JP7651152B2 - Spontaneously emulsifiable composition and method for producing same - Google Patents

Description

The present invention relates to a novel spontaneously emulsifiable composition using polymeric porous particles as a substrate and a method for producing the same.

To improve the solubility and absorption of poorly water-soluble drugs, a method of encapsulating poorly water-soluble drugs in the oil phase of an oil-in-water (O/W) emulsion is used. An O/W emulsion is a state in which oil is dispersed in water at submicron size, and its preparation methods are broadly divided into mechanical emulsification and physicochemical emulsification. Mechanical emulsification using a high-speed homogenizer that generates high shear force is generally used. Since emulsions are physicochemically metastable systems, long-term stability is an issue. In mechanical emulsification, stabilization is aimed at by controlling the preparation conditions and composition. On the other hand, there is also the idea of preparing an emulsion at the time of use rather than storing it in an emulsion state. In preparing an emulsion at the time of use, it is necessary to be able to easily prepare an emulsion when it is needed without requiring special equipment, and physicochemical emulsification methods have been investigated to achieve this. As a result, formulation technology that allows emulsion formation to be easily performed at the time of use has been developed.

Emulsions designed to emulsify spontaneously in digestive fluids are called self-emulsifying drug delivery systems (SEDDS). They are characterized by an oil-based formulation in which the drug is dissolved or dispersed in a mixture of oil and surfactant (and sometimes co-surfactant), and instantly form an emulsion when water is added.

However, this method requires the mixing of a large amount of surfactant to incorporate water into the oil phase and emulsify it. Therefore, a method of encapsulating oil in the pores of porous silica is known as a method of emulsifying with a small amount of surfactant (see Non-Patent Document 1). When the porous silica particles are added to water, the oil is released as it penetrates into the water, forming an O/W emulsion.

It is also known that a freeze-dried solid preparation containing (a) an active pharmaceutical ingredient (API), (b) a gelling agent, and (c) a bioadhesive polymer uses poloxamer 407 or the like as the gelling agent and a cellulose derivative or the like as the bioadhesive polymer (see Patent Document 1).

The porous silica particles of Non-Patent Document 1 are useful as a self-emulsifying composition using a small amount of surfactant, but have problems such as a large amount of oil remaining in the silica particles, low emulsification efficiency, and insoluble silica particles remaining in water after emulsification.
The freeze-dried preparation in Patent Document 1 is in the form of porous particles, but the API is contained inside the porous particles, and poloxamer 407 is a gelling agent that swells with the solvent when it comes into contact with water or saliva in the oral cavity, providing a large adhesive surface and ensuring the time required for the drug to permeate through the mucous membrane. In addition, the cellulose derivative also adheres the freeze-dried preparation to a specific position on the mucous membrane in the oral cavity, and there is no specific description or suggestion of spontaneous emulsification.

Special Publication No. 2010-523678

Journal of Oleo Science, 2018, 67(3), 303-306.

In consideration of the above problems, the present invention aims to provide a spontaneously emulsifying composition that has good emulsification efficiency even when a small amount of surfactant is used, and that can be adjusted according to use without leaving any insoluble matter after emulsification.

As a result of intensive research into solving the above problems, the inventors discovered that the above problems can be solved by using hydrophilic polymers as porous particles and absorbing lipophilic substances into the pores of the porous particles, thus completing the present invention.

That is, the present invention is as follows, which is specified by the following items.
[1] A step (I) of freeze-drying droplets of an aqueous hydrophilic polymer solution to prepare porous particles;
a step (II) of incorporating a lipophilic substance into the obtained porous particles;
A method for producing a spontaneously emulsifiable composition, comprising:
[2] A method for producing the spontaneously emulsifiable composition described in [1], characterized in that the freeze-drying in step (I) is spray freeze-drying.
[3] A method for producing a spontaneously emulsifiable composition according to [1] or [2], characterized in that step (II) is a step of impregnating the obtained porous particles with a lipophilic substance.
[4] A method for producing a spontaneously emulsifiable composition according to any one of [1] to [3], characterized in that the lipophilic substance comprises an oil or an oil-like substance.
[5] The method for producing the spontaneously emulsifiable composition according to any one of [1] to [4], characterized in that step (II) is a step of incorporating a lipophilic substance and a surfactant into the obtained porous particles.
[6] A method for producing a spontaneously emulsifiable composition according to any one of [1] to [5], characterized in that the spontaneously emulsifiable composition is a composition for oral or nasal ingestion.
[7] A spontaneously emulsifiable composition for preparation when used, comprising porous particles made of a hydrophilic polymer, and a lipophilic substance absorbed in the pores of the porous particles.
[8] The spontaneously emulsifiable composition according to [7], characterized in that the lipophilic substance comprises an oil or an oil-like substance.
[9] The spontaneously emulsifiable composition according to [7], characterized in that the lipophilic substance comprises an oil or an oil-like substance and a surfactant.
[10] The spontaneously emulsifiable composition according to any one of [7] to [9], which is a composition for oral or nasal ingestion.

