JPH04134093A - Poly-gamma-cyclodextrin clathrate compound - Google Patents
Poly-gamma-cyclodextrin clathrate compoundInfo
- Publication number
- JPH04134093A JPH04134093A JP2253504A JP25350490A JPH04134093A JP H04134093 A JPH04134093 A JP H04134093A JP 2253504 A JP2253504 A JP 2253504A JP 25350490 A JP25350490 A JP 25350490A JP H04134093 A JPH04134093 A JP H04134093A
- Authority
- JP
- Japan
- Prior art keywords
- cyclodextrin
- poly
- fluorometholone
- gamma
- cyd
- 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.)
- Granted
Links
- 229920000858 Cyclodextrin Polymers 0.000 title claims abstract description 60
- 150000001875 compounds Chemical class 0.000 title claims abstract description 26
- 229940080345 gamma-cyclodextrin Drugs 0.000 title claims abstract description 24
- 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 title claims abstract description 23
- 229960001048 fluorometholone Drugs 0.000 claims abstract description 25
- FAOZLTXFLGPHNG-KNAQIMQKSA-N fluorometholone Chemical compound C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@]2(F)[C@@H](O)C[C@]2(C)[C@@](O)(C(C)=O)CC[C@H]21 FAOZLTXFLGPHNG-KNAQIMQKSA-N 0.000 claims abstract description 25
- 239000003862 glucocorticoid Substances 0.000 claims abstract description 18
- 238000006116 polymerization reaction Methods 0.000 claims abstract description 10
- 238000002360 preparation method Methods 0.000 claims description 9
- 239000003889 eye drop Substances 0.000 claims description 5
- 230000003110 anti-inflammatory effect Effects 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims description 2
- 239000002552 dosage form Substances 0.000 claims 1
- 229920000642 polymer Polymers 0.000 abstract description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 10
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 abstract description 3
- 229940124599 anti-inflammatory drug Drugs 0.000 abstract description 3
- 238000004132 cross linking Methods 0.000 abstract description 2
- 229920001353 Dextrin Polymers 0.000 abstract 1
- 239000004375 Dextrin Substances 0.000 abstract 1
- 239000003470 adrenal cortex hormone Substances 0.000 abstract 1
- 239000002260 anti-inflammatory agent Substances 0.000 abstract 1
- RKHQGWMMUURILY-UHRZLXHJSA-N cortivazol Chemical compound C([C@H]1[C@@H]2C[C@H]([C@]([C@@]2(C)C[C@H](O)[C@@H]1[C@@]1(C)C2)(O)C(=O)COC(C)=O)C)=C(C)C1=CC1=C2C=NN1C1=CC=CC=C1 RKHQGWMMUURILY-UHRZLXHJSA-N 0.000 abstract 1
- 235000019425 dextrin Nutrition 0.000 abstract 1
- 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 description 18
- 239000001116 FEMA 4028 Substances 0.000 description 9
- 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 9
- 229960004853 betadex Drugs 0.000 description 9
- 229940037128 systemic glucocorticoids Drugs 0.000 description 9
- 235000011175 beta-cyclodextrine Nutrition 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 229940097362 cyclodextrins Drugs 0.000 description 6
- 239000003814 drug Substances 0.000 description 5
- 230000002335 preservative effect Effects 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 229940012356 eye drops Drugs 0.000 description 4
- 230000003381 solubilizing effect Effects 0.000 description 4
- -1 cyclic oligosaccharide Chemical class 0.000 description 3
- 230000002949 hemolytic effect Effects 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 239000008363 phosphate buffer Substances 0.000 description 3
- 239000003755 preservative agent Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- 239000013011 aqueous formulation Substances 0.000 description 2
- 229960000686 benzalkonium chloride Drugs 0.000 description 2
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 2
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 2
- 239000004327 boric acid Substances 0.000 description 2
- 238000004455 differential thermal analysis Methods 0.000 description 2
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 2
- 229910000397 disodium phosphate Inorganic materials 0.000 description 2
