WO2018146829A1 - Fat emulsion and method for producing same, method for improving stability of fat emulsion, and agent for improving stability of fat emulsion - Google Patents

Fat emulsion and method for producing same, method for improving stability of fat emulsion, and agent for improving stability of fat emulsion Download PDF

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Publication number
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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French (fr)
Japanese (ja)
Inventor
陽平 天野
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キユーピー株式会社
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Priority to JP2017526605A priority Critical patent/JP6368862B1/en
Priority to KR1020217034425A priority patent/KR102421538B1/en
Priority to KR1020197023284A priority patent/KR20190110563A/en
Priority to CN201780001246.2A priority patent/CN108712902A/en
Publication of WO2018146829A1 publication Critical patent/WO2018146829A1/en

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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

The present invention pertains to a fat emulsion which comprises flurbiprofen axetil, water, a vegetable oil, egg yolk lecithin, glycerol and histidine or a salt thereof, wherein the total content of histidine or a salt thereof is 0.025-0.19 part by mass inclusive, in terms of histidine, per part by mass of flurbiprofen axetil.

Description

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Fat emulsion, method for producing the same, method for improving stability of fat emulsion, and stability improver for fat emulsion
　本発明は、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に関する。より具体的には、本発明は、フルルビプロフェンアキセチルを含有する脂肪乳剤、及びその製造方法、フルルビプロフェンアキセチルを含有する脂肪乳剤の安定性を向上させる方法、並びにフルルビプロフェンアキセチルを含有する脂肪乳剤の安定性向上剤に関する。 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.
　一般に、医療用医薬品の使用期限は、常温保存で３年程度となっていることが多い。一方、油分、乳化剤及び水を含む水中油型エマルションからなる脂肪乳剤は、一般の医薬品と比べて保存安定性に劣っており、その使用期限は常温保存で通常２年程度である（例えば、非特許文献１及び２）。 Generally, the expiration date of ethical drugs is often about 3 years when stored at room temperature. On the other hand, a fat emulsion comprising an oil-in-water emulsion containing an oil, an emulsifier and water is inferior in storage stability compared to general pharmaceuticals, and its expiration date is usually about two years when stored at room temperature (for example, Patent Documents 1 and 2).
　フルルビプロフェンアキセチルを含有する脂肪乳剤は、フルルビプロフェンアキセチルの鎮痛作用を利用した鎮痛剤として販売されている（例えば、非特許文献３）。 A fat emulsion containing flurbiprofen axetil is sold as an analgesic using the analgesic action of flurbiprofen axetil (for example, Non-Patent Document 3).
　非特許文献３に記載されるとおり、フルルビプロフェンアキセチルを含有する脂肪乳剤の使用期限は、常温保存で１８ヶ月（１年半）であり、脂肪乳剤の中でも使用期限が短いものとなっている。これは、保存時に主剤（フルルビプロフェンアキセチル）が分解すること、及び脂肪乳剤のｐＨが低下することが主な要因であると考えられる。 As described in 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.
　本発明は、保存安定性が向上したフルルビプロフェンアキセチルを含有する脂肪乳剤の提供を目的とする。 An object of the present invention is to provide a fat emulsion containing flurbiprofen axetil with improved storage stability.
　本発明者は、フルルビプロフェンアキセチルを含有する脂肪乳剤のｐＨ緩衝剤としてヒスチジン又はその塩を採用することにより、当該脂肪乳剤を加熱加圧滅菌処理したときの主剤の分解及びｐＨの低下を顕著に抑制できると共に、長期間保存したときの主剤の分解及びｐＨの低下も顕著に抑制できることを見出した。本発明は、この新規な知見に基づくものである。 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.
　すなわち、本発明は、例えば、以下の各発明に関する。
（１）フルルビプロフェンアキセチルと、水と、植物油と、卵黄レシチンと、グリセリンと、ヒスチジン又はその塩と、を含有し、
　ヒスチジン又はその塩の含有量が、フルルビプロフェンアキセチル１質量部に対して、ヒスチジン換算の総量で０．０２５質量部以上０．１９質量部以下である、脂肪乳剤。
（２）リン酸、クエン酸、コハク酸、マレイン酸及びマロン酸からなる群より選択される少なくとも１種の酸の総含有量が、脂肪乳剤の全量を基準として、０．０５質量％以下である、（１）に記載の脂肪乳剤。
（３）加熱加圧滅菌した直後のフルルビプロフェンの含有量が、脂肪乳剤の全量を基準として、０．１ｍｇ／ｍＬ以下である、（１）又は（２）に記載の脂肪乳剤。
（４）前記卵黄レシチンは、ホスファチジルエタノールアミンの含有量が０質量％以上２０質量％以下である、（１）～（３）のいずれかに記載の脂肪乳剤。
（５）フルルビプロフェンアキセチルを含有する脂肪乳剤の製造方法であって、
　フルルビプロフェンアキセチル、水、植物油、卵黄レシチン、グリセリン及びヒスチジン又はその塩を含有する乳化組成物を調製する工程と、
　前記乳化組成物を加熱加圧滅菌する工程と、を含む、製造方法。
（６）前記乳化組成物中のヒスチジン又はその塩の含有量が、フルルビプロフェンアキセチル１質量部に対して、ヒスチジン換算の総量で０．０２５質量部以上０．１９質量部以下である、（５）に記載の製造方法。
（７）フルルビプロフェンアキセチルを含有する脂肪乳剤の安定性を向上させる方法であって、
　フルルビプロフェンアキセチル、水、植物油、卵黄レシチン、グリセリン及びヒスチジン又はその塩を含有する乳化組成物を調製する工程と、
　前記乳化組成物を加熱加圧滅菌する工程と、を含む、方法。
（８）前記乳化組成物中のヒスチジン又はその塩の含有量が、フルルビプロフェンアキセチル１質量部に対して、ヒスチジン換算の総量で０．０２５質量部以上０．１９質量部以下である、（７）に記載の方法。
（９）フルルビプロフェンアキセチルを含有する脂肪乳剤の安定性向上剤であって、
　ヒスチジン又はその塩を有効成分として含有する、安定性向上剤。 That is, 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.
(2) 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).
(3) The fat emulsion according to (1) or (2), wherein the content of flurbiprofen immediately after heat and autoclaving is 0.1 mg / mL or less based on the total amount of the fat emulsion.
(4) The fat emulsion according to any one of (1) to (3), wherein the egg yolk lecithin has a phosphatidylethanolamine content of 0% by mass to 20% by mass.
(5) 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.
(6) 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 manufacturing method as described in (5).
(7) 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.
(8) 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.
