WO2023145886A1

WO2023145886A1 - Nanofibers

Info

Publication number: WO2023145886A1
Application number: PCT/JP2023/002672
Authority: WO
Inventors: 耕平田原; 理帆小川; 文香小林; 延能吉村; 豊谷口
Original assignee: 三菱ケミカル株式会社
Priority date: 2022-01-31
Filing date: 2023-01-27
Publication date: 2023-08-03

Abstract

The present invention provides nanofibers which control the elution behavior of a water-soluble medical polymer and make the water-soluble medical polymer sustained-release, and a production method for the nanofibers. The nanofibers according to the present invention are nanofibers including a polyvinyl alcohol resin and the water-soluble medical polymer, wherein the molecular weight of the water-soluble medical polymer is 1,000 to 50,000, or are nanofibers including a polyvinyl alcohol resin and the water-soluble medical polymer, wherein the water-soluble medical polymer is a protein pharmaceutical.

Description

nanofiber

The present invention relates to nanofibers containing a polyvinyl alcohol-based resin (A) and a water-soluble pharmaceutical polymer (B), and a method for producing the same.

In the design of various formulations for oral administration, transmucosal administration, etc., designing sufficiently high bioavailability of a drug is emphasized from the viewpoint of efficacy and safety of the drug.
Drug solubility is one of the important factors that affect the bioavailability of drugs. It is actively researched and developed because it can reduce the frequency of administration and side effects associated with retention.
Since water-soluble drugs are highly soluble in the body, methods such as dispersing them in a base or coating the surface are known methods for controlling the release rate. formulations have been proposed.

For example, Patent Document 1 describes drug-containing ultrafine fibers. Further, Patent Document 2 discloses a method for improving the elution rate of a sparingly soluble drug by converting the sparingly soluble drug into nanofibers using a polyvinyl alcohol-based resin.

Japanese Patent Application Laid-Open No. 2014-55119 Japanese Patent Application Laid-Open No. 2021-88552

However, all of the drugs used for nanofiber formation were sparingly soluble low-molecular-weight drugs. Low-molecular-weight drugs have stable chemical structures, but high-molecular-weight drugs such as protein drugs have complex and heterogeneous structures. They also behave differently.
In addition, high-molecular-weight drugs are less stable than low-molecular-weight drugs, and there is a concern that they may decompose in nanofiber formation processes such as electrospinning.
Furthermore, due to the properties of water-soluble high-molecular drugs, they are rapidly released from the matrix even if sustained release is desired, making it difficult to achieve sustained release using existing techniques. Therefore, there has been a demand for a method of forming nanofibers from water-soluble pharmaceutical macromolecules and controlling their release behavior.

In view of the above problems, the object of the present invention is to provide nanofibers in which the elution of water-soluble pharmaceutical polymers is controlled to be released, and formulations made of the nanofibers.

However, as a result of intensive research in view of such circumstances, the present inventors unexpectedly found that a mixture containing a water-soluble pharmaceutical polymer having a molecular weight of 1000 or more and 50000 or less was made into nanofibers. It was found that the elution of

That is, the gist of the present invention is as follows.
(1) A nanofiber comprising a polyvinyl alcohol-based resin (A) and a water-soluble medicinal polymer (B), wherein the water-soluble medicinal polymer (B) has a molecular weight of 1,000 or more and 50,000 or less.
(2) A nanofiber comprising a polyvinyl alcohol-based resin (A) and a water-soluble pharmaceutical polymer (B), wherein the water-soluble pharmaceutical polymer (B) is a protein drug.
(3) The content ratio of the polyvinyl alcohol-based resin (A) and the water-soluble pharmaceutical polymer (B) is, by mass ratio, polyvinyl alcohol-based resin (A):water-soluble pharmaceutical polymer (B)=10:90. The nanofiber according to (1) or (2) above, which is ~90:10.
(4) The nanofiber according to any one of (1) to (3) above, wherein the polyvinyl alcohol resin (A) has a saponification degree of 75 to 99.9 mol%.
(5) The nanofiber according to any one of (1) to (4) above, wherein the polyvinyl alcohol resin (A) has an average degree of polymerization of 300 to 4,000.
(6) The nanofiber according to any one of (1) to (5) above, wherein the nanofiber has a single fiber diameter of 1 nm to 10 μm.
(7) A method for producing nanofibers containing a polyvinyl alcohol-based resin and a water-soluble medicinal polymer, comprising electrospinning or melt blowing using a mixed solution containing the polyvinyl alcohol-based resin and the water-soluble medicinal polymer. A method for producing nanofibers, comprising a step of producing nanofibers by
(8) The method for producing nanofibers according to (7) above, wherein the solvent of the mixture is water.
(9) A formulation comprising the nanofibers according to any one of (1) to (6) above.

