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
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
• • 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
• • 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
  • 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
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like

Definitions

• the present invention relates to a biocompatible material and a method for producing the biocompatible material.
• 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.
• 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 of Sarcote (R) capsule external use, Teijin Pharma Co., Ltd .; active ingredient beclomethasone propionate).
• 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.
• the biocompatible material has excellent storage stability. More specifically, it is desired that when the biocompatible material is left unattended, changes in appearance such as shine and oil bleeding do not occur.
• an object of the present invention is to provide a biocompatible material capable of forming a gel having excellent retention and scratch resistance and having excellent storage stability.
• the oil-based substrate contains a gelled hydrocarbon and a liquid oil-based substrate.
• At least one selected from the group consisting of sugar alcohols and sugars is at least one selected from the group consisting of erythritol, xylitol, mannitol, sorbitol, glucose, galactose, sucrose, trehalose and lactose.
• a method for producing a biocompatible material which comprises producing a biocompatible material using a planetary mixer having two or more axes.
• the method for producing a biocompatible material according to any one of (1) to (22).
• Step 2 and step 2 in which one of the alginate, the aluminum compound, and the carboxyvinyl polymer other than the component added in step 1 is added to the mixture obtained in step 1 and mixed.
• one of alginate, an aluminum compound, and a carboxyvinyl polymer other than the components added in steps 1 and 2 is added and mixed with step 3.
• biocompatible material capable of forming a gel having excellent retention and scratch resistance and having excellent storage stability.
• the range represented by using “-" includes both ends of “-”.
• the range represented by "A to B” includes A and B.
• the biocompatible material of the present invention contains an alginate having a weight average molecular weight of 1 million or more, an aluminum compound, a carboxyvinyl polymer, and an oil-based base material, which is substantially free of water, and further contains an oil-based base material. Contains gelled hydrocarbon and liquid oily substrate in a predetermined mass ratio.
• the biocompatible material means a material that adheres well to a biological surface (for example, skin, mucous membrane (for example, mucous membrane in the oral cavity), eyes, teeth, tongue, nails, and hair). do.
• 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 biosurface is determined by the biomaterial 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 (mouse, rat, etc.), rabbits, dogs, cats, pigs, cows, sheep, and horses.
• the weight average molecular weight of alginate is not particularly limited as long as it is 1 million or more, but is preferably 2 million or more, more preferably 3 million or more, still more preferably 3.5 million or more, and even more preferably 4 million. That is all.
• the weight average molecular weight of alginate is 4 million or more, the scratch resistance becomes more excellent. If the weight average molecular weight of the alginate is less than 1 million, the scratch resistance when the biocompatible material is gelled 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, and further 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.
• PWXL -Eluent 0.2 mol / L sodium nitrate-Flow velocity: 0.7 mL / min ⁇
• Injection amount 50 ⁇ L -Sample concentration: 0.1% -Analysis time: 60 minutes-Detection: RI (Refractive Index: differential refractometer)
• 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 diameter 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 or an ammonium salt of alginic acid is preferable, and at least one selected from the group consisting of sodium alginate, potassium alginate and ammonium alginate is more preferable, and sodium alginate is more preferable. Is even more preferable.