　本発明によれば、保存安定性が向上したフルルビプロフェンアキセチルを含有する脂肪乳剤が提供される。本発明の脂肪乳剤は、主剤（フルルビプロフェンアキセチル）の分解、及び脂肪乳剤のｐＨ低下が顕著に抑制されているため、使用期限（品質保証期間）を延長することができる。 According to the present invention, a fat emulsion containing flurbiprofen axetil having improved storage stability is provided. In the fat emulsion of the present invention, since 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.
試験例１の結果を示すグラフである。6 is a graph showing the results of Test Example 1. 試験例２の結果を示すグラフである。6 is a graph showing the results of Test Example 2. 試験例３の結果を示すグラフである。10 is a graph showing the results of Test Example 3. 試験例４の結果を示すグラフである。10 is a graph showing the results of Test Example 4. 試験例５の結果を示すグラフである。10 is a graph showing the results of Test Example 5.
　以下、本発明を実施するための形態について詳細に説明する。ただし、本発明は以下の実施形態に限定されるものではない。 Hereinafter, embodiments for carrying out the present invention will be described in detail. However, the present invention is not limited to the following embodiments.
＜本発明の特徴＞
（脂肪乳剤）
　本発明は、フルルビプロフェンアキセチルと、水と、植物油と、卵黄レシチンと、グリセリンと、ヒスチジン又はその塩と、を含有し、ヒスチジン又はその塩の含有量が、フルルビプロフェンアキセチル１質量部に対して、ヒスチジン換算の総量で０．０２５質量部以上０．１９質量部以下である、脂肪乳剤を提供することに特徴を有する。 <Features of the present invention>
(Fat emulsion)
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.
（脂肪乳剤の製造方法）
　本発明はまた、フルルビプロフェンアキセチル、水、植物油、卵黄レシチン、グリセリン及びヒスチジン又はその塩を含有する乳化組成物を調製する工程と、当該乳化組成物を加熱加圧滅菌する工程と、を含む、フルルビプロフェンアキセチルを含有する脂肪乳剤の製造方法を提供することに特徴を有する。 (Method for producing fat emulsion)
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.
（脂肪乳剤の安定性を向上させる方法）
　本発明はさらに、フルルビプロフェンアキセチル、水、植物油、卵黄レシチン、グリセリン及びヒスチジン又はその塩を含有する乳化組成物を調製する工程と、当該乳化組成物を加熱加圧滅菌する工程と、を含む、フルルビプロフェンアキセチルを含有する脂肪乳剤の安定性を向上させる方法を提供することに特徴を有する。 (Method to improve the stability of fat emulsion)
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.
（安定性向上剤）
　本発明はさらにまた、ヒスチジン又はその塩を有効成分として含有する、フルルビプロフェンアキセチルを含有する脂肪乳剤の安定性向上剤を提供することに特徴を有する。 (Stability improver)
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.
＜フルルビプロフェンアキセチル＞
　フルルビプロフェンアキセチルは、（±）－１－アセトキシエチル２－（２－フルオロ－４－ビフェニリル）プロピオネートとも称される化合物である。フルルビプロフェンアキセチルには、鎮痛作用が知られており、鎮痛剤として利用されている。フルルビプロフェンアキセチルとしては、薬学上許容されるものであれば、特に制限なく使用することができる。 <Flurbiprofen axetyl>
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.
＜脂肪乳剤中のフルルビプロフェンアキセチルの含有量＞
　本実施形態に係る脂肪乳剤中のフルルビプロフェンアキセチルの含有量は、脂肪乳剤の用法及び用量、脂肪乳剤に含まれる他の成分等に応じて適宜設定することができる。フルルビプロフェンアキセチルの含有量は、脂肪乳剤全量を基準として、通常１ｍｇ／ｍＬ以上２０ｍｇ／ｍＬ以下であり、８ｍｇ／ｍＬ以上１２ｍｇ／ｍＬ以下であってもよい。 <Content of flurbiprofen axetil in fat emulsion>
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.
＜フルルビプロフェンアキセチルの入手方法＞
　フルルビプロフェンアキセチルは、常法に従って合成したものを使用してもよく、また市販されているものを使用してもよい。 <How to obtain flurbiprofen axetil>
Flurbiprofen axetil may be synthesized according to a conventional method or may be commercially available.
＜ヒスチジン又はその塩＞
　ヒスチジンは、アミノ酸の一種であり、２－アミノ－３－（１Ｈ－イミダゾ－４－イル）プロピオン酸とも称される。ヒスチジンとしては、薬学上許容されるものであれば、特に制限なく使用することができる。 <Histidine or its salt>
Histidine is a kind of amino acid and is also called 2-amino-3- (1H-imidazo-4-yl) propionic acid. As histidine, any pharmaceutically acceptable one can be used without particular limitation.
　ヒスチジンの塩としては、薬学上許容される塩であれば特に制限されない。ヒスチジンの塩の具体例としては、ナトリウム、カリウム等のアルカリ金属との塩、カルシウム、マグネシウム等のアルカリ土類金属との塩、塩酸、臭化水素酸、硝酸等の無機酸との塩が挙げられる。ヒスチジンの塩には、塩の溶媒和物及び水和物が含まれる。 The 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.
　ヒスチジン又はその塩は、１種を単独で使用してもよく、２種以上を組み合わせて使用してもよい。 Histidine or a salt thereof may be used alone or in combination of two or more.
＜脂肪乳剤中のヒスチジン又はその塩の含有量＞
　本実施形態に係る脂肪乳剤中のヒスチジン又はその塩の含有量は、脂肪乳剤の用法及び用量、脂肪乳剤に含まれる他の成分等に応じて適宜設定することができる。ヒスチジン又はその塩の含有量は、脂肪乳剤全量を基準として、ヒスチジン換算の総量で通常０．０２５質量％以上０．２質量％以下であり、０．０５質量％以上０．１５質量％以下であってもよい。本明細書において、「ヒスチジン換算の含有量」とは、ヒスチジンの塩の分子量をヒスチジンの分子量に換算したときの含有量を意味し、「ヒスチジン換算の総量」とは、ヒスチジン換算の含有量の総和を意味する。 <Content of histidine or salt thereof in fat emulsion>
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. In the present specification, “histidine equivalent content” means the content when the molecular weight of a histidine salt is converted to the molecular weight of histidine, and the “total amount in terms of histidine” means the content of the histidine equivalent content. Means the sum.
