Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
  • A61Q17/04—Topical preparations for affording protection against sunlight or other radiation; Topical sun tanning preparations
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7004—Monosaccharides having only carbon, hydrogen and oxygen atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7016—Disaccharides, e.g. lactose, lactulose
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/19—Cosmetics or similar toiletry preparations characterised by the composition containing inorganic ingredients
  • A61K8/26—Aluminium; Compounds thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
  • A61K8/4973—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/60—Sugars; Derivatives thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
  • A61K8/73—Polysaccharides
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
  • A61K8/73—Polysaccharides
  • A61K8/732—Starch; Amylose; Amylopectin; Derivatives thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
  • A61K8/73—Polysaccharides
  • A61K8/735—Mucopolysaccharides, e.g. hyaluronic acid; Derivatives thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/08—Antiallergic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q19/00—Preparations for care of the skin
  • A61Q19/08—Anti-ageing preparations
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
  • A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
  • A61K2800/58—Metal complex; Coordination compounds
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
  • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
  • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

• the present invention relates to the use of sucralfate as tissue regenerative, anti-allergic, antiinfective, antiviral, immunomodula- ting, antineoplastic and anti-inflammatory agent.
• drugs are employed to suppress the manifestations of inflam ⁇ mation, including the adrenocorticosteroids, the large group compri ⁇ sing the so called non-steroid anti-inflammatory drugs or NSAIDs, and drugs such as immunosuppressive agents, chloroquine, penicillami- ne and gold salts.
• NSAIDs are chemically a heterogeneous group of drugs, mainly consti ⁇ tuting aromatic substituted carboxylic acids. Pharmacologically, they have anti-inflammatory, antipyretic and analgetic ef ects, and they inhibit prostaglandin synthesis and decrease thrombocyte aggregation. The mode of action of NSAIDs is not yet fully understood, although
• SUBSTITUTE SHEET it is known that they inhibit one or more of the mediator substances of inflammation.
• the main indication for NSAIDs is rheumatic diseases, particularly where inflammatory processes in supporting tissues give rise to pain and joint-stiffness.
• the analgetic effects can be used as symptomatic pain relief in cases where the prostaglandin inhibitory effect can be utilized, such as dysmennorrhoea, urolithiasis, etc.
• Some of the drugs, including indomethacin have also been used topi- cally on the skin in the treatment of various dermatoses and as a topical anti-inflammatory agent in the eye.
• NSAIDs give rise to a broad spectrum of side effects. Severe and often fatal blood dyscrasias are often seen, notably following the use of phenylbutazone, and gastrointestinal side ef- fects are common with phenylbutazone, salicylates and indomethacin. Allergic reactions are common and may in some cases be due to pro ⁇ staglandin inhibition with a resulting secondary increase in leu- cotriene levels. Hepatotoxicity and 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 thereby granulo- cyt migration. Glucocorticoids also interfere with late inflammatory and reparative processes, in that they inhibit the proliferation of mesenchymale cells and the production of intercellulare macromolecu- les, including proteoglycanes and collagen. It has been shown ex ⁇ perimentally that glucocorticoids inhibit, for example, macrophage function, production of humoral antibodies, cellular immunity, and possibly the release of lysosomal enzymes.
• glucocorticoids are apart from substitution therapy very limited, because of side effects, and should be restricted to severe inflammatory rheumatic diseases, severe cases of allergic diseases such as asthma bronchiale and status asthmaticus and cases of haematological, renal, and gastrointestinal immunological disea-
• Topical use 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 cases of dermatosis and for injection in joints, bursae, tendons, etc., as well as for topi- cal 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. In the eye, corneal ulceration, glaucoma and viral superinfections are feared and serious side effects, and steroids are in fact contraindicated in many cases.
• anti-inflammatory drugs include penicillamine, chloroquine, gold salts and cytostatics.
• penicillamine chloroquine
• gold salts gold salts
• cytostatics The main indication for these drugs is severe rheumatoid arthritis. The drugs are all given systemically, and they all exert a number of severe side effects.
• sucralfate 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).
• sucralfate 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).
