WO2021054440A1 - 医薬組成物 - Google Patents

医薬組成物 Download PDF

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Publication number
WO2021054440A1
WO2021054440A1 PCT/JP2020/035438 JP2020035438W WO2021054440A1 WO 2021054440 A1 WO2021054440 A1 WO 2021054440A1 JP 2020035438 W JP2020035438 W JP 2020035438W WO 2021054440 A1 WO2021054440 A1 WO 2021054440A1
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Prior art keywords
sulfate
nasal
chondroitin
polysaccharide
sulfated
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PCT/JP2020/035438
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English (en)
French (fr)
Japanese (ja)
Inventor
重治 藤枝
哲司 高林
加奈子 吉田
英基 渡部
昂樹 藤川
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Maruho Co Ltd
University of Fukui NUC
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Maruho Co Ltd
University of Fukui NUC
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Priority to CN202411053759.6A priority Critical patent/CN118976045A/zh
Priority to PH1/2022/550661A priority patent/PH12022550661A1/en
Priority to CN202410519891.5A priority patent/CN118416094A/zh
Priority to AU2020349263A priority patent/AU2020349263B2/en
Priority to CN202080064874.7A priority patent/CN114650828B/zh
Priority to JP2021546977A priority patent/JP7313019B2/ja
Priority to BR112022003464A priority patent/BR112022003464A2/pt
Priority to US17/760,901 priority patent/US20220347093A1/en
Priority to CA3154360A priority patent/CA3154360C/en
Priority to EP20864928.5A priority patent/EP4032535A4/en
Priority to MYPI2022001387A priority patent/MY206715A/en
Publication of WO2021054440A1 publication Critical patent/WO2021054440A1/ja
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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
    • A61K31/702—Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0043—Nose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • 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
    • A61K31/727—Heparin; Heparan
    • 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
    • A61K31/733—Fructosans, e.g. inulin
    • 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
    • A61K31/736—Glucomannans or galactomannans, e.g. locust bean gum, guar gum
    • 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
    • A61K31/737—Sulfated polysaccharides, e.g. chondroitin sulfate, dermatan sulfate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants

Definitions

  • the present invention relates to a pharmaceutical composition containing a predetermined polysaccharide used as a shrinking agent for nasal polyps, a method for treating nasal polyps using a predetermined polysaccharide, and the like.
  • Nasal polyps also called nasal polyps
  • nasal polyps are fleshy growths of the nasal mucosa that form at the site of dependent edema in the lamina basement (usually around the opening of the maxillary sinus). It is a disease that often accompanies chronic sinusitis and exacerbates the nasal congestion symptoms of chronic sinusitis, and is one of the major diseases of nasal diseases (MSD Manual Professional Edition https://www.msdmanuals.com/). ja-jp).
  • Various causes of nasal polyps such as edema due to increased vascular permeability, lamina limbal prolapse, and extracellular matrix accumulation are considered, and their association with various cytokines and growth factors has also been reported. ..
  • As a growth factor the relationship between vascular endothelial growth factor and platelet-derived growth factor and nasal polyps has been reported (Non-Patent Document 1: Kawasaki Medical Association 35 (1): 39-50, 2009).
  • Chronic sinusitis is said to have persistent respiratory symptoms such as nasal congestion, rhinorrhea, postnasal drip, and cough for more than 3 months, and its cause is viral, bacterial, fungal, allergic, or pathological condition.
  • eosinophilia There is unknown eosinophilia, and other factors such as differences in nasal cavity morphology, living environment, and inheritance affect the formation of complex pathological conditions including nasal polyps (Non-Patent Document 2: Non-Patent Document 2:). Japan Otolaryngology Society Bulletin 2018, 121, 1118-1120).
  • diseases associated with nasal polyps include eosinophil sinusitis and non-eosinophil sinusitis.
  • eosinophil sinusitis is a designated intractable disease, and is an adult-onset intractable sinusitis showing severe nasal congestion and olfaction disorder due to bilateral multiple nasal polyps and viscous nasal discharge. Antibiotics are ineffective in treating the disease and respond only to oral steroids. Since the nasal cavity is filled with nasal polyps, nasal sinus surgery was performed to remove the nasal polyps, but there was a problem that the nasal polyps recurred immediately.
  • Non-Patent Document 3 Japanese Patent Application Laid-Open No. 10-203988) and / or hyaluronic acid (Non-Patent Document 3: Indian Journal of Otolaryngology and Head & Neck Surgery 67 (3): 299-307, September 2015) and the like are used. Has been reported.
  • Non-Patent Document 4 Ear-nasal immunoallergy 29 (3): 221-227, 2011
  • Non-Patent Document 5 Allergology International 66 (2017) 594-602
  • Patent 6436351 Japanese Patent Application Laid-Open No. 09-104636 Japanese Patent Application Laid-Open No. 10-203988
  • the present invention provides a safe nasal polyp reducing agent or a method for treating nasal polyps, which exhibits an excellent shrinking effect on nasal polyps.
  • a predetermined polysaccharide particularly a heparinoid or pentosan polysulfate (PPS), which is a kind of sulfated polysaccharide, significantly reduces nasal polyps, and completes the present invention.
  • PPS pentosan polysulfate
  • the present invention is as follows.
  • Polysaccharide selected from polysulfated chondroitin sulfate, chondroitin sulfate, dermatan sulfate, keratan sulfate, heparan sulfate, dextran sulfate, pentosanpoly sulfate, chondroitin, glucomannan, inulin, and xylooligosaccharide as active ingredients.
  • a nasal mushroom reducing agent selected from polysulfated chondroitin sulfate, chondroitin sulfate, dermatan sulfate, keratan sulfate, heparan sulfate, dextran sulfate, pentosanpoly sulfate, chondroitin, glucomannan, inulin, and xylooligosaccharide as active ingredients.
  • the polysaccharide or a salt thereof is selected from polysulfated chondroitin sulfate, chondroitin sulfate, keratan sulfate, heparan sulfate, dextran sulfate, pentosanpoly sulfate, chondroitin, glucomannan, and inulin, according to (1).
