JP2010260808A - Oral pharmaceutical composition for improving skin condition - Google Patents

Abstract

[PROBLEMS] To provide an oral composition for alleviating symptoms of urticaria, eczema / dermatitis and rash and treating skin swelling and itching, which has a high effect in a short period of time. Moreover, the method of effectively enhancing the skin barrier function improvement effect of nicotinic acid amide, pantothenic acid, or those related substances is provided.
An oral pharmaceutical composition containing one or more selected from the group consisting of (i) azelastine or a salt thereof, and (ii) nicotinamide, pantothenic acid, and related substances, and A method of coexisting azelastine or a salt thereof and one or more selected from the group consisting of nicotinamide, pantothenic acid, and related substances.
[Selection figure] None

Description

The present invention relates to an oral pharmaceutical composition for alleviating symptoms of urticaria, eczema / dermatitis and rash, and treating skin swelling and itching.
The present invention also relates to a method for enhancing the skin barrier function improving effect of nicotinamide, pantothenic acid, or a related substance thereof.

  Deterioration of skin condition such as skin dryness, skin barrier function decline, etc. is caused by internal factors such as aging and various diseases, hormonal imbalance, or lifestyle such as excessive bathing and excessive use of detergent, It is caused by external environmental factors such as ultraviolet rays and a decrease in winter humidity. The skin barrier function is an important function that the skin basically has, and is a function for preventing a substance harmful to the living body from entering the body and maintaining a constant moisture in the living tissue. . This decrease in function is likely to cause skin diseases such as inflammation, resulting in symptoms such as urticaria, eczema / dermatitis, and rash, resulting in skin swelling and itching. Therefore, it is an important issue to improve the decrease in skin barrier function caused by various factors.

For the purpose of preventing skin dryness, polyhydric alcohols such as glycerin, 1,3-butylene glycol and sorbitol, natural plant-derived extract components, amino acids that are skin constituents, natural moisturizing factors such as pyrrolidone carboxylic acid, ceramide Intracellular lipid components such as cholesterol and cholesterol and in vivo polymers such as collagen and hyaluronic acid have been used for external use.
Furthermore, as an oral composition as a skin condition improving composition, a composition containing ceramide, amino acid, hyaluronic acid, glucosamine and analogs thereof, health foods derived from natural plants, vitamin preparations and the like have been developed (Patent Document 1, 2, 3). These oral compositions have been reported to provide limited effects upon long-term administration.
In addition, as an effect of nicotinamide on the skin, in combination with amino acids, vitamins, extracts, etc., ceramide synthesis promoting effect (Patent Document 4), whitening effect (Patent Document 5), anti-aging effect (Patent Document 6) The skin beautifying effect (Patent Document 7) has been reported.
Pantothenic acid is also called vitamin B5 and becomes a coenzyme CoA in vivo, and is involved in various metabolic systems such as fatty acids, proteins, and carbohydrates. It is known to have an effect of improving skin cell activity, elasticity and water retention for the skin. As an effect on the skin of pantothenic acid and its derivatives, in combination with other compounds, skin barrier function improving effect (Patent Document 8), whitening effect (Patent Document 9), skin beautifying effect (Patent Document 10), anti-inflammatory effect (patent Reference 11) has been reported.
On the other hand, azelastine hydrochloride, which is a kind of antihistamine, has the effects and effects of bronchial asthma, allergic rhinitis, hives, eczema / dermatitis, atopic dermatitis, skin pruritus, and urticaria as medical drugs. These effects and effects of azelastine hydrochloride are considered to be based on an antihistamine action and an inhibitory action on the release of histamine and leukotriene by stabilizing the membrane of mast cells. In addition, as a report in which azelastine hydrochloride and other compounds are combined, anticholinergic drugs or ephedrine drugs are combined to show goblet cell hyperplasia inhibitory action (Patent Documents 12 and 13), epinastine is combined and skin diseases such as eczema The thing which improved the therapeutic effect (patent document 14) etc. is reported.

