WO2003033004A1 - Agents permettant le traitement des affections abdominales inflammatoires - Google Patents
Agents permettant le traitement des affections abdominales inflammatoires Download PDFInfo
- Publication number
- WO2003033004A1 WO2003033004A1 PCT/JP2002/010799 JP0210799W WO03033004A1 WO 2003033004 A1 WO2003033004 A1 WO 2003033004A1 JP 0210799 W JP0210799 W JP 0210799W WO 03033004 A1 WO03033004 A1 WO 03033004A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- hyaluronic acid
- agent
- inflammatory bowel
- pharmaceutically acceptable
- acceptable salt
- Prior art date
Links
- 208000022559 Inflammatory bowel disease Diseases 0.000 title claims abstract description 45
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 65
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 claims abstract description 41
- 229920002674 hyaluronan Polymers 0.000 claims abstract description 41
- 229960003160 hyaluronic acid Drugs 0.000 claims abstract description 39
- 150000003839 salts Chemical class 0.000 claims abstract description 33
- 239000004480 active ingredient Substances 0.000 claims abstract description 16
- 208000024891 symptom Diseases 0.000 claims abstract description 13
- 230000003449 preventive effect Effects 0.000 claims description 24
- 230000000968 intestinal effect Effects 0.000 claims description 16
- 230000004083 survival effect Effects 0.000 claims description 15
- 206010030113 Oedema Diseases 0.000 claims description 14
- 206010012735 Diarrhoea Diseases 0.000 claims description 12
- 230000004580 weight loss Effects 0.000 claims description 10
- 239000003112 inhibitor Substances 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 8
- 238000004904 shortening Methods 0.000 claims description 6
- 208000011231 Crohn disease Diseases 0.000 claims description 3
- 201000010099 disease Diseases 0.000 claims description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 3
- 206010009900 Colitis ulcerative Diseases 0.000 claims description 2
- 201000006704 Ulcerative Colitis Diseases 0.000 claims description 2
- 230000004709 cell invasion Effects 0.000 claims description 2
- 230000002757 inflammatory effect Effects 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 239000003814 drug Substances 0.000 description 23
- 229940124597 therapeutic agent Drugs 0.000 description 21
- 230000000694 effects Effects 0.000 description 11
- 230000008595 infiltration Effects 0.000 description 9
- 238000001764 infiltration Methods 0.000 description 9
- 241001465754 Metazoa Species 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- 239000007924 injection Substances 0.000 description 7
- 238000002347 injection Methods 0.000 description 7
- 230000000069 prophylactic effect Effects 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- 239000002253 acid Substances 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 239000002158 endotoxin Substances 0.000 description 5
- 230000006872 improvement Effects 0.000 description 5
- 230000002265 prevention Effects 0.000 description 5
- NHJVRSWLHSJWIN-UHFFFAOYSA-N 2,4,6-trinitrobenzenesulfonic acid Chemical compound OS(=O)(=O)C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O NHJVRSWLHSJWIN-UHFFFAOYSA-N 0.000 description 4
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 4
- -1 alkali metal salts Chemical class 0.000 description 4
- 230000000144 pharmacologic effect Effects 0.000 description 4
- 239000002504 physiological saline solution Substances 0.000 description 4
- 230000001629 suppression Effects 0.000 description 4
- 230000009471 action Effects 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- KIUKXJAPPMFGSW-MNSSHETKSA-N hyaluronan Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)C1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H](C(O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-MNSSHETKSA-N 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 238000007911 parenteral administration Methods 0.000 description 3
- 208000016261 weight loss Diseases 0.000 description 3
- WCDDVEOXEIYWFB-VXORFPGASA-N (2s,3s,4r,5r,6r)-3-[(2s,3r,5s,6r)-3-acetamido-5-hydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-4,5,6-trihydroxyoxane-2-carboxylic acid Polymers CC(=O)N[C@@H]1C[C@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](O)[C@H](O)[C@H]1O WCDDVEOXEIYWFB-VXORFPGASA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 229920002683 Glycosaminoglycan Polymers 0.000 description 2
- 238000012404 In vitro experiment Methods 0.000 description 2
- 238000000585 Mann–Whitney U test Methods 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 208000012876 acute enteritis Diseases 0.000 description 2
- 208000021735 chronic enteritis Diseases 0.000 description 2
- 230000002354 daily effect Effects 0.000 description 2
- 230000006866 deterioration Effects 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 229940099552 hyaluronan Drugs 0.000 description 2
- 229940125700 inflammatory bowel disease agent Drugs 0.000 description 2
