JP6121796B2 - Method for increasing the content of non-steroidal anti-inflammatory drugs in fat emulsions and pharmaceutical compositions - Google Patents

Description

  The present invention relates to a fat emulsion having an increased embedding rate of a poorly soluble drug that is water-insoluble and oil-insoluble in emulsified particles, and a method for increasing the content of a nonsteroidal anti-inflammatory drug in a pharmaceutical composition About.

  Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) is a general term for anti-inflammatory drugs that are not steroids, and is widely used for the treatment of pain, fever, and inflammation. However, non-steroidal anti-inflammatory drugs have a high incidence of side effects, and it is known that ulcers with severe bleeding can occur in addition to the most common gastroenteritis, and there is a need to reduce these side effects .

  Reduction of the above-mentioned side effects can be expected by making a non-steroidal anti-inflammatory drug into a fat emulsion to give an injection. However, non-steroidal anti-inflammatory drugs other than some highly oil-soluble drugs (for example, flurbiprofen axetil, Patent Document 1) are both water-soluble and oil-soluble. It was difficult.

  In addition, even if fat emulsification can be achieved by adjusting emulsification conditions, there remains a problem that the encapsulation rate of the drug in the emulsified particles remains low. In order to efficiently accumulate the drug at the target site, the encapsulation rate A high fat emulsion was demanded.

JP-A-6-192084

Accordingly, an object of the present invention is to contain a fat emulsion that is highly water-insoluble and non-oil-soluble, poorly soluble drug in an emulsified particle, and contains a nonsteroidal anti-inflammatory drug in the pharmaceutical composition. It provides a way to increase the amount.

The fat emulsion according to one aspect of the present invention is:
Contains at least drugs, fats and oils, water, and phospholipids;
Non-steroidal anti-inflammatory, wherein the drug has a solubility in water of 1 × 10 ⁻¹ mg / mL or less, a solubility in soybean oil of 10 mg / mL or less, and contains a carboxyl group in the chemical structural formula Medicine,
The pH of the fat emulsion is 3-6,
The inclusion rate of the drug in the emulsified particles is 80% or more.
In addition, a method for increasing the content of a nonsteroidal anti-inflammatory drug in the pharmaceutical composition according to one embodiment of the present invention,
In a pharmaceutical composition containing a non-steroidal anti-inflammatory drug,
The non-steroidal anti-inflammatory drug is
The solubility in water is 1 × 10 ⁻¹ mg / mL or less,
Solubility in soybean oil is 10 mg / mL or less,
It contains a carboxyl group in the chemical structural formula,
Preparing a fat emulsion by emulsifying said non-steroidal anti-inflammatory drug, oil, water, and phospholipid;
Adjusting the pH of the fat emulsion to 3-6;
Containing
The encapsulation rate of the non-steroidal anti-inflammatory drug in the emulsified particles is 80% or more.

  According to the present invention, by providing a fat emulsion containing a poorly soluble drug and having an increased encapsulation rate of the drug in emulsified particles, the drug can be efficiently accumulated at a target site such as an inflammatory site, Reduction of drug dosage and side effects can be expected.

  Hereinafter, the present invention will be described in detail. In the present invention, “%” means “mass%”.

1. Fat Emulsion The fat emulsion according to this embodiment is an emulsion (oil-in-water emulsion) containing a drug (active ingredient), oil and fat, water, and phospholipid (emulsifier). That is, the fat emulsion according to the present embodiment is an emulsion in which emulsified particles are dispersed in water. In the emulsified particles, fats and oils are mainly included inside the film containing phospholipids. Drugs are included at the interface or inside.
Hereinafter, each component constituting the fat emulsion according to this embodiment will be described.