• sucralfate exerts an anti-in ⁇ flammatory effect when applied topically to the skin and to mucosal surfaces, and that sucralfate exerts a beneficial effect on wounds when applied topically on epithelial surfaces outside the digestive tract.
• the present invention relates to the use of sucralfate for the preparation of a medicament for topical appli ⁇ cation to the skin or to any non-gastrointestinal, non-oral mucosal surface of an animal or a human, including the lining of body caviti ⁇ es, for the prophylaxis or treatment of any manifestation of inflam ⁇ mation or infection, for modification or facilitation of tissue regenerative processes, for the modulation of immune reactions, for the treatment or prophylaxis of non-bladder pre-malignant or malig- nant disorders, or for the prophylaxis or treatment of irritation, burns, or ulceration of the skin, connective tissue, or non-gastroin ⁇ testinal, non-oral mucosa; or for the preparation of a medicament for topical application to the skin or any non-oral mucosal surface of an animal or a human for the treatment of laceration, lesions, or surgi- cal wounds of the skin, connective tissue, or non-
• sucralfate in effecting anti-inflammatory properties is surprising in view of the fact that the published literature only discloses sucralfate for use in the gastrointestinal tract, primarily for the treatment of peptic ulcers.
• sucralfate gives rise to inflammatory reactions when applied to a wound. It is also stated that low levels of 0.1 to 1 mg/ml of the polysulphated saccharide is preferred in order to avoid local haemorrhage or inflammation at the wound site.
• excellent wound-healing and anti-inflammatory ef ⁇ fects have been obtained according to the present invention, by using sucralfate topically on skin and mucosas.
• sucralfate showed properties which make it undesirable for wound healing. It was concluded that wound healing with neovasculari- zation and fibroblast (rather than macrophage) migration was not observed with sucralfate. In contradiction to this, we have observed an accelerated wound healing when sucralfate is applied topically to full-thickness skin wounds. In an animal study with small pigs, it was specifically observed that there was very little inflammatory reaction in the wound edge area (Example 8). In an in vitro model, the anti-inflammatory effect of sucralfate was studied.
• sucralfate exerted a dose-related inhibition of the PHA-activated production of the cytokines inter- feron gamma and interleukin 2 from human normal mononuclear cells, indicating an anti-inflammatory effect of sucralfate. It has been possible to demonstrate experimentally in animals that sucralfate exerts an anti-inflammatory effect which is comparable to that of indomethacin, when the drug is administered topically to the skin in order to protect against light-induced erythema (Example 10).
• Example 9 In human clinical studies (Example 9) a powder containing 50% sucral ⁇ fate was used in the treatment of severe diaper rash in children with a short bowel following colectomy, and later the powder was used in the treatment of ulcerative skin inflammations around ileostomies. In all cases, the effect was dramatic and suggested a strong anti-in ⁇ flammatory action of sucralfate. As the next step, a wound paste containing sucralfate was tested in the management of leg ulcers. Chronic ulcers of both arteriosclerotic and venous stasis etiology were selected for the study. Approximately half of the patients showed marked wound-healing. However, the most glaring effect was the pain relief spontaneously reported by all the patients, and the decrease in tissue oedema and in skin inflammatory reactions seen in the wound surroundings.
• sucralfate exerts an anti-inflammatory effect which is at least comparable to that of corticosteroids, in the management of steroid responding skin di ⁇ seases (Example 9) .
• sucralfate an interesting compound to be used as an alternative to conventional anti-inflammatory drugs. Furthermore, sucralfate's extremely high tolerability, as documented by the total absence of side-effects following its use in the treatment of peptic ulcer, and the very high tolerability of sucralfate when used topically on the skin and mucosa makes sucralfate very attractive as an alternative to conventional anti-inflammatory drugs.
• sucralfate modifies or inhibits inflammatory reactions and/or stimulate tissue regenerative processes via other, not yet fully understood mechanisms.