  • Nasal mushroom reducing agent A nasal polyp reducing agent containing a sulfated polysaccharide or a salt thereof as an active ingredient.
  • the sulfated polysaccharide is composed of a monosaccharide selected from D-galactosamine, D-glucuronic acid, L-iduronic acid, D-glucose, D-galactose, D-xylose, and L-arabinose.
  • the nasal mushroom reducing agent according to (1b), wherein the monosaccharide may be partially acetylated.
  • chondroitin sulfate Polysulfated chondroitin sulfate, chondroitin sulfate, dermatan sulfate, keratan sulfate, heparan sulfate, dextran sulfate, pentosanpolysulfate, chondroitin, glucomannan, inulin, and xylooligo, which are used to reduce nasal mushrooms in patients with chronic sinusitis.
  • a pharmaceutical composition containing a polysaccharide selected from sugars or a salt thereof.
  • the sulfated polysaccharide is composed of a monosaccharide selected from D-galactosamine, D-glucuronic acid, L-iduronic acid, D-glucose, D-galactose, D-xylose, and L-arabinose.
  • the pharmaceutical composition according to (5b), wherein the monosaccharide may be partially acetylated.
  • the pharmaceutical composition according to (5b) or (6), wherein the sulfated polysaccharide is polysulfated chondroitin sulfate, polysulfated dermatan sulfate, or pentosan polysulfate.
  • the polysaccharide or a salt thereof is selected from polysulfated chondroitin sulfate, chondroitin sulfate, keratan sulfate, heparan sulfate, dextran sulfate, pentosanpoly sulfate, chondroitin, glucomannan, and inulin, according to (11).
  • Method. (13) A method for reducing nasal polyps, which comprises administering an effective amount of a sulfated polysaccharide or a salt thereof to a patient in need of treatment for nasal polyps.
  • the sulfated polysaccharide is composed of a monosaccharide selected from D-galactosamine, D-glucuronic acid, L-iduronic acid, D-glucose, D-galactose, D-xylose, and L-arabinose.
  • the method according to (13), wherein the monosaccharide may be partially acetylated.
  • the sulfated polysaccharide is polysulfated chondroitin sulfate, polysulfated dermatan sulfate, or pentosan polysulfate.
  • Predetermined polysaccharides especially sulfated polysaccharides such as heparinoids and pentosan polysulfate, are useful as effective and safe nasal polyp reducing agents at low doses.
  • the polysaccharides used in the present invention include sulfated mucopolysaccharides and sulfated mucopolysaccharides selected from polysulfated mucopolysaccharides such as chondroitin sulfate, chondroitin, dermatan sulfate, keratane sulfate, heparan sulfate, and polysulfated chondroitin sulfate.
  • sulfated polysaccharides including dextran sulfate and pentosanpolysulfate, and polysaccharides selected from glucomannan, inulin, and xylooligosaccharides.
  • it is a polysaccharide selected from polysulfated chondroitin sulfate, chondroitin sulfate, keratan sulfate, heparan sulfate, dextran sulfate, pentosan polysulfate, chondroitin, glucomannan, and inulin.
  • the sulfated polysaccharide in the present invention is selected from D-glucosamine, D-galactosamine, D-glucuronic acid, L-isulonic acid, D-galacturonic acid, D-glucose, D-galactose, D-xylose, and L-arabinose.
  • These monosaccharides may be partially acetylated, and are composed of a polysaccharide having one or more of the monosaccharides as a repeating unit and having a sulfate group.
  • the sulfated polysaccharide used in the present invention has an average of 0.55 to 4 molecules, preferably an average of 0.6 to 2.9 molecules, and more preferably an average of 0.7 to 2 molecules per molecule of monosaccharide. Is.
  • the sulfated polysaccharide used in the present invention has a sulfated group content of 10 to 70 w / w% according to the quantitative method specified in "Heparin-like substance" of the Japanese Pharmacy Non-Pharmaceutical Standard 2002. Some are preferred, more preferably sulfated polysaccharides having an organic sulfate group content of 10-65 w / w%.
  • the main constituent monosaccharides are selected from D-galactosamine, D-glucuronic acid, L-iduronic acid, D-glucose, D-galactose, D-xylose and L-arabinose, some of which are monosaccharides.
  • partially acetylated monosaccharides include naturally occurring monosaccharides such as acetylglucose, N-acetylglucosamine, acetylgalactose, N-acetylgalactosamine, and acetylxylose.
  • the weight average molecular weight of the sulfated polysaccharide or salt thereof used in the present invention is about 1000 to 10,000,000, preferably about 4000 to 1,000,000.
  • the weight average molecular weight used in the present specification is the following formula when there are Ni polymers having a molecular weight of Mi.
  • Weight average molecular weight (Mw) ⁇ (Ni ⁇ Mi 2 ) / ⁇ (Ni ⁇ Mi) ) It is a value represented by.
  • the weight average molecular weight means a value measured by gel permeation chromatography (GPC).
  • the weight average molecular weight is, for example, the weight average molecular weight in terms of pullulan or polyethylene glycol measured by GPC using pullulan or polyethylene glycol as a reference substance.
  • the weight average molecular weight can be measured by, for example, high performance liquid chromatography (Waters or Shimadzu Corporation), and Ohpak SB-804 and SB-803 (both Showa Denko KK) can be used as columns. ..
  • As the mobile phase an aqueous solvent such as an aqueous solution of ammonium acetate or an aqueous solution of sodium chloride can be used, and the flow velocity can be 1.0 mL / min.
  • a differential refractive index can be used in the detection method.
  • the various sulfated polysaccharides used in the present invention can be obtained by the following methods.
  • Sulfated polysaccharides are obtained by subjecting a sulfation reaction to a polysaccharide composed of a monosaccharide which may be partially acetylated and introducing a sulfate group.
