WO2001038399A1

WO2001038399A1 - Method of treating surface tissue diseases

Info

Publication number: WO2001038399A1
Application number: PCT/JP2000/008281
Authority: WO
Inventors: Seiichi Isaki; Mamoru Kyogashima; Yusuke Hori; Tokiko Sakai
Original assignee: Seikagaku Corporation
Priority date: 1999-11-24
Filing date: 2000-11-24
Publication date: 2001-05-31

Abstract

Surface tissue diseases are treated by using medicinal compositions which contain as the active ingredient a galactosaminoglycan having a specific uronic acid composition, chondroitinase B-digestion ratio, sulfate group number and disaccharide composition or a pharmacologically acceptable salts thereof. Thus, wounds in surface tissues (in particular, burn, skin ulcer, bedsore, etc.), on which no sufficient clinical effect can be achieved by the conventional therapy and remedies, can be efficaciously treated without causing any significant side effects. Moreover, itching associating chronic diseases (atopic dermatitis, urticaria, eczema, pruritus cutaneus, prurigo, vulgar psoriasis with itching, etc.) can be efficaciously prevented and treated thereby.

Description

Description Method for treating surface tissue diseases

The present invention relates to a method for treating surface tissue diseases and the use of certain galactosaminoglycans for said treatment.

More specifically, the present invention relates to a method for treating a wound on a surface tissue such as skin or mucous membrane, and more particularly, to a method for treating a wound on a surface tissue capable of treating burns, skin ulcers, pressure ulcers, and the like. .

More specifically, the present invention is directed to the treatment of itch on surface tissues such as skin and mucous membranes, and in particular, the treatment of itch on surface tissues which can be used for the prevention and treatment of itch on skin induced by allergy. About the method. More specifically, it can prevent and treat pruritus in atopic dermatitis, prurigo herpes, eczema, pruritus cutaneous, prurigo or psoriasis vulgaris with pruritus, etc. The present invention relates to a method for treating itching of surface tissues, which makes it possible to prevent bacterial infections caused by destruction of skin barrier function.

Furthermore, the present invention relates to a novel galactosaminoglycan and a pharmaceutical composition containing the same. Background art

A superficial tissue wound is a wound of a superficial tissue such as a wound, burn, frostbite, laceration (tear), abrasion, cut wound, skin ulcer or pressure ulcer due to a surgical incision.

The formation of the epidermis is essential for wound healing, but it is often difficult to form the epidermis due to impaired blood flow due to continuous physical stimulation and the effects of underlying diseases. At present, artificial skin is used as a treatment method for wounds, but surgical operation is required, and it is a disadvantage that it is vulnerable to bacterial infection.

Currently, olsenone ointment, actosin ointment, prostandin ointment (all of which are trade names), etc. are used clinically to treat pressure ulcers and skin ulcers. Sufficient effects were not obtained on the wound.

Although a wound healing agent comprising an oily base and chondroitin sulfate is known (Japanese Patent Application Laid-Open No. 10-120577), the effect is actually exhibited unless an ointment containing chondroitin sulfate is used at a considerably high dose. Since this is not done, not only did the formulation need to be devised, but also the cost increased.

It is also known to use a composition comprising dermatan sulfate and a specific polyoxyethylene-polyoxypropylene block copolymer which is a gel at body temperature as a treatment for tissue damaged by burns or the like; (Japanese Patent Publication No. 7-76175), it was not known that a normal preparation containing only a specific galactosaminoglycan as an active ingredient exerts a wound treatment effect.

On the other hand, atopic dermatitis, jungle rash, eczema, pruritus cutis, prurigo or psoriasis vulgaris with itch, etc. have skin lesions with chronic itch and itching. However, skin barrier dysfunction is thought to be involved in the onset of the disease, in addition to immunological functions mainly based on allergic inflammation, and various treatments have been sought by focusing on these causes. Was. For example, due to immunological abnormalities, topical steroid preparations or immunosuppressants are mainly administered to alleviate skin inflammation. However, adrenocortical steroids have an inhibitory effect on adrenocortical function, cause susceptibility to infection, or develop peptic ulcers, hypertension, osteoporosis, and rosacea-like dermatitis especially when used on the face as a topical agent for a long time. There are various very serious side effects such as the onset of Immunosuppressants also have extremely serious side effects such as myelosuppression, gastrointestinal disorders, liver disorders, interstitial pneumonia, renal disorders, and hemorrhagic cystitis. Attempts have been made to avoid contact with allergens as a two-dimensional treatment, but avoiding contact with allergens often hinders everyday life.

In atopic dermatitis, eczema, eczema, pruritus cutis, prurigo or pruritus or vulgaris with pruritus, etc. Prevention of pruritus is a major point in the treatment of these diseases. The main purpose of preventing pruritus is to use so-called anti-allergic drugs such as histamine antagonists and drugs that suppress the release of chemical messenger from Tsukuba Manzoku cells. Drugs are used, and specifically include zazydene, azeptine, Celtec, Intal, Rizaben, etc. However, these drugs have side effects such as malaise and drowsiness, and some are contraindicated for use in pregnant women due to their ability to transfer to breast milk. Disclosure of

Therefore, the present invention relates to a method for treating a disease of a surface tissue, for which a sufficient therapeutic effect and a therapeutic agent have not been recognized by conventional therapeutic methods and therapeutic agents, a therapeutic agent, and use (use) of a specific galactosaminodalican for these. Specifically, the present invention can effectively treat wounds of superficial tissues, particularly wounds such as burns, skin ulcers, and pressure ulcers, and furthermore, are capable of treating wounds of superficial tissues that do not show serious side effects. It is intended to provide novel methods of treatment, therapeutic agents and specific galactosaminodarican uses:

The present invention is also directed to the treatment of itching of surface tissues, that is, the alleviation of itching of the skin and mucous membranes, and in particular, the treatment of chronic atopic dermatitis, jungle rash, eczema, pruritus cutaneous, prurigo or pruritic or pruritic vulgaris. A method for treating itch on a surface tissue, which can effectively prevent and treat pruritus of a disease passing through, and exhibit no significant side effects, a therapeutic agent for itch on a surface tissue, and a specific galactosaminoglycan. The purpose is to provide new uses.

The present inventors tested the effect of galactosaminoglycan having specific properties or a pharmacologically acceptable salt thereof on a wound healing promoting effect in a skin defect model using a diabetic mouse, and as a result, Alternatively, it has been found that a pharmacologically acceptable salt exhibits a wound healing promoting effect, is excellent in safety, and can be used for a long time.

In addition, the present inventors have developed NC / Nga mouse, an animal model of atopic dermatitis.

