JP7151070B2 - Particles and method for producing same - Google Patents

Description

TECHNICAL FIELD The present invention relates to particles, a method for producing the same, and the like.

Particles made of polymers and having a certain mechanical strength have been developed for various applications. For example, such particles include lubricity imparting agents, toners, matting agents for paints, additives for light diffusion, anti-blocking agents for packaging materials, insulating fillers, crystal nucleating agents, fillers for chromatography, abrasives. , carriers for immunodiagnostic reagents, and spacers for liquid crystal displays. A particle's mechanical strength affects its durability. Particles with low mechanical strength are limited in their applications, and therefore the development of particles with a certain level of mechanical strength is desired.

Particles consisting of cellulose or its derivatives as a polymer have also been developed for various applications such as those mentioned above.

For example, Patent Document 1 describes (1) (i) mixing a cuprammonium solution containing cellulose with a coagulating liquid, (ii) neutralization and regeneration treatment using sulfuric acid, and (iii) treatment with a high-pressure homogenizer. , that cellulose particles with high mechanical strength could be produced (Examples 1-13), (2) such cellulose particles could be used as paints (Examples 14, 15), and (3) patent It is described that the particles described in Document 1 can be used for various applications as described above (industrial applicability).

Patent Document 2 discloses (1) (i) mixing of a cuprammonium solution containing cellulose and a coagulation liquid, (ii) neutralization and regeneration treatment using sulfuric acid, (iii) treatment with a high-pressure homogenizer, and (iv) ) By derivatization treatment of cellulose, water-insoluble and highly hydrophilic cellulose particles could be produced (Examples 1 to 15); (Example 16); Example 17) and (4) that the particles described in Patent Document 2 are useful as diagnostic reagents (industrial applicability).

Patent Document 3 discloses (1) (i) mixing of a cuprammonium solution containing cellulose and a coagulation liquid, (ii) neutralization and regeneration treatment using sulfuric acid, (iii) treatment with a high-pressure homogenizer, and (iv) ) that dyed cellulose particles could be produced by treatment with dyes (Examples 1 to 9), (2) antibodies were bound to stained cellulose particles by physical adsorption (performance evaluation 1), (3) stained cellulose (Examples 10 to 14), (4) covalently binding the antibody to the dyed cellulose particles to which the reactive active group was introduced (performance evaluation 2), and ( 5) It is stated that the particles described in Patent Document 3 are useful as labels for immunodiagnosis and immunochromatography (industrial applicability).

Patent Document 4 discloses that (1) gelatin particles containing an active ingredient (average particle diameter of about 5 μm) were prepared by dissolving the active ingredient in a gelatin solution and then spray-drying it by a spray drying method, and ( 2) The prepared gelatin particles are dispersed in a copolymer-containing solution, and then the dispersion is added dropwise to a surfactant (e.g., sorbitan monooleate)-containing solution while stirring, acetonitrile is evaporated, and the appropriate treatment ( (e.g., hexane treatment), biodegradable and absorbable microcapsules (average particle size: about 10 μm) containing an active ingredient were prepared. Also, US Pat. No. 5,300,001 describes the use of a surfactant (sorbitan monooleate) and residual organic solvent (hexane) in the preparation of particles.

In Patent Document 5, (1) nanoscale particles made of a highly hydrophobic hydrocarbon compound copolymer (e.g., styrene-acrylate copolymer) are stirred in an aqueous solution containing an active ingredient. , the preparation of particles with adsorbed active ingredients, (2) the need for neutralization in the preparation of the particles, and (3) particles with adsorbed active ingredients.

Patent Document 6 describes hydrophobic hydrocarbon compound copolymers called non-biodegradable polymers (e.g., copolymers of methacrylic acid and methacrylic acid methyl ester, and copolymers of vinyl chloride and vinyl acetate). Coalescing), long-acting nanoparticles containing sunscreen agents (active ingredients) encapsulated in an oily phase are described. In addition, Patent Document 6 describes a method for producing such nanoparticles by preparing an aqueous solution containing a condensate of ethylene oxide and propylene oxide, containing a hydrophobic hydrocarbon compound copolymer and a sunscreen agent (active ingredient). to prepare a nanocapsule dispersion by mixing with anhydrous alcohol, and then evaporating a portion of the alcohol and water in the prepared nanocapsule dispersion to prepare a colloidal dispersion (aqueous alcohol solution containing nanoparticles). is described.

Patent Document 7 describes preparation of polyvinyl alcohol particles (microcapsules having an average particle size of 50 to 500 μm) containing an active ingredient.

Patent Document 8 describes (1) particles (lyophilized powder having an average particle size of 50 to 3,000 nm) composed of a block copolymer in which a hydrophobic polymer block and a hydrophilic polymer block are bonded and containing an active ingredient. and (2) evaluating the encapsulation rate and release capacity of the active ingredient in the particles.

Patent Document 9 discloses that (1) a substantially homogeneous liquid composition containing an active ingredient and essential components of a volatile solvent, and optionally a hydrophilic polymer and a hydrophobic polymer was prepared by stirring, and (2) When the skin permeability of a substantially homogeneous liquid composition containing the essential ingredient and the polymer was evaluated, the % active ingredient in the epidermis was 0.8 to 2.1%, and ( 3) Skin permeability of a substantially homogenous liquid composition containing the essential ingredients but not the polymer was evaluated, and the % active ingredient in the epidermis was 2.5% ("no polymer ”) that the active ingredient % in the epidermis was improved under the conditions of

Patent Document 10 describes (1) preparation of an oral administration preparation containing nanoparticles and/or microparticles (e.g., particle size 10 nm to 1000 μm) in which an active ingredient is dispersed, (2) preparation of the oral administration preparation, which is difficult to (3) the ability to achieve high bioavailability by increasing the solubility of water-soluble therapeutic agents, targeting specific parts of the gastrointestinal tract (GIT), and/or reducing the first-pass effect; describes the use of aqueous surfactants in the preparation of

By the way, skin is a biological tissue to which pharmaceuticals, quasi-drugs and cosmetics are applied. The skin has a structure composed of the epidermis (the stratum corneum (stratum corneum), the stratum granulosum, the stratum spinosum and the stratum basale), the dermis, and the subcutaneous tissue. Although the skin tissue under the stratum corneum has hydrophilic properties (pH 6.8-7.5), the surface of the skin (stratum corneum) has lipophilic properties (pH 4.5-5.3). It is known that active ingredients (eg, water-soluble ingredients, hydrophobic ingredients) hardly permeate into the skin tissue in the stratum corneum and under the stratum corneum. For example, if an active ingredient can be permeated into the stratum corneum, it is considered that the active ingredient can be effectively utilized as cosmetics. In addition, if the active ingredient can be permeated into the skin tissue under the stratum corneum (e.g., basal layer), it is considered that the active ingredient can be effectively utilized as a quasi-drug (e.g., whitening agent, anti-wrinkle agent). . Furthermore, if an active ingredient can be permeated deep under the epidermis (eg, subcutaneous tissue), it is considered that the active ingredient can be easily utilized as a medicine. Therefore, there is a need to provide a means to allow permeation of active ingredients through the skin.

WO2008/084854 WO2009/123148 WO2011/062157 JP-A-4-36233 JP-A-3-63210 Japanese Patent Publication No. 6-502874 JP-A-2-293041 JP 2006-321763 A Japanese Patent Publication No. 2005-538095 Japanese Patent Publication No. 2016-539953

It is an object of the present invention to provide a means that allows permeation of active ingredients through the skin.

The inventors have conceived the use of defined particles composed of polymers for the permeation of active ingredients in the skin. As a result of intensive studies based on this idea, the present inventors succeeded in developing predetermined particles that enable a high degree of permeation of the active ingredient through the skin by a simple production method. Since the particles of the present invention can highly permeate biological tissues (e.g., skin) that have both lipophilic and hydrophilic properties, they are also highly permeable to other tissues that have only one of lipophilic or hydrophilic properties. It is expected to be possible.

None of the above-mentioned Patent Documents 1 to 3 teach or suggest the particles of the present invention and the method for producing the same. For example, the technical concept of the particles of the present invention is significantly different from the particles of the prior art mentioned above.
Specifically, any of the above prior art particles should maintain their particle shape when used in applications such as those described above. Indeed, US Pat. Nos. 6,000,000 and 6,000,001 disclose particles with a stable structure in which antibodies are covalently attached to the particles. The particles of the present invention, on the other hand, need not maintain their particle shape, but rather release the active ingredient upon disintegration of the particles.
In addition, in the above Patent Documents 2 and 3, the antibody is covalently bound to the particles, and as is clear from the fact that the antibody is treated so as not to be released from the particles, the present invention of releasing the active ingredient from the particles. does not disclose the technical idea of
Furthermore, as is clear from the fact that the particles of Patent Documents 2 and 3 are treated with antibodies after the production of the particles, antibodies are attached to the particle surfaces, and the particles contain the antibodies inside. It can be understood that, unlike the particles of the present invention, the particles do not contain antibodies inside. Focusing on the diagnostic application of the particles of US Pat. This is because when the particles contain antibodies, the antibodies cannot bind to the target substance, and the original purpose of immunoassay using the antibodies for diagnosis cannot be achieved.

The method for producing particles of the present invention is also significantly different from the methods for producing particles in Patent Documents 1-3.
Specifically, the methods of Patent Documents 1 to 3 all use copper that can be toxic to animals such as humans, and the produced particles can contain copper, so the produced particles are safe. It is thought that it is not suitable for products that require high quality and high quality (eg, pharmaceuticals, quasi-drugs, cosmetics). On the other hand, since the method of the present invention does not use copper and the produced particles cannot contain copper, the particles of the present invention obtained by such a method have the advantage of being highly safe and easy to meet high quality requirements. have
In addition, the methods of Patent Documents 1 to 3 all require neutralization and regeneration operations. Therefore, in the methods of Patent Documents 1 to 3, centrifugation and decantation must be repeated multiple times, and the operation is complicated. Furthermore, all of the methods of Patent Documents 1 to 3 require a high-pressure homogenizer treatment, an operation that requires strong energy, for the formation of particles. On the other hand, the method of the present invention has the advantage that the particles can be easily produced since the operations of neutralization and regeneration and operations requiring strong energy are not required.

In Patent Document 4 described above, since spray drying is used in the preparation of particles, microcapsules (that is, microscale particles) can be prepared. Preparation of nanoscale particles may be difficult due to their tendency to increase in size. In fact, although the examples state that microcapsules (average particle size about 10 μm) can be prepared, the preparation of nanoscale particles is not described. Especially for cellulosic particles, it cannot be said that nanoscale particles can be prepared in light of the lack of any demonstration of particle preparation regardless of particle size.
In addition, considering that the method of Patent Document 4 uses a surfactant (sorbitan monooleate) in the preparation of the particles and that the surfactant is not removed from the particles, the prepared particles have It is considered that the surfactant is mixed. However, contamination with a surfactant is not desirable in terms of application to a living body (eg, skin) because it may accompany irritation caused by the surfactant.
Furthermore, since hexane is used in the preparation of particles in the method of Patent Document 4, it is believed that the final product is likely to be contaminated with hexane as a residual organic solvent. However, since hexane is suspected to be carcinogenic and there are various regulations (eg, wastewater standards, standards for residual organic solvents under the Industrial Safety and Health Act), it is desirable to avoid using hexane.

The above-mentioned Patent Document 5 describes that particles made of a highly hydrophobic hydrocarbon compound copolymer and an active ingredient are brought into contact with each other in an aqueous solution, and that the active ingredient is adsorbed to the particles. Also, considering that it is not shown that the active ingredient is contained inside the particles, it cannot be said that the particles of Patent Document 5 contain the active ingredient inside the particles. In particular, with regard to cellulosic particles, in light of the fact that the preparation of particles has not been demonstrated, it cannot be said that particles containing an active ingredient inside the particles can be prepared.
In addition, in the method of Patent Document 5, since the salt tends to remain in the particle-containing solution due to neutralization during preparation of the particles, the electrostatic repulsive force of the prepared particles is weakened by the salt, making it easier for the particles to aggregate. Also, it is thought that when an emulsion is prepared using these particles, the high salt concentration tends to cause demulsification.
Furthermore, Patent Document 5 describes that the particles are applied to the skin, but does not describe that the particles permeate the skin.

