WO2022114111A1 - Pharmaceutical or cosmetic composition - Google Patents
Pharmaceutical or cosmetic composition Download PDFInfo
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- 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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- WIPO (PCT)
- Prior art keywords
- vascular
- composition
- examples
- sodium
- acid
- Prior art date
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Images
Classifications
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- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
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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).
Abstract
[Problem] To provide a composition that can mature or stabilize blood vessels. [Solution] This composition contains pentosan polysulfate and/or a salt thereof as an active ingredient, and is useful for treating and/or preventing diseases associated with vascular lesions and/or lymphatic lesions, or for improving the state of the skin by improving vascular function and/or lymphatic function.
Description
本発明は、血管の成熟化作用及び/又は血管の安定化作用を有する組成物、例えば、医薬組成物、及び化粧品組成物に関する。
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.
血管は全身に張り巡らされており、血液を循環させることで、さまざまな臓器、組織、細胞への酸素及び栄養の供給や老廃物の排出を担い、組織の恒常性維持に重要な役割を果たしている。血管は、血管内皮細胞からなる層と、その外側に接着した血管壁細胞(血管平滑筋細胞やペリサイト)からなる層とを有する2層構造からなり、脈管形成、血管新生、血管成熟化の過程を経て形成され、安定的な構造を有する。
血管成熟化の過程では、血管内皮細胞から分泌される血小板由来因子(Platelet derived growth factor:以下、「PDGF」という)の一つのアイソフォームであるPDGF-BBが、血管壁細胞に発現する受容体であるPDGFR-βの活性化を介して、血管壁細胞を血管内皮細胞へと遊走させる。
さらに、血管壁細胞(ペリサイト)から分泌されるアンジオポエチン-1(angiopoietin-1 以下、「Ang-1」という)は、血管内皮細胞に発現するTie2受容体を活性化し、壁細胞と内皮細胞との接着を誘導して、血管構造を安定化させる。一方、アンジオポエチン-2(angiopoietin-2 以下、「Ang-2」という)は、主に血管内皮細胞から分泌され、Ang-1/Tie2シグナルに対して拮抗的に作用する。つまり、Ang-2は、Ang-1/Tie2の血管安定化シグナルを遮断することで、血管構造を不安定化し、血管新生の誘導に関与することが示唆されている。
このような血管成熟化の過程におけるPDGF-BB/PDGFR-βシグナルやAng-1/Tie2シグナルの低下は、血管透過性の亢進及び血漿成分の漏出を誘発し、その結果、構造的に不安定で未成熟な血管が形成されることが知られている。このような構造的に不安定な血管は、様々な血管病変を伴う疾患において認められている。さらに、加齢に伴ってPDGF-BB/PDGFR-βシグナルやAng-1/Tie-2シグナルが減少することも知られており、血管の不安定化と老化との関連性も示唆されている。
また、Ang-1/Tie-2シグナルは、血管の成熟化、及び安定化のみならず、リンパ管の安定化に寄与し、リンパの流れを促進することも明らかにされている。 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. There is. 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.
In the process of vascular maturation, PDGF-BB, which is one isoform of platelet-derived growth factor (hereinafter referred to as "PDGF") secreted from vascular endothelial cells, is a receptor expressed on vascular wall cells. Through activation of PDGFR-β, vascular wall cells migrate to vascular endothelial cells.
Furthermore, angiopoietin-1 (hereinafter referred to as "Ang-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. On the other hand, 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-β 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. Furthermore, it is known that PDGF-BB / PDGFR-β 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.
血管成熟化の過程では、血管内皮細胞から分泌される血小板由来因子(Platelet derived growth factor:以下、「PDGF」という)の一つのアイソフォームであるPDGF-BBが、血管壁細胞に発現する受容体であるPDGFR-βの活性化を介して、血管壁細胞を血管内皮細胞へと遊走させる。
さらに、血管壁細胞(ペリサイト)から分泌されるアンジオポエチン-1(angiopoietin-1 以下、「Ang-1」という)は、血管内皮細胞に発現するTie2受容体を活性化し、壁細胞と内皮細胞との接着を誘導して、血管構造を安定化させる。一方、アンジオポエチン-2(angiopoietin-2 以下、「Ang-2」という)は、主に血管内皮細胞から分泌され、Ang-1/Tie2シグナルに対して拮抗的に作用する。つまり、Ang-2は、Ang-1/Tie2の血管安定化シグナルを遮断することで、血管構造を不安定化し、血管新生の誘導に関与することが示唆されている。
このような血管成熟化の過程におけるPDGF-BB/PDGFR-βシグナルやAng-1/Tie2シグナルの低下は、血管透過性の亢進及び血漿成分の漏出を誘発し、その結果、構造的に不安定で未成熟な血管が形成されることが知られている。このような構造的に不安定な血管は、様々な血管病変を伴う疾患において認められている。さらに、加齢に伴ってPDGF-BB/PDGFR-βシグナルやAng-1/Tie-2シグナルが減少することも知られており、血管の不安定化と老化との関連性も示唆されている。
また、Ang-1/Tie-2シグナルは、血管の成熟化、及び安定化のみならず、リンパ管の安定化に寄与し、リンパの流れを促進することも明らかにされている。 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. There is. 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.
In the process of vascular maturation, PDGF-BB, which is one isoform of platelet-derived growth factor (hereinafter referred to as "PDGF") secreted from vascular endothelial cells, is a receptor expressed on vascular wall cells. Through activation of PDGFR-β, vascular wall cells migrate to vascular endothelial cells.
Furthermore, angiopoietin-1 (hereinafter referred to as "Ang-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. On the other hand, 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-β 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. Furthermore, it is known that PDGF-BB / PDGFR-β 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.
従来から、Ang-1/Tie-2シグナルやPDGF-BB/PDGFR-βシグナルについて研究されているが(例えば、非特許文献1及び非特許文献2参照)、このようなメカニズムに基づく医薬品はほとんど開発されていない。そこで、Tie2活性化作用、PDGF-BBの産生作用等を有し、血管の成熟化作用若しくは血管の安定化、又はリンパ管の安定化をもたらす安全性の高い物質について、速やかな開発が強く望まれているのが現状である。
Conventionally, Ang-1 / Tie-2 signal and PDGF-BB / PDGFR-β signal have been studied (see, for example, Non-Patent Document 1 and Non-Patent Document 2), but most drugs based on such a mechanism are used. Not developed. Therefore, there is a strong desire for rapid development of highly safe substances that have Tie2 activating action, PDGF-BB production action, etc., and bring about blood vessel maturation action, blood vessel stabilization, or lymphatic vessel stabilization. The current situation is that it is rare.
したがって、本発明は、血管の壁細胞、血管の内皮細胞、及び/又はリンパ管内皮細胞に作用することにより、Ang-1/Tie2シグナルの活性化、PDGF-BBの産生増加等が可能である組成物を提供することを課題とする。
Therefore, 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.
本発明者らは、上記課題を解決するために、各種多糖類について検討を行った結果、ペントサンポリ硫酸及びその塩が、優れたAng-1/Tie2シグナルの活性化作用、PDGF-BBの産生増加作用等を有することを見出して、本発明を完成した。
As a result of investigating various polysaccharides in order to solve the above-mentioned problems, the present inventors have found that 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.
本発明は、以下に示す、ペントサンポリ硫酸及び/又はその塩を含む組成物に関する。
(1)ペントサンポリ硫酸及び/又はその塩を含む組成物であって、血管病変もしくはリンパ管病変の少なくとも1つを伴う疾患の治療及び/又は予防のため、又は、血管機能もしくはリンパ管機能の少なくとも1つの向上による皮膚状態の改善のための組成物。
(2)前記ペントサンポリ硫酸及び/又はその塩が、ペントサンポリ硫酸ナトリウムである、上記(1)に記載の組成物。
(3)前記ペントサンポリ硫酸及び/又はその塩の重量平均分子量が、1,000~30,000である、上記(1)又は(2)に記載の組成物。
(4)Tie2活性化剤、PDGF-BB産生促進剤、血管正常化剤、血管安定化剤、及び/又は、リンパ管安定化剤である、上記(1)~(3)のいずれかに記載の組成物。
(5)前記組成物が医薬組成物であり、前記血管病変を伴う疾患が、アテローム性動脈硬化症及びくも膜下出血を含む末梢動脈疾患、血管性浮腫、リンパ脈管筋腫、尋常性乾癬及びシュニッツラー症候群を含む炎症性疾患、尋常性疣贅、結節性硬化症、全身性強皮症、カポジ肉腫、皮膚血管肉腫、しわ、むくみ、網膜症、黄斑浮腫、皮膚潰瘍、創傷、腎症、末梢神経障害、糖尿病、光老化、未熟児における及び糖尿病による網膜症、腫瘍、急性骨髄性白血病、肝炎、及び、敗血症からなる群より選択される少なくとも1つの疾患である、上記(1)~(3)のいずれかに記載の組成物。
(6)前記組成物が化粧品組成物であり、前記皮膚状態の改善が、しわ、しみ、むくみ、及び、脱毛症からなる群より選択される少なくとも1つの状態の改善である、上記(1)~(3)のいずれかに記載の組成物。 The present invention relates to a composition comprising pentosan polysulfuric acid and / or a salt thereof, as shown below.
(1) A composition containing pentosanpolysulfuric acid and / or a salt thereof for the treatment and / or prevention of diseases associated with at least one of vascular lesions or lymphatic lesions, or for vascular function or lymphatic function. A composition for improving skin condition by at least one improvement.
(2) The composition according to (1) above, wherein the pentosan polysulfate and / or a salt thereof is sodium pentosan polysulfate.
(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.
(4) The above-mentioned (1) to (3), 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.
(5) The 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.
(6) The above (1), wherein the composition is a cosmetic composition, and the 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).
(1)ペントサンポリ硫酸及び/又はその塩を含む組成物であって、血管病変もしくはリンパ管病変の少なくとも1つを伴う疾患の治療及び/又は予防のため、又は、血管機能もしくはリンパ管機能の少なくとも1つの向上による皮膚状態の改善のための組成物。
(2)前記ペントサンポリ硫酸及び/又はその塩が、ペントサンポリ硫酸ナトリウムである、上記(1)に記載の組成物。
(3)前記ペントサンポリ硫酸及び/又はその塩の重量平均分子量が、1,000~30,000である、上記(1)又は(2)に記載の組成物。
(4)Tie2活性化剤、PDGF-BB産生促進剤、血管正常化剤、血管安定化剤、及び/又は、リンパ管安定化剤である、上記(1)~(3)のいずれかに記載の組成物。
(5)前記組成物が医薬組成物であり、前記血管病変を伴う疾患が、アテローム性動脈硬化症及びくも膜下出血を含む末梢動脈疾患、血管性浮腫、リンパ脈管筋腫、尋常性乾癬及びシュニッツラー症候群を含む炎症性疾患、尋常性疣贅、結節性硬化症、全身性強皮症、カポジ肉腫、皮膚血管肉腫、しわ、むくみ、網膜症、黄斑浮腫、皮膚潰瘍、創傷、腎症、末梢神経障害、糖尿病、光老化、未熟児における及び糖尿病による網膜症、腫瘍、急性骨髄性白血病、肝炎、及び、敗血症からなる群より選択される少なくとも1つの疾患である、上記(1)~(3)のいずれかに記載の組成物。
(6)前記組成物が化粧品組成物であり、前記皮膚状態の改善が、しわ、しみ、むくみ、及び、脱毛症からなる群より選択される少なくとも1つの状態の改善である、上記(1)~(3)のいずれかに記載の組成物。 The present invention relates to a composition comprising pentosan polysulfuric acid and / or a salt thereof, as shown below.
(1) A composition containing pentosanpolysulfuric acid and / or a salt thereof for the treatment and / or prevention of diseases associated with at least one of vascular lesions or lymphatic lesions, or for vascular function or lymphatic function. A composition for improving skin condition by at least one improvement.
(2) The composition according to (1) above, wherein the pentosan polysulfate and / or a salt thereof is sodium pentosan polysulfate.
(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.
(4) The above-mentioned (1) to (3), 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.
(5) The 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.
(6) The above (1), wherein the composition is a cosmetic composition, and the 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).
本発明の組成物は、優れたTie2活性化作用、PDGF-BBの産生増加作用等を有する。このような組成物は、血管の成熟化作用、血管の安定化作用、及び/又は、リンパ管安定化作用を有するため、血管機能、及び/又はリンパ管機能の低下等に起因する様々な疾患の予防及び/又は治療に有用である。
又、有効成分であるペントサンポリ硫酸及び/又はその塩は、安全性が高いために、副作用の少ない医薬組成物等を提供することができる。 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.
又、有効成分であるペントサンポリ硫酸及び/又はその塩は、安全性が高いために、副作用の少ない医薬組成物等を提供することができる。 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.
