JP2008255017A - Adapalene-containing composition for external use - Google Patents
Adapalene-containing composition for external use Download PDFInfo
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- JP2008255017A JP2008255017A JP2007095798A JP2007095798A JP2008255017A JP 2008255017 A JP2008255017 A JP 2008255017A JP 2007095798 A JP2007095798 A JP 2007095798A JP 2007095798 A JP2007095798 A JP 2007095798A JP 2008255017 A JP2008255017 A JP 2008255017A
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- menthol
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- 239000000203 mixture Substances 0.000 title claims abstract description 32
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 claims abstract description 25
- DSSYKIVIOFKYAU-XCBNKYQSSA-N (R)-camphor Chemical compound C1C[C@@]2(C)C(=O)C[C@@H]1C2(C)C DSSYKIVIOFKYAU-XCBNKYQSSA-N 0.000 claims abstract description 25
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- 229940041616 menthol Drugs 0.000 claims abstract description 25
- ZAKOWWREFLAJOT-CEFNRUSXSA-N D-alpha-tocopherylacetate Chemical compound CC(=O)OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C ZAKOWWREFLAJOT-CEFNRUSXSA-N 0.000 claims abstract description 24
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- UYRUBYNTXSDKQT-UHFFFAOYSA-N glycyrrhizic acid Natural products CC1(C)C(CCC2(C)C1CCC3(C)C2C(=O)C=C4C5CC(C)(CCC5(C)CCC34C)C(=O)O)OC6OC(C(O)C(O)C6OC7OC(O)C(O)C(O)C7C(=O)O)C(=O)O UYRUBYNTXSDKQT-UHFFFAOYSA-N 0.000 description 2
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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、アダパレンと共にユビデカレノン、グリチルリチン酸二カリウム、酢酸トコフェロール、カンフル又はメントール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-mentioned problems, the present inventors have combined adapalene with ubidecarenone, dipotassium glycyrrhizinate, tocopherol acetate, camphor or menthol, so that adapalene can penetrate into keratin and skin. As a result, the present 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）ユビデカレノン、グリチルリチン酸二カリウム、酢酸トコフェロール、カンフル及びメントールの少なくとも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, an aspect of the present invention is an external preparation composition containing (a) adapalene and (b) at least one of ubidecalenone, dipotassium glycyrrhizinate, tocopherol acetate, camphor and menthol.
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.
「ユビデカレノン」は、ミトコンドリア賦活作用によるエネルギー供給と還元型による抗酸化作用を有した補酵素Ｑの１種である。ユビキノン、コエンザイムＱ１０とも呼ばれる．ユビデカレノンの含有（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、０．５〜５質量部が好ましい。ユビデカレノンの含有量が０．５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、２５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。なお、ユビデカレノンを含有する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、アダパレンの有する抗シワ効果を増強するものと予想される。 “Ubidecarenone” is a type of coenzyme Q that has energy supply by mitochondrial activation and antioxidant activity by reduced form. Also called ubiquinone, coenzyme Q10. The content (formulation) of ubidecarenone is 0.5 to 25 parts by mass with respect to 1 part by mass of adapalene, and 0.5 to 5 parts by mass is preferable in terms of enhancing the permeability of adapalene to the skin. This is because if the content of ubidecarenone is less than 0.5 parts by mass, the permeability of adapalene to the skin is considered insufficient, and if it exceeds 25 parts by mass, the permeability of adapalene to the skin decreases. The external preparation composition of the present invention containing ubidecarenone is expected not only to enhance adapalene's keratin and skin permeability but also to enhance the anti-wrinkle effect of adapalene.
「グリチルリチン酸二カリウム」は抗炎症剤であり、炎症を速やかに鎮静させる作用がある。グリチルリチン酸二カリウムの含有（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、０．５〜２．５質量部が好ましい。グリチルリチン酸二カリウムの含有量が０．５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、２５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。なお、グリチルリチン酸二カリウムを含有する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、痒みを伴う乾燥肌、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。 “Dipotassium glycyrrhizinate” is an anti-inflammatory agent and has an action of quickly sedating inflammation. The content (formulation) of dipotassium glycyrrhizinate is 0.5 to 25 parts by mass with respect to 1 part by mass of adapalene, and 0.5 to 2.5 in terms of increasing the permeability of adapalene to the skin. Part by mass is preferred. If the content of dipotassium glycyrrhizinate is less than 0.5 parts by mass, it is considered that the permeability of adapalene to the skin is not sufficient, and if it exceeds 25 parts by mass, the permeability of adapalene to the skin decreases instead. is there. The external preparation composition of the present invention containing dipotassium glycyrrhizinate is effective not only for enhancing the permeability of adapalene to the keratin and skin but also for treating keratosis and psoriasis accompanied by inflammatory symptoms. In addition, it is expected to exhibit an excellent therapeutic effect in acne, wrinkles, and skin diseases such as wrinkles that have dry skin, sensitive skin, and atopic skin with itching.
