WO2001038399A1 - Procede de traitement des maladies des tissus superficiels - Google Patents

Procede de traitement des maladies des tissus superficiels Download PDF

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Publication number
WO2001038399A1
WO2001038399A1 PCT/JP2000/008281 JP0008281W WO0138399A1 WO 2001038399 A1 WO2001038399 A1 WO 2001038399A1 JP 0008281 W JP0008281 W JP 0008281W WO 0138399 A1 WO0138399 A1 WO 0138399A1
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Prior art keywords
acid
galactosaminoglycan
deoxy
tissue
disease
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PCT/JP2000/008281
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English (en)
Japanese (ja)
Inventor
Seiichi Isaki
Mamoru Kyogashima
Yusuke Hori
Tokiko Sakai
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Seikagaku Corporation
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Priority claimed from JP33277399A external-priority patent/JP2001151680A/ja
Priority claimed from JP2000005305A external-priority patent/JP2001187740A/ja
Application filed by Seikagaku Corporation filed Critical Seikagaku Corporation
Publication of WO2001038399A1 publication Critical patent/WO2001038399A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L5/00—Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans

Definitions

  • the present invention relates to a method for treating surface tissue diseases and the use of certain galactosaminoglycans for said treatment.
  • 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. .
  • 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.
  • 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.
  • the present invention relates to a novel galactosaminoglycan and a pharmaceutical composition containing the same.
  • 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.
  • 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.
  • olsenone ointment 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.
  • atopic dermatitis, jungle rash, eczema, pruritus cutis, prurigo or psoriasis vulgaris with itch, etc. have skin lesions with chronic itch and itching.
  • 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.
  • topical steroid preparations or immunosuppressants are mainly administered to alleviate skin inflammation.
  • 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.
  • 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.
  • 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.
  • NC / Nga mouse an animal model of atopic dermatitis.
  • 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.
  • the digestibility by chondroitinase B is about 40% by weight to about 100% by weight.
  • the number of sulfate groups per constituent disaccharide is from about 0.9 to about 1.3.
  • the molar ratio of iduronic acid to dalcuronic acid in the constituent sugars is from about 40:60 to about 100: 0.
  • the digestibility by chondroitinase B is about 40% by weight to about 100% by weight.
  • 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.
  • 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.
  • 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.
  • the present invention provides, as a second form, galactosaminoglycan or a salt thereof having the following characteristics.
  • the molar ratio of iduronic acid to glucuronic acid in the constituent sugars is from about 65:35 to about 90:10.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • RRR 3 represents a hydrogen atom or SO 3 —
  • Ac represents an acetyl group.
  • Di-OS 2-acetamide 1- 2-deoxy-1 3-O- (4-deoxy-1 ⁇ -L-threo-1-14-1 enopyranosylperonic acid) 1-D-galactose
  • Di-4S 2-acetoamide-1 2-deoxy-3-O- (4-deoxy ⁇ -L-threo-1-hex-1-enopyranosylperonic acid) 1-41-sulfo D-galactose
  • ADi-diS D 2-Acetamide 2-Doxy 3-D- (4-Doxy 2-O-Snorreho a-L-Threorhex-1- 4-Enopyranosinoleronic acid) 1 6- ⁇ -Sulfoe D— Garaku Tooth
  • 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— ⁇ _ (4-deoxy-1 2—O—sulfo ⁇ —L—threohexyl 1—4-enopyranosinoleronic acid) 1,4,6-bis ⁇ —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
  • Hep / HS heparin and heparan sulfate
  • the recovered precipitate is treated with nitrous acid as described below (Shively and Conrad's method, Biochemistry, 15, 3932-3942 (1976) )
  • nitrous acid as described below
  • 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
  • Dermatan sulfate 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 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.
  • 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.
  • the term “galactosaminoglycan” is used in a meaning including a pharmacologically acceptable salt thereof. ).
  • 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.
  • 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.
  • Constituent disaccharide composition 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.
  • chondroitinase ABC chondroitin ABC lyase
  • 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.
  • the digestibility is about 40% to about 100% by weight, preferably about 65% to 95% by weight.
  • 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.
  • 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 .
  • 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 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 ashamed 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.
  • 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.
  • 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
  • humans primates such as humans, companion animals such as dogs and cats, livestock such as cattle, pigs, and horses
  • birds such as chickens
  • protease protease, manufactured by Kaken Pharmaceutical Co., Ltd.
  • protease manufactured by Kaken Pharmaceutical Co., Ltd.
  • 32 L of benzalkonium chloride solution was added to the hydrolyzed solution, the solution was filtered through diatomaceous earth, and the filtration supernatant was discarded to obtain 180 kg of diatomaceous earth.
  • 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.
  • 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.
  • 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).
  • 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.
  • UV-8020, A230 nm, manufactured by Tohso Soichi Co., Ltd. an ultraviolet-visible detector
  • 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. .
  • 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, ⁇ 7.0) The dissolved product was added, digested at 37 ° C for 24 hours, and insoluble material was removed by centrifugation.
  • 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 ( ⁇ 2.6 ⁇ 250 mm, manufactured by YMC Corporation).
  • 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 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.
  • 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.
  • 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
  • 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.
  • ccgg ointment 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.
  • 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.
  • the hair was removed using a hair removal cream.
  • 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.
  • 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.
  • 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.
  • the hair was removed using a hair removal cream.
  • 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.
  • ccgg ointment 0.1 g 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. .
  • 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.
  • mice 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.
  • 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.
  • 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.
  • 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.

