US20050048116A1 - Porous drug matrices and methods of manufacture thereof - Google Patents

Porous drug matrices and methods of manufacture thereof Download PDF

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US20050048116A1
US20050048116A1 US10/924,642 US92464204A US2005048116A1 US 20050048116 A1 US20050048116 A1 US 20050048116A1 US 92464204 A US92464204 A US 92464204A US 2005048116 A1 US2005048116 A1 US 2005048116A1
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drug
matrix
hydrochloride
solution
pore forming
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Julie Straub
David Altreuter
Howard Bernstein
Donald Chickering
Sarwat Khattak
Greg Randall
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Acusphere Inc
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Assigned to ACUSPHERE, INC. reassignment ACUSPHERE, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: KHATTAK, SARWAT, RANDALL, GREG, ALTREUTER, DAVID, BERNSTEIN, HOWARD, CHICKERING, III, DONALD E., STRAUB, JULIE
Publication of US20050048116A1 publication Critical patent/US20050048116A1/en
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Priority to US13/022,776 priority patent/US8821938B2/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1611—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A61K9/1688—Processes resulting in pure drug agglomerate optionally containing up to 5% of excipient
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • This invention generally relates to formulations of drugs, especially drugs having low solubility, and more particularly to methods of making formulations of such drugs to enhance their rate of dissolution, and optionally, to enhance their stability through the inclusion of hydrophobic or hydrophilic excipients that enhance dissolution rate, stabilize drug in crystalline form by inhibiting crystal growth or stabilize drug in amorphous form by preventing crystallization.
  • the bioavailability of a drug can be limited by poor dissolution of the drug into aqueous bodily fluids following administration. This rate-limiting step may therefore be critical to rapidly attaining therapeutically effective drug levels.
  • Traditional approaches to parenteral delivery of poorly soluble drugs include using large volumes of aqueous diluents, solubilizing agents, detergents, non-aqueous solvents, or non-physiological pH solutions. These formulations, however, can increase the systemic toxicity of the drug composition or damage body tissues at the site of administration.
  • Nanoparticles can be difficult to produce and maintain in a stable form due to the tendency of the nanoparticles to flocculate or agglomerate, particularly without the presence of surface modifying agents adsorbed or coated onto the particles.
  • milling or wet grinding techniques which are typically employed for nanonization, can be undesirable, as it can take several days to process a single batch, scaling-up of the milling or grinding process can be difficult and/or costly, the process can be difficult to conduct aseptically, and it is difficult to eliminate shedding of milling media into the product.
  • compositions enhancing the dissolution rate of drugs especially drugs having low aqueous solubility, and optionally, to enhance the stability of the drug through the inclusion of hydrophobic or hydrophilic excipients that stabilize the drug in crystalline form by inhibiting crystal growth or stabilize the drug in amorphous form by preventing crystallization, and to provide methods of making such compositions.
  • compositions providing enhanced rate of dissolution of drugs, especially drugs of low aqueous solubility, in a formulation suitable for administration by a variety of routes, including, but not limited to, parenteral, mucosal, oral, and topical administration, for local, regional, or systemic effect.
  • compositions for administration as a bolus injection instead of by infusion are provided.
  • Drugs are provided in a porous matrix form wherein the dissolution rate of the drug is enhanced when the matrix is contacted with an aqueous medium.
  • low aqueous solubility drugs are provided in a porous matrix form that forms microparticles when the matrix is contacted with an aqueous medium.
  • the porous matrix containing low aqueous solubility drugs yields microparticles having a mean diameter between about 0.1 and 5 ⁇ m and a total surface area greater than about 0.9 m 2 /mL.
  • the dry porous matrix is in a dry powder form having a TAP density less than or equal to 1.0 g/mL and/or having a total surface area (sum of internal and external surface area) of greater than or equal to 0.2 m 2 /g.
  • the porous matrices that contain the drug are preferably made using a process that includes (i) dissolving a drug in a volatile solvent to form a drug solution, (ii) combining at least one pore forming agent with the drug solution to form an emulsion, suspension, or second solution, and (iii) removing the volatile solvent and pore forming agent from the emulsion, suspension, or second solution to yield the dry porous matrix of drug.
  • the resulting porous matrix has a faster rate of dissolution following administration to a patient, as compared to non-porous matrix forms of the drug.
  • the pore forming agent can be either a volatile liquid that is immiscible with the drug solvent or a volatile solid compound, preferably a volatile salt. If the pore forming agent is a liquid, the agent is emulsified with the drug solution. If the pore forming agent is a solid, the agent is (i) dissolved in the drug solution, (ii) dissolved in a solvent that is not miscible in the drug solvent and then emulsified with the drug solution, or (iii) suspended as solid particulates in the drug solution.
  • hydrophilic or hydrophobic excipients may be added to the drug solvent, the pore forming agent solvent, or both.
  • at least one excipient incorporated into the emulsion, suspension, or second solution is a hydrophobic and hydrophilic excipient which enhances dissolution rate, which stabilizes drug in amorphous form by preventing crystallization, or which stabilizes drug in crystalline form by inhibiting crystal growth.
  • the matrix further includes a pegylated excipient, such as pegylated phospholipid, with the drug.
  • the pegylated excipient shields the drug from macrophage uptake, which prolong its half-life or enhance bioavailability of the drug.
  • the solution, emulsion, or suspension of the pore forming agent in the drug solution is then processed to remove the drug solvent and the pore forming agent, as well as any pore forming agent solvent.
  • spray drying optionally followed by lyophilization, fluid bed drying, or vacuum drying, is used to remove the solvents and the pore forming agent.
  • Sugars, amino acids, or polymers can all stabilize the drug forming the porous drug matrix, depending on the molecule to be stabilized.
  • formulations can be administered as a bolus, when the drug normally must be infused to avoid precipitation of the drug. By avoiding precipitation of drug in vivo, the formulations can also be administered parenterally. An additional advantage is the formulations can be administered in reduced volumes.
  • the porous drug matrix is reconstituted with an aqueous medium and administered parenterally, such as intramuscularly, subcutaneously, or intravenously.
  • the porous drug matrix can be further processed using standard techniques into tablets or capsules for oral administration or into rectal suppositories, delivered using a dry powder inhaler for pulmonary administration, or mixed/processed into a cream or ointment for topical administration.
  • FIG. 1 is a graph of the in vitro dissolution rate (percent dissolved versus time) for non-formulated prednisone and prednisone in porous matrix form.
  • FIG. 2 is a graph of the in vitro dissolution rate (percent dissolved versus time) for non-formulated griseofulvin and griseofulvin in porous matrix form.
  • FIG. 3 is a graph of the in vitro dissolution rate (percent dissolved versus time) for non-formulated nifedipine and nifedipine in porous matrix form.
  • FIG. 4 is a graph of the in vitro dissolution rate (percent dissolved versus time) for non-formulated naproxen and naproxen in a porous matrix form.
  • FIG. 5 is a graph of the in vitro dissolution rate (percent dissolved versus time) for non-formulated paclitaxel and paclitaxel in a porous matrix form.
  • FIG. 6 is a graph of the in vitro dissolution rate (percent dissolved versus time) for various porous matrix forms of nifedipine.
  • FIG. 7 is a graph of the in vitro dissolution rate (percent dissolved versus time) for various porous matrix forms of griseofulvin.
  • FIG. 8 is a graph of nifedipine plasma levels versus time post intravenous administration of reconstituted nifedipine matrix in dogs.
  • the rate of dissolution of drugs can be enhanced by making the drug into a porous matrix form, substantially increasing the surface area of the drug available to contact aqueous biological fluids at the site of administration of the drug composition.
  • the drug has low aqueous solubility, as commonly defined by those skilled in the art.
  • the porous drug matrix is at least 1 to 95%, preferably at least about 10%, and more preferably between about 10 and 60%, drug by weight.
  • the matrices also may contain hydrophilic or hydrophobic excipients such as water-soluble polymers, amino acids or sugars, wetting agents such as surfactants, and tonicity agents.
  • the form of the drug matrix (dry powder) is critical to the dissolution rate.
  • the matrix must contain microparticles of drug, which preferably have a diameter between about 100 nm and 5 ⁇ m, more preferably between about 500 nm and 5 ⁇ m.
  • the average total surface area of the drug microparticles contained within the porous matrix is 0.9 m 2 /mL of microparticles or greater. Total surface area values can be determined using standard Coulter Counter equipment and techniques.
  • the drug matrix must be sufficiently porous to yield microparticles having these parameters. Measurements useful in characterizing the porosity of the drug matrix are the bulk density or the transaxial pressure (“TAP”) density of the dry porous matrix (dry powder) and the total surface area (sum of internal and external surface area) of the dry porous matrix .
  • TAP density preferably is less than about 1.0 g/ml, more preferably less than 0.8 g/ml. This level of porosity of the matrix, characterized by density, provides sufficient surface area to enhance wetting of the dry porous matrix and enhance the rate of drug dissolution.
  • the total surface area of the porous matrix can be measured, for example, by BET surface area analysis.
  • the total surface area of the porous matrix preferably is greater than 0.1 m 2 /g, more preferably greater than or equal to 0.2 m 2 /g. This level of total surface area provides sufficient surface area to enhance wetting of the dry porous matrix and enhance the rate of drug dissolution.
  • the drug is a low aqueous solubility drug.
  • low aqueous solubility means that the drug has a solubility of less than about 10 mg/mL, and preferably less than about 5 mg/mL, in aqueous media at approximately physiological temperatures and pH.
  • drug refers to chemical or biological molecules providing a therapeutic, diagnostic, or prophylactic effect in vivo.
  • Drugs contemplated for use in the compositions described herein include the following categories and examples of drugs and alternative forms of these drugs such as alternative salt forms, free acid forms, free base forms, and hydrates:
  • drugs useful in the compositions and methods described herein include ceftriaxone, ketoconazole, ceftazidime, oxaprozin, albuterol, valacyclovir, urofollitropin, famciclovir, flutamide, enalapril, mefformin, itraconazole, buspirone, gabapentin, fosinopril, tramadol, acarbose, lorazepan, follitropin, glipizide, omeprazole, fluoxetine, lisinopril, tramsdol, levofloxacin, zafirlukast, interferon, growth hormone, interleukin, erythropoietin, granulocyte stimulating factor, nizatidine, bupropion, perindopril, erbumine, adenosine, alendronate, alprostadil, benazepril, betaxo
  • Preferred drugs include albuterol, adapalene, doxazosin mesylate, mometasone furoate, ursodiol, amphotericin, enalapril maleate, felodipine, nefazodone hydrochloride, valrubicin, albendazole, conjugated estrogens, medroxyprogesterone acetate, nicardipine hydrochloride, zolpidem tartrate, amlodipine besylate, ethinyl estradiol, omeprazole, rubitecan, amlodipine besylate/benazepril hydrochloride, etodolac, paroxetine hydrochloride, paclitaxel, atovaquone, felodipine, podofilox, paricalcitol, betamethasone dipropionate, fentanyl, pramipexole dihydrochloride, Vitamin D 3 and related analogue
  • the matrices may contain hydrophilic or hydrophobic excipients such as polymers, including water soluble polymers, amino acids or sugars which can serve as bulking agents or as wetting agents, wetting agents such as surfactants, amino acids or sugars, preservatives and tonicity agents.
  • the polymers, amino acids sugars, or preservatives may improve the storage stability of the matrices by stabilizing the drug in a crystalline form by inhibiting crystal growth or by preventing crystallization of the drug when the drug is present in an amorphous state. Upon contact with an aqueous medium, water penetrates through the highly porous matrix to dissolve the water-soluble excipients in the matrix.
  • excipients for use in the drug matrix compositions, considering a variety of factors, such as the drug to be administered, the route of administration, the dosage, and the preferred dissolution rate.
  • the excipients can function as bulking agents, release-modifiers, wetting agents, tonicity agents, or combinations thereof.
  • Preferred excipients include water soluble polymers, amino acids, wetting agents, and sugars.
  • hydrophilic or hydrophobic excipients, wetting agents, and tonicity agents may be added to the drug solution, the pore forming agent, or both, during production of the matrix.
  • the polymers that can be used in the drug matrices described herein include both synthetic and natural polymers, either non-biodegradable or biodegradable and either water soluble or water insoluble.
  • Representative synthetic polymers include polyethylene glycol (“PEG”), polyvinyl pyrrolidone, polymethacrylates, polylysine, poloxamers, polyvinyl alcohol, polyacrylic acid, polyethylene oxide, and polyethyoxazoline.
  • Representative natural polymers include albumin, alginate, gelatin, acacia, chitosan, cellulose dextran, ficoll, starch, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxy-propylmethyl cellulose, hyaluronic acid, carboxyethyl cellulose, carboxymethyl cellulose, deacetylated chitosan, dextran sulfate, and derivatives thereof.
  • Preferred polymers include PEG, polyvinyl pyrrolidone, poloxamers, hydroxypropyl cellulose, and hydroxyethyl cellulose.
  • the polymer selected for use in a particular drug matrix formulation is based on a variety of factors, such as the polymer molecular weight, polymer hydrophilicity, and polymer inherent viscosity.
  • the polymer can be used as a bulking agent, as an anti-crystallization agent for drugs in an amorphous state, as a crystal growth inhibitor for drugs in a crystalline state or as a wetting agent.
  • the amount of polymer in the drug matrix is less than about 95%, more preferably less than about 80%, by weight of the drug matrix when used as a bulking agent.
  • the amount of polymer in the drug matrix is less than about 50%, more preferably less than about 40%, by weight of the drug matrix when used as an anti-crystallization agent for drugs in an amorphous state or as a crystal growth inhibitor for drugs in a crystalline state.
  • the amount of polymer in the drug matrix is less than about 30%, more preferably less than about 20%, by weight of the drug matrix when used a wetting agent.
  • sugars that can be used in the drug matrices include mannitol, sorbitol, xylitol, glucitol, ducitol, inositiol, arabinitol, arabitol, galactitol, iditol, allitol, fructose, sorbose, glucose, xylose, trehalose, allose, dextrose, altrose, gulose, idose, galactose, talose, ribose, arabinose, xylose, lyxose, sucrose, maltose, lactose, lactulose, fucose, rhamnose, melezitose, maltotriose, and raffinose.
  • Preferred sugars include mannitol, lactose, sucrose, sorbitol, trehalose, glucose, and are adjusted to provide osmolality if administered parenterally.
  • the sugarscan serve as a bulking agent or as an anti-crystallization agent for drugs in the amorphous state, or as a crystal growth inhibitor for drugs in the crystalline state or to provide wetting of the porous drug matrix or the drug microparticles within the matrix.
  • the amount of sugar in the drug matrix is less than about 95%, more preferably less than about 80%, by weight of the drug matrix when used as a bulking agent.
  • the amount of sugar in the drug matrix is less than about 50%, more preferably less than about 40%, by weight of the drug matrix when used as an anti-crystallization agent for drugs in an amorphous state or as a crystal growth inhibitor for drugs in a crystalline state.
  • the amount of sugar in the drug matrix is less than about 30%, more preferably less than about 20%, by weight of the drug matrix when used a wetting agent.
  • amino acids that can be used in the drug matrices include both naturally occurring and non-naturally occurring amino acids.
  • the amino acids can be hydrophobic or hydrophilic and may be D amino acids, L amino acids or racemic mixtures.
  • Amino acids which can be used include, but are not limited to: glycine, arginine, histidine, threonine, asparagine, aspartic acid, serine, glutamate, proline, cysteine, methionine, valine, leucine, isoleucine, tryptophan, phenylalanine, tyrosine, lysine, alanine, glutamine.
  • the amino acid can be used as a bulking agent, or as an anti-crystallization agent for drugs in the amorphous state, or as a crystal growth inhibitor for drugs in the crystalline state or as a wetting agent.
  • Hydrophobic amino acids such as leucine, isoleucine, alanine, glucine, valine, proline, cysteine, methionine, phenylalanine, tryptophan are more likely to be effective as anticrystallization agents or crystal growth inhibitors.
  • amino acids can serve to make the matrix have a pH dependency that can be used to influence the pharmaceutical properties of the matrix such as solubility, rate of dissolution or wetting.
  • the amount of amino acid in the drug matrix is less than about 95%, more preferably less than about 80%, by weight of the drug matrix when used as a buiking agent.
  • the amount of amino acid in the drug matrix is less than about 50%, more preferably less than about 40%, by weight of the drug matrix when used as an anti-crystallization agent for drugs in an amorphous state or as a crystal growth inhibitor for drugs in a crystalline state.
  • the amount of amino acid in the drug matrix is less than about 30%, more preferably less than about 20%, by weight of the drug matrix when used a wetting agent.
  • Preservatives such as parabens or benzoic acids can be used directly for inhibition of microbial growth.
  • Preferred parabens include methyl paraben, ethyl paraben and butyl paraben.
  • the preservatives can be used to interact with the drug to inhibit crystal formation or growth.
  • the amount of preservative in the drug matrix is less than about 50%, more preferably less than about 40%, by weight of the drug matrix when used as an anti-crystallization agent for drugs in an amorphous state or as a crystal growth inhibitor for drugs in a crystalline state.
  • Wetting agents can be used to facilitate water ingress into the matrix and wetting of the drug particles in order to facilitate dissolution.
  • wetting agents include gelatin, casein, lecithin (phosphatides), gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers (e.g., macrogol ethers such as cetomacrogol 1000), polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters (e.g., TWEENTMs), polyethylene glycols, polyoxyethylene stearates, colloidal silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxy propylcellulose, hydroxypropylmethylcellulose phthlate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol,
  • Tyloxapol a nonionic liquid polymer of the alkyl aryl polyether alcohol type, also known as superinone or triton
  • Most of these wetting agents are known pharmaceutical excipients and are described in detail in the Handbook of Pharmaceutical Excipients, published jointly by the American Pharmaceutical Association and The Pharmaceutical Society of Great Britain (The Pharmaceutical Press, 1986).