以下に本発明について詳細に説明する。本発明の組成物には、詳細を後述するように、医薬組成物及び化粧品組成物が含まれる。
医薬組成物としては、例えば、「医薬品、医療機器等の品質、有効性及び安全性の確保等に関する法律」に規定される医療用医薬品、要指導医薬品、一般用医薬品、又は医薬部外品に該当する組成物等が挙げられる。
化粧品組成物としては、例えば、「医薬品、医療機器等の品質、有効性及び安全性の確保等に関する法律」に規定される化粧品、又は薬用化粧品である医薬部外品に該当する組成物等が挙げられる。 The present invention will be described in detail below. The 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.
医薬組成物としては、例えば、「医薬品、医療機器等の品質、有効性及び安全性の確保等に関する法律」に規定される医療用医薬品、要指導医薬品、一般用医薬品、又は医薬部外品に該当する組成物等が挙げられる。
化粧品組成物としては、例えば、「医薬品、医療機器等の品質、有効性及び安全性の確保等に関する法律」に規定される化粧品、又は薬用化粧品である医薬部外品に該当する組成物等が挙げられる。 The present invention will be described in detail below. The 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.
[医薬組成物]
本発明の医薬組成物は、血管機能及び/又はリンパ管機能の低下を防止し、様々な疾患、特に、血管及び/又はリンパ管に関する疾患の予防、治療に有用である。 [Pharmaceutical composition]
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.
本発明の医薬組成物は、血管機能及び/又はリンパ管機能の低下を防止し、様々な疾患、特に、血管及び/又はリンパ管に関する疾患の予防、治療に有用である。 [Pharmaceutical composition]
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.
<有効成分>
本発明の医薬組成物においては、有効成分としてペントサンポリ硫酸又はその塩が含まれる。
ペントサンポリ硫酸は、多価陰イオン性多糖の混合物を含む、半合成ポリ硫酸化多糖である。ペントサンポリ硫酸は、木本、例えばブナから得られる多糖(例えばキシラン)の化学的硫酸化により生成される。ペントサンポリ硫酸は、一般に、キシラン鎖に側鎖としてO-メチルグルクロン酸が結合したものの多硫酸化体と考えられている。この際、ペントサンポリ硫酸は、塩の形態で存在していてもよく、好ましい塩としては、ペントサンポリ硫酸ナトリウム及びペントサンポリ硫酸カリウム塩等のアルカリ金属塩、ペントサンポリ硫酸カルシウム等のアルカリ土類金属塩、ペントサンポリ硫酸マグネシウム等が挙げられる。特に好ましい塩は、ペントサンポリ硫酸ナトリウムである。 <Active ingredient>
In the pharmaceutical composition of the present invention, 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. At this time, pentosanpolysulfuric acid may exist in the form of a salt, and preferred salts include alkali metal salts such as sodium pentosanpolysulfate and potassium pentosanpolysulfate, and alkaline earth metals such as calcium pentosanpolysulfate. Examples thereof include salts and pentosanpoly magnesium sulfate. A particularly preferred salt is pentosan polysodium sulfate.
本発明の医薬組成物においては、有効成分としてペントサンポリ硫酸又はその塩が含まれる。
ペントサンポリ硫酸は、多価陰イオン性多糖の混合物を含む、半合成ポリ硫酸化多糖である。ペントサンポリ硫酸は、木本、例えばブナから得られる多糖(例えばキシラン)の化学的硫酸化により生成される。ペントサンポリ硫酸は、一般に、キシラン鎖に側鎖としてO-メチルグルクロン酸が結合したものの多硫酸化体と考えられている。この際、ペントサンポリ硫酸は、塩の形態で存在していてもよく、好ましい塩としては、ペントサンポリ硫酸ナトリウム及びペントサンポリ硫酸カリウム塩等のアルカリ金属塩、ペントサンポリ硫酸カルシウム等のアルカリ土類金属塩、ペントサンポリ硫酸マグネシウム等が挙げられる。特に好ましい塩は、ペントサンポリ硫酸ナトリウムである。 <Active ingredient>
In the pharmaceutical composition of the present invention, 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. At this time, pentosanpolysulfuric acid may exist in the form of a salt, and preferred salts include alkali metal salts such as sodium pentosanpolysulfate and potassium pentosanpolysulfate, and alkaline earth metals such as calcium pentosanpolysulfate. Examples thereof include salts and pentosanpoly magnesium sulfate. A particularly preferred salt is pentosan polysodium sulfate.
本発明で用いられるペントサンポリ硫酸又はその塩の重量平均分子量は、特に限定されないが、1,000~30,000であることが好ましく、2,000~10,000であることがより好ましく、4,000~6,500であることがさらに好ましい。
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.
ペントサンポリ硫酸及び/又はその塩は、植物由来原料から製造することができるため、宗教上の理由などにより動物由来原料から製造された物質の使用を避ける国や地域でも、及びそのような患者にも使用することができる。
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.
ペントサンポリ硫酸及びその塩は、詳細を後述するように、Tie2の活性化、及びPDGF-BB産生の促進を可能にし、血管及び/又はリンパ管の機能低下の防止、血管成熟化、及び/又は血管安定化に貢献する。このため、ペントサンポリ硫酸、及び/又はペントサンポリ硫酸の塩(ペントサンポリ硫酸ナトリウムなど)を含む組成物は、Tie2活性化剤、PDGF-BB産生促進剤、血管の正常化剤、血管安定化剤、及び/又はリンパ管安定化剤等としても用いられ得る。
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.
<医薬組成物の剤形>
本発明の医薬組成物は、剤形に特に限定されるものではなく、例えば、経口剤、注射剤、点眼剤、点鼻剤、及び皮膚外用剤が挙げられ、薬学的に許容される添加剤と共に医薬組成物として使用することができる。皮膚外用剤としては、外用固形剤;リニメント剤及びローション剤などの外用液剤;外用エアゾール剤及びポンプスプレー剤などのスプレー剤;軟膏剤;クリーム剤;ゲル剤;並びに硬膏(プラスター剤)、パッチ剤、テープ剤及びパップ剤などの貼付剤が挙げられる。 <Dosage form of pharmaceutical composition>
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. Can be used as a pharmaceutical composition together with. 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.
本発明の医薬組成物は、剤形に特に限定されるものではなく、例えば、経口剤、注射剤、点眼剤、点鼻剤、及び皮膚外用剤が挙げられ、薬学的に許容される添加剤と共に医薬組成物として使用することができる。皮膚外用剤としては、外用固形剤;リニメント剤及びローション剤などの外用液剤;外用エアゾール剤及びポンプスプレー剤などのスプレー剤;軟膏剤;クリーム剤;ゲル剤;並びに硬膏(プラスター剤)、パッチ剤、テープ剤及びパップ剤などの貼付剤が挙げられる。 <Dosage form of pharmaceutical composition>
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. Can be used as a pharmaceutical composition together with. 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.
<医薬組成物における添加剤等>
<Additives, etc. in pharmaceutical compositions>
本発明の医薬組成物が軟膏剤の製剤形態である場合に、当該軟膏剤に使用される添加剤としては、基剤、保湿剤、増粘剤、乳化剤等が挙げられる。基剤には高級炭化水素、油脂類、ロウ類、脂肪酸、高級アルコール、エステル類等を用いることができる。高級炭化水素としては、例えば、スクワラン、合成パラフィン、流動パラフィン、白色ワセリン、マイクロクリスタリンワックス等が挙げられ、ロウ類としては、ミツロウ、サラシミツロウ、ラノリン、セレシンロウ等が挙げられ、脂肪酸としては、ステアリン酸、オレイン酸等が挙げられ、高級アルコールとしては、ラノリンアルコール、セトステアリルアルコール等が挙げられ、エステル類としては、ミリスチン酸イソプロピル、ミリスチン酸ステアリル等が挙げられる。
When the pharmaceutical composition of the present invention is in the form of an ointment, 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, and examples of fatty acids include stearic acid. Examples thereof include acids and oleic acids, examples of higher alcohols include lanolin alcohol and cetostearyl alcohol, and examples of esters include isopropyl myristate and stearyl myristate.
保湿剤としては、グリセリン、1,3-ブチレングリコール等が挙げられ、増粘剤としては、カルボキシビニルポリマー、カルボキシメチルセルロース等が挙げられ、乳化剤としては、陽イオン性界面活性剤、陰イオン性界面活性剤、両性界面活性剤、非イオン性界面活性剤等が挙げられる。
Examples of the moisturizing agent include glycerin, 1,3-butylene glycol and the like, examples of the thickener include carboxyvinyl polymer and carboxymethyl cellulose, and examples of the emulsifier include a cationic surfactant and an anionic surfactant. Examples include active agents, amphoteric surfactants, nonionic surfactants and the like.
貼付剤に使用される添加剤としては、増粘剤、保湿剤、充填剤、架橋剤、溶解剤、乳化剤等が挙げられる。具体的には、増粘剤としては、アルギン酸ナトリウム、ゼラチン、メチルセルロース、カルボキシビニルポリマー、ポリアクリル酸ナトリウム等が挙げられ、保湿剤としてはグリセリン等が挙げられ、充填剤としてはカオリン、二酸化チタン、亜鉛華等が挙げられ、架橋剤としては、アセトアルデヒド、ジメチルケトン、硫酸アルミニウム等が挙げられ、溶解剤としては、エタノール及びイソプロパノール等のアルコール類等が挙げられ、乳化剤としては、陰イオン性界面活性剤、非イオン性界面活性剤等が挙げられる。
硬膏(プラスター剤)又はパッチ剤に使用される添加剤としては、例えば、不織布等の支持体、天然ゴム又はイソプレンゴム等の弾性体、亜鉛華及び酸化チタン等の充填剤、テルペン樹脂等の粘着付与剤、酢酸ビニル等の剥離処理剤、流動パラフィン等の軟化剤、ジブチルヒドロキシトルエン(BHT)等の保存剤等を適宜組合せて使用することができる。
パップ剤に使用される添加剤としては、例えば、ポリアクリル酸、ポリビニルアルコールもしくはポリビニルピロリドン等の水溶性高分子化合物等が挙げられる。 Examples of the additive used for the patch include thickeners, moisturizers, fillers, cross-linking agents, solubilizers, emulsifiers and the like. Specifically, 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, and examples of the filler include kaolin and titanium dioxide. Examples include zinc flower, 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, and examples of the emulsifier include anionic surfactants. Agents, nonionic surfactants and the like can be mentioned.
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.
Examples of the additive used for the poultice include a water-soluble polymer compound such as polyacrylic acid, polyvinyl alcohol or polyvinylpyrrolidone.
硬膏(プラスター剤)又はパッチ剤に使用される添加剤としては、例えば、不織布等の支持体、天然ゴム又はイソプレンゴム等の弾性体、亜鉛華及び酸化チタン等の充填剤、テルペン樹脂等の粘着付与剤、酢酸ビニル等の剥離処理剤、流動パラフィン等の軟化剤、ジブチルヒドロキシトルエン(BHT)等の保存剤等を適宜組合せて使用することができる。
パップ剤に使用される添加剤としては、例えば、ポリアクリル酸、ポリビニルアルコールもしくはポリビニルピロリドン等の水溶性高分子化合物等が挙げられる。 Examples of the additive used for the patch include thickeners, moisturizers, fillers, cross-linking agents, solubilizers, emulsifiers and the like. Specifically, 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, and examples of the filler include kaolin and titanium dioxide. Examples include zinc flower, 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, and examples of the emulsifier include anionic surfactants. Agents, nonionic surfactants and the like can be mentioned.
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.
Examples of the additive used for the poultice include a water-soluble polymer compound such as polyacrylic acid, polyvinyl alcohol or polyvinylpyrrolidone.
クリーム剤に使用される添加剤としては、油溶性物質、水溶性物質、乳化剤等が挙げられる。油溶性物質には高級炭化水素、油脂類、ロウ類、脂肪酸、高級アルコール、エステル類等を用いることができる。高級炭化水素としては、例えば、スクワラン、合成パラフィン、流動パラフィン、白色ワセリン、マイクロクリスタリンワックス等が挙げられ、ロウ類としては、ミツロウ、サラシミツロウ、ラノリン、セレシンロウ等が挙げられ、脂肪酸としては、ステアリン酸、オレイン酸等が挙げられ、高級アルコールとしては、ラノリンアルコール、ミリスチルアルコール、セチルアルコール、ステアリルアルコール、セトステアリルアルコール、コレステロール等が挙げられ、エステル類としては、ミリスチン酸イソプロピル、ミリスチン酸ステアリル等が挙げられる。
Examples of additives used in creams include oil-soluble substances, water-soluble substances, emulsifiers and the like. As the oil-soluble substance, higher hydrocarbons, oils and fats, waxes, fatty acids, higher alcohols, esters and the like can be used. Examples of higher hydrocarbons include squalane, synthetic paraffin, liquid paraffin, white vaseline, microcrystallin wax and the like, examples of waxes include honeydew, sarashimitsuro, lanolin, selecin wax and the like, and examples of fatty acids include stearer. 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.
