AU664419B2 - Use of sulphated sugars - Google Patents

Description

AUSTRALIA

Patents Act 1990 BUKH MEDITEK A/S

ORIGINAL

COMPLETE SPECIFICATION STANDARD PATENT

D

Invention Title: r r o o "Use of Sulphated Sugars" The following statement is a full description of this invention including the best method of performing it known to us:- 2 USES OF SULPHATED SUGARS Field of Invention The present invention relates to the use of sulphated saccharides to combat or prevent ageing of skin, skin wrinkles or dandruff and the manufacture of a topical composition therefor.

Technical Background While it is difficult to give an adequate description of the inflammatory phonemena in terms of underlying cellular events in the injured tissue, there are certain features of the process that are generally agreed to be characteristic. These include fenestration of the micro-vasculature, leakage of the elements of blood into the interstitial spaces and migration of leukocytes into 15 the inflamed tissue. On a macroscopic level, this is usually accompanied by the familiar clinical signs of erythema, oedema, tenderness and pain. During this complex response, chemical mediators such as histamine, eserotonine, leukotrienes, prostaglandines, various 20 chemotactic factors, bradykinin, lymphokines, kinin and complement system, lysosomal enzymes and cyclic nucleotides are liberated locally. Phagocytic cells migrate into the area, and cellular lysosomal membranes may be ruptured, releasing lytic enzymes. All these 25 events contribute to the inflammatory response.

~Several drugs are employed to suppress the manifestations of inflammation, including the adrenocorticosteroids, the large group comprising the so-called non-steroid anti-inflammatory drugs or NS.IDs, and drugs such as immmunosuppressive agents, chloroquine, penicillamine and gold salts.

NSAIDs are chemically a heterogeneous group of drugs, mainly constituting aromatic substituted carbodylic acids. Pharmacologically, they have anti-inflammatory, antipyretic and analgetic effects, and they inhibit 3 prostaglandin synthesis and decrease thrombocyte aggregation. The mode of action of NSAIDs is not yet fully understood, although it is known that they inhibit one or more of the mediator substances of inflammation.

However, there is no good correlation between inhibition of prostaglandin synthesis and anti-inflammatory effect.

The main indication for NSAIDs is rheumatic diseases, particularly where inflammatory processes in supporting tissues give rise to pain and joint-stiffness.

Furthermore, the analgetic effects can be used as symptomatic pain relief in cases where the prostaglandin inhibitory effec' can be utilized, such as dysmennorrhoea, urolithiasis, etc. Some of the drugs, including indomethacin, having also been used topically on the skin 15 in the treatment of various dermatoses and as a topical :anti-inflammatory agent in the eye.

The use of NSAIDs gives rise to a broad spectrum of side effects. Severe and often fatal blood dyscasias are often seen, notably following the use of phenylbutazone, 20 and gastrointestinal side effects are commmon with phenylbutazone, salicylates and indomethacin. Allergic reactions are common and may in some cases be due to prostaglandin inhibition with a resulting secondary increase in leukotriene levels. Hepatotoxicity and 25 nephrotoxicity as well as side effects of the central nervous system are also common with these drugs.

Adrenocorticosteroids, and especially glucocorticoids, have potent anti-inflammatory effects when used in pharmacological doses. They specifically inhibit the early vascular phase of the inflammatory process by decreasing the vascular permeability and therefore granulocyte migration. Glucocorticoids also interfere with late inflammatory and reparative processes, in that they inhibit the proliferation of mesenchymal cells and the production of intercellular macromolecules, 4 including proteoglycanes and collagen. It has been shown experimentally that glucocorticoids inhibit, for example, macrophase function, production of humoral antibodies, cellular immunity, and possibly the release of lysosomal enzymes. The indications for systematic use of glucocorticoids are apart from substitution therapy very limited, because of side effects, and should be restricted to severe inflammatory rheumatic disease, severe cases of allergic diseases such as asthma bronchiale and status asthmaticus and cases of haematological, renal, and gastrointestinal immunological diseases. Topical use S" involves a much lower risk of side effects, and glucocorticoids are widely used for inhalation therapy in asthma, for topical application to the skin in nearly all 15 cases of dermatosis and for injection in joints, bursae, :'tendons, etc, as well as for topical anti-inflammatory treatment of the eye, ear and nose. The most important side effects following topical use are skin and mucosal atrophy and acne, as well as microbial superinfections.

20 In the eye, corneal ulceration, glaucoma and viral superinfections are feared and serious side effects, and :'steroids are in fact contraindicated in many cases.

Other anti-inflammatory drugs include penicillamine, chloroquine, gold salts and cytostatics. The main 25 indication for these drugs is severe rheumatoid arthritis. The drugs are all given systemically, and they all exert a number of severe side effects.

Thus there would seem to be a need for alternative drugs to be used both topically and systemically to suppress or modify inflammatory reactions.

