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WO2000069917A1 - Compositions medicinales destinees a inhiber le systeme kallikreine-kinine ou la phospholipase a¿2? - Google Patents

Compositions medicinales destinees a inhiber le systeme kallikreine-kinine ou la phospholipase a¿2? Download PDF

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Publication number
WO2000069917A1
WO2000069917A1 PCT/JP1999/002592 JP9902592W WO0069917A1 WO 2000069917 A1 WO2000069917 A1 WO 2000069917A1 JP 9902592 W JP9902592 W JP 9902592W WO 0069917 A1 WO0069917 A1 WO 0069917A1
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WO
WIPO (PCT)
Prior art keywords
polysulfated
pharmaceutical composition
phospholipase
composition according
mucopolysaccharide
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP1999/002592
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English (en)
Japanese (ja)
Inventor
Junji Umemoto
Hiroyuki Shiraishi
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Maruho Co Ltd
Original Assignee
Maruho Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Maruho Co Ltd filed Critical Maruho Co Ltd
Priority to PCT/JP1999/002592 priority Critical patent/WO2000069917A1/fr
Publication of WO2000069917A1 publication Critical patent/WO2000069917A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
    • C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan

Definitions

  • the present invention relates to a pharmaceutical composition for inhibiting a kallikrein-kinin system (hereinafter referred to as “k-k system”) or phospholipase A 2 , and more particularly, to a pharmaceutical composition for inhibiting plasma-potential lycrein activity or phospholipase A 2 activity. containing screened acid mucopolysaccharides by the effect as an active ingredient k- about k-based or phospholipase eight 2 inhibitor pharmaceutical composition.
  • k-k system kallikrein-kinin system
  • phospholipase A 2 phospholipase A 2
  • kininogens are degraded by plasma kallikrein, a type of serine protease, to produce the bioactive peptide bradykinin.
  • the kallikrein-kinin system (k-k system) It is called. Bradykinin osteoarthritis generated by the k one k system, rheumatoid arthritis, in many inflammatory diseases including psoriatic arthritis, etc., ⁇ pain, increased blood flow, plasma leakage, prostaglandin E 2 production, histamine Yu (Rahman M. N. et al., Ann. Rheu. Dis, 54, 345-350, 1995), (Takagi A. et al., Eds., Chemical transmission of inflammation, Medical Co., Ltd.) Research Center, 85-104, 1983).
  • bradykinin is greatly involved in rhinitis due to infectious diseases caused by influenza virus and rhinitis virus (Yogi Shibayama et al., Immunopharmacology, 33, 311-313, 1996), viruses, bacteria, etc.
  • the relationship between enteritis caused by infectious disease and the kk system has also been reported (Standnicki A et al., Digestive Diseases and Science, 912-920, 1996).
  • kk system is inhibited, many inflammatory diseases including osteoarthritis, rheumatoid arthritis, psoriatic arthritis, etc. and various allergic reactions such as allergic rhinitis and allergic asthma can be observed. Can be suppressed. In addition, various symptoms such as rhinitis and enteritis caused by viral infection and bacterial infection can be suppressed.
  • phospholipase eight 2 are enzymes that hydrolyze Ashiru group glycerin port phosphorus 2-position of the lipid is a major component of biological membranes, are present widely in every cell. Phospholipase eight 2, there are roughly divided into secreted and intracellular standing type, this secreted form of the enzyme, there is a further secreted type I and two secreted Type II.
  • This secreted type I enzyme is abundant in organs, especially in the kidney, and is thought to be closely involved in the metabolism of phospholipids mainly in food.
  • secreted type II enzymes are ubiquitous in the inflammatory site and in body fluids in various inflammatory diseases, and release arachidonic acid, a precursor of eicosanoides such as prostaglandins, from cell membranes and mast cells. Is known as an inflammatory enzyme that causes histamine secretion by degranulation
  • This secreted type II enzyme has a high affinity for acid mucopolysaccharides, such as heparin.
  • acid mucopolysaccharides such as heparin.
  • arachidonic acid binds to heparan sulfate, a heparin-like acidic mucopolysaccharide present on the cell surface. free are known to promote (Murakami Makotora, modern medicine, 25, p923 ⁇ 955, 1993 and Efuji Ichiro, inflammation, 14, p455 ⁇ 465,1994) 0