The spontaneously emulsifiable composition of the present invention can be emulsified with a small amount of surfactant and has good emulsification efficiency. The spontaneously emulsifiable composition of the present invention leaves no insoluble matter after emulsification, so it can be used in vivo without leaving any solid residue. The spontaneously emulsifiable composition of the present invention can be emulsified simply by adding it to the aqueous phase at the time of use, so it can be adjusted according to the purpose. The method for producing the spontaneously emulsifiable composition of the present invention can produce the spontaneously emulsifiable composition.

1A shows a scanning ion microscope photograph of the entire polymeric porous particle 1 obtained in Example 1. FIG. 1B shows a scanning ion microscope photograph of a cross section of the polymeric porous particle 1 obtained in Example 1. 1A shows a scanning ion microscope photograph of the entire polymeric porous particle 2 obtained in Example 1. FIG. 1B shows a scanning ion microscope photograph of a cross section of the polymeric porous particle 2 obtained in Example 1. 1A shows a scanning ion microscope photograph of the entire polymeric porous particle 3 obtained in Example 1. FIG. 1B shows a scanning ion microscope photograph of a cross section of the polymeric porous particle 3 obtained in Example 1. 1A shows a scanning ion microscope photograph of the entire polymeric porous particle 4 obtained in Example 1. FIG. 1B shows a scanning ion microscope photograph of a cross section of the polymeric porous particle 4 obtained in Example 1. 1A shows a scanning ion microscope photograph of the entire polymeric porous particle 5 obtained in Example 1. FIG. 1B shows a scanning ion microscope photograph of a cross section of the polymeric porous particle 5 obtained in Example 1. 1 shows the change in turbidity over time in the spontaneous emulsification evaluation-1 of Example 1. 1 shows the particle size distribution of emulsified particles in Evaluation-2 of spontaneous emulsification property of Example 1. 1 shows the change over time in the median size of emulsified particles in Evaluation-2 of spontaneous emulsification property of Example 1. 1 shows the particle size distribution of emulsified particles in Evaluation of spontaneous emulsification property-3 of Example 1. 1 shows the change over time in the median size of emulsified particles in Evaluation of spontaneous emulsification property-3 of Example 1. 1 shows the change in turbidity over time in the spontaneous emulsification evaluation 4 of Example 1. 1 shows the particle size distribution of emulsified particles in Evaluation of spontaneous emulsification property-5 in Example 1. 1 shows the change over time in the median size of emulsified particles in Evaluation of spontaneous emulsification property-5 in Example 1.

The spontaneously emulsifiable composition of the present invention is characterized by containing porous particles made of a hydrophilic polymer, and a lipophilic substance absorbed in the pores of the porous particles. Alternatively, the spontaneously emulsifiable composition of the present invention is used for preparation just before use. The spontaneously emulsifiable composition of the present invention can be emulsified with a small amount of surfactant, has good emulsification efficiency, and can be emulsified without using a surfactant.

The term "spontaneous emulsification" used in the present invention refers to the phenomenon in which emulsification occurs when different substances come into contact with each other without the application of external force, and is a concept that includes "self-emulsification."
"Self-emulsification" refers to the phenomenon of spontaneous emulsification due to the action of a surfactant.
The emulsifiable composition of the present invention has spontaneous emulsification properties since emulsification occurs when prepared just before use without using a surfactant.

