EP2323635A2

EP2323635A2 - Fibrous surface structure containing active ingredients with controlled release of active ingredients, use thereof and method for the production thereof

Info

Publication number: EP2323635A2
Application number: EP09781627A
Authority: EP
Inventors: Burghard Liebmann; Evgueni Klimov
Original assignee: BASF SE
Current assignee: BASF SE
Priority date: 2008-08-08
Filing date: 2009-08-07
Publication date: 2011-05-25
Also published as: US20110129510A1; JP2011530661A; WO2010015709A3; CN102176905A; WO2010015709A2

Abstract

The invention relates to a fibrous surface structure containing active ingredients with an adjustable active ingredient release profile, comprising a fibrous, polymeric, soluble and/or decomposable active ingredient substrate and at least one active ingredient that is associated with the substrate and can be released from the fibrous surface structure; to formulations containing active ingredients, comprising said fibrous surface structures; to the use of fibrous surface structures containing active ingredients according to the invention for producing formulations containing active ingredients; and to a method for producing fibrous surface structures according to the invention.

Description

Active-ingredient adjustable-release fiber sheets, their applications and methods of making the same

The invention relates to active ingredient-containing fiber fabrics having an adjustable active ingredient release profile, comprising a fibrous, polymeric soluble and / or degradable active substance carrier and at least one active ingredient associated with the carrier and releasable from the fiber fabric; active ingredient-containing formulations comprising such fiber fabrics; the use according to the invention of active ingredient-containing fibrous sheets for the production of active ingredient-containing formulations; and processes for the production of fiber fabrics according to the invention.

State of the art

For the production of nanofibres and mesofibers, a multitude of methods are known to the person skilled in the art, of which the electrospinning method (electrospinning) is of greatest importance at present, In this method, which is described, for example, by DH Reneker, HD Chun in Nanotechn. 1996), page 216 f., A polymer melt or a polymer solution is usually exposed to a high electric field at an edge serving as an electrode, which can be achieved, for example, by passing the polymer melt or polymer solution under low pressure through an electric field Due to the resulting electrostatic charging of the polymer melt or polymer solution, a flow of material directed towards the counterelectrode, which solidifies on the way to the counterelectrode, is produced with this method Obtained nonwovens or ensembles of ordered fibers.

DE-A1-10133393 discloses a process for producing hollow fibers having an inner diameter of 1 to 100 nm, in which a solution of a water-insoluble polymer - for example a poly-L-lactide solution in dichloromethane or a polyamide-46 Solution in pyridine - is electrospun. A similar method is also known from W0-A1 -01 / 09414 and DE-A1-10355665.

From DE-A1-19600162 a method for the production of lawn mower wire or textile fabrics is known in which polyamide, polyester or polypropylene as filament-forming polymer, a maleic anhydride-modified polyethylene / polypropylene rubber and one or more aging stabilizers combined, melted and mixed together before this melt is melt-spun.

DE-A1-10 2004 009 887 relates to a process for producing fibers with a diameter of <50 μm by electrostatic spinning or spraying a melt of at least one thermoplastic polymer.

A detailed description of electrospinning processes, properties of fibers and their possible applications can be found in A. Greiner and J. Wendorff, Angew. Chemistry Int. Ed., 2007, 119, 5770-5805.

Another suitable process for the production of fiber webs is the so-called centrifugal process (also called rotor spinning). EP 624 665B1 and EP 1 088 918 A1 (both BASF applications) disclose a process for the production of fiber structures of melamine-formaldehyde resin and their blends with thermoplastic polymers by centrifugal spinning on a spinner.

A method and an apparatus for producing fibers from the melt of different polymer materials by means of centrifugal forces are also described in DE10 2005 048 939 A1.

WO-A-2001/54667 and WO-A-2004/014304 disclose amorphous pharmaceutical formulations and processes for their preparation. Electrospinning of polymer-drug solutions has enabled the generation of stable amorphous formulations. However, no specific information on drug release and its control are made.

WO-A-2007/082936 describes the use of amphiphilic, self-assembling proteins for the formulation of sparingly water-soluble effect substances by dispersing the effect substances in a protein-containing protective colloid. After mixing the sparingly water-soluble effect substances and the amphiphilic, self-assembling proteins in a common disperse phase and subsequent phase separation into a protein- and effect-rich phase and a protein and low-phase phase Protein microbeads into which the poorly water-soluble effect substances are encapsulated.

WO-A-2007/093232 describes nanoparticulate formulations of crop protection active ingredients in which the nanoparticles have core-shell structures with an average particle diameter of 0.05 to 2.0 μm and the crop protection active ingredient in the core is X-ray amorphous together with one or more Polymer is present, wherein the polymer is not or only partially soluble in water or aqueous solutions or water-solvent mixtures and the shell consists of a stabilizing shell matrix. These formulations are preparable by a process which comprises (a) preparing a solution of the crop protection agent in a water immiscible organic solvent, (b) dissolving the core polymer in a water immiscible organic solvent; and emulsifying the mixture resulting from (a) and (b) with an aqueous solution comprising components of the shell matrix by injecting the respective solutions into a mixing chamber and removing the organic solvent after emulsifying.

Summary of the invention:

The hitherto known polymer-based formulations of active substances and effect substances are still subject to disadvantages. In particular, the targeted cessation of release of the formulated drugs, e.g. over longer periods, represents a previously unsatisfactory solved problem.

The inclusion of agrochemical, pharmaceutical and cosmetic effect substances in synthetic polymers or polymer blends in the temperature range of 5-90 ⁰ C, under normal pressure from a dilute polymer-drug solution would be particularly advantageous for sparingly soluble and temperature-sensitive effect substances. Of particular value would be the use of biodegradable or biocompatible polymers.

It was therefore an object to provide a method which allows the formulation of such active ingredients using polymeric materials as formulation auxiliaries and thereby allows a better adjustment of drug release than is known from the prior art. In the following, the terms active substances and effect substances are used synonymously

Brief Description:

In the accompanying figures shows:

FIG. 1A SEM photographs of PVP polymer fibers obtainable by electrospinning PVP polymer solutions with different contents of the active ingredient epoxiconazole.

FIG. 1B shows the recovery rates for the active ingredient epoxiconazole in various PVP matrices produced according to the invention (nonwoven fabrics 1 and 2) in comparison to corresponding calibration samples.

Figure 2 shows the results of WAXS measurements on freshly prepared fibrous sheets of PVP-Epoxiconazol at levels of 9, 23 and 33 wt .-% epoxiconazole compared to pure PVP or crystalline Epoxiconazol.

Figure 3 shows the results of WAXS measurements on fibrous webs of PVP-epoxiconazole prepared according to the invention which had been stored at different temperatures compared to pure PVP or crystalline epoxiconazole; each sample was stored for 24 hours at +40 ⁰ C, -10 ° C and 0 ⁰ C and then for 72 hrs. At 20 ⁰ C stored.

FIG. 4A shows SEM images of PVP-β-carotene fibers produced according to the invention with different β-carotene contents.

FIG. 4B shows the recovery rates for the active ingredient β-carotene in various PVP matrices produced according to the invention (nonwoven fabrics 1 and 2) in comparison to corresponding calibration samples.

FIG. 5 shows the results of WAXS measurements on fibrous structures of PVP-β-carotene produced according to the invention. in comparison to pure PVP or crystalline ß-carotene. FIG. 6 shows the results of WAXS measurements on fibrous structures of PVP-β-carotene produced according to the invention, which had been stored at different temperatures, in comparison with pure PVP or crystalline β-carotene; each sample was stored for 24 hours at +40 ⁰ C, -10 ° C and 0 ⁰ C and then for 72 hrs. At 20 ⁰ C stored.

FIG. 7 shows SEM images of PMMA epoxiconazole fibers produced according to the invention with different epoxiconazole contents.

FIG. 8 shows the results of the WAXS measurements on fiber surfaces of PMMA-epoxiconazole at different epoxiconazole contents.

FIG. 9 shows the respective release profiles of epoxiconazole from the biodegradable polyester Ecoflex® as a film or fibrous sheet.

Figure 10 shows the different release profiles of Epoxiconazole from biodegradable polyester Exoflex®, PVP and PMMA.

FIG. 11 shows the different release profiles of epoxiconazole from fiber surface structures made from PVP, PMMA and 1: 1 or 1: 5 blends of PVP and PMMA.

FIG. 12 shows micrographs of cross sections through active ingredient-free fibers of PMMA and PVP;

FIG. 13 shows the different release profiles of epoxiconazole from fibrous sheets made from PVP, Ecoflex® and a 1: 1 blend of PVP and Ecoflex;

FIG. 14 shows electron micrographs (SEM) of C16 spider silk protein sheets (fibers) with encapsulated active ingredient clotrimazole;

FIG. 15 shows crystallinity studies (WAXS in transmission) of the active ingredient clotrimazole in the electrospun-derived C16-spider silk protein formulations in comparison with pure clotrimazole substance; FIG. 16 shows the release of the active ingredient clotrimazole from a tablet-compressed C16 spider silk protein formulation obtained by electrospinning in potassium phosphate buffer (control) and artificial gastric and intestinal juice. The 100% value used was the total active substance concentrations listed in the table according to Example 10.

Detailed description of the invention:

1. Definition of terms used

Unless otherwise specified, the following meanings of technical terms apply within the scope of the present description:

A "carrier polymer" is understood as meaning synthetic polymers or their mixtures, biopolymers or their mixtures, or else mixtures of at least one synthetic and one biopolymer, the carrier polymer having the ability not to be formulated with the active substance (s) to be formulated - enter into covalent interactions, or to enclose particulate active ingredients (dispersed or crystalline).

A "non-covalent" interaction is any type of bond known to those skilled in the art, with no formation of covalent bonds between the active agent and the carrier polymer, by way of example but not limited to: hydrogen bonding; Complex formation, ion interaction.

An "active ingredient" or "effect substance" is understood as meaning synthetic or natural, low molecular weight substances having hydrophilic, lipophilic or amphiphilic properties which can be used in the agrochemical, pharmaceutical, cosmetic or food and feed industries; as well as biological active macromolecules which can be embedded in or adsorbed to a fibrous sheet according to the invention, such as peptides (such as oligopeptides having 2 to 10 amino acid residues and polypeptides having more than 10, such as 1 to 100 amino acid residues) as well as enzymes and individual or double-stranded nucleic acid molecules (such as oligonucleotides having 2 to 50 nucleic acid tests and polynucleotides having more than 50 nucleic acid residues). "Low molecular weight" means molar masses of less than 5000, in particular less than 2000, such as 100 to 1000 grams per mole.

"High molecular weight" means molar masses of more than 5000, in particular less than 10,000, such as 10,000 to 1,000,000 grams per mole.

The terms "drug" and "effect substance" are used synonymously.

The term "fibrous sheet" according to the invention comprises both individual polymer fibers and the assembly of a plurality of such fibers, for example non-woven fabrics.

An "active ingredient carrier" is fibrous and carries, preferably in adsorbed, non-covalently bonded form on the fiber surface and / or integrated into the fiber material, the active ingredient (s) to be processed according to the invention The active ingredient can be distributed uniformly or unevenly over the fiber. The active substance can also be reversibly adsorbed in amorphous, partially crystalline or crystalline form on / in the active substance carrier.

A "soluble" drug carrier is partially or completely soluble in an aqueous or organic solvent, preferably an aqueous solvent, such as water or a water-based solvent, in a pH range of pH 2 to 13, such as 4 to 11 Thus, solubility in water can vary over a wide range - ie, from good, ie, rapid and complete or substantially complete solubility, to very slow and complete or incomplete solubility.

In principle, all polymers which are in a temperature range between 0 and 240 ^° C., a pressure range between 1 and 100 bar, a pH range of 0 to 14 or ionic strengths of up to 10 mol / l in water are suitable as polymeric constituents of the active substance preparations according to the invention or / and are soluble in organic solvents.

A "degradable" drug carrier is present when the fiber structure by chemical see, biological or physical processes, such as exposure light or other radiation, solvents, chemical or biochemical oxidation, hydrolysis, proteolysis is partially or completely destroyed.

Biochemical processes can be carried out by enzymes or microorganisms, such as, for example, prokaryotes or eukaryotes, e.g. Bacteria, yeasts, fungi are mediated.

By "miscibility" of polymers is meant according to the invention that in a mixture of at least two different polymers, one polymer may act as the other solvent, which means that a single-phase system is formed between the two different polymers two different phases are present.

According to the invention, a "composite polymer" is understood as meaning a homogeneous or inhomogeneous mixture of at least one fiber-forming polymer component having at least one low molecular weight or high molecular weight additive, such as, in particular, a nonpolymerizable additive, such as, for example, an active substance or effect substance as defined above.

By a "processed form" of a fibrous sheet is meant that the product originally obtained in the manufacture of the fibrous sheet is further processed, for example, that the fibers are compressed or tableted, applied to another support and / or subjected to comminution to shorten the fiber length become.

Unless otherwise specified, molecular weight data for polymers are Mn or Mw values.

