JP5113328B2 - Emulsion, method for producing target substance particles using the same, and pharmaceutical product - Google Patents

Description

  The present invention relates to an emulsion containing a target substance, a method for producing target substance particles using the emulsion, and a pharmaceutical product.

  In various scenes such as industry and medicine, a composition in which a hardly soluble substance is dispersed in a continuous phase may be used. For example, a substance that is difficult to dissolve in water may be made into fine particles and dispersed in water. As a specific example, this is the case when a poorly water-soluble drug, that is, a drug that is difficult to dissolve in water is used for medical purposes.

  In particular, in the field of pharmaceutical preparations, as described above, when a poorly water-soluble drug is administered to the human body, the drug is often dispersed in water and administered. Since poorly water-soluble drugs are difficult to be absorbed into the circulatory system after administration, it takes a long time for the medicinal effects to start, or they are excreted outside the body before being absorbed into the circulatory system, and sufficient medicinal effects can be obtained. There is no fear. Therefore, in recent years, in the field of pharmaceutical preparations, in the research on practical application of poorly water-soluble drugs, methods for making fine particles of drugs are widely studied as methods for drug delivery into the body. It is considered that by making the drug fine particles, the dispersion stability of the drug in water is improved, absorption into the body is further promoted, and drug efficacy can be enhanced.

  Various methods for making such a slightly water-soluble drug into fine particles have been studied. For example, a method of pulverizing a large solid of a poorly water-soluble drug by a mechanical method using a surface modifier such as a surfactant, a method of spraying a poorly water-soluble drug dissolved in an organic solvent with a spray, a water-soluble organic A method of precipitating a poorly water-soluble drug into a poor solvent by dissolving the poorly water-soluble drug in a solvent and developing it in water, and dissolving the poorly water-soluble drug in a water-insoluble organic solvent to form an emulsion with a surfactant or the like Then, the method (patent documents 1-8) etc. which remove a water-insoluble organic solvent are mentioned.

  On the other hand, phase separation between water-soluble organic solvent and water that are compatible with each other is caused by adding an electrolyte to water, and research has been continued from an academic viewpoint (Non-patent Document 1).

US Pat. No. 5,145,684 Japanese Patent Laid-Open No. 63-232840 JP-A-57-27128 JP-A-63-122620 Japanese Patent No. 3244502 JP-A-1-156912 JP-T 61-63613 Japanese National Publication No. 4-46115 J. et al. Phys. Chem. B, 105, 10101-10110 (2001).

  By the way, in each industrial field, when a hardly soluble substance in a continuous phase is miniaturized and dispersed in water, further performance improvement is required depending on its use, and a new technology that satisfies the improvement request is desired. It had been. For example, taking the case of the above-mentioned poorly water-soluble drug as an example, the conventional methods include points that require a large amount of energy for miniaturization and that the particle size of the miniaturized drug is still large.

  Therefore, for example, in the medical field, there has been a demand for a method for obtaining a poorly water-soluble drug that has been sufficiently miniaturized at low cost. In particular, when a drug is micronized by a submerged drying method using a water-insoluble organic solvent, the target product does not necessarily have sufficient solubility in the water-insoluble organic solvent, leaving a problem in productivity. There was a need to solve it.

Furthermore, with the recent advancement of medicines, pharmaceutical molecules have been complicated in structure and high molecular weight. As a result, they have poor water-soluble and oil-soluble properties, that is, only soluble in limited solvents. There is something that does not appear, and the development of a miniaturization method that can cope with these is also desired.
In addition, when miniaturization is performed by the above-described submerged drying method, a halogen-based organic solvent such as chloroform or dichloromethane may be used as an applicable water-insoluble organic solvent. However, in that case, a halogen-based organic solvent may remain, which is not preferable.

  The present invention was devised in view of the above-described problems, and includes a novel water-soluble organic solvent containing water and a water-soluble organic solvent, which is capable of miniaturizing and dispersing a hardly soluble target substance. It is an object to provide a novel emulsion, a method for producing particles of the target substance using the emulsion, and a pharmaceutical product.

As a result of intensive studies to solve the above problems, the present inventors have found that a mixture of a predetermined water-soluble organic solvent, a predetermined target substance, and water is in a water-soluble organic solvent concentrated phase and a water-rich phase. The knowledge that it isolate | separated was acquired. Then, by adding a surfactant to this mixture, it was found that an emulsion using a water-soluble organic solvent containing a micronized target substance could be prepared, and the present invention was completed.
Thus, for example, by dissolving an agent having a conventional poorly water-soluble and hardly oil-soluble property in a water-soluble organic solvent, and preparing an emulsion using this solution and a poorly soluble continuous phase in which the agent cannot be dissolved. Even in the hardly soluble continuous phase, the drug can be made fine in a mixed state (that is, a dispersed state or a dissolved state) and dispersed in the continuous phase.

That is, the gist of the present invention, a water-soluble organic solvents having 5% by weight or more solubility in water at normal temperature and pressure, and water, and the poorly water-soluble drugs which can be incorporated into the water-soluble organic solvent medium, the interface containing an active agent, to form an emulsion droplets containing the flame-soluble drugs Do Ri from a water-soluble organic solvent rich phase is dispersed in a continuous phase consisting of water rich phase from the emulsion, the The present invention resides in a method for producing poorly water-soluble drug particles, comprising a water-soluble organic solvent or a removing step of removing the water-soluble organic solvent and the water (claim 1).

At this time, it is preferable that 0.1% by weight or more of the electrolyte is dissolved in the water.
Further, it is preferable that the average particle size of the droplets is 10μm or less (claim 3).

Also, the concentration of the slightly water-soluble drug in the above water-soluble organic solvent medium is preferably at least 0.005 mg / mL (claim 4).
The water-soluble organic solvent preferably has a solubility of 20% by weight or more with respect to water (claim 5).
Moreover, it is preferable that this water-soluble organic solvent is a thing freely mixed with water (Claim 6).
Further, the solubility of the poorly water-soluble drug in water is preferably 10 g / liter or less (Claim 7).
In the removing step, it is preferable to remove the water-soluble organic solvent and the water from the emulsion.
Furthermore, in the removing step, it is preferable to remove the water-soluble organic solvent and the water by lyophilization (claim 9).

In addition , it is preferable to wash the poorly water-soluble drug particles after the removing step (claim 10 ).

Another subject matter of the present invention lies in a pharmaceutical comprising the poorly water-soluble drug particles formed by the above-mentioned method for producing poorly water-soluble drug particles (claim 11 ).

According to the emulsion of the present invention, in a new and unprecedented manner, a target substance that contains water and a water-soluble organic solvent and is sparingly soluble in the water or water-soluble organic solvent can be micronized and dispersed. New emulsions can be provided. Moreover, according to the emulsion of this invention, a microemulsion (thermodynamically stable emulsion) can be formed spontaneously.
Moreover, according to the method for producing target substance particles of the present invention, target substance particles having a small particle size can be easily produced.
Furthermore, according to the pharmaceutical product of the present invention, the pharmaceutical product can be easily administered to a treatment target appropriately.

  Hereinafter, the present invention will be described with reference to examples and the like. However, the present invention is not limited to the following examples and the like, and can be implemented with arbitrary modifications without departing from the gist of the present invention. .

[I. Emulsion]
[I-1. Overview]
The emulsion of the present invention is miscible with a water-soluble organic solvent having a solubility of 5% by weight or more with respect to water at normal temperature and pressure (that is, 25 ° C., 1013 hPa), water, and the water-soluble organic solvent or water. Contains a target substance and a surfactant. Then, as schematically shown in FIG. 1, droplets 1 composed of a water-soluble organic solvent rich phase or a water-rich phase are dispersed in a continuous phase 2. At this time, when the droplet 1 is a water-soluble organic solvent rich phase, the continuous phase 2 is formed by a water-rich phase, and when the droplet 1 is a water-rich phase, the continuous phase 2 is a water-soluble organic solvent rich phase. Formed by the phases. The droplet 1 is dispersed in the continuous phase 2 while being phase-separated from the continuous phase 2. The surfactant 3 stabilizes the droplet 1.

  That is, the emulsion of the present invention consists of a state in which a water-soluble organic solvent and water are separated into two liquid phases. At this time, each phase includes a phase in which the water-soluble organic solvent is concentrated (phase 1; hereinafter referred to as “water-soluble organic solvent concentrated phase”) and a phase in which the water-soluble organic solvent is diluted (phase 2; hereinafter referred to as appropriate). It is divided into “water-rich phase”. Here, the water-soluble organic solvent concentrated phase means a phase having a higher content of the water-soluble organic solvent than the water-rich phase, and the water-rich phase is water compared to the water-soluble organic solvent concentrated phase. It means a phase having a high content (that is, a low content of water-soluble organic solvent).

  Therefore, the water-soluble organic solvent concentrated phase is the ratio of the water-soluble organic solvent contained (composition; usually, “(weight of water-soluble organic solvent in phase) / {(weight of water in phase) + (phase As long as the water-soluble organic solvent weight}}) is larger than the water-rich phase, a phase containing no water may be used. On the other hand, the water-rich phase may be a phase containing no water-soluble organic solvent as long as the ratio of the water-soluble organic solvent contained is smaller than that of the water-rich phase. Further, as will be described later, the ratio of the water-soluble organic solvent does not necessarily have to be higher than that of water in the water-soluble organic solvent concentrated phase. Similarly, the ratio of water does not need to be higher than that of the water-soluble organic solvent even in the water-rich phase.