1.1. Drug 1.1.1. Non-steroidal anti-inflammatory drugs (NSAIDs)
Non-steroidal anti-inflammatory drugs are a group of compounds that are used clinically for the treatment of a range of disorders related to pain and inflammation. Nonsteroidal anti-inflammatory drugs are known to inhibit the cyclooxygenase (“COX”) enzyme that catalyzes the conversion of arachidonic acid to prostaglandins, and the analgesic and anti-inflammatory effects of the drug are due to inhibition of COX. It is thought that it is demonstrated.

  The non-steroidal anti-inflammatory drug used in the fat emulsion according to this embodiment is not particularly limited as long as it satisfies the characteristics of the drug described below, but is acidic from the viewpoint of easily achieving the effects of the present invention. Non-steroidal anti-inflammatory drugs are preferred. Acidic non-steroidal anti-inflammatory drugs include phenyl acid-based non-steroidal anti-inflammatory drugs such as indomethacin, acemetacin, diclofenac, felbinac and sulindag; Inflammatory drugs, etodolac, mefenamic acid and the like. Among these, phenyl acid non-steroidal anti-inflammatory drugs such as indomethacin, acemetacin, felbinac, sulindag, or propionic acid non-steroidal anti-inflammatory drugs such as ibuprofen are highly soluble and easy to achieve the effects of the present invention. A drug is preferable, and indomethacin, acemetacin, and ibuprofen are more preferable.

1.1.2. Solubility of drug in water The drug used in the fat emulsion according to this embodiment has a lower solubility in water and is difficult to prepare an injection. The solubility in 20 ° C. is 1 × 10 ⁻¹ mg / mL or less, preferably 1 × 10 ⁻² mg / mL or less, and more preferably 1 × 10 ⁻³ mg / mL or less. In other words, it is preferable to use a drug for which the term “almost insoluble” is used in the solubility described in the 16th revision Japanese Pharmacopoeia, General Rules.

The solubility of the drug in water can be confirmed by the following method. That is, water (20 ° C.) was mixed with the drug so that the drug concentration would be 1 × 10 ⁻¹ mg / mL, stirred for 30 seconds every 5 minutes, and when 30 minutes passed at 20 ° C. When the drug is dispersed or precipitated, the solubility in water is 1 × 10 ⁻¹ mg / mL or less. Similarly, water (20 ° C.) is further mixed so that the drug concentration becomes 1 × 10 ⁻³ mg / mL, and stirred for 30 seconds every 5 minutes. When the drug is dispersed or precipitated, the solubility in water is 1 × 10 ⁻³ mg / mL or less.

1.1.3. Solubility of Drug in Soybean Oil The drug used in the fat emulsion according to the present embodiment is more likely to exhibit the effects of the present invention as the drug is less soluble in oil and fat and more difficult to prepare an injection. The solubility in soybean oil (20 ° C.) is 10 mg / mL or less, preferably 5 mg / mL or less, more preferably 1 mg / mL or less.

  The solubility of the drug in soybean oil can be confirmed by the following method. That is, when the drug is mixed with soybean oil (20 ° C.) so that the drug concentration is 10 mg / mL, and the drug is visually dispersed or precipitated after 30 minutes at 20 ° C., The solubility in soybean oil is 10 mg / mL or less. Similarly, when soybean oil (20 ° C.) is further mixed so that the concentration of the drug becomes 1 mg / mL, and the drug is visually dispersed or precipitated after 30 minutes at 20 ° C., The solubility in soybean oil is 1 mg / mL or less.

1.1.4. Chemical structure of drug The drug used in the fat emulsion according to this embodiment is characterized by containing a carboxyl group in the chemical structural formula. “Containing a carboxyl group” means containing at least one or more carboxyl groups in the chemical structural formula of the drug. By adjusting the pH of the fat emulsion containing the drug to 3 to 6, a fat emulsion having an encapsulation rate of the drug in the emulsified particles of 80% or more can be prepared.

