WO2018146829A1 - Émulsion de graisse ainsi que procédé de fabrication de celle-ci, procédé d'amélioration de stabilité d'émulsion de graisse, et agent d'amélioration de stabilité d'émulsion de graisse - Google Patents

Émulsion de graisse ainsi que procédé de fabrication de celle-ci, procédé d'amélioration de stabilité d'émulsion de graisse, et agent d'amélioration de stabilité d'émulsion de graisse Download PDF

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WO2018146829A1
WO2018146829A1 PCT/JP2017/017378 JP2017017378W WO2018146829A1 WO 2018146829 A1 WO2018146829 A1 WO 2018146829A1 JP 2017017378 W JP2017017378 W JP 2017017378W WO 2018146829 A1 WO2018146829 A1 WO 2018146829A1
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Prior art keywords
fat emulsion
histidine
mass
emulsion
salt
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PCT/JP2017/017378
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English (en)
Japanese (ja)
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陽平 天野
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キユーピー株式会社
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Priority to KR1020217034425A priority Critical patent/KR102421538B1/ko
Priority to JP2017526605A priority patent/JP6368862B1/ja
Priority to CN201780001246.2A priority patent/CN108712902A/zh
Priority to KR1020197023284A priority patent/KR20190110563A/ko
Publication of WO2018146829A1 publication Critical patent/WO2018146829A1/fr

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    • 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
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • 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
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • 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
    • A61K47/16—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
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • 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
    • A61K47/44—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
    • A61K9/10—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]

Definitions

  • the present invention relates to a fat emulsion, a method for producing the same, a method for improving the stability of the fat emulsion, and a stability improver for the fat emulsion. More specifically, the present invention relates to a fat emulsion containing flurbiprofen axetil, a method for producing the same, a method for improving the stability of a fat emulsion containing flurbiprofen axetil, and flurbipro The present invention relates to a stability improver of a fat emulsion containing phenaxetyl.
  • a fat emulsion containing flurbiprofen axetil is sold as an analgesic using the analgesic action of flurbiprofen axetil (for example, Non-Patent Document 3).
  • the expiration date of the fat emulsion containing flurbiprofen axetil is 18 months (one and a half years) when stored at room temperature, and the expiration date is short among the fat emulsions. ing. This is considered to be caused mainly by the decomposition of the main agent (flurbiprofen axetil) during storage and the pH of the fat emulsion being lowered.
  • An object of the present invention is to provide a fat emulsion containing flurbiprofen axetil with improved storage stability.
  • the present inventor employs histidine or a salt thereof as a pH buffer for a fat emulsion containing flurbiprofen axetil, thereby decomposing the main ingredient and lowering the pH when the fat emulsion is subjected to heat and autoclaving treatment. It has been found that the degradation of the main ingredient and the decrease in pH when stored for a long period of time can be significantly suppressed.
  • the present invention is based on this novel finding.
  • the present invention relates to the following inventions, for example.
  • (1) contains flurbiprofen axetil, water, vegetable oil, egg yolk lecithin, glycerin, and histidine or a salt thereof, A fat emulsion in which the content of histidine or a salt thereof is 0.025 parts by mass or more and 0.19 parts by mass or less in terms of histidine in terms of 1 part by mass of flurbiprofen axetil.
  • the total content of at least one acid selected from the group consisting of phosphoric acid, citric acid, succinic acid, maleic acid and malonic acid is 0.05% by mass or less based on the total amount of the fat emulsion.
  • the fat emulsion according to (1) contains flurbiprofen axetil, water, vegetable oil, egg yolk lecithin, glycerin, and histidine or a salt thereof, A fat emulsion in which the content of histidine or a salt thereof is 0.0
  • a method for producing a fat emulsion containing flurbiprofen axetil Preparing an emulsion composition containing flurbiprofen axetil, water, vegetable oil, egg yolk lecithin, glycerin and histidine or a salt thereof; And heating and autoclaving the emulsion composition.
  • the content of histidine or a salt thereof in the emulsion composition is 0.025 parts by mass or more and 0.19 parts by mass or less in terms of histidine conversion with respect to 1 part by mass of flurbiprofen axetil.
