WO2019230207A1 - Method for producing oil-in-water type emulsion composition - Google Patents

Abstract

A method for producing an oil-in-water type emulsion composition, comprising: step A of subjecting a material to be emulsified to an emulsification treatment by applying a pressure of 20 to 350 MPa inclusive to produce an emulsion, wherein the material to be emulsified contains a phospholipid, a triglyceride, at least one compound selected from flurbiprofen axetil and flurbiprofen, and water; and step B of subjecting a material to be heated to a heating treatment, wherein the material to be heated contains at least the emulsion produced in step A, and also contains at least one surfactant selected from the group consisting of a sorbitan fatty acid ester and a polyoxyethylene sorbitan fatty acid ester, and wherein the total amount of the sorbitan fatty acid ester and the polyoxyethylene sorbitan fatty acid ester is 0.6 to 1.8% by mass inclusive relative to the total mass of the material to be heated.

Description

Method for producing oil-in-water emulsion composition

The present disclosure relates to a method for producing an oil-in-water emulsion composition.

Conventionally, fat emulsions containing medicinal ingredients, phospholipids, triglycerides, and surfactants are known as pharmaceuticals. The fat emulsion is administered to the patient by direct injection, for example, in the medical field, or mixed with an infusion solution such as physiological saline and administered to the patient by instillation.
For example, Chinese Patent Application No. 1070656575 includes flurbiprofen axetil, phospholipid, triglyceride, and surfactant, and a solution composition that spontaneously emulsifies upon mixing with an infusion such as physiological saline. Things are disclosed.

By the way, when an oil-in-water emulsion composition containing flurbiprofen axetil is placed in a container and heat-treated, for example, the emulsion particles in the emulsion composition aggregate to produce coarse particles on the order of μm. There is a case. For example, in an oil-in-water emulsion composition administered by intravenous injection, if a large amount of coarse particles are present in the oil-in-water emulsion composition, a problem may occur in that blood vessels are blocked after administration. Therefore, it is desirable that there are few coarse particles.

In regard to the above points, while Chinese Patent Application No. 1070656575 describes a fat emulsion containing flurbiprofen axetil, the heating that can occur in an emulsified composition comprising flurbiprofen axetil. There is no description about the production | generation of the coarse particle resulting from a process. In addition, in the specification of Chinese Patent Application No. 10706575, no attention is paid to suppressing the generation of coarse particles due to heat treatment.

A problem to be solved by an embodiment of the present invention is an oil-in-water emulsion composition comprising at least one compound of flurbiprofen axetil and flurbiprofen, which is produced through a heat treatment step. The present invention also provides a method for producing an oil-in-water emulsion composition with few coarse particles.

Means for solving the above problems include the following aspects.
<1> With respect to an emulsified product containing phospholipid, triglyceride, at least one compound selected from flurbiprofen axetil and flurbiprofen, and water, the pressure is 20 MPa or more and 350 MPa or less. Step A to obtain an emulsion by applying an emulsification treatment;
A to-be-heated product containing at least the emulsion obtained in step A, comprising at least one surfactant selected from the group consisting of sorbitan fatty acid ester and polyoxyethylene sorbitan fatty acid ester, and sorbitan fatty acid The step of subjecting the object to be heated, in which the total content of the ester and the polyoxyethylene sorbitan fatty acid ester is 0.6% by mass or more and 1.8% by mass or less based on the total mass of the object to be heated. B and
The manufacturing method of the oil-in-water emulsion composition which has NO.
<2> The process for producing an oil-in-water emulsion composition according to <1>, wherein in step B, the heat-treated object is subjected to heat treatment at a temperature of 90 ° C. or higher and 140 ° C. or lower.
<3> The oil-in-water emulsification according to <1> or <2>, wherein at least one surfactant selected from the group consisting of sorbitan fatty acid esters and polyoxyethylene sorbitan fatty acid esters is a polyoxyethylene sorbitan fatty acid ester. A method for producing the composition.
<4> In step A, selected from the group consisting of phospholipid, triglyceride, at least one compound selected from flurbiprofen axetil and flurbiprofen, sorbitan fatty acid ester and polyoxyethylene sorbitan fatty acid ester Any one of <1> to <3>, wherein an emulsified product is obtained by subjecting an emulsified product containing at least one surfactant and water to an emulsified treatment at a pressure of 20 MPa to 350 MPa. The manufacturing method of the oil-in-water type emulsion composition as described in one.
<5> Step A includes phospholipid, triglyceride, at least one compound selected from flurbiprofen axetil and flurbiprofen, and water, and sorbitan fatty acid ester and polyoxyethylene. Any one of <1> to <3> to obtain an emulsion by performing an emulsification treatment with a pressure of 20 MPa or more and 350 MPa or less on an article to be emulsified containing no surfactant selected from sorbitan fatty acid esters The manufacturing method of the oil-in-water type emulsion composition of description.
<6> In the step A, an oil-in-water mold according to any one of <1> to <5>, wherein an emulsion is obtained by performing an emulsification treatment with a pressure of 80 MPa or more and 350 MPa or less on the article to be emulsified A method for producing an emulsified composition.
<7> The method for producing an oil-in-water emulsion composition according to any one of <1> to <6>, wherein the pH of the object to be heated in step B is 6.0 or more and 10.0 or less.
<8> The method for producing an oil-in-water emulsion composition according to any one of <1> to <7>, wherein the pH of the object to be heated in step B is 7.0 or more and 9.0 or less.
<9> The method for producing an oil-in-water emulsified composition according to any one of <1> to <8>, in which the product to be emulsified contains a polyhydric alcohol.

According to one embodiment of the present invention, an oil-in-water emulsion composition comprising at least one compound of flurbiprofen axetil and flurbiprofen, even when manufactured through a heat treatment step, A method for producing an oil-in-water emulsion composition with few coarse particles is provided.

Hereinafter, an example of an embodiment of a method for producing an oil-in-water emulsion composition to which the present invention is applied will be described. However, the present invention is not limited to the following embodiments, and can be implemented with appropriate modifications within the scope of the object of the present invention.

In the present disclosure, a numerical range indicated by using “to” means a range including the numerical values described before and after “to” as the minimum value and the maximum value, respectively.
In a numerical range described in stages in the present disclosure, an upper limit value or a lower limit value described in a numerical range may be replaced with an upper limit value or a lower limit value in another numerical range. Further, in the numerical ranges described in the present disclosure, the upper limit value or the lower limit value described in a certain numerical range may be replaced with the values shown in the examples.
In the present disclosure, a combination of two or more preferred embodiments is a more preferred embodiment.

In the present disclosure, the amount of each component means the total amount of a plurality of types of substances unless there is a specific case when there are a plurality of types of substances corresponding to each component.

In the present disclosure, the “small amount of coarse particles” oil-in-water emulsion composition means that the oil-in-water emulsion composition has a diameter of 5 μm to 50 μm with respect to the total volume of the emulsion particles contained in the oil-in-water emulsion composition. It means an oil-in-water emulsion composition in which the volume ratio of particles is 0.05% by volume or less.
In the present disclosure, “the volume ratio (unit: volume%) of particles having a diameter of 5 μm to 50 μm in the oil-in-water emulsion composition to the total volume of the emulsion particles contained in the oil-in-water emulsion composition” is expressed as “PFAT5 Sometimes referred to as “value”.
The PFAT5 value is preferably 0.03% by volume or less, more preferably 0.01% by volume or less, and particularly preferably no particles having a diameter of 5 μm or more and 50 μm or less, that is, 0% by volume. .

In the present disclosure, the “PFAT5 value” is a value obtained by the following method.
The oil-in-water emulsion composition is diluted 10 times with water to prepare a sample solution for evaluation. 1 mL of the prepared sample solution for evaluation is injected into a number counting particle size distribution device, and the total volume of particles having a diameter of 5 μm or more and 50 μm or less in 1 mL of the sample solution for evaluation is automatically calculated by the function of the device. Based on the following formula (1), the volume ratio of particles having a diameter of 5 μm or more and 50 μm or less in the evaluation sample liquid to the total volume of the emulsified particles contained in the evaluation sample liquid (that is, PFAT5 value) (unit) : Volume%).
In the following formula (1), it is assumed that the total volume of the emulsified particles contained in the evaluation sample liquid is approximately the same as the volume of the triglyceride contained in the evaluation sample liquid. In addition, the volume of the triglyceride contained in the sample liquid for evaluation is calculated based on the following formula (2).
As the number-counting particle size distribution device, for example, AccuSizer 780AS (product name) manufactured by Nihon Integris Co., Ltd. can be preferably used. However, the number counting type particle size distribution apparatus is not limited to this.

PFAT5 value (unit: volume%) = [total volume of particles having a diameter of 5 μm to 50 μm in 1 mL of sample liquid for evaluation] ÷ [volume of triglyceride in 1 mL of sample liquid for evaluation] × 100 (1)

Triglyceride volume in 1 mL of sample solution for evaluation (unit: mL) = triglyceride content in oil-in-water emulsion composition (unit: g) ÷ triglyceride density (unit: g / mL) ÷ 10 (dilution ratio) ... (2)

In the present disclosure, the term “process” is not limited to an independent process, and is included in the term if the intended purpose of the process is achieved even if it cannot be clearly distinguished from other processes.

[Method for producing oil-in-water emulsion composition]
The method for producing an oil-in-water emulsion composition of the present disclosure (hereinafter, also simply referred to as “manufacturing method”) is at least one selected from phospholipids, triglycerides, flurbiprofen axetil and flurbiprofen. Step A and Step of obtaining an emulsion by subjecting an emulsified product containing the above compound (hereinafter also referred to as “specific compound”) and water to an emulsified treatment with a pressure of 20 MPa to 350 MPa. A to-be-heated product containing at least the emulsion obtained in A, and comprising at least one surfactant selected from the group consisting of sorbitan fatty acid ester and polyoxyethylene sorbitan fatty acid ester (hereinafter referred to as “specific surfactant”) And the total content of sorbitan fatty acid ester and polyoxyethylene sorbitan fatty acid ester is To be heated product is 0.6 wt% to 1.8 wt% or less based on the total weight of the heat treatment product, and a step B of performing heat treatment.
The manufacturing method of this indication may have other processes as needed.

Generally, in the manufacturing process of an emulsified composition, after the emulsified composition is contained in a container, a heat treatment for sterilization is performed.
When the inventors of the present invention put an oil-in-water emulsion composition containing at least one of flurbiprofen axetil and flurbiprofen in a container and heat-treated, the oil-in-water emulsion composition is coarse. It has been found that particles may form. When there are many coarse particles in the oil-in-water emulsion composition, for example, when the oil-in-water emulsion composition is administered by intravenous injection, it may lead to occlusion of blood vessels.