  • For the sulfation reaction prepare 10 to 30 mL of an ice-cooled solvent with respect to 1 g of the raw material polysaccharide, add a sulfate agent 2 to 6 times to 1 g of the raw material polysaccharide, and add 1 g of the raw material polysaccharide to this solution. Is added and reacted at 0 ° C. to 100 ° C.
  • sulfated polysaccharide composed of a partially acetylated monosaccharide used in the present invention preferably 0% to 60% (molar ratio) of the constituent sugars of the sulfated polysaccharide is N-acetylated. Or it is O-acetylated.
  • the sulfated polysaccharide may be used as a physiologically acceptable salt form, and the physiologically acceptable salt includes an alkali metal salt such as a sodium salt and a potassium salt, and an alkaline soil such as a calcium salt. Examples thereof include metal salts and magnesium salts, and a plurality of these salts are also included.
  • sulfated polysaccharide in the present invention examples include sulfated mucopolysaccharide, dextran sulfate, pentosan polysulfate and the like.
  • Preferred are polysulfated chondroitin sulfate, chondroitin sulfate, chondroitin, dermatan sulfate, keratan sulfate, heparan sulfate, dextran sulfate and pentosan polysulfate.
  • polysulfated mucopolysaccharides such as chondroitin sulfate, chondroitin, dermatan sulfate, keratan sulfate and heparan sulfate, and polysulfated chondroitin sulfate are classified as sulfated mucopolysaccharides.
  • Glucomannan, inulin, and xylooligosaccharides are classified as polysaccharides that do not fall under the above.
  • the "mucopolysaccharide” is a long-chain amino sugar having a repeating unit of a disaccharide consisting of hexosamine and uronic acid or galactose as a basic structure.
  • "Sulfated mucopolysaccharide” means a mucopolysaccharide having a sulfate group.
  • the sulfated mucopolysaccharide of the present invention also includes naturally occurring mucopolysaccharides having a sulfate group in the sugar chain, mucopolysaccharides, and those obtained by further chemically modifying natural sulfated mucopolysaccharides.
  • Polysulfated mucopolysaccharide is a sulfated mucopolysaccharide having more sulfate groups in the sugar chain, and in addition to naturally-derived polysulfated mucopolysaccharides, mucopolysaccharides and natural sulfated mucopolysaccharides are used. Further, chemically sulfated products are also included. Examples of sulfated mucopolysaccharides will be described below, but the overall structure depends on the type of proteoglycan formed by these sulfated mucopolysaccharides, the animal species in which these sulfated mucopolysaccharides are present, the tissue, the stage of development, and the like.
  • Hexosamine broadly means a compound in which the hydroxyl group of hexose is replaced with an amino group, and specific examples thereof include D-glucosamine and D-galactosamine.
  • uronic acid broadly means an aldose primary alcohol that has been oxidized to a carboxyl group, and specifically, D-glucuronic acid, L-iduronic acid, D-galacturonic acid and the like. Examples include naturally occurring uronic acid.
  • Chodroitin sulfate is a substance separated from animal mucous secretions and cartilage tissue.
  • chondroitin sulfate A and chondroitin sulfate C are chondroitin sulfate as sulfated mucopolysaccharides.
  • D and E are sulfated mucopolysaccharides, which are also classified as polysulfated mucopolysaccharides.
  • Chondroitin sulfate A (chondroitin tetrasulfate) has a repeating structure of N-acetyl-D-galactosamine (GalNAc) and D-glucuronic acid (GlcA) disaccharides having a sulfate group at the 4-position as a basic structure.
  • Chondroitin sulfate C (chondroitin 6 sulfate) has a repeating structure of GalNAc and GlcA disaccharides having a sulfate group at the 6-position as a basic structure.
  • low molecular weight chondroitin sulfate having a weight average molecular weight of 100,000 or less, preferably 10,000 to 50,000, can also be used.
  • Low-molecular-weight chondroitin sulfate is obtained by decomposing natural chondroitin sulfate using an enzyme such as chondroitinase or chondroitin sulfate lyase.
  • "Dermatan sulfate” is composed of a repeating disaccharide of iduronic acid (IdouA) and GalNAc, and has a basic structure having a sulfate group at the 4-position of GalNAc. Sometimes referred to as chondroitin sulfate B.
  • Keatan sulfate consists of a repeating disaccharide in which galactose (Gal) and N-acetyl-D-glucosamine (GlcNAc) are alternately bound by ⁇ (1 ⁇ 4) and ⁇ (1 ⁇ 3) bonds, respectively, and is composed of GlcNAc.
  • the 6-position always has a sulfated structure as a basic structure.
  • Heparan sulfate is a polysaccharide N-acetyl, N-sulfate, or O-sulfate substituent containing D-glucosamine, D-glucuronic acid, and L-iduronic acid as constituent sugars.
  • Chodroitin is a mucopolysaccharide having a basic structure of repeating disaccharides of GalNAc and GlcA and having a particularly small number of sulfate groups (usually 0.7 molecules or less per disaccharide unit). In addition to naturally derived substances such as bovine cornea, it can also be obtained by chemically desulfating chondroitin sulfate.
  • the sulfated mucopolysaccharide used in the present invention is preferably a sulfated mucopolysaccharide having a repeating unit of a disaccharide consisting of N-acetyl-D-galactosamine or N-acetyl-D-glucosamine and uronic acid or galactose, and chondroitin sulfate.
  • a disaccharide consisting of N-acetyl-D-galactosamine or N-acetyl-D-glucosamine and uronic acid or galactose
  • chondroitin sulfate Dermatan sulfate, keratan sulfate, and heparan sulfate are more preferred.
  • the sulfated mucopolysaccharide used in the present invention also includes a polysulfated mucopolysaccharide obtained by further sulfated chondroitin sulfate, dermatan sulfate, keratan sulfate and the like.
  • the number of sulfate groups contained in the sulfated mucopolysaccharide of the present invention is not particularly limited, but usually an average of 0.55 to 4 molecules, preferably an average of 0.6 to 2.9 molecules, and more preferably an average of 0. It has a ratio of 7 to 2 molecules.
