WO2006106514A2

WO2006106514A2 - Electrospun dosage form and method of producing the same

Info

Publication number: WO2006106514A2
Application number: PCT/IL2006/000430
Authority: WO
Inventors: Alexander Dubson; Alon Shalev
Original assignee: Nicast Ltd.
Priority date: 2005-04-06
Filing date: 2006-04-05
Publication date: 2006-10-12
Also published as: WO2006106514A3

Abstract

A formulation, comprising one or more electrospun polymers incorporating one or more chemicals is disclosed. In one embodiment, the electrospun polymer is pharmaceutically acceptable, and the chemical comprise one or more pharmaceutically active ingredients. The shape and size of the electrospun polymer is can be adapted for oral, vaginal or rectal administration.

Description

ELECTROSPUN DOSAGE FORM AND METHOD OF PRODUCING THE SAME

FIELD AND BACKGROUND OF THE INVENTION

The present invention relates to a formulation and, more particularly, but not exclusively, to a formulation made of electrospun polymer fiber.

Orally administered pharmaceuticals are in the form of solid shaped articles such as tablets, pills and capsules. Generally the solid shaped article has to be swallowed from the mouth to the stomach to enable the pharmaceutical to be absorbed in the gastro-enteric system. However, in some cases there is the problem that swallowing is difficult or not feasible. Some subjects, particularly paediatric and geriatric patients, may be unco-operative and spit the tablet out instead of swallowing it. A similar difficulty can be present in administering pharmaceuticals to non-human animals in veterinary treatment in that animals may also be unco-operative about taking tablets. Many types of oral dosage form exist. One type of oral dosage form which is designed to address the problem of swallowing is known as "chewable tablets". These tablets, however, are not fully satisfactory because they require mastication.

Another type of oral dosage form known as the "effervescent tablet" comprises a solid adjuvant of an acid and a base. The reaction between the acid and the base in the presence of water gives off carbon dioxide which "blows apart" the tablet to facilitate its dissolution. One type of effervescent tablet that must dissolve in a glass of water for administration requires that the patient drink the water. Aside from the problem of leaving a small amount of residual active agent in the glass, this dosing method is impractical for very young patients. Another type of effervescent tablet that "bubbles" and then dissolves in the mouth is also objectionable to some patient populations, especially the very young. Both types of effervescent tablets are thus not fully satisfactory.

An additional type of oral dosage form, known as the "enteric tablet", is designed to release the pharmaceutical agent in the upper small intestine. A limitation of enteric tablets is that those that fail to disintegrate rapidly in the intestine could pass the "window of absorption" and result in poor bioavailability.

Also known in the art, are rapidly disintegrating dosage forms which facilitate oral administration to persons advanced in age, children, unco-operative subjects or animals. Representative examples of rapidly disintegrating pharmaceutical dosage forms are found in U.S. Patent Nos. 4,371,516, 4,305,502 5,466,464, 5,837,285, 5,876,759, 5,501,861 and 6,497,899. Additional prior art of relevance includes: U.S. Patent Nos. 4,072,535, 4,863,655, 5,035,930, 5,043,196, 5,286,769, 5,405,564 and 5,849,233.

Some rapidly disintegrating dosage forms, for example, dissolve in the saliva of the mouth in one or two seconds. The rapid disintegration rate makes the dosage forms suitable for patients who have difficulty swallowing or refuse to swallow conventional tablets containing such medicaments. Further, the dosage form is convenient since it does not require the aid of water in order to be swallowed. As such, the rapidly disintegrating nature of the dosage form and the convenience associated with its use offer dramatic improvement in patient compliance and treatment of disease states.

Many rapidly disintegrating dosage tablets are formed of an open matrix into which saliva rapidly moves to disintegrate the medicament after it is placed in a subject's mouth. Although the open matrix network facilitates rapid disintegration in water or saliva, a drawback is that such tablets are very fragile, and their handling prior to placing in the mouth must be severely restricted.

An additional type of dosage form is known as controlled release dosage form. Controlled release dosage forms are designed to contain higher concentrations of the drug, and are prepared in such a manner as to effect controlled release of drugs into the gastrointestinal digestive tract of humans or animals over an extended period of time. Controlled release profiles include, for example, sustained release, prolonged release, pulsatile release and delayed release profiles. The use of controlled release products allows administration of fewer doses per day, makes patient compliance more likely and, for some controlled release profiles, reduces the frequency of swings of drug levels in the patient's system.

Representative examples of controlled release dosage forms are found in U.S. Patent Nos. 4,572,833, 4,861,598, 5,458,888, 5,458,887, 6,020,002, 6,709,676, 6,770,297, 6,770,299, 6,787,156, 6,858,634, 6,861,072, 6,887,493, 6,905,708, 6,905,709, 6,908,626, 6,911,217, 6,964,780, 6,974,591, 6,979,463, 6,979,463 and 6,998,128. A controlled release product has to effect an effective dissolution of the drugs at the desired profile. Additionally, is it is desired that such product will meet several other criteria, including uniformity of the product and simplicity as well as and reproducibility of the manufacturing process. One technique for preparing controlled release formulations involves surrounding an osmotically active drug core with a semipermeable membrane. The drug is released from the drug core over time by allowing body fluids (such as gastric or intestinal fluids) to permeate the membrane and dissolve the drug such that an efflux of the dissolved drug is generated. Another common technique is to encapsulate a plurality of beads, pellets or tablets, coated with varying levels of a diffusion barrier or different types of the diffusion barriers.

