WO2020017571A1 - Émulsion de graisse contenant du flurbiprofène-axétil et son procédé de fabrication - Google Patents

Émulsion de graisse contenant du flurbiprofène-axétil et son procédé de fabrication Download PDF

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Publication number
WO2020017571A1
WO2020017571A1 PCT/JP2019/028181 JP2019028181W WO2020017571A1 WO 2020017571 A1 WO2020017571 A1 WO 2020017571A1 JP 2019028181 W JP2019028181 W JP 2019028181W WO 2020017571 A1 WO2020017571 A1 WO 2020017571A1
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Prior art keywords
flurbiprofen axetil
flurbiprofen
axetil
lecithin
fat
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PCT/JP2019/028181
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English (en)
Japanese (ja)
Inventor
喜一郎 鍋田
Original Assignee
テイコク ファーマ ユーエスエー インコーポレーテッド
テクノガード株式会社
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Priority to CN201980003764.7A priority Critical patent/CN111032033A/zh
Priority to JP2020531351A priority patent/JPWO2020017571A1/ja
Publication of WO2020017571A1 publication Critical patent/WO2020017571A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/222—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having aromatic groups, e.g. dipivefrine, ibopamine
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • 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
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • 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
    • 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
    • A61K47/30—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
    • A61K47/38—Cellulose; Derivatives thereof
    • 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
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • 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
    • A61K9/10—Dispersions; Emulsions
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a flurbiprofen axetil-containing fat emulsion having transparency and excellent stability and safety, and a method for producing the same.
  • Flurbiprofen axetil represented by the following chemical structural formula has an excellent anti-inflammatory effect, but is an oily substance and is hardly soluble in water (water specified in the Japanese Pharmacopoeia, general rules). Is almost insoluble (the amount of solvent required to dissolve 1 g or 1 mL of solute is 10,000 mL or more: the solute is equivalent to a drug and the solvent is equivalent to water). Is a fact well known to those skilled in the art.
  • the drug-containing fat emulsion proposed by the present inventors in Patent Document 1 can be produced by adjusting the content of fats and oils to a maximum of 2 mg / mL, and has high transparency and excellent stability. It is evaluated as an emulsion. However, since this drug-containing fat emulsion has a low fat content of 2 mg / mL at the maximum, the amount of the drug that can be carried by the fat emulsion is limited. There is a need for drug-containing fat emulsions that are more transparent and have better stability while still using larger amounts of fats and oils to be supported.
  • lecithin has a weak emulsifying power and is not always easy to handle because of its high viscosity at high concentrations.
  • the present inventor has attempted to develop it to meet such demands, but has not yet found any effective solution.
  • the present invention has excellent transparency and stability, despite the high content of fats and oils so that the fat emulsion can carry a large amount of flurbiprofen axetil.
  • An object of the present invention is to provide a flurbiprofen axetil-containing fat emulsion excellent in safety by using lecithin and a method for producing the same.
  • the present inventor has conducted intensive studies in view of the above points, the content of fats and oils, the weight ratio of flurbiprofen axetil to fats and oils, the total content of flurbiprofen axetil and fats and oils, the content of lecithin as an emulsifier
  • the composition has transparency and excellent stability despite being a flurbiprofen axetil-containing fat emulsion using an oil and fat in an amount exceeding 2 mg / mL. It has been found that by using lecithin as an emulsifier, a flurbiprofen axetil-containing fat emulsion excellent in safety can be produced.
  • the present invention based on the above findings is a flurbiprofen axetil-containing fat emulsion containing flurbiprofen axetil, an oil and fat, an emulsifier, and an aqueous medium as at least components as described in claim 1.
  • the content of the fat and oil is 3 to 50 mg / mL, and the weight ratio of flurbiprofen axetil to the fat and oil (flurbiprofen axetil / oil and fat) is 0.1 to 5 (however, the sum of flurbiprofen axetil and the fat and oil)
  • the content of lecithin as an emulsifier is 20 to 150 mg / mL (50% by weight or less of the lecithin used may be replaced with an emulsifier other than lecithin), and the turbidity is 0.5 or less. It is characterized by being.
  • the flurbiprofen axetil-containing fat emulsion according to claim 2 is characterized in that the average particle diameter of the fat particles is 1 to 150 nm in the flurbiprofen axetil-containing fat emulsion according to claim 1. I do. Further, the flurbiprofen axetil-containing fat emulsion according to claim 3 is the same as the flurbiprofen axetil-containing fat emulsion according to claim 1, except that propylene glycol, glycerin, macrogol, lactic acid, N, N-dimethylacetamide are used.
  • a flurbiprofen axetil-containing fat emulsion according to a fourth aspect is characterized in that, in the flurbiprofen axetil-containing fat emulsion according to the first aspect, a saccharide is further included as a component.
