。Therefore, it is an object of the present invention to provide an FP clathrate compound that has excellent solubility and absorbability and is less irritating, and
An object of the present invention is to provide an anti-inflammatory analgesic agent containing a P-clathrate compound as an active ingredient.
［課題を解決するための手段］
本発明は上記目的を達成するためになされたものであり
、本発明は、フルルビプロフェン（Ｆ Ｐ）を、平均数
で２〜１０のヒドロキシプロピル基を有するヒドロキシ
プロピル−β−シクロデキストリンで包接してなり、前
記フルルビプロフェン（ＦＰ）１モルに対する前記ヒド
ロキシプロピル−β−シクロデキストリンの量が１〜２
．５モルであることを特徴とする、フルルビプロフェン
（Ｆ Ｐ）のヒドロキシプロピル−β−シクロデキスト
リン包接化合物を要旨とするものである。[Means for Solving the Problems] The present invention was made to achieve the above object, and the present invention provides flurbiprofen (FP) with an average number of 2 to 10 hydroxypropyl groups. hydroxypropyl-β-cyclodextrin containing hydroxypropyl-β-cyclodextrin, and the amount of the hydroxypropyl-β-cyclodextrin per 1 mole of flurbiprofen (FP) is 1 to 2.
．． The subject matter is a hydroxypropyl-β-cyclodextrin clathrate of flurbiprofen (FP), characterized by a 5 mol.
また本発明は、前記のフルルビプロフェン（ＦＰ）のヒ
ドロキシプロピル−β−シクロデキストリン包接化合物
を有効成分とすることを特徴とする消炎鎮痛剤を要旨と
するものでもある。The gist of the present invention is also an anti-inflammatory analgesic agent characterized by containing the above-mentioned hydroxypropyl-β-cyclodextrin clathrate compound of flurbiprofen (FP) as an active ingredient.
本発明においてＦＰを包接するために用いられる、ヒド
ロキシプロピル−β−シクロデキストリン（以下、ＨＰ
−β−ＣＶＤと称す）は、アルカリ存在下でβ−ＣＶＤ
とプロピレンオキサイドとを反応させる方法等により、
β−ＣＶＤの水酸基にヒドロキシプロピル基を導入する
ことにより得ることができる。Hydroxypropyl-β-cyclodextrin (hereinafter referred to as HP) used for inclusion of FP in the present invention
-β-CVD) is β-CVD in the presence of alkali.
By a method of reacting with propylene oxide, etc.
It can be obtained by introducing a hydroxypropyl group into the hydroxyl group of β-CVD.
得られたＨＰ−β−ＣＶＤは、平均数で２〜１０のヒド
ロキシプロピル基を含有するものに限定される。その理
由は、ヒドロキシプロピル基の平均数が２未満または１
０を超えると、溶解性が低くなるからである。特に好ま
しいヒドロキシプロピル基の平均数は、４〜８である。The resulting HP-β-CVD is limited to containing an average number of 2 to 10 hydroxypropyl groups. The reason is that the average number of hydroxypropyl groups is less than 2 or 1.
This is because when it exceeds 0, solubility becomes low. A particularly preferred average number of hydroxypropyl groups is 4-8.
ヒドロキシプロピル基の数の調整は、プロピレンオキサ
イドのβ−ＣＶＤに対する添加量を変えることにより行
うことができる。The number of hydroxypropyl groups can be adjusted by changing the amount of propylene oxide added to β-CVD.
このようにして得られたＨＰ−β−ＣＶＤの溶血活性は
、メチル化−７ｓ＝ｃｙＤの溶血活性より低く、さらに
β−ＣＶＤの溶血活性より低い。また、マウスに対する
毒性試験の結果、高用量経口投与した場合でも毒性は検
出されていない。The hemolytic activity of HP-β-CVD thus obtained is lower than that of methylated-7s=cyD, and further lower than that of β-CVD. Furthermore, as a result of toxicity tests on mice, no toxicity was detected even when high doses were administered orally.
本発明のＦＰ−（ＨＰ−β−ＣＶＤ）包接化合物は、水
溶液法あるいは混線法により、ＦＰをＨＰ−β−ＣＶＤ
で包接することにより得ることができる。The FP-(HP-β-CVD) clathrate compound of the present invention can be prepared by converting FP to HP-β-CVD by an aqueous solution method or crosstalk method.
It can be obtained by inclusion with .
水溶液法では、まずＨＰ−β−ＣｙＤを水に溶解させ、
予め算出した包接モル比よりも過剰量のＦＰを加えて、
液温を室温〜６０℃、好ましくは２０〜４０℃とし、８
時間〜５日間撹拌する。この後、過剰のＦＰを濾取し、
濾液を凍結乾燥法、スプレードライ法等により乾燥する
ことにより、ＦＰ−（ＨＰ−β−ＣｙＤ）包接化合物を
得ることができる。In the aqueous solution method, HP-β-CyD is first dissolved in water,
Adding an excess amount of FP than the pre-calculated clathrate molar ratio,
The liquid temperature is room temperature to 60°C, preferably 20 to 40°C, and 8
Stir for hours to 5 days. After this, excess FP is filtered off,
The FP-(HP-β-CyD) clathrate compound can be obtained by drying the filtrate by a freeze-drying method, a spray-drying method, or the like.
