JP2024030725A - Drug-containing fibers and oral preparations made from the fibers - Google Patents

Abstract

The present invention provides a drug-containing fiber that exhibits good drug dissolution properties and has excellent storage stability that can maintain a high dissolution rate even when stored for a long period of time, and an oral preparation made from the fiber. [Solution] A drug-containing fiber containing a polyvinyl alcohol resin and a drug and further containing solid particles, and an oral preparation made of the fiber. [Selection diagram] Figure 3

Description

The present invention relates to a polyvinyl alcohol resin, a drug, a drug-containing fiber containing solid particles, and an oral preparation comprising the fiber.

In designing various preparations for oral administration, etc., it is important to design drugs with sufficiently high bioavailability from the viewpoint of drug efficacy and safety.
Drug solubility is one of the important factors that affects the bioavailability of drugs, and many studies have been conducted on the relationship between solubility and gastrointestinal absorption. . It is known that, particularly for poorly soluble drugs, the rate of dissolution is the rate-limiting step for absorption.

Various formulation methods are known to improve the solubility of poorly soluble drugs. Specifically, there is a method using a solid dispersion, and manufacturing methods include a solvent method, a melt method, and a mixed pulverization method. (mechanochemical method), etc., but in recent years, preparations made of nanofibers have been considered.
As a preparation made into nanofibers, for example, there is a method of using drug-containing fibers characterized by containing a polyvinyl alcohol resin and an amorphous drug (Patent Document 1).
However, with the technique of Patent Document 1, there is room for improvement in the dissolution rate of the drug, and the bioavailability cannot be designed to be sufficiently high.
Therefore, Patent Document 2 proposes a drug-containing fiber containing a polyvinyl alcohol resin, a surfactant, and a drug, in which the drug is in a nanocrystalline state, as a method for further improving the drug dissolution rate. ing.

However, the present inventors have discovered that the drug-containing fiber containing a surfactant as disclosed in Patent Document 2 has poor storage stability, and a problem arises in that the dissolution rate decreases when stored for a long period of time.
Therefore, there is a need for drug-containing fibers with good dissolution properties that can maintain a high dissolution rate even after long-term storage.

JP 2021-88552 Publication JP2022-81718A

In view of the above problems, the present invention aims to provide a drug-containing fiber that exhibits good drug dissolution properties and has excellent storage stability, and an oral preparation made from the fiber.

However, the present inventors have conducted extensive research in view of the above circumstances, and have found that by using polyvinyl alcohol resin, solid particles, and drug-containing fibers containing drugs, the amorphous state of the drug can be maintained and a favorable effect can be achieved. It has been found that drug fibers with excellent drug elution properties and storage stability can be obtained.

That is, the gist of the present invention is the following [1] to [6].
[1] A drug-containing fiber containing a polyvinyl alcohol resin and a drug, and further containing solid particles.
[2] The drug-containing fiber according to [1], wherein the content of the solid particles is 0.01 to 50% by weight based on 100% by weight of the polyvinyl alcohol resin.
[3] The drug-containing fiber according to [1] or [2], wherein the content of the solid particles is 20% by weight or less based on the entire drug-containing fiber.
[4] The drug-containing fiber according to any one of [1] to [3], wherein the solid particles are inorganic fine particles.
[5] The drug-containing fiber according to any one of [1] to [4], wherein the polyvinyl alcohol resin has a saponification degree of 75 to 99.9 mol%.
[6] An oral preparation comprising the drug-containing fiber according to any one of [1] to [5].

According to the drug-containing fiber of the present invention, a drug-containing fiber with excellent drug dissolution properties and good storage stability, and an oral preparation made of the drug-containing fiber can be obtained.

1 is a chart showing the results of elution rates of Examples 1 and 2 and Comparative Examples 1 and 2. 3 is a chart showing the storage stability results of Example 2. 3 is a chart showing the DSC results of Example 2.

Hereinafter, the present invention will be explained in detail, but these are examples of desirable embodiments.

The drug-containing fiber of the present invention contains a polyvinyl alcohol resin, solid particles, and a drug. First, polyvinyl alcohol resin (hereinafter also referred to as "PVA resin") will be explained.

<PVA 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, and contains vinyl alcohol structural units corresponding to the degree of saponification and residual unsaponified units. Composed of vinyl ester structural units.

The lower limit of the degree of saponification of the PVA resin used in the present invention is preferably 75 mol% or more, more preferably 80 mol% or more, still more preferably 83 mol% or more, and particularly preferably 85 mol% or more. The upper limit is preferably 99.9 mol% or less, more preferably 95 mol% or less, still more preferably 93 mol% or less, particularly preferably 90 mol% or less. If the saponification degree 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 saponification degree of the PVA-based resin is a value determined by a method based on JIS K 6726.