（フルルビプロフェンアキセチルとの含有割合）
　本実施形態に係る脂肪乳剤中のヒスチジン又はその塩の含有量は、フルルビプロフェンアキセチル１質量部に対して、ヒスチジン換算の総量で０．０２５質量部以上０．１９質量部以下である。ヒスチジン又はその塩の含有量がこの範囲内にあることで、主剤（フルルビプロフェンアキセチル）の分解抑制効果、及び脂肪乳剤のｐＨ低下抑制効果が顕著に発揮される。また、ヒスチジン又はその塩の含有量が０．１９質量％以下であると、加熱加圧滅菌した後の脂肪乳剤の平均粒子径を４００ｎｍ以下に保つことができるため、乳化をより安定化することができる。これらの効果をより一層顕著に発揮できることから、ヒスチジン又はその塩の含有量は、フルルビプロフェンアキセチル１質量部に対して、ヒスチジン換算の総量で０．０２５質量部以上０．１５質量部以下であることが好ましく、０．０５質量部以上０．１５質量部以下であることがより好ましい。 (Content ratio with flurbiprofen axetil)
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. . When 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. Further, when 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.
（卵黄レシチンとの含有割合）
　本実施形態に係る脂肪乳剤中のヒスチジン又はその塩の含有量は、卵黄レシチン１質量部に対して、ヒスチジン換算の総量で０．０２質量部以上０．１５質量部以下であることが好ましい。ヒスチジン又はその塩の含有量がこの範囲内にあることで、主剤（フルルビプロフェンアキセチル）の分解抑制効果、及び脂肪乳剤のｐＨ低下抑制効果が顕著に発揮される。これらの効果をより一層顕著に発揮できることから、ヒスチジン又はその塩の含有量は、卵黄レシチン１質量部に対して、ヒスチジン換算の総量で０．０４質量部以上０．１５質量部以下であることがより好ましい。 (Content ratio with egg yolk lecithin)
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. When 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. Since these effects can be exhibited more remarkably, 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.
＜ヒスチジン又はその塩の入手方法＞
　ヒスチジン又はその塩は、常法に従って合成又は精製したものを使用してもよく、また市販されているものを使用してもよい。 <How to obtain 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.
＜植物油＞
　植物油は、薬学上許容されるものであれば、特に制限なく使用することができる。植物油の具体例としては、ダイズ油、オリーブ油、ゴマ油、ナタネ油、ラッカセイ油、ヒマワリ油、トウモロコシ油、サフラワー油、綿実油及び中鎖脂肪酸トリグリセリド（ＭＣＴ）が挙げられる。植物油としては、ダイズ油、オリーブ油及びゴマ油が好ましく、ダイズ油がより好ましい。植物油は、１種を単独で使用してもよく、２種以上を組み合わせて使用してもよい。 <Vegetable oil>
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). As the vegetable oil, 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.
＜脂肪乳剤中の植物油の含有量＞
　本実施形態に係る脂肪乳剤中の植物油の含有量は、脂肪乳剤の用法及び用量、脂肪乳剤に含まれる他の成分等に応じて適宜設定することができる。植物油の含有量は、脂肪乳剤全量を基準として、通常５０ｍｇ／ｍＬ以上１５０ｍｇ／ｍＬ以下であり、８０ｍｇ／ｍＬ以上１２０ｍｇ／ｍＬ以下であってもよい。 <Content of vegetable oil in fat emulsion>
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.
＜植物油の入手方法＞
　植物油は、常法に従って搾取又は精製したものを使用してもよく、また市販されているものを使用してもよい。市販されている植物油としては、例えば、「日本薬局方　ダイズ油」（カネダ株式会社製）、「大豆油ＹＭ」（日清オイリオグループ株式会社製）、「日本薬局方　ゴマ油」（カネダ株式会社製）、「日本薬局方　オリブ油」（カネダ株式会社製）、「ココナードＭＴ」（花王株式会社製）、「ココナードＲＫ」（花王株式会社製）、「日本薬局方　ラッカセイ油」（カネダ株式会社製）、「日本薬局方　トウモロコシ油」（カネダ株式会社製）、「日本薬局方　ナタネ油」（カネダ株式会社製）等が挙げられる。 <How to obtain 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. Examples of 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). ), “Japanese Pharmacopoeia Olive Oil” (manufactured by Kaneda Corporation), “Coconard MT” (manufactured by Kao Corporation), “Coconard RK” (manufactured by Kao Corporation), “Japan Pharmacopoeia Peanut Oil” (manufactured by Kaneda Corporation) ), “Japanese Pharmacopoeia Corn Oil” (manufactured by Kaneda Corporation), “Japanese Pharmacopoeia Rapeseed Oil” (manufactured by Kaneda Corporation), and the like.
＜卵黄レシチン＞
　卵黄レシチンは、卵黄由来のリン脂質を主成分とする脂質である。卵黄由来のリン脂質には、ホスファチジルコリン、ホスファチジルエタノールアミン、ホスファチジルセリン、ホスファチジルイノシトール、ホスファチジン酸等のグリセロリン脂質、スフィンゴミエリン等のスフィンゴリン脂質等の１種又は２種以上が含まれ得る。卵黄レシチンとしては、薬学上許容されるものであれば、特に制限なく使用することができる。卵黄レシチンは、１種を単独で使用してもよく、２種以上を組み合わせて使用してもよい。 <Yeast yolk lecithin>
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.
＜卵黄レシチン中のホスファチジルエタノールアミンの含有量＞
　卵黄レシチンは、卵黄レシチン中のホスファチジルエタノールアミンの含有量が０質量％以上２０質量％以下であることが好ましい。卵黄レシチン中のホスファチジルエタノールアミンの含有量がこのように低減されていることにより、主剤（フルルビプロフェンアキセチル）の分解抑制効果、及び脂肪乳剤のｐＨ低下抑制効果がより一層顕著に発揮される。同様の観点から、卵黄レシチン中のホスファチジルエタノールアミンの含有量が０質量％以上１０質量％以下であることがより好ましい。なお、２種以上の卵黄レシチンを組み合わせて使用する場合は、組み合わせた卵黄レシチンの全量を基準として、ホスファチジルエタノールアミンの総含有量が上記範囲内にあればよい。 <Content of phosphatidylethanolamine in egg yolk lecithin>
The yolk lecithin preferably has a content of phosphatidylethanolamine in the yolk lecithin of 0 to 20% by mass. By reducing the content of phosphatidylethanolamine in egg yolk lecithin in this way, the effect of inhibiting the decomposition of the main agent (flurbiprofen axetil) and the effect of reducing the pH of fat emulsions are more prominently exhibited. The From the same viewpoint, the content of phosphatidylethanolamine in egg yolk lecithin is more preferably 0% by mass or more and 10% by mass or less. In addition, when using combining 2 or more types of egg yolk lecithin, 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.
＜脂肪乳剤中の卵黄レシチンの含有量＞
　本実施形態に係る脂肪乳剤中の卵黄レシチンの含有量は、脂肪乳剤の用法及び用量、脂肪乳剤に含まれる他の成分等に応じて適宜設定することができる。卵黄レシチンの含有量は、脂肪乳剤全量を基準として、通常１０ｍｇ／ｍＬ以上２０ｍｇ／ｍＬ以下であり、１２ｍｇ／ｍＬ以上１８ｍｇ／ｍＬ以下であってもよい。 <Content of egg yolk lecithin in fat emulsion>
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.