  • Preferred wetting agents include polyvinylpyrrolidone, polyethylene glycol, tyloxapol, poloxamers such as PLURONICTM F68, F127, and F108, which are block copolymers of ethylene oxide and propylene oxide, and polyxamines such as TETRONICTM 908 (also known as POLOXAMINETM 908), which is a tetrafunctional block copolymer derived from sequential addition of propylene oxide and ethylene oxide to ethylenediamine (available from BASF), dextran, lecithin, dialkylesters of sodium sulfosuccinic acid such as AEROSOLTM OT, which is a dioctyl ester of sodium sulfosuccinic acid (available from American Cyanimid), DUPONOLTM P, which is a sodium lauryl sulfate (available from DuPont), TRITONTM X-200, which is an alkyl aryl polyether sulfonate (
  • Wetting agents which have been found to be particularly useful include Tetronic 908, the Tweens, Pluronic F-68 and polyvinylpyrrolidone.
  • Other useful wetting agents include decanoyl-N-methylglucamide; n-decyl- ⁇ -D-glucopyranoside; n-decyl- ⁇ -D-maltopyranoside; n-dodecyl- ⁇ -D-glucopyranoside; n-dodecyl ⁇ -D-maltoside; heptanoyl-N-methylglucamide; n-heptyl- ⁇ -D-glucopyranoside; n-heptyl- ⁇ -D-thioglucoside; n-hexyl- ⁇ D-glucopyranoside; nonanoyl-N-methylglucamide; n-noyl- ⁇ -D-glucopyranoside; octanoyl-N-methylglucamide; n-
  • Another preferred wetting agent is p-isononylphenoxypoly(glycidol), also known as Olin-10G or Surfactant 10-G (commercially available as 10G from Olin Chemicals). Two or more wetting agents can be used in combination.
  • the amount of wetting agent in the drug matrix is less than about 30%, more preferably less than about 20%, by weight of the drug matrix.
  • the porous drug matrices may include one or more tonicity agents, such as salts (e.g., as sodium chloride or potassium chloride) or sugars (such as mannitol, dextrose, sucrose, or trehalose) to adjust a hypotonic solution of a drug to isotonic so that the drug, when in solution, is physiologically compatible with the cells of the body tissue of the patient.
  • tonicity agents such as salts (e.g., as sodium chloride or potassium chloride) or sugars (such as mannitol, dextrose, sucrose, or trehalose) to adjust a hypotonic solution of a drug to isotonic so that the drug, when in solution, is physiologically compatible with the cells of the body tissue of the patient.
  • tonicity agents such as salts (e.g., as sodium chloride or potassium chloride) or sugars (such as mannitol, dextrose, sucrose, or trehalose) to adjust a hypotonic
  • the matrix further includes a pegylated excipient.
  • pegylated excipients include, but are not limited to, pegylated phospholipids, pegylated proteins, pegylated peptides, pegylated sugars, pegylated polysaccharides, pegylated block-co-polymers with one of the blocks being PEG, and pegylated hydrophobic compounds such as pegylated cholesterol.
  • the pegylated excipient beneficially envelops or shields the drug from macrophage uptake, which prolongs its half-life or enhances bioavailability of the drug.
  • pegylated phospholipids include 1,2-diacyl-sn-glycero-3-phosphoethanolamine-N-[Poly(ethylene glycol) 2000] (“PEG 2000 PE”) and 1,2-diacyl-sn-glycero-3-phosphoethanolamine-N-[Poly(ethylene glycol) 5000] (“PEG 5000 PE”), where the acyl group is selected, for example, from dimyristoyl, dipalmitoyl, distearoyl, diolcoyl, and 1-palmitoyl-2-oleoyl.
  • polyalkyleneoxides can be used in the place of the polyethylene glycol moiety.
  • the solvent is an organic solvent that is volatile, has a relatively low boiling point, or can be removed under vacuum, and which is acceptable for administration to humans in trace amounts.
  • Representative solvents include acetic acid, acetaldehyde dimethyl acetal, acetone, acetonitrile, chloroform, chlorofluorocarbons, dichloromethane, dipropyl ether, diisopropyl ether, N,N-dimethlyformamide (DMF), foramide, demethyl sulfoxide (DMSO), dioxane, ethanol, ethyl acetate, ethyl formate, ethyl vinyl ether, methyl ethyl ketone (MEK), glycerol, heptane, hexane, isopropanol, methanol, isopropanol, butanol, triethylamine, nitromethane, octan
  • aqueous solvents or mixtures of aqueous and organic solvents such as water-alcohol mixtures, can be used to dissolve the drug.
  • Pore forming agents are volatile materials that are used during the process to create porosity in the resultant matrix.
  • the pore forming agent can be a volatilizable solid or volatilizable liquid.
  • the liquid pore forming agent must be immiscible with the drug solvent and volatilizable under processing conditions compatible with the drug.
  • the pore forming agent first is emulsified with the drug solvent. Then, the emulsion is further processed to remove the drug solvent and the pore forming agent simultaneously or sequentially using evaporation, vacuum drying, spray drying, fluid bed drying, lyophilization, or a combination of these techniques.
  • liquid pore forming agents include water; dichloromethane; alcohols such as ethanol, methanol, or isopropanol; acetone; ethyl acetate; ethyl formate; dimethylsulfoxide; acetonitrile; toluene; xylene; dimethylforamide; ethers such as THF, diethyl ether, or dioxane; triethylamine; foramide; acetic acid; methyl ethyl ketone; pyridine; hexane; pentane; furan; water; and cyclohexane.
  • the liquid pore forming agent is used in an amount that is between 1 and 50% (v/v), preferably between 5 and 25% (v/v), of the drug solvent emulsion.
  • the solid pore forming agent must be volatilizable under processing conditions which do not harm the drug compositions.
  • the solid pore forming agent can be (i) dissolved in the drug solution, (ii) dissolved in a solvent which is not miscible with the drug solvent to form a solution which is then emulsified with the drug solution, or (iii) added as solid particulates to the drug solution.
  • the solution, emulsion, or suspension of the pore forming agent in the drug solution then is further processed to remove the drug solvent, the pore forming agent, and, if appropriate, the solvent for the pore forming agent simultaneously or sequentially using evaporation, spray drying, fluid bed drying, lyophilization, vacuum drying, or a combination of these techniques.
  • the solid pore forming agent is a volatile salt, such as salts of volatile bases combined with volatile acids.
  • Volatile salts are materials that can transform from a solid or liquid to a gaseous state using added heat and/or vacuum.
  • volatile bases include ammonia, methylamine, ethylamine, dimethylamine, diethylamine, methylethylamine, trimethylamine, triethylamine, and pyridine.
  • volatile acids include carbonic acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, formic acid, acetic acid, propionic acid, butyric acid, and benzoic acid.
  • Preferred volatile salts include ammonium bicarbonate, ammonium acetate, ammonium chloride, ammonium benzoate and mixtures thereof.
  • solid pore forming agents include iodine, phenol, benzoic acid (as acid not as salt), and naphthalene.
  • the solid pore forming agent is used in an amount between 5 and 1000% (w/w), preferably between 10 and 600% (w/w), and more preferably between 10 and 200% (w/w), of the drug.
  • the porous drug matrices preferably are made by (i) dissolving a drug, preferably one having low aqueous solubility, in a volatile solvent to form a drug solution, (ii) combining at least one pore forming agent with the drug solution to form an emulsion, suspension, or second solution, and (iii) removing the volatile solvent and pore forming agent from the emulsion, suspension, or second solution.
  • spray drying optionally followed by lyophilization or vacuum drying, is used to remove the solvents and the pore forming agent.
  • the removal of the pore forming agent can be conducted simultaneously with or following removal of enough solvent to solidify the droplets. Production can be carried out using continuous, batch, or semi-continuous processes.
  • the selected drug is dissolved in an appropriate solvent.
  • the concentration of the drug in the resulting drug solution typically is between about 0.01 and 80% (w/v), preferably between about 0.025 and 30% (w/v).
  • the drug solution is combined, typically under mixing conditions, with the pore forming agent or solution thereof. If a liquid pore forming agent is used, it is first emulsified with the drug solution to form droplets of pore forming agent dispersed throughout the drug solution. If a solid pore forming agent is used, it is dissolved either directly in the drug solution to form a solution of drug/pore forming agent, or it is first dissolved in a second solvent which is immiscible with the drug solvent to form a solution which subsequently is emulsified with the drug solution to form droplets of the pore forming agent solution dispersed throughout the drug solution.
  • a solid pore forming agent alternatively can be added directly to the drug solution as solid particulates, preferably between about 100 nm and 10 ⁇ m in size, to form a suspension of pore forming agent in the drug solution. Subsequently, the solid pore forming agent particle size can be reduced by further processing the resulting suspension, for example, using homogenization or sonication techniques known in the art. In the preferred embodiment, excipient(s) are added to the emulsion, suspension or second solution before, with or after the pore-forming agent.
  • the solution, emulsion, or suspension is further processed to remove the drug solvent and the pore forming agent simultaneously or sequentially, using evaporation, spray drying, fluid bed drying, lyophilization, vacuum drying, or a combination of these techniques.
  • the solution, emulsion, or suspension is spray-dried.
  • spray dry means to atomize the solution, emulsion, or suspension to form a fine mist of droplets (of drug solution having solid or liquid pore forming agent dispersed throughout), which immediately enter a drying chamber (e.g., a vessel, tank, tubing, or coil) where they contact a drying gas.
  • the solvent and pore forming agents evaporate from the droplets into the drying gas to solidify the droplets, simultaneously forming pores throughout the solid.
  • the solid typically in a powder, particulate form) then is separated from the drying gas and collected.
  • the temperature of the inlet and outlet ports of the drying chamber, as well as the flow rates of the feed solution, atomization gas, and drying gas, can be controlled to produce the desired products.
  • the spray drying methods described in U.S. Pat. No. 5,853,698 to Straub et al., which is hereby incorporated by reference, are adapted to make the drug matrices described herein.
  • the drug present in the solids or powder produced may be in a crystalline or an amorphous state, or may be mixture of such states.
  • the state generally depends on how the droplets are dried and the excipients present.
  • a surfactant or emulsifying agent can be added to enhance the stability of the emulsion.
  • a variety of surfactants may be incorporated in this process, preferably to an amount between 0.1 and 5% by weight.
  • Exemplary emulsifiers or surfactants which may be used include most physiologically acceptable emulsifiers, for instance egg lecithin or soya bean lecithin, or synthetic lecithins such as saturated synthetic lecithins, for example, dimyristoyl phosphatidyl choline, dipalmitoyl phosphatidyl choline or distearoyl phosphatidyl choline or unsaturated synthetic lecithins, such as dioleyl phosphatidyl choline or dilinoleyl phosphatidyl choline.
  • Other hydrophobic or amphipathic compounds can be used in place of the phospholipid, for example, cholesterol.
  • Emulsifiers also include surfactants such as free fatty acids, esters of fatty acids with polyoxyalkylene compounds like polyoxpropylene glycol and polyoxyethylene glycol; ethers of fatty alcohols with polyoxyalkylene glycols; esters of fatty acids with polyoxyalkylated sorbitan; soaps; glycerol-polyalkylene stearate; glycerol-polyoxyethylene ricinoleate; homo- and co-polymers of polyalkylene glycols; polyethoxylated soya-oil and castor oil as well as hydrogenated derivatives; ethers and esters of sucrose or other carbohydrates with fatty acids, fatty alcohols, these being optionally polyoxyalkylated; mono-, di- and tri-glycerides of saturated or unsaturated fatty acids, glycerides of soya-oil and sucrose.
  • surfactants such as free fatty acids, esters of fatty acids with polyoxyalkylene
  • emulsifiers include natural and synthetic forms of bile salts or bile acids, both conjugated with amino acids and unconjugated such as taurodeoxycholate and cholic acid.
  • porous drug matrices described herein are useful in formulations for administration to a patient in need of the drug.
  • patient refers to animals, including mammals, preferably humans.
  • the formulations deliver a therapeutically or prophylactically effective amount of the drug to the patient.
  • the porous matrices, or formulations thereof, are suitable for administration of drug by a variety of routes, for example, parenteral, mucosal, oral, topical/transdermal administration, for local, regional, or systemic effect.
  • parenteral routes include intraveneous, intraarterial, intracardiac, intrathecal, intraosseous, intraarticular, intrasynovial, intracutaneous, subcutaneous, and intramuscular administration.
  • mucosal routes include pulmonary (intrarespiratory), buccal, sublingual, intranasal, rectal, and vaginal administration.
  • the porous matrices also can be formulated for intraocular, conjunctival, aural, urethral, intracranial, intralesional, and intratumoral administration.
  • the drug matrix is in the form of powder, which can be reconstituted with an aqueous medium, such as physiological saline, and administered parenterally, such as intramuscularly, subcutaneously, or intravenously.
  • aqueous medium such as physiological saline
  • parenterally such as intramuscularly, subcutaneously, or intravenously.
  • the matrix can be further processed using standard techniques into tablets or capsules for oral administration, into rectal suppositories, into a dry powder inhaler for pulmonary administration, or mixed/processed into a cream or ointment for topical administration.
  • standard techniques are described, for example, in Ansel, et al., “ Pharmaceutical Dosage Forms and Drug Delivery Systems,” 6th Ed., (Williams & Wilkins 1995), which is incorporated herein by reference.
  • Examples 1-10 demonstrate production of porous drug matrices using different pore forming agents, different drugs, and different solvents. Examples 1-8 use emulsion formulations to produce the matrices, whereas Examples 9 and 10 use solution formulations to produce the matrices.
  • Examples 11-13 describe the analyses which were used to characterize the porous drug matrices produced in Examples 1-10. These characteristics include density, drug integrity, and dissolution properties.
  • Example 14 describes particle size analysis and surface area analysis of low water solubility drug particles incorporated into the porous drug matrices.
  • Examples 15-17 describe experiments demonstrating the increased internal surface area of porous drug matrices produced with pore forming agents.
  • Examples 18-21 describe experiments demonstrating the advantage or need to include a wetting agent as a component of the porous drug matrices.
  • Example 22 describes an experiment demonstrating the administration of porous drug matrices as an intravenous bolus.
  • Examples 23 and 24 describe the production of porous drug matrices produced with pore forming agents and pegylated phospholipids.
  • PEG 3350, PEG 8000, polyvinylpyrrolidone K-15, nifedipine, naproxen, prednisone, SPANTM 40, lecithin, TWEENTM 80, PLURONICTM F127, ammonium chloride, ammonium bicarbonate, and ammonium acetate were obtained from Spectrum Chemicals (Gardena, Calif.). Griseofulvin was obtained from Aldrich Chemicals (Milwaukee, Wis.). Paclitaxel was obtained from Hauser (Boulder, Colo.).
  • 1,2-Dimyristoyl-sn-Glycero-3-Phosphoethanolamine-N-[Poly(ethylene glycol)-5000] (PEG 5000 PE) and 1,2-Dimyristoyl-sn-Glycero-3-Phosphoethanolamine-N-[Poly(ethylene glycol)-2000] (PEG 2000 PE) were obtained from Avanti Polar Lipids Inc. (Alabaster, Ala.). Methylene chloride was obtained from EM Science (Gibbstown, N.J.). All emulsions were produced using a Virtis IQ 2 homogenizer (Virtis, Gardiner, N.Y.). Formulations were spray dried on a benchtop spray dryer using an air atomizing nozzle.
  • a prednisone-loaded organic solution was prepared as described in Example 2.
  • An aqueous solution was prepared by dissolving 3.27 g of ammonium acetate in 18.2 mL of DI water. The aqueous and organic solutions were homogenized and spray dried as described in Example 2.
  • a prednisone-loaded organic solution was prepared as described in Example 2.
  • An aqueous solution was prepared by dissolving 3.27 g of ammonium chloride in 18.2 mL of DI water.
  • the aqueous and organic solutions were homogenized as described in Example 1.
  • the resulting emulsion was spray dried as described in Example 2.
  • a naproxen-loaded organic solution was prepared by dissolving 10.91 g of PEG 3350, 2.73 g of naproxen, and 0.109 g of lecithin in 182 mL of methylene chloride.
  • An aqueous solution was prepared as described in Example 4.
  • the aqueous and organic solutions were homogenized as described in Example 1, and the resulting emulsion was spray dried using process conditions of 20 ml/min solution flow rate, 100 kg/hr drying gas rate, and 20° C. outlet temperature.
  • a paclitaxel-loaded organic solution was prepared by dissolving 3.0 g of paclitaxel, 15.0 g of PEG 3350, and 15.7 mg of lecithin in 100 mL of methylene chloride.
  • An aqueous solution composed of 1.8 g of ammonium bicarbonate and 0.6 g of PEG 3350 in 10 mL of DI water was added to the organic solution (phase ratio 1:10).
  • the mixture was homogenized for 5 minutes at 16,000 RPM.
  • the resulting emulsion was spray dried using process conditions of 10 mL/min solution flow rate, 60 kg/hr drying gas rate, and 25° C. outlet temperature.
  • a nifedipine-loaded organic solution was prepared by dissolving 0.76 g of nifedipine, 0.28 g of PEG 3350, and 2.72 g of polyvinylpyrrolidone K-15 in 170 mL of ethanol.
  • An aqueous solution composed of 1.62 g of ammonium bicarbonate and 3 mg of TWEENTM 80 in 30 mL of DI water was added to the ethanol solution and mixed.
  • the resulting solution was spray dried using process conditions of 20 mL/min solution flow rate, 100 kg/hr drying gas rate, and 36° C. outlet temperature.
  • a nifedipine-loaded organic solution was prepared by dissolving 0.76 g of nifedipine, 0.28 g of PEG 3350, and 2.72 g of polyvinylpyrrolidone K-15 in 170 mL of ethanol.
  • An aqueous solution composed of 1.62 g of ammonium bicarbonate and 3 mg of PLURONICTM F127 in 30 mL of DI water was added to the ethanol solution and mixed.
  • the resulting solution was spray dried using process conditions of 20 mL/min solution flow rate, 100 kg/hr drying gas rate, and 36° C. outlet temperature.
  • nifedipine PBS (600 mL) was added to an appropriate amount of material being tested to contain 2.4 mg of nifedipine. All vessels containing nifedipine as a solid or in solution were protected from light. UV analysis was performed at 237 nm.
  • prednisone PBS (250 mL) was added to an appropriate amount of material being tested to contain 5 mg of prednisone. UV analysis was performed at 244 nm.