水溶性物質としては、水(精製水)、増粘剤、保湿剤等を用いることができる。増粘剤としては、カルボキシビニルポリマー、カルボキシメチルセルロース等が挙げられ、保湿剤としては、グリセリン、プロピレングリコール、1,3-ブチレングリコール等が挙げられる。
As the water-soluble substance, water (purified water), thickener, moisturizer and the like can be used. Examples of the thickener include carboxyvinyl polymer and carboxymethyl cellulose, and examples of the moisturizer include glycerin, propylene glycol and 1,3-butylene glycol.
乳化剤としては、陽イオン性界面活性剤、陰イオン性界面活性剤、両性界面活性剤、非イオン性界面活性剤等が挙げられる。
Examples of the emulsifier include cationic surfactants, anionic surfactants, amphoteric surfactants, nonionic surfactants and the like.
ローション剤としては、懸濁型、乳剤型又は溶液型ローション剤が挙げられる。
ローション剤に使用される添加剤としては、油溶性物質、水溶性物質、乳化剤等が挙げられる。油溶性物質には炭化水素類、油脂類、ロウ類、脂肪酸、高級アルコール、エステル類等を用いることができる。炭化水素類としては、例えば、スクワラン、α-オレフィンオリゴマー、合成パラフィン、流動パラフィン、白色ワセリン、マイクロクリスタリンワックス等が挙げられ、ロウ類としては、ミツロウ、サラシミツロウ、ラノリン、セレシンロウ等が挙げられ、脂肪酸としては、ステアリン酸、オレイン酸等が挙げられ、高級アルコールとしては、ラノリンアルコール、セチルアルコール、ステアリルアルコール、セトステアリルアルコール等が挙げられ、エステル類としては、ミリスチン酸イソプロピル、ミリスチン酸ステアリル、ミリスチン酸オクチルドデシル等が挙げられる。 Examples of the lotion include suspension type, emulsion type and solution type lotions.
Examples of additives used in lotions include oil-soluble substances, water-soluble substances, emulsifiers and the like. Hydrocarbons, oils and fats, waxes, fatty acids, higher alcohols, esters and the like can be used as the oil-soluble substance. Examples of the hydrocarbons include squalane, α-olefin oligomer, synthetic paraffin, liquid paraffin, white vaseline, microcrystalin wax and the like, and examples of the waxes include honeydew, sardine wax, lanolin, selecin wax 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, and examples of the esters include isopropyl myristate, stearyl myristate and myristin. Examples thereof include octyldodecyl acid.
ローション剤に使用される添加剤としては、油溶性物質、水溶性物質、乳化剤等が挙げられる。油溶性物質には炭化水素類、油脂類、ロウ類、脂肪酸、高級アルコール、エステル類等を用いることができる。炭化水素類としては、例えば、スクワラン、α-オレフィンオリゴマー、合成パラフィン、流動パラフィン、白色ワセリン、マイクロクリスタリンワックス等が挙げられ、ロウ類としては、ミツロウ、サラシミツロウ、ラノリン、セレシンロウ等が挙げられ、脂肪酸としては、ステアリン酸、オレイン酸等が挙げられ、高級アルコールとしては、ラノリンアルコール、セチルアルコール、ステアリルアルコール、セトステアリルアルコール等が挙げられ、エステル類としては、ミリスチン酸イソプロピル、ミリスチン酸ステアリル、ミリスチン酸オクチルドデシル等が挙げられる。 Examples of the lotion include suspension type, emulsion type and solution type lotions.
Examples of additives used in lotions include oil-soluble substances, water-soluble substances, emulsifiers and the like. Hydrocarbons, oils and fats, waxes, fatty acids, higher alcohols, esters and the like can be used as the oil-soluble substance. Examples of the hydrocarbons include squalane, α-olefin oligomer, synthetic paraffin, liquid paraffin, white vaseline, microcrystalin wax and the like, and examples of the waxes include honeydew, sardine wax, lanolin, selecin wax 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, and examples of the esters include isopropyl myristate, stearyl myristate and myristin. Examples thereof include octyldodecyl acid.
水溶性物質としては、水(精製水)、エタノール及びイソプロパノール等のアルコール、増粘剤、保湿剤等を用いることができる。増粘剤としては、カルボキシビニルポリマー、カルボキシメチルセルロース等が挙げられ、保湿剤としては、グリセリン、プロピレングリコール、1,3-ブチレングリコール等が挙げられる。乳化剤としては、陽イオン性界面活性剤、陰イオン性界面活性剤、両性界面活性剤、非イオン性界面活性剤等が挙げられる。
懸濁型ローションの添加物としては、上記に加え、アラビアゴム及びトラガントゴム等のゴム類、メチルセルロース及びヒドロキシエチルセルロース等のセルロース類、ベントナイト等の粘土類のような懸濁剤が挙げられる。 As the water-soluble substance, water (purified water), alcohols such as ethanol and isopropanol, thickeners, moisturizers and the like can be used. Examples of the thickener include carboxyvinyl polymer and carboxymethyl cellulose, and examples of the moisturizer include glycerin, propylene glycol and 1,3-butylene glycol. Examples of the emulsifier include cationic surfactants, anionic surfactants, amphoteric surfactants, nonionic surfactants and the like.
In addition to the above, 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.
懸濁型ローションの添加物としては、上記に加え、アラビアゴム及びトラガントゴム等のゴム類、メチルセルロース及びヒドロキシエチルセルロース等のセルロース類、ベントナイト等の粘土類のような懸濁剤が挙げられる。 As the water-soluble substance, water (purified water), alcohols such as ethanol and isopropanol, thickeners, moisturizers and the like can be used. Examples of the thickener include carboxyvinyl polymer and carboxymethyl cellulose, and examples of the moisturizer include glycerin, propylene glycol and 1,3-butylene glycol. Examples of the emulsifier include cationic surfactants, anionic surfactants, amphoteric surfactants, nonionic surfactants and the like.
In addition to the above, 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.
リニメント剤に使用される添加剤としては、例えば、オリーブ油等の植物油類、エタノールもしくはイソプロパノール等のアルコール類、或いはそれらと水との混合物等が挙げられる。
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.
ゲル剤に配合される添加剤としては、基剤、粘稠剤等が挙げられ、基剤にはイソプロパノール、プロピレングリコール等が挙げられる。粘稠剤としては、例えば、カルボキシビニルポリマー、カルボキシメチルセルロース等が挙げられる。
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.
スプレー剤に配合される添加剤としては、基剤、起泡剤等が挙げられる。
基剤としては、例えば、水、グリセリン、1,3-ブチレングリコール、ジプロピレングリコール、プロピレングリコール、D-ソルビトール、ポリエチレングリコール、2-エチルヘキサンジオール、イソステアリルアルコール、オクチルドデカノール、ヘキシルデカノール、オレイルアルコール、イソステアリン酸、オレイン酸、オレイン酸オレイル、ミリスチン酸イソプロピル、ミリスチン酸オクチルドデシル、トリイソオクタン酸グリセリル、2-エチルヘキサン酸セチル、パルミチン酸イソステアリル、中鎖脂肪酸トリグリセリド、ヒマシ油、オリーブ油、トリアセチン、スクワラン、軽質流動パラフィン、流動パラフィン、スクワレン、白色ワセリン、ゲル化炭化水素等が挙げられる。
起泡剤としては、例えば、モノステアリン酸ポリオキシエチレンソルビタン、トリステアリン酸ポリオキシエチレンソルビタン、ポリオキシエチレンポリオキシプロピレングリコール、ステアリン酸グリセリル、ポリオキシエチレン硬化ヒマシ油、トリオレイン酸デカグリセリル、ポリオキシエチレンセチルエーテル、テトラオレイン酸ポリオキシエチレンソルビット、ショ糖ステアリン酸エステル、ポリオキシエチレンポリオキシプロピレンセチルエーテル、ポリオキシエチレンソルビットミツロウ、モノステアリン酸ポリオキシエチレングリセリル、ポリオキシエチレンラウリルエーテル、自己乳化型モノステアリン酸グリセリル、モノオレイン酸ポリオキシエチレンソルビタン、モノオレイン酸デカグリセリル、モノステアリン酸デカグリセリル、モノステアリン酸ポリエチレングリコール、ポリオキシエチレンベへニルエーテル、ラウリン酸ポリオキシエチレンソルビタン、ショ糖ラウリン酸エステル、ポリオキシエチレンステアリルエーテル、ラウリン酸ナトリウム、パルミチン酸カリウム、ステアリン酸アルギニン、ラウリル硫酸ナトリウム、ラウリル硫酸カリウム、セチル硫酸ナトリウム、ポリオキシエチレンラウリル硫酸トリエタノールアミン、ラウロイルサルコシンナトリウム、N-ステアロイル-N-メチルタウリンナトリウム、N-ミリストイル-N-メチルタウリンナトリウム、モノステアリルリン酸ナトリウム、ポリオキシエチレンオレイルエーテルリン酸ナトリウム、ポリオキシエチレンステアリルエーテルリン酸ナトリウム、ポリオキシエチレンセチルエーテルリン酸ナトリウム、ジ-2-エチルヘキシルスルホコハク酸ナトリウム、N-ラウロイルグルタミン酸モノナトリウム、N-ステアロイル-L-グルタミン酸ナトリウム、N-ステアロイル-L-グルタミン酸アルギニン、N-ミリストイル-L-グルタミン酸ナトリウム等が挙げられる。 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. , Isosteaic acid, oleic acid, oleyl oleate, isopropyl myristate, octyldodecyl myristate, glyceryl triisooctanoate, cetyl 2-ethylhexanate, isostearyl palmitate, medium chain fatty acid triglyceride, castor oil, olive oil, triacetin, squalane , Light liquid paraffin, liquid paraffin, squalane, white vaseline, gelled hydrocarbon and the like.
Examples of the foaming agent include polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan tristearate, polyoxyethylene polyoxypropylene glycol, glyceryl stearate, polyoxyethylene hydrogenated castor oil, decaglyceryl trioleate, and poly. Oxyethylene cetyl ether, polyoxyethylene sorbit tetraoleate, sucrose stearate, polyoxyethylene polyoxypropylene cetyl ether, polyoxyethylene sorbit beeswax, polyoxyethylene glyceryl monostearate, polyoxyethylene lauryl ether, self-emulsifying Type Glyceryl monostearate, polyoxyethylene sorbitan monooleate, decaglyceryl monooleate, decaglyceryl monostearate, polyethylene glycol monostearate, polyoxyethylene behenyl ether, polyoxyethylene sorbitan laurate, sucrose lauric acid Estel, Polyoxyethylene Stearyl Ether, Sodium Laurate, Potassium Palmitate, Arginine Stearate, Sodium Lauryl Sulfate, Potassium Lauryl Sulfate, Sodium Cetyl Sulfate, Triethanolamine Polyoxyethylene Lauryl Sulfate, Sodium Lauroyl Sarcosin, N-Stearoyl-N -Sodium Methyl Taurine, N-Millistoyl-N-Sodium Methyl Taurine, Sodium Monostearyl Phosphate, Sodium Polyoxyethylene Oleyl Ether Phosphate, Sodium Polyoxyethylene Stearyl Ether Phosphate, Sodium Polyoxyethylene Cetyl Ether Phosphate, Di- Examples thereof include sodium 2-ethylhexyl sulfosuccinate, monosodium N-lauroyl glutamate, sodium N-stearoyl-L-glutamate, arginine N-stearoyl-L-glutamate, sodium N-myristoyl-L-glutamate and the like.
