Sheet and method for manufacturing same

Abstract

Provided is a sheet exhibiting high drug delivery efficiency to the posterior part of the eye and excellent retentivity, which could not be achieved with a conventional method.　The present invention provides a sheet containing nanofibers including a water-soluble polymer (A), wherein the water-soluble polymer (A) contains at least one selected from the group consisting of a polyvinyl alcohol-based resin, a hydroxyalkyl cellulose, and a polyethylene oxide; and the sheet comes into contact with at least one selected from the group consisting of the cornea, conjunctiva, and sclera, and maintains 50% or more of the mass after being immersed in phosphate-buffered saline at 37°C for 1 minute.

Description

Sheet and manufacturing method thereof

[0001] The present invention relates to a sheet containing a water-soluble polymer and a method for producing the same.

[0002] Many ocular diseases affecting the posterior segment of the eye, such as the retina, choroid, optic nerve, vitreous body, and sclera, are intractable, and the development of effective drug treatments for these diseases is desired. However, locally administered drug treatments for diseases or disorders in the posterior segment of the eye have had difficulty in delivering the drug to the target site.

[0003] Conventionally, drug treatments for diseases of the posterior segment of the eye have employed intravitreal injection methods such as those described in Patent Documents 1 and 2, and eye drops as described in Patent Document 3. Furthermore, more recently, formulations using liposomes for drug delivery to the posterior segment of the eye, such as those described in Patent Document 4, have also been investigated.

[0004] JP 2024-12435 A JP 2023-120431 A JP 2022-132196 A International Publication No. 2009 / 107753

[0005] For example, the administration methods by injection into the vitreous body described in Patent Documents 1 and 2 lack convenience and have invasive issues such as concerns about complications due to injection and pain to the patient. Non-invasive methods include eye drops as described in Patent Document 3, but the present inventors have found that eye drops have issues such as a shortened drug retention time due to tears and the barrier on the ocular surface, resulting in low bioavailability and the need for continuous repeated administration. On the other hand, the present inventors have found that liposomal formulations such as those described in Patent Document 4 still have issues such as insufficient drug delivery and retention in the posterior segment of the eye due to the high barrier function of the eye that prevents the drug from migrating to the posterior segment.

[0006] Under these circumstances, the present invention provides a sheet that exhibits high drug delivery efficiency and excellent retention to the posterior segment of the eye, which could not be achieved by conventional methods.

[0007] However, in order to solve the above problems, the inventors have conducted extensive research and have found an alternative treatment method that is less invasive, has excellent posterior segment delivery properties, and enables sustained drug release due to excellent retention.

[0008] The present invention encompasses the following aspects. [1] A sheet containing nanofibers comprising a water-soluble polymer (A), wherein the water-soluble polymer (A) comprises at least one selected from the group consisting of a polyvinyl alcohol-based resin, a hydroxyalkyl cellulose, and polyethylene oxide; the sheet is used in contact with at least one selected from the group consisting of the cornea, the conjunctiva, and the sclera, and the sheet maintains at least 50% of its mass after immersion in phosphate-buffered saline at 37°C for 1 minute. [2] The sheet according to [1], wherein the water-soluble polymer (A) is contained in the nanofibers in an amount of 70% by mass or more. [3] The sheet according to [1] or [2], wherein the water-soluble polymer (A) comprises an unmodified polyvinyl alcohol-based resin. [4] The sheet according to [3], wherein the unmodified polyvinyl alcohol-based resin has a degree of saponification of 70 to 100 mol %. [5] The sheet according to [3] or [4], wherein the product of the degree of polymerization of the unmodified polyvinyl alcohol-based resin and the content of the unmodified polyvinyl alcohol-based resin in the nanofibers is 200 to 3,000. [6] The sheet according to any one of [1] to [5], having a thickness of 0.01 to 200 μm. [7] The sheet according to any one of [1] to [6], further comprising a drug. [8] The sheet according to [7], wherein the drug is in an amorphous state. [9] The sheet according to any one of [1] to [8], further comprising a surfactant.

[10] A method for producing a sheet, comprising a step of producing nanofibers by electrospinning or melt-blowing using a mixed solution containing a water-soluble polymer (A) and a drug.

[11] Use of a sheet containing nanofibers comprising a water-soluble polymer (A), wherein the water-soluble polymer (A) contains at least one selected from the group consisting of polyvinyl alcohol resin, hydroxyalkyl cellulose, and polyethylene oxide, as a sheet to be used in contact with at least one selected from the group consisting of the cornea, conjunctiva, and sclera.

[12] A method for using a sheet containing nanofibers containing a water-soluble polymer (A), the method comprising a step of contacting the sheet, wherein the water-soluble polymer (A) contains at least one selected from the group consisting of a polyvinyl alcohol-based resin, a hydroxyalkyl cellulose, and polyethylene oxide, with at least one selected from the group consisting of the cornea, the conjunctiva, and the sclera.

[0009] Surprisingly, the sheet containing nanofibers containing a water-soluble polymer of the present invention exhibited high drug delivery efficiency and excellent retention to the posterior segment of the eye, which could not be achieved by conventional methods.

[0010] The sheet of the present invention will be described in detail below, but these are examples of preferred embodiments and the present invention is not limited to these details.

[0011] As used herein, "x and / or y (x and y are any configuration)" refers to at least one of x and y, and can mean three things: x only, y only, or x and y. In this specification, when "X to Y" (X and Y are any numbers) is used, unless otherwise specified, it also means "X or more and Y or less," as well as "preferably more than X" or "preferably less than Y." In this specification, when "X or more" (X is any number) or "Y or less" (Y is any number) is used, it also means "preferably more than X" or "preferably less than Y." For numerical ranges described in stages in this specification, the upper or lower limit of a certain numerical range can be arbitrarily combined with the upper or lower limit of another numerical range. Furthermore, in the numerical ranges described herein, the upper or lower limit of the numerical range can also be replaced with the values ​​shown in the examples.

[0012] In this specification, polyvinyl alcohol may be abbreviated as "PVA." Furthermore, the term "sheet" includes "film" and "tape."

[0013] The sheet of the present invention contains nanofibers containing a water-soluble polymer (A). By including the water-soluble polymer (A), the nanofibers can efficiently adhere to the mucous membrane on the surface of the eyeball, maintaining a high drug concentration in the eye. As a result, the sheet exhibits high drug delivery efficiency and excellent retention in the posterior segment of the eye.

[0014] A sheet according to one embodiment of the present invention (hereinafter, sometimes referred to as "the sheet") is a sheet in which the water-soluble polymer (A) contains at least one selected from the group consisting of a PVA-based resin, a hydroxyalkyl cellulose, and a polyethylene oxide, the sheet comes into contact with at least one selected from the group consisting of the cornea, the conjunctiva, and the sclera, and is characterized in that 50% or more of its mass is maintained after immersion in phosphate-buffered saline at 37°C for 1 minute.

[0015] This sheet comes into contact with at least one tissue selected from the group consisting of the cornea, conjunctiva, and sclera. "At least one tissue selected from the group consisting of the cornea, conjunctiva, and sclera" refers to the outer tissue of the eyeball, and by directly contacting this sheet with the outer tissue, it is possible to increase penetration into the interior of the eyeball. It is also less invasive than injections and the like.

[0016] The present sheet maintains at least 50% of its mass after immersion in phosphate buffered saline (PBS) at 37°C for 1 minute, preferably at least 60%, and more preferably at least 70%, in order to maintain the sheet in contact for a certain period of time. There is no upper limit, but it is usually 80%. The mass retention of the present sheet after immersion in phosphate buffered saline at 37°C for 1 minute can be measured, for example, by measuring the change in mass of the sheet after immersion.

