JP2012012331A - Propofol-containing oil-in-water type emulsion composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a propofol-containing oil-in-water type emulsion composition which has reduced adverse influence of fat load and fully reduces angialgia at the injection thereof.SOLUTION: The propofol-containing oil-in-water type emulsion composition includes: an oily ingredient including 70 mass% or more of a medium-chain fatty acid triglyceride; 1.5 mass% or more with respect to total volume of the composition, and 30 mass% or less with respect to the oily ingredient, of propofol; water; and a surfactant.

Description

  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 hardly soluble in water, and therefore has been used as a fat emulsion as an intravenous general anesthetic and in recent years as an intravenous sedative. This fat emulsion has features such as prompt induction of anesthesia, prompt awakening, less nausea after awakening, and less discomfort such as vomiting, and has been widely used in surgical operations. It is also used.

  However, since the propofol fat emulsion contains fats and oils, adverse effects on the administration subject due to fat load such as hypertriglyceridemia caused by administration of the preparation may be problematic. As a method for reducing the adverse effects due to fat loading, a method of increasing the amount of propofol relative to the whole composition has been reported. When comparing a group administered with a formulation containing 1% by mass of propofol relative to the whole composition and a group administered with a 2% by mass formulation, the incidence of hypertriglyceridemia was significant in the group administered with 2% by mass (Non-patent Document 1)

  2% propofol injection “Maruishi” (Maruishi Pharmaceutical Co., Ltd.) and Propofol Lipuro 2% (above, B. Braun Melsungen) are commercially available as preparations with 2% by mass of propofol based on the total composition.

  On the other hand, propofol fat emulsion has been reported to have many side effects in which strong vascular pain occurs frequently at the time of intravenous injection (Non-patent Document 2). The incidence of vascular pain correlates with the concentration of free propofol present in the aqueous phase of the emulsion, and it is known that the incidence of vascular pain increases with increasing free propofol concentration (Propofol Archives No. 6). , http://www.maruishi-pharm.co.jp/med/masuika/propo1/index.php).

In the emulsion, most propofol is dissolved in the oily component. Increasing the amount of propofol relative to the total composition will increase the amount of propofol relative to the oil functioning as a solvent, thus increasing the concentration of free propofol in the aqueous phase. That is, there is a problem that the incidence of vascular pain increases by increasing the amount of propofol in order to reduce the adverse effects of excessive administration of fat.

  To alleviate vascular pain, various methods are known including intravenous injection after cooling to 4 ° C, mixed injection with lidocaine hydrochloride or nafamostat mesylate, and intravenous injection of narcotics such as fentanyl several minutes before administration. It has been. However, these methods are not sufficiently effective even when used alone, and are cumbersome and lack convenience.

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. (Non-patent Document 3).

On the other hand, in order to relieve vascular pain, Patent Document 1 discloses a propofol preparation in which a local anesthetic such as lidocaine can be pre-mixed or mixed at the time of use, and this propofol preparation is specified as a stabilizer. Of phospholipids, phospholipid derivatives or fatty acids.
Patent Document 2 discloses a propofol-containing fat emulsion containing propofol, an oily component, and an emulsifier in predetermined amounts in order to reduce vascular pain, and having an average particle size of emulsified particles of 180 nm or less, This propofol-containing fat emulsion is described as having excellent emulsion stability without containing an emulsion stabilizer or the like.

International Publication No. 2004/052354 Pamphlet International Publication No. 2006/112276 Pamphlet

Crit Care Med 2001, Vol.29: pp.317-322 British Journal of Anaethsia, 1991, Vol. 67, pp.281-284 Anesth Analg 1997, Vol.85, pp.1399-1403

  However, when the amount of propofol relative to the whole composition is increased in order to reduce the adverse effects due to fat loading, the method of preparing a mixture of soybean oil and medium chain fatty acid triglyceride in a mass ratio of 50:50, and the blending amount of each component Even the method of adjusting and making the emulsified particles 180 nm or less is not sufficient for reducing vascular pain. It has also been reported that the incorporation of a local anesthetic such as lidocaine into a propofol formulation may destroy the emulsion structure of propofol and impair the stability of the formulation. Furthermore, the combination and combination of a plurality of drugs is not preferable from the viewpoint of safety. Moreover, preparation at the time of use of the medicine which requires urgency may cause an increase in the burden on the medical site.