In light of the fact that the above-mentioned Patent Document 6 does not demonstrate any preparation of cellulosic particles, it cannot be said that nanoscale cellulosic particles can be prepared.
In addition, since Patent Document 6 describes encapsulation of the oily phase, it does not describe that the water-soluble active ingredient is contained inside the particle, although the hydrophobic active ingredient may be contained inside the particle. not
Furthermore, Patent Document 6 only describes the difference in the effect (protection index) of nanoparticles depending on the presence or absence of a sunscreen agent, and does not show that nanoparticles have a skin permeation effect.

The above-mentioned US Pat. No. 6,200,000 does not describe the preparation of nanoscale particles. Especially for cellulosic particles, it cannot be said that nanoscale particles can be prepared in light of the lack of any demonstration of particle preparation regardless of particle size.

The above-mentioned US Pat. No. 6,200,000 does not describe the preparation of particles of non-block copolymers, particularly cellulosic particles.
Moreover, Patent Document 8 does not describe that the particles permeate the skin.

The above-mentioned US Pat. No. 6,200,000 does not describe the preparation of particles, in particular nanoparticles and cellulosic particles.
In addition, in light of the fact that the active ingredient % in the epidermis was improved under the condition of "no polymer" in Patent Document 9, it can be said that the use of a polymer is not desired for skin permeation.

The above-mentioned Patent Document 10 describes preparation of particles having a wide range of particle diameters (10 nm to 1000 μm). A specific method (eg, types and amounts of components and solvents, processing conditions such as stirring conditions) for preparing particles with diameters on a particular scale (eg, nanoscale) is also not described.
In addition, Patent Document 10 does not describe external use of the particles (eg, cosmetics).
Furthermore, considering that in US Pat. presumably mixed. However, contamination with an aqueous surfactant may be accompanied by irritation (eg, rough skin) due to the aqueous surfactant, which is not desirable in terms of application to the living body (eg, skin).

As described above, the present inventors have succeeded in developing the following particles of the present invention, which can be greatly different from the particles of the prior art in terms of technical concept and manufacturing method, and have completed the present invention.

That is, the present invention is as follows.
[1] Particles having the following properties:
(a) comprising a cellulose derivative and an active ingredient;
(b) the active ingredient is contained inside the particles; and (c) the volume distribution average particle size is 1-1000 nm.
[2] The particles of [1] having one or more properties selected from the group consisting of (i) to (iii) below:
(i) the contact angle of water on the particle film is 20-70 degrees;
(ii) the ratio of the contact angle of water on the particle film to the contact angle of water on the polystyrene substrate is within the range of 0.2 to 0.9;
(iii) The absolute value of mobility by electrophoresis is 2 μm cm/Vs or more.
[3] The particles of [1] or [2], wherein the particles contain a mixture of two or more cellulose derivatives.
[4] The cellulose derivative is a cellulose derivative having a substituent of R- or RC(=O)- (wherein R represents an optionally substituted hydrocarbon group) [1 ] to [3].
[5] The particles of [4], wherein the cellulose derivative is hydroxypropyl cellulose, ethyl cellulose, hypromellose or an ester derivative thereof.
[6] The particles of any one of [1] to [5], which contain a mixture of a cellulose derivative and a polymer other than the cellulose derivative.
[7] The particles of [6], wherein the polymer other than the cellulose derivative is a polymer containing an optionally substituted divalent hydrocarbon group as a monomer unit.
[8] The particle of [7], wherein the optionally substituted divalent hydrocarbon group is optionally substituted alkylene.
[9] The particles of [8], wherein the optionally substituted alkylene is optionally substituted ethylene.
[10] The particles of any one of [6] to [9], wherein the polymer other than the cellulose derivative is a methacrylic acid copolymer.
[11] The particles of any one of [3] to [10], wherein the mixture is a mixture of a hydrophilic polymer and a hydrophobic polymer.
[12] The particles of any one of [1] to [11], wherein the active ingredient is a low-molecular-weight compound.
[13] The particles of any one of [1] to [12], wherein the amount of active ingredient is 0.01 to 80% (wt) with respect to the weight of the particles.
[14] The particles of any one of [1] to [13], wherein the amount of active ingredient is 0.1 to 15% (wt) with respect to the weight of the particles.
[15] A biological tissue permeation agent as an active ingredient, comprising the particles of any one of [1] to [14].
[16] The agent of [15], wherein the living tissue is skin.
[17] The agent of [15] or [16], wherein the living tissue is stratum corneum.
[18] A method for producing particles,
(i) an organic solvent containing a cellulose derivative and (ii) an aqueous solution are mixed to form a W/O dispersion as a mixture of the organic solvent and the aqueous solution to precipitate the particles;
The active ingredient is contained in an organic solvent or aqueous solution,
A method wherein the particles have the following properties:
(a) comprising a cellulose derivative and an active ingredient;
(b) the active ingredient is contained inside the particles; and (c) the volume distribution average particle size is 1-1000 nm.
[19] The method of [18], wherein the aqueous solution contains an active ingredient.
[20] (i′) an organic solvent containing the first polymer and (ii′) an aqueous solution containing both the active ingredient and the second polymer are mixed to form a W/O type dispersion. The method of [19], comprising precipitating the particles by mixing as follows.
[21] The method according to any one of [18] to [20], wherein the mixing is performed under conditions in which the state of the mixed liquid changes from an O/W type dispersion to a W/O type dispersion.

The particles of the present invention allow active ingredients such as water-soluble ingredients to permeate biological tissues such as skin (eg, stratum corneum).

FIG. 1 shows a scanning electron micrograph of the particles obtained in Example 1 (see Example 1). FIG. 2 is a scanning electron micrograph of the particles prepared in Example 3 after air drying (see Test Example 3).

The present invention provides particles having the following properties:
(a) comprising a cellulose derivative and an active ingredient;
(b) the active ingredient is contained inside the particles; and (c) the volume distribution average particle size is 1-1000 nm.

The particles of the present invention may contain only one type of cellulose derivative as a polymer, but may be a mixture of two or more (eg, two, three, four or five) types of polymers containing a cellulose derivative. may Therefore, the particles of the present invention may be a mixture of two or more cellulosic derivatives, or a mixture of cellulosic derivatives and polymers other than cellulosic derivatives (hereinafter sometimes referred to as non-cellulosic polymers).

The polymer contained in the particles of the present invention is not particularly limited as long as it has any weight-average molecular weight capable of stabilizing the morphology of the particles of the present invention. More preferably 30,000 or more, still more preferably 40,000 or more. The weight average molecular weight is also, from the viewpoint of availability of materials, for example, 1,000,000 or less, 800,000 or less, 600,000 or less, 400,000 or less, 300,000 or less, or 200,000 It may be below.

In the present invention, a cellulose derivative indicates a cellulose having a substituent. Therefore, cellulose derivatives do not include cellulose itself without substituents. In the cellulose derivative, not all monomer units (glucose) need to have a substituent, and only a part of the monomer units have a substituent. In cellulose derivatives, hydrogen atoms in monomer units are substituted with substituents. The number of substituents in a monomer unit is 1-5, preferably 1-3, more preferably 1 or 2.

In a preferred embodiment, the cellulose derivative is hydroxyalkylcellulose, hydroxycellulose, carboxyalkylcellulose, carboxycellulose, alkylcellulose, or hydroxyalkylalkylcellulose, cationized cellulose, hydrophobized cellulose, or ester derivatives thereof, or salts thereof. is.

Salts include, for example, metal salts, acid addition salts, and salts with bases. Metal salts include, for example, salts with monovalent metals (eg, sodium and potassium) and salts with divalent metals (eg, calcium and magnesium). Acid addition salts include, for example, salts with inorganic acids (e.g., hydrogen chloride, hydrogen bromide, sulfuric acid, and phosphoric acid), and organic acids (e.g., acetic acid, lactic acid, citric acid, tartaric acid, maleic acid, fumaric acid). , and monomethyl sulfate). Examples of salts with bases include salts with inorganic bases (e.g., ammonia) and salts with organic bases (e.g., ethylenediamine, propylenediamine, ethanolamine, monoalkylethanolamine, dialkylethanolamine, diethanolamine, triethanolamine). salt of As the salt, a metal salt is preferred.

Alkyl in hydroxyalkyl cellulose, carboxyalkyl cellulose, and alkyl cellulose is the same as alkyl which is an example of a monovalent hydrocarbon group described later, and the preferred range is also the same. The two alkyl groups in the hydroxyalkylalkyl cellulose may be the same or different, and are the same as the alkyls that are examples of the above monovalent hydrocarbon groups, and the preferred ranges are also the same.

Hydroxyalkyl celluloses include, for example, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxybutyl cellulose, hydroxypentyl cellulose, and hydroxyhexyl cellulose.

Carboxyalkyl celluloses include, for example, carboxymethyl cellulose, carboxyethyl cellulose, carboxypropyl cellulose, carboxybutyl cellulose, carboxypentyl cellulose, and carboxyhexyl cellulose.

Alkyl celluloses include, for example, methyl cellulose, ethyl cellulose, propyl cellulose, butyl cellulose, pentyl cellulose, and hexyl cellulose.

Hydroxyalkylalkylcellulose is cellulose with both hydroxyalkyl and alkyl. Examples of hydroxyalkylalkylcelluloses include celluloses having hydroxymethyl and alkyl (e.g., hydroxymethylmethylcellulose, hydroxymethylethylcellulose, hydroxymethylpropylcellulose, hydroxymethylbutylcellulose), celluloses having hydroxyethyl and alkyl (e.g., hydroxyethyl methylcellulose, hydroxyethylethylcellulose, hydroxyethylpropylcellulose, hydroxyethylbutylcellulose), celluloses with hydroxypropyl and alkyl (e.g., hydroxypropylmethylcellulose (hypromellose), hydroxypropylethylcellulose, hydroxypropylpropylcellulose, hydroxypropylbutylcellulose), Celluloses with hydroxybutyl and alkyl (eg, hydroxybutylmethylcellulose, hydroxybutylethylcellulose, hydroxybutylpropylcellulose, and hydroxybutylbutylcellulose) are included.

Cationized cellulose refers to cellulose having a cationic group or a cellulose derivative having a cationic group. Cationic groups include, for example, trialkylammonium. The three alkyls in the trialkylammonium may be the same or different, and are the same as the alkyls described later, and the preferred ranges are also the same.

Hydrophobized cellulose refers to cellulose having a hydrophobic group or a cellulose derivative having a hydrophobic group. Hydrophobized cellulose includes, for example, acetylated cellulose.

In the ester derivative, the hydrogen atom in the hydroxy in the cellulose derivative is substituted with R—C(═O)—(R represents an optionally substituted monovalent hydrocarbon group.) to form an ester moiety. It is a derivative that forms The monovalent hydrocarbon group represented by R is the "monovalent hydrocarbon group" in the "monovalent hydrocarbon group optionally having substituent(s)" represented by R ₁ to R ₃ as described later. and the preferred ranges are also the same. The number of carbon atoms in the monovalent hydrocarbon group does not include the number of carbon atoms in the substituent. When the monovalent hydrocarbon group is substituted, the substituent is the same as the secondary substituent described later, and the preferred range is also the same.

The non-cellulose polymer that can be contained in the particles of the present invention is not particularly limited as long as it can stabilize the morphology of the particles of the present invention. Composed heteropolymers (eg, random copolymers, alternating copolymers, block copolymers, graft copolymers, comb copolymers). Such polymers are also linear polymers in which the main chain is linear, or branched polymers in which the main chain is non-linear (e.g. graft polymers, comb polymers, hyperbranched polymers, ladder polymers), but Linear polymers are preferred.

Monomer units constituting the non-cellulose polymer that can be contained in the particles of the present invention include, for example, optionally substituted divalent hydrocarbon groups, optionally substituted saccharides, and optionally substituted amino acids. , optionally substituted nucleotides.

