JP2008137936A - Adapalene-containing composition for external use - Google Patents
Adapalene-containing composition for external use Download PDFInfo
- Publication number
- JP2008137936A JP2008137936A JP2006325265A JP2006325265A JP2008137936A JP 2008137936 A JP2008137936 A JP 2008137936A JP 2006325265 A JP2006325265 A JP 2006325265A JP 2006325265 A JP2006325265 A JP 2006325265A JP 2008137936 A JP2008137936 A JP 2008137936A
- Authority
- JP
- Japan
- Prior art keywords
- adapalene
- mass
- diphenhydramine
- skin
- agent
- 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.)
- Granted
Links
- 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 92
- 229960002916 adapalene Drugs 0.000 title claims abstract description 92
- 239000000203 mixture Substances 0.000 title claims abstract description 25
- 229960000520 diphenhydramine Drugs 0.000 claims abstract description 29
- DBAKFASWICGISY-BTJKTKAUSA-N Chlorpheniramine maleate Chemical compound OC(=O)\C=C/C(O)=O.C=1C=CC=NC=1C(CCN(C)C)C1=CC=C(Cl)C=C1 DBAKFASWICGISY-BTJKTKAUSA-N 0.000 claims abstract description 22
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical compound C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 claims abstract 3
- 238000002360 preparation method Methods 0.000 claims description 23
- 229940046978 chlorpheniramine maleate Drugs 0.000 claims description 21
- 239000003795 chemical substances by application Substances 0.000 claims description 19
- 239000007788 liquid Substances 0.000 claims description 18
- 239000006071 cream Substances 0.000 claims description 6
- 239000000443 aerosol Substances 0.000 claims description 4
- 239000002674 ointment Substances 0.000 claims description 4
- 239000006210 lotion Substances 0.000 claims description 3
- 230000035699 permeability Effects 0.000 abstract description 17
- 102000011782 Keratins Human genes 0.000 abstract description 9
- 108010076876 Keratins Proteins 0.000 abstract description 9
- SPCKHVPPRJWQRZ-UHFFFAOYSA-N 2-benzhydryloxy-n,n-dimethylethanamine;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 SPCKHVPPRJWQRZ-UHFFFAOYSA-N 0.000 description 26
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 20
- 229910052710 silicon Inorganic materials 0.000 description 20
- 239000010703 silicon Substances 0.000 description 20
- 210000003491 skin Anatomy 0.000 description 18
- 230000000052 comparative effect Effects 0.000 description 17
- 230000005012 migration Effects 0.000 description 14
- 238000013508 migration Methods 0.000 description 14
- 230000001965 increasing effect Effects 0.000 description 11
- 238000012360 testing method Methods 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- MRAMPOPITCOOIN-VIFPVBQESA-N (2r)-n-(3-ethoxypropyl)-2,4-dihydroxy-3,3-dimethylbutanamide Chemical compound CCOCCCNC(=O)[C@H](O)C(C)(C)CO MRAMPOPITCOOIN-VIFPVBQESA-N 0.000 description 6
- 239000004094 surface-active agent Substances 0.000 description 6
- 206010000496 acne Diseases 0.000 description 5
- 230000001419 dependent effect Effects 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 238000002156 mixing Methods 0.000 description 5
- 208000002874 Acne Vulgaris Diseases 0.000 description 4
- 239000000499 gel Substances 0.000 description 4
- 210000000434 stratum corneum Anatomy 0.000 description 4
- 150000005846 sugar alcohols Polymers 0.000 description 4
- 206010020649 Hyperkeratosis Diseases 0.000 description 3
- 208000001126 Keratosis Diseases 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 201000004681 Psoriasis Diseases 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- -1 oxygen scavenger Substances 0.000 description 3
- 231100000245 skin permeability Toxicity 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 238000012546 transfer Methods 0.000 description 3
- 230000037303 wrinkles Effects 0.000 description 3
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 206010040954 Skin wrinkling Diseases 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 229960003291 chlorphenamine Drugs 0.000 description 2
- SOYKEARSMXGVTM-UHFFFAOYSA-N chlorphenamine Chemical compound C=1C=CC=NC=1C(CCN(C)C)C1=CC=C(Cl)C=C1 SOYKEARSMXGVTM-UHFFFAOYSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 239000003349 gelling agent Substances 0.000 description 2
- 210000003780 hair follicle Anatomy 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 239000003002 pH adjusting agent Substances 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 150000004492 retinoid derivatives Chemical class 0.000 description 2
- 229920002379 silicone rubber Polymers 0.000 description 2
- 208000017520 skin disease Diseases 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 230000007704 transition Effects 0.000 description 2
- FPIPGXGPPPQFEQ-UHFFFAOYSA-N 13-cis retinol Natural products OCC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-UHFFFAOYSA-N 0.000 description 1