[0017] The raw material components constituting the sheet will be described below.

[0018] <Water-Soluble Polymer (A)> The water-soluble polymer (A) used in this embodiment contains at least one polymer selected from the group consisting of a PVA-based resin, a hydroxyalkyl cellulose, and a polyethylene oxide. It is preferable to contain at least one of these as the main component, and it is particularly preferable to contain a PVA-based resin as the main component. As used herein, the term "main component" refers to a component that significantly affects the properties of the target object. The content of this component is typically 50% by mass or more, preferably 55% by mass or more, more preferably 60% by mass or more, and even more preferably 70% by mass or more, or even 100% by mass, of the target object. The content range is, for example, 50 to 100% by mass.

[0019] [PVA-based resin] Examples of PVA-based resins include unmodified PVA resins and modified PVA-based resins, with unmodified PVA being preferred. Unmodified PVA resins can be produced by saponifying a vinyl ester polymer obtained by polymerizing a vinyl ester compound. Unmodified PVA resins are resins obtained by saponifying a polyvinyl ester polymer obtained by polymerizing a vinyl ester monomer, and are composed of vinyl alcohol structural units corresponding to the degree of saponification and vinyl ester structural units remaining unsaponified.

[0020] The saponification degree of the PVA-based resin (especially unmodified PVA-based resin) used in this embodiment is preferably 70 to 100 mol%, more preferably 75 mol% or more, and even more preferably 78 mol% or more. The upper limit is preferably 99.99 mol% or less, more preferably 95 mol% or less. When the saponification degree of the PVA-based resin is equal to or greater than the lower limit, the solubility of the resulting nanofibers tends to be excellent. When the saponification degree of the PVA-based resin is equal to or less than the upper limit, the drug content in the nanofibers tends to be easily maintained. In this embodiment, the saponification degree of the PVA-based resin is a value determined by a method in accordance with JIS K 6726.

[0021] The lower limit of the average degree of polymerization of the PVA-based resin (especially the unmodified PVA-based resin) used in this embodiment is preferably 300 or more, more preferably 400 or more, even more preferably 600 or more, particularly preferably 800 or more, and especially preferably 1000 or more. The upper limit is preferably 4000 or less, more preferably 3500 or less, and even more preferably 3000 or less. The range of such an average degree of polymerization is, for example, 300 to 4000. When the average degree of polymerization of the PVA-based resin is equal to or greater than the lower limit, the strength of the nanofiber tends to be maintained and the stability during use tends to be excellent. When the average degree of polymerization is equal to or less than the upper limit, the viscosity of the PVA-based resin solution during nanofiber formation, as described below, tends to be appropriate, making it easier to form the fiber. Note that in this embodiment, the average degree of polymerization of the PVA-based resin is determined by a method in accordance with JIS K 6726.

[0022] The content of the PVA-based resin in the nanofiber is preferably 50% by mass or more, more preferably 60% by mass or more, even more preferably 65% ​​by mass or more, particularly preferably 70% by mass or more, and especially preferably 80% by mass or more. Having the PVA-based resin content within the above range tends to increase the mucoadhesion of the nanofiber and further facilitates retention of the drug in an amorphous state, which is preferable. The upper limit is preferably 99% by mass or less, and the range of such a content is, for example, 50 to 99% by mass.

[0023] The product of the degree of polymerization of the PVA-based resin (especially unmodified PVA-based resin) in the nanofibers used in this embodiment and the content of the PVA-based resin (especially unmodified PVA-based resin) in the nanofibers is preferably 200 to 3000, more preferably 400 to 2500, and even more preferably 450 to 2300. By satisfying this range, the PVA content in the nanofibers becomes suitable, and uniform nanofibers can be obtained, which is preferable.

[0024] The PVA-based resin may be used alone or in combination of two or more. When used in combination, PVA-based resins with different degrees of saponification or average degrees of polymerization may be used in combination. An unmodified PVA resin may be used in combination with a modified PVA-based resin described below, but it is preferable to use only an unmodified PVA resin. When PVA-based resins with different degrees of saponification or average degrees of polymerization are used, the degrees of saponification and average degrees of polymerization are calculated as averages for the entire PVA-based resin.

[0025] A method for producing the PVA-based resin used in this embodiment will be described in detail. The PVA-based resin can be 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, vinyl benzoate, and vinyl versatate, with vinyl acetate being practically preferred.

[0026] Furthermore, modified PVA-based resins obtained by copolymerizing a monomer copolymerizable with the vinyl ester-based monomer may be used 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; hydroxyl-containing α-olefins such as 3-buten-1-ol, 4-penten-1-ol, 5-hexen-1-ol, and 3,4-dihydroxy-1-butene, and derivatives thereof such as acylated products; unsaturated acids and salts thereof such as acrylic acid, methacrylic acid, crotonic acid, maleic acid, maleic anhydride, itaconic acid, and undecylenic acid; monoesters, dialkyl esters, nitriles such as acrylonitrile and methacrylonitrile; amides such as diacetone acrylamide, acrylamide, and methacrylamide; ethylene sulfonic acid, allyl sulfonic acid, methacrylonitrile, and methacrylonitrile; Examples of suitable copolymerizable monomers include olefin sulfonic acids and salts thereof, such as olefin sulfonic acid and olefin sulfonic acid; vinyl compounds such as alkyl vinyl ethers, dimethyl allyl vinyl ketone, N-vinylpyrrolidone, vinyl chloride, vinyl ethylene carbonate, 2,2-dialkyl-4-vinyl-1,3-dioxolane, and glycerin monoallyl ether; substituted vinyl acetates such as isopropenyl acetate and 1-methoxyvinyl acetate; and hydroxymethyl vinylidene diacetates such as vinylidene chloride, 1,4-diacetoxy-2-butene, 1,4-dihydroxy-2-butene, vinylene carbonate, 1,3-diacetoxy-2-methylenepropane, 1,3-dipropionyloxy-2-methylenepropane, and 1,3-dibutyronyloxy-2-methylenepropane. The content of structural units derived from such copolymerizable monomers is typically 10 mol % or less, preferably 5 mol % or less, and more preferably 1 mol % or less, based on the total amount of the polymer. The range of the content is, for example, 0 to 10 mol %.

[0027] The method for polymerizing the vinyl ester-based monomer and copolymerizable monomer is not particularly limited, and known methods such as bulk polymerization, solution polymerization, suspension polymerization, dispersion polymerization, and emulsion polymerization can be used, but solution polymerization is usually carried out.

[0028] Examples of the solvent 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, and methanol is preferably used industrially.

[0029] The polymerization reaction is carried out using a known radical polymerization catalyst such as azobisisobutyronitrile, acetyl peroxide, benzoyl peroxide, lauroyl peroxide, or any of various known low-temperature active catalysts, and the reaction temperature is selected from the range of 35°C to the boiling point.

[0030] The resulting polyvinyl ester polymer is then saponified in a continuous or batch process. Either alkali saponification or acid saponification can be used for the saponification, but industrially it is preferred to dissolve the polymer in alcohol and carry out the saponification in the presence of an alkali catalyst. Examples of alcohol include methanol, ethanol, and butanol.

[0031] The concentration of the polymer in the alcohol is selected from the range of 20 to 60% by mass. 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) may be added.

[0032] Specific examples of the saponification catalyst include alkali catalysts such as hydroxides and alcoholates of alkali metals, such as sodium hydroxide, potassium hydroxide, sodium methylate, sodium ethylate, potassium methylate, etc. The amount of such catalyst used is preferably 1 to 100 millimole equivalents relative to the monomer.