なお、水溶液法においては、ＨＰ−β−ＣＹＤとＦＰと
を同時に水に溶解させてもよい。In addition, in the aqueous solution method, HP-β-CYD and FP may be dissolved in water at the same time.
混練法では、予め算出した包接モル比のＦＰおよびＨＰ
−β−ＣｙＤを混和し、次に少量の水、好ましくはＦＰ
およびＨＰ−β−ＣｙＤの総量の０．１〜３倍量の水を
加え、１０〜４０℃、好ましくは２０〜３０℃で１〜８
時間、好ましくは２〜３時間、ペースト状になるまで十
分に練合する。In the kneading method, the inclusion molar ratio of FP and HP is calculated in advance.
- mix β-CyD, then add a small amount of water, preferably FP
Add 0.1 to 3 times the amount of water to the total amount of HP-β-CyD, and heat to 1 to 40°C, preferably 20 to 30°C.
Thoroughly knead for an hour, preferably 2 to 3 hours, until it becomes a paste.
この後、通気あるいは減圧乾燥等により乾燥することに
より、ＦＰ−（ＨＰ−β−ＣＹＤ）包接化合物を得るこ
とができる。Thereafter, the FP-(HP-β-CYD) clathrate compound can be obtained by drying by aeration or vacuum drying.
水溶液法または混練法で得られたＦＰ−（ＨＰ−β−Ｃ
ｙＤ）包接化合物において、ＦＰ １モルニ対ｔ ル
ＨＰ −７３−Ｃｙ Ｄ Ｏ’）ｊＪハ、１〜２．５モ
ルに限定される。その理由は、ＦＰ １モルに対する
ＨＰ−β−ＣｙＤの量が１モル未満であると、包接が不
十分となり未包接のＦＰが混在して刺激性が残るため好
ましくな（、一方、２．５モルを超えると、非包接のＨ
Ｐ−β−ＣｙＤが混在してカサ高検、経済性の点で不利
となるため好ましくないからである。ＦＰ １モルに
対するＨＰ−β−ＣｙＤの量は、１．８〜２．３モルで
あることが特に好ましい。最も好ましいＨＰ−β−Ｃｙ
Ｄの命は、ＦＰ １モルに対して２．０モルである。FP-(HP-β-C obtained by aqueous solution method or kneading method)
yD) In the clathrate compound, 1 mol of FP to 1 mol of HP-73-CyDO')jJ is limited to 1 to 2.5 mol. The reason for this is that if the amount of HP-β-CyD per mole of FP is less than 1 mole, inclusion will be insufficient and uninclusion of FP will be mixed in, resulting in irritation, which is undesirable (on the other hand, If it exceeds .5 mol, non-inclusion H
This is because P-β-CyD is mixed, which is disadvantageous in terms of bulkiness and economical efficiency, which is not preferable. It is particularly preferable that the amount of HP-β-CyD per mol of FP is 1.8 to 2.3 mol. Most preferred HP-β-Cy
The life of D is 2.0 mol per 1 mol of FP.
このようにして得られたＦＰ−（ＨＰ−β−ＣｙＤ）包
接化合物は、水に対する溶解度が高く、吸収性に優れ、
刺激性はほとんど認められない。The FP-(HP-β-CyD) clathrate compound thus obtained has high solubility in water, excellent absorbency,
Almost no irritation is observed.
本発明のＦＰ−（ＨＰ−β−ｃｙＤ）包接化合物を有効
成分とする消炎鎮痛剤は、ＦＰ−（ＨＰ−β−ＣＹＤ）
包接化合物の上記特性を利用して、粉末剤、細粒剤、シ
ロップ剤、カプセル剤および錠剤等の経口投与剤の他、
舌下投与剤、直腸投与剤、経皮吸収製剤、注射剤等の投
与剤型をとることができる。The anti-inflammatory analgesic agent containing the FP-(HP-β-cyD) clathrate compound of the present invention as an active ingredient includes FP-(HP-β-CYD)
Utilizing the above properties of clathrate compounds, in addition to oral preparations such as powders, fine granules, syrups, capsules, and tablets,
Dosage forms such as sublingual preparations, rectal preparations, transdermal absorption preparations, and injections can be taken.
粉末剤、細粒剤、カプセル剤あるいは錠剤を調製する場
合には、ＦＰ−（ＨＰ−β−ＣｙＤ）包接化合物をその
まま、または賦形剤、結合剤、崩壊剤もしくはその他の
適当な添加剤を加えて均等に混和したものを適当な方法
で粉末または粒状として、粉末剤、細粒剤を得る。また
同様の方法により得た粉末、粒状物または単なる混和物
をカプセルに充填し、カプセル剤とする。また圧縮成形
することにより錠剤とする。When preparing powders, fine granules, capsules, or tablets, the FP-(HP-β-CyD) clathrate compound may be used as is or with excipients, binders, disintegrants, or other suitable additives. The mixture is evenly mixed and turned into powder or granules using an appropriate method to obtain powders or fine granules. In addition, a powder, granule, or simple mixture obtained by a similar method is filled into capsules to prepare a capsule. It can also be made into tablets by compression molding.
シロップ剤を調製する場合には、白糖等の糖類もしくは
甘味剤の溶液または単シロップにＦＰ−（ＨＰ−β−Ｃ
ｙＤ）包接化合物を加えて溶解、混和または懸濁する。When preparing a syrup, FP-(HP-β-C
yD) Add the clathrate and dissolve, mix or suspend.