  • the present invention provides a flurbiprofen axetil-containing fat having a turbidity of 0.5 or less, comprising at least a flurbiprofen axetil, an oil or fat, an emulsifier, and an aqueous medium as constituents according to the present invention.
  • a method for producing an emulsion wherein the content of fat and oil is 3 to 50 mg / mL, and the weight ratio of flurbiprofen axetil to fat and oil (flurbiprofen axetil / fat and fat) is 0.1 to 5 (provided that flurbiprofen The total content of fenaxetil and fat is 100 mg / mL at maximum, and the content of lecithin as an emulsifier is 20 to 150 mg / mL (50% by weight or less of the lecithin used may be replaced with an emulsifier other than lecithin). Is emulsified.
  • the emulsification is performed at a pressure of 350 to 1500 bar.
  • the fat emulsion can carry a large amount of flurbiprofen axetil, it has excellent transparency and stability, in addition to the emulsifier
  • lecithin as the above can provide a flurbiprofen axetil-containing fat emulsion excellent in safety and a method for producing the same.
  • the present invention relates to a flurbiprofen axetil-containing fat emulsion comprising at least flurbiprofen axetil, an oil and fat, an emulsifier, and an aqueous medium, wherein the content of the oil and fat is 3 to 50 mg / mL,
  • the weight ratio of profenaxetil is 0.1 to 5 (however, the total content of flurbiprofen axetil and the oil / fat is 100 mg / mL at maximum), and the content of lecithin as an emulsifier Is from 20 to 150 mg / mL (50% by weight or less of the lecithin used may be replaced with an emulsifier other than lecithin), and the turbidity is 0.5 or less.
  • the fats and oils include soybean oil, corn oil, coconut oil, safflower oil, perilla oil, olive oil, castor oil, vegetable oils such as cottonseed oil, animal oils such as lanolin, egg yolk oil, fish oil, liquid paraffin and the like.
  • oils and fats that can be used as oils and fats, such as mineral oils, medium-chain fatty acid triglycerides, chemically synthesized triglycerides, and gelled hydrocarbons, may be used.
  • lecithin is used as an emulsifier.
  • it may be a known lecithin that can be used as an emulsifier, such as egg yolk lecithin, soy lecithin, hydrogenated egg yolk lecithin, hydrogenated soybean lecithin, and the like.
  • 50% by weight or less of lecithin to be used is used as an emulsifier so that the safety of lecithin is exhibited while supplementing the emulsifying power of lecithin or suppressing the increase in viscosity when lecithin is used at a high concentration.
  • polysorbates polyoxyethylene sorbitan fatty acid esters
  • polysorbates 20 40, 60, 65, 80
  • polyoxyethylene castor oil polyoxyethylene hydrogenated castor oil, etc.
  • examples of the aqueous medium include water (pure water, purified water, water for injection, etc.), acetic acid-sodium acetate, boric acid-sodium carbonate, boric acid-sodium tetraborate, hydrochloric acid-sodium tetraborate, Phosphoric acid-sodium phosphate, sodium dihydrogen phosphate-disodium hydrogen phosphate, citric acid-sodium hydroxide, hydrochloric acid-potassium hydrogen phthalate, sodium hydroxide-potassium hydrogen phthalate, citric acid-disodium hydrogen phosphate , Succinic acid-sodium tetraborate, ammonia-ammonium chloride, potassium dihydrogen phosphate-disodium hydrogen phosphate-phosphoric acid, potassium dihydrogen phosphate-disodium hydrogen phosphate-sodium hydroxide, potassium dihydrogen phosphate -Disodium hydrogen phosphate, potassium di
  • the content of fats and oils is defined as 3 to 50 mg / mL because if the amount is less than 3 mg / mL, the amount of flurbiprofen axetil that can be supported by the fat emulsion will decrease, while If the amount is too large, emulsification becomes difficult due to an excessive amount of fats and oils, making it difficult to obtain a fat emulsion having transparency.
  • the content of the fat is preferably 5 to 40 mg / mL, more preferably 7 to 35 mg / mL, and still more preferably 10 to 30 mg / mL.
  • the weight ratio of flurbiprofen axetil to fats and oils is defined as 0.1 to 5 (however, the total content of flurbiprofen axetil and fats and oils is 100 mg / mL at the maximum).
  • the reason is that if it is smaller than 0.1, the amount of fat and oil becomes excessive with respect to flurbiprofen axetil, and unnecessary fats and oils will be administered to patients. This is because the amount of flurbiprofen axetil becomes excessive, the stability of flurbiprofen axetil is impaired, and flurbiprofen axetil is easily aggregated or precipitated.
  • the weight ratio of flurbiprofen axetil to fats and oils is preferably 0.2 to 3, more preferably 0.3 to 2.