(Matsuda H. et al, Development of atopic dermatitis- 1 ike skin lesion with IgE hyperproduction in NC / Nga mice., International Immunology. Vol. 9, No. 3, pp. 101 106) The antipruritic effect of a physiologically acceptable salt was tested, and as a result, certain galactosaminoglycans or their pharmacologically acceptable salts, even at low doses, were caused by itching. Effective suppression of reptile behavior and slowing the progress of the disease, that is, it has a significant antipruritic effect, is safe, and can be used for a long time. did.

Therefore, the present invention provides, as a first form, a method of administering an effective amount of galactosaminoglycan having the following characteristics ^ or a pharmacologically acceptable salt thereof to a subject in need of treatment for a surface tissue disease. The present invention provides a method for treating a disease of a superficial tissue.

(A) The molar ratio between iduronic acid and dalconic acid in the constituent sugars is about 40:60 to about 100: 0.

(B) The digestibility by chondroitinase B is about 40% by weight to about 100% by weight.

(C) The number of sulfate groups per constituent disaccharide is from about 0.9 to about 1.3.

(D) In the disaccharide composition calculated by digestion with chondroitinase ABC and analysis by high-performance liquid chromatography, 2-acetamido 2-deoxy-1 3-O— (4-deoxy) indicated by ADi-OS 1-α-L-threo-1-hexyl 4-enopyranosylperonic acid) —D-galactose, 2-acetamide-2-dioxy 3-A represented by A Di-4S — O— (4-dexoxy ct — L-threau Hexa-4-1-enopyranosylperonic acid) 1-4-ΟSulfo D-galactose and 2-acetamido represented by A Di-6S 2 Deoxy-1 3--1- (4-Deoxy-1 a-L-Sleo-1) Hexa-4-enopyranosylperonic acid) The total of 16-O-sulfo-D-galactose is about 71 mol% to about 94 mol. /. It is.

The present invention also provides use of a pharmaceutical composition containing galactosaminodarican or a pharmacologically acceptable salt thereof having the following properties as an active ingredient for treating a surface tissue disease.

(A) The molar ratio of iduronic acid to dalcuronic acid in the constituent sugars is from about 40:60 to about 100: 0.

(C) The number of sulfate groups per constituent disaccharide is about 0.9 to about :! 3.

(D) Constituent disaccharide composition calculated by high-performance liquid chromatography after digestion with chondroitinase ABC, and 2-Acetamido represented by A Di-OS 2-Deoxy 3-O- (4-Dexoxy-α-L-Threo-Hex-1-4-Enopyranosylperonic acid) 1-D-galactose, 2-acetoamide-2-Doxy represented by A Di-4S I 3-I-I (4-Doxy α-L-Threo-hexyl 4-enopyranosylperonic acid) I 4-I-Sulfo D-Galactose and 2-acetoamide shown by A Di-6S 2-Dethoxy-1 3—O— (4-deoxy-a-L-sero-hexyl-4-enoviranosylperonic acid) 1-6—◦sulfo-D-galactose in total of about 71 mol% to about 9 mol% 4 mol%.

The use of the method and the pharmaceutical composition for treating a superficial tissue disease of the present invention is preferably applied to superficial tissue wounds such as burns, skin ulcers, and pressure ulcers.

Also, the use of the method and the pharmaceutical composition for treating the above-mentioned surface tissue disease of the present invention is preferably performed for atopic dermatitis, juniper, eczema, cutaneous pruritus, prurigo, or psoriasis vulgaris It is used to treat itching of surface tissues such as itching.

A method for treating a wound on a surface tissue and a method for treating itch on a surface tissue according to the present invention, use of a pharmaceutical composition for treating a wound on a surface tissue, and treatment of itch on a surface tissue The use of the pharmaceutical composition for the purpose of the present invention can also be applied to a surface tissue which requires the treatment of a wound and the treatment of itch simultaneously since the same substance is used as an active ingredient.

Incidentally, the wound treating agent comprising an oleaginous base and chondroitin sulfate described in Japanese Patent Application Laid-Open No. H10-120577 actually uses a considerably high dose of chondroitin sulfate. No specific properties of galactosaminodalican such as those used in the invention are disclosed.

Also, in the use of the method and the pharmaceutical composition for treating a wound of a superficial tissue according to the present invention, the method can be carried out without combining with a carrier or a base such as a specific polyoxyethylene-polyoxypropylene block copolymer. It differs from known treatment agents as disclosed in Japanese Patent Publication No. 7-76175 in that it can exert a therapeutic effect.Also, in this patent publication, galactosaminoglycan having specific properties used in the present invention is also described. Is not disclosed at all. Further, the pharmaceutical composition for treating a wound of a surface tissue of the present invention can exert an excellent therapeutic effect not only on a burn but also on an intractable skin ulcer. Furthermore, Japanese Patent Application Laid-Open No. Hei 9-1286731 discloses a therapeutic agent for psoriasis containing a polysulfate ester of chondroitin sulfate (generally containing 26 to 37% by weight of an organic sulfate group) as an active ingredient. Since the use of chondroitin sulfate polysulfate as the above, the anticoagulant effect may be a problem.

It has been known that chondroitin polysulfate is used in combination with zinc oxide as an external preparation for skin to prevent recurrence of atopic dermatitis (JP-A-11-60494). Galactosaminoglycan, which is an active ingredient in the method for treating pruritus and the use of a pharmaceutical composition, is different from chondroitin polysulfate in that it contains iduronic acid and has a sulfate group content. However, it shows an excellent effect that it is sufficiently effective even when used alone at a low dose. Further, the present invention provides, as a second form, galactosaminoglycan or a salt thereof having the following characteristics.

(A) The molar ratio of iduronic acid to glucuronic acid in the constituent sugars is from about 65:35 to about 90:10.

(B) The digestibility by chondroitinase B is about 65% by weight to about 95% by weight. The galactosaminoglycan of the present invention more preferably has the following properties.

(C) The number of sulfate groups per constituent disaccharide is about 0.9 to about: I · 1.

(D) The composition of disaccharides calculated by digestion with chondroitinase-BC and analysis by high performance liquid chromatography, and the 2_acetoamide 2-Doxy-1-0- represented by A Di-OS (4-Deoxy ct-L-threo-1-hexyl 4-enopyranosylperonic acid) 1-D-galactose is about 2 moles ⁰ /. ~ About 15 mol ⁰ /. It is. The galactosaminodalican is preferably derived from a bird tissue or organ.

The above galactosaminoglycan is a novel substance, and is useful as an active ingredient in the use of the above-mentioned treatment method and pharmaceutical composition of the present invention. Accordingly, the present invention provides, as a third form, a pharmaceutical composition comprising, as an active ingredient, the galactosaminodalican of the present invention or a pharmaceutically acceptable salt thereof.