According to the nanofiber of the present invention, a nanofiber preparation in which the water-soluble pharmaceutical polymer (B) is eluted in a controlled release can be obtained.

The present invention will be described in detail below, but these show examples of preferred embodiments.
In this specification, "mass" is synonymous with "weight".

The nanofiber of the present invention contains a polyvinyl alcohol resin (A) and a water-soluble medicinal polymer (B). A first form provides a nanofiber containing a water-soluble medicinal polymer (B) having a molecular weight of 1,000 or more and 50,000 or less. In a second form, a nanofiber containing a water-soluble drug polymer (B), which is a protein drug, is provided.

First, the polyvinyl alcohol-based resin (hereinafter also referred to as "PVA-based resin") will be described.

<PVA-based resin>
The PVA-based resin of the present invention is a resin obtained by saponifying a polyvinyl ester-based polymer obtained by polymerizing a vinyl ester-based monomer. It is composed of vinyl ester structural units.

The saponification degree of the PVA-based resin used in the present invention is preferably 75 to 99.9 mol%, more preferably 80 to 95 mol%, still more preferably 83 to 93 mol%, particularly preferably 85 to 90 mol %. If the degree of saponification of the PVA-based resin is too high or too low, it tends to be difficult to obtain the effects of the present invention.
In the present invention, the degree of saponification of the PVA-based resin is a value determined by a method conforming to JIS K 6726, and is an average degree of saponification determined as an average value.

The average degree of polymerization of the PVA-based resin used in the present invention is preferably 300 to 4000, more preferably 500 to 3500, still more preferably 1000 to 3000, particularly preferably 1300 to 2800, particularly preferably 1500 to 2600.
If the average degree of polymerization of the PVA-based resin is too low, the strength of the nanofibers tends to be insufficient and the stability during use tends to decrease. Tend.
In addition, in this invention, the average degree of polymerization calculated|required by the method based on JISK6726 shall be used for the average degree of polymerization of PVA-type resin.

A method for producing the PVA-based resin used in the present invention will be described in detail.
A PVA-based resin is obtained, for example, by saponifying a polyvinyl ester-based polymer obtained by polymerizing a vinyl ester-based monomer.
Examples of such vinyl ester monomers include vinyl formate, vinyl acetate, vinyl propionate, vinyl valerate, vinyl butyrate, vinyl isobutyrate, vinyl pivalate, vinyl caprate, vinyl laurate, vinyl stearate, and vinyl benzoate. , vinyl versatate, etc., and vinyl acetate is practically preferred.

Further, a monomer having copolymerizability with the vinyl ester monomer can be copolymerized to the extent that the effect of the present invention is not impaired. Examples of such copolymerizable monomers include olefins such as ethylene, propylene, isobutylene, α-octene, α-dodecene and α-octadecene; - hydroxy group-containing α-olefins such as hexen-1-ol and 3,4-dihydroxy-1-butene, and derivatives such as acylated products thereof; acrylic acid, methacrylic acid, crotonic acid, maleic acid, maleic anhydride, itacon acids, unsaturated acids such as undecylenic acid and salts thereof; nitriles such as monoesters or dialkyl esters, acrylonitrile and methacrylonitrile; amides such as diacetone acrylamide, acrylamide and methacrylamide; ethylenesulfonic acid, allylsulfonic acid, Olefinsulfonic acids such as methallylsulfonic acid and salts thereof; vinyl compounds such as glycerin monoallyl ether; substituted vinyl acetates such as isopropenyl acetate and 1-methoxyvinyl acetate; vinylidene chloride, 1,4-diacetoxy-2-butene, 1,4-dihydroxy-2-butene, vinylene carbonate , 1,3-diacetoxy-2-methylenepropane, 1,3-dipropionyloxy-2-methylenepropane, hydroxymethylvinylidene diacetate such as 1,3-dibutyronyloxy-2-methylenepropane; 3-chloro - 2-Hydroxypropyltrimethylammonium chloride, 3-chloroethyltrimethylammonium chloride, 3-chloropropyltrimethylammonium chloride, etc. and polyvinyl alcohol resin, or N-acrylamidotrimethylammonium chloride, N-acrylamidoethyltrimethylammonium chloride, N-acrylamidopropyltrimethylammonium chloride, 2-acryloxyethyltrimethylammonium chloride, N-methyldimethylaminoacrylamide, allyltrimethylammonium chloride, methallyltrimethylammonium chloride, dimethylallylamine, dimethylmethacrylamine, dimethyldiallylammonium chloride, Examples thereof include compounds having a cationic group such as diethyldiallylammonium chloride, ethyldiallylamine, and methyldiallylamine.
The content of such copolymerizable monomers is preferably 10 mol % or less, more preferably 5 mol % or less, based on the total amount of the polymer.

