WO2011145660A1 - Propofol-containing oil-in-water emulsion composition - Google Patents

Propofol-containing oil-in-water emulsion composition Download PDF

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Publication number
WO2011145660A1
WO2011145660A1 PCT/JP2011/061452 JP2011061452W WO2011145660A1 WO 2011145660 A1 WO2011145660 A1 WO 2011145660A1 JP 2011061452 W JP2011061452 W JP 2011061452W WO 2011145660 A1 WO2011145660 A1 WO 2011145660A1
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propofol
fatty acid
oil
emulsion composition
mass
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PCT/JP2011/061452
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French (fr)
Japanese (ja)
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泰之 泉
幸三 永田
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富士フイルム株式会社
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives

Definitions

  • the present invention relates to a propofol-containing oil-in-water emulsion composition.
  • Propofol (chemical name 2,6-diisopropylphenol) is an oil-soluble drug that is almost insoluble in water, so it has been used as a fat emulsion in the form of an intravenous general anesthetic and recently an intravenous sedative. .
  • This fat emulsion has features such as rapid induction of anesthesia, rapid arousal, less nausea after awakening, and vomiting, and has been widely used in surgical operations. It is also used for purposes.
  • propofol fat emulsion has been reported to have many side effects such as strong vascular pain occurring frequently during intravenous injection (see British (Journal of Anaethsia, 1991, Vol.67, pp.281-284).
  • a method for relieving this vascular pain a method of intravenous injection after cooling to 4 ° C., a method of intravenous injection mixed with lidocaine hydrochloride or naphthostat mesylate, and a narcotic such as fentanyl are intravenously administered several minutes before administration.
  • Various methods are known including a method for performing such a method. However, even if these methods are used alone, there is no sufficient effect, and each method itself is complicated and lacks convenience.
  • the oily component used in the oil phase of the fat emulsion is changed from conventional soybean oil to a mixture of soybean oil and medium-chain fatty acid triglyceride in a mass ratio of 50:50, thereby reducing pain during injection. (See Anesth Analg 1997, Vol.85, pp.1399-1403).
  • WO 2004/052354 pamphlet discloses a propofol preparation for mixing a local anesthetic such as lidocaine at the time of use. It has been proposed to utilize specific phospholipids, phospholipid derivatives or fatty acids.
  • International Publication No. 2006/112276 pamphlet discloses a propofol-containing fat emulsion containing propofol, an oil component and an emulsifier in predetermined amounts to reduce vascular pain, and having an average particle size of emulsified particles of 180 nm or less. The propofol-containing fat emulsion is described as having excellent emulsion stability without containing an emulsion stabilizer or the like.
  • an object of the present invention is to provide a propofol-containing oil-in-water emulsion composition in which vascular pain at the time of injection is sufficiently reduced.
  • propofol-containing oil-in-water emulsion composition comprising propofol, an oily component containing 30% by mass or more of a medium-chain fatty acid triglyceride having an average number of carbon atoms in the fatty acid chain of 9.9 or less, water, and a surfactant. object.
  • [3] The propofol-containing oil-in-water emulsion composition according to [1] or [2], wherein the average carbon number of the fatty acid chain of the medium chain fatty acid triglyceride is 8.2 or less.
  • [4] The propofol-containing oil-in-water emulsion composition according to any one of [1] to [3], wherein the content of medium chain fatty acid triglyceride in the oil component is 45% by mass or more.
  • [5] The propofol-containing oil-in-water emulsion composition according to any one of [1] to [4], wherein the content of medium-chain fatty acid triglyceride in the oil component is 45% by mass to 55% by mass.
  • the propofol-containing oil-in-water emulsion composition of the present invention includes propofol, an oily component containing 30% by mass or more of a medium chain fatty acid triglyceride having an average number of carbon atoms of a fatty acid chain of 9.9 or less, water, and a surfactant. ,including.
  • propofol-containing oil-in-water that can sufficiently reduce vascular pain at the time of injection by containing 30% by mass or more of medium-chain fatty acid triglycerides having an average fatty acid chain carbon number of 9.9 or less in the oil component.
  • Type emulsion compositions can be provided.
  • the propofol-containing oil-in-water emulsion composition is sometimes simply referred to as “emulsion composition” or “composition”.
  • the term “process” is not limited to an independent process, and is included in this term if the intended action of this process is achieved even when it cannot be clearly distinguished from other processes. .
  • a numerical range indicated by using “to” indicates a range including the numerical values described before and after “to” as the minimum value and the maximum value, respectively.
  • “w / v%” used for the blending amount (concentration) of each component constituting the emulsion composition of the present invention is “the mass of each component (g) / the volume of the total composition 100 mL”. means.
  • Propofol is a general name for 2,6-diisopropylphenol, and as described in, for example, JP-A-2002-179562, a general anesthetic or a sedative is used in the pharmaceutical field. It is a known compound that can be used as such. The solubility of the compound in water is considerably lower when used at its effective dosage compared to other drugs with a similar effective dosage.
  • the propofol is generally present in an amount of 0.1 w / v% to 5 w / v% in the total emulsion composition.
  • the emulsion composition of the present invention contains a medium chain fatty acid triglyceride as an oil component.
  • the medium chain fatty acid triglyceride means an oil or fat having an average carbon number of fatty acid chains constituting the triglyceride contained in the medium chain fatty acid triglyceride of 12 or less.
  • fatty acid triglycerides having an average fatty acid chain carbon number of 9.9 or less are used as medium chain fatty acid triglycerides.
  • the average carbon number of the fatty acid in the medium-chain fatty acid triglyceride is the number of carbon atoms (for example, caprylic acid in the fatty acid chain constituting the triglyceride contained in the medium-chain fatty acid triglyceride). 8 if present, and 10) if capric acid, the weighted average by the composition ratio of the constituent fatty acids.
  • the average carbon number of the fatty acid chain of the medium-chain fatty acid triglyceride is preferably 8.8 or less, more preferably 8.6 or less, and even more preferably 8.2 or less. Preferably, it is 8.0 or less.
  • the medium fatty acid triglyceride used in the present invention is not particularly limited as long as the average carbon number of the constituent fatty acid chain is within the above-mentioned range, and examples thereof include fatty acids having 6 to 12 carbon atoms. .
  • These constituent fatty acids in the medium-chain fatty acid triglyceride may be saturated or unsaturated.
  • the medium chain fatty acid triglyceride is mainly composed of a triglyceride of a saturated fatty acid having 6 to 12 carbon atoms.
  • the medium-chain fatty acid triglyceride may be derived from natural vegetable oils or may be a synthetic fatty acid triglyceride. You may use these individually or in combination of 2 or more types.
  • the medium chain fatty acid triglyceride may be used alone if the average carbon number of the constituent fatty acid chain is within the above-mentioned range, and two or more kinds of medium chain fatty acids having different average carbon numbers of the constituent fatty acid chain may be used. It may be a mixture of triglycerides. When two or more kinds of medium chain fatty acid triglycerides are mixed, the average number of carbon atoms of the constituent fatty acids may be within the above-described range as a whole of the mixture of medium chain fatty acid triglycerides.
  • Examples of the medium chain fatty acid triglyceride that can be used in the present invention include those that meet the standard of “medium chain fatty acid triglyceride” of “Pharmaceutical Additives Standard 2003 (Pharmaceutical Daily)”.
  • As commercial products of medium-chain fatty acid triglycerides trade names: “COCONARD” (COCONARD TM , Kao), “ODO TM ” (Nisshin Oil Co., Ltd.), “Miglyol” (Myglyol TM , SASOL), or “Panasate” (Panasate TM , Nippon Oil & Fats Co., Ltd.).
  • cocoonades cocoonado RK, cocoonado MT, and the like
  • miglyol 810 and the like each correspond to a medium chain fatty acid triglyceride having an average fatty acid carbon number of 9.9 or less.
  • the medium chain fatty acid triglyceride in the present invention is contained in the oil component at 30% by mass or more based on the total mass of the oil component. If the medium-chain fatty acid triglyceride is less than 30% by mass, it cannot be said that the effect of alleviating vascular pain is sufficient, and the effect of the present invention cannot be obtained. From the viewpoint of the effect of alleviating vascular pain, the proportion of medium-chain fatty acid triglycerides in the oil component is preferably 45% by mass or more, more preferably 70% by mass or more, and further preferably 95% by mass or more. preferable. When mixing 2 or more types of medium chain fatty acid triglycerides, the total amount after mixing may be 30% by mass or more in the oil component.
  • the oil component in the emulsion composition is a mixture with other oil components such as a long chain fatty acid triglyceride (for example, soybean oil). It is preferable that In the case of such a mixture, the medium-chain fatty acid triglyceride is preferably 80% by mass or less, more preferably 45% by mass or more and 55% by mass or less of the oil component from the viewpoint of the stability of the emulsion composition. .
  • the emulsion composition may contain an oil component other than the medium chain fatty acid triglyceride without particular limitation as long as it is a pharmaceutically acceptable oil component.
  • the “oil component” broadly means a component that can constitute an oil phase in an oil-in-water emulsion composition.
  • oily components in the present invention include, for example, vegetable oils (that is, natural triglycerides), long-chain fatty acid triglycerides such as chemically synthesized triglycerides, or animal oils; mineral oils; synthetic oils; essential oils; ester oils, etc., or mixtures thereof Is mentioned.
  • the oily component in the present invention does not include propofol, a surfactant described later, and fatty acids and salts thereof.
  • the other oily component is preferably a long-chain fatty acid triglyceride from the viewpoint of use in injections.
  • the “long-chain fatty acid triglyceride” means an oil or fat having an average carbon number of fatty acid chains constituting the triglyceride to be contained is larger than 12.
  • the fatty acid constituting the fatty acid chain of the long-chain fatty acid triglyceride may be a saturated fatty acid or an unsaturated fatty acid.
  • long-chain fatty acid triglycerides include vegetable oils corresponding to natural triglycerides and chemically synthesized triglycerides.
  • soybean oil is a vegetable oil obtained from the seed of a plant belonging to the leguminous soybean genus, and can be obtained from the seed using a known extraction method or a known purification method. For example, those that meet the standards of “soybean oil” described in the Japanese Pharmacopoeia can be used.
  • soybean oils examples include “Japanese Pharmacopoeia Soybean Oil” (Kaneda), “Soybean Oil YM” (Nisshin Oilio), SR-SOYBEAN-LQ- (JP) (Croda Japan) .
  • Examples of chemically synthesized triglycerides include 2-linoleoyl-1,3-dioctanoylglycerol.