[0033] The degree of saponification of the PVA-based resin can be adjusted by the amount of catalyst, saponification time, solvent, and saponification temperature.

[0034] After saponification, the resulting PVA resin is preferably washed with a washing liquid, such as an alcohol such as methanol, ethanol, isopropyl alcohol, or butanol, with methanol being preferred from the viewpoints of washing efficiency and drying efficiency.

[0035] The washing method may be a known method, and may be a continuous method (rotating cylinder type, countercurrent contact type, centrifugal separation and sprinkling washing, etc.), but a batch method is usually adopted. Examples of the stirring method (apparatus) during washing include a screw blade, ribbon blender, kneader, etc.

[0036] The washed PVA-based resin can be dried by a known method, specifically, a method in which the particles are dried with hot air or the like in a continuous or batch manner.

[0037] The content of the solvent in the dried PVA-based resin is preferably 10% by mass or less, more preferably 5% by mass or less, and even more preferably 1% by mass or less, for example, in the range of 0 to 10% by mass.

[0038] PVA-based resins typically contain alkali metal salts of acetic acid derived from the alkali catalyst used during saponification. The lower limit of the alkali metal salt content relative to the PVA-based resin is preferably 0.001% by mass or more, more preferably 0.005% by mass or more, and even more preferably 0.01% by mass or more. The upper limit is preferably 2% by mass or less, more preferably 1% by mass or less, and even more preferably 0.1% by mass or less. Examples of the range of the alkali metal salt content include 0.001 to 2% by mass. Examples of methods for adjusting the alkali metal salt content include adjusting the amount of alkali catalyst used during saponification and washing the PVA-based resin with an alcohol such as ethanol or methanol. The alkali metal salt content used in this embodiment can be determined by dissolving the PVA-based resin in water and performing neutralization titration with hydrochloric acid using methyl orange as an indicator.

[0039] [Hydroxyalkyl Cellulose] Examples of the hydroxyalkyl cellulose used in the present embodiment include hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxybutyl cellulose, etc. These can be used alone or in combination of two or more.

[0040] The weight-average molecular weight (Mw) of the hydroxyalkyl cellulose is 80,000 to 1,200,000, and preferably 150,000 to 900,000. If the Mw is equal to or greater than the lower limit, the resulting nanofibers tend to have excellent mechanical strength, while if the Mw is equal to or less than the upper limit, the solution tends to have an appropriate viscosity, making it easier to form uniform nanofibers.

[0041] The weight-average molecular weight (Mw) of hydroxyalkyl cellulose was measured by dissolving the hydroxyalkyl cellulose in phosphate-buffered saline to prepare a measurement sample, and calculating the Mw by gel permeation chromatography (GPC) using a calibration curve prepared using pullulan as a standard substance.

[0042] The hydroxyalkyl cellulose preferably has a molar degree of substitution (MS) and / or degree of substitution (DS) within the following ranges. The molar degree of substitution (MS) is 1.0 to 4.5, preferably 1.5 to 4.0. The degree of substitution (DS) is 0.6 to 2.2, preferably 0.8 to 2.0. By using a hydroxyalkyl cellulose having a molar degree of substitution (MS) and degree of substitution (DS) within the above ranges, nanofibers with excellent solubility and dispersion stability can be obtained. The degree of substitution (DS) and molar degree of substitution (MS) of the hydroxyalkyl cellulose are mainly determined by １ It can be calculated by H-NMR spectrum analysis.

[0043] From the viewpoint of spinnability, the content of hydroxyalkyl cellulose in the nanofiber is preferably 50 to 99% by mass of the entire nanofiber, more preferably 60% by mass or more, even more preferably 70% by mass or more, and particularly preferably 80% by mass or more.

[0044] [Polyethylene oxide] Preferred examples of polyethylene oxide include linear polyethylene oxide, branched polyethylene oxide, and terminally modified polyethylene oxide. These may be used alone or in combination of two or more. Specific examples include polyethylene oxide (PEO), polypropylene oxide (PPO), and polybutylene oxide (PBO).

[0045] The weight-average molecular weight (Mw) of polyethylene oxide is 100,000 to 8,000,000, and preferably 400,000 to 4,000,000. When the molecular weight is equal to or less than the upper limit, the resulting nanofibers tend to have excellent mechanical strength, while when the molecular weight is equal to or greater than the lower limit, the solution tends to have an appropriate viscosity, resulting in excellent spinnability.

[0046] The weight-average molecular weight (Mw) of polyethylene oxide was measured by dissolving polyethylene oxide in a buffer solution to prepare a measurement sample, and calculating the Mw by gel permeation chromatography (GPC) using a calibration curve prepared using polyethylene glycol standards.

[0047] The polydispersity (Mw / Mn) of polyethylene oxide is preferably 1.1 to 3.0. The narrower the polydispersity, the more uniform the nanofibers tend to be.

[0048] The crystallinity of the polyethylene oxide is preferably in the range of 50 to 85%. By using polyethylene oxide with an appropriate crystallinity, the balance between mechanical strength and flexibility of the nanofiber tends to be improved.

[0049] Examples of the terminal group of polyethylene oxide include a hydroxy group, a methoxy group, an amino group, etc. In particular, polyethylene oxide having hydroxy groups at both ends (PEO-diol) has excellent compatibility with hydroxyalkyl cellulose and is advantageous for forming uniform nanofibers.

[0050] The content of polyethylene oxide in the nanofibers is preferably 3 to 50% by mass, more preferably 5 to 30% by mass, of the entire nanofibers. When the content is equal to or less than the upper limit, the effect of improving spinnability due to the addition of polyethylene oxide tends to be sufficiently obtained, while when the content is equal to or more than the lower limit, uniform nanofibers tend to be easily obtained.

[0051] <Drug> From the viewpoint of eye treatment, it is preferable that the sheet further contains a drug. Such a drug is not particularly limited as long as it is used as an active ingredient in pharmaceuticals, but in order to make the effects of the present invention more evident, a poorly soluble drug is preferred.

[0052] The drug used in this embodiment is not particularly limited as long as it is effective in treating the eyes, and examples thereof include glaucoma treatment agents such as prostaglandin preparations, β-blockers, α-receptor agonists, sympathomimetics, α-blockers, carbonic anhydrase inhibitors, anticholinesterase agents, and Rho-kinase inhibitors, steroidal anti-inflammatory agents, nonsteroidal anti-inflammatory drugs (NSAIDs), parasympathomimetics, analgesics, immunosuppressants, antivirals, antibiotics, anti-VEGF antibodies, nucleic acid drugs, etc. These can be used alone or in combination of two or more.

[0053] Examples of prostaglandin preparations include isopropyl unoprostone, latanoprost, travoprost, tafluprost, and bimatoprost.

[0054] Preferred examples of the β-blocker include timolol maleate, befunolol hydrochloride, carteolol hydrochloride, betaxolol hydrochloride, nipradilol, levobunolol hydrochloride, etc.

[0055] Examples of α-receptor agonists include brimonidine tartrate.

[0056] Examples of sympathomimetics include dipivefrine hydrochloride, pilocarpine hydrochloride, etc.

[0057] Examples of α-blockers include bunazosin hydrochloride.

[0058] Carbonic anhydrase inhibitors include, for example, dorzolamide hydrochloride, brinzolamide, etc.

[0059] Anticholinesterase agents include, for example, distigmine bromide.

[0060] Examples of Rho kinase inhibitors include ripasudil hydrochloride hydrate.