Two or more types of PVA-based resins can be used in combination. When used in combination, PVA-based resins having different saponification degrees, average polymerization degrees and block properties, and modified PVA-based resins copolymerized with copolymerizable monomers can be used in combination.

The method of polymerizing the vinyl ester monomer and the copolymerizable monomer is not particularly limited, and known methods such as bulk polymerization, solution polymerization, suspension polymerization, dispersion polymerization, or emulsion polymerization can be employed. , solution polymerization is preferred.

Solvents used in such polymerization include aliphatic alcohols having 1 to 4 carbon atoms such as methanol, ethanol, isopropyl alcohol, n-propanol and butanol, and ketones such as acetone and methyl ethyl ketone. is preferably used.

In addition, the polymerization reaction is carried out using known radical polymerization catalysts such as azobisisobutyronitrile, acetyl peroxide, benzoyl peroxide, and lauroyl peroxide, and various known low temperature active catalysts. Also, the reaction temperature is selected from the range of about 35° C. to the boiling point.

The obtained polyvinyl ester polymer is then saponified in a continuous or batch manner. Either alkali saponification or acid saponification can be employed for such saponification, but it is industrially preferable to dissolve the polymer in alcohol and perform the saponification in the presence of an alkali catalyst. Examples of alcohols include methanol, ethanol, butanol, and the like. The concentration of polymer in alcohol is selected from the range of 20-60% by weight. In addition, if necessary, about 0.3 to 10% by mass of water may be added, and further, various esters such as methyl acetate, benzene, hexane, and various solvents such as DMSO (dimethyl sulfoxide) are added. You may

Specific examples of saponification catalysts include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, sodium methylate, sodium ethylate and potassium methylate, and alkali catalysts such as alcoholates. The amount of such catalyst used is preferably 1 to 100 millimol equivalents relative to the monomer.

The saponification degree of the PVA-based resin can be adjusted by adjusting the saponification catalyst amount, saponification time, saponification solvent, and saponification temperature.

After saponification, it is preferable to wash the obtained PVA-based resin with a washing liquid. Examples of the cleaning liquid include alcohols such as methanol, ethanol, isopropyl alcohol, and butanol, and methanol is preferable from the viewpoint of cleaning efficiency and drying efficiency.

The washing method may be a continuous type (rotating cylinder type, countercurrent contact type, centrifugal sprinkle washing, etc.), but usually a batch type is adopted. Examples of the stirring method (apparatus) for washing include a screw blade, a ribbon blender, and a kneader. The bath ratio (mass of cleaning solution/mass of polyvinyl ester polymer particles) is preferably 1-30, more preferably 2-20. If the bath ratio is too large, a large washing apparatus is required, which tends to lead to an increase in cost.

The temperature during washing is preferably 10-80°C, particularly preferably 20-70°C. If the temperature is too high, the amount of volatilization of the cleaning liquid increases, and there is a tendency to require a reflux facility. If the temperature is too low, cleaning efficiency tends to decrease. The washing time is preferably 5 minutes to 12 hours, particularly preferably 30 minutes to 4 hours. If the cleaning time is too long, the production efficiency tends to decrease, and if the cleaning time is too short, the cleaning tends to be insufficient. Also, the number of times of washing is preferably 1 to 10 times, particularly preferably 1 to 5 times. Too many washes tend to reduce productivity and increase costs.

The washed PVA-based resin particles are dried continuously or batchwise with hot air or the like to obtain the PVA-based resin used in the present invention in powder form. The drying temperature is preferably 50 to 150°C, more preferably 60 to 130°C, still more preferably 70 to 110°C. If the drying temperature is too high, the PVA-based resin tends to be thermally deteriorated, and if the drying temperature is too low, drying tends to take a long time. The drying time is preferably 1 to 48 hours, more preferably 2 to 36 hours. If the drying time is too long, the PVA-based resin tends to be thermally deteriorated.

The content of the solvent contained in the PVA-based resin after drying is preferably 0 to 10% by mass, more preferably 0.01 to 5% by mass, and still more preferably 0.1 to 1% by mass. .

