Porous particles containing lipophilic aggregates capable of spontaneously dispersing in water, and method for producing the same

Abstract

To provide porous particles in which a medicinal ingredient consisting of a biopolymer such as a protein can be stably stored in a solid state, sprayed into a nasal cavity, and spontaneously formed into nanoparticles with excellent mucosal permeability after reaching a nasal mucosa, and to provide methods for manufacturing the same.SOLUTION: Provided are a spontaneously dispersible composition in water, characterized by comprising porous particles made of a hydrophilic polymer and lipophilic aggregates encapsulated in pores of the porous particles, and a method for producing the composition, including the steps of: freeze-drying droplets of an aqueous solution of a hydrophilic polymer to prepare porous particles; and encapsulating lipophilic aggregates in the obtained porous particles.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to porous particles containing a lipophilic aggregate that is spontaneously dispersible in water, and a method for producing the same. [Background technology]

[0002] In recent years, biomedicines using biopolymers (peptides, proteins, DNA, RNA, vaccine antigens, etc.) have been actively developed. These biomedicines are mainly administered by injection, and there is a demand for the establishment of a less invasive and simpler administration method. Nasal administration is quick, safe, non-invasive, and can reduce systemic side effects, and is also a very simple administration method. In addition, compared to oral administration, nasal administration has the advantage of avoiding the degradation and metabolism of drugs in the stomach and small intestine, and avoiding the hepatic first-pass effect. Furthermore, in recent years, nasal administration has attracted attention as a drug delivery route from the nose to the brain, and research and development is being actively conducted. The background to this is that the incidence of central neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease is exponentially increasing with the arrival of the super-aging era, and there is no effective drug administration route because many drugs cannot penetrate the blood-brain barrier.

[0003] For nasal administration, drugs with molecular weights of less than 300 Da in the spray solution are rapidly and efficiently absorbed by the nasal mucosa. However, it is known that there is a negative correlation between the human nasal absorption rate and the molecular weight of the water-soluble compound as a drug (300-5,000 Da), and water-soluble compounds with molecular weights larger than that are hardly absorbed when administered nasally in their original form. In addition, as the lipid solubility of a drug increases, the penetration of the drug into the entire mucosa increases, but if the drug's lipid solubility is too high, the dissolution of the drug in nasal mucus becomes an obstacle and the absorption efficiency decreases. Therefore, it is known that biopolymers such as proteins and DNA are hardly absorbed when administered nasally in their original form.

[0004] Previous studies aimed at protein absorption through the nasal mucosa have attempted the development of nanoparticulate carriers that protect proteins and improve permeability, as well as the use of absorption enhancers. However, these studies have been conducted under the assumption that the proteins will reach the nasal mucosa, which is the site of absorption, and remain on the mucosal surface.

[0005] On the other hand, for the transport of drugs including biopharmaceuticals to the olfactory mucosa, which is the site of absorption, via nasal administration, the main focus has been on droplet spraying. The aforementioned nanoparticle carriers under development are also expected to be sprayed as suspensions. However, droplets are easily affected by the cleaning action of intranasal mucus and rarely remain on the mucosal surface. In addition, when considering the delivery of drugs from the nasal cavity to the brain, it is necessary to transport droplets to the olfactory mucosa, but the rate of droplets reaching the olfactory mucosa is low (5% or less). Therefore, research is being conducted on how to transport drugs efficiently to the olfactory mucosa, which is the site of absorption. Recent research has reported that by using a powder sprayer (Aptar UDS powder), about 30% of the powder can be accumulated in the olfactory mucosa, and the use of solid particles for spraying has great advantages in terms of the stability of the formulation and the high retention after adhesion to the mucosa.

[0006] Patent Document 1 describes a method in which a surfactant-drug complex exhibiting high biomembrane affinity obtained by coating a hydrophilic drug such as a low molecular weight compound or a protein composition with a lipophilic surfactant is emulsified and dispersed in an organic solvent containing a lipophilic surfactant to prepare an O / W type emulsion, which is then freeze-dried. However, the technology described in Patent Document 1 has an issue of suppressing leakage of the hydrophilic drug from the surfactant-drug complex into the aqueous phase, and there is no description of its application to nasal administration. In addition, since the surfactant-drug complex of the hydrophilic drug does not disperse even when added to water, it is difficult to effectively contact and absorb the drug into the mucosa as it is.