In a process known as film coating, a uniform film is deposited onto the surface of a substrate. Film coating was introduced to the pharmaceutical industry in the 1950's with certain advantages inherent in the process. Film coating involves the deposition of a thin, uniform, typically polymeric membrane to the substrate usually by a spray technique. Certain of the advantages include minimal weight increase of the ultimate dosage form, reduction in processing times, improved resistance to chipping and the like. However, notwithstanding these advantages certain difficulties are attendant with the film coating process including the tendency to laminate if the tablets being coated are not of sufficient strength, the inability to hide defects in the tablet core, mottling and the like.

Modification of constituent release of core tablet have been achieved via enteric coating wherein the polymer employed in the coating is essentially impervious to gastric pH while being soluble in the increased pH of the intestines. In film coating, extended release is typically achieved by diffusion coating which involves the deposit of a coating (usually from an organic solvent) on a soluble substrate core with a porous, water-permeable but insoluble membrane. The release profile of the therapeutic agent can be modified by the inclusion of water soluble substances within the membrane. These substances are dissolved by the gastrointestinal fluids thereby creating pores within the film. The pores allow the gastrointestinal fluids to pass through the membrane and dissolve the therapeutic agent within the tablet core. The diffusion rate can be controlled by the thickness and composition of the diffusion membrane. For such system to function properly, the constituents of the diffusion coating formulation must exhibit good mechanical strength and flexibility.

However, it is a frequently encountered problem that the coating formulation lacks the requisite mechanical strength and flexibility. When such coating formulation is deposited on the substrate, the deposited film is ruptured during dissolution in the gastrointestinal tract. This in turn permits the sudden release of the entire contents of the substrate containing the therapeutic agent in a phenomenon referred to as "dose dumping". Such a situation is clearly undesirable for extended release dosage forms given the higher amount of therapeutic agent found therein as compared to conventional formulations.

There is thus a widely recognized need for, and it would be highly advantageous to have an electrospun dosage form and a method of producing the same devoid of the above limitations.

SUMMARY OF THE INVENTION

The present embodiments comprise a formulation and method which can be used for administrating medicament pharmaceuticals to a subject. For example, the present embodiments can be used as a rapidly disintegrating and/or controlled release dosage form. Thus, according to one aspect of the present invention there is provided a formulation comprising one or more electrospun polymers. The electrospun polymer serves as a vehicle which incorporates one or more chemicals. In the preferred embodiments in which the formulation is used for delivering pharmaceutical agents to the body of human or animals, the electrospun polymer or polymers is/are pharmaceutically acceptable, and the chemical or chemicals comprise one or more pharmaceutically active ingredients. The shape and size of the electrospun polymer is preferably adapted for oral, vaginal or rectal administration.

According to another aspect of the present invention there is provided a method of treating a subject, comprising administering to a subject in need thereof a therapeutically effective amount of the formulation.

The release rate of pharmaceutically active ingredient from the electrospun polymer of the present embodiments can be controlled during the manufacturing process of the formulation. Specifically, release rate can be controlled by a judicious selection of at least one of (i) the type of polymer, (ii) the chemical means binding the pharmaceutically active ingredient to the polymer, (iii) the area of contact between the body fluids and the polymer, and (iv) the method employed for incorporating the pharmaceutically active ingredient within the polymer. Thus, according to still another aspect of the present invention there is provided a method of producing the formulation the formulation, comprising: mixing the pharmaceutically active ingredient(s) with at least one pharmaceutically acceptable liquefied polymer; and electrospinning the pharmaceutically acceptable liquefied polymer(s) onto a collecting element thereby providing the at least one pharmaceutically acceptable electrospun polymer incorporating the at least one pharmaceutically active ingredient.

According to yet another aspect of the present invention there is provided a method of producing the formulation, comprising: electrospinning at least one pharmaceutically acceptable liquefied polymer onto a collecting element thereby providing the at least one pharmaceutically acceptable electrospun polymer; and incorporating the at least one pharmaceutically active ingredient into the pharmaceutically acceptable electrospun polymer so as to provide the at least one pharmaceutically acceptable electrospun polymer incorporating the at least one pharmaceutically active ingredient. According to further features in preferred embodiments of the invention described below, the method further comprises shaping the at least one pharmaceutically acceptable electrospun polymer.

According to still further features in the described preferred embodiments the incorporating the at least one pharmaceutically active ingredient comprises constituting the at least one pharmaceutically active ingredient into compact objects, and distributing the compact objects between polymer fibers produced during the step of electrospinning.

According to still further features in the described preferred embodiments the distribution of the compact objects is by spraying. According to still further features in the described preferred embodiments the pharmaceutically active ingredient comprises donepezil hydrochloride.

According to an additional aspect of the present invention there is provided a method of treating a disease accompanied by acetylcholinesterase activity, comprising to a subject in need thereof a therapeutically effective amount of the formulation, for inhibiting or substantially reducing the acetylcholinesterase activity.

According to still further features in the described preferred embodiments the electrospun polymer is soluble in a liquid medium. According to still further features in the described preferred embodiments the electrospun polymer is capable of disintegrating in the liquid medium within less than a minute. According to still further features in the described preferred embodiments the liquid medium is an aqueous medium.

According to still further features in the described preferred embodiments the electrospun polymer is shaped as a tablet.

