WO2014131376A1

WO2014131376A1 - Electrospun nanofibers comprising pharmaceutically active agents

Info

Publication number: WO2014131376A1
Application number: PCT/CZ2013/000025
Authority: WO
Inventors: Denisa Stranska; Pavel Dolezal; Pavel BERKA; Petr VRBATA; Jan HONEGR; Marie MUSILOVA
Original assignee: Elmarco S.R.O.
Priority date: 2013-02-26
Filing date: 2013-02-26
Publication date: 2014-09-04
Also published as: CZ2013144A3; CZ308409B6

Abstract

The invention relates to a preparation for the administration of at least one biologically and/or pharmaceutically active substance, by which at least one biologically and/or pharmaceutically active substance is deposited in and/or on at least one active layer of nanofibers of biologically compatible material.

Description

ELECTROSPUN NANOFIBERS COMPRISING PHARMACEUTICALLY ACTIVE

AGENTS

Technical field

The invention relates to a preparation for the administration of at least one biologically and/or pharmaceutically active substance.

Background art

Nowadays, prevention, diagnostics, therapy, mitigating effects of numerous diseases as well as influencing of some physiological functions by humans and animals is connected with use of various biologically and/or pharmaceutically active substances (biologically active substances - BAS, active pharmaceutical ingredients - API). Preferential and the most usual form of administration of those active substances is their administration by mouth connected with swallowing of tablets or capsules by which the biologically and/or pharmaceutically active substance/substances passes through the gastrointestinal tract - GIT in which, especially in the stomach and in the intestine, is acted on them by aqueous biological body fluids. However, the problem of numerous biologically and/or pharmaceutically active substances is their rather bad solubility in these biological fluids or, in some cases, also their low permeability, which result in bad absorption of these active substances from GIT and their low bioavailability in the organism, which in consequence decreases their effect. The biggest problems occur especially with biologically and/or pharmaceutically active substances from the BCS II. group (substances with bad solubility and high permeability) and from the BCS IV. group (substances with bad solubility and bad permeability) according to the biopharmaceutics classification system (BCS) - see e.g. publication G. L. Amidon, H. Lennernas, V. P. Shah and J. R. Crison: "A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability", 1995. Nevertheless, it is estimated, that about 90 % of all biologically and/or pharmaceutically active substances included today in the pharmaceutical programs for development of new pharmaceuticals are of bad solubility in water - see e.g. S. R. Page, CRC Meeting, 2008; .In: S. Koltzenburg: "Formulation of problem drugs - and they are all problem drugs. Solubility enhancement with BASF Pharma Polymers." 2008, p. 9.

At present, the problem is solved by means of chemical or physical modifications of biologically and/or pharmaceutically active substances and their dosage forms. Fundamental disadvantage of chemical modifications is however, that by them, molecules of biologically and/or pharmaceutically active substances are modified, as a result of which it is necessary to define again and to verify their fundamental properties, including their toxicity profile. By that, significant increase of needed investments - either money or time is also caused, which influences the final price of the pharmaceutical and thus also of the therapy as whole.

Unsuitable technical-economic parameters such as low yield, demands on time, risk of contamination and symptoms of instability are problem also at physical modifications of biologically and/or pharmaceutically active substances including especially micronization and nanosizing, complexation with cyclodextrins and/or polymers, formation of nanocrystals, co-crystals, solvates including hydrates, liposomes, microemulsions, nanoemulsions, solid lipid nanoparticles, solid solutions, hot-melts, systems formed through amorphisation of biologically and/or pharmaceutically active substances, e.g. by means of spray drying or freeze-drying (lyophilisation) techniques. However, even more significant disadvantage of those types of modifications is thermodynamic instability of formed systems of sub-micron particles, which increases tendency of such particles to agglomerate into bigger formations resulting in reduction of size of their surface accessible for. a solvent or for biological body fluids, and thus of their solubility.

The goal of the invention is to design a preparation for administration of at least one biologically and/or pharmaceutically active substance which would remove at least some disadvantages of the background art and would especially cause increase of solubility of biologically and/or pharmaceutically active substances, in particular those included in the BCS II. and BCS IV. groups of the biopharmaceutics classification system (BCS), by means of which it would also widen possibilities of profiling the kinetics of release of these active substances and possibilities for their administration into the human or animal organism with higher therapeutic efficiency, safety and more favourable technical-economic parameters.

Principle of the invention

The goal of the invention is achieved by means of preparation for administration of at least one biologically and/or pharmaceutically active substance, the principle of which lies in that, that at least one biologically and/or pharmaceutically active substance is deposited in and/or on at least one active layer of nanofibers of biologically compatible material. The small size combined with large specific surface of formations of the biologically and/or pharmaceutically active substance provide significant increase of solubility of such active substance in biological fluids, e.g. in gastric or intestinal juices, this especially when biologically and/or pharmaceutically active substances of the BCS II. and BCS IV. groups of the biopharmaceutics classification system (BCS) are considered. Together with that, the overall solubility and rate of dissolution of such biologically and/or pharmaceutically active substance increases, is followed by increase in their bioavailability. Thereat, this effect is most significant in variants, by which is the biologically and/or pharmaceutically active substance incorporated directly in material of the nanofibers of the active layer.

The most suitable biologically compatible material for production of the active layer is biologically compatible polymer, especially polymer from group of polyvinyl alcohols (PVA), polyactides (PLA), polycaprolactones (PCL), polyvinylpyrrolidones (PVP), polyurethanes (PUR), their copolymers, cellulose derivatives such as for example hydroxypropyl cellulose (HPC), hydroxypropyl methycellulose (HPMC), polyethylene glycol/polyvinylcaprolactam/polyvinyl acetate copolymer, chitosan derivatives, their mixtures as well as numerous polymerizable monomers, mixtures of at least two of these. To speed up the release of the biologically and/or pharmaceutically active substance from the active layer of nanofibers, it is possible to create the active layer from biologically degradable material. The advantage of this variant is also that after and/or during the release of the biologically and/or pharmaceutically active substance, the active layer of nanofibers decomposes in the body of the recipient, so it is not necessary to remove it additionally.

