Method for preparing electrospun fibers with high content of bioadhesive substances

Abstract

The invention relates to a method for preparing electrospun fibers, the method comprising: v) dissolving a fiber forming hydrophilic polymer in an alcohol selected from C1-C3 alcohols, vi) dissolving a bioadhesive substance in water, wherein the bioadhesive substance has a solubility in water of 3 g / 100 ml or more at 25 °C or 10 g / 100 ml or more at 25 °C, and wherein the bioadhesive substance has a solubility in an alcohol selected from C1-C3 alcohols of 0.5 g / 100 ml or less at 25 °C or 0.1 g / 100 ml or less at 25 °C, vii) adding the resulting solution from ii) to the resulting solution from i) under stirring, whereby the bioadhesive substance precipitates and forms a homogeneous suspension, wherein the bioadhesive substance is suspended as particles, and viii) electrospinning the homogeneous suspension to obtain hydrophilic fibers.

Description

Invention Field

[0001] This invention relates to bioadhesive electrospun fibers with a high content of bioadhesive substances, specifically, a concentration of 30% w / w or higher of bioadhesive substances in the fiber based on dry weight. These fibers are used in pharmaceutical or cosmetic compositions, applied to mucous membranes or skin, particularly the oral mucosa, to deliver pharmaceutical substances into systemic circulation via the oral mucosa or skin. Background of the Invention

[0003] Many substances possess bioadhesive properties. In the preparation of electrospun fibers containing bioadhesive substances, the challenge lies in balancing the components to ensure that the amount of bioadhesive incorporated is sufficient to achieve the desired adhesion duration on mucous membranes or skin, while also ensuring that the fibers (e.g., in pharmaceutical or cosmetic formulations) do not release or detach from the application site.

[0004] This invention is a further development of the applicant's prior patent application, WO2015189212, which relates to bioadhesive electrospun fibers. It is clear from this disclosure that, for example, polyethylene oxide (PEO) can be used as a bioadhesive material, and high molecular weight polyethylene oxide, such as that having a molecular weight of 2,000,000 Daltons, is preferred due to its adhesiveness and solubility. The electrospinning method described in WO 2015189212 involves the use of a solvent in which the hydrophilic fiber-forming polymer is soluble, while the bioadhesive material is insoluble and added to the solvent in solid form.

[0005] Xin et al.: Fluorescent poly(p-phenylene vinylen) / poly(ethylene oxide) nanofibers obtained by electrospinning, Journal or Polymer Research, Vol. 18, No. 4, April 27, 2010. This invention relates to fluorescent PPV / PEO nanofibers obtained by electrospinning. PPV is a hydrophobic polymer. This invention relates to hydrophilic fiber-forming polymers.

[0006] Invention Description

[0007] This invention solves these problems by providing a method for preparing electrospun fibers, the method comprising adding a solution of a bioadhesive substance to a solution of a hydrophilic fiber-forming polymer, the addition of which causes precipitation of the bioadhesive substance.

[0008] Therefore, the present invention provides a method for preparing electrospun fibers, the method comprising:

[0009] i) Dissolve the hydrophilic polymer that forms the fiber in an alcohol selected from C1-C3 alcohols.

[0010] ii) The bioadhesive material is dissolved in water, wherein the bioadhesive material has a solubility of 3 g / 100 ml or more in water at 25°C, or 10 g / 100 ml or more at 25°C, and wherein the bioadhesive material has a solubility of 0.5 g / 100 ml or less in alcohols selected from C1-C3 alcohols at 25°C, or 0.1 g / 100 ml or less at 25°C.

[0011] iii) The solution obtained from ii) is added to the solution obtained from i) under stirring, thereby causing the bioadhesive material to precipitate and form a homogeneous suspension in which the bioadhesive material is suspended as particles, and

[0012] iv) Electrospinning a uniform suspension to obtain hydrophilic fibers.

[0013] Therefore, this invention is based on the difference in solubility of bioadhesive substances in water—where it is soluble—and in alcohol—where it precipitates. As can be seen from the above, the water content of the alcohol in step i) must be relatively low; this is because of the fact that hydrophilic polymers are soluble in alcohol, and care should be taken to ensure that the final water content in the suspension prepared for electrospinning does not exceed 20-50% w / w, since hydrophilic fiber-forming polymers typically swell in water or aqueous media, and it is important to control the swelling to avoid a suspension with excessively thick viscosity, such that the suspension does not coagulate and fail to form fibers, thus preventing delivery through the needle. If the amount of water is, for example, 50% w / w, it is expected that the spinning process will begin shortly after mixing the ethanol and aqueous solution (within 30 minutes to 1 hour) to avoid swelling.

[0014] Therefore, the solubility of the hydrophilic fibroblast polymer in alcohol and in the resulting alcohol-water mixture is important. The solubility of the hydrophilic polymer in alcohol and the resulting alcohol-water mixture is 3 g / 100 ml or more at 25°C or 10 g / 100 ml or more at 25°C.

[0015] Furthermore, the solubility of the bioadhesive in the resulting alcohol-water mixture is 0.5 g / 100 ml or less at 25 °C, or 0.1 g / 100 ml or less at 25 °C.

[0016] The pharmaceutical substance may be included in step i) or ii) of the method, depending on its solubility.

