ELECTROSPUN FIBERS COMPRISING SURFACE-REACTED CALCIUM CARBONATE AND ACTIVE INGREDIENTS

Abstract

 The present invention relates to an electrospun fiber, a process for preparing the same, a nonwoven fabric comprising the electrospun fiber, as well as corresponding uses and articles. The inventive electrospun fiber comprises a polymer, a surface-reacted calcium carbonate and a pharmaceutically or nutraceutically active ingredient, wherein at least a part of the pharmaceutically or nutraceutically active ingredient is present within the pores of the surface-reacted calcium carbonate. The inventive fibers may be used e.g. in yarns, transdermal patches, intrabuccal patches, implantable textiles, wound dressings and/or medical tapes.

Description

[0001] The present invention relates to an electrospun fiber, a process for preparing the same, a nonwoven fabric comprising the electrospun fiber, as well as corresponding uses and articles.

[0002] Electrospinning is a technique for producing fibers from polymeric solutions, suspensions or melts, which involves emitting a stream of said solution, suspension or melt from a charged spinneret, such as a needle, under the influence of an electrostatic force induced by a sufficiently high voltage. If the molecular cohesion of the polymers in the stream is sufficiently high, the stream does not break up into droplets, but is transformed into a stable jet which travels to the oppositely charged ground collector, is at least partially dried during travel, and accumulates on said collector. The fibers obtained in an electrospinning process typically are considerably smaller in fiber diameter compared to those obtained by conventional polymer fiber production processes, such as melt spinning.

[0003] Therefore, electrospun fibers and (nonwoven) fabrics formed therefrom have attracted great interest in a variety of applications, such as filtration, textile manufacturing, medical applications, composite materials, catalysis, and others. Especially with regard to medical applications, the interconnected pore-structure and fiber diameter of electrospun fiber materials make them suitable inter alia as wound dressings, implants and drug delivery systems. However, active ingredients must be compatible with the solvent (and, most importantly, soluble), the polymer, and the conditions of the electrospinning process (for example, the temperature). Therefore, drug delivery applications typically are limited to specific active ingredients and the components required in the electrospinning process cannot be freely selected.

[0004] The incorporation of certain inorganic particles into specific fibers is described in the art. For example, Almuhamed et al. (European Polymer Journal 2014, 54, 71-78) report on the incorporation of mesoporous SBA-15 rods, having a size of about 0.9-1.0 µm × 0.18 µm, into polyacrylonitrile electrospun fibers. Fujihara et al. (Biomaterials 2005, 26, 4139-4147) obtained electrospun fibers of polycaprolactone comprising nanoparticulate cubic calcium carbonate for guided bone regeneration. X. Yang et al. (Regenerative Biomaterials 2018, 229) incorporated silica nanoparticles into poly(lactic-co-glycolic acid) electrospun fibers as a bone tissue engineering scaffold. A. Guo et al. (Materials Letters 2013, 95, 74-77) disclose an electrospun fiber comprising silica nanoparticles, tetraethylorthosilicate and poly(vinyl pyrrolidone). US20140242186 A1 relates to a guided bone regeneration material formed from electrospun fibers of poly(lactic acid) and vaterite particles.

[0005] However, the resulting fibers with the particles being contained in the fibers do not provide a pore structure and/or capacity specifically tailored or being suitable for loading active ingredients. In particular, the employed inorganic particles are typically located within the polymeric fiber due to their small size, which renders the particles not or less accessible. Electrospun fibers of the prior art typically do not provide a porous structure or intra-particle pores with, e.g., pores having an equivalent Laplace throat diameter of 0.3 µm or below. Consequently, for drug delivery applications, the amount of active ingredient that could be introduced into such fibers or that is released from the fibers is very limited.

[0006] It is therefore one object of the present invention to provide an electrospun fiber that has an improved pore structure, which is specifically designed for hosting and releasing a multitude of different active agents, preferably fibers, which host high amounts of inorganic particles and active ingredients.

[0007] This and other objects are solved by the subject-matter of the appended claims.

[0008] According to a first aspect of the present invention, an electrospun fiber is provided, which comprises a polymer, a surface-reacted calcium carbonate and a pharmaceutically or nutraceutically active ingredient,

wherein the surface-reacted calcium carbonate is a reaction product of natural ground or precipitated calcium carbonate with carbon dioxide and one or more H₃O⁺ ion donors in an aqueous medium, wherein the carbon dioxide is formed in situ by the H₃O⁺ ion donor treatment and/or is supplied from an external source, and

wherein at least a part of the pharmaceutically or nutraceutically active ingredient is present within the pores of the surface-reacted calcium carbonate.

[0009] The present inventors surprisingly found that relatively large surface-reacted calcium carbonate particles can be incorporated into an electrospun fiber in high amounts. More precisely, the particle size of such surface-reacted calcium carbonate is typically larger than the fiber diameter of an electrospun fiber not containing inorganic particles, such that the surface-reacted calcium carbonate protrudes, or "sticks out", from the fiber surface, which renders at least a part of its pores accessible. That is, the pore openings either are not covered by the polymer, or are only covered with a very thin layer of polymer that is removed before or during the intended application. The inventive fibers, however, are nevertheless stable and can be processed into different products. Because surface-reacted calcium carbonate is a highly porous material, the corresponding electrospun fiber also has a large portion of pores, especially pores with an equivalent Laplace throat diameter of 0.3 µm or below. The pores of the surface-reacted calcium carbonate can be loaded with high amounts of active ingredients that remain within the pores during the electrospinning process, such that the final electrospun fiber also contains high amounts of active ingredients. Additionally, the active ingredient does not need to be soluble in the solvent used for electrospinning, such that virtually any active ingredient can be incorporated into the inventive electrospun fiber. The invention, therefore, also allows for the incorporation of sensitive pharmaceutically or nutraceutically active ingredients, e.g., proteins or enzymes, which reside in the pores and are protected at least to some extent from the solvent. The active ingredient then can be released from the electrospun fiber in a sustained-release or triggered-release manner as described herein.

[0010] A second aspect of the present invention relates to a process for the preparation of a fiber, comprising the steps of

a) providing a polymer,

b) providing a surface-reacted calcium carbonate,
wherein the surface-reacted calcium carbonate is a reaction product of natural ground or precipitated calcium carbonate with carbon dioxide and one or more H₃O⁺ ion donors in an aqueous medium, wherein the carbon dioxide is formed in situ by the H₃O⁺ ion donor treatment and/or is supplied from an external source,

c) providing a pharmaceutically or nutraceutically active ingredient,

d) loading the pharmaceutically or nutraceutically active ingredient of step c) onto the surface-reacted calcium carbonate of step b) to obtain a loaded surface-reacted calcium carbonate,

e) mixing the polymer of step a) with the loaded surface-reacted calcium carbonate of step d) to obtain a mixture,

f) electrospinning the mixture of step e) into an electrospun fiber.

[0011] The inventive process allows for the production of the inventive electrospun fiber and is compatible with a wide range of polymers, solvents, and electrospinning conditions.

[0012] A third aspect of the present invention relates to a nonwoven fabric comprising, preferably consisting essentially of, the inventive electrospun fiber. Preferably, the nonwoven fabric has

• an occlusion specific pore volume in the range from 0.8 to 6.0 cm³/g, preferably from 1.0 to 5.0 cm³/g, determined by mercury porosimetry measurement, and/or
• a mode average inter-fiber pore diameter in the range from 10 to 100 µm, preferably in the range from 10 to 50 µm, determined by mercury porosimetry measurement, and/or
• a BET specific surface area in the range from 1 to 100 m²/g, as measured by the BET method according to ISO 9277:2010.

[0013] In a fourth aspect, the present invention concerns the use of an electrospun fiber material containing a polymer, a surface-reacted calcium carbonate and a pharmaceutically or nutraceutically active ingredient for drug delivery,

wherein the surface-reacted calcium carbonate is a reaction product of natural ground or precipitated calcium carbonate with carbon dioxide and one or more H₃O⁺ ion donors in an aqueous medium, wherein the carbon dioxide is formed in situ by the H₃O⁺ ion donor treatment and/or is supplied from an external source,

wherein at least a part of the pharmaceutically or nutraceutically active ingredient is present in the pores of the surface-reacted calcium carbonate.

[0014] A fifth aspect of the present invention concerns an article comprising the inventive electrospun fiber, or the inventive nonwoven fabric, wherein the article preferably is selected from the group consisting of yarns, transdermal patches, intrabuccal patches, implantable textiles, wound dressings and medical tapes.

[0015] A sixth aspect of the present invention relates to the use of an inventive article in drug delivery applications.

[0016] Advantageous embodiments of the present invention are defined in the corresponding dependent claims.

[0017] In a preferred embodiment of the present invention, the surface-reacted calcium carbonate has

i) an intra-particle intruded specific pore volume in the range from 0.1 to 3.0 cm³/g, more preferably from 0.1 to 2.3 cm³/g, still more preferably from 0.2 to 2.0 cm³/g and most preferably from 0.4 to 1.8 cm³/g, determined by mercury porosimetry measurement, and/or

ii) a specific surface area (BET) from 15 to 200 m²/g, preferably of from 27 to 180 m²/g, more preferably from 30 to 160 m²/g, and most preferably from 45 to 150 m²/g, as measured by the BET method according to ISO 9277:2010.

[0018] In another preferred embodiment of the present invention, the surface-reacted calcium carbonate has

i) a volume median particle size (d₅₀) from 1 to 75 µm, preferably from 2 to 50 µm, more preferably from 3 to 40 µm, and most preferably from 4 to 30 µm, and/or

ii) a top cut (d₉₈) value from 2 to 150 µm, preferably from 4 to 100 µm, more preferably from 6 to 80 µm, and most preferably from 8 to 60 µm.

[0019] In yet another preferred embodiment of the present invention, the electrospun fiber has

• an intra-particle intruded specific pore volume in the range from 0.05 to 0.5 cm³/g, preferably in the range from 0.1 to 0.3 cm³/g, determined by mercury porosimetry measurement, and/or
• an inter-particle/inter-fiber specific pore volume in the range from 1.0 to 4.0, cm³/g, preferably from 1.5 to 3.5 cm³/g, determined by mercury porosimetry measurement, and/or
• an average fiber diameter of less than 2 µm, preferably in the range from 1 nm to 1.5 µm, more preferably in the range from 10 nm to 1.0 µm, and/or
• a titer of below 0.5 dtex, preferably in the range from 0.0001 to 0.4 dtex, more preferably in the range from 0.001 to 0.1 dtex.

[0020] In a preferred embodiment of the present invention, the electrospun fiber comprises the surface-reacted calcium carbonate in an amount from 5 to 80 wt.-%, preferably from 30 to 70 wt.-%, more preferably from 40 to 60 wt.-%, based on the total weight of the fiber, and/or the fiber comprises the pharmaceutically or nutraceutically active ingredient in an amount from 0.1 to 30 wt.-%, preferably from 1 to 25 wt.-%, more preferably from 3 to 20 wt.-% and most preferably from 5 to 20 wt.-%, based on the total weight of the fiber.

[0021] In still another preferred embodiment of the present invention, the polymer is selected from the group consisting of polyesters, polypeptides, polyethers, poly(meth)acrylates, polysaccharides and derivatives thereof, polyurethanes, polyimides, polyamides, poly(acrylonitrile), poly(vinyl pyrrolidone), poly(vinyl alcohol), polyaniline, poly(vinylidene fluoride), aryl polysulfones, and mixtures and co-polymers of the foregoing.

[0022] In yet another preferred embodiment of the present invention, the volume median particle size d₅₀ is at least 5 % greater than the average fiber diameter, preferably at least 10 % greater than the fiber diameter, more preferably at least 20 % greater than the average fiber diameter, wherein the average fiber diameter is determined via scanning electron microscopy (SEM) at a fiber section not comprising a visible surface-reacted calcium carbonate particle.

[0023] In a preferred embodiment of the process of the present invention,

• in mixing step e) the polymer and the loaded surface-reacted calcium carbonate are mixed with a solvent such that the polymer is essentially completely dissolved in the solvent to obtain the mixture; and
• electrospinning step f) is a suspension electrospinning step comprising the sub-steps of

  f1) feeding the mixture to a spinneret,

  f2) applying an electrostatic potential on the spinneret and a collector to form the filament fiber,

  f3) collecting the filament fiber at the collector, preferably in order to form a nonwoven fabric,

wherein the electrospinning step preferably is performed at a temperature in the range from 0 °C to 50 °C.

[0024] Preferably, in such process, the solvent

• is selected from the group consisting of ketones, such as acetone and butanone, alcohols, such as methanol, ethanol, 1-propanol and 2-propanol, fluorinated solvents, such as 2,2,2-trifluoroethanol, hexafluoroacetone and hexafluoroisopropanol, water, dimethylformamide, dimethylsulfoxide, tetrahydrofuran, chlorinated solvents, such as chloroform and ethylene dichloride, acetic acid, formic acid and mixtures thereof, and/or
• further comprises an electrolyte, preferably selected from the group consisting of alkali metal halides, such as sodium chloride and potassium chloride, alkaline earth metal halides, such as magnesium chloride and magnesium bromide, pyridinium formate, cationic surfactants, such as dodecyltrimethylammonium bromide, tetrabutyl ammonium chloride and tetrabutyl ammonium bromide, and mixtures thereof.
  In another preferred embodiment of the process of the present invention, the mixture of step e) comprises
• the polymer in an amount of from 1 to 60 wt.-%, preferably in an amount from 2 to 40 wt-%, based on the total weight of the mixture, and/or
• the surface-reacted calcium carbonate and/or the loaded surface-reacted calcium carbonate in a total amount from 1 to 25 wt.-%, preferably 2 to 20 wt.-%, more preferably 5 to 15 wt.-%, based on the total weight of the mixture, and/or
• the pharmaceutically or nutraceutically active ingredient in an amount from 0.1 to 10 wt.-%, preferably from 0.5 to 8 wt.-%, and more preferably from 1 to 5 wt.-%, based on the total weight of the mixture, and/or
• optionally the electrolyte in an amount from 0.1 to 10 wt.-%, preferably from 0.5 to 5 wt.-%, based on the total weight of the mixture.

[0025] In yet another preferred embodiment of the process of the present invention, the mixture of step e) has

• a Brookfield viscosity in the range from 100 to 1 000 000 mPas, and/or
• a conductivity in the range from 0.001 µS/m to 10 S/m,

[0026] In still another preferred embodiment of the process of the present invention, the electrostatic potential applied in step f2) is from 1 to 100 kV, preferably from 2 to 75 kV, more preferably from 5 to 50 kV, and most preferably from 10 to 20 kV.

[0027] In a preferred embodiment of the present invention, the inventive electrospun fiber is obtained by the inventive process.

Brief description of the Figures

[0028] 

Figure 1 shows the cumulative release of fluorescein from the electrospun fibers of Example 1 upon triggering release by pH change.

Figure 2 shows the pore size distribution of electrospun fibers of Example 1 with different amounts of fluorescein-loaded SRCC.

Figure 3 shows the electrospinning setup used in the present invention. The photograph a) shows the bottom to top spray setup with laterally oscillating emitter and rotating collector. Drawing b) shows a partial crosscut through the emitters equipped with gas-jackets. Solvent vapor surrounds the needle tips to reduce clogging and beard formation.

Figure 4 shows the schematic of the dissolution setup used in Example 2. Legend: USP 1 dissolution basket (a), electrospun sample (b), parafilm (c), USP 1 dissolution vessel (d).

Figure 5 shows the results of the release of acyclovir from the electrospun PCL fibers of Example 2. Values are normalized to max. achieved concentration during dissolution testing. Values are averages from triplicates with indicated standard deviation (n=3±StDev). Legend: triangles (▲) - Sample S10, squares (▪) - Sample S11, crosses (x) - Sample S12.

Figure 6 is a detailed representation of the first 8 hours of the release results of Figure 5. Legend: triangles (▲) - Sample S10, squares (▪) - Sample S11, crosses (x) - Sample S12.

Figure 7 shows the pore size distribution of samples with and without SRCC particles (thick line - sample S1, dashed-dotted line - sample S7, dashed line - sample S8, thin line - sample S9 dotted line - sample S12).

Figure 8 shows the fine pore size distribution of Lidocaine loaded fibers with increasing SRCC content (dotted line - sample S5, continuous line - sample S6, dashed-dotted line - Sample S7).

Figure 9 shows SEM images of samples S12 (top) and S7 (bottom) at different magnifications.

Figure 10 shows SEM images of Sample S1 at different magnifications.

[0029] It should be understood that, for the purposes of the present invention, the following terms have the following meanings.

[0030] An "electrospun fiber" refers to a fiber obtained by an electrospinning process, which is a process that involves fiber formation by expelling a polymeric solution, suspension or melt from a spinneret under the influence of an electric force. Such process is known to the skilled person and described, e.g., by W.E. Teo et al. (Nanotechnology 2006, 17, R89-R106), B. Bera (Imperial Journal of Interdisciplinary Research 2016, 2, 972-984) and Q.P. Pham et al. (Tissue Engineering 2006, 12, 1197-1211) and references cited therein. An electrospun fiber can be readily distinguished from other types of polymeric fibers by their relatively small fiber diameter and, for the fibers of the present invention, by the protrusion, or 'sticking out', of the inorganic SRCC particles, whose pores remain accessible and are not completely obstructed by the polymer constituting the fiber.

[0031] An "active ingredient" in the meaning of the present document is understood to be a chemical compound which causes a specific activity when applied to a target organism (e.g., human body, animal body or plant). The term active ingredient as used herein thus includes both active forms and inactive precursors (e.g., prodrugs).

[0032] An "inactive precursor" of the active ingredient is understood to be a chemical compound, which is transformed into or releases an active ingredient by means of an activation step, e.g., upon exposure to a chemical stimulus, e.g., an acid, a base or an enzyme, in particular during metabolization, upon exposure to infrared radiation, visible light, ultraviolet light, X-ray or microwave radiation, or upon exposure to elevated temperature.

[0033] A "pharmaceutically active ingredient" in the meaning of the present invention refers to a pharmaceutically active ingredient of synthetic origin, semi-synthetic origin, and/or natural origin as well as a prodrug thereof. The activation of such prodrugs is known to the skilled person and commonly includes, e.g. activation in the stomach and/or gastro-intestinal pathway such as acidic activation or tryptic- or chimotryptic cleavage. It lies within the understanding of the skilled person that the mentioned activation methods are of mere illustrative character and are not intended to be of limiting character.

[0034] For the purposes of the present invention, the term "prodrug" refers to an inactive precursor of a pharmaceutically active ingredient, i.e., a pharmaceutically inactive precursor, which is transformed into a pharmaceutically active ingredient after administration, preferably by metabolization.

[0035] A "nutraceutically active ingredient" in the meaning of the present invention refers to a nutraceutically active ingredient of synthetic origin, semi-synthetic origin, and/or natural origin as well as an inactive precursor thereof.

[0036] A "surface-reacted calcium carbonate" (SRCC) according to the present invention is a reaction product of ground natural calcium carbonate (GNCC) or precipitated calcium carbonate (PCC) treated with carbon dioxide and one or more H₃O⁺ ion donors, wherein the carbon dioxide is formed in situ by the H₃O⁺ ion donors treatment. An H₃O⁺ ion donor in the context of the present invention is a Brønsted acid and/or an acid salt.

[0037] The "particle size" of surface-reacted calcium carbonate herein, if not explicitly stated otherwise, is described as volume-based particle size distribution d_x(vol), or d_x. Therein, the value d_x(vol) represents the diameter relative to which x % by volume of the particles have diameters less than d_x(vol). This means that, for example, the d₂₀(vol) value is the particle size at which 20 vol.% of all particles are smaller than that particle size. The d₅₀(vol) value is thus the volume median particle size, also referred to as average particle size, i.e. 50 vol.% of all particles are smaller than that particle size and the d₉₈(vol) value, referred to as volume-based top cut particle size, is the particle size at which 98 vol.% of all particles are smaller than that particle size. If a particle size is given herein as weight-based particle size, then, e.g., the d₂₀(wt) value is the particle size at which 20 wt.-% of all particles are smaller than that particle size. The d₅₀(wt) value is thus the volume median particle size, also referred to as weight median particle size, i.e. 50 wt.-% of all particles are smaller than that particle size and the dsa(wt) value, referred to as weight-based top cut particle size, is the particle size at which 98 wt.-% of all particles are smaller than that particle size. The term "grain diameter" is used synonymously with the term "particle size".

[0038] The "porosity" or "pore volume", when used in connection with the surface-reacted calcium carbonate, refers to the intra particle intruded specific pore volume. The term "porosity" or "pore volume", when used in connection with the electrospun fiber or the nonwoven fabric formed therefrom, refers to the intra-particle intruded specific pore volume and the inter-particle/inter-fiber specific pore volume.

[0039] In the context of the present invention, the term "pore" is to be understood as describing the space that is found between and/or within particles, i.e. that is formed by the particles as they pack together under nearest neighbour contact (interparticle pores), such as in a powder, a compact or a coating layer, and/or the void space within porous particles (intraparticle pores), and that allows the passage of liquids under pressure when saturated by the liquid and/or supports absorption of surface wetting liquids.

