Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/02—Inorganic compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents

Definitions

• the present invention relates to biocompatible materials.
• cancer treatment affects the mucous membrane of the mouth and mouth ulcer is likely to occur.
• anti-cancer drug treatment when a drug that easily causes mouth ulcer is administered, and in radiation therapy for head and neck cancer (cancer in the range from head to neck), when radiation directly hits the mucous membrane of the mouth. Mouth ulcer is inevitable. The pain of mouth ulcer is so strong that it is impossible to eat by mouth.
• a patch to be applied directly to the affected area for example, Afterseal (R) 25 ⁇ g, manufactured by Taisho Tomiyama Pharmaceutical Co., Ltd .; active ingredient triamcinolone acetonide), an ointment to be applied to the affected area (for example, dexartin oral ointment, Nippon Kayaku Co., Ltd .; active ingredient dexamethasone) and a spray agent sprayed on the affected area (for example, 50 ⁇ g for external use of Salcote (R) capsule, Teijin Pharma Co., Ltd .; active ingredient beclomethasone propionate) and the like.
• R Afterseal
• an ointment to be applied to the affected area for example, dexartin oral ointment, Nippon Kayaku Co., Ltd .; active ingredient dexamethasone
• a spray agent sprayed on the affected area for example, 50 ⁇ g for external use of Salcote (R) capsule, Teijin Pharma Co
• these therapeutic agents contain steroids, which are immunosuppressive agents, as active ingredients, and are not desirable for cancer patients.
• the patch attached to the affected area may come off, or the ointment or spray applied to the affected area may be lost, and the pain of mouth ulcer cannot be suppressed.
• a biocompatible material capable of suppressing such pain of mouth ulcer is desired.
• Patent Document 1 states that "one or more selected from the group consisting of compounds having a fatty acid having 18 carbon atoms in the molecule among monofatty acid polyethylene glycol and trifatty acid polyoxyethylene sorbitan, and glycyrrhetinic acid and its derivatives.
• a composition for external use which comprises one or more selected from the above group. ”(Claim 1).
• Patent Document 2 describes "an oral adhesive film preparation containing at least one selected from a carboxyvinyl polymer and tragant gum, xanthan gum, gellan gum, carrageenan and sodium alginate.” Claim 1).
• Patent Document 1 has scratch resistance (residuality on the mucous membrane when friction is applied) and retention (adhesion to the mucous membrane in a moist environment) when applied to the oral mucosa and moistened. Gender) was not enough.
• an object of the present invention is to provide a biocompatible material capable of forming a gel having excellent scratch resistance and retention.
• the oil-based substrate contains a gelled hydrocarbon.
• the value of the mass ratio of the content of alginate to the content of the oil-based base material is 0.20 or more and less than 0.35. ..
• At least one selected from the group consisting of sugar alcohols and sugars is at least one selected from the group consisting of xylitol, glucose, erythritol, mannitol, sorbitol, galactose, sucrose, trehalose, and lactose. , (18).
• the range represented by using “-” shall include both ends of “-”.
• the range represented by “A to B” includes A and B.
• the biocompatible material of the present invention contains alginate having a weight average molecular weight of 1 million or more, a predetermined polyvalent metal compound, a carboxyvinyl polymer, and an oil-based substrate, and is substantially free of water.
• the biocompatible material means a material that adheres well to the surface of a living body (for example, skin, mucous membrane (for example, mucous membrane in the oral cavity), eyes, teeth, radula, nails, and hair). Further, as will be described later, since the biocompatible material of the present invention absorbs water to form a crosslinked structure, the gel formed from the biocompatible material of the present invention is stronger against the surface of the living body. Can adhere.
• the biocompatible material of the present invention does not adversely affect the living body and is well compatible with the living body.
• the surface of the living body may be in a healthy state or may have a wound or an ulcer.
• the biocompatible material of the present invention can form a crosslinked structure when in contact with water.
• water those existing on the surface of the living body (for example, the surface in the oral cavity) may be used, or water may be added for the purpose of promoting adhesion.
• the adhesion of the formed gel to the biological surface is determined by the biocompatibility of the biocompatible material before forming the crosslinked structure. It becomes stronger than the adhesiveness to the surface.