Non-cellulosic polymers that can be included in the particles of the present invention are also natural (eg, microbial, plant or animal-derived polymers), semi-synthetic, or synthetic polymers. Natural polymers include, for example, polysaccharides (e.g. cellulose, guar gum, locust bean gum, quinseed gum, carrageenan, pectin, mannan, starch, agar, xanthan gum, succinoglycan, curdlan, hyaluronic acid, dextran), proteins (eg, gelatin, casein, albumin, collagen, alginic acid), polynucleotide chains (eg, DNA, RNA), and salts thereof. Semi-synthetic polymers include, for example, modified polysaccharides obtained by modifying the above polysaccharides [e.g., starch-based polymers (e.g., solubilized starch, carboxymethyl starch)], modified proteins obtained by modifying the above proteins [e.g., alginic acid-based polymer (eg, propylene glycol alginate)] and salts thereof. Examples of synthetic polymers include vinyl polymers, polyalkylene oxides [e.g., polyethylene oxide (PEO), polypropylene oxide (PPO), polybutylene oxide (PBO)], polyalkylene glycols [e.g., polyethylene glycol (PEG), polypropylene Glycols (PPG), polybutylene glycols (PBG), and copolymers thereof and salts thereof. Salts are as described above.

In the present invention, the X-based polymer (X indicates the name of the polymer) indicates X having a substituent. All of the monomer units of the X-based polymer do not need to have substituents, as long as some of the monomer units have substituents. In X-based polymers, hydrogen atoms in monomer units are substituted with substituents. The number of substituents in a monomer unit is 1-5, preferably 1-3, more preferably 1 or 2.

In the present invention, a Y-based polymer (where Y indicates the name of a monomer unit) indicates a polymer of Y in which part or all of Y, which is a monomer unit, has a substituent. For example, if Y is vinyl, vinyl polymers include vinyl polymers having substituents, but do not include vinyl polymers having no substituents. In the Y-based polymer, hydrogen atoms in Y are substituted with substituents. The number of substituents in Y is 1 to 5, preferably 1 to 3, more preferably 1 or 2.

Examples of substituents that X and/or Y have in the X-based polymer and/or Y-based polymer include the following;
(i) a halogen atom, carboxy, sulfo, cyano, nitro, mercapto, oxo, or guanidino;
(ii) R ₁ -, R ₁ -O-, R ₁ -C(=O)-, R ₁ -O-C(=O)-, or R ₁ -C(=O)-O-; or ( iii) NR ₂ R ₃ -, NR ₂ R ₃ -C(=O)-, NR ₂ R ₃ -C(=O)-O-, R ₂ -C(=O)-NR ₃ -, R ₂ - O—C(═O)—NR ₃ —.

In (i), the halogen atom includes, for example, a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

In (ii), R ₁ represents a hydrogen atom, an optionally substituted monovalent hydrocarbon group, or an optionally substituted monovalent heterocyclic group. In (iii), R ₂ and R ₃ are the same or different, and are a hydrogen atom, an optionally substituted monovalent hydrocarbon group, or an optionally substituted monovalent Indicates a ring group.

The "monovalent hydrocarbon group" in the "optionally substituted monovalent hydrocarbon group" includes, for example, a monovalent chain hydrocarbon group, a monovalent alicyclic hydrocarbon group, and monovalent aromatic hydrocarbon groups.

A monovalent chain hydrocarbon group means a hydrocarbon group composed only of a chain structure, and the main chain does not contain a cyclic structure. However, the chain structure may be linear or branched. Examples of monovalent chain hydrocarbon groups include alkyl, alkenyl, and alkynyl. Alkyl, alkenyl and alkynyl can be straight or branched.
The alkyl is preferably an alkyl having 1 to 12 carbon atoms, more preferably an alkyl having 1 to 6 carbon atoms, and still more preferably an alkyl having 1 to 4 carbon atoms. The above number of carbon atoms does not include the number of carbon atoms of substituents. Examples of alkyl having 1 to 12 carbon atoms include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl and decyl. , dodecyl.
Alkenyl is preferably alkenyl having 2 to 12 carbon atoms, more preferably alkenyl having 2 to 6 carbon atoms, and even more preferably alkenyl having 2 to 4 carbon atoms. The above number of carbon atoms does not include the number of carbon atoms of substituents. Examples of alkenyl having 2 to 12 carbon atoms include vinyl, propenyl and n-butenyl.
Alkynyl is preferably alkynyl having 2 to 12 carbon atoms, more preferably alkynyl having 2 to 6 carbon atoms, and even more preferably alkynyl having 2 to 4 carbon atoms. The above number of carbon atoms does not include the number of carbon atoms of substituents. Examples of alkynyl having 2 to 12 carbon atoms include ethynyl, propynyl and n-butynyl.
Alkyl is preferred as the monovalent chain hydrocarbon group.

A monovalent alicyclic hydrocarbon group means a hydrocarbon group that contains only an alicyclic hydrocarbon as a ring structure and does not contain an aromatic ring. may be However, it does not have to be composed only of alicyclic hydrocarbons, and may partially contain a chain structure. Examples of monovalent alicyclic hydrocarbon groups include cycloalkyl, cycloalkenyl, and cycloalkynyl, which may be either monocyclic or polycyclic.
As cycloalkyl, cycloalkyl having 3 to 12 carbon atoms is preferable, cycloalkyl having 3 to 6 carbon atoms is more preferable, and cycloalkyl having 5 to 6 carbon atoms is even more preferable. The above number of carbon atoms does not include the number of carbon atoms of substituents. Examples of cycloalkyl having 3 to 12 carbon atoms include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
As cycloalkenyl, cycloalkenyl having 3 to 12 carbon atoms is preferable, cycloalkenyl having 3 to 6 carbon atoms is more preferable, and cycloalkenyl having 5 to 6 carbon atoms is even more preferable. The above number of carbon atoms does not include the number of carbon atoms of substituents. Cycloalkenyl having 3 to 12 carbon atoms includes, for example, cyclopropenyl, cyclobutenyl, cyclopentenyl and cyclohexenyl.
As cycloalkynyl, cycloalkynyl having 3 to 12 carbon atoms is preferable, cycloalkynyl having 3 to 6 carbon atoms is more preferable, and cycloalkynyl having 5 to 6 carbon atoms is even more preferable. The above number of carbon atoms does not include the number of carbon atoms of substituents. Cycloalkynyl having 3 to 12 carbon atoms includes, for example, cyclopropynyl, cyclobutynyl, cyclopentynyl and cyclohexynyl.
Cycloalkyl is preferred as the monovalent alicyclic hydrocarbon group.

A monovalent aromatic hydrocarbon group means a hydrocarbon group containing an aromatic ring structure. However, it does not have to be composed only of aromatic rings, and may contain a chain structure or alicyclic hydrocarbon in part, and the aromatic ring may be monocyclic or polycyclic. good. The monovalent aromatic hydrocarbon group is preferably an aryl having 6 to 12 carbon atoms, more preferably an aryl having 6 to 10 carbon atoms, and still more preferably an aryl having 6 carbon atoms. The above number of carbon atoms does not include the number of carbon atoms of substituents. Examples of aryl having 6 to 12 carbon atoms include phenyl and naphthyl.
Phenyl is preferred as the monovalent aromatic hydrocarbon group.

Among these, the monovalent hydrocarbon group is preferably alkyl, cycloalkyl or aryl, more preferably alkyl.

The “monovalent heterocyclic group” in the “optionally substituted monovalent heterocyclic group” refers to a group obtained by removing one hydrogen atom from the heterocyclic ring of a heterocyclic compound. A monovalent heterocyclic group is a monovalent aromatic heterocyclic group or a monovalent non-aromatic heterocyclic group. The heteroatom constituting the heterocyclic group preferably contains one or more selected from the group consisting of an oxygen atom, a sulfur atom, a nitrogen atom, a phosphorus atom, a boron atom and a silicon atom, and an oxygen atom, a sulfur atom and a nitrogen atom. More preferably, it contains one or more selected from the group consisting of atoms.

The monovalent aromatic heterocyclic group is preferably an aromatic heterocyclic group having 3 to 15 carbon atoms, more preferably an aromatic heterocyclic group having 3 to 9 carbon atoms, and an aromatic heterocyclic group having 3 to 6 carbon atoms. Group heterocyclic groups are more preferred. The above number of carbon atoms does not include the number of carbon atoms of substituents. Monovalent aromatic heterocyclic groups include, for example, pyrenyl, pyrrolyl, furanyl, thiophenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolinyl, piperidinyl, triazonyl, purinyl, carbazonyl, fluorenyl, quinolinyl, and isoquinolinyl. . Pyrimidinyl, with the given substituents, constitutes the nucleobase, adenyl, or guanyl. Purinyl, with the given substituents, constitutes the nucleobases cytosyl, thyminyl, or uracil.

The monovalent non-aromatic heterocyclic group is preferably a non-aromatic heterocyclic group having 3 to 15 carbon atoms, more preferably a non-aromatic heterocyclic group having 3 to 9 carbon atoms, and 3 to 3 carbon atoms. 6 non-aromatic heterocyclic groups are more preferred. The above number of carbon atoms does not include the number of carbon atoms of substituents. Examples of monovalent non-aromatic heterocyclic groups include oxiranyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, dihydrofuranyl, tetrahydrofuranyl, dioxolanyl, tetrahydrothiophenyl, imidazolidinyl, oxazolidinyl, piperidinyl, dihydropyranyl, tetrahydro Pyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, piperazinyl, dihydrooxazinyl, tetrahydrooxazinyl, dihydropyrimidinyl, and tetrahydropyrimidinyl.

R ₁ , R ₂ and R ₃ are preferably a hydrogen atom or an optionally substituted monovalent hydrocarbon group, more preferably a hydrogen atom or an optionally substituted alkyl. preferable.

When a "monovalent hydrocarbon group" or "monovalent heterocyclic group" has a substituent, a hydrogen atom in the "monovalent hydrocarbon group" or "monovalent heterocyclic group" is substituted. The number of substituents in the "monovalent hydrocarbon group" or "monovalent heterocyclic group" is 1 to 5, preferably 1 to 3, more preferably 1 or 2.

Examples of substituents (also referred to as secondary substituents) that the "monovalent hydrocarbon group" and "monovalent heterocyclic group" may have include halogen atoms (e.g., fluorine atom, chlorine atom, bromine atom, iodine atom), carboxy, sulfo, cyano, nitro, mercapto, oxo, guanidino, hydroxy, alkyl, alkyloxy, alkylcarbonyl, alkyloxycarbonyl, alkylcarbonyloxy, alkyl mono- or disubstituted and amino-carbonyl optionally mono- or di-substituted with alkyl (eg amido). "Alkyl" in alkyl, alkyloxy, alkylcarbonyl, alkyloxycarbonyl, alkylcarbonyloxy, amino optionally mono- or di-substituted with alkyl, and amino-carbonyl optionally mono- or di-substituted with alkyl is It is the same as alkyl, which is an example of the above monovalent hydrocarbon group, and the preferred range is also the same.

In certain embodiments, the non-cellulosic polymer that may be included in a mixture with the cellulosic polymer in the particles of the present invention is a polymer containing optionally substituted divalent hydrocarbon groups as monomer units. Two or more (eg, two, three, four, or five) divalent hydrocarbon groups may be contained in one polymer.

The divalent hydrocarbon group is a straight-chain, branched-chain or cyclic divalent hydrocarbon group, preferably a straight-chain or branched-chain divalent hydrocarbon group. Examples of such divalent hydrocarbon groups include alkylene, alkenylene, alkynylene, and arylene.
As alkylene, alkylene having 1 to 12 carbon atoms is preferable, alkylene having 1 to 6 carbon atoms is more preferable, and alkylene having 1 to 4 carbon atoms is particularly preferable. The above number of carbon atoms does not include the number of carbon atoms of substituents. Alkylene may be linear, branched or cyclic, but linear alkylene is preferred. Such alkylenes include, for example, methylene, ethylene, propylene, butylene, pentylene, hexylene.
As alkenylene, alkenylene having 2 to 12 carbon atoms is preferable, alkenylene having 2 to 6 carbon atoms is more preferable, and alkenylene having 2 to 4 carbon atoms is particularly preferable. The above number of carbon atoms does not include the number of carbon atoms of substituents. Alkenylene may be linear, branched or cyclic, but linear alkenylene is preferred. Examples of such alkenylene include ethylenylene, propynylene, butenylene, pentenylene, and hexenylene.
As alkynylene, alkynylene having 2 to 12 carbon atoms is preferable, alkynylene having 2 to 6 carbon atoms is more preferable, and alkynylene having 2 to 4 carbon atoms is particularly preferable. The above number of carbon atoms does not include the number of carbon atoms of substituents. Alkynylene may be linear, branched or cyclic, but linear alkynylene is preferred. Examples of such alkynylene include ethynylene, propynylene, butynylene, pentynylene, and hexynylene.
As arylene, arylene having 6 to 18 carbon atoms is preferable, arylene having 6 to 14 carbon atoms is more preferable, and arylene having 6 to 10 carbon atoms is even more preferable. The above number of carbon atoms does not include the number of carbon atoms of substituents. Arylene includes, for example, phenylene and naphthylene.