[0017] Although polyethylene oxide, for example, with a molecular weight of 2,000,000 Daltons, exhibits excellent bioadhesion properties, the inventors have found that electrospinning is not optimal when using PEO 2,000,000. Due to the high molecular weight of PEO, which involves relatively long PEO chains, PEO 2,000,000 tends to mix with the hydrophilic polymers that form the fibers in the fiber. However, due to the chain length, the distribution of PEO 2,000,000 in the PEO may be too random, for example, due to the small surface area of ​​PEO 2,000,000. To mitigate this situation and to obtain a more uniform distribution, experiments have been conducted with micronized PEO 2,000,000. However, it is not possible to obtain sufficiently small PEO 2,000,000 particle sizes. Therefore, the needles used in the spinning process—when using micronized PEO 2,000,000—are obviously prone to clogging, and the resulting fibers are obviously not as strong as expected.

[0018] Furthermore, as can be seen from the embodiments described herein, even with a significant reduction in the molecular weight of PEO, the suspension of PEO in an alcohol solvent along with the hydrophilic polymer still leads to uneven distribution of PEO in the electrospun material. However, by applying the method of the present invention, in which PEO is first dissolved in water and then the aqueous solution is mixed with an alcohol solution containing the hydrophilic polymer to precipitate PEO, the desired result is obtained, wherein PEO is uniformly distributed on the fibrous material obtained by electrospinning. It is anticipated that PEO is not a bulk component of the fibrous material, but rather is positioned on the fibers as extremely fine particles.

[0019] When the molecular weight of the bioadhesive is reduced compared to the disclosure in WO 2015 / 189212, it is expected that an increase in the concentration of the bioadhesive in the fiber is necessary to obtain the desired bioadhesion.

[0020] To achieve strong bioadhesion, bioadhesive materials must be used in electrospun fibers at relatively high concentrations, such as 30% w / w. This further complicates the fiber manufacturing process.

[0021] Of particular interest are compositions prepared according to the present invention, which contain anti-inflammatory pharmaceutical substances, such as corticosteroids. The corticosteroids may be selected from: ancinonide, betamethasone, budesonide, clobetasol, clobetasol, cortisone, desonide, deoxycortisone, dexamethasone, diflucorlonone, difluralasone, flucortisone, flumethasone, flunicolone acetonide, fluocinolone acetonide, fluocinolone acetonide, fluocinolone acetonide, fluticasone propionate, fluticasone propionate, fluticasone propionate, cloflucortisone propionate, halobetasol, hydrocortisone propionate, methylprednisolone, methylprednisolone, mometasone, peramisone, prednicarbamate, prednisolone, and triamcinolone acetonide, or pharmaceutically acceptable esters or acetone compounds thereof. Corticosteroids are preferably selected from betamethasone, budesonide, clobetasol, deoxythiophene, difluralasone, difluorothiazide, fluoroquinolones, fluoroquinolones, halocinonide, halosalicylates, hydrocortisone, mometasone, and triamcinolone, or their pharmaceutically acceptable esters. Corticosteroid esters are preferably selected from, for example, betamethasone acetate, betamethasone dipropionate, betamethasone valerate, clobetasol propionate, dexamethasone acetate, fludexamethasone pentanoate, fluticasone propionate, hydrocortisone acetate, hydrocortisone butyrate, or mometasone furoate. Acetone compounds may be selected from fluocinolone acetonide or triamcinolone acetonide. The preferred corticosteroids are betamethasone dipropionate, betamethasone valerate, or clobetasol propionate. In the context of this paper, clobetasol or its derivatives, such as clobetasol propionate, are preferred.

[0022] Corticosteroids are a class of steroid hormones produced in the adrenal cortex of vertebrates.

[0023] Corticosteroids can be used to treat a variety of conditions / diseases, including

[0024] i) Allergies and respiratory diseases, such as asthma (severe exacerbation), chronic obstructive pulmonary disease (CPOD), allergic rhinitis, atopic dermatitis, urticaria, angioedema, allergic reactions, food allergies, drug allergies, nasal polyps, allergic pneumonia, sarcoidosis, eosinophilic pneumonia, and interstitial lung disease;

[0025] ii) Skin diseases, such as pemphigus vulgaris and contact dermatitis;

[0026] iii) Endocrinology, including adrenal insufficiency and congenital adrenal hyperplasia;

[0027] iv) Gastroenterology, including ulcerative colitis, Crohn's disease, and autoimmune hepatitis;

[0028] v) Hematology, such as lymphoma, leukemia, hemolytic anemia, and idiopathic thrombocytopenic purpura;

[0029] vi) Rheumatology / Immunology, including rheumatoid arthritis, systemic lupus erythematosus, polymyalgia rheumatica, polymyositis, dermatomyositis, polyarteritis, and vasculitis;

[0030] vii) Ophthalmology, including uveitis and keratoconjunctivitis;

[0031] viii) Other conditions, including multiple sclerosis, organ transplantation, nephrotic syndrome, chronic hepatitis (sudden onset), and cerebral edema.

