JP2723473B2 - Uses of sulfated saccharides - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a cosmetic composition, and more particularly to a cosmetic composition effective for preventing or preventing aging of the skin and for preventing or preventing dandruff.

[0002]

BACKGROUND OF THE INVENTION Although it is difficult to adequately explain the phenomenon of inflammation by the potential cellular events of damaged tissue, it has been recognized that the process is generally unique. There are several features that have been described. These features include perforation of the microvasculature, leakage of blood components into the intervening space, and migration of leukocytes to inflamed tissue. In addition to these features, visible features are commonly associated with the well-known clinical signs of erythema, edema, tenderness and pain. During this complex reaction, chemical mediators such as histamine, serotonin, leukotrienes, prostaglandins, various chemotactic factors, bradykinin, lymphokines, quinine and complement, lysosomal enzymes and cyclic nucleotides (Medi
ator) is released locally. Phagocytic cells migrate to the damaged area, disrupting the cell's lysosomal membrane and releasing lytic enzymes. All of these phenomena are involved in the inflammatory response.

[0003] A number of drugs have been utilized to suppress the development of inflammation, including a large group of drugs consisting of corticosteroids, so-called non-steroidal anti-inflammatory drugs or NSAIDs, and immunosuppressive drugs. There are agents such as chloroquine, penicillamine and gold salts. NSAIDs are a class of chemically heterogeneous pharmaceuticals that are primarily composed of aromatic substituted carboxylic acids. This drug has pharmacologically anti-inflammatory, antipyretic and analgesic effects and inhibits prostaglandin synthesis and reduces platelet aggregation. Although the mode of action of NSAIDs is not yet fully understood, NSAIDs are known to inhibit one or more inflammatory mediators. However, there is no sufficient correlation between inhibition of prostaglandin synthesis and anti-inflammatory effects. The main indications for NSAIDs are
Rheumatism, especially when inflammatory effects in the supporting tissue cause pain and joint ankylosis. In addition, its analgesic effect can be used to reduce symptomatic pain in patients who can take advantage of prostaglandin inhibitory effects, such as dysmenorrhea, urolithiasis, and the like. Some drugs, including indomethacin, are also used topically on the skin to treat various dermatoses and as anti-inflammatory agents for topical use in the eye.

[0004] The use of NSAIDs has wide spectrum side effects. Serious and often fatal blood disorders are often present, especially when phenylbutazone is used, and gastrointestinal side effects commonly occur with phenylbutazone, salicylate and indomethacin. Allergic reactions are commonplace, but in some patients, prostaglandin inhibition is caused by a secondary increase in leukotriene levels. Hepatotoxicity and nephrotoxicity and central nervous system side effects are also common to these drugs.

[0005] Corticosteroids and especially glucocorticoids have strong anti-inflammatory effects when used in pharmacological doses. These drugs specifically inhibit the inflammatory effects of the early vascular phase by reducing vascular permeability and consequently granulocyte migration. Glucocorticoids also inhibit the growth of mesenchymal cells and the production of intercellular macromolecules, including proteoglycans and collagen,
Inhibits late-stage inflammatory and repair actions. Experiments have shown that glucocorticoids, for example, inhibit macrophage function, production of humoral antibodies, cellular immunity, and sometimes lysosomal enzyme release. The applicability of using glucocorticoids systemically is very limited, apart from replacement therapy, due to side effects, and is associated with severe rheumatic diseases, tracheal anti-asthma, and allergic diseases such as helplessness. Severe patients and patients with blood, kidney and gastrointestinal immune disorders must be restricted. Glucocorticoids can be used in inhaled treatments for asthma, topical application to the skin of almost all patients with dermatosis, injection into joints, bursae, tendons, etc., because the risk of side effects is very low for topical use.
And widely used for topical anti-inflammatory treatment of the eyes, ears and nose. The most serious side effects associated with this topical use are:
Atrophy of skin and mucous membranes, acne and microbial superinfection. In the eye, steroids are in fact contraindicated in many patients because corneal ulceration, glaucoma, and viral superinfection are serious side effects that are feared.

Other anti-inflammatory drugs include penicillamine,
There are chloroquine, gold salts, and cytostatics. The main indication for these drugs is severe rheumatoid arthritis. All of these drugs are administered systemically and cause many serious side effects. Thus, there appears to be a need for other agents that are used locally and systemically to suppress or modify the inflammatory response. Sucralfate, a sulfated saccharide, is primarily used to treat gastric and duodenal ulcers (see US Pat. Nos. 3,432,489, EP 161816 and 192640) and to treat vomiting and diarrhea in dogs and cats (Europe). And Japanese Patent No. 133880). Sucralfate in a form labeled with radioactivity is used as a diagnostic agent for imaging the gastrointestinal mucosa. This is because the substance selectively binds to ulcerated areas in the stomach and upper small intestine (see EP 107209).

[0007] American Journal of Gastroenterology,
80 (3), pp. 206-209, 1985, “Sucralfate: New A
spects in Therapy of Ulcers and Lesions ”and Second International Sucralfate in Stockholm
Symposium Together With the World Congress of Gast
Roenterology suggests the use of sucralfate for a variety of non-ulcer applications, including the treatment of stomatitis, post-sclerosing ulcers, ruminant esophagitis and bile ruminant esophagitis, and treatments that interfere with the ulcerogenic effects of aspirin. ing.

[0008]

Surprisingly, it is surprising that polysulfated saccharide is applied to the skin and mucous membranes topically and when injected systemically, it has an anti-inflammatory effect and very interesting other It was found to be effective. Thus, in one embodiment, the invention is directed to the prevention or treatment of the development of inflammation or infection, the treatment or prevention of non-bladder precancerous or cancerous diseases, the stimulation of skin, connective tissue or non-oral mucosa or the prevention of burns. Or treatment,
Or topical application to animal or human skin, non-gastrointestinal or non-oral mucosal surfaces, including lining of body cavities, for the prevention or treatment of skin, connective tissue or mucosal aging, or animal or human, A medicament for injection into tissues including joints or transplantation into a surgical wound or body cavity; or a medicament for systemic injection for treatment or prevention of infectious, malignant or allergic / immune diseases. Sulphated sugars for production;
It relates to the use of the salt or the complex compound.