「酢酸トコフェロール」は、ビタミンＥとも呼ばれ血行促進作用、過酸化脂質分解作用、抗酸化作用を有する。酢酸トコフェロールの含有（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。酢酸トコフェロールの含有量が０．５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、２５質量部を超えると脂溶性である酢酸トコフェロールの溶解性が懸念されるからである。なお、酢酸トコフェロールを含有する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、肌荒れを伴う角化症や乾癬、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。 “Tocopherol acetate” is also called vitamin E, and has blood circulation promoting action, lipid peroxide decomposition action, and antioxidant action. The content (formulation) of tocopherol acetate is 0.5 to 25 parts by mass with respect to 1 part by mass of adapalene, and 2.5 to 25 parts by mass is preferable in terms of increasing the permeability of adapalene to the skin. . If the content of tocopherol acetate is less than 0.5 parts by mass, the penetration of adapalene into the skin is considered insufficient, and if it exceeds 25 parts by mass, there is a concern about the solubility of fat-soluble tocopherol acetate. is there. The external preparation composition of the present invention containing tocopherol acetate not only enhances the penetration of adapalene into the keratin and skin, but also skin such as keratosis, psoriasis, acne, wrinkles and spots with rough skin. Expected to exert excellent therapeutic effects in disease.
「カンフル」は、ｄ体、ｄｌ体とあるがそのいずれをも含み、それぞれ樟脳、合成樟脳とも呼ばれる。清涼化剤、局所刺激剤として用いられる。カンフルの含有（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、０．５〜１５質量部が好ましい。カンフルの含有量が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、２５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。なお、カンフルは清涼化作用による痒みや痛みのマスキング効果を有しているため、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、痒みや痛みの症状を伴う角化症や乾癬、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。 “Camphor” includes d-form and dl-form, both of which are also called camphor and synthetic camphor, respectively. Used as a refreshing agent and local stimulant. The content (formulation) of camphor is 0.5 to 25 parts by mass with respect to 1 part by mass of adapalene, and 0.5 to 15 parts by mass is preferable in terms of enhancing the permeability of adapalene to the skin. This is because if the content of camphor is less than 0.25 parts by mass, the permeability of adapalene to the skin is considered insufficient, and if it exceeds 25 parts by mass, the permeability of adapalene to the skin decreases. In addition, since camphor has the effect of masking itchiness and pain due to a refreshing action, the composition for external use of the present invention not only enhances the penetration of adapalene into the keratin and skin but also itching and pain. It is expected to exhibit excellent therapeutic effects in keratosis with symptoms and skin diseases such as psoriasis, acne, wrinkles and stains.
「メントール」には、ｄ体、ｌ体及びｄｌ体があるがそのいずれをも含み、清涼化作用、局所消炎作用及び鎮痛作用を有する。メントールの含有（配合）量は、アダパレンの１質量部に対して０．５〜２５質量部である。メントールの含有量が０．５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、２５質量部を超えるとメントールの皮膚への刺激が問題となる。なお、メントールは清涼化作用や鎮痛作用による痒みや痛みのマスキング効果を有しているため、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、痒みや痛みの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。 “Menthol” includes d-form, l-form and dl-form, all of which have a cooling effect, a local anti-inflammatory effect and an analgesic action. The content (formulation) of menthol is 0.5 to 25 parts by mass with respect to 1 part by mass of adapalene. If the content of menthol is less than 0.5 parts by mass, it is considered that the permeability of adapalene to the skin is insufficient, and if it exceeds 25 parts by mass, irritation to the skin of menthol becomes a problem. Since menthol has an itching and pain masking effect due to a refreshing action and an analgesic action, the external preparation composition of the present invention not only enhances adapalene's keratin and skin penetration, but also itching. Effective for the treatment of keratosis, psoriasis, etc. accompanied by pain and symptom, and exhibits excellent therapeutic effect on acne, wrinkles and skin diseases such as acne, dry skin, sensitive skin, and atopic skin Expected.