[0032] Corticosteroids are generally classified into glucocorticoids and mineralocorticoids. In the context of this paper, glucocorticoids are of particular interest. Specifically, the glucocorticoids of interest in this context are those commonly used to treat diseases in which compositions comprising electrospun fibers can be applied in a relatively easy manner. Regarding corticosteroids, many compositions are expected to be applied to the skin or mucous membranes, and the application of such compositions includes:

[0033] i) Applied directly to mucous membranes, such as oral, nasal, rectal, or vaginal mucosa;

[0034] ii) Applied directly to the skin;

[0035] iii) During transplantation to the transplant tissue - the composition is provided in a sterile form;

[0036] iv) Applied to infected or diseased areas of the body during surgery;

[0037] v) Apply directly to the wound - external or internal wounds.

[0038] Other drugs of interest in the context of this article include: analgesics or anesthesias (e.g., lidocaine, capsaicin), immune response modulators (e.g., imiquimod), and inflammatory diseases such as lichen planus, including genital lichen planus, including vulvovaginal-ginival syndrome.

[0039] However, it is expected to include any pharmaceutical substance.

[0040] hydrophilic electrospun layer

[0041] Hydrophilic polymers are essential components of hydrophilic materials, possessing the ability to form fibrous materials. To avoid confusion with other components present in electrospun fibers or their compositions, the term "fiber-forming hydrophilic polymer" is used. Suitable fiber-forming hydrophilic polymers are polymers soluble in or gel-forming in C1-C3 alkanols, such as methanol, ethanol, propanol, or isopropanol, particularly ethanol, propanol, or isopropanol, or aqueous mixtures thereof, wherein the water content is at most 20% w / w, preferably much lower, for example, at most 5-10% w / w or 3-5% w / w. The spinning process requires the polymer, as the main component of the fiber, to be in a dissolved form so that a stable flow of the dissolved polymer flows in a jet-like manner from the needle to a grounded collection plate during spinning.

[0042] Suitable hydrophilic polymers for fiber formation are polyvinylpyrrolidone (PVP), acrylates, and acrylic copolymers (e.g.) ), and mixtures thereof. Other polymers, such as ethyl cellulose (EC), hydroxypropyl cellulose (HPC), or mixtures thereof, may also be used. Ethyl cellulose (EC), hydroxypropyl cellulose (HPC), or mixtures thereof may be used particularly in combination with polyvinylpyrrolidone (PVP) and / or acrylates, including acrylic copolymers (e.g. In the examples, PVP and acrylic acid copolymers have been used in particular. Other hydrophilic polymers may be polyvinyl alcohol and carboxymethyl cellulose (including its alkali metal salts), and mixtures thereof.

[0043] Polyvinylpyrrolidone (PVP) can be used in molecular weight ranges from about 2,500 Da to 3,000,000 Da (e.g., polyvinylpyrrolidone with a K-value of 12 to 120). PVP can be used in... Purchased:

[0044]

[0045] In the low MW range, suitable grades are expected to have MW of approximately 25,000 to approximately 120,000, particularly approximately 70,000 to approximately 100,000. In the embodiments described herein, primarily using... 90F, therefore, the preferred PVP has an M of about 900,000 to about 3,000,000, particularly about 1,000 to about 1,500,000. w .

[0046] Ethyl cellulose is marketed under the trademark ETHOCEL TM(Dow Chemical Company) sells ethyl cellulose, and it comes in many different grades. Dow Chemical Company produces two ethoxylated types of ethyl cellulose (labeled as standard and medium). Depending on its ethoxy content, ethyl cellulose can have different softening points and melting temperatures. Ethyl cellulose is also produced in many different viscosities. A list of available ethyl cellulose is given in the table below.

[0047] ETHOCEL polymer

[0048]

[0049] In its plasticized form, it exhibits excellent thermoplasticity and can be used in compositions prepared by molding, extrusion, or lamination. Ethyl cellulose is also an excellent film-forming agent and is used, for example, in tablet coating. The aforementioned ethyl celluloses have an ethoxylate content of at least 45.0%, thus they are soluble in ethanol but practically insoluble in water.

[0050] Acrylates and acrylic acid derivatives include polymethacrylates, methacrylate copolymers, acrylic acid copolymers, and methacrylate polymers. Preferred acrylates are those marketed under trademarks. Those sold are soluble in ethanol or acrylate / octaacrylamide copolymer (sold under the trade name DERMACRYL 79). They include... E12,5 (amino methacrylate copolymer), E100 (Amino methacrylate copolymer; Basic butylated methacrylate copolymer) EPO (amino methacrylate copolymer) L100-55 L 100 (methacrylic acid-methyl methacrylate copolymer 1:1), S100 (methacrylic acid-methyl methacrylate copolymer 1:2) RL100 RL100 (Ammonium methacrylate copolymer type A), RL PO, RS100 (Ammonium methacrylate copolymer, type B) RSPO. E is a cationic polymer based on dimethylaminoethyl methacrylate and other neutral methacrylates: L and S are methacrylic acid copolymers, and are cationic copolymers of methacrylic acid and methyl methacrylate. RL or RS is an ammonium methacrylate copolymer synthesized from acrylic acid and methacrylic acid.

[0051] E 100 is soluble up to pH 5.5, and E 12.5 is soluble above pH 5.

[0052] L30 D-55, L-100-55 (methacrylic acid-ethyl acrylate copolymer 1:1), L100, L12, 5 are typically used in enteric-coated formulations, but can be used to delay the release of pharmaceutical substances from the fibers of this invention. L30D-55 and L-100-55 dissolve at approximately pH 5.5, while grades L100 and L12,5 dissolve at pH 6 or above.