＜卵黄レシチンの入手方法＞
　卵黄レシチンは、卵黄を原料として常法に従って得ることができる。卵黄レシチンは、市販されているものを使用してもよい。市販されている卵黄レシチンとしては、例えば、卵黄レシチンＰＬ－１００Ｍ（キユーピー株式会社製）、精製卵黄レシチンＰＣ－９８Ｎ（キユーピー株式会社製）が挙げられる。ホスファチジルエタノールアミンの含有量が低減された卵黄レシチンは、例えば、カラムクロマトグラフィーを用いた精製により得ることができ、また、市販されているものとして、例えば、精製卵黄レシチンＰＣ－９８Ｎ（キユーピー株式会社製）が挙げられる。 <How to obtain egg yolk lecithin>
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).
＜グリセリン＞
　グリセリンとしては、薬学上許容されるものであれば、特に制限なく使用することができる。 <Glycerin>
Glycerin can be used without particular limitation as long as it is pharmaceutically acceptable.
＜脂肪乳剤中のグリセリンの含有量＞
　本実施形態に係る脂肪乳剤中のグリセリンの含有量は、脂肪乳剤の用法及び用量、脂肪乳剤に含まれる他の成分等に応じて適宜設定することができる。グリセリンの含有量は、脂肪乳剤全量を基準として、通常１０ｍｇ／ｍＬ以上３０ｍｇ／ｍＬ以下であり、２０ｍｇ／ｍＬ以上２５ｍｇ／ｍＬ以下であってもよい。 <Content of glycerin in fat emulsion>
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.
＜グリセリンの入手方法＞
　グリセリンは、常法に従って合成又は精製したものを使用してもよく、また市販されているものを使用してもよい。 <How to obtain glycerin>
Glycerin may be synthesized or purified according to a conventional method, or may be commercially available.
＜水＞
　本実施形態に係る脂肪乳剤に使用する水は、薬学上許容できるものであれば特に制限されない。水としては、例えば、第十六改正日本薬局方に定義される、蒸留水、常水、精製水、滅菌精製水、注射用水及び注射用蒸留水等を挙げることができる。水は、脂肪乳剤の量が所望の量になるよう残部に添加すればよい。 <Water>
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.
＜乳化組成物の調製方法＞
　本実施形態に係る乳化組成物は、種々の公知の乳化方法により調製することができる。乳化組成物の調製方法の一例として、例えば、以下の方法が挙げられる。植物油中に卵黄レシチン及びフルルビプロフェンアキセチルを分散させた後、水、グリセリン及びヒスチジン又はその塩を添加し、激しく振盪攪拌し予備乳化を行う。予備乳化した混合液を乳化機で乳化する。乳化液にｐＨ調整剤を添加し、目的のｐＨに調整することで乳化組成物を得ることができる。ヒスチジン又はその塩は、ｐＨ調整剤と共に乳化液に添加してもよい。 <Method for preparing emulsified composition>
The emulsified composition according to this embodiment can be prepared by various known emulsification methods. As an example of the preparation method of an emulsion composition, the following method is mentioned, for example. After 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.
（加熱加圧滅菌処理）
　上述した方法により調製された乳化組成物は、目的とする製剤形態に応じた容器等に封入した後、加熱加圧滅菌処理を行ってもよい。加熱加圧滅菌は、例えば、１１０℃以上１３０℃以下の温度、０．１ＭＰａ以上０．３ＭＰａ以下の圧力で１分以上１時間以下処理することで行うことができる。容器としては、例えば、アンプル管、バイアル瓶、プレフィルドシリンジ等が挙げられる。本実施形態に係る乳化組成物は、ヒスチジン又はその塩を含有しているため、加熱加圧滅菌処理したときの主剤（フルルビプロフェンアキセチル）の分解及びｐＨの低下を顕著に抑制できる。 (Heat and pressure sterilization treatment)
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. Examples of the container include an ampule tube, a vial bottle, and a prefilled syringe. Since 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.
＜脂肪乳剤＞
　本実施形態に係る脂肪乳剤は、上述した方法により調製された乳化組成物そのものであってもよく、また加熱加圧滅菌処理を経て製剤化されたものであってもよい。 <Fat emulsion>
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.
＜脂肪乳剤中のクエン酸等の含有量＞
　本実施形態に係る脂肪乳剤は、リン酸、クエン酸、コハク酸、マレイン酸及びマロン酸からなる群より選択される少なくとも１種の酸を実質的に含有しないことが好ましい。これらの酸は、主剤（フルルビプロフェンアキセチル）の分解、及び脂肪乳剤のｐＨ低下を抑制できないのみならず、逆に促進する場合があるからである。したがって、本実施形態に係る脂肪乳剤は、リン酸、クエン酸、コハク酸、マレイン酸及びマロン酸からなる群より選択される少なくとも１種の酸の総含有量が、脂肪乳剤の全量を基準として、０．０５質量％以下であることが好ましく、０．０２５質量％以下であることがより好ましい。これらの酸の総含有量の下限は０質量％であってよい。 <Content of citric acid and the like in the fat emulsion>
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.
＜脂肪乳剤中のフルルビプロフェンの含有量＞
　本実施形態に係る脂肪乳剤は、当該脂肪乳剤を加熱加圧滅菌処理したときの主剤（フルルビプロフェンアキセチル）の分解を顕著に抑制できると共に、長期間保存したときの主剤の分解も顕著に抑制されている。フルルビプロフェンは、フルルビプロフェンアキセチルが分解することで生じる成分の一つである。したがって、本実施形態に係る脂肪乳剤は、当該脂肪乳剤中のフルルビプロフェンアキセチルの分解物であるフルルビプロフェンの含有量が所定値以下であってもよい。 <Content of flurbiprofen in fat emulsion>
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.
　本実施形態に係る脂肪乳剤は、例えば、当該脂肪乳剤を加熱加圧滅菌した直後のフルルビプロフェンの含有量が、脂肪乳剤全量を基準として、０．１ｍｇ／ｍＬ以下であってよく、０．０５ｍｇ／ｍＬ以下であってもよい。フルルビプロフェンの含有量の下限は、０ｍｇ／ｍＬであってよい。本実施形態に係る脂肪乳剤は、例えば、当該脂肪乳剤を加熱加圧滅菌した直後のフルルビプロフェンアキセチルに対するフルルビプロフェンの比率が、質量比で、０．０１以下であってよく、０．００５以下であってもよい。当該比率の下限は、０であってもよい。 In the fat emulsion according to the present embodiment, for example, 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. In the fat emulsion according to the present embodiment, for example, 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.
