KR20020082212A - Electrospun pharmaceutical compositions - Google Patents

Abstract

The present invention relates to an electrospinning pharmaceutical composition containing a pharmaceutically acceptable active ingredient and a pharmaceutically acceptable polymer carrier for use in therapy.

Description

Electrospinning pharmaceutical composition {ELECTROSPUN PHARMACEUTICAL COMPOSITIONS}

It is known that the dissolution rate of particulate drugs can increase with increasing surface area, ie with decreasing particle size. Therefore, methods for preparing finely divided drugs have been studied and efforts have been made to control the size and size range of drug particles in pharmaceutical compositions. For example, dry grinding techniques were used to reduce particle size and thus affect drug absorption. However, in conventional dry grinding, as mentioned in Lachman, et al., The Theory and Practice of Industrial Pharmacy, Chapter 2, "Milling", p. 45 (1986), The limit of fineness is reached in parts of 100 microns (100,000 nm). Lachman et al. Pointed out that wet grinding is advantageous for further reducing the particle size, but flocculation limits the smaller particle size limit to about 10 microns (10,000 nm). However, due to problems with contamination there is a tendency in the pharmaceutical field to be biased towards wet grinding. Commercial airjet grinding techniques provide particles in the average particle size range as low as about 1-50 μm (1,000-50,000 nm).

Other techniques for preparing pharmaceutical compositions include, for example, loading drugs into liposomes or polymers during emulsion polymerization. However, this technique has problems and limitations. For example, fat soluble drugs often require the preparation of suitable liposomes. In addition, the production of drug dosage units often requires unacceptably large amounts of liposomes or polymers. In addition, the techniques for preparing such pharmaceutical compositions tend to be complex. The main technical difficulty faced by emulsion polymerization is to remove contaminants such as unreacted monomers or initiators that can be toxic at the end of the manufacturing process.

U.S. Patent No. 4,540,602 (Motoyama et al.) Describes a solid drug powdered in an aqueous solution of a water soluble polymer using a wet mill. However, Motoyama et al. Noted that as a result of this wet grinding, the drug was formed into finely ground particles ranging from 0.5 .mu.m (500 nm) or less in diameter to 5.mu.m (5,000 nm). It suggests that it is formed.

U. S. Patent No. 5,145, 684 to Liversidge et al. Describes a dispersible crystalline drug substance having a particle size of less than 400 nm produced by wet grinding for increased bioavailability.

EPO 275,796 describes the production of colloidal dispersion systems containing materials in the form of spherical particles smaller than 500 nm. However, this method involves precipitation caused by mixing a solution of a substance with a miscible nonsolvent for the substance, resulting in the formation of amorphous nanoparticles. In addition, precipitation techniques for preparing particles tend to provide particles contaminated with solvents. Such solvents are often toxic and can be very difficult but not impossible to properly remove to a pharmaceutically acceptable level to be practical.

U. S. Patent No. 4,107, 288 describes particles in the 10 to 1,000 nm size range containing biological or pharmacokinetic actives. However, the particles consist of a crosslinked matrix of macromolecules having an active material supported on or integrated in the matrix.

Solid dispersions of drugs in polymers have been studied to address the problem of reduced bioavailability of poorly water-soluble drugs (Recent Reference: Serajuddin, Journal of Pharmaceutical Sciences, 1999, 88 (10), 1058).

Areas of great interest are fast-acting dosage forms aimed at the specific needs of children, the elderly and patients with dysphagia.

U. S. Patent No. 4,855, 326 describes the mixing of a meltspun carrier component, such as sugar, with a medicament and then converting it into a fiber form by melt spinning using a "cotton candy" manufacturing device. The spun product is converted into compressed unit dosage forms. In certain medicines, a binder is added to the carrier component. Examples include oral administration, topical application, systemic and non-systemic, intravenous and intramuscular infusion via multicameral containers. All applications utilize a surprisingly fast introduction into the solution upon contact with the solvent.

US Patent No. 4,946,684; 5,298261; 5,466,464; 5,501,861; 5,762,961; 5,866.163 describes that taste-blocked, fast-acting dosage forms with sensory acceptable properties disintegrate quickly in the oral cavity of a patient without chewing or using minimal amounts of water.

U. S. Patent No. 5,948, 430 describes a polymer film composition which provides immediate hydration when administered orally and then quickly dissolves / disintegrates. This only applies to soluble drugs.

Dosage forms for immediate and modified release in the lungs are being actively studied.

U.S. Patent 5,747,001 describes the benefits of aerosolized nanoparticles in pulmonary delivery.

WO 99/48476 describes the use of drug / carrier particles with elongation ratios of 1.6 or greater to provide improved delivery by inhalation. These particles are produced by SCF technology or by complex precipitation methods. Electrospinning provides a direct, scalable process for the production of nanoparticles with higher stretch ratios.

U. S. Patent No. 5,985, 309 describes macroporous biodegradable microspheres containing proteins and peptides for intrapulmonary delivery.

Drug nanoparticles can be produced in a homogeneously embedded polymer carrier matrix so that convenient dosage forms such as fast solubility, immediate release, delayed release, and modified release can be produced by simply selecting the appropriate polymer without changing the method of preparation. It is desirable to design simple pharmaceutical compositions that provide all the positive attributes of the dosage form by combining enhanced bioavailability and physico-chemical properties of the nanofibers.

Summary of the Invention

One object of the present invention is a method of electrospinning a pharmaceutically acceptable active ingredient or ingredients in the presence of a high molecular weight carrier which acts as a viscosity enhancer and a fiber former. The method of preparing the electrospinning pharmaceutical composition may be from a solution or melt.

The present invention also relates to pharmaceutical compositions containing the electrospun fibers of a pharmaceutically acceptable polymer carrier in combination with a pharmaceutically acceptable active ingredient.

The present invention is also intended for dissolution in a liquid medium for direct oral administration, for pulmonary administration, or in a liquid medium for administration such as a suspension or solution, or by parenteral / muscular or intracavity injection. It relates to the use of an electrospinning pharmaceutical composition containing an acceptable active ingredient and a pharmaceutically acceptable polymer carrier.

The present invention relates to nanofibers (nanofibers) of drug particles, methods for their preparation and pharmaceutical compositions containing these nanofibers. The present invention also relates to the use of such nanofibers in designing various dosage forms to reach the maximum bioavailability of the drug site.

1 illustrates a process for producing nanofibers by electrospinning a viscous drug / polymer composition in solution or melt form.

Figure 2 shows the dissolution rate of nabumetone containing nanofibers normalized to the nanoparticles of nabumetone (nabumetone).

3 shows a picture Poly Ox ^(POLYOX?) Injection of a 60% w / w Nauvoo meton radiation with fibers electron microscope (SEM).

The present invention relates to a novel composition of electrospun fibers produced as a result of spinning a high molecular weight polymer carrier which acts as a viscosity enhancer and a fiber forming agent together with a pharmaceutically acceptable component or drug.

As used herein, the term "integrated" means combining, mixing, mixing, or blending a drug together with a carrier. It is not coated on the surface of electrospun fibers (woven or nonwoven). In particular, the fibers preferably contain both the component and the carrier together in a uniform manner. Although it is recognized that incomplete agitation of the solution or pure / melted composition can cause some non-uniformity in the resulting fiber, the precondition is that the drug and carrier are spun together rather than being applied to the fiber in subsequent steps.

The electrospun fibers of the present invention are expected to have diameters in the nanometer range, thus providing very large surface areas. This method produces fibers in which a large surface-to-volume ratio is important. This very large surface area has a significant impact on the bioavailability of poorly water soluble drugs because the increased surface area is known to lead to increased dissolution rates.

