JPS6245846B2 - - Google Patents
Info
- Publication number
- JPS6245846B2 JPS6245846B2 JP49072169A JP7216974A JPS6245846B2 JP S6245846 B2 JPS6245846 B2 JP S6245846B2 JP 49072169 A JP49072169 A JP 49072169A JP 7216974 A JP7216974 A JP 7216974A JP S6245846 B2 JPS6245846 B2 JP S6245846B2
- Authority
- JP
- Japan
- Prior art keywords
- methyl
- corticoid
- pregnadiene
- acid
- group
- 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.)
- Expired
Links
- 239000003470 adrenal cortex hormone Substances 0.000 claims description 10
- 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 claims description 10
- 239000002245 particle Substances 0.000 claims description 6
- -1 hydroxymethylene group Chemical group 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 125000001153 fluoro group Chemical group F* 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 125000001183 hydrocarbyl group Chemical group 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 239000007787 solid Substances 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims 1
- 239000000460 chlorine Substances 0.000 claims 1
- 230000000144 pharmacologic effect Effects 0.000 claims 1
- 239000000843 powder Substances 0.000 claims 1
- 239000013543 active substance Substances 0.000 description 9
- 239000000203 mixture Substances 0.000 description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000002775 capsule Substances 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 208000026935 allergic disease Diseases 0.000 description 5
- 210000002345 respiratory system Anatomy 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 4
- 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 4
- 239000008101 lactose Substances 0.000 description 4
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 206010039083 rhinitis Diseases 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 229930182555 Penicillin Natural products 0.000 description 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 239000004098 Tetracycline Substances 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 208000006673 asthma Diseases 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229960003276 erythromycin Drugs 0.000 description 2
- 208000030603 inherited susceptibility to asthma Diseases 0.000 description 2
- 229940049954 penicillin Drugs 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 229960002180 tetracycline Drugs 0.000 description 2
- 229930101283 tetracycline Natural products 0.000 description 2
- 235000019364 tetracycline Nutrition 0.000 description 2
- 150000003522 tetracyclines Chemical class 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- DDMOUSALMHHKOS-UHFFFAOYSA-N 1,2-dichloro-1,1,2,2-tetrafluoroethane Chemical compound FC(F)(Cl)C(F)(F)Cl DDMOUSALMHHKOS-UHFFFAOYSA-N 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- VOPWNXZWBYDODV-UHFFFAOYSA-N Chlorodifluoromethane Chemical compound FC(F)Cl VOPWNXZWBYDODV-UHFFFAOYSA-N 0.000 description 1
- 208000014311 Cushing syndrome Diseases 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- OJMMVQQUTAEWLP-UHFFFAOYSA-N Lincomycin Natural products CN1CC(CCC)CC1C(=O)NC(C(C)O)C1C(O)C(O)C(O)C(SC)O1 OJMMVQQUTAEWLP-UHFFFAOYSA-N 0.000 description 1
- 229930189077 Rifamycin Natural products 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 229960005091 chloramphenicol Drugs 0.000 description 1
- WIIZWVCIJKGZOK-RKDXNWHRSA-N chloramphenicol Chemical compound ClC(Cl)C(=O)N[C@H](CO)[C@H](O)C1=CC=C([N+]([O-])=O)C=C1 WIIZWVCIJKGZOK-RKDXNWHRSA-N 0.000 description 1
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 1
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 229960005287 lincomycin Drugs 0.000 description 1
- OJMMVQQUTAEWLP-KIDUDLJLSA-N lincomycin Chemical compound CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@@H](C)O)[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](SC)O1 OJMMVQQUTAEWLP-KIDUDLJLSA-N 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 201000009240 nasopharyngitis Diseases 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 1
- 201000009395 primary hyperaldosteronism Diseases 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229960003292 rifamycin Drugs 0.000 description 1
- HJYYPODYNSCCOU-ODRIEIDWSA-N rifamycin SV Chemical compound OC1=C(C(O)=C2C)C3=C(O)C=C1NC(=O)\C(C)=C/C=C/[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@H](C)[C@@H](OC)\C=C\O[C@@]1(C)OC2=C3C1=O HJYYPODYNSCCOU-ODRIEIDWSA-N 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt 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
- 239000002904 solvent Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
- A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
- A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
Description
【発明の詳細な説明】
本発明は呼吸器系路のアレルギー性疾患の治療
に有利に使用することのできる、コルチコイド含
有の吸入剤に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to inhalants containing corticoids, which can be used advantageously for the treatment of allergic diseases of the respiratory tract.