[0007] Patent Document 2 describes a spontaneously emulsifying composition containing porous particles made of hydrophilic polymers and a lipophilic substance absorbed in the pores of the porous particles. The spontaneously emulsifying composition, which is a solid particle, spontaneously emulsifies even when left to stand by simply contacting an aqueous phase, and quickly forms an O / W emulsion. However, the lipophilic substance is oil or oil-like substances and surfactants, and biopolymers used in biopharmaceuticals, such as proteins, DNA, and RNA, are not absorbed into the pores of the porous particles. Moreover, since the emulsion obtained is a lipophilic substance, there is a problem that the fine particles become large and the fine particles coalesce with each other in water, making the emulsion unstable.

[0008] As described above, it is possible to prepare an O / W type emulsion from a surfactant-drug complex, or to form an O / W emulsion from solid particles on the mucous membrane as the aqueous phase by using porous particles and a lipophilic substance. However, these techniques are emulsion-related techniques, and there is a limit to how fine the emulsion droplet size can be made in order to disperse drugs, etc. in the oil phase of the emulsion. In addition, there is a limit to the types of drugs that can be encapsulated in the formulation, making it difficult to increase the amount that can be encapsulated. [Prior art documents] [Patent documents]

[0009] [Patent Document 1] JP 2004-43355 A [Patent Document 2] JP 2022-22638 A Summary of the Invention [Problem to be solved by the invention]

[0010] The object of the present invention is to provide porous particles capable of stably storing a medicinal ingredient consisting of a biopolymer such as a protein in a solid state, spraying it into the nasal cavity, and spontaneously forming nanoparticles with excellent mucosal permeability after it reaches the nasal mucosa. Also, the object of the present invention is to provide a method for producing porous particles capable of stably storing a medicinal ingredient consisting of a biopolymer such as a protein in a solid state, spraying it into the nasal cavity, and spontaneously forming nanoparticles with excellent mucosal permeability after it reaches the nasal mucosa. [Means for solving the problem]

[0011] The present inventors have found that by spray-freezing and drying a water-soluble polymer to obtain porous particles, and by introducing the particles in which an oil or oil-like substance and a surfactant are encapsulated in the pores into water, the water-soluble polymer dissolves, and the oil or oil-like substance and the surfactant spontaneously emulsify. However, when an oil or oil-like substance is used, the particles become large when emulsified, and the particles become unstable due to their coalescence with each other, and it is difficult to encapsulate a water-soluble biopolymer. Therefore, instead of the oil or oil-like substance, a fat-soluble assembly in which a biopolymer such as a protein is coated with a fat-soluble surfactant is used, and the porous particles in which the fat-soluble assembly is encapsulated are administered to the aqueous phase of the olfactory mucosa in the nasal cavity, etc., and the fat-soluble assembly spontaneously micellizes (spontaneously disperses in water), and the particles in the aqueous phase can be kept small and stable, thereby completing the present invention.

[0012] That is, the present invention is specified by the following items. (1) A spontaneously dispersible composition in water, comprising porous particles made of a hydrophilic polymer, and fat-soluble aggregates encapsulated within the pores of the porous particles. (2) The spontaneously dispersible composition in water according to (1), wherein the fat-soluble aggregate contains a medicinal ingredient and a fat-soluble surfactant. (3) The spontaneously dispersible composition in water according to (2), wherein the fat-soluble surfactant has an HLB value in the range of 1 to 6. (4) The spontaneously dispersible composition in water according to (2), wherein the fat-soluble aggregate further contains a hydrophilic surfactant. (5) The spontaneously dispersible composition in water according to (2), wherein the medicinal ingredient is a biopolymer selected from the group consisting of proteins, DNA, RNA, and antigens. (6) The spontaneously dispersible composition in water according to any one of (1) to (5), which is a composition for nasal administration. (7) freeze-drying the droplets of the aqueous hydrophilic polymer solution to prepare porous particles; and encapsulating fat-soluble aggregates within the pores of the resulting porous particles; A method for producing a spontaneously water-dispersible composition, comprising: Regarding (7), the following aspects are included: (8) The method for producing the spontaneously dispersible composition in water according to (7), wherein the freeze-drying is spray-freeze-drying. (9) The method for producing the spontaneously dispersible composition in water according to (7), wherein the encapsulating step is a step of impregnating the obtained porous particles with a fat-soluble aggregate. Effect of the Invention

