DK174560B1 - Topical pharmaceutical compsns. - contg. sucralfate, for treating skin and mucosal disorders - Google Patents

Abstract

Pharmaceutical compsns, esp for topical application to skin or non-bladder, non-gastrointestinal, non-oral mucosa, comprise sucralfate (I) and a carrier or excipient. (I) is a sucrose octasulphate Al complex (see US3432489). The compsns pref contain 0.001-99 (esp 1-10) wt% (I), opt together with a non-sulphonated polysaccharide, e.g. hyaluronic acid. (I) has a particle size of up to 200 (e.g. 1-5) microns. The compsns are formulated as powders, pastes, ointments, lotions, gels, creams, salves, emulsions, suspensions, sprays, sponges, strips, plasters, pads, dressings or ostomy plates, and are applied 1-10 times a day.

Description

Λ-.

in DK 174560 B1

The present invention relates to the use of a sulfated mono- or disaccharide or a salt or complex thereof for the preparation of a composition for topical application for the prevention or treatment of dandruff.

Sulfated 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 diarrhea in dogs and cats (cf. EP 133880). In radiolabelled form, sucralfate has also been used as a diagnostic agent for visualizing gastrointestinal mucosa, with the substance selectively binding to ulcerated areas of the stomach and upper small intestine 10 (cf. EP 107209).

In The American Journal of Gastroenterology, 80 (3), 1985, page 206209; "Sucralfate: New Aspects in Therapy of Ulcers and Lesions" and in "Second International Sucralfate Symposium Together with the World Congress of Gastroenterology in Stockholm" proposes the use of sucralfate in a variety of non-ulcer areas, including treatment of stomatitis, post- sclerotic ulcer, reflux oesophagitis and biliary reflux oesophagitis as well as to counteract the ulcerogenic effects of aspirin.

Surprisingly, it has been found that polysulfated mono- and disaccharides exert a great deal of interesting effects when applied topically to the skin.

Thus, in one aspect, the present invention relates to the use of a sulfated mono or disaccharide or a salt or a complex thereof for the preparation of a composition for topical application to the skin for the prevention or treatment of dandruff.

EP 230023 discloses the use of sulfated saccharides to improve wound healing and that sucralfate gives rise to inflammatory reactions when wound is applied. It is also stated that low levels of 0.1-1.0 mg / ml of the polysulfated sucrose sucrose octasulfate in the form of the potassium salt thereof are preferred to avoid local hemorrhage or inflammation in the wound area.

Clinical studies in animals have shown that the potassium salt of sucrose octasulfate is well tolerated when applied topically in surgical wounds and when given as an intravenous injection. For surgical intervention, dogs and cats received a post-operative solution of 20 mg / ml of the potassium salt of sucrose octasulfate at a dose of 5 mg / kg body weight. Rapid normalization of temperature was observed and the wound healing was without suppuration or inflammation.

2 DK 174560 B1

The tolerance of a 2% aqueous suspension of micronized sucralfate has been studied in a rabbit eye model. There was no evidence of any irritation or inflammatory reactions in the conjunctiva, cornea or eye environment and it was concluded that the test preparation was not eye irritant.

5

A significant clinical effect could be observed in the treatment of dermatoses such as atopic dermatitis, psoriasis and toxic hand eczema (Example 8).

Sucralfate, the aluminum complex of sucrose octasulfate, exhibits an extremely good tolerance, documented through a complete absence of side effects after use in the treatment of peptic ulcer, and that both sucralfate and sucrose octasulfate have shown a very good tolerance used topically on the skin. .

It is also conceivable that sulfated mono- or disaccharides such as sucrose-octasulfate 15 modify or inhibit inflammatory responses and / or stimulate tissue regenerative processes through other, yet to be fully elucidated, mechanisms.

It has been observed that one sulphated saccharide, sucralfate, when used internally in the treatment of peptic ulcer, preferably binds to the ulcer surface itself. It is presently believed that this is a property common to sulfated saccharides and that this binding is due to the ability of sulfated saccharides to bind to proteoglycans and hyaluronic acid. These structures are surface components of many cells and they protect and stabilize the cell and help maintain the outer cell surface intact. In other cases, for example, in the dermis and in connective tissue, proteoglycans and hyaluronic acid form a protective matrix in which the cells are embedded. Furthermore, it is known that certain sulfated saccharides, e.g., heparan sulfate, dextran sulfate and xylose sulfate, are hyaluronidase inhibitors.