  • the molecular weight of the sulfated mucopolysaccharide or a salt thereof used in the present invention varies depending on the type of polysaccharide and is not limited, but the average molecular weight thereof is about 10,000 to 1,000,000 by weight average, preferably 10000. It is preferably about 50,000.
  • the origin of the sulfated mucopolysaccharide of the present invention is not particularly limited, but more preferable one is, for example, the above-mentioned naturally-derived mucopolysaccharide being sulfated by artificially performing a sulfate treatment. Can be mentioned.
  • polysulfated mucopolysaccharide means a mucopolysaccharide in which more sulfate groups are substituted among the above-mentioned sulfated mucopolysaccharides, and specific examples thereof include polysulfated chondroitin sulfate and polysulfated dermatan sulfate. It is preferably polysulfated chondroitin sulfate.
  • a method for further introducing a sulfate group into a sulfated mucopolysaccharide such as chondroitin sulfate A or C to obtain a polysulfated mucopolysaccharide a known method, for example, heating in a suitable solvent in the presence of a sulfate agent, is performed.
  • a method of reacting can be mentioned.
  • the sulfate agent is not particularly limited as long as it can achieve the purpose of polysulfation, but it is preferable to use a complex of anhydrous sulfuric acid and pyridine or triethylamine.
  • the proportion of the sulfated agent used can be arbitrarily selected according to the desired sulfation rate (or sulfur content) of the sulfated mucopolysaccharide and the reaction conditions, but in general, 1 part by weight of the sulfated mucopolysaccharide to be multisulfated. It is used at a ratio of 2 to 10 parts by weight.
  • the solvent include protic and aprotic solvents such as dimethylformamide.
  • the reaction temperature and reaction time are not particularly limited as long as the desired sulfation rate can be achieved, but for example, the reaction is carried out at 40 to 90 ° C. for about 30 minutes to 20 days.
  • the polysulfated mucopolysaccharide produced as described above can be purified by a purification operation commonly used for various modified polysaccharides. For example, an operation of neutralizing, desalting by dialysis, an operation of recovering a precipitate by adding an organic solvent, a recovery operation by freeze-drying, and the like can be mentioned.
  • the polysulfated mucopolysaccharide may be used as a physiologically acceptable salt form, and the physiologically acceptable salts include alkali metal salts such as sodium salt and potassium salt, calcium salts and the like. Examples include alkaline earth metal salts and magnesium salts, and a plurality of these salts are also included.
  • the "polysulfated chondroitin sulfate” is a polymer containing about 2 to 4 molecules, preferably about 2 to 3 molecules of sulfate groups per disaccharide unit composed of D-acetylgalactosamine and D-glucuronic acid.
  • Examples of the polysulfated chondroitin sulfate include chondroitin sulfate D, chondroitin sulfate E, and heparinoids described in the Japanese Pharmacopoeia Non-Pharmaceutical Standards.
  • it is a heparinoid substance described in the Japanese Pharmacopoeia Non-Pharmaceutical Standards.
  • Polysulfated chondroitin sulfate includes naturally obtained ones such as chondroitin sulfate D and chondroitin sulfate E, as well as chondroitin components such as chondroitin and chondroitin sulfate (A, C, D, E), and chlorosulfate, concentrated sulfuric acid, and tri. It can be easily produced by a known method of reacting a sulfate agent such as a sulfur oxide-pyridine complex.
  • Preferred polysulfated chondroitin sulfates include heparinoids described in the Japanese Pharmacopoeia Non-Pharmaceutical Ingredient Standards. Specifically, it is polysulfated chondroitin sulfate which shows the following values as physicochemical properties. a) Sulfate group content: 25.8-37.3% b) Extreme viscosity: 0.09 to 0.18
  • Polysulfated chondroitin sulfate may be used in the form of a free acid derived from a sulfuric acid residue, but usually a base salt is used.
  • Examples of the base salt include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt, and magnesium salt.
  • Chondroitin sulfate D is isolated from shark cartilage and has a structure similar to chondroitin sulfate C, and its basic structure has sulfate groups at positions 2 and 3 of GlcA in addition to the 6-position of GalNAc.
  • Chondroitin sulfate E (chondroitin 4,6 sulfate) is isolated from Japanese flying squid cartilage and has a structure similar to chondroitin sulfate C, and its basic structure has sulfate groups at positions 4 and 6 of GalNAc.
  • Polysulfated dermatan sulfate is synthesized by chemically introducing a sulfate group into dermatan sulfate, which is a natural sulfated mucopolysaccharide having a repeating sugar unit consisting of N-acetylgalactosamine and L-iduronic acid. It means dermatan polysulfate that is naturally occurring and dermatan polysulfate, or one that is synthesized by chemically introducing a sulfate group into the sulfate.
  • the number of sulfate groups introduced is not particularly limited, for example, more than 1 per repeating sugar unit, up to 4, preferably 1.3-4, more preferably 2-4. Can be mentioned.
  • the weight average molecular weight of the polysulfated dermatan sulfate of the present invention is, for example, about 1,000 to tens of thousands. Sulfated polysaccharides other than the above used in the present invention will be described below.
  • “Dextran sulfate” is a straight chain of glucose bound to ⁇ (1 ⁇ 6) and a variety of usual from 1000 to thousands of daltons (Da) to hundreds of thousands of Da starting from the branch of ⁇ (1 ⁇ 3) bond.
  • Pentosan polysulfate is a semi-synthetic sulfated polysaccharide containing a mixture of polyvalent anionic polysaccharides with D-xylose and / or L-arabinose as the constituent monosaccharides. Pentosan polysulfate is produced by the chemical sulfation of polysaccharides (eg, xylan) obtained from wood, such as beech.
  • Pentsanpolysulfate may be used as a physiologically acceptable salt form, and the physiologically acceptable salts include alkali metal salts such as sodium salt and potassium salt, and alkaline earth metal salts such as calcium salt. , And magnesium salts.