  • secreted type II enzymes are known to be activated by Parinyako chondroitin sulfate to the concentration of up to 1 0 _ 4 M (Peter Sartipy et al, J. Biol Chem 271, p26307 - 26314, 1996).
  • the acidic mucopolysaccharides and their physiologically acceptable kallikrein one kinin system comprising as an active ingredient at least one selected from a salt or Ranaru group or phospholipase eight 2 for inhibiting A pharmaceutical composition.
  • FIG. 1 is a graph showing the phospholipase A 2 residual activity depending on the concentration of the acidic mucopolysaccharide of the present invention.
  • FIG. 2 is a graph showing the rise in intranasal pressure of guinea pigs sensitized with the acidic mucopolysaccharide of the present invention induced by antigen.
  • FIG. 3 is a graph showing AUC (area under the response curve) 0 to 25 calculated from the graph of FIG. BEST MODE FOR CARRYING OUT THE INVENTION
  • the acidic mucopolysaccharide of the present invention is a high-molecular polysaccharide having a repeating saccharide unit composed of hexosamine and hexuronic acid or galactose. Includes both polysulfated mucopolysaccharides synthesized by introducing groups.
  • hexosamine widely refers to a compound in which a hydroxy group of hexose is substituted with an amino group, and specific examples include D-glucosamine and D-galactosamine.
  • hexuronic acid means that a primary alcohol of aldohexose is oxidized to a carboxyl group, and specifically, D-glucuronic acid, D-galacturonic acid, L-iduronic acid, etc. No.
  • natural acidic mucopolysaccharides include hyaluronic acid (having a repeating saccharide unit composed of N-acetylglucosamine and glucuronic acid), chondroitin tetrasulfate and hexasulfate, chondroitin, dermatan sulfate (N-acetyl) It has a repeating sugar unit composed of galactosamine and iduronic acid) Keratan sulfate and the like.
  • hyaluronic acid having a repeating saccharide unit composed of N-acetylglucosamine and glucuronic acid
  • chondroitin tetrasulfate and hexasulfate chondroitin, dermatan sulfate (N-acetyl) It has a repeating sugar unit composed of galactosamine and iduronic acid) Keratan sulfate and the like.
  • polysulfated mucopolysaccharides obtained by chemically sulfating naturally occurring acidic mucopolysaccharides include polysulfated hyaluronic acid, polysulfated dermatan sulfate, and polysulfated chondroitin sulfate.
  • the number of sulfate groups in the polysulfated mucopolysaccharide is not particularly limited.
  • the number of sulfate groups is more than 1 per repeating sugar unit, and preferably 1.3 to 4 Preferably, 2 to 4 are more preferable.
  • the molecular weight of the acidic mucopolysaccharide or a salt thereof in the present invention varies depending on the type of polysaccharide, and for example, a number average molecular weight of about several thousands to several hundred thousand.
  • Polysulfation of a naturally occurring acidic mucopolysaccharide can be carried out by a known method, for example, a method of dissolving a naturally occurring acidic mucopolysaccharide and a sulfating agent in a suitable solvent, and reacting by heating. .
  • the sulfating agent is not particularly limited as long as it can achieve the purpose of polysulfation.
  • a complex of sulfuric anhydride and an organic base such as pyridine or trimethylamine is used. Can be.
  • the ratio of the naturally occurring acidic mucopolysaccharide to the sulfating agent can be appropriately selected according to the sulfation rate (or sulfur content) of the target polysulfated mucopolysaccharide and the reaction conditions. For example, about 1: 2 to 10 (weight ratio) of acidic mucopolysaccharide: sulfating agent.
  • the solvent examples include an organic solvent that does not adversely affect the reaction, for example, a pro-philic solvent such as dimethylformamide.
  • a pro-philic solvent such as dimethylformamide.
  • pyridine, trieramine and the like can also be used as the solvent.
  • reaction temperature and reaction time are not particularly limited as long as a desired sulfation ratio can be achieved.For example, at about 40 to 90 ° C., 10 minutes
  • ⁇ 20 days preferably about 30 minutes to 7 days.
  • the reaction product can be purified by a purification operation commonly used for various modified polysaccharides.