粉末剤あるいは細粒剤と同様の方法でドライシロップを
得ることもできる。Dry syrups can also be obtained in the same manner as powders or granules.
基剤には、芳香剤、着色剤、保存剤、安定剤、懸濁化剤
、乳化剤、粘稠剤等を加えることもできる。Flavoring agents, coloring agents, preservatives, stabilizers, suspending agents, emulsifying agents, thickening agents, etc. can also be added to the base.
舌下投与剤を調製する場合には、ＦＰ−（ＨＰ−β−Ｃ
ｙＤ）包接化合物をそのまま、または賦形剤、結合剤も
しくはその他の適当な添加剤を加えて均等に混和したも
のを、顆粒状にし、滑沢剤等を加えて圧縮成形する。あ
るいは、均等に混和したものを顆粒状とせずに直接圧縮
成形する。When preparing sublingual preparations, FP-(HP-β-C
yD) The clathrate compound as it is, or an excipient, a binder or other suitable additives added thereto and mixed uniformly, is made into granules, and a lubricant etc. are added thereto, followed by compression molding. Alternatively, the homogeneously mixed mixture is directly compression molded without being made into granules.
直腸投与剤を調製する場合には、油脂性基剤、水溶性基
剤またはその他の適当な物質を基剤とし、必要に応じて
乳化剤、懸濁化剤等を加え、これにＦＰ−（ＨＰ−β−
ＣｙＤ）包接化合物を加え、混和して均等にした後、適
当な形状とする。When preparing a preparation for rectal administration, use an oil-based base, a water-soluble base, or other suitable substance as a base, add emulsifiers, suspending agents, etc. as necessary, and add FP-(HP −β−
Add the CyD) clathrate compound, mix to make it homogeneous, and then give it a suitable shape.
経皮吸収製剤を調製する場合には、ＦＰ−（ＨＰ−β−
ＣｙＤ）包接化合物に、脂肪、プラスチック、グリコー
ル類、高級アルコール、グリセリン、水、乳化剤、懸濁
化剤もしくはその他の適当な添加剤を原料または基剤と
して加え、混和して金賞を均等にする。あるいは、布、
高分子フィルム、不織布等よりなる支持体の上に下引剤
を塗布し、その上に、ゴム系粘着剤またはアクリル系粘
着剤等とＦＰ−（ＨＰ−β−ＣＹＤ）包接化合物および
その他の適当な添加剤とを混和したものを展延し、その
上をポリエチレンフィルム等により被覆する。When preparing transdermal absorption preparations, FP-(HP-β-
CyD) Add fats, plastics, glycols, higher alcohols, glycerin, water, emulsifiers, suspending agents or other suitable additives as raw materials or bases to the clathrate compound and mix to equalize the gold medal. . Or cloth,
A subbing agent is applied onto a support made of a polymer film, non-woven fabric, etc., and a rubber adhesive or acrylic adhesive, etc., and a FP-(HP-β-CYD) clathrate compound and other A mixture of appropriate additives is spread, and then covered with a polyethylene film or the like.
注射剤を調製する場合には、ＦＰ−（ＨＰ−β−ＣｙＤ
）包接化合物の一定量を溶剤に溶解して一定容量とする
か、この溶液を凍結乾燥し、用時溶解して用いる。また
は、ＦＰ−（ＨＰ−β−ＣｙＤ）包接化合物の一定量を
とり、注射剤用の容器に密封し、用時溶解する。When preparing an injection, FP-(HP-β-CyD
) Dissolve a certain amount of the clathrate compound in a solvent to make a certain volume, or freeze-dry this solution and dissolve it before use. Alternatively, a certain amount of the FP-(HP-β-CyD) clathrate is taken, sealed in an injection container, and dissolved before use.
本発明のＦＰ−（ＨＰ−β−ＣｙＤ）包接化合物を有効
成分とする消炎鎮痛剤の投与量は、病気の種類、病状の
程度、罹患者の年齢、健康状態、投与剤型等により異な
るため特定することはできないが、成人の場合、ＦＰの
量で概ね１０〜８０ｍｇ／回の割合で投与することによ
り、所望の効果を得ることができる。The dosage of the anti-inflammatory and analgesic agent containing the FP-(HP-β-CyD) clathrate compound of the present invention as an active ingredient varies depending on the type of disease, the severity of the condition, the age and health condition of the patient, the dosage form, etc. For adults, the desired effect can be obtained by administering FP at a rate of approximately 10 to 80 mg/dose, although it cannot be specified.
［実施例］ 以下、本発明の詳細な説明する。[Example] The present invention will be explained in detail below.
実施例１（包接化合物の製造例）
ヒドロキシプロピル基の平均数が６．２であるＨＰ−β
−ＣｙＤ ３０ｇ （２０，１ｍｍｏりとＦＰ ３
． ０ｇ （１２，３ｍｍｏｌ）とを精製水１００ｍ１
に加え、２０〜２５℃で５日間撹拌した後、孔径０．４
５μｍのメンブランフィルタ−で濾過し、濾液を凍結乾
燥して調製物を得た。Example 1 (Production example of clathrate compound) HP-β having an average number of hydroxypropyl groups of 6.2
-CyD 30g (20.1mm and FP 3
．． 0g (12.3mmol) and 100ml of purified water
After stirring at 20-25℃ for 5 days, the pore size was 0.4.
The mixture was filtered through a 5 μm membrane filter, and the filtrate was freeze-dried to obtain a preparation.
