RU2401100C2 - Acid and buffer skin care compositions containing nicotinamide and absorbing agent - Google Patents

Abstract

FIELD: medicine. ^ SUBSTANCE: absorbing agent is specified from the group consisting of starch, talc, kaolin, aluminium stearate, magnesium carbonate, titanium dioxide, titanium dioxide or zinc oxide processed with methicone, dimethicone, cyclopentasiloxane, stearic or myristinic acid, or their mixture. Buffer agents consist of citrates, phosphates or their mixture. Besides the invention refers to medicinal agents containing mentioned compositions and used for treatment and/or prevention of mild skin irritations, especially of diaper dermatitis. Also the invention refers to the application of the mentioned compositions as anti-urease agents. ^ EFFECT: environmental improvement of skin condition in a diaper and prevention or treatment of the irritated skin, diaper dermatitis and miliaria caused by the presence of urine or excrements. ^ 13 cl, 3 dwg, 11 tbl, 4 ex

Description

The invention relates to skin care compositions comprising nicotinamide and an absorbent substance. The invention also relates to medicines containing said compositions, successfully used to treat and / or prevent mild to moderate skin irritation.

Several babies got rid of one or more episodes of diaper dermatitis, which in its more general form is irritating contact dermatitis. The skin under the diaper of infants is often exposed to heat, a moist environment, and, as you know, increased hydration of the skin leads to increased friction and scratching, increased permeability and an increase in the number of microbes.

It is assumed that ammonia is involved in the formation of diaper dermatitis. More recently, it has been discovered that ammonia can play an indirect role, including the interaction between urine and feces. A direct effect on the skin can be attributed to fecal enzymes, especially proteases and lipases, which become more active and, thus, more damaging with increasing pH. An increase in pH is the result of the release of ammonia from urine urea by fecal urease. Urine and feces are usually present in the diaper at the same time, and exposure to the skin of these materials for several hours is not unusual, especially in the diaper at night, providing suitable conditions and sufficient time for such interaction and leading to noticeable damage to the skin. Thus, it is believed that lipases and proteases are skin irritants that may be involved in causing diaper dermatitis (Etiologic factors inndiaper dermatitis: the role of urine, Ronald W. Berg et al., Pediatric Dermatology, Vol. 3 No. 2. 102 -106).

In addition to its potential to make feces an irritant, urine also contains components that directly irritate the skin, especially after prolonged exposure.

For many years, studies have been conducted to find the causes and drugs for mild skin rashes in humans. Such rashes are usually caused by allergies, exposure to the skin during periods of cold weather, or exposure to hot, humid conditions, such as washing dishes or the like, or exposure to irritating materials in topical products or ingredients (e.g. retinoids, hydroxy acids, keto acids). Such rashes can also be caused by dry skin without adequate skin hydration.

Because the causes may vary, symptoms usually include mild skin irritation, skin rashes, cuts and cracks, accompanied by a burning sensation, acute pain, irritation and discomfort. Over the years, numerous attempts have been made to develop topical effects of creams, ointments, and pharmaceuticals to relieve and soothe pain and / or itching, usually associated with such skin irritations.

Patent Application WO 99/47141 describes compositions for treating mild skin irritations, containing a safe and effective amount of natural or synthetic vitamin B3 compounds as an irritant. The compositions contain, as essential components, a component of vitamin B3 and a dermatologically acceptable carrier. Compositions may contain optional components, but the disclosed compositions do not contain an absorbent agent. The compositions have a pH of from about 4 to about 7.

Patent application WO 99/63982 describes a method for treating diaper dermatitis in humans, which comprises the steps of:

(A) providing a therapeutic composition for the healing of wounds of diaper dermatitis, comprising:

(a) a therapeutically effective amount of a mono-adenosine diphosphate ribosyl transferase inhibitor for inhibiting adenosine diphosphate ribosylation of vascular endothelial growth factor;

(b) a buffering agent for maintaining the pH of dermatitis in the range of from about 5 to about 8; and

(c) an anti-inflammatory agent; and

(B) the interaction of the composition, healing wounds of diaper dermatitis, with diaper dermatitis in humans.