- 235000019800 disodium phosphate Nutrition 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 2
- 238000002329 infrared spectrum Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000006069 physical mixture Substances 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000002562 thickening agent Substances 0.000 description 2
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- JRLTTZUODKEYDH-UHFFFAOYSA-N 8-methylquinoline Chemical group C1=CN=C2C(C)=CC=CC2=C1 JRLTTZUODKEYDH-UHFFFAOYSA-N 0.000 description 1
- 229920001450 Alpha-Cyclodextrin Polymers 0.000 description 1
- 206010018910 Haemolysis Diseases 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 241000270666 Testudines Species 0.000 description 1
- JVFGXECLSQXABC-UHFFFAOYSA-N ac1l3obq Chemical compound O1C(C(C2O)O)C(COCC(C)O)OC2OC(C(C2O)O)C(COCC(C)O)OC2OC(C(C2O)O)C(COCC(C)O)OC2OC(C(C2O)O)C(COCC(C)O)OC2OC(C(C2O)O)C(COCC(C)O)OC2OC(C(O)C2O)C(COCC(O)C)OC2OC(C(C2O)O)C(COCC(C)O)OC2OC2C(O)C(O)C1OC2COCC(C)O JVFGXECLSQXABC-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 229940043377 alpha-cyclodextrin Drugs 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
- 238000004458 analytical method Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000008588 hemolysis Effects 0.000 description 1
- 229960000890 hydrocortisone Drugs 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 238000004898 kneading Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229920001542 oligosaccharide Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 229960005205 prednisolone Drugs 0.000 description 1
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
- Steroid Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
「産業上の利用分野」
本発明は糖質コルチコイドを重合度２〜４のポリ−γ−
シクロデキストリンに包接させた包接化合物およびそれ
を有効成分とする抗炎症水性製剤に関する。DETAILED DESCRIPTION OF THE INVENTION "Industrial Application Field" The present invention provides glucocorticoids with poly-γ-
The present invention relates to a clathrate compound clathrated in cyclodextrin and an anti-inflammatory aqueous preparation containing the clathrate compound as an active ingredient.
「従来技術」
水に難溶な物質を水性製剤に応用する研究は古くからな
されており、各種シクロデキストリンを用い可溶化させ
る方法もその一つとして研究が行われている。"Prior Art" Research has been conducted for a long time to apply substances that are sparingly soluble in water to aqueous preparations, and one such study is on methods of solubilizing substances using various cyclodextrins.
環状オリゴ糖であるシクロデキストリンにはαβ−およ
びγ−型があり、各々の異なった性質を利用して、種々
の技術に利用されている。医薬分野への応用について本
、水難溶性物質の可溶化、薬物の安定性向上等の目的で
数多くの研究がなされている。それらの研究はβ−シク
ロデキストリンを用いる亀のが中心であるが、高濃度の
β−シクロデキストリンには溶血作用が見られることも
あって、溶血作用の少ないγ−シクロデキストリンを用
いた研究も報告されている（特公昭６４−９９９６号）
。一方、これらの天然産シクロデキストリンのほかに、
シクロデキストリンを化学的に修飾したマルシトルシク
ロデキストリン（％開昭６２−２８１８５５号）、グル
コシルシクロデキストリン（特開昭６３−２７４４０号
）、ヒドロキシプロピルシクロデキストリン（特開昭６
１−２７５３０１号）等を用いる研究も報告されている
。さらに、シクロデキストリンの重合体を用いた研究と
してβ−シクロデキストリンポリマーＣ％開昭６１−９
７０２５号）や、医薬としての応用ではないがγ−シク
ロデキストリン高重合体（特開昭６０−１１９６１号）
等が報告されている。Cyclodextrin, which is a cyclic oligosaccharide, has αβ- and γ-types, and each type is used in various technologies by taking advantage of their different properties. Many studies have been conducted on applications in the pharmaceutical field, with the aim of solubilizing poorly water-soluble substances, improving the stability of drugs, etc. These studies have mainly focused on turtles using β-cyclodextrin, but since high concentrations of β-cyclodextrin can have hemolytic effects, some studies have also used γ-cyclodextrin, which has less hemolytic effect. Reported (Special Publication No. 64-9996)
. On the other hand, in addition to these naturally occurring cyclodextrins,
Chemically modified cyclodextrin: malcitol cyclodextrin (% 1982-281855), glucosyl cyclodextrin (1982-27440), hydroxypropyl cyclodextrin (1987 27440),
1-275301) etc. have also been reported. Furthermore, as research using cyclodextrin polymers, β-cyclodextrin polymer C%
No. 7025), and γ-cyclodextrin high polymer (Japanese Patent Application Laid-open No. 11961/1982), although it is not used as a medicine.
