WO1994005272A1

WO1994005272A1 - Skin treatment compositions containing dimethylsulphone and dimethylsulphoxide

Info

Publication number: WO1994005272A1
Application number: PCT/GB1993/001876
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: AU4974793A

Abstract

The present invention relates to synergistic compositions comprising methylsulphonylmethane and dimethylsulphoxide substantially free of urea and their use in formulations and methods of treatment and prophylaxis of dermatological disorders and improving skin conditions.

Description

SKIN TREATMENT COMPOSITIONS CONTAINING DIMETHYLSULPHONE AND DIMETHYLSULPHOXIDE

The present invention relates to a pharmaceutical synergistic composition for the treatment of dermatological disorders and for improving the condition of the skin, which composition comprises methylsulphonylmethane with dimethylsulphoxide.

Due to its susceptibility to environmental pollutants, irritants and noxious agents and due to its large surface area, the skin is a common site for a wide variety of diseases and disorders be they degenerative, inflammatory, endocrinal, metabolic or neoplastic. While there is a large number of dermatological agents on the market, these do little to combat the mediators of skin injury or diseases, or to enhance the repair of skin in the aftermath of injury or diseases, or to sustain the integrity of skin against recurrence of such disorders or protect against their development. Moreover, many of the therapeutic modalities currently available have limitations pertaining to patient selection or application.

It is an object of the present invention to introduce a synergistic pharmaceutical composition which not only overcomes these limitations but also combats the forces directly involved in mediating disease or injury processes in the skin, enhances the repair of any injury or damage sustained and upholds the integrity of the skin by increasing its resistance against the recurrence of the diseases or disorders which had been treated.

The present invention provides a composition comprising methyl sulphonylmethane and dimethylsulphoxide. In a further aspect the present invention provides a composition comprising methyl sulphonylmethane and dimethylsulphoxide for use in the preparation of a medicament for the treatment of dermatological disorders and for improving the condition of the skin of a human.

While it has unexpectedly been found that methyl sulphonylmethane reverses the degenerative and ageing processes occurring in the skin, affords therapy against a wide variety of diseases be they inflammatory, metabolic, endocrinal or traumatic such as wounds and ulcers, and protects the skin against the recurrence of these diseases and disorders by sustaining its physiochemical properties thereby increasing its resistance; it was particularly suprising to discover that the addition of dimethylsulphoxide augments and enhances these therapeutic advantages in a synergistic manner. This action refers to the sum of the individual efficacy of the ingredients being less than that of their composition. It was also observed that the composition has the advantageous property of adhesion to the skin thereby affording prolonged contact with the treatment area and an enhanced therapeutic delivery. In vivo and in vitro experiments demonstrated that the compositions of the present invention exhibit the following actions:

1. scavenging oxygen-derived free radicals which are cytotoxic agents implicated in tissue damage and injury besides impairing the process of healing and repair.

2. cytoprotection which refers to sustaining the physio-chemical properties of biological tissues, thus increasing their resistance to noxious stimuli. 3. biosynthesis and donation of a methyl group and sulphur which effect enhanced repair and healing.

While not limiting the scope of this invention, it is believed that one or more of these actions is to a greater or lesser extent responsible for the beneficial effects afforded by the composition of the invention.

Application of compositions of the present invention onto the skin improves its condition in a number of ways including:

a. ameliorating the severity of degenerative changes that had already occurred.

b. protection against the progression of such changes.

c. increasing the resistance of the skin to damage or degeneration, by sustaining its physiochemical properties, thus affording protection against the adverse effects of environmental irritants, pollutants and noxious agents.

d. affording a potent sunscreening effect thereby protecting against ultraviolet sunrays which precipitate skin degeneration and premature ageing besides increasing susceptibility to malignant transformation.

e. enhancing the healing of inflammatory, endocrinal and metabolic disorders.

f. enhancing the healing of wounds, ulcers, fissures and sinuses in addition to increasing the take and healing of skin grafts. The improvement in skin condition can also include maintenance of its vitality, smoothness, firmness and texture.

Advantageously, there is also included a vasodilator substance such as menthol in order to further increase the effectiveness of the composition in the skin. Moreover, enhanced therapeutic gains have been noted with the incorporation of vitamins A and E in compositions of the present invention.