[0009] The means commonly used in conventional skin care are often inadequate for treating irritation and inflammation, such as eczema, rashes and burns, caused by re-contacting the skin with irritants. Because burn patients are more likely to become infected in other ways, it is desirable to heal the skin quickly. This is also true for patients with ostomy, where they often become inflamed, sometimes causing ulcers, presumably due to prolonged contact with body secretions. Ostomy instruments currently in use are not completely liquid-tight, and water is often formed where they are sealed to the skin. Persistent ulcers or inflammation may cause moderate to severe discomfort such as pain, itching, and tingling. Despite strong research to solve the problems associated with treating skin and mucous membrane disorders and similar conditions as described above, no successful treatment or prevention has yet been invented .

[0010] The efficacy of polysulfated sugars such as sucralfate for their anti-inflammatory effect has only been disclosed in published literature using sucralfate in the gastrointestinal tract, primarily for the treatment of peptic ulcers. Absent. In addition, European Patent Application No. 230023, which relates to the use of sulfated sugars to promote wound healing, states that when sucralfate is applied to a wound, it produces an inflammatory response. It is also stated that a low level of 0.1 to 1 mg / ml of the potassium salt of sucrose octasulfate, a polysulfated sugar, is preferred to avoid local bleeding or inflammation of the wound. Contrary to this,
According to the present invention, an excellent anti-inflammatory effect was obtained by using sucralfate topically on the skin and mucous membranes. This invention has demonstrated that the potassium salt of sucrose octasulfate has a strong anti-inflammatory effect when used topically and systemically.

In an in vitro model, an aqueous suspension of sucralfate, upon administration, inhibits PHA-activated production of cytokines interferon gamma and interleukin-2 from normal human mononuclear cells. It turned out that. This suggests that sucralfate and possibly the dissolved and ionized sulfated sugar sucrose octasulfate exert a potent anti-inflammatory effect (Example 14).

[0012] Clinical animal studies have shown that the potassium salt of sucrose octasulfate has good solubility resistance when applied topically to surgical wounds and when given intravenously. Following surgery, cats and dogs were administered a 20 mg / ml solution of potassium sucrose octasulfate at a dose of 5 mg / kg body weight following surgery. Body temperature quickly normalized and the wound healed without suppuration or inflammation.
Similar treatment was effective in treating chronic rhinitis associated with influenza in cats and in dogs with aspiration pneumonia. These results suggest that sucrose octasulfate, a polysulfated sugar, exerts potent anti-inflammatory and anti-infective effects (Example 13).

It has been shown that sucrose octasulfate potassium salt exerts an anti-inflammatory effect comparable to indomethacin when applied topically to the skin to protect against light-induced erythema. This could be demonstrated in animal experiments (Example 9). The tolerance of the 2% aqueous suspension of finely ground sucralfate was tested in a rabbit eye test. It was concluded that the test article did not irritate the eye because there was no sign of any irritation or inflammatory response around the conjunctiva, cornea or eye (Example 11). Clinically, this suspension showed significant anti-inflammatory effects and anti-infective results when treating eye diseases in dogs and cats (Example 10).

In a human clinical trial (Example 8), 50
% Of sucralfate was used to treat rashes due to severe tanning in children who had a short bowel following colectomy, and then the powder was used to treat inflammation of ulcerative skin around ileostomy. In all patients, the effect was dramatic and suggested a strong anti-inflammatory effect of sucralfate. As a next step, wound pasta containing sucralfate was tested to treat foot ulcers. Chronic ulcers of the etiology of arteriosclerosis and venous stasis were selected for study. About half of the patients showed significant wound healing. However, the most glamorous effect is that all patients
Immediate reports of pain relief and a reduction in tissue edema and skin inflammatory response around the wound.

Based on the observation of the possible anti-inflammatory effect of sucralfate, tests were carried out on drugs topically administered as creams or ointments for various dermatoses.
Significant clinical effects were noted when treating atopic dermatitis, psoriasis and toxic hand eczema. The effect obtained is
Sucralfate has been shown to cause an anti-inflammatory effect at least comparable to that of corticosteroids in treating steroid-responsive skin diseases (Example 8).

The entire group of sucrose octasulphate and possibly polysulphated saccharides has a unique combination of anti-inflammatory and wound healing or tissue stimulating activity (known anti-inflammatory activities such as steroids and NSAIDs). (As opposed to drugs) have become an interesting new class of compounds to be used as a replacement for traditional anti-inflammatory drugs.
Furthermore, it has been reported that sucralfate, an aluminum complex of sucrose octasulfate, has extremely high solubility resistance, as reported to have no side effects after being used for the treatment of peptic ulcers. Due to the very high solubility resistance of sucralfate and sucrose octasulfate when used regularly, sucrose octasulfate and possibly other polysulfated sugars are very attractive alternatives to conventional anti-inflammatory drugs Became.

In addition, sulfated sugars such as sucrose octasulfate are expected to modify or block the inflammatory response and / or stimulate the tissue regeneration process through other steps. However, the mechanism is not fully understood.
One sulfated sugar, sucralfate, has been observed to preferentially bind to the surface of ulcers when used internally in treating peptic ulcers. This is a property common to sulfated sugars, and it is presently believed that the above linkages are the result of the binding properties of sulfated sugars to proteoglycans and hyaluronic acid. These structures are components of the surface of many cells that protect and stabilize cells and keep the surface of outer cells intact. In other cases, for example, in the dermis and supporting tissues, proteoglycans and hyaluronic acid form a protective matrix in which cells are embedded. Some more sulfated sugars, such as heparan sulfate,
Dextran sulfate and xylose sulfate are hyaluronidase inhibitors.

Hyaluronidase is an enzyme that catalyzes the cleavage of the glycosidic bond between hyaluronic acid and glycosaminoglycan. Therefore, by the breakdown of hyaluronic acid and glycosaminoglycans by hyaluronidase, the cell surface or supporting matrix material is disrupted and the cells are exposed and exposed to pathogens, inflammatory mediators, inflammatory agents, and corrosives. It is damaged by various drugs. Therefore, by inhibiting hyaluronidase, it is thought that the sulfated saccharide promotes the regeneration of the cell surface and the matrix of the protective connective tissue, and thus has an anti-inflammatory effect and a tissue regeneration effect.