  Then, one of the water-soluble organic solvent concentrated phase and the water-rich phase forms a droplet 1, and the other of the water-soluble organic solvent concentrated phase and the water-rich phase forms a continuous phase 2. An emulsion in which the droplets 1 are dispersed is formed. Furthermore, the target substance is mixed in one of the water-soluble organic solvent concentrated phase and the water-rich phase that have undergone phase separation.

[I-2. Water-soluble organic solvent]
The water-soluble organic solvent used in the present invention is an organic solvent that is easily dissolved in water. Specifically, it refers to an organic solvent having a solubility of usually 5% by weight or more, preferably 10% by weight or more, more preferably 20% by weight or more in water at normal temperature and pressure. Particularly preferred is an organic solvent freely mixed with water. Here, free mixing means that it can be mixed with water at an arbitrary ratio.

In addition, as the water-soluble organic solvent, those satisfying the following condition (S1) or condition (S2) under the condition of use (usually normal temperature and normal pressure) are used.
Condition (S1): The target substance can be mixed, and when the target substance is mixed, the phase can be separated from the water-rich phase. In the water-rich phase, an electrolyte may be appropriately dissolved.
Condition (S2): When the target substance is mixed with water, the phase can be separated from the water-rich phase. In the water-rich phase, an electrolyte may be appropriately dissolved.

In order to satisfy the above condition (S1), for example, the following conditions (i) and (ii) are required for the water-soluble organic solvent. However, even if the following conditions (i) and (ii) are not satisfied, the above condition may be satisfied.
(I) The water-soluble organic solvent is usually 0.1% by weight or more, preferably 1% by weight or more, more preferably 3% by weight or more, particularly preferably 5% by weight or more as the saturation miscibility (saturation solubility) of the target substance. It is preferable that This is because the target substance interacts with the water-soluble organic solvent at the molecular level, affects the hydrogen bonding of the water-soluble organic solvent with water, and facilitates phase separation. That is, the target substance works to lower the solubility of water in the water-soluble organic solvent. The upper limit is not particularly limited, but is usually 90% by weight or less.

  In order to examine the saturation miscibility (saturated solubility), it can be determined that no precipitate is present when a predetermined amount of the target substance is mixed (dispersed or dissolved) in a water-soluble organic solvent. However, here, it is only necessary to show that the target substance and the water-soluble organic solvent interact at the molecular level. When the emulsion of the present invention is prepared, the above-mentioned saturation miscibility (saturation solubility) is not necessarily increased. It is not necessary for the organic solvent to be retained.

  (Ii) The water-soluble organic solvent has a relative dielectric constant of usually 1.8 or more, preferably 1.9 or more, more preferably 2.0 or more, and usually 40 or less, preferably 30 or less, more preferably 25. The following range is desirable. If the relative permittivity of the water-soluble organic solvent is larger than 40, the hydrogen bond between the water-soluble organic solvent and water is too strong, and the water-soluble organic solvent and water may not be easily phase separated. On the other hand, if the relative dielectric constant is less than 1.8, the target substance (poor oil-soluble) may be difficult to mix with the water-soluble organic solvent. Therefore, it effectively prevents hydrogen bonding between the water-soluble organic solvent and water. In addition to being unable to affect the water-soluble organic solvent and water, it is difficult for the water-soluble organic solvent and water to phase separate, and the emulsion of the present invention may not retain the target substance and may precipitate.

On the other hand, in order to satisfy the above condition (S2), for example, the following conditions (iii) and (iv) are required for the water-soluble organic solvent. However, even if the following conditions (iii) and (iv) are not satisfied, the above condition may be satisfied.
(Iii) The water-soluble organic solvent is usually 5% by weight or less, preferably 3% by weight or less, and more preferably 1% by weight or less as the saturation miscibility (saturated solubility) of the target substance. At this time, the target substance usually exists on the water-rich phase side. However, if the compound has a miscibility (saturation solubility) higher than this, the target substance elutes on the water-soluble organic solvent side, effectively. The solubility of water in a water-soluble organic solvent cannot be reduced, and phase separation between water and the water-soluble organic solvent may not be caused.

  (Iv) The water-soluble organic solvent preferably has a relative dielectric constant of usually 40 or less, preferably 30 or less, more preferably 25 or less. If the relative dielectric constant is greater than 40, the hydrogen bond between the water-soluble organic solvent and water is too strong, and the water-soluble organic solvent and water are difficult to phase separate. Similarly, the target substance that is miscible with water begins to mix with the concentrated phase of the water-soluble organic solvent, and the solubility of water in the water-soluble organic solvent cannot be sufficiently reduced. Phase separation is difficult to occur. The lower limit is not particularly limited, but is usually 1.8 or more.

  Furthermore, preferable examples of the water-soluble organic solvent include alcohols, ethers, ketones and the like. Among these, cyclic ethers are particularly preferable. Since such a solvent dissolves in water by hydrogen bonding with water, it is easy to affect the hydrogen bonding by mixing and dissolving the target substance and / or dissolving the electrolyte in water, and further phase separation. It is because it is easy to cause. Therefore, in any of the above conditions (S1) and (S2), it is preferable to use the water-soluble organic solvent as described above as the water-soluble organic solvent.

  The boiling point of the water-soluble organic solvent is arbitrary as long as the effects of the present invention are not significantly impaired, but is usually 200 ° C. or lower, preferably 190 ° C. or lower, more preferably 180 ° C. or lower. Those having a boiling point higher than this have the disadvantage that complicated operations are required to remove the solvent when the emulsion is dried to produce powder particles (target substance particles, which will be described later). In addition, although there is no restriction | limiting in the minimum of a boiling point, it is 25 degreeC or more normally.

  Further, the freezing point of the water-soluble organic solvent is arbitrary as long as the effect of the present invention is not significantly impaired, but is usually −180 ° C. or higher, preferably −150 ° C. or higher, more preferably −120 ° C. or higher. Below these, there is an inconvenience that a complicated operation is required for removing the solvent when the target substance particles are produced by freeze-drying the emulsion. In addition, although there is no restriction | limiting in the upper limit of a freezing point, it is 100 degrees C or less normally.

  Usually, the water-soluble organic solvent is contained in both the droplets and the continuous phase. As described above, the liquid droplet and the continuous phase containing a larger amount of the water-soluble organic solvent are referred to as a water-soluble organic solvent concentrated phase, and the smaller one is referred to as a water-rich phase. Here, when the content of the water-soluble organic solvent in the droplet is larger than that in the continuous phase, the state of the emulsion is appropriately referred to as “Solvent in Water”. The situation in the opposite case is referred to as “Water in Solvent” as appropriate.

In order to maintain the strength of the droplet interface, it is desirable that the liquid composition inside the droplet and the liquid composition of the continuous phase differ greatly. The difference in composition in that case can be represented by, for example, the difference between the composition of the water-soluble organic solvent in the droplet and the composition of the water-soluble organic solvent in the continuous phase. A specific example is that the value C ^* of the absolute value obtained by subtracting the composition (content ratio) Cb of the water-soluble organic solvent in the continuous phase from the composition (content ratio) Ca of the water-soluble organic solvent inside the droplet is: Usually, it is 0.001 or more, preferably 0.01 or more, more preferably 0.03 or more.

Here, the composition Ca, the composition Cb, and the absolute value C ^* of the difference are as follows.
[Definition of Ca]
Ca = (weight of water-soluble organic solvent inside droplet) / {(weight of water-soluble organic solvent inside droplet) + (weight of water inside droplet)}
[Definition of Cb]
Cb = (weight of water-soluble organic solvent in continuous phase) / {(weight of water-soluble organic solvent in continuous phase) + (weight of water in continuous phase)}
[Definition of C ^* ]
C ^* = | Ca-Cb |

  The water-soluble organic solvent and water content in each of the water-soluble organic solvent concentrated phase and the water-rich phase are separated into an upper phase and a lower phase in a composition not containing a surfactant, and are contained in each phase. The amount of the water-soluble organic solvent can be measured by chromatography.

  More preferably, in addition to the above requirements, in the water-soluble organic solvent concentrated phase, the ratio of the water-soluble organic solvent to the total weight of the water-soluble organic solvent and water is usually 30% by weight or more, preferably 40% by weight. More preferably, it is 50% by weight or more. In the water-rich phase, the ratio of the water-soluble organic solvent to the total weight of the water-soluble organic solvent and water is usually 50% by weight or less, preferably 40% by weight or less, more preferably 30% by weight or less. preferable. Thereby, many target substances can be hold | maintained inside a droplet, and the advantage that the elution to the continuous phase side can be prevented can be acquired.