• the gel formed from the biocompatible material of the present invention preferably has a function of protecting the biological surface, which is the surface to be adhered, from external stimuli.
• the gel formed from the biocompatible material of the present invention has a certain level of physical strength or higher. Further, the gel formed from the biocompatible material of the present invention may have lubricity on the surface of the non-adhesive surface.
• the living body includes humans or animals other than humans (for example, mammals). Non-human animals include, for example, primates, rodents (mouses and rats, etc.), rabbits, dogs, cats, pigs, cows, sheep, and horses. The fact that at least one of scratch resistance and retention is excellent is hereinafter referred to as the effect of the present invention being more excellent.
• the biocompatible material of the present invention contains alginate having a weight average molecular weight of 1 million or more.
• the weight average molecular weight of alginate is 1 million or more. Among them, 2 million or more is preferable, 3 million or more is more preferable, 3.5 million or more is further preferable, and 4 million or more is particularly preferable, in that the effect of the present invention is more excellent. When the weight average molecular weight of alginate is 4 million or more, the scratch resistance becomes more excellent.
• the weight average molecular weight of the alginate is less than 1 million, the scratch resistance of the gel is not sufficient and the residual property on the mucous membrane is low.
• the upper limit of the weight average molecular weight of alginate is not particularly limited, but is preferably 10 million or less, more preferably 5 million or less, still more preferably 4.5 million or less.
• the weight average molecular weight of alginate can be measured using gel permeation chromatography (GPC).
• GPC measurement conditions for measuring the weight average molecular weight of alginate are described below.
• GPC measurement conditions Column: TSKgel G6000 + G4000 + G2500 PWXL Eluent: 0.2 mol / L Sodium nitrate Flow rate: 0.7 mL / min Injection volume: 50 ⁇ L Sample concentration: 0.1% Analysis time: 60 minutes Detection: RI (Refractive Index)
• the alginate may be in the form of particles.
• the average particle size of the alginate particles is not particularly limited, but is preferably 50 ⁇ m or more and less than 300 ⁇ m, and more preferably 110 ⁇ m or more and less than 200 ⁇ m. When the average particle size of alginate is 110 ⁇ m or more and less than 200 ⁇ m, the scratch resistance becomes more excellent.
• the average particle size of the alginate particles is the average particle size measured using a wet / dry particle size distribution measuring device (LS13320, manufactured by Beckman Coulter).
• the alginate is not particularly limited as long as it is a salt of alginic acid, but a monovalent metal salt of alginic acid or an ammonium salt is preferable, and at least one selected from the group consisting of sodium alginate, potassium alginate, and ammonium alginate is selected. More preferred, sodium alginate is even more preferred.
• the content of alginate in the biocompatible material of the present invention is not particularly limited, but is preferably 5.0% by mass to 35.0% by mass with respect to the total mass of the biocompatible material of the present invention. More preferably, it is 0.0% by mass to 30.0% by mass.
• the content of alginate is 10.0% by mass to 30.0% by mass with respect to the total mass of the biocompatible material of the present invention, the scratch resistance when the biocompatible material is gelled is more excellent. It will be.
• Alginate may be used alone or in combination of two or more.
• the biocompatible material of the present invention contains certain polyvalent metal compounds.
• the polyvalent metal compound is at least one selected from the group consisting of calcium compounds, iron compounds, and magnesium compounds. Among them, the calcium compound is preferable as the polyvalent metal compound in that when the biocompatible material is applied to the oral cavity, there is no taste such as bitterness and acidity derived from the metal compound and the palatability is excellent.
• the multivalent metal compound is a calcium compound, the retention of the biocompatible material when gelled is more excellent, and the preference of the biocompatible material is also excellent.
• the polyvalent metal compound means a compound containing a polyvalent metal.
• the polyvalent metal compound is preferably a water-soluble polyvalent metal compound (a compound that dissolves in water and dissociates polyvalent metal ions), and more preferably a polyvalent metal salt.
• the polyvalent metal salt may be an inorganic salt or an organic salt. Further, it may be a hydrate or may be composed of two or more kinds of metal species.
• the polyvalent metal compound examples include water-soluble metal oxides, inorganic salts, and organic salts.
