WO1994005255A1

WO1994005255A1 - Skin moisturizer compositions containing dimethylsulphydryl group releasing agent

Info

Publication number: WO1994005255A1
Application number: PCT/GB1993/001872
Authority: WO
Inventors: Aws Shakir Mustafa Salim
Original assignee: Aws Shakir Mustafa Salim
Priority date: 1992-09-04
Filing date: 1993-09-03
Publication date: 1994-03-17
Also published as: GB9218715D0; AU4974393A; CN1108522A

Abstract

The present invention relates to synergistic compositions comprising methylsulphonylmethane and a physiologically acceptable, organic, in vivo sulphydryl group releasing agent and their use in formulations and methods of treatment for protecting and improving skin condition.

Description

SKIN MOISTURIZER COMPOSITIONS CONTAINING DIMETHYLSULPHYDRYL GROUP RELEASING AGENT

The present invention relates to the improvement of skin condition and more particularly to a synergistic biologically active moisturizer.

Exposure to sunlight, air pollutants and environmental irritants is a key factor in rendering the skin dry and in impairing its vitality. While the net result is loss of water and oils from the skin, the mechanism responsible for the development of these effects is much more complex. Although an extensive range of products is available on the cosmetic market which allegedly improve the skin condition, these generally comprise little more than a physical barrier that attempts to control water balance in the skin.

It is crucial to note that none of these known products combat the mediators of skin damage that represent the final common pathway through which factors such as sunlight, environmental irritants and air pollutants dry and irritate the skin. Current evidence indicates that these mediators are the oxygen-derived free radicals which are cytotoxic agents that produce tissue injury, retard the physio-chemical processes that maintain its vitality, and induce its premature ageing. The present invention aims at directly addressing these issues by providing a synergistic composition which protects against tissue injury and enhances its healing thereby, and when applied to the skin can improve its condition, and maintain its texture and vitality, thus, providing an ideal moisturizing effect.

The present invention provides a synergistic composition, which composition comprises methylsulphonylmethane and a physiologically acceptable, organic, in vivo sulphydryl group releasing agent such as cysteine. Other preferred sulphydryl group releasing agents include cysteamine, cystine, dimethylsulphoxide, methionine wherein the carboxyl group has been esterified, preferably by lower alkyl having 1 to 6 carbon atoms, e.g. methyl, S-methyl substituted, ternary sulphonium, derivatives of methionine such as methionine-S-methyl sulphonium bromide, iodide or chloride.

It will be noted that at least some of the abovementioned compounds have one or more optically active centres, in particular in the case of the a ino acids at the amino-and carboxyl-substituted carbon. For the avoidance of doubt, therefore, it is observed that the present invention extends to both individual isomers such as D-and L- isomers and enantiomers, and, in the case where two or more optically active centres are present, diastereoiso ers, as well as mixtures of isomers including racemic DL mixtures.

Application of the compositions of the present invention to the skin, has been found to improve its condition in a surprising manner in a number of ways including protection against irritation, maintenance of texture and vitality, and moisturization. It was also noted that the compositions have the advantageous property of adhesion to the skin thereby affording prolonged contact and enhanced therapeutic delivery. Moreover, the active ingredients of the composition interact in a synergistic manner in that the sum total action of the ingredients is less than that of the composition itself.

Advantageously, there is also included with the composition a vasodilator such as menthol in order to further increase the effectiveness of the composition in the skin.

Moreover, further enhanced therapeutic gains have also been noted by the incorporation of vitamins A and E.

In a further aspect, the present invention provides a composition of the invention in intimate admixture with a physiologically acceptable carrier for use in improving the condition of the skin.

In another aspect, the present invention provides a topical formulation comprising a composition of the invention in intimate admixture with a pharmaceutically acceptable vehicle. The vehicle should be 'acceptable' in terms of being generally non-deleterious to the skin of the subject being treated and compatible with the other ingredients of the formulation. It will of course be appreciated that certain individuals have significantly more sensitive skins than the average and that in these special cases alternative vehicles to those normally used may need to be utilized.

