WO2022114111A1 - Composition pharmaceutique ou cosmétique - Google Patents

Composition pharmaceutique ou cosmétique Download PDF

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Publication number
WO2022114111A1
WO2022114111A1 PCT/JP2021/043348 JP2021043348W WO2022114111A1 WO 2022114111 A1 WO2022114111 A1 WO 2022114111A1 JP 2021043348 W JP2021043348 W JP 2021043348W WO 2022114111 A1 WO2022114111 A1 WO 2022114111A1
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vascular
composition
examples
sodium
acid
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PCT/JP2021/043348
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English (en)
Japanese (ja)
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勇輝 上田
直樹 山中
栞 藤原
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マルホ株式会社
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Priority to JP2022565438A priority Critical patent/JPWO2022114111A1/ja
Publication of WO2022114111A1 publication Critical patent/WO2022114111A1/fr

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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
    • A61K31/715—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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/73—Polysaccharides
    • 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
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/08—Anti-ageing preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q7/00—Preparations for affecting hair growth

Definitions

  • the present invention relates to a composition having a blood vessel maturation action and / or a blood vessel stabilizing action, for example, a pharmaceutical composition and a cosmetic composition.
  • Blood vessels are stretched throughout the body, and by circulating blood, they are responsible for supplying oxygen and nutrients to various organs, tissues, and cells and discharging waste products, and play an important role in maintaining homeostasis of tissues.
  • Blood vessels are composed of a two-layer structure having a layer consisting of vascular endothelial cells and a layer consisting of vascular wall cells (vascular smooth muscle cells and pericite) adhering to the outside thereof, and have angiogenesis, angiogenesis, and vascular maturation. It is formed through the process of and has a stable structure.
  • PDGF-BB which is one isoform of platelet-derived growth factor (hereinafter referred to as "PDGF") secreted from vascular endothelial cells
  • PDGF platelet-derived growth factor
  • Ang-1 angiopoietin-1 secreted from vascular wall cells (perisite) activates the Tie2 receptor expressed in vascular endothelial cells, and the wall cells and endothelial cells Induces adhesion and stabilizes vascular structure.
  • angiopoietin-2 (hereinafter referred to as "Ang-2”) is mainly secreted from vascular endothelial cells and acts antagonistically on the Ang-1 / Tie2 signal. That is, it is suggested that Ang-2 destabilizes the vascular structure and is involved in the induction of angiogenesis by blocking the vascular stabilizing signal of Ang-1 / Tie2.
  • the decrease in PDGF-BB / PDGFR- ⁇ signal and Ang-1 / Tie2 signal in the process of vascular maturation induces increased vascular permeability and leakage of plasma components, resulting in structural instability. It is known that immature blood vessels are formed in. Such structurally unstable blood vessels are found in diseases associated with various vascular lesions.
  • PDGF-BB / PDGFR- ⁇ signal and Ang-1 / Tie-2 signal decrease with aging, suggesting a relationship between vascular destabilization and aging. .. It has also been clarified that the Ang-1 / Tie-2 signal contributes not only to the maturation and stabilization of blood vessels but also to the stabilization of lymphatic vessels and promotes lymphatic flow.
  • the present invention can activate Ang-1 / Tie2 signals, increase PDGF-BB production, and the like by acting on vascular wall cells, vascular endothelial cells, and / or lymphatic endothelial cells.
  • the subject is to provide the composition.
  • pentosan polysulfuric acid and a salt thereof have an excellent activating action of Ang-1 / Tie2 signal and production of PDGF-BB.
  • the present invention has been completed by finding that it has an increasing action and the like.
  • the present invention relates to a composition comprising pentosan polysulfuric acid and / or a salt thereof, as shown below.
  • (3) The composition according to (1) or (2) above, wherein the pentosan polysulfuric acid and / or a salt thereof has a weight average molecular weight of 1,000 to 30,000.
  • composition which is a Tie2 activator, a PDGF-BB production promoter, a blood vessel normalizing agent, a blood vessel stabilizing agent, and / or a lymphatic vessel stabilizing agent.
  • Composition is a pharmaceutical composition, and the diseases associated with the vascular lesions are peripheral arterial diseases including atherosclerosis and submucosal hemorrhage, vascular edema, lymphovascular myoma, psoriasis vulgaris and Schnitzler.
  • Inflammatory diseases including syndrome, vulgaris vulgaris, nodular sclerosis, systemic scleroderma, Kaposi sarcoma, cutaneous angiosarcoma, wrinkles, swelling, retinopathy, luteal edema, skin ulcers, wounds, nephropathy, peripheral nerves At least one disease selected from the group consisting of disorders, diabetes, photoaging, premature infants and diabetic retinopathy, tumors, acute myeloid leukemia, hepatitis, and edema, the above (1)-(3).
  • the composition according to any one of.
  • composition is a cosmetic composition
  • improvement of the skin condition is an improvement of at least one condition selected from the group consisting of wrinkles, blemishes, swelling, and alopecia.
  • the composition according to any one of (3).
