JP2021088552A - Drug-containing fiber, method for producing the same, and oral preparation composed of the fiber - Google Patents

Abstract

To provide a fiber having an improved dissolution rate of a drug, particularly a poorly-soluble drug.SOLUTION: A drug-containing fiber contains a polyvinyl alcohol-based resin and an amorphous drug.SELECTED DRAWING: None

Description

The present invention relates to a drug-containing fiber containing an amorphous drug, a method for producing the same, and an oral preparation comprising the fiber.

In the design of various preparations for oral administration, it is important to design the bioavailability of the drug to be sufficiently high from the viewpoint of the efficacy and safety of the drug.
One of the important factors affecting the bioavailability of drugs is the solubility of drugs, and many studies have been conducted on the relationship between solubility and gastrointestinal absorption. .. Especially for poorly soluble drugs, it is known that the dissolution rate is the rate-determining step of absorption.

Various methods are known as a pharmaceutical method for improving the solubility of a poorly soluble drug, and a method using a solid dispersion is particularly noteworthy (for example, Patent Document 1). The solid dispersion is a poorly soluble drug dispersed in a base for a solid dispersion (inert carrier) in a solid state, and its production method includes a solvent method, a melting method and a mixed pulverization method (mechanochemical method). ) Etc., but in recent years, nanofiber-based formulations have been proposed.
However, in 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.

Japanese Unexamined Patent Publication No. 2014-55119

In view of the above problems, an object of the present invention is to provide a drug-containing fiber having an improved dissolution rate of a drug, particularly a poorly soluble drug, a method for producing the same, and an oral preparation comprising the fiber.

However, as a result of intensive studies in view of such circumstances, the present inventors have found that the drug becomes amorphous and the elution rate is improved by fiberizing the mixture containing the polyvinyl alcohol resin and the drug. It was. In particular, it has been found that a nanofiber preparation having an excellent drug elution rate can be obtained by spinning an emulsion in which a polyvinyl alcohol-based resin is used as a dispersant and a solution containing a drug is used as a dispersoid.

That is, the present invention is a drug-containing fiber characterized by containing a polyvinyl alcohol-based resin and an amorphous drug.

Further, the present invention is a method for producing a drug-containing fiber containing a polyvinyl alcohol-based resin and a drug, wherein the polyvinyl alcohol-based resin is used as a dispersant and a solution containing the drug is used as a dispersoid. It is a method having a step of producing a fiber by an electrospinning method or a melt blow method for a liquid.

Furthermore, the present invention is an oral preparation comprising the drug-containing fiber of the present invention.

According to the drug-containing fiber of the present invention, a fiber preparation having an excellent drug elution rate can be obtained.

It is a chart which shows the result of DSC of Examples 1-4, PBC, PVA1.

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

The drug-containing fiber of the present invention contains a polyvinyl alcohol-based resin and an amorphous drug. First, a polyvinyl alcohol-based resin (hereinafter, also referred to as “PVA-based resin”) will be described.

<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 remains unkeratinized with a vinyl alcohol structural unit corresponding to the degree of saponification. 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 95 mol%, more preferably 80 to 93 mol%, further preferably 83 to 90 mol%, and particularly preferably 85 to 90 mol%. %. If the saponification degree of the PVA-based resin is too high or too low, it tends to be difficult to obtain the effect of the present invention.
In the present invention, the saponification degree of the PVA-based resin is a value obtained by a method conforming to JIS K 6726.

The average degree of polymerization of the PVA-based resin used in the present invention is preferably 300 to 4000, more preferably 400 to 3000, still more preferably 500 to 2000, and particularly preferably 600 to 1000.
If the average degree of polymerization of the PVA resin is too low, the strength of the fiber tends to be insufficient and the stability during use tends to decrease, and if the average degree of polymerization is too high, the viscosity of the aqueous solution becomes high and it tends to be difficult to form fibers. is there.
In the present invention, the average degree of polymerization of the PVA-based resin shall be the average degree of polymerization obtained by a method according to JIS K 6726.