  • a method for improving the stability of a fat emulsion containing flurbiprofen axetil Preparing an emulsion composition containing flurbiprofen axetil, water, vegetable oil, egg yolk lecithin, glycerin and histidine or a salt thereof; Heating and autoclaving the emulsion composition.
  • the content of histidine or a salt thereof in the emulsion composition is 0.025 parts by mass or more and 0.19 parts by mass or less in terms of histidine conversion with respect to 1 part by mass of flurbiprofen axetil.
  • the method according to (7) (9) A stability improver of a fat emulsion containing flurbiprofen axetil, A stability improver containing histidine or a salt thereof as an active ingredient.
  • a fat emulsion containing flurbiprofen axetil having improved storage stability is provided.
  • the decomposition of the main agent (flurbiprofen axetil) and the pH drop of the fat emulsion are remarkably suppressed, the expiration date (quality assurance period) can be extended.
  • 6 is a graph showing the results of Test Example 1.
  • 6 is a graph showing the results of Test Example 2.
  • 10 is a graph showing the results of Test Example 3.
  • 10 is a graph showing the results of Test Example 4.
  • 10 is a graph showing the results of Test Example 5.
  • the present invention contains flurbiprofen axetil, water, vegetable oil, egg yolk lecithin, glycerin, and histidine or a salt thereof, and the content of histidine or a salt thereof is flurbiprofen axetil It is characterized by providing a fat emulsion that is 0.025 parts by mass or more and 0.19 parts by mass or less in terms of histidine in terms of 1 part by mass.
  • the present invention also includes a step of preparing an emulsion composition containing flurbiprofen axetil, water, vegetable oil, egg yolk lecithin, glycerin and histidine or a salt thereof, and a step of heat and autoclaving the emulsion composition. And a method for producing a fat emulsion containing flurbiprofen axetil.
  • the present invention further includes a step of preparing an emulsified composition containing flurbiprofen axetil, water, vegetable oil, egg yolk lecithin, glycerin and histidine or a salt thereof, a step of heat and autoclaving the emulsified composition, And a method for improving the stability of a fat emulsion containing flurbiprofen axetil.
  • the present invention is further characterized by providing a stability improver for a fat emulsion containing flurbiprofen axetil containing histidine or a salt thereof as an active ingredient.
  • Flurbiprofen axetyl is a compound also called ( ⁇ ) -1-acetoxyethyl 2- (2-fluoro-4-biphenylyl) propionate.
  • Flurbiprofen axetil is known for its analgesic action and is used as an analgesic. Flurbiprofen axetil can be used without particular limitation as long as it is pharmaceutically acceptable.
  • the content of flurbiprofen axetil in the fat emulsion according to this embodiment can be appropriately set according to the usage and dosage of the fat emulsion, other components contained in the fat emulsion, and the like.
  • the content of flurbiprofen axetil is usually 1 mg / mL or more and 20 mg / mL or less, and may be 8 mg / mL or more and 12 mg / mL or less based on the total amount of the fat emulsion.
  • Flurbiprofen axetil may be synthesized according to a conventional method or may be commercially available.
  • Histidine is a kind of amino acid and is also called 2-amino-3- (1H-imidazo-4-yl) propionic acid.
  • Histidine any pharmaceutically acceptable one can be used without particular limitation.
  • histidine salt is not particularly limited as long as it is a pharmaceutically acceptable salt.
  • specific examples of histidine salts include salts with alkali metals such as sodium and potassium, salts with alkaline earth metals such as calcium and magnesium, and salts with inorganic acids such as hydrochloric acid, hydrobromic acid and nitric acid. It is done.
  • Histidine salts include salt solvates and hydrates.
  • Histidine or a salt thereof may be used alone or in combination of two or more.
  • the content of histidine or a salt thereof in the fat emulsion according to this embodiment can be appropriately set according to the usage and dosage of the fat emulsion, other components contained in the fat emulsion, and the like.
  • the content of histidine or a salt thereof is usually 0.025% by mass or more and 0.2% by mass or less, and 0.05% by mass or more and 0.15% by mass or less in terms of the total amount in terms of histidine based on the total amount of the fat emulsion. There may be.