[0053] Since the pH of saliva is typically around 5-6, these polymers are meaningful for orally administered fibers. If sustained or prolonged release is required, polymers that are soluble at lower pH levels at higher concentrations may be more suitable.

[0054] The products can also be used in sustained-release formulations, and these grades may be meaningfully incorporated into the fibers of the present invention, alone or together with another hydrophilic polymer. Relevant grades belong to the RL, RS, NE, and NM series, such as RL 100, RL PO, RL 30D, and RL 12,5, RS 100, RS PO, RS 30D, and RS 12,5, NE 30D, NE 40D, and NM 30D.

[0055] Hydroxypropyl cellulose is a nonionic, water-soluble cellulose ether. It combines the solubility, thermoplasticity, and surface activity of organic solvents with thickening and stabilizing properties. The fiber exhibits flexibility and non-stickiness at high humidity. Hydroxypropyl cellulose is marketed under the brand name KLUCEL. TM The name is sold.

[0056] Carboxymethyl cellulose is available in a wide range of grades. Viscosities range from 10 to 100,000 mPa*s. It can also be used as a sodium salt with a wide range of substitution levels. Dow Chemical Company uses WALOCEL... TM It sells sodium carboxymethyl cellulose under the name [name omitted].

[0057] Polyvinyl alcohol can be used in grades with molecular weights ranging from about 20,000 Da to 200,000 Da.

[0058] The preferred hydrophilic polymers for forming fibers are selected from PVP, hydroxypropyl cellulose (HPC), acrylates and acrylic acid derivatives, and mixtures thereof.

[0059] Hydrophilic materials in the form of electrospun fiber layers may also contain one or more pharmaceutical substances, one or more bioadhesive substances, and one or more pharmaceutically or cosmetically acceptable excipients. These excipients include pH adjusters, preservatives, flavor masking agents, antioxidants, stabilizers, and penetration enhancers. Furthermore, depending on the intended use, other excipients may be present, such as plasticizers and surfactants.

[0060] In the hydrophilic materials of the present invention, the concentration of the hydrophilic polymer forming the fibers is typically at most 100% w / w. When other components are included, the minimum concentration of the hydrophilic polymer forming the fibers is typically about 25% w / w to ensure the formation of fibers containing all components. Notably, the concentration is about 40% to about 92% w / w, particularly about 50% to about 85% w / w or about 60% to 75% w / w.

[0061] In cases where the composition is designed for use on mucosal surfaces, it may be of interest to include bioadhesive substances to promote adhesion to the mucosa.

[0062] If strong bioadhesion is required, the concentration of bioadhesive material in the electrospun fibers must be relatively high, such as 20% w / w or above, especially 40% w / w or above. To obtain fibers with such a high bioadhesive content, it is necessary to select bioadhesive materials with low solubility in the solvents used during electrospinning—if they are soluble, they will swell and make electrospinning impossible or at least very difficult.

[0063] If mild bioadhesion is required, the concentration of bioadhesive in the electrospun fibers must be at most 20% w / w or less, especially 10% w / w or less.

[0064] The fibers of the present invention also contain bioadhesive substances. To ensure ease of fiber manufacture and to achieve the desired bioadhesive properties in situ upon application to a mucosa, it is important that the bioadhesive itself does not significantly contribute to the viscosity of the solution containing the fibroblast-forming hydrophilic polymer.

[0065] In the context of this document, the term "bioadhesion," or "bioattachment," means attachment to a specific biological location, such as attachment to a skin surface, lip, or mucous membrane surface. Bioadhesive substances impart bioadhesiveness to the medicamentous fibers of the present invention, or in some cases, it may be included in the compositions of the present invention, for example as a separate layer that, upon application, is an inner layer facing the skin or mucous membrane, i.e., the layer in contact with the skin or mucous membrane.

[0066] The bioadhesive material used in this invention may be selected from dextran, polyethylene oxide, alginate, tragacanth gum, carrageenan, pectin, gelatin, guar gum, xanthan gum, gelling sugar, methylcellulose, hydroxypropyl methylcellulose (HPMC), carboxymethyl cellulose and its alkali metal salts, acrylic polymers (PAA derivatives), deacetylated chitosan, exogenous lectins, thiolized polymers, polyox WSRA, PAA-co-PEG (PEG is polyethylene glycol), and mixtures thereof.

[0067] Generally, the adhesive effect of a polymer is expected to increase with increasing molecular weight. Therefore, adhesive polymers with relatively high molecular weights are generally preferred.

[0068] Polyethylene oxide can be used in grades with molecular weights ranging from approximately 100,000 to 4,000,000. Polyethylene oxide is packaged in POLYOX... TM Sold under the name (Dow Chemical Company), with molecular weights from 100,000 to 700,000 Da, as previously stated. PEOs with molecular weights below 500,000 Daltons are preferred, particularly those with molecular weights from about 100,000 to about 400,000 Daltons, such as polyethylene oxide with a molecular weight of about 200,000 Daltons. This can be attributed to the solubility issues discussed herein.

[0069] Similar considerations apply to other bioadhesive materials cited in this article. Experiments with, for example, high molecular weight dextran have shown that the micronization of dextran is also difficult; that is, it is difficult to obtain micronized forms of dextran when the molecular weight is greater than 1,000,000 Daltons.

