Particles, methods for producing the same, and pharmaceutical compositions

Abstract

To provide a method for producing particles that can suppress the decrease in physiological activity during particle production. [Solution] A method for producing particles, comprising: a bioactive substance-containing solution preparation step of preparing a bioactive substance-containing solution containing a bioactive substance; a discharge step of dispensing the bioactive substance-containing solution as droplets; and a granulation step of removing the solvent from the droplets to form particles, characterized in that the bioactivity ratio {(bioactive amount B / bioactive amount A) × 100} of the bioactive amount B in the particles after the granulation step relative to the bioactive amount A in the bioactive substance before the bioactive substance-containing solution preparation step is 80% or more.

Description

Technical Field

[0001] The present invention relates to particles, a method for producing the same, and a pharmaceutical composition.

Background Art

[0002] In recent years, research on drug delivery systems, which are technologies for efficiently and safely administering drug components to diseased sites, has been actively conducted. As part of this, in order to deliver drug components into blood vessels, there is an increasing demand for fine particles having a particle diameter of several hundred nm or less and containing or supporting bioactive substances such as drug components.

[0003] Examples of methods for producing fine particles in which a bioactive substance is dispersed in the particles include, for example, the emulsion solvent diffusion method (ESD method) and the spray drying method. The ESD method is a method for producing fine particles by stirring a liquid containing an organic polymer, a bioactive substance, and a good solvent while diffusing it into a poor solvent. The spray drying method is a method for producing fine particles by spraying a liquid containing an organic polymer and a bioactive substance and heating and drying it.

[0004] For example, Patent Document 1 discloses a powder obtained by spray-drying a water-soluble substance selected from peptides, proteins, glycoproteins, saccharides, and nucleic acids. For example, Patent Document 2 discloses particles in which a bioactive substance is dispersed and contained in a base material.

Summary of the Invention

Problems to be Solved by the Invention

[0005] An object of the present invention is to provide a method for producing particles capable of suppressing a decrease in the bioactive amount during particle production.

Means for Solving the Problems

[0006] The method for producing particles of the present invention as means for solving the problems is A process for preparing a physiologically active substance-containing solution, which involves preparing a physiologically active substance-containing solution containing a physiologically active substance, A dispensing step in which the physiologically active substance-containing solution is dispensed as droplets, A granulation step in which the solvent is removed from the aforementioned droplets to form particles, A method for producing particles containing, The physiological activity ratio {(physiological activity amount B / physiological activity amount A) × 100} of the physiological activity amount B in the particles after the granulation process relative to the physiological activity amount A in the physiologically active substance before the preparation process of the physiologically active substance-containing liquid is 80% or more. [Effects of the Invention]

[0007] According to the present invention, it is possible to provide a method for producing particles that can suppress the decrease in physiological activity during particle production. [Brief explanation of the drawing]

[0008] [Figure 1] This is a schematic diagram showing an example of a particle manufacturing apparatus according to the first embodiment of the present invention. [Figure 2] This is a schematic cross-sectional view showing an example of a liquid column resonance droplet dispensing means 3021 as a dispensing means 302 in a particle manufacturing apparatus 300 of a first embodiment of the present invention. [Figure 3] This is a schematic cross-sectional view showing an example of a discharge means 3022 utilizing the Rayleigh fission method as a discharge means 302 in a particle manufacturing apparatus 300 of a first embodiment of the present invention. [Figure 4] This is a schematic diagram showing another example of a particle manufacturing apparatus according to the first embodiment of the present invention. [Figure 5] This is a schematic diagram showing an example of a particle manufacturing apparatus 400 according to a second embodiment of the present invention. [Figure 6] This is a schematic diagram showing an example of a particle manufacturing apparatus 500 according to a third embodiment of the present invention. [Modes for carrying out the invention]

[0009] In the prior art, including the inventions described in Patent Documents 1 and 2, problems arose during the process of producing particles containing physiologically active substances in a substrate, such as the deactivation of the physiologically active substance due to heating, shaking, and stirring, or the elution of the physiologically active substance into a solvent. Therefore, in the prior art, there were concerns that the particles might not contain the physiologically active substance or that the amount of physiological activity in the particles might decrease.

[0010] The particle manufacturing method of the present invention can sufficiently resolve various concerns in the prior art. More specifically, it can realize a particle manufacturing method that can suppress the decrease in physiological activity during particle manufacturing.

[0011] The details of the present invention are described below.

[0012] (Method for manufacturing particles, and apparatus for manufacturing particles) The present invention provides a method for producing particles, comprising a bioactive substance preparation step of preparing a bioactive substance-containing solution containing a bioactive substance, a discharge step of dispensing the bioactive substance-containing solution as droplets, and a granulation step of removing the solvent from the droplets to form particles, and may optionally include other steps.

[0013] The particle manufacturing apparatus according to the present invention includes a dispensing means for dispensing a physiologically active substance-containing liquid as droplets, and a granulation means for removing the solvent from the droplets to granulate particles, and may optionally include a container for the physiologically active substance-containing liquid and other means.

[0014] The particle manufacturing method can be suitably carried out by a particle manufacturing apparatus, the discharge process can be suitably carried out by a discharge means, the granulation process can be suitably carried out by a granulation means, and the other processes can be suitably carried out by other means.

[0015] The method for producing the particles of the present invention preferably does not apply heat and external stress to the physiologically active substance-containing liquid and the droplets. In other words, the method for producing the particles of the present invention preferably does not apply external stress (such as shaking or stirring) that changes the physiological activity of the physiologically active substance and heat (heating) that changes the physiological activity of the physiologically active substance to the physiologically active substance-containing liquid and the droplets. Although details will be described later, by having such a configuration in the method for producing the particles of the present invention, even when the physiologically active substance having a property that its physiological activity changes by applying heat or external stress is included as a material of the particles, it is possible to suppress the change in the physiological activity of the physiologically active substance, and as a result, it is possible to suppress the decrease in the amount of physiological activity during particle production.

[0016] <Physiologically active substance-containing liquid preparation step> The physiologically active substance-containing liquid preparation step is a step of preparing a physiologically active substance-containing liquid containing a physiologically active substance. Note that the method for preparing the physiologically active substance-containing liquid is not particularly limited and can be appropriately selected according to the purpose. For example, a method of adjusting a mixed solution of various materials by passing it through a filter can be mentioned.

[0017] <<Physiologically active substance-containing liquid>> The physiologically active substance-containing liquid contains a physiologically active substance and may contain a substrate, a solvent, and other components as necessary.

[0018] <<<Physiologically active substance>>> The physiologically active substance is an active ingredient used to exert a physiological effect on a living body. Here, the "physiological effect" is an effect caused by the physiologically active substance exerting physiological activity at the target site, and for example, it is to bring about quantitative and / or qualitative changes and effects on a living body, tissue, cell, protein, DNA, RNA, etc.

[0019] In this specification, "bioactive activity" refers to the effect of a bioactive substance on a target site (e.g., target tissue) by causing a change or influence. Examples of target sites include receptors present on the cell surface or within cells. In this case, the bioactive activity of the bioactive substance binding to a specific receptor transmits a signal to the cell, resulting in a physiological effect. A physiologically active substance may be a substance that, after being converted to its mature form by enzymes in the body, binds to a specific receptor and exerts a physiological effect. In this specification, substances before conversion to their mature form are also included as physiologically active substances.

[0020] Bioactive substances may be substances produced by living organisms (humans or non-human organisms) or substances that are artificially synthesized.

[0021] The physiologically active substance may have the property of changing its physiological activity in response to at least one of heat and / or external stress. When the particle manufacturing method of the present invention does not involve heating or applying external stress to the physiologically active substance-containing liquid and droplets, using such a physiologically active substance further suppresses the decrease in the amount of physiological activity during particle manufacturing.

[0022] In this specification, "properties that change physiological activity" include, for example, properties that increase or decrease the amount of physiological activity, properties that increase or decrease the efficiency of physiological activity, and properties that change the type of physiological activity. Among these, properties that decrease the amount of physiological activity or properties that decrease the efficiency of physiological activity are preferred, and properties that decrease the amount of physiological activity are more preferred. The property of changing the type of physiological activity may be reversible or irreversible, but it is preferable that it be irreversible.

[0023] In this specification, "bioactive amount" refers to a measured value obtained when the bioactive activity of a bioactive substance is quantitatively measured. Here, "quantitative measurement" is not limited to a direct method of quantitatively measuring the bioactive amount itself, but may also refer to a relative quantitative measurement method, for example, in which the bioactive amount is measured by comparing it with a predetermined standard.

[0024] In this specification, "heating" refers to applying thermal energy to a physiologically active substance (or a solution containing a physiologically active substance). Such "heating" may alter the physiological activity of the physiologically active substance due to changes in its molecular structure or three-dimensional structure. Specific examples include, if the physiologically active substance is a protein, thermal denaturation of the protein, and thermal denaturation of the protein. If the physiologically active substance is a nucleic acid, degradation of the nucleic acid may occur. There are no particular restrictions on the heating temperature; it can be appropriately selected depending on the type of physiologically active substance.

[0025] In this specification, "external stress" refers to a force applied from the outside to a physiologically active substance (or a solution containing a physiologically active substance). Examples of such external stresses include shaking, stirring, and shear stress. When these external stresses are applied, the physiological activity of the physiologically active substance may change due to changes in its molecular structure or three-dimensional structure. For example, if the physiologically active substance is a protein, the protein may become inactive due to changes in its higher-order structure. Proteins that are easily inactivated by external stress include, for example, proteins that form polymers (enzymes, antibodies, etc.). There are no particular restrictions on the treatment that generates external stress, and it can be appropriately selected depending on the type of physiologically active substance. Examples include shaking, stirring, grinding, ultrasonic treatment, homogenizing, and spraying.

[0026] There are no particular restrictions on the physiologically active substances, and they can be appropriately selected according to the purpose. Examples include physiologically active substances contained in pharmaceutical compositions, physiologically active substances contained in functional foods, and physiologically active substances contained in functional cosmetics. These can be used individually or in combination of two or more.

[0027] -Physiologically active substances contained in pharmaceutical compositions- There are no particular restrictions on the physiologically active substances contained in the pharmaceutical composition, and they can be appropriately selected according to the purpose. Examples include nucleic acids, polypeptides containing proteins, carbohydrates, lipids, and low molecular weight compounds. These can be used individually or in combination of two or more.

[0028] --Nucleic acid-- Nucleic acids typically include DNA, RNA, and combinations thereof. Furthermore, some or all of these sequences may be replaced with chemically modified nucleic acids.

[0029] Nucleic acids also include chemically synthesized nucleic acid analogs such as PNA (peptide nucleic acid) and Morpholino antisense oligos.

[0030] When the objective is to suppress the expression of a target gene, the nucleic acid may be, for example, an antisense nucleic acid against the transcript or a part thereof of the target gene, a nucleic acid having ribozyme activity that specifically cleaves the transcript of the target gene, a short-chain nucleic acid that inhibits the expression of the target gene by RNAi, microRNA (miRNA), aptamers, and locked nucleic acids (OLIs) that have been modified.

[0031] -- polypeptide -- Polypeptides are polymers composed of multiple amino acids, and among them, polypeptides that have a higher-order structure and exhibit functions derived from this higher-order structure are called proteins.

[0032] The polypeptide may be optionally modified. There are no particular restrictions on modifications, and they can be appropriately selected according to the purpose. Examples include acetylation, acylation, ADP-ribosylation, amidation, covalent bonding of flavin, covalent bonding of heme moiety, covalent bonding of nucleotides or nucleotide derivatives, covalent bonding of lipids or lipid derivatives, covalent bonding of phosphatidylinositol, crosslinking, cyclization, disulfide bond formation, demethylation, covalent crosslinking, cystine formation, pyroglutamate formation, formylation, γ-carboxylation, glycosylation, GPI anchor formation, hydroxylation, iodization, methylation, myristoylation, oxidation, proteolysis, phosphorylation, prenylation, racemization, selenoylation, sulfated arginylation, RNA-mediated addition of amino acids to proteins, and ubiquitination.

[0033] When the objective is to inhibit or suppress the function of a target protein, examples of the protein include a target protein mutant that has dominant-negative properties with respect to the target protein, and an antibody that binds to the target protein.

[0034] The antibody may be a polyclonal antibody or a monoclonal antibody, as long as it binds to the target protein. It may also be a multispecific antibody, such as a bispecific or tripspecific antibody.

[0035] The antibody may be derived from any animal species as long as it exerts a physiological effect, but human antibodies, human-type chimeric antibodies, and humanized antibodies are preferred.

[0036] Antibodies include, for example, immunoglobulin molecules such as IgG, IgE, IgM, IgA, and IgD. They also include antibody fragments (e.g., F(ab')2 fragments, Fab' fragments, Fab fragments, Fv fragments, rIgG fragments, single-chain antibodies, etc.) and antibody modifiers (labeled antibodies, etc.) that have an antigen-binding region, as long as they can bind to a specific antigen.

[0037] Enzymes can also be cited as examples of proteins. There are no particular restrictions on the enzymes used; they can be appropriately selected according to the purpose. Examples include hydrolases, phosphorylation enzymes, dephosphorylation enzymes, transferases, oxidoreductases, leaching enzymes, isomerases, and synthases.

[0038] Specific examples of proteins include quercetin, testosterone, indomethacin, tranilast, and tacrolimus.

[0039] --Carbohydrates-- There are no particular restrictions on carbohydrates, and they can be selected appropriately depending on the purpose. Examples include monosaccharides, disaccharides, oligosaccharides, and polysaccharides. In addition, complex carbohydrates, in which these carbohydrates are covalently bonded to proteins or lipids, and glycosides, in which aglycones such as alcohols, phenols, saponins, or pigments are bonded to the reducing group of a sugar, are also included in the category of carbohydrates.

[0040] --Lipids-- There are no particular restrictions on the lipids used; they can be appropriately selected according to the purpose, and examples include simple lipids, complex lipids, and derived lipids.

[0041] --Low molecular compounds-- Low molecular weight compounds generally include substances with molecular weights ranging from several hundred to several thousand.

[0042] Examples of low-molecular-weight compounds include substances that are poorly soluble in water and substances that are water-soluble. Furthermore, low-molecular-weight compounds may be in any form, such as salts or hydrates, as long as they function as physiologically active substances.

[0043] There are no particular restrictions on water-soluble substances, and they can be appropriately selected depending on the purpose. Examples include griseofulvin, itraconazole, norfloxacin, tamoxifen, cyclosporine, glibenclamide, troglitazone, nifedipine, phenacetin, phenytoin, digitoxin, nilvadipine, diazepam, chloramphenicol, indomethacin, nimodipine, dihydroergotoxin, cortisone, dexamethasone, naproxen, trubuterol, beclomethasone propionate, fluticasone propionate, and pranluca. Examples include tranilast, loratidine, tacrolimus, amprenavir, bexarotene, calcitrol, clofazimine, digoxin, doxelcalciferol, dronabinol, etopozide, isotretinoin, lopinavir, ritonavir, progesterone, saquinavir, sirolimus, tretinoin, amphotericin, phenoldopam, melphalan, paricalcitol, propofol, voriconazole, ziprasidone, docetaxel, haloperidol, lorazepam, tenipozide, testosterone, and barrubicin. These can be used individually or in combination of two or more.

