JP4974535B2 - External preparation and method for producing the same - Google Patents
External preparation and method for producing the same Download PDFInfo
- Publication number
- JP4974535B2 JP4974535B2 JP2006026034A JP2006026034A JP4974535B2 JP 4974535 B2 JP4974535 B2 JP 4974535B2 JP 2006026034 A JP2006026034 A JP 2006026034A JP 2006026034 A JP2006026034 A JP 2006026034A JP 4974535 B2 JP4974535 B2 JP 4974535B2
- Authority
- JP
- Japan
- Prior art keywords
- weight
- parts
- ketoprofen
- dibutylhydroxytoluene
- external preparation
- 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.)
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- 235000010354 butylated hydroxytoluene Nutrition 0.000 claims description 43
- SPSPIUSUWPLVKD-UHFFFAOYSA-N 2,3-dibutyl-6-methylphenol Chemical compound CCCCC1=CC=C(C)C(O)=C1CCCC SPSPIUSUWPLVKD-UHFFFAOYSA-N 0.000 claims description 41
- 239000012535 impurity Substances 0.000 claims description 21
- 238000002156 mixing Methods 0.000 claims description 16
- BIOCOYIPJQMGTN-UHFFFAOYSA-N methyl 2-(3-benzoylphenyl)propanoate Chemical compound COC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 BIOCOYIPJQMGTN-UHFFFAOYSA-N 0.000 claims description 15
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Landscapes
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
本発明は、外用製剤及びその製造方法に関する。 The present invention relates to an external preparation and a method for producing the same.
ケトプロフェンは優れた抗炎症作用及び鎮痛作用を有するため、湿布剤又はプラスター剤等といった貼付剤、ゲル剤、クリーム剤、軟膏剤、リニメント剤のような各種形態の外用製剤に薬効成分として配合されている。 Since ketoprofen has excellent anti-inflammatory and analgesic effects, it is formulated as a medicinal ingredient in various forms of external preparations such as patches, gels, creams, ointments, liniments such as poultices or plasters. Yes.
一方、ケトプロフェンは外用製剤の薬効成分として用いた場合に比較的不安定であることが知られており、ケトプロフェンの安定性向上のため種々検討が行われてきた。例えば特許文献１には種々の紫外線吸収剤と抗酸化剤とを併用することによりケトプロフェンを安定化させる技術が開示されている。さらに特許文献１には、抗酸化剤としてジブチルヒドロキシトルエンを用いケトプロフェンを安定化させる技術が開示されている。
本発明者らは、外用製剤中におけるケトプロフェンの抗酸化剤としてジブチルヒドロキシトルエンを用い、ケトプロフェンの安定性の検討を行ったところ、ケトプロフェンの安定性は増すが、同時にケトプロフェンメチルエステルが生成することを見出した。さらなる検討を行った結果、ジブチルヒドロキシトルエンに不純物として含まれるメタノールとケトプロフェンが反応し、ケトプロフェンメチルエステルが生成することが明らかとなった。 The present inventors investigated the stability of ketoprofen using dibutylhydroxytoluene as an antioxidant of ketoprofen in an external preparation, and found that ketoprofen methyl ester was formed at the same time, although the stability of ketoprofen was increased. I found it. As a result of further investigation, it was found that ketoprofen methyl ester was produced by reaction of methanol and ketoprofen contained as impurities in dibutylhydroxytoluene.
ケトプロフェンメチルエステルは不純物であり、一定量以上存在すると薬効成分の減少や、かゆみ、かぶれ及びその他の皮膚アレルギー等の副作用等といった不利益が生じる可能性がある。 Ketoprofen methyl ester is an impurity, and if it is present in a certain amount or more, there may be disadvantages such as a decrease in medicinal ingredients and side effects such as itching, rash and other skin allergies.
本発明は、このような実情に鑑みてなされたものであり、外用製剤中でケトプロフェンが安定であり、かつケトプロフェンメチルエステルの量が一定量未満に抑えられるケトプロフェン含有外用製剤を提供することを目的とする。 The present invention has been made in view of such circumstances, and an object of the present invention is to provide a ketoprofen-containing external preparation in which ketoprofen is stable in an external preparation and the amount of ketoprofen methyl ester is suppressed to less than a certain amount. And
上記課題を解決するために、本発明は、１〜７質量％のケトプロフェン及び２．１〜１０質量％のジブチルヒドロキシトルエンを含有し、ケトプロフェンメチルエステルの生成率が０．２％以下である外用製剤を提供する。ここで、外用製剤は貼付剤であることが好ましい。 MEANS TO SOLVE THE PROBLEM In order to solve the said subject, this invention contains 1-7 mass% ketoprofen and 2.1-10 mass% dibutylhydroxytoluene, and the production rate of ketoprofen methyl ester is 0.2% or less A formulation is provided. Here, the external preparation is preferably a patch.
本発明の外用製剤によれば、薬効成分であるケトプロフェンの減少や、かゆみ、かぶれ及びその他の皮膚アレルギー等の副作用等といった不利益が生じる可能性を減少させることができる。 According to the preparation for external use of the present invention, it is possible to reduce the possibility of disadvantages such as a decrease in ketoprofen, which is a medicinal ingredient, and side effects such as itching, rash, and other skin allergies.
また、本発明は、上記外用製剤の製造方法であって、ジブチルヒドロキシトルエンを予め加熱した後、ケトプロフェンと混合することを特徴とする製造方法を提供する。外用製剤が貼付剤の場合、本発明の製造方法は、スチレン−イソプレン−スチレンブロック共重合体、ポリイソブチレン、水添ロジンエステル、流動パラフィン及ジブチルヒドロキシトルエンを不活性ガス雰囲気下で加熱撹拌し、続いてケトプロフェンを添加し、均一な溶解物を得る工程を含むことが好ましく、さらに、均一な溶解物を支持体に展延塗布した後に剥離被覆物で覆う工程と、を含むことがより好ましい。 Moreover, this invention is a manufacturing method of the said external preparation, Comprising: After heating dibutylhydroxytoluene beforehand, it mixes with a ketoprofen, The manufacturing method characterized by the above-mentioned is provided. When the preparation for external use is a patch, the production method of the present invention involves heating and stirring styrene-isoprene-styrene block copolymer, polyisobutylene, hydrogenated rosin ester, liquid paraffin and dibutylhydroxytoluene in an inert gas atmosphere, Subsequently, it is preferable to include a step of adding ketoprofen to obtain a uniform dissolved product, and it is more preferable to include a step of spreading the uniform dissolved product on the support and then covering with a release coating.
ジブチルヒドロキシトルエンは、一般に低級アルコール溶媒から再結晶して精製する。そのようにして得られたジブチルヒドロキシトルエンは、不純物としてメタノール、エタノール、イソプロパノール等の低級アルコールを含有する。このため、本発明においてジブチルヒドロキシトルエンをそのまま用いると低級アルコール、特にメタノールとケトプロフェンとが反応し、不純物であるケトプロフェン（メチル）エステルが生成する。 Dibutylhydroxytoluene is generally purified by recrystallization from a lower alcohol solvent. The dibutylhydroxytoluene thus obtained contains lower alcohols such as methanol, ethanol and isopropanol as impurities. For this reason, when dibutylhydroxytoluene is used as it is in the present invention, lower alcohol, particularly methanol, and ketoprofen react with each other to produce an impurity ketoprofen (methyl) ester.
本発明の製造方法により、ジブチルヒドロキシトルエンを加熱して不純物である低級アルコールを取り除いた後にケトプロフェンと配合することにより、ケトプロフェンエステル、特にケトプロフェンメチルエステルの生成率を一定値以下とすることができる。 According to the production method of the present invention, dibutylhydroxytoluene is heated to remove impurities, lower alcohol, and then blended with ketoprofen, whereby the production rate of ketoprofen ester, particularly ketoprofen methyl ester, can be kept below a certain value.