  • the reason why the total content of flurbiprofen axetil and the fat or oil is specified as a maximum of 100 mg / mL is that if it is more than 100 mg / mL, emulsification for obtaining a transparent fat emulsion becomes difficult.
  • the total content of flurbiprofen axetil and fat is preferably 3 to 90 mg / mL.
  • the content of lecithin as an emulsifier is defined as 20 to 150 mg / mL.
  • the content is less than 20 mg / mL, emulsification becomes difficult because the amount of fats and oils is too large relative to the amount of lecithin, while the content is more than 150 mg / mL. This is because emulsification becomes difficult because the viscosity of lecithin increases.
  • 50% by weight or less of the lecithin used may be replaced with an emulsifier other than lecithin.
  • the total content of lecithin and an emulsifier other than lecithin is 20 to 150 mg / mL, and is composed of 50% by weight or more of lecithin and 50% by weight or less of an emulsifier other than lecithin.
  • the content of lecithin is preferably 30 to 140 mg / mL, more preferably 50 to 130 mg / mL.
  • the content of flurbiprofen axetil may be, for example, 1 to 30 mg / mL.
  • flurbiprofen axetil having fat solubility is dissolved in the fat or oil, and flurbiprofen axetil which cannot be completely dissolved in the fat or oil can be obtained by mixing water and fat or oil.
  • a greater amount is carried on the fat emulsion.
  • the flurbiprofen axetil-containing fat emulsion of the present invention has a fat content, a weight ratio of flurbiprofen axetil to a fat or oil, a total content of flurbiprofen axetil and a fat, and a lecithin content as an emulsifier.
  • emulsification may be performed a plurality of times (for example, 3 to 50 times) in order to narrow the particle size distribution of fat particles.
  • the fat particles have an average particle size of 150 nm or less, preferably 140 nm or less, by emulsifying using a high-pressure emulsifier, for example, at a pressure of 1500 bar or less, preferably 350 to 1000 bar.
  • a flurbiprofen axetil-containing fat emulsion having a transparency and excellent stability of 0.2 or less is easily obtained.
  • propylene glycol, glycerin, macrogol, lactic acid, N, N-dimethylacetamide, polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, chondroitin sulfate or a salt thereof (sodium) is used as a component of the flurbiprofen axetil-containing fat emulsion of the present invention.
  • the stability of flurbiprofen axetil may be improved, and the fat emulsion may be made isotonic.
  • These contents are desirably 1 to 100 mg / mL, and more desirably 10 to 50 mg / mL.
  • the amount is less than 1 mg / mL, the effect is less likely to be exhibited, while if it is more than 100 mg / mL, the viscosity increases, making emulsification difficult or the fat emulsion being acidified and becoming unstable.
  • a higher fatty acid such as oleic acid, stearic acid, linoleic acid, linolenic acid, palmitic acid, palmitoleic acid, and myristic acid is further used as a component of the flurbiprofen axetil-containing fat emulsion of the present invention, whereby the fat emulsion is obtained. May be stabilized.
  • the content of higher fatty acid is preferably 0.001 to 10 mg / mL, more preferably 0.01 to 5 mg / mL. When the amount is less than 0.001 mg / mL, the effect is difficult to be exerted. On the other hand, when the amount is more than 10 mg / mL, there is a risk that flurbiprofen axetil is deteriorated.
  • a saccharide as a component of the flurbiprofen axetil-containing fat emulsion of the present invention, it is possible to effectively suppress the generation of a precipitate floating which may sometimes occur.
  • Suitable saccharides include monosaccharides such as inositol, glucose, sorbitol, fructose and mannitol, disaccharides such as trehalose, lactose, sucrose and maltose, as well as dextrin, cyclodextrin, dextran and xylitol.
  • the saccharide content is desirably 10 to 600 mg / mL.
  • a pH adjuster or an osmotic pressure adjuster known per se is further used to adjust the pH (for example, 3.5 to 9.0),
  • the fat emulsion may be stabilized by adjusting the pressure.
  • a substance that functions as a preservative, antioxidant, stabilizer, or the like for example, a metal salt of tocopherol or ethylenediaminetetraacetic acid
  • the flurbiprofen axetil-containing fat emulsion of the present invention does not prevent using other drugs in addition to flurbiprofen axetil as a component.
  • the flurbiprofen axetil-containing fat emulsion of the present invention can be easily sterilized by filtration, for example, by setting the average particle size to 150 nm or less, and can also be subjected to high-pressure steam sterilization.
  • the high-pressure steam sterilization is carried out under a general condition (eg, 120 to 122 ° C. ⁇ 10 to 15 minutes) after filling the flurbiprofen axetil-containing fat emulsion of the present invention into a glass ampoule or a synthetic resin container. Just do it.
  • the flurbiprofen axetil-containing fat emulsion of the present invention has excellent stability and can be stored at room temperature (eg, 5 to 30 ° C.).