2. Preferred embodiments

A first object of the invention relates to active ingredient-containing fibrous sheet comprising a fibrous, polymeric soluble and / or degradable drug carrier and, associated with the carrier, and releasable from the fibrous sheet low molecular weight drug or more agents, such as. B. 2, 3, 4 or 5 agents, from the same or different classes of drugs or with the same or different mode of action, wherein the carrier is a composite polymer, the a mixture of two or more, such as. B. 2, 3, 4 or 5 polymer components, said at least two polymer components differ in at least one property which is selected from a) solubility in aqueous or non-aqueous solvents, b) molecular weight (Mn or Mw) c) glass transition temperature (Tg) / melting point (mp); and d) degradability, such as chemical or in particular biodegradability, such as by at least one enzyme or at least one microorganism, oxidative or / and hydrolytic and / or by radiation.

In particular, the polymer components differ in terms of solubility and / or degradability.

Furthermore, the at least two polymer components may differ

(i) different loading densities with the agent (s);

(ii) different specific surface area of the fibers (i.e., diameter);

(iii) different physical structuring of the fibers, e.g. in the form of different porosity and / or surface roughness (topography), phase separation.

In particular, the at least one active ingredient is contained in amorphous or partially crystalline form

For example, in the fibrous sheet, the active ingredient may be integrated (embedded) in the carrier and / or adsorbed thereon.

Particularly preferably, the fibrous, active substance-containing carrier is obtainable by a spinning process.

In particular, the fibrous, active substance-containing carrier is prepared by an electrospinning process with an electro-spinnable solution containing, in each case in dissolved form, the at least one active ingredient and the mixture of at least two polymer components. The polymer components contained in the fibrous sheet of the present invention are miscible with each other or at least two of the polymer components are not miscible with each other.

The polymer components used according to the invention are selected in particular from synthetic polymers and natural polymers (biopolymers), in particular amphiphilic self-assembling proteins, the biopolymers being optionally additionally chemically and / or enzymatically modified.

The amphiphilic self-assembling proteins are e.g. Microbead-forming proteins, or intrinsically unfolded proteins. For example, the amphiphilic self-assembling protein is a silk protein, in particular a spider silk protein, preferably a C16, R16 or S16 protein (see SEQ ID NO: 2, 4 or 6); or a spinnable protein derived from these proteins having a sequence identity of at least about 50%, e.g. at least 60, 70, 80, 90, 95, 96, 97, 98 or 99% sequence identity.

The synthetic polymer is either a homo- or a copolymer.

The carrier polymer is in particular selected from a) mixtures of at least 2 miscible synthetic homopolymers or copolymers; b) mixtures of at least 2 immiscible synthetic homo- or copolymer c) mixtures of at least 2 miscible biopolymers; d) mixtures of at least 2 immiscible biopolymers; e) mixtures of at least one synthetic homo- or copolymer and at least one biopolymer which are miscible with one another; and f) mixtures of at least one synthetic homo- or copolymer and at least one biopolymer which are immiscible with each other.

The polymer components independently have molecular weights in the range of about 500 to 10,000,000, such as e.g. 1,000 - 1,000,000 or 10,000 - 500,000 or 20,000 - 250,000.

The diameter of the drug carrier fibers is about 10 nm to 100 microns, such as 50 nm to 10 μm, or 100 nm to 2 μm.

Furthermore, according to the invention, the drug loading about 0.01 to 80 wt .-%, such as. B. 1 to 70 wt .-% or 10 to 50 wt .-%, based on the solids content of the fiber fabric.

In particular, the fibrous sheet according to the invention is selected from polymer fibers and polymer nonwovens.

In addition, the fibers may have additional physical structuring, such as e.g. Porosity. Furthermore, at least one further polymer may be present to increase the viscosity or viscoelasticity and to improve the spinnability of the solution. In addition, at least one low molecular weight additive such. As an organic or inorganic salt to increase the electrical conductivity of the spinnable solution, penetration aids for drugs, excipients to increase bioavailability, etc., be included.

In the fibrous sheets, the active ingredient is particularly molecularly disperse (ie, the drug molecules are individually present in the polymer matrix, thus dissolved therein) or nanoparticulate dispersed (ie, the molecules are aggregated into particles (clusters) with dimensions in the range of a few nanometers) in the fibers ,

The invention also relates to active ingredient-containing formulations comprising a fibrous sheet as defined above in processed form, optionally in combination with at least one further formulation auxiliary, which comprises the fibrous sheet in comminuted or non-comminuted form. For example, the fibrous sheet may be in compacted (compressed) form (such as tablets or capsules), in powder form, or coated on a support substrate.

Formulations according to the invention are selected in particular from cosmetic (especially skin and hair cosmetic), human and animal pharmaceutical, agrochemical (especially fungicides, herbicides, insecticides and other crop protection formulations) formulations, food and feed additives (such as food and feed supplements). The invention also provides the use of an active-ingredient-containing fibrous sheet as defined above for the production of an active ingredient-containing formulation as defined above, and in particular the use of an active ingredient-containing formulation according to the above definition for the controlled release of a substance contained therein.

Finally, the invention relates to a process for producing a fibrous sheet as defined above, comprising: a) mixing the at least one active ingredient together with the carrier polymer components in a common liquid phase and b) subsequently embedding the active ingredient in a polymeric composite fiber by spinning.

In this case, mixing the at least one active ingredient and the polymer components in a solvent phase and spinning this mixture.

However, it is also possible for the at least one active substance and the polymer components to be mixed in a mixture of at least two mutually miscible solvents, active substances and polymers being soluble in at least one of the solvents, and the mixture thus obtained being spun.

The spinning process may be an electrospinning process or a centrifugal (rotor) spinning process. In particular, the spinning process is carried out at a temperature in the range of about 0 to 90 ⁰ C.

The present invention also relates to the fibrous webs, wherein

(i) the diameter of the fibers is 10 nm to 100 μm, preferably 50 nm to 10 μm, particularly preferably 100 nm to 2 μm, (ii) the effect material loading is from 0.01 to 80% by weight, preferably from 1 to 60% by weight. %, particularly preferably 5 to 50 wt .-%, based on the total solids of the formulation is, (iii) the effect substance X-ray amorphous or partially crystalline (as a finely divided dispersion) in the

Fibers are present together with the polymers and optionally additives For certain applications, it may be advantageous if the polymers segregate after removal from the common solvent and form two or more phases.

Spinning processes can be used to produce fabrics (fibers, nonwovens, coatings) from aqueous solutions or organic solvents in which synthetic or biopolymers and effect substances are dissolved or dispersed.

These polymer- and drug-rich phases can be separated off as coatings (layers on a substrate), used as mechanically stable active ingredient-containing polymer structures and optionally dried, and processed into tablets or capsules.

The invention further fiber fabrics according to the above definition, which is substantially free of low molecular weight drugs and / or high molecular weight drugs.

Finally, the invention relates to the use of such an active ingredient-free fibrous sheet for producing a formulation containing active ingredient, in particular wherein the formulation is selected from cosmetic, human and animal pharmaceutical, agrochemical formulations, food and feed additives.

For this, e.g. the active ingredient-free fibrous sheet is prepared substantially as described herein by spinning suitable polymers and in a next step associates one or more active agents therewith, e.g. adsorbed, i. non-covalently bound.

3. Further embodiments of the invention

(i) formulation of active ingredients

The formulations of active ingredients according to the invention can be prepared by using synthetic and / or biopolymers in various ways by known methods. The active ingredients can be packaged or encapsulated, for example by spinning processes in fiber fabrics. The fibers and fabrics of polymer-active substance compositions can be prepared with all spinning processes known to those skilled in the art starting from a solution or a finely divided dispersion or a gel. Particularly suitable are spinning processes from the solution or a finely divided dispersion, among which particularly preferred are centrifugal spinning (rotor spinning) and electrospinning (electrostatic spinning).

When spinning formulations into fibers, fiber diameters of 10 nm to 100 μm, preferably with a diameter of 50 nm to 10 μm, particularly preferably of 100 nm to 2 μm, are fundamentally suitable.

In electrospinning (electrostatic spinning), the solution or finely divided dispersion to be formulated in an electric field with the strength between 0.01 to 10 kV / cm, more preferably between 1 and 6 kV / cm and most preferably between 2 and 4 kV / cm, introduced. As soon as the electrical forces exceed the surface tension of the formulation, the mass transport takes place in the form of a jet on the opposite electrode. The solvent evaporates in the interelectrode space and the solid of the formulation is then present as fibers on the counter electrode. The spinning electrode may be nozzle or syringe based or have roll geometry. Spinning can be done in both vertical directions (bottom to top and top to bottom) and in horizontal direction.

Another method suitable according to the invention is centrifuge spinning (rotor spinning). In this method, the starting material is introduced as a solution or finely divided dispersion in a field with gravitational forces. For this purpose, the fiber raw material is placed in a container and the container is rotated, wherein the fluidized fiber raw material is discharged by centripetal or centrifugal forces from the container in the form of fibers. The fibers can then be removed by gas flow and combined to form sheets.

The formulation of the active ingredients can be carried out according to the invention by inclusion in the fiber fabrics produced by the processes according to the invention. This process usually involves two steps. In the first step, a spinning solution of active ingredient (s) and carrier polymer (s) is prepared by mixing the components in a common phase. For this purpose, the active ingredient and polymers can be directly through Solvent or a solvent mixture are brought into solution. Alternatively, active ingredient and polymers can first be dissolved in different solvents and the solutions subsequently mixed together, so that in turn a common phase is formed. The common phase may also be a molecular disperse phase or a colloidally disperse phase.

The dissolution of active ingredient and polymer in various solvents and the subsequent mixing of both solutions are particularly advantageous if the active ingredient and polymer can not be dissolved in a common solvent or solvent mixture. In this way, colloidally disperse solutions of hydrophobic active ingredients can be prepared by diluting the active ingredient dissolved in a suitable solvent into another solvent in which this active ingredient is insoluble.

In principle, suitable solvents should not impede the formation of fibrous sheets and should not irreversibly inactivate the active ingredient.

Suitable solvents include water and also mixtures of water and water-miscible organic solvents. Examples of suitable water-miscible solvents include, but are not limited to, alcohols such as methanol, ethanol and isopropanol, fluorinated alcohols such as hexafluoroisopropanol and trifluoroethanol, alkanones such as acetone; or sulfoxides, e.g. dimethyl sulfoxide; or formamides such as dimethylformamide; or other organic solvents, such as e.g. Tetrahydrofuran and acetonitrile or N-methyl-2-pyrrolidone or formate. In general, it is possible to work with all solvents and solvent mixtures in which the carrier polymers can be dissolved. Further examples of suitable solvents are ionic liquids, e.g. 1-Ethyl (3-methylimidazoline (EMIM) acetate, aqueous solutions of chaotropic salts such as urea, guanidinium hydrochloride and guanidinium thiocyanate, or organic acids such as formic acid, acetic acid, etc.

In a further embodiment, it is possible to use solvents or solvent mixtures which are immiscible with water. The term "non-water-miscible organic solvent" describes organic solvents which have a solubility in water of less than 50%, preferably less than 25%, in particular preferably less than 10%, even more preferably 40 less than 10%, in an extremely preferred embodiment less than 5%.

The following solvents may be mentioned as examples, but without limitation: cyclohexane, cyclopentane, pentane, hexane, heptane, 2-methylpentane, 3-methylpentane, 2-methylhexane, 3-methylhexane, 2-methylbutane, 2,3-dimethylbutane, methylcyclopentane , Methylcyclohexane, 2,3-dimethylpentane, 2,4-dimethylpentane, benzene, I-pentene, 2-pentene, 1-hexene, 1-heptene, cyclohexene, 1-butanol, ethyl vinyl ether, propyl ether, isopropyl ether, butylvinyl ether, butyl ethyl ether , 1, 2-epoxybutane, furan, tetrahydropyran, 1-butanal, 2-methylpropanal, 2-pentanone, 3-pentanone, cyclohexanone, fluorobenzene, hexafluorobenzene, ethyl formate, propyl formate, isopropyl formate, ethyl acetate, vinyl acetate, isopropyl acetate, ethyl propionate , Methyl acrylate, ethyl acrylate, methyl methacrylate, chloroethane, 1-chloropropane, 2-chloropropane, 1-chlorobutane, 2-chlorobutane, 1-chloro-2-methylpropane, 2-chloro-2-methylpropane, 1-chloro-3-methylbutane , 3-chloropropene, dichloromethane, trichloromethane, tetrachloromethane, 1-dichloroethane, 1, 2-dichlorores than, 1, 2-dichloropropane, 1, 1, 1-trichloroethane, 1, 2-dichloroethylene, 1, 2-dichloroethylene, trichlorethylene, bromomethane, I-bromopropane, 2-bromopropane, 1-bromobutane, 2-bromobutane, 2-bromo-2-methylpropane, bromomethylene, iodomethane, iodoethane, 2-iodopropane, trichlorofluoromethane, dichlorofluoromethane, dibromofluoromethane, bromochloromethane, bromochlorofluoromethane, 1, 1, 2-trichloro-1, 2,2-trifluoroethane, 1, 1, 2,2-tetrachlorodifluoroethane, 1, 2-dibromotetrafluoroethane, 1, 2-dibromo-1, 1-difluoroethane, 1, 1-dichloro-2,2-difluoroethylene, propionitrile, acrylonitrile, methacrylonitrile, triethylamine, carbon disulfide, Butanethiol, methyl sulfide, ethyl sulfide and tetramethylsilane.

ii) Fibrous sheets and their polymer components

The fibers of the invention in fibrous sheets may consist of one, two, three or more phases.