  • T80/PBS PBS containing 0.08% TWEENTM 80
  • T80/PBS 10 mL was added to an appropriate amount of material being tested to contain 5 mg of paclitaxel in a 15 mL polypropylene conical tube, and the suspension was vortexed for 3-4 minutes. The suspension (0.25 mL) was then added to 250 mL of T80/PBS in a 600 mL glass beaker for dissolution analysis. HPLC analysis was performed directly on the filtered aqueous solutions using the paclitaxel HPLC method described in Example 13.
  • the in vitro dissolution rates of the porous drug matrices produced in examples 1-10 are provided in FIGS. 1-6 .
  • the in vitro dissolution of the porous drug matrices are compared to the bulk drug of interest. In all cases, the time for 80% dissolution of the porous drug matrices is 4-50 times shorter than the time for 80% of the bulk drug to dissolve.
  • the rate of dissolution which is approximated as the slope of the curve is 10 to 1400 times greater for the porous drug matrices of Examples 1-10 as compared to the specific bulk drug of interest.
  • the densities of the dry powder produced in Examples 1-7 are summarized in Table 1. Density was measured using Transaxial Pressure (“TAP”) with a Micromeritics GeoPyc 1360 using a consolidation force of 8 Newtons. The matrices are less dense than the starting bulk drug in all cases, indicating that the porous drug matrices are more porous than the commercially available bulk drug. TABLE 1 Particle Density Analysis Material Density (g/mL) Prednisone Bulk 0.68 Example 1 0.48 Example 2 0.55 Example 3 0.51 Example 4 0.49 Griseofulvin Bulk 0.80 Example 5 0.55 Nifedipine Bulk 1.01 Example 6 0.56 Naproxen Bulk 0.69 Example 7 0.58
  • HPLC High Pressure Liquid Chromatography
  • USP chromatography conditions were used for prednisone, naproxen, nifedipine, and griseofulvin. Vessels and vials containing naproxen or nifedipine solutions were protected from light.
  • the chromatographic conditions included a Nucleosil column (5:m, C18, 100A, 250 ⁇ 4.6 mm), a mobile phase of 2 mM H 3 PO 4/ Acetonitrile (2:3) at a flow rate of 1.5 mL/min, UV detection at 227 nm, and a run time of 25 min.
  • Particle size analysis was performed using the Coulter Multisizer II with a 50 micron aperture using siphon mode. Electrolyte was pre-saturated with the drug of interest, and filtered through a 0.22 micron filter prior to addition of lots for analysis to ensure that no portion of the drug within the lot would dissolve during the analysis.
  • Example 3 The mean particle size and total surface area of the drug particles generated when the porous drug matrices produced in Examples 1-7 were reconstituted in aqueous media are summarized in Table 3.
  • Table 3 TABLE 3 Particle Size and Surface Area Analysis Surface Area (m 2 /mL of Material Size (microns) microparticles) Prednisone Powder 2.07 1.43
  • Example 1 1.58 1.66
  • Example 2 1.39 2.53
  • Example 3 1.39 3.02
  • Example 4 1.24 3.36 Griseofulvin Bulk 2.42 0.88
  • Example 5 2.16 1.28 Nifedipine Bulk 2.64 0.57
  • Example 6 1.78 1.98 Naproxen Bulk 2.89 0.66
  • Example 7 1.34 2.79
  • the particle size of the drug particles which resulted from wetting of the porous drug matrices was reduced relative to the starting bulk material by 10 to 54%, and the total surface area of the particles was increased relative to the starting bulk drug by approximately 16-320%.
  • a nifedipine/PEG solution was prepared by dissolving 2.0 g of nifedipine, 8.0 g of PEG 3350, and 8 mg of lecithin in 200 mL of methylene chloride (Example 15A).
  • a second identical nifedipine-loaded organic solution was prepared.
  • An aqueous solution composed of 1.8 g of ammonium bicarbonate in 20 mL of DI water was added to the first nifedipine organic solution (phase ratio 1:10). The mixture was homogenized for 5 minutes at 16,000 RPM.
  • nifedipine solution (Example 15A) and the nifedipine emulsion (Example 15B) were separately spray dried using process conditions of 20 mL/min solution flow rate, 60 kg/hr drying gas rate, and 21° C. outlet temperature.
  • a griseofulvin/PEG solution was prepared by dissolving 5.0 g of griseofulvin, 11.2 g of PEG 3350, 11 mg of TWEENTM 80, and 11 mg of lecithin in 200 mL of methylene chloride (Example 16A).
  • a second identical griseofulvin-loaded organic solution was prepared.
  • An aqueous solution composed of 1.8 g of ammonium bicarbonate in 20 mL of DI water was added to the first organic solution (phase ratio 1:10). The mixture was homogenized for 5 minutes at 16,000 RPM.
  • the griseofulvin solution (Example 16A) and griseofulvin emulsion (Example 16B) were spray dried on a benchtop spray dryer using process conditions of 20 mL/min solution flow rate, 80 kg/hr drying gas rate, and 13° C. outlet temperature.
  • the internal surface areas of the drug matrices produced in Examples 15 and 16 were assessed by Krypton BET. BET specific surface area analysis was performed using multi-point surface area analysis with krypton as the gas. Samples were outgassed to 20 micron vacuum at 20° C. prior to analysis.
  • a 5% nifedipine solution was prepared by dissolving 10.0 g of nifedipine in 200 mL of methylene chloride. The solution was spray dried on a benchtop spray dryer using the following conditions: 20 mL/min solution flow rate, 60 kg/hr drying gas rate, and 22° C. outlet temperature.
  • An 8.1% griseofulvin solution was prepared by dissolving 16.2 g of griseofulvin in 200 mL of methylene chloride. The solution was spray dried on a benchtop spray dryer using process conditions of 20 mL/min solution flow rate, 80 kg/hr drying gas rate, and 13° C. outlet temperature.
  • the in vitro dissolution rates of the nifedipine matrices produced in Examples 15 and 18 are shown in FIG. 6 .
  • the in vitro dissolution of the drug matrices produced with either wetting agent or wetting agent and pore forming agent have increased dissolution rates as compared to the drug matrix produced with the drug alone.
  • the matrix produced with both the wetting agent and the pore forming agent has the greatest dissolution rate.
  • the in vitro dissolution rates of the griseofulvin matrices produced in examples 16 and 19 are provided in FIG. 7 .
  • the in vitro dissolution of the drug matrices produced with either wetting agent or wetting agent and pore forming agent have increased dissolution rates as compared to the drug matrix produced with the drug alone.
  • the matrix produced with both the wetting agent and the pore forming agent has the greatest dissolution rate.
  • a nifedipine-loaded organic solution was prepared by dissolving 9.09 g of PEG 3350, 2.27 g of nifedipine, and 0.009 g of lecithin in 182 mL of methylene chloride.
  • An aqueous solution was prepared by dissolving 3.27 g of ammonium bicarbonate and 0.91 g of PEG 3350 in 18.2 mL of deionized water at room temperature.
  • the aqueous and organic solutions were homogenized as described in Example 1, and the resulting emulsion was spray dried using process conditions of 20 mL/min solution flow rate, 60 kg/hr drying gas rate, and 20° C. outlet temperature.
  • a suspension of the porous nifedipine drug matrix was prepared in 5% dextrose solution at a concentration of 2.5 mg/mL.
  • the suspension (2 mL) was administered as a bolus to four beagle dogs, which weighed 8-10 kg.
  • Blood samples were taken at time-points ranging from 1 minute to 24 hours. The samples were processed into plasma, were stored frozen, and were protected from light until analysis via liquid chromatography-mass spectrometry.
  • a nifedipine-loaded organic solution was prepared by dissolving 2.0 g of nifedipine, 30.0 g of PEG 3350, 4 mg of lecithin, and 4 mg of 1,2-Dimyristoyl-sn-Glycero-3-Phosphoethanolamine-N-[Poly(ethylene glycol)-5000] (PEG 5000 PE) in 202 mL of methylene chloride.
  • An aqueous solution of 1.8 g of ammonium bicarbonate in 20 mL of DI water was added to the organic solution (phase ratio 1:10). The mixture was homogenized for 5 minutes at 16,000 RPM.
  • the resulting emulsion was spray dried using process conditions of 20 mL/min solution flow rate, 60 kg/hr drying gas rate, and 21° C. outlet temperature.
  • a nifedipine-loaded organic solution was prepared by dissolving 2.0 g of nifedipine, 30.0 g of PEG 3350, 4 mg of lecithin, and 4 mg of 1 2-Dimyristoyl-sn-Glycero-3-Phosphoethanolamine-N-[Poly(ethylene glycol)-2000] (PEG 2000 PE) in 202 mL of methylene chloride.
  • An aqueous solution composed of 1.8 g of ammonium bicarbonate in 20 ml of DI water was added to the organic solution (phase ratio 1:10).
  • the mixture was homogenized for 5 minutes at 16,000 RPM.
  • the resulting emulsion was spray dried using process conditions of 20 mL/min solution flow rate, 60 kg/hr drying gas rate, and 21° C. outlet temperature.

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Abstract

Drugs, especially low aqueous solubility drugs, are provided in a porous matrix form, preferably microparticles, which enhances dissolution of the drug in aqueous media. The drug matrices preferably are made using a process that includes (i) dissolving a drug, preferably a drug having low aqueous solubility, in a volatile solvent to form a drug solution, (ii) combining at least one pore forming agent with the drug solution to form an emulsion, suspension, or second solution and hydrophilic or hydrophobic excipients that stabilize the drug and inhibit crystallization, and (iii) removing the volatile solvent and pore forming agent from the emulsion, suspension, or second solution to yield the porous matrix of drug. Hydrophobic or hydrophilic excipients may be selected to stabilize the drug in crystalline form by inhibiting crystal growth or to stabilize the drug in amorphous form by preventing crystallization. The pore forming agent can be either a volatile liquid that is immiscible with the drug solvent or a volatile solid-compound, preferably a volatile salt. In a preferred embodiment, spray drying is used to remove the solvents and the pore forming agent. The resulting porous matrix has a faster rate of dissolution following administration to a patient, as compared to non-porous matrix forms of the drug. In a preferred embodiment, microparticles of the porous drug matrix are reconstituted with an aqueous medium and administered parenterally, or processed using standard techniques into tablets or capsules for oral administration.

Description

    CROSS-REFERENCE TO RELATED APPLICATIONS
  • Priority is claimed to U.S. Ser. No. 09/433,486 filed Nov. 4, 1999, which claims priority to U.S. provisional applications Ser. No. 60/136,323, filed May 27, 1999, and Ser. No. 60/158,659, filed Oct. 8, 1999.
    • BACKGROUND OF THE INVENTION
  • This invention generally relates to formulations of drugs, especially drugs having low solubility, and more particularly to methods of making formulations of such drugs to enhance their rate of dissolution, and optionally, to enhance their stability through the inclusion of hydrophobic or hydrophilic excipients that enhance dissolution rate, stabilize drug in crystalline form by inhibiting crystal growth or stabilize drug in amorphous form by preventing crystallization.
  • The bioavailability of a drug can be limited by poor dissolution of the drug into aqueous bodily fluids following administration. This rate-limiting step may therefore be critical to rapidly attaining therapeutically effective drug levels. Traditional approaches to parenteral delivery of poorly soluble drugs include using large volumes of aqueous diluents, solubilizing agents, detergents, non-aqueous solvents, or non-physiological pH solutions. These formulations, however, can increase the systemic toxicity of the drug composition or damage body tissues at the site of administration.
  • Other approaches have focused on the physical form of the drug itself. Since the dissolution rate of a drug particle is directly related to its surface area available to contact the aqueous media at the site of administration or site of absorption, methods ofpreparing drugs in nanoparticulate form have been developed in an effort to maximize the drug surface area, as described, for example, in U.S. Pat. No. 5,534,270 to De Castro and U.S. Pat. No. 5,587,143 to Wong. Nanoparticles, however, can be difficult to produce and maintain in a stable form due to the tendency of the nanoparticles to flocculate or agglomerate, particularly without the presence of surface modifying agents adsorbed or coated onto the particles. Furthermore, milling or wet grinding techniques, which are typically employed for nanonization, can be undesirable, as it can take several days to process a single batch, scaling-up of the milling or grinding process can be difficult and/or costly, the process can be difficult to conduct aseptically, and it is difficult to eliminate shedding of milling media into the product.
  • Other efforts directed at enhancing the rate of dissolution have focused on delivering the drug as a dispersion in a water-soluble or biodegradable matrix, typically in the form of polymeric microparticles. For example, the dissolution rate of dexamethasone reportedly was improved by entrapping the drug in chitosan microspheres made by spray-drying (Genta, et al., S.T.P. Pharma Sciences 5(3):202-07 (1995)). Similarly, others have reported enhanced dissolution rates by mixing a poorly soluble drug powder with a water-soluble gelatin, which purportedly makes the surface of the drug hydrophilic (Imai, et al., J. Pharm. Pharmacol., 42:615-19 (1990)).
  • Related efforts have been directed to forming relatively large, porous matrices of low solubility drugs. For example, Roland & Paeratakul, “Spherical Agglomerates of Water-Insoluble Drugs,” J. Pharma. Sci., 78(11):964-67 (1989) discloses preparing beads having a low solubility drug content up to 98%, wherein the beads have a porous internal structure. Such large beads, however, are unsuitable for parenteral administration, and the beads have less surface area and slower dissolution rates than smaller particles.
  • It is therefore an object of the present invention to provide compositions enhancing the dissolution rate of drugs, especially drugs having low aqueous solubility, and optionally, to enhance the stability of the drug through the inclusion of hydrophobic or hydrophilic excipients that stabilize the drug in crystalline form by inhibiting crystal growth or stabilize the drug in amorphous form by preventing crystallization, and to provide methods of making such compositions.
  • It is another object of the present invention to provide compositions providing enhanced rate of dissolution of drugs, especially drugs of low aqueous solubility, in a formulation suitable for administration by a variety of routes, including, but not limited to, parenteral, mucosal, oral, and topical administration, for local, regional, or systemic effect.
  • It is further object of the present invention to provide compositions for administration as a bolus injection instead of by infusion.
    • SUMMARY OF THE INVENTION
  • Drugs are provided in a porous matrix form wherein the dissolution rate of the drug is enhanced when the matrix is contacted with an aqueous medium. In a preferred embodiment, low aqueous solubility drugs are provided in a porous matrix form that forms microparticles when the matrix is contacted with an aqueous medium. Upon contact with an aqueous medium, the porous matrix containing low aqueous solubility drugs yields microparticles having a mean diameter between about 0.1 and 5 μm and a total surface area greater than about 0.9 m2/mL. The dry porous matrix is in a dry powder form having a TAP density less than or equal to 1.0 g/mL and/or having a total surface area (sum of internal and external surface area) of greater than or equal to 0.2 m2/g. The porous matrices that contain the drug are preferably made using a process that includes (i) dissolving a drug in a volatile solvent to form a drug solution, (ii) combining at least one pore forming agent with the drug solution to form an emulsion, suspension, or second solution, and (iii) removing the volatile solvent and pore forming agent from the emulsion, suspension, or second solution to yield the dry porous matrix of drug. The resulting porous matrix has a faster rate of dissolution following administration to a patient, as compared to non-porous matrix forms of the drug. The pore forming agent can be either a volatile liquid that is immiscible with the drug solvent or a volatile solid compound, preferably a volatile salt. If the pore forming agent is a liquid, the agent is emulsified with the drug solution. If the pore forming agent is a solid, the agent is (i) dissolved in the drug solution, (ii) dissolved in a solvent that is not miscible in the drug solvent and then emulsified with the drug solution, or (iii) suspended as solid particulates in the drug solution. Optionally, hydrophilic or hydrophobic excipients, polymers, pegylated agents, wetting agents, and/or tonicity agents may be added to the drug solvent, the pore forming agent solvent, or both. In the preferred embodiment, at least one excipient incorporated into the emulsion, suspension, or second solution, is a hydrophobic and hydrophilic excipient which enhances dissolution rate, which stabilizes drug in amorphous form by preventing crystallization, or which stabilizes drug in crystalline form by inhibiting crystal growth. In another embodiment, the matrix further includes a pegylated excipient, such as pegylated phospholipid, with the drug. The pegylated excipient shields the drug from macrophage uptake, which prolong its half-life or enhance bioavailability of the drug. The solution, emulsion, or suspension of the pore forming agent in the drug solution is then processed to remove the drug solvent and the pore forming agent, as well as any pore forming agent solvent. In a preferred embodiment, spray drying, optionally followed by lyophilization, fluid bed drying, or vacuum drying, is used to remove the solvents and the pore forming agent. Sugars, amino acids, or polymers can all stabilize the drug forming the porous drug matrix, depending on the molecule to be stabilized.
  • An advantage of the formulations is that they can be administered as a bolus, when the drug normally must be infused to avoid precipitation of the drug. By avoiding precipitation of drug in vivo, the formulations can also be administered parenterally. An additional advantage is the formulations can be administered in reduced volumes.
  • In a preferred embodiment, the porous drug matrix is reconstituted with an aqueous medium and administered parenterally, such as intramuscularly, subcutaneously, or intravenously. Alternatively, the porous drug matrix can be further processed using standard techniques into tablets or capsules for oral administration or into rectal suppositories, delivered using a dry powder inhaler for pulmonary administration, or mixed/processed into a cream or ointment for topical administration.
    • BRIEF DESCRIPTION OF THE DRAWINGS
  • FIG. 1 is a graph of the in vitro dissolution rate (percent dissolved versus time) for non-formulated prednisone and prednisone in porous matrix form.
  • FIG. 2 is a graph of the in vitro dissolution rate (percent dissolved versus time) for non-formulated griseofulvin and griseofulvin in porous matrix form.
  • FIG. 3 is a graph of the in vitro dissolution rate (percent dissolved versus time) for non-formulated nifedipine and nifedipine in porous matrix form.
  • FIG. 4 is a graph of the in vitro dissolution rate (percent dissolved versus time) for non-formulated naproxen and naproxen in a porous matrix form.
  • FIG. 5 is a graph of the in vitro dissolution rate (percent dissolved versus time) for non-formulated paclitaxel and paclitaxel in a porous matrix form.