Suitable dosage forms, such as oral or parenteral forms, including intrapulmonary administration, can be designed with careful consideration of these polymer carriers in view of the physical-chemical properties of the polymer carriers and their control. Other pharmaceutically acceptable excipients can be included to improve stabilization or de-agglomeration of drug nanoparticles. Pharmaceutical excipients may also have substances of other properties, such as absorption enhancers.

Electrospun pharmaceutical dosage forms can be designed to provide modified dissolution such as rapid dissolution, immediate, delayed, or sustained and / or pulsatile release properties.

Taste shielding of the active ingredient may also be accomplished using polymers having functional groups that can facilitate specific interactions with drug sites. Electrospinning dosage forms can be made into compressed tablets, sachets or films. Immediately, conventional dosage forms such as delayed and modified release systems can be designed by appropriate choice of polymer carriers, drug combinations as described in the art.

One object of the present invention is to provide pharmaceutically acceptable drug nanoparticles uniformly embedded in polymer nanofibers to facilitate bioavailability of the drug regardless of the route of administration.

Electrospinning, commonly called electrostatic spinning, is a method of producing fibers having a diameter in the range of 100 nm. The method consists in applying a high voltage to the polymer solution or melt to produce a polymer jet. As the jet moves in the air, the jet is stretched under repulsive electrostatic forces to produce nanofibers. This method has been described in the literature since 1930. Nanofibers were prepared by electrospinning various polymers with optimal properties, both natural and synthetic, under appropriate conditions (Reneker et al., Nanotechnology, 1996, 7, 216). Various applications have been proposed for these electrospun nanofibers, such as air filters, molecular complexes, vascular grafts and wound dressings.

US Patent No. 4,043,331 is intended for use as a wound dressing, while US Patent No. 4,044,404 and US Pat. No. 4,878,908 have been modified to generate blood compatible linings for prosthetics. While not all of the described water-insoluble polymers are pharmaceutically acceptable for use herein, it is believed that the described water-soluble polymers are pharmaceutically acceptable. None of the formulations in these patents describe examples of electrospun fibers with active ingredients. These patents claim the use of enzymes, drugs and / or activated carbon on the surface of nanofibers prepared by immobilizing the active site so that the active site acts on the application site and does not “exudate through the body”.

EP 542514, US Pat. No. 5,311,884 and US Pat. No. 5,522,879 relate to the use of spinning fibers for piezoelectric biomedical devices. The piezoelectric properties of fluorinated polymers, such as those derived from copolymers of vinylidene fluoride and tetrafluoroethylene, are not considered to be pharmaceutically acceptable polymers for use herein.

U. S. Patent No. 5,024, 671 uses electrospun porous fibers as drug-filled vascular grafts to allow direct delivery of the drug to the suture. Porous implants are impregnated with the drug (not electrospun) and biodegradable polymers are added to control drug release. Angiografts are also made from non-pharmaceutically acceptable polymers such as polytetrafluoroethylene or combinations thereof.

U.S. Pat.Nos. 5,376,116, 5,575,818, 5,632,772, 5,639,278, and 5,724,004 are one form of prosthetic devices having coatings or linings of electrospun non-pharmaceutical acceptable polymers. Or another form. The electrospinning outer layer is post-treated with a drug as described in the '116 patent (for breast prostheses). Other patents describe the same techniques and polymers, but apply the technique to other applications such as luminal grafts or endovascular stents.

Accordingly, the present invention first relates to the production of pharmaceutical compositions of the active ingredient (s) and pharmaceutically acceptable polymers into electrospun fibers. The uniform nature of this method produces an amount of fiber that allows nanoparticles of the drug to be dispersed throughout. The size of the particles and the quality of the dispersion define the large surface area of the drug. One use of the increased surface area of the drug is to improve bioavailability in the case of poorly water soluble drugs. Other uses are to reduce drug-drug or enzymatic interactions.

Accordingly, the present invention relates to the use of the drug in the form of nanofibers alone or in combination with a pharmaceutically acceptable polymer (or combination thereof) to enhance the bioavailability of the drug, preferably a poorly water soluble drug. .

The present invention also relates to a fast dissolving dosage form which contains an electrospun water soluble polymer in combination with the active ingredient and disintegrates in a rapid manner over a short time period in the oral cavity or other suitable body cavity. In the oral environment, this produces small particulate matter, which can be ingested without the need for water.

The fast dissolving dosage forms can include drugs that are water soluble or water insoluble. Expression of rapid action is not a prerequisite for the fast dissolving dosage form. In the case of a bitter drug, it may be advantageous to be in an insoluble form by its own solubility properties or by polymer coating. Thus, the main attribute of the fast dissolving dosage forms is that the excipient exposes the drug particles so that they disintegrate rapidly in the oral cavity and are readily swallowed. If this is the case, it may be suitable for the electrospun polymer (water soluble) nanofibers to be premixed with the drug during spinning or postmixed during the preparation of the fast dissolving dosage form.

Application of this method can be used to incorporate pharmaceutically acceptable drugs for local delivery, but this is primarily indicated by oral, intravenous, intramuscular or inhalation regimens.

A pharmaceutically acceptable ingredient, active agent or drug as used herein is meant to include an active ingredient having pharmacological activity for use in a mammal, preferably a human. Pharmacological activity may be prophylactic or for the treatment of a disease state. By usage is meant to include agricultural or pesticide usage for application to plants or soil. The use of electrospun fibers, woven or nonwoven fabrics, for direct application in topical treatment in wound dressings or garments is also not an aspect of the present invention. However, the use of fibers in pharmaceutical formulations for topical administration is considered to be within the scope of the present invention.

As used herein, the terms "active ingredient", "drug site" or "drug" are used interchangeably.

The water solubility of the active ingredient is defined in the US Pharmacopoeia. Thus, the active ingredients that fall within the categories of well soluble, well soluble, soluble, and slightly soluble as defined herein are included in the present invention. Electrospun polymer compositions are believed to be most beneficial for these drugs, which are insoluble or slightly soluble.

Suitable drug components include, for example, analgesics, anti-inflammatory agents, antiparasitic agents, antiarrhythmics, antibiotics (including penicillin), anticoagulants, antidepressants, antidiabetics, antiepileptic drugs, antihistamines, antihypertensives, antimuscarinics, antimycobacterial agents Anti-tumor, immunosuppressive, anti-thyroid, antiviral, anti-anxiety (hypnotic and neuroleptic), astringents, beta-adrenergic receptor blockers, blood products and substitutes, cardiac metabolites, corticosteroids, cough suppressants (expectorants and mucus) Solubilizers), diagnostic agents, diuretics, dopamine agonists (antiparkinson's), hemostatic agents, immunological agents, lipid modulators, muscle relaxants, parasympathetic neurostimulants, parathyroid calcitonin and biphosphonates, prostaglandins, radiopharmaceuticals, sex hormones (including steroids) , Anti-allergic, stimulant and appetite suppressant, sympathomimetic, thyroid, PDE IV inhibitor, NK3 inhibitor, CSBP / RK / p38 billion Agent, can be selected from a class of drugs known variety, including antipsychotics, vasodilators and xanthine.

Preferred drug components include those intended for oral and intravenous administration. A description of these classes of drugs and a list of drug classes belonging to each class are described in Martindale, The Extra Pharmacopoeia, Twenty-ninth Edition, The Pharmaceutical Press, London, 1989, the contents of which are hereby incorporated by reference in their entirety. ). Drug components may use commercially available products and / or may be prepared by techniques known in the art.