基剤としては、例えば、水、グリセリン、1,3-ブチレングリコール、ジプロピレングリコール、プロピレングリコール、D-ソルビトール、ポリエチレングリコール、2-エチルヘキサンジオール、イソステアリルアルコール、オクチルドデカノール、ヘキシルデカノール、オレイルアルコール、イソステアリン酸、オレイン酸、オレイン酸オレイル、ミリスチン酸イソプロピル、ミリスチン酸オクチルドデシル、トリイソオクタン酸グリセリル、2-エチルヘキサン酸セチル、パルミチン酸イソステアリル、中鎖脂肪酸トリグリセリド、ヒマシ油、オリーブ油、トリアセチン、スクワラン、軽質流動パラフィン、流動パラフィン、スクワレン、白色ワセリン、ゲル化炭化水素等が挙げられる。
起泡剤としては、例えば、モノステアリン酸ポリオキシエチレンソルビタン、トリステアリン酸ポリオキシエチレンソルビタン、ポリオキシエチレンポリオキシプロピレングリコール、ステアリン酸グリセリル、ポリオキシエチレン硬化ヒマシ油、トリオレイン酸デカグリセリル、ポリオキシエチレンセチルエーテル、テトラオレイン酸ポリオキシエチレンソルビット、ショ糖ステアリン酸エステル、ポリオキシエチレンポリオキシプロピレンセチルエーテル、ポリオキシエチレンソルビットミツロウ、モノステアリン酸ポリオキシエチレングリセリル、ポリオキシエチレンラウリルエーテル、自己乳化型モノステアリン酸グリセリル、モノオレイン酸ポリオキシエチレンソルビタン、モノオレイン酸デカグリセリル、モノステアリン酸デカグリセリル、モノステアリン酸ポリエチレングリコール、ポリオキシエチレンベへニルエーテル、ラウリン酸ポリオキシエチレンソルビタン、ショ糖ラウリン酸エステル、ポリオキシエチレンステアリルエーテル、ラウリン酸ナトリウム、パルミチン酸カリウム、ステアリン酸アルギニン、ラウリル硫酸ナトリウム、ラウリル硫酸カリウム、セチル硫酸ナトリウム、ポリオキシエチレンラウリル硫酸トリエタノールアミン、ラウロイルサルコシンナトリウム、N-ステアロイル-N-メチルタウリンナトリウム、N-ミリストイル-N-メチルタウリンナトリウム、モノステアリルリン酸ナトリウム、ポリオキシエチレンオレイルエーテルリン酸ナトリウム、ポリオキシエチレンステアリルエーテルリン酸ナトリウム、ポリオキシエチレンセチルエーテルリン酸ナトリウム、ジ-2-エチルヘキシルスルホコハク酸ナトリウム、N-ラウロイルグルタミン酸モノナトリウム、N-ステアロイル-L-グルタミン酸ナトリウム、N-ステアロイル-L-グルタミン酸アルギニン、N-ミリストイル-L-グルタミン酸ナトリウム等が挙げられる。 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. , Isosteaic acid, oleic acid, oleyl oleate, isopropyl myristate, octyldodecyl myristate, glyceryl triisooctanoate, cetyl 2-ethylhexanate, isostearyl palmitate, medium chain fatty acid triglyceride, castor oil, olive oil, triacetin, squalane , Light liquid paraffin, liquid paraffin, squalane, white vaseline, gelled hydrocarbon and the like.
Examples of the foaming agent include polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan tristearate, polyoxyethylene polyoxypropylene glycol, glyceryl stearate, polyoxyethylene hydrogenated castor oil, decaglyceryl trioleate, and poly. Oxyethylene cetyl ether, polyoxyethylene sorbit tetraoleate, sucrose stearate, polyoxyethylene polyoxypropylene cetyl ether, polyoxyethylene sorbit beeswax, polyoxyethylene glyceryl monostearate, polyoxyethylene lauryl ether, self-emulsifying Type Glyceryl monostearate, polyoxyethylene sorbitan monooleate, decaglyceryl monooleate, decaglyceryl monostearate, polyethylene glycol monostearate, polyoxyethylene behenyl ether, polyoxyethylene sorbitan laurate, sucrose lauric acid Estel, Polyoxyethylene Stearyl Ether, Sodium Laurate, Potassium Palmitate, Arginine Stearate, Sodium Lauryl Sulfate, Potassium Lauryl Sulfate, Sodium Cetyl Sulfate, Triethanolamine Polyoxyethylene Lauryl Sulfate, Sodium Lauroyl Sarcosin, N-Stearoyl-N -Sodium Methyl Taurine, N-Millistoyl-N-Sodium Methyl Taurine, Sodium Monostearyl Phosphate, Sodium Polyoxyethylene Oleyl Ether Phosphate, Sodium Polyoxyethylene Stearyl Ether Phosphate, Sodium Polyoxyethylene Cetyl Ether Phosphate, Di- Examples thereof include sodium 2-ethylhexyl sulfosuccinate, monosodium N-lauroyl glutamate, sodium N-stearoyl-L-glutamate, arginine N-stearoyl-L-glutamate, sodium N-myristoyl-L-glutamate and the like.
皮膚外用剤の各製剤で使用できる陽イオン性界面活性剤の具体例としては、例えば、セチルトリメチルアンモニウムクロリド、ラウリルジメチルベンジルアンモニウムクロリド、テトラブチルアンモニウムクロリド、ジオクタデシルジメチルアンモニウムクロリド等が挙げられる。
陰イオン性界面活性剤としては、例えばアルキルベンゼンスルホン酸ナトリウム、ドデシル硫酸ナトリウム、ヤシアルコールエトキシ硫酸ナトリウム、α-オレフィンスルホン酸ナトリウム、乳化セトステアリルアルコール等が挙げられる。
非イオン性界面活性剤としては、ポリオキシエチレンオレイルエーテル及びポリオキシエチレンオクチルドデシルエーテル等のポリオキシエチレンアルキルエーテル;ポリオキシエチレンアルキルフェノールエーテル;ポリオキシエチレン硬化ヒマシ油;ステアリン酸ポリオキシル;モノステアリン酸グリセリル、自己乳化型モノステアリン酸グリセリル、モノイソステアリン酸グリセリル、パルミチン酸グリセリル、ミリスチン酸グリセリル、オレイン酸グリセリル、及びトリイソオクタン酸グリセリル等のグリセリン脂肪酸エステル;ラウリン酸ジグリセリル、ステアリン酸ジグリセリル、及びオレイン酸ジグリセリル等のジグリセリン脂肪酸エステル;モノパルミチン酸ソルビタン、モノステアリン酸ソルビタン、モノオレイン酸ソルビタン、ヤシ油脂肪酸ソルビタン、トリステアリン酸ソルビタン、及びトリオレイン酸ソルビタン等のソルビタン脂肪酸エステル;モノラウリン酸ポリエチレングリコール、モノステアリン酸ポリエチレングリコール、及びモノオレイン酸ポリエチレングリコール等のポリエチレングリコール脂肪酸エステル等;が挙げられる。
両性界面活性剤としては、例えば、N-アルキル-N,N-ジメチルアンモニウムベタイン、イミダゾリン型両性界面活性剤等が挙げられる。
上記界面活性剤はいずれも、単独又は組み合わせて使用することができる。 Specific examples of the cationic surfactant that can be used in each preparation of the external skin preparation include cetyltrimethylammonium chloride, lauryldimethylbenzylammonium chloride, tetrabutylammonium chloride, dioctadecyldimethylammonium chloride and the like.
Examples of the anionic surfactant include sodium alkylbenzene sulfonate, sodium dodecyl sulfate, sodium coconut alcohol ethoxysulfate, sodium α-olefin sulfonate, emulsified cetostearyl alcohol and the like.
Examples of the nonionic surfactant include polyoxyethylene alkyl ethers such as polyoxyethylene oleyl ether and polyoxyethylene octyldodecyl ether; polyoxyethylene alkylphenol ethers; polyoxyethylene hydrogenated castor oil; polyoxyl stearate; glyceryl monostearate. , Self-emulsifying glyceryl monostearate, glyceryl monoisostearate, glyceryl palmitate, glyceryl myristate, glyceryl oleate, and glyceryl triisooctanoate glycerin fatty acid esters; diglyceryl laurate, diglyceryl stearate, and oleic acid. 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.
陰イオン性界面活性剤としては、例えばアルキルベンゼンスルホン酸ナトリウム、ドデシル硫酸ナトリウム、ヤシアルコールエトキシ硫酸ナトリウム、α-オレフィンスルホン酸ナトリウム、乳化セトステアリルアルコール等が挙げられる。
非イオン性界面活性剤としては、ポリオキシエチレンオレイルエーテル及びポリオキシエチレンオクチルドデシルエーテル等のポリオキシエチレンアルキルエーテル;ポリオキシエチレンアルキルフェノールエーテル;ポリオキシエチレン硬化ヒマシ油;ステアリン酸ポリオキシル;モノステアリン酸グリセリル、自己乳化型モノステアリン酸グリセリル、モノイソステアリン酸グリセリル、パルミチン酸グリセリル、ミリスチン酸グリセリル、オレイン酸グリセリル、及びトリイソオクタン酸グリセリル等のグリセリン脂肪酸エステル;ラウリン酸ジグリセリル、ステアリン酸ジグリセリル、及びオレイン酸ジグリセリル等のジグリセリン脂肪酸エステル;モノパルミチン酸ソルビタン、モノステアリン酸ソルビタン、モノオレイン酸ソルビタン、ヤシ油脂肪酸ソルビタン、トリステアリン酸ソルビタン、及びトリオレイン酸ソルビタン等のソルビタン脂肪酸エステル;モノラウリン酸ポリエチレングリコール、モノステアリン酸ポリエチレングリコール、及びモノオレイン酸ポリエチレングリコール等のポリエチレングリコール脂肪酸エステル等;が挙げられる。
両性界面活性剤としては、例えば、N-アルキル-N,N-ジメチルアンモニウムベタイン、イミダゾリン型両性界面活性剤等が挙げられる。
上記界面活性剤はいずれも、単独又は組み合わせて使用することができる。 Specific examples of the cationic surfactant that can be used in each preparation of the external skin preparation include cetyltrimethylammonium chloride, lauryldimethylbenzylammonium chloride, tetrabutylammonium chloride, dioctadecyldimethylammonium chloride and the like.
Examples of the anionic surfactant include sodium alkylbenzene sulfonate, sodium dodecyl sulfate, sodium coconut alcohol ethoxysulfate, sodium α-olefin sulfonate, emulsified cetostearyl alcohol and the like.
Examples of the nonionic surfactant include polyoxyethylene alkyl ethers such as polyoxyethylene oleyl ether and polyoxyethylene octyldodecyl ether; polyoxyethylene alkylphenol ethers; polyoxyethylene hydrogenated castor oil; polyoxyl stearate; glyceryl monostearate. , Self-emulsifying glyceryl monostearate, glyceryl monoisostearate, glyceryl palmitate, glyceryl myristate, glyceryl oleate, and glyceryl triisooctanoate glycerin fatty acid esters; diglyceryl laurate, diglyceryl stearate, and oleic acid. 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.
上記の皮膚外用剤の剤形において、必要によりpH調節剤、保存剤、マクロゴール類等が使用される。
In the dosage form of the above-mentioned external skin preparation, a pH regulator, a preservative, macrogol, etc. are used as necessary.
pH調節剤としては、例えば、ジイソプロパノールアミン、トリイソプロパノールアミン、トリエタノールアミン、水酸化カリウム、水酸化ナトリウム、クエン酸ナトリウム、リン酸、酒石酸、dl-リンゴ酸、氷酢酸等が挙げられ、保存剤としては、チモール、ジブチルヒドロキシトルエン、エデト酸ナトリウム水和物、パラオキシ安息香酸メチル、パラオキシ安息香酸エチル、パラオキシ安息香酸プロピル等が挙げられる。
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.
また、医薬組成物が経口剤の製剤形態である場合には、安定性や取り扱い易さ、あるいはコンプライアンスの向上のために必要な、味、臭い、色を改善するために、必要により、各種添加剤を選択して用いることができる。例えば(1)乳糖、デンプン、結晶セルロース、D-マンニトール、ぶどう糖及びリン酸カルシウムなどの賦形剤、(2)デンプン、及びクロスカルメロースナトリウムなどの崩壊剤、(3)D-マンニトール、D-ソルビトール、アスパルテーム及びクエン酸などの甘味剤や矯味剤、(4)ポリエチレングリコール等の可塑剤、(5)EDTAなどのポリアミノカルボン酸系キレート化剤及びその塩、ピロ亜硫酸ナトリウム、及び1-アスコルビン酸などの安定化剤、(6)パラオキシ安息香酸エステルや塩化ベンザルコニウムなどの保存剤、及び/又は、その他の添加剤(着色剤や着香剤など)を用いることができる。
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. For example, (1) excipients such as lactose, starch, crystalline cellulose, D-mannitol, glucose and calcium phosphate, (2) disintegrants such as starch and croscarmellose sodium, (3) D-mannitol, D-sorbitol, Sweeteners and excipients such as aspartame and citric acid, (4) 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.
これらの添加剤の種類及び配合量は、有効成分の安定性や味などの特性を考慮して、適宜設定することができる。また、医薬組成物として水に溶解する性質が必要な場合、添加剤は、水への溶解性を考慮して適宜選択することができる。
さらに、経口粒剤の速やかな崩壊性や溶解性を損なわない範囲で、ヒドロキシプロピルセルロースやポリビニルピロリドン等の結合剤を必要により医薬組成物中に配合することもできる。速やかな崩壊性や溶解性を確保するためには、結合力の弱い結合剤が望ましく、さらに結合剤の配合量は、組成物重量に対して、5重量%以下、特に望ましくは2重量%以下が好ましい。 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.
さらに、経口粒剤の速やかな崩壊性や溶解性を損なわない範囲で、ヒドロキシプロピルセルロースやポリビニルピロリドン等の結合剤を必要により医薬組成物中に配合することもできる。速やかな崩壊性や溶解性を確保するためには、結合力の弱い結合剤が望ましく、さらに結合剤の配合量は、組成物重量に対して、5重量%以下、特に望ましくは2重量%以下が好ましい。 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.
