WO2019044670A1

WO2019044670A1 - Topical skin composition for treatment or prevention of acne-like disease

Info

Publication number: WO2019044670A1
Application number: PCT/JP2018/031244
Authority: WO
Inventors: 和義河府; 安啓藤貫; 博実田澤
Original assignee: ひまわり製薬株式会社
Priority date: 2017-08-31
Filing date: 2018-08-23
Publication date: 2019-03-07
Also published as: JP2019043865A

Abstract

The problem addressed by the present invention is to provide a topical skin composition that has low skin irritancy (such as desquamation and erythema) and an excellent therapeutic or prophylactic effect on acne-like disease. A topical skin composition for treating or preventing acne-like disease that includes tamibarotene as an active ingredient.

Description

Skin external composition for treating or preventing acne-like diseases

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. In addition, 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.
Major therapeutic agents have been developed according to the cause of the onset, and retinoid agents (tretinoin, isotretinoin, tazarotene, adapalene etc.) are effective in normalizing abnormal keratinization and sebum secretion, and in Japan, 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. Among the endogenous retinoids, all-trans retinoic acid (also known as tretinoin) may actually be used as a treatment for acute promyelocytic leukemia (APL) in the hematologic cancer area and as a treatment for acne in the dermatological area It has become.
On the other hand, since 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.
One example is Tamibarotene. 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, RARα, RARβ, and RARγ, 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 RARα and RARγ, and RARβ is not detected (see, for example, Non-Patent Document 3).
In Japan, tretinoin and isotretinoin have not been approved as a therapeutic agent for acne, and adapalene (a naphthoic acid derivative exhibiting retinoid-like activity) is used as the only retinoid compound for acne treatment (eg, diff. (Trademark) gel (0.1%), which activate RARγ in the skin because they act specifically on RARβ and RARγ.
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. It is reported that the treatment effect is reduced by 50 to 60% as the treatment effect, but on the other hand, there are many patients who strongly irritate the skin and give up treatment, but there is room for improvement of the side effects (erythema, irritability, scaling, etc.) was there.
In addition, it is suggested from analysis using a mouse that the action on RARγ enhances skin irritation (see Non-patent Document 4).

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.

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.
Specifically, the present invention is as follows.

(1) A composition for external use on the skin for treating or preventing acne-like diseases, which comprises tamibarotene as an active ingredient.
(2) The external composition for skin as described in (1) above, wherein the content of Tamivarotene is 0.0001 to 0.05% by mass of the total composition for external application on skin.
(3) The external skin composition as described in (1) or (2) above, wherein the acne-like disease is acne vulgaris.
(4) The composition for external use on skin according to any one of the above (1) to (3), wherein the dosage form is a gel.

(5) Application of 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).
(6) A method for treating or preventing acne-like diseases, which comprises applying to the skin a composition comprising tamibarotene as an active ingredient.

The 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.

It is a figure which shows the diameter d of the surface opening of the surface opening, and the diameter D of the center part of the depth of the surface. Diagram showing hematoxylin-eosin staining results of sliced sections of each of 0.004% by mass Tamibarotene gel, gel as a control (0% by mass Tamivarotene) as a control, and 0.1% by mass gel as a positive control. It is. It is a figure which shows distribution of the area | region size in each group. It is a figure which shows the number of faces in each group. It is a figure which shows the skin thickness (micrometer) in each group. It is a figure which shows the 22nd day photographic image in each group. It is a figure which shows the scaling score in each group. It is a figure which shows the number of mice in which desquamation was observed in each administration day of each group. It is a figure which shows the number of mice in which the erythema was observed in each administration day of each group. It is a figure which shows the scaling score with respect to each administration day of each group. It is a figure which shows the scaling score with respect to each administration day of each group.

Hereinafter, embodiments of the present invention will be described in detail, but the present invention is not limited to the following embodiments at all, and can be implemented with appropriate modifications within the scope of the object of the present invention. .

<External skin composition for treating or preventing acne-like diseases>
The composition for external use on the skin for treating or preventing acne-like diseases of the present invention 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. As 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. 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.