[0013] Since the spontaneously dispersible composition of the present invention is in a solid state, the fat-soluble aggregate containing the medicinal ingredient can be stably stored, and since the composition is sprayed as solid particles, it has high retention after adhering to the nasal mucosa when administered nasally, and further, after reaching the nasal mucosa, it spontaneously disperses and can form stable nanoparticles with excellent mucosal permeability. [Brief description of the drawings]

[0014] [Figure 1] A scanning ion microscope photograph of a porous particle prepared using Eudragit L100 is shown in (a). Further, a scanning ion microscope photograph of a cross section of the porous particle thus prepared is shown. (b) shows the state before impregnation with the fat-soluble aggregate, and (c) shows the state after encapsulation of the fat-soluble aggregate. [Diagram 2] (a) shows the average particle size of fat-soluble aggregates dispersed in cyclohexane, and (b) shows the average particle size of fat-soluble aggregates encapsulated in the pores of porous particles and then dispersed in water. [Diagram 3]1 shows the effect of a hydrophilic surfactant on the average particle size of lipophilic aggregates. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] The spontaneously dispersible composition of the present invention is characterized by comprising porous particles made of a hydrophilic polymer and fat-soluble aggregates encapsulated in the pores of the porous particles. Since the spontaneously dispersible composition of the present invention is in a solid state, it can be stably stored and can be used as a composition that can be prepared when needed.

[0016] The term "spontaneous dispersibility in water" used in the present invention can be defined as the property of causing dispersion (micelle formation) without the application of external force when water comes into contact with a substance other than water, and specifically refers to the property of fat-soluble aggregates dispersing (micelle formation) without the application of external force when the composition of the present invention comes into contact with an aqueous phase, such as when it is poured into water.

[0017] The hydrophilic polymer used in the spontaneously dispersible composition in water of the present invention is not particularly limited as long as it is a polymer compound exhibiting hydrophilicity. Specific examples of the hydrophilic polymer include water-swellable cellulose derivatives such as sodium carboxymethylcellulose, crosslinked hydroxypropylcellulose, hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), hydroxyisopropylcellulose, hydroxybutylcellulose, hydroxyphenylcellulose, hydroxyethylcellulose (HEC), hydroxypentylcellulose, hydroxypropylethylcellulose, hydroxypropylbutylcellulose, and hydroxypropylethylcellulose; polyvinyl alcohol, polyalkylene glycols such as polyethylene glycol, polypropylene glycol, and copolymers of polyethylene glycol and polypropylene glycol (e.g., poloxamer); poly(ethylene oxide), poly(propylene oxide), and the like. Examples of suitable hydrophilic colloids include thermoplastic polyalkylene oxides such as polyacrylic acid, polymethacrylic acid, and methacrylic acid-methacrylic acid ester copolymers (e.g., Eudragit (registered trademark), Carbopol (registered trademark)); hydrophilic colloids such as alginates, agar, guar gum, locust bean gum, kappa carrageenan, iota carrageenan, tara, gum arabic, tragacanth, pectin, xanthan gum, gellan gum, maltodextrin, galactomannan, pustulan, laminarin, scleroglucan, gum arabic, inulin, pectin, gelatin, welan, rhamsan, zooglulan, methylan, chitin, cyclodextrin, and chitosan; gelling starches such as acid hydrolyzed starch, swelling starches such as sodium starch glycolate and derivatives thereof; and swelling cross-linked polymers such as cross-linked polyvinylpyrrolidone, cross-linked agar, and cross-linked sodium carboxymethylcellulose. These hydrophilic polymers can be used alone or in combination of two or more. The molecular weight of the hydrophilic polymer used is not particularly limited as long as it dissolves in water at a concentration of 0.1 to 50 w / v % and is solid at room temperature; for example, in the case of poloxamer, the molecular weight is preferably 10,000 or more.