  • having transparency facilitates the visual confirmation of the presence or absence of alteration or contamination of foreign matter, and the change in the composition, and also gives a patient a sense of security.
  • Example 1 Flurbiprofen axetil 100 mg, commercially available medium-chain fatty acid triglyceride 200 mg, purified egg yolk lecithin (PC-98: manufactured by KUP Corporation, the same applies hereinafter) 500 mg, polysorbate 80 (GS: manufactured by NOF CORPORATION, the same applies hereinafter) 500 mg, propylene glycol 500 mg was weighed, and 500 mg of fructose was added thereto under heating and stirring at about 50 ° C. using a hot stirrer, and mixed uniformly to obtain an oil phase.
  • PC-98 purified egg yolk lecithin
  • polysorbate 80 GS: manufactured by NOF CORPORATION
  • a citric acid-disodium hydrogen phosphate buffer solution (0.18 mol / L, pH 6.0) was prepared, and 7 mL of the buffer solution was added to the oil phase under stirring using a stirrer while adding an ultrasonic emulsifier (SMT). Emulsified for 15 minutes (under water cooling).
  • SMT ultrasonic emulsifier
  • the above-mentioned buffer solution was added to the thus obtained emulsion to make the total volume 10 mL, followed by filtration and sterilization with a cellulose acetate membrane (CA membrane, the same applies hereinafter) of 0.22 ⁇ m ⁇ to obtain the desired turbid flurbiprofen.
  • An axetil-containing fat emulsion was obtained.
  • the physical properties are shown in Table 1.
  • Example 2 A target turbid flurbiprofen axetil-containing fat emulsion was obtained in the same manner as in Example 1 except that the amount of purified egg yolk lecithin was changed to 800 mg and the amount of polysorbate 80 was changed to 200 mg. Was. The physical properties are shown in Table 1.
  • Example 3 Flurbiprofen axetil 100 mg, commercially available medium-chain fatty acid triglyceride 200 mg, purified egg yolk lecithin (PC-98) 500 mg, polysorbate 80 500 mg, and propylene glycol 200 mg were weighed and placed therein at about 50 ° C. using a hot stirrer. Under heating and stirring, 500 mg of trehalose was added and mixed uniformly to obtain an oil phase. On the other hand, a citric acid-disodium hydrogen phosphate buffer solution (0.18 mol / L, pH 6.0) was prepared, and 8 mL of the buffer solution was added to the oil phase while stirring with a stirrer while adding 20 mL to the oil phase using an ultrasonic emulsifier.
  • PC-98 purified egg yolk lecithin
  • the mixture was emulsified for minutes (under water cooling).
  • the above buffer solution was added to the thus obtained emulsion to make the total volume 10 mL, and the solution was sterilized by filtration through a CA membrane having a diameter of 0.22 ⁇ m to obtain a target turbid flurbiprofen axetil-containing fat emulsion. .
  • the physical properties are shown in Table 1.
  • Example 4 Performed except that the citric acid-disodium hydrogen phosphate buffer (0.18 mol / L, pH 6.0) was changed to the citric acid-disodium hydrogen phosphate buffer (0.018 mol / L, pH 6.0) In the same manner as in Example 3, the intended transparent flurbiprofen axetil-containing fat emulsion was obtained.
  • the physical properties are shown in Table 1.
  • Example 5 Flurbiprofen axetil 200 mg, commercially available medium-chain fatty acid triglyceride 400 mg, purified egg yolk lecithin (PC-98) 1 g, polysorbate 80 1 g, propylene glycol 1 g, tocopherol 20 mg, disodium ethylenediaminetetraacetate 2 mg were weighed and taken. While heating and stirring at about 50 ° C. using a hot stirrer, 1 g of fructose was added and uniformly mixed to obtain an oil phase. This oil phase was emulsified with an ultrasonic emulsifier for 20 minutes while adding 15 mL of pure water under stirring using a stirrer.
  • PC-98 purified egg yolk lecithin
  • the pH of the thus obtained emulsion was adjusted to 6.0 by adding a 1N aqueous sodium hydroxide solution, and the mixture was further emulsified by an ultrasonic emulsifier for 5 minutes. Then, pure water was added to adjust the total volume to 20 mL. The solution was sterilized by filtration through a CA membrane having a diameter of 22 ⁇ m to obtain the desired transparent flurbiprofen axetil-containing fat emulsion.
  • the physical properties are shown in Table 1.
  • Example 6 Except that the fructose was changed to trehalose, the same procedure as in Example 5 was carried out to obtain a desired transparent flurbiprofen exetil-containing fat emulsion.
  • the physical properties are shown in Table 1.