On the other hand, in the production method of the present disclosure, at least an emulsion obtained by subjecting an emulsion to be processed containing phospholipid, triglyceride, specific compound, and water to an emulsion that applies a high pressure of 20 MPa or more. Due to the heat treatment of the heat-treated object including the specific compound by performing the heat treatment on the heat-treated object including the specific surfactant having the content in the specific range. Generation of coarse particles can be suppressed. Therefore, in the oil-in-water emulsion composition obtained by the production method of the present disclosure, the volume ratio of coarse particles (that is, particles having a diameter of 5 μm or more and 50 μm or less) is the sum of the emulsion particles contained in the oil-in-water emulsion composition. It becomes 0.05 volume% or less with respect to the volume, and there are few coarse particles.
Although the reason why the manufacturing method of the present disclosure has such an effect is not clear, the present inventors presume as follows.

In the production method of the present disclosure, the object to be heated to be subjected to the heat treatment includes an emulsion obtained through an emulsification treatment in which a high pressure of 20 MPa or more is applied. Therefore, the emulsified particles contained in the object to be heated are It is fine and stable.
In addition, it is considered that the generation of coarse particles generated during the heat treatment is caused by the fact that the emulsified particles existing in the vicinity of the gas-liquid interface in the container adhere to the inner surface of the container. When the to-be-heated material to be subjected to the heat treatment contains the specific surfactant with a content in a specific range, the emulsion particles are prevented from adhering to the inner surface of the container during the heat treatment.
That is, in the production method of the present disclosure, the emulsified particles in the heat-treated product to be subjected to the heat treatment are fine and stable, and are difficult to adhere to the inner surface of the container, so that there are few coarse particles in water. It is presumed that an oil-type emulsion composition can be produced.

In the manufacturing method of the present disclosure, in Chinese Patent Application No. 1070656575, an oil-in-water emulsion composition is added to a fat emulsion containing flurbiprofen axetil and lightly stirred. It is not obtained by the emulsification treatment in which a high pressure of 20 MPa or more is applied. The fat emulsion described in Chinese Patent Application No. 1070656575 contains flurbiprofen axetil, but the oil-in-water emulsion composition containing flurbiprofen axetil is contained in a container and heat-treated. In addition, no attention is paid to the problem that coarse particles are generated. In addition, Chinese Patent Application No. 1070656575 does not describe a technique for suppressing the generation of coarse particles that may occur during the heat treatment of an oil-in-water emulsion composition.

In general, in heat treatment such as sterilization, decomposition of raw materials may occur.
The oil-in-water emulsion composition obtained by the production method of the present disclosure has few decomposition products (specifically, hydrolyzates) of the specific compound and is excellent in stability of the specific compound during storage.
As described above, in the manufacturing method of the present disclosure, the object to be heated to be subjected to the heat treatment includes an emulsion obtained through a high-pressure emulsification treatment having a pressure of 20 MPa or more, and thus is included in the object to be heated. The emulsified particles are stable. Moreover, the to-be-heated material used for a heat processing contains the specific surfactant by the content rate of a specific range, and the emulsified particle contained in a to-be-heated material becomes still more stable. When the emulsified particles are stabilized, the specific compound included in the emulsified particles is less likely to come into contact with water. Therefore, the oil-in-water emulsion composition obtained by the production method of the present disclosure is a decomposition product of the specific compound generated by heat treatment. It is estimated that the stability of the specific compound during storage is excellent.

The oil-in-water emulsion composition obtained by the production method of the present disclosure has few fatty acids generated by the decomposition of phospholipids and triglycerides, and is excellent in stability of phospholipids and triglycerides during storage.
As described above, in the production method of the present disclosure, the heat-treated product to be subjected to the heat treatment is obtained through a high-pressure emulsification treatment with a pressure of 20 MPa or more. Therefore, the emulsified particles contained in the heat-treated material are: It will be stable. Moreover, the to-be-heated material used for a heat processing contains the specific surfactant by the content rate of a specific range, and the emulsified particle contained in a to-be-heated material becomes still more stable. When the emulsified particles are stabilized, the phospholipids and triglycerides that form the emulsified particles are also stabilized. Therefore, the oil-in-water emulsion composition obtained by the production method of the present disclosure is derived from the phospholipids and triglycerides generated by the heat treatment. It is estimated that fatty acids, that is, fatty acids produced by the degradation of phospholipids and triglycerides are small, and that the stability of phospholipids and triglycerides during storage is excellent.

Note that the above estimation does not limit the manufacturing method of the present disclosure, and is described as an example.

Hereinafter, each step in the manufacturing method of the present disclosure will be described in detail.

[Process A]
Step A is for an emulsified product containing phospholipid, triglyceride, at least one compound selected from flurbiprofen axetil and flurbiprofen (that is, a specific compound), and water. This is a step of obtaining an emulsion by performing an emulsification treatment with a pressure of 20 MPa or more and 350 MPa or less.
The emulsification treatment with a pressure of 20 MPa or more and 350 MPa or less in Step A means an emulsification treatment in which a pressure of 20 MPa or more and 350 MPa or less is added to the product to be emulsified.
In step A, an oil-in-water emulsion in which emulsified particles containing the specific compound and triglyceride are dispersed in water can be obtained. The emulsified particles in the emulsion obtained in step A are fine and stable.

The emulsified processed product containing phospholipid, triglyceride, specific compound and water may be a mixture containing phospholipid, triglyceride, specific compound and water, and this mixture is a crude emulsion obtained by emulsifying the mixture. It may be.
That is, step A may include step A-1 for preparing a mixture containing phospholipid, triglyceride, specific compound, and water, and the mixture prepared in step A-1 is subjected to an emulsification treatment. Step A-2 may be provided to give a crude emulsion.

In Step A-1, a method for preparing a mixture containing phospholipid, triglyceride, specific compound, and water is not particularly limited.
Each component contained in a mixture should just be mixed, and it is preferable that it is mixed uniformly.
Each component contained in the mixture may be mixed at one time, or may be mixed while adding another component dividedly into one component.
The method for mixing each component contained in the mixture is not particularly limited, and examples thereof include a method of mixing by stirring.
There is no restriction | limiting in particular as a stirring means, A common stirring instrument or stirring apparatus can be used.
The stirring time is not particularly limited, and can be appropriately set according to the type of stirring tool or stirring device, the composition (ie, type and amount) of the components to be stirred, and the like.
The temperature at the time of mixing each component contained in a mixture is not restrict | limited in particular, For example, it can set to the range of 5 to 90 degreeC.
There is no restriction | limiting in particular as a means to adjust temperature, A general heating apparatus can be used.

The method for the emulsification treatment in step A-2 is not particularly limited.
There is no restriction | limiting in particular as a means of the emulsification process for obtaining a rough emulsion, For example, the means using a general emulsification apparatus is mentioned.
Examples of the emulsifier include a homogenizer, a homomixer, and an ultrasonic homogenizer.
The emulsification time is not particularly limited, and can be appropriately set according to the type of the emulsifying device, the composition of the mixture, and the like.
When a homogenizer is used as a means for the emulsification treatment, for example, the rotation speed can be set to 1,000 rpm (revolutions per minute; hereinafter the same) to 100,000 rpm, and the emulsification time can be set to 1 to 30 minutes.
When an ultrasonic homogenizer is used as the emulsifying means, for example, the frequency can be set to 15 kHz to 40 kHz, and the energy density of the dispersed portion can be set to 100 W / cm ² or more.

The processed product to be emulsified may contain components other than phospholipids, triglycerides, specific compounds, and water as necessary. The processed product to be emulsified may contain, for example, at least one surfactant selected from the group consisting of sorbitan fatty acid ester and polyoxyethylene sorbitan fatty acid ester (that is, a specific surfactant). Moreover, the to-be-emulsified processed material may contain the other additive (for example, polyhydric alcohol) mentioned later.

In step A, an emulsified product is subjected to an emulsification treatment with a pressure of 20 MPa or more and 350 MPa or less with respect to an emulsified treatment containing phospholipid, triglyceride, specific compound, specific surfactant, and water. It may be obtained, and emulsification treatment with a pressure of 20 MPa or more and 350 MPa or less is performed on an article to be emulsified containing phospholipid, triglyceride, specific compound, and water and not containing a specific surfactant. From the above, an emulsion may be obtained.

In Step A, if an emulsified treatment containing a phospholipid, a triglyceride, a specific compound, a specific surfactant, and water is subjected to an emulsification treatment at a pressure of 20 MPa to 350 MPa, it is specified. There is a tendency to obtain an oil-in-water emulsion composition in which the decomposition product of the compound is less.
In Step A, when an emulsified treatment containing a phospholipid, a triglyceride, a specific compound, and water and containing no specific surfactant is subjected to an emulsification treatment at a pressure of 20 MPa to 350 MPa. Tends to provide an oil-in-water emulsion composition with fewer fatty acids resulting from the degradation of phospholipids and triglycerides. Further, when the emulsified treatment containing the specific surfactant is subjected to an emulsification treatment with a pressure of 20 MPa or more and 350 MPa or less, foaming is likely to occur, but when the emulsified treatment does not contain the specific surfactant, Foaming does not easily occur and tends to be more excellent in production suitability.

The ratio of the phospholipid content to the triglyceride content in the processed product to be emulsified (that is, the phospholipid content / the triglyceride content) is not particularly limited. For example, the oil-in-water type is better. From the standpoint of obtaining an emulsion to be retained in the film, it is preferably 0.03 or more and 2.0 or less, more preferably 0.06 or more and 1.0 or less, and more preferably 0.12 or more and 0.5 on a mass basis. More preferably, it is as follows.

There is no restriction | limiting in particular as content rate of the triglyceride in a to-be-emulsified processed material.
From the viewpoint of increasing the content of the specific compound dissolved in the triglyceride, the content of triglyceride in the processed product is preferably 2% by mass or more, and preferably 5% by mass with respect to the total mass of the processed product. The above is more preferable, and 10 mass% or more is still more preferable.
Further, the content of triglyceride in the product to be emulsified is preferably 40% by mass or less, and preferably 30% by mass with respect to the total mass of the product to be emulsified from the viewpoint of obtaining an emulsion containing finer emulsified particles. % Or less is more preferable, and 20% by mass or less is still more preferable.

There is no restriction | limiting in particular as content rate of the specific compound in an to-be-emulsified processed material.
The content of the specific compound in the processed product to be emulsified is, for example, from 0.01% by mass to 2.0% by mass with respect to the total mass of the processed product from the viewpoint of the dose of the specific compound per one time. The following is preferred.

There is no restriction | limiting in particular as content rate of the water in a to-be-emulsified processed material.
For example, from the viewpoint of obtaining an oil-in-water emulsion, the content of water in the emulsion to be processed is preferably 30% by mass or more, more preferably, based on the total mass of the emulsion to be processed. It is 40 mass% or more, More preferably, it is 50 mass% or more.
Moreover, the content rate of water in the to-be-emulsified processed material is, for example, from the same viewpoint as described above, preferably 99% by mass or less, more preferably 98% by mass or less, with respect to the total mass of the emulsified processed product. More preferably, it is 97 mass% or less.