• inorganic salts such as hydrochlorides, carbonates, hydrobromates, sulfates, hydroiodates, nitrates, hydroxides, and phosphates; lactates, citrates, Succinate, acetate, formate, propionate, benzoate, trifluoroacetate, maleate, salicylate, ascorbate, tartrate, glycerate, gluconate, methanesulfonate, Benzene sulfonates and organic acid salts such as sulfonates; organic base salts such as triethylammonium salt, triethanolammonium salt, pyridinium salt and diisopropylammonium salt; arginine salt, asparagate and glutamate And other amino acid salts.
• the polyvalent metal compound is preferably a hydrochloride or a lactate in that
• Examples of calcium compounds include calcium chloride, calcium lactate, calcium carbonate, calcium oxide, calcium nitrite, calcium nitrate, calcium hydroxide, calcium hypophosphite, calcium L-aspartate, calcium gluconate, calcium polystyrene sulfonate, and benzoate.
• Calcium acid, calcium salicylate, calcium phthalate, calcium maleate, calcium acetate, calcium propionate, calcium citrate, calcium glycerate, calcium tartrate, calcium phytate, and calcium ascorbate can be mentioned.
• the calcium compound is preferably calcium chloride or calcium lactate, and more preferably calcium chloride, in that the effect of the present invention is more excellent.
• iron compounds include iron chloride, iron citrate, iron sulfite, iron sulfate, iron gluconate, iron hypochlorite, iron chlorite, iron sulfate, iron thiosulfate, iron selenate, iron nitrite, and the like.
• iron nitrate, iron carbonate, and iron hydroxide examples include iron nitrate, iron carbonate, and iron hydroxide.
• the iron compound may be monovalent to trivalent iron. Among them, iron (II) chloride is preferable as the iron compound in that the effect of the present invention is more excellent.
• magnesium compounds include magnesium chloride, magnesium carbonate, magnesium sulfate, magnesium nitrate, magnesium silicate, magnesium hydroxide, magnesium citrate, magnesium benzoate, magnesium salicylate, magnesium phthalate, magnesium acetate, magnesium propionate, and water.
• magnesium oxide, magnesium aluminometasilicate, and magnesium aluminomerate silicate examples include magnesium chloride or magnesium lactate is preferable, and magnesium chloride is more preferable, as the magnesium compound, in that the effect of the present invention is more excellent.
• the content of the polyvalent metal compound is preferably 0.1% by mass to 5.0% by mass, preferably 1.0% by mass or more, based on the total mass of the biocompatible material, in that the effect of the present invention is more excellent. 4.5% by mass is more preferable.
• the content of the polyvalent metal compound is 1.0% by mass to 4.5% by mass with respect to the total mass of the biocompatible material of the present invention, the retention property when the biocompatible material is gelled. Becomes better.
• polyvalent metal compound one type may be used alone, or two or more types may be used in combination.
• the biocompatible material of the present invention comprises a carboxyvinyl polymer.
• the carboxyvinyl polymer is a water-soluble vinyl polymer having a carboxy group, and specifically, a polymer having a crosslinked structure with acrylic acid and / or methacrylic acid as a main chain.
• Examples of the crosslinked structure include a crosslinked structure with allyl sucrose, allyl ether of pentaerythritol, and the like.
• the biocompatible material of the present invention gels when contacted with water, but has a network of alginate gels formed by cross-linking alginate with metal ions dissociated from a predetermined polyvalent metal compound, and a carboxyvinyl polymer. Excellent scratch resistance and retention due to the network of.
• the viscosity of the carboxyvinyl polymer is preferably 20000 cP or less, more preferably 2000 cP to 20000 cP, in a 0.5 mass% aqueous solution (25 ° C.) adjusted to pH 7.5, in that the effect of the present invention is more excellent.
• the viscosity of the 0.5 mass% aqueous solution (25 ° C.) of the carboxyvinyl polymer at pH 7.5 is 20000 cP or less, the scratch resistance and retention when the biocompatible material is gelled are more excellent. Become.
• the viscosity of the carboxyvinyl polymer is 0.5% by mass of the carboxyvinyl polymer, and an aqueous solution adjusted to pH 7.5 is used in a rheometer (MCR301, manufactured by Anton Pearl Co., Ltd.) with shear rate 1 (1 / s) and GAP 0. It is a value measured at 0.05 mm and a temperature of 25 ° C.