- 206010003645 Atopy Diseases 0.000 description 1
- 206010006784 Burning sensation Diseases 0.000 description 1
- 206010013786 Dry skin Diseases 0.000 description 1
- 208000010201 Exanthema Diseases 0.000 description 1
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerol Natural products OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 1
- 108010047294 Lamins Proteins 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 239000004909 Moisturizer Substances 0.000 description 1
- 229940123973 Oxygen scavenger Drugs 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 102100026531 Prelamin-A/C Human genes 0.000 description 1
- 239000004820 Pressure-sensitive adhesive Substances 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- 206010040844 Skin exfoliation Diseases 0.000 description 1
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 description 1
- FPIPGXGPPPQFEQ-BOOMUCAASA-N Vitamin A Natural products OC/C=C(/C)\C=C\C=C(\C)/C=C/C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-BOOMUCAASA-N 0.000 description 1
- 239000006096 absorbing agent Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical compound OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000001387 anti-histamine Effects 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000000043 antiallergic agent Substances 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000003908 antipruritic agent Substances 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 239000000306 component Substances 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000002826 coolant Substances 0.000 description 1
- 210000004207 dermis Anatomy 0.000 description 1
- 230000035618 desquamation Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 230000037336 dry skin Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 210000002615 epidermis Anatomy 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 201000005884 exanthem Diseases 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 210000005053 lamin Anatomy 0.000 description 1
- 239000003915 liquefied petroleum gas Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 239000003589 local anesthetic agent Substances 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 230000007721 medicinal effect Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 230000001333 moisturizer Effects 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 239000012466 permeate Substances 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 206010037844 rash Diseases 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 210000001732 sebaceous gland Anatomy 0.000 description 1
- 230000037307 sensitive skin Effects 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000017423 tissue regeneration Effects 0.000 description 1
- 238000002834 transmittance Methods 0.000 description 1
- 239000005526 vasoconstrictor agent Substances 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 235000019155 vitamin A Nutrition 0.000 description 1
- 239000011719 vitamin A Substances 0.000 description 1
- 229940045997 vitamin a Drugs 0.000 description 1
Images
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、アダパレンと共にジフェンヒドラミンやマレイン酸クロルフェニラミン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 diphenhydramine or chlorpheniramine maleate together with adapalene, the permeability of adapalene to the keratin and skin is improved, 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)ジフェンヒドラミン及びマレイン酸クロルフェニラミンの少なくとも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 diphenhydramine and chlorpheniramine maleate.
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.
「ジフェンヒドラミン」には、遊離体だけでなく塩酸塩等の塩も含まれる。ジフェンヒドラミンの含有(配合)量は、アダパレンの1質量部に対して0.25〜25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質量部が好ましく、2.5〜15質量部がより好ましい。ジフェンヒドラミンの含有量が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。 “Diphenhydramine” includes not only a free form but also a salt such as hydrochloride. The content (formulation) of diphenhydramine is 0.25 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 enhancing the permeability of adapalene to the skin. 2.5-15 mass parts is more preferable. This is because if the diphenhydramine content is less than 0.25 parts by mass, the permeability of adapalene to the skin is considered to be insufficient, and if it exceeds 25 parts by mass, the permeability of adapalene to the skin decreases.
「マレイン酸クロルフェニラミン」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、5〜25質量部が好ましい。マレイン酸クロルフェニラミンの含有量が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。 The content (formulation) of “chlorpheniramine maleate” is 0.5 to 25 parts by mass with respect to 1 part by mass of adapalene, and 5 to 25 masses in terms of increasing the permeability of adapalene to the skin. Part is preferred. If the content of chlorpheniramine maleate 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. It is.