  • the composition of the present invention has an excellent Tie2 activating effect, PDGF-BB production increasing effect, and the like. Since such a composition has a vascular maturation action, a vascular stabilizing action, and / or a lymphatic vessel stabilizing action, various diseases caused by deterioration of vascular function and / or lymphatic vessel function and the like. It is useful for the prevention and / or treatment of. Further, since the active ingredient pentosan polysulfate and / or a salt thereof has high safety, it is possible to provide a pharmaceutical composition or the like having few side effects.
  • compositions of the present invention include pharmaceutical compositions and cosmetic compositions, the details of which will be described later.
  • Pharmaceutical compositions include, for example, ethical drugs, drugs requiring guidance, over-the-counter drugs, or quasi-drugs specified in the "Act on Securing Quality, Effectiveness, and Safety of Pharmaceuticals, Medical Devices, etc.” Applicable compositions and the like can be mentioned.
  • the cosmetic composition includes, for example, cosmetics stipulated in the "Act on Securing Quality, Effectiveness, and Safety of Pharmaceuticals, Medical Devices, etc.” or quasi-drugs, which are medicinal cosmetics. Can be mentioned.
  • the pharmaceutical composition of the present invention prevents deterioration of vascular function and / or lymphatic function, and is useful for prevention and treatment of various diseases, particularly diseases related to blood vessels and / or lymphatic vessels.
  • Pentosan polysulfate or a salt thereof is contained as an active ingredient.
  • Pentosan polysulfate is a semi-synthetic polysulfated polysaccharide containing a mixture of polyvalent anionic polysaccharides.
  • Pentosan polysulfate is produced by the chemical sulfation of polysaccharides (eg, xylan) obtained from wood, such as beech.
  • Pentosan polysulfate is generally considered to be a polysulfated product of a xylan chain bound to O-methylglucuronic acid as a side chain.
  • the weight average molecular weight of pentosan polysulfuric acid or a salt thereof used in the present invention is not particularly limited, but is preferably 1,000 to 30,000, more preferably 2,000 to 10,000, and 4 It is more preferably 000 to 6,500.
  • Pentsanpolysulfuric acid and / or its salts can be made from plant-derived ingredients, so even in countries and regions that avoid the use of substances made from animal-derived ingredients for religious reasons, and to such patients. Can also be used.
  • Pentosan polysulfuric acid and its salts allow activation of Tie2 and promotion of PDGF-BB production, preventing vascular and / or lymphatic dysfunction, vascular maturation, and / or, as described in detail below. Contributes to blood vessel stabilization. Therefore, the composition containing pentosan polysulfate and / or a salt of pentosan polysulfate (sodium pentosan polysulfate, etc.) is a Tie2 activator, PDGF-BB production promoter, blood vessel normalizing agent, vascular stabilizing agent. And / or can also be used as a lymphatic vessel stabilizer and the like.
  • the pharmaceutical composition of the present invention is not particularly limited to a dosage form, and examples thereof include oral preparations, injections, eye drops, nasal drops, and external skin preparations, which are pharmaceutically acceptable additives.
  • External skin preparations include external solids; external liquids such as liniments and lotions; sprays such as external aerosols and pump sprays; ointments; creams; gels; and plasters (plasters) and patches. , Tapes and patches such as poultices.
  • examples of the additive used in the ointment include a base, a moisturizer, a thickener, an emulsifier and the like.
  • Higher hydrocarbons, fats and oils, waxes, fatty acids, higher alcohols, esters and the like can be used as the base.
  • examples of higher hydrocarbons include squalane, synthetic paraffin, liquid paraffin, white vaseline, microcrystalin wax and the like
  • examples of waxes include honeybee, sarashimitsuro, lanolin, selecin wax and the like
  • examples of fatty acids include stearic acid.
  • examples thereof include acids and oleic acids
  • examples of higher alcohols include lanolin alcohol and cetostearyl alcohol
  • examples of esters include isopropyl myristate and stearyl myristate.
  • Examples of the moisturizing agent include glycerin, 1,3-butylene glycol and the like
  • examples of the thickener include carboxyvinyl polymer and carboxymethyl cellulose
  • examples of the emulsifier include a cationic surfactant and an anionic surfactant.
  • examples include active agents, amphoteric surfactants, nonionic surfactants and the like.
  • Examples of the additive used for the patch include thickeners, moisturizers, fillers, cross-linking agents, solubilizers, emulsifiers and the like.
  • examples of the thickener include sodium alginate, gelatin, methylcellulose, carboxyvinyl polymer, sodium polyacrylate and the like
  • examples of the moisturizing agent include glycerin and the like
  • examples of the filler include kaolin and titanium dioxide.
  • examples of the cross-linking agent include acetaldehyde, dimethylketone, aluminum sulfate and the like
  • examples of the solubilizer include alcohols such as ethanol and isopropanol
  • examples of the emulsifier include anionic surfactants.
  • Additives used for plasters or patches include, for example, supports such as non-woven fabrics, elastic materials such as natural rubber or isoprene rubber, fillers such as zinc flower and titanium oxide, and adhesion of terpene resin and the like.