[0061] Examples of steroidal anti-inflammatory agents include hydroxyltriamcinolone, α-methyldexamethasone, β-methyl β-methasone, beclomethasone dipropionate, β-methasone benzoate, β-methasone dipropionate, β-methasone valerate, clobetasol valerate, desonide, desoximethasone, dexamethasone, diflorasone diacetate, diflucortolone valerate, fluadrenolone, flucloronide, flumethasone pivalate, fluocinolone acetonide, fluocinonide, flucortine butyl ester, fluocortolone, fluprednidene (fluprednylidene) acetate, flurandrenolone, and halcinonide. , hydrocortisone acetate, hydrocortisone butyrate, methylprednisolone, triamcinolone acetonide, cortisone, cortodoxone, flucetonide, fludrocortisone, difluorosone diacetate, fluradrenolon acetonide, medrysone, amcinafide, amcinafide, betamethasone and its remaining esters, chloroprednisone, clocortelone, clesinolone, dichlorisone, difluprednate, flucloronide, flunisolide, fluoromethalone, fluprednisolone, hydrocortisone, meprednisone, paramethasone, prednisolone, prednisone, beclomethasone dipropionate, and the like.

[0062] Examples of non-steroidal anti-inflammatory agents include nepafenac, bromfenac, salicylates, diclofenac, flurbiprofen, piroxicam, indomethacin, ibuprofen, naproxen, and nabumetone.

[0063] Examples of parasympathomimetics include pilocarpine hydrochloride, carbachol, phosphorin iodine, physostigmine, salicylate, acetylcholine chloride, eserine, diisopropyl fluorophosphate, demecarium bromide, etc.

[0064] Examples of analgesics include benzodiazepam, acetaminophen, acetaminosalol, aminochlorthenoxazine, acetylsalicyl 2-amino-4-picolinic acid, acetylsalicylsalicylic acid, anileridine, benoxaprofen, benzylmorphine, 5-bromosalicylacetic acid, bucetin, buprenorphine, butorphanol, capsaicin, cinchophen, ciramadol, clometacin, clonixin, codeine, desomorphine, dezocine, dihydrocodeine, dihydromorphine, dimepheptanol, dipyrocetyl, eptazocine, ethoxazene, ethylmorphine, Examples include eugenol, floctafenine, fosfosal, glafenine, hydrocodone, hydromorphone, hydroxypethidine, ibufenac, p-lactophenetide, levorphanol, meptazinol, metazocine, metopon, morphine, nalbuphine, nicomorphine, norlevorphanol, normorphine, oxycodone, oxymorphone, pentazocine, phenazocine, fenocol, phenoperidine, phenylbutazone, phenylsalicylate, phenylramidol, salicin, salicylamide, thiorphan, tramadol, diacerein, and actarit.

[0065] Examples of immunosuppressants include cyclosporine, mTOR inhibitors (e.g., rapamycin, tacrolimus, temsirolimus, sirolimus, everolimus, KU-0063794, WYE-354, AZD8055, metformin, or Torin-2), cyclophosphamide, atoposide, thiotepa, methotrexate, azathioprine, mercaptopurine, interferon, infliximab, etanercept, mycophenolate mofetil, 15-deoxyspergualin, thalidomide, glatiramer, leflunomide, vincristine, and cytarabine.

[0066] Examples of antiviral agents include abacavir, acyclovir, adefovir, amantadine, amprenavir, ampligen, arbidol, atazanavir, boceprevir, cidofovir, darunavir, delavirdine, didanosine, docosanol, edoxudine, efavirenz, emtricitabine, enfuvirtide, entecavir, famciclovir, fomivirsen, fosamprenavir, foscarnet, phosphonet, ganciclovir, ibacitabine, immunovir, idoxuridine, and imiquimo. , indinavir, inosine, interferon type III, interferon type II, interferon type I, interferon, lamivudine, lopinavir, loviride, maraviroc, moroxydine, methisazone, nelfinavir, nevirapine, nexavir, oseltamivir, peginterferon alfa-2a, penciclovir, peramivir, pleconaril, podophyllotoxin, raltegravir, ribavirin, rimantadine, ritonavir, pyramiding saquinavir saquinavir), stavudine, tenofovir, tenofovir disoproxil, tipranavir, trifluridine, trizivir, tromantadine, truvada, valacyclovir, valganciclovir, vicriviroc, vidarabine, viramidine, zalcitabine, zanamivir, zidovudine and the like.

[0067] Examples of antibiotics include penicillin, cephalosporin, fluoroquinolone, macrolide, and the like.

[0068] Examples of anti-VEGF antibodies include Eylea (registered trademark) (aflibercept), Lucentis (registered trademark) (ranibizumab), Beovu (registered trademark) (brolucizumab), endostatin, and Avastin (registered trademark) (bevacizumab).

[0069] Examples of nucleic acid drugs include decoy nucleic acids (decoy RNA, etc.), antisense nucleic acids (antisense DNA, antisense RNA, etc.), siRNA, miRNA, ribozymes, and aptamers (Macugen (registered trademark) (pegaptanib sodium), etc.).

[0070] The drug in this embodiment may be in the form of an anhydrate, a hydrate, a solvate, or a pharmaceutically acceptable salt. The form of the drug used as a raw material is not particularly limited, and may be crystalline, amorphous, or a mixture thereof. The crystal may be any of known crystalline polymorphs.

[0071] The manner in which the drug is contained in this embodiment is not particularly limited, and for example, the drug may be incorporated into the fiber structure of the nanofiber, the drug may be present in a state where it is trapped in the gaps between the entangled structure of the nanofibers, or the drug may be attached to or adsorbed onto the surface of the nanofiber fibers.

[0072] In the present sheet, regardless of whether the drug is crystalline or amorphous before mixing with the water-soluble polymer (A), the drug is preferably in an amorphous state, whereby no endothermic peak is observed near the melting temperature by differential scanning calorimetry.

[0073] In this embodiment, the drug content in the nanofiber is preferably 5 to 98% by mass, more preferably 8 to 95% by mass, and even more preferably 10 to 90% by mass. If the drug content is equal to or greater than the lower limit, the drug efficacy tends to be excellent, and if the drug content is equal to or less than the upper limit, the fiber formability tends to be excellent.

[0074] <Other Components> The sheet may further contain a surfactant. The surfactant is not particularly limited, and examples thereof include nonionic surfactants, anionic surfactants, cationic surfactants, and amphoteric surfactants. Any of these may be used, but nonionic surfactants are particularly preferred.

[0075] Examples of the nonionic surfactants include polyglyceryl diisostearate, diglyceryl polyhydroxystearate, isostearyl glyceryl ether, polyoxyalkylene ethers, polyoxyalkylene alkyl ethers, polyoxyalkylene fatty acid esters, polyoxyalkylene fatty acid diesters, polyoxyalkylene resin acid esters, polyoxyalkylene (hydrogenated) castor oils, polyoxyalkylene alkylphenols, polyoxyalkylene alkylphenyl ethers, polyoxyalkylene phenylphenyl ethers, polyoxyalkylene alkyl esters, polyoxyalkylene alkyl esters, sorbitan fatty acid esters, polyoxyalkylene sorbitan alkyl esters, poly Examples of surfactants include oxyalkylene sorbitan fatty acid esters, polyoxyalkylene sorbitan fatty acid esters, polyoxyalkylene glycerin fatty acid esters, polyglycerin alkyl ethers, polyglycerin fatty acid esters, sucrose fatty acid esters, fatty acid alkanolamides, alkylglucosides, polyoxyalkylene fatty acid bisphenyl ethers, polypropylene glycol, diethylene glycol, polyoxyethylene-polyoxypropylene block polymers, alkyl polyoxyethylene-polyoxypropylene block polymer ethers, polyoxyethylene-polyoxypropylene block polymers, alkyl polyoxyethylene-polyoxypropylene block polymer ethers, and fluorine-based surfactants.