The PVA-based resin usually contains an alkali metal salt of acetic acid derived from the alkali catalyst used for saponification. The content of the alkali metal salt is preferably 0.001-2% by mass, more preferably 0.005-1% by mass, and still more preferably 0.01-0. It is 1% by mass.
Methods for adjusting the content of the alkali metal salt include, for example, adjusting the amount of alkali catalyst used in saponification and washing the PVA-based resin with an alcohol such as ethanol or methanol.
As a method for quantifying the alkali metal salt used in the present invention, there is a method of dissolving PVA-based resin powder in water, using methyl orange as an indicator, and performing neutralization titration with hydrochloric acid.

<Water-soluble pharmaceutical polymer>
In the present invention, the water solubility of the water-soluble medicinal polymer refers to a substance that is highly soluble in water. It means that the amount of water required for dissolution is usually less than 30 mL. The amount of water required to dissolve 1 g of water-soluble pharmaceutical polymer is preferably less than 10 mL, more preferably less than 1 mL.

The molecular weight of the water-soluble medicinal polymer contained in the nanofibers of the first embodiment of the present invention is 1,000 or more and 50,000 or less, preferably 1,000 or more and 30,000 or less, and more preferably 1,000 or more and 20,000 or less.
If the molecular weight is too low, entanglement with the molecular chains of the PVA-based resin is unlikely to occur, and the water-soluble pharmaceutical polymer tends not to be sustained release.
On the other hand, if the molecular weight is too large, there is a tendency that the water-soluble medicinal polymer cannot be absorbed into the body, which is not preferable.

The water-soluble pharmaceutical polymer contained in the nanofiber of the second embodiment of the present invention is registered in Article 2, Paragraph 1 of the Pharmaceuticals and Medical Devices Law and the Japanese Pharmacopoeia 18th Edition, and is a protein drug. use.
A protein drug is a drug that is composed of amino acids and exhibits therapeutic or preventive effects on diseases through protein activity. Examples of protein pharmaceuticals include peptides, proteins, fusion proteins, antigens, growth factors, growth factors, cytokines, interferons, hormones, blood coagulation fibrinolytic factors, enzymes, conjugate proteins, protein vaccines, antibody-like proteins, cells, tissues etc. Protein pharmaceuticals also include biopharmaceuticals, which are pharmaceuticals containing proteins produced using biotechnology as active ingredients. Biopharmaceuticals include, for example, vaccines, antibody drugs, cellular drugs, and nucleic acid drugs.

By containing a water-soluble PVA-based resin and a water-soluble pharmaceutical polymer, the nanofiber of the present invention can release the water-soluble pharmaceutical polymer in a controlled manner. The reason why sustained release is possible is not clear, but the base material has a gel-like property due to the entanglement of the molecular chains of the PVA-based resin or the formation of a network structure, and the PVA-based resin and the water-soluble pharmaceutical polymer interact with each other. It is thought that it is due to the action.

<Nanofiber>
The nanofibers of the present invention are ultrafine fibers containing a polyvinyl alcohol-based resin and a water-soluble medicinal polymer, and are formed into fibers by spinning a forming material containing at least a PVA-based resin and a water-soluble medicinal polymer. be.
The nanofiber of the present invention preferably has a single fiber diameter (fiber diameter) of 1 nm to 10 μm, more preferably 1 to 2000 nm, particularly preferably 5 to 1000 nm, still more preferably 10 to 700 nm. If the fiber diameter is too large, the nanofibers will not be mixed uniformly when producing a formulation, and the nanofibers will tend to aggregate, which tends to reduce the production efficiency of the formulation. On the other hand, if the fiber diameter is too small, it becomes difficult to exhibit sufficient strength, and problems such as handling during use tend to occur, and production efficiency of the formulation tends to decrease.
The fiber diameter of nanofibers is measured using an electron microscope.

The average fiber length of the nanofibers is not particularly limited, but from the viewpoint of ease of handling, it is preferably 10 times or more, more preferably 100 times or more, and still more preferably 1000 times or more the diameter of the nanofibers (fiber diameter). . As the aspect ratio (fiber length/fiber diameter) of the nanofibers increases, the nanofibers are entangled with each other and the strength of the formulation increases, which is preferable, so the upper limit is not particularly limited. Further, it is more preferable that the nanofibers are continuous fibers.