  • An excipient, a stripping agent such as vinyl acetate, a softening agent such as liquid paraffin, a preservative such as dibutylhydroxytoluene (BHT), and the like can be appropriately combined and used.
  • the additive used for the poultice include a water-soluble polymer compound such as polyacrylic acid, polyvinyl alcohol or polyvinylpyrrolidone.
  • examples of the acid, oleic acid and the like examples of the higher alcohol include lanolin alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, cetostearyl alcohol, cholesterol and the like, and examples of the esters include isopropyl myristate, stearyl myristate and the like. Can be mentioned.
  • water purified water
  • thickener examples include carboxyvinyl polymer and carboxymethyl cellulose
  • moisturizer examples include glycerin, propylene glycol and 1,3-butylene glycol.
  • emulsifier examples include cationic surfactants, anionic surfactants, amphoteric surfactants, nonionic surfactants and the like.
  • Examples of the fatty acid include stearic acid and oleic acid
  • examples of the higher alcohol include lanolin alcohol, cetyl alcohol, stearyl alcohol and cetostearyl alcohol
  • examples of the esters include isopropyl myristate, stearyl myristate and myristin. Examples thereof include octyldodecyl acid.
  • water water (purified water), alcohols such as ethanol and isopropanol, thickeners, moisturizers and the like can be used.
  • the thickener include carboxyvinyl polymer and carboxymethyl cellulose
  • examples of the moisturizer include glycerin, propylene glycol and 1,3-butylene glycol.
  • the emulsifier include cationic surfactants, anionic surfactants, amphoteric surfactants, nonionic surfactants and the like.
  • examples of the suspension-type lotion additive include rubbers such as Arabica rubber and tragant rubber, celluloses such as methyl cellulose and hydroxyethyl cellulose, and suspending agents such as clays such as bentonite.
  • Examples of the additive used for the liniment agent include vegetable oils such as olive oil, alcohols such as ethanol or isopropanol, or a mixture thereof and water.
  • Examples of the additive to be blended in the gel agent include a base, a viscous agent and the like, and examples of the base include isopropanol and propylene glycol.
  • examples of the viscous agent include carboxyvinyl polymers and carboxymethyl cellulose.
  • Examples of the additive to be blended in the spray agent include a base, a foaming agent and the like.
  • Examples of the base include water, glycerin, 1,3-butylene glycol, dipropylene glycol, propylene glycol, D-sorbitol, polyethylene glycol, 2-ethylhexanediol, isostearyl alcohol, octyldodecanol, hexyldecanol, and oleyl alcohol.
  • foaming agent examples include polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan tristearate, polyoxyethylene polyoxypropylene glycol, glyceryl stearate, polyoxyethylene hydrogenated castor oil, decaglyceryl trioleate, and poly.
  • anionic surfactant include sodium alkylbenzene sulfonate, sodium dodecyl sulfate, sodium coconut alcohol ethoxysulfate, sodium ⁇ -olefin sulfonate, emulsified cetostearyl alcohol and the like.
  • nonionic surfactant examples include polyoxyethylene alkyl ethers such as polyoxyethylene oleyl ether and polyoxyethylene octyldodecyl ether; polyoxyethylene alkylphenol ethers; polyoxyethylene hydrogenated castor oil; polyoxyl stearate; glyceryl monostearate.
  • Diglycerin fatty acid esters such as diglyceryl; sorbitan fatty acid esters such as sorbitan monopalmitate, sorbitan monostearate, sorbitan monooleate, sorbitan coconut oil, sorbitan tristearate, and sorbitan trioleate; polyethylene glycol monolaurate, Examples thereof include polyethylene glycol monostearate and polyethylene glycol fatty acid esters such as polyethylene glycol monooleate.
  • Examples of the amphoteric tenside include N-alkyl-N, N-dimethylammonium betaine, and an imidazoline-type amphoteric tenside. All of the above surfactants can be used alone or in combination.
  • a pH regulator In the dosage form of the above-mentioned external skin preparation, a pH regulator, a preservative, macrogol, etc. are used as necessary.
  • Examples of the pH adjusting agent include diisopropanolamine, triisopropanolamine, triethanolamine, potassium hydroxide, sodium hydroxide, sodium citrate, phosphoric acid, tartrate acid, dl-apple acid, glacial acetic acid and the like, and are stored.
  • Examples of the agent include timol, dibutylhydroxytoluene, sodium edetate hydrate, methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate and the like.
  • the pharmaceutical composition When the pharmaceutical composition is in the form of an oral preparation, various additives are added as necessary to improve the taste, odor and color necessary for improving stability, ease of handling, or compliance.
  • the agent can be selected and used.
  • excipients such as lactose, starch, crystalline cellulose, D-mannitol, glucose and calcium phosphate
  • disintegrants such as starch and croscarmellose sodium
  • D-mannitol, D-sorbitol Sweeteners and excipients such as aspartame and citric acid
  • plasticizers such as polyethylene glycol, (5) polyaminocarboxylic acid-based chelating agents such as EDTA and salts thereof, sodium pyrosulfate, 1-ascorbic acid and the like.