• carboxyvinyl polymer In the biocompatible material of the present invention, a commercially available product can be used as the carboxyvinyl polymer.
• Specific examples of commercially available carboxyvinyl polymers include “Carbopole 971", “Carbopole 974", “Carbopole 980", and “Carbopole 981” manufactured by Hybrid Advanced Materials Co., Ltd .; Sumitomo Seika Chemical Co., Ltd. "AQUAPEC HV805", “AQUAPEC HV-501E”, and “AQUAPEC HV-505E”; "Hibiswaco 103", “Hibiswaco 104", and “Hibiswaco 105" manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.
• the content of the carboxyvinyl polymer is preferably 1.0% by mass to 30.0% by mass, and 1.0% by mass or more, 20% by mass or more, based on the total mass of the biocompatible material, in that the effect of the present invention is more excellent. Less than 0.0% by mass is more preferable, and 10.0% by mass to 15.0% by mass is further preferable.
• carboxyvinyl polymer may be used alone, or two or more types may be used in combination.
• the value of the mass ratio of the alginate content to the carboxyvinyl polymer content [alginate content / carboxyvinyl polymer content] is not particularly limited, but is 0.5.
• ⁇ 6.0 is preferable, 1.0 or more and less than 3.0 is more preferable, and 1.0 or more and 2.0 or less is further preferable.
• the mass ratio is in the range of 0.5 to 6.0, the scratch resistance of the formed gel becomes more excellent, and when it is in the range of 1.0 or more and less than 3.0, the scratch resistance becomes higher. In addition, the retention will be better.
• the biocompatible material of the present invention includes an oil-based substrate.
• the oil-based base material means a component that does not mix with water.
• the viscosity of the oil-based substrate is not particularly limited, but 100 to 1000000 cP is preferable, and 1000 to 100,000 cP is more preferable, because the effect of the present invention is more excellent.
• the viscosity is measured using a viscoelasticity measuring device (MCR302) at a temperature of 25 ° C. and a shear rate of 1 (1 / s).
• MCR302 viscoelasticity measuring device
• Examples of the oil-based base material include raw materials used for ordinary oil-based ointments.
• oil-based substrate examples include hydrocarbons (preferably gelled hydrocarbons), waxes, vegetable oils, animal oils, neutral lipids, synthetic fats and oils, sterol derivatives, monoalcohol carboxylic acid esters, and oxyacid esters.
• hydrocarbons preferably gelled hydrocarbons
• waxes vegetable oils, animal oils, neutral lipids, synthetic fats and oils
• sterol derivatives monoalcohol carboxylic acid esters
• oxyacid esters examples include polyhydric alcohol fatty acid esters, silicones, higher alcohols, higher fatty acids, and fluorine-based oils.
• One type of oil-based base material may be used alone, or two or more types may be used in combination.
• a combination of hydrocarbons (preferably gelled hydrocarbons) and liquid paraffin is preferable.
• the gelled hydrocarbon one conforming to the "gelled hydrocarbon" of the pharmaceutical additive standard can be used, and more specifically, a gelled hydrocarbon obtained by gelling liquid paraffin with polyethylene is preferably used. can.
• the gelled hydrocarbon Plastibase (manufactured by Taisho Toyama Pharmaceutical Co., Ltd.) or Hicol Gel (manufactured by Kaneda Co., Ltd.) is preferable.
• Hydrocarbons include, for example, liquid paraffin (mineral oil), heavy liquid isoparaffin, light liquid isoparaffin, ⁇ -olefin oligomer, polyisobutene, hydrogenated polyisobutene, polybutene, squalane, olive-derived squalane, squalene, vaseline, and solids. Paraffin is mentioned.
• the petrolatum is preferably selected from those conforming to the Japanese Pharmacopoeia or similar standards "Vaseline”, “white petrolatum”, or "yellow petrolatum”.
• waxes examples include candelilla wax, carnauba wax, rice wax, wood wax, honey wax, montan wax, ozokerite, ceresin, microcrystalline wax, petrolatum, fishertroph wax, polyethylene wax, and ethylene-propylene copolymer. Can be mentioned.