Sulphated saccharides, primarily sucralfate, have previously been indicated for the treatment of gastric and duodenal ulcers (cf. US 3,432,489; EP 161816; EP 192640) and for the treatment of emesis and diarrhoea in dogs and cats (cf. EP 133880). In radio-labelled form, sucralfate 5 has also been used as a diagnostic agent for the imaging of gastrointestinal mucosa, since the substance binds selectively to ulcerated areas in the stomach and upper small intestine (cf. EP 107209).

The American Journal of Gastroenterology, 80(3), 1985, pp. 206-209; "Sulcralfate: New Aspects in Therapy of Ulcers and Lesions" and the Second International Sucralfate Symposium Together With The World Congress of Gastroenterology in Stockholm, suggest the use of sucralfate for a variety of non-ulcer applications, including the treatment of stomatitis, post-sclerotic ulcer, reflux oesophagitis and bile reflux oesophagitis as well as for counteracting the ulcerogenic effects of aspirin.

15 Summary of the Invention It has surprisingly been found that polysulphated saccharides exert very interesting effects when applied topically to the skin systemically.

Accordingly, in one aspect, the present invention 20 provides for the use of a sulphated mono- or disaccharide or a salt or complex thereof for combating or preventing ageing of skin, including treating or preventing skin wrinkles.

In a second aspect, the present invention provides 25 for the use of a sulphated mono- or disaccharide or a salt or complex thereof for combating or preventing dandruff.

The present invention yet further provides for the use of a mono- or disaccharide or a salt or complex thereof for the manufacture of a composition for topical application for combating or preventing ageing of skin, including treating and preventing skin wrinkles and/or for combating or preventing dandruff.

6 Detailed Disclosure of the Invention The sulphated saccharide used in accordance with the invention may be a monosaccharide, for instance xylose, fructose or glucose, or a disaccharide such as sucrose, lactose, maltose or cellobiose, for example.

In certain cases, it may be an advantage ot use the sulphated saccharide in combination with a non-sulphated polysaccharide, for instance hyaluronic acid.

Saccharide is preferably a polysulphated or persulphated saccharide, which means that two or more, possibly all, sulphur-containing moieties are present as .substituents on the carbohydrate moiety.

In some cases, the sulphated saccharide may be ;complexed with or form a salt with a metal, eg, an alkali S 15 or alkaline earth metal such as Na, K, Ca, Mg or Ba, or Al, Zn, Cu, Zr, Ti, Bi, Mn or Os, or with an organic base (eg, an amino acid). The currently preferred salts are potassium and sodium salts.

Preferably, the composition of the invention contains 20 a persulphated disaccharide, optionally sucrose octasulphate.

The substance may, for instance, be prepared as disclosed in EP230023.

Although there may be cases where the sulphated 25 saccharide may be administered as such, it will typically be compounded with one or more pharmaceutically acceptable carriers or excipients to present it in a form which is suitable for topical application. In other words, it will be in the form of a liquid, semi-solid or solid topical preparation such as a powder, paste, ointment, lotion, gel, cream, salve, emulsion, solution, suspension, spray, sponge, strip, plaster, pad or dressing.

For topical application, the preparation may be formulated in accordance with conventional pharmaceutical 7 practice with pharmaceutical excipients conventionally used for topical applications such as pectin, gelatin and derivatives thereof, polylactic acid or polyglycolic acid polymers or copolymers thereof, cellulose derivatives such as methyl cellulose, carboxymethyl cellulose or oxidised cellulose, guar gum, acacia gum, karaya gum, tragacanth gum, bentonite, agar, carbomer, bladderwrack, ceratonia, dextran and derivatives thereof, ghatti gum, hectorite, ispaghula husk, polyvinylpyrrolidone, silica and derivatives thereof, paraffin, water, vegetable and animal oils, polyethylene, polyethylene oxide, polyethylene glycol, polypropylene glycol, glycerol, ethanol, propanol, propylene glycol (glycols, alcohols), fixed oils, sodium, potassium, aluminium, magnesium or calcium salts (such as 15 the chloride, carbonate, bicarbonate, citrate, gluconate, lactate, acetate, gluceptate or tartrate).

The preparation of the invention may also contain other additives such as emulsifiers, stabilizing agents, preservatives, etc.

20 Plasters, sponges, strips, pads or other dressings may be prepared by impregnating a dressing material such as cotton wool or gauze or a polymeric substance with a solution or suspension of the sulphated saccharide followed by drying. Alternatively, a paste, lotion, cream S: 25 or gel containing the sulphated saccharide may be spread over the dressing material, conveniently immediately prior to use.

The pharmaceutical preparation of the invention generally comprises the sulphated saccharide in an amount of 0.001-99%, typically 0.01-75%, more typically 0.1-20%, especially 1-10% by weight of the total preparation. In particular, when the sulphated saccharide is sucrose octasulphate, a preferred concentration thereof in the preparation is often 0.5-50%, especially 0.5-25%, such as 1-10%. It is suitably applied 1-10 times a day, dependent 8 on the type and severity of the condition to be treated.