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Abstract

Des maladies des tissus superficiels sont traitées au moyen de compositions médicinales qui renferment en tant qu'ingrédient actif un galactosaminoglycane ayant une composition d'acide uronique, un rapport de digestion chondroitinase B, et un nombre de groupes sulfates spécifiques, et une composition disaccharide ou un de ses sels pharmacologiquement acceptables. Il est possible, au moyen de ces compositions, de traiter efficacement sans provoquer d'effets secondaires significatifs, des blessures des tissus superficiels (plus particulièrement, les brûlures, les ulcères cutanés, les escarres de décubitus et autres) pour lesquels la thérapie et les remèdes classiques n'ont pas un effet clinique suffisant. De plus, les maladies chroniques associées à des états prurigineux (la dermatite atopique, l'urticaire, l'eczéma, le prurit cutané, le prurigo, le psoriasis ordinaire avec prurit et autres) peuvent être évitées et traitées efficacement au moyen de ces compositions.
PCT/JP2000/008281 1999-11-24 2000-11-24 Procede de traitement des maladies des tissus superficiels WO2001038399A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP33277399A JP2001151680A (ja) 1999-11-24 1999-11-24 鎮痒剤
JP11/332773 1999-11-24
JP2000005305A JP2001187740A (ja) 2000-01-05 2000-01-05 創傷治療剤
JP2000-5305 2000-01-05

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2001151680A (ja) * 1999-11-24 2001-06-05 Seikagaku Kogyo Co Ltd 鎮痒剤
JP2001187740A (ja) * 2000-01-05 2001-07-10 Seikagaku Kogyo Co Ltd 創傷治療剤
US6962699B2 (en) 2002-06-03 2005-11-08 Massachusetts Institute Of Technology Rationally designed polysaccharide lyases derived from chondroitinase B
WO2011027128A1 (fr) * 2009-09-03 2011-03-10 The University Of Manchester Utilisation d'oligosaccharides non digestibles

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996001648A1 (fr) * 1994-07-08 1996-01-25 Ibex Technologies R And D, Inc. Attenuation des processus de cicatrisation
JPH10287570A (ja) * 1997-04-09 1998-10-27 Seikagaku Kogyo Co Ltd 角膜障害症治癒促進剤
WO1999042084A1 (fr) * 1998-02-18 1999-08-26 The Research Foundation Of State University Of New York Matrice extracellulaire a base de galactosaminoglycan utilisee dans la cicatrisation des blessures

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996001648A1 (fr) * 1994-07-08 1996-01-25 Ibex Technologies R And D, Inc. Attenuation des processus de cicatrisation
JPH10287570A (ja) * 1997-04-09 1998-10-27 Seikagaku Kogyo Co Ltd 角膜障害症治癒促進剤
WO1999042084A1 (fr) * 1998-02-18 1999-08-26 The Research Foundation Of State University Of New York Matrice extracellulaire a base de galactosaminoglycan utilisee dans la cicatrisation des blessures

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2001151680A (ja) * 1999-11-24 2001-06-05 Seikagaku Kogyo Co Ltd 鎮痒剤
JP2001187740A (ja) * 2000-01-05 2001-07-10 Seikagaku Kogyo Co Ltd 創傷治療剤
US6962699B2 (en) 2002-06-03 2005-11-08 Massachusetts Institute Of Technology Rationally designed polysaccharide lyases derived from chondroitinase B
US7105334B2 (en) 2002-06-03 2006-09-12 Massachusetts Institute Of Technology Rationally designed polysaccharide lyases derived from chondroitinase B and methods of specifically cleaving therewith
US7129335B2 (en) 2002-06-03 2006-10-31 Massachusetts Institute Of Technology Methods for purifying and isolating recombinant chondroitinases
WO2011027128A1 (fr) * 2009-09-03 2011-03-10 The University Of Manchester Utilisation d'oligosaccharides non digestibles
AU2010290985B2 (en) * 2009-09-03 2016-12-15 Curapel (Scotland) Limited Use of non-digestible oligosaccharides

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