  • Specific purification operations include steps such as neutralization, desalting by dialysis, recovery by precipitation with addition of an organic solvent, and recovery by freeze-drying.
  • the chemically synthesized polysulfated mucopolysaccharide thus obtained generally has a sulfation rate of several 10 to 100% per total hydroxyl groups of naturally occurring acidic mucopolysaccharide. It is.
  • the polysulfated mucopolysaccharide of the present invention uses, if necessary, a hydroxide or carbonate of an alkali metal such as sodium or potassium, or an amine. It can also be used as a physiologically acceptable salt form obtained by a salt formation reaction.
  • compositions containing the above-mentioned acidic mucopolysaccharide of the present invention as an active ingredient for inhibiting the k-k system or phospholipase 2 include osteoarthritis, rheumatoid arthritis, shoulder periarthritis, psoriasis Remedies for inflammatory diseases caused by viral or bacterial infections such as arthritis such as osteoarthritis, acute enteritis, chronic enteritis and rhinitis, allergic diseases such as allergic rhinitis, allergic asthma, allergic conjunctivitis and atopic dermatitis And can be used as a prophylactic agent.
  • Naturally occurring acidic mucopolysaccharides, chemically synthesized polysulfated mucopolysaccharides or physiologically acceptable salts thereof are excipients, extenders, binders used in the production of ordinary pharmaceutical preparations.
  • One or more additives such as wetting agents, disintegrants, surfactants, lubricants, dispersants, buffers, preservatives, dissolution aids, preservatives, flavoring / flavoring agents, stabilizers, etc.
  • preparations such as nasal drops and eye drops are preferable.
  • the pharmaceutical preparation of the present invention can be administered topically, mucosally, dermally, intravenously, intraarterially, orally, or pulmonary in the above-mentioned formulation form.
  • the content of acidic mucopolysaccharide in the preparation varies depending on the dosage form and administration route, but is generally about 0.001 to 50 (weight Z weight)%, 0.05 to 1 (weight / weight). %) Is more preferable.
  • the dosage as an active ingredient can be appropriately adjusted depending on the age, sex, type and degree of disease, and dosage form and administration form of a patient.
  • the acidic mucopolysaccharide may be instilled several times a day so that the daily dose of the active ingredient is about 0.01 to 10 mg.
  • an ointment containing about 0.1 to 10% of acidic mucopolysaccharide the daily dose as an active ingredient is about 1 to 100 mg. And several times a day. Even when an ointment containing about 0.1 to 10% of acidic mucopolysaccharide is applied to the skin, no side effects such as inflammation are observed.
  • the sulfation rate can be determined by dividing the number of sulfate groups in hexosamine calculated by measuring the amount of hexosamine and the sulfate group content in the polysulfated mucopolysaccharide, by 4.
  • the molecular weight of the obtained polysulfated hyaluronic acid was about 900 dalton.
  • the molecular weight of the polysulfated mucopolysaccharide was determined by assaying the gel filtration column with a commercially available polysaccharide molecular weight sample (dextran sulfate: manufactured by Sigma) and measuring the molecular weight of the polysulfated mucopolysaccharide using the column.
  • the intrinsic viscosity was measured to obtain a regression equation between the molecular weight of gel filtration and the intrinsic viscosity, and then the intrinsic viscosity of the obtained polysulfated hyaluronic acid was measured and calculated from the above regression equation.
  • the molecular weight of the obtained polysulfated hyaluronic acid was about 12,000 daltons.
  • Production Example 1 for various acidic mucopolysaccharides was performed by changing the temperature in an oil bath or If the reaction time is changed, polysulfated mucopolysaccharides having different sulfation rates can be obtained.
  • the kk system inhibitory effect of the acidic mucopolysaccharide in the present invention was evaluated based on the effect on plasma recruitment activity.
  • N-Benzoyl-Pro-Phe-Arg-P-Nitroanilide as a substrate, human plasma kallikrein was added to this substrate, and the amount of P-Nitroanilide produced was measured by absorbance at a wavelength of 405 nm.