It is preferable to use a PVA-based resin having a high blocking property as the PVA-based resin from the viewpoint of dispersibility. The blocking property indicates the continuity between the vinyl alcohol structural unit and the vinyl ester structural unit.

The blocking property in the present invention is evaluated by the degree of iodine coloration. Specifically, a solution of potassium iodide and iodine is mixed with an aqueous PVA solution to develop a color, and the absorbance at a wavelength of 490 nm is read using a spectrophotometer. The higher the iodine coloration degree, the longer the average chain length of the vinyl ester unit. In the present invention, when the iodine coloration degree is less than 0.5, the blocking property is "low", 0.5 or more and less than 0.7 is the blocking property "medium", and 0.7 or more is the blocking property "high". Is preferably "medium" or higher (ie, "medium" or "high" rating).

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

The method for producing the PVA-based resin used in the present invention will be described in detail.
The 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-based 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 acetate and the like, and vinyl acetate is practically preferable.

Further, a monomer having copolymerizability with the vinyl ester-based monomer can be copolymerized to the extent that the effect of the present invention is not impaired. Examples of such copolymerization monomers include olefins such as ethylene, propylene, isobutylene, α-octene, α-dodecene, and α-octadecene; 3-butene-1-ol, 4-pentene-1-ol, and 5 Derivatives of hydroxy group-containing α-olefins such as −hexene-1-ol, 3,4-dihydroxy-1-butene and their acylates; acrylic acid, methacrylic acid, crotonic acid, maleic acid, maleic anhydride, itacon Unsaturated acids such as acid and undesylene acid and salts thereof; monoesters or nitriles such as dialkyl ester, acrylonitrile and metaacrylonitrile; amides such as diacetoneacrylamide, acrylamide and methacrylicamide; ethylenesulfonic acid, allylsulfonic acid, Olefin sulfonic acids such as metaallyl sulfonic acid and salts thereof; alkyl vinyl ethers, dimethyl allyl 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, hydroxymethylvinylidene diacetate such as 1,3-dibutyronyloxy-2-methylenepropane and the like. The content of the copolymerization monomer is usually 10 mol% or less, preferably 5 mol% or less, and particularly preferably 1 mol% or less, based on the total amount of the polymer.

The method for polymerizing the vinyl ester-based monomer and the copolymerization monomer is not particularly limited, and for example, known methods such as bulk polymerization, solution polymerization, suspension polymerization, dispersion polymerization, and emulsion polymerization can be adopted. , Usually solution polymerization is performed.

Examples of the solvent 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, which are industrially used. Methanol is preferably used.

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

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

Specific examples of the saponification catalyst include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, sodium methylate, sodium ethylate, and potassium methylate, and alkali catalysts such as alcoholate. The amount of such catalyst used is preferably 1 to 100 mmol equivalent with respect to the monomer.

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

Examples of the method for obtaining a PVA-based resin having a high blocking property include a method of controlling the dielectric constant of the solvent at the time of saponification in the manufacturing process of the PVA-based resin. Specifically, when saponifying the polyvinyl ester-based polymer, a solvent having a dielectric constant of 32 c.g.s.e.s.u. Or less may be used.

Examples of the solvent having a dielectric constant of 32c.gsesu or less include methanol (31.2c.gsesu), a mixed solvent of methyl acetate / methanol = 1/3 (mass ratio) (25.2c.gsesu), and methyl acetate / methanol. = 1/1 (mass ratio) mixed solvent (19.1c.gsesu), methyl acetate / methanol = 3/1 (mass ratio) mixed solvent (13.1c.gsesu), methyl acetate (7.03c.gsesu) ), Isopropylacetate (6.3c.gsesu), trichloroethylene (3.42c.gsesu), xylene (2.37c.gsesu), toluene (2.38c.gsesu), benzene (2.28c.gsesu) and acetone (. 21.4c.gsesu) and the like. The dielectric constant of the solvent at the time of saponification can also be adjusted by adding water (86.4 c.g.s.e.s.u.).

