WO1994005293A1

WO1994005293A1 - Skin treatment compositions containing dimethylsulphone and allopurinol or oxypurinol

Info

Publication number: WO1994005293A1
Application number: PCT/GB1993/001877
Authority: WO
Inventors: Aws Shakir Mustafa Salim
Original assignee: Individual
Current assignee: Individual
Priority date: 1992-09-04
Filing date: 1993-09-03
Publication date: 1994-03-17
Anticipated expiration: 1995-03-04
Also published as: AU4974893A

Abstract

The present invention relates to synergistic compositions comprising methylsulphonylmethane and at least one of oxypurinol and allopurionol and their use in formulations and methods of treatment and prophylaxis of one or more of skin conditions, diseases and injuries.

Description

SKIN TREATMENT COMPOSITIONS CONTAINING DIMETHYLSULPHONE AND ALLOPURINOL OR OXYPURINOL

The present invention pertains to pharmaceutically synergistic compositions suitable for use in improving the condition of the skin, which compositions comprise allopurinol or oxypurinol together with methylsulphonylmethane.

Complex mechanisms interact at cellular level to initiate the vast spectrum of dermatological disorders which are encountered in routine clinical practice. An ideal therapeutic approach would, therefore, be one aimed at combating the forces directly involved in mediating the disease or injury processes in the skin, enhancing the repair of any injury or damage that has already occured, and sustaining the integrity of the tissues of the skin by increasing their resistance against recurrence of the original disease, disorder or injury after it had been successfully eliminated. These objectives are not adequately fulfilled by the large number of dermatological agents currently available on the market. Moreover, many of these agents have limitations pertaining to patient selection or application.

It is an object of this invention to minimise these limitations.

The present invention now provides a synergistic composition comprising allopurinol and/or oxypurinol with methylsulphonylmethane.

The composition of the invention has been found surprisingly and unexpectedly to improve the condition of the skin by protecting it against many disorders . such as non-mechanical injury and degenerative disorders; affords a very effective therapy for a wide range of diseases be they inflammatory, endocrinal, metabolic or traumatic; besides enhancing the regenerative power of the skin as for example in wound healing. Consequently, the compositions of this invention are equipped with the novelty of combating the disease process while enhancing the repair of any damage that has been inflicted and increasing the resistance against recurrence of the disease.

Laboratory and clinical studies have demonstrated some very unexpected therapeutic properties exhibited by methylsulphonylmethane. These have been largely in relation to ameliorating the severity of the degenerative and ageing processes which occur in the skin; providing therapy against a wide range of dermatological diseases be they inflammatory, metabolic, endocrinal or traumatic such as wounds and ulcers; protecting the skin against recurrence of such diseases and disorders by sustaining the physiochemical properties of its tissues thereby increasing the skin's resistance thereto. It has, however, been even more surprising to discover that these advantages are significantly enhanced and in a synergistic manner by the addition of allopurinol and/or oxypurinol. The synergistic effect means that the activity of the composition is larger than the sum of the separate individual activities of its ingredients. In addition, it has been observed that the composition of the present invention has the advantageous property of adhesion to the skin, thereby affording prolonged contact with the treatment area with 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 methyl groups 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 are to a greater or lesser extent responsible for the beneficial effects incurred by the compositions of the invention.

In accordance with the present invention application onto the skin improves its condition in a number of ways including:

a. ameliorating the severity of degenerative changes that have already occured;

b. protection against the progression of such changes;

c. increasing the resistance of the skin to damage by" sustaining its physio-chemical 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 the 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 the 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 the compositions of the invention.

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

In a further aspect, this invention introduces a topical formulation consisting of the above composition 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 ointments and creams 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 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.

The topical formulations of the invention contain at least 0.5% w/w of each of its ingredients, preferably from 1 to 30% w/w and most preferably from 1 to 10% w/w, e.g. 5% methyl sulphonylmethane and 1% allopurinol or oxypurinol. Where menthol is included, this is generally used in an amount of from 1 to 30% w/w and most preferably from 1 to 5% w/w.