  Specific examples of the water-soluble organic solvent include carbon such as methyl alcohol, ethyl alcohol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, sec-butyl alcohol, tert-butyl alcohol, isobutyl alcohol, and n-amyl alcohol. Alkyl alcohols of 1 to 5; Amides of dimethylformamide and dimethylacetamide; Ketones or ketoalcohols such as acetone and diacetone alcohol; Ethers such as tetrahydrofuran and dioxane; Polyalkylene glycols such as polyethylene glycol and polypropylene glycol Class: ethylene glycol, diethylene glycol, propylene glycol, butylene glycol, triethylene glycol, 1,2,6-hexanetriol, thio Alkylene glycols having 2 to 6 carbon atoms, such as glycol and hexylene glycol; ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, triethylene glycol monomethyl ether, triethylene glycol Lower alkyl ethers of polyhydric alcohols such as ethylene glycol monoethyl ether; lower dialkyl ethers of polyhydric alcohols such as triethylene glycol dimethyl ether and triethylene glycol diethyl ether; glycerin, sulfolane, N-methyl-2-pyrrolidone, 1,3-dimethyl-2-imidazolidinone and the like can be mentioned.

Of these, alcohols, ethers and ketones are preferable, and cyclic ethers are more preferable. Specific examples thereof include tetrahydrofuran and 1,4 dioxane.
Moreover, these water-soluble organic solvents may be used individually by 1 type, and 2 or more types of water-soluble organic solvents can also be mixed and used for them.

  Further, in the emulsion of the present invention, the presence state of the water-soluble organic solvent is arbitrary as long as it is not significantly contrary to the gist of the present invention. Therefore, the water-soluble organic solvent may be in a liquid state or a solid state. As a specific example, even if the water-soluble organic solvent is in a liquid state at the time of use but is in a solid state at the time of storage (for example, water freezes into ice), the emulsion of the present invention is a water-soluble organic solvent. The right range is not affected by the state of the solvent, and the composition of any state is the emulsion of the present invention.

[I-3. water]
Water is contained in at least the other of the droplets and the continuous phase in the emulsion of the present invention. In this case, as described above, one of the droplet and the continuous phase becomes a water-soluble organic solvent concentrated phase, and the other of the droplet and the continuous phase becomes a water-rich phase.

  Furthermore, in the emulsion of the present invention, the presence state of water is arbitrary as long as it is not significantly contrary to the spirit of the present invention. Accordingly, the water may be in a liquid state or a solid state. To give a specific example, even if water is in a liquid state at the time of use but freezes to ice during storage, the emulsion of the present invention does not depend on the scope of rights depending on the state of water. Even the composition in the state is the emulsion of the present invention.

[I-4. Target substance]
The target substance is a substance that is finely dispersed in the emulsion of the present invention. Moreover, as a target substance, by mixing with a water-soluble organic solvent or water, the water-soluble organic solvent rich phase and the water-rich phase are phase-separated under the conditions of use (usually normal temperature and normal pressure), It is desirable to use a substance capable of phase-separating the droplet and the continuous phase. For this purpose, the target substance is required to have the following properties, for example.

  (A) When the target substance is miscible with a water-soluble organic solvent, in order to phase-separate a water-soluble organic solvent concentrated phase and a water-rich phase to separate a droplet from a continuous phase, [ I-2. It is preferable to satisfy the same condition as the condition (i) described in [Water-soluble organic solvent]. That is, the saturation miscibility (saturated solubility) of the target substance with respect to the water-soluble organic solvent is usually 0.1% by weight or more, preferably 1% by weight or more, more preferably 3% by weight or more, and particularly preferably 5% by weight or more. It is desirable to be. This is because the target substance interacts with the water-soluble organic solvent at the molecular level, affects the hydrogen bonding of the water-soluble organic solvent with water, and facilitates phase separation. That is, the target substance works to lower the solubility of water in the water-soluble organic solvent. The upper limit is not particularly limited, but is usually 90% by weight or less.

  In order to examine the saturation miscibility (saturated solubility), it can be determined that no precipitate is present when a predetermined amount is mixed (dispersed or dissolved). However, here, it is only necessary to show that the target substance and the water-soluble organic solvent interact at the molecular level. When the emulsion of the present invention is prepared, the above-mentioned saturation miscibility (saturation solubility) is not necessarily increased. It is not necessary for the organic solvent to be retained.

(B) When the target substance is miscible with the water-soluble organic solvent, in order to phase-separate the water-soluble organic solvent rich phase and the water-rich phase to separate the droplet and the continuous phase, It is preferable that the substance has at least one polar group in its molecule. This is because the effect of hydrogen bonding between the water-soluble organic solvent and water is weakened by mixing (dispersing or dissolving) the target substance in the water-soluble organic solvent, and phase separation is facilitated.
Here, the polar group may be any functional group that weakens the hydrogen bond between the water-soluble organic solvent and water, and is not particularly limited. For example, a carboxyl group, a sulfo group, a hydroxyl group, an amino group, An ethylene oxide group etc. are mentioned.

  In this case, the target substance is usually present in the water-soluble organic solvent concentrated phase. Therefore, in order to prevent the target substance from moving to the water-rich phase side, the target substance preferably has at least one nonpolar group in the molecule. Here, examples of the nonpolar group include an alkyl group, a phenyl group, and a naphthyl group, but are not limited thereto.

  (C) When the target substance is miscible with water, in order to phase-separate the water-soluble organic solvent concentrated phase and the water-rich phase to separate the droplet from the continuous phase, [I-2 . It is preferable to satisfy the same condition as the condition (iii) described in [Water-soluble organic solvent]. That is, the target substance preferably has the property that the saturation miscibility (saturated solubility) of the target substance with respect to the water-soluble organic solvent is usually 5% by weight or less, preferably 3% by weight or less, more preferably 1% by weight or less. At this time, the target substance usually exists on the water-rich phase side. However, if the compound has a higher saturation (saturation solubility) than this, the target substance will elute on the water-soluble organic solvent-rich phase side. In particular, the solubility of water in a water-soluble organic solvent cannot be reduced, and phase separation between water and the water-soluble organic solvent may not be caused.

  However, even when the target substance does not have the above properties, the water-soluble organic solvent concentrated phase and the water-rich phase may be phase-separated in the emulsion of the present invention. For example, this applies to the case where an electrolyte described later is used. Therefore, when the electrolyte is used, the target substance does not necessarily satisfy the above condition.

  In addition, the target substance may be present in either the droplet or the continuous phase in the emulsion. However, in order to effectively utilize one of the advantages of the present invention of miniaturizing and dispersing a material that has been difficult to disperse in the past, the target material should be dispersed in the droplet. It is desirable. That is, it is desirable that the droplet contains the target substance.

Furthermore, the target substance may be used alone or in combination of two or more in any combination and ratio.
In addition, in order to obtain the emulsion of the present invention in which the target substance is present in the droplet, an appropriate target substance is selected depending on whether the state of the emulsion is Solvent in Water or Water in Solvent. Should. Hereinafter, each case will be described.

[I-4-1. For Solvent in Water]
When the emulsion of the present invention is Solvent in Water, in order for the target substance to be present in the droplets, a target substance that is miscible with a water-soluble organic solvent is used. The mixing state may be dissolution or dispersion, but it is usually preferable to dissolve. Here, that the target substance is soluble (soluble) in the water-soluble organic solvent means that the target substance can be dissolved in the water-soluble organic solvent to such an extent that the emulsion of the present invention can be produced. Specifically, the target substance is usually 0.01% by weight or more, preferably 0.05% by weight or more, more preferably 0.1% by weight or more in a water-soluble organic solvent under normal temperature and pressure conditions. Represents a thing.

  When the emulsion of the present invention is Solvent in Water, a water-insoluble one is used as the target substance. Here, that the target substance is sparingly water-soluble means that the target substance is not soluble in water to the extent that the emulsion of the present invention can be formed. Specifically, it represents that the target substance has a solubility in water of usually 100 g / liter or less, preferably 50 g / liter or less, more preferably 10 g / liter or less under conditions of normal temperature and pressure.

  Furthermore, when the emulsion of the present invention is Solvent in Water, it is preferable to use a hardly oil-soluble target substance. Specifically, the target substance is hardly oil-soluble. Specifically, the solubility in soybean oil is usually 100 g / liter or less, preferably 50 g / liter or less, more preferably 10 g / liter under normal temperature and normal pressure conditions. Indicates that: In conventional oil-in-water type emulsions (that is, emulsions in which droplets made of an oil phase are dispersed in a continuous phase made of an aqueous phase), when the target substance is encapsulated in the droplets (oil phase), the lipophilic or oily If it was not a soluble target substance, a desired emulsion could not be formed. However, with the emulsion of the present invention, a Solvent in Water type emulsion containing a water-soluble organic solvent in droplets can be prepared. Therefore, any emulsion that is miscible with a water-soluble organic solvent can be used regardless of its solubility in oil. The target substance can be contained in the droplet. Therefore, the use of a poorly oil-soluble target substance as a target substance more effectively exhibits the advantage of the present invention that a target substance that cannot be solubilized or dispersed by conventional methods can be miniaturized and dispersed in a new manner. Can be preferred.

  In addition, it is more preferable to use a water-insoluble and oil-insoluble material as the target substance. Even a poorly water-soluble and poorly oil-soluble substance that has been difficult to disperse in the past can be used as a target substance in the emulsion of the present invention. That is, even a target substance that is hardly water-soluble and hardly oil-soluble can be included in a droplet (Solvent phase). Therefore, the advantage of the present invention that a target substance that cannot be solubilized or dispersed by conventional methods can be miniaturized and dispersed in a new manner can be more effectively exhibited.

