Classifications

• • D—TEXTILES; PAPER
  • D01—NATURAL OR MAN-MADE THREADS OR FIBRES; SPINNING
  • D01D—MECHANICAL METHODS OR APPARATUS IN THE MANUFACTURE OF ARTIFICIAL FILAMENTS, THREADS, FIBRES, BRISTLES OR RIBBONS
  • D01D5/00—Formation of filaments, threads, or the like
  • D01D5/0007—Electro-spinning
  • D01D5/0015—Electro-spinning characterised by the initial state of the material
  • D01D5/003—Electro-spinning characterised by the initial state of the material the material being a polymer solution or dispersion
  • D01D5/0038—Electro-spinning characterised by the initial state of the material the material being a polymer solution or dispersion the fibre formed by solvent evaporation, i.e. dry electro-spinning
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  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
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  • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
  • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
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• • A—HUMAN NECESSITIES
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• • A—HUMAN NECESSITIES
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• • A—HUMAN NECESSITIES
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• • A—HUMAN NECESSITIES
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• • A—HUMAN NECESSITIES
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• • A—HUMAN NECESSITIES
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• • A—HUMAN NECESSITIES
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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• • A—HUMAN NECESSITIES
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• • A—HUMAN NECESSITIES
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• • A—HUMAN NECESSITIES
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• • A—HUMAN NECESSITIES
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• • A—HUMAN NECESSITIES
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• • A—HUMAN NECESSITIES
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• • A—HUMAN NECESSITIES
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• • D—TEXTILES; PAPER
  • D01—NATURAL OR MAN-MADE THREADS OR FIBRES; SPINNING
  • D01D—MECHANICAL METHODS OR APPARATUS IN THE MANUFACTURE OF ARTIFICIAL FILAMENTS, THREADS, FIBRES, BRISTLES OR RIBBONS
  • D01D5/00—Formation of filaments, threads, or the like
  • D01D5/0007—Electro-spinning
  • D01D5/0015—Electro-spinning characterised by the initial state of the material
  • D01D5/0023—Electro-spinning characterised by the initial state of the material the material being a polymer melt
• • D—TEXTILES; PAPER
  • D01—NATURAL OR MAN-MADE THREADS OR FIBRES; SPINNING
  • D01F—CHEMICAL FEATURES IN THE MANUFACTURE OF ARTIFICIAL FILAMENTS, THREADS, FIBRES, BRISTLES OR RIBBONS; APPARATUS SPECIALLY ADAPTED FOR THE MANUFACTURE OF CARBON FILAMENTS
  • D01F1/00—General methods for the manufacture of artificial filaments or the like
  • D01F1/02—Addition of substances to the spinning solution or to the melt
  • D01F1/10—Other agents for modifying properties

Definitions

• This invention relates to nanofibers of drug particles, method of preparation thereof and pharmaceutical compositions containing these nanofibers. This invention further relates to the use of such nanofibers in designing various dosage forms to achieve maximum bioavailability of a drug moiety.
• compositions include loading drugs into liposomes or polymers, e.g., during emulsion polymerization.
• a lipid soluble drug is often required in preparing suitable liposomes.
• unacceptably large amounts of the liposome or polymer are often required to prepare unit drug doses.
• techniques for preparing such pharmaceutical compositions tend to be complex.
• a principal technical difficulty encountered with emulsion polymerization is the removal of contaminants, such as unreacted monomer or initiator, which can be toxic, at the end of the manufacturing process.
• U.S. Pat. No. 4,540,602 discloses a solid drug pulverized in an aqueous solution of a water-soluble high molecular substance using a wet grinding machine.
• Motoyama et al. teach that as a result of such wet grinding, the drug is formed into finely divided particles ranging from 0.5 .mu.m (500 nm) or less to 5 .mu.m (5,000 nm) in diameter.
• US Patent No. 5,145,684 discloses dispersible crystalline drag substances having particle sizes lower than 400nm, for increased bioavailability, produced by wet milling.
• EPO 275,796 describes the production of colloidal dispersible systems comprising a substance in the form of spherical particles smaller than 500 nm.
• the method involves a precipitation effected by mixing a solution of the substance and a miscible non-solvent for the substance and results in the formation of non-crystalline nanoparticle.
