JPH07112975B2 - solid preparations - Google Patents

solid preparations

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Publication number
JPH07112975B2
JPH07112975B2 JP3-512846A JP51284691A JPH07112975B2 JP H07112975 B2 JPH07112975 B2 JP H07112975B2 JP 51284691 A JP51284691 A JP 51284691A JP H07112975 B2 JPH07112975 B2 JP H07112975B2
Authority
JP
Japan
Prior art keywords
organic solvent
powder
bof
mixed
solid formulation
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 - Lifetime
Application number
JP3-512846A
Other languages
Japanese (ja)
Other versions
JPH07112975B1 (en
JPWO1992001453A1 (en
Inventor
徹 西林
良博 礎
光三 石田
正則 久保
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Otsuka Pharmaceutical Co Ltd
Original Assignee
Otsuka Pharmaceutical Co Ltd
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Filing date
Publication date
Application filed by Otsuka Pharmaceutical Co Ltd filed Critical Otsuka Pharmaceutical Co Ltd
Priority to JP3-512846A priority Critical patent/JPH07112975B2/en
Publication of JPWO1992001453A1 publication Critical patent/JPWO1992001453A1/en
Publication of JPH07112975B1 publication Critical patent/JPH07112975B1/ja
Publication of JPH07112975B2 publication Critical patent/JPH07112975B2/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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Classifications

    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Inorganic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

【発明の詳細な説明】 産業上の利用分野 本発明は、固型製剤に関する。[Detailed Description of the Invention] Industrial Application Field The present invention relates to solid formulations.

発明の開示 ３−［３−（６−ベンゾイルオキシ−３−シアノ−２−
ピリジルオキシカルボニル）ベンゾイル］−１−エトキ
シメチル−５−フルオロウラシル（以下「BOF−A2」と
いう）は、生体内に投与された後、化学的加水分解及び
酵素分解により１−エトキシメチル−５−フルオロウラ
シル（以下「EM−FU」という）と３−シアノ−2,6−ジ
ヒドロピリジン（以下「CNDP」という）とになり、EM−
FUは徐々に５−フルオロウラシル（以下「５−FU」とい
う）に変換され、CNDPは５−FUの代謝阻害剤として働
き、持続的で強力な制癌作用を示すことが知られてい
る。Disclosure of the Invention 3-[3-(6-benzoyloxy-3-cyano-2-
After administration to the body, [(pyridyloxycarbonyl)benzoyl]-1-ethoxymethyl-5-fluorouracil (hereinafter referred to as "BOF-A2") is converted into 1-ethoxymethyl-5-fluorouracil (hereinafter referred to as "EM-FU") and 3-cyano-2,6-dihydropyridine (hereinafter referred to as "CNDP") by chemical hydrolysis and enzymatic decomposition.
FU is gradually converted into 5-fluorouracil (hereinafter referred to as "5-FU"), and CNDP acts as a metabolic inhibitor of 5-FU, and is known to exhibit a long-lasting and potent anticancer effect.

しかしながら、BOF−A2は水に対して難溶性であるた
め、通常の製剤技術、例えば賦形剤等を加えて顆粒剤や
錠剤とする技術では、調製した製剤からの溶解性が極め
て悪く、その結果消化官からの速かな吸収が維持できな
いという欠点を有する。However, because BOF-A2 is poorly soluble in water, conventional formulation techniques, such as adding excipients to form granules or tablets, result in extremely poor solubility in the prepared formulation, which has the disadvantage that rapid absorption from the digestive tract cannot be maintained.

