KR20210132228A - Fat emulsion and method for producing same, method for improving stability of fat emulsion, and agent for improving stability of fat emulsion - Google Patents

Abstract

The present invention contains flurbiprofenaxetil, water, vegetable oil, egg yolk lecithin, glycerin, histidine or a salt thereof, and the content of histidine or a salt thereof is 1 mass of flurbiprofenaxetil. It relates to a fat emulsion, wherein the total amount in terms of histidine is 0.025 parts by mass or more and 0.19 parts by mass or less with respect to parts.

Description

FAT EMULSION AND METHOD FOR PRODUCING SAME, METHOD FOR IMPROVING STABILITY OF FAT EMULSION, AND AGENT FOR IMPROVING STABILITY OF FAT EMULSION

The present invention relates to a fat emulsion, and a method for preparing the same, a method for improving the stability of a fat emulsion, and a stability improving agent for a fat emulsion. More specifically, the present invention relates to a fat emulsion containing flurbiprofenaxetil, and a method for preparing the same, a method for improving the stability of a fat emulsion containing flurbiprofenaxetil, and flurbif It relates to an agent for improving the stability of fat emulsions containing lofenaxetyl.

In general, the shelf life of medical drugs is about 3 years from storage at room temperature in many cases. On the other hand, a fat emulsion composed of an oil-in-water emulsion containing oil, an emulsifier and water has inferior storage stability compared to general pharmaceuticals, and the shelf life is usually about 2 years when stored at room temperature (eg, non-patent literature). 1 and 2).

A fat emulsion containing flurbiprofenaxetil is marketed as an analgesic using the analgesic action of flurbiprofenaxetil (for example, Non-Patent Document 3).

Pharmaceutical interview form (synthetic corticosteroid drug rimetasone (registered trademark) intravenous 2.5 mg), revised in February 2012 (10th edition) Pharmaceutical interview form (general anesthetic/sedative 1% Dipriban (registered trademark) Note), revised in January 2015 (15th edition) Pharmaceutical interview form (Nonsteroidal analgesic for intravenous use, Ropion (registered trademark) intravenous 50 mg), revised in September 2015 (9th edition)

As described in Non-Patent Document 3, the shelf life of a fat emulsion containing flurbiprofenaxetyl is 18 months (1 year and a half) when stored at room temperature, and among fat emulsions, the shelf life is short. It is considered that the main factors for this are the decomposition of the main ingredient (flurbiprofenaxetyl) during storage and the decrease in the pH of the fat emulsion.

An object of the present invention is to provide a fat emulsion containing flurbiprofenaxetyl with improved storage stability.

By employing histidine or a salt thereof as a pH buffering agent for a fat emulsion containing flurbiprofenaxetil, the present inventor remarkably suppresses the degradation of the main agent and a decrease in pH when the fat emulsion is heat autoclaved. While being able to do it, it discovered that the decomposition|disassembly of the main ingredient and the fall of pH at the time of long-term storage can also be suppressed remarkably. This invention is based on this novel knowledge.

That is, this invention relates to each of the following inventions, for example.

(1) containing flurbiprofenaxetyl, water, vegetable oil, egg yolk lecithin, glycerin, histidine or a salt thereof,

The fat emulsion wherein the content of histidine or a salt thereof is 0.025 parts by mass or more and 0.19 parts by mass or less in terms of histidine with respect to 1 part by mass of flurbiprofenaxetyl.

(2) The fat according to (1), wherein the total content of at least one acid selected from the group consisting of phosphoric acid, citric acid, succinic acid, maleic acid and malonic acid is 0.05 mass% or less based on the total amount of the fat emulsion. emulsion.

(3) The fat emulsion according to (1) or (2), wherein the content of flurbiprofen immediately after heat autoclaving is 0.1 mg/ml or less based on the total amount of the fat emulsion.

(4) The fat emulsion according to any one of (1) to (3), wherein the egg yolk lecithin has a content of phosphatidylethanolamine of 0% by mass or more and 20% by mass or less.

(5) A method for producing a fat emulsion containing flurbiprofenaxetil, comprising:

preparing an emulsion composition containing flurbiprofenaxetil, water, vegetable oil, egg yolk lecithin, glycerin, and histidine or a salt thereof;

A manufacturing method comprising the step of heat autoclaving the emulsion composition.

(6) The production method according to (5), wherein the content of histidine or its salt in the emulsion composition is 0.025 parts by mass or more and 0.19 parts by mass or less in terms of histidine, based on 1 part by mass of flurbiprofenaxetyl.

