JPH07507809A - 3-substituted-2-oxindole-1-carboxamide pharmaceutical composition - Google Patents

3-substituted-2-oxindole-1-carboxamide pharmaceutical composition

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JPH07507809A
JPH07507809A JP6509043A JP50904394A JPH07507809A JP H07507809 A JPH07507809 A JP H07507809A JP 6509043 A JP6509043 A JP 6509043A JP 50904394 A JP50904394 A JP 50904394A JP H07507809 A JPH07507809 A JP H07507809A
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アーメツド，イムラン
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フアイザー・インコーポレイテツド
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    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

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  • Biomedical Technology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Indole Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

(57)【要約】本公報は電子出願前の出願データであるため要約のデータは記録されません。 (57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

【発明の詳細な説明】 本発明は、特定の３−置換−２−オキシインドール−１−カルボキサミドと中鎖 （Ｃｍ　−Ｃ＋。）の脂肪酸トリグリセリド及びプロピレングリコールジエステ ルを含む医薬組成物に関する。これらのカルボキサミドは、米国特許第４゜５５ ６、６７２号及び第５．０４７．５５４号に記載されているように、ヒトを含め た哺乳類に使用するための鎮痛薬として、また手術若しくは他の外傷からの回復 期に経験する疼痛の軽減若しくは緩和、又は慢性関節リューマチ及び変形性関節 症にかかわる炎症及び疼痛のような慢性疾患の症状の改善に有用である。カルボ キサミドは、米国特許第５．００８．２８３号に示されているように、哺乳類の 骨吸収疾患、角膜潰瘍、歯周病、炎症性疾患並びに皮膚の創傷及び火傷のような コラゲナーゼ媒介疾患及び障害の治療にも有用である。[Detailed description of the invention] The present invention relates to specific 3-substituted-2-oxindole-1-carboxamides and medium-chain (Cm-C+) fatty acid triglyceride and propylene glycol diester The present invention relates to a pharmaceutical composition comprising the following. These carboxamides are described in U.S. Pat. 6,672 and 5.047.554, including humans. as an analgesic for use in treated mammals, and for recovery from surgery or other trauma. Reduction or alleviation of pain experienced during period, or chronic rheumatoid arthritis and osteoarthritis It is useful in improving symptoms of chronic diseases such as inflammation and pain associated with the disease. Calbo Xamide is a mammalian compound as shown in U.S. Pat. such as bone resorption diseases, corneal ulcers, periodontal diseases, inflammatory diseases and skin wounds and burns. It is also useful in treating collagenase-mediated diseases and disorders.

式Ｉで示されているカルボキサミドは、水中では化学的に不安定である。不安定 な薬剤の保護、例えば、ミセルの疎水性コアにおける金属イオン封鎖作用、又は 低水活性で非水性溶媒をベースとするビヒクル、即ち、精油中での処方により加 水分解率が低減され得ることが知られて（Ｘる。Carboxamides of formula I are chemically unstable in water. unstable protection of drugs, e.g. sequestration in the hydrophobic core of micelles, or Added by formulation in low water activity, non-aqueous solvent-based vehicles, i.e. essential oils. It is known that the water splitting rate can be reduced (X).

さらにカルボキサミドは、加水分解不安定性であること（こ加えて、水のような 水性ビヒクル及び油のような非水性ビヒクル中で酸化分解を受け易い。酸化不安 定性は、飽和油に酸化防止剤を入れるか、又はそれ自身を選択的に酸化させるこ とにより薬剤を保護する不飽和曲中で配合することにより低減可能である。しか し、式Ｉで示されてＧ）るカルボキサミドは、医薬製剤に一般に用いられてＬす る油類、ｆｌｌえば、胡麻油、落花生油、サフラワー油、綿実油中で１ま安定化 しに（い。Furthermore, carboxamides are hydrolytically unstable (in addition, Susceptible to oxidative degradation in aqueous vehicles and non-aqueous vehicles such as oils. oxidative anxiety Qualification involves adding antioxidants to saturated oils or selectively oxidizing them themselves. This can be reduced by formulating the drug in an unsaturated compound that protects the drug. deer However, carboxamides of formula I and G) are commonly used in pharmaceutical formulations. Stabilized in oils such as sesame oil, peanut oil, safflower oil, and cottonseed oil. Shini (I.