[0040] Throughout the present document, the term "specific surface area" (in m²/g), which is used to define functionalized calcium carbonate or other materials, refers to the specific surface area as determined by using the BET method (using nitrogen as adsorbing gas), according to ISO 9277:2010.

[0041] For the purposes of the present invention, the term "fiber diameter" or "fiber thickness" refers to the thickness of a single fiber orthogonal to the fiber direction, as determined by microscopy, or by calculation using the following equation (i), according to Hans J. Koslowski, Dictionary of Man-Made fibers, 2nd Edition, 2010, Deutscher Fachverlag, page 279.

[0042] The average fiber diameter may also be determined by scanning electron microscopy (SEM), wherein 30 fibers are randomly chosen and measured using imaging software.

[0043] For the purposes of the present invention, the "titer" of a fiber is a measure of the linear mass density, wherein the linear mass density is given by the density of the polymer and by the density and concentration of each filler, including the surface-reacted calcium carbonate, in the fiber. The titer represents an average value of the mass of a single fiber strand per unit of length of the single fiber strand. The unit dtex (decitex) is given in grams per 10 000 meters of fiber. The fiber titer can be determined according to EN ISO 2062:2009. Alternatively, the fiber titer can be calculated according to the following equation (ii).

wherein d - average fiber diameter; and ρ - fiber density.

[0044] Where an indefinite or definite article is used when referring to a singular noun, e.g., "a", "an" or "the", this includes a plural of that noun unless anything else is specifically stated.

[0045] Where the term "comprising" is used in the present description and claims, it does not exclude other elements. For the purposes of the present invention, the term "consisting of" is considered to be a preferred embodiment of the term "comprising". If hereinafter a group is defined to comprise at least a certain number of embodiments, this is also to be understood to disclose a group, which preferably consists only of these embodiments.

[0046] Whenever the terms "including" or "having" are used, these terms are meant to be equivalent to "comprising" as defined hereinabove.

[0047] Terms like "obtainable" or "definable" and "obtained" or "defined" are used interchangeably. This, for example, means that, unless the context clearly dictates otherwise, the term "obtained" does not mean to indicate that, for example, an embodiment must be obtained by, for example, the sequence of steps following the term "obtained" though such a limited understanding is always included by the terms "obtained" or "defined" as a preferred embodiment.

[0048] When in the following reference is made to embodiments or technical details of the inventive electrospun fiber, it is to be understood that these embodiments or technical details also refer to the inventive process for obtaining the electrospun fiber, the inventive nonwoven fabric, the inventive use of an electrospun fiber material, the inventive article and the inventive use of the article.

The Polymer

[0049] All aspects of the present invention involve the use of a polymer.

[0050] The present invention is not limited to any specific types of polymers, as long as the polymer can be dissolved in an appropriate solvent or molten and the corresponding solution or melt has a suitable viscosity so that it can be transformed into fibers via electrospinning. The required conditions for obtaining corresponding fibers are addressed in detail hereinbelow and can be adjusted by routine experimentation.

[0051] The polymer may be composed of one type of homo- or copolymer or may be a blend of two or more homo- or copolymers.

[0052] The polymer may be selected from hydrocarbon polymers, i.e., polymers being composed essentially of carbon and hydrogen atoms, e.g., comprising more than 95 mol-% of carbon and hydrogen atoms. Examples include polyolefins and polystyrene.

[0053] For example, the polyolefin can be polyethylene and/or polypropylene and/or polybutylene homopolymers or copolymers. Accordingly, if the polyolefin is polyethylene, the polyolefin is selected from the group comprising homopolymers and/or copolymers of polyethylene like high-density polyethylene (HDPE), medium-density polyethylene (MDPE), low-density polyethylene (LDPE), very low-density polyethylene (VLDPE), linear low-density polyethylene (LLDPE) and ultra-high molecular weight polyethylene (UHMWPE).

[0054] In case the polymer comprises a copolymer of polyethylene, the polyethylene preferably contains units derivable from ethylene as major components. The copolymer of polyethylene preferably comprises, preferably consists of, units derived from ethylene and C2 and/or at least one C4 to C10 α-olefin. In one embodiment of the present invention, the copolymer of polyethylene comprises, preferably consists of, units derived from ethylene and at least one α-olefin selected from the group consisting of propylene, 1-butene, 1-pentene, 1-hexene and 1-octene.

[0055] In case the polymer comprises a copolymer of polypropylene, the polypropylene preferably contains units derivable from propylene as major components. The copolymer of polypropylene preferably comprises, preferably consists of, units derived from propylene and C2 and/or at least one C4 to C10 α-olefin. In one embodiment of the present invention, the copolymer of polypropylene comprises, preferably consists of, units derived from propylene and at least one α-olefin selected from the group consisting of ethylene, 1-butene, 1-pentene, 1-hexene and 1-octene.

[0056] If hydrocarbon polymers are employed as the polymer, it is preferred to prepare the electrospun fiber using melt electrospinning.

[0057] Alternatively, the polymer may be a halogen-containing polymer, i.e. hydrocarbon polymers additionally comprising chlorine, bromine, fluorine and iodine moieties. The halogen-containing polymer preferably is selected from polyvinylchloride (PVC), polyvinylidene chloride (PVDC), polyvinylidene fluoride (PVDF) and polytetrafluoroethylene (PTFE).

[0058] In a preferred embodiment, the polymer is selected from the group consisting of polyesters, polypeptides, polyethers, poly(meth)acrylates, polysaccharides and derivatives thereof, polyurethanes, polyimides, polyamides, polyethylene imine), poly(acrylonitrile), poly(vinyl pyrrolidone), poly(vinyl alcohol), polyaniline, poly(vinylidene fluoride), aryl polysulfones, and mixtures and co-polymers of the foregoing.

[0059] The polyesters may be selected from aromatic polyesters, such as polyethylene terephthalate), aliphatic polyesters, such as polylactones, and/or biodegradable polyesters, such as poly(lactic acid). In a preferred embodiment, the polyesters are selected from the group consisting of polyethylene terephthalate), polyethylene naphthalate), poly(trimethylene terephthalate), poly(butylene terephthalate), poly(lactic acid), poly-(L-lactide), poly(glycolic acid), poly-ε-caprolactone, poly(3-hydroxy butyrate-co-3-hydroxyvalerate), and mixtures thereof.

[0060] The polyethers may be selected from polyalkylene glycols, preferably polyethylene glycols. The term polyethylene oxide is considered synonymous to polyethylene glycol.

[0061] The poly(meth)acrylates may be selected from the group consisting of poly(alkyl acrylates), poly(alkyl methacrylates), poly(methyl acrylate), poly(ethyl acrylate), poly(methyl methacrylate), poly(ethyl methacrylate), copolymers thereof, and copolymers of the foregoing with acrylic acid and/or methacrylic acid and/or salts thereof.

[0062] The polypeptides may be selected from the group consisting of fibroin, collagen, soy proteins, bovine serum albumine (BSA), elastin, and mixtures thereof.

[0063] The polysaccharides and derivatives thereof may be selected from the group consisting of starch, cellulose, alkyl celluloses, such as methyl and ethyl cellulose, hydroxyalkyl celluloses, such as hydroxypropyl methyl cellulose and hydroxyethyl cellulose, gelatin, chitosan, carboxyethyl chitosan, cellulose acetate, alginates, crosslinked polysaccharides, and mixtures thereof. In the case of crosslinked polysaccharides, the polysaccharides preferably are crosslinked after the fiber has been electrospun, e.g., by immersing the electrospun fiber in a solution containing a crosslinking agent, such as epichlorohydrin, aldehydes, or multivalent metal cations, such as aluminum, calcium or zirconium cations.

[0064] The polyimides may be selected from the group consisting of poly(succinimide) (PSI), poly(bismaleic imide) (PBMI), poly(imidosulfone) (PISO), poly(methacrylimide) (PMI), and mixtures thereof.

[0065] The polyamides may be selected from the group consisting of aliphatic polyamides, polyphthalamides, aramids, and mixtures thereof, preferably polyamide-6, polyamide-6,6, poly-N-isopropylacrylamide and mixtures thereof.

[0066] The aryl polysulfones may be selected from the group consisting of poly(phenylene sulfone), poly(arylene sulfone) (PAS), poly(bisphenol-A sulfone) (PSF), polyether sulfone (PES), polyphenylenesulfone (PPSU), poly(oxy-1,4-phenylenesulfonyl-1,4-phenylene), and mixtures thereof.

[0067] The copolymers may be selected from the group consisting of polyethylene terephthalate)-co-poly(ethylene imine), poly(dioxanone-co-L-lactide)-block-poly(ethylene glycol), poly(ethylene-co-vinyl alcohol) and mixtures thereof.

[0068] In a preferred embodiment, the polymer is biocompatible. Non-limiting examples of such biocompatible polymers include, e.g., poly(glycolic acid), poly(lactic acid), poly(ε-caprolactone), poly(lactic-co-glycolic acid), poly(N-isopropylacrylamide), chitin, chitosan, alginate, collagen, gelatin, cellulose, poly(vinyl alcohol), polyethylene glycol), albumen, poly(glycerol-co-sebacate), and poly(dimethylsiloxane).

[0069] There are no particular limitations regarding the molecular weight of the polymer, as long as the solution or melt has a suitable viscosity so that it can be transformed into fibers via electrospinning. In a preferred embodiment, the weight-average molecular weight of the polymer is in a range from 1500 g/mol to 1 000 000 g/mol. A higher molecular weight allows for obtaining electrospun fibers at a lower polymer concentration, which is preferred, because the relative amount of the surface-reacted calcium carbonate in the fibers can be increased. Therefore, in a particularly preferred embodiment, the polymer has a weight-average molecular weight in the range from 25 000 to 850 000 g/mol, even more preferably from 50 000 to 750 000 g/mol. At a lower molecular weight, the obtained electrospun fibers may be smaller in diameter.

The Surface-Reacted Calcium Carbonate (SRCC)

[0070] All aspects of the present invention involve the use of a surface-reacted calcium carbonate.

[0071] The surface-reacted calcium carbonate is a reaction product of natural ground calcium carbonate or precipitated calcium carbonate with carbon dioxide and one or more H₃O⁺ ion donors, wherein the carbon dioxide is formed in situ by the H₃O⁺ ion donors treatment and/or is supplied from an external source.

[0072] A H₃O⁺ ion donor in the context of the present invention is a Brønsted acid and/or an acid salt.

[0073] In a preferred embodiment of the invention the surface-reacted calcium carbonate is obtained by a process comprising the steps of: (a) providing a suspension of natural or precipitated calcium carbonate, (b) adding at least one acid having a pK_a value of 0 or less at 20°C or having a pK_a value from 0 to 2.5 at 20°C to the suspension of step (a), and (c) treating the suspension of step (a) with carbon dioxide before, during or after step (b). According to another embodiment the surface-reacted calcium carbonate is obtained by a process comprising the steps of: (A) providing a natural or precipitated calcium carbonate, (B) providing at least one water-soluble acid, (C) providing gaseous CO₂, (D) contacting said natural or precipitated calcium carbonate of step (A) with the at least one acid of step (B) and with the CO₂ of step (C), characterised in that: (i) the at least one acid of step B) has a pK_a of greater than 2.5 and less than or equal to 7 at 20°C, associated with the ionisation of its first available hydrogen, and a corresponding anion is formed on loss of this first available hydrogen capable of forming a water-soluble calcium salt, and (ii) following contacting the at least one acid with natural or precipitated calcium carbonate, at least one water-soluble salt, which in the case of a hydrogen-containing salt has a pK_a of greater than 7 at 20°C, associated with the ionisation of the first available hydrogen, and the salt anion of which is capable of forming water-insoluble calcium salts, is additionally provided.

[0074] "Natural ground calcium carbonate" (GCC) preferably is selected from calcium carbonate containing minerals selected from the group comprising marble, chalk, limestone and mixtures thereof. Natural calcium carbonate may comprise further naturally occurring components such as alumino silicate etc.

[0075] In general, the grinding of natural ground calcium carbonate may be a dry or wet grinding step and may be carried out with any conventional grinding device, for example, under conditions such that comminution predominantly results from impacts with a secondary body, i.e. in one or more of: a ball mill, a rod mill, a vibrating mill, a roll crusher, a centrifugal impact mill, a vertical bead mill, an attrition mill, a pin mill, a hammer mill, a pulveriser, a shredder, a de-clumper, a knife cutter, or other such equipment known to the skilled man. In case the calcium carbonate containing mineral material comprises a wet ground calcium carbonate containing mineral material, the grinding step may be performed under conditions such that autogenous grinding takes place and/or by horizontal ball milling, and/or other such processes known to the skilled man. The wet processed ground calcium carbonate containing mineral material thus obtained may be washed and dewatered by well-known processes, e.g. by flocculation, filtration or forced evaporation prior to drying. The subsequent step of drying (if necessary) may be carried out in a single step such as spray drying, or in at least two steps. It is also common that such a mineral material undergoes a beneficiation step (such as a flotation, bleaching or magnetic separation step) to remove impurities.

[0076] "Precipitated calcium carbonate" (PCC) in the meaning of the present invention is a synthesized material, generally obtained by precipitation following reaction of carbon dioxide and calcium hydroxide in an aqueous environment or by precipitation of calcium and carbonate ions, for example CaCl₂ and Na₂CO₃, out of solution. Further possible ways of producing PCC are the lime soda process, or the Solvay process in which PCC is a by-product of ammonia production. Precipitated calcium carbonate exists in three primary crystalline forms: calcite, aragonite and vaterite, and there are many different polymorphs (crystal habits) for each of these crystalline forms. Calcite has a trigonal structure with typical crystal habits such as scalenohedral (S-PCC), rhombohedral (R-PCC), hexagonal prismatic, pinacoidal, colloidal (C-PCC), cubic, and prismatic (P-PCC). Aragonite is an orthorhombic structure with typical crystal habits of twinned hexagonal prismatic crystals, as well as a diverse assortment of thin elongated prismatic, curved bladed, steep pyramidal, chisel shaped crystals, branching tree, and coral or worm-like form. Vaterite belongs to the hexagonal crystal system. The obtained PCC slurry can be mechanically dewatered and dried.

[0077] According to one embodiment of the present invention, the precipitated calcium carbonate is precipitated calcium carbonate, preferably comprising aragonitic, vateritic or calcitic mineralogical crystal forms or mixtures thereof.

[0078] Precipitated calcium carbonate may be ground prior to the treatment with carbon dioxide and at least one H₃O⁺ ion donor by the same means as used for grinding natural calcium carbonate as described above.

[0079] According to one embodiment of the present invention, the natural or precipitated calcium carbonate is in form of particles having a weight median particle size d₅₀ of 0.05 to 10.0 µm, preferably 0.2 to 5.0 µm, more preferably 0.4 to 3.0 µm, most preferably 0.6 to 1.2 µm, especially 0.7 µm. According to a further embodiment of the present invention, the natural or precipitated calcium carbonate is in form of particles having a top cut particle size d₉₈ of 0.15 to 55 µm, preferably 1 to 40 µm, more preferably 2 to 25 µm, most preferably 3 to 15 µm, especially 4 µm.

[0080] The natural and/or precipitated calcium carbonate may be used dry or suspended in water. Preferably, a corresponding slurry has a content of natural or precipitated calcium carbonate within the range of 1 wt.-% to 90 wt.-%, more preferably 3 wt.-% to 60 wt.-%, even more preferably 5 wt.-% to 40 wt.-%, and most preferably 10 wt.-% to 25 wt.-% based on the weight of the slurry.

[0081] The one or more H₃O⁺ ion donor used for the preparation of surface reacted calcium carbonate may be any strong acid, medium-strong acid, or weak acid, or mixtures thereof, generating H₃O⁺ ions under the preparation conditions. According to the present invention, the at least one H₃O⁺ ion donor can also be an acidic salt, generating H₃O⁺ ions under the preparation conditions.

[0082] According to one embodiment, the at least one H₃O⁺ ion donor is a strong acid having a pK_a of 0 or less at 20°C.

[0083] According to another embodiment, the at least one H₃O⁺ ion donor is a medium-strong acid having a pK_a value from 0 to 2.5 at 20°C. If the pK_a at 20°C is 0 or less, the acid is preferably selected from sulphuric acid, hydrochloric acid, or mixtures thereof. If the pK_a at 20°C is from 0 to 2.5, the H₃O⁺ ion donor is preferably selected from H₂SO₃, H₃PO₄, oxalic acid, or mixtures thereof. The at least one H₃O⁺ ion donor can also be an acidic salt, for example, HSO₄ or H₂PO₄^-, being at least partially neutralized by a corresponding cation such as Li⁺, Na⁺ or K⁺, or HPO₄^2-, being at least partially neutralised by a corresponding cation such as Li⁺, Na⁺, K⁺, Mg²⁺ or Ca²⁺. The at least one H₃O⁺ ion donor can also be a mixture of one or more acids and one or more acidic salts.

[0084] According to still another embodiment, the at least one H₃O⁺ ion donor is a weak acid having a pK_a value of greater than 2.5 and less than or equal to 7, when measured at 20°C, associated with the ionisation of the first available hydrogen, and having a corresponding anion, which is capable of forming water-soluble calcium salts. Subsequently, at least one water-soluble salt, which in the case of a hydrogen-containing salt has a pK_a of greater than 7, when measured at 20°C, associated with the ionisation of the first available hydrogen, and the salt anion of which is capable of forming water-insoluble calcium salts, is additionally provided. According to the preferred embodiment, the weak acid has a pK_a value from greater than 2.5 to 5 at 20°C, and more preferably the weak acid is selected from the group consisting of acetic acid, formic acid, propanoic acid, citric acid, and mixtures thereof. Exemplary cations of said water-soluble salt are selected from the group consisting of potassium, sodium, lithium and mixtures thereof. In a more preferred embodiment, said cation is sodium or potassium. Exemplary anions of said water-soluble salt are selected from the group consisting of phosphate, dihydrogen phosphate, monohydrogen phosphate, oxalate, silicate, mixtures thereof and hydrates thereof. In a more preferred embodiment, said anion is selected from the group consisting of phosphate, dihydrogen phosphate, monohydrogen phosphate, mixtures thereof and hydrates thereof. In a most preferred embodiment, said anion is selected from the group consisting of dihydrogen phosphate, monohydrogen phosphate, mixtures thereof and hydrates thereof. Water-soluble salt addition may be performed dropwise or in one step. In the case of drop wise addition, this addition preferably takes place within a time period of 10 minutes. It is more preferred to add said salt in one step.

[0085] According to one embodiment of the present invention, the at least one H₃O⁺ ion donor is selected from the group consisting of hydrochloric acid, sulphuric acid, sulphurous acid, phosphoric acid, citric acid, oxalic acid, acetic acid, formic acid, and mixtures thereof. Preferably the at least one H₃O⁺ ion donor is selected from the group consisting of hydrochloric acid, sulphuric acid, sulphurous acid, phosphoric acid, oxalic acid, H₂PO₄^-; being at least partially neutralised by a corresponding cation such as Li⁺, Na⁺ or K⁺, HPO₄^2-, being at least partially neutralised by a corresponding cation such as Li⁺, Na⁺, K⁺, Mg²⁺, or Ca²⁺ and mixtures thereof, more preferably the at least one acid is selected from the group consisting of hydrochloric acid, sulphuric acid, sulphurous acid, phosphoric acid, oxalic acid, or mixtures thereof, and most preferably, the at least one H₃O⁺ ion donor is phosphoric acid.

[0086] The one or more H₃O⁺ ion donor can be added to the suspension as a concentrated solution or a more diluted solution. Preferably, the molar ratio of the H₃O⁺ ion donor to the natural or precipitated calcium carbonate is from 0.01 to 4, more preferably from 0.02 to 2, even more preferably 0.05 to 1 and most preferably 0.1 to 0.58.

[0087] As an alternative, it is also possible to add the H₃O⁺ ion donor to the water before the natural or precipitated calcium carbonate is suspended.

[0088] In a next step, the natural or precipitated calcium carbonate is treated with carbon dioxide. If a strong acid such as sulphuric acid or hydrochloric acid is used for the H₃O⁺ ion donor treatment of the natural or precipitated calcium carbonate, the carbon dioxide is automatically formed. Alternatively or additionally, the carbon dioxide can be supplied from an external source.

[0089] H₃O⁺ ion donor treatment and treatment with carbon dioxide can be carried out simultaneously which is the case when a strong or medium-strong acid is used. It is also possible to carry out H₃O⁺ ion donor treatment first, e.g. with a medium strong acid having a pK_a in the range of 0 to 2.5 at 20°C, wherein carbon dioxide is formed in situ, and thus, the carbon dioxide treatment will automatically be carried out simultaneously with the H₃O⁺ ion donor treatment, followed by the additional treatment with carbon dioxide supplied from an external source.

[0090] In a preferred embodiment, the H₃O⁺ ion donor treatment step and/or the carbon dioxide treatment step are repeated at least once, more preferably several times. According to one embodiment, the at least one H₃O⁺ ion donor is added over a time period of at least about 5 min, preferably at least about 10 min, typically from about 10 to about 20 min, more preferably about 30 min, even more preferably about 45 min, and sometimes about 1 h or more.