After saponification, it is preferable to wash the obtained PVA-based resin with a cleaning 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.

As the cleaning method, a continuous type (rotary cylindrical type, countercurrent contact type, centrifugal sprinkle cleaning, etc.) may be used, but a batch type is usually adopted. Examples of the stirring method (device) during cleaning include screw blades, ribbon blenders, and kneaders. The bath ratio (mass of cleaning liquid / mass of polyvinyl ester-based polymer particles) is usually 1 to 30, and particularly preferably 2 to 20. If the bath ratio is too large, a large cleaning device is required, which tends to increase the cost, and if the bath ratio is too small, the cleaning effect tends to decrease and the number of cleanings tends to increase.

The temperature at the time of washing is usually 10 to 80 ° C, particularly preferably 20 to 70 ° C. If the temperature is too high, the amount of volatilization of the cleaning liquid increases, and a reflux facility tends to be required. If the temperature is too low, the cleaning efficiency tends to decrease. The washing time is usually 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. The number of washings is usually 1 to 10 times, and particularly preferably 1 to 5 times. Excessive cleaning tends to reduce productivity and increase costs.

The washed PVA-based resin particles are dried by hot air or the like in a continuous or batch manner to obtain the PVA-based resin used in the present invention in powder form. The drying temperature is usually 50 to 150 ° C, preferably 60 to 130 ° C, 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, the drying tends to take a long time. The drying time is usually 1 to 48 hours, preferably 2 to 36 hours. If the drying time is too long, the PVA-based resin tends to be thermally deteriorated, and if the drying time is too short, the drying tends to be insufficient or high temperature drying tends to be required.

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

The PVA-based resin usually contains an alkali metal salt of acetic acid derived from an alkali catalyst used during saponification. The content of the alkali metal salt is usually 0.001 to 2% by mass, preferably 0.005 to 1% by mass, and more preferably 0.01 to 0.1% by mass with respect to the PVA-based resin powder. ..
Examples of the method for adjusting the content of the alkali metal salt include adjusting the amount of the alkali catalyst when used for saponification and washing the PVA-based resin with an alcohol such as ethanol or methanol.
Examples of the method for quantifying the alkali metal salt used in the present invention include a method in which a PVA-based resin powder is dissolved in water, methyl orange is used as an indicator, and neutralization titration is performed with hydrochloric acid to determine the content of the alkali metal salt.

<Drug>
The drug in the present invention is not particularly limited as long as it is used as an active ingredient of a pharmaceutical product, but a poorly soluble drug is preferable in order to make the effect of the present invention more obvious.

A poorly soluble drug is a drug that falls under the category of "difficult to dissolve", "extremely insoluble", or "almost insoluble" in water in terms of solubility specified in the general rules of the 17th revised Japanese Pharmacopoeia. Specifically, take 1 g or 1 mL of the drug in a beaker, add water, shake vigorously every 5 minutes at 20 ± 5 ° C. for 30 seconds, and dissolve the drug within 30 minutes in an amount of 100 mL or more. It is called a "poorly soluble drug".
If the drug is solid, it should be powdered and then placed in a beaker. Further, when the amount of water is 100 mL or more and less than 1000 mL, it can be called a “difficult to dissolve” drug, when 1000 mL or more and less than 10000 mL is called an “extremely insoluble” drug, and when it is 10,000 mL or more, it can be called a “almost insoluble” drug.