  • Stabilizers (6) preservatives such as paraoxybenzoic acid ester and benzalconium chloride, and / or other additives (colorants, flavoring agents, etc.) can be used.
  • the type and blending amount of these additives can be appropriately set in consideration of characteristics such as stability and taste of the active ingredient. Further, when the pharmaceutical composition is required to have the property of being soluble in water, the additive can be appropriately selected in consideration of the solubility in water. Further, a binder such as hydroxypropyl cellulose or polyvinylpyrrolidone can be added to the pharmaceutical composition, if necessary, as long as the rapid disintegration and solubility of the oral granules are not impaired. In order to ensure rapid disintegration and solubility, a binder having a weak binding force is desirable, and the blending amount of the binder is 5% by weight or less, particularly preferably 2% by weight or less, based on the weight of the composition. Is preferable.
  • a useful dosage form of oral granules is dry syrup.
  • Dry syrup is a syrup agent that is used by dissolving it at the time of use or suspending it at the time of use. And, it is an excellent preparation that is easier to take because it can be adjusted to a preferable color tone by an appropriate coloring agent.
  • a liquid containing water such as juice or milk can be used in addition to water as a solvent.
  • oral granules similar to dry syrup that is, granules, powders, fine granules, etc., which contain a large amount of sucrose and are substantially dissolved or suspended at the time of use, are also suitable as embodiments of the pharmaceutical composition. Is.
  • the additives include pH adjusters, buffers, stabilizers, tonicity agents, local anesthetics, painkillers, diluents, surfactants and the like.
  • pH adjuster and buffer hydrochloric acid, citric acid, sodium citrate, sodium acetate, sodium phosphate, sodium hydroxide and the like are used, and as stabilizers, sodium pyrosulfate, ethylenediamine tetraacetic acid, thioglycolic acid, etc. Thiolactic acid or the like is used.
  • buffering agent sodium citrate, phosphoric acid, sodium phosphate, potassium phosphate, sodium acetate, boric acid and the like are preferably used.
  • procaine hydrochloride, lidocaine hydrochloride and the like can be used, and as the tonicity agent, sodium chloride, D-mannitol, D-sorbitol, glucose, glycerin and the like can be used.
  • the pain-relieving agent procaine hydrochloride or the like can be used.
  • the diluent include water, ethyl alcohol, macrogol, propylene glycol and the like.
  • examples of the additive include a solvent, an isotonic agent, a preservative, a viscous agent, a pH adjuster and the like.
  • examples of the solvent include sterile purified water, physiological saline, buffer solution, vegetable oil, propylene glycol, liquid paraffin and the like.
  • examples of the tonicity agent include sodium chloride, boric acid, sodium nitrate, potassium nitrate and the like.
  • examples of the preservative include paraoxybenzoic acid esters, vesalconium chloride, chlorobutanol, sodium dehydroacetate, polymyxin B sulfate and the like.
  • examples of the viscous agent include methyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol, sodium chondroitin sulfate and the like.
  • examples of the pH adjusting agent include acids and bases, examples of the acid include hydrochloric acid, phosphoric acid, citric acid, acetic acid and the like, and examples of the base include sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogencarbonate and the like. Can be mentioned.
  • examples of the additive include a solubilizer, an isotonic agent, a pH adjuster and the like.
  • a dispersant or a stabilizer may be added as necessary in order to obtain a uniform state of the active ingredient.
  • a preservative or the like may be added as necessary.
  • the pharmaceutical composition of the present invention can be produced by a conventional preparation method.
  • a conventional preparation method For example, for an ointment or cream, the raw material of the base is kneaded, emulsified or suspended according to each dosage form to prepare a base, and then an active ingredient or the like is added and the mixture is placed in a mixer such as a screw mixer. It can be manufactured by mixing.
  • the lotion agent can be produced, for example, by adding various additive components to purified water, mixing and stirring, adding an active ingredient and the like, mixing, and filtering if desired.
  • the liniment agent can be produced, for example, by dissolving the active ingredient in an additive and, if desired, adding other ingredients to the additive and mixing them.
  • the poultice can be produced, for example, by mixing the active ingredient and the additive, heating and then cooling.
  • the plaster (plaster agent), patch agent and the like can be produced by a conventional method such as a solution method or a thermal pressure method.
  • the gel agent includes an aqueous gel agent, an oil-based gel agent and the like.
  • Aqueous gel preparations are produced by adding a polymer compound, other additives and purified water to the active ingredient to dissolve or suspend it, and then heating and cooling it, or by adding a gelling agent and cross-linking. be able to.
  • the oily gel agent can be produced by adding a liquid oily base such as glycols and higher alcohols and other additives to the active ingredient and mixing them.
  • the spray agent can usually be produced by preparing a solution or suspension of the active ingredient, filtering it if necessary, and then filling it in a container.
  • the oral pharmaceutical composition can be produced according to a conventional method for producing oral granules.