In a further embodiment of the present invention, the fiber of the fiber fabrics according to the invention consists of at least three phases, one phase consisting of amorphous or partially crystalline or crystalline particles of the active ingredient, the other phase is a molecular disperse distribution of the active ingredient in a polymer matrix, and the third phase represents a drug-free polymer phase. In a further embodiment of the present invention, the fiber of the fiber structures according to the invention consists of at least two phases, one phase consisting of amorphous or partially crystalline or crystalline particles of the active ingredient, the other phase is a molecular disperse distribution of the active ingredient in a polymer matrix.

In a further embodiment of the present invention, the fiber of the fibrous sheets according to the invention consists of at least two phases, one phase consisting of amorphous or semi-crystalline or crystalline active ingredient, and the other phase is a drug-free polymer matrix.

In a further, preferred embodiment of the present invention, the fiber of the fiber fabrics according to the invention consists of a molecular dispersion of the active ingredient in a polymer matrix.

When using immiscible polymers A and B, it may be necessary to form further phases, e.g. consisting of active ingredient and polymer A with small amounts of polymer B, or of active ingredient and polymer B with small amounts of polymer A.

As polymeric components of the active compound formulations according to the invention are in principle all natural and synthetic polymers in a temperature range from 0 to 240 ⁰ C, a pressure range between 1 and 100 bar, a pH range of 0 to 14, or ionic strengths to 10 mol / l in suitable Water or / and are soluble in organic solvents.

One or more polymers can be used. The molar masses of the polymers used are in the range from 500 to 10,000,000 g / mol, preferably in the range from 1,000 to 1,000,000 g / mol. In principle, all suitable for the application of pharmacology, crop protection, cosmetics, food and feed polymers are suitable.

The high molecular weight polymers (from 500,000) are advantageous if a sparingly soluble effect substance should be formulated. These polymers require a very low concentration in the formulation to make fiber webs to obtain. The effect concentration in the formulation will be correspondingly low.

When it is intended to obtain preparations of an amorphous active agent with improved long-term stability, the polymers should either have a strong non-covalent interaction with active ingredient or preferably have their glass transition temperature (Tg) above the spinning temperature. In this case, the active substance remains dissolved in the polymer molecularly dispersed or finely dispersed after removal of the solvent in the polymer, since in the first case the interaction with the support and in the second case the lack of mobility of the polymer chains below the glass transition temperature hinder the movement of the active substance molecules. Optionally, at least one additive may be present, which prevents the agglomeration of the active ingredient.

Suitable synthetic polymers are, for. B. selected from the group consisting of homo- and copolymers of aromatic vinyl compounds, homopolymers and copolymers of alkyl acrylates, homo- and copolymers of alkyl methacrylates, homopolymers and copolymers of α-olefins, homopolymers and copolymers of aliphatic dienes , Homo- and copolymers of vinyl halides, homo- and copolymers of vinyl acetates, homo- and copolymers of acrylonitriles, homopolymers and copolymers of urethanes, homopolymers and copolymers of vinyl amides and copolymers composed of two or more of the monomer units forming the abovementioned polymers.

Suitable carrier polymers are, in particular, polymers based on the following monomers:

Acrylamide, adipic acid, allyl methacrylate, alpha-methylstyrene, butadiene, butanediol, butanediol dimethacrylate, butanediol divinyl ether, butanediol dimethacrylate, butanediol monoacrylate, butanediol monomethyl ether, butyl acrylate, butyl methacrylate, cyclohexyl vinyl ether, diethylene glycol divinyl ether, diethylene glycol monovinyl ether, ethyl acrylate, ethyl diglycol acrylate, ethylene, ethylene glycol butyl vinyl ether, Ethylene glycol dimethacrylate, ethylene glycol divinyl ether, ethylhexyl acrylate, ethylhexyl methacrylate, ethyl methacrylate, ethyl vinyl ether, glycidyl methacrylate, hexanediol divinyl ether, hexanediol monovinyl ether, isobutene, isobutyl acrylate, isobutyl methacrylate, isoprene, isopropyl acrylamide, methyl acrylate, methylenebisacrylamide, methyl methacrylate, methyl vinyl ether, n-butyl vinyl ether, methylene N-vinylacetamide, N-vinylcaprolactam, N-vinylimidazole, N-vinylpiperidone, NVinylpyrrolidone, octadecyl vinyl ether, phenoxyethyl acrylate, polytetra- hydrofuran-2-divinyl ether, propylene, styrene, terephthalic acid, tert-butylacrylamide, tert-butyl acrylate, tert-butyl methacrylate, tetraethylene glycol divinyl ether, triethylene glycol dimethacrylate, triethylene glycol divinyl ether, triethylene glycol divinyl methyl ether, trimethylolpropane trimethacrylate, trimethylolpropane trivinyl ether, vinyl (2-ethylhexyl) ether, vinyl 4-tert-butyl benzoate, vinyl acetate, vinyl chloride, vinyl dodecyl ether, vinylidene chloride, vinyl isobutyl ether, vinyl isopropyl ether, vinyl propyl ether and vinyl tert-butyl ether.

The term "polymers" encompasses both homopolymers and copolymers Suitable copolymers are both random and alternating systems, block copolymers or graft copolymers The term copolymers encompasses polymers which are made up of two or more different monomers or in which the Incorporation of at least one monomer in the polymer chain can be realized in various ways, as is the case, for example, with the stereo block copolymers.

It may also be blends of homopolymers and copolymers. The homo- and copolymers can be miscible and immiscible.

The following polymers may preferably be mentioned: polyvinyl ethers such as polybenzyloxyethylene, polyvinyl acetals, polyvinyl esters such as polyvinyl acetate, polyoxytetramethylene, polyamides, polycarbonates, polyesters, polysiloxanes, polyurethanes, polyacrylamides such as poly (N-isopropylacrylamide), polymethacrylamide, polyhydroxybutyrates, Polyvinyl alcohols, acetylated polyvinyl alcohols, polyvinylformamide, polyvinylamines, polycarboxylic acids (polyacrylic acid, polymethacrylic acid), polyacrylamide, polyitaconic acid, poly (2-hydroxyethyl acrylate), poly (N-isopropylacrylamide), polysulfonic acid (poly (2-acrylamido-2-methyl) 1-propanesulfonic acid) or PAMPS), polymethacrylamide, polyalkylene oxides, e.g. For example, polyethylene oxides; Poly-N-vinylpyrrolidone; Maleic acids, poly (ethyleneimine), polystyrenesulfonic acid, polyacrylates, such as, for example, polyphenoxyethyl acrylate, polymethyl acrylate, polyethyl acrylate, polydodecyl acrylate, poly (ibornyl acrylate), poly (n-butyl acrylate), poly (t-butyl acrylate), polycyclohexyl acrylate, poly (2 ethylhexyl acrylate), polyhydroxypropyl acrylate, polymethacrylates such as polymethyl methacrylate, poly (n-amyl methacrylate), poly (n-butyl methacrylate), polyethyl methacrylate, poly (hydroxypropyl methacrylate), polycyclohexyl methacrylate, poly (2-ethylhexyl methacrylate), polylauryl methacrylate, poly ( t-butyl methacrylate), polybenzyl methacrylate, poly (ibornyl methacrylate), polyglycidyl methacrylate and polystearyl methacrylate, polystyrene, as well as copolymers based on styrene, eg with maleic anhydride, Styrene-butadiene copolymers, methylmethacrylate-styrene copolymers, N-vinylpyrrolidone copolymers, polycaprolactones, polycaprolactams, poly (N-vinylcaprolactam).

Very particular preference is given to poly-N-vinylpyrrolidone, polymethyl methacrylate, acrylate-styrene copolymers, polyvinyl alcohol, polyvinyl acetate, polyamide, polyester

Furthermore, natural polymers or biopolymers are suitable:

Nonlimiting examples include: cellulose, cellulose ethers such as e.g. Methylcellulose (degree of substitution 3 - 40%), ethylcellulose, butylcellulose, hydroxymethylcelluloses; hydroxyethylcelluloses; Hydroxypropylcelluloses, isopropylcellulose,

Cellulose esters, e.g. Cellulose acetate, starches, modified starches such as methyl ether starch, gum arabic, chitin, shellac, gelatin, chitosan, pectin, casein,

Alginate, as well as copolymers and block copolymers of the monomers of the above. Fertilize compound .; and nucleic acid molecules.

In particular, biopolymers used according to the invention are biodegradable.

Other suitable biodegradable biopolymers are amphiphilic self-assembling proteins. Amphiphilic, self-assembling proteins consist of polypeptides composed of amino acids, in particular of the 20 naturally occurring amino acids. The amino acids may also be modified, for example, acetylated, glycosylated, farnesylated.

Suitable amphiphilic, self-assembling proteins are, in particular, those proteins which can form protein microbeads and which are described in WO-A-20077082936, to which reference should here be expressly made.

Other suitable proteins for the formulation of active ingredients by means of spinning processes are silk proteins. By this we mean hereinafter those proteins which contain highly repetitive amino acid sequences and which are stored in the animal in a liquid form and whose secretion by shearing or spinning results in fibers (Craig, CL (1997) Evolution of arthropod silks. Annu. Rev. Entomol. 42: 231-67). Particularly suitable proteins for the formulation of active ingredients by means of spinning processes are spider silk proteins, which could be isolated in their original form from spiders.

Especially suitable proteins are silk proteins which could be isolated from the "major ampullate" gland of spiders.

Preferred silk proteins are ADF3 and ADF4 from the "major ampullate" gland of Araneus diadematus (Guerette et al., Science 272, 5258: 1 12-5 (1996)).

Likewise suitable proteins for the formulation of active substances by means of spinning processes are natural or synthetic proteins which are derived from natural silk proteins and which have been prepared hologrologically in prokaryotic or eukaryotic expression systems using genetic engineering working methods. Non-limiting examples of prokaryotic expression organisms are Escherichia coli, Bacillus subtilis, Bacillus megaterium, Corynebacterium glutamicum, etc. Nonlimiting examples of eukaryotic expression organisms are yeasts such as Saccharomyces cerevisiae, Pichia pastoris and others, filamentous fungi such as Aspergillus niger, Aspergillus oryzae and Aspergillus nidulans. Trichoderma reesei, Acremonium chrysogenum and others, mammalian cells, such as Heia cells, COS cells, CHO cells and others, insect cells, such as Sf9 cells, MEL cells and others.

Particularly preferred for the formulation of active ingredients by means of spinning processes are synthetic proteins which are based on repeating units of natural silk proteins. In addition to the synthetic repetitive silk protein sequences, these may additionally contain one or more natural non-repetitive silk protein sequences (Winkler and Kaplan, J Biotechnol 74: 85-93 (2000)).

Among the synthetic silk proteins preferred for the formulation of active agents by means of spinning processes are synthetic spider silk proteins which are based on repeating units of natural spider silk proteins. In addition to the synthetic repetitive spider silk protein sequences, these may additionally contain one or more natural non-repetitive spider silk protein sequences. Among the synthetic spider silk proteins, preference is given to the so-called C16 protein (Huemmerich et al., Biochemistry, 43 (42): 13604-13612 (2004)). This protein has the polypeptide sequence shown in SEQ ID NO: 2.

In addition to the polypeptide sequence shown in SEQ ID NO: 2, particularly functional equivalents, functional derivatives and salts of this sequence are also preferred.

Furthermore, for the formulation of active ingredients by means of spinning processes, synthetic proteins are preferred which are based on repeating units of natural silk proteins combined with sequences of insect structural proteins such as the Resilin (Elvin et al., 2005, Nature 437: 999-1002).

Particularly preferred among the combination proteins of silk proteins and resilins are the R16 and S16 proteins. These proteins have the polypeptide sequences set forth in SEQ ID NO: 4 and SEQ ID NO: θ.

In addition to the polypeptide sequences shown in SEQ ID NO: 4 and SEQ ID NO: 6, particularly functional equivalents, functional derivatives and salts of these sequences are also preferred.

According to the invention, "functional equivalents" are in particular also understood as meaning mutants which have a different amino acid than the one specifically mentioned in at least one sequence position of the abovementioned amino acid sequences and nevertheless possess the property of packaging effect substances. "Functional equivalents" thus include ie, one or more mutant amino acid additions, substitutions, deletions, and / or inversions, wherein said changes may occur in any sequence position as long as they result in a mutant having the property profile of the invention. Functional equivalence is given in particular even if the reactivity patterns between the mutant and the unchanged polypeptide match qualitatively.

"Functional equivalents" in the above sense are also "precursors" of the described polypeptides as well as "functional derivatives" and "salts" of the polypeptides.