Among these, straight-chain alkylene is preferable as the divalent hydrocarbon group.

Linear alkylene contained as a monomer unit is preferably vinyl (ethylene), propylene, or butylene, or a mixture thereof, from the viewpoint of versatility and/or availability as a polymer raw material.

An optionally substituted divalent hydrocarbon group means an unsubstituted divalent hydrocarbon group or a substituted divalent hydrocarbon group. When a divalent hydrocarbon group is substituted, a hydrogen atom in the divalent hydrocarbon group is substituted. The number of substituents in the divalent hydrocarbon group is 1-5, preferably 1-3, more preferably 1 or 2.

The substituents that the divalent hydrocarbon group may have are the same as the substituents (i) to (iii) above, and the preferred ranges are also the same.

Polymers containing optionally substituted divalent hydrocarbon groups as monomer units may contain only such divalent hydrocarbon groups as monomer units, or may contain such divalent hydrocarbon groups as monomer units. In addition to, other divalent groups may be included as monomer units. Examples of other divalent groups include -C(=O)-, -C(=O)-O-, -NR ₄ - (R ₄ represents a hydrogen atom or a substituent), -C( ═O)—NR ₄ — (R ₄ represents a hydrogen atom or a substituent), —PO ₂ —O—, and —PO(S)—O—.

The substituent represented by R ₄ is the “monovalent hydrocarbon group optionally having substituent(s)” represented by R ₁ to R ₃ or the “monovalent heterovalent hydrocarbon group optionally having substituent(s)” represented by R 1 to R 3 cyclic group”, and the preferred range is also the same. More preferably, the substituent represented by R ₄ is optionally substituted alkyl. The alkyl is preferably an alkyl having 1 to 12 carbon atoms, more preferably an alkyl having 1 to 6 carbon atoms, and still more preferably an alkyl having 1 to 4 carbon atoms. The above number of carbon atoms does not include the number of carbon atoms of substituents. Examples of alkyl having 1 to 12 carbon atoms include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl and decyl. , dodecyl. The substituents that alkyl may have are the same as the above secondary substituents, and the preferred ranges are also the same.

Preferably, the polymer containing an optionally substituted divalent hydrocarbon group as a monomer unit is a hydrocarbon chain polymer containing only such a divalent hydrocarbon group as a monomer unit. Examples of hydrocarbon chain polymers include vinyl (ethylene)-based polymers, propylene-based polymers, and butylene-based polymers.

More preferably, the polymer containing an optionally substituted divalent hydrocarbon group as a monomer unit is an alkylene polymer.

The alkylene-based polymer is preferably a vinyl (ethylene)-based polymer, a propylene-based polymer, a butylene-based polymer, or a copolymer thereof from the viewpoint of versatility and/or availability as a polymer raw material.

Preferably, the alkylene-based polymer is an alkylene polymer having substituents such as (i) to (iii) above.

More preferably, the alkylene-based polymer is a halogen atom (e.g., fluorine atom, chlorine atom, bromine atom, iodine atom), carboxy, sulfo, cyano, nitro, mercapto, oxo, guanidino, hydroxy, alkyl, alkyloxy, alkylcarbonyl , alkyloxycarbonyl, alkylcarbonyloxy, amino optionally mono- or di-substituted with alkyl (eg, amino), and amino-carbonyl optionally mono- or di-substituted with alkyl (eg, amido) It is an alkylene polymer having 1 to 5, preferably 1 to 3, more preferably 1 or 2 substituents selected from among the substituents. "Alkyl" in alkyl, alkyloxy, alkylcarbonyl, alkyloxycarbonyl, alkylcarbonyloxy, amino optionally mono- or di-substituted with alkyl, and amino-carbonyl optionally mono- or di-substituted with alkyl is It is the same as alkyl, which is an example of the above monovalent hydrocarbon group, and the preferred range is also the same.

In preferred embodiments, the alkylene-based polymer is a vinyl-based polymer. Examples of vinyl-based polymers include polymers containing one or more monomer units selected from the group consisting of vinyl alcohol, acrylic acid or its ester derivatives, methacrylic acid or its ester derivatives, and vinylpyrrolidone. Preferably, the vinyl-based polymer may be polyvinyl alcohol, polyacrylic acid or its ester derivative, polymethacrylic acid or its ester derivative, polyvinylpyrrolidone.

In the ester derivative, the OH group in the carboxy (C(=O)-OH) of the alkylene polymer is R'-O- (R' represents an optionally substituted monovalent hydrocarbon group. ) to form an ester moiety. The monovalent hydrocarbon group represented by R' is the same as the "monovalent hydrocarbon group" in the "monovalent hydrocarbon group optionally having substituent(s)" represented by R ₁ to R ₃ . and the preferred range is also the same. The number of carbon atoms in the monovalent hydrocarbon group does not include the number of carbon atoms in the substituent. When the monovalent hydrocarbon group is substituted, the substituent is the same as the above secondary substituent, and the preferred range is also the same.

A polymer containing an optionally substituted divalent hydrocarbon group as a monomer unit can be produced by any method known in the art. For example, since various divalent hydrocarbon groups are known, it is possible to obtain a target polymer containing a substituted divalent hydrocarbon group by appropriately polymerizing such divalent hydrocarbon groups. can be done.

In preferred embodiments, the particles of the invention comprise a mixture of two or more polymers. By including a mixture of two or more polymers, there is an advantage that the particle surface can be imparted with an appropriate degree of hydrophobicity while having a hydrophilic site that is well compatible with a hydrophilic substance inside the particle. Preferably, the mixture of two or more polymers is a mixture of two or more (eg 2, 3, 4 or 5) polymers comprising a hydrophilic polymer and a hydrophobic polymer.

In the present invention, a hydrophilic polymer refers to a polymer having a solubility of 1% (wt) or more in an aqueous solution (preferably water). For water-soluble polymers, the solubility in an aqueous solution (preferably water) is preferably 5% (wt) or more, more preferably 7% (wt) or more. Hydrophilic polymers include, for example, polymers containing, as monomeric units, saccharides substituted with hydroxyalkyl, hydroxy, carboxyalkyl, carboxy, or cationic groups. The alkyl in hydroxyalkyl and carboxyalkyl, and the polymer containing saccharide as a monomer unit are the same as those described above, and the preferred ranges are also the same. Specific examples of hydrophilic polymers include hydroxyalkylcellulose, hydroxycellulose, carboxyalkylcellulose, carboxycellulose, cationized cellulose, ester derivatives thereof, and and salts thereof.

Preferably, the hydrophilic polymer may be a hydrophilic polymer that easily migrates to an organic solvent. Hydrophilic polymers that easily migrate to organic solvents include , for example, polymers containing saccharides substituted with hydroxyalkyl, carboxyalkyl, or cationic groups as monomer units. The alkyl in hydroxyalkyl and carboxyalkyl, and the polymer containing saccharide as a monomer unit are the same as those described above, and the preferred ranges are also the same. Specific examples of hydrophilic polymers that easily migrate to organic solvents include hydroxyalkylcellulose, carboxyalkylcellulose, cationized cellulose, ester derivatives thereof, and and salts thereof.

For purposes of the present invention, a hydrophobic polymer refers to a polymer that has a solubility of less than 1% (wt) in an aqueous solution (preferably water). For water-soluble polymers, the solubility in an aqueous solution (preferably water) is preferably 0.1% (wt) or less, more preferably 0.01% (wt) or less. Hydrophobic polymers include, for example, polymers containing saccharides substituted with monovalent hydrocarbon groups as monomer units, and polymers containing optionally substituted divalent hydrocarbon groups as monomer units.

Preferably, the hydrophobic polymer is a polymer containing an alkyl-substituted saccharide as a monomer unit or an alkylene-based polymer from the viewpoint of material availability. Alkyl is the same as alkyl, which is an example of the above monovalent hydrocarbon group, and the preferred range is also the same. Specific examples of the hydrophobic polymer include alkyl cellulose, hydroxyalkylalkyl cellulose, hydrophobized cellulose, ester derivatives thereof, and salts thereof; and Vinyl (ethylene) based polymers, propylene based polymers, and butylene based polymers, and copolymers thereof.

The active ingredient is contained inside the particles. It has been confirmed that the active ingredient is contained in the particles of the invention even after multiple washings of the particles of the invention with the solution. The active ingredient contained in the particles of the present invention is the ingredient that is not covalently bound to the polymer and is free from the polymer. Active ingredients include, for example, low-molecular-weight compounds, polysaccharides, peptides, oligopeptides, polypeptides (e.g., enzymes, ligands, antibodies, extracellular matrix proteins), polysaccharides, polynucleotides (e.g., DNA, RNA, artificial nucleic acids). ), oligonucleotides (eg, oligoDNA, oligoRNA, oligonucleic acid). The term "low molecular weight compound" refers to a compound having a molecular weight of 1500 or less. Small compounds are natural or synthetic compounds. The molecular weight of the low molecular compound may be 1200 or less, 1000 or less, 900 or less, 800 or less, 700 or less, 600 or less, 500 or less, 400 or less, or 300 or less. The molecular weight of the small molecule compound may also be 30 or greater, 40 or greater, or 50 or greater. Low-molecular-weight compounds include, for example, amino acids, vitamins, nucleosides, nucleotides, oligonucleotides, monosaccharides, opioids, lipids, fatty acids, metabolites thereof, and salts thereof (e.g., metal salts as described above, acid addition a salt, or a salt with a base (the same shall apply hereinafter). Active ingredients also include pharmaceutical ingredients (e.g., therapeutic agents, preventive agents), ingredients for quasi-drugs (e.g., whitening ingredients, anti-wrinkle ingredients, rough skin improvement ingredients, hair growth ingredients), cosmetic ingredients (e.g., glycerin, etc.). alcohols, oils, extracts), food ingredients (eg nutritional ingredients), diagnostic ingredients (eg contrast agents), hair care ingredients (eg coloring agents), nail polish ingredients. The active ingredient contained in the particles of the present invention may be one kind, or a mixture of two or more kinds. The active ingredient can exist dispersed in a solution (aqueous solution or organic solvent) within the polymer particles. The particles of the present invention may also contain other ingredients such as additives (eg, preservatives such as methylparaben, antioxidants) in addition to the active ingredient.

The active ingredient may be a water-soluble ingredient or a hydrophobic ingredient. A water-soluble component as an active ingredient is a component that dissolves more easily in an aqueous solution (preferably water) than in an organic solvent used in the method for producing particles described below. A hydrophobic component as an active ingredient is a component that dissolves more easily in an organic solvent than in an aqueous solution (preferably water) used in the method for producing particles described below.

In preferred embodiments, the active ingredient is an amino acid, or salt thereof. Examples of amino acids include α-amino acids (e.g., alanine, asparagine, cysteine, glutamine, isoleucine, leucine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, aspartic acid, glutamic acid, arginine, histidine, lysine, , glycine), β-amino acids (eg, β-alanine, pantothenic acid), γ-amino acids (eg, γ-aminobutyric acid), δ-amino acids, ε-amino acids (eg, tranexamic acid). Amino acids may be in the L- or D-configuration.

In another preferred embodiment, the active ingredient is an oligopeptide, or salt thereof. Oligopeptides include, for example, dipeptides (eg, glutamyllysine, γ-glutamylcysteine), tripeptides (eg, glutamylvalylglycine, glutathione), tetrapeptides (eg, capixyl), and pentapeptides (eg, leuphacil). . Amino acids constituting an oligopeptide may be in the L-form or the D-form.

