JP2012214445A - Loxoprofen-containing external preparation - Google Patents
Loxoprofen-containing external preparation Download PDFInfo
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- JP2012214445A JP2012214445A JP2012059522A JP2012059522A JP2012214445A JP 2012214445 A JP2012214445 A JP 2012214445A JP 2012059522 A JP2012059522 A JP 2012059522A JP 2012059522 A JP2012059522 A JP 2012059522A JP 2012214445 A JP2012214445 A JP 2012214445A
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- 229960002373 loxoprofen Drugs 0.000 title claims abstract description 68
- 238000002360 preparation method Methods 0.000 title claims abstract description 25
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- 230000002378 acidificating effect Effects 0.000 claims abstract description 14
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- 229940055577 oleyl alcohol Drugs 0.000 claims abstract description 7
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- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
本発明は、ロキソプロフェン及び／又はその医学的に許容できる塩を含有する外用剤の分野に関する。さらに詳しくは、本分野で、酸性条件で生じる析出あるいは沈殿の生成を防止する技術に関する。 The present invention relates to the field of external preparations containing loxoprofen and / or a medically acceptable salt thereof. More specifically, the present invention relates to a technique for preventing precipitation or precipitation generation that occurs under acidic conditions.
ロキソプロフェン(正式名：２−[p−(２−オキソシクロペンチルメチル)フェニル]プロピオン酸)のナトリウム塩、すなわちロキソプロフェンナトリウムはフェニルプロピオン酸系の非ステロイド性消炎鎮痛剤の一つである。関節リウマチ、変形性関節症、腰痛症、肩関節周囲炎、頸肩腕症候群、歯痛、外傷後並びに抜歯後の鎮痛・消炎、急性上気道炎の解熱・鎮痛に対して効果を示し、汎用されている(非特許文献１)。ロキソプロフェンナトリウムは、生体内で作用の強い活性代謝物に変換されたのち作用を発揮するいわゆるプロドラッグであり、この薬物は消化管傷害が比較的少ないという特性を有するものの、消化管潰瘍の既往歴のある患者または長期投与する時には慎重に投与することが必要である。このため、係る副作用を軽減することを目的として、炎症部位での局所薬物濃度を高め全身性の副作用を回避する目的で経皮投与型の外用剤が考えられる(特許文献１)。 Loxoprofen (formal name: 2- [p- (2-oxocyclopentylmethyl) phenyl] propionic acid) sodium salt, that is, loxoprofen sodium is one of the non-steroidal anti-inflammatory analgesics based on phenylpropionic acid. Rheumatoid arthritis, osteoarthritis, low back pain, periarthritis, neck-shoulder arm syndrome, toothache, post-traumatic and post-extraction analgesia / anti-inflammation, acute upper respiratory tract antipyretic / analgesic (Non-patent Document 1). Loxoprofen sodium is a so-called prodrug that acts after being converted to a strong active metabolite in vivo, and this drug has the characteristic of relatively little gastrointestinal damage, but has a history of gastrointestinal ulcers It is necessary to administer with caution in patients with or for long-term administration. Therefore, for the purpose of reducing such side effects, an external preparation of a transdermal administration type can be considered for the purpose of increasing the local drug concentration at the site of inflammation and avoiding systemic side effects (Patent Document 1).
ロキソプロフェンナトリウムはｐＫａ４．２０の水に極めて溶けやすい薬物であるが(非特許文献２)、精製水に溶解させるとほとんどがイオン型として存在するため、ｐＨ−分配仮説によると皮膚透過性が良好でないことが予測される。 Loxoprofen sodium is a drug that is extremely soluble in water with pKa 4.20 (Non-patent Document 2), but most of it exists as an ionic form when dissolved in purified water. Therefore, according to the pH-partition hypothesis, skin permeability is not good. It is predicted.
本発明者らは、精製水等に溶解したイオン型のロキソプロフェンを、溶液のｐＨを低下させることによりイオンに解離していない分子型とし、皮膚透過性を向上させることを考えた。しかし、分子型ロキソプロフェンの割合が増える酸性条件では、析出もしくは沈殿を生じるため、製造上問題があり、また、商品性を損なうという問題があった。 The present inventors considered that the ionic form of loxoprofen dissolved in purified water or the like is made into a molecular form that is not dissociated into ions by lowering the pH of the solution to improve skin permeability. However, under acidic conditions in which the proportion of molecular type loxoprofen is increased, precipitation or precipitation occurs, so that there are problems in production, and there is a problem that merchantability is impaired.
皮膚透過性を確認する方法としては、フランツ型拡散セルを用いた摘出皮膚透過性試験等が挙げられる。また、皮膚透過性を予測する方法としては、シリコンゴム膜を用いたin vitro放出試験（田中重男ほか、基礎と臨床、22(7) 、1775-1779（1988））等が挙げられる。 Examples of the method for confirming skin permeability include an excised skin permeability test using a Franz diffusion cell. Examples of methods for predicting skin permeability include an in vitro release test using a silicone rubber membrane (Shigeo Tanaka et al., Basic and Clinical, 22 (7), 1775-1779 (1988)).
本発明は、ロキソプロフェンを配合した外用剤のｐＨを酸及び／又は酸性物質により低下させた際に、析出あるいは沈殿の生成を防止することを課題とする。 This invention makes it a subject to prevent the production | generation of precipitation or precipitation, when the pH of the external preparation which mix | blended loxoprofen is lowered | hung with an acid and / or an acidic substance.
本発明者らは、かかる課題を解決するために鋭意検討した結果、特定の高級アルコールを配合することにより、酸性条件においても析出あるいは沈殿の生成を防止可能なことを見出し、本発明を完成した。
すなわち本発明は、
（１） a）ロキソプロフェン及び／又はその医学的に許容できる塩、b）炭素数が６以上２０未満の高級アルコール、c）酸及び／又は酸性物質を配合し、ロキソプロフェンを溶解したことを特徴とする外用剤、
（２） b）の高級アルコールが、ヘキシルデカノール、イソステアリルアルコール、オレイルアルコールからなる群から選ばれる少なくとも１種である請求項１に記載の外用剤、
（３）分子型ロキソプロフェン、及び炭素数が６以上２０未満の高級アルコールを含有し、分子型ロキソプロフェンを溶解したことを特徴とする外用剤、
（４）分子型ロキソプロフェンを、炭素数が６以上２０未満の高級アルコールに溶解する方法、
である。
As a result of diligent studies to solve such problems, the present inventors have found that by adding a specific higher alcohol, precipitation or precipitation can be prevented even under acidic conditions, and the present invention has been completed. .
That is, the present invention
(1) a) Loxoprofen and / or a medically acceptable salt thereof, b) a higher alcohol having 6 to less than 20 carbon atoms, c) an acid and / or an acidic substance, and loxoprofen dissolved therein External preparations,
(2) The external preparation according to claim 1, wherein the higher alcohol of b) is at least one selected from the group consisting of hexyldecanol, isostearyl alcohol, and oleyl alcohol.
(3) An external preparation containing a molecular type loxoprofen and a higher alcohol having 6 to 20 carbon atoms, wherein the molecular type loxoprofen is dissolved,
(4) A method of dissolving molecular loxoprofen in a higher alcohol having 6 to 20 carbon atoms,
It is.
本発明により、酸性条件においても析出あるいは沈殿の生成を防止した外用剤の提供が可能となった。 According to the present invention, it is possible to provide an external preparation that prevents precipitation or precipitation even under acidic conditions.
本発明に用いられるロキソプロフェン及び／又はその医学的に許容できる塩としては、特にロキソプロフェンナトリウムが好ましい。本発明の外用剤におけるロキソプロフェンナトリウムの配合濃度は適用する疾病の症状に応じて適宜増減することができるが、ロキソプロフェンナトリウム無水物として、外用剤全体の０．５〜１０．０ｗ／ｖ％であることが好ましく、１．０〜５．０ｗ／ｖ％であることが更に好ましい。ただし、その剤形によって適宜変えることができる。 As loxoprofen and / or a medically acceptable salt thereof used in the present invention, loxoprofen sodium is particularly preferable. The compounding concentration of loxoprofen sodium in the external preparation of the present invention can be appropriately increased or decreased depending on the symptoms of the disease to be applied, but it is 0.5 to 10.0 w / v% of the total external preparation as loxoprofen sodium anhydride. It is preferably 1.0 to 5.0 w / v%. However, it can be appropriately changed depending on the dosage form.
本発明における高級アルコールとは、アルコール類のうち、炭素数６以上の１価アルコールを指す（化粧品事典、日本化粧品技術者会編、丸善株式会社、ｐ４５６、２００５）。また、皮膚透過性の観点から、本発明における高級アルコールとしては常温（２５℃）で液体であることが好ましい。本発明における炭素数が６以上２０未満の高級アルコールとしては、カプロイルアルコール、カプリリルアルコール、カプリルアルコール、ラウリルアルコール、オクチルドデカノール、ヘキシルデカノール、イソステアリルアルコール、オレイルアルコールが好ましく、ヘキシルデカノール、イソステアリルアルコール、オレイルアルコールが更に好ましい。高級アルコールの配合濃度は、外用剤全体の０．１ｗ／ｖ％〜３５．０ｗ／ｖ％であることが好ましく、溶解性の面から外用剤全体の０．２ｗ／ｖ％〜３５．０ｗ／ｖ％であることが更に好ましい。 The higher alcohol in the present invention refers to a monohydric alcohol having 6 or more carbon atoms among alcohols (Cosmetics Encyclopedia, edited by Japan Cosmetic Engineers Association, Maruzen Co., Ltd., p456, 2005). From the viewpoint of skin permeability, the higher alcohol in the present invention is preferably liquid at normal temperature (25 ° C.). As the higher alcohol having 6 to 20 carbon atoms in the present invention, caproyl alcohol, caprylyl alcohol, capryl alcohol, lauryl alcohol, octyldodecanol, hexyldecanol, isostearyl alcohol, and oleyl alcohol are preferable, and hexyldecanol, isostearyl alcohol More preferred is oleyl alcohol. The blending concentration of the higher alcohol is preferably 0.1 w / v% to 35.0 w / v% of the whole external preparation, and from the viewpoint of solubility, 0.2 w / v% to 35.0 w / w of the whole external preparation. More preferably, it is v%.
本発明における外用剤のｐＨは、酸及び／又は酸性物質及び／又は塩基により調整し、３．５〜６．２であることが好ましく、３．５〜５．８であることが更に好ましい。 The pH of the external preparation in the present invention is adjusted with an acid and / or an acidic substance and / or a base, and is preferably 3.5 to 6.2, and more preferably 3.5 to 5.8.
本発明における酸としては、特に制限されないが、通常外用剤に配合される適当な酸を使用することができる。そのような酸の例としては、例えば、塩酸、クエン酸、乳酸、リン酸、酒石酸、グルコン酸等を挙げることができる。 Although it does not restrict | limit especially as an acid in this invention, The suitable acid normally mix | blended with an external preparation can be used. Examples of such acids include hydrochloric acid, citric acid, lactic acid, phosphoric acid, tartaric acid, gluconic acid and the like.
本発明における酸性物質とは、通常外用剤に配合される外用剤のｐＨを低下させる物質のことであり、例えば、Ｌ−アスパラギン酸、Ｌ−グルタミン酸、グリチルレチン酸、Ｌ−アスコルビン酸、カルボキシビニルポリマー、イソステアリン酸、オレイン酸等を挙げることができる。 The acidic substance in the present invention is a substance that lowers the pH of an external preparation that is usually blended with an external preparation. For example, L-aspartic acid, L-glutamic acid, glycyrrhetinic acid, L-ascorbic acid, carboxyvinyl polymer , Isostearic acid, oleic acid and the like.
ｐＨ調節の際には、これらの酸及び／又は酸性物質及び／又は塩基を１種又は２種以上組み合わせて使用することができる。 In adjusting the pH, these acids and / or acidic substances and / or bases can be used alone or in combination of two or more.
本発明の外用剤の剤形は、特に限定されるものではないが、例えば、ローション剤、液剤、乳液、クリーム剤、軟膏剤、ゲル剤、エアゾール剤、チック剤等が挙げられ、これらは公知の方法で製造することができる。製造に際しては、本発明の効果を損なわない範囲で、他の非ステロイド性消炎鎮痛剤、局所刺激剤、清涼化剤、血行促進剤、抗炎症剤、抗ヒスタミン剤、生薬等の外用剤に用いる他の有効成分、ｐＨ調節剤、抗酸化剤、界面活性剤、紫外線吸収剤、経皮吸収促進剤等の添加物を適宜添加してもよい。 The dosage form of the external preparation of the present invention is not particularly limited, and examples thereof include lotions, liquids, emulsions, creams, ointments, gels, aerosols, tics, and the like. It can be manufactured by the method. In the production, other non-steroidal anti-inflammatory analgesics, topical stimulants, cooling agents, blood circulation promoters, anti-inflammatory agents, antihistamines, herbal medicines and other external preparations are used as long as the effects of the present invention are not impaired. You may add suitably additives, such as an active ingredient, a pH adjuster, an antioxidant, surfactant, a ultraviolet absorber, and a percutaneous absorption enhancer.
以下に、実施例、試験例を示し、本発明を詳細に説明する。なお、本発明はこれら実施例に限定されるものでは無い。 Hereinafter, the present invention will be described in detail with reference to Examples and Test Examples. The present invention is not limited to these examples.
実施例１
ロキソプロフェンナトリウム ３．４ｇ
ヘキシルデカノール １２ｇ
プロピレングリコール ５ｇ
モノステアリン酸ソルビタン ２ｇ
ポリソルベート６０ ２ｇ
ポリソルベート８０ ４ｇ
ヒドロキシプロピルセルロース ２ｇ
精製水 ６９．６ｇ
リン酸 適量
ロキソプロフェンナトリウム３．４ｇを精製水６９．６ｇに溶解し水相とした。別に、ヘキシルデカノール１２ｇ、プロピレングリコール５ｇ、モノステアリン酸ソルビタン２ｇ、ポリソルベート６０ ２ｇ、ポリソルベート８０ ４ｇを約８０℃に加温し、撹拌して油相とした。約８０℃に加温した水相に油相を加え、攪拌しながら室温まで冷却し、リン酸適量を加えて、ｐＨを５．４に調節した。これにヒドロキシプロピルセルロースを２ｇ、リン酸適量を加え、撹拌してｐＨ５．３の乳液を得た。
Example 1
Loxoprofen sodium 3.4g
Hexyldecanol 12g
5g propylene glycol
2g sorbitan monostearate
Polysorbate 60 2g
Polysorbate 80 4g
Hydroxypropylcellulose 2g
69.6g of purified water
Phosphoric acid A suitable amount of loxoprofen sodium (3.4 g) was dissolved in purified water (69.6 g) to obtain an aqueous phase. Separately, 12 g of hexyldecanol, 5 g of propylene glycol, 2 g of sorbitan monostearate, 20.2 g of polysorbate, and 4 g of polysorbate 804 were heated to about 80 ° C. and stirred to obtain an oil phase. The oil phase was added to the aqueous phase heated to about 80 ° C., cooled to room temperature with stirring, and an appropriate amount of phosphoric acid was added to adjust the pH to 5.4. To this was added 2 g of hydroxypropylcellulose and an appropriate amount of phosphoric acid, followed by stirring to obtain an emulsion having a pH of 5.3.
（酸性条件におけるロキソプロフェンの溶解性）
Ｈｅｎｄｅｒｓｏｎ−Ｈａｓｓｅｌｂａｌｃｈの式より、溶液中の分子型のロキソプロフェンの割合を求めると、ｐＨ６．２より高いｐＨでは分子型のロキソプロフェンはほとんど存在しない。そこで、希塩酸を適量加えてｐＨを６．２以下に調節し、分子型ロキソプロフェンの割合が増える酸性条件で、ロキソプロフェンの溶解性を析出、沈殿の有無より確認した。溶解性の確認は、２５℃±５℃の室温で、ガラス容器にロキソプロフェンナトリウム水溶液を入れ、マグネチックスターラーで撹拌しながら、希塩酸を加え、数分撹拌した後、外観を目視で観察した。また、外観観察後にｐＨを測定した。試験液１〜１０の外観及びｐＨの結果を表１に示す。外観の欄の○は、澄明な状態、×は、析出あるいは沈殿が認められた状態を示す。
(Solubility of loxoprofen in acidic conditions)
When the ratio of molecular loxoprofen in the solution is determined from the Henderson-Hasselbalch equation, there is almost no molecular loxoprofen at a pH higher than pH 6.2. Therefore, an appropriate amount of dilute hydrochloric acid was added to adjust the pH to 6.2 or lower, and the solubility of loxoprofen was confirmed from the presence or absence of precipitation under acidic conditions in which the proportion of molecular type loxoprofen increased. The solubility was confirmed by adding a loxoprofen sodium aqueous solution to a glass container at room temperature of 25 ° C. ± 5 ° C., adding dilute hydrochloric acid while stirring with a magnetic stirrer, stirring for several minutes, and visually observing the appearance. Moreover, pH was measured after appearance observation. Table 1 shows the appearance and pH results of the test solutions 1 to 10. ○ in the column of appearance indicates a clear state, and × indicates a state where precipitation or precipitation is observed.
（試験液１）
精製水にロキソプロフェンナトリウム１ｇ(無水物として)を溶解後、精製水で全量を１００ｍＬとした。
(Test solution 1)
After dissolving 1 g of loxoprofen sodium (as an anhydride) in purified water, the total volume was adjusted to 100 mL with purified water.
（試験液２）
精製水にロキソプロフェンナトリウム１ｇ(無水物として)を溶解後、精製水で全量を１００ｍＬとした。そのうち１０ｍＬを量り取り、希塩酸適量を加え、ｐＨを５．４に調節した。
(Test solution 2)
After dissolving 1 g of loxoprofen sodium (as an anhydride) in purified water, the total volume was adjusted to 100 mL with purified water. 10 mL of the solution was weighed out and an appropriate amount of diluted hydrochloric acid was added to adjust the pH to 5.4.
（試験液３）
精製水にロキソプロフェンナトリウム１ｇ(無水物として)を溶解後、精製水で全量を１００ｍＬとした。そのうち１０ｍＬを量り取り、希塩酸適量を加え、ｐＨを５．０に調節した。
(Test solution 3)
After dissolving 1 g of loxoprofen sodium (as an anhydride) in purified water, the total volume was adjusted to 100 mL with purified water. 10 mL of the solution was weighed out and an appropriate amount of diluted hydrochloric acid was added to adjust the pH to 5.0.
（試験液４）
精製水にロキソプロフェンナトリウム３ｇ(無水物として)を溶解後、精製水で全量を１００ｍＬとした。
(Test solution 4)
After dissolving 3 g of loxoprofen sodium (as an anhydride) in purified water, the total volume was adjusted to 100 mL with purified water.
（試験液５）
精製水にロキソプロフェンナトリウム３ｇ(無水物として)を溶解後、精製水で全量を１００ｍＬとした。そのうち１０ｍＬを量り取り、希塩酸適量を加え、ｐＨを５．７に調節した。
(Test solution 5)
After dissolving 3 g of loxoprofen sodium (as an anhydride) in purified water, the total volume was adjusted to 100 mL with purified water. Of these, 10 mL was weighed out and an appropriate amount of dilute hydrochloric acid was added to adjust the pH to 5.7.
（試験液６）
精製水にロキソプロフェンナトリウム３ｇ(無水物として)を溶解後、精製水で全量を１００ｍＬとした。そのうち１０ｍＬを量り取り、希塩酸適量を加え、ｐＨを５．５に調節した。
(Test solution 6)
After dissolving 3 g of loxoprofen sodium (as an anhydride) in purified water, the total volume was adjusted to 100 mL with purified water. Of these, 10 mL was weighed out and an appropriate amount of dilute hydrochloric acid was added to adjust the pH to 5.5.
（試験液７）
精製水にロキソプロフェンナトリウム５ｇ(無水物として)を溶解後、精製水で全量を１００ｍＬとした。
(Test solution 7)
After dissolving 5 g of loxoprofen sodium (as an anhydride) in purified water, the total volume was adjusted to 100 mL with purified water.
（試験液８）
精製水にロキソプロフェンナトリウム５ｇ(無水物として)を溶解後、精製水で全量を１００ｍＬとした。そのうち１０ｍＬを量り取り、希塩酸適量を加え、ｐＨを６．４に調節した。
(Test solution 8)
After dissolving 5 g of loxoprofen sodium (as an anhydride) in purified water, the total volume was adjusted to 100 mL with purified water. 10 mL of the solution was weighed out and an appropriate amount of diluted hydrochloric acid was added to adjust the pH to 6.4.
（試験液９）
精製水にロキソプロフェンナトリウム５ｇ(無水物として)を溶解後、精製水で全量を１００ｍＬとした。そのうち１０ｍＬを量り取り、希塩酸適量を加え、ｐＨを６．０に調節した。
(Test solution 9)
After dissolving 5 g of loxoprofen sodium (as an anhydride) in purified water, the total volume was adjusted to 100 mL with purified water. Of these, 10 mL was weighed out and an appropriate amount of dilute hydrochloric acid was added to adjust the pH to 6.0.
（試験液１０）
精製水にロキソプロフェンナトリウム５ｇ(無水物として)を溶解後、精製水で全量を１００ｍＬとした。そのうち１０ｍＬを量り取り、希塩酸適量を加え、ｐＨを５．８に調節した。
(Test solution 10)
After dissolving 5 g of loxoprofen sodium (as an anhydride) in purified water, the total volume was adjusted to 100 mL with purified water. Of these, 10 mL was weighed out and an appropriate amount of dilute hydrochloric acid was added to adjust the pH to 5.8.
表１に示すように、１％ロキソプロフェンナトリウムの場合はｐＨ５．０以下、３％ロキソプロフェンナトリウムの場合はｐＨ５．５以下、５％ロキソプロフェンナトリウムの場合はｐＨ５．８以下に調節すると、析出あるいは沈殿が認められた。 As shown in Table 1, when 1% loxoprofen sodium is adjusted to pH 5.0 or lower, 3% loxoprofen sodium is adjusted to pH 5.5 or lower, and 5% loxoprofen sodium is adjusted to pH 5.8 or lower to cause precipitation or precipitation. Admitted.
本試験を行った際に、生じた析出あるいは沈殿は分子型ロキソプロフェンと考えられる。本発明はまた、ロキソプロフェンナトリウムを配合した外用剤において、ロキソプロフェンナトリウムが分子型ロキソプロフェンとして析出あるいは沈殿を生じるｐＨ領域において、分子型ロキソプロフェンの析出あるいは沈殿の生成を防止するものである。 Precipitation or precipitation that occurs during this test is considered to be molecular loxoprofen. The present invention also prevents molecular loxoprofen precipitation or precipitation in a pH range where loxoprofen sodium precipitates or precipitates as molecular loxoprofen in an external preparation containing loxoprofen sodium.
（高級アルコール及び多価アルコールの比較）
分子型ロキソプロフェンが存在するｐＨ条件で、高級アルコール及び多価アルコールの効果を比較した。２５℃±５℃の室温で、ガラス容器に試験液を入れ、希塩酸を適量添加し、約１２時間マグネチックスターラーで撹拌後静置し、目視で外観を観察して比較した。また、外観観察後にｐＨを測定した。試験液１１〜１９の調製直後及び室温条件下１ヶ月保存後の外観を観察した結果及びｐＨの結果を表２に示す。外観の欄の○は、析出あるいは沈殿が認められず、分子型のロキソプロフェンが溶解していると考えられる状態、×は、析出あるいは沈殿が認められた状態を示す。
(Comparison of higher alcohol and polyhydric alcohol)
The effects of higher alcohols and polyhydric alcohols were compared under pH conditions where molecular loxoprofen was present. At room temperature of 25 ° C. ± 5 ° C., the test solution was put in a glass container, an appropriate amount of diluted hydrochloric acid was added, and the mixture was stirred for about 12 hours and then left to stand. Moreover, pH was measured after appearance observation. Table 2 shows the results of observation of the appearance immediately after the preparation of the test solutions 11 to 19 and after storage for 1 month at room temperature, and the results of pH. ○ in the column of the appearance indicates a state where no precipitation or precipitation is observed and the molecular type loxoprofen is considered dissolved, and x indicates a state where precipitation or precipitation is observed.
（試験液１１）
精製水にロキソプロフェンナトリウム３ｇ(無水物として)を溶解後、精製水で全量を１００ｍＬとした。そのうち１０ｍＬを量り取り、ヘキシルデカノールを０．５ｇ加え攪拌し、試験液とした。さらに、希塩酸適量を加え、ｐＨを５．４に調節した。
(Test solution 11)
After dissolving 3 g of loxoprofen sodium (as an anhydride) in purified water, the total volume was adjusted to 100 mL with purified water. Of these, 10 mL was weighed, 0.5 g of hexyldecanol was added and stirred to obtain a test solution. Further, an appropriate amount of dilute hydrochloric acid was added to adjust the pH to 5.4.
（試験液１２）
精製水にロキソプロフェンナトリウム３ｇ(無水物として)を溶解後、精製水で全量を１００ｍＬとした。そのうち１０ｍＬを量り取り、イソステアリルアルコールを０．５ｇ加え攪拌し、試験液とした。これに、希塩酸適量を加え、ｐＨを５．４に調節した。
(Test solution 12)
After dissolving 3 g of loxoprofen sodium (as an anhydride) in purified water, the total volume was adjusted to 100 mL with purified water. Of these, 10 mL was weighed, 0.5 g of isostearyl alcohol was added and stirred to prepare a test solution. An appropriate amount of dilute hydrochloric acid was added thereto to adjust the pH to 5.4.
（試験液１３）
精製水にロキソプロフェンナトリウム３ｇ(無水物として)を溶解後、精製水で全量を１００ｍＬとした。そのうち１０ｍＬを量り取り、オレイルアルコールを０．５ｇ加え攪拌し、試験液とした。これに、希塩酸適量を加え、ｐＨを５．５に調節した。
(Test solution 13)
After dissolving 3 g of loxoprofen sodium (as an anhydride) in purified water, the total volume was adjusted to 100 mL with purified water. Of these, 10 mL was weighed, 0.5 g of oleyl alcohol was added and stirred to prepare a test solution. To this, an appropriate amount of dilute hydrochloric acid was added to adjust the pH to 5.5.
（試験液１４）
精製水にロキソプロフェンナトリウム３ｇ(無水物として)を溶解後、精製水で全量を１００ｍＬとした。そのうち１０ｍＬを量り取り、オクチルドデカノールを０．５ｇ加え攪拌し、試験液とした。これに、希塩酸適量を加え、ｐＨを５．３に調節した。
(Test solution 14)
After dissolving 3 g of loxoprofen sodium (as an anhydride) in purified water, the total volume was adjusted to 100 mL with purified water. 10 mL of the solution was weighed out, 0.5 g of octyldodecanol was added and stirred to obtain a test solution. To this, an appropriate amount of dilute hydrochloric acid was added to adjust the pH to 5.3.
（試験液１５）
精製水にロキソプロフェンナトリウム３ｇ(無水物として)を溶解後、精製水で全量を１００ｍＬとした。そのうち１０ｍＬを量り取り、１，３−ブチレングリコールを１．０ｇ加え攪拌し、試験液とした。これに、希塩酸適量を加え、ｐＨを５．２に調節した。
(Test solution 15)
After dissolving 3 g of loxoprofen sodium (as an anhydride) in purified water, the total volume was adjusted to 100 mL with purified water. Of these, 10 mL was weighed, 1.0 g of 1,3-butylene glycol was added and stirred to obtain a test solution. To this was added an appropriate amount of dilute hydrochloric acid to adjust the pH to 5.2.
（試験液１６）
精製水にロキソプロフェンナトリウム３ｇ(無水物として)を溶解後、精製水で全量を１００ｍＬとした。そのうち１０ｍＬを量り取り、プロピレングリコールを１．０ｇ加え攪拌し、試験液とした。これに、希塩酸適量を加え、ｐＨを５．２に調節した。
(Test solution 16)
After dissolving 3 g of loxoprofen sodium (as an anhydride) in purified water, the total volume was adjusted to 100 mL with purified water. Of these, 10 mL was weighed, 1.0 g of propylene glycol was added and stirred to prepare a test solution. To this was added an appropriate amount of dilute hydrochloric acid to adjust the pH to 5.2.
（試験液１７）
精製水にロキソプロフェンナトリウム３ｇ(無水物として)を溶解後、精製水で全量を１００ｍＬとした。そのうち１０ｍＬを量り取り、ジプロピレングリコールを１．０ｇ加え攪拌し、試験液とした。これに、希塩酸適量を加え、ｐＨを５．３に調節した。
(Test solution 17)
After dissolving 3 g of loxoprofen sodium (as an anhydride) in purified water, the total volume was adjusted to 100 mL with purified water. Of these, 10 mL was weighed, 1.0 g of dipropylene glycol was added and stirred to prepare a test solution. To this, an appropriate amount of dilute hydrochloric acid was added to adjust the pH to 5.3.
（試験液１８）
精製水にロキソプロフェンナトリウム３ｇ(無水物として)を溶解後、精製水で全量を１００ｍＬとした。そのうち１０ｍＬを量り取り、グリセリンを１．０ｇ加え攪拌し、試験液とした。これに、希塩酸適量を加え、ｐＨを５．４に調節した。
(Test Solution 18)
After dissolving 3 g of loxoprofen sodium (as an anhydride) in purified water, the total volume was adjusted to 100 mL with purified water. Of these, 10 mL was weighed out, 1.0 g of glycerin was added and stirred to obtain a test solution. An appropriate amount of dilute hydrochloric acid was added thereto to adjust the pH to 5.4.
（試験液１９）
精製水にロキソプロフェンナトリウム３ｇ(無水物として)を溶解後、精製水で全量を１００ｍＬとした。そのうち１０ｍＬを量り取り、ポリエチレングリコール４００を１．０ｇ加え攪拌し、試験液とした。これに、希塩酸適量を加え、ｐＨを５．４に調節した。
(Test solution 19)
After dissolving 3 g of loxoprofen sodium (as an anhydride) in purified water, the total volume was adjusted to 100 mL with purified water. Of these, 10 mL was weighed out, 1.0 g of polyethylene glycol 400 was added and stirred to obtain a test solution. An appropriate amount of dilute hydrochloric acid was added thereto to adjust the pH to 5.4.
表２に示すように、オクチルドデカノール及び多価アルコールでは、析出あるいは沈殿が認められ、ヘキシルデカノール、イソステアリルアルコール、オレイルアルコールに特異的に、析出あるいは沈殿の生成を防止する効果があった。
本発明により、皮膚透過性が良好な分子型のロキソプロフェンの割合が高いと考えられる酸性のｐＨ領域において、析出あるいは沈殿の生成を防止した外用剤を提供することが可能となった。
As shown in Table 2, precipitation or precipitation was observed with octyldodecanol and polyhydric alcohol, and there was an effect of preventing the formation of precipitation or precipitation specifically with hexyldecanol, isostearyl alcohol, and oleyl alcohol.
INDUSTRIAL APPLICABILITY According to the present invention, it is possible to provide an external preparation that prevents precipitation or formation of precipitates in an acidic pH region where the ratio of molecular type loxoprofen having good skin permeability is considered high.
（高級アルコールの下限濃度設定）
分子型ロキソプロフェンが存在するｐＨ条件で、高級アルコールの析出あるいは沈殿の生成を防止する効果発現濃度の下限を検討した。２５℃±５℃の室温で、ガラス容器に試験液を入れ、希塩酸を適量添加し、約１２時間マグネチックスターラーで撹拌後静置し、目視で外観を観察して比較した。また、外観観察後にｐＨを測定した。試験液２０〜２２の調製直後の外観を観察した結果を表３に示す。外観の欄の○は、析出あるいは沈殿が認められず、分子型のロキソプロフェンが溶解していると考えられる状態、×は、析出あるいは沈殿が認められた状態を示す。
(Lower alcohol concentration setting)
Under the pH conditions where molecular loxoprofen is present, the lower limit of the concentration of effect to prevent precipitation of higher alcohols or formation of precipitates was examined. At room temperature of 25 ° C. ± 5 ° C., the test solution was put in a glass container, an appropriate amount of diluted hydrochloric acid was added, and the mixture was stirred for about 12 hours and then left to stand. Moreover, pH was measured after appearance observation. Table 3 shows the results of observation of the appearance immediately after the preparation of the test solutions 20 to 22. ○ in the column of the appearance indicates a state where no precipitation or precipitation is observed and the molecular type loxoprofen is considered dissolved, and x indicates a state where precipitation or precipitation is observed.
（試験液２０）
精製水にロキソプロフェンナトリウム１ｇ(無水物として)を溶解後、精製水で全量を１００ｍＬとした。そのうち１０ｍＬを量り取り、ヘキシルデカノールを０．０２ｇ加え攪拌し、試験液とした。さらに、希塩酸適量を加え、ｐＨを５．０に調節した。
(Test solution 20)
After dissolving 1 g of loxoprofen sodium (as an anhydride) in purified water, the total volume was adjusted to 100 mL with purified water. Of these, 10 mL was weighed, 0.02 g of hexyldecanol was added and stirred to obtain a test solution. Further, an appropriate amount of dilute hydrochloric acid was added to adjust the pH to 5.0.
（試験液２１）
精製水にロキソプロフェンナトリウム１ｇ(無水物として)を溶解後、精製水で全量を１００ｍＬとした。そのうち１０ｍＬを量り取り、ヘキシルデカノールを０．１ｇ加え攪拌し、試験液とした。さらに、希塩酸適量を加え、ｐＨを５．０に調節した。
(Test solution 21)
After dissolving 1 g of loxoprofen sodium (as an anhydride) in purified water, the total volume was adjusted to 100 mL with purified water. Of these, 10 mL was weighed, 0.1 g of hexyldecanol was added and stirred to obtain a test solution. Further, an appropriate amount of dilute hydrochloric acid was added to adjust the pH to 5.0.
（試験液２２）
精製水にロキソプロフェンナトリウム１ｇ(無水物として)を溶解後、精製水で全量を１００ｍＬとした。そのうち１０ｍＬを量り取り、ヘキシルデカノールを０．２５ｇ加え攪拌し、試験液とした。さらに、希塩酸適量を加え、ｐＨを５．０に調節した。
(Test solution 22)
After dissolving 1 g of loxoprofen sodium (as an anhydride) in purified water, the total volume was adjusted to 100 mL with purified water. Of these, 10 mL was weighed out and 0.25 g of hexyldecanol was added and stirred to prepare a test solution. Further, an appropriate amount of dilute hydrochloric acid was added to adjust the pH to 5.0.
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| JP2014166979A (en) * | 2012-06-28 | 2014-09-11 | Kowa Company Ltd | Loxoprofen-containing solid formulation for external application |
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