本発明によれば、不純物であるケトプロフェンメチルエステルの含有量が一定量未満である、ケトプロフェンとジブチルヒドロキシトルエンとを含有する外用製剤が提供される。 ADVANTAGE OF THE INVENTION According to this invention, the external preparation containing ketoprofen and dibutylhydroxytoluene whose content of ketoprofen methyl ester which is an impurity is less than a fixed amount is provided.
本発明の外用製剤は、特定の配合割合のケトプロフェン及びジブチルヒドロキシトルエンを含有し、ケトプロフェンとケトプロフェンメチルエステルの総モル数に対するケトプロフェンメチルエステルの生成率がケトプロフェン質量に換算して一定値以下である。 The external preparation of the present invention contains ketoprofen and dibutylhydroxytoluene in a specific blending ratio, and the production rate of ketoprofen methyl ester relative to the total number of moles of ketoprofen and ketoprofen methyl ester is less than a certain value in terms of ketoprofen mass.
ケトプロフェンの配合量は、貼付剤全体の１〜７質量％であり、１〜３質量％であることが好ましい。ケトプロフェンの配合量が１質量％未満では消炎鎮痛効果が十分に発揮されなくなる傾向にあり、７質量％より大きい場合には含有量に見合った消炎鎮痛効果が得られない恐れがある。 The blending amount of ketoprofen is 1 to 7% by mass, preferably 1 to 3% by mass, based on the whole patch. If the blending amount of ketoprofen is less than 1% by mass, the anti-inflammatory analgesic effect tends to be insufficient, and if it is greater than 7% by mass, the anti-inflammatory analgesic effect commensurate with the content may not be obtained.
ジブチルヒドロキシトルエンの配合量は、貼付剤全体の２．１〜１０質量％であり、２．１〜５質量％であることがより好ましい。ジブチルヒドロキシトルエンの配合量が２．１質量％未満では抗酸化作用が十分に発揮されなくなる傾向にあり、１０質量％より大きい場合には含有量に見合った抗酸化作用が得られない恐れがある。 The compounding quantity of dibutylhydroxytoluene is 2.1-10 mass% of the whole patch, and it is more preferable that it is 2.1-5 mass%. When the blending amount of dibutylhydroxytoluene is less than 2.1% by mass, the antioxidant effect tends not to be sufficiently exerted, and when it is greater than 10% by mass, the antioxidant effect corresponding to the content may not be obtained. .
本発明の外用製剤は、ケトプロフェンに対するケトプロフェンメチルエステルの生成率が０．２％以下である。生成率が０．２％より大きい場合には、薬効成分であるケトプロフェンの減少や、かゆみ、かぶれ及びその他の皮膚アレルギー等の副作用等といった不利益が生じる可能性がある。ここで、ケトプロフェンメチルエステルの生成率が０．２％以下とは、外用製剤中のケトプロフェンメチルエステルのモル数を、ケトプロフェンとケトプロフェンメチルエステルとの総モル数で除した値が０．２％以下であることをいう。 In the external preparation of the present invention, the production rate of ketoprofen methyl ester relative to ketoprofen is 0.2% or less. If the production rate is greater than 0.2%, there may be disadvantages such as a decrease in ketoprofen, which is a medicinal ingredient, and side effects such as itching, rash and other skin allergies. Here, the production rate of ketoprofen methyl ester is 0.2% or less, the value obtained by dividing the number of moles of ketoprofen methyl ester in the external preparation by the total number of moles of ketoprofen and ketoprofen methyl ester is 0.2% or less It means that.
本発明の外用製剤の製造方法は、ジブチルヒドロキシトルエンを予め加熱した後、ケトプロフェンと混合することを特徴とする。加熱の方法は、特に限定されず、例えば、ジブチルヒドロキシトルエンのみを加熱してもよいし、ケトプロフェンを除く他の外用製剤組成物とジブチルヒドロキシトルエンとを混合し、加熱してもよい。 The method for producing an external preparation of the present invention is characterized in that dibutylhydroxytoluene is preheated and then mixed with ketoprofen. The heating method is not particularly limited. For example, only dibutylhydroxytoluene may be heated, or other external preparation composition excluding ketoprofen and dibutylhydroxytoluene may be mixed and heated.
加熱する温度は、ジブチルヒドロキシトルエンに含まれるメタノールが揮発する温度であれば特に限定されないが、７０〜２００℃が好ましく、１００〜２００℃であることがより好ましい。 The temperature to be heated is not particularly limited as long as methanol contained in dibutylhydroxytoluene volatilizes, but is preferably 70 to 200 ° C, and more preferably 100 to 200 ° C.
本発明の外用製剤においては、必須成分である上述のケトプロフェン及びジブチルヒドロキシトルエンに加えて、その製剤の剤型に応じて各製剤の基剤が含有されていることが好ましい。本発明の外用製剤の剤型としては、軟膏剤、ゲル剤、クリーム剤、ゲル状クリーム剤、湿布剤、貼付剤、坐剤、リニメント剤、点眼剤、エアゾール剤等が挙げられる。以下に本発明の外用製剤の各剤型に応じた基剤及び処方例について説明する。 In the external preparation of the present invention, in addition to the above-mentioned ketoprofen and dibutylhydroxytoluene which are essential components, it is preferable that a base of each preparation is contained according to the dosage form of the preparation. Examples of the dosage form of the external preparation of the present invention include ointments, gels, creams, gel creams, poultices, patches, suppositories, liniments, eye drops, aerosols and the like. The bases and formulation examples according to each dosage form of the external preparation of the present invention will be described below.
まず、軟膏剤について説明する。本発明の軟膏剤に用いられる軟膏基剤は特に制限されず、公知あるいは通常使用されているものの中より選択される。このような軟膏基剤に含まれる成分としては、例えば、高級脂肪酸又はそれらのエステル類（例：アジピン酸、ミリスチン酸、パルミチン酸、ステアリン酸、オレイン酸、アジピン酸エステル、ミリスチン酸エステル、パルミチン酸エステル、セバシン酸ジエチル、ラウリン酸ヘキシル、イソオクタン酸セチル等）、ロウ類（例：鯨ロウ、ミツロウ、セレシン等）、界面活性剤（例：ポリオキシエチレンアルキルエーテルリン酸エステル等）、高級アルコール（例：セタノール、ステアリルアルコール、セトステアリルアルコール等）、シリコーン油（例：ジメチルポリシロキサン、メチルフェニルポリシロキサン、グリコールメチルポリシロキサン、シリコーングリコールコポリマー等）、炭化水素類（例：親水ワセリン、白色ワセリン、精製ラノリン、流動パラフィン等）、水、吸収促進剤（例：炭酸プロピレン、ジイソプロピルアジペート、クロタミトン、エイゾン等）、保湿剤（例：グリセリン、プロピレングリコール、ブチレングリコール、ソルビトール等）、かぶれ防止剤、その他の添加物（例：サリチル酸、サリチル酸メチル、サリチル酸グリコール、ｌ−メントール、カンフル、ハッカ油等）等が挙げられ、これらの中から選択される諸成分を混合してなる軟膏基剤に上述の必須成分を配合することにより本発明の軟膏剤を得ることができる。 First, the ointment will be described. The ointment base used in the ointment of the present invention is not particularly limited, and is selected from those known or commonly used. The components contained in such an ointment base include, for example, higher fatty acids or esters thereof (eg adipic acid, myristic acid, palmitic acid, stearic acid, oleic acid, adipic acid ester, myristic acid ester, palmitic acid Esters, diethyl sebacate, hexyl laurate, cetyl isooctanoate, etc.), waxes (eg, whale wax, beeswax, ceresin, etc.), surfactants (eg, polyoxyethylene alkyl ether phosphates, etc.), higher alcohols (eg Examples: cetanol, stearyl alcohol, cetostearyl alcohol, etc.), silicone oil (eg: dimethylpolysiloxane, methylphenylpolysiloxane, glycolmethylpolysiloxane, silicone glycol copolymer, etc.), hydrocarbons (eg, hydrophilic petrolatum, white petrolatum, Lanolin, liquid paraffin, etc.), water, absorption promoters (eg, propylene carbonate, diisopropyl adipate, crotamiton, aison), moisturizers (eg, glycerin, propylene glycol, butylene glycol, sorbitol, etc.), anti-rash agents, etc. (E.g., salicylic acid, methyl salicylate, glycol salicylate, l-menthol, camphor, mint oil, etc.), etc., and the above-mentioned essential to an ointment base formed by mixing various components selected from these The ointment of the present invention can be obtained by blending the components.