　また、本実施形態に係る脂肪乳剤は、例えば、当該脂肪乳剤を加熱加圧滅菌した後、６０℃で６週間保存したときのフルルビプロフェンの含有量が、脂肪乳剤全量を基準として、０．０１ｍｇ／ｍＬ以上１．５ｍｇ／ｍＬ以下であってよく、０．０１ｍｇ／ｍＬ以上１．２ｍｇ／ｍＬ以下であってもよい。本実施形態に係る脂肪乳剤は、例えば、当該脂肪乳剤を加熱加圧滅菌した後、６０℃で６週間保存したときのフルルビプロフェンアキセチルに対するフルルビプロフェンの比率が、質量比で、０．００１以上０．１５以下であってよく、０．００１以上０．１２以下であってもよい。 In addition, 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. In the fat emulsion according to this embodiment, for example, 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.
　更に、本実施形態に係る脂肪乳剤は、常温保存２年間に相当する苛酷試験（６０℃で４週間保存）に供したときでも、フルルビプロフェンの含有量が０．６５ｍｇ／ｍＬ以下に抑えられることが多い。したがって、本実施形態に係る脂肪乳剤は、例えば、フルルビプロフェンの含有量が、脂肪乳剤全量を基準として、０．２ｍｇ／ｍＬ以上０．６５ｍｇ／ｍＬ以下であってもよい。本実施形態に係る脂肪乳剤は、例えば、フルルビプロフェンアキセチルに対するフルルビプロフェンの比率が、質量比で、０．０２以上０．０６５以下であってもよい。 Furthermore, 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.
＜脂肪乳剤のｐＨ＞
　本実施形態に係る脂肪乳剤のｐＨは、脂肪乳剤の用法及び用量、脂肪乳剤に含まれる成分等に応じて適宜設定することができる。本実施形態に係る脂肪乳剤のｐＨは、通常３以上８以下であり、４以上７以下であってもよい。 <PH of fat emulsion>
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.
＜脂肪乳剤の平均粒子径＞
　本実施形態に係る脂肪乳剤の平均粒子径は、特に制限されるものではないが、４５０ｎｍ以下であってもよい。これにより、注射剤として適したものとなる。同様の観点から、脂肪乳剤の平均粒子径は、１５０ｎｍ以上４００ｎｍ以下であってもよい。本明細書において、脂肪乳剤の平均粒子径とは、体積基準の平均粒子径を意味する。脂肪乳剤の平均粒子径は、例えば、粒度分布測定装置（例えば、コールターＮ４Ｐｌｕｓサブミクロン粒度分布測定装置，ベックマン・コールター株式会社製）により測定することができる。脂肪乳剤の平均粒子径は、例えば、乳化条件を変更することにより調整することができる。より具体的には、例えば、乳化機の処理圧力を５０ＭＰａ以上２００ＭＰａ以下とすること、乳化機に通液するパス回数を３パス以上３０パス以下とすること等により、脂肪乳剤の平均粒子径を上述の範囲内に調整することができる。 <Average particle size of fat emulsion>
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.
＜脂肪乳剤の製剤形態＞
　本実施形態に係る脂肪乳剤の製剤形態は、特に制限されないが、例えば、注射剤、経口剤等であってもよい。 <Form of fat emulsion>
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.
＜脂肪乳剤の安定性を向上させる方法＞
　本発明は、フルルビプロフェンアキセチル、水、植物油、卵黄レシチン、グリセリン及びヒスチジン又はその塩を含有する乳化組成物を調製する工程と、乳化組成物を加熱加圧滅菌する工程と、を含む、フルルビプロフェンアキセチルを含有する脂肪乳剤の安定性を向上させる方法と捉えることもできる。 <Method for improving stability of fat emulsion>
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.
＜安定性向上剤＞
　本発明は、ヒスチジン又はその塩が、フルルビプロフェンアキセチルを含有する脂肪乳剤において、当該脂肪乳剤を加熱加圧滅菌処理したときの主剤（フルルビプロフェンアキセチル）の分解及びｐＨの低下を顕著に抑制できると共に、長期間保存したときの主剤の分解及びｐＨの低下も顕著に抑制できることを見出したことに基づいている。したがって、本発明の一側面として、ヒスチジン又はその塩を有効成分として含有する、フルルビプロフェンアキセチルを含有する脂肪乳剤の安定性向上剤が提供される。 <Stability improver>
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.
　本実施形態に係る安定性向上剤は、ヒスチジン又はその塩そのものであってもよく、必要に応じて薬学上許容できる添加剤（賦形剤、結合剤、滑沢剤、崩壊剤、基剤、溶解補助剤等）を更に含有するものであってもよい。本実施形態に係る安定性向上剤には、ヒスチジン又はその塩を１種単独で使用してもよく、２種以上を組み合わせて使用してもよい。 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). As the stability improver according to this embodiment, histidine or a salt thereof may be used alone, or two or more kinds may be used in combination.
　上述した安定性向上剤に係る態様は、フルルビプロフェンアキセチルを含有する脂肪乳剤の安定性を向上させるための、ヒスチジン又はその塩を有効成分として含有する安定性向上剤の使用又は応用と捉えることもできる。 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.
　以下、実施例等に基づいて、本発明をより具体的に説明する。ただし、本発明は以下の実施例に限定されるものではない。 Hereinafter, the present invention will be described more specifically based on examples and the like. However, the present invention is not limited to the following examples.
［試験方法］
＜フルルビプロフェンの定量＞
　フルルビプロフェンアキセチルの分解産物の一つであるフルルビプロフェンは、高速液体クロマトグラフィー（日本ウォーターズ社製）を使用し、以下の条件により定量した。
　カラム：Ｗａｔｅｒｓ　Ｅｃｌｉｐｓｅ　ＸＤＢ－Ｃ１８（４．６×１５０ｍｍ，５μｍ）
　移動相：アセトニトリル：水：トリフルオロ酢酸＝６０：４０：０．１
　検出方法：ＵＶ（２６４ｎｍ）
　流速：１ｍＬ／ｍｉｎ
　温度：５０℃ [Test method]
<Quantification of flurbiprofen>
Flurbiprofen, one of the degradation products of flurbiprofen axetil, was quantified using high performance liquid chromatography (Nippon Waters) under the following conditions.
Column: Waters Eclipse XDB-C18 (4.6 × 150 mm, 5 μm)
Mobile phase: acetonitrile: water: trifluoroacetic acid = 60: 40: 0.1
Detection method: UV (264 nm)
Flow rate: 1 mL / min
Temperature: 50 ° C
＜平均粒子径の測定＞
　乳化組成物又は脂肪乳剤の平均粒子径は、粒度分布測定装置（コールターＮ４Ｐｌｕｓサブミクロン粒度分布測定装置，ベックマン・コールター株式会社製）を使用し、体積基準の平均粒子径として求めた。 <Measurement of average particle diameter>
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測定＞
　乳化組成物又は脂肪乳剤のｐＨは、ｐＨメーター（卓上型ｐＨメータ，株式会社堀場製作所製）により測定した。 <PH measurement>
The pH of the emulsified composition or fat emulsion was measured with a pH meter (desktop pH meter, manufactured by Horiba, Ltd.).