Suitable vehicles are well known in the art being noted for example in such standard works as the British Pharmacopoeia and the British National Formulary, and include ointment bases and cream bases as well as lotions, pastes, jellies, sprays, aerosols and bath oils. Ointments and creams may contain oleaginous absorption colloidal clays, thickening agents such as gum tragacanth or sodium alginate and other pharmaceutically acceptable accessory ingredients such as humectants, preservatives, buffers and antioxidants which have utility in such formulations.

Cream formulations are usually preferred as being most acceptable to the majority of users. A particularly convenient base is one utilizing cetomacrogol, comprising for example 30% w/v cetomacrogol emulsifying ointment (30% w/v cetomacrogol emulsifying wax, 20% w/v liquid paraffin wax, 50% w/v white soft paraffin) in freshly boiled and cooled purified water with for example 0.1% w/v chlorocresol or 0.08% w/v propyl hydroxybenzoate, 0.15% w/v methyl hydroxybenzoate and 1.5% w/v benzyl alcohol.

In general, the topical formulations of the invention contain at least 0.5% w/w of each of methylsulphonyl methane and cysteine, preferably from 1 to 20% w/w, and most preferably from 2 to 10% w/w.

In addition, the compositions of the invention (optionally with other active ingredients and/or a suitable vehicle) can be administered orally or parenterally, in particular by intramuscular injection.

For oral administration, the compositions of the invention and any accompanying material may be presented as a draught in water or in a syrup, in capsules, sachets, boluses or tablets, as an aqueous or oleaginous solution or suspension or in suspension in a syrup, such suspensions optionally including suspending agents or as an oil-in-water or water-in-oil emulsion. Where desirable or necessary, flavouring, sweetening, preserving, thickening or emulsifying agents may be included in the formulation. Tablets may contain the combinations of the invention and any accompanying material as a powder or granules optionally mixed with binders, lubricants, inert diluents or surface-active or dispersing agents.

For parenteral administration, the compositions of the invention and any accompanying material may be presented in sterile solutions or suspensions in aqueous or oleaginous vehicles, which may also contain preservatives and material for rendering the solution or suspension isotonic with the blood of the intended recipient. Such formulations >may conveniently be presented in unit-dose or multi-dose sealed containers.

For administration orally in liquid form or parenterally, the active ingredients of the invention are preferably presented in solution or suspension or emulsion at a concentration of'from 0.5 to 15% w/v more preferably 2 to 5% w/v in unit multidose form. When presented in unit dose form, each unit dose preferably contains from 50 to 500 mg of each of methylsulphonylmethane and cysteine. The dosage may be administered in one or more doses per day and preferably given at intervals of from 2 to 8 hours, most preferably every 6 hours.

Advantageously, the compositions of the invention are administered in a slow release or sustained release vehicle, various suitable vehicles of this type being well known in the art.

Where skin is being treated, the compositions of the invention will normally be applied topically at least once a day, preferably 2 or 3 times a day. The formulation is genrally spread over the area to be treated and gently rubbed in for a few minutes. It is advisable to leave the evening application overnight if repair of any skin damage incurred by exposure to environmental factors is to be realized. It is not necessary to wash away the previous application in order to apply a fresh one, however if this is desirable, it may be done using warm water alone. While not restricting the scope of the present invention, it is believed that the mechanism of action behind its beneficial effects is scavenging of the cytotoxic oxygen-derived free radicals which are implicated in tissue injury and delayed healing or repair; cytoproteσtion via sustaining the integrity of tissues thereby increasing their resistance to detrimental factors; and biosynthesis which effects an enhanced healing and repair of already injured tissues.

Further preferred features and advantages of the invention will be realised from the following examples given by way of illustration only.

Example 1 - Preparation of Cream for Treating Skin

A. methylsulphonylmethane cysteine hydrochloride cetomacrogol 'A' B.P.

B. methylsulphonylmethane cysteine hydrochloride menthol crystals cetomacrogol 'A' B.P.

C. methylsulphonylmethane 2g cysteine hydrochloride 2g vitamin A B.P. (retinol) 100,000 units vitamin E B.P. (alpha tocopheryl acetate) lg menthol crystals lg cetomacrogol 'A' B.P. add to lOOg

The formulation is prepared at a temperature of 25°C. Two grams of each of ethylsulphonyl methane and cysteine are thoroughly mixed together in a glass or stainless steel container and the appropriate amount of cetomacrogol 'A' is added and mixed for 10 minutes. After standing for 30 minutes, the vitamins are added as shown above then one gram of finely ground menthol is added and the whole composition is mixed for 10 minutes and thereafter allowed to stand for 30 minutes. The preparation is placed in an airtight dark coloured non-transparent glass container and stored at temperatures not exceeding 26°C. After preparation the formulation should not be used for at least 12 hours, and should not be left exposed to the air or direct sunlight for long periods.