- 229910052742 iron Inorganic materials 0.000 description 2
- 210000002429 large intestine Anatomy 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000000691 measurement method Methods 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000002689 soil Substances 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- KIUKXJAPPMFGSW-UHFFFAOYSA-N 6-[3-acetamido-2-[6-[3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Polymers CC(=O)NC1C(O)OC(CO)C(O)C1OC1C(O)C(O)C(OC2C(C(OC3C(C(O)C(O)C(O3)C(O)=O)O)C(O)C(CO)O2)NC(C)=O)C(C(O)=O)O1 KIUKXJAPPMFGSW-UHFFFAOYSA-N 0.000 description 1
- 241000561734 Celosia cristata Species 0.000 description 1
- 241001529572 Chaceon affinis Species 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 241000239218 Limulus Species 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 229920002385 Sodium hyaluronate Polymers 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 210000001520 comb Anatomy 0.000 description 1
- 150000003946 cyclohexylamines Chemical class 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical class OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000012812 general test Methods 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 230000008407 joint function Effects 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- 238000001325 log-rank test Methods 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000006166 lysate Substances 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 238000000879 optical micrograph Methods 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 229940010747 sodium hyaluronate Drugs 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(2s,3s,4s,5r,6r)-6-[(2s,3r,4r,5s,6r)-3-acetamido-2-[(2s,3s,4r,5r,6r)-6-[(2r,3r,4r,5s,6r)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2- Chemical compound [Na+].CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate group Chemical group S(=O)(=O)([O-])[O-] QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 210000003954 umbilical cord Anatomy 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
- A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
- A61K31/728—Hyaluronic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/12—Antidiarrhoeals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- the present invention relates to a therapeutic agent for inflammatory bowel disease, comprising hyaluronic acid or a pharmaceutically acceptable salt thereof as an active ingredient.
- the present invention provides various symptoms associated with inflammatory bowel disease (diarrhea, weight loss, intestinal tissue edema, cell infiltration, shortened survival time, etc.) containing hyaluronic acid or a pharmaceutically acceptable salt thereof as an active ingredient.
- Japanese Patent Application Laid-Open No. 11-147901 discloses a kallikrein-kinin inhibitor containing, as an active ingredient, at least one selected from the group consisting of acidic mucopolysaccharide and a physiologically acceptable salt thereof. And hyaluronic acid as a specific example of acidic mucopolysaccharide.
- the publication discloses a therapeutic or preventive agent for acute enteritis and chronic enteritis, which contains polysulfuric acid hyaluronic acid as an active ingredient.
- polysulfated hyaluronic acid has a sulfate group. It is a substance completely different from hyaluronic acid in terms of physical properties and pharmacological actions. Therefore, even if this “polysulfuric acid hyaluronic acid” is replaced with “hyaluronic acid”, it can be said that the same action as that of the polysulfuric acid hyaluronic acid is not necessarily exerted.
- An object of the present invention is to provide a highly safe and clinically extremely effective therapeutic agent for inflammatory bowel disease comprising hyaluronic acid or a pharmaceutically acceptable salt thereof as an active ingredient.
- the present invention provides a highly safe and clinically effective agent for preventing or ameliorating various symptoms associated with inflammatory bowel disease (diarrhea, weight loss, edema of intestinal tissue, cell infiltration, shortened survival time, etc.).
- the purpose is to provide.
- the present invention provides a therapeutic agent for inflammatory bowel disease (hereinafter, referred to as “the therapeutic agent of the present invention”), comprising hyaluronic acid or a pharmaceutically acceptable salt thereof as an active ingredient.
- the present invention is directed to a preventive or ameliorating agent for various symptoms associated with inflammatory bowel disease comprising hyaluronic acid or a pharmaceutically acceptable salt thereof as an active ingredient (hereinafter referred to as “the preventive / improving agent of the present invention”).
- the preventive / improving agent of the present invention a preventive or ameliorating agent for various symptoms associated with inflammatory bowel disease comprising hyaluronic acid or a pharmaceutically acceptable salt thereof as an active ingredient.