The 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. In 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 method of such formulation can be carried out in accordance with the method described in JP General Formula.
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 agents such as antioxidants (ascorbic acid, tocopherol, etc.) may contain a base formed by blending the like. These may be used alone or in combination of two or more.
The 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. In addition, the composition for external use on the skin of the present invention can be used as medicines, quasi-drugs, cosmetics and the like.
When the composition for external application to the skin is a coating agent, 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 μl, preferably 10 to 300 μl). 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. Preferably, 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.

EXAMPLES The present invention will be more specifically described below with reference to examples, but the scope of the present invention is not limited to these examples.

«Face model mouse test»
Example 1
The comet model mouse, Rhino mouse, is a mutant mouse that shows skin abnormalities, and hair loss is lost several weeks after birth, and sebum and the like accumulate in hair follicles with loss of hair (R. E. Ashton et al: Histologic changes in the skin of the rhino mouse (hrrhhrrh) induced by retinoids. J Invest Dermatol. 1984 Jun; 82 (6): 623-5.
This comedone is non-inflammatory and corresponds to mild acne in humans, but it is a standard model system that has been used for more than 30 years to verify the comedogenic effect of retinoid compounds. As a result of comedone treatment, sebum retention has disappeared, and it has been found that when the spread comed is reduced and returned to the original shape of the hair follicle, the therapeutic effect is obtained. However, the hair follicle does not disappear completely.

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. Was set, and as a positive 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.

Apply to n = 10 (5 males and 5 females) Rhino mice each for a total of 6 conditions, and apply 50 μl 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.
<Pathological tissue analysis>
The skin condition after euthanasia is photographed, and the pathological tissue sample at the administration site is collected by biopsy trepang, fixed in 10% formalin solution and embedded in paraffin, and sliced section (about 5 μm thick) Pathological analysis (hematoxylin and eosin staining and image analysis under a microscope) was performed.
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. We used "Excel Area and Length Measurement II" as image analysis software.

(Result of pathological tissue analysis)
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.
As is clear from the results of 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. 3 is a view showing the distribution of the area size in each group.
As apparent from FIG. 3, in the base administration group (graph 1) which is a control, many large comets exceeding 100 μm are observed, but in the tamibarotene gel administration group (graphs 2 to 5), the comedone size decreases in a concentration dependent manner. Was observed.

<Reducing effect of face number>
(How to measure the number of faces)
In pathological analysis, the number of faces present in a 6 mm size epidermal section sample was counted and graphed as the number of faces per 1 cm. The comed was measured both in the opening in the epidermis and in the subcutaneous.
(Result of measurement of the number of faces)
The results are shown in Table 1 below and FIG.

Data are mean ± standard deviation.
Significant difference test with vehicle group (*: p <0.05, **: p <0.01;Dunnett's test).
Significant difference test with vehicle group (##: p <0.01; Student t test).

In addition, 36.8 ± 2.2 ^# (number of faces per cm of skin) of Differin gel (0.01% by mass) in “Diffelin (registered trademark) Gel 0.1%-Interview Form” Mean value ± standard error, n = 10, #: p <0.05;Tukey's multiple comparison test with gel base) is described.

The comedones regress with retinoid treatment and can be histologically restored to normal hair follicle shape.
As apparent from the results shown in the above Table 1 and FIG. 4, 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.

<Increase in skin thickness>
Epidermal thickening is not a direct indicator of comedo healing, but it is expected to be an indicator of efficacy against acne-like diseases including similar diseases of acne, as it is an effect exhibited by physiological activity of retinoid-like action. Ru.
(Method of measuring skin thickness)
The skin thickness was calculated using the skin thickness area (S) and the long side (L) of the skin thickness area according to the following formula.
Skin thickness = S / L
(Measurement result of skin thickness)
The results are shown in Table 2 below and FIG.

Data are mean ± standard deviation.
Significant difference test with vehicle group (**: p <0.01;Dunnett's test).

In addition, 38.6 ± 1.17 ^* (average value ± standard error) of the skin thickness (μm) of differin gel (0.01% by mass) in “Diferin (registered trademark) gel 0.1%-interview form” , N = 10, *: p <0.05;Tukey's multiple comparison test against gel base).