このようにして得られた調製物中のＦＰとＨＰ−β−Ｃ
ｙＤとの割合を吸光度法により測定したところ、ＦＰ
１モルに対してＨＰ−β−ＣｙＤが１．９モルであっ
た。FP and HP-β-C in the preparation thus obtained
When the ratio with yD was measured by absorbance method, it was found that FP
HP-β-CyD was 1.9 mol per 1 mol.
また、本調製物の粉末Ｘ線回折、赤外線吸収スペクトル
、示差走査熱量測定の結果、本調製物は包接化合物であ
ることが確認された。この粉末Ｘ線回折の結果を第１図
（ａ）に、赤外線吸収スペクトルを第２図（ａ）に、示
差走査熱量測定の結果を第３図（ａ）にそれぞれ示す。Further, as a result of powder X-ray diffraction, infrared absorption spectrum, and differential scanning calorimetry of this preparation, it was confirmed that this preparation is an clathrate compound. The results of this powder X-ray diffraction are shown in FIG. 1(a), the infrared absorption spectrum is shown in FIG. 2(a), and the result of differential scanning calorimetry is shown in FIG. 3(a).
なお参考として、ＦＰＳＨＰ−β−ＣｙＤについての粉
末Ｘ線回折の結果を第１図（ｂ）、（Ｃ）に、赤外線吸
収スペクトルを第２図（ｂ）、（Ｃ）に、示差走査熱量
測定の結果を第３図（ｂ）、（Ｃ）に、それぞれ示し、
ＦＰとＨＰ−β−ＣＹＤとの物理的混合物の示差走査熱
量測定の結果を第３図（ｄ）に示す。For reference, the powder X-ray diffraction results for FPSHP-β-CyD are shown in Figures 1 (b) and (C), the infrared absorption spectrum is shown in Figures 2 (b) and (C), and the differential scanning calorimetry results are shown in Figures 2 (b) and (C). The results are shown in Figures 3(b) and (C), respectively.
The results of differential scanning calorimetry of the physical mixture of FP and HP-β-CYD are shown in FIG. 3(d).
実施例２．３（包接化合物の製造例）
ヒドロキシプロピル基の平均数が４．３であるＨＰ−β
−ｃｙｐ （実施例２）およびヒドロキシプロピル基の
平均数が７．４であるＨＰ−β−ＣｙＤ（実施例３）を
用いた以外は実施例１と同様にして、ＦＰ １モルに
対するＨＰ−β−ＣｙＤの量が２．３モルである包接化
合物（実施例２）および２．１モルである包接化合物（
実施例３）を得た。Example 2.3 (Production example of clathrate compound) HP-β having an average number of hydroxypropyl groups of 4.3
-cyp (Example 2) and HP-β-CyD with an average number of hydroxypropyl groups of 7.4 (Example 3) were used in the same manner as in Example 1. The clathrate in which the amount of -CyD is 2.3 mol (Example 2) and the clathrate in which the amount of -CyD is 2.1 mol (
Example 3) was obtained.
包接化合物の溶解度試験
実施例１〜３で得られたＦＰ−（ＨＰ−β−ＣｙＤ）包
接化合物の水（２５℃）に対する溶解度を測定したとこ
ろ、ＦＰの溶解度に換算した値で、４５０００〜５５０
００．ｃｚｇ／ｍｌという高い値が得られ、いずれの実
施例で得られたＦＰ−（ＨＰ−β−ＣｙＤ）包接化合物
も、水溶性に優れていることが確認された。Solubility test of clathrate compounds When the solubility of the FP-(HP-β-CyD) clathrate compounds obtained in Examples 1 to 3 in water (25°C) was measured, the value converted to the solubility of FP was 45,000. ~550
00. A high value of czg/ml was obtained, and it was confirmed that the FP-(HP-β-CyD) clathrate compounds obtained in all Examples had excellent water solubility.
なお、比較のため、ＦＰ−（α−ＣｙＤ）包接化合物、
ＦＰ−（β−ＣｙＤ）包接化合物、ＦＰ−（γ−ＣｙＤ
）包接化合物およびＦＰ単独の水（２５℃）に対する溶
解度を測定したところ、ＦＰの溶解度に換算した値で、
１０〜７５０μｇ／ｍｌであり、実施例１〜３の各ＦＰ
−（ＨＰ−β−ＣｙＤ）包接化合物の水（２５°Ｃ）に
対する溶解度に比べて著しく低い値であった。For comparison, FP-(α-CyD) clathrate compound,
FP-(β-CyD) inclusion compound, FP-(γ-CyD
) When the solubility of the clathrate compound and FP alone in water (25°C) was measured, the value converted to the solubility of FP was,
10 to 750 μg/ml, and each FP of Examples 1 to 3
This value was significantly lower than the solubility of the -(HP-β-CyD) clathrate in water (25°C).
これらの測定結果を表−１に示す。The results of these measurements are shown in Table-1.
（以下、余白） 均数を表す。(Hereafter, margin) Represents an even number.