Depending on the type of biologically and/or pharmaceutically active substance and required profile of its release, the active substance is incorporated in the material of the nanofibers of the active layer and/or is deposited on the surface of the nanofibers of the active layer and/or in the inter- fibrous areas of the active layer and/or on at least one of the surfaces of the active layer of nanofibers. Thereat, it can be bonded to the nanofibers of the active layer by means of chemical bond based on ester bond and/or by means of biologically compatible bonding agent being soluble or dispersible in aqueous environment or miscible with it at temperature of living human or animal body. Such bonding agents include for instance substances from the group of polyethylene glycols, polysorbates, polyvinyl alcohols, polyvinylpyrrolidones, monoglycerides, diglycerides, triglycerides, esters of isopropyl alcohol and other waxes, esters of sorbitan, monosaccharides, disaccharides, calcium hydrogen phosphate dihydrate, calcium phosphate, calcium sulphate or mixture of at least two of these.

Also in such bonding or impregnating material may be incorporated at least one biologically and/or pharmaceutically active substance, which may be the same as, or different from the biologically and/or pharmaceutically active substance deposited in and/or on the active layer of nanofibers.

It is advantageous for easier handling and subsequent processing to impregnate at least one surface of at least one active layer of nanofibers with hydrophilic excipient or mixture of excipients which is/are solid at room temperature and which softens/soften and/or dissolves/dissolve in water and/or mixes/mix with water at temperature of living human or animal body, and/or with hydrophilic excipient or mixture of excipients, which is/are solid at room temperature and which softens/soften and/or becomes/become dispersible in the biological body fluids at temperature of living human or animal body.

Also in such material may be incorporated at least one biologically and/or pharmaceutically active substance, which may be the same as, or different from the biologically and/or pharmaceutically active substance deposited in and/or on the active layer of nanofibers.

The active layer of nanofibers including at least one biologically and/or pharmaceutically active substance is further used either separately as planar layer, or is processed in suitable way - for instance is folded and/or lapped and/or rolled into shape of a cylinder or a hollow tube and/or wound up and/or wound up into full or hollow structure with subsequent reinforcement by twisting and/or wound/wrapped around suitable core and/or is transformed into formations of size and/or weight and/or shape and/or content of biologically and/or pharmaceutically active substance determined in advance, such as crushed material and/or powder and/or fragments and/or bunches/clusters and/or bands and/or twists etc. Those formations can also be further processed - for instance cut and/or sheared and/or folded and/or lapped and/or layered onto each other and/or bound to each other etc.

If case of need, for instance for easier handling and/or influencing the release of the biologically and/or pharmaceutically active substance, at least one covering layer consisting of a film or a layer of nanofibers of a biologically compatible material may be deposited on at least one surface of the active layer of polymeric nanofibers. Thereat, these layers may be bonded together by means of at least one biologically compatible bonding agent and/or mutual folding and/or lapping and/or cabling and/or winding around a core and/or winding up and/or winding up into a full or hollow structure with subsequent reinforcement by twisting.

For practical application, the active layer of nanofibers and/or its fragments and/or bunches/clusters and/or bands and/or twists are then placed in a sack, tablet, multi-layer tablet, tablet with a core, film, plug, globule or another insert from biologically compatible and biologically degradable hydrophilic filler or mixture of at least two such fillers for peroral, oral, mucosal, rectal, vaginal, urethral, intrauterine, nasal, auricular, ocular or invasive parenteral administration. Suitable hydrophilic filler or bonding agents is e.g. mannitol and/or sorbitol and/or glucose and/or lactose and/or saccharose and/or mixture of lactose and povidone and/or crospovidone etc.

In another variant, the active layer of nanofibers and/or its fragments and/or bunches/clusters and/or bands and/or twists are placed in a sack or capsule of biologically degradable and biologically compatible material for peroral, oral, mucosal, rectal, vaginal, intrauterine or invasive parenteral administration. Suitable material for the capsule is e.g. gelatine, hydroxypropyl cellulose or hypromellose.

The active layer of nanofibers is advantageously prepared by means of nozzleless electrostatic spinning, which provides its highest evenness in all directions.

As the biologically and/or pharmaceutically active substance, any active substance of the group BCS II. and BCS IV. of the biopharmaceutics classification system (BCS) can be used, among others.

Description of the drawings

In the enclosed drawing, Fig. 1 schematically represents the basic types of processing of the active layer of nanofibers comprising at least one biologically and/or pharmaceutically active substance diminished/powderized and mixed with binders/fillers into different types of preparations for the administration of at least one biologically and/or pharmaceutically active substance according to the invention for peroral administration, Fig. 2 schematically represents the basic types of processing of the active layer of nanofibers comprising at least one biologically and/or pharmaceutically active substance or their formations, Fig. 3 schematically represents the basic stages of processing the active layer of nanofibers including at least one biologically and/or pharmaceutically active substance into the form of a tablet, Fig. 4 represents a photograph of cross-section of compressed tablet with deposited active layer of nanofibers containing diosmin, and Fig. 5 represents the kinetic profile of dissolution of dabigatran deposited in the active layer of nanofibers into aqueous medium at pH 6.0.