Degradation products of hyaluronic acid glycosaminoglycan also act as mediators of inflammation itself, and by inhibiting or modifying the above-mentioned degradation reaction, sucrose octasulfate and other sulfated sugars cause the inflammatory response. Inhibit or modify to facilitate and modify tissue regeneration. Therefore, it is believed that the above pharmacological effects of sucrose octasulfate and other sulfated sugars "enhance" the epithelial and mucosal lining. Apart from exerting an anti-inflammatory effect, this enhancement of the outer surface of the cells and the connective tissue matrix makes it more difficult for bacteria and viruses to penetrate cells and tissues and colonize them. Instead of a direct antimicrobial effect, an indirect effect is obtained by applying sucrose octasulphate or other sulfated sugars to the mucosal and epithelial surfaces. Thus, these compounds can be used topically in the treatment of bacterial, viral or fungal infections of the skin and mucous membranes. This antimicrobial effect can be exploited by applying sucrose octasulfate or other sulfated sugars directly to the supporting tissue in connection with the surgical procedure. Many infections are spread in tissues by hyaluronidase produced or induced by the pathogen itself. It is believed that the hyaluronidase inhibitory effect of sucrose octasulfate or other sulfated sugars prevents such infections from spreading.

Such anti-inflammatory and anti-infective effects can be further utilized when implanting or inserting a medical device into a body. The incorporation of sucrose octasulfate or other sulfated sugars into the surface coating of the device or the material of the device itself reduces the inflammatory tissue reactions that occur around the device, including infection and thrombophlebitis response (Example 12). Examples of devices that can use such techniques include urinary catheters, peritoneal catheters, such as dural spinal catheters, venous and arterial catheters, electrodes, breast prostheses, pacemakers, middle ear tubes, eyepieces, blood vessels Prostheses, hip prostheses, and the like. Other uses include the coating of materials that are placed on the skin or mucous membranes for an extended period of time, such as atomic plates, external prostheses and the like.

It is further believed that the "enhancing / decorating" effects of sucrose octasulfate and other sulfated sugars on the cell surface can be used to treat malignant diseases. Examples include topical application of sucrose octasulfate or other sulfated sugars to lesions of superficial skin and mucosal malignancies such as basal cell carcinoma, cervical dysplasia and cervical cancer, etc. This is sometimes the treatment by placing a depot preparation that releases sucrose octasulfate and other sulfated sugars in the surrounding tissue that has undergone surgery for the malignancy.
Injecting sucrose octasulfate or other suitable preparations of sulfated sugars into the bloodstream is believed to be effective against the following diseases due to its cell surface repair effect. Leukemias and other types of hematological or systemic malignancies characterized by the infectivity of blood cells by the virus or virus-like body; allergic blood diseases; AIDS and other types of viral infections; bacteria It is effective against septicemia; and infectious diseases that cause malaria and other types of blood cells. Also,
It is believed that sucrose octasulfate or other sulfated sugars can be used systemically to treat immune diseases and restore a systemic immune response. An example of the latter type is an LED (lupus erythematosus
disseminatus), dermatomyositis,
These include amylopathy, osteoarthritis, scleroderma, sarcoidosis and the like.

Furthermore, sucrose octasulfate and other sulfated saccharides have a cell surface repairing action,
Useful as an additive to the growth medium of cell cultures in vitro. The invention further relates to pharmaceutical preparations, in particular for use in any of the above uses, wherein the preparations are sucrose octasulphate and other sulfated sugars or salts or complexes thereof alone, or as a pharmaceutical with these compounds. And acceptable excipients.

In yet another aspect, the invention is directed to the prevention or treatment of non-bladder precancerous or cancerous diseases; the prevention or treatment of skin, connective tissue or non-oral mucosa irritation or burns; Or to prevent or treat mucosal aging; including lining a body cavity, comprising applying a therapeutically or prophylactically effective amount of a sulfated sugar or salt or complex thereof to skin, mucous membranes or tissues. A method of preventing or treating the occurrence of inflammation or infectious disease on animal or human skin, non-gastrointestinal or non-oral mucosal surface, and a therapeutically or prophylactically effective amount of sulfated saccharide or a salt or complex thereof, Infectious, malignant or allergic / immune in animals or humans consisting of systemic injection into animals or humans To a method of preventing or treating disease.

Important aspects of the invention are apparent from the claims. The sulfated sugars used according to the invention are monosaccharides such as xylose, fructol or glucose; oligosaccharides, especially disaccharides such as sucrose, lactose, maltose, cellobiose; or dextran, heparin, dermatan, proteodermatan, heparin. , Chondroitin, amylose, glucosamine, glucosaminoglycans and polysaccharides such as mucopolysaccharides or subunits thereof.

For some patients, the sulfated saccharide may be advantageous when used in combination with other wound healing substances such as non-sulfated polysaccharides, for example, hyaluronic acid (Example 7).
reference). The saccharide is preferably a polysulphated saccharide or a persulphated saccharide, meaning that two or more, preferably all, sulfur-containing molecules are present as substituents on the carbohydrate moiety. I have.

In some cases, the sulfated sugar is a metal such as an alkali metal or alkaline earth metal such as N
a, K, Ca, Mg or Ba or Al, Zn, C
It is complexed with u, Zr, Ti, Bi, Mn or Os or forms a salt with the metal. Currently preferred salts are the potassium and sodium salts. Preferred oligosaccharides are monosaccharides and disaccharides. Most preferably, the compositions of the present invention contain a persulfated disaccharide, optionally sucrose octasulfate.

This material is described, for example, in EP 2300
Manufactured as disclosed in No. 23. The sulfated saccharide may be administered neat, but is generally provided in a form suitable for topical or systemic application in combination with one or more pharmaceutically acceptable carriers or excipients. In other words, powders, pastes, ointments, lotions, gels, creams, paints (salve), emulsions, solutions,
In the form of a liquid, semi-solid or solid topical formulation such as a suspension, spray, sponge, strip, plaster, pad, dressing or ostomy plate.

For topical application, the formulations can be prepared according to normal pharmaceutical practice, using pharmaceutical excipients commonly used for topical application as described below. That is, as excipients, pectin, gelatin and derivatives thereof, polymers or copolymers of polylactic acid or polyglycolic acid, cellulose derivatives such as methylcellulose or carboxymethylcellulose or oxidized cellulose, guar gum, gum arabic, gum karaya, gum tragacanth, bentonite , Agar, carbomer, bladder lac, seratonia, dextran and its derivatives, Guatei gum, hectorite, Ispagra fsk, polyvinylpyrrolidone, silica and its derivatives, xanthan gum, kaolin, talc, starch and its derivatives, paraffin, water, vegetable oil and Animal oil, polyethylene, polyethylene oxide, polyethylene glycol, polypropylene glycol, glycerol, ethanol, propanol, professional Lenglycols (glycols, alcohols), fixed oils, sodium, potassium, aluminum, magnesium or calcium salts (eg chloride, carbonate, bicarbonate, citrate, gluconate, lactate, acetate, Gluceptanoate or tartrate).