etc. have been reported.
「発明が解決しようとする課題
糖質コルチコイドは抗炎症薬物として医薬に広く用いら
れているが、水に難溶で水性製剤の場合、実際には懸濁
型製剤として用いられている。この糖質コルチコイドを
可溶化することは大きな課題であり、各種シクロデキス
トリンを用いる方法が研究されている。``Problems to be Solved by the Invention Glucocorticoids are widely used in medicine as anti-inflammatory drugs, but they are poorly soluble in water, and in the case of aqueous preparations, they are actually used as suspension preparations. Solubilizing various corticoids is a major challenge, and methods using various cyclodextrins are being studied.
しかしながら包接化合物を作るには、ゲスト分子の大き
さとシクロデキストリンの種類の選択が重要なポイント
となる。また、それらの種類にょつて生成する包接化合
物の性質も大きく左右される。However, in making clathrate compounds, the important points are the size of the guest molecule and the selection of the type of cyclodextrin. Furthermore, the properties of the clathrate compounds that are produced are also greatly influenced by their types.
さらに、医薬として応用するには、安定性、副作用の問
題も解決しなければならない。Furthermore, in order to apply it as a medicine, problems of stability and side effects must also be resolved.
「課題を解決するだめの手段」
本発明者等は、糖質コルチコイドの包接化合物を研究す
るに当たり、水に対する溶解度が高く、安定性が優れ、
副作用の少ないシクロデキストリンについて鋭意研究し
た結果、重合度が２〜４のポリ−Ｔ−シクロデキストリ
ンを用いるとこれらの課題が一挙に解決することを見い
出した。"An unsuccessful means to solve the problem" In researching glucocorticoid clathrate compounds, the present inventors found that they have high solubility in water and excellent stability.
As a result of intensive research on cyclodextrins with fewer side effects, it was discovered that these problems could be solved at once by using poly-T-cyclodextrin with a degree of polymerization of 2 to 4.
「発明の構成」
本発明は糖質コルチコイドを重合度２〜４のポリ−γ−
シクロデキストリンに包接した包接化合物およびその水
性製剤への応用に関する。"Structure of the Invention" The present invention provides glucocorticoids with poly-γ-
This article relates to cyclodextrin-based clathrate compounds and their application to aqueous preparations.
糖質コルチコイドとしては、フルオロメトロン、デキサ
メタシン、ペタメタシン、ヒドロコルチゾン、プレドニ
ゾロン等が挙げられる。Examples of glucocorticoids include fluorometholone, dexamethacin, petamethacin, hydrocortisone, prednisolone, and the like.
重合度２〜４のポリ−γ−シクロデキストリンとは、γ
−シクロデキストリンをエピクロルヒドリンを用いて架
橋したγ−シクロデキストリンを２〜４個含むポリマー
を示す。Poly-γ-cyclodextrin with a degree of polymerization of 2 to 4 is γ
- Shows a polymer containing 2 to 4 γ-cyclodextrins, which is obtained by crosslinking cyclodextrin with epichlorohydrin.