  • Example 7 Flurbiprofen axetil 200 mg, commercially available medium-chain fatty acid triglyceride 400 mg, purified egg yolk lecithin (PC-98) 1 g, polysorbate 80 1 g, glycerin 400 mg, tocopherol 20 mg, disodium ethylenediaminetetraacetate 2 mg were weighed, and then hot-dried. 1 g of fructose was added to the mixture under heating and stirring at about 50 ° C. using a stirrer, followed by uniform mixing to obtain an oil phase. This oil phase was emulsified with an ultrasonic emulsifier for 25 minutes while adding 15 mL of pure water under stirring using a stirrer.
  • PC-98 purified egg yolk lecithin
  • the pH of the thus obtained emulsion was adjusted to 6.0 by adding a 1N aqueous sodium hydroxide solution, and the mixture was further emulsified by an ultrasonic emulsifier for 5 minutes. Then, pure water was added to adjust the total volume to 20 mL. The solution was sterilized by filtration through a CA membrane having a diameter of 22 ⁇ m to obtain the desired transparent flurbiprofen axetil-containing fat emulsion.
  • the physical properties are shown in Table 1.
  • Example 8 A target turbid flurbiprofen axetil-containing fat emulsion was obtained in the same manner as in Example 7 except that glycerin was changed to propylene glycol and fructose was changed to trehalose. The physical properties are shown in Table 1.
  • Example 9 400 mg of flurbiprofen axetil, 800 mg of commercially available medium-chain fatty acid triglyceride, 2 g of purified egg yolk lecithin (PC-98), 2 g of polysorbate 80, and 2 g of propylene glycol are weighed, and heated and stirred at about 50 ° C. using a hot stirrer. And uniformly mixed to obtain an oil phase. This oil phase was emulsified with an ultrasonic emulsifier for 40 minutes while adding 28 mL of pure water under stirring using a stirrer. Thereafter, 2 g of fructose was added and dissolved by stirring using a stirrer.
  • PC-98 purified egg yolk lecithin
  • propylene glycol propylene glycol
  • Example 10 A target transparent flurbiprofen axetil-containing fat emulsion was obtained in the same manner as in Example 9 except that propylene glycol was changed to Macrogol 400 and fructose was changed to mannitol. The physical properties are shown in Table 1.
  • Example 11 Except that the amount of purified egg yolk lecithin used was changed to 3 g, the amount of polysorbate 80 used was changed to 1 g, and the fructose was changed to mannitol, the same procedure as in Example 9 was carried out to obtain the desired turbid flurbiprofen. An axetil-containing fat emulsion was obtained. The physical properties are shown in Table 1.
  • Example 12 1 g of flurbiprofen axetil, 2 g of commercially available medium-chain fatty acid triglyceride, 10 g of purified egg yolk lecithin (PC-98), and 10 g of propylene glycol are weighed and uniformly mixed under heating and stirring at about 60 ° C. using a hot stirrer. To the oil phase. To this oil phase, 75 mL of pure water was added little by little under stirring using a Hyflex Disperser (manufactured by SMT, the same applies hereinafter), and after completion of the addition, the mixture was roughly emulsified at 12,000 rpm for 10 minutes.
  • PC-98 purified egg yolk lecithin
  • Example 13 40 mg of flurbiprofen axetil and 80 mg of commercially available medium-chain fatty acid triglyceride were weighed and uniformly mixed under heating and stirring at about 50 ° C. using an ultrasonic cleaner. Separately, 200 mg of purified egg yolk lecithin (PC-98), 200 mg of polysorbate 80 and 200 mg of Macrogol 400 were weighed and uniformly mixed under heating and stirring at about 50 ° C. using an ultrasonic cleaner. After mixing both to form an oil phase, the mixture was emulsified with an ultrasonic emulsifier for 10 minutes while adding 2.5 mL of pure water. Thereafter, 400 mg of trehalose was added and dissolved by stirring using a mixer.
  • PC-98 purified egg yolk lecithin
  • Macrogol 400 200 mg of purified egg yolk lecithin (PC-98), 200 mg of polysorbate 80 and 200 mg of Macrogol 400 were weighed and uniformly mixed under heating and stirring at about 50 ° C. using an ultras
  • the pH of the thus obtained emulsion was adjusted to 6.0 by adding a 1N aqueous solution of sodium hydroxide, and then pure water was added to make the total volume 4 mL. Then, the solution was sterilized by filtration through a CA membrane of 0.22 ⁇ m ⁇ . As a result, a clear flurbiprofen axetil-containing fat emulsion was obtained.
  • the physical properties are shown in Table 1.
  • Example 14 1 g of flurbiprofen axetil, 1 g of commercially available purified soybean oil, 12 g of purified egg yolk lecithin (PC-98), and 5 g of propylene glycol are weighed and uniformly mixed under heating and stirring at about 60 ° C. using a hot stirrer. Oil phase. To this oil phase, 70 mL of pure water was added little by little under stirring using a Hyflex disperser, and after the addition was completed, the mixture was coarsely emulsified at 12,000 rpm for 10 minutes. Pure water was further added to make the total amount 100 mL, followed by precision emulsification using a high-pressure homogenizer.
