JP2001302507A - Perfluorocarbon emulsion - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a perfluorocarbon emulsion which comprises very fine particles and show excellent stability with time. SOLUTION: The objective perfluorocarbon emulsion comprises (A) 10-80 wt.% of perfluorocarbon; (B) 0.1-20 wt.%, based on the component A, of a compound represented by the following general formula (1) R1-X-R2 (1) (wherein R1 is a perfluoroalkyl of 6-12 carbon atoms; R2 is an alkyl group of 12-22 carbon atoms and X is represented by the following formulas (1)-(8) where R3 is an alkylene of 2-8 carbon atoms); (C) 0.1-10 wt.% of a medically acceptable emulsifier; and (D) the aqueous phase component.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a perfluorocarbon emulsion, and more particularly to a perfluorocarbon emulsion comprising a perfluorocarbon compound, an emulsifier, and an aqueous phase component, which is useful as an oxygen carrier, an organ preservation solution, or a contrast agent.

[0002]

2. Description of the Related Art A perfluorocarbon compound is capable of dissolving and transporting a large amount of oxygen despite its chemical inertness. Therefore, a physical therapy such as an oxygen carrier, an organ preservation solution, or ultrasound or X-rays is required. Is expected as an active ingredient such as a contrast agent. In these medical uses, it is necessary to stably form the perfluorocarbon compound into fine particles, and therefore, it is generally prepared as an emulsion. As such a perfluorocarbon emulsion,
For example, "Fluosol DA20%" (Midori Cross Co., Ltd.) is widely known. It consists of two perfluorocarbon compounds, perfluorodecalin and perfluorotripropylamine, and two surfactants, egg yolk phospholipid and polyoxyethylene polyoxypropylene glycol (Pluronic F-68, BASF). Is a formulation emulsified and dispersed in water using the mixture of However, since this emulsion is unstable in a liquid state, it has a problem in use in medical applications. Generally, since these perfluorocarbon compounds have strong water repellency, it is very difficult to stably emulsify and disperse them in water. Therefore, many studies have been made to prepare stable emulsions. For example, Japanese Patent Publication No. 1-2812
And JP-A-3-72423 disclose emulsions using a cyclic perfluoronitrogen-containing compound as the perfluorocarbon compound. These are intended to obtain a highly stable emulsion with a general composition by adopting a specific perfluorocarbon nitrogen-containing compound as an active ingredient. It had to be stored at a low temperature of ° C. Japanese Patent Application Laid-Open No. 4-154718 discloses that a composition comprising a perfluorocarbon, a phospholipid and an aqueous solvent, which is emulsified using three components, and a liquid containing a polymer nonionic surfactant are mixed. A perfluorocarbon emulsion is shown. This is a highly stable emulsion by mixing an emulsified composition consisting of a perfluorocarbon, a phospholipid and an aqueous solvent with a liquid containing a high-molecular nonionic surfactant such as polyoxyethylene polyoxypropylene glycol. However, it cannot be said that long-term stability is still sufficient. In addition, Tokuhei 8
JP-A-22815 discloses an emulsion comprising a perfluorocarbon compound, an oil, a surfactant and water. In this method, a perfluorocarbon compound is dispersed in oil, and the mixture is emulsified in water with a surfactant.However, in most cases, the perfluorocarbon compound is hardly miscible with oil because of oil repellency, and in most cases, Since the perfluorocarbon compound has a higher specific gravity than oil, it is still insufficient in stability.

[0003]

As described above, all of the conventionally known methods are not suitable for pharmaceutical emulsions, especially for preparations which are supposed to be administered intravenously, in terms of particle size and stability. It was not enough and practical. In particular, for medical applications, it is necessary to sterilize the emulsion by heat as much as possible because sterilization by filtration is difficult, but the stability is maintained even after heat sterilization as well as normal storage stability. It was extremely difficult to prepare a perfluorocarbon emulsion to be prepared. In particular, although perfluorohydrocarbons are excellent in terms of oxygen transportability and half-life in vivo, fine and stable emulsions can be prepared due to their molecular structure and polarity. Because of the difficulty, when only perfluorohydrocarbon is selected as the active ingredient, a method for preparing an emulsion composed of fine particles and having high stability has been eagerly desired. The present invention seeks to solve the above problems. That is, an object of the present invention is to provide a perfluorocarbon emulsion comprising fine particles and having excellent stability over time.