  Furthermore, a crystalline compound or a compound that becomes solid at room temperature is suitable as a target substance. This is because the advantage of the present invention that a target substance that is difficult to solubilize or disperse by conventional methods can be miniaturized and dispersed in a new manner can be effectively exhibited.

  Examples of the target substance when the emulsion of the present invention is Solvent in Water include drugs such as poorly water-soluble drugs, poorly water-soluble dyes, pigments, inorganic substances (including metal colloids) and the like.

  Examples of the drug that can be used as the target substance include compounds having physiological activity. For example, analgesics, anti-inflammatory drugs, anthelmintic drugs, antiarrhythmic drugs, antibiotics (including penicillins), anticoagulants, antihypertensive drugs, antidiabetic drugs, antiepileptic drugs, antihistamines, antihypertensive drugs, antimuscarinic Drugs, antimycobacterial drugs, antineoplastic drugs, immunosuppressive drugs, antithyroid drugs, antiviral drugs, anxiolytic drugs (hypnotics and neuroleptic drugs), astringents, adrenergic beta-receptor blockers, blood products and substitutes Plasma, myocardial degenerative medicine, contrast medium, corticosteroid, cough suppressant (an expectorant and mucus destroyer), diagnostic agent, diagnostic imaging agent, diuretic, dopaminergic agent (anti-Parkinso's disease agent), hemostatic agent , Immune drugs, lipid modulators, muscle relaxants, parasympathomimetics, parathyroid calcitonin and biphosphonates, prostaglandins, radiopharmaceuticals, sex hormones (steroids Including), anti-allergic agents, stimulants and anorexigenic agents, sympathomimetics, thyroid agents, such as various known drugs such containing vasodilator and xanthines can be mentioned.

  Specific examples of particularly preferred drugs are 17-α-pregno-2,4-diene-20-ino- [2,3-d] -isoxazol-17-ol (danazol), 5α, 17α. , -1 '-(methylsulfonyl) -1'Hpregno-20-ino- [3,2-c] -pyrazol-17-ol (steroid A), [6-methoxy-4- (1-methylethyl) -3-oxo-1,2-benzisothiazol-2 (3H) -yl] methyl 2,6-dichlorobenzoate-1,1-dioxide, 3-amino-1,2,4-benzotriazine-1,4 -Dioxide, piposulfame, piposulfan, captothecin, acetominophen, acetylacetylicylic acid, amiodarone, colestifmine, colestipol, chromoline sodium, albutero , Sucralfate, sulfasalazine, minoxidil, tempazepam, albrazolam, propoxyphene, auranofin, erythromycin, cyclosporine, acyclovir, ganciclovir, etoposide, mephalan, methotrexate, minoxantrone, daunorubicin, megasterol, tamoxifen, medroxyprogesterone Nystatin, terbutaline, amphotericin B, aspirin, ibuprofen, naproxen, indomethacin, diclofenac, ketoprofen, flupiprofen, diflumisal, ethyl-3,5-diacetamide-2,4,6-triiodobenzoate, ethyl (3,5-bis (Acetylamino) -2,4,6-triiodobenzoyloxy) acetate and ethyl- - (3,5-bis (acetylamino) -2,4,6-triiodo-benzoyloxy acetate). Among these, naproxen, indomethacin and the like are particularly preferable. Thereby, a chemical | medical agent can be contained and used for the droplet of the emulsion of this invention.

  Examples of dyes that can be used as target substances include dyes commonly used in writing recording liquids, such as coumarin, perylene, dicyanopinyl, azo (for example, pyridoneazo, disazo, trisazo, benzeneazo And quinophthalone series, aminopyrazole series, methine series, dicyanoimidazole series, indoaniline series, and phthalocyanine series. Among these, azo, phthalocyanine, anthraquinone, and the like are preferable. Accordingly, the dye can be used by being contained in the droplets of the emulsion of the present invention.

  Furthermore, examples of pigments that can be used as target substances include quinacridone pigments, quinacridone quinone pigments, dioxazine pigments, phthalocyanine pigments, anthrapyrimidine pigments, ansanthrone pigments, indanthrone pigments, and flavanthrone pigments. Perylene pigments, diketopyrrolopyrrole pigments, perinone pigments, quinophthalone pigments, anthraquinone pigments, thioindigo pigments, metal complex pigments, azomethine pigments and azo pigments. Of these, phthalocyanine-based or diketopyrrolopyrrole-based pigments are preferable. Thereby, a pigment can be used by making it contain in the droplet of the emulsion of this invention.

  Examples of inorganic substances that are examples of target substances include metals such as gold, silica, titanium oxide, clay, and talc. Thereby, metal particles such as gold colloid and inorganic fine particles can be used by being included in the droplets of the emulsion of the present invention.

[I-4-2. For Water in Solvent]
When the emulsion of the present invention is Water in Solvent, in order for the target substance to be present in the droplets, a substance that is miscible with water is used as the target substance. The mixing state may be dissolution or dispersion, but it is usually preferable to dissolve. Here, that the target substance is soluble (soluble) in water means that the target substance can be dissolved in water to the extent that the emulsion of the present invention can be produced. Specifically, the target substance is usually 0.01% by weight or more, preferably 0.05% by weight or more, more preferably 0.1% by weight or more in water under normal temperature and normal pressure conditions. Represent.

  In addition, when the emulsion of the present invention is Water in Solvent, a target substance that is hardly soluble in a water-soluble organic solvent is used. Here, that the target substance is hardly soluble in the water-soluble organic solvent means that the target substance is not soluble in the water-soluble organic solvent to such an extent that the emulsion of the present invention can be formed. Specifically, it represents that the target substance has a solubility in a water-soluble organic solvent of usually 100 g / liter or less, preferably 50 g / liter or less, more preferably 10 g / liter or less under normal temperature and normal pressure conditions.

Furthermore, when the emulsion of the present invention is Water in Solvent, it is preferable to use a hardly oil-soluble target substance as the target substance, as in the case of Solvent in Water. Furthermore, the use of a target substance that is sparingly soluble in both a water-soluble organic solvent and oil is the same as the use of a sparingly water-soluble and sparingly oil-soluble target substance in the case of Solvent in Water. It is more preferable.
A crystalline compound or a compound that becomes solid at room temperature is also suitable when the emulsion of the present invention is Water in Solvent, as in the case of the emulsion of the present invention being Solvent in Water.

Examples of target substances when the emulsion of the present invention is Water in Solvent include drugs such as water-soluble drugs, water-soluble dyes, pigments, inorganic substances, and the like.
Examples of water-soluble drugs that can be used as the target substance include compounds having physiological activity. Specific examples include antibiotics, antiviral agents, antitumor agents, steroids, immunosuppressants, whitening agents, anti-inflammatory agents, antibacterial agents, hormones, vitamins, enzymes, antioxidants, blood circulation promoters, amino acids And hair growth medicines. Thereby, a water-soluble chemical | medical agent can be contained and used for the droplet of the emulsion of this invention.

  Examples of water-soluble dyes that can be used as the target substance include direct dyes, acid dyes, food dyes, basic dyes, and reactive dyes. Specifically, examples include azo dyes, methine dyes, azomethine dyes, xanthene dyes, quinone dyes, phthalocyanine dyes, triphenylmethane dyes, diphenylmethane dyes, and the like. Accordingly, the water-soluble dye can be used by being contained in the droplets of the emulsion of the present invention.

  Furthermore, examples of the pigment and the inorganic substance that can be used as the target substance include the same pigments and inorganic substances described as examples when the emulsion of the present invention is Solvent in Water. Thereby, a pigment and an inorganic substance can be contained in the droplets of the emulsion of the present invention and used.

[I-5. Electrolytes]
The emulsion of the present invention may optionally contain an electrolyte. Here, the electrolyte refers to a substance that dissociates into ions in a solution. This electrolyte is usually present dissolved in a water-rich phase. At this time, the solubility of the electrolyte in water is usually 0.1% by weight or more, preferably 1% by weight or more, and more preferably 3% by weight or more.

In addition, by dissolving the electrolyte in the water-rich phase, the solubility of the water-soluble organic solvent in water can be reduced, and phase separation (salting out) between the water-rich phase and the water-soluble organic solvent rich phase is promoted. To do.
Also, some electrolytes have the action of blocking or hydrating the water-soluble organic solvent and water, and causing or promoting the phase separation between the water-soluble organic solvent concentrated phase and the water concentrated phase. There is also. Therefore, if such an electrolyte is used, phase separation between the water-soluble organic solvent rich phase and the water-rich phase can be promoted, and an emulsion can be easily formed.
Any electrolyte may be used as long as the emulsion of the present invention can be formed, but an inorganic salt is preferably used.