  • histidine equivalent content means the content when the molecular weight of a histidine salt is converted to the molecular weight of histidine
  • total amount in terms of histidine means the content of the histidine equivalent content. Means the sum.
  • the content of histidine or a salt thereof in the fat emulsion according to the present embodiment is 0.025 parts by mass or more and 0.19 parts by mass or less in terms of histidine conversion with respect to 1 part by mass of flurbiprofen axetil. .
  • the content of histidine or a salt thereof is within this range, the decomposition inhibitory effect of the main agent (flurbiprofen axetil) and the pH reduction inhibitory effect of the fat emulsion are remarkably exhibited.
  • the content of histidine or a salt thereof is 0.19% by mass or less, the average particle size of the fat emulsion after heat and pressure sterilization can be maintained at 400 nm or less, so that the emulsification is further stabilized. Can do. Since these effects can be more remarkably exhibited, the content of histidine or a salt thereof is 0.025 parts by mass or more and 0.15 parts by mass in terms of histidine in terms of 1 part by mass of flurbiprofen axetil. Or less, more preferably 0.05 parts by mass or more and 0.15 parts by mass or less.
  • the content of histidine or a salt thereof in the fat emulsion according to the present embodiment is preferably 0.02 parts by mass or more and 0.15 parts by mass or less in terms of histidine conversion with respect to 1 part by mass of egg yolk lecithin.
  • the content of histidine or a salt thereof is within this range, the decomposition inhibitory effect of the main agent (flurbiprofen axetil) and the pH reduction inhibitory effect of the fat emulsion are remarkably exhibited.
  • the content of histidine or a salt thereof is 0.04 parts by mass or more and 0.15 parts by mass or less in terms of histidine conversion with respect to 1 part by mass of egg yolk lecithin. Is more preferable.
  • histidine or a salt thereof As histidine or a salt thereof, one synthesized or purified according to a conventional method may be used, or a commercially available one may be used.
  • the vegetable oil can be used without particular limitation as long as it is pharmaceutically acceptable.
  • Specific examples of vegetable oils include soybean oil, olive oil, sesame oil, rapeseed oil, peanut oil, sunflower oil, corn oil, safflower oil, cottonseed oil and medium chain fatty acid triglycerides (MCT).
  • MCT medium chain fatty acid triglycerides
  • soybean oil, olive oil and sesame oil are preferable, and soybean oil is more preferable.
  • a vegetable oil may be used individually by 1 type, and may be used in combination of 2 or more type.
  • the content of vegetable oil in the fat emulsion according to the present embodiment can be appropriately set according to the usage and dosage of the fat emulsion, other components contained in the fat emulsion, and the like.
  • the vegetable oil content is usually 50 mg / mL or more and 150 mg / mL or less, and may be 80 mg / mL or more and 120 mg / mL or less based on the total amount of the fat emulsion.
  • vegetable oil As the vegetable oil, one extracted or refined according to a conventional method may be used, or a commercially available one may be used.
  • commercially available vegetable oils include “Japanese Pharmacopoeia Soybean Oil” (manufactured by Kaneda Corporation), “Soybean Oil YM” (manufactured by Nisshin Oillio Group Inc.), “Japanese Pharmacopoeia Sesame Oil” (manufactured by Kaneda Corporation).
  • Egg yolk lecithin is a lipid mainly composed of phospholipid derived from egg yolk.
  • Egg yolk-derived phospholipids may include one or more phosphatidylcholines, phosphatidylethanolamines, phosphatidylserine, phosphatidylinositol, glycerophospholipids such as phosphatidic acid, and sphingophospholipids such as sphingomyelin.
  • Egg yolk lecithin can be used without particular limitation as long as it is pharmaceutically acceptable.
  • Egg yolk lecithin may be used alone or in combination of two or more.
  • the yolk lecithin preferably has a content of phosphatidylethanolamine in the yolk lecithin of 0 to 20% by mass.
  • a content of phosphatidylethanolamine in the yolk lecithin of 0 to 20% by mass.
  • the content of phosphatidylethanolamine in egg yolk lecithin is more preferably 0% by mass or more and 10% by mass or less.