[0070] Dextran can be used in molecular weight ranges from 400,000 Da to approximately 1,000,000 Da. Dextran has a molecular weight of approximately 400,000 to approximately 700,000 Daltons.

[0071] Cellulose derivatives include hydroxypropyl methylcellulose, methylcellulose, and carboxymethylcellulose.

[0072] Methylcellulose with METHOCEL TM Sold under the name (Dow Chemical Company) and available in a wide range of viscosity grades (from less than 3 to over 100,000 mPa*s).

[0073] HPMC is sold in various qualities, depending on viscosity. HPMC is... and Sold under the name of HPMC. Suitable HPMC has an average molecular weight of approximately 80,000 to approximately 140,000.

[0074] Preferred bioadhesives are polyethylene oxide, dextran, or combinations thereof.

[0075] The hydrophilic material used to manufacture the bilayer product of the present invention may contain a pharmaceutical substance. Generally, the pharmaceutical substance can be any pharmaceutical substance suitable for application to mucous membranes or skin to treat a disease or condition. Of particular interest are pharmaceutical substances selected from those indicated for the treatment of skin, lip, or mucous membrane diseases, or, where the fibers are included in a composition applied to an inner surface as described herein, any pharmaceutical substance designated for a specific treatment. In the context of this document, the pharmaceutical substance may be selected from those used to treat oral diseases, for example, pharmaceutical substances indicating topical treatment of oral diseases. The pharmaceutical substance may be present in a soluble, undissolved, or partially dissolved form, depending on the drug solubility in the hydrophilic polymer and biological mixture used.

[0076] Hydrophobic electrospun layers and their application in hydrophilic electrospun layers

[0077] Hydrophobic materials are hydrophobic electrospun layers. It is noteworthy that they are impermeable to water, for example, capable of producing a occlusive effect and / or protection against fluids such as bodily fluids. The latter is relevant to the use of bilayer products in particularly humid environments, where it is desirable to protect pharmaceutical substances within the hydrophilic material from dissolution in the fluid. Suitable materials for providing impermeable coatings include polyethylene-co-vinyl acetate, ethyl cellulose, poly(caprolactone), carbothane, or polysoftane.

[0078] As described with respect to hydrophilic materials, such materials may contain one or more acceptable excipients. Excipients mentioned in the section on hydrophilic materials may also be used in hydrophobic materials, and vice versa.

[0079] Hydrophilic fibers are prepared into thin layers. For example, another electrospun layer of a hydrophobic fiber-forming polymer can be attached to the hydrophilic layer. This can be accomplished by a method involving pressure and heat, suitable for manufacturing bilayer products comprising a first hydrophilic material made of electrospun fibers, which is connected to a second hydrophobic material made of electrospun fibers, wherein the first material may contain a drug, and the method is characterized by:

[0080] The method involves using a press comprising a first surface and a second surface, wherein the second surface has a temperature higher than that of the first surface.

[0081] The first and second materials are arranged in a layered configuration between the first and second surfaces of the press, wherein pressure is applied from the first and second surfaces of the press toward the layered configuration, and thereby the first material contacts the first surface of the press.

[0082] -The combination of pressure between the first and second surfaces and temperature of the second material bonds the first and second materials together to form the bilayer product.

[0083] The term "layered combination" refers to the arrangement of the first and second materials such that their principal planes are parallel, i.e., the materials are stacked on top of each other, similar to a layer or sandwich.

[0084] The connection between the first and second materials refers to any kind of physical and / or chemical connection that ensures the materials do not accidentally separate. Physical connections can be entanglements between electrospun fibers, while chemical connections can manifest as chemical bonds. Connections are established through physical linkages or weak interactions at the molecular level (ion-ion interactions, van der Waals forces).

[0085] Heating the hydrophobic second material on the second surface increases the bonding strength between the hydrophilic first and hydrophobic second materials. More specifically, this is achieved by heating the polymer of the hydrophobic second material to a temperature below its melting point, or to a temperature at or above its melting point, but for a relatively short period, to avoid complete melting of the polymer and adhesion between the polymer and the second surface. By subsequently cooling the bilayer product through a terminating heating process, the hydrophilic and hydrophobic electrospun layers are locked in their new positions.

[0086] The hydrophilic first material may contain the pharmaceutical substance of the present invention, and elevated temperatures of the hydrophilic first material can alter the properties of the pharmaceutical substance. Therefore, it is desirable to avoid heating the first hydrophilic material. However, this may depend on the pharmaceutical substance used.

[0087] The heating device can be any device capable of heating the surface of the press to a predetermined temperature. Heating can originate from resistance, a hot fluid that transfers heat to the surface, or any other heating device that can be incorporated into the press as disclosed.

[0088] The press surface material that comes into contact with the material to be bonded can be any material that does not damage the chemical composition of the electrospun fibers. Furthermore, a material with excellent heat transfer capacity and a material capable of withstanding high pressure is required. Therefore, metals are preferred materials, but ceramics are also anticipated to be within the scope of this invention.

