GB2110084A

GB2110084A - Therapeutic use of diazolidinyl urea

Info

Publication number: GB2110084A
Application number: GB08135667A
Authority: GB
Inventors: A R Harrison; A M Morrison
Original assignee: Wigglesworth Ltd
Current assignee: Wigglesworth Ltd
Priority date: 1981-11-26
Filing date: 1981-11-26
Publication date: 1983-06-15

Abstract

Diazolidinyl urea has been found to be therapeutically effective in the treatment of humans and animals, especially in the treatment of diseases and malconditions of the skin and other membranes. Compositions may also contain methyl or propyl hydroxy benzoate, basic fushgin, 2,2-dimethyl-1,3- dioxalane 4-methanol, sodium sulphacetamide, lignocaine hydrochloride, cetyl pyridinium chloride and/ or prednisolone.

Description

SPECIFICATION Therapeutic use of diazolidinyl urea The present invention relates to the therapeutic use of diazolidinyl urea for the treatment of humans and animals.

Diazolidinyl urea is a common name for the compound N-(hydroxymethyl)-N-(1 3-dihydroxy- methyl-2,5-dioxo-4-imidazolidinyl)-N'-hydroxymethyl-urea, and having the formula

Diazolidinyl urea is an allantoin-formaldehyde condensation product and may be manufactured as described in U.S. Patent 3 248 285 (P.A. Berke; issued 26 April 1 966). It has been described for use as an antimicrobial preservative in various cosmetic formulations, especially in creams and lotions, such as shampoos, in a manner similar to that described for imidazolidinyl urea, inter alia, by P.A. Berke and W.E.Rosen in "Germall, a new family of antimicrobial preservatives for cosmetics", American Perfumer and Cosmetics 85(3), 55-59 (March 1970); by the same authors in "Germall 11 5-a safe and effective modern cosmetic preservative", Cosmetics and Toiletries 92(3), 88-89 (March 1977); by the same authors in "Imidazolidinyl urea activity against Pseudomonas", Journal of the Society of Cosmetic Chemists 29, 757-766 (December 1978); and in "Final report of the safety assessment for imidazolidinyl urea" (by the Cosmetic Ingredient Review Expert Panel of the Cosmetic, Toiletry and Fragrance Association, Inc., U.S.A.), Journal of Environmental Pathology and Toxicology 4(4), 133-146 (October 1980).

Imidazolidinyl urea has been used in a wide variety of cosmetic products and much work has been published regarding its antimicrobial properties in that respect, both alone and in conjunction with other preservatives. There had, however, been no suggestion that those properties could be useful beyond the field of cosmetic preservation, until our Patent Application No. 81.33259 described the therapeutic use of imidazolidinyl urea for both pharmaceutical and veterinary purposes.

Diazolidinyl urea has properties similar to those of imidazolidinyl urea and that compound may also be used for both pharmaceutical and veterinary purposes; that is to say, it may be used for the therapeutic treatment of the human or animal body.

Diazolidinyl urea may be used against a wide range of diseases and disorders of the human or animal body, especially in the treatment of diseases and other disorders of the skin and other membranes of the human or animal body.

The bactericidal and bacteriostatic properties of diazolidinyl urea may be used against a wide range of pathogens associated with diseases and other disorders in both humans and animals.

In particular, diazolidinyl urea may be used for the non-antibiotic chemotherapeutic treatment of both humans and animals for both prophylactic (i.e. preventive) and curative purposes. (The term "therapeutic treatment" and like terms as used herein includes both prophylactic treatment and curative treatment unless the context obviously requires otherwise.) Diazolidinyl urea has been found to be effective against all microorganisms previously found to be killed by imidazolidinyl urea. It has, for example, been found to be effective, at a concentration of 0.2%, against gram-negative bacteria, for example Pseudomonas aeruginosa (ATCC 9027) and Escherichia coli (ATCC 10536), and against P. cepacia at a concentration of 0.5% or at a concentration of 0.3% in combination with parabens.In fact, diazolidinyl urea is about 20% more effective against Pseudomonas, which is an important pathogen to be able to combat, than is imidazolidinyl urea. Moreover, diazolidinyl urea has also been found to be effective against yeasts and moulds. It has, for example, been found to be effective against A.

niger (ATCC 16404) at a concentration as low as 0.1 % and against C. albicans(ATCC 10231) at a concentration of 0.3 to 0.4%.