  • the long-chain fatty acid triglyceride when contained in the present emulsion composition, it can be less than 70% by mass, preferably 20% to 65% by mass, based on the total mass of the oil component. From the viewpoint of stability, specifically, it is particularly preferably 55% by mass or less, particularly more than 45% by mass and less than 55% by mass based on the total mass of the oil component.
  • the content of the long-chain fatty acid triglyceride is more than 44% by mass and less than 55% by mass with respect to the total mass of the oil component, and is combined with the medium chain fatty acid triglyceride of 45% to 55% by mass of the total mass of the oil component Is particularly preferable from the viewpoint of the stability of the emulsion composition.
  • oil components can be used alone or in combination of two or more.
  • each component used together does not need to be selected from the same group, such as vegetable oil, medium chain fatty acid triglyceride, animal oil, or mineral oil, but should select from a different group. Is possible.
  • the oil component is preferably 2 to 30 w / v%, more preferably 5 to 25 w / v%, based on the total volume of the emulsion composition. If it is 2 w / v% or more, a sufficient concentration of drug can be contained in the emulsion composition, and if it is 30 w / v% or less, the stability of the emulsion composition is not impaired, and each is preferable.
  • the emulsion composition of the present invention contains a surfactant to constitute an emulsion composition containing propofol.
  • a phospholipid can be included as a surfactant from the viewpoint of the stability of the emulsion composition.
  • Examples of the surfactant include phospholipids, and examples of phospholipids include lecithin, which is a natural phospholipid.
  • Examples of lecithin include egg yolk lecithin, egg yolk phosphatidylcholine, soybean lecithin, soybean phosphatidylcholine, hydrogenated egg yolk lecithin hydrogenated with them, hydrogenated egg yolk phosphatidylcholine, hydrogenated soybean lecithin or hydrogenated soybean phosphatidylcholine.
  • the surfactant may be a chemically synthesized phospholipid.
  • Examples of the chemically synthesized phospholipids include phosphatidylcholine (dipalmitoylphosphatidylcholine, dimyristoylphosphatidylcholine, distearoylphosphatidylcholine, dioleoylphosphatidylcholine, etc.), phosphatidylglycerol (dipalmitoylphosphatidylglycerol, dimyristoylphosphatidylglycerol, distearoylphosphatidylglycerol, Dioleoyl phosphatidylglycerol), phosphatidylethanolamine (dipalmitoyl phosphatidylethanolamine, dimyristoyl phosphatidylethanolamine, distearoyl phosphatidylethanolamine, dioleoylphosphatidylethanolamine, etc.).
  • phosphatidylcholine dipalmitoylphosphatidylcholine, dimyristoylphosphatid
  • surfactants include pharmaceutically acceptable nonionic surfactants and pharmaceutically acceptable ionic surfactants.
  • examples of such other surfactants include, for example, poloxamer and pluronic surfactants, polycamines (tetronic surfactants), polyoxyethylene sorbitan esters, polyvinyl pyrrolidone, desoxycholic acids, gelatin , Polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, albumins, polyoxyethylene hydroxystearate (for example, SolutollutHS-15, BASF Japan Ltd.), and the like.
  • the surfactant in the present invention preferably contains a phospholipid from the viewpoint of biocompatibility.
  • lecithin such as egg yolk lecithin, egg yolk phosphatidylcholine, soybean lecithin or soybean phosphatidylcholine is more preferable, and egg yolk lecithin is particularly preferable.
  • the content of the surfactant is not particularly limited as long as the oil-in-water emulsion composition can be formed, but it is preferably 0.4 to 10 w / v% with respect to the total volume of the emulsion composition. 0.5 to 7 w / v% is more preferable, and 0.6 to 2 w / v% is particularly preferable. If it is 0.4 w / v% or more, the stability of the obtained emulsion composition is sufficient, and if it is 10 w / v% or less, there is almost no need to consider the influence at the time of administration to the administration subject.
  • the emulsion composition of the present invention can be prepared by a method known in the art (emulsification dispersion method). For example, it is possible to use a method of emulsifying (precise emulsifying) a crude emulsion obtained by mixing an aqueous phase and crude oil and roughly emulsifying the mixture using a suitable high-pressure emulsifier. The rough emulsification is more specifically described in, for example, T.K. K. Using a homomixer such as a homomixer, it can be carried out usually at 5000 rpm / min for 5 minutes or more. An ultrasonic homogenizer can also be used.
  • emulsification dispersion method for example, it is possible to use a method of emulsifying (precise emulsifying) a crude emulsion obtained by mixing an aqueous phase and crude oil and roughly emulsifying the mixture using a suitable high-pressure emulsifier.
  • the fine emulsification can be performed using a high-pressure homogenizer, an ultrasonic homogenizer, or the like.
  • a high-pressure homogenizer it can be carried out generally by passing it about 1 to 50 times, preferably about 1 to 20 times under a pressure condition of about 200 kg / cm 2 or more.
  • These mixing and emulsifying operations may be performed at room temperature, or may be performed by employing a slight heating operation (usually about 40 to 80 ° C.).
  • a stabilizer for improving emulsification stability may be further added separately from the surfactant described above.
  • examples of such stabilizers include fatty acids and salts thereof, and these can be used alone or in combination of two or more.
  • fatty acids preferably used in the present invention include fatty acids having 12 to 18 carbon atoms, such as lauric acid, myristic acid, palmitic acid, oleic acid, stearic acid, isostearic acid, and linoleic acid. , ⁇ -linolenic acid, ⁇ -linolenic acid and the like.
  • fatty acid salts include salts with metals such as sodium and potassium, salts with basic amino acids such as L-arginine, L-histidine and L-lysine, and salts with alkanolamines such as triethanolamine. Etc.
  • the type of salt is appropriately selected depending on the type of fatty acid used and the like, but a metal such as sodium is preferable from the viewpoints of solubility and dispersion stability.
  • the content of the stabilizer in the emulsion composition is not particularly limited, but from the viewpoint of the stability of the emulsion composition, it is 0.01 w / v% to 0.1 w / v% with respect to the volume of the emulsion composition. It is preferably 0.02 w / v% to 0.09 w / v%.
  • the emulsion composition of the present invention may further be added with appropriate amounts of various additives known to be added and blended into this type of emulsion composition, if desired.
  • various additives known to be added and blended into this type of emulsion composition, if desired. it can.
  • the additive include an antioxidant, an antibacterial agent, a pH adjuster, and an isotonic agent.
  • antioxidant examples include sodium metabisulfite (also acting as an antibacterial agent), sodium sulfite, sodium bisulfite, potassium metabisulfite, potassium sulfite, sodium thiosulfate and the like.
  • antibacterial agent examples include sodium caprylate, methyl benzoate, sodium metabisulfite (also acting as an antioxidant), sodium edetate, and the like.
  • pH adjuster hydrochloric acid, acetic acid, lactic acid, malic acid, citric acid, sodium hydroxide and the like can be used.
  • tonicity agents include glycerin; sugars such as glucose, fructose, and maltose; sugar alcohols such as sorbitol and xylitol; salts such as sodium chloride and magnesium chloride.
  • the oil-soluble substance can be used by being mixed in advance with an oil-based component constituting the emulsion composition.
  • the water-soluble substance can be mixed with water for injection or added and blended in the aqueous phase of the resulting emulsion.
  • this emulsion composition can be made into a product by filtering and sterilizing according to a conventional method.
  • a filtration method for example, a known method using a membrane filter may be applied, and as a sterilization method, for example, high pressure steam sterilization (for example, 121 ° C., 12 minutes), hot water immersion sterilization, shower sterilization, and the like are known. The method described above may be applied.
  • the pH of the emulsion composition can usually be pH 5.0 to 9.0, preferably pH 6.0 to 8.0.
  • the vascular pain alleviation effect at the time of injection of this emulsion composition can be evaluated by, for example, the propofol concentration in the aqueous phase. That is, it is known that there is a correlation between the concentration of free propofol present in the aqueous phase and the incidence of vascular pain, and a mixture of soybean oil and medium-chain fatty acid triglycerides in a mass ratio of 50:50 was used as the oil phase. It has been reported that the factor that reduces vascular pain in fat emulsions is thought to be a decrease in the concentration of free propofol present in the aqueous phase. (Propofol Archives No.6, http://www.maruishi-pharm.co.jp/med/masuika/propo1/index.php).
  • the fatty acid composition was measured by the following method for Coconut RK, Coconut ML (above, Kao) or Miglyol 810 (Sasol), which are medium chain fatty acid triglycerides. 0.030 g of a sample was collected, 1.5 mL of a 0.5 mol / L sodium hydroxide methanol solution was added, and saponification was performed by heating at 100 ° C. for 9 minutes. Methyl esterification was performed by adding 2.0 mL of boron trifluoride methanol complex methanol solution and heating at 100 ° C. for 7 minutes.
  • Purified egg yolk lecithin was added to the oil phase and mixed, then the aqueous phase was added, and the mixture was coarsely emulsified by applying ultrasonic waves for 4 minutes with an ultrasonic homogenizer (US-600T, Nippon Seiki Seisakusho). This was passed once under the condition of 245 MPa using a high-pressure emulsifier (Starburst Minilab Machine, Sugino Machine Co.). This was autoclaved using an autoclave (Autoclave SP200, Yamato Scientific Co., Ltd.) to prepare an emulsion composition.
  • an autoclave Autoclave SP200, Yamato Scientific Co., Ltd.
  • Measurement method B Using a dialysis device (RED Device, Thermo Fisher Scientific), 0.5 mL of each measurement target emulsion composition (sample) and an aqueous glycerin solution (the same glycerin concentration as the glycerin concentration of each measurement target emulsion composition) 0.3 mL was brought into contact with the dialysis membrane. In this state, after shaking at 25 ° C.
  • the trends in the aqueous phase propofol concentration were the same between the measurement method A and the measurement method B, although the measurement values were different.
  • the medium chain fatty acid triglyceride having a fatty acid chain having an average carbon number of 9.9 or less is contained in an oil component in an amount of 30% by mass or more, the fatty acid chain having an average carbon number of 10.0 or more
  • Comparative Example 1 containing medium chain fatty acid triglyceride having a ratio of 25% by mass in the oil component of medium chain fatty acid triglyceride the aqueous phase propofol concentration could be reduced.
  • the aqueous phase propofol concentration of the emulsion compositions of Examples 1 to 4 was lower than the aqueous phase propofol concentration of Comparative Example 3. Comparing the aqueous phase propofol concentration measured by the measuring method A with the aqueous phase propofol concentration measured by the measuring method B for the sample having a mass ratio of 50% in the oil component of the medium chain fatty acid triglyceride, the value of the measuring method A is It was 87% to 91% of the value of the measuring method B, and averaged 89%. From this, a value corresponding to the measuring method A of Comparative Example 3 is estimated to be about 11.6.
  • the average carbon number of the fatty acid chain in the medium-chain fatty acid triglyceride is 9.9 or less, and such medium-chain fatty acid triglyceride is 30% by mass or more in the oil component.
  • the containing emulsion composition can reduce the aqueous phase propofol concentration. Therefore, according to this invention, the vascular pain of the propofol containing oil-in-water emulsion composition can be relieved compared with a prior art.