(7) a method for improving the stability of a fat emulsion containing flurbiprofenaxetyl, comprising:

preparing an emulsion composition containing flurbiprofenaxetil, water, vegetable oil, egg yolk lecithin, glycerin, and histidine or a salt thereof;

A method comprising the step of heat autoclaving the emulsion composition.

(8) The method according to (7), wherein the content of histidine or a salt thereof in the emulsion composition is 0.025 parts by mass or more and 0.19 parts by mass or less in terms of histidine, based on 1 part by mass of flurbiprofenaxetyl.

(9) as a stability enhancing agent for a fat emulsion containing flurbiprofenaxetyl,

A stability improving agent comprising histidine or a salt thereof as an active ingredient.

According to the present invention, there is provided a fat emulsion containing flurbiprofenaxetyl having improved storage stability. The fat emulsion of the present invention can extend the shelf life (quality assurance period) because the decomposition of the main agent (flurbiprofenaxetil) and the pH drop of the fat emulsion are remarkably suppressed.

BRIEF DESCRIPTION OF THE DRAWINGS It is a graph which shows the result of Test Example 1. FIG.
2 is a graph showing the results of Test Example 2. FIG.
3 is a graph showing the results of Test Example 3. FIG.
4 is a graph showing the results of Test Example 4;
5 is a graph showing the results of Test Example 5;

EMBODIMENT OF THE INVENTION Hereinafter, the form for implementing this invention is demonstrated in detail. However, this invention is not limited to the following embodiment.

<Features of the present invention>

(fat emulsion)

The present invention contains flurbiprofenaxetil, water, vegetable oil, egg yolk lecithin, glycerin, histidine or a salt thereof, and the content of histidine or a salt thereof is 1 mass of flurbiprofenaxetil. It is characterized in providing a fat emulsion having 0.025 parts by mass or more and 0.19 parts by mass or less in total in terms of histidine with respect to parts.

(Method for preparing fat emulsion)

The present invention also comprises the steps of preparing an emulsion composition containing flurbiprofenaxetil, water, vegetable oil, egg yolk lecithin, glycerin and histidine or a salt thereof, and heat autoclaving the emulsion composition; It is characterized to provide a method for preparing a fat emulsion containing flurbiprofenaxetil.

(How to improve the stability of fat emulsions)

The present invention further comprises the steps of preparing an emulsion composition containing flurbiprofenaxetil, water, vegetable oil, egg yolk lecithin, glycerin and histidine or a salt thereof, and heat autoclaving the emulsion composition. , to provide a method for improving the stability of a fat emulsion containing flurbiprofenaxetil.

(stability improver)

The present invention is further characterized by providing a stability improving agent for a fat emulsion containing flurbiprofenaxetil, which contains histidine or a salt thereof as an active ingredient.

<flurbiprofen axetyl>

Flurbipropeneaxetyl is a compound also called (±)-1-acetoxyethyl 2-(2-fluoro-4-biphenylyl)propionate. Flurbiprofenaxetyl has known analgesic action, and is used as an analgesic. Flurbiprofen axetil can be used without particular limitation, as long as it is pharmaceutically acceptable.

<Content of flurbiprofenaxetyl in fat emulsion>

The content of flurbiprofenaxetyl in the fat emulsion according to the present embodiment can be appropriately set according to the usage and dose of the fat emulsion, other components contained in the fat emulsion, and the like. The content of flurbiprofenaxetil is usually 1 mg/ml or more and 20 mg/ml or less, and may be 8 mg/ml or more and 12 mg/ml or less, based on the total amount of the fat emulsion.

<How to obtain flurbiprofen axetil>

As flurbiprofen axetil, what was synthesize|combined according to a normal method may be used, and what is marketed may be used.

<Histidine or its salt>

Histidine is a type of amino acid, and is also called 2-amino-3-(1H-imidazo-4-yl)propionic acid. Histidine may be used without particular limitation, as long as it is pharmaceutically acceptable.

The histidine salt is not particularly limited as long as it is a pharmaceutically acceptable salt. Specific examples of the histidine salt include salts with alkali metals such as sodium and potassium, salts with alkaline earth metals such as calcium and magnesium, and salts with inorganic acids such as hydrochloric acid, hydrobromic acid and nitric acid. Salts of histidine include solvates and hydrates of the salt.

Histidine or its salt may be used individually by 1 type, and may be used in combination of 2 or more type.

<Content of histidine or salt thereof in fat emulsion>

The content of histidine or a salt thereof in the fat emulsion according to the present embodiment can be appropriately set according to the usage and dose of the fat emulsion, other components contained in the fat emulsion, and the like. The content of histidine or its salt is usually 0.025 mass% or more and 0.2 mass% or less, and may be 0.05 mass% or more and 0.15 mass% or less, in terms of histidine, based on the total amount of the fat emulsion. In the present specification, "content in terms of histidine" means content when the molecular weight of the histidine salt is converted to the molecular weight of histidine, and "total amount in terms of histidine" means the total amount of content in terms of histidine.