[0076] Of these, polyoxyalkylene sorbitan fatty acid esters are preferred, and more specifically, polyoxyethylene sorbitan esters such as polyoxyethylene (20) sorbitan monooleate (polysorbate 20), polyoxyethylene sorbitan monostearate (polysorbate 60), polyoxyethylene sorbitan tristearate (polysorbate 65), and polyoxyethylene (20) sorbitan monooleate (polysorbate 80) are more preferred.

[0077] These surfactants may be synthesized by known methods or may be commercially available products. The surfactants may be used alone or in any combination of two or more.

[0078] The content of the surfactant in this embodiment can be set appropriately depending on the type of surfactant and the types and amounts of other components. However, the lower limit of the content of the surfactant relative to 100 parts by mass of the water-soluble polymer (A) is preferably 0.1 parts by mass or more, more preferably 0.5 parts by mass or more. The upper limit is preferably 10 parts by mass or less, more preferably 7 parts by mass or less, and even more preferably 5 parts by mass or less. The content ranges, for example, from 0.1 to 10 parts by mass. When the content of the surfactant is equal to or greater than the lower limit, the stability of the emulsion is maintained, the drug distribution is uniform, and solubility tends to be excellent. Furthermore, when the content is equal to or less than the upper limit, the viscosity of the aqueous solution during fiber formation becomes appropriate, and fiber production stability tends to be excellent.

[0079] The content of the surfactant relative to the entire sheet is not particularly limited, but the lower limit is preferably 0.1 parts by mass or more, more preferably 0.5 parts by mass or more. The upper limit is preferably 10 parts by mass or less, more preferably 7 parts by mass or less, and even more preferably 5 parts by mass or less. The content ranges from 0.1 to 10 parts by mass, for example. When the content of the surfactant is equal to or greater than the lower limit, the stability of the emulsion is maintained, the drug distribution is uniform, and solubility tends to be excellent. Furthermore, when the content is equal to or less than the upper limit, the viscosity of the aqueous solution during fiber formation becomes appropriate, and fiber production stability tends to be excellent.

[0080] In addition to the PVA-based resin, hydroxyalkyl cellulose, and polyethylene oxide, the sheet may also contain other water-soluble or water-dispersible resins. Examples of water-soluble or water-dispersible resins that can be used in combination include starch derivatives such as starch, oxidized starch, and cation-modified starch; natural proteins such as gelatin and casein; cellulose derivatives such as methyl cellulose, ethyl cellulose, and carboxymethyl cellulose (CMC); natural polymeric polysaccharides such as sodium alginate and pectinic acid; water-soluble resins such as polyvinylpyrrolidone and poly(meth)acrylate; latexes such as styrene-butadiene rubber (SBR) latex and nitrile rubber (NBR) latex; and 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. These may be used alone or in combination.

[0081] In this specification, (meth)acrylic means acrylic or methacrylic. The content may be within a range that does not impair the effects of the present invention, and is preferably 10 parts by mass or less, more preferably 5 parts by mass or less, and even more preferably 2 parts by mass or less, based on the entire sheet. The content range is, for example, 0.1 to 10 parts by mass.

[0082] The sheet may further contain one or more pharmaceutically acceptable additives. For example, well-known additives such as plasticizers, lubricants, pigment dispersants, thickeners, anti-sticking agents, flow improvers, antifoaming agents, release agents, penetrating agents, dyes, pigments, fluorescent brighteners, UV absorbers, antioxidants, preservatives, anti-fungal agents, paper strength agents, and crosslinking agents may be appropriately blended. The content may be within a range that does not impair the effects of the present invention, and is preferably 10 parts by weight or less, more preferably 5 parts by weight or less, and even more preferably 2 parts by weight or less, based on the total weight of the sheet.

[0083] <Nanofibers> The nanofibers contained in this sheet contain a water-soluble polymer (A). The nanofibers are formed into fibers by spinning a solution of the water-soluble polymer (A) described below as a forming material. The nanofibers are primarily composed of the water-soluble polymer (A) and contain 50% by mass or more of the water-soluble polymer (A). While there is no upper limit, the nanofiber content is preferably 70% by mass or more, and more preferably 90% by mass or more. The nanofibers used in this embodiment preferably have a single fiber diameter (fiber diameter) of 1 nm to 10 μm, more preferably 1 to 2000 nm, even more preferably 5 to 1000 nm, and particularly preferably 10 to 700 nm. When the fiber diameter is equal to or less than the upper limit, the drug tends to be amorphous, resulting in excellent drug release control. When the fiber diameter is equal to or greater than the lower limit, sufficient strength is easily exhibited, resulting in excellent handling during use and excellent production efficiency. The fiber diameter of the nanofibers is measured using an electron microscope.

[0084] The average fiber length of the nanofibers used in this embodiment 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 even more preferably 1000 times or more of the diameter. Furthermore, it is more preferable that the nanofibers are continuous fibers.

[0085] The content of the water-soluble polymer (A) in the nanofibers used in this embodiment is preferably 50% by mass or more, more preferably 60% by mass or more, even more preferably 65% ​​by mass or more, particularly preferably 70% by mass or more, and especially preferably 80% by mass or more. Having the water-soluble polymer (A) content within this range tends to increase the mucoadhesiveness of the nanofibers and further facilitates retention of the drug in an amorphous state, which is preferable. The upper limit is preferably 99% by mass or less, and the range of such a content is, for example, 50 to 99% by mass.

[0086] The content of the drug in the nanofibers used in this embodiment varies depending on the physical properties of the drug, but is preferably 0.001 to 10 parts by mass, more preferably 0.005 to 5 parts by mass, and even more preferably 0.01 to 3 parts by mass, per 100 parts by mass of the water-soluble polymer (A).

[0087] [Method for producing nanofibers] The nanofibers contained in the present sheet are preferably formed into a sheet shape from the viewpoint of ease of handling, and for example, it is preferable to form a nonwoven fabric from the nanofibers. Hereinafter, a method for forming a nonwoven fabric from the nanofibers (hereinafter also referred to as a "fiber nonwoven fabric") will be described.

[0088] The fiber nonwoven fabric can be obtained by using a water-soluble polymer (A) solution, in which the water-soluble polymer (A) is dissolved in a solvent, as a forming material and applying this solution to an electrospinning method (electrostatic spinning method) or a melt-blowing method.

[0089] The viscosity of the water-soluble polymer (A) solution is preferably adjusted to 1 to 10,000 mPa·s, more preferably 10 to 5,000 mPa·s, and even more preferably 100 to 3,000 mPa·s. The viscosity of the water-soluble polymer aqueous solution is measured using a Brookfield viscometer.

[0090] The solvent for dissolving the water-soluble polymer (A) (hereinafter also referred to as solvent (I)) may be, for example, water or an organic solvent such as an alcohol. Among these, water is preferably used in consideration of environmental issues during production.

[0091] When preparing a dispersion containing the water-soluble polymer (A) and a drug described below, it is preferable to use a homogenizer, and any of a high-pressure homogenizer, an ultrasonic homogenizer, and an ultra-high-speed homogenizer can be used.

[0092] A preferred method for incorporating a drug into nanofibers is to dissolve the drug in a solvent (hereinafter also referred to as solvent (II)) and then mix it with a solution of the water-soluble polymer (A) to form an emulsion, and use this dispersion as the forming material. The drug must be soluble in solvent (II), but in order to form an emulsion, a solvent that is immiscible with solvent (I) is preferred. Furthermore, when forming the nanofiber into fibers, it is preferred that the boiling point of solvent (II) be similar to or lower than that of solvent (I).