[0091] Subsequent to the H₃O⁺ ion donor treatment and carbon dioxide treatment, the pH of the aqueous suspension, measured at 20°C, naturally reaches a value of greater than 6.0, preferably greater than 6.5, more preferably greater than 7.0, even more preferably greater than 7.5, thereby preparing the surface-reacted natural or precipitated calcium carbonate as an aqueous suspension having a pH of greater than 6.0, preferably greater than 6.5, more preferably greater than 7.0, even more preferably greater than 7.5.

[0092] In a particular preferred embodiment the surface reacted calcium carbonate is a reaction product of natural ground calcium carbonate (GNCC) with carbon dioxide and phosphoric acid, wherein the carbon dioxide is formed in situ by the phosphoric acid treatment.

[0093] Further details about the preparation of the surface-reacted natural calcium carbonate are disclosed in WO 00/39222 A1, WO 2004/083316 A1, WO 2005/121257 A2, WO 2009/074492 A1, EP 2 264 108 A1, EP 2 264 109 A1 and US 2004/0020410 A1, the content of these references herewith being included in the present application.

[0094] Similarly, surface-reacted precipitated calcium carbonate is obtained. As can be taken in detail from WO 2009/074492 A1, surface-reacted precipitated calcium carbonate is obtained by contacting precipitated calcium carbonate with H₃O⁺ ions and with anions being solubilized in an aqueous medium and being capable of forming water-insoluble calcium salts, in an aqueous medium to form a slurry of surface-reacted precipitated calcium carbonate, wherein said surface-reacted precipitated calcium carbonate comprises an insoluble, at least partially crystalline calcium salt of said anion formed on the surface of at least part of the precipitated calcium carbonate.

[0095] Said solubilized calcium ions correspond to an excess of solubilized calcium ions relative to the solubilized calcium ions naturally generated on dissolution of precipitated calcium carbonate by H₃O⁺ ions, where said H₃O⁺ ions are provided solely in the form of a counterion to the anion, i.e. via the addition of the anion in the form of an acid or non-calcium acid salt, and in absence of any further calcium ion or calcium ion generating source.

[0096] Said excess solubilized calcium ions are preferably provided by the addition of a soluble neutral or acid calcium salt, or by the addition of an acid or a neutral or acid non-calcium salt which generates a soluble neutral or acid calcium salt in situ.

[0097] Said H₃O⁺ ions may be provided by the addition of an acid or an acid salt of said anion, or the addition of an acid or an acid salt which simultaneously serves to provide all or part of said excess solubilized calcium ions.

[0098] In a further preferred embodiment of the preparation of the surface-reacted natural or precipitated calcium carbonate, the natural or precipitated calcium carbonate is reacted with the one or more H₃O⁺ ion donors and/or the carbon dioxide in the presence of at least one compound selected from the group consisting of silicate, silica, aluminium hydroxide, earth alkali aluminate such as sodium or potassium aluminate, magnesium oxide, or mixtures thereof. Preferably, the at least one silicate is selected from an aluminium silicate, a calcium silicate, or an earth alkali metal silicate. These components can be added to an aqueous suspension comprising the natural or precipitated calcium carbonate before adding the one or more H₃O⁺ ion donors and/or carbon dioxide.

[0099] Alternatively, the silicate and/or silica and/or aluminium hydroxide and/or earth alkali aluminate and/or magnesium oxide component(s) can be added to the aqueous suspension of natural or precipitated calcium carbonate while the reaction of natural or precipitated calcium carbonate with the one or more H₃O⁺ ion donors and carbon dioxide has already started. Further details about the preparation of the surface-reacted natural or precipitated calcium carbonate in the presence of at least one silicate and/or silica and/or aluminium hydroxide and/or earth alkali aluminate component(s) are disclosed in WO 2004/083316 A1, the content of this reference herewith being included in the present application.

[0100] The surface-reacted calcium carbonate can be kept in suspension, optionally further stabilised by a dispersant. Conventional dispersants known to the skilled person can be used. A preferred dispersant is comprised of polyacrylic acids and/or carboxymethylcelluloses.

[0101] Alternatively, the aqueous suspension described above can be dried, thereby obtaining the solid (i.e. dry or containing as little water that it is not in a fluid form) surface-reacted natural or precipitated calcium carbonate in the form of granules or a powder.

[0102] In a preferred embodiment, the surface-reacted calcium carbonate has a specific surface area of from 15 m²/g to 200 m²/g, preferably from 27 m²/g to 180 m²/g, more preferably from 30 m²/g to 160 m²/g, even more preferably from 45 m²/g to 150 m²/g, most preferably from 48 m²/g to 140 m²/g, measured using nitrogen and the BET method. For example, the surface-reacted calcium carbonate has a specific surface area of from 55 m²/g to 100 m²/g, measured using nitrogen and the BET method. The BET specific surface area in the meaning of the present invention is defined as the total surface area of the particles divided by the mass of the particles. As used therein the specific surface area is measured by adsorption using the BET isotherm (ISO 9277:2010) and is specified in m²/g.

[0103] It is furthermore preferred that the surface-reacted calcium carbonate particles have a volume median grain diameter d₅₀ (vol) of from 1 to 75 µm, preferably from 2 to 50 µm, more preferably 3 to 40 µm, even more preferably from 4 to 30 µm, and most preferably from 5 to 15 µm.

[0104] It may furthermore be preferred that the surface-reacted calcium carbonate particles have a grain diameter d₉₈ (vol) of from 2 to 150 µm, preferably from 4 to 100 µm, more preferably 6 to 80 µm, even more preferably from 8 to 60 µm, and most preferably from 10 to 30 µm.

[0105] The value d_x represents the diameter relative to which x % of the particles have diameters less than d_x. This means that the d₉₈ value is the particle size at which 98 % of all particles are smaller. The d₉₈ value is also designated as "top cut". The d_x values may be given in volume or weight percent. The d₅₀ (wt) value is thus the weight median particle size, i.e. 50 wt.-% of all grains are smaller than this particle size, and the d₅₀ (vol) value is the volume median particle size, i.e. 50 vol.-% of all grains are smaller than this particle size.

[0106] Volume median grain diameter d₅₀ was evaluated using a Malvern Mastersizer 2000 or 3000 Laser Diffraction System. The d₅₀ or d₉₈ value, measured using a Malvern Mastersizer 2000 or 3000 Laser Diffraction System, indicates a diameter value such that 50 % or 98 % by volume, respectively, of the particles have a diameter of less than this value. The raw data obtained by the measurement are analysed using the Mie theory, with a particle refractive index of 1.57 and an absorption index of 0.005.

[0107] The weight median grain diameter is determined by the sedimentation method, which is an analysis of sedimentation behaviour in a gravimetric field. The measurement is made with a Sedigraph^™ 5100 or 5120, Micromeritics Instrument Corporation. The method and the instrument are known to the skilled person and are commonly used to determine grain size of fillers and pigments. The measurement is carried out in an aqueous solution of 0.1 wt.-% Na₄P₂O₇. The samples were dispersed using a high speed stirrer and sonicated.

[0108] The processes and instruments are known to the skilled person and are commonly used to determine grain size of fillers and pigments.

[0109] The specific pore volume is measured using a mercury intrusion porosimetry measurement using a Micromeritics Autopore V 9620 mercury porosimeter having a maximum applied pressure of mercury 414 MPa (60 000 psi), equivalent to a Laplace throat diameter of 0.004 µm (~ nm). The equilibration time used at each pressure step is 20 seconds. The sample material is sealed in a 5 cm³ chamber powder penetrometer for analysis. The data are corrected for mercury compression, penetrometer expansion and sample material compression using the software Pore-Comp (Gane, P.A.C., Kettle, J.P., Matthews, G.P. and Ridgway, C.J., "Void Space Structure of Compressible Polymer Spheres and Consolidated Calcium Carbonate Paper-Coating Formulations", Industrial and Engineering Chemistry Research, 35(5), 1996, 1753-1764.).

[0110] The total pore volume seen in the cumulative intrusion data can be separated into two regions with the intrusion data from 214 µm down to about 1 - 4 µm showing the coarse packing of the sample between any agglomerate structures contributing strongly. Below these diameters lies the fine interparticle packing of the particles themselves. If they also have intraparticle pores, then this region appears bi modal, and by taking the specific pore volume intruded by mercury into pores finer than the modal turning point, i.e. finer than the bi-modal point of inflection, the specific intraparticle pore volume is defined. The sum of these three regions gives the total overall pore volume of the powder, but depends strongly on the original sample compaction/settling of the powder at the coarse pore end of the distribution.

[0111] By taking the first derivative of the cumulative intrusion curve the pore size distributions based on equivalent Laplace diameter, inevitably including pore-shielding, are revealed. The differential curves clearly show the coarse agglomerate pore structure region, the interparticle pore region and the intraparticle pore region, if present. Knowing the intraparticle pore diameter range it is possible to subtract the remainder interparticle and interagglomerate pore volume from the total pore volume to deliver the desired pore volume of the internal pores alone in terms of the pore volume per unit mass (specific pore volume). The same principle of subtraction, of course, applies for isolating any of the other pore size regions of interest.

[0112] Preferably, the surface-reacted calcium carbonate has an intra-particle intruded specific pore volume in the range from 0.1 to 3.0 cm³/g, more preferably from 0.1 to 2.3 cm³/g, still more preferably from 0.2 to 2.0 cm³/g, especially preferably from 0.4 to 1.8 cm³/g and most preferably from 0.6 to 1.6 cm³/g, calculated from mercury porosimetry measurement.

[0113] The intra-particle pore size of the surface-reacted calcium carbonate preferably is in a range of from 0.004 to 1.6 µm, more preferably in a range of from 0.005 to 1.3 µm, especially preferably from 0.006 to 1.15 µm and most preferably of 0.007 to 1.0 µm, e.g. 0.007 to 0.6 µm determined by mercury porosimetry measurement.

[0114] In a preferred embodiment of the present invention, the surface-reacted calcium carbonate further comprises a surface-treatment layer on at least a part of the surface of the surface-reacted calcium carbonate, wherein the surface-treatment layer is formed by contacting the untreated surface-reacted calcium carbonate with a surface-treatment composition comprising at least one surface-treatment agent.

[0115] Preferably, the surface-treatment layer is formed by contacting the surface-reacted calcium carbonate with a surface-treatment composition in an amount from 0.07 to 9 mg / m² of the surface-reacted calcium carbonate surface, preferably 0.1 to 8 mg / m², more preferably 0.11 to 3 mg / m². The surface-treatment composition comprises at least one surface-treatment agent.

[0116] A "surface-treatment agent" in the meaning of the present invention is any material, which is capable of reacting and/or forming an adduct with the surface of surface-reacted calcium carbonate, thereby forming a surface-treatment layer on at least a part of the surface of the surface-reacted calcium carbonate, which preferably renders the carrier surface more hydrophobic. It should be understood that the present invention is not limited to any particular surface-treatment agents. The skilled person knows how to select suitable materials for use as surface-treatment agents.

[0117] The present inventors found that a surface-treatment, which renders the surface of the surface-reacted calcium carbonate more hydrophobic, reduces the interaction of the surface-reacted calcium carbonate with the pharmaceutically or nutraceutically active ingredient loaded thereon, which facilitates liberation of the pharmaceutically or nutraceutically active ingredient during application. However, it is not a requirement that the surface-reacted calcium carbonate is surface-treated prior to the loading of the pharmaceutically or nutraceutically active ingredient.

[0118] In a preferred embodiment, the at least one surface-treatment agent is selected from the group consisting of

a. at least one mono-substituted succinic anhydride and/or mono-substituted succinic acid and/or a salt thereof, preferably wherein the at least one mono-substituted succinic anhydride and/or mono-substituted succinic acid and/or a salt thereof comprises a linear, branched, aliphatic or cyclic group having a total amount of carbon atoms from at least C₂ to C₃₀ in the substituent, and/or

b. at least one carboxylic acid and/or a salt thereof, preferably at least one aliphatic carboxylic acid having a total amount of carbon atoms from C₄ to C₂₄ and/or a salt thereof, more preferably at least one aliphatic carboxylic acid having a total amount of carbon atoms from C₁₂ to C₂₀ and/or a salt thereof, most preferably at least one aliphatic carboxylic acid having a total amount of carbon atoms from C₁₆ to C₁₈ and/or a salt thereof, and/or

c. a phosphoric acid ester blend of one or more phosphoric acid mono-ester and/or salts thereof and/or one or more phosphoric acid di-ester and/or salts thereof, and/or

d. at least one aldehyde, and/or

e. abietic acid and/or salts thereof, and/or

f. at least one polydialkylsiloxane, and/or

g. at least one trialkoxysilane, and/or

h. mixtures of the materials according to a. to g..

[0119] Suitable surface-treatment agents are disclosed in WO2022013339 A1, which is incorporated herein by reference as to the specification of said surface-treatment agents.

The Active Ingredient

[0120] All aspects of the present invention involve the use of an active ingredient, which is a pharmaceutically or nutraceutically active ingredient.

[0121] The present invention is not limited to specific kinds of active ingredients. Virtually any active ingredient can be loaded into the pores of the surface-reacted calcium carbonate and thereby be introduced into the electrospun fiber. Therefore, it is also a requirement of the present invention that at least a part of the pharmaceutically or nutraceutically active ingredient is present within the pores of the surface-reacted calcium carbonate in the electrospun fiber.

[0122] The pharmaceutically or nutraceutically active ingredient may comprise, preferably consist of, only one type of active ingredient or an inactive precursor thereof. Alternatively, the active ingredient may comprise, preferably consist of, a mixture of two or more types of active ingredients or inactive precursors thereof. Furthermore, also mixtures of one or more active ingredients and one or more inactive precursors of the same or different active ingredient may be used in the present invention. When in the following reference is made to an active ingredient, it is to be understood that also inactive precursors of said active ingredient are to be encompassed.

[0123] Preferably, the pharmaceutically or nutraceutically active ingredient is a pharmaceutically active ingredient, a pro-drug or a mixture thereof.

[0124] In one embodiment, the active ingredient is selected from pharmaceutically active ingredients.

[0125] A "pharmaceutically active ingredient" in the meaning of the present invention refers to a pharmaceutically active ingredient of synthetic origin, semi-synthetic origin, and/or natural origin as well as a prodrug thereof. The activation of such prodrugs is known to the skilled person and commonly includes, e.g. activation in the stomach and/or gastro-intestinal pathway such as acidic activation or tryptic- or chimotryptic cleavage. It lies within the understanding of the skilled person that the mentioned activation methods are of mere illustrative character and are not intended to be of limiting character.

[0126] The pharmaceutically active ingredient may be selected from any suitable compound known to the skilled person, and may include any compound that provides prophylactic and/or therapeutic properties when administered to humans and/or animals. Alternatively, the pharmaceutically active ingredient may be selected from compounds exerting an antimicrobial effect when applied onto a surface.

[0127] According to one embodiment, the pharmaceutically active ingredient is an anti-tartar agent. Anti-tartar agents useful herein include phosphates, preferably pyrophosphates, polyphosphates, polyphosphonates, or mixtures thereof. Pyrophosphates are among the best known phosphates for use in dental care products. Pyrophosphate ions delivered to the teeth derive from pyrophosphate salts. The pyrophosphate salts that may be useful in the present invention include dialkali metal pyrophosphate salts, tetra-alkali metal pyrophosphate salts, and mixtures thereof. Disodium dihydrogen pyrophosphate (Na₂H₂P₂O₇), tetrasodium pyrophosphate (Na₄P₂O₇), and tetrapotassium pyrophosphate (K₄P₂O₇) in their non-hydrated as well as hydrated forms may also be preferred. Examples of suitable anticalculus phosphates may include potassium and sodium pyrophosphates, sodium tripolyphosphate, diphosphonates, such as ethane-1-hydroxy-1,1-diphosphonate; 1-azacycloheptane-1,1-diphosphonate, and linear alkyl diphosphonates. Other examples of suitable anti-tartar agents are linear carboxylic acids, sodium citrate, or zinc citrate.

[0128] Agents that may be used in place of or in combination with the above pyrophosphate salt include materials such as synthetic anionic polymers including polyacrylates and copolymers of maleic anhydride or acid and methyl vinyl ether, e.g. Gantrez, as described, for example, in U. S. Patent Number 4,627,977, to Gaffar et al., herein incorporated by reference in its entirety as to the description of such agents, as well as e.g. polyamino propane sulphonic acid (AMPS), zinc citrate trihydrate, polyphosphates, e.g. tripolyphosphate and hexametaphosphate, diphosphonates, e.g. EHDP and AMP, polypeptides, such as polyaspartic and polyglutamic acids, and mixtures thereof.

[0129] In another embodiment, the pharmaceutically active ingredient is an antimicrobial agent. The antimicrobial agent may be an oral active agent and/or a systemic active agent. Examples of antimicrobial agents may include, but are not limited to, 5-chloro-2-(2,4-dichlorophenoxy)-phenol, commonly referred to as triclosan, chlorhexidine, alexidine, hexetidine, sanguinarine, benzalkonium chloride, salicylamide, domiphen bromide, cetylpyridinium chloride (CPC), tetradecyl pyridinium chloride (TPC), N-tetradecyl-4-ethyl pyridinium chloride (TDEPC), octenidine, delmopinol, octapinol, and other piperidino derivatives, niacin preparations, zinc/stannous ion agents, antibiotics such as augmentin, amoxycillin, tetracycline, doxycyline, minocycline, and metronidazole, and analogues, derivatives and salts of the above antimicrobial agents and mixtures thereof.

[0130] In still another embodiment, the pharmaceutically active ingredient is an anti-inflammatory agent. Examples of anti-inflammatory agents may include, but are not limited to, non-steroidal anti-inflammatory agents or NSAIDs, such as propionic acid derivatives, acetic acid derivatives, fenamic acid derivatives, biphenylcarboxylic acid derivative, and oxicams. NSAIDs are described e.g. in U.S. patent no. 4 985 459. Examples of suitable NSAIDs include acetylsalicylic acid, ibuprofen, naproxen, benoxaprofen, flurbiprofen, fenoprofen, fenbufen, ketoprofen, indoprofen, pirprofen, carprofen, oxaprozin, pranoprofen, microprofen, tioxaprofen, suprofen, alminoprofen, tiaprofenic acid, fluprofen, bucloxic acid, or mixtures thereof. Other suitable anti-inflammatory agents are steroidal anti-inflammatory agents such as hydrocortisone, and COX-2 inhibitors such as meloxicam, celecoxib, rofecoxib, valdecoxib, etoricoxib, or mixtures thereof.

[0131] In yet another embodiment, the pharmaceutically active ingredient is an upper respiratory agent such as phenylephrine, diphenhydramine, dextromethorphan, bromhexine and chiorpheniramine, a gastrointestinal agent such as famotidine, loperamide and simethicone, an antifungal such as miconazole nitrate, an antibiotic or an analgesic such as ketoprofen and fluribuprofen.

[0132] In one embodiment of the present invention, the pharmaceutically active ingredient may be selected from vitamin E, i.e. tocopheroles, vitamin C, i.e. ascorbic acid and its salts.

[0133] In another embodiment of the present invention, the pharmaceutically active ingredient may be selected from vitamins, such as vitamins B, C and E; minerals, such as fluorides, especially sodium fluoride, sodium monofluorophosphate and stannous fluoride; anti-odours, such as zinc and cyclodextrins; propellants, such as 1,1,2,2-tetrafluoroethane (HFC-134a), optionally being liquefied, and 1,1,1,2,3,3,3-heptafluororpropane (HFC-227), optionally being liquefied.