Examples of embodiment

A preparation for administration of at least one biologically and/or pharmaceutically active substance according to the invention comprises at least one active layer of nanofibers of biologically compatible material, while given at least one biologically and/or pharmaceutically active substance is deposited in and/or on this active layer. This active substance can be deposited in and/or on the active layer of nanofibers having the form of molecules, nanoparticles and/or nanofibers and/or microparticles and/or microfibers and/or crystals and/or amorphous nanocompartments loosely scattered in the inter-fibrous areas among nanofibers of the active layer, and/or bonded to the nanofibers of this layer by means of physical and/or chemical bond (based on e.g. an ester bond), and/or it can be incorporated directly in the material of its nanofibers, and/or can be deposited in the form of nanoparticles and/or nanofibers and/or microparticles and/or microfibers and/or crystals and/or layer and/or film and/or impregnation comprising solution and/or dispersion of amorphous nanocompartments and/or nano/microsuspension and/or nano/microemulsion on surface of nanofibers of the active layer and/or on at least one surface of this layer.

The basic methods for depositing the biologically and/or pharmaceutically active substance into the active layer of nanofibers include especially coating of the nanofibers, embedding (see below) or encapsulation by means of coaxial or emulsion electrostatic spinning.

To deposit the biologically and/or pharmaceutically active substance onto surface and/or into inter-fibrous areas of the active layer of nanofibers e.g. distribution of such active substance and/or its precursor onto layer of nanofibers prepared in advance can be used, the active substance and/or its precursor having the form of solution and/or another dispersion, by means of soaking and/or spreading and/or spraying etc. In case of depositing the precursor of the biologically and/or pharmaceutically active substance, a chemical and/or physical modification is performed subsequently, transforming the precursor into required biologically and/or pharmaceutically active substance.

For bonding at least one biologically and/or pharmaceutically active substance to the surface of the active layer of nanofibers and/or its nanofibers, it is advantageous to use biologically compatible bonding agent. Advantageously, it is bonding agent which, at temperature of living human or animal body, is soluble or dispersible in aqueous environment or in biological body fluids, or miscible with it/them, and which thus enables release of given biologically and/or pharmaceutically active substance/substances after administration of the preparation for administration of active substance into such body/environment. In case of need, such bonding material may directly comprise biologically and/or pharmaceutically active substance, which is either the same as, or different from the one contained in the active layer of nanofibers. Suitable biologically compatible bonding material is e.g. substances from the group of polyethylene glycols, polysorbates, polyvinyl alcohols, polyvinylpyrrolidones, monoglycerides, diglycerides, triglycerides, esters of isopropyl alcohol and other waxes, esters of sorbitan, monosaccharides, disaccharides (such as lactose), or mixtures of at least two such substances (such as mixtures of lactose monohydrate with polyvinylpyrrolidone and crospovidone etc.), calcium hydrogen phosphate dihydrate, calcium phosphate, calcium sulphate etc.

In advantageous variant of the preparation according to the invention, the biologically and/or pharmaceutically active substance/substances is/are incorporated directly in the material of nanofibers as their integral amorphous part and/or as nanoparticles and/or microparticles or nanocrystals and/or microcrystals, projecting onto its surface. The incorporation of biologically and/or pharmaceutically active substance into the material of nanofibers is achieved by means of embedding - i.e. by single or continuous addition of such biologically and/or pharmaceutically active substance and/or its precursor into liquid solution, dispersion or melt of material, from which subsequently the nanofibers are prepared by means of electrostatic spinning. If the given biologically and/or pharmaceutically active substance or its precursor is/are soluble in the same biologically compatible solvent as used material, its simultaneous partial or complete dissolution may occur. Thereat, the given biologically and/or pharmaceutically active substance becomes a part of nanofibers, while it is advantageous, that relatively low concentration of such active substance and its reduced movability within the material of the nanofibers prevent its agglomeration into larger agglomerates, by means of which the maximum size of its specific surface is provided in principle, resulting in its increased solubility and rate of dissolving at the same time.

As it is advantageous for the practical use the layer of nanofibers to be as even as possible, which simultaneously provides high evenness of distribution of biologically and/or pharmaceutically active substance/substances in it, it is suitable to use so called nozleless electrostatic spinning for its production. With this method of electrostatic spinning the liquid solution, dispersion or melt of the material is spun in an electric field created between a collecting and a spinning electrode of an oblong shape, being simultaneously brought into this electrostatic field on the surface of this spinning electrode or being applied onto the surface of the spinning electrode in the spinning area. Thereat, the spinning electrode comprises of e.g. rotating oblong body, e.g. a cylinder (see e.g. EP 1673493 or EP 2059630), a spiral, a disc or another rotating body, or a string moving in direction of its length, either continuously or intermittently (see e.g. EP 2173930), etc. Such method of electrostatic spinning is applied within commercially used Nanospider™ technology of Elmarco company, Czech Republic.

In other variants, other methods of electrostatic spinning for production of active layer of nanofibers can be used as well - e.g. methods using static spinning electrodes comprising especially of a nozzle, a needle, a stick, a molding, a static string etc. (see e.g. EP 2173930), etc., or a group of such, etc. Besides that, methods for production of nanofibers based on other principles can be used as well, such as methods based on principle of phase separation, interphase separation, self-assembly, drawing, centrifugation, pressure nozzle techniques, syntheses of scaffold networks or the method described in publication Kumar A. (Ed.) "Nanofibers." InTech Publ., 2010, p. 438.

Based on specific requirements and the material used the basis weight of the active layer of nanofibers prepared in that way usually varies from 0.1 to 100 g/m², containing 1 to 70 % (w/w) of biologically and/or pharmaceutically active substance/substances. However, both values can be almost arbitrarily adapted to specific requirements, while at least one of them can exceed the above mentioned range for some applications.