According to still further features in the described preferred embodiments the electrospun polymer is shaped as a suppository.

According to still further features in the described preferred embodiments the electrospun polymer is shaped as a film. According to still further features in the described preferred embodiments the electrospun polymer is shaped as a capsule.

According to still further features in the described preferred embodiments the pharmaceutically active ingredient is encapsulated within the capsule.

According to still further features in the described preferred embodiments the pharmaceutically active ingredient(s) is/are embedded in the electrospun polymer in a form of compact objects.

According to still further features in the described preferred embodiments the electrospun polymer has a fiber matrix morphology.

According to still further features in the described preferred embodiments the at least one pharmaceutically active ingredient is distributed between fibers of the fiber matrix in a form of compact objects.

According to still further features in the described preferred embodiments the at least one chemical is distributed between fibers of the fiber matrix in a form of compact objects.

According to still further features in the described preferred embodiments the compact objects comprise capsules. According to still further features in the described preferred embodiments the compact objects are in a powder form.

According to still further features in the described preferred embodiments the compact objects comprise agglomerates. According to still further features in the described preferred embodiments the compact objects comprise a core made of the at least one pharmaceutically active ingredient coated by at least one coat of a pharmaceutical active material.

According to still further features in the described preferred embodiments the at least one coat is selected to effect controlled release profile of the pharmaceutically active ingredient from the compact objects.

According to still further features in the described preferred embodiments the fiber matrix is characterized by a porosity of from about 20 % to about 95 %, more preferably from about 40 % to about 80 %.

According to still further features in the described preferred embodiments the fiber matrix is characterized by an average pore diameter of from about 1 micrometer to about 20 micrometers, more preferably from about 5 micrometers to about 10 micrometers

According to still further features in the described preferred embodiments the fiber matrix comprises a plurality of distinct layers. According to still further features in the described preferred embodiments the plurality of layers are distinguishable by at least one of: polymer type, fiber thickness, layer thickness, porosity, average pore diameter.

According to still further features in the described preferred embodiments at least two of the plurality of distinct layers incorporate different pharmaceutically active ingredients.

According to still further features in the described preferred embodiments at least two of the plurality of distinct layers incorporate pharmaceutically active ingredients having different forms.

According to still further features in the described preferred embodiments the formulation further comprising at least one pharmaceutically acceptable carrier.

According to still further features in the described preferred embodiments the at least one pharmaceutically acceptable electrospun polymer is biodegradable. According to still further features in the described preferred embodiments the at least one pharmaceutically acceptable electrospun polymer is water soluble.

According to still further features in the described preferred embodiments the at least one pharmaceutically acceptable electrospun polymer is capable of disintegrating in body fluids with less than a minute.

According to still further features in the described preferred embodiments an amount and type of the at least one pharmaceutically acceptable electrospun polymer is selected so as to provide a predetermined disintegrating rate of the polymer, thereby facilitating a predetermined control release profile of the at least one pharmaceutically active ingredient.

The present invention successfully addresses the shortcomings of the presently known configurations by providing a formulation and method of fabricating the same. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below, hi case of conflict, the patent specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention is herein described, by way of example only, with reference to the accompanying drawings. With specific reference now to the drawings in detail, it is stressed that the particulars shown are by way of example and for purposes of illustrative discussion of the preferred embodiments of the present invention only, and are presented in the cause of providing what is believed to be the most useful and readily understood description of the principles and conceptual aspects of the invention. In this regard, no attempt is made to show structural details of the invention in more detail than is necessary for a fundamental understanding of the invention, the description taken with the drawings making apparent to those skilled in the art how the several forms of the invention may be embodied in practice.

In the drawings: FIGs. la-d are schematic illustrations of several preferred shapes of a formulation made of an electrospun polymer, according to various exemplary embodiments of the present invention;

FIGs. 2a-b are schematic illustrations a portion of the electrospun polymer in the preferred embodiment in which electrospun polymer has a matrix morphology, according to various exemplary embodiments of the present invention; and

FIG. 3 is a flowchart diagram of a method for producing a formulation according to various exemplary embodiments of the present invention.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present embodiments comprise a formulation and method which can be used for administrating medicament pharmaceuticals to a subject. Specifically, the present embodiments can be used as a rapidly disintegrating dosage form. The present embodiments can also be used as a controlled release dosage form. The principles and operation of a formulation and method according to the present invention may be better understood with reference to the drawings and accompanying descriptions.

Before explaining at least one embodiment of the invention in detail, it is to be understood that the invention is not limited in its application to the details of construction and the arrangement of the components set forth in the following description or illustrated in the drawings. The invention is capable of other embodiments or of being practiced or carried out in various ways. Also, it is to be understood that the phraseology and terminology employed herein is for the purpose of description and should not be regarded as limiting. Numerous types of rapidly disintegrating or controlled released formulations are known in the art. Although the problem of preparing a formulation which can rapidly disintegrated in the saliva has been addressed in some prior art formulations, there remains a need for a polymeric formulation which enjoys enhanced physical properties and which is capable of releasing chemicals at a predetermined rate. While reducing the present invention to practice, the present inventors have devised a formulation which overcomes the limitations of prior art formulations. The present inventors have postulated that, whereas woven or extruded-foam polymeric formulations are suitable for use in various dosage forms, a fibrous structure, specifically a non-woven (preferably electrospun) polymer structure, could provide an exceptionally good interface for releasing chemicals to the biological environment at a predetermined rate. Moreover, selecting suitable polymers and process parameters would significantly improve the physical properties of the formulation. The present inventors have further devised a formulation which can be used as vehicle carrying a chemical which is not necessarily a pharmaceutical to a liquid (e.g., aqueous) medium which is not necessarily a biological medium. For example, the formulation of the present embodiments can be used for adding a diagnostic compound to a biological sample, such as a sample of urine or blood, for determining the amount of a particular constituent present in the sample.