Example 2 - Use of Topical Cream

The creams illustrated in Example 1 may be used from 1 to 3 times daily depending on whether the application is for protective or therapeutic reasons. To protect the skin against adverse environmental agents and to maintain its texture and prevent drying up, a once daily application prior to exposure is generally recommended. A liberal amount of the cream is spread over the skin, e.g. face, hands and arms, and gently rubbed in for a few minutes. For therapeutic purposes, treatment of irritation-induced skin damage - manifested by roughening, scaling, fissuring with various degrees of erythema and itching - a second application is indicated and preferably used in the evening and left overnight. While a fresh application may be used without having to wash away the previous one, this may be effected using warm water alone or with any convenient type of soap.

Treatment may be for a few days or weeks depending on each case, and in particular the individual's existing skin condition and requirements. Example 3 - Detailed Evaluation of the Composition

A. In groups of twenty Sprague-Dawley rats of either sex allocated at random and weighing 220 to 290g, the influence of methylsulphonylmethane and cysteine on acute damage of the gastric mucosa was studied. Solutions of cysteine or methylsulphonylmethane were prepared with double distilled water. All drugs were gavaged into the stomach under light ether anaesthesia by orogastric instillation using a 6 FG feeding tube. Animals were fasted for 24 hours then one ml of cysteine and/or methylsulphonylmethane or double distilled water was instilled into the stomach. One hour later, gavage with 1 ml of 40% ethanol or double distilled water was carried out. Animals were killed two hours later by ether overdose, their gastric acid secretion was collected then analysed for the H+ output by titration to pH7 with 0.1M NaOH, and their stomachs were pinned out and examined for the extent of alcohol-induced acute gastric mucosal injury (mm² surface area expressed as the mean + the standard error of the mean, SEM, for each group) . The following observations were made.

Experimental group %incidence Injury area (n = 20) of animals in mm² showing injury (means + SEM)

distilled water + distilled water 0%

distilled water + ethanol

0.5% MSM + ethanol 1% MSM + ethanol 5% MSM + ethanol 10% MSM + ethanol 20% MSM + ethanol

0.5% cysteine + ethanol 1% cysteine + ethanol 5% cysteine + ethanol 10% cysteine + ethanol 20% cysteine + ethanol

0.5% MSM + 0.5% cysteine + ethanol 1% MSM + 1% cysteine + ethanol 5% MSM + 5% cysteine + ethanol 10% MSM + 10% cysteine + ethanol 20% MSM + 20% cysteine + ethanol

MSM : methylsulphonylmethane

Alcohol disrupts the gastric mucosal barrier causing back diffusion of hydrogen ions and coagulative necrosis. The alcohol-induced acute gastric mucosal injury has been shown to be mediated by oxygen-derived free radicals. Dose dependent protection against this injury was afforded by each of cysteine and methylsulphonylmethane. Moreover, administration of these agents together exhibited a synergistic influence on the protection against tissue damage. No influence on the gastric acid secretion was associated with these actions.

It is accordingly construed that each of cysteine and methylsulphonylmethane exhibits cytoprotective activities against tissue injury, which obviously applies to skin tissues as well, and that they interact with each other synergistically in this respect. The mechanism of this action is believed to be scavenging the oxygen-derived free radicals which mediate tissue damage.