"Precursors" are natural or synthetic precursors of the polypeptides with or without the desired biological activity. Examples of suitable amino acid substitutions are shown in the following table:

Original rest Examples of substitution

AIa Ser

Arg Lys

Asn GIn; His

Asp Glu

Cys Ser

GIn Asn

Giu Asp

GIy Pro

His Asn; Gin

Ne Leu; Val

Leu Ne; Val

Lys Arg; GIn; Glu

Met Leu; ne

Phe Met; Leu; Tyr

Ser Thr

Thr Ser

Trp Tyr

Tyr Trp; Phe

VaI Ne; Leu

Salts are understood as meaning both salts of carboxyl groups and acid addition salts of amino groups of the protein molecules of the invention Salts of carboxyl groups can be prepared in a manner known per se and include inorganic salts such as, for example, sodium, calcium, ammonium, iron and zinc salts, and salts with organic bases such as amines such as triethanolamine, arginine, lysine, piperidine and the like, acid addition salts such as salts with mineral acids such as hydrochloric acid or sulfuric acid and salts with organic acids such as acetic acid and oxalic acid also the subject of the invention.

"Functional derivatives" of polypeptides of the invention may also be produced at functional amino acid side groups or at their N- or C-terminal end by known techniques Such derivatives include, for example, aliphatic esters of carboxylic acid groups, amides of carboxylic acid groups obtainable by reaction with ammonia or with a primary or secondary amine; N-acyl derivatives of free amino groups prepared by reaction with acyl groups; or O-acyl derivatives of free hydroxy groups, prepared by reaction with acyl groups.

Homologs to the specific proteins / polypeptides disclosed herein include at least 60%, such as 70, 80, or 85%, such as 90, 91, 92, 93, 94, 95, 96, 97 , 98 or 99% identity to one of the specifically disclosed amino acid sequences.

By "identity" between two sequences is meant, in particular, the identity of the residues over the respective entire sequence length, in particular the identity which is determined by comparison with the aid of the Vector NTI Suite 7.1 (Vector NTI Advance 10.3.0, Vitrogen Corp.) (or Software from Informax (USA) using Clustal

Method (Higgins DG, Sharp PM, Fast and Sensitive Multiple Sequence Alignments on a Microcomputer, Comput Appl. Biosci 1989 Apr; 5 (2): 151-1) is calculated by setting the following parameters:

Multiple ahgnment parameter:

Gap opening penalty 10

Gap extension penalty 0.05

Gap Separation penalty ranks 8

Gap separation penalty off

% identity for alignment delay 40

Residue specific gaps off

Hydrophilic residues gap off

Transition weighing 0

Pairwise alignment parameter:

FAST algorithm off

K-tuple size 1

Gap penalty 3

Window size 5

Number of best diagonals 5

Of particular interest are synthetic, biodegradable polymers. The term "biodegradable polymers" is intended to include all polymers which meet the definition of biodegradability given in DIN V 54900, in particular compostable polyesters.

In general, biodegradability means that the polymers, such as polyesters, decompose in a reasonable and detectable time. Degradation may be hydrolytic and / or oxidative, and for the most part effected by the action of microorganisms such as bacteria, yeasts, fungi and algae. Biodegradability can be determined, for example, by mixing polyesters with compost and storing them for a certain period of time. According to ASTM D 5338, ASTM D 6400 and DIN V 54900, CO ₂ -free air, for example, is allowed to flow through ripened compost during composting and subjected to a defined temperature program. Here, the biodegradability is defined as the ratio of the net CO ₂ release of the sample (after subtraction of CO ₂ release by the compost without sample) to the maximum CO ₂ release of the sample (calculated from the carbon content of the sample) as biodegradability , Biodegradable polyester usually show after a few days of composting significant degradation phenomena such as fungal growth, crack and hole formation. Examples of biodegradable polymers are biodegradable polyesters such as, for example, polylactide, polycaprolactone, polyalkylene adipate terephthalates, polyhydroxyalkonates (polyhydroxybutyrate) and polylactide glycoside. Particularly preferred are biodegradable polyalkylene adipate terephthalates, preferably polybutylene adipate terephthalates. Suitable polyalkylene adipate terephthalates are, for example, in DE

4,440,858 (and are commercially available, e.g., Ecoflex from BASF).

The polymer structures can be prepared as active ingredient-containing fibrous webs (e.g., polymer fibers, polymer nonwoven webs) and coated on substrates such as e.g. B. microfiber webs are stored. Then they can be pressed into tablets or capsules.

In addition, additional materials may be added to the spinning solution, e.g. To later influence (e.g., inhibit) crystallization of the active ingredient in the fibers or to achieve preferred application properties, such as bioavailability. Preferred additives are e.g. ionic (cationic or anionic) and nonionic surfactants. Suitable amounts of the additives in the spinning solution are 0.01% by weight to

5% by weight. In addition, it is possible to add substances to the spinning solution or to the polymer fabrics produced therefrom which permit the tablets or capsules to be blown up and hence improved dispersion of the polymer sheets pressed into the tablets or capsules.

According to the invention, it has been observed, in particular, that its active substance release properties can be influenced in a targeted manner by suitable combination of polymer components for the formation of the active-ingredient-containing fiber fabric of the invention. In particular, this is achieved by combining at least two polymer components which differ in at least one of the following properties: a) solubility in aqueous or nonaqueous solvents, b) molecular weight c) glass transition temperature and / or melting point c) degradability (in particular biological or chemical degradability where biodegradability can be induced in particular by at least one enzyme or a microorganism and the chemical degradability can be carried out, for example, by hydrolytic or oxidative means Moreover, decomposition can also be induced physically, in particular by the action of light)

In this way, the present invention can be used to tailor the drug release to the particular needs of the user. The release profile to be provided in each case can be determined empirically on the basis of systematic considerations or by a few preliminary experiments. As explained in more detail in the included embodiments, new release profiles for active compounds can be produced according to the invention by combining different polymer components, which clearly differ from the release profiles observed for the polymer individual components. Thus, it can be observed, for example, that release of active substance by the polymer combination commences much earlier compared to release by the polymer individual components, or that the release profiles for polymer combinations according to the invention are higher or lower in comparison to the individual components over the entire or over one Part of the observation period. Non-limiting examples of particularly suitable polymer combinations are, in addition to the combinations illustrated in the examples:

Polyester / polyacrylate (immiscible)

Polyester / polystyrene or styrene copolymer (acrylate or butadiene) (immiscible) polyamide / spider silk protein (miscible)

Styrene or styrene copolymer / spider silk protein

PVP / spider silk protein (mixable)

PVA / spider silk protein

PEO / spider silk protein polyamide / PVP (miscible)

Polyamide / polyacrylic acid (miscible)

Polylactic acid / PVP (possibly immiscible)

Polylactic acid / polyacrylate

Polyester / polyacrylate / PVP (immiscible) Polyester / polylactic acid / PVP (immiscible or miscible)

Polyester / starch (mixable)

PVP / strength

Cellulose or derivatives / polyacrylate

Cellulose acetate / polyethylene-vinyl acetate (miscible) polyvinyl alcohol / polyvinyl acetate (miscible)

Collagen / PVA

Collagen / PEO

Chitosan / PVA (PEO)

Polyurethane / PVP (miscible) polyurethane / polyester (possibly not miscible)

Polyurethane / spider silk protein (miscible)

Polycarbonate / Polycaprolactone (Miscible)

Polycarbonate / polyester (mixable)

Polyacrylate / polyvinyl chloride (miscible)

(iii) agents

In the following, the terms active substances and effect substances are used synonymously. These are both water-soluble and difficult-to-water-soluble effect substances. The terms heavy-water-soluble and hydrophobic active or effect substances are used synonymously. As sparingly water-soluble active ingredients are referred to below those compounds whose water solubility at 20 ⁰ C <1 wt .-%, preferably <0.5 wt .-%, more preferably <0.25 wt .-%, most preferably <0 , 1 wt .-% is. Water-soluble active ingredients are referred to below as those compounds whose water solubility at 20 ^° C. is> 1% by weight, preferably> 10% by weight, more preferably> 40% by weight, very particularly preferably> 70% by weight ,

Suitable effect substances are dyes, in particular those mentioned in the following table:

Particularly advantageous dyes are the oil-soluble or oil-dispersible compounds mentioned in the following list. The Color Index Numbers (CIN) are taken from the Rowe Color Index, 3rd Edition, Society of Dyers and Colourists, Bradford, England, 1971.

Further preferred effect substances are fatty acids, in particular saturated fatty acids, which carry an alkyl branching, particularly preferably branched eicosanoic acids, such as 18-methyl-eicosanoic acid. Further preferred effect substances are carotenoids. According to the invention, carotinoids are to be understood as meaning the following compounds and their esterified or glycosylated derivatives: β-carotene, lycopene, lutein, astaxanthin, zeaxanthin, cryptoxanthin, citraaxanthin, canthaxanthin, bixin, β-apo-4-carotenal, β-apo-8 -carotinal, β-apo-8-carotenoic acid ester, neurospores, echinenone, adonirubin, violaxanthin, torulen, torularyhodine, singly or as a mixture. Preferably used carotenoids are β-carotene, lycopene, lutein, astaxanthin, zeaxanthin, citranaxanthin and canthaxanthin.

Further preferred effect substances are vitamins, in particular retinoids and their esters.

By retinoids in the context of the present invention is meant vitamin A alcohol (retinol) and its derivatives such as vitamin A aldehyde (retinal), vitamin A acid (retinoic acid) and vitamin A esters (e.g., retinyl acetate, retinyl propionate and retinyl palmitate). The term retinoic acid encompasses both all-trans retinoic acid and 13-cis retinoic acid. The terms retinol and retinal preferably include the all-trans compounds. The preferred retinoid used for the formulations according to the invention is all-trans-retinol, hereinafter referred to as retinol.

Further preferred effect substances are vitamins, provitamins and vitamin precursors from groups A, B, C, E and F, in particular 3,4-didehydroretinol, .beta.-carotene (provitamin of vitamin A), palmitic acid ester of ascorbic acid, tocopherols, especially .alpha.-tocopherol and its esters, eg the acetate, nicotinate, phosphate and succinate; vitamin F, which is understood as meaning essential fatty acids, especially linoleic acid, linolenic acid and arachidonic acid.

Further preferred effect substances are lipophilic, oil-soluble antioxidants from the group vitamin E, i. Tocopherol and its derivatives, gallic acid esters, flavonoids and carotenoids, and butylhydroxytoluene / anisole.

Another preferred effect substance is lipoic acid and suitable derivatives (salts, esters, sugars, nucleotides, nucleosides, peptides and lipids).

Further preferred effect substances are UV light protection filters. These are organic substances that are able to absorb ultraviolet rays and to release the absorbed energy in the form of longer-wave radiation, eg heat.

As oil-soluble UV-B filters, e.g. the following substances are used:

3-benzylidene camphor and its derivatives, e.g. 3- (4-methylbenzylidene) camphor; 4-aminobenzoic acid derivatives, preferably 2-ethylhexyl 4- (dimethylamino) benzoate, 2-octyl 4- (dimethylamino) benzoate and 4- (dimethylamino) benzoic acid ester; Esters of cinnamic acid, preferably 4-methoxycinnamic acid 2-ethylhexyl ester, 4-propyl methoxycinnamate, isoamyl 4-methoxycinnamate, 4-isopentyl methoxycinnamate, 2-cyano-3-phenylcinnamic acid 2-ethylhexyl ester (tocylenes);

Esters of salicylic acid, preferably 2-ethylhexyl salicylate, 4-isopropylbenzyl salicylate, homomenthyl salicylate; Derivatives of benzophenone, preferably 2-hydroxy-4-methoxybenzophenone, 2-hydroxy-4-methoxy-4'-methylbenzophenone, 2,2'-dihydroxy-4-methoxybenzophenone; Esters of benzalmalonic acid, preferably di-2-ethylhexyl 4-methoxybenzmalonate; Triazine derivatives such as 2,4,6-trianilino (p-carbo-2'-ethyl-1 ^' -hexyloxy) -1, 3,5-triazine (octyl triazone) and dioctyl butamido triazone (Uvasorb® HEB):

Propane-1,3-diones, e.g. 1- (4-tert-butylphenyl) -3- (4'-methoxyphenyl) propane-1,3-dione.

Especially preferred is the use of esters of cinnamic acid, preferably 4-methoxycinnamic acid 2-ethylhexyl ester, 4-methoxycinnamic acid isopentyl ester, 2-cyano-3-phenylcinnamic acid 2-ethylhexyl ester (octocrylene).

Furthermore, the use of derivatives of benzophenone, in particular 2-hydroxy-4-methoxybenzophenone, 2-hydroxy-4-methoxy-4 ^" -methylbenzophenone, 2,2'-dihydroxy-4-methoxybenzophenone and the use of propane-1, 3-diones, such as 1- (4-tert-butylphenyl) -3- (4-methethoxyphenyl) propane-1,3-dione.

Typical UV-A filters are:

Derivatives of benzoylmethane, such as 1- (4'-tert-butylphenyl) -3- (4'-methoxyphenyl) propane-1,3-dione, 4-tert. Butyl 4'-methoxydibenzoylmethane or 1-phenyl-3- (4'-isopropylphenyl) -propane-1,3-dione; Amino-hydroxy-substituted derivatives of benzophenones such as N, N-diethylamino-hydroxybenzoyl-n-hexyl benzoate.