  • the acidic mucopolysaccharides (hyaluronic acid used as the starting material in Preparation Example 1, dermatan sulfate used as the raw material in Production Example 3, chondroitin 4 sulfate was used as the starting material in Preparation Example 5) it it 10- 8
  • the effect on plasma kallikrein activity was examined from the absorbance without addition and the ratio of the absorbance when each test substance was added, and the kk-system inhibitory effect was evaluated.
  • Aprotinin a known plasma kallikrein inhibitor, was used as a control and tested in the same manner as in Examples 1-3.
  • the k-k system inhibitory effect of the polysulfated mucopolysaccharide in the present invention was evaluated based on the effect on the plasma recruitment activity.
  • a test was performed in the same manner as in Examples 4 to 6, except that a mesylate power moststat known as a plasma power reclein inhibitor was used as a control.
  • Table 2 shows the results of Examples 4 to 6 and Comparative Example 2.
  • Each of the polysulfated mucopolysaccharides of Examples 4 to 6 inhibits plasma recruitment activity, and the inhibition is significantly stronger than that of the mesylate power state known as a k-k system inhibitor. The system was inhibited. Evaluation test of phospholipase A 7 inhibitory effect of polysulfated mucopolysaccharides
  • Phospholipase A 2 inhibitory action is a secreted type II enzyme (E. Diseases, 14, 455-465, was evaluated by the effect of polysulfated hyaluronic port phosphate and polysulfated dermatan Yun sulfate for phospholipase A 2 activity from bi venom to 1994) of Hibikio snake family.
  • a 6-week-old male Hartley guinea pig was commercially available from the group treated with polysulfated hyaluronic acid obtained in Production Example 1 (3 groups of 7 animals), a control group administered with purified water for injection (1 group), and a commercially available group. It was classified into the fluticasone propionate administration group (1 group) used as the active ingredient in nasal drops.
  • Sensitization was performed by the method of Yajnasaki et al. (Yamasaki et al, J. Pharmacol. Exp. 280, 1471-1479, 1997), and intranasal pressure was measured according to the method of Mizuno et al. (Mizuno et al, Japan J. Pharmacol., 55, 321-328, 1991).
  • guinea pigs belonging to each administration group were given aerosolized 1% ovalbumin (OVA, Sigma Chemical Co., Ltd.) twice a week, using an ultrasonic nebulizer (NE-U12, OMRON Corporation) twice a week. ) Was inhaled for 10 minutes to give active sensitization.
  • OVA ovalbumin
  • NE-U12 ultrasonic nebulizer
  • guinea pigs were fixed in a dorsal position under urethane (1.6 g / k :, i.p.) anesthesia.
  • the trachea was incised to maintain respiration, a tracheal force neuron was inserted into the lung side, and the esophagus was ligated.
  • the hole in the oral cavity, located in the center of the upper jaw, was glued to the hole leading into the nasal cavity with aron alpha A, and was further filled with absorbent cotton soaked with glycerin in the oral cavity to block communication between the oral cavity and the nasal cavity.
  • a forcenula was inserted into the nasal cavity from the tracheotomy.
  • the nasal cavity was connected to an artificial respirator, and air was supplied into both nasal cavities at an insufflation rate of 4 mlZ and an insufflation frequency of 70 times / min.
  • Polysulfated hyaluronic acid solution (0.1 mgZml, 2 ⁇ gx2 holes: lmg / ml 20 gx 2 holes: 1 OmgZml 200 gx 2 holes), purified water for injection (20 / gx2 holes), and fluticasone probionate aqueous solution (0.
  • A was aerosolized and inhaled into the nasal cavity for 5 minutes to elicit an antigen-antibody reaction.
  • Intranasal pressure was measured as a change in insufflation pressure by a differential pressure transducer connected to the collateral bypass of the nasal cavity force neuron.
  • FIG. 2 shows the change in intranasal pressure up to 25 minutes after the start of the induction.
  • FIG. 3 shows the AUC up to 25 minutes after the start of the induction in FIG.
  • the group administered with polysulfated hyaluronic acid showed almost no inhibitory effect on the increase in intranasal pressure.
  • the increase in intranasal pressure and AUC (mean 1153% ⁇ min) 3 to 5 minutes after the start of challenge were significantly suppressed.
  • the increase in intranasal pressure and the increase in AUC (mean 1 050% ⁇ min) at 5, 7, 10 and 15 minutes were significantly suppressed.