Hyaluronidases are enzymes that catalytically cleave the glycoside bonds of hyaluronic acid and glycosaminoglycans. Therefore, the degradation of hyaluronidases by hyaluronic acid and glycosaminoglycans causes the cells to be exposed to and damaged by various agents such as pathogens, inflammatory mediator substances, inflammatory and corrosive agents via destruction of the cell surface or connective tissue matrix. Thus, by inhibiting hyaluronidases, sulfated saccharides are believed to promote regeneration of the cell surface and protective connective tissue matrix and thereby exert an anti-inflammatory and tissue regenerating effect.

Degradation products of hyaluronic acid and glycosaminoglycans can themselves act as mediators of inflammation, and through inhibition or modification of this degradation, sucrose octasulfate and other sulfated saccharides can exert an inhibitory or modifying effect on inflammatory responses and inflammatory responses and .

Thus, it is believed that the above pharmacological effects of sucrose octasulfate and 5 other sulfated saccharides result in a "strengthening" of epithelial and mucosa surfaces. In addition to exerting an anti-inflammatory effect, this strengthening of the outer cell surface and connective tissue cell matrix also means that it will be more difficult for bacteria and viruses to penetrate and colonize the cells and tissue. Thus, instead of a direct antimicrobial effect, an indirect effect is obtained by applying sucrose octasulfate or other sulphated saccharides to epithelial surfaces. Thus, the compounds can be used topically for bacterial, viral or mycotic infections on the skin and mucosa.

A pharmaceutical composition for the use of the invention comprises sucrose octasulfate or another sulfated saccharide or salt or complex thereof, alone or in combination with a pharmaceutically acceptable excipient.

For example, the sulfated mono- or disaccharide used in the invention may be a monosaccharide such as xylose, fructose or glucose or a disaccharide such as sucrose, lactose, maltose or cellobiose. In some cases, it may be advantageous to use the sulfated saccharide in combination with another substance such as a non-sulfated polysaccharide, e.g., hyaluronic acid.

The mono or disaccharide is preferably a polysulfated or persulfated saccharide, meaning that two or more, if any, sulfur-containing units are present as 25 substituents on carbohydrate units.

In some cases, the mono- or disulfated saccharide may be in the form of a complex or form a salt with a metal, for example an alkali 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 (e.g., an amino acid). The preferred salts are potassium and sodium salts.

The composition preferably contains a persulfated disaccharide, optionally sucrose octasulfate.

For example, the substance may be prepared as disclosed in EP 230023.

Although there may be cases where the sulfated mono- or disaccharide may be administered as such, it will typically be formulated with one or more pharmaceutically acceptable carriers or excipients to appear in a form suitable for use in topical application. In other words, it will be in the form of a liquid, semi-solid or solid topical composition such as a powder, paste, ointment, lotion, gel, cream, emulsion, solution, suspension, spray, sponge , a strip, a patch, a pillow, a dressing or an ostomy plate.

5

For topical application, the composition may be formulated according to conventional pharmaceutical principles using pharmaceutical adjuvants conventionally used in connection with topical applications such as pectin, gelatin and derivatives thereof, polylactic acid or polyglycolic acid polymers or copolymers thereof, cellulose derivatives such as methyl cellulose cellulose, or oxidized cellulose, guar gum, acacia gum, karaya gum, tragacanth gum, bentonite, agar, carbomer, bladder, ceratonla, dextran and its derivatives, ghattl gum, hectorite, ispaghula husk, polyvinylpyrrolidone, silica derivative, silicon dioxide and derivatives thereof, paraffin, water, vegetable and animal oils, polyethylene, polyethylene oxide, polyethylene glycol, polypropylene glycol, glycerol, ethanol, propanol, propylene glycol (glycols and alcohols), solid oils, sodium, potassium, aluminum, magnesium or calcium salts (such as chlorides, carbonates, hydrogen carbonates, citrates, gluconates, lactates, acetates, gluceptates or tartrates).

The composition may also contain other additives such as emulsifiers, stabilizers, preservatives, etc.

Patches, sponges, strips, pads or other types of dressings can be made by impregnating a dressing material such as cotton or gauze or a polymeric substance 25 with a solution or suspension of the sulfated mono- or disaccharide, followed by drying. Alternatively, a paste, lotion, cream or gel containing the sulfated mono- or disaccharide may be spread over the dressing material conveniently immediately prior to use.

The composition is made according to the invention, usually the sulfated mono or disaccharide comprises in the amount of 0.001-99% by weight, typically 0.01-75% by weight, more typically 0.1-20% by weight, especially 1-10% by weight, of the total composition. Particularly when the sulfated mono- or disaccharide is sucrose-octasulfate, a preferred concentration thereof in the composition is often 0.5-50% by weight, especially 0.5-25% by weight such as 1-10% by weight. It is conveniently applied 1-10 times a day, depending on the type and severity of the disorder to be treated.