経口粒剤の有用な剤形としてドライシロップがある。ドライシロップは、用時溶解又は用時懸濁して用いるシロップ剤であり、医薬品の苦味や不味を、甘味作用と粘稠性を有する糖類、及び添加される種々の着香剤などによって隠ぺいできるため、及び、適当な着色料により好ましい色調に調節できるため、より服用しやすい優れた製剤である。ドライシロップを溶解又は懸濁する際に、溶媒として水以外にも、ジュース又は牛乳などの水を含む液体を用いることができる。
また、ドライシロップに類似した経口粒剤、すなわち、白糖を多く含み実質的に用時溶解又は用時懸濁して用いられる顆粒剤、散剤及び細粒剤なども、医薬組成物の実施の態様として好適である。 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. When dissolving or suspending dry syrup, a liquid containing water such as juice or milk can be used in addition to water as a solvent.
In addition, 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.
また、ドライシロップに類似した経口粒剤、すなわち、白糖を多く含み実質的に用時溶解又は用時懸濁して用いられる顆粒剤、散剤及び細粒剤なども、医薬組成物の実施の態様として好適である。 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. When dissolving or suspending dry syrup, a liquid containing water such as juice or milk can be used in addition to water as a solvent.
In addition, 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.
医薬組成物が注射剤の製剤形態である場合、添加剤としては、pH調整剤、緩衝剤、安定化剤、等張化剤、局所麻酔剤、無痛化剤、希釈剤、界面活性剤などが挙げられる。
pH調整剤及び緩衝剤としては、塩酸、クエン酸、クエン酸ナトリウム、酢酸ナトリウム、リン酸ナトリウム、水酸化ナトリウム等が用いられ、安定化剤としてはピロ亜硫酸ナトリウム、エチレンジアミン四酢酸、チオグリコール酸、チオ乳酸等が用いられる。また、緩衝剤としては、クエン酸ナトリウム、リン酸、リン酸ナトリウム、リン酸カリウム、酢酸ナトリウム、ホウ酸などが好適に用いられる。
局所麻酔剤としては塩酸プロカイン、塩酸リドカイン等が、また等張化剤としては塩化ナトリウム、D-マンニトール、D-ソルビトール、ブドウ糖あるいはグリセリン等が使用できる。
無痛化剤としては、塩酸プロカイン等を使用できる。
また、希釈剤としては、例えば水、エチルアルコール、マクロゴール、プロピレングリコール等を挙げることができる。 When the pharmaceutical composition is in the form of an injection, the additives include pH adjusters, buffers, stabilizers, tonicity agents, local anesthetics, painkillers, diluents, surfactants and the like. Can be mentioned.
As the 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. Further, as the buffering agent, sodium citrate, phosphoric acid, sodium phosphate, potassium phosphate, sodium acetate, boric acid and the like are preferably used.
As the local anesthetic, 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.
As the pain-relieving agent, procaine hydrochloride or the like can be used.
Examples of the diluent include water, ethyl alcohol, macrogol, propylene glycol and the like.
pH調整剤及び緩衝剤としては、塩酸、クエン酸、クエン酸ナトリウム、酢酸ナトリウム、リン酸ナトリウム、水酸化ナトリウム等が用いられ、安定化剤としてはピロ亜硫酸ナトリウム、エチレンジアミン四酢酸、チオグリコール酸、チオ乳酸等が用いられる。また、緩衝剤としては、クエン酸ナトリウム、リン酸、リン酸ナトリウム、リン酸カリウム、酢酸ナトリウム、ホウ酸などが好適に用いられる。
局所麻酔剤としては塩酸プロカイン、塩酸リドカイン等が、また等張化剤としては塩化ナトリウム、D-マンニトール、D-ソルビトール、ブドウ糖あるいはグリセリン等が使用できる。
無痛化剤としては、塩酸プロカイン等を使用できる。
また、希釈剤としては、例えば水、エチルアルコール、マクロゴール、プロピレングリコール等を挙げることができる。 When the pharmaceutical composition is in the form of an injection, the additives include pH adjusters, buffers, stabilizers, tonicity agents, local anesthetics, painkillers, diluents, surfactants and the like. Can be mentioned.
As the 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. Further, as the buffering agent, sodium citrate, phosphoric acid, sodium phosphate, potassium phosphate, sodium acetate, boric acid and the like are preferably used.
As the local anesthetic, 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.
As the pain-relieving agent, procaine hydrochloride or the like can be used.
Examples of the diluent include water, ethyl alcohol, macrogol, propylene glycol and the like.
医薬組成物が点眼剤の製剤形態である場合、添加剤としては、溶剤、等張化剤、保存剤、粘稠剤、pH調節剤などが挙げられる。
溶剤としては、滅菌精製水、生理食塩水、緩衝液、植物油、プロピレングリコール、流動パラフィン等が挙げられる。等張化剤としては、塩化ナトリウム、ホウ酸、硝酸ナトリウム、硝酸カリウム等が挙げられる。保存剤としては、パラオキシ安息香酸エステル類、塩化ベザルコニウム、クロロブタノール、デヒドロ酢酸ナトリウム、硫酸ポリミキシンB等が挙げられる。粘稠剤としては、メチルセルロース、カルボキシメチルセルロースナトリウム、ヒドロキシプロピルセルロース、ポリビニルアルコール、コンドロイチン硫酸ナトリウム等が挙げられる。pH調節剤としては、酸又は塩基が挙げられ、酸としては、塩酸、リン酸、クエン酸、酢酸等が挙げられ、塩基としては、水酸化ナトリウム、水酸化カリウム、炭酸ナトリウム、炭酸水素ナトリウム等が挙げられる。 When the pharmaceutical composition is in the form of an eye drop, 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.
溶剤としては、滅菌精製水、生理食塩水、緩衝液、植物油、プロピレングリコール、流動パラフィン等が挙げられる。等張化剤としては、塩化ナトリウム、ホウ酸、硝酸ナトリウム、硝酸カリウム等が挙げられる。保存剤としては、パラオキシ安息香酸エステル類、塩化ベザルコニウム、クロロブタノール、デヒドロ酢酸ナトリウム、硫酸ポリミキシンB等が挙げられる。粘稠剤としては、メチルセルロース、カルボキシメチルセルロースナトリウム、ヒドロキシプロピルセルロース、ポリビニルアルコール、コンドロイチン硫酸ナトリウム等が挙げられる。pH調節剤としては、酸又は塩基が挙げられ、酸としては、塩酸、リン酸、クエン酸、酢酸等が挙げられ、塩基としては、水酸化ナトリウム、水酸化カリウム、炭酸ナトリウム、炭酸水素ナトリウム等が挙げられる。 When the pharmaceutical composition is in the form of an eye drop, 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.
医薬組成物が点鼻剤の製剤形態である場合、添加剤としては、可溶化剤、等張化剤、pH調節剤等が挙げられる。懸濁液の点鼻剤においては、有効成分の均一な状態を得るために、必要に応じて分散剤又は安定化剤などを加えてもよい。また、充填容器等に保管する場合、必要に応じて保存剤などを加えてもよい。
When the pharmaceutical composition is in the form of a nasal drop, examples of the additive include a solubilizer, an isotonic agent, a pH adjuster and the like. In the nasal drops of the suspension, a dispersant or a stabilizer may be added as necessary in order to obtain a uniform state of the active ingredient. Further, when storing in a filling container or the like, a preservative or the like may be added as necessary.
<医薬組成物の製造方法>
本発明の医薬組成物は、慣用の調製方法によって製造することができる。例えば、軟膏剤又はクリーム剤は、それぞれの剤形に応じて基剤の原料を混練、乳化又は懸濁せしめて基剤を調製した後、有効成分等を加え、スクリューミキサー等の混合機中で混合することにより製造することができる。 <Manufacturing method of pharmaceutical composition>
The pharmaceutical composition of the present invention can be produced by 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.
本発明の医薬組成物は、慣用の調製方法によって製造することができる。例えば、軟膏剤又はクリーム剤は、それぞれの剤形に応じて基剤の原料を混練、乳化又は懸濁せしめて基剤を調製した後、有効成分等を加え、スクリューミキサー等の混合機中で混合することにより製造することができる。 <Manufacturing method of pharmaceutical composition>
The pharmaceutical composition of the present invention can be produced by 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.
ローション剤は、例えば、精製水に種々の添加剤成分を添加して混合、攪拌した後、有効成分等を加えて混合し、所望に応じて濾過を行なうことにより、製造することができる。
リニメント剤は、例えば、添加剤に有効成分を溶解し、所望により、これに他の成分を加えて混合することにより、製造することができる。 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.
リニメント剤は、例えば、添加剤に有効成分を溶解し、所望により、これに他の成分を加えて混合することにより、製造することができる。 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.
パップ剤は、例えば、有効成分、及び添加剤を混合し、加熱後冷却することにより、製造することができる。
The poultice can be produced, for example, by mixing the active ingredient and the additive, heating and then cooling.
硬膏(プラスター剤)、パッチ剤等は、溶液法や熱圧法などの常法により製造することができる。
ゲル剤には、水性ゲル剤、油性ゲル剤などが含まれる。水性ゲル剤は、有効成分に高分子化合物、その他の添加剤及び精製水を加えて溶解又は懸濁させ、次いで加温及び冷却することにより、又はゲル化剤を加えて架橋させることにより製造することができる。油性ゲル剤は、有効成分に、グリコール類及び高級アルコールなどの液状の油性基剤及びその他の添加剤を加えて混和することにより製造することができる。
スプレー剤は、通常、有効成分の溶液又は懸濁液を調製し、必要に応じて濾過した後、容器に充填することにより製造することができる。 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.
ゲル剤には、水性ゲル剤、油性ゲル剤などが含まれる。水性ゲル剤は、有効成分に高分子化合物、その他の添加剤及び精製水を加えて溶解又は懸濁させ、次いで加温及び冷却することにより、又はゲル化剤を加えて架橋させることにより製造することができる。油性ゲル剤は、有効成分に、グリコール類及び高級アルコールなどの液状の油性基剤及びその他の添加剤を加えて混和することにより製造することができる。
スプレー剤は、通常、有効成分の溶液又は懸濁液を調製し、必要に応じて濾過した後、容器に充填することにより製造することができる。 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.
なお、上述の製造方法における有効成分又は添加剤を混合させる工程において、さらに各種の製剤用添加物等を併せて混合させてもよい。
In addition, in the step of mixing the active ingredient or the additive in the above-mentioned production method, various additives for pharmaceuticals and the like may be further mixed together.
経口医薬組成物は、経口粒剤を製する常法に従って製造することができる。造粒方法としては、押し出し造粒法、攪拌造粒法、転動造粒法、流動層造粒法、解砕造粒法、及び破砕造粒法などの一般的な造粒法を用いることができるが、1)空隙率が高い、2)嵩密度が低い、3)水への分散性が良い、といった特徴のある造粒物を得ることが容易な流動層造粒法を特に好適に用いることができる。
The oral pharmaceutical composition can be produced according to a conventional method for producing oral granules. As the granulation method, 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. However, 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.
また、医薬組成物を用いて、顆粒剤、散剤及び細粒剤といった経口粒剤を製造することもできる。これらの製剤は、直接、経口的に服用することができるほか、水を含む溶媒に用時溶解又は用時懸濁させた状態で用いることができる。用時溶解又は用時懸濁する製剤とは、製品出荷時の形態としては固形であるが、医薬品の開封後から適用までの間に溶解又は懸濁する製剤のことであり、通常は適用の直前に溶解又は懸濁される。
It is also possible to produce 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.
注射剤としての医薬組成物を調製する場合は、常法により、例えば、注射用水、他の水性若しくは非水性の溶剤に、有効成分を溶解、懸濁若しくは乳化させて、静脈内、筋肉内、皮下又は皮内用の注射剤を製造することができる。なお注射剤は、殺菌し、また血液と等張とすることが好ましい。
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.
点眼剤は、有効成分に、必要に応じて上述の添加剤を加え、次いで溶剤に溶解若しくは懸濁させることにより製造できる。
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.
また、液状の点鼻剤を調製する場合は、溶剤に、有効成分及び必要に応じて上述の添加剤を加え、溶解又は懸濁させる。さらに、必要に応じて、上述の添加剤の追加、ろ過等の工程により、液状の点鼻剤を製造する。なお、微粉状の点鼻剤は、有効成分の微細な粒子を、必要に応じて添加剤と混和させ、均質とすることにより製造できる。
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.
<各成分の配合量>
本発明の医薬組成物中の有効成分であるペントサンポリ硫酸及び/又はその塩(ペントサンポリ硫酸ナトリウム等)の含有率は、医薬組成物の全重量を基準として、0.0001~30重量%であることが好ましく、0.001~10重量%であることがより好ましく、0.01~1重量%であることが特に好ましい。
また、上述の添加剤の総含有率は、医薬組成物の全重量を基準として、例えば、70重量%以上、90重量%以上、99重量%以上等である。 <Amount of each ingredient>
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.