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

For oral administration, the active 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 orally 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 invention can be added to fruit juices, mineral waters be they carbonated or not, and to all forms of soft drinks. 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 ingredients 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 recipient. Such formulations may conveniently be presented in unit-dose or multi-dose sealed containers.

For administration orally or parenterally, the 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 from 1 to 5% w/v, advantageously in unit multi-dose form. When presented in unit dose form each of these doses contains 500mg methyl sulphonylmethane and 50mg allopurinol or oxypurinol. The dosage may be given one or more times a day, preferably at intervals of from 2 to 8 hours, most preferably every 6 hours. Advantageously, the ingredients 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. 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 invention may also be included as a solution or powder in cigarette filters or small delivery compartments incorporated in the cigarette. These compartments may also contain .the compositions of the invention in granules which evaporate upon contact with the smoke thereby delivering their substances to be carried by the smoke.

For topical therapy, the formulation is applied onto the skin and/or mucosa from 1 to 3 times a day then 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 is to be effected. It is not necessary to wash away the previous application in order to apply a fresh one, this however may simply be carried out using warm water alone or with soap.

Further preferred features and advantages of this invention will appear from the following detailed examples given by way of illustration only.

Example 1 - Preparation of Creams for Treating Skin

A. methyl sulphonylmethane allopurinol cetomacrogol'A' B.P.

B. methyl sulphonylmethane oxypurinol cetomacrogol'A' B.P.

C. methyl sulphonylmethane allopurinol menthol crystals cetomacrogol'A' B.P.

D. methylsulphonylmethane oxypurinol menthol crystals cetomacrogol'A' B.P.

E. methylsulphonylmethane allopurinol menthol crystals vitamin A (retinol)

vitamin E (alpha tocopheryl acetate) lg cetomacrogol 'A' B.P. add to lOOg

F. methylsulphonylmethane 5g oxypurinol lg menthol crystals lg vitamin A (retinol) 100,000 units vitamin E (alpha tocopheryl acetate) lg cetomacrogol'A' B.P. add to lOOg

The formulae were prepared at a temperature of 25°C. Five grams of methyl sulphonylmethane are mixed with one gram of allopurinol or oxypurinol in a glass or stainless steel container then 94 grams of cetomacrogol 'A' (or 93 grams if menthol is to be used) are added and mixed for 10 minutes. After standing for 30 minutes, one gram of finely ground menthol crystals alone or with the above mentioned amounts of vitamins A and/or E can be added and mixed for 10 minutes. The product is then placed in a dark-coloured airtight glass container and stored at an optimal temperature of 26°c, and most preferably no higher, 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 Topical Cream Compositions

The creams described in Example 1 can be applied several times a day. 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. For protection against sun irritation, the daily application is limited to the period of exposure and is preferably twice a day, where one of the applications is used prior to the exposure to afford protection, and the other is used before retiring to bed and left overnight to induce therapy for any ultraviolet-induced damage to the skin. On the other hand, when protection is desired against milder forms of irritants, e.g. environmental, the formulation may be applied once daily onto the parts of the skin to be protected such as the face and limbs prior to the exposure. Application for therapeutic purposes is determined by the nature of the disease or 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 180 to 260 grams, the ability of allopurinol, oxypurinol and methylsulphonylmethane (MSM) to protect biological tissues in vivo, represented by the ability to protect against the ethanol-induced acute gastric mucosal injury, was examined. Solutions of allopurinol, oxypurinol and MSM were prepared using double distilled water (after the allopurinol and oxypurinol powders were first dissolved in a few drops of 0.1M NaOH) . All drugs were gavaged into the stomach under light ether anaesthesia by orogastric instillation using a 6FG tube. Animals were fasted for 24 hours then one ml of allopurinol, oxypurinol, MSM (alone or in composition) or double distilled water was instilled into the stomach. One hour later, gavage with 1ml of 40% ethanol or double distilled water, as described above, was carried out. Animals were killed two hours later by an overdose of ether, 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 means + the standard error of the mean, SEM, for each group) . The following observations were made: Experimental Group % Incidence of Injury animals showing area in injury mm² (mean + SEM)