• sucralfate when used internally in the treatment of peptic ulcers, binds preferentially to the surface of the ulcer. It is currently believed that this is a property common to sulphated saccharides, and that this binding is the result of an ability of sulphated saccharides to bind to proteoglycanes and hya ⁇ luronic acid. These structures are components of the surface of many cells, and they protect and stabilize the cell so the exterior cell surface remains intact. In other cases, e.g. in dermis and supportive tissue, proteoglycanes and hyaluronic acid form a protective matrix in which cells are embedded. Furthermore, it is known that certain sulphated saccharides, e.g. heparan sulphate, dextran sulphate and xylose sulphate, are hyaluronidase inhibitors.
• Hyaluronidases are enzymes which catalytically cleave the glycosidic bonds of hyaluronic acid and glycosaminoglycanes.
• the decomposition of hyaluronic acid and glycosaminoglycanes by hyaluronidases there ⁇ fore leads to exposure of the cells, via destruction of the cell surface or the supportive matrix substance, as well as to damage from various agents such as pathogens, inflammatory mediator substances, inflammatory agents and corrosive agents.
• sulphated saccharides promote the rege ⁇ neration of the cell surface and the protective connective tissue matrix, and thereby effect an anti-inflammatory and tissue regenera ⁇ tive action.
• Decomposition products of hyaluronic acid and glycosaminoglycanes may also act as mediator substances of inflammation themselves, and via inhibition or modification of such decomposition, sucralfate may inhibit or modify inflammatory reactions and facilitate and modify tissue regeneration.
• sucralfate results in a "strengthening" of epithelial and mucosal linings. Apart from effecting an anti-inflammatory action, this strengthening of the exterior cell surface and connective tissue cell matrix will also make it more difficult for bacteria and virus to penetrate and colonize the cells and the tissue. Instead of a direct antimicrobial effect, an indirect effect will thus be obtai-
• sucralfate may be used topically in the treatment of bacterial, viral or mycotic infections of skin and mucosa.
• the antimicrobial effect may possibly also be utilized by applying sucralfate directly to supportive tissues in connection with surgery.
• Many infections spread in the tissue by means of hyaluronidases produced or induced by the pathogens themselves. It is contemplated that the hyaluronidase inhibiting effect of sucralfate prevents the spreading of such infec ⁇ tions,
• Such anti-inflammatory and anti-infective actions may furthermore be utilized when implanting or inserting medicotechnical devices into the body.
• sucralfate into the surface coating of a device or into the material of the device itself, it is contemplated that infections and inflammatory tissue reactions, including throm- bophlebitic reactions, around the device can be diminished (see
• Example 13 Examples of devices where such a technique could be used are urethral catheters, peritoneal dialysis catheters, e.g. dural and spinal catheters, venous and arterial catheters, electrodes, breast protheses, pacemakers, middle ear tubes, eye lenses, vascular pro- stheses, hip prostheses, etc.
• Other uses may comprise coating of any material to be placed directly on the skin or mucosa for longer periods, such as ostomy plates, external prostheses, etc.
• sucralfate may be utilized in the management of malignant disorders. Examples are treatment of superfi ⁇ cial skin and mucosal malignancies such as basal cell carcinomas, cervical dysplasia and carcinoma, etc. by topical application of sucralfate or another sulphated saccharide on the lesions, and pos ⁇ sibly also by placing depot preparations which release sucralfate into the surrounding tissue in connection with surgery for malignant diseases. It is furthermore contemplated that sucralfate might be useful as an addition to cell cultures in vitro because of its cell surface modifying action.
• the present invention further relates to a pharmaceutical prepara- tion, in particular for any of the uses stated above, which comprises
• SUBSTITUTE SHEET sucralfate alone or together with a pharmaceutically acceptable excipient relates additionally to a topical prepara ⁇ tion for the prophylaxis or treatment of laceration or lesions of skin, the preparation comprising sucralfate together with a pharma- ceutically acceptable carrier or excipient.
• the invention relates to a method for preventing or treating any manifestation of inflammation or infection of the skin or any non-gastrointestinal, non-oral mucosal surface of an animal or a human, including the lining of body cavities; for modifying or facilitating tissue regenerative processes; for modula ⁇ ting immune reactions; for preventing or treating non-bladder pre- malignant or malignant disorders; for preventing or treating irrita ⁇ tion, burns, or ulceration of the skin, connective tissue, or non- gastrointestinal, non-oral mucosa; for the treatment of laceration, lesions, or surgical wounds of the skin, connective tissue, or non- oral mucosa; or for preventing or treating skin, connective tissue, or mucosal aging, the method comprising applying to the skin, mucosa or tissue a therapeutically or prophylactically effective amount of sucralfate.
