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WO2019044670A1 - Composition topique pour la peau destinée au traitement ou à la prévention de maladies de type acné - Google Patents

Composition topique pour la peau destinée au traitement ou à la prévention de maladies de type acné Download PDF

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Publication number
WO2019044670A1
WO2019044670A1 PCT/JP2018/031244 JP2018031244W WO2019044670A1 WO 2019044670 A1 WO2019044670 A1 WO 2019044670A1 JP 2018031244 W JP2018031244 W JP 2018031244W WO 2019044670 A1 WO2019044670 A1 WO 2019044670A1
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WO
WIPO (PCT)
Prior art keywords
skin
acne
mass
composition
gel
Prior art date
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Ceased
Application number
PCT/JP2018/031244
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English (en)
Japanese (ja)
Inventor
和義 河府
安啓 藤貫
博実 田澤
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Himawari Pharma Co Ltd
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Himawari Pharma Co Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Himawari Pharma Co Ltd filed Critical Himawari Pharma Co Ltd
Publication of WO2019044670A1 publication Critical patent/WO2019044670A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
    • A61K8/42—Amides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin

Definitions

  • the present invention relates to a composition for external use on the skin for treating or preventing acne-like diseases, which comprises Tamibarotene as an active ingredient.
  • Acne vulgaris (acne) is caused by sebaceous hair follicles in the face, anterior chest and upper back mainly due to abnormal keratinization of the follicular funnel and increased sebum secretion, and increased acne bacteria. It is a skin disease that occurs.
  • Acne vulgaris is a chronic inflammatory disease that causes comedones (Comedes) as a primary rash, reddish papules, pustules, cysts, and formation of induration, and also has problems such as scarring after healing.
  • the main patients are adolescent to adolescent young people, and there were many cases where acne treatment was not actively performed, but the following acne treatment has been developed.
  • retinoid agents tretinoin, isotretinoin, tazarotene, adapalene etc.
  • retinoid agents are effective in normalizing abnormal keratinization and sebum secretion, and in Japan, adapalene external preparation
  • retinoid agents tretinoin, isotretinoin, tazarotene, adapalene etc.
  • adapalene external preparation There is only one case, for example, "Diferin.RTM. Gel 0.1%”, “Epidio.RTM. Gel” approved as pharmaceutical.
  • Retinoids are physiologically active substances that are biosynthesized from vitamin A in vivo, and are important factors controlling various life phenomena such as early development of animals to maintenance of homeostasis in various organs of adults (eg, non-patented) Reference 1.). Retinoids take on various chemical structures in vivo, but they control the target gene responsible for the basis of physiological activity by binding to retinoic acid receptor, which is an intranuclear receptor and also a transcriptional regulator in cells. doing.
  • all-trans retinoic acid also known as tretinoin
  • APL acute promyelocytic leukemia
  • acne acne in the dermatological area It has become.
  • tretinoin is limited in its use as a drug from the viewpoint of its stability and resistance, etc.
  • a search for retinoid compounds having higher pharmacological effects has been tried for half a century, and as a result, various retinoid compounds It has been developed.
  • Tamibarotene is a search for retinoid compounds having higher pharmacological effects.
  • this retinoid compound Since this retinoid compound has strong retinoid-like activity without being affected by retinoic acid binding protein present in cells, it shows high therapeutic effect on patients who have relapsed APL despite tretinoin treatment (eg, See Non-Patent Document 2.). Tamivarotene, like other retinoids, is also effective against keratinizing disorders of the skin, but although clinical development has been made for psoriasis as an indication, development has been discontinued, and other treatments such as acne It is not known as a medicine.
  • Endogenous tretinoin and the like activate retinoic acid receptors present in vivo.
  • the retinoic acid receptor has three subtypes, RAR ⁇ , RAR ⁇ , and RAR ⁇ , whose function is conserved but their tissue distribution is different, but tretinoin has equal affinity for all of them. (See, for example, Non-Patent Document 1). Although retinoid compounds that exert an acne therapeutic effect mainly act on keratinocytes of skin tissue, these cells express RAR ⁇ and RAR ⁇ , and RAR ⁇ is not detected (see, for example, Non-Patent Document 3).
  • tretinoin and isotretinoin have not been approved as a therapeutic agent for acne
  • adapalene a naphthoic acid derivative exhibiting retinoid-like activity
  • Adapalene is used as the only retinoid compound for acne treatment (eg, diff. (Trademark) gel (0.1%), which activate RAR ⁇ in the skin because they act specifically on RAR ⁇ and RAR ⁇ .
  • Adapalene is a standard acne treatment that has been approved in the United States more than 20 years ago and has become ubiquitous in the world, and now has generics in circulation.