Despite such discoveries in the field of skin care, there remains a need for additional compositions providing improved symptomatic relief of mild skin irritations.

Regular use of an acidic drug containing nicotinamide as a urease inhibitor could prevent an increase in pH and protect the skin while maintaining its physiological pH of about 5.5.

Thus, it is an object of the present invention to provide acidic and buffered topical skin preparations for alleviating the symptoms of mild skin rash, redness, itching, dryness, rashes and cracks in mammals, especially in humans.

The invention relates to acidic and buffered compositions containing:

a) from 0.1% to 4% by weight of the nicotinamide composition;

b) from 5% to 20% by weight of an absorbent agent composition selected from the group consisting of titanium dioxide, titanium dioxide treated with a silicone derivative or fatty acids, zinc oxide treated with a silicone derivative or fatty acids, and mixtures thereof.

As used herein, the term “acidic composition” means that said composition has a pH below 7.

It was determined that the buffer composition provides the ability to withstand the increase in pH induced by the addition of an alkaline agent. The composition may acquire buffering properties by adding buffering agents that include but are not limited to citrates (disodium citrate / trisodium citrate) or phosphates (potassium dihydrogen phosphate and disodium hydrogen phosphate). Preference is given to buffer compositions containing disodium citrate, trisodium citrate, potassium dihydrogen phosphate, disodium hydrogen phosphate, or mixtures thereof.

The buffer capacity can be measured using the volume of alkaline solution added to achieve a fixed pH.

According to the invention, the composition preferably has a pH in the range from 4 to 7, more preferably from 4.4 to 6.0, and even more preferably from 5.0 to 6.0.

Nicotinamide is a vitamin B ₃ compound having the following formula:

Salts of the vitamin B ₃ compound are also applicable here. Unlimited examples of the salts of the Vitamin B ₃ compound used herein include organic or inorganic salts, such as inorganic salts with anionic inorganic particles (e.g., chlorides, bromides, iodides, carbonates), and organic salts of carboxylic acids (including salts of mono-, di- and three -C ₁ -C ₁₈ carboxylic acids, for example acetates, salicylates, glycolates, lactates, maleates, citrates). These and other nicotinamide salts can be readily prepared by one of ordinary skill in the art.

The absorbent agents used herein are finely divided materials incorporated in high concentration into semi-solid preparations (pastes), imparting absorption properties to the preparations. The literature describes several methods for quantifying their absorption properties by measuring the amount of water absorbed either after incubation or through a permeable film (Juch; Rufi; Surber; in Dermatology 1994; 189: 373-377 and Rae in Brit. J. Dermat. 1947 ; 59, 338-39). According to the invention, absorbent agents include zinc oxide, titanium dioxide, starch, talc, kaolin, aluminum stearate, magnesium carbonate, or a mixture thereof, which are, but are not limited to, the most widely used absorbent agents. Preference is given to compositions containing talc, titanium dioxide, titanium dioxide treated with a silicone derivative or fatty acids, zinc oxide treated with a silicone derivative or fatty acids, or a mixture thereof.

According to the invention, when the absorbing agent is titanium dioxide treated with a silicone derivative or zinc oxide treated with a silicone derivative, the silicone derivative is preferably selected from the group consisting of methicone, dimethicone and cyclopentasiloxane. In the case where the absorbing agent is titanium dioxide treated with fatty acids or zinc oxide treated with fatty acids, the fatty acids are preferably selected from the group consisting of stearic acid, mistiric acid and mixtures thereof. In accordance with one embodiment of the invention, the absorbing agent is titanium dioxide. Titanium dioxide is mainly used in anatase crystalline form with an average primary crystal size in the range of 0.2 to 0.4 microns.

In accordance with one embodiment of the present invention, the composition comprises from 5% to 20% by weight of the composition of one of said absorbent agents, preferably from 5% to 15% by weight of the composition of one of said absorbent agents. If a mixture of absorbent agents is used, the total amount of absorbent agents in the composition is from 5% to 40%, preferably from 10% to 30%, more preferably from 15% to 25% by weight of the composition.