(Content ratio with flurbiprofen axetil)

The content of histidine or its salt in the fat emulsion according to the present embodiment is 0.025 parts by mass or more and 0.19 parts by mass or less in terms of histidine with respect to 1 part by mass of flurbiprofenaxetyl. When the content of histidine or its salt is within this range, the decomposition inhibitory effect of the main agent (flurbiprofenaxetyl) and the pH decrease inhibitory effect of the fat emulsion are remarkably exhibited. Moreover, when the content of histidine or its salt is 0.19 mass% or less, the average particle diameter of the fat emulsion after heat autoclaving can be maintained at 400 nm or less, so that emulsification can be further stabilized. From the viewpoint that these effects can be more significantly exhibited, the content of histidine or its salt is preferably 0.025 parts by mass or more and 0.15 parts by mass or less, in terms of histidine, based on 1 part by mass of flurbiprofenaxetyl, It is more preferable that they are 0.05 mass part or more and 0.15 mass part or less.

(Content ratio with egg yolk lecithin)

The content of histidine or its salt in the fat emulsion according to the present embodiment is preferably 0.02 parts by mass or more and 0.15 parts by mass or less in terms of histidine, based on 1 part by mass of egg yolk lecithin. When the content of histidine or its salt is within this range, the decomposition inhibitory effect of the main agent (flurbiprofenaxetyl) and the pH decrease inhibitory effect of the fat emulsion are remarkably exhibited. From the viewpoint of being able to exhibit these effects more remarkably, the content of histidine or its salt is more preferably 0.04 parts by mass or more and 0.15 parts by mass or less in terms of histidine with respect to 1 part by mass of egg yolk lecithin.

<Method for obtaining histidine or a salt thereof>

Histidine or its salt may be synthesized or purified according to a conventional method, or may be commercially available.

<vegetable oil>

Vegetable oil may be used without particular limitation, as long as it is pharmaceutically acceptable. Specific examples of the vegetable oil include soybean oil, olive oil, sesame oil, rapeseed oil, peanut oil, sunflower oil, corn oil, saffron oil, cottonseed oil, and medium-chain fatty acid triglycerides (MCT). As vegetable oil, soybean oil, olive oil, and sesame oil are preferable, and soybean oil is more preferable. A vegetable oil may be used individually by 1 type, and may be used in combination of 2 or more type.

<Content of vegetable oil in fat emulsion>

The content of vegetable oil in the fat emulsion according to the present embodiment can be appropriately set according to the usage and dose of the fat emulsion, other components contained in the fat emulsion, and the like. The content of the vegetable oil is usually 50 mg/ml or more and 150 mg/ml or less, and may be 80 mg/ml or more and 120 mg/ml or less, based on the total amount of the fat emulsion.

<How to obtain vegetable oil>

As vegetable oil, what was exploited or refined according to a conventional method may be used, and a commercially available thing may be used. Commercially available vegetable oils include, for example, "Japan Pharmacopoeia soybean oil" (manufactured by Kaneda Corporation), "soybean oil YM" (manufactured by Nisshin Oilio Group Co., Ltd.), "Japan Pharmacopoeia sesame oil" (manufactured by Kaneda Corporation), "Japan Pharmacopoeia" Olive oil" (manufactured by Kaneda Corporation), "Coconard MT" (manufactured by Kao Corporation), "Coconard RK" (manufactured by Kao Corporation), "Nippon Pharmacy Peanut Oil" (manufactured by Kaneda Corporation), "Nippon Pharmacy Corn Oil" (Kaneda) Co., Ltd.), "Nippon Pharmacopoeia rapeseed oil" (manufactured by Kaneda Co., Ltd.), etc. are mentioned.

<Egg yolk lecithin>

Egg yolk lecithin is a lipid whose main component is a phospholipid derived from egg yolk. Phospholipids derived from egg yolk may contain one or more types, such as glycerophospholipids such as phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, and phosphatidic acid, and sphingophospholipids such as sphingomyelin. Egg yolk lecithin may be used without particular limitation, as long as it is pharmaceutically acceptable. Egg yolk lecithin may be used individually by 1 type, and may be used in combination of 2 or more type.