  • a particularly preferred salt is sodium pentosan polysulfate.
  • the pentosan polysulfate is not particularly limited, but one having a weight average molecular weight of 1000 to 30,000 is preferably used, more preferably 2000 to 10000, and even more preferably 4000 to 6500.
  • Glucomannan is mainly composed of glucose and mannose, and both are ⁇ (1 ⁇ 4) bonded to form a main chain, and partly branched by ⁇ (1 ⁇ 3) bond or ⁇ (1 ⁇ 6) bond.
  • Insulin is a substance in which fructose having terminal glucose is ⁇ (2 ⁇ 1) bound and 2 to 140 molecules are bound.
  • Xylooligosaccharide is a hydrolyzate of xylan, and is an oligosaccharide having a structure in which about 2 to 7 xyloses are ⁇ (1 ⁇ 4) bound.
  • the above-mentioned polysaccharide may be used as a physiologically acceptable salt form, and examples of the physiologically acceptable salt include alkali metal salts such as sodium salt and potassium salt, and alkaline earth metal salts such as calcium salt. And magnesium salts and the like, and a plurality of these salts are also included.
  • the above-mentioned polysaccharide can be extracted and recovered from animals, plant tissues, microorganisms such as Streptococcus microorganisms, animal cells, or cultures of plant cells. Moreover, a commercially available product can also be used.
  • a medicine effective for reducing nasal polyps which contains the above-mentioned predetermined polysaccharide, preferably a predetermined sulfated polysaccharide as an active ingredient.
  • the medicament of the present invention has a nasal polyp reducing effect, diseases presenting nasal polyps, specifically, chronic sinusitis including eosinophil sinusitis and non-eosinophil sinusitis, and chronic sinusitis including non-eosinophil sinusitis, It can also be expected to improve symptoms such as allergic rhinitis.
  • nasal polyps also called nasal polyps
  • nasal polyps are fleshy growths of the nasal mucosa at the site of lamina basement where subordinate edema occurs (usually around the opening of the maxillary sinus).
  • Patients in need of treatment for nasal polyps are those with nasal polyps, specifically those with sinusitis, preferably those with chronic sinusitis.
  • Chronic sinusitis includes eosinophilic sinusitis and non-eosinophil sinusitis.
  • Treatment of nasal polyps includes ameliorating symptoms such as nasal congestion caused by nasal polyps, reducing nasal polyps, or treating nasal polyps, that is, reducing nasal polyps and improving symptoms such as nasal congestion.
  • the improvement of symptoms such as nasal congestion caused by nasal polyps is that clinical symptoms such as nasal congestion are improved as compared with the polysaccharide non-administered group used in the present invention, even if the number and size of nasal polyps are not reduced.
  • Means. Shrinkage of nasal polyps means that there is at least one reduction in the number and size of nasal polyps (area and weight per nasal polyp).
  • the concentration of the polysaccharide used in the present invention is preferably about 3 ⁇ 10 -7 to 30 w / v%, more preferably about 0.003 to 10 w / v% in the case of a liquid preparation.
  • the polysaccharide used in the present invention is used as an intranasal administration preparation delivered into the nasal cavity presenting nasal polyps by intranasal administration.
  • the nasal administration preparation is a form of a drug intended for intranasal administration, and specifically, is a liquid preparation, a suspension preparation, a powder preparation, a solid preparation, or a semi-solid preparation.
  • Suspensions are liquid formulations containing solid particles dispersed in a liquid medium.
  • Preferable dosage forms of intranasal administration preparations include nasal drops.
  • Nasal drops are preparations to be administered to the nasal cavity or nasal mucosa, and are classified into nasal drops and nasal powders.
  • nasal drops can be sprayed and inhaled, if necessary, using a spraying device having an appropriate spray amount uniformity such as a spray pump.
  • the dose of nasal drops can be adjusted by using a spraying device capable of adjusting the amount of spray.
  • Nasal drops are liquid nasal drops that are administered to the nasal cavity, or solid nasal drops that are used by dissolving or suspending before use, and usually dissolve or dissolve the active ingredient as it is or by adding a solvent or other appropriate additives. It can be produced by suspending and, if necessary, filtering. Alternatively, an appropriate dissolution solution or suspension solution can be used, and the solution can be dissolved or suspended before use.
  • a solubilizing agent, an tonicity agent, a buffering agent, a pH adjusting agent, or the like can be added to the nasal drops.
  • a suspending agent, a dispersant, a stabilizer, or the like can be added, if necessary, in order to obtain a uniform state of the active ingredient.
  • Dosage forms of nasal drops include, for example, spray nasal drops, nasal aerosols, and nasal nebulizers. Spray nasal drops usually contain a polysaccharide dissolved or suspended in a solution or mixture in a non-pressurized dispenser. Spray nasal drops have the advantages of a small delivery device, convenience and ease of use, and the ability to accurately measure delivery dosages of 25-200 ⁇ L.
  • a liquid containing a polysaccharide or a suspending agent can be used as the spray-type nasal spray.
  • Another intranasal morphology is the nasal aerosol.
  • the nasal aerosol dispenses the drug due to excessive pressure and releases it through the valve.
  • the drug is forcibly dispensed by a micropump bucket, but the vial pressure is similar to atmospheric pressure.
  • Nasal aerosols have similar advantages to sprays.
  • the nasal nebulizer is an administration form using a device that emits a drug into a fine mist by ultrasonic waves.
  • nasal drops are to be filled in a multi-dose container, add an appropriate preservative in an amount sufficient to inhibit the growth of microorganisms, if necessary.
  • the container used for the nasal drops is usually an airtight container.
  • Nasal drops are fine powdered nasal drops that are administered to the nasal cavity, and are usually manufactured by making the active ingredient into moderately fine particles and, if necessary, mixing them with an appropriate additive to make them homogeneous. Can be done.
  • the container used for the nasal drop powder is usually a closed container. Moisture proof is added as needed.