実施例４（錠剤の製剤例）
実施例１て得られた、ヒドロキンプロピル基の平均数が
６．２のＨＰ−β−ＣｙＤを用いたＦＰ（ＨＰ−β−Ｃ
ＹＤ）包接化合物［以下、ＦＰ−（ＨＰ−β−ＣｙＤ）
（６，２）と称す］を打錠して、１錠（２５５ｍｇ）中
にＦＰを２０ｍｇ含有するＦＰ−（ＨＰ−β−ＣｙＤ）
（６，２）錠剤を得た。Example 4 (Example of tablet formulation) FP (HP-β-C
YD) clathrate compound [hereinafter referred to as FP-(HP-β-CyD)
FP-(HP-β-CyD) containing 20 mg of FP in one tablet (255 mg)
(6,2) Tablets were obtained.
錠剤の溶出試験
実施例４で得られた錠剤の溶出試、験を、日周溶出試験
法のパドル法に基づき、試験液として日局第１液（ｐ
Ｈ１，２）および日局第２液（ｐＨ６゜８）を用いて、
試、験液量９００ｍ１．パドル回転数１１００ｒｐで行
った。この結果を第４図（ｐＨ１゜２）および第５図（
ｐＨ６，８）に示す。Tablet dissolution test The tablet dissolution test obtained in Example 4 was conducted based on the paddle method of the diurnal dissolution test method, using Japanese Pharmacopoeia No. 1 liquid (p
H1, 2) and Japanese Pharmacopoeia No. 2 solution (pH 6°8),
Test, test liquid volume 900ml1. The paddle rotation speed was 1100 rpm. The results are shown in Figure 4 (pH 1°2) and Figure 5 (
pH 6,8).
なお、比較のため、１錠（１１８ｍｇ）中にＦＰを２０
ｍｇ含有するＦＰ−（β−ＣｙＤ）錠剤、１錠（１３３
ｍｇ）中にＦＰを２０ｍｇ含有するＦＰ−（ＤＭ−β−
ＣｙＤ）錠剤および２０ｍｇのＦＰと４８ｍｇの結晶セ
ルロースと５２ｍｇの乳糖とからなるＦＰ錠剤の溶出試
験を同様にして行った。この結果も第４図（、ｐＨ１，
２）および第５図（ｐＨ６，８）に示す。For comparison, one tablet (118 mg) contains 20 FP.
FP-(β-CyD) tablet containing mg (133
FP-(DM-β-) containing 20 mg of FP in
CyD) tablets and FP tablets consisting of 20 mg of FP, 48 mg of crystalline cellulose, and 52 mg of lactose were similarly subjected to dissolution tests. This result is also shown in Figure 4 (, pH 1,
2) and Figure 5 (pH 6, 8).
第４図および第５図から明らかなように、実施例４で得
られたＦＰ−（ＨＰ−β−Ｃｙ Ｄ） （６゜２）錠
剤の溶出速度は、比較のためのＦＰ−（β−ＣｙＤ）錠
剤、ＦＰ−（ＤＭ−β−ＣｙＤ）錠剤およびＦＰ錠剤よ
り極めて速く、かつｐＨ依存性を示さなかった。As is clear from FIGS. 4 and 5, the dissolution rate of the FP-(HP-β-Cy D) (6°2) tablet obtained in Example 4 was higher than that of the FP-(β-Cy D) (6°2) tablet obtained in Example 4. CyD) tablets, FP-(DM-β-CyD) tablets, and FP tablets were significantly faster and did not show pH dependence.
錠剤の血漿中濃度推移試験
実施例４で得られたＦＰ−（ＨＰ−β−ＣｙＤ）（６，
２）錠剤２錠を、ヒトに舌下投与および経口投与して、
ＦＰの血漿中濃度の時間的推移を測定した。この結果を
第６図に示す。FP-(HP-β-CyD) (6,
2) Two tablets were administered sublingually and orally to humans,
The time course of the plasma concentration of FP was measured. The results are shown in FIG.
なお、比較の１こめ、２０ｍｇのＦＰと４８ｍｇの結晶
セルロースと５２ｍｇの乳糖とからなるＦＰ錠剤２錠を
ヒトに舌下投与および経口投与した場合の、ＦＰの血漿
中濃度の時間的推移も測定した。この結果も第６図に示
す。For comparison, we also measured the time course of the plasma concentration of FP when two FP tablets consisting of 20 mg of FP, 48 mg of crystalline cellulose, and 52 mg of lactose were administered sublingually and orally to humans. did. The results are also shown in FIG.
第６図から明らかなように、実施例４で得られたＦＰ−
（ＨＰ−β−ＣｙＤ）（６，２）錠剤投与後のＦＰの血
漿中濃度の時間的推移は、比較のためのＦＰ錠剤投与後
のＦＰの血漿中濃度の時間的推移に比べて、最高血漿中
濃度に到達するに必要な時間Ｔｍａｘが短く、かつ最高
血漿中濃度も高い。このことから、ＦＰ−（ＨＰ−β−
ＣＹＤ）（６，２）錠剤は、舌下投与の場合および経口
投与の場合ともに、ＦＰ錠剤よりも消化管における吸収
性に優れていることが確認された。As is clear from FIG. 6, the FP-
(HP-β-CyD) (6,2) The time course of the plasma concentration of FP after administration of the tablet was the highest compared to the time course of the plasma concentration of FP after administration of the FP tablet for comparison. The time Tmax required to reach the plasma concentration is short, and the maximum plasma concentration is also high. From this, FP-(HP-β-
It was confirmed that the CYD) (6,2) tablet had better absorption in the gastrointestinal tract than the FP tablet both when administered sublingually and when administered orally.