JP-A-11-113530 Japanese Patent Laid-Open No. 2001-48789 JP 2007-84460 A Japanese Patent No. 3129646 JP 2007-176810 A JP 2005-298370 A JP-A-9-315931 Japanese Patent No. 3948588 JP-A-5-186324 JP-A-5-262635 JP-A-6-128136 JP 2008-110970 A JP 2009-7332 A JP 2005-53907 A

The present invention provides an oral pharmaceutical composition having a high skin barrier function improving effect, particularly an effect of suppressing a decrease in the amount of horny water, after a short-term administration. In particular, the present invention provides an oral pharmaceutical composition for alleviating symptoms of urticaria, eczema / dermatitis and rash, and treating skin swelling and itching.
The present invention also provides a method for enhancing the effect of nicotinamide, pantothenic acid, or a similar substance on improving the skin barrier function, particularly the effect of suppressing the decrease in the amount of horny water.

As a result of diligent studies to solve the above-mentioned problems, the present inventors have found that (i) azelastine or a salt thereof, and (ii) nicotinamide, pantothenic acid, and a related substance thereof are selected from the group consisting of Alternatively, the inventors have found that the effect of improving the skin barrier function becomes remarkable by orally ingesting a composition containing two or more kinds, and have completed the present invention.
That is, the present invention is an oral pharmaceutical composition containing one or more selected from the group consisting of (i) azelastine or a salt thereof, and (ii) nicotinamide, pantothenic acid, and related substances. is there.
In particular, the present invention is an oral pharmaceutical composition that can improve skin barrier function and thereby improve skin condition. More specifically, the oral pharmaceutical composition of the present invention is a pharmaceutical composition that suppresses a decrease in the amount of keratinous moisture in the skin. More specifically, the pharmaceutical composition of the present invention is a pharmaceutical composition for alleviating symptoms of urticaria, eczema / dermatitis and rash, and treating skin swelling and itching.
The present invention also relates to nicotinic acid amide, pantothenic acid, which comprises coexisting with azelastine or a salt thereof and one or more selected from the group consisting of nicotinic acid amide, pantothenic acid, and related substances. Or a method for enhancing the effect of improving the skin barrier function of these related substances. In particular, the method of the present invention can enhance the inhibitory effect on the decrease in keratin water content by nicotinamide, pantothenic acid, or related substances.

  According to the present invention, the skin barrier function is effectively improved by short-term administration, and the decrease in keratin water content of the skin is suppressed. More specifically, the oral administration of the pharmaceutical composition of the present invention improves skin conditions such as dry skin and reduced skin barrier function, thereby alleviating symptoms of urticaria, eczema / dermatitis and rash. Skin swelling and itching can be treated. In addition, according to the present invention, nicotinamide, pantothenic acid, or a related substance thereof effectively enhances the skin barrier function improving effect, suppresses a decrease in skin keratin water content, and is administered by oral administration of these substances. The effect of relieving symptoms of urticaria, eczema / dermatitis and rash, and the effect of treating skin swelling and itching are enhanced.

FIG. 1 shows skin when azelastine hydrochloride, nicotinamide and calcium pantothenate are administered alone, and when a composition containing azelastine hydrochloride and nicotinamide and a composition containing azelastine hydrochloride and calcium pantothenate are administered. The water reduction rate (%) is shown. ◆: Control, □: Administration of azelastine hydrochloride alone, ○: Administration of nicotinamide alone, Δ: Administration of calcium pantothenate alone, ●: Administration of a composition containing azelastine hydrochloride and nicotinamide, ▲: Composition containing azelastine hydrochloride and calcium pantothenate Administration.

  As described above, several substances have been conventionally used for the purpose of preventing skin dryness, and oral compositions aimed at improving the skin condition are also known. However, these skin barrier function improving effects are not always satisfactory, and these effects were confirmed for the first time by long-term administration when taken orally. The composition of the present invention effectively improves the skin barrier function by short-term administration, for example, administration 1 to 3 times a day, preferably 2 to 14 days, at least 2 to 7 days, thereby improving the skin The status can be changed. More specifically, the oral pharmaceutical composition of the present invention can suppress a decrease in the amount of stratum corneum. By exhibiting such effects, the pharmaceutical composition of the present invention can relieve symptoms of urticaria, eczema / dermatitis and rash, and can treat skin swelling and itching.

  “Azelastine or a salt thereof” used in the present invention is not particularly limited as long as it is a pharmacologically acceptable salt. For example, inorganic acid salts (eg, hydrochloride, hydrobromide, sulfate, phosphate, etc.); organic carboxylic acid or sulfonic acid addition salts (eg, formate, acetate, trifluoroacetate, maleate) , Tartrate, citrate, fumarate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.); and acidic amino acid salts (for example, aspartic acid, glutamic acid, etc.). Suitably, in the present invention, “azelastine salt” is “azelastine hydrochloride” which is a hydrochloride. Azelastine hydrochloride is commercially available as a pharmaceutical and can be easily obtained (for example, Sanyo Chemical Co., Ltd.).