  • FIG. 6 is a graph of the in vitro dissolution rate (percent dissolved versus time) for various porous matrix forms of nifedipine.
  • FIG. 7 is a graph of the in vitro dissolution rate (percent dissolved versus time) for various porous matrix forms of griseofulvin.
  • FIG. 8 is a graph of nifedipine plasma levels versus time post intravenous administration of reconstituted nifedipine matrix in dogs.
    • DETAILED DESCRIPTION OF THE INVENTION
  • The rate of dissolution of drugs can be enhanced by making the drug into a porous matrix form, substantially increasing the surface area of the drug available to contact aqueous biological fluids at the site of administration of the drug composition. In a preferred embodiment, the drug has low aqueous solubility, as commonly defined by those skilled in the art.
  • I. Drug Matrix Compositions
  • The porous drug matrix is at least 1 to 95%, preferably at least about 10%, and more preferably between about 10 and 60%, drug by weight. The matrices also may contain hydrophilic or hydrophobic excipients such as water-soluble polymers, amino acids or sugars, wetting agents such as surfactants, and tonicity agents.
  • The form of the drug matrix (dry powder) is critical to the dissolution rate. The matrix must contain microparticles of drug, which preferably have a diameter between about 100 nm and 5 μm, more preferably between about 500 nm and 5 μm. The average total surface area of the drug microparticles contained within the porous matrix, which typically is in the form of a dry powder, is 0.9 m2/mL of microparticles or greater. Total surface area values can be determined using standard Coulter Counter equipment and techniques.
  • The drug matrix must be sufficiently porous to yield microparticles having these parameters. Measurements useful in characterizing the porosity of the drug matrix are the bulk density or the transaxial pressure (“TAP”) density of the dry porous matrix (dry powder) and the total surface area (sum of internal and external surface area) of the dry porous matrix . The TAP density preferably is less than about 1.0 g/ml, more preferably less than 0.8 g/ml. This level of porosity of the matrix, characterized by density, provides sufficient surface area to enhance wetting of the dry porous matrix and enhance the rate of drug dissolution. The total surface area of the porous matrix can be measured, for example, by BET surface area analysis. The total surface area of the porous matrix preferably is greater than 0.1 m2/g, more preferably greater than or equal to 0.2 m2/g. This level of total surface area provides sufficient surface area to enhance wetting of the dry porous matrix and enhance the rate of drug dissolution.
  • 1. Drugs
  • A wide variety drugs are useful in the methods and compositions described herein. In a preferred embodiment, the drug is a low aqueous solubility drug. As used herein, the term “low aqueous solubility” means that the drug has a solubility of less than about 10 mg/mL, and preferably less than about 5 mg/mL, in aqueous media at approximately physiological temperatures and pH. As used herein, the term “drug” refers to chemical or biological molecules providing a therapeutic, diagnostic, or prophylactic effect in vivo.
  • Drugs contemplated for use in the compositions described herein include the following categories and examples of drugs and alternative forms of these drugs such as alternative salt forms, free acid forms, free base forms, and hydrates:
    • analgesics/antipvretics (e.g., aspirin, acetaminophen, ibuprofen, naproxen sodium, buprenorphine, propoxyphene hydrochloride, propoxyphene napsylate, meperidine hydrochloride, hydromorphone hydrochloride, morphine, oxycodone, codeine, dihydrocodeine bitartrate, pentazocine, hydrocodone bitartrate, levorphanol, diflunisal, trolamine salicylate, nalbuphine hydrochloride, mefenamic acid, butorphanol, choline salicylate, butalbital, phenyltoloxamine citrate, diphenhydramine citrate, methotrimeprazine, cinnamedrine hydrochloride, and meprobamate);
    • antiasthamatics (e.g., ketotifen and traxanox);
    • antibiotics (e.g., neomycin, streptomycin, chloramphenicol, cephalosporin, ampicillin, penicillin, tetracycline, and ciprofloxacin);
    • antidepressants (e.g., nefopam, oxypertine, doxepin, amoxapine, trazodone, amitriptyline, maprotiline, phenelzine, desipramine, nortriptyline, tranylcypromine, fluoxetine, doxepin, imipramine, imipramine pamoate, isocarboxazid, trimipramine, and protriptyline);
    • antidiabetics (e.g., biguanides and sulfonylurea derivatives);
    • antifingal agents (e.g., griseofulvin, ketoconazole, itraconizole, amphotericin B, nystatin, and candicidin);
    • antihypertensive agents (e.g., propanolol, propafenone, oxyprenolol, nifedipine, reserpine, trimethaphan, phenoxybenzamine, pargyline hydrochloride, deserpidine, diazoxide, guanethidine monosulfate, minoxidil, rescinnamine, sodium nitroprusside, rauwoffia serpentina, alseroxylon, and phentolamine);
    • anti-inflammatories (e.g., (non-steroidal) indomethacin, ketoprofen, flurbiprofen, naproxen, ibuprofen, ramifenazone, piroxicam, (steroidal) cortisone, dexamethasone, fluazacort, celecoxib, rofecoxib, hydrocortisone, prednisolone, and prednisone);
    • antineoplastics (e.g., cyclophosphamide, actinomycin, bleomycin, daunorubicin, doxorubicin, epirubicin, mitomycin, methotrexate, fluorouracil, carboplatin, carmustine (BCNU), methyl-CCNU, cisplatin, etoposide, camptothecin and derivatives thereof, phenesterine, paclitaxel and derivatives thereof, docetaxel and derivatives thereof, vinblastine, vincristine, tamoxifen, and piposulfan);
    • antianxiety agents (e.g., lorazepam, buspirone, prazepam, chlordiazepoxide, oxazepam, clorazepate dipotassium, diazepam, hydroxyzine pamoate, hydroxyzine hydrochloride, alprazolam, droperidol, halazepam, chlormezanone, and dantrolene);
    • immunosuppressive agents (e.g., cyclosporine, azathioprine, mizoribine, and FK506 (tacrolimus));
    • antimigraine agents (e.g., ergotamine, propanolol, isometheptene mucate, and dichloralphenazone);
    • sedatives/hypnotics (e.g., barbiturates such as pentobarbital, pentobarbital, and secobarbital; and benzodiazapines such as flurazepam hydrochloride, triazolam, and midazolam);
    • antianginal agents (e.g., beta-adrenergic blockers; calcium channel blockers such as nifedipine, and diltiazem; and nitrates such as nitroglycerin, isosorbide dinitrate, pentaerythritol tetranitrate, and erythrityl tetranitrate);
    • antipsychotic agents (e.g., haloperidol, loxapine succinate, loxapine hydrochloride, thioridazine, thioridazine hydrochloride, thiothixene, fluphenazine, fluphenazine decanoate, fluphenazine enanthate, trifluoperazine, chlorpromazine, perphenazine, lithium citrate, and prochlorperazine);
    • antimanic agents (e.g., lithium carbonate);
    • antiarrhythmics (e.g., bretylium tosylate, esmolol, verapamil, amiodarone, encainide, digoxin, digitoxin, mexiletine, disopyramide phosphate, procainamide, quinidine sulfate, quinidine gluconate, quinidine polygalacturonate, flecainide acetate, tocainide, and lidocaine);
    • antiarthritic agents (e.g., phenylbutazone, sulindac, penicillamine, salsalate, piroxicamn, azathioprine, indomethacin, meclofenamate, gold sodium thiomalate, ketoprofen, auranofin, aurothioglucose, and tolmetin sodium);
    • antigout ajents (e.g., colchicine, and allopurinol);
    • anticoagulants (e.g., heparin, heparin sodium, and warfarin sodium);
    • thrombolytic agents (e.g., urokinase, streptokinase, and alteplase);
    • antifibrinolytic agents (e.g., aminocaproic acid);
    • hemorheologic agents (e.g., pentoxifylline);
    • antiplatelet agents (e.g., aspirin);
    • anticonvulsants (e.g., valproic acid, divalproex sodium, phenytoin, phenytoin sodium, clonazepam, primidone, phenobarbitol, carbamazepine, amobarbital sodium, methsuximide, metharbital, mephobarbital, mephenytoin, phensuximide, paramethadione, ethotoin, phenacemide, secobarbitol sodium, clorazepate dipotassium, and trimethadione);
    • antiparkinson agents (e.g., ethosuximide);
    • antihistamines/antipruritics (e.g., hydroxyzine, diphenhydramine, chlorpheniramine, brompheniramine maleate, cyproheptadine hydrochloride, terfenadine, clemastine fumarate, triprolidine, carbinoxamine, diphenylpyraline, phenindamine, azatadine, tripelennamine, dexchlorpheniramine maleate, methdilazine, and);
    • agents usefuil for calcium regulation (e.g., calcitonin, and parathyroid hormone);
    • antibacterial agents (e.g., amikacin sulfate, aztreonam, chloramphenicol, chloramphenicol palmitate, ciprofloxacin, clindamycin, clindamycin palmitate, clindamycin phosphate, metronidazole, metronidazole hydrochloride, gentamicin sulfate, lincomycin hydrochloride, tobramycin sulfate, vancomycin hydrochloride, polymyxin B sulfate, colistimethate sodium, and colistin sulfate);
    • antiviral agents (e.g., interferon alpha, beta or gamma, zidovudine, amantadine hydrochloride, ribavirin, and acyclovir);
    • antimicrobials (e.g., cephalosporins such as cefazolin sodium, cephradine, cefaclor, cephapirin sodium, ceftizoxime sodium, cefoperazone sodium, cefotetan disodium, ceftiroxime e azotil, cefotaxime sodium, cefadroxil monohydrate, cephalexin, cephalothin sodium, cephalexin hydrochloride monohydrate, cefamandole nafate, cefoxitin sodium, cefonicid sodium, ceforanide, ceftriaxone sodium, ceftazidime, cefadroxil, cephradine, and cefuroxime sodium; penicillins such as ampicillin, amoxicillin, penicillin G benzathine, cyclacillin, ampicillin sodium, penicillin G potassium, penicillin V potassium, piperacillin sodium, oxacillin sodium, bacampicillin hydrochloride, cloxacillin sodium, ticarcillin disodium, aziocillin sodium, carbenicillin indanyl sodium, penicillin G procaine, methicillin sodium, and nafcillin sodium; erythromycins such as erythromycin ethylsuccinate, erythromycin, erythromycin estolate, erythromycin lactobionate, erythromycin stearate, and erythromycin ethylsuccinate; and tetracyclines such as tetracycline hydrochloride, doxycycline hyclate, and minocycline hydrochloride, azithromycin, clarithromycin);
    • anti-infectives (e.g., GM-CSF);
    • bronchodilators (e.g., sympathomimetics such as epinephrine hydrochloride, metaproterenol sulfate, terbutaline sulfate, isoetharine, isoetharine mesylate, isoetharine hydrochloride, albuterol sulfate, albuterol, bitolterolnesylate, isoproterenol hydrochloride, terbutaline sulfate, epinephrine bitartrate, metaproterenol sulfate, epinephrine, and epinephrine bitartrate; anticholinergic agents such as ipratropium bromide; xanthines such as aminophylline, dyphylline, metaproterenol sulfate, and aminophylline; mast cell stabilizers such as cromolyn sodium; inhalant corticosteroids such as beclomethasone dipropionate (BDP), and beclomethasone dipropionate monohydrate; salbutamol; ipratropium bromide; budesonide; ketotifen; salmeterol; xinafoate; terbutaline sulfate; triamcinolone; theophylline; nedocromil sodium; metaproterenol sulfate; albuterol; flunisolide; fluticasone proprionate
    • steroidal compounds and hormones (e.g., androgens such as danazol, testosterone cypionate, fluoxymesterone, ethyltestosterone, testosterone enathate, methyltestosterone, fluoxymesterone, and testosterone cypionate; estrogens such as estradiol, estropipate, and conjugated estrogens; progestins such as methoxyprogesterone acetate, and norethindrone acetate; corticosteroids such as triamcinolone, betamethasone, betamethasone sodium phosphate, dexamethasone, dexamethasone sodium phosphate, dexamethasone acetate, prednisone, methylprednisolone acetate suspension, triamcinolone acetonide, methylprednisolone, prednisolone sodium phosphate, methylprednisolone sodium succinate, hydrocortisone sodium succinate, triamcinolone hexacetonide, hydrocortisone, hydrocortisone cypionate, prednisolone, fludrocortisone acetate, paramethasone acetate, prednisolone tebutate, prednisolone acetate, prednisolone sodium phosphate, and hydrocortisone sodium succinate; and thyroid hormones such as levothyroxine sodium);
    • hypoglycemic agents (e.g., human insulin, purified beef insulin, purified pork insulin, glyburide, chlorpropamide, glipizide, tolbutamide, and tolazamide);
    • hypolipidemic agents (e.g., clofibrate, dextrothyroxine sodium, probucol, pravastitin, atorvastatin, lovastatin, and niacin);
    • proteins (e.g., DNase, alginase, superoxide dismutase, and lipase);
    • nucleic acids (e.g., sense or anti-sense nucleic acids encoding any therapeutically useful protein, including any of the proteins described herein);
    • agents useful for erythropoiesis stimulation (e.g., erythropoietin);
    • antiulcer/antireflux agents (e.g., famotidine, cimetidine, and ranitidine hydrochloride);
    • antinauseants/antiemetics (e.g., meclizine hydrochloride, nabilone, prochlorperazine, dimenhydrinate, promethazine hydrochloride, thiethylperazine, and scopolamine);
    • oil-soluble vitamins (e.g., vitamins A, D, E, K, and the like); as well as other drugs such as mitotane, halonitrosoureas, anthrocyclines, and ellipticine. A description of these and other classes of useful drugs and a listing of species within each class can be found in Martindale, The Extra Pharmacopoeia, 30th Ed. (The Pharmaceutical Press, London 1993), the disclosure of which is incorporated herein by reference in its entirety.
  • Examples of other drugs useful in the compositions and methods described herein include ceftriaxone, ketoconazole, ceftazidime, oxaprozin, albuterol, valacyclovir, urofollitropin, famciclovir, flutamide, enalapril, mefformin, itraconazole, buspirone, gabapentin, fosinopril, tramadol, acarbose, lorazepan, follitropin, glipizide, omeprazole, fluoxetine, lisinopril, tramsdol, levofloxacin, zafirlukast, interferon, growth hormone, interleukin, erythropoietin, granulocyte stimulating factor, nizatidine, bupropion, perindopril, erbumine, adenosine, alendronate, alprostadil, benazepril, betaxolol, bleomycin sulfate, dexfenfluramine, diltiazem, fentanyl, flecainid, gemcitabine, glatiramer acetate, granisetron, lamivudine, mangafodipir trisodium, mesalamine, metoprolol fumarate, metronidazole, miglitol, moexipril, monteleukast, octreotide acetate, olopatadine, paricalcitol, somatropin, sumatriptan succinate, tacrine, verapamil, nabumetone, trovafloxacin, dolasetron, zidovudine, finasteride, tobramycin, isradipine, tolcapone, enoxaparin, fluconazole, lansoprazole, terbinafine, pamidronate, didanosine, diclofenac, cisapride, venlafaxine, troglitazone, fluvastatin, losartan, imiglucerase, donepezil, olanzapine, valsartan, fexofenadine, calcitonin, and ipratropium bromide. These drugs are generally considered to be water-soluble.
  • Preferred drugs include albuterol, adapalene, doxazosin mesylate, mometasone furoate, ursodiol, amphotericin, enalapril maleate, felodipine, nefazodone hydrochloride, valrubicin, albendazole, conjugated estrogens, medroxyprogesterone acetate, nicardipine hydrochloride, zolpidem tartrate, amlodipine besylate, ethinyl estradiol, omeprazole, rubitecan, amlodipine besylate/benazepril hydrochloride, etodolac, paroxetine hydrochloride, paclitaxel, atovaquone, felodipine, podofilox, paricalcitol, betamethasone dipropionate, fentanyl, pramipexole dihydrochloride, Vitamin D3 and related analogues, finasteride, quetiapine fumarate, alprostadil, candesartan, cilexetil, fluconazole, ritonavir, busulfan, carbamazepine, flumazenil, risperidone, carbemazepine, carbidopa, levodopa, ganciclovir, saquinavir, amprenavir, carboplatin, glyburide, sertraline hydrochloride, rofecoxib carvedilol, halobetasolproprionate, sildenafil citrate, celecoxib, chlorthalidone, imiquimod, simvastatin, citalopram, ciprofloxacin, irinotecan hydrochloride, sparfloxacin, efavirenz, cisapride monohydrate, lansoprazole, tamsulosin hydrochloride, mofafinil, clarithromycin, letrozole, terbinafine hydrochloride, rosiglitazone maleate, diclofenac sodium, lomefloxacin hydrochloride, tirofiban hydrochloride, telmisartan, diazapam, loratadine, toremifene citrate, thalidomide, dinoprostone, mefloquine hydrochloride, trandolapril, docetaxel, mitoxantrone hydrochloride, tretinoin, etodolac, triamcinolone acetate, estradiol, ursodiol, nelfinavir mesylate, indinavir, beclomethasone dipropionate, oxaprozin, flutamide, famotidine, nifedipine, prednisone, cefuroxime, lorazepam, digoxin, lovastatin, griseofulvin, naproxen, ibuprofen, isotretinoin, tamoxifen citrate, nimodipine, amiodarone, and alprazolam.
  • 2. Excipients
  • The matrices may contain hydrophilic or hydrophobic excipients such as polymers, including water soluble polymers, amino acids or sugars which can serve as bulking agents or as wetting agents, wetting agents such as surfactants, amino acids or sugars, preservatives and tonicity agents. In addition, the polymers, amino acids sugars, or preservatives may improve the storage stability of the matrices by stabilizing the drug in a crystalline form by inhibiting crystal growth or by preventing crystallization of the drug when the drug is present in an amorphous state. Upon contact with an aqueous medium, water penetrates through the highly porous matrix to dissolve the water-soluble excipients in the matrix. In the case of low aqueous solubility drugs, a suspension of drug particles in the aqueous medium is left. The total surface area of the resultant low aqueous solubility drug microparticles is increased relative to the unprocessed drug and the dissolution rate of the drug is increased.