• the content of alginate in the biocompatible material of the present invention is not particularly limited, but may be 5.0% by mass to 35.0% by mass with respect to the total mass of the biocompatible material of the present invention. It is preferably 10.0% by mass to 30.0% by mass, and more preferably 10.0% by mass.
• the scratch resistance when the biocompatible material is gelled is more excellent. It becomes a thing.
• the aluminum compound is not particularly limited as long as it is a compound containing aluminum, but a water-soluble aluminum compound is preferable, an aluminum carboxylate is more preferable, an aluminum hydroxycarboxylate is more preferable, and aluminum lactate is even more preferable. When the aluminum compound is aluminum lactate, the retention of the biocompatible material when gelled becomes better.
• water-soluble aluminum compounds examples include aluminum chloride (AlCl 3 ), aluminum sulfate (Al 2 (SO 4 ) 3 ), aluminum nitrate (Al (NO 3 ) 3 ), ammonium myoban (AlNH 4 (SO 4 ) 2 ). ⁇ 12H 2 O), potassium myoban (AlK (SO 4 ) 2 ⁇ 12H 2 O), aluminum acetate, aluminum propionate, aluminum glycolate (aluminum hydroxyacetate), aluminum lactate, aluminum malate, aluminum tartrate, aluminum citrate And aluminum isocitrate, but are not limited to these.
• aluminum carboxylates are, but are limited to, aluminum acetate, aluminum propionate, aluminum glycolate (aluminum hydroxyacetate), aluminum lactate, aluminum malate, aluminum tartrate, aluminum citrate and aluminum isocitrate. It is not something that is done.
• hydroxycarboxylic acid of aluminum examples include aluminum glycolate (aluminum hydroxyacetate), aluminum lactate, aluminum malate, aluminum tartarate, aluminum citrate and aluminum isocitric acid.
• the content of the aluminum compound in the biocompatible material of the present invention is not particularly limited, but may be 0.1% by mass to 5.0% by mass with respect to the total mass of the biocompatible material of the present invention. It is preferably 1.0% by mass to 4.5% by mass, more preferably 1.0% by mass. When the content of the aluminum 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 of the biocompatible material when gelled is more excellent. It becomes a thing.
• 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 using allyl sucrose, allyl ether of pentaerythritol, and the like.
• the biocompatible material of the present invention gels when contacted with water, but has excellent scratch resistance due to the network of alginate gel formed by cross-linking alginate with aluminum ions and the network of carboxyvinyl polymer. And achieve retention.
• the viscosity of the carboxyvinyl polymer is not particularly limited, but is preferably 20000 cP or less, and more preferably 2000 cP to 20000 cP in a 0.5 mass% aqueous solution (25 ° C.) adjusted to pH 7.5.
• a 0.5 mass% aqueous solution (25 ° C.) adjusted to 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 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 Rubyzol Advanced Materials, Fujifilm Wako Pure Chemical Industries, Ltd. Company-made “Hibis Wako 103", “Hibis Wako 104" and “Hibis Wako 105", Toa Synthetic Co., Ltd.
• one type of carboxyvinyl polymer may be used alone, or two or more types may be used in combination.
• the mass ratio of the alginate content to the carboxyvinyl polymer content is not particularly limited, but is 0.5 to 5 It is preferably 5.5, more preferably 1.0 to 5.5.
• the mass ratio is in the range of 0.5 to 5.5, the retention of the formed gel becomes more excellent, and when it is in the range of 1.0 to 5.5, in addition to the retention. Therefore, the scratch resistance becomes better.
• the oil-based base material contained in the biocompatible material of the present invention includes a gelled hydrocarbon and a liquid oil-based base material.
• the biocompatible material of the present invention contains the above-mentioned predetermined oil-based base material, the biocompatible material has more excellent spreadability and storage stability.
• the oil-based base material means a component that does not mix with water.
• Gelled hydrocarbons are gel-like hydrocarbons.
• the gelled hydrocarbon means that the value of the storage elastic modulus G'(Pa) is the loss elastic modulus G''(when the dynamic viscoelasticity is measured and the shear strain is 1%. It means a hydrocarbon larger than the value of Pa).
• the dynamic viscoelasticity measurement is performed using a viscoelasticity measuring device (MCR302) at a measuring jig CP50, a measuring temperature of 25 ° C., and a measuring frequency of 1 (Hz).