The formulation of the present invention may also use other additives such as emulsions, stabilizers, preservatives and the like. For use in the treatment of respiratory disorders, the formulations of the present invention are formulated as powders, solutions or suspensions for inhalation, spray formulations or similar suitable formulations. Dressings such as plasters, sponges, strips, pads and the like can be manufactured by impregnating a dressing material such as cotton wool or gauze or a polymeric substance with a solution or suspension of sulfated sugar and then drying. Alternatively, a paste, lotion, cream or gel containing a sulfated sugar can be conveniently cast onto a dressing just prior to use.

For example, for the treatment of mucous membranes such as the mucous membranes of the cavities, nose and eyes, the formulations of the invention may be used, for example, for suppositories for cavities,
Gels, ointments, solutions or suspensions or cavity inserts, nasal solutions, suspensions, gels, ointments or inserts, or ophthalmic solutions or suspensions, gels or ointments Alternatively, it is prepared in the form of an insert for the eye. Such formulations may be manufactured according to normal pharmaceutical practices using some of the above conventional excipients.

In general, the pharmaceutical preparation of the present invention contains the sulfated saccharide in an amount of 0.001 to 99% by weight, generally 0.01 to 75% by weight, more generally 0.1 to 20% by weight, especially 1 to 10% by weight based on the total preparation. Contains. In particular, when the sulfated sugar is sucrose octasulfate, the preferred concentration in the preparation is 0.
5 to 50%, especially 0.5 to 25%, for example 1 to 10%.
Depending on the type and severity of the condition to be treated, 1 to 10 per day
It is appropriate to apply once.

The concentration of sulfated saccharide used for a particular nuclear patient depends, of course, not only on the type of the preparation and the intended use, but also on the solubility characteristics of the sulfated saccharide. The sugar content also depends on the particle size and form of the preparation. In addition, the smaller the particle diameter, the faster the partitioning of the sparingly soluble or substantially insoluble sulfated sugar or its complex. Insoluble or hardly soluble salts or complexes of sulfated saccharides are preferably used in the form of fine powder having a particle diameter of, for example, 200 μm or less, more preferably 100 μm or less. An example of a very small particle size that is desirable for some purposes is 50 μm.
m, and even 20 μm or less, and in some cases,
It is 10 μm or less and further 5 μm or less.

The preparation of the present invention may contain the following active agents in addition to the sulfated saccharide. That is, antibacterial agents, antiviral agents, antifungal agents, anthelmintics, tanning agents, vitamins and vitamin derivatives or their analogs, antineoplastic agents, antifibrinolytic agents, blood coagulation modifiers, preservatives, analgesics , Local anesthetics or anti-inflammatory agents. as mentioned above,
Sulfated sugars are useful in applications related to skin, mucosal or tissue conditions, including irritation, inflammation or burns, or in the prevention of skin ulceration. In addition, contact with external chemicals (eg, allergens or corrosive substances such as acids or bases) or body secretions such as urine, sweat or gastrointestinal secretions and external pressure, heat, ionizing radiation or light ( Treating skin conditions caused by sulfated sugars caused by the present specification and claims (including ultraviolet light); or as a preventive measure to prevent skin damage caused by the above drugs or secretions. The addition of sulfated sugar has proven to be particularly advantageous.

Examples of specific diseases for which the use of sulfated saccharide is therapeutically or prophylactically necessary are as follows.

[0035]Skin diseases (lip, vaginal mucosa and anal area)
Area) Sweat rash: eg adhesive plaster patch or excessive heat
Less dangerous skin, such as (tanning, diapers, exercise)
Blocked sweat glands, often caused by skin irritation
It is defined as the production of acute inflammatory prurigo resulting from

Intertrigo: defined as acute superficial inflammation of the opposing skin surface characterized by erythema, abrasion, maceration and, in some patients, superficial cracks. Prurigo: Defined as a general or localized pruritus sensation in which the patient instinctively escapes pain by scratching. Acne and rosacea: Defined as inflammation of the sebaceous glands characterized by seborrheic comedones, pustules, papules and nodules.

Superficial bacterial skin infections such as erythema rubrum; superficial fungal infections such as ringworm and Candida; herpes simplex, shingles, measles, chickenpox, warts, damp warts; nonspecific Vaginosis caused by mycoplasma, fungi of the Mycoplasma, Chlamydia, Candida, Tricomonas, etc. Dermatitis: Defined as acute or chronic superficial inflammation of the skin, with or without microbial infection, characterized by erythema, exudate, scab, scaling and sometimes vesicles. Contact dermatitis, atopic dermatitis, seborrheic dermatitis, neurodermatitis, lichen simplest, drug rash, erythema nodosum,
Includes erythema multiforme, pityriasis rosacea, lichen planus, psoriasis, ichthyosis, congestive dermatitis, and chronic dermatitis of the limbs.

Protective agent against superficial burns such as acute sunburn and sunburn. Secondary skin irritation by placing prosthetic devices, diapers, ostomy pads or the like, bandages, plasters, electrodes, catheters, etc. directly on the skin. Prevention against pressure injuries. Swelling, bunches, swelling, sweat glands and fistulas.

Hemorrhoids, pruritus around the anus and vulvitis.
Active and prophylactic cosmetic treatment for wrinkles and aging skin and dandruff.

Respiratory disease allergic rhinitis: seasonal or perennial sneezing,
It is characterized by rhinorrhea, nasal congestion, and conjunctivitis and pharyngitis.

Acute rhinitis: edema of the nasal mucosa, nasal discharge and nasal congestion, most often caused by the cold virus. Lung disease: intrinsic or extrinsic bronchial asthma, secondary pulmonary inflammatory response to chronic bronchitis, pulmonary dust, pulmonary fibrosis, Goodpasture's syndrome. Inflammatory reaction of the lungs.