When the to-be-emulsified processed product contains a specific surfactant, the content of the specific surfactant in the to-be-emulsified processed product is preferably 0.6% by mass or more and 2.25 with respect to the total mass of the to-be-emulsified processed product. % By mass or less, more preferably 0.8% by mass or more and 2.2% by mass or less, still more preferably 1.0% by mass or more and 1.9% by mass or less, and particularly preferably 1.25% by mass. The content is 1.9% by mass or less.
When the content of the specific surfactant in the emulsion to be emulsified is within the above range, an oil-in-water emulsion composition with few coarse particles can be obtained even after the heat treatment step (ie, step B). Tend.

When the product to be emulsified contains polyhydric alcohol, the content of the polyhydric alcohol in the product to be emulsified is, for example, from the viewpoint of obtaining an emulsion containing finer emulsified particles, to the total mass of the product to be emulsified. On the other hand, 0.5 mass% or more is preferable, 1.0 mass% or more is more preferable, and 2.0 mass% or more is still more preferable.
In addition, the content of the polyhydric alcohol in the emulsified treatment is, for example, from the viewpoint of further reducing the possibility of tissue damage due to osmotic pressure difference when administered by injection, with respect to the total mass of the emulsified treatment, 10 mass% or less is preferable, 5 mass% or less is more preferable, and 3 mass% or less is still more preferable.

In step A, there is no particular limitation on the means for performing an emulsification treatment with a pressure of 20 MPa or more and 350 MPa or less on the product to be emulsified.
As a means for the emulsification treatment, for example, a high-pressure homogenizer is suitable.
Dispersion by a high-pressure homogenizer is dispersion due to a large shear force generated when a liquid passes through a very narrow gap at high speed.
Examples of the high-pressure homogenizer include a chamber-type high-pressure homogenizer having a chamber for fixing the flow path of the processing liquid and a homogeneous valve-type high-pressure homogenizer having a homogeneous valve.
Examples of the chamber type high-pressure homogenizer include microfluidizer [Paurec Co., Ltd.], nanomizer [Nanomizer Co., Ltd.], and optimizer [Sugino Machine Co., Ltd.].
The homogeneous valve type high-pressure homogenizer includes Gorin type homogenizer [SMT Co., Ltd.], Lanier type homogenizer [SMT Co., Ltd.], high-pressure homogenizer (Niro Soabi), homogenizer [Sanwa Machinery Co., Ltd.], high-pressure homogenizer [ Izumi Food Machinery Co., Ltd.], ultra-high pressure homogenizer (IKA Co., Ltd.) and the like.

In step A, an emulsification treatment is performed on the object to be emulsified with a pressure of 20 MPa to 350 MPa, preferably 80 MPa to 350 MPa.
In step A, when an emulsification treatment is performed on the product to be emulsified with a pressure of 20 MPa or more, an oil-in-water emulsion composition with few coarse particles is obtained even after the heat treatment step (that is, step B). Tend.
The upper limit value of 350 MPa is a limit value of a commercially available apparatus.
The lower limit of the pressure is preferably 40 MPa or more, more preferably 60 MPa or more, further preferably 75 MPa or more, and particularly preferably 80 MPa or more.
The upper limit of the pressure is preferably 245 MPa or less.
The pressure may be 40 MPa or more and 245 MPa or less, 60 MPa or more and 245 MPa or less, 75 MPa or more and 245 MPa or less, or 80 MPa or more and 245 MPa or less.

The number of times of emulsification treatment (so-called number of treatments) may be one, but from the viewpoint of more uniformly emulsifying and dispersing, it is preferably performed twice or more, more preferably 5 to 30 times.

The temperature during the emulsification treatment is not particularly limited and can be set, for example, in the range of 5 ° C to 80 ° C.

Hereinafter, each component of the to-be-emulsified processed product in step A will be described in detail.

(Phospholipid)
The product to be emulsified contains phospholipid.
Phospholipids mainly function as emulsifiers.
Examples of the phospholipid include lecithin, which is a phospholipid derived from a natural product.
Lecithin is phosphatidylcholine itself or a mixture containing at least phosphatidylcholine.
A mixture containing at least phosphatidylcholine generally includes, in addition to phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, phosphatidylinositol, N-acylphosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, lysophosphatidylcholine, lysophosphatidic acid, sphingomyelin, It is a mixture that may contain sphingoethanolamine and the like.
The lecithin in the present disclosure is preferably lecithin containing phosphatidylcholine and having a phosphatidylcholine content of 80% by mass or more.

Examples of lecithin include egg yolk lecithin, soybean lecithin, cottonseed lecithin, rapeseed lecithin, corn lecithin, hydrogenated egg yolk lecithin, hydrogenated soybean lecithin and the like.
In the present disclosure, “yolk lecithin” means lecithin derived from egg yolk, “soy lecithin” means lecithin derived from soybean, and “cotton seed lecithin” means lecithin derived from cotton seed. “Rapeseed lecithin” means rapeseed-derived lecithin, and “corn lecithin” means corn-derived lecithin.

The phospholipid is not limited to a phospholipid derived from a natural product, and may be a chemically synthesized phospholipid.
Examples of chemically synthesized phospholipids include phosphatidylcholines (eg, dipalmitoylphosphatidylcholine, dimyristoylphosphatidylcholine, distearoylphosphatidylcholine, and dioleoylphosphatidylcholine), phosphatidylglycerols (eg, dipalmitoylphosphatidylglycerol, dimyristoylphosphatidylglycerol, distearoyl Phosphatidylglycerol, and dioleoylphosphatidylglycerol), phosphatidylethanolamine (for example, dipalmitoyl phosphatidylethanolamine, dimyristoyl phosphatidylethanolamine, distearoyl phosphatidylethanolamine, and dioleoylphosphatidylethanolamine).

As the phospholipid, for example, lecithin is preferable, at least one selected from egg yolk lecithin and soybean lecithin is more preferable, and egg yolk lecithin is still more preferable.
As egg yolk lecithin, purified egg yolk lecithin obtained by purifying egg yolk lecithin or highly purified egg yolk lecithin is preferable.

A commercially available product can be used as the phospholipid.
Examples of commercially available phospholipids include egg yolk lecithin PL-100M [trade name; purified egg yolk lecithin, Kewpie Co., Ltd.], egg yolk lecithin PC-98N [trade name; highly purified egg yolk lecithin, Kewpie Corporation], egg yolk Examples include lecithin Lipoid E80 [trade name; purified egg yolk lecithin, H. Holstein Co., Ltd.].

The processed product to be emulsified may contain only one type of phospholipid or two or more types.

(Triglyceride)
The emulsified product contains triglyceride.
Triglycerides are acylglycerols in which three molecules of fatty acid are ester-bonded to one molecule of glycerin.

The triglyceride is not particularly limited, and may be a medium chain fatty acid triglyceride or a long chain fatty acid triglyceride.
For example, from the viewpoint of easy availability, the triglyceride is preferably a long-chain fatty acid triglyceride.

In the present disclosure, the “medium chain fatty acid triglyceride” means a triglyceride having an average number of carbon atoms in the fatty acid chain of 6 or more and 12 or less.
The average carbon number of the fatty acid chain is the number of carbon atoms of fatty acids (ie, constituent fatty acids) constituting triglycerides [for example, 8 if caprylic acid (IUPAC system name: octanoic acid), capric acid (IUPAC system name: decanoic acid) Is 10 and lauric acid (IUPAC system name: dodecanoic acid is 12)] is weighted average by the composition ratio of the constituent fatty acids. The constituent fatty acid may be a saturated fatty acid or an unsaturated fatty acid, and is preferably a saturated fatty acid. The medium-chain fatty acid triglyceride may be derived from a natural product or a synthetic fatty acid triglyceride.

In the present disclosure, the “long chain fatty acid triglyceride” means a triglyceride having an average fatty acid chain carbon number of more than 12.
As the long-chain fatty acid triglyceride, a long-chain fatty acid triglyceride having an average fatty acid chain carbon number of 14 to 24 is preferable.
The fatty acid constituting the long-chain fatty acid triglyceride may be a saturated fatty acid or an unsaturated fatty acid.
The long-chain fatty acid triglyceride may be a vegetable oil corresponding to a natural long-chain fatty acid triglyceride, an animal oil corresponding to a natural long-chain fatty acid triglyceride, or a synthetic fatty acid triglyceride.
For example, vegetable oil is more preferable as the long-chain fatty acid triglyceride from the viewpoint that the melting point is low and the emulsion stability of the oil-in-water emulsion composition is high.
Vegetable oils as long-chain fatty acid triglycerides are oils derived from plant seeds or nuts. Specific examples include soybean oil, cottonseed oil, rapeseed oil, sesame oil, safflower oil, corn oil, peanut oil, olive oil, coconut oil, perilla Oil, castor oil, rose oil and the like.
Among these, as the vegetable oil, for example, at least one selected from the group consisting of soybean oil, sesame oil, and olive oil is preferable from the viewpoint of use results for injection applications, and soybean oil is more preferable from the viewpoint of availability. preferable.
Animal oils as long chain fatty acid triglycerides are fats and oils derived from animals or fish, and specific examples include beef tallow, pork tallow, whale oil, fish oil and the like.

A commercially available product can be used as the triglyceride.
Examples of commercially available products of medium-chain fatty acid triglycerides include “Miglyol (registered trademark) 812” (component name: tri (caprylic acid / capric acid) glyceryl) and “Miglyol (registered trademark) 810” (component name: “Coconard (registered trademark) RK” (component name: glyceryl tricaprylate), Kao Co., Ltd., “Coconard (registered trademark) MT” (component name: tri (caprylic acid), such as tri (caprylic acid / capric acid) glyceryl) / Glyceryl caprate), “Coconard (registered trademark) MT-N” (component name: tri (caprylic acid / capric acid) glyceryl), “Coconard (registered trademark) ML” (component name: tri (caprylic acid / caprin) Acid / lauric acid) glyceryl), etc., “TCG-M” (component name: tri (caprylic acid / capric acid) (Glyceryl phosphate), “O.D.O” (component name: tri (caprylic acid / capric acid) glyceryl) of Nisshin Oilio Co., Ltd., “Clodamole (registered trademark) GTCC” of Croda Japan Co., Ltd. ( Ingredient name: tri (caprylic acid / capric acid) glyceryl), NOF Corporation "Pasenate (registered trademark) 810" (component name: tri (caprylic acid / capric acid) glyceryl), and the like.
Examples of commercial products of long-chain fatty acid triglycerides include Kaneda Corporation's “Japanese Pharmacopoeia Soybean Oil (trade name)”, “Japanese Pharmacopoeia Sesame Oil (trade name)”, “Japanese Pharmacopoeia Castor Oil (trade name)” ", Japanese Pharmacopoeia Refined Soybean Oil (trade name)", "Japanese Pharmacopoeia Refined Olive Oil (trade name)", "Japanese Pharmacopoeia Olive Oil (trade name)", "Japanese Pharmacopoeia Rapeseed Oil (trade name)""Super Refined Soybean (trade name)", Super Refined Live (trade name) "," Super Refined Same (trade name) "of Croda," Olive Oil "(trade name) of Sigma-Aldrich, etc. Is mentioned.