As mentioned, the electrospinning compositions can also tastefully mask a number of bitter or unpleasant drugs regardless of their water solubility. Suitable active ingredients for incorporation into the fibers of the present invention include histamine H ₂ -antagonists such as cimetidine, ranitidine, pamotidine, nizatidine, ethinidine; Lufitidine, nifenidine, niferotidine, roxatidine, sulfodinedine, tuvatidine and zaltidine; Antibiotics such as penicillin, ampicillin, amoxicillin and erythromycin; Acetaminophen; aspirin; Caffeine, dextromethorphan, diphenhydramine, bromopheniramine, chloropheniramine, theophylline, spironolactone, NSAID's such as ibuprofen, ketoprofen, naprocin, and nabumethone; 5HT ₃ inhibitors such as Granistron (Kytril ^? ) Or Ondansetron (Zofran ^? ); Serotonin reuptake inhibitors such as paroxetine, fluoxetine, fluvoxamine and sertraline; Vitamins such as ascorbic acid, vitamin A, and vitamin D; Numerous bitter or unpleasant taste drugs include, but are not limited to, dietary minerals and nutrients such as calcium carbonate, calcium lactate, and the like.

Suitably the aforementioned active ingredient, in particular anti-inflammatory agent, may be combined with other active therapeutic ingredients such as various steroids, decongestants, antihistamines and the like, if appropriate.

Preferably the active ingredient is nabumethone, cis-4-cyano-4- [3-cyclopentyloxyl) -4-methoxyphenyl] cyclohexanecarboxylic acid, ASA, paroxetine (Seroxat ^? ), Ariflo ( Ariflo), lopyrinol (Requip ^? ), Rosiglitazone (Avandia ^? ), Or hydrochlorothiazine and trimesterene (Dyazide ^? ).

Other suitable active ingredients are Ampenerase (Agenerase ^? ), Lamivudine (Epivir ^? ), Epoprostenol (Flolan ^? ), Janamivir (Relenza ^? ), Allosetron (Lotronex ^? ), Alclometa Aclovate ^?, Beclovent ^? And Beconase ^?, Malparan ^?, Naratriptan ^? Amerge ^?, Succinylcholine, Ceftin ^?, Ceptazidime ^{? ?),} sepyu roksim ^(Zinacef?), zidovudine ^(Retrovir?), flu Romantica John ^(Flonase? or ^Cutivate?), flute meta Min ^(Daraprim?), kolpo Sheryl (colfosceril), may Mart leaf Tan ^(Imitrex?), lamotrigine ^(Lamictal?), chlorambucil ^(Leukeran?), Ato Baku on ^(Malaron? or ^Mepron?), the US bakyu Leeum ^(Mivacron?), laying plates ^(Myleran?), vinorelbine ^{(Navelbine?),} suggested trad queue Solarium ^(Nimbex?), Viper queue Solarium ^(Nuromax?), Atta queue Solarium ^(Tracrium?), oxy nose sol ^(Oxistat?), mercapto-purine ^{(Purinethol?)} and thioguanine ^(Tabloid?), that Far flock Reaper ^(Raxar?), Salmeterol ^(Serevent?), Chloe beta sol ^(Temovate?), Ranitidine, famotidine, omeprazole (R and S isomers), remifentanil ^(Ultiva?), Rub cycles Birr (Valtrex ^?), O cycloalkyl Birr ^(Zovirax?), farm cycloalkyl Birr ^(Famvir?), pen cycloalkyl Birr ^(Denavir?), albuterol ^(Ventolin?), bupropion ^(Wellbutrin? or ^Zyban?), or Ava Kabir ^(Ziagen?) , 4- (3,4-dihydro-1-methyl-2 (1H) -isoquinolinyl) -N- (4-fluorophenyl) -5,6-dimethyl-2-pyrimidinamine, (N -(2,6-dichlorobenzoyl) -4- (2,6-dimethoxyphenyl) -L-phenylalanine); Telmisartan, racidipine, eniluracil, amoxicillin (Amoxcil ^? ), Clavulanate, mupirosine, ticarcillin, cerivastatin (Baycol ^? ), Carvedilol (Coreg ^? ), Topotecan (Hycamtin ^? ), Executive Park (Factive), rosil Rex (Locilex), Nova Stan (Novastan), tranilast (tranilast), roteuri piban ^{(Lotrifiban), 8 -??} ? [(4- amino-1-methylbutyl) amino ] -2,6-dimethoxy-4-methyl-5- (3-trifluoromethylphenoxy) quinoline succinate, (1S, 2R, 3S) -1- (1,3-benzodioxol-5- Yl) -2,3-dihydro-3- [2- (2-hydroxyethoxy) -4-methoxyphenyl] -5-propoxy-1H-indene-2-carboxylic acid, nelarabine ), Dutasteride, maribavir, 3- (3- {1-[(isopropyl-phenyl-carbamoyl) -methyl] -2,4-dioxo-5-phenyl-2 , 3,4,5-tetrahydro-1H-benzo [b] [1,4] diazepin-3-yl} -ureido) -benzoic acid; 6-amino-3- (2,3,5-trichlorophenyl) pyrazin-2-ylamine; (2R, 3R, 4S, 5R) -2- [6-Amino-2- (1S-hydroxymethyl-2-phenyl-ethylamino) -purin-9-yl] -5- (2-ethyl-2H- Tetrazol-5-yl) -tetrahydro-furan-3,4-diol; (6α, 11β, 16α, 17α) -6,9-difluoro-11-hydroxy-16-methyl-3-oxo-17-({[(3S) -2-oxotetrahydrofuran-3-yl ] Thio} carbonyl) androsta-1,4-diene-17-yl propionate; (3S) -tetrahydrofuran-3-yl (1S, 2R) -3-[[(4-aminophenyl) sulfonyl] (isobutyl) amino] -1-benzyl-2- (phosphonooxy) propylcart Barmate; (3R, 5R) -3-butyl-3-ethyl-7,8-dimethoxy-5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide; (1S, 3S, 4S, 8R) -3- (3,4-dichlorophenyl) -7-azatricyclo [5.3.0.0 ^4,8 ] decan-5-ol; (2S, 3S, 5R) -2- (3,5-difluorophenyl) -3,5-dimethyl-2-morpholinol; (S) -2- (2-benzoyl-phenylamino) -3- {4- [2- (5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -phenyl} -propionic acid; 3 '-[(2-{[(2R) -2- (3-chlorophenyl) -2-hydroxyethyl] amino} ethyl) amino] [1,1'-biphenyl] -3-carboxylic acid; (2S) -2-{[(1Z) -1-methyl-3-oxo-3-phenylprop-1-enyl] amino} -3- {4- [2- (5-methyl-2-phenyl- 1,3-oxazol-4-yl) ethoxy] phenyl} propanoic acid; Or combinations and mixtures of all compounds mentioned herein.

That is, the weakly soluble drug for use in the present invention should have good solubility in organic solvents, or the weakly soluble drug should be able to be used for melt processing as further described below.

The nanofibers of the present invention contain high molecular weight polymer carriers. These polymers, due to their high molecular weight, form viscous solutions that can produce nanofibers when applied to electrostatic potentials.

Suitable polymer carriers can preferably be selected from known pharmaceutical excipients. The physico-chemical properties of these polymers dictate the design of dosage forms such as rapid release, immediate release, delayed release, sustained release or modified release such as sustained release or controlled release.