次に、軟膏剤の好適な一製造例（処方例）を示す。ジブチルヒドロキシトルエン２．１〜５重量部を加熱し不純物を取り除いた後に、それを室温又は加温下、高級脂肪酸エステル５〜１５重量部、界面活性剤１〜１０重量部及びケトプロフェン１〜７重量部の混合物中に加え混合する。この混合物にロウ類４〜１０重量部、炭化水素５０〜９０重量部を加え加温し、５０〜１００℃に保つ。全成分が透明溶解液となった後ホモミキサーで均一に混和する。その後、得られた混和物を撹拌しながら室温まで下げることにより本発明の軟膏剤が得られる。 Next, a suitable production example (formulation example) of an ointment will be shown. After removing 2.1 to 5 parts by weight of dibutylhydroxytoluene and removing impurities, it is heated at room temperature or under heating at 5 to 15 parts by weight of a higher fatty acid ester, 1 to 10 parts by weight of a surfactant and 1 to 7 parts by weight of ketoprofen. Add to the mixture and mix. 4-10 parts by weight of waxes and 50-90 parts by weight of hydrocarbons are added to the mixture, and the mixture is heated and maintained at 50-100 ° C. After all the components become a transparent solution, mix uniformly with a homomixer. Then, the ointment of the present invention is obtained by lowering the resulting mixture to room temperature while stirring.
次に、ゲル剤について説明する。本発明のゲル剤に用いられるゲル基剤は特に制限されず、公知あるいは通常使用されているものの中より選択される。このようなゲル基剤に含まれる成分としては、例えば、低級アルコール（例：エタノール、イソプロピルアルコール等）、水、ゲル化剤（例：カルボキシビニル重合体、ヒドロキシエチルセルロース、ヒドロキシプロピルセルロース、メチルセルロース、エチルセルロース、カルボキシメチルセルロース、アルギン酸プロピレングリコールエステル等）、中和剤（例：トリエタノールアミン、ジイソプロパノールアミン、水酸化ナトリウム等）、界面活性剤（例：セスキオレイン酸ソルビタン、トリオレイン酸ソルビタン、モノオレイン酸ソルビタン、モノステアリン酸ソルビタン、モノラウリン酸ソルビタン、モノステアリン酸ポリエチレングリコール、ポリオキシエチレンノニルフェニルエーテル、ポリオキシエチレンセチルエーテル、ポリオキシエチレンラウリルエーテル等）、吸収促進剤（例：炭酸プロピレン、ジエチルセバケート、ジイソプロピルアジペート、クロタミトン、エイゾンＲ、プロピレングリコール等）、かぶれ防止剤、その他の添加物（例：サリチル酸、サリチル酸メチル、サリチル酸グリコール、ｌ-メントール、カンフル、ハッカ油等）が挙げられ、これらの中から選択される諸成分を混合してなるゲル基剤に上述の必須成分を配合することにより本発明のゲル剤を得ることができる。 Next, the gel agent will be described. The gel base used in the gel of the present invention is not particularly limited, and is selected from those known or commonly used. Examples of components contained in such a gel base include lower alcohols (eg, ethanol, isopropyl alcohol, etc.), water, gelling agents (eg, carboxyvinyl polymer, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose). , Carboxymethylcellulose, propylene glycol alginate, etc.), neutralizing agents (eg: triethanolamine, diisopropanolamine, sodium hydroxide, etc.), surfactants (eg: sorbitan sesquioleate, sorbitan trioleate, monooleic acid) Sorbitan, sorbitan monostearate, sorbitan monolaurate, polyethylene glycol monostearate, polyoxyethylene nonylphenyl ether, polyoxyethylene cetyl ether, Polyoxyethylene lauryl ether, etc.), absorption promoters (e.g., propylene carbonate, diethyl sebacate, diisopropyl adipate, crotamiton, Azone R, propylene glycol, etc.), an irritation inhibitor, and other additives (e.g. salicylic acid, methyl salicylate, Glycolic salicylate, l-menthol, camphor, mint oil, etc.), and the gel agent of the present invention can be prepared by blending the above-mentioned essential components into a gel base obtained by mixing various components selected from these. Obtainable.
次に、ゲル剤の好適な一製造例（処方例）を示す。まず、水５５重量部以下にゲル化剤０．５〜５重量部を加えて膨潤させ膨潤物Ａを得る。一方、ケトプロフェン１〜７重量部を溶解剤０．１〜１０重量部に溶解、もしくは懸濁させ、これに予め加熱し不純物を取り除いたジブチルヒドロキシトルエン２．１〜５重量部を加える。さらに、これをグリコール類４０重量部以下と低級アルコール６０重量部以下の混合物に溶解させて溶解物Ｂを得る。次いで、溶解物Ｂを膨潤物Ａに加えた後に中和剤を添加してｐＨが４〜７になるよう調整することにより本発明のゲル剤が得られる。 Next, a preferred production example (formulation example) of the gel is shown. First, 0.5 to 5 parts by weight of a gelling agent is added to 55 parts by weight or less of water and swollen to obtain a swollen material A. On the other hand, 1 to 7 parts by weight of ketoprofen is dissolved or suspended in 0.1 to 10 parts by weight of a solubilizing agent, and 2.1 to 5 parts by weight of dibutylhydroxytoluene that has been heated in advance to remove impurities is added thereto. Further, this is dissolved in a mixture of 40 parts by weight or less of glycols and 60 parts by weight or less of lower alcohol to obtain a dissolved product B. Subsequently, after adding the melt | dissolution material B to the swelling material A, the neutralizing agent is added and it adjusts so that pH may become 4-7, and the gel agent of this invention is obtained.
次に、クリーム剤について説明する。本発明のクリーム剤に用いられるクリーム基剤は特に制限されず、公知あるいは通常使用されているものの中より選択される。このようなクリーム基剤に含まれる成分としては、例えば、高級脂肪酸エステル類（例：ミリスチン酸エステル、パルミチン酸エステル、セバシン酸ジエチル、ラウリン酸ヘキシル、イソオクタン酸セチル等）、低級アルコール（例：エタノール、イソプロパノール等）、炭水化物（例：流動パラフィン、スクワラン等）、多価アルコール（例：プロピレングリコール、１，３−ブチレングリコール等）、高級アルコール（例：２−ヘキシルデカノール、セタノール、２−オクチルドデカノール等）、乳化剤（例：ポリオキシエチレンアルキルエーテル類、脂肪酸エステル類、ポリエチレングリコール脂肪酸エステル等）、防腐剤（例：パラオキシ安息香酸エステル）、吸収促進剤（例：炭酸プロピレン、ジエチルセバケート、ジイソプロピルアジペート、クロタミトン、エイゾンＲ等）、かぶれ防止剤、その他の添加物（例：サリチル酸、サリチル酸メチル、サリチル酸グリコール、ｌ−メントール、カンフル、ハッカ油等）が挙げられ、これらの中から選択される諸成分を混合してなるクリーム基剤に上述の必須成分を配合することにより本発明のクリーム剤を得ることができる。 Next, the cream will be described. The cream base used in the cream of the present invention is not particularly limited, and is selected from those known or commonly used. Examples of components contained in such a cream base include higher fatty acid esters (eg, myristic acid ester, palmitic acid ester, diethyl sebacate, hexyl laurate, cetyl isooctanoate), lower alcohol (eg, ethanol) , Isopropanol, etc.), carbohydrates (eg, liquid paraffin, squalane, etc.), polyhydric alcohols (eg, propylene glycol, 1,3-butylene glycol, etc.), higher alcohols (eg, 2-hexyldecanol, cetanol, 2-octyldodecanol) Etc.), emulsifiers (eg: polyoxyethylene alkyl ethers, fatty acid esters, polyethylene glycol fatty acid esters, etc.), preservatives (eg: paraoxybenzoic acid esters), absorption promoters (eg: propylene carbonate, diethyl sebacate, diisopropyl) Adipate, crotamiton, Azone R, etc.), an irritation inhibitor, and other additives (e.g. salicylic acid, methyl salicylate, glycol salicylate, l-menthol, camphor, peppermint oil, etc.), with various chosen from among these The cream of this invention can be obtained by mix | blending the above-mentioned essential component with the cream base formed by mixing an ingredient.