[0134] In yet another embodiment of the present invention, the pharmaceutically active ingredient may be selected from ephedrine, magaldrate, pseudoephedrine, sildenafil, xylocaine, benzalkonium chloride, caffeine, phenylephrine, amfepramone, orlistat, sibutramine, acetaminophen, aspirin, aluminium amino acetate, aluminium amino acetate in combination with magnesium oxide, aluminium oxide hydrate in combination with magnesium oxide, calcium carbonate in combination with magnesium hydroxide, calcium carbonate, dihydroxy aluminium sodium carbonate, magnesium oxide, glitazones, metformin, chlorpromazine, dimenhydrinat, domperidone, meclozine, metoclopramide, odansetron, prednisolone, promethazine, acrivastine, cetirizine, cinnarizine, clemastine, cyclizine, desloratadine, dexchlorpheniramine, dimenhydrinate, ebastine, fexofenadine, ibuprofen, levolevoproricin, loratadine, meclozine, mizolastine, promethazine, miconazole, vitamin B12, folic acid, ferro compounds, vitamin C, chlorhexidine diacetate, fluoride, decapeptide KSL, aluminium fluoride, aminochelated calcium, ammonium fluoride, ammonium fluorosilicate, ammonium monofluorphosphate, calcium fluoride, calcium gluconate, calcium glycerophosphate, calcium lactate, calcium monofluorphosphate, calciumcarbonate, carbamide, cetyl pyridinium chloride, chlorhexidine, chlorhexidine digluconate, chlorhexidine chloride, chlorhexidine diacetate, CPP caseine phospho peptide, hexetedine, octadecentyl ammonium fluoride, potassium fluorosilicate, potassium chloride, potassium monofluorophosphate, sodium bi carbonate, sodium carbonate, sodium fluoride, sodium fluorosilicate, sodium monofluorophosphate, sodium tripolyphosphate, stannous fluoride, stearyl trihydroxyethyl propylenediamine dihydrofluoride, strontium chloride, tetra potassium pyrophosphate, tetra sodium pyrophosphate, tripotassium orthophosphate, trisodium orthophosphate, alginic acid, aluminium hydroxide, sodium bicarbonate, sildenafil, tadalafil, vardenafil, yohimbine, cimetidine, nizatidine, ranitidine, acetylsalicylic acid, clopidogrel, acetylcysteine, bromhexine, codeine, dextromethorphan, diphenhydramine, noscapine, phenylpropanolamine, vitamin D, simvastatin, bisacodyl, lactitol, lactulose, magnesium oxide, sodium picosulfate, senna glycosides, benzocaine, lidocaine, tetracaine, almotriptan, eletriptan, naratriptan, rizatriptan, sumatriptan, zolmitriptan, calcium, chromium, copper, iodine, iron, magnesium, manganese, molybdenium, phosphor, selenium, zinc, chloramine, hydrogenperoxide, metronidazole, triamcinolonacetonide, benzethonium chloride, cetyl pyridinium chloride, chlorhexidine, fluoride, lidocaine, amphotericin, miconazole, nystatin, fish oil, ginkgo biloba, ginseng, ginger, purple coneflower, saw palmetto, cetirizine, levocetirizine, loratadine, diclofenac, flurbiprofen, acrivastine pseudoephedrine, loratadine pseudoephedrine, glucosamine, hyaluronic acid, decapeptide KSL-W, decapeptide KSL, resveratrol, misoprostol, bupropion, ondansetron HCl, esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole, bacteria and the like, loperamide, simethicone, acetylsalicylic acid and others, sucralfate, vitamin A, vitamin B1, vitamin B12, vitamin B2, vitamin B6, biotin, vitamin C, vitamin D, vitamin E, folinic acid, vitamin K, niacin, Q10, clotrimazole, fluconazole, itraconazole, ketoconazole, terbinafine, allopurinol, probenecid, atorvastatin, fluvastatin, lovastatin, nicotinic acid, pravastatin, rosuvastatin, simvastatin, pilocarpine, naproxen, alendronate, etidronate, raloxifene, risedronate, benzodiazepines, disulfiram, naltrexone, buprenorphine, codeine, dextropropoxyphene, fentanyl, hydromorphone, ketobemidone, ketoprofen, methadone, morphine, naproxen, nicomorphine, oxycodone, pethidine, tramadol, amoxicillin, ampicillin, azithromycin, ciprofloxacin, clarithromycin, doxycyclin, erythromycin, fusidic acid, lymecycline, metronidazole, moxifloxacin, ofloxacin, oxytetracycline, phenoxymethylpenicillin, rifamycins, roxithromycin, sulfamethizole, tetracycline, trimethoprim, vancomycin, acarbose, glibenclamide, gliclazide, glimepiride, glipizide, insulin, repaglinide, tolbutamide, oseltamivir, aciclovir, famciclovir, penciclovir, valganciclovir, amlopidine, diltiazem, felodipine, nifedipine, verapamil, finasteride, minoxidil, cocaine, buphrenorphin, clonidine, methadone, naltrexone, calcium antagonists, clonidine, ergotamine, β-blockers, aceclofenac, celecoxib, dexiprofen, etodolac, indometacin, ketoprofen, ketorolac, lornoxicam, meloxicam, nabumetone, oiroxicam, parecoxib, phenylbutazone, piroxicam, tiaprofenic acid, tolfenamic acid, aripiprazole, chlorpromazine, chlorprothixene, clozapine, flupentixol, fluphenazine, haloperidol, lithium carbonate, lithium citrate, melperone, penfluridol, periciazine, perphenazine, pimozide, pipamperone, prochlorperazine, risperidone, thioridizin, fluconazole, itraconazole, ketoconazole, voriconazole, opium, benzodiazepines, hydroxine, meprobamate, phenothiazine, aluminiumaminoacetate, esomeprazole, famotidine, magnesium oxide, nizatide, omeprazole, pantoprazole, fluconazole, itraconazole, ketoconazole, metronidazole, amphetamine, atenolol, bisoprolol fumarate, metoprolol, metropolol, pindolol, propranolol, auranofin, and bendazac.

[0135] In still another embodiment of the present invention, the pharmaceutically active ingredient may be selected from the group comprising analgesic, anaesthetic, antipyretic, anti-allergic, anti-arrhythmic, appetite suppressant, antifungal, anti-inflammatory, broncho dilator, cardiovascular, coronary dilator, cerebral dilator, peripheral vasodilator, anti-infective, psychotropic, anti-manic, stimulant, antihistamine, laxative, decongestrant, gastro-intestinal sedative, sexual dysfunction agent, desinfectants, anti-diarrheal, anti-anginal, vasodilator, anti-hypertensive, vasoconstrictor, migraine treating, antibiotic, tranquilizer, antipsychotic, anti-tumour, anticoagulant, antithrombotic, hypnotic, sedative, anti-emetic, anti-nauseant, anticonvulsant, neuromuscular, hyper- and hypoglycaemic, thyroid and antithyroid, diuretic, antispasmodic, uterine relaxant, anti-obesity, anoretic, spasnolytics, anabolic, erythropoietic, anti-asthmatic, expectorant, cough suppressant, mucolytic, anti-uricemic agent, dental vehicle, breath freshener, antacid, anti-diuretic, anti-flatulent, beta-blocker, teeth whitener, enzyme, co-enzyme, protein, energy booster, fibre, probiotic, prebiotic, antimicrobial, NSAID, anti-tussive, decongestrant, anti-histamine, expectorant, anti-diarrheal, hydrogen antagonist, proton pump inhibitor, general nonselective CNS depressant, general nonselective CNS stimulant, selectively CNS function modifying, antiparkinsonism, narcotic-analgetic, analgetic-antipyretic, psychopharmacological, and sexual dysfunction agents.

[0136] In still another embodiment of the present invention, the pharmaceutically active ingredient may be selected from the group comprising casein glyco-macro-peptide (CGMP), triclosan, cetyl pyridinium chloride, domiphen bromide, quaternary ammonium salts, zinc components, sanguinarine, fluorides, alexidine, octonidine, EDTA, aspirin, acetaminophen, ibuprofen, ketoprofen, diflunisal, fenoprofen calcium, naproxen, tolmetin sodium, indomethacin, benzonatate, caramiphen edisylate, menthol, dextromethorphan hydrobromide, theobromine hydrochloride, chlophendianol hydrochloride, pseudoephedrine hydrochloride, phenylephrine, phenylpropanolamine, pseudoephedrine sulphate, brompheniramine maleate, chlorpheniramine maleate, carbinoxamine maleate, clemastine fumarate, dexchlorpheniramine maleate, dephenhydramine hydrochloride, diphenpyralide hydrochloride, azatadine maleate, diphenhydramine citrate, doxylamine succinate, promethazine hydrochloride, pyrilamine maleate, tripellenamine citrate, triprolidine hydrochloride, acrivastine, loratadine, brompheniramine, dexbrompheniamine, guaifenesin, ipecac, potassium iodide, terpin hydrate, loperamide, famotidine, ranitidine, omeprazole, lansoprazole, aliphatic alcohols, barbiturates, caffeine, strychnine, picrotoxin, pentyenetetrazol, phenyhydantoin, phenobarbital, primidone, carbamazapine, etoxsuximide, methsuximide, phensuximide, trimethadione, diazepam, benzodiazepines, phenacemide, pheneturide, acetazolamide, sulthiame, bromide, levodopa, amantadine, morphine, heroin, hydromorphone, metopon, oxymorphone, levophanol, codeine, hydrocodone, xycodone, nalorphine, naloxone, naltrexone, salicylates, phenylbutazone, indomethacin, phenacetin, chlorpromazine, methotrimeprazine, haloperidol, clozapine, reserpine, imipramine, tranylcypromine, phenelzine, lithium, sildenafil citrate, tadalafil, and vardenafil HCl.

[0137] In one embodiment of the present invention, the pharmaceutically active ingredient may be selected from the group comprising ACE-inhibitors, antianginal drugs, anti-arrhythmias, anti-asthmatics, anti-cholesterolemics, analgesics, anesthetics, anticonvulsants, anti-depressants, anti-diabetic agents, anti-diarrhea preparations, antidotes, anti-histamines, anti-hypertensive drugs, anti-inflammatory agents, anti-lipid agents, anti-manics, anti-nauseants, anti-stroke agents, anti-thyroid preparations, anti-tumour drugs, anti-viral agents, acne drugs, alkaloids, amino acid preparations, anti-tussives, anti-uricemic drugs, anti-viral drugs, anabolic preparations, systemic and non-systemic antiinfective agents, anti-neoplasties, antiparkinsonian agents, anti-rheumatic agents, appetite stimulants, biological response modifiers, blood modifiers, bone metabolism regulators, cardiovascular agents, central nervous system stimulates, cholinesterase inhibitors, contraceptives, decongestants, dietary supplements, dopamine receptor agonists, endometriosis management agents, enzymes, erectile dysfunction therapies such as sildenafil citrate, which is currently marketed as Viagra^™, fertility agents, gastrointestinal agents, homeopathic remedies, hormones, hypercalcemia and hypocalcemia management agents, immunomodulators, immunosuppressives, migraine preparations, motion sickness treatments, muscle relaxants, obesity management agents, osteoporosis preparations, oxytocics, parasympatholytics, parasympathomimetics, prostaglandins, psychotherapeutic agents, respiratory agents, sedatives, smoking cessation aids such as bromocriptine, sympatholytics, tremor preparations, urinary tract agents, vasodilators, laxatives, antacids, ion exchange resins, anti-pyretics, appetite suppressants, expectorants, anti-anxiety agents, anti-ulcer agents, anti-inflammatory substances, coronary dilators, cerebral dilators, peripheral vasodilators, psycho-tropics, stimulants, anti-hypertensive drugs, vasoconstrictors, migraine treatments, antibiotics, tranquilizers, anti-psychotics, anti-tumour drugs, anti-coagulants, antithrombotic drugs, hypnotics, anti-emetics, anti-nauseants, anti-convulsants, neuromuscular drugs, hyper- and hypo-glycemic agents, thyroid and anti-thyroid preparations, diuretics, anti-spasmodics, terine relaxants, anti-obesity drugs, erythropoietic drugs, anti-asthmatics, cough suppressants, mucolytics, DNA and genetic modifying drugs, and combinations thereof.

[0138] In another embodiment of the present invention, the pharmaceutically active ingredient may be selected from the group comprising antacids, H2-antagonists, and analgesics. For example, antacid dosages can be prepared using the ingredients calcium carbonate alone or in combination with magnesium hydroxide, and/or aluminium hydroxide, or using aluminium hydroxide, dihydroxyaluminium aminoacetate, aminoacetic acid, aluminium phosphate, dihydroxyaluminium sodium carbonate, bicarbonate, bismuth aluminate, bismuth carbonate, bismuth subcarbonate, bismuth subgallate, bismuth subnitrate, bismuth subsilysilate, calcium phosphate, citrate ion (acid or salt), amino acetic acid, hydrate magnesium aluminate sulfate, magaldrate, magnesium aluminosilicate, magnesium carbonate, magnesium glycinate, magnesium hydroxide, magnesium oxide, magnesium trisilicate, milk solids, aluminium mono-ordibasic calcium phosphate, tricalcium phosphate, potassium bicarbonate, sodium tartrate, sodium bicarbonate, magnesium aluminosilicates, tartaric acids and salts. Moreover, antacids can be used in combination with H2-antagonists, such as cimetidine, ranitidine hydrochloride, famotidine, nizatidien, ebrotidine, mifentidine, roxatidine, pisatidine and aceroxatidine. Analgesics include opiates and opiate derivatives, such as Oxycontin^™, ibuprofen, aspirin, acetaminophen, and combinations thereof that may optionally include caffeine.

[0139] In yet another embodiment of the present invention, the pharmaceutically active ingredient may be selected from the group comprising anti-diarrheals such as Immodium^™ AD, anti-histamines, anti-tussives, decongestants, vitamins, breath fresheners, anxiolytics such as Xanax^™; anti-psychotics such as Clozaril^™ and Haldol^™; non-steroidal anti-inflammatories (NSAIDs) such as ibuprofen, naproxen sodium, Voltaren^™ and Lodine^™, anti-histamines such as Claritin^™, Hismanal^™, Relafen^™, and Tavist^™; antiemetics such as Kytril^™ and Cesamet^™; bronchodilators such as Bentolin^™, Proventil^™; anti-depressants such as Prozac^™, Zoloft^™, and Paxil^™; anti-migraines such as Imigra^™, ACE-inhibitors such as Vasotec^™, Capoten^™ and Zestril^™; anti-Alzheimer's agents, such as Nicergoline^™; CaH-antagonists such as Procardia^™, Adalat^™, and Calan^™; analgesics/anesthetics such as menthol, phenol, hexylresorcinol, benzocaine, dyclonine hydrochloride, benzyl alcohol, salicyl alcohol, and combinations thereof; demulcents such as slippery elm bark, pectin, gelatin, and combinations thereof; antiseptic ingredients such as cetylpyridinium chloride, domiphen bromide, dequalinium chloride, and combinations thereof; antitussive ingredients such as chlophedianol hydrochloride, codeine, codeine phosphate, codeine sulfate, dextromethorphan, dextromethorphan hydrobromide, diphenhydramine citrate, and diphenhydramine hydrochloride, and combinations thereof; and throat soothing agents such as honey, propolis, aloe vera, glycerine, menthol and combinations thereof.

[0140] In still another embodiment of the present invention, the pharmaceutically active ingredient may be selected from the group comprising cough suppressants. Such cough suppressants can fall into two groups: those that alter the texture or production of phlegm such as mucolytics and expectorants; and those that suppress the coughing reflex such as codeine (narcotic cough suppressants), antihistamines, dextromethorphan and isoproterenol (non-narcotic cough suppressants). In some embodiments, ingredients from either or both groups can be included.

[0141] In yet another embodiment of the present invention, the pharmaceutically active ingredient may be selected from the group comprising antitussives, such as codeine, dextromethorphan, dextrorphan, diphenhydramine, hydrocodone, noscapine, oxycodone, pentoxyverine and combinations thereof; antihistamines, such as acrivastine, azatadine, brompheniramine, chlorphen[ir]amine, clemastine, cyproheptadine, dexbrompheniramine, dimenhydrinate, diphenhydramine, doxylamine, hydroxyzine, meclizine, phenindamine, phenyltoloxamine, promethazine, pyrilamine, tripelennamine, triprolidine and combinations thereof; non-sedating antihistamines such as astemizole, cetirizine, ebastine, fexofenadine, loratidine, terfenadine, and combinations thereof; expectorants such as ammonium chloride, guaifenesin, ipecac fluid extract, potassium iodide and combinations thereof; mucolytics, such as acetylcycsteine, ambroxol, bromhexine and combinations thereof; analgesic, antipyretic and anti-inflammatory agents, such as acetaminophen, aspirin, diclofenac, diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, ketoprofen, ketorolac, nabumetone, naproxen, piroxicam, caffeine and mixtures thereof; local anesthetics, such as lidocaine, benzocaine, phenol, dyclonine, benzonotate and mixtures thereof; nasal decongestants, such as phenylpropanolamine, pseudoephedrine, ephedrine, phenylephrine, oxymetazoline, and combinations thereof; ingredients that provide a perception of nasal clearing such as menthol, camphor, borneol, ephedrine, eucalyptus oil, peppermint oil, methyl salicylate, bornyl acetate, lavender oil, wasabi extracts, horseradish extracts, odoriferous essential oils, extracts from woods, gums, flowers and other botanicals, resins, animal secretions, and synthetic aromatic materials.

[0142] Thus, in a preferred embodiment, the pharmaceutically active ingredient is selected from the group comprising anti-tartar agents, anti-microbial agents, anti-inflammatory agents, upper respiratory agents, vitamins, antacids, H2-antagonists, analgesics, anti-diarrheals, cough suppressants and antitussives. In another preferred embodiment of the present invention, the pharmaceutically active ingredient is paracetamol.

[0143] In one embodiment, the pharmaceutically active ingredient is a macromolecular pharmaceutically active ingredient. Such ingredient may include the macromolecular pharmaceutically active ingredients as defined hereinabove, prokaryotic proteins, eukaryotic proteins (e.g., mammalian, plant), chimeric proteins, viral proteins and peptides, antibodies, hormones, growth factors, bone growth factors, proteases, extra-cellular matrix proteins (e.g., collagen), enzymes, the infectious bursal disease virus viral protein VPII, Human interferon beta, Human clotting factor, Human factor X, Human lysosomal enzyme, Human glucocerebrosidase, human alpha galactosidase, and acetyl choline esterase and high mannose proteins, e.g., Human Cox-2, Human EGF, Human uterine tissue plasminogen activator (tPA), Human DNase I, recombinant G 120, Human tissue plasminogen activator, Human thyro globulin (hTG), Human CD4 and Human plasminogen; peginterferon alfa-2a, peginterferon alfa-2b, pegaspargase, colestipol, inulin, icodextrin, hydroxypropyl cellulose, iron dextran, quinidine, pramlintide, tolevamer, cholestyramine, cellobiose, maltotetraose, trehalose-6-phosphate, cellotetraose, maltose, paraformaldehyde, crofelemer, SP1049C, PEG-uricase, carbopol 974P, PRO 2000, LJP 1082, MAXY-G34, IT-101, XMT-1001, sugammadex, endostatin, tyloxapol, pegsunercept, sodium cellulose phosphate, nonoxynol-9, polidocanol, povidone, povidone-iodine, peginesatide, certolizumab pegol, ferric carboxymaltose, naloxegol, hydroxyethyl starch, methoxy polyethylene glycol-epoetin beta, pentastarch, peginterferon beta-1a, pegloticase, dextran, patiromer, polyethylene glycol, polycarbophil, ferumoxsil, ferumoxides, simethicone, karaya gum, tragacanth, carob, carboxymethylcellulose, polyvinyl alcohol, povidone, povidone iodine, polysorbate 80, dimethicone, hypromellose, polyethylene glycol 400, turpentine, pectin, polyethylene glycol 300, rosin, polysorbate 20, tolu balsam, methylcellulose, poliglusam, poloxamer 407, poloxamer 188,gleptoferron, poloxalene, balsam of peru, insulin peglispro, drometrizole trisiloxane, starch, corn, hydroxyethyl cellulose, astodrimer, 2-octyl cyanoacrylate, trehalose, enbucrilate, pegamotecan, sizofiran, guar gum, sodium apolate, lentinan, dextranomer, oxidized cellulose, nonacog beta pegol, carbomer homopolymer type C, cyclomethicone, hydroxyethyl ethylcellulose, microcrystalline cellulose, amber, antihemophilic factor (recombinant), pegylated, calcium polycarbophil, triglyme, triethylene glycol, betadex,calaspargase pegol, pegargiminase, phenyl trimethicone, dextrin 2-sulfate, peginterferon lambda-1a, polyacrylamide (crosslinked; 2 mole percent bisacrylamide), polydioxanone, polydextrose, prm-151, amylopectin, etirinotecan pegol, firtecan pegol, poly(lactic acid), somatropin pegol, amylose, hydroxypropyl betadex, lulizumab pegol, pegfilgrastim, endostar, brexanolone, lipegfilgrastim, ocrylate, bempegaldesleukin, pegilodecakin, pegbelfermin, silk sericin or combinations thereof. Suitable macromolecular inactive precursors of pharmaceutically active ingredients include the macromolecular pharmaceutically active ingredients as defined hereinabove, which are attached (e.g., covalently or non-covalently attached) to a macromolecule and can be released upon exposure to a chemical stimulus, e.g., an acid or an enzyme, or upon exposure to visible or UV light.

[0144] In another embodiment of the present invention, the active ingredient is a nutraceutical active ingredient.

[0145] In one embodiment of the present invention, the nutraceutical active ingredient is selected from vitamins, such as vitamin A, vitamin B1, vitamin B6, vitamin B12, vitamin B2, vitamin B6, vitamin C, vitamin D, vitamin E, i.e. tocopheroles, vitamin K, thiamine, riboflavin, biotin, folic acid, niacin, pantothenic acid, Q10, alpha lipoic acid, dihydrolipoic acid, curcumin, xanthophylls, beta cryptoxanthin, lycopene, lutein, zeaxanthin, astaxanthin, beta-carotene, carotenes, mixed carotenoids, polyphenols, flavonoids and mixtures thereof; minerals, such as sodium, potassium, calcium, magnesium, sulphur, chlorine, choline, manganese, iron, zinc, copper, fluorine, molybdenum, iodine, cobalt, chromium, selenium, phosphorous, and mixtures thereof; and/or phytochemicals, such as carotenoids, chlorophyll, chlorophyllin, fibre, flavanoids, anthocyanins, cyaniding, delphinidin, malvidin, pelargonidin, peonidin, petunidin, flavanols, catechin, epicatechin, epigallocatechin, epigallocatechingallate, theaflavins, thearubigins, proanthocyanins, flavonols, quercetin, kaempferol, myricetin, isorhamnetin, flavononeshesperetin, naringenin, eriodictyol, tangeretin, flavones, apigenin, luteolin, lignans, phytoestrogens, resveratrol, isoflavones, daidzein, genistein, glycitein, soy isoflavones, and combinations thereof. Further examples of nutraceutical active ingredients suitable for use in the present invention are set forth in US 2003/0157213 A1, US 2003/0206993 A1 and US 2003/0099741 A1.