Diazolidinyl urea is particularly useful in situations where antibiotics (especially fi-lactam antibiotics, such as penicillins and cephalosporins) cannot, or cannot effectively, be used, and where the use of antibiotics would be undesirable. It can, for example, be used for the treatment of pathogens that have become resistant to certain antibiotics. Because of its low toxicity, it can also be used in higher concentration than those in which antibiotics can be used, and because of its low irritancy it can also be used in higher concentrations than those in which many other non-antibiotic chemotherapeutic substances can be used.

In the veterinary field, diazolidinyl urea may be used in the treatment of mastitis, primarily in cattle. It may also be used in the treatment of various enteric infections, for example neo-natal scour and gastro-enteritis in various animals including, for example, cattle, lambs, foals, pigs, poultry, fish, and exotic animals; in the treatment of uterine infections, such as acute endometritis, which can occur in many animals, especially horses; in the treatment of animal hooves, to counteract foul-in-the-foot and other types of foot rot; and also in the treatment of the ears and eyes of animals.

In the pharmaceutical field, diazolidinyl urea may be used in the treatment of malconditions of the skin including, especially, ammoniacal dermatitis (in the form of nappy rash and bed sores, for example), and also acne, ulcers, and other dermatological conditions. It may also be used in the chemotherapeutic treatment of burns, skin grafts and skin lacerations of the human body.

Furthermore, it may be used in the treatment of the ears and eyes of humans, and also in a mouthwash for, for example, pre-dental or post-dental treatment.

Diazolidinyl urea may be formulated for pharmaceutical or veterinary use, that is to say, for the therapeutic treatment of the human or animal body, in a variety of forms depending on the particular intended use.

Examples of types of formulation suitable for the treatment of animals include formulations for parenteral or external application to cattle udders, for example in the form of a gel or jelly, or in the form of a solution or other liquid; formulation for enteral application to animals, for example as a bolus (for use with larger animals, for example calves, sheep and other ruminants) or as a capsule or tablet (for use with smaller animals, for example cats and dogs); formulation as a uterine infusion; formulation for external application to animal hooves, for example as a spray, especially a water-based spray; formulation for external application to the ears or eyes of animals, for example as an ointment or as ear or eye drops; and formulation as an aqueous solution, for a variety of applications.

Examples of types of formulation suitable for the treatment of humans include various preparations for application to the skin of humans, for example creams, jellies, gels, ointments, sprays and the like; as well as preparations for external application to the ears or eyes of humans, for example ointments and ear and eye drops; formulation as a mouthwash; formulation as capsules, tablets and the like for enteral application; and formulation for use for pre-operative swabs.

Formulations of diazolidinyl urea for the therapeutic treatment of animals may contain the diazolidinyl urea in concentrations of anything up to 100%, depending on the intended use of the particular formulation. Advantageously concentrations of from 1 to 50% by weight, preferably from 1 to 20% by weight, based on the total weight of the formulation, are used.

Formulations for the therapeutic treatment of humans advantageously contain the diazolidinyl urea in concentrations of from 1 to 10% by weight, preferably from 1 to 5% by weight, especially from 1 to 3% by weight, based on the total weight of the formulation in each case.

The formulations of diazolidinyl urea accordirig to the invention may contain emulsifiers, dispersants, propellants, thickening agents, colouring agents, buffers, excipients, carriers, solvents, diluents, and other conventional auxiliaries. The choice of auxiliaries for any particular formulation will, of course, be affected by the type of formulation, whether the formulation is intended for internal or external application and whether it is intended for animal or human use.