糖質コルチコイドのシクロデキストリン包接化合物につ
いて種々研究されているが、α−シクロデキストリンは
包接能が小さく、糖質コルチコイドのような分子には適
していない。β−シクロデキストリンは数多くの研究に
用いられているシクロデキストリンであるが、後述の試
験例で示すように糖質コルチコイドに応用する場合、溶
解度が十分上がらず、また、β−シクロデキストリンの
溶血作用の点からも適切とけ言えない。γ−シクロデキ
ストリンを用いると溶血性の問題は解決できるが、溶解
度の点から改良すべき余地がある。Although various studies have been conducted on cyclodextrin inclusion compounds of glucocorticoids, α-cyclodextrin has a small inclusion ability and is not suitable for molecules such as glucocorticoids. β-cyclodextrin is a cyclodextrin used in many studies, but as shown in the test examples below, when applied to glucocorticoids, the solubility is not sufficiently increased, and the hemolytic effect of β-cyclodextrin It cannot be said that it is appropriate from this point of view. Although the problem of hemolysis can be solved by using γ-cyclodextrin, there is still room for improvement in terms of solubility.
シクロデキストリンのポリマーに関して言えば、β−シ
クロデキストリンのポリマーでは満足すべきものが得ら
れず、また、重合度が大きいγ−シクロデキストリンで
は水に難溶となってしまう。As for cyclodextrin polymers, β-cyclodextrin polymers are not satisfactory, and γ-cyclodextrin with a high degree of polymerization is poorly soluble in water.
詳細は後述の試験例で説明するが、本発明者等は重合度
２〜４のポリ−γ−シクロデキストリンを用いると、溶
解度や安定性が優れ、かつ副作用も少々い糖質コルチコ
イドの包接化合物が得られることを見い出した。The details will be explained in the test examples below, but the present inventors have found that using poly-γ-cyclodextrin with a degree of polymerization of 2 to 4, the inclusion of glucocorticoids has excellent solubility and stability, and has few side effects. It has been found that a compound can be obtained.
との包接化合物は汎用される技術を用いて水性製剤とす
ることができる。点眼剤を例にとって説明すると、点眼
剤に汎用される塩化ナトリウム、塩化カリウム、ホウ酸
等の等張化剤、リン酸水素ナトリウム等の緩衝化剤、塩
化ベンザルコニウム、パラオキシ安息香酸エステル等の
防腐剤、ポリビニルアルコール、カルポキシビニルホリ
マー等ノ粘稠化剤、塩徽、水酸化ナトリウム等のｐＨ調
整剤を必要に応じて加え、点眼剤として処方すればよい
。The clathrate compound can be made into an aqueous formulation using commonly used techniques. Taking eye drops as an example, we will use tonicity agents commonly used in eye drops such as sodium chloride, potassium chloride, and boric acid, buffering agents such as sodium hydrogen phosphate, benzalkonium chloride, paraoxybenzoic acid ester, etc. Preservatives, thickening agents such as polyvinyl alcohol and carboxyvinyl polymers, and pH adjusters such as saltwater and sodium hydroxide may be added as necessary to formulate eye drops.
また、点眼剤において防腐剤を処方する場合、防腐効果
を考慮する必要がある。シクロデキストリンを用いると
防腐剤まで包接され防腐効果が一般に低下するとされて
いるが、ポリ−γ−シクロデキストリンの場合には防腐
効果の低下は少ないというメリットを有している。Furthermore, when prescribing a preservative for eye drops, it is necessary to consider the preservative effect. It is said that when cyclodextrin is used, the preservative is included and the preservative effect is generally reduced, but poly-γ-cyclodextrin has the advantage that the preservative effect is less reduced.
さらに、水性製剤の場合は、−旦溶解した包接化合物が
再度析出する危険性を防ぐ必要がある。Furthermore, in the case of aqueous preparations, it is necessary to prevent the risk of the once-dissolved clathrate compound precipitating out again.
ポリ−β−シクロデキストリンを用いると後述するよう
に粘度が上がり、この再析出を防ぐ効果も合わせ持つも
のである。もちろん、粘稠化剤を併用することにより粘
度を上げることもできる。When poly-β-cyclodextrin is used, the viscosity increases as will be described later, and it also has the effect of preventing this redeposition. Of course, the viscosity can also be increased by using a thickening agent.