一般に難溶性の医薬物質の溶出を高める手段としては、
（１）医薬物質を可溶性の誘導体に変換し、その誘導体
を使用する、（２）製剤化の際に界面活性剤等の溶解補
助剤を添加する、等が挙げられるが、BOF−A2の場合に
はこれらの手段によっては未だ満足すべき結果が得られ
ていない。即ち、BOF−A2の場合、比較的分子量が大き
くまた加水分解を受けやすいため、親水基の導入による
溶解性の改善は極めて困難である。また一般的に溶解補
助剤として用いられるポリソルベート80、ラウリル硫酸
ナトリウム、ステアリン酸ポリオキシリル40等の界面活
性剤を添加した製剤においても、その溶出改善効果は小
さく、実用上満足できるものではない。Generally, the following methods are used to enhance the dissolution of poorly soluble pharmaceutical substances:
These include (1) converting the drug substance into a soluble derivative and using that derivative, and (2) adding a solubilizing agent such as a surfactant during formulation. However, in the case of BOF-A2, these methods have not yet produced satisfactory results. In other words, because BOF-A2 has a relatively large molecular weight and is susceptible to hydrolysis, it is extremely difficult to improve its solubility by introducing hydrophilic groups. Furthermore, even in formulations where surfactants, such as polysorbate 80, sodium lauryl sulfate, and polyoxylyl 40 stearate, which are commonly used as solubilizing agents, have been added, the effect of improving dissolution is small and not practically satisfactory.

本発明者らは、斯かる現状に鑑みBOF−A2の溶解性の改
善を図るべく鋭意研究を重ね、遂に本発明を完成するに
至った。In view of the above-mentioned circumstances, the present inventors have conducted extensive research to improve the solubility of BOF-A2, and have finally completed the present invention.

即ち、本発明は、BOF−A2とヒドロキシプロピルメチル
セルロースまたはヒドロキシプロピルセルロースとを有
機溶媒に完全に溶解し、次いで有機溶媒を除去して非晶
質化させた粉末を製剤化してなることを特徴とする固型
製剤に係る。That is, the present invention relates to a solid preparation characterized by being prepared by completely dissolving BOF-A2 and hydroxypropylmethylcellulose or hydroxypropylcellulose in an organic solvent, then removing the organic solvent to form an amorphous powder.

BOF−A2と配合される成分としては、ヒドロキシプロピ
ルメチルセルロースとヒドロキシプロピルセルロースが
吸収性の点から好ましく、ヒドロキシプロピルメチルセ
ルロースが保存安定性の点から特に好ましい。As the components to be blended with BOF-A2, hydroxypropyl methylcellulose and hydroxypropyl cellulose are preferred in terms of absorbency, and hydroxypropyl methylcellulose is particularly preferred in terms of storage stability.

本発明で用いられるヒドロキシプロピルメチルセルロー
スには、メトキシル基を19〜30％、ヒドロキシプロピル
基を４〜12％含有し、粘度が３〜30000cps（２％水溶
液、20℃）、好ましくは３〜4000cpsの範囲にあるもの
が包含される。The hydroxypropyl methylcellulose used in the present invention includes those containing 19 to 30% methoxyl groups and 4 to 12% hydroxypropyl groups and having a viscosity in the range of 3 to 30,000 cps (2% aqueous solution, 20°C), preferably 3 to 4,000 cps.

本発明において、有機溶媒としては、BOF−A2及びヒド
ロキシプロピルメチルセルロースおよびヒドロキシプロ
ピルセルロースを完全に溶解し得るものである限り従来
公知のものをいずれも使用でき、具体的にはメタノー
ル、エタノール、イソプロパノール等の低級アルコール
類、アセトン、メチルエチルケトン等のケトン類、ジク
ロロメタン、ジクロロエタン、クロロホルム、四塩化炭
素等のハロゲン化炭化水素類等やこれらの混合溶媒等を
例示できる。更に必要ならばこれら溶媒に精製水を添加
したものでもよい。これらの有機溶媒の中でも、低級ア
ルコール類とハロゲン化炭化水素類との混合溶媒が、溶
解性およびその後の除去の面から好ましく、メタノール
もしくはエタノールと塩化メチレンとの混合溶媒が特に
好適である。In the present invention, any conventionally known organic solvent can be used as long as it can completely dissolve BOF-A2, hydroxypropylmethylcellulose, and hydroxypropylcellulose. Specific examples include lower alcohols such as methanol, ethanol, and isopropanol; ketones such as acetone and methyl ethyl ketone; halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, and carbon tetrachloride; and mixed solvents thereof. Furthermore, if necessary, purified water may be added to these solvents. Among these organic solvents, mixed solvents of lower alcohols and halogenated hydrocarbons are preferred in terms of solubility and subsequent removal, and mixed solvents of methanol or ethanol and methylene chloride are particularly preferred.