Diseases of the ears, nose and throat. Acute otitis externa, furuncleosis of the outer ear and otomycosis.

Traumatic and infectious myringitis. Acute Eustachian otitis. Acute serous otitis. Acute and chronic sinusitis.

Eye Disease Edema in the area of the eye caused by trauma or foreign body or inflammation after surgery.

Eyelid allergy and blepharitis; stye and chalazion. Microbial etiology of acute and chronic catarrhal conjunctivitis. Allergic (spring) conjunctivitis. Trachoma. Scleritis, episcleritis.

Superficial spot keratitis, dendritic (herpes) keratitis, discoid keratitis and corneal wounds. Iritis,
Iridocyclitis. Systemic I. as anti-allergy / immunomodulation, anti-inflammatory treatment for the following diseases: V. Treatment

Diseases of the connective tissue Systemic lupus erythematosus, polyarteritis nodosa, scleroderma, polymyositis, dermatomyositis, rheumatoid arthritis. Allergy / immune disease hypersensitivity, serum disease, hemolytic anemia, allergy / toxic agranulocytosis. Malignant disease acute leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia,
Hodkin's disease, lymphosarcoma, myeloma, metastatic cancer of any origin, metastatic myeloma. Infectious disease AIDS, cellular sepsis, systemic fungal infection, ricketsia disease, toxic shock syndrome, infectious monocytosis, cytomegalovirus infection, influenza, polio, malaria, leishmaniasis, trypanosomiasis, toxoplasmosis, Lassa fever, yellow fever.

Local injection or transplantation or topical application of the following precancerous or cancerous diseases: situ colli u
Teri cancer, jaw cancer, endometrial cancer, cancer at the surgical site of cancer of any origin, basal cell carcinoma. Treatment of the following tissue, bone, joint or musculoskeletal disorders by injection.

Tendonitis, tenosynovitis, fibrotitis, bursitis,
Fibromyositis, myositis, connective tissue and epicondylitis, overwork and sprains, torsion, dislocation, carpal tunnel syndrome, fasciitis, rheumatoid arthritis synovitis, infectious arthritis, arthritis uric
a monoarthritis, myelitis, chondrosclerosis, Rieter syndrome, osteomyelitis, osteomyelitis. A method of tissue transplantation associated with a surgical procedure at a surgical site to achieve an anti-infective, anti-inflammatory, and tissue organizing / regenerating effect.

As mentioned above, when sucralfate is applied internally to the treatment of gastric ulcers, it is observed that it preferentially binds to the surface of the mucosa of the wound, which is a property common to polysulfated sugars. Conceivable. Thus, when the mucosal lining is destroyed by ulcers or malignant effects, polysulfated sugars specifically bind to that area. This property is based on barium, zirconium, titanium, osmium salts,
Alternatively, sucrose octasulfate or other polysulfated sugar X-ray dense formulations can be used for X-ray diagnostics.

The present invention will be described with reference to the following examples, but is not limited thereto.

[0052]

【Example】

Example 1 A topical powder formulation was prepared from the following ingredients. Sucralfate * 30g Pectin 10g Gelatin 10g Carboxymethylcellulose 10g * Abic Laboratories,
Provided in fine powder form by Israel.

Fine powdered sucralfate (particle size 2 to 100)
μm) was sufficiently mixed with other fine powder components (particle size <250 μm) to obtain a powder.

Example 2 A topical ointment preparation was prepared from the following components. Sucralfate 30 g Pectin 10 g Gelatin 10 g Carboxymethylcellulose 10 g Fractionated coconut oil 60 g Finely ground sucralfate (particle diameter 2 to 100 μm) was thoroughly mixed with other fine powder components. Fractionated coconut oil is added to the obtained powder to obtain an appropriate consistency.
In y), a dispersion having a substantially uniform particle component was obtained.

Example 3 A topical ointment preparation was prepared from the following components.

Sucralfate 30 g Hyaluronic acid 0.6 g Pectin 10 g Gelatin 10 g CMC 10 g Fractionated coconut oil 60 g Fine sucralfate (particle diameter 2 to 100 μm) was mixed well with other fine powder components. Fractionated coconut oil was added to the obtained powder to obtain an appropriate consistency to obtain a dispersion having a substantially uniform particle component.

Example 4 A topical ophthalmic preparation was prepared from the following components.

Sucralfate * 2% Carbopol 934 0.5 Mannitol 5% Benzalkonium chloride 0.01% EDTA sodium 0.05% Sodium hydroxide Adjust to appropriate pH 6 Add sterilized water to 100% * Guilini Chemie, manufactured by West Germany Powdered sucralfate (particle size 10 μm).

Example 5 Ophthalmic Preparation An ophthalmic preparation was prepared from the following components.

Sucralfate * 2% Propylmethylcellulose 0.35% Benzalkonium chloride 0.01% Sodium EDTA 0.05% Sodium chloride 0.8% Sterilized water qs * Guilini Chemical Ludwigshahen (Guilin
i Chemie Ludwigshafen, West Germany, fine powder (10μ)
m).

Example 6 A topical preparation for skin and mucous membrane was prepared by adding 5% by weight of sucralfate powder (particle size: 50 to 100 μm, Guilini Chemical Ludwighagen, West Germany) to cetyl alcohol,
Wool oil concentrate, isopropyl myristate, Tween
60, span 60, dimeticone, glycerin, sorbic acid and a mixture of sterile water to prepare.

Example 7 A topical preparation for skin and mucous membrane was prepared from the following components.

Sucralfate powder * 5% Paraffin oil, glycerin, cetyl alcohol 55% Quaternary ammonium compound 0.7% Stearyl alcohol 3% Eucalyptus oil qs * Fine powdered sucralfate (Guirini Chemical Co., West Germany) (≦ 10 μm).

Example 8 Human Clinical Trials A) Two infants (boys and girls) who underwent surgery to cure congenital megacolon (Hirsisprung's disease)
Severe rash with erythema, inflammation and pustules occurred (presumably due to shortened intestine, possibly due to contact with digestive enzymes and sometimes acid). The formulation of Example 1 was applied to the affected skin each time the diaper was changed. 1 to treat
Symptoms improved dramatically after a day and the rash disappeared completely 2-3 days after treatment. This treatment continued for 6 months. During the first 4 months after surgery, the eruption recurred if daily application of the sucralfate-containing powder was interrupted. However, after six months, treatment could be stopped, for example, occasionally recurring after diarrhea.