In yet another preferred embodiment, the active ingredient is a water-soluble or fat-soluble vitamin, or salt thereof. Water-soluble vitamins include, for example, vitamin B, vitamin C, and derivatives thereof. Examples of vitamin B include vitamin B1 (thiamine), vitamin B2 (riboflavin), vitamin B3 (eg, niacin, nicotinamide), vitamin B5 (eg, pantothenic acid, dexpanthenol, pantethine), vitamin B6 (eg, pyridoxine, pyridoxal phosphate, pyridoxamine), vitamin B7 (biotin), vitamin B9 (eg, folic acid, dihydrofolic acid, folinic acid), vitamin B12 (eg, cyanocobalamin, hydroxocobalamin, methylcobalamin, cobamamide). Vitamin B derivatives include, for example, thiamine disulfide, benfotiamine, fursultiamine. Vitamin C includes, for example, ascorbic acid and dehydroascorbic acid. Examples of vitamin C derivatives include ascorbic acid 2-glucoside (AA-2G), ascorbic acid phosphate, ethyl ascorbyl, ascopyrmagnesium phosphate, trisodium ascopylate phosphate, and ascobyl tetraisopalmitate (VC-IP). be done. Fat-soluble vitamins include, for example, vitamin D, vitamin E, vitamin K, vitamin A, and derivatives thereof.

In another preferred embodiment, other active ingredients include, for example, whitening ingredients (e.g., cysteine, vitamin C, vitamin C derivatives, tranexamic acid, arbutin, ceramide, kojic acid, ellagic acid), anti-wrinkle ingredients (e.g., ceramide), moisturizing ingredients (e.g. pyrrolidone carboxylic acid, 3-acetyl-2-ethoxycarbonyl-2-methyl-1,3-thiazolidine-4-carboxylate Na), hair growth ingredients (e.g. minoxidil), metabolism improving ingredients (e.g. , dihydroxycapsiate), and salts thereof.

The ratio of the weight of the active ingredient to the weight of the particles of the present invention (the total weight of the polymer and active ingredients that make up the particles of the present invention) depends on the type of the polymer and the active ingredient that make up the particles of the present invention, and the method for preparing the particles. Although it is not particularly limited, it is, for example, 0.01 to 80%. The ratio of the weight of the active ingredient to the weight of the particles of the invention is preferably 0.05-40%, more preferably 0.1-15%, even more preferably 0.2-14%, particularly preferably 0.2-14%. 5-12% or 1.0-10%. Alternatively, the concentration of the active ingredient inside the particles of the present invention is, for example, 0.01-50% (wt), preferably 0.02-40% (wt), more preferably 0.05-30% (wt). , and even more preferably from 0.1 to 20% (wt).
Determination of the weight of active ingredient can be done by any method known in the art. Such methods include, for example, methods using high performance liquid chromatography (HPLC) and spectrophotometers (eg, UV-VIS spectrophotometers). Alternatively, the concentration of the active ingredient can be evaluated from the concentration of the active ingredient in the aqueous solution containing the active ingredient, or the aqueous solution containing both the active ingredient and the second polymer, used in the production of the particles of the present invention.

The particles of the present invention also contain certain components such as surfactants (e.g. sorbitan monooleate), residual organic solvents (e.g. hydrocarbon compounds such as hexane), etc. (e.g. component) may be substantially free. The particles of the present invention can avoid the contamination of these components, since they do not essentially need to be used in their manufacturing process. In the particles of the present invention, the expression "substantially free" means that the particles of the present invention do not completely contain the predetermined component, or even if the particles of the present invention contain the predetermined component, 3. It means containing in an amount of 0% (wt) or less. Preferably, the expression "substantially free" means "completely free". With respect to the expression "substantially free", the particles of the present invention, when containing certain ingredients, are preferably 2.0% (wt) or less, more preferably 1.5% (wt) or less, even more preferably 1.5% (wt) or less. preferably 1.0% (wt) or less, particularly preferably 0.5% (wt) or less, 0.4% (wt) or less, 0.3% (wt) or less, 0.2% (wt) or It is contained in an amount of 0.1% (wt) or less. More specifically, the particles of the present invention are preferably substantially free of either surfactants or residual organic solvents, and more preferably substantially free of both surfactants and residual organic solvents. .

The particles of the present invention can also be produced by using acetone, an alcohol (eg, methanol), or an acetone-alcohol mixture, which may be rich in acetone, as the preferred organic solvent, as described below. Thus, the particles of the present invention may be substantially free of organic solvents other than acetone, alcohol, or acetone-alcohol mixtures. According to the method for producing particles of the present invention, such particles can be produced, but conventional methods for producing particles generally cannot produce such particles.

The particles of the present invention may contain other ingredients in addition to the active ingredient. Other ingredients include, for example, active ingredient stabilizers (eg, antioxidants), surfactants, dispersants, and antifoaming agents.

The particles of the present invention have a volume distribution average particle size of 1-1000 nm. The volume distribution average particle size is preferably 5 nm or more, more preferably 10 nm or more, still more preferably 20 nm or more, or 50 nm or more. The volume distribution average particle size is also preferably 900 nm or less, more preferably 800 nm or less.
The volume distribution average particle size can be measured by measuring the particle size distribution by laser diffraction. Preferably, the measurement of the particle size distribution by the laser diffraction method can be performed using a laser diffraction particle size distribution analyzer (ZetasizerNanoS manufactured by Malvern Instruments Ltd.).

The particles of the present invention may also have the property that the contact angle of water on the particle film is 20-70 degrees. If the contact angle of water on the particle membrane is 20 degrees or more, it is preferable because it has appropriate hydrophilicity and the distribution of the active ingredient to intercellular lipids in the stratum corneum is improved. In addition, if the contact angle of water on the particle membrane is 70 degrees or less, it is preferable because it has appropriate hydrophobicity and is compatible with intercellular lipids in the stratum corneum. The contact angle may be preferably 25 degrees or more, more preferably 30 degrees or more, even more preferably 35 degrees or more, and particularly preferably 40 degrees or more. The contact angle may also be preferably 65 degrees or less, more preferably 60 degrees or less, even more preferably 55 degrees or less, and particularly preferably 50 degrees or less. When calculating the ratio, the internal angle is measured as the contact angle.
The contact angle of water on the particle film can be measured as follows. First, a film of particles (particle film) of the present invention is obtained. For example, a solution containing the particles of the present invention is dropped onto a polystyrene substrate and air-dried at an appropriate temperature (eg, room temperature (27° C., etc.)) to completely cover the polystyrene substrate with the film of the particles of the present invention (particle film). ). Next, after dropping a water droplet of 20 μL on the particle film thus obtained, an image is taken from the side. The contact angle value is measured from the image.

The particles of the present invention may have the property that the ratio of the contact angle of water on the particle film to the contact angle of water on the polystyrene substrate is within the range of 0.2 to 0.9. If the said ratio is 0.2 or more, it can be said that it has moderate hydrophilicity with respect to the polystyrene substrate surface. In this case, it is considered that separation becomes difficult when blended into a formulation containing water. Therefore, it is preferable that the ratio is 0.2 or more. Moreover, if the said ratio is 0.9 or less, it can be said that it has moderate hydrophobicity. In this case, it is considered that separation becomes difficult when blended into formulations containing oil. Therefore, it is preferable that the ratio is 0.9 or less. The above ratio may be preferably 0.3 or more, more preferably 0.4 or more, even more preferably 0.5 or more. The ratio may also preferably be 0.8 or less, more preferably 0.7 or less, even more preferably 0.6 or less. When calculating the ratio, the internal angle is measured as the contact angle.
The contact angle of water on the particle film can be measured in the same manner as described above.
Measurement of the contact angle of water on a polystyrene substrate can be performed as follows. After dropping 20 μL of water droplets onto the polystyrene substrate, the contact angle value is measured by the same method as the measurement of the contact angle of water on the particle film.
Calculate the ratio of the contact angle of water on the particle film to the contact angle of water on the polystyrene substrate by dividing the contact angle value of water on the particle film by the contact angle value of water on the polystyrene substrate. be able to.

The particles of the present invention may also have the property of having an absolute value of electrophoretic mobility of 2 μmcm/Vs or more. If the absolute value is 0.22 μmcm/Vs or more, the particles do not have a complete gel-like surface and the active ingredient can be retained inside the particles, which is preferable. Therefore, the particles of the present invention have a well-bounded property rather than a gel-like surface. The absolute value of the mobility may be preferably 2.5 μmcm/Vs or more, more preferably 3.0 μmcm/Vs or more, and even more preferably 3.5 μmcm/Vs or more. The absolute value of the mobility may also preferably be 6.0 μmcm/Vs or less. If the absolute value is 6.0 μm cm / Vs or less, the particles do not have hard and medium-impermeable surface properties (e.g., surface properties of polystyrene particles), but when in contact with biological tissue such as the skin surface It is preferred because it has surface properties that allow it to release the active ingredient with the vehicle at the appropriate time. The absolute value may be more preferably 5.5 μmcm/Vs or less, still more preferably 5.0 μmcm/Vs or less.
Measurement of the electrophoretic mobility of the particles of the present invention by electrophoresis is carried out by analyzing the mobility of the particles of the present invention in a 1 mM NaCl aqueous solution using Zetasizer NanoS (manufactured by Malvern Instruments Ltd.). can be done.

The polymer particles may also be composite particles or non-composite particles. The term "composite particle" refers to a particle aggregate formed by the binding (eg, adsorption, adhesion) of two or more dissimilar particles. Such composite particles can be produced from two or more different particles by a predetermined method (eg, granulation method, particle composite method). On the other hand, non-composite particles are not such composite particles, and are not formed by bonding two or more different types of particles. Polymer particles can be suitably used in either the form of composite particles or non-composite particles. Moreover, since the desired properties can be sufficiently exhibited even in the form of non-composite particles, the form of non-composite particles can be preferably used.

Particles of the invention may also have a hard or soft surface. The particles of the present invention may also have a spherical, elliptical, golf ball, Janus particle, or other shape, but preferably have a spherical shape. These properties of the particles of the present invention can be confirmed by observing their appearance with a scanning electron microscope.

The particles of the invention also have high liquid stability. For example, the particles of the present invention can maintain the particle state without agglomeration even after being stored in a refrigerator (eg, 4° C.) for 6 months or longer, 12 months or longer, or 18 months or longer.

The particles of the invention can be powdered. Examples of powdering methods include freeze drying, spray drying, fluid bed granulation, stirring granulation, supercritical granulation, and natural drying. The particles of the present invention also have the property of being dispersible in a solvent (for example, the solvent described below, preferably an aqueous solution such as water) after pulverization.

The particles of the invention can be provided in liquid or powdered form. When the particles of the invention are provided in liquid form, the particles of the invention are provided as a solution containing the particles of the invention.
Solutions include, for example, aqueous solutions and organic solvents.
Aqueous solutions include, for example, water (eg, distilled water, sterile distilled water, purified water, physiological saline), and buffer solutions. Examples of buffers include phosphate buffer, Tris-hydrochloric acid buffer, TE (Tris-EDTA) buffer, carbonate-bicarbonate buffer, borate buffer, tartrate buffer, hydrochloric acid-potassium chloride buffer, glycine-hydrochloric acid buffer, glycine-sodium hydroxide buffer, citrate buffer, citrate-phosphate buffer, acetate buffer.
The organic solvent is the same as that described later, and the preferred range is also the same.
Preferably the solution is an aqueous solution, more preferably water.

The present invention also provides an active tissue-penetrating agent comprising the particles of the present invention. The agent of the present invention includes, for example, pharmaceuticals (e.g., therapeutic agents, preventive agents), quasi-drugs (e.g., whitening agents, anti-wrinkle agents, rough skin ameliorating agents, hair restorers), cosmetics, and foods (e.g., nutritional supplements). , diagnostic agents (eg, contrast agents), hair care products, and manicure products. Examples of biological tissue through which the agent of the present invention can permeate the active ingredient include skin tissue (eg, stratum corneum), oral cavity, digestive tract, eye, and ear and nose cavity. The agent of the present invention can be used either as an agent for parenteral administration (eg, an external agent) or an agent for oral administration. The agent of the present invention can be prepared by conventional methods into solid formulations such as powders, granules, capsules, tablets and chewable formulations, semi-solid formulations such as liniments and ointments, solutions, syrups, lotions, milky lotions, It can be formulated into liquids such as creams, injections, sprays, and the like.