• the gelled hydrocarbon for example, 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 can be preferably used. .. Of these, gelled hydrocarbons formed using 100 parts by mass of liquid paraffin and 5 to 10 parts by mass of polyethylene are preferable.
• liquid paraffin include light liquid paraffin and heavy liquid paraffin.
• liquid paraffin having a carbon number in the range of 15 to 60 is preferable. Among them, it is preferable that the liquid paraffin has the highest content of hydrocarbons in the range of 30 to 40 carbon atoms.
• the number average molecular weight of polyethylene is not particularly limited, but is preferably 1,000 to 50,000, more preferably 10,000 to 30,000.
• the polyethylene having the number average molecular weight is usually solid at 25 ° C. and has a melting point in the range of 37.5 to 145 ° C. in many cases.
• a predetermined amount of liquid paraffin and polyethylene are heated at a temperature in the range of the temperature at which polyethylene melts (for example, 110 to 130 ° C.). It can be prepared by mixing and cooling.
• Vaseline is also preferably used in addition to the gelled hydrocarbon obtained by gelling the liquid paraffin with polyethylene.
• plastic base manufactured by Taisho Toyama Pharmaceutical Co., Ltd.
• white petrolatum manufactured by Toyo Pharmaceutical Kasei Co., Ltd.
• Hicol Gel manufactured by Kaneda Co., Ltd.
• the gelled hydrocarbon may be used alone or in combination of two or more.
• the liquid oil-based base material is a liquid oil-based base material.
• the value of the storage elastic modulus G'(Pa) is the loss elastic modulus G''(when the dynamic viscoelasticity is measured and the shear strain is 1%. It means an oil-based substrate smaller than the value of Pa).
• the dynamic viscoelasticity measurement is performed using a viscoelasticity measuring device (MCR302) at a measuring jig CP50, a measuring temperature of 25 ° C., and a measuring frequency of 1 (Hz).
• liquid oil-based substrate examples include hydrocarbons, esters, triglycerides, vegetable oils, animal oils, and silicones.
• hydrocarbons liquid hydrocarbons
• liquid hydrocarbons include liquid paraffin, ⁇ -olefin oligomer, light isoparaffin, light liquid isoparaffin, squalane, polybutene, polyisobutene, and hydrogenated polyisobutene, with liquid paraffin being preferred.
• liquid paraffin include light liquid paraffin and heavy liquid paraffin.
• liquid paraffin liquid paraffin having a carbon number in the range of 15 to 60 is preferable. Among them, it is preferable that the liquid paraffin has the highest content of hydrocarbons in the range of 30 to 40 carbon atoms.
• esters examples include isopropyl myristate, octyldodecyl myristate, and cetyl 2-ethylhexanoate.
• triglycerides examples include glyceryl tri2-ethylhexanoate and glyceryl tri (capryl caproic acid).
• 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.
• silicones examples include dimethicone (dimethylpolysiloxane), highly polymerized dimethicone (highly polymerized dimethylpolysiloxane), cyclomethicone (cyclic dimethylsiloxane, decamethylcyclopentasiloxane), and phenyltrimethicone.
• the liquid oil-based base material may be used alone or in combination of two or more.
• the viscosity of the liquid oil-based substrate is not particularly limited, but 100 to 1000000 cP is preferable, and 1000 to 100,000 cP is more preferable, in that the adhesion when the biocompatible material of the present invention is gelled is more excellent.
• the viscosity is measured using a viscoelasticity measuring device (MCR302) at a measurement temperature of 25 ° C. and a shear rate of 1 (1 / s).
• the mass ratio of the gelled hydrocarbon content to the content of the liquid oily substrate in the biocompatible material of the present invention is more than 1.0.
• the mass ratio is preferably 1.5 or more, more preferably 2.0 or more, still more preferably 3.0 or more, in that the storage stability of the biocompatible material is more excellent.
• the upper limit of the mass ratio is not particularly limited, but 8.0 or less is preferable, and 6.0 or less is more preferable.
• the biocompatible material of the present invention may contain an oil-based substrate other than the gelled hydrocarbon and the liquid oil-based substrate described above.
• the content of the oil-based base material in the biocompatible material of the present invention is not particularly limited, but is preferably 40% by mass to 80% by mass, preferably 50% by mass, based on the total mass of the biocompatible material of the present invention. More preferably, it is by mass% to 70% by mass.