1.2. Phospholipid As the phospholipid used in the fat emulsion according to the present embodiment, both natural and synthetic phospholipids can be used. Examples of natural phospholipids include egg yolk phospholipid, egg yolk phosphatidylcholine, soybean phospholipid, soybean phosphatidylcholine, hydrogenated egg yolk phospholipid, hydrogenated egg yolk phosphatidylcholine, hydrogenated soybean phosphatidylcholine, hydrogenated soybean phosphatidylcholine, etc. be able to. Examples of chemically synthesized phospholipids include phosphatidylcholine, phosphatidylglycerol, and phosphatidylethanolamine.

  In the fat emulsion according to this embodiment, the above phospholipids can be used alone or in admixture of two or more. Of the above phospholipids, egg yolk phospholipid, egg yolk phosphatidylcholine, soybean phospholipid and soybean phosphatidylcholine are preferably used, and egg yolk phospholipid is more preferred.

  The phospholipid used in the fat emulsion according to this embodiment is preferably a purified phospholipid purified by a known method such as a fractionation method using an organic solvent. Specifically, the phospholipid purity is preferably 85% by weight or more, and more preferably 90% by weight or more.

1.3. Fats and oils used in the fat emulsion according to the present embodiment include, for example, soybean oil, sesame oil, rapeseed oil, safflower oil, olive oil, castor oil, corn oil, cottonseed oil, rice oil, sunflower oil, grape seed oil, Examples include vegetable oils such as wheat germ oil and medium chain fatty acid triglycerides (MCT). The vegetable oil is preferably a refined vegetable oil.

  The content of each component in the fat emulsion according to the present embodiment is not particularly limited as long as the drug contains an effective amount showing a medicinal effect. For example, in the case of indomethacin, acemetacin or ibuprofen, the drug content is preferably 0.1 to 30 mg / mL. Moreover, it is preferable that fats and oils are 5 to 50% with respect to the total amount of fat emulsion, and phospholipids are 1 to 100% with respect to fats and oils.

1.4. Other components In the fat emulsion according to the present embodiment, as required, isotonic agents (for example, glycerin, glucose, sodium chloride), antioxidants (for example, ascorbic acid and its salts, benzoic acid, citric acid and its) Salt, dibutylhydroxyanisole, dibutylhydroxytoluene, α-tocopherol, D-sorbitol) and a pH adjuster (sodium hydroxide, hydrochloric acid, various phosphates) may be contained.

1.5. Fat emulsion pH
The fat emulsion according to this embodiment has a pH of 3 to 6, preferably 3.5 to 5.5, and more preferably 4 to 5. If the pH of the fat emulsion is higher than the above range, it is not preferable because the encapsulation rate of the drug in the emulsified particles is lowered. On the other hand, if the pH of the fat emulsion is lower than the above range, it is difficult to maintain the stability of emulsification. Since the fat emulsion is used as an injection, the pH of the fat emulsion is generally adjusted to 8 to 9, which is the same as that in blood. The fat emulsion of the present invention succeeded in increasing the encapsulation rate of the drug in the emulsified particles by adjusting to 3-6, which is lower than the blood pH.

1.6. Encapsulation rate of drug in emulsified particles The fat emulsion according to this embodiment has an encapsulation rate of drug in emulsified particles of 80% or more, preferably 90% or more, and more preferably 95% or more. When the encapsulation rate is in the above range, it is possible to efficiently accumulate the drug on the target site such as the inflammatory site, and it can be expected to reduce the drug dose and the side effects.

  The encapsulation rate of the drug in the fat emulsion in the emulsified particles is calculated as the ratio (%) of the content of the drug in the oil phase to the content of the drug in the fat emulsion. The content of the drug in the oil phase is calculated by subtracting the content of the drug in the aqueous phase from the content of the drug in the fat emulsion. The content of the drug in the fat emulsion and the aqueous phase is described below. Measure according to the example measurement method.