Specific examples of hydrophilic polymers used in the spontaneously emulsifiable composition of the present invention 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); and thermoplastic polyalkylenes such as poly(ethylene oxide) and poly(propylene oxide). Examples of suitable hydrophilic colloids include hydrophilic colloids such as cellulose acetate oxide, polyacrylic acid, polymethacrylic acid, and methacrylic acid-methacrylic acid ester copolymers (e.g., Eudragit (registered trademark), Carbopol (registered trademark)), 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.

The step of preparing the porous particles made of a hydrophilic polymer is not particularly limited, but step (I) of preparing the 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 by applying pressure from the outlet of a thin tube. In order to obtain finer droplets, a preferred example of the method is atomization and spraying using a nozzle (nozzle method) or a disk (rotary atomizer method) used in a conventional spray drying method.

Freeze-drying droplets of the hydrophilic polymer aqueous solution refers to freezing the droplets of the hydrophilic polymer aqueous solution obtained as described above at 0° C. or lower, preferably −30° C. or lower, −70° C. or lower, or −100° C. or lower, and then drying the frozen droplets by removing water by sucking them under reduced pressure at 0° C. or lower, preferably −30° C. or lower.
The process of spraying droplets to form the porous particles used in the present invention and freeze-drying the formed droplets will be described in detail below.

The concentration and viscosity of the hydrophilic polymer aqueous solution must be within a range in which the hydrophilic polymer aqueous solution can be sprayed from an opening into the gas phase at a constant flow rate in the form of a homogeneous solution, and then the sprayed hydrophilic polymer aqueous solution can be turned into droplets of uniform size while being subjected to a constant periodic disturbance, and the formed droplets can then be cooled to solidify and freeze the hydrophilic polymer aqueous solution into granules.

For this reason, the concentration of the hydrophilic polymer in the aqueous hydrophilic polymer solution is preferably in the range of 0.1 to 50 w/v%, and more preferably in the range of 1 to 40 w/v%, 2 to 30 w/v%, 3 to 25 w/v%, 4 to 20 w/v%, or 5 to 15 w/v%.
If the concentration is less than 0.1 w/v%, when the droplets of the hydrophilic polymer aqueous solution are cooled and solidified, the strength of the droplets or droplets in the process of solidifying is poor, making it difficult to maintain the granular shape, and not only does it make operation such as transportation to the next step difficult, but also the amount of solvent is large, which may result in a large facility scale for each step. Also, if the concentration exceeds 50 w/v%, it may be difficult to dissolve the hydrophilic polymer and form droplets, making it difficult to form porous particles.

The viscosity of the hydrophilic polymer aqueous solution is preferably in the range of 200 to 1000 cP, and more preferably in the range of 400 to 1000 cP. If the viscosity is less than 200 cP, when the droplets of the hydrophilic polymer aqueous solution are cooled and solidified, the strength of the droplets or droplets in the process of solidifying is poor, making it difficult to maintain a granular shape, which may adversely affect operation such as transportation to the next process. On the other hand, if the viscosity exceeds about 1000 cP, it may become difficult to form uniform droplets from the hydrophilic polymer aqueous solution.

The temperature at which the hydrophilic polymer aqueous solution is sprayed is not particularly limited as long as it is within a range in which the hydrophilic polymer aqueous solution can maintain a homogeneous solution state and droplets can be formed and the shape of the coagulated product can be maintained, but is preferably in the range of -20°C to 120°C, and more preferably in the range of 10 to 80°C.

The flow rate when the hydrophilic polymer aqueous solution is sprayed from an opening into the gas phase varies depending on the aperture diameter of the opening, and is not particularly limited. For example, when the hydrophilic polymer aqueous solution is sprayed from an opening with an aperture diameter in the range of 0.5 to 1.6 mm, the flow rate is preferably in the range of 0.3 to 4.0 m/sec, and more preferably in the range of 0.5 to 2.5 m/sec. If the flow rate is less than 0.3 m/sec, not only is it difficult to form uniform droplets, but productivity may also decrease. Furthermore, if the flow rate exceeds 4.0 m/sec, the smooth flow region suitable for uniform droplets is no longer present, and fine droplets are generated by atomization, which may make it difficult to form uniform droplets.