  • the total content of phosphatidylethanolamine should just exist in the said range on the basis of the whole quantity of the combined egg yolk lecithin.
  • the content of egg yolk lecithin in the fat emulsion according to this embodiment can be appropriately set according to the usage and dosage of the fat emulsion, other components contained in the fat emulsion, and the like.
  • the content of egg yolk lecithin is usually 10 mg / mL or more and 20 mg / mL or less, and may be 12 mg / mL or more and 18 mg / mL or less based on the total amount of the fat emulsion.
  • Egg yolk lecithin can be obtained according to a conventional method using egg yolk as a raw material.
  • a commercially available egg yolk lecithin may be used.
  • Examples of commercially available egg yolk lecithin include egg yolk lecithin PL-100M (manufactured by QP Corporation) and purified egg yolk lecithin PC-98N (manufactured by QP Corporation).
  • Egg yolk lecithin with a reduced content of phosphatidylethanolamine can be obtained, for example, by purification using column chromatography, and is commercially available, for example, purified egg yolk lecithin PC-98N (Kewpie Corporation). Manufactured).
  • Glycerin can be used without particular limitation as long as it is pharmaceutically acceptable.
  • the content of glycerin in the fat emulsion according to this embodiment can be appropriately set according to the usage and dosage of the fat emulsion, other components contained in the fat emulsion, and the like.
  • the content of glycerin is usually 10 mg / mL or more and 30 mg / mL or less, and may be 20 mg / mL or more and 25 mg / mL or less based on the total amount of the fat emulsion.
  • Glycerin may be synthesized or purified according to a conventional method, or may be commercially available.
  • the water used in the fat emulsion according to this embodiment is not particularly limited as long as it is pharmaceutically acceptable.
  • examples of water include distilled water, ordinary water, purified water, sterilized purified water, water for injection, and distilled water for injection as defined in the 16th revised Japanese Pharmacopoeia. Water may be added to the balance so that the amount of the fat emulsion becomes a desired amount.
  • the emulsified composition according to this embodiment can be prepared by various known emulsification methods.
  • the following method is mentioned, for example.
  • egg yolk lecithin and flurbiprofen axetil are dispersed in vegetable oil, water, glycerin and histidine or a salt thereof are added, and the mixture is vigorously shaken and pre-emulsified.
  • the pre-emulsified mixture is emulsified with an emulsifier.
  • An emulsified composition can be obtained by adding a pH adjuster to the emulsified liquid and adjusting the pH to a desired value. Histidine or a salt thereof may be added to the emulsion together with a pH adjuster.
  • the emulsified composition prepared by the above-described method may be subjected to heat and pressure sterilization after enclosing it in a container or the like corresponding to the intended preparation form.
  • the heat and pressure sterilization can be performed, for example, by treating at a temperature of 110 ° C. or higher and 130 ° C. or lower and a pressure of 0.1 MPa or higher and 0.3 MPa or lower for 1 minute or longer and 1 hour or shorter.
  • the container include an ampule tube, a vial bottle, and a prefilled syringe.
  • the emulsified composition according to the present embodiment contains histidine or a salt thereof, degradation of the main agent (flurbiprofen axetil) and a decrease in pH when subjected to heat and pressure sterilization can be significantly suppressed.
  • the fat emulsion according to this embodiment may be an emulsified composition itself prepared by the above-described method, or may be formulated through a heat and pressure sterilization treatment.
  • the fat emulsion according to this embodiment preferably does not substantially contain at least one acid selected from the group consisting of phosphoric acid, citric acid, succinic acid, maleic acid and malonic acid. This is because these acids can not only suppress the decomposition of the main agent (flurbiprofen axetil) and the pH drop of the fat emulsion, but may also promote the reverse. Therefore, in the fat emulsion according to this embodiment, the total content of at least one acid selected from the group consisting of phosphoric acid, citric acid, succinic acid, maleic acid and malonic acid is based on the total amount of the fat emulsion. 0.05 mass% or less, and more preferably 0.025 mass% or less. The lower limit of the total content of these acids may be 0% by mass.