distilled water + distilled water 0% distilled water + ethanol 100% 42.1 + 1.7

0.5% allopurinol + ethanol 80% 35.2 + 1.2

1% allopurinol + ethanol 70% 31.1 + 0.9

5% allopurinol + ethanol 60% 24.3 + 0.7

10% allopurinol + ethanol 60% 23.8 + 0.5

20% allopurinol + ethanol 60% 22.9 + 0.6

0.5% oxypurinol + ethanol 80% 34.3 + 1.1

1% oxypurinol + ethanol 70% 30.1 + 1.3

5% oxypurinol + ethanol 70% 25.4 + 0.9

10% oxypurinol + ethanol 60% 24.8 + 0.6

20% oxypurinol + ethanol 60% 23.8 + 0.3

0.5% MSM + ethanol 80% 30.1 + 1.8 1% MSM + ethanol 70% 25.3 + 1.2 5% MSM + ethanol 60% 19.1 + 1.3 10% MSM + ethanol 50% 18.3 + 0.9 20% MSM + ethanol 50% 17.4 + 0.7

0.5% MSM + 0.5% allopurinol + ethanol 50% 14.1 + 1.6

1% MSM + 1% allopurinol + ethanol 20% 4.2 + 0.3

5% MSM + 5% allopurinol + ethanol 0%

10% MSM + 10% allopurinol + ethanol 0%

20% MSM + 20% allopurinol + ethanol 0% Experimental Group % Incidence of Injury animals showing area in injury m² (mean + SEM)

0.5% MSM + 0.5% oxypurinol + ethanol 50% 12.8 + 1.1

1% MSM + 1% oxypurinol + ethanol 25% 3.9 + 0.9

5% MSM + 5% oxypurinol + ethanol 0%

10% MSM + 10% oxypurinol + ethanol 0%

20% MSM + 20% oxypurinol + ethanol 0%

MSM: methylsulphonylmethane

Alcohol is a noxious substance which can produce direct and lasting damage to living tissues. Application of this agent in high concentrations to the gastric mucosa disrupts its barrier causing hydrogen ion back diffusion and coagulative necrosis. The alcohol-induced acute gastric mucosal injury is mediated by oxygen-derived free radicals. This injury offers a good experimental model for use in the study of the mechanisms of tissue injury in living bodies and the various means which can be utilized in the protection against such injuries. Dose dependant protection against the alcohol-induced acute gastric mucosal injury was afforded by each of allopurinol, oxypurinol and MSM. However, the administration of combinations of allopurinol or oxypurinol with MSM enhanced the protection in a synergistic manner. This protection was not associated with any influences on gastric acid secretion, thus, reflecting cytoprotection.

•

Consequently, each of allopurinol, oxypurinol and MSM affords cytoprotective activities against tissue injury but combinations of MSM and oxypurinol or allopurinol provide synergistically enhanced levels of activity. The mechanism of this action is believed to be scavenging the oxygen derived free radicals which mediate tissue injury.

B. Influences on the healing rate of the alcohol-induced acute gastric mucosal injury by allopurinol, oxypurinol and MSM were then studied. Groups of twenty Sprague-Dawley rats of either sex allocated at random and weighing 240 to 290 grams were fasted for 24 hours, then 1ml 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 1ml of double distilled water or the solutions of allopurinol, oxypurinol and MSM, 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 % of animals showing injury (n=20) after the after the second dose third dose

distilled water + distilled water 0% 0%

80% 80% 70% 60% 60% 60%

80% 80% 60% 60% 60%

60% 50% 50% 50% 50%

20%

10%

0%

0% Experimental Group % of animals showing injury (n=20) after the after the second dose third dose