[0089] In one embodiment, the press is a roll press with two opposing rotating rollers, also known as a calender. The rollers can be driven by any machinery commonly used in the field of such presses. The two rollers are parallel to each other and aligned with a gap of a size that facilitates the pressure required to bond the first and second materials to the bilayer product. The surface of one roller is heated to a temperature higher than the surface temperature of the other roller. An input is created as the rollers rotate in opposite directions, where the surfaces of the two rollers converge into the gap, and an output is created where the surfaces of the two rollers deviate from the gap. To obtain the bilayer product, a hydrophobic and a hydrophilic material are arranged in a layered combination and fed into the input path such that the hydrophobic material contacts the roller with the heated surface. Due to the rotation of the rollers, the size of the gap ensuring sufficient pressure, and the temperature of the roller surfaces, the two materials are bonded to the bilayer product and exited through the output path of the rollers.

[0090] In one embodiment, the press is a platen press comprising first and second surfaces that are substantially flat and parallel to each other. The two parallel surfaces are retractable and can move closer together relative to each other. One of the surfaces is heated to a temperature higher than that of the other surface. Prior to bonding, a first hydrophilic material and a second hydrophobic material to be bonded are arranged between the two surfaces in a layered combination with the hydrophobic material to contact the heated surface. By moving the first and second surfaces closer together, pressure is applied to the layered combination, and bonding occurs in combination with the surface temperatures. Subsequently, the parallel surfaces are retracted, and the double-layered product formed by bonding is removed from the press. The press can be hydraulically driven, but other machine presses are contemplated within the scope of this invention.

[0091] A press can be a combination of a flat surface and rollers configured to roll over said surface. The roller surface or the flat surface is heated to a temperature higher than the relative surface temperature. A hydrophilic first material and a hydrophobic second material are arranged in a layered combination on the flat surface, with the second hydrophobic material in contact with the heated surface. The rollers are configured to roll over said layered combination, applying pressure sufficient to bond the first and second materials to the bilayer product. The press can be applied by being positioned at a predetermined distance above the flat surface, or by pressing further down onto the layered combination using external machinery (e.g., hydraulic pressure).

[0092] In one embodiment, the hydrophobic and hydrophilic materials are formed into sheets or layers prior to the bonding process, wherein the thickness of the sheet is significantly smaller than any other size of the sheet.

[0093] The thicknesses of hydrophilic and hydrophobic materials do not need to be the same. The thicker the hydrophobic layer, the less flexible it is. Therefore, to obtain a flexible layer, the coating thickness of the hydrophobic layer should be equal to or less than that of the hydrophilic layer. In those cases, the function of the hydrophobic layer is to prevent water or bodily fluids from passing through it into the hydrophilic layer; this layer must be thick enough and robust to withstand the impact of water or bodily fluids. Typically, the concentration of the hydrophobic layer is 10-50 g / m³. 2 Typically, a thickness of less than 100 μm is obtained.

[0094] There may also be cases where hydrophobic materials have greater extension than hydrophilic materials, causing the hydrophobic material to also cover the edge of the hydrophilic material.

[0095] In one embodiment, both the first and second surfaces of the press are heated to a predetermined temperature, or both surfaces may be capable of being heated. The surface temperatures have a temperature difference.

[0096] In addition to the excipients mentioned earlier, hydrophobic and / or hydrophilic fibers may contain plasticizers. Plasticizers impart a degree of plasticity to the fibers, which can facilitate the manufacturing process and / or improve the flexibility and processability of the polymer. Examples of suitable plasticizers are citrates such as acetyl triethyl citrate, tributyl citrate or triethyl citrate, castor oil, diacetylated monoglycerides, dibutyl sebacate, diethyl phthalate, sorbitol, glycerol or glycerol derivatives such as triacetin or tributyl ester, cellulose derivatives such as nitrocellulose, glycols such as polyethylene glycol, especially polyethylene glycol with a molecular weight of about 100 to about 1500, polyethylene glycol monomethyl ether, propylene glycol or mixtures thereof. Attached Figure Description

[0097] Figure 1 The electrospun membranes are derived from: A) the original formulation solution, and B) the formulation for the precipitation of PEO as described in this invention. Example

[0098] Solution preparation and electrospinning methods

[0099] a) Comparative methods for fiber preparation:

[0100] Weigh anhydrous ethanol. Slowly add 6.52 wt.% Kollidon 90F and 8.15 wt.% Eudragit RS100 (alcohol content) while stirring. Continue stirring for 24 hours. Slowly add 13.05 wt.% Polyox WSR N-80 (PEO 200,000 Mw) while stirring. Continue stirring until a homogeneous suspension is formed. The final mixture has 27.72% total solids (66% of the original formulation).

[0101] Processing was performed using a single-needle syringe (15G) at a rate of 2 mL / h, with a needle tip-to-collector distance of 10 cm, and a difference of 13 kV over 3 hours. The final membrane (fiber layer) yielded 147.4 g / m³. 2 .

[0102] b) The formulation of the present invention:

[0103] Weigh anhydrous ethanol. While stirring, slowly add 8 wt.% Kollidon 90F and 10 wt.% Eudragit RS100 (alcohol amount). Continue stirring for 24 hours.

[0104] Weigh the distilled water. Slowly add 16 wt.% Polyox WSR N-80 (PEO 200,000 Mw) while stirring. Keep stirring for 24 hours.

[0105] The alcohol solution was slowly added to the aqueous solution while stirring. Stirring continued until a homogeneous mixture was formed. The final mixture contained 17% total solids.