Abstract

The disclosed propofol-containing oil-in-water emulsion composition contains: propofol; an oily component that contains at least 30% by mass of medium-chain triglycerides, the fatty acid chains of which have a mean carbon number of 9.9 or less; water; and a surfactant.

Description

プロポフォール含有水中油型エマルション組成物Oil-in-water emulsion composition containing propofol
　本発明は、プロポフォール含有水中油型エマルション組成物に関する。 The present invention relates to a propofol-containing oil-in-water emulsion composition.
　プロポフォール（化学名２，６－ジイソプロピルフェノール）は、水にほとんど溶けない油溶性薬物であるため、脂肪乳剤の形態として、静注用全身麻酔剤および近年は静注用鎮静剤として使用されている。この脂肪乳剤は、速やかな麻酔導入、速やかな覚醒、覚醒後の吐き気、嘔吐等の不快感が少ない等の特徴を有し、外科手術に広く使用されており、近年は集中治療室等において鎮静目的にも使用されている。しかしながらプロポフォール脂肪乳剤には、静注時に高い頻度で強い血管痛が発現するといった副作用が多く報告されている（British Journal of Anaethsia,1991, Vol.67, pp.281－284参照）。この血管痛を緩和するための方法として、４℃に冷却して静注する方法、塩酸リドカイン又はメシル酸ナフアモスタットと混合して静注する方法、投与数分前にフェンタニルなどの麻薬を静注する方法などを含む各種方法が知られている。しかしながらこれらの方法を単独で用いても十分な効果はなく、またそれぞれの方法それ自体が煩雑で簡便性に欠ける。 Propofol (chemical name 2,6-diisopropylphenol) is an oil-soluble drug that is almost insoluble in water, so it has been used as a fat emulsion in the form of an intravenous general anesthetic and recently an intravenous sedative. . This fat emulsion has features such as rapid induction of anesthesia, rapid arousal, less nausea after awakening, and vomiting, and has been widely used in surgical operations. It is also used for purposes. However, propofol fat emulsion has been reported to have many side effects such as strong vascular pain occurring frequently during intravenous injection (see British （Journal of Anaethsia, 1991, Vol.67, pp.281-284). As a method for relieving this vascular pain, a method of intravenous injection after cooling to 4 ° C., a method of intravenous injection mixed with lidocaine hydrochloride or naphthostat mesylate, and a narcotic such as fentanyl are intravenously administered several minutes before administration. Various methods are known including a method for performing such a method. However, even if these methods are used alone, there is no sufficient effect, and each method itself is complicated and lacks convenience.
　血管痛を緩和するその他の方法としては、溶媒を変更する方法が報告されている。
　具体的には、脂肪乳剤の油相に用いる油性成分を、従来のダイズ油から、ダイズ油と中鎖脂肪酸トリグリセリドとの質量比５０対５０の混合物とすることにより、注射時の疼痛が軽減されたとの報告がある（Anesth Analg 1997, Vol.85, pp.1399-1403参照）。 As another method for alleviating vascular pain, a method of changing a solvent has been reported.
Specifically, the oily component used in the oil phase of the fat emulsion is changed from conventional soybean oil to a mixture of soybean oil and medium-chain fatty acid triglyceride in a mass ratio of 50:50, thereby reducing pain during injection. (See Anesth Analg 1997, Vol.85, pp.1399-1403).
　油性成分としてダイズ油と中鎖脂肪酸トリグリセリドとの質量比５０対５０の混合物を用いた製剤として、１％プロポフォール注「マルイシ」、２％プロポフォール注「マルイシ」（以上、丸石製薬社）、Propofol Lipuro 1%、Propofol Lipuro 2%（以上、B. Braun Melsungen社）が市販されている。 As a formulation using a 50:50 mass ratio mixture of soybean oil and medium-chain fatty acid triglycerides as the oil component, 1% propofol injection "Maruishi", 2% propofol injection "Maruishi" (above, Maruishi Pharmaceutical), Propofol 、 Lipuro 1%, Propofol Lipuro 2% (above B. Braun Melsungen) is commercially available.
　一方、血管痛を緩和するために、国際公開２００４／０５２３５４号パンフレットには、リドカイン等の局所麻酔剤を用時混合するためのプロポフォール製剤が開示されており、このプロポフォール製剤に、安定化剤として特定のリン脂質、リン脂質誘導体または脂肪酸を利用することが提案されている。
　また、国際公開２００６／１１２２７６号パンフレットには、血管痛を軽減させるため、プロポフォール、油性成分及び乳化剤をそれぞれ所定の配合量で含み、乳化粒子の平均粒径が１８０ｎｍ以下のプロポフォール含有脂肪乳剤が開示されており、このプロポフォール含有脂肪乳剤は、乳化安定化剤等を含まずに優れた乳化安定性を有すると記載されている。 On the other hand, in order to relieve vascular pain, WO 2004/052354 pamphlet discloses a propofol preparation for mixing a local anesthetic such as lidocaine at the time of use. It has been proposed to utilize specific phospholipids, phospholipid derivatives or fatty acids.
In addition, International Publication No. 2006/112276 pamphlet discloses a propofol-containing fat emulsion containing propofol, an oil component and an emulsifier in predetermined amounts to reduce vascular pain, and having an average particle size of emulsified particles of 180 nm or less. The propofol-containing fat emulsion is described as having excellent emulsion stability without containing an emulsion stabilizer or the like.
　しかしながら、ダイズ油と中鎖脂肪酸トリグリセリドとの質量比５０対５０の混合物とした場合や、各成分の配合量を調整すると共に乳化粒子を１８０ｎｍ以下とした場合でも、血管痛の低減としては改善の余地がある。また、局所麻酔剤を配合することは、プロポフォール製剤自身による血管痛の緩和を達成するものではなく、更には局所麻酔剤の配合によって製剤の安定性を損う場合がある。 However, even when a mixture of soybean oil and medium-chain fatty acid triglyceride in a mass ratio of 50:50, or when the amount of each component is adjusted and the emulsified particles are 180 nm or less, the reduction in vascular pain is not improved. There is room. In addition, the formulation of a local anesthetic does not achieve the relief of vascular pain by the propofol formulation itself, and further the stability of the formulation may be impaired by the formulation of the local anesthetic.
　従って本発明は、注射時の血管痛が充分に低減されたプロポフォール含有水中油型エマルション組成物を提供することを目的とする。 Therefore, an object of the present invention is to provide a propofol-containing oil-in-water emulsion composition in which vascular pain at the time of injection is sufficiently reduced.
　本発明の各態様によれば、以下のプロポフォール含有水中油型エマルション組成物が提供される。
　［１］　プロポフォールと、脂肪酸鎖の平均炭素数が９．９以下である中鎖脂肪酸トリグリセリドを３０質量％以上含む油性成分と、水と、界面活性剤と、を含むプロポフォール含有水中油型エマルション組成物。
　［２］　前記中鎖脂肪酸トリグリセリドの脂肪酸鎖の平均炭素数が８．８以下である［１］に記載のプロポフォール含有水中油型エマルション組成物。
　［３］　前記中鎖脂肪酸トリグリセリドの脂肪酸鎖の平均炭素数が８．２以下である［１］または［２］に記載のプロポフォール含有水中油型エマルション組成物。
　［４］　前記油性成分中の中鎖脂肪酸トリグリセリドの含有量が４５質量％以上である［１］～［３］のいずれかに記載のプロポフォール含有水中油型エマルション組成物。
　［５］　前記油性成分中の中鎖脂肪酸トリグリセリドの含有量が４５質量％～５５質量％である［１］～［４］のいずれかに記載のプロポフォール含有水中油型エマルション組成物。
　［６］　前記油性成分が、長鎖脂肪酸トリグリセリドを含む［１］～［５］のいずれかに記載のプロポフォール含有水中油型エマルション組成物。
　［７］　前記長鎖脂肪酸トリグリセリドが、ダイズ油である［６］に記載のプロポフォール含有水中油型エマルション組成物。
　［８］　前記界面活性剤が、リン脂質を含む［１］～［７］のいずれかに記載のプロポフォール含有水中油型エマルション組成物。
　［９］　前記界面活性剤の含有量が、組成物全体の容積に対して０．４質量％～１０質量％である［１］～［８］のいずれかに記載のプロポフォール含有水中油型エマルション組成物。
　［１０］　前記リン脂質が、レシチンである［８］または［９］に記載のプロポフォール含有水中油型エマルション組成物。
　［１１］　更に、安定化剤を含む［１］～［１０］のいずれかに記載のプロポフォール含有水中油型エマルション組成物。
　［１２］　前記安定化剤が、脂肪酸及び脂肪酸塩からなる群より選択された少なくとも一種である［１１］に記載のプロポフォール含有水中油型エマルション組成物。
　［１３］　前記安定化剤の含有量が組成物全体の容積に対して０．０１質量％～０．１質量％である［１１］または［１２］に記載のプロポフォール含有水中油型エマルション組成物。
　［１４］　前記油性成分の含有量が、組成物全体の容積に対して２質量％～３０質量％である［１］～［１３］のいずれかに記載のプロポフォール含有水中油型エマルション組成物。
　［１５］前記長鎖脂肪酸トリグリセリドの含有量が、前記油性成分の全質量に対して７０質量％未満である［６］～［１４］のいずれかに記載のプロポフォール含有水中油型エマルション組成物。 According to each aspect of the present invention, the following propofol-containing oil-in-water emulsion composition is provided.
[1] A propofol-containing oil-in-water emulsion composition comprising propofol, an oily component containing 30% by mass or more of a medium-chain fatty acid triglyceride having an average number of carbon atoms in the fatty acid chain of 9.9 or less, water, and a surfactant. object.
[2] The propofol-containing oil-in-water emulsion composition according to [1], wherein an average carbon number of the fatty acid chain of the medium chain fatty acid triglyceride is 8.8 or less.
[3] The propofol-containing oil-in-water emulsion composition according to [1] or [2], wherein the average carbon number of the fatty acid chain of the medium chain fatty acid triglyceride is 8.2 or less.
[4] The propofol-containing oil-in-water emulsion composition according to any one of [1] to [3], wherein the content of medium chain fatty acid triglyceride in the oil component is 45% by mass or more.
[5] The propofol-containing oil-in-water emulsion composition according to any one of [1] to [4], wherein the content of medium-chain fatty acid triglyceride in the oil component is 45% by mass to 55% by mass.
[6] The propofol-containing oil-in-water emulsion composition according to any one of [1] to [5], wherein the oily component includes a long-chain fatty acid triglyceride.
[7] The propofol-containing oil-in-water emulsion composition according to [6], wherein the long-chain fatty acid triglyceride is soybean oil.
[8] The propofol-containing oil-in-water emulsion composition according to any one of [1] to [7], wherein the surfactant includes a phospholipid.
[9] The propofol-containing oil-in-water emulsion according to any one of [1] to [8], wherein the content of the surfactant is 0.4% by mass to 10% by mass with respect to the total volume of the composition. Composition.
[10] The propofol-containing oil-in-water emulsion composition according to [8] or [9], wherein the phospholipid is lecithin.
[11] The propofol-containing oil-in-water emulsion composition according to any one of [1] to [10], further comprising a stabilizer.
[12] The propofol-containing oil-in-water emulsion composition according to [11], wherein the stabilizer is at least one selected from the group consisting of fatty acids and fatty acid salts.
[13] The propofol-containing oil-in-water emulsion composition according to [11] or [12], wherein the content of the stabilizer is 0.01% by mass to 0.1% by mass with respect to the total volume of the composition. .
[14] The propofol-containing oil-in-water emulsion composition according to any one of [1] to [13], wherein the content of the oil component is 2% by mass to 30% by mass with respect to the total volume of the composition.
[15] The propofol-containing oil-in-water emulsion composition according to any one of [6] to [14], wherein the content of the long-chain fatty acid triglyceride is less than 70% by mass with respect to the total mass of the oil component.
　本発明のプロポフォール含有水中油型エマルション組成物は、プロポフォールと、脂肪酸鎖の平均炭素数が９．９以下である中鎖脂肪酸トリグリセリドを３０質量％以上含む油性成分と、水と、界面活性剤と、を含む。