[0093] Examples of such solvent (II) 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-propanol, pentane, and propyl acetate. A solvent suitable for the drug can be used as appropriate, but ethyl acetate is particularly preferred from the viewpoints of safety and dispersibility.

[0094] The content ratio of solvent (I) to solvent (II) in the dispersion is preferably 50:50 to 99:1, more preferably 60:40 to 98:2, and even more preferably 70:30 to 95:5, in mass ratio of solvent (I):solvent (II).

[0095] The nanofiber manufacturing method used in this embodiment includes an electrospinning method using a spinning nozzle, an electrospinning method not using a spinning nozzle, and a melt-blowing method, and these methods will be described below.

[0096] Using the electrospinning method that uses a spinning nozzle, a fiber nonwoven fabric can be obtained, for example, as follows. The fiber nonwoven fabric is obtained by applying a high voltage to the spinning nozzle when the dispersion is extruded from the spinning nozzle, applying an electric field to the dispersion to stretch it, forming fibers, and depositing the fibers on the counter electrode. Note that a voltage may also be applied to the counter electrode instead of the spinning nozzle, and an electric field may be applied between the spinning nozzle and the counter electrode.

[0097] The concentration of the water-soluble polymer (A) in the dispersion varies depending on the type of water-soluble polymer (A), but is preferably 1 to 30% by mass, more preferably 1.5 to 25% by mass. Furthermore, in the case of a water-soluble polymer (A) having an average degree of polymerization of 200 or more and 1000 or less, the concentration is preferably 1 to 30% by mass, more preferably 8 to 28% by mass, even more preferably 10 to 25% by mass, and particularly preferably 15 to 23% by mass. In the case of a water-soluble polymer (A) having an average degree of polymerization of more than 1000 and 4000 or less, the concentration is preferably 1 to 30% by mass, more preferably 1.5 to 20% by mass, even more preferably 2 to 15% by mass, and particularly preferably 2.5 to 12% by mass. Meeting the above water-soluble polymer (A) concentration is preferred because it allows the solution to have an appropriate viscosity and nanofibers with a uniform fiber diameter to be obtained.

[0098] The extrusion direction of the dispersion is not particularly limited, but it is preferable that the extrusion direction from the nozzle does not coincide with the direction of gravity so as to prevent the dispersion from dripping. It is particularly preferable to extrude the dispersion in the opposite direction to the direction of gravity or in the direction perpendicular to the direction of gravity.

[0099] The diameter (inner diameter) of the spinning nozzle extruding the dispersion varies depending on the fiber diameter, but when forming nanofibers with a fiber diameter of 1 to 1000 nm, for example, it is usually 0.1 to 5 mm, and particularly preferably 0.5 to 2 mm. If the diameter is equal to or less than the upper limit, dripping tends to be prevented and electrospinning tends to be easier, and conversely, if the diameter is equal to or greater than the lower limit, the dispersion tends to be easier to extrude and productivity tends to be improved.

[0100] 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 electrode can be installed inside the spinning nozzle to apply an electric field to the dispersion.

[0101] After the dispersion is extruded from such a spinning nozzle, an electric field is applied to the extruded dispersion to stretch it and form fibers. This electric field is not particularly limited, as it varies depending on the fiber diameter, the distance between the spinning nozzle and the collector that accumulates the fibers, the viscosity of the dispersion, etc., but for the fibers used in this embodiment, it is preferably 0.2 to 5 kV / cm. If the applied electric field is strong, the fiber diameter tends to become thinner as the electric field value increases. However, if the electric field value is below the upper limit, dielectric breakdown of the air tends to be prevented, and conversely, if it is above the lower limit, the fiber shape tends to be easily formed.

[0102] By applying an electric field to the extruded dispersion in this way, electrostatic charges accumulate in the dispersion, which are electrically pulled by the electrode on the collector side and stretched to form fibers. Because the fibers are electrically stretched, the electric field accelerates the fiber speed as they approach the collector, resulting in water-soluble polymer fibers with smaller fiber diameters. Furthermore, it is thought that the fibers thin due to evaporation of the solvent, increasing the electrostatic density, and the resulting electrical repulsion causes them to split, resulting in water-soluble polymer fibers with even smaller fiber diameters.

[0103] Such an electric field can be applied, for example, by creating a potential difference between the spinning nozzle (the nozzle itself in the case of a metallic nozzle, or an electrode inside the nozzle in the case of a non-metallic nozzle such as glass or resin) and the collector. 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.

[0104] The applied voltage is not particularly limited as long as it can achieve the electric field strength 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 below the upper limit, sparks tend to be prevented and spinning tends to be easier, while if the voltage is above the lower limit, the force that electrically attracts the solution becomes sufficient and spinning tends to be easier. 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.

[0105] The polarity of the applied voltage may be either positive or negative. However, it is preferable to make the spinning nozzle side a positive potential so that the fibers can be collected with small pore diameters and a narrow pore diameter distribution, thereby suppressing the spread of the fibers. In particular, it is preferable to earth the counter electrode on the collector side and apply a positive voltage to the spinning nozzle side, thereby making the spinning nozzle side a positive potential, so that corona discharge can be easily suppressed when voltage is applied.

[0106] The collector for collecting and depositing the fibers is not particularly limited, and examples thereof include a collector in the form of a drum, nonwoven fabric, flat plate, or belt, and made of a conductive material such as metal or carbon, or a non-conductive material such as an organic polymer. The collector does not need to be made of a conductive material as described above, and it is sufficient that a counter electrode is placed behind the collector. In this case, the collector and the counter electrode may be in contact with each other or may be spaced apart.

[0107] The electrospinning method is preferably carried out in an atmosphere with a relative humidity of typically 30 to 80%, particularly 35 to 70%. If the relative humidity is above the lower limit, the dispersion will dry slowly at the outlet of the spinning nozzle, tending to prevent solidification and clogging of the nozzle. If the relative humidity is below the upper limit, the dispersion will dry moderately and tend to form fibers more easily.

[0108] To maintain the above-mentioned relative humidity, it is preferable to place the spinning nozzle and collector in a sealed container and to supply humidity-controlled air via a valve or the like so that the humidity inside the sealed container can be adjusted to within the above-mentioned range. In addition, it is preferable that an exhaust device be connected to the sealed container so as not to increase the pressure inside the sealed container and so that the solvent volatilized from the dispersion can be discharged.

[0109] Examples of electrospinning methods that do not use a spinning nozzle include a method in which a magnetic fluid is used as an electrode and electrospinning is performed from the surface of a dispersion of a water-soluble polymer (see A.L.Yarin, E.Zussman, "Polymer", 45 (2004) 2977-2980). Examples of electrospinning methods include a method in which a rotating roll is immersed in a bath filled with a dispersion of a water-soluble polymer, the water-soluble polymer dispersion is deposited on the roll surface, a high voltage is applied to this surface, and electrospinning is performed (see http: / / www.elmarco.com). Examples of electrospinning methods include a method in which a high voltage is applied to bubbles continuously generated in a water-soluble polymer dispersion (see "NONWOVENS REVIEW", Vol. 18, No. 2 (2007) 17-20, JP 2008-25057 A).

[0110] In the melt-blowing method, the dispersion is discharged from a spinning nozzle, and simultaneously, heated air is blown from both sides of the spinning nozzle at high speed in the direction of the dispersion, causing the dispersion to be blown out in the form of threads, thereby thinning the threads. The nozzle holes generally have a diameter of about 0.2 mm, and are preferably arranged in a row at intervals of about 1 mm. The discharge rate per minute per nozzle is about 0.5 g, and a lower discharge rate is used to obtain thinner fibers.