また、ＦＰ−（ＨＰ−β−ＣｙＤ）（６，２）錠剤の舌
下投与および経口投与に際しては、刺激性および苦みは
全く認められなかったが、ＦＰ錠剤の舌下投与および経
口投与に際しては、口腔粘膜に対する刺激性および苦み
が認められた。In addition, no irritation or bitterness was observed when FP-(HP-β-CyD)(6,2) tablets were administered sublingually or orally; however, when FP tablets were administered sublingually or orally, , irritation to oral mucosa and bitter taste were observed.
実施例５（半割の製剤例）
実施例１で得られたＦＰ−（ＨＰ−β−ＣｙＤ）（６，
２）２５５ｍｇと、基剤として適量のウイテプゾール
Ｈ−５を用い、両者を６０°Ｃの加温下で十分に撹拌し
た後、プラスチックのモールドに流し、室温まで冷却し
て、１坐剤（２０００ｍｇ）中にＦＰを２０ｍｇ含有す
るＦＰ−（ＨＰ−β−ＣＶＤ） （６，２）半割を調
製した。Example 5 (Half formulation example) FP-(HP-β-CyD) (6,
2) 255mg and appropriate amount of Witepsol as base
Using H-5, both were sufficiently stirred under heating at 60°C, poured into a plastic mold, cooled to room temperature, and FP-(1 suppository (2000 mg) containing 20 mg of FP) was prepared. HP-β-CVD) (6,2) half was prepared.
半割の放出試験
実施例５で得られた半割の放出試験を、日周溶出試験法
のパドル法に基づき、試験液としてｐＨ７，４のリン酸
緩衝液５００ｍ１を用い、パドル回転数１０ Ｏｒｐｍ
で行った。この結果を第７図に示す。Half-split release test The half-split release test obtained in Example 5 was conducted based on the paddle method of the diurnal dissolution test method, using 500 ml of a phosphate buffer solution with a pH of 7.4 as the test solution, and using a paddle rotation speed of 10 Orpm.
I went there. The results are shown in FIG.
また、比較のため、１１８ｍｇのＦＰ−（β−ＣＶＤ）
と適量のウイテプゾール Ｈ−５とからなり１坐剤（２
０００ｍｇ）中にＦＰを２０ｍｇ含有するＦＰ−（β−
ＣＶＤ）半割、１３３ｍｇのＦＰ−（ＤＭ−β−ＣＶＤ
）と適量のウイテプゾールＨ−５とからなり１坐剤（２
０００ｍｇ）中にＦＰを２０■含有するＦＰ−（ＤＭ−
β−ＣＶＤ）半割、ＦＰと適量のウイテプゾール Ｈ−
５とからなり１坐剤（２０００ｍｇ）中にＦＰを２０ｍ
ｇ含有するＦＰ坐半割放出試験も同様にして行った。こ
の結果も第７図に示す。For comparison, 118 mg of FP-(β-CVD)
and an appropriate amount of Witepsol H-5, 1 suppository (2
FP-(β-
CVD) in half, 133 mg of FP-(DM-β-CVD
) and an appropriate amount of Witepsol H-5.
FP-(DM-) containing 20μ of FP in 000mg)
β-CVD) halved, FP and appropriate amount of Witepsol H-
5 and 20m of FP in 1 suppository (2000mg)
A FP seat half-split release test containing g was conducted in the same manner. This result is also shown in FIG.
第７図から明らかなように、実施例５で得られたＦＰ−
（ＨＰ−β−ＣＶＤ）（６，２）半割の放出速度は、比
較のためのＦＰ−（β−ＣＶＤ）半割、ＦＰ−（ＤＭ−
β−ＣＶＤ）半割およびＦＰの放出速度に比べて速かっ
た。As is clear from FIG. 7, the FP-
The release rate of (HP-β-CVD) (6,2) half is the same as that of FP-(β-CVD) half and FP-(DM-
The release rate was faster than that of β-CVD) and FP.
半割の局所刺激性試験
実施例５で得られた、ＦＰ １モルに対する（ＨＰ−
β−ＣＶＤ）（６，２）の量が１．９モルであるＦＰ−
（ＨＰ−β−ＣＶＤ）（６，２）半割を直腸に投与して
、局所刺激性試験を行った。(HP-
FP- in which the amount of β-CVD) (6,2) is 1.9 mol
A local irritation test was conducted by administering half of (HP-β-CVD) (6,2) into the rectum.
この試験結果を表−２に示す。The test results are shown in Table-2.
なお、比較のため、ＦＰ １モルに対する（ＨＰ−β
−ＣＶＤ）（６，２）の量が本発明の範囲外の０．８モ
ルであるＦＰ−（ＨＰ−β−ＣＶＤ）（６，２）包接化
合物を調製し、その１１９ｍｇと適量のウイテプゾール
Ｈ−５を用い、両者を６０℃の加温下で十分に撹拌し
た後、プラスチックのモールドに流し、室温まで冷却し
て、１坐剤（２０００ｍｇ）中にＦＰを２０ｍｇ含有す
る、比較のためのＦＰ−（ＨＰ−β−ＣＶＤ）（６，２
）半割を調製し、この半割の局所刺激性試験を同様にし
て行った。さらに、ＦＰと適量のウイテブゾール Ｈ−
５とからなり１坐剤（２０００ｍｇ）中にＦＰを２０ｍ
ｇ含有するＦＰ坐半割局所刺激性試験も同様にして行っ
た。これらの試験結果も表−２に示す。For comparison, (HP-β
A FP-(HP-β-CVD)(6,2) clathrate in which the amount of -CVD)(6,2) is 0.8 mol, which is outside the range of the present invention, was prepared, and 119 mg thereof and an appropriate amount of Witepsol were prepared. Using H-5, both were thoroughly stirred under heating at 60°C, then poured into a plastic mold and cooled to room temperature. For comparison, 1 suppository (2000 mg) contained 20 mg of FP. FP-(HP-β-CVD)(6,2
) A half cut was prepared, and a local irritation test on this half was conducted in the same manner. Furthermore, FP and an appropriate amount of Uitebuzol H-
5 and 20m of FP in 1 suppository (2000mg)
A local irritation test using a half-split FP seat containing g was conducted in the same manner. The results of these tests are also shown in Table-2.