<Content of phosphatidylethanolamine in egg yolk lecithin>

In egg yolk lecithin, it is preferable that the content of phosphatidylethanolamine in egg yolk lecithin is 0 mass % or more and 20 mass % or less. When the content of phosphatidylethanolamine in egg yolk lecithin is reduced in this way, the decomposition inhibitory effect of the main agent (flurbiprofenaxetil) and the pH lowering inhibitory effect of the fat emulsion are exhibited more remarkably. From the same viewpoint, it is more preferable that the content of phosphatidylethanolamine in egg yolk lecithin is 0 mass% or more and 10 mass% or less. In addition, when using two or more types of egg yolk lecithin in combination, the total content of phosphatidylethanolamine should just be within the said range based on the total amount of combined egg yolk lecithin.

<Content of egg yolk lecithin in fat emulsion>

The content of egg yolk lecithin in the fat emulsion according to the present embodiment can be appropriately set according to the usage and dose of the fat emulsion, other components contained in the fat emulsion, and the like. The content of egg yolk lecithin is usually 10 mg/ml or more and 20 mg/ml or less, and may be 12 mg/ml or more and 18 mg/ml or less, based on the total amount of the fat emulsion.

<Method of obtaining egg yolk lecithin>

Egg yolk lecithin can be obtained by a conventional method using egg yolk as a raw material. As the egg yolk lecithin, commercially available ones may be used. Examples of commercially available egg yolk lecithin include egg yolk lecithin PL-100M (manufactured by QP Corporation) and purified egg yolk lecithin PC-98N (manufactured by QP Corporation). Egg yolk lecithin with a reduced content of phosphatidylethanolamine can be obtained, for example, by purification using column chromatography, and is commercially available, for example, purified egg yolk lecithin PC-98N (manufactured by QP Corporation). can be heard

<Glycerin>

Glycerin may be used without particular limitation as long as it is pharmaceutically acceptable.

<Content of glycerin in fat emulsion>

The content of glycerin in the fat emulsion according to the present embodiment can be appropriately set according to the usage and dose of the fat emulsion, other components contained in the fat emulsion, and the like. The content of glycerin is usually 10 mg/ml or more and 30 mg/ml or less, and may be 20 mg/ml or more and 25 mg/ml or less, based on the total amount of the fat emulsion.

<How to obtain glycerin>

As glycerin, what was synthesized or purified according to a conventional method may be used, and a commercially available thing may be used.

<Water>

The water used for the fat emulsion according to the present embodiment is not particularly limited as long as it is pharmaceutically acceptable. As water, distilled water, tap water, purified water, sterile purified water, water for injection, distilled water for injection, etc. are mentioned, for example as defined in the 16th revision Japanese Pharmacopoeia. Water may be added to the balance so that the amount of the fat emulsion becomes a desired amount.

<Method for preparing emulsion composition>

The emulsion composition according to the present embodiment can be prepared by various known emulsification methods. As an example of the preparation method of an emulsion composition, the following method is mentioned, for example. After dispersing egg yolk lecithin and flurbiprofenaxetyl in vegetable oil, water, glycerin, and histidine or a salt thereof are added thereto, followed by vigorous shaking and stirring to perform preliminary emulsification. The pre-emulsified liquid mixture is emulsified with an emulsifier. An emulsion composition can be obtained by adding a pH adjuster to an emulsion liquid and adjusting to target pH. Histidine or a salt thereof may be added to the emulsion together with a pH adjuster.

(heat autoclaving treatment)

The emulsion composition prepared by the above-described method may be subjected to heat autoclaving after sealing in a container or the like corresponding to the target formulation form. Heat autoclaving can be carried out, for example, by treatment at a temperature of 110°C or more and 130°C or less and a pressure of 0.1 MPa or more and 0.3 MPa or less for 1 minute or more and 1 hour or less. As a container, an ampoule tube, a vial bottle, a prefilled syringe, etc. are mentioned, for example. Since the emulsion composition according to the present embodiment contains histidine or a salt thereof, decomposition of the main agent (flurbiprofenaxetil) and a decrease in pH when subjected to heat autoclaving can be significantly suppressed.

<Fat emulsion>

The fat emulsion according to the present embodiment may be the emulsion composition itself prepared by the method described above, or may be formulated through heat autoclaving treatment.

<Content of citric acid in the fat emulsion>

It is preferable that the fat emulsion according to the present embodiment contains substantially no at least one acid selected from the group consisting of phosphoric acid, citric acid, succinic acid, maleic acid and malonic acid. This is because these acids cannot suppress the decomposition of the main agent (flurbiprofenaxetyl) and the pH drop of the fat emulsion, but conversely promote it in some cases. Therefore, in the fat emulsion according to the present embodiment, the total content of at least one acid selected from the group consisting of phosphoric acid, citric acid, succinic acid, maleic acid and malonic acid is 0.05% by mass based on the total amount of the fat emulsion. It is preferable that it is less than or equal, and it is more preferable that it is 0.025 mass % or less. The lower limit of the total content of these acids may be 0 mass %.