  • the fat emulsion according to this embodiment can remarkably suppress the decomposition of the main agent (flurbiprofen axetil) when the fat emulsion is subjected to heat and autoclaving treatment, and the decomposition of the main agent when stored for a long period of time is also remarkable. Is suppressed.
  • Flurbiprofen is one of the components produced by the decomposition of flurbiprofen axetil. Therefore, the content of flurbiprofen, which is a degradation product of flurbiprofen axetil, in the fat emulsion according to this embodiment may be a predetermined value or less.
  • the content of flurbiprofen immediately after sterilizing the fat emulsion by heating and autoclaving may be 0.1 mg / mL or less based on the total amount of the fat emulsion. .05 mg / mL or less.
  • the lower limit of the content of flurbiprofen may be 0 mg / mL.
  • the ratio of flurbiprofen to flurbiprofen axetil immediately after sterilization by heating and autoclaving the fat emulsion may be 0.01 or less by mass, It may be 0.005 or less.
  • the lower limit of the ratio may be zero.
  • the fat emulsion according to the present embodiment has, for example, a flurbiprofen content of 0 when the fat emulsion is heated and sterilized and stored at 60 ° C. for 6 weeks, based on the total amount of the fat emulsion. It may be from 0.01 mg / mL to 1.5 mg / mL, and may be from 0.01 mg / mL to 1.2 mg / mL.
  • the ratio of flurbiprofen to flurbiprofen axetil when the fat emulsion is sterilized by heating and autoclaving and then stored at 60 ° C. for 6 weeks is a mass ratio, It may be 0.001 or more and 0.15 or less, and may be 0.001 or more and 0.12 or less.
  • the fat emulsion according to the present embodiment has a flurbiprofen content of 0.65 mg / mL or less even when subjected to a severe test (stored at 60 ° C. for 4 weeks) corresponding to two years of storage at room temperature. It is often done. Therefore, in the fat emulsion according to this embodiment, for example, the content of flurbiprofen may be 0.2 mg / mL or more and 0.65 mg / mL or less based on the total amount of the fat emulsion. In the fat emulsion according to this embodiment, for example, the ratio of flurbiprofen to flurbiprofen axetil may be 0.02 or more and 0.065 or less in terms of mass ratio.
  • the pH of the fat emulsion according to this embodiment can be appropriately set according to the usage and dosage of the fat emulsion, the components contained in the fat emulsion, and the like.
  • the pH of the fat emulsion according to this embodiment is usually 3 or more and 8 or less, and may be 4 or more and 7 or less.
  • the average particle size of the fat emulsion according to this embodiment is not particularly limited, but may be 450 nm or less. Thereby, it becomes a thing suitable as an injection. From the same viewpoint, the average particle size of the fat emulsion may be 150 nm or more and 400 nm or less. In the present specification, the average particle size of the fat emulsion means a volume-based average particle size.
  • the average particle size of the fat emulsion can be measured by, for example, a particle size distribution measuring device (for example, Coulter N4Plus submicron particle size distribution measuring device, manufactured by Beckman Coulter, Inc.).
  • the average particle size of the fat emulsion can be adjusted, for example, by changing the emulsification conditions. More specifically, for example, by setting the processing pressure of the emulsifier to 50 MPa or more and 200 MPa or less, and setting the number of passes through the emulsifier to 3 passes or more and 30 passes or less, the average particle size of the fat emulsion is increased. Adjustment can be made within the above-mentioned range.
  • the preparation form of the fat emulsion according to the present embodiment is not particularly limited, and may be, for example, an injection or an oral preparation.
  • the present invention includes a step of preparing an emulsion composition containing flurbiprofen axetil, water, vegetable oil, egg yolk lecithin, glycerin and histidine or a salt thereof, and a step of heat and autoclaving the emulsion composition. It can also be regarded as a method for improving the stability of a fat emulsion containing flurbiprofen axetil.
  • the present invention relates to a fat emulsion in which histidine or a salt thereof contains flurbiprofen axetil, and the decomposition of the main agent (flurbiprofen axetil) and a decrease in pH when the fat emulsion is subjected to heat and autoclaving treatment. This is based on the finding that it is possible to remarkably suppress the degradation of the main ingredient and a decrease in pH when stored for a long period of time. Therefore, as one aspect of the present invention, there is provided a fat emulsion stability improver containing flurbiprofen axetil containing histidine or a salt thereof as an active ingredient.