It is preferable to apply vibration when the hydrophilic polymer aqueous solution is sprayed from the opening into the gas phase. This vibration is affected by the concentration and viscosity of the hydrophilic polymer aqueous solution, the flow rate when sprayed from the opening into the gas phase, the size of the opening, and the like. In the present invention, when attempting to obtain a granular coagulated material, a range of 50 to 600 Hz is usually required, and if it is less than 50 Hz or exceeds 600 Hz, it may be difficult to form uniform droplets. Of these, the range of 50 to 300 Hz is more preferable, and the range of 100 to 250 Hz is particularly preferable.

The openings are usually multiple holes provided in the center of multiple nozzles or nozzles in the device, and are generally circular in shape, with a hole diameter preferably in the range of 0.1 to 2.0 mm, more preferably in the range of 0.2 to 1.6 mm. The specific size and shape of the openings can be appropriately selected depending on the size of the polymeric porous particles to be obtained.

A case where a two-fluid nozzle is used as the nozzle will be described.
When a two-fluid nozzle is used, a spray gas is collided with the aqueous hydrophilic polymer solution to disperse the aqueous solution. Although air may be used as the spray gas, an inert gas such as nitrogen is preferably used.
The pressure of the spray gas colliding with the solution (spray pressure) is preferably in the range of 0.05 to 1 MPa, and more preferably in the range of 0.1 to 0.5 MPa. If the spray pressure is less than 0.05 MPa, the dispersion of the solution due to the collision of the spray gas may be insufficient, and the diameter of the obtained porous particles may be large. If the spray pressure is more than 1.0 MPa, the pressure when entering a cooling medium such as liquid nitrogen becomes high, and the particles may collapse, and sufficient pores may not be formed.
The flow rate of the atomizing gas is preferably in the range of 1 to 3 L/min, and more preferably in the range of 1.5 to 2.5 L/min.

The flow rate of the hydrophilic polymer aqueous solution supplied to the nozzle opening is preferably in the range of 100 to 1000 mL/h per hole, more preferably in the range of 150 to 500 mL/h. If the flow rate is less than 100 mL/h, the amount of porous carbon obtained per unit time decreases, and the production efficiency may decrease. If the flow rate is more than 1000 mL/h, the cooling by the cooling medium such as liquid nitrogen may be insufficient, and sufficient pores may not be formed.

Specific examples of the gas phase into which the hydrophilic polymer aqueous solution is ejected include nitrogen and air.
The distance that the droplets fly in the gas phase is not particularly limited when they are rapidly frozen in the cooled gas phase. In addition, the flight distance when the formed droplets are immersed in a cooling medium such as liquid nitrogen to solidify and freeze the hydrophilic polymer aqueous solution into particles, or more precisely, the distance from the opening from which the hydrophilic polymer aqueous solution is ejected to the cooling medium liquid surface, is not particularly limited as long as the droplets can be formed, but is usually preferably in the range of 0.2 to 5.0 m, more preferably in the range of 0.5 to 3.0 m. If the distance is less than 0.2 m, the formation of uniform droplets tends to become unstable, and if the distance exceeds about 5.0 m, the impact when the droplets fall on the cooling medium liquid surface becomes large, and it may be difficult for the solidified product to maintain a granular form.

As a cooling medium for solidifying the droplets of the hydrophilic polymer aqueous solution in the present invention, a solvent that is miscible with water and insoluble or poorly soluble in the hydrophilic polymer can be used, but it is preferable to use a cryogenic refrigerant such as liquid nitrogen, which can rapidly freeze the water and form porous particles. When using the above-mentioned solvent, it is necessary to penetrate the droplets and solidify them by rapid freezing, so a solvent with a relatively low surface tension and a low freezing point is preferable.

If spray drying is used instead of spray freeze drying as in the present invention, particles with a nanoscale phase separation structure containing water molecules are not formed, and porous particles may not be obtained.

In the present invention, after the droplets of the hydrophilic polymer aqueous solution are frozen, the frozen water is removed, preferably by freeze-drying.
The drying temperature, drying pressure, drying time, etc. are not particularly limited and can be appropriately selected depending on the purpose.
The drying temperature is preferably in the range of -196 to 0°C, more preferably in the range of -150 to -20°C, and more preferably in the range of -100 to -30°C.
The drying pressure is preferably in the range of 10 ⁻⁵ to 100 Pa, more preferably in the range of 0.01 to 30 Pa, and even more preferably in the range of 1 to 3 Pa.
The drying time is usually preferably in the range of 1 to 200 hours, more preferably in the range of 5 to 100 hours, and even more preferably in the range of 10 to 50 hours.