• Examples of vegetable oils include soybean oil, sesame oil, olive oil, palm oil, palm oil, rice bran oil, cottonseed oil, sunflower oil, rice bran oil, cacao butter, corn oil, beni flower oil, and rapeseed oil.
• animal oils include mink oil, turtle oil, fish oil, cow oil, horse oil, lard, and shark squalane.
• Neutral lipids include, for example, triolein, triolein, trimyristin, tristearin, and triarachidonin.
• Examples of synthetic fats and oils include phospholipids and azone.
• Sterol derivatives include, for example, dihydrocholesterol, lanosterol, dihydrolanosterol, phytosterols, cholic acid, and cholesteryl linoleate.
• monoalcohol carboxylic acid esters include octyldodecyl myristate, hexyldecyl myristate, octyldodecyl isostearate, and cetyl palmitate.
• the oxyacid esters include cetyl lactate, diisostearyl malate, and hydrogenated castor oil monoisostearate.
• polyhydric alcohol fatty acid esters examples include glyceryl trioctanoate, glyceryl trioleate, glyceryl triisostearate, glyceryl diisostearate, and tri (caprylic acid / capric acid) glyceryl.
• silicones include dimethicone (dimethylpolysiloxane), highly polymerized dimethicone (highly polymerized dimethylpolysiloxane), cyclomethicone (cyclic dimethylsiloxane, decamethylcyclopentasiloxane), and phenyltrimethicone.
• higher alcohols include cetanol, myristyl alcohol, oleyl alcohol, lauryl alcohol, cetostearyl alcohol, and stearyl alcohol.
• higher fatty acids include lauric acid, myristic acid, palmitic acid, stearic acid, isostearic acid, behenic acid, undecylenic acid, 12-hydroxystearic acid, and palmitoleic acid.
• fluorine-based oils include perfluorodecane, perfluorooctane, and perfluoropolyether.
• the content of the oil-based base material is preferably 40% by mass to 80% by mass, more preferably 50% by mass to 70% by mass, based on the total mass of the biocompatible material, in that the effect of the present invention is more excellent. When the content of the oil-based base material is within this range, the effect of the present invention is more excellent.
• oil-based base material one type may be used alone, or two or more types may be used in combination.
• the value of the mass ratio of the content of hydrocarbons to the content of liquid paraffin is a point in which the effect of the present invention is more excellent. Therefore, 0.1 to 10.0 is preferable, and 1.0 to 6.0 is more preferable.
• the value of the mass ratio of the content of alginate to the content of the oil-based base material is a point in which the effect of the present invention is more excellent. Therefore, 0.10 to 0.70 is preferable, 0.20 to 0.50 is more preferable, and 0.20 or more and less than 0.35 is further preferable.
• the biocompatible material of the present invention is substantially water-free.
• substantially free of water means that it is acceptable to contain a small amount of water (for example, a trace amount of water contained in the raw material) that does not affect the effect of the present invention.
• substantially water-free means that the content of water in the biocompatible material is 5% by mass or less with respect to the total mass of the biocompatible material. .. Of these, 3% by mass or less is preferable. The lower limit is not particularly limited, but 0% by mass is preferable.
• the adhesiveness of the gel formed when the biocompatible material of the present invention is applied to a living body is further improved, and the protective performance is also improved. Examples of the method for measuring the water content in the biocompatible material include a Karl Fischer water content measurement method (coulometric method) based on JIS K0068: 2001.
• the biocompatible material may contain components other than those described above.
• the biocompatible material of the present invention may further contain a sugar alcohol and at least one selected from the group consisting of sugars.
• the biocompatible material contains at least one selected from the group consisting of sugar alcohol and sugar, the scratch resistance when the biocompatible material is gelled is more excellent.
• the sugar alcohol is an organic compound having a structure in which the carbonyl group of aldose or ketose is reduced.
• Specific examples of sugar alcohols include xylitol, erythritol, mannitol, and sorbitol. Among them, at least one sugar alcohol selected from the group consisting of xylitol, erythritol, mannitol, and sorbitol is preferable, and xylitol is more preferable, because the effect of the present invention is more excellent.
• the sugar is, for example, a monosaccharide or a disaccharide.
• Specific examples of the sugar include glucose, galactose, sucrose, trehalose, and lactose.
• at least one sugar selected from the group consisting of glucose and galactose is preferable, and glucose is more preferable, in that the effect of the present invention is more excellent.