<Content of flurbiprofen in fat emulsion>

The fat emulsion according to the present embodiment can significantly suppress the decomposition of the main ingredient (flurbiprofenaxetil) when the fat emulsion is heat and autoclaved, and the degree of decomposition of the main substance when stored for a long period of time markedly suppressed. Flurbiprofen is one of the components produced by decomposition of flurbiprofen axetil. Therefore, in the fat emulsion according to the present embodiment, the content of flurbiprofen, which is a decomposition product of flurbiprofen axetil, in the fat emulsion may be less than or equal to a predetermined value.

In the fat emulsion according to the present embodiment, for example, the content of flurbiprofen immediately after heat and autoclaving of the fat emulsion may be 0.1 mg/ml or less based on the total amount of the fat emulsion, or 0.05 mg /ml or less may be sufficient. The lower limit of the content of flurbiprofen may be 0 mg/ml. In the fat emulsion according to the present embodiment, for example, the ratio of flurbiprofen to flurbiprofen axetil immediately after heat and autoclaving of the fat emulsion may be 0.01 or less by mass ratio, or 0.005 or less may be The lower limit of the said ratio may be 0.

In the fat emulsion according to the present embodiment, for example, the content of flurbiprofen when the fat emulsion is heat and autoclaved and then stored at 60° C. for 6 weeks is based on the total amount of the fat emulsion. Therefore, 0.01 mg/ml or more and 1.5 mg/ml or less may be sufficient, and 0.01 mg/ml or more and 1.2 mg/ml or less may be sufficient. For the fat emulsion according to the present embodiment, for example, the ratio of flurbiprofen to flurbiprofen axetil when the fat emulsion is heat autoclaved and then stored at 60° C. for 6 weeks is, By mass ratio, 0.001 or more and 0.15 or less may be sufficient, and 0.001 or more and 0.12 or less may be sufficient.

In addition, when the fat emulsion according to the present embodiment is subjected to a severe test equivalent to 2 years of storage at room temperature (storage at 60°C for 4 weeks), the content of flurbiprofen is suppressed to 0.65 mg/ml or less there are many Therefore, in the fat emulsion according to the present embodiment, for example, the content of flurbiprofen may be 0.2 mg/ml or more and 0.65 mg/ml or less based on the total amount of the fat emulsion. In the fat emulsion according to the present embodiment, for example, the ratio of flurbiprofen to flurbiprofen axetil may be 0.02 or more and 0.065 or less by mass ratio.

<pH of fat emulsion>

The pH of the fat emulsion according to the present embodiment can be appropriately set according to the usage and dose of the fat emulsion, components contained in the fat emulsion, and the like. The pH of the fat emulsion according to the present embodiment is usually 3 or more and 8 or less, and may be 4 or more and 7 or less.

<Average particle diameter of fat emulsion>

The average particle diameter of the fat emulsion according to the present embodiment is not particularly limited, but may be 450 nm or less. Thereby, it becomes a thing suitable as an injection. From the same viewpoint, the average particle diameter of the fat emulsion may be 150 nm or more and 400 nm or less. In the present specification, the average particle diameter of the fat emulsion means the average particle diameter on a volume basis. The average particle diameter of the fat emulsion can be measured, for example, by a particle size distribution analyzer (eg, Coulter N4Plus submicron particle size distribution analyzer, manufactured by Beckman Coulter Corporation). The average particle diameter of the fat emulsion can be adjusted, for example, by changing the emulsification conditions. More specifically, for example, the average particle diameter of the fat emulsion can be decreased by, for example, setting the processing pressure of the emulsifier to 50 MPa or more and 200 MPa or less, and setting the number of passes through the emulsifier to 3 or more and 30 or less. It can adjust within the range mentioned above.

<Formulation form of fat emulsion>

The formulation form of the fat emulsion according to the present embodiment is not particularly limited, and may be, for example, an injection, an oral preparation, or the like.

<Method for improving the stability of fat emulsion>

The present invention relates to a method for preparing an emulsion composition containing flurbiprofenaxetil, water, vegetable oil, egg yolk lecithin, glycerin, and histidine or a salt thereof, and a step for autoclaving the emulsion composition by heat. It can also be considered as a method of improving the stability of fat emulsions containing bipropeneaxetyl.