コルチコイド含有の医薬を、呼吸器系路のアレ
ルギー性疾患、例えば鼻炎又は気管支喘息の治療
に使用することができることは公知である。しか
しながら、該医薬をこの種の疾患の治療に使用す
ることは該医薬の良好な作用にもかかわらず、懸
念がないわけではない。それというのもこの目的
の為に使用されるコルチコイドは高い用量及び長
期連続治療の場合にはしばしば重大な幅作用、例
えばいわゆるクツシング症候群を惹起するからで
ある〔ブリテツシユ・メデカル・ジヤーナル
(Brit.Med.J.)1966,2,796及びザ・ランセツ
ト(The Lancet)1970,733〕。 It is known that medicines containing corticoids can be used for the treatment of allergic diseases of the respiratory tract, such as rhinitis or bronchial asthma. However, the use of the drug in the treatment of diseases of this type is not without concerns, despite its good action. This is because the corticoids used for this purpose, in the case of high doses and long-term continuous treatment, often cause serious side effects, such as the so-called Cushing's syndrome [Brit.Med. J.) 1966, 2, 796 and The Lancet 1970, 733].
呼吸器系路のアレルギー性疾患をコルチコイド
を用いて治療する際に生じる副作用を減少させる
ために、コルチコイドを以前のように経口的に適
用するのではなくエーロゾルとして吸入させるよ
うにする〔ザ・ランセツト、1963,147;アーチ
ブス・インターナシヨナレス・デ・メデシーネ・
エクスペリメンタル(Arch.lntern.Med.)115
(1965)602;ブリテツシユ・メデカル・ジヤーナ
ル1972,1,585〕。この適用形式により、生じる
副作用を減少させることは可能となつたが;吸入
する際に常に一部の吸入剤が胃−腸−経路
(Magen−Darm−Trakt)に達するので好ましか
らぬ副作用を回避することはできなかつた。 In order to reduce the side effects that occur when treating allergic diseases of the respiratory tract with corticoids, corticoids are now inhaled as an aerosol rather than being applied orally as before [The Lancet] , 1963, 147;
Experimental (Arch.lntern.Med.) 115
(1965) 602; British Medical Journal 1972, 1, 585]. This mode of application makes it possible to reduce the side effects that occur; however, it also avoids undesirable side effects, since during inhalation some inhalant always reaches the gastro-intestinal route (Magen-Darm-Trakt). I couldn't do that.
本発明の根底をなす課題は、呼吸器系路のアレ
ルギー性疾患に対して良好な作用を有しかつ実際
に不所望なコルチコイド副作用を有しない、コル
チコイド含有の吸入剤を開発することである。 The problem underlying the present invention is to develop corticoid-containing inhalants that have a good effect on allergic diseases of the respiratory tract and have virtually no undesired corticoid side effects.
該課題は本発明によれば、作用物質として一般
式:
〔式中Xは弗素原子を表わし、Yは水素原子、
弗素原子又は塩素原子を表わし、Zはヒドロキシ
メチレン基を表わすか、もしくはYが塩素原子を
表わす場合にZはクロルメチレン基であつてもよ
く、R1はメチル基を表わし、R2は水素原子を表
わし、R3は炭素原子数4の炭化水素基を表わ
す〕のコルチコイドを含有する吸入剤によつて解
決された。 According to the invention, the object is to use as active substance the general formula: [In the formula, X represents a fluorine atom, Y represents a hydrogen atom,
represents a fluorine atom or a chlorine atom, Z represents a hydroxymethylene group, or when Y represents a chlorine atom, Z may be a chlormethylene group, R 1 represents a methyl group, and R 2 represents a hydrogen atom and R 3 is a hydrocarbon group having 4 carbon atoms].