The composition preferably contains from 0.1% to 4%, preferably from 0.3% to 2.5% by weight of the nicotinamide composition.

The composition may also contain physiological skin lipids, which include, but are not limited to, ceramide, cholesterol, palmitic acid and linoleic acid; other vitamins, in particular specific vitamins that promote the healing process, which include, but are not limited to dexpanthenol and vitamin E; antipruritic agents that include, but are not limited to glycine; moisturizing agents that include, but are not limited to, glycerol, sorbitol, and xylitol. According to one advantageous embodiment of the invention, the composition comprises dexpanthenol and vitamin E.

In accordance with one embodiment of the present invention, the composition comprises dexpanthenol in an amount of from 3% to 10%, preferably from 4% to 8%, by weight of the composition.

The composition may also contain a vitamin C compound in combination with or instead of nicotinamide.

According to one advantageous embodiment of the invention, the composition does not contain ethanol or preservatives; the composition is free of preservatives and ethanol. The composition may contain a synthetic or natural emulsifier, which includes, but is not limited to, cetearyl glucoside, cocoyl glucoside, bis-PEG / PPG-16/16 PEG / PPG-16/16 dimethicone, tribechenin PEG-20 esters, glyceryl stearate, PEG-75 stearate , cetet-20, cetearet-12, cetearet-20, stearet-20, polyglyceryl-3-diisostearate, polyglyceryl-2-dihydroxystearate, PEG-30 dipolyhydroxystearate, cetyl PEG / PPG-10/1 dimethicone PP-bis / 14 dimethicone.

Other conventional skin care product additives may also be included in the composition of the present invention, which include, but are not limited to, viscosifiers and emulsion stabilizers such as xanthan gum, cetearyl alcohol, PVP, PEG-75, sodium alginate, carbomer, guar gum, emollients such as caprylic / capric acid triglycerides, squalane, dimethicone, waterproof and film forming agents, such as PVP eicosene copolymer, C20-22 alkyl phosphate / C20-22 alcohols, dyes such as hydroxy s iron.

The composition complies with EP standards for the effectiveness of antimicrobial conservation, which means that after applying from 10 ⁵ to 10 ⁶ microorganisms log reduction should be as follows:

2 days 7 days 14 days 28 days Criterion A bacteria 2 3 - Does not increase (OU) Criterion B bacteria - - 3 (WELL) Criteria A mushrooms - - 2 (WELL) Mushrooms of criterion B - - one (WELL) Table 1

The composition of the present invention also contains a dermatologically acceptable carrier. The term “dermatologically acceptable carrier” as used herein means that the carrier is suitable for topical application to the skin, has good aesthetic properties, is compatible with the active components of the present invention or any other components, and will not cause any adverse safety concerns or toxicity. A safe and effective amount of carrier is from about 40% to about 90%, preferably from about 45% to about 85%, more preferably from about 50% to about 80% of the weight of the composition.

The carrier may be in the form of a wide variety of forms. For example, emulsion carriers, including, but not limited to, oil-in-water emulsions (eg, emulsifier), water-in-oil, water-in-oil-in-water, and oil-in-water in silicone are suitable herein. Preferred cosmetically and / or pharmaceutically acceptable topical carriers include oil-in-water emulsions.

These emulsions can also be produced in the form of sprays, using either containers with a mechanical pump or aerosol containers under pressure using standard propellants. These carriers can also be issued in the form of a mousse. Other suitable topical carriers include anhydrous liquid solvents such as oils and silicones; water-based single-phase liquid solvents; and thickened versions of these anhydrous carriers and single-phase water-based carriers.

The compositions of the present invention are usually obtained using standard methods, such as methods known in the art for the preparation of topical compositions.

Such methods typically include mixing the ingredients in one or more steps to a relatively uniform state with or without heating, cooling, applying a vacuum, and the like. Unlimited examples of the form of the product can be a cream, paste, gel, emulsion, lotion, ointment, solution, liquid, mousse, foam, etc.