• precipitation techniques for preparing particles tend to provide particles contaminated with solvents. Such solvents are often toxic and can be very difficult, if not impossible, to adequately remove to pharmaceutically acceptable levels to be practical.
• U.S. Pat. No. 4,107,288 describes particles in the size range from 10 to 1,000 nm containing a biologically or pharmacodynamically active material.
• the particles comprise a crosslinked matrix of macromolecules having the active material supported on or incorporated into the matrix.
• U.S. Pat. No. 4,855,326 describes a melt spinnable carrier agent such as sugar is combined with a medicament then converted into fiber form by melt spinning with "cotton candy" fabricating equipment. The as-spun product is converted to compacted individual dosage units.
• a binding agent is added to the carrier agent. Examples are presented for oral administration, topical application, systemic and non-systemic, intravenous and intra-muscular infusion via multicameral containers. All applications utilize the extraordinarily rapid entry into solution upon contact with a solvent.
• U.S. Pat. No. 5,948,430 discloses a polymeric film composition providing instant wetability followed by rapid dissolution/disintegration upon administration in the oral cavity. This may be applicable only to soluble drags.
• Pulmonary delivery both as immediate and modified release, dosage forms are being actively investigated.
• U.S. Pat. No. 5,747,001 discloses the advantages of aerosolized nanoparticles in pulmonary delivery.
• WO 99/48476 describes the use of drug/carrier particles having elongation ratio greater than 1.6 for improved delivery by inhalation. Such particles are either produced by SCF technique or by a complex precipitation process. Electrospinning provides a direct, scalable process for the production of nanoparticles having greater elongation ratios.
• US 5, 985,309 discloses large porous biodegradable microspheres containing proteins and peptides for pulmonary delivery.
• One object of the present invention is a process for electrospinning a pharmaceutically acceptable active agent, or agents, in the presence of a high molecular weight polymeric carrier that acts as viscosity enhancer and fiber forming agent.
• the process of making the electrospun pharmaceutical composition may be from a solution or a melt.
• the present invention is also directed to a pharmaceutical composition
• a pharmaceutical composition comprising an electrospun fiber of a pharmaceutically acceptable polymeric carrier integrated with a pharmaceutically acceptable active agent.
• the present invention is also directed to use of an electrospun pharmaceutical composition
• an electrospun pharmaceutical composition comprising a pharmaceutically acceptable active agent, and a pharmaceutically acceptable polymeric carrier directly for oral administration, pulmonary administration, or for dissolution into a liquid media for administration, such as a suspension or solution or by parenteral/intramuscular or intracavernosum injection.
• Figure 1 demonstrates electrospinning of viscous drug/polymer compositions either in solution or in melt form to produce nanofibers.
• Figure 2 shows the dissolution rate of nanofibers containing nabumetone normalized with respect to nanoparticles of nabumetone.
• Figure 3 shows a scanning electron microscope (SEM) of 60% w/w nabumetone spun with POLYOX® fibers.
• the present invention is directed to a novel composition of an electrospun fiber which fiber is the result of a high molecular weight polymeric carrier that acts as viscosity enhancer and fiber forming agent, and which carrier is spun with a pharmaceutically acceptable agent or drug.
• the term "integrated" means that the drag is integrated with, admixed with, comingled with, or intermixed with the carrier. It is not coated on the surface of an electrospun fiber (woven or non- woven). Specifically the fiber contains both the agent and the carrier together, preferably in a homogeneous manner. While it is recognized that incomplete stirring of the solutions or the neat/melted compositions may result in some heterogenicity of the resultant fiber, the premise is that the drag and the carrier are spun together, rather than being applied in a later step to a fiber.
• the electrospun fibers of the present invention are expected to have diameters in the nanometer range, and hence provide a very large surface area.
• the process generates fibers where a high surface to volume ratio is important. This extremely high surface area has profound influence on the bioavailability of a poorly water soluble drug, since it is known that increased surface can lead to increased dissolution rate.
• a suitable dosage form such as oral or parenteral form, including pulmonary administration, may be designed by judicious consideration of polymeric carriers, in terms of their physico-chemical properties as well as their regulatory status.
• Other pharmaceutically acceptable excipients may be included to ameliorate the stabilization or de-agglomeration of the drug nanoparticles.