表−２から明らかなように、実施例５のＦＰ−（ＨＰ−
β−ＣＶＤ）（６，２）半割には局所刺激性がほとんど
認められなかったが、比較のためのＦＰ−（ＨＰ−β−
ＣＶＤ）（６，２）半割およびＦＰ坐半割は、強い局所
刺激性が認められた。As is clear from Table 2, FP-(HP-
Almost no local irritation was observed in half of β-CVD) (6,2), but for comparison, FP-(HP-β-
CVD) (6,2) half-split and FP sitting half-split were found to have strong local irritation.
（以下、余白） （６，２）を１．９モル含有する。(Hereafter, margin) Contains 1.9 mol of (6,2).
＊２：この半割はＦＰ １モルに対して（ＨＰ−β−
ＣＶＤ）（６゜２）を０．８モル含有する。*2: This half is calculated based on 1 mole of FP (HP-β-
Contains 0.8 mol of CVD) (6°2).
＊３−：全く感じない。*3-: I don't feel it at all.
±：僅かに感じる。±: Slightly felt.
＋：少し感じる。+: I feel it a little.
＋＋：中程度感じる。++: Feels moderate.
＋＋＋：強く感じる。+++: I feel it strongly.
実施例６（注射剤の製剤例）
実施例３で得られた、ヒドロキシプロピル基の平均数が
７．４であるＨＰ−β−ＣＶＤを用いたＦＰ−（ＨＰ−
β−ＣＶＤ）包接化合物５．７８０ｇを、注射用蒸留水
１００ｍ１に溶解させ、除菌用フィルターで濾過した後
、バイアルに各１０ｍ１充填し、これを凍結乾燥して、
ＦＰを４０ｍｇ含有する用時溶解型注射剤を得た。Example 6 (Formulation example of injection) FP-(HP-
5.780 g of β-CVD) clathrate compound was dissolved in 100 ml of distilled water for injection, filtered through a sterilization filter, and filled into 10 ml each vial, which was freeze-dried.
A ready-to-use injection containing 40 mg of FP was obtained.
［発明の効果］
以上説明したように、本発明のフルルビプロフェンのヒ
ドロキシプロピル−β−シクロデキストリン包接化合物
は、溶解性に優れているとともに、吸収性にも優れ、か
つ刺激性はほとんど認められない。[Effects of the Invention] As explained above, the hydroxypropyl-β-cyclodextrin clathrate of flurbiprofen of the present invention has excellent solubility and absorbability, and has almost no irritation. unacceptable.
したがって、吸収速度が速く、吸収性に優れ、かつ安全
性に優れた消炎鎮痛剤を得ることが可能となる。Therefore, it is possible to obtain an anti-inflammatory analgesic agent that has a fast absorption rate, excellent absorbability, and excellent safety.
第１図は、実施例１で得られたＦＰ−（ＨＰ−β−ＣＶ
Ｄ）包接化合物等の粉末Ｘ線回折の結果を表すり゛ラフ
、第２図は、実施例１て得られたＦＰ−（ＨＰ−β−Ｃ
ＶＤ）包接化合物等の赤外線吸収スペクトルを表すグラ
フ、第３図は、実施例１で得られたＦＰ−（ＨＰ−β−
ＣｙＤ）包接化合物等の示差走査熱量測定の結果を表す
グラフ、第４図は、実施例４で得られたＦＰ−（ＨＰ−
β−ＣｙＤ）（６，２）錠剤等の、ｐＨ１，２における
溶出試、験を表すグラフ、第５図は、実施例４で得られ
たＦＰ−（ＨＰ−β−ＣｙＤ）（６，２）錠剤等の、ｐ
Ｈ６，８における溶出試験を表すグラフ、第６図は、実
施例４て得られたＦＰ−（ＨＰ−β−ＣｙＤ）（６，２
）錠剤等をヒトに舌下投与および経口投与した場合のＦ
Ｐの血漿中濃度の時間的推移の測定結果を表すグラフ、
第７図は、実施例５で得られたＦＰ−（ＨＰ−β−ＣＶ
Ｄ）（６，２）半割等の放出試、験結果を表すグラフで
ある。FIG. 1 shows the FP-(HP-β-CV obtained in Example 1).
D) Figure 2 shows the results of powder X-ray diffraction of clathrate compounds, etc.
VD) A graph showing the infrared absorption spectrum of clathrate compounds, etc., FIG. 3 shows the FP-(HP-β-
FIG. 4 is a graph showing the results of differential scanning calorimetry of FP-(HP-CyD) clathrate compounds etc. obtained in Example 4.