B) A tumor patient having an ileal fistula that developed an ulcer around the ileal fistula (fistula: ileostomy) was treated with the preparation of Example 1. A control group of 10 other patients who also developed ulcers around the ileal fistula was treated with a powder formulation containing the same amounts of pectin, gelatin and carboxymethylcellulose (ie the formulation of Example 1 without sucralfate) did. Each patient applied the powder every time he changed the ostomy bag over a two week period.

Three days after the start of the treatment, no ulcers were found around the ileal fistula in the group of patients treated with the sucralfate-containing powder, while seven of the patients in the control group had greater than The ileum showed an ulcer around the fistula. After two weeks of treatment, one of the patients in the group treated with the sucralfate-containing powder developed ulceration in two periods of the following three days, one died and the other remained ulcer-free throughout the period. Was. In the control group, two patients did not develop ulcers during the entire period, while all other patients developed ulceration and severe irritation for more than the next two days.
Two of the patients developed ulcers around the ileal fistula over the entire period.

Based on these studies, it was concluded that the formulations of the present invention were successful in treating skin ulcers and similar conditions caused by gastrointestinal secretions. Test B)
Indicates that sucralfate is more involved in the improvement than the other components in the composition. C) Fourteen elderly patients (49-86 years, average 70 years) with ischemic or venous stasis chronic leg ulcers were treated with the formulation of Example 2. At the start of treatment, a debridement operation was performed. The wound was then filled with paste and, depending on the nature of the surrounding skin, the area of the wound was covered with a plastic film or parchment paper. When changing weekly, if excess paste was present, the treatment was repeated with careful removal of excess paste so as not to destroy the granulation tissue. That is, the wound was filled with fresh paste and covered the wound area. Seven patients had a complete or almost complete healing 2-3 months after treatment. The wound healing effect was evaluated by measuring the wound size of each control. During the first month of treatment, the wound size of nine patients decreased, with the initial wound size decreasing to an average of 76% for nine patients. Three patients had no effect on wound size and the last two patients did not measure. Wound pain is 0 =
No pain-rated on a scale of 3 = strong. For all patients, pain was generally significantly reduced within hours after application of the paste to the wound. Edema in surrounding tissues is reduced,
Healing of the macerated and inflamed skin around the wound was observed. Most wounds initially had fibrin, pus, and yellow necrosis. These turned into "red wounds" with uninfected, clean red granulation tissue after treatment in all patients. Table 1 shows the average scores of pain and burning during the baseline and the following 4 weeks of treatment.

[0068]

[Table 1]

Sucralfate, used topically for chronic leg ulcers, appears to have a distinct wound healing effect. At the same time, there was a pronounced anti-inflammatory effect of the sucralfate wound paste. In other words, the edema in the tissue was slightly increased, the inflammation around the wound was caused, and the macerated skin was healed. D) The anti-inflammatory effect of sucralfate on various skin diseases was evaluated in adult patients with atopic dermatosis, psoriasis, toxic hand eczema and folliculitis. A formulation containing 5% by weight sucralfate powder was mixed with a fat excipient containing chamomile (6%) and arnica (4%) herbal extract. The resulting ointment was applied in the morning and evening. Table 2 shows the demographic data and diagnosis results for the treatment of the patients included in the study.

[0070]

[Table 2]

When topical sucralfate ointment was applied twice daily, all 51 patients improved or healed completely. All but two women with local psoriasis and seven men with beard folliculitis had previously received extensive topical treatment with steroids. Patients with atopic dermatitis had a history of 10 to 20 years, and all had rebound after steroid use. Significantly improved 10 days after treatment with sucralfate ointment, 10 out of 14 patients with atopic dermatitis healed in the sense that there was no dermatitis symptoms during the treatment period of up to 8 months. Patients with psoriasis showed improvement after 2-4 weeks of treatment, and the improvement was maintained for all patients during the entire treatment period. Patients with toxic hand eczema showed improvement after one week and three patients were completely cured. About beard folliculitis,
A good effect was obtained with a treatment period of a few months, and women with symptoms of vulvar vaginitis disappeared their pruritus. 156
No side effects were seen during treatment with sucralfate ointment for the entire patient month.

In some clinical patients, topical application of sucralfate to the skin and mucous membranes resulted in significant antimicrobial effects. E) Two patients with superficial fungal skin infections (ringy)
The kralphate formulation of Example 6 was applied. There was a significant improvement after one day. When the sucralfate formulation was applied twice a day for three days, the skin had no clinical signs of a fungal infection.

F) Two women with severe long-term nonspecific vaginitis suspected of being infected were administered the sucralfate formulation of Example 7. The ointment was applied to the vaginal mucosa twice a day. After two weeks of treatment, both patients had a complete clinical cure. Both patients had previously received any kind of topical treatment, including steroids and antimicrobial agents, but had been ineffective for years.

G) Sucralfate ointment of Example 6 was used topically for herpes labialis. The ointment was applied six times a day and treatment was started as soon as possible after the herpes rash. Four young women were evaluated. The treatment was successful for all four patients with reduced pain and reduced herpes incidence. The skin was completely healed within 2-4 days after starting treatment.

H) The sucralfate ointment of Example 6 was tested in the treatment of acne vulgaris. To three women 16-20 years old,
Ointments were applied topically in the morning and evening. One day after treatment the inflammatory response of the skin was significantly reduced, and one week later the number of vesicles was reduced. Three anterior patients had previously attempted a variety of anti-acne treatments, including vitamin A and systemic antibiotics. Sucralfate had a more permanent effect. And there was no repulsion during the treatment period of up to 3 months.

I) Example 8 The sucralfate ointment described in D) was tested for facial wrinkles around the eyes. 38
Five women aged ~ 45 years used this ointment twice a day,
A beneficial effect was reported after 1-2 weeks of treatment.

Example 9 * Test of UV sunburn (erythema) in guinea pigs 12 young mature SPF albino guinea pigs (male and female, 10
Weekly, 350-400g; Maellegaard Breeding Center
Ltd. (Dunkin Hartley strain).

The animals were placed in an opaque PPL (Type IV) basket
３3 males and females were stored separately. The cages were also allowed free access to pellet feed "3113 Altromin" and tap water enriched with vitamin C. Room temperature was set at 21 ± 2 ° C. and relative humidity at 55 ± 15%. The air was changed six times an hour and the light was irradiated for 6-18 hours. The adaptation period was one week.