  • An object of the present invention is, in view of the problems of the prior art, to provide a composition for external use on the skin which is low in skin irritation (e.g. scaling, erythema) and is excellent in therapeutic or preventive effect on acne-like diseases.
  • skin irritation e.g. scaling, erythema
  • the present inventors have found that the skin irritation of Tamibarotene having strong retinoid-like activity is unexpectedly low without being affected by retinoic acid binding proteins present in cells, and has completed the present invention.
  • the present invention is as follows.
  • a composition for external use on the skin for treating or preventing acne-like diseases which comprises tamibarotene as an active ingredient.
  • Tamibarotene for the manufacture of a composition for external use on skin for treating or preventing acne-like diseases according to any one of the above (1) to (4).
  • a method for treating or preventing acne-like diseases which comprises applying to the skin a composition comprising tamibarotene as an active ingredient.
  • composition for external application to the skin of the present invention is low in skin irritation (for example, scaling, erythema), and is excellent in the treatment or prevention effect against acne-like diseases.
  • composition for treating or preventing acne-like diseases contains tamivarotene as an active ingredient (pharmacological ingredient or pharmacologically active ingredient).
  • Tamibarotene which is an active ingredient of the present invention is 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) carbamoyl] benzoic acid.
  • Tamibarotene any of crystals or crystalline powder obtained by ordinary production can be used. Examples of the method for producing Tamibarotene include the methods described in Japanese Patent No. 3001632, JP-A-61-76440, and WO 2002/018322.
  • Acne-like diseases in the present invention include acne vulgaris, pustular acne, concentrated acne, artificial acne (occasional acne, oily acne), senile comedone, acne mite, suppurative acne Infection inflammation, acne rosacea, acne associated with polycystic ovary syndrome, neonatal acne, steroid acne, malassetia folliculitis, acne in the summer, acne caused by drugs, oral dermatitis, etc. It is preferable that it is acne.
  • the content of tamibarotene contained in the composition for external use on the skin of the present invention is not particularly limited as long as the effects of the present invention are not impaired, and, for example, 0.00001 to 5% by mass of the entire composition for external use on skin can be mentioned.
  • the lower limit value of the content of Tamibarotene is preferably 0.0001% by mass or more, more preferably 0.0005% by mass or more, and more preferably 0.002% by mass or more of the total composition for external use on the skin. Is more preferable, particularly preferably 0.004% by mass or more, and most preferably 0.008% by mass or more.
  • the upper limit value of the content of Tamibarotene is preferably 0.5% by mass or less, more preferably 0.1% by mass or less, and more preferably 0.05% by mass or less of the total composition for external use on the skin. Is more preferable, and particularly preferably 0.016% by mass or less (specifically, 0.012% by mass or less or 0.008% by mass or less).
  • the composition for external use on the skin of the present invention is an ingredient effective for preventing or treating acne and an ingredient for enhancing an ingredient effective for preventing or treating acne (hereinafter, also simply referred to as "enhancing ingredient"), the effect of the present invention.
  • enhancing ingredient an ingredient effective for preventing or treating acne
  • Can be blended within a range that does not impair the Examples of the enhancing component include vitamins such as vitamin A, vitamin B2, vitamin B6, vitamin C, vitamin D and vitamin E; dipotassium glycyrrhizinate, glycyrrhizinic acid, allantoin, anti-inflammatory agents such as ibuprofen piconol; salicylic acid, Exfoliants such as benzoyl peroxide and sulfur; and fungicides and antibiotics such as nadifloxacin, clindamycin, erythromycin, chloramphenicol and benzoic acid.
  • composition for external application to the skin of the present invention is not particularly limited as long as it is a composition applied to (for example, applied to) the skin, and it is, for example, a composition for external application for skin or a cosmetic composition for medical use.
  • this composition in addition to vitamin A; vitamin C; vitamin D and vitamin E and other enhancing ingredients, ingredients generally used in medical external composition for skin care such as pharmaceuticals, quasi-drugs, cosmetics etc., for example, aqueous Ingredients, oily ingredients, powder ingredients, alcohols, moisturizers, thickeners, UV absorbers, skin lightening agents, preservatives, antioxidants, surfactants, perfumes, pigments, etc. may be added as needed. it can.