  • the medicament of the present invention can be a highly viscous liquid or suspension applied to solid, semi-solid or nasal mucosa such as ointments, ointments, creams and gels. , It may be administered by applying it into the nasal cavity. Dosage forms of these nasal drops, ointments, ointments, creams, gels and the like are prepared for each dosage form together with the polysaccharides and pharmaceutically acceptable additives used in the present invention.
  • the pharmaceutically acceptable additive used in the medicament of the present invention include additives usually used in the art, that is, pharmaceutical excipients and pharmaceutical carriers as shown below. , These additives can be appropriately used to prepare a pharmaceutical composition suitable for each administration form by a commonly used method.
  • the pharmaceutically acceptable additive used in the medicament of the present invention is not particularly limited as long as it is an additive usually used in the art, and for example, a base, a solubilizing agent, an excipient, and a dispersion.
  • Agents, emulsifiers, thickeners, tonicity agents, buffers, pH regulators, stabilizers, chelating agents, preservatives, antioxidants, absorption enhancers, moisturizers, fillers, cross-linking agents, refreshing agents And a film agent, and these additives can be appropriately used to prepare a pharmaceutical composition suitable for each administration form by a commonly used method.
  • Examples of the base used in the medicament of the present invention include a hydrophobic base, a hydrophilic base and water.
  • the hydrophobic base is not particularly limited, but higher hydrocarbons, fats and oils, waxes, fatty acids, higher alcohols, fatty acid esters and the like can be used.
  • Examples of higher hydrocarbons include squalane, synthetic paraffin, liquid paraffin, white petrolatum, microcrystalline wax and the like.
  • Examples of fats and oils include sesame oil, corn oil, olive oil and cacao fat.
  • Examples of waxes include beeswax, beeswax, lanolin, reduced lanolin, and selecin wax.
  • Examples of fatty acids include stearic acid and oleic acid.
  • Examples of the higher alcohol include lanolin alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, cetostearyl alcohol and cholesterol.
  • Examples of fatty acid esters include isopropyl myristate, stearyl myristate, and medium-chain fatty acid triglycerides.
  • Examples of the hydrophilic base include ethanol, propanol, isopropanol, butanol, isobutanol, propylene glycol, polyethylene glycol and macrogol.
  • the solubilizing agent is not particularly limited, and examples thereof include propylene glycol, D-mannitol, benzyl benzoate, ethanol, isopropanol, triethanolamine, sodium carbonate, sodium citrate, and the like.
  • Excipients are not particularly limited, but include, for example, sugar alcohols such as erythritol, martitol, mannitol, sorbitol, xylitol and lactitol, sucrose, lactose, reduced maltose water candy, powdered reduced maltose water candy, glucose and maltose.
  • sugar alcohols such as erythritol, martitol, mannitol, sorbitol, xylitol and lactitol
  • sucrose, lactose reduced maltose water candy, powdered reduced maltose water candy, glucose and maltose.
  • examples thereof include sugars, corn starch, crystalline cellulose, calcium monohydrogen phosphate, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, light anhydrous silicic acid, hydrous silicon dioxide and silicon dioxide.
  • a dispersant is used as an additive, if desired.
  • the dispersant is not particularly limited, and is, for example, celluloses such as methyl cellulose, sodium carboxymethyl cellulose and hydroxypropyl methyl cellulose, synthetic polymer compounds such as polyvinyl alcohol, polyvinylpyrrolidone and carboxyvinyl polymer, polyoxyethylene alkyl ether and polyoxy.
  • the emulsifier examples include cationic surfactants, anionic surfactants, amphoteric surfactants and nonionic surfactants.
  • the cationic surfactant is not particularly limited, and examples thereof include cetyltrimethylammonium chloride, lauryldimethylbenzylammonium chloride, tetrabutylammonium chloride, and dioctadecyldimethylammonium chloride.
  • the anionic surfactant is not particularly limited, and examples thereof include sodium alkylbenzene sulfonate, sodium dodecyl sulfate, sodium coconut alcohol ethoxysulfate, sodium ⁇ -olefin sulfonate, and emulsified cetostearyl alcohol.
  • the nonionic surfactant is not particularly limited, and is, for example, polyoxyethylene alkyl ether, polyoxyethylene alkyl phenol ether, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyl stearate, glycerin fatty acid ester, and the like. Examples include diglycerin fatty acid ester.
  • amphoteric tenside is not particularly limited, and examples thereof include N-alkyl-N, N-dimethylammonium betaine and imidazoline type amphoteric tenside.
  • the above surfactants can be used alone or in combination.
  • the viscous agent is not particularly limited, and examples thereof include sodium alginate, gelatin, methyl cellulose, carboxyvinyl polymer, carboxymethyl cellulose, and sodium polyacrylate.
  • the tonicity agent is not particularly limited, and examples thereof include saccharides such as sorbitol, glucose and mannitol, polyhydric alcohols such as glycerin, polyethylene glycol and propylene glycol, and inorganic salts such as sodium chloride and potassium chloride. ..
  • the buffer is not particularly limited, and examples thereof include boric acid, borax, sodium monohydrogen phosphate, sodium dihydrogen phosphate, citric acid, sodium citrate, sodium dihydrogen citrate, and disodium citrate.
  • the pH regulator is not particularly limited, but for example, diisopropanolamine, triisopropanolamine, triethanolamine, potassium hydroxide, sodium hydroxide, sodium citrate, phosphoric acid, tartaric acid, dl-malic acid, glacial acetic acid and the like. Can be mentioned.
  • the stabilizer is not particularly limited, and examples thereof include sodium edetate, sodium oleate, casein, and sodium casein salt.
  • the chelating agent is not particularly limited, and examples thereof include edetic acid, oxalic acid, citric acid, pyrophosphate, hexametaphosphate, gluconic acid, and salts thereof.