The lower limit of the average degree of polymerization of the PVA resin used in the present invention is preferably 300 or more, more preferably 400 or more, still more preferably 500 or more, particularly preferably 600 or more. The upper limit is preferably 4000 or less, more preferably 3500 or less, still more preferably 3000 or less.
If the average degree of polymerization of the PVA resin is too low, the strength of the drug-containing fibers will be insufficient and the stability during use will tend to decrease; if the average degree of polymerization is too high, the viscosity of the aqueous solution will increase and drug-containing fibers will be formed. It tends to be difficult.
In the present invention, the average degree of polymerization of the PVA-based resin is determined by a method based on JIS K 6726.

It is also possible to use two or more types of PVA-based resins in combination. When used in combination, PVA resins having different degrees of saponification, average degree of polymerization, and blocking properties can be used together.

The method for producing the PVA resin used in the present invention will be explained in detail.
The PVA resin can be obtained, for example, by saponifying a polyvinyl ester polymer obtained by polymerizing a vinyl ester 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.

Furthermore, a monomer having copolymerizability with the vinyl ester monomer may be copolymerized to the extent that the effects of the present invention are not impaired. Examples of such copolymerizable monomers include olefins such as ethylene, propylene, isobutylene, α-octene, α-dodecene, and α-octadecene; 3-buten-1-ol, 4-penten-1-ol, 5 - Hydroxy group-containing α-olefins such as hexen-1-ol and 3,4-dihydroxy-1-butene, and derivatives such as their acylated products; acrylic acid, methacrylic acid, crotonic acid, maleic acid, maleic anhydride, itacon acids, unsaturated acids such as undecylenic acid and their salts; monoesters or dialkyl esters, nitriles such as acrylonitrile and methacrylonitrile; amides such as diacetone acrylamide, acrylamide and methacrylamide; ethylene sulfonic acid, allylsulfonic acid, Olefin sulfonic acids and their salts such as metaallylsulfonic acid; alkyl vinyl ethers, dimethylallyl vinyl ketone, N-vinylpyrrolidone, vinyl chloride, vinyl ethylene carbonate, 2,2-dialkyl-4-vinyl-1,3-dioxolane, 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, 1,3-dibutyronyloxy-2-methylenepropane and other hydroxymethylvinylidene diacetates. The content of such copolymerizable monomers is usually 10 mol% or less, preferably 5 mol% or less, particularly preferably 1 mol% or less, based on the total amount of the polymer.

There are no particular limitations on the method of polymerizing the vinyl ester monomer and copolymerizable monomer, and for example, known methods such as bulk polymerization, solution polymerization, suspension polymerization, dispersion polymerization, or emulsion polymerization can be employed. , usually solution polymerization is carried out.

Solvents used in such polymerization usually 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. Methanol is preferably used.

Further, the polymerization reaction is carried out using a known radical polymerization catalyst such as azobisisobutyronitrile, acetyl peroxide, benzoyl peroxide, lauroyl peroxide, or various known low-temperature active catalysts. Further, the reaction temperature is selected from a range of about 35° C. to the boiling point.

The obtained polyvinyl ester polymer is then saponified continuously or batchwise. In such saponification, either alkali saponification or acid saponification can be employed, but industrially it is preferable to dissolve the polymer in alcohol and conduct it in the presence of an alkali catalyst. Examples of the alcohol include methanol, ethanol, butanol, and the like. The concentration of polymer in the alcohol is selected from the range 20-60% by weight. Additionally, if necessary, approximately 0.3 to 10% by weight of water may be added, and various esters such as methyl acetate and various solvents such as benzene, hexane, and DMSO (dimethyl sulfoxide) may be added. You may.

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

The degree of saponification of the PVA resin can be adjusted by the amount of saponification catalyst, 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, butanol, and methanol is preferred from the viewpoint of cleaning efficiency and drying efficiency.

The cleaning method may be a continuous type (rotating cylinder type, countercurrent contact type, centrifugal separation sprinkle cleaning, etc.), but a batch type is usually adopted. Stirring methods (devices) used during cleaning include screw blades, ribbon blenders, kneaders, and the like. The bath ratio (weight of cleaning liquid/weight of polyvinyl ester polymer particles) is usually 1 or more, particularly 2 or more, and 30 or less, particularly preferably 20 or less. If the bath ratio is too large, a large cleaning device will be required, which tends to increase costs, and if the bath ratio is too small, the cleaning effect will decrease and the number of cleanings will tend to increase.

The lower limit of the temperature during washing is usually 10°C or higher, particularly preferably 20°C or higher. The upper limit is 80°C or less, particularly preferably 70°C or less. If the temperature is too high, the amount of volatilization of the cleaning liquid increases, which tends to require reflux equipment. Furthermore, if the temperature is too low, cleaning efficiency tends to decrease. The lower limit of the washing time is usually 5 minutes or more, particularly preferably 30 minutes or more. The upper limit is 12 hours or less, particularly preferably 4 hours or less. If the cleaning time is too long, production efficiency tends to decrease, and if the cleaning time is too short, cleaning tends to be insufficient. Further, the lower limit of the number of times of washing is usually one or more times. The upper limit is preferably 10 times or less, particularly 5 times or less. Too many washings tend to reduce productivity and increase costs.