Fibers were also formed by electrospinning with DNA fibers [Fang et al., J. Macromol. Sci.-Phys., B 36 (2), 169-173 (1997). Incorporation of pharmaceutically acceptable active ingredients such as biological components, vaccines or peptides with DNA, RNA or derivatives thereof as radiofibers is also within the scope of the present invention.

The fiber forming properties of the polymers are used to make nanofibers. Thus, the molecular weight of the polymer is the single most important parameter for the selection of the polymer. As mentioned above, cellulose acetate, PVA, PEO, PVP, polyacrylamide, polyurethane, polycarbonate, PTFE, PE, PP, polyacrylate, Kevlar, PHB, polyaniline, DNA, poly (phenyl Many polymers such as lene terephthalamide) and silk have already been electrospun.

However, further representative examples of suitable polymers for pharmaceutical applications for the purposes of the present invention include poly (ethylene oxide), polyvinyl alcohol, polyvinyl acetate, polyvinyl pyrrolidone, hyaluronic acid, alginate, carrageenan, carboxymethylcellulose Cellulose derivatives such as sodium, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, celluloseacetate phthalate, amorphous cellulose, starch and hydroxyethyl starch, Derivatives of starch, such as sodium starch glycolate, chitosan and derivatives thereof, albumin, gelatin, collagen, polyacrylates and derivatives thereof, such as the Eudragit class of polymers available from Rohm Pharma, Poly (alpha-hydroxy) Acids) and copolymers thereof, such as poly (caprolactone), poly (lactide-co-glycolide), poly (alpha-amino acids) and copolymers thereof, poly (orthoesters), polyphosphazenes, poly ( Phosphoesters), and polyanhydrides and mixtures thereof.

Most of these pharmaceutically acceptable polymers are described in detail in the Handbook of Pharmaceutical excipients, published by jointly by the American Pharmaceutical association and the Pharmaceutical society of Britain.

Preferably, the polymer carriers fall into three categories: (1) water soluble polymers useful for the rapid and immediate release of the active ingredient, (2) water insoluble polymers useful for the controlled release of the active ingredient, and (3) the active ingredient. PH sensitive polymers for the pulsatile or targeted release of. It is appreciated that a combination of two carriers may be used in the present invention. It is also recognized that some polyacrylates are pH dependent on solubility and can be included in both categories.

Water-soluble polymers include poly (ethylene oxide), polyvinyl alcohol, polyvinyl pyrrolidone, hyaluronic acid, alginate, carrageenan, cellulose derivatives, such as carboxymethylcellulose sodium, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropyl Methylcellulose, hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, starch and derivatives thereof, such as hydroxyethyl starch, sodium starch glycolate, dextrin, chitosan and derivatives thereof, albumin, zein, gelatin and collagen It is not limited to.

Preferably, the water-soluble polymer for use in the present invention are polyethylene oxide, such as the trade name Poly Ox ^(POLYOX?). Polymers can be used in a variety of molecular weights, and it is recognized that a combination of molecular weights may be used for one polymer, such as 100K, 200K, 300K, 400K, 900K and 2000K. Sentry POLYOX is a water soluble resin described in NF and has a molecular weight approximation of 100K to 900K and 1000K to 7000K. Polymers available for these commercially available products can be used in 1%, 2% and 5% solutions (depending on molecular weight).

The NF grade of Sentry POLYOX, a water soluble resin, is available in various molecular weights as mentioned above. The table presented below also provides additional information on grade to molecular weight approximations for use in the examples of the present invention.

Viscosity range at 25 ° C., cP NF rating Molecular weight approximation 5% solution 2% solution 1% solution WSRN-10 100,000 30-50 WSRN-80L 200,000 500 WSRN-80H 200,000 90-105 WSRN-750 300,000 500-1200 WSRN-3000 400,000 1,250-4,500 WSR-20S 600,000 4,500-8,800 WSR-1105 900,000 8,800-17,600 WSRN-12K 1,000,000 400-800 WSRN-60K 2,000,000 2,000-4,000 WSR-301 4,000,000 1,500-4,500 WSR flocculant 5,000,000 4,500-7,500 WSR-303 7,000,000 7,500-10,000

Further preferred polymers include povidones having K values and molecular weight ranges set forth below.

K value Molecular Weight 12 25 15 8,000 17 10,000 25 30,000 30 50,000 60 400 K 90 1000 K 120 3000 K

Water-soluble polymers include polyvinyl acetate, methylcellulose, ethylcellulose, amorphous cellulose, polyacrylates and derivatives thereof, such as the Eudragit class of polymers available from Rohm Pharma; Germany, Poly (alpha-hydroxy acids) and copolymers thereof, such as poly (ε-caprolactone), poly (lactide-co-glycolide), poly (alpha-amino acids) and copolymers thereof, poly (orthoesters) ), Polyphosphazenes, poly (phosphoesters) and polyanhydrides.

These pharmaceutically acceptable polymers and derivatives thereof may utilize commercially available products and / or may be prepared by techniques known in the art. By derivative is meant polymers of various molecular weights, modifications of functional groups of polymers, or copolymers of these components or mixtures thereof.

In addition, two or more polymers may be used in the blend to form the fibers as mentioned herein. Such formulations can enhance fiber formation or achieve the desired drug release profile.

The choice of polymer entrained by the active ingredient can provide adequate taste masking function for the active ingredient. For example, the desired result can be obtained using an ionic polymer of opposite charge, such as a cationic polymer combined with an anionic active ingredient or an anionic polymer combined with a cationic active ingredient. Addition of a second taste masking agent, such as a suitable cyclodextrin or derivative thereof, may also be used in the present invention.

The polymer composition can be electrospun from a solvent based or as is (as a melt). The choice of solvent is preferably based on the solubility of the active ingredient. Suitably, water is the best solvent for water soluble active ingredients and water soluble polymers such as POLYOX. Alternatively, water and water miscible organic solvents may be used. However, if the drug is water insoluble or slightly soluble, it is necessary to prepare a homogeneous solution of the polymer and drug using an organic solvent.

It is recognized that these polymer compositions spun as such may also contain additional additives such as plasticizers. Plasticizers are used to aid the melting properties of the composition. Examples of plasticizers that can be used in the present invention are triethyl citrate, triacetin, tributyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, dibutyl phthalate, dibutyl sebacate, vinylpyrrolidone, propylene Glycols, glycoltriacetate, polyethyleneglycol or polyoxyethylene sorbitan monolaurate and combinations or mixtures thereof.

Preferably, the solvent selected is a GRASS approved organic solvent, but the solvent may not necessarily be "pharmaceutically acceptable" because the amount obtained may fall below a detectable amount, or they may be used in humans. It may not be necessary to set a threshold for consumption. It is proposed that ICH guidelines should be used for selection. GRASS stands for "generally recognized as safe."

Suitable solvents for use in the present invention are acetic acid, acetone, acetonitrile, methanol, ethanol, propanol, ethyl acetate, propyl acetate, butyl acetate, butanol, N, N-dimethylacetamide, N, N-dimethylformamide, 1 -Methyl-2-pyrrolidone, dimethyl sulfoxide, diethyl ether, diisopropyl ether, tetrahydrofuran, pentane, hexane, 2-methoxyethanol, formamide, formic acid, hexane, heptane, ethylene glycol, dioxane , 2-ethoxyethanol, trifluoroacetic acid, methyl isopropyl ketone, methyl ethyl ketone, dimethoxypropane, methylene chloride, and the like, or mixtures thereof, but is not limited thereto.

Preferred solvents are mixtures of water and acetonitrile, or mixtures of water and acetone.

The solvent to polymer composition ratio is suitably determined by the desired viscosity of the resulting formulation.