ethanol + 0.5% oxypurinol +

0.5% MSM 60% 30% ethanol + 1% oxypurinol +

1% MSM 30% 10% ethanol + 5% oxypurinol +

5% MSM 10% 0% ethanol + 10% oxypurinol

+ 10% MSM ^ 0% 0% ethanol + 20% oxypurinol

+ 20% MSM 0% 0%

MSM: methylsulphonylmethane

Alcohol-induced acute gastric mucosal injury has been utilized to study the influence of allopurinol, oxypurinol and MSM on the healing rate of biological tissues in vivo. Administration of these agents stimulated the healing of the alcohol-induced injury and interacted to provide synergism without affecting the state of gastric acid secretion. Consequently, it appears that the advantageous action of stimulating the healing of tissue injury was achieved by mechanisms operating at cellular levels such as promotion of biosynthesis by sulphur and methyl group donation besides scavenging the oxygen-derived free radicals which impair healing by a direct deleterious effect upon tissues. The results achieved in the above mentioned experiments indicate that MSM, allopurinol and oxypurinol protect tissues in vivo, including the skin, against injury by a cytoprotective property and enhance the healing rate of these tissues and that administration of MSM with allopurinol or oxypurinol enhances these actions in a synergistic manner. In addition, it appears that the dosages listed in Example 1 are the optimal ones.

Example 4 - Clinical Trials

Prospective randomized double blind controlled trials were carried out in patients who were randomized to the control (cetomacrogol A) or 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 under 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.A and its ability to protect patients against skin burns, erythema, itching and scaling, which occur following a few hours' exposure to the sun, was examined. There were 22 controls (12 women and 10 men, age range 19 to 43 years, mean 27) and 24 treatment cases (15 women and 9 men, age range 20 to 46 years, mean, 26) , who were treated for 7 days (the period of direct exposure to sunlight) by the daily application, prior to the exposure, of a liberal amount of cream 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 also extended to the prevention of skin burns or irritation. Controls had no such protection at all.

B. The therapeutic efficacy of the formulation listed under Example l.A for the treatment of contact dermatitis was examined. Treatment was applied twice every day for 5 days. There were 16 controls (8 men and 8 women, age range 18 to 40 years, mean 26) and 14 treatment cases (8 men and 6 women, age range 19 to 46 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 (13%) 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 listed under Example l.E for four weeks (18 cases, 10 women and 8 men with.an age range of 53 to 69 years, mean 61) 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 (21 patients, 12 women and 9 men with an age range of 55 to 71 years, mean 64) . It is, thus, construed that the formulation used stimulates repair of skin lesions.

D. The therapeutic efficacy of the formulation listed under Example l.C 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 15 treatment cases (7 men and 8 women of an age range of 18 to 39 years, mean 25) and 14 controls (8 women and 6 men of an age range of 19 to 36 years, mean 28) . Within 24 hours of treatment all the symptoms of the burns (hyperaesthesia, itching, pain) were completely controlled in all of the 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 (21%) had symptomatic relief within 24 hours and 5 controls only (36%) 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 listed under Example l.F 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. Treatment was applied for 2 months. There were 32 cases in the active therapy group (age range 18 to 34 years, mean 26) and 34 cases in the control group (age range 18 to 36 years, mean 27) . At the end of the study, 5 controls (15%) and 30 active therapy cases (94%) 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 enviromental 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 be treated with the formulation listed under Example l.F or to the control group and were treated twice daily for six months, then with a single overnight application each day for another six months. There were 26 active treatment (age range 49 to 65 years, mean 54) and 25 control (age range 51 to 67 years, mean 55) 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 without any keratosis and the wrinkles were much less conspicuous and almost invisible in at least 21 cases (81%) . These gains were not realized in any member of the control group.