• sucralfate in combination with another wound-healing substance such as a non-sul- phated polysaccharide, for instance hyaluronic acid, vide Example 7,
• Sucralfate may be represented by the following formula:
• the substance may, for instance, be prepared as disclosed in US 3,432,489 by reacting a 1-105. aqueous solution of sucrose octasul ⁇ phate or an alkali metal or alkaline earth metal salt thereof with a 1-10% aqueous solution containing aluminium ions, preferably AlCl- (OH)2 at room temperature and a pH of 4-4.5.
• the sucrose octasulphate may be prepared by reacting sucrose with CISO3H, H2SO or H 2 S0 4 -C 5 H 5 N.
• Sucralfate may also be termed sucrose octakis(hydrogen sulphate) aluminium complex. Its CAS number is 54182-58-0.
• the commercial product is a white powder which is practically insoluble in water and most organic solvents; it is soluble in acids and alkalis. In prac ⁇ tice, there may be slight variations in the chemical composition, e.g., due to the fact that the sulphation may be slightly incomplete so that the product may, e.g., contain a certain proportion of mole- cules which are not octasulphated (persulphated) , but rather less sulphated such as heptasulphated.
• sucralfate also comprises such generally accepted minor varia ⁇ tions. Although there may be cases where the sucralfate may be ad ⁇ ministered 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.
• liquid, semi-solid or solid topical pre ⁇ paration such as a powder, paste, ointment, lotion, gel, cream, salve, emulsion, solution, suspension, spray, sponge, strip, plaster, pad, dressing or ostomy plate.
• the preparation may be formulated in accor- dance with conventional pharmaceutical practice with pharmaceutical excipients conventionally used for topical applications such as pectin, gelatin and derivatives thereof, polylactic acid or polygly- colic 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,
• the preparation of the invention may also contain other additives such as emulsifiers, stabilizing agents, preservatives, etc.
• 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 suspension of sucralfate followed by drying.
• a paste, lotion, cream or gel containing the sucralfa ⁇ te may be spread over the dressing material, conveniently immediately prior to use.
• a suitable starting material for the preparation of an ointment, paste, lotion, cream, suspension, or gel is a micronized suspension of sucralfate in polyethylene glycol.
• the sucralfate powder is ground together with a liquid polyethylene glycol, e.g., PEG 400, and the resulting preparation contains up to 60-75% by weight of sucralfate particles with a fairly uniform par ⁇ ticle size of about 5-10 ⁇ m or less, evenly suspended in the polyet- hylene glycol.
• Suitable polyethylene glycols are in the range of mw 200-6000. Such a paste can then be further suspended in any suitable pharmaceutical preparation using well-known pharmaceutical methods.
• the preparation of the invention may for instance be for- mulated in the form of a vaginal suppository, a nasal drop or insert or eye drops or eye salve.
• Such formulations may be prepared in accordance with conventional pharmaceutical practice using conventio ⁇ nal excipients such as some of those mentioned above.
• the pharmaceutical preparation of the invention generally comprises the sucralfate in an amount of 0.001-99%, typically 0.01-75%, more typically 0.1-20%, especially 1-10% by weight of the total prepara ⁇ tion.
• 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 on the type and severity of the condition to be treated.
• sucralfate concentration of the sucralfate to be used in each particular case will of course depend upon the type of preparation and the intended use, but also on the particle size and shape thereof; the smaller the particle size, the faster will be the distribution of the sucralfate.
• Sucralfate is often preferably used in the form of a fine powder, for example having a particle size of 200 ⁇ m or less, such as 100 ⁇ m or less. Examples of very small particle sizes which may be desirable for certain purposes are e.g. 50 ⁇ m or less, such as 20 ⁇ m or less, in certain cases 10 ⁇ m or less, such as 5 ⁇ m or less.