The processed product to be emulsified may contain only one type of triglyceride or two or more types.

(Specific compounds)
The product to be emulsified contains at least one compound selected from flurbiprofen axetil and flurbiprofen (that is, a specific compound).

Flurbiprofen axetil is a non-steroidal analgesic agent that has an analgesic action against post-surgical pain and cancer pain, and is marketed by API Chem under the product name “Flrubiprofen axetil”.
Flurbiprofen is for osteoarthritis, shoulder periarthritis, tendinitis, tendonitis, peritonitis, humerus condylaritis (eg tennis elbow), muscle pain, and post-traumatic swelling and pain It is a non-steroidal analgesic / anti-inflammatory agent having analgesic action and anti-inflammatory action, and is marketed by Tokyo Chemical Industry Co., Ltd. under the trade name “Flurbiprofen”.

The emulsified product may contain only one of flurbiprofen axetil or flurbiprofen, or may contain both flurbiprofen axetil and flurbiprofen.

(water)
The emulsified product contains water.
Water functions as a dispersion medium.
Water is not particularly limited as long as it can be used for pharmaceuticals.
Examples of water include purified water, sterilized purified water, and water for injection.

(Specific surfactant)
The product to be emulsified may contain at least one surfactant selected from the group consisting of sorbitan fatty acid ester and polyoxyethylene sorbitan fatty acid ester (that is, a specific surfactant).
The specific surfactant is preferably, for example, a polyoxyethylene sorbitan fatty acid ester from the viewpoint of stabilizing the emulsified particles.
If the product to be emulsified contains polyoxyethylene sorbitan fatty acid ester, it is considered that a form in which the polyoxyethylene chain is exposed is formed on at least a part of the surface of the emulsified particles. It is considered that the presence of this polyoxyethylene chain causes steric repulsion between adjacent emulsified particles and stabilizes the emulsified particles.

There is no restriction | limiting in particular as polyoxyethylene sorbitan fatty acid ester.
The polyoxyethylene sorbitan fatty acid ester may be a compound having one ester bond in one molecule (that is, a mono-fatty acid ester), or a compound having two or more ester bonds in one molecule (that is, a di-fatty acid ester). Fatty acid ester, trifatty acid ester, etc.), or a mixture of two or more compounds having different numbers of ester bonds in one molecule.

The average number of moles of oxyethylene groups added in the polyoxyethylene sorbitan fatty acid ester is not particularly limited, but is preferably 5 to 60, for example, from the viewpoint of obtaining an oil-in-water emulsion composition with fewer coarse particles. 40 is more preferable, and 15 to 25 is even more preferable.

The carbon number of the fatty acid in the polyoxyethylene sorbitan fatty acid ester is not particularly limited, and is preferably 8 or more, and more preferably 12 or more.

Specific examples of polyoxyethylene sorbitan fatty acid esters include polysorbate 20 (also known as polyoxyethylene sorbitan monolaurate), polysorbate 40 (also known as polyoxyethylene sorbitan palmitate), polysorbate 60 (also known as polyoxymonostearate). And polysorbates such as polysorbate 65 (also known as polyoxyethylene sorbitan tristearate) and polysorbate 80 (also known as polyoxyethylene sorbitan oleate).
Among these, polyoxyethylene sorbitan fatty acid esters include, for example, polysorbate 80 (also known as polyoxyethylene sorbitan oleate) and polysorbate 20 (also known as polyoxyethylene sorbitan monolaurate) from the viewpoint of actual use in injection applications. ) Is preferred.
Polysorbate is a polyoxyethylene ether of sorbitan fatty acid ester obtained by condensing about 20 molecules of ethylene oxide to sorbitan fatty acid ester.

A commercially available product can be used as the polyoxyethylene sorbitan fatty acid ester.
Examples of commercially available products of polyoxyethylene sorbitan fatty acid ester include “NIKKOL (registered trademark) TO-10MV” of Nikko Chemicals Co., Ltd., which is polysorbate 80 (also known as polyoxyethylene sorbitan oleate), NOF Corporation ) “Polysorbate 80”, “Polysorbate 80 GS”, “Polysorbate 80 HX2”, “Nonion OT-221”, “MONTANOX (registered trademark) 80” of SEPPIC, “Reodol (registered trademark) TW of Kao Corporation -O120V "," Solgen (registered trademark) TW-80V "of Daiichi Kogyo Seiyaku Co., Ltd.," Krillet 4HP "of Croda Japan Co., Ltd., polysorbate 20 (also known as polyoxyethylene sorbitan monolaurate), “NIKKOL (registered trader) of Nikko Chemicals Co., Ltd. Standard) TL-10 ", Kao's" Leodol (registered trademark) TW-L120V ", NOF's" Nonion LT-221 ", Croda Japan's" Krillet 1HP ", etc. .

There is no restriction | limiting in particular as sorbitan fatty acid ester.
There is no restriction | limiting in particular in carbon number of the fatty acid in sorbitan fatty acid ester, For example, 8 or more are preferable and 12 or more are more preferable.
Examples of sorbitan fatty acid esters include sorbitan sesquioleate, sorbitan monocaprylate, sorbitan monolaurate, sorbitan monostearate, sorbitan sesquistearate, sorbitan tristearate, sorbitan isostearate, sorbitan sesquiisostearate, sorbitan oleate And sorbitan trioleate.

A commercial item can be used as sorbitan fatty acid ester.
Examples of commercially available sorbitan fatty acid esters include “NIKKOL (registered trademark) SO-15MV” (component name: sorbitan sesquioleate) from Nikko Chemicals Co., Ltd., “Leodol (registered trademark) AO” from Kao Corporation. -15V "(component name: sorbitan sesquioleate)," Span 83 "(component name: sorbitan sesquioleate) from Tokyo Chemical Industry Co., Ltd.," Span 80 "(component name: sorbitan monooleate) “Nonion OP-83R NOFA-BLESO” (component name: sorbitan sesquioleate), “NOFABLE (registered trademark) 80-582S” (component name: sorbitan sesquioleate), etc. “Cosmall (registered trademark) 82” by Kiyo Oilio Group Co., Ltd. Name: Sorbitan Sesquioleate), “Sorgen (registered trademark) 30V” from Daiichi Kogyo Seiyaku Co., Ltd. (Component name: Sorbitan Sesquioleate), “Ionet” (registered trademark) from Sanyo Chemical Industries, Ltd. S ”(component name: sorbitan fatty acid ester),“ Cadenax (registered trademark) SO-80C ”(component name: sorbitan fatty acid ester) of Lion Specialty Chemicals Co., Ltd., and the like.

When the emulsified product contains a specific surfactant, it may contain only one type of specific surfactant or two or more types.

(Polyhydric alcohol)
The emulsified product preferably contains a polyhydric alcohol.
When the processing object contains a polyhydric alcohol, the stability of the emulsified particles tends to be improved.
There is no restriction | limiting in particular as a polyhydric alcohol.
Examples of the polyhydric alcohol include glycerin, concentrated glycerin, propylene glycol, 1,3-butylene glycol, polyethylene glycol [eg, polyethylene glycol 300 (so-called macrogol 300), polyethylene glycol 400 (so-called macrogol 400), Polyethylene glycol 600 (so-called macrogol 600) and polyethylene glycol 1000 (so-called macrogol 1000)], dipropylene glycol, diethylene glycol and the like.
Among these, as the polyhydric alcohol, for example, concentrated glycerin is preferable from the viewpoint of obtaining finer emulsified particles.

When the emulsified processed product contains a polyhydric alcohol, it may contain only one kind of polyhydric alcohol or two or more kinds.

(Other additives)
The processed product to be emulsified may further contain other additives as necessary within the range not impairing the effects of the production method of the present disclosure, in addition to the components described above.
Examples of other additives include pharmaceutically acceptable additives.
For example, when the oil-in-water emulsion composition obtained by the production method of the present disclosure is administered by intravenous injection, it is preferable to further use an additive suitable for intravenous injection.
Examples of other additives include antioxidants (eg, ascorbic acid, D-α-tocopherol, butylhydroxyanisole (BHA), and dibutylhydroxytoluene (BHT)), stabilizers (eg, sodium citrate) And preservatives (for example, methyl paraoxybenzoate and propyl paraoxybenzoate).
However, other additives are not limited to these.

When the emulsified product contains other additives, it may contain only one type of other additive or two or more types.

[Process B]
Step B is a heat-treated product containing at least the emulsion obtained in Step A, and is at least one surfactant selected from the group consisting of sorbitan fatty acid esters and polyoxyethylene sorbitan fatty acid esters (ie, Specific surfactant), and the total content of sorbitan fatty acid ester and polyoxyethylene sorbitan fatty acid ester is 0.6% by mass or more and 1.8% by mass or less with respect to the total mass of the object to be heated. This is a step of performing heat treatment on the object to be heated.
The process B is a so-called sterilization process by heating.

The to-be-heated product in Step B may be the emulsion obtained in Step A using a specific surfactant, and the emulsion obtained in Step A without using the specific surfactant, It may be an emulsion obtained by mixing with a specific surfactant.

The content of the specific surfactant in the object to be heated is 0.6% by mass or more and 1.8% by mass or less, preferably 0.8% by mass or more and 1% by mass with respect to the total mass of the object to be heated. It is 0.75 mass% or less, More preferably, it is 1.0 mass% or more and 1.5 mass% or less, More preferably, it is 1.25 mass% or more and 1.5 mass% or less.
There exists a tendency for the oil-in-water-type emulsion composition with few coarse particles to be obtained as the content rate of the specific surfactant in a to-be-heated material is in said range.

In step B, there is no particular limitation on the method for performing the heat treatment on the object to be heated.
For example, an autoclave is suitable as the heating means.
In Step B, it is preferable to heat-treat the object to be heated at a temperature of 90 ° C. or higher and 140 ° C. or lower, more preferably 100 ° C. or higher and 135 ° C. or lower, and further preferably 105 ° C. or higher and 130 ° C. or lower.
When the temperature of the heat treatment is 90 ° C. or higher, the object to be heated can be sterilized more effectively.
When the temperature of the heat treatment is 140 ° C. or less, decomposition of the components contained in the heat-treated object due to heat is less likely to occur.
“Temperature” here means the ambient temperature.
The heating time is not particularly limited and can be appropriately set according to the heating temperature and the like.
When using an autoclave as the heating means, for example, it is preferable to set the heating temperature to 90 ° C. to 140 ° C. and heat for 1 minute to 60 minutes.