発明の要旨 本発明は、 （Ａ）少なくとも１種の分別椰子油脂肪酸トリグリセリド又はプロピレングリコ ールジエステル：及び（Ｂ）少なくとも１種の式Ｉ： 〔式中、Ｒ１、Ｒ２及びＲ３はそれぞれ独立に、水素、フルオロ、ブロモ又はク ロロである〕 の化合物又は医薬上許容可能なその塩を含み、（Ａ）と（Ｂ）の重量比が５．６ 〜９９９の範囲である医薬製剤に関する。Summary of the invention The present invention (A) at least one fractionated coconut oil fatty acid triglyceride or propylene glycolide; and (B) at least one of formula I: [In the formula, R1, R2 and R3 are each independently hydrogen, fluoro, bromo or carbon. It's Rolo] or a pharmaceutically acceptable salt thereof, and the weight ratio of (A) and (B) is 5.6. -999.

該医薬製剤は、（Ａ）８５〜９９重量％及び（Ｂ）０．１〜１５重量％を含む。The pharmaceutical formulation contains (A) 85-99% by weight and (B) 0.1-15% by weight.

Ｒ５、Ｒ２及びＲ３がそれぞれ独立にフルオロ又はクロロであるのが好ましい。Preferably, R5, R2 and R3 are each independently fluoro or chloro.

好ましい式Ｉの化合物には、 ５−クロロ−２，３−ジヒドロ−２−オキソ−３−（２−チエニル力ルボニル） −インドール−カルボキサミド。Preferred compounds of formula I include: 5-chloro-2,3-dihydro-2-oxo-3-(2-thienylcarbonyl) -Indole-carboxamide.

６−クロロ−５−フルオロ−２，３−７ヒドロー２−オキソ−３−（２−チェニ ルカルボニル）−インドールーカルホキサミド：及び ６−クロロ−５−フルオロ−２，３−ジヒドロ−２−オキソ−３−（２−（４− クロロ）−チェニルカルボニル）−インドール−カルボキサミド。6-chloro-5-fluoro-2,3-7hydro-2-oxo-3-(2-cheni carbonyl)-indolecarboxamide: and 6-chloro-5-fluoro-2,3-dihydro-2-oxo-3-(2-(4- Chloro)-thenylcarbonyl)-indole-carboxamide.

が含まれる。is included.

本発明はさらにコラゲナーゼの活性化を阻害する方法に関する。The invention further relates to methods of inhibiting collagenase activation.

さらに本発明は、炎症性疾患の治療法にも関する。The invention further relates to methods of treating inflammatory diseases.

本発明はまた、鎮痛応答を誘導する方法をも包含する。The invention also includes methods of inducing an analgesic response.

発明の詳細な説明 式ＩのカルボキサミドとＣｍ　−Ｃｏｏ飽和脂肪酸トリグリセリド及びプロピレ ングリコールジエステルとを含む医薬製剤は非常に優れた製品生存度（ｐｒｏｄ ｕｃｔ　ｖｉａｂｉｌｉｔｙ）及び貯蔵寿命を有することが見いだされた。その ような処方を用いた結果、カルボキサミドは、該カルボキサミドを劣化させ且つ 最終的に無効にし得る加水分解及び酸化を受けにくい。これらの製剤では、カル ボキサミドを安定化するために酸化防止剤又は他の補助安定剤を添加する必要は ない。Detailed description of the invention Carboxamide of formula I and Cm-Coo saturated fatty acid triglyceride and propylene Pharmaceutical formulations containing glycol diesters have very good product viability (prod uct viability) and shelf life. the As a result of using such a formulation, the carboxamide degrades and Resistant to hydrolysis and oxidation which may ultimately render it ineffective. These formulations contain There is no need to add antioxidants or other co-stabilizers to stabilize boxamide. do not have.