本発明によるコルチコイド含有吸入剤において
使用可能な作用物質としては例えば次のものが挙
げられる:
6α−フルオル−11β−ヒドロキシ−3,20−
ジオキソ−16α−メチル−1,4−プレグナジエ
ン−21−酸−ブチルエステル
6α−フルオル−9α,11β−ジクロル−3,
20−ジオキソ−16α−メチル−1,4−プレグナ
ジエン−21−酸−ブチルエステル
6α−フルオル−9α−クロル−11β−ヒドロ
キシ−3,20−ジオキソ−16α−メチル−1,4
−プレグナジエン−21−酸−イソブチルエステル
6α,9α−ジフルオル−11β−ヒドロキシ−
3,20−ジオキソ−16α−メチル−1.4−プレグ
ナジエン−21−酸−ブチルエステル
本発明による吸入剤に使用されるコルチコイド
作用物質は、例えば特許第118075号、及びベルギ
ー国特許第779869号明細書に記載されているよう
な方法により製造することができる。 Active substances that can be used in the corticoid-containing inhalation preparations according to the invention include, for example: 6α-fluoro-11β-hydroxy-3,20-
Dioxo-16α-methyl-1,4-pregnadiene-21-acid-butyl ester 6α-fluoro-9α,11β-dichloro-3,
20-dioxo-16α-methyl-1,4-pregnadiene-21-acid-butyl ester 6α-fluoro-9α-chloro-11β-hydroxy-3,20-dioxo-16α-methyl-1,4
-Pregnadiene-21-acid-isobutyl ester 6α,9α-difluoro-11β-hydroxy-
3,20-dioxo-16α-methyl-1,4-pregnadiene-21-acid-butyl ester The corticoid active substances used in the inhalation preparation according to the invention are described, for example, in Patent No. 118075 and Belgian Patent No. 779869. It can be manufactured by the method as described.
本発明による吸入剤を製造するための作用物質
としては大抵は1種類のコルチコイド又は2種類
のコルチコイドの混合物を使用するが、しかしな
がらコルチコイド作用物質の他になお付加的にそ
の他の作用物質、例えば抗生物質、例えばクロラ
ムフエニコール、テトラサイクリン、ペニシリ
ン、セフアロスポリン、リンコマイシン、エリス
ロマイシン又はリフアマイシンを含有する吸入剤
を製造することも可能である。 The active substance for preparing the inhalants according to the invention is usually one corticoid or a mixture of two corticoids; however, in addition to the corticoid active substance, it is also possible to use other active substances, for example antibiotics. It is also possible to prepare inhalants containing substances such as chloramphenicol, tetracycline, penicillin, cephalosporin, lincomycin, erythromycin or rifamycin.
微細化されたコルチコイドと混合される20〜
200μの平均粒度を有する固体の薬理作用のない
水溶性賦形剤としては例えばデキストラン、マン
ニツト、グリコース又は乳糖が好適である。付加
的になおその他の添加剤、例えば矯味剤(例えば
サツカリン)又は抗生物質(例えばペニシリン、
テトラサイクリン又はエリスロマイシン)を添加
してもよい、この粉末状の吸入剤は大抵はコルチ
コイド作用物質を0.1%から含有する。粉末状の
吸入剤の製造及びその使用は例えば西ドイツ特許
公開公報第1792207号及び同第2229981号明細書に
詳説されている。 20~ mixed with micronized corticoids
Suitable solid, non-pharmacologically active, water-soluble excipients with an average particle size of 200μ are, for example, dextran, mannite, glycose or lactose. Additionally still other additives, such as flavoring agents (e.g. saccharin) or antibiotics (e.g. penicillin,
Tetracycline or erythromycin) may be added, and these powdered inhalants usually contain corticoid active substances from 0.1%. The production of powdered inhalants and their use is described in detail, for example, in DE 1792 207 and DE 2 229 981.