＜乳化組成物の調製＞
　各試験例において特記しない限り、乳化組成物は以下の方法により調製した。
　卵黄レシチン６ｇ（卵黄レシチンＰＬ－１００Ｍ，キユーピー株式会社製）フルルビプロフェンアキセチル５ｇ（和光純薬工業株式会社製）を大豆油５０ｇ（日局　ダイズ油，カネダ株式会社製）に分散させた後、水４００ｍＬ、グリセリン２２ｇ（日局　濃グリセリン，阪本薬品工業株式会社製）を添加し、激しく振盪攪拌して予備乳化を行った。予備乳化した混合液を乳化機（高圧ホモジェナイザーＬＡＢ２００，株式会社エスエムテー製）で７０ＭＰａ　１０パスの条件で乳化した。乳化液に各種緩衝剤又はヒスチジン（Ｌ－ヒスチジン，関東化学株式会社製）を添加した後、ｐＨ調整剤（塩酸又は水酸化ナトリウム）を添加し、目的のｐＨ（６．０以上７．０以下）に調整し、全体の重量が５００ｇになるように水を添加することで乳化組成物を得た。 <Preparation of emulsion composition>
Unless otherwise specified in each test example, 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). Thereafter, 400 mL of water and 22 g of glycerin (Nippon Densetsu glycerin, manufactured by Sakamoto Yakuhin Kogyo Co., Ltd.) were added, and 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. After adding various buffers or histidine (L-histidine, manufactured by Kanto Chemical Co., Inc.) to the emulsion, a pH adjuster (hydrochloric acid or sodium hydroxide) is added, and the target pH (6.0 to 7.0) is added. The emulsion composition was obtained by adding water so that the total weight was 500 g.
＜加熱加圧滅菌処理＞
　加熱加圧滅菌処理（以下、単に「滅菌処理」ともいう。）は、乳化組成物を５ｍＬアンプルに分注した後、１２１℃、０．１ＭＰａの条件下で２０分間行った。 <Heat and pressure sterilization>
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.
＜苛酷試験＞
　苛酷試験は、脂肪乳剤を６０℃で６週間保存することにより行った。フルルビプロフェンの定量、及びｐＨ測定は、苛酷試験開始後０週間、２週間、４週間及び６週間の時点で実施した。なお、苛酷試験４週間は、常温保存２年間に相当する。 <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.
［試験例１：緩衝剤の種類の検討］
　緩衝剤として、リン酸とクエン酸の併用（比較例１：リン酸０．０３５質量％，クエン酸０．０１５質量％）、クエン酸（比較例２）、リン酸（比較例３）、コハク酸（比較例４）、マレイン酸（比較例５）、マロン酸（比較例６）又はヒスチジン（実施例１）をそれぞれ０．０５質量％となるように添加して、フルルビプロフェンアキセチルを含有する乳化組成物を調製した。各実施例及び比較例の乳化組成物に対して、滅菌処理を行い、各実施例及び比較例の脂肪乳剤を得た。 [Test Example 1: Examination of buffer type]
As a buffering agent, a combination of phosphoric acid and citric acid (Comparative Example 1: 0.035% by mass of phosphoric acid, 0.015% by mass of citric acid), citric acid (Comparative Example 2), phosphoric acid (Comparative Example 3), and amber An acid (Comparative Example 4), maleic acid (Comparative Example 5), malonic acid (Comparative Example 6) or histidine (Example 1) was added to 0.05% by mass, respectively, and flurbiprofen axetyl was added. An emulsified composition containing was prepared. The emulsified composition of each Example and Comparative Example was sterilized to obtain a fat emulsion of each Example and Comparative Example.
　各実施例及び比較例の脂肪乳剤に対し、滅菌処理前後でのフルルビプロフェンの定量、及びｐＨ測定を実施した。滅菌処理後、各実施例及び比較例の脂肪乳剤を苛酷試験に供し、定期的にフルルビプロフェンの定量、及びｐＨ測定を実施した。結果を表１～２、及び図１（Ａ）～（Ｄ）に示す。 Quantification of flurbiprofen before and after sterilization and pH measurement were carried out on the fat emulsions of the examples and comparative examples. 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 1 and 2 and FIGS. 1 (A) to (D).
　図１（Ａ）及び（Ｂ）は、滅菌処理前後のフルルビプロフェンの定量結果、及びｐＨ測定結果を示す。緩衝剤としてヒスチジンを添加した実施例１の脂肪乳剤では、滅菌前後でフルルビプロフェン（分解物）の量、及びｐＨはほとんど変化していない。一方、比較例１～６の脂肪乳剤では、滅菌前後でフルルビプロフェン（分解物）の量が大きく増加し、ｐＨが大きく低下していた。ヒスチジン以外の緩衝剤は、滅菌処理前後で明らかに主剤（フルルビプロフェンアキセチル）の分解が認められた。 1 (A) and 1 (B) show the quantitative results of flurbiprofen before and after the sterilization treatment, and the pH measurement results. In the fat emulsion of Example 1 to which histidine was added as a buffering agent, the amount of flurbiprofen (degraded product) and the pH were hardly changed before and after sterilization. On the other hand, in the fat emulsions of Comparative Examples 1 to 6, the amount of flurbiprofen (decomposed product) was greatly increased and the pH was greatly decreased before and after sterilization. With the buffer agents other than histidine, degradation of the main agent (flurbiprofen axetil) was clearly observed before and after sterilization.
　図１（Ｃ）及び（Ｄ）は、苛酷試験時のフルルビプロフェンの定量結果、及びｐＨ測定結果を示す。緩衝剤としてヒスチジンを添加した実施例１の脂肪乳剤は、比較例１～６の脂肪乳剤と比べて、主剤（フルルビプロフェンアキセチル）の分解、及びｐＨの低下が抑制されていた。 1 (C) and (D) show the results of quantitative determination of flurbiprofen and the pH measurement results during a severe test. In the fat emulsion of Example 1 to which histidine was added as a buffering agent, decomposition of the main agent (flurbiprofen axetil) and a decrease in pH were suppressed as compared with the fat emulsions of Comparative Examples 1 to 6.