[0044] There are no particular restrictions on water-soluble substances, and they can be appropriately selected according to the purpose. Examples include abacavir, acetaminophen, acyclovir, amiloride, amitriptyline, antipyrine, atropine, buspirone, caffeine, captopril, chloroquine, chlorpheniramine, cyclophosphamide, diclofenac, desipramine, diazepam, diltiazem, diphenhydramine, disopyramide, doxin, doxycycline, enalapril, ephedrine, and ethane. Examples include butol, ethinylestradiol, fluoxetine, imipramine, glucose, ketol, ketoprofen, labetalol, levodopa, levofloxacin, metoprolol, metronidazole, midazolam, minocycline, misoprostol, metformin, nifedipine, phenobarbital, prednisolone, promazine, propranolol, quinidine, rosiglitazone, salicylic acid, theophylline, valproic acid, verapamil, and zidovudine. These can be used individually or in combination of two or more.

[0045] Specific examples of small molecule compounds include kinase inhibitors such as gefitinib, erlotinib, osimertinib, bosunitib, vandetanib, alectinib, lorlatinib, abemaciclib, thyrofostine AG494, sorafenib, dasatinib, lapatinib, imatinib, motesanib, restaurtinib, tanzutinib, dorsomorphine, axitinib, and 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione.

[0046] - Bioactive substances contained in functional foods - There are no particular restrictions on the physiologically active substances contained in functional foods, and they can be appropriately selected according to the purpose. Examples include vitamin A, vitamin D, vitamin E, lutein, zeaxanthin, lipoic acid, flavonoids, and fatty acids. These can be used individually or in combination of two or more.

[0047] Examples of fatty acids include omega-3 fatty acids and omega-6 fatty acids.

[0048] - Bioactive substances contained in functional cosmetics - There are no particular restrictions on the physiologically active substances contained in functional cosmetics, and they can be appropriately selected according to the purpose. For example, alcohols, fatty alcohols, polyols, aldehydes, alkanolamines, alkoxylated alcohols (e.g., polyethylene glycol derivatives of alcohols, fatty alcohols, etc.), alkoxylated amides, alkoxylated amines, alkoxylated carboxylic acids, amides containing salts (e.g., ceramides, etc.), amines, amino acids containing salts and alkyl-substituted derivatives, esters, alkyl-substituted and acyl derivatives, polyacrylic acids, acrylamide copolymers, adipic acid copolymers, aminosilicones, biological polymers and their derivatives, butylene copolymers, carbohydrates (e.g., polysaccharides, chitosan, and their derivatives, etc.), carboxylic acids, carbomers, etc. Examples include ethers, polymer ethers (e.g., PEG derivatives, PPG derivatives, etc.), glyceryl esters and their derivatives, halogen compounds, heterocyclic compounds containing salts, hydrophilic colloids and derivatives containing salts and rubber (e.g., cellulose derivatives, gelatin, xanthan gum, natural rubber, etc.), imidazolines, inorganic substances (clay, TiO2, ZnO, etc.), ketones (e.g., camphor, etc.), isethionates, lanolin and its derivatives, organic salts, phenols containing salts (e.g., parabens, etc.), phosphorus compounds (e.g., phosphoric acid derivatives, etc.), polyacrylates and acrylate copolymers, protein and enzyme derivatives (e.g., collagen, etc.), synthetic polymers containing salts, siloxanes and silanes, sorbitan derivatives, sterols, sulfonic acids and their derivatives, waxes, and the like. These can be used individually or in combination of two or more.

[0049] The physiologically active substance is preferably a physiologically active substance contained in the pharmaceutical composition, more preferably at least one selected from proteins and nucleic acids, and even more preferably at least one selected from antibodies and enzymes.

[0050] There are no particular restrictions on the content of physiologically active substances, and they can be appropriately selected according to the purpose, but it is preferably 1% to 100% by mass, and more preferably 25% to 99% by mass, relative to the total amount of particles. By ensuring that the bioactive substance content is 25% or more by mass relative to the total amount of particles, sustained-release particles that stably release the bioactive substance over a long period of time can be obtained. Furthermore, by ensuring that the bioactive substance content is 95% or more by mass relative to the total amount of particles, the amount of drug administered per dose can be increased, and the number of administrations can be reduced.

[0051] The amount of bioactive substances contained in the particles can be controlled by adjusting the formulation of the bioactive substance-containing solution used in manufacturing the particles.

[0052] <<<Base material>>> The base material is the material that forms the basis of the particles. The base material is preferably solid at room temperature.

[0053] As for the base material, there are no particular restrictions as long as it does not adversely affect the physiologically active substance, and it can be appropriately selected according to the purpose. It may be a low molecular weight substance or a high molecular weight substance.

[0054] -Low molecular weight substances- As for low molecular weight substances, compounds with a weight-average molecular weight of less than 15,000 are preferred. There are no particular restrictions on low molecular weight substances, and they can be appropriately selected depending on the purpose. Examples include lipids, sugars, cyclodextrins, amino acids, and organic acids. These can be used individually or in combination of two or more.

[0055] --Lipids-- There are no particular restrictions on the lipids used, and they can be appropriately selected depending on the purpose. Examples include medium-chain or long-chain monoglycerides, medium-chain or long-chain diglycerides, medium-chain or long-chain triglycerides, phospholipids, vegetable oils (e.g., soybean oil, avocado oil, squalene oil, sesame oil, olive oil, corn oil, rapeseed oil, safflower oil, sunflower oil, etc.), fish oil, flavoring oils, water-insoluble vitamins, fatty acids, medium-chain fatty acid triglycerides, mixtures thereof, and derivatives thereof. These can be used individually or in combination of two or more.

[0056] --Sugars-- There are no particular restrictions on the sugars used, and they can be appropriately selected depending on the purpose. Examples include monosaccharides and polysaccharides such as glucose, mannose, idose, galactose, fucose, ribose, xylose, lactose, sucrose, maltose, trehalose, turanose, raffinose, maltotriose, acarbose, cyclodextrins, amylose (starch), and cellulose, as well as sugar alcohols (polyols) such as glycerin, sorbitol, lactitol, maltitol, mannitol, xylitol, and erythritol, and their derivatives. These can be used individually or in combination of two or more.

[0057] --Cyclodextrins-- There are no particular restrictions on the cyclodextrins used, and they can be appropriately selected depending on the purpose. Examples include hydroxypropyl-β-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, α-cyclodextrin, and cyclodextrin derivatives. These can be used individually or in combination of two or more.

[0058] --Amino acids-- There are no particular restrictions on the amino acids used, and they can be appropriately selected depending on the purpose. Examples include valine, lysine, leucine, threonine, isoleucine, asparagine, glutamine, phenylalanine, aspartic acid, serine, glutamic acid, methionine, arginine, glycine, alanine, tyrosine, proline, histidine, cysteine, tryptophan, and their derivatives. These can be used individually or in combination of two or more.

[0059] --Organic acids-- There are no particular restrictions on the organic acids used, and they can be appropriately selected depending on the purpose. Examples include adipic acid, ascorbic acid, citric acid, fumaric acid, gallic acid, glutaric acid, lactic acid, malic acid, maleic acid, succinic acid, tartaric acid, and their derivatives. These can be used individually or in combination of two or more.

[0060] -High molecular weight substances- As for the high molecular weight substance, it is preferable that it be a compound with a weight-average molecular weight of 15,000 or more. There are no particular restrictions on high molecular weight substances, and they can be appropriately selected depending on the purpose. Examples include water-soluble cellulose, polyalkylene glycol, poly(meth)acrylamide, poly(meth)acrylic acid, poly(meth)acrylic acid esters, polyallylamine, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, biodegradable polyester, polyglycolic acid, polyamino acids, gelatin, proteins such as fibrin, polysaccharides, and derivatives thereof. These can be used individually or in combination of two or more.

[0061] --Water-soluble cellulose-- There are no particular restrictions on the water-soluble cellulose, and it can be appropriately selected depending on the purpose. Examples include alkyl celluloses such as methylcellulose and ethylcellulose, hydroxyalkyl celluloses such as hydroxyethylcellulose and hydroxypropylcellulose, and hydroxyalkylalkyl celluloses such as hydroxyethylmethylcellulose and hydroxypropylmethylcellulose. Among these, hydroxypropylcellulose and hydroxypropylmethylcellulose are preferred, and hydroxypropylcellulose is more preferred, due to their high biocompatibility and high solubility in the solvent used when manufacturing the particles. These can be used individually or in combination of two or more.

[0062] The viscosity of a 2% by mass aqueous solution of hydroxypropyl cellulose (at 20°C) is not particularly limited and can be appropriately selected depending on the purpose, but a viscosity of 2.0 mPa·s (centipoise, cps) or more and 4,000 mPa·s (centipoise, cps) or less is preferred.

[0063] The viscosity of hydroxypropyl cellulose is thought to depend on the weight-average molecular weight, degree of substitution, and molecular weight of the hydroxypropyl cellulose. There are no particular restrictions on the weight-average molecular weight of hydroxypropyl cellulose, and it can be appropriately selected depending on the purpose, but a range of 15,000 to 400,000 is preferred. The weight-average molecular weight can be measured, for example, using gel permeation chromatography (GPC).

[0064] There are no particular restrictions on commercially available hydroxypropyl cellulose products, and they can be appropriately selected according to the purpose. For example, HPC-SSL (molecular weight: 15,000 to 30,000, viscosity: 2.0 mPa·s to 2.9 mPa·s), HPC-SL (molecular weight: 30,000 to 50,000, viscosity: 3.0 mPa·s to 5.9 mPa·s), HPC-L (molecular weight: 55,000 Examples include HPC-M (molecular weight: 0 to 70,000, viscosity: 6.0 mPa·s to 10.0 mPa·s), HPC-M (molecular weight: 110,000 to 150,000, viscosity: 150 mPa·s to 400 mPa·s), and HPC-H (molecular weight: 250,000 to 400,000, viscosity: 1,000 mPa·s to 4,000 mPa·s) (all manufactured by Nippon Soda Co., Ltd.). Among these, HPC-SSL is preferred. These can be used individually or in combination of two or more. In the above-mentioned commercially available products, the molecular weight is measured using gel permeation chromatography (GPC), and the viscosity is measured using a 2% by mass aqueous solution (at 20°C).

[0065] There are no particular restrictions on the hydroxypropyl cellulose content, and it can be appropriately selected depending on the purpose, but it is preferably 50% by mass or more relative to the total amount of the base material, more preferably 50% by mass or more and 99% by mass or less, even more preferably 75% by mass or more and 99% by mass or less, and particularly preferably 80% by mass or more and 99% by mass or less.

[0066] --Polyalkylene glycol-- There are no particular restrictions on the polyalkylene glycol, and it can be appropriately selected depending on the purpose. Examples include polyethylene glycol (PEG), polypropylene glycol, polybutylene glycol, and copolymers thereof. These can be used individually or in combination of two or more.

[0067] --Poly(meth)acrylamide-- There are no particular restrictions on the poly(meth)acrylamide, and it can be appropriately selected depending on the purpose. Examples include polymers of monomers such as N-methyl(meth)acrylamide, N-ethyl(meth)acrylamide, N-propyl(meth)acrylamide, N-butyl(meth)acrylamide, N-benzyl(meth)acrylamide, N-hydroxyethyl(meth)acrylamide, N-phenyl(meth)acrylamide, N-tolyl(meth)acrylamide, N-hydroxyphenyl(meth)acrylamide, N-(hydroxyphenyl)(meth)acrylamide, N-(sulfamoylphenyl)(meth)acrylamide, N-phenylsulfonyl(meth)acrylamide, N,N-dimethyl(meth)acrylamide, N-methylN-phenyl(meth)acrylamide, and N-hydroxyethyl-N-methyl(meth)acrylamide. These monomers may be polymerized individually or in combination of two or more. Furthermore, these polymers may be used individually or in combination of two or more.

[0068] --Poly(meth)acrylic acid-- There are no particular restrictions on the poly(meth)acrylic acid, and it can be appropriately selected depending on the purpose. Examples include homopolymers such as polyacrylic acid and polymethacrylic acid, and copolymers such as acrylic acid-methacrylic acid copolymers. These can be used individually or in combination of two or more.

[0069] --Poly(meth)acrylic acid ester-- There are no particular restrictions on the poly(meth)acrylic acid ester, and it can be appropriately selected depending on the purpose. Examples include polymers of monomers such as ethylene glycol di(meth)acrylate, diethylene glycol di(meth)acrylate, propylene glycol di(meth)acrylate, glycerol poly(meth)acrylate, polyethylene glycol (meth)acrylate, trimethylolpropane tri(meth)acrylate, pentaerythritol tetra(meth)acrylate, and 1,3-butylene glycol di(meth)acrylate. These monomers may be polymerized individually or in combination of two or more. Furthermore, these polymers may be used individually or in combination of two or more.

[0070] --Polyarylamine-- There are no particular restrictions on the polyallylamine used; it can be appropriately selected depending on the purpose. Examples include diallylamine and triallylamine. These can be used individually or in combination of two or more.

[0071] --Polyvinylpyrrolidone-- There are no particular restrictions on the polyvinylpyrrolidone used; it can be selected appropriately depending on the purpose. Polyvinylpyrrolidone can be synthesized as appropriate or a commercially available product can be used. Examples of commercially available polyvinylpyrrolidones include Plasdon C-15 (manufactured by ISP TECHNOLOGIES), Coridon VA64, Coridon K-30, Coridon CL-M (all manufactured by KAWARLAL), and Coricoat IR (manufactured by BASF). These can be used individually or in combination of two or more.

[0072] --Polyvinyl alcohol-- There are no particular restrictions on the polyvinyl alcohol used, and it can be appropriately selected depending on the purpose. Examples include silanol-modified polyvinyl alcohol, carboxyl-modified polyvinyl alcohol, and acetoacetyl-modified polyvinyl alcohol. These can be used individually or in combination of two or more.

[0073] --Polyvinyl acetate-- There are no particular restrictions on the polyvinyl acetate, and it can be appropriately selected depending on the purpose. Examples include vinyl acetate-crotonic acid copolymer and vinyl acetate-itaconic acid copolymer. These can be used individually or in combination of two or more.

[0074] --Biodegradable polyester-- There are no particular restrictions on the biodegradable polyester, and it can be appropriately selected depending on the purpose. Examples include succinate polymers such as polylactic acid, poly-ε-caprolactone, polyethylene succinate, polybutylene succinate, and polybutylene succinate adipate, polyhydroxyalkanoates such as polyhydroxypropionate, polyhydroxybutyrate, and polyhydroxyparylate, and polyglycolic acid. Among these, polylactic acid is preferred because of its high biocompatibility and the ability to release physiologically active substances gradually. These can be used individually or in combination of two or more.