FP-(HP-β-CyD)(6,2) obtained in Example 4 is a graph showing the dissolution test and test at pH 1,2 for β-CyD)(6,2) tablets, etc. ) of tablets, etc.
FIG. 6 is a graph showing the elution test in H6,8.FP-(HP-β-CyD)(6,2
)F when tablets, etc. are administered sublingually and orally to humans.
A graph showing the measurement results of the time course of the plasma concentration of P,
FIG. 7 shows the FP-(HP-β-CV obtained in Example 5).
D) (6,2) This is a graph showing the results of a halved release test and the test.
Claims (2)
ロキシプロピル基を有するヒドロキシプロピル−β−シ
クロデキストリンで包接してなり、前記フルルビプロフ
ェン１モルに対する前記ヒドロキシプロピル−β−シク
ロデキストリンの量が１〜２．５モルであることを特徴
とするフルルビプロフェンのヒドロキシプロピル−β−
シクロデキストリン包接化合物。(1) Flurbiprofen is clathrated with hydroxypropyl-β-cyclodextrin having an average number of 2 to 10 hydroxypropyl groups, and the hydroxypropyl-β-cyclodextrin per mole of flurbiprofen hydroxypropyl-β- of flurbiprofen, characterized in that the amount of
Cyclodextrin inclusion compound.
キシプロピル−β−シクロデキストリン包接化合物を有
効成分とすることを特徴とする消炎鎮痛剤。(2) An anti-inflammatory analgesic agent comprising the hydroxypropyl-β-cyclodextrin clathrate compound of flurbiprofen according to claim (1) as an active ingredient.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1138096A JPH035438A (en) | 1989-05-31 | 1989-05-31 | Flurbiprofen clathrate compound and anti-inflammatory and analgesic agent using the same clathrate compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1138096A JPH035438A (en) | 1989-05-31 | 1989-05-31 | Flurbiprofen clathrate compound and anti-inflammatory and analgesic agent using the same clathrate compound |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH035438A true JPH035438A (en) | 1991-01-11 |
Family
ID=15213855
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP1138096A Pending JPH035438A (en) | 1989-05-31 | 1989-05-31 | Flurbiprofen clathrate compound and anti-inflammatory and analgesic agent using the same clathrate compound |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH035438A (en) |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH05178765A (en) * | 1991-06-21 | 1993-07-20 | Takeda Chem Ind Ltd | Sparingly water-soluble medicinal composition improved in solubility |
| JPH0753396A (en) * | 1993-08-19 | 1995-02-28 | Ensuiko Sugar Refining Co Ltd | Cyclodextrin clathrate of taxol, its production method and use |
| JPH08510232A (en) * | 1993-05-12 | 1996-10-29 | キノイン・ジヨージセル・エーシユ・ベジエーセテイ・テルメーケク・ジヤーラ・エル・テー | Inclusion complex consisting of taxol or taxotere or yew extract and cyclodextrin, production and use of the complex |
| JP2004525104A (en) * | 2000-12-19 | 2004-08-19 | セフアロン・インコーポレーテツド | Complex of modafinil and cyclodextrin |
| JP2006521403A (en) * | 2003-03-28 | 2006-09-21 | アイバックス コーポレイション | Cladribine oral formulation |
| JP2006526009A (en) * | 2003-03-28 | 2006-11-16 | アイバックス コーポレイション | Cladribine formulations for improved oral and transmucosal delivery |
| US7704975B2 (en) | 2000-12-19 | 2010-04-27 | Cephalon, Inc. | Modafinil compound and cyclodextrin mixtures |
| US8785418B2 (en) | 2009-04-03 | 2014-07-22 | Cephalon, Inc. | Lyophilization cakes of proteasome inhibitors |
-
1989
- 1989-05-31 JP JP1138096A patent/JPH035438A/en active Pending
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH05178765A (en) * | 1991-06-21 | 1993-07-20 | Takeda Chem Ind Ltd | Sparingly water-soluble medicinal composition improved in solubility |
| JPH08510232A (en) * | 1993-05-12 | 1996-10-29 | キノイン・ジヨージセル・エーシユ・ベジエーセテイ・テルメーケク・ジヤーラ・エル・テー | Inclusion complex consisting of taxol or taxotere or yew extract and cyclodextrin, production and use of the complex |
| JPH0753396A (en) * | 1993-08-19 | 1995-02-28 | Ensuiko Sugar Refining Co Ltd | Cyclodextrin clathrate of taxol, its production method and use |
| JP2004525104A (en) * | 2000-12-19 | 2004-08-19 | セフアロン・インコーポレーテツド | Complex of modafinil and cyclodextrin |
| US7704975B2 (en) | 2000-12-19 | 2010-04-27 | Cephalon, Inc. | Modafinil compound and cyclodextrin mixtures |
| JP2006521403A (en) * | 2003-03-28 | 2006-09-21 | アイバックス コーポレイション | Cladribine oral formulation |
| JP2006526009A (en) * | 2003-03-28 | 2006-11-16 | アイバックス コーポレイション | Cladribine formulations for improved oral and transmucosal delivery |
| US8623408B2 (en) | 2003-03-28 | 2014-01-07 | Ares Trading S.A. | Cladribine formulations for improved oral and transmucosal delivery |
| US8785418B2 (en) | 2009-04-03 | 2014-07-22 | Cephalon, Inc. | Lyophilization cakes of proteasome inhibitors |
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