The control substance was 10% by weight indomethacin PE
In the G400 suspension, the test substance was sucrose octasulphate, in the form of a 1,3 and 10% by weight suspension of its potassium salt with PEG400. Control excipient is PEG
400. The day before treatment, the animals were shaved on both flanks and shaved with an electric razor. The next day, non-anesthetized animals were fixed on the side opposite to the side exposed to light. A rubber sheet (about 12.5 cm ² each) with ^two openings with a diameter of 4 cm was placed on the flank of each animal's hair which had been slid up and raised, and the rest of the body was protected from UV radiation except for the two treatment sites. Covered to protect animals. Then, two guinea pigs at a time were exposed to ultraviolet light (T1 20/12, JVB, P
(Hilips) at a distance of 6 cm for 20 minutes.

In the center of the two erythema treatment sites (5 cm ² each), 0.05 ml of test substance, control substance or excipient was applied respectively. After application, the substance was rubbed into the skin with the fingertip for about 30 seconds. To determine the protective effect, application was performed 30 minutes before UV exposure. 12 in the positive test group
Each of the 24 flanks of the head animals was treated with both the test substance and 10% indomethacin or vehicle as a positive control. Application of two substances per flank was performed according to a specific system to support random reading quality, except for changes due to anatomical and structural differences in the flank dermis.

At 2, 4, 6 and 24 hours after stopping the UV exposure, the treatment site was read and evaluated according to the following scale.

[0082]

[Table 3]

Animals were read at random and the erythema reduction scores for each material were averaged. The mean value of the vehicle control was subtracted from each of the mean value of the positive control and the mean value of the test substance to give a net erythema reducing activity. The following erythema reducing activities were found. Excipient (PEG 400) 0% Positive control (indomethacin 10%) 100% Test substance 1% (sucrose octasulfate) 5% Test substance 3% (sucrose octasulfate) 22% Test substance 10% ( Sucrose octasulfate) 62% The dose-response relationship shows both the test substance in question and the number of animals is very small, but in this experiment sucrose octasulfate was tanned in guinea pigs to the same extent as indomethacin (UV Irradiation) It can be concluded that erythema of the skin is reduced.

Example 10 * Drops of sucralfate on the eyes and nose of dogs and cats The formulation of Example 5 was evaluated in 20 dogs with chronic red eyes, presumably due to infection and allergic reactions . Eye drops were applied under the fornix in the morning and evening. Of the 20 animals, 14 responded to the treatment, 5 of which
He had not responded to previous treatments with topical ocular antibiotics, including chloramphenicol and fusidin. The effect is seen after 1-5 days and the treatment period is 2 for most patients.
~ 3 weeks. The same formulation was used to treat lacrimal gland chronic depression in purebred cats. 10 cats tested but 10
All cats in the head were completely healed within 2 to 3 days of treatment with no tears flowing out. This therapeutic effect was at least as good as that obtained with steroid treatment. Finally,
The same formulation was used as a nasal drop for three cats with chronic recurrent infections in the upper airflow channel. One drop was used in the nostrils in the morning and evening, and no other treatment was given. All three cats had no signs of airflow infection 2-3 days after starting treatment.

Example 11 * Rabbit eye resistance test of sucralfate ophthalmic drops The primary eye irritation effect of sucralfate ophthalmic drops of Example 5 was tested in rabbits. The test was performed on four SPF albino female rabbits. Only the left eye was treated and the right eye was an untreated control. The lower eyelid of the eye was gently pulled off the eyeball, forming a cup into which the test substance was placed, and containing about 0.1 ml of the test formulation. Next, both eyelids were gently adjusted for about one second.
The eyes were examined and the grade of the eye response was recorded after 1 hour.
Twenty-four hours later, tests were performed before and after instillation of ocoluguttae fluoresceini. After performing the examination, the eyes were rinsed with 20 ml of 0.9% sodium chloride solution. Eyes were examined 48 and 72 hours after treatment. The corneal iris and conjunctiva (including secretions) were examined and reactions and changes were observed and scored. Slight secretions of the conjunctiva were noted in two rabbits on initial examination. The reaction of the conjunctiva, iris or cornea
None of the rabbits were detected at 24.48 and 72 hours post examination.

For corneal opacity, iris lesions, conjunctival redness and conjunctival edema (conjunctival edema), the average score values determined by a variety of different standard criteria were all 0.0. Official Journal of the Europea
n Criteria of Communities, L257, 1983, the directive of
The commissiom, 83/467 / EEC, July 29, 1983, concludes that, according to the above averages, test sucralfate in a 2% aqueous suspension is not classified as an eye irritant.

Example 12 * Prevention of thrombus formation by central vein catheter coated with sucralfate The formation of thrombus by a central venous silicone resin catheter was tested in a guinea pig model with and without sucralfate coating. The local tissue response to this catheter embedded in muscle tissue was also tested. 8
Silicone catheter (7 French Silicon)
e, Durascau Medical Products A / S, obtained from Odense). Each catheter was approximately 15 cm in length.
The four catheters were coated with a microcrystalline suspension of sucralfate (40% by weight) using a dip coating method and sterilized with radiation.

A silicone resin catheter (2 mm) was inserted into the jugular vein by surgery, and the tip was bijugular junction.
Level. The outer end of the catheter was bent to secure it to muscle tissue near the vein. The skin was closed in a conventional manner. Two other catheters were inserted laterally into the hips of the longest back muscle. Each catheter is inserted through a small wound on the middle skin and exited through another small skin,
It is then withdrawn from the first skin wound and passed under the skin.
The first guinea pig had the coated catheter inserted on the right, the uncoated control catheter was inserted on the left, and the second guinea pig had the catheter reversed.

Both guinea pigs have undergone a surgical procedure and
One week later, anesthesia was performed and whole blood was collected. The amount of thrombus clot around the catheter in the blood vessel and in the vein was recorded. The catheter inserted into the muscle was removed, and a piece of muscle tissue and a piece of subcutaneous tissue around the catheter canal were separated, fixed, and subjected to microscopic examination. During the week from the surgical procedure to the complete blood draw, no obvious signs of a reaction to the catheter were noted. The weight of the thrombus found at the front end of the catheter is as follows:

[0090]

[Table 4]

No response was observed in the subcutaneous tissue around any of the catheter canals. A very light gray area was found around the catheter canal in muscle tissue from both the right and left sides. In this regard, there was no difference between the left and right sides. Microscopic examination revealed a subcutaneous membrane rich in mononuclear cells and small vacuoles along the catheter canal, and giant foreign cells were found in the surrounding connective tissue. In these respects, there were no significant differences between the coated and control sites.