  • PC-98 purified egg yolk lecithin
  • the emulsification pressure was 1400 bar and the number of emulsifications was 15 (circulation emulsification).
  • the pH of the emulsion thus obtained was adjusted to 6.0 by adding a 1N aqueous solution of sodium hydroxide, and then sterilized by filtration through a CA membrane having a diameter of 0.22 ⁇ m to obtain the desired turbid flurbiprofen axetil.
  • the resulting fat emulsion was obtained.
  • the physical properties are shown in Table 1.
  • Example 15 A target transparent flurbiprofen axetil-containing fat emulsion was obtained in the same manner as in Example 13 except that the amount of the medium-chain fatty acid triglyceride was changed to 40 mg and macrogol 400 was changed to propylene glycol. .
  • the physical properties are shown in Table 1.
  • Example 16 1 g of flurbiprofen axetil, 2 g of medium-chain fatty acid triglyceride, 5 g of purified egg yolk lecithin (PL-100M, manufactured by KUPI), and 5 g of propylene glycol are weighed and uniformly mixed under heating and stirring at about 60 ° C. using a hot stirrer. To obtain an oil phase. To this oil phase, 80 mL of pure water was added little by little under stirring using a Hyflex disperser, and after the addition was completed, the mixture was coarsely emulsified at 12,000 rpm for 10 minutes. Pure water was further added to make the total amount 100 mL, followed by precision emulsification using a high-pressure homogenizer.
  • PL-100M purified egg yolk lecithin
  • the emulsification pressure was 1400 bar and the number of emulsifications was 15 (circulation emulsification).
  • the pH of the emulsion thus obtained was adjusted to 6.4 by adding a 1N aqueous solution of sodium hydroxide, and then sterilized by filtration through a CA membrane having a diameter of 0.22 ⁇ m to obtain the desired turbid flurbiprofen axetil.
  • the resulting fat emulsion was obtained.
  • the physical properties are shown in Table 1.
  • Example 17 Except that propylene glycol was changed to Macrogol 400, a target turbid flurbiprofen axetil-containing fat emulsion was obtained in the same manner as in Example 4. The physical properties are shown in Table 1.
  • Example 18 A desired transparent flurbiprofen axetil-containing fat emulsion was obtained in the same manner as in Example 4 except that propylene glycol was changed to glycerin. The physical properties are shown in Table 1.
  • Example 19 Except that propylene glycol was changed to glycerin, a target turbid flurbiprofen axetil-containing fat emulsion was obtained in the same manner as in Example 3. The physical properties are shown in Table 1.
  • Example 20 200 mg of flurbiprofen axetil, 200 mg of commercially available medium-chain fatty acid triglyceride, 1 g of purified egg yolk lecithin (PC-98), 500 mg of polysorbate 80, and 300 mg of propylene glycol are weighed and placed therein at about 50 ° C. using a hot stirrer. Under heating and stirring, 1 g of trehalose was added and uniformly mixed to obtain an oil phase.
  • PC-98 purified egg yolk lecithin
  • a citric acid-disodium hydrogen phosphate buffer solution (0.018 mol / L, pH 6.0) was prepared, and 16 mL of the buffer solution was added to the oil phase with stirring using a stirrer while adding 20 mL to the oil phase using an ultrasonic emulsifier. The mixture was emulsified for minutes (under water cooling). The above-mentioned buffer solution was added to the thus obtained emulsion to make the total volume 20 mL, and the solution was sterilized by filtration through a CA membrane having a diameter of 0.22 ⁇ m to obtain a desired turbid flurbiprofen axetil-containing fat emulsion. .
  • Table 1 The physical properties are shown in Table 1.
  • Example 21 A desired turbid flurbiprofen axetil-containing fat emulsion was obtained in the same manner as in Example 20, except that propylene glycol was changed to glycerin. The physical properties are shown in Table 1.
  • Example 22 Except that the amount of medium-chain fatty acid triglyceride used was changed to 100 mg and the amount of polysorbate 80 used was changed to 600 mg, a target finely turbid flurbiprofen axetil-containing fat emulsion was prepared in the same manner as in Example 20. Obtained. The physical properties are shown in Table 1.
  • Example 23 Flurbiprofen axetil 150 mg, commercially available medium-chain fatty acid triglyceride 75 mg, purified egg yolk lecithin (PC-98) 750 mg, polysorbate 80 375 mg, macrogol 400 750 mg are weighed and heated at about 50 ° C. using a hot stirrer. Under stirring, the mixture was uniformly mixed to obtain an oil phase. On the other hand, a citric acid-disodium hydrogen phosphate buffer solution (0.018 mol / L, pH 6.0) was prepared, and 12 mL of the buffer solution was added to the oil phase with stirring using a stirrer, while adding 30 mL with an ultrasonic emulsifier.