In all cases, however, the auxiliaries used should, of course, be physiologically tolerable.

Formulations of diazolidinyl urea according to the invention may be prepared in a conventional manner known to those skilled in the art.

One important veterinary application of diazolidinyl urea is its use as an intramammary product, especially for the treatment of mastitis in cattle. The udder tissue of cattle provides a very good breeding ground for a wide variety of both gram negative and gram positive pathogens including, for example, Staphylococcus aureus, Streptococcus bovis, Str. aqalactia, Str. Disgalactia, Str. uberis, Escherichia coli, Corynebactrium pyogens, and Pseudomonas aeruginosa. The udder tissue is very sensitive and it is therefore important that any formulations or other preparations used for treating the udder should have a low irritancy.Intramammary treatment of cattle has hitherto generally been carried out using antibiotics, but their prolonged use can create problems of the pathogens developing resistance to the antibiotics used, and many of the pathogens mentioned above are now considered to be penicillin-resistant as a result of over-exposure to sub-lethal doses of various antibiotics. Moreover, the use of antibiotics on lactating cows can create public health problems, and for antibiotics to be fully effective clinical typing is necessary.

Intramammary products based on diazolidinyl urea may be used for the non-antibiotic chemotherapeutic treatment of mastitis without many of the disadvantages associated with the use of antibiotics. Diazolidinyl urea has a bactericidal action against many of the pathogens associated with mastitis, of both gram negative and gram positive types, and including penicillin-resistant strains. It could, therefore, be effective in overcoming a situation where a disease had become endemic.Diazolidinyl urea also has several other advantages rendering it very suitable for this purpose: it has a very low degree of irritancy in the udder; it has a very low toxicity, which means that it can be used in suckled cows without danger to the calves and also that there is no danger to human consumers of milk from treated cows; it is water-soluble and is therefore effective when used in a medium such as milk; and it is not inhibited by the presence of proteins such as are present in milk--on the contrary, there is a potentiating effect, which can be valuable.

Diazolidinyl urea intended for the treatment of lactating cows may suitable be formulated for parenteral application, the diazolidinyl urea being present in a concentration of from 1 to 50%, preferably from 1 to 5% especially about 2%, by weight, based on the total weight of the formulation. For the treatment of dry cows, the diazolidinyl urea may be formulated for external application, with an active substance concentration of from 1 to 50%, preferably from 5 to 20%, especially about 10%, by weight, based on the total weight of the formulation. It may also be formulated as an aqueous solution for use as an udder wash and for washing teat tips.

Another veterinary application of diazolidinyl urea is its use in the treatment of enteric infections, for example neo-natal scour and gastro-enteritis in calves, lambs, foals, and other animals. Pathogens associated with these conditions include Escherichia coli and Salmonella group, both of which inhabit the intestines and, under disease conditions, can cause severe damage or even death. These conditions have previously been treated with antibiotics, sulphonamide drugs, and chloramphenicol. The use of chloramphenicol for this purpose is, however, now banned in the United Kingdom, and the pathogens have developed strains that are resistant to antibiotics and even to trimethoprim/sulphonamide products.

The low irritancy and low toxicity of diazolidinyl urea mean that it can safely be given to animals in sufficiently large doses for bactericidal effectiveness in enteral use. Because it is water-soluble, it will diffuse through the contents of the gut quickly, thus improving its effectiveness. It has been found to be effective against both types of pathogens mentioned above, including penicillin-resistant strains, and, moreover, as mentioned previously, there is a potentiating effect in the presence of proteins, which usually constitute an important component in the diet of young animals.

Diazolidinyl urea intended for the treatment of enteric infections may be formulated as oral preparations, such as a bolus f r use with larger animals, and capsules or tablets for use with smaller animals. The bolus pre arations may contain the diazolidinyl urea in concentrations of from 1 to 50% by weight, based on the total weight of the bolus, and the capsules and tablets may contain the diazolidinyl urea in concentrations of up to 100% by weight, based on the total weight of the capsule contents or of the tablet. Capsules and tablets may, for example, be prepared in two sizes: a capsule contents or a tablet of up to 0.8 9 for use with small animals, such as cats and small dogs, and a capsule contents or a tablet of up to 2 g for use with slightly larger animals, such as large dogs.