Although the dosage of the pharmaceutical composition of the present invention varies depending on the indication and age, the dosage of azelastine is usually 0.2 to 10 mg per day, and this is preferably administered 1 to 3 times a day. In the case of a solid preparation containing the pharmaceutical composition of the present invention, the content of azelastine is typically 0.1 to 10 mg per day, and preferably 0.5 to 4 mg.
In the case of a liquid preparation containing the pharmaceutical composition of the present invention, the content of azelastine is usually 0.05 to 4 mg / mL, preferably 0.1 to 2 mg / mL.
Good results are obtained when the compositions of the invention are administered preferably for 2 to 14 days, at least 2 to 7 days.

“Nicotinamide or related substances” used in the present invention includes, but is not limited to, nicotinic acid and pharmaceutically acceptable salts thereof.
Examples of “pantothenic acid or related substances” used in the present invention include, but are not limited to, calcium pantothenate, sodium pantothenate, panthenol, pantothenyl ethyl ether, and acetyl pantothenyl ethyl ether.
In the present invention, one or more of the above-mentioned nicotinamide, pantothenic acid, and related substances may be used in combination.
There are no particular restrictions on the compounding ratio of azelastine to nicotinamide, pantothenic acid, and related substances contained in the oral pharmaceutical composition of the present invention. Preferably, nicotinamide, pantothenic acid, and their related substances are 1 to 200 with respect to azelastine 1 by weight.

Examples of methods for evaluating the effect of improving the skin barrier function include peeling of the stratum corneum by tape stripping on the skin of humans, rats, mice, etc., degreasing with a surfactant (for example, sodium dodecyl sulfate), or degreasing with an organic solvent (for example, acetone) There is a method for evaluating the process of destroying the skin barrier function and restoring the original state by measuring TEWL.
When the skin barrier function is reduced due to air drying or physiological function changes, not only fat-soluble moisturizing components such as sebum membranes and intercellular lipids but also water-soluble moisturizing components such as natural moisturizing factors are decreased.
Therefore, in order to evaluate the effect of improving the skin barrier function of this oral pharmaceutical composition, the following model animals can also cause a decrease in the fat-soluble moisturizing component by the acetone / diethyl ether mixture and the decrease in the water-soluble moisturizing component by distilled water. Can be used.

Specifically, for example, the skin barrier function improving effect of the oral pharmaceutical composition can be evaluated as follows.
(1) Preparation method of skin barrier function lowering model A portion of the mouse rostral dorsal skin, for example, about 2 cm square, is shaved, and a mixed solution of acetone and diethyl ether (1: 1) is added several days after the shaving, for example, 4 days later. The shaved part is covered with a dipped absorbent cotton for 10 to 60 seconds, then wiped to remove excess solvent, and subsequently covered and wiped with absorbent cotton soaked in distilled water for 30 to 60 seconds. By performing this treatment twice a day for several days continuously, for example, for 3 to 7 days, at intervals of 7 hours or more, a skin barrier function-reduced model mouse can be produced.
(2) Administration of test substance The test substance is orally administered every time immediately after the above treatment (2 to 3 times a day, about 5 to 7 days). The amount and ratio of azelastine hydrochloride, nicotinamide and calcium pantothenate are adjusted as appropriate and administered orally.
(3) Measurement of skin moisture content The stratum corneum moisture content can be based on the relative capacitance measured with Corneometer CM825 (Courage + Khazaka electronics, Cologne, Germany).
From the measured amount of stratum corneum, the water reduction rate can be obtained by the following formula and used as an index of the effect of improving the skin barrier function.
Moisture reduction rate (%) = (Keratin moisture at the start / Kerato moisture in each measurement day−1) × 100