本発明の固型製剤を製造するに当っては、まずBOF−A2
とヒドロキシプロピルメチルセルロースまたはヒドロキ
シプロピルセルロースとを上記有機溶媒に完全に溶解さ
せる。BOF−A2とヒドロキシプロピルメチルセルロース
またはヒドロキシプロピルセルロースとの混合割合とし
ては、特に限定されるものではないが、通常は前者に対
して後者を重量比で0.01倍量以上、好ましくは0.05〜３
倍量程度とするのが良く、特に好ましくは0.05〜１倍量
程度とするのが良い。BOF−A2に対するヒドロキシプロ
ピルメチルセルロースまたはヒドロキシプロピルセルロ
ースの混合割合が少なすぎると非晶質となりにくく、混
合割合が高すぎるとBOF−A2の安定性が悪くなる。In producing the solid preparation of the present invention, first, BOF-A2
The mixing ratio of BOF-A2 and hydroxypropyl methylcellulose or hydroxypropyl cellulose is not particularly limited, but the latter is usually 0.01 times or more, preferably 0.05 to 3 times the amount of the former by weight.
It is preferable to use an amount of about 1:1, and particularly preferably about 0.05 to 1:1. If the mixing ratio of hydroxypropyl methylcellulose or hydroxypropyl cellulose to BOF-A2 is too low, it will be difficult to obtain an amorphous substance, and if the mixing ratio is too high, the stability of BOF-A2 will be reduced.

本発明では、次に有機溶媒を除去して非晶質化された粉
末を得る。有機溶媒を除去する手段としては、特に限定
されるものではなく従来公知の方法を広く採用でき、例
えばエバポレーターを用いる方法、凍結乾燥法、噴霧乾
燥法等が挙げられる。この中でも噴霧乾燥法が特に好適
である。In the present invention, the organic solvent is then removed to obtain an amorphous powder. The means for removing the organic solvent is not particularly limited, and a wide variety of conventionally known methods can be used, including methods using an evaporator, freeze-drying, and spray-drying. Among these, spray-drying is particularly preferred.

斯くして得られる非晶質粉末は、慣用の固型剤の製剤化
方法を用いて各種の固型製剤に調製される。即ち、該非
晶質粉末に、更に賦形剤、崩壊剤、結合剤、滑沢剤等を
加え、常法の製剤化方法により、散剤、細粒剤、顆粒
剤、カプセル剤、錠剤等の内服用固型製剤に調製するこ
とができる。The amorphous powder thus obtained can be formulated into various solid preparations using conventional solid formulation methods. That is, by further adding excipients, disintegrants, binders, lubricants, etc., the amorphous powder can be formulated into solid oral preparations such as powders, fine granules, granules, capsules, tablets, etc. using conventional formulation methods.

実 施 例 以下に実施例及び比較例を掲げて本発明をより一層明ら
かにする。EXAMPLES The present invention will be further clarified by the following examples and comparative examples.

実施例１ BOF−A2 4g及びヒドロキシプロピルメチルセルロース
0.04gをアセトン19g及び塩化メチレン75gの混合溶媒に
溶解し、次いで噴霧乾燥し、粉末を得た。得られた噴霧
乾燥粉末2.2gに乳糖7.8gを加えて混合し、散剤とした。Example 1 4 g of BOF-A2 and hydroxypropyl methylcellulose
0.04 g of the compound was dissolved in a mixed solvent of 19 g of acetone and 75 g of methylene chloride, and then spray-dried to obtain a powder. 2.2 g of the resulting spray-dried powder was mixed with 7.8 g of lactose to obtain a powder formulation.