It was, thus, construed that the formula 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 faβcial wrinkles were randomized to receive the formulation listed under Example l.C 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=32, age range 41 to 52 years, mean 45) had after six months a 4% improvement, the active therapy group (n=34, age range 39 to 55 years, mean 47) achieved a 60% improvement at this period. At the end of the study (2 years) , the percentage improvement in the control group had extended to 8% but this improvement had reached 84% 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 fascial 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 with subcuticular approximation of the skin for upper midline laparotomy incisions, 27 patients were randomized to the active treatment group (14 men and 13 women of an age range of 19 to 59 years, mean 32) where the formulation listed under Example l.B was applied once every day with a conventional dressing onto the wound for 10 days, and another 25 patients (15 men and 10 women of an age range of 20 to 54 years, mean 29) 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, one patient (4%) developed wound dehiscence, one patient (4%) developed an incisional hernia, 2 patients (8%) developed wound hyperpigmentation, and another 2 patients (8%) developed keloids.

It is, consequently concluded that the formula 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 18 to 51 years, mean 33) were randomized to twice daily application of the formulation listed under Example l.F with physiotherapy for six months, and another 9 patients (6 men and 3 women, age range 20 to 48 years, mean 29) 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 2 members of the control group (22%) .

Further evidence is, therefore, provided that the formula used increases the resistance of the skin to mechanical trauma.

J. In patients who had sustained a third degree burn extending over 9 to 18% of the surface area of the body, treatment was applied onto the burnt area twice daily for 3 weeks. Twenty patients (11 men and 9 women, age range 20 to 39 years, mean 27) were randomized to receive the formulation listed^" under Example l.D and another 19 patients were randomized to the control group (9 men and 10 women, age range 21 to 35 years, mean 29) . 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 a surface area of 9 to 12% of the lower limbs, a liberal amount of the formulation listed under Example l.B or the control cream was applied over the grafted area before dressing it. Fifteen patients were randomized to the active therapy group (9 women and 6 men, age range 19 to 45 years, mean 31) and 16 patients were randomized to the control group (8 women and 8 men, age range 18 to 51 years, mean 34) . When the dressing was removed five days after grafting, ^ι completely successful take was observed in all members of the active therapy group. Two controls (13%) , 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 listed under Example l.E 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 (TM) and cotton gauze dressings. The compression bandages exerted an ankle pressure of around 40 mmHg falling to around 17 mmHg below the knee and provided by a layer of crepe bandages followed by a layer of Elset bandages then a layer of Coban cohesive bandages. Thirty-five patients (23 women and 12 men, age range 33 to 74 years, mean 58) were randomized to the active treatment group and 37 patients (20 women and 17 men, age range 30 to 70 years, mean 54) were randomized to the control group. At the end of the study, all the active treatment cases (100%) had complete healing of the dermatitis with a return to a healthy skin state. Only 25 patients (68%) 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 formula listed under Example l.F or to the control group. Thirty-four patients (20 women and 14 men, age range 31 to 74 years, mean 52) were randomized to the active treatment group and 32 patients (18 women and 14 men, age range 34 to 69 years, mean 53) 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 (TM) 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 30 patients (88%) and in 21 controls (66%) thus demonstrating the ability of the formula used to stimulate the healing of varicose ulceration.

N. Pruritis ani caused by anal warts may produce itching which is very difficult to treat until the warts have been removed. A study was carried out on patients with this pruritis who were on the waiting list for some form of treatment for the warts to examine the therapeutic efficacy of the formulation listed under Example l.F in controlling symptoms. Twelve patients (7 women and 5 men, age range 18 to 28 years, mean 21) were randomized to the active therapy group and 10 patients (6 women and 4 men, age range 18 to 31 years, mean 25) were randomized to the control.-group. Patients were instructed to maintain a high degree of self hygiene, to wash the perinium with soap and water after every motion, and to apply the cream onto the perianal region 3 times every day for 5 days. Complete symptomatic control was achieved within 24 hours by all members of the active therapy group, but in none of the control patients.