  • PC-98 purified egg yolk lecithin
  • the mixture was emulsified for minutes (under water cooling).
  • the above-mentioned buffer solution was added to the thus obtained emulsion to make the total volume 15 mL, and the solution was sterilized by filtration through a CA membrane having a diameter of 0.22 ⁇ m to obtain a desired turbid flurbiprofen axetil-containing fat emulsion. .
  • the physical properties are shown in Table 1.
  • Example 24 150 mg of flurbiprofen axetil, 75 mg of commercially available medium-chain fatty acid triglyceride, 750 mg of purified egg yolk lecithin (PC-98), and 375 mg of polysorbate 80 were weighed, and heated and stirred at about 50 ° C. using a hot stirrer. , Trehalose and 750 mg of trehalose were added and mixed uniformly to obtain an oil phase. On the other hand, a citric acid-disodium hydrogen phosphate buffer solution (0.018 mol / L, pH 6.0) was prepared, and 12 mL of the buffer solution was added to the oil phase with stirring using a stirrer, while adding 30 mL with an ultrasonic emulsifier.
  • a citric acid-disodium hydrogen phosphate buffer solution (0.018 mol / L, pH 6.0) was prepared, and 12 mL of the buffer solution was added to the oil phase with stirring using a stirrer, while adding 30 mL
  • the mixture was emulsified for minutes (under water cooling).
  • the above-mentioned buffer solution was added to the thus obtained emulsion to make the total volume 15 mL, and the solution was sterilized by filtration through a CA membrane having a diameter of 0.22 ⁇ m to obtain a desired turbid flurbiprofen axetil-containing fat emulsion. .
  • the physical properties are shown in Table 1.
  • Example 25 150 mg of flurbiprofen axetil, 75 mg of commercially available medium-chain fatty acid triglyceride, 450 mg of purified egg yolk lecithin (PC-98), 300 mg of polysorbate 80, and 225 mg of propylene glycol are weighed and heated and stirred at about 50 ° C. using a hot stirrer. Below, it was uniformly mixed to obtain an oil phase. On the other hand, a citric acid-disodium hydrogen phosphate buffer solution (0.018 mol / L, pH 6.0) was prepared, and 12 mL of the buffer solution was added to the oil phase with stirring using a stirrer, while adding 30 mL with an ultrasonic emulsifier.
  • PC-98 purified egg yolk lecithin
  • the mixture was emulsified for minutes (under water cooling).
  • the above-mentioned buffer solution was added to the thus obtained emulsion to make the total volume 15 mL, and the solution was sterilized by filtration through a CA membrane having a diameter of 0.22 ⁇ m to obtain a target turbid flurbiprofen axetil-containing fat emulsion. .
  • the physical properties are shown in Table 1.
  • Example 26 150 mg of flurbiprofen axetil, 450 mg of commercially available medium-chain fatty acid triglyceride, 750 mg of purified egg yolk lecithin (PC-98), 750 mg of polysorbate 80, and 300 mg of propylene glycol are weighed and placed therein at about 50 ° C. using a hot stirrer. Under heating and stirring, 450 mg of trehalose was added and uniformly mixed to obtain an oil phase.
  • PC-98 purified egg yolk lecithin
  • propylene glycol 300 mg
  • a citric acid-disodium hydrogen phosphate buffer solution (0.018 mol / L, pH 6.0) was prepared, and 12 mL of the buffer solution was added to the oil phase with stirring using a stirrer, while adding 30 mL with an ultrasonic emulsifier. The mixture was emulsified for minutes (under water cooling). The above-mentioned buffer solution was added to the thus obtained emulsion to make the total volume 15 mL, and the solution was sterilized by filtration through a CA membrane having a diameter of 0.22 ⁇ m to obtain a desired turbid flurbiprofen axetil-containing fat emulsion. .
  • Table 1 The physical properties are shown in Table 1.
  • Example 27 The intended transparent flurbiprofen axetil-containing fat emulsion was obtained in the same manner as in Example 26 except that the amount of polysorbate 80 used was changed to 480 mg. The physical properties are shown in Table 1.
  • Example 28 Flurbiprofen axetil 150 mg, commercially available medium-chain fatty acid triglyceride 450 mg, purified egg yolk lecithin (PC-98) 750 mg, polysorbate 80 750 mg, propylene glycol 200 mg, macrogol 400 300 mg were weighed, and a hot stirrer was used there. Under heating and stirring at about 50 ° C., 450 mg of trehalose was added and uniformly mixed to obtain an oil phase.