In the present invention, in addition to the above components, other vitamins, amino acids, anti-inflammatory components, sympathomimetic components, herbal medicine components, calcium agents, and the like are included as long as they do not impair the effects of the present invention. The following components are exemplified.
Vitamins: Vitamin A [retinol and its derivatives, and pharmaceutically acceptable salts thereof (eg, retinal, retinoic acid, retinol palmitate, retinol acetate, etc.)], vitamin B1 [thiamine and its derivatives, and Pharmaceutically acceptable salts thereof (eg, thiamine hydrochloride, thiamine nitrate, and fursultiamine)], vitamin B2 [riboflavin and its derivatives, and pharmaceutically acceptable salts thereof (eg, riboflavin phosphate, Riboflavin sodium phosphate, riboflavin butyrate, and flavin adenine dinucleotide sodium)], vitamin B6s [pyridoxine and its derivatives, and pharmaceutically acceptable salts thereof (for example, pyridoxine hydrochloride, pyridoxine phosphate, and pyridoxal) ], Bi Min B12 [cobalamin and its derivatives, and pharmaceutically acceptable salts thereof (for example, cyanocobalamin, mecobalamin, and hydroxocobalamin hydrochloride)], biotin, folic acid or a pharmaceutically acceptable salt thereof, vitamin C [ascorbine Acids and derivatives thereof, and pharmaceutically acceptable salts thereof (for example, erythorbic acid, sodium ascorbate, and sodium erythorbate), vitamin Ds [calciferol and derivatives thereof, and pharmaceutically acceptable salts thereof (For example, ergocalciferol, cholecalciferol, and hydroxycholecalciferol)], vitamin E [tocopherol, ubiquinone and derivatives thereof, and pharmaceutically acceptable salts thereof (for example, tocopherol acetate, tocofu succinate) And other vitamins (eg, hesperidin, carnitine, ferulic acid, γ-oryzanol, orotic acid, rutin, eriocitrin, inositol, and pharmaceutically acceptable salts thereof), etc. .
Preferably, pyridoxine hydrochloride and ascorbic acid are used.

  Amino acids: glutamic acid, aspartic acid, glycine, alanine, serine, aminoethylsulfonic acid (taurine), and pharmaceutically acceptable salts thereof (for example, ephedrine hydrochloride, methylephenoline hydrochloride, etc.) and the like.

  Anti-inflammatory components: allantoin, glycyrrhetinic acid, glycyrrhizic acid, diclofenac sodium, and pharmaceutically acceptable salts thereof (for example, monoammonium glycyrrhizinate, potassium glycyrrhizinate, dipotassium glycyrrhizinate) and the like.

  Sympathomimetic component: ephedrine, methylephedrine, pseudoephedrine, trimethquinol, methoxyphenamine, and pharmaceutically acceptable salts thereof.

  Herbal medicine ingredients: Psycho, Buddlefish, Keihi, Kanzo, Ogon, Oubak, Auren, Sanshishi, Giou, Peonies, Senkyu, Toki, Hamaboufu, Bowfuu, Ouhi, Kyo, Shokyo, Dokukatsu, Keigai, Mokutsu, Moboi, Mochi Kujin, Sojitsu, Inchinkou, etc.

  Calcium agents: calcium citrate, calcium gluconate, calcium lactate, calcium hydrogen phosphate, etc.

  The dosage form of the preparation is not particularly limited as long as it is an internal preparation, but specific dosage forms include tablets (plain tablets, multilayer tablets, dry tablets, chewable tablets, etc.), fine granules (granules, powders) And powders), capsules (hard capsules, soft capsules, etc.), pills, liquids (including syrups) and the like.

In the above dosage forms, various commonly used additives can be used depending on the dosage form. For example, stabilizers, surfactants, plasticizers, lubricants, solubilizers, buffers, sweeteners, bases, corrigents, binders, suspending agents, antioxidants, coating agents, wetting agents , Filler, colorant, fragrance, sugar coating, tonicity agent, thickener, pH adjuster, excipient, dispersant, disintegrant, disintegration aid, disintegration extender, moisture-proofing agent, preservative, storage Formulation additives such as agents, solubilizers, solubilizers, solvents, fluidizing agents and the like.
The additives and bases suitable for each of these dosage forms can be used as appropriate, and can be produced according to the usual methods described in the Japanese Pharmacopoeia.
Hereinafter, the present invention will be described in detail with reference to examples and test examples, but the scope of the present invention is not limited thereto.

Preparation of Tablets The ingredients and amounts shown in the following table were taken, and tablets were produced according to the section “General Tablet Preparations” “Tablets”.