Examples of the poorly soluble drug in the present invention include Probucol, Barsartan, Cymbastatin, Lansoprazole, Olanzapine, Omeprazole, Ezetimib, Lisperidone, Pioglycetyl, Alipiprazole, Candesartan cilexetil, Ilbesartan, Docetaxel, Celecoxib, Ormesartan medoxyb. Ciprofloxacin, thermisartane, tacrolimus, mometazone furancarboxylic acid ester, mycophenolate mofetil, ratanoprost, levothyroxine sodium, clarisromycin, ritonavir, cyclosporine, nifedipine, paclitaxel, tadalafil, dexamethasone, bicartamide, carvegilol , Glymepyrid, retrozole, loratazine, naproxene, dutasteride, dipyridamole, crotrimazole, oxycarbazepine, paricalsitol, felodipine, calcipotriol, meroxycam, cepixim, entacapon, isotretinoin, glycrazide, ursodeoxycholic acid, diosmine , Frosemide, orristat, silostazole, itraconazole, glybenclamid, isosorbide nitrate, bosentan, spironolactone, cefdinyl, lorazepam, metaxalon, ketoconazole, methotrexate, exemestane, neviborol, imikimod, etricoxyb , Chronazepam, Robastatin, Felodipine, Nevilapin, Pariperidone, Planlucast, Visacodil, Calcitriol, Shirolimus, Atobacon, Bromazepam, Leflunomide, Amisulfride, Nateglunide, Zopiclone, Niselgoline, Cefditoren pivoxil, Cefditoren pivoxil, Roll, trasemido, sulfasalazine, eprosartane, chlortalidone, gripidide, aceclophenac, mycophenolic acid, etodrac, fervinac, pyroxicum, rubiproston, mephenamic acid, diacerein, proguanyl, haloperidol, tamoxyphencitrate, nifedipine, turobterol, norfloxacin. Enoxolone, Loxythromycin, Eprarestat, Bezafibrate, Rifaximin, Sulpyride, A Citretin, Spiramycin, Sylnidipine, Didrogesterone, Brothizolam, Nisoldipine, Manidipine, Noscapin, Posaconazole, Maxacalcitol, Diflucortron, Berteporfin, Sulfaziazine, Labatinib, Lolmetazepam, Etizolam, Cremastine, Nabumetone, Lornoxicam Fluorometron, Ubidecarenone, Triazolam, Albendazole, Levocabastine, Cholestiramine, Bromocryptin, Mitotane, Ibuprofen, Indomethacin, Flutamide, Gefitinib, Ramatroban, Laftidine, Pimobendan, Ceratrodust, Azernidipine, Everolimus, Mequitazine, Eberolimus, Mequitazine Examples include mosupride citrate. The poorly soluble drug is not limited to these, and includes pharmaceutical compounds newly found in the future.

As the poorly soluble drug in the present invention, any of anhydrous, hydrate, solvate, and pharmaceutically acceptable salt form can be used. The form of the poorly soluble drug used as a raw material is not particularly limited, and may be crystalline or amorphous, or a mixture thereof. The crystal may be any of the known polymorphs of crystals. The drug-containing fiber of the present invention is characterized in that it becomes an amorphous drug regardless of whether the drug before being mixed with the PVA-based resin is crystalline or amorphous.
The amorphous state refers to a state in which an endothermic peak is not confirmed near the melting temperature by differential scanning calorimetry.

<Drug-containing fiber>
The drug-containing fiber of the present invention is an ultrafine fiber formed into a fibrous form by spinning a forming material containing at least a PVA-based resin and an amorphous drug.
The drug-containing fiber of the present invention has a single fiber diameter (fiber diameter) of preferably 1 nm to 10 μm, more preferably 1 to 2000 nm, particularly preferably 5 to 1000 nm, and further preferably 10 to 700 nm. If the fiber diameter is too large, the drug is less likely to be in an amorphous state, and the dissolution rate of the drug tends to decrease. Further, if the fiber diameter is too small, it becomes difficult to exhibit sufficient strength, problems such as handling during use tend to occur, and production efficiency tends to decrease. If the fiber diameter is set large, the drug release time becomes long, and conversely, if the fiber diameter is set small, the release time can be shortened, so that the drug release can be controlled.
The fiber diameter of the fiber is measured using an electron microscope.