実施例２ BOF−A2 4g及びヒドロキシプロピルメチルセルロース
0.04gをメタノール19g及び塩化メチレン75gの混合溶媒
に溶解し、次いで噴霧乾燥し、粉末を得た。得られた噴
霧乾燥粉末2.2gに乳糖7.8gを加えて混合し、散剤とし
た。Example 2 BOF-A2 4 g and hydroxypropyl methylcellulose
0.04 g of the compound was dissolved in a mixed solvent of 19 g of methanol and 75 g of methylene chloride, and then spray-dried to obtain a powder. 2.2 g of the resulting spray-dried powder was mixed with 7.8 g of lactose to obtain a powder formulation.

実施例３ BOF−A2 4g及びヒドロキシプロピルメチルセルロース
0.04gをメタノール19g及び塩化メチレン75gの混合溶媒
に溶解し、次いで噴霧乾燥し、粉末を得た。得られた噴
霧乾燥粉末4gに乳糖6gを加えて混合し、散剤とした。Example 3 BOF-A2 4 g and hydroxypropyl methylcellulose
0.04 g of the compound was dissolved in a mixed solvent of 19 g of methanol and 75 g of methylene chloride, and then spray-dried to obtain a powder. 4 g of the resulting spray-dried powder was mixed with 6 g of lactose to obtain a powder.

実施例４ BOF−A2 2g及びヒドロキシプロピルメチルセルロース4
gをメタノール19g及び塩化メチレン75gの混合溶媒に溶
解し、次いで噴霧乾燥し、粉末を得た。得られた噴霧乾
燥粉末3gに乳糖2gを加えて混合し、散剤とした。Example 4 2 g of BOF-A2 and 4 g of hydroxypropyl methylcellulose
3 g of the resulting spray-dried powder was mixed with 2 g of lactose to prepare a powder.

実施例５ BOF−A2 2g及びヒドロキシプロピルメチルセルロース6
gをエタノール19g及び塩化メチレン75gの混合溶媒に溶
解し、次いで噴霧乾燥し、粉末を得た。得られた噴霧乾
燥粉末3gに乳糖2gを加えて混合し、散剤とした。Example 5 2 g of BOF-A2 and 6 g of hydroxypropyl methylcellulose
3 g of the resulting spray-dried powder was mixed with 2 g of lactose to prepare a powder.

実施例６ BOF−A2 2g及びヒドロキシプロピルメチルセルロース4
gをメタノール19g及び塩化メチレン75gの混合溶媒に溶
解し、次いで噴霧乾燥し、粉末を得た。得られた噴霧乾
燥粉末3gに乳糖2gを加えて混合し、散剤とした。Example 6 2 g of BOF-A2 and 4 g of hydroxypropyl methylcellulose
3 g of the resulting spray-dried powder was mixed with 2 g of lactose to prepare a powder.

比較例１ BOF−A2原末20gを気流式微粉砕機で粉砕し、平均粒子径
約５μｍの微粉末とし、この微粉末3gに乳糖2gを加えて
混合し、散剤とした。Comparative Example 1 20 g of BOF-A2 bulk powder was pulverized in an airflow mill to obtain a fine powder with an average particle size of about 5 μm, and 3 g of this fine powder was mixed with 2 g of lactose to obtain a powder.

実施例８ BOF−A2 300g及びヒドロキシプロピルメチルセルロー
ス15gをエタノール270g及び塩化メチレン2415gの混合溶
媒に溶解し、次いで噴霧乾燥し、粉末を得た。Example 8 300 g of BOF-A2 and 15 g of hydroxypropylmethylcellulose were dissolved in a mixed solvent of 270 g of ethanol and 2415 g of methylene chloride, and then the solution was spray-dried to obtain a powder.

噴霧乾燥粉末 105g 乳糖 59g 結晶セルロース 27g 軽質無水珪酸 2gヒドロキシプロピルメチルセルロース 7g 全量 200g 噴霧乾燥粉末、乳糖及び結晶セルロースを混合し、結合
液として４％ヒドロキシプロピルメチルセルロース水溶
液を使用し、流動造粒した後、軽質無水珪酸を加えて混
合し、50％細粒を得た。Spray-dried powder 105g Lactose 59g Microcrystalline cellulose 27g Light anhydrous silicic acid 2g Hydroxypropyl methylcellulose 7g Total 200g The spray-dried powder, lactose and crystalline cellulose were mixed and fluidized using a 4% aqueous solution of hydroxypropyl methylcellulose as a binding liquid. Light anhydrous silicic acid was then added and mixed to obtain 50% fine granules.