As the material of nanofibers of the active layer virtually any biocompatible organic or inorganic material which meets the requirements of the EMA (European Medicines Agency) standards, the valid pharmacopoeia, such as PhEur 2012, the FDA (Food and Drug Administration) standards or belongs into GRAS (Generally Recommended As Safe) group of substances and is spinnable into the form of nanofibers can be used. Such materials include for instance polyvinyl alcohols (PVA), polyactides (Pl-A), polycaprolactones (PCL), polyvinylpyrrolidones (PVP), polyurethanes (PUR), their copolymers, cellulose derivatives such as hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), polyethylene glycol/polyvinylcaprolactam/polyvinyl acetate copolymers, chitosan derivatives, poloxamers, their mixtures etc.

Based on application of the preparation according to the invention, the biologically and/or pharmaceutically active substance deposited in and/or on the active layer of nanofibers can consist of various biologically and/or pharmaceutically active substances, especially active substances belonging depending on their solubility and permeability into BCS II. and BCS IV. groups of the biopharmaceutics classification system (BCS). From nowadays known and used substances it is for instance amiodarone, atorvastatin, azathioprim, carbamazepine, cisapride, chlorpromazin, dabigatran, danazol, diflunisal, diklofenac, flurbiprofen, griseofulvin, glipizide, glyburide, indinavir, indomethacin, itraconazole, ketoconazole, ketoprofen, lansoprazole, lopinavir, lovastatin, nalidixic acid, naproxen, nelfinavir, oxaprozin, piroxicam, praziquantel, rifampicin, ritonavir, saquinavir, sulfamethoxazole, tacrolimus, talinolol, warfarin belonging to BCS II. group and/or e.g. amfotericine B, ciprofloxacin, furosemide, phenazopyridine, hydrochlorthiazide, chlorthalidone, chlorothiazide, colistin, mebendazole, methotrexate, neomycin, nystatin, ofloxacin, talinolol belonging to BCS IV. group, or other biologically and/or pharmaceutically active substances or their mixtures.

It is advantageous for further handling with the active layer of nanofibers and its processing, if at least one its surface is impregnated with hydrophilic excipient or mixture of excipients which is/are solid at room temperature and which softens/soften and/or dissolves/dissolve in water and/or mixes/mix with water at temperature of living human or animal body such as e.g. the mixtures of polyeythylene glycol 300 and polyethylene glycol 1500 in the rate of 3:4 or with e.g. 2% addition of polysorbate 80, which prevents the sticking of nanofibers to each other .

In another variant of embodiment, at least one surface of the active layer of nanofibers is impregnated with hydrophobic excipient or mixture of excipients which is/are solid at room temperature and which, at temperature of living human or animal body, softens/soften and/or becomes/become dispersible in biological body fluids. Such excipients include e.g. mixture of monoglycerides, diglycerides and triglycerides with thaw point of 30 °C to 45 °C, or e.g. with additional 2 % portion of sorbitan monostearate preventing sticking of nanofibers to each other.

This impregnation enables not only better handling with the active layer of nanofibers and its further processing, but it also allows additional adjustment of the rate of dissolving/releasing of the biologically and/or pharmaceutically active substance from the active layer of nanofibers, this e.g. by means that it influences the rate of penetration of biological body fluids to the nanofibers. The excipient itself or mixture of excipients can be used as reservoir for at least one biologically and/or pharmaceutically active substance which is the same as, or different from the biologically and/or pharmaceutically active substance deposited in and/or on the active layer of nanofibers.

To prevent sticking and to provide stability of nanofibers, it is in other variants possible to use another substance as well, e.g. antioxidants etc. Directly in hydrophilic or hydrophobic excipient may also be incorporated at least one biologically and/or pharmaceutically active substance, which can be the same as, or different from the biologically and/or pharmaceutically active substance deposited in and/or on the active layer of nanofibers.

In another variant, there is a layer of powdery bonding agent or mixture of bonding agents deposited on at least one surface of the active layer of nanofibers, allowing several layers of nanofibers to physically birid with each other or to bind the covering layer to the active layer of nanofibers after application of pressure. Such bonding agents include for instance substances of the group of polyethylene glycols, polysorbates, polyvinyl alcohols, polyvinylpyrrolidones, monoglycerides, diglycerides, triglycerides, esters of isopropyl alcohol and other waxes, esters of sorbitan, monosaccharides, disaccharides (such as lactose), calcium hydrogen phosphate dihydrate, calcium phosphate, calcium sulphate or mixtures of at least two of such substances (such as mixtures of lactose monohydrate with polyvinylpyrrolidone and crospovidone etc.) etc.

It is possible to mutually combine these coatings of the active layer of nanofibers to achieve suitable qualities, especially as far as considers kinetics of releasing of the biologically and/or farmaceutically active substance and/or substances.

Prepared active layer of nanofibers comprising at least one biologically and/or pharmaceutically active substance is further used either separately as planar layer, or is processed in suitable way - for instance is folded and/or lapped and/or rolled into a cylinder or a tube (hollow) and/or wound up and/or wound up into full or hollow structure with subsequent reinforcement by twisting and/or wound around suitable core and/or is transformed into formations of size and/or weight and/or shape and/or content of biologically and/or pharmaceutically active substance determined in advance, such as crushed material and/or powder and/or fragments and/or bunches/clusters and/or bands and/or twists etc.,. Those formations can also be further processed - for instance cut and/or sheared and/or folded and/or lapped and/or layered onto each other and/or bound to each other, rolled into a cylinder or a tube (hollow) and/or wound around suitable core and/or twisted etc. See e.g. Fig. 1 in which a) represents a rolled tube (hollow), b) a twist wound round by a tube (hollow), c) a twine, and d) a wick.