  • a general granulation method such as an extrusion granulation method, a stirring granulation method, a rolling granulation method, a fluidized layer granulation method, a crushing granulation method, and a crushing granulation method should be used.
  • a fluidized layer granulation method is particularly preferable because it is easy to obtain granulated products having characteristics such as 1) high void ratio, 2) low bulk density, and 3) good dispersibility in water. Can be used.
  • oral granules such as granules, powders and fine granules using the pharmaceutical composition.
  • These preparations can be taken directly orally, or can be used in a state of being dissolved at the time of use or suspended at the time of use in a solvent containing water.
  • a product that dissolves or suspends before use is a product that is solid in the form at the time of shipment of the product, but dissolves or suspends between the time the drug is opened and the time it is applied, and is usually applied. Dissolved or suspended immediately before.
  • the active ingredient When preparing a pharmaceutical composition as an injection, the active ingredient is dissolved, suspended or emulsified in, for example, water for injection or another aqueous or non-aqueous solvent by a conventional method, and intravenously or intramuscularly. Injections for subcutaneous or intradermal use can be produced. The injection is preferably sterilized and isotonic with blood.
  • Eye drops can be produced by adding the above-mentioned additives to the active ingredient as needed, and then dissolving or suspending them in a solvent.
  • a liquid nasal drop When preparing a liquid nasal drop, add the active ingredient and, if necessary, the above-mentioned additive to the solvent to dissolve or suspend it. Further, if necessary, a liquid nasal drop is produced by a process such as addition of the above-mentioned additive and filtration.
  • the nasal drops in the form of fine powder can be produced by mixing fine particles of the active ingredient with an additive as necessary to make them homogeneous.
  • the content of pentosan polysulfuric acid and / or a salt thereof (sodium pentosan polysulfate, etc.) as an active ingredient in the pharmaceutical composition of the present invention is 0.0001 to 30% by weight based on the total weight of the pharmaceutical composition. It is preferably 0.001 to 10% by weight, more preferably 0.01 to 1% by weight, and particularly preferably 0.01 to 1% by weight.
  • the total content of the above-mentioned additives is, for example, 70% by weight or more, 90% by weight or more, 99% by weight or more, etc., based on the total weight of the pharmaceutical composition.
  • the dose / frequency of the pharmaceutical composition according to the present invention depends on the degree of the target disease and its symptoms, the concentration of pentosanpolysulfuric acid and / or a salt thereof (sodium pentosanpolysulfate, etc.) in the composition, the age and weight of the patient, and the like. It may be adjusted as appropriate. For example, in the case of systemic administration, 50 mg to 5 g, preferably 100 mg to 1 g of pentosan polysulfuric acid may be administered daily, for example, 1 to 3 times a day. For local administration, 0.03 ⁇ g to 30 mg, preferably 0.3 ⁇ g to 3 mg per cm 2 may be applied once or several times a day.
  • Diseases caused by decreased PDGF-BB / PDGFR- ⁇ signal and / or Ang-1 / Tie2 signal include tumors, rheumatoid arthritis, diabetes, hyperlipidemia, hypertension, hepatitis, psoriasis, vascular edema, Diseases associated with vascular lesions such as systemic rheumatism, angiosarcoma, hemangiomas, psoriasis, and rheumatism.
  • a prophylactic and / or a therapeutic agent for a disease associated with a lesion of a blood vessel and / or a lymphatic vessel which comprises the above-mentioned pentosan polysulfuric acid and / or a salt thereof as an active ingredient.
  • the above-mentioned pharmaceutical composition is a preventive agent for age-based diseases. And / or it is also expected to be a therapeutic agent.
  • the pharmaceutical composition containing Pentsanpolysulfate and / or a salt thereof activates the Ang-1 / Tie2 signal and / or increases the production of PDGF-BB, and thus has an anti-angiogenic effect. It exhibits vascular maturation, vascular normalization, vascular stabilizing and / or lymphatic stabilizing, improves vascular and / or lymphatic function, and is associated with vascular and / or lymphatic lesions. It can be used for the treatment or prevention of the following diseases considered to be. That is, cardiovascular disease; skin disease; endocrine, nutritional and metabolic disease; age-based disease; eye disease; other diseases.
  • Cardiovascular diseases include capillary leak syndrome, coronary artery disease, chronic heart failure, peripheral arterial disease (atherosclerosis, microvascular angina, myocardial infarction, stroke, submucosal bleeding), hypertension, vascular edema, Examples thereof include ischemic diseases caused by side effects of surgery or organ tissue damage, lymphatic vessel myoma, disorders caused by leakage of lymph from lymph vessels, Reynaud's disease and the like.
  • the pharmaceutical composition is considered to be particularly effective for the treatment and prevention of peripheral arterial diseases including atherosclerosis and subarachnoid hemorrhage, vascular edema, lymphatic vessel myoma and the like.