実施例９ 実施例４の噴霧乾燥粉末 105g 乳糖 22g コーンスターチ 15g 軽質無水珪酸 1gヒドロキシプロピルメチルセルロース 7g 全量 150g 噴霧乾燥粉末、コーンスターチ及び軽質無水珪酸を混合
し、これに乳糖を加え、結合液として４％ヒドロキシプ
ロピルメチルセルロース水溶液を使用し、流動造粒した
後、軽質無水珪酸を加えて混合し、カプセル用粉末と
し、ゼラチンカプセルに充填し、BOF−A2 100mgカプセ
ルを得た。Example 9 Spray-dried powder of Example 4 105 g Lactose 22 g Corn starch 15 g Light anhydrous silicic acid 1 g Hydroxypropyl methylcellulose 7 g Total 150 g The spray-dried powder, corn starch, and light anhydrous silicic acid were mixed, and lactose was added to the mixture. A 4% aqueous solution of hydroxypropyl methylcellulose was used as a binding liquid, and the mixture was fluidized and granulated. Light anhydrous silicic acid was then added and mixed to form a powder for capsules. This was then filled into gelatin capsules to obtain BOF-A2 100 mg capsules.

実施例10 BOF−A2 200g及びヒドロキシプロピルメチルセルロー
ス20gをエタノール180g及び塩化メチレン1610gの混合溶
媒に溶解し、次いで噴霧乾燥し、粉末を得た。Example 10 200 g of BOF-A2 and 20 g of hydroxypropylmethylcellulose were dissolved in a mixed solvent of 180 g of ethanol and 1610 g of methylene chloride, and then spray-dried to obtain a powder.

噴霧乾燥粉末 110 ｇ 乳糖 22.5g 結晶セルロース 10 ｇ クロスカルメロースナトリウム 5.3g 軽質無水珪酸 1.5gステアリン酸マグネシウム 0.7g 全量 200 ｇ 噴霧乾燥粉末、乳糖、結晶セルロース及び軽質無水珪酸
を混合し、更に滑沢剤としてステアリン酸マグネシウム
を加えて直接打錠し、BOF−A2 100mg錠を得た。Spray-dried powder 110 g, lactose 22.5 g, crystalline cellulose 10 g, croscarmellose sodium 5.3 g, light anhydrous silicic acid 1.5 g, magnesium stearate 0.7 g, total amount 200 g. The spray-dried powder, lactose, crystalline cellulose, and light anhydrous silicic acid were mixed, and magnesium stearate was added as a lubricant. The mixture was then directly compressed into tablets to obtain BOF-A2 100 mg tablets.

実施例11 BOF−A2 200g及びヒドロキシプロピルメチルセルロー
ス20gをエタノール180g及び塩化メチレン1610gの混合溶
媒に溶解後、噴霧乾燥し、粉末を得た。Example 11 200 g of BOF-A2 and 20 g of hydroxypropylmethylcellulose were dissolved in a mixed solvent of 180 g of ethanol and 1610 g of methylene chloride, and then spray-dried to obtain a powder.

噴霧乾燥粉末 110g ヒドロキシプロピルメチルセルロース 8g 軽質無水珪酸 3gステアリン酸マグネシウム 1g 全量 122g この粉末と軽質無水珪酸を混合し、結合液として４％ヒ
ドロキシプロピルメチルセルロース水溶液を使用し、流
動造粒した後、ステアリン酸マグネシウムを加えて混合
し、この粉末122mgを１カプセルに充填し、カプセル剤
とする。Spray-dried powder 110 g Hydroxypropylmethylcellulose 8 g Light anhydrous silicic acid 3 g Magnesium stearate 1 g Total 122 g Mix this powder and light anhydrous silicic acid, use a 4% aqueous solution of hydroxypropylmethylcellulose as a binding liquid, fluidize, then add magnesium stearate and mix. Fill 122 mg of this powder into one capsule to make a capsule formulation.