The main parameters for the electrospinning of pharmaceutical polymer compositions are the viscosity, surface tension, and electrical conductivity of the solvent / polymer composition.

As used herein, the term “nanoparticulate drug” means the nanoparticle size of the active ingredient in the electrospun fiber.

The polymer carrier may also act as a surface modifier for the nanoparticulate drug. However, a second oligomeric surface modifier can also be added to the electrospinning solution. All of these surface modifiers can be physically adsorbed on the surface of the drug nanoparticles to prevent their aggregation.

Representative examples of these second oligomeric surface modifier or excipients of the flu Optronics ^(Pluronics?) (Block copolymer of ethylene oxide and propylene oxide), lecithin, Aerosol (Aerosol) OT ™ (carbonate when pitching sodium dioctyl tilseol), sodium Laurylsulfate, polyoxyethylene sorbitan fatty acid esters, ie polysorbates such as Tween ™, sorbitan fatty acid esters such as Tween 20, 60 and 80, ie sorbitan monolaurate, mono Oleate, monopalmitate, monostearate and the like, for example Span ™ or Arlacel ™, Emsorb ™, Capmul ™, or Sorbester ™ Triton X-200, polyethylene glycol, glyceryl monostearate, vitamin E-TPGS ™ (d-alpha-tocopheryl polyethylene glycol 1000 succinate), sucrose fatty acid esters, for example Sucrose stearate, sucrose oleate, sucrose palmitate, sucrose laurate, and sucrose acetate butyrate, etc., including, but, not limited to these.

Surfactants are added to the drug composition on a weight / weight basis. Suitably, the surfactant is added in an amount of about 10%, preferably about 5% or less. Surfactants can lower the viscosity and surface tension of the formulation, and large amounts can adversely affect the quality of the electrospun fibers.

Surfactant selection can be driven by HLB values but is not necessarily a useful category. HLB surfactants such as Tween ™ 80 (HLB = 10), Pluronic F68 (HLB = 28), and SDS (HLB> 40) are used in the present invention, but Pluronic F92 Lower HLB values, such as surfactants, may be used.

Another pharmaceutically acceptable excipient may be added to the electrospinning composition. These excipients can generally be classified as absorption enhancers, additional surfactants, fragrances, dyes, and the like.

Flavors suitable for use in the present invention include, but are not limited to, wintergreen, orange, grapefruit, and cherry-raspberry. While w / w% may vary for each composition, the fragrance should be present from about 0.25 to about 5% w / w of the total formulation.

Suitable colorants, pigments or dyes such as FD & C or D & C approved lakes and dyes, iron oxides and titanium dioxide may also be included in the formulation. The amount of pigment present can be from about 0.1% to about 2.0% by weight of the composition.

In addition, the formulations may also contain various natural sugars, sweeteners such as aspartame, sodium cyclate and sodium saccharate, and fragrances as mentioned above.

If polymer carriers or secondary oligomer surface modifiers are appropriately selected, they may themselves act as absorption enhancers, depending on the drug. Absorption enhancers suitable for use in the present invention include chitosan, lecithin, lectins, sucrose fatty acid esters, such as those derived from stearic acid, oleic acid, palmitic acid, lauric acid, and vitamin E-TPGS. It is not limited to these.

In the present invention, the electrospinning composition can be used as a conventional capsule or tablet fill. In another way, the fibers may be ground by cryogenic means suitably for compression into tablets or capsules, for use by inhalation, or for parenteral administration. The fibers can also be dispersed in an aqueous solution, which can then be administered directly by inhalation or by oral administration. The fibers can also be cut and processed as a sheet for further administration with the drug to form a polymer film that can be quickly dissolved.

Another aspect of the invention is an alternative electrospinning method for preparing the pharmaceutical compositions described herein. Embodiments herein may electrostatically charge a solution, while the pharmaceutical composition may also be discharged from the nebulizer on a receiving surface that is electrostatically charged and disposed at a suitable distance from the nebulizer. As the ejectant moves from the sprayer toward the charged collector in the air, fibers form. The collector may be a metal screen or in the form of a moving belt. The fibers can be deposited on the moving belt, which can be continuously separated as needed for further processing.

In a preferred embodiment of the present invention for a water soluble agent, the active nabumetone is from 0 to 82% of 200K, 400K, 900K and 2000K POLYOX and Tween 80, SDS, Pluronic F68 or TPGS electrospinning in the / w% range. Preferred solvent systems are water / acetonitrile.

The invention is described with reference to the following examples, which are merely illustrative and are not intended to limit the scope of the invention. All temperatures are given in degrees Celsius, and all solvents are of the highest purity available unless otherwise indicated.

Example 1

Electrospinning of 25% (w / w) Aspirin Compositions

Poly Ox (POLYOX) WSR N-60K ™ mm queue by gently mixing a stock solution of 2.5% solution of (Union Carbide) in a shaking water bath ^(MilliQ?) Was prepared in water. Ten milliliters (hereinafter “mL” or “mL”) of this polyox solution was added to a solution of 0.12 grams of acetylsalicylic acid (Sigma) (hereinafter “g”) in 0.5 mL of acetone. The contents were mixed thoroughly and 1 ml of acetone was added to give a clear solution. The solution is placed in a 25 ml glass vessel with a 0.03 millimeter (hereinafter "mm") capillary outlet at the bottom and two inlets, one for applying helium (He) positive pressure and the other for introducing electrodes. Transferred to. The electrode was connected to the positive terminal of a high voltage power supply (ModelD-ES30P / M692, Gamma High Voltage Research Inc. FL). The ground from the high voltage power supply was connected to a rotating drum coated with aluminum foil. The inlet helium pressure was 2.5 psi and a voltage of +14.5 KV was applied to the solution. Dry fibers were collected on a drum rotating at a speed of 50-60 rpm. The fibers were peeled off the drums.

Electrospinning methods are described in more detail in J. Doshi's Dissertation, of "The ElectroSpinning Process and Applications of Electrospun Fibers", August 1994, University of Akron, which is hereby incorporated by reference in its entirety.

Example 2

Electrospinning of 25% Nabumetone Composition

A stock solution of 30% polyethylene oxide (molecular weight 400K, Aldrich) was prepared in MilliQ ™ water by gentle shaking. 5 ml of this 30% solution was added to 0.5 g of nabumethone (SB Corporation) dissolved in 6 ml of acetonitrile. The contents were stirred gently and a further 5 ml of acetonitrile were added in portions until a clear solution was obtained. 0.1 mL of Tween ™ 80 (Sigma) was added to this solution. This solution was electrospun using the same conditions as described in Example 1 above. The fibers were collected on a drum and separated.

Example 3

Electrospinning of 30% Nabumetone Composition

7.5% (w / v) stock solution of poly Oaks ^{(POLYOX?) WSR N-3000} ( molecular weight of about 400 K, Union Carbide) was prepared by mixing 15 g of PEO from 50 ㎖ and acetonitrile 150 ㎖ water.

To 10 ml of this solution was added 0.4 g of nabumethone together with 1 ml of acetonitrile and 0.2 ml of Tween ™ 80 to obtain a uniform solution. This solution was electrospun under the same conditions as described in Example 1 above to obtain 1.3 g of fiber.

Example 4

Electrospinning of 50% Nabumetone Composition

To 10 ml of the stock solution of water / acetonitrile from Example 3, 0.8 g of nabumethone was added. This solution was homogenized by adding 1 ml of acetonitrile with 0.2 ml of Tween ™ 80. The solution was spun using a condition similar to that described in Example 1 above but using a feed pressure of 2 psi and 16 KV to give 1.2 g of fiber.