Of course, the UV-A and UV-B filters can also be used in mixtures.

Suitable UV filter substances are mentioned in the following table.

In addition to the two aforementioned groups of primary light stabilizers, it is also possible to use secondary light stabilizers of the antioxidant type which interrupt the photochemical reaction chain which is triggered when UV radiation penetrates into the skin. Typical examples are tocopherols (vitamin E) and oil-soluble ascorbic acid derivatives (vitamin C).

According to the invention, suitable derivatives (salts, esters, sugars, nucleotides, nucleosides, peptides and lipids) of the compounds mentioned can be used as effect substances.

Further preferred are so-called peroxide decomposers, ie compounds which are capable of decomposing peroxides, particularly preferably lipid peroxides. These include organic substances, such as 5-pyrimidinol and 3-pyridinol derivatives and probucol. Furthermore, the peroxide decomposers mentioned are preferably the substances described in the patent applications WO-A-02/07698 and WO-A03 / 059312, the content of which is hereby incorporated by reference, preferably the boron-containing or nitrogen-containing compounds described therein. containing compounds which can reduce peroxides or hydroperoxides to the corresponding alcohols without radical radical formation steps. Furthermore, sterically hindered amines can be used for this purpose.

Another group are anti-irritants, which have an anti-inflammatory effect on UV-damaged skin. Such substances are, for example, bisabolol, phytol and phytantriol.

Another group of effect substances are active substances that can be used in crop protection, for example herbicides, insecticides and fungicides.

The following list of insecticides indicates, but is not limited to, possible crop protection agents:

A.1. Organo (thio) phosphates: azinphos-methyl, chloropyrifos, chlorpyrifos-methyl, chlorophenvinphos, diazinon, disulphoton, ethion, fenitrothion, fenthion, isoxathione, malathion, methidathione, methyl-parathion, oxydemeton-methyl, paraoxone, parathion, phenthoate, phosalone, phosmet, phosphamidone, phorate, phoxim, pirimiphos-methyl, profenofos, prothiofos, sulprophos, tetrachlorvinphos, terbufos, triazophos, trichlorophone;

A.2. Carbamates: alanycarb, bendiocarb, benfuracarb, carbaryl, carbofuran, carbosulphane, fenoxycarb, furathiocarb, methiocarb, methomyl, oxamyl, pirimicarb, thiodicarb, triazamate;

A.3. Pyrethroids: allethrin, bifenthrin, cyfluthrin, cyhalothrin, cyphenothrin, cyper-5-methrin, alpha-cypermethrin, beta-cypermethrin, zeta-cypermethrin, deltamethrin, fenvalerate, etofenprox, fenpropathrin, fenvalerate, imiprothrin, lambda-cyhalothrin, permethrin, prallethrin , pyrethrin I and II, resmethrin, silafluofen, tau-fluvalinate, tefluthrin, tetramethrin, tralomethrin, transfluthrin; A.4. Growth regulators: a) chitin synthesis inhibitors: benzoylureas: chlorofluorotron, cyramazine, diflubenzuron, flucycloxuron, flufenoxuron, hexaflumuron, lufenuron, novaluron, teflubenzuron, triflumuron; buprofezin, diofenolan, hexythiazox, etoxazole, clofentazine; b) ecdysone antagonists: halofenozides, methoxyfenozide, tebufenozide, azadirachtin; c) juvenoids: pyriproxyfen, methoprene, fenoxycarb; d) lipid biosynthesis inhibitors: spirodiclofen, spiromesifen, a tetronic acid derivative of formula D1,

A.5. Nicotine receptor agonist antagonists: clothianidin, dinotefuran, thiacloprid;

A.6. GABA antagonists: acetoprole, endosulfan, ethiprole, fipronil, vaniliprole;

A.7. Macrolide insecticides: abamectin, emamectin, milbemectin, lepimectin, spinosad;

A.8. MET1 I acaricides: fenazaquin, pyridaben, tebufenpyrad, tolfenpyrad;

A.9. MET1 II and III compound: acequinocyl, fluacyrim, hydramethylnone; A.10. Decoupler compounds: chlorfenapyr;

A.11. Inhibitors of oxidative phosphorylation: cyhexatin, diafenthiuron, fenbutatin oxide, propargite;

A.12. Moulting Compounds: cryomazine;

A.13. Inhibitors of mixed-function oxidase: piperonyl butoxide; A.14. Sodium channel blocker: indoxacarb, metaflumizone;

A.15. Various: benclothiaz, bifenazate, flonicamid, pyridalyl, pymetrozine, sulfur, thiocyclam and aminoisothiazole compounds of formula D2,

where R ^{1 is} -CH ₂ OCH ₂ CH ₃ or H and R ^{H is} CF ₂ CF ₂ CF ₃ or CH ₂ CH (CH ₃ ) ₃ , anthranilamide compounds of the formula D3:

where B ^{1 is} hydrogen or chlorine, B ^{2 is} bromine or CF ₃ , and R ^{B is} CH ₃ or CH (CHs) ₂ , and malononitrile compounds as described in JP 2002 284608, WO 02/189579, WO 02/190320, WO 02/190321, WO 04/106677, WO 04/120399, or JP 2004 99597, N-R'-2,2-dihalo-1R "cyclopropanecarboxamide-2- (2,6-dichloro-α, a , α, ω-trifluoro-pt-olyl) hydrazo or N-R'-2,2-di (R "') propionamide-2- (2,6-dichloro-α, α, α, α-trifluoro- p-tolyl) hydrazone, wherein R 'is methyl or ethyl, Halo is chloro or bromo, R "is hydrogen or methyl and R'" is methyl or ethyl;

The following list of fungicides indicates, but is not limited to, possible drugs:

1. strobilurins

Azoxystrobin, dimoxystrobin, enestroburine, fluoxastrobin, kresoxim-methyl, metominostrobin, picoxystrobin, pyraclostrobin, trifloxystrobin, orysastrobin, (2-chloro-5- [1- (3-methyl-benzyloxyimino) -ethyl] -benzyl) -carbamic acid methyl ester, (2-Chloro-5- [1- (6-methylpyridin-2-ylmethoxyimino) ethyl] benzyl) -carbamic acid methyl ester, 2- (ortho - ((2,5-dimethylphenyl-oxymethylene) -phenyl) - 3-methoxy-methyl acrylate;

2. Carboxylic acid amides

- Carboxylic acid anilides: benalaxyl, benodanil, boscalid, carboxin, mepronil, fenfuram, fenhexamide, flutolanil, furametpyr, metalaxyl, ofurace, oxadixyl, oxycarboxin,

Penthiopyrad, thifluzamide, tiadinil, 4-difluoromethyl-2-methyl-thiazole-5-carboxylic acid

(4'-Bromo-biphenyl-2-yl) -amide, 4-difluoro-2-methyl-triazole-5-carboxylic acid- (4'-trifluoromethyl-biphenyl-2-yl) -amide, 4- Difluoro-2-methyl-triazole-5-carboxylic acid (4'-chloro-3'-fluoro-biphenyl-2-yl) -amide, 3-difluoro-1-methyl-pyrazole-4-carboxylic acid (3 ', 4'-dichloro-4-fluoro-biphenyl-2-yl) -amide; - Carboxylic acid morpholides: Dimethomorph, Flumorph;

Benzoic acid amides: flumetover, fluopicolide (picobenzamide), zoxamide;

Other carboxamides: carpropamide, diclocymet, mandipropamide, N- (2- (4- [3- (4-chloro-phenyl) -prop-2-ynyloxy] -3-methoxyphenyl) -ethyl) -2-methanesulfonylamino 3-methyl-butyramide, N- (2- (4- [3- (4-chloro-phenyl) -prop-2-ynyloxy] -3-methoxy-phenyl) -ethyl) -2-ethanesulfonyl-amino-3-methyl- butyramide;

3. Azoles

- triazoles: bitertanol, bromuconazoles, cyproconazole, difenoconazole, diniconazole,

Enilconazole, epoxiconazole, fenbuconazole, flusilazole, fluquinconazole, flutriol, hexaconazole, imibenconazole, ipconazole, metconazole, myclobutanil, penconazole, propiconazole, prothioconazole, simeconazole, tebuconazole, tetraconazole, iadimenol, triadimefon, triticonazole;

- imidazoles: cyazofamide, imazalil, pefurazoate, prochloraz, triflumizole;

Benzimidazoles: benomyl, carbendazim, fuberidazole, thiabendazole; - Other: Ethaboxam, Etridiazole, Hymexazole;

4. Nitrogen-containing heterocyclyl compounds:

Pyridines: fluazinam, pyrifenox, 3- [5- (4-chlorophenyl) -2,3-dimethylisoxazolidin-3-yl] pyridine;

Pyrimidines: bupirimate, cyprodinil, ferimzone, fenarimol, mepanipyrim, nuarimol, pyrimethanil;

- piperazines: triforins;

- Pyrroles: fludioxonil, fenpiclonil;

- Morpholines: aldimorph, dodemorph, fenpropimorph, tridemorph;

Dicarboximides: iprodione, procymidone, vinclozolin; - Other: acibenzolar-S-methyl, anilazine, captan, captafol, dazomet, diclomethine, fenoxanil, folpet, fenpropidin, famoxadone, fenamidone, octhilinone, probenazole, proquinazide, quinoxyfen, tricyclazole, 5-chloro-7- (4-methyl- piperidin-1-yl) -6- (2,4,6-trifluorophenyl) - [1, 2,4] triazolo [1,5-alpirimidine, 2-butoxy-6-iodo-3-propyl-chromene 4-one, 3- (3-bromo-6-fluoro-2-methyl-indole-1-sulfonyl) - [1, 2,4] triazole-1-sulfonic acid dimethylamide;

5. carbamates and dithiocarbamates

Carbamates: diethofencarb, flubenthiavalicarb, iprovalicarb, propamocarb, 3- (4-chlorophenyl) -3- (2-isopropoxycarbonylamino-3-methylbutyrylamino) -propionic acid methyl ester, N- (1- (1- (4- cyanophenyl) ethanesulfonyl) -but-2-yl) carbamate (4-fluoro-25-phenyl) ester; 6. Other fungicides

Organometallic compounds: fentin salts;

Sulfur-containing heterocyclyl compounds: isoprothiolanes, dithianone; Organophosphorus compounds: edifenphos, fosetyl, fosetyl-aluminum, Iprobenfos, pyrazophos, tolclofos-methyl, phosphorous acid and their salts;

Organochlorine compounds: thiophanates methyl, chlorothalonil, dichlofluanid, toluylfluanid, flusulfamides, phthalides, hexachlorobenzene, pencycuron, quintozene;

Nitrophenyl derivatives: binapacryl, dinocap, dinobuton; - Other: Spiroxamine, Cyflufenamid, Cymoxanil, Metrafenone.

The following list of herbicides indicates, but is not limited to:

Compounds that inhibit the biosynthesis of lipids, e.g. Chlorazifop, Clodina-fop, Clofop, Cyhalofop, Ciclofop, Fenoxaprop, Fenoxaprop-p, Fenthiaprop, Fluazifop, Fluazifop-P, Haloxyfop, Haloxyfop-P, Isoxapyrifop, Metamifop, Propaquizafop, Quizalofop, Quizalofop-P, Trifop, or their esters, butroxydim, cycloxydim, profoxydim, sethoxydim, tepraloxydim, tralkoxydim, butylates, cycloate, dialkylate, dimepiperate, EPTC, esprocarb, ethiolates, isopolinates, methiobencarb, molinates, orbencarb, pebulates, prochlorocarb, sulfolate, thiobencarb, thiocarbazil, triallate Vernolat, Benfuresat, Ethofu-5 mesate and Bensulid;

ALS inhibitors such as amidosulfuron, azimsulfuron, bensulfuron, chlorimuron, chlorosulfuron, cinosulfuron, cyclosulfamuron, ethametsulfuron, ethoxysulfuron, flazasulfuron,

Flupyrsulfuron, foramsulfuron, halosulfuron, imazosulfuron, lodosulfuron, mesosulfuron, metsulfuron, nicosulfuron, oxasulfuron, primisulfuron, prosulfuron, pyrazosulfuron, rimsulfuron, sulfometuron, sulfosulfuron, thifensulfuron, triasulfuron, tribenuron,

Trifloxysulfuron, triflusulfuron, tritosulfuron, imazamethabenz, imazamox, imazapic, imazapyr, imazaquin, imazethapyr, cloransulam, diclosulam, florasulam, flumetsulam, metosulam, penoxsulam, bispyribac, pyriminobac, propoxycarbazone, flucarba- zone, pyribenzoxim, pyriftalid and pyrithiobac; if the pH is 8 <;

Compounds that inhibit photosynthesis such as Atraton, Atrazine, Ametryne, Aziprotron, Cyanazine, Cyanatryn, Chlorazine, Cyprazine, Desmetryne, Dimethametry- ne, dipropetryn, eglinazine, ipazine, mesoprazine, methometon, methoprotryne, procyazine, proglubazine, prometon, prometryne, propazine, sebuthylazine, secbumetone, simazine, simeton, simetryne, terbumeton, terbuthylazine and terbutryne;