• At least one selected from the group consisting of sugar alcohols and sugars is preferably at least one selected from the group consisting of xylitol, glucose, erythritol, mannitol, sorbitol, galactose, sucrose, trehalose, and lactose, preferably xylitol, Alternatively, glucose is more preferred.
• sugar alcohol and sugar content When the biocompatible material of the present invention contains at least one selected from the group consisting of sugar alcohol and sugar, the total content of sugar alcohol and sugar is biocompatible in that the effect of the present invention is more excellent. It is preferably 0.5% by mass to 20.0% by mass, more preferably 5.0% by mass to 15.0% by mass, based on the total mass of the material. When the total content of sugar alcohol and sugar is within the above range, the effect of the present invention is more excellent.
• sugar alcohol and sugar one type may be used alone, or two or more types may be used in combination.
• the biocompatible material of the present invention may further contain a refreshing agent, a sweetener, or a flavoring agent.
• a refreshing agent e.g., a peppermint, a satulose, a maltitol, a maltitol, a maltitol, a maltitol, a maltitol, a maltitol, a maltitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, a maltitol, a maltitol, a maltitol, a maltitol, a maltitol, a maltitol, a maltitol, mannitol, mannitol, mannitol, manni
• the biocompatible material of the present invention may further contain excipients.
• the biocompatible material of the present invention is one or more components selected from the group consisting of crystalline cellulose, magnesium aluminate metasilicate, and silicic acid-treated crystalline cellulose for the purpose of enhancing scratch resistance. May include.
• the biocompatible material of the present invention may further contain an anti-inflammatory agent (a component having an anti-inflammatory effect).
• an anti-inflammatory agent a component having an anti-inflammatory effect.
• the biocompatible materials of the present invention include azulene, sodium azulene sulfonate, triamcinolone acetonide, tranexamic acid, allantoin, glycyrrhetinic acid, dipotassium glycyrrhizinate, panthenol, cicon extract, bredonizolone acetate, bredonizolone, dexamethasone, And, it may contain one or more components selected from the group consisting of triamcinolone acetonide.
• the biocompatible material of the present invention preferably contains one or more components selected from the group consisting of sodium azulenate, triamcinolone acetonide, tranexamic acid, allantoin, and glycyrrhetinic acid.
• the biocompatible material of the present invention may further contain an antibacterial agent (a component having an antibacterial action).
• an antibacterial agent a component having an antibacterial action.
• the biocompatible material of the present invention comprises the group consisting of cetylpyridinium chloride, hinokithiol, chlorhexidine hydrochloride, iodine, potassium iodide, phenol, thymol, benzalkonium chloride, benzethonium chloride, and isopropylmethylphenol. It preferably contains one or more selected components.
• the biocompatible material of the present invention may further contain a preservative (a component having an antiseptic action).
• a preservative a component having an antiseptic action.
• the biocompatible material of the present invention is from the group consisting of methylparaben, ethylparaben, propylparaben, isopropylparaben, butylparaben, isobutylparaben, benzylparaben, paraoxybenzoic acid ester, phenoxyethanol, and sodium benzoate. It preferably contains one or more selected components.
• the biocompatible material of the present invention can be produced by mixing alginate having a weight average molecular weight of 1 million or more, a predetermined polyvalent metal compound, a carboxyvinyl polymer, and an oil-based base material. If necessary, dehydration treatment may be carried out.
• the mixing method is not particularly limited, and a conventionally known method used when mixing the powder components can be used.
• a stepwise mixing method may be carried out in which some of the components constituting the biocompatible material are mixed in advance and then mixed with the remaining components.
• alginate having a weight average molecular weight of 1 million or more, a predetermined polyvalent metal compound, a carboxyvinyl polymer, sugar alcohols and It is preferable to mix at least one selected from the group consisting of sugars to obtain a mixture, and then mix the obtained mixture with an oil-based substrate. According to the above procedure, a biocompatible material in which the components are more uniformly dispersed can be obtained.
• the mixture and the oil-based base material may be mixed at once, or the mixture may be added to the oil-based base material in a plurality of times and mixed. After mixing each component, it is preferable that the obtained biocompatible material is degassed to remove water from the biocompatible material.