本発明において、ジフェンヒドラミンとマレイン酸クロルフェニラミンは何れか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, not only one kind of diphenhydramine and chlorpheniramine maleate may be used, but two kinds may be used in combination.
なお、ジフェンヒドラミン及びマレイン酸クロルフェニラミンは抗ヒスタミン作用を有し、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、掻痒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。 In addition, diphenhydramine and chlorpheniramine maleate have an antihistamine 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 with pruritus and It is effective for the treatment of psoriasis and the like, and is expected to exert an excellent therapeutic effect on 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、ジフェンヒドラミン及び/又はマレイン酸クロルフェニラミンを、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、ジフェンヒドラミンや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, diphenhydramine and / or chlorpheniramine maleate in water, lower alcohol, polyhydric alcohol or a mixture thereof. If diphenhydramine or 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ジフェンヒドラミン及び/又はマレイン酸クロルフェニラミン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. Add the dissolved phase of diphenhydramine and / or chlorpheniramine maleate heated from the hopper and the oil phase in which the oil and surfactant are dissolved, stir at high speed (homogenize), and then cool to room temperature by cooling to room temperature Can be prepared. 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、ジフェンヒドラミン及び/又はマレイン酸クロルフェニラミンを加え、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。 The aqueous ointment takes polyethylene glycol that is solid at room temperature and polyhydric alcohol that is liquid at room temperature, and after heating and melting, adapalene, diphenhydramine and / or chlorpheniramine maleate are added and dispersed, It can be prepared by cooling to room temperature.
本発明の外用剤組成物には、抗菌剤、抗炎症剤、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, anti-inflammatory agent, analgesic agent, local anesthetic agent, tissue repair agent, antipruritic agent, moisturizer, vasoconstrictor, antiallergic agent, cooling agent, oxygen scavenger, Vitamins, ultraviolet absorbers, ultraviolet scattering agents 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1〜4及び実施例1〜10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2〜4及び実施例1〜10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、実施例1〜6はジフェンヒドラミンを種々の濃度で配合した液剤であり、実施例7〜10はマレイン酸クロルフェニラミン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 4 and Examples 1 to 10 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 preparation in which adapalene, ethanol and purified water are mixed, and Comparative Examples 2 to 4 and Examples 1 to 10 change the concentration of compounding ingredients other than adapalene by changing their concentrations, ethanol, pH adjuster and purification. A solution prepared by dissolving adapalene after being dissolved in a mixture of water. Comparative Examples 2 to 4 are solutions prepared by mixing pantothenyl ethyl ether with various concentrations in the composition of Comparative Example 1, and Examples 1 to 6 are solutions prepared by mixing diphenhydramine at various concentrations. Is a solution containing chlorpheniramine maleate 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1〜4及び実施例1〜10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。実施例1〜6については30分後、それ以外については1時間後(ただし、比較例1については30分後及び1時間後の両方で実施)、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それぞれの処理時間(30分又は1時間)における比較例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 4 and Examples 1 to 10 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 30 minutes for Examples 1 to 6 and 1 hour for the others (however, Comparative Example 1 was carried out after 30 minutes and 1 hour), the silicon rubber film was taken out of the incubator, and on the surface The liquid was thoroughly rinsed with water, and the moisture was wiped off. This was left overnight in methanol, and adapalene was completely extracted from the silicon film with an ultrasonic generator, and the content of adapalene in the extract was measured with a liquid chromatograph. The adapalene silicon film migration of each liquid agent was determined as a migration rate value when the silicon film migration rate of Comparative Example 1 was 1 in each treatment time (30 minutes or 1 hour).