  • One of skill in the art can select appropriate excipients for use in the drug matrix compositions, considering a variety of factors, such as the drug to be administered, the route of administration, the dosage, and the preferred dissolution rate. For example, the excipients can function as bulking agents, release-modifiers, wetting agents, tonicity agents, or combinations thereof. Preferred excipients include water soluble polymers, amino acids, wetting agents, and sugars.
  • The hydrophilic or hydrophobic excipients, wetting agents, and tonicity agents may be added to the drug solution, the pore forming agent, or both, during production of the matrix.
  • (i) Polymers
  • The polymers that can be used in the drug matrices described herein include both synthetic and natural polymers, either non-biodegradable or biodegradable and either water soluble or water insoluble. Representative synthetic polymers include polyethylene glycol (“PEG”), polyvinyl pyrrolidone, polymethacrylates, polylysine, poloxamers, polyvinyl alcohol, polyacrylic acid, polyethylene oxide, and polyethyoxazoline. Representative natural polymers include albumin, alginate, gelatin, acacia, chitosan, cellulose dextran, ficoll, starch, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxy-propylmethyl cellulose, hyaluronic acid, carboxyethyl cellulose, carboxymethyl cellulose, deacetylated chitosan, dextran sulfate, and derivatives thereof. Preferred polymers include PEG, polyvinyl pyrrolidone, poloxamers, hydroxypropyl cellulose, and hydroxyethyl cellulose.
  • The polymer selected for use in a particular drug matrix formulation is based on a variety of factors, such as the polymer molecular weight, polymer hydrophilicity, and polymer inherent viscosity. The polymer can be used as a bulking agent, as an anti-crystallization agent for drugs in an amorphous state, as a crystal growth inhibitor for drugs in a crystalline state or as a wetting agent.
  • The amount of polymer in the drug matrix is less than about 95%, more preferably less than about 80%, by weight of the drug matrix when used as a bulking agent. The amount of polymer in the drug matrix is less than about 50%, more preferably less than about 40%, by weight of the drug matrix when used as an anti-crystallization agent for drugs in an amorphous state or as a crystal growth inhibitor for drugs in a crystalline state. The amount of polymer in the drug matrix is less than about 30%, more preferably less than about 20%, by weight of the drug matrix when used a wetting agent.
  • (ii) Sugars
  • Representative sugars that can be used in the drug matrices include mannitol, sorbitol, xylitol, glucitol, ducitol, inositiol, arabinitol, arabitol, galactitol, iditol, allitol, fructose, sorbose, glucose, xylose, trehalose, allose, dextrose, altrose, gulose, idose, galactose, talose, ribose, arabinose, xylose, lyxose, sucrose, maltose, lactose, lactulose, fucose, rhamnose, melezitose, maltotriose, and raffinose. Preferred sugars include mannitol, lactose, sucrose, sorbitol, trehalose, glucose, and are adjusted to provide osmolality if administered parenterally. The sugarscan serve as a bulking agent or as an anti-crystallization agent for drugs in the amorphous state, or as a crystal growth inhibitor for drugs in the crystalline state or to provide wetting of the porous drug matrix or the drug microparticles within the matrix.
  • The amount of sugar in the drug matrix is less than about 95%, more preferably less than about 80%, by weight of the drug matrix when used as a bulking agent. The amount of sugar in the drug matrix is less than about 50%, more preferably less than about 40%, by weight of the drug matrix when used as an anti-crystallization agent for drugs in an amorphous state or as a crystal growth inhibitor for drugs in a crystalline state. The amount of sugar in the drug matrix is less than about 30%, more preferably less than about 20%, by weight of the drug matrix when used a wetting agent.
  • (iii) Amino Acids
  • Representative amino acids that can be used in the drug matrices include both naturally occurring and non-naturally occurring amino acids. The amino acids can be hydrophobic or hydrophilic and may be D amino acids, L amino acids or racemic mixtures. Amino acids which can be used include, but are not limited to: glycine, arginine, histidine, threonine, asparagine, aspartic acid, serine, glutamate, proline, cysteine, methionine, valine, leucine, isoleucine, tryptophan, phenylalanine, tyrosine, lysine, alanine, glutamine. The amino acid can be used as a bulking agent, or as an anti-crystallization agent for drugs in the amorphous state, or as a crystal growth inhibitor for drugs in the crystalline state or as a wetting agent. Hydrophobic amino acids such as leucine, isoleucine, alanine, glucine, valine, proline, cysteine, methionine, phenylalanine, tryptophan are more likely to be effective as anticrystallization agents or crystal growth inhibitors. In addition, amino acids can serve to make the matrix have a pH dependency that can be used to influence the pharmaceutical properties of the matrix such as solubility, rate of dissolution or wetting.
  • The amount of amino acid in the drug matrix is less than about 95%, more preferably less than about 80%, by weight of the drug matrix when used as a buiking agent. The amount of amino acid in the drug matrix is less than about 50%, more preferably less than about 40%, by weight of the drug matrix when used as an anti-crystallization agent for drugs in an amorphous state or as a crystal growth inhibitor for drugs in a crystalline state. The amount of amino acid in the drug matrix is less than about 30%, more preferably less than about 20%, by weight of the drug matrix when used a wetting agent.
  • iv) Preservatives
  • Preservatives such as parabens or benzoic acids can be used directly for inhibition of microbial growth. Preferred parabens include methyl paraben, ethyl paraben and butyl paraben. In addition, the preservatives can be used to interact with the drug to inhibit crystal formation or growth. The amount of preservative in the drug matrix is less than about 50%, more preferably less than about 40%, by weight of the drug matrix when used as an anti-crystallization agent for drugs in an amorphous state or as a crystal growth inhibitor for drugs in a crystalline state.
  • iv) Wetting Agents
  • Wetting agents can be used to facilitate water ingress into the matrix and wetting of the drug particles in order to facilitate dissolution.
  • Representative examples of wetting agents include gelatin, casein, lecithin (phosphatides), gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers (e.g., macrogol ethers such as cetomacrogol 1000), polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters (e.g., TWEEN™s), polyethylene glycols, polyoxyethylene stearates, colloidal silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxy propylcellulose, hydroxypropylmethylcellulose phthlate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, and polyvinylpyrrolidone (PVP). Tyloxapol (a nonionic liquid polymer of the alkyl aryl polyether alcohol type, also known as superinone or triton) is another useful wetting agent. Most of these wetting agents are known pharmaceutical excipients and are described in detail in the Handbook of Pharmaceutical Excipients, published jointly by the American Pharmaceutical Association and The Pharmaceutical Society of Great Britain (The Pharmaceutical Press, 1986).
  • Preferred wetting agents include polyvinylpyrrolidone, polyethylene glycol, tyloxapol, poloxamers such as PLURONIC™ F68, F127, and F108, which are block copolymers of ethylene oxide and propylene oxide, and polyxamines such as TETRONIC™ 908 (also known as POLOXAMINE™ 908), which is a tetrafunctional block copolymer derived from sequential addition of propylene oxide and ethylene oxide to ethylenediamine (available from BASF), dextran, lecithin, dialkylesters of sodium sulfosuccinic acid such as AEROSOL™ OT, which is a dioctyl ester of sodium sulfosuccinic acid (available from American Cyanimid), DUPONOL™ P, which is a sodium lauryl sulfate (available from DuPont), TRITON™ X-200, which is an alkyl aryl polyether sulfonate (available from Rohm and Haas), TWEEN™ 20 and TWEEN™ 80, which are polyoxyethylene sorbitan fatty acid esters (available from ICI Specialty Chemicals), Carbowax 3550 and 934, which are polyethylene glycols (available from Union Carbide), Crodesta F-110, which is a mixture of sucrose stearate and sucrose distearate, and Crodesta SL-40 (both available from Croda Inc.), and SA90HCO, which is C18H37—CH2(CON(CH3)CH2(CHOH)4CH2OH)2.
  • Wetting agents which have been found to be particularly useful include Tetronic 908, the Tweens, Pluronic F-68 and polyvinylpyrrolidone. Other useful wetting agents include decanoyl-N-methylglucamide; n-decyl-β-D-glucopyranoside; n-decyl-β-D-maltopyranoside; n-dodecyl-β-D-glucopyranoside; n-dodecyl β-D-maltoside; heptanoyl-N-methylglucamide; n-heptyl-β-D-glucopyranoside; n-heptyl-β-D-thioglucoside; n-hexyl-βD-glucopyranoside; nonanoyl-N-methylglucamide; n-noyl-β-D-glucopyranoside; octanoyl-N-methylglucamide; n-octyl-β-D-glucopyranoside; and octyl-β-D-thioglucopyranoside. Another preferred wetting agent is p-isononylphenoxypoly(glycidol), also known as Olin-10G or Surfactant 10-G (commercially available as 10G from Olin Chemicals). Two or more wetting agents can be used in combination. The amount of wetting agent in the drug matrix is less than about 30%, more preferably less than about 20%, by weight of the drug matrix.
  • (vi) Tonicity or Osmolality Agents
  • The porous drug matrices may include one or more tonicity agents, such as salts (e.g., as sodium chloride or potassium chloride) or sugars (such as mannitol, dextrose, sucrose, or trehalose) to adjust a hypotonic solution of a drug to isotonic so that the drug, when in solution, is physiologically compatible with the cells of the body tissue of the patient. The type and amount of tonicity agent can be selected by one of skill in the art using known techniques.
  • (vii) PEGylated Excipients
  • In one embodiment, the matrix further includes a pegylated excipient. Such pegylated excipients include, but are not limited to, pegylated phospholipids, pegylated proteins, pegylated peptides, pegylated sugars, pegylated polysaccharides, pegylated block-co-polymers with one of the blocks being PEG, and pegylated hydrophobic compounds such as pegylated cholesterol. The pegylated excipient beneficially envelops or shields the drug from macrophage uptake, which prolongs its half-life or enhances bioavailability of the drug.
  • Representative examples of pegylated phospholipids include 1,2-diacyl-sn-glycero-3-phosphoethanolamine-N-[Poly(ethylene glycol) 2000] (“PEG 2000 PE”) and 1,2-diacyl-sn-glycero-3-phosphoethanolamine-N-[Poly(ethylene glycol) 5000] (“PEG 5000 PE”), where the acyl group is selected, for example, from dimyristoyl, dipalmitoyl, distearoyl, diolcoyl, and 1-palmitoyl-2-oleoyl.
  • Other polyalkyleneoxides can be used in the place of the polyethylene glycol moiety.
  • II. Volatile Solvents
  • The choice of solvent depends on the drug. In a preferred embodiment, the solvent is an organic solvent that is volatile, has a relatively low boiling point, or can be removed under vacuum, and which is acceptable for administration to humans in trace amounts. Representative solvents include acetic acid, acetaldehyde dimethyl acetal, acetone, acetonitrile, chloroform, chlorofluorocarbons, dichloromethane, dipropyl ether, diisopropyl ether, N,N-dimethlyformamide (DMF), foramide, demethyl sulfoxide (DMSO), dioxane, ethanol, ethyl acetate, ethyl formate, ethyl vinyl ether, methyl ethyl ketone (MEK), glycerol, heptane, hexane, isopropanol, methanol, isopropanol, butanol, triethylamine, nitromethane, octane, pentane, tetrahydrofuran (THF), toluene, 1,1,1 -trichloroethane, 1,1,2-trichloroethylene, water, xylene, and combinations thereof. In general, the drug is dissolved in the volatile solvent to form a drug solution having a concentration of between 0.01 and 80% weight to volume (w/v), more preferably between 0.025 and 30% (w/v).
  • When the drug is a water-soluble drug, aqueous solvents or mixtures of aqueous and organic solvents, such as water-alcohol mixtures, can be used to dissolve the drug.
  • III. Pore Forming Agents
  • Pore forming agents are volatile materials that are used during the process to create porosity in the resultant matrix. The pore forming agent can be a volatilizable solid or volatilizable liquid.
  • 1. Liquid Pore Forming Agent
  • The liquid pore forming agent must be immiscible with the drug solvent and volatilizable under processing conditions compatible with the drug. To effect pore formation, the pore forming agent first is emulsified with the drug solvent. Then, the emulsion is further processed to remove the drug solvent and the pore forming agent simultaneously or sequentially using evaporation, vacuum drying, spray drying, fluid bed drying, lyophilization, or a combination of these techniques.
  • The selection of liquid pore forming agents will depend on the drug solvent. Representative liquid pore forming agents include water; dichloromethane; alcohols such as ethanol, methanol, or isopropanol; acetone; ethyl acetate; ethyl formate; dimethylsulfoxide; acetonitrile; toluene; xylene; dimethylforamide; ethers such as THF, diethyl ether, or dioxane; triethylamine; foramide; acetic acid; methyl ethyl ketone; pyridine; hexane; pentane; furan; water; and cyclohexane.
  • The liquid pore forming agent is used in an amount that is between 1 and 50% (v/v), preferably between 5 and 25% (v/v), of the drug solvent emulsion.
  • 2. Solid Pore Forming Agent
  • The solid pore forming agent must be volatilizable under processing conditions which do not harm the drug compositions. The solid pore forming agent can be (i) dissolved in the drug solution, (ii) dissolved in a solvent which is not miscible with the drug solvent to form a solution which is then emulsified with the drug solution, or (iii) added as solid particulates to the drug solution. The solution, emulsion, or suspension of the pore forming agent in the drug solution then is further processed to remove the drug solvent, the pore forming agent, and, if appropriate, the solvent for the pore forming agent simultaneously or sequentially using evaporation, spray drying, fluid bed drying, lyophilization, vacuum drying, or a combination of these techniques.
  • In a preferred embodiment, the solid pore forming agent is a volatile salt, such as salts of volatile bases combined with volatile acids. Volatile salts are materials that can transform from a solid or liquid to a gaseous state using added heat and/or vacuum. Examples of volatile bases include ammonia, methylamine, ethylamine, dimethylamine, diethylamine, methylethylamine, trimethylamine, triethylamine, and pyridine. Examples of volatile acids include carbonic acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, formic acid, acetic acid, propionic acid, butyric acid, and benzoic acid. Preferred volatile salts include ammonium bicarbonate, ammonium acetate, ammonium chloride, ammonium benzoate and mixtures thereof.
  • Other examples of solid pore forming agents include iodine, phenol, benzoic acid (as acid not as salt), and naphthalene.
  • The solid pore forming agent is used in an amount between 5 and 1000% (w/w), preferably between 10 and 600% (w/w), and more preferably between 10 and 200% (w/w), of the drug.
  • IV. Method of Making the Porous Drug Matrix
  • The porous drug matrices preferably are made by (i) dissolving a drug, preferably one having low aqueous solubility, in a volatile solvent to form a drug solution, (ii) combining at least one pore forming agent with the drug solution to form an emulsion, suspension, or second solution, and (iii) removing the volatile solvent and pore forming agent from the emulsion, suspension, or second solution. In a preferred embodiment, spray drying, optionally followed by lyophilization or vacuum drying, is used to remove the solvents and the pore forming agent. The removal of the pore forming agent can be conducted simultaneously with or following removal of enough solvent to solidify the droplets. Production can be carried out using continuous, batch, or semi-continuous processes. First, the selected drug is dissolved in an appropriate solvent. The concentration of the drug in the resulting drug solution typically is between about 0.01 and 80% (w/v), preferably between about 0.025 and 30% (w/v).
  • Next, the drug solution is combined, typically under mixing conditions, with the pore forming agent or solution thereof. If a liquid pore forming agent is used, it is first emulsified with the drug solution to form droplets of pore forming agent dispersed throughout the drug solution. If a solid pore forming agent is used, it is dissolved either directly in the drug solution to form a solution of drug/pore forming agent, or it is first dissolved in a second solvent which is immiscible with the drug solvent to form a solution which subsequently is emulsified with the drug solution to form droplets of the pore forming agent solution dispersed throughout the drug solution. A solid pore forming agent alternatively can be added directly to the drug solution as solid particulates, preferably between about 100 nm and 10 μm in size, to form a suspension of pore forming agent in the drug solution. Subsequently, the solid pore forming agent particle size can be reduced by further processing the resulting suspension, for example, using homogenization or sonication techniques known in the art. In the preferred embodiment, excipient(s) are added to the emulsion, suspension or second solution before, with or after the pore-forming agent.
  • Then, the solution, emulsion, or suspension is further processed to remove the drug solvent and the pore forming agent simultaneously or sequentially, using evaporation, spray drying, fluid bed drying, lyophilization, vacuum drying, or a combination of these techniques. In a preferred embodiment, the solution, emulsion, or suspension is spray-dried. As used herein, “spray dry” means to atomize the solution, emulsion, or suspension to form a fine mist of droplets (of drug solution having solid or liquid pore forming agent dispersed throughout), which immediately enter a drying chamber (e.g., a vessel, tank, tubing, or coil) where they contact a drying gas. The solvent and pore forming agents evaporate from the droplets into the drying gas to solidify the droplets, simultaneously forming pores throughout the solid. The solid (typically in a powder, particulate form) then is separated from the drying gas and collected.
  • The temperature of the inlet and outlet ports of the drying chamber, as well as the flow rates of the feed solution, atomization gas, and drying gas, can be controlled to produce the desired products. In a particularly preferred embodiment, the spray drying methods described in U.S. Pat. No. 5,853,698 to Straub et al., which is hereby incorporated by reference, are adapted to make the drug matrices described herein.
  • The drug present in the solids or powder produced may be in a crystalline or an amorphous state, or may be mixture of such states. The state generally depends on how the droplets are dried and the excipients present.