[0146] In a preferred embodiment of the present invention, the nutraceutical active ingredient is selected from the group comprising ascorbic acid, citric acid, rosemary oil, vitamin A, vitamin E, vitamin E phosphate, tocopherols, di-alpha-tocopheryl phosphate, tocotrienols, alpha lipoic acid, dihydrolipoic acid, xanthophylls, beta cryptoxanthin, lycopene, lutein, zeaxanthin, astaxanthin, beta-carotene, carotenes, mixed carotenoids, polyphenols, flavonoids, and combinations thereof.

[0147] In yet another embodiment of the present invention, the nutraceutical active ingredient is a phytochemical preferably selected from the group comprising carotenoids, chlorophyll, chlorophyllin, fibre, flavanoids, anthocyanins, cyanidin, delphinidin, malvidin, pelargonidin, peonidin, petunidin, flavanols, catechin, epicatechin, epigallocatechin, epigallocatechingallate, theaflavins, thearubigins, proanthocyanins, flavonols, quercetin, kaempferol, myricetin, isorhamnetin, flavononeshesperetin, naringenin, eriodictyol, tangeretin, flavones, apigenin, luteolin, lignans, phytoestrogens, resveratrol, isoflavones, daidzein, genistein, glycitein, soy isoflavones, and combinations thereof.

[0148] In still another embodiment of the present invention, the nutraceutical active ingredient is selected from the group comprising L-carnitine, choline, coenzyme Q10, alpha-lipoic acid, omega-3 - fatty acids, pepsin, phytase, trypsin, lipases, proteases, cellulases, and combinations thereof.

[0149] In one embodiment of the present invention, the nutraceutical active ingredient is a flavoring agent. Suitable flavouring agents include the compounds described as fragrances hereinabove.

[0150] In still another embodiment of the present invention, the nutraceutical active ingredient is an essential oil. The essential oil may be a herbal extract and/or fruit extract. Essential oils are generally extracts of aromatic plants, plant parts, fruit or fruit parts that can be used medicinally or for flavouring. Suitable herbal extracts and/or fruit extracts can be used singly or in various mixtures.

[0151] Examples of suitable essential oils are alfalfa oil, allspice oil, almond oil, ambrette (seed) oil, angelica root oil, angelica seed oil, angelica stem oil, angostura (cusparia bark) oil, anise oil, asafetida oil, balm (lemon balm) oil, balsam of peru, basil oil, bay leaves oil, bay (myrcia) oil, bergamot (bergamot orange) oil, bitter almond oil (free from prussic acid), bois de rose oil, cacao oil, camomile (chamomile) flowers (Hungarian) oil, camomile (chamomile) flowers (Roman or English) oil, cananga oil, capsicum oil, caraway oil, cardamom seed (cardamon) oil, carob bean oil, carrot oil, cascarilla bark oil, cassia bark (Chinese) oil, cassia bark (Padang or Batavia) oil, cassia bark (Saigon) oil, celery seed oil, wild cherry bark oil, chervil oil, chicory oil, cinnamon bark (Ceylon) oil, cinnamon bark (Chinese) oil, cinnamon bark (Saigon) oil, cinnamon leaf (Ceylon) oil, cinnamon leaf (Chinese) oil, cinnamon leaf (Saigon) oil, citronella oil, citrus peels oil, clary (clary sage) oil, clover oil, coca oil (decocainized), coffee oil, cola nut oil, coriander oil, cumin oil, curacao orange peel (orange, bitter peel) oil, cusparia bark oil, dandelion oil, dandelion root oil, dog grass (quackgrass, triticum) oil, elder flowers oil, estragole oil, estragon (tarragon) oil, fennel oil, fenugreek oil, galanga (galangal) oil, geranium oil, geranium (East Indian) oil, geranium rose oil, ginger oil, grapefruit oil, guava oil, hickory bark oil, horehound (hoarhound) oil, hops oil, horsemint oil, hyssop oil, immortelle oil, jasmine oil, juniper (berries) oil, kola nut oil, laurel berries oil, laurel leaves oil, lavender oil, lavender (spike) oil, lavandin oil, lemon oil, lemon balm oil, lemon grass oil, lemon peel oil, lime oil, linden flowers oil, locust bean oil, lupulin oil, mace oil, mandarin oil, marjoram oil, mate oil, melissa oil, menthol oil, menthyl acetate oil, molasses (extract), mustard oil, naringin oil, neroli oil, bigarade oil, nutmeg oil, onion oil, bitter orange flowers oil, bitter orange peel oil, orange leaf oil, sweet orange oil, sweet orange flowers oil, sweet orange peel oil, origanum oil, palmarosa oil, paprika oil, parsley oil, black pepper oil, white pepper oil, peppermint oil, peruvian balsam oil, petitgrain oil, petitgrain lemon oil, petitgrain mandarin or tangerine oil, pimenta oil, pimenta leaf oil, pipsissewa leaves oil, pomegranate oil, prickly ash bark oil, rose absolute oil, rose oil, rose buds oil, rose flowers oil, rose fruit (hips) oil, rose geranium oil, rose leaves oil, rosemary oil, saffron oil, sage oil, sage (Greek) oil, sage (Spanish) oil, St. John's wort oil, summer savory oil, winter savory oil, Schinus Molle oil, sloe berries (blackthorn berries) oil, spearmint oil, spike lavender oil, tamarind oil, tangerine oil, tarragon oil, tea oil, thyme oil, thyme (white) oil, thyme (wild or creeping) oil, triticum oil, tuberose oil, turmeric oil, vanilla oil, violet flowers oil, violet leaves oil, violet leaves absolute oil, wild cherry bark oil, ylang-ylang oil, zedoary bark oil, echinacea oil, goldenseal oil, calendula oil, kava kava oil, aloe oil, blood root oil, grapefruit seed extract oil, black cohosh oil, ginseng oil, guarana oil, cranberry oil, ginko biloba oil, evening primrose oil oil, yohimbe bark oil, green tea oil, ma huang oil, maca oil, bilberry oil, lutein oil, and ginger oil.

[0152] In one embodiment, the nutraceutical active ingredient is a macromolecular nutraceutical active ingredient, for example those as defined hereinabove, food and/or feed proteins, enzymes, α-lactalbumin, beta-lactoglobulin, casein, conalbumin, lysozyme, ovoglobulin, ovomucoid, avidin, protamines, histones, plant-derived proteins such as edestin from hemp, amandin from almonds, concanavalin A and B and canavalin from jack beans, cereal seed proteins such as gliadin, soy protein, wheat protein, nut proteins, seed proteins and fruit proteins. Enzymes can include coenzyme Q10, pepsin, phytase, trypsin, lipases, proteases, cellulases, lactase and combinations thereof. Food and/or feed proteins are those found in high quality protein feed such as soy bean meal, bean meal, cottonseed meal, feather meal, blood meal, silages, meat and bone meal, sunflower seed meal, canola meal, peanut meal, safflower meal, linseed meal, sesame meal, early bloom legumes, fish products, milk products, poultry products, hays, corn, wheat, alfalfa, barley, milo, sorghum and mixtures thereof. Suitable macromolecular inactive precursors of nutraceutical active ingredients include the macromolecular nutraceutical active ingredients as defined hereinabove, which are attached (e.g., covalently or non-covalently attached) to a macromolecule and can be released upon exposure to a chemical stimulus, e.g., an acid or an enzyme, or upon exposure to visible or UV light.

The Electrospun Fiber

[0153] According to a first aspect of the present invention, an electrospun fiber is provided, which comprises a polymer, a surface-reacted calcium carbonate and a pharmaceutically or nutraceutically active ingredient,

wherein the surface-reacted calcium carbonate is a reaction product of natural ground or precipitated calcium carbonate with carbon dioxide and one or more H₃O⁺ ion donors in an aqueous medium, wherein the carbon dioxide is formed in situ by the H₃O⁺ ion donor treatment and/or is supplied from an external source, and

wherein at least a part of the pharmaceutically or nutraceutically active ingredient is present within the pores of the surface-reacted calcium carbonate.

[0154] It is appreciated that the polymer, the surface-reacted calcium carbonate and the pharmaceutically or nutraceutically active ingredient are described in detail hereinabove.

[0155] According to the invention, at least a part of the pharmaceutically or nutraceutically active ingredient is present within the pores of the surface-reacted calcium carbonate. Additionally, at least a part of the pharmaceutically or nutraceutically active ingredient may be present on the surface of a surface-reacted calcium carbonate particle. For the purposes of the present invention, it is considered that "at least a part of the pharmaceutically or nutraceutically active ingredient is present within the pores of the surface-reacted calcium carbonate", if at least 5 wt.-%, preferably at least 10 wt.-%, and more preferably at least 20 wt.-% of the total amount of the pharmaceutically or nutraceutically active ingredient is present within the pores of the surface-reacted calcium carbonate. The corresponding amount may be determined by methods commonly known and available to the skilled person, e.g., by microspectrophotometry.

[0156] In one embodiment of the present invention, the electrospun fiber comprises at least two different pharmaceutically or nutraceutically active ingredients, which may be located in separate pores of the surface-reacted calcium carbonate. For example, separate surface-reacted calcium carbonate particles may be provided, i.e., a first surface-reacted calcium carbonate is loaded with a first pharmaceutically or nutraceutically active ingredient and a second surface-reacted calcium carbonate is loaded with a second pharmaceutically or nutraceutically active ingredient. The first and second surface-reacted calcium carbonates may be the same or different. Alternatively, the second surface-reacted calcium carbonate is loaded with a reagent, which preferably activates the first pharmaceutically or nutraceutically active ingredient. Thereby, the pharmaceutically or nutraceutically active ingredient(s) and/or reagent remain physically separated in the electrospun fiber and only come into contact once they are released from the electrospun fiber. Thus, it is possible, e.g., to avoid incompatibilities or to activate an inactive precursor at the point of use. Alternatively, at least two pharmaceutically or nutraceutically active ingredients may be present as a mixture within the pores of the surface-reacted calcium carbonate.

[0157] In a preferred embodiment of the present invention, the fiber has an intra-particle intruded specific pore volume in the range from 0.05 to 0.5 cm³/g, preferably in the range from 0.1 to 0.3 cm³/g, determined by mercury porosimetry measurement.

[0158] Additionally or alternatively, the fiber may have an inter-particle/inter-fiber specific pore volume in the range from 1.0 to 4.0, cm³/g, preferably from 1.5 to 3.5 cm³/g, determined by mercury porosimetry measurement.

[0159] The pore volume is determined in analogy to the method described in C. J. Ridgway, P. A. C. Gane, "On bulk density measurement and coating porosity calculation for coated paper samples", Nordic Pulp and Paper Research Journal 2003, 18, 24-31. In brief, a nonwoven fabric consisting of the electrospun fiber (e.g., obtained by depositing the electrospun fiber onto a flat grounded collector) is coated onto an impermeable substrate (e.g., the flat collector, such as aluminum foil or PET film), the impermeable substrate is removed and the nonwoven fabric is characterized using a Micromeritics Autopore V mercury porosimeter in an equivalent Laplace diameter range from 208 µm to 0.004 µm (corresponding to a maximum applied pressure of mercury of 414 MPa). The specific pore volume is given relative to the weight of the nonwoven fabric.

[0160] The total pore volume seen in the cumulative intrusion data can be separated into several regions. The regions of interest are the intra-particle intruded specific pore volume and the interparticle/inter-fiber pore volume. The intra-particle intruded specific pore volume corresponds to pores having an equivalent Laplace diameter in the range from 4 nm to 0.4 µm and reflects the accessible portion of the intra-particle pores of the surface-reacted calcium carbonate being located in or on the electrospun fibers. The inter-particle/inter-fiber specific pore volume corresponds to pores having an equivalent Laplace diameter in the range from 4 nm up to the inflection point d**, which represents the sum of the intra-particle pores of the surface-reacted calcium carbonate and the pores between the individual electrospun fibers within the nonwoven. The inflection point d** represents the point where the internal intrusion occurs into the inter-particle/inter-fiber region of the samples and is determined by direct comparison of the truncated curves. For the inventive electrospun fibers, d** may be in a range from 5 to 50 µm.

[0161] By taking the first derivative of the cumulative intrusion curve, the pore size distributions based on equivalent Laplace diameter, inevitably including pore-shielding, are revealed. The differential curves clearly show the occlusion pore structure region, the inter-particle/inter-fiber pore region and the intraparticle pore region, if present. Knowing the intraparticle pore diameter range, it is possible to subtract the remainder inter-particle/inter-fiber and occlusion pore volume from the total pore volume to deliver the desired pore volume of the internal pores alone in terms of the pore volume per unit mass (specific pore volume). The same principle of subtraction, of course, applies for isolating any of the other pore size regions of interest.

[0162] Additionally or alternatively, the inventive fibers may have an average fiber diameter of less than 2 µm, preferably in the range from 1 nm to 1.5 µm, more preferably in the range from 10 nm to 1.0 µm, e.g., from 100 nm to 1.0 µm or from 300 nm to 1.0 µm.

[0163] Additionally or alternatively, the inventive fibers may have a titer of below 0.5 dtex, preferably in the range from 0.0001 to 0.4 dtex, more preferably in the range from 0.001 to 0.1 dtex.

[0164] In a preferred embodiment, the fiber comprises the surface-reacted calcium carbonate in an amount from 5 to 80 wt.-%, preferably from 30 to 70 wt.-%, more preferably from 40 to 60 wt.-%. The weight percentages correspond to the surface-reacted calcium carbonate excluding the pharmaceutically or nutraceutically active ingredient and are based on the total weight of the fiber.

[0165] Additionally or alternatively, the fiber may comprise the pharmaceutically or nutraceutically active ingredient in an amount from 0.1 to 30 wt.-%, preferably from 1 to 25 wt.-%, more preferably from 3 to 20 wt.-% and most preferably from 5 to 20 wt.-%, based on the total weight of the fiber.

[0166] Additionally or alternatively, the fiber may comprise the polymer in an amount from 20 to 95 wt.-%, preferably from 30 to 70 wt.-%, and more preferably from 40 to 60 wt.-%, based on the total weight of the fiber.

[0167] The electrospun fiber may comprise further additives, preferably selected from the group consisting of UV-absorbers, light stabilizers, processing stabilizers, antioxidants, heat stabilizers, nucleating agents, metal deactivators, impact modifiers, plasticizers, lubricants, rheology modifiers, processing aids, pigments, dyes, optical brighteners, antimicrobials, antistatic agents, slip agents, antiblock agents, coupling agents, dispersants, compatibilizers, oxygen scavengers, acid scavengers, markers, antifogging agents, surface modifiers, flame retardants, blowing agents, smoke suppressors, or mixtures of the foregoing additives. Preferred pigments are titanium dioxide as white pigment and color pigments, such as blue, green and red pigments. The further additives may be present in the fiber in an amount of up to 5 wt.-% each, preferably up to 2 wt.-% each, based on the total weight of the electrospun fiber.

[0168] It is appreciated that the amount of the polymer, the surface-reacted calcium carbonate, the pharmaceutically or nutraceutically active ingredient, and the optional further additives add up to 100 wt.-%, based on the total weight of the electrospun fiber. Thus, in one embodiment, the electrospun fiber does not comprise further additives, and the polymer, the surface-reacted calcium carbonate, the pharmaceutically or nutraceutically active ingredient add up to 100 wt.-%, based on the total weight of the electrospun fiber.

[0169] Suitable rheology modifiers are viscosity modifiers, including thickening agents. The viscosity modifier may be a linear polymer, a branched polymer, a comb polymer, or a mixture thereof. In one embodiment of the present invention, the viscosity modifier is selected from the group comprising starch, modified starch, maltodextrin, dextran, vegetable gums, pectin, proteins (e.g., collagen, egg white, gelatin, casein, albumin), arrowroot, cornstarch, kuzu starch, katakuri starch, potato starch, sago, wheat flour, almond flour, tapioca, konyak, aiyu jelly, alginines (e.g., alginic acid, sodium alginate, potassium alginate, ammonium alginate, calcium alginate and propylene glycol alginate), guar gum, locust bean gum, oat gum, xanthan gum, acacia gum, karaya gum, tara gum, gellan gum, gum ghatti, agar, gum Arabic, baker's yeast glycan, arabinogalactan, tragacanth, cellulose, cellulose derivatives (e.g., carboxymethyl cellulose, sodium carboxymethyl cellulose, ethyl cellulose, methyl cellulose, hydroxypropylmethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, ethyl methyl cellulose, microcrystalline cellulose, ethyl hydroxyethyl cellulose, croscarmellose), pectin, carrageenan, processed eucheuma seaweed, curdlan, konjac gum, cassia gum, fumed silica, polyacrylic acid, glycated gelatin gels, and/or salts thereof and mixtures thereof.

[0170] In a preferred embodiment of the present invention, the electrospun fiber contains a dispersant.

[0171] In one embodiment of the present invention, the dispersant is selected from the group comprising homopolymers or copolymers of a polycarboxylic acid and/or a salt and/or derivative thereof, based on, for example, acrylic acid, methacrylic acid, maleic acid, fumaric acid or itaconic acid and acrylamide or mixtures thereof. Homopolymers or copolymers of acrylic acid and/or a salt and/or derivative thereof are especially preferred. The molecular weight M_w of such products is preferably in the range of 1000 to 15000 g/mol, with a molecular weight M_w of 1500 to 6000 g/mol being especially preferred. The molecular weight of the dispersants is selected so that they do not act as a binder but instead act as a parting compound. The polymers and/or copolymers may be neutralized with monovalent and/or polyvalent cations or they may have free acid groups. Suitable monovalent cations include, for example, sodium, lithium, potassium or ammonium. Suitable polyvalent cations include, for example, calcium, magnesium, strontium or aluminum. The combination of sodium and magnesium is especially preferred.

[0172] In another embodiment of the present invention, the dispersant is selected from the group comprising starch, carboxymethyl cellulose, glycols, polyglycols, e.g., polyethylene glycols, ethylene oxide-propylene oxide-ethylene oxide block copolymers sodium polyphosphates and/or polyaspartic acid as well as their alkali and/or alkaline earth salts, sodium citrate and amines, alkanolamines, such as triethanolamine and triisopropanolamine and mixtures thereof. It is also possible to use other monomers or polymer additives such as ethylene-acrylic acid copolymers alone or in combination. The ratio of acrylic acid monomers in the copolymer with ethylene monomers is preferably 1:4 to 1:50, especially preferably 1:4 to 1:10, particularly 1:5. Dispersants based on organometallic compounds may also be employed. However, it is also possible to use any other dispersant.

[0173] In a preferred embodiment of the present invention, the dispersant is selected from polyacrylic acid having a molecular weight in the range of 1000 to 15000 g/mol, salts thereof, derivatives thereof, starch, carboxymethyl cellulose or mixtures thereof. More preferably, the dispersant is polyacrylic acid being partially or fully neutralized by alkali metal ions, such as lithium, sodium, potassium, cesium, and mixtures thereof, preferably sodium and having a molecular weight in the range of 1500 to 6000 g/mol.

[0174] For the purposes of the present invention, the term "partially neutralized" means that at least 10 mol-%, preferably at least 25 mol-%, more preferably at least 50 mol-% of the hydrogen atoms of the carboxylic groups of the polyacrylic acid are replaced by alkali metal ions. For the purposes of the present invention, the term "fully neutralized" means that at least 90 mol-%, preferably at least 95 mol-%, more preferably at least 98 mol-%, and most preferably at least 99 mol-% of the hydrogen atoms of the carboxylic groups of the polyacrylic acid are replaced by alkali metal ions.

[0175] Most preferably, the dispersant is polyacrylic acid being partially or fully neutralized by sodium ions and having a molecular weight in the range of 1500 to 6000 g/mol.

[0176] The electrospun fiber may comprise the dispersant in an amount from 0.1 to 10 wt.-%, preferably from 0.5 to 7 wt.-% and more preferably from 1.0 to 4 wt.-%, based on the total weight of the electrospun fiber.

[0177] The dispersant may be contained in the electrospun fiber in order to improve dispersion of the surface-reacted calcium carbonate evenly throughout the electrospun fiber and in order to reduce the occurrence of aggregates of the surface-reacted calcium carbonate. At the same time, the specified amount can help to retain the accessibility of the intra-particle pores of the surface-reacted calcium carbonate comprising the pharmaceutically or nutraceutically active ingredient to a large extent.

[0178] In a preferred embodiment, the volume median particle size d₅₀ of the surface-reacted calcium carbonate is at least 5 % greater than the volume median fiber diameter, preferably at least 10 % greater than the fiber diameter, more preferably at least 20 % greater than the volume median fiber diameter, wherein the volume median fiber diameter is determined via scanning electron microscopy (SEM) at a fiber section not comprising a visible surface-reacted calcium carbonate particle. The fiber diameters are determined as described herein, i.e., 30 fiber sections are selected each and the corresponding diameters are averaged.