Example 5

Electrospinning of 70% Nabumetone Composition

Poly Ox ^(POLYOX?) N-3000 5 ㎖ solution from Example 3 was added to 0.86 g Nauvoo meton. This solution was homogenized by adding 1.6 ml of acetonitrile with 0.1 ml of Tween ™ 80. This solution was spun with a supply pressure of 0.5 psi and 16 KV using conditions similar to those described in Example 1 above to yield 0.93 g of fiber.

Example 6

Electrospinning of 80% Nabumetone Composition

Nauvoo meton 2 g, SDS (JT Baker) 0.1 g , and poly Oaks ^{(POLYOX?) WSR-1105 (} 900 K) mm queue in a mixture of 0.4 g ^(MilliQ?) Was added to the water and acetonitrile, 1.2 ㎖ 10.5 ㎖. This mixture was left in a shaking water bath at 37 ° C. until all solids dissolved to form a viscous solution. The resulting solution was electrospun using a condition similar to that described in Example 1 above but using a feed pressure of 2 psi and 18 KV to yield 2.1 g of fiber.

Example 7

Electrospinning of 80% Nabumetone Composition

Nauvoo meton 2 g, Pluronic ^{(Pluronic?) F68 (BASF)} 0.05 g , and poly Oaks ^{(POLYOX?) WSR-1105 (} 900 K) mm in a mixture of 0.4 g queue ^(MilliQ?) 1 ㎖ and acetonitrile 12 water Ml was added. This mixture was left in a shaking water bath at 37 ° C. until all solids dissolved to form a viscous solution. The resulting solution was electrospun using a condition similar to that described in Example 1 above but using a feed pressure of 2 psi and 18 KV to yield 2.1 g of fiber.

Example 8

Electrospinning of 80% Nabumetone Composition

2 g of nabumethone were dissolved in 11 ml of acetonitrile. To the solution was added to vitamin E-TPGS (Eastman) 0.1 g, and poly Oaks ^{(POLYOX?) WSR-1105 (} 900 K) 0.4 g. This mixture was prevented in a shaking water bath at 37 ° C. until all solids dissolved to form a viscous solution. The resulting solution was electrospun using a condition similar to that described in Example 1 above but using a feed pressure of 0.5 psi and 16 KV to give 2 g of fiber.

Example 9

Determination of Nabumetone Content in Nanofiber Compositions

20-50 mg (depending on anticipated drug content) of the nanofiber composition as described above were accurately weighed in a scintillation vial and dissolved in 5 ml of acetonitrile / water (80/20) mixture. This solution was quantitatively transferred to a 50 ml volumetric flask using acetonitrile / water (80/20) and supplemented with volume (50 ml) using acetonitrile / water as diluent. Three different samples taken from various parts of the fibrous sheet were prepared to measure the macroscopic uniformity in the fiber.

A standard solution of nabumethone was prepared using a correctly weighed sample of 20 mg of nabumethone in a 100 ml volumetric flask. Samples were made using acetonitrile / water (80:20) as diluent. 20 μl of this solution was injected into a Waters HPLC system equipped with a Waters 550 pump, a 717 plus autosampler and a Spectroflow 783 UV detector. Data acquisition was performed via PE Nelson Box and Turbochrom (PE) software. The mobile phase consisted of acetonitrile / water / acetic acid at a volume ratio of 44/55/1. The flow rate was 1.4 ml / min and detection was carried out at 254 nm.

Nabumetone Content (wt%) Sample # 1 Sample # 2 Sample # 3 Example 8 81.2 79.5 81.2 Example 6 82.9 82.8 83.0 Example 5 59 61.2 60.8 Example 4 36 36.9 35 Example 3 30 30.5 29.8

Example 10

Residual Solvent Analysis in Nabumetone Nanofibers

Residual solvent analysis was performed in QTI (Whitehouse, NJ) using samples dissolved in DMSO (dimethylsulfoxide) and quantified by capillary gas chromatography. The results presented in the table below demonstrated that all samples analyzed contained less than 100 ppm acetonitrile.

Acetonitrile content Example 5 <100 ppm Example 4 <100 ppm Example 3 <100 ppm

Example 11

In vitro dissolution test

The device used for this method is a modified USP4, the main difference being: 1) a low volume cell; 2) stirred cell; 3) Retaining filter suitable for retaining sub-micron material. The total run time using 2.5 mg of drug (proportional basis weight of more formulated material) is 20 minutes.

Flow Cell Specification: A Swinnex filter assembly with 0.2 micron cellulose nitrate membrane (Millipore, MA) as internal filter was obtained from Millipore. The internal volume of the cell is about 2 ml. Use a small PTFE stirrer (Radleys Lab Equipment Halfround Spinvane F37136) fitted to mount the Swinex assembly. The dissolution medium is water at a flow rate of 5 ml / min. The whole installation is placed in a thermostat at 37 ° C. Drug concentration is measured by passing the eluent through a UV detector with a flow rate size of 10 mm. UV detection is performed at 284 nm.

Measurement of the range of drug solubility

Experiments are designed to assess drug dissolution rates. As such, it dissolves 100% of the drug during the 20 minute test period, unlike water as a weakly soluble drug and dissolution medium. To determine the range of drug solubility over this period, a total of 100 ml of solution eluting from the dissolution cell is collected. A conventional UV spectrophotometer is used to compare this solution against a control solution of active ingredient dissolved in 50/50 methanol / water, such as 2.5 mg of nabumethone (in the case of nabumetone, this is 50/50 methanol / Prepared by 10-fold dilution of a solution containing 25 mg of nabumethone in 100 ml of water). Suitable wavelength for comparison is 260 nm.

Example 12

Measurement of enumeration copper of nanofibers containing nabumethone

Thermal tests on nabumethone nanofibers were performed on MDSC TA (Wilmington, DE). Samples were heated from 0 to 120 ° C. at 2 ° C./min at a modulation cycle of ± 0.159 ° C. every 30 seconds. Nanofibers containing nabumetone have a polyox when the nabumetone content is greater than 30% (wt) (less than one can see only one melt endothermic reaction due to the formation of eutectic mixtures or due to the overlap of endotherms). Two distinct endotherms at 50 ° C. and 75 ° C., corresponding to the melting points of (POLYOX) and Nabumetone, respectively.

Nabumetone content (wt%) Melt ° C and ΔH of Polyox Melt ℃ and ΔH of Nabumetone Example 8 81.2 49.4 (22.2 J / g) 75 (80 J / g) Example 7 84.4 51.5 (22.4 J / g) 75.3 (82.4 J / g) Example 6 82.9 50.5 (19.6 J / g) 75.3 (87.3 J / g) Example 5 60.3 49.2 (87.4 J / g) 69 (86.2 J / g) Example 4 35.9 45.1 (69.1 J / g) 59 (7.39 J / g) Example 3 30.1 47 (101 J / g) Example 2 29.3 48 (94.5 J / g)

Example 13

Electrospinning of 40% Cis-4-cyano-4- [3-cyclopentyloxyl) -4-methoxyphenyl] cyclohexanecarboxylic Acid Composition

Cis-4-cyano-4- [3-cyclopentyloxyl) -4 with 1 mL of acetonitrile and 0.1 mL of Tween ™ 80 in 10 mL of the POLYOX WSRN-3000 solution from Example 3 0.5 g of -methoxyphenyl] cyclohexanecarboxylic acid was added to obtain a uniform solution. This solution was electrospun under the same conditions as described in Example 1 above to obtain nanofibers containing the title compound.