[0111] A fiber nonwoven fabric can be obtained by the above method, and this fiber nonwoven fabric becomes the present sheet. That is, the method for producing the present sheet preferably includes a step of producing nanofibers by electrospinning or melt-blowing using a mixed solution containing the water-soluble polymer (A) and the drug.

[0112] <Sheet> The sheet contains the nanofibers described above and is preferably in the form of a fiber nonwoven fabric. The fiber nonwoven fabric can be administered together with the collector described above or detached from the collector as a formulation. The preferred route of administration is application to the eyeball or eyelid. The fiber nonwoven fabric may also be a laminate including the collector and other layers.

[0113] The sheet maintains a dissolution rate of 50% by mass or more after immersion in phosphate buffered saline at 37°C for 1 minute. By maintaining a dissolution rate of 50% by mass or more after immersion in phosphate buffered saline at 37°C for 1 minute, the sheet can be maintained in contact with at least one outer surface selected from the group consisting of the cornea, conjunctiva, and sclera for a certain period of time or more. Preferably, the sheet dissolves at a rate of 50% by mass or more after immersion in phosphate buffered saline at 37°C for 6 hours.

[0114] The thickness of the present sheet is usually 0.01 to 200 μm, preferably 0.1 to 150 μm, more preferably 0.5 to 100 μm. The basis weight of the fiber nonwoven fabric of the present sheet is appropriately set depending on the application, but is usually 0.1 to 40 g / m, for example. ２ , preferably 0.5 to 20 g / m ２ , more preferably 1 to 10 g / m ２ is.

[0115] The drug delivery efficiency of this sheet is preferably such that, when the fluorescence intensity of autofluorescence in untreated retinal IPL 30 minutes after application to at least one selected from the group consisting of the cornea, conjunctiva, and sclera is taken as 1, the relative fluorescence intensity per amount of the model drug Coumarin-6 (C-6) is 45 or more, more preferably 50 or more. There is no particular upper limit, but it is usually 500, and the range of such drug delivery efficiency is, for example, 45 to 500. The drug delivery efficiency can be measured, for example, using the measurement method described in the Examples below.

[0116] The drug retention in this sheet is preferably 1.95% or more, more preferably 2.00% or more, even more preferably 2.10% or more, and particularly preferably 2.20% or more. There is no particular upper limit, but it is usually 20%, and the range of such retention is, for example, 1.95 to 20%. The drug retention is calculated by dividing the fluorescence intensity in the retina after 6 hours by the fluorescence intensity after 30 minutes, and more specifically, the measurement method described in the Examples below is used.

[0117] The sheet preferably contains nanofibers on the outermost surface in order to adhere to the mucous membrane of the eyeball.

[0118] The present sheet is suitable for use as a sheet because the water-soluble polymer (A) contains at least one selected from the group consisting of a PVA-based resin, a hydroxyalkyl cellulose, and polyethylene oxide. For example, a method for using the present sheet preferably includes a step of contacting the sheet with the eyeball.

[0119] The sheet is used by physically contacting at least one outer surface selected from the group consisting of the cornea, conjunctiva, and sclera, and the nanofibers are preferably located on the outermost surface that comes into contact with the outer surface. A sheet containing nanofibers containing a water-soluble polymer slowly dissolves in tears on the ocular surface when in contact with at least one outer surface selected from the group consisting of the cornea, conjunctiva, and sclera, and adheres well to the mucous membrane, resulting in a high drug concentration on the ocular surface and a high concentration gradient, enabling excellent delivery to the posterior segment of the eye and sustained drug release due to excellent retention.

[0120] Furthermore, the nanofibers used in this embodiment are flexible and can be applied to the ocular surface without damaging the eyeball, and when used, they gel and become transparent upon contact with tears, making them useful without obstructing the field of vision. Note that this sheet is used by physical contact, and is different from sheets that are used by bonding with ocular tissues such as the conjunctiva.

[0121] The present invention will be explained 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 depart from the gist of the invention.

[0122] The components used in the examples are as follows:

[0123] <Water-soluble polymer (A)> Polyvinyl alcohol 1: manufactured by Mitsubishi Chemical Corporation, saponification degree 88 mol%, degree of polymerization 2400 Polyvinyl alcohol 2: manufactured by Mitsubishi Chemical Corporation, saponification degree 88 mol%, degree of polymerization 500 Polyvinyl alcohol 3: manufactured by Mitsubishi Chemical Corporation, saponification degree 80 mol%, degree of polymerization 2500 Polyvinyl alcohol 4: manufactured by Mitsubishi Chemical Corporation, saponification degree 99.9 mol%, degree of polymerization 1800 <Model drugs> Coumarin-6 (C-6): Mp, manufactured by Biomedicals <Liposomes> Phospholipid: distearoylphosphatidylcholine (DSPC), manufactured by NOF Corporation

[0124] Example 1 Tween 80 (polysorbate 80, nonionic surfactant) was mixed with an aqueous solution of polyvinyl alcohol 1 in the amounts shown in Table 1, followed by the addition of C-6 solution (C-6: 0.001 g, ethyl acetate: 1.9 g). The mixture was emulsified and dispersed for 10 minutes at a stirring speed of 8000 rpm using a homogenizer (POLYTRON PT10 / 35, manufactured by KINEMATICA) to obtain an emulsion with a PVA concentration of 4%. The emulsion was filled into a 1 mL plastic syringe and placed in the syringe pump (manufactured by Yutaka Electronics Manufacturing Co., Ltd.) of an electrospinning device. After connecting the syringe to a nozzle (diameter 22G) with a silicone tube, a high voltage was applied using a high-voltage generator (HVU-30P100, manufactured by MEC Corporation) under conditions of 10 kV inter-electrode voltage, 12 cm distance from the needle tip to the collection plate, and 0.5 mL / h discharge rate of the dispersion for 2 hours to prepare nanofibers 1 for Example 1. Furthermore, a fiber nonwoven fabric, Sheet 1 (thickness 20 μm), was produced by accumulating these nanofibers. The mass residue of Sheet 1, measured by the following measurement method, was 98% by mass.

[0125] (Mass Residual Measurement) The obtained sheet was cut into 10 mm squares and the mass was measured. Next, the sheet was placed on aluminum foil with holes, which was then placed on a 12-well plate. 7 μL of phosphate-buffered saline (PBS) prepared by dissolving 9.6 g of D-PBS(-) (Shimadzu Diagnostics, tissue culture Acudia powder Code 05913) in 1000 mL of distilled water, which was kept at 37°C, was added dropwise, and the sheet was immersed. After standing for 1 minute, the sheet was wiped to remove dissolved components. The sheet was then dried under reduced pressure for 3 hours on a hot plate set at 105°C. After drying, the remaining sheet mass was measured, and the mass residual was calculated from the change in mass before and after immersion.

[0126] Example 2 Nanofibers 2 for Example 2 were prepared and sheets 2 were produced in the same manner as in Example 1, except that the blending ratios of the various components were changed as shown in Table 1.

[0127] [Example 3] Nanofiber 3 for Example 3 was prepared and sheet 3 was produced in the same manner as in Example 1, except that polyvinyl alcohol 2 was used instead of polyvinyl alcohol 1 and the blending ratios of various components were changed as shown in Table 1.

[0128] [Example 4] Nanofiber 4 for Example 4 was prepared and sheet 4 was produced in the same manner as in Example 1, except that polyvinyl alcohol 3 was used instead of polyvinyl alcohol 1 and the blending ratios of various components were changed as shown in Table 1.