A further veterinary application of diazolidinyl urea is the treatment of uterine infections, especially acute endometritis. This can occur in most animals, but can be an especial problem in horses. It is caused by the presence in the uterine of pathogens such as Streptococcus zoeipidemieus, haemolytic Escherichia coli, the Klebsiella group, and Staphyloccocus aureus all of which have been found to be vulnerable to diazolidinyl urea. Drugs intended for use as uterine infusions need to be water-soluble, of low irritancy, of low toxicity, and effective in the biological environment of the uterus; diazolidinyl urea meets all those desiderata. Moreover, because of its low toxicity and low irritancy, diazolidinyl ura can be incorporated in the uterine infusion in a relatively high concentration if that should be necessary.The high degree of efficacy and safety of diazolidinyl urea make it a valuable product for use in animals of high commercial value, such as horses.

A formulation in the form of a uterine infusion may contain the diazolidinyl urea in a concentration of from 1 to 10%, preferably from 2 to 5%, especially about 3% by weight, based on the total weight of the formulation. It will generally be prepared in buffered normal saline solution.

Diazolidinyl urea may also be used in the treatment of foul-in-the-foot, which can be a serious winter problem with both cattle and sheep. This disease is caused by Fusi form is necrophorus and Fusiform's nodosus; it can be especially prevalent in wet muddy conditions and it is easily transmitted. It has in the past been treated with chloramphenicol, but the use of that drug for this purpose is now banned in the United Kingdom. Again the low irritancy and low toxicity of diazolidinyl urea means that it can be used in high concentrations when necessary, and its low toxicity also means that there is little risk to humans in the vicinity even during long treatment sessions. Persistance of a drug is important in any type of treatment of hooves and diazolidinyl urea has that property, which is also aided by its film-forming property.

For use in the treatment of animal hooves, diazolidinyl urea may suitable be formulated for application as a spray. It may be used in a concentration of from 1 to 50%, preferably from 10 to 30%, especially about 20%, by weight, based on the total weight of the formulation.

An important pharmaceutical application of diazolidinyl urea is its use in the treatment of dermatological conditions. One dermatological condition where it may be particularly useful is ammoniacal dermatitis. This condition occurs, generally as a result of urinary incontinence, primarily in paediatric and geriatric patients, in the form of nappy rash or bed sores, for example. Urine on the skin is decomposed by bacteria of the Proteus group with the liberation of ammonia, thus resulting in the establishment of a local alkaline environment on the skin. This enables pathogens such as Pseudomonas, Escherichia coli, the Klebsiella group, and the Citrobactic group to thrive, with resulting inflammation of the skin.

Effective treatment of this condition can be difficult. It is necessary to use a substance that is effective against pathogens such as Pseudomonas, which can be difficult to combat, and that is effective in both alkaline and acid environments, because the local alkaline environment has to be changed to the natural acid mantle of the skin. It is also important that the substance used should have a low irritancy, in order that the skin should not be irritated further, and that it should have a low toxicity, because in the treatment of conditions of this nature the drug is spread over a large absorbtive area. Few materials have previously been found that satisfy all those conditions, and some of the substances currently used for treating ammoniacal dermatitis are not adequately effective against Pseudomas.Diazolidinyl urea is effective in acid conditions, and has low irritancy and low toxicity, and it may therefore be used against ammonical dermatitis.

Another dermatological condition against which diazolidinyl urea may be used is acne, which is a form of pustular dermatitis associated with pathogens of the Staphylococcus group, for example. S. aureus, S. albus, and S. epidermidis. Those pathogens have a particular ability to produce mutants and resistant strains, which make it difficult to treat this condition successfully by means of antibiotics. Diazolidinyl urea is effective against those pathogens and has the advantages mentioned above in relation to ammoniacal dermatitis resulting from its low irritancy and low toxicity. Those properties also mean that it may be used in concentrations adequate to counteract even acute chronic conditions of acne.