• the preparation may contain other active agents than the sucralfate, such as antibacterial agents, antiviral agents, antimycotic agents, antiparasitic agents, sun protective agents, vitamins and vitamin derivatives or analogues, antineoplastic agents, antifibrinolytic agents, blood coagulation modifying agents, antiseptic agents, anal ⁇ gesics, topical anesthetics or anti-inflammatory agents.
• active agents such as antibacterial agents, antiviral agents, antimycotic agents, antiparasitic agents, sun protective agents, vitamins and vitamin derivatives or analogues, antineoplastic agents, antifibrinolytic agents, blood coagulation modifying agents, antiseptic agents, anal ⁇ gesics, topical anesthetics or anti-inflammatory agents.
• the sucralfate is indicated for use in connection with any skin, mucosa or tissue condition involving irritation, inflammation or burns, or for the prevention of ulceration of the skin. Furthermore, it has been found particularly advantageous to treat skin conditions caused by contact with an external chemical agent (e.g. an allergen or an irritant or a corrosive substance such as an acid or a base) or with body secretions such as urine, sweat or gastrointestinal secretions, or by external pressure, or by heat, or ionizing radiation, or light (which in the present specification and claims includes ultraviolet light) by means of the sucralfate, or to add the sucralfate as a prophylactic measure to prevent skin damages resulting from these agents or secretions.
• an external chemical agent e.g. an allergen or an irritant or a corrosive substance such as an acid or a base
• body secretions such as urine, sweat or gastrointestinal secretions, or by external pressure, or by heat, or ionizing radiation, or light (which in the present specification and claims includes ultraviolet
• sucralfate SB examples of particular conditions for which use of sucralfate is therapeutically or prophylactically indicated include:
• Skin diseases including lips, vaginal mucosa and perianal areas
• Skin diseases including lips, vaginal mucosa and perianal areas
• Miliaria defined as an acute inflammatory pruritic eruption resulting from obstructed sweat glands, often precipitated by even minor skin irritation, e.g. application of adhesive pla ⁇ sters or excessive moist heat (sunburn, diaper, exercise).
• Intertrigo defined as acute superficial inflammation of op- posing skin surfaces, characterized by erythema, abrasion, maceration, and, in some cases, superficial fissuring.
• Pruritus defined as a generalized or localized itching sensa ⁇ tion, which the patient instinctively attempts to relieve by scratching.
• Acne and rosacea defined as inflammation of the sebaceous glands and characterized by seborrhoea comedones, pustules, papules and nodules.
• Superficial bacterial skin infections such as erythrasma
• super ⁇ ficial fungal infections such as ringworm and Candida
• viral infections such as herpes simplex, herpes zoster, measles, varicella, warts, Condyloma acuminata
• vaginosis either non ⁇ specific or caused by mycoplasma, chlamydia, Candida, Thrichomo- nas , etc.
• Dermatitis defined as an acute or chronic superficial inflamma- tion of the skin, whether microbially infected or not, charac ⁇ terized by erythema, oozing, crusting, scaling, and sometimes by vesicles. Included are contact dermatitis, atopic dermatitis, seborrhoeic dermatitis, neurodermatitis, lichen simplex, drug eruption, erythema nodosum, erythema multiforme, pityriasis
• Boils furuncles, carbuncles, hidrosadenitis and fistules.
• Respiratory diseases such as:
• Allergic rhinitis characterized by seasonal or perennial snee- zing, rhinorrhea, nasal congestion, and often conjunctivitis and pharyngitis.
• Acute rhinitis characterized by oedema of the nasal mucosa, nasal discharge and obstruction. In most cases caused by a common virus.
• Pulmonary diseases such as intrinsic or extrinsic asthma bron- chiale, pulmonal inflammatory reactions secondary to chronic bronchitis, pneumoconioses, pulmonary fibrosis, Goodpasture's syndrome, etc.
• Ear, nose and throat disorders such as:
• Eye diseases such as:
• Oedema in the eye region caused by trauma or foreign bodies, or postoperative inflammation.
• Malignant and premalignant disorders such as basal cell car ⁇ cinoma, cancer in situ colli uteri.
• a topical powder preparation was prepared from the following ingredi ⁇ ents:
• the finely divided sucralfate (particle size 2-100 ⁇ m) was thoroughly mixed with the other ingredients in finely divided form (particle size ⁇ 250 ⁇ m) to produce a powder.