The active layer of nanofibers and/or its formations are for practical use advantageously incorporated into suitable material, such as biologically degradable and biologically compatible hydrophilic filler or mixture of at least two such fillers, while the mixture prepared in that way is filled into dispensary sacks and/or is processed in one of known manners into a tablet, a multi-layer tablet, a granule, a compact, a pellet, a plug, a globule, a film or another insert for peroral, oral, mucosal, rectal, vaginal, urethral, intrauterine, nasal, auricular, ocular or invasive parenteral administration for human or animal recipient - see Fig. 2, where mix. represents macro dispersion mixture of crushed material of the active layer of nanofibers, cps. represents capsules, tbl. represents pressed tablets, gra. represents granules and sacc. represents sack for dispensation (of powder or granules).

The suitable hydrophilic fillers is e.g. mannitol and/or sorbitol and/or glucose and/or lactose and/or saccharose and/or mixture of lactose and povidone and/or crospovidone, or other known substances, that will not affect advantageous features of active layer of nanofibers and/or the biologically and/or pharmaceutically active substance contained in it.

A similar procedure allows through combination of active layer of nanofibers and/or its formations and biologically degradable and biologically compatible material, such as gelatine, hydroxypropyl cellulose or hypromellose, production of e.g. a capsule or a sack for some of above mentioned applications. Thereat, the active layer and/or its formations may be supplemented by different auxiliary substances, e.g. in the form of powder and/or pellets and/or granules, e.g. by mixture of mannitol and colloidal silica in the rate of 380:1 , or by an excipient of arbitrary kind.

Upon thought administration and/or required effect to achieve and/or the time profile of releasing the biologically and/or pharmaceutically active substance, it is possible within one film, sack, tablet, chewing tablet, sublingual tablet, buccal tablet, multi-layer tablet, granule, compact, pellet, plug, globule or another insert or capsule to combine several active layers of nanofibers which can be the same, or can differ from each other by material and/or diameter of nanofibers and/or content of the active substance and/or method of deposition of the active substance and/or type of the active substance and/or basis weight, and/or the same or different formations of single or several active layers of nanofibers which can be the same, or can differ from each other by material and/or diameter of nanofibers and/or content of the active substance and/or method of deposition the active substance and/or type of the active substance and/or basis weight. One of the layers of nanofibers used can include a substance which supports/speeds up or reduces/slows down or otherwise influences and/or supplements the effect of at least one biologically and/or pharmaceutically active substance contained in this layer or in another active layer of nanofibers.

In other variant the active layer of nanofibers or its formations can be supplemented by at least one covering layer of biologically compatible material before it is processed into a film, a sack, a tablet, a chewing tablet, a sublingual tablet, a buccal tablet, a multi-layer tablet, a granule, a compact, a pellet, a plug, a globule or another insert. Advantageously, such layer can be e.g. a film and/or another layer of nanofibers. Thereat, such covering layer may contain a substance which supports/speeds up or reduces/slows down or otherwise influences and/or supplements the effect of at least one biologically and/or pharmaceutically active substance contained in active layer of nanofibers, or may contain at least one biologically and/or pharmaceutically active substance which is the same as, or different from the active layer of nanofibers. In case, when the layer of nanofibers is used as the covering layer, it can be prepared in the same way as the active layer of nanofibers, or can differ from it by material and/or diameter of nanofibers and/or basis weight.

The covering layer of nanofibers can be bind with the active layer of nanofibers by means of at least one biologically compatible substance acting as binder. Suitable biologically compatible materials include e.g. substances of the group of polyethylene glycols, polysorbates, polyvinyl alcohols, polyvinylpyrrolidones, monoglycerides, diglycerides, triglycerides, esters of isopropyl alcohol and other waxes, esters of sorbitan, monosaccharides, disaccharides (such as lactose), or mixtures of at least two such substances (such as mixtures of lactose monohydrate with polyvinylpyrrolidone and crospovidone etc.), calcium hydrogen phosphate dihydrate, calcium phosphate, calcium sulphate etc., and/or are the layers bind by mutual or common folding and/or lapping and/or rolling up into a cylinder or a tube (hollow) and/or cabling and/or twisting around a core and/or winding up and/or winding up into full or hollow structure with subsequent reinforcement by twisting. The same applies analogically also for interconnection of the formations of active layer of nanofibers with covering layer and/or formations of the covering layer. By any of these means, it is possible to almost arbitrarily combine at least one active layer of nanofibers with other active layers of nanofibers and/or covering layers to achieve the required therapeutic effect and/or profile of releasing of the biologically and/or pharmaceutically active substance/substances.

The small size combined with large specific surface of formations of biologically and/or pharmaceutically active substance enable significant increase of solubility of this active substance in biological fluids, e.g. in gastric or intestinal juices, this also by biologically and/or pharmaceutically active substances of BCS II. and BCS IV. groups of the biopharmaceutics classification system (BCS). Together with that, the overall solubility and rate of dissolving of this biologically and/or pharmaceutically active substance increases, being followed by increase in their bioavailability. Thereat, this effect is most significant by variants, when the biologically and/or pharmaceutically active substance is incorporated directly in the material of nanofibers of the active layer. By targeted design of parameters of active layer of nanofibers or combination of different kinds of active layers and/or its/their formations and/or material of a film, a sack, a tablet, a chewing tablet, a sublingual tablet, a buccal tablet, a multi-layer tablet, a granule, a compact, a pellet, a plug, a globule or another insert or a capsule and/or a concentration of the active layer in the preparation for administration of at least one biologically and/or pharmaceutically active substance according to the invention and/or by concentration of biologically and/or pharmaceutically active substance in and/or on the active layer a suitable time profile of releasing of the biologically and/or pharmaceutically active substance can be achieved, ranging from rapid (fast), immediate, through sustained to prolonged release, including fluctuating profiles.