The content ratio of the PVA-based resin and the water-soluble pharmaceutical polymer in the nanofiber varies depending on the physical properties of the water-soluble pharmaceutical polymer, but the PVA-based resin:water-soluble pharmaceutical polymer (mass ratio) is preferably 10:90 to 90. :10, more preferably 20:80 to 80:20, still more preferably 30:70 to 75:25, and particularly preferably 35:65 to 70:30.

[Manufacturing method of nanofiber]
The method for producing nanofibers of the present invention has a step of producing nanofibers by an electrospinning method or a meltblowing method using a mixed solution containing a PVA-based resin and a water-soluble medicinal polymer.
From the viewpoint of ease of handling, the nanofibers of the present invention are preferably formed in a sheet form, and it is preferable to form a nonwoven fabric from the nanofibers obtained by the above production method. Hereinafter, a method for forming nanofibers and a nonwoven fabric (hereinafter also referred to as "nanofiber nonwoven fabric") will be described.

Nanofibers are obtained by applying a mixed liquid containing a PVA-based resin and a water-soluble medicinal polymer as a forming material to an electrospinning method (electrostatic spinning method) or a meltblowing method. The PVA-based resin is preferably dissolved in a solvent and used as a PVA-based resin solution.

Examples of solvents for dissolving PVA-based resins include alcohols (methanol, ethanol, butanol, hexafluoro-2-propanol, etc.), esters (methyl acetate, ethyl acetate, etc.), and organic solvents such as DMSO (dimethyl sulfoxide). and water, and water is preferable from the viewpoint of reducing the environmental load. The solvent containing water may contain other solvents (organic solvents exemplified above such as methanol, ethanol, methyl acetate, ethyl acetate and DMSO). The concentration of the PVA-based resin in the PVA-based resin solution is preferably 1 to 40% by mass, more preferably 2 to 30% by mass, and even more preferably 5 to 20% by mass.

The PVA-based resin solution can contain a water-soluble resin or a water-dispersible resin different from the water-soluble pharmaceutical polymer. Examples of water-soluble resins or water-dispersible resins that can be contained include starch derivatives such as starch, oxidized starch and cationic modified starch; natural proteins such as gelatin and casein; methylcellulose, ethylcellulose, hydroxyethylcellulose, carboxymethylcellulose (CMC ); Natural polymer polysaccharides such as sodium alginate and pectic acid; Water-soluble resins such as polyvinylpyrrolidone and poly(meth)acrylate; Styrene-butadiene rubber (SBR) latex, nitrile rubber (NBR) latex latexes; vinyl acetate resin emulsions, ethylene-vinyl acetate copolymer emulsions, (meth)acrylic ester resin emulsions, vinyl chloride resin emulsions, urethane resin emulsions, and the like. In this specification, (meth)acryl means acryl or methacryl.

In addition, the PVA-based resin solution can contain an alkali metal salt or an alkaline earth metal salt. Examples of the alkali metal salts include potassium salts and sodium salts of organic acids and inorganic acids. Examples of organic acids include acetic acid, propionic acid, butyric acid, lauric acid, stearic acid, oleic acid, and behenic acid. Examples of inorganic acids include sulfuric acid, sulfurous acid, carbonic acid, and phosphoric acid. Examples of alkaline earth metal salts include calcium salts and magnesium salts of organic acids and inorganic acids. Examples of organic acids include acetic acid, propionic acid, butyric acid, lauric acid, stearic acid, oleic acid, and behenin. acids, and examples of inorganic acids include sulfuric acid, sulfurous acid, carbonic acid, and phosphoric acid.

In the PVA-based resin solution, components other than the above include, for example, plasticizers, lubricants, pigment dispersants, thickeners, anti-adhesives, fluidity improvers, surfactants, antifoaming agents, release agents, Well-known additives such as mold agents, penetrants, dyes, pigments, fluorescent brighteners, ultraviolet absorbers, antioxidants, preservatives, antifungal agents, paper strength enhancers, cross-linking agents, etc. can be added as appropriate. .

The PVA-based resin solution preferably has a viscosity of 1 to 10,000 mPa·s at 25° C. in order to facilitate spinning of the nanofiber-forming material. The viscosity of the PVA-based resin solution at 25° C. is more preferably 10 to 5000 mPa·s, particularly preferably 100 to 3000 mPa·s.
The viscosity of the PVA-based resin solution is measured with a Brookfield viscometer.

A liquid mixture that is a nanofiber-forming material is obtained by adding a water-soluble medicinal polymer to the above PVA-based resin solution and mixing them uniformly. The water-soluble pharmaceutical polymer may be dissolved or dispersed in the PVA-based resin solution, but is preferably dissolved from the viewpoint of uniformity.