- FIG. 1 is a graph showing the improvement of survival rate (suppression of shortening of survival time) by administration of sodium hyaluronate (hereinafter, referred to as HA).
- FIG. 2 is a photograph showing an optical microscopic image (magnification: 640) of an intestinal tissue section specimen in a control group.
- FIG. 3 is a photograph showing an optical microscope image (magnification: 320) of an intestinal tissue section specimen in the post-HA administration group.
- the present inventors have conducted intensive studies to solve the above problems, and found that hyaluronan, inflammatory bowel disease, various symptoms associated with inflammatory bowel disease (diarrhea, weight loss, edema of intestinal tissue, cell infiltration, etc.) , Shortening of survival time, etc.), and high safety.
- the present invention has been completed based on such findings.
- the preventive or ameliorating agent of the present invention is preferably a diarrhea preventing or ameliorating agent, a weight loss preventing or ameliorating agent, an intestinal tissue edema inhibitor, a cell infiltration inhibitor, or a survival time shortening inhibitor.
- the therapeutic agent of the present invention and the preventive / improving agent of the present invention are preferably administered intravenously.
- the weight-average molecular weight of hyalbutanoic acid or a pharmaceutically acceptable salt thereof, which is an active ingredient of the therapeutic agent of the present invention or the preventive / ameliorating agent of the present invention is from 600,000 to 1,200,000. It is preferably from 700,000 to 110,000, more preferably from 800,000 to 100,000.
- the inflammatory bowel disease to which the treatment agent of the present invention or the preventive / improving agent of the present invention is applied is preferably Crohn's disease or ulcerative colitis.
- the origin of the hyaluronic acid or a pharmaceutically acceptable salt thereof used in the present invention is not particularly limited, and hyaluronic acid isolated and purified from a cockscomb, an umbilical cord, a microorganism producing hyaluronic acid and the like can be used.
- those that are highly purified and substantially do not contain substances that are not allowed to be mixed as pharmaceuticals are preferable.
- salts of hyaluronic acid include, for example, alkali metal salts
- salts with inorganic bases such as alkaline earth metal salts and ammonium salts
- salts with organic bases such as diethanolamine salt, cyclohexylamine salt and amino acid salt
- pharmaceutically acceptable salts can be used.
- HA is preferred.
- the weight average molecular weight of the hyaluronic acid or a pharmaceutically acceptable salt thereof used in the present invention is not particularly limited, but is preferably 600,000 to 1200,000, more preferably 700,000 to 110,000. And 800,000 to 100,000, more preferably 850,000 to 950,000, particularly preferably about 900,000.
- the weight-average molecular weight of the hyaluronic acid or a pharmaceutically acceptable salt thereof used in the present invention is determined by measuring the intrinsic viscosity according to the 13th Revised Japanese Pharmacopoeia: General Test Method ⁇ Article 36 Viscosity Measurement Method. It can be calculated by the formula of Laurent et al. (Biochim. Biophys. Acta, 42, 476 (I960)).
- the limiting viscosity of hyaluronic acid having a weight average molecular weight of 600,000 to 1,200,000 or a pharmaceutically acceptable salt thereof is 11.5 to 20 dlZg, and that of 700,000 to 110,000 is 13 to: 18.5 dl / g, for 800,000 to 1,000,000, 14.5 to 17.5 dl / g, for 85,000 to 950,000, 15.0 to 16.5 d
- Those with 1 / g and about 900,000 are about 16 d 1 / g.
- the concentration of endotoxin in the hyaluronic acid or a pharmaceutically acceptable salt thereof used in the present invention is preferably 0.3 EU / mL or less when the agent is in the form of a solution.
- the endotoxin concentration can be measured using a commonly used endotoxin measurement method known to those skilled in the art, but a Limulus test method using a horseshoe crab / mebosite / lysate component is preferred.
- the EU endotoxin unit
- the iron content is preferably 20 ppm or less.
- the method of administration of the treatment agent of the present invention and the preventive and ameliorating agent of the present invention is not particularly limited as long as these agents exert an effect on inflammatory bowel disease and various symptoms associated therewith.
- Administration methods such as oral administration and the like can be mentioned. Of these, parenteral administration is preferred, administration into blood vessels (intravenous or intraarterial) is more preferred, and administration into veins is particularly preferred.