In addition, the present invention provides a pharmaceutical composition comprising methylsulphonylmethane with dimethylsulphoxide in intimate admixture with a physiologically acceptable carrier for use in improving the condition of the skin.

In a further aspect, this invention provides a topical formulation comprising methylsulphonylmethane with dimethylsulphoxide in intimate admixture with a pharmaceutically acceptable vehicle. This vehicle should not be deleterious to biological tissues or incompatible with any of the ingredients of the formulation. Since some individuals have more sensitive skin than others, alternative vehicles to those used normally may have to be tried.

Suitable vehicles are well known in the art and are presented in all its standard publications such as the British National Formulary and British Pharmacopoeia. They include ointment and cream bases, 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. In general cream formulations are preferred as being most acceptable to the majority of users. A particularly convenient base is one utilizing cetomacrogol, comprising for example 30% w/v cetomacrσgol 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.

The topical formulations of the invention contain at least 0.5% w/w of each of its ingredients, preferably from 1 to 20% w/w and most preferably from 1 to 10% w/w, e.g. 5% methyl sulphonylmethane and dimethylsulphoxide. Where menthol is included, this is generally used in an amount of from 1 to 20% w/w and most preferably from 1 to 5% w/w.

In addition, the invention being presented can be administered orally or parenterally in a suitable vehicle, in particular by intravenous injection.

For oral administration, the ingredients 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.

Included in the oral route, the compositions of the invention can be taken in an alcoholic drink be that a spirit, wine or beer. The non-alcoholic forms of these drinks may also serve as vehicles for the oral consumption of the invention. Moreover, the compositions of the present invention may be presented in fruit juices, mineral waters be they carbonated or not, and to all forms of soft drinks.

The compositions of the invention can be directly delivered to the lung via smoke and in this respect, they can be added as a powder or solution to tobacco leaves or to the tobacco of cigarettes, cigars and pipes. The compositions of the invention may also be included as a solution or powder in cigarette filters or small delivery compartments incorporated in the cigarette. This compartment may also contain the composition of the invention in granules which evaporate upon contact with the smoke thereby delivering their active ingredients to be carried by the smoke.

Where desirable or necessary flavouring, sweetening, preserving, thickening or emulsifying agents may be included in the formulation.

Tablets may contain the ingredients 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 this invention and any accompanying material may be presented in sterile solutions or suspensions in aqueous or oleaginous vehicles, which may also contain preservatives, antioxidants and material for rendering the solution or suspension isotonic with the recipient's blood. Such formulations may conveniently be presented in unit-dose or multi-dose sealed containers. For administration orally or parenterally, the compositions of this invention are preferably presented in solution, suspension, or emulsion at a concentration of from 0.5% to 20% 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 100 to 500mg of each of its active ingredients. This dosage may be given once or more daily, preferably at intervals of from 2 to 8 hours, most preferably every 6 hours. Advantageously, the active ingredients of the compositions of the invention are administered in a slow release or a sustained release vehicle, various suitable vehicles of this type being known in the art.

For topical therapy the composition is applied onto the skin from 1 to 3 times a day whereby it is spread over the whole area to be treated and massaged in for about 3 to 5 minutes. It is advisable to leave the evening application overnight if repair of any skin damage is to be realised. It is not necessary to wash away the previous application in order to apply a fresh one. However this may be simply done using warm water alone.

Further preferred features and advantages of the invention will be realized by way of the following examples which are being presented for illustration purposes only.

Example 1 - Preparation of Topical Creams for skin

Treatment

A. methylsulphonylmethane 5g dimethylsulphoxide 5g cetomacrogol 'A' add to lOOg

B. methylsulphonylmethane 5g dimethylsulphoxide 5g menthol crystals lg cetomacrogol 'A' add to lOOg

C. methylsulphonylmethane 5g dimethylsulphoxide 5g menthol crystals lg vitamin A (B.P.) - retinol 100,000 units vitamin E (B.P.) - alpha tocopheryl acetate lg cetomacrogol 'A' add to lOOg These formulations were prepared at a temperature of 25°C by mixing the ingredients in a glass or stainless steel container. One gram of finely ground menthol may then be added if indicated. Addition of cetomacrogol to lOOg is undertaken and the whole composition mixed for 10 minutes. The product is then left to stand for at least 15 minutes before being placed in opaque airtight glass containers and stored at an optimal temperature of 26°C, and most preferably no more, away from direct sunlight. After preparation, none of these formulations should be used for at least 24 hours, should not be left exposed to the air for long periods of time and should not be directly exposed to the sun. Example 2 - Use of the Topical Cream