[0179] Thereby, the surface-reacted calcium carbonate particles protrude, or 'stick out', of the fiber, which increases the surface area and the porosity of the electrospun fiber. Without wishing to be bound by any particular theory, the surface-reacted calcium carbonate may act as a spacer, which increases the distance between the individual electrospun fibers.

[0180] In a preferred embodiment, the electrospun fiber is obtained by a process as described hereinbelow.

The Process for Preparing the Electrospun Fiber

[0181] A second aspect of the present invention relates to a process for the preparation of a fiber, comprising the steps of

a) providing a polymer,

b) providing a surface-reacted calcium carbonate,
wherein the surface-reacted calcium carbonate is a reaction product of natural ground or precipitated calcium carbonate with carbon dioxide and one or more H₃O⁺ ion donors in an aqueous medium, wherein the carbon dioxide is formed in situ by the H₃O⁺ ion donor treatment and/or is supplied from an external source,

c) providing a pharmaceutically or nutraceutically active ingredient,

d) loading the pharmaceutically or nutraceutically active ingredient of step c) onto the surface-reacted calcium carbonate of step b) to obtain a loaded surface-reacted calcium carbonate,

e) mixing the polymer of step a) with the loaded surface-reacted calcium carbonate of step d) to obtain a mixture,

f) electrospinning the mixture of step e) into an electrospun fiber.

[0182] It is appreciated that the polymer, the surface-reacted calcium carbonate and the pharmaceutically or nutraceutically active ingredient are described hereinabove.

Loading Step d)

[0183] According to step d) of the inventive process, the pharmaceutically or nutraceutically active ingredient is loaded onto the surface-reacted calcium carbonate to obtain a loaded surface-reacted calcium carbonate. For obtaining the loaded surface-reacted calcium carbonate, the surface-reacted calcium carbonate and the pharmaceutically or nutraceutically active ingredient are brought into contact.

[0184] In general, the surface-reacted calcium carbonate and the pharmaceutically or nutraceutically active ingredient can be brought into contact by any conventional means known to the skilled person. For example, the surface-reacted calcium carbonate and the pharmaceutically or nutraceutically active ingredient may be mixed in the absence or presence of a solvent. Suitable mixing devices are known to the skilled person and may include mixers or blenders, e.g., a tumbling mixer, a vertical or horizontal ploughshare mixer, such as a Ploughshare^® mixer available from Gebrüder Lödige Maschinenbau GmbH or a laboratory mixer, such as an MP mixer available from Somakon Verfahrenstechnik UG. The skilled person will adapt the mixing conditions (such as the configuration or mixing speed) according to his needs and available equipment.

[0185] The loading of surface-reacted calcium carbonate with the pharmaceutically or nutraceutically active ingredient in step d) may be carried out in any order. According to one embodiment, the surface-reacted calcium carbonate is provided in a first step, and subsequently, the pharmaceutically or nutraceutically active ingredient is added. According to another embodiment, the pharmaceutically or nutraceutically active ingredient is provided in a first step, and subsequently, the surface-reacted calcium carbonate is added. According to still another embodiment, the surface-reacted calcium carbonate and the pharmaceutically or nutraceutically active ingredient are contacted simultaneously, for example, by adding both compounds simultaneously into a vessel.

[0186] According to one exemplary embodiment, the pharmaceutically or nutraceutically active ingredient is in form of a suspension or solution, and the loading step is carried out by dropwise addition of the pharmaceutically or nutraceutically active ingredient to an agitated powder of the surface-reacted calcium carbonate. According to another exemplary embodiment, the pharmaceutically or nutraceutically active ingredient is provided in molten form and added to the surface-reacted calcium carbonate. According to yet another embodiment, the pharmaceutically or nutraceutically active ingredient is provided in gaseous form, e.g., via sublimation, and added to the surface-reacted calcium carbonate, resulting in capillary condensation of the active ingredient in the pores of the surface-reacted calcium carbonate. An exemplary pharmaceutically or nutraceutically active ingredient for provision via sublimation is caffeine.

[0187] The suspension or solution may be obtained by mixing the pharmaceutically or nutraceutically active ingredient or the surface-reacted calcium carbonate with any suitable liquid or supercritical fluid. For example, loading step d) may be carried out in the presence of ketones, such as acetone and butanone, alcohols, such as methanol, ethanol, 1-propanol and 2-propanol, fluorinated solvents, such as 2,2,2-trifluoroethanol, hexafluoroacetone and hexafluoroisopropanol, water, dimethylformamide, dimethylsulfoxide, tetrahydrofuran, chlorinated solvents, such as chloroform and ethylene dichloride, acetic acid, formic acid, supercritical carbon dioxide, and mixtures thereof.

[0188] According to still another exemplary embodiment, the pharmaceutically or nutraceutically active ingredient is provided in form of a suspension or solution and the surface-reacted calcium carbonate is added to said suspension or solution, wherein preferably the suspension or solution is agitated. The solution or suspension may comprise the pharmaceutically or nutraceutically active ingredient in a concentration from 0.1 to 500 mg/mL, preferably from 0.5 to 250 mg/mL, more preferably from 1 to 250 mg/mL, yet more preferably from 5 to 100 mg/mL, and most preferably from 10 to 50 mg/mL. According to one embodiment, the pharmaceutically or nutraceutically active ingredient is comprised in the solution or suspension in an amount from 5 to 200 wt.-%, preferably 10 to 150 wt.-%, more preferably 15 to 100 wt.-%, and most preferably 20 to 50 wt.-%, relative to the weight of the surface-reacted calcium carbonate.

[0189] Preferably, the surface-reacted calcium carbonate is provided in solid form and suspended in the suspension or solution of the pharmaceutically or nutraceutically active ingredient.

[0190] The loading step d) may be carried out for a time period in the range of several seconds to several minutes, e.g. 20 s or more, preferably 30 s or more, more preferably 60 s or more, and most preferably for a period of 120 s or more. According to one embodiment step d) is carried out for at least 3 min, at least 4 min, at least 5 min, at least 10 min, at least 20 min, or at least 30 min.

[0191] Loading step d) may be carried out at a temperature of up to 200 °C, preferably from -20 °C to 150 °C, more preferably from 0 °C to 100 °C, for example from 20 °C to 50 °C. Especially preferably, loading step d) is performed at room temperature, i.e., at 25 ± 5 °C.

[0192] It is appreciated that during loading of the pharmaceutically or nutraceutically active ingredient onto the surface-reacted calcium carbonate, the pharmaceutically or nutraceutically active ingredient will be deposited within the accessible pores and/or onto the surface of the surface-reacted calcium carbonate, i.e., will be adsorbed onto and/or absorbed into the surface-reacted calcium carbonate. The loaded surface-reacted calcium carbonate may comprise the pharmaceutically or nutraceutically active ingredient in an amount from at least 1.5 wt.-%, preferably at least 3 wt.-%, more preferably at least 25 wt.-%, and most preferably of at least 50 wt.-% to, e.g., less than 100 wt.-%.

[0193] After the loading step, the loaded surface-reacted calcium carbonate may be separated from the liquid medium, if present. For example, the loaded surface-reacted calcium carbonate may be separated from the liquid medium by evaporating the liquid medium, by filtration and/or by centrifugation. Furthermore, the loaded surface-reacted calcium carbonate may be washed after separation, for example, with water.

[0194] In an embodiment, the inventive process comprises a further loading step d1) of loading a second pharmaceutically or nutraceutically active ingredient or a reagent onto a second surface-reacted calcium carbonate. In this embodiment, loading step d) corresponds to loading a first pharmaceutically or nutraceutically active ingredient onto a first surface-reacted calcium carbonate. Loading step d1) can be carried out as described hereinabove for loading step d).

Mixing Step e)

[0195] In mixing step e), the polymer of step a) and the loaded surface-reacted calcium carbonate(s) of step d) and optionally step d1) are mixed to obtain a mixture. The properties of the mixture are adjusted such that the mixture can be used in the following electrospinning step, as will be described hereinbelow.

[0196] Preferably, the so-obtained mixture comprises the surface-reacted calcium carbonate in an amount from 5 to 80 wt.-%, preferably from 30 to 70 wt.-% and more preferably from 40 to 60 wt.-%, based on the total dry weight of the mixture, and/or the pharmaceutically or nutraceutically active ingredient in an amount from 0.1 to 30 wt.-%, preferably from 1 to 25 wt.-% and more preferably from 3 to 20 wt.-%, based on the total dry weight of the mixture and/or the polymer in an amount from 20 to 95 wt.-%, preferably from 30 to 70 wt.-%, and more preferably from 40 to 60 wt.-%, based on the total dry weight of the mixture.

[0197] It is appreciated that the amount of the surface-reacted calcium carbonate, the polymer, the pharmaceutically or nutraceutically active ingredient, and optional further additives add up to 100 wt.-%, based on the total dry weight of the mixture. Thus, in one embodiment, the coating layer does not comprise further additives, and the amount of the surface-reacted calcium carbonate, the polymer, and the pharmaceutically or nutraceutically active ingredient add up to 100 wt.-%, based on the total dry weight of the mixture.

[0198] The mixture obtained in step e) may be stored under inert gas atmosphere, e.g. under nitrogen, when temporarily stored until its further processing or use.

[0199] Preferably, mixing step e) is performed in the presence of a solvent. Thus, the mixture is obtained in the form of a suspension.

[0200] Alternatively, mixing step e) may be performed in the absence of a solvent, e.g., in a melt electrospinning method. Such mixing step e) may be performed, e.g., by any compounding method known to the skilled person. Preferably, compounding is performed by a kneading process, wherein a premix of the loaded surface-reacted calcium carbonate of step c) and the polymer of step a) is continuously fed to an extruder, such as a single screw or twin screw extruder. The extruder is heated to a temperature sufficiently high to allow for efficient mixing of the loaded surface-reacted calcium carbonate of step c) and the polymer of step a). A suitable temperature range is 100 to 250°C.

[0201] If mixing step e) is performed in the presence of a solvent, the solvent may be any solvent allowing for the dispersion of the loaded surface-reacted calcium carbonate within the mixture, such as water, acetone, alcohols or halogenated solvents (preferably chlorinated and/or fluorinated solvents). The solvent preferably is selected such that the polymer is soluble therein. For example, if the polymer is polyethylene glycol) or poly(vinyl alcohol), the solvent may be water. If the polymer is polycaprolactone, the solvent may be acetone, THF, 2,2,2-trifluoroethanol, or a mixture of acetone and chloroform, e.g., in a weight ratio from 40:60 to 60:40, or a mixture of acetone and methanol. If the polymer is poly(acrylonitrile), the solvent may be DMF. If the polymer is poly(lactic-co-glycolic acid), the solvent may be HFIP.

[0202] The mixture may be obtained by dissolving the polymer in a solvent and subsequently adding the loaded surface-reacted calcium carbonate. Alternatively, the polymer and the loaded surface-reacted calcium carbonate may be mixed in solid form, e.g., as powders or pellets, and subsequently, the solvent is added.

[0203] Alternatively, the mixture may be obtained by (i) dissolving the polymer in a first solvent to obtain a polymer solution, (ii) dispersing the loaded surface-reacted calcium carbonate in a second solvent to obtain a dispersion and (iii) mixing the polymer solution and the dispersion. The first and the second solvent may be the same or different, preferably the same solvent.

[0204] In a preferred embodiment, the solvent is selected from the group consisting of ketones, such as acetone and butanone, alcohols, such as methanol, ethanol, 1-propanol and 2-propanol, fluorinated solvents, such as 2,2,2-trifluoroethanol (TFE), hexafluoroacetone and hexafluoroisopropanol (HFIP), water, dimethylformamide (DMF), dimethylsulfoxide (DMSO), tetrahydrofuran (THF), chlorinated solvents, such as chloroform and ethylene dichloride, acetic acid, formic acid and mixtures thereof.

[0205] Thus, in a preferred embodiment of the present invention, in mixing step e) the polymer and the loaded surface-reacted calcium carbonate are mixed with a solvent such that the polymer is essentially completely dissolved in the solvent to obtain the mixture. The term "essentially completely dissolved" means that at least 95 wt.-%, preferably at least 98 wt.-%, and most preferably at least 99 wt.-% of the polymer are dissolved in the solvent, based on the total amount of polymer.

[0206] Without wishing to be bound by any theory, the inventors believe that, since the pharmaceutically or nutraceutically active ingredient is present within the porous structure of the surface-reacted calcium carbonate, only a small or limited amount of the ingredient at the outer surface area of the surface-reacted calcium carbonate is accessible to the solvent. Therefore, the pharmaceutically or nutraceutically active ingredient only slowly dissolves in the solvent during this mixing step e) and remains within the pores of the surface-reacted calcium carbonate. However, most preferably, the solvent is selected such that the polymer is soluble therein, but the pharmaceutically or nutraceutically active ingredient is at most sparingly soluble, preferably at most slightly soluble, more preferably at most very slightly soluble therein. Thereby, the amount of pharmaceutically or nutraceutically active ingredient interacting with or being dissolved in the solvent during mixing step e) is minimized. The term "sparingly soluble" as defined in the US Pharmacopoeia and the Pharmacopoea Europaea refers to a solute that can be dissolved in the solvent in an amount of 10 to 33 g/L. Similarly, the term "slightly soluble" refers to a solute that can be dissolved in the solvent in an amount of 1 to 10 g/L and the term "very slightly soluble" refers to a solute that can be dissolved in the solvent in an amount of 0.1 to 1 g/L.

[0207] Optionally, the solvent may further comprise an electrolyte, preferably selected from the group consisting of alkali metal halides, such as sodium chloride and potassium chloride, alkaline earth metal halides, such as magnesium chloride and magnesium bromide, pyridinium formate, cationic surfactants, such as dodecyltrimethylammonium bromide, tetrabutyl ammonium chloride and tetrabutyl ammonium bromide, and mixtures thereof. The electrolyte may be added to adjust the conductivity of the solution as required for the electrospinning step.

[0208] The solids content of the mixture preferably is in the range from 10 to 80 wt.-%, more preferably 15 to 70 wt.-%, even more preferably 20 to 60 wt.-%, and most preferably 30 to 55 wt.-%, based on the total weight of the mixture.

[0209] During mixing step e), optionally further additives such as an electrolyte, a rheology modifier, a viscosity enhancer, a wetting agent, a wax, an antistatic agent, a dispersant and/or an antifoaming agent may be added. Suitable rheology modifiers include viscosity modifiers, i.e., thickening agents, such as the thickening agents described hereinabove. According to one embodiment, the further additive may be added in an amount of from 0.05 to 5.0 wt.-%, preferably from 0.1 to 2.0 wt.-%, more preferably from 0.2 to 1.0 wt.-%, based on the total dry weight of the mixture.

[0210] The mixture of step e) may comprise the polymer in an amount of from 1 to 60 wt.-%, preferably in an amount from 2 to 40 wt.-%, based on the total weight of the mixture.

[0211] The mixture of step e) may comprise the surface-reacted calcium carbonate and/or the loaded surface-reacted calcium carbonate in a total amount from 1 to 25 wt.-%, preferably 2 to 20 wt.-%, more preferably 5 to 15 wt.-%, based on the total weight of the mixture.

[0212] The mixture of step e) may comprise the pharmaceutically or nutraceutically active ingredient in an amount from 0.1 to 10 wt.-%, preferably from 0.5 to 8 wt.-%, and more preferably from 1 to 5 wt.-%, based on the total weight of the mixture.

[0213] The mixture of step e) may comprise the electrolyte in an amount from 0.1 to 10 wt.-%, preferably from 0.5 to 5 wt.-%, based on the total weight of the mixture.

[0214] It is appreciated that the amount of the surface-reacted calcium carbonate, the polymer, the pharmaceutically or nutraceutically active ingredient, electrolyte, optional further additives, and the solvent add up to 100 wt.-%, based on the total weight of the mixture. Thus, in one embodiment, the coating layer does not comprise further additives, and the amount of the surface-reacted calcium carbonate, the polymer, and the pharmaceutically or nutraceutically active ingredient add up to 100 wt.-%, based on the total weight of the mixture.

[0215] In a preferred embodiment of the present invention, the mixture of step e) has a Brookfield viscosity in the range from 100 to 1 000 000 mPas, preferably in the range from 300 to 100 000 mPas, more preferably in the range from 500 to 75 000 mPas. The viscosity is measured with a viscometer (DV2T, Brookfield with a SC4 DIN-82 spindle at 5.5 mL sample volume. An adapter for small volume is used. The present invention is not particularly limited to specific viscosities of the suspension to be spun. However, below the lower threshold, it may be difficult to obtain electrospun fibers at all. Instead, beads may be formed. If the viscosity is above the upper threshold, the solution may become too thick to be electrospun or the initially formed droplet may dry out before a jet can be formed.

[0216] The required minimum viscosity and, accordingly, the amount of polymer, depends on the type of polymer and its molecular weight. On a molecular basis, it is required that the different polymer chains show a minimum degree of chain entanglement. For example, poly(vinyl alcohol) fibers can be spun in a range where [η]c is from about 5 to about 12 (Koski et al., Materials Letters 2004, 58, 493-497), with [η] being the intrinsic viscosity of the polymer and c being the concentration of the polymer. For polyethylene oxide), fibers can be spun where [η]c is greater than 10 (Q.P. Pham et al., Tissue Engineering 2006, 12, 1197-1211).

[0217] The intrinsic viscosity of a polymer can be derived from the Mark-Houwink equation [η] = K . M_r^a, with K and a being constants, which are dependent on the nature of the polymer, the solvent and the temperature, and which can be taken from standard textbooks. M_r is the molecular weight of the polymer. The following definitions are applicable: Intrinsic viscosity (Purple Book, 1^st ed., p. 63; https://goldbook.iupac.org/terms/view/103140), Mark-Houwink equation (Purple Book, 1^st ed., p. 64; https://goldbook.iupac.org/terms/view/M03706), molecular weight (Green Book, 2^nd ed., p. 41; https://goldbook.iupac.org/terms/view/R05271).

[0218] In a preferred embodiment of the present invention, the mixture of step e) has a conductivity in the range from 0.001 µS/m to 10 S/m. Thus, although the conductivity of the mixture is not particularly limited, a certain minimum conductivity may be required so that the electrostatic forces can accelerate the jet. Mixtures of higher conductivity may be more conducive to jet formation. The required conductivity depends on the type of polymer and may be adjusted by adding electrolytes, as described above.

[0219] In general, the loaded surface-reacted calcium carbonate, the polymer and the solvent can be brought into contact in mixing step e) by any conventional means known to the skilled person. Suitable mixing devices are known to the skilled person and may include mixers or blenders, e.g., magnetic stirrers, propeller/impeller mixers and high-shear mixers, such as a Polytron^® immersion disperser available from Kinematica AG. The skilled person will adapt the mixing conditions (such as the configuration of mixing speed) according to his needs and available equipment.

Electrospinning Step f)

[0220] In step f) of the inventive process, the mixture of step e) is electrospun into an electrospun fiber.

[0221] Electrospinning step f) makes use of an electrospinning apparatus. Corresponding electrospinning apparatuses are known to the skilled person and comprise a spinneret from which the mixture of step e) is expelled and a grounded collector onto which the electrospun fiber is deposited. The spinneret and the grounded collector are connected to a high-voltage direct current power supply. Suitable set-ups are known to the skilled person and are described, inter alia, by W.E. Teo et al. (Nanotechnology 2006, 17, R89-R106) and references cited therein. The electrospinning step can be a needle electrospinning step or a needle-less electrospinning step.

[0222] Suitable spinnerets for use in a needle electrospinning step include single needle spinnerets, multi needle spinnerets and co-axial (e.g., bi-axial or tri-axial) spinnerets. Suitable spinnerets for use in a needle-less electrospinning step include rotary spinnerets (e.g., cylinder spinnerets, ball spinnerets, disc spinnerets, beaded chain spinnerets, spinal coil spinnerets, and cone spinnerets) and static spinnerets (e.g., static cylinder spinnerets, conical wire coil spinnerets, ferromagnetic liquid spinnerets, bubble spinnerets, static plate spinnerets, bowl spinnerets and ultrasound-enhanced spinnerets), e.g., those described by I. Partheniadis et al. (Processes 2020, 8, 673).

[0223] Suitable collectors include rotating drum collectors, parallel electrode collectors, rotating wire drum collectors, drum collectors with wire wound on it, rotating tube collectors with knife-edge electrodes below, disc collectors, arrays of counter electrodes, rotating drum collectors with sharp pins inside, blade collectors placed in line, ring collectors placed in parallel and water baths, such as those described by Teo et al. (Nanotechnology 2006, 17, R89-R106).

[0224] Thus, electrospinning step f) preferably comprises the sub-steps of

f1) feeding the mixture to a spinneret,

f2) applying an electrostatic potential on the spinneret and a collector to form the filament fiber,

f3) collecting the filament fiber at the collector, preferably in order to form a nonwoven fabric.

[0225] Several operation parameters are relevant for the electrospinning process and can be adjusted by the skilled person to adjust the size, shape and arrangement of the fibers as required by the envisaged application.

[0226] With regard to the mixture of step e), the concentration and the molecular weight of the polymer influence the viscosity, which can be increased to increase the fiber diameter. At high viscosity, the fibers transition from round or oval fibers to flat fibers. At lower viscosity, the fibers may comprise beads formed from the polymer. The conductivity of the solution can be increased by adding an electrolyte as described hereinabove or by adding and/or selecting a more polar solvent, to increase the uniformity of the fibers and reduce the amount of polymer beads present within the fiber.