• the value of the ratio (mass ratio) of the content of alginate to the content of the oil-based base material is not particularly limited.
• the formed gel has more excellent scratch resistance and the biocompatible material has more excellent spreadability.
• 0.20 to 0.50 is more preferable, and 0.20 to 0.40 is even more 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 of the present invention is 5% by mass or less with respect to the total mass of the biocompatible material of the present invention. Means that Above all, it is preferably 3% by mass or less. The lower limit is not particularly limited, but 0% by mass can be mentioned.
• 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.
• the storage stability of the biocompatible material of the present invention is further improved.
• the Karl Fischer water content measuring method is preferable. The measurement conditions are described in JIS K0068: 2001.
• the biocompatible material of the present invention may contain components other than those described above.
• the biocompatible material of the present invention may further contain at least one selected from the group consisting of sugar alcohols and sugars.
• the biocompatible material of the present invention contains at least one selected from the group consisting of sugar alcohols and sugars, the scratch resistance when the biocompatible material is gelled becomes more excellent.
• the sugar alcohol is an organic compound having a structure in which the carbonyl group of aldose or ketose is reduced, and specific examples thereof include erythritol, xylitol, mannitol and sorbitol, which are selected from the group consisting of erythritol, xylitol, mannitol and sorbitol. At least one of them is preferable, and xylitol is more preferable.
• the sugar is not particularly limited, but is, for example, a monosaccharide or a disaccharide, and specific examples thereof include glucose, galactose, sucrose, trehalose and lactose, and at least one selected from the group consisting of glucose and galactose is preferable. , Trehalose is more preferred.
• At least one selected from the group consisting of sugar alcohols and sugars may be at least one selected from the group consisting of erythritol, xylitol, mannitol, sorbitol, glucose, galactose, sucrose, trehalose, and lactose. preferable.
• the total content of sugar alcohol and sugar in the biocompatible material of the present invention when the biocompatible material of the present invention contains at least one selected from the group consisting of sugar alcohol and sugar is not particularly limited. 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 biocompatible material of the present invention. When the total content of sugar alcohol and sugar is within this range, the effect of including at least one selected from the group consisting of sugar alcohol and sugar in the biocompatible material of the present invention is more exerted. Become.
• 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, l-menthol, camphor, fruit-derived flavors (lemon flavor, lime flavor, strawberry flavor, etc.) and sodium saccharin for the purpose of enhancing palatability. It may contain one or more components to be made.
• 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 strengthening the scratching system. 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 comprises 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, an aluminum compound, a carboxyvinyl polymer, a gelled hydrocarbon, and a liquid oil-based substrate. If necessary, dehydration treatment may be carried out.
• the mixing method is not particularly limited, and a conventionally known mixer can be used.
• Mixers include Combimix (PRIMIX), Hibismix (PRIMIX), Hibis Dispermix (PRIMIX), Adihomo Mixer (Tajima Chemical Machinery Co., Ltd.), and Awatori Rentaro (Shinky).
• Planetary mixer Mozuho Kogyo Co., Ltd.
• raikai machine Ishikawa factory
• CDM mixer Inoue Seisakusho
• mixing device Dalton Co., Ltd.
• hibismix (biaxial planet), hibis disperser mix (triaxial planet), and the like correspond to planetary kneaders with two or more axes.
• Mizuho Kogyo Co., Ltd. and Dalton Corporation also sell planetary mixers with two or more axes.
• the planetary mixer include a mixer in which two or more rotation axes are connected to the revolution axis, and stirring blades provided on the respective rotation axes perform planetary motion.
• shape of the stirring blade (blade)