結果:実施例1〜6(アダパレンの1質量部に対して0.25〜25質量部のジフェンヒドラミン)、実施例7〜10(アダパレンの1質量部に対して0.5〜25質量部のマレイン酸クロルフェニラミン)、比較例1〜4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 6 (0.25 to 25 parts by weight of diphenhydramine with respect to 1 part by weight of adapalene), Examples 7 to 10 (0.5 to 25 parts by weight of male with respect to 1 part by weight of adapalene) FIG. 1 shows the results of the silicon film migration test in Comparative Examples 1-4. 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0.25質量部のジフェンヒドラミン)で約2倍、実施例5(アダパレンの1質量部に対して15質量部のジフェンヒドラミン)で約4.5倍と濃度依存的に増大した。実施例6(アダパレンの1質量部に対して25質量部のジフェンヒドラミン)でのアダパレン移行性は実施例5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。このように、ジフェンヒドラミン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質量部のジフェンヒドラミン)。 The migration rate relative to Comparative Example 1 is about twice that in Example 1 (0.25 part by mass of diphenhydramine relative to 1 part by mass of adapalene), and Example 5 (15 parts by mass of diphenhydramine per 1 part by mass of adapalene). ) Increased by about 4.5 times in a concentration-dependent manner. Although the adapalene transferability in Example 6 (25 parts by mass of diphenhydramine with respect to 1 part by mass of adapalene) was lower than that in Example 5, it still showed a transfer rate of about 2.5 times. Thus, diphenhydramine had an amount suitable for adapalene migration (2.5 to 25 parts by mass of diphenhydramine with respect to 1 part by mass of adapalene).
また、実施例7(アダパレンの1質量部に対して0.5質量部のマレイン酸クロルフェニラミン)は約1.5倍、実施例9(アダパレンの1質量部に対して5質量部のマレイン酸クロルフェニラミン)は約5.5倍と濃度依存的に増大したが、実施例10(アダパレンの1質量部に対して25質量部のマレイン酸クロルフェニラミン)でのアダパレン移行性は実施例9に比べ低下したがそれでも約3倍の移行率を示した。このように,マレイン酸クロルフェニラミン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5〜25質量部のマレイン酸クロルフェニラミン)の存在が明らかになった。 In addition, Example 7 (0.5 part by mass of chlorpheniramine maleate with respect to 1 part by mass of adapalene) was about 1.5 times, Example 9 (5 parts by mass of male with respect to 1 part by mass of adapalene) Acid chlorpheniramine) increased by about 5.5 times in a concentration-dependent manner, but adapalene transferability in Example 10 (25 parts by mass of chlorpheniramine maleate per 1 part by mass of adapalene) Although it was lower than 9, it still showed a transition rate of about 3 times. Thus, the presence of an amount suitable for migration in chlorpheniramine maleate (5 to 25 parts by mass of chlorpheniramine maleate with respect to 1 part by mass of adapalene) was revealed.
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、ジフェンヒドラミン及びマレイン酸クロルフェニラミンは、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はパラレルであると考えられるため、ジフェンヒドラミン及びマレイン酸クロルフェニラミン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 diphenhydramine and chlorpheniramine maleate have an effect of increasing the migration of adapalene to a silicon film. Since the silicon membrane transferability and skin permeability are considered to be parallel, diphenhydramine and chlorpheniramine maleate are thought 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1〜4、実施例1〜4及び実施例6〜10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 4, Examples 1 to 4 and Examples 6 to 10 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質量部のジフェンヒドラミン)では1.5倍、実施例6(アダパレンの1質量部に対して25質量部のジフェンヒドラミン)では8.2倍と、やはりジフェンヒドラミンの濃度依存的にアダパレンの溶解度比率は増大した。これに対して、実施例7〜10(アダパレンの1質量部に対して0.5〜25質量部のマレイン酸クロルフェニラミン)では、マレイン酸クロルフェニラミンの濃度が増大してもアダパレンの溶解度比率は増大しなかった。
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 Example 2 (0.5 parts by mass of diphenhydramine with respect to 1 part by mass of adapalene), 1.5 times, and in Example 6 (25 parts by mass of diphenhydramine with respect to 1 part by mass of adapalene), 8.2 times. Doubled, the solubility ratio of adapalene increased depending on the concentration of diphenhydramine. On the other hand, in Examples 7 to 10 (0.5 to 25 parts by mass of chlorpheniramine maleate with respect to 1 part by mass of adapalene), the solubility of adapalene even when the concentration of chlorpheniramine maleate increases. The ratio did not increase.