The concentration of the sulphated saccharide to be used in each particular case will of course depend upon the type of preparation and the intended use, but also on the solubility characteristics of the sulphated saccharide and, for sparingly soluble and substantially insoluble sulphated saccharides, on the particle size thereof; the smaller the particle size, the faster will be the distribution of even sparingly soluble or even substantially insoluble sulphated saccharides or complexes thereof. Insoluble or sparingly soluble salts or complexes of sulphated saccharides are preferably used in the form of a fine powder, for example having a particle size of 200pm or less, such as 100pm or less.

15 Examples of very small particle sizes which may be desirable for certain purposes are, eg. 50pm or less, such as 20pm or less, in certain cases 10pm or less, such as 5pm or less.

The preparation may contain other active agents than 20 the sulphated saccharide, such as antibacterial agents, antiviral agents, antiparasitic agents, sun protective agents, vitamins and vitamin derivatives or analogues, antineoplastic agents, antimycotic agents, antifibrinolytic agents, blood coagulation modifying 25 agents, antiseptic agents, analgesics, topical anesthetics or anti-inflammatory agents.

Example The effect of sucralfate ointment was tested on wrinkles around the eyes. The preparation comprised 5% by weight of sucralfate powder mixed in a fatty vehicle containing herbal extracts of chamomile and arnica Three females aged 38-45 have used the ointment twice daily, and a beneficial effect has been reported after 1-2 weeks of treatment.

Claims (15)

1. A method for combatting or preventing aging of skin, including treating or preventing skin wrinkles, the method comprising topically applying to the skin of an individual in need of such treatment, an effective amount of a composition comprising at least one compound selected from the group consisting of a sulphated mono- or disaccharide or a salt or complex thereof.

2. The method according to claim 1 wherein the saccharide is a monosaccharide selected from the group consisting of xylose, fructose and glucose.

3. The method according to claim 1 wherein the saccharide is a disaccharide selected from the group consisting of sucrose, lactose, maltose and cellobiose.

4. The method according to any one of claims 1-3 wherein the sulphated :mono- or disaccharide is combined with a non-sulphated polysaccharide, for instance hyaluronic acid.

5. The method according to any one of claims 1-4 20 wherein the mono- or disaccharide is a polysulphated mono- or disaccharide, in particular a persulphated mono- or disaccharide.

6. The method according to claim 5 wherein the polysulphated saccharide is sucrose octasulfate. 25

7. The method according to any one of claims 1-6 wherein the substance with which the sulphated mono- or disaccharide is complexed or with which it forms a salt is S":a metal, e.g. an alkali or alkaline earth metal Na, K, Ca, Mg or Ba) or Al, Zn, Cu, Zr, Ti, Bi, Mn or Os, or is an organic base an amino acid).

8. The method according to claim 6 wherein the polysulphated saccharide is the potassium or sodium salt of sucrose octasulphate.

9. The method according to any one of claims 1-8 wherein the composition comprising sucrose octasulfate further comprises one or more ingredients selected from the group consisting of sodium, potassium, aluminium, magnesium and calcium salts (such as the chloride, carbonate, bicarbonate, citrate, gluconate, lactate, acetate, gluceptate and tratrate).

10. The method according to claim 6 wherein the polysulphated saccharide is the aluminium complex of sucrose octasulphate, sucralfate.

11. A method according to any one of claims 1-10 wherein the sulphated mono- or disaccharide is in the form of ionized sulphated saccharide.

12. The method according to claim 6 wherein the sucrose octasulphate is topically applied to the skin in an aqueous suspension comprising 0.001-99% by weight ionised sucrose octasulphate.

13. The method according to claim 12 wherein the aqueous suspension comprises 0.01-75% by weight ionised sucrose octasulphate.

14. The method according to claim 12 wherein the aqueous suspension comprises 0.1-20% by weight ionised sucrose 20 octasulphate.

15. The method arcording to claim 12 wherein the aqueous Ssuspension comprises 1-10% by weight ionised sucrose octasulphate. DATED this 19th day of September 1995 BUKH MEDITEC A/S Patent Attorneys for the Applicant: F.B. RICE CO. ABSTRACT Use of a sulphated mono- or disaccharide or salt or complex thereof for combating or preventing ageing of skin, skin wrinkles, or dandruff, or for the manufacture of a composition for topical application for combating or preventing ageing of the skin, skin wrinkles, or dandruff. The sulphated saccharide, eg, sucrose octasulphate, may be in the form of a complex or a salt with an alkali or alkaline earth metal (eg, Na, K, Ca, Mg or Ba) or Al, Zn, Cu, Zr, Ti, Bi, Mn or Os, or an organic base (eg, an amino acid). The composition may be a powder, paste, ointment, lotion, gel, cream, salve, S. emulsion, solution, suspension, spray, sponge, strip, plaster, pad or dressing. The sulphated saccharide may be used in an amount of 0.001-99%. p e S S* *S