• various shapes such as a frame type, a key type, a screw type, an X shape, and a J type can be used.
• the mixing method is not particularly limited, and examples thereof include a method of mixing each component collectively and a method of sequentially mixing each component.
• the entire amount of each component may be mixed all at once, or may be mixed in small portions in several batches.
• Step 1 Add the alginate, the aluminum compound, and one of the carboxyvinyl polymers to the oil-based substrate and mix them.
• Step 2 Add the alginate to the mixture obtained in step 1.
• the aluminum compound and one of the carboxyvinyl polymers other than the components added in step 1 are added and mixed.
• Step 3 The mixture obtained in step 2 is mixed with the alginate and aluminum.
• the above aluminum compound is added to the oil-based substrate in step 1. It is preferable to add the carboxyvinyl polymer to the mixture obtained in step 1 in step 2 and to add the alginate to the mixture obtained in step 2 in step 3.
• the biocompatible material contains a sugar alcohol, it is preferable to add it to the oil-based substrate at the same time as the aluminum compound in step 1.
• 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 an aluminum compound is formed. Further, when the biocompatible material of the present invention contains at least one selected from the group consisting of sugar alcohols and sugars, a first crosslinked structure formed by cross-linking alginate and an aluminum compound and a carboxyvinyl polymer. A gel containing two types of crosslinked structures is formed, which is formed by cross-linking with at least one selected from the group consisting of sugar alcohol and sugar. 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 the gel on the surface of the living body.
• the method of forming is mentioned.
• the biomaterial on which the biocompatible material of the present invention is placed the mucosal surface in the oral cavity is preferably mentioned.
• the viscosity of the biocompatible material of the present invention is not particularly limited, but it is often 100,000 to 600,000 cP, and 200,000 to 500,000 cP is preferable in that the biocompatible material of the present invention has more excellent spreadability.
• the viscosity is measured using a viscoelasticity measuring device (MCR302) at a measurement temperature of 25 ° C. and a shear rate of 1 (1 / s).
• the form (property) of the biocompatible material of the present invention is not particularly limited, and examples thereof include an ointment, a cream, and a semi-solid.
• biocompatible material of the present invention includes, but are not limited to, 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 for a 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 gel 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 from the biocompatible material of the present invention is considered to exhibit excellent scratch resistance and excellent retention, but is not limited to this.
• the biocompatible material of the present invention by adjusting the blending amount of the gelled hydrocarbon and the liquid oil-based base material, it is possible to suppress the change in appearance of the biocompatible material with time, and excellent storage stability can be obtained. It is thought that it will be demonstrated.
• the type of sustained-release drug is not particularly limited, and known drugs can be mentioned.
• Examples 1 to 39, Comparative Examples 1 to 12 ⁇ Preparation of biocompatible materials> Each component shown in Table 1 was mixed by the content shown in Table 1 and the mixing method shown in Table 1 to prepare biocompatible materials of Examples 1 to 39 and Comparative Examples 1 to 12. The content of water in the biocompatible materials prepared in Examples 1 to 39 and Comparative Examples 1 to 12 was 3% by mass or less based on the total mass of the biocompatible materials in each case. .. That is, none of the biocompatible materials of Examples and Comparative Examples contained substantially water. In addition, below, the manufacturing procedure of the biocompatible material of Example 1 and 38-39 is described typically. In Examples 2 to 37 and Comparative Examples 1 to 12, the amount of each component used was adjusted and production was carried out in the same procedure as in Example 1.