[0075] There are no particular restrictions on the weight-average molecular weight of polylactic acid, and it can be appropriately selected depending on the purpose, but it is preferably 5,000 to 100,000, more preferably 10,000 to 70,000, even more preferably 10,000 to 50,000, and particularly preferably 10,000 to 30,000.

[0076] There are no particular restrictions on the polylactic acid content, and it can be appropriately selected depending on the purpose, but it is preferably 50% by mass or more relative to the total mass of the base material, more preferably 50% by mass or more and 99% by mass or less, even more preferably 75% by mass or more and 99% by mass or less, and particularly preferably 80% by mass or more and 99% by mass or less.

[0077] --Polyglycolic acid-- There are no particular restrictions on polyglycolic acid, and it can be appropriately selected depending on the purpose. Examples include lactic acid-glycolic acid copolymers, which are copolymers having structural units derived from lactic acid and structural units derived from glycolic acid; glycolic acid-caprolactone copolymers, which are copolymers having structural units derived from glycolic acid and structural units derived from caprolactone; and glycolic acid-trimethylene carbonate copolymers, which are copolymers having structural units derived from glycolic acid and structural units derived from trimethylene carbonate. Among these, lactic acid-glycolic acid copolymers are preferred because they have high biocompatibility, can release physiologically active substances gradually, and can store physiologically active substances for a long period of time. These can be used individually or in combination of two or more.

[0078] There are no particular restrictions on the weight-average molecular weight of the lactic acid-glycolic acid copolymer, and it can be appropriately selected depending on the purpose, but it is preferably 2,000 to 250,000, more preferably 2,000 to 100,000, even more preferably 3,000 to 50,000, and particularly preferably 5,000 to 10,000.

[0079] In lactic acid-glycolic acid copolymers, there are no particular restrictions on the molar ratio (L:G) of constituent units derived from lactic acid (L) to constituent units derived from glycolic acid (G). It can be appropriately selected depending on the purpose, but 1:99 to 99:1 is preferred, 25:75 to 99:1 is more preferred, 30:70 to 90:10 is even more preferred, and 50:50 to 85:15 is particularly preferred.

[0080] There are no particular restrictions on the content of the lactic acid-glycolic acid copolymer, and it can be appropriately selected depending on the purpose, but it is preferably 50% by mass or more relative to the total amount of the base material, more preferably 50% by mass or more and 99% by mass or less, even more preferably 75% by mass or more and 99% by mass or less, and particularly preferably 80% by mass or more and 99% by mass or less.

[0081] --Polyamino acids-- There are no particular restrictions on the polyamino acids, and they can be appropriately selected depending on the purpose. These may include valine, lysine, leucine, threonine, isoleucine, asparagine, glutamine, phenylalanine, aspartic acid, serine, glutamic acid, methionine, arginine, glycine, alanine, tyrosine, proline, histidine, cysteine, tryptophan, their derivatives, and polymers formed by any combination thereof. As for the polyamino acid, a polymer of a single amino acid is preferred. Preferred polyamino acids include, for example, amino acid homopolymers such as poly-α-glutamic acid, poly-γ-glutamic acid, polyaspartic acid, polylysine, polyarginine, polyornithine, and polyserine, or copolymers thereof. These can be used individually or in combination of two or more.

[0082] --gelatin-- There are no particular restrictions on the type of gelatin used, and it can be appropriately selected depending on the purpose. Examples include lime-treated gelatin, acid-treated gelatin, gelatin hydrolysates, gelatin enzyme dispersions, or derivatives thereof. These can be used individually or in combination of two or more.

[0083] Gelatin derivatives refer to gelatin that has been derivatized by covalently bonding a hydrophobic group to a gelatin molecule. There are no particular restrictions on the hydrophobic group, and it can be appropriately selected depending on the purpose. Examples include polyesters such as polylactic acid, polyglycolic acid, and poly-ε-caprolactone; lipids such as cholesterol and phosphatidylethanolamine; alkyl groups; aromatic groups containing benzene rings; heteroaromatic groups; or mixtures thereof.

[0084] There are no particular restrictions on the natural dispersant polymers used in gelatin derivatives; they can be appropriately selected depending on the purpose. Examples include proteins, polysaccharides, and nucleic acids. These also include copolymers composed of natural or synthetic dispersant polymers. These can be used individually or in combination of two or more.

[0085] As for proteins used as natural dispersant polymers, there are no particular restrictions as long as they do not adversely affect the physiological activity of the physiologically active substance; they can be appropriately selected according to the purpose. Examples include collagen, fibrin, and albumin. These can be used individually or in combination of two or more.

[0086] There are no particular restrictions on the polysaccharides used as natural dispersant polymers; they can be appropriately selected depending on the purpose. Examples include chitin, chitosan, hyaluronic acid, alginic acid, starch, and pectin. These can be used individually or in combination of two or more.

[0087] The particles obtained by the particle manufacturing method of the present invention may contain two or more base materials. When one of the multiple base materials is contained predominantly on the surface side of the particles, there are no particular restrictions on the base materials and they can be appropriately selected according to the purpose, but it is preferable that at least one of the base materials is pH-responsive, and it is more preferable that the base material contained predominantly on the surface side of the particles is pH-responsive.

[0088] Here, pH responsiveness means that the solubility changes in response to pH. For example, by incorporating a pH-responsive base material that dissolves at pH 5.0 or higher, predominantly on the surface side of the particles, enteric-coated particles can be manufactured.

[0089] There are no particular limitations on the pH-responsive substrate, and it can be appropriately selected depending on the purpose. Examples include cellulose polymers, methacrylic acid polymers, vinyl polymers, amino acids, chitosan, pectin, and alginic acid. Among these, it is preferable to use at least one selected from cellulose polymers and methacrylic acid polymers, as this makes it easier to incorporate the substrate unevenly on the surface side of the particles during particle manufacturing and improves enteric coating. These can be used individually or in combination of two or more.

[0090] Examples of cellulose polymers include hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, carboxymethyl ethylcellulose, and cellulose acetate trimellitate. Among these, it is preferable to use at least one selected from hydroxypropyl methylcellulose acetate succinate and hydroxypropyl methylcellulose phthalate, as this makes it easier to incorporate the polymer unevenly into the surface of the particles during particle manufacturing and improves enteric coating. These can be used individually or in combination of two or more.

[0091] Examples of methacrylic acid polymers include aminoalkyl methacrylic acid copolymers, methacrylic acid copolymers, methacrylic acid ester copolymers, and ammoniaalkyl methacrylic acid copolymers. Among these, ammoniaalkyl methacrylic acid copolymers are preferred because they are easy to incorporate unevenly on the surface side of the particles during particle manufacturing, thereby improving enteric coating. These can be used individually or in combination of two or more.

[0092] There are no particular restrictions on the combination of base materials, and they can be appropriately selected according to the purpose. However, if there are two types of base materials, for example, a combination of one selected from poly(meth)acrylic acid, polyglycolic acid, and hydroxypropyl methylcellulose and one selected from hydroxypropyl cellulose, polyethylenepyrrolidone, and polyalkylene glycol is preferred.

[0093] From the viewpoint of being applicable to living organisms, the base material is preferably a substance that is not toxic to living organisms, and more preferably a biodegradable substance such as a biodegradable polymer.

[0094] The base material content is preferably 5% to 95% by mass, and more preferably 50% to 95% by mass, relative to the total mass of the particles. A base material content of 5% to 95% by mass relative to the total mass of particles is preferable because it improves the redispersibility of physiologically active substances in water.

[0095] <<<Solvent>>> There are no particular restrictions on the solvent, and it can be appropriately selected depending on the purpose. Examples include water, aliphatic halogenated hydrocarbons (e.g., dichloromethane, dichloroethane, chloroform, etc.), alcohols (e.g., methanol, ethanol, propanol, etc.), ketones (e.g., acetone, methyl ethyl ketone, etc.), ethers (e.g., diethyl ether, dibutyl ether, 1,4-dioxane, etc.), aliphatic hydrocarbons (e.g., n-hexane, cyclohexane, n-heptane, etc.), aromatic hydrocarbons (e.g., benzene, toluene, xylene, etc.), organic acids (e.g., acetic acid, propionic acid, etc.), esters (e.g., ethyl acetate, etc.), amides (e.g., dimethylformamide, dimethylacetamide, etc.), or mixed solvents thereof. Among these, aliphatic halogenated hydrocarbons, alcohols, or mixed solvents thereof are preferred in terms of solubility, and dichloromethane, 1,4-dioxane, methanol, ethanol, or mixed solvents thereof are more preferred. These can be used individually or in combination of two or more.

[0096] The solvent content is preferably 70% to 99.8% by mass, and more preferably 90% to 99% by mass, relative to the total amount of the physiologically active substance-containing solution. A solvent content of 70% to 99.8% by mass relative to the total volume of the physiologically active substance-containing solution is preferable because it improves production stability in terms of material solubility and viscosity.

[0097] <<<Other ingredients>>> Other components are not particularly limited as long as they do not adversely affect the physiological activity of the physiologically active substance, and can be appropriately selected according to the purpose. Examples include surfactants. Furthermore, when contained in pharmaceutical compositions, functional foods, and functional cosmetics, it is preferable that the physiologically active substance-containing solution is substantially free of other components from the viewpoint of improving safety. In this specification, "substantially absent" means that the amount is below the detection limit.

[0098] There are no particular restrictions on the form of the solution containing the physiologically active substance; it can be appropriately selected according to the purpose. For example, a W / O (Water in Oil) emulsion may be used. When the liquid containing physiologically active substances is in the form of a W / O emulsion, drying at low temperatures is possible by using an organic solvent with a low boiling point. Even if the physiologically active substances contained are prone to changes in physiological activity due to heating, the changes in the physiological activity of the physiologically active substances can be suppressed, and as a result, the decrease in the amount of physiological activity can be suppressed.

[0099] There are no particular restrictions on the method for producing a W / O emulsion, and it can be appropriately selected depending on the purpose. For example, a W / O emulsion can be prepared by mixing liquid A, which is obtained by dissolving a physiologically active substance in solvent A, with liquid B (solvent B), and stirring, in which liquid A is dispersed in liquid B. The W / O emulsion may be an emulsion containing air during stirring, or it may be an emulsion from which the air has been removed. In the W / O emulsion prepared in this manner, liquid A exists as droplets in liquid B. The physiologically active substance is also present in the droplets of liquid A. The presence of the physiologically active substance in the droplets of liquid A protects it, suppressing changes in its physiological activity due to stirring, and consequently preventing a decrease in its physiological activity.

[0100] It is preferable that liquid A and liquid B are immiscible solvents, and more preferably that solvent A is water and liquid B (solvent B) is dichloromethane.

[0101] A method for producing a W / O emulsion may include a dispersion step of preparing a dispersion using liquid A and liquid B. There are no particular restrictions on the dispersion process, and it can be appropriately selected according to the purpose. For example, one method is to mix and stir liquid A and liquid B. Specific stirring methods include stirring using a stirring bar or a homogenizer.

[0102] Herein, "dispersion" as used herein means a suspension in which one substance (dispersed phase, liquid A) is suspended as fine particles in another substance (dispersion medium, liquid B).

[0103] -Solvent A- Solvent A is not particularly limited as long as it can dissolve the physiologically active substance, and can be appropriately selected depending on the purpose. Examples include water and hexafluoro-2-propanol (HFIP).

[0104] There are no particular restrictions on the content of solvent A, and it can be appropriately selected depending on the purpose, but it is preferably 50% by mass or more and 99.9% by mass or less, and more preferably 90% by mass or more and 99.9% by mass or less, relative to the total amount of liquid A. A stable dispersion can be prepared if the content of solvent A is between 50% by mass and 99.9% by mass relative to the total volume of liquid A.

[0105] -solvent B- There are no particular restrictions on solvent B, and it can be appropriately selected depending on the purpose. Examples include dichloromethane, methyl acetate, and hexafluoro-2-propanol.

[0106] There are no particular restrictions on the content of solvent B, and it can be appropriately selected depending on the purpose, but it is preferably 50% by mass or more and 99.9% by mass or less, and more preferably 70% by mass or more and 99.9% by mass or less, relative to the total amount of liquid B. A stable dispersion can be prepared if the content of solvent B is between 50% by mass and 99.9% by mass relative to the total volume of liquid B.

[0107] The preferred ratio of liquid A to liquid B in the dispersion is 0.1:99.9 to 40:70 in terms of the mass of liquid A to the mass of liquid B, and more preferably 0.5:99.5 to 30:80.

[0108] There are no particular restrictions on the droplet size of liquid A in the dispersion, and it can be appropriately selected according to the purpose, but it is preferably 50 nm to 10 μm, and more preferably 100 nm to 5 μm. If the droplet diameter of liquid A in the dispersion is 50 nm or larger, the occurrence of dispensing failures during droplet dispensing due to droplet coalescence can be suppressed. If the droplet diameter of liquid A in the dispersion is 10 μm or less, the occurrence of dispensing failures during droplet ejection can be suppressed.

[0109] There are no particular restrictions on the content of the physiologically active substance in the dispersion, and it can be appropriately selected according to the purpose, but it is preferably 0.05% by mass or more and 50% by mass or less relative to the total amount of liquid A, and more preferably 0.1% by mass or 20% by mass or less.

[0110] Other additives besides physiologically active substances may be dissolved in solutions A and B. There are no particular restrictions on the additives, and they can be appropriately selected depending on the purpose. Examples include surfactants and buffer solutions. Among these, it is preferable to add a surfactant to solution B from the viewpoint of stabilizing the W / O emulsion.

[0111] There are no particular restrictions on the surfactant, and it can be appropriately selected according to the purpose. Examples include benzalkonium chloride, lecithin, sorbitan fatty acid esters, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene glycol, polyoxyethylene sorbitan monooleate, polyvinyl alcohol, sorbitan monooleate, glyceryl monostearate, glyceryl monostearate, polyglycerin fatty acid esters, polysorbates such as polysorbate 80, polyoxyethylene-polyoxypropylene copolymers, and sodium lauryl sulfate. These can be used individually or in combination of two or more.

[0112] There are no particular restrictions on the hydrophilic-lipophilic balance, which is an indicator of a surfactant, and it can be appropriately selected according to the purpose, but a value of 1 to 8 is preferred, and a value of 3 to 6 is more preferred. Among these, sorbitan sesquioleate (hydrophilic-lipophilic balance: 4) is particularly preferred.

[0113] There are no particular restrictions on the surfactant content, and it can be appropriately selected depending on the purpose, but it is preferably 0.05% by mass or more and 5% by mass or less, and more preferably 0.05% by mass or more and 1% by mass or less, relative to the total amount of liquid B. A surfactant content of 0.05% by mass or more and 5% by mass or less is preferable because it can be recovered as a powder when atomized. In other words, if the surfactant content is less than 0.05% by mass, the substrate cannot be sufficiently dispersed, and if the surfactant content exceeds 5% by mass, the interfacial tension of the substrate becomes too weak, making it impossible to recover it as a powder.