The creams mentioned in Example 1 can be applied several times a day and the evening application may be left overnight and washed away the following morning using warm water with or without soap. Treatment may be for a few days or months depending on each case. Generally, for protective purposes the formula is applied once daily onto the parts of the skin to be protected, e.g. face and limbs, prior to exposure to environmental irritants or sunlight. For therapeutic purposes, application is governed by the nature of the disorder to be treated, e.g. dermatitis 5-10 days (unless caused by varicose veins when treatment is extended to 4 weeks) , wound healing 2-3 weeks, varicose ulceration 12-16 weeks. In these cases, the application is 2 to 3 times daily, most preferably at 8 hourly intervals. Maintenance therapy after successful treatment, or to sustain the condition of skin, may require a once daily application to a particular part of the skin for months, years or even indefinitely.

Example 3 - Detailed Evaluation of the Composition

A. In groups of twenty Sprague-Dawley rats of either sex allocated at random and weighing 200 to 270g, the influence of methylsulphonylmethane and dimethylsulphoxide on acute gastric mucosal injury was investigated. Solutions of methylsulphonylmethane (MSM) and/or dimethylsulphoxide (DMSO) were prepared using double distilled water. Solutions were administered into the stomach by gavage under light ether anaesthesia using a 6FG feeding tube. Animals were fasted for 24 hours then one ml of MSM and/or DMSO 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, their gastric acid secretion was collected then analysed for the H⁺ output by titration to pH 7.0 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 of Injury area animals showing mm' injury (mean + SEM)

distilled water + distilled water distilled water + ethanol 100? 41.6 + 0.9

0.5% MSM + ethanol 90% 32.1 + 1.1 1% MSM + ethanol 80% 24.2 + 0.8 5% MSM + ethanol 60% 17.4 + 0.6 10% MSM + ethanol 60% 15.7 + 0.5 20% MSM + ethanol 60% 15.2 + 0.4

0.5% DMSO + ethanol 80? 30.2 + 0.8 1% DMSO + ethanol 70? 25.7 + 1.1 5% DMSO + ethanol 50? 16.1 + 0.9 10% DMSO + ethanol 50? 15.5 + 0.4 20% DMSO + ethanol 50? 15.2 + 0.3

0.5% MSM + 0.5% DMSO + ethanol 50? 10.1 + 0.9 1% MSM + 1% DMSO + 20? 4.7 + 0.6 ethanol 5% MSM + 5% DMSO + ethanol 10% MSM + 10% DMSO + ethanol 0% 0 20% MSM + 20% DMSO + 0% 0 ethanol

(MSM = methylsulphonylmethane, DMSO = dimethylsulphoxide) A. Alcohol disrupts the gastric mucosal barrier causing hydrogen ion back diffusion and coagulative necrosis. The alcohol-induced acute gastric mucosal injury has been shown to be mediated by oxygen-derived free radials. Dose dependent protection against this injury was afforded by each of DMSO and MSM. Moreover, the combination of these two agents exhibited a synergistic influence in protection against tissue damage. No influence on the gastric acid secretion was associated with any of these actions.

It is, thus, construed that each of MSM and DMSO exhibit cytoprotection against tissue injury and interact with each other in this respect synergistically. The mechanism of this action is believed to be scavenging oxygen-derived free radicals which mediate tissue damage.