• Example 1 400 g of liquid paraffin (manufactured by Kaneda Co., Ltd., HYCOAL M-352) and 800 g of ointment base plastic base (manufactured by Taisho Pharmaceutical Co., Ltd.) are charged into Hibis Dispermix 3D-5 type (3-axis planetary method), and a planetary mixer is used. The mixture was vacuum-stirred for 25 minutes at a setting of 5 rpm (without homodisper) and mixed uniformly.
• Hibis Dispermix 3D-5 type 3-axis planetary method
• the obtained biocompatible material was filled in two aluminum tubes (manufactured by Kansai Tube) in an amount of 5 g each, and each tube was charged under room temperature conditions (25 ° C., 60% RH) and acceleration conditions (40 ° C., 75% relative humidity). ) was stored until use under each condition.
• Example 38 200 g of xylitol (Mitsubishi Shoji Food Tech Co., Ltd., Xylitol P) was charged into a Raikai machine (Ishikawa Factory, Inc.) and stirred for 5 minutes to crush xylitol. Next, 400 g of liquid paraffin (manufactured by Kaneda Co., Ltd., HYCOAL M-352) was added to the obtained xylitol and stirred for 10 minutes, then 800 g of plastic base (manufactured by Taisho Pharmaceutical Co., Ltd.) was added and stirred for 2 minutes. ..
• xylitol Mitsubishi Shoji Food Tech Co., Ltd., Xylitol P
• Raikai machine Ishikawa Factory, Inc.
• the obtained biocompatible material was filled in two aluminum tubes (manufactured by Kansai Tube) in an amount of 5 g each, and each tube was charged under room temperature conditions (25 ° C., 60% RH) and acceleration conditions (40 ° C., 75% relative humidity). ) was stored until use under each condition.
• Example 39 400 g of liquid paraffin (manufactured by Kaneda Co., Ltd., HYCOAL M-352) and 800 g of ointment base plastic base (manufactured by Taisho Pharmaceutical Co., Ltd.) are charged into Hibis Dispermix 3D-5 type (3-axis planetary method), and a planetary mixer is used. The mixture was vacuum-stirred for 25 minutes at a setting of 5 rpm (without homodisper) and mixed uniformly.
• the biocompatible material of Example 39 was obtained by repeating the operation of vacuum stirring for 10 minutes at a setting of 10 rpm three times.
• the obtained biocompatible material was filled in two aluminum tubes (manufactured by Kansai Tube) in an amount of 5 g each, and each tube was charged under room temperature conditions (25 ° C., 60% RH) and acceleration conditions (40 ° C., 75% relative humidity). ) was stored until use under each condition.
• TDAB tetradodecyl ammonium bromide, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd .; 50 mg
• polyvinyl chloride manufactured by Fujifilm Wako Pure Chemical Industries, Ltd .; 800 mg
• DOPP di-n-octylphosphonate, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.
• THF tetrahydrofuran, Fujifilm Wako Pure Chemical Industries, Ltd .; 10 mL
• agar Calicolican (registered trademark), manufactured by Ina Food Industry Co., Ltd .; 0.5 g
• gellan gum Kelcogel (registered trademark), manufactured by CP Kelco Co., Ltd .; 0.1 g
• the prepared lipid film was attached to the gel.
• 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
• 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 more than 700 times ... S Peeled after 500 times or more and less than 700 times ... A Peeled 100 times or more and less than 500 times ... B Peeled less than 100 times ... C The evaluation results are shown in the "Evaluation" column of Table 1.
• Viscosity value at shear rate 1s- 1 is 500,000 cP or less ...
• Example 39 In the "Mixing method” column in the table, “A” represents the procedure of Example 1 in which each component is sequentially added to an oil-based substrate using Hibis Dispermix 3D-5 type (3-axis planetary method), and “B”. “” Indicates the procedure of Example 38 in which each component is sequentially added to the oil-based substrate using a Raikai machine (Ishikawa Plant Co., Ltd.), and “C” uses Hibis Dispermix 3D-5 type (3-axis planetary method). The procedure of Example 39 in which each component is mixed at once is shown.
• Mw represents a weight average molecular weight.
• biocompatible materials of Examples 1 to 39 were evaluated as SB in all of scratch resistance, retention and storage stability, and were excellent in all of scratch resistance, retention and storage stability.
• biocompatible materials of Comparative Examples 1 to 12 had at least one rating of C for scratch resistance, retention and storage stability, and were inferior in at least one of scratch resistance, retention and storage stability. rice field.
• Examples 1, 5 and 6 in which the weight average molecular weight of alginate is 4 million or more are compared with Examples 2, 3 and 4 in which the weight average molecular weight of alginate is less than 4 million. And the scratch resistance was better.