  • Skin diseases include alcohol, inflammatory diseases (prunia vulgaris, atopic dermatitis, Schnitzler syndrome), vulgaris vulgaris, wounds, decubitus, frost wounds, nodular sclerosis, multiple sclerosis, and systemic strength. Examples include dermatosis, Kaposi sarcoma, cutaneous angiosarcoma, purpura, severe wrinkles, blemishes, and swelling.
  • the pharmaceutical composition includes inflammatory diseases such as psoriasis vulgaris and Schnitzler's syndrome, vulgaris vulgaris, tuberous sclerosis, systemic scleroderma, Kaposi's sarcoma, cutaneous angiosarcoma, severe wrinkles, etc. It is considered to be effective for the treatment and prevention of swelling and the like.
  • Endocrine, nutritional and metabolic disorders include diabetes and diabetes-related disorders (eg, retinopathy, macular edema, skin ulcers, wounds, nephropathy, and peripheral neuropathy); hyperlipidemia; gout and the like.
  • the pharmaceutical composition is considered to be particularly effective for the treatment and prevention of diseases related to diabetes including retinopathy, macular edema, skin ulcer, wound, nephropathy, peripheral neuropathy and the like.
  • Diseases based on aging include alopecia, osteoporosis, cutaneous dementia, dementia, photoaging, age-related yellow spot degeneration, Alzheimer's disease, vascular dementia, moyamoya disease and the like.
  • the pharmaceutical composition is considered to be particularly effective for the treatment and prevention of photoaging and the like.
  • Eye diseases include age-related yellow spot degeneration, retinopathy (retinopathy associated with premature infants or diabetes), choroidal angiogenesis, retinal vein occlusion, vasculitis, premature ischemia, and the like.
  • the pharmaceutical composition is considered to be particularly effective in the treatment and prevention of retinopathy (retinopathy in premature infants and retinopathy due to diabetes).
  • Other diseases include allergic diseases such as low back pain, tumor, acute myeloid leukemia, rheumatoid arthritis, Sjogren's syndrome, hepatitis, sepsis, renal failure, and pollinosis.
  • other diseases include drug-induced purpura and angiopathy associated with chemotherapy.
  • the pharmaceutical composition is considered to be particularly effective in the treatment and prevention of tumors, acute myeloid leukemia, hepatitis, and sepsis.
  • the composition of the present invention is also useful as a cosmetic composition, and such a cosmetic composition also contains at least pentosan polysulfuric acid and / or a salt thereof.
  • Such cosmetic compositions can also activate Ang-1 / Tie2 signals and / or increase the production of PDGF-BB. Therefore, the cosmetic composition can be used not only for cosmetic purposes, but also for improving deterioration of skin condition due to functional deterioration of blood vessels and / or lymphatic vessels, prevention of diseases associated with vascular lesions, and the like.
  • the cosmetic composition is not used for as severe a symptom as the above-mentioned diseases, but is useful for improving the skin condition by improving the vascular function and / or the lymphatic function.
  • the skin condition to be improved examples include wrinkles, age spots, swelling, alopecia and the like.
  • the cosmetic composition has the above-mentioned active ingredients, it is useful as a cosmetic product even though it has medicinal properties, and it is also a quasi-drug (“Ensuring the quality, effectiveness and safety of pharmaceuticals, medical devices, etc.” It may include quasi-drugs as stipulated in the Act on Securing Drugs.
  • Cosmetic compositions include, for example, wash pigments, skin lotions, lotions, emulsions, creams, gels, sunscreens, ointments, lotions, packs, wrinkle cosmetics, foundations, makeup bases, beauty liquids, whitening agents, deodorants. It is used as an agent, a cleaning agent, a hair cosmetic (hair nourishing agent, shampoo, rinse, hair tonic, etc.), a make-up cosmetic (lipstick, cheek red, etc.), an aerosol, a liquid agent, and the like.
  • the cosmetic composition may contain the following additives together with or in place of the components of the pharmaceutical composition described above.
  • surfactants emulsifiers
  • moisturizers emulsifiers
  • antioxidants emulsifiers
  • thickeners emulsifiers
  • chelating agents oily ingredients, resins
  • UV absorbers emulsifiers
  • surfactants thickeners
  • alcohols emulsifiers
  • powder ingredients e.g., PH adjusters, fragrances, acidulants, sweeteners, seasonings, colorants, various medicinal ingredients, chelating agents, preservatives, moisture-proofing agents, excipients, disinfectants, deodorants, blood circulation promoters, salts, etc.
  • Refreshing agents whitening agents, animal or plant-derived extracts, astringents, anti-inflammatory agents, active oxygen scavengers, anti-fat leaks, cell activators, enzymes, hormones, vitamins, aqueous components, water (preferably purified) Water) and the like can be appropriately added to the cosmetic composition.
  • these additives can be used alone or in combination.
  • the content of pentosanpolysulfuric acid and / or a salt thereof in the cosmetic composition of the present invention is preferably 0.0001 to 30% by weight, preferably 0.001 to 10% by weight, based on the total weight of the composition. Is more preferable, and 0.01 to 1% by weight is particularly preferable.