According to the present invention, the conventional therapeutic methods and therapeutic agents do not show sufficient clinical effects It is possible to provide an agent for treating surface tissue wounds, which can effectively treat wounds, particularly burns, skin ulcers, pressure ulcers, etc., and have no serious side effects. it can.

Furthermore, it is possible to effectively prevent and treat surface tissue pruritus in atopic dermatitis, jungle rash, eczema, pruritus cutaneous, prurigo or psoriasis vulgaris with itch with a low dose of galactosaminoglycan, and It is possible to provide an agent for treating itching of surface tissue which does not show significant side effects. According to the present invention, it is possible to reduce the amount of other therapeutic agents for atopic dermatitis, for example, agents having serious side effects such as corticosteroid hormones and immunosuppressants.

FIG. 1 is a diagram showing the results of measuring izuronic acid and glucuronic acid by high-performance liquid chromatography in Reference Example 2 (e).

FIG. 2 is a graph showing the wound healing effect of the galactosaminodalican of the present invention on a rat back skin defect model. * Indicates that there is a significant difference at 5% risk.

FIG. 3 is a graph showing the wound healing effect of the galactosaminoglycan of the present invention on a spontaneously diabetic mouse back skin defect model. * Indicates that there is a significant difference at 5% risk.

FIG. 4 is a graph showing the results confirming the antipruritic effect of the administration of the galactosamine of the present invention to mice grown under itch-inducing conditions. BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, embodiments of the present invention will be described.

Generally, “galactosaminoglycan” refers to the basic skeleton of a repeating structure of a disaccharide composed of N-acetyl-D-galactosamine and D-darconic acid or L-iduronic acid, and the constituent sugar N-acetyl (1) A generic term for daricosaminoglycans having a sulfate group at the 4-position or 6-position of D-galactosamine, and / or the 2-position of L-iduronic acid or D-darctoic acid, and dermatan sulfate and chondroitin sulfate (Annu. Rev. Biochem., 60, 443-457, 1991).

Degradation of galactosaminodalican with an enzyme (lyase) produces an unsaturated disaccharide represented by the following general formula I. By analyzing the composition of the unsaturated disaccharide, it is possible to analyze the number and the bonding position of the sulfate groups in the above constituent disaccharide unit of galactosaminoglycan. Table 1 below summarizes the isomers of such unsaturated disaccharides depending on the number and position of sulfate groups.

OH [I]

In the formula, RRR ³ represents a hydrogen atom or SO ₃ —, and Ac represents an acetyl group.

The chemical names of the isomers are as follows.

Di-OS: 2-acetamide 1- 2-deoxy-1 3-O- (4-deoxy-1α-L-threo-1-14-1 enopyranosylperonic acid) 1-D-galactose Di-4S: 2-acetoamide-1 2-deoxy-3-O- (4-deoxyα-L-threo-1-hex-1-enopyranosylperonic acid) 1-41-sulfo D-galactose

A Di-6S: 2-acetamide-l-doxy-l-O- (4-doxyl-L-threo-hex-l-l-enopyranosyl-peronic acid) l-6-l-sulpho-D Garrak Tooth

ADi-diS _D : 2-Acetamide 2-Doxy 3-D- (4-Doxy 2-O-Snorreho a-L-Threorhex-1- 4-Enopyranosinoleronic acid) 1 6-Ο-Sulfoe D— Garaku Tooth

A Di-diS _E : 2-acetoamide 2-deoxy-1-O- (4-deoxy-α-L-threo-hex-1- 4-enopyranosyl-peronic acid) 1,4,6-bis- —Sulfoe D—Galactoose

A Di-diS _B : 2-acetamide-l-doxy-l-O- (4-doxyl-l-O-sulfo-alpha-L-threo-l-hex-l-l-enopyranosinoleuronic acid)- 4—Sulfur D—Galactos

ADi-triS: 2-acetamide 1-doxy-1 3—〇_ (4-deoxy-1 2—O—sulfo α—L—threohexyl 1—4-enopyranosinoleronic acid) 1,4,6-bis Ο—Sulfo D—Galacto

The above galactosaminoglycan is usually used in the intestinal mucosa, skin, lung, kidney, liver, knee, aorta, spleen, brain, thymus, mammals such as pests, pigs, etc., or birds such as chickens, ahinoles, turkeys, ducks A method usually used for the separation and purification of glycosaminodalican, using crushing, extraction, enzymatic degradation, organic solvent precipitation, salting out, salt solution, various types of chromatography, etc., using tissues or organs such as cartilage, umbilical cord or coronary crown as raw materials Can be separated and purified by appropriately combining them. Preferably, for example, the cockscomb is hydrolyzed with protease to degrade the protein, the hydrolyzed solution is filtered, and the filtrate is precipitated with an alcohol such as ethanol in the presence of sodium chloride to precipitate a galactosaminodalican fraction. Can be obtained. If necessary, if the content of heparin and heparan sulfate (Hep / HS) is to be reduced, the recovered precipitate is treated with nitrous acid as described below (Shively and Conrad's method, Biochemistry, 15, 3932-3942 (1976) ) Or ion exchange chromatography Galactosaminoglycan is obtained by removing impurities such as Hep / HS by matrix chromatography (WO95 / 09188) or a combination of both processing operations, and by alcohol precipitation, filtration and desalting as necessary. be able to.

The method for separating galactosaminodalican is not limited to the above method, but may be appropriately modified according to a known method described in JP-B-60-9042, JP-B-61-21241 and the like. It can also be obtained by extraction and purification.

Dermatan sulfate, an example of galactosaminoglycan, is known to have different average molecular weight, sulfate content, sulfate bond position, and D-darctic acid content depending on the animal species and tissue or organ from which it is derived. Have been. Table 2 below shows examples of the physical properties and disaccharide composition of dermatan sulfate obtained from typical raw materials (see Reference Example 1). Table 2 Origin and physical properties of various dermatan sulfates

Dermatan sulfate in the above table is an example of the galactosaminoglycan of the present invention. The dermatan sulfate derived from bovine intestine, pig intestine, pig skin, and cockscomb was obtained by the method described in W095 / 09188.

The galactosaminoglycan as an active ingredient in the method and use of the present invention is not particularly limited as long as it has the above-mentioned properties (A) to (D), but is preferably a bird tissue or organ, more preferably It is extracted and separated from the cockscomb.

The type of the galactosaminoglycan salt used in the present invention is not particularly limited as long as it is a pharmacologically acceptable salt, and examples thereof include an alkali metal salt and an alkaline earth metal salt, for example, a sodium salt, A potassium salt, a lithium salt, a calcium salt and the like are preferable, and a sodium salt is particularly preferable. (Hereinafter, unless otherwise specified, the term “galactosaminoglycan” is used in a meaning including a pharmacologically acceptable salt thereof. ).