本発明に用いられるトリグリセリドは、分別椰子油とも称される中鎖（Ｃｓ−Ｃ ｏｏ）脂肪酸エステルから構成される天然油である。これらの脂肪酸はグリセリ ン又はプロピレングリコールによりエステル化され、ＭＩＧＬＹＯＬ　（登録商 標）〔即チ、ｔＩＧＬＹＯＬ　（ｕ録商標）　８１０．　ＭＩＧＬＹＯＬ　（ｕ 録商ｔｌＡ）　８１２及ヒＭＩＧＬＹＯＬ　（登録商標）　８４０）という商品 名で販売されている。ＭＩＧＬＹＯＬ類は、分別椰子油脂肪酸トリグリセリド又 はカプリル酸／カプリン酸トリグリセリドとも称されている。分別椰子油は、Ｃ ｏｃｏｓ　ｎｕｃｉｆｅｒａ　Ｌの胚乳の乾燥固体部分から得た脂肪油から、遊 離脂肪酸の加水分解、分別及びグリセロール又はプロピレングリコールによる再 エステル化により製造される。分別椰子油は、短鎖及び中鎖の飽和脂肪酸、主と してオクタン酸及びデカン酸の混合物から構成される。Ｍｉｇｌｙｏｌ　（登録 商標）は、独国及び英国のＤｙｎａｍｉｔ　Ｎｏｂｅｌ　Ｌｔｄ、から販売され ている分別椰子油又はカプリル酸／カプリン酸トリグリセリドの商標名である。The triglycerides used in the present invention are medium chain (Cs-C oo) A natural oil composed of fatty acid esters. These fatty acids are glycerin MIGLYOL (registered trademark) tIGLYOL (u registered trademark) 810. MIGLYOL (u A product called Rokusho tlA) 812 and Hi MIGLYOL (registered trademark) 840) sold under the name MIGLYOLs are fractionated coconut oil fatty acid triglycerides or is also called caprylic/capric triglyceride. Fractionated coconut oil is C From the fatty oil obtained from the dry solid part of the endosperm of ocos nucifera L. Hydrolysis, fractionation and reconstitution of isolated fatty acids with glycerol or propylene glycol Produced by esterification. Fractionated coconut oil contains mainly short and medium chain saturated fatty acids. It is composed of a mixture of octanoic acid and decanoic acid. Miglyol (registration) Trademark) is sold by Dynamit Nobel Ltd in Germany and the UK. It is a trade name for fractionated coconut oil or caprylic/capric acid triglyceride.

これらのビヒクルは、酸化及び酸敗化に対して安定性を有することに加えて、そ の優れた安全性及び生体適合性も実証された。さらに、飽和脂肪酸のみを用いる ことから、油類中に内包されている医薬品を不安定にし得る過酸化物又は池のラ ジカルを生成しない。含水量が低いことにより、カルボキサミドの加水分解も最 小限に抑制される。好ましい組成においては、式■のカルボキサミドを、撹拌し ながらＭｉｇｌｙｏｌ　（登録商標）８１２及び下記の他の油溶性添加剤を含む 油性ビヒクル中に分散させ、油性ビヒクル中の薬剤物質の均質懸濁液を生成する 。In addition to being stable against oxidation and rancidity, these vehicles Excellent safety and biocompatibility were also demonstrated. Additionally, only saturated fatty acids are used. Therefore, peroxides or pond lanterns that can destabilize pharmaceuticals contained in oils are Does not generate radicals. The low water content also minimizes the hydrolysis of carboxamides. suppressed to a minimum. In a preferred composition, the carboxamide of formula Contains Miglyol® 812 and other oil-soluble additives listed below. Disperse in an oil vehicle to produce a homogeneous suspension of the drug substance in the oil vehicle .

医薬製剤中に存在し得る他の添加剤には、例えば、プロピレングリコール、ポリ エチレングリコール、グリセリン、ソルビトール、ベンジルアルコール、レシチ ン又はステアリン酸アルミニウムのような凝結防止剤が含まれてよい。Other excipients that may be present in the pharmaceutical formulation include, for example, propylene glycol, poly Ethylene glycol, glycerin, sorbitol, benzyl alcohol, lecithyl Anticaking agents such as aluminum or aluminum stearate may be included.

凝結防止剤の量は、約０．０５〜５重量％の範囲であってよい。The amount of anticaking agent may range from about 0.05 to 5% by weight.

さらに医薬製剤は、０．５〜２．０重量％の範囲の量の保存料を含んでいてよい 。そのような保存料には、例えば、フェノール、ベンジルアルコール、パラベン 、クロルブタノール及び安息香酸ベンジルが含まれ得る。モノステアリン酸アル ミニウムのようなゲル化剤も医薬製剤中０．５〜３．０容量％の範囲の量で含ま れていてよい。Furthermore, the pharmaceutical formulation may contain a preservative in an amount ranging from 0.5 to 2.0% by weight. . Such preservatives include, for example, phenol, benzyl alcohol, and parabens. , chlorbutanol and benzyl benzoate. Al monostearate Gelling agents such as minium are also included in the pharmaceutical formulation in amounts ranging from 0.5 to 3.0% by volume. It's good that it is.