- Hyaluronic acid or a pharmaceutically acceptable salt thereof can be appropriately formulated according to the administration method to obtain the therapeutic agent of the present invention or the preventive / ameliorating agent of the present invention.
- Dosage forms include injections (solutions, suspensions, emulsions, solids for dissolution at the time of use, etc.), tablets, capsules, liquids and the like. Of these, injections are preferred.
- the concentration of hyaluronic acid or a pharmaceutically acceptable salt thereof in the therapeutic agent of the present invention and the prophylactic and / or therapeutic agent of the present invention is not particularly limited, either.However, in the case of a solution form, 0.05 to 1% (w / v).
- the amount should be about 0.1 to 0.5% (w / v). It is preferably about 0.2 to 0.4% (w / v), more preferably about 0.3% (w / v).
- Oral administration of the therapeutic agent of the present invention or the preventive / improving agent of the present invention In the case of a preparation for use as a liquid preparation, for example, it is preferably at least 0.1% (w / v), more preferably about 0.2 to 1% (w / v).
- the form may be any of a solution, a frozen form, or a lyophilized form.
- a suitable container such as an ampoule, a vial, or a syringe for injection, sealed, and then distributed or stored as it is, and can be administered as an injection.
- the preparation of the therapeutic agent of the present invention or the preventive / improving agent of the present invention can be performed by a known method.
- other pharmaceutically active ingredients conventional stabilizers, emulsifiers, and the like, as long as they do not adversely affect hyaluronic acid or a pharmaceutically acceptable salt thereof and do not affect the effects of the present invention.
- Components commonly used in pharmaceuticals such as osmotic pressure adjusting agents, buffers, isotonic agents, preservatives, soothing agents, coloring agents, S-shaped agents, binders, lubricants, and disintegrating agents can be used. . ⁇ 3> Administration target of the treatment agent of the present invention, etc.
- Animals to which the therapeutic agent of the present invention and the preventive / ameliorating agent of the present invention are administered include humans and non-human animals. Among them, vertebrates are preferred, mammals are particularly preferred, and humans are particularly preferred. .
- the therapeutic agent of the present invention can be administered for the treatment of inflammatory bowel disease in these animals, for example, for the prevention, suppression of progression (prevention of deterioration), improvement, and treatment of inflammatory bowel disease. That is, the therapeutic agent of the present invention includes, for example, the concept of a preventive agent for inflammatory bowel disease, an agent for suppressing progression (preventing deterioration), an ameliorating agent, a therapeutic agent and the like.
- the prophylactic / ameliorating agent of the present invention can be administered for the purpose of preventing or ameliorating the above-mentioned various symptoms associated with inflammatory bowel disease in animals.
- prevention or improvement of various symptoms associated with inflammatory bowel disease include, for example, prevention or improvement of diarrhea, prevention or improvement of weight loss, suppression of intestinal tissue edema, suppression of cell invasion, and reduction of survival time. Control, etc., to prevent or improve diarrhea and prevent or improve weight loss. It will provide beneficial agents, inhibitors of intestinal tissue edema, inhibitors of cell infiltration, and inhibitors of shortening survival time.
- the therapeutic agent of the present invention and the preventive and ameliorating agent of the present invention can be widely applied to inflammatory bowel diseases, and are not limited to specific diseases among inflammatory bowel diseases. As shown in the examples, it is particularly effective as a model of inflammatory bowel disease induced by trinitrobenzene sulfonic acid (TNBS), which has been established as a model of inflammatory disease and is widely used in patients with Crohn's disease and ulcer disease. It can be applied favorably to Otsuki fire.
- TNBS trinitrobenzene sulfonic acid
- the therapeutic agent of the present invention and the preventive / ameliorating agent of the present invention are It can be preferably applied as an agent.
- the amount of hyaluronic acid or a pharmaceutically acceptable salt thereof, the dose per administration, the administration interval, etc., of the treatment agent of the present invention and the preventive and ameliorating agent of the present invention are determined by the treatment agent of the present invention. It should be determined individually according to the patient's specific symptoms, age, gender, body weight, etc., such as the method of administration, dosage form, purpose of use, etc., and is not particularly limited as long as the effective amount is administered.