The median diameter of the polymeric porous particles 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, or 2 to 10 μm. The median diameter of the polymeric 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 polymeric porous particles is within the above range. If the median diameter of the polymeric porous particles is less than 0.5 μm, this means that the size of the droplets of the sprayed polymer aqueous solution is small, and the amount of water desorbed is small, so pores may not be formed sufficiently. If the median diameter of the polymeric porous particles is more than 30 μm, the surface area relative to the volume becomes small, and spontaneous emulsification may not occur smoothly.

The polymeric 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 in the range of 1.1 to 1.5, an average pore size in the range of 0.001 to 0.5 μm, a specific surface area in the range of 50 to 150 m ² /g, a porosity in the range of 5 to 50, a porosity in the range of 10 to 60%, and a spherical shape.
As described above, by using the preparation step (I) of the polymeric porous particles of the present invention, the particle size, pore density and solubility can be controlled by the type, concentration and spraying conditions of the polymer.

The spontaneously emulsifying composition of the present invention contains a lipophilic substance absorbed within the pores of the porous particles.
The lipophilic substance is not particularly limited as long as it is a substance that has the property of being easily dissolved in oil or a non-polar solvent, and specifically, preferred examples include oils and oil-like substances.

Specific examples of oils include apricot oil, almond oil, avocado oil, castor oil, coconut oil, cocoa butter, corn oil, cottonseed oil, grape seed oil, jojoba oil, linseed oil, corn oil, olive oil, palm oil, peanut oil, persil oil, poppy seed oil, rapeseed oil, sesame oil, soybean oil, sunflower oil, thistle seed oil, walnut oil, wheat germ oil, rice oil, beef tallow, lard, tall oil, and whale oil.

Specific examples of oil-like substances include linear saturated hydrocarbons; sorbitan esters; paraffin; polyether glycol esters; higher fatty acids such as stearic acid, myristic acid, palmitic acid, etc.; higher alcohols such as cetanol, stearyl alcohol, myristyl alcohol, etc.; substituted and/or unsubstituted monoglycerides such as glyceryl monostearate and glyceryl monooleate, substituted and/or unsubstituted diglycerides, and substituted and/or unsubstituted triglycerides; low-melting waxes such as yellow beeswax, white beeswax, carnauba wax, castor wax, Japan wax, and acetylate monoglycerides; poly(vinylpyrrolidone), acrylic polymers, etc.

When the spontaneously emulsifying composition of the present invention is used as a preparation in the fields of medicine, agrochemicals, functional foods, etc., it may further contain an active ingredient, such as abiraterone acetate, acitretin, allylestrenol, alpha-tocopherol, amidarone, aprepitant, atorvastatin, bexarotene, bromocriptine, candesartan, cinacalcet, clomiphene, diethylstilbestrol, dihomo-gamma-linoleic acid, ebastine, ergocalciferol, fenofibrate, fusidic acid, halofantrine, irbesartan, or isotretinoin. Examples of such pharmaceutical compounds include pharmaceutical compounds such as itraconazole, lapatinib, liraglutide, loratidine, nandrolone decanoate, nelfinavir, olmesartan, orlistat, posaconazole, probucol, raloxifene, ritonavir, tamoxifen, telmisartan, teprenone, tipranavir, valsartan, and zuclopenthixol; agricultural chemicals such as insecticides, herbicides, and pheromones; nutritional supplements such as nutritional supplements and medicinal herbs.
These active ingredients can be formulated by dissolving, emulsifying or suspending them in a lipophilic substance and absorbing them into polymeric porous particles.