Upon application of the preparation for administration of at least one biologically and/or pharmaceutically active substance according to the invention, the active layer of nanofibers or its formations gradually come into contact with biological body fluids of the recipient, causing the release of the biologically and/or pharmaceutically active substance from it. The rate of releasing can be increased by forming the active layer of biologically degradable material. Another advantage of this variant is that the active layer of nanofibers decomposes upon action of biological body fluids so that it does not remain in the place of administration, thanks to which is not necessary to remove it additionally.

Below, some exemplary embodiments of some variants of the preparation for administration of at least one biologically and/or pharmaceutically active substance according to the invention are described.

Example 1

25.0 g of naproxen were dissolved in 5.6% solution of polyvinylpyrrolidone (Povidone K-90) in 99.9% ethanol. An active layer of polymer nanofibers of basis weight (grammage) of 5 g/m², containing 10 % (w/w) of naproxen was subsequently prepared by electrostatic spinning on the Nanospider™ device using a spinning electrode in shape of a string according to EP 2059630.

This layer was diminished/powderized after its removal from an underlying spunbond textile, onto which it was deposited during its production, and 50.0 g of the resulting powder material were mixed with 45.4 g of microcrystalline cellulose (Avicel PH-102), 2.5 g of hypromellose (Methocel K5), 2.0 g of croscarmellose (Ac-Di-Sol) and 0.1 g of sodium lauryl sulphate. Such mixture in the form of composite powder was then filled in PE laminated paper sacks with weldable PE foil. The total prepared quantity of the mixture equals to 100 pes. of sacks (each of 1.0 g), containing 50 mg of naproxen each. Example 2

20.0 g of piroxicam were dissolved in 5.6% solution of polyvinylpyrrolidone (Povidone K-90) in 99.9% ethanol. An active layer of polymer nanofibers of basis weight of 5 g/m², containing 8 % (w/w) of piroxicam was subsequently prepared by electrostatic spinning on the Nanospider™ device using a spinning electrode in shape of a string according to EP 2059630.

This layer was diminished/powderized after its removal/separation from an underlying spunbond textile, onto which it was deposited during its production, and 40.0 g of the resulting powder material were mixed with 23.5 g of lactose monohydrate (FlowLad OO), 0.7 g of sodium lauryl sulphate, 0.7 g of magnesium stearate and 0.1 g of colloidal silica (Aerosil 200). Such mixture in the form of composite powder was then filled in solid gelatine capsules. The total prepared quantity of the mixture equals to 100 pes. of solid gelatine capsules (each of 650 mg), containing 40 mg of piroxicam each. Example 3

50.0 g of diosmin were dissolved in solution of hydroxypropyl cellulose, polyethylene oxide and polyvinyl alcohol in the ratio of 6:1 :6 in water. An active layer of polymer nanofibers of basis weight of 5 g/m², containing 20 % (w/w) of diosmin was subsequently prepared by electrostatic spinning on the Nanospider™ device using a spinning electrode in shape of a string according to EP 2059630.

This layer was pulverized after its removal/separation from an underlying spunbond textile, onto which it was deposited during its production, and 50.0 g of the resulting powder were mixed with 445.0 g of mannitol (Pearlitol SD 100) and 5.0 g of colloidal silica (Aerosil 200). Thus a material for production of solid gelatine capsules containing diosmin was prepared. The total prepared quantity of the material equals to 1000 pes. of solid gelatine capsules (each of 0.5 g), containing 10 mg of diosmin each.

Example 4

50.0 g of fenofibrate were dissolved in 15% solution of polyurethane in cyclohexanone. An active layer of polymer nanofibers of basis weight of 14 g/m², containing 23 % (w/w) of fenofibrate was prepared subsequently by electrostatic spinning on the Nanospider™ device using a spinning electrode in shape of a string according to EP 2059630.

This layer was pulverized after its removal/separation from an underlying spunbond textile, onto which it was deposited during its production, and 50.0 g of the resulting powder were mixed with 13.0 g of lactose monohydrate (FlowLad OO), 1.5 g of sodium starch glycolate, 0.3 g of magnesium stearate and 0.15 g of colloidal silica. Thus a material for production of solid gelatine capsules containing fenofibrate was prepared. The total prepared quantity equals to 100 pes. of solid gelatine capsules (each of 650 mg), containing 20 mg fenofibrate each.

Example 5

40.0 g of dabigatran were dissolved in 5.6% solution of polyvinylpyrrolidone (Povidone K-90) in 99.9% ethanol. An active layer of polymer nanofibers of basis weight of 14 g/m², containing 33 % (w/w) of dabigatran was prepared subsequently by electrostatic spinning on the Nanospider™ device using a spinning electrode in shape of a string according to EP 2059630.

This layer was pulverized after its removal/separation from an underlying spunbond textile onto which it was deposited during its production, and 27.5 g of the resulting powder were mixed with 71.5 g of a mixture of lactose, polyvidone and crospovidone (Ludipress®) and 1.0 g of magnesium sulphate. After mixing, the resulting powdery mixture was directly pressed into tablets of diameter of 10 mm and weight of approx. 580 mg. Example 6

40.0 g of ciprofloxacin were dissolved in a mixture of 10% solution of chitosan in 60% acetic acid and 3% solution of PEO in water in the ratio of 92:8. An active layer of polymer nanofibers of basis weight of 9 g/m², containing 23 % (w/w) of ciprofloxacin was prepared subsequently by electrostatic spinning on the Nanospider™ device using a spinning electrode in shape of a string according to EP 2059630.

After mixing, the prepared tableting powder blend was directly pressed into tablets of diameter of 13 mm and weight of approx. 880 mg.

Example 7

40.0 g of dabigatran were dissolved in 5.6% solution of polyvinylpyrrolidone (Povidone K-90) in 99.9% ethanol. An active layer of polymer nanofibers of basis weight of 14 g/m², containing 33 % (w/w) of dabigatran was prepared subsequent by electrostatic spinning on the Nanospider™ device using a spinning electrode in shape of a string according to EP 2059630.