- the clinically effective dose of the acid or its pharmaceutically acceptable salt is: parenteral administration by injection, adult: 100-200 Omg per dose, 200-4000 mg per day, oral: 1 adult
- the dosage is, for example, about 500 to 2500 mg per dose and about 1000 to 5000 mg per day.
- the administration interval of the therapeutic agent of the present invention and the prophylactic / ameliorating agent of the present invention may be about once a day, or may be divided into two or three times a day. Also, it may be administered about once a day to three days.
- test substances and the like used in this example will be described.
- HA was used by dissolving in physiological saline so as to be 0.3% (w / v).
- the endotoxin concentrations after dissolution in saline were all less than 0.3 EU / mL, and the iron content was less than 20 ppm.
- An inflammatory bowel disease model was prepared by injecting 0.5 ml of 5 OmgZrn 1 TNBS (50% ethanol solution) into rats.
- This TNBS-induced inflammatory bowel disease model has been established and widely used as a model of inflammatory bowel disease (eg, GASTROENTEROLOGY, Vol. 109, No. 4, p. 1344-1367 (1995), etc.). See).
- the inflammatory bowel disease model animals are divided into the following groups for each test substance, and 2 ml of a physiological saline solution (0.3% (w / v)) of the following test substance is injected into the tail vein of each experimental animal did.
- HA pre-administration group 10
- the control group was administered for the first time immediately after the model was prepared, and then once daily for 20 days.
- the post-HA administration group was administered for the first time immediately after the model was prepared, and then administered once a day for 20 consecutive days.
- the HA pre-administration group was initially administered 24 hours before the above-described model preparation, and then administered once a day for 20 days every day.
- the survival rate of each of the HA-administered groups was significantly improved as compared with the control group. Also, among the HA-administered groups, the survival rate of the pre-administration group was 100% until 200 hours later, and the survival rate was improved compared to the post-administration group. From these results, it was clarified that HA has an effect of suppressing the shortening of the survival time associated with inflammatory bowel disease.
- HA has a preventive or ameliorating effect on diarrhea associated with inflammatory bowel disease.
- Control group 1 7 5 ⁇ 4 g
- Post-HA administration group 203 ⁇ 3 g
- the large intestine was excised and cut open, and the contents were washed with physiological saline. The attached water was removed, the weight of the large intestine tissue was measured, and the weight per 1 cm of the intestine tissue was calculated. The results are shown below. The following figures are shown as “average soil standard error”. ⁇
- Control group 448 ⁇ 60mg / cm intestinal tissue
- HA post-administration group 51 ⁇ lmg / cm intestinal tissue
- Section specimens of intestinal tissue were prepared and observed under a light microscope.
- the treatment agent of the present invention and the prophylactic and / or ameliorating agent of the present invention containing hyaluronic acid or a pharmaceutically acceptable salt thereof as an active ingredient are, as is clear from the results of the above-mentioned pharmacological tests, inflammatory bowel diseases and various accompanying diseases. It is extremely useful for the treatment of inflammatory bowel disease, etc., because it has an extremely excellent effect on symptoms and is extremely safe. In addition, since the treatment agent of the present invention and the preventive and ameliorating agent of the present invention have been shown to exhibit even more excellent effects when administered (pre-administered) to the administration subject in advance, they can be used as prophylactic agents. Particularly useful.