<Stability improver>

In the present invention, in a fat emulsion containing histidine or a salt thereof, flurbiprofenaxetil, the decomposition and pH of the main agent (flurbiprofenaxetil) when the fat emulsion is heat autoclaved. While being able to suppress the fall of , it is based on discovering that the decomposition|disassembly of the main ingredient and the fall of pH at the time of long-term storage can also be suppressed remarkably. Accordingly, as an aspect of the present invention, there is provided an agent for improving the stability of a fat emulsion containing flurbiprofenaxetyl, which contains histidine or a salt thereof as an active ingredient.

The stability improving agent according to the present embodiment may be histidine or a salt thereof, and, if necessary, further containing pharmaceutically acceptable additives (excipients, binders, lubricants, disintegrants, bases, dissolution aids, etc.) okay Histidine or its salt may be used individually by 1 type for the stability improving agent which concerns on this embodiment, and may be used in combination of 2 or more type.

The above-described aspect related to the stability improving agent can also be grasped as the use or application of a stability improving agent containing histidine or a salt thereof as an active ingredient for improving the stability of a fat emulsion containing flurbiprofenaxetil.

Example

Hereinafter, the present invention will be described in more detail based on Examples and the like. However, the present invention is not limited to the following examples.

[Test Methods]

<Amount of flurbiprofen>

Flurbiprofen, which is one of the decomposition products of flurbiprofen axetil, was quantified under the following conditions using high performance liquid chromatography (manufactured by Nippon Waters).

Column: Waters Eclipse XDB-C18 (4.6 × 150 mm, 5 μm)

Mobile phase: acetonitrile: water: trifluoroacetic acid = 60: 40: 0.1

Detection method: UV (264 nm)

Flow rate: 1 ml/min

Temperature: 50℃

<Measurement of average particle diameter>

The average particle diameter of the emulsion composition or fat emulsion was determined as the average particle diameter on a volume basis using a particle size distribution analyzer (Coulter N4Plus submicron particle size distribution analyzer, manufactured by Beckman Coulter Corporation).

<pH measurement>

The pH of the emulsion composition or the fat emulsion was measured with a pH meter (a desk-type pH meter, manufactured by Horiba Corporation).

<Preparation of emulsion composition>

In each test example, unless otherwise indicated, an emulsion composition was prepared by the following method.

After dispersing 6 g of egg yolk lecithin (egg yolk lecithin PL-100M, manufactured by QP Co., Ltd.) and 5 g of flurbiprofenaxetyl (manufactured by Wako Pure Chemical Industries, Ltd.) in 50 g of soybean oil (Japanese Pharmacopoeia soybean oil, manufactured by Kaneda Corporation), 400 ml of water and 22 g of glycerin (Nippon Pharmacopoeia Nong Glycerin, manufactured by Sakamoto Chemical Industry Co., Ltd.) were added, vigorously shaking and stirring, and preliminary emulsification was performed. The pre-emulsified liquid mixture was emulsified with an emulsifier (high-pressure homogenizer LAB200, manufactured by SMT Co., Ltd.) under conditions of 70 MPa 10 passes. After adding various buffers or histidine (L-histidine, manufactured by Kanto Chemical Co., Ltd.) to the emulsion, a pH adjuster (hydrochloric acid or sodium hydroxide) is added to adjust to the desired pH (6.0 or more and 7.0 or less), and the total weight is 500 An emulsion composition was obtained by adding water so that it might become g.

<Heat autoclaving treatment>

Heat autoclaving treatment (hereinafter also simply referred to as “sterilization treatment”) was performed for 20 minutes at 121°C and 0.1 MPa after separately injecting the emulsion composition into a 5 ml ampule.

＜Severe test＞

The harsh test was conducted by storing the fat emulsion at 60°C for 6 weeks. Quantification of flurbiprofen and measurement of pH were performed at the time points of 0 weeks, 2 weeks, 4 weeks, and 6 weeks after the start of the harsh test. In addition, 4 weeks of severe testing is equivalent to 2 years of storage at room temperature.

[Test Example 1: Review of Buffer Types]

As a buffer, a combination of phosphoric acid and citric acid (Comparative Example 1: 0.035 mass% of phosphoric acid, 0.015 mass% of citric acid), citric acid (Comparative Example 2), phosphoric acid (Comparative Example 3), succinic acid (Comparative Example 4), maleic acid (Comparative Example) 5), malonic acid (Comparative Example 6) or histidine (Example 1) were added so as to be 0.05 mass %, respectively, to prepare an emulsion composition containing flurbiprofenaxetyl. The emulsion composition of each Example and Comparative Example was sterilized, and the fat emulsion of each Example and the comparative example was obtained.

For the fat emulsions of Examples and Comparative Examples, quantification of flurbiprofen before and after sterilization and measurement of pH were performed. After sterilization, the fat emulsions of Examples and Comparative Examples were subjected to a severe test, and flurbiprofen quantification and pH measurement were performed periodically. A result is shown to Tables 1-2, and FIGS. 1(A)-(D).