Examples of electrolytes include alkali metal hydroxides [sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.], alkali metal carbonates [sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, lithium carbonate, etc.] , Alkali metal sulfates [sodium sulfate, potassium sulfate, etc.], alkali metal nitrates [sodium nitrate, potassium nitrate, etc.], alkali metal phosphates [sodium phosphate, sodium hydrogen phosphate, potassium phosphate, etc.], alkali metal sulfites Alkali metals such as [sodium sulfite, sodium hydrogen sulfite, potassium sulfite, etc.], alkali metal halides (chlorine, bromine, iodine or fluorine) [sodium chloride, potassium chloride, sodium bromide, potassium iodide, potassium fluoride, etc.] Salt; alkaline earth metal (calcium , Magnesium, barium, strontium, etc.) hydroxides [calcium hydroxide, magnesium hydroxide, strontium hydroxide, etc.], alkaline earth metal carbonates [calcium carbonate, magnesium carbonate, etc.], alkaline earth metal sulfates [calcium sulfate] , Magnesium sulfate, etc.], alkaline earth metal nitrates [calcium nitrate, magnesium nitrate, etc.], alkaline earth metal phosphates [calcium hydrogen phosphate, magnesium hydrogen phosphate, etc.], alkaline earth metal sulfites [calcium sulfite, Magnesium sulfite, etc.] Alkaline earth metal salts such as alkaline earth metal halides (chlorine, bromine, iodine or fluorine) [calcium chloride, magnesium chloride, calcium bromide, calcium iodide, magnesium fluoride, etc.]; halides [Ammonium chloride , And ammonium salts such as ammonium bromide, etc.] and the like. Examples of the polymer electrolyte include polyacrylic acid, sodium polyacrylate, polysulfonic acid, and sodium polysulfonate.
In addition, these electrolytes may be used individually by 1 type, and may use 2 or more types together by arbitrary combinations and a ratio.

[I-6. Surfactant]
As the surfactant used in the emulsion of the present invention, any surfactant may be used as long as it can form the emulsion of the present invention. For example, an anionic surfactant, a cationic surfactant, a nonionic surfactant, or the like can be used. Among these, when using electrolyte, a nonionic surfactant is preferable. In addition, a polymer having surface activity can also be used as a surfactant.

Specific examples of anionic surfactants include dodecyl sulfonic acid, dodecyl benzene sulfonic acid, decyl benzene sulfonic acid, undecyl benzene sulfonic acid, tridecyl benzene sulfonic acid, and nonyl benzene sulfonic acid, and their sodium, potassium, and ammonium salts. Etc.
Furthermore, specific examples of the cationic surfactant include cetyltrimethylammonium promide, hexadecylpyridinium chloride, hexadecyltrimethylammonium chloride and the like.

  Specific examples of nonionic surfactants include polyoxyethylene sorbitan fatty acid esters (specifically, commercially available products such as polysorbate 80 and polysorbate 20), polyoxyethylene hydrogenated castor oil (specifically, commercially available products such as HCO 60). And ethylene glycol / propylene glycol block copolymers (specifically, commercially available products such as Pluronic F68).

In addition, examples of polymers having surface activity include natural polymers such as dextran, pectin, dextrin, chondroitin sulfate, hyaluronic acid, heparin, gum arabic, albumin, casein, gelatin, collagen, and polyamino acids and synthetic proteins. Is mentioned. A synthetic polymer having a hydrophilic group and a hydrophobic group such as a styrene-acrylic acid copolymer can also be used as a surfactant.
In addition, surfactant may be used individually by 1 type and may use 2 or more types together by arbitrary combinations and a ratio.

[I-7. Other additives]
The emulsion of the present invention may contain other components (additives) as long as the effects of the present invention are not significantly impaired. Therefore, components other than those described above may be contained in the water-soluble organic solvent rich phase or the water rich phase. There are no restrictions on such additives, and any known substance can be used as long as it is not significantly contrary to the spirit of the present invention. These additives may be appropriately contained in the dispersion or powder after removing the continuous phase component from the emulsion of the present invention.

  For example, a water-insoluble organic solvent can be used as an additive. Here, the water-insoluble organic solvent means an organic solvent other than the water-soluble organic solvent, that is, an organic solvent having a solubility in water of less than 5% by weight at normal temperature and pressure. However, from the gist of the present invention, the amount used can be used so as not to exceed the amount of the water-soluble organic solvent.

  As this water-insoluble organic solvent, for example, oil can be used. Specific examples of oils include vegetable oils such as soybean oil, sesame oil, olive oil, cottonseed oil, animal oils such as tallow, cocoa butter, fatty acid triglycerides, difatty acid esters of propylene glycol, medium chain or higher fatty acid alkyl esters, Lactic acid alkyl esters, aromatic monomers, dicarboxylic acid alkyl esters, and the like can be used.

  As other water-insoluble organic solvents, specific examples include: halogenated hydrocarbons such as dichloromethane, chloroform, dichloroethane, trichloroethane and carbon tetrachloride; ethers such as ethyl ether and isopropyl ether; methyl ethyl ketone and the like. Ketones; fatty acid esters such as ethyl acetate and butyl acetate; aromatic hydrocarbons such as benzene, toluene and xylene; alcohols such as octanol;

The role of these water-insoluble organic solvents is not particularly limited, but contributes to the form and physical / chemical stability of the emulsion, and further contributes to the form and physical / chemical stability of the target substance.
These water-insoluble organic solvents may be used alone or in combination of two or more in any combination and ratio.

  For example, a polymer can be used as an additive. For example, when the emulsion of the present invention is used for medical purposes, examples of the polymer include biodegradable polymer compounds. Specific examples of the biodegradable polymer compound include aliphatic polyesters, poly-α-cyanoacrylic acid esters, polyamino acids, maleic anhydride copolymers, and the like.

  Among these, typical examples of the aliphatic polyester include glycolic acid, lactic acid, 2-hydroxybutyric acid, 2-hydroxyvaleric acid, 2-hydroxy-3-methylbutyric acid, and 2-hydroxycaproic acid. , Α-hydroxy acids such as 2-hydroxyisocaproic acid and 2-hydroxycaprylic acid, cyclic dimers of α-hydroxy acids such as glycolide and lactide, hydroxydicarboxylic acids such as malic acid, and hydroxytricarboxylic acids such as citric acid Examples include homopolymers such as acids, copolymers, homopolymers and / or mixtures of copolymers. Examples of polymers include lactic acid polymers and the like as homopolymers, and examples of copolymers include lactic acid / glycolic acid copolymers and 2-hydroxybutyric acid / glycolic acid copolymers. Examples of the mixture of a homopolymer and / or a copolymer include a mixture of a lactic acid polymer and a 2-hydroxybutyric acid / glycolic acid copolymer.

Examples of polyamino acids include poly-γ-benzyl-L-glutamic acid, poly-L-alanine, poly-γ-methyl-L-glutamic acid, and the like.
Furthermore, examples of maleic anhydride copolymers include styrene / maleic acid copolymers.

In addition, as a polymer that can be used as an additive, a biocompatible polymer compound can also be preferably used. Examples include polystyrene, polymethacrylic acid, copolymers of acrylic acid and methacrylic acid, polyamino acids, dextranstearate, ethylcellulose, acetylcellulose, nitrocellulose, maleic anhydride copolymers, ethylene vinyl acetate. Copolymers, polyvinyl acetate, polyacrylamide, polyurethane, polyethylene and the like are used.
In addition, a polymer may be used individually by 1 type and may use 2 or more types together by arbitrary combinations and a ratio.

  Furthermore, as additives that induce phase separation between a water-rich phase and a water-soluble organic solvent-rich phase, sugars and polysaccharides such as sucrose, maltose, and dextran; water-soluble polymers such as polyethylene glycol; Water-soluble substances such as molecules may be used. By dissolving these in water, the solubility of the water-soluble organic solvent in water can be reduced, and phase separation can be induced.

  Examples of other additives that can be used include buffers, pH adjusters, viscosity adjusters, colorants, preservatives, fungicides, anti-evaporants, and fragrances. In addition, these additives may be used individually by 1 type, and may use 2 or more types together by arbitrary combinations and ratios.

[I-8. Phase separation conditions]
The emulsion of the present invention basically has a phase separation between a water-soluble organic solvent concentrated phase and a water-rich phase, and the phase separation domain is covered with a surfactant to form an emulsion. Usually, the water-soluble organic solvent and water are compatible, but phase separation can be caused by mixing (dissolving or dispersing) the above-mentioned target substance in the water-soluble organic solvent. From another point of view, the phase separation between the water-soluble organic solvent rich phase and the water-rich phase can be caused or promoted by containing an electrolyte in water. These phase separation phenomena are considered to be caused by shielding the hydration of water and water-soluble organic solvent with the target substance or electrolyte.

  The above phase separation usually occurs when each component appropriately satisfies each condition described in the above description of each component. However, the conditions under which the emulsion of the present invention undergoes phase separation are arbitrary as long as the emulsion of the present invention can be obtained, and are not limited to the conditions described above.

When the water-soluble organic solvent, the target substance, and the electrolyte are selected experimentally, for example, the following operation is performed, and whether or not two liquid phase separation occurs can be determined.
For example, in the case of a Solvent in Water type emulsion, a water-soluble organic solvent containing the target substance and the same volume of water may be mixed at normal temperature and pressure. On the other hand, in the case of a Water in Solvent type emulsion, water containing the target substance at room temperature and normal pressure and a water-soluble organic solvent having the same volume may be mixed. When mixing these, mixing is performed under the same conditions (amount used, concentration, composition ratio, etc.) as the emulsion to be prepared. When these liquids are mixed, if two-liquid phase separation occurs, the target substance and the water-soluble organic solvent used for the mixing operation are suitable as components of the emulsion of the present invention.