Example 13 The clinical effect of the potassium salt of sucrose octasulfate was tested on various infectious / inflammatory diseases of dogs and cats. The animals were replenished from pet hospitals and the disease treated in this way reflects a clinically relevant situation.
A sterile solution of potassium salt 20 mg / ml was used in the following test animals: Test preparation 5 / kg body weight in dogs with fractured femurs
mg was administered intravenously. After surgery, there was no increase in body temperature or other clinical signs due to inflammation or infection.

A dog whose total uterus was removed due to chronic endometriosis was intravenously injected with 5 mg of the test preparation per 1 kg of body weight. After surgery, there was no increase in body temperature, neutrophils (white blood cells) rapidly decreased, and a rapid recovery of physical strength was observed. Dogs with traumatic wounds and torn tendons received 1 ml of the 20 mg / ml test formulation topically at the wound site. After the operation, healed rapidly without purulence.

The cat from which the uterus was removed was administered intravenously with 5 mg of the test preparation per 1 kg of body weight, but after the operation, no inflammatory reaction was observed in the wound at the time of the operation. Two dogs that had undergone surgical treatment for arthritis were topically applied with 5 ml of the test formulation (concentration: 1 mg / ml) to the joint and surrounding tissue during surgery. After surgery,
With little swelling of the joints, the dogs were able to stand on their feet one day after surgery.

Five cats suffering from chronic rhinitis due to influenza in a cat were given a single intravenous injection of the test preparation at a concentration of 1 mg / ml at a dose of 1 mg / kg body weight, and the preparation was administered to each nostril (Nostri
l) Dropwise applied topically to BD). The symptoms of the four cats were greatly improved, nasal secretions were reduced, wateriness was reduced, and leukocytosis was reduced. In a dog suffering from swallowing pneumonia due to gastric vomiting, 5 mg of the test preparation was administered at a concentration of 20 mg / ml.
/ Kg body weight B. D. Was administered by intravenous injection. 2
After a day, body temperature is normal, lung changes due to auscultation have improved,
After 4 days, dyspnea and cough disappeared.

[0096] Even if a potassium sulfate of polysulfated saccharide, sucrose octasulfate is applied to the wound of a surgical operation by topical application (application) or intravenous injection, a microtolerant which is intolerant to any subject. No weather appeared. Treatment with systemic intravenous injections showed clinical improvement in all cases, suggesting a strong anti-inflammatory and strong anti-infective effect of the drug.

Example 14 Interleukin-2 by Spontaneous and Induced Passive Hemagglutination (PHA-induced) Production from Normal Human Mononuclear Cells
(IL-2) and γ-interferon (INF-gamma)
The effect of sucralfate on the production of was tested. Aqueous suspension of micronized sucralfate (10 μm) 10
0 mg / ml was diluted to 10, 1 and 0.1 mg / ml. as a result,
Sucralfate has shown that it does not activate the production of these two cytokins by itself. IL-2 (4,4
PHA of 0,70 U / ml) and γ-INF (0,100,> 100 U / ml)
Activation production was blocked in a dose-related manner. When tested in this in vitro model, it was concluded that sucralfate exhibited an anti-inflammatory effect. The stock suspension of sucralfate 100 mg / ml had sediment,
When preparing diluents of 1 and 0.1 mg / ml, mainly the supernatant was used. Therefore, the above-mentioned anti-inflammatory action is mainly based on sucralfate in a dissolved state, and it is considered that sucralfate exists in the form of almost ionized sucrose octasulfate and aluminum separately. Therefore, it can be said that the anti-inflammatory effect shown in this in vitro model is almost based on polysulfated sugar and sucrose octasulfate.

Industrial Applicability The cosmetic composition of the present invention is effective for preventing or preventing aging of the skin and for preventing or preventing dandruff.

Continuation of the front page (51) Int.Cl. ⁶ Identification code Agency reference number FI Technical display location A61K 31/70 ABJ A61K 31/70 ABJ ADA ADA ADU ADU ADZ ADZ // C07H 11/00 C07H 11/00

Claims (14)

(57) [Claims] 1. A cosmetic composition comprising sulfated sucrose or a salt or complex thereof and an excipient or diluent. 2. The composition according to claim 1, which is applied topically to prevent or prevent skin aging, including the treatment or prevention of skin wrinkles. 3. The composition of claim 1 which is applied topically to prevent or prevent dandruff. 4. The composition according to claim 1, wherein the sulfated sucrose is polysulfated sucrose. 5. The composition according to claim 4, wherein the polysulfated sucrose is sucrose octasulfate. 6. The compound for complexing or salifying a sulfated sucrose is a metal or an organic base.
A composition according to any one of the preceding claims. 7. The metal is an alkali metal or alkaline earth metal selected from the group consisting of sodium, potassium, calcium, magnesium or barium; aluminum; zinc; copper; zirconium; titanium; bismuth; manganese or osmium; The composition according to claim 6, wherein the organic base is an amino acid. 8. The composition according to claim 4, wherein the polysulfated sucrose is a potassium or sodium salt of sucrose octasulfate. 9. The composition according to claim 4, wherein the polysulfated sucrose is sucralfate, which is an aluminum complex of sucrose octasulfate. 10. The preparation for topical application to the skin is a powder, paste, ointment, lotion, gel, cream, paint, emulsion, suspension, spray, sponge, strip, plaster, pad or pad. The composition according to any one of claims 1 to 9, which is in the form of a dressing. 11. A topical preparation containing sulfated sucrose in an amount of 0.001 to 99% by weight.
0. The composition according to any one of 0. 12. Sulfated sucrose in an amount of 0.01 to 75% by weight
11. A topical formulation in the form of a topical formulation.
A composition according to any one of the preceding claims. 13. Sulfated sucrose in an amount of 0.1 to 20% by weight
11. A topical formulation in the form of a topical formulation.
A composition according to any one of the preceding claims. 14. The composition according to claim 1, which is in the form of a topical formulation containing sulfated sucrose in an amount of 1 to 10% by weight.