  • the preservative is not particularly limited, but for example, quaternary ammonium salts such as benzalkonium chloride, benzoxoneium chloride, benzododecinium bromide, benzethonium chloride, cetylpyridinium chloride and cetrimid, benzoic acid and salts thereof, acceptable hydroxy C 1 -C 7 alkyl esters and salts of benzoic acid 4-hydroxybenzoic acid, such as methyl and propyl 4-hydroxybenzoate, chlorhexidine digluconate, chlorhexidine and its intranasal such chlorhexidine acetate and chlorhexidine chloride Examples thereof include salts that can be used, 2-phenylethanol, 2-phenoxyethanol, chlorobutanol and sorbic acid.
  • quaternary ammonium salts such as benzalkonium chloride, benzoxoneium chloride, benzododecinium bromide, benzethonium chloride, cetylpyridinium chloride and ce
  • the antioxidant is not particularly limited, and examples thereof include polyphenol, ascorbic acid, t-butylhydroquinone, butylhydroxyanisole, butylhydroxytoluene, L-cysteine hydrochloride, sodium bisulfite, ⁇ -tocopherol and its derivatives. ..
  • the absorption enhancer is not particularly limited, and for example, diisopropyl adipate, lecithin, squalane, squalene, l-menthol, polyethylene glycol, isopropyl myristate, dimethyl sulfoxide, peppermint oil, eucalyptus oil, d-limonene and dl-limonene and the like. Can be mentioned.
  • the moisturizer is not particularly limited, and examples thereof include glycerin, propylene glycol, and 1,3-butylene glycol.
  • the filler is not particularly limited, and examples thereof include kaolin, titanium dioxide, and zinc oxide.
  • the cross-linking agent is not particularly limited, and examples thereof include acetaldehyde, dimethyl ketone, and aluminum sulfate.
  • the refreshing agent is not particularly limited, and examples thereof include l-menthol, dl-camphor, d-borneol, fennel oil, peppermint oil, and peppermint water.
  • the nasal drops containing the medicament of the present invention may contain an acceptable film agent in the nose.
  • an acceptable film agent in the nose.
  • the coating agent is not particularly limited, and is, for example, a water-soluble or swellable cellulose material such as hydroxypropylmethyl cellulose, hydroxypropyl cellulose, methyl cellulose, hydroxyethyl methyl cellulose and sodium carboxymethyl cellulose, polyvinylpyrrolidone (povidone) and crosslinked polyvinyl. Pyrrolidone (crosspovidone) can be mentioned.
  • the medicament of the present invention varies depending on the age, weight, sex, degree (amount, range) of nasal polyps, etc. of the patient, and is not particularly limited, and the applied amount varies depending on the degree of nasal polyps. In the nasal cavity, 5 ⁇ 10-11 to 1 g per day is applied once to several times.
  • the medicament of the present invention can be used for asthma treatment for patients with chronic sinusitis who also have asthma. It can also be administered in combination with drugs.
  • the asthma therapeutic agent include the following agents.
  • Inhaled steroids or nasal spray steroids beclomethasone propionate, fluticasone propionate, budesonide, ciclesonide, mometasone furancarboxylic acid ester, etc.;
  • Combination of inhaled corticosteroids and long-acting ⁇ 2-agonists combination with salmeterol xinafoate, combination with formoterol fumarate hydrate;
  • Theophylline sustained-release preparations Theophylline, Theorong, Slowbid, Unifil, Unicon, Neophyllin, Theophylline, etc .
  • Short-acting theophylline drugs neophyllin, theophylline, monophyllin, astomoridin D / M, astophyllin, albina suppositories, etc.
  • Long-acting ⁇ 2-agonist Inhalant (LABA) / Celevent, patch / Hokunarin tape, Oral drug / Meptin, Spiropent,
  • Mediator release inhibitors Intal, Rezaben, Solfa, Romet, Ketotifen, Allegisal, Pemilaston, Tazanol, Tazarest, etc.; Thromboxane A2 inhibitor: Vega, Domenan, etc .; Thromboxane A2 antagonists: Bronica, Vinas, etc .; Oral steroids: prednisolone, prednisolone, medrol, linderon, redacoat, decadron, corson, dexamethasone, paramaison, etc.; Immunosuppressive drugs: cyclosporine, etc .; Interleukin 4R (IL-4R) inhibitor: dupyrimab, etc .; Iodine preparation: Ioletin, etc.
  • IL-4R Interleukin 4R
  • the drug of the present invention can be administered in combination with a vasoconstrictor.
  • vasoconstrictor include naphazoline hydrochloride, tetrahydrozoline hydrochloride, phenylephrine hydrochloride, epinephrine hydrochloride, dl-methylephedrine hydrochloride, tetrahydrozoline nitrate, naphazoline nitrate, and epinephrine.
  • Example 1 Nasal polyp-reducing action of a heparinoid on nasal polyps in patients with eosinusitis
  • Eosinophilic sinusitis Reduced pressure-dried heparinoids (organic sulfate groups 25.8 to 37.3% w / w, D-glucuronic acid 19.0 to 24.0% w) / W, Maruho Co., Ltd.) was dissolved in physiological saline to prepare heparinoid solutions (0.3, 30 and 3000 ⁇ g / mL).
  • a nasal polyp sample removed from a patient with eosinophil sinusitis was cut into small pieces of about 5 mm square, and the water was wiped off and the weight was measured.
  • Each sample was transferred to a 12-well plate, 1 mL of saline or a heparinoid solution of each concentration was added, and the mixture was incubated at 37 ° C for about 24 hours. The sample was taken out from the plate, the water was wiped off, and the weight was measured. The difference in sample weight before and after incubation was evaluated as an index of nasal polyp reduction effect. The number of cases in the physiological saline group and the heparinoid solution group at each concentration in FIG. 1 was 6.
  • Figure 1 shows the change in sample weight before and after incubation. * And ** in FIG. 1 show significant differences in nasal polyp weight before and after incubation by paired t-test (* P ⁇ 0.05, ** P ⁇ 0.01). Incubation with saline did not show a significant change in nasal polyp weight, whereas incubation with heparinoid solution (0.3, 30 and 3000 ⁇ g / mL) significantly reduced nasal polyp weight. From this, it was suggested that heparinoids have a nasal polyp reducing effect.