　本発明によれば、脂肪酸鎖の平均炭素数が９．９以下の中鎖脂肪酸トリグリセリドを油性成分中に３０質量％以上含むことによって、注射時の血管痛を充分に低減可能なプロポフォール含有水中油型エマルション組成物を提供することができる。なお、本発明においてプロポフォール含有水中油型エマルション組成物を、単に「エマルション組成物」又は「組成物」ということがある。 The propofol-containing oil-in-water emulsion composition of the present invention includes propofol, an oily component containing 30% by mass or more of a medium chain fatty acid triglyceride having an average number of carbon atoms of a fatty acid chain of 9.9 or less, water, and a surfactant. ,including.
According to the present invention, propofol-containing oil-in-water that can sufficiently reduce vascular pain at the time of injection by containing 30% by mass or more of medium-chain fatty acid triglycerides having an average fatty acid chain carbon number of 9.9 or less in the oil component. Type emulsion compositions can be provided. In the present invention, the propofol-containing oil-in-water emulsion composition is sometimes simply referred to as “emulsion composition” or “composition”.
　本明細書において「工程」との語は、独立した工程だけでなく、他の工程と明確に区別できない場合であっても本工程の所期の作用が達成されれば、本用語に含まれる。
　また、本明細書において「～」を用いて示された数値範囲は、「～」の前後に記載される数値をそれぞれ最小値及び最大値として含む範囲を示す。
　本明細書において、例えば本発明のエマルション組成物を構成する各成分の配合量（濃度）について用いられる「ｗ／ｖ％」は、「各成分質量（ｇ）／全組成物の容積１００ｍＬ」を意味する。組成物の全容積に対する質量で表現する場合も、特に断らない限り、同様に、全組成物の容積１００ｍＬに対する各成分質量（ｇ）を意味する。
　また、本発明において、組成物中の各成分の量について言及する場合、組成物中に各成分に該当する物質が複数存在する場合には、特に断らない限り、組成物中に存在する当該複数の物質の合計量を意味する。
　以下、本発明について説明する。 In this specification, the term “process” is not limited to an independent process, and is included in this term if the intended action of this process is achieved even when it cannot be clearly distinguished from other processes. .
In the present specification, a numerical range indicated by using “to” indicates a range including the numerical values described before and after “to” as the minimum value and the maximum value, respectively.
In this specification, for example, “w / v%” used for the blending amount (concentration) of each component constituting the emulsion composition of the present invention is “the mass of each component (g) / the volume of the total composition 100 mL”. means. When expressed in terms of mass relative to the total volume of the composition, unless otherwise specified, it means the mass (g) of each component relative to the volume of 100 mL of the total composition.
Further, in the present invention, when referring to the amount of each component in the composition, when there are a plurality of substances corresponding to each component in the composition, the plurality present in the composition unless otherwise specified. Means the total amount of substances.
The present invention will be described below.
　プロポフォール（propofol）は、２，６－ジイソプロピルフェノール (2,6-diisopropylphenol)の一般名であり、例えば特開２００２－１７９５６２号公報にも記載されているとおり、医薬品分野で全身麻酔薬又は鎮静薬などとして利用できることの知られている化合物である。該化合物の水に対する溶解性は、その有効投与量で使用する場合、同様の有効投与量の他の薬剤と比較してかなり低い。本発明のエマルション組成物において、該プロポフォールは、一般には、全エマルション組成物中、０．１ｗ／ｖ％～５ｗ／ｖ％の量で存在する。 Propofol is a general name for 2,6-diisopropylphenol, and as described in, for example, JP-A-2002-179562, a general anesthetic or a sedative is used in the pharmaceutical field. It is a known compound that can be used as such. The solubility of the compound in water is considerably lower when used at its effective dosage compared to other drugs with a similar effective dosage. In the emulsion composition of the present invention, the propofol is generally present in an amount of 0.1 w / v% to 5 w / v% in the total emulsion composition.
　本発明のエマルション組成物は、油性成分として、中鎖脂肪酸トリグリセリドを含む。
　本発明において、中鎖脂肪酸トリグリセリドとは、当該中鎖脂肪酸トリグリセリドに含有されるトリグリセリドを構成する脂肪酸鎖の平均炭素数が、１２以下の油脂を意味する。
　本発明において、中鎖脂肪酸トリグリセリドとして、脂肪酸鎖の平均炭素数が９．９以下の脂肪酸トリグリセリドが使用される。中鎖脂肪酸トリグリセリドにおける脂肪酸の平均炭素数とは、中鎖脂肪酸トリグリセリドに含まれるトリグリセリドを構成する脂肪酸鎖（本明細書中では「構成脂肪酸」ということがある）の炭素数（例えば、カプリル酸であれば８、カプリン酸であれば１０）を構成脂肪酸の組成比によって加重平均したものである。
　血管痛緩和の観点から中鎖脂肪酸トリグリセリドの脂肪酸鎖の平均炭素数は、８．８以下であることが好ましく、８．６以下であることがより好ましく、８．２以下であることが更により好ましく、８．０以下であることが最も好ましい。 The emulsion composition of the present invention contains a medium chain fatty acid triglyceride as an oil component.
In the present invention, the medium chain fatty acid triglyceride means an oil or fat having an average carbon number of fatty acid chains constituting the triglyceride contained in the medium chain fatty acid triglyceride of 12 or less.
In the present invention, fatty acid triglycerides having an average fatty acid chain carbon number of 9.9 or less are used as medium chain fatty acid triglycerides. The average carbon number of the fatty acid in the medium-chain fatty acid triglyceride is the number of carbon atoms (for example, caprylic acid in the fatty acid chain constituting the triglyceride contained in the medium-chain fatty acid triglyceride). 8 if present, and 10) if capric acid, the weighted average by the composition ratio of the constituent fatty acids.
From the viewpoint of alleviating vascular pain, the average carbon number of the fatty acid chain of the medium-chain fatty acid triglyceride is preferably 8.8 or less, more preferably 8.6 or less, and even more preferably 8.2 or less. Preferably, it is 8.0 or less.
　本発明に使用する中鎖脂肪酸トリグリセリドは、構成脂肪酸鎖の平均炭素数が上述した範囲内であれば、構成脂肪酸に特に制限はなく、例えば炭素数が６以上１２以下の脂肪酸を挙げることができる。前記中鎖脂肪酸トリグリセリドにおけるこれらの構成脂肪酸は飽和又は不飽和であってもよい。好ましくは、前記中鎖脂肪酸トリグリセリドは、主として炭素数６以上１２以下の飽和脂肪酸のトリグリセリドで構成されたものである。また、前記中鎖脂肪酸トリグリセリドは、天然植物油由来のものであってもよく、合成脂肪酸のトリグリセリドであってもよい。これらを単独で又は２種以上を組み合わせて使用してよい。また、中鎖脂肪酸トリグリセリドは、構成脂肪酸鎖の平均炭素数が上述した範囲内であれば、１種単独で用いられてもよく、構成脂肪酸鎖の平均炭素数が異なる２種以上の中鎖脂肪酸トリグリセリドの混合物であってもよい。２種以上の中鎖脂肪酸トリグリセリドを混合する場合には、中鎖脂肪酸トリグリセリドの混合物の全体として、構成脂肪酸の平均炭素数が上述した範囲内になればよい。 The medium fatty acid triglyceride used in the present invention is not particularly limited as long as the average carbon number of the constituent fatty acid chain is within the above-mentioned range, and examples thereof include fatty acids having 6 to 12 carbon atoms. . These constituent fatty acids in the medium-chain fatty acid triglyceride may be saturated or unsaturated. Preferably, the medium chain fatty acid triglyceride is mainly composed of a triglyceride of a saturated fatty acid having 6 to 12 carbon atoms. The medium-chain fatty acid triglyceride may be derived from natural vegetable oils or may be a synthetic fatty acid triglyceride. You may use these individually or in combination of 2 or more types. Further, the medium chain fatty acid triglyceride may be used alone if the average carbon number of the constituent fatty acid chain is within the above-mentioned range, and two or more kinds of medium chain fatty acids having different average carbon numbers of the constituent fatty acid chain may be used. It may be a mixture of triglycerides. When two or more kinds of medium chain fatty acid triglycerides are mixed, the average number of carbon atoms of the constituent fatty acids may be within the above-described range as a whole of the mixture of medium chain fatty acid triglycerides.
　本発明に使用可能な中鎖脂肪酸トリグリセリドとしては、例えば、「医薬品添加物規格２００３（薬事日報社）」の「中鎖脂肪酸トリグリセリド」の規格に適合するものを挙げることができる。中鎖脂肪酸トリグリセリドの市販品としては、商品名:「ココナード」(COCONARD　TM　、花王社)、「ODO　TM　」(日清製油社)、「ミグリオール」(Myglyol　TM　、SASOL社)、又は「パナセート」(Panasate　TM　、日本油脂社)などを例示できる。例えば上述のココナードのうち、ココナードＲＫ及びココナードMTなどが、また、上述のミグリオールのうち、ミグリオール８１０などが、それぞれ、脂肪酸の平均炭素数が９．９以下の中鎖脂肪酸トリグリセリドに該当する。 Examples of the medium chain fatty acid triglyceride that can be used in the present invention include those that meet the standard of “medium chain fatty acid triglyceride” of “Pharmaceutical Additives Standard 2003 (Pharmaceutical Daily)”. As commercial products of medium-chain fatty acid triglycerides, trade names: “COCONARD” (COCONARD ™ , Kao), “ODO ™ ” (Nisshin Oil Co., Ltd.), “Miglyol” (Myglyol ™ , SASOL), or “Panasate” (Panasate ™ , Nippon Oil & Fats Co., Ltd.). For example, among the above-mentioned cocoonades, cocoonado RK, cocoonado MT, and the like, and among the above-mentioned miglycols, miglyol 810 and the like each correspond to a medium chain fatty acid triglyceride having an average fatty acid carbon number of 9.9 or less.
　本発明における中鎖脂肪酸トリグリセリドは、前記油性成分の全質量に対して３０質量％以上で当該油性成分に含有される。中鎖脂肪酸トリグリセリドが３０質量％未満では、血管痛緩和効果が充分とは言えず、本発明の効果を得ることができない。血管痛緩和効果の観点から、中鎖脂肪酸トリグリセリドの油性成分中の割合は、４５質量％以上であることが好ましく、７０質量％以上であることがより好ましく、９５質量％以上であることが更に好ましい。
　２種以上の中鎖脂肪酸トリグリセリドを混合する場合には、混合後の合計量が油性成分中の３０質量％以上であればよい。 The medium chain fatty acid triglyceride in the present invention is contained in the oil component at 30% by mass or more based on the total mass of the oil component. If the medium-chain fatty acid triglyceride is less than 30% by mass, it cannot be said that the effect of alleviating vascular pain is sufficient, and the effect of the present invention cannot be obtained. From the viewpoint of the effect of alleviating vascular pain, the proportion of medium-chain fatty acid triglycerides in the oil component is preferably 45% by mass or more, more preferably 70% by mass or more, and further preferably 95% by mass or more. preferable.
When mixing 2 or more types of medium chain fatty acid triglycerides, the total amount after mixing may be 30% by mass or more in the oil component.
　また、中鎖脂肪酸トリグリセリドは、含水率が高く、加水分解を生じやすい場合があるため、本エマルション組成物における油性成分は、長鎖脂肪酸トリグリセリド（例えば、ダイズ油）などの他の油性成分と混合物であることが好ましい。このような混合物の場合、中鎖脂肪酸トリグリセリドは、エマルション組成物の安定性の観点から前記油性成分の８０質量％以下であることが好ましく、４５質量％以上５５質量％以下であることが更に好ましい。 In addition, since the medium chain fatty acid triglyceride has a high water content and may easily be hydrolyzed, the oil component in the emulsion composition is a mixture with other oil components such as a long chain fatty acid triglyceride (for example, soybean oil). It is preferable that In the case of such a mixture, the medium-chain fatty acid triglyceride is preferably 80% by mass or less, more preferably 45% by mass or more and 55% by mass or less of the oil component from the viewpoint of the stability of the emulsion composition. .