[0004]

Means for Solving the Problems As a result of intensive studies to achieve the above object, the present inventors have identified a perfluorocarbon emulsion comprising a perfluorocarbon compound, an emulsifier, and an aqueous phase component, and furthermore, a specific intramolecular molecule. By blending a specific amount of an ester or an ether having a specific alkyl group and a perfluoroalkyl group of the formula (1), an emulsion having excellent stability can be prepared without depending on the molecular structure of the perfluorocarbon compound. It was completed. That is, the present invention is as follows. (1) A perfluorocarbon emulsion comprising 10 to 80% by weight of a perfluorocarbon compound (A), 0.1 to 10% by weight of a pharmaceutically acceptable emulsifier (C), and an aqueous phase component (D). The compound (B) represented by the general formula (1) is used in an amount of 0.1 to 20 with respect to the component (A).
R ¹ -XR ² (1) wherein R ¹ is a perfluoroalkyl group having 6 to 12 carbon atoms, and R ² is a perfluoroalkyl group having 12 to 22 carbon atoms. X represents an alkyl group;
Is

[0005]

Embedded image

[0006] Here, R ³ is an alkylene group having 2 to 8 carbon atoms. (2) The compound (B) represented by the general formula (1) is treated at 40 ° C.
(3) the perfluorocarbon emulsion according to the above (1), which is liquid at the temperature of (1), (3) the perfluorocarbon emulsion according to the above (1), wherein the pharmaceutically acceptable emulsifier (C) contains a phospholipid, The perfluorocarbon emulsion according to the above (3), wherein the medically acceptable emulsifier (C) is a mixture containing a phospholipid and a nonionic surfactant in a ratio of 10:90 to 100: 0, (5) The phospholipid constituting the medically acceptable emulsifier (C) is a perfluorocarbon emulsion according to the above (3) or (4) containing a phospholipid having a polyethylene glycol chain, and (6) the phospholipid has The perfluorocarbon emulsion according to the above (5), wherein the polyethylene glycol chain has a molecular weight of 400 to 20,000.

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in more detail. The perfluorocarbon compound which is the component (A) used in the perfluorocarbon emulsion of the present invention is appropriately selected from those having an oxygen-carrying ability and a low adverse reaction to a living body according to the purpose of the present invention. can do. Such perfluorocarbon compounds include:
For example, perfluoro hydrocarbons, perfluoroalkylamines, perfluoroalkyl bromide and the like can be mentioned.

In the present invention, by using a compound represented by the following general formula (1), a perfluorocarbon emulsion composed of fine particles and having excellent stability can be obtained. Even when perfluoroalkylamines having relatively high polarity and low-perfluorocarbon compounds having low polarity, which have been difficult to emulsify stably with conventional techniques, emulsions with excellent stability can be obtained. Accordingly, examples of the perfluorocarbon compound as the component (A) in the present invention include perfluorocycloalkanes such as perfluorocyclohexane, perfluoroalkylcycloalkanes such as perfluorotrimethylcyclohexane and perfluoroisopropylcyclohexane, and perfluoromethyldecalin. These compounds may be used alone or in combination of two or more of compounds having a short in vivo half-life and excellent safety such as perfluoroalkyldecalin, perfluorodecalin and perfluoroalkane.

The content of the perfluorocarbon compound in the emulsion is 10 to 80% by weight, preferably 20 to 70% by weight.
It is adjusted to be within the range of% by weight. When the content exceeds 80% by weight, the viscosity of the finally prepared emulsion is increased, and the stability may be lowered. On the contrary, when the content is less than 10% by weight, the oxygen transport of the emulsion may be reduced. The performance decreases, which is not preferable. In the perfluorocarbon emulsion of the present invention, in addition to the perfluorocarbon compound (component A), the emulsifier (component C), and the aqueous phase component (component D), the component (B) is represented by the general formula (1). Selected from esters or ethers having specific perfluoroalkyl and alkyl groups in the molecule.
The species or two or more species are used in an amount of 0.1 to
By incorporating 20% by weight, a stable emulsion composed of fine particles can be prepared. R ¹ -XR ² (1) In the formula, R ¹ is a perfluoroalkyl group having 6 to 12 carbon atoms, and R ² is an alkyl group having 12 to 22 carbon atoms. X indicates that R ¹ and R ² are in an ester bond or an ether bond. For example, in the case of an ester bond, X is