• the pharmaceutical excipients might also have other attributes, such as absorption enhancers.
• Electrospun pharmaceutical dosage form may be designed to provide rapid dissolution, immediate, delayed, or modified dissolution, such as sustained and /or pulsatile release characteristics.
• taste masking of the active agent can also be achieved by using polymers having functional groups capable of promoting specific interactions with the drag moiety.
• the electrospun dosage forms may be presented as compressed tablets, sachets or films.
• Conventional dosage forms such as immediate, delayed and modified release systems can be designed by appropriate choice of the polymeric carrier, drug combination, as described in the art.
• Electrospinning is a process of producing fibers, with diameters in the range of lOOnm.
• the process consists of applying a high voltage to a polymer solution or melt to produce a polymer jet. As the jet travels in air, the jet is elongated under repulsive electrostatic force to produce nanofibers.
• the process has been described in the literature since the 1930.
• a variety of polymers both natural and synthetic having optimal characteristics have been elctrospun under appropriate conditions to produce nanofibers, (see Reneker et al., Nanotechnology, 1996, 7, 216). Different applications have been suggested for these electrospun nanofibers, such as air filters, molecular composites, vascular grafts, and wound dressings.
• U.S. Patent No. 4,043,331 is intended for use as a wound dressing whereas U.S. Patent No. 4,044,404, and US Patent No. 4,878,908 are tailored towards creating a blood compatible lining for a prosthetic device.
• All of the disclosed water insoluble polymers are not pharmaceutically acceptable for use herein, however the water soluble polymers disclosed are believed to be pharmaceutically acceptable. None of the preparations in these patents disclose a working example of an electrospun fiber with an active agent.
• the patents claim the use of enzymes, drags and/or active carbon on the surface of the nanofibers, prepared by immobilizing the active moieties so that they act at the site of application and "do not percolate throughout the body".
• EP 542514, US 5,311,884 and US 5,522,879 pertain to use of spun fibers for a piezoelectric biomedical device.
• the piezoelectric properties of fluorinated polymers such as those derived from a copolymer of vinylidene fluoride and tetrafluoroethylene are not considered pharmaceutically acceptable polymers for use herein.
• US Patent 5,024,671 uses the electrospun porous fibers as a vascular graft material which is filled with a drug in order to achieve a direct delivery of the drug to the suture site.
• the porous graft material is impregnated (not electrospun) with the drug and a biodegradable polymer is added to modulate the drag release.
• the vascular grafts are also made from non-pharmaceutically acceptable polymers, such as the polytetrafluorethylene or blends thereof.
• US Patent No. 5,376,116, US Patent No. 5,575,818, US Patent No. 5,632,772, US Patent No. 5,639,278 and US Patent No. 5,724,004 describe one form or another of a prosthetic device having a coating or lining of an electrospun non-pharmaceutically acceptable polymer.
• the electrospun outer layer is post-treated with a drug such as disclosed in the 16 patent (for breast prosthesis).
• the other patents describe the same technology and polymers but apply the technique to other applications, such as endoluminal grafts or endo vascular stents. Consequently, the present invention is the first to produce a pharmaceutical composition of an active agent(s) and a pharmaceutically acceptable polymer as an electrospun fiber.
• the homogenous nature of this process produces a quantity of fibers which allow for nanoparticles of drags to be dispersed throughout.
• the size of particle, and quality of dispersion provide for a high surface area of drug.
• One use of the increased surface area of drag is improved bioavailability in the case of a poorly water soluble drag.
• Other uses would be for decreased drug-drug or enzymatic interactions.
• the present invention is therefore directed to use in any form of a nanofibrous drag either alone, or in combination with a pharmaceutically acceptable polymer (or combination thereof) for enhancing the bioavailability of a drag, preferably a poorly water soluble drag.
• the present invention is also directed to a rapidly dissolving dosage form comprising an electrospun water soluble polymer in combination with an active agent, such that the rapid dissolving dosage form disintegrates in a rapid manner, over a short time period, in the mouth or other suitable body cavity. In the oral context this would produce small particulate matter, which could be ingested without needing water.
• a rapid dissolve dosage form may include a drug which is either water soluble or water insoluble.
• a rapid onset of action is a not prerequisite for a rapid dissolve dosage form.