また、クリーム剤とゲル剤の中間の性質を有する本発明のゲル状クリーム剤は、上記のクリーム剤にゲル化剤（例：カルボキシビニル重合体、ヒドロキシエチルセルロース、ヒドロキシプロピルセルロース、エチルセルロース、カルボキシメチルセルロース等）、及び中和剤（例：ジイソプロパノールアミン、トリエタノールアミン、水酸化ナトリウム等）を加え、ｐＨを４〜８、好ましくは５〜６．５に調整することにより得ることができる。 The gel cream of the present invention having intermediate properties between cream and gel is a gelling agent (eg, carboxyvinyl polymer, hydroxyethyl cellulose, hydroxypropyl cellulose, ethyl cellulose, carboxymethyl cellulose, etc.). ) And a neutralizing agent (eg, diisopropanolamine, triethanolamine, sodium hydroxide, etc.), and the pH is adjusted to 4 to 8, preferably 5 to 6.5.
次に、ゲル状クリーム剤の好適な一製造例（処方例）を示す。ケトプロフェン１〜７重量部を高級脂肪酸エステル２５重量部以下と低級アルコール４０重量部以下の混合物に溶解させ、これに予め加熱し不純物を取り除いたジブチルヒドロキシトルエン２．１〜５重量部を添加する。更に防腐剤０．５重量部以下、乳化剤５重量部以下を加え、溶解物Ｃを得る。一方、水にゲル化剤０．５〜５重量部を加えて膨潤させ、膨潤物Ｄを得る。次いで膨潤物Ｄに溶解物Ｃを加えてホモミキサーで均一に乳化させ、乳化後中和剤を添加し、ｐＨ値を４〜８に調整することにより本発明のゲル状クリーム剤が得られる。 Next, a preferred production example (formulation example) of a gel cream will be shown. 1 to 7 parts by weight of ketoprofen is dissolved in a mixture of 25 parts by weight or less of a higher fatty acid ester and 40 parts by weight or less of a lower alcohol, and 2.1 to 5 parts by weight of dibutylhydroxytoluene previously heated to remove impurities is added thereto. Further, 0.5 parts by weight or less of an antiseptic and 5 parts by weight or less of an emulsifier are added to obtain a dissolved product C. On the other hand, 0.5 to 5 parts by weight of a gelling agent is added to water and swollen to obtain a swollen product D. Next, the lysate C is added to the swelled product D and uniformly emulsified with a homomixer. After emulsification, a neutralizing agent is added, and the pH value is adjusted to 4 to 8 to obtain the gel cream of the present invention.
次に、湿布剤について説明する。本発明の湿布剤に用いられる湿布基剤は特に制限されず、公知あるいは通常使用されているものの中より選択される。このような湿布基剤に含まれる成分としては、例えば、増粘剤（例：ポリアクリル酸ソーダ、ポリアクリル酸、ポバール、ポリビニルピロリドン、ポリエチレンオキサイド、ポリビニルメタアクリレート等の合成水溶性高分子、アラビアゴム、デンプン、ゼラチン等の天然物、メチルセルロース、ヒドロキシプロピルセルロース、アルギン酸、アルギン酸ナトリウム、アルギン酸アンモニウム、カルボキシメチルセルロースナトリウム等）、湿潤剤（例：尿素、グリセリン、プロピレングリコール、ブチレングリコール、ソルビトール等）、充填剤（例：カオリン、酸化亜鉛、タルク、チタン、ベントナイト、エポキシ樹脂類、有機酸（クエン酸、酒石酸、マレイン酸、無水マレイン酸、コハク酸等）、カルシウム、マグネシウム、アルミニウム等）、水、溶解補助剤（例：炭酸プロピレン、クロタミトン、ジイソプロピルアジペート等）、粘着付与剤（例：ロジン、エステルガム、ポリブテン、ポリアクリル酸エステル等）、かぶれ防止剤（例：塩酸ジフェンヒドラミン、マレイン酸クロルフェニラミン、グリチルリチン酸、デキサメタゾン、ベタメタゾン、フルオシノロンアセトニド等）、その他の添加物（例：サリチル酸、サリチル酸メチル、サリチル酸グリコール、ｌ−メントール、カンフル、ノニル酸ワニリルアミド、チモール、トウガラシエキス、ハッカ油、エイゾンＲ等）等が挙げられる。これらの中から選択される諸成分に上述の必須成分を配合し、この配合物を伸縮性又は非伸縮性の支持体に展延塗布した後、その上に剥離被覆物を貼付することにより本発明の湿布剤を得ることができる。かかる支持体としては、例えば、ポリプロピレン、ポリエステル、ポリウレタン、レーヨン、木綿、エチレン−酢酸ビニル共重合体等から選択されるフィルム、布等が挙げられ、剥離被覆物としては、例えば、ポリエチレン、ポリプロピレン、ポリエステル、シリコーン加工紙等が挙げられる。 Next, the poultice will be described. The poultice base used in the poultice of the present invention is not particularly limited, and is selected from those known or commonly used. The components contained in such a poultice base include, for example, thickeners (for example, synthetic water-soluble polymers such as sodium polyacrylate, polyacrylic acid, poval, polyvinylpyrrolidone, polyethylene oxide, polyvinyl methacrylate, Natural products such as rubber, starch, gelatin, methylcellulose, hydroxypropylcellulose, alginic acid, sodium alginate, ammonium alginate, sodium carboxymethylcellulose, etc.), wetting agents (eg urea, glycerin, propylene glycol, butylene glycol, sorbitol, etc.), filling Agents (eg, kaolin, zinc oxide, talc, titanium, bentonite, epoxy resins, organic acids (citric acid, tartaric acid, maleic acid, maleic anhydride, succinic acid, etc.), calcium, magnesium, aluminum Etc.), water, solubilizers (eg, propylene carbonate, crotamiton, diisopropyl adipate, etc.), tackifiers (eg, rosin, ester gum, polybutene, polyacrylates, etc.), anti-rash agents (eg, diphenhydramine hydrochloride) , Chlorpheniramine maleate, glycyrrhizic acid, dexamethasone, betamethasone, fluocinolone acetonide, etc.), other additives (eg salicylic acid, methyl salicylate, glycol salicylate, l-menthol, camphor, nonylic acid vanillylamide, thymol, red pepper Extract, mint oil, Azone R, etc.). By blending the above-mentioned essential components into various components selected from these, and spreading and applying this formulation to a stretchable or non-stretchable support, a release coating is applied thereon. The poultice of the invention can be obtained. Examples of such a support include films, cloths and the like selected from polypropylene, polyester, polyurethane, rayon, cotton, ethylene-vinyl acetate copolymer, etc., and examples of the release coating include polyethylene, polypropylene, Examples include polyester and silicone processed paper.