Diazolidinyl urea may also be used against the skin condition known as ichthyosis, which is very difficult to treat by means of known drugs.

For use in the treatment of dermatological conditions, diazolidinyl urea may be formulated as a cream or ointment advantageously containing the active substance in a concentration of up to 10%, preferably up to 3%, especially about 1% by weight, based on the total weight of the formulation.

Diazolidinyl urea may also be used in the therapeutic treatment of tissue damaged by burns (of first, second or minor degree), lacerations and the like in both humans and animals. Tissue that has been damaged in that manner is highly sensitive and any substance used to treat it must therefore have a very low irritancy even at high concentrations. The damaged tissue is liable to invasion by environmental pathogens and can readily absorb the toxins that they produce. One of the most persistent pathogens, and also one of the most difficult to combat, is Pseudomonas. That pathogen cannot easily be controlled by antibiotics but, on the other hand, most non-antibiotic chemotherapeutic agents are too irritant to use on damaged tissue.

Diazolidinyl urea is, however, very suitable for this purpose because of its effectiveness against Pseudomonas, combined with it low irritancy. Moreover, because it is water-soluble, it can be used in an aqueous medium which is compatible with tissue fluids.

For use in the therapeutic treatment of damaged skin, diazolidinyl urea may be formulated as a gel or jelly, as an ointment, or an an aqueous spray. In each case, the formulation may contain the diazolidinyl urea in a concentration of from 1 to 10%, preferably from 1 to 3%, especially about 2%, by weight, based on the total weight of the formulation. An aqueous spray is particularly suitable for the treatment of large areas of damaged tissue, especially that damaged by burns, including cases where skin grafting is to be carried out. A gel or jelly is more suitable for the treatment of smaller areas of damaged tissue, especially that damaged by burns; and an ointment is generally suitable for use where the skin has been lacerated.

Diazolidinyl urea may also be used for the treatment of ear and eye infections in both humans and animals. For this purpose, it may suitably be formulated as an ointment, advantageously containing the diazolidinyl urea in an amount of from 1 to 10% by weight, preferably from 1 to 3% by weight, especially about 2% by weight, based on the total weight of the formulation.

Alternatively, it may be formulated as drops.

Diazolidinyl urea may, furthermore, be formulated as a mouthwash for use before and/or after dental treatment. Such a mouthwash advantageously contains the diazolidinyl urea in a concentration of from 1 to 20% by weight, preferably from 5 to 15% by weight, especially about 10% by weight, based on the total weight of the formulation.

Further examples of formulations of diazolidinyl urea for human use include formulation as antimicrobial capsules for general systemic applications, formulation as a gel or jelly for mouth ulcers and vaginal infections, and formulation as a water-based spray for foot treatment.

Diazolidinyl urea may also be used in fish tanks and fish farms, especially when combined with a fungicide.

Diazolidinyl urea has a number of important advantages over substances previously used for the treatment of many of the infections and diseases mentioned. The combination of its low toxicity, low irritancy and wide range of antimicrobial activity is particularly important. Various non-antibiotic chemotherapeutic substances already known have a wide range of antimicrobial activity, but have the disadvantage of a high irritancy and therefore cannot be used in certain applications and in relatively high concentrations and/or have a relatively high toxicity, also preventing them from being used in relatively high concentrations.On the other hand, antibiotic substances have a low irritancy, but their action tends to be fairly specific and many pathogens exist in strains that are resistant to anitbiotics, and antibiotic substances also have the disadvantage of having to be used in carefully controlled doses.

Diazolidinyl urea thus combines the advantages of antibiotic substances with those of non antibiotic chemotherapeutic substances. It also has the advantage of being soluble in water, a high degree of safety in use, leaving little or no tissue residue, and having few or no side effects.