1(A) and (B) show the quantitative results of flurbiprofen before and after the sterilization treatment, and the pH measurement results. In the fat emulsion of Example 1 to which histidine was added as a buffer, the amount of flurbiprofen (lysate) and pH hardly changed before and after sterilization. On the other hand, in the fat emulsions of Comparative Examples 1 to 6, the amount of flurbiprofen (lysate) increased significantly before and after sterilization, and the pH was greatly reduced. In buffers other than histidine, decomposition of the subject (flurbiprofenaxetil) was clearly observed before and after sterilization treatment.

1(C) and (D) show the quantitative results of flurbiprofen at the time of the harsh test, and the pH measurement results. In the fat emulsion of Example 1 to which histidine was added as a buffer, the decomposition of the main agent (flurbiprofenaxetyl) and the decrease in pH were suppressed, compared to the fat emulsions of Comparative Examples 1 to 6.

[Test Example 2: Examination of Histidine Content]

Histidine content was set to 0.025 mass% (Example 2), 0.05 mass% (Example 3), 0.1 mass% (Example 4), 0.2 mass% (Example 5), or 0.3 mass% (Example 6). An emulsion composition was prepared. Moreover, the emulsion composition of Comparative Example 7 (phosphoric acid 0.02 mass %, citric acid 0.01 mass %) which used phosphoric acid and citric acid together as a buffer, and the emulsion composition (comparative example 8) to which the buffer was not added were prepared. The emulsion composition of each Example and Comparative Example was sterilized, and the fat emulsion of each Example and the comparative example was obtained.

With respect to the fat emulsions of Examples and Comparative Examples, quantification of flurbiprofen, measurement of average particle diameter, and pH measurement were performed before and after sterilization treatment. After sterilization, the fat emulsions of Examples and Comparative Examples were subjected to a severe test, and flurbiprofen quantification and pH measurement were performed periodically. The results are shown in Tables 3 to 5 and Figs. 2 (A) to (D).

2(A) and (B) show the quantitative results of flurbiprofen before and after the sterilization treatment and the pH measurement results. In the fat emulsions of Examples 2 to 6 to which histidine was added, the amount and pH of flurbiprofen (degradate) hardly changed before and after sterilization. On the other hand, in the fat emulsion of Comparative Example 7 in which phosphoric acid and citric acid were used in combination as buffers, the amount of flurbiprofen (decomposition product) was greatly increased before and after sterilization, and the pH was greatly reduced. Also, in the fat emulsion of Comparative Example 8, in which no buffer was added, the amount of flurbiprofen (degradate) almost did not change before and after sterilization (about the same as in Examples 2 to 6), but the pH was significantly lowered. there was. From the comparison between Comparative Example 7 and Comparative Example 8, it is considered that phosphoric acid and citric acid promote decomposition of the main agent (flurbiprofenaxetyl).

2(C) and (D) show the quantitative results of flurbiprofen at the time of the harsh test, and the pH measurement results. In addition, the results in the fat emulsion of Comparative Example 8 are not shown in Figs. 2(C) and (D). In the fat emulsions of Examples 2 to 6 to which histidine was added as a buffer, the decomposition of the main agent (flurbiprofenaxetyl) and the decrease in pH were suppressed as compared with the fat emulsions of Comparative Example 7. In particular, when the content of histidine was 0.05 mass% or more, this inhibitory effect was remarkably exhibited.

Table 5 shows the measurement results of the average particle diameter of the fat emulsion before and after the sterilization treatment. The fat emulsions of Examples 2 to 4, whose histidine content was less than 0.20 parts by mass based on 1 part by mass of flurbiprofenaxetil, had an average particle diameter of 400 nm or less even after sterilization, resulting in more stable emulsification. there was.

[Test Example 3: Comparative review with commercial formulations]

As a buffer, an emulsion composition containing 0.1 mass % of histidine (Example 7) and an emulsion composition using phosphoric acid and citric acid in combination (Comparative Example 9: phosphoric acid 0.02 mass %, citric acid 0.01 mass %) were prepared and sterilized, Fat emulsions of Example 7 and Comparative Example 9 were obtained. In addition, as a comparative control, a commercially available fat emulsion containing flurbiprofenaxetil (Ropion (registered trademark), Kaken Pharmaceutical Co., Ltd.) (Comparative Example 10) was prepared.

The fat emulsions of Examples and Comparative Examples were subjected to a severe test, and flurbiprofen was regularly quantified. The results are shown in Table 6 and FIG. 3 .