The washed PVA resin particles are dried with hot air or the like in a continuous or batch method to obtain the PVA resin used in the present invention in powder form. The lower limit of the drying temperature is usually 50°C or higher, preferably 60°C or higher, and more preferably 70°C or higher. The upper limit is 150°C or less, preferably 130°C or less, more preferably 110°C or less. If the drying temperature is too high, the PVA resin tends to be thermally degraded, and if the drying temperature is too low, the drying tends to take a long time. The lower limit of the drying time is usually 1 hour or more, preferably 2 hours or more. The upper limit is 48 hours or less, preferably 36 hours or less. If the drying time is too long, the PVA resin tends to be thermally degraded, and if the drying time is too short, the drying tends to be insufficient or high temperature drying is required.

The lower limit of the content of the solvent contained in the PVA-based resin after drying is usually 0% by weight or more, preferably 0.01% by weight or more, and more preferably 0.1% by weight or more. The upper limit is 10% by weight or less, preferably 5% by weight or less, more preferably 1% by weight or less.

Note that the PVA-based resin usually contains an alkali metal salt of acetic acid derived from the alkali catalyst used during saponification. The lower limit of the content of the alkali metal salt based on the PVA resin powder is usually 0.001% by weight or more, preferably 0.005% by weight or more, and preferably 0.01% by weight or more. The upper limit is 2% by weight or less, preferably 1% by weight or less, and more preferably 0.1% by weight or less.
Examples of methods for adjusting the alkali metal salt content include a method of adjusting the amount of an alkali catalyst used in saponification, and a method of washing the PVA resin with alcohol such as ethanol and methanol.
A method for quantifying the alkali metal salt used in the present invention includes a method of dissolving PVA-based resin powder in water, using methyl orange as an indicator, and performing neutralization titration with hydrochloric acid.

<Solid particles>
The drug-containing fibers of the present invention include solid particles. The type of solid particles is not particularly limited, and examples thereof include organic fine particles and inorganic fine particles, and either of them may be used, but inorganic fine particles are more preferably used.
These solid particles can be used in any combination regardless of whether they are organic or inorganic.
Furthermore, the drug-containing fiber of the present invention exhibits good dissolution properties and storage stability. Although the reason for this is not certain, it is thought that the inclusion of solid particles makes it possible to suppress moisture absorption of the drug-containing fiber.

The organic fine particles include polymethacrylic acid methyl acrylate resin particles, acrylic styrene resin particles, polymethyl methacrylate resin particles, silicone resin particles, polystyrene resin particles, polycarbonate resin particles, benzoguanamine resin particles, and melamine resin particles. , polyolefin resin particles, polyester resin particles, polyamide resin particles, polyimide resin particles, cellulose ester resins, and the like. Among these, polystyrene resin fine particles are preferred. A plurality of types of these organic fine particles may be used in combination.

Examples of the inorganic fine particles include compounds containing silicon, nanosilica such as silicon dioxide, aluminum oxide, zirconium oxide, calcium carbonate, talc, clay, calcined kaolin, calcined calcium silicate, hydrated calcium silicate, aluminum silicate, Examples include magnesium silicate and calcium phosphate. A plurality of types of these inorganic fine particles may be used in combination.
In addition, among inorganic fine particles, nanosilica can be suitably used. Nanosilica includes hydrophilic nanosilica and hydrophobic nanosilica, but hydrophilic nanosilica in particular improves the wettability of fibers and improves dissolution. preferred. A plurality of types of these inorganic fine particles may be used in combination.

Examples of hydrophilic nanosilica include AEROSIL50, AEROSIL90G, AEROSIL130, AEROSIL200, AEROSIL200CF, AEROSIL200V, AEROSIL 200 FAD, AEROSIL 300, AEROSIL 300 CF, and AE. ROSIL OX 50, AEROSIL TT 600, AEROSIL MOX80, AEROSIL MOX170, AEROSIL COK84, AEROSIL Alu C , AEROSIL Alu 65, AEROSIL Alu130, etc. (Nippon Aerosil Co., Ltd.).

Examples of hydrophobic nanosilica include AEROSIL R 972, AEROSIL R 972 CF, AEROSIL R 972 V, AEROSIL R 974, AEROSIL R 976, AEROSIL R 976 S, AEROSIL RX 50, AEROSIL L NAX 50, AEROSIL NX 90G, AEROSIL NX130, AEROSIL RX200, AEROSIL RX300, AEROSIL R 812, AEROSIL R 8200, AEROSIL RY50, AEROSIL RY51, AEROSIL NY50, AEROSIL NY50L, AEROSIL RY200 S, AEROSIL RY200, AEROSIL NA50H, AEROSIL NA50Y, AEROSIL R504, AEROSIL RY200HS, AEROSIL REA90, AEROSIL REA200, Examples include AEROSIL RY200L, AEROSIL RY300, AEROSIL R202, AEROSIL RY805, AEROSIL RM50, AEROSIL RY711, AEROSIL RY7200 (Japan Aerosil Co., Ltd.).