本発明において、ユビデカレノン、グリチルリチン酸二カリウム、酢酸トコフェロール、カンフル及びメントールは何れか１種を用いるだけでなく、２種以上を併用してもよい。 In the present invention, ubidecalenone, dipotassium glycyrrhizinate, tocopherol acetate, camphor and menthol may be used alone or in combination of two or more.
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、ユビデカレノン等を、水、低級アルコール、多価アルコール又はこれらの混液を用いて溶解・分散させて調製することができる。なお、ユビデカレノン、酢酸トコフェロール、カンフル及びメントールといった油性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 agent can be prepared by dissolving and dispersing adapalene, ubidecarenone, etc. using water, lower alcohol, polyhydric alcohol or a mixture thereof. If oily components such as ubidecarenone, tocopherol acetate, camphor and menthol 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ユビデカレノン等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 agent can be prepared by adding a dissolved phase such as ubidecalenone heated from a hopper or an oil phase in which an oil and a surfactant are dissolved, stirring at high speed (homogenizing), and then cooling to room temperature. 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、ユビデカレノン等を加え、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 is prepared by taking any amount of polyethylene glycol that is solid at room temperature and polyhydric alcohol that is liquid at room temperature, adding adapalene, ubidecarenone, etc. after heating and melting, and then cooling to room temperature. it can.
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、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。 Antibacterial agents, bactericides, analgesics, local anesthetics, tissue repair agents, antipruritics, moisturizers, vasoconstrictors, antiallergic agents, oxygen scavengers, vitamins, ultraviolet absorbers In addition, an ultraviolet scattering agent or 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。
下表１に示した比較例１〜７及び実施例１〜１８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２〜７及び実施例１〜１８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は比較例１の組成に血液凝固作用を持つフィロキノン（ビタミンＫ１）をアダパレンの１質量部に対して２．５質量部で配合した液剤であり、比較例６〜７は比較例１の組成にP.acnes増殖抑制効果を持つメナジオン（ビタミンＫ３）をアダパレンの１質量部に対して０．５、２．５質量部で配合した液剤であり、実施例１〜４はユビデカレノンを、実施例５〜７はグリチルリチン酸二カリウムを、実施例８〜１０は酢酸トコフェロールを、実施例１１〜１５はカンフルを、実施例１６〜１８はメントール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。
Hereinafter, the present invention will be described in more detail with reference to Examples, Comparative Examples and Test Examples.
Each liquid agent of Comparative Examples 1 to 7 and Examples 1 to 18 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. Comparative Examples 2 to 7 and Examples 1 to 18 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 mixed with the composition of Comparative Example 1 at various concentrations, and Comparative Example 5 is a blood coagulation effect on the composition of Comparative Example 1. Is a solution containing 2.5 parts by mass of phylloquinone (vitamin K 1 ) with respect to 1 part by mass of adapalene, and Comparative Examples 6 to 7 are menadione having the composition of Comparative Example 1 having a P. acnes growth inhibitory effect. (Vitamin K 3 ) is a solution containing 0.5 and 2.5 parts by mass with respect to 1 part by mass of adapalene. Examples 1 to 4 are ubidecarenone, Examples 5 to 7 are dipotassium glycyrrhizinate. Examples 8 to 10 are tocopherol acetates, Examples 11 to 15 are camphors, and Examples 16 to 18 are liquids containing menthol in 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１〜７及び実施例１〜１８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 7 and Examples 1 to 18 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質量部のユビデカレノン）、実施例５〜７（アダパレンの１質量部に対して０．５〜２５質量部のグリチルリチン酸二カリウム）、実施例８〜１０（アダパレンの１質量部に対して０．５〜２５質量部の酢酸トコフェロール）、実施例１１〜１５（アダパレンの１質量部に対して０．５〜２５質量部のカンフル）、実施例１６〜１８（アダパレンの１質量部に対して０．