• Examples 1 and 5 in which the average particle size of the alginate particles is in the range of 110 ⁇ m or more and less than 200 ⁇ m are in Examples 2 to 4 in which the average particle size of the alginate particles is outside the range of 110 ⁇ m or more and less than 200 ⁇ m. And, as compared with Example 6, the scratch resistance was more excellent.
• the alginate content is in the range of 10.0% by mass to 30.0% by mass with respect to the total mass of the biocompatible material, and the alginate content is biocompatible.
• the scratch resistance was more excellent than in Example 7, which was less than 10.0% by mass based on the total mass of the material.
• Example 1 Using aluminum lactate as an aluminum compound, as compared to ammonium alum (Na (NH 4) (SO 4) 2 ⁇ 12H 2 O) Example 9 using, retention were superior.
• Examples 1 and 11 in which the content of the aluminum compound is in the range of 1.0% by mass to 4.5% by mass with respect to the total mass of the biocompatible material are compared with Example 10 in which the content is out of the range. And the retention was better.
• Example 1 having a viscosity of a 0.5% by mass aqueous solution (25 ° C.) of a carboxyvinyl polymer at pH 7.5 of 20000 cP or less has more scratch resistance and retention than Example 12 having a viscosity of more than 20000 cP. Both were better.
• Examples 1 and 13 to 15 containing sugar alcohol and Examples 17 to 21 containing sugar were more excellent in scratch resistance than Example 16 containing neither sugar alcohol nor sugar.
• Example 1 in which the value of the ratio (mass ratio) of the content of alginate to the content of carboxyvinyl polymer [alginate content / carboxyvinyl polymer content] is in the range of 0.5 to 5.5.
• Example 7, Example 8, Example 10, Example 11, and Example 23 to 24 have better retention and are in the range of 1.0 to 5.5.
• Examples 10, 11, and 23 to 24 were more excellent in scratch resistance in addition to retention.
• Example 1 From the comparison between Example 1 and Example 39, it was confirmed that the procedure of Example 1 in which each component is sequentially added to the oil-based substrate gives a better effect.
• Example 40 The performance of astaxanthin as a sustained-release base material in the oral cavity was evaluated.
• the content of plastibase in the formulation of Example 1 was changed from 40 parts by mass to 35 parts by mass, the content of liquid paraffin was changed from 20 parts by mass to 15 parts by mass, and ASTOTS-S (Fujifilm) was changed to 10 parts.
• a dark red biocompatible material A was obtained in the same manner as in Example 1 except that parts were added by mass.
• the sustained release performance of astaxanthin of the biocompatible material A under conditions simulating the oral environment was evaluated.
• the artificial saliva continued to be colored red derived from astaxanthin for 3 hours immediately after being immersed in artificial saliva. From this result, it was shown that the biocompatible material of the present invention has a function of slowly releasing components such as astaxanthin when placed in an environment such as the oral cavity.
• Hibismix type 2P-03 manufactured by CPL 130 g
• aluminum lactate manufactured by Musashino Chemical Laboratory Co., Ltd.
• carboxyvinyl polymer manufactured by Lubrizol, CARBOPOL 971PNF

Landscapes

• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• Medicinal Chemistry (AREA)
• Animal Behavior & Ethology (AREA)
• Pharmacology & Pharmacy (AREA)
• Epidemiology (AREA)
• General Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Engineering & Computer Science (AREA)
• Oil, Petroleum & Natural Gas (AREA)
• Inorganic Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Molecular Biology (AREA)
• Organic Chemistry (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Biochemistry (AREA)
• Biophysics (AREA)
• Dermatology (AREA)
• Medicinal Preparation (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Materials For Medical Uses (AREA)

Priority Applications (1)

Applications Claiming Priority (2)

Publications (1)

Family

ID=76864620

Family Applications (1)

Country Status (2)

Cited By (1)

Citations (8)

• 2021
  • 2021-01-14 WO PCT/JP2021/001083 patent/WO2021145385A1/ja not_active Ceased
  • 2021-01-14 JP JP2021571233A patent/JP7523473B2/ja active Active

Patent Citations (8)

Also Published As

Similar Documents

Legal Events