In many applications, diazolidinyl urea is advantageously used in conjunction with a paraben, such as methyl or propyl hydroxybenzoate or a like substance having a potentiating effect.

The following examples illustrate the manufacture of formulations for various applications.

All percentages given are calculated by weight and are based on the total weight of the formulation, unless otherwise stated.

Example 1Formulation for intramammary use on a lactating cow diazolidinyl urea 2.00% glycerine 25.00% methyl hydroxybenzoate 0.05% propyl hydroxybenzoate 0.05% sodium carboxymethycellulose 4.50% water to 100.00% The methyl hydroxybenzoate and the propyl hydroxybonzoate are mixed with cold water and heated until dissolution occurs, and the solution is cooled and filtered. The diazolidinyl urea is dissolved in cold water and the solution is filtered. The two solutions are then mixed, together with further water and stirred thoroughly. The pH is adjusted to about 6.3 using normal sodium hydroxide solution or 10% hydrochloric acid. The glycerine and sodium carboxymethylcellulose are mixed and stirred to form the paste. The solution is then added to the paste, made up to final volume with water, and stirred thoroughly.

A sample is then autoclaved at about 1 5 Ib/in2 (about 1 bar) for about 40 minutes and then its viscosity is checked. If the viscosity is not within the range of from 8000 to 1 5000 cP.s, an additional portion of sodium carboxymethylcellulose is added to a second sample, which is then autoclaved as before, after which its viscosity is checked as before. When an autoclaved sample of the correct viscosity has been obtained, any necessary adjustments are made to the remaining bulk, and that is then autoclaved for 40 minutes.

The autoclaved product may then be filled into plastic syringes with, for example, a 10 9 fill.

Example 2-Formulation for intramammary use on a dry cow diazolidinyl urea 8.0% aluminium stearate 65.0% liquid paraffin 20.0% Tween 80 5.0% methylhydroxybenzoate 1.0% propyl hydroxybenzoate 1.0% The aluminium stearate, liquid paraffin and Tween 80 are mixed and heated at 1 50 C for 1 hour and then allowed to cool to 35-40"C. The methyl hydroxybenzoate and propyl hydroxybenzoate are added to the resulting mixture, while being stirred, and the diazoiidinyl urea is then added with further stirring, which is then continued for about 1 5 minutes after all ingredients have been added. The mixture is then passed through a colloid mill, and finally mixed with a high-speed stirrer for about 30 minutes.

Example Bolus (for enteric infections in larger animals) diazolidinyl urea 10.0% microcrystalline cellulose 10.4% starch 19.5% magnesium stearate 0.5% colour 0.5% lactose to 100.0% Example capsules (for enteric infections in smaller animals) diazolidinyl urea 5.00% starch 94.65% stearic acid 0.35% The percentages given above are based on the capsule contents.

The diazolidinyl urea and the starch are blended in a drum blender and then compacted under a pressure of about 701b/in2 (about 4.75 bar) on a roller compactor operated at slow speed.

The resulting granules are passed through a 1 mm mesh sieve, blended with the stearic acid, and then filled into gelatine shells.

Example Uterine infusion diazolidinyl urea 3.00% methyl hydroxybenzoate 1.00% propyl hydroxybenzoate 1.00% dye 0.05% water 5.00% buffered normal saline to 100.00% The methyl hydroxybenzoate and propyl hydroxybenzoate are added to water heated to about 80"C, and the mixture is stirred until a clear solution is formed. The diazolidinyl urea is dissolved in cold water and the dye is added to the resulting solution. The two solutions are then mixed together, stirred, and made up to final volume with the buffered normal saline. The pH is adjusted to between 6.0 and 6.5 by adding normal sodium hydroxide solution or 10% hydrochloric acid as necessary.