• a topical ointment preparation was prepared from the following ingre ⁇ terminals:
• the finely divided sucralfate (particle size 2-100 ⁇ m) was thoroughly mixed with the other ingredients in finely divided form.
• the frac ⁇ tionated coconut oil was added to the resulting powder to a suitable consistency and a substantially homogeneous dispersion of the parti- culate components.
• a topical ointment preparation was prepared from the following ingre ⁇ terminals:
• the finely divided sucralfate (particle size 2-100 ⁇ m) was thoroughly mixed with the other ingredients in finely divided form.
• the frac ⁇ tionated coconut oil was added to the resulting powder to a suitable consistency and a substantially homogeneous dispersion of the parti- culate components.
• a topical eye preparation was prepared from the following ingredi ⁇ ents:
• An eye preparation was prepared from the following ingredients:
• a topical preparation for skin and mucosa was prepared by mixing 5% by weight of a sucralfate powder (particle size 50-100 ⁇ m, provided by Guilini Chemie, W. Germany) with a mixture of cetanole, adeps lanae purificatae, isopropyl myristas, Tween 60, Span 60, dimeticone, glycerol, sorbic acid and sterile water.
• a sucralfate powder particle size 50-100 ⁇ m, provided by Guilini Chemie, W. Germany
• a topical preparation for mucosa and skin was prepared from the following ingredients:
• the present example illustrates the wound-healing effect of sucralfa- te and also the surprising anti-inflammatory effect of sucralfate.
• the pigs Twice daily, the pigs were offered a standard granulated pig diet, 0A Baconblanding 20, from ⁇ stsj-ellands Andel a.m.b.a. At week-ends they were only fed once but received double ration. At each feeding time they were given tap water at libitum.
• the pigs were housed separately in wire mesh metal cages.
• the room temperature was set at 19°C and the relative humidity at 55%.
• the light was on from 06 to 18 h.
• test substance (sucralfate) was administered as the ointment de ⁇ scribed in Example 3.
• the control was treated with DuoDerm ""(a com ⁇ dismissal product by ConvaTec, USA) .
• the pigs were anaesthetized with Sedaperone® (i.m.) and Hypnodil® (i.p.). Atropin (i.m.) was administered at the same time to prevent salivation.
• the hair of the back was clipped with an electric clipper before washing with soap and water followed by disinfection with 70% ethanol. Before surgery the skin of the back was rinsed with sterile 0.9% saline.
• the wounds were prepared surgically using a scalpel and a template with an area of 12 x 25 mm.
• test wounds were treated with the ointment and covered with Tegaderm and control wounds were treated with DuoDerm adhering dress ⁇ ings providing an occlusive dressing.
• the dressings were covered with gauze packs fixed with Scanport tape.
• the pigs During the entire study period the pigs wore nylon mesh jackets in order to prevent dislodgement of the wound dressing.
• the pigs were sacrificed while anaesthetized by exsan- guination after cutting the subclavian artery.
• the wounds were ex ⁇ cised and fixed to a piece of cardboard paper in order to prevent shrinkage during fixation in 4% buffered formaldehyde solution.
• Paraffin sections of biopsies and wounds were stained with haematoxy- lin and eosin for microscopic examination.
• the microscopic examination at 4 x 10 times magnification included semiquantitative quantification of the area of the wound surface which was not covered with epithelium.
• the plastic films were photocopied at 40% magnification. Each wound area was quantified by weighing the photocopy paper wound area after excision with a pair of scissors.
• Example 1 Two babies (a boy and a girl) who had been operated to correct congenital megacolon (Hirschsprung's disease) developed a severe rash with erythema, inflammation and pustules (presumed to be caused by contact with digestive enzymes and possibly acid due to the shorten ⁇ ing of the intestines) .
• the preparation of Example 1 was applied to the affected skin at each change of diapers. After one day of treat ⁇ ment the condition had improved dramatically, and the rash disap- peared completely after two to three days of treatment. The treatment was continued for six months. For the first four months after the operation, interruptions in the daily application of the sucralfate- containing powder resulted in recurrence of the rash. After six months, however, it was possible to discontinue the treatment with occasional resumption after, for instance, diarrhea.