Protoporphyrinogen IX oxidase inhibitors such as acifluorfen, bifenox, chlomethoxyfen, chlornitrofen, ethoxyfen, fluorodifene, fluoroglycofen, fluoronitrofen, fomesafen, furyloxyfen, halosafen, lactofen, nitrofen, nitrofluorfen, oxyfluorfen, fluazolates, pyrafluids, cinidon-ethyl, flumiclorac , Flumioxazine, flumipropyne, fluthiacet, thidiazimine, oxadiazone, oxadiargyl, azafenidine, carfentrazone, sulfentrazone, pentoxazone, benzfendizone, butafenacil, pyraclonil, profluazole, flufenpyr, flupropacil, nipyraclofen and etnipromide;

Herbicides such as metflurazon, norflurazon, flufenican, diflufenican, picolinafen, beflubutamide, fluridone, flurochloridone, flurtamone, mesotrione, sulcotrione, isoxachlorotole, isoxaflutole, benzofenap, pyrazolynate, pyrazoxyfen, benzobicyclone, amitrole, cloma- zone, aclonifen, 4- (3 -trifluoromethylphenoxy) - 2- (4-trifluoromethylphenyl) pyrimidine, and 3-heterocyclyl-substituted benzoyl derivatives of the formula (see WO-A-96/26202, WO-A-97/411 16, WO-A-97/41 117 and WO-A-97/41 1 18)

wherein the substituents R ⁸ to R ^{13 have the} following meaning:

R ^8, R ¹⁰ is hydrogen, halogen, C _r C ₅ alkyl, C _r C ₅ haloalkyl, C _r C ₅ alkoxy, haloalkoxy, d-Cs-alkylthio, C _r C ₅ alkylsulfinyl or C _r C ₅ - alkylsulfonyl; R ^{9 represents} a heterocyclic radical selected from the group consisting of thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, 4,5 dihydroisoxazol-3-yl, 4,5-dihydroisoxazol-4-yl and 4,5-dihydroisoxazol-5-yl, wherein said radicals may carry one or more substituents, for example mono-, di-, tri or tetrasubstituiert sein may be prepared by halogen, C _C4 alkyl, Ci-C ₄ -alkoxy, dC ₄ haloalkyl, dC ₄ -haloalkoxy or C _r C ₄ alkylthio;

R ¹¹ = hydrogen, halogen or C _r C ₅ alkyl; R ¹² = dC ₆ alkyl;

R ¹³ = hydrogen or C 1 -C ₆ -alkyl, if the pH is <8;

Mitosis inhibitors such as Benfluralin, Butraline, Dinitramine, Ethalfluralin, Fluchloralin, i-Sopropalin, Methalpropalin, Nitralin, Oryzalin, Pendimethalin, Prodiamine, Profluralin, Trifluralin, Amiprofos-methyl, Butamifos, Dithiopyr, Thiazopyr, Propyzamide, Chlorthal, Carbetamide, Chlorpropham and propham;

VLCFA inhibitors such as acetochlor, alachlor, butachlor, butenachlor, delachlor, diethyl, dimethachlor, dimethenamid, dimethenamid-P, metazachlor, metolachlor, SMetolachlor, pretilachlor, propisochlor, prynachlor, terbuchlor, thenylchloro, xylachlor,

CDEA, Epronaz, Diphenamid, Napropamide, Naproanilide, Pethoxamide, Flufenacet,

Mefenacet, Fentrazamide, Anilofos, Piperophos, Cafenstrole, Indanofan and Tridiphan;

Cellulose biosynthesis inhibitors such as dichlobenil, chlorthiamide, isoxaben and flupoxam;

Herbicides such as dinofenate, dinoprop, dinosam, dinoseb, dinoterb, DNOC, etinofen and

Medinoterb;

also: benzoylprop, flamprop, flamprop-M, bromobutide, chlorofluorol, cin-methylin, methyldymron, etobenzanide, pyributicarb, oxaziclomefone, triaziflam and methyl bromide.

Active ingredients used in crop protection can also be used to combat pests (eg cockroaches, ants, termites, etc.) in urban areas (eg housing estates, home and garden areas, restaurants, parks, industrial areas, etc.) and are a further group of applications especially for these applications suitable effect materials.

Also, agents for control of vertebrate pests (e.g., rats, mice and the like) can be formulated by the methods of the invention and the resulting drug formulations used for pest control in agricultural and urban environments.

Also suitable are active ingredients for pharmaceutical use, in particular those for oral administration. The method according to the invention is basically irrespective of the medical indication applicable to any number of active substances.

Particular mention should be made of water-soluble active substances for pharmaceutical use, in particular those for oral administration. This applies to both prescription and non-prescription drugs. The invention is applicable in principle, regardless of the medical indication on a variety of drugs.

Non-limiting examples of suitable sparingly water-soluble pharmaceutical agents are listed in the following table.

Examples of water-soluble active pharmaceutical ingredients are cough and expectorant agents, in particular guaiacol glycol ether (also called guaifenesin) and its derivatives.

Other preferred pharmaceutical agents are antibodies and other proteins used in pharmacy, e.g. As enzymes or peptides, or nucleic acids.

(iv) drug release from the formulations

The release of the active compounds from the formulations prepared by the process according to the invention can be achieved by desorption into suitable solvents, by degradation of the fibrous structures by hydrolysis, oxidation or biologically by enzymes such as proteases or whole microorganisms or by dissolution of the fibrous sheet by suitable solvents done and by diffusion of the Active ingredient on the fiber surface. Suitable solvents for the desorption are all solvents or solvent mixtures in which the active ingredient can be dissolved. Solvents which can dissolve the fibrous webs may be solvents only suitable for the carrier polymer system or suitable for the carrier polymer system and the active ingredient.

A particular advantage of this invention is the sustained release of the drug, with chemical factors such as e.g. Composition of the carrier can be combined with a defined configuration of the nano- and mesofibers (controlled specific surface area). This allows the release to be controlled much more precisely.

The kinetics and the profile of the release of the effect substance molecules can e.g. controlled by: (i) the loading density of the carrier polymer with active ingredients; (ii) by specific surface area of the fibers (i.e., diameter); (iii) by using a polymer mixture of at least 2 polymers as the carrier polymer, which are not equally soluble in the same solvent. That by varying the ratio of soluble and difficult or insoluble polymer in the particular solvent;

(iv) by using a biodegradable synthetic polymer or a

Biopolymers as carrier; (v) by varying the ratio in the mixture of a non-biodegradable

Polymer with a biodegradable polymer; (vi) by varying the chemical structure of the non-biodegradable polymer (e.g., water-soluble / water-insoluble) in the blend of a non-biodegradable polymer with a biodegradable polymer; (vii) by varying the ratio in the mixture of a non-biodegradable

Polymer with a biodegradable polymer; (viii) by using a polymer blend of at least 2 non-biodegradable polymers as a carrier polymer which are not equally well soluble in the release medium and a biodegradable polymer; (ix) by using a mixture of immiscible polymers, said fibers having a chemical structuring (phase separation); (x) By using homopolymers, copolymers or polymer blends having at least one phase with Tg below the application temperature. (xi) by physical structuring in the form of porosity and / or surface roughness (topography); and (xii) combination of the above measures.

Another object of the invention is the use of the fiber fabrics produced using the described polymers for the storage, transport or release of active ingredients in cosmetic products, human and animal pharmaceutical products, crop protection products, food and feed. The fibrous webs continue to serve to protect the packaged knit fabrics from environmental influences, such as e.g. oxidative processes or UV radiation, or from destruction by reaction with other constituents of the products or from biodegradation by enzymes (e.g., proteases) or microorganisms. The active substance can be released from the fibrous surfaces by desorption, biodegradation, targeted release or slow release or combination of these mechanisms.

By varying the amino acid sequence of the amphiphilic self-assembling proteins described, or by fusing with additional protein or peptide sequences, it is possible to generate structures which have certain surfaces, e.g. Skin, hair, leaves, roots specifically recognize or be recognized and bound by these surfaces or the receptors contained.

This makes it possible to more effectively bring the active ingredients formulated with the described amphiphilic self-assembling proteins to the desired site of action or to improve the active ingredient to a minimum.

Furthermore, by varying the amino acid sequence of the amphiphilic self-assembling proteins described for the active ingredient formulation, or by fusing with additional protein or peptide sequences, it is possible to target active ingredients to desired sites of action, in order to produce e.g. a higher specificity, lower drug consumption or drug dose to achieve a faster or stronger effect.

EXPERIMENTAL PART general part

a) electrospinning process

The device suitable for carrying out the method according to the invention for electrospinning comprises a syringe provided at its tip with a capillary nozzle connected to one pole of a voltage source for receiving the formulation according to the invention. Opposite the outlet of the capillary nozzle, a square counterelectrode connected to the other pole of the voltage source is arranged at a distance of about 20 cm, which acts as a collector for the fibers formed. During operation of the device, a voltage of between 15 kV and 35 kV is set at the electrodes and the formulation is discharged under low pressure through the syringe capillary nozzle. Due to the electrostatic charging of the formulation due to the strong electric field of 0.9 to 2 kV / cm, a material flow directed towards the counterelectrode solidifies on the way to the counterelectrode with formation of fibers, as a result of which fibers on the counterelectrode Separate diameters in the micro and nanometer range.

Another possible device for carrying out the method according to the invention comprises a roller which rotates in a container with spinning solution. The roller may be smooth or have a physical structuring, eg needles or grooves. The spinning solution gets into the strong electric field with each rotation of the roller and several streams of material are formed. The counter electrode is located above the spinning electrode. The fibers are deposited on a carrier fleece, eg polypropylene. For example, a Nanospider apparatus from Elmarco can be used. The voltage is about 82 kV with an electrode distance of 18cm. The temperature is about 23 ⁰ C and the relative humidity 35%. A serrated electrode is used for spinning. In order to achieve as thick a protein sheet as possible (eg protein films, protein fibers, protein nonwovens), the carrier fleece is left stationary. Alternatively, however, the carrier web can also be moved under advance in order to achieve defined protein layer structures.

b) Sample preparation for WAXS measurement The samples were prepared between two strips of adhesive tape (Scotch commercial product) and their transmission was measured.

c) drug release experiments

The investigations of the release of the active ingredients from the fiber fabrics were carried out according to the Long Time Encapsulation Analysis method. In this method, the encapsulated active ingredients in a defined concentration below the Löslichkeitsgrenze of the drug in demineralized (VE) water are used. The samples are kept stirring for a period of minutes to several weeks. In each case a sample is taken in logarithmic graduated intervals and the free active substance contained therein is examined chromatographically. On the basis of the previously performed calibration of the drug thus the amount released can be determined.

Drug release experiments with protein-containing formulations can also be carried out in two further batch variants:

Peroral oral formulations (such as clotrimazole - compressed into tablets) may be incorporated into artificial gastric juice (0.1 g NaCl, 0.16 g pepsin, 0.35 ml HCl to 50 ml, pH 1-2) and artificial intestinal juice (Dissolve 3.4 g of KH ₂ PO ₄ in 12.5 ml of water + 3.85 ml of 0.2N NaOH to make up to 25 ml + 0.5 g of pancreatin to make up to 50 ml, pH 6.8) to analyze the To simulate drug release under proteolytically active conditions in the digestive tract. Control preparations (without proteases) were carried out in 5 mM potassium phosphate buffer (pH 8.0), whereby only a small release of active substance should be observed under these conditions. Per tablet, 20 ml of the respective digestive juice or buffer were added and the batches incubated at 37 ⁰ C and 80 rpm gently shaking. At various times, 500 μl of sample are taken for each drug quantification by means of HPLC or photometer. In order to detect active ingredient aggregates formed after the release in the case of poorly water-soluble active substances, eg clotrimazole, absorption photometric quantification after extraction with THF (3 ml of supernatant + 3 ml of THF + spatula tip NaCl, vigorous vortexing, 1 min 15,000 × g, Measure upper phase, dilute if necessary). For other active ingredients (other than orally ingested pharmaceutical or other active substances), eg Uvinul A + and Metazach Lor, the release analysis can be carried out by displacing defined amounts of protein-drug sheets with nonspecific proteinase K solution. The protein-drug sheets were incubated in 0.25-0.5% [w / v] proteinase K (Roche, Germany, dissolved in 5 mM potassium phosphate buffer) shaking at 120-150 rpm. At various times, the still intact protein-drug sheets were separated by centrifugation, the supernatants with a 4-5-fold excess of THF and the drug content then determined by absorption photometry. For all batches, the amounts of active substance released were determined after comparison with a drug-specific calibration series.

Example 1 - Preparation and properties of the composite fibers of PVP and epoxiconazole

For the production of composite fibers polymer solutions of poly (I -vinyl-2-pyrrolidinone) Kollidon K-90 (PVP) (Mw = 1,100,000 g / mol, Tg = 180 ⁰ C, BASF SE) and fungicide epoxiconazole (1 - { [3- (2-chlorophenyl) -2- (4-fluorophenyl) oxiran-2-yl] methyl} -1H-1,2,4-triazole) in ethanol / water mixture (90:10) and made into fibers spun. The solutions were spun with a syringe system under voltages between 35 and 45 kV.