B. The ability of methylsulphonylmethane and/or dimethylsulphoxide to influence the healing rate of the alcohol-induced acute gastric mucosal injury was then investigated. Groups of 20 Sprague-Dawley rats of either sex allocated at random and weighing 200 to 290g were fasted for 24 hours then 1 ml of 40% ethanol or double distilled water was gavaged into the stomach by orogastric instillation under light 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 methylsulphonylmethane (MSM) and/or dimethylsulphoxide

(DMSO) 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:

Treatment % incidence of animals showing injury (n=20) after the after the second dose third dose

distilled water + distilled water ethanol + distilled water 80% ethanol + 0.5% MSM 60% ethanol + 1% MSM 60% ethanol + 5% MSM 50% ethanol + 10% MSM 50% ethanol + 20% MSM 50%

ethanol + 0.5% DMSO 70% ethanol + 1% DMSO 60% ethanol + 5% DMSO 60% ethanol + 10% DMSO 60% ethanol + 20% DMSO

60%

50? 20?

30? 10?

0%

0% 0?

0% 0% Administration of methylsulphonylmethane and/or dimethylsulphoxide did not influence gastric acid secretion in a significant manner, thus, the actions of these agents is independent of and not mediated via acid secretion. The results show that each of methylsulphonylmethane and dimethylsulphoxide stimulates the healing of acute mucosal damage and that they interact synergistically with each other towards this objective. The enhanced healing being independent of acid secretion suggests mechanisms operating at cellular levels such as biosynthesis, transmethylation, sulphur donation and scavenging the oxygen-derived free radicals which impair healing by a direct deleterious effect upon tissues.

On the basis of these two sets of experiments it is realized that methylsulphonylmethane and dimethylsulphoxide protect tissues, including the skin, against injury (cytoprotection) and enhance the healing of the damage they have incurred and that these beneficial actions are synergistically enhanced by their administration together. Moreover, it appears that the concentrations of each of these two agents as illustrated in Example 1 are generally optimal.

Example 4 - Clinical Trials

Prospective randomized double blind controlled trials were carried out in patients who were randomized to the control (cetomacrogol A) or to the active therapy groups by drawing sealed envelopes. The treatment code was only broken at the end of the trial period. All the formulations used were prepared as detailed in Example 1.

After exclusion of the patients who were not fully evaluable, the following observations were made:

A. The sunscreening effect of the formulation listed under Example l.B and its ability to protect patients against skin burns, erythema, itching and scaling following a few hours' exposure to the sun was examined. There were 15 controls (11 women and 4 men, age range 18 to 37 years, mean 28) and 17 treatment cases (10 women and 7 men, age range 18 to 35 years, mean 24) , who were treated for 7 days (the period of direct exposure to sunlight) by the daily application of their cream prior to the exposure, in a liberal amount over the area to be protected. Complete protection (100%) was afforded by active therapy against all the adverse effects produced by exposure to the sunlight. This protection extended to prevention of skin burns or irritation. Controls had no protection at all.

B. The therapeutic effect of the formulation listed under Example l.A in the treatment of contact dermatitis was examined. Treatment was applied twice every day for 5 days. There were 14 controls (9 men and 5 women, age range 20 to 36 years, mean 25) and 17 treatment cases (10 men and 7 women, age range 19 to 40 years, mean

28) . While complete healing of the dermatitis was noted at the end of the study in all the active treatment cases (100%) , only 2 controls (14%) demonstrated this favourable response.

C. Hyperkeratosis is a proliferative skin disorder which represents hyperplasia of the epidermis and may have a malignant potential. The condition affects the exposed parts of the skin of middle aged people, particularly the face and upper limbs. Treatment of these lesions by the twice daily application of the formulation described in Example l.C for four weeks (24 cases, 10 women and 14 men with an age range of 54 to 71 years, mean 64) caused complete shedding of the lesions and their replacement by normal skin in all cases. No response was noted in any of the control cases (25 patients, 12 women and 13 men with an age range of 55 to 69 years, mean 62) . It is, thus, construed that the formulation used stimulates repair of skin lesions.

D. The therapeutic efficacy of the formulation described in Example l.B in controlling the symptoms caused by skin burns resulting from exposure to the sun and in treating this condition was examined by its application onto the affected parts of skin every 8 hours for 10 days. There were 20 treatment cases (8 men and 12 women with an age range of 19 to 37 years, mean 25) and 18 controls (11 women and 7 men with an age range of 20 to 34 years, mean 24). Within 24 hours of treatment all the symptoms of the burns (hyperaesthesia, itching, pain) were completely controlled in all members of the active therapy group, but in none of the controls. By the 5th to the 7th day of active treatment all the burnt skin had been shed off and a return to normal skin was achieved by the 10th day of treatment in all cases. Only 3 controls (17%) had symptomatic relief within 24 hours and 4 controls only (31%) had shedding of their burnt skin after 5 to 7 days and the appearance of normal skin by the 10th day of treatment.