1.7. Uses and Properties The fat emulsion according to this embodiment can be used for intravenous injection. In this case, after adjusting the pH of the fat emulsion obtained according to the present embodiment, it can be filled in an airtight or sealed container such as an ampoule, a vial, or a prefilled syringe container, and subjected to high-temperature heat treatment or the like.

  The average particle size of the fat emulsion according to this embodiment is preferably 300 nm or less, and more preferably in the range of 150 to 250 nm. When the average particle size is larger than this, the emulsion system of the fat emulsion may become unstable. In particular, when administered intravenously, if it is smaller than 150 nm, the rate of accumulation at the inflammatory site (especially the inner wall of the peripheral blood vessel) may be delayed, and the physiological activity after administration may be insufficient. .

1.8. Administration Form The fat emulsion according to this embodiment is preferably administered to a human or non-human mammal by a parenteral administration route, and more preferably administered by intravenous injection (including intravenous infusion). preferable. For example, the fat emulsion according to this embodiment containing 0.1 to 30 mg / mL acemetacin can be administered as it is or mixed with an infusion solution by intravenous injection.

2. Method for Producing Fat Emulsion The method for producing a fat emulsion according to this embodiment includes a step of emulsifying the aforementioned drug, fat, phospholipid, and water. For example, phospholipids, drugs, and other additives (for example, glycerin) are mixed and homogenized with a conventional homogenizer to a predetermined amount of oil (for example, soybean oil), and then a necessary amount of water is added thereto. Thereafter, the fat emulsion according to this embodiment can be produced by performing homogenization again with the homogenizer and converting it to an oil-in-water emulsion. The obtained fat emulsion may be further subjected to a sterilization treatment such as filtration or high-temperature heat treatment.

  Moreover, in order to set the pH of the fat emulsion according to the present embodiment to 3 to 6, it is possible to include a step of adjusting the pH in the method of manufacturing a fat emulsion. The method for adjusting the pH is not particularly limited as long as the pH of the fat emulsion according to this embodiment falls within the above range, but when sterilization is performed, it is preferably performed before sterilization in consideration of hygiene.

  When high-temperature heat treatment is performed as a sterilization treatment, the pH of the fat emulsion may vary before and after the high-temperature heat treatment. Therefore, the pH of the fat emulsion before the high temperature heat treatment may be adjusted in consideration of the change in pH due to the high temperature heat treatment. The pH of the fat emulsion can be adjusted using, for example, an acidic aqueous solution (for example, hydrochloric acid or phosphoric acid) or an alkaline aqueous solution (for example, sodium hydroxide aqueous solution).

  Furthermore, in the method for producing a fat emulsion according to an embodiment of the present invention, after adjusting the pH of the fat emulsion to 3 to 6, the fat emulsion is placed in an airtight or sealed container and subjected to high-temperature heat treatment at a predetermined temperature. A step of performing a predetermined time can be included. The fat emulsion can be sterilized by the high-temperature heat treatment. Here, the high-temperature heat treatment is preferably high-pressure steam heat sterilization or spray heat sterilization.

  The temperature and time of the high-pressure steam heat sterilization or spray heat sterilization are preferably 110 to 140 ° C. and 0.5 to 30 minutes, respectively. For example, the high-pressure steam heat treatment can be performed at 121 ° C. for 20 minutes.

3. Method for increasing content of non-steroidal anti-inflammatory drug in pharmaceutical composition Method for increasing content of non-steroidal anti-inflammatory drug in pharmaceutical composition according to one embodiment of the present invention is a non-steroidal anti-inflammatory drug. In which the non-steroidal anti-inflammatory drug has a water solubility of 1 × 10 ⁻¹ mg / mL or less, a soybean oil solubility of 10 mg / mL or less, and a chemical structural formula A step for preparing a fat emulsion by emulsifying the non-steroidal anti-inflammatory drug, oil and fat, water, and phospholipid, and adjusting the pH of the fat emulsion to 3 to 6 And the inclusion rate of the non-steroidal anti-inflammatory drug in the emulsified particles is 80% or more.