　本エマルション組成物は、中鎖脂肪酸トリグリセリド以外の油性成分を、薬学的に許容可能な油性成分であれば特に制限はなく、含むことができる。本発明において「油性成分」とは、水中油型エマルション組成物において油相を構成し得る成分を広く意味する。本発明のおけるこのような油性成分としては、例えば、植物油（即ち天然のトリグリセリド）、化学合成トリグリセリド、若しくは動物油などの長鎖脂肪酸トリグリセリド；鉱油；合成油；精油；エステル油など、又はこれらの混合物が挙げられる。ただし、本発明における油性成分には、プロポフォール、後述する界面活性剤並びに、脂肪酸及びその塩は含まれない。 The emulsion composition may contain an oil component other than the medium chain fatty acid triglyceride without particular limitation as long as it is a pharmaceutically acceptable oil component. In the present invention, the “oil component” broadly means a component that can constitute an oil phase in an oil-in-water emulsion composition. Such oily components in the present invention include, for example, vegetable oils (that is, natural triglycerides), long-chain fatty acid triglycerides such as chemically synthesized triglycerides, or animal oils; mineral oils; synthetic oils; essential oils; ester oils, etc., or mixtures thereof Is mentioned. However, the oily component in the present invention does not include propofol, a surfactant described later, and fatty acids and salts thereof.
　他の油性成分としては、注射剤への使用実績の観点から長鎖脂肪酸トリグリセリドであることが好ましい。本明細書において「長鎖脂肪酸トリグリセリド」とは、含有するトリグリセリドを構成する脂肪酸鎖の平均炭素数が１２より大きい油脂を意味する。長鎖脂肪酸トリグリセリドの脂肪酸鎖を構成する脂肪酸は飽和脂肪酸であっても不飽和脂肪酸であってもよい。長鎖脂肪酸トリグリセリドの例としては、天然のトリグリセリドに相当する植物油と、化学合成トリグリセリドとを挙げることができる。 The other oily component is preferably a long-chain fatty acid triglyceride from the viewpoint of use in injections. In the present specification, the “long-chain fatty acid triglyceride” means an oil or fat having an average carbon number of fatty acid chains constituting the triglyceride to be contained is larger than 12. The fatty acid constituting the fatty acid chain of the long-chain fatty acid triglyceride may be a saturated fatty acid or an unsaturated fatty acid. Examples of long-chain fatty acid triglycerides include vegetable oils corresponding to natural triglycerides and chemically synthesized triglycerides.
　植物油の具体例としては、例えばダイズ油、綿実油、菜種油、胡麻油、サフラワー油、コーン油、落花生油、オリーブ油、ヤシ油、シソ油、及びヒマシ油などを挙げることができる。中でも、注射剤への使用実績の観点からダイズ油が好ましい。
　ダイズ油（大豆油）とは、マメ科ダイズ属の植物の種子から得た植物油であり、公知の搾取方法又は公知の精製方法を用いて種子から得ることができる。例えば日本薬局方に記載の「ダイズ油」の規格に適合するものを使用できる。ダイズ油の市販品としては、「日本薬局方　ダイズ油」（カネダ社）、「大豆油YM」（日清オイリオ社）、SR-SOYBEAN-LQ-(JP) (クローダジャパン社)などを例示できる。
　化学合成トリグリセリドの例としては、例えば２－リノレオイル－１，３－ジオクタノイルグリセロールを例示できる。 Specific examples of vegetable oils include soybean oil, cottonseed oil, rapeseed oil, sesame oil, safflower oil, corn oil, peanut oil, olive oil, coconut oil, perilla oil, and castor oil. Among these, soybean oil is preferable from the viewpoint of use in injections.
Soybean oil (soybean oil) is a vegetable oil obtained from the seed of a plant belonging to the leguminous soybean genus, and can be obtained from the seed using a known extraction method or a known purification method. For example, those that meet the standards of “soybean oil” described in the Japanese Pharmacopoeia can be used. Examples of commercially available soybean oils include “Japanese Pharmacopoeia Soybean Oil” (Kaneda), “Soybean Oil YM” (Nisshin Oilio), SR-SOYBEAN-LQ- (JP) (Croda Japan) .
Examples of chemically synthesized triglycerides include 2-linoleoyl-1,3-dioctanoylglycerol.
　長鎖脂肪酸トリグリセリドは、本エマルション組成物に含まれる場合、油性成分の全質量に対して７０質量％未満とすることができ、２０質量％～６５質量％であることが好ましく、エマルション組成物の安定性の観点から、具体的には油性成分の全質量の５５質量％以下、特に４５質量％よりも多く５５質量％未満であることが特に好ましい。例えば、長鎖脂肪酸トリグリセリドの含有量を油性成分の全質量に対して４４質量％を超え５５質量％未満として、油性成分の全質量の４５質量％以上５５質量％以下の中鎖脂肪酸トリグリセリドと組み合わせることが、エマルション組成物の安定性の観点から特に好ましい。 When the long-chain fatty acid triglyceride is contained in the present emulsion composition, it can be less than 70% by mass, preferably 20% to 65% by mass, based on the total mass of the oil component. From the viewpoint of stability, specifically, it is particularly preferably 55% by mass or less, particularly more than 45% by mass and less than 55% by mass based on the total mass of the oil component. For example, the content of the long-chain fatty acid triglyceride is more than 44% by mass and less than 55% by mass with respect to the total mass of the oil component, and is combined with the medium chain fatty acid triglyceride of 45% to 55% by mass of the total mass of the oil component Is particularly preferable from the viewpoint of the stability of the emulsion composition.
　これらの油性成分は、１種を単独で利用することもでき、２種以上を併用することもできる。なお、油性成分の２種以上を併用する場合は、併用される各成分は、植物油、中鎖脂肪酸トリグリセリド、動物油又は、鉱油などの同一群から選択される必要はなく、異なる群から選択することが可能である。 These oil components can be used alone or in combination of two or more. In addition, when using 2 or more types of oil-based components together, each component used together does not need to be selected from the same group, such as vegetable oil, medium chain fatty acid triglyceride, animal oil, or mineral oil, but should select from a different group. Is possible.
　油性成分は、エマルション組成物の全容積に対して２～３０ｗ／ｖ％であることが好ましく、５～２５ｗ／ｖ％であることがより好ましい。２ｗ／ｖ％以上であれば、エマルション組成物中に十分な濃度の薬剤を含有することができ、３０ｗ／ｖ％以下であれば、エマルション組成物の安定性を損なうことがなく、それぞれ好ましい。 The oil component is preferably 2 to 30 w / v%, more preferably 5 to 25 w / v%, based on the total volume of the emulsion composition. If it is 2 w / v% or more, a sufficient concentration of drug can be contained in the emulsion composition, and if it is 30 w / v% or less, the stability of the emulsion composition is not impaired, and each is preferable.
　本発明のエマルション組成物は、プロポフォールを含むエマルション組成物を構成するために界面活性剤を含む。
　本発明においては、エマルション組成物の安定性の観点から界面活性剤としてリン脂質を含むことができる。 The emulsion composition of the present invention contains a surfactant to constitute an emulsion composition containing propofol.
In the present invention, a phospholipid can be included as a surfactant from the viewpoint of the stability of the emulsion composition.
　前記界面活性剤としてはリン脂質を挙げることができ、リン脂質としては、天然のリン脂質であるレシチンを挙げることができる。レシチンの例としては、卵黄レシチン、卵黄ホスファチジルコリン、大豆レシチン、大豆ホスファチジルコリン、それらを水素添加した水添卵黄レシチン、水添卵黄ホスファチジルコリン、水添大豆レシチン又は、水添大豆ホスファチジルコリンなどを挙げることができる。
　また、界面活性剤は化学合成したリン脂質でもよい。該化学合成したリン脂質の例には、ホスファチジルコリン(ジパルミトイルホスファチジルコリン、ジミリストイルホスファチジルコリン、ジステアロイルホスファチジルコリン、ジオレオイルホスファチジルコリンなど)、ホスファチジルグリセロール（ジパルミトイルホスファチジルグリセロール、ジミリストイルホスファチジルグリセロール、ジステアロイルホスファチジルグリセロール、ジオレオイルホスファチジルグリセロールなど）、ホスファチジルエタノールアミン（ジパルミトイルホスファチジルエタノールアミン、ジミリストイルホスファチジルエタノールアミン、ジステアロイルホスファチジルエタノールアミン、ジオレオイルホスファチジルエタノールアミンなど）などが含まれる。 Examples of the surfactant include phospholipids, and examples of phospholipids include lecithin, which is a natural phospholipid. Examples of lecithin include egg yolk lecithin, egg yolk phosphatidylcholine, soybean lecithin, soybean phosphatidylcholine, hydrogenated egg yolk lecithin hydrogenated with them, hydrogenated egg yolk phosphatidylcholine, hydrogenated soybean lecithin or hydrogenated soybean phosphatidylcholine.
The surfactant may be a chemically synthesized phospholipid. Examples of the chemically synthesized phospholipids include phosphatidylcholine (dipalmitoylphosphatidylcholine, dimyristoylphosphatidylcholine, distearoylphosphatidylcholine, dioleoylphosphatidylcholine, etc.), phosphatidylglycerol (dipalmitoylphosphatidylglycerol, dimyristoylphosphatidylglycerol, distearoylphosphatidylglycerol, Dioleoyl phosphatidylglycerol), phosphatidylethanolamine (dipalmitoyl phosphatidylethanolamine, dimyristoyl phosphatidylethanolamine, distearoyl phosphatidylethanolamine, dioleoylphosphatidylethanolamine, etc.).
　また他の界面活性剤の例としては、医薬として許容可能な非イオン性界面活性剤及び医薬として許容可能なイオン性界面活性剤を挙げることができる。このような他の界面活性剤の例としては、例えば、ポロキサマー及びプルロニック系の界面活性剤、polycamines（テトロニック系の界面活性剤）、ポリオキシエチレンソルビタンエステル、ポリビニルピロリドン、デスオキシコール酸類、ゼラチン類、ポリオキシエチレン硬化ヒマシ油類、ポリオキシエチレンヒマシ油類、アルブミン類、ポリオキシエチレンヒドロキシステアレート（例えば、Solutol HS 15、ＢＡＳＦジャパン社）などを例示することができる。 Examples of other surfactants include pharmaceutically acceptable nonionic surfactants and pharmaceutically acceptable ionic surfactants. Examples of such other surfactants include, for example, poloxamer and pluronic surfactants, polycamines (tetronic surfactants), polyoxyethylene sorbitan esters, polyvinyl pyrrolidone, desoxycholic acids, gelatin , Polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, albumins, polyoxyethylene hydroxystearate (for example, SolutollutHS-15, BASF Japan Ltd.), and the like.
　これらの界面活性剤は１種を単独でまたは２種以上を混合して利用することができる。
　本発明における界面活性剤としては、生体適合性の観点からリン脂質を含むことが好ましく、中でも、卵黄レシチン、卵黄ホスファチジルコリン、大豆レシチン又は大豆ホスファチジルコリンなどのレシチンがより好ましく、特に卵黄レシチンが好ましい。 These surfactants can be used singly or in combination of two or more.
The surfactant in the present invention preferably contains a phospholipid from the viewpoint of biocompatibility. Among them, lecithin such as egg yolk lecithin, egg yolk phosphatidylcholine, soybean lecithin or soybean phosphatidylcholine is more preferable, and egg yolk lecithin is particularly preferable.
　界面活性剤は、水中油型エマルション組成物を形成できる範囲であればその含有量に特に制限はないが、エマルション組成物の全容積に対して０．４～１０ｗ／ｖ％であることが好ましく、０．５～７ｗ／ｖ％であることがより好ましく、０．６～２ｗ／ｖ％が特に好ましい。０．４ｗ／ｖ％以上であれば、得られたエマルション組成物の安定性が充分であり、１０ｗ／ｖ％以下であれば、投与対象への投与時の影響をほとんど考慮する必要がない The content of the surfactant is not particularly limited as long as the oil-in-water emulsion composition can be formed, but it is preferably 0.4 to 10 w / v% with respect to the total volume of the emulsion composition. 0.5 to 7 w / v% is more preferable, and 0.6 to 2 w / v% is particularly preferable. If it is 0.4 w / v% or more, the stability of the obtained emulsion composition is sufficient, and if it is 10 w / v% or less, there is almost no need to consider the influence at the time of administration to the administration subject.
　本発明のエマルション組成物は、当業界で公知の方法（乳化分散方法）によって調製することができる。
　例えば、水相と油粗を混合して粗乳化後、得られる粗乳化液を適当な高圧乳化機などを利用して乳化（精乳化）する方法によることができる。粗乳化は、より詳しくは、例えば特殊機化工業社製Ｔ．Ｋ．ホモミキサーなどのホモミキサーを用いて、通常５０００回転／分以上で５分間以上を要して実施できる。また、超音波ホモジナイザーを用いることもできる。精乳化は、高圧ホモジナイザー、超音波ホモジナイザーなどを用いて実施できる。高圧ホモジナイザーを用いる場合、一般には約２００ｋｇ／ｃｍ２以上の圧力条件下に、１～５０回程度、好ましくは１～２０回程度通過させることにより実施することができる。これらの混合乳化操作は、常温下に実施してもよく、若干の加温操作（通常４０～８０℃程度）を採用して実施してもよい。 The emulsion composition of the present invention can be prepared by a method known in the art (emulsification dispersion method).