The composition is suitable for the treatment or prevention of mild skin rashes, redness, itching, dryness, rashes and cracks in mammals, especially humans.

The composition is preferably applied topically to the skin.

The invention also relates to a medicament containing the composition described above.

The drug is suitable for treating or preventing skin irritation in mammals.

The drug is suitable for the treatment or prevention of skin rashes, itching, rashes and cracks in mammals, especially in humans. The drug, in particular, is intended for the treatment and / or prevention of diaper dermatitis.

The drug is preferably applied topically to the skin. The drug may be in the form of a cream, paste, skin lotion, gel, or the like, intended to be left on the skin. The amount of drug used, the frequency of use and the frequency of use can vary widely depending on the level of desired reduction in irritation.

The invention also relates to the use of the above composition as an anti-urease agent, i.e. the composition described above can be used to inhibit urease activity.

The following examples further describe and demonstrate embodiments of the invention within the scope of the present invention.

Example 1: formulas containing Nicotinamide according to the invention.

Example 2: Buffer Capacity of the Compositions of the Invention

The buffer capacity can be quantified by the volume of alkaline solution added to achieve a fixed pH.

Protocol: Analysis performed by titrimetry

Dilute 10 g of cream to 100 ml with water

Titrate 50 ml of 0.1 M ammonia to pH 8

Lock volume

Results: the results are presented in table 8

5V 5F 5H 4F Glycine 2% 2% 2% 2% Disodium phosphate 0.5% 1,0% 0.7% - Potassium phosphate 1,0% 1,0% 1,0% - Disodium citrate - - - 1,315% Trisodium Citrate - - - 3.14% Lipacid C8G 0.5% one% 0.7% one% Lipacid UG 0% 0% 0% one% pH (at start) 5.3 5.1 5.3 5.3 Results: in ml 0.1 M ammonia to achieve a pH of 8 4.9 7.8 5,6 6.5 Table 8

Proposed conditions: more than 3.0 ml, preferably more than 4.5 ml of 0.1 M ammonia to achieve a pH of 8.

These results confirm that the compositions of the invention may be referred to as buffer compositions.

Example 3: Urease Inhibition

The purpose of this example is to test the inhibitory effect of certain molecules on urease activity. Suitable conditions have been determined (T °, time, concentration) under which urease produces measurable amounts of ammonia. Under the same conditions, increasing nicotinamide concentrations were added.

Method

Principle: Enzymatic activity was determined by incubating the sample with urease and then determining the released ammonia using the indophenol reaction along with parallel standardization with ammonia.

Analysis Method: Suitable urease and ammonia concentrations were determined using preliminary tests giving a linear signal (between 0 and 1.2 O.D. (optical density) at 630 nm) after a 30 'colorimetric reaction.

Serial dilutions of samples were prepared to obtain a reliable inhibition curve. A standard curve for ammonia was also obtained in parallel. Each test was performed twice. The well volume was 100 μl. All sample and urea solutions were adjusted to pH 5.5. We used 3 control values and a zero inhibition point:

- zero inhibition test: 25 μl of 4% wt./about. urea +50 μl urease 0.4 mg / ml +25 μl acetate buffer;

- sample controls: 25 μl of sample 25 mg / ml + 25 μl of urea + 50 μl of acetate buffer;

- urease control: 50 μl of urease 0.4 mg / ml + 50 μl of acetate buffer;

- standard control: 25 μl 4% wt./about. urea +75 μl acetate buffer;

The sample curves included 8 concentrations (2/5 dilution from 25 mg / ml to 0.01 mg / ml):

- test samples: 25 μl of the sample (for each concentration) +25 μl of 4% wt./about. urea +50 μl urease 0.4 mg / ml

Standard curves also included 8 concentrations (two-fold dilution from 100 mg / L to 0.8 mg / ml)

- standard tests: 50 μl standard (for each concentration) +25 μl 4% w / v. urea +25 μl acetate buffer.

The microplate was incubated for 15 ′ at room temperature after the addition of urease (enzymatic reaction) and then incubated 30 ′ after the addition of reagent A and reagent B (60 μl and 90 μl, respectively >> indophenol colorimetric reaction).