When the active ingredient is not sufficiently dissolved in the lipophilic substance, it is preferable to use a surfactant. The surfactant to be used is not particularly limited, and any of anionic surfactants, cationic surfactants, nonionic surfactants, amphoteric surfactants, etc. can be used. Specific examples of such surfactants include anionic surfactants such as alkyl sulfates (sodium lauryl sulfate, etc.), fatty acid monocarboxylates (laurates, palmitates, etc.), polyoxyethylene alkyl ether carboxylates, N-acylsarcosine salts, N-acylamino acid salts (N-acylglutamates, etc.), dialkyl sulfosuccinates, alkanesulfonates (alkyl sulfonates), α-olefin sulfonates, linear alkyl benzene sulfonates, alkyl (branched) benzene sulfonates, N-methyl-N-acyltaurates, polyoxyethylene alkyl ether sulfates, alkyl phosphates, polyoxyethylene alkyl ether phosphates, polyoxyethylene alkyl phenyl ether phosphates, monoalkylamine salts, dialkylamine salts, trialkylamine salts, alkyl phosphates, polyoxyethylene alkyl ether phosphates, polyoxyethylene alkyl phenyl ether phosphates, etc. cationic surfactants such as trimethylammonium, dialkyldimethylammonium salts, and alkylbenzalkonium chloride; sorbitan fatty acid esters such as sorbitan monoisostearate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, diglycerol sorbitan penta-2-ethylhexyl acid, and diglycerol sorbitan tetra-2-ethylhexyl acid; polyoxyethylene (20) sorbitan monolaurate (polysorbate 20), polyoxyethylene (20) sorbitan monostearate (polysorbate 60), polyoxyethylene (20) sorbitan monooleate (polysorbate 80), and polyoxyethylene (20) sorbitan isostearate; polyethylene glycol monooleate, monolaurate, and polyoxyethylene (20) sorbitan fatty acid esters; Polyethylene glycol fatty acid esters such as polyethylene glycol urate; propylene glycol fatty acid esters such as propylene glycol monostearate; hydrogenated castor oil derivatives such as polyoxyethylene hydrogenated castor oil 40 (HCO-40), polyoxyethylene hydrogenated castor oil 50 (HCO-50), polyoxyethylene hydrogenated castor oil 60 (HCO-60), and polyoxyethylene hydrogenated castor oil 80; fatty acid alkanolamides such as lauric acid diethanolamide; glycerin alkyl ethers; alkyl glucosides such as lauryl glucoside and decyl glucoside; polyoxyethylene (20) oleyl ether, polyoxyethylene cetyl ether, and other polyoxyalkylene alkyl ethers; polyglycerin fatty acid esters, polyoxyethylene glycerin fatty acid esters, polyoxyalkylene fatty acid esters, and other polyoxyethylene glycerin fatty acid esters. Examples of such surfactants include glycerin fatty acid esters such as glyceryl esters and glyceryl monostearate, sugar fatty acid esters such as sucrose fatty acid esters and maltose fatty acid esters; sugar alcohol fatty acid esters such as maltitol fatty acid esters; nonionic surfactants such as polyoxyethylene lauryl alcohol ether; imidazolinium betaines such as 2-alkyl-N-carboxymethyl-N-hydroxyethyl-N-imidazolinium betaine; alkyl sulfobetaines such as lauryl sulfobetaine and lauryl hydroxysulfobetaine; acetate betaines such as lauryl dimethylaminoacetate betaine; coconut oil fatty acid amidoalkyl betaines such as coconut oil fatty acid amidopropyl betaine; and amphoteric surfactants such as long-chain alkyl imidazoline betaine salts such as sodium N-alkyl-1-hydroxyethyl imidazoline betaine.

Other surfactants include, for example, silicone-based surfactants such as polyoxyethylene-methylpolysiloxane copolymer, lauryl PEG-9 polydimethylsiloxyethyl dimethicone, and PEG-9 polydimethylsiloxyethyl dimethicone.

The amount of the surfactant used is not particularly limited and is appropriately set depending on the type of surfactant, the type and content of the active ingredient, the formulation form, the method of use, etc., but is preferably in the range of 0.1 to 20 mass %, more preferably in the range of 0.5 to 10 mass %, even more preferably in the range of 1 to 7.5 mass %, and particularly preferably in the range of 2 to 5 mass %, based on the total amount of the lipophilic substance.
Furthermore, by adding a surfactant to a lipophilic substance, it is expected that the particle size of the emulsified particles can be made smaller, and the spontaneously emulsifying composition of the present invention can be used even when the active ingredient is hydrophilic.