Example Aqueous spray (for treatment of foot rot) diazolidinyl urea 20.0% polyvinyl pyrollidone 2.0% ethanol 10.0% water 10.0% basic fuchsin 1.0% 2, 2-dimethyl-1 , 3-dioxalane-4-methanol to 100.0% The ethanol and polyvinyl pyrollidone are mixed, with stirring, until a clear solution is formed.

The diazolidinyl urea is dissolved in cold water, the basic fuchsin is added to the resulting solution, stirring is continued for about 1 5 minutes, and the mixture is filtered through a sieve.

First the diazolidinyl urea solution and then the ethanol solution are added to the solvent, and the final solution is stirred for 1 5 minutes.

Example 7-Ointment (for ear and eye infections) diazolidinyl urea 2.0% methyl hydroxybenzoate 0.5% propyl hydroxybenzoate 0.5% sodium sulphacetamide 6.0% lignocaine hydrochloride 0.5% liquid paraffin 60.8% white soft paraffin 29.4% The liquid paraffin and white soft paraffin are heated at 1 50"C for 1 hour and then cooled to 35-40"C. The lignocaine hydrochloride, sodium sulphacetamide, methyl and propyl hydroxybenzoates, and diazolidinyl urea are then added, in turn, to the resulting mixture, with 10 minutes' stirring after each addition. The final mixture is passed through a colloidal mill and the stirred for 30 minutes.

Example SCream (for treatment of dermatological conditions) diazolidinyl urea 1.0% cetyl pyridinium chloride 1.0% cetostearyl alcohol 10.8% methyl hydroxybenzoate 0.5% propyl hydroxybenzoate 1 0.1 % liquid paraffin 10.1% glycerol 6.7% silicone fluid 200/50 10.3% water to 100.0% The water is boiled and then allowed to cool to 80"C, after which the methyl hydroxybenzoate, propyl hydroxybenzoate, cetyl pyridinium chloride, and diazolidinyl urea are added to the water, and stirred until a clear solution is formed.The cetostearyl alcohol and liquid paraffin are stirred together while being heated until a homogeneous solution has formed, after which it is allowed to cool to 70 to 75"C. The aqueous solution is then carefully added to the paraffin solution, with constant stirring and slow cooling. The glycerin and silicone fluid are added to the resulting emulsion and stirred until a homogeneous mixture has formed.

Example Jelly (for treatment of burns) diazolidinyl urea 2.0% glycerine 25.0% methyl hydroxybenzoate 0.5% propyl hydroxybenzoate 0.5% sodium carboxymethylcellulose 4.5% lignocaine hydrochloride 2.0% water to 100.0% The methyl hydroxybenzoate and propyl hydroxybenzoate are added, with stirring, to a portion of the water heated to boiling. When a clear solution has been formed, it is cooled and filtered.

The glycerine is stirred at high speed while the sodium carboxymethylcellulose is added thereto, and stirring is continued until a smooth paste has been formed. The diazolidinyl urea and lignocaine hydrochloride are stirred in cold water until they have dissolved and the resulting solution is filtered.

The two aqueous solutions are mixed together and most of the remaining water required is added thereto. The pH is checked and adjusted as necessary to about 6.3 by adding normal sodium hydroxide solution or 10% hydrochloric acid. The solution is then added to the glycerine paste and adjusted to volume with further water. It is then stirred, initially slowly and then at high speed, for about 20 minutes.

A sample is then autoclaved, the viscosity is checked and adjusted, and the bulk is autoclaved, as described in Example 1.

Example 1 > Aqueous spray (for treatment of burns and skin grafts) diazolidinyl urea 2.0% methyl hydroxybenzoate 0.5% propyl hydroxybenzoate 0.5% water 5.0% buffered normal saline to 100.0% A portion of the water is boiled and allowed to cool to 80"C, and the methyl hydroxybenzoate and propyl hydroxybenzoate are added thereto and stirred until dissolved. The diazolidinyl urea is dissolved in a second portion of the water. The two solutions are mixed and adjusted to volume. The pH is adjusted as necessary to between 6.0 and 6.5 by adding normal sodium hydroxide solution or 10% hydrochloric acid.