  • the stability improver according to this embodiment may be histidine or a salt thereof itself, and if necessary, a pharmaceutically acceptable additive (excipient, binder, lubricant, disintegrant, base, It may further contain a solubilizing agent or the like).
  • a pharmaceutically acceptable additive excipient, binder, lubricant, disintegrant, base, It may further contain a solubilizing agent or the like.
  • histidine or a salt thereof may be used alone, or two or more kinds may be used in combination.
  • the aspect related to the stability improver described above is the use or application of a stability improver containing histidine or a salt thereof as an active ingredient for improving the stability of a fat emulsion containing flurbiprofen axetil. It can also be captured.
  • the average particle size of the emulsion composition or fat emulsion was determined as a volume-based average particle size using a particle size distribution analyzer (Coulter N4Plus submicron particle size distribution analyzer, manufactured by Beckman Coulter, Inc.).
  • ⁇ PH measurement> The pH of the emulsified composition or fat emulsion was measured with a pH meter (desktop pH meter, manufactured by Horiba, Ltd.).
  • the emulsion composition was prepared by the following method. 6 g of egg yolk lecithin (yolk lecithin PL-100M, manufactured by QP Corporation) and 5 g of flurbiprofen axetil (manufactured by Wako Pure Chemical Industries, Ltd.) were dispersed in 50 g of soybean oil (Japanese soybean oil, manufactured by Kaneda Corporation).
  • glycerin Natural Densetsu glycerin, manufactured by Sakamoto Yakuhin Kogyo Co., Ltd.
  • pre-emulsification was performed by vigorous shaking and stirring.
  • the pre-emulsified mixed solution was emulsified with an emulsifier (high pressure homogenizer LAB200, manufactured by SMT Co., Ltd.) under conditions of 70 MPa and 10 passes.
  • emulsifier high pressure homogenizer LAB200, manufactured by SMT Co., Ltd.
  • a pH adjuster hydroochloric acid or sodium hydroxide
  • the emulsion composition was obtained by adding water so that the total weight was 500 g.
  • the heat and pressure sterilization treatment (hereinafter, also simply referred to as “sterilization treatment”) was performed for 20 minutes under the conditions of 121 ° C. and 0.1 MPa after dispensing the emulsified composition into 5 mL ampules.
  • ⁇ Severe test> The severe test was conducted by storing the fat emulsion at 60 ° C. for 6 weeks. Flurbiprofen quantification and pH measurement were performed at 0, 2, 4, and 6 weeks after the start of the severe test. The severe test of 4 weeks corresponds to 2 years of normal temperature storage.
  • Example 2 Examination of histidine content
  • the content of histidine is 0.025% by mass (Example 2), 0.05% by mass (Example 3), 0.1% by mass (Example 4), 0.2% by mass (Example 5) or 0.
  • An emulsified composition having a content of 3% by mass (Example 6) was prepared.
  • the emulsion composition of the comparative example 7 which used phosphoric acid and citric acid together as a buffering agent phosphoric acid 0.02 mass%, citric acid 0.01 mass
  • the emulsion composition which does not add a buffering agent (Comparative Example 8) was prepared.
  • the emulsified composition of each Example and Comparative Example was sterilized to obtain a fat emulsion of each Example and Comparative Example.
  • the fat emulsions of each Example and Comparative Example were subjected to quantification of flurbiprofen, measurement of average particle diameter, and pH measurement before and after sterilization treatment. After the sterilization treatment, the fat emulsions of the examples and comparative examples were subjected to a severe test, and flurbiprofen was quantitatively measured and pH measurements were periodically performed. The results are shown in Tables 3 to 5 and FIGS. 2 (A) to (D).
  • FIGS. 2 (C) and (D) show the quantitative results of flurbiprofen and the pH measurement results during a severe test.
  • the results for the fat emulsion of Comparative Example 8 are not shown in FIGS. 2 (C) and (D).
  • the decomposition of the main agent (flurbiprofen axetil) and the decrease in pH were suppressed as compared with the fat emulsion of Comparative Example 7.