[0010]

Embedded image And in the case of ether, X ³ : —O—. In addition, as a bonding mode of other esters or ethers,

[0011]

Embedded image (In the formula, R ³ is an alkylene group having 2 to 8 carbon atoms.)
R ¹ on each side of the alkanedicarboxylic acid
And R ² are an ester bond, or

[0012]

Embedded image

(In the formula, R ³ is the same as in the case of X ⁴ above.)
And R ¹ and R 2 on both sides of the alkanediol, respectively.
Those in which ² is an ester or ether bond are exemplified. The component (B) used in the perfluorocarbon emulsion of the present invention includes a perfluoroalkyl group (R ¹ ) having 6 to 12 carbon atoms and an alkyl group (R ¹ ) having 12 to 22 carbon atoms.
One or more of the compounds represented by the general formula (1) having ² ) can be appropriately selected and used. The perfluoroalkyl group (R ¹ ) may partially have a hydrocarbon group as long as the carbon chain consisting of only carbon and fluorine has at least 6 carbon atoms. At this time, the chain length (number of carbon atoms) of the perfluoroalkyl group (R ¹ )
Is less than 6, the effect of adding the component (B) is not sufficiently obtained. Conversely, if the chain length (carbon number) exceeds 12, the melting point of the component (B) increases, and the resulting par. The stability of the fluorocarbon emulsion may be reduced. Similarly, in the case of the alkyl group (R ² ), if the chain length (the number of carbon atoms) is smaller than 12, the effect of adding the component (B) cannot be sufficiently obtained. If it exceeds 22, the melting point of the component (B) will be high, and the compatibility with the perfluorocarbon compound will be low, and the stability of the resulting perfluorocarbon emulsion may be reduced.

Accordingly, the component (B) used in the perfluorocarbon emulsion of the present invention comprises
2 perfluoroalkyl group (R ¹ ) and 12 to 2 carbon atoms
A compound having an alkyl group (R ² ) of ² and preferably liquid at a temperature of 40 ° C. is desirable. As the component (B) in the present invention, a compound represented by the general formula (1) is selected from the viewpoints of availability, economy, ease of purification (or generation of impurities by a side reaction during synthesis), and the like. However, examples of such a compound include an ester obtained from a perfluoroalkyl alcohol and a fatty acid. For example, a primary alcohol having 6 to 12 carbon atoms having a perfluoroalkyl group having 6 or more carbon atoms and a primary alcohol having 12 carbon atoms One or two or more of them can be appropriately selected and used from the esters with fatty acids Nos. To 22.
Among them, in consideration of the stability of the finally obtained perfluorocarbon emulsion, those which are liquid at a temperature of 40 ° C. are preferably used.
6 to 10 carbon atoms having a perfluoroalkyl group of from 8 to 10
An ester obtained from a primary alcohol and an unsaturated fatty acid having 16 to 20 carbon atoms is preferably selected.

Preferred examples of the above-mentioned esters include those having 1 carbon atom such as palmitoleic acid, oleic acid, linoleic acid, linolenic acid, gondolic acid and erucic acid.
6 to 22 fatty acids having an unsaturated alkyl group in the molecule, and (perfluorohexyl) octanol;
(Perfluorooctyl) decanol, etc., having 6 to 6 carbon atoms
And an ester with a perfluoroalkyl alcohol having 12 perfluoroalkyl groups. The content of the component (B) in the present invention is adjusted to be in the range of 0.1 to 20% by weight, preferably 0.5 to 10% by weight based on the perfluorocarbon compound (A). At this time, if the content exceeds 20% by weight,
Depending on the molecular structure of the component (A), the compatibility of the component (B) may be reduced, and as a result, the stability may be reduced. Conversely, when the content is less than 0.1% by weight, the effect of the addition of the component (B) is reduced. Is not sufficiently obtained, and as a result, the stability of the emulsion also decreases, which is not preferable. Therefore, as for the content of the component (B), it is desirable that the amount dissolved in the perfluorocarbon compound is appropriately selected and used within the above range according to the selected perfluorocarbon compound.