• compositions, actives or drags as used herein is meant to include active agents having a pharmacological activity for use in a mammal, preferably a human.
• the pharmacological activity may be prophylactic or for treatment of a disease state.
• the usage is not meant to include agricultural or insecticide usage for application to plants or soil.
• Use of the electrospun fiber as a woven or non-woven fabric for direct application as a topical treatment in wound dressing or in clothing is also not an aspect of the present invention. However, use of the fibers in a pharmaceutical formulation for topical administration are considered within the scope of the present invention.
• Suitable drug substances can be selected from a variety of known classes of drags including, for example, analgesics, anti-inflammatory agents, anthelmintics, anti- arrhythmic agents, antibiotics (including penicillin's), anticoagulants, antidepressants, antidiabetic agents, antiepileptics, antihistamines, antihypertensive agents, antimuscarinic agents, antimycobactefial agents, antineoplastic agents, immunosuppressants, antithyroid agents, antiviral agents, anxiolytic sedatives (hypnotics and neuroleptics), astringents, beta-adrenoceptor blocking agents, blood products and substitutes, cardiac inotropic agents, corticosteroids, cough suppressants (expectorants and mucolytics), diagnostic agents, diuretics, dopaminergics (antiparkinsonian agents), haemostatics, immunological agents, lipid regulating agents, muscle relaxants, parasympathomimetics, parathyroid
• Preferred drug substances include those intended for oral administration and intravenous administration.
• a description of these classes of drugs and a listing of species within each class can be found in Martindale, The Extra Pharmacopoeia, Twenty-ninth Edition, The Pharmaceutical Press, London, 1989, the disclosure of which is hereby incorporated herein by reference in its entirety.
• the drag substances are commercially available and/or can be prepared by techniques known in the art.
• the electrospun composition may also be able to taste mask the many bitter or unpleasant tasting drags, regardless of their solubility.
• Suitable active ingredients for incorporation into fibers of the present invention include the many bitter or unpleasant tasting drags including but not limited to the histamine ⁇ -antagonists, such as, cimetidine, ranitidine, famotidine, nizatidine, etinidine; lupitidine, nifenidine, niperotidine, roxatidine, sulfotidine, tuvatidine and zaltidine; antibiotics, such as penicillin, ampicillin, amoxycillin, and erythromycin; acetaminophen; aspirin; caffeine, dextromethorphan, diphenhydramine, bromopheniramine, chloropheniramine, theophylline, spironolactone, NSAIDS's such as ibuprofen, ketoprofen, naprosyn, and nabumetone
• the above noted active agents in particular the anti-inflammatory agents, may also be combined with other active therapeutic agents, such as various steroids, decongestants, antihistamines, etc., as may be appropriate.
• active therapeutic agents such as various steroids, decongestants, antihistamines, etc., as may be appropriate.
• the active agent is nabumetone, cis-4-Cyano-4-[3-cyclopentyloxyl)-4- methoxyphenyljcyclohexanecarboxylic acid, ASA, paroxetine (Seroxat®), Ariflo, ropirinole (Requip®), rosiglitazone (Avandia®), or hydrochlorothyazie and traimeterene (Dyazide®).
• Suitable active agents are amprenavir (Agenerase®), lamivudine (Epivir ®), epoprostenol (Flolan®), zanamivir (Relenza®), alosetron (Lotronex®), alclometasone (Aclovate®), beclomethasone (Beclovent® and Beconase®), malphalan (Aleran®), naratriptan (Amerge ®), succinylcholine, cefuroxiime (Ceftin®), ceftazidime (Ceptaz®), cefuroxime (Zinacef®), zidovudine (Retro vir®), fluticasone (Flonase® or Cutivate®), pyrimethamine (Daraprim®), colfosceril, sumatriptan (Imitrex®), lamotrigine (Lamictal®), chlorambucil (Leukeran®), atovaquone (Malaron® or
• a poorly soluble drug should have good solubility in an organic solvent, or a poorly soluble drug must be useable in a melt process as further described below.
• the nanofibers of this invention will contain high molecular weight polymeric carriers. These polymers, by virtue of their high molecular weight, form viscous solutions which can produce nanofibers, when subjected to an electrostatic potential. Suitable polymeric carriers can be preferably selected from known pharmaceutical excipients. The physico-chemical characteristics of these polymers dictate the design of the dosage form, such as rapid dissolve, immediate release, delayed release, modified release such as sustained release, or controlled release, pulsatile release etc.