• a gel having a crosslinked structure By contacting the biocompatible material of the present invention with water, a gel having a crosslinked structure is formed. More specifically, when the biocompatible material of the present invention is brought into contact with water, a gel containing a crosslinked structure formed by cross-linking alginate and metal ions dissociated from a predetermined polyvalent metal compound is formed. NS. Further, when the biocompatible material of the present invention contains at least one selected from the group consisting of sugar alcohols and sugars, alginate and metal ions dissociated from a predetermined polyvalent metal compound are crosslinked and formed.
• a gel containing two types of crosslinked structures is formed: a first crosslinked structure and a second crosslinked structure formed by crosslinking a carboxyvinyl polymer with at least one selected from the group consisting of sugar alcohols and sugars. .. That is, the biocompatible material of the present invention absorbs water to spontaneously form a crosslinked structure.
• the biocompatible material of the present invention can be applied on the surface of a living body to form a gel.
• a method for forming a gel the biocompatible material of the present invention is placed on the surface of the living body, and the biocompatible material placed on the surface of the living body is brought into contact with water to form a gel on the surface of the living body.
• the method of forming is mentioned.
• the surface of the mucous membrane in the oral cavity is preferably used as the surface of the living body on which the biocompatible material of the present invention is placed.
• the viscosity of the biocompatible material of the present invention is not particularly limited, but is often 100,000 to 600,000 cP, preferably 200,000 to 500,000 cP.
• the viscosity is measured using a viscoelasticity measuring device (MCR302) at a temperature of 25 ° C. and a shear rate of 1 (1 / s).
• Examples of the form (property) of the biocompatible material of the present invention include ointment, cream, and semi-solid.
• biocompatible material of the present invention includes, for example, bioprotective applications.
• the biocompatible material of the present invention can be used, for example, as a mucosal protective agent, and more specifically, as an oral mucosal protective agent.
• the biocompatible material of the present invention also has applications such as a wound dressing, a drug sustained-release base material, an oral wetting material, and a hemostatic material.
• the biocompatible material of the present invention When the biocompatible material of the present invention is used on the mucous membrane, if the biocompatible material of the present invention is placed on the mucous membrane and water or a solution containing water is added, a gel formed by gelation is obtained. It adheres more firmly to the mucous membrane. That is, as a method of using the biocompatible material of the present invention (or a method of producing a gel), the biocompatible material of the present invention is arranged on the mucous membrane, and the biocompatible material and water arranged on the mucous membrane are used. A method of forming a gel on the mucous membrane by contacting the cells can be mentioned.
• the biocompatible material of the present invention when the biocompatible material of the present invention is applied to the oral mucosa, if the biocompatible material of the present invention is attached to the oral mucosa, the biocompatible material of the present invention is gelled by the moisture in saliva. Therefore, it is easy to handle. If the amount of saliva is small, the biocompatible material of the present invention may be attached to the oral mucosa and then water or artificial saliva may be sprayed to supply water.
• the formation of the crosslinked structure is started by the water in saliva, and at the same time, mucin and alginate on the surface of the oral mucosa are adhered by hydrogen bonds.
• the gel formed by the biocompatible material of the present invention is considered to exhibit excellent scratch resistance and excellent retention, but is not limited to this. Further, it is considered that the biocompatible material of the present invention has excellent palatability when the biocompatible material is used in the oral cavity by containing a predetermined multivalent metal compound.
• the type of the drug to be sustained-release is not particularly limited, and known drugs can be mentioned.
• Examples 1 to 25 and Comparative Examples 1 to 7 ⁇ Preparation of biocompatible materials>
• the biocompatible materials of Examples 1 to 25 and Comparative Examples 1 to 7 were prepared by mixing the components shown in Tables 1-1 to 1-3 with the contents shown in Tables 1-1 to 1-3. bottom.
• the content of water in the biocompatible materials prepared in Examples 1 to 25 and Comparative Examples 1 to 7 was 3% by mass or less with respect to the total mass of the biocompatible materials in each case. .. That is, none of the biocompatible materials of the Examples contained substantially water.
• the manufacturing procedure of the biocompatible material of Example 1 is typically described below. In Examples 2 to 25 and Comparative Examples 1 to 7, the amount of each component used was adjusted and production was carried out in the same procedure as in Example 1.