比較例２ 微粉砕原末（BOF−A2平均粒子径約５μｍ） 100g 乳糖 64g 結晶セルロース 28gヒドロキシプロピルメチルセルロース 8g 全量 200g 微粉砕原末、乳糖及び結晶セルロースを混合し、結合液
として４％ヒドロキシプロピルメチルセルロース水溶液
を使用し、流動造粒して50％細粒を得た。Comparative Example 2 Finely ground bulk powder (BOF-A2, average particle size approximately 5 μm) 100 g Lactose 64 g Microcrystalline cellulose 28 g Hydroxypropyl methylcellulose 8 g Total 200 g The finely ground bulk powder, lactose, and crystalline cellulose were mixed and fluidized using a 4% aqueous solution of hydroxypropyl methylcellulose as a binding liquid to obtain 50% fine granules.

試験例１（溶解性試験） 実施例２〜４、実施例６及び比較例１の各試料につきBO
F−A2 100mgに対応する量をそれぞれ精密に量り、溶出
試験液に投入し、５分、10分、20分、30分、40分、50
分、60分後のBOF−A2の溶出率を全自動溶出試験機（JAS
CO製DT−610）を用いて求めた。溶出試験液は精製水に
0.5％ヒドロキシプロピルメチルセルロース及びポリオ
キシエチレンセチルエーテルを1.5％添加した溶液500ml
を用いた。またBOF−A2の溶出率の測定は、BOF−A2100m
gをアセトニトリル200mlに溶解し、標準溶液とし、この
標準溶液と試料溶液につき、波長266nmと360nmの吸光度
差の測定により行なった。結果を第１表に示す。Test Example 1 (Solubility Test) For each sample of Examples 2 to 4, Example 6 and Comparative Example 1, BO
Accurately measure an amount corresponding to 100 mg of F-A2 and add it to the dissolution test solution.
The dissolution rate of BOF-A2 after 1 minute and 60 minutes was measured using a fully automatic dissolution tester (JAS
The dissolution test was performed using purified water.
500ml of a solution containing 0.5% hydroxypropyl methylcellulose and 1.5% polyoxyethylene cetyl ether
The elution rate of BOF-A2 was measured using BOF-A2 100m
The difference in absorbance between this standard solution and the sample solution at wavelengths of 266 nm and 360 nm was measured. The results are shown in Table 1.

試験例２（ビーグル犬での吸収試験） 体重10kg前後のビーグル犬３〜４頭を用い、実施例８〜
11及び比較例２の各製剤を１頭当りBOF−A2 100mgに対
応する量を経口投与し、１〜24時間の血漿中EM−FU濃度
（μg/ml）を測定し、最高血漿中濃度［Cmax（μg/m
l）］、血漿中濃度・時間曲線下面積［AUC（μｇ・hr/m
l）］を求めた。尚、未変化体であるBOF−A2は血漿中に
認められないため、全て代謝物であるEM−FU濃度を吸収
の指標とした。結果を第２表に示す。 Test Example 2 (Absorption test in beagle dogs) Three to four beagle dogs weighing about 10 kg were used, and the same test as in Examples 8 to 10 was carried out.
Each formulation of Comparative Example 11 and Comparative Example 2 was orally administered to each animal in an amount corresponding to 100 mg of BOF-A2, and the plasma EM-FU concentration (μg/ml) was measured from 1 to 24 hours. The maximum plasma concentration [Cmax (μg/ml
l)], area under the plasma concentration/time curve [AUC (μg・hr/m
The absorption index was calculated based on the concentration of EM-FU, which is a metabolite, because unchanged BOF-A2 was not detected in plasma. The results are shown in Table 2.