[0114] There are no particular restrictions on the viscosity of the physiologically active substance-containing solution, and it can be appropriately selected according to the purpose, but a viscosity of 0.5 mPa·s to 15.0 mPa·s is preferred, and a viscosity of 0.5 mPa·s to 10.0 mPa·s is more preferred. A viscosity of the physiologically active substance-containing liquid between 0.5 mPa·s and 15.0 mPa·s is preferable because it allows for effective dispensing of droplets.

[0115] The viscosity of a solution containing physiologically active substances is measured, for example, using a viscoelasticity measuring device (device name: MCR rheometer, manufactured by Anton Paar) at 25°C and a shear rate of 10s. -1 It can be measured under these conditions.

[0116] There are no particular restrictions on the surface tension of the physiologically active substance-containing solution, and it can be appropriately selected depending on the purpose, but it is preferably 10 mN / m to 60 mN / m, and more preferably 20 mN / m to 50 mN / m.

[0117] The surface tension of a solution containing a physiologically active substance can be measured, for example, using a handheld surface tensimeter (device name: PocketDyne, manufactured by KRUSS) by the maximum bubble pressure method at 25°C and with a lifetime of 1,000 ms.

[0118] <Container for containing physiologically active substance liquid> A container for a solution containing a physiologically active substance is a container that holds a solution containing a physiologically active substance. There are no particular restrictions on the material of the container for the physiologically active substance-containing liquid; it can be appropriately selected according to the purpose, and it may be flexible or non-flexible, made of resin or metal. There are no particular restrictions on the structure of the container for the liquid containing the physiologically active substance, and it can be appropriately selected according to the purpose. For example, it may be a sealed structure or an open structure.

[0119] <Discharge process and discharge means> The dispensing process is the process of dispensing a solution containing physiologically active substances as droplets. The dispensing means is a means for dispensing a solution containing a physiologically active substance as droplets.

[0120] The dispensing means is connected, for example, to a container holding a liquid containing a physiologically active substance by a pipe (tube, etc.).

[0121] <<Discharge process of the first embodiment>> The discharge step of the first embodiment involves discharging a physiologically active substance-containing liquid into a gas.

[0122] <<Discharge process of the second embodiment>> The discharge step of the second embodiment involves discharging a physiologically active substance-containing liquid into a vacuum.

[0123] <<Discharge process of the third embodiment>> The discharge step of the third embodiment involves discharging a physiologically active substance-containing liquid into a liquefied gas.

[0124] The following describes matters common to the discharge process of the first to third embodiments.

[0125] There are no particular restrictions on the method of dispensing droplets, and it can be appropriately selected depending on the purpose. For example, the following methods can be used. (i) A method using a dispensing means that dispenses a pressurized liquid containing a physiologically active substance as droplets from holes provided on a flat nozzle forming surface, such as an inkjet nozzle. (ii) A method using a dispensing means that dispenses a pressurized solution containing a physiologically active substance as droplets from pores having an irregular shape, such as an SPG membrane. (iii) A method using a dispensing means that dispenses a physiologically active substance-containing liquid from a dispensing port by vibration. Among these, (iii) is preferred.

[0126] When the dispensing method of (iii) is adopted as the method for dispensing droplets, it is preferable that the dispensing means has a vibration-applying member that applies vibration to the physiologically active substance-containing liquid to dispense droplets. There are no particular restrictions on the vibration-applying member, and it can be appropriately selected according to the purpose; for example, an inkjet nozzle can be used.

[0127] In the ejection method of (iii), examples of ejection mechanisms for the inkjet nozzle include ejection means that do not easily apply external stress to the physiologically active substance-containing liquid itself, such as ejection means that utilize the membrane vibration method, ejection means that utilize the Rayleigh splitting method, ejection means that utilize the liquid vibration method, and ejection means that utilize the liquid column resonance method. With these ejection methods, it is possible to suppress changes in the physiological activity of the physiologically active substance due to vibration. Furthermore, these dispensing means may include means for dispensing a physiologically active substance-containing liquid under pressure. Among these, a dispensing method that utilizes liquid column resonance and further uses a means for dispensing by applying pressure to a physiologically active substance-containing liquid is preferred.

[0128] Discharge methods utilizing liquid column resonance include, for example, a method in which vibrations are applied to a liquid containing a physiologically active substance contained in a liquid column resonance chamber to form standing waves due to liquid column resonance, and the liquid containing the physiologically active substance is discharged from discharge holes formed in the direction of the amplitude of the standing waves in the antinode region of the standing waves.

[0129] Examples of discharge methods utilizing membrane vibration include the discharge method described in Japanese Patent Publication No. 2008-292976.

[0130] Examples of discharge means utilizing the Rayleigh splitting method include the discharge means described in Japanese Patent Publication No. 4647506.

[0131] Examples of discharge means utilizing the liquid vibration method include the discharge means described in Japanese Patent Publication No. 2010-102195.

[0132] As an example of a dispensing process, we will explain again a method of dispensing a liquid containing a physiologically active substance as droplets by vibration.

[0133] There are no particular limitations on the method for discharging a liquid containing a physiologically active substance by vibration, but examples include the following methods. (a) A method using a volume-changing means that changes the volume of the liquid container using vibration. (b) A method using a constriction generating means, in which a liquid containing a physiologically active substance is released from multiple discharge holes provided in the liquid container while vibration is applied to the liquid container, and the liquid containing the physiologically active substance is transformed from a columnar shape to a constricted state and then into a droplet. (c) A method using a nozzle vibrating means that vibrates a thin film on which a nozzle is formed.

[0134] As for the means of changing the volume, there are no particular restrictions as long as the volume of the liquid container can be changed, and it can be appropriately selected according to the purpose. For example, a piezoelectric element (piezo element) that expands and contracts when a voltage is applied can be used.

[0135] Examples of means for generating constriction include methods using the technology described in Japanese Patent Publication No. 2007-199463. Japanese Patent Publication No. 2007-199463 describes a method in which vibration is applied to the liquid container using a piezoelectric element in contact with a part of the liquid container, while releasing liquid from a plurality of nozzle holes provided in the liquid container, thereby converting the liquid from a columnar shape to a constricted state and then into droplets.

[0136] Examples of nozzle vibration means include methods using the technology described in Japanese Patent Publication No. 2008-292976. Japanese Patent Publication No. 2008-292976 describes a means for releasing liquid from multiple nozzle holes and forming it into droplets, using a thin film in which multiple nozzles are formed in a liquid-containing section, and piezoelectric elements arranged around a deformable region of the thin film to vibrate the thin film.

[0137] There are no particular restrictions on the piezoelectric element; its shape, size, and material can be appropriately selected. For example, piezoelectric elements used in conventional inkjet ejection systems can be suitably used.

[0138] There are no particular restrictions on the shape and size of the piezoelectric element, and they can be appropriately selected according to the shape of the discharge hole, etc. There are no particular restrictions on the material of the piezoelectric element, and it can be appropriately selected according to the purpose. Examples include piezoelectric ceramics such as lead zirconate titanate (PZT), piezoelectric polymers such as polyvinylidene fluoride (PVDF), and single crystals such as quartz, LiNbO3, LiTaO3, and KNbO3.

[0139] There are no particular restrictions on the discharge port, and it can be appropriately selected according to the purpose. For example, it can be an opening provided in a nozzle plate or the like.

[0140] There are no particular restrictions on the cross-sectional shape of the discharge port, and it can be appropriately selected according to the purpose. Examples include: (1) a tapered shape in which the opening diameter decreases from the inside (liquid containment side) to the outside (side from which the physiologically active substance-containing liquid is discharged); (2) a shape in which the opening diameter narrows while having a rounded shape from the inside (liquid containment side) to the outside (side from which the physiologically active substance-containing liquid is discharged); (3) a shape in which the opening diameter narrows with a constant nozzle angle from the inside (liquid containment side) to the outside (side from which the physiologically active substance-containing liquid is discharged); and (4) a combination of the shapes of (1) and (2). Among these, shape (3) is preferred because it provides the maximum pressure on the physiologically active substance-containing liquid at the discharge port.

[0141] There are no particular restrictions on the nozzle angle in the shape of (3), and it can be appropriately selected according to the purpose, but from the viewpoint of stabilizing the discharge of the physiologically active substance-containing liquid, 60° to 90° is preferred.

[0142] There are no particular restrictions on the size of the discharge hole, and it can be appropriately selected according to the purpose, but it is preferable that the diameter is less than 1,000 μm, more preferably that the diameter is 1.0 μm or more and less than 1,000 μm, even more preferably that the diameter is 1.0 μm or more and 500 μm or less, and particularly preferably that the diameter is 1.0 μm or more and 50 μm or less. If the shape of the discharge hole is not a perfect circle, the diameter of a perfect circle with an area equivalent to the area of ​​the discharge hole shall be adopted as the diameter of the discharge hole.

[0143] There are no particular restrictions on the vibration, and it can be appropriately selected according to the purpose, but it is preferable that the frequency is 1 kHz or higher, more preferably 150 kHz or higher, and even more preferably 300 kHz to 500 kHz. When the frequency is 1 kHz or higher, the liquid column ejected from the discharge port can be reliably atomized into droplets, and when the frequency is 150 kHz or higher, production efficiency can be improved.

[0144] <Granulation process and granulation means> The granulation process is a process of removing the solvent from a liquid droplet to form particles. The granulation method is a means of granulating particles by removing the solvent from a liquid droplet.

[0145] In this specification, "removal" means that the solvent contained in the liquid phase is removed from the liquid phase, but is not limited to the case where all of the solvent contained in the liquid phase is removed; some of the solvent contained in the liquid phase may remain as long as particles can be granulated.

[0146] There are no particular restrictions on the removal method, and it can be appropriately selected depending on the purpose. For example, methods include contacting a liquid phase with a gas to diffuse the solvent contained in the liquid phase into another gas phase, or vaporizing the solvent contained in the liquid phase in a vacuum or in a liquefied gas, freezing the liquid phase in the process, and then freeze-drying it.

[0147] <<Granulation process of the first embodiment>> The granulation process in the first embodiment is carried out in a gas. Specifically, it is preferable that the granulation process is carried out while the droplets discharged into the gas in the discharge process are flying through the gas. By going through such a granulation process, the resulting particles can be in the form of a solid dispersion, that is, a form in which a physiologically active substance is dispersed in a substrate.

[0148] Various dry granulation methods are known for granulating particles in a gas, such as the granulation process of the first embodiment. For example, there are gas pulverization methods such as a method in which particulate material is melted and kneaded to uniformly disperse the material, the molten mixture is cooled, and then pulverized using a pulverizer to obtain finely sized pulverized particles; a method in which a liquid containing particulate material is freeze-dried and then pulverized using a pulverizer to obtain finely sized pulverized particles; and a spray drying method (spray drying method) in which a liquid containing particulate material is sprayed into the air and dried to obtain finely sized spray particles. Methods for spraying liquid into the air include pressurized nozzle systems, which pressurize the liquid and eject it from a nozzle, and disc systems, which send the liquid to a rapidly rotating disc and disperse it using centrifugal force.

[0149] While the air-based pulverization method uses simple equipment, it has the drawback of being difficult to produce particles with a narrow particle size distribution. In a method for pulverizing a molten compound, if the particle material includes a physiologically active substance whose physiological activity changes upon heating, the physiological activity of the physiologically active substance may change, resulting in a decrease in the amount of physiological activity in the particles. In a method for pulverizing freeze-dried materials, if the particle material includes a physiologically active substance whose physiological activity changes upon cooling, the physiological activity of the physiologically active substance may change, resulting in a decrease in the amount of physiological activity in the particles. In the air-pulverization method, large external stresses are generated during the pulverization process. Therefore, if the particle material contains a physiologically active substance whose physiological activity changes due to external stress, the physiological activity of that substance may change, resulting in a decrease in the amount of physiological activity in the particles.

[0150] While spray drying can produce particles with a high proportion of bioactive substances retained within them (bioactive substance retention rate), it is difficult to produce small particles. Although it is sometimes possible to produce small particles using a disc-type spraying method, this requires large-scale equipment. The spray drying method makes it difficult to produce particles with a narrow particle size distribution because droplets tend to adhere to each other in the air. To suppress droplet adhesion in the air, it is necessary to heat the droplets immediately after spraying so that they dry quickly. However, if the particle material contains a physiologically active substance whose physiological activity changes with heating, the physiological activity of that substance may change, resulting in a decrease in the amount of physiological activity in the particles. In spray drying, the spraying process generates significant external stress due to the high shear force. If the particle material contains a physiologically active substance whose physiological activity changes under external stress, the physiological activity of that substance may change, resulting in a decrease in the amount of physiological activity in the particles.

[0151] The particle manufacturing method of the present invention does not correspond to the above-described air pulverization method and spray drying method, and does not require drying with heating or external stress for droplet miniaturization. Therefore, even if the particle material contains a physiologically active substance whose physiological activity changes due to heating or external stress, it is possible to suppress the change in the physiological activity of the physiologically active substance, and as a result, it is possible to suppress the decrease in the amount of physiological activity during particle manufacturing.

[0152] In the particle manufacturing method of the present invention, droplets of substantially uniform size can be dispensed and granulated while controlling that the droplets do not adhere to each other, making it possible to stably produce particles of uniform size. In other words, particles with a narrow particle size distribution can be obtained.

[0153] In the granulation process of the first embodiment, since the particles do not come into contact with a solvent such as water during granulation, the proportion of physiologically active substances retained in the particles (physiologically active substance retention rate) can be increased. The physiologically active substance retention rate can be, for example, 80% or more.

[0154] In the granulation process of the first embodiment, droplets may be discharged into a transport airflow and the solvent may be vaporized from the droplets to form particles. In this case, the granulation means of the first embodiment may include a transport airflow forming means for forming the transport airflow. There are no particular restrictions on the method of vaporizing a solvent from a droplet using a transport airflow, and it can be appropriately selected according to the purpose. For example, the transport direction of the transport airflow may be approximately perpendicular to the direction in which the droplet is discharged, or the transport direction of the transport airflow may be the same as the direction in which the droplet is discharged. It is preferable to appropriately adjust the temperature, vapor pressure, and type of gas of the conveying airflow. If heating is performed to adjust the temperature of the conveying airflow, it is preferable to set the temperature to a level that does not alter the physiological activity of the physiologically active substance.

[0155] If the particles collected after the granulation process in the first embodiment are in a solid state, the solvent does not need to be completely vaporized. In that case, a separate drying process or a process to vaporize the solvent from the droplets using temperature changes or chemical changes may be provided in a later step.

[0156] When granulating particles in which a physiologically active substance-containing liquid contains two or more substrates, and one of these substrates is biased towards the surface side of the particle, it is preferable that the contact angles of at least two of the substrates are different. With such a configuration, the interaction between the substrates increases, making it easier for the substrates to phase separate when the solvent vaporizes during the granulation process, and resulting in the formation of particles in which at least one of the two substrates is biased towards the surface side.