Here, the two-liquid phase separation means having an interface in a liquid state. At this time, a precipitate (solid) may be generated.
Furthermore, when performing said mixing operation, in order to make it easy to cause phase separation, it is preferable to contain electrolyte in water. At this time, if phase separation occurs, the electrolyte can be suitably used in the emulsion of the present invention.

[I-9. Emulsion composition]
[I-9-1. Amount of target substance]
The amount of the target substance in the emulsion of the present invention is arbitrary as long as it is not significantly contrary to the gist of the present invention, but is usually 0.005 mg / mL or more, preferably 0.01 mg / mL or more, with respect to the emulsion of the present invention. More preferably, it is 0.05 mg / mL or more, and usually 500 mg / mL or less, preferably 400 mg / mL or less, more preferably 300 mg / mL or less. Below the lower limit of this range, the target substance may leak out to the continuous phase side when the target substance is present in the droplet. On the other hand, if the upper limit is exceeded, the stability of the emulsion of the present invention may not be maintained, and the target substance may be precipitated.

  Further, when the water-soluble organic solvent rich phase and the water-rich phase are phase-separated, the amount of the water-soluble organic solvent or the target substance to be contained in water is arbitrary as long as it is not significantly contrary to the gist of the present invention. However, among the water-soluble organic solvent and water, the medium containing the target substance (ie, when the target substance is contained in the water-soluble organic solvent concentrated phase, the target substance is contained in the water-soluble organic solvent and water-rich phase). In the case of water, the concentration of the target substance in water) is usually 0.01 mg / mL or more, preferably 0.05 mg / mL or more, more preferably 0.1 mg / mL or more, and usually 800 mg / mL or less, Preferably it is 700 mg / mL or less, More preferably, it is 600 mg / mL or less. Below the lower limit of this range, the water-soluble organic solvent rich phase and the water-rich phase are not sufficiently phase-separated, and a stable emulsion may not be obtained, and productivity may be reduced. On the other hand, if the upper limit is exceeded, the stability of the emulsion is not maintained and the target substance may be precipitated.

[I-9-2. Amount of medium forming droplets]
When the emulsion of this invention is Solvent in Water, the usage-amount of a water-soluble organic solvent is arbitrary unless the effect of this invention is impaired remarkably. However, in this case, the amount of the water-soluble organic solvent in the emulsion of the present invention is usually 0.5% by weight or more, preferably 1.0% by weight or more, more preferably 5.0%, based on the emulsion of the present invention. % By weight or more, usually 80% by weight or less, preferably 70% by weight or less, more preferably 60% by weight or less. If the lower limit of this range is not reached, phase separation does not occur and the emulsion may not be formed. If the upper limit is exceeded, a water-in-solvent emulsion may be formed.

  On the other hand, when the emulsion of the present invention is Water in Solvent, the amount of water used is arbitrary as long as the effects of the present invention are not significantly impaired. However, in this case, the amount of water in the emulsion of the present invention is usually 0.5% by weight or more, preferably 1.0% by weight or more, more preferably 5.0% by weight or more based on the emulsion of the present invention. Further, it is usually 80% by weight or less, preferably 70% by weight or less, more preferably 60% by weight or less. If the lower limit of this range is not reached, phase separation does not occur and the emulsion may not be formed. If the upper limit is exceeded, droplets that become a Solvent in Water type emulsion may not be formed.

[I-9-3. Amount of surfactant]
The amount of the surfactant in the emulsion of the present invention is arbitrary as long as it is equal to or higher than the critical micelle concentration, but is usually 0.01% by weight or higher, preferably 0.05% by weight or higher, based on the emulsion of the present invention. The content is preferably 0.1% by weight or more, and is usually 50% by weight or less, preferably 40% by weight or less, and more preferably 30% by weight or less. If the lower limit of this range is not reached, the emulsion may not be stable, and if it exceeds this upper limit, the surfactant may form a structure such as a lamellar structure and the target emulsion may not be obtained.

[I-9-4. Amount of electrolyte]
The amount of the electrolyte in the emulsion of the present invention is arbitrary as long as the emulsion of the present invention can be formed, as long as it is not significantly contrary to the gist of the present invention. However, when an electrolyte is used, it is usually 0.01% by weight or more, preferably 0.05% by weight or more, more preferably 0.1% by weight or more, and usually 0.1% by weight or more based on the emulsion of the present invention. It is 50% by weight or less, preferably 40% by weight or less, more preferably 30% by weight or less. If the lower limit of this range is not reached, there is a possibility that the hydration of the water-soluble organic solvent and water cannot be effectively shielded. If this upper limit is exceeded, the surfactant may not work effectively and an emulsion may not be formed. is there.

  In addition, the density | concentration of said each component contained in the emulsion of this invention can be measured by a liquid chromatography, for example.

[I-10. Emulsion physical properties]
In the emulsion of the present invention, the size of the droplets is arbitrary as long as it is not significantly contrary to the spirit of the present invention. However, the average particle size of the droplets is usually 10 μm or less, preferably 5 μm or less, more preferably 1 μm or less, and particularly preferably 500 nm or less. When this upper limit is exceeded, the emulsion becomes unstable and may be easily united. The average particle diameter can be measured using a dynamic light scattering apparatus such as “FPAR-1000” manufactured by Otsuka Electronics Co., Ltd. or “Microtrack UPA” manufactured by Microtrack. Moreover, it can also measure with the apparatus using laser diffraction methods, such as "LA920" by Horiba, Ltd., for example. Among these, measurement using a dynamic light scattering method is preferable.

  In addition, the emulsion of the present invention is stable because the target substance does not precipitate even when left standing. Specifically, the emulsion of the present invention is a product in which the target substance precipitates even after standing at room temperature and normal pressure for 12 hours or longer, preferably 1 day or longer, more preferably 2 weeks or longer, and more preferably 1 month or longer. Stable enough to not. Thus, one of the advantages of the present invention is that a thermodynamically stable emulsion (microemulsion) can be spontaneously formed.

[II. Method for producing emulsion of the present invention]
The method for producing the emulsion of the present invention is arbitrary as long as it does not significantly contradict the gist of the present invention. A preferable production method is illustrated below.
First, a medium for forming droplets and a continuous phase, that is, a water-soluble organic solvent and water are prepared. At this time, the target substance is mixed in advance in a medium that is more contained in the phase containing the target substance. Therefore, if the target substance is to be contained in the droplets, when producing a Solvent in Water type emulsion, the target substance is mixed with a water-soluble organic solvent to produce a Water in Solvent type emulsion. In some cases, the target substance is mixed in water.

  Then, a medium that is more contained in the continuous phase is added to a medium that is more contained in the droplets. Conversely, if a medium rich in droplets is added to a medium rich in continuous phase, the medium rich in droplets may be rapidly diluted and the target substance may cause poor solvent precipitation. is there. That is, for example, when producing a Solvent in Water type emulsion, water is added to the water-soluble organic solvent. On the other hand, when producing a Water in Solvent type emulsion, a water-soluble organic solvent is added to water.

In addition, the surfactant may be mixed with the water-soluble organic solvent and / or water in any of the steps before, during and after the above mixing. For example, it may be preliminarily contained in a water-soluble organic solvent and / or water before the above mixing, or may be mixed in the water-soluble organic solvent and / or water after the above mixing.
Further, when an electrolyte or additive is contained in the emulsion of the present invention, the electrolyte and additive may be mixed with a water-soluble organic solvent and / or water in any step before, during, or after the above mixing. Good. However, when using an electrolyte that has an action of causing or promoting phase separation between a water-soluble organic solvent rich phase and a water-rich phase, the electrolyte is previously contained in water before the above mixing. It is preferable to keep.

  Next, the water-soluble organic solvent and water are mixed to form droplets to form the emulsion of the present invention. At this time, an emulsion may be spontaneously formed when mixing a water-soluble organic solvent and water, but from the viewpoint of reducing the particle size of the droplets in the emulsion and promoting the miniaturization of the target substance. In order to promote the formation of the emulsion, it is preferable to carry out micronization such as stirring using a mixing device or the like.

  When a mixing device is used, the specific method of mixing performed by the mixing device is not limited and is arbitrary. For example, the mixing apparatus may be subjected to a micronization process such as stirring to perform an operation capable of causing the emulsion to proceed. Examples of the mixing apparatus include a disperser such as a bead mill, a roll mill, a sand mill, a paint shaker, an ultrasonic disperser, a microfluidizer, and a high-pressure homogenizer. Among these, it is particularly preferable to use an ultrasonic disperser.

The temperature condition and pressure condition when performing the above operation are not particularly limited as long as the emulsion of the present invention is obtained.
In terms of temperature conditions, a temperature range in which both the water-soluble organic solvent and water are liquid is preferable. Specifically, it is usually 0 ° C. or higher, preferably 5 ° C. or higher, and usually 100 ° C. or lower, preferably 80 ° C. or lower.
As for pressure conditions, any of reduced pressure, normal pressure, and increased pressure may be used. From the viewpoint of ease of handling, it is preferably carried out under atmospheric pressure. However, this is not the case when a high-pressure homogenizer is used as a disperser.
By the above operation, the emulsion of the present invention can be obtained.