In the present invention, the medically acceptable emulsifier, which is the component (C), can be selected from emulsifiers generally used for pharmaceutical applications.
Alternatively, a combination of a phospholipid and a nonionic surfactant is preferably selected. Particularly, a phospholipid is suitably selected, and preferably 10 to 100% by weight in the emulsifier (C),
More preferably, it is used in the range of 20 to 100% by weight. Examples of the phospholipid used as the component (C) include natural phospholipids such as egg yolk phospholipid and soybean phospholipid, hydrogenated phospholipids obtained by hydrogenating those natural phospholipids, and C12 to C22. And a synthetic phospholipid into which an acyl group has been introduced.

Preferred examples of the phospholipid include:
Natural phospholipids such as egg yolk phosphatidylcholine and soy phosphatidylcholine, hydrogenated phospholipids such as hydrogenated egg yolk phosphatidylcholine and hydrogenated soybean phosphatidylcholine, dimyristoyl phosphatidylcholine, dimyristoyl phosphatidylethanolamine, dipalmitoyl phosphatidylcholine, dipalmitoyl phosphatidylethanolamine, distearoylphosphyl And synthetic phospholipids such as distearoyl phosphatidylethanolamine, dioleoylphosphatidylcholine, dioleoylphosphatidylethanolamine, 1-palmitoyl-2-oleoylphosphatidylcholine, and the like. Among them, in consideration of the stability of the obtained emulsion, it is preferable to use natural or synthetic phosphatidylcholine, and particularly preferred is yolk phosphatidylcholine, which is a naturally occurring diacylphosphatidylcholine, or hydrogenated egg yolk phosphatidylcholine.

The component (C) used in the perfluorocarbon emulsion of the present invention contains various acyl groups in addition to the phospholipids described above, as long as the stability of the finally obtained emulsion is not affected. Phosphatidic acid, phosphatidylinositol, phosphatidyl glycerol,
Phospholipids such as phosphatidylserine and sphingomyelin may be contained, and furthermore, lysophospholipids may be contained in the phospholipids as long as they do not affect the stability and hemolysis of the finally obtained emulsion. Good. Examples of the nonionic surfactant used in combination with the phospholipid as the component (C) include polyoxyethylene polyoxypropylene glycol, polyoxyethylene hydrogenated castor oil, and polyoxyethylene sorbitan fatty acid ester. Among them, it is preferable to use polyoxyethylene polyoxypropylene glycol.

The content of the component (C) in the present invention is 0.1 to 10% by weight, preferably 0.5 to 10% by weight in the emulsion.
It is adjusted to be within the range of 5% by weight. At this time,
If the used amount is less than 0.1% by weight, the effect as an emulsifier cannot be obtained, and the stability of the prepared emulsion is reduced. As a result, the emulsion may be separated, and conversely, the amount exceeds 10% by weight. In such a case, the viscosity of the emulsion may increase, and as a result, the fluidity of the emulsion decreases, which is not preferable.

The perfluorocarbon emulsion of the present invention can be prepared by adding a phospholipid having a polyethylene glycol chain to the above-mentioned emulsifier (C) in addition to the above-mentioned phospholipid, thereby stabilizing the finally obtained perfluorocarbon emulsion. Properties can be further improved. In the present invention, the phospholipid having a polyethylene glycol chain (hereinafter referred to as PEGylated phospholipid) contained in the emulsifier (C) has a structure in which polyethylene glycol is bonded to a hydrophilic group of the phospholipid. The terminal on the side of the polyethylene glycol chain not bonded to the phospholipid may be a hydroxyl group or a terminal hydroxyl group modified with a methyl group, an ethyl group, or the like. PE above
In the G-phospholipid, the phospholipid that binds the polyethylene glycol chain is not particularly limited as long as it is a phospholipid, but it is relatively easy to introduce the polyethylene glycol chain and has a low degree of hydrolysis after introduction. Desirably, phosphatidylethanolamine is preferably selected (phosphatidylethanolamine having a polyethylene glycol chain is hereinafter referred to as “PEGylated phosphatidylethanolamine”).

In the present invention, PEGylated phosphatidylethanolamine refers to yolk phospholipid, soybean phospholipid,
Alternatively, they can be obtained by using phosphatidylethanolamine contained in hydrogenated phospholipids or diacylphosphatidylethanolamine prepared as a synthetic phospholipid, and binding polyethylene glycol or a derivative thereof. Examples of a method for binding phosphatidylethanolamine to polyethylene glycol or a derivative thereof include a method using cyanuric chloride, a method using carbodiimide, a method using glutaraldehyde, a method using carbamate, and the like.