次に、湿布剤の好適な一製造例（処方例）を示す。ケトプロフェン１〜７重量部を溶解剤０．５〜８重量部と混合、溶解させ均一なものとし、さらに予め加熱し不純物を取り除いたジブチルヒドロキシトルエン２．１〜５重量部を添加し、溶解物Ｅを得る。次に増粘剤５〜２０重量部、好ましくは１０〜１５重量部を湿潤剤５〜４０重量部、水１０〜８０重量部に混合し溶解させ、充填剤２０重量部以下を加え均一な混合物Ｆをとする。次いで溶解物Ｅを混合物Ｆに加え混合し、均一な練合物を得る。この練合物を通常の方法で支持体上に展延塗布した後、その上に剥離被覆物を貼付することにより本発明の湿布剤が得られる。なお、支持体としては伸縮性又は非伸縮性の支持体を用いることができる。 Next, a suitable production example (formulation example) of the poultice is shown. 1 to 7 parts by weight of ketoprofen and 0.5 to 8 parts by weight of a solubilizer are mixed and dissolved to make it uniform, and further 2.1 to 5 parts by weight of dibutylhydroxytoluene that has been preheated to remove impurities is added, and the dissolved product Get E. Next, 5 to 20 parts by weight of a thickener, preferably 10 to 15 parts by weight are mixed and dissolved in 5 to 40 parts by weight of a wetting agent and 10 to 80 parts by weight of water. Let F be. Next, the melt E is added to the mixture F and mixed to obtain a uniform kneaded product. After this kneaded material is spread-coated on a support by a normal method, a poultice according to the present invention is obtained by applying a release coating on it. In addition, as a support body, a stretchable or non-stretchable support body can be used.
次に、貼付剤について説明する。本発明の貼付剤に用いられる貼付基剤は特に制限されず、公知あるいは通常使用されているものの中より選択される。このような貼付基剤に含まれる成分としては、公知の高分子基剤（例：メタアクリル酸エステル類、アクリルニトリル、酢酸ビニル、プロピオン酸ビニル等のビニルモノマーとの共重合物であるアクリル系組成物、シリコーン樹脂、ポリイソプレンゴム、ポリイソブチレンゴム、天然ゴム、アクリルゴム、スチレン−ブタジエン−スチレンブロック共重合体、スチレン−イソプレン−スチレンブロック共重合体等）、油脂又は高級脂肪酸（例：アーモンド油、オリブ油、ツバキ油、パーシック油、ラッカセイ油、オレイン油、流等パラフィン、ポリブテン等）、粘着付与剤（例：ロジン、ロジン変性マレイン酸、水添ロジンエステル等）、かぶれ防止剤、その他の添加物（例：サリチル酸、サリチル酸メチル、サリチル酸グリコール、ｄｌ−カンフル、ｌ−メントール、チモール、ノニル酸ワニリルアミド、トウガラシチンキ、ハッカ油、クロタミトン、ペパーミントオイル、エイゾンＲ等）、紫外線吸収剤又は必要に応じ抗酸化剤が挙げられる。これらの中から選択される諸成分に上記の必須成分を配合し、この配合物を伸縮性又は非伸縮性の支持体に展延塗布した後、その上に剥離被覆物を貼付することにより本発明の貼付剤を得ることができる。かかる支持体としては、例えば、ポリプロピレン、ポリエステル、ポリ塩化ビニリデン、ポリアクリル、ポリウレタン、レーヨン、木綿、エチレン−酢酸ビニル共重合体、布、不織布、不織紙等が挙げられ、剥離被覆物としては、例えば、ポリエチレン、ポリプロピレン、ポリ塩化ビニル、ポリエステル、ポリ塩化ビニリデン、シリコーン加工紙等が挙げられる。 Next, the patch will be described. The patch base used in the patch of the present invention is not particularly limited, and is selected from those known or commonly used. As a component contained in such a patch base, an acrylic polymer which is a copolymer with a known polymer base (e.g., methacrylic acid esters, acrylonitrile, vinyl acetate, vinyl propionate, etc.) is used. Composition, silicone resin, polyisoprene rubber, polyisobutylene rubber, natural rubber, acrylic rubber, styrene-butadiene-styrene block copolymer, styrene-isoprene-styrene block copolymer, etc.), fat or higher fatty acid (eg, almond) Oil, olive oil, camellia oil, persic oil, peanut oil, olein oil, liquid paraffin, polybutene, etc.), tackifier (eg rosin, rosin-modified maleic acid, hydrogenated rosin ester, etc.), rash prevention agent, etc. Additives such as salicylic acid, methyl salicylate, glycol salicylate, dl- Nfuru, l-menthol, thymol, nonylic acid vanillylamide, red pepper tincture, peppermint oil, crotamiton, peppermint oil, Azone R, etc.), antioxidants and the like according to the ultraviolet absorber or necessary. By blending the above-mentioned essential components into various components selected from these, and spreading and applying this formulation to a stretchable or non-stretchable support, a release coating is applied thereon. The patch of the invention can be obtained. Examples of such a support include polypropylene, polyester, polyvinylidene chloride, polyacryl, polyurethane, rayon, cotton, ethylene-vinyl acetate copolymer, cloth, nonwoven fabric, and non-woven paper. Examples thereof include polyethylene, polypropylene, polyvinyl chloride, polyester, polyvinylidene chloride, and silicone-processed paper.
本発明の外用製剤が貼付剤である場合の好ましい製造方法は、スチレン−イソプレン−スチレンブロック共重合体、ポリイソブチレン、水添ロジンエステル、流動パラフィン及ジブチルヒドロキシトルエンを不活性ガス雰囲気下で加熱撹拌し、続いてケトプロフェンを添加し、均一な溶解物を得る工程を含む。さらに好ましい製造方法は、スチレン−イソプレン−スチレンブロック共重合体、ポリイソブチレン、水添ロジンエステル、流動パラフィン及ジブチルヒドロキシトルエンを不活性ガス雰囲気下で加熱撹拌し、続いてケトプロフェンを添加し、均一な溶解物を得る工程と、均一な溶解物を支持体に展延塗布した後に剥離被覆物で覆う工程と、を含む。 When the preparation for external use of the present invention is a patch, a preferred method for production is to stir styrene-isoprene-styrene block copolymer, polyisobutylene, hydrogenated rosin ester, liquid paraffin and dibutylhydroxytoluene in an inert gas atmosphere. And subsequently adding ketoprofen to obtain a uniform lysate. A more preferable production method is as follows. Styrene-isoprene-styrene block copolymer, polyisobutylene, hydrogenated rosin ester, liquid paraffin and dibutylhydroxytoluene are heated and stirred under an inert gas atmosphere, followed by addition of ketoprofen. A step of obtaining a melt, and a step of spreading a uniform melt on a support and then covering with a release coating.
貼付剤の製造例の好適な一製造例（処方例）を示す。スチレン−イソプレン−スチレンブロック共重合体２１重量部、ポリイソブチレン２２重量部、水添ロジンエステル１２重量部、流動パラフィン４０重量部及びジブチルヒドロキシトルエン３重量部に、窒素ガス雰囲気下１１０〜２００℃の温度範囲で撹拌しながらケトプロフェン２重量部を添加し、更に５〜３０分混合して均一な溶解物を得る。この溶解物を７０ｃｍ２あたり１ｇとなるように、シリコーン処理したポリエステルフィルムに展延し、これに支持体を積層することにより本発明の貼付剤が得られる。 A suitable production example (formulation example) of the production example of the patch is shown. Styrene-isoprene-styrene block copolymer 21 parts by weight, polyisobutylene 22 parts by weight, hydrogenated rosin ester 12 parts by weight, liquid paraffin 40 parts by weight and dibutylhydroxytoluene 3 parts by weight under a nitrogen gas atmosphere at 110 to 200 ° C. While stirring in the temperature range, 2 parts by weight of ketoprofen is added and further mixed for 5 to 30 minutes to obtain a uniform dissolved product. The patch of the present invention is obtained by spreading the melted product on a silicone-treated polyester film so as to be 1 g per 70 cm 2 and laminating a support on this.