  • PC-98 purified egg yolk lecithin
  • a citric acid-disodium hydrogen phosphate buffer solution (0.018 mol / L, pH 6.0) was prepared, and 12 mL of the buffer solution was added to the oil phase with stirring using a stirrer, while adding 30 mL with an ultrasonic emulsifier. The mixture was emulsified for minutes (under water cooling). The above buffer solution was added to the thus obtained emulsion to make the total volume 15 mL, and then the solution was sterilized by filtration through a CA membrane having a diameter of 0.22 ⁇ m to obtain the intended transparent flurbiprofen axetil-containing fat emulsion.
  • Table 1 The physical properties are shown in Table 1.
  • the measurement of the average particle diameter was performed using a particle diameter measuring apparatus (Zetasizer @ Nano ZS: manufactured by Malvern Co.) using a photon correlation method.
  • Example 29 Flurbiprofen having the same physical property values as the flurbiprofen axetil-containing fat emulsion obtained in Example 4 in the same manner as in Example 4 except that the amount of flurbiprofen axetil used is changed to 50 mg. A fenaxetil-containing fat emulsion was obtained.
  • Example 30 Flurbiprofen axetil obtained in Example 4 was obtained in the same manner as in Example 4 except that the amount of flurbiprofen axetil was changed to 200 mg and the amount of medium chain fatty acid triglyceride was changed to 400 mg. A flurbiprofen axetil-containing fat emulsion having the same physical properties as the fat-containing emulsion was obtained.
  • Example 31 Physical properties equivalent to the flurbiprofen axetil-containing fat emulsion obtained in Example 4 in the same manner as in Example 4 except that the citrate-sodium hydrogen phosphate buffer was changed to an acetic acid-sodium acetate buffer. A flurbiprofen axetil-containing fat emulsion having a specific value was obtained.
  • Example 32 Flurbiprofen axetil-containing fat obtained in Example 4 in the same manner as in Example 4 except that the citric acid-disodium hydrogen phosphate buffer is changed to potassium dihydrogen phosphate-sodium hydroxide buffer. A flurbiprofen axetil-containing fat emulsion having the same physical property values as the emulsion was obtained.
  • the present invention has high transparency and excellent stability despite the high content of fats and oils so that the fat emulsion can carry a large amount of flurbiprofen axetil, and additionally has lecithin as an emulsifier. It has industrial applicability in that it can provide a flurbiprofen axetil-containing fat emulsion excellent in safety and a method for producing the same.

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Abstract

Le problème décrit par la présente invention est de fournir : une émulsion de graisse contenant du flurbiprofène-axétil qui, même si la teneur en graisse et en huile est élevée, de telle sorte que l'émulsion de graisse peut transporter une grande quantité de flurbiprofène axétil, possède une transparence et une excellente stabilité, et qui permet en outre d'obtenir une excellente sécurité en conséquence de l'utilisation de lécithine en tant qu'émulsifiant; et un procédé de fabrication de ladite émulsion de graisse contenant du flurbiprofène-axétil. La solution selon l'invention porte sur une émulsion de graisse contenant du flurbiprofène-axétil comprend au moins du flurbiprofène axétil, de la graisse et de l'huile, un émulsifiant et un milieu aqueux en tant que composants constitutifs, l'émulsion de graisse contenant du flurbiprofène-axétil étant caractérisée en ce que : la teneur en graisse et en huile est de 3 à 50 mg/mL; le rapport en poids (flurbiprofène axétil/graisse et huile) du flurbiprofène axétil par rapport à la graisse et à l'huile est de 0,1 à 5 (la teneur totale du flurbiprofène axétil et de la graisse et de l'huile étant de 100 mg/mL au maximum); la teneur en lécithine, qui sert d'émulsifiant, est de 20 à 150 mg/mL (50 % en poids ou moins de la lécithine à employer peut être remplacée par un émulsifiant autre que la lécithine); et la turbidité est de 0,5 ou moins.
PCT/JP2019/028181 2018-07-18 2019-07-18 Émulsion de graisse contenant du flurbiprofène-axétil et son procédé de fabrication WO2020017571A1 (fr)

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Publication number Priority date Publication date Assignee Title
WO2009063962A1 (fr) * 2007-11-16 2009-05-22 Techno Guard Co. Ltd. Emulsion grasse contenant un agent médicinal, et procédé de production de celle-ci
CN104188905A (zh) * 2014-08-28 2014-12-10 河北一品制药有限公司 一种稳定的氟比洛芬酯微纳米乳液及其制备方法

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CN103393631B (zh) * 2013-08-22 2015-04-08 北京蓝丹医药科技有限公司 一种氟比洛芬酯药物组合物

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009063962A1 (fr) * 2007-11-16 2009-05-22 Techno Guard Co. Ltd. Emulsion grasse contenant un agent médicinal, et procédé de production de celle-ci
CN104188905A (zh) * 2014-08-28 2014-12-10 河北一品制药有限公司 一种稳定的氟比洛芬酯微纳米乳液及其制备方法

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