本発明による吸入剤は、既に詳説したように、
呼吸器系路のアレルギー性疾患、例えば鼻炎性疾
患、枯草性鼻カタル又は気管支喘息に有利に使用
される。 As already detailed, the inhalant according to the present invention includes:
It is advantageously used in allergic diseases of the respiratory tract, such as rhinitis, nasal catarrh or bronchial asthma.
1回の吸入当り及び1日当りに適用すべき吸入
剤の量は病気の重さ及び治療される者の体質によ
り変わる。通常1回の吸入当りコルチコイド作用
物質約0.01〜100mg、有利には0.1〜10mgが適用さ
れる。所望される1日の用量は通常0.02〜1000
mg、有利には0.1〜50mgである。 The amount of inhalant to be applied per inhalation and per day varies depending on the severity of the disease and the constitution of the person being treated. Usually about 0.01 to 100 mg, preferably 0.1 to 10 mg, of corticoid active substance are applied per inhalation. The desired daily dose is usually 0.02-1000
mg, advantageously from 0.1 to 50 mg.
次に、本発明を実施例につき詳説する。 Next, the present invention will be explained in detail with reference to examples.
例 1
微細にした6α−フルオル−11β−ヒドロキシ
−3,20−ジオキソ−16α−メチル−1,4−プ
レグナジエン−21−酸−ブチルエステル−(平均
粒度:7μより小)1000g及び粉砕した乳糖
39000gを混合する。混合物各40mgを差込みカプ
セル(Steckkapsel)に充填する。吸入剤はカプ
セルを開けた後に吸入することによつて、有利に
は嗅ぐことによつて適用することができ又は吸入
剤を適用するためにシユピンハーレル
(Spinhaler)を使用する。Example 1 1000 g of finely divided 6α-fluoro-11β-hydroxy-3,20-dioxo-16α-methyl-1,4-pregnadiene-21-acid-butyl ester (average particle size: smaller than 7μ) and ground lactose
Mix 39000g. Fill 40 mg of each mixture into insert capsules (Steckkapsel). The inhalant can be applied by inhaling after opening the capsule, advantageously by sniffing or using a Spinhaler to apply the inhalant.
本例で使用した6α−フルオル−11β−ヒドロ
キシ−3,20−ジオキシ−16α−メチル−1,4
−プレグナジエン−21−酸−ブチルエステルは次
のようにして製造しうる。 6α-fluoro-11β-hydroxy-3,20-dioxy-16α-methyl-1,4 used in this example
-Pregnadiene-21-acid-butyl ester can be produced as follows.
(a) 6α−フルオル−11β,21−ジヒドロキシ−
16α−メチル−1,4−プレグナジエン−3,
20−ジオン10gをメタノール125mlに溶かしか
つメタノール125ml中の酢酸銅()250mgの溶
液を添加する。混合物を空気の導通下に室温で
15分間撹拌する。塩化メチレンで希釈し、5%
の塩化アンモニウム溶液及び水で洗浄し、硫酸
ナトリウム上で乾燥させかつ溶剤を40℃で真空
中で蒸発する。収率:粗生成物として6α−フ
ルオル−11β−ヒドロキシ−3,20−ジオキソ
−16α−メチル−1,4−プレグナジエン−21
−アール1.05g。(a) 6α-fluoro-11β,21-dihydroxy-
16α-methyl-1,4-pregnadiene-3,
10 g of 20-dione are dissolved in 125 ml of methanol and a solution of 250 mg of copper acetate () in 125 ml of methanol is added. The mixture was kept at room temperature under air circulation.
Stir for 15 minutes. Diluted with methylene chloride, 5%
ammonium chloride solution and water, dried over sodium sulfate and the solvent was evaporated in vacuo at 40°C. Yield: 6α-fluoro-11β-hydroxy-3,20-dioxo-16α-methyl-1,4-pregnadiene-21 as crude product
-R 1.05g.