  Accordingly, an object of the present invention is to provide a propofol-containing oil-in-water emulsion composition in which adverse effects due to fat loading are reduced and vascular pain upon injection is sufficiently reduced.

The present invention is as follows.
[1] An oily component containing 70% by mass or more of medium chain fatty acid triglyceride, 1.5% by mass or more of propofol with respect to the volume of the whole composition and 30% by mass or less of the oily component, water, and surface activity An oil-in-water emulsion composition containing propofol.
[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 9.9 or less.
[3] 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.
[4] 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 8.2 or less.
[5] The propofol-containing oil-in-water emulsion composition according to any one of [1] to [4], wherein the oil phase component contains 95% by mass or more of the medium chain fatty acid triglyceride.
[6] The propofol-containing oil-in-water emulsion composition according to any one of [1] to [5], further comprising a stabilizer.
[7] The propofol-containing oil-in-water emulsion composition according to [6], wherein the stabilizer is at least one selected from the group consisting of fatty acids and fatty acid salts.
[8] The propofol-containing oil-in-water emulsion composition according to [6] or [7], wherein the content of the stabilizer is 0.01% by mass to 0.05% by mass with respect to the total volume of the composition. .
[9] The propofol-containing oil-in-water emulsion composition according to any one of [1] to [8], wherein the surfactant includes a phospholipid.
[10] The propofol-containing oil-in-water emulsion according to any one of [1] to [9], 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.
[11] The propofol-containing oil-in-water emulsion composition according to [9] or [10], wherein the phospholipid is lecithin.

  According to the present invention, it is possible to provide a propofol-containing oil-in-water emulsion composition in which adverse effects on the administration subject due to fat loading are reduced and vascular pain at the time of injection is sufficiently reduced.

The propofol-containing oil-in-water emulsion composition of the present invention comprises an oil component containing 70% by mass or more of medium-chain fatty acid triglycerides, 1.5% by mass or more with respect to the total volume of the composition, and 30% by mass with respect to the oily component. The following propofol, water, and a surfactant are included.
According to the present invention, by including 70% by mass or more of medium chain fatty acid triglyceride in the oil component and by including 1.5% by mass or more of propofol with respect to the total volume of the composition, adverse effects due to fat loading are reduced. Thus, it is possible to provide a propofol-containing oil-in-water emulsion composition that can sufficiently reduce vascular pain at the time of injection without including a local anesthetic such as lidocaine. In the present invention, the propofol-containing oil-in-water emulsion composition is sometimes simply referred to as “emulsion composition” or “composition”.

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. .
Moreover, the numerical value range shown using "to" in this specification shows the range which includes the numerical value described before and behind "to" as a minimum value and a 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 means each component mass (g) / 100 mL of the total composition. . 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.

  Propofol is a general name of 2,6-diisopropylphenol, and as described in, for example, JP-A-2002-179562, general anesthetics and sedatives are also used in the pharmaceutical field. It is a known compound that can be used as such. The solubility of the compound in water is much lower in relation to its effective dosage. In the emulsion composition of the present invention, the propofol is generally present in an amount of 1.5-5 w / v% based on the volume of the total emulsion composition. More preferably, it is 2-3 w / v%.

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 12 or less in the fatty acid chain constituting the contained triglyceride.
In the present invention, from the viewpoint of alleviating vascular pain, the medium chain fatty acid triglyceride preferably has an average fatty acid chain carbon number of 9.9 or less, more preferably 8.8 or less, and 8.6 or less. Are more preferable, those of 8.2 or less are particularly preferable, and those of 8.0 or less are most preferable. 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 medium-chain fatty acid triglyceride used in the present invention is not particularly limited as long as the average number of carbon atoms of the constituent fatty acid chain is within the above-described range, and examples thereof include fatty acids having 6 to 12 carbon atoms. These fatty acids may be saturated or unsaturated. Preferably, it is mainly composed of triglycerides of saturated fatty acids having 6 to 12 carbon atoms. Moreover, the thing derived from natural vegetable oil may be sufficient and the triglyceride of a synthetic fatty acid may be sufficient. 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.