• DNA fibers have been used to form fibers by electrospinning, Fang et al., J. Macromol. Sci.-Phys., B36(2), 169-173 (1997).
• a pharmaceutically acceptable active agent such as a biological agent, a vaccine, or a peptide
• DNA, RNA or derivatives thereof as a spun fiber is also within the scope of this invention.
• molecular weight of the polymer is the single most important parameter for choice of polymer.
• polymers such as cellulose acetate, PNA, PEO, PVP, polyacrylamide, polyurethane, polycarbonate, PTFE, PE, PP, polyacrylate, Kevlar, PHB, polyaniline, D ⁇ A, poly (phenylene terphthalamide) and silk.
• polymers suitable for pharmaceutical applications include, but are not limited to, poly(ethylene oxide), polyvinyl alcohol, polyvinyl acetate, polyvinyl pyrrolidone, hyaluronic acid, alginates, carragenen, cellulose derivatives such as carboxymethyl cellulose sodium, methyl cellulose, ethylcellulose, hydroxyethyl cellulose, hydroxypropylcellulose, hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose phthalate, cellulose acetate phthalate, noncrystalline cellulose, starch and its derivatives such as hydroxyethyl starch, sodium starch glycolate, chitosan and its derivatives, albumen, gelatin, collagen, polyacrylates and its derivatives such as the Eudragit family of polymers available from Rohm Pharma, poly(alpha-hydroxy acids) and its copolymers such poly(caprolactone), poly(lactide-co-glycolide), poly(alpha-amino
• the polymeric carriers are divided into three categories: (l)water soluble polymers useful for rapid dissolve and immediate release of active agents, (2) water insoluble polymers useful for controlled release of the active agents; and (3) pH sensitive polymers for pulsatile or targeted release of active agents. It is recognized that combinations of both carriers may be used herein. It is also recognized that several of the polyacrylates are pH dependent for the solubility and may fall into both categories.
• Water soluble polymers include but are not limited to, poly(ethylene oxide), polyvinyl alcohol, polyvinyl pyrrolidone, hyaluronic acid, alginates, carragenen, cellulose derivatives such as carboxymethyl cellulose sodium, hydroxyethyl cellulose, hydroxypropylceUulose, hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose phthalate, cellulose acetate phthalate, starch and its derivatives such as hydroxyethyl starch, sodium starch glycolate, dextrin, chitosan and its derivatives, albumen, zein, gelatin, and collagen.
• a water soluble polymer for use herein is polyethylene oxide, such as the brand name POLYOX®. It is recognized that the polymers may be used in varying molecular weights, with combinations of molecular weights for one polymer being used, such as 100K, 200K, 300K, 400K, 900K and 2000K.
• Sentry POLYOX is a water soluble resin which is listed in the NF and have approximate molecular weights from 100K to 900K and 1000K to 7000K. These commercially available polymers may be used as 1%, 2% and 5% solutions (depending upon molecular weight).
• NF grades of Sentry POLYOX a water soluble resin is available with varying molecular weights as noted above.
• a table, shown below, provides further information on the grade vs. approx. molecular weight for use in the examples herein.
• Additional preferred polymers include povidone, having K values and molecular weight ranges from :
• Water insoluble polymers include but are not limited to, polyvinyl acetate, methyl cellulose, ethylcellulose, noncrystalline cellulose, polyacrylates and its derivatives such as the Eudragit family of polymers available from Rohm Pharma (Germany), poly(alpha-hydroxy acids) and its copolymers such as poly( ⁇ -caprolactone), poly(lactide-co-glycolide), poly(alpha-aminoacids) and its copolymers, poly(orthoesters), polyphosphazenes, poly(phosphoesters), and polyanhydrides.
• These pharmaceutically acceptable polymers and their derivatives are commercially available and/or be prepared by techniques known in the art. By derivatives it is meant, polymers of varying molecular weight, modification of functional groups of the polymers, or co-polymers of these agents, or mixtures thereof.
• two or more polymers can be used in combination to form the fibers as noted herein. Such combination may enhance fiber formation or achieve a desired drug release profile.