これらの医薬製剤の安定度は、例えば、ガラスノくイアルに封入されたカルボキ サミド（薬剤物質の６重量％）懸濁液を９週目までに７０℃までの高温にした後 で促進貯蔵条件下で評価することが可能である。安定度試験の間、加水分解及び 酸化的分解生成物に加えて、製剤中に残存する影響を受けていない薬剤の量を高 速液体クロマトグラフィー（ＨＰ　Ｌ　Ｃ）により定量する。検定用には、懸濁 液をメタノール／トリエチルアミン１００／１（容量／容量）で希釈して、０． ６〜１．２ｍｇ／ａ＋１という最終薬剤濃度にする。この溶媒により懸濁薬剤が 溶解して、直接ＨＰＬＣカラムに注入し得る溶液が生成される。クロマトグラフ ィー用には、移動相はメタノール／水（９０／１０ｖ／ｖ）　＋１％トリエチル アミンであり、カラムは逆相オクタデカシランであり、溶媒の移動速度は１ｍｌ ／分である。薬剤は、２４６ｎａ＋での紫外線吸光度により検出する。そのよう な検定により、カルボキサミドは９週間後にも懸濁液中で全く分解していないこ とが判明した。The stability of these pharmaceutical formulations is determined by, for example, carboxyl encapsulated in glass vials. After heating the samide (6% by weight of drug substance) suspension to elevated temperatures up to 70°C by the 9th week. It is possible to evaluate under accelerated storage conditions. During stability testing, hydrolysis and In addition to oxidative degradation products, it increases the amount of unaffected drug remaining in the formulation. Quantitated by high performance liquid chromatography (HPLC). For assay, suspension The solution was diluted with methanol/triethylamine 100/1 (vol/vol) to a concentration of 0. A final drug concentration of 6-1.2 mg/a+1 is achieved. This solvent allows the drug to be suspended. A solution is produced that can be dissolved and injected directly into an HPLC column. chromatograph For water, the mobile phase was methanol/water (90/10v/v) + 1% triethyl amine, the column was reverse phase octadecasilane, and the solvent transfer rate was 1 ml. /minute. Drugs are detected by UV absorbance at 246na+. Like that A thorough assay showed that the carboxamide did not degrade at all in the suspension after 9 weeks. It turned out that.

式Ｉの化合物又はその塩をヒトの患者に用いる場合、−日の用量は一般に処方す る医師によって決定される。さらに用量は、個々の患者の年齢、体重及び応答に 加えて、患者の症状の重篤度及び投与される特定の化合物の力価により異なるで あろう。しかし疼痛緩和のための急性期投与では、有効用量は殆どの場合、必要 に応じて（例えば、１日１回〜４回）０．０１〜０．２５ｇの範囲となろう。長 期的な投与では、有効用量は殆どの場合、１回又は分割投与で１日当たり０．０ １〜０．５ｇの範囲、好ましくは０．１〜０．２５ｇの範囲であろう。しかし、 これらの限度を超える用量を用いることが必要な場合もあり得る。When a compound of formula I or a salt thereof is used in human patients, the -day dose will generally be less than the prescribed dose. determined by the attending physician. Additionally, dosage will depend on the age, weight and response of the individual patient. In addition, it may vary depending on the severity of the patient's symptoms and the potency of the particular compound administered. Probably. However, for acute administration for pain relief, the effective dose is almost always It will range from 0.01 to 0.25 g depending on the situation (e.g., 1 to 4 times a day). long For chronic administration, the effective dose is most often 0.0 ml per day in single or divided doses. It will be in the range 1-0.5g, preferably in the range 0.1-0.25g. but, It may be necessary to use doses above these limits.

本発明の医薬組成物が非経口医薬組成物であるのが好ましい。本発明の医薬組成 物は、単位剤型中に式Ｉの化合物（有効成分として）を配合して製造され得る。Preferably, the pharmaceutical composition of the invention is a parenteral pharmaceutical composition. Pharmaceutical composition of the present invention Products may be prepared incorporating a compound of Formula I (as the active ingredient) in unit dosage form.

単位剤型の例をいくつか挙げると、筋肉内、皮下又は関節内注射用の滅菌懸濁剤 、眼への局所投与用の滅菌眼科用懸濁剤、経口投与用のカプセル剤、直腸用座薬 又は皮膚若しくは頭皮への適用用４局所用ローションがある。Some examples of unit dosage forms include: sterile suspensions for intramuscular, subcutaneous or intraarticular injection; , sterile ophthalmic suspensions for topical administration to the eye, capsules for oral administration, rectal suppositories There are also four topical lotions for application to the skin or scalp.

経口投与用に好適な医薬剤型の例としては、軟質ゼラチンカプセル剤がある。経 口投与される懸濁剤は、例えば、軟質ゼラチンカプセル中に、油、即ち旧ｇｌｙ ｏｌ　８１２中の式■の化合物懸濁液を封入して投与することが可能である。An example of a pharmaceutical dosage form suitable for oral administration is a soft gelatin capsule. Sutra Suspensions for oral administration can be prepared, for example, in soft gelatin capsules containing oil, i.e. A suspension of the compound of formula (1) in ol 812 can be administered in an encapsulated manner.