Example 14

Electrospinning of (S) -3-hydroxy-2-phenyl-N- (1-phenylpropyl) -4-quinolinecarboxamide composition

400 mg of (S) -3-hydroxy-2-phenyl-N- (1-phenylpropyl) -4-quinolinecarboxamide was dissolved in 5 ml of tetrahydrofuran (GT Baker). To this solution was added poly Oaks ^{(POLYOX?) WSR-1105 (} 900 K) 450 ㎎ and Vitamin E-TPGS (Eastman) were added to a 50 ㎎. This mixture was left in a shaking water bath at 37 ° C. until all solids dissolved to form a viscous solution. 5 ml of acetonitrile were added to reduce the viscosity of the solution. The resulting solution was electrospun using conditions similar to Example 1 above but with a supply pressure of 0.5 psi and 16 KV to yield 0.5 g of fiber.

Example 15

Electrospinning of 4- [2- (dipropylamino) ethyl] -1,3-dihydro-2H-indol-2-one monohydrochloride

200 mg of Ropirinole was dissolved in 15 ml of MilliQ water. The solution Poly Ox ^(POLYOX?) To WSR N3000 NF and 1g were added to the Tween (Tween) 80 50 ㎎. This mixture was left in a shaking water bath at 37 ° C. until all solids dissolved to form a clear viscous solution. This solution was electrospun using a condition similar to Example 1 but using a feed pressure of 1 psi and 16 KV to yield 0.8 g of material.

Example 16

Electrospinning of 4- [2- (dipropylamino) ethyl] -1,3-dihydro-2H-indol-2-one monohydrochloride

350 mg of Ropirinole was dissolved in 15 ml of MilliQ water. The solution Poly Ox ^(POLYOX?) To WSR N3000 NF was added to 650 ㎎ and Tween (Tween) 80 50 ㎎. This mixture was left in a shaking water bath at 37 ° C. until all solids dissolved to form a clear viscous solution. This solution was electrospun using conditions similar to Example 1 but using a feed pressure of 1 psi and 16 KV to yield 0.7 g of material.

Example 17

Electrospinning of Paroxetine

100 mg of paroxetine was dissolved in 20 ml of MilliQ water. The solution Poly Ox ^(POLYOX?) To WSR N3000 NF was added to 800 ㎎ and Tween (Tween) 80 50 ㎎. The mixture was left to shake in a 37 ° C. water bath until all solids dissolved to form a clear viscous solution. This solution was electrospun using conditions similar to Example 1 but using a feed pressure of 1 psi and 16 KV to yield 0.75 g of material.

Example 18

Electrospinning of Kyrtil

300 mg of Kytril was dissolved in 15 ml of MilliQ water. The solution Poly Ox ^(POLYOX?) To WSR N3000 NF was added to 650 ㎎ and Tween (Tween) 80 50 ㎎. The mixture was left to shake in a 37 ° C. water bath until all solids dissolved to form a clear viscous solution. This solution was electrospun using conditions similar to Example 1 but using a feed pressure of 1 psi and 16 KV to yield 0.7 g of material.

Example 19

10% 2,3-dihydro-5-methyl-N- [6- (2-pyridinylmethoxy) -3-pyridinyl] -6- (trifluoromethyl) -1H-indole-1-carbox Electrospinning of Amide Compositions

Poly Ox ^(POLYOX?) And WSR-1105 (900K) was shaken overnight in a water bath at 35 ℃ ㎎ 850 was dissolved in acetonitrile 20 ㎖. This resulted in a thick viscous solution. To this solution 5 ml of n-methylpyrrolidone (NMP) and 50 mg of vitamin E-TPGS (Eastman) were added and stirred. To the polymer solution was added 100 mg of the title compound dissolved in 1 ml of NMP. The resulting clear solution was electrospun under the same conditions as in Example 1 to give 0.5 g of the product.

Example 20

20% 2,3-dihydro-5-methyl-N- [6- (2-pyridinylmethoxy) -3-pyridinyl] -6- (trifluoromethyl) -1H-indole-1-carbox Electrospinning of Amide Compositions

Poly Ox ^(POLYOX?) And WSR-1105 (900K) was shaken overnight in a water bath at 35 ℃ ㎎ 750 was dissolved in acetonitrile 20 ㎖. This resulted in a thick viscous solution. To this solution was added 5 ml of n-methylpyrrolidone (NMP) and 50 mg of vitamin E-TPGS (Eastman) and stirred. To the polymer solution was added 200 mg of the title compound dissolved in 1 ml of NMP. The obtained clear solution was electrospun under the same conditions as in Example 1 to obtain 0.7 g of the product.

Example 21

Electrospinning of 68% Nabumetone Composition

3 g of nabumethone were dissolved in 20 ml of acetonitrile. To this solution was added 0.25 g of vitamin E-TPGS (Eastman), 0.8 g of POLYOX ™ WSR-1105 (900K) and 0.25 g of Tween 80. This mixture was left in a shaking water bath at 37 ° C. until all solids dissolved to form a viscous solution. The resulting solution was electrospun using conditions similar to Example 1 above but with a supply pressure of 0.5 psi and 16 KV to yield 3.5 g of fibers.

All publications, including, but not limited to, patents and patent applications cited herein, are incorporated herein by reference, as specifically and individually, to be incorporated herein by reference as if each publication were sufficiently described. It is included by reference.

The foregoing description sets forth the invention in detail, including its preferred embodiments. Modifications and improvements of the embodiments specifically described herein also fall within the scope of the following claims. Without further adjustment, it is believed that one skilled in the art can, using the foregoing description, utilize the present invention to its fullest extent. Accordingly, the embodiments herein are to be construed as illustrative only, without limiting in any way the scope of the present invention. Embodiments of the invention for which exclusive features or rights are claimed are defined below.

Claims (42)