Others: SYLOPHOBIC 100, SYLYSIA 320, SYLYSIA 350, SYLOSPHERE C-1504, SYLOSPHERE C-1510, SYLOPURE 25, SYLOPURE 30, SYLOPURE 35, SYLOPURE 39 , SYLOPURE 40, SYLOPURE 50, SYLOPURE 60, SYLOPURE 65, SYLOPURE P100 (Fuji Syria) Co., Ltd.) etc. can be used.

The upper limit of the content of solid particles in the present invention in the drug-containing fiber is preferably 20% by weight or less, more preferably 15% by weight or less, even more preferably 10% by weight or less, and particularly preferably 5% by weight or less. Further, the lower limit is preferably 0.01% by weight or more, more preferably 0.05% by weight or more, and even more preferably 0.1% by weight or more.
If the content of solid particles is too large or too small, the dispersion will foam and a uniform drug-containing fiber cannot be obtained, which is not preferable. Although the drug-containing fiber can be obtained from a dispersion (emulsion) in which a PVA-based resin is dispersed, as will be described later, it is thought that almost no solvent remains in the obtained drug-containing fiber.

The content of solid particles in the present invention varies depending on the type, particle size, physical properties, etc. of the solid particles, but the lower limit is preferably 0.01% by weight or more, and 0.1% by weight based on 100% by weight of the PVA resin. It is more preferably at least 0.5% by weight, even more preferably at least 0.5% by weight. Further, the upper limit is preferably 50% by weight or less, more preferably 25% by weight or less, even more preferably 10% by weight or less, and particularly preferably 5% by weight or less.
If the content of solid particles is too small, the effect derived from the solid particles cannot be obtained, and if the content of solid particles is too large, the drug tends to crystallize and the dissolution properties are unfavorable. .

The particle diameter of the solid particles in the present invention is preferably 0.01 to 10,000 nm, more preferably 0.1 to 1,000 nm, and even more preferably 1 to 100 nm.
When the solid particles satisfy the above range, the emulsion becomes smaller in particle size, and the diameter (fiber diameter) of single fibers of the obtained drug-containing fibers also becomes smaller, which tends to improve dissolution properties, which is preferable.

<Drugs>
The drug in the present invention is not particularly limited as long as it can be used as an active ingredient of pharmaceuticals, but in order to make the effects of the present invention more obvious, poorly soluble drugs are preferred.

A poorly soluble drug refers to a drug that falls into the categories of ``poorly soluble,'' ``extremely soluble,'' and ``almost insoluble'' in water as described in the 17th edition of the Japanese Pharmacopoeia. Specifically, when you put 1 g or 1 mL of a solid drug in a beaker, add water, and shake it vigorously for 30 seconds every 5 minutes at 20±5℃, "hard to dissolve" means that it is 100 mL or more and less than 1000 mL within 30 minutes. It refers to the degree of solubility in "Extremely difficult to dissolve" similarly refers to the degree of dissolution within 30 minutes in 1000 mL or more and less than 10000 mL. Similarly, "almost insoluble" refers to something that requires 10,000 mL or more to dissolve within 30 minutes.

Examples of poorly soluble drugs in the present invention include probucol, valsartan, simvastatin, lansoprazole, olanzapine, omeprazole, ezetimibe, risperidone, pioglitazone, aripiprazole, candesartan cilexetil, irbesartan, docetaxel, celecoxib, olmesartan medoxomil, efavirenz, fenofibrate, Ciprofloxacin, telmisartan, tacrolimus, mometasone furoate, mycophenolate mofetil, latanoprost, levothyroxine sodium, clarithromycin, ritonavir, cyclosporine, nifedipine, paclitaxel, tadalafil, dexamethasone, bicalutamide, carvedilol, ziprasidone, finasteride , glimepiride, letrozole, loratadine, naproxen, dutasteride, dipyridamole, clotrimazole, oxcarbazepine, paricalcitol, felodipine, calcipotriol, meloxicam, cefixime, entacapone, isotretinoin, gliclazide, ursodeoxycholic acid, diosmin , Flocemide, Orlistat, Sirostazole, Itlaconazole, Griven Chestnut, Iseosorbide, Bossentan, Spironoracton, Spironolacton, Sefjinyl, Lorazepam, Metakonazole, Ketokonazole, Metotrexate, Equisemastan, Nevollol, Imikimodo, Etricoxy, Etricoxib Levamipide, Alpha Cars Doll, Tretinoin, Sorafenibsilate, Ziazepam , clonazepam, lovastatin, phenytoin, nevirapine, paliperidone, pranlukast, bisacodyl, calcitriol, sirolimus, atovaquone, bromazepam, leflunomide, amisulpride, nateglinide, zopiclone, nicergoline, cefditoren pivoxil, mosapride, hydroxyzine, aprepitant, megest Lor, torasemide, sulfasalazine, eprosartan, chlorthalidone, glipizide, aceclofenac, mycophenolic acid, etodolac, felbinac, piroxicam, lubiprostone, mefenamic acid, diacerein, proguanil, haloperidol, tamoxifen citrate, nimodipine, tulobuterol, norfloxacin, pimecrolimus, Enoxolone, roxithromycin, eprarestat, bezafibrate, rifaximin, sulpiride, acitretin, spiramycin, cilnidipine, dydrogesterone, brotizolam, nisoldipine, manidipine, noscapine, posaconazole, maxacalcitol, diflucortolon, verteporfin, sulfadiazine, lavatinib , lormetazepam, etizolam, clemastine, nabumetone, lornoxicam, estriol, cinepazed, fluorometholone, ubidecarenone, triazolam, albendazole, levocabastine, cholestyramine, bromocriptine, mitotane, ibuprofen, indomethacin, flutamide, gefitinib, ramatroban, lafutidine, pimobendan, seratrodast , azelnidipine, everolimus, mequitazine, mitotane, zafirlukast, ampiroxicam, ebastine, mosapride citrate, and the like. Note that poorly soluble drugs are not limited to these, but also include pharmaceutical compounds that will be newly discovered in the future.