The weights are listed in the following table.

The information on the concentration of the active ingredient epoxiconazole refers to the total solids (PVP + active substance). The concentration of the carrier polymer refers to the total mass of solvent and polymer prior to the addition of the active ingredient.

FIG. 1A shows the fiber morphology as a function of the active ingredient content.

In order to be able to make statements about the proportion of Epoxiconazol in the fibers, a calibration was carried out at the beginning. To this was added solutions of epoxiconazole at concentrations of 10 to 40% by weight (based on solids content) and 5.7% by weight PVP (based on the total weight of the formulation prior to the addition of the active ingredient) in ethanol / water (90/10). prepared, applied to a Si wafer and whose transmission was examined by IR spectroscopy. The ratio of the specific bands of PVP and epoxiconazole was evaluated and used to make a calibration line.

The active-ingredient-containing fiber fabrics produced were likewise dissolved in the ethanol / water mixture and applied to Si wafers as a film analogously to the calibration samples, measured by IR spectroscopy, and the calibration line was used to determine the concentrations of epoxiconazole. The calibration values together with the findings from fibrous sheets are shown in FIG. 1B.

The graph shows that after the spinning of the fibers still about the same amount of epoxiconazole used is present. Several measurements show that the result is reproducible.

The active ingredient epoxiconazole is in the fiber fabric in an amorphous state. This is confirmed by the X-ray wide-angle measurements (WAXS), which were carried out with a Bruker diffractometer D5005 (monochromatized Cu-Kα radiation) in transmission. Results of the WAXS measurements on freshly prepared fiber surface structures of PVP-epoxiconazole are shown in FIG.

The samples were enclosed on or between two strips of adhesive tape. The sharp peak at about 2Θ = 18 ° is an impurity since this peak can already be observed in pure PVP and can not be assigned to the epoxiconazole. To check the storage stability of these fiber sheet, the sample -10 ° C and 0 ⁰ C every 24 hrs. And 72 hrs were incubated at +40 ⁰ C,. Stored at 20 ⁰ C and then re-examined by wide angle X-ray control.

The results of the WAXS measurements on PVP-epoxiconazole fiber sheets stored at different temperatures are shown in FIG.

FIG. 3 clearly shows that the preparations are storage-stable-active substance does not change its amorphous morphology during storage at different temperatures.

Example 2 Production and Properties of the Composite Fibers of PVP and Ca-Carotene.

ß-carotene is used for coloring fatty foods such as butter, margarine, cheese, mayonnaise and - in water-dispersible form - also water-containing foods such as fruit drinks, puddings, sugar confectionery. Beta-carotene is also used as a dye for cosmetics and as a feed additive. For the production of composite fibers were polymer solutions of poly (I -vinyl-2-pyrrolidinone) Kollidon K-90 (PVP) (Mw = 1,100,000 g / mol, Tg = 180 ⁰ C, BASF SE) and the dye ß-carotene im Chloroform produced and spun into fibers. For this purpose, the solutions were spun with a syringe system under voltages between 40 and 45 kV. In addition, 0.5% by weight, based on the total formulation of benzyltributylammonium bromide, was added to increase the electrical conductivity of the solution. This has a positive effect on the fiber morphology and diameter distribution: namely, fewer beads (beads) are formed and the fiber diameter distribution becomes narrower.

The weights are listed in the following table.

The information on the concentration of the effect substance ß-carotene refer to the total mass of PVP and effect substance. The concentration of the carrier polymer refers to the total mass of solvent and polymer.

FIG. 4A shows the fiber morphology as a function of the effect content.

In order to be able to make statements about the proportion of ß-carotene in the fibers, a calibration was carried out at the beginning. To this end, solutions of .beta.-carotene having concentrations of from 10 to 40% by weight (based on the solids content) and 6% by weight of PVP (based on the total weight of the formulation prior to the addition of the active ingredient) in chloroform were prepared Si wafers and their transmission was examined by IR spectroscopy. The ratio of the specific bands of PVP and ß-carotene was evaluated and a calibration line created.

The fabric-containing fiber fabrics produced were dissolved in chloroform and, like the calibration samples, applied to Si wafers as a film, measured by IR spectroscopy and the β-carotene concentrations were evaluated on the calibration line. The calibration values together with the findings from fibrous structures are shown in FIG. 4B.

The diagram of FIG. 4B shows that after spinning, the fibers still have approximately the amount of β-carotene used. Several measurements show that the result is reproducible.

The effect substance ß-carotene is in an amorphous state. This is shown by the X-ray wide-angle scattering measurements (WAXS), which were carried out with a Bruker diffractometer D5005 (monochromatized Cu-Kα radiation) in transmission.

The samples were enclosed between two strips of adhesive tape. FIG. 5 shows the results of the WAXS measurements on freshly prepared fiber surface structures of PVP-β-carotene

To check the storage stability of these fiber fabric, the samples were at least 72 hours at +40 ⁰ C, -10 ° C and 0 ⁰ C every 24 hrs. And at 20 ⁰ C. Stored and then re-examined by wide angle X-ray control.

FIG. 6 shows results of the WAXS measurements on fiber sheets of PVP-β-carotene stored at different temperatures.

FIG. 6 clearly shows that the preparations are storage-stable. The active ingredient does not change its amorphous morphology during storage at different temperatures.

Example 3 - Preparation and properties of composite fibers of PMMA and epoxiconazole.

To further demonstrate the broad applicability of the method, composite fibers of poly (methyl methacrylate) and fungicide epoxiconazole were prepared.

Z represents H e rstellung composite fibers were polymer solutions from Po ly (methyl methacrylate) Plexiglas® (PMMA) (Mw = 430 000 g / mol, Tg = 1 10 ⁰ C (ISO 11357)), and fungicide epoxiconazole (1 - {[3 - (2-chlorophenyl) -2- (4-fluorophenyl) oxiran-2-yl] methyl} -1 H-1, 2,4-triazole) in an ethanol / chloroform mixture (6: 1 1) and prepared Spun fibers. For this purpose, the solutions were spun with a syringe system under voltages between 40 and 45 kV.

The weights are listed in the following table.

The information on the concentration of the active ingredient epoxiconazole refers to the total solids (PMMA + active substance). The concentration of the carrier polymer refers to the total mass of solvent and polymer before the drug is input.

FIG. 7 shows the fiber morphology as a function of the active ingredient content.

The active ingredient epoxiconazole is in the fiber surfaces in the amorphous state. This is shown by the X-ray wide-angle scattering measurements (WAXS), which were carried out with a Bruker diffractometer D5005 (monochromatized Cu-Kα radiation) in transmission. The samples were prepared on or between scotch tape.

FIG. 8 shows the results of the WAXS measurements on fiber surfaces of PMMA-epoxiconazole

Example 4 - Influence of specific surface area on drug release

The further advantage of the fibers is their large specific surface area compared to films or other formulation forms. To prove this, the release of the active substance from fibers and films was investigated.

The fiber fabrics for the release tests were from a solution containing 12 wt .-% Ecoflex® (aliphatic-aromatic copolyester BASF SE based on butanediol, adipic acid and terephthalic acid, Tg = -30 ° C, Tm = 1 15 ° C, Mn = 35,000;

Mw = 1 18,000; compare also http://www.plasticsportal.com/products/ecoflex.html)

(based on the total weight of the formulation before the input of the active ingredient),

Solvent mixture of chloroform / i-propanol (95: 5) and 10 wt .-% epoxiconazole (based on solid (polymer + active ingredient)) spun. As a comparative sample to the fiber fabric was on a slide, the same polymer-active solution from 12 wt .-% Ecoflex (based on total mass of the formulation prior to the addition of the active ingredient) and 10 wt .-% Epoxiconazole (based on solids content) painted, the solvent evaporates and then with a razor blade the polymer / drug film separated from the slide.

The two samples were weighed into deionized water at a concentration of 7 mg / l and stirred continuously in a 0.5 liter Erlenmeyer flask at constant speed on a magnetic stirrer. The measurement was carried out according to the method described above. The samples taken were analyzed for free drug on Agilent Series 1100 HPLC at a wavelength of 220 nm.

FIG. 9 shows the release profiles of epoxiconazole from biodegradable polyester Ecoflex as a film and as a fibrous sheet

From Figure 9 it can be seen that the release is dependent on the specific surface of the carrier and can be controlled in this way.

Example 5: Release of active ingredient from polymers with different solubility.

The release can additionally be controlled via the solubility of the carrier polymer in the solvent. As an example, fibrous webs of polyvinylpyrrolidone, polymethymethacrylate and Ecoflex with epoxiconazole were prepared and the release in demineralized water was measured by the method described in Example 4. The samples were prepared as follows: a) 5% by weight of PVP, 20% by weight of epoxiconazole in ethanol-water mixture (9: 1); b) 12% by weight of Ecoflex, 20% by weight of epoxiconazole in chloroform-i-propanol mixture (95: 5); c) 6% by weight of PMMA, 20% by weight of epoxiconazole in chloroform-ethanol mixture (11: 6)).

The information on the concentration of the active ingredient epoxiconazole refers to the total solids (PVP + active substance). The concentration of the carrier polymer refers to the total weight of solvent and polymer prior to the input of the drug. FIG. 10 shows the release profiles of epoxiconazole from biodegradable polyester Ecoflex, PVP and PMMA.

The water-soluble PVP releases epoxiconazole relatively quickly. After just 2 minutes, about 40% of the epoxiconazole has escaped from the fibers. Delayed from Ecoflex fibers Epoxiconazole is released slowly after about 10 min. Only after one day have 40% of the active ingredient escaped from the fibers. Ecoflex is not water soluble. The delayed and slow release could therefore be due to diffusion of Epoxiconazols to the surface of the fibers or to a partial degradation of the polyester. Unlike PVP and Ecoflex fibers, no epoxiconazole is released from PMMA fibers in the first two days. PMMA fibers are not water soluble and apparently the diffusion of epoxiconazole from the fibers in water is also very slow or not possible.

Example 6 - Release from a blend of poorly miscible polymers

The release profile can also be influenced by the polymer composition of chippings. So poor or limited miscible carrier polymers can be used. The release of epoxiconazole from PVP and PMMA fibers as well as fibers from their blends PVP-PMMA (1: 1) and PVP-PMMA (1: 5) was tested on the following samples:

a) 5% by weight of PVP, 20% by weight of epoxiconazole in ethanol-water mixture (9: 1); b) 2.5% by weight PVP, 2.5% by weight PMMA, 20% by weight. Epoxiconazole in chloroform-ethanol mixture (11: 6); c) 1 wt% PVP, 5 wt% PMMA, 20 wt% epoxiconazole in chloroform-ethanol (1: 6); d) 6% by weight of PMMA, 20% by weight of epoxiconazole in chloroform-ethanol mixture (11: 6).

The information on the concentration of the active ingredient epoxiconazole refers to the total solids (carrier polymer + active ingredient). The concentration of the carrier polymer refers to the total weight of solvent and polymer prior to the input of the drug.

Figure 11 shows the release profiles of epoxiconazole from fiber sheets made of PVP and its blends with PMMA. The release from the polymer blends corresponds very well to the expected behavior from the release profiles of the fibers of PVP or PMMA. Thus, the release decreases with increasing PMMA content. The rapid initial release - the first measurement point is already well over 0% - can be observed in the fiber fabrics. This behavior can be explained by the fact that the two carrier polymers are immiscible and form a structure in which there are PVP-rich and PVP-poor domains. This structuring is very clearly visible in TEM images. Acrylate is displayed brightly. Figure 12 shows cross sections of the fibers of PMMA and PVP (5: 1).

It can be seen that the PVP-rich phase is preferentially located on the fiber surface, while the acrylate phase dominates in the interior. Rapid release can be explained by the dissolution of the PVP-rich phase.

Example 7 - Release from the blend of miscible polymers

If miscible polymers are used, this results in fiber surface structures with homogeneous component distribution over the entire fibers. The following samples were used for the investigations of the release profile:

a) 5% by weight of PVP, 20% by weight of epoxiconazole in ethanol-water mixture (9: 1); b) 4% by weight of PVP, 4% by weight of Ecoflex, 20% by weight of epoxiconazole in chloroform-i-propanol mixture (95: 5); c) 12% by weight of Ecoflex, 20% by weight of epoxiconazole in chloroform-i-propanol mixture (95: 5).

Figure 13 shows the release profiles of epoxiconazole from fiber sheets made from PVP and its blends with Ecoflex. It is observed that the rapid, PVP-typical drug release is no longer present in the blend; the profile corresponds to the least soluble polymer Ecoflex and has become faster over time.

Example 8 - Preparation of the C16 spider silk protein

The preparation of the C16 spider silk protein was carried out biotechnologically using plasmid-containing Escherichia coli expression strains. Design and cloning of the C16 spider silk protein (also called ADF4) are described in Hümmerich et al. (Biochemistry 43, 2004, 13604-13012). In contrast to the method described there, C16 spider silk protein was produced in E. coli strain BL21 Gold (DE3) (Stratagene). Cultivation is carried out in Techfors fermenters (Infors HAT, Switzerland) using a minimal medium and fed-batch techniques.