  • Example 2 Nasal polyp-reducing effect of heparinoid on nasal polyps of patients with eosinophil sinusitis 0.003, 0.03, 0.3 and 30 ⁇ g / mL heparinoid-reducing effect of heparinoid solution by the same method as in Example 1. was evaluated. The number of cases in the physiological saline group and the heparinoid solution group at each concentration in FIG. 2 was 6.
  • Figure 2 shows the change in sample weight before and after incubation. ** in FIG. 2 indicates a significant difference in nasal polyp weight before and after incubation by paired t-test (** P ⁇ 0.01). Incubation with saline did not show a significant change in nasal polyp weight, whereas incubation with heparinoid solutions (0.003, 0.03, 0.3 and 30 ⁇ g / mL) significantly reduced nasal polyp weight. This suggests that heparinoids have a nasal polyp-reducing effect.
  • Example 3 Nasal polyp reducing action of pentosan polysulfate (PPS) on nasal polyps of patients with eosinophil sinusitis
  • PPS pentosan polysulfate
  • a PPS solution (0.003 ⁇ g / mL) was prepared by the same method as in Example 1 to reduce nasal polyps.
  • PPS sodium pentosan polysulfate manufactured by Molclone Labs (weight average molecular weight 4000 to 6500, sulfur content 13.0 to 20.0% w / w, glucuronic acid content 2.5 to 4.0% w / w) was used. used.
  • the number of cases in the physiological saline group and the PPS solution group in FIG. 3 was 6.
  • Figure 3 shows the change in sample weight before and after incubation. Incubation with saline showed almost no decrease in nasal polyp weight, whereas incubation with PPS solution (0.003 ⁇ g / mL) significantly reduced nasal polyp weight, indicating that PPS is eosinophil. It was suggested that it has a nasal polyp reducing effect in patients with sinusitis.
  • Example 4 Nasal polyp reduction effect of each polysaccharide on nasal polyps of patients with eosinophil sinusitis
  • the following 11 types of polysaccharide solutions 300 ⁇ g / mL and gluco, respectively, except for glucomannan.
  • 30 ⁇ g / mL of mannan was prepared and the nasal polyp reducing effect was evaluated.
  • the number of examples of the physiological saline group and each polysaccharide solution group in Tables 1 to 4 was set to 1 example.
  • Chondroitin was synthesized by desulfurizing sodium chondroitin sulfate (manufactured by Bioiberica) by the same method as in Japanese Patent Application Laid-Open No. 07-062001. Low-molecular-weight chondroitin sulfate was synthesized by hydrolyzing sodium chondroitin sulfate (manufactured by Bioiberica) under acidic conditions. For other polysaccharides, the commercially available products described were used.
  • Tables 1 to 4 show changes in sample weight before and after incubation. Incubation with physiological saline showed almost no reduction in nasal polyp weight, whereas incubation with 11 types of polysaccharide solutions (300 ⁇ g / mL for each other than glucomannan and 30 ⁇ g / mL for glucomannan) resulted in nasal polyps. The significant weight loss suggests that the 11 polysaccharides have a nasal polyp-reducing effect in patients with eosinophilia sinusitis.
  • Example 5 Nasal polyp reducing effect of heparinoid and PPS on nasal polyps of patients with non-eosinophil sinusitis
  • Heparinoid solution and PPS solution (0.03, 0.3, 30 and 300 ⁇ g, respectively) by the same method as in Example 1. / mL) was prepared and the effect of reducing nasal polyps on nasal polyp samples removed from patients with non-eosinophil sinusitis was evaluated.
  • the heparinoids and PPS used were the same as those used in Examples 1 and 3.
  • the number of examples in the physiological saline group, heparinoid solution, and PPS solution group in Table 5 was one.
  • Table 5 shows the change in sample weight before and after incubation. Incubation with saline did not reduce nasal polyp weight, whereas incubation with heparinoid solution and PPS solution (0.03, 0.3, 30 and 300 ⁇ g / mL, respectively) significantly reduced nasal polyp weight. Therefore, it was suggested that heparinoids and PPS also have a reducing effect on nasal polyps in patients with non-eosinophil sinusitis.

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SHINOBU SAKAI, HIROSHI AKIYAMA, YUJI SATO, YASUO YOSHIOKA, ROBERT J LINHARDT, YUKIHIRO GODA, TAMIO MAITANI, TOSHIHIKO TOIDA: "Chondroitin Sulfate Intake Inhibits the IgE-mediated Allergic Response by Down-regulating Th2 Responses in Mice", J BIOL CHEM., vol. 281, no. 29, 21 July 2006 (2006-07-21), pages 19872 - 19880, XP055807386 *
TETSUJI TAKABAYASHI , ATSUSHI KATO, ANJU T PETERS, KATHRYN E HULSE, LYDIA A SUH, RODERICK CARTER, JAMES NORTON, LESLIE C GRAMMER, : "Excessive Fibrin Deposition in Nasal Polyps Caused by Fibrinolytic Impairment through Reduction of Tissue Plasminogen Activator Expression", AM J RESPIR GRIT CARE MED., vol. 187, no. 1, 2013, pages 49 - 57, XP055807393 *

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CN114650828A (zh) 2022-06-21
CA3154360C (en) 2024-01-23
AU2020349263B2 (en) 2023-08-17
CA3154360A1 (en) 2021-03-25
BR112022003464A2 (pt) 2022-05-24
CN118976045A (zh) 2024-11-19
CN118416094A (zh) 2024-08-02
JPWO2021054440A1 (https=) 2021-03-25
US20220347093A1 (en) 2022-11-03
MY206715A (en) 2025-01-03
EP4032535A4 (en) 2023-10-25
JP7313019B2 (ja) 2023-07-24
AU2020349263A1 (en) 2022-04-14
PH12022550661A1 (en) 2023-03-27
CN114650828B (zh) 2024-08-06

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