[0106] Treatment was performed using a multi-needle syringe (56 needles, 20G) at a rate of 110 mL / h, with a needle tip-to-collector distance of 19 cm, and a voltage difference of 60 kV over several hours. The final membrane (fiber layer) had a voltage of 160 / m. 2 A small 12x5cm piece was cut off for further analysis.

[0107] Membrane morphology characterization

[0108] The two membranes (fiber layers) were examined using a scanning electron microscope. The sample was sputtered with a gold-palladium mixture over a period of 180 seconds and observed in a Hitachi S4800 with an accelerating voltage of 5 kV and a working distance of 8 mm.

[0109] Figure 1 Images of the two membranes taken at 1500x magnification are shown. The sample prepared according to the invention has a smaller fiber diameter, mainly due to the lower total solids content and higher applied voltage difference. As observed above, the control sample shows large PEO particles between the fibers.

Claims

1. A method for preparing electrospun fibers, the method comprising: i) Dissolve the hydrophilic polymer that forms the fiber, selected from polyvinylpyrrolidone, ethyl cellulose, hydroxypropyl cellulose, acrylates and acrylic copolymers and mixtures thereof, in an alcohol selected from C1-C3 alcohols. ii) Dissolving the bioadhesive in water, wherein the bioadhesive is a polyethylene oxide (PEO) having a molecular weight of 200,000-500,000 Daltons, having a solubility of ≥3 g / 100 ml in water at 25°C and a solubility of ≤0.5 g / 100 ml in alcohols selected from C1-C3 alcohols at 25°C. iii) The solution obtained from ii) is added to the solution obtained from i) under stirring to form a homogeneous mixture containing 20-50% w / w water. iv) Electrospinning a homogeneous mixture to obtain electrospun fibers, wherein the concentration of PEO in the fibers is 30%-60% w / w, based on the total dry weight. The premise is that if the water content in the homogeneous mixture formed in iii) is 50% w / w, then electrospinning in iv) must begin within 30 minutes to 1 hour.

2. The method according to claim 1, further comprising dissolving or suspending the drug substance in step i) or step ii).

3. The method of claim 1 or 2, wherein the bioadhesive is a polyethylene oxide having a molecular weight of 200,000 Daltons.

4. The method of claim 1 or 2, wherein the fiber comprises a hydrophilic polymer selected from polyvinylpyrrolidone, acrylates and acrylic copolymers and mixtures thereof.

5. The method according to claim 1 or 2, wherein the concentration of the hydrophilic polymer forming the fiber in the fiber is 40%-85% w / w, based on the total dry weight.

6. The method according to claim 1 or 2, wherein the concentration of the hydrophilic polymer forming the fiber in the fiber is 45%-70% w / w, based on the total dry weight.

7. The method according to claim 1 or 2, wherein the concentration of the hydrophilic polymer forming the fiber in the fiber is 50%-70% w / w, based on the total dry weight.

8. The method according to claim 1 or 2, wherein the concentration of the bioadhesive in the fiber is 35%-60% w / w, based on the total dry weight.

9. The method according to claim 1 or 2, wherein the concentration of the bioadhesive in the fiber is 40%-55% w / w, based on the total dry weight.

10. The method according to claim 1 or 2, wherein the C1-C3 solvent is ethanol.

11. The method of claim 1, further comprising adding the pharmaceutical substance to step i).

12. The method of claim 11, wherein the pharmaceutical substance is an anti-inflammatory pharmaceutical substance.

13. The method of claim 11, wherein the pharmaceutical substance is a corticosteroid.

14. The method of claim 1 or 2, further comprising the step of contacting the electrospun fibers with an impermeable hydrophobic layer.

15. The method of claim 13, wherein the corticosteroid is clobetasol propionate.

16. The method according to claim 1 or 2, wherein the hydrophilic polymer is selected from polyvinylpyrrolidone, ammonium methacrylate copolymer type B, and mixtures thereof.

17. The method of claim 16, wherein the polyvinylpyrrolidone has a weight-average molecular weight of 900,000 Da to 3,000,000 Da.

18. The method of claim 16, wherein the polyvinylpyrrolidone has a weight-average molecular weight of 1,500,000 Da.

19. The method of claim 16, wherein the concentration of the hydrophilic polymer forming the fiber in the fiber is 40% to 85% w / w, based on the total dry weight.

20. The method of claim 16, wherein the concentration of the hydrophilic polymer forming the fiber in the fiber is 45% to 70% w / w, based on the total dry weight.

21. The method of claim 16, wherein the concentration of the bioadhesive in the fiber is 35% to 60% based on the total dry weight.

22. The method of claim 16, wherein the concentration of the bioadhesive in the fiber is 40% to 55% based on the total dry weight.

23. The method of claim 16, wherein the concentration of the bioadhesive in the fiber is 40% w / w, based on the total dry weight.

24. The method of claim 14, wherein the hydrophobic layer comprises polycaprolactone.

25. The electrospun fiber prepared by the method of claim 1, comprising: Hydrophilic fiber-forming polymers selected from polyvinylpyrrolidone, ethyl cellulose, hydroxypropyl cellulose, acrylates and acrylic copolymers and mixtures thereof; A bioadhesive material, wherein the bioadhesive material is PEO having a molecular weight of 200,000 to 500,000 Daltons, wherein the PEO has a solubility in water of ≥3 g / 100 ml at 25°C and a solubility in alcohols selected from C1-C3 alcohols of ≤0.5 g / 100 ml at 25°C, and wherein the concentration of PEO in the fiber is 30%-60% w / w, based on the total dry weight; and Drug substances.