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

The content ratio of the PVA-based resin and the drug in the above-mentioned forming material varies depending on the physical characteristics of the drug, but the PVA-based resin: drug (weight ratio) is preferably 0.1 to 100: 1, and more preferably 0.5. ~ 100: 1, particularly preferably 1 to 70: 1.

Further, in order to facilitate spinning of the forming material, the viscosity of the PVA aqueous solution is preferably adjusted to 1 to 10000 mPa · s, more preferably 10 to 5000 mPa · s, and particularly preferably 100 to 3000 mPa · s.
The viscosity of the PVA-based resin aqueous solution is measured by a Brookfield viscometer.

As the forming material, in addition to the PVA-based resin, another water-soluble or water-dispersible resin can be used in combination. Examples of the water-soluble or water-dispersible resin that can be used in combination include 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). ) And other cellulose derivatives; natural high molecular weight polysaccharides such as sodium alginate and pectinic acid; water-soluble resins such as polyvinylpyrrolidone and poly (meth) acrylates; styrene-butadiene rubber (SBR) latex and nitrile rubber (NBR) latex. Latex; Emulsions such as vinyl acetate resin emulsion, ethylene-vinyl acetate copolymer emulsion, (meth) acrylic ester resin emulsion, vinyl chloride resin emulsion, urethane resin emulsion and the like can be mentioned. In addition, in this specification, (meth) acrylic means acrylic or methacrylic.

Further, an alkali metal salt or an alkaline earth metal salt can be blended with the forming material. Examples of the alkali metal salt 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 the inorganic acid include sulfuric acid, sulfite, carbonic acid, and phosphoric acid. Examples of alkaline earth metal salts include calcium salts and magnesium of organic acids and inorganic acids, and examples of organic acids include acetic acid, propionic acid, butyric acid, lauric acid, stearic acid, oleic acid, and behenin. Acids and the like can be mentioned, and examples of the inorganic acid include sulfuric acid, sulfite, carbonic acid, phosphoric acid and the like.

In addition to the above alkali metal salts and alkaline earth metal salts, the forming materials include, for example, plasticizing agents, lubricants, pigment dispersants, thickeners, anti-sticking agents, fluidity improving agents, surfactants, and defoamers. Well-known additives such as foaming agents, mold release agents, penetrants, dyes, pigments, optical brighteners, ultraviolet absorbers, antioxidants, preservatives, fungicides, paper strength enhancers, and cross-linking agents are appropriately mixed. can do.

[Manufacturing method of drug-containing fiber]
The drug-containing fiber of the present invention is preferably formed in the form of a sheet from the viewpoint of ease of handling, and for example, it is preferable to form a non-woven fabric from the drug-containing fiber. Hereinafter, a method for forming a non-woven fabric (hereinafter, also referred to as “fiber non-woven fabric”) from drug-containing fibers will be described.

(Manufacturing of fiber non-woven fabric)
In the fiber non-woven fabric, a PVA-based resin solution in which a PVA-based resin is dissolved in a solvent is used as a dispersant, and a dispersion obtained by using a drug-containing solution as a dispersoid is used as a forming material, and this dispersion is used by an electrospinning method (electrospinning method). Obtained by applying to the electrostatic spinning method) or the melt blow method.
When the drug is a poorly soluble drug, it is preferable to dissolve it in a solvent in which the drug dissolves and then mix it with a PVA-based resin.
The solvent in this case needs to dissolve the drug, but is preferably a solvent that is immiscible with water in order to form an emulsion. Further, when it is made into a fibrous form, it is preferable that the boiling point is about the same as or lower than that of water.
Examples of such a solvent include anisole, 1-butanol, n-butyl acetate, ethyl acetate, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methyl isobutyl ketone and 2-methyl-1-. Examples include propanol, pentane, and propyl acetate.
Further, as the solvent, a solvent suitable for the drug to be used is used. For example, when probucol is used as a drug, it is preferably dissolved in ethyl acetate.