[0157] There are no particular restrictions on the difference in contact angles between at least two types of substrates, and they can be appropriately selected depending on the purpose. However, from the viewpoint of facilitating phase separation between the substrates, a difference of 1.0° or more is preferred, and a difference of 10.0° or more is more preferred.

[0158] There are no particular restrictions on the method for measuring the contact angle of a substrate; it can be appropriately selected depending on the purpose. For example, one method is to measure it using a contact angle meter. An example of a contact angle meter is the FIBRO system portable contact angle meter PG-X+ / mobile contact angle meter.

[0159] There are no particular restrictions on the method for confirming whether or not phase separation occurs in at least two types of substrates, and a suitable method can be selected depending on the purpose. For example, a method can be used in which a solution of at least two types of substrates dissolved in a good solvent is formed into a thin film using a bar coater, and the state before drying, during drying, and after drying is confirmed using an optical microscope (for example, an OLYMPUS BX51 manufactured by Olympus Corporation).

[0160] When the solvent used with the substrate is lipophilic, one substrate that is biased towards the surface is selected to have a larger contact angle than the other substrates that are biased towards the inside of the particles. As a result, the substrate with a larger contact angle has a greater affinity for the solvent than the other substrates that are biased towards the inside of the particles, and therefore tends to be biased towards the solvent side, i.e., the surface side. For example, if you want to produce particles containing a water-soluble physiologically active substance, by using a lipophilic solvent, you can create a structure in which the physiologically active substance is concentrated on the inside of the particles, and the inside is coated with a substrate that concentrates the physiologically active substance on the surface.

[0161] When the solvent used with the substrate is hydrophilic, one substrate that is biased towards the surface is selected to have a smaller contact angle than the other substrates that are biased towards the inside of the particles. As a result, the substrate with the smaller contact angle has a lower affinity for the solvent than the other substrates that are biased towards the inside of the particles, and therefore tends to be biased towards the solvent side, i.e., the surface side. For example, if you want to produce particles containing an oil-soluble physiologically active substance, by making the solvent hydrophilic, you can create a structure in which the physiologically active substance is biased towards the inside of the particle, and the inside is coated with a substrate that biases the physiologically active substance towards the surface.

[0162] As one of the substrates to be incorporated predominantly on the surface side, it is preferable to use a pH-responsive material. Furthermore, when producing particles to be incorporated into an enteric-coated pharmaceutical composition, it is even more preferable to use at least one of cellulose-based polymers and methacrylic acid-based polymers as the pH-responsive material, from the viewpoint of having a larger contact angle compared to other substrates.

[0163] Among cellulosic polymers, it is preferable to use at least one selected from hydroxypropyl methylcellulose acetate succinate and hydroxypropyl methylcellulose phthalate, from the viewpoint of having a larger contact angle compared to other substrates.

[0164] Among methacrylic acid polymers, ammoniaalkyl methacrylic acid ester copolymers are preferred from the viewpoint of having a larger contact angle compared to other substrates.

[0165] There are no particular restrictions on the combination of one substrate that is predominantly contained on the surface side and the other substrate that is predominantly contained on the inside, and they can be appropriately selected according to the purpose. However, from the viewpoint of mutual immismatch and phase separation, a combination of one selected from poly(meth)acrylic acid, polyglycolic acid, and hydroxypropyl methylcellulose and one selected from hydroxypropyl cellulose, polyethylenepyrrolidone, and polyalkylene glycol is preferred.

[0166] <<Granulation process of the second embodiment>> The granulation process in the second embodiment is carried out in a vacuum. Specifically, it is preferable to vaporize the solvent from the droplets discharged into the vacuum in the discharge process, freeze the liquid phase in that process, and then remove the solvent by freeze-drying. In the second embodiment, descriptions that overlap with those in the first embodiment will be omitted.

[0167] The effects obtained by the granulation process of the second embodiment are the same as those obtained by the granulation process of the first embodiment. In addition, unlike the conventional spray drying method, the granulation process of the second embodiment freezes rapidly after discharge. Therefore, even if the granulation process contains physiologically active substances that are particularly susceptible to changes in physiological activity due to heating, the change in the physiological activity of such substances can be suppressed, and as a result, the decrease in the amount of physiological activity can be suppressed.

[0168] The granulation means of the second embodiment may include a freeze-drying means. There are no particular restrictions on the freeze-drying means, and it can be appropriately selected depending on the purpose.

[0169] <<Granulation process of the third embodiment>> The granulation process in the third embodiment is carried out in a liquefied gas. Specifically, it is preferable to cool the droplets discharged into the liquefied gas in the discharge process, freeze the liquid phase in the process, and then remove the solvent by freeze-drying. In the third embodiment, descriptions that overlap with those in the first and second embodiments will be omitted.

[0170] The effects obtained by the granulation process of the third embodiment are the same as those obtained by the granulation process of the second embodiment.

[0171] The granulation means of the third embodiment is the same as that of the second embodiment.

[0172] In the particle manufacturing method of the present invention, the physiological activity ratio {(physiological activity amount B / physiological activity amount A) × 100} of the physiological activity amount B in the particles after the granulation step relative to the physiological activity amount A in the physiologically active substance before the preparation step of the physiologically active substance-containing liquid is 80% or more.

[0173] The rate of biological activity is affected by factors such as the rate of maintenance of biological activity and the rate of retention of biologically active substances. The bioactivity retention rate represents the proportion of bioactive substances in a particle whose bioactivity is maintained throughout the particle manufacturing process. Since the bioactivity of bioactive substances can change due to heating or external stress, if processes involving heating, shaking, or stirring are performed during the particle manufacturing process, the bioactivity retention rate decreases, and as a result, the bioactivity rate also decreases. The bioactive substance retention rate refers to the proportion of bioactive substances retained within a particle. For example, during the particle manufacturing process, bioactive substances may be lost due to decomposition or leakage, resulting in a decrease in the total amount of bioactive substances retained within the particle. In this case, the bioactive substance retention rate decreases, and consequently, the bioactivity rate also decreases.

[0174] There are no particular restrictions on the method for producing particles with a biological activity rate of 80% or higher, and a suitable method can be selected depending on the purpose. For example, a method that does not involve heating or applying external stress to the liquid and droplets containing the biologically active substance can be used.

[0175] <Other processes and other means> Other processes are not particularly limited and can be selected as appropriate depending on the purpose; for example, a particle collection process is one such example. Other methods are not particularly limited and can be selected as appropriate depending on the purpose, and examples include particle collection methods.

[0176] The particle collection process is the process of collecting the manufactured particles. There are no particular restrictions on the particle collection method, and it can be appropriately selected according to the purpose. Examples include cyclone collection and back filters.

[0177] Here, a particle manufacturing apparatus according to the present invention will be described with reference to the drawings. However, the present invention is not limited in any way to these embodiments. In addition, the same reference numerals are used for identical components in each drawing, and redundant explanations may be omitted. Furthermore, the number, position, shape, etc. of the components are not limited to this embodiment, and can be set to a number, position, shape, etc. that is preferable for carrying out the present invention.

[0178] [Figure 1] Figure 1 is a schematic diagram showing an example of a particle manufacturing apparatus according to a first embodiment of the present invention.

[0179] As shown in Figure 1, the particle manufacturing apparatus 300 includes a discharge means 302, a drying and collection unit 360, a conveying airflow outlet 365, and a particle storage unit 363.

[0180] The discharge means 302 is connected to a physiologically active substance-containing liquid container 313 that contains the physiologically active substance-containing liquid 314, and a liquid circulation pump 315 that pumps the physiologically active substance-containing liquid 314 from the liquid supply pipe 316.

[0181] The liquid circulation pump 315 supplies the physiologically active substance-containing liquid 314 contained in the physiologically active substance-containing liquid container 313 to the discharge means 302 through the liquid supply pipe 316, and returns the physiologically active substance-containing liquid 314 to the physiologically active substance-containing liquid container 313 through the liquid return pipe 322. Therefore, the physiologically active substance-containing liquid 314 is supplied to the discharge means 302 as needed.

[0182] A pressure measuring device P1 is provided in the liquid supply pipe 316. A pressure measuring device P2 is provided in the drying and collection unit 360. The liquid supply pressure to the discharge means 302 and the pressure inside the drying and collection unit 360 are controlled by pressure measuring devices P1 and P2. It is preferable that the pressure readings from pressure measuring device P1 and pressure readings from pressure measuring device P2 be controlled to be approximately the same. If the pressure reading from pressure measuring device P1 is greater than the pressure reading from pressure measuring device P2, there is a risk that the physiologically active substance-containing liquid 314 may leak out of the discharge port. If the pressure reading from pressure measuring device P1 is less than the pressure reading from pressure measuring device P2, there is a risk that gas may enter the discharge means 302 and the discharge may stop.

[0183] Inside the chamber 361, a transport airflow 301 (downward airflow) is formed from the transport airflow inlet 364. The droplets 321 discharged from the discharge means 302 are transported downward by gravity and the transport airflow 301, pass through the transport airflow outlet 365, are collected by the particle collection means 362, and stored in the particle storage section 363.

[0184] In the dispensing process, if dispensed droplets come into contact with each other before drying, they may stick together. Specifically, although dispensed droplets have a certain initial velocity, they lose speed due to air resistance. As a result, they may be overtaken by droplets dispensed later, and if these droplets are not sufficiently dried, they may stick together. Therefore, from the viewpoint of suppressing the decrease in droplet velocity and preventing contact between droplets, it is preferable to dry and transport the droplets using a transport airflow.

[0185] The transport airflow 301 is positioned near the discharge means 302 in the same direction as the droplet discharge direction.

[0186] [Figure 2] Figure 2 is a schematic cross-sectional view showing an example of a liquid column resonance droplet dispensing means 3021 as a dispensing means 302 in a particle manufacturing apparatus 300 according to a first embodiment of the present invention.

[0187] The liquid column resonance droplet dispensing means 3021 has a common liquid supply passage 317 and a liquid column resonance liquid chamber 319.

[0188] The liquid column resonance chamber 319 is connected to a common liquid supply passage 317 provided on one of the walls at both ends in the longitudinal direction.

[0189] The liquid column resonant chamber 319 has a discharge hole 318 for discharging droplets 321 from one of the walls connected to both ends, and a vibration generating means 320 provided on the wall opposite the discharge hole 318, which generates high-frequency vibrations to form a liquid column resonant standing wave. A high-frequency power supply is connected to the vibration generating means 320.

[0190] The liquid column resonance droplet discharge means 3021 may be provided with an airflow passage that supplies an airflow to transport the discharged droplets 321.

[0191] The physiologically active substance-containing liquid 314 flows through the liquid supply pipe via a liquid circulation pump into the common liquid supply passage 317 of the liquid column resonance droplet discharge means 3021 and is supplied to the liquid column resonance liquid chamber 319.

[0192] In the liquid column resonance chamber 319, which is filled with a physiologically active substance-containing liquid 314, a pressure distribution is formed by liquid column resonance standing waves generated by the vibration generating means 320. Droplets 321 are discharged from discharge holes 318 located in the antinode region of the liquid column resonance standing wave (the region with large amplitude and large pressure fluctuations).

[0193] The regions that become antinodes of standing waves due to liquid column resonance are regions other than the nodes of the standing waves, and are preferably regions in which the pressure fluctuations of the standing waves have an amplitude large enough to discharge the physiologically active substance-containing liquid 314. More preferably, the region is ±1 / 4 wavelength from the position where the amplitude of the pressure standing wave is maximum (node ​​as a velocity standing wave) toward the position where it is minimum.

[0194] In regions that form antinodes of standing waves, even if there are multiple discharge holes, nearly uniform droplets can be formed from each, droplets can be discharged efficiently, and clogging of the discharge holes becomes less likely.

[0195] The physiologically active substance-containing liquid 314 that has passed through the common liquid supply channel 317 is circulated by the liquid return pipe. When the amount of physiologically active substance-containing liquid 314 in the liquid column resonance chamber 319 decreases due to the discharge of droplets 321, an attractive force due to the action of liquid column resonance standing waves in the liquid column resonance chamber 319 acts, and the flow rate of physiologically active substance-containing liquid 314 supplied from the common liquid supply channel 317 increases. Then, the physiologically active substance-containing liquid 314 is replenished in the liquid column resonance chamber 319.

[0196] The liquid column resonant liquid chamber 319 in the liquid column resonant droplet dispensing means 3021 is formed by a frame made of a material with high rigidity that does not affect the resonant frequency of the liquid at the driving frequency. Examples of such high-rigidity materials include metals, ceramics, and silicone.

[0197] As shown in Figure 2, the length L between the walls at both ends in the longitudinal direction of the liquid column resonance chamber 319 is determined based on the principle of liquid column resonance.

[0198] It is preferable that multiple liquid column resonance chambers 319 are arranged for a single droplet formation unit in order to dramatically improve productivity. There are no particular restrictions on the number of liquid column resonant liquid chambers 319, and they can be appropriately selected according to the purpose, but it is preferable to have between 1 and 2,000.

[0199] Each liquid column resonance chamber 319 is connected to a common liquid supply passage 317 for liquid supply, and the common liquid supply passage 317 may be configured to communicate with multiple liquid column resonance chambers 319.

[0200] The vibration generating means 320 in the liquid column resonant droplet ejection means 3021 is not particularly limited as long as it can be driven at a predetermined frequency and can be appropriately selected according to the purpose, but it is preferable that the piezoelectric body is attached to an elastic plate 309 which constitutes part of the wall of the liquid column resonant chamber so that it does not come into contact with the liquid. Furthermore, from a productivity standpoint, a frequency of 150 kHz or higher is preferable, and 300 kHz to 500 kHz is more preferable.

[0201] Examples of piezoelectric materials include piezoelectric ceramics such as lead zirconate titanate (PZT), which are often used in stacked form due to their generally small displacement. Other examples include piezoelectric polymers such as polyvinylidene fluoride (PVDF), and single crystals such as quartz, LiNbO3, LiTaO3, and KNbO3.

[0202] It is preferable that the vibration generating means 320 be arranged so that each liquid column resonant liquid chamber 319 can be controlled individually.

[0203] The number of discharge holes 318 may be increased to improve production efficiency. In this case, it is preferable that the discharge holes 318 be arranged in the width direction within the liquid column resonance chamber 319. The liquid column resonance frequency fluctuates depending on the arrangement of the discharge holes 318, so it is desirable to determine it appropriately by checking the discharge of liquid droplets.

[0204] If the amount of residual solvent in the particles obtained by the particle collection means 362 is large, it is preferable to perform secondary drying. For secondary drying, commonly known drying methods such as fluidized bed drying or vacuum drying can be used.

[0205] [Figure 3] The particle manufacturing apparatus 300 may employ a discharge means 3022 utilizing the Rayleigh splitting method instead of the liquid column resonance droplet discharge means 3021 described above. Figure 3 is a schematic cross-sectional view showing an example of a discharge means 3022 utilizing the Rayleigh splitting method as the discharge means 302 in the particle manufacturing apparatus 300 of the first embodiment of the present invention.