(b) こうして得た生成物をブタノール50mlに溶か
しかつ溶液をシアン化カリウム165mg、酢酸1.0
ml、二酸化マンガン()5gを添加した後室
温で30分間撹拌する。二酸化マンガン()を
濾過することによつて除去し、濾液を塩化メチ
レンで希釈し、水で洗浄し、有機相を硫酸ナト
リウム上で乾燥させかつ真空中で蒸発乾固す
る。残渣を珪酸ゲルを用いてクロマトグラフイ
ーにかける。アセトン12〜15%/ヘキサンを用
いて粗生成物840mgを溶離させ、該生成物か
ら、アセトン/ヘキサンから再結晶させた後、
6α−フルオル−11β−ヒドロキシ−3,20−
ジオキソ−16α−メチル−1,4−プレグナジ
エン−21−酸−ブチルエステル735mgが得られ
る。融点195℃。(b) Dissolve the product thus obtained in 50 ml of butanol and mix the solution with 165 mg of potassium cyanide and 1.0 mL of acetic acid.
ml, and 5 g of manganese dioxide () and stirred at room temperature for 30 minutes. The manganese dioxide () is removed by filtration, the filtrate is diluted with methylene chloride, washed with water, the organic phase is dried over sodium sulfate and evaporated to dryness in vacuo. The residue is chromatographed using silicic acid gel. 840 mg of the crude product was eluted with 12-15% acetone/hexane, from which, after recrystallization from acetone/hexane,
6α-fluoro-11β-hydroxy-3,20-
735 mg of dioxo-16α-methyl-1,4-pregnadiene-21-acid-butyl ester are obtained. Melting point 195℃.
〔α〕D25=134゜(クロロホルム)。 [α] D 25 = 134° (chloroform).
例 2
微細にした6α−フルオル−9α−11β−ジク
ロル−3,20−ジオキソ−16α−メチル−1,4
−プレグナジエン−21−酸−ブチルエステル(平
均粒度:7μより小)1000g及び粉砕した乳糖
39000gを混合する。混合物各40mgを差込みカプ
セルに充填する。吸入剤はカプセルを開けた後、
吸入することによつて、有利には嗅ぐことによつ
て適用させることができ、又は吸入剤を適用させ
るためにスピンハーレルを使用する。Example 2 Finely divided 6α-fluoro-9α-11β-dichloro-3,20-dioxo-16α-methyl-1,4
- 1000 g of pregnadiene-21-acid-butyl ester (average particle size: smaller than 7μ) and ground lactose
Mix 39000g. Fill 40 mg of each mixture into insert capsules. After opening the inhaler capsule,
It can be applied by inhalation, advantageously by sniffing or using a spin harrell to apply the inhalant.
例 3
微細にした6α−フルオル−9α−クロル−11
β−ヒドロキシ−3,20−ジオキソ−16α−メチ
ル−1,4−プレグナジエン−21−酸−イソブチ
ルエステル(平均粒度:7μより小)1000g及び
粉砕した乳糖39000gを混合する。混合物各40mg
を差込みカプセルに充填する。吸入剤はカプセル
を開けた後に吸入することによつて、有利には嗅
ぐことによつて適用することができるし又は吸入
剤を適用するためにスピンハーレルを使用す
る。Example 3 Finely divided 6α-fluoro-9α-chloro-11
1000 g of β-hydroxy-3,20-dioxo-16α-methyl-1,4-pregnadiene-21-acid isobutyl ester (average particle size: smaller than 7 μm) and 39000 g of ground lactose are mixed. Mixture 40mg each
Insert and fill into the capsule. The inhalant can be applied by inhaling after opening the capsule, advantageously by sniffing or using a spin harrell to apply the inhalant.
例 4
配量添加弁(1用量=200mg;これは作用物質
1mgに相応する)を具備した噴霧容器に6α−フ
ルオル−11β−ヒドロキシ−3,20−ジオキソ−
16α−メチル−1,4−プレグナジエン−21−酸
−ブチルエステル25mg及びフリゲン12/114
(40:60)5.0mlを充填する。吸入剤は常法で適用
する。Example 4 6α-fluoro-11β-hydroxy-3,20-dioxo-
16α-Methyl-1,4-pregnadiene-21-acid-butyl ester 25mg and Frigen 12/114
(40:60) Fill 5.0ml. Inhalants are applied in the usual manner.