Additionally, the formulation of the present embodiments can be used for adding a predetermined amount of chemical reagent to a known amount of liquid to produce a liquid which can be used, e.g., in chemical analysis. The formulation of the present embodiments can also be used for adding a water soluble or water dispersible pharmaceutical to a known amount of aqueous medium to form a pharmaceutical solution or dispersion which can be used in a suitable route of administration, such as, but not limited to, oral, rectal, transmucosal, especially transnasal, intestinal, or parenteral delivery, including intramuscular, subcutaneous, and intramedullary injections, as well as intrathecal, direct intraventricular, intravenous, inrtaperitoneal, intranasal, or intraocular injections.

The formulation of the present embodiments is also useful for handling chemicals which are difficult or hazardous to handle in solution or suspension. In such cases the chemicals are loaded to the formulation, as further detailed hereinunder, which serves as a solid vehicle for carrying the chemicals. The solid formulation can be subsequently added to a liquid medium to produce a solution or dispersion of the chemical.

While the embodiments below are described with a particular emphasis to formulations for delivering pharmaceuticals to biological media, it is to be understood that more detailed reference to such formulations is not to be interpreted as limiting the scope of the invention in any way.

Thus, in various exemplary embodiments of the invention there is provided a formulation comprising one or more electrospun polymers. The electrospun polymer serves as a vehicle which incorporates one or more chemicals. In various exemplary embodiments of the invention the formulation is used for the preparation of a medicament, in which case the electrospun polymer or polymers is/are pharmaceutically acceptable, and the chemical or chemicals comprise one or more pharmaceutically active ingredients. The formulation preferably contains a therapeutically effective amount of the pharmaceutically active ingredient(s). In preferred embodiments of the invention the formulation can also comprise one or more pharmaceutically acceptable carriers, other than the pharmaceutically acceptable polymer(s).

As used herein, "pharmaceutically acceptable polymers," or "pharmaceutically acceptable carrier," refer to a polymer or a substance that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound. The term "pharmaceutically acceptable carrier," as used herein, also includes adjuvant.

For example, the formulation of the present embodiments can incorporate an adjuvant, such as, but not limited to, a coloring agent, a flavoring agent, a preservative and the like. The formulation of the present embodiments may incorporate taste maskers for the oral delivery of bitter medicaments. In the case of veterinary drugs, the formulation of the present embodiments may be formulated to possess a desirable taste so that dosing of the animal with medicament may be readily performed. Formulations suitable for use in the context of the present embodiments include active ingredients which are contained in an amount effective to achieve the intended purpose. More specifically, a "therapeutically effective amount" means an amount of active ingredients effective to prevent, alleviate, or ameliorate symptoms of a disorder or prolong the survival of the subject being treated. The formulation of the present embodiments is preferably, but not obligatorily has a matrix morphology, whereby the electrospun polymer forms a three-dimensional structure of polymeric fibers forming a matrix. Alternatively, the formulation can have a less porous morphology, in which case the electrospun polymer preferably forms a substantially continuous two-dimensional layer or three-dimensional bulk. The formulation can also have a more complex structure, including, without limitation, a stack of substantially continuous layers, a stack of porous layers, a stack of matrices or any combination thereof. The shape and size of the electrospun polymer of the present embodiments is preferably adapted for oral, vaginal or rectal administration of the electrospun polymer. Generally, the larger the aggregate volume of the electrospun polymer, the larger its capacity to store the pharmaceutically active ingredient.

Referring now to the drawings, Figures la-d illustrates the electrospun polymer 10. Shown in Figures 1-d are several preferred shapes of the electrospun polymer: a tablet (Figure Ia), a suppository (Figure Ib), a film (Figure Ic) and a capsule (Figure Id). Other shapes for the electrospun polymer are also contemplated. The formulation of the present embodiments can thus be used for delivering pharmaceutical agents to the body of humans or animals. Specifically, the formulation can be used for treating a subject in need thereof, by administering to the subject a therapeutically effective amount of the formulation. For example, as further detailed in the Example section that follows, the formulation of the present embodiments can comprise donepezil hydrochloride. In this embodiment, the administration of the formulation can inhibit or substantially reduce acetylcholinesterase activity.

The therapeutically effective amount can be administered either as a single dose (e.g., a single tablet, suppository, film, capsule, etc.) in which case or as a plurality of doses (e.g., two or more tablets, suppositories, films, capsules, etc.), as desired.

In various exemplary embodiments of the invention pharmaceutically acceptable electrospun polymer is selected so as to provide a predetermined disintegrating rate of polymer, thereby facilitating a predetermined control release profile of at least one pharmaceutically active ingredient. According to a preferred embodiment of the present invention the pharmaceutically acceptable electrospun polymer is capable of disintegrating in body fluids with less than a minute, e.g., a few, say less than 10 seconds, more preferably less than 5 seconds or less, even more preferably 1 or 2 seconds. For example, it was found by the inventors of the present invention that when the electrospun polymer comprises a high molecular weight poly(ethylene glycol), the electrospun polymer disintegrates in aqueous solution within 1 or 2 seconds.