[0129] [Example 5] Nanofiber 5 for Example 5 was prepared and sheet 5 was produced in the same manner as in Example 1, except that polyvinyl alcohol 4 was used instead of polyvinyl alcohol 1 and the blending ratios of various components were changed as shown in Table 1.

[0130] Comparative Example 1 A dispersion of 0.05 mg / μL of C-6 in water was prepared.

[0131] Comparative Example 2: DSPC / cholesterol (Chol, manufactured by Sigma) was dissolved in chloroform to a molar ratio of 8 / 1, DSPC at 10.2 mM, and C-6 at 0.05 mg / mL in a recovery flask. The solvent was then removed under reduced pressure using a rotary evaporator in a water bath at 40°C to prepare a thin film. The thin film was then dried under reduced pressure overnight and hydrated with ultrapure water in a water bath at 60°C. Subsequent passage through a 100 nm pore size filter (Nucleporo Track-Etoch Membrane, manufactured by Whatman) 41 times using an extruder (LiposoFast™-Pneumatic, manufactured by Avestin) at a pressure of 200-300 kPa was used to prepare submicron-sized liposomes (particle size 100 nm).

[0132]

[0133] The following evaluations were carried out for Examples 1 to 5 and Comparative Examples 1 and 2, and the results are shown in Table 2.

[0134] <Fiber Shape Evaluation> Using a scanning electron microscope (JCM7000 NeoScope™, manufactured by JEOL Ltd.), the nanofiber fibers were observed under the following conditions, and the fiber shape was evaluated according to the following evaluation criteria. (Measurement conditions) Sputtering time: 90 seconds Applied voltage: 10 kV Magnification: 200 x 1000 x 5000 x 200 x 1000 x 5000 (Evaluation criteria) ◎ (Excellent): Fiber diameter is uniform. ○ (Very good): Fiber diameter varies, but no beads are observed. △ (Good): Beads are observed in the fiber. × (Poor): No fiber is obtained.

[0135] <Observation of Crystalline State> A differential scanning calorimeter (DSC8000 manufactured by PerkinElmer) was used to confirm the presence of C-6 crystals in the sheet under the following conditions. Measurement was also performed on bulk C-6 powder, and if the endothermic peak observed in C-6 had disappeared, it was determined that C-6 was in an amorphous state. (Measurement Conditions) Measurement range: 25 to 250°C Heating rate: 10°C / min Measurement sample amount: 5 to 10 mg

[0136] <Drug Content> The prepared nanofibers were cut and their masses were measured. The nanofibers were dissolved in ultrapure water for 24 hours. The solution was diluted 5-fold with acetonitrile to completely dissolve C-6, and then the solution was filtered using a 0.45 μm hydrophilic PTFE filter (13HP045AN, manufactured by Advantec Co., Ltd.). The C-6 concentration in the solution was quantified using high-performance liquid chromatography (EXTREMA HPLC System, manufactured by JASCO Corporation) under the following conditions, and the drug content was calculated using the following formula (1): (Measurement conditions) Detector: FP-2020 (JASCO Corporation) Wavelength: Excitation: 465 nm, Emission: 502 nm Column: 5C18-MS-II 4.6 ID x 250 mm Temperature: Room temperature (23°C) Injection volume: 20 µL Analysis time: 10 minutes Mobile phase: Methanol / Milli-Q = 95 / 5 Flow rate: 1 mL / min (Calculation formula) Drug content (%) = Drug content in nanofibers / Theoretical drug content at the time of nanofiber preparation x 100 (1)

[0137] <Drug delivery efficiency> The sheets of the examples were cut into 3 x 3 mm pieces and applied to the corneas of anesthetized ddY mice (4-week-old, male, manufactured by Japan SLC Co., Ltd.) administered 0.2 mL of triple-mix anesthesia intraperitoneally. The eyeballs were removed 30 minutes or 6 hours after application, and the tissues were immersed in 4% paraformaldehyde overnight at 4°C to fix them. The tissues were then immersed in 20% sucrose (manufactured by Nacalai Tesque) solution (in phosphate buffer) at 4°C for one day, after which they were fixed by dripping tissue freezing solution (Tissue-Tek O.C.T. Compound, manufactured by Sakura Finetech Co., Ltd.) in a Cryomold No. 1 (Tissue-Tek Cryomold, manufactured by Funakoshi Co., Ltd.). The tissues were then rapidly frozen in liquid nitrogen and embedded. The eyeballs were horizontally split using a Cryostat (Leica CM1520, Leica), and 10 μm-thick slices were cut at the position where the optic nerve was exposed to prepare sections for observation. Observation was performed using an epifluorescence microscope (BX50, Olympus). Photographs of the retina, iris, and cornea 500 μm from the optic nerve of the prepared sections were taken. The mean fluorescence intensity within a given area of ​​the inner plexiform layer (IPL) of the retina was quantified using ImageJ (National Institutes of Health, USA). The fluorescence intensity of the autofluorescence in the untreated retinal IPL was set as 1, and the relative fluorescence intensity of the C-6-administered group was calculated. The relative fluorescence intensity per C-6 amount in each sample was compared. As comparative examples, 30 μL of the C-6 dispersion in Comparative Example 1 and 3 μL of the C-6 / liposome dispersion in Comparative Example 2 were instilled into the eyes of mice.

[0138] <Retention> From the results of the delivery efficiency measurement, retention was calculated by dividing the fluorescence intensity in the retina after 6 hours by the fluorescence intensity after 30 minutes.

[0139]

[0140] In Examples 1 to 5, drug delivery to the retina was confirmed after 30 minutes, and particularly excellent drug delivery was observed after 6 hours, confirming high drug delivery efficiency and excellent retention. In Comparative Examples 1 and 2, drug delivery and retention after 6 hours were significantly inferior to those of the Examples.

[0141] Although the above examples show specific embodiments of the present invention, the examples are merely illustrative and should not be construed as limiting. Various modifications that are obvious to those skilled in the art are intended to fall within the scope of the present invention.

[0142] The sheet contains nanofibers containing a water-soluble polymer, which allows for high drug delivery efficiency and excellent retention in the posterior segment of the eye, making it suitable for use in formulations for the treatment of ocular diseases.

Claims

1. A sheet containing nanofibers containing a water-soluble polymer (A), wherein the water-soluble polymer (A) contains at least one selected from the group consisting of polyvinyl alcohol resin, hydroxyalkyl cellulose, and polyethylene oxide, and wherein the sheet is used by contacting at least one selected from the group consisting of the cornea, the conjunctiva, and the sclera, and wherein at least 50% of the mass is maintained after immersion in phosphate-buffered saline at 37°C for 1 minute.

2. The sheet according to claim 1, wherein the water-soluble polymer (A) is contained in the nanofibers in an amount of 70% by mass or more.

3. The sheet according to claim 1, wherein the water-soluble polymer (A) comprises an unmodified polyvinyl alcohol resin.

4. The sheet according to claim 3, wherein the degree of saponification of the unmodified polyvinyl alcohol resin is 70 to 100 mol %.

5. The sheet according to claim 3, wherein the product of the degree of polymerization of the unmodified polyvinyl alcohol resin and the content of the unmodified polyvinyl alcohol resin in the nanofibers is 200 to 3,000.

6. The sheet according to claim 1, having a thickness of 0.01 to 200 μm.

7. The sheet of claim 1, further comprising a drug.

8. The sheet of claim 7, wherein the drug is in an amorphous state.

9. The sheet of claim 1, further comprising a surfactant.

10. A method for producing a sheet, comprising a step of producing nanofibers by electrospinning or melt-blowing using a mixed liquid containing a water-soluble polymer (A) and a drug.

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