A pharmaceutical composition comprising electrospun fibers of a pharmaceutically acceptable polymer carrier in association with a pharmaceutically acceptable active ingredient. The composition of claim 1 wherein the active ingredient is nanoparticles in size. The composition of claim 1 or 2, wherein the active ingredient is water soluble. The composition of claim 1 or 2, wherein the active ingredient is water insoluble. The composition of claim 1 wherein the active ingredient is poorly water soluble. The composition of claim 1 or 2, wherein the polymer carrier is water soluble. The composition of claim 1 or 2, wherein the polymer carrier is water insoluble. A block copolymer of ethylene oxide and propylene oxide, lecithin, sodium dioctylsulfosuccinate, sodium laurylsulfate, Tween 20, 60 and 80, Span ™, Arlacel ™), Triton X-200, polyethylene glycol, glyceryl monostearate, d-alpha-tocopheryl polyethylene glycol 1000 succinate, sucrose fatty acid esters such as sucrose stearate, sucrose oleate, And a surfactant which is sucrose palmitate, sucrose laurate, sucrose acetate butyrate, or a mixture thereof. The composition of claim 1 or 8, further comprising an absorption enhancer. The composition of claim 1, which provides a taste shielding effect of the active ingredient. 7. The polymer carrier according to claim 6, wherein the polymer carrier is poly (ethylene oxide), polyvinyl alcohol, polyvinyl pyrrolidone, hyaluronic acid, alginate, carrageenan, carboxymethylcellulose sodium, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropyl Methylcellulose, hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, starch, hydroxyethyl starch, sodium starch glycolate, chitosan and derivatives thereof, albumin, gelatin or collagen. The method of claim 1 wherein the polymer carrier is polyvinyl acetate, methylcellulose, ethylcellulose, amorphous cellulose, polyacrylates and derivatives thereof, poly (alpha-hydroxy acids) and copolymers thereof, such as poly (caprolactone) ), Poly (lactide-co-glycolide), poly (alpha-amino acid) and copolymers thereof, poly (orthoesters), polyphosphazenes, poly (phosphoesters) or polyanhydrides. The method of claim 1, wherein the drug component is analgesic, anti-inflammatory, antiparasitic, antiarrhythmic, antibiotic, anticoagulant, antidepressant, antidiabetic, antiepileptic, antihistamine, antihypertensive, antimuscarinic, antimycobacterial, antitumor , Immunosuppressant, antithyroid, antiviral, anti-anxiety, astringent, beta-adrenergic receptor blocker, control medium, corticosteroid, cough suppressant, diuretic, dopamine agonist, hemostatic agent, immunological agent, lipid modulator, muscle relaxant, parasympathetic nerve A composition that is a stimulant, parathyroid, calcitonin, prostaglandin, radiopharmaceuticals, sex hormones, steroids, antiallergic agents, antihistamines, stimulants, sympathomimetic agents, thyroid agents, vasodilators, PDE IV inhibitors, or mixtures thereof. The composition of claim 13, wherein the drug component is an anti-inflammatory or PDE IV inhibitor. 15. The active ingredient according to claim 14, wherein the active ingredient is nabumethone, aspirin, cis-4-cyano-4- [3-cyclopentyloxyl) -4-methoxyphenyl] -cyclohexanecarboxylic acid or (S) -3- Hydroxy-2-phenyl-N- (1-phenylpropyl) -4-quinolinecarboxamide. The composition of claim 13 wherein the active ingredient is Ropirinole, Paroxetine or Kytil. The composition of claim 1 for the purpose of oral administration. The composition of claim 1 wherein the active ingredient exhibits improved bioavailability. The composition of claim 1 wherein the electrospun fibers are encapsulated or compressed into tablets. The composition according to claim 1, wherein the electrospun fibers are further ground. The composition of claim 1 which causes rapid dissolution of the fibers. A composition according to claim 1 which causes controlled release, sustained release or pulsatile release of the active ingredient. The composition of claim 1 which results in immediate release of the active ingredient. a) using a pharmaceutically acceptable solvent to form a solution of the active ingredient and a pharmaceutically acceptable polymer carrier, b) electrospinning the solution of step (a) with fibers, A method of making an electrospinning pharmaceutical composition containing a pharmaceutically acceptable active ingredient and a pharmaceutically acceptable polymer carrier. The method of claim 24, wherein the solvent is water miscible. The method of claim 24, wherein the solvent is water immiscible. The composition of claim 24, wherein the solution is a mixture of one or more solvents. 28. The method of claim 27, wherein the solvent is a mixture of water and a water miscible solvent. 25. The polymer carrier of claim 24 wherein the polymer carrier is poly (ethylene oxide), polyvinyl alcohol, polyvinyl pyrrolidone, hyaluronic acid, alginate, carrageenan, carboxymethylcellulose sodium, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropyl Methylcellulose, hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, starch, hydroxyethyl starch, sodium starch glycolate, chitosan and derivatives thereof, albumin, gelatin or collagen. The method of claim 24 wherein the polymer carrier is selected from polyvinyl acetate, methylcellulose, ethylcellulose, amorphous cellulose, polyacrylates and derivatives thereof, poly (alpha-hydroxy acids) and copolymers thereof, such as poly (caprolactone). ), Poly (lactide-co-glycolide), poly (alpha-amino acid) and copolymers thereof, poly (orthoesters), polyphosphazenes, poly (phosphoesters) or polyanhydrides. The drug composition according to claim 24, wherein the drug component is analgesic, anti-inflammatory, antiparasitic, antiarrhythmic, antibiotic, anticoagulant, antidepressant, antidiabetic, antiepileptic, antihistamine, antihypertensive, antimuscarinic, antimycobacterial, antitumor , Immunosuppressant, antithyroid, antiviral, anti-anxiety, astringent, beta-adrenergic receptor blocker, control medium, corticosteroid, cough suppressant, diuretic, dopamine agonist, hemostatic agent, immunological agent, lipid modulator, muscle relaxant, parasympathetic nerve Stimulant, parathyroid, calcitonin, prostaglandin, radiopharmaceuticals, sex hormones, steroids, antiallergic agents, antihistamines, stimulants, sympathomimetics, thyroids, vasodilators, PDE IV inhibitors, or mixtures thereof. The method of claim 24, wherein the active ingredient is an anti-inflammatory agent, a PDE IV inhibitor, nabumethone, aspirin, cis-4-cyano-4- [3-cyclopentyloxyl) -4-methoxyphenyl] -cyclohexanecarboxylic acid or (S) -3-hydroxy-2-phenyl-N- (1-phenylpropyl) -4-quinolinecarboxamide, Kytil, Zofran, Paroxetine, Ariflo ) Or Requip. Product produced by the method according to claim 24. a) melting the active ingredient and the polymer carrier, b) electrospinning the melt of step (a) with fibers, A method of making an electrospinning pharmaceutical composition containing a pharmaceutically acceptable active ingredient and a pharmaceutically acceptable polymer carrier. 35. The polymer carrier of claim 34, wherein the polymer carrier is poly (ethylene oxide), polyvinyl alcohol, polyvinyl pyrrolidone, hyaluronic acid, alginate, carrageenan, carboxymethylcellulose sodium, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropyl Methylcellulose, hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, starch, hydroxyethyl starch, sodium starch glycolate, chitosan and derivatives thereof, albumin, gelatin or collagen. The method of claim 34 wherein the polymer carrier is polyvinyl acetate, methylcellulose, ethylcellulose, amorphous cellulose, polyacrylate and derivatives thereof, poly (alpha-hydroxy acid) and copolymers thereof, such as poly (caprolactone). ), Poly (lactide-co-glycolide), poly (alpha-amino acid) and copolymers thereof, poly (orthoesters), polyphosphazenes, poly (phosphoesters) or polyanhydrides. 35. The method according to claim 34, wherein the drug component is analgesic, anti-inflammatory, antiparasitic, antiarrhythmic, antibiotic, anticoagulant, antidepressant, antidiabetic, antiepileptic, antihistamine, antihypertensive, antimuscarinic, antimycobacterial, antitumor , Immunosuppressant, antithyroid, antiviral, anti-anxiety, astringent, beta-adrenergic receptor blocker, control medium, corticosteroid, cough suppressant, diuretic, dopamine agonist, hemostatic agent, immunological agent, lipid modulator, muscle relaxant, parasympathetic nerve Stimulant, parathyroid, calcitonin, prostaglandin, radiopharmaceuticals, sex hormones, steroids, antiallergic agents, antihistamines, stimulants, sympathomimetics, thyroids, vasodilators, PDE IV inhibitors, or mixtures thereof. The method of claim 34, wherein the active ingredient is an anti-inflammatory agent, a PDE IV inhibitor, nabumethone, aspirin, cis-4-cyano-4- [3-cyclopentyloxyl) -4-methoxyphenyl] -cyclohexanecarboxylic acid or (S) -3-hydroxy-2-phenyl-N- (1-phenylpropyl) -4-quinolinecarboxamide, Kytil, Zofran, Paroxetine, Ariflo ) Or Requip. Product produced by the method according to claim 34. Use of a composition according to claim 1 for inhalation therapy. Use of the composition according to claim 1 for dispersion in aqueous solution. The composition of claim 1 wherein the active ingredient is uniformly dispersed with the carrier in the fiber.