E. The efficacy of the formulation described in Example l.C. in maintaining the skin smoothness and avoiding its roughening and/or fissuring was examined in a group of women who were already using some form of beauty cream to this end and who had no previous history of any skin diseases. All the cases entered into the study abstained from using their original cream and were then randomized to the control or active therapy group and instructed to use their respective cream whether for the hands and/or face once daily before retiring to bed and to leave it overnight for 2 months. There were 24 cases in the active therapy group (age range 18 to 29 years, mean 24) and 26 cases in the control group (age range 19 to 31 years, mean 25) . At the end of the study, 5 controls (19%) and 21 active therapy cases (88%) stated that the cream they had used was superior to their original one in terms of acting as a beauty cream which keeps the skin smooth and avoids its roughening. Thus, the ability of the formulation used in maintaining the vitality of the skin and in increasing its resistance to environmental irritants and damage is established.

F. Women who presented with obvious dermatological signs of skin ageing mainly manifested on the face and hands (loss of firmness, roughening, thickening, keratosis, fissuring and wrinkles) , were randomized to the formulation described in Example l.A or to the control group and were treated twice daily for six months then a single overnight application for another six months. There were 30 active treatment (age range 48 to 63 years, mean 55) and 29 control (age range 49 to 67 years, mean 54) cases who were fully evaluable. After 3 months, all cases in the active therapy group were observed to have acquired smoother non-fissured skin, which had shed off all the keratotic lesions. By six months, these advantages had extended to making the skin firmer with much less conspicuous wrinkles. None of the cases in the control group realized any benefits in terms of ameliorating the severity of degenerative changes. After one year of treatment, all the active therapy cases had smooth, firm, non-fissured skin without¹ any keratosis and the wrinkles were much less conspicuous and almost invisible in at least 24 cases (80%) . These gains were not realized in any member of the control group.

It was, thus, construed that the formulation used is extremely effective in arresting the degenerative skin changes incurred by ageing and in ameliorating the severity of those changes which have already occurred.

G. Women with obvious facial wrinkles were randomized to receive the formulation described in Example l.B or to the control group and were treated twice daily for 6 months then once daily (overnight application) for 18 months. The wrinkles were mapped on special charts and any improvements in their appearance, in terms of making them less visible, were calculated as percentage improvement. While the control group (n=35, age range 44 to 58 years, mean 51) had after six months an 8% improvement, the active therapy group (n= 33, age range 41 to 61 years, mean 50) achieved a 68% improvement over this time period. At the end of the study (2 years) , the percentage improvement in the control group had extended to 14% but this improvement had reached 91% in the active therapy group. The significant improvement in the wrinkles' appearance was associated with a similar improvement in the smoothness and firmness of the facial skin. The latter is probably a major factor behind the wrinkles becoming less conspicuous and apparent. Moreover, at the end of the study, no new wrinkles were observed to have developed.

These advantages reflect the benefits of the formula used in combating the severity of skin degenerative changes and in impairing their progression.

H. Following mass closure and subcuticular approximation of the skin for upper midline laparotomy incisions, 45 patients were randomized to the active treatment group (20 men and 25 women with an age range of 18 to 63 years, mean 37) where the formulation described in Example l.B was applied once every day with a conventional dressing onto the wound for 10 days and another 3 patients (18 men and 25 women with an age range of 19 to 61 years, mean 32) were randomized to the control group and similarly treated. None of the active treatment cases were observed throughout one year and six months of follow-up to develop wound dehiscence, incisional herniation, wound pigmentation or hypertrophic scarring. In the control group, 2 patients (5%) developed wound dehiscence, one patient (2%) developed incisional herniation, 4 patients (9%) developed wound hyperpigmentation, and another 2 patients (5%) developed keloids.