• Example 1 Sodium alginate (Kimika Co., Ltd., Kimika Argin IS) 324 g, calcium chloride dihydrate (Fujifilm Wako Pure Chemical Industries, Ltd.) 36 g, xylitol (Mitsubishi Corporation Food Tech, Xylit P) 180 g, and carboxyvinyl 180 g of a polymer (manufactured by Lubrizol, CARBOPOL 971PNF) was uniformly powder-mixed and divided into three equal parts.
• each powder took 1 minute, and after the addition, the mixture was stirred for 1 minute. After 1 minute had passed after the completion of the final addition, the inside of the system was evacuated and stirring was continued for another 20 minutes to obtain 1800 g of the biocompatible material of Example 1.
• the obtained biocompatible material was filled in two aluminum tubes (manufactured by Kansai Tube) in an amount of 7 g each, and each tube was stored under room temperature conditions (temperature 25 ° C., relative humidity 60%) until use.
• TDAB tetradodecyl ammonium bromide, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.
• polyvinyl chloride manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.
• DOPP di-n-octylphosphonate, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.
• THF tetrahydrofuran, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.
• agar Calicolican (registered trademark), manufactured by Ina Food Industry Co., Ltd.
• the prepared lipid film was pasted together.
• the surface of the lipid membrane was coated with an MPC (2-methacryloyloxyethyl phosphorylcholine) polymer (LIPIDURE (registered trademark) -CM5206, manufactured by NOF CORPORATION) to obtain a pseudo biological membrane.
• MPC 2-methacryloyloxyethyl phosphorylcholine
• the prepared biocompatible material is applied onto the prepared pseudobiological membrane (1 cm ⁇ , film thickness 500 ⁇ m), artificial saliva (Salibate (registered trademark), manufactured by Teijin Pharma Limited) is sprayed, and then smoothed with a finger for 1 minute.
• the sample was gelled to prepare a sample for evaluation.
• the prepared evaluation sample is repeatedly worn with a wear tester (surface quality measuring machine Tribogear TYPE: 14 FW, manufactured by Shinto Kagaku Co., Ltd.), and the number of times (reciprocating) until the sample peels off or dissolves from the pseudo biological membrane is measured. , Scratch resistance was evaluated according to the following criteria.
• a triangular eraser core (Ain CLIC, manufactured by Pentel) was set on the head of the wear tester, and the test was conducted under the conditions of a load of 30 g, an amplitude of 30 mm, and a speed of 6000 mm / min. (Evaluation criteria for scratch resistance) Endured 250 times or more ... S Peeled 200 times or more and less than 250 times ... A Peeled 100 times or more and less than 200 times ... B Peeled less than 100 times ... C The evaluation results are shown in the "Evaluation" column of Tables 1-1 to 1-3.
• the prepared biocompatible material is applied onto the prepared pseudobiological membrane (1 cm ⁇ , film thickness 500 ⁇ m), artificial saliva (Salibate (registered trademark), manufactured by Teijin Pharma Limited) is sprayed, and then allowed to stand for 1 minute.
• the sample was gelled to prepare a sample for evaluation.
• the prepared evaluation sample was placed in a petri dish and filled with artificial saliva (Salibate (registered trademark), manufactured by Teijin Pharma Limited) until the evaluation sample was immersed.
• This petri dish was placed in a constant temperature shaker (AS ONE Small Shaking Thermostat 1-6142-01) (37 ° C.) and shaken at a medium speed (scale 6).
• Example 1 From the comparison between Example 1 and Examples 9 to 10, it was confirmed that when the polyvalent metal compound is a calcium compound, the effect is more excellent. From the comparison between Example 25 and Examples 23 to 24, it was confirmed that when the polyvalent metal compound is a calcium compound, the effect is more excellent.
• Example 1 From the comparison between Example 1 and Examples 11 to 12, when the content of the multivalent metal compound is 1.0% by mass to 4.5% by mass with respect to the total mass of the biocompatible material, It was confirmed that the effect was superior.
• Example 13 From the comparison between Example 1 and Example 13, it was confirmed that the effect was more excellent when the viscosity of the 0.5% by mass aqueous solution of the carboxyvinyl polymer at pH 7.5 was 20000 cP or less.

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