4 tablets (mg)

Manufacture of granules The ingredients and amounts shown in the table below were taken, and granules were manufactured according to the section of the Japanese general formulation “Granule”.
2 capsules (mg)

Preparation of Capsule The ingredients and amounts shown in the following table were taken, and a fine granule was produced according to the section of the Japanese Pharmacopoeia General Rules “Powder”, and then filled into a capsule to produce a hard capsule.
In 2 capsules (mg)

Preparation of syrup The syrup was prepared by taking the components and amounts shown in the following table and producing a syrup according to the section of the Japanese Pharmacopoeia General Rules “Syrup,” and then filling it into a brown glass bottle.
In 20 mL (mg)

Skin barrier function improvement effect test (1) Test composition As test compositions, a composition containing azelastine hydrochloride and nicotinamide and a composition containing azelastine hydrochloride and calcium pantothenate were tested, and azelastine hydrochloride and nicotinamide were tested. Calcium pantothenate was also tested alone. Sanyo Chemical Co., Ltd. was used for azelastine hydrochloride, DSM Nutrition Japan Co., Ltd. was used for nicotinamide, and Daiichi Fine Chemical was used for calcium pantothenate.
Each test substance was dissolved in water so as to give a dose of 0.1 ml per 10 g of mouse body weight. The control received water only.
(2) Animals Male ICR mice (5-6 weeks old) purchased from Japan SLC were used for the test. The animals were preliminarily raised for 7 days, and the environment was maintained at a temperature of 22 to 23 ° C., a humidity of 45 to 50%, a lighting time of 12 hours (7 to 19 o'clock), and feed and water were freely consumed.
(3) Preparation of a model with reduced skin barrier function About 2 cm square of mouse rostral dorsal skin was shaved and shaved with 2 cm square absorbent cotton soaked with acetone / diethyl ether (1: 1) mixture for 15 seconds after 4 days of shaving. The part was covered and then wiped to remove excess solvent, and subsequently covered and wiped with absorbent cotton soaked in distilled water for 30 seconds. By carrying out this treatment twice a day for 6 days at intervals of 7 hours or more, a model mouse with reduced skin barrier function was produced.
(4) Administration of test substance The test substance was orally administered immediately after the treatment of (3) (twice a day for 6 days). Azelastine hydrochloride was orally administered at a dose of 1 mg / kg, and nicotinamide and calcium pantothenate were orally administered at a dose of 100 mg / kg (each group n = 8).
(5) Measurement of skin water content The keratin water content was determined by using the relative capacitance measured by Corneometer CM825 (Courage + Khazaka electronics, Cologne, Germany) as an index. The water reduction rate was determined from the measured amount of horny water according to the following formula, and was used as an index of the skin barrier function improvement effect.
Moisture reduction rate (%) = (Keratin moisture at the start / Kerato moisture in each measurement day−1) × 100
(6) Data analysis The test results were calculated by calculating the average value and standard error of each water loss rate, and analyzing differences between groups by Tukey-Kramer's multiple comparison study.

^**ｐ＜０．０１ ｖｓ 対照 (7) Results Table 1. Moisture reduction rate by each test substance

^** p <0.01 vs control

From this result, it can be said from Table 1 that there is no significant difference in the water decrease rate of each group administered alone with azelastine hydrochloride, nicotinamide or calcium pantothenate, and there is an effect of improving the skin barrier function. Absent.
However, the rate of water loss in the azelastine hydrochloride and nicotinamide combination administration group, or the azelastine hydrochloride and calcium pantothenate combination administration group was smaller than that of each single administration group, and showed a significant improvement in skin barrier function compared to the control group. It was.
Therefore, the skin barrier function improvement effect which was not recognized by single administration was recognized notably by combined administration, and the enhancement of the synergistic improvement effect with respect to the skin barrier function of each component was confirmed.

Claims (4)

  An oral pharmaceutical composition comprising one or more selected from the group consisting of (i) azelastine or a salt thereof, and (ii) nicotinamide, pantothenic acid, and related substances.   The oral pharmaceutical composition according to claim 1, wherein the pantothenic acid-related substance is selected from the group consisting of calcium pantothenate, sodium pantothenate, panthenol, pantothenyl ethyl ether, and acetyl pantothenyl ethyl ether.   The oral pharmaceutical composition according to claim 1 or 2, wherein the salt of azelastine is azelastine hydrochloride, and the daily dose of azelastine hydrochloride is 0.1 to 10 mg.   Nicotinamide, pantothenic acid, or a related substance thereof, comprising coexisting with azelastine or a salt thereof and one or more selected from the group consisting of nicotinamide, pantothenic acid, and a related substance To enhance the skin barrier function improving effect.

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