  • the total content of the above-mentioned additives is, for example, 70% by weight or more, 90% by weight or more, 99% by weight or more, etc., based on the total weight of the cosmetic composition.
  • the components of the cosmetic composition that is, the types of active ingredients and additives, dosage forms, usages, dosages, uses, etc., may be common to those of pharmaceutical compositions. Therefore, the above-mentioned ingredients, dosage forms, usages, dosages, uses, etc. relating to the pharmaceutical composition can be applied to the cosmetic composition.
  • sodium pentosanpolysulfate manufactured by Mollclone 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.
  • hyaluronic acid abbreviation: HA, Tokyo Kasei Kogyo Co., Ltd.
  • chondroitin sulfate abbreviation: Chs, organic sulfate group: 15 to 17% w / w, Maruho Co., Ltd.
  • xylohexaose abbreviation: Malho Co., Ltd.
  • O-XHE Megazyme
  • Example 1 Effect of PPS on Ang-1 production from human placenta-derived wall cells
  • Human placenta-derived wall cells (PromoCell) (1 ⁇ 10 5 cells) were seeded in a medium (Pericyte Growth Medium + Pericyte Growth Medium Supplement Mix (PromoCell)) at 37 ° C. After culturing at 5, 5% CO 2 , 95% air for 4 days, the medium was replaced with a medium containing PPS, HA, Chs or O-XHE (Pericyte Growth medium) at each concentration, and the temperature was 37 ° C., 5% CO 2 . , 95% air for an additional 48 hours.
  • a medium Pericyte Growth Medium + Pericyte Growth Medium Supplement Mix (PromoCell)
  • the Ang-1 concentration in the culture supernatant was measured by an ELISA kit (Human Angiopoietin-1 Quantikine ELISA Kit (R & D Systems)).
  • FIG. * The effects of PPS, HA, Chs and O-XHE on Ang-1 production are shown in FIG. * In the figure indicates a significant difference from the solvent group (in the absence of drug: see (-) in FIG. 1) (P ⁇ 0.05). From the results shown in FIG. 1, a significant increase in the amount of Ang-1 was observed at a concentration of PPS of 100 ⁇ g / mL as compared with the solvent group. On the other hand, the amount of Ang-1 in the HA, Chs and O-XHE groups was not significantly different from that in the solvent group.
  • Example 2 Effect of PPS on Ang-2 production from human skin microvascular endothelial cells
  • Human skin microvascular endothelial cells (PromoCell) (1 ⁇ 10 5 cells) (Endothelial Cell Growth Medium MV2 + Endothelial Cell Growth Medium MV2 Supplement Mix (PromoCell)) After seeding in 37 ° C. and culturing at 5% CO 2 , 95% air for 4 days, this medium was used as a medium containing PPS, HA, Chs or O-XHE at each concentration (Endothelial Cell Growth Medium MV2 + Endothelial Cell Growth Medium MV2 Supplement).
  • Example 3 Effect of PPS on Tie2 phosphorylation of human skin microvascular endothelial cells Seed human skin microvascular endothelial cells (PromoCell) (1 ⁇ 10 6 cells) in a medium (Endothelial Cell Growth Medium MV2 + Endothelial Cell Growth Medium MV2 Supplement Mix (PromoCell)). Then, after culturing at 37 ° C., 5% CO 2 , 95% air for 2 days, transfer the cells to a medium from which serum was removed (Endothelial Cell Growth Medium MV2), and transfer the cells to 37 ° C., 5% CO 2 , 95% air, 3 at 37 ° C., 5% CO 2, 95% air. Cultured for hours.
  • this medium was replaced with a medium containing PPS (Endothelial Cell Growth Medium MV2) at each concentration, and cultured at 37 ° C., 5% CO 2 , 95% air for another 10 minutes.
  • PPS Endothelial Cell Growth Medium MV2
  • the cells were washed with cold TBS (Tris-Buffered Saline), RIPA Buffer (Radio Immunoprecipitation Assay Buffer) containing a phosphatase inhibitor (Thermo scientific) was added, and the cells were ultrasonically disrupted. After making each protein concentration constant, Sample buffer was added, and SDS-PAGE was performed at 100 V for 60 minutes using a 5-20% polyacrylamide gel.
  • the action of PPS on Tie2 phosphoric acid is shown in FIG.
  • the density of the detected band is proportional to the amount of protein in phosphorylated Tie2 (P-tie2). From the results shown in FIG. 3, at any concentration, Tie2 phosphorylation in the PPS group was significantly increased as compared with the solvent group (in the absence of drug: see (-) in FIG. 3).
  • Example 4 Effect of PPS on PDGF-BB production from human skin microvascular endothelial cells
  • Human skin microvascular endothelial cells (PromoCell) (1 ⁇ 10 5 cells) (Endothelial Cell Growth Medium MV2 + Endothelial Cell Growth Medium MV2 Supplement Mix (PromoCell))
  • this medium was used as a medium containing PPS, HA, Chs or O-XHE at each concentration (Endothelial Cell Growth Medium MV2 + Endothelial Cell Growth Medium MV2 Supplement).