The spontaneously emulsified composition of the present invention is characterized in that the lipophilic substance is absorbed into the pores of the polymeric porous particles.
The step (II) of impregnating the obtained porous particles with an oleophilic substance is not particularly limited, but is preferably a step of impregnating the obtained porous particles with an oleophilic substance. Specific examples of the step include a method of immersing the particles in an oleophilic substance under normal pressure and incorporating the oleophilic substance into the pores by capillary action, a method of immersing polymeric porous particles in an oleophilic substance and placing the oleophilic substance under a pressure higher than normal pressure, and a method of placing polymeric porous particles under reduced pressure and introducing and immersing the oleophilic substance.
The step of incorporating a lipophilic substance into the polymeric 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.
The spontaneously emulsifiable composition of the present invention can be emulsified with a small amount of surfactant, and can maintain a stable fine emulsion for about 4 hours even without adding a surfactant to the lipophilic substance, which solves the problem of surfactants irritating mucous membranes, skin, etc. This is thought to be because, by making the hydrophilic polymer into porous particles, when added to the aqueous phase, the lipophilic substance forms oil droplets and is easily dispersed, and the dispersed oil droplets are stably maintained by the polymer that constitutes the dissolved porous particles. Therefore, the lipophilic substance can be emulsified without remaining in the porous particles, and the emulsification efficiency can be improved.

The spontaneously emulsifiable composition of the present invention can be suitably used for preparation when needed. Usually, it can be stored as a stable solid, and can be easily made into an emulsion by simply contacting it with water when used. Since an emulsion is in a thermodynamically metastable state, it becomes unstable over time or under storage conditions, but the spontaneously emulsifiable composition of the present invention can be treated as a solid powder because it is formulated by impregnating a lipophilic substance into a polymeric porous particle. Then, it can be emulsified simply by adding it to the aqueous phase when used. Therefore, it can be stored in a stable state. When insoluble particles are used as a formulation, there is concern about the effect of solid residues on the living body depending on the administration site, but in the spontaneously emulsifiable composition of the present invention, since particles are formed from a hydrophilic component, no solid residues are left in the living body.
The spontaneously emulsifiable composition of the present invention can be used as an oral preparation as it is, but can also be put into a capsule to be used as a capsule preparation, or can be used together with a suitable excipient and binder to be used as a tablet.

The present invention will be described in more detail below using examples, but the technical scope of the present invention is not limited to the examples.

[Preparation of Porous Particles]
The prepared polymer aqueous solution was sprayed onto the surface of liquid nitrogen using a two-fluid nozzle (nozzle diameter: 0.4 mm) attached to a spray dryer (SD-100, manufactured by Tokyo Rikakikai Co., Ltd.). The liquid nitrogen was stirred with a magnetic stirrer to prevent condensation between droplets. The frozen droplets were freeze-dried (FD-1000, manufactured by Tokyo Rikakikai Co., Ltd.) to obtain polymer porous particles. The spraying conditions and freeze-drying conditions are summarized in Table 1. Polymer porous particles 1 to 5 obtained as described above are summarized in Table 2 by type of polymer and concentration of the polymer aqueous solution.
Photographs of the surfaces and cross sections of the obtained polymeric porous particles 1 to 5 taken with a scanning ion microscope (JEM-9320FIB, manufactured by JEOL Ltd.) are shown in FIGS. 1 to 5, respectively.

[Preparation of spontaneously emulsifiable composition]
The obtained polymeric porous particles were placed in a beaker, and 20 μL of soybean oil, or 20 μL of soybean oil and 4.7 mg of sucrose erucate (ER290, manufactured by Mitsubishi Chemical Foods Corporation) were added as a lipophilic substance per 20 mg of polymeric porous particles, and the mixture was left to stand in a desiccator for 24 hours to obtain spontaneously emulsifying compositions 1 to 7 in which the porous particles were impregnated with the lipophilic substance.

The spontaneously emulsifying compositions 1 to 7 obtained by the above manufacturing method are summarized in Table 3 according to the polymeric porous particles used and the presence or absence of sucrose erucate ester.

[Evaluation of spontaneous emulsification-1]
0.01 g each of the spontaneously emulsifying compositions 2 and 3 was added to 3 ml of phosphate buffered saline (PBS, pH = 7.4) and allowed to stand, and the optical density (OD) of the PBS containing the spontaneously emulsifying compositions was measured at 600 nm over time using a spectrophotometer (ASV11D, AS ONE Corporation) and evaluated as turbidity. The results are shown in Figure 6.