The agent of the present invention may contain polymer particles of the same kind as the polymer particles, or may contain polymer particles of different types. The term "homogeneous polymer particles" refers to polymer particles that are similar in size and composition. Polymer particles that are produced under the same conditions (eg, similar types and amounts of components, and similar processing modes) can be considered homogenous polymer particles. On the other hand, the term "heterogeneous polymer particles" refers to polymer particles that differ in particle size and/or composition. Polymer particles that are produced under different conditions (eg, different in either the type and amount of ingredients and in the processing conditions) can be considered heterogeneous polymer particles. The agent of the present invention can sufficiently exhibit the desired properties even if it contains only polymer particles of the same type as polymer particles. Therefore, from the viewpoint of reducing the burden of preparing/obtaining particles, etc., it is preferable to: It may contain only homogenous polymer particles. Therefore, the agent of the present invention may preferably be free of polymer particles with an average particle size exceeding 1 μm.

The agent of the present invention can be applied to animals (preferably mammals such as humans). Although the dosage varies depending on the type, age, body weight, disease state, administration method, etc. of the target animal, it can be appropriately set according to the type of active ingredient contained in the particles of the present invention.

The agent of the present invention may also be added to the particles of the present invention, if necessary, with appropriate pharmaceutically acceptable carriers such as excipients, solvents, suspending agents, emulsifiers, tonicity agents, Stabilizers, preservatives, antioxidants, colorants and the like may be blended into formulations.

Examples of excipients that can be used include sugars such as lactose, glucose and D-mannitol, organic excipients such as celluloses such as crystalline cellulose, and inorganic excipients such as calcium carbonate and kaolin. can. Aqueous solutions such as purified water and physiological saline can be used as the solvent. Suspending or emulsifying agents include sodium lauryl sulfate, gum arabic, gelatin, lecithin, glyceryl monostearate, polyvinyl alcohol, polyvinylpyrrolidone, celluloses such as sodium carboxymethylcellulose, polysorbates, and polyoxyethylene hydrogenated castor oil. ingredients can be used. Components such as sodium chloride, potassium chloride, sugars, glycerin, and urea can be used as isotonic agents. Components such as polyethylene glycol, sodium dextran sulfate, and other amino acids can be used as stabilizers. Examples of preservatives that can be used include paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, and sorbic acid. Components such as sulfites and ascorbic acid can be used as antioxidants. As the coloring agent, coloring ingredients commonly used in the fields of medicine, cosmetics and foods can be used.

The invention also provides a method of making the particles of the invention. In the method of the present invention, (i) an organic solvent containing a cellulose derivative and (ii) an aqueous solution are mixed so as to form a W/O dispersion as a mixture of the organic solvent and the aqueous solution, thereby precipitating particles. including letting The active ingredient may be contained in either an organic solvent or an aqueous solution, or both, but is preferably contained in an aqueous solution.

In (i), the cellulose derivative contained in the organic solvent is not particularly limited as long as it is soluble in the organic solvent, but is preferably a hydrophobic polymer as described above. The amount of the cellulose derivative in the organic solvent is not particularly limited as long as the cellulose derivative can be dissolved in the organic solvent. wt), more preferably 0.2-10% (wt), even more preferably 0.3-7% (wt).

In (ii), the active ingredient and aqueous solution are the same as those described above. The amount of the active ingredient in the organic solvent or aqueous solution is particularly limited as long as the active ingredient can be dissolved in the organic solvent or aqueous solution and the amount of the active ingredient for the intended use of the particles of the present invention (e.g., medicine) can be achieved. but for example 0.01 to 50% (wt), preferably 0.02 to 40% (wt), more preferably 0.05 to 30% (wt), even more preferably 0.1 to 20% ( wt). As the active ingredient, both water-soluble ingredients and hydrophobic ingredients as described above can be used.

The organic solvent containing the cellulose derivative is dissolved in an aqueous solution (preferably an effective An aqueous solution containing components) is used that can be phase-separated by a cellulose derivative dissolved in an organic solvent. Examples of such organic solvents include ketone solvents (eg, acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl butyl ketone), ether solvents (eg, diethyl ether, tetrahydrofuran, diisopropyl ether, dioxane), alcohol solvents (eg, methanol , ethanol, propanol, butanol), aprotic polar solvents (e.g., N-methyl-2-pyrrolidone (NMP), dimethylsulfoxide (DMSO), N,N-dimethylformamide (DMF), N,N-dimethylacetamide ( DMA)), carboxylic acid solvents (e.g. formic acid, acetic acid, propionic acid, butyric acid, lactic acid), ester solvents (e.g. ethyl acetate, butyl acetate, butyl propionate, butyl butyrate), halogenated hydrocarbon solvents (e.g. chloroform, methylene chloride, carbon tetrachloride, dichloroethane, trichloroethane, chlorobenzene), non-aromatic hydrocarbon solvents (e.g. pentane, hexane, heptane, octane, cyclohexane, cyclopentane), aromatic hydrocarbon solvents (e.g. benzene , toluene, xylene), and mixtures thereof.

Preferably, the organic solvent is an organic solvent miscible with an aqueous solution (preferably water) from the viewpoint of efficiently producing the particles of the present invention. Organic solvents miscible with the aqueous solution include, for example, ketone solvents, ether solvents, alcohol solvents, aprotic polar solvents, carboxylic acid solvents, and ester solvents. In view of the use of organic solvents that are miscible with aqueous solutions but not azeotropic with water, preferred organic solvents are acetone, alcohols (eg, methanol), or acetone-alcohol mixtures, which may be enriched with acetone.

The temperature during mixing is not particularly limited as long as the organic solvent and the aqueous solution are in a liquid state, and is, for example, 5 to 50°C, preferably 15 to 40°C. The mixing time is not particularly limited as long as the particles of the present invention are formed, but is for example 5 to 60 minutes, preferably 15 to 30 minutes.

In one embodiment, the mixing to form a W/O dispersion is performed, for example, by slowly adding (I) (i) an organic solvent containing a cellulose derivative to (ii) an aqueous solution of It can be carried out. The active ingredient may be contained in either an organic solvent or an aqueous solution, or both, but is preferably contained in an aqueous solution. In this case, the state of the solution can be changed from the O/W type dispersion to the W/O type dispersion by increasing the amount of the organic solvent containing the cellulose derivative added. In this case, it has been confirmed that the particles of the invention are formed (see Examples 1-19). By inducing a change in solution state from an O/W dispersion to a W/O dispersion, the yield of the particles of the present invention can be increased.

In another embodiment, the mixing to form a W/O dispersion is performed, for example, by slowly adding (II)(ii) the aqueous solution to (i) the organic solvent containing the cellulose derivative. ,It can be carried out. The active ingredient may be contained in either an organic solvent or an aqueous solution, or both, but is preferably contained in an aqueous solution. In this case, (ii) the addition amount of the aqueous solution containing the active ingredient is kept lower than the amount of (i) the organic solvent containing the cellulose derivative, whereby the W/O type dispersion is changed to the O/W type dispersion. It can be set so that the state of the solution does not change (in other words, the state of the W/O type dispersion is maintained). In this case, it has been confirmed that the particles of the invention are formed (see Example 20).

In a preferred embodiment, the method of the present invention comprises (i′) an organic solvent containing the first polymer and (ii′) an aqueous solution containing both the active ingredient and the second polymer, W Precipitating the particles of the present invention by mixing to form a /O dispersion. In the method for producing the particles of the present invention, by using both the first polymer in the organic solvent and the second polymer in the aqueous solution, the particles of the present invention to be produced have properties of both water-soluble gel and hard. It has the advantage of being able to

Definitions, examples and preferred examples of the first polymer, the organic solvent, and the amount of the first polymer in the organic solvent in (i′) are the cellulose derivative, the organic solvent, and the cellulose in the organic solvent mentioned in (i). Similar to the amount of derivatives.

Definitions, examples and preferred examples of the active ingredient, the aqueous solution, and the amount of the active ingredient in the aqueous solution in (ii') are the same as those described in (ii).

In (ii'), the second polymer contained in the aqueous solution is not particularly limited as long as it is soluble in the aqueous solution, but is preferably a hydrophilic polymer as described above. The amount of the polymer in the aqueous solution is not particularly limited as long as the polymer can be dissolved in the aqueous solution. Preferably from 0.005 to 7% (wt), even more preferably from 0.01 to 5% (wt).

In certain preferred embodiments, said mixing to form a W/O dispersion comprises, for example, (I′) (i′) an organic solvent comprising the first polymer, (ii′) an active ingredient and It can be done by gradually adding to an aqueous solution containing both of the second polymers. In this case, the state of the solution can be changed from the O/W type dispersion to the W/O type dispersion by increasing the amount of the organic solvent containing the cellulose derivative added. In this case, it has been confirmed that the particles of the invention are formed (see Examples 1-19). By inducing a change in solution state from an O/W dispersion to a W/O dispersion, the yield of the particles of the present invention can be increased.

In another embodiment, the mixing to form a W/O dispersion comprises, for example, (II') (ii') an aqueous solution containing both the active ingredient and the second polymer, (i') It can be carried out by gradually adding to the organic solvent containing the first polymer. In this case, (ii′) the addition amount of the aqueous solution containing both the active ingredient and the second polymer is kept low compared to the amount of (i′) the organic solvent containing the first polymer, whereby the W/O type dispersion to an O/W dispersion (in other words, the W/O dispersion is maintained). In this case, it has been confirmed that the particles of the invention are formed (see Example 20).

The addition can preferably be effected dropwise. During the addition, the solution can be placed under stirring conditions. Stirring conditions can be appropriately set according to the amount of the solution. For example, it is 200-800 rpm (preferably 400 rpm) on a scale with a final liquid volume of about 45 mL, and 80-230 rpm on a scale with a final liquid volume of about 1 L.

EXAMPLES Next, the present invention will be described in more detail with reference to examples, but the present invention is not limited to the following examples.

[Example 1] Preparation of Particle 1 First, the following three kinds of solutions were prepared.
(1) Polymer liquid 1
Polymer liquid 1 was prepared by dissolving 0.4 g of ethyl cellulose (STD7FP manufactured by Dow Chemical Co., weight average molecular weight: 55,025) in 30 mL of acetone.
(2) Polymer liquid 2
Polymer liquid 2 was prepared by dissolving 0.1 g of hydroxypropyl cellulose (manufactured by Nippon Soda Co., Ltd., SL; weight average molecular weight: 100,000) in 15 mL of water.
(3) Active ingredient-containing liquid An active ingredient-containing liquid was prepared by dissolving 0.1 g of tranexamic acid (manufactured by Maruzen Pharmaceutical Co., Ltd.) in 1.5 mL of water.

Next, the active ingredient-containing liquid was added dropwise to the polymer liquid 2 stirred at 40° C. and 400 rpm to obtain a uniform liquid. Polymer liquid 1 was gradually added dropwise to this uniform liquid. During the addition of polymer liquid 1, the homogeneous liquid was stirred at 400 rpm. Dropping of the polymer liquid 1 caused the liquid to become cloudy, and the state of the suspension changed from an O/W type dispersion to a W/O type dispersion as the dropping amount increased. As a result, particles containing tranexamic acid, hydroxypropyl cellulose, and ethyl cellulose spontaneously and rapidly precipitated by dropping polymer liquid 1, and a suspension (W/O type dispersion) containing such particles was obtained. . This suspension was aspirated under reduced pressure while stirring to remove acetone, thereby obtaining a particle liquid dispersed in water. After that, the particle size distribution was evaluated with a laser diffraction particle size analyzer (ZetasizerNanoS, manufactured by Malvern Instruments Ltd.) (see Table 1 below).

Also, the obtained particles were photographed with a scanning electron microscope. A scanning electron micrograph is shown in FIG.

[Example 2] Preparation of particles 2 The amount of tranexamic acid in Example 1 was changed to 2.0 g, and tranexamic acid was added directly to polymer liquid 2 without preparing a solution in which tranexamic acid was dissolved in the active ingredient-containing liquid. A particle liquid was prepared in the same manner as in Example 1 except that polymer liquid 1 and polymer liquid 2 were used, and the particle size distribution was measured (see Table 1 below).