The concentration of the sulfated mono- or disaccharide used in each case will, of course, depend on the type of preparation and the intended purpose, but will also depend on the solubility characteristics of the sulphated mono- or disaccharide and for the highly soluble and substantially soluble insoluble mono- or disulfated saccharides as well as their particle size; the smaller the particle size, the faster the dissolution of even heavily soluble or substantially insoluble sulfated mono- or disaccharides 5 or complexes thereof. Insoluble or heavily soluble salts or complexes of sulfated mono- or disaccharides are preferably used in the form of a fine powder, for example, with a particle size of 200 µm or less, such as 100 µm or less. Examples of very small particle sizes that may be desirable for particular purposes are, for example, 50 µm or less, such as 20 µm or less, in some cases 10 µm or less, such as 10 µm or less.

The composition may contain active agents other than the sulfated saccharide such as antibacterial agents, antiviral agents, antiparasitic agents, sunscreen agents, vitamins and vitamin derivatives or analogues, antineoplastic agents, antimycotic agents, antifibrinolytic agents, blood coagulation modifiers, antiseptics, antiseptics, anti-inflammatory agents.

As stated above, the sulfated saccharide is indicated for use in connection with any skin disorder involving irritation. Furthermore, it has been found particularly advantageous to treat skin disorders caused by contact with an external chemical agent (e.g., an allergen or a corrosive substance such as an acid or a base) by means of the sulfated mono- or disaccharide, or to administer the sulfated mono-agent. or disaccharide as a preventive measure to prevent skin damage caused by such agents or secretions.

25

Examples of specific disorders for which the use of the sulfated mono- or disaccharide is therapeutically or prophylactically Indicated include skin disorders characterized by peeling. Included are contact dermatitis, atopic dermatitis, seborrheic dermatitis, neurodermatitis, lichen simplex, drug rash, erythema nodosum, erythema 30 multiforme, pityriasis, rosacea, lichen planus, psoriasis, ichthyosis (fish skin), stasis dermatitis, and chronic hand dermatitis and chronic dandruff.

The invention is further illustrated by the following examples.

EXAMPLE 1

A topical powder preparation was prepared from the following ingredients: 5 Sucralfate * 30 grams

Pectin 10 grams

Gelatin 10 grams

Carboxymethyl cellulose 10 grams 10 ^ Delivered by Abic Laboratories, Israel, in comminuted form.

The finely divided sucralfate (particle size 2-100 µm) was thoroughly mixed with the other constituents in finely divided form (particle size <250 µm) to make a powder.

EXAMPLE 2

A topical ointment preparation was prepared from the following ingredients: 20 Sucralfate 30 grams

Pectin 10 grams

Gelatin 10 grams

Carboxymethyl cellulose 10 grams

Fractionated coconut oil 60 grams 25

The finely divided sucralfate (particle size 2-100 µm) was carefully mixed with the other components in finely divided form. Fractionated coconut oil was added to the resulting powder to provide a suitable consistency and a substantially homogeneous dispersion of the particulate components.

EXAMPLE 3

A topical ointment preparation was prepared from the following ingredients: 5 Sucralfate 30 grams

Hyaluronic acid 0.6 grams

Pectin 10 grams

Gelatin 10 grams CMC 10 grams 10 Fractionated coconut oil 60 grams

The finely divided sucralfate (particle size 2-100 µm) was carefully mixed with the other components in finely divided form. Fractured coconut oil was added to the resulting powder to provide a suitable consistency and a substantially homogeneous dispersion of the 15 particulate components.

EXAMPLE 4 A topical skin and mucosal preparation was prepared by mixing 5% by weight of a sucralfate powder (particle size 50-100 µm, supplied by Glulini Chemie, West Germany) with a mixture of cetanol, adeps lanae purificatae, isopropyl myristas, Tween 60, Span 60, dimeticone, glycerol, sorbic acid and sterile water.

EXAMPLE 5 A) A topical preparation for skin and mucosa was prepared from the following ingredients; Sucralfate powder * 5%

Paraffin oils, glycerin, cetyl alcohol 55%

Quaternary ammonium compounds 0.7%

Stearic alcohol 3%

Eucalyptus oil q.s.

35 * Micronized sucralfate (<10 pm) provided by Giulini Chemie, West Germany.

EXAMPLE 6 8 DK 174560 B1

Human Clinical Studies 5 D) The anti-inflammatory effect of sucralfate in various forms of dermatoses was studied in adult patients with atopic dermatitis, psoriasis, toxic hand eczema and folliculitis. The composition comprised 5% by weight of sucralfate powder mixed in a fat vehicle consisting of chamomile herbal extracts (6%) and arnica (4%). The ointment was applied morning and evening. Table 2 shows demographic data and treatment diagnosis for the 10 patients included in the study.