A mixture of polyethylene glycol 300 and polyethylene glycol 1500 warmed up to the temperature of 45 °C was spread on one surface of the active layer of nanofibers prepared that way, and it was then left to cool down to room temperature. After removal/separation of this active layer of polymer nanofibers from an underlying spunbond textile onto which it was deposited during its production, square segments sized 8 x 8 mm were cut out from it and piled onto each other in groups of 5 or 10 pieces and pressed together. 125 g of such segments were mixed with powder blend containing 520 g of mannitol (Pearlitol SD 100), 5.0 g of sodium lauryl sulphate, 5.0 g of magnesium stearate and 5.0 g of croscarmellose sodium salt (Ac-Di-Sol). 150 mg of such mixture were fed into tablet press machine dies of diameter of 13 mm on top of 250 mg of the above mentioned tableting powder blend without nanofibrous segments and were overlaid with another 250 mg of the above mentioned tableting powder blend without nanofibrous segments, and biconvex tablets of diameter of 13 mm were pressed, containing 4 mg, resp. 8 mg of dabigatran - see Fig. 3, where UP represents the upper punch, LP represents the lower punch, Fig. 3 a) represents the preliminary filling with the tableting powder blend, Fig. 3 b) represents the input of piled square segments of the active layer of nanofibers, Fig. 3 c) represents the adding of the tableting powder blend and Fig. 3 d) represents the compaction of nanocomposite tablet.

The total amount of the material produced equalled to 1000 pes. of tablets of weight of 650 mg, containing 4 mg, resp. 8 mg of dabigatran each.

Experimentally determined amount and kinetics of release of dabigatran from the tablet prepared by the above described method with content of 8 mg of dabigatran are represented by the upper curve in the graph in Fig. 5. Two other curves in the graph represent release of dabigatran from an adequate quantity of micropellets of commercially available preparation and from adequate quantity of micronized powder of dabigatran (the lowest curve). Thereat, it is clear that with the preparation according to the invention the releasing is faster and the released quantity is at the same time higher.

Example 8

75 g of diosmin were dissolved in solution of hydroxypropyl cellulose, polyethylene oxide and polyvinyl alcohol in the ratio of 6:1 :6 in water. An active layer of polymer nanofibers of basis weight of 5 g/m² containing 30 % (w/w) of diosmin was prepared subsequently by electrostatic spinning on the Nanospider™ device using a spinning electrode in shape of a string according to EP 2059630.

A mixture of triglycerides, diglycerides and monoglycerides warmed up to the temperature of 40 °C was spread on one surface of the active layer of nanofibers prepared that way, and it was then left to cool down to room temperature. After removal/separation of this active layer of polymer nanofibers from an underlying spunbond textile onto which it was deposited during its production, square segments sized 8 x 8 mm were cut out from it and piled onto each other in groups of 5 or 10 pieces and pressed together. These segments were subsequently mixed with tableting powder blend as mentioned in example 7 and tablets were made from them in the same way. Photograph of cross-section of the resulting tablet can be seen on Fig. 4.

Example 9

50 g of fenofibrate were dispersed in solution of polyurethane in cyclohexanone. An active layer of polymer nanofibers of basis weight of 14 g/m² containing 23 % (w/w) of fenofibrate was prepared subsequently by electrostatic spinning on the Nanospider™ device using a spinning electrode in shape of a string according to EP 2059630.

A mixture of triglycerides, diglycerides and monoglycerides warmed up to the temperature of 40 °C was spread on one surface of the active layer of nanofibers prepared by that way, and was then left to cool down to room temperature. After removing this active layer of polymer nanofibers from an underlying spunbond textile onto which it was deposited during its production, square segments sized 8 x 8 mm were cut out from it and piled onto each other in groups of 5 or 10 pieces and pressed together. Those segments were subsequently mixed with the tableting powder blend as mentioned in example 7 and tablets were made from them in the same way. Example 10

40 g of naproxen were dissolved in solution of polyprolactone in mixture of acetic acid and formic acid in the ratio of 2:1. An active layer of polymer nanofibers of basis weight of 11 g/m² containing 30 % (w/w) of naproxen was prepared subsequently by electrostatic spinning on the Nanospider™ device using a spinning electrode in shape of a string according to EP 2059630.

From that layer, a band of width of 8 mm was cut out, and the band was rolled up into the shape of a tube and immersed into mixture of triglycerides, diglycerides and monoglycerides with addition of 3% of sorbitan monostearate warmed up to 40 °C. The tube impregnated that way was then left to cool down and after the impregnation was solidified, it was cut into segments of length of 12 mm. Each of those segments was then inserted into a cavity of a suppository mould, suffused by hydrophobic suppository base and left to cool down. 60 pes. of suppositories with content of 10 mg of naproxen in each of them were prepared/cast that way.

Example 11

An active layer of polymer nanofibers containing naproxen was prepared in the same way as in example 10. From that layer, a band of width of 8 mm was cut out and rolled up into the shape of a twine and immersed in anhydrous mixture of polyethylene glycol 300 and polyethylene glycol 4000 (2:3) warmed up to 40 °C. The twist impregnated that way was then left to cool down and after the impregnation was solidified it was cut into segments of length of 12 mm. Each of those segments was then inserted into a cavity of a mould for vaginal globules, suffused by hydrophilic polyethylene globule base and left to cool down. 40 pes. of vaginal globules with content of 10 mg of naproxen in each of them were prepared/cast that way.

Claims

1. A preparation for the administration of at least one biologically and/or pharmaceutically active substance, characterized by that, at least one biologically and/or pharmaceutically active substance is deposited in and/or on at least one active layer of nanofibers of biologically compatible material.