The pharmaceutically acceptable electrospun polymer of the present embodiments is preferably dissolvable in many body fluids, such as the body fluids present in the mouse, vagina, rectum, nasal cavity or the eyes. The formulation of the present embodiments is therefore suitable for rapid oral, vaginal, rectal, nasal or ophthalmologic drug delivery, in humans or animals. For example, the formulation of the present embodiments can dissolve in the mouth within with less than a minute {e.g., a few seconds). This embodiment is particularly useful for subjects that require or desire oral medication but have difficulty swallowing standard oral dosage forms such as tablets. This embodiment is also useful for subjects suffering from emesis.

The preferred manufacturing process of the formulation is the electrospinning process, which is known to be suitable for fabrication various types of polymeric structures. One advantage of the electrospinning process for fabricating the formulation of the present embodiments is that such production process can be executed in relatively low temperatures, thus enabling to incorporate the drug in an early stage of the process. Another advantage is that the electrospun polymer of the present embodiments is capable of carrying a relatively high amount of active pharmaceutical substances. The use of electrospinning for the preparation of a formulation has the advantage of providing the formulation of the present embodiments with a very fast disintegration rate. In experiments performed by the present Inventors it was found that the use of electrospun polymer can increase the disintegration rate by more than an order of magnitude, compared to conventional oral dissolving tablets. A further advantage of the present embodiments is that the electrospinning process can provide the electrospun polymer, hence also the formulation of the present embodiments, with enhanced mechanical properties far exceeding the mechanical properties of traditional formulations.

The release rate of pharmaceutically active ingredient from the electrospun polymer depends on several variants, which may be controlled during the manufacturing process. One variant is the chemical nature of the carrier polymer and the chemical means binding the pharmaceutically active ingredient to it. This variant may be controlled by a suitable choice of the polymer(s) used in the electrospinning process. Another variant is the area of contact between the body fluids and the electrospun polymer, which can be controlled, for example, by varying the free surface of the electrospun polymer fibers. Also affecting the release rate is the method used to incorporate the pharmaceutically active ingredient within the electrospun polymer, as further detailed hereinbelow.

Hence, in one preferred embodiment the pharmaceutically active ingredient is mixed with a liquefied polymer, and the mixture is used in the preparation process of the formulation.

In another preferred embodiment, the pharmaceutically active ingredient is in a form of compact objects 12, such as, but not limited to, particles, agglomerates, coated cores and the like. The compact objects can be in a form of a powder and/or micrometric capsules containing the particles, agglomerates or coated cores.

A particle is a finely divided primary particle which is substantially devoid of smaller primary particles.

An agglomerate is a coalesced lump of two or more primary particles adhered together in a three dimensional structure in which each particle is joined to at least one adjacent particle. An agglomerate typically includes a particle binder material present therein as a discontinuous phase and is located in the form of bond posts linking adjacent particles. When the pharmaceutically active ingredient is in the form of agglomerates, each agglomerate can comprise primary particles of the pharmaceutically active ingredient and optionally also primary particles of a pharmaceutically acceptable inert substance, which can serve as an excipient to the pharmaceutically active ingredient.

A coated core of pharmaceutically active ingredient is a primary particle or an agglomerate of the pharmaceutically active ingredient coated by one or more layers of a pharmaceutically acceptable substance. "Pharmaceutically acceptable substance," refer to a carrier or a diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the pharmaceutically active ingredient. An adjuvant is included under these phrases.

The type of compact object depends on the desired release rate of the pharmaceutically active ingredient. For example, when the compact object is a coated core or a capsule, the layer of the coat or the encapsulation of the capsule can be selected to effect a predetermined controlled release profile of the pharmaceutically active ingredient from the compact object. Preferred controlled release profiles include, without limitation, sustained release, prolonged release, pulsatile release and delayed release profiles.

When the pharmaceutically active ingredient is in the form of compact objects, it can be incorporated into the electrospun polymer in more than one way. For example, when the electrospun polymer has the form of a capsule (see, e.g., Figure Id), it can serve as an encapsulation for holding compact objects 12.

Alternatively, compact objects 12 can be embedded in the electrospun polymer. This can be done by mixing compact objects 12 with a liquefied polymer, and using the mixture in the preparation process of the formulation., Also contemplated is a configuration in which the compact objects are distributed over electrospun polymer 10. This embodiment is particularly useful when the electrospun polymer has matrix morphology. Thus, according to the presently preferred embodiment of the invention the compact objects are distributed between fibers of the fiber matrix. Reference is now made to Figures 2a-b, which are schematic illustrations of a portion of the electrospun polymer in the preferred embodiment in which electrospun polymer has a matrix morphology. Shown in Figures 2a-b is a non-woven matrix 20 of polymer fibers 22 used to fabricate formulation. In the embodiment shown in Figure 2a, compact objects 12 are distributed between the electrospun polymer fibers 22 of matrix 20. hi the embodiment shown in Figure 2b, compact objects 12 are embedded in electrospun polymer fibers 22.