In addition, as Comparative Example 1, an aqueous solution was prepared by adding 0.01 g of the polymer of the polymeric porous particle 2 to 3 ml of PBS, and 10 μl of soybean oil containing 2.3 mg of sucrose erucate was added to the aqueous solution and allowed to stand, and the turbidity was determined by measurement in the same manner as above. The results are shown in FIG.
As is clear from FIG. 6, the spontaneously emulsifiable compositions 2 and 3 of the present invention instantly dissolved and finely emulsified after addition, and emulsification was completed in about 30 minutes.
In contrast, in Comparative Example 1, no emulsification occurred at all.

[Evaluation of spontaneous emulsification property-2]
The particle size distribution of the emulsified particles in the emulsion prepared in spontaneous emulsification evaluation-1 was measured using a laser diffraction particle size distribution analyzer (SALD-7100, manufactured by Shimadzu Corporation). The results are shown in FIG.
In addition, the particle size distribution meter was used to measure the change over time (1 minute, 30 minutes, and 4 hours after addition) in the median size of emulsified particles in the PBS solutions of spontaneously emulsifiable compositions 2 and 3 prepared in spontaneous emulsifiable evaluation-1. The results are shown in FIG.

Figures 7 and 8 show that the emulsion can be kept stable even without using a surfactant as a lipophilic substance.

[Evaluation of spontaneous emulsification - 3]
The particle size distribution and the change over time in the median size were measured for the spontaneously emulsifying compositions 1, 2, and 4 in the same manner as in spontaneous emulsifying property evaluation 2. The results are shown in Figs. 9 and 10.
9 and 10 show that the emulsified state can be kept stable regardless of the concentration of the aqueous polymer solution.

[Evaluation of spontaneous emulsification property-4]
For the spontaneously emulsifiable composition 5, the turbidity was measured in the same manner as in spontaneous emulsifiable evaluation-1, except that PBS (pH=7.4) and citrate phosphate buffer (pH=4.0) were used. The results are shown in FIG.
At pH 4, the polymeric porous particles did not dissolve, and therefore no emulsification occurred.

[Evaluation of spontaneous emulsification-5]
The particle size distribution and the change over time in the median size were measured for the spontaneously emulsifying compositions 5 and 6 in the same manner as in Evaluation of spontaneous emulsifying property-2. The results are shown in Figs. 12 and 13.
As is clear from Figs. 12 and 13, even when a surfactant was added as a lipophilic substance, the state of the emulsified particles did not change from that when no surfactant was added.

Table 4 shows the median diameter measurement results for each spontaneous emulsifying composition shown in Figures 8, 10, and 13 above.

The spontaneously emulsifiable composition of the present invention can be used in the pharmaceutical field as a preparation for improving the solubility in water and promoting mucosal absorption of poorly absorbed drugs, or as a minimally invasive administration method such as oral, nasal, or pulmonary administration.
Furthermore, it can be used in the fields of functional foods and cosmetics, where enhanced absorption into the body is required.

Claims (8)

A step (I) of freeze-drying droplets of the hydrophilic polymer aqueous solution to prepare porous particles;
a step (II) of incorporating a lipophilic substance into the obtained porous particles;
A method for producing a spontaneously emulsifiable composition, comprising: The method for producing the spontaneously emulsifiable composition according to claim 1, characterized in that the freeze-drying in step (I) is spray freeze-drying. The method for producing a spontaneously emulsifiable composition according to claim 1 or 2, characterized in that step (II) is a step of impregnating the obtained porous particles with a lipophilic substance. The method for producing the spontaneously emulsifiable composition according to any one of claims 1 to 3, characterized in that step (II) is a step of incorporating a lipophilic substance and a surfactant into the obtained porous particles. The method for producing the spontaneously emulsifying composition according to any one of claims 1 to 4, characterized in that the spontaneously emulsifying composition is a composition for oral or nasal intake. A spontaneously emulsifiable composition for preparation at the time of use , comprising porous particles made of a hydrophilic polymer and a lipophilic substance absorbed within the pores of the porous particles, and comprising no surfactant . 7. The spontaneously emulsifying composition of claim 6, wherein the lipophilic substance comprises an oil or an oil-like substance . The spontaneously emulsifying composition according to claim 6 or 7, characterized in that it is a composition for oral or nasal ingestion.