[III. Production method of target substance particles]
When the emulsion of the present invention contains a target substance in the droplet, particles of the target substance are removed from the droplet by removing a medium (ie, a water-soluble organic solvent and / or water) that is contained in the droplet more. Target substance particles) can be obtained. Moreover, you may make it perform the washing | cleaning process which wash | cleans a target substance particle after a removal process. Hereinafter, a method for producing the target substance particles will be described.

[III-1. Removal process]
In the removing step, the medium that is contained more in the droplets, that is, one of the water-soluble organic solvent and water is removed from the droplets in the emulsion of the present invention. Therefore, when the emulsion of the present invention is a Solvent in Water type, at least the water-soluble organic solvent is removed, and when it is a Water in Solvent type, at least water is removed. Thereby, a dispersion liquid in which the target substance is dispersed in the continuous phase can also be obtained. Furthermore, particles containing the target substance as powder can be obtained by removing the medium containing more of the continuous phase in addition to the medium containing more of the droplets.

  As described above, in the emulsion of the present invention, usually, water may be mixed in the water-soluble organic solvent concentrated phase, or water-soluble organic solvent may be mixed in the water-rich phase. Therefore, usually, both water-soluble organic solvent and water are contained in the droplet. However, even in this case, if the medium rich in droplets (that is, water-soluble organic solvent in Solvent in Water emulsion and water in Water in Solvent emulsion) is removed, the emulsion changes from a two-phase system to a one-phase system. In order to change, the target substance contained in the droplets can be precipitated in the continuous phase to form particles. This is because the target substance cannot be dissolved in a medium that is more contained in the continuous phase.

  However, when removing the water-soluble organic solvent in the removing step, it is preferable to use a water-soluble organic solvent used in the emulsion of the present invention having a boiling point that can be removed by drying. Specifically, it is preferable to use a water-soluble organic solvent having a boiling point of usually 200 ° C. or lower, preferably 190 ° C. or lower, more preferably 180 ° C. or lower. If this upper limit is exceeded, it may be difficult to dry and remove the water-soluble organic solvent.

  There is no restriction | limiting in the method of removing a water-soluble organic solvent and / or water. For example, a method of evaporating water-soluble organic solvent and / or water under normal pressure or gradually reducing pressure while stirring with a stirring device such as a propeller type stirrer or a magnetic stirrer, and adjusting the degree of vacuum using a rotary evaporator or the like. However, a water-soluble organic solvent and / or a method of evaporating water, a freeze-drying method, or the like can be used. Of these, it is preferable to use a freeze-drying method.

  By the way, even when a water-soluble organic solvent and / or water is removed by a freeze-drying method, unification of target substances may occur depending on conditions. In order to prevent this, the above-mentioned electrolyte is preferably contained in the emulsion of the present invention. If the electrolyte is contained, when removing the water-soluble organic solvent and / or water, the fine crystals of the electrolyte can prevent the coalescence of these target substances and effectively produce fine particles. .

  Furthermore, by adding a medium (ie, water in Solvent in Water emulsion, water-soluble organic solvent in Water in Solvent emulsion) to the emulsion of the present invention that is more abundant in the continuous phase, It is also possible to remove the medium contained in a large amount and produce the target substance particles. As described above, the emulsion of the present invention shields the hydration of the water-soluble organic solvent and induces phase separation between the water-soluble organic solvent and water by using the target substance and the electrolyte to be used as appropriate. Is formed. For this reason, the medium (water-soluble organic solvent and / or water) in the droplet is dissolved in the continuous phase by using a predetermined amount or more of the medium that is contained in the emulsion in a larger amount in the continuous phase, and as a result, The medium can be removed and the target substance can be granulated.

  A specific example of this method will be given. For example, in the case of a Solvent in Water type emulsion, by adding water (medium that is more contained in the continuous phase) to the emulsion, the system in the emulsion is transferred from the two-liquid phase separation region to the one-phase uniform region, and droplets are dropped. Remove the water-soluble organic solvent in it. Thereby, the target substance can be atomized and the target substance particles can be obtained in the continuous phase. In addition, the target substance particles can be obtained in the same manner even with a Water in Solvent type emulsion. The target substance particles can be used in the state of a dispersion (composition) dispersed in the continuous phase, or part or all of the continuous phase can be removed for use.

[III-2. Cleaning process]
In the cleaning process, the target substance particles are cleaned after the removing process. Specifically, electrolytes other than the target substance, surfactants and other additives are washed and removed.
The specific method of the cleaning method is arbitrary as long as it is not significantly contrary to the gist of the present invention. For example, in the case of, for example, a Solvent in Water type emulsion, a continuous phase that forms a continuous phase is added to the target substance, and electrolytes, surfactants, and other additives can be removed by methods such as centrifugation, dialysis, and filtration. it can. This utilizes the property that the target substance is difficult to mix in the medium that is more contained in the continuous phase, and the electrolyte and surfactant are easy to mix.

  Further, the target substance after washing may be dried by a known drying method to remove the medium that is more contained in the continuous phase. However, in order to suppress the coalescence of target substances and the occurrence of crystal growth, it is preferable to remove the medium that is more contained in the continuous phase by freeze-drying for drying.

[III-3. Physical properties of target substance particles]
The particle size of the target substance particles obtained by the method for producing target substance particles of the present invention is usually 10 μm or less, preferably 5 μm or less, more preferably 1 μm or less in the dry state. In addition, although the method of measuring the particle size of the above-mentioned emulsion can be used for the measuring method of the particle size of the target substance particle, Preferably it is dynamic light scattering. Moreover, it can also measure by SEM (scanning electron microscope). In addition, when measuring a particle size by dynamic light scattering, an average particle diameter becomes said range.

[III-4. yield]
According to the method for producing target substance particles of the present invention, among the target substances contained in the emulsion of the present invention, usually 1% or more, preferably 3% or more, more preferably 10% or more is obtained in a dry state. Can do. This yield can be measured by analyzing by liquid chromatography or the like.

[IV. effect]
As described above in detail, according to the emulsion of the present invention, in a new and unprecedented manner, the target substance contains water and a water-soluble organic solvent and is hardly soluble in the water or the water-soluble organic solvent. It is possible to provide a novel emulsion that can be dispersed in a fine form. In addition to this, the target substance, which has been difficult to be miniaturized in the past, can be appropriately miniaturized and dispersed in the continuous phase, and the selection range of the continuous phase and target substance to be used can be expanded as compared to the conventional case. Advantages such as the ability to spontaneously form microemulsions (thermodynamically stable emulsions) can also be obtained.

  Furthermore, according to the method for producing target substance particles of the present invention, target substance particles having a small particle size can be easily produced. Further, according to the method for producing target substance particles of the present invention, since the production method is simple, it is possible to obtain an advantage that the production cost of the target substance particles can be reduced.

[V. Field of use]
The emulsion of the present invention, and the method for producing the target substance particles of the present invention and the target substance fine particles obtained by the production method can use a water-soluble organic solvent, and can retain a large amount of the target substance in the emulsion. It can be used in various industrial fields by taking advantage of the point and the small particle size of droplets and target substance particles.

  For example, the emulsion of the present invention and the target substance particles obtained by the production method of the target substance particles of the present invention can be used for pharmaceuticals. As a specific example, the pharmaceutical which has the emulsion of this invention or the target substance particle obtained by the manufacturing method of the target substance particle of this invention can be used. Thereby, it becomes possible to facilitate the appropriate administration of the drug to the treatment target.

In this regard, for example, if the emulsion of the present invention is formed so as to contain a drug as a target substance, the drug can be stably dispersed in water even if the drug is poorly soluble in water. And the drug can be miniaturized. Therefore, it can be appropriately administered to a living body that requires administration of a drug.
However, when the emulsion or target substance particle of the present invention is used in the medical field, each element constituting the emulsion or target substance particle of the present invention such as water, target substance, surfactant, electrolyte, and other additives is included. It is preferable to use those approved as pharmaceuticals.

Furthermore, when a drug is used as a target substance as described above, the emulsion and target substance particles of the present invention help the drug to be absorbed into the body by increasing its specific surface area, and further by miniaturization, Has great advantages in delivery and its storage.
Further, by applying the method for producing target substance particles of the present invention to the production of a poorly water-soluble drug, the drug can be made into fine particles without requiring a large amount of energy and without being greatly influenced by the characteristics of the drug. It can be adopted as a general technique that can be used.

  Furthermore, the method for producing target substance particles of the present invention has an advantage that the target substance particles can be easily produced from droplets having a very small particle diameter. Therefore, if the target substance particles are produced using a pigment or dye whose particle size is desired to be reduced, such as a toner of an image forming apparatus, as a target substance, a high-quality target substance having a very small particle diameter Particles can be easily obtained.

  Moreover, the emulsion and target substance fine particles of the present invention can be used in a wide range of fields in addition to the above fields. For example, when a dye or pigment is used as the target substance, it can be used as ink for inkjet printers, toner, resist for color filters, other inks or paints.