直腸用座薬は、カルボキサミドを、体温を超える融点を有するココアバター若し くはＷｈｉｔｅｐｓｏｌ　Ｗ３５のような適合性座薬基剤と共に中性油中に分散 させて処方すればよい。皮膚に適用するための局所用製品は、活性剤としてのカ ルボキサミドを中性油、例えばＭｉｇｌｙｏｌ　８１２中に分散して含み、さら に希釈剤及び保存料として、セチルアルコール、ステアリン酸、プロピレングリ コール、モノステアリン酸アルミニウム、ベンジルアルコールのような１種以上 の不活性医薬成分を含んでいる。非経口組成物は、中性油中のカルボキサミド懸 濁液であるのが好ましく、さらに保存料としてのベンジルアルコール、ゲル化剤 としてのモノステアリン酸アルミニウム及び分散剤としてのプロピレングリコー ルのような他の不活性医薬成分を含んでいてもよい。Rectal suppositories contain carboxamides such as cocoa butter, which has a melting point above body temperature. or dispersed in a neutral oil with a compatible suppository base such as Whitepsol W35. You can prescribe it. Topical products for application to the skin contain calcium as an active agent. Contains ruboxamide dispersed in a neutral oil, such as Miglyol 812, and further Cetyl alcohol, stearic acid, propylene glycerin as diluents and preservatives. one or more such as alcohol, aluminum monostearate, benzyl alcohol Contains inactive pharmaceutical ingredients. Parenteral compositions contain carboxamides suspended in neutral oil. Preferably, it is a cloudy liquid, and further contains benzyl alcohol as a preservative and a gelling agent. Aluminum monostearate as a and propylene glycol as a dispersant It may also contain other inactive pharmaceutical ingredients such as drugs.

下記の実施例は、医薬製剤の製造法を示している。市販の試薬をさらに精製する ことなく用いてよい。The examples below demonstrate methods of manufacturing pharmaceutical formulations. Further purify commercially available reagents It can be used without exception.

実施例１ 撹拌器及びホモジナイザーを備えた配合容器中で、８００Ｉ１１１のＭｉｇｌｙ ｏｌ　８１２を４５℃に加熱した。ベンジルアルコール１０ｇを撹拌（約６０− ８ＯＲ０Ｐ、Ｍ、）Ｌながら油に添加した。油溶液を、撹拌器及びホモジナイザ ーを備えた滅菌配合容器中に滅菌濾過した。カルボキサミドの滅菌超微粉１２０ ｇを撹拌しながら油性相に分散させた。懸濁液を高剪断力下に１０分間ホモジナ イズし、次いでゆるやかに撹拌（６０−８ＯＲ，Ｐ、Ｍ。Example 1 In a blending vessel equipped with a stirrer and homogenizer, mix 800I111 Migly ol 812 was heated to 45°C. Stir 10g of benzyl alcohol (approximately 60- 8OR0P,M,)L was added to the oil. Oil solution with stirrer and homogenizer Sterile filter into a sterile compounding container equipped with a Sterilized ultrafine carboxamide powder 120 g was dispersed in the oily phase with stirring. Homogenize the suspension under high shear for 10 min. and then gently stir (60-8OR, P, M.

）しながら室温に冷却した。懸濁液に所要量の滅菌Ｍｉｇｌｙ。) while cooling to room temperature. Sterile Migly in the required amount for suspension.