[Example 3] Preparation of particles 3 First, the following three types of solutions were prepared.
(1) Polymer liquid 1
Polymer liquid 1 was prepared by dissolving 8 g of ethyl cellulose (STD7FP manufactured by Dow Chemical Co., weight average molecular weight: 55,025) in 600 mL of acetone.
(2) Polymer liquid 2
Polymer liquid 2 was prepared by dissolving 2 g of hydroxypropyl cellulose (manufactured by Nippon Soda Co., Ltd., SL; weight average molecular weight: 100,000) in 300 mL of water.
(3) Active ingredient-containing liquid An active ingredient-containing liquid was prepared by dissolving 2 g of tranexamic acid (manufactured by Maruzen Pharmaceutical Co., Ltd.) in 30 mL of water.

Next, the active ingredient-containing liquid was added dropwise to the polymer liquid 2 being stirred at 40° C. and 230 rpm to obtain a uniform liquid. Polymer liquid 1 was gradually added dropwise to this uniform liquid. During the addition of polymer liquid 1, the homogeneous liquid was stirred at 400 rpm. Dropping of the polymer liquid 1 caused the liquid to become cloudy, and the state of the suspension changed from an O/W type dispersion to a W/O type dispersion as the dropping amount increased. As a result, particles containing tranexamic acid, hydroxypropyl cellulose, and ethyl cellulose spontaneously and rapidly precipitated by dropping polymer liquid 1, and a suspension (W/O type dispersion) containing such particles was obtained. . This suspension was aspirated under reduced pressure while stirring to remove acetone, thereby obtaining a particle liquid dispersed in water. After that, the particle size distribution was evaluated with a laser diffraction particle size analyzer (ZetasizerNanoS, manufactured by Malvern Instruments Ltd.) (see Table 1 below).

[Example 4] Preparation of Particle 4 The ethyl cellulose of Example 1 was added to hypromellose acetate succinate (Shin-Etsu Chemical Co., Ltd., AS-MG, weight average molecular weight: 18,000), and the acetone of polymer liquid 1 was added to methanol. A particle liquid was prepared and the particle size distribution was measured in the same manner as in Example 1, except that it was changed to (see Table 1 below).

[Example 5] Preparation of Particle 5 The same procedure as in Example 1 was repeated except that ethyl cellulose in Example 1 was changed to hypromellose phthalate (Shin-Etsu Chemical Co., Ltd., HP-55, weight average molecular weight: 84,000). A particle liquid was similarly prepared and the particle size distribution was measured (see Table 1 below). The hypromellose phthalate ester (HP-55) used has a pH solubility of ≧5.5 and a display viscosity of 40 mPa s [10% solution viscosity of a methanol/dichloromethane solution (1:1) at 20° C. (Japan Pharmacopoeia)] properties.

[Example 6] Preparation of Particle 6 A particle liquid was prepared in the same manner as in Example 1, except that the ethyl cellulose in Example 1 was changed to methacrylic acid copolymer S (S-100, manufactured by Evonik, weight average molecular weight: 125,000). were prepared and the particle size distribution was measured (see Table 1 below).

[Comparative Example 1] Preparation of Comparative Particle 1 Example 1 (3) Active ingredient-containing liquid (0.1 g of tranexamic acid dissolved in 1.5 mL of water) was changed to 1.5 mL of water. A particle liquid was prepared as in Example 1 and the particle size distribution was measured (see Table 1 below).

(Summary of results of Examples 1 to 6 and Comparative Example 1)
Table 1 shows the particle size distribution results measured in Examples 1 to 6 and Comparative Example 1.

[Example 7] Preparation of Particle 7 An experiment was conducted in the same manner as in Example 1, except that 0.1 g of tranexamic acid in Example 1 was changed to 0.01 g of Food Red No. 3 (manufactured by Hodogaya Chemical Industry Co., Ltd.). . As a result, formation of particles was confirmed.

Examples 8-11 Preparation of Particles 8-11 The experiment was conducted in the same manner as in Example 3, except that any one substance selected from the group consisting of Kasei Kogyo Co., Ltd. was changed. As a result, the formation of particles was confirmed when any substance was used.

[Examples 12 and 13] Preparation of particles 12 and 13 The tranexamic acid in Example 3 was changed to either L-valine (manufactured by Ajinomoto) or sodium L-glutamate (manufactured by Ajinomoto), and acetone was changed to methanol. An experiment was conducted in the same manner as in Example 3 except for the above. As a result, the formation of particles was confirmed when any substance was used.

[Example 14] Preparation of Particle 14 Same as Example 3 except that 2 g of tranexamic acid in Example 3 was changed to 4 g of pyrrolidone carboxylic acid (PCA) sodium salt 50% (wt) aqueous solution (NL-50, manufactured by Ajinomoto). and conducted an experiment. As a result, formation of particles was confirmed.

[Example 15] Examination of grade of hydroxypropyl cellulose An experiment was conducted in the same manner as in Example 7, except that the grade of hydroxypropyl cellulose (HPC) in Example 7 was changed as shown in Table 2 below. As a result, the formation of particles was confirmed (Table 2).

[Example 16] Examination of grade of ethyl cellulose An experiment was conducted in the same manner as in Example 7, except that the grade of ethyl cellulose (EC) in Example 7 was changed as shown in Table 3 below. As a result, the formation of particles was confirmed (Table 3).

[Example 17] Examination of grade of hypromellose acetate succinate The grade of hypromellose acetate succinate (Shin-Etsu Chemical Co., Ltd., AS-MG) in Example 4 was changed as shown in Table 4 below. was conducted in the same manner as in Example 4. As a result, formation of particles was confirmed.

[Example 18] Examination of grade of methacrylic acid copolymer Methacrylic acid copolymer S (manufactured by Evonik, S-100) of Example 6 was converted to methacrylic acid copolymer L (manufactured by Evonik, L100. Weight average molecular weight: 125,000). An experiment was conducted in the same manner as in Example 6, except that the conditions were changed. As a result, formation of particles with an average particle diameter of 747 nm was confirmed in methacrylic acid copolymer L (L100).

[Example 19] Examination of preparation of particles using one type of polymer (1) Use of organic solvent containing no hydrophobic polymer 0.1 g of tranexamic acid in Example 1 was ) The experiment was conducted in the same manner as in Example 1, except that the amount was 0.01 g and ethyl cellulose was not used. As a result, no particle formation was confirmed.
From the above, it was confirmed that particles were not formed when an organic solvent containing no hydrophobic polymer (non-polymer liquid instead of polymer liquid 1) and an aqueous solution containing a hydrophilic polymer (polymer liquid 2) were used. rice field.
(2) Use of aqueous solution containing no hydrophilic polymer 0.1 g of tranexamic acid in Example 1 was changed to 0.01 g of food red No. 3 (manufactured by Hodogaya Chemical Industry Co., Ltd.), and hydroxypropyl cellulose was not used. An experiment was carried out in the same manner as in Example 1. As a result, the formation of particles was confirmed (result of dynamic light scattering measurement: average particle size 217 nm).
From the above, it was confirmed that particles were formed when an organic solvent containing a hydrophobic polymer (polymer liquid 1) and an aqueous solution containing no hydrophilic polymer (non-polymer liquid instead of polymer liquid 2) were used. was done.

[Example 20] Preparation of particles without change in state from O/W type dispersion to W/O type dispersion ) The experiment was conducted in the same manner as in Example 1, except that the mixture of the polymer liquid 2 and the active ingredient-containing liquid was added dropwise to the polymer liquid 1 to 0.01 g. Under the present experimental conditions, a small amount of aqueous solution is added to a large amount of organic solvent, so the change in state from the O/W type dispersion to the W/O type dispersion confirmed in Example 1 does not occur. As a result, the formation of particles was confirmed without the change in the above state.

[Examples 21, 22, 23] Preparation of particles 15, 16, 17 In place of tranexamic acid in Example 1, methyl 4-hydroxybenzoate (methylparaben, manufactured by Junsei Chemical Co., Ltd.), minoxidil (manufactured by Tokyo Chemical Industry Co., Ltd.), or dihydroxy An experiment was conducted in the same manner as in Example 1, except that any active ingredient of capsiate (manufactured by Ajinomoto Co., Ltd.) was dissolved in polymer liquid 1 without preparing an active ingredient-containing liquid. As a result, the formation of particles was confirmed when any substance was used. It was also confirmed that particles containing an active ingredient can be obtained by dissolving the active ingredient in an organic solvent (polymer liquid 1) instead of an aqueous solution.

[Test Example 1] Epidermal model permeability evaluation 1
First, the particle liquid prepared in Example 3 was centrifuged at a centrifugal acceleration of 21500×g for 15 minutes in a centrifuge (CF-15RN, manufactured by Hitachi Koki Co., Ltd.), and the same amount of water as the removed supernatant was added. A washing operation for re-dispersing the particles was performed to obtain a purified particle liquid. A part of this purified particle liquid is centrifuged again to separate the washing liquid and the particles, and the liquid obtained by extracting tranexamic acid from the particle part with a high-speed chromatographic mobile phase containing methanol etc. is analyzed, and the tranexamic acid in the particles is analyzed. pre-determined amount. As a result, the amount of tranexamic acid relative to the weight of the particles was 6% (wt).

Next, the permeability was evaluated using a human three-dimensional cultured epidermis model in which human normal epidermal cells were overlaid and cultured. The donor side of a jacketed stationary Franz cell (manufactured by Permegia) in which a three-dimensional cultured epidermis model (manufactured by Japan Tissue Engineering Co., Ltd., Epi Model 12) is set, so that 0.2 mg of tranexamic acid is included. After 24 hours from placing the purified particle liquid, the concentration of tranexamic acid on the receiver side was measured with a high-speed chromatograph (H-CLASS, manufactured by Nippon Waters Co., Ltd.) to determine the amount of permeation (see Table 5 below).

[Test Example 2] Epidermal model permeability evaluation 2
The epidermal model permeability was evaluated in the same manner as in Test Example 1, except that the particle liquid prepared in Example 4 was used instead of the particle liquid used for centrifugal purification in Test Example 1 (see Table 5 below).

[Comparative Test Example 1] Epidermal model permeability evaluation 3
The epidermal model permeability was evaluated in the same manner as in Test Example 1, except that the purified particle liquid in Test Example 1 was changed to a 4 mg/mL tranexamic acid aqueous solution (see Table 5 below).

[Comparative Test Example 2] Epidermal model permeability evaluation 4
Epidermal model permeability was evaluated in the same manner as in Test Example 1, except that the particle liquid used for centrifugal purification in Test Example 1 was changed to the particle liquid prepared in Comparative Example 1, and 0.2 mg of tranexamic acid was added later. (See Table 5 below).

(Summary of results of Test Examples 1 and 2 and Comparative Test Examples 1 and 2)
Table 5 shows the results of the amount of permeation after 24 hours in Test Examples 1 and 2 and Comparative Test Examples 1 and 2.

[Test Example 3] Confirmation of Properties of Particles The particle liquid obtained in Example 3 was air-dried and observed with a scanning electron microscope. The surface of the particles obtained in Example 3 was found to be hard and , it was confirmed that the particles were spherical (Fig. 2).

In addition, 50 μL of the particle liquid obtained in Example 3 was dropped onto a polystyrene substrate and allowed to air dry at room temperature (25° C.) for 24 hours. The image was taken from the side by dripping water droplets. When the contact angle was measured from the image using image processing software image J, the contact angle (inner angle) of water on the particle film was 43.9 degrees. On the other hand, when 20 μL of water droplets were dropped on the polystyrene substrate and the contact angle was similarly measured, the contact angle (inner angle) of water on the polystyrene substrate was 78.4 degrees. Since the contact angle of water on the particle film showed a smaller value than the contact angle of water on the polystyrene substrate, the surface of the particles obtained in Example 3 had hydrophilic properties. confirmed.

Furthermore, the particles prepared in Example 3 were subjected to electrophoretic mobility measurements in 1 mM NaCl aqueous solution (Zetasizer NanoS, Malvern Instruments Ltd.). As a result, the mobility by electrophoresis was −4.1±0.12 μm cm/Vs. The large absolute value from 0 μmcm/Vs confirmed that the particles were not hydrophilic gel particles.