  In the method for increasing the content of the non-steroidal anti-inflammatory drug according to this embodiment, the non-steroidal anti-inflammatory drug used is the above-mentioned 1.1.1. Non-steroidal anti-inflammatory drugs described in 1) may be used.

  In the method for increasing the content of the non-steroidal anti-inflammatory drug according to this embodiment, the step of emulsifying the non-steroidal anti-inflammatory drug, oil, fat, water, and phospholipid to prepare a fat emulsion is the above-mentioned 2. May be carried out in the same manner as the step of emulsifying the drug, oil, fat, phospholipid and water described in 1. The step of adjusting the pH of the fat emulsion to 3 to 6 is the above-mentioned 2. It may be performed by the same method as the step of adjusting pH described in 1.

  The content of the non-steroidal anti-inflammatory drug in the pharmaceutical composition can be increased by including the above steps and setting the encapsulation rate of the non-steroidal anti-inflammatory drug in the emulsified particles to 80% or more. Increasing the content of non-steroidal anti-inflammatory drug means that the content (mg / mL) of non-steroidal anti-inflammatory drug in fat emulsion is the solubility of non-steroidal anti-inflammatory drug in water (20 ° C) ( mg / mL), which is preferably 500 times or more, more preferably 1000 times or more.

4). Examples Hereinafter, the present invention will be described in more detail by way of examples. However, the present invention is not limited to the examples.

4.1. Evaluation method In this example, the drug content in the fat emulsion, the drug content in the aqueous phase of the fat emulsion, the encapsulation rate of the drug in the emulsified particles, and the average particle size of the emulsified particles in the fat emulsion are as follows. Measured by.

4.1.1. Drug content in fat emulsion The drug content in fat emulsion was determined by HPLC method on fat emulsion. The operating conditions were as follows.
Detector: UV spectrophotometer (measurement wavelength: 254 nm)
Column: Octadecylsilylated silica gel (inner diameter 4.6 mm, length 25 cm)
Column temperature: about 40 ° C
Mobile phase: To a solution made up to 1,000 mL by adding water to 6 g of acetic acid (100), a solution prepared by dissolving 1.36 g of sodium acetate trihydrate in 100 mL of water was added to adjust the pH to 3.2. To 400 mL of this solution, 600 mL of acetonitrile was added.
Mobile phase flow rate: 0.7 mL / min

4.1.2. Drug content in the aqueous phase of the fat emulsion The drug content in the aqueous phase of the fat emulsion was measured by HPLC by subjecting the fat emulsion to an aqueous phase by ultrafiltration. The operating conditions were the same as those for measuring the drug content in the fat emulsion. The conditions for ultrafiltration were as follows.
A fat emulsion 0.5 mL was added to a centrifugal filter unit (manufactured by Nippon Millipore) of a low adsorption regenerated cellulose membrane, and centrifuged at 7,000 rpm for 10 minutes to separate an aqueous phase. The same operation was repeated to obtain 0.75 mL of an aqueous phase sample of a fat emulsion.

4.1.3. Encapsulation rate of drug in emulsified particles The drug encapsulation rate in the fat emulsion is calculated by the following formula (1) based on the drug content of the fat emulsion and the drug content in the aqueous phase of the fat emulsion. Is done. Measure the drug content in the fat emulsion and in the water phase and calculate the drug content in the oil phase by subtracting the drug content in the water phase from the drug content in the fat emulsion. It was calculated as the ratio (%) of the content of the drug in the oil phase to the content of the drug in.
Encapsulation rate of drug in emulsified particles (%) = (Drug content of fat emulsion−Drug content in water phase of fat emulsion) / Drug content of fat emulsion × 100
... (1)

4.1.4. Average particle size of emulsified particles The average particle size of the emulsified particles in the fat emulsion was measured with an N4PLUS submicron particle size distribution analyzer (manufactured by Beckman Coulter, Inc.).