The mixing ratio of the PVA-based resin solution and the water-soluble medicinal polymer may be appropriately adjusted according to the physical properties of the water-soluble medicinal polymer. Mixing in the range of 10:90 to 90:10 is preferred. The mass ratio of the PVA-based resin and the water-soluble medicinal polymer (PVA-based resin:water-soluble medicinal polymer) in the mixed solution is more preferably 20:80 to 80:20, more preferably 30:70 to 75:25. , particularly preferably 35:65 to 70:30.

The viscosity of the mixed liquid at 25°C is preferably in the range of 1 to 10,000 mPa·s, more preferably 10 to 5,000 mPa·s, and particularly preferably 100 to 3,000 mPa·s.

The mixed solution prepared as above is spun to obtain nanofibers.

The nanofiber spinning method of the present invention includes "(i) an electrospinning method using a spinning nozzle", "(ii) an electrospinning method not using a spinning nozzle", and "(iii) a melt blowing method". . These methods will be described in sequence below.

(i) Electrospinning method using a spinning nozzle In the electrospinning method using a spinning nozzle, a high voltage is applied to the spinning nozzle side when extruding the above-mentioned mixed solution, which is a forming material, from the spinning nozzle, and an electric field is applied to the mixed solution. is stretched to form nanofibers. Then, a nanofiber nonwoven fabric is obtained by depositing nanofibers on the counter electrode side. An electric field may be applied between the spinning nozzle and the counter electrode by applying a voltage to the counter electrode instead of the spinning nozzle.

The concentration of the PVA-based resin in the mixed solution is preferably 1 to 40% by weight, more preferably 2 to 30% by weight, and still more preferably 5 to 20% by weight, but is not particularly limited, and is arbitrary. can be set to

Although the direction in which the mixture is extruded is not particularly limited, it is preferable that the direction in which the mixture is extruded from the nozzle does not coincide with the direction in which gravity acts so that the mixture is less likely to drip. In particular, it is preferable to extrude the liquid mixture in a direction opposite to the direction of action of gravity or in a direction perpendicular to the direction of action of gravity.

The diameter (inner diameter) of the spinning nozzle for extruding this mixed solution varies depending on the fiber diameter, but when forming nanofibers with a fiber diameter of 1 to 1000 nm, for example, it is preferably 0.1 to 5 mm, particularly It is preferably 0.5 to 2 mm. If the diameter is too large, there will be a tendency for a large amount of liquid to drip and electrospinning will be difficult.

Also, the spinning nozzle may be made of metal or non-metal. If the spinning nozzle is made of metal, the spinning nozzle can be used as one of the electrodes, and if the spinning nozzle is made of non-metal, an electric field can be applied to the mixed solution by installing an electrode inside the spinning nozzle. can work.

After extruding the mixed liquid from such a spinning nozzle, the extruded mixed liquid is stretched into fibers by applying an electric field. This electric field is not particularly limited because it varies depending on the fiber diameter of the nanofiber, the distance between the spinning nozzle and the collecting body where the fibers are accumulated, the viscosity of the liquid mixture, and the like. It is preferably 2 to 10 kV/cm. If the applied electric field is large, the fiber diameter of nanofibers tends to decrease as the electric field value increases. If it is too much, it tends to be difficult to form a fibrous shape.

By applying an electric field to the mixed liquid extruded in this way, static charge is accumulated in the mixed liquid, and it is electrically pulled by the electrode on the collector side, stretched, and made into fibers. Since the fibers are stretched electrically, the speed of the fibers is accelerated by the electric field as the fibers approach the collector, resulting in PVA-based resin fibers having a smaller fiber diameter. In addition, it is thought that the evaporation of the solvent makes the fibers thinner, the static electricity density increases, and the electric repulsive force causes the fibers to split and become PVA-based resin fibers with a smaller fiber diameter.

Such an electric field, for example, provides a potential difference between the spinning nozzle (the nozzle itself in the case of a metallic nozzle, or the electrode inside the nozzle in the case of a non-metallic nozzle such as glass or resin) and the collector. can be made to work by For example, the potential difference can be established by applying a voltage to the spinning nozzle and grounding the collector, or conversely, by applying a voltage to the collector and grounding the spinning nozzle.

The applied voltage is not particularly limited as long as the electric field intensity as described above can be obtained, but is preferably 1 to 30 kV, more preferably 5 to 20 kV, and still more preferably 10 to 20 kV. If the voltage is too high, sparks will occur and spinning will tend to be difficult. Conversely, if the voltage is too low, the power to electrically pull the solution will be insufficient and spinning will tend to be difficult. . The voltage application device is not particularly limited, but a DC high voltage generator can be used, and a Van de Graaff generator can also be used.