Then, the absorbance at 630 nm was determined.

Results:

Each result corresponds to the average of two repetitions. For samples, the control value is the sum of the urease control and the sample control. For standards, control value means control of the standard.

Holes ABSORPTION (630 nm) Nicotinamide control 0,038 urease control 0,049 Control Standard 0,061 urease (zero inhibition) 1,3755 Table 9

Nicotinamide

Holes Concentration Absorption (630 nm) Absorption-Control (630 nm) BUT 6.25 0,072 -0.015 AT 2.5 0.0835 -0.0035 FROM one 0.1065 0.0195 D 0.4 0.151 0,064 E 0.16 0.2595 0.1725 F 0,064 0.497 0.41 G 0,0256 0.7325 0.6455 N 0,01024 1,058 0.971 Urease 0 1,3755 1.2885 Table 10

Standard

Holes Concentration Absorption (630 nm) Absorption Control (630 nm) BUT* one hundred NA NA AT fifty 0.9535 0.8925 FROM 25 0.543 0.482 D 12.5 0,309 0.248 E 6.25 0.1865 0.1255 F 3,125 0.124 0,063 G 1,5625 0,093 0,032 N 0.78125 0,0775 0.0165 The control 0 0,061 0 * 100 mg / ml was not used due to the significant spread between duplicate absorption values (1.102-1.574) Table 11

Under test conditions, significant inhibition of urease activity is observed between 0.01 and 1 mg / ml; above this last concentration, complete inhibition of urease was obtained.

Example 4 Inhibition of Canavalia Urease Activity by Xiphoid Compositions of the Invention

The purpose of this example is to compare the inhibition of urease activity with a placebo cream and a cream containing 0.5%, 1%, 2% nicotinamide.

Optimum conditions will be investigated to achieve a significant inhibitory effect.

Product: Formulas 5B, 5C, 5E and Formula 5E 'were tested, which is the same as Formula 5E provided that it contains 47.5% w / w. water instead of 47% wt./mass. and 0% wt./mass. nicotinamide instead of 0.5% w / w

add buffer to full volume

Composition: Sample with 2%, 1%, 0.5%, 0% nicotinamide

- General Method: Urease Inhibition Assay

Each analysis is divided into three stages:

1) Sample preparation

2) Detection

3) Measurement of absorption at 630 nm

1. Sample preparation

The sample and placebo were diluted in buffer (sodium acetate buffer 0.33 M pH 5.5).

2. Detection: Analysis, urease

Each test tube contained

250 μl of urea 4%,

250 μl of urease 2.5 mg / l,

500 μl of a diluted sample or diluted placebo.

Each tube was incubated 15 'at room temperature with urease.

30 μl of 30% HCl and 400 μl of chloroform were added to each tube.

The tubes were centrifuged 15 'at 10,000 rpm.

The supernatant was removed.

100 μl of supernatant, 60 μl of Reagent A and 90 μl of Reagent B were added to each well and incubated for 1 h at room temperature.

3. Measurement of absorption at 630 nm

The absorption was measured at 630 nm.

The average urease control value was subtracted from each “activity tube” value.

Mean values and relative standard deviation were calculated for each series.

- Results and discussion

In this example, the inhibitory effect of serial cream dilutions (placebo, nicotinamide 0.5% and 2%) on urease activity was tested. The method described in Example 3 was applied. In the second stage, the inhibitory effect of a placebo cream or containing 0.5%, 1% and 2% nicotinamide was compared.

1. Search for cream dilution with optimal inhibitory effect

The two main results of cream dilution are a reduced matrix effect and a decrease in the concentration of nicotinamide. Such an inhibitory effect of nicotinamide was shown by comparing the results obtained for placebo and for the sample. The optimal dilution will be selected for its best balance between the inhibitory effects of placebo and the sample. Tested 200,400, 600 and 800-fold dilutions of the cream - nicotinamide 2%. 100, 200 and 300-fold dilutions are tested for cream - nicotinamide 0.5%. Duplicates were prepared for each dilution and tested in triplicate. Mean values and relative standard deviation were calculated for each series (8 results).