As shown in Fig. 3 , the fat emulsion of Example 7 clearly suppressed the decomposition of the main agent (flurbiprofenaxetyl), compared with the fat emulsion of Comparative Example 9 and the commercial formulation of Comparative Example 10. .

[Test Example 4: Review of histidine and phosphate buffer combination]

An emulsion composition using phosphoric acid and citric acid together as a buffer (Comparative Example 11: phosphoric acid 0.02 mass%, citric acid 0.01 mass%) was prepared and sterilized to obtain a fat emulsion of Comparative Example 11. Moreover, the emulsion composition (Example 8) which further added 0.1 mass % of histidine to the emulsion composition of Comparative Example 11 was prepared, it sterilized and the fat emulsion of Example 8 was obtained.

The fat emulsions of each Example and Comparative Example were subjected to a severe test, and quantification of flurbiprofen and pH measurement were performed periodically. The results are shown in Tables 7 to 8 and Figs. 4 (A) to (B).

By further adding histidine to the fat emulsion in which phosphoric acid and citric acid were used in combination, decomposition of the main agent (flurbiprofenaxetyl) and a decrease in pH could be suppressed.

[Test Example 5: Examination of the effect of reducing the content of phosphatidylethanolamine]

As a buffer, an emulsion composition containing 0.1 mass% of histidine (Example 9) and an emulsion composition using a combination of phosphoric acid and citric acid (Comparative Example 12: phosphoric acid 0.02 mass%, citric acid 0.01 mass%) were prepared and sterilized, Fat emulsions of Example 9 and Comparative Example 12 were obtained. In addition, as egg yolk lecithin, PL-100M (manufactured by QP Corporation) and PC-98N (manufactured by QP Corporation, phosphatidylethanolamine content of 0.1 mass% or less) were mixed at 1:2 (PE content of 6%) using, As a buffer, an emulsion composition (Example 10) to which 0.1 mass % of histidine was added was prepared and sterilized to obtain a fat emulsion of Example 10.

Fat emulsions of Examples and Comparative Examples were subjected to a severe test, and flurbiprofen was quantified immediately before the start of the test and 6 weeks after the start of the test. The results are shown in Table 9 and FIG. 5 .

Compared to the fat emulsion of Comparative Example 12 in which phosphoric acid and citric acid were used as buffers in combination, the fat emulsion of Example 9 using histidine clearly suppressed the decomposition of the main ingredient (flurbiprofenaxetil). In addition, the fat emulsion of Example 10 using egg yolk lecithin with a reduced phosphatidylethanolamine content (PE content) showed significantly less decomposition of the main ingredient (flurbiprofenaxetyl) compared to the fat emulsion of Example 9. was restrained

Claims (9)

A method for improving the stability of a fat emulsion containing flurbiprofenaxetyl, comprising:
preparing an emulsion composition containing flurbiprofenaxetil, water, vegetable oil, egg yolk lecithin, glycerin, and histidine or a salt thereof;
A step of autoclaving the emulsion composition by heat,
The method, wherein the stability improvement is suppression of decomposition of flurbiprofenaxetil and/or suppression of lowering of pH of the fat emulsion. The method of claim 1,
The method according to claim 1, wherein the content of histidine or a salt thereof in the emulsion composition is 0.025 parts by mass or more and 0.19 parts by mass or less in terms of histidine, based on 1 part by mass of flurbiprofenaxetyl. 3. The method according to claim 1 or 2,
a total content of at least one acid selected from the group consisting of phosphoric acid, citric acid, succinic acid, maleic acid and malonic acid in the fat emulsion is 0 mass % or more and 0.03 mass % or less based on the total amount of the fat emulsion; Way. 3. The method according to claim 1 or 2,
A method, wherein the content of flurbiprofen immediately after heat autoclaving is 0 mg/ml or more and 0.1 mg/ml or less based on the total amount of the fat emulsion. 3. The method according to claim 1 or 2,
The method, wherein the egg yolk lecithin has a content of phosphatidylethanolamine of 0% by mass or more and 20% by mass or less. 3. The method according to claim 1 or 2,
and a content of citric acid in the fat emulsion is 0 mass % or more and 0.01 mass % or less based on the total amount of the fat emulsion. 3. The method according to claim 1 or 2,
The method according to claim 1, wherein the content of phosphoric acid in the fat emulsion is 0 mass% or more and 0.02 mass% or less based on the total amount of the fat emulsion. 3. The method according to claim 1 or 2,
The method of claim 1, wherein the fat emulsion has an average particle diameter of 450 nm or less. 3. The method according to claim 1 or 2,
The method of claim 1, wherein the fat emulsion has an average particle diameter of 150 nm or more and 400 nm or less.

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