The poorly soluble drug in the present invention may be in the form of an anhydride, hydrate, solvate, or pharmaceutically acceptable salt. The form of the poorly soluble drug used as a raw material is not particularly limited, and may be either crystalline or amorphous, or a mixture thereof. The crystal may be any known crystal polymorph. The drug-containing fiber of the present invention is characterized in that the drug is in an amorphous state, regardless of whether the drug is crystalline or amorphous before being mixed with the PVA resin.
Note that the amorphous state refers to a state in which no endothermic peak is observed near the melting temperature by differential scanning calorimetry.

<Drug-containing fiber>
The drug-containing fiber of the present invention is a fiber formed into a fibrous shape by spinning a forming material containing at least a PVA resin, a drug, and solid particles.
In the drug-containing fiber of the present invention, the lower limit of the single fiber diameter (fiber diameter) is preferably 1 nm or more, more preferably 5 nm or more, even more preferably 10 nm or more, and the upper limit is 10 μm or less, more preferably 2000 nm or less, especially It is preferably 1000 nm or less, particularly preferably 700 nm or less.
If the fiber diameter is too large, it becomes difficult for the drug to be in an amorphous state, and the dissolution of the drug tends to decrease. Furthermore, if the fiber diameter is too small, it becomes difficult to exhibit sufficient strength, which tends to cause problems such as handling during use and to reduce production efficiency.
If the fiber diameter is set thick, the drug release time will be prolonged, and if the fiber diameter is set thin, the release time can be shortened, so that drug release can be controlled. Note that the fiber diameter of the drug-containing fiber is measured using an electron microscope.

The average fiber length of the drug-containing fiber is not particularly limited, but from the viewpoint of ease of handling, it is preferably 10 times or more, preferably 100 times or more, and more preferably 1000 times or more the diameter. Moreover, it is more preferable that the drug-containing fiber is a continuous fiber.

The blending ratio of PVA resin and drug in the above-mentioned forming material varies depending on the physical properties of the drug, but the blending ratio (weight ratio) of PVA resin:drug is preferably 1:100 to 5000:100, and 10:100 to The ratio is more preferably 2500:100, even more preferably 50:100 to 1000:100, and particularly preferably 100:100 to 500:100.

The blending ratio of solid particles and drug in the above-mentioned forming material varies depending on the physical properties of the drug, but the solid particle:drug (weight ratio) is preferably 0.1:100 to 500:100, and 0.5:100 to The ratio is more preferably 100:100, even more preferably 1:100 to 50:100, and particularly preferably 1:100 to 20:100.

Further, in order to make it easier to spin the forming material, it is preferable to adjust the viscosity of the PVA aqueous solution during spinning to usually 1 mPa·s or more, more preferably 10 mPa·s or more, particularly preferably 100 mPa·s or more. good. Further, it is preferable to adjust the pressure to 10,000 mPa·s or less, more preferably to 5,000 mPa·s or less, particularly preferably to 3,000 mPa·s or less.
Note that the viscosity of the PVA resin aqueous solution is measured using a Brookfield viscometer.

In addition to the PVA-based resin, the above-mentioned molding material can also contain other water-soluble or water-dispersible resins. Water-soluble or water-dispersible resins that can be used in combination include, for example, starch derivatives such as starch, oxidized starch, and cationically modified starch; natural proteins such as gelatin and casein; methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, and carboxymethyl cellulose (CMC). ); natural polymeric 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 (N
BR) Latexes: Examples include emulsions such as vinyl acetate resin emulsions, ethylene-vinyl acetate copolymer emulsions, (meth)acrylic ester resin emulsions, vinyl chloride resin emulsions, and urethane resin emulsions.
In this specification, (meth)acrylic means acrylic or methacryl.

Moreover, an alkali metal salt or an alkaline earth metal salt can be blended into the above-mentioned forming material. Examples of the alkali metal salts include potassium salts and sodium salts of organic acids and inorganic acids, and examples of the 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 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. Examples of inorganic acids include sulfuric acid, sulfurous acid, carbonic acid, and phosphoric acid.