１８１２を添加し、懸濁液を総バッチ重量１．０００ｇに調整して、最終処方物 におけるカルボキサミドの最終濃度を１２重量％にした。懸濁液を自動充填装置 を用いて５０ｃｃの■型フリントガラスバイアル中に無菌充填した。テフロン被 覆ゴムストッパーでバイアルに蓋をし、アルミニウムシェルでクリ撹拌器及びホ モジナイザーを備えた配合容器中で、８００ｍ１のＭｉｇｌｙｏｌ　８１２を４ ５℃に加熱した。ベンフルアルコール１０ｇを撹拌（約６０−８ＯＲ，Ｐ、Ｍ、 ）Ｌながら油に添加した。撹拌器及びホモジナイザーを備えた滅菌配合容器中に 油溶液を滅菌濾過した。滅菌モノステアリン酸アルミニウム粉末２０ｇを撹拌し ながら少しずつ油溶液に添加して油をゲル化した。ゲル化した油を室温に冷却し 、撹拌せずに６時間放置した。次いでカルボキサミドの滅菌超微粉１２０ｇを撹 拌しながらゲル化した油中に分散させた。懸濁液に所要量の滅菌ゲル化Ｍｉｇｌ ｙｏｌ　８１２を添加して、懸濁液を総ノく・ソチ重量１．０００ｇに調整して 、最終処方物におけるカルボキサミドの最終濃度を１２重量％にした。自動充填 装置を用いて懸濁液を５０ｃｃのＩ型フリントガラスバイアル中に無菌棲遥充填 した。1812 and adjust the suspension to a total batch weight of 1.000 g to give the final formulation. The final concentration of carboxamide in was 12% by weight. Automatic suspension filling device The mixture was aseptically filled into a 50 cc type flint glass vial using a . Teflon coated Cap the vial with a rubber stopper and attach the aluminum shell to the stirrer and bottle. In a blending vessel equipped with a modifier, add 800 ml of Miglyol 812 to 4 Heated to 5°C. Stir 10g of benflu alcohol (approximately 60-8OR, P, M, ) L was added to the oil. in a sterile compounding container equipped with a stirrer and homogenizer. The oil solution was sterile filtered. Stir 20g of sterile aluminum monostearate powder. The oil was added little by little to the oil solution to gel the oil. Cool the gelled oil to room temperature , and left for 6 hours without stirring. Next, stir 120 g of sterile ultrafine powder of carboxamide. It was dispersed in the gelled oil with stirring. Add the required amount of sterile gelled Migl to the suspension. Add yol 812 and adjust the suspension to a total weight of 1.000 g. , the final concentration of carboxamide in the final formulation was 12% by weight. automatic filling Aseptically fill the suspension into 50 cc type I flint glass vials using a device. did.

テフロン被覆ゴムストッパーでバイアルに蓋をし、アルミニウムシェルでクリン プした。Cap the vial with a Teflon-coated rubber stopper and secure with an aluminum shell. I typed it.

実施例３ 撹拌器及びホモジナイザーを備えた配合容器中で、８００ｍ１のＭｉｇｌｙｏｌ 　８１２を４５℃に加熱した。ベンジルアルコール１０ｇを撹拌（約６０−８Ｏ Ｒ，Ｐ、Ｍ、）Ｌなから油に添加した。カルボキサミドの滅菌超微粉１２０ｇを 撹拌しながら油性相に分散させた。懸濁液を高剪断力下に１０分間ホモジナイズ し、次いでゆるやかに撹拌（６０−８ＯＲ，Ｐ、Ｍ、）　Ｌ、ながら室温に冷却 した。懸濁液に所要量のＭｉｇｌｙｏｌ　８１２を添加し、懸濁液を総バッチ重 量１．０００ｇに調整して、最終処方物におけるカルボキサミドの最終濃度を１ ２重量％にした。経口投与用の自動充填装置を用いて懸濁液を軟質ゼラチンカプ セルに充撹拌器及びホモジナイザーを備えた配合容器中で、２００ｇのＭｉｇｌ ｙｏｌ　８１２及び８００ｇのＷｈｉｔｅｐｓｏｌ　１３５を６０°Ｃに加熱し た。Example 3 In a blending vessel equipped with a stirrer and homogenizer, add 800 ml of Miglyol. 812 was heated to 45°C. Stir 10g of benzyl alcohol (approximately 60-80 R, P, M, ) L was added to the oil. 120g of sterilized ultrafine powder of carboxamide Disperse in the oily phase with stirring. Homogenize the suspension under high shear for 10 min. Then cool to room temperature while stirring gently (60-8OR, P, M,) L. did. Add the required amount of Miglyol 812 to the suspension and bring the suspension to the total batch weight. The final concentration of carboxamide in the final formulation was adjusted to 1.000 g. 2% by weight. Fill the suspension into soft gelatin capsules using automatic filling equipment for oral administration. In a blending vessel equipped with a cell charging stirrer and homogenizer, 200 g of Migl. Heat yol 812 and 800g Whitepsol 135 to 60°C. Ta.

得られた油溶液にカルボキサミド粉末を撹拌しながら分散させた。懸濁液を座薬 型に充填し、室温に冷却して固化した。Carboxamide powder was dispersed in the obtained oil solution with stirring. suspension suppositories It was filled into a mold, cooled to room temperature, and solidified.