５〜２５質量部のメントール）、比較例１〜７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 ubidecarenone to 1 part by mass of adapalene), Examples 5 to 7 (0.5 to 25 parts by mass of glycyrrhizin to 1 part by mass of adapalene) Acid dipotassium), Examples 8 to 10 (0.5 to 25 parts by mass of tocopherol acetate to 1 part by mass of adapalene), Examples 11 to 15 (0.5 to 25 to 1 part by mass of adapalene) FIG. 1 shows the results of the silicon film migration test in Comparative Examples 1 to 7, and Examples 16 to 18 (0.5 to 25 parts by mass of menthol with respect to 1 part by mass of adapalene). 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質量部のユビデカレノン）で約２．８倍、実施例２（アダパレンの１質量部に対して２．５質量部のユビデカレノン）で約４．３倍、実施例３（アダパレンの１質量部に対して５質量部のユビデカレノン）で約５．４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質量部のユビデカレノン）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１．６倍の移行率を示した。また、実施例５（アダパレンの１質量部に対して０．５質量部のグリチルリチン酸二カリウム）で約２．８倍、実施例６（アダパレンの１質量部に対して２．５質量部のグリチルリチン酸二カリウム）で約３．３倍と濃度依存的に増大した。実施例７（アダパレンの１質量部に対して２５質量部のグリチルリチン酸二カリウム）でのアダパレン移行性は実施例６に比べ低下していたが、それでも約２．５倍の移行率を示した。実施例８（アダパレンの１質量部に対して０．５質量部の酢酸トコフェロール）で約１．５倍、実施例９（アダパレンの１質量部に対して２．５質量部の酢酸トコフェロール）で約６．１倍、実施例１０（アダパレンの１質量部に対して２５質量部の酢酸トコフェロール）で約１９．４倍と濃度依存的に増大した。実施例１１（アダパレンの１質量部に対して０．５質量部のカンフル）は約２．４倍、実施例１３（アダパレンの１質量部に対して５質量部のカンフル）で約３．１倍と濃度依存的にシリコン膜移行性が増大した。実施例１４（アダパレンの１質量部に対して１５質量部のカンフル）、実施例１５（アダパレンの１質量部に対して２５質量部のカンフル）のアダパレン移行性は実施例１３に比べ低下していたが、それでも実施例１４で約２．６倍、実施例１５で約１．８倍の移行率を示した。実施例１６（アダパレンの１質量部に対して０．５質量部のメントール）で約２．４倍、実施例１７（アダパレンの１質量部に対して５質量部のメントール）で約２．７倍、実施例１８（アダパレンの１質量部に対して２５質量部のメントール）で約２．６倍と濃度によらずほぼ一定の増大効果を示した。 The migration rate relative to Comparative Example 1 was about 2.8 times in Example 1 (0.5 parts by mass of ubidecalenone relative to 1 part by mass of adapalene), and Example 2 (2.5 parts per 1 part by mass of adapalene). The concentration increased in a concentration-dependent manner by about 4.3 times in terms of mass part of ubidecarenone) and about 5.4 times in Example 3 (5 parts by mass of ubidecalenone relative to 1 part by mass of adapalene). The adapalene migration in Example 4 (25 parts by mass of ubidecalenone relative to 1 part by mass of adapalene) was lower than that in Example 3, but still showed a migration rate of about 1.6 times. Moreover, about 2.8 times in Example 5 (0.5 mass part dipotassium glycyrrhizinate with respect to 1 mass part of adapalene), Example 6 (2.5 mass parts with respect to 1 mass part of adapalene) (Dipotassium glycyrrhizinate) increased in a concentration-dependent manner about 3.3 times. The adapalene transferability in Example 7 (25 parts by mass of dipotassium glycyrrhizinate relative to 1 part by mass of adapalene) was lower than that in Example 6, but still showed a transfer rate of about 2.5 times. . In Example 8 (0.5 parts by mass of tocopherol acetate to 1 part by mass of adapalene), about 1.5 times in Example 9 (2.5 parts by mass of tocopherol acetate to 1 part by mass of adapalene) The concentration increased about 6.1 times in Example 10 (25 parts by mass of tocopherol acetate to 1 part by mass of adapalene), about 19.4 times. Example 11 (0.5 parts by mass camphor with respect to 1 part by mass of adapalene) is about 2.4 times, and Example 13 (5 parts by mass camphor with respect to 1 part by mass of adapalene) is about 3.1. The silicon film migration increased in a double and concentration dependent manner. The adapalene transferability in Example 14 (15 parts by mass camphor per 1 part by mass of adapalene) and Example 15 (25 parts by mass camphor in 1 part by mass of adapalene) is lower than that in Example 13. However, the migration rate was still about 2.6 times in Example 14 and about 1.8 times in Example 15. About 2.4 times in Example 16 (0.5 part by mass menthol with respect to 1 part by mass of adapalene), about 2.7 in Example 17 (5 parts by mass menthol with respect to 1 part by mass of adapalene) In Example 18 (25 parts by mass of menthol with respect to 1 part by mass of adapalene), the increase effect was almost 2.6 times, regardless of the concentration.