次に、リニメント剤について説明する。本発明のリニメント剤に用いられるリニメント基剤は特に制限されず、通常使用されているものの中より選択される。このようなリニメント基剤としては、例えば、アルコール類（エタノール、プロパノール、イソプロパノール等の１価のアルコール、ポリエチレングリコール、プロピレングリコール、ブチレングリコール等の多価アルコール等）１０〜７０重量部、水５５重量部以下、脂肪酸エステル（アジピン酸、セバチン酸、ミリスチン酸の各種エステル等）６０重量部以下、界面活性剤（ポリオキシエチレンアルキルエーテル）１０重量部以下を混合してなるものが挙げられ、このようなリニメント基剤に上述の必須成分であるケトプロフェン０．２〜５重量部、及び予め加熱し不純物を取り除いたジブチルヒドロキシトルエン０．２〜５重量部を配合することにより本発明のリニメント剤を得ることができる。なお、本発明のリニメント剤においては、必要に応じてｐＨ調整の為の中和剤あるいはメチルセルロース、カルボキシビニルポリマー、ヒドロキシプロピルセルロース等の粘性付与剤、かぶれ防止剤、その他の添加物（サリチル酸、サリチル酸メチル、サリチル酸グリコール、ｌ−メントール、カンフル、ハッカ油、トウガラシエキス、ノニル酸ワニリルアミド、クロタミトン、エイゾンR、炭酸プロピレン、ジイソプロピルアジペート等）等を配合してもよい。 Next, the liniment is described. The liniment base used in the liniment of the present invention is not particularly limited, and is selected from those usually used. Examples of such a liniment base include alcohols (monohydric alcohols such as ethanol, propanol and isopropanol, polyhydric alcohols such as polyethylene glycol, propylene glycol and butylene glycol) and the like, and water 55 weights. Part or less, fatty acid ester (adipic acid, sebacic acid, various esters of myristic acid, etc.) 60 parts by weight or less, surfactant (polyoxyethylene alkyl ether) 10 parts by weight or less are mixed, such as The liniment of the present invention is obtained by blending 0.2 to 5 parts by weight of the above-mentioned essential component ketoprofen with 0.2 to 5 parts by weight of dibutylhydroxytoluene that has been preheated to remove impurities. be able to. In the liniment of the present invention, if necessary, a neutralizing agent for adjusting pH, a viscosity imparting agent such as methylcellulose, carboxyvinyl polymer, hydroxypropylcellulose, anti-rash agent, and other additives (salicylic acid, salicylic acid) methyl, glycol salicylate, l-menthol, camphor, peppermint oil, red pepper extract, nonylic acid vanillylamide, crotamiton, Azone R, propylene carbonate, may be added diisopropyl adipate, etc.) and the like.
なお、これらの外用製剤の製造方法には、公知の方法を用いことができる。公知の方法を用いる場合には、公知の外用製剤における薬効成分をケトプロフェンに置換し、さらにジブチルヒドロキシトルエンを加熱して不純物を取り除いた後に配合することにより本発明の外用製剤を得ることができる。 In addition, a well-known method can be used for the manufacturing method of these external preparations. When a known method is used, the topical preparation of the present invention can be obtained by substituting ketoprofen for a medicinal component in a known external preparation, and further mixing dibutylhydroxytoluene after removing impurities by heating.
以上、本発明の外用製剤の各剤型に応じた基剤及び処方例の好適な実施形態について説明したが、剤型及び処方例はこれらのものに限定されず、各成分の配合順序も特に限定されるものではない。 The preferred embodiments of the base and formulation examples according to each dosage form of the external preparation of the present invention have been described above, but the dosage forms and formulation examples are not limited to these, and the blending order of each component is also particularly It is not limited.
以下、本発明の外用製剤について実施例及び比較例を示して、より具体的に説明するが本発明の外用製剤は下記の実施例に記載のものに限定されるものではない。 Hereinafter, the external preparation of the present invention will be described more specifically with reference to Examples and Comparative Examples, but the external preparation of the present invention is not limited to those described in the following Examples.
（実施例１）
カルボキシビニルポリマー２重量部を精製水２５重量部に膨潤させた。これに、エタノール４０重量部及びジイソプロピルアジベート２重量部にケトプロフェン３重量部、及び予め加熱し不純物を取り除いたジブチルヒドロキシトルエン２．１重量部を溶解させた溶液を加え攪拌した。さらに、これにヒドロキシプロピルセルセロケース２重量部をプロピレングリコール１５重量部に溶解させた溶液を加え攪拌した後、ジイソプロパノールアミン２．５重量部を精製水６．４部に溶解させたものを加え、全体が均一になるまで十分攪拌することによりゲル剤を得た。
Example 1
2 parts by weight of carboxyvinyl polymer was swollen in 25 parts by weight of purified water. A solution in which 40 parts by weight of ethanol and 2 parts by weight of diisopropyl adipate were dissolved in 3 parts by weight of ketoprofen and 2.1 parts by weight of dibutylhydroxytoluene that had been preliminarily heated to remove impurities was added and stirred. Further, after adding a solution prepared by dissolving 2 parts by weight of hydroxypropyl cellulocase in 15 parts by weight of propylene glycol and stirring the mixture, 2.5 parts by weight of diisopropanolamine was dissolved in 6.4 parts of purified water. In addition, the gel was obtained by sufficiently stirring until the whole became uniform.
（実施例２）
ケトプロフェン７重量部をエタノール５０重量部に溶解せしめ、その中に予め加熱し、不純物を取り除いたジブチルヒドロキシトルエン３重量部を加えた。次にジイソプロピルアジベート４０重量部を加え、全体が均一になるよう十分に攪拌することにより、リニメント剤を得た。
(Example 2)
7 parts by weight of ketoprofen was dissolved in 50 parts by weight of ethanol, and 3 parts by weight of dibutylhydroxytoluene that had been heated in advance and removed impurities was added thereto. Next, 40 parts by weight of diisopropyl adipate was added, and the mixture was sufficiently stirred to obtain a liniment.
（実施例３）
ケトプロフェン１重量部、４−ｔｅｒｔ−ブチル−４’−メトキシジベンゾイルメタン０．５重量部、セバシン酸ジエチル１０重量部、鯨ロウ５重量部、ポリオキシエチレンラウリルエーテルリン酸ナトリウム２重量部、白色ワセリン７８．９５重量部、パラオキシ安息香酸ブチル０．０５重量部、及び予め加熱し不純物を取り除いたジブチルヒドロキシトルエン２．５重量部を配合し、加熱融解させた後、４０〜１００℃に保った。融解液が透明になった後、ホモミキサーで全体が均一になるよう混合した。その後攪拌しながら室温まで冷却することにより軟膏剤を得た。
(Example 3)
1 part by weight of ketoprofen, 0.5 part by weight of 4-tert-butyl-4′-methoxydibenzoylmethane, 10 parts by weight of diethyl sebacate, 5 parts by weight of whale wax, 2 parts by weight of sodium polyoxyethylene lauryl ether phosphate, white Vaseline 78.95 parts by weight, parabutyl oxybenzoate 0.05 parts by weight, and 2.5 parts by weight of dibutylhydroxytoluene that had been preheated to remove impurities were blended, heated and melted, and then maintained at 40 to 100 ° C. . After the melt became transparent, it was mixed with a homomixer so that the whole was uniform. Thereafter, the mixture was cooled to room temperature with stirring to obtain an ointment.