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

Examples of the method for producing the drug-containing fiber of the present invention include "(a) electrospinning method using a spinning nozzle", "(b) electrospinning method not using a spinning nozzle", and "(c) melt blow method". These methods will be described below.

(A) Electrospinning method using a spinning nozzle Using an electrospinning method using a spinning nozzle, for example, a fiber nonwoven fabric can be obtained as follows. When the dispersion liquid is extruded from the spinning nozzle, the fiber non-woven fabric is stretched by applying a high voltage to the spinning nozzle side and applying an electric field to the dispersion liquid to form fibers, and the fibers are deposited on the counter electrode side. Obtained by A voltage may be applied to the counter electrode side instead of the spinning nozzle side to cause an electric field to act between the spinning nozzle and the counter electrode side.

The concentration of the PVA-based resin in the above dispersion is usually preferably 1 to 40% by weight, particularly preferably 2 to 30% by weight, further preferably 5 to 20% by weight, but is not particularly limited and is optional. Can be set.

The pushing direction of the dispersion liquid is not particularly limited, but it is preferable that the pushing direction from the nozzle and the acting direction of gravity do not match so that the dispersion liquid does not easily drip. In particular, it is preferable to push out the dispersion liquid in a direction opposite to the direction of action of gravity or 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. For example, when forming nanofibers having a fiber diameter of 1 to 1000 nm, it is usually 0.1 to 5 mm, particularly 0.5 to 5. It is preferably 2 mm. If the diameter is too large, there is a lot of dripping and electrospinning tends to be difficult. On the contrary, if the diameter is too small, the dispersion liquid tends to be difficult to extrude and the productivity tends 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-metal, an electric field is applied to the dispersion liquid by installing an electrode inside the spinning nozzle. Can act.

After the dispersion liquid is extruded from such a spinning nozzle, the extruded dispersion liquid is stretched and made into fibers by applying an electric field. This electric field is not particularly limited because it changes depending on the fiber diameter of the fiber, the distance between the spinning nozzle and the collector that accumulates the fiber, the viscosity of the dispersion liquid, and the like, but 0.2 to 0.2 to obtain the fiber according to the present invention. It is preferably 5 kV / cm. If the applied electric field is large, the fiber diameter of the fiber tends to decrease as the electric field value increases, but if the electric field value is too large, air dielectric breakdown tends to occur, and conversely, it is too small. And, it tends to be difficult to form a fiber shape.

By applying an electric field to the dispersion liquid extruded in this way, an electrostatic charge is accumulated in the dispersion liquid, and it is electrically pulled by the electrode on the collector side and stretched to become fibrous. Since the fibers are electrically stretched, the velocity 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. Further, it is considered that the fiber becomes thinner due to evaporation of the solvent, the electrostatic density increases, and the fiber is split by the electric repulsive force to become a PVA-based resin fiber having a smaller fiber diameter.

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

The applied voltage is not particularly limited as long as it can have the electric field strength as described above, but is usually 1 to 30 kV, preferably 5 to 20 kV, and 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 force that electrically pulls the solution will be insufficient and spinning will tend to be difficult. .. The voltage applying 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 that the spinning nozzle side has a positive potential so that the spread of the fibers is suppressed, the pore diameter is small, and the fibers can be assembled in a state where the pore diameter distribution is narrow. In particular, it is preferable that the counter electrode on the collector side is grounded and the spinning nozzle side is positively applied so that the spinning nozzle side has a positive potential so that the corona discharge when the voltage is applied can be easily suppressed.

The collector for collecting and depositing fibers is not particularly limited, and is, for example, a conductive material having a drum, non-woven fabric, flat plate, or belt shape and made of metal, carbon, or the like, an organic polymer, or the like. Examples thereof include non-conductive materials made of.
The collector does not have 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 carried out in an atmosphere having a relative humidity of usually 30 to 80%, particularly 35 to 70%. If the relative humidity is too low, the dispersion at the outlet of the spinning nozzle dries quickly and tends to solidify and block the nozzle. If the relative humidity is too high, it becomes difficult to dry and forms fibers. It tends to be difficult.