The pH of the object to be heated in step B is preferably 6.0 or more and 10.0 or less, more preferably 7.0 or more and 10.0 or less, and even more preferably 7.0 or more and 9.0 or less.
When the pH of the material to be heated in Step B is 6.0 or more, the emulsion stability of the oil-in-water emulsion composition is improved, and the generation of coarse particles after the heat treatment tends to be suppressed. Moreover, there exists a tendency for the production | generation of the fatty acid after the heat processing produced by decomposition | disassembly of a phospholipid and a triglyceride to be suppressed.
There exists a tendency for the production | generation of the hydrolyzate of the specific compound after heat processing to be suppressed as pH of the to-be-heated material in process B is 10.0 or less.

When the pH of the object to be heated is not 6.0 or more and 10.0 or less, the step B is a step of adjusting the pH of the object to be heated to 6.0 or more and 10.0 or less (hereinafter referred to as “pH adjustment”). It is also preferable to include a “step”.
When step B includes a pH adjustment step, in the pH adjustment step, it is more preferable to adjust the pH of the object to be heated to 7.0 or higher and 10.0 or lower, and to 7.0 or higher and 9.0 or lower. Is more preferable.
The pH of the object to be heated can be adjusted using, for example, a pH adjuster.
There is no restriction | limiting in particular as a pH adjuster, Well-known pH adjusters, such as a sodium hydroxide solution and hydrochloric acid, can be used.

In the present disclosure, the pH of the object to be heated is measured by setting the temperature of the object to be heated to 25 ° C. For the measurement of pH, a general method can be used as a pH measurement method. For example, the pH of the object to be heated can be measured with a pH meter. As the pH meter, a pH meter (model number: F-73) manufactured by HORIBA, Ltd. can be preferably used. However, the pH meter is not limited to this.

The heat treatment is performed on the object to be heated contained in the container. The container for storing the object to be heated is preferably a container used for a distribution product.
Prior to storing the object to be heated in the container, the object to be heated may be filtered using a filter.
The pore size of the filter is not particularly limited, and is preferably 50 μm or less, more preferably 20 μm or less, still more preferably 10 μm or less, particularly preferably 5 μm or less, and most preferably 0.8 μm or less.
The container containing the object to be heated is preferably sealed.
The accommodation of the object to be heated and the sealing of the container containing the object to be heated are preferably performed in an inert atmosphere such as a nitrogen atmosphere.
The type of the container that accommodates the object to be heated is not particularly limited, and examples include ampules, vials, syringes, and bags.
Among these, as the type of container for storing the object to be heated, for example, a vial is preferable from the viewpoint of handling at medical sites, and an ampoule is preferable from the viewpoint of high sealing performance of the container. From the viewpoint that administration is possible, a syringe or a bag is preferable.
The material of the container is not particularly limited, and may be glass or resin.
For example, the container is preferably a glass container from the viewpoint of oxygen permeability of the container.

[Oil-in-water emulsion composition]
According to the production method of the present disclosure, an oil-in-water emulsion composition containing phospholipid, triglyceride, specific compound, specific surfactant, and water can be obtained.
Since the oil-in-water emulsion composition obtained by the production method of the present disclosure has few coarse particles, it is suitable, for example, for injection (particularly for intravenous injection).
When a large amount of coarse particles are present in the oil-in-water emulsion composition, when administered by intravenous injection, blood vessels may be blocked after administration. On the other hand, since the oil-in-water emulsion composition obtained by the production method of the present disclosure has few coarse particles, the blood vessel is less likely to be blocked due to the coarse particles.

Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention is not limited to the following examples as long as the gist thereof is not exceeded.

Details of each component used in this example are shown below.

<Phospholipid>
・ Purified egg yolk lecithin [Brand name: Egg yolk lecithin PL-100M, Kewpie Co., Ltd., indicated as “lecithin” in the table]
<Triglyceride>
-Long-chain fatty acid triglycerides-
・ Soybean oil [Brand name: Japanese Pharmacopoeia Soybean oil, Kaneda Corporation]
<Specific surfactant>
-Polyoxyethylene sorbitan fatty acid ester-
Polysorbate 80 [trade name: NIKKOL (registered trademark) TO-10MV, also known as: polyoxyethylene sorbitan oleate, Nikko Chemicals Co., Ltd.]
Polysorbate 20 [trade name: NIKKOL (registered trademark) TL-10, also known as: polyoxyethylene sorbitan monolaurate, Nikko Chemicals Co., Ltd.]
-Sorbitan fatty acid ester-
・ Sorbitan sesquioleate [trade name: NIKKOL (registered trademark) SO-15MV, Nikko Chemicals Co., Ltd.]
<Surfactants other than specific surfactants>
・ Polyoxyethylene hydrogenated castor oil 60 [trade name: NIKKOL (registered trademark) HCO-60, Nikko Chemicals Co., Ltd.]

<Specific compounds>
Flurbiprofen axetil (trade name: Flurbiprofen axtil, diastereomeric mixture, API Chem)
Flurbiprofen [trade name: Flurbiprofen, Tokyo Chemical Industry Co., Ltd.]
<Water>
・ Water [Product name: Water for injection (1000 mL plastic bottle wide-opening type), Hikari Pharmaceutical Co., Ltd.]

<Polyhydric alcohol>
・ Concentrated glycerin [Brand name: Japanese Pharmacopoeia Concentrated glycerin, Sakamoto Pharmaceutical Co., Ltd.]
<Other additives>
・ Oleic acid [Brand name: Oleic acid, FUJIFILM Wako Pure Chemical Industries, Ltd.]
・ Sodium hydroxide solution [trade name: 0.1 mol / L sodium hydroxide solution, FUJIFILM Wako Pure Chemical Industries, Ltd.]
Hydrochloric acid [trade name: 0.1 mol / L hydrochloric acid, FUJIFILM Wako Pure Chemical Industries, Ltd.]

[Production of oil-in-water emulsion composition]
<Examples 1 to 5, Example 10, and Example 11>
Among the components listed in Table 1, components other than the specific surfactant were stirred and mixed at room temperature (ie, 25 ° C.) to obtain a mixture. Subsequently, the obtained mixture was stirred for a predetermined time at 10,000 rpm using a homogenizer [product name: ULTRA-TURRAX (registered trademark), IKA Corporation] to obtain a crude emulsion. Next, an emulsion X was obtained by subjecting the obtained crude emulsion to an emulsification treatment by the number of treatments described in Table 1 at a pressure described in Table 1 using a high-pressure homogenizer. Next, an emulsion Y was obtained by stirring and mixing the obtained emulsion X and the specific surfactant described in Table 1. Next, the pH of the emulsion Y is adjusted as shown in Table 1 by adding at least one of a sodium hydroxide solution and hydrochloric acid, which are pH adjusting agents, and water to the obtained emulsion Y. It was adjusted. Next, the emulsion Y after pH adjustment was filtered using a filter having a pore diameter of 0.8 μm. Next, 2 mL of the emulsion Y after filtration was stored in a glass container [trade name: CS-2, container type: vial, Fuji Glass Co., Ltd.] under a nitrogen atmosphere, and then a rubber stopper and an aluminum seal Was used to seal the container. Next, the emulsion Y contained in the container is subjected to a heat treatment at 121 ° C. for 15 minutes using an autoclave [Product name: Autoclave SP200, Yamato Scientific Co., Ltd.], whereby an oil-in-water emulsion composition Got.
Table 1 shows the blending ratio (unit: mass%) of each component used in the preparation of the oil-in-water emulsion composition.

<Examples 6 to 9, Example 12 and Example 13>
Each component described in Table 1 was stirred and mixed at room temperature (ie, 25 ° C.) to obtain a mixture. Subsequently, the obtained mixture was stirred for a predetermined time at 10,000 rpm using a homogenizer [product name: ULTRA-TURRAX (registered trademark), IKA Corporation] to obtain a crude emulsion. Next, the obtained crude emulsion was subjected to an emulsification treatment with the number of treatments shown in Table 1 at a pressure shown in Table 1 using a high-pressure homogenizer to obtain an emulsion. Next, the pH of the emulsion was adjusted as described in Table 1 by adding at least one of a sodium hydroxide solution and hydrochloric acid, which are pH adjusting agents, and water to the obtained emulsion. . Next, the pH-adjusted emulsion was filtered using a filter having a pore size of 0.8 μm. Next, 2 mL of the emulsion after filtration was placed in a glass container [trade name: CS-2, container type: vial, Fuji Glass Co., Ltd.] under a nitrogen atmosphere, and then a rubber stopper and an aluminum seal were attached. Used to seal the container. Next, the emulsion contained in the container is subjected to a heat treatment at 121 ° C. for 15 minutes using an autoclave [product name: Autoclave SP200, Yamato Scientific Co., Ltd.], whereby an oil-in-water emulsion composition is obtained. Obtained.
Table 1 shows the blending ratio (unit: mass%) of each component used in the preparation of the oil-in-water emulsion composition.

<Comparative Example 1>
Each component described in Table 2 was stirred and mixed at room temperature (ie, 25 ° C.) to obtain a mixture. Subsequently, the obtained mixture was stirred for a predetermined time at 10,000 rpm using a homogenizer [product name: ULTRA-TURRAX (registered trademark), IKA Corporation] to obtain a crude emulsion. Next, the obtained crude emulsion was subjected to an emulsification treatment with the number of treatments described in Table 2 at a pressure described in Table 2 using a high-pressure homogenizer to obtain an emulsion. Next, the pH of the emulsion was adjusted as shown in Table 2 by adding at least one of a sodium hydroxide solution and hydrochloric acid, which are pH adjusting agents, and water to the obtained emulsion. . Next, the pH-adjusted emulsion was filtered using a filter having a pore size of 0.8 μm. Next, 2 mL of the emulsion after filtration was placed in a glass container [trade name: CS-2, container type: vial, Fuji Glass Co., Ltd.] under a nitrogen atmosphere, and then a rubber stopper and an aluminum seal were attached. Used to seal the container. Next, the emulsion contained in the container is subjected to a heat treatment at 121 ° C. for 15 minutes using an autoclave [product name: Autoclave SP200, Yamato Scientific Co., Ltd.], whereby an oil-in-water emulsion composition is obtained. Obtained.
Table 2 shows the blending ratio (unit: mass%) of each component used for preparing the oil-in-water emulsion composition.