2. The preparation according to the claim 1 , characterized by that, the biologically compatible material is biologically compatible polymer.

3. The preparation according to the claim 2, characterized by that, the biologically compatible polymer is a polymer from the group of polyvinyl alcohols (PVA), polyactides (PLA), polycaprolactones (PCL), polyvinylpyrrolidones (PVP), polyurethanes (PUR), their copolymers, cellulose derivatives such as hydroxypropyl cellulose (HPC), hydroxypropyl methycellulose (HPMC), polyethylene glycol/polyvinylcaprolactam/polyvinyl acetate copolymer, chitosan derivatives, polyrrierizable monomers, mixtures of at least two of them.

4. The preparation according to any of the previous claims, characterized by that, the material of the active layer of nanofibers is biologically degradable.

5. The preparation according to any of the previous claims, characterized by that, at least one biologically and/or pharmaceutically active substance is deposited in the material of the nanofibers of the active layer and/or on the surface of the nanofibers of the active layer and/or in the inter- fibrous areas of the active layer and/or on at least one surface of the active layer of nanofibers.

6. The preparation according to the claim 5, characterized by that, at least one biologically and/or pharmaceutically active substance is bonded to nanofibers of the active layer of nanofibers by means of chemical bond based on ester bond.

7. The preparation according to the claim 5, characterized by that, at least one biologically and/or pharmaceutically active substance is bonded to nanofibers of the active layer of nanofibers by means of biologically compatible bonding agent soluble or dispersible in an aqueous environment or miscible with it at temperature of living human or animal body.

8. The preparation according to the claim 7, characterized by that, in the biologically compatible bonding agent, there is incorporated at least one biologically and/or pharmaceutically active substance.

9. The preparation according to the claim 7 or 8, characterized by that, the biologically compatible bonding agent is a substance from group of polyethylene glycols, polysorbates, polyvinyl alcohols, polyvinylpyrrolidones, monoglycerides, diglycerides, triglycerides, esters of isopropyl alcohol and other waxes, esters of sorbitan, monosaccharides, disaccharides, calcium hydrogen phosphate dihydrate, calcium phosphate, calcium sulphate or mixture of at least two of them.

10. The preparation according to any of the previous claims, characterized by that, surface of at least one active layer of nanofibers is impregnated by hydrophilic excipient or mixture of excipients which is/are solid at room temperature and which softens/soften and/or dissolves/dissolve in water and/or mixes/mix with water at temperature of living human or animal body.

11. The preparation according to any of the previous claims, characterized by that, surface of at least one active layer of nanofibers is impregnated by hydrophobic excipient or mixture of excipients which is/are solid at room temperature and which softens/soften and/or becomes/become dispersible in biological body fluids at temperature of living human or animal body.

12. The preparation according to the claim 10 or 11, characterized by that, in the hydrophilic and/or hydrophobic excipient, there is incorporated at least one biologically and/or pharmaceutically active substance.

13. The preparation according to any of the previous claims, characterized by that, the active layer of nanofibers is folded and/or lapped and/or rolled up into the shape of a cylinder or a tube (hollow) and/or wound up and/or wound up and reinforced by a twist and/or wound around a core.

14. The preparation according to any of the claims 1 to 12, characterized by that, the active layer of nanofibers has the form of crushed material and/or powder and/or fragments and/or bunches/clusters and/or bands and/or twists.

15. The preparation according to the claim 14, characterized by that, the fragments and/or bands and/or twists of the active layer of nanofibers are folded and/or lapped and/or rolled up into the shape of a cylinder and/or a tube (hollow) and/or cabled and/or wound around a suitable core and/or twisted and/or layered onto each other and/or bonded by means of biologically compatible bonding agent.

16. The preparation according to any of the claims 13 to 15, characterized by that, on at least one surface of the active layer of nanofibers, there is deposited at least one covering layer composed of a film or a layer of nanofibers of biologically compatible material.

17. The preparation according to the claim 16, characterized by that, the active layer of nanofibers and the covering layer are bonded by means of at least one biologically compatible bonding agent and/or by mutual folding and/or lapping and/or cabling and/or twisting around a core and/or winding up and/or winding up into full or hollow structure with subsequent reinforcing by twisting.

18. The preparation according to any of the previous claims, characterized by that, the active layer of nanofibers and/or its fragments and/or bunches/clusters and/or bands and/or twists is deposited in a sack, a tablet, a multi-layer tablet, a tablet with a core, a film, a plug, a globule or another insert of biologically compatible and biologically degradable hydrophilic filler or mixture of at least two such fillers for peroral, oral, mucosal, rectal, vaginal, urethral, intrauterine, nasal, auricular, ocular or invasive parenteral administration.

19. The preparation according to the claim 18, characterized by that, the hydrophilic filler is mannitol and/or sorbitol and/or glucose and/or lactose and/or saccharose and/or mixture of lactose and povidone and/or crospovidone.

20. The preparation according to any of the claims 1 to 17, characterized by that, the active layer of nanofibers and/or its fragments and/or bunches/clusters and/or bands and/or twists is deposited in a sack or a capsule of biologically degradable and biologically compatible material for peroral, oral, mucosal, rectal, vaginal, urethral, intrauterine, nasal, auricular, ocular or invasive parenteral administration.

,

21. The preparation according to the claim 20, characterized by that, the active layer of nanofibers is deposited in a capsule made of gelatine, hydroxypropyl cellulose or hypromellose.

22. The preparation according to any of the previous claims, characterized by that, the active layer of nanofibers is prepared by means of nozzleless electrostatic spinning.

23. The preparation according to any of the previous claims, characterized by that, the biologically and/or pharmaceutically active substance is active substance from BCS II. or BCS IV. group of the biopharmaceutics classification system (BCS).