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）、比較例５（アダパレンの１質量部に対して２．５質量部のフィロキノン）、比較例６〜７（アダパレンの１質量部に対して０．５〜２．５質量部のメナジオン）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, Comparative Examples 2 to 4 (2.5 to 25 parts by mass of pantothenyl ethyl ether with respect to 1 part by mass of adapalene), Comparative Example 5 (2.5 parts by mass of phylloquinone with respect to 1 part by mass of adapalene) In Comparative Examples 6 to 7 (0.5 to 2.5 parts by mass of menadione with respect 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、ユビデカレノン、グリチルリチン酸二カリウム、酢酸トコフェロール、カンフル及びメントールは、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、ユビデカレノン、グリチルリチン酸二カリウム、酢酸トコフェロール、カンフル及びメントール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 ubidecarenone, dipotassium glycyrrhizinate, tocopherol acetate, camphor and menthol 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, ubidecarenone, dipotassium glycyrrhizinate, tocopherol acetate, camphor and menthol 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１〜７、実施例１〜４及び実施例５〜７及び実施例８〜１０及び実施例１１〜１５及び実施例１６〜１８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: Filter the liquids of Comparative Examples 1-7, Examples 1-4, Examples 5-7, Examples 8-10, Examples 11-15 and Examples 16-18 listed in Table 1, and in the filtrate The amount of adapalene 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。比較例５（アダパレンの１質量部に対して２．５質量部のフィロキノン）では１．６倍、比較例６（アダパレンの１質量部に対して０．５質量部のメナジオン）では１．１倍、比較例７（アダパレンの１質量部に対して２．５質量部のメナジオン）では１．３倍とフィロキノン、メナジオンにおいてもアダパレンの溶解度比率をやや増大させる効果があった。実施例８（アダパレンの１質量部に対して０．５質量部の酢酸トコフェロール）では２．３倍、実施例１０（アダパレンの１質量部に対して２５質量部の酢酸トコフェロール）では２．３倍、実施例１２（アダパレンの１質量部に対して２．５質量部のカンフル）では１．３倍、実施例１５「（アダパレンの１質量部に対して２５質量部のカンフル）では６．２倍、実施例１７（アダパレンの１質量部に対して５質量部のメントール）では１．９倍、実施例１８（アダパレンの１質量部に対して２５質量部のメントール）では３．０倍と酢酸トコフェロール、カンフル及びメントールはアダパレンの溶解度比率を増大させた。一方、実施例１（アダパレンの１質量部に対して０．５質量部のユビデカレノン）では０．９倍、実施例４（アダパレンの１質量部に対して２５質量部のユビデカレノン）では１．０倍、実施例５（アダパレンの１質量部に対して０．５質量部のグリチルリチン酸二カリウム）では０．８倍、実施例７（アダパレンの１質量部に対して２５質量部のグリチルリチン酸二カリウム）では０．７倍となり、ユビデカレノン及びグリチルリチン酸二カリウムではアダパレンの溶解度比率を増大させる効果はなかった。
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 Comparative Example 5 (2.5 parts by mass of phylloquinone relative to 1 part by mass of adapalene), 1.6 times, in Comparative Example 6 (0.5 parts by mass of menadione relative to 1 part by mass of adapalene), 1.1 times. In Comparative Example 7 (2.5 parts by mass of menadione with respect to 1 part by mass of adapalene), there was an effect of slightly increasing the solubility ratio of adapalene by 1.3 times in phylloquinone and menadione. In Example 8 (0.5 parts by mass of tocopherol acetate to 1 part by mass of adapalene), 2.3 times in Example 10 (25 parts by mass of tocopherol acetate to 1 part by mass of adapalene), 2.3 In Example 12 (2.5 parts by mass camphor per 1 part by weight of adapalene), 1.3 times in Example 15 “(25 parts by weight camphor per 1 part by weight of adapalene). 2 times, 1.9 times in Example 17 (5 parts by weight menthol for 1 part by weight of adapalene), 3.0 times in Example 18 (25 parts by weight menthol for 1 part by weight of adapalene) And tocopherol acetate, camphor and menthol increased the solubility ratio of adapalene, whereas in Example 1 (0.5 parts by weight of ubidecarenone relative to 1 part by weight of adapalene), 0.9 times, Example 4 (adapa 1.0 times for 25 parts by weight of ubidecalenone relative to 1 part by weight of water, 0.8 times for Example 5 (0.5 parts by weight of dipotassium glycyrrhizinate for 1 part by weight of adapalene) In Example 7 (25 parts by mass of dipotassium glycyrrhizinate relative to 1 part by mass of adapalene), the ratio was 0.7 times, and ubidecarenone and dipotassium glycyrrhizinate had no effect of increasing the solubility ratio of adapalene.