<Comparative Example 2 to Comparative Example 7>
Among the components listed in Table 2, components other than the specific surfactant were stirred and mixed at room temperature (ie, 25 ° C.) to obtain a mixture. Next, the obtained mixture was stirred at 10,000 rpm for a predetermined time using a homogenizer [product name: ULTRA-TURRAX (registered trademark), IKA Corporation] to obtain a crude emulsion. Next, an emulsion X was obtained by subjecting the obtained crude emulsion to an emulsification treatment with the number of treatments shown in Table 2 at a pressure shown in Table 2 using a high-pressure homogenizer. Next, an emulsion Y was obtained by stirring and mixing the obtained emulsion X and the specific surfactant described in Table 2. Next, the pH of the emulsion Y is adjusted as shown in Table 2 by adding at least one of a sodium hydroxide solution and hydrochloric acid, which are pH adjusting agents, and water to the obtained emulsion Y. It was adjusted. Next, the emulsion Y after pH adjustment was filtered using a filter having a pore diameter of 0.8 μm. Next, 2 mL of the emulsion Y after filtration was stored in a glass container [trade name: CS-2, container type: vial, Fuji Glass Co., Ltd.] under a nitrogen atmosphere, and then a rubber stopper and an aluminum seal Was used to seal the container. Next, the emulsion Y contained in the container is subjected to a heat treatment at 121 ° C. for 15 minutes using an autoclave [Product name: Autoclave SP200, Yamato Scientific Co., Ltd.], whereby an oil-in-water emulsion composition Got.
Table 2 shows the blending ratio (unit: mass%) of each component used for preparing the oil-in-water emulsion composition.

<Comparative Example 8>
Each component described in Table 2 was stirred and mixed at room temperature (ie, 25 ° C.) to obtain a mixture. Subsequently, the obtained mixture was stirred for a predetermined time at 10,000 rpm using a homogenizer [product name: ULTRA-TURRAX (registered trademark), IKA Corporation] to obtain a crude emulsion. Next, the obtained crude emulsion was subjected to an emulsification treatment with the number of treatments described in Table 2 at a pressure described in Table 2 using a high-pressure homogenizer to obtain an emulsion. Next, the pH of the emulsion was adjusted as shown in Table 2 by adding at least one of a sodium hydroxide solution and hydrochloric acid, which are pH adjusting agents, and water to the obtained emulsion. . Next, 2 mL of the emulsion after pH adjustment was placed in a glass container [trade name: CS-2, container type: vial, Fuji Glass Co., Ltd.] under a nitrogen atmosphere, and then a rubber stopper and an aluminum seal Was used to seal the container. Next, the emulsion contained in the container is subjected to a heat treatment at 121 ° C. for 15 minutes using an autoclave [product name: Autoclave SP200, Yamato Scientific Co., Ltd.], whereby an oil-in-water emulsion composition is obtained. Obtained.
Table 2 shows the blending ratio (unit: mass%) of each component used for preparing the oil-in-water emulsion composition.

[Measurement and evaluation]
1. PFAT5 value The oil-in-water emulsion compositions obtained by the production methods of Examples 1 to 13 and Comparative Examples 1 to 8 were diluted 10 times with water to prepare sample solutions for evaluation. 1 mL of the prepared sample solution for evaluation is injected into a number counting type particle size distribution apparatus [product name: AccuSizer 780AS, Nihon Entegris Co., Ltd.], and the total volume of particles having a diameter of 5 μm to 50 μm in 1 mL of the sample solution for evaluation is determined. It was automatically calculated according to the function of the apparatus. Based on the following formula (1), the volume ratio of particles having a diameter of 5 μm or more and 50 μm or less in the evaluation sample liquid to the total volume of the emulsified particles contained in the evaluation sample liquid (that is, PFAT5 value) (unit) : Volume%) was calculated. The calculated value was rounded off to the third decimal place.
In the following formula (1), it is assumed that the total volume of the emulsified particles contained in the evaluation sample liquid is approximately the same as the volume of the triglyceride contained in the evaluation sample liquid. In addition, the volume (unit: mL) of the triglyceride contained in the sample solution for evaluation was calculated based on the following formula (2).
Based on the calculated PFAT5 value, the effect of suppressing the formation of coarse particles was evaluated according to the following evaluation criteria. Tables 1 and 2 show measured values and evaluation results of PFAT5 values.
If the evaluation result was “AA” or “A”, it was judged as acceptable.

PFAT5 value (unit: volume%) = [total volume of particles with a diameter of 5 μm to 50 μm in 1 mL of sample liquid for evaluation (unit: mL)] ÷ [volume of triglyceride in 1 mL of sample liquid for evaluation (unit: mL) ] X 100 ... (1)

Triglyceride volume in 1 mL of sample solution for evaluation (unit: mL) = triglyceride content in oil-in-water emulsion composition (unit: g) ÷ triglyceride density (unit: g / mL) ÷ 10 (dilution ratio) ... (2)

For example, in the case of Example 1, the PFAT5 value was calculated as follows.
[Total volume of particles having a diameter of 5 μm or more and 50 μm or less in 1 mL of the sample solution for evaluation (unit: mL)] was 3.361 × 10 ⁻⁶ mL.
Triglyceride volume in 1 mL of sample solution for evaluation (unit: mL) = content of triglyceride in container-packed oil-in-water emulsion composition (unit: g) ÷ density of triglyceride (unit: g / mL) ÷ 10 (dilution Magnification) = 0.1 ÷ 0.92 ÷ 10 = 1.087 × 10 ⁻² mL
PFAT5 value (unit: volume%) = [total volume of particles having a diameter of 5 μm to 50 μm in 1 mL of evaluation sample liquid (unit: mL)] ÷ [volume of triglyceride in 1 mL of evaluation sample liquid (unit: mL) ] × 100 = 3.361 × 10 ⁻⁶ ÷ 1.087 × 10 ⁻² × 100≈0.031% by volume

-Evaluation criteria-
AA: PFAT5 value is less than 0.03% by volume.
A: The PFAT5 value is 0.03% by volume or more and 0.05% by volume or less.
B: The PFAT5 value is more than 0.05% by volume and less than 0.11% by volume.
C: The PFAT5 value is 0.11% by volume or more.

In Tables 1 and 2, “-” means that the corresponding component is not blended.
In Tables 1 and 2, the descriptions “before emulsification” and “after emulsification” in the column of the type of specific surfactant indicate the timing of blending the specific surfactant, and “before emulsification” It means that an emulsification treatment has been performed on the product to be emulsified with an activator, and “after emulsification” means that a specific surfactant is blended after the emulsification treatment.
The water described in Table 1 and Table 2 includes water derived from sodium hydroxide solution and hydrochloric acid which are pH adjusters.

As shown in Tables 1 and 2, the oil-in-water emulsion compositions obtained by the production methods of Examples 1 to 13 are oil-in-water emulsions obtained by the production methods of Comparative Examples 1 to 8. It became clear that there were few coarse particles compared with the composition.
From these results, it was clarified that the production methods of Examples 1 to 13 are production methods capable of producing an oil-in-water emulsion composition with few coarse particles even after the heat treatment step. .

[Production of oil-in-water emulsion composition]
<Examples 14 to 19>
Each component described in Table 3 was stirred and mixed at room temperature (ie, 25 ° C.) to obtain a mixture. Subsequently, the obtained mixture was stirred for a predetermined time at 10,000 rpm using a homogenizer [product name: ULTRA-TURRAX (registered trademark), IKA Corporation] to obtain a crude emulsion. Next, the obtained crude emulsion was subjected to an emulsification treatment with the number of treatments described in Table 3 at a pressure described in Table 3 using a high-pressure homogenizer to obtain an emulsion. Next, the pH of the emulsion was adjusted as shown in Table 3 by adding at least one of a sodium hydroxide solution and hydrochloric acid, which are pH adjusting agents, and water to the obtained emulsion. . Subsequently, the emulsion after pH adjustment was filtered using a filter having a pore diameter of 0.8 μm as necessary. In Example 14, filtration was performed, and in Examples 15 to 19, filtration was not performed. Next, 2 mL of the emulsion after pH adjustment (for Example 14, which was filtered after pH adjustment) was placed in a glass container [trade name: CS-2, type of container] under a nitrogen atmosphere. : Vial, Fuji Glass Co., Ltd.], and the container was sealed using a rubber stopper and an aluminum seal. Next, the emulsion contained in the container is subjected to a heat treatment at 121 ° C. for 15 minutes using an autoclave [product name: Autoclave SP200, Yamato Scientific Co., Ltd.], whereby an oil-in-water emulsion composition is obtained. Obtained.
Table 3 shows the blending ratio (unit: mass%) of each component used in the preparation of the oil-in-water emulsion composition.

<Example 20>
Among the components listed in Table 3, components other than the specific surfactant were stirred and mixed at room temperature (ie, 25 ° C.) to obtain a mixture. Subsequently, the obtained mixture was stirred for a predetermined time at 10,000 rpm using a homogenizer [product name: ULTRA-TURRAX (registered trademark), IKA Corporation] to obtain a crude emulsion. Next, an emulsion X was obtained by subjecting the obtained crude emulsion to an emulsification treatment by the number of treatments described in Table 3 at a pressure described in Table 3 using a high-pressure homogenizer. Next, an emulsion Y was obtained by stirring and mixing the obtained emulsion X and the specific surfactant described in Table 3. Next, the pH of the emulsion Y is adjusted as shown in Table 3 by adding at least one of a sodium hydroxide solution and hydrochloric acid, which are pH adjusting agents, and water to the obtained emulsion Y. It was adjusted. Next, the emulsion Y after pH adjustment was filtered using a filter having a pore diameter of 0.8 μm. Next, 2 mL of the emulsion Y after filtration was stored in a glass container [trade name: CS-2, container type: vial, Fuji Glass Co., Ltd.] under a nitrogen atmosphere, and then a rubber stopper and an aluminum seal Was used to seal the container. Next, the emulsion Y contained in the container is subjected to a heat treatment at 121 ° C. for 15 minutes using an autoclave [Product name: Autoclave SP200, Yamato Scientific Co., Ltd.], whereby an oil-in-water emulsion composition Got.
Table 3 shows the blending ratio (unit: mass%) of each component used in the preparation of the oil-in-water emulsion composition.