The use of electrospun matrix which incorporates the pharmaceutically active ingredient has many advantageous. Firstly, the porosity of the electrospun matrix can be controlled to create evenly distributed pores of predetermined size and orientation for to allow body fluids (e.g., gastrointestinal fluids, saliva) to pass through the matrix and dissolve fibers and/or the pharmaceutically active ingredient. The diffusion rate can be controlled by the thickness and composition of the matrix as well as the individual fibers within the matrix. Secondly, the polymer types and fibers thickness can be selected to provide a matrix having the required combination of strength, elasticity and other mechanical properties. Thirdly, being ultra-thin, the electrospun fibers have an exceptionally large surface area, which allows a high quantity of the pharmaceutically active ingredient to be incorporated thereon as well as good interaction with the body fluids. The surface area of the electrospun polymer fibers approaches that of activated carbon, thereby making the non-woven matrix of polymer fibers an efficient vehicle for drug delivery.

According to a preferred embodiment of the present invention the fiber matrix is characterized by a porosity of from about 20 % to about 95 %, more preferably from about 40 % to about 80 %. The fiber matrix is preferably characterized by an average pore diameter of from about 0.1 micrometer to about 20 micrometers, more preferably from about 5 micrometers to about 10 micrometers. The fibers of the matrix are preferably from about 50 nanometers to about 5 micrometers in diameter, more preferably from about 100 nanometers to about 500 nanometers in diameter. As used herein the term "about" refers to ± 10 %.

As stated, the formulation of the present embodiments can have a complex structure, such as a stack of layers, and the like. In various exemplary embodiments of the invention the fiber matrix of the electrospun polymer comprises a plurality of distinct layers. Different layers can be made of different types of polymers and/or can have different geometrical properties (e.g., fiber thickness, layer thickness, porosity, average pore diameter). Additionally, different layers can incorporate different types and/or forms of pharmaceutically active ingredient. For example, in one layer can the pharmaceutically active ingredient can be dissolved in the liquefied polymer used for forming the matrix, in a second layer the pharmaceutically active ingredient can be embedded as compact objects within the fibers and in a third layer the pharmaceutically active ingredient can be entrapped in the interstices of the matrix.

The multilayer structure of the formulation facilitates complex release profile, whereby different pharmaceutically active ingredient or different amounts of pharmaceutically active ingredients can be released over different predetermined period, and at different predetermined rate (which is not necessarily a constant rate). For example, the outermost layer can be loaded with the amount and type of pharmaceutically active ingredient which is to be release over a first predetermined period at a first predetermined rate, the next-to-outermost layer can be loaded with the amount and type of pharmaceutically active ingredient which is to be release over a second predetermined period at a second predetermined rate, and so on. Each layer is preferably made of a biodegradable and/or water soluble polymer which interacts with the body fluids and disintegrates at a suitable rate, depending on the desired release profile. The electrospun polymer can be any biodegradable and/or water soluble polymer known in the art, include, without limitation, starch, gelatin, dextran, dextrin, alginate, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl alcohol, poly (L-lactic acid), poly (lactide-co-glycolide), poly(ethylene glycol), poly(ethylene oxide), polycaprolactone, polyphosphate ester, poly (glycolic acid), poly (DL-lactic acid), poly (amino acid), poly(ethylene carbonate), poly(α-hydroxyester), poly(β- hydroxybutyrate), poly(amides), ethylene vinil acetate , poly(dimethylsiloxane), chitozan, collagen, cellulose. The electrospun polymer can also be made of mixtures of two or more of the above or other biodegradable and/or water soluble polymers. Additional biostable polymers can be used, either by mixing them with the biodegradable and/or water soluble polymers, or by introducing biostable polymer fibers into the matrix. Representative of biostable polymerizable materials, include, without limitation, polycarbonate based aliphatic polyurethanes, siloxane based aromatic polyurethanes, polydimethylsiloxane and other silicone rubbers, polyester, polyolefins, polymethyl- methacrylate, vinyl halide polymer and copolymers, polyvinyl aromatics, polyvinyl esters, polyamides, polyimides and polyethers.

Biostable polymers are advantageous because their drug release behavior is more predictable.

According to another aspect of the present invention there is provided a method suitable for producing the formulation of the present embodiments.

Figure 3 is a flowchart diagram of the method according to various exemplary embodiments of the present invention. It is to be understood that, unless otherwise defined, the method steps described hereinbelow can be executed either contemporaneously or sequentially in many combinations or orders of execution. Specifically, the ordering of the flowchart of Figure 3 is not to be considered as limiting. For example, two or more method steps, appearing in the following description or in the flowchart of Figure 3 in a particular order, can be executed in a different order (e.g., a reverse order) or substantially contemporaneously.

The method begins at step 30 and, optionally and preferably, continues to step 32 in which one or more chemicals (e.g., one or more pharmaceutically active ingredients) is mixed with one or more liquefied polymers (e.g., one or more pharmaceutically acceptable liquefied polymers). The chemical can be constituted by compact objects as explained above or it can be in a dissolved form. The chemical may be in amorphous form and may be stabilized with other additives or may also be in the form of an amorphous dispersion. The chemical is preferably homogeneously mixed with the liquefied polymer. The mixing can be performed using any suitable method, for example by dissolving or suspending the chemical in the liquefied polymer.