本発明の医薬組成物中の有効成分であるペントサンポリ硫酸及び/又はその塩(ペントサンポリ硫酸ナトリウム等)の含有率は、医薬組成物の全重量を基準として、0.0001~30重量%であることが好ましく、0.001~10重量%であることがより好ましく、0.01~1重量%であることが特に好ましい。
また、上述の添加剤の総含有率は、医薬組成物の全重量を基準として、例えば、70重量%以上、90重量%以上、99重量%以上等である。 <Amount of each ingredient>
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.
<医薬組成物の適用>
本発明に係る医薬組成物の用量・頻度は、対象疾患及びその症状の程度、組成物中のペントサンポリ硫酸及び/又はその塩(ペントサンポリ硫酸ナトリウム等)の濃度、患者の年齢・体重等に応じて適宜調節すればよい。例えば、全身投与であれば、ペントサンポリ硫酸として、1日量として50mg~5g、好ましくは100mg~1gを、例えば、1日1~3回投与すればよい。局所投与であれば1cm2あたり0.03μg~30mg、好ましくは0.3μg~3mgを、1日1回又は数回塗布すればよい。 <Application of 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 μg to 30 mg, preferably 0.3 μg to 3 mg per cm 2 may be applied once or several times a day.
本発明に係る医薬組成物の用量・頻度は、対象疾患及びその症状の程度、組成物中のペントサンポリ硫酸及び/又はその塩(ペントサンポリ硫酸ナトリウム等)の濃度、患者の年齢・体重等に応じて適宜調節すればよい。例えば、全身投与であれば、ペントサンポリ硫酸として、1日量として50mg~5g、好ましくは100mg~1gを、例えば、1日1~3回投与すればよい。局所投与であれば1cm2あたり0.03μg~30mg、好ましくは0.3μg~3mgを、1日1回又は数回塗布すればよい。 <Application of 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 μg to 30 mg, preferably 0.3 μg to 3 mg per cm 2 may be applied once or several times a day.
<医薬組成物の適用対象となる疾患>
PDGF-BB/PDGFR-βシグナル、及び/又はAng-1/Tie2シグナルの低下により引き起こされる疾患としては、腫瘍、慢性関節リウマチ、糖尿病、高脂血症、高血圧、肝炎、敗血症、血管性浮腫、全身性強皮症、血管肉腫、血管腫、乾癬、及び疣贅などの血管病変を伴う疾患が挙げられる。
本発明によれば、上述したペントサンポリ硫酸及び/又はその塩を有効成分として含む、血管及び/又はリンパ管の病変を伴う疾患の予防薬及び/又は治療薬の提供が可能となる。
また、加齢によってPDGF-BB/PDGFR-βシグナル、及び/又はAng-1/Tie2シグナルが低下することが知られていることから、上述の医薬組成物は、加齢に基づく疾患の予防薬及び/又は治療薬となることも期待される。 <Disease to which the pharmaceutical composition is applied>
Diseases caused by decreased PDGF-BB / PDGFR-β 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.
INDUSTRIAL APPLICABILITY According to the present invention, it is possible to provide 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.
Further, since it is known that the PDGF-BB / PDGFR-β signal and / or the Ang-1 / Tie2 signal decrease with aging, the above-mentioned pharmaceutical composition is a preventive agent for age-based diseases. And / or it is also expected to be a therapeutic agent.
PDGF-BB/PDGFR-βシグナル、及び/又はAng-1/Tie2シグナルの低下により引き起こされる疾患としては、腫瘍、慢性関節リウマチ、糖尿病、高脂血症、高血圧、肝炎、敗血症、血管性浮腫、全身性強皮症、血管肉腫、血管腫、乾癬、及び疣贅などの血管病変を伴う疾患が挙げられる。
本発明によれば、上述したペントサンポリ硫酸及び/又はその塩を有効成分として含む、血管及び/又はリンパ管の病変を伴う疾患の予防薬及び/又は治療薬の提供が可能となる。
また、加齢によってPDGF-BB/PDGFR-βシグナル、及び/又はAng-1/Tie2シグナルが低下することが知られていることから、上述の医薬組成物は、加齢に基づく疾患の予防薬及び/又は治療薬となることも期待される。 <Disease to which the pharmaceutical composition is applied>
Diseases caused by decreased PDGF-BB / PDGFR-β 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.
INDUSTRIAL APPLICABILITY According to the present invention, it is possible to provide 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.
Further, since it is known that the PDGF-BB / PDGFR-β signal and / or the Ang-1 / Tie2 signal decrease with aging, the above-mentioned pharmaceutical composition is a preventive agent for age-based diseases. And / or it is also expected to be a therapeutic agent.
ペントサンポリ硫酸及び/又はその塩を含む医薬組成物は、上述のように、Ang-1/Tie2シグナルを活性化させ、及び/又はPDGF-BBの産生を増加させることから、血管新生抑制作用、血管の成熟化作用、血管の正常化作用、血管の安定化作用及び/又はリンパ管安定化作用を示し、血管機能及び/又はリンパ管機能を向上させ、血管及び/又はリンパ管の病変を伴うと考えられる以下の疾患の治療又は予防に用いられ得る。すなわち、循環器系疾患;皮膚疾患;内分泌、栄養及び代謝疾患;加齢に基づく疾患;眼疾患;その他の疾患である。
As described above, 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.
循環器系疾患としては、毛細血管漏出症候群、冠動脈疾患、慢性心不全、末梢動脈疾患(アテローム性動脈硬化症、微小血管狭心症、心筋梗塞、脳卒中、くも膜下出血)、高血圧、血管性浮腫、外科手術の副作用又は臓器組織障害に起因する虚血性疾患、リンパ脈管筋腫、リンパ管からのリンパ液漏出による障害、レイノー病等が挙げられる。これらのうち、特に、医薬組成物は、アテローム性動脈硬化症及びくも膜下出血等を含む末梢動脈疾患、血管性浮腫、リンパ脈管筋腫等の治療及び予防に有効であると考えられる。
皮膚疾患としては、酒さ、炎症性疾患(尋常性乾癬、アトピー性皮膚炎、シュニッツラー症候群)、尋常性疣贅、創傷、褥創、凍傷、結節性硬化症、多発性硬化症、全身性強皮症、カポジ肉腫、皮膚血管肉腫、紫斑病、重度のしわ、しみ、むくみ等が挙げられる。これらのうち、特に、医薬組成物は、尋常性乾癬及びシュニッツラー症候群等の炎症性疾患、尋常性疣贅、結節性硬化症、全身性強皮症、カポジ肉腫、皮膚血管肉腫、重度のしわ、むくみ等の治療及び予防に有効であると考えられる。 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. Among these, 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. Among these, in particular, 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.
皮膚疾患としては、酒さ、炎症性疾患(尋常性乾癬、アトピー性皮膚炎、シュニッツラー症候群)、尋常性疣贅、創傷、褥創、凍傷、結節性硬化症、多発性硬化症、全身性強皮症、カポジ肉腫、皮膚血管肉腫、紫斑病、重度のしわ、しみ、むくみ等が挙げられる。これらのうち、特に、医薬組成物は、尋常性乾癬及びシュニッツラー症候群等の炎症性疾患、尋常性疣贅、結節性硬化症、全身性強皮症、カポジ肉腫、皮膚血管肉腫、重度のしわ、むくみ等の治療及び予防に有効であると考えられる。 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. Among these, 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. Among these, in particular, 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.
内分泌、栄養及び代謝疾患としては、糖尿病及び糖尿病に関連する疾患(例えば、網膜症、黄斑浮腫、皮膚潰瘍、創傷、腎症、及び末梢神経障害);高脂血症;痛風等が挙げられる。これらのうち、特に、医薬組成物は、網膜症、黄斑浮腫、皮膚潰瘍、創傷、腎症、末梢神経障害等を含む糖尿病に関連する疾患の治療及び予防に有効であると考えられる。
加齢に基づく疾患としては、脱毛症、骨粗鬆症、皮膚粗鬆症、認知症、光老化、加齢黄斑変性症、アルツハイマー病、血管性認知症、モヤモヤ病等が挙げられる。これらのうち、特に、医薬組成物は、光老化等の治療及び予防に有効であると考えられる。 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. Among these, 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. Of these, the pharmaceutical composition is considered to be particularly effective for the treatment and prevention of photoaging and the like.
加齢に基づく疾患としては、脱毛症、骨粗鬆症、皮膚粗鬆症、認知症、光老化、加齢黄斑変性症、アルツハイマー病、血管性認知症、モヤモヤ病等が挙げられる。これらのうち、特に、医薬組成物は、光老化等の治療及び予防に有効であると考えられる。 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. Among these, 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. Of these, the pharmaceutical composition is considered to be particularly effective for the treatment and prevention of photoaging and the like.
眼疾患としては、加齢黄斑変性症、網膜症(未熟児又は糖尿病に関連する網膜症)、脈絡膜血管新生、網膜静脈閉塞、ブドウ膜炎、未眼虚血等が挙げられる。これらのうち、特に、医薬組成物は、網膜症(未熟児における網膜症、及び糖尿病による網膜症)の治療及び予防に有効であると考えられる。
その他疾患として、腰痛症、腫瘍、急性骨髄性白血病、慢性関節リウマチ、シェーグレン症候群、肝炎、敗血症、腎不全、花粉症などのアレルギー疾患等が挙げられる。また、その他疾患として、薬剤性の紫斑、及び、化学療法に伴う血管障害等も挙げられる。これらのうち、特に、医薬組成物は、腫瘍、急性骨髄性白血病、肝炎、及び敗血症の治療及び予防に有効であると考えられる。 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. Of these, 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. In addition, other diseases include drug-induced purpura and angiopathy associated with chemotherapy. Of these, the pharmaceutical composition is considered to be particularly effective in the treatment and prevention of tumors, acute myeloid leukemia, hepatitis, and sepsis.
その他疾患として、腰痛症、腫瘍、急性骨髄性白血病、慢性関節リウマチ、シェーグレン症候群、肝炎、敗血症、腎不全、花粉症などのアレルギー疾患等が挙げられる。また、その他疾患として、薬剤性の紫斑、及び、化学療法に伴う血管障害等も挙げられる。これらのうち、特に、医薬組成物は、腫瘍、急性骨髄性白血病、肝炎、及び敗血症の治療及び予防に有効であると考えられる。 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. Of these, 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. In addition, other diseases include drug-induced purpura and angiopathy associated with chemotherapy. Of these, the pharmaceutical composition is considered to be particularly effective in the treatment and prevention of tumors, acute myeloid leukemia, hepatitis, and sepsis.
本発明の医薬組成物を用いるのに特に適した疾患として、全身性強皮症、糖尿病に関連する疾患(糖尿病に関連する網膜症、黄斑浮腫、皮膚潰瘍、創傷、末梢神経障害を含む)、網膜症(未熟児における網膜症、及び糖尿病による網膜症を含む)、腫瘍が挙げられる。
Diseases particularly suitable for using the pharmaceutical composition of the present invention include systemic retinopathy, diabetes-related diseases (including diabetes-related retinopathy, luteal edema, skin ulcers, wounds, and peripheral neuropathy). Retinopathy (including retinopathy in premature infants and retinopathy due to diabetes), tumors include.
[化粧品組成物]
本発明の組成物は、化粧品組成物としても有用であり、このような化粧品組成物も、少なくともペントサンポリ硫酸及び/又はその塩を含む。このような化粧品組成物もまた、Ang-1/Tie2シグナルを活性化させ、及び/又はPDGF-BBの産生を増加させることができる。このため、化粧品組成物は、化粧品としての用途に加え、血管及び/又はリンパ管の機能低下に伴う皮膚状態の劣化の改善や、血管病変を伴う疾患の予防等にも用いられ得る。
具体的には、化粧品組成物は、上述の疾患ほど重い症状に用いられるわけではないものの、血管機能及び/又はリンパ管機能の向上による皮膚状態の改善に有用である。改善される皮膚状態としては、例えば、しわ、しみ、むくみ、脱毛症等が挙げられる。化粧品組成物は、上述の有効成分を有しているため薬効を有するものの化粧品としても有用であり、また、医薬部外品(「医薬品、医療機器等の品質、有効性及び安全性の確保等に関する法律」に規定される医薬部外品)を含み得る。 [Cosmetic composition]
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.
Specifically, 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. Examples of the skin condition to be improved include wrinkles, age spots, swelling, alopecia and the like. Since 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.
本発明の組成物は、化粧品組成物としても有用であり、このような化粧品組成物も、少なくともペントサンポリ硫酸及び/又はその塩を含む。このような化粧品組成物もまた、Ang-1/Tie2シグナルを活性化させ、及び/又はPDGF-BBの産生を増加させることができる。このため、化粧品組成物は、化粧品としての用途に加え、血管及び/又はリンパ管の機能低下に伴う皮膚状態の劣化の改善や、血管病変を伴う疾患の予防等にも用いられ得る。
具体的には、化粧品組成物は、上述の疾患ほど重い症状に用いられるわけではないものの、血管機能及び/又はリンパ管機能の向上による皮膚状態の改善に有用である。改善される皮膚状態としては、例えば、しわ、しみ、むくみ、脱毛症等が挙げられる。化粧品組成物は、上述の有効成分を有しているため薬効を有するものの化粧品としても有用であり、また、医薬部外品(「医薬品、医療機器等の品質、有効性及び安全性の確保等に関する法律」に規定される医薬部外品)を含み得る。 [Cosmetic composition]
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.