In addition, the galactosaminodalican used in the present invention includes not only substances which have not been subjected to the above-mentioned modification and decomposition obtained by extraction and purification from raw materials, but also chemically Modified or degraded ones are also included. For example, a relatively low molecular weight dermatan sulfate having a molecular weight of about 1600 Da to about 10,000 Da obtained by decomposing dermatan sulfate derived from mammals is also known (Dol, F. et al., J. Lab. Clin. Med "1990, vol. 115, 43-51, Bianchini, P. et al., Thrombosis and Heamostasis, 1991, vol. 65, 1315. Barbanti, M. et al" Thrombosis and Heamostasis, 1993, vol. 69, 147-151), and such a low molecular weight dermatan sulfate is also included in the galactosaminodalican of the present invention as long as it has the above-mentioned properties (A) to (D).

The term “constituent disaccharide composition” in the present invention refers to a high-performance liquid obtained by decomposing galactosaminodalican into unsaturated disaccharides with chondroitinase ABC (chondroitin ABC lyase), and enzymatically decomposed products using a polyamine silica carrier column. A known method for fractionating by chromatography and analyzing the content of each unsaturated disaccharide isomer (Yoshida K. et al., Anal. Biochem. 1989, vol. 177, No. 2, 327-332). it is intended to refer to the resulting unsaturated disaccharide composition (molar ^_0/0).

The weight average molecular weight of the galactosaminoglycan is about 1,600 Da to about 100,000 Da, preferably about 23 kDa to about 45 kDa. The molar ratio of iduronic acid to dalcuronic acid in the constituent sugars of galactosaminoglycan is in the range of about 40:60 to about 100: 0, and preferably in the range of about 65:35 to about 90:10.

When chondroitinase B is allowed to act on the galactosaminoglycan, the digestibility is about 40% to about 100% by weight, preferably about 65% to 95% by weight. Here, the digestibility when chondroitinase B is applied is a value obtained by analyzing the chondroitinase B digestion pattern, and means the percentage (% by weight) of the digestion by chondroitinase B digestion. I do.

Further, the number of sulfate groups per constituent disaccharide of the galactosaminoglycan is in the range of about 0.9 to 1.3, and preferably in the range of about 0.9 to 1.1.

The total of A Di-0S, A Di-4S and A Di-6S of the above galactosaminoglycans is about 71 mol. /. To about 94 mol%, preferably about 90 mol% to about 94 mol%.

Each composition ratio of the constituting disaccharide is not particularly limited, about 0 mol% to 15 mol% for A Di-OS, it is preferably exemplified about 2 moles ^_0/0 to about 15 mole ^_0/0 . In particular, galactosaminodalican derived from avian tissues or organs has a relatively high ratio of A Di-OS, usually about 2 mol ^0/0 . To about 15 mole ^_0/0, preferably about 4 mol. /. About 10 mol%. A The Di-6S about 4 moles ⁰ Zo～ about 40 mole ^_0/0, preferably from about 45 mole ^_0/0 to about about about 4 mole ^_0/0 to about 30 mole ^_0/0, A Di-4S 100 mol ⁰ /. , Preferably, from about 60 mole% to about 90 mole%, A Di-diS _D about 0 mole% to about 5 mol% for, good Mashiku about 0 mole% to about 2 moles ^_0/0, A Di -dis _B Nitsure, Te about 1 mole ^_0/0 to about 15 molar percent, preferably from about 0 mole% to about 2 moles ^_0/0, A Di-diS _E about 0 mole ^_0/0 ~ A ratio of about 3 mol%, preferably about 0 mol% to about 2 mol% can be exemplified. The route of administration of the pharmaceutical composition used in the present invention containing galactosaminodalican as an active ingredient as described above is not particularly limited, but parenteral administration is preferable, and usually it is mixed, dissolved, and dispersed in a suitable base. The galactosaminoglycan thus obtained is applied transdermally or topically to a diseased site in a surface tissue, more specifically, to a wound site or a pruritic skin or mucous membrane by application, application, spraying or the like. It may be administered to mucous membranes such as eyes, nose and mouth, and other sites. Also, dissolve in a suitable solvent such as water to subcutaneously, intradermally, or muscle It can also be injected inside. Although the dosage form of the pharmaceutical composition used in the present invention is not particularly limited, ointments, plasters, patches, liquids, lotions, creams, gels, airsols, sprays (sprays), Examples include nasal drops and injections.

In addition, the pharmaceutical composition used in the present invention comprises, in addition to galactosaminoglycan as an active ingredient, a hydrophilic base, a hydrophobic base, an oil and fat, a wax, and a wax necessary for forming the above-mentioned dosage form. It may contain a base such as cholesterol.

Furthermore, the pharmaceutical composition used in the present invention may contain, if necessary, pharmaceutically acceptable ordinary stabilizers, emulsifiers, solubilizers, thickeners, surfactants, osmotic pressure regulators, pH regulators, etc. Auxiliaries can be included as appropriate.

Furthermore, in the treatment of the present invention, drugs such as steroids, antihistamines, immunosuppressants, antibacterials, antibiotics, and anti-inflammatory agents can be used in combination with the galactosaminodalican of the present invention or the pharmaceutical composition of the present invention.

In the present invention, the term “treatment” refers to not only the treatment in the usual sense that is performed afterward on the patient after the target disease has been affected, but also in particular for the prevention of the occurrence of ulcers, pressure ulcers, etc. It also includes prophylactic treatment.

The amount and amount of galactosaminodalican, which is an active ingredient of the pharmaceutical composition used in the present invention, depends on the method of administration of the preparation, the dosage form, the purpose of use, the specific symptoms of the patient, the weight of the patient, and the like. The amount of galactosaminoglycan administered to a patient is, for example, about 1 mg / kg to 200 mg / kg, preferably 2.5 mg / day for an adult. / kg ~: About 150 mg / kg can be exemplified.

In addition, the pharmaceutical composition used in the present invention may be administered once a day, or may be administered two to four times a day or more times a day. Depending on the dose, a certain number of days can be administered for an appropriate number of days.

The method of treating a wound of a surface tissue of the present invention and the use of the pharmaceutical composition for the treatment are not particularly limited as long as the wound is a surface tissue, and abrasions, bruises, lacerations, cut wounds, punctures, and the like are applicable. Wounds caused by external forces such as wounds, split wounds, shot wounds and bite wounds; chronic recurrent aphtha; aphtha with epidermal wounds caused by Behcet's disease etc .; herpes simplex, heaven Vulvar ulcers mainly caused by pox, necrotizing dermatoses, etc .; mainly ulcers of lower extremities caused by venous (congestive) syndrome, systemic lupus erythematosus, polyarteritis nodosa, etc .; basement membrane cell type, spiny Mainly facial ulcers caused by cell types, keratoacantoma, etc .; diabetic skin ulcers; physical and chemical skin disorders, such as light-induced skin disorders, burns, frostbite, decubitus, chemical burns, etc. Can be widely applied to.