In order to maintain the relative humidity, the spinning nozzle and the collector are installed in a closed container, and humidity-controlled 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 preferable. Further, it is preferable that the exhaust device is connected to the closed container so as not to increase the pressure in the closed container and to discharge the volatile solvent from the dispersion liquid.

(B) Electrospinning method that does not use a spinning nozzle As an electrospinning method that does not use a spinning nozzle, for example, a method of electrostatically spinning from the surface of a dispersion liquid of a PVA-based resin using a magnetic fluid as an electrode (AL). . Yarin, E. Zussuman, "Polymer", 45 (2004) 2977-2980). Further, as an electrospinning method, a rotating roll is immersed in a bath filled with a dispersion liquid of PVA-based resin, a PVA-based resin dispersion liquid is adhered on the surface of the roll, a high voltage is applied to the surface, and static electricity is applied. Examples thereof include a method of spinning (see http://www.elmarco.com), and further, a method of performing electrostatic spinning by applying a high voltage to bubbles continuously generated in a PVA-based resin dispersion liquid and the like. (See "NONWOVENS REVIEW", Vol. 18, No. 2 (2007) 17-20, JP-A-2008-25057).

(C) Melt blow method In the melt blow method, the dispersion liquid is discharged from the spinning nozzle, and at the same time as the dispersion liquid is discharged, heated air is blown out from both sides of the spinning nozzle at high speed in the discharge direction of the dispersion liquid, and the dispersion liquid is discharged. The thread can be thinned by blowing it out in the form of a thread.
The nozzle hole diameter generally used is about 0.2 mm, and the nozzle holes are arranged in a row at intervals of about 1 mm. The discharge amount per minute per nozzle is about 0.5 g, and a low discharge amount is adopted in order to obtain finer fibers.

The thickness of the fibrous nonwoven fabric obtained by the above method is usually 0.1 to 500 μm, preferably 0.3 to 300 μm, and more preferably 0.5 to 100 μm. The basis weight of the obtained fiber-woven fabric is appropriately set according to the intended use, and is usually 0.1 to 40 g / m ² , preferably 0.5 to 20 g / m ² , more preferably 1 to 1. It is 10 g / m ² .

<Oral formulation>
The oral preparation of the present invention comprises the above-mentioned drug-containing fibers, preferably in the form of a fibrous nonwoven fabric.
The fibrous nonwoven fabric can be administered as a preparation together with the above-mentioned collector or exfoliated from the collector. As the administration route, oral administration or sublingual administration is preferable. The fiber non-woven fabric may be a laminate containing a collector or another layer.
Since the drug contained in the administered fiber non-woven fabric is in an amorphous state, the dissolution rate of the drug is excellent and the bioavailability is sufficiently high. Therefore, the drug-containing fiber of the present invention is excellent in terms of drug efficacy and safety.

Hereinafter, the present invention will be described in more detail with reference to Examples and Comparative Examples, but the present invention is not limited to the following Examples as long as the gist of the present invention is not exceeded.
In addition, "%" in an example means a mass reference.

As the PVA-based resin, PVAs 1 to 5 having the saponification degree and the degree of polymerization shown in Table 1 were used.

[Preparation of dispersion liquid containing PVA resin and drug]
A PVA aqueous solution (PVA 4 g, distilled water 36 g, viscosity about 2000 mPa · s) and a Probucol (PBC) solution (PBC 0.5 g, ethyl acetate 9 g) are mixed, and using KINEMATICA's Polytron Homogenizer PT10 / 35, 8000 rpm × The dispersion was prepared by stirring for 10 minutes and emulsifying. The dispersions of Examples 2 to 5 were prepared in the same manner with the compositions shown in Table 2.