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000002
［試験例２：ヒスチジン含有量の検討］
　ヒスチジンの含有量を０．０２５質量％（実施例２）、０．０５質量％（実施例３）、０．１質量％（実施例４）、０．２質量％（実施例５）又は０．３質量％（実施例６）とした乳化組成物を調製した。また、緩衝剤として、リン酸とクエン酸を併用した比較例７の乳化組成物（リン酸０．０２質量％，クエン酸０．０１質量％）と、緩衝剤を添加していない乳化組成物（比較例８）を調製した。各実施例及び比較例の乳化組成物に対して、滅菌処理を行い、各実施例及び比較例の脂肪乳剤を得た。 [Test 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. Moreover, 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%), and 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.
　各実施例及び比較例の脂肪乳剤に対し、滅菌処理前後でフルルビプロフェンの定量、平均粒子径の測定、及びｐＨ測定を実施した。滅菌処理後、各実施例及び比較例の脂肪乳剤を苛酷試験に供し、定期的にフルルビプロフェンの定量、及びｐＨ測定を実施した。結果を表３～５、及び図２（Ａ）～（Ｄ）に示す。 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).
　図２（Ａ）及び（Ｂ）は、滅菌処理前後のフルルビプロフェンの定量結果、及びｐＨ測定結果を示す。ヒスチジンを添加した実施例２～６の脂肪乳剤では、滅菌前後でフルルビプロフェン（分解物）の量、及びｐＨはほとんど変化していない。一方、緩衝剤としてリン酸とクエン酸を併用した比較例７の脂肪乳剤は、滅菌前後でフルルビプロフェン（分解物）の量が大きく増加し、ｐＨが大きく低下していた。また、緩衝剤を添加していない比較例８の脂肪乳剤は、滅菌前後でフルルビプロフェン（分解物）の量はほとんど変化しなかった（実施例２～６と同程度）ものの、ｐＨが著しく低下していた。比較例７と比較例８の対比から、リン酸及びクエン酸は、主剤（フルルビプロフェンアキセチル）の分解を促進していると考えられる。 2 (A) and 2 (B) show the quantitative results of flurbiprofen before and after the sterilization treatment and the pH measurement results. In the fat emulsions of Examples 2 to 6 to which histidine was added, the amount of flurbiprofen (degraded product) and the pH were hardly changed before and after sterilization. On the other hand, in the fat emulsion of Comparative Example 7 in which phosphoric acid and citric acid were used in combination as the buffering agent, the amount of flurbiprofen (degraded product) increased greatly before and after sterilization, and the pH decreased significantly. Further, in the fat emulsion of Comparative Example 8 to which no buffer was added, although the amount of flurbiprofen (degraded product) hardly changed before and after sterilization (same as in Examples 2 to 6), the pH was It was significantly reduced. From the comparison between Comparative Example 7 and Comparative Example 8, it is considered that phosphoric acid and citric acid promote the decomposition of the main agent (flurbiprofen axetyl).
　図２（Ｃ）及び（Ｄ）は、苛酷試験時のフルルビプロフェンの定量結果、及びｐＨ測定結果を示す。なお、比較例８の脂肪乳剤における結果は、図２（Ｃ）及び（Ｄ）には示していない。緩衝剤としてヒスチジンを添加した実施例２～６の脂肪乳剤は、比較例７の脂肪乳剤と比べて、主剤（フルルビプロフェンアキセチル）の分解、及びｐＨの低下が抑制されていた。特に、ヒスチジンの含有量が０．０５質量％以上である場合に、この抑制効果が顕著に奏されていた。 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). In the fat emulsions of Examples 2 to 6 to which histidine was added as a buffering agent, 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. In particular, when the histidine content is 0.05% by mass or more, this suppression effect is remarkably exhibited.
　表５は、滅菌処理前後の脂肪乳剤の平均粒子径の測定結果を示す。ヒスチジンの含有量が、フルルビプロフェンアキセチル１質量部に対して、０．２０質部未満である実施例２～４の脂肪乳剤は、滅菌後も平均粒子径が４００ｎｍ以下に保たれており、乳化がより安定化されていた。 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.
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000004
Figure JPOXMLDOC01-appb-T000004
Figure JPOXMLDOC01-appb-T000005
Figure JPOXMLDOC01-appb-T000005
［試験例３：市販製剤との比較検討］
　緩衝剤として、ヒスチジンを０．１質量％添加した乳化組成物（実施例７）及びリン酸とクエン酸を併用した乳化組成物（比較例９：リン酸０．０２質量％，クエン酸０．０１質量％）を調製し、滅菌処理を行い実施例７及び比較例９の脂肪乳剤を得た。また、比較対照として、市販されているフルルビプロフェンアキセチル含有脂肪乳剤（ロピオン（登録商標），科研製薬株式会社）（比較例１０）を用意した。 [Test Example 3: Comparison with commercially available preparation]
As 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. As a comparative control, a commercially available fat emulsion containing flurbiprofen axetil (Lopion (registered trademark), Kaken Pharmaceutical Co., Ltd.) (Comparative Example 10) was prepared.
　各実施例及び比較例の脂肪乳剤を苛酷試験に供し、定期的にフルルビプロフェンの定量を実施した。結果を表６及び図３に示す。 The fat emulsions of each Example and Comparative Example were subjected to a severe test, and flurbiprofen was regularly quantified. The results are shown in Table 6 and FIG.
　図３に示すとおり、実施例７の脂肪乳剤は、比較例９の脂肪乳剤及び比較例１０の市販製剤と比べて、明らかに主剤（フルルビプロフェンアキセチル）の分解が抑制されていた。 As shown in Fig. 3, 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.
Figure JPOXMLDOC01-appb-T000006
Figure JPOXMLDOC01-appb-T000006
［試験例４：ヒスチジンとリン酸緩衝剤の併用の検討］
　緩衝剤として、リン酸とクエン酸を併用した乳化組成物（比較例１１：リン酸０．０２質量％，クエン酸０．０１質量％）を調製し、滅菌処理を行い比較例１１の脂肪乳剤を得た。また、比較例１１の乳化組成物に更にヒスチジン０．１質量％を添加した乳化組成物（実施例８）を調製し、滅菌処理を行い実施例８の脂肪乳剤を得た。 [Test Example 4: Examination of combined use of histidine and phosphate buffer]
As a buffering agent, an emulsion composition (comparative example 11: phosphoric acid 0.02 mass%, citric acid 0.01 mass%) using phosphoric acid and citric acid in combination was prepared, sterilized and subjected to fat emulsion of comparative example 11 Got. In addition, an emulsion composition (Example 8) in which 0.1% by mass of histidine was further added to the emulsion composition of Comparative Example 11 was prepared and sterilized to obtain the fat emulsion of Example 8.