[0018] The process for preparing porous particles made of a hydrophilic polymer is not particularly limited, but a process for preparing porous particles by freeze-drying droplets of an aqueous solution of the hydrophilic polymer is preferred. The method for producing droplets of the aqueous polymer solution is not particularly limited, and the solution can be produced by dripping the solution naturally or under pressure from the outlet of a thin tube. In order to obtain finer droplets, a preferred example is a method in which the solution is atomized and sprayed using a nozzle (nozzle method) or a disk (rotary atomizer method) used in a conventional spray drying method.

[0019] Freeze-drying droplets of an aqueous hydrophilic polymer solution refers to freezing the droplets of the aqueous hydrophilic polymer solution obtained as described above at 0°C or lower, preferably at -30°C or lower, -70°C or lower, or -100°C or lower, and then removing water from the frozen droplets by sucking them under reduced pressure at 0°C or lower, preferably at -30°C or lower, to dry them. The process of freeze-drying the droplets obtained by spraying to prepare the porous particles used in the present invention can be carried out according to a conventional method, but for example, the process and conditions described in JP-A-2022-22638 can be used as a reference.

[0020] The median diameter of the porous particles made of hydrophilic polymer obtained as described above is preferably in the range of 0.5 to 30 μm, more preferably in the range of 1 to 20 μm, 2 to 10 μm. The median diameter of the porous particles is mainly determined by the size of the droplets of the hydrophilic polymer aqueous solution to be sprayed, and this size is mainly determined by the spray pressure and the liquid feed rate, so it is preferable to adjust the spray pressure and the liquid feed rate so that the median diameter of the porous particles is within the above range. When the median diameter of the porous particles is less than 0.5 μm, it means that the size of the droplets of the sprayed polymer aqueous solution is small, and the amount of water desorbed is small, so that pores may not be formed sufficiently. When the median diameter of the polymer porous particles is more than 30 μm, the surface area relative to the volume is small, so spontaneous dispersion in water may not occur smoothly. The spray pressure and liquid feed rate can also be carried out according to a conventional method as described above.

[0021] The porous particles obtained as described above preferably have a particle size distribution index (volume average particle size / number average particle size) in the range of 1.0 to 2.0, more preferably 1.1 to 1.5, an average pore size in the range of 0.001 to 0.5 μm, and a specific surface area in the range of 50 to 150 m. 2 / g, the porosity is preferably in the range of 5 to 50, the porosity is preferably in the range of 10 to 60%, and the shape is preferably spherical.

[0022] As described above, the porous particles of the present invention are made of a hydrophilic polymer, and therefore dissolve quickly when they come into contact with water, and release the encapsulated fat-soluble aggregates quickly, compared to porous particles made of a water-insoluble base material such as silica. This causes the concentration of the fat-soluble aggregates to increase rapidly in the nasal mucosa, for example, and works in favor of absorption due to the concentration gradient.

[0023] The spontaneously water-dispersible composition of the present invention comprises a fat-soluble aggregate encapsulated in the pores of a porous particle made of a hydrophilic polymer. The fat-soluble aggregate comprises a water-soluble biopolymer such as a protein, which is a medicinal ingredient, and a fat-soluble surfactant, and is preferably a water-soluble biopolymer, which is a medicinal ingredient, coated with a fat-soluble surfactant. The fat-soluble aggregate is preferably a nanoparticle having an average particle size of, for example, 150 to 1200 nm, 200 to 1100 nm, or 250 to 600 nm, more preferably 200 to 550 nm, in view of the amount of medicinal ingredient that can be supported and the absorption efficiency.