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2003535806A JP4335005B2 (ja) | 2001-10-18 | 2002-10-17 | 炎症性腸疾患処置剤 |
US10/492,947 US7354910B2 (en) | 2001-10-18 | 2002-10-17 | Agent for treating inflammatory bowel diseases |
EP02777868.7A EP1444983B1 (en) | 2001-10-18 | 2002-10-17 | Agents for treating inflammatory bowel diseases |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2001320658 | 2001-10-18 | ||
JP2001-320658 | 2001-10-18 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2003033004A1 true WO2003033004A1 (fr) | 2003-04-24 |
Family
ID=19138010
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP2002/010799 WO2003033004A1 (fr) | 2001-10-18 | 2002-10-17 | Agents permettant le traitement des affections abdominales inflammatoires |
Country Status (4)
Country | Link |
---|---|
US (1) | US7354910B2 (ja) |
EP (1) | EP1444983B1 (ja) |
JP (1) | JP4335005B2 (ja) |
WO (1) | WO2003033004A1 (ja) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2006036666A (ja) * | 2004-07-26 | 2006-02-09 | Japan Science & Technology Agency | ケモカイン受容体ccr10の発現誘導剤 |
JP2011037853A (ja) * | 2009-08-14 | 2011-02-24 | Holy Stone Healthcare Co Ltd | 炎症性腸疾患(ibd)治療及び予防に使用するヒアルロン酸混合物 |
JP2014501733A (ja) * | 2010-11-30 | 2014-01-23 | リチェルファルマ ソシエタ レスポンサビリタ リミタータ | 粘膜の無傷の状態を保存または回復するための局所用組成物 |
JP2014502642A (ja) * | 2011-07-07 | 2014-02-03 | アイホル コーポレーション | 炎症関連障害の治療および予防に使用するための組成物 |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8575130B2 (en) * | 2010-01-04 | 2013-11-05 | Holy Stone Healthcare Co., Ltd. | Mixture of hyaluronic acid for treating and preventing inflammatory bowel disease |
US20110166098A1 (en) * | 2010-01-04 | 2011-07-07 | Wu Tsung-Chung | Mixture of hyaluronic acid for treating and preventing inflammatory bowel disease |
US9029347B2 (en) | 2010-08-05 | 2015-05-12 | Holy Stone Healthcare Co., Ltd. | Method and mixture for treating and preventing inflammatory bowel disease |
US20140072621A1 (en) * | 2011-05-09 | 2014-03-13 | The Cleveland Clinic Foundation | Composition and method to improve intestinal health |
EP2545925B1 (en) | 2011-07-12 | 2018-02-14 | Holy Stone Healthcare Co.,Ltd. | Compositions comprising hyaluronic acid for treating and preventing mucosa related diseases |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000029030A1 (en) * | 1998-11-13 | 2000-05-25 | Continental Projects Limited | Complexes of hyaluronic acid/carnitines and pharmaceutical and cosmetic compositions |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4141973A (en) | 1975-10-17 | 1979-02-27 | Biotrics, Inc. | Ultrapure hyaluronic acid and the use thereof |
US4725585A (en) * | 1985-04-26 | 1988-02-16 | Pharmacia Ab | Method of enhancing the host defense |
CA1340994C (en) * | 1989-09-21 | 2000-05-16 | Rudolf Edgar Dr. Falk | Treatment of conditions and disease |
US5234914A (en) | 1991-06-11 | 1993-08-10 | Patent Biopharmaceutics, Inc. | Methods of treating hemorrhoids and anorecial disease |
JPH11147901A (ja) * | 1997-11-19 | 1999-06-02 | Maruho Co Ltd | カリクレイン−キニン系阻害剤 |
GB0003048D0 (en) * | 2000-02-11 | 2000-03-29 | Dealler Stephen F | The therapeutic use of polysulphonated polyglycosides or other polyanionic compounds in autism |
-
2002
- 2002-10-17 JP JP2003535806A patent/JP4335005B2/ja not_active Expired - Fee Related
- 2002-10-17 WO PCT/JP2002/010799 patent/WO2003033004A1/ja active Application Filing
- 2002-10-17 EP EP02777868.7A patent/EP1444983B1/en not_active Expired - Fee Related
- 2002-10-17 US US10/492,947 patent/US7354910B2/en not_active Expired - Fee Related
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000029030A1 (en) * | 1998-11-13 | 2000-05-25 | Continental Projects Limited | Complexes of hyaluronic acid/carnitines and pharmaceutical and cosmetic compositions |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2006036666A (ja) * | 2004-07-26 | 2006-02-09 | Japan Science & Technology Agency | ケモカイン受容体ccr10の発現誘導剤 |