Table 2

Diagnosis Number Gender Age Drug 15 patients tested in

Atopic dermatitis 8 F 18-44 1-8 months.

Atopic dermatitis 6 M 21-33 1-5 months.

Psoriasis (universal) 3 M 33 - 39 1 - 4 months

20 Psoriasis (universal) 5 F 19 - 28 3 - 8 months.

Psoriasis (local) 6 M 19-31 1-6 months.

Psoriasis (local) 7 F 22 - 33 1 - 8 months.

Toxic hand eczema 5 F 35 - 48 5 - 8 months.

Folliculitis (beard) 7 M 30 - 60 2 - 3 months

25 Anal vulval pruritus 4 F 48-71 4 months.

Topical application of sucralfate ointment twice daily resulted in improvement or total cure in all 51 cases. All patients, except two women with local psoriasis and 30 seven men with beard folliculitis, had previously received extensive topical treatment with steroids. Patients with atopic dermatitis had a history of 10-20 years, and they had all developed the rebound phenomenon after steroid use. A marked improvement was seen after 10 days of treatment with sucralfat ointment and 10 out of 14 patients with atopic dermatitis were cured in the sense that they have been completely free of dermatitis symptoms 35 during treatment periods of up to 8 months. Patients with psoriasis showed improvement after 2 to 4 weeks of treatment and the improvement was present in all cases throughout the treatment period. Patients with toxic hand eczema showed improvement after one week, and in three cases there was a total cure of the patients. A good effect was seen in beard folliculitis over one

Claims (15)

There was a sediment in the stock suspension of sucralfate 100 mg / ml and preferably the supernatant was used in preparing the dilutions of 10, 1 and 0.1 mg / ml sucralfate. Therefore, the above anti-inflammatory effects must be predominantly conditioned by sucralfate in solution, which is most likely in the form of ionized sucrose octasulfate and aluminum ions, respectively. The anti-inflammatory effect demonstrated in this in vitro model. is therefore an effect that is most likely attributable to the polysulfated saccharide sucrose octasulfate. 35 Use of a sulfated mono- or disaccharide or a salt or complex thereof for the manufacture of a composition for topical application for the prevention or treatment of dandruff. DK 174560 B1 Use according to claim 1, characterized in that the sulfated saccharide is a monosaccharide selected from xylose, fructose and glucose. Use according to claim 1, characterized in that the sulfated saccharide is a disaccharide selected from sucrose, lactose, maltose and cellobiose. Use according to any one of claims 1-3, 10, characterized in that the sulfated mono- or disaccharide is combined with a non-sulfated polysaccharide, for example hyaluronic acid. Use according to any one of claims 1-4, characterized in that the sulfated mono- or disaccharide is a polysulfated mono- or disaccharide, preferably a persulphated mono- or disaccharide. Use according to any one of claims 1-5, characterized in that the substance with which the sulfated mono- or disaccharide is complexed or with which it forms a salt is a metal selected from Al, Na, K, Ca . 20 Mg, Ba, Zn, Cu, Zr, Ti, Bi, Mn and Os, or an amino acid. Use according to claim 3, characterized in that the sulfated disaccharide is sucrose octasulfate, a complex or salt of sucrose octasulfate with a metal selected from Al, Na, K, Ca, Mg, Ba, Zn, Cu, Zr, 25 Ti, Bi, Mn and Os, or a salt of sucrose octasulfate with an amino acid. Use according to claim 7, characterized in that the sulfated disaccharide is sucrose octasulfate or a sodium or potassium salt thereof or the aluminum complex of sucrose octasulfate, sucralfate. 30 Use according to any one of claims 1-8, for the preparation of a composition for topical use in the form of a paste, an ointment, a lotion, a gel, a cream, an emulsion, a solution, a suspension, a spray, a sponge or a pillow. Use according to any of claims 1-9, characterized in that the concentration of the sulfated mono- or disaccharide in the composition is 0.01-75% by weight, typically 0.1-20% by weight, in particular 1-10% by weight. composition. DK 174560 B1 Use according to claim 7, characterized in that the composition in aqueous solution is in the form of ionized sucrose octasulfate. Use according to any one of claims 1-11, characterized in that the composition further contains one or more substances selected from sodium, potassium, aluminum, magnesium or calcium salts (such as chlorides, carbonates, hydrogen carbonates, citrates). gluconates, lactates, acetates, gluceptates or tartrates). 10