糖質コルチコイドの代表例としてフルオロメトロンを用
い、以下、実施例で詳細に説明する。Fluorometholone is used as a representative example of glucocorticoid, and will be explained in detail in Examples below.
［実施例
（製造例）
フルオロメトロンのポリ−γ−シクロデキストリン（重
合度３）包接化合物の製造
水素化ホウ素ナトリウム（０，４ｇ ’）を２（ｌ水酸
化す） ＩＪウム水溶液（９０ｍｌ）に溶解し、水（５
０ｍｌ）とγ−７クロデキストリン（１００ｇ）の練合
物に加え５０℃で撹拌する。γ−シクロデキストリンが
完全に溶解した後、エピクロルヒドリン（３０ｍｌ→を
３０分で滴下する。滴下終了後さらに５０℃で３時間撹
拌後希塩酸で中和する。[Example (Production Example) Production of poly-γ-cyclodextrin (degree of polymerization 3) clathrate compound of fluorometholone Sodium borohydride (0.4 g') is hydroxylated with 2 (l) IJium aqueous solution (90 ml) Dissolved in water (5
0ml) and γ-7 clodextrin (100g) and stirred at 50°C. After γ-cyclodextrin is completely dissolved, epichlorohydrin (30 ml→) is added dropwise over 30 minutes. After the addition is complete, the mixture is further stirred at 50° C. for 3 hours, and then neutralized with dilute hydrochloric acid.
イオン交換樹脂を用いて脱塩し、減圧濃縮後スプレード
ライを用いて粉末化しポリ−γ−シクロデキストリンを
得る。こうして得られたポリ−γ−シクロデキストリン
（３，８ｇ ）に少量の水を加えペースト状とし、これ
にフルオロメトｔ：ｌ ：／（０，３８ｇ）を加え十分
混練する。混練終了後ペーストを乾燥し粉末状の包接化
合物を得る（定量的）。The product is desalted using an ion exchange resin, concentrated under reduced pressure, and then powdered using spray drying to obtain poly-γ-cyclodextrin. A small amount of water was added to the thus obtained poly-γ-cyclodextrin (3.8 g) to form a paste, and fluoromethot t:l:/(0.38 g) was added thereto and thoroughly kneaded. After kneading, the paste is dried to obtain a powdered clathrate compound (quantitative).
ＩＲスペクトル
フルオロメトロン単独の場合、カルボニル伸縮振動に基
づく３本のピーク（１７１８，１６６０゜１６１８ ｃ
ｍ−” ）が見られるが、包接化合物の場合には１７１
８ ｃｍ−”が１７１６ ｃｍ−’に低周波シフトした
。尚、フルオロメトロンとポリ−γ−シクロデキストリ
ン１：１（モル比）の物理的混合物の場合、これらのピ
ークに変化は見られなかった。In the case of fluorometholone alone, the IR spectrum has three peaks based on carbonyl stretching vibrations (1718, 1660°, 1618 c
m-”), but in the case of clathrate compounds, 171
8 cm-'' shifted to 1716 cm-' in low frequency. In addition, in the case of a physical mixture of fluorometholone and poly-γ-cyclodextrin 1:1 (molar ratio), no change was observed in these peaks. .
第１図にフルオロメトロン単独のものと、包接化合物の
スペクトルを示す。Figure 1 shows the spectra of fluorometholone alone and of the clathrate compound.
示差熱分析
フルオロメトロン単独の場合、２９３°Ｃ付近に薬物の
融解に基づく吸熱ピークが観察されたが、包接化合物の
場合この吸熱ピークは完全に消失［７た。Differential thermal analysis In the case of fluorometholone alone, an endothermic peak due to the melting of the drug was observed around 293°C, but in the case of the clathrate compound, this endothermic peak completely disappeared [7].