• the choice of polymers taken with the active agent may provide suitable taste masking functions for the active agents.
• an ionic polymer of contrasting charge such as a cationic polymer complexed with an anionic active agent, or an anionic polymer complexed with a cationic active agent may produce the desired results.
• Addition of a second taste masking agent, such as a suitable cyclodextrin, or its derivatives may also be used herein.
• the polymeric composition may be electrospun from a solvent base or neat (as a melt).
• Solvent choice is preferably based upon the solubility of the active agent.
• water is the best solvent for a water soluble active agent, and a water soluble polymer like POLYOX.
• a water soluble polymer like POLYOX.
• water and a water-miscible organic solvent may be used.
• plasticizers are employed to assist in the melting characteristics of the composition.
• plasticizers that may be employed in this invention are triethyl citrate, triacetin, tributyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, dibutyl phthalate, dibutyl sebacate, vinyl pyrrolidone, propylene glycol, glycol tiracetate, polyethylene glycol, or polyoxyethylene sorbitan monolaurate and combinations or mixtures thereof.
• the solvent of choice is a GRASS approved organic solvent, although the solvent may not necessarily be “pharmaceutically acceptable” one, as the resulting amounts may fall below detectable, or set limits for human consumption they may be used. It is suggested that ICH guidelines be used for selection. GRASS in an anacronym for "generally recognized as safe”.
• Suitable solvents for use herein include, but are not limited to acetic acid, acetone, acetonitrile, methanol, ethanol, propanol, ethyl acetate, propyl acetate, butyl acetate, butanol, N,N dimethyl acetamide, N,N dimethyl formamide, l-methyl-2- pyrrolidone, dimethyl sulfoxide, diethyl ether, disisopropyl ether, tetrahydrofuran, pentane, hexane, 2-methoxyethanol, formamide, formic acid, hexane, heptane, ethylene glycol, dioxane, 2-ethoxyethanol, trifluoroacetic acid, methyl isopropyl ketone, methyl ethyl ketone, dimethoxy propane, methylene chloride etc., or mixtures thereof.
• a preferred solvent is a mixture of water and acetonitrile, or water and acetone.
• the solvent to polymeric composition ratio is suitable determined by the desired viscosity of the resulting formulation.
• key parameters are viscosity, surface tension, and electrical conductivity of the solvent/polymeric composition.
• nanoparticulate drug as used herein, is meant, nanoparticule size of an active agent within the electrospun fiber.
• the polymeric carriers may also act as surface modifiers for the nanoparticulate drag.
• a second oligomeric surface modifier may also be added to the electrospinning solution. All of these surface modifiers may physically adsorb to the surface of the drug nanoparticles, so as to prevent them agglomerating.
• these second oligomeric surface modifier or excipients include but are not limited to: Pluronics ® (block copolymers of ethylene oxide and propylene oxide), lecithin, Aerosol OTTM (sodium dioctyl sulfosuccinate), sodium lauryl sulfate, polyoxyethylene sorbitan fatty acid esters, i.e., the polysorbates such as TweenTM, such as Tween 20, 60 & 80, the sorbitan fatty acid esters, i.e., sorbitan monolaurate, monooleate, monopalmitate, monosterate, etc.
• Pluronics ® block copolymers of ethylene oxide and propylene oxide
• Aerosol OTTM sodium dioctyl sulfosuccinate
• sodium lauryl sulfate sodium lauryl sulfate
• polyoxyethylene sorbitan fatty acid esters i.e., the polysorbates such as
• Surfactants are added on a weight/weight basis to the drag composition.
• the surfactants are added in amounts of about 10%, preferably about 5% or less. Surfactants can lower the viscosity and surface tension of the formulation, and in higher amounts can adversely effect the quality of the electrospun fibers.
• HLB HLB surfactant
• excipients may be added to the electrospinning composition. These excipients may be generally classified as absorption enhancers, additional surfactants, flavouring agents, dyes, etc.
• Suitable flavoring agents for use herein include, but are not limited to, wintergreen orange, grapefruit, and cherry-raspberry: While w/w% will vary for each composition, the flavouring agent should be present from about 0.25 to about 5% w/w of the total formulation.