[0227] In feeding step f1), the flow rate of the mixture may be adjusted as required. Lower flow rates may yield fibers with smaller diameters. If the flow rate is set too high, the fibers cannot sufficiently dry until they reach the collector, so that the fibers may be less uniform. The flow rate will depend on the type and size of the spinneret that is used in the electrospinning process and the applied electrostatic potential. A higher flow rate can be used when applying a higher electrostatic potential in step f2). If one or more needles are used as spinneret, the flow rate may be from about 0.1 to 10 mL of mixture per hour and needle, e.g., from about 0.5 to 10 mL per hour and needle or from about 0.1 to 5 mL per hour and needle.

[0228] In step f2), the electrostatic potential may be adjusted as required for the electrospinning process and the desired electrospun fiber. The applied potential has to be high enough so that the mixture can be emitted from the spinneret, but should not be too high to disrupt the Taylor cone. If required, the electrostatic potential is adjusted accordingly during the electrospinning process.

[0229] In a preferred embodiment of the present invention, the electrostatic potential applied in step f2) is from 1 to 100 kV, preferably from 2 to 75 kV, more preferably from 5 to 50 kV, and most preferably from 10 to 20 kV.

[0230] In step f3), the distance between spinneret and grounded collector may be adjusted. The distance should be sufficiently high so that the jet can at least partially dry during travel to the collector. If the distance, however, is too high, the quality of the electrospun fiber may deteriorate. Further factors influencing the obtained electrospun fibers are the design and arrangement of the spinneret and the composition, arrangement and geometry of the grounded collector, as described by Q.P. Pham et al. (Tissue Engineering 2006, 12, 1197-1211) and by W.E. Teo (Nanotechnology 2006, 17, R89-R106).

[0231] Additionally or alternatively, the ambient parameters of the electrospinning process may be controlled and/or adjusted.

[0232] The electrospinning step f) may be performed under ambient air or under an inert gas, at atmospheric pressure, reduced pressure or elevated pressure. Suitable inert gases include nitrogen, argon and helium. Suitable reduced pressures range from 10 to 850 hPa, e.g., from 100 to 600 hPa. Suitable elevated pressures range from 1100 hPa to 5000 hPa, preferably from 1500 to 3000 hPa. If the electrospinning step f) is performed under reduced pressure, e.g., by placing the electrospinning apparatus in a vacuum chamber, and/or under an inert atmosphere, higher electrostatic potentials and higher temperatures can be used.

[0233] Preferably, the electrospinning step is performed at a temperature in the range from 0°C to 50°C, more preferably from 10 to 30°C, e.g., at about room temperature (i.e., 20°C ± 5 %). At a higher temperature, the fiber diameter may decrease due to the decreased viscosity of the mixture. The temperature at the collector preferably is selected below the glass transition temperature of the polymer, and more preferably is in the range from 0°C to 50°C, more preferably from 10 to 30°C, e.g., at about room temperature (i.e., 20°C ± 5 %). Furthermore, for active agents which are susceptible to the thermal degradation, it is preferred to perform the electrospinning step at low temperature, for example, at room temperature.

[0234] The relative humidity may also be adjusted as required in order to alter the shape of the fibers.

[0235] Electrospinning step f) may alternatively be a coaxial electrospinning step, an emulsion electrospinning step, or a melt electrospinning step.

[0236] In a preferred embodiment of the present invention,

• in mixing step e) the polymer and the loaded surface-reacted calcium carbonate are mixed with a solvent such that the polymer is essentially completely dissolved in the solvent to obtain the mixture; and
• electrospinning step f) is a suspension electrospinning step comprising the sub-steps of

  f1) feeding the mixture to a spinneret,

  f2) applying an electrostatic potential on the spinneret and a collector to form the filament fiber,

  f3) collecting the filament fiber at the collector, preferably in order to form a nonwoven fabric,

wherein the electrospinning step preferably is performed at a temperature in the range from 0°C to 50°C.

Optional Steps

[0237] The inventive process may comprise one or more of the steps described hereinbelow.

[0238] Preferably, the process comprises a step g) of drying the fiber or nonwoven fabric obtained in step f) to obtain a dried fiber or nonwoven fabric. For example, the fiber or nonwoven fabric may be dried by air blowing or tumble drying, or IR drying, optionally under reduced pressure. It is appreciated that the drying step is performed at a temperature well below the glass transition temperature of the polymer to avoid thermobonding of the fibers or the web, which may increase sticking of the fibers and lead to the deterioration of the nonwoven fabric. Furthermore, the temperature should be low enough not to decompose the pharmaceutically or nutraceutically active ingredient. Preferably, drying is performed at a temperature below 135 °C, more preferably below 120 °C, even more preferably below 100 °C, for example in a range from 50 to 90 °C.

[0239] The process may also comprise a step h) of bonding the nonwoven fabric obtained in step f) or the dried nonwoven fabric obtained in step g) to obtain a bonded nonwoven fabric. The bonding step h) may be a step of calendaring, air-through-bonding, needle punching, hydroentanglement, stitchbonding, chemical bonding or combinations thereof. Preferably, bonding step h) is a hydroentanglement process.

[0240] The process may also comprise a step i) of post-treating the nonwoven fabric obtained in either step f), g) or h). The post-treatment step i) may be a step of printing, dyeing, embossing, creping, raising, coating, or perforation.

The Nonwoven Fabric

[0241] A third aspect of the present invention relates to a nonwoven fabric comprising, preferably consisting essentially of, the inventive electrospun fiber.

[0242] It is appreciated that the nonwoven fabric may be prepared by a process as described hereinabove and comprises an electrospun fiber as described in detail hereinabove. A "nonwoven fabric" is considered a flexible sheet or web structure, which is composed of interlocking or connected networks of fibers.

[0243] The nonwoven fabric, thus, comprises a pharmaceutically or nutraceutically active ingredient, preferably in an amount from 0.1 to 30 wt.-%, preferably from 1 to 25 wt.-%, more preferably from 3 to 20 wt.-% and most preferably from 5 to 20 wt.-%, based on the total weight of the nonwoven fabric. The pharmaceutically or nutraceutically active ingredient may be released from the nonwoven fabric under certain conditions in a sustained-release, controlled release or triggered release manner.

[0244] Furthermore, it is appreciated that the nonwoven fabric has a specific porosity and pore structure. The porosity and pore structure can be controlled by adjusting the parameters of the electrospinning step by which the nonwoven fabric is produced. For example, it is known that the specific surface area of the nonwoven fabric increases with decreasing fiber diameter. Therefore, the above-described parameters relevant for adjustment of fiber diameter can also be used for adjusting the specific surface area of the nonwoven fabric. Furthermore, the presence of the surface-reacted calcium carbonate ensures that intra-particle pores are present, which host the pharmaceutically or nutraceutically active ingredient.

[0245] Preferably, the nonwoven fabric has an occlusion specific pore volume in the range from 0.8 to 6.0 cm³/g, preferably from 1.0 to 5.0 cm³/g, determined by mercury porosimetry measurement. The occlusion specific pore volume corresponds to pores having an equivalent Laplace diameter in the range from d** to 208.0 µm.

[0246] Preferably, the nonwoven fabric has a mode average inter-fiber pore diameter in the range from 10 to 100 µm, preferably in the range from 10 to 50 µm, determined by mercury porosimetry measurement. The mode average inter-fiber pore diameter reflects the mode average equivalent Laplace diameter of the pores between the individual electrospun fibers within the nonwoven fabric.

[0247] Preferably, the nonwoven fabric has a BET specific surface area in the range from 1 to 100 m²/g, more preferably in the range from 2 to 50 m²/g, as measured by the BET method according to ISO 9277:2010.

[0248] The nonwoven fabric may consist essentially of the electrospun fiber as described hereinabove. However, also mixtures of different fibers which are made of different materials and/or by different fiber formation processes can be used. The nonwoven fabric may also be a multilayered nonwoven fabric, i.e., comprise different layers of fibers. For example, the nonwoven fabric may comprise two or three layers, wherein at least one layer is a layer formed by the inventive nonwoven fiber.

Use for Drug Delivery

[0249] In a fourth aspect, the present invention concerns the use of an electrospun fiber material containing a polymer, a surface-reacted calcium carbonate and a pharmaceutically or nutraceutically active ingredient for drug delivery,

wherein the surface-reacted calcium carbonate is a reaction product of natural ground or precipitated calcium carbonate with carbon dioxide and one or more H₃O⁺ ion donors in an aqueous medium, wherein the carbon dioxide is formed in situ by the H₃O⁺ ion donor treatment and/or is supplied from an external source,

wherein at least a part of the pharmaceutically or nutraceutically active ingredient is present in the pores of the surface-reacted calcium carbonate.

[0250] The term "drug delivery" refers to the administration of the pharmaceutically or nutraceutically active ingredient to a subject. The electrospun fiber material may be an electrospun fiber as described hereinabove or a nonwoven fabric as described hereinabove. Accordingly, the pharmaceutically or nutraceutically active ingredient is delivered to a subject, as it is released from the electrospun fiber material upon contact with the subject. Thus, the electrospun fiber material preferably is an article as described hereinbelow, and is preferably selected from the group comprising mats, scaffolds, films, yarns, transdermal patches, intrabuccal patches, implantable textiles, wound dressings and medical tapes or from the group consisting of yarns, transdermal patches, intrabuccal patches, implantable textiles, wound dressings and medical tapes.

[0251] Thus, the present invention also refers to an electrospun fiber material containing a polymer, a surface-reacted calcium carbonate and a pharmaceutically or nutraceutically active ingredient for use in drug delivery,

wherein the surface-reacted calcium carbonate is a reaction product of natural ground or precipitated calcium carbonate with carbon dioxide and one or more H₃O⁺ ion donors in an aqueous medium, wherein the carbon dioxide is formed in situ by the H₃O⁺ ion donor treatment and/or is supplied from an external source,

wherein at least a part of the pharmaceutically or nutraceutically active ingredient is present in the pores of the surface-reacted calcium carbonate.

The Inventive Article and its Uses

[0252] A fifth aspect of the present invention concerns an article comprising the inventive electrospun fiber or the inventive nonwoven fabric.

[0253] It is appreciated that the electrospun fiber and the inventive nonwoven fabric are described in detail hereinabove. The article is preferably selected from the group comprising hygiene products, medical and healthcare products, filter products, geotextile products, agriculture and horticulture products, clothing, footwear and baggage products, household and industrial products, packaging products, construction products and the like.

[0254] In view of the properties of the nonwoven fabric as described herein, it is particularly preferred that the article comprising the nonwoven fabric is selected from the group consisting of hygiene products, medical and healthcare products. Accordingly, the article preferably is selected from the group consisting of yarns, transdermal patches, intrabuccal patches, implantable textiles, wound dressings and medical tapes. As an illustrative example, an implantable textile may be used as a bone scaffolding material. Therein, the pharmaceutically active ingredient may be an antimicrobial active ingredient or a bone growth factor. Additionally or alternatively, the polymer may be a biodegradable polymer, for example, a poly(lactic acid) as described hereinabove.

[0255] Another specific example relates to intrabuccal patches. Many oral mucosal conditions cause considerable and prolonged pain that is difficult to alleviate via topical delivery, and the use of injection causes many patients dental anxiety and needle-prick pain. Therefore, the provision of a noninjectable drug delivery system as an alternative administration procedure provides a significant advantage to these patients. The inventive mucoadhesive electrospun patches for the direct delivery of therapeutics to the oral mucosa can be used as a vehicle for rapid uptake and sustained anesthetic drug delivery, e.g. to treat or prevent oral pain.

[0256] Also transdermal patches may represent very suitable articles made from the inventive fibers. It is noted that electrospinning has been used to fabricate dermal patches for wound healing and drug delivery. Electrospun dermal patches exhibit several advantages including high surface area and exceptional flexibility. For practical application as dermal patch, its flexibility allows it to maintain close proximity to the contours of the skin surface and, thus, controlled and continuous delivery.

[0257] As another illustrative example for the inventive articles and uses, reference is made to wound dressings or scaffolds. A critical aspect on the current research on skin tissue engineering is to develop matrices that promote growth and uniform distribution of cells across the wound area, and at the same time offer protection, as well as deliver drugs that help wound healing and tissue regeneration. The inventive electrospun scaffolds or wound dressings are suitable for such purpose and especially as carrier for drugs, e.g. as carriers for the bioactive natural products alkannin and shikonin (A/S). The fibers of such article may be made from e.g. cellulose acetate (CA) or poly(ε-caprolactone) (PCL).

[0258] In another embodiment of the present invention, the inventive article is applied onto an animate or inanimate surface for protecting them against microbial contamination. In this embodiment, the pharmaceutically active ingredient preferably is an antimicrobial active ingredient.

[0259] A sixth aspect of the present invention relates to the use of an inventive article in drug delivery applications. Preferably, the inventive article is used as described hereinabove.

[0260] The present invention, therefore, also relates to the inventive article for use in drug delivery applications.

[0261] The present invention will now be further described by reference to the following specific examples, without being limited thereto.

Examples

Preparation of SRCC

[0262] Surface-reacted calcium carbonate (SRCC) (d₅₀ (vol)= 6.6 µm, d₉₈ (vol)= 13.7 µm, SSA = 59.9 m²g^-1) with an intra-particle intruded specific pore volume of 0.939 cm³/g (for the pore diameter range of 0.004 to 0.51 µm).

[0263] SRCC was obtained by preparing 350 litres of an aqueous suspension of ground calcium carbonate in a mixing vessel by adjusting the solids content of a ground limestone calcium carbonate from Omya SAS, Orgon having a weight based median particle size of 1.3 µm, as determined by sedimentation, such that a solids content of 10 wt.-%, based on the total weight of the aqueous suspension, is obtained.

[0264] Whilst mixing the slurry at a speed of 6.2 m/s, 11.2 kg phosphoric acid was added in form of an aqueous solution containing 30 wt.-% phosphoric acid to said suspension over a period of 20 minutes at a temperature of 70°C. After the addition of the acid, the slurry was stirred for additional 5 minutes, before removing it from the vessel and drying using a jet-dryer.

Example 1. Triggered release of a model substance from an inventive nonwoven fiber.

Methods:

Fluorescein loading into surface-reacted calcium carbonate (SRCC)

[0265] Fluorescein was used as a model substance to study the release from electrospun fiber-SRCC composites. 100 mg of Fluorescein sodium was dissolved in 2 ml of ethanol and the solution was subsequently mixed with 1g of SRCC in order to get paste like consistency. The paste was then dried in a vacuum oven at 40°C and 100 mbar for 12 h.

Preparation of electrospun fiber-SRCC composite material

[0266] Eudragit polymer (L100-55, Evonik, Essen, Germany) was dissolved in Methanol using a magnetic stirrer. Polymer concentration was 25 %, w/v. The solution was stirred overnight to get a homogenous and clear solution. Subsequently, Fluorescein-loaded SRCC was added to the polymer solution in order to create a dispersion with an SRCC content of 5 to 10%, w/v. The dispersion was stirred for 2 h on a magnetic stirrer followed by sonication for 30 min to eliminate agglomerates and air bubbles. Before spinning, the dispersion was stirred again using a magnetic stirrer at low rpm to avoid formation of air bubbles. Dispersions were then filled into a 12 ml syringe and pumped through teflon tubing with inner diameter of 1 mm and length of 50 cm to a blunt 19G needle. The needle was connected to a high voltage supply. Flowrate of the pump was 1-5 ml/h. Electric potential was between 10 and 20 kV. The collector was a stainless steel plate (dimensions were 20X20 cm), that was covered with aluminum foil. Collector plate was connected to earth ground. Distance from the needle tip to the grounded collector plate was 20 cm. The electrospinning setup was operated horizontally from bottom to top, to avoid deposition of large droplets or accumulated material from the needle tip (formation of crust). The tip of the needle was cleaned several times manually during the fiber production using ethanol and paper towels. After spinning for approx. 1h, the non-woven composite material was carefully removed from the collector and cut into pieces for further analysis.

[0267] The method to produce fluorescein-loaded fiber-SRCC composites was also used in combination with other polymers and solvents:

Polyethyleneglycol (Alfa Aesar, Massachusetts, US) was dissolved in deionized water up to concentrations of 4%, w/v.

Polycaprolactone (Capa 6505, Perstorp, Warrington, UK) was dissolved in Acetone at a concentration of 10%, w/v.

Results

Release

[0268] The pH triggered release of Fluorescein from fiber-SRCC composites (Eudragit) was tested in a modified USP 1 dissolution apparatus. Non-woven composites were wrapped around the cylindrical baskets and covered with parafilm, so that only the one side of the non-wovens was exposed to the dissolution medium. The pH of the dissolution medium (Phosphate buffer) was changed from pH 1 to pH 10 after 60 minutes in order to trigger the release of Fluorescein by titrating 10 M NaOH. Baskets were rotating at a speed of 50 rpm and the temperature was 37°C. Optical density was measured by in-line UV-spectrophotometer at 475 nm. The result is shown in Figure 1.

Mercury porosimetry

[0269] Porosimetry of samples with different loaded SRCC/Eudragit ratios was measured by mercury porosimetry (Micromeritics, Autopore IV, Germany). The porosimetry plot shows increasing pore volume overall and additional volume in the size below 100nm. The results are shown in Figure 2.

Example 2. Incorporation of Pharmaceutically Active Ingredients

Materials

[0270] The materials employed in Example 2 are shown in Table 1.

Table 1. Materials used in Example 2.

Substance	Trade name/Grade	Manufacturer/ Distributor
Surface-Reacted Calcium Carbonate	-	As above
Polycaprolactone	Capa 6800	Perstorp UK limited
Stearic Acid	(Art. Nr. 9459.1)	Carl Roth
Acyclovir Sodium	Acyclovir Labatec	Labatec Pharma SA
Acyclovir	OR-5147-25G	Combi Blocks
Lidocaine	L7757-25G	Sigma-Aldrich
Acetone	Acetone for analysis	MERCK
Chloroform	Chloroform for analysis	MERCK
Methanol	Reag. Ph. Eur.	Sigma Aldrich
Ethanol	>99.8%, for HPLC	Fluka
Dimethylsulfoxide	USP, Ph. Eur.	Gaylord Chemical
Diethylamine	>99.5%	Sigma Aldrich
Acetonitrile	Rotisolv HPLC	Carl Roth
Polyacrylic Acid	Carbopol 981	Lubrizol
Di-Sodiumhydrogenphosphate (Dodecahydrate)	>99%, p.a., ISO	Carl Roth
Sodium di-hydrogenphosphate	>99%, p.a., ISO	Carl Roth
Potassium di-hydrogenphosphate	>99, p.a., ACS

Methods

Production of stearic acid treated surface-reacted calcium carbonate (SASRCC)

[0271] 1g of stearic acid was dispersed in 80ml of distilled water, 10 Drops of NaOH were added and stirred using a magnetic stirrer for 10 minutes.

[0272] In a separate Erlenmeyer flask, 120 ml of water and 200 ml of EtOH were mixed and heated until boiling, then 40g of SRCC and the previously prepared stearic acid dispersion were added to the boiling solution. A reflux condenser was added to avoid evaporation. The suspension was then boiled for 2h. Subsequently, the suspension was vacuum filtered through a paper filter and washed 2 times with 200 ml of water and dried at 100 °C and 40 mbar in a rotary evaporator.

Drug loading into SRCC and SASRCC

[0273] SRCC was loaded with 10, 20, and 30 % (w/w) of drug (Lidocaine, Acyclovir sodium and Acyclovir). Therefore, appropriate amount of drug was dissolved in 40 ml of solvent and the corresponding amount of SRCC or SASRCC was added. Majority of solvent was then removed using a rotary evaporator (Büchi, Switzerland) at P1 and the corresponding temperature listed in Table 3. Finally, the pressure was reduced to P2 for to completely dry the product. Table 2 shows the composition of the obtained formulations.

Table 2. Produced drug-loaded SRCCs.

Formulation	Drug Load [%]	SRCC (amount [g])	Drug (amount [g])	Solvent (40 mL)
F1	10	SRCC (9)	Lidocaine (1)	Methanol
F2	20	SRCC (8)	Lidocaine (2)	Methanol
F3	30	SRCC (7)	Lidocaine (3)	Methanol
F4	10	SASRCC (9)	Lidocaine (1)	Methanol
F5	10	SRCC (9)	Acyclovir-Na (1)	Water
F6	10	SASRCC (9)	Acyclovir-Na (1)	Methanol (50 °C)
F7	30	SRCC (7)	Acyclovir (3)	DMSO

Table 3. Conditions for solvent removal during drug loading process.

Solvent	Temp. [°C]	P1 (solvent removal) [mbar]	P2 (final drying) [mbar]
Methanol	70	300	<10
Water	55	120	<10
DMSO	90	30	<10

Preparation of spinning-dispersion

[0274] The spinning dispersion was prepared by mixing the solid carriers into a 15%, w/w solution of PCL, that was dissolved in a mix of chloroform/acetone, (40/60,w/w). The polymer solution was prepared separately. Therefore, the polymer was added slowly to avoid formation of clumps and subsequently stirred for at least 24 h at room temperature.