尚、フルオロメトロンとポリ−γ−シクロデキストリン
１：１（モル比）の物理的混合物の場合、２９３℃の吸
熱ピークがショルダーとして観察された。In addition, in the case of a physical mixture of fluorometholone and poly-γ-cyclodextrin in a 1:1 (molar ratio), an endothermic peak at 293° C. was observed as a shoulder.
第２図にフルオロメトロン単独のものと、包接化合物の
分析結果を示す。Figure 2 shows the analysis results for fluorometholone alone and for inclusion compounds.
（試験例）
糖質コルチコイドとしてフルオロメトロンを、ポリ−γ
−シクロデキストリン（Ｐｏ １ ｙ−γ−ＣｙＤ）と
しては重合度３のものを用い以下の試験を行なった。(Test example) Fluorometholone was used as a glucocorticoid, and poly-γ
- The following tests were conducted using a cyclodextrin (Po 1 y-γ-CyD) with a polymerization degree of 3.
１、各種シクロデキストリンを用い、フルオロメトロン
の包接能を調べ安定度定数（Ｋｃ）を算出した。1. Using various cyclodextrins, the inclusion ability of fluorometholone was investigated and the stability constant (Kc) was calculated.
結果を第３図に示すが、γ−シクロデキストリン（γ−
ＣｙＤ）、β−シクロデキストリン（β−ＣｙＤ）、ポ
リ−β−シクロデキストリン（Ｐｏｌｙ−β−ＣｙＤ）
、ヒドロキシプロピル−γ−シクロデキストリン（ＨＰ
−γ−ＣｙＤ）、ジヒドロキシプロピル−γ−シクロデ
キストリン（ＤＨＰ−γ−ＣｙＤ）ト比較したところＰ
ｏ １ｙ−γ−ＣｙＤの包接能は特に優れたものであっ
た。The results are shown in Figure 3, and γ-cyclodextrin (γ-
CyD), β-cyclodextrin (β-CyD), poly-β-cyclodextrin (Poly-β-CyD)
, hydroxypropyl-γ-cyclodextrin (HP
-γ-CyD) and dihydroxypropyl-γ-cyclodextrin (DHP-γ-CyD).
o The inclusion ability of 1y-γ-CyD was particularly excellent.
２、フルオロメトロンの各種シクロデキストリン包接化
合物の溶解性を調べた。2. The solubility of various cyclodextrin inclusion compounds of fluorometholone was investigated.
結果を表に示すが、ｒ−ＣｙＤ、β−ＣｙＤ、 Ｐｏ
ｌｙβ−ＣＯＤＳＨＰ−γ−ＣＯＤ、 ＤＨＰ−γ−Ｃ
ｙＤを用いた場合に比べてＰｏ ｌｙ−γ−ＣｙＤを用
いたものの溶解性は特に優れたものであった。The results are shown in the table, r-CyD, β-CyD, Po
lyβ-CODSHP-γ-COD, DHP-γ-C
The solubility using Poly-γ-CyD was particularly superior to that using yD.
表 フルオロメトロンの溶解度に対する各種シクロデキ
ストリンの効果（２５℃、リン酸緩衝１ｐＨ７，４）β
−ＣｙＤ
Ｐｏｌｙ−β−ＣｙＤ
γ−ＣｙＤ
ＨＰ−γ−ＣｙＤ
ＤＨＰ−γ−ＣｙＤ
ＰＯｌｙ−γ−ＣｙＤ
０．０８
０．２３
０．５９
０．４４
０．１４
０．８２
１３．５
３６．７
９４．０
７０．４
２２．５
１ ３ ０．７
※ フルオロメトロン自体の溶解度を１とした場合の溶
解度
３、Ｐｏ１７−γ
Ｃ７Ｄの粘度上昇能
− ｌ Ｏ−
水性製剤において粘度上昇は、包接化合物の再析出を防
ぐ効果があることから、Ｐｏ１７−γ−ＣｙＤの粘度上
昇能を調べた。Table Effect of various cyclodextrins on the solubility of fluorometholone (25°C, phosphate buffer 1 pH 7,4) β
-CyD Poly-β-CyD γ-CyD HP-γ-CyD DHP-γ-CyD POly-γ-CyD 0.08 0.23 0.59 0.44 0.14 0.82 13.5 36.7 94 .0 70.4 22.5 1 3 0.7 * Solubility 3 when the solubility of fluorometholone itself is 1, viscosity increasing ability of Po17-γ C7D - l O- In aqueous formulations, the viscosity increase is due to the clathrate compound. The viscosity increasing ability of Po17-γ-CyD was investigated because it has the effect of preventing redecipitation of Po17-γ-CyD.