Among them, as a method using carbodiimide, for example, a reaction between monomethoxypolyethylene glycol and succinic anhydride to introduce a carboxyl group (of succinic acid) into a hydroxyl group of monomethoxypolyethylene glycol, By reacting ethanolamine in the presence of carbodiimide,
PEGylated phosphatidylethanolamine having a polyethylene glycol chain introduced through an amide bond can be prepared. As a method using carbamate, for example, after reacting monomethoxypolyethylene glycol with carbonyldiimidazole to obtain imidazole carbamate of methoxypolyethylene glycol, then reacting this with phosphatidylethanolamine in the presence of triethylamine. Is used to introduce a polyethylene glycol chain through a urethane bond.
EGylated phosphatidylethanolamine can be prepared.

In the present invention, the molecular weight of the polyethylene glycol bound to the phospholipid is preferably 400 to
20,000, more preferably 1,000 to 10,000,
Especially preferably, it is 2000-8000. When the molecular weight of polyethylene glycol exceeds 20,000, the above P
Since the water solubility of the EGylated phospholipid is increased, as a result,
There is a possibility that the stability of the obtained perfluorocarbon emulsion may be reduced. On the contrary, if it is less than 400, the effect of improving the stability by adding the PEGylated phospholipid may be reduced.
In the present invention, when a phospholipid in which polyethylene glycol is bonded to a hydrophilic group is contained in the emulsifier (C), the PEGylated phospholipid is added in an amount of 0.1 to 30% by weight in the emulsifier as the component (C). %, Preferably 0.5 to 20% by weight. At this time, if the amount used exceeds 30% by weight, the hydrophilicity of the entire component (C) becomes high, and as a result, the stability of the finally obtained perfluorocarbon emulsion may be reduced. If the amount is less than 0.1% by weight, the effect of improving the stability by the addition of the component may not be sufficiently obtained.

The aqueous phase component (D) in the present invention is an aqueous solvent constituting the continuous phase of the emulsion, and is not particularly limited as long as it is physiologically acceptable, and is generally used in pharmaceutical applications. Selected from those that are used. Specific examples of such an aqueous phase component include, for example, distilled water for injection, physiological saline, phosphate buffered saline, phosphate buffered saline, lactated Ringer's solution, and the like. Can also be used. Further, the aqueous phase component which is the component (D) of the present invention naturally includes, in addition to the aqueous solvent, an isotonic agent such as glycerol, sucrose, glucose, mannitol and the like, polyethylene glycol, dextran and the like. It is also possible to use stabilizers. In the present invention, the amount of the component (D) used may be adjusted as the balance of the components (A), (B) and (C).

In the perfluorocarbon emulsion of the present invention, an antioxidant such as tocopherol can be used in addition to the above components, as long as the stability of the finally obtained perfluorocarbon emulsion is not hindered. The method for producing the perfluorocarbon emulsion of the present invention can be selected from various methods generally used for producing a pharmaceutical emulsion. That is, the perfluorocarbon emulsion of the present invention is prepared by, for example, adding an emulsifier (C) such as egg yolk phosphatidylcholine to distilled water for injection (aqueous phase component D) isotonicized with glycerol or the like, and dispersing the resulting mixture. ) And the mixture of component (D)
It can be prepared by adding a mixture of the perfluorocarbon compound (A) and the compound (B) of the general formula (1), performing preliminary emulsification, and then further emulsifying using a suitable emulsifier.