（実施例４）
カルボキシビニルポリマー１重量部を水６２．９重量部に膨潤させ、膨潤物Ａを得た。一方、ミリスチン酸イソプロピル１０重量部とエタノール５重量部及び２−ヒドロキシ−４−メトキシベンゾフェノン０．８重量部を混合し、これにケトプロフェン３重量部を溶解させた後、更に、ポリエチレングリコールモノステアレート１重量部、パラオキシ安息香酸メチル０．２重量部を混合し、予め加熱し不純物を取り除いたジブチルヒドロキシトルエン２．１重量部を配合した。これに膨潤物Ａを添加し、ホモミキサーで均一に乳化した。乳化後、ヤシ油脂肪酸ジエタノールアミド３重量部を水１１重量部に溶解させたものを添加し、全体が均一になるまで十分に攪拌することによりクリーム剤を得た。
Example 4
1 part by weight of carboxyvinyl polymer was swollen in 62.9 parts by weight of water to obtain a swelling product A. On the other hand, 10 parts by weight of isopropyl myristate, 5 parts by weight of ethanol and 0.8 part by weight of 2-hydroxy-4-methoxybenzophenone were mixed, and 3 parts by weight of ketoprofen was dissolved therein, and then polyethylene glycol monostearate. 1 part by weight and 0.2 part by weight of methyl paraoxybenzoate were mixed, and 2.1 parts by weight of dibutylhydroxytoluene that had been preheated to remove impurities was blended. Swelled product A was added thereto, and the mixture was uniformly emulsified with a homomixer. After emulsification, a solution obtained by dissolving 3 parts by weight of coconut oil fatty acid diethanolamide in 11 parts by weight of water was added, and the mixture was sufficiently stirred until the whole became uniform to obtain a cream.
（実施例５）
ゼラチン５重量部、ソルビトール１０重量部、カオリン７重量部、精製水４１．９重量部を混合機内に入れ、約５０〜６０℃にて溶解し、均一な分散液を得た。これに予め調製しておいたグリセリン２５重量部、ポリアクリル酸ソーダ３重量部、カルボキシメチルセルロース３．５重量部の分散液を投入し、そして予め加熱し不純物を取り除いたジブチルヒドロキシトルエン２．１重量部を配合し攪拌練合し、均一な練合物Ｂを得た。また、水浴上にてクロタミトン１重量部、２−ヒドロキシ−４−メトキシベンゾフェノン０．５重量部及びケトプロフェン１重量部を加温混合攪拌し、均一な溶解液Ｃを得た。次に練合物Ｂに溶解液Ｃを投入、攪拌し均一な練合物を得た。これを、展延機を用いて厚さ２ｍｍに塗布した後、ポリプロピレンフィルムに覆い、所望の大きさに切断することにより湿布剤を得た。
(Example 5)
5 parts by weight of gelatin, 10 parts by weight of sorbitol, 7 parts by weight of kaolin and 41.9 parts by weight of purified water were placed in a mixer and dissolved at about 50-60 ° C. to obtain a uniform dispersion. A dispersion of 25 parts by weight of glycerin, 3 parts by weight of sodium polyacrylate, and 3.5 parts by weight of carboxymethylcellulose prepared in advance was added thereto, and 2.1 weights of dibutylhydroxytoluene that had been preheated to remove impurities. Parts were blended and stirred and kneaded to obtain a uniform kneaded product B. Further, 1 part by weight of crotamiton, 0.5 part by weight of 2-hydroxy-4-methoxybenzophenone and 1 part by weight of ketoprofen were heated and mixed and stirred on a water bath to obtain a uniform solution C. Next, the solution C was added to the kneaded product B and stirred to obtain a uniform kneaded product. This was applied to a thickness of 2 mm using a spreader, then covered with a polypropylene film, and cut into a desired size to obtain a poultice.
（実施例６）
スチレン−イソプレン−スチレンテレブロック共重合体１２重量部、スチレン−イソプレン−スチレンラジアルテレブロック共重合体８重量部、水添ロジンエステル１２重量部、ロジン変性マレイン酸樹脂３重量部、流動パラフィン５５重量部を窒素ガス気流中で融解混合し、この融液（約１５０℃）を約１２０℃まで冷却した後、ケトプロフェン５重量部を及び２−ヒドロキシ−４−メトキシベンゾフェノン２．５重量部を添加、そして予め加熱し不純物を取り除いたジブチルヒドロキシトルエン２．５重量部を混合して均一なものとした。これを展延機を用いて不織布上に厚さ約５０μｍに展延した後、離型処理を施した剥離紙で覆い所望の大きさに切断することにより貼付剤を得た。
(Example 6)
Styrene-isoprene-styrene teleblock copolymer 12 parts by weight, styrene-isoprene-styrene radial teleblock copolymer 8 parts by weight, hydrogenated rosin ester 12 parts by weight, rosin-modified maleic resin 3 parts by weight, liquid paraffin 55 parts by weight Parts were melt-mixed in a nitrogen gas stream, and the melt (about 150 ° C.) was cooled to about 120 ° C., and then 5 parts by weight of ketoprofen and 2.5 parts by weight of 2-hydroxy-4-methoxybenzophenone were added. Then, 2.5 parts by weight of dibutylhydroxytoluene previously heated to remove impurities was mixed to make uniform. This was spread on a nonwoven fabric to a thickness of about 50 μm using a spreader, then covered with a release paper that had been subjected to a release treatment, and cut into a desired size to obtain a patch.
（参考例７）
スチレン−イソプレン−スチレンブロック共重合体２１重量部、ポリイソブチレン２２重量部、水添ロジンエステル１２重量部、流動パラフィン４０重量部、ジブチルヒドロキシトルエン（ヨシノックスＢＨＴ、ＡＰＩコーポレーション）３重量部を、窒素ガス雰囲気下１１０〜２００℃の温度範囲で撹拌しながらケトプロフェン２重量部を添加し、更に５〜３０分混合して均一な溶解物を得た。これを７０ｃｍ２あたり１ｇとなるように、シリコーン処理したポリエステルフィルムに展延し、支持体を積層することにより貼付剤を得た。
( Reference Example 7)
Styrene-isoprene-styrene block copolymer 21 parts by weight, polyisobutylene 22 parts by weight, hydrogenated rosin ester 12 parts by weight, liquid paraffin 40 parts by weight, dibutylhydroxytoluene (Yosinox BHT, API Corporation) 3 parts by weight, nitrogen gas 2 parts by weight of ketoprofen was added with stirring in a temperature range of 110 to 200 ° C. in an atmosphere, and further mixed for 5 to 30 minutes to obtain a uniform dissolved product. This was spread on a silicone-treated polyester film so as to be 1 g per 70 cm 2, and a support was laminated to obtain a patch.
（参考例８）
スチレン−イソプレン−スチレンブロック共重合体２１重量部、ポリイソブチレン２２重量部、水添ロジンエステル１２重量部、流動パラフィン４０重量部、ジブチルヒドロキシトルエン（ＢＨＴタケダ、武田キリン食品）３重量部を、窒素ガス雰囲気下１１０〜２００℃の温度範囲で撹拌しながらケトプロフェン２重量部を添加し、更に５〜３０分混合して均一な溶解物を得た。この溶解物を７０ｃｍ２あたり１ｇとなるように、シリコーン処理したポリエステルフィルムに展延し、支持体を積層することにより貼付剤を得た。
( Reference Example 8)
Styrene-isoprene-styrene block copolymer 21 parts by weight, polyisobutylene 22 parts by weight, hydrogenated rosin ester 12 parts by weight, liquid paraffin 40 parts by weight, dibutylhydroxytoluene (BHT Takeda, Takeda Kirin Foods) 3 parts by weight, nitrogen While stirring in a temperature range of 110 to 200 ° C. in a gas atmosphere, 2 parts by weight of ketoprofen was added and further mixed for 5 to 30 minutes to obtain a uniform dissolved product. This melt was spread on a silicone-treated polyester film so as to be 1 g per 70 cm 2 , and a support was laminated to obtain a patch.