Claims (9)

【特許請求の範囲】[Claims] 【請求項１】３−［３−（６−ベンゾイルオキシ−３−
シアノ−２−ピリジルオキシカルボニル）ベンゾイル］
−１−エトキシメチル−５−フルオロウラシルとヒドロ
キシプロピルメチルセロースまたはヒドロキシプロピル
セルロースとを有機溶媒に完全に溶解し、次いで有機溶
媒を除去して非晶質化させた粉末を製剤化してなること
を特徴とする固型製剤。Claim 1: 3-[3-(6-benzoyloxy-3-
cyano-2-pyridyloxycarbonyl)benzoyl]
1. A solid preparation comprising 1-ethoxymethyl-5-fluorouracil and hydroxypropylmethylcellulose or hydroxypropylcellulose completely dissolved in an organic solvent, and then the organic solvent is removed to form an amorphous powder, which is then formulated. 【請求項２】３−［３−（６−ベンゾイルオキシ−３−
シアノ−２−ピリジルオキシカルボニル）ベンゾイル］
−１−エトキシメチル−５−フルオロウラシルとヒドロ
キシプロピルメチルセルロースとを有機溶媒に完全に溶
解し、次いで有機溶媒を除去して非晶質化させた粉末を
製剤化してなることを特徴とする請求項１に記載の固型
製剤。Claim 2: 3-[3-(6-benzoyloxy-3-
cyano-2-pyridyloxycarbonyl)benzoyl]
2. The solid formulation according to claim 1, characterized in that it is prepared by completely dissolving 1-ethoxymethyl-5-fluorouracil and hydroxypropyl methylcellulose in an organic solvent, and then removing the organic solvent to form an amorphous powder. 【請求項３】３−［３−（６−ベンゾイルオキシ−３−
シアノ−２−ピリジルオキシカルボニル）ベンゾイル］
−１−エトキシメチル−５−フルオロウラシルに対して
ヒドロキシプロピルメチルセルロースを重量比で約0.05
〜約３倍量使用する請求項２に記載の固型製剤。Claim 3: 3-[3-(6-benzoyloxy-3-
cyano-2-pyridyloxycarbonyl)benzoyl]
- hydroxypropyl methylcellulose in a weight ratio of about 0.05 to 1-ethoxymethyl-5-fluorouracil
The solid formulation according to claim 2, wherein the amount is from about 1 to about 3 times the amount of the solid formulation. 【請求項４】有機溶媒が低級アルコール類とハロゲン化
炭化水素との混合溶媒である請求項３に記載の固型製
剤。4. The solid formulation according to claim 3, wherein the organic solvent is a mixed solvent of a lower alcohol and a halogenated hydrocarbon. 【請求項５】有機溶媒がメタノールあるいはエタノール
と塩化メチレンとの混合溶媒である請求項４に記載の固
型製剤。5. The solid formulation according to claim 4, wherein the organic solvent is a mixed solvent of methanol or ethanol and methylene chloride. 【請求項６】３−［３−（６−ベンゾイルオキシ−３−
シアノ−２−ピリジルオキシカルボニル）ベンゾイル］
−１−エトキシメチル−５−フルオロウラシルに対して
ヒドロキシプロピルメチルセルロースまたはヒドロキシ
プロピルセルロースを重量比で約0.05〜約３倍量使用す
る請求項１に記載の固型製剤。6. 3-[3-(6-benzoyloxy-3-
cyano-2-pyridyloxycarbonyl)benzoyl]
2. The solid formulation according to claim 1, wherein the amount of hydroxypropylmethylcellulose or hydroxypropylcellulose is about 0.05 to about 3 times the weight of 1-ethoxymethyl-5-fluorouracil. 【請求項７】有機溶媒が低級アルコール類とハロゲン化
炭化水素との混合溶媒である請求項６に記載の固型製
剤。7. The solid formulation according to claim 6, wherein the organic solvent is a mixed solvent of a lower alcohol and a halogenated hydrocarbon. 【請求項８】有機溶媒が低級アルコール類とハロゲン化
炭化水素との混合溶媒である請求項１に記載の固型製
剤。8. The solid formulation according to claim 1, wherein the organic solvent is a mixed solvent of a lower alcohol and a halogenated hydrocarbon. 【請求項９】有機溶媒がメタノールあるいはエタノール
と塩化メチレンとの混合溶媒である請求項８に記載の固
型製剤。9. The solid preparation according to claim 8, wherein the organic solvent is a mixed solvent of methanol or ethanol and methylene chloride.
JP3-512846A 1990-07-19 1991-07-17 solid preparations Expired - Lifetime JPH07112975B2 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP3-512846A JPH07112975B2 (en) 1990-07-19 1991-07-17 solid preparations