For example, it is possible to use a method of emulsifying (precise emulsifying) a crude emulsion obtained by mixing an aqueous phase and crude oil and roughly emulsifying the mixture using a suitable high-pressure emulsifier. The rough emulsification is more specifically described in, for example, T.K. K. Using a homomixer such as a homomixer, it can be carried out usually at 5000 rpm / min for 5 minutes or more. An ultrasonic homogenizer can also be used. The fine emulsification can be performed using a high-pressure homogenizer, an ultrasonic homogenizer, or the like. In the case of using a high-pressure homogenizer, it can be carried out generally by passing it about 1 to 50 times, preferably about 1 to 20 times under a pressure condition of about 200 kg / cm 2 or more. These mixing and emulsifying operations may be performed at room temperature, or may be performed by employing a slight heating operation (usually about 40 to 80 ° C.).
　本発明では、所望により、上述した界面活性剤とは別に、乳化安定性を改善するための安定化剤を更に添加してもよい。このような安定化剤の例としては、脂肪酸及びその塩を挙げることができ、これらを１種単独で、又は２種以上を組み合わせて使用することができる。 In the present invention, if desired, a stabilizer for improving emulsification stability may be further added separately from the surfactant described above. Examples of such stabilizers include fatty acids and salts thereof, and these can be used alone or in combination of two or more.
　本発明で好ましく用いられる脂肪酸としては、脂肪酸の炭素数が１２以上１８以下の脂肪酸を例示することができ、例えば、ラウリン酸、ミリスチン酸、パルミチン酸、オレイン酸、ステアリン酸、イソステアリン酸、リノール酸、α－リノレン酸、γ－リノレン酸等が挙げられる。また、脂肪酸塩の例としては、ナトリウム、カリウム等の金属との塩や、Ｌ－アルギニン、Ｌ－ヒスチジン、Ｌ－リジン等の塩基性アミノ酸との塩、トリエタノールアミン等のアルカノールアミンとの塩等が挙げられる。塩の種類は、用いられる脂肪酸の種類等により適宜選択されるが、溶解性及び分散液の安定性の観点から、ナトリウムなどの金属が好ましい。 Examples of fatty acids preferably used in the present invention include fatty acids having 12 to 18 carbon atoms, such as lauric acid, myristic acid, palmitic acid, oleic acid, stearic acid, isostearic acid, and linoleic acid. , Α-linolenic acid, γ-linolenic acid and the like. Examples of fatty acid salts include salts with metals such as sodium and potassium, salts with basic amino acids such as L-arginine, L-histidine and L-lysine, and salts with alkanolamines such as triethanolamine. Etc. The type of salt is appropriately selected depending on the type of fatty acid used and the like, but a metal such as sodium is preferable from the viewpoints of solubility and dispersion stability.
　これらの安定化剤の中でも、注射剤への使用実績の観点から、オレイン酸、又はオレイン酸ナトリウムであることが好ましく、オレイン酸ナトリウムであることが更に好ましい。
　安定化剤のエマルション組成物における含有量には特に制限はないが、エマルション組成物の安定性の観点から、エマルション組成物の容積に対して０．０１ｗ／ｖ％～０．１ｗ／ｖ％であることが好ましく、０．０２ｗ／ｖ％～０．０９ｗ／ｖ％であることがより好ましい。 Among these stabilizers, oleic acid or sodium oleate is preferable, and sodium oleate is more preferable from the viewpoint of actual use for injections.
The content of the stabilizer in the emulsion composition is not particularly limited, but from the viewpoint of the stability of the emulsion composition, it is 0.01 w / v% to 0.1 w / v% with respect to the volume of the emulsion composition. It is preferably 0.02 w / v% to 0.09 w / v%.
　本発明のエマルション組成物には、更に、特に必要ではないが、所望により、この種のエマルション組成物中に添加配合できることの知られている各種の添加剤の適当量を更に添加配合することもできる。該添加剤としては、例えば酸化防止剤、抗菌剤、ｐＨ調整剤、等張化剤などを挙げることができる。 Although not particularly necessary, the emulsion composition of the present invention may further be added with appropriate amounts of various additives known to be added and blended into this type of emulsion composition, if desired. it can. Examples of the additive include an antioxidant, an antibacterial agent, a pH adjuster, and an isotonic agent.
　酸化防止剤の具体例としては、メタ重亜硫酸ナトリウム（抗菌剤としても作用する）、亜硫酸ナトリウム、重亜硫酸ナトリウム、メタ重亜硫酸カリウム、亜硫酸カリウム、チオ硫酸ナトリウムなどを例示することができる。抗菌剤としては、例えばカプリル酸ナトリウム、安息香酸メチル、メタ重亜硫酸ナトリウム（酸化防止剤としても作用する）、エデト酸ナトリウムなどが挙げられる。
　ｐＨ調整剤の例としては、塩酸、酢酸、乳酸、リンゴ酸、クエン酸、水酸化ナトリウムなどを使用できる。
　等張化剤の例としてはグリセリン；ブドウ糖、果糖、マルトースなどの糖類；ソルビトール、キシリトールなどの糖アルコール類；塩化ナトリウム、塩化マグネシウムなどの塩類などを使用できる。 Specific examples of the antioxidant include sodium metabisulfite (also acting as an antibacterial agent), sodium sulfite, sodium bisulfite, potassium metabisulfite, potassium sulfite, sodium thiosulfate and the like. Examples of the antibacterial agent include sodium caprylate, methyl benzoate, sodium metabisulfite (also acting as an antioxidant), sodium edetate, and the like.
As examples of the pH adjuster, hydrochloric acid, acetic acid, lactic acid, malic acid, citric acid, sodium hydroxide and the like can be used.
Examples of tonicity agents include glycerin; sugars such as glucose, fructose, and maltose; sugar alcohols such as sorbitol and xylitol; salts such as sodium chloride and magnesium chloride.
　これらの内、油溶性物質は、エマルション組成物を構成する油性成分などに予め混合して利用することができる。水溶性物質は、注射用水に混合するか、または得られる乳化液の水相中に添加配合することができる。これらの添加配合量は、当業者にとり自明であり、従来知られているそれらの添加配合量と特に異ならない。 Among these, the oil-soluble substance can be used by being mixed in advance with an oil-based component constituting the emulsion composition. The water-soluble substance can be mixed with water for injection or added and blended in the aqueous phase of the resulting emulsion. These addition amounts are obvious to those skilled in the art, and are not particularly different from those addition amounts conventionally known.
　本エマルション組成物は、必要に応じてｐＨを調整した後、常法に従って、濾過、滅菌して製品とすることができる。濾過方法としては、例えばメンブランフィルターを用いた公知の方法を適用すればよく、また滅菌方法としては、例えば高圧蒸気滅菌（例えば、１２１℃、１２分）、熱水浸漬滅菌及びシャワー滅菌などの公知の方法を適用すればよい。
　本エマルション組成物のｐＨは、通常、ｐＨ５．０～９．０、好ましくはｐＨ６．０～８．０とすることができる。 After adjusting pH as needed, this emulsion composition can be made into a product by filtering and sterilizing according to a conventional method. As a filtration method, for example, a known method using a membrane filter may be applied, and as a sterilization method, for example, high pressure steam sterilization (for example, 121 ° C., 12 minutes), hot water immersion sterilization, shower sterilization, and the like are known. The method described above may be applied.
The pH of the emulsion composition can usually be pH 5.0 to 9.0, preferably pH 6.0 to 8.0.
　本エマルション組成物の注射時における血管痛緩和効果は、例えば、水相中のプロポフォール濃度により評価することができる。
　即ち、水相中に存在する遊離プロポフォール濃度と血管痛の発生率に相関があることが知られており、ダイズ油と中鎖脂肪酸トリグリセリドとの質量比５０対５０の混合物を油相として用いた脂肪乳剤で血管痛が減少する要因は、水相中に存在する遊離プロポフォール濃度の低下であると考えられることが報告されている。（Propofol Archives No.6, http://www.maruishi-pharm.co.jp/med/masuika/propo1/index.php）。 The vascular pain alleviation effect at the time of injection of this emulsion composition can be evaluated by, for example, the propofol concentration in the aqueous phase.
That is, it is known that there is a correlation between the concentration of free propofol present in the aqueous phase and the incidence of vascular pain, and a mixture of soybean oil and medium-chain fatty acid triglycerides in a mass ratio of 50:50 was used as the oil phase. It has been reported that the factor that reduces vascular pain in fat emulsions is thought to be a decrease in the concentration of free propofol present in the aqueous phase. (Propofol Archives No.6, http://www.maruishi-pharm.co.jp/med/masuika/propo1/index.php).
　以下、本発明を実施例にて詳細に説明する。しかしながら、本発明はそれらに何ら限定されるものではない。なお、特に断りのない限り、「％」は質量基準である。 Hereinafter, the present invention will be described in detail with reference to examples. However, the present invention is not limited to them. Unless otherwise specified, “%” is based on mass.
（実施例で使用した原料）
　プロポフォール：　「２，６－ジイソプロピルフェノール」（和光純薬工業社）
　日本薬局方ダイズ油：　「日本薬局方　ダイズ油」（カネダ社）
　日本薬局方濃グリセリン：　「日本薬局方濃グリセリン」（坂本薬品工業社）
　オレイン酸ナトリウム：　「オレイン酸ナトリウム」（和光純薬工業社）
　精製卵黄レシチン：　「卵黄レシチンＰＬ１００－Ｍ」（キユーピー社） (Raw materials used in the examples)
Propofol: “2,6-Diisopropylphenol” (Wako Pure Chemical Industries, Ltd.)
Japanese Pharmacopoeia Soybean Oil: “Japanese Pharmacopoeia Soybean Oil” (Kaneda)
Japanese Pharmacopoeia Concentrated Glycerin: “Japanese Pharmacopoeia Concentrated Glycerin” (Sakamoto Pharmaceutical Co., Ltd.)
Sodium oleate: “Sodium oleate” (Wako Pure Chemical Industries, Ltd.)
Purified egg yolk lecithin: “yolk lecithin PL100-M” (Kewpie Corporation)
（脂肪酸組成の測定）
　中鎖脂肪酸トリグリセリドであるココナードＲＫ、ココナードＭＬ（以上、花王社）、又はミグリオール８１０（Sasol社）につき、下記の方法で脂肪酸組成を測定した。
　試料を０．０３０ｇ採取し、０．５ｍｏｌ／Ｌの水酸化ナトリウムのメタノール溶液１．５ｍＬを添加し、１００℃で９分間加熱してけん化を行った。三ふっ化ホウ素メタノール錯体メタノール溶液２．０ｍＬを添加して１００℃で７分間加熱し、メチルエステル化を行った。 (Measurement of fatty acid composition)
The fatty acid composition was measured by the following method for Coconut RK, Coconut ML (above, Kao) or Miglyol 810 (Sasol), which are medium chain fatty acid triglycerides.
0.030 g of a sample was collected, 1.5 mL of a 0.5 mol / L sodium hydroxide methanol solution was added, and saponification was performed by heating at 100 ° C. for 9 minutes. Methyl esterification was performed by adding 2.0 mL of boron trifluoride methanol complex methanol solution and heating at 100 ° C. for 7 minutes.
　ヘキサン３ｍＬおよび飽和食塩水５ｍＬを添加し、ヘキサン相を採取し、ガスクロマトグラフ法［機種：ＧＣ－１７００（島津製作所社、検出器：ＦＩＤ、カラム：ＤＢ－２３（Ｊ＆Ｗ　ＳＣＩＥＮＴＩＦＩＣ社）φ０．２５ｍｍ×３０ｍ、膜厚０．２５μｍ、温度：試料注入口　２５０℃、検出器　２５０℃、カラム　５０℃（１分保持）→１０℃／分昇温→１７０℃→１．２℃／分昇温→２１０℃、試料導入系：スプリットレス、ガス流量：ヘリウム（キャリヤーガス）１．５ｍＬ／分、ヘリウム（メイクアップガス）８０ｋＰａ、ガス圧力：水素６０ｋＰａ、空気５０ｋＰａ］にて測定を行った。得られた結果を表１に示す。 3 mL of hexane and 5 mL of saturated saline were added, and the hexane phase was collected and gas chromatograph method [model: GC-1700 (Shimadzu Corporation, detector: FID, column: DB-23 (J & W SCIENTIFIC)) φ0.25 mm × 30 m, film thickness 0.25 μm, temperature: sample inlet 250 ° C., detector 250 ° C., column 50 ° C. (1 minute hold) → 10 ° C./min temperature rise → 170 ° C. → 1.2 ° C./min temperature rise → 210 The measurement was performed at 0 ° C., sample introduction system: splitless, gas flow rate: helium (carrier gas) 1.5 mL / min, helium (makeup gas) 80 kPa, gas pressure: hydrogen 60 kPa, air 50 kPa. The results are shown in Table 1.
Figure JPOXMLDOC01-appb-T000001
 