• Suitable coloring agents, pigments, or dyes such as FD&C or D&C approved lakes and dyes, iron oxide and titanium dioxide may also be included in the formulations.
• the amount of pigment present may be from about 0.1% to about 2.0% by weight of the composition.
• the formulation may also contain sweeteners such as various natural sugars, aspartame, sodium cyclamate and sodium saccharinate; as well as the flavorants such as those noted above.
• sweeteners such as various natural sugars, aspartame, sodium cyclamate and sodium saccharinate
• flavorants such as those noted above.
• the polymeric carriers or the second oligomeric surface modifiers may themselves act as absorption enhancers, depending on the drag.
• Suitable absorption enhancers for use herein include but are not limited to, chitosan, lecithin, lectins, sucrose fatty acid esters such as the ones derived from stearic acid, oleic acid, palmitic acid, lauric acid, and Vitamin E-TPGS.
• the fibers may be ground, suitably by cryogenic means, for compression into a tablet or capsule, for use by inhalation, or parenteral administration.
• the fibers may also be dispersed into an aqueous solution which may then be directly administered by inhaled or given orally.
• the fibers may also be cut and processed as a sheet for further administration with agents to form a polymeric film, which may be quick-dissolving.
• Another aspect of the present invention is an alternative electrospinning process for making the pharmaceutical compositions described herein.
• the working examples herein electrostatically charge the solution whereas the pharmaceutical composition may also be ejected from a sprayer onto a receiving surface which is electrostatically charged and placed at an appropriate distance from the sprayer.
• the collectors can be either a metal screen, or in the form of a moving belt. : The fibers may be deposited on a moving belt which could be continuously removed and taken away for further processing as desired.
• nabumetone in a preferred embodiment of the invention for water insoluble agents, is the active nabumetone, electrospun in w/w% ranges from 0 to 82 %, with 200K, 400K; 900K and 2000K POLYOX, and Tween 80, SDS, Pluronic F68, or TPGS.
• a preferred solvent system is water/acetonitrile.
• a stock solution of 2.5% solution of POLYOX WSR N-60KTM (Union Carbide) was prepared in MilliQTM water by gentle mixing in a shaking water bath. 10 milliliters (hereinafter “rnL” or “ml”) of this POLYOX solution was added to a solution of 0.12 grams (hereinafter “g") Acetylsalicylic acid (Sigma) in 0.5 mL acetone. The contents were thoroughly mixed and ImL of acetone was added to obtain a clear solution. This solution was transferred to a 25mL glass vessel having a 0.03millimeter (hereinafter "mm”) capillary outlet at the bottom and two inlets, one for applying a positive Helium (He) pressure and the other for introducing the electrode.
• rnL 0.12 grams
• g Acetylsalicylic acid
• 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 dram covered with aluminum foil.
• the inlet Helium pressure was at 2.5psi and a voltage of +14.5KV was applied to the solution.
• the dry fibers were collected on a dram rotating a speed of 50-60 rpm. The fibers were peeled off the dram.
• a stock solution of 30% Polyethylene oxide (Molecular weight 400K, Aldrich) was prepared in MilliQTM water by gentle shaking. 5mL of this 30% solution was added to 0.5g nabumetone (SB Corporation) dissolved in 6ml of acetonitrile. The contents were gently stirred and another 5mL acetonitrile was added in small portions until a clear solution was obtained. 0.1ml of TweenTM 80 (Sigma) was added to the solution. This solution was electrospun using the same conditions described above in Example 1. Fibers were collected and removed from the dram.
• a stock solution of 7.5% (w/v) POLYOX® WSR N-3000 (Molecular weight of approx. 400K, Union Carbide) in MilliQTM water/acetonitrile was prepared by mixing 15g of PEO in 50ml water and 150mL acetonitrile.
• Example 3 To lOmL of the stock solution of water/acetonitrile from Example 3 above was added 0.8g nabumetone. The solution was homogenized by adding ImL acetonitrile along with 0.2mL TweenTM 80. The solution was spun using similar conditions to Example 1 above, but using a feed pressure of 2psi and 16KV to yield 1.2g of fibers.