The method for treating itch on the surface tissue and the use of the pharmaceutical composition for the treatment are not particularly limited as long as the disease is chronic and has itch, and atopic dermatitis, juniper Pruritus such as eczema, pruritus cutaneous, prurigo or pruritus, and pruritus associated with metabolic diseases such as cirrhosis, uremia and chronic renal failure, endocrine diseases such as diabetes and hyperthyroidism Pruritus associated with malignant lymphoma (Hodgkin's disease, mycosis fungoides, etc.), pruritus associated with parasitosis due to roundworm, duodenum, etc., psychogenic pruritus due to neurosis, senile pruritus, It can be widely applied to itching associated with infections such as vaginal candidiasis and trichomoniasis.

Atopic dermatitis is defined by the Japanese Dermatological Association as a `` disease with repetition of hatred and remission, with pruritic eczema as the main lesion, and many patients have a predisposition to atopy. '' Many patients suffer from itching that makes it difficult to go to bed. By administering the agent for treating itching of surface tissue of the present invention, itching by atopic dermatitis is prevented, thereby suppressing reptile behavior. As a result, bacterial infection and inflammatory hatching caused by reptile behavior are prevented and treated. Or they can be reduced. Prevention of itching in atopic dermatitis also improves the patient's quality of life. In addition, the prevention of bacterial infection and inflammation hate caused by reptile behavior can be reduced by the use of other drugs for treating atopic dermatitis, such as drugs that cause serious side effects, such as corticosteroid hormones and immunosuppressants. It is effective for reduction.

The animals to which the method and use of the present invention are applicable include mammals including humans (primates such as humans, companion animals such as dogs and cats, livestock such as cattle, pigs, and horses), and birds such as chickens These animals can be used for treatment such as prevention, treatment or alleviation of the above-mentioned symptoms. Example Hereinafter, the present invention will be described with reference examples and examples, but the present invention is not limited to these. Reference example 1

Preparation of galactosaminoglycan sodium salt (ccgg)

After adding 4000 L of water to 1,500 kg of cockscomb, minced and boiled, and cooled, protease (pronase, manufactured by Kaken Pharmaceutical Co., Ltd.) was added and hydrolyzed overnight. After adding 32 L of benzalkonium chloride solution to the hydrolyzed solution, the solution was filtered through diatomaceous earth, and the filtration supernatant was discarded to obtain 180 kg of diatomaceous earth.

350 L of water and 42 kg of sodium chloride were added to the diatomaceous earth, followed by filtration. 250 L of ethanol was added to the filtrate, and the obtained precipitate was dried to obtain 1.3 kg of powder.

The above powder was dissolved in 1.3 L of water to prepare a 10% solution, and treated with nitrite according to the method of Shively and Conrad (supra) to remove heparin and heparan sulfate.

That is, a solution in which the above powder was dissolved was mixed with a 0.1% nitrous acid aqueous solution, allowed to stand at room temperature for 10 minutes, and then the precipitate was removed by filtration. The pH of the filtrate was adjusted to 10.5, sodium chloride was added to a final concentration of 1%, and ethanol was added to the final concentration of 48% with stirring over 30 to 40 minutes. Activated carbon was added to the obtained precipitate, and the mixture was filtered by suction. The filtrate was passed through an ion exchange resin Diaion SA-12A (manufactured by Mitsubishi Chemical Corporation) to desalinate. Ethanol was added to the filtrate, and galactosaminodalican sodium was added. 105 g of a purified salt (ccgg) was obtained.

Furthermore, 18 lots of galactosaminoglycan sodium salt purified product were prepared in the same manner as above. Reference example 2

Analysis of galactosaminoglycan

(a) Measurement of weight average molecular weight

The weight average molecular weight was determined in accordance with the method of Arai et al. (Biochim. Biophys. Acta, 1117, 60-70, 1992). That is, chondroitin sulfate of known molecular weight (weight average The molecular weight was determined by elution time in gel filtration (GPC-HPLC) using high performance liquid chromatography using sodium hyaluronate (weight average molecular weight: 104000) as standard. The column used was a column to which TSK gel G4000 PW _XL , G3000 PW _XL and G2500 PW _XL (7.8 X 300 mm each, manufactured by Tosoh Corporation) were connected. The solvent used was a 0.2 mol / L sodium chloride solution, the flow rate was 0.6 ml / min, and the detector was a differential refractive index detector (RI-8100, manufactured by Tosoh Corporation).

(b) Analysis of chondroitinase B digestion pattern

Buffer solution A (0.001 mol / L calcium acetate, 0.02 mol / L Tris-HCl, pH 7.5) dissolved in 10 ccggl% solution 100 and 0.03 U chondroitinase B (manufactured by Seikagaku Corporation) And digested at 37 ^DC for 2 hours. The reaction was stopped by heating in a boiling water bath for 1 minute, and 10 L corresponding to 100 g of digest was analyzed at 40 ° C using GPC-HPLC. The column used was connected to TSK gel G4000 PW ^, G3000 PW ^ and G2500 PW _XL (7.8 X 300 mm each, manufactured by Tosoh Corporation). The solvent used was 0.2 mol / L sodium chloride solution, the flow rate was 0.6 mL / min, and the detector was a differential refractive index detector.

011-8100, manufactured by Tohoku Soichi Co., Ltd.) and an ultraviolet-visible detector (UV-8020, A230 nm, manufactured by Tohso Soichi Co., Ltd.).

(c) Composition analysis of constituent disaccharides

Analysis of the position of the sulfate group was carried out by a known method, "Biochemical Experiment Lecture 3, Carbohydrate II, p49-62 (1991, published by Tokyo Chemical Co., Ltd.)", "2.8 Combination of glycosaminoglycan enzyme and HPLC". Structural analysis ") as follows.

That is, ccgg was completely digested into disaccharides by chondroitinase ABC (manufactured by Seikagaku Corporation), and the resulting disaccharides containing unsaturated bonds (unsaturated disaccharides) were analyzed by GPC-HPLC. .

To further separate the inseparable A Di-diS _B and A Di-diS _E under these conditions, it was digested with digests further Kondoro 6- sulfatase Ichize (Seikagaku Corp.), A the Di-diS _E is shifted to a Di-4S, and analyzed by GPC-HPLC as well. The two results were compared and analyzed to calculate the constituent disaccharide composition. Details are described below.