It is, consequently, concluded that the formulation used not only stimulates wound healing but also sustains the integrity of the repair.

I. Ten quadriplegic patients (6 men and 4 women, age range 21 to 42 years, mean 29) were randomized to twice daily application of the formulation listed under Example l.C with physiotherapy for six months, and another 11 patients (7 men and 4 women, age range 19 to 39 years, mean 26) were randomized to the control group and similarly treated. No pressure ulceration (bed sores) occurred in any member of the active therapy group but developed in 3 members of the control group (27%) . Further evidence is, therefore, provided that the formulation used increases the resistance of the skin to mechanical trauma.

J. In patients who had sustained a third degree burn of a surface area of from 9 to 18%, treatment was applied onto the burnt area twice daily for 3 weeks. Twenty patients (12 men and 8 women, age range 18 to 39 years, mean 26) were randomized to receive the formulation listed under Example l.B and another 23 patients were randomized to the control group (11 men and 12 women, age range 18 to 40 years, mean 25) . Active treatment was significantly more effective than the control cream in reducing the degree of pain, discomfort, and itching produced by the burn and resulted in a cosmetically superior healing with much less pigmentation or discolouration. Therefore, the formulation used enhances the healing process of the skin.

K. Following excision and partial thickness skin grafting for deep burns extending over and area of 9 to 12% of the lower limbs, a liberal amount of the formulation described in Example l.A or the control cream were applied over the grafted area before dressing it up. Eighteen patients were randomized to the active therapy group (8 women and 10 men, age range 19 to 36 years, mean 24) and 19 patients were randomized to the control group (7 women and 12 men, age range 18 to 39 years, mean 26). When the dressing was removed five days after grafting, a completely successful take was observed in all members of the active therapy group. Three controls (16%) , however, showed failure of graft taking. This study reflects the ability of the active treatment employed to enhance skin grafting.

L. Patients who presented with dermatitis of the medial side of the lower third of the leg caused by incompetent perforating veins and manifested by itching, oozing, erythema and scaling, were randomized to receive the formulation described in Example l.C or to the control group and were treated for four weeks by elevation of the foot overnight and when sitting or resting, once daily application of the cream and below knee graduated compression bandages applied over the open-weave Terylene and cotton gauze dressings. The compression bandages exerted an ankle pressure of around 40mmHg falling to around 16 mmHg below the knee and comprised a layer of crepe bandages followed by a layer of Elset bandages and then a layer of Coban cohesive bandages. Forty-one patients (24 women and 17 men, age range 32 to 69 years, mean 53) were randomized to the active treatment group and 39 patients (21 women and 18 men, age range 34 to 70 years, mean 55) were randomized to the control group. At the end of the study, all the active treatment cases (100%) had complete healing of the dermatitis and a return to a healthy skin state. Only 28 patients (72%) in the control group reached this satisfactory outcome.

M. Patients presenting with varicose ulceration on the medial side of the lower part of the leg, less than 10cm² surface area, not previously treated and not infected or associated with gross leg oedema were randomized to treatment with the formulation described in Example l.B or to the control group. Thirty-seven patients (25 women and 12 men, age range 29 to 72 years, mean 58) were randomized to the active treatment group and 35 patients (21 women and 14 men, age range 33 to 71 years, mean 54) were randomized to the control group. Any devitalized skin surrounding the ulceration was removed by warm olive oil and the ulcer was then washed with physiological saline and any loose tissue removed. After application of the cream, the ulcer was dressed by open-weave Terylene and cotton gauze. The skin surrounding the ulcer was treated with propylene glycol monostearate then a below knee graduated compression bandage as described above was applied over the dressing. This procedure was repeated every day for 7 days then weekly until the ulceration had healed or until the end point of the study at 3 months. Patients were advised to sleep with the foot of the bed raised, to avoid long periods of standing without exercising the calf pump, to walk whenever possible and to elevate the leg when sitting. Active treatment produced complete healing of the ulceration in 33 patients (89%) and in 24 controls (69%) thereby reflecting actual stimulation of varicose ulcer healing by the formulation used.