The polarity of the applied voltage may be either positive or negative. However, it is preferable to set the spinning nozzle side to a positive potential so that the spreading of the fibers can be suppressed and the fibers can be aggregated with a small pore size and a narrow pore size distribution. In particular, in order to easily suppress corona discharge during voltage application, it is preferable to ground the counter electrode on the collector side, apply a positive voltage to the spinning nozzle side, and set the spinning nozzle side to a positive potential.

The collector for collecting and depositing the nanofibers is not particularly limited, and examples thereof include a drum, a nonwoven fabric, a flat plate, or a belt-shaped conductive material made of metal or carbon, or an organic polymer. Non-conductive materials such as.
The collector does not need to be a conductive material as described above, and the counter electrode can be arranged behind the collector. In this case, the collector and the counter electrode may be in contact with each other or may be separated from each other.

The electrospinning method is preferably performed in an atmosphere with a relative humidity of 30 to 80%, more preferably in an atmosphere of 35 to 70%. If the relative humidity is too low, the mixed solution at the exit of the spinning nozzle dries quickly and tends to solidify and block the nozzle. tends to become weaker.

In order to maintain the above relative humidity, the spinning nozzle and collector are installed in a closed container, and humidified air is sent through a valve or the like so that the humidity in the closed container can be adjusted within the above range. is preferred. In addition, it is preferable that an exhaust device is connected to the closed container so as not to increase the pressure in the closed container and to discharge the solvent volatilized from the mixed liquid.

(ii) Electrospinning method not using a spinning nozzle As an electrospinning method not using a spinning nozzle, for example, a magnetic fluid is used as an electrode, and electrospinning is performed from the surface of the mixed solution that is the forming material (A L. Yarin, E. Zussman, "Polymer", 45 (2004), p.2977-2980). In addition, as the electrospinning method, a rotating roll is immersed in a bath filled with the above mixed solution, the mixed solution is adhered to the surface of the roll, and a high voltage is applied to this surface to perform electrospinning (http://www. http://www.elmarco.com), and furthermore, a method of performing electrostatic spinning by applying a high voltage to bubbles continuously generated in the mixed solution, etc. (“NONWOVENS REVIEW”, Vol. .18, No. 2 (2007), p.17-20, Japanese Patent Laid-Open No. 2008-25057, see).

(iii) Melt blowing method In the melt blowing method, the mixed liquid is discharged from a spinning nozzle, and at the same time as the mixed liquid is discharged, heated air is blown from both sides of the spinning nozzle at high speed in the direction of discharging the mixed liquid, so that the mixed liquid is The thread can be thinned by blowing out in the form of a thread.
It should be noted that the nozzle hole diameter generally used is about 0.2 mm, and the nozzles are arranged in a row at intervals of about 1 mm. The ejection amount per minute is about 0.5 g per nozzle, and a low ejection amount is adopted in order to obtain finer fibers.
A nanofiber nonwoven fabric is formed by entangling and/or fusing the blown nanofibers.

The thickness of the nanofiber nonwoven fabric obtained by the above method is preferably 0.1 to 500 μm, more preferably 0.3 to 300 μm, still more preferably 0.5 to 100 μm. The basis weight of the obtained nanofiber nonwoven fabric is appropriately set according to its application, preferably 0.1 to 40 g/m ² , more preferably 0.5 to 20 g/m ² , still more preferably 1 ˜10 g/m ² .

The present invention will be described in more detail below with reference to examples and comparative examples, but the present invention is not limited to the following examples as long as it does not exceed the gist thereof.

PVA 1 to 4 having saponification degrees and polymerization degrees shown in Table 1 were used as PVA-based resins.

[Preparation of mixed liquid containing PVA-based resin and water-soluble pharmaceutical polymer]
Lysozyme (molecular weight 14300) was used as a model for water-soluble pharmaceutical macromolecules. A previously prepared 8% by mass PVA aqueous solution (PVA1; 2.0 g, distilled water; 23 g, viscosity at 25° C. of about 2000 mPa s) and 4.7 g of lysozyme were added to a flask equipped with a stirring blade and stirred at 200 rpm for 10 minutes. By mixing, the mixture of Example 1 was prepared.
Mixtures of Examples 2 to 9 were prepared in the same manner as in Example 1, except that the type and amount of PVA used were changed to those shown in Table 2.