In the above-mentioned forming material, components other than those mentioned above include, for example, a plasticizer, a lubricant, a pigment dispersant, a thickener, an anti-stick agent, a fluidity improver, an antifoaming agent, a mold release agent, a penetrant, a dye, Well-known additives such as pigments, optical brighteners, ultraviolet absorbers, antioxidants, preservatives, antifungal agents, paper strength enhancers, and crosslinking agents can be appropriately blended.

[Method for manufacturing drug-containing fiber]
The drug-containing fiber of the present invention can be used as oral preparations in various forms, but from the viewpoint of ease of handling, it is preferable to form it into a sheet form. For example, it is preferable to form a nonwoven fabric from the drug-containing fiber. . A method for forming a nonwoven fabric (hereinafter also referred to as "fiber nonwoven fabric") from drug-containing fibers will be described below.

(Manufacture of fiber nonwoven fabric)
The fiber nonwoven fabric contains solid particles, a PVA resin solution containing solid particles dissolved in a PVA resin solvent is used as a dispersant, a solution containing a drug is used as a dispersoid, and the obtained dispersion is used as a forming material. It is obtained by applying a dispersion liquid to an electrospinning method (electrostatic spinning method) or a melt blowing method.
The method for preparing the solid particle-containing PVA resin solution is not particularly limited, and includes a method of dissolving the PVA resin in a solvent and then adding and dissolving the solid particles, a method of dissolving the PVA resin and the solid particles in the solvent, Examples include a method of dissolving the solid particles after addition, and a method of dissolving the PVA resin after adding solid particles to the solvent.
Furthermore, when the drug is a poorly soluble drug, it is preferable to dissolve the drug in a solvent and then mix it with the solid-containing particle PVA resin.
The solvent in this case needs to dissolve the drug, but in order to form an emulsion, a solvent that is immiscible with water is preferred. Further, when forming into a fiber, it is preferable that the boiling point is the same as or lower than that of water.
Examples of such solvents include anisole, 1-butanol, n-butyl acetate, ethyl acetate, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methyl isobutyl ketone, 2-methyl-1- Examples include propanol, pentane, and propyl acetate.
Furthermore, a solvent suitable for the drug used is used. For example, when using probucol as a drug, it is preferable to dissolve it in ethyl acetate.

As the solvent for dissolving the PVA resin, for example, water, alcohols, and other organic solvents can be used. Among these, water is preferably used in consideration of manufacturing environment problems.
When preparing a dispersion containing a PVA-based resin, solid particles, and a drug, it is preferable to use a homogenizer, and any of a high-pressure homogenizer, an ultrasonic homogenizer, and an ultrahigh-speed homogenizer can be used.

Methods for producing the drug-containing fiber of the present invention include known methods such as electrospinning using a spinning nozzle, electrospinning without using a spinning nozzle, and melt blowing, and any of these methods can be used. However, the present invention employs an electrospinning method using a spinning nozzle.

The electrospinning method using a spinning nozzle will be described in detail.
Using an electrospinning method using a spinning nozzle, a fiber nonwoven fabric can be obtained, for example, as follows. When extruding the dispersion liquid from a spinning nozzle, the fiber nonwoven fabric is stretched and made into fibers by applying a high voltage to the spinning nozzle side and applying an electric field to the dispersion liquid, and depositing the fibers on the counter electrode side. It is obtained by Note that a voltage may be applied to the counter electrode side instead of the spinning nozzle side, and an electric field may be applied between the spinning nozzle side and the spinning nozzle side.

The concentration of the PVA resin in the dispersion is not particularly limited, but the lower limit is preferably 0.5% by weight or more, more preferably 1% by weight or more, still more preferably 5% by weight or more. The upper limit is preferably 40% by weight or less, more preferably 30% by weight or less, still more preferably 20% by weight or less.

The concentration of solid particles in the dispersion is not particularly limited, but the lower limit is preferably 0.001% by weight or more, more preferably 0.01% by weight or more, still more preferably 0.05% by weight or more. The upper limit is preferably 10% by weight or less, more preferably 5% by weight or less, still more preferably 1% by weight or less.

The extrusion direction of this dispersion liquid is not particularly limited, but it is preferable that the extrusion direction from the nozzle does not coincide with the direction of gravity so that the dispersion liquid is less likely to drip. In particular, it is preferable to extrude the dispersion liquid 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 that extrudes this dispersion varies depending on the fiber diameter, but for example, when forming fibers with a fiber diameter of 1 nm or more and 1000 nm or less, the lower limit of the diameter of the spinning nozzle is usually 0.1 mm or more. In particular, it is preferably 0.5 mm or more, and the upper limit is preferably 5 mm or less, particularly 2 mm or less. If the diameter is too large, there will be a lot of liquid dripping, making electrospinning difficult. On the other hand, if the diameter is too small, it will be difficult to extrude the dispersion, and productivity will tend to decrease.

Further, 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-metallic material, an electric field can be applied to the dispersion by installing an electrode inside the spinning nozzle. It can be made to work.