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)”. Commercially available products of medium-chain fatty acid triglycerides include “Coconard” (COCONARD ™, Kao Corporation), “ODO ™” (Nisshin Oil Industries), “Miglyol” (Myglyol ™).
And SASOL), “Panasate” (Nippon Yushi Co., Ltd.) and the like. For example, among the above-mentioned cocoonades, cocoonado RK and cocoonado MT, and among the above-mentioned miglycols, miglyol 810 and the like correspond to medium chain fatty acid triglycerides having an average fatty acid carbon number of 9.9 or less.

The medium-chain fatty acid triglyceride in the present invention is 70% by mass or more based on the total mass of the oil component. When the medium-chain fatty acid triglyceride is less than 70% 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 vascular pain alleviating effect, the ratio of the medium chain fatty acid triglyceride in the oil component is more preferably 95% by mass or more.
When two or more kinds of medium chain fatty acid triglycerides are mixed, the total amount after mixing may be 70% by mass or more in the oily component.

  The present emulsion composition is not particularly limited as long as it is a pharmaceutically acceptable oily component as the oily component other than the medium chain fatty acid triglyceride, and can be contained. Examples of the oily component in the present invention include vegetable oils (that is, natural triglycerides), long-chain fatty acid triglycerides such as chemically synthesized triglycerides, animal oils, mineral oils, synthetic oils, essential oils, ester oils, and mixtures thereof. However, the oil component in the present invention does not include propofol, a surfactant and a fatty acid described later.

  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 contained triglyceride of greater than 12. The fatty acid constituting the fatty acid chain 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.

Specific examples of the vegetable oil include soybean oil, cottonseed oil, rapeseed oil, sesame oil, safflower oil, corn oil, peanut oil, olive oil, coconut oil, perilla oil, castor oil and the like. Among these, soybean oil is preferable from the viewpoint of use in injections.
Soybean oil (soybean oil) is a vegetable oil obtained from the seeds of leguminous soybeans, and can be obtained from the seeds 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 the chemically synthesized triglyceride include 2-linoleoyl-1,3-dioctanoylglycerol.

  These oily components can be used alone or in combination of two or more. In addition, when using 2 or more types 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, mineral oil, but can be selected from a different group. .

  The amount of propofol relative to the oil component is preferably 10% by mass to 30% by mass, and more preferably 15% by mass to 25% by mass. If it is 10% by mass or more, there is little concern about adverse effects due to fat loading, and if it is 30% by mass or less, the degree of vascular pain at the time of injection is small.

  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.
In the present invention, a phospholipid can be included as a surfactant from the viewpoint of the stability of the emulsion composition.

Surfactants can include phospholipids, and 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 obtained by hydrogenation thereof, hydrogenated egg yolk phosphatidylcholine, hydrogenated soybean lecithin, hydrogenated soybean phosphatidylcholine and the like.
The surfactant may be a chemically synthesized phospholipid. The chemically synthesized phospholipids include phosphatidylcholine (dipalmitoylphosphatidylcholine, dimyristoylphosphatidylcholine, distearoylphosphatidylcholine, dioleoylphosphatidylcholine, etc.), phosphatidylglycerol (dipalmitoylphosphatidylglycerol, dimyristoylphosphatidylglycerol, distearoylphosphatidylglycerol, Oil phosphatidylglycerol), phosphatidylethanolamine (dipalmitoyl phosphatidylethanolamine, dimyristoyl phosphatidylethanolamine, distearoyl phosphatidylethanolamine, dioleoylphosphatidylethanolamine, etc.).