  • Emulsion Stabilization
  • In embodiments in which at least one pore forming agent is combined with the drug solution to form an emulsion, a surfactant or emulsifying agent can be added to enhance the stability of the emulsion. A variety of surfactants may be incorporated in this process, preferably to an amount between 0.1 and 5% by weight. Exemplary emulsifiers or surfactants which may be used include most physiologically acceptable emulsifiers, for instance egg lecithin or soya bean lecithin, or synthetic lecithins such as saturated synthetic lecithins, for example, dimyristoyl phosphatidyl choline, dipalmitoyl phosphatidyl choline or distearoyl phosphatidyl choline or unsaturated synthetic lecithins, such as dioleyl phosphatidyl choline or dilinoleyl phosphatidyl choline. Other hydrophobic or amphipathic compounds can be used in place of the phospholipid, for example, cholesterol. Emulsifiers also include surfactants such as free fatty acids, esters of fatty acids with polyoxyalkylene compounds like polyoxpropylene glycol and polyoxyethylene glycol; ethers of fatty alcohols with polyoxyalkylene glycols; esters of fatty acids with polyoxyalkylated sorbitan; soaps; glycerol-polyalkylene stearate; glycerol-polyoxyethylene ricinoleate; homo- and co-polymers of polyalkylene glycols; polyethoxylated soya-oil and castor oil as well as hydrogenated derivatives; ethers and esters of sucrose or other carbohydrates with fatty acids, fatty alcohols, these being optionally polyoxyalkylated; mono-, di- and tri-glycerides of saturated or unsaturated fatty acids, glycerides of soya-oil and sucrose.
  • Other emulsifiers include natural and synthetic forms of bile salts or bile acids, both conjugated with amino acids and unconjugated such as taurodeoxycholate and cholic acid.
  • V. Porous Drug Matrix Applications
  • The porous drug matrices described herein are useful in formulations for administration to a patient in need of the drug. As used herein, “patient” refers to animals, including mammals, preferably humans. The formulations deliver a therapeutically or prophylactically effective amount of the drug to the patient.
  • The porous matrices, or formulations thereof, are suitable for administration of drug by a variety of routes, for example, parenteral, mucosal, oral, topical/transdermal administration, for local, regional, or systemic effect. Examples of parenteral routes include intraveneous, intraarterial, intracardiac, intrathecal, intraosseous, intraarticular, intrasynovial, intracutaneous, subcutaneous, and intramuscular administration. Examples of mucosal routes include pulmonary (intrarespiratory), buccal, sublingual, intranasal, rectal, and vaginal administration. The porous matrices also can be formulated for intraocular, conjunctival, aural, urethral, intracranial, intralesional, and intratumoral administration.
  • In a preferred embodiment, the drug matrix is in the form of powder, which can be reconstituted with an aqueous medium, such as physiological saline, and administered parenterally, such as intramuscularly, subcutaneously, or intravenously. An advantage of the formulations described herein is that they can be used to convert drugs which must be infused (e.g., to avoid precipitation of the drug following bolus injection) to a bolus formulation, avoiding unacceptable precipitation of drug in vivo or for local delivery.
  • Alternatively, the matrix can be further processed using standard techniques into tablets or capsules for oral administration, into rectal suppositories, into a dry powder inhaler for pulmonary administration, or mixed/processed into a cream or ointment for topical administration. These standard techniques are described, for example, in Ansel, et al., “Pharmaceutical Dosage Forms and Drug Delivery Systems,” 6th Ed., (Williams & Wilkins 1995), which is incorporated herein by reference.
  • The present invention will be further understood with reference to the following non-limiting examples.
  • Overview
  • Examples 1-10 demonstrate production of porous drug matrices using different pore forming agents, different drugs, and different solvents. Examples 1-8 use emulsion formulations to produce the matrices, whereas Examples 9 and 10 use solution formulations to produce the matrices.
  • Examples 11-13 describe the analyses which were used to characterize the porous drug matrices produced in Examples 1-10. These characteristics include density, drug integrity, and dissolution properties. Example 14 describes particle size analysis and surface area analysis of low water solubility drug particles incorporated into the porous drug matrices.
  • Examples 15-17 describe experiments demonstrating the increased internal surface area of porous drug matrices produced with pore forming agents. Examples 18-21 describe experiments demonstrating the advantage or need to include a wetting agent as a component of the porous drug matrices.
  • Example 22 describes an experiment demonstrating the administration of porous drug matrices as an intravenous bolus.
  • Examples 23 and 24 describe the production of porous drug matrices produced with pore forming agents and pegylated phospholipids.
  • Materials and Equipment
  • The following materials and equipment were used in the examples. PEG 3350, PEG 8000, polyvinylpyrrolidone K-15, nifedipine, naproxen, prednisone, SPAN™ 40, lecithin, TWEEN™ 80, PLURONIC™ F127, ammonium chloride, ammonium bicarbonate, and ammonium acetate were obtained from Spectrum Chemicals (Gardena, Calif.). Griseofulvin was obtained from Aldrich Chemicals (Milwaukee, Wis.). Paclitaxel was obtained from Hauser (Boulder, Colo.). 1,2-Dimyristoyl-sn-Glycero-3-Phosphoethanolamine-N-[Poly(ethylene glycol)-5000] (PEG 5000 PE) and 1,2-Dimyristoyl-sn-Glycero-3-Phosphoethanolamine-N-[Poly(ethylene glycol)-2000] (PEG 2000 PE) were obtained from Avanti Polar Lipids Inc. (Alabaster, Ala.). Methylene chloride was obtained from EM Science (Gibbstown, N.J.). All emulsions were produced using a Virtis IQ2 homogenizer (Virtis, Gardiner, N.Y.). Formulations were spray dried on a benchtop spray dryer using an air atomizing nozzle.
    • EXAMPLE 1 Production of a Porous Prednisone Matrix Using Ammonium Bicarbonate as a Pore Forming Agent with SPAN™ 40 and PEG 8000 as Wetting Agents
  • 5.46 g of PEG 8000, 0.545 g of prednisone, and 0.055 g of SPAN™ 40 were dissolved in 182 mL of methylene chloride. An aqueous solution was prepared by dissolving 3.27 g of ammonium bicarbonate in 18.2 mL of deionized (DI) water. The aqueous solution was added to the organic solution (phase ratio 1:10) and homogenized for 5 minutes at 16,000 RPM. The resulting emulsion was spray dried on a benchtop spray dryer using an air-atomizing nozzle and nitrogen as the drying gas. Spray drying process conditions were 20 mL/min solution flow rate, 60 kg/hr drying gas rate, and 36° C. outlet temperature.
    • EXAMPLE 2 Production of a Porous Prednisone Matrix Using Ammonium Bicarbonate as a Pore Forming Agent with PEG 8000, TWEEN™ 80, Lecithin as Wetting Agents
  • 5.46 g of PEG 8000, 0.545 g of prednisone, 0.003 g of TWEEN™ 80, and 0.003 g of lecithin were dissolved in 182 mL of methylene chloride. An aqueous solution was prepared as described in Example 1. The aqueous solution was added to the organic solution (phase ratio 1:10) and homogenized for 15 minutes as described in Example 1. The resulting emulsion was spray dried as described in Example 1 using process conditions of 20 mL/min solution flow rate, 60 kg/hr drying gas rate, and 35° C. outlet temperature.
    • EXAMPLE 3 Production of a Porous Prednisone Matrix Using Ammonium Acetate as a Pore Forming Agent, and PEG 8000, TWEEN™ 80, and Lecithin as Wetting Agents
  • A prednisone-loaded organic solution was prepared as described in Example 2. An aqueous solution was prepared by dissolving 3.27 g of ammonium acetate in 18.2 mL of DI water. The aqueous and organic solutions were homogenized and spray dried as described in Example 2.
    • EXAMPLE 4 Production of a Porous Prednisone Matrix Using Ammonium Chloride as a POre Forming Agent, and PEG 8000, TWEEN™ 80, and Lecithin as Wetting Agents
  • A prednisone-loaded organic solution was prepared as described in Example 2. An aqueous solution was prepared by dissolving 3.27 g of ammonium chloride in 18.2 mL of DI water. The aqueous and organic solutions were homogenized as described in Example 1. The resulting emulsion was spray dried as described in Example 2.
    • EXAMPLE 5 Production of a Porous Griseofulvin Matrix Using Ammonium Bicarbonate as a Pore Forming Agent, and PEG 3350, TWEEN™ 80, and Lecithin as Wetting Agents
  • 9.09 g of PEG 3350, 4.55 g of griseofulvin, 0.01 g of TWEEN™ 80, and 0.01 g of lecithin were dissolved in 182 mL of methylene chloride. An aqueous solution was prepared by dissolving 3.27 g of ammonium bicarbonate and 1.09 g of PEG 3350 in 18.2 mL of DI water. The aqueous and organic solutions were homogenized as described in Example 1. The resulting emulsion was spray dried as described in Example 1 using process conditions of 20 ml/min solution flow rate, 80 kg/hr drying gas rate, and 12° C. outlet temperature.
    • EXAMPLE 6 Production of a Porous Nifedipine Matrix Using Ammonium Bicarbonate as a Pore Forming Agent, and PEG 3350 and Lecithin as Wetting Agents
  • 9.09 g of PEG 3350, 2.27 g of nifedipine, and 0.009 g of lecithin were dissolved in 182 mL of methylene chloride. An aqueous solution was prepared by dissolving 3.27 g of ammonium bicarbonate in 18.2 mL of DI water. The aqueous and organic solutions were homogenized in described in Example 1. The resulting emulsion was spray dried as described in Example 1 using process conditions of 20 ml/min solution flow rate, 60 kg/hr drying gas rate, and 20° C. outlet temperature.
    • EXAMPLE 7 Production of a Porous Naproxen Matrix Using Ammonium Chloride as a Pore Forming Agent, and PEG 3350 and Lecithin as Wetting Agents
  • A naproxen-loaded organic solution was prepared by dissolving 10.91 g of PEG 3350, 2.73 g of naproxen, and 0.109 g of lecithin in 182 mL of methylene chloride. An aqueous solution was prepared as described in Example 4. The aqueous and organic solutions were homogenized as described in Example 1, and the resulting emulsion was spray dried using process conditions of 20 ml/min solution flow rate, 100 kg/hr drying gas rate, and 20° C. outlet temperature.
    • EXAMPLE 8 Production of a Porous Paclitaxel Matrix Using Ammonium Bicarbonate as a Pore Forming Agent, and PEG 3350 and Lecithin as Wetting Agents
  • A paclitaxel-loaded organic solution was prepared by dissolving 3.0 g of paclitaxel, 15.0 g of PEG 3350, and 15.7 mg of lecithin in 100 mL of methylene chloride. An aqueous solution composed of 1.8 g of ammonium bicarbonate and 0.6 g of PEG 3350 in 10 mL of DI water was added to the organic solution (phase ratio 1:10). The mixture was homogenized for 5 minutes at 16,000 RPM. The resulting emulsion was spray dried using process conditions of 10 mL/min solution flow rate, 60 kg/hr drying gas rate, and 25° C. outlet temperature.
    • EXAMPLE 9 Production of a Porous Nifedipine Matrix Using Ammonium Bicarbonate as a Pore Forming Agent, PEG 3350 and TWEEN™ 80 as Wetting Agents, Polyvinylpyrrolidone as a Bulking Agent, and Ethanol as a Solvent
  • A nifedipine-loaded organic solution was prepared by dissolving 0.76 g of nifedipine, 0.28 g of PEG 3350, and 2.72 g of polyvinylpyrrolidone K-15 in 170 mL of ethanol. An aqueous solution composed of 1.62 g of ammonium bicarbonate and 3 mg of TWEEN™ 80 in 30 mL of DI water was added to the ethanol solution and mixed. The resulting solution was spray dried using process conditions of 20 mL/min solution flow rate, 100 kg/hr drying gas rate, and 36° C. outlet temperature.
    • EXAMPLE 10 Production of a Porous Nifedipine Matrix Using Ammonium Bicarbonate as a Pore Forming Agent, PEG 3350 and PLURONIC™ F127 as Wetting Agents, Polyvinylpyrrolidone as a Bulking Agent, and Ethanol as a Solvent
  • A nifedipine-loaded organic solution was prepared by dissolving 0.76 g of nifedipine, 0.28 g of PEG 3350, and 2.72 g of polyvinylpyrrolidone K-15 in 170 mL of ethanol. An aqueous solution composed of 1.62 g of ammonium bicarbonate and 3 mg of PLURONIC™ F127 in 30 mL of DI water was added to the ethanol solution and mixed. The resulting solution was spray dried using process conditions of 20 mL/min solution flow rate, 100 kg/hr drying gas rate, and 36° C. outlet temperature.
    • EXAMPLE 11 In Vitro Dissolution of Porous Drug Matrices
  • The in vitro dissolution rates of the powders produced in Examples 1-10 were compared to the dissolution rates of the bulk drug of interest.
  • Analytical Method
  • All dissolution studies were conducted in PBS (phosphate buffered saline) at room temperature in a glass beaker using overhead mixing. The mixer used was an IKARW16 Basic Mixer with a R1342 impeller shaft running at stirring rate 5. Samples were removed via pipet, filtered through 0.22 micron CA syringe filter, and then analyzed. UV-vis spectroscopy was conducted on an Hewlett Packard Model 8453. Dissolution curves are presented as percent of complete dissolution.
  • For griseofulvin, PBS (600 mL) was added to an appropriate amount of material being tested to contain 2.4 mg of griseofulvin. UV analysis was performed at 291 nm.
  • For naproxen, PBS (100 mL) was added to an appropriate amount of material being tested to contain 100 mg of naproxen. All vessels containing naproxen as a solid or as a solution were protected from light. UV analysis was performed at 332 nm.
  • For nifedipine, PBS (600 mL) was added to an appropriate amount of material being tested to contain 2.4 mg of nifedipine. All vessels containing nifedipine as a solid or in solution were protected from light. UV analysis was performed at 237 nm.
  • For prednisone, PBS (250 mL) was added to an appropriate amount of material being tested to contain 5 mg of prednisone. UV analysis was performed at 244 nm.
  • For paclitaxel, studies were conducted in PBS containing 0.08% TWEEN™ 80 (T80/PBS). T80/PBS (10 mL) was added to an appropriate amount of material being tested to contain 5 mg of paclitaxel in a 15 mL polypropylene conical tube, and the suspension was vortexed for 3-4 minutes. The suspension (0.25 mL) was then added to 250 mL of T80/PBS in a 600 mL glass beaker for dissolution analysis. HPLC analysis was performed directly on the filtered aqueous solutions using the paclitaxel HPLC method described in Example 13.
  • Results
  • The in vitro dissolution rates of the porous drug matrices produced in examples 1-10 are provided in FIGS. 1-6. The in vitro dissolution of the porous drug matrices are compared to the bulk drug of interest. In all cases, the time for 80% dissolution of the porous drug matrices is 4-50 times shorter than the time for 80% of the bulk drug to dissolve. The rate of dissolution which is approximated as the slope of the curve is 10 to 1400 times greater for the porous drug matrices of Examples 1-10 as compared to the specific bulk drug of interest.
    • EXAMPLE 12 Density of Porous Drug Matrices
  • The densities of the dry powder produced in Examples 1-7 are summarized in Table 1. Density was measured using Transaxial Pressure (“TAP”) with a Micromeritics GeoPyc 1360 using a consolidation force of 8 Newtons. The matrices are less dense than the starting bulk drug in all cases, indicating that the porous drug matrices are more porous than the commercially available bulk drug.
    TABLE 1
    Particle Density Analysis
    Material Density (g/mL)
    Prednisone Bulk 0.68
    Example 1 0.48
    Example 2 0.55
    Example 3 0.51
    Example 4 0.49
    Griseofulvin Bulk 0.80
    Example 5 0.55
    Nifedipine Bulk 1.01
    Example 6 0.56
    Naproxen Bulk 0.69
    Example 7 0.58
    • EXAMPLE 13 Integrity of the Drug in Porous Drug Matrices
  • Analytical Method
  • Drug integrity post processing was assessed by High Pressure Liquid Chromatography (“HPLC”) (Hewlett Packard Series 1100 HPLC). USP chromatography conditions were used for prednisone, naproxen, nifedipine, and griseofulvin. Vessels and vials containing naproxen or nifedipine solutions were protected from light. For paclitaxel, the chromatographic conditions included a Nucleosil column (5:m, C18, 100A, 250×4.6 mm), a mobile phase of 2 mM H3PO4/Acetonitrile (2:3) at a flow rate of 1.5 mL/min, UV detection at 227 nm, and a run time of 25 min.
  • Results
  • The integrities of the drugs following the processing in Examples 1-9 are shown in Table 2 as purities. The process of forming the drug into porous matrices does not appear to alter the purity of the drug.
    TABLE 2
    Drug Integrity Analysis
    Material Purity (%)
    Prednisone Powder 100
    Example 1 99.8
    Example 2 99.8
    Example 3 99.8
    Example 4 99.8
    Griseofulvin Bulk 95.7
    Example 5 95.7
    Nifedipine Bulk 100
    Example 6 100
    Example 9 100
    Example 10 100
    Naproxen Bulk 100
    Example 7 100
    Paclitaxel Bulk 100
    Example 8 100
    • EXAMPLE 14 Particle Size Analysis and Surface Area Analysis of Drug Particles in Wetted Porous Drug Matrices
  • Analytical Methods
  • Particle size analysis was performed using the Coulter Multisizer II with a 50 micron aperture using siphon mode. Electrolyte was pre-saturated with the drug of interest, and filtered through a 0.22 micron filter prior to addition of lots for analysis to ensure that no portion of the drug within the lot would dissolve during the analysis.
  • Results
  • The mean particle size and total surface area of the drug particles generated when the porous drug matrices produced in Examples 1-7 were reconstituted in aqueous media are summarized in Table 3.
    TABLE 3
    Particle Size and Surface Area Analysis
    Surface Area
    (m2/mL of
    Material Size (microns) microparticles)
    Prednisone Powder 2.07 1.43
    Example 1 1.58 1.66
    Example 2 1.39 2.53
    Example 3 1.39 3.02
    Example 4 1.24 3.36
    Griseofulvin Bulk 2.42 0.88
    Example 5 2.16 1.28
    Nifedipine Bulk 2.64 0.57
    Example 6 1.78 1.98
    Naproxen Bulk 2.89 0.66
    Example 7 1.34 2.79

    In all cases, the particle size of the drug particles which resulted from wetting of the porous drug matrices was reduced relative to the starting bulk material by 10 to 54%, and the total surface area of the particles was increased relative to the starting bulk drug by approximately 16-320%.