結果を第４図に示すが、同じポリマーであるＰｏ１）’
−β−ＣｙＤに比べてＰｏ１ａｒ −”ｒ−Ｃ）’Ｄの
粘度上昇能ははるかに優れたものであった。The results are shown in Figure 4, and the same polymer Po1)'
The viscosity increasing ability of Po1ar-"r-C)'D was far superior to that of -β-CyD.
（処方例） 処方の一例を下記に示す。(Prescription example) An example of the formulation is shown below.
処方例１
フルオロメトロン ０．０２（ｗｔチ）Ｐ
ｏｌｙ−γ−ＣＯＤ ０．２塩化ナト
リウム ０．８リン酸水素ナトリウム
０．４塩化ベンザルコニウム ０．０
０５希塩酸 適量
滅菌精製水 適量
処方例２
フルオロメトロン ０．０２（ｗｔチ）Ｐ
ｏｌｙ−７−ｃｙＤＯ，２
ホウ酸 １．８
パラオキシ安息香酸メチル （１０２６パラオキシ
安息香酸プロピル ０．０１４水酸化ナトリウム
適量
滅菌精製水 適量
「発明の効果」
本発明によれば、抗炎症薬物として有用であるが水に難
溶な糖質コルチコイドを可溶化できるという優れた効果
をあげることができるのである。Prescription example 1 Fluorometholone 0.02 (wt)P
oly-γ-COD 0.2 Sodium chloride 0.8 Sodium hydrogen phosphate
0.4 Benzalkonium chloride 0.0
05 Dilute hydrochloric acid Appropriate amount Sterilized purified water Appropriate amount Prescription example 2 Fluorometholone 0.02 (wt) P
oly-7-cyDO,2 Boric acid 1.8 Methyl paraoxybenzoate (1026 Propyl paraoxybenzoate 0.014 Sodium hydroxide
Appropriate amount of sterile purified water Appropriate amount ``Effects of the Invention'' According to the present invention, it is possible to achieve the excellent effect of solubilizing glucocorticoids, which are useful as anti-inflammatory drugs but are poorly soluble in water.
第１図はフルオロメトロン単独のものとフルオロメトロ
ンのポリ−γ−シクロデキストリン包接化合物のＩＲス
ペクトルを示す。
第２図はフルオロメトロン単独のものとフルオロメトロ
ンのポリ−γ−シクロデキストリン包接化合物の示差熱
分析の結果を示す。
第３図は２５℃、１０ｍＭのリン酸緩衝液（ｐＨ７，４
）中でのフルオロメトロンと種々のシフロブキストリ／
誘導体との安定度定数（Ｋｃ）を求めた図で、横軸はシ
クロデキストリンの濃度、縦軸はフルオロメトロンの濃
度を表わし、−〇−はＰｏ１ｙ−γ−ｃｙｎ、−一一は
γ−Ｃ７Ｄ、−口−はＵＰ−γ−ＣＯＤ。
−・−はＰｏ ｌｙ−β−ＣｙＤ、−△−はＤＨＰ −
”ｒ−ＣｙＩ）のデータを示す。
第４図は２５℃、１０ｍＭのリン酸緩衝液（ｐ’Ｈ７，
４）中でのシクロデキストリンポリマーの粘度を示すも
ので、横軸はシクロデキストリンポリマーの濃度、縦軸
は粘度を表わし、−・−はＰｏ１７−γ−ｃｙｐ、−〇
−はＰｏ１ｙ−β−ＣｙＤのデータを示す。FIG. 1 shows the IR spectra of fluorometholone alone and the poly-γ-cyclodextrin inclusion compound of fluorometholone. FIG. 2 shows the results of differential thermal analysis of fluorometholone alone and the poly-γ-cyclodextrin inclusion compound of fluorometholone. Figure 3 shows the temperature of 10mM phosphate buffer (pH 7,4
) in fluorometholone and various siphlobuchistries/
This figure shows the stability constant (Kc) with the derivative, where the horizontal axis represents the concentration of cyclodextrin, the vertical axis represents the concentration of fluorometholone, -〇- is Po1y-γ-cyn, -11 is γ-C7D , -mouth- is UP-γ-COD. −・− is Poly-β-CyD, −△− is DHP −
"r-CyI). Figure 4 shows the data of 10mM phosphate buffer (p'H7,
4) shows the viscosity of the cyclodextrin polymer in the cyclodextrin polymer, the horizontal axis shows the concentration of the cyclodextrin polymer, and the vertical axis shows the viscosity. The following data is shown.