[0024] The water-soluble biopolymer that is the medicinal ingredient is not particularly limited as long as it is a water-soluble polymer produced by a living body and has been found to have medicinal effects, and examples of the water-soluble biopolymer include peptides, proteins, DNA, RNA, and vaccine antigens.

[0025] The fat-soluble surfactant for coating the water-soluble biopolymer, which is a medicinal ingredient, preferably has an HLB value in the range of 1 to 6. By using a fat-soluble surfactant having an HLB value in this range, the water-soluble biopolymer, which is a medicinal ingredient, can be dispersed in mucous membranes (in water) together with the hydrophilic polymer constituting the porous particles. The fat-soluble surfactant is not particularly limited as long as it has an HLB value in the above range, but in the surfactant, the unsaturated fatty acid forming the hydrophobic part includes palmitoleic acid, oleic acid, erucic acid, etc., and among them, erucic acid is preferred, and the polyhydric alcohol forming the hydrophilic part includes sucrose, lactose, glucose, polyglycerin, sorbitol, sorbitan, etc. Preferred fat-soluble surfactants include sucrose erucate, sucrose oleate, or sucrose laurate, which have an HLB of 1 to 3, and decaglycerin erucate, which has an HLB of 6 or less, and those in the form of a viscous liquid are more preferred.

[0026] The means for coating the water-soluble biopolymer, which is the medicinal ingredient, with the fat-soluble surfactant is not particularly limited, and coating can be performed according to a conventional method. For example, the fat-soluble aggregate can be obtained by emulsifying and dispersing an aqueous solution containing the medicinal ingredient in an organic solvent containing a fat-soluble surfactant to prepare a W / O type emulsion, and then drying the obtained W / O type emulsion by a conventional method such as freeze-drying or vacuum drying. The organic solvent is not particularly limited as long as it can dissolve the fat-soluble surfactant and can be removed by volatilization by freeze-drying, but lower alcohols such as ethanol and low-boiling point hydrocarbons such as hexane are usually used. Emulsification and dispersion can be performed with a stirrer such as a propeller mixer or a disperser.

[0027] The fat-soluble aggregate of the present invention can further contain a hydrophilic surfactant. By mixing the fat-soluble aggregate with a hydrophilic surfactant in advance, the fat-soluble aggregate can be more dispersed and made finer. The hydrophilic surfactant has the effect of preventing the fat-soluble aggregate from coalescing during spontaneous dispersion in water, and dispersing it as a single fat-soluble aggregate. Examples of hydrophilic surfactants that can be used include known hydrophilic surfactants such as polysorbate 20 (Tween 20), polysorbate 40 (Tween 40), polysorbate 60 (Tween 60), polysorbate 65 (Tween 65), polysorbate 80 (Tween 80), polysorbate 85 (Tween 85), decaglyceryl laurate, polyoxyethylene sorbitol monolaurate, polyoxyethylene sorbitol tetraoleate, polyoxyethylene hydrogenated castor oil 20, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene cetyl ether, polyoxyethylene oleyl ether, polyoxyethylene castor oil, and polyoxyl 35 castor oil. The hydrophilic surfactant can be used in an amount of about 5 to 15% by mass in the solution of the spontaneously dispersible in water composition of the present invention, although this amount depends on the type of hydrophilic surfactant.

[0028] The spontaneously water-dispersible composition of the present invention can be produced by encapsulating the fat-soluble aggregates in the pores of the porous particles prepared as described above. As a means for encapsulating the fat-soluble aggregates in the pores of the porous particles, the fat-soluble aggregates are dissolved and dispersed in an organic solvent such as cyclohexane, and then impregnated into the porous particles. The process of impregnating the fat-soluble aggregates into the porous particles is not particularly limited as long as the fat-soluble aggregates are encapsulated in the pores of the porous particles, but specifically, the process of immersing the porous particles in a lipophilic substance under normal pressure and taking them into the pores by capillary action, the process of immersing the porous particles in a lipophilic substance and placing the lipophilic substance under a pressure higher than normal pressure, the process of placing the porous particles under reduced pressure and introducing the lipophilic substance to immerse them, etc. are included. It should be noted that the process of encapsulating the fat-soluble aggregates in the pores of the porous particles is preferably carried out under dry conditions, for example, in a desiccator, in order to avoid the influence of moisture in the air.