(i) Digestion with chondroitinase ABC

In 50 L of 1% ccgg solution, add Buffer B (0.01 mol / L sodium acetate, 0.05 mol / L Tris-HCl, pH 7.5) A solution prepared by dissolving 0.5 U of chondroitinase ABC in 10 L was added, and the mixture was digested at 37 ° C for 2 hours. The reaction was stopped by heating in a boiling water bath for 1 minute, and impurities were removed by centrifugation. To this degradation product, a solution prepared by dissolving 0.5 U of chondroitinase ABC in buffer BOL was added and digested at 37 ° C for 6 hours. The reaction was stopped by heating in a boiling water bath for 1 minute, and insoluble materials were removed by centrifugation.

(ii) Digestion with chondro 6-sulfatase

To 100 g of chondroitinase ABC digestion product, 0.25 U of chondro-6-sulfatase (manufactured by Seikagaku Corporation) was added to 50 L of buffer C (0.02 mol / L Tris-AcOH, ρΗ7.0) The dissolved product was added, digested at 37 ° C for 24 hours, and insoluble material was removed by centrifugation.

(iii) HPLC analysis

The digested product, that is, chondroitinase ABC digested solution or digested solution obtained by further digesting it with chondro-6-sulfatase was analyzed by HPLC. The column used was a YMC-Pack PA-120-S5 ion exchange column (φ2.6 × 250 mm, manufactured by YMC Corporation).

0.8 mol / L sodium hydrogen phosphate was flowed at a flow rate of 1.5 mL / min for 60 minutes with a linear concentration gradient from 2% to 100%. Based on the elution position of the unsaturated chondro disaccharide kit (manufactured by Seikagaku Corporation), various unsaturated disaccharides eluted during this period were identified at 232 nm, and the peak area identified as unsaturated disaccharide was determined. The disaccharide composition was determined by calculating the sum as 100%.

(d) Measurement of intrinsic viscosity

The measurement of the intrinsic viscosity was performed according to the 13th revised Japanese Pharmacopoeia. An automatic viscosity measurement device (VMC-052, manufactured by Rigosha Co., Ltd.) was used as the measurement device. The solvent used was a 0.2 mol / L sodium chloride solution, and the same solution was used for measuring the flow time of an Ubbelohde type viscosity tube. Measurement of viscosity is 30 ± 0.1. The measurement was performed at C, and the one hundredth second of the flow-down time was rounded off, and the measured value having a difference within 0.1 second for three consecutive times was used for the calculation of the intrinsic viscosity.

The limiting viscosity is the reduced viscosity (r) red = (ts / t ₍₎ — 1) / C) [ts: flow time of solution, t ₀ : flow time of solvent, C: sample concentration (% by weight)] The concentration was plotted on the axis and the line obtained by plotting the concentration on the horizontal axis was calculated from the intercept when the concentration was extrapolated to zero. (e) Analysis of the molar ratio of isuronic acid to glucuronic acid

Determination of the content of iduronic acid (IdoA) and darconic acid (GlcA) in galactosaminoglycan

This measurement was performed according to the method of Karamanos et al. (Analytical Biochemistry 172, 410-419, 1988). That is, 5 mg of ccgg was dissolved in 500 g of distilled water, and 50 11 ^ of 1-ethyl-3,3-dimethylaminopropyl carbodiimide (EDC) was added and stirred. After standing at 37 ° C. for 20 minutes, the pH of the solution was kept between 4 and 5 by adding 50 mM HC1 501 each 6-7 times over the next hour. In the next hour, 1 ml of 2 M sodium tetrahydroborate (NaBH solution was added twice and the reduction reaction was carried out at 50 ° C. After the reaction was completed, the mixture was cooled to room temperature, and glacial acetic acid was added. Excess NaBH was decomposed to remove the salt by running water dialysis in the next step, and the dialysis solution was freeze-dried.

Next, 200 1 of 2 M TFA (trifluoroacetic acid) was added to 700 ^ g of the ccgg reduced product, and the tube was sealed and hydrolyzed at 105 ° C for 6 hours. After completion of the reaction, 3 ml of distilled water was added and freeze-dried. Next, 5001 of distilled water was added to the dried product, and the mixture was applied to Dowex 50-X8 (H ⁺ type) equilibrated with distilled water, and the non-adsorbed fraction was recovered in 2 ml of distilled water. After freeze-drying, add 500 1 of a pyridine solution (1 g of benzoic anhydride and 0.5 g of 4-dimethylaminoviridine adjusted to 10 ml with pyridine), and add 90 ml at 37 ° C for 90 minutes. Heated. After the reaction was stopped by adding 4.5 ml of distilled water and stirring, desalting treatment was performed with a SepPak-Cl8 force column. The benzoylated neutral sugar derived from peronic acid of ccgg generated as described above was analyzed by HPLC. That is, using a Shimadzu HPLC system equipped with a Cosmosil-5C18-P column (φ4.6 x 150 mm) equilibrated with 75% acetonitrile, conditions of lmiy flow rate, and column temperature of 40 ° C The analysis was performed below with detection by UV at 230 nm. Benzoylated 1,6-anhydride and benzoylated glucose were used as standard products.

As a result, benzoylated 1,6-anhydroidose was eluted as a single peak at a retention time of about 5.7 minutes, while benzoylated glucose was eluted at a retention time of about 12 minutes. It eluted as one peak (see Figure 1). Also, at the detection wavelength of UV 230 nm, if the detection intensity of benzoylated glucose is 5, then that of benzoylated 1,6-anhydroidose is 3. In consideration of the peak area and detection intensity, the peronic acid composition was calculated as IdoA: GlcA (iduronic acid: dalcuronic acid) = 76.5: 23.5.

(f) Measurement of the number of sulfate groups

The number of sulfate groups per constituent disaccharide was obtained by multiplying the unsaturated disaccharide composition (mol%) of each galactosaminoglycan by the coefficient of the number of sulfate groups, and was determined by the following equation.