As apparent from the above Table 2 and FIG. 5, in the tamibarotene gel administration group (0.004% by mass and 0.008% by mass), 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.

<Skin irritation evaluation of Tamibaroten gel>
(Skin condition observation)
After administration for 21 days, photographic images of day 22 Rhino mice were analyzed.
The results are shown in FIG.
As apparent from FIG. 6, there was less desquamation in the tamibarotene-administered mice as compared to the diffferin gel-administered mice in which the desquamation of the skin was remarkable.
(Evaluation of scrap weight)
The skin condition photographed after euthanasia on the 22nd day was scored on a scale of 5 degrees of scale from 0 to 4 to evaluate the degree of scale (scale).
The scale score is as follows: 0: no scale, 1: very slight scale, 2: slight scale, 3: clear scale, 4: large amount of scale, scale is each group (n = 10) (mean ± standard deviation).
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.

(Evaluation of skin condition)
The skin condition was observed daily (days of administration 0 to 22), the presence or absence of erythema and desquamation was recorded, and the skin irritation of Tamibarotene gel was evaluated.
The results are shown in Table 3 below and in Figures 8 and 9.

As apparent from the above Table 3 and FIG. 8, on the 11th day of administration for Tamibarotene 0.002% by mass gel, 11th day of administration for 0.004% by mass gel and 0.008% by mass for 0.004% by mass gel from the 12th day of administration A reduction is seen, and it can be seen that scaling is transient.
On the other hand, no reduction in desquamation was observed in the observation period up to the 22nd day of administration in the differin 0.1 mass% gel administration group.
Further, as is apparent from Table 3 and FIG. 9 above, erythema was observed in the diphenylamine 0.1 mass% gel administration group on the 5th to 7th days of administration, while erythema was observed in any of the Tamibarotene gel administration groups. It was not done.

In addition, as a result of Phase III clinical trial of Differin 0.1% by mass gel conducted for Acne vulgaris patients, adverse effects (clinical test value) in 429 cases (78.9%) of 544 patients for safety evaluation Abnormal side effects are observed, and the main side effects are skin dryness (305 cases, 56.1%), skin discomfort (259 cases, 47.6%), skin exfoliation (182 cases, 33.5%), It is known that it was erythema (119 cases, 21.9%) (Dephelin® Gel 0.1%-see drug package insert).

Example 2
The same procedure as in Example 1 was carried out except that 0.008% by mass, 0.012% by mass and 0.016% by mass tamibarotene gel was used as a test substance, and each group of n = 10 (5 male and female) rhino mice The degree of desquamation at the administration site was scored and evaluated in five steps from 0 to 4 on the 1st (pre-administration), 8th, 15th and 22nd day of administration on 21 days of administration.
Further, as in Example 1, only the base (0% by mass of Tamivarotene) was used as a control, and an adapalene gel (0.1% by mass gel of differin) was used as a positive control.
The results are shown in the following Table 4, FIGS. 10 and 11.

Data are mean ± standard deviation.
Significant difference test with base group (*: p <0.05, **: p <0.01; multi-group comparison test).
Significant difference test with vehicle group (#: p <0.05, ##: p <0.01; 2 group comparison test).

From the results shown in Table 4 and FIGS. 10 and 11, it can be seen that descaling significantly occurs with respect to the base group at 22 days of administration. In the base group, no scaling occurred.
On the other hand, as apparent from FIGS. 10 and 11, in the administration days of 22 days, even in the Tamivaroten 0.016% by mass gel administration group, there is significantly less desquamation compared to the differin 0.1% by mass gel administration group I understand.

Claims

An external skin composition for treating or preventing acne-like diseases, which comprises Tamibarotene as an active ingredient.
The composition for external use on the skin according to claim 1, wherein the content of Tamivarotene is 0.0001 to 0.05% by mass of the total composition for external use on skin.
The dermatological composition according to claim 1 or 2, wherein the acne-like disease is acne vulgaris.
The composition for external use on skin according to any one of claims 1 to 3, wherein the dosage form is a gel.
The application of tamibarotene for the preparation of a skin care composition for treating or preventing acne-like diseases according to any one of claims 1 to 4.