[0029] The spontaneously dispersible composition of the present invention disperses fat-soluble aggregates without the application of external force when it is put into water or otherwise comes into contact with an aqueous phase, and therefore disperses fat-soluble aggregates as nanoparticles with excellent mucosal permeability when it is put into the nasal cavity and comes into contact with the aqueous phase (nasal mucosa) in the nasal cavity. Furthermore, since the spontaneously dispersible composition of the present invention is a solid particle, it has the characteristic of having a high retention after adhering to the nasal mucosa when administered nasally. Therefore, the spontaneously dispersible composition of the present invention is particularly excellent as a composition for nasal inoculation. EXAMPLES

[0030] The present invention will be described in more detail below using examples, but the present invention is not limited to these examples. EXAMPLES

[0031] [Preparation of porous particles] Methacrylic acid copolymer L (Eudragit L100, Degussa Japan Co., Ltd.) was added to 0.4M NaOH aqueous solution to prepare a 10wt% Eudragit L100 solution. The prepared polymer aqueous solution was sprayed onto the liquid nitrogen surface using a two-fluid nozzle (nozzle diameter: 0.4mm) attached to a spray dryer (SD-100, Tokyo Rikakikai Co., Ltd.). After spraying, the mixture was freeze-dried for two days using a freeze dryer FD-1000 (Tokyo Rikakikai Co., Ltd.) to obtain porous particles. The average particle diameter of the obtained porous particles was 13.35μm, which was calculated by importing the photos taken with a scanning ion microscope into image processing software and arithmetically averaging the major axes of 100 particles. A scanning ion microscope photograph of the obtained porous particles is shown in Figure 1(a), and a scanning ion microscope photograph of the cross section of the porous particles is shown in Figure 1(b). The spraying conditions and freeze-drying conditions are shown in Table 1.

[0032] [Table 1]

[0033] [Preparation of lipophilic aggregates] A 1 mg / ml albumin (derived from bovine serum, manufactured by Wako Pure Chemical Industries, Ltd.) solution and an organic solvent containing 10 wt% surfactant were prepared. Then, these were mixed so that the volume ratio was 1:2, and the mixture was stirred at 22,000 rpm for 5 minutes using a homogenizer to prepare a W / O emulsion. Then, the mixture was pre-frozen with liquid nitrogen for 20 minutes. Then, the mixture was put into a freeze dryer for 2 days to prepare a fat-soluble aggregate. 5 ml of organic solvent was added to the fat-soluble aggregate and dissolved in an ultrasonic bath. This was used as an S / O suspension. The types of fat-soluble surfactants used are shown in Table 2. The "state" in Table 2 refers to the state of the fat-soluble surfactant at room temperature to 37°C. In addition, the organic solvent used to prepare the fat-soluble aggregate and the organic solvent used to form the S / O suspension were both cyclohexane (Fujifilm Wako Pure Chemical Industries, Ltd.).

[0034] [Table 2] Polyglycerol erucic acid ester (OE-750) Hanshin Pharmaceutical Industries, Ltd. · Sucrose erucate (ER-290) Mitsubishi Chemical Foods Sucrose oleate (O-170) Mitsubishi Chemical Foods Sucrose laurate (L-195) Mitsubishi Chemical Foods Sucrose palmitate (P170) Mitsubishi Chemical Foods · Sucrose stearate (S-170) Mitsubishi Chemical Foods

[0035] [Preparation of spontaneously water-dispersible composition] Tween 80 was added to and dissolved in this S / O suspension to give concentrations of 0, 5, 10, and 15 wt % to prepare Tween 80-containing S / O suspensions. 200μl of the prepared S / O suspension containing Tween 80 was dropped onto 0.05g of the prepared Eudragit L100 porous particles. The mixture was then freeze-dried for 2 days. This was used as a spontaneously dispersible composition in water. A scanning ion microscope photograph of the cross section of the obtained spontaneously dispersible composition in water is shown in Figure 1(c).