B. The ability of methylsulphonylmethane and/or cysteine to influence the healing rate of the alcohol-induced acute gastric mucosal injury was then examined. Groups of twenty Sprague-Dawley rats of either sex allocated at random and weighing 190 to 243 g were fasted for 24 hours then 1 ml of 40% ethanol or double distilled water was gavaged into the stomach by orogastric instillation under ether anaesthesia using a 6FG feeding tube. One hour, 24 hours and 48 hours later, animals were similarly gavaged with 1 ml of double distilled water or solutions of cysteine and/or methylsulphonylmethane prepared in double distilled water. Ten animals from each group were killed by ether overdose six hours after each of the second and third instillations, their gastric acid secretion collected and analysed for the H⁺ output as stated above, and their stomachs pinned out and examined to assess the integrity of the mucosa and to determine the presence or absence of injury. The following observations were made: Experimental group % Incidence of animals showing (n = 20) injury after the second after the dose third dose distilled water + distilled water

ethanol + distilled water 100? 80?

ethanol + 0.5% MSM ethanol + 1% MSM ethanol + 5% MSM ethanol + 10% MSM ethanol + 20% MSM

ethanol + 0.5% cysteine ethanol + 1% cysteine ethanol + 5% cysteine ethanol + 10% cysteine ethanol + 20% cysteine

ethanol + 0.5% MSM + 0.5% cysteine ethanol + 1% MSM + 1% cysteine ethanol + 5% MSM + 5% cysteine ethanol + 10% MSM + 10% cysteine ethanol + 20% MSM + 20% cysteine

MSM : methylsulphonylmethane

Administration of methylsulphonylmethane and/or cysteine did not influence gastric acid secretion in a significant manner. Thus, the actions of these agents is independent of and not mediated by the acid output. The results show that each of cysteine and methylsulphonylmethane stimulates the healing of acute mucosal damage and that they interact synergistically with each other in this context. Since no influences on the state of acid secretion were noted, it is construed that the enhancement of healing was achieved via mechanisms operating at cellular levels such as biosynthesis and sulphur donation in addition to scavenging the oxygen-derived free radicals which impair healing by a direct deleterious effect upon tissues. These conclusions apply to tissues be they of the stomach or skin.

On the basis of these two sets of experiments it is demonstrated that cysteine and methylsulphonylmethane protect tissues against injury (cytoprotection) and enhance the healing of the damage that has already occurred and that these beneficial actions are synergistically enhanced by their administration together in combination. Moreover, it appears that approximately 2% concentrations of each of these two agents is an optimum dose.

Example 4 - Clinical Trials

Prospective randomized controlled double blind trials were carried out in groups of twenty women. Controls received cetomacrogol 'A' . Randomization was effected by drawing sealed envelopes. All the preparations used were made as detailed under Example 1. The treatment code was only broken at the end of the trial.

A. Females suffering from rapid drying up of the face upon exposure in hot climates to the outdoors weather, who were already using one of the moisturizers on the market, were instructed to stop using their usual cream for 3 days then to commence the treatment given to them according to their randomization. This treatment was applied on the face once daily before exposure to the outdoors weather. The following results were obtained after one week's treatment expressed as the percentage of women who experienced a beneficial effect in terms of avoidance of skin dryness and preference to their original cream.

Treatment, n = 20 % completely % preferring this (age range, mean) satisfied and treatment to their having no skin original dryness moisturizer

cetomacrogol 'A' 5%

(21 - 32 years, 27) menthol lg cetomacrogol 'A' add to lOOg 10% 10%

(20 - 28 years, 23) vitamin A 100000 units vitamin E lg menthol lg cetomacrogol 'A' add to lOOg 20% 20?

(19 - 34 years, 25) cysteine 2g menthol lg cetomacrogol 'A' add to lOOg 30% 30?

(20 - 33 years, 26) methylsulphonylmethane 2g menthol lg cetomacrogol 'A' add to lOOg 30% 30?

(19 - 36 years, 27) methylsulphonylmethane 2g cysteine 2g menthol lg cetomacrogol 'A' add to lOOg 80% 80?

(21 - 34 years, 28) cysteine 2g methylsulphonylmethane 2g vitamin A 100000 units vitamin E lg menthol lg cetomacrogol 'A' add to 100 g 100% 100?

(19 - 36 years, 29)

The results demonstrate that each of cysteine and methylsulphonylmethane interact synergistically to protect the skin against dryness and to maintain its softness and moistness. This action has also been further potentiated in a synergistic manner by the addition of vitamins A and E. No skin allergies or adverse effects occurred in any case.