    • EXAMPLE 15 Nifedipine Drug Matrices Containing a Wetting Agent Produced With and Without a Pore Forming Agent
  • A nifedipine/PEG solution was prepared by dissolving 2.0 g of nifedipine, 8.0 g of PEG 3350, and 8 mg of lecithin in 200 mL of methylene chloride (Example 15A). A second identical nifedipine-loaded organic solution was prepared. An aqueous solution composed of 1.8 g of ammonium bicarbonate in 20 mL of DI water was added to the first nifedipine organic solution (phase ratio 1:10). The mixture was homogenized for 5 minutes at 16,000 RPM. The nifedipine solution (Example 15A) and the nifedipine emulsion (Example 15B) were separately spray dried using process conditions of 20 mL/min solution flow rate, 60 kg/hr drying gas rate, and 21° C. outlet temperature.
    • EXAMPLE 16 Griseofulvin Drug Matrices Containing a Wetting Agent Produced With and Without a Pore Forming Agent
  • A griseofulvin/PEG solution was prepared by dissolving 5.0 g of griseofulvin, 11.2 g of PEG 3350, 11 mg of TWEEN™ 80, and 11 mg of lecithin in 200 mL of methylene chloride (Example 16A). A second identical griseofulvin-loaded organic solution was prepared. An aqueous solution composed of 1.8 g of ammonium bicarbonate in 20 mL of DI water was added to the first organic solution (phase ratio 1:10). The mixture was homogenized for 5 minutes at 16,000 RPM. The griseofulvin solution (Example 16A) and griseofulvin emulsion (Example 16B) were spray dried on a benchtop spray dryer using process conditions of 20 mL/min solution flow rate, 80 kg/hr drying gas rate, and 13° C. outlet temperature.
    • EXAMPLE 17 Internal Surface Area of Porous Drug Matrices Containing a Wetting Agent and Produced With and Without a Pore Forming Agent
  • The internal surface areas of the drug matrices produced in Examples 15 and 16 were assessed by Krypton BET. BET specific surface area analysis was performed using multi-point surface area analysis with krypton as the gas. Samples were outgassed to 20 micron vacuum at 20° C. prior to analysis.
  • The results, shown in Table 4, illustrate that the use of the pore forming agent led to an increase of between 2.3 and 3.5 fold in the internal surface area of the resultant drug matrix.
    TABLE 4
    Internal Surface Area of Drug Matrices
    Surface Area (m2/g
    Matrix (Example No.) matrix)
    Nifedipine with wetting agent (15A) 0.40
    Nifedipine with wetting agent and 1.4
    Ammonium Bicarbonate (15B)
    Griseofulvin with wetting agent (16A) 0.41
    Griseofulvin with wetting agent and 0.95
    Ammonium Bicarbonate (16B)
    • EXAMPLE 18 Nifedipine Drug Matrix Produced Without a Pore Forming Agent or Wetting Agent
  • A 5% nifedipine solution was prepared by dissolving 10.0 g of nifedipine in 200 mL of methylene chloride. The solution was spray dried on a benchtop spray dryer using the following conditions: 20 mL/min solution flow rate, 60 kg/hr drying gas rate, and 22° C. outlet temperature.
    • EXAMPLE 19 Griseofulvin Drug Matrix Produced Without a Pore Forming Agent or Wetting Agent
  • An 8.1% griseofulvin solution was prepared by dissolving 16.2 g of griseofulvin in 200 mL of methylene chloride. The solution was spray dried on a benchtop spray dryer using process conditions of 20 mL/min solution flow rate, 80 kg/hr drying gas rate, and 13° C. outlet temperature.
    • EXAMPLE 20 In Vitro Dissolutiom of Nifedipine Drug Matrices Produced With/Without Pore Forming Agent and Wetting Agent
  • The in vitro dissolution rates of the nifedipine matrices produced in Examples 15 and 18 are shown in FIG. 6. The in vitro dissolution of the drug matrices produced with either wetting agent or wetting agent and pore forming agent have increased dissolution rates as compared to the drug matrix produced with the drug alone. The matrix produced with both the wetting agent and the pore forming agent has the greatest dissolution rate.
    • EXAMPLE 21 In Vitro Dissolution of Griseofulvin Drug Matrices Produced With/Without Pore Forming Agent and Wetting Agent
  • The in vitro dissolution rates of the griseofulvin matrices produced in examples 16 and 19 are provided in FIG. 7. The in vitro dissolution of the drug matrices produced with either wetting agent or wetting agent and pore forming agent have increased dissolution rates as compared to the drug matrix produced with the drug alone. The matrix produced with both the wetting agent and the pore forming agent has the greatest dissolution rate.
    • EXAMPLE 22 Administration of Porous Drug Matrices as an Intravenous Bolus to Dogs
  • A nifedipine-loaded organic solution was prepared by dissolving 9.09 g of PEG 3350, 2.27 g of nifedipine, and 0.009 g of lecithin in 182 mL of methylene chloride. An aqueous solution was prepared by dissolving 3.27 g of ammonium bicarbonate and 0.91 g of PEG 3350 in 18.2 mL of deionized water at room temperature. The aqueous and organic solutions were homogenized as described in Example 1, and the resulting emulsion was spray dried using process conditions of 20 mL/min solution flow rate, 60 kg/hr drying gas rate, and 20° C. outlet temperature.
  • A suspension of the porous nifedipine drug matrix was prepared in 5% dextrose solution at a concentration of 2.5 mg/mL. The suspension (2 mL) was administered as a bolus to four beagle dogs, which weighed 8-10 kg. Blood samples were taken at time-points ranging from 1 minute to 24 hours. The samples were processed into plasma, were stored frozen, and were protected from light until analysis via liquid chromatography-mass spectrometry.
  • All animals tolerated the suspension administered as a bolus. The average plasma levels of the intravenously administered suspension is shown in FIG. 8.
    • EXAMPLE 23 Production of a Porous Nifedipine Matrix Using a Pegylated Phospholipid, 1,2-Dimyristoyl-sn-Glycero-3-Phosphoethanolamine-N-[Poly(ethylene glycol)-5000]
  • A nifedipine-loaded organic solution was prepared by dissolving 2.0 g of nifedipine, 30.0 g of PEG 3350, 4 mg of lecithin, and 4 mg of 1,2-Dimyristoyl-sn-Glycero-3-Phosphoethanolamine-N-[Poly(ethylene glycol)-5000] (PEG 5000 PE) in 202 mL of methylene chloride. An aqueous solution of 1.8 g of ammonium bicarbonate in 20 mL of DI water was added to the organic solution (phase ratio 1:10). The mixture was homogenized for 5 minutes at 16,000 RPM. The resulting emulsion was spray dried using process conditions of 20 mL/min solution flow rate, 60 kg/hr drying gas rate, and 21° C. outlet temperature.
    • EXAMPLE 24 Production of a Porous Nifedipine Matrix Using a Pegylated Phospholipid, 1,2-Dimyristoyl-sn-Glycero-3-Phosphoethanolamine-N-[Poly(ethylene glycol)-2001]
  • A nifedipine-loaded organic solution was prepared by dissolving 2.0 g of nifedipine, 30.0 g of PEG 3350, 4 mg of lecithin, and 4 mg of 1 2-Dimyristoyl-sn-Glycero-3-Phosphoethanolamine-N-[Poly(ethylene glycol)-2000] (PEG 2000 PE) in 202 mL of methylene chloride. An aqueous solution composed of 1.8 g of ammonium bicarbonate in 20 ml of DI water was added to the organic solution (phase ratio 1:10). The mixture was homogenized for 5 minutes at 16,000 RPM. The resulting emulsion was spray dried using process conditions of 20 mL/min solution flow rate, 60 kg/hr drying gas rate, and 21° C. outlet temperature.
  • Modifications and variations of the present invention will be obvious to those of skill in the art from the foregoing detailed description. Such modifications and variations are intended to come within the scope of the following claims.

Claims (16)

1. A pharmaceutical composition comprising a porous matrix formed of a hydrophilic or hydrophobic excipient and microparticles of a drug,
wherein the microparticles have a mean diameter between about 0.1 and 5 μm and a total surface area greater than about 0.5 m2/mL, and
wherein the dry porous matrix is in a dry powder form having a TAP density less than or equal to 1.0 g/mL and having a total surface area of greater than or equal to 0.2 m2/g.
2. The pharmaceutical composition of claim 1 comprising between 1 and 95% drug by weight in combination with at least one hydrophilic or hydrophobic excipient which enhances the rate of drug dissolution, stabilizes the drug in crystalline form by inhibiting crystal growth or stabilizes the drug in amorphous form by preventing crystallization.
3. The pharmaceutical composition of claim 1 comprising between about 5 and 60% drug.
4. The pharmaceutical composition of claim 1 comprising one or more hydrophobic or hydrophilic excipients selected from the group consisting of polymers, amino acids, sugars, preservatives, wetting agents, tonicity agents, pegylated excipients, and combinations thereof.
5. The pharmaceutical composition of claim 1 wherein the excipient is hydrophobic or hydrophilic amino acid.
6. The composition of claim 1 wherein the drug is a low aqueous solubility drug.
7. The composition of claim 1 wherein the drug is a low aqueous solubility drug, wherein the porous matrix upon contact with an aqueous medium yields microparticles having a mean diameter between about 0.1 and 5 μm and a total surface area greater than about 0.5 m2/mL, and
wherein the dry porous matrix is in a dry powder form having a TAP density less than or equal to 1.0 g/mL and having a total surface area of greater than or equal to 0.2 m2/g.
8. The composition of claim 1 wherein the drug is selected from the group consisting of albuterol, adapalene, doxazosin mesylate, mometasone furoate, ursodiol, amphotericin, enalapril maleate, felodipine, nefazodone hydrochloride, valrubicin, albendazole, estrogens conjugated, medroxyprogesterone acetate, nicardipine hydrochloride, zolpidem tartrate, amlodipine besylate, ethinyl estradiol, omeprazole, rubitecan, amlodipine besylate/benazepril hydrochloride, etodolac, paroxetine hydrochloride, paclitaxel, atovaquone, felodipine, podofilox, paricalcitol, betamethasone dipropionate, fentanyl, pramipexole dihydrochloride, Vitamin D3 and related analogues, finasteride, quetiapine fulmarate, alprostadil candesartan, cilexetil, fluconazole, ritonavir, busulfan, carbamazepine, flumazenil, risperidone, carbemazepine, carbidopa/levodopa, ganciclovir, saquinavir, amprenavir, carboplatin, glyburide, sertraline hydrochloride, rofecoxib carvedilol, halobetasolproprionate, sildenafil citrate, celecoxib, chlorthalidone, imiquimod, simvastatin, citalopram, ciprofloxacin, irinotecan hydrochloride, sparfloxacin, efavirenz, cisapride monohydrate, lansoprazole, tamsulosin hydrochloride, mofafinil, azithromycin, clarithromycin, letrozole, terbinafine hydrochloride, rosiglitazone maleate, diclofenac sodium, lomefloxacin hydrochloride, tirofiban hydrochloride, telmisartan, diazapam, loratadine, toremifene citrate, thalidomide, dinoprostone, mefloquine hydrochloride, trandolapril, docetaxel, mitoxantrone hydrochloride, tretinoin, etodolac, triamcinolone acetate, estradiol, ursodiol, nelfinavir mesylate, indinavir, beclomethasone dipropionate, oxaprozin, flutamide, famotidine, nifedipine, prednisone, cefuiroxime, lorazepam, digoxin, lovastatin, griseofulvin, naproxen, ibuprofen, isotretinoin, tamoxifen citrate, nimodipine, amiodarone, and alprazolam.
9. The composition of claim 1 wherein the drug is water-soluble.
10. The composition of claim 1 wherein the drug is selected from the group consisting of ceftriaxone, ketoconazole, ceftazidime, oxaprozin, albuterol, valacyclovir, urofollitropin, famciclovir, fluticasone, budesonide, flutamide, enalapril, mefformin, itraconazole, buspirone, gabapentin, fosinopril, tramadol, acarbose, lorazepam, follitropin, glipizide, omeprazole, fluoxetine, lisinopril, levofloxacin, zafirlukast, interferon, growth hormone, interleukin, erythropoietin, granulocyte stimulating factor, nizatidine, bupropion, perindopril, erbumine, adenosine, alendronate, alprostadil, benazepril, betaxolol, bleomycin sulfate, dexfenfluramine, diltiazem, fentanyl, flecainid, gemcitabine, glatiramer acetate, granisetron, lamivudine, mangafodipir trisodium, mesalamine, metoprolol fumarate, metronidazole, miglitol, moexipril, monteleukast, octreotide acetate, olopatadine, paricalcitol, somatropin, sumatriptan succinate, tacrine, verapainil, nabumetone, trovafloxacin, dolasetron, zidovudine, finasteride, tobramycin, isradipine, tolcapone, enoxaparin, fluconazole, lansoprazole, terbinafine, pamidronate, didanosine, diclofenac, cisapride, venlafaxine, troglitazone, fluvastatin, losartan, imiglucerase, donepezil, olanzapine, valsartan, fexofenadine, calcitonin, and ipratropium.
11. The composition of claim 1 wherein the mean diameter of the microparticles is between about 1 and 5 μm.
12. The composition of claim 1 wherein the microparticles are suspended in an aqueous solution suitable for parenteral administration.
13. The composition of claim 1 wherein the matrix is processed into tablets or capsules suitable for oral administration.
14. The composition of claim 1 wherein the matrix is formed into suppositories suitable for vaginal or rectal administration.