Other surfactants include pharmaceutically acceptable nonionic surfactants and pharmaceutically acceptable ionic surfactants. Examples of such other surfactants include poloxamer and pluronic surfactants, polycamines (tetronic surfactants), polyoxyethylene sorbitan esters, polyvinyl pyrrolidone, desoxycholic acids, gelatins, Examples include polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, albumins, polyoxyethylene hydroxystearate (for example, Solutol HS 15, BASF Japan).

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, egg yolk lecithin, egg yolk phosphatidylcholine, soybean lecithin and soybean phosphatidylcholine are more preferable, and egg yolk lecithin is particularly preferable.

  The content of the surfactant is not particularly limited as long as the emulsion composition can be formed, but is preferably 0.4 to 10 w / v% based on the total volume of the emulsion composition. More preferably, it is 5-7 w / v%, and 0.6-2 w / v% is especially preferable. If it is 0.4 w / v% or more, the stability of the emulsion composition is sufficient, and if it is 10 w / v% or less, there is almost no need to consider the influence of overdose.

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 emulsification operations may be performed at room temperature, or may be performed by employing a slight cooling operation or heating operation.

  In the present invention, if desired, a stabilizer for improving the emulsion stability may be further added separately from the above-described surfactant. Examples of such stabilizers include fatty acids and salts thereof, and these can be used alone or in combination of two or more.

  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 the salt constituting the fatty acid salt include metal salts such as sodium and potassium, and basic amino acids such as L-arginine, L-histidine and L-lysine. Examples thereof include salts and alkanolamine salts such as triethanolamine. Although the kind of salt is suitably selected according to the kind of fatty acid used, etc., a metal salt such as sodium is preferable from the viewpoints of solubility and dispersion stability.

Among these stabilizers, oleic acid or sodium oleate is preferable, and sodium oleate is more preferable from the viewpoint of actual use for injections.
Although there is no restriction | limiting in particular in content in the emulsion composition of a stabilizer, From a viewpoint of stability of an emulsion composition, 0.01 w / v% or more and less than 0.05 w / v% with respect to the volume of an emulsion composition It is preferable that it is 0.015 w / v% or more and 0.04 w / v% or less, and it is especially preferable that it is 0.02 w / v% or more and 0.03 w / v% or less. If it is 0.01 w / v% or more, the stability of the emulsion composition is sufficient, and if it is less than 0.05 w / v%, there is little need to consider the influence of overdose.

  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.

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 the pH adjuster, hydrochloric acid, acetic acid, lactic acid, malic acid, citric acid, sodium hydroxide and the like can be used.
As the isotonizing agent, glycerin; sugars such as glucose, fructose and maltose; sugar alcohols such as sorbitol and xylitol; salts such as sodium chloride and magnesium chloride can be used.

  Among these, the oil-soluble material can be used by being mixed in advance with an oil-based component constituting the emulsion composition. The water-soluble material 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.

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 present emulsion composition is usually 5.0 to 9.0, preferably 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, as described above, 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 is used. It has been reported that the cause of the decrease in vascular pain in the fat emulsion used as the oil phase 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).

  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, “part” is based on mass.

(Raw materials used in the examples)
Propofol: “2,6-Diisopropylphenol” (Wako Pure Chemical Industries)
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)

(Measurement of fatty acid composition)
The fatty acid composition was measured by the following method for coconut RK, cocoonado ML, cocoonado MT (above, Kao), miglyol 810, and miglyol 812 (above, 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.

  Hexane 3mL and saturated saline 5mL were added, the hexane layer was collected, and gas chromatograph method [model: GC-1700 (Shimadzu Corporation, detector: FID, column: DB-23 (J & W SCIENTIFIC)) φ0.25mm × 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.

[Examples 1 to 10, Comparative Examples 1 to 4]
(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. After adding refined egg yolk lecithin to the oil phase and mixing, the aqueous phase was added, and ultrasonic emulsification was performed for 8 minutes with an ultrasonic homogenizer (US-600T, Nippon Seiki Seisakusho) to coarsely emulsify. 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.