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、ジフェンヒドラミンを配合した実施例1〜6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、マレイン酸クロルフェニラミンを配合した実施例7〜10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には大差が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, no increase in the migration of adapalene to the silicon film was observed, but Example 1 containing diphenhydramine was added. In the case of ˜6, the silicon film migration increased substantially in a concentration-dependent manner. Further, in Examples 7 to 10 in which chlorpheniramine maleate was blended, the silicon film transferability increased substantially in a concentration-dependent manner, but it was found that there was no significant difference in the solubility ratio of adapalene (see FIG. 1 above). 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、ジフェンヒドラミンやマレイン酸クロルフェニラミンの配合により、その濃度依存的に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 diphenhydramine or maleic acid. It is considered that the addition of chlorpheniramine increases the migration of adapalene to the silicon film depending on its concentration.
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、ジフェンヒドラミンやマレイン酸クロルフェニラミンの配合により、その濃度依存的に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 stratum corneum 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 diphenhydramine or chlorphenic acid maleate. It is considered that the blending of lamin increases the permeability of adapalene to the keratin and skin depending on its concentration.
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.
Claims (5)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2006325265A JP4835411B2 (en) | 2006-12-01 | 2006-12-01 | Adapalene-containing external preparation composition |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2006325265A JP4835411B2 (en) | 2006-12-01 | 2006-12-01 | Adapalene-containing external preparation composition |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2008137936A true JP2008137936A (en) | 2008-06-19 |
JP4835411B2 JP4835411B2 (en) | 2011-12-14 |
Family
ID=39599790
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2006325265A Expired - Fee Related JP4835411B2 (en) | 2006-12-01 | 2006-12-01 | Adapalene-containing external preparation composition |
Country Status (1)
Country | Link |
---|---|
JP (1) | JP4835411B2 (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2014508793A (en) * | 2011-03-25 | 2014-04-10 | アイアイエーエー リミテッド | Composition for treating skin conditions comprising diindolylmethane and retinoid |
JP2019218345A (en) * | 2018-06-16 | 2019-12-26 | ロート製薬株式会社 | External composition |
CN111671707A (en) * | 2020-07-16 | 2020-09-18 | 林淑娴 | Oil-control acne-removing mask and preparation method thereof |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS61254532A (en) * | 1985-05-02 | 1986-11-12 | Showa Denko Kk | Skin external preparation having high endermic absorption |
JPS61260026A (en) * | 1985-05-14 | 1986-11-18 | Showa Denko Kk | External dermatic agent having improved transcutaneous absorbability |
JPS63201119A (en) * | 1987-02-17 | 1988-08-19 | Kao Corp | Plaster composition |
JP2002128698A (en) * | 2000-10-26 | 2002-05-09 | Sankyo Co Ltd | Pharmaceutical composition of antiphlogistic analgesic for external use |
WO2004080468A1 (en) * | 2003-03-07 | 2004-09-23 | Yu Ruey J | Improved bioavailability and improved delivery of alkaline pharmaceutical drugs |
WO2004082628A2 (en) * | 2003-03-17 | 2004-09-30 | Yu Ruey J | Improved bioavailability and improved delivery of acidic pharmaceutical drugs |
-
2006
- 2006-12-01 JP JP2006325265A patent/JP4835411B2/en not_active Expired - Fee Related
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS61254532A (en) * | 1985-05-02 | 1986-11-12 | Showa Denko Kk | Skin external preparation having high endermic absorption |
JPS61260026A (en) * | 1985-05-14 | 1986-11-18 | Showa Denko Kk | External dermatic agent having improved transcutaneous absorbability |
JPS63201119A (en) * | 1987-02-17 | 1988-08-19 | Kao Corp | Plaster composition |
JP2002128698A (en) * | 2000-10-26 | 2002-05-09 | Sankyo Co Ltd | Pharmaceutical composition of antiphlogistic analgesic for external use |
WO2004080468A1 (en) * | 2003-03-07 | 2004-09-23 | Yu Ruey J | Improved bioavailability and improved delivery of alkaline pharmaceutical drugs |