The solution is then filled into spray packs using, for example, Arctons as a propellant or, if the solution and the propellant are kept separate by means of a plastics membrane, using nitrogen or carbon dioxide, for example, as the propellant.

Example ? skin ointment (for treatment of lacerations in humans and animals) diazolidinyl urea 2.0% methyl hydroxybenzoate 0.5% propyl hydroxybenzoate 0.5% prednisolone 0.3% cod liver oil 10.0% chlorophyll 2.0% polyethylene glycol 4000 40.0% propylene glycol 45.0% neoroli oil up to 2.0% abietis oil up to 2.0% The prednisolone and half the polypropylene glycol are stirred together until the former had dissolved in the latter, and then the polyethylene glycol is added thereto, with stirring and gentle heating to a temperature not exceeding 55"C. The remainder of the polypropylene glycol is then added to the mixture, followed by the cod liver oil and then by the methyl hydroxybenzoate, propyl hydroxybenzoate and chlorophyll, with continuous stirring. The neoroli oil and abietis oil are then added, and the mixture is allowed to cool, with intermittent stirring until the bulk begins to thicken and set.

Example 12-Mouthwash diazolidinyl urea 10.0% methyl hydroxybenzoate 0.5% propyl hydroxybenzoate 0.5% sodium saccharin 0.04% flavouring 0.5% dye 0.01% sodium carboxymethylcellulose 2.7% water to 100.0% A portion of water is heated to boiling and allowed to cool slightly, and then the methyl hydroxybenzoate and propyl hydroxybenzoate are added thereto, with stirring until a clear solution has formed. The dye, flavouring and saccharin are dissolved or well dispersed in a further portion of water. The diazolidinyl urea is dissolved in a third portion of water. The sodium carboxymethylcellulose is slowly added to a fourth portion of water stirred at high speed, and stirring is continued for about 1 5 minutes, until a fairly viscous gel has formed. The benzoate solution is then added to the gel, with stirring, followed by addition of the dye solution and then the diazolidinyl solution. Water is added to final volume, and stirring is continued for about 20 minutes.

Claims

1. The use of diazolidinyl urea for pharmaceutical purposes.

2. The use of diazolidinyl urea for veterinary purposes.

3. The use of diazolidinyl urea for the therapeutic treatment of the human or animal body.

4. The use of diazolidinyl urea for the treatment of diseases and other disorders of the skin and other membranes of the human or animal body.

5. The use of diazolidinyl urea for the treatment of mastitis.

6. The use of diazolidinyl urea for the treatment of mastitis in cattle.

7. The use of diazolidinyl urea for the treatment of cattle udders.

8. The use of diazolidinyl urea for the treatment of enteric infections in animals.

9. The use of diazolidinyl urea for the treatment of the uterus of an animal.

10. The use of diazolidinyl urea for the treatment of animal hooves.

11. The use of diazolidinyl urea for the treatment of malconditions of the skin of humans or animals.

1 2. The use of diazolidinyl urea for the treatment of ears and eyes of humans and animals.

1 3. The use of diazolidinyl urea for the chemotherapeutic treatment of burns, skin grafts and skin lacerations of the human or animal body.

1 4. Diazolidinyl urea formulated for pharmaceutical or veterinary use.

1 5. Diazolidinyl urea formulated for the therapeutic treatment of the human or animal body.

16. Diazolidinyl urea formulated for parenteral or external application to cattle udders.

1 7. Diazolidinyl urea formulated for external application to animals.

1 8. Diazolidinyl urea formulated for uterine infusion in animals.

1 9. Diazolidinyl urea formulated for external application to animal hooves.

20. Diazolidinyl urea formulated for external application to the ears or eyes of humans or animals for therapeutic purposes.

21. Diazolidinyl urea formulated as a cream, jelly, gel, ointment, spray or other preparation for application to the skin of humans or animals for therapeutic purposes.

22. Diazolidinyl urea formulated as a mouthwash for human use.