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Application Number Priority Date Filing Date Title
JP2-192112 1990-07-19
JP19211290 1990-07-19
JP3-512846A JPH07112975B2 (en) 1990-07-19 1991-07-17 solid preparations

Publications (3)

Publication Number Publication Date
JPWO1992001453A1 JPWO1992001453A1 (en) 1993-01-14
JPH07112975B1 JPH07112975B1 (en) 1995-12-06
JPH07112975B2 true JPH07112975B2 (en) 1995-12-06

Family

ID=16285866

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JP (1) JPH07112975B2 (en)
KR (1) KR0172134B1 (en)
AU (1) AU641267B2 (en)
DE (1) DE69122478T2 (en)
DK (1) DK0489181T3 (en)
ES (1) ES2093106T3 (en)
WO (1) WO1992001453A1 (en)

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GEP20053427B (en) 1999-12-23 2005-01-25 Pfizer Prod Inc Pharmaceutical Compositions Providing Enhanced Drug Concentrations
AU2002309172A1 (en) * 2001-06-22 2003-01-08 Pfizer Products Inc. Pharmaceutical compositions containing polymer and drug assemblies
MY169670A (en) 2003-09-03 2019-05-08 Tibotec Pharm Ltd Combinations of a pyrimidine containing nnrti with rt inhibitors
DE10351644A1 (en) 2003-11-05 2005-06-09 Bayer Technology Services Gmbh Process for the preparation of storage-stable multiple emulsions
CL2008000746A1 (en) * 2007-03-14 2008-09-22 Tibotec Pharm Ltd PHARMACEUTICAL COMPOSITION IN SOLUTION INCLUDING TMC278 AND A WATER SOLUBLE POLYMER; PREPARATION PROCESS OF SUCH COMPOSITION; AND USE OF A POWDER UNDERSTANDING TMC278 TO TREAT AIDS.
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CA1018456A (en) * 1972-06-26 1977-10-04 Hans Lowey Prolonged release lozenges
US4127647A (en) * 1975-04-08 1978-11-28 Meiji Seika Kaisha, Ltd. Process for preparation of stable amorphous macrolide antibiotic solids
GB1579818A (en) * 1977-06-07 1980-11-26 Yamanouchi Pharma Co Ltd Nifedipine-containing solid preparation composition
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JPS5899411A (en) * 1981-12-05 1983-06-13 Shoichiro Ozaki Carcinostatic agent
JPS58109411A (en) * 1981-12-23 1983-06-29 Shionogi & Co Ltd Nifedipine composition for solid preparation
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GB8608080D0 (en) * 1986-04-02 1986-05-08 Fujisawa Pharmaceutical Co Solid dispersion composition
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JPS63201127A (en) * 1987-02-17 1988-08-19 Otsuka Pharmaceut Co Ltd Carcinostatic agent containing 5-fluorouracil derivative
JPS63115817A (en) * 1986-11-04 1988-05-20 Mitsubishi Kasei Corp Hepatic disease remedy composition
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Also Published As

Publication number Publication date
DK0489181T3 (en) 1996-11-18
ES2093106T3 (en) 1996-12-16
DE69122478T2 (en) 1997-05-28
EP0489181A1 (en) 1992-06-10
EP0489181B1 (en) 1996-10-02
WO1992001453A1 (en) 1992-02-06
US5316773A (en) 1994-05-31
KR920702221A (en) 1992-09-03
AU641267B2 (en) 1993-09-16
JPH07112975B1 (en) 1995-12-06
KR0172134B1 (en) 1999-02-01
DE69122478D1 (en) 1996-11-07
EP0489181A4 (en) 1992-09-30
AU8219091A (en) 1992-02-18

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