Figure JPOXMLDOC01-appb-T000001
 
［実施例１～４、比較例１～２］
（プロポフォール含有エマルション組成物の作製）
　表２に記載の各成分を表中の含有量となるように用いて、以下の手順でプロポフォール含有水中油型エマルション組成物を作製した。
　各中鎖脂肪酸トリグリセリドとダイズ油を混合し、プロポフォールを添加し、４０℃で攪拌して溶解して、油相を作製した。グリセリンを水に溶解し、水相を作製した。油相に精製卵黄レシチンを添加して混合した後、水相を添加し、超音波ホモジナイザー（ＵＳ－６００Ｔ、日本精機製作所社）で４分間超音波を照射し、粗乳化した。これを高圧乳化機（スターバースト　ミニラボ機、スギノマシン社）を用いて２４５ＭＰａの条件で１回通過させた。これを、オートクレーブ（オートクレーブＳＰ２００、ヤマト科学社）を用いて高圧蒸気滅菌し、エマルション組成物を作製した。 [Examples 1 to 4, Comparative Examples 1 and 2]
(Preparation of propofol-containing emulsion composition)
Propofol-containing oil-in-water emulsion compositions were prepared by the following procedure using the components shown in Table 2 so as to have the contents in the table.
Each medium-chain fatty acid triglyceride and soybean oil were mixed, propofol was added, and the mixture was stirred and dissolved at 40 ° C. to prepare an oil phase. Glycerin was dissolved in water to prepare an aqueous phase. Purified egg yolk lecithin was added to the oil phase and mixed, then the aqueous phase was added, and the mixture was coarsely emulsified by applying ultrasonic waves for 4 minutes with an ultrasonic homogenizer (US-600T, Nippon Seiki Seisakusho). This was passed once under the condition of 245 MPa using a high-pressure emulsifier (Starburst Minilab Machine, Sugino Machine Co.). This was autoclaved using an autoclave (Autoclave SP200, Yamato Scientific Co., Ltd.) to prepare an emulsion composition.
Figure JPOXMLDOC01-appb-T000002
 
Figure JPOXMLDOC01-appb-T000002
 
［エマルション組成物の評価］
　上記の実施例１～４及び比較例１～２と、比較例３として市販品（１％プロポフォール注「マルイシ」、丸石製薬社）について、水相プロポフォール濃度を測定した。測定方法は、以下の２種類を使用した。なお、測定方法Ａでは、各エマルション組成物について、オレイン酸ナトリウムを含有しないものに代えて行った。結果をそれぞれ表３に示す。表３において「N.T.」は未確認を意味する。
　なお、上記市販品の組成（１ｍＬ中）は、以下のとおりである。
　　プロポフォール　　　　　　　　１０ｍｇ
　　ダイズ油　　　　　　　　　　　５０ｍｇ
　　中鎖脂肪酸トリグリセリド　　　５０ｍｇ
　　精製卵黄レシチン　　　　　　　１２ｍｇ
　　濃グリセリン　　　　　　　　　２５ｍｇ
　　オレイン酸ナトリウム　　　　０．３ｍｇ [Evaluation of emulsion composition]
The aqueous phase propofol concentration of the above-mentioned Examples 1 to 4 and Comparative Examples 1 to 2 and Comparative Example 3 (1% propofol injection “Maruishi”, Maruishi Pharmaceutical Co., Ltd.) was measured. The following two types of measurement methods were used. In addition, in the measuring method A, it replaced with what does not contain sodium oleate about each emulsion composition. The results are shown in Table 3, respectively. In Table 3, “NT” means unconfirmed.
In addition, the composition (in 1 mL) of the said commercial item is as follows.
Propofol 10mg
Soybean oil 50mg
Medium chain triglyceride 50mg
Purified egg yolk lecithin 12mg
Concentrated glycerin 25mg
Sodium oleate 0.3mg
（測定方法Ａ）
　エマルション組成物中の油相中および水相中のプロポフォール濃度は、プロポフォールの油相と水相における分配係数によって決まると考えられる。そのため、プロポフォールを溶解させた油相と水相とを接触させて長時間静置した後、水相濃度を測定することにより、油相の組成と水相中プロポフォール濃度の関係を調べることができる。 (Measurement method A)
It is believed that the propofol concentration in the oil and water phases in the emulsion composition is determined by the partition coefficient in the oil and water phases of propofol. Therefore, the relationship between the composition of the oil phase and the propofol concentration in the aqueous phase can be examined by measuring the aqueous phase concentration after contacting the oil phase in which propofol is dissolved with the aqueous phase for a long time. .
　測定は以下のように行った。油相と水相を接触させた状態で、振とう試験機（SHAKER SRR-2、アズワン社）を用いて毎分１００往復で１時間振とうした後、２３℃で１６時間静置した。その後、水相を採取し、高速液体クロマトグラフィー［カラム：ＴＳＫ－ｇｅｌ　ＯＤＳ－１００Ｚ（東ソー社）、溶離液Ａ：０．１質量％酢酸水溶液、溶離液Ｂ：０．１質量％酢酸含有メタノール、流量：溶離液Ａ０．２５ｍＬ／分、溶離液Ｂ０．７５ｍＬ／分、カラム温度：４０℃、検出器：ＵＶ検出器、検出波長：２７０ｎｍ、注入量：１０μＬ］にてプロポフォール濃度の測定を行った。結果を表３に示した。 Measured as follows. In a state where the oil phase and the aqueous phase were in contact with each other, the mixture was shaken for 1 hour at 100 reciprocations per minute using a shaking tester (SHAKER SRR-2, ASONE), and then allowed to stand at 23 ° C. for 16 hours. Thereafter, the aqueous phase was collected and subjected to high performance liquid chromatography [column: TSK-gel ODS-100Z (Tosoh Corporation), eluent A: 0.1% by mass acetic acid aqueous solution, eluent B: 0.1% by mass acetic acid-containing methanol] , Flow rate: eluent A 0.25 mL / min, eluent B 0.75 mL / min, column temperature: 40 ° C., detector: UV detector, detection wavelength: 270 nm, injection volume: 10 μL] It was. The results are shown in Table 3.
（測定方法Ｂ）
　透析デバイス（RED Device、サーモフィッシャーサイエンティフィック社）を用いて、各測定対象のエマルション組成物（試料）０．５ｍＬとグリセリン水溶液（各測定対象のエマルション組成物のグリセリン濃度と同一のグリセリン濃度）０．３ｍＬとを透析膜をはさんで接触させた。この状態で、毎分５０往復の条件で２５℃にて４時間振とうした後、グリセリン水溶液を回収して高速液体クロマトグラフィー［カラム：ＴＳＫ－ｇｅｌ　ＯＤＳ－１００Ｚ（東ソー社）、溶離液Ａ：０．１質量％酢酸水溶液、溶離液Ｂ：０．１質量％酢酸含有メタノール、流量：溶離液Ａ０．２５ｍＬ／分、溶離液Ｂ０．７５ｍＬ／分、カラム温度：４０℃、検出器：ＵＶ検出器、検出波長：２７０ｎｍ、注入量：１０μＬ］にてプロポフォール濃度を測定した。結果を表３に示した。 (Measurement method B)
Using a dialysis device (RED Device, Thermo Fisher Scientific), 0.5 mL of each measurement target emulsion composition (sample) and an aqueous glycerin solution (the same glycerin concentration as the glycerin concentration of each measurement target emulsion composition) 0.3 mL was brought into contact with the dialysis membrane. In this state, after shaking at 25 ° C. for 4 hours under conditions of 50 reciprocations per minute, the aqueous glycerin solution was collected and subjected to high performance liquid chromatography [column: TSK-gel ODS-100Z (Tosoh Corp.), eluent A: 0.1 mass% acetic acid aqueous solution, eluent B: methanol containing 0.1 mass% acetic acid, flow rate: eluent A 0.25 mL / min, eluent B 0.75 mL / min, column temperature: 40 ° C., detector: UV detection The concentration of propofol was measured using an instrument, detection wavelength: 270 nm, injection amount: 10 μL]. The results are shown in Table 3.
Figure JPOXMLDOC01-appb-T000003
 