Example 5 - Toxicity Studies

Solutions of methylsulphonylmethane (MSM) with dimethylsulphoxide (DMSO) were prepared in double distilled water to provide:

1. 1% MSM + 1% DMSO

2. 5% MSM + 5% DMSO

3. 10% MSM + 10% DMSO

4. 15% MSM + 15% DMSO

5. 20% MSM + 20% DMSO

Groups of ten Sprague-Dawley rats of either sex weighing 220 to 280 grams were fasted for 24 hours then given one ml of one of the above mentioned formulations by intraperitoneal injection into the left iliac fossa, intramuscular injection or orogastric instillation under light ether anaesthesia. Animals were observed for 24 hours then allowed access to food and drink and observed for another six days. They were then killed by ether overdose and subjected to a full necropsy. The same study was repeated in the Syrian Golden Hamster (weighing 140 to 190 grams) and in nude mice (40 to 50 grams of weight) . In the latter species the fast before and after drug administration was reduced to 12 hours and only 0.25 ml of each formulation was given.

There were no deaths among the groups and no discomfort or obvious distress, excitation, drowsiness, withdrawal, depression, vomiting or diarrhoea was encountered in any case. Necropsy showed no changes caused by the medication.

It is, thus, construed that over a wide dosage range, the formulations employed do no exhibit any adverse effects or noticeable acute toxicity making them safe to use within the elected therapeutic range.

In groups of ten healthy male volunteers of ages ranging between 19 to 36 years, 5 grams of each of the formulations described in Example 1 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 study. Similarly, standard haematological and biochemical tests (including liver and renal fuction tests, blood glucose, serum amylase and blood gases) with urine examination were made every day. An electrocardiogram with cardiac enzymes' level estimation were performed every other day.

All the therapeutic regimens were comfortably tolerated without any apparent allergic or adverse reactions. In addition, no toxicity was produced by the treatment used. It is, therefore, concluded that the formulations described in Example 1 are safe for use in man within the recommended dosage ranges.

It will be appreciated that although the methylsuphonylmethane and dimethylsulphoxide 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 ration 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 dimethylsulphoxide, and which composition is substantially free of urea.

2. A composition according to claim 1 wherein said methylsulphonylmethane and dimethylsulphoxide are present in a ratio of from 1:5 to 5:1 by weight.

3. A composition as claimed in claim 1 or claim 2 which includes a vasodilator.

4. A composition as claimed in any one of claims 1 to 3 which includes at least one of an anti-ischaemic anti-cholinergic and vagal nerve blocking agent.

5. A composition comprising methylsulphonylmethane and dimethylsulphoxide, which composition is substantially free of urea, for use in the preparation of a formaulation for the treatment or prophylaxis of dermatological disorders and improving skin condition.

6. A formulation comprising a composition according to any one of claims l to 4 in intimate admixture with a physiologically acceptable carrier therefor, for use in the treatment or prophylaxis of dermatological disorders and improving skin condition.

7. A liquid formulation according to claim 6 which contains at least 0.5% w/w of each of methylsulphonyl¬ methane and dimethylsulphoxide.

8. A formulation according to claim 7 which contains from 1 to 10% w/w of each of methylsulphonylmethane and dimethylsulphoxide.

9. An oral formulation according to claim 7 or claim 8 which is in unit dosage form, each unit dose containing from 200 to 1000 mg of each of methylsylphonylmethane and dimethylsulphoxide.

10. An inhalation formulation according to claim 6 which includes a smoking product, formed and arranged for delivery of the methylsulphonylmethane and dimethylsulphoxide in the smoking product smoke, in use thereof.

11. A topical formulation according to claim 6 which contains at least 0.5% of each of the methylsulphonylmethane and dimethylsulphoxide.

12. A method of treatment or prophylaxis of dermatological disorders and improving skin condition which comprises administering an effective dosage of a formulation according to claim 6.

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

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

15. A method of treatment or prophylaxis of a skin disorder selected from: varicose ulceration, contact dermatitis, hyperkeratosis, sunburn, wound healing and pressure ulceration, which method comprises administering an effective dosage of methylsulphonylmethane and dimethylsulphoxide.

16. A method according to claim 15 wherein said methylsulphonylmethane and dimethylsulphoxide are usedin a ratio of from 1:5 to 5:1 by weight.