例 5
配量添加弁(1用量=200mg;これは作用物質
1mgに相当する)を具備した噴霧容器に6α,9
α−ジフルオル−11β−ヒドロキシ−3,20−ジ
オキソ−16α−メチル−1,4−プレグナジエン
−21−酸−ブチルエステル25mg及びフリゲン1
2/114(40:60)50mlを充填する。吸入剤は常法
で適用する。Example 5 In a spray container equipped with a dosing valve (1 dose = 200 mg; this corresponds to 1 mg of active substance)
α-difluoro-11β-hydroxy-3,20-dioxo-16α-methyl-1,4-pregnadiene-21-acid-butyl ester 25 mg and Frigen 1
Fill with 50ml of 2/114 (40:60). Inhalants are applied in the usual manner.
Claims (1)
弗素原子又は塩素原子を表わし、Zはヒドロキシ
メチレン基を表わすか、もしくはYが塩素を表わ
す場合にZはクロルメチレン基であつてもよく、
R1はメチル基を表わし、R2は水素原子を表わ
し、R3は炭素原子数4の炭化水素基を表わす〕
で示される、0.01〜20μの平均粒度を有する微細
化されたコルチコイドを、20〜200μの平均粒度
を有する固体の薬理作用のない水溶性賦形剤と密
に混合することを特徴とするコルチコイド含有粉
末吸入剤の製法。[Claims] 1 General formula (): [In the formula, X represents a fluorine atom, Y represents a hydrogen atom,
represents a fluorine atom or a chlorine atom, Z represents a hydroxymethylene group, or when Y represents chlorine, Z may be a chlormethylene group,
R 1 represents a methyl group, R 2 represents a hydrogen atom, and R 3 represents a hydrocarbon group having 4 carbon atoms]
corticoid-containing, characterized in that a micronized corticoid with an average particle size of 0.01 to 20 μ is intimately mixed with a solid non-pharmacological water-soluble excipient with an average particle size of 20 to 200 μ Method of manufacturing powder inhaler.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE2332663A DE2332663C2 (en) | 1973-06-23 | 1973-06-23 | Use of corticosteroid active ingredients for inhalation therapy |
Publications (2)
Publication Number | Publication Date |
---|---|
JPS5047967A JPS5047967A (en) | 1975-04-28 |
JPS6245846B2 true JPS6245846B2 (en) | 1987-09-29 |
Family
ID=5885228
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP49072169A Expired JPS6245846B2 (en) | 1973-06-23 | 1974-06-24 |
Country Status (13)
Country | Link |
---|---|
JP (1) | JPS6245846B2 (en) |
BE (1) | BE816709A (en) |
DD (1) | DD112437A5 (en) |
DE (1) | DE2332663C2 (en) |
DK (1) | DK337574A (en) |
ES (1) | ES427480A1 (en) |
FR (1) | FR2233987B1 (en) |
GB (1) | GB1479488A (en) |
IE (1) | IE39516B1 (en) |
IL (1) | IL45087A (en) |
NL (1) | NL184724C (en) |
SE (1) | SE7408091L (en) |
ZA (1) | ZA744022B (en) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
MX3864E (en) * | 1975-05-27 | 1981-08-26 | Syntex Corp | A PROCESS TO PREPARE THE CRYSTALLINE COMPOUND 6-FLUIRO-11B 21-DIHIROXI-16 17-ISOPROPILIDENDIOXIPREGNA-1 4-DIEN-3 20-DIONA |
DE2829953A1 (en) * | 1978-07-03 | 1980-01-24 | Schering Ag | PHARMACEUTICAL PREPARATION FOR TREATING THE KOLITIS ULCEROSA AND KOLITIS GRANULOMATOSA |
US5215979A (en) * | 1985-12-19 | 1993-06-01 | Aktiebolaget Draco | 16,17-acetalsubstituted pregnane 21-oic acid derivatives |
WO2006043655A1 (en) * | 2004-10-22 | 2006-04-27 | Ono Pharmaceutical Co., Ltd. | Medicinal composition for inhalation |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE1792207A1 (en) * | 1967-08-08 | 1971-11-04 | Fisons Pharmaceuticals Ltd | Pharmaceutical preparations |