4.2. Example 1
70 g of soybean oil as fat and oil and 8.4 g of purified egg yolk lecithin PL-100M (manufactured by QP Corporation) as phospholipid were dispersed with a homomixer and homogenized. To this was added 1.05 g of indomethacin, and then water for injection in which 14 g of Japanese Pharmacopoeia concentrated glycerin was dissolved was added and mixed to obtain 700 g of a crude emulsion. Next, the crude emulsion was passed through a Menton-Gaurin type homogenizer (manufactured by APV) 13 times under a pressure of 660 kgf / cm ² to obtain a fine emulsion.
Next, the obtained fat emulsion was filtered through a membrane filter having a pore size of 0.45 μm, adjusted to pH 4.5 with hydrochloric acid, and dispensed into a 15 mL vial to obtain the fat emulsion of the present invention. The obtained fat emulsion had a pH of 4.5, and the average particle size of the emulsified particles was 211 nm. The content of indomethacin in the fat emulsion was 1.51 mg / mL, and the encapsulation rate of indomethacin in the emulsified particles was 100%.
Indomethacin used as a drug has a solubility in water (20 ° C.) of 0.973 × 10 ⁻³ mg / mL, a solubility in soybean oil (20 ° C.) of 1 mg / mL or less, and has a chemical structure It contains a carboxyl group in the formula.

4.3. Example 2
The fat emulsion of Example 2 (average particle size of 191 nm) was obtained in the same manner as in Example 1 except that 10.5 g of ibuprofen was used as the method for producing the fat emulsion in Example 1.
The resulting fat emulsion of Example 2 had a pH of 4.5, the ibuprofen content in the fat emulsion was 14.8 mg / mL, and the encapsulation rate of ibuprofen in the emulsified particles was 99%.
In addition, ibuprofen used as a drug has a solubility in water (20 ° C.) of 0.01 mg / mL or less and a solubility in soybean oil (20 ° C.) of 10 mg / mL or less. Contains groups.

4.4. Test example 1
In the fat emulsions of Examples 1 and 2, the following test was conducted in order to examine the relationship between the pH of the fat emulsion and the encapsulation rate of the drug in the emulsified particles. Specifically, in the method for producing the fat emulsion of Examples 1 and 2, the pH after filtration through the membrane filter was adjusted to the pH (6.0, 7.5, 9.0) described in Table 1 with sodium hydroxide. A fat emulsion was obtained in the same manner as in Examples 1 and 2 except that the preparation was performed using an aqueous solution (Examples 3 and 4 and Comparative Examples 1 to 4). The pH of the obtained fat emulsion, the average particle diameter of the emulsified particles, the drug content in the fat emulsion and the encapsulation rate were analyzed in the same manner as in Example 1. The results are shown in Table 1.

  From the results shown in Table 1, despite the fact that the drugs indomethacin and ibuprofen used are poorly soluble drugs, an emulsion emulsion having an average particle diameter of 300 nm or less and excellent emulsion stability can be obtained. I understand that. Moreover, it can be understood that a fat emulsion having a high encapsulation rate of the drug in emulsified particles can be obtained by setting the pH of the fat emulsion to 3 to 6.

4.5. Examples 5 and 6
In the method for producing a fat emulsion in Example 1, except that the poorly soluble drug was acemetacin 1.05 g, the pH was adjusted to 4.5 with hydrochloric acid, and 6.0 with an aqueous sodium hydroxide solution. By the same method, the fat emulsions (average particle size 204 nm) of Examples 5 and 6 were obtained.
The pH of the obtained fat emulsion of Example 5 was 4.5, the content of acemethacin in the fat emulsion was 1.45 mg / mL, and the encapsulation rate of acemetacin in the emulsified particles was 99%. The pH of the fat emulsion of Example 6 was 6, the content of acemetacin in the fat emulsion was 1.46 mg / mL, and the encapsulation rate of acemetacin in the emulsified particles was 94%.
In addition, acemetacin used as a drug has a solubility in water (20 ° C.) of 0.143 × 10 ⁻³ mg / mL, a solubility in soybean oil (20 ° C.) of 1 mg / mL or less, and a chemical structure It contains a carboxyl group in the formula.