[0275] The mixing step was carried out in a homogenizer, Polytron PT 3000 (Kinematika AG, Switzerland). The dispersion was mixed at 12'000 rpm for 4 minutes. External cooling was applied to compensate the heat that resulted from the mixing process. Ice water was used as a coolant. The temperature of the coolant was approx. 0°C. The resulting dispersion was sonicated for 15 minutes in an ice bath to remove air bubbles and then filled into 10ml plastic syringes.

Electrospinning Setup

[0276] The electrospinning setup was designed and built in house.

[0277] The setup consisted of an emitter that is connected to a high voltage supply and a collector that is connected to earth ground. The emitter was installed on a laterally oscillating carriage, for homogenous distribution of the fibers on the collector. Electrospinning was performed from bottom to top. (Figure 3 a))

[0278] The electrospinning process was started immediately after preparation of the spinning solution. Dispersion was filled into four 10ml syringes which were connected separately via PTFE tubing with the emitter.

[0279] The emitter was an assembly of 4 blunt needles (21G) that were surrounded by nitrogen gas saturated with acetone (Figure 3 b)) to avoid bearding at the tip of the needles due to fast evaporation of solvents from the polymer solution. The lateral movement was adapted to the width of the drum collector (0.3 m) at a speed of approx. 0.1 m/s. Working distance (distance between emitter and collector) was 0.2 m and liquid feed rate was kept at 3ml/h for each needle using a syringe pump. A total of 30 ml was spun. The potential was adjusted to approx. -20kV ± 2kV in order to maintain a stable spray. The dimensions of the collector (rotating drum) were 0.3 m in width and a diameter of 0.1 m. The drum was rotated at 500 rpm. The drum was covered with aluminum and finally coated with magnesium-stearate to avoid the product from adhering/sticking to the aluminum foil. The process was constantly supervised. Needles were cleaned and the electric potential was adjusted when necessary to maintain a stable spinning process. The following samples were produced (Table 4):

Drugload (DL) determination of Lidocaine-containing fibers

[0280] The obtained fiber samples containing Lidocaine were selected for the determination of the drug load. Drug loaded nonwovens were dissolved in THF and sonicated for 3h. Subsequently the samples were centrifuged at 4000 rpm for 10 min to separate undissolved SRCC-particles. Finally, the supernatant was analyzed by HPLC at 230nm using a modified Pharmacopoeia method. Instead of isocratic method, a gradient was used: Mobile phase A was a solution of potassium dihydrogen phosphate (4.85 g/l) adjusted to pH 8 using NaOH. Mobile phase B was acetonitrile. Table 5 shows the time program of the method. After elution of lidocaine at 2.7 min, acetonitrile concentration was increased to 100% in order to wash out PCL, which is not soluble in the aqueous phase. Flowrate was 1.5 ml/min and oven temperature was 40°C, and total runtime was 10 min. Drug-load was calculated by using equation 1:

where DL is drug-load [%, w/w], mD is the mass of the drug, and mE is the mass of the excipients. Loading efficiency was calculated by using equation 2

where Leff is loading efficiency, DLm is the measured drug load, and DLc is the calculated/theoretical drug-load.

Table 5. Time program for HPLC method (Drugload of Lidocaine): After elution of Lidocaine, concentration of mobile phase B was increased to 100% in order to wash out PCL residues.

Time [min]:	0	3	5	7	8	10
Mobile phase B concentration [%]:	50	65	100	100	50	50

Dissolution experiments of Acyclovir-containing fibers

[0281] The obtained fiber samples containing Acyclovir were selected for the dissolution experiments. Dissolution experiments were carried out in a modified USP 1 dissolution apparatus. Therefore, the samples were removed from the aluminum support and cut into sections of 28 mm X 70 mm. These sections were wrapped around the baskets and fixed with parafilm. The bottom of the baskets was left uncovered. The baskets were rotated at 50 rpm in 500 ml of 50 mM phosphate buffer, pH 6.8. Figure 4 shows the schematic of the dissolution setup. Samples of 1 ml were manually withdrawn and passed through 0.45 µm PTFE filters.

[0282] Concentrations of the withdrawn samples were determined via HPLC (Nexera X2, Shimadzu, Japan), using a C 18 column (symmetry, Waters, Massachusetts). The mobile phase was 95% (v/v) water and 5% (v/v) acetonitrile, flowrate was 0.8 ml/h, oven temperature was 40°C, absorbance was measured at 254nm, retention time was 2 min, and total runtime was 4 minutes. Release rates were normalized to the maximum achieved concentrations that were measured at the end of the release.

Mercury intrusion porosimetry

[0283] The specific pore volume is measured using a mercury intrusion porosimeter (Micromeritics Autopore V 9620) having a maximum applied pressure of mercury 414 MPa (60 000 psi), equivalent to a Laplace throat diameter of 0.004 µm (~ 4 nm). The equilibration time used at each pressure step is 20 s. The sample material is sealed in a 3 cm³ chamber powder penetrometer for analysis. The data are corrected for mercury compression, penetrometer effects and elastic sample compression if applicable.

Results

Process

[0284] It was demonstrated that integration of porous SRCC particles into PCL fibers can be achieved by the electrospinning process. SRCC particles were loaded with model drugs such as Lidocaine and Acyclovir with drug loads of 10, 20, and 30% (w/w) using a solvent evaporation technique. Polymer solutions containing 5 and 10% (w/w) of these loaded particles were produced, leading to theoretical drug-loads of 2.6 to 12.8% (w/w) in the nonwoven product. SRCC content in the final product reached from 18 to 38% (w/w) based on calculations.

[0285] Spinning from bottom to top increased the stability of the process and prevented the product from splashes and bigger particles that originated from the needles.

[0286] Acyclovir Sodium loaded fibers without SRCC could only be produced up to a drug load of 3.39%, w/w by dispersing (and partially dissolving) the drug in the spinning solution. This was only possible, because the drug was available as a lyophilizate (small particle size).

[0287] When Acyclovir was used without SRCC, the production of fibers was not possible, since the solubility of Acyclovir in the spinning solution is too low, and particle size is too large.

Drug load of Lidocaine-containing fibers

[0288] Formulations with a theoretical drug-load of 2.6 to 12.77%, w/w were produced. The loading efficiency reached from 28 % to virtually complete incorporation. Formulations that do not contain SRCC show the lowest loading efficiency (28-61%). Table 6 shows the composition of the produced batches.

Table 6. Theoretical and actual composition of produced formulations.

Formulation	Drug-load [%]			SRCC-load [%]		Polymer-load [%]		Efficiency [%]
	Aim	HPLC	CHNS	Aim	CHNS	Aim	CHNS	HPLC
S1	2.60	2.27	2.51	23.38	21.50	74.03	75.98	87.27
S2	5.19	4.49		20.78		74.03		86.42
S3	7.79	6.69		18.18		74.03		85.90
S4	12.77	12.95		29.79		57.45		>99
S5	2.60	2.32	1.91	23.38	21.97	74.03	76.12	89.45
S6	4.26	3.47		38.30		57.45		81.44
S7	3.39	2.07		0		96.61		61.07
S8	6.56	1.85		0		93.44		28.26
S9	9.52	4.43		0		90.48		46.48

Dissolution of Acyclovir from electrospun PCL-fibers

[0289] Figure 5 shows the release of Acyclovir from PCL fibers (Legend: triangles (▲) - Sample S10, squares (▪) - Sample S11, crosses (x) - Sample S12). Fastest release is observed for the fibers that do not contain SRCC (Sample S12), which is characterized by a burst release of more than 80% within the first hour. Slowest release is observed for Sample S10, where Acyclovir was loaded into SRCC prior to mixing with the PCL solution and spinning. It takes approx. 6 h to achieve 80% of release.

[0290] Figure 6 shows in detail the release kinetics during the first 8 hours. It shows clearly that formulations containing SRCC (stearic acid treated or untreated) have a less pronounced burst release. After 15 minutes, Sample S12 reaches 50% whereas Samples S10 and S11 only show a released fraction of 21 % and 30%, respectively.

Porosimetry

[0291] Figure 7 shows the pore size distribution of samples with and without SRCC particles (thick line - sample S1, dashed-dotted line - sample S7, dashed line - sample S8, thin line - sample S9, dotted line - sample S12). It can be seen, that the integration of active ingredient-loaded SRCC particles into electrospun PCL fibers shifts the main peak of the plot towards larger pore diameters. The samples without SRCC have a similar main peak at around 5-6 µm. When active ingredient-loaded SRCC particles are integrated, the fiber mats are not as dense, since the particles would act as spacers between the fibers, hence creating larger pores.

[0292] Figure 8 shows the fine pore size distribution of Lidocaine loaded fibers with increasing loaded SRCC content (dotted line - sample S5, continuous line - sample S6, dashed-dotted line - Sample S7). The addition of loaded SRCC clearly increases the porosity in the range between 30 and 300 nm.

SEM Images

[0293] Figure 9 shows SEM images of samples S12 (top) and S7 (bottom) at different magnifications. It can be gathered that the active ingredient, in the absence of SRCC, is mostly deposited on the surface of the fibers.

[0294] Figure 10 shows SEM images of Sample S1 at different magnifications. The images are representative for most of the drug loaded samples. All samples show agglomeration of particles in an elongated shape, which are integrated within the PCL fibers. Only a small fraction of the particles is individually distributed along the fibers. In contrast to the samples, which do not contain carrier particles, no externally deposited material is present.

Example 3. Physical properties of the mixture as used for electrospinning and the obtained electrospun fibers

Conductivity of polymer solutions

[0295] Conductivity of the polymer solution that was used for all the experiments was measured with a conductivity probe (Inlab 730, Mettler Toledo). The compositions of the solutions, whose conductivities were measured, are shown in Tables 7 and 8. The results are shown in Table 9.

Table 7: Composition of polymer solution without SRCC

Substance	[wt.-%]
Chloroform	34

Acetone	51
Polycaprolactone (PCL)	15
Total	100

Table 8: Composition of polymer solution with SRCC

Substance	[wt.-%]
Chloroform	30.6
Acetone	45.9
Polycaprolactone (PCL)	13.5
Surface-reacted calcium carbonate (SRCC)	10
	100

Table 9: Electric conductivity of the of the polymer solutions/dispersions.

Sample	Electrical conductivity [mS/cm]
Chloroform/Acetone (40/60, wt)	0.24
15 wt.-% PCL in Chloroform/Acetone (40/60, wt)	0.11
(15 wt.-% PCL in Chloroform/Acetone (40/60, wt))+10 wt.-% SRCC	0.00008

Viscosity of polymer solutions

[0296] Viscosity of the polymer solution, that was used for all the experiments was measured with a viscometer (DV2T, Brookfield). Spindle that was used for the measurement was a SC4 DIN-82 spindle. An adapter for small volume was used. Sample volume was 5.5 ml. The results are shown in Table 10.

Table 10: Viscosity of the polymer solutions/dispersions.

Sample	Viscosity [mPa*s]
15 wt.-% PCL in Chloroform/Acetone (40/60, wt)	931
(15 wt.-% PCL in Chloroform/Acetone (40/60, wt))+10 wt.-% SRCC	56800

Specific Surface Area

[0297] Specific surface area of 3 different samples was measured with a BET- specific surface analyzer (ASAP 2460, Micromeritics). The results are shown in Table 11.

Table 11: Specific Surface Area of the tested formulations.

Sample	BET- specific surface area [m2/g]	Single point specific surface [m2/g]
S4	3.09	2.38
S6	4.99	3.78
S12	3.86	2.76

Titer of the fibers

[0298] Titer of the fibers was calculated based on the fibers diameter. Therefore, a representative SEM picture was used to measure the average fiber diameter using imaging software (Image J, FIJI). Average fiber diameter was calculated based on 30 randomly chosen fiber sections not containing visible SRCC particles. The titer (dTex) [g/10000m] was then calculated assuming a material density of 1.21 g/cm³ for PCL, using the following formula,

where d is the average diameter of the fibers and ρ is the density of PCL. The results are shown in table 12.

Table 12 : Calculated titer from Image analysis.

Sample	Fiber diameter [µm] n=30±SD	Titer [dTex]
Pure PCL fibers	1.53 ±0.82	0.022
S2	1.17±0.77	0.012
S3	1.46±1.39	0.020
S10	0.87±0.55	0.007

Claims

1. An electrospun fiber comprising a polymer, a surface-reacted calcium carbonate and a pharmaceutically or nutraceutically active ingredient,

wherein the surface-reacted calcium carbonate is a reaction product of natural ground or precipitated calcium carbonate with carbon dioxide and one or more H₃O⁺ ion donors in an aqueous medium, wherein the carbon dioxide is formed in situ by the H₃O⁺ ion donor treatment and/or is supplied from an external source, and

wherein at least a part of the pharmaceutically or nutraceutically active ingredient is present within the pores of the surface-reacted calcium carbonate.

2. The fiber of claim 1, wherein the surface-reacted calcium carbonate has

i) an intra-particle intruded specific pore volume in the range from 0.1 to 3.0 cm³/g, more preferably from 0.1 to 2.3 cm³/g, still more preferably from 0.2 to 2.0 cm³/g and most preferably from 0.4 to 1.8 cm³/g, determined by mercury porosimetry measurement, and/or

ii) a specific surface area (BET) from 15 to 200 m²/g, preferably of from 27 to 180 m²/g, more preferably from 30 to 160 m²/g, and most preferably from 45 to 150 m²/g, as measured by the BET method according to ISO 9277:2010.

3. The fiber of claim 1 or 2, wherein the surface-reacted calcium carbonate has

i) a volume median particle size (d₅₀) from 1 to 75 µm, preferably from 2 to 50 µm, more preferably from 3 to 40 µm, and most preferably from 4 to 30 µm, and/or

ii) a top cut (d₉₈) value from 2 to 150 µm, preferably from 4 to 100 µm, more preferably from 6 to 80 µm, and most preferably from 8 to 60 µm.

4. The fiber of any one of the preceding claims, wherein the fiber has

- an intra-particle intruded specific pore volume in the range from 0.05 to 0.5 cm³/g, preferably in the range from 0.1 to 0.3 cm³/g, determined by mercury porosimetry measurement, and/or

- an inter-particle/inter-fiber specific pore volume in the range from 1.0 to 4.0, cm³/g, preferably from 1.5 to 3.5 cm³/g, determined by mercury porosimetry measurement, and/or

- an average fiber diameter of less than 2 µm, preferably in the range from 1 nm to 1.5 µm, more preferably in the range from 10 nm to 1.0 µm, and/or

- a titer of below 0.5 dtex, preferably in the range from 0.0001 to 0.4 dtex, more preferably in the range from 0.001 to 0.1 dtex.

5. The fiber of any one of the preceding claims,

wherein the fiber comprises the surface-reacted calcium carbonate in an amount from 5 to 80 wt.-%, preferably from 30 to 70 wt.-%, more preferably from 40 to 60 wt.-%, based on the total weight of the fiber, and/or

wherein the fiber comprises the pharmaceutically or nutraceutically active ingredient in an amount from 0.1 to 30 wt.-%, preferably from 1 to 25 wt.-%, more preferably from 3 to 20 wt.-% and most preferably from 5 to 20 wt.-%, based on the total weight of the fiber.

6. The fiber of any one of the preceding claims, wherein the polymer is selected from the group consisting of polyesters, polypeptides, polyethers, poly(meth)acrylates, polysaccharides and derivatives thereof, polyurethanes, polyimides, polyamides, poly(acrylonitrile), poly(vinyl pyrrolidone), poly(vinyl alcohol), polyaniline, poly(vinylidene fluoride), aryl polysulfones, and mixtures and copolymers of the foregoing.

7. The fiber of any one of the preceding claims, wherein the volume median particle size d₅₀ is at least 5 % greater than the average fiber diameter, preferably at least 10 % greater than the fiber diameter, more preferably at least 20 % greater than the average fiber diameter, wherein the average fiber diameter is determined via scanning electron microscopy (SEM) at a fiber section not comprising a visible surface-reacted calcium carbonate particle.

8. A process for the preparation of a fiber, comprising the steps of

a) providing a polymer,

b) providing a surface-reacted calcium carbonate,
wherein the surface-reacted calcium carbonate is a reaction product of natural ground or precipitated calcium carbonate with carbon dioxide and one or more H₃O⁺ ion donors in an aqueous medium, wherein the carbon dioxide is formed in situ by the H₃O⁺ ion donor treatment and/or is supplied from an external source,

c) providing a pharmaceutically or nutraceutically active ingredient,

d) loading the pharmaceutically or nutraceutically active ingredient of step c) onto the surface-reacted calcium carbonate of step b) to obtain a loaded surface-reacted calcium carbonate,

e) mixing the polymer of step a) with the loaded surface-reacted calcium carbonate of step d) to obtain a mixture,

f) electrospinning the mixture of step e) into an electrospun fiber.

9. The process of claim 8, wherein

- in mixing step e) the polymer and the loaded surface-reacted calcium carbonate are mixed with a solvent such that the polymer is essentially completely dissolved in the solvent to obtain the mixture; and

- electrospinning step f) is a suspension electrospinning step comprising the sub-steps of

f1) feeding the mixture to a spinneret,

f2) applying an electrostatic potential on the spinneret and a collector to form the filament fiber,

f3) collecting the filament fiber at the collector, preferably in order to form a nonwoven fabric,

wherein the electrospinning step preferably is performed at a temperature in the range from 0 °C to 50 °C.

10. The process of claim 9, wherein the solvent

- is selected from the group consisting of ketones, such as acetone and butanone, alcohols, such as methanol, ethanol, 1-propanol and 2-propanol, fluorinated solvents, such as 2,2,2-trifluoroethanol, hexafluoroacetone and hexafluoroisopropanol, water, dimethylformamide, dimethylsulfoxide, tetrahydrofuran, chlorinated solvents, such as chloroform and ethylene dichloride, acetic acid, formic acid and mixtures thereof, and/or

- further comprises an electrolyte, preferably selected from the group consisting of alkali metal halides, such as sodium chloride and potassium chloride, alkaline earth metal halides, such as magnesium chloride and magnesium bromide, pyridinium formate, cationic surfactants, such as dodecyltrimethylammonium bromide, tetrabutyl ammonium chloride and tetrabutyl ammonium bromide, and mixtures thereof.

11. The process of any one of claims 8 to 10, wherein the mixture of step e) comprises

- the polymer in an amount of from 1 to 60 wt.-%, preferably in an amount from 2 to 40 wt-%, based on the total weight of the mixture, and/or

- the surface-reacted calcium carbonate and/or the loaded surface-reacted calcium carbonate in a total amount from 1 to 25 wt.-%, preferably 2 to 20 wt.-%, more preferably 5 to 15 wt.-%, based on the total weight of the mixture, and/or

- the pharmaceutically or nutraceutically active ingredient in an amount from 0.1 to 10 wt.-%, preferably from 0.5 to 8 wt.-%, and more preferably from 1 to 5 wt.-%, based on the total weight of the mixture, and/or

- optionally the electrolyte in an amount from 0.1 to 10 wt.-%, preferably from 0.5 to 5 wt.-%, based on the total weight of the mixture.

12. The process of any one of claims 8 to 11, wherein the mixture of step e) has

- a Brookfield viscosity in the range from 100 to 1 000 000 mPas, and/or

- a conductivity in the range from 0.001 µS/m to 10 S/m,

13. The process of any one of claims 9 to 11, wherein the electrostatic potential applied in step f2) is from 1 to 100 kV, preferably from 2 to 75 kV, more preferably from 5 to 50 kV, and most preferably from 10 to 20 kV.

14. An electrospun fiber according to any one of claims 1 to 7, obtainable by a process according to any one of claims 8 to 13.

15. A nonwoven fabric comprising, preferably consisting essentially of, the electrospun fiber of any one of claims 1 to 7 or 14, preferably wherein the nonwoven fabric has

- an occlusion specific pore volume in the range from 0.8 to 6.0 cm³/g, preferably from 1.0 to 5.0 cm³/g, determined by mercury porosimetry measurement, and/or

- a mode average inter-fiber pore diameter in the range from 10 to 100 µm, preferably in the range from 10 to 50 µm, determined by mercury porosimetry measurement, and/or

- a BET specific surface area in the range from 1 to 100 m²/g, as measured by the BET method according to ISO 9277:2010.

16. Use of an electrospun fiber material comprising a polymer, a surface-reacted calcium carbonate and a pharmaceutically or nutraceutically active ingredient for drug delivery,

wherein the surface-reacted calcium carbonate is a reaction product of natural ground or precipitated calcium carbonate with carbon dioxide and one or more H₃O⁺ ion donors in an aqueous medium, wherein the carbon dioxide is formed in situ by the H₃O⁺ ion donor treatment and/or is supplied from an external source,

wherein at least a part of the pharmaceutically or nutraceutically active ingredient is present in the pores of the surface-reacted calcium carbonate.

17. An article comprising the electrospun fiber of any one of claims 1 to 7 or 14, or the nonwoven fabric of claim 15, wherein the article preferably is selected from the group consisting of yarns, transdermal patches, intrabuccal patches, implantable textiles, wound dressings and medical tapes.

18. Use of an article according to claim 17 in drug delivery applications.

Drawing