After extruding a dispersion liquid from such a spinning nozzle, an electric field is applied to the extruded dispersion liquid to draw it into fibers. This electric field is not particularly limited as it changes depending on the fiber diameter of the fiber, the distance between the spinning nozzle and the collecting body that collects the fibers, the viscosity of the dispersion liquid, etc. Preferably it is 5 kV/cm. If the applied electric field is large, the fiber diameter of the fiber tends to become thinner as the electric field value increases, but if the electric field value is too large, air dielectric breakdown tends to occur, and conversely, if the electric field value is too small, the fiber diameter tends to become smaller. , there is a tendency that it is difficult to form a fiber shape.

By applying an electric field to the extruded dispersion liquid, electrostatic charges are accumulated in the dispersion liquid, and the dispersion liquid is electrically pulled by the electrode on the collection body side, and is elongated to form fibers. Since the fibers are electrically stretched, as the fibers approach the collector, the speed of the fibers is accelerated by the electric field, resulting in PVA-based resin fibers having a smaller fiber diameter. It is also believed that the fibers become thinner due to evaporation of the solvent, increase their electrostatic density, and split due to the electrical repulsion to become PVA-based resin fibers with a smaller fiber diameter, yielding nanofibers.

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

The applied voltage is not particularly limited as long as it can achieve the electric field strength as described above, but the lower limit is preferably 1 kV or more, more preferably 5 kV or more, more preferably 10 kV or more, and the upper limit is 30 kV or less. is preferable, and more preferably 20 kV or less. If the voltage is too high, sparks will occur and spinning will tend to be difficult; conversely, if the voltage is too low, there will be insufficient power to electrically pull the solution, making spinning difficult. . The voltage application device is not particularly limited, but in addition to a DC high voltage generator, a Van de Graaf generator can also be used.

Note that 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 in order to suppress the spread of the fibers and allow the fibers to gather in a state where the pore diameter is small and the pore diameter distribution is narrow. In particular, in order to easily suppress corona discharge when voltage is applied, it is preferable to ground the opposing electrode on the collector side and apply a positive voltage to the spinning nozzle side so that the spinning nozzle side has a positive potential.

The collecting body for collecting and depositing fibers is not particularly limited, and includes, for example, a drum, a nonwoven fabric, a flat plate, or a belt shape, a conductive material made of metal or carbon, an organic polymer, etc. Non-conductive materials such as
The collector does not need to be made of a conductive material as described above, and a counter electrode can be placed 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.

Note that this electrospinning method is preferably carried out in an atmosphere where the relative humidity is 30% or more, particularly 35% or more, and 80% or less, particularly 70% or less. If the relative humidity is too low, the dispersion at the exit of the spinning nozzle will tend to dry quickly and solidify, clogging the nozzle. If the relative humidity is too high, it will be difficult to dry and form fibers. It tends to get harder.

In order to maintain the above relative humidity, the spinning nozzle and collector are installed in a sealed container, and humidity-controlled air is sent in through a valve, etc., so that the humidity inside the sealed container can be adjusted within the above range. It is preferable. Further, it is preferable that an exhaust device is connected to the closed container so as not to increase the pressure inside the closed container and to discharge the solvent volatilized from the dispersion liquid.

<Oral preparation>
The oral preparation of the present invention is composed of the above drug-containing fiber, preferably in the form of a fiber nonwoven fabric.
The fiber nonwoven fabric can be administered as a preparation together with the above-mentioned collector or after being peeled from the collector. As for the route of administration, intraoral administration and sublingual administration are preferred. Note that the fiber nonwoven fabric may be a laminate including a collector and other layers.
The fiber nonwoven fabric using the drug-containing fiber of the present invention has excellent drug dissolution properties because it can maintain the amorphous state of the drug contained therein by containing solid particles, and also has good storage stability. , a high dissolution rate can be maintained for a long period of time. Therefore, the drug-containing fiber of the present invention is excellent in drug efficacy and safety.

Hereinafter, the present invention will be explained in more detail with reference to Examples and Comparative Examples, but the present invention is not limited to the following Examples unless it exceeds the gist thereof.

<Preparation of dispersion containing PVA resin, solid particles, and drug>
(Manufacturing example 1)
8 parts by weight of polyvinyl alcohol (PVA) (product name: GOHSENOL ^TM EG-40P, degree of saponification 88 mol%, manufactured by Mitsubishi Chemical Corporation) and 0.1 parts by weight of silica (product name: Aerosil 200, manufactured by Evonik) were added to 71.9 parts by weight of purified water. By adding parts by weight and heating and stirring, a mixed solution adjusted to 10 parts by weight was obtained.
A probucol (PBC) solution (4 parts by weight of PBC, 16 parts by weight of ethyl acetate) previously dissolved in ethyl acetate was added to the mixed solution, and the mixture was stirred for 10 minutes at 8000 rpm using a Polytron homogenizer PT10/35 manufactured by KINEMATICA. Production Example 1) was prepared.

(Manufacturing example 2)
A dispersion liquid was prepared in the same manner as in Production Example 1, except that the blending amounts were changed as shown in Table 1.

(Manufacturing example 3)
A dispersion liquid was prepared in the same manner as in Production Example 1, except that silica was not blended and the blending amount was changed as shown in Table 1.