<Comparative Example 9 to Comparative Example 13>
Each component described in Table 3 was stirred and mixed at room temperature (ie, 25 ° C.) to obtain a mixture. Subsequently, the obtained mixture was stirred at 10,000 rpm using a homogenizer [product name: ULTRA-TURRAX (registered trademark), IKA Corporation] to obtain a crude emulsion. Next, the obtained crude emulsion was subjected to an emulsification treatment with the number of treatments described in Table 3 at a pressure described in Table 3 using a high-pressure homogenizer to obtain an emulsion. Next, the pH of the emulsion was adjusted as shown in Table 3 by adding at least one of a sodium hydroxide solution and hydrochloric acid, which are pH adjusting agents, and water to the obtained emulsion. . Subsequently, the emulsion after pH adjustment was filtered using a filter having a pore diameter of 0.8 μm as necessary. In Comparative Example 9, Comparative Example 10 and Comparative Example 12, filtration was performed, and in Comparative Example 11 and Comparative Example 13, filtration was not performed. Next, 2 mL of the emulsion after pH adjustment (for the Comparative Example 9, Comparative Example 10 and Comparative Example 12 after filtration after pH adjustment) 2 mL of a glass container [trade name : CS-2, container type: vial, Fuji Glass Co., Ltd.], and the container was sealed using a rubber stopper and an aluminum seal. Next, the emulsion contained in the container is subjected to a heat treatment at 121 ° C. for 15 minutes using an autoclave [product name: Autoclave SP200, Yamato Scientific Co., Ltd.], whereby an oil-in-water emulsion composition is obtained. Obtained.
Table 3 shows the blending ratio (unit: mass%) of each component used in the preparation of the oil-in-water emulsion composition.

[Measurement and evaluation]
1. PFAT5 value The oil-in-water emulsion compositions obtained by the production methods of Examples 14 to 20 and Comparative Examples 9 to 13 were diluted 10-fold with water to prepare sample solutions for evaluation. 1 mL of the prepared sample solution for evaluation is injected into a number-counting particle size distribution apparatus [Product name: AccuSizer 780AS, Nihon Entegris Co., Ltd.] It was automatically calculated according to the function of the apparatus. Then, in the same manner as described above, the volume ratio of particles having a diameter of 5 μm or more and 50 μm or less in the evaluation sample liquid to the total volume of the emulsified particles contained in the evaluation sample liquid (that is, PFAT5 value) (unit) : Volume%) was calculated. The calculated value was rounded off to the third decimal place.
Based on the calculated PFAT5 value, the effect of suppressing the formation of coarse particles was evaluated according to the same evaluation criteria as described above. Table 3 shows the measured values and evaluation results of the PFAT5 value.
If the evaluation result was “AA” or “A”, it was judged as acceptable.

2. Hydrolyzate Amount of Specific Compound The oil-in-water emulsion composition obtained by each of the production methods of Examples 14 to 20 and Comparative Examples 9 to 13 was diluted 100 times with ethanol, and an evaluation sample solution Was prepared. Using the prepared sample liquid for evaluation, the amount of hydrolyzate of flurbiprofen axetyl, which is a specific compound, was determined by HPLC (high performance liquid chromatography).
Specifically, under the following HPLC measurement conditions, the peak of flurbiprofen axetyl hydrolyzate detected at a retention time of 4.3 minutes, detection at a retention time of 8.7 minutes and a retention time of 8.9 minutes Among the peaks of flurbiprofen axetil (so-called diastereomeric mixture) to be detected and all peaks detected other than these peaks, the peaks with a peak area of 0.01 area% or more were picked up and picked up. The ratio of the peak area of the hydrolyzate of flurbiprofen axetil detected at a retention time of 4.3 minutes with respect to all the peak areas (hereinafter referred to as “the peak area ratio of the hydrolyzate”. Unit: area% ) Was automatically calculated. The calculated value was rounded off to the third decimal place.
The calculated peak area ratio of the flurbiprofen axetil hydrolyzate was defined as the amount of flurbiprofen axetil hydrolyzate, and the stability of the specific compound was evaluated according to the following evaluation criteria.
Table 3 shows measured values and evaluation results of the amount of flurbiprofen axetyl hydrolyzate.
If the evaluation result was “AA” or “A”, it was judged as acceptable.

(HPLC measurement conditions)
Detector: UV detector (detection wavelength: 254 nm)
Column: TSKgel ODS-100Z [Product name, average particle size: 5 μm, column size: 4.6 mm (inner diameter) × 150 mm (length), Tosoh Corporation]
Column temperature: 40 ° C
Eluent A: 0.1% by mass phosphoric acid aqueous solution Eluent B: 0.1% by mass phosphoric acid acetonitrile solution Gradient conditions (volume fraction of eluent B, time): (60%, 0.1 min) → (80%, 10 minutes) → (100%, 10.1 to 15.0 minutes) → (60%, 15.1 minutes) → Stop at 30 minutes Flow rate: 1 mL / min Injection volume: 10 μL

-Evaluation criteria-
AA: The peak area ratio of the hydrolyzate is less than 0.5 area%.
A: The peak area ratio of the hydrolyzate is 0.5 area% or more and less than 1.0 area%.
B: The peak area ratio of the hydrolyzate is 1.0 area% or more and less than 2.0 area%.
C: The peak area ratio of the hydrolyzate is 2.0 area% or more.

In Table 3, “-” means that the corresponding component is not blended.
In Table 3, the descriptions “before emulsification” and “after emulsification” in the column of the type of specific surfactant indicate the timing of blending the specific surfactant, and “before emulsification” It means that an emulsification treatment was performed on the blended product to be emulsified, and “after emulsification” means that a specific surfactant was blended after the emulsification treatment. The same applies to the descriptions of “before emulsification” and “after emulsification” in the column of other additive types.
The water described in Table 3 includes water derived from sodium hydroxide solution and hydrochloric acid which are pH adjusters.

As shown in Table 3, the oil-in-water emulsion compositions obtained by the production methods of Examples 14 to 20 are the same as the oil-in-water emulsion compositions obtained by the production methods of Comparative Examples 9 to 13. In comparison, there were few coarse particles.
From these results, it was clarified that the production methods of Examples 14 to 20 were production methods capable of producing an oil-in-water emulsion composition with few coarse particles even after the heat treatment step. .

In addition, the oil-in-water emulsion compositions obtained by the production methods of Examples 14 to 20 had few hydrolysates of flurbiprofen axetyl, which is a specific compound.
From these results, it was revealed that the production methods of Examples 14 to 20 are production methods in which the specific compound is difficult to hydrolyze and the specific compound is excellent in stability.

[Production of oil-in-water emulsion composition]
<Examples 21 to 24 and Examples 26 to 29>
Among the components listed in Table 4, the components other than the specific surfactant were stirred and mixed at room temperature (ie, 25 ° C.) to obtain a mixture. Subsequently, the obtained mixture was stirred for a predetermined time at 10,000 rpm using a homogenizer [product name: ULTRA-TURRAX (registered trademark), IKA Corporation] to obtain a crude emulsion. Next, an emulsion X was obtained by subjecting the obtained crude emulsion to an emulsification treatment at the pressure shown in Table 4 and the number of treatments shown in Table 4, using a high-pressure homogenizer. Next, an emulsion Y was obtained by stirring and mixing the obtained emulsion X and the specific surfactant described in Table 4. Next, the pH of the emulsion Y is adjusted as shown in Table 4 by adding at least one of a sodium hydroxide solution and hydrochloric acid, which are pH adjusting agents, and water to the obtained emulsion Y. It was adjusted. Next, the emulsion Y after pH adjustment was filtered using a filter having a pore diameter of 0.8 μm. Next, 2 mL of the emulsion Y after filtration was stored in a glass container [trade name: CS-2, container type: vial, Fuji Glass Co., Ltd.] under a nitrogen atmosphere, and then a rubber stopper and an aluminum seal Was used to seal the container. Next, the emulsion Y contained in the container is subjected to a heat treatment at 121 ° C. for 15 minutes using an autoclave [Product name: Autoclave SP200, Yamato Scientific Co., Ltd.], whereby an oil-in-water emulsion composition Got.
Table 4 shows the blending ratio (unit: mass%) of each component used for preparing the oil-in-water emulsion composition.

<Example 25, Example 30 and Example 31>
Each component described in Table 4 was stirred and mixed at room temperature (ie, 25 ° C.) to obtain a mixture. Subsequently, the obtained mixture was stirred for a predetermined time at 10,000 rpm using a homogenizer [product name: ULTRA-TURRAX (registered trademark), IKA Corporation] to obtain a crude emulsion. Next, the obtained crude emulsion was subjected to an emulsification treatment with the number of treatments shown in Table 4 at a pressure shown in Table 4 using a high-pressure homogenizer to obtain an emulsion. Next, the pH of the emulsion was adjusted as shown in Table 4 by adding at least one of a sodium hydroxide solution and hydrochloric acid, which are pH adjusting agents, and water to the obtained emulsion. . Subsequently, the emulsion after pH adjustment was filtered using a filter having a pore diameter of 0.8 μm as necessary. In Example 25, filtration was performed, and in Examples 30 and 31, filtration was not performed. Next, 2 mL of the emulsion after pH adjustment (for Example 25 after filtration after pH adjustment, the emulsion after filtration) was placed in a glass container [trade name: CS-2, type of container under a nitrogen atmosphere] : Vial, Fuji Glass Co., Ltd.], and the container was sealed using a rubber stopper and an aluminum seal. Next, the emulsion contained in the container is subjected to a heat treatment at 121 ° C. for 15 minutes using an autoclave [product name: Autoclave SP200, Yamato Scientific Co., Ltd.], whereby an oil-in-water emulsion composition is obtained. Obtained.
Table 4 shows the blending ratio (unit: mass%) of each component used for preparing the oil-in-water emulsion composition.

<Comparative example 14>
Each component described in Table 4 was stirred and mixed at room temperature (ie, 25 ° C.) to obtain a mixture. Subsequently, the obtained mixture was stirred for a predetermined time at 10,000 rpm using a homogenizer [product name: ULTRA-TURRAX (registered trademark), IKA Corporation] to obtain a crude emulsion. Next, the obtained crude emulsion was subjected to an emulsification treatment with the number of treatments shown in Table 4 at a pressure shown in Table 4 using a high-pressure homogenizer to obtain an emulsion. Next, the pH of the emulsion was adjusted as shown in Table 4 by adding at least one of a sodium hydroxide solution and hydrochloric acid, which are pH adjusting agents, and water to the obtained emulsion. . Next, the pH-adjusted emulsion was filtered using a filter having a pore size of 0.8 μm. Next, 2 mL of the emulsion after filtration was placed in a glass container [trade name: CS-2, container type: vial, Fuji Glass Co., Ltd.] under a nitrogen atmosphere, and then a rubber stopper and an aluminum seal were attached. Used to seal the container. Next, the emulsion contained in the container is subjected to a heat treatment at 121 ° C. for 15 minutes using an autoclave [product name: Autoclave SP200, Yamato Scientific Co., Ltd.], whereby an oil-in-water emulsion composition is obtained. Obtained.
Table 4 shows the blending ratio (unit: mass%) of each component used for preparing the oil-in-water emulsion composition.