Sulfate groups per disaccharide (number) = [ADi-OS mole ^_0/0 X0 + (Monore ^_0/0 mole ^_0/0 + △ Di-4S of ADi-6S) of xi + (the ADi-diS _n Monore ^_0/0 + ADi-diS mole ^_0/0 of Monore ^{_{0/0 + Δ Di-diS}} E of _B) X2 + _ADi-triS mole ^_0/0 X3] ÷ 100

(g) Result

Table 3 shows the results for the ccgg prepared in Reference Example 1 and Table 4 shows the results for (a) to (c) of 18-galactosaminoglycan sodium salt other than the ccgg prepared in Reference Example 1. The results obtained by analysis in the same manner as (f) were summarized. Table 3

Table 4 Composition of constituent disaccharides (mole ⁰ / o) ADi-0S, ADi-4S, chondroitinase 'B per constituent disaccharide

Di-Number of sulfate groups △ Total digestibility of Di-6S

Lot No. _{_{OS 6S 4S S D s B +}} S E triS ( number) (mol ^0/0) (%)

1 5.9 12.0 74.6 1.2 6.3 0.0 1.016 92.5 92.9

2 8.0 12.8 71.8 1.5 5.8 0.0 0.992 92.6 92.5

3 7.0 12.9 72.0 1.5 6.5 0.0 1.009 91.9 92.5

4 6.8 14.1 70.8 1.3 7.0 0.0 1.015 91.7 92.8

5 5.7 11.5 76.2 1.3 5.3 0.0 1.008 93.4 ―

6 5.8 10.9 76.5 1.4 5.4 0.0 1.011 93.2 ―

7 5.7 7.8 79.2 1.2 6.1 0.0 1.016 92.7 _

8 6.0 11.5 75.3 1.4 5.9 0.0 1.013 92.7

9 5.7 8.8 78.2 1.3 6.0 0.0 1.016 92.7 One

10 6.0 11.4 75.5 1.3 5.8 0.0 1.012 92.9-o

11 6.1 11.5 75.4 1.4 5.6 0.0 1.009 93.0

12 6.3 6.6 77.7 1.3 8.2 0.0 1.033 90.6 100.0

13 4.7 4.9 82.4 1.0 7.0 0.0 1.033 92.0 100.0

14 4.6 3.8 82.8 0.8 7.9 0.0 1.042 91.2 100.0

15 4.8 5.2 81.8 1.1 7.2 0.0 1.035 91J 100.0

16 6.3 7.3 77.1 1.3 8.0 0.0 1.030 90.7 100.0

17 5.9 7.5 77.3 1.3 8.0 0.0 1.034 90.7 100.0

18 7.1 8.6 73.5 1.5 9.3 0.0 1.037 89.2 100.0

Reference example 3

Analysis of dermatan sulfate from sources other than cockscomb

As an example of galactosamine derived from sources other than the cockscomb, dermatan sulfate was produced using pig skin or bovine kidney as a raw material according to the method described in Reference Example 1, and analyzed by the method described in Reference Example 2. Table 5 shows the results. The dermatan sulfate derived from pig skin used here is different from the dermatan sulfate derived from pig skin described in Table 2. Table 5

Example 1 (Formulation example)

An ointment (ccgg ointment) was prepared by preparing a 5% aqueous solution of the galactosaminodalican sodium salt (ccgg) obtained in Reference Example 1 and mixing it with hydrophilic petrolatum having the following composition until uniform.

Salami beeswax (Ceralica NODA) 80 g Stearyl alcohol or setanol (Nippon Oil & Fats Co., Ltd.) 30 g Cholesterol (Kanto Chemical Co., Ltd.) 30 g White petrolatum (Shima Trading Co., Ltd.) A total amount of 1000 g was also formulated in the same manner for 18 lots of galactosaminodalicannadium salt other than ccgg in Table 4. Example 2

Examination of wound healing effect of galactosaminoglycan using rat back skin defect model

(1) Experimental material

Animals were 10-week-old Sprague-Dawley female rats (SPF, Japan

The cc _gg ointment of Example 1 was used as the drug. The control group used was an emulsion prepared by adding water to hydrophilic serine (hydrophilic vaseline emulsion). No preservatives were added to the ccgg ointment or the hydrophilic seline emulsion.

(2) Preparation of model animals

After shaving the back of the rat with a hair clipper, the hair was removed using a hair removal cream. Next, the skin was incised subcutaneously with an ophthalmic trepan having a diameter of 8 mm, peeled off using ophthalmic scissors and tweezers, and two complete skin defect wounds were created on the back.

(3) Experimental method

O.lg ccgg ointment was applied to 10 rats once daily for 14 days from the day of skin defect wound creation, and hydrophilic rats were similarly treated with 10 rats as a control group. Applied.

A photograph of the skin defect site was taken, and the value obtained by subtracting the area at the time of measurement from the area immediately after the creation of the defect was defined as the wound healing area.

(4) Result

In the control group, the size of the defective area was reduced from 3 days after the generation of the defective area, and 47% of the defective area was reduced on the seventh day. In the ccgg ointment group, the wound healing effect was observed from 3 days after administration, and the defect was reduced by 74% on the 7th day. The result is shown in figure 2. Example 3

The effect of galactosaminoglycan on wound healing using a diabetic mouse skin defect model Consideration

(1) Experimental material

The animal used was a 22-week-old spontaneously diabetic female mouse (SPF, Claire Co., Ltd.), and the drug used was the ccgg ointment of Example 1. As a control, hydrophilic Serine Margillon was used. No preservatives were added to ccgg ointment or hydrophilic seline emulsion.

(2) Preparation of model animals

After shaving the back of the mouse with a hair clipper, the hair was removed using a hair removal cream. Next, the skin was cut into the skin subcutaneously with an ophthalmic trepan having a diameter of 8 mm, and peeled off using ophthalmic scissors and tweezers.

(3) Experimental method

0.1 g of ccgg ointment was applied to 10 mice once a day for 10 consecutive days from the day of skin defect wound creation for 21 consecutive days, and hydrophilic petrolatum emulsion was similarly applied to 10 mice as a control group. .

(4) Result

In the control group, the size of the defective area was reduced 11 days after the creation of the defective area, and about 15% of the defective area was reduced on the 14th day. In the ccgg ointment group, the effect of promoting wound treatment was observed on the 11th day after administration, and the defect was reduced by 53% on the 14th day after administration. The results are shown in Figure 3.

The above results indicate that galactosaminodalican ointment is effective in promoting the healing of intractable skin ulcers due to diabetes and the like. Example 4

Examination of itch-inhibitory effect of galactosaminoglycan in atopic dermatitis model mouse (NC / Nga mouse)

(1) Experimental material

6-week-old male NC / Nga mouse as atopic dermatitis model mouse Was used. As a drug, galactosaminoglycan sodium salt (ccgg) derived from cockscomb prepared in Reference Example 1 was sterilized and used in physiological saline.

(2) Experimental method

Eight NC / Nga mice were divided into two groups of four. All mice were caged one by one and reared under mite-positive rearing conditions. Of these, one group of 4 animals as a non-treated control group received only physiological saline, and the other group of 4 animals had a ccgg of 60 jug / mouse three times a week (Monday, Wednesday, Friday) Was injected subcutaneously. After the injection, observation was performed for 10 minutes, and the number of reptile movements for 10 minutes was recorded. Here, the term “mite-positive breeding conditions” refers to conditions that are bred in an isolation facility and that the presence of ticks in animal colonies has been confirmed.