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、フィロキノン及びメナジオンを配合した比較例２〜７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、ユビデカレノンを配合した実施例１〜４及びグリチルリチン酸二カリウムを配合した実施例５〜７では、アダパレンの溶解度比率は変わらないが、ほぼ濃度依存的にシリコン膜移行性が増大した。また、酢酸トコフェロールを配合した実施例８〜１０、カンフルを配合した実施１１〜１５及びメントールを配合した実施例１６〜１８では、アダパレンの溶解度比率を増大させ、シリコン膜移行性も増大させた（以上、図１及び２参照）。 In the liquid preparations of Comparative Examples 2 to 7 in which pantothenyl ethyl ether, phylloquinone and menadione having an increased solubility ratio of adapalene were added, no increase in the migration of adapalene to the silicon film was observed, but Example 1 in which ubidecarenone was added. In Examples 5 to 7 containing ˜4 and dipotassium glycyrrhizinate, the solubility ratio of adapalene did not change, but the silicon film migration increased substantially in a concentration-dependent manner. Further, in Examples 8 to 10 containing tocopherol acetate, Examples 11 to 15 containing camphor and Examples 16 to 18 containing menthol, the solubility ratio of adapalene was increased, and the silicon film migration was also increased ( (See FIGS. 1 and 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、ユビデカレノン、グリチルリチン酸二カリウム、酢酸トコフェロール、カンフル及びメントールの配合により、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, and ubidecarenone, glycyrrhizic acid It is considered that the adapalene migration into the silicon film is increased by the combination of dipotassium, tocopherol acetate, camphor and menthol.
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、ユビデカレノン、グリチルリチン酸二カリウム、酢酸トコフェロール、カンフル、メントールの配合により、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, and it does not change even if adapalene is present in a dispersed state in the solution, and ubidecarenone, dipotassium glycyrrhizinate. It is considered that adapalene's keratin and skin permeability are increased by the combination of tocopherol acetate, camphor and menthol.
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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| JPH11147826A (en) * | 1997-11-13 | 1999-06-02 | Lion Corp | Improvement of percutaneous absorption and preparation for external use for skin |
| JP2004083450A (en) * | 2002-08-26 | 2004-03-18 | Nissan Chem Ind Ltd | External application preparation |
| WO2006003299A1 (en) * | 2004-06-11 | 2006-01-12 | Galderma Research & Development, S.N.C. | Hydroalcoholic depigmentation gel comprising mequinol and adapalene |
| JP2006022101A (en) * | 2004-07-07 | 2006-01-26 | Johnson & Johnson Consumer Co Inc | Composition containing anti-acne agent and method for using the same |
| WO2006070093A1 (en) * | 2004-12-22 | 2006-07-06 | Galderma Research & Development | Composition comprising solubilized adapalene with cyclodextrins |
| WO2006107825A2 (en) * | 2005-04-01 | 2006-10-12 | Zymes, Llc | Skin enrichment using coq10 as the delivery system |
| JP2006298774A (en) * | 2005-04-15 | 2006-11-02 | Lead Chemical Co Ltd | Percutaneous absorption type free radical-inhibiting preparation |
| JP2008184446A (en) * | 2007-01-31 | 2008-08-14 | Taisho Pharmaceutical Co Ltd | Adapalene-containing external preparation composition |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2014208623A (en) * | 2013-03-29 | 2014-11-06 | 小林製薬株式会社 | External pharmaceutical composition |
| JP2019034978A (en) * | 2013-03-29 | 2019-03-07 | 小林製薬株式会社 | Pharmaceutical composition for external application |
| 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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| JP5233149B2 (en) | 2013-07-10 |
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