WO2004082628A2 (en) * | 2003-03-17 | 2004-09-30 | Yu Ruey J | Improved bioavailability and improved delivery of acidic pharmaceutical drugs |
Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2014508793A (en) * | 2011-03-25 | 2014-04-10 | アイアイエーエー リミテッド | Composition for treating skin conditions comprising diindolylmethane and retinoid |
US9351958B2 (en) | 2011-03-25 | 2016-05-31 | Skintech Life Science Limited | Composition comprising a diindolylmethane and a retinoid to treat a skin condition |
JP2017178944A (en) * | 2011-03-25 | 2017-10-05 | スキンテック ライフ サイエンス リミテッド | Composition comprising diindolylmethane and retinoid to treat skin condition |
US9907785B2 (en) | 2011-03-25 | 2018-03-06 | Skintech Life Science Limited | Composition comprising a diindolylmethane and a retinoid to treat a skin condition |
US10500189B2 (en) | 2011-03-25 | 2019-12-10 | Skintech Life Sciences Limited | Composition comprising a diindolylmethane and a retinoid to treat a skin condition |
US10966958B2 (en) | 2011-03-25 | 2021-04-06 | Skintech Life Science Limited | Composition comprising a diindolylmethane and a retinoid to treat a skin condition |
US11911365B2 (en) | 2011-03-25 | 2024-02-27 | Skintech Life Science Limited | Composition comprising a diindolylmethane and a retinoid to treat a skin condition |
JP2019218345A (en) * | 2018-06-16 | 2019-12-26 | ロート製薬株式会社 | External composition |
JP7299766B2 (en) | 2018-06-16 | 2023-06-28 | ロート製薬株式会社 | external composition |
CN111671707A (en) * | 2020-07-16 | 2020-09-18 | 林淑娴 | Oil-control acne-removing mask and preparation method thereof |
Also Published As
Publication number | Publication date |
---|---|
JP4835411B2 (en) | 2011-12-14 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP5453093B2 (en) | Antifungal pharmaceutical composition | |
JPWO2009031642A1 (en) | Pharmaceutical composition | |
JP2007503428A (en) | Osmotic pharmaceutical foaming agent | |
US20130059021A1 (en) | Perfluoro(n-butylcyclohexane) compositions and uses thereof | |
WO2008047680A1 (en) | External preparation for skin | |
JP2021042241A (en) | Composition for external use | |
JP2004307491A (en) | Skin care preparation for external use containing heparinoid | |
JP4835411B2 (en) | Adapalene-containing external preparation composition | |
JP5125122B2 (en) | Adapalene-containing external preparation composition | |
JP5061984B2 (en) | Adapalene-containing external preparation composition | |
JP5109382B2 (en) | Adapalene-containing external preparation composition | |
JP5338030B2 (en) | Adapalene-containing external preparation composition | |
JP4806601B2 (en) | Liquid bath agent | |
JP5233149B2 (en) | Adapalene-containing external preparation composition | |
JP5109383B2 (en) | Adapalene-containing external preparation composition | |
JP5670008B2 (en) | Adapalene-containing external preparation composition | |
JP5646129B2 (en) | Adapalene-containing external preparation composition | |
JP6503627B2 (en) | Pharmaceutical liquid composition | |
JP6503626B2 (en) | Pharmaceutical composition | |
JP2011079771A (en) | Skin care preparation | |
JP3441387B2 (en) | Moisturizer, skin cosmetics and bath additives | |
JP5980171B2 (en) | Adapalene-containing external preparation composition | |
JPH0892062A (en) | External preparation | |
JP2003206239A (en) | Warming composition and external agent composition | |
WO2019167728A1 (en) | Diclofenac-containing emulsified gel composition |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
RD07 | Notification of extinguishment of power of attorney |
Free format text: JAPANESE INTERMEDIATE CODE: A7427 Effective date: 20090624 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20091013 |
|
A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20110725 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20110830 |
|
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20110912 |
|
FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20141007 Year of fee payment: 3 |
|
R150 | Certificate of patent or registration of utility model |
Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20141007 Year of fee payment: 3 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
LAPS | Cancellation because of no payment of annual fees |