Minimal medium: 2.5 g / l citric acid monohydrate 4 g / l glycerol

12.5 g / l potassium dihydrogen phosphate 6.25 g / l ammonium sulfate 1.88 g / l magnesium sulfate heptahydrate

0.13 g / l calcium chloride dihydrate

15.5 ml / l of trace element solution (40 g / l citric acid monohydrate;

1 1 g / l zinc (II) sulfate heptahydrate; 8.5 g / l of diammonium (II) sulfate heptahydrate; 3 g / l manganese (II) sulfate monohydrate; 0.8 g / l copper (II) sulfate pentahydrate; 0.25 g / l cobalt (II) sulphate heptahydrate) 3 ml / l vitamin solution (6.3 mg / ml thiamine hydrochloride, 0.67 mg / ml

Vitamin B12) pH 6.3

Feed solution: 790 g / l glycerol

6.9 g / l citric acid monohydrate

13.6 g / l sodium sulfate

1, 05 g / l diammonium iron (II) sulfate heptahydrate 13 mg / l thiamine hydrochloride The cells were grown at 37 ° C to an OD ₆ oo of 100, followed by induction of protein expression with 0.1 mM isopropyl β-D-1-thiogalactopyranoside (IPTG). At the end of the fermentation (8 to 12 hours after induction), the cultures were harvested. The main part of the protein was in "inclusion bodies".

After cell harvest, the pellet was resuspended in 2OmM 3 - (- N-morpholino) propanesulfonic acid (MOPS) pH 7.0 (5L buffer per kilogram wet weight). Subsequently, cell digestion was carried out using a Micofluidizer M-1 10EH (Microfluidics, US) at pressures of 1200 to 1300 bar. After sedimentation, the pellet, after disruption, contained cell debris and membrane constituents in addition to the inclusion bodies, which were removed by two washes In a first washing step, the pellet was suspended in 2.5 volumes of Tris buffer (50 mM Tris / HCl, 0.1 % Triton X-100, pH 8.0) and then the remaining solid was sedimented by centrifugation A second washing step was carried out using Tris buffer (50 mM Tris / HCl, 5 mM EDTA, pH 8.0) Once again pellet obtained after sedimentation was almost free of membrane and cell debris.

The purified "inclusion bodies" were dissolved in guanidinium thiocyanate (Roth, Germany), 1 g of guanidinium thiocyanate being added per 1 g of pellet (wet mass) The "inclusion bodies" were dissolved with gentle heating (50 ^° C.) with stirring. To separate off any non-soluble constituents, a centrifugation was then carried out. To obtain an aqueous C16 spider silk protein solution, dialysis was then carried out for 16 hours against 5 mM potassium phosphate buffer (pH 8.0) (dilution factor of dialysis: 200).

Contaminating E. coli plants on dialysis formed aggregates which could be separated by centrifugation. The resulting protein solution had a purity of -95% C16 spider silk protein.

The resulting aqueous protein solution can either be used directly for electrospinning or further processed to protein microbeads for better shelf life. To prepare C16 protein microbeads, the aqueous C16 spider silk protein solution is added with 0.25 volume of a 4 molar ammonium sulfate solution. Under the action of ammonium sulfate, the protein monomers assemble into spherical structures, which are referred to here as microbeads. The microbeads were separated by centrifugation, washed three times with distilled water and then freeze-dried.

Example 9 - Formulation of clotrimazole as effect substance by means of electrospinning

In order to demonstrate the utility of the described method for the formulation of active substances, in particular sparingly water-soluble, the pharmaceutical active ingredient clotrimazole was encapsulated by means of electrospinning in C 1-6 spider silk protein sheets by way of example.

For the preparation of a spinnable solution, C16-spider silk protein microbeads (14% [w / w]) and the active ingredient clotrimazole (10% [w / w]) were dissolved together in formic acid (98-100% p.a.). 200 ml of formic acid were placed in a beaker and then successively 50.4 g of C16 spider silk protein and 36 g of clotrimazole (from Sigma, Germany) were stirred in. After the substances were completely dissolved, the solution was made up to 360 g with formic acid (98-100%).

Alternatively, water-soluble C16 spider silk protein solution (see Example 1) can also be used as starting material base. The active ingredient is then dissolved directly in the aqueous protein solution or predissolved using higher concentrations of active agent in an alternative solvent (e.g., formic acid) and then mixed with the protein solution. In order to increase the viscosity of the spinning solution, it is then additionally possible to admix water-soluble polymers or polymer dispersions.

The solution of C16 spider silk protein and clotrimazole was spun for three hours in a Nanospider Elmarco apparatus. The voltage was 82 kV with an electrode distance of 18 cm. The temperature was 23 ⁰ C and the relative humidity 35%. A serrated electrode was used for spinning. In order to achieve as thick a protein sheet as possible, the carrier fleece was left standing. Alternatively, however, the carrier web can be moved under feed to achieve defined thinner protein sheet layers. The protein fibers obtained from the batch were then dried at 40 ^° C. and under vacuum overnight. T heeliccemicmicroscopic coalescedresistant C 1 6- spider silk protein sheets with entrapped clotrimazole revealed that they are predominantly fibers with a diameter of about 50 nm to 1 μm (FIG. 14). ,

In contrast to the pure clotrimazole, no crystalline peaks show up in the C16-spider silk protein / clotrimazole formulation in the X-ray diffraction (FIG. 15). Accordingly, it can be assumed that the active substance was amorphous or encapsulated as a solid solution, which can positively influence its bioavailability.

In order to check the release of active ingredient from a form of application that is as relevant as possible, tablets were pressed from the C16 spider silk protein sheets. In each case, 300 mg of material were pressed under vacuum and 100 bar pressure for about 10 minutes in a KBr press (company: Paul-Otto-Weber, Germany). The tablets had a diameter of about 13 mm and a thickness of about 2 mm.

The release of clotrimazole from the tablets was tested in two different approaches. Artificial gastric juice (0.1 g NaCl, 0.16 g pepsin, 0.35 ml HCl to 50 ml, pH 1-2) and artificial intestinal juice (3.4 g KH ₂ PO ₄ in 12.5 ml water dissolve + 3.85 ml of 0.2N NaOH to 25 ml + 0.5 g pacreatin to 50 ml make up, pH 6.8) to simulate drug release under proteolytically active conditions in the digestive tract. Another approach was carried out in 5 mM potassium phosphate buffer (pH 8.0), which should be observed under these Kotrollbedingungen only a small release of active ingredient. 20 ml of the JE weiligen digestive juice or buffer was added per tablet and the lugs at 37 ⁰ C and incubated 80 rpm slightly shaking. The quantification of the liberated clotrimazole was due to its poor water solubility (and thus tendency to aggregate formation in aqueous systems) after extraction of the supernatant with THF by absorption photometric determination at 262 nm (3 ml supernatant + 3 ml THF + Spätspitze NaCI, vigorous vortexing , 1 min 15,000 xg, upper phase measured, dilute if necessary).

Whereas in the control batch (buffer without proteases) only a maximum of 2% of the encapsulated amount of active substance is released, in gastric juice controlled by the existing enzymatic activity (proteases), about 50% release is achieved within 24 h (FIG. 16). The active substance clotrimazole is released continuously. in the By contrast, intestinal juice releases only about 20% of the active ingredient after 24 h (FIG. 16). The C16 spider silk protein / clotrimazole formulation appears to be so stable under the more predominantly neutral pH values over the time range considered that only a weaker release is observed.

In order to determine the proportion of clotrimazole not yet released from the formulation after 24 h, 3 ml of tetrahydrofuran (THF) were added to the batches containing the non-proteolytically degraded C16 spider silk protein fibers and incubated at max. Shaking for 48 h. Subsequently, the content of active substance was quantified by absorption spectometry at 262 nm. From the final value and the previously determined intermediate values, it was possible to determine the loading density of the C16 spider silk protein formulation with the active ingredient clotrimazole. The loading density was between 27% and 33% [w / w] for all tablets examined, which resulted in an average loading density of the tablet-compressed C16 spider silk protein sheet with about 30% [w / w] clotrimazole (see table below). ,

Loading densities of the C16 spider silk protein formulation (tablets) with the active ingredient clotrimazole.

Reference is expressly made to the disclosure of the references cited herein

Claims

claims

An active agent-containing fibrous sheet comprising a fibrous, polymeric soluble and / or degradable drug carrier and at least one low molecular weight or molecular weight drug associated with the carrier and releasable from the fibrous sheet, the carrier being a composite polymer comprising a mixture of at least two Polymer components, these at least two polymer components differing in at least one property selected from a) solubility in solvents, b) molecular weight c) glass transition temperature / melting point; and d) degradability.

2. Fibrous sheet according to claim 1, wherein the at least one active ingredient is in amorphous, partially crystalline or crystalline form.

3. A fibrous sheet according to any one of the preceding claims wherein the active ingredient is incorporated in and / or adsorbed to the carrier.

4. A fibrous sheet according to any one of the preceding claims, wherein the one fibrous, drug-containing carrier is obtainable by a spinning process.

5. The fibrous sheet according to claim 4, wherein the fibrous, drug-containing carrier by an electrospinning process with an electro-spinnable solution containing, in each case in dissolved form, the at least one active ingredient and the mixture of at least two polymer components, is obtainable.

6. The fibrous sheet according to any one of the preceding claims, wherein the polymer components are miscible with each other or at least two of the polymer components are immiscible with each other.

7. Fibrous sheet according to any one of the preceding claims, wherein the polymer components are selected from synthetic polymers and natural polymers, in particular amphiphilic selbstassemblieren- the proteins, wherein the biopolymers are optionally additionally chemically and / or enzymatically modified.

The fibrous web of claim 7, wherein the synthetic polymer is a homo- or copolymer.

9. Fibrous sheet according to one of the preceding claims, wherein the

Composite polymer is selected from a) mixtures of at least 2 miscible, synthetic homo- or copolymers; b) mixtures of at least 2 immiscible synthetic homo- or copolymer c) mixtures of at least 2 miscible biopolymers; d) mixtures of at least 2 immiscible biopolymers; e) mixtures of at least one synthetic homo- or copolymer and at least one biopolymer which are miscible with one another; f) mixtures of at least one synthetic homo- or copolymer and at least one biopolymer which are immiscible with one another

The fibrous web of any of the preceding claims, wherein the polymer components independently have molecular weights in the range of about 500 to 10,000,000.

1 1. A fibrous sheet according to any one of the preceding claims, wherein diameter of the drug carrier fibers 10 nm to 100 microns, such as 50 nm to 10 microns, or 100 nm to 2 microns, is

12. The fibrous sheet according to any one of the preceding claims, wherein the active ingredient loading is about 0.1 to 80 wt .-%, based on the solids content of the fiber fabric.

13. A fibrous sheet according to any one of the preceding claims, selected from polymer fibers and polymer nonwovens.

14. Fibrous sheet according to any one of the preceding claims, wherein the active ingredient is molecularly disperse or nanoparticulate disperse in the fibers.

15. Active substance-containing formulation comprising a fibrous sheet material according to one of the preceding claims in processed form, optionally in combination with at least one further formulation auxiliary.

A formulation according to claim 15 comprising the fibrous sheet in comminuted or non-comminuted form.

17. A formulation according to claim 15 or 16, comprising the fibrous sheet in compacted form in powder form, or applied to a carrier substrate.

18. A formulation according to any one of claims 15 to 17 selected from cosmetic, human and animal pharmaceutical, agrochemical formulations,

Food and feed additives.

19. Use of a medicated fiber sheet according to any one of claims 1 to 14 for the preparation of an active ingredient-containing formulation according to any one of claims 15 to 18.

20. Use of a drug-containing formulation according to any one of claims 15 to 18 for the controlled release of an active ingredient contained therein.

21. A process for the production of a fibrous sheet material according to claim 1, wherein a) the at least one active substance is mixed together with the Trägerpolymerkom- ponnten in a common liquid phase and b) then the embedding of the active ingredient in a polymeric Komposit- fiber Performs spinning process.

22. The method of claim 21, wherein mixing the at least one active ingredient and the polymer components in a solvent phase and spun from this mixture.

23. The method of claim 21, wherein mixing the at least one active ingredient and the polymer components in a mixture of at least two mutually miscible solvents, wherein active ingredients and polymers are soluble in at least one of the solvents, and spun from this mixture.

24. The method according to any one of claims 21 to 23, wherein the spinning process is an electrospinning process or a centrifugal spinning process.

25. The method according to any one of claims 21 to 24 wherein one operates at a temperature in the range of about 0 to 90 ⁰ C.

26. A fibrous sheet according to any one of claims 1 to 14, which is substantially free of low molecular weight drugs.

27. Use of a fibrous sheet according to claim 26, for the preparation of an active ingredient-containing formulation.

28. Use according to claim 27, wherein the formulation is selected from cosmetic, human and animal pharmaceutical, agrochemical formulations, food and feed additives.