The perfluorocarbon emulsion of the present invention can be prepared, for example, by injecting emulsifier (C) consisting of egg yolk phosphatidylcholine and PEGylated phosphatidylethanolamine into distilled water for injection (aqueous phase component D), which has been made isotonic with glycerol or the like. In addition, it is well dispersed and this (C)
To the mixture of the component and the component (D), a mixture of the perfluorocarbon compound (A) and the compound (B) of the general formula (1) is added to carry out preliminary emulsification, and then a suitable emulsifier is further provided. It is prepared by emulsification using Examples of the emulsifier used for preparing the perfluorocarbon emulsion of the present invention include, for example, a rotary homogenizer such as a homomixer, a high-pressure homogenizer such as a Menton-Gaulin type, a microfluidizer, and an ultra-high-pressure emulsifier such as a high-pressure jet emulsifier. Can be

[0027]

EXAMPLES Next, the present invention will be described more specifically with reference to examples, but the present invention is not limited to these examples. Examples 1 to 8 and Comparative Examples 1 to 4 [Preparation of Perfluorocarbon Emulsion] Perfluorocarbon emulsions were prepared according to the compositions shown in Table 1. At this time, for the emulsions of Examples 1 and 6 and Comparative Examples 1 to 3, glycerol was previously dissolved in distilled water for injection (Table 1,
The mixture obtained by adding the emulsifier (C component) to the (D component) is first stirred separately at 5000 rpm using a CLEAR MIX (Model CLM-0.8S, manufactured by Createch Co., Ltd.), and the perfluorocarbon (A component) is separately prepared in advance. , And a mixture of the component (B) or its comparative product (the component B ') was gradually added, followed by stirring at 10,000 rpm for 5 minutes to perform preliminary emulsification. Further, thereafter, using a microfluidizer (Model 110Y, manufactured by Microfluidics), emulsification was performed by passing 10 times at 1.2 × 10 ⁸ Pa while cooling to prepare a perfluorocarbon emulsion. The component (B) is represented by the general formula (1)
In the formula, R ¹ is C ₆ F ₁₃ C ₂ H ₄ −, R ² is C ₁₇ H ₃₃ −, X
Is -OOC-, (perfluorohexyl) octyl-oleate was used. This compound was liquid at 40 ° C.

In Examples 2, 3, 5, 7 and 8,
Is distilled water for injection in which glycerol is dissolved in advance.
(D component) has PEGylated phosphatidylethanolamid
Emulsifier (C component) was added and mixed in warm water.
What is CLEAR MIX (ModelCLM-0.8S,
Using ATEC) while stirring at 5000 rpm.
Separately with perfluorocarbon (component A)
A mixture of the component (B) (see Table 1) is gradually added.
And further stirred at 10,000 rpm for 5 minutes to pre-emulsify
Was done. After that, a microfluidizer (Mo
del 110Y, manufactured by Microfluidics)
1.2 × 10⁸Emulsification by passing 10 times with Pa
Was done. In addition, as the component (B), the above (Perful
(Orohexyl) octyl-oleate, (Perfluo
Lohexyl) octanoic acid and oleyl alcohol
Teryl oleyl- (perfluorohexyl) octa
Noate (R¹: C₆F₁₃C_TwoH_Four-, R^Two: C₁₇H₃₃
-, X: -COO-) and (perfluorohexyl) O
Ether derived from kutanol and oleyl alcohol
(Perfluorohexyl) octyl-oleylue
-Tel (R¹: C₆F₁₃C _TwoH_Four-, R^Two: C₁₇H
₃₃-, X: -O-). These are all 40 ° C
Was liquid.

Further, in Example 4, only the hydrogenated egg yolk lecithin among the components (C) was added to distilled water for injection (component D) in which glycerol was dissolved in advance, and the mixture was sufficiently mixed in warm water. , CLEARMIX (Model CLM-0.8S,
While stirring at 5000 rpm using (Cleatech Co., Ltd.), a mixture of perfluorocarbon (component A) and (perfluorohexyl) octyl-oleate as component (B) was gradually added separately, Further, the mixture was stirred at 10,000 rpm for 5 minutes to perform preliminary emulsification. Separately, PEGylated phosphatidylethanolamine (component c in the table) is added to distilled water for injection (component d in the table) isotonicized with glycerol or the like and dispersed well beforehand. The emulsified emulsion and the dispersion are mixed, and further mixed using a microfluidizer (Model 110Y, manufactured by Microfluidics).
Emulsification was performed by passing 10 times at 1.2 × 10 ⁸ Pa while cooling. In Comparative Example 4, glycerol was previously dissolved in distilled water for injection (D component in Table 1).
The mixture to which the emulsifier (C component) was added was first stirred using a CLEARMIX (ModelCLM-0.8S, manufactured by Createch Co., Ltd.) at 5000 rpm, and the perfluorocarbon (A component) was mixed without mixing the B component. Was gradually added, and the mixture was further stirred at 10,000 rpm for 5 minutes to perform preliminary emulsification. After that, using a microfluidizer (Model 110Y, manufactured by Microfluidics),
Emulsification was performed by passing 10 times at 1.2 × 10 ⁸ Pa while cooling to prepare a perfluorocarbon emulsion.