4.6. Test example 2
In the fat emulsion of Example 5, the following test was conducted in order to investigate the relationship between the content of the drug and the average particle diameter of the emulsified particles and the encapsulation rate of the drug in the emulsified particles. Specifically, in the method for producing the fat emulsion of Example 5, the amount of acemetacin was changed to the amount described in Table 2, and the amount of purified egg yolk lecithin PL-100M was changed from 8.4 g to 35 g. Obtained fat emulsions in the same manner as in Example 5 (Examples 7 to 14). In addition, the fine emulsification step uses an optimizer (manufactured by Sugino Machine Co., Ltd.), Examples 8, 10, 12, and 14 were passed 7 times under a pressure of 70 MPa, and Examples 7, 9, 11, and 13 were 245 MPa. The solution was passed 7 to 10 times under pressure. The pH of the obtained fat emulsion, the average particle diameter of the emulsified particles, the drug content in the fat emulsion and the encapsulation rate were analyzed in the same manner as in Example 1. The results are shown in Table 2.

  From the results shown in Table 2, even if the compounding amount of the drug is increased to 4 mg / mL or the average particle diameter of the emulsified particles is reduced to 100 nm, the pH of the fat emulsion is adjusted to 3 to 6, It can be understood that a fat emulsion having a high encapsulation rate of the drug in the emulsified particles can be obtained.

  This is the end of the description of the embodiment according to the present invention. The present invention includes configurations that are substantially the same as the configurations described in the embodiments (for example, configurations that have the same functions, methods, and results, or configurations that have the same purposes and results). In addition, the invention includes a configuration in which a non-essential part of the configuration described in the embodiment is replaced. In addition, the present invention includes a configuration that exhibits the same operational effects as the configuration described in the embodiment or a configuration that can achieve the same object. Further, the invention includes a configuration in which a known technique is added to the configuration described in the embodiment.

Claims (2)

A fat emulsion containing at least a drug, oil, water, and phospholipid,
The drug is
The solubility in water is 1 × 10 ⁻¹ mg / mL or less,
Solubility in soybean oil is 10 mg / mL or less,
Containing a carboxyl group in the chemical structure,
A non-steroidal anti-inflammatory drug,
Emulsifying a mixture of the non-steroidal anti-inflammatory drug, oil and fat, and phospholipid in water in which glycerin is dissolved to prepare a fat emulsion;
Adjusting the pH of the fat emulsion to 3-6;
Containing
10 to 50% of the fat and oil with respect to the total amount of the fat emulsion,
Phospholipids are 12-100% of fats and oils,
The inclusion rate in the emulsified particles of the drug is 80% or more,
A method for producing a fat emulsion .
In a pharmaceutical composition containing a non-steroidal anti-inflammatory drug,
The non-steroidal anti-inflammatory drug is
The solubility in water is 1 × 10 ⁻¹ mg / mL or less,
Solubility in soybean oil is 10 mg / mL or less,
It contains a carboxyl group in the chemical structural formula,
Preparing a fat emulsion by emulsifying a mixture of the non-steroidal anti-inflammatory drug, oil and fat, and phospholipid in water in which glycerin is dissolved;
Adjusting the pH of the fat emulsion to 3-6;
Containing
10-50% of the fat and oil is based on the total amount of the fat emulsion
Phospholipids are 12-100% of fats and oils,
The inclusion rate in the emulsified particles of the non-steroidal anti-inflammatory drug is 80% or more,
A method for increasing the content of a non-steroidal anti-inflammatory drug in a pharmaceutical composition.