DE2150268A1 (en) * | 1971-10-04 | 1973-04-12 | Schering Ag | 3, 20-dioxo-pregnene and pregnadiene 21-acids - antiinflammatories for topical application |
JPS4828620A (en) * | 1971-08-06 | 1973-04-16 | ||
JPS5046820A (en) * | 1971-06-22 | 1975-04-25 |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB799902A (en) * | 1954-08-11 | 1958-08-13 | Merck & Co Inc | Therapeutic preparations |
US3320125A (en) * | 1964-04-28 | 1967-05-16 | Merck & Co Inc | Inhalation aerosol composition |
GB1387911A (en) * | 1971-10-04 | 1975-03-19 | Schering Ag | Pregnane acid derivatives |
DE2264003C2 (en) * | 1972-12-22 | 1982-11-04 | Schering Ag, 1000 Berlin Und 4619 Bergkamen | New pregnanic acid derivatives, processes for their production and pharmaceutical preparations containing them |
DE2319479C2 (en) * | 1973-04-14 | 1982-10-28 | Schering Ag, 1000 Berlin Und 4619 Bergkamen | Pregnanic acid derivatives, processes for their production and pharmaceutical preparations containing them |
-
1973
- 1973-06-23 DE DE2332663A patent/DE2332663C2/en not_active Expired
-
1974
- 1974-06-19 SE SE7408091A patent/SE7408091L/ not_active Application Discontinuation
- 1974-06-20 ES ES427480A patent/ES427480A1/en not_active Expired
- 1974-06-20 IE IE1292/74A patent/IE39516B1/en unknown
- 1974-06-21 BE BE145751A patent/BE816709A/en not_active IP Right Cessation
- 1974-06-21 ZA ZA00744022A patent/ZA744022B/en unknown
- 1974-06-21 NL NLAANVRAGE7408421,A patent/NL184724C/en not_active IP Right Cessation
- 1974-06-21 IL IL45087A patent/IL45087A/en unknown
- 1974-06-24 GB GB27902/74A patent/GB1479488A/en not_active Expired
- 1974-06-24 JP JP49072169A patent/JPS6245846B2/ja not_active Expired
- 1974-06-24 DK DK337574A patent/DK337574A/da unknown
- 1974-06-24 DD DD179417A patent/DD112437A5/xx unknown
- 1974-06-24 FR FR7421859A patent/FR2233987B1/fr not_active Expired
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE1792207A1 (en) * | 1967-08-08 | 1971-11-04 | Fisons Pharmaceuticals Ltd | Pharmaceutical preparations |
JPS5046820A (en) * | 1971-06-22 | 1975-04-25 | ||
JPS4828620A (en) * | 1971-08-06 | 1973-04-16 | ||
DE2150268A1 (en) * | 1971-10-04 | 1973-04-12 | Schering Ag | 3, 20-dioxo-pregnene and pregnadiene 21-acids - antiinflammatories for topical application |
Also Published As
Publication number | Publication date |
---|---|
JPS5047967A (en) | 1975-04-28 |
BE816709A (en) | 1974-12-23 |
ES427480A1 (en) | 1976-07-16 |
DD112437A5 (en) | 1975-04-12 |
NL184724C (en) | 1989-10-16 |
AU7042174A (en) | 1976-01-08 |
GB1479488A (en) | 1977-07-13 |
DE2332663A1 (en) | 1975-01-16 |
NL184724B (en) | 1989-05-16 |
DE2332663C2 (en) | 1986-07-31 |
IL45087A0 (en) | 1974-09-10 |
SE7408091L (en) | 1974-12-23 |
IE39516B1 (en) | 1978-10-25 |
IL45087A (en) | 1978-04-30 |
ZA744022B (en) | 1975-06-25 |
DK337574A (en) | 1975-03-17 |
IE39516L (en) | 1974-12-23 |
FR2233987B1 (en) | 1977-07-08 |
NL7408421A (en) | 1974-12-30 |
FR2233987A1 (en) | 1975-01-17 |
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