Figure JPOXMLDOC01-appb-T000003
 
　水相プロポフォール濃度は、表３に示されるように測定方法Ａと測定方法Ｂとでは測定値は異なるものの、傾向は一致した。
　実施例１～４のエマルション組成物では、平均炭素数が９．９以下の脂肪酸鎖を有する中鎖脂肪酸トリグリセリドを油性成分中３０質量％以上含むので、平均炭素数が１０．０以上の脂肪酸鎖を有する中鎖脂肪酸トリグリセリドを含有する比較例１及び、中鎖脂肪酸トリグリセリドの油性成分中の割合が２５質量％の比較例２と比較して、水相プロポフォール濃度を低減できた。また、実施例１～４のエマルション組成物の水相プロポフォール濃度は、比較例３の水相プロポフォール濃度よりも低かった。
　中鎖脂肪酸トリグリセリドの油性成分中の質量比が５０％の試料について測定方法Ａで測定した水相プロポフォール濃度と、測定方法Ｂで測定した水相プロポフォール濃度とを比較すると、測定方法Ａの値が測定方法Ｂの値の８７％～９１％となり、平均８９％となった。このことから比較例３の測定方法Ａに相当する値を推測すると、１１．６程度となる。 As shown in Table 3, the trends in the aqueous phase propofol concentration were the same between the measurement method A and the measurement method B, although the measurement values were different.
In the emulsion compositions of Examples 1 to 4, since the medium chain fatty acid triglyceride having a fatty acid chain having an average carbon number of 9.9 or less is contained in an oil component in an amount of 30% by mass or more, the fatty acid chain having an average carbon number of 10.0 or more Compared with Comparative Example 1 containing medium chain fatty acid triglyceride having a ratio of 25% by mass in the oil component of medium chain fatty acid triglyceride, the aqueous phase propofol concentration could be reduced. In addition, the aqueous phase propofol concentration of the emulsion compositions of Examples 1 to 4 was lower than the aqueous phase propofol concentration of Comparative Example 3.
Comparing the aqueous phase propofol concentration measured by the measuring method A with the aqueous phase propofol concentration measured by the measuring method B for the sample having a mass ratio of 50% in the oil component of the medium chain fatty acid triglyceride, the value of the measuring method A is It was 87% to 91% of the value of the measuring method B, and averaged 89%. From this, a value corresponding to the measuring method A of Comparative Example 3 is estimated to be about 11.6.
　このように、実施例１～４に示されるように、中鎖脂肪酸トリグリセリド中の脂肪酸鎖の平均炭素数が９．９以下であり、このような中鎖脂肪酸トリグリセリドを油性成分中３０質量％以上含有するエマルション組成物は、水相プロポフォール濃度を低減することができる。
　従って本発明によれば、プロポフォール含有水中油型エマルション組成物の血管痛を従来技術と比較して緩和することができる。 Thus, as shown in Examples 1 to 4, the average carbon number of the fatty acid chain in the medium-chain fatty acid triglyceride is 9.9 or less, and such medium-chain fatty acid triglyceride is 30% by mass or more in the oil component. The containing emulsion composition can reduce the aqueous phase propofol concentration.
Therefore, according to this invention, the vascular pain of the propofol containing oil-in-water emulsion composition can be relieved compared with a prior art.
　２０１０年５月２１日に出願された日本国特許出願第２０１０－１１７６３４号の開示及び２０１０年６月３０日に出願された日本国特許出願第２０１０－１５０３２４号の開示は、その全体が参照により本明細書に取り込まれる。
　本明細書に記載された全ての文献、特許出願、および技術規格は、個々の文献、特許出願、および技術規格が参照により取り込まれることが具体的かつ個々に記された場合と同程度に、本明細書中に援用されて取り込まれる。 The disclosure of Japanese Patent Application No. 2010-117634 filed on May 21, 2010 and the disclosure of Japanese Patent Application No. 2010-150324 filed on June 30, 2010 are incorporated by reference in their entirety. Incorporated herein.
All documents, patent applications, and technical standards mentioned in this specification are to the same extent as if each individual document, patent application, and technical standard were specifically and individually described to be incorporated by reference, Incorporated herein by reference.

Claims (15)

  1. 　プロポフォールと、
    　脂肪酸鎖の平均炭素数が９．９以下である中鎖脂肪酸トリグリセリドを３０質量％以上含む油性成分と、
    　水と、
    　界面活性剤と、
    を含むプロポフォール含有水中油型エマルション組成物。     Propofol,
    An oil component containing 30% by mass or more of a medium chain fatty acid triglyceride having an average number of carbon atoms in the fatty acid chain of 9.9 or less;
    water and,
    A surfactant,
    An oil-in-water emulsion composition containing propofol.
  2. 　前記中鎖脂肪酸トリグリセリドの脂肪酸鎖の平均炭素数が８．８以下である請求項１に記載のプロポフォール含有水中油型エマルション組成物。 The propofol-containing oil-in-water emulsion composition according to claim 1, wherein the average carbon number of the fatty acid chain of the medium chain fatty acid triglyceride is 8.8 or less.
  3. 　前記中鎖脂肪酸トリグリセリドの脂肪酸鎖の平均炭素数が８．２以下である請求項１または請求項２に記載のプロポフォール含有水中油型エマルション組成物。 The propofol-containing oil-in-water emulsion composition according to claim 1 or 2, wherein an average carbon number of a fatty acid chain of the medium chain fatty acid triglyceride is 8.2 or less.
  4. 　前記油性成分中の中鎖脂肪酸トリグリセリドの含有量が４５質量％以上である請求項１～請求項３のいずれか一項に記載のプロポフォール含有水中油型エマルション組成物。 The propofol-containing oil-in-water emulsion composition according to any one of claims 1 to 3, wherein the content of medium-chain fatty acid triglycerides in the oil component is 45% by mass or more.
  5. 　前記油性成分中の中鎖脂肪酸トリグリセリドの含有量が４５質量％～５５質量％である請求項１～請求項４のいずれか一項に記載のプロポフォール含有水中油型エマルション組成物。 The propofol-containing oil-in-water emulsion composition according to any one of claims 1 to 4, wherein the content of medium-chain fatty acid triglycerides in the oily component is 45 mass% to 55 mass%.
  6. 　前記油性成分が、長鎖脂肪酸トリグリセリドを含む請求項１～請求項５のいずれか一項に記載のプロポフォール含有水中油型エマルション組成物。 The propofol-containing oil-in-water emulsion composition according to any one of claims 1 to 5, wherein the oil component comprises a long-chain fatty acid triglyceride.
  7. 　前記長鎖脂肪酸トリグリセリドが、ダイズ油である請求項６に記載のプロポフォール含有水中油型エマルション組成物。 The propofol-containing oil-in-water emulsion composition according to claim 6, wherein the long-chain fatty acid triglyceride is soybean oil.
  8. 　前記界面活性剤が、リン脂質を含む請求項１～請求項７のいずれか一項に記載のプロポフォール含有水中油型エマルション組成物。 The propofol-containing oil-in-water emulsion composition according to any one of claims 1 to 7, wherein the surfactant contains a phospholipid.
  9. 　前記界面活性剤の含有量が、組成物全体の容積に対して０．４質量％～１０質量％である請求項１～請求項８のいずれか一項に記載のプロポフォール含有水中油型エマルション組成物。 The propofol-containing oil-in-water emulsion composition according to any one of claims 1 to 8, wherein a content of the surfactant is 0.4% by mass to 10% by mass with respect to a total volume of the composition. object.
  10. 　前記リン脂質が、レシチンである請求項８または請求項９に記載のプロポフォール含有水中油型エマルション組成物。 The propofol-containing oil-in-water emulsion composition according to claim 8 or 9, wherein the phospholipid is lecithin.
  11. 　更に、安定化剤を含む請求項１～請求項１０のいずれか一項に記載のプロポフォール含有水中油型エマルション組成物。 The propofol-containing oil-in-water emulsion composition according to any one of claims 1 to 10, further comprising a stabilizer.
  12. 　前記安定化剤が、脂肪酸及び脂肪酸塩からなる群より選択された少なくとも一種である請求項１１に記載のプロポフォール含有水中油型エマルション組成物。 The propofol-containing oil-in-water emulsion composition according to claim 11, wherein the stabilizer is at least one selected from the group consisting of fatty acids and fatty acid salts.
  13. 　前記安定化剤の含有量が組成物全体の容積に対して０．０１質量％～０．１質量％である請求項１１または請求項１２に記載のプロポフォール含有水中油型エマルション組成物。 The propofol-containing oil-in-water emulsion composition according to claim 11 or 12, wherein the content of the stabilizer is 0.01% by mass to 0.1% by mass with respect to the total volume of the composition.
  14. 　前記油性成分の含有量が、組成物全体の容積に対して２質量％～３０質量％である請求項１～請求項１３のいずれか一項に記載のプロポフォール含有水中油型エマルション組成物。 The propofol-containing oil-in-water emulsion composition according to any one of claims 1 to 13, wherein the content of the oil component is 2% by mass to 30% by mass with respect to the total volume of the composition.
  15. 　前記長鎖脂肪酸トリグリセリドの含有量が、前記油性成分の全質量に対して７０質量％未満である請求項６～請求項１４のいずれか一項に記載のプロポフォール含有水中油型エマルション組成物。  The propofol-containing oil-in-water emulsion composition according to any one of claims 6 to 14, wherein the content of the long-chain fatty acid triglyceride is less than 70% by mass with respect to the total mass of the oil component.
PCT/JP2011/061452 2010-05-21 2011-05-18 Propofol-containing oil-in-water emulsion composition WO2011145660A1 (en)

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WO2015132985A1 (en) * 2014-03-03 2015-09-11 丸石製薬株式会社 Sevoflurane-containing emulsion composition
CN107823138A (en) * 2017-12-14 2018-03-23 广州白云山汉方现代药业有限公司 A kind of fatty acid triglycercide emulsion and preparation method thereof
WO2020017578A1 (en) * 2018-07-18 2020-01-23 テクノガード株式会社 Oxycam-based drug-containing injection agent

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JP2003535884A (en) * 2000-06-16 2003-12-02 スカイファーマ・カナダ・インコーポレーテッド Improved injectable dispersion of propofol
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JP2002523356A (en) * 1998-08-19 2002-07-30 アールティーピー・ファーマ・インコーポレーテッド Injectable aqueous dispersion of propofol
JP2003535884A (en) * 2000-06-16 2003-12-02 スカイファーマ・カナダ・インコーポレーテッド Improved injectable dispersion of propofol
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WO2015132985A1 (en) * 2014-03-03 2015-09-11 丸石製薬株式会社 Sevoflurane-containing emulsion composition
CN107823138A (en) * 2017-12-14 2018-03-23 广州白云山汉方现代药业有限公司 A kind of fatty acid triglycercide emulsion and preparation method thereof
WO2020017578A1 (en) * 2018-07-18 2020-01-23 テクノガード株式会社 Oxycam-based drug-containing injection agent

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