  • the histidine content is 0.05% by mass or more, this suppression effect is remarkably exhibited.
  • Table 5 shows the measurement results of the average particle size of the fat emulsion before and after sterilization.
  • the fat emulsions of Examples 2 to 4 having a histidine content of less than 0.20 parts by mass with respect to 1 part by mass of flurbiprofen axetil maintained an average particle size of 400 nm or less even after sterilization. And the emulsification was more stabilized.
  • Example 3 Comparison with commercially available preparation
  • a buffering agent an emulsified composition to which 0.1% by mass of histidine was added (Example 7) and an emulsified composition in which phosphoric acid and citric acid were used together (Comparative Example 9: 0.02% by mass of phosphoric acid, 0. 1% of citric acid). 01 mass%) was prepared and sterilized to obtain fat emulsions of Example 7 and Comparative Example 9.
  • a commercially available fat emulsion containing flurbiprofen axetil Lipion (registered trademark), Kaken Pharmaceutical Co., Ltd.) (Comparative Example 10) was prepared.
  • the fat emulsion of Example 7 clearly inhibited the decomposition of the main agent (flurbiprofen axetil) as compared with the fat emulsion of Comparative Example 9 and the commercial preparation of Comparative Example 10.
  • Example 5 Examination of reduction effect of phosphatidylethanolamine content
  • a buffering agent As a buffering agent, an emulsified composition to which 0.1% by mass of histidine was added (Example 9) and an emulsified composition in which phosphoric acid and citric acid were used in combination (Comparative Example 12: phosphoric acid 0.02% by mass, citric acid 0. 01 mass%) was prepared and sterilized to obtain fat emulsions of Example 9 and Comparative Example 12.
  • Example 10 egg yolk lecithin, PL-100M (manufactured by QP Corporation) and PC-98N (manufactured by QP Corporation, phosphatidylethanolamine content 0.1 mass% or less) mixed at 1: 2 (PE content 6%) ) was used, and an emulsified composition (Example 10) with 0.1% by mass of histidine added as a buffer was prepared and sterilized to obtain a fat emulsion of Example 10.
  • the fat emulsion of Example 9 using histidine clearly inhibited the decomposition of the main agent (flurbiprofen axetil). It was. Furthermore, the fat emulsion of Example 10 using egg yolk lecithin with a reduced phosphatidylethanolamine content (PE content) was more decomposed than the fat emulsion of Example 9 (flurbiprofen axetil). Was significantly suppressed.

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Abstract

L'invention concerne une émulsion de graisse qui comprend un flurbiprofène axétil, une eau, une huile végétale, une lécithine de jaune d'œuf, une glycérine, et une histidine ou un sel de celle-ci. La teneur en histidine ou sel de celle-ci est supérieure ou égale à 0,025 partie en masse et inférieure ou égale à 0,19 partie en masse, au total en termes d'histidine, pour 1 partie en masse de flurbiprofène axétil.
PCT/JP2017/017378 2017-02-07 2017-05-08 Émulsion de graisse ainsi que procédé de fabrication de celle-ci, procédé d'amélioration de stabilité d'émulsion de graisse, et agent d'amélioration de stabilité d'émulsion de graisse WO2018146829A1 (fr)

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KR1020217034425A KR102421538B1 (ko) 2017-02-07 2017-05-08 지방 유제, 및 그 제조 방법, 지방 유제의 안정성을 향상시키는 방법, 그리고 지방 유제의 안정성 향상제
JP2017526605A JP6368862B1 (ja) 2017-02-07 2017-05-08 脂肪乳剤、及びその製造方法、脂肪乳剤の安定性を向上させる方法、並びに脂肪乳剤の安定性向上剤
CN201780001246.2A CN108712902A (zh) 2017-02-07 2017-05-08 脂肪乳剂、及其制造方法、提高脂肪乳剂的稳定性的方法、以及脂肪乳剂的稳定性提高剂
KR1020197023284A KR20190110563A (ko) 2017-02-07 2017-05-08 지방 유제, 및 그 제조 방법, 지방 유제의 안정성을 향상시키는 방법, 그리고 지방 유제의 안정성 향상제

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