B. The protective effect of the formulation of Example l.C against irritation of the facial skin caused by exposure to the outdoors environment, was investigated in women who complained of this condition and manifested it by dryness, erythema and itching but who had not used any moisturizers for their complaints (treatment age range 20 to 41 years, mean 29; control age range 22 to 36 years, mean 25) . The once daily application of treatment for one week completely protected 18 women (90%) against the mentioned irritation and maintained a normal and moist facial skin texture, an effect only encountered in one of the women in the control group (5%) . No adverse skin effects or allergies were noted in any case.

C. The therapeutic effect of the fomulation described in Example l.C for the treatment of facial skin itching, erythema, roughening and scaling caused by environmental irritation was investigaged. Women complaining of this condition were treated for 10 days by an evening application which was kept overnight and another morning application just before exposure to the outdoors weather. The treatment age range was 27 to 43 years

(mean 30) and that of the control group was 29 to 41 years (mean 32) . Control of all the complaints mentioned above with a return to normal skin appearance that also felt soft and smooth was encountered in all (100%) the active therapy cases. Only two women (10%) in the control group had a similar outcome. No adverse events or any form of allergic reactions were produced in any member of the active therapy group. Moreover, the treatment was very well tolerated.

Example 5 - Acute Toxicity Studies

In groups of ten healthy male volunteers of ages ranging between 20 and 43 years, 5 grams of the fomula given in Example l.C was applied onto the face, neck and shoulders once in the morning, once in the morning and again in the evening, or once every eight hours. Treatment lasted for ten days and the applications were spread over the skin of the face, neck and shoulders, gently rubbed in for a few minutes then left for at least 3 hours before being washed away with warm water.

Physical examination was carried out once every day during the ten days of the study. Similarly, standard haematological and biochemical tests (including liver and urinary function tests, blood glucose, serum amylase and blood gases) with urine examination were made every day. An electrocardiogram with cardiac enzymes' level estimation were carried out every other day.

All the therapeutic regimens were comfortably tolerated without any apparent allergic or adverse reactions. In addition, no toxicity was incurred by the treatments used. It is, thus, concluded that the formulation of Example l.C (as well as the other formulations mentioned in the same Example) are safe for use in man within the recommended dose ranges. It will be appreciated that although the methylsulphonylmethane and sulphydryl group releasing agent are advantageously used in equal amounts, by weight, in the synergistic compositions of the invention, other ratios may also be used. Generally there is used a ratio of from 10:1 to 1:10, preferably from 5:1 to 1:5, most preferably about 1:1, by weight.

Claims

1. A synergistic composition, which composition comprises methylsulphonylmethane and a physiologically acceptable, organic, in vivo sulphydryl group releasing agent.

2. A composition as claimed in claim 1 wherein said sulphydryl group releasing agent is selected from cysteine, cysteamine, cystine, dimethylsulphoxide, methionine wherein the carboxyl group has been esterified, and S-methyl substituted, ternary sulphonium, derivatives of methionine.

3. A composition as claimed in claim 2 wherein said carboxyl group has been esterified by lower alkyl having from 1 to 6 carbon atoms.

4. A composition as claimed in claim 2 wherein said methionine derivative comprises methionine-S-methyl sulphonium bromide, iodide or chloride.

5. A composition according to any one of claims 1 to 4 wherein said methylsulponyl methane and sulphydryl group releasing agent are present in a ratio of from 1:5 to 5:1 by weight.

6. A composition comprising methylsulphonylmethane and a physiologically acceptable, organic, in vivo sulphydryl group releasing agent for use in the preparation of a formulation for the protection and moisturization of skin.

7. A formulation comprising a composition according to any one of claims 1 to 5 in intimate admixture with a physiologically acceptable carrier therefor, for use in improving the condition of the skin.

8. A topical formulation according to claim 7 which contains at least 0.5% w/w of each of methylsulphonyl methane and the sulphydryl group releasing agent.

9. A formulation according to claim 8 which contains from 1 to 20% w/w of each of methylsulphonyl methane and the sulphydryl group releasing agent.

10. An oral formulation according to claim 7 which is in unit dosage form, each unit dose containing from 50 to 500 mg of each of methylsulphonylmethane and the sulphydryl group releasing agent.

11. A method of protecting and improving skin condition which comprises administering an effective dosage of a formulation according to claim 7.

12. A method according to claim 11 wherein is applied to the skin a topical formulation according to claim 8.

13. A method according to claim 12 wherein said topical formulation is applied to the skin at least 2 times per day.