Specifically, 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. Examples of the skin condition to be improved include wrinkles, age spots, swelling, alopecia and the like. Since 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.
化粧品組成物は、例えば、洗顔料、外皮用の化粧料、化粧水、乳液、クリーム、ジェル、日焼け止め、軟膏、ローション、パック、しわたるみ化粧品、ファンデーション、化粧下地、美容液、美白剤、デオドラント剤、洗浄剤、毛髪用化粧料(養毛料、シャンプー、リンス、ヘアトニック等)、メイクアップ化粧品(口紅、頬紅等)、エアゾール、液剤等として用いられる。
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.
化粧品組成物は、上述の医薬組成物の成分とともに、あるいは、医薬組成物の成分に代えて、以下の添加剤を含み得る。
例えば、界面活性剤(乳化剤)、保湿剤、酸化防止剤、増粘剤、キレート剤、油性成分、樹脂、紫外線吸収剤、乳化剤、界面活性剤、増粘剤、アルコール類、粉末成分、色材、pH調整剤、香料、酸味料、甘味料、調味料、着色料、各種の薬効成分、キレート剤、防腐剤、防湿剤、賦形剤、殺菌剤、消臭剤、血行促進剤、塩類、清涼剤、美白剤、動物又は植物由来抽出物、収斂剤、抗炎症剤、活性酸素消去剤、抗脂漏剤、細胞賦活剤、酵素、ホルモン類、ビタミン類、水性成分、水(好ましくは精製水)等を適宜、化粧品組成物に配合することができる。また、これらの添加剤を単独で、あるいは組み合わせて使用することができる。 The cosmetic composition may contain the following additives together with or in place of the components of the pharmaceutical composition described above.
For example, surfactants (emulsifiers), moisturizers, antioxidants, thickeners, chelating agents, oily ingredients, resins, UV absorbers, emulsifiers, surfactants, thickeners, alcohols, powder ingredients, coloring materials. , 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. In addition, these additives can be used alone or in combination.
例えば、界面活性剤(乳化剤)、保湿剤、酸化防止剤、増粘剤、キレート剤、油性成分、樹脂、紫外線吸収剤、乳化剤、界面活性剤、増粘剤、アルコール類、粉末成分、色材、pH調整剤、香料、酸味料、甘味料、調味料、着色料、各種の薬効成分、キレート剤、防腐剤、防湿剤、賦形剤、殺菌剤、消臭剤、血行促進剤、塩類、清涼剤、美白剤、動物又は植物由来抽出物、収斂剤、抗炎症剤、活性酸素消去剤、抗脂漏剤、細胞賦活剤、酵素、ホルモン類、ビタミン類、水性成分、水(好ましくは精製水)等を適宜、化粧品組成物に配合することができる。また、これらの添加剤を単独で、あるいは組み合わせて使用することができる。 The cosmetic composition may contain the following additives together with or in place of the components of the pharmaceutical composition described above.
For example, surfactants (emulsifiers), moisturizers, antioxidants, thickeners, chelating agents, oily ingredients, resins, UV absorbers, emulsifiers, surfactants, thickeners, alcohols, powder ingredients, coloring materials. , 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. In addition, these additives can be used alone or in combination.
本発明の化粧品組成物中のペントサンポリ硫酸及び/又はその塩の含有率は、組成物の全重量を基準として、0.0001~30重量%であることが好ましく、0.001~10重量%であることがより好ましく、0.01~1重量%であることが特に好ましい。
また、上述の添加剤の総含有率は、化粧品組成物の全重量を基準として、例えば、70重量%以上、90重量%以上、99重量%以上等である。 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.
また、上述の添加剤の総含有率は、化粧品組成物の全重量を基準として、例えば、70重量%以上、90重量%以上、99重量%以上等である。 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.
なお、化粧品組成物の成分、すなわち、有効成分と添加剤の種類、剤形、用法、用量、用途等は、医薬組成物と共通し得る。よって、医薬組成物に関する上述の成分、剤形、用法、用量、用途等を化粧品組成物に適用することもできる。
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.
以下、本発明の実施例を示して本発明を具体的に説明するが、本発明は下記の実施例に制限されるものではない。
Hereinafter, the present invention will be specifically described with reference to examples of the present invention, but the present invention is not limited to the following examples.
ペントサンポリ硫酸の塩として、Molclone Labs社製のペントサンポリ硫酸ナトリウム(重量平均分子量4000~6500、硫黄含量13.0~20.0%w/w、グルクロン酸含量2.5~4.0%w/w)を使用した。
比較用の対照物質としては、ヒアルロン酸(略称:HA、東京化成工業株式会社)、コンドロイチン硫酸(略称:Chs、有機硫酸基:15~17%w/w、マルホ株式会社)及びキシロヘキサオース(略称:O-XHE、Megazyme社)を用いた。 As a salt of pentosanpolysulfate, sodium pentosanpolysulfate manufactured by Mollclone Labs (weight averagemolecular 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.
As control substances for comparison, hyaluronic acid (abbreviation: HA, Tokyo Kasei Kogyo Co., Ltd.), chondroitin sulfate (abbreviation: Chs, organic sulfate group: 15 to 17% w / w, Maruho Co., Ltd.) and xylohexaose (abbreviation: Malho Co., Ltd.) Abbreviation: O-XHE, Megazyme) was used.
比較用の対照物質としては、ヒアルロン酸(略称:HA、東京化成工業株式会社)、コンドロイチン硫酸(略称:Chs、有機硫酸基:15~17%w/w、マルホ株式会社)及びキシロヘキサオース(略称:O-XHE、Megazyme社)を用いた。 As a salt of pentosanpolysulfate, sodium pentosanpolysulfate manufactured by Mollclone Labs (weight average
As control substances for comparison, hyaluronic acid (abbreviation: HA, Tokyo Kasei Kogyo Co., Ltd.), chondroitin sulfate (abbreviation: Chs, organic sulfate group: 15 to 17% w / w, Maruho Co., Ltd.) and xylohexaose (abbreviation: Malho Co., Ltd.) Abbreviation: O-XHE, Megazyme) was used.
[実施例1]
ヒト胎盤由来壁細胞からのAng-1産生に対するPPSの作用
ヒト胎盤由来壁細胞(PromoCell)(1×105細胞)を培地(Pericyte Growth Medium+Pericyte Growth Medium Supplement Mix (PromoCell))に播種して37℃、5%CO2、95%airで4日間培養後、この培地を、各濃度のPPS、HA、Chs又はO-XHE含有培地(Pericyte Growth medium)に交換して、37℃、5%CO2、95%airでさらに48時間培養した。培養終了後、培養上清中のAng-1濃度をELISAキット(Human Angiopoietin-1 Quantikine ELISA Kit (R&D Systems))により測定した。各評価物質添加群及び溶媒群は3例(n=3)とした。 [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. After completion of the culture, the Ang-1 concentration in the culture supernatant was measured by an ELISA kit (Human Angiopoietin-1 Quantikine ELISA Kit (R & D Systems)). The group to which each evaluation substance was added and the solvent group were 3 cases (n = 3).
ヒト胎盤由来壁細胞からのAng-1産生に対するPPSの作用
ヒト胎盤由来壁細胞(PromoCell)(1×105細胞)を培地(Pericyte Growth Medium+Pericyte Growth Medium Supplement Mix (PromoCell))に播種して37℃、5%CO2、95%airで4日間培養後、この培地を、各濃度のPPS、HA、Chs又はO-XHE含有培地(Pericyte Growth medium)に交換して、37℃、5%CO2、95%airでさらに48時間培養した。培養終了後、培養上清中のAng-1濃度をELISAキット(Human Angiopoietin-1 Quantikine ELISA Kit (R&D Systems))により測定した。各評価物質添加群及び溶媒群は3例(n=3)とした。 [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. After completion of the culture, the Ang-1 concentration in the culture supernatant was measured by an ELISA kit (Human Angiopoietin-1 Quantikine ELISA Kit (R & D Systems)). The group to which each evaluation substance was added and the solvent group were 3 cases (n = 3).
Ang-1産生に対するPPS、HA、Chs及びO-XHEの作用を図1に示す。図中の*は溶媒群(薬物非存在下:図1における(-)参照)に対する有意差を示す(P<0.05)。図1の結果から、PPS100μg/mLの濃度で、溶媒群と比較して、Ang-1量に有意な増加が認められた。
一方、HA、Chs及びO-XHE群のAng-1量は、溶媒群と比較して有意な差は認められなかった。 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 μg / 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.
一方、HA、Chs及びO-XHE群のAng-1量は、溶媒群と比較して有意な差は認められなかった。 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 μg / 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.
[実施例2]
ヒト皮膚微小血管内皮細胞からのAng―2産生に対するPPSの作用
ヒト皮膚微小血管内皮細胞(PromoCell)(1×105細胞)を培地(Endothelial Cell Growth Medium MV2+Endothelial Cell Growth Medium MV2 Supplement Mix (PromoCell))に播種して37℃、5%CO2、95%airで4日間培養後、この培地を、各濃度のPPS、HA、Chs又はO-XHE含有培地(Endothelial Cell Growth Medium MV2+Endothelial Cell Growth Medium MV2 Supplement Mix (PromoCell))に交換して、37℃、5%CO2、95%airでさらに48時間培養した。培養終了後、培養上清中のAng―2濃度をELISAキット(Human Angiopoietin-2 Quantikine ELISA Kit (R&D Systems))により測定した。各評価物質添加群及び溶媒群は3例(n=3)とした。 [Example 2]
Effect of PPS on Ang-2 production from human skin microvascular endothelial cells Medium for 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). The cells were replaced with Mix (PromoCell)) and cultured at 37 ° C., 5% CO 2 , 95% air for an additional 48 hours. After completion of the culture, the Ang-2 concentration in the culture supernatant was measured by an ELISA kit (Human Angiopoietin-2 Quantikine ELISA Kit (R & D Systems)). The group to which each evaluation substance was added and the solvent group were 3 cases (n = 3).
ヒト皮膚微小血管内皮細胞からのAng―2産生に対するPPSの作用
ヒト皮膚微小血管内皮細胞(PromoCell)(1×105細胞)を培地(Endothelial Cell Growth Medium MV2+Endothelial Cell Growth Medium MV2 Supplement Mix (PromoCell))に播種して37℃、5%CO2、95%airで4日間培養後、この培地を、各濃度のPPS、HA、Chs又はO-XHE含有培地(Endothelial Cell Growth Medium MV2+Endothelial Cell Growth Medium MV2 Supplement Mix (PromoCell))に交換して、37℃、5%CO2、95%airでさらに48時間培養した。培養終了後、培養上清中のAng―2濃度をELISAキット(Human Angiopoietin-2 Quantikine ELISA Kit (R&D Systems))により測定した。各評価物質添加群及び溶媒群は3例(n=3)とした。 [Example 2]
Effect of PPS on Ang-2 production from human skin microvascular endothelial cells Medium for 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). The cells were replaced with Mix (PromoCell)) and cultured at 37 ° C., 5% CO 2 , 95% air for an additional 48 hours. After completion of the culture, the Ang-2 concentration in the culture supernatant was measured by an ELISA kit (Human Angiopoietin-2 Quantikine ELISA Kit (R & D Systems)). The group to which each evaluation substance was added and the solvent group were 3 cases (n = 3).
Ang―2産生に対するPPS、HA、Chs及びO-XHEの作用を図2に示す。図中の**は溶媒群(薬物非存在下:図2における(-)参照)に対する有意差を示す(P<0.01)。図2の結果から、PPS10μg/mL以上の濃度で、溶媒群と比較して、Ang―2量に有意な減少が認められた。
一方、HA、Chs及びO-XHE群のAng―2量は、溶媒群と比較して有意な差は認められなかった。 The effects of PPS, HA, Chs and O-XHE on Ang-2 production are shown in FIG. ** in the figure indicates a significant difference from the solvent group (in the absence of drug: see (-) in FIG. 2) (P <0.01). From the results shown in FIG. 2, a significant decrease in the amount of Ang-2 was observed at a concentration of PPS of 10 μg / mL or more as compared with the solvent group.
On the other hand, the amount of Ang-2 in the HA, Chs and O-XHE groups was not significantly different from that in the solvent group.
一方、HA、Chs及びO-XHE群のAng―2量は、溶媒群と比較して有意な差は認められなかった。 The effects of PPS, HA, Chs and O-XHE on Ang-2 production are shown in FIG. ** in the figure indicates a significant difference from the solvent group (in the absence of drug: see (-) in FIG. 2) (P <0.01). From the results shown in FIG. 2, a significant decrease in the amount of Ang-2 was observed at a concentration of PPS of 10 μg / mL or more as compared with the solvent group.