[0030]

[Table 1]

[0031]

[Table 2]

[Emulsification Stability] With respect to each of the perfluorocarbon emulsions prepared in the above Examples, each emulsion was placed in a glass vial, sealed, and sterilized by heating in an autoclave (121 ° C., 20 minutes). ° C and 2
The emulsion stability was evaluated by measuring the particle size distribution over time while storing at 0 ° C. Measurement of particle size distribution
This was performed by a dynamic light scattering method using NICOMP model370 (Particle sizing systems). The results are shown in Table 2.

[0033]

[Table 3]

As shown in Table 2, it was difficult to maintain the stability of the emulsion prepared using only the perfluorocarbon, the emulsifier and water. ), And a perfluorocarbon emulsion containing a compound represented by the general formula (1) and a phospholipid having a polyethylene glycol chain showed high stability. [Rat administration test] In order to confirm the safety of the perfluorocarbon emulsion of the present invention, the emulsion prepared in the examples was actually administered to rats, and clinical observation was performed. For the test, 8-week-old male Wister rats were used, and under pentobarbital anesthesia, the right femoral artery of the rat was cannulated, and the emulsion prepared in Examples 1 to 4 and 7 from the femoral vein was 30 mL / ml.
kg was injected by syringe pump over 20 minutes. As a result of conducting clinical observations during administration and up to 8 hours after administration and examining the effects of perfluorocarbon emulsion administration, no changes were observed in rats in any of the emulsions, and the safety of the perfluorocarbon emulsion of the present invention was observed. It was confirmed that there was no problem.

[0035]

According to the present invention, in a perfluorocarbon emulsion comprising a perfluorocarbon compound, an emulsifier and an aqueous phase component, a compound having a perfluoroalkyl group and an alkyl group in a molecule represented by the general formula (1) is prepared. By blending in a specific amount, an emulsion having excellent stability can be prepared.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) // B01F 17/14 B01F 17/14 17/42 17/42 B01J 13/00 B01J 13/00 A (72 Inventor Yoshikazu Takeuchi 6-15-7 Takaoka, Okubo-cho, Akashi-shi, Hyogo F term (reference) 4C076 AA17 BB13 DD35F DD63F FF16 4C085 HH01 JJ03 KB39 4C206 AA01 AA02 CA23 DB03 DB06 MA42 MA86 NA14 ZA52 4D077 AA04 DC 4G065 AA01 AB10Y AB11Y AB26Y AB29X BA07 BA15 BB01 CA01 DA02 EA01 EA02

Claims (6)

[Claims] 1. A perfluorocarbon compound (A) 10
~ 80% by weight, medically acceptable emulsifier (C) 0.1
And a perfluorocarbon emulsion comprising the aqueous phase component (D), and the following general formula (1):
With respect to the component (A).
A perfluorocarbon emulsion containing 1 to 20% by weight. R ¹ —X—R ² (1) (wherein, R ¹ represents a perfluoroalkyl group having 6 to 12 carbon atoms; R ² represents an alkyl group having 12 to 22 carbon atoms;
Is Represents Here, R ³ is an alkylene group having 2 to 8 carbon atoms. ) 2. The compound (B) represented by the general formula (1)
2. The perfluorocarbon emulsion according to claim 1, which is liquid at a temperature of 40 ° C. 3. The perfluorocarbon emulsion according to claim 1, wherein the medically acceptable emulsifier (C) contains a phospholipid. 4. A medically acceptable emulsifier (C) comprising a phospholipid and a nonionic surfactant in a ratio of 10:90 to 100:
The perfluorocarbon emulsion according to claim 3, which is a mixture containing 0 at a rate. 5. The perfluorocarbon emulsion according to claim 3, wherein the phospholipid constituting the medically acceptable emulsifier (C) contains a phospholipid having a polyethylene glycol chain. 6. The perfluorocarbon emulsion according to claim 5, wherein the polyethylene glycol chain of the phospholipid has a molecular weight of 400 to 20,000.