<Comparative Example 15>
Each component described in Table 4 was stirred and mixed at room temperature (ie, 25 ° C.) to obtain a mixture. Subsequently, the obtained mixture was stirred for a predetermined time at 10,000 rpm using a homogenizer [product name: ULTRA-TURRAX (registered trademark), IKA Corporation] to obtain a crude emulsion. Next, the obtained crude emulsion was subjected to an emulsification treatment with the number of treatments described in Table 4 at a pressure described in Table 4 using a high-pressure homogenizer to obtain an emulsion. Next, the pH of the emulsion was adjusted as shown in Table 4 by adding at least one of a sodium hydroxide solution and hydrochloric acid, which are pH adjusting agents, and water to the obtained emulsion. . Next, 2 mL of the emulsion after pH adjustment was placed in a glass container [trade name: CS-2, container type: vial, Fuji Glass Co., Ltd.] under a nitrogen atmosphere, and then a rubber stopper and an aluminum seal Was used to seal the container. Next, the emulsion contained in the container is subjected to a heat treatment at 121 ° C. for 15 minutes using an autoclave [product name: Autoclave SP200, Yamato Scientific Co., Ltd.], whereby an oil-in-water emulsion composition is obtained. Obtained.
Table 4 shows the blending ratio (unit: mass%) of each component used for preparing the oil-in-water emulsion composition.

[Measurement and evaluation]
The oil-in-water emulsion compositions obtained by the production methods of Examples 21 to 31, Comparative Example 14 and Comparative Example 15 were subjected to a severe test in which they were stored for 2 weeks in an environment at an ambient temperature of 60 ° C. The following measurement and evaluation were performed using this oil-in-water emulsion composition after the severe test.

1. PFAT5 value The oil-in-water emulsion composition after the severe test was diluted 10 times with water to prepare a sample solution for evaluation. 1 mL of the prepared sample solution for evaluation is injected into a number-counting particle size distribution apparatus [Product name: AccuSizer 780AS, Nihon Entegris Co., Ltd.] It was automatically calculated according to the function of the apparatus. Then, in the same manner as described above, the volume ratio of particles having a diameter of 5 μm or more and 50 μm or less in the evaluation sample liquid to the total volume of the emulsified particles contained in the evaluation sample liquid (that is, PFAT5 value) (unit) : Volume%) was calculated. The calculated value was rounded off to the third decimal place.
Based on the calculated PFAT5 value, the effect of suppressing the formation of coarse particles was evaluated according to the same evaluation criteria as described above. Table 4 shows the measured values and evaluation results of the PFAT5 value.
If the evaluation result was “AA” or “A”, it was judged as acceptable.

2. Hydrolyzate Amount of Specific Compound An oil-in-water emulsion composition after a severe test was diluted 100 times with ethanol to prepare a sample solution for evaluation. Using the prepared sample liquid for evaluation, the peak area ratio of the hydrolyzate of flurbiprofen axetil was calculated in the same manner as described above. The calculated value was rounded off to the second decimal place.
The calculated peak area ratio of the flurbiprofen axetil hydrolyzate was defined as the amount of flurbiprofen axetil hydrolyzate, and the stability of the specific compound was evaluated according to the following evaluation criteria.
Table 4 shows measured values and evaluation results of the amount of flurbiprofen axetyl hydrolyzate.
If the evaluation result was “AA” or “A”, it was judged as acceptable.

-Evaluation criteria-
AA: The amount of flurbiprofen axetil hydrolyzate is less than 3.5 area%.
A: The amount of hydrolyzate of flurbiprofen axetil is 3.5 area% or more and less than 4.5 area%.
B: The amount of hydrolyzate of flurbiprofen axetil is 4.5 area% or more.

3. Fatty acid amount The oil-in-water emulsion composition after the severe test was diluted 100 times with ethanol to prepare a sample solution for evaluation. Using the prepared sample solution for evaluation, the amount of palmitic acid, which is a fatty acid, was determined by LC-MS (liquid chromatography-mass spectrometry).
Specifically, from the peak area of m / z (so-called mass-to-charge ratio) = 225.20 detected at a retention time of 14.8 minutes under the following LC-MS measurement conditions, using a calibration curve, palmitin The amount of acid was determined. The calculated value was rounded off to the fourth decimal place.
Based on the amount of palmitic acid obtained, the stability of phospholipids and triglycerides was evaluated according to the following evaluation criteria.
Table 4 shows measured values and evaluation results of the amount of palmitic acid.
If the evaluation result was “AA” or “A”, it was judged as acceptable.

(LC-MS measurement conditions)
Ionization methods: ESI (ElectroSpray Ionization) and APCI (Atomic Pressure Chemical Ionization)
Detection method: m / z = 225.20 (Nega, mode: SIM (Selected Ion Monitoring)
Column: Capcellpak (registered trademark) C18 [Product name, average particle size: 3 μm, column size: 2.0 mm (inner diameter) × 150 mm (length), Shiseido Co., Ltd.]
Column temperature: 40 ° C
Eluent A: 10 mM ammonium acetate aqueous solution Eluent B: 10 mM ammonium acetate methanol solution Gradient conditions (volume fraction of eluent B, time): (75%, 0.1 min) → (91%, 16 min) → (100%, 16.1 to 21.0 minutes) → (75%, 21.1 minutes) → Stop at 36 minutes Flow rate: 0.2 mL / min Injection volume: 4 μL

-Evaluation criteria-
AA: The amount of palmitic acid is less than 0.03% by mass.
A: The amount of palmitic acid is 0.03% by mass or more and less than 0.05% by mass.
B: The amount of palmitic acid is 0.05% by mass or more.

In Table 4, “-” means that the corresponding component is not blended.
In Table 4, the descriptions “before emulsification” and “after emulsification” in the column of the type of specific surfactant indicate the timing of blending the specific surfactant, and “before emulsification” It means that an emulsification treatment was performed on the blended product to be emulsified, and “after emulsification” means that a specific surfactant was blended after the emulsification treatment.
The water described in Table 4 includes water derived from sodium hydroxide solution and hydrochloric acid which are pH adjusters.

As shown in Table 4, the oil-in-water emulsion compositions produced by the production methods of Examples 21 to 31 and then stored in a harsh environment were obtained by the production methods of Comparative Examples 14 and 15. There were few coarse particles compared with the obtained oil-in-water emulsion composition.
From these results, it became clear that according to the production methods of Examples 21 to 31, an oil-in-water emulsion composition with few coarse particles can be produced even after the heat treatment step. Further, it was revealed that the oil-in-water emulsion compositions obtained by the production methods of Examples 21 to 31 are difficult to produce coarse particles even when stored in a harsh environment.

In addition, the oil-in-water emulsion composition produced by the production method of Examples 21 to 31 and stored in a harsh environment had a small amount of the hydrolyzate of flurbiprofen axetyl, which is a specific compound. .
From these results, it was revealed that the production methods of Examples 21 to 31 are production methods in which the specific compound is difficult to hydrolyze in the heat treatment step and is excellent in stability of the specific compound. In addition, the oil-in-water emulsion compositions obtained by the production methods of Examples 21 to 31 are resistant to hydrolysis of the specific compound even when stored in a harsh environment, and are excellent in stability of the specific compound. Became clear.

In addition, the oil-in-water emulsion composition produced by the production method of Examples 21 to 31 and stored in a harsh environment had a small amount of palmitic acid, which is a fatty acid produced by the decomposition of phospholipids and triglycerides. .
From these results, it is clear that the production methods of Examples 21 to 31 are production methods in which phospholipids and triglycerides are hardly decomposed in the heat treatment step and phospholipids and triglycerides are excellent in stability. It became. In addition, the oil-in-water emulsion compositions obtained by the production methods of Examples 21 to 31 hardly generate fatty acids derived from phospholipids and triglycerides even when stored in a harsh environment. It was revealed that the triglyceride was excellent in stability.

The disclosure of Japanese Patent Application No. 2018-105305 filed on May 31, 2018 is incorporated herein by reference in its entirety.
All documents, patent applications, and technical standards described in this specification are specifically and individually incorporated by reference as if individual documents, patent applications, and technical standards were incorporated by reference. To the extent it is incorporated herein by reference.

Claims (9)

An emulsification treatment with a pressure of 20 MPa or more and 350 MPa or less is performed on an article to be emulsified containing phospholipid, triglyceride, at least one compound selected from flurbiprofen axetyl and flurbiprofen, and water. Step A to obtain an emulsion by applying,
A to-be-heated product containing at least the emulsion obtained in step A, comprising at least one surfactant selected from the group consisting of sorbitan fatty acid ester and polyoxyethylene sorbitan fatty acid ester, and sorbitan fatty acid The step of subjecting the object to be heated, in which the total content of the ester and the polyoxyethylene sorbitan fatty acid ester is 0.6% by mass or more and 1.8% by mass or less based on the total mass of the object to be heated. B and
The manufacturing method of the oil-in-water emulsion composition which has NO. In the process B, the manufacturing method of the oil-in-water emulsion composition of Claim 1 which heat-processes to a to-be-heated material at the temperature of 90 to 140 degreeC. The oil-in-water emulsion composition according to claim 1 or 2, wherein at least one surfactant selected from the group consisting of sorbitan fatty acid esters and polyoxyethylene sorbitan fatty acid esters is polyoxyethylene sorbitan fatty acid ester. Production method. In step A, at least one compound selected from the group consisting of phospholipid, triglyceride, at least one compound selected from flurbiprofen axetil and flurbiprofen, sorbitan fatty acid ester and polyoxyethylene sorbitan fatty acid ester. The emulsion according to any one of claims 1 to 3, wherein an emulsion is obtained by subjecting an emulsion to be treated containing a surfactant of a kind and water to an emulsion to be emulsified with a pressure of 20 MPa to 350 MPa. The manufacturing method of the oil-in-water type emulsion composition of description. Step A includes phospholipid, triglyceride, at least one compound selected from flurbiprofen axetyl and flurbiprofen, and water, and sorbitan fatty acid ester and polyoxyethylene sorbitan fatty acid ester The underwater solution according to any one of claims 1 to 3, wherein an emulsified product is obtained by performing an emulsification treatment with a pressure of 20 MPa or more and 350 MPa or less on an emulsified product selected from A method for producing an oil-type emulsion composition. The oil-in-water emulsion composition according to any one of claims 1 to 5, wherein in step A, an emulsion is obtained by subjecting the product to be emulsified to an emulsification treatment at a pressure of 80 MPa to 350 MPa. Manufacturing method. The method for producing an oil-in-water emulsion composition according to any one of claims 1 to 6, wherein the pH of the material to be heated in step B is 6.0 or more and 10.0 or less. The method for producing an oil-in-water emulsion composition according to any one of claims 1 to 7, wherein the pH of the material to be heated in Step B is 7.0 or more and 9.0 or less. The method for producing an oil-in-water emulsion composition according to any one of claims 1 to 8, wherein the emulsified product contains a polyhydric alcohol.