  EXAMPLES Hereinafter, the present invention will be described in more detail with reference to examples. However, the present invention is not limited to the following examples, and may be arbitrarily modified without departing from the gist of the present invention. be able to.

[Example 1]
(1) Preparation of emulsion In a 50 mL vial, s-naproxen ((S)-(+)-6-Methoxy-α-methyl-2-naphthaleneacetic-acid, ALDRICH: Sigma) 0.06 g was dissolved in 5.04 g of THF (tetrahydrofuran: manufactured by Junsei Chemical Co., Ltd.). In a separate container, 0.3 g of surfactant Pluronic F68 (Asahi Denka Kogyo Co., Ltd.) is dissolved in 26.7 g of 10 wt% NaCl aqueous solution, and this surfactant / NaCl aqueous solution is added to the previously prepared drug-containing THF solution. Added.

Then, the emulsion was disperse | distributed using the ultrasonic disperser (The ULTRA SONIC HOMOGENIZER UH-600S by STM). At the time of dispersion, the ultrasonic disperser was set using an output chip of 7φ, an output level of 5, an ultrasonic irradiation interval level of 50%, and an ultrasonic irradiation time of 15 minutes. Thus, a slightly cloudy drug-containing emulsion A was obtained.
The particle size distribution of the resulting drug-containing emulsion A was measured with a particle size distribution meter FPAR-1000 (using a thick probe) manufactured by Otsuka Electronics. The measurement results are shown in FIG. From this result, it was found that the average particle diameter of the droplets in the drug-containing emulsion A was about 275 nm.

  Furthermore, 2 mL of the drug-containing emulsion A was taken, put into a 100 mL eggplant flask, and frozen while rotating in a rotor at −40 ° C. for 30 minutes. The frozen drug-containing emulsion A was lyophilized while decompressing. At this time, in order not to dissolve the drug-containing emulsion A, a −40 ° C. refrigerant was put in a heat-retaining stainless steel bottle and immersed in the whole eggplant flask. The mixture was left for about 4 hours to remove THF and water. The powder thus obtained is designated as drug-containing powder A.

<Washing of drug-containing powder A>
100 mg of this drug-containing powder A was taken up to 5 mL with demineralized water. The mixture was well dispersed with an ultrasonic washer, divided into 1 mL eppendorf tubes, treated with a centrifuge at 10,000 rpm for 30 minutes, and the supernatant was rinsed to obtain a precipitate. Further, 1 mL of demineralized water was added to the resulting precipitate, and the mixture was well dispersed with an ultrasonic cleaner. The dispersion thus obtained is referred to as a drug-containing dispersion A. The particle size was measured with FPAR-1000. The result is shown in FIG.

  Further, the drug-containing dispersion A was treated with a centrifuge at 10,000 rpm for 30 minutes, and the supernatant was rinsed to obtain a precipitate. Further, 1 mL of demineralized water was added to the resulting precipitate, and the mixture was well dispersed with an ultrasonic cleaner. 5 mL of this dispersion was placed in a 100 mL eggplant flask and lyophilized. The obtained powder is referred to as drug fine particles A.

<SEM observation>
SEM photographs of drug-containing powder A and drug fine particles A are shown in FIGS. In FIG. 5, fine particles having a particle diameter of about 200 to 300 nm were confirmed.

<HPLC analysis>
The drug contained in the drug fine particle A was analyzed. For the analysis, one eppendorf tube before lyophilization was used and HPLC measurement was performed. Ethanol was added to the sample, the volume was made up to 10 mL, filtered through a 0.45 μm filter, and used for analysis. The HPLC analysis conditions are shown below.

<HPLC conditions>
Column: TSKgel superODS (4.6 x 50 mm), 40 ° C
Eluent: 0.1% phosphoric acid aqueous solution / acetonitrile = 60/40, 0.8 mL / min
Detection: 272nm
Injection volume: 5μL

  As a result of the measurement, 180 μg of naproxen was observed per Eppendorf tube. When calculated from the preparation, if the yield is 100%, it is estimated that there is about 400 μg of naproxen. Therefore, the yield of naproxen obtained in this embodiment was 45%.

[Example 2: Emulsion containing PLA and oil]
The drug is 0.3 g of indomethacin (manufactured by SIGMA) and 0.15 g of poly-L-lactic acid (molecular weight 10,000, manufactured by Nacalai Tesque Co., Ltd.), 0.15 g of soybean oil (manufactured by Wako Pure Chemical Industries, Ltd.) An emulsion was prepared in the same manner as in Example 1 except that was added.
The particle size of the emulsion was evaluated in the same manner as in Example 1. As a result, the average particle size of the droplets in the obtained emulsion was estimated to be 252 nm.
Further, in the measurement after one week, the average particle diameter was estimated to be 249 nm, and it was confirmed that there was almost no change with time.

[Example 3: Other drug-containing microemulsion]
0.3 g of s-naproxen, which is a drug (target substance), was dissolved in 5.7 g of THF. In another container, 0.41 g of NaCl and 1.1 g of a surfactant HCO 60 (manufactured by Nippon Surfactant Co., Ltd.) were dissolved in demineralized water. These two liquids were mixed while stirring with a magnetic stirrer.
The particle size of droplets in the obtained drug-containing emulsion was measured with HPPS 3.3 (Malvern). The results are shown in FIG. As a result, it was shown that the average particle size of the droplets was 39 nm.
Further, when the obtained drug-containing emulsion was allowed to stand for 3 days, no precipitate was observed.

[Example 4: Other drug-containing microemulsion]
0.1 g of s-naproxen, which is a drug (target substance), was dissolved in 1.9 g of 1.4 dioxane (manufactured by Wako Pure Chemical Industries, Ltd.) to obtain a drug dioxane solution. In another container, 4.0 g of NaCl and surfactant F68 (manufactured by SIGMA) were dissolved in 15.2 g of demineralized water. 6 g of this aqueous solution was added dropwise to the previously prepared drug dioxane solution and mixed with a magnetic stirrer.
The particle size of droplets of the obtained drug-containing emulsion was measured with HPPS 3.3. The results are shown in FIG. As a result, it was shown that the average particle diameter of the droplets was 43.7 nm.

  The present invention can be widely used in any industrial field, and is particularly suitable for pharmaceuticals such as drugs, toners for image forming apparatuses, and the like.

It is a figure showing typically an outline of one embodiment of an emulsion of the present invention. It is a graph showing distribution of the particle size of the droplet in the medicine containing emulsion A measured in Example 1 of the present invention. It is a graph showing distribution of the particle size of the medicine containing powder A measured in Example 1 of the present invention. It is a drawing substitute photograph of the chemical | medical agent containing powder A image | photographed with SEM in Example 1 of this invention. It is a drawing substitute photograph of the chemical | medical agent microparticles | fine-particles A image | photographed with SEM in Example 1 of this invention. It is a graph showing distribution of the particle size of the droplet in the medicine containing emulsion adjusted in Example 3 of the present invention. It is a graph showing the distribution of the particle size of the droplet in the medicine containing emulsion adjusted in Example 4 of this invention.

Explanation of symbols

1 droplet 2 continuous phase 3 surfactant

Claims (11)

A water-soluble organic solvent having a solubility of 5% by weight or more in water at normal temperature and pressure,
water and,
A poorly water-soluble drug miscible in the water-soluble organic solvent;
Containing a surfactant,
Forming an emulsion consisting of a water-soluble organic solvent concentrated phase and droplets containing the poorly water-soluble drug dispersed in a continuous phase consisting of a water-rich phase;
  A removal step of removing the water-soluble organic solvent or the water-soluble organic solvent and the water from the emulsion
A method for producing poorly water-soluble drug particles. Electrolyte to the water wherein the dissolved 0.1% by weight or more, the production method of the poorly water-soluble drug particles of claim 1. The method for producing poorly water-soluble drug particles according to claim 1 or 2, wherein the droplets have an average particle size of 10 µm or less. The concentration of the slightly water-soluble drug in the water-soluble organic solvent medium in, characterized in that at least 0.005 mg / mL, of poorly water-soluble drug particles as claimed in any one of claims 1 to 3 Manufacturing method .   The water-soluble organic solvent has a solubility of 20% by weight or more with respect to water.
The method for producing poorly water-soluble drug particles according to any one of claims 1 to 4, wherein   The water-soluble organic solvent is freely mixed with water.
The method for producing poorly water-soluble drug particles according to any one of claims 1 to 4, wherein   The solubility of the poorly water-soluble drug in water is 10 g / liter or less.
The method for producing poorly water-soluble drug particles according to any one of claims 1 to 6, wherein:   In the removing step, the water-soluble organic solvent and the water are removed from the emulsion.
The method for producing poorly water-soluble drug particles according to any one of claims 1 to 7, wherein   In the removal step, the water-soluble organic solvent and the water are removed by lyophilization.
The method for producing poorly water-soluble drug particles according to claim 8, wherein: The method for producing poorly water-soluble drug particles according to any one of claims 1 to 9, wherein the poorly water- soluble drug particles are washed after the removing step. Characterized in that it has a poorly water-soluble drug particles formed by the method for producing a poorly water soluble drug particles as claimed in any one of claims 1-10, pharmaceuticals.