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Abstract

Le problème à résoudre par la présente invention est de fournir une composition qui peut mûrir ou stabiliser des vaisseaux sanguins. La solution selon l'invention porte sur une composition qui contient du polysulfate de pentosanne et/ou un sel de ce dernier en tant que principe actif, et est utile pour traiter et/ou prévenir des maladies associées à des lésions vasculaires et/ou à des lésions lymphatiques, ou pour améliorer l'état de la peau par l'amélioration de la fonction vasculaire et/ou de la fonction lymphatique.
PCT/JP2021/043348 2020-11-27 2021-11-26 Composition pharmaceutique ou cosmétique WO2022114111A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024050599A1 (fr) * 2022-09-06 2024-03-14 Paradigm Biopharmaceuticals Ltd Traitement du psoriasis, du rhumatisme psoriasique et de la dermatite

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JPH05310597A (ja) * 1992-04-30 1993-11-22 Furukawa Co Ltd 接触治療剤
JPH08502295A (ja) * 1992-10-13 1996-03-12 大塚製薬株式会社 悪液質の治療およびｉｌ−６活性の阻害
JPH11501035A (ja) * 1995-02-28 1999-01-26 ハンデルマン，ジョセフ エイチ． 毛髪成長を抑制するための脈管形成抑制剤の使用
JP2007145793A (ja) * 2005-02-01 2007-06-14 Ajinomoto Co Inc 血行促進外用剤及びこれを含有してなる皮膚毛髪用化粧料及び入浴剤
JP2007525414A (ja) * 2003-01-31 2007-09-06 ジェシー エル エス オウ スラミン、ペントサン・ポリサルフェート、テロメラーゼアンチセンス、及びテロメラーゼ阻害剤を用いるための方法及び成分
JP2007238569A (ja) * 2006-03-10 2007-09-20 Kanebo Cosmetics Inc 頭髪化粧料
JP2009221136A (ja) * 2008-03-14 2009-10-01 Tatsuo Kaneko 糖誘導体製剤
WO2018221547A1 (fr) * 2017-05-31 2018-12-06 王子ホールディングス株式会社 Préparation topique hydratante
WO2019124363A1 (fr) * 2017-12-20 2019-06-27 王子ホールディングス株式会社 Pentosane polysulfate et médicament contenant du pentosane polysulfate
WO2019151285A1 (fr) * 2018-01-31 2019-08-08 マルホ株式会社 Composition pour la peau à usage externe
WO2019151286A1 (fr) * 2018-01-31 2019-08-08 マルホ株式会社 Composition dermatologique topique
WO2019151287A1 (fr) * 2018-01-31 2019-08-08 マルホ株式会社 Composition externe pour la peau
JP2019214571A (ja) * 2012-12-12 2019-12-19 メソブラスト、インコーポレイテッド 内皮機能不全及び炎症の疾患の治療

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH05310597A (ja) * 1992-04-30 1993-11-22 Furukawa Co Ltd 接触治療剤
JPH08502295A (ja) * 1992-10-13 1996-03-12 大塚製薬株式会社 悪液質の治療およびｉｌ−６活性の阻害
JPH11501035A (ja) * 1995-02-28 1999-01-26 ハンデルマン，ジョセフ エイチ． 毛髪成長を抑制するための脈管形成抑制剤の使用
JP2007525414A (ja) * 2003-01-31 2007-09-06 ジェシー エル エス オウ スラミン、ペントサン・ポリサルフェート、テロメラーゼアンチセンス、及びテロメラーゼ阻害剤を用いるための方法及び成分
JP2007145793A (ja) * 2005-02-01 2007-06-14 Ajinomoto Co Inc 血行促進外用剤及びこれを含有してなる皮膚毛髪用化粧料及び入浴剤
JP2007238569A (ja) * 2006-03-10 2007-09-20 Kanebo Cosmetics Inc 頭髪化粧料
JP2009221136A (ja) * 2008-03-14 2009-10-01 Tatsuo Kaneko 糖誘導体製剤
JP2019214571A (ja) * 2012-12-12 2019-12-19 メソブラスト、インコーポレイテッド 内皮機能不全及び炎症の疾患の治療
WO2018221547A1 (fr) * 2017-05-31 2018-12-06 王子ホールディングス株式会社 Préparation topique hydratante
WO2019124363A1 (fr) * 2017-12-20 2019-06-27 王子ホールディングス株式会社 Pentosane polysulfate et médicament contenant du pentosane polysulfate
WO2019151285A1 (fr) * 2018-01-31 2019-08-08 マルホ株式会社 Composition pour la peau à usage externe
WO2019151286A1 (fr) * 2018-01-31 2019-08-08 マルホ株式会社 Composition dermatologique topique
WO2019151287A1 (fr) * 2018-01-31 2019-08-08 マルホ株式会社 Composition externe pour la peau

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024050599A1 (fr) * 2022-09-06 2024-03-14 Paradigm Biopharmaceuticals Ltd Traitement du psoriasis, du rhumatisme psoriasique et de la dermatite

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