[Evaluation of emulsion composition]
As for Examples 1 to 10 and Comparative Examples 1 to 4 and Comparative Example 5, commercially available products (2% propofol injection “Marushi”, Maruishi Pharmaceutical Co., Ltd.) were measured for aqueous phase propofol concentration. The following two types of measurement methods were used. 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 20mg
Soybean oil 50mg
Medium chain triglyceride 50mg
Purified egg yolk lecithin 12mg
Concentrated glycerin 25mg
Sodium oleate 0.3mg

(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. .

The measurement was performed 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 Corp.), eluent A: 0.1 mass% acetic acid aqueous solution, eluent B: 0.1 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 amount: 10 μL], the propofol concentration was measured. The results are shown in Table 3.

(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, a glycerin aqueous solution was recovered 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.

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. The value of measurement method A with respect to the value of measurement method B is 86% on average, and the value corresponding to measurement method A of Comparative Example 4 is estimated to be about 21.9.
In the emulsion composition of Examples 1-10, since medium chain fatty acid triglyceride is contained in 70% by mass or more of the oily component, the ratio of the medium chain fatty acid triglyceride in the oily component is 50% by mass compared with Comparative Examples 1-2. The aqueous phase propofol concentration could be reduced. Moreover, in the emulsion composition of Examples 1-10, since the mass ratio with respect to the oil component of propofol is 30% or less, compared with Comparative Examples 3 to 4 with a mass ratio of propofol to the oil component of 40%, The aqueous phase propofol concentration could be reduced.
The aqueous phase propofol concentration of the emulsion compositions of Examples 1 to 10 was lower than the aqueous phase propofol concentration of Comparative Example 5.

  When the Examples were compared, the shorter the average carbon number of the fatty acid chain in the medium chain fatty acid triglyceride, the lower the aqueous phase propofol concentration. In addition, when Examples using the same average carbon number medium chain fatty acid triglyceride (Examples 1 and 6, 2 and 7, 3 and 8, 4 and 9, 5 and 10) are compared, the oiliness of the medium chain fatty acid triglyceride The aqueous phase propofol concentration was lower in Examples (1-5) in which the ratio in the component was 100% by mass than in Examples (6-10) in which the ratio was 75% by mass.

Thus, as shown in Examples 1 to 10, the emulsion composition containing 70% by mass or more of such medium chain fatty acid triglycerides in the oil component has a ratio of propofol to the total volume of the composition of 1.5. It is possible to reduce the emulsion aqueous phase propofol concentration which is at least mass%.
Therefore, according to this invention, the vascular pain at the time of the injection of the propofol containing oil-in-water emulsion composition which reduced the bad influence to the administration subject by fat load can be relieved compared with a prior art.

Claims (11)

An oil component containing 70% by mass or more of medium-chain fatty acid triglycerides;
1.5% by mass or more of propofol with respect to the volume of the whole composition and 30% by mass or less with respect to the oil component;
water and,
A surfactant,
An oil-in-water emulsion composition containing propofol.   2. 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 9.9 or less.   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.   2. The propofol-containing oil-in-water emulsion composition according to claim 1, wherein an average carbon number of the fatty acid chain of the medium chain fatty acid triglyceride is 8.2 or less.   The propofol-containing oil-in-water emulsion composition according to any one of claims 1 to 4, wherein the oil phase component contains 95% by mass or more of the medium chain fatty acid triglyceride.   Furthermore, the propofol containing oil-in-water emulsion composition as described in any one of Claims 1-5 containing a stabilizer.   The propofol-containing oil-in-water emulsion composition according to claim 6, wherein the stabilizer is at least one selected from the group consisting of fatty acids and fatty acid salts.   The propofol-containing oil-in-water emulsion composition according to claim 6 or 7, wherein the content of the stabilizer is 0.01% by mass to 0.05% by mass with respect to the total volume of the composition.   The propofol-containing oil-in-water emulsion composition according to any one of claims 1 to 8, wherein the surfactant comprises a phospholipid.   The propofol-containing oil-in-water emulsion composition according to any one of claims 1 to 9, wherein a content of the surfactant is 0.4% by mass to 10% by mass with respect to a volume of the entire composition. object.   The propofol-containing oil-in-water emulsion composition according to claim 9 or 10, wherein the phospholipid is lecithin.