• Example 3 To 5mL of the POLYOX ® N-30.00 solution from Example 3 was added 0.86g of nabumetone. The solution, was made homogeneous by adding 1.6mL of acetonitrile along with O.lmL TweenTM 80. The solution was spun using similar conditions to Example 1 above, but using a feed pressure of 0.5psi and 16KV to yield 0.93g of fibers. ⁇ .* .*. '
• a standard solution of nabumetone was prepared using accurately weighed sample of 20mg nabumetone in a lOOmL volumetric flask. The sample was made up using acetonitrile/water(80:20) as a diluent. 20uL of this solution was injected in Waters HPLC system equipped with Waters 550 pumps, 717plus autosampler, and
• Spectroflow 783 UV detector The data acquisition was carried out through a PE Nelson Box and Turbochrom (PE) software.
• the mobile phase consisted of acetonitrile/water/acetic acid in the volume ratio of 44/55/1.
• the flow rate was 1.4ml/min and the detection was done at 254nm.
• Residual solvent analysis was carried out at QTI (Whitehouse, NJ) using samples dissolved in DMSO (dimethyl sulfoxide) and quantitated by capillary Gas Chromatography. The results, shown in the Table below demonstrate that all the samples analyzed contained less lOOppm of acetonitrile.
• the equipment used for this procedure is a modified USP4, the major differences being: 1) low volume cell; 2)stirred cell; 3) retaining filters which are adequate at retaining sub micron material.
• the total run time is 20 minutes, with 2.5mg of drug (weigh proportionally more formulated material).
• Swinnex filter assemblies obtained from Millipore, having 0.2 micron Cellulose Nitrate membranes. (Millipore, MA) as internal filters. The internal volume of the cell is approximately 2 mL. A Small PTFE stirrer customized to fit the Swinnex assembly (Radleys Lab Equipment Halfround Spinvane F37136) is used. The dissolution medium is water at a flow rate of 5mL/min. The whole set up is placed at a thermostat of 37°C. The drag concentration is measured by passing the elutent through a UV detector having a flow cell dimension of 10mm. The UV detection is carried out at 284nm.
• the experimentation is designed to evaluate drag dissolution rate. As such it is unlikely with poorly soluble drags and with water as the dissolution medium that 100% of the drag will dissolve in the 20 minute duration of the test.
• To determine the extent of drug solubility over this period collect all 100ml of solution that elutes from the dissolution cell.
• Using a conventional UV spectrophotometer compare this solution against a reference solution of 2.5mg of active agent, for instance Nabumetone, dissolved in 50/50 mefhanol/water. (For Nabumetone this can be prepared by 10 fold dilution of a solution containing 25mg Nabumetone in lOOmls of 50/50 methanol/water).
• a suitable wavelength for comparison is 260nm.
• Example 12 Determination of thermal behavior of nabumetone containing nanofibers.
• nabumetone nanofibers Thermal studies on nabumetone nanofibers were performed on a MDSC TA (Wilmington, DE). The samples were heated from 0 to 120°C at 2°C/min at a modulation frequency of ⁇ 0.159°C every 30 seconds.
• the nanofibers containing nabumetone two distinct endotherms at 50°C and 75°C corresponding to the melting of POLYOX and nabumetone respectively, when the nabumetone content is above 30% (wt), below which only one melting endotherm is visible either due to the formation of a eutectic mixture or because the endotherms overlap.
• Ropirinole Two hundred milligrams of Ropirinole was dissolved in 15ml of milliQ water. To this solution was added lg of POLYOX ® WSR N3000 NF and 50mg of Tween 80. The mixture was left shaking in a water bath at 37 °C until all solid material dissolved to form a clear viscous solution. This solution was electrospun using a conditions similar to Example 1, at a feed pressure of 1 psi and 16 KV to yield 0.8g of the material.
• paroxetine was dissolved in 20ml of milliQ water. To this solution was added 800mg of POLYOX ® WSR N3000 NF and 50mg of Tween 80. The mixture was left shaking in a water bath at 37 °C until all solid material dissolved to form a clear viscous solution. This solution was electrospun using a conditions similar to Example 1,. at a feed pressure of 1 psi and 16 KV to yield 0.75g of the material. "
• Vitamin E-TPGS Eastman
• 200mg of the title compound dissolved' in 1ml of NMP was added to the polymer solution.
• the clear solution obtained was electrospun under identical conditions to Example 1, to yield

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