The method continues to step 34 in which, via electrospinning process, the liquefied polymer is dispensed onto a collecting element, to form an electrospun polymer. The electrospinning steps may be performed using any electrospinning apparatus known in the art. Suitable electrospinning techniques are disclosed, e.g., in International Patent Application, Publication Nos. WO2002/049535, WO2002/049536, WO2002/049536, WO2002/049678, WO2002/074189, WO2002/074190, WO2002/074191, WO2005/032400 and WO2005/065578, the contents of which are hereby incorporated by reference.

Thus, the liquefied polymer (with or without the additional chemical) is extruded, for example under the action of hydrostatic pressure, through capillary apertures of a dispenser which holds the liquefied polymer. The dispenser is spaced apart from a collecting element which is an electrode or surface mounted on an electrode. The dispenser and collection element are kept at different electric potentials thereby forming an electric field therebetween. The extrusion of the liquefied polymer results in a formation of meniscus, and a process of solvent evaporation or cooling begins. Because the liquefied polymer possesses a certain degree of electrical conductivity, it becomes charged. The electric field stretches the extruded polymer leading to spraying of ultra-thin jets of liquefied polymer from the dispenser. Under the effect of a Coulomb force, the jets depart from the dispenser and travel towards the collecting element. Moving with high velocity, the jet cools or solvent therein evaporates, thus forming electrospun polymer collected on the surface of the collecting element.

In various exemplary embodiments of the invention the method continues to step 36 in which the chemical is incorporated into the electrospun polymer. This can be done, for example, by constituting the chemical into compact objects (e.g., objects

12), and distributing the compact objects between polymer fibers produced during the electrospinning step. The distribution of the compact objects can be performed, for example, by a suitable sprayer (e.g., an electrostatic sprayer). The compact objects

(e.g., powder, capsules) are fed to the sprayer, whose output is sprayed to yield a spray of compact objects which are directed toward electrospun polymer.

The method preferably continues to step 38 in which the electrospun polymer is shaped according to the selected shape (tablet, suppository, film, capsule, etc.) of the formulation. The shaping can be performed by any known technique, such as, but not limited to, thermoforming, vacuumforming, pressing, cutting and the like. Suitable shaping techniques are disclosed, e.g., in U.S. Patent Nos. 5,290,490, 4,567,089, 4,526,831, 4,489,034, 4,457,797, 5,620,715, 6,878,437 and 6,444,073. When thermoforming is employed, the electrospun polymer is brought to a suitable temperature and introduced to a mold having the desired shape. The electrospun polymer is then shaped by increasing the pressure in the mold. When vacuumforming is employed, the electrospun polymer is brought to a suitable temperature and introduced to a mold having the desired shape. A vacuum is applied through the base of the mold to suck the electrospun polymer about the mold. The pulled electrospun polymer takes the form of the mold, and is allowed to cool in its desired shape. Further operations, such as cutting, trimming, etc., can also be employed. The method ends at step 40. Additional objects, advantages and novel features of the present invention will become apparent to one ordinarily skilled in the art upon examination of the following example, which is not intended to be limiting. Additionally, each of the various embodiments and aspects of the present invention as delineated hereinabove and as claimed in the claims section below finds experimental support in the following example.

EXAMPLE

Reference is now made to the following example, which together with the above descriptions illustrates the invention in a non limiting fashion.

Donepezil hydrochloride shows the acetylcholine esterase-inhibitory action and is useful for the treatment of all kinds of senile dementia, in particular being useful for prevention, treatment and amelioration of Alzheimer Disease. Donepezil hydrochloride is typically administered orally and it may be placed for distribution and storage in a period of time before the administration. A fibrous matrix incorporating 75 % lactose and 25 % donepezil hydrochloride was fabricated in accordance with the teachings of the present embodiments. The matrix was formed by electrospinning on the basis of polyethylene oxide with molecular weight of 600K Daltons. The mix included methyl alcohol with tetrahydrofuran and dimetylformamid in a proportion 1:2:3, respectively.

The specific weight of the matrix was 60 g/m², the porosity was 55 % and the root-mean-square fiber diameter was about 450 nanometers. The matrix facilitated an increased disintegrating rate which is about 70 times larger than the disintegrating rate of a conventional pellet of the same substance.

It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

Although the invention has been described in conjunction with specific embodiments thereof, it is evident that many alternatives, modifications and variations will be apparent to those skilled in the art. Accordingly, it is intended to embrace all such alternatives, modifications and variations that fall within the spirit and broad scope of the appended claims. All publications, patents and patent applications mentioned in this specification are herein incorporated in their entirety by reference into the specification, to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated herein by reference. In addition, citation or identification of any reference in this application shall not be construed as an admission that such reference is available as prior art to the present invention.

Claims

WHAT IS CLAIMED IS:

1. A formulation comprising at least one pharmaceutically acceptable electrospun polymer incorporating at least one pharmaceutically active ingredient, wherein a shape and size of said electrospun polymer is adapted for oral, vaginal or rectal administration.

2. A method of treating a subject, comprising administering to a subject in need thereof a therapeutically effective amount of the formulation of claim 1.

3. The use of the formulation of claim 1, for the preparation of a medicament.

4. A method of producing the formulation of claim 1, comprising: mixing said at least one pharmaceutically active ingredient with at least one pharmaceutically acceptable liquefied polymer; and electrospinning said at least one pharmaceutically acceptable liquefied polymer onto a collecting element thereby providing said at least one pharmaceutically acceptable electrospun polymer incorporating said at least one pharmaceutically active ingredient.