Claims (20)

【特許請求の範囲】[Claims] １．（Ａ）少なくとも１種の分別椰子油脂肪酸トリグリセリド又はプロピレング リコールジエステル；及び（Ｂ）少なくとも１種の式Ｉ： ▲数式、化学式、表等があります▼Ｉ 〔式中、Ｒ１、Ｒ２及びＲ３はそれぞれ独立に、水素、フルオロ、ブロモ又はク ロロである〕 の化合物又は医薬上許容可能なその塩を含み、（Ａ）と（Ｂ）の重量比が５．６ 〜９９９の範囲である医薬製剤。1. (A) at least one fractionated coconut oil fatty acid triglyceride or propylene; recall diester; and (B) at least one of formula I: ▲There are mathematical formulas, chemical formulas, tables, etc.▼I [In the formula, R1, R2 and R3 are each independently hydrogen, fluoro, bromo or carbon. It's Rolo] or a pharmaceutically acceptable salt thereof, and the weight ratio of (A) and (B) is 5.6. Pharmaceutical formulations ranging from ~999. ２．前記製剤が、（Ａ）８５〜９９重量％と（Ｂ）０．１〜１５重量％を含む請 求項１に記載の医薬製剤。2. The formulation contains (A) 85 to 99% by weight and (B) 0.1 to 15% by weight. The pharmaceutical formulation according to claim 1. ３．Ｒ１、Ｒ２及びＲ３がそれぞれ独立にフルオロ又はクロロである請求項１に 記載の医薬製剤。3. Claim 1, wherein R1, R2 and R3 are each independently fluoro or chloro. Pharmaceutical formulations as described. ４．式Ｉの化合物が、 ５−クロロ−２，３−ジヒドロ−２−オキソ−３−（２−チエニルカルボニル） −インドールーカルボキサミド；６−クロロ−５−フルオロ−２，３−ジヒドロ −２−オキソ−３−（２−チエニルカルボニル）−インドール−カルボキサミド ；及び ６−クロロ−５−フルオロ−２，３−ジヒドロ−２−オキソ−３−（２−（４− クロロ）−チエニルカルボニル）−インドールーカルボキサミド； からなる群から選択される請求項１に記載の医薬製剤。4. The compound of formula I is 5-chloro-2,3-dihydro-2-oxo-3-(2-thienylcarbonyl) -indolecarboxamide; 6-chloro-5-fluoro-2,3-dihydro -2-oxo-3-(2-thienylcarbonyl)-indole-carboxamide ;as well as 6-chloro-5-fluoro-2,3-dihydro-2-oxo-3-(2-(4- chloro)-thienylcarbonyl)-indolecarboxamide; A pharmaceutical formulation according to claim 1 selected from the group consisting of. ５．式Ｉの化合物が５−クロロ−２，３−ジヒドロ−２−オキソ−３−（２−チ エニルカルボニル）−インドールーカルボキサミドである請求項１に記載の医薬 製剤。5. If the compound of formula I is 5-chloro-2,3-dihydro-2-oxo-3-(2-thi The medicament according to claim 1, which is an enylcarbonyl)-indole carboxamide. formulation. ６．式Ｉの化合物が６−クロロ−５−フルオロ−２，３−ジヒドロ−２−オキソ −３−（２−チエニルカルボニル）−インドールーカルボキサミドである請求項 １に記載の医薬製剤。6. If the compound of formula I is 6-chloro-5-fluoro-2,3-dihydro-2-oxo -3-(2-thienylcarbonyl)-indolecarboxamide 1. Pharmaceutical formulation according to item 1. ７．式Ｉの化合物が６−クロロ−５−フルオロ−２，３−ジヒドロ−２−オキソ −３−（２−（４−クロロ）−チエニルカルボニル）−インドールーカルボキサ ミドである請求項１に記載の医薬製剤。7. If the compound of formula I is 6-chloro-5-fluoro-2,3-dihydro-2-oxo -3-(2-(4-chloro)-thienylcarbonyl)-indolecarboxa The pharmaceutical formulation according to claim 1, which is a mido. ８．前記椰子油脂肪酸がＣ８−Ｃ１０脂肪酸を含む請求項１に記載の医薬製剤。8. The pharmaceutical formulation according to claim 1, wherein the coconut oil fatty acids comprise C8-C10 fatty acids. ９．前記椰子油脂肪酸がカプリル酸、カプロン酸、ラウリン酸及びリノール酸を 含む請求項８に記載の医薬製剤。9. The coconut oil fatty acids include caprylic acid, caproic acid, lauric acid and linoleic acid. A pharmaceutical formulation according to claim 8, comprising: １０．凝結防止剤０．０５〜５重量％をさらに含む請求項１に記載の医薬製剤。10. The pharmaceutical formulation according to claim 1, further comprising 0.05-5% by weight of an anti-caking agent. １１．前記凝結防止剤が、プロピレングリコール、ポリエチレングリコール、グ リセリン、ソルビトール、ベンジルアルコール、レシチン又はステアリン酸アル ミニウムである請求項１０に記載の医薬製剤。11. The anti-caking agent may be propylene glycol, polyethylene glycol, glycol, etc. Lyserine, sorbitol, benzyl alcohol, lecithin or stearic acid 11. The pharmaceutical formulation according to claim 10, which is a minium. １２．保存料０．５〜２．０重量％をさらに含む請求項１０に記載の医薬製剤。