26. The electrospun fiber of claim 25, wherein the polymer that forms the hydrophilic fiber is selected from polyvinylpyrrolidone, ammonium methacrylate copolymer type B, and mixtures thereof.

27. The electrospun fiber of claim 25 or 26, wherein the weight-average molecular weight of polyvinylpyrrolidone is 900,000 Da to 3,000,000 Da.

28. The electrospun fiber of claim 25 or 26, wherein the weight-average molecular weight of polyvinylpyrrolidone is 1,500,000 Da.

29. The electrospun fiber of claim 25 or 26, wherein the concentration of the hydrophilic polymer forming the fiber in the fiber is 50% to 85% w / w, based on the sum of the total dry weight.

30. The electrospun fiber of claim 25 or 26, wherein the concentration of the hydrophilic polymer forming the fiber in the fiber is 45% to 70% w / w, based on the total dry weight.

31. The electrospun fiber of claim 25 or 26, wherein the bioadhesive is polyethylene oxide having a molecular weight of 200,000 Daltons.

32. The electrospun fiber of claim 25 or 26, wherein the concentration of the bioadhesive in the fiber is 35% to 60% based on the total dry weight.

33. The electrospun fiber of claim 25 or 26, wherein the concentration of the bioadhesive in the fiber is 40% to 55% based on the total dry weight.

34. The electrospun fiber of claim 25 or 26, wherein the concentration of the bioadhesive in the fiber is 40% w / w, based on the total dry weight.

35. The electrospun fiber of claim 25 or 26, wherein the pharmaceutical substance is an anti-inflammatory pharmaceutical substance.

36. The electrospun fiber of claim 25 or 26, wherein the pharmaceutical substance is a corticosteroid.

37. The electrospun fiber of claim 36, wherein the corticosteroid is clobetasol propionate.

38. Electrospun fibers prepared according to the method of claim 1 or 2.

39. A layered pharmaceutical composition comprising: (a) A hydrophilic electrospun layer comprising the electrospun fiber prepared according to claim 1, comprising: (i) A hydrophilic fiber-forming polymer selected from polyvinylpyrrolidone, ethyl cellulose, hydroxypropyl cellulose, acrylates and acrylic copolymers and mixtures thereof; (ii) a bioadhesive material, wherein the bioadhesive material is a polyethylene oxide (PEO) having a molecular weight of 200,000 to 500,000 Daltons, wherein the PEO has a solubility in water of ≥3 g / 100 ml at 25°C and a solubility in alcohols selected from C1-C3 alcohols of ≤0.5 g / 100 ml at 25°C, and wherein the concentration of PEO in the fiber is 30%-60% w / w, based on the total dry weight; and (iii) Drug substances; and (b) Hydrophobic layer.

40. The layered pharmaceutical composition of claim 39, comprising a hydrophilic fiber-forming polymer selected from polyvinylpyrrolidone, ammonium methacrylate copolymer type B, and mixtures thereof.

41. The layered pharmaceutical composition of claim 39 or 40, wherein the polyvinylpyrrolidone has a weight-average molecular weight of 900,000 Da to 3,000,000 Da.

42. The layered pharmaceutical composition of claim 39 or 40, wherein the polyvinylpyrrolidone has a weight-average molecular weight of 1,500,000 Da.

43. The layered pharmaceutical composition of claim 39 or 40, wherein the concentration of the hydrophilic polymer forming the fiber in the fiber is 50% to 85% w / w, based on the total dry weight.

44. The layered pharmaceutical composition of claim 39 or 40, wherein the concentration of the hydrophilic polymer forming the fiber in the fiber is 45% to 70% w / w, based on the total dry weight.

45. The layered pharmaceutical composition of claim 39 or 40, wherein the pharmaceutical composition comprises an electrospun fiber prepared by the method of claim 1, and wherein the bioadhesive is polyethylene oxide with a molecular weight of 200,000 Daltons.

46. ​​The layered pharmaceutical composition of claim 39 or 40, wherein the concentration of the bioadhesive in the fiber is 35%-60% based on the total dry weight.

47. The layered pharmaceutical composition of claim 39 or 40, wherein the concentration of the bioadhesive in the fiber is 40% to 55% based on the total dry weight.

48. The layered pharmaceutical composition of claim 39 or 40, wherein the pharmaceutical substance is an anti-inflammatory pharmaceutical substance.

49. The layered pharmaceutical composition of claim 39 or 40, wherein the pharmaceutical substance is a corticosteroid.

50. The layered pharmaceutical composition of claim 49, wherein the electrospun fibers are prepared by the method of claim 1, and wherein the corticosteroid is clobetasol propionate.

51. The layered pharmaceutical composition of claim 39 or 40, wherein the electrospun fibers are prepared by the method of claim 1, and wherein the hydrophobic layer comprises a polymer selected from polycaprolactone, polyethylene-co-vinyl acetate, ethyl cellulose, carbothane, and polysoftane.

52. The layered pharmaceutical composition of claim 39 or 40, wherein the hydrophobic layer comprises polycaprolactone.

Images