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  • Health & Medical Sciences (AREA)
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Abstract

L'invention concerne des compositions médicinales destinées à inhiber le système kallikréine-kinine ou la phospholipase A2 contenant en tant que principe actif au moins un élément choisi dans le groupe comprenant des mucopolysaccharides acides et leurs sels acceptables sur le plan physiologique. Ces compositions médicinales sont très puissantes et présentent peu d'effets secondaires.
PCT/JP1999/002592 1999-05-18 1999-05-18 Compositions medicinales destinees a inhiber le systeme kallikreine-kinine ou la phospholipase a¿2? Ceased WO2000069917A1 (fr)

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PCT/JP1999/002592 WO2000069917A1 (fr) 1999-05-18 1999-05-18 Compositions medicinales destinees a inhiber le systeme kallikreine-kinine ou la phospholipase a¿2?

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PCT/JP1999/002592 WO2000069917A1 (fr) 1999-05-18 1999-05-18 Compositions medicinales destinees a inhiber le systeme kallikreine-kinine ou la phospholipase a¿2?

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002032407A3 (fr) * 2000-10-19 2003-11-20 Knoell Hans Forschung Ev Utilisation de derives d'acide hyaluronique pour inhiber les arthrites inflammatoires
KR20110117118A (ko) * 2009-02-02 2011-10-26 오츠카 세이야쿠 가부시키가이샤 저분자량 다황산화 히알루론산 유도체 및 이를 함유하는 의약
CN101511868B (zh) * 2006-07-24 2013-03-06 比奥雷克西斯制药公司 毒蜥外泌肽融合蛋白
EP3417855A1 (fr) * 2009-05-14 2018-12-26 Fidia Farmaceutici S.p.A. Compositions pharmaceutiques pour usage topique à base d'acide hyaluronique sulfaté comme promoteur de l'absorption cutanee
CN114650828A (zh) * 2019-09-20 2022-06-21 国立大学法人福井大学 药物组合物

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH08277224A (ja) * 1995-02-07 1996-10-22 Shiseido Co Ltd 抗炎症剤
JPH08301772A (ja) * 1995-05-01 1996-11-19 Nippon Oil Co Ltd 硫酸多糖類のカルシウム塩を含んで成る抗ウイルス剤
JPH10195107A (ja) * 1997-01-10 1998-07-28 Shiseido Co Ltd オリゴ硫酸化ヒアルロン酸

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH08277224A (ja) * 1995-02-07 1996-10-22 Shiseido Co Ltd 抗炎症剤
JPH08301772A (ja) * 1995-05-01 1996-11-19 Nippon Oil Co Ltd 硫酸多糖類のカルシウム塩を含んで成る抗ウイルス剤
JPH10195107A (ja) * 1997-01-10 1998-07-28 Shiseido Co Ltd オリゴ硫酸化ヒアルロン酸

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002032407A3 (fr) * 2000-10-19 2003-11-20 Knoell Hans Forschung Ev Utilisation de derives d'acide hyaluronique pour inhiber les arthrites inflammatoires
CN101511868B (zh) * 2006-07-24 2013-03-06 比奥雷克西斯制药公司 毒蜥外泌肽融合蛋白
KR20110117118A (ko) * 2009-02-02 2011-10-26 오츠카 세이야쿠 가부시키가이샤 저분자량 다황산화 히알루론산 유도체 및 이를 함유하는 의약
EP2392579A4 (fr) * 2009-02-02 2012-09-26 Otsuka Chemical Co Ltd Dérivé d'acide hyaluronique polysulfaté de faible masse moléculaire et médicament le contenant
US8993536B2 (en) 2009-02-02 2015-03-31 Otsuka Chemical Co., Ltd. Low-molecular polysulfated hyaluronic acid derivative and medicine containing same
KR101678429B1 (ko) 2009-02-02 2016-11-22 오츠카 세이야쿠 가부시키가이샤 저분자량 다황산화 히알루론산 유도체 및 이를 함유하는 의약
EP3417855A1 (fr) * 2009-05-14 2018-12-26 Fidia Farmaceutici S.p.A. Compositions pharmaceutiques pour usage topique à base d'acide hyaluronique sulfaté comme promoteur de l'absorption cutanee
CN114650828A (zh) * 2019-09-20 2022-06-21 国立大学法人福井大学 药物组合物

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