(3) Result

Fig. 4 shows the results of measurement of repelling behavior on the first day of administration and on days 14, 21, and 28 after administration. The error in the figure indicates the value of the standard error.

As shown in FIG. 4, there is no difference in the number of reptiles between the groups immediately after the start of administration. Raising for more than 14 days in a tick-positive environment increases the number of reptiles in the untreated control group. This is a characteristic of NC / Nga mice and presents allergic symptoms from the rearing environment. Specifically, erythema, alopecia, bleeding, and crust formation, especially around the neck and auricles, are seen from about 7 weeks of age. It has been reported in the aforementioned literature that these symptoms do not appear when reared in a mite-negative environment.

Galactosaminoglycan significantly reduced the number of reptiles on the 14th and 21st days in the 60 g / mouse group (P <0.05). On the 28th day after the start of the administration, galactosaminoglycan showed an improving effect. No gross findings (such as subcutaneous hemorrhage at the injection site) were observed during the administration period in the galactosaminoglycan administration group during the administration period.

Claims

The scope of the claims

1. A method for treating a disease of a superficial tissue comprising administering an effective amount of galactosaminoglycan or a pharmacologically acceptable salt thereof having the following properties to a subject in need of the treatment of the superficial tissue disease: .

(A) The molar ratio of iduronic acid to dalcuvic acid in the constituent sugars is about 40:60 to about 100: 0.

(B) The digestibility by chondroitinase B is about 40% by weight. /. About 100% by weight.

(D) In the disaccharide composition calculated by digestion with chondroitinase ABC and analysis by high-performance liquid chromatography, the 2-diacetoamide 2-deoxy 3 _〇-1 (4- Deoxy ct—L—Threoxy-1-4-enopyranosylperonic acid) 1-D-galactose, 2-Diacetamide represented by A Di-4S 2-Doxy-1 3-O— (4-Doxy-Hi-L-Sleo-1) Hex-4-enopyranosylperonic acid) 4-O-sulfo-D-galactose and A-di-6S represented by 2-acetoamide-2-deoxy 3-O- (4-deoxy ct-L-thread The total of 1-6-O-sulfo-1D-galactose is about 71 mol% to about 94 mol ⁰ /. It is.

2. The method according to claim 1, wherein the superficial tissue disease is a superficial tissue wound.

3. The method of claim 2, wherein the surface tissue wound is due to one or more diseases selected from the group consisting of burns, skin ulcers, and pressure ulcers.

4. The method according to claim 1, wherein the disease of the surface tissue is a disease accompanied by itching of the surface tissue.

5. Diseases with itching of surface tissues include atopic dermatitis, juniper, eczema, and skin The method according to claim 4, which is caused by one or more diseases selected from the group consisting of pruritus, prurigo and psoriasis vulgaris.

6. Use of a pharmaceutical composition containing galactosaminoglycan having the following properties or a pharmaceutically acceptable salt thereof as an active ingredient for treating a disease of a surface tissue.

(D) The disaccharide composition calculated by digestion with chondroitinase ABC and analysis by high-performance liquid chromatography indicates that 2-acetoamide-l-deoxy-l-O- (4- Deoxy-a-L-Threo-hexyl-1-enopyranosyl-peronic acid) D-Galactose, A 2-Acetamide represented by A Di-4S -2-Doxy-1 3--0- (4-Doxy-1 a- L-threo-hex-1-oxy 4-enopyranosylperonic acid) 14 -—- sulfo D-galactose and 2-acetamide represented by A Di-6S 2-deoxy-1- 3--1- (4-deoxy-a - L-Threading O one to carboxymethyl one 4-eno Vila waves * roux Ron acid) total one 6-o-sulfo-one D- galactosamine toe scan of about 7 1 mole ^_0/0 to about 9 4 mol%.

7. The use according to claim 6, wherein the superficial tissue disease is a superficial tissue wound.

8. The use according to claim 7, wherein the superficial tissue wound is due to one or more diseases selected from the group consisting of burns, skin ulcers and pressure ulcers.

9. The use according to claim 6, wherein the disease of the surface tissue is a disease accompanied by itching of the surface tissue.

10. Diseases associated with itching of surface tissue include atopic dermatitis, juniper, eczema, and skin The use according to claim 9, which is associated with one or more diseases selected from the group consisting of pruritus, prurigo and psoriasis vulgaris.

11. The method or use according to any one of claims 1 to 10, wherein the molar ratio of iduronic acid to dalcuronic acid in the constituent sugars of galactosaminodalican is from about 65:35 to about 90:10.

12. The digestibility of galactosaminoglycan by chondroitinase B is about 65% by weight. /. 11. The method or use according to any of the preceding claims, wherein the amount is between about 95% by weight.

13. The method or use according to any one of claims 1 to 10, wherein the galactosaminoglycan is derived from a bird tissue or organ.

14. The method or use according to any one of claims 1 to 10, wherein the weight average molecular weight of the galactosaminoglycan is from about 1,600 Da to about 100,000 Da.

15. The method or use according to any one of claims 1 to 10, wherein the weight average molecular weight of the galactosaminoglycan is from about 23 kDa to about 45 kDa.

16. Galactosaminoglycan is digested with chondroitinase ABC and analyzed by high performance liquid chromatography. The resulting disaccharide composition is calculated to be 2-acetoamido 2-deoxy-1 3- される represented by ADi-OS. 1- (4-doxy α-L-threo-hex-1-oxy 4-enopyranosylperonic acid) 1-D-galactose about 2 to about

The method or use according to any of claims 1 to 10, characterized in that it is 15%.

17. Galactosaminodalican or a salt thereof having the following properties.

(Α) The molar ratio of iduronic acid to dalcuronic acid in the constituent sugars is about 65:35 to about 9 0: It is 10

(B) digestibility by chondroitinase B is about 6 5 wt% to about 9 5 weight ^_0/0.

18. The galactosaminodalican or a salt thereof according to claim 17, which further has the following characteristics.

(C) The number of sulfate groups per constituent disaccharide is from about 0.9 to about 1.1.

(D) The disaccharide composition calculated by digestion with chondroitinase ABC and analysis by high-performance liquid mouth chromatography was used to determine the 2-acetoamide-1 2-deoxy1-3_〇-1 (ADi-OS) carboxymethyl one to 4 Dokishi one alpha-L-Sureo 4 Enopi Ranoshiruu port phosphate) Single D- galactose is about 2 moles ^_0/0 to about 1 5 mole ^_0/0.

19. The galactosaminoglycan or a salt thereof according to claim 17, which is derived from a bird tissue or organ.

20. A pharmaceutical composition comprising the galactosaminoglycan according to claim 17 or a pharmacologically acceptable salt thereof as an active ingredient.