（比較例１）
スチレン−イソプレン−スチレンブロック共重合体２１重量部、ポリイソブチレン２２重量部、水添ロジンエステル１２重量部、流動パラフィン４０重量部を、窒素ガス雰囲気下１１０〜２００℃の温度範囲で撹拌しながらケトプロフェン２重量部、ジブチルヒドロキシトルエン（ヨシノックスＢＨＴ、ＡＰＩコーポレーション）３重量部を添加し、更に５〜３０分混合して均一な溶解物を得た。これを７０ｃｍ２あたり１ｇとなるように、シリコーン処理したポリエステルフィルムに展延し、支持体を積層することにより、比較の為の貼付剤を得た。
(Comparative Example 1)
While stirring 21 parts by weight of a styrene-isoprene-styrene block copolymer, 22 parts by weight of polyisobutylene, 12 parts by weight of a hydrogenated rosin ester, and 40 parts by weight of liquid paraffin in a nitrogen gas atmosphere at a temperature range of 110 to 200 ° C., ketoprofen. 2 parts by weight and 3 parts by weight of dibutylhydroxytoluene (Yosinox BHT, API Corporation) were added and further mixed for 5 to 30 minutes to obtain a uniform dissolved product. This was spread on a polyester film treated with silicone so as to be 1 g per 70 cm 2, and a support was laminated to obtain a patch for comparison.
（ケトプロフェンの定量方法）
貼付剤の場合、製剤１枚（７０ｃｍ２）を取り、質量を精密に量り、テトラヒドロフラン４０ｍＬを加え、３０分間超音波処理し、得られた抽出液にメタノールを加えて１００ｍＬとし、これをメタノールで５倍に希釈して試料液とした。得られた試料液につき、高速液体クロマトグラフを用い、下記条件でケトプロフェン（以下、ＫＰという）を定量した。
(Quantitative method for ketoprofen)
In the case of a patch, take one preparation (70 cm 2 ), weigh accurately, add 40 mL of tetrahydrofuran, sonicate for 30 minutes, add methanol to the resulting extract to make 100 mL, and use methanol for this. The sample solution was diluted 5 times. About the obtained sample liquid, ketoprofen (henceforth KP) was quantified on the following conditions using the high performance liquid chromatograph.
高速液体クロマトグラフィーの操作条件は、カラムがＴＳＫｇｅｌ ＯＤＳ−８０ＴＳ（カラムオーブン４０℃）、検出ＵＶ波長が２５４ｎｍ、移動相がアセトニトリル／０．２％酢酸水溶液＝１／１、移動相の流速が１．０ｍＬ／ｍｉｎであった。この時、ＫＰのリテンションタイムは約５分であった。 The operating conditions of the high performance liquid chromatography are as follows: TSKgel ODS-80TS (column oven 40 ° C.) column, detection UV wavelength 254 nm, mobile phase acetonitrile / 0.2% acetic acid aqueous solution = 1/1, mobile phase flow rate 1 0.0 mL / min. At this time, the retention time of KP was about 5 minutes.
（ＫＰメチルエステルの定量方法）
貼付剤の場合、製剤０．５枚（３５ｃｍ２）を取り、質量を精密に量り、テトラヒドロフラン４０ｍＬを加え、３０分間超音波処理し、得られた抽出液にメタノールを加えて５０ｍＬとし、これをメタノールで５０倍に希釈して試料液とした。得られた試料液につき、高速液体クロマトグラフを用い、下記条件でＫＰメチルエステルを定量した。
(Quantitative method of KP methyl ester)
In the case of a patch, take 0.5 preparations (35 cm 2 ), weigh accurately, add 40 mL of tetrahydrofuran, sonicate for 30 minutes, add methanol to the resulting extract to make 50 mL, The sample solution was diluted 50 times with methanol. About the obtained sample liquid, KP methyl ester was quantified on the following conditions using the high performance liquid chromatograph.
高速液体クロマトグラフィーの操作条件は、カラムがＴＳＫｇｅｌ ＯＤＳ−８０ＴＳ（カラムオーブン４０℃）、検出ＵＶ波長が２５４ｎｍ、移動相がアセトニトリル／０．２％酢酸水溶液、グラジエント条件が１／１（１５ｍｉｎ、保持）→（５ｍｉｎ、グラジエント）→８５／１５（１５ｍｉｎ、保持）→（５ｍｉｎ、グラジエント）→１／１（１５ｍｉｎ、保持）、移動相の流速が１．０ｍＬ／ｍｉｎであった。この時、ＫＰメチルエステル体のリテンションタイムは約１２分であった。 The operating conditions of high performance liquid chromatography are as follows: TSKgel ODS-80TS (column oven 40 ° C.), UV detection wavelength 254 nm, mobile phase acetonitrile / 0.2% acetic acid aqueous solution, gradient condition 1/1 (15 min, hold) ) → (5 min, gradient) → 85/15 (15 min, hold) → (5 min, gradient) → 1/1 (15 min, hold), the mobile phase flow rate was 1.0 mL / min. At this time, the retention time of the KP methyl ester was about 12 minutes.
なお、ＫＰのメチルエステル化体の生成率は、定量されたＫＰのモル数を、定量されたＫＰメチルエステルのモル数とＫＰのモル数との総和で除した値をパーセント換算であらわしたものである。 The production rate of the methyl esterified product of KP is obtained by dividing the number of moles of quantified KP by the sum of the quantified number of moles of KP methyl ester and the number of moles of KP in percent conversion. It is.
参考例７及び比較例１について、ＫＰの定量及びＫＰメチルエステルの定量により得られた結果を表１に示す。また、参考例７について、３ロットを調製し定量を行った。これを表２に示す。さらに、表３は、参考例８について定量を行った結果である。 For Reference Example 7 and Comparative Example 1, the results obtained by quantification of KP and quantification of KP methyl ester are shown in Table 1. For Reference Example 7, three lots were prepared and quantified. This is shown in Table 2. Further, Table 3 shows the results of quantification for Reference Example 8.
表１〜３に示した結果から明らかな通り、本発明によりＫＰメチルエステルの生成率が一定値以下に抑えられることが確認された。
As is apparent from the results shown in Tables 1 to 3, it was confirmed that the production rate of KP methyl ester was suppressed to a certain value or less according to the present invention.
Claims (4)
予め単独で加熱し不純物を取り除いたジブチルヒドロキシトルエンと、ケトプロフェンとを混合することを特徴とする外用製剤の製造方法。 A method for producing an external preparation containing 1 to 7% by mass of ketoprofen and 2.1 to 10% by mass of dibutylhydroxytoluene, wherein the production rate of ketoprofen methyl ester is 0.2% or less ,
A method for producing an external preparation characterized by mixing dibutylhydroxytoluene, which has been previously heated alone to remove impurities, and ketoprofen.
スチレン−イソプレン−スチレンブロック共重合体、ポリイソブチレン、水添ロジンエステル、流動パラフィン、ケトプロフェン及び予め単独で加熱し不純物を取り除いたジブチルヒドロキシトルエンを不活性ガス雰囲気下で加熱撹拌して、均一な溶解物を得る工程を含む、製造方法。 It is a manufacturing method of the patch of Claim 2,
Styrene - isoprene - styrene block copolymer, polyisobutylene, hydrogenated rosin ester, liquid paraffin, ketoprofen and advance alone heated dibutylhydroxytoluene removing the impurities was stirred and heated in an inert gas atmosphere, uniform dissolution The manufacturing method including the process of obtaining a thing.
スチレン−イソプレン−スチレンブロック共重合体、ポリイソブチレン、水添ロジンエステル、流動パラフィン、ケトプロフェン及び予め単独で加熱し不純物を取り除いたジブチルヒドロキシトルエンを不活性ガス雰囲気下で加熱撹拌して、均一な溶解物を得る工程と、均一な溶解物を支持体に展延塗布した後に剥離被覆物で覆う工程と、を含む、製造方法。 It is a manufacturing method of the patch of Claim 2,
Styrene - isoprene - styrene block copolymer, polyisobutylene, hydrogenated rosin ester, liquid paraffin, ketoprofen and advance alone heated dibutylhydroxytoluene removing the impurities was stirred and heated in an inert gas atmosphere, uniform dissolution The manufacturing method including the process of obtaining a thing, and the process of spread-coating a uniform melt | dissolution to a support body, and covering with a peeling coating.
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