• Example 2 Ten oncological patients with ileostomies who had developed ulcer- ations around the ileostomies were treated with the preparation of Example 1.
• a control group of ten other patients who had similarly developed ulcerations around ileostomies were treated with a powder preparation containing equal amounts of pectin, gelatin and carboxy ⁇ methylcellulose (i.e. the preparation of Example 1 without any su ⁇ cralfate). In each case, the powder was applied at each change of the ostomy bag for two weeks.
• Example 2 Fourteen elderly patients (aged 49-86 years, mean 70), with chro ⁇ nic leg ulcers of either ischaemic or venous stasis etiology, were treated with the preparation of Example 2. At the start of the thera ⁇ py, surgical debridement was made. The wounds were then filled up with the paste, and according to the nature of the surrounding skin, the wound area was covered with either a plastic film or with parch ⁇ ment paper. At the weekly changes, surplus paste was carefully remo ⁇ ved so as not to destroy granulation tissue, if present, and the treatment was repeated, i.e. the wound was filled with new paste and the wound area covered. In seven patients, there was a complete or nearly complete wound healing after two to three months of therapy.
• the wound-healing effect was evaluated by measuring the size of the wound at each control. During the first month of therapy, there was a reduction in the size of the wound in nine cases, the initial wound size being reduced by an average of 76% in the nine cases. In three cases there was no effect on wound size, and in the last two cases this measurement was not made. Pain in the wound was assessed on a scale from 0 - absent to 3 - severe. In all cases there was a marked pain relief, typically within a few hours after application of the wound paste. It was observed that the oedema in the surrounding tissue decreased and that the macerated and inflamed skin in the wound surroundings healed. Most of the wounds had fibrin, pus, and yellow necrosis at the start. They had in all cases turned into "red wounds" after treatment, with clean red granulation tissue free of infection. The mean scores for pain and eschar at baseline and during the following four weeks of treatment are shown in Table 3:
• sucralfate used topically on chronic leg ulcers exerts a definite wound-healing effect.
• there was a marked anti-inflammatory effect of the sucralfate wound paste in that oedema in the tissue decreased and inflammated and macerated skin around the wound healed.
• sucralfate The anti-inflammatory effect of sucralfate on various types of dermatosis was evaluated in adult patients with atopic dermatitis, psoriasis, toxic hand eczema and folliculitis.
• the preparation com ⁇ prised 5% by weight of sucralfate powder mixed in a fatty vehicle containing herbal extracts of chamomile (6%) and arnica (4%). The ointment was applied morning and evening.
• Table 4 summarizes the demographic data and diagnostics of treatment of the patients in ⁇ cluded in the study.
• Patients with psoriasis have shown improvement after 2 to 4 weeks of treatment, and the improve ⁇ ment has in all cases been maintained for the entire treatment peri ⁇ od.
• Patients with toxic hand eczema have shown improvement after one week, and the patients have been completely cured in three cases.
• a good effect has been shown with beard folliculitis over a treatment period of 2 to 3 months, and females with vulvovaginitis symptoms were freed of their pruritus. No side effects have been seen during treatment with sucralfate ointment covering a total period of 156 patient months.
• SUBSTITUTE SHEET E Two patients with a superficial fungal skin infection (ringworm) , received the sucralfate preparation of Example 6. After one day there was a marked improvement, and after three days of application of the sucralfate preparation two times a day, the skin was completely free of clinical signs of any fungal infections.
• sucralfate ointment of Example 7 has been used topically on herpes labialis. The ointment was applied three to six times daily, and the treatment was started as soon as possible after the herpetic eruption. Four young females have been evaluated, and in all four cases treatment has been successful in the sense that pain was redu ⁇ ced and there was a reduction in eruption of blisters. The skin was completely healed within two to four days after the start of treat- ment.
• sucralfate ointment of Example 7 was tested in the treatment of acne vulgaris.
• Sucralfate resulted in a more lasting effect, and there have been no rebound phenomena during treatment periods of up to 3 months.