  • the composition for external use on the skin of the present invention includes polysorbates (eg, polysorbate 40, polysorbate 80, etc.), polyethylene glycols (eg, macrogol 400, etc.), glycols (eg, propylene glycol, etc.), polyoxyethylene polyoxypropylene Glycols (eg, polyoxyethylene (20) polyoxypropylene (20) glycol etc.), glycerin, parahydroxybenzoic acid esters (eg, methyl parahydroxybenzoate, propyl parahydroxybenzoate etc.), stabilizers (eg, edeto) Acid salts), cellulose thickeners (eg hydroxypropyl methylcellulose etc.), carboxyvinyl polymers, organic acids or inorganic acids (eg citric acid, acetic acid, hydrochloric acid, phosphoric acid etc.), inorganic bases or organic acids Min (such as sodium hydroxide, triethanolamine) pH adjusting
  • composition for external application to the skin of the present invention can be, for example, a gel containing a base obtained by blending polysorbate 80, propylene glycol, methyl parahydroxybenzoate, carboxyvinyl polymer, sodium hydroxide and the like.
  • the external preparation composition of the present invention is not particularly limited as long as it can be applied to the skin as a "form", but it may be a gel, a cream, an ointment, a liquid, a coating such as a lotion, a patch, Patches such as tapes and patches are preferred, and even if they are gels, they are less irritating to the skin of the active ingredient Tamivaroten, and they are more preferable because they are non-greasy.
  • the composition for external use on the skin of the present invention can be used as medicines, quasi-drugs, cosmetics and the like.
  • the method of use is a suitable amount (for example, 0.1 to 5 g, preferably 0.5 to 3 g; eg 1 to 500 ⁇ l, preferably 10 to 300 ⁇ l).
  • Etc. and can be applied to the skin once to several times a day (eg, twice or three times).
  • the present invention suppresses the occurrence of desquamation and erythema due to its low skin irritation, can be rapidly recovered, and can be continuously administered daily for one week or more.
  • it can be continuously administered daily for 2 weeks or more, more preferably, can be continuously administered daily for 3 weeks or more, and still more preferably, can be continuously administered daily for 4 weeks or more.
  • the upper limit value of the number of continuous administration days is not particularly limited, and for example, it may be within 1 year, preferably within 6 months, more preferably within 3 months.
  • the test substance Tamivarotene gel has a content of Tamivarotene of 0.0005% by mass, 0.002% by mass, 0.004% by mass and 0.008% by mass, and 5 conditions of base only (0% by mass of Tamivarotene) as a control.
  • adapalene gel (differentin 0.1 mass% gel) was set.
  • As the base a composition comprising polysorbate 80, propylene glycol, methyl parahydroxybenzoate, carboxyvinyl polymer and sodium hydroxide was used.
  • n 10 (5 males and 5 females) Rhino mice each for a total of 6 conditions, and apply 50 ⁇ l once a day transdermally for 2 days to 2 cm 2 from the base of the back ear for 21 days. He was euthanized on the 22nd day.
  • FIG. 1 is a diagram showing the diameter d of the comer opening on the skin surface and the diameter D of the central part of the comer depth.
  • the D size of the comers (the diameter of the central part of the comers) was classified by size, and the distribution is shown in the graph in FIG.
  • FIG. 2 shows hematoxylin-eosin staining of sliced sections of each of 0.004% by weight Tamivarotene, a gel of base only (0% by weight of Tamibarotene) as a control, and a 0.1% by weight gel of Differin as a positive control It is a figure which shows a result.
  • hematoxylin and eosin staining shown in FIG. 2 in particular, with a maximum dose of 0.004% by mass Tamibarotene gel, a pathological image in which the comell reduction is almost equal to that of the diffelin gel is obtained, and the acne treatment effect is I understand that it is high.
  • FIG. 2 shows hematoxylin-eosin staining of sliced sections of each of 0.004% by weight Tamivarotene, a gel of base only (0% by weight of Tamibarotene) as a control, and a 0.1% by weight gel of Differin as a positive control It is a figure which shows
  • FIG. 3 is a view showing the distribution of the area size in each group.
  • the base administration group which is a control
  • many large comets exceeding 100 ⁇ m are observed, but in the tamibarotene gel administration group (graphs 2 to 5), the comedone size decreases in a concentration dependent manner. Was observed.
  • the comedones regress with retinoid treatment and can be histologically restored to normal hair follicle shape.
  • the comedality reducing action by Tamivaroten is concentration dependent, and in the administration group of 0.008% by mass of Tamibarotene at the maximum dose, 0.1% by mass of differin gel administration group It is understood that the acne treatment effect is high although the face number is somewhat larger compared to the above. Furthermore, at a high dose of 0.012% by mass, 0.016% by mass, etc. of Tamivarotene, a therapeutic effect equal to or higher than that of the differin gel 0.1% by mass administration group is expected.
  • the skin thickness was significantly increased as compared with the base group.
  • the epidermal thickness thickening effect of Tamivarotene was higher than that of the diffferin gel administration group (0.1% by mass), and a high retinoid-like action of Tamibarotene was shown.
  • the results are shown in FIG. As apparent from FIG. 7, the average scaling score is 1.2 in the 0.008% by mass gel administration group of Tamivarotene, and is significantly lower than 3.0 in the 0.1% by mass gel administration group of differin. Was shown quantitatively.