12. The pharmaceutical formulation according to claim 10, further comprising 0.5-2.0% by weight of a preservative. １３．前記保存料が、フェノール、ベンジルアルコール、バラベン、クロルブタ ノール又は安息香酸ベンジルである請求項１２に記載の医薬製剤。13. The preservatives include phenol, benzyl alcohol, paraben, chlorbutane The pharmaceutical formulation according to claim 12, which is benzyl benzoate. １４．前記医薬製剤が、経口、局所用、眼用、非経口又は直腸内投与用に適して いる請求項１に記載の医薬製剤。14. The pharmaceutical preparation is suitable for oral, topical, ophthalmic, parenteral or rectal administration. The pharmaceutical formulation according to claim 1. １５．前記医薬製剤が式Ｉの化合物０．０１〜１．０ｇを含む請求項１に記載の 医薬製剤。15. 2. The pharmaceutical formulation according to claim 1, wherein the pharmaceutical formulation contains 0.01 to 1.0 g of the compound of formula I. Pharmaceutical formulations. １６．前記医薬製剤が式Ｉの化合物２０〜２５０ｍｇを含む請求項１５に記載の 医薬製剤。16. 16. The pharmaceutical formulation according to claim 15, wherein the pharmaceutical formulation comprises 20 to 250 mg of the compound of formula I. Pharmaceutical formulations. １７．哺乳類にコラゲナーゼの活性化阻害量の請求項１の医薬製剤を投与するこ とを含む、コラゲナーゼの活性化阻害を要する哺乳類のコラゲナーゼの活性化阻 害法。17. Administering to a mammal the pharmaceutical preparation of claim 1 in an amount that inhibits the activation of collagenase. Inhibition of collagenase activation in mammals that requires inhibition of collagenase activation, including Harm law. １８．哺乳類に鎮痛応答誘導量の請求項１に記載の医薬製剤を投与することを含 む、哺乳類の鎮痛応答誘導法。18. comprising administering to a mammal an analgesic response-inducing amount of the pharmaceutical formulation according to claim 1. A method for inducing analgesic responses in mammals. １９．哺乳類に炎症性疾患治療量の請求項１に記載の医薬製剤を投与することを 含む、哺乳類の炎症性疾患治療法。19. administering to a mammal an inflammatory disease therapeutic amount of a pharmaceutical formulation according to claim 1. Treatment of inflammatory diseases in mammals, including. ２０．（Ａ）少なくとも１種の分別椰子油脂肪酸トリグリセリド又はプロピレン グリコールジエステル；（Ｂ）少なくとも１種の式Ｉ： ▲数式、化学式、表等があります▼Ｉ 〔式中、Ｒ１、Ｒ２及びＲ３はそれぞれ独立に、水素、フルオロ、ブロモ若しく はクロロである〕 の化合物又は医薬上許容可能なその塩；（Ｃ）凝結防止剤０〜５重量％；及び （Ｄ）保存料０〜２．０重量％ を含み、（Ａ）と（Ｂ）の重量比が５．６〜９９９の範囲である医薬製剤。20. (A) at least one fractionated coconut oil fatty acid triglyceride or propylene; Glycol diester; (B) at least one of formula I: ▲There are mathematical formulas, chemical formulas, tables, etc.▼I [In the formula, R1, R2 and R3 are each independently hydrogen, fluoro, bromo or is Chloro] or a pharmaceutically acceptable salt thereof; (C) 0 to 5% by weight of an anticaking agent; and (D) Preservative 0-2.0% by weight A pharmaceutical formulation comprising: (A) and (B) in a weight ratio of 5.6 to 999.
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TW438798B (en) 2001-06-07
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BR9307182A (en) 1999-03-30
FI934387A7 (en) 1994-04-08
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ZA937405B (en) 1995-04-06
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FI934387L (en) 1994-04-08
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HU9302821D0 (en) 1993-12-28
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EG20289A (en) 1998-07-30
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HUT68533A (en) 1995-04-27
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IL107122A (en) 1998-08-16
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CN1089138A (en) 1994-07-13
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