[0206] The discharge means 3022, which utilizes the Rayleigh splitting method, has a storage section 601 for storing a liquid containing a physiologically active substance, a vibrating means 602, and a plurality of through holes 603.

[0207] There are no particular restrictions on the material of the storage section 601, and it can be appropriately selected according to the purpose. However, from the viewpoint of holding the physiologically active substance-containing liquid under pressure, a material with a pressure resistance of about 10 MPa is preferred. Specific materials include, for example, metals such as SUS and aluminum.

[0208] The storage unit 601 is connected to the storage unit 601 by a supply pipe 604 that supplies a liquid containing a physiologically active substance to the storage unit 601.

[0209] The storage section 601 is provided with a through-holding mechanism 605 that holds a plate having through-holes 603 for discharging droplets 609.

[0210] A vibration means 602 for vibrating the entire storage section 601 is provided in contact with the storage section 601. The vibration means 602 is connected to a vibration generator 606 and a conductive wire 607.

[0211] The vibration means 602 is preferably one that excites the entire storage section 601. The vibration means 602 is not particularly limited as long as it can provide vibration at a constant frequency and can be appropriately selected according to the purpose. For example, it may be one in which vibration at a constant frequency is formed by the expansion and contraction of a piezoelectric body.

[0212] There are no particular restrictions on the constant frequency, and it can be appropriately selected depending on the purpose, but a range of 10 kHz to 10 MHz is preferred, and a range of 50 kHz to 2 MHz is more preferred from the viewpoint of generating fine droplets with extremely uniform particle size.

[0213] The storage section 601 is provided with an opening valve 608 for adjusting the pressure and removing internal air bubbles, from the viewpoint of stably forming the liquid column.

[0214] [Figure 4] Figure 4 is a schematic diagram showing another example of a particle manufacturing apparatus according to the first embodiment of the present invention. Note that the same configuration as that of the particle manufacturing apparatus in the first embodiment is omitted from the description.

[0215] As shown in Figure 4, in the airflow passage 312, the conveying airflow 301 may be approximately perpendicular to the discharge direction.

[0216] The transport airflow 301 may have an angle, as long as it moves the droplets 321 away from the discharge means 302, from the viewpoint of preventing droplets from sticking together. It is preferable to adjust the position of the discharge holes 318 so that the trajectories of the droplets 321 transported by the transport airflow 301 do not overlap. Alternatively, after preventing the droplets 321 from adhering to each other using the transport airflow 301, the particles may be transported to the particle collection means using a separate airflow.

[0217] The velocity of the conveying airflow 301 is preferably equal to or greater than the discharge velocity. If the velocity of the conveying airflow is faster than the discharge velocity, the adhesion of droplets can be suppressed.

[0218] The conveying airflow 301 may contain a chemical substance that promotes the drying of the droplets 321.

[0219] The state of the conveying airflow 301 is not particularly limited and can be appropriately selected according to the purpose; for example, it may be laminar flow, swirling flow, or turbulent flow.

[0220] There are no particular restrictions on the type of gas that constitutes the conveying airflow 301; it can be appropriately selected according to the purpose. Examples include air, non-flammable gases such as nitrogen, etc.

[0221] [Figure 5] Figure 5 is a schematic diagram showing an example of a particle manufacturing apparatus 400 according to a second embodiment of the present invention.

[0222] The particle manufacturing apparatus 400 shown in Figure 5 includes a discharge means 402, a chamber 461, a vacuum pump 460, and a freeze-drying apparatus 463.

[0223] The discharge means 402 is connected to a physiologically active substance-containing liquid container 413 that contains the physiologically active substance-containing liquid 414, and a liquid circulation pump 415 that pumps the physiologically active substance-containing liquid 414 from the liquid supply pipe 416.

[0224] The liquid circulation pump 415 supplies the physiologically active substance-containing liquid 414 contained in the physiologically active substance-containing liquid container 413 to the discharge means 402 through the liquid supply pipe 416, and returns the physiologically active substance-containing liquid 414 to the physiologically active substance-containing liquid container 413 through the liquid return pipe 422. Therefore, the physiologically active substance-containing liquid 414 is supplied to the discharge means 402 as needed.

[0225] Chamber 461 is a sealed container and is equipped with a cooling jacket through which the refrigerant 464 flows.

[0226] Chamber 461 is sucked by a vacuum pump 460 and a vacuum is maintained. When a droplet 421 is discharged into chamber 461, the solvent evaporates, and the latent heat of evaporation causes the droplet 421 to freeze, becoming a frozen product 462.

[0227] In the discharge process, if the discharged droplets 421 come into contact with each other before freezing, they may adhere to one another. From the viewpoint of obtaining particles with a narrow particle size distribution, it is preferable that sufficient distance is maintained between the discharged droplets 421. From the viewpoint of preventing the droplets 421 from adhering to each other, a conveying airflow may be arranged to freeze the droplets 421 while they are being conveyed.

[0228] The frozen material 462 is removed from the particle manufacturing apparatus 400 and freeze-dried in the freeze-drying apparatus 463 to obtain dried particles. There are no particular restrictions on the freeze-drying apparatus, and it can be appropriately selected according to the purpose. For example, it may be a batch type or a continuous type. Among these, a continuous freeze-drying apparatus is preferred from the viewpoint of productivity.

[0229] [Figure 6] Figure 6 is a schematic diagram showing an example of a particle manufacturing apparatus 500 according to a third embodiment of the present invention.

[0230] As shown in Figure 6, the particle manufacturing apparatus 500 includes a discharge means 502, a chamber lid 560, a chamber 561, and a freeze-drying apparatus 563.

[0231] The discharge means 502 is connected to a physiologically active substance-containing liquid container 513 that contains the physiologically active substance-containing liquid 514 and a liquid circulation pump 515 that pumps the physiologically active substance-containing liquid 514 in the liquid supply pipe 516.

[0232] The liquid circulation pump 515 supplies the physiologically active substance-containing liquid 514 contained in the physiologically active substance-containing liquid container 513 to the discharge means 502 through the liquid supply pipe 516, and returns the physiologically active substance-containing liquid 514 to the physiologically active substance-containing liquid container 513 through the liquid return pipe 522. Therefore, the physiologically active substance-containing liquid 514 is supplied to the discharge means 502 as needed.

[0233] The chamber 561 is an insulated container and preferably has a Dewar flask structure. The chamber 561 is filled with liquefied gas 523.

[0234] It is preferable that the liquefied gas 523 be stirred by an external stirring device such as a magnetic stirrer.

[0235] The chamber lid 560 is preferably an open-type container so that the liquefied gas 523 can evaporate and flow out.

[0236] In the chamber 561, the droplets 521 ejected from the ejection means 502 are conveyed downward by gravity and the conveying air flow 501, and are cooled by the liquefied gas 523 so that the droplets are frozen. The frozen droplets are dispersed in the liquefied gas 523.

[0237] In the ejection process, if the ejected droplets come into contact with each other before freezing, the droplets may merge together. Specifically, although the ejected droplets have a certain initial velocity, they stall due to air resistance. Then, they may be caught up by the droplets ejected later, and if the drying of the droplets at this time is insufficient, the droplets may merge together. Therefore, from the viewpoint of suppressing the decrease in the velocity of the droplets and preventing the droplets from contacting each other, it is preferable to convey the droplets while drying them by the conveying air flow 501.

[0238] The conveying air flow 501 is preferably arranged in the same direction as the ejection direction of the droplets 521 in the vicinity of the ejection means 502.

[0239] The frozen droplets 521 dispersed in the liquefied gas 523 are taken out from the particle production apparatus 500 while remaining in the chamber 561, and are freeze-dried by the freeze-drying apparatus 563 to obtain dried particles.

[0240] (Particles) The particles of the present invention are particles produced by the above-described particle production method.

[0241] In this specification, "particles" means a population of a physiologically active substance-containing liquid unless otherwise specified.

[0242] The particles of the present invention are preferably functional particles that exhibit a desired function. The functional particles can be designed to exhibit a desired function by appropriately selecting a base material contained in the physiologically active substance-containing liquid. Examples of functional particles include particles that deliver physiologically active substances to target sites to exert desired physiological effects, i.e., particles used in drug delivery systems (DDS); sustained-release particles that continuously release drugs over a long period; solubilizing particles for solubilizing poorly soluble physiologically active substances; immediate-release particles; pH-dependent release particles; pH-independent release particles; enteric-coated particles; release-controlled coated particles; and nanocrystal-containing particles.

[0243] Examples of particle forms used in drug delivery systems (DDS) include particles in which the physiologically active substance itself is in particulate form, capsule particles in which the physiologically active substance is encapsulated in a substrate, carrier particles in which the physiologically active substance is supported on the surface of a substrate, and other forms of particles.

[0244] Examples of capsule particles include dispersed encapsulation particles in which a physiologically active substance is dispersed and enclosed within a substrate, and unevenly distributed encapsulation particles in which a physiologically active substance is unevenly distributed and enclosed within a substrate. Furthermore, the term "encapsulation" in capsule particles is not particularly limited as long as the physiologically active substance is temporarily or continuously retained within the substrate.

[0245] The dispersed encapsulation particles are not particularly limited as long as the physiologically active substance is dispersed and encapsulated within the substrate, and the degree of dispersion of the physiologically active substance within the substrate does not need to be uniform. Furthermore, if the particles contain multiple types of substrates, and one of these substrates is unevenly distributed within the particles, the degree of dispersion may differ depending on the type of substrate at the location where the physiologically active substance is encapsulated. Examples of particles equivalent to dispersed inclusion particles include particles produced using the emulsion solvent diffusion (ESD) method and particles produced using the spray drying method.

[0246] Eccentrically distributed inclusion particles are a form in which a physiologically active substance is encapsulated within a substrate in an eccentric manner. In other words, it is a form in which the physiologically active substance is encapsulated within the substrate by the substrate and the physiologically active substance being substantially separated in position within the particle. An example of an eccentrically distributed inclusion particle is a particle having a central part containing the physiologically active substance and an outer periphery containing the substrate and enclosing the central part. Examples of particles corresponding to eccentrically distributed inclusion particles include liposomes, micelles, and coated particles.

[0247] Supported particles are a form in which physiologically active substances are supported by adsorption or bonding to the surface of a substrate. Types of adsorption include chemiadsorption and physiadsorption. Types of bonding include hydrogen bonds, covalent bonds, ionic bonds, and chelate bonds. Examples of particles corresponding to carrier particles include porous particles on which a physiologically active substance is supported on the porous surface of a substrate (including not only the outer surface but also the inner surface).

[0248] The particles of the present invention may contain two or more substrates, and if they contain two or more substrates, one of the substrates may be contained predominantly on the surface side of the particles. In this case, the physiologically active substance can be dispersed and encapsulated in both the substrate contained predominantly on the surface side of the particles (hereinafter also referred to as the "surface substrate") and the substrates other than the surface substrate (hereinafter also referred to as the "internal substrate"). Specific examples of this embodiment include forms in which the physiologically active substance is predominantly contained on the surface substrate side, and forms in which the physiologically active substance is predominantly contained on the internal substrate side. Among these, the form in which the physiologically active substance is predominantly contained on the internal substrate side is preferred. By predominantly containing the physiologically active substance on the internal substrate side, sustained-release particles can be obtained in which the elution rate of the physiologically active substance is suppressed.

[0249] There are no particular limitations on the method for confirming that the particles contain at least two types of substrates, and that one of the at least two substrates is biased towards the surface side of the particles. Such methods can be appropriately selected depending on the purpose. For example, one method is to observe the cross-section of the particles using a scanning electron microscope, a transmission electron microscope, or a scanning probe microscope. Another example involves using time-of-flight secondary ion mass spectrometry to measure the composition of the surface substrate and confirming that it is the aforementioned particle if it is determined to be different from the composition of the internal substrate. Furthermore, other confirmation methods include pretreatment such as electron staining or dissolution. For example, in the case of the above-mentioned particles consisting of a water-soluble component substrate and a water-insoluble component substrate, the particle cross-section can be immersed in water to completely dissolve the water-soluble component. By observing the cross-section with a scanning electron microscope, it can be determined that the water-insoluble component is distributed in the remaining portion of the particle cross-section and the water-soluble component is distributed in the voids, thereby identifying the particles as described above.

[0250] The RSF (Relative Span Factor) of the particles is 1.5 or less, from the perspective of drying the particles at low temperatures and preventing a decrease in the bioactivity rate. Here, RSF is an index that represents the size of the particle size distribution and is defined as (D90-D10) / D50. D90 represents the cumulative 90 volume percent from the small particle side of the cumulative particle size distribution, D50 represents the cumulative 50 volume percent from the small particle side of the cumulative particle size distribution, and D10 represents the cumulative 10 volume percent from the small particle side of the cumulative particle size distribution.

[0251] A higher RSF value indicates a broader particle size distribution, resulting in a higher proportion of coarse powder particles. These coarse powder particles require high drying temperatures, which can lead to a decrease in physiological activity. Therefore, a RSF of 1.2 or less is preferable, 1.0 or less is more preferable, and 0.6 or less is even more preferable.

[0252] The method for measuring the R.S.F. is not particularly limited and can be appropriately selected according to the purpose. For example, a method of measurement using a thick system analyzer by dynamic light scattering method (「FPAR-1000」, manufactured by Otsuka Electronics Co., Ltd.) can be mentioned.

[0253] The volume average particle size (Dv) of the particles is 1 μm or more and 50 μm or less. When the volume average particle size (Dv) of the particles is 1 μm or more and 50 μm or less, a sufficient amount of the physiologically active substance can be retained. For example, particles capable of sustained release of the physiologically active substance over a long period can be produced.

[0254] The method for measuring the volume average particle size (Dv) of the particles is not particularly limited and can be appropriately selected according to the purpose. For example, a method of measurement using a thick system analyzer by dynamic light scattering method (「FPAR-1000」, manufactured by Otsuka Electronics Co., Ltd.), a method of measurement using a laser diffraction / scattering type particle size distribution measuring device (device name: Microtrac MT3000II, manufactured by Microtrac Bell Co., Ltd.) can be mentioned.

[0255] The volume average particle size (Dv) / number average particle size (Dn) of the particles is not particularly limited and can be appropriately selected according to the purpose. However, from the viewpoint of drying the particles at a low temperature and preventing a decrease in the physiological activity rate, it is preferably 1.00 or more and 2.0 or less, and more preferably 1.00 or more and 1.50 or less.

[0256] The method for measuring the number average particle size (Dn) is not particularly limited and can be appropriately selected according to the purpose. For example, a method of measurement using a laser diffraction / scattering type particle size distribution measuring device (device name: Microtrac MT3000II, manufactured by Microtrac Bell Co., Ltd.) can be mentioned.