　各実施例及び比較例の脂肪乳剤を苛酷試験に供し、定期的にフルルビプロフェンの定量、及びｐＨ測定を実施した。結果を表７～８、及び図４（Ａ）～（Ｂ）に示す。 The fat emulsions of each Example and Comparative Example were subjected to a severe test, and flurbiprofen was quantitatively determined and pH was measured periodically. The results are shown in Tables 7 to 8 and FIGS. 4 (A) to (B).
　リン酸とクエン酸を併用した脂肪乳剤に更にヒスチジンを添加することで、主剤（フルルビプロフェンアキセチル）の分解、及びｐＨの低下を抑制することができた。 By further adding histidine to the fat emulsion using phosphoric acid and citric acid in combination, decomposition of the main agent (flurbiprofen axetil) and pH reduction could be suppressed.
Figure JPOXMLDOC01-appb-T000007
Figure JPOXMLDOC01-appb-T000007
Figure JPOXMLDOC01-appb-T000008
Figure JPOXMLDOC01-appb-T000008
［試験例５：ホスファチジルエタノールアミン含有量の低減効果の検討］
　緩衝剤として、ヒスチジンを０．１質量％添加した乳化組成物（実施例９）及びリン酸とクエン酸を併用した乳化組成物（比較例１２：リン酸０．０２質量％，クエン酸０．０１質量％）を調製し、滅菌処理を行い実施例９及び比較例１２の脂肪乳剤を得た。また、卵黄レシチンとして、ＰＬ－１００Ｍ（キユーピー株式会社製）及びＰＣ－９８Ｎ（キユーピー株式会社製，ホスファチジルエタノールアミン含有量０．１質量％以下）を１：２で混合したもの（ＰＥ含量６％）を使用し、緩衝剤として、ヒスチジンを０．１質量％添加した乳化組成物（実施例１０）を調製し、滅菌処理を行い実施例１０の脂肪乳剤を得た。 [Test Example 5: Examination of reduction effect of phosphatidylethanolamine content]
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. Further, as 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.
　各実施例及び比較例の脂肪乳剤を苛酷試験に供し、試験開始直前及び試験開始後６週間の時点でフルルビプロフェンの定量を実施した。結果を表９及び図５に示す。 The fat emulsions of each Example and Comparative Example were subjected to a severe test, and flurbiprofen was quantified immediately before the start of the test and at 6 weeks after the start of the test. The results are shown in Table 9 and FIG.
　緩衝剤としてリン酸とクエン酸を併用した比較例１２の脂肪乳剤に比べて、ヒスチジンを使用した実施例９の脂肪乳剤は、明らかに主剤（フルルビプロフェンアキセチル）の分解が抑制されていた。更に、ホスファチジルエタノールアミン含有量（ＰＥ含量）が低減された卵黄レシチンを使用した実施例１０の脂肪乳剤は、実施例９の脂肪乳剤と比べても、主剤（フルルビプロフェンアキセチル）の分解が顕著に抑制されていた。 Compared with the fat emulsion of Comparative Example 12 in which phosphoric acid and citric acid were used in combination as a buffering agent, 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.
Figure JPOXMLDOC01-appb-T000009
Figure JPOXMLDOC01-appb-T000009

Claims (9)

  1. 　フルルビプロフェンアキセチルと、水と、植物油と、卵黄レシチンと、グリセリンと、ヒスチジン又はその塩と、を含有し、
    　ヒスチジン又はその塩の含有量が、フルルビプロフェンアキセチル１質量部に対して、ヒスチジン換算の総量で０．０２５質量部以上０．１９質量部以下である、脂肪乳剤。     Containing 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.
  2. 　請求項１に記載の脂肪乳剤において、
    　リン酸、クエン酸、コハク酸、マレイン酸及びマロン酸からなる群より選択される少なくとも１種の酸の総含有量が、脂肪乳剤の全量を基準として、０．０５質量％以下である、脂肪乳剤。     The fat emulsion according to claim 1,
    A 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, emulsion.
  3. 　請求項１又は２に記載の脂肪乳剤において、
    　加熱加圧滅菌した直後のフルルビプロフェンの含有量が、脂肪乳剤の全量を基準として、０．１ｍｇ／ｍＬ以下である、脂肪乳剤。     In the fat emulsion according to claim 1 or 2,
    A fat emulsion in which the content of flurbiprofen immediately after heat and autoclaving is 0.1 mg / mL or less based on the total amount of the fat emulsion.
  4. 　請求項１～３のいずれか一項に記載の脂肪乳剤において、
    　前記卵黄レシチンは、ホスファチジルエタノールアミンの含有量が０質量％以上２０質量％以下である、脂肪乳剤。     In the fat emulsion according to any one of claims 1 to 3,
    The egg yolk lecithin is a fat emulsion in which the content of phosphatidylethanolamine is 0% by mass or more and 20% by mass or less.
  5. 　フルルビプロフェンアキセチルを含有する脂肪乳剤の製造方法であって、
    　フルルビプロフェンアキセチル、水、植物油、卵黄レシチン、グリセリン及びヒスチジン又はその塩を含有する乳化組成物を調製する工程と、
    　前記乳化組成物を加熱加圧滅菌する工程と、を含む、製造方法。     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.
  6. 　請求項５に記載の製造方法において、
    　前記乳化組成物中のヒスチジン又はその塩の含有量が、フルルビプロフェンアキセチル１質量部に対して、ヒスチジン換算の総量で０．０２５質量部以上０．１９質量部以下である、製造方法。     In the manufacturing method of Claim 5,
    The manufacturing method whose content of histidine or its salt in the said emulsion composition is 0.025 mass part or more and 0.19 mass part or less in the total amount of histidine conversion with respect to 1 mass part of flurbiprofen axetil. .
  7. 　フルルビプロフェンアキセチルを含有する脂肪乳剤の安定性を向上させる方法であって、
    　フルルビプロフェンアキセチル、水、植物油、卵黄レシチン、グリセリン及びヒスチジン又はその塩を含有する乳化組成物を調製する工程と、
    　前記乳化組成物を加熱加圧滅菌する工程と、を含む、方法。     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.
  8. 　請求項７に記載の方法において、
    　前記乳化組成物中のヒスチジン又はその塩の含有量が、フルルビプロフェンアキセチル１質量部に対して、ヒスチジン換算の総量で０．０２５質量部以上０．１９質量部以下である、方法。     The method of claim 7, wherein
    The method whose content of histidine or its salt in the said emulsion composition is 0.025 mass part or more and 0.19 mass part or less by the total amount of histidine conversion with respect to 1 mass part of flurbiprofen axetil.
  9. 　フルルビプロフェンアキセチルを含有する脂肪乳剤の安定性向上剤であって、
    　ヒスチジン又はその塩を有効成分として含有する、安定性向上剤。     A fat emulsion stability improver containing flurbiprofen axetil,
    A stability improver containing histidine or a salt thereof as an active ingredient.
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