JP4528898B2 (ja) * | 2004-07-26 | 2010-08-25 | 独立行政法人科学技術振興機構 | ケモカイン受容体ccr10の発現誘導剤 |
JP2011037853A (ja) * | 2009-08-14 | 2011-02-24 | Holy Stone Healthcare Co Ltd | 炎症性腸疾患(ibd)治療及び予防に使用するヒアルロン酸混合物 |
JP2014501733A (ja) * | 2010-11-30 | 2014-01-23 | リチェルファルマ ソシエタ レスポンサビリタ リミタータ | 粘膜の無傷の状態を保存または回復するための局所用組成物 |
JP2014502642A (ja) * | 2011-07-07 | 2014-02-03 | アイホル コーポレーション | 炎症関連障害の治療および予防に使用するための組成物 |
US9370575B2 (en) | 2011-07-07 | 2016-06-21 | Aihol Corporation | Composition for use in treating and preventing inflammation related disorder |
Also Published As
Publication number | Publication date |
---|---|
JPWO2003033004A1 (ja) | 2005-02-03 |
US20050043270A1 (en) | 2005-02-24 |
EP1444983B1 (en) | 2015-09-16 |
EP1444983A4 (en) | 2006-11-08 |
EP1444983A1 (en) | 2004-08-11 |
US7354910B2 (en) | 2008-04-08 |
JP4335005B2 (ja) | 2009-09-30 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP1392329B1 (en) | Use of sulodexide for the treatment of inflammatory bowel disease | |
US8575130B2 (en) | Mixture of hyaluronic acid for treating and preventing inflammatory bowel disease | |
US20050209188A1 (en) | Methods using glycosaminoglycans for the treatment of nephropathy | |
AU2002304265A1 (en) | Use of sulodexide for the treatment of inflammatory bowel disease | |
RU2242232C2 (ru) | Фармацевтические комбинации | |
JP7359396B2 (ja) | 細胞外ヒストンによって媒介される病理を処置及び予防するための化合物 | |
KR20010110788A (ko) | 저분자량 트롬빈 억제제 및 이의 프로드러그를 포함하는제약학적 제제 | |
WO2003033004A1 (fr) | Agents permettant le traitement des affections abdominales inflammatoires | |
BG64458B1 (bg) | Използване на цинков хиалуронат срещу пептична язва | |
US20120291789A1 (en) | Medical composition for protuberance of epithelium | |
AP619A (en) | Use of hyaluronic acid or salt for the treatment of a human having a stroke or myocardial infarction. | |
KR0131330B1 (ko) | 피브린 침착 또는 유착을 방지하기 위한 방법 및 치료 조성물 | |
Lambrecht et al. | Role of eicosanoids, nitric oxide, and afferent neurons in antacid induced protection in the rat stomach. | |
JP4627580B2 (ja) | 肝疾患処置剤 | |
JP4554910B2 (ja) | 血糖低下剤 | |
TWI281861B (en) | A pharmaceutical composition comprising SANORG 34006 for treatment and secondary prophylaxis of venous thromboembolic events in patients with deep venous thrombosis | |
JP4587637B2 (ja) | 神経ペプチドの産生・放出抑制剤 | |
JPH08165243A (ja) | 抗炎症剤 | |
US20030139355A1 (en) | Medicine for orthopaedic surgical application and a treating method using thereof | |
Porter et al. | Iron chelation | |
US9095551B2 (en) | Combined preparation for treating joint diseases | |
US9051456B2 (en) | Agent for drug clearance and accelerator for drug clearance | |
JPH11510515A (ja) | 白血球による組織浸潤を阻害するための薬剤 | |
FR2616661A1 (fr) | Composition a base de mucopolysaccharides hepariniques, active par voie orale | |
CZ20001455A3 (cs) | Použití glykosaminoglykanů pro přípravu farmaceutických přípravků pro léčení očních poruch spojených s diabetem |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BY BZ CA CH CN CO CR CU CZ DE DM DZ EC EE ES FI GB GD GE GH HR HU ID IL IN IS JP KE KG KP KR LC LK LR LS LT LU LV MA MD MG MN MW MX MZ NO NZ OM PH PL PT RU SD SE SG SI SK SL TJ TM TN TR TZ UA UG US UZ VC VN YU ZA ZM |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): GH GM KE LS MW MZ SD SL SZ UG ZM ZW AM AZ BY KG KZ RU TJ TM AT BE BG CH CY CZ DK EE ES FI FR GB GR IE IT LU MC PT SE SK TR BF BJ CF CG CI GA GN GQ GW ML MR NE SN TD TG |
|
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
WWE | Wipo information: entry into national phase |
Ref document number: 2003535806 Country of ref document: JP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2002777868 Country of ref document: EP |
|
WWP | Wipo information: published in national office |
Ref document number: 2002777868 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 10492947 Country of ref document: US |