[0257] The particle size distribution of the particles is not particularly limited and can be appropriately selected according to the purpose. However, it is preferable that the R.S.F. is 1.2 or less and the volume average particle size (Dv) / number average particle size (Dn) is 1.00 or more and 1.50 or less. When the particle size distribution falls within the above range, the proportion of coarse particles can be reduced. This allows for simple and efficient sterilization without clogging the sterilization filter, even when the pharmaceutical composition containing particles needs to be sterilized by filtration before use. Furthermore, by making the particle size uniform, the content of bioactive substances and base materials in each particle, as well as the surface area of ​​each particle, become uniform. As a result, the amount of bioactive substances eluted from each particle becomes uniform, making it possible to obtain particles that allow for highly controlled sustained release of bioactive substances. Furthermore, by achieving uniform particle size, the generation of small-particle-sized particles consisting of individual physiologically active substances not present in the substrate can be suppressed, resulting in particles with suppressed initial bursts and sustained release properties.

[0258] [Application] The particles obtained by the particle production method of the present invention can be used in pharmaceutical compositions, functional foods, and functional cosmetics, for example, by combining them with other components such as dispersants and additives as needed.

[0259] <Pharmaceutical composition> The pharmaceutical composition of the present invention comprises particles obtained by the particle production method described above, lipids, and may optionally contain other components. Since the particles in the pharmaceutical composition are the same as those described above, redundant descriptions are omitted.

[0260] <<Lipids>> There are no particular restrictions on the lipids used, and they can be appropriately selected depending on the purpose. Examples include medium-chain or long-chain monoglycerides, medium-chain or long-chain diglycerides, medium-chain or long-chain triglycerides, phospholipids, vegetable oils (e.g., soybean oil, avocado oil, squalene oil, sesame oil, olive oil, corn oil, rapeseed oil, safflower oil, canola oil, sunflower oil, castor oil, coconut oil, palm oil, and corn oil), fish oil, flavoring oils, water-insoluble vitamins, fatty acids, medium-chain fatty acid triglycerides, mixtures thereof, and derivatives thereof. These can be used individually or in combination of two or more.

[0261] When preparing a pharmaceutical composition for injection by dispersing particles containing physiologically active substances in lipids, it is necessary to minimize the force required to extrude the composition from the syringe. As the particle content of the pharmaceutical composition increases, its viscosity also increases. Therefore, it is preferable that the particle content dispersed in the lipids be between 1 mg / mL and 500 mg / mL.

[0262] When the viscosity of a pharmaceutical composition is 400 mg / mL, let μ1 be the viscosity, and when the viscosity of a pharmaceutical composition is 0 mg / mL, let μ0 be the viscosity. In such cases, the ratio of viscosity μ1 to viscosity μ0 (μ1 / μ0) is preferably 10 or less. Having such a configuration is preferable because, when the pharmaceutical composition is used as an injectable material, the force required to extrude the composition from the syringe can be reduced.

[0263] Other ingredients are not particularly limited and can be selected as appropriate depending on the purpose. Examples include excipients, flavoring agents, disintegrants, fluidizers, adsorbents, lubricants, deodorizers, surfactants, fragrances, colorants, antioxidants, opacifiers, antistatic agents, and wetting agents. These can be used individually or in combination of two or more.

[0264] - Excipients - There are no particular restrictions on excipients, and they can be appropriately selected according to the purpose. Examples include lactose, sucrose, mannitol, glucose, fructose, maltose, erythritol, maltitol, xylitol, palatinose, trehalose, sorbitol, crystalline cellulose, talc, anhydrous silicic acid, anhydrous calcium phosphate, precipitated calcium carbonate, and calcium silicate. These can be used individually or in combination of two or more.

[0265] - Flavoring agent - There are no particular restrictions on the flavoring agents, and they can be appropriately selected according to the purpose. Examples include L-menthol, sucrose, D-sorbitol, xylitol, citric acid, ascorbic acid, tartaric acid, malic acid, aspartame, acesulfame potassium, thaumatin, sodium saccharin, dipotassium glycyrrhizin, monosodium glutamate, sodium 5'-inosinate, and sodium 5'-guanylate. These can be used individually or in combination of two or more.

[0266] - Fluidizing agent - There are no particular restrictions on the fluidizing agent, and it can be appropriately selected depending on the purpose. Examples include light anhydrous silicic acid, hydrated silicon dioxide, and talc. These can be used individually or in combination of two or more. Commercially available light anhydrous silicic acid can be used. There are no particular restrictions on the commercially available light anhydrous silicic acid, and it can be appropriately selected according to the purpose. For example, Adsolider 101 (manufactured by Freund Industrial Co., Ltd.: average pore size: 21 nm) can be used.

[0267] -Adsorbent- Commercially available adsorbents can be used. There are no particular restrictions on the commercially available adsorbents, and they can be appropriately selected according to the purpose. Examples include: product name: Carplex (ingredient name: synthetic silica, registered trademark of DSL. Japan Co., Ltd.), product name: Aerosil (registered trademark of Nippon Aerosil Co., Ltd.) 200 (ingredient name: hydrophilic fumed silica), product name: Cylysia (ingredient name: amorphous silicon dioxide, registered trademark of Fuji Silysia Chemical Co., Ltd.), and product name: Alkamac (ingredient name: synthetic hydrotalcite, registered trademark of Kyowa Chemical Co., Ltd.). These can be used individually or in combination of two or more.

[0268] -lubricant- There are no particular restrictions on the lubricant, and it can be appropriately selected depending on the purpose. Examples include magnesium stearate, calcium stearate, sucrose fatty acid ester, sodium stearyl fumarate, stearic acid, polyethylene glycol, and talc. These can be used individually or in combination of two or more.

[0269] -Deodorizer- There are no particular restrictions on the odorants used, and they can be selected appropriately depending on the purpose. Examples include trehalose, malic acid, maltose, potassium gluconate, anise essential oil, vanilla essential oil, and cardamom essential oil. These can be used individually or in combination of two or more.

[0270] - Surfactants - There are no particular restrictions on the surfactant, and it can be appropriately selected depending on the purpose. Examples include polysorbates such as polysorbate 80, polyoxyethylene-polyoxypropylene copolymers, and sodium lauryl sulfate. These can be used individually or in combination of two or more.

[0271] -Fragrance- There are no particular restrictions on the fragrances used; they can be selected appropriately depending on the purpose. Examples include lemon oil, orange oil, and peppermint oil. These can be used individually or in combination of two or more.

[0272] -Colorants- There are no particular restrictions on the coloring agents, and they can be appropriately selected depending on the purpose. Examples include titanium dioxide, Food Yellow No. 5, Food Blue No. 2, ferric oxide, and yellow ferric oxide. These can be used individually or in combination of two or more.

[0273] -Antioxidant- There are no particular restrictions on antioxidants, and they can be appropriately selected depending on the purpose. Examples include sodium ascorbate, L-cysteine, sodium sulfite, and vitamin E. These can be used individually or in combination of two or more.

[0274] -Concealing agent- There are no particular restrictions on the type of concealing agent; it can be appropriately selected depending on the purpose. Examples include titanium dioxide. These can be used individually or in combination of two or more.

[0275] -Antistatic agent- There are no particular restrictions on the antistatic agent, and it can be appropriately selected depending on the purpose. Examples include talc and titanium dioxide. These can be used individually or in combination of two or more.

[0276] -Wetting agent- There are no particular restrictions on the humectant, and it can be appropriately selected depending on the purpose. Examples include polysorbate 80, sodium lauryl sulfate, sucrose fatty acid ester, macrogol, and hydroxypropyl cellulose (HPC). These can be used individually or in combination of two or more.

[0277] There are no particular restrictions on the formulation of the pharmaceutical composition, and it can be appropriately selected according to the purpose. Examples include colonic delivery formulations, lipid microsphere formulations, dry emulsion formulations, self-emulsifying formulations, dry syrups, nasal administration powder formulations, pulmonary administration powder formulations, wax matrix formulations, hydrogel formulations, polymer micelle formulations, mucosal adhesion formulations, gastric suspension formulations, liposome formulations, and solid dispersion formulations. These can be used individually or in combination of two or more.

[0278] Examples of dosage forms for pharmaceutical compositions include tablets, capsules, suppositories, and other solid dosage forms; aerosols for intranasal or pulmonary administration; and liquid preparations such as injectable preparations, intraocular preparations, intraocular preparations, and oral preparations.

[0279] There are no particular restrictions on the route of administration of the pharmaceutical composition, and it can be appropriately selected depending on the purpose. Examples include oral administration, nasal administration, rectal administration, vaginal administration, subcutaneous administration, intravenous administration, and pulmonary administration. Among these, oral administration is preferred.

[0280] <Functional foods> The functional product according to the present invention includes particles obtained by the particle manufacturing method described above, and optionally includes other additives. There are no particular restrictions on the types of food products that can be selected as appropriate depending on the purpose. Examples include frozen desserts, noodles, confectionery, seafood, processed seafood and livestock products, dairy products, oils and fats, processed oils and fats products, seasonings, retort pouch foods, health foods, and nutritional supplements.

[0281] <Functional Cosmetics> The functional cosmetic according to the present invention contains particles obtained by the particle manufacturing method described above, and optionally contains other additives. There are no particular restrictions on cosmetics; they can be selected appropriately according to their purpose. Examples include skincare cosmetics, makeup cosmetics, hair care cosmetics, body care cosmetics, and fragrance cosmetics. [Examples]

[0282] The present invention will be specifically described below with reference to examples and comparative examples, but the present invention is not limited in any way to these examples.

[0283] <Example of Particle 1A-1 Production (First Embodiment, Liquid Column Resonance)> HRP (horseradish-derived peroxidase, product code: PEO-131, manufactured by Toyobo Co., Ltd.) as a physiologically active substance and lactose monohydrate (product code: 124-00092, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) as a base material were added to pure water as a solvent to prepare aqueous solutions with an HRP content of 0.97 mg / mL and a lactose content of 0.03 mg / mL. The solid content of this mixture was 1% by mass. Subsequently, the obtained mixture was passed through a filter (CES-005-M47DK) with an average pore size of 0.45 μm to obtain particle material mixture 1A. The obtained particle material mixture 1A was then discharged into a gas using a liquid column resonance droplet dispensing device to obtain particle 1A-1. The manufacturing conditions were as follows. -Particle production conditions- • Outlet shape: Circular • Outlet diameter: 8.0 μm • Airflow temperature for conveying air: 40°C • Dry air flow rate: Dry nitrogen 50 L / min

[0284] <Example of Particle 1A-2 Production (First Embodiment, Rayleigh Splitting)> The resulting particle material mixture 1A was discharged into a gas using a Rayleigh splitting discharge mechanism to obtain particles 1A-2. The manufacturing conditions were as follows. -Particle production conditions- • Outlet shape: Circular • Outlet diameter: 5.0 μm • Airflow temperature for conveying air: 40°C • Airflow rate for transport: 50m 3 / h • Dispensing pressure of the prescription liquid: 0.4 MPa

[0285] <Example of Particle 1A-3 Production (Second Embodiment, Rayleigh Splitting)> The obtained particle material mixture 1A was ejected into a vacuum as droplets using a Rayleigh splitting ejection device to obtain particles 1A-3. The manufacturing conditions were as follows. -Particle production conditions- • Outlet shape: Circular • Outlet diameter: 5.0 μm • Dry air flow rate: None • Dispensing pressure of the prescription liquid: 0.4 MPa Chamber vacuum level: 10 Pa • Cooling jacket temperature: -20℃ -Freeze-drying conditions- • Pre-freezing: -20°C for 30 minutes ·Primary freezing: -20℃, 6 hours ·Secondary freezing: 10℃, 24 hours

[0286] <Example of Particle 1A-4 Production (Third Embodiment, Rayleigh Fission)> The resulting particle material mixture 1A was discharged into a liquefied gas using a Rayleigh splitting discharge means to obtain particles 1A-4. The manufacturing conditions were as follows. -Particle production conditions- • Outlet shape: Circular • Outlet diameter: 5.0 μm • Conveyor airflow temperature: 20°C • Airflow rate for transport: 50m 3 / h • Liquefied gas: liquid nitrogen -Freeze-drying conditions- • Pre-freezing: -20°C for 30 minutes ·Primary freezing: -20℃, 6 hours ·Secondary freezing: 10℃, 24 hours

[0287] <Example of Particle 1A-5 Production> A solution was obtained by dissolving HRP (horseradish-derived peroxidase, product code: PEO-131, manufactured by Toyobo Co., Ltd.) as a physiologically active substance and PVA (polyvinyl alcohol, product code: 165-17915, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) as a base material in water at a concentration of 0.5% by mass each. This solution was added dropwise to acetonitrile using a syringe (25G syringe with needle, manufactured by Terumo Corporation) to obtain a dispersion in which HRP and PVA were atomized. Particle 1A-5 was obtained by vacuum drying this dispersion. -Vacuum drying conditions- ·Vacuum degree: 10Pa ·Drying temperature: 20℃ • Drying time: 24 hours

[0288] <Example of Particle 2A-1 Production (First Embodiment, Liquid Column Resonance)> Anti-rabbit IgG goat antibody (polyclonal, manufactured by Sigma, product code: R5506) was added to pure water as a solvent to prepare an aqueous solution containing 1.0 mg / mL of anti-rabbit IgG goat antibody as a physiologically active substance. Subsequently, the obtained mixture was passed through a filter with an average pore size of 0.45 μm (CES-005-M47DK) to obtain particle material mixture 2A. Except for using particle material mixture 2A instead of particle material mixture 1A, particle 2A-1 was obtained in the same manner as in <Production Example of Particle 1A-1 (First Embodiment, Liquid Column Resonance)>.

[0289] <Example of particle 2A-2 production (first embodiment, Rayleigh fission)> Particle 2A-2 was obtained in the same manner as in <Production Example of Particle 1A-2 (First Embodiment, Rayleigh Splitting)>, except that particle material mixture 2A was used instead of particle material mixture 1A.

[0290] <Example of particle 2A-3 production (second embodiment, Rayleigh fission)> Particle 2A-3 was obtained in the same manner as in <Production Example of Particle 1A-3 (Second Embodiment, Rayleigh Splitting)>, except that particle material mixture 2A was used instead of particle material mixture 1A.

[0291] <Example of particle 2A-4 production (third embodiment, Rayleigh fission)> Particle 2A-4 was obtained in the same manner as in <Production Example of Particle 1A-4 (Third Embodiment, Rayleigh Splitting)>, except that particle material mixture 2A was used instead of particle material mixture 1A.

[0292] <Example of Particle 3A-1 Production (First Embodiment, Liquid Column Resonance)> Solution A1 was prepared by adding anti-rabbit IgG goat antibody (polyclonal, manufactured by Sigma, product code: R5506) as a physiologically active substance to pure water, which was used as solvent A. The physiologically active substance content of Solution A1 was adjusted to 50.0 mg / mL relative to the total volume of Solution A1. Solution B1 was prepared by adding sorbitan sesquioleate (SPAN83, manufactured by Tokyo Chemical Industry Co., Ltd.) as a surfactant to dichloromethane (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) as solvent B. The sorbitan sesquioleate content of Solution B1 was adjusted to 0.1% by mass relative to the total volume of Solution B1. Next, liquid A1 and liquid B1 were mixed in a mass ratio of liquid A1:liquid B1 = 5:95. The mixed solution was homogenized using a homogenizer (device name: sonicstar85, manufactured by AS ONE Corporation) at 90% output for 10 minutes to prepare dispersion 1 (W / O emulsion), thereby obtaining particle material mixture 3A. The droplet size of liquid A1 in the dispersion was measured using a concentrated system analyzer ("FPAR-1000", manufactured by Otsuka Electronics Co., Ltd.) by dynamic light scattering and was found to be 450 nm. Except for using particle material mixture 3A instead of particle material mixture 1A, particle 3A-1 was obtained in the same manner as in <Production Example of Particle 1A-1 (First Embodiment, Liquid Column Resonance)>.