15. The composition of claim 1 wherein the matrix is in a dry powder form suitable for pulmonary administration.
16.-33. (Canceled)
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Cited By (46)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050143404A1 (en) * 2003-08-28 2005-06-30 Joerg Rosenberg Solid pharmaceutical dosage formulation
US20060246003A1 (en) * 2004-12-27 2006-11-02 Eisai Co. Ltd. Composition containing anti-dementia drug
US20060280789A1 (en) * 2004-12-27 2006-12-14 Eisai Research Institute Sustained release formulations
US20080213368A1 (en) * 2004-12-27 2008-09-04 Eisai R & D Management Co., Ltd. Method for Stabilizing Anti-Dementia Drug
USRE40493E1 (en) * 1999-05-27 2008-09-09 Acusphere, Inc. Porous paclitaxel matrices and methods of manufacture thereof
US20080226721A1 (en) * 2004-01-28 2008-09-18 Andrew Ian Cooper Porous Bodies and Method of Production Thereof
US20080262100A1 (en) * 2005-01-28 2008-10-23 Andrew Ian Cooper Method of Preparing Carrier Liquids
US20090169622A1 (en) * 2007-12-27 2009-07-02 Roxane Laboratories, Inc. Delayed-release oral pharmaceutical composition for treatment of colonic disorders
US20090208579A1 (en) * 2004-12-27 2009-08-20 Eisai R & D Management Co., Ltd. Matrix Type Sustained-Release Preparation Containing Basic Drug or Salt Thereof, and Method for Manufacturing the Same
US20090239749A1 (en) * 2006-07-13 2009-09-24 David John Duncalf Biocidal compositions
US20100081628A1 (en) * 2008-06-11 2010-04-01 Pharmasset, Inc. Nucleoside cyclicphosphates
WO2010075517A2 (en) 2008-12-23 2010-07-01 Pharmasset, Inc. Nucleoside analogs
WO2010075554A1 (en) 2008-12-23 2010-07-01 Pharmasset, Inc. Synthesis of purine nucleosides
WO2010075549A2 (en) 2008-12-23 2010-07-01 Pharmasset, Inc. Nucleoside phosphoramidates
WO2010135569A1 (en) 2009-05-20 2010-11-25 Pharmasset, Inc. N- [ (2 ' r) -2 ' -deoxy-2 ' -fluoro-2 ' -methyl-p-phenyl-5 ' -uridylyl] -l-alanine 1-methylethyl ester and process for its production
WO2010144865A2 (en) 2009-06-12 2010-12-16 Meritage Pharma, Inc. Methods for treating gastrointestinal disorders
US20110008430A1 (en) * 2003-08-28 2011-01-13 Abbott Laboratories Solid Pharmaceutical Dosage Form
EP2349336A1 (en) * 2008-10-28 2011-08-03 Agency For Science, Technology And Research Mesoporous material excipients for poorly aqueous soluble ingredients
US20110237614A1 (en) * 2008-09-16 2011-09-29 Nektar Therapeutics Pegylated Opioids with Low Potential for Abuse
WO2011123668A2 (en) 2010-03-31 2011-10-06 Pharmasset, Inc. Stereoselective synthesis of phosphorus containing actives
WO2011123672A1 (en) 2010-03-31 2011-10-06 Pharmasset, Inc. Purine nucleoside phosphoramidate
WO2011141721A3 (en) * 2010-05-14 2012-02-02 Iota Nanosolutions Limited Compositions
WO2012075140A1 (en) 2010-11-30 2012-06-07 Pharmasset, Inc. Compounds
US8470347B2 (en) 2000-05-30 2013-06-25 AbbVie Deutschland GmbH and Co KG Self-emulsifying active substance formulation and use of this formulation
US8563530B2 (en) 2010-03-31 2013-10-22 Gilead Pharmassel LLC Purine nucleoside phosphoramidate
US8569343B2 (en) 2007-03-12 2013-10-29 Nektar Therapeutics Oligomer-opioid agonist conjugates
US8633178B2 (en) 2011-11-23 2014-01-21 Therapeuticsmd, Inc. Natural combination hormone replacement formulations and therapies
US8933059B2 (en) 2012-06-18 2015-01-13 Therapeuticsmd, Inc. Natural combination hormone replacement formulations and therapies
US9180091B2 (en) 2012-12-21 2015-11-10 Therapeuticsmd, Inc. Soluble estradiol capsule for vaginal insertion
US9289382B2 (en) 2012-06-18 2016-03-22 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US9931349B2 (en) 2016-04-01 2018-04-03 Therapeuticsmd, Inc. Steroid hormone pharmaceutical composition
US10052386B2 (en) 2012-06-18 2018-08-21 Therapeuticsmd, Inc. Progesterone formulations
US10206932B2 (en) 2014-05-22 2019-02-19 Therapeuticsmd, Inc. Natural combination hormone replacement formulations and therapies
US10258630B2 (en) 2014-10-22 2019-04-16 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US10286077B2 (en) 2016-04-01 2019-05-14 Therapeuticsmd, Inc. Steroid hormone compositions in medium chain oils
US10328087B2 (en) 2015-07-23 2019-06-25 Therapeuticsmd, Inc. Formulations for solubilizing hormones
US10471148B2 (en) 2012-06-18 2019-11-12 Therapeuticsmd, Inc. Progesterone formulations having a desirable PK profile
US10471072B2 (en) 2012-12-21 2019-11-12 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US10512644B2 (en) 2007-03-12 2019-12-24 Inheris Pharmaceuticals, Inc. Oligomer-opioid agonist conjugates
US10537581B2 (en) 2012-12-21 2020-01-21 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US10806740B2 (en) 2012-06-18 2020-10-20 Therapeuticsmd, Inc. Natural combination hormone replacement formulations and therapies
US10806770B2 (en) 2014-10-31 2020-10-20 Monash University Powder formulation
US11246875B2 (en) 2012-12-21 2022-02-15 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US11266661B2 (en) 2012-12-21 2022-03-08 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US11413296B2 (en) 2005-11-12 2022-08-16 The Regents Of The University Of California Viscous budesonide for the treatment of inflammatory diseases of the gastrointestinal tract
US11633405B2 (en) 2020-02-07 2023-04-25 Therapeuticsmd, Inc. Steroid hormone pharmaceutical formulations

Families Citing this family (114)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9006175B2 (en) 1999-06-29 2015-04-14 Mannkind Corporation Potentiation of glucose elimination
GB9922271D0 (en) * 1999-09-21 1999-11-17 Zeneca Ltd Formulation
TWI312285B (en) 2001-10-25 2009-07-21 Depomed Inc Methods of treatment using a gastric retained gabapentin dosage
US7612112B2 (en) 2001-10-25 2009-11-03 Depomed, Inc. Methods of treatment using a gastric retained gabapentin dosage
ES2425392T3 (en) 2002-03-20 2013-10-15 Mannkind Corporation Cartridge for an inhalation device
WO2004006959A1 (en) * 2002-07-16 2004-01-22 Elan Pharma International, Ltd Liquid dosage compositions of stable nanoparticulate active agents
DE10244847A1 (en) 2002-09-20 2004-04-01 Ulrich Prof. Dr. Speck Medical device for drug delivery
US20080220074A1 (en) * 2002-10-04 2008-09-11 Elan Corporation Plc Gamma radiation sterilized nanoparticulate docetaxel compositions and methods of making same
KR100592512B1 (en) * 2002-11-22 2006-07-03 서울약품공업(주) Extended Release Formulation of Tamsulosin or Pharmaceutically Acceptable Salt for Treating Evacuatory Insufficiency
SG176314A1 (en) * 2002-12-31 2011-12-29 Altus Pharmaceuticals Inc Human growth hormone crystals and methods for preparing them
WO2004064834A1 (en) * 2003-01-21 2004-08-05 Ranbaxy Laboratories Limited Co-precipitated amorphous losartan and dosage forms comprising the same
IL154370A0 (en) * 2003-02-10 2003-09-17 Chemagis Ltd Solid amorphous mixtures, processes for the preparation thereof and pharmaceutical compositions containing the same
PT1615959E (en) 2003-04-10 2013-08-29 Evonik Corp A method for the production of emulsion-based micro particles
US20070207211A1 (en) * 2003-04-10 2007-09-06 Pr Pharmaceuticals, Inc. Emulsion-based microparticles and methods for the production thereof
AU2004259208B2 (en) * 2003-07-15 2011-04-28 Evonik Corporation Method for the preparation of controlled release formulations
US20050042177A1 (en) * 2003-07-23 2005-02-24 Elan Pharma International Ltd. Novel compositions of sildenafil free base
AU2004259209A1 (en) * 2003-07-23 2005-02-03 Pr Pharmaceuticals, Inc. Controlled release compositions
EP1732513A2 (en) * 2003-12-31 2006-12-20 Alpharma, Inc. Rosiglitazone formulations
US20050163842A1 (en) * 2003-12-31 2005-07-28 Garth Boehm Rosiglitazone and metformin formulations
US7468428B2 (en) 2004-03-17 2008-12-23 App Pharmaceuticals, Llc Lyophilized azithromycin formulation
DE102004028940A1 (en) * 2004-06-15 2006-01-12 Krka Tovarna Zdravil, D.D. Orally disintegrating pharmaceutical composition containing risperidone
US7858115B2 (en) * 2004-06-24 2010-12-28 Idexx Laboratories Phospholipid gel compositions for drug delivery and methods of treating conditions using same
US7618651B2 (en) * 2004-06-24 2009-11-17 Idexx Laboratories Pharmaceutical compositions for drug delivery and methods of treating or preventing conditions using same
US7854943B2 (en) * 2004-06-24 2010-12-21 Idexx Laboratories Phospholipid gel compositions for drug delivery and methods of treating conditions using same
US7772182B2 (en) * 2004-08-05 2010-08-10 Alza Corporation Stable suspension formulations of erythropoietin receptor agonists
PL1786784T3 (en) 2004-08-20 2011-04-29 Mannkind Corp Catalysis of diketopiperazine synthesis
US7820676B2 (en) 2004-08-23 2010-10-26 Mannkind Corporation Diketopiperazine salts for drug delivery and related methods
US20060045914A1 (en) * 2004-08-26 2006-03-02 Isp Investments Inc. Matrix composition for stable microemulsions
CA2581926A1 (en) * 2004-09-29 2006-04-06 Chemagis Ltd. Use of purified donepezil maleate for preparing pharmaceutically pure amorphous donepezil hydrochloride
EA200701442A1 (en) * 2005-01-06 2008-02-28 Элан Фарма Интернэшнл Лтд. COMPOSITIONS OF KANDESARTANA NANOPARTICLES
CA2598410A1 (en) * 2005-02-21 2006-08-24 Flamel Technologies Oral pharmaceutical for of losartan
US20060223882A1 (en) * 2005-03-23 2006-10-05 Venkataraman Sundaram Amorphous simvastatin
US8524734B2 (en) 2005-05-18 2013-09-03 Mpex Pharmaceuticals, Inc. Aerosolized fluoroquinolones and uses thereof
US7838532B2 (en) * 2005-05-18 2010-11-23 Mpex Pharmaceuticals, Inc. Aerosolized fluoroquinolones and uses thereof
CN101272769B (en) * 2005-07-28 2013-04-24 Isp投资有限公司 Benzoquinones of enhanced bioavailability
ES2640282T3 (en) 2005-09-14 2017-11-02 Mannkind Corporation Drug formulation method based on increasing the affinity of crystalline microparticle surfaces for active agents
AU2006307470A1 (en) * 2005-10-27 2007-05-03 Lupin Limited Pharmaceutical formulation of losartan
CN101312953B (en) 2005-11-17 2013-09-04 强恩有限公司 Pharmacologically active compounds containing sulfur
WO2007070843A2 (en) * 2005-12-15 2007-06-21 Acusphere, Inc. Processes for making particle-based pharmaceutical formulations for oral administration
CA2634053A1 (en) * 2005-12-23 2007-07-05 Altus Pharmaceuticals Inc. Compositions comprising polycation-complexed protein crystals and methods of treatment using them
US20090176882A1 (en) 2008-12-09 2009-07-09 Depomed, Inc. Gastric retentive gabapentin dosage forms and methods for using same
US7919108B2 (en) * 2006-03-10 2011-04-05 Cook Incorporated Taxane coatings for implantable medical devices
US20080286325A1 (en) * 2006-01-05 2008-11-20 Med Institute, Inc. Cyclodextrin elution media for medical device coatings comprising a taxane therapeutic agent
US8252328B2 (en) * 2006-01-06 2012-08-28 Acelrx Pharmaceuticals, Inc. Bioadhesive drug formulations for oral transmucosal delivery
US8753308B2 (en) 2006-01-06 2014-06-17 Acelrx Pharmaceuticals, Inc. Methods for administering small volume oral transmucosal dosage forms using a dispensing device
US8202535B2 (en) 2006-01-06 2012-06-19 Acelrx Pharmaceuticals, Inc. Small-volume oral transmucosal dosage forms
US8865743B2 (en) 2006-01-06 2014-10-21 Acelrx Pharmaceuticals, Inc. Small volume oral transmucosal dosage forms containing sufentanil for treatment of pain
US9289583B2 (en) 2006-01-06 2016-03-22 Acelrx Pharmaceuticals, Inc. Methods for administering small volume oral transmucosal dosage forms using a dispensing device
US9066847B2 (en) * 2007-01-05 2015-06-30 Aceirx Pharmaceuticals, Inc. Storage and dispensing devices for administration of oral transmucosal dosage forms
US8357114B2 (en) 2006-01-06 2013-01-22 Acelrx Pharmaceuticals, Inc. Drug dispensing device with flexible push rod
US8252329B2 (en) 2007-01-05 2012-08-28 Acelrx Pharmaceuticals, Inc. Bioadhesive drug formulations for oral transmucosal delivery
US8535714B2 (en) 2006-01-06 2013-09-17 Acelrx Pharmaceuticals, Inc. Small volume oral transmucosal dosage forms containing sufentanil for treatment of pain
CA2643464C (en) * 2006-02-22 2018-09-04 Mannkind Corporation A method for improving the pharmaceutic properties of microparticles comprising diketopiperazine and an active agent
US7875284B2 (en) * 2006-03-10 2011-01-25 Cook Incorporated Methods of manufacturing and modifying taxane coatings for implantable medical devices
US20070292503A1 (en) * 2006-06-16 2007-12-20 Gorissen Henricus R Oral pharmaceutical composition of poorly water-soluble active substance
US20100239629A1 (en) * 2006-07-31 2010-09-23 Isp Investments Inc. Delivery system for delivering bioactive materials
US20100260691A1 (en) * 2006-07-31 2010-10-14 Narayanan Kolazi S Aqueous compositions containing a hydrophobic material
CN101528224A (en) * 2006-09-05 2009-09-09 阿斯利康(瑞典)有限公司 Pharmaceutical composition comprising candesartan cilexetil
US8747871B2 (en) * 2006-09-28 2014-06-10 Isp Investments Inc. Synergistic matrix composite for making stable microemulsions of active ingredients
JP2010515753A (en) * 2007-01-10 2010-05-13 ボード・オブ・リージエンツ，ザ・ユニバーシテイ・オブ・テキサス・システム Enhanced delivery of an immunosuppressant composition for intrapulmonary delivery
WO2008118754A2 (en) * 2007-03-23 2008-10-02 Elan Corporation Plc Gamma radiation sterilized nanoparticulate docetaxel compositions and methods for making the same
TWI405590B (en) * 2007-04-06 2013-08-21 Activus Pharma Co Ltd Method of producing pulverized organic compound particle
WO2009051628A2 (en) * 2007-09-06 2009-04-23 Arezou Petrie Transdermal treatment device and method
WO2011163272A1 (en) 2010-06-21 2011-12-29 Mannkind Corporation Dry powder drug delivery system and methods
WO2009152421A1 (en) * 2008-06-12 2009-12-17 Scinopharm Taiwan, Ltd. Crystalline polymorphs of gemcitabine base
US8485180B2 (en) 2008-06-13 2013-07-16 Mannkind Corporation Dry powder drug delivery system
IL279542B2 (en) 2008-06-13 2023-10-01 Mannkind Corp A dry powder inhaler and system for drug delivery
EP2300083B1 (en) 2008-06-20 2013-05-22 MannKind Corporation An interactive apparatus and method for real-time profiling of inhalation efforts
TWI532497B (en) 2008-08-11 2016-05-11 曼凱公司 Use of ultrarapid acting insulin
WO2010042549A1 (en) 2008-10-07 2010-04-15 Mpex Pharmaceuticals, Inc. Inhalation of levofloxacin for reducing lung inflammation
CA2739897C (en) 2008-10-07 2017-10-03 Mpex Pharmaceuticals, Inc. Aerosol fluoroquinolone formulations for improved pharmacokinetics
US8945592B2 (en) 2008-11-21 2015-02-03 Acelrx Pharmaceuticals, Inc. Sufentanil solid dosage forms comprising oxygen scavengers and methods of using the same
US8314106B2 (en) 2008-12-29 2012-11-20 Mannkind Corporation Substituted diketopiperazine analogs for use as drug delivery agents
WO2010102066A1 (en) 2009-03-05 2010-09-10 Bend Research, Inc. Dextran polymer powder for inhalation administration of pharmaceuticals
PL2405963T3 (en) 2009-03-11 2014-04-30 Mannkind Corp Apparatus, system and method for measuring resistance of an inhaler
EP2411137B1 (en) 2009-03-27 2016-09-07 Bend Research, Inc. Spray-drying process
GB0908129D0 (en) * 2009-05-12 2009-06-24 Innovata Ltd Composition
AU2010259943C1 (en) 2009-06-12 2016-03-03 Mannkind Corporation Diketopiperazine microparticles with defined specific surface areas
PT2473170T (en) 2009-09-04 2019-08-23 Horizon Orphan Llc Use of aerosolized levofloxacin for treating cystic fibrosis
WO2011041595A1 (en) 2009-09-30 2011-04-07 Microdose Therapeutx, Inc. Methods and compositions for treatment of raynaud's phenomenon
CA2778698A1 (en) 2009-11-03 2011-05-12 Mannkind Corporation An apparatus and method for simulating inhalation efforts
WO2012031129A2 (en) 2010-09-03 2012-03-08 Bend Research, Inc. Spray-drying apparatus and methods of using the same
WO2012031133A2 (en) 2010-09-03 2012-03-08 Bench Research, Inc. Spray-drying apparatus and methods of using the same
US8815294B2 (en) 2010-09-03 2014-08-26 Bend Research, Inc. Pharmaceutical compositions of dextran polymer derivatives and a carrier material
WO2012040502A1 (en) 2010-09-24 2012-03-29 Bend Research, Inc. High-temperature spray drying process and apparatus
RU2013139247A (en) 2011-02-23 2015-03-27 Церулеус Лтд. FLUMAZENIL COMPLEXES CONTAINING THEIR COMPOSITIONS AND THEIR APPLICATIONS
SG194034A1 (en) 2011-04-01 2013-11-29 Mannkind Corp Blister package for pharmaceutical cartridges
US9060938B2 (en) 2011-05-10 2015-06-23 Bend Research, Inc. Pharmaceutical compositions of active agents and cationic dextran polymer derivatives
WO2012174472A1 (en) 2011-06-17 2012-12-20 Mannkind Corporation High capacity diketopiperazine microparticles
MX2014004983A (en) 2011-10-24 2014-09-22 Mannkid Corp Methods and compositions for treating pain.
ES2624294T3 (en) 2012-07-12 2017-07-13 Mannkind Corporation Dry powder drug delivery systems
US10159644B2 (en) 2012-10-26 2018-12-25 Mannkind Corporation Inhalable vaccine compositions and methods
US9757529B2 (en) 2012-12-20 2017-09-12 Otitopic Inc. Dry powder inhaler and methods of use
US9757395B2 (en) 2012-12-20 2017-09-12 Otitopic Inc. Dry powder inhaler and methods of use
FR3002735B1 (en) * 2013-03-04 2015-07-03 Virbac ORAL NUTRITIONAL COMPOSITION AND MEDICAMENT FOR VETERINARY USE
FR3002736B1 (en) 2013-03-04 2015-06-26 Virbac ORAL NUTRITIONAL COMPOSITION AND MEDICAMENT FOR VETERINARY USE
KR102499439B1 (en) 2013-03-15 2023-02-13 맨카인드 코포레이션 Microcrystalline diketopiperazine compositions and methods
CA2910766C (en) 2013-04-30 2020-12-15 Otitopic Inc. Dry powder formulations and methods of use
KR102465025B1 (en) 2013-07-18 2022-11-09 맨카인드 코포레이션 Heat-stable dry powder pharmaceutical compositions and methods
CA2920488C (en) 2013-08-05 2022-04-26 Mannkind Corporation Insufflation apparatus and methods
EP3082428A4 (en) 2013-12-09 2017-08-02 Respira Therapeutics, Inc. Pde5 inhibitor powder formulations and methods relating thereto
CN112656780A (en) 2014-02-20 2021-04-16 奥迪托皮克股份有限公司 Dry powder formulations for inhalation
WO2015148905A1 (en) 2014-03-28 2015-10-01 Mannkind Corporation Use of ultrarapid acting insulin
US9855234B2 (en) 2014-07-08 2018-01-02 Insys Development Company, Inc. Diclofenac sublingual spray
US10561806B2 (en) 2014-10-02 2020-02-18 Mannkind Corporation Mouthpiece cover for an inhaler
WO2016067132A1 (en) 2014-10-31 2016-05-06 Bend Research Inc. Process for forming active domains dispersed in a matrix
US9508891B2 (en) 2014-11-21 2016-11-29 Epistar Corporation Method for making light-emitting device
MX2017008428A (en) 2014-12-23 2018-03-23 Acelrx Pharmaceuticals Inc Systems, devices and methods for dispensing oral transmucosal dosage forms.
SG11202006080SA (en) 2017-12-26 2020-07-29 Ftf Pharma Private Ltd Liquid oral formulations for pde v inhibitors
CN112272554A (en) * 2018-02-22 2021-01-26 艾维奥尔股份有限公司 Transmucosal film compositions and methods of making and using same
US11819488B2 (en) * 2018-02-23 2023-11-21 Rhnanopharma Nanosuspensions of salsalate and methods of using the same
US11318107B2 (en) 2019-02-22 2022-05-03 Avior, Inc. Pharmaceutical active-containing film delivery device for oral transmucosal administration
KR20220044160A (en) * 2019-05-10 2022-04-06 아노메라 아이엔씨. Porous Cellulose Microparticles and Method for Preparing Same
WO2024150261A1 (en) * 2023-01-10 2024-07-18 Zarqa University An oral pharmaceutical formulation and a method of preparation thereof

Citations (41)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4818542A (en) * 1983-11-14 1989-04-04 The University Of Kentucky Research Foundation Porous microspheres for drug delivery and methods for making same
US5271961A (en) * 1989-11-06 1993-12-21 Alkermes Controlled Therapeