JP2008184446A - Adapalene-containing external preparation composition - Google Patents
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- LZCDAPDGXCYOEH-UHFFFAOYSA-N adapalene Chemical compound C1=C(C(O)=O)C=CC2=CC(C3=CC=C(C(=C3)C34CC5CC(CC(C5)C3)C4)OC)=CC=C21 LZCDAPDGXCYOEH-UHFFFAOYSA-N 0.000 title claims abstract description 98
- 229960002916 adapalene Drugs 0.000 title claims abstract description 98
- 238000002360 preparation method Methods 0.000 title claims abstract description 30
- 239000000203 mixture Substances 0.000 title claims abstract description 27
- MPDGHEJMBKOTSU-YKLVYJNSSA-N 18beta-glycyrrhetic acid Chemical compound C([C@H]1C2=CC(=O)[C@H]34)[C@@](C)(C(O)=O)CC[C@]1(C)CC[C@@]2(C)[C@]4(C)CC[C@@H]1[C@]3(C)CC[C@H](O)C1(C)C MPDGHEJMBKOTSU-YKLVYJNSSA-N 0.000 claims abstract description 57
- ACEWLPOYLGNNHV-UHFFFAOYSA-N Ibuprofen piconol Chemical compound C1=CC(CC(C)C)=CC=C1C(C)C(=O)OCC1=CC=CC=N1 ACEWLPOYLGNNHV-UHFFFAOYSA-N 0.000 claims abstract description 31
- 229960003720 enoxolone Drugs 0.000 claims abstract description 31
- 229950005954 ibuprofen piconol Drugs 0.000 claims abstract description 31
- MPDGHEJMBKOTSU-UHFFFAOYSA-N Glycyrrhetinsaeure Natural products C12C(=O)C=C3C4CC(C)(C(O)=O)CCC4(C)CCC3(C)C1(C)CCC1C2(C)CCC(O)C1(C)C MPDGHEJMBKOTSU-UHFFFAOYSA-N 0.000 claims abstract description 30
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- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
本発明は、角質及び皮膚への浸透性に優れたアダパレン含有外用剤組成物に関する。 The present invention relates to an adapalene-containing external preparation composition excellent in permeability to keratin and skin.
アダパレンは、第三世代の合成レチノイド類の１つで、脂腺、毛包に浸透して効果を発揮し、ニキビの初発疹である面皰のサイズを縮小することが知られており、また、アダパレン含有製剤については、従来の外用レチノイド剤の高い治療効果を維持しつつ、落屑、灼熱感などの副作用が少ないという報告がある（非特許文献１参照）。 Adapalene is one of the third-generation synthetic retinoids that are known to penetrate the sebaceous glands and hair follicles and reduce the size of comedones, the first acne rash. Regarding adapalene-containing preparations, there are reports that side effects such as desquamation and burning sensation are few while maintaining the high therapeutic effects of conventional external retinoid agents (see Non-Patent Document 1).
しかしながら、本来、皮膚は、外界からの異物の侵入を防ぐバリアー機能（角質層）を有しているため、単に外用剤中に薬効成分を配合しただけでは、充分な皮膚浸透性が得られず、充分な薬効を発現できないことが多い。 However, since the skin inherently has a barrier function (stratum corneum) that prevents foreign substances from entering from the outside, sufficient skin permeability cannot be obtained simply by blending a medicinal component into an external preparation. In many cases, sufficient medicinal effects cannot be expressed.
そして、０．１％アダパレン含有ゲル剤について、拡散セルを用いたin vitro経皮吸収性試験を実施したところ、毛包への素早い浸透が確認されたものの、投与１５時間後においてもアダパレンは対投与量で僅か０．０１％しかレシーバ液に移行しないことが報告されており（非特許文献２参照）、角質を介した皮膚への浸透性が低いことが推察される。 Then, when an in vitro transdermal absorbability test using a diffusion cell was performed on a gel containing 0.1% adapalene, quick penetration into the hair follicle was confirmed, but adapalene was not treated even 15 hours after administration. It has been reported that only 0.01% of the dose is transferred to the receiver solution (see Non-Patent Document 2), and it is presumed that the permeability to the skin through the stratum corneum is low.
アダパレンはレチノイド類であるため、ビタミンＡ類と同様にニキビ、角化症、乾癬、シワ及びシミ等の皮膚疾患に有効であることが期待される。しかしながら、上述したようにアダパレンは角質や皮膚への浸透性が低く、表皮や真皮で起こる疾患に対しては充分な治療効果を発揮できていないと考えられる。 Since adapalene is a retinoid, it is expected to be effective for skin diseases such as acne, keratosis, psoriasis, wrinkles, and spots as well as vitamin A. However, as described above, adapalene has a low permeability to the keratin and skin, and it is considered that it does not exhibit a sufficient therapeutic effect for diseases that occur in the epidermis and dermis.
そこで、本発明は、角質や皮膚への浸透性に優れたアダパレン含有外用剤組成物を提供することを課題とする。 Then, this invention makes it a subject to provide the adapalene containing external preparation composition excellent in the permeability | transmittance to a keratin and skin.
本発明者らは、前記課題を解決すべく鋭意検討を重ねた結果、アダパレンと共にイブプロフェンピコノールやグリチルレチン酸を配合することによって、アダパレンの角質や皮膚への浸透性が向上することを見出し、本発明を完成するに至った。 As a result of intensive studies to solve the above problems, the present inventors have found that by adding ibuprofen piconol and glycyrrhetinic acid together with adapalene, the permeability of adapalene to the keratin and skin is improved. The invention has been completed.
すなわち、本発明の態様は、（ａ）アダパレン、並びに（ｂ）イブプロフェンピコノール及びグリチルレチン酸の少なくとも１種、を含有することを特徴とする外用剤組成物である。 That is, the aspect of the present invention is an external preparation composition containing (a) adapalene and (b) at least one of ibuprofen piconol and glycyrrhetinic acid.
本発明により、角質や皮膚への浸透性に優れたアダパレン含有外用剤組成物を提供することが可能となった。 According to the present invention, it is possible to provide an adapalene-containing external preparation composition excellent in permeability to keratin and skin.
「アダパレン」は、アダマンチル骨格を持った分子量４１２．５２の化合物で、テトラヒドロフランに溶解するが、エタノールにやや溶け難く、水に不溶といった特徴を有する（THE MERCK INDEX参照）。アダパレンの含有（配合）量は、本外用剤組成物中０．０１〜１．０質量％であり、アダパレンの有効性と安全性のバランスから０．０５〜０．５質量％が好ましい。 “Adapalene” is a compound having an adamantyl skeleton and a molecular weight of 412.52, which is soluble in tetrahydrofuran but slightly soluble in ethanol and insoluble in water (see THE MERCK INDEX). The content (formulation) of adapalene is 0.01 to 1.0% by mass in the external preparation composition, and 0.05 to 0.5% by mass is preferable from the balance between the effectiveness and safety of adapalene.
「イブプロフェンピコノール」の含有（配合）量は、アダパレンの１質量部に対して０．５〜２５質量部であり、アダパレンの皮膚への浸透性を高めるという点で、２．５〜２５質量部が好ましい。イブプロフェンピコノールの含有量が０．２５質量部未満であるとアダパレンの皮膚への浸透性が充分でないと考えられ、好ましくないからである。一方、本外用剤組成物を用いて外用剤を調製するときにアダパレンが外用剤中に１．０質量％を超えて含有されていると、アダパレンの１質量部に対して２５質量部を超えるイブプロフェンピコノールを配合した際に、アダパレンの皮膚への浸透性は充分にあると思われるが、イブプロフェンピコノールの配合量が多くなりすぎて、皮膚に対する刺激が強くなり、また、溶解し難くなって製剤化が困難になるなど好ましくないからである。 The content (formulation) of “ibuprofen piconol” is 0.5 to 25 parts by mass with respect to 1 part by mass of adapalene, and 2.5 to 25 masses in terms of increasing the permeability of adapalene to the skin. Part is preferred. This is because if the content of ibuprofen piconol is less than 0.25 parts by mass, the penetration of adapalene into the skin is considered insufficient, which is not preferable. On the other hand, when preparing external preparation using this external preparation composition, if adapalene is contained in the external preparation in an amount exceeding 1.0% by mass, it exceeds 25 parts by mass with respect to 1 part by mass of adapalene. When ibuprofen piconol is added, adapalene seems to have sufficient permeability to the skin, but the amount of ibuprofen piconol increases too much and irritation to the skin becomes strong and difficult to dissolve. This is because it is not preferable because formulation becomes difficult.
「グリチルレチン酸」の含有（配合）量は、アダパレンの１質量部に対して０．５〜５質量部である。グリチルレチン酸の含有量が０．５質量部未満であってもアダパレンの皮膚への浸透性あると考えられるが、アダパレンを０．０１質量％含有する外用剤を調製する際に、アダパレンの１質量部に対して０．５質量部未満のグリチルレチン酸を配合すると、グリチルレチン酸の配合量が少なすぎて、その抗炎症効果が期待できないからである。一方、５質量部を超えるとアダパレンの皮膚への浸透性が却って低下するからである。 The content (formulation) of “glycyrrhetinic acid” is 0.5 to 5 parts by mass with respect to 1 part by mass of adapalene. Even if the content of glycyrrhetinic acid is less than 0.5 parts by mass, adapalene is considered to be permeable to the skin, but when preparing an external preparation containing 0.01% by mass of adapalene, 1 mass of adapalene This is because when less than 0.5 parts by mass of glycyrrhetinic acid is blended with respect to part, the blending amount of glycyrrhetinic acid is too small to expect its anti-inflammatory effect. On the other hand, when the amount exceeds 5 parts by mass, the permeability of adapalene to the skin is reduced instead.
本発明において、イブプロフェンピコノールとグリチルレチン酸は何れか１種を用いるだけでなく、２種を併用してもよい。 In the present invention, ibuprofen piconol and glycyrrhetinic acid may be used alone or in combination of two.
なお、イブプロフェンピコノール及びグリチルレチン酸は抗炎症作用を有し、本発明の外用剤組成物は単にアダパレンの角質や皮膚への浸透性を増強するだけでなく、炎症症状を伴う角化症や乾癬等の治療に有効であり、また、乾燥肌、敏感肌、アトピー性肌を併有するニキビ、シワ及びシミ等の皮膚疾患において優れた治療効果を発揮するものと予想される。 Note that ibuprofen piconol and glycyrrhetinic acid have an anti-inflammatory action, and the external preparation composition of the present invention not only enhances the permeability of adapalene to the keratin and skin, but also causes keratosis and psoriasis accompanied by inflammatory symptoms. In addition, it is expected to exhibit an excellent therapeutic effect in skin diseases such as acne, wrinkles and stains having dry skin, sensitive skin, and atopic skin.
本発明のアダパレン含有外用剤組成物は、液剤、ローション剤、ゲル剤、エアゾール剤、クリーム剤、水性軟膏剤等の各種外用剤として提供される。 The adapalene-containing external preparation composition of the present invention is provided as various external preparations such as liquids, lotions, gels, aerosols, creams and aqueous ointments.
液剤は、アダパレン、イブプロフェンピコノール及び/又はグリチルレチン酸を、水、低級アルコール、多価アルコール又はこれらの混液に溶解・分散させて調製することができる。なお、イブプロフェンピコノールやグリチルレチン酸、油成分を完全に溶解できない場合には可溶化するのに必要な界面活性剤を配合すればよい。また、このような液剤と適当な液化ガス（液化石油ガス、ジメチルエーテルなど）をアルミ製耐圧容器等に入れてエアゾール剤を調製することもできる。さらに、このような液剤に適当なゲル化剤を配合してゲル剤を調製することも可能である。 The liquid preparation can be prepared by dissolving and dispersing adapalene, ibuprofen piconol and / or glycyrrhetinic acid in water, lower alcohol, polyhydric alcohol or a mixture thereof. If ibuprofen piconol, glycyrrhetinic acid, and the oil component cannot be completely dissolved, a surfactant necessary for solubilization may be added. Further, an aerosol agent can be prepared by putting such a liquid agent and an appropriate liquefied gas (liquefied petroleum gas, dimethyl ether, etc.) in an aluminum pressure vessel or the like. Furthermore, it is also possible to prepare a gel agent by blending such a liquid agent with an appropriate gelling agent.
クリーム剤も常法により調製が可能である。例えば、水と多価アルコール相にアダパレン及び界面活性剤を添加して、ホモミキサー用容器に入れて脱気・加温する。ホッパーから加温したイブプロフェンピコノール及び/又はグリチルレチン酸の溶解相や油分及び界面活性剤を溶解させた油相を添加し、高速攪拌（ホモジナイズ）した後、室温まで冷却することによってクリーム剤を調製することができる。ここで、ＨＬＢの高い界面活性剤を用いればＯ／Ｗクリーム剤が調製できるし、ＨＬＢの低い界面活性剤を用いればＷ／Ｏクリーム剤が調製できる。 Creams can also be prepared by conventional methods. For example, adapalene and a surfactant are added to water and a polyhydric alcohol phase, and the mixture is put into a homomixer container and deaerated and heated. A cream is prepared by adding a dissolved phase of ibuprofen piconol and / or glycyrrhetinic acid heated from a hopper and an oil phase in which an oil and a surfactant are dissolved, stirring at high speed (homogenizing), and then cooling to room temperature. can do. Here, an O / W cream can be prepared by using a surfactant having a high HLB, and a W / O cream can be prepared by using a surfactant having a low HLB.
水性軟膏剤は、室温で固体のポリエチレングリコールと室温で液状の多価アルコールをそれぞれ任意の量とり、加温融解後、アダパレン、イブプロフェンピコノール及び／又はグリチルレチン酸を加え、分散させた後、室温まで冷却することによって調製できる。 Aqueous ointment takes polyethylene glycol which is solid at room temperature and polyhydric alcohol which is liquid at room temperature, and after heating and melting, adapalene, ibuprofen piconol and / or glycyrrhetinic acid is added and dispersed, It can be prepared by cooling to.
本発明の外用剤組成物には、抗菌剤、殺菌剤、鎮痛剤、局所麻酔剤、組織修復剤、鎮痒剤、保湿剤、血管収縮剤、抗アレルギー剤、清涼化剤、酸素除去剤、ビタミン、紫外線吸収剤、紫外線散乱剤などを本発明の効果を損なわない範囲で適宜に配合することができる。 The external preparation composition of the present invention includes an antibacterial agent, bactericidal agent, analgesic agent, local anesthetic agent, tissue repair agent, antipruritic agent, moisturizer, vasoconstrictor, antiallergic agent, cooling agent, oxygen scavenger, vitamin In addition, an ultraviolet absorber, an ultraviolet scattering agent, and the like can be appropriately blended within a range not impairing the effects of the present invention.
本発明の外用剤組成物には、医薬品や医薬部外品に配合可能な種々の基剤成分を本発明の効果を損なわない範囲で適宜に配合することができる。このような基剤成分としては、精製水、低級アルコールや多価アルコール等の溶解補助剤、炭化水素、グリセリン脂肪酸エステル、ワックス成分、界面活性剤、抗酸化剤、乳化安定剤、ゲル化剤、粘着剤等、各種動植物からの抽出物、ｐＨ調整剤、防腐剤、キレート剤、香料、色素、液化ガスなどが挙げられる。 In the external preparation composition of the present invention, various base components that can be blended with pharmaceuticals and quasi drugs can be appropriately blended within a range not impairing the effects of the present invention. Examples of such base components include purified water, solubilizing agents such as lower alcohols and polyhydric alcohols, hydrocarbons, glycerin fatty acid esters, wax components, surfactants, antioxidants, emulsion stabilizers, gelling agents, Examples include extracts from various animals and plants such as pressure-sensitive adhesives, pH adjusters, preservatives, chelating agents, fragrances, pigments, and liquefied gases.
以下に、実施例、比較例及び試験例を挙げ、本発明をさらに詳細に説明する。 Hereinafter, the present invention will be described in more detail with reference to Examples, Comparative Examples and Test Examples.
下表１に示した比較例１〜５及び実施例１〜７の各液剤は、アダパレンを配合して２４時間攪拌したアダパレンの分散液である。すなわち、比較例1はアダパレン、エタノール及び精製水を混合した液剤であり、比較例２〜５及び実施例１〜７は、アダパレン以外の配合成分をその濃度を変えてエタノール、ｐＨ調整剤及び精製水の混液に溶解させた後、さらにアダパレンを分散させて調製した液剤である。比較例２〜４は比較例１の組成に外用剤の有効成分として汎用されているパントテニルエチルエーテルを種々の濃度で配合した液剤であり、比較例５はグリチルレチン酸を５．０重量％で配合した液剤である。実施例１〜４はイブプロフェンピコノールを種々の濃度で配合した液剤であり、実施例５〜７はグリチルレチン酸を種々の濃度で配合した液剤である。なお、ｐＨ調整剤としては、水酸化ナトリウム、リン酸二水素カリウム及び希塩酸を用い、各液剤のｐＨを約８に調整した。 Each liquid agent of Comparative Examples 1 to 5 and Examples 1 to 7 shown in Table 1 below is a dispersion of adapalene in which adapalene is blended and stirred for 24 hours. That is, Comparative Example 1 is a liquid agent in which adapalene, ethanol and purified water are mixed, and Comparative Examples 2 to 5 and Examples 1 to 7 are ethanol, pH adjuster and purified by changing the concentration of compounding ingredients other than adapalene. A solution prepared by dissolving adapalene after being dissolved in a mixture of water. Comparative Examples 2 to 4 are solutions in which pantothenyl ethyl ether, which is widely used as an active ingredient for external preparations, is blended in various concentrations in the composition of Comparative Example 1, and Comparative Example 5 is glycyrrhetinic acid at 5.0% by weight. It is a mixed liquid. Examples 1 to 4 are solutions containing ibuprofen piconol at various concentrations, and Examples 5 to 7 are solutions containing glycyrrhetinic acid at various concentrations. In addition, as a pH adjuster, sodium hydroxide, potassium dihydrogen phosphate, and dilute hydrochloric acid were used, and pH of each liquid agent was adjusted to about 8.
試験例１ アダパレンのシリコン膜移行性試験
前提：Tanakaらによれば、開放系でのシリコン膜を用いた移行性試験は局所投与製剤の経皮吸収性の評価に適しているとされている（S.Tanaka, et al., International Journal of Pharmaceutics, 27:29-38(1985)）ことから、角質への浸透性をシリコン膜移行性試験により評価した。また、シリコン膜にすることで、アダパレンが浸透しやすい毛穴の影響を排除することができるので、単純にアダパレンの角質への移行性を評価できると考えられる。
Test Example 1 Silicon film transferability test of adapalene Premise: According to Tanaka et al., Transferability test using silicon film in open system is said to be suitable for evaluation of transdermal absorbability of topically administered preparations ( S. Tanaka, et al., International Journal of Pharmaceutics, 27: 29-38 (1985)), the permeability to the stratum corneum was evaluated by a silicon membrane transfer test. Further, by using a silicon film, it is possible to eliminate the influence of pores through which adapalene easily permeates, so that it is considered that adapalene's ability to move to the keratin can be simply evaluated.
方法：シリコンゴム膜（２．５ｃｍ×２．５ｃｍ×０．５ｍｍ）上に比較例１〜５及び実施例１〜７の液剤を均一に塗布するためのガーゼを置き、各液剤を全体に広がるように１５０μＬずつ塗布し、直ちに恒温器（約３５℃，湿度成行）に投入した。1時間後、恒温器からシリコンゴム膜を取り出し、表面上の液剤を水で良く洗い流し、水気を良く拭き取った。これをメタノール中に１晩放置し、さらに超音波発生器にて完全にアダパレンをシリコン膜から抽出し、抽出液中のアダパレンの含有量を液体クロマトグラフィーにて測定した。各液剤のアダパレンのシリコン膜移行性を比較例１のシリコン膜移行率を１とした場合の移行率値として求めた。 Method: A gauze for uniformly applying the liquid agents of Comparative Examples 1 to 5 and Examples 1 to 7 is placed on a silicon rubber film (2.5 cm × 2.5 cm × 0.5 mm), and each liquid agent is spread throughout. 150 μL each was applied and immediately put into a thermostat (about 35 ° C., humidity control). After 1 hour, the silicon rubber film was taken out of the thermostat, the liquid on the surface was thoroughly washed with water, and the moisture was wiped off well. This was left in methanol overnight, and adapalene was completely extracted from the silicon film with an ultrasonic generator, and the content of adapalene in the extract was measured by liquid chromatography. The adapalene migration of each liquid agent was determined as a migration rate value when the silicon migration rate of Comparative Example 1 was 1.
結果：実施例１〜４（アダパレンの１質量部に対して０．５〜２５質量部のイブプロフェンピコノール）、実施例５〜７（アダパレンの１質量部に対して０．５〜５質量部のグリチルレチン酸）、比較例１〜５におけるシリコン膜移行性試験結果を図１に示す。なお、相対的移行率が１．４倍以上で効果ありと判断した。 Results: Examples 1 to 4 (0.5 to 25 parts by mass of ibuprofen piconol with respect to 1 part by mass of adapalene), Examples 5 to 7 (0.5 to 5 parts by mass with respect to 1 part by mass of adapalene) Of glycyrrhetinic acid) and silicon film migration test results in Comparative Examples 1 to 5 are shown in FIG. In addition, it was judged that the relative transition rate was 1.4 times or more and there was an effect.
比較例１に対する移行率は、実施例１（アダパレンの１質量部に対して０．５質量部のイブプロフェンピコノール）で約１．７倍、実施例２（アダパレンの１質量部に対して２．５質量部のイブプロフェンピコノール）で約２．６倍、実施例３（アダパレンの１質量部に対して５質量部のイブプロフェンピコノール）で約３．５倍と濃度依存的に増大した。実施例４（アダパレンの１質量部に対して２５質量部のイブプロフェンピコノール）でのアダパレン移行性は実施例３に比べ低下していたが、それでも約３倍の移行率を示した。このように、イブプロフェンピコノールにはアダパレンの移行性に適した量があった（アダパレンの１質量部に対して２．５〜２５質量部のイブプロフェンピコノール）。 The migration rate relative to Comparative Example 1 is about 1.7 times in Example 1 (0.5 part by weight of ibuprofenpiconol relative to 1 part by weight of adapalene), and Example 2 (2 parts per part by weight of adapalene). The concentration increased approximately 2.6 times with .5 parts by mass of ibuprofen piconol, and about 3.5 times with Example 3 (5 parts by mass of ibuprofen piconol relative to 1 part by mass of adapalene). The adapalene migration in Example 4 (25 parts by mass of ibuprofen piconol with respect to 1 part by mass of adapalene) was lower than that in Example 3, but still showed a migration rate of about 3 times. Thus, ibuprofen piconol had an amount suitable for the migration of adapalene (2.5 to 25 parts by mass of ibuprofen piconol relative to 1 part by mass of adapalene).
また、実施例５（アダパレンの１質量部に対して０．５質量部のグリチルレチン酸）は約３．４倍、実施例６（アダパレンの１質量部に対して２．５質量部のグリチルレチン酸）は約２．９倍、実施例７（アダパレンの１質量部に対して５質量部のイブプロフェンピコノール）で約１．８倍と濃度依存的にシリコン膜移行性が低下し、比較例５（アダパレンの１質量部に対して２５質量部のイブプロフェンピコノール）で約０．５倍と比較例１より低下した。このように，グリチルレチン酸においても移行性に適した量（アダパレンの１質量部に対して０．５〜５質量部のグリチルレチン酸）の存在が明らかになった。 In addition, Example 5 (0.5 parts by mass of glycyrrhetinic acid with respect to 1 part by mass of adapalene) is about 3.4 times, Example 6 (2.5 parts by mass of glycyrrhetinic acid with respect to 1 part by mass of adapalene) ) Is about 2.9 times, and in Example 7 (5 parts by mass of ibuprofenpiconol for 1 part by mass of adapalene), about 1.8 times, the silicon film migration is reduced in a concentration-dependent manner. It was about 0.5 times lower than that of Comparative Example 1 (25 parts by mass of ibuprofen piconol with respect to 1 part by mass of adapalene). Thus, the presence of an amount suitable for migration in glycyrrhetinic acid (0.5 to 5 parts by mass of glycyrrhetic acid relative to 1 part by mass of adapalene) was clarified.
一方、比較例２〜４（アダパレンの１質量部に対して２．５〜２５質量部のパントテニルエチルエーテル）においては、薬物によってアダパレンのシリコン膜移行性は殆ど増大しなかった。 On the other hand, in Comparative Examples 2 to 4 (2.5 to 25 parts by mass of pantothenyl ethyl ether relative to 1 part by mass of adapalene), the migration of adapalene to the silicon film was hardly increased by the drug.
以上の結果より、イブプロフェンピコノール及びグリチルレチン酸は、アダパレンのシリコン膜移行性を増大させる効果を有していることが明らかとなった。シリコン膜移行性と皮膚浸透性には相関関係があると考えられるため、イブプロフェンピコノール及びグリチルレチン酸はアダパレンの皮膚浸透性を増大させると考えられる。 From the above results, it has been clarified that ibuprofen piconol and glycyrrhetinic acid have an effect of increasing the migration of adapalene to a silicon film. Since it is considered that there is a correlation between the transferability of the silicon film and the skin permeability, ibuprofen piconol and glycyrrhetinic acid are considered to increase the skin permeability of adapalene.
試験例２ アダパレンの溶解度のシリコン膜移行性に対する影響
表１記載の各液剤中に溶解しているアダパレン量に依存してアダパレンのシリコン膜移行性が増大しているとも考えられることから、各液剤のアダパレンの溶解度とシリコン膜移行性との関係を調べるため、各液剤中のアダパレンの飽和溶解度を測定した。
Test Example 2 Influence of Solubility of Adapalene on Silicon Film Mobility Since each of the liquid agents is considered to have increased the silicon film mobility of adapalene depending on the amount of adapalene dissolved in each liquid listed in Table 1. In order to investigate the relationship between the solubility of adapalene and the migration of silicon film, the saturation solubility of adapalene in each solution was measured.
方法：表１に記載の比較例１〜５、実施例１〜４及び実施例５〜７の液剤を濾過し、濾液中のアダパレン量を、液体クロマトグラフィーを用いて定量した。各液剤の飽和溶解度を比較例１の溶解度を１としたときの溶解度比率として求めた。 Method: The liquid agents of Comparative Examples 1 to 5, Examples 1 to 4 and Examples 5 to 7 described in Table 1 were filtered, and the amount of adapalene in the filtrate was quantified using liquid chromatography. The saturation solubility of each solution was determined as the solubility ratio when the solubility of Comparative Example 1 was 1.
結果：結果を図２に示す。
比較例２（アダパレンの１質量部に対して２．５質量部のパントテニルエチルエーテル）では１．５倍、比較例４（アダパレンの１質量部に対して２５質量部のパントテニルエチルエーテル）では約３倍と、アダパレンの溶解補助剤であるパントテニルエチルエーテルの濃度依存的にアダパレンの溶解度比率は増大した。また、実施例２（アダパレンの１質量部に対して０．５質量部のイブプロフェンピコノール）では１．５倍、実施例４（アダパレンの１質量部に対して２５質量部のイブプロフェンピコノール）では３．６倍、実施例５（アダパレンの１質量部に対して０．５質量部のグリチルレチン酸）では０．７倍、実施例７（アダパレンの１質量部に対して５質量部のグリチルレチン酸）では１．８倍、比較例５（アダパレンの１質量部に対して２５質量部のグリチルレチン酸）では１．６倍と、イブプロフェンピコノール、グリチルレチン酸の濃度依存的にアダパレンの溶解度比率は増大した。
Results: The results are shown in FIG.
Comparative Example 2 (2.5 parts by mass of pantothenyl ethyl ether with respect to 1 part by mass of adapalene) 1.5 times, Comparative Example 4 (25 parts by mass of pantothenyl ethyl ether with respect to 1 part by mass of adapalene) Then, the solubility ratio of adapalene increased about 3 times depending on the concentration of pantothenyl ethyl ether, which is a solubilizing agent for adapalene. In Example 2 (0.5 part by weight of ibuprofen piconol with respect to 1 part by weight of adapalene), 1.5 times, Example 4 (25 parts by weight of ibuprofen piconol with respect to 1 part by weight of adapalene) 3.6 times, Example 5 (0.5 parts by mass of glycyrrhetinic acid to 1 part by mass of adapalene) 0.7 times, Example 7 (5 parts by mass of glycyrrhetin to 1 part by mass of adapalene) Acid) and 1.8 times in Comparative Example 5 (25 parts by mass of glycyrrhetinic acid relative to 1 part by mass of adapalene), and the solubility ratio of adapalene depends on the concentration of ibuprofenpiconol and glycyrrhetic acid Increased.
濃度依存的にアダパレンの溶解度比率を増大させたパントテニルエチルエーテルを配合した比較例２〜４の液剤では、アダパレンのシリコン膜移行性の増大は見られなかったが、イブプロフェンピコノールを配合した実施例１〜４ではほぼ濃度依存的にシリコン膜移行性が増大した。また、グリチルレチン酸を配合した実施例５〜７ではほぼ濃度依存的にシリコン膜移行性は増大しているが、アダパレンの溶解度比率は比較例１と大差ないことがわかった（以上、図１及び２参照）。 In the liquid preparations of Comparative Examples 2 to 4 containing pantothenyl ethyl ether in which the solubility ratio of adapalene was increased in a concentration-dependent manner, the increase in the migration of adapalene to the silicon film was not observed. In Examples 1 to 4, the silicon film migration increased substantially in a concentration-dependent manner. Further, in Examples 5 to 7 in which glycyrrhetinic acid was blended, the silicon film transferability increased in a concentration-dependent manner, but it was found that the solubility ratio of adapalene was not significantly different from that of Comparative Example 1 (see FIG. 1 and FIG. 1). 2).
以上のことを勘案すると、アダパレンのシリコン膜移行性は液剤中に溶解しているアダパレンの濃度に無関係で、アダパレンが液剤中に分散状態で存在していても変わらず、また、イブプロフェンピコノールやグリチルレチン酸の配合により、アダパレンのシリコン膜移行性が増大していると考えられる。 Considering the above, the migration of adapalene to the silicon film is independent of the concentration of adapalene dissolved in the solution, and does not change even if adapalene is present in a dispersed state in the solution. It is considered that the adapalene migration into the silicon film is increased by the addition of glycyrrhetinic acid.
すなわち、アダパレンの角質や皮膚への浸透性は液剤中に溶解しているアダパレンの濃度に無関係で、アダパレンが液剤中に分散状態で存在していても変わらず、また、イブプロフェンピコノールやグリチルレチン酸の配合により、アダパレンの角質や皮膚への浸透性が増大すると考えられる。 That is, the permeability of adapalene to the keratin and skin is independent of the concentration of adapalene dissolved in the solution, it does not change even if adapalene is present in a dispersed state in the solution, and ibuprofen piconol or glycyrrhetic acid It is considered that adapalene increases the permeability of adapalene to skin and skin.
本発明により、アダパレンを含有し、ニキビ、角化症、乾癬、シワ及びシミ等に有効な液剤、ローション剤、ゲル剤、エアゾール剤、クリーム剤、水性軟膏剤等の各種外用剤を提供することが期待される。 According to the present invention, there are provided various external preparations containing adapalene and effective for acne, keratosis, psoriasis, wrinkles and stains, lotions, gels, aerosols, creams, aqueous ointments and the like. There is expected.
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| JP2008255017A (en) * | 2007-03-31 | 2008-10-23 | Taisho Pharmaceutical Co Ltd | Adapalene-containing composition for external use |
| JP6311049B1 (en) * | 2016-11-25 | 2018-04-11 | ロート製薬株式会社 | Acne prevention and / or treatment for back acne |
| JP2019218345A (en) * | 2018-06-16 | 2019-12-26 | ロート製薬株式会社 | External composition |
| JPWO2019240290A1 (en) * | 2018-06-16 | 2021-06-24 | ロート製薬株式会社 | Topical composition |
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| JPS62223118A (en) * | 1986-03-12 | 1987-10-01 | Hisamitsu Pharmaceut Co Inc | Cream composition for external use |
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| JP2005239678A (en) * | 2004-02-27 | 2005-09-08 | Hisamitsu Pharmaceut Co Inc | Creamy preparation for external use having improved retainability in horny layer |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2008255017A (en) * | 2007-03-31 | 2008-10-23 | Taisho Pharmaceutical Co Ltd | Adapalene-containing composition for external use |
| JP6311049B1 (en) * | 2016-11-25 | 2018-04-11 | ロート製薬株式会社 | Acne prevention and / or treatment for back acne |
| JP2019218345A (en) * | 2018-06-16 | 2019-12-26 | ロート製薬株式会社 | External composition |
| JPWO2019240290A1 (en) * | 2018-06-16 | 2021-06-24 | ロート製薬株式会社 | Topical composition |
| JP7299766B2 (en) | 2018-06-16 | 2023-06-28 | ロート製薬株式会社 | external composition |
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