On the other hand, the amount of Ang-2 in the HA, Chs and O-XHE groups was not significantly different from that in the solvent group.
[実施例3]
ヒト皮膚微小血管内皮細胞のTie2リン酸化に対するPPSの作用
ヒト皮膚微小血管内皮細胞(PromoCell)(1×106細胞)を培地(Endothelial Cell Growth Medium MV2+Endothelial Cell Growth Medium MV2 Supplement Mix (PromoCell))に播種して37℃、5%CO2、95%airで2日間培養後、血清を除いた培地(Endothelial Cell Growth Medium MV2)に細胞を移して、37℃、5%CO2、95%airで3時間培養した。その後、この培地を、各濃度のPPS含有培地(Endothelial Cell Growth Medium MV2)に交換して、37℃、5%CO2、95%airでさらに10分間培養した。
培養終了後、冷TBS(Tris-Buffered Saline)で洗浄し、ホスファターゼ阻害剤(Thermo scientific)を含んだRIPA Buffer(Radio Immunoprecipitation Assay Buffer)を添加し、細胞を超音波破砕した。各タンパク質濃度を一定にした後Sample bufferを加えて、5-20%のポリアクリルアミドゲルを用いて、100Vで60分間SDS-PAGEを行った。Transfer-Blot Turbo Transfer Pack(BIO-RAD)を用いてPVDF膜へ転写後、Blocking One-Pにより20分間、ブロッキングを行った。その後一次抗体液(Anti-phospho-Tie-2(Tyr922)Antibody (Cell signaling))を加え、4℃で一晩静置した。次いで、二次抗体液(Anti-rabbit IgG HRP-linked Antibody (Cell Signaling、#7074S))を加え、室温で1時間静置した。化学発光検出(Thermo scientific)により、タンパク質のバンドを検出した。 [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. Then, 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.
After completion of the culture, 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. After transfer to the PVDF membrane using Transfer-Blot Turbo Transfer Pack (BIO-RAD), blocking was performed for 20 minutes by Blocking One-P. Then, a primary antibody solution (Anti-phospho-Tie-2 (Tyr922) Antibody (Cell signaling)) was added, and the mixture was allowed to stand overnight at 4 ° C. Then, a secondary antibody solution (Anti-rabbit IgG HRP-linked Antibody (Cell Signaling, # 7074S)) was added, and the mixture was allowed to stand at room temperature for 1 hour. Protein bands were detected by chemiluminescence detection (Thermo scientific).
ヒト皮膚微小血管内皮細胞のTie2リン酸化に対するPPSの作用
ヒト皮膚微小血管内皮細胞(PromoCell)(1×106細胞)を培地(Endothelial Cell Growth Medium MV2+Endothelial Cell Growth Medium MV2 Supplement Mix (PromoCell))に播種して37℃、5%CO2、95%airで2日間培養後、血清を除いた培地(Endothelial Cell Growth Medium MV2)に細胞を移して、37℃、5%CO2、95%airで3時間培養した。その後、この培地を、各濃度のPPS含有培地(Endothelial Cell Growth Medium MV2)に交換して、37℃、5%CO2、95%airでさらに10分間培養した。
培養終了後、冷TBS(Tris-Buffered Saline)で洗浄し、ホスファターゼ阻害剤(Thermo scientific)を含んだRIPA Buffer(Radio Immunoprecipitation Assay Buffer)を添加し、細胞を超音波破砕した。各タンパク質濃度を一定にした後Sample bufferを加えて、5-20%のポリアクリルアミドゲルを用いて、100Vで60分間SDS-PAGEを行った。Transfer-Blot Turbo Transfer Pack(BIO-RAD)を用いてPVDF膜へ転写後、Blocking One-Pにより20分間、ブロッキングを行った。その後一次抗体液(Anti-phospho-Tie-2(Tyr922)Antibody (Cell signaling))を加え、4℃で一晩静置した。次いで、二次抗体液(Anti-rabbit IgG HRP-linked Antibody (Cell Signaling、#7074S))を加え、室温で1時間静置した。化学発光検出(Thermo scientific)により、タンパク質のバンドを検出した。 [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
After completion of the culture, 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. After transfer to the PVDF membrane using Transfer-Blot Turbo Transfer Pack (BIO-RAD), blocking was performed for 20 minutes by Blocking One-P. Then, a primary antibody solution (Anti-phospho-Tie-2 (Tyr922) Antibody (Cell signaling)) was added, and the mixture was allowed to stand overnight at 4 ° C. Then, a secondary antibody solution (Anti-rabbit IgG HRP-linked Antibody (Cell Signaling, # 7074S)) was added, and the mixture was allowed to stand at room temperature for 1 hour. Protein bands were detected by chemiluminescence detection (Thermo scientific).
Tie2リン酸に対するPPSの作用を図3に示す。検出されたバンドの濃さは、リン酸化Tie2(P-tie2)のタンパク質量に比例している。図3の結果から、いずれの濃度においても、PPS群のTie2リン酸化は、溶媒群(薬物非存在下:図3における(-)参照)と比較して、顕著に増加した。
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).
[実施例4]
ヒト皮膚微小血管内皮細胞からのPDGF-BB産生に対するPPSの作用
ヒト皮膚微小血管内皮細胞(PromoCell)(1×105細胞)を培地(Endothelial Cell Growth Medium MV2+Endothelial Cell Growth Medium MV2 Supplement Mix (PromoCell))に播種して37℃、5%CO2、95%airで4日間培養後、この培地を、各濃度のPPS、HA、Chs又はO-XHE含有培地(Endothelial Cell Growth Medium MV2+Endothelial Cell Growth Medium MV2 Supplement Mix (PromoCell))に交換して、37℃、5%CO2、95%airでさらに48時間培養した。培養終了後、培養上清中のPDGF-BB濃度をBio-Plexキット(ヒトサイトカインアッセイキット(BIO-RAD))により測定した。各評価物質添加群及び溶媒群は3例(n=3)とした。 [Example 4]
Effect of PPS on PDGF-BB production from human skin microvascular endothelial cells Medium 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). The cells were replaced with Mix (PromoCell)) and cultured at 37 ° C., 5% CO 2 , 95% air for an additional 48 hours. After completion of the culture, the PDGF-BB concentration in the culture supernatant was measured by the Bio-Plex kit (Human Cytokine Assay Kit (BIO-RAD)). Each evaluation substance addition group and solvent group were set to 3 cases (n = 3).
ヒト皮膚微小血管内皮細胞からのPDGF-BB産生に対するPPSの作用
ヒト皮膚微小血管内皮細胞(PromoCell)(1×105細胞)を培地(Endothelial Cell Growth Medium MV2+Endothelial Cell Growth Medium MV2 Supplement Mix (PromoCell))に播種して37℃、5%CO2、95%airで4日間培養後、この培地を、各濃度のPPS、HA、Chs又はO-XHE含有培地(Endothelial Cell Growth Medium MV2+Endothelial Cell Growth Medium MV2 Supplement Mix (PromoCell))に交換して、37℃、5%CO2、95%airでさらに48時間培養した。培養終了後、培養上清中のPDGF-BB濃度をBio-Plexキット(ヒトサイトカインアッセイキット(BIO-RAD))により測定した。各評価物質添加群及び溶媒群は3例(n=3)とした。 [Example 4]
Effect of PPS on PDGF-BB production from human skin microvascular endothelial cells Medium 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). The cells were replaced with Mix (PromoCell)) and cultured at 37 ° C., 5% CO 2 , 95% air for an additional 48 hours. After completion of the culture, the PDGF-BB concentration in the culture supernatant was measured by the Bio-Plex kit (Human Cytokine Assay Kit (BIO-RAD)). Each evaluation substance addition group and solvent group were set to 3 cases (n = 3).
PDGF-BB産生に対するPPS、HA、Chs及びO-XHEの作用を図4に示す。図中の*、**は溶媒群(薬物非存在下:図4における(-)参照)に対する有意差を示す(*P<0.05、**P<0.01)。図4の結果から、PPS群のPDGF-BB量は濃度依存的に増加し、10μg/mL以上の濃度で、溶媒群と比較して有意な差が認められた。
一方、HA、Chs群、及びO-XHE群のPDGF-BB量は、溶媒群と比較して有意な増加は認められなかった。 The effects of PPS, HA, Chs and O-XHE on PDGF-BB production are shown in FIG. * And ** in the figure indicate a significant difference from the solvent group (in the absence of drug: see (-) in FIG. 4) (* P <0.05, ** P <0.01). From the results shown in FIG. 4, the amount of PDGF-BB in the PPS group increased in a concentration-dependent manner, and a significant difference was observed at a concentration of 10 μg / mL or more as compared with the solvent group.
On the other hand, the amount of PDGF-BB in the HA, Chs group, and O-XHE group did not increase significantly as compared with the solvent group.
一方、HA、Chs群、及びO-XHE群のPDGF-BB量は、溶媒群と比較して有意な増加は認められなかった。 The effects of PPS, HA, Chs and O-XHE on PDGF-BB production are shown in FIG. * And ** in the figure indicate a significant difference from the solvent group (in the absence of drug: see (-) in FIG. 4) (* P <0.05, ** P <0.01). From the results shown in FIG. 4, the amount of PDGF-BB in the PPS group increased in a concentration-dependent manner, and a significant difference was observed at a concentration of 10 μg / mL or more as compared with the solvent group.
On the other hand, the amount of PDGF-BB in the HA, Chs group, and O-XHE group did not increase significantly as compared with the solvent group.
Claims (6)
- ペントサンポリ硫酸及び/又はその塩を含む組成物であって、血管病変もしくはリンパ管病変の少なくとも1つを伴う疾患の治療及び/又は予防のため、又は、血管機能もしくはリンパ管機能の少なくとも1つの向上による皮膚状態の改善のための組成物。 A composition comprising pentosanpolysulfate and / or a salt thereof for the treatment and / or prevention of a disease associated with at least one of vascular or lymphatic lesions, or at least one of vascular or lymphatic function. A composition for improving skin condition by improving.
- 前記ペントサンポリ硫酸及び/又はその塩が、ペントサンポリ硫酸ナトリウムである、請求項1に記載の組成物。 The composition according to claim 1, wherein the pentosan polysulfate and / or a salt thereof is sodium pentosan polysulfate.
- 前記ペントサンポリ硫酸及び/又はその塩の重量平均分子量が、1,000~30,000である、請求項1又は2に記載の組成物。 The composition according to claim 1 or 2, wherein the pentosan polysulfuric acid and / or a salt thereof has a weight average molecular weight of 1,000 to 30,000.
- Tie2活性化剤、PDGF-BB産生促進剤、血管正常化剤、血管安定化剤、及び/又は、リンパ管安定化剤である、請求項1~3のいずれか1項に記載の組成物。 The composition according to any one of claims 1 to 3, 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.
- 前記組成物が医薬組成物であり、前記血管病変を伴う疾患が、アテローム性動脈硬化症及びくも膜下出血を含む末梢動脈疾患、血管性浮腫、リンパ脈管筋腫、尋常性乾癬及びシュニッツラー症候群を含む炎症性疾患、尋常性疣贅、結節性硬化症、全身性強皮症、カポジ肉腫、皮膚血管肉腫、しわ、むくみ、網膜症、黄斑浮腫、皮膚潰瘍、創傷、腎症、末梢神経障害、糖尿病、光老化、未熟児における及び糖尿病による網膜症、腫瘍、急性骨髄性白血病、肝炎、及び、敗血症からなる群より選択される少なくとも1つの疾患である、請求項1~3のいずれか1項に記載の組成物。 The composition is a pharmaceutical composition, and the diseases associated with the vascular lesions include peripheral arterial diseases including atherosclerosis and submucosal hemorrhage, vascular edema, lymphovascular myoma, psoriasis vulgaris and Schnitzler syndrome. Inflammatory diseases, vulgaris vulgaris, nodular sclerosis, systemic sclerosis, Kaposi sarcoma, cutaneous angiosarcoma, wrinkles, swelling, retinopathy, luteal edema, skin ulcers, wounds, nephropathy, peripheral neuropathy, diabetes , Photoaging, in premature infants and at least one disease selected from the group consisting of retinopathy due to diabetes, tumors, acute myeloid leukemia, hepatitis, and edema, according to any one of claims 1 to 3. The composition described.
- 前記組成物が化粧品組成物であり、前記皮膚状態の改善が、しわ、しみ、むくみ、及び、脱毛症からなる群より選択される少なくとも1つの状態の改善である、請求項1~3のいずれか1項に記載の組成物。 3. The composition according to item 1.
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WO2024050599A1 (en) * | 2022-09-06 | 2024-03-14 | Paradigm Biopharmaceuticals Ltd | Treatment of psoriasis, psoriatic arthritis and dermatitis |
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