• the animals were housed in opaque PPL (type IV) cages, two or three to a cage, males and females separated. They had free access to a pellet diet, "3113 Altromin", and vitamin C enriched tap water.
• the room temperature was set at 21 ⁇ C ⁇ 2 ⁇ C and the relative humidity at 55% ⁇ 15%.
• the air was changed 6 times an hour, and the light was on from 06 to 18 h.
• the acclimatization period was one week.
• control substance was Indomethacin 10%, and the test substance was sucralfate 5%, both in a vehicle of paraffin oil, Ph.N.
• both flanks of the animals were clipped free of hair and shaved with an electric razor.
• the unaneasthetized animals were restrained on the side opposite that which was to be exposed to the light.
• a rubber sheet with two ope ⁇ nings with a diameter of 4 cm (each about 12.5 c ⁇ r) was placed on the clipped and shaved flank of each animal and the rest of the body was covered in order to protect the animal from the UV-light, except for the two treatment sites.
• Two guinea pigs at a time were subsequ ⁇ ently exposed to light from ultraviolet lamps (Tl 20/12, UVB, Phi ⁇ lips), at a distance of 6 cm for 20 minutes.
• the animals were read blindly, and the erythema reduction scores for each substance were averaged.
• the vehicle control average has been substracted from the positive control average and test substance average, respectively, to yield the net erythema reduction activity.
• sucralfate exerts the same protection as indomethacin against the development of light-induced erythema, when
• SUBSTITUTE SH applied topically to the skin of guinea pigs 2 hours before UV-ex- posure.
• Example 7 B The preparation of Example 7 B was evaluated in 20 dogs with chronic red eyes presumably due to infections and allergic reactions.
• the eye drops were applied to fornix inferior morning and evening.
• the same preparation was used in the treatment of chronic congestion of the tear canals of purebred cats.
• Ten cats were investigated, and in all ten cases there was a complete cure with cessation of tear flooding within 2-3 days of treatment. The effect of the treatment was at least as good as that obtained with steroid therapy.
• the same preparation was used as nasal drops for three cats with chronic recurrent upper air passage infections. One drop was applied to the nostrils morning and evening, and no other treatment was given. In all three cases the cats were completely free of symptoms of air passage infection after 2-3 days of treatment.
• the primary eye irritative effect of the sucralfate eye drops of Example 7 B) was tested in rabbits. The testing was done on four SPF albino female rabbits. Only the left eye was treated and the right eye served as an untreated control. About 0.1 ml of the test prepara ⁇ tion was applied to the eye by gently pulling the lower eyelid away from the eyeball to form a cup into which the test substance was placed. The lids were then gently held together for about one second.
• Mean score values as determined by a variety of different standard criteria, for cornea opacity, iris lesion, redness of conjunctiva and oedema of conjunctiva (chemosis) were all 0.0.
• Thrombus formation due to a central vein silicone catheter was in ⁇ vestigated with and without a sucralfate coating in a guinea pig model.
• the local tissue reaction to such catheters implanted in muscle tissue was also studied.
• Each catheter had a length of about 15 cm.
• Four catheters were coated by a dip-coating technique with a microcrystalline suspension of sucralfa ⁇ te (40% w/w) , and the catheters were sterilized by radiation.
• Silicone catheters (2 mm) were inserted surgically in the jugular vein, until the tip reached the level of the bijugular junction. The outer end of the catheter was bent and fixed to the muscle tissue close to the vein. The skin was closed according to routine proce ⁇ dures. Two other catheters were inserted transversely in the lumbar part of the longissimus dorsi muscle. Each catheter was inserted via a small medial skin wound and led out through another small skin wound, and then subcutaneously tunnelled back to the first skin wound. In guinea pig no. 1 the coated catheters were inserted on the right side and uncoated controls on the left side. In guinea pig no. 2 the position of catheters was the opposite.
• Both guinea pigs were anaesthetized and exsanguinated one week after surgery.
• the quantity of thrombus masses around the intravasal cathe ⁇ ters and on the vein was recorded.
• the intramuscular catheters were removed and pieces of muscle tissue and subcutaneous tissue around the catheter canal were isolated and fixed for subsequent microscopy.

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