(Manufacturing example 4)
A dispersion was prepared in the same manner as in Production Example 1, except that 0.1 part by weight of Tween 80 was added as a surfactant instead of silica, and the amounts were changed as shown in Table 1.

[Preparation of drug-containing fiber nonwoven fabric]
(Example 1)
Using the dispersion of Production Example 1, a drug-containing fiber nonwoven fabric was prepared by electrospinning. The diameter of the needle used was 22G, the voltage between the electrodes was 10kV, the distance from the needle tip to the collection plate was 12cm, the dispersion liquid discharge rate was 0.5ml/hour, and ultrafine fiber formation was performed for 2 hours. A drug-containing fiber nonwoven fabric (Example 1) was prepared by forming a nonwoven fabric on a collection plate.

(Example 2, Comparative Examples 1 and 2)
In the same manner as in Example 1, drug-containing fiber nonwoven fabrics of Production Example 2 and Comparative Examples 1 and 2 were prepared with the compositions shown in Table 1, and the fiber diameter and dissolution properties were measured. The measurement results are shown in Table 2.

[Fiber diameter]
The fiber diameter of the nanofibers was calculated from a SEM image obtained using a scanning electron microscope (SM-6510LV, manufactured by JEOL Ltd.). Note that image processing software (ImageJTM, NIH) was used to calculate the fiber diameter.

[Evaluation of dissolution]
Regarding the drug-containing fiber nonwoven fabrics obtained using the dispersions of Examples 1 and 2 and Comparative Examples 1 and 2, the dissolution rate was measured and the dissolution properties were evaluated as described below.

According to the dissolution test paddle method of the 17th edition of the Japanese Pharmacopoeia, 900 ml of a 0.1% Tween 80 aqueous solution was placed in a glass vessel for a dissolution tester and immersed in a 37°C hot bath. Subsequently, a fiber containing the equivalent of 5 mg of drug was added and dissolved at a rotational speed of 50 rpm, and an aqueous solution was sampled over time to measure the PBC concentration of the aqueous solution. Note that the amount of PBC contained in the fiber nonwoven fabric is calculated by determining the amount of PBC contained in around 1 mg of the fiber nonwoven fabric by HPLC measurement. After the collected solution was sieved through a 0.45 μm filter, it was subjected to HPLC (manufactured by JASCO Corporation) under the conditions shown in Table 3 (using COSMOSIL 5C18-MS-II 4.6 mm I.D. × 250, manufactured by Nacalai Tesque). ) The dissolved concentration was determined by quantitative measurement, and the dissolution property was evaluated according to the following criteria.
○: The elution rate after 2 hours is more than 45% and not more than 70%, and the elution rate after 10 hours is more than 70% and not more than 100%.
Δ: The elution rate after 2 hours is more than 25% and not more than 45%, and the elution rate after 10 hours is more than 60% and not more than 100%.
×: Elution rate after 2 hours is less than 40% or 60% or more.
Furthermore, the results of the elution rate are shown in Figure 1.

[Storage stability]
The drug-containing fiber nonwoven fabric obtained using the dispersion of Example 2 was stored for 4 weeks at 40°C and 75RH%.
Immediately after producing the drug-containing fiber nonwoven fabric, and after storage for 4 weeks, the dissolution rate and crystallinity were measured to evaluate storage stability.
Crystallinity was measured using differential scanning calorimetry (manufactured by PerkinElmer, DSC8000) at a measurement range of 25 to 250°C and a heating rate of 10°C/min. For comparison, the crystalline state of PBC powder was also confirmed.
The results of elution rate measurement when evaluating storage stability are shown in FIG. 2, and the results of crystallinity measurement when evaluating storage stability are shown in FIG.

The dissolution evaluation showed that Examples 1 and 2 containing solid particles had better drug dissolution than Comparative Example 1 containing a surfactant (Tween 80) and Comparative Example 2 containing neither. .
Furthermore, from the storage stability evaluation results, it was confirmed that Example 2 containing solid particles exhibited physical properties equivalent to those immediately after the preparation of the drug-containing fiber nonwoven fabric even after 4 weeks.

The drug-containing fiber of the present invention can be suitably used in various preparations, especially oral preparations such as intrabuccal administration and sublingual administration.

Claims (7)

A drug-containing fiber containing polyvinyl alcohol resin and a drug, and further containing solid particles. The drug-containing fiber according to claim 1, wherein the content of the solid particles is 0.0150% by weight based on 100% by weight of the polyvinyl alcohol resin. The drug-containing fiber according to claim 1 or 2, wherein the content of the solid particles is 20% by weight or less based on the entire drug-containing fiber. The drug-containing fiber according to claim 1 or 2, wherein the solid particles are inorganic fine particles. The drug-containing fiber according to claim 1 or 2, wherein the polyvinyl alcohol resin has a saponification degree of 75 to 99.9 mol%. An oral preparation comprising the drug-containing fiber according to claim 1 or 2. An oral preparation comprising the drug-containing fiber according to claim 4.