5. A method of producing the formulation of claim 1, comprising: electrospinning at least one pharmaceutically acceptable liquefied polymer onto a collecting element thereby providing said at least one pharmaceutically acceptable electrospun polymer; and incorporating said at least one pharmaceutically active ingredient into said pharmaceutically acceptable electrospun polymer so as to provide said at least one pharmaceutically acceptable electrospun polymer incorporating said at least one pharmaceutically active ingredient.

6. The method of claim 4 or 5, further comprising shaping said at least one pharmaceutically acceptable electrospun polymer.

7. The method of claim 5, wherein said incorporating said at least one pharmaceutically active ingredient comprises constituting said at least one pharmaceutically active ingredient into compact objects, and distributing said compact objects between polymer fibers produced during said step of electrospinning.

8. The method of claim 7, wherein said distribution of said compact objects is by spraying.

9. The formulation of claim 1, wherein said pharmaceutically active ingredient comprises donepezil hydrochloride.

10. A method of treating a disease accompanied by acetylcholinesterase activity, comprising to a subject in need thereof a therapeutically effective amount of the formulation of claim 9, for inhibiting or substantially reducing the acetylcholinesterase activity.

11. The use of the formulation of claim 9, for inhibiting or substantially reducing acetylcholinesterase activity of a subject.

12. A formulation comprising at least one electrospun polymer incorporating at least one chemical, said at least one electrospun polymer being soluble in a liquid medium.

13. The formulation of claim 12, wherein said electrospun polymer is capable of disintegrating in said liquid medium within less than a minute.

14. The formulation of claim 12, wherein said liquid medium is an aqueous medium.

15. The formulation, method or use of claim 1, 2, 3, 5, 6, 7 or 11, wherein said electrospun polymer is shaped as a tablet.

16. The formulation, method or use of claim 1, 2, 3, 5, 6, 7 or 11, wherein said electrospun polymer is shaped as a suppository.

17. The formulation, method or use of claim 1, 2, 3, 5, 6, 7 or 11, wherein said electrospun polymer is shaped as a film.

18. The formulation, method or use of claim 1, 2, 3, 5, 6, 7 or 11, wherein said electrospun polymer is shaped as a capsule.

19. The formulation, method or use of claim 18, wherein said pharmaceutically active ingredient is encapsulated within said capsule.

20. The formulation, method or use of claim 1, 2, 3, 9 or 10 wherein said at least one pharmaceutically active ingredient is embedded in said electrospun polymer in a form of compact objects.

21. The formulation, method or use of claim 1, 2, 3, 3, 4, 9 or 10, wherein said electrospun polymer has a fiber matrix morphology.

22. The formulation, method or use of claim 21, wherein said at least one pharmaceutically active ingredient is distributed between fibers of said fiber matrix in a form of compact objects.

23. The formulation, method or use of claim 12, wherein said electrospun polymer has a fiber matrix morphology.

24. The formulation, method or use of claim 23, wherein said at least one chemical is distributed between fibers of said fiber matrix in a form of compact objects.

25. The formulation, method or use of claim 4, 5, 20, 22 or 24, wherein said compact objects comprise capsules.

26. The formulation, method or use of claim 4, 5, 20, 22 or 24, wherein said compact objects are in a powder form.

27. The formulation, method or use of claim 4, 5, 20, 22 or 24, wherein said compact objects comprise agglomerates.

28. The formulation, method or use of claim 4, 5, 20 or 22 wherein said compact objects comprise a core made of said at least one pharmaceutically active ingredient coated by at least one coat of a pharmaceutical active material.

29. The formulation, method or use of claim 28, wherein said at least one coat is selected to effect controlled release profile of said pharmaceutically active ingredient from said compact objects.

30. The formulation, method or use of claim 21 or 23, wherein said fiber matrix is characterized by a porosity of from about 20 % to about 95 %.

31. The formulation, method or use of claim 21 or 23, wherein said fiber matrix is characterized by an average pore diameter of from about 1 micrometer to about 20 micrometers.

32. The formulation, method or use of claim 21 or 23, wherein said fiber matrix comprises a plurality of distinct layers.

33. The formulation, method or use of claim 32, wherein said plurality of layers are distinguishable by at least one of: polymer type, fiber thickness, layer thickness, porosity, average pore diameter.

34. The formulation, method or use of claim 32, wherein at least two of said plurality of distinct layers incorporate different pharmaceutically active ingredients.

35. The formulation, method or use of claim 32, wherein at least two of said plurality of distinct layers incorporate pharmaceutically active ingredients having different forms.

36. The formulation, method or use of claim 1, 2, 3, 3, 4, 9 or 10, wherein the formulation further comprising at least one pharmaceutically acceptable carrier.

37. The formulation, method or use of claim 1, 2, 3, 3, 4, 9 or 10, wherein said at least one pharmaceutically acceptable electrospun polymer is biodegradable.

38. The formulation, method or use of claim 37, wherein said at least one pharmaceutically acceptable electrospun polymer is water soluble.

39. The formulation, method or use of claim 38, wherein said at least one pharmaceutically acceptable electrospun polymer is capable of disintegrating in body fluids with less than a minute.

40. The formulation, method or use of claim 37, wherein an amount and type of said at least one pharmaceutically acceptable electrospun polymer is selected so as to provide a predetermined disintegrating rate of said polymer, thereby facilitating a predetermined control release profile of said at least one pharmaceutically active ingredient.