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  • Health & Medical Sciences (AREA)
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  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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Abstract

Le problème que cherche à résoudre la présente invention est de fournir une composition topique pour la peau qui ait un faible potentiel d'irritation de la peau (de type desquamation et érythème), et qui procure un excellent effet thérapeutique ou prophylactique sur des maladies de type acné. L'invention concerne une composition topique pour la peau destinée au traitement ou à la prévention de maladies de type acné qui comprend du tamibarotène en tant que principe actif.
PCT/JP2018/031244 2017-08-31 2018-08-23 Composition topique pour la peau destinée au traitement ou à la prévention de maladies de type acné Ceased WO2019044670A1 (fr)

Applications Claiming Priority (2)

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JP2017166793A JP2019043865A (ja) 2017-08-31 2017-08-31 ざ瘡様疾患を治療又は予防するための皮膚外用組成物
JP2017-166793 2017-08-31

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WO2019044670A1 true WO2019044670A1 (fr) 2019-03-07

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11039995B2 (en) 2013-03-15 2021-06-22 Samson Pharma, Llc Topical compositions for reducing the effects of aging

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4516299A4 (fr) * 2022-04-28 2025-12-17 National Univ Corporation Tokai National Higher Education And Research System Composition pharmaceutique de traitement d'insuffisance cardiaque avec dysfonctionnement diastolique

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005087220A1 (fr) * 2004-03-11 2005-09-22 R & R Inc. Préparation antirides
JP2014144929A (ja) * 2013-01-29 2014-08-14 Daiichi Sankyo Healthcare Co Ltd ビタミン類を含有するニキビの予防又は治療用組成物
WO2016161107A1 (fr) * 2015-03-31 2016-10-06 Syros Pharmaceuticals, Inc. Procédés de stratification de patients pour un traitement au moyen d'agonistes du récepteur α de l'acide rétinoïque

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005087220A1 (fr) * 2004-03-11 2005-09-22 R & R Inc. Préparation antirides
JP2014144929A (ja) * 2013-01-29 2014-08-14 Daiichi Sankyo Healthcare Co Ltd ビタミン類を含有するニキビの予防又は治療用組成物
WO2016161107A1 (fr) * 2015-03-31 2016-10-06 Syros Pharmaceuticals, Inc. Procédés de stratification de patients pour un traitement au moyen d'agonistes du récepteur α de l'acide rétinoïque

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
NAKAYAMA, YASUHISA: "Quasi drug as external preparation for acne, Development and challenges of cosmetics", FRAGRANCE JOURNAL, no. 74, 1985, pages 25 - 29 *
TOMONO, NORIHIRO: "Multifaceted approach to acne care by natural raw materials", FRAGRANCE JOURNAL, vol. 35, no. 5, 2007, pages 36 - 41 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11039995B2 (en) 2013-03-15 2021-06-22 Samson Pharma, Llc Topical compositions for reducing the effects of aging

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