Example 5 - Toxicity Studies

Allopurinol or oxypurinol powder was dissolved in a few drops of 0.1M aqueous NaOH and then added to a solution of methyl sulphonylmethane (MSM) in double distilled water to prepare the following formulations:

1. 0.1% allopurinol + 1% MSM

2. 0.1% oxypurinol + 1% MSM

3. 1% allopurinol + 5% MSM

4. 1% oxypurinol + 5% MSM

5. 5% allopurinol + 10% MSM

6. 5% oxypurinol + 10% MSM Groups of ten Sprague-Dawley rats of either sex weighing 200 to 300 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 Syrian Golden Hamsters weighing 150 to 200 grams and in nude mice (40 to 50 grams of weight) except that 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 not 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 with ages ranging between 18 and 30 years, treatment with one of the following capsules (made by bringing into mixture the powders) four times a day was administered for ten days.

1. Allopurinol lOmg + MSM 50mg

2. Oxypurinol lOmg + MSM 50mg

3. Allopurinol 50mg + MSM lOO g

4. Oxypurinol 50mg + MSM lOOmg

5. Allopurinol lOOmg + MSM 500mg

6. Oxypurinol lOOmg + MSM 500mg Similarly, in other groups of ten healthy volunteers of ages ranging between 20 and 41 years, 5 grams of each of the formulations presented under Example 1 were applied onto the face, neck and shoulders once in the morning, once again in the morning and once in the evening, or once every 8 hours. Treatment was carried out for ten days. Each application was spread over 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 twice daily and standard haematological and biochemical tests (including liver and renal 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.

No toxicity or obvious adverse events were noted in any case, thus, demonstrating the safety of the formulations used. In addition, it was noted that all the doses were very well tolerated. The clinical safety of the therapeutic doses employed in this invention has, therefore, been established.

It will be appreciated that although the methylsulponylmethane and oxypurinol and/or allopurinol are advantageously used in amounts in the ratio 5:1, by weight, in the synergistic compositions of the invention, other ratios may also be used. Generally there is used a ratio of from 20:1 to 1:1, preferably from 10:1 to 3:1 most preferably about 5:1, by weight.

Claims

1. A synergistic composition, which composition comprises methylsulphonylmethane and at least one of oxypurinol and allopurinol.

2. A composition as claimed in claim 1 wherein is included a vasodilator.

3. A composition as claimed in claim 2 wherein said vasodilator comprises menthol.

4. A composition according to any one of claims 1 to 3 wherein said methylsulphonylmethane and oxypurinol and/or allopurinol are present in a ratio of from 1:1 to 20:1 by weight.

5. A composition according to claim 4 wherein said methylsulphonylmethane and oxypurinol and/or allopurinol are present in a ratio of approximately 5:1 by weight.

6. A composition comprising methylsulphonylmethane and at least one of oxypurinol and allopurinol for use in the preparation of a formulation for the treatment or prophylaxis of one or more of skin conditions, diseases and injuries.

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 the treatment or prophylaxisof one or more of skin conditions, diseases and injuries.

8. A topical formulation according to claim 7 which contains at least 0.5% w/w of methylsulphonylmethane and at least 0.1% of oxypurinol and/or allopurinol.

9. A formulation according to claim 8 which contains from 1 to 10% w/w of methylsulphonylmethane and from 0.2 to 2% oxypurinol and/or allopurinol.

10. An oral formulation according to claim 7 which is in unit dosage form, each unit .dose containing from 50 to 500 mg of methylsulphonylmethane and from 5 to 50 mg of oxypurinol and/or allopurinol.

11. An inhalation formulation according to claim 7 which includes a smoking product, formed and arranged for delivery of the methylsulphonylmethane and at least one of oxypurinol and allopurinol in the smoking product smoke, in use thereof.^~

12. A method of treatment or prophylaxis of one or more of skin conditions, diseases and injuries which comprises administering an effective dosage of a formulation according to claim 7.

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

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