[0036] [Micelle formation and particle size measurement] 0.01 g of the spontaneously dispersible composition in water was added to 20 ml of phosphate buffered saline (PBS, pH = 7.4) and allowed to stand (room temperature 24 ° C.) to form micelles. The average particle size was then measured by dynamic light scattering using a Zetasizer Ultra (Malvern Panalytical).

[0037] The average particle size of the fat-soluble aggregates dispersed in cyclohexane before the fat-soluble aggregates prepared were impregnated into the porous particles and encapsulated in the pores of the porous particles is shown in Figure 2(a), and the average particle size of the fat-soluble aggregates released when the fat-soluble aggregates were impregnated into the porous particles, encapsulated in the pores of the porous particles, contacted with an aqueous phase, and dispersed in the aqueous phase is shown in Figure 2(b). In most cases of the fat-soluble surfactants used, the average particle size of the fat-soluble aggregates was smaller when released from the porous particles than when dispersed in cyclohexane. This indicates that the fat-soluble aggregates that condense (coalesce) in an organic solvent such as cyclohexane are encapsulated in the pores of the porous particles, and when the water-soluble polymers that compose the porous particles come into contact with the aqueous phase and dissolve, the fat-soluble aggregates do not aggregate (coalesce) in water, and the dispersibility is improved. In other words, it was found that the porous particles are not only effective as a substrate for stably storing fat-soluble aggregates by encapsulating them within the pores, but also contribute to the dispersion of the fat-soluble aggregates, confirming the usefulness of the spontaneously water-dispersible composition of the present invention in a nasal administration method. EXAMPLES

[0038] In order to further disperse and refine the fat-soluble aggregates dispersed in water, the hydrophilic surfactant Tween 80 was added to the S / O suspension before encapsulation in porous particles, and the effect of the hydrophilic surfactant on the dispersibility of the fat-soluble aggregates was confirmed. ER-290 was used as the fat-soluble surfactant to prepare the fat-soluble aggregates. The results are shown in Figure 3. As the amount of Tween 80 added increased, the average particle size of the fat-soluble aggregates decreased, and it was confirmed that they tended to approach monodisperse particles. When 15% Tween 80 was added, a dispersed state with an average particle size of 300 nm or less was obtained, confirming the possibility of use in nasal administration methods. [Industrial Applicability]

[0039] The spontaneously dispersible composition of the present invention can disperse lipid-soluble aggregates containing biopolymers encapsulated within the pores of porous particles into particles of 300 nm or less in water, and therefore can be used for minimally invasive nasal administration methods. Furthermore, by utilizing the spontaneous water dispersibility of the composition of the present invention, it is possible to apply the composition not only to pharmaceuticals but also to the fields of cosmetics, food, etc.

Claims

1. A spontaneously dispersible composition in water, comprising: porous particles made of a hydrophilic polymer; and fat-soluble aggregates encapsulated within the pores of the porous particles.

2. 2. The spontaneously dispersible composition in water according to claim 1, wherein the fat-soluble aggregate comprises a medicinal ingredient and a fat-soluble surfactant.

3. 3. The spontaneously dispersible composition in water according to claim 2, wherein the fat-soluble surfactant has an HLB value in the range of 1 to 6.

4. The spontaneously dispersible composition in water of claim 2 , wherein the lipophilic aggregate further comprises a hydrophilic surfactant.

5. 3. The spontaneously dispersible composition in water according to claim 2, wherein the medicinal ingredient is a biopolymer selected from the group consisting of proteins, DNA, RNA, and antigens.

6. The spontaneously dispersible composition in water according to any one of claims 1 to 5, which is a composition for nasal administration.

7. freeze-drying droplets of the aqueous hydrophilic polymer solution to prepare porous particles; and encapsulating fat-soluble aggregates within the pores of the resulting porous particles; A method for producing a spontaneously water-dispersible composition, comprising:

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