The results are shown in FIGS. 1 and 2. FIG. 1 describes, for a cream containing 2% nicotinamide, O.D values. at 630 nm after 60 ', respectively, for

1 - sample - breeding 800 ×

1 '- placebo - breeding 800 ×

2 - sample - breeding 600 ×

2 '- placebo - breeding 600 ×

3 - sample - breeding 400 ×

3 '- placebo - breeding 400 ×

4 - sample - breeding 200 ×

4 '- placebo - breeding 200 ×

Figure 2 describes for a cream containing 0.5% nicotinamide, O.D. at 630 nm after 60 ', respectively, for

1 - sample - breeding 300 ×

1 '- placebo - breeding 300 ×

2 - sample - breeding 200 ×

2 '- placebo - breeding 200 ×

3 - sample - breeding 100 ×

3 '- placebo - breeding 100 ×

Together, these results suggest that 200-fold dilution is the most effective analysis condition.

2. Inhibitory effects of diluted, placebo cream or diluted cream containing 0.5%, 1% and 2% nicotinamide

200-fold dilutions of each of the cream and placebo formulations were tested for their inhibitory effect on urease activity. Duplicates were prepared for each dilution and tested in triplicate. Mean values and relative standard deviation were calculated for each series (8 results).

The result is shown in FIG. 3, which describes the values of O.D. at 630 nm after 60 ', respectively, for

1 - placebo - breeding 200 ×

2 - cream with 0.5% nicotinamide - a dilution of 200 ×

3 - cream with 1% nicotinamide - dilution 200 ×

4 - cream with 2% nicotinamide - dilution 200 ×

Difference O.D. between a diluted placebo cream and a diluted cream containing 0.5% nicotinamide is more pronounced than O.D. differences between diluted samples containing 0.5% -1% and 2% nicotinamide. However, as it turned out, the inhibitory effect gradually increases with the concentration of nicotinamide.

Conclusion

Together, these results convincingly suggest that a cream containing 0.5%, 1%, 2% nicotinamide gradually inhibits urease activity.

Claims (13)

1. An acidic and buffered skin care composition comprising:
a) from 0.1 to 4% by weight of the nicotinamide composition; and
b) from 5 to 20% by weight of an absorbent agent composition selected from the group consisting of starch, talc, kaolin, aluminum stearate, magnesium carbonate, titanium dioxide, titanium dioxide or zinc oxide treated with methicone, dimethicone, cyclopentasiloxane, stearic or myristic acid, or a mixture thereof,
c) buffering agents selected from the group consisting of citrates, phosphates or mixtures thereof. 2. The composition according to claim 1, characterized in that the composition contains from 5 to 15% by weight of the composition of said absorbent agent. 3. The composition according to claim 1, characterized in that the absorbing agent is titanium dioxide. 4. The composition according to claim 1, characterized in that the composition contains from 0.3 to 2.5% by weight of the composition of nicotinamide. 5. The composition according to claim 1, characterized in that the composition has a pH value in the range from 4 to 7. 6. The composition according to claim 1, characterized in that the composition also contains physiological skin lipids, other vitamins, an antipruritic agent and / or moisturizing agents. 7. The composition according to claim 6, characterized in that as other vitamins it contains dexpanthenol and vitamin E. 8. The composition according to claim 1, characterized in that the composition is an oil-in-water emulsion. 9. The composition according to claim 1, characterized in that the composition is free of preservative and ethanol. 10. The composition according to any one of claims 1 to 9, characterized in that to achieve a pH of 8 more than 3 ml of an aqueous solution of 0.1 M ammonia is necessary for titration of 50 ml of the solution obtained by diluting 10 g of the composition in 100 ml of water. 11. The composition according to any one of claims 1 to 9 for use as a medicine for the treatment and / or prevention of diaper dermatitis. 12. The use of a composition according to any one of claims 1 to 10 as an anti-urine agent. 13. The use of a composition according to any one of claims 1 to 10 for the manufacture of a medicament for the treatment and / or prevention of diaper dermatitis.

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