Claims (1)
クロデキストリンに包接させた包接化合物を有効成分と
する抗炎症水性製剤。 （２）糖質コルチコイドがフルオロメトロンである請求
項（１）記載の抗炎症水性製剤。（３）剤形が点眼剤で
ある請求項（１）記載の抗炎症水性製剤。 （４）糖質コルチコイドを重合度２〜４のポリ−γ−シ
クロデキストリンに包接させた包接化合物。 （５）糖質コルチコイドがフルオロメトロンである請求
項（４）記載の包接化合物。[Scope of Claims] (1) An anti-inflammatory aqueous preparation containing as an active ingredient an inclusion compound in which a glucocorticoid is included in poly-γ-cyclodextrin with a degree of polymerization of 2 to 4. (2) The anti-inflammatory aqueous preparation according to claim (1), wherein the glucocorticoid is fluorometholone. (3) The anti-inflammatory aqueous preparation according to claim (1), whose dosage form is an eye drop. (4) A clathrate compound in which a glucocorticoid is included in poly-γ-cyclodextrin having a degree of polymerization of 2 to 4. (5) The clathrate compound according to claim (4), wherein the glucocorticoid is fluorometholone.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2253504A JP2805539B2 (en) | 1990-09-20 | 1990-09-20 | Poly-γ-cyclodextrin inclusion compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2253504A JP2805539B2 (en) | 1990-09-20 | 1990-09-20 | Poly-γ-cyclodextrin inclusion compound |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH04134093A true JPH04134093A (en) | 1992-05-07 |
| JP2805539B2 JP2805539B2 (en) | 1998-09-30 |
Family
ID=17252301
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2253504A Expired - Fee Related JP2805539B2 (en) | 1990-09-20 | 1990-09-20 | Poly-γ-cyclodextrin inclusion compound |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2805539B2 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0709099A2 (en) | 1994-09-28 | 1996-05-01 | Senju Pharmaceutical Co., Ltd. | An aqueous nasal suspension comprising cyclodextrin |
| WO2018230713A1 (en) | 2017-06-16 | 2018-12-20 | 学校法人同志社 | Compounds having caspase inhibitory activity, pharmaceutical agent containing said compounds and for treating or preventing corneal endothelial symptoms, disorders, or diseases, and application of said pharmaceutical agent |
-
1990
- 1990-09-20 JP JP2253504A patent/JP2805539B2/en not_active Expired - Fee Related
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0709099A2 (en) | 1994-09-28 | 1996-05-01 | Senju Pharmaceutical Co., Ltd. | An aqueous nasal suspension comprising cyclodextrin |
| WO2018230713A1 (en) | 2017-06-16 | 2018-12-20 | 学校法人同志社 | Compounds having caspase inhibitory activity, pharmaceutical agent containing said compounds and for treating or preventing corneal endothelial symptoms, disorders, or diseases, and application of said pharmaceutical agent |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2805539B2 (en) | 1998-09-30 |
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