From the above results, it was confirmed that the particles prepared in Example 3 had both a hard surface like polystyrene particles and a soft gel-like surface like polyacrylamide or polyN,N isopropylacrylamide particles. was done. It was also confirmed that the particles, once formed, do not instantly dissolve and break even when dispersed in oil, an organic solvent, or water.

[Test Example 4] Evaluation of storability and cohesiveness of particles (1) Evaluation of storability under non-freezing conditions The particle liquids prepared in Examples 1 to 20 were refrigerated (4°C) for 1.5 years. The particle state was maintained without aggregation even after storage. Therefore, it was confirmed that the particles of the present invention are excellent in storage stability.
(2) Evaluation of Particle Dispersibility after Freeze-Drying The particle liquid prepared in Example 3 was agitated and sucked under reduced pressure to reduce the amount of water to 1/10, followed by freeze-drying to obtain a powder. It was confirmed that when this powder was again dispersed in water so that the solid content concentration was 3% (wt), the original particle liquid was obtained.
(3) Evaluation of particle dispersibility after spray drying The particle liquid prepared in Example 3 was agitated and vacuum-sucked to reduce water to 1/10, followed by spray drying (B-290 manufactured by Nippon Buchi Co., Ltd.) to obtain powder. Obtained. It was confirmed that when this powder was again dispersed in water so that the solid content concentration was 3% (wt), the original particle liquid was obtained.

[Test Example 5] Epidermal model permeability evaluation 5
Particles 15, 16, and 17 obtained as described above were evaluated for skin model permeability in the same manner as in Test Examples 1 and 2 and Comparative Test Examples 1 and 2. The results confirmed that these particles containing the active ingredient were more permeable in the epidermal model than a simple solution of the active ingredient.

[Comparative Examples 2 to 19] Preparation of Comparative Particles 2 to 19 0.4 g of ethyl cellulose in polymer liquid 1 of Example 7 was mixed with polylactic-co-glycolic acid block copolymer (PLGA5015, manufactured by Wako Pure Chemical Industries), cetanol (NAA-44 , NOF), white petrolatum (manufactured by Ogi Pharmaceutical), castor wax (manufactured by NOF), stearyl alcohol (NAA-45, manufactured by NOF), stearic acid (NAA-180P-1, manufactured by NOF), propylene glycol Caprylic acid ester (SEFSOL-218, manufactured by Nikko Chemicals), propylene glycol dicaprylic acid ester (SEFSOL-228, manufactured by Nikko Chemicals), lipophilic glyceryl monooleate (MGO, manufactured by Nikko Chemicals), lipophilic glyceryl monostearate (MGS-AMV, manufactured by Nikko Chemicals), lipophilic glyceryl monostearate (MGS-BMV, manufactured by Nikko Chemicals), polyethylene glycol distearate (CDS-6000P, manufactured by Nikko Chemicals), sucrose fatty acid ester (L-595, Mitsubishi Kagaku Foods), sucrose fatty acid ester (S-570, Mitsubishi Kagaku Foods), sucrose fatty acid ester (S-770, Mitsubishi Kagaku Foods), polyoxyl 40 stearate (NIKKOL MYS-40MV, Nikko Chemicals) , Cetomacrogol 1000 (NIKKOL BC-23, manufactured by Nikko Chemicals), polyoxyethylene (160) polyoxypropylene (30) glycol (Pronon #188, manufactured by NOF), povidone (K-30, manufactured by BASF), copolyvidone (VA64, manufactured by BASF), saturated polyglycolized glyceride (Gelucire 50/13, manufactured by Gattefosse), PEG20000 (manufactured by Wako Pure Chemical Industries), polyvinyl alcohol (JMP-10L, manufactured by Nippon Vinyl Acetate and Poval), polyvinyl alcohol (LL- 810, made by Japan Vinyl Acetate and Poval), polyvinyl alcohol (LL-920, made by Japan Vinyl Acetate and Poval), polyvinyl alcohol (LL-940, made by Japan Vinyl Acetate and Poval) 0.1 g, acetone 30 mL to 15 mL, 0.1 g of hydroxypropyl cellulose of polymer liquid 2 was changed to 0.6 g of polyvinyl alcohol (EG-05, manufactured by Nippon Synthetic Chemical Industry Co., Ltd.), 15 mL of water was changed to 30 mL, and 0.13 g of polysorbate 80 was added. Experiments were carried out as in 7 (Tables 6, 7). As a result, the formation of particles was confirmed when any substance was used. However, the evaluation of permeability using a three-dimensional cultured epidermis model showed no permeability within 24 hours.

[Comparative Examples 20 to 27] Preparation of Comparative Particles 20 to 27 Experiments were conducted in the same manner as in Comparative Example 2, except that water was used instead of acetone in the polymer liquid 1 of Comparative Example 2 (Table 8). . As a result, the formation of particles was confirmed when any substance was used. However, the evaluation of permeability using a three-dimensional cultured epidermis model showed no permeability within 24 hours.

[Comparative Examples 28 and 29] Preparation of Comparative Particles 28 and 29 Either povidone (K-90, manufactured by BASF) or PEG6000 (manufactured by Wako Pure Chemical Industries, Ltd.) was used instead of polyvinyl alcohol in the polymer liquid 2 of Comparative Example 2. An experiment was conducted in the same manner as in Comparative Example 2, except that the components of were used (Table 8). As a result, the formation of particles was confirmed when any substance was used. However, the evaluation of permeability using a three-dimensional cultured epidermis model showed no permeability within 24 hours.

The particles of the present invention are useful for products such as medicines, quasi-drugs and cosmetics.

Claims (20)

A water-soluble active ingredient skin penetration agent comprising particles having the following properties:
(a) (i-1) a mixture of two or more cellulose derivatives, or (i-2) a mixture of cellulose derivatives and polymers other than cellulose derivatives, and (ii) a water-soluble active ingredient;
(b) a water-soluble active ingredient is contained inside the particles; and (c) a volume distribution average particle size of 1 to 900 nm,
Here, (i-1) a mixture of two or more cellulose derivatives, (α-1) a cellulose derivative selected from the group consisting of hydroxyalkyl cellulose, carboxyalkyl cellulose, and ester derivatives thereof, and (β-1 ) a mixture of cellulose derivatives selected from the group consisting of alkylcellulose, hydroxyalkylalkylcellulose, hydrophobized cellulose, and ester derivatives thereof, or (i-2) a mixture of cellulose derivatives and polymers other than cellulose derivatives, (α-2) cellulose derivatives selected from the group consisting of hydroxyalkyl cellulose, carboxyalkyl cellulose, and ester derivatives thereof, and (β-2) vinyl-based polymers, propylene-based polymers, butylene-based polymers, and copolymers thereof A mixture of polymers other than cellulose derivatives, selected from the group consisting of
The particles have a contact angle of water on the particle film of 20 to 70 degrees,
The water-soluble active ingredient is a low-molecular-weight compound having a molecular weight of 1,500 or less. The epidermal penetration agent according to claim 1, which has one or more properties selected from the group consisting of (i) and (ii) below:
(i) the ratio of the contact angle of water on the particle film to the contact angle of water on the polystyrene substrate is within the range of 0.2 to 0.9;
(ii) The absolute value of mobility by electrophoresis is 2 μm cm/Vs or more. 3. The epidermal permeable agent according to claim 1, wherein the cellulose derivatives (α-1), (β-1) and (α-2) are hydroxypropyl cellulose, ethyl cellulose, hypromellose or ester derivatives thereof. The epidermal permeation agent according to any one of claims 1 to 3, wherein the polymer other than the cellulose derivative is a methacrylic acid copolymer. The epidermal permeation agent according to any one of claims 1 to 3, wherein the mixture of two or more cellulose derivatives is a mixture of alkyl cellulose and hydroxyalkyl cellulose. 6. The epidermal permeation agent according to claim 5, wherein the alkylcellulose is ethylcellulose and the hydroxyalkylcellulose is hydroxypropylcellulose. The epidermal permeation agent according to any one of claims 1 to 3, wherein the mixture of two or more cellulose derivatives is a mixture of an alkylcellulose and an ester derivative of hydroxyalkylalkylcellulose. 8. The epidermal permeation agent according to claim 7, wherein the alkylcellulose is ethylcellulose and the ester derivative of hydroxyalkylalkylcellulose is an ester derivative of hypromellose. 9. The epidermal penetration agent according to claim 8, wherein the ester derivative of hypromellose is hypromellose acetate succinate. The epidermal permeation according to any one of claims 1 to 9, wherein (i-1) two or more cellulose derivatives or (i-2) a cellulose derivative and a polymer other than a cellulose derivative are in contact in the mixture. agent. 11. The epidermal penetration agent according to any one of claims 1 to 10, wherein the amount of water-soluble active ingredient relative to the weight of the particles is 0.01-80% (wt). The epidermal penetration agent according to any one of claims 1 to 11, wherein the amount of water-soluble active ingredient relative to the weight of the particles is 0.1-15% (wt). The epidermal permeation agent according to any one of claims 1 to 12, wherein the water-soluble active ingredient is an amino acid, oligopeptide, water-soluble vitamin, or salt thereof. The amount of (i-1) a mixture of two or more cellulose derivatives relative to the weight of the particles, or the amount of a mixture of (i-2) a cellulose derivative and a polymer other than a cellulose derivative relative to the weight of the particles is 20% (wt) or more. The epidermal penetration agent according to any one of claims 1 to 13 . The epidermal penetration agent according to any one of claims 1 to 14 , wherein the particles are non-composite particles. The epidermal permeable agent according to any one of claims 1 to 15, which is a stratum corneum permeable agent. 17. The epidermal penetration agent according to any one of claims 1 to 16, comprising only homogenous polymer particles. A method for producing particles,
(i) adding an organic solvent containing the first polymer to (ii) an aqueous solution containing both the water-soluble active ingredient and the second polymer in increasing amounts to precipitate particles;
the first polymer is a cellulose derivative selected from the group consisting of alkylcellulose, hydroxyalkylalkylcellulose, hydrophobized cellulose, and ester derivatives thereof; or vinyl-based polymer, propylene-based polymer, and butylene-based polymer; A polymer other than a cellulose derivative selected from the group consisting of copolymers thereof,
the second polymer is a cellulose derivative selected from the group consisting of hydroxyalkylcellulose, carboxyalkylcellulose, and ester derivatives thereof ;
A method, wherein the particles have the following properties:
(a) (i-1) a mixture of two or more cellulose derivatives, or (i-2) a mixture of cellulose derivatives and polymers other than cellulose derivatives, and (ii) an active ingredient;
(b) the active ingredient is contained within the particle; and
(c) a volume distribution average particle size of 1 to 900 nm,
Here, (i-1) a mixture of two or more cellulose derivatives, (α-1) a cellulose derivative selected from the group consisting of hydroxyalkyl cellulose, carboxyalkyl cellulose, and ester derivatives thereof, and (β-1 ) a mixture of cellulose derivatives selected from the group consisting of alkylcellulose, hydroxyalkylalkylcellulose, hydrophobized cellulose, and ester derivatives thereof, or
(i-2) a mixture of cellulose derivatives and polymers other than cellulose derivatives, (α-2) cellulose derivatives selected from the group consisting of hydroxyalkylcelluloses, carboxyalkylcelluloses, and ester derivatives thereof; and (β-2) A mixture of polymers other than cellulose derivatives selected from the group consisting of vinyl-based polymers, propylene-based polymers, butylene-based polymers, and copolymers thereof,
The particles have a contact angle of water on the particle film of 20 to 70 degrees,
The active ingredient is a low-molecular-weight compound having a molecular weight of 1,500 or less. the alkyl in hydroxyalkyl cellulose, carboxyalkyl cellulose and alkyl cellulose is alkyl having 1 to 4 carbon atoms;
The method according to claim 18, wherein two alkyls in the hydroxyalkylalkylcellulose may be the same or different and are alkyls having 1 to 4 carbon atoms. The amount of (i-1) a mixture of two or more cellulose derivatives relative to the weight of the particles, or the amount of a mixture of (i-2) a cellulose derivative and a polymer other than a cellulose derivative relative to the weight of the particles is 20% (wt) or more. 20. A method according to claim 18 or 19.

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