[0293] <Example of Particle 3A-2 Production (First Embodiment, Rayleigh Splitting)> Particle 3A-2 was obtained in the same manner as in <Production Example of Particle 1A-2 (First Embodiment, Rayleigh Splitting)>, except that particle material mixture 3A was used instead of particle material mixture 1A and the conveying airflow temperature was set to 30°C.

[0294] <Example of Particle 3A-3 Production (Second Embodiment, Rayleigh Splitting)> Particle 3A-3 was obtained in the same manner as in <Production Example of Particle 1A-3 (Second Embodiment, Rayleigh Splitting)>, except that particle material mixture 3A was used instead of particle material mixture 1A and the conveying airflow temperature was set to 30°C.

[0295] <Example of particle 3A-4 production (third embodiment, Rayleigh fission)> Particle 3A-4 was obtained in the same manner as in <Production Example of Particle 1A-4 (Third Embodiment, Rayleigh Splitting)>, except that particle material mixture 3A was used instead of particle material mixture 1A.

[0296] <Example of manufacturing particle 3A-5 (spray nozzle)> Using a spray nozzle (Trispire nozzle, manufactured by GF Corporation), particles 3A-5 were obtained from the particle material mixture 3A. -Particle production conditions- Dryer size: Diameter 150mm, Height 500mm • Dispensing rate of the prescribed solution (under Trispier nozzle spraying conditions): 10g / min • Compressed air volume (Trispire nozzle injection conditions): 0.6 MPa, 40 NL / min • Airflow rate for transport: 50m 3 / h • Dry airflow temperature: 30°C

[0297] <Example of Particle 2B Production> Particle material mixture 2A was dried using a spray drying method (rotary disc atomizer, manufactured by Okawara Chemical Machinery Co., Ltd.) to obtain particles 2B. -Particle production conditions- ·Spray dryer model: L-8 • Rotary disc atomizer rotation speed: 10,000 rpm • Dispensing rate of prescription solution: 2 kg / hour • Airflow rate for transport: 50m 3 / h • Dry airflow temperature: 80℃

[0298] (Examples 1-14 and Comparative Example 1) For each particle, various parameters were measured and evaluated. The measurements and evaluations for particles 1A-1 to 3A-5 were given in Examples 1 to 14, and the measurements and evaluations for particle 2B were given in Comparative Example 1.

[0299] [Quantitative determination of the content of bioactive substances (HRP)] A calibration curve was created showing the relationship between the concentration of HRP (horseradish-derived peroxidase, PEO-131, manufactured by Toyobo Co., Ltd.) dissolved in pure water and the absorbance at a measurement wavelength of 400 nm. A micro-sample spectrophotometer (simplinano, manufactured by GE Health) was used to measure the absorbance. Next, the absorbance of each particle at a measurement wavelength of 400 nm was measured, and the HRP content of each particle was calculated based on the calibration curve created. The results are shown in Table 1 below. Note that the content values ​​shown in Table 1 represent the values ​​when the total amount of HRP in particle material mixture 1A is contained in the manufactured particles (theoretical value) is set to 100%.

[0300] [Quantitative determination of bioactive substance (HRP) activity] HRP activity in each particle was evaluated according to the protocol of the kit (Pierce TMB Substrate Kit, Thermo Fisher Scientific, product code: 34021). The equipment and reagents used are as follows. -Equipment used- • Absorbance microplate reader Maltiskan GO (manufactured by Thermo Fisher Scientific) • Nunc Edge 2.0 96-Well Plates (Product Code: 167425, manufactured by Thermo Fisher Scientific) -Reagents used- • HRP (Peroxidase derived from horseradish, product code: PEO-131, manufactured by Toyobo Co., Ltd.) • HPC (Hydroxypropylcellulose 2.0-2.9%, Product Code: 082-07925, Manufactured by Fujifilm Wako Pure Chemical Corporation) • Pierce TMB Substrate Kit (Product Code: 34021, manufactured by Thermo Fisher Scientific) The results are shown in Table 1 below. Note that the activity values ​​shown in Table 1 represent the values ​​when the total amount of HRP in particle material mixture 1A is considered to be active in the particles after manufacturing (theoretical value), which is set to 100%.

[0301] [Quantitative determination of the content of bioactive substances (anti-rabbit IgG goat antibodies)] A calibration curve was created showing the relationship between the concentration of anti-rabbit IgG goat antibody (polyclonal, product code: R5506, manufactured by Sigma) dissolved in pure water and the absorbance at a measurement wavelength of 280 nm. A micro-sample spectrophotometer (simplinano, manufactured by GE Health) was used to measure the absorbance. Next, the absorbance at a measurement wavelength of 280 nm was measured for each particle, and the anti-rabbit IgG goat antibody content in each particle was calculated based on the created calibration curve. The results are shown in Table 1 below. Note that the content values ​​shown in Table 1 represent the values ​​when the total amount of anti-rabbit IgG goat antibody in particle material mixture 2A is contained in the manufactured particles (theoretical value) is set to 100%.

[0302] [Quantitative analysis of the activity of a bioactive substance (anti-rabbit IgG goat antibody)] The activity of anti-rabbit IgG goat antibody in each particle was evaluated using ELISA (sandwich method). The ELISA (sandwich method) was performed according to standard procedures, and the equipment and reagents used are as follows. -Equipment used- • Absorbance microplate reader Maltiskan GO (manufactured by Thermo Fisher Scientific) • Nunc MaxiSorp flat-bottom (product code 44-2404-21, manufactured by Thermo Fisher Scientific) -Reagents used- • Primary antibody: Anti-rabbit IgG goat antibody (polyclonal, product code: R5506, manufactured by Sigma) • Antigen: Rabbit serum-derived IgG (Product code: I5006, manufactured by Sigma) • Secondary antibody: Anti-rabbit IgG goat antibody - peroxidase labeled (polyclonal, product code: A0545, manufactured by Sigma) • HPC (Hydroxypropylcellulose 2.0-2.9%, Product Code: 082-07925, Manufactured by Fujifilm Wako Pure Chemical Corporation) • Bovine serum albumin (BSA) (pH 7.0, product code: 019-23293, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) • Polyoxyethylene (20) sorbitan monolaurate (product code: 166-21213, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) • Pierce TMB Substrate Kit (Product Code 34021, manufactured by Thermo Fisher Scientific)

[0303] [Quantitative determination of viscosity μ1 / viscosity μ0] When each particle was dispersed in MCT oil (Coconad RK, manufactured by Kao Corporation) at a concentration of 400 mg / ml, the viscosity was defined as viscosity μ1, and the viscosity without particles was defined as viscosity μ0. The viscosity ratio (viscosity μ1 / viscosity μ0) was then calculated. The results are shown in Table 1.

[0304] [Table 1]

[0305] Examples of the present invention are as follows: <1> A process for preparing a physiologically active substance-containing solution, which involves preparing a physiologically active substance-containing solution containing a physiologically active substance, A dispensing step in which the physiologically active substance-containing solution is dispensed as droplets, A granulation step in which the solvent is removed from the aforementioned droplets to form particles, A method for producing particles containing, The present invention relates to a method for producing particles, characterized in that the physiological activity ratio {(physiological activity amount B / physiological activity amount A) × 100} of the physiological activity amount B in the particles after the granulation step relative to the physiological activity amount A in the physiologically active substance before the preparation step of the physiologically active substance-containing liquid is 80% or more. <2> No external stress is applied to the physiologically active substance-containing liquid and the droplets. <1> This is a method for producing the particles described above. <3> The discharge step involves discharging the physiologically active substance-containing liquid into a gas. <1> or <2> This is a method for producing the particles described above. <4> The discharge step involves discharging the physiologically active substance-containing liquid into a vacuum. <1> or <2> This is a method for producing the particles described above. <5> The discharge step involves discharging the physiologically active substance-containing liquid into a liquefied gas. <1> or <2> This is a method for producing the particles described above. <6> The aforementioned dispensing step involves dispensing the physiologically active substance-containing liquid from the dispensing port by vibration. <1> from <3> This is a method for producing particles as described in any of the above. <7> The aforementioned solution containing the physiologically active substance is a W / O (Water in oil) emulsion. The droplet size of the physiologically active substance-containing solution in the W / O (Water in Oil) emulsion is 100 nm or more and 5 μm or less. <1> and <3> from <6> This is a method for producing particles as described in any of the above. <8> The aforementioned W / O (Water in oil) emulsion contains a surfactant having a hydrophilic-lipophilic balance of 1 to 8. <7> This is a method for producing the particles described above. <9> The surfactant is sorbitan sesquioleate. <8> This is a method for producing the particles described above. <10> <1> from <9> Particles produced by the particle manufacturing method described in any of the following: The volume-average particle size of the aforementioned particles is 1 μm or more and 50 μm or less. The aforementioned particles are characterized by having an RSF (Relative Span Factor) of 1.5 or less. <11> The aforementioned physiologically active substance comprises at least one selected from proteins and nucleic acids. <10> These are the particles described in [the document]. <12> The aforementioned physiologically active substance comprises at least one selected from antibodies and enzymes. <10> or <11> These are the particles described in [the document]. <13> The content of the aforementioned physiologically active substance is 95% by mass or more relative to the total amount of the particles. <10> from <12> These are particles described in any of the following. <14> <10> from <13> This pharmaceutical composition is characterized by containing particles described in any of the above and lipids. <15> When the viscosity of the pharmaceutical composition is 400 mg / mL of the particles, let μ1 be the viscosity, and when the viscosity of the pharmaceutical composition is 0 mg / mL of the particles, let μ0 be the viscosity. Then the ratio of μ1 to μ0 (μ1 / μ0) is 10 or less. <14> This is the pharmaceutical composition described in [the relevant document]. <16> The aforementioned lipids are selected from soybean oil, olive oil, fish oil, sesame oil, canola oil, sunflower oil, castor oil, coconut oil, palm oil, corn oil, and medium-chain triglycerides. <14> or <15> This is the pharmaceutical composition described in [the relevant document]. <17> The content of the particles dispersed in the lipids is 1 mg / mL or more and 500 mg / mL or less. <14> from <16> It is a pharmaceutical composition as described in any of the above. <18> Including excipients, <14> from <17> It is a pharmaceutical composition as described in any of the above.

[0306] <1> from <9> A method for producing particles as described in any of the following: <10> from <13> Particles described in any of the following: <14> from <18> According to any of the pharmaceutical compositions described herein, the conventional problems can be solved and the objectives of the present invention can be achieved. [Explanation of Symbols]

[0307] 300 particle manufacturing equipment 301 Downdraft 302 Discharge means 313 Container for containing physiologically active substance liquid 314 Physiologically active substance-containing liquid 315 Liquid circulation pump 316 Liquid supply pipe 321 Droplet 322 Liquid return tube 360 Drying and Collection Unit 361 Chambers 362 Particle collection means 363 Particle storage section 364 Conveyor Airflow Inlet 365 Conveyor Airflow Outlet P1 Pressure Gauge P2 Pressure Gauge [Prior art documents] [Patent Documents]

[0308] [Patent Document 1] Japanese Patent Application Publication No. 11-114027 [Patent Document 2] Japanese Patent Publication No. 2021-28305

Claims

1. A process for preparing a physiologically active substance-containing solution, which involves preparing a physiologically active substance-containing solution containing a physiologically active substance, A dispensing step in which the physiologically active substance-containing solution is dispensed as droplets, A granulation step in which the solvent is removed from the aforementioned droplets to form particles, A method for producing particles containing, A method for producing particles, characterized in that the physiological activity ratio {(physiological activity amount B / physiological activity amount A) × 100} of the physiological activity amount B in the particles after the granulation step relative to the physiological activity amount A in the physiologically active substance before the preparation step of the physiologically active substance-containing liquid is 80% or more.

2. A method for producing particles according to claim 1, wherein no external stress is applied to the physiologically active substance-containing liquid and the droplets.

3. The method for producing particles according to claim 1 or 2, wherein the discharge step involves discharging the physiologically active substance-containing liquid into a gas.

4. The method for producing particles according to claim 1 or 2, wherein the discharge step involves discharging the physiologically active substance-containing liquid into a vacuum.

5. The method for producing particles according to claim 1 or 2, wherein the discharge step involves discharging the physiologically active substance-containing liquid into a liquefied gas.

6. The method for producing particles according to claim 1 or 2, wherein the discharge step involves discharging the physiologically active substance-containing liquid from a discharge hole by vibration.

7. The aforementioned solution containing the physiologically active substance is a W / O (Water in oil) emulsion. The method for producing particles according to claim 1, wherein the droplet size of the physiologically active substance-containing solution in the W / O (Water in Oil) emulsion is 100 nm or more and 5 μm or less.

8. The method for producing particles according to claim 7, wherein the W / O (Water in oil) emulsion contains a surfactant having a hydrophilic-lipophilic balance of 1 or more and 8 or less.

9. The method for producing particles according to claim 8, wherein the surfactant is sorbitan sesquioleate.

10. Particles produced by the particle manufacturing method described in claim 1 or 2, The volume-average particle size of the aforementioned particles is 1 μm or more and 50 μm or less. The particle is characterized in that its R.S.F (Relative Span Factor) is 1.5 or less.

11. The particles according to claim 10, wherein the bioactive substance comprises at least one selected from proteins and nucleic acids.

12. The particles according to claim 10, wherein the physiologically active substance comprises at least one selected from antibodies and enzymes.

13. The particle according to claim 10, wherein the content of the physiologically active substance is 95% by mass or more of the total amount of the particles.

14. A pharmaceutical composition characterized by comprising the particles described in claim 10 and lipids.

15. The pharmaceutical composition according to claim 14, wherein when the content of the particles in the pharmaceutical composition is 400 mg / mL, the viscosity is defined as viscosity μ1, and when the content of the particles in the pharmaceutical composition is 0 mg / mL, the viscosity is defined as viscosity μ0, and the ratio of viscosity μ1 to viscosity μ0 (viscosity μ1 / viscosity μ0) is 10 or less.

16. The pharmaceutical composition according to claim 14, wherein the lipids are selected from soybean oil, olive oil, fish oil, sesame oil, canola oil, sunflower oil, castor oil, coconut oil, palm oil, corn oil, and medium-chain triglycerides.

17. The pharmaceutical composition according to claim 14, wherein the content of the particles dispersed in the lipids is 1 mg / mL or more and 500 mg / mL or less.

18. The pharmaceutical composition according to claim 14, comprising an excipient.

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