[Preparation of lysozyme-containing nanofibers]
A lysozyme-containing nanofiber nonwoven fabric was prepared by an electrospinning method using a spinning nozzle using the mixtures of Examples 1 to 8 in Table 2. Specifically, the diameter of the needle used was 22 G, the voltage between the electrodes was 10 kV, the distance from the tip of the needle to the collection plate was 12 cm, and the ejection speed of the mixed solution was 0.5 ml/hour. Nanofibers were formed and nonwoven fabrics were formed on the collection plate to prepare nanofiber nonwoven fabrics of Examples 1 to 8.
Also, using the water-soluble pharmaceutical polymer solution of Example 9, a nanofiber nonwoven fabric of Comparative Example 1 was prepared in the same manner as in Examples 1 to 8.

[Evaluation of elution rate]
The elution rates of the lysozyme-containing nanofiber nonwoven fabrics of Examples 1 to 8 and Comparative Example 1 were measured as follows.

According to the dissolution test paddle method of the 18th revision of the Japanese Pharmacopoeia, a glass vessel for a dissolution tester was charged with 900 ml of distilled water and immersed in a hot bath at 37°C. Subsequently, the nanofibers of Examples 1 to 8 and Comparative Example 1 were weighed in an amount containing 12 mg of lysozyme, added to distilled water, and stirred at a rotation speed of 50 rpm. After collecting the aqueous solution over time and sieving the collected solution with a 0.45 μm filter, the absorbance at 281 nm was measured with a UV-visible spectrophotometer (UV-1800, manufactured by Shimadzu Corporation). The dissolved lysozyme was quantified to determine the dissolved concentration. Table 3 shows the dissolution rate results.
The amount of lysozyme contained in the nanofibers was calculated by measuring the amount of lysozyme contained in 1 mg of the nanofibers by HPLC.

From Table 3, by using nanofibers containing a PVA-based resin and a water-soluble medicinal polymer, the release behavior of the water-soluble medicinal polymer could be controlled.
In addition, regarding the content ratio of the PVA-based resin and the water-soluble medicinal polymer, there was a tendency that the more the PVA-based resin, the more the water-soluble medicinal polymer was released in a sustained manner.

Although the present invention has been described in detail and with reference to specific embodiments, it will be apparent to those skilled in the art that various changes and modifications can be made without departing from the spirit and scope of the invention. This application is based on a Japanese patent application (Japanese Patent Application No. 2022-012541) filed on January 31, 2022, the contents of which are incorporated herein by reference.

According to the present invention, it is possible to release water-soluble pharmaceutical macromolecules such as protein drugs, and the nanofibers of the present invention can be applied to oral drugs, patches, and tapes. As a result, it is expected to be effective for diseases for which no therapeutic drugs have been available so far, and diseases for which conventional pharmaceuticals have not been able to sufficiently treat.

Claims

A nanofiber containing a polyvinyl alcohol-based resin (A) and a water-soluble pharmaceutical polymer (B), wherein the water-soluble pharmaceutical polymer (B) has a molecular weight of 1000 or more and 50000 or less.
A nanofiber comprising a polyvinyl alcohol-based resin (A) and a water-soluble pharmaceutical polymer (B), wherein the water-soluble pharmaceutical polymer (B) is a protein drug.
The content ratio of the polyvinyl alcohol-based resin (A) and the water-soluble pharmaceutical polymer (B) is, by mass ratio, polyvinyl alcohol-based resin (A):water-soluble pharmaceutical polymer (B)=10:90 to 90: 3. The nanofiber according to claim 1 or 2, which is 10.
The nanofiber according to any one of claims 1 to 3, wherein the polyvinyl alcohol resin (A) has a saponification degree of 75 to 99.9 mol%.
The nanofiber according to any one of claims 1 to 4, wherein the polyvinyl alcohol resin (A) has an average degree of polymerization of 300 to 4000.
The nanofiber according to any one of claims 1 to 5, wherein the nanofiber single fiber has a diameter of 1 nm to 10 μm.
A method for producing nanofibers containing a polyvinyl alcohol-based resin and a water-soluble medicinal polymer, wherein the nanofibers are produced by an electrospinning method or a meltblowing method using a mixed solution containing the polyvinyl alcohol-based resin and the water-soluble medicinal polymer. A method for producing nanofibers, comprising the step of producing
The method for producing nanofibers according to claim 7, wherein the solvent of the mixed solution is water.
A formulation comprising the nanofibers according to any one of claims 1 to 6.