[Preparation of PBC-containing fiber non-woven fabric]
A PBC-containing fiber nonwoven fabric was prepared by an electrospinning method using the dispersions of Examples 1 to 5. Specifically, the diameter of the needle used was 22 G, the voltage between the electrodes was 20 kV, the distance from the tip of the needle to the collection plate was 12 cm, the discharge rate of the dispersion liquid was 0.5 ml / hour, and it was ultrafine for 2 hours. Fiber formation was performed to form a non-woven fabric on the collection plate to prepare a PBC-containing fiber non-woven fabric.

[Evaluation of crystallinity]
Crystals of probucol (PBC) were confirmed by DSC (Differential Scanning Calorimetry) for the PBC-containing fiber nonwoven fabrics of Examples 1 to 4. The result is shown in FIG.
For the measurement of DSC, DSC6200 manufactured by Seiko Instruments Inc. was used, the measurement range was 25 to 300 ° C., and the temperature rising rate was 10 ° C./min.
As a comparison target, crystals of PBC powder and PVA1 were also confirmed and shown in FIG.

From the results shown in FIG. 1, it can be seen that in Examples 1 to 3, the endothermic peak observed in the PBC powder disappeared, and the PBC was in an amorphous state.

[Evaluation of emulsified state and elution rate]
The emulsified state of the dispersions of Examples 1 to 5 was observed, and the time until gelation was measured. Further, the elution rate of the PBC-containing fiber nonwoven fabric obtained by using the dispersions of Examples 1 to 5 was measured by the following method. For the blank, the elution rate of PBC alone was measured.

17th revision According to the dissolution test paddle method of the Japanese Pharmacopoeia, 900 ml of 0.1% Tween 80 aqueous solution is placed in a glass vessel for an dissolution tester and immersed in a warm bath at 37 ° C. Subsequently, a fiber nonwoven fabric containing 5 mg of the drug is added, and the aqueous solution is collected over time while being dissolved at a rotation speed of 50 rpm. The amount of PBC contained in the PBC-containing fiber non-woven fabric is calculated by measuring the amount of PBC contained in about 1 mg of the PBC-containing fiber non-woven fabric by HPLC (manufactured by JASCO Corporation) under the conditions shown in Table 3.
After sieving the collected aqueous solution with a 0.45 μm filter, the concentration of the drug in the aqueous solution is determined by quantifying by HPLC (manufactured by JASCO Corporation) measurement under the conditions shown in Table 3. Further, the dissolution amount of the drug is calculated from the dissolved concentration of the drug thus obtained, and the dissolution rate is obtained by dividing by the content of the drug contained in the fiber nonwoven fabric.
The results of emulsification status and elution rate are summarized in Table 4.

Since the drug is in an amorphous state, the drug-containing fiber of the present invention has an excellent drug elution rate and high bioavailability. Therefore, it can be suitably used for various preparations, particularly oral preparations such as oral administration and sublingual administration.

Claims (7)

A drug-containing fiber containing a polyvinyl alcohol-based resin and an amorphous drug. The drug-containing fiber according to claim 1, wherein the polyvinyl alcohol-based resin has a saponification degree of 75 to 95 mol%. The drug-containing fiber according to claim 1 or 2, wherein the polyvinyl alcohol-based resin has an average degree of polymerization of 300 to 4000. The drug-containing fiber according to any one of claims 1 to 3, wherein the diameter of the single fiber of the drug-containing fiber is 1 nm to 10 μm. The drug-containing fiber according to any one of claims 1 to 4, wherein the drug is a poorly soluble drug. A method for producing a drug-containing fiber containing a polyvinyl alcohol-based resin and a drug.
A method having a step of producing fibers by an electrospinning method or a melt blow method using a dispersion liquid obtained by using the polyvinyl alcohol-based resin as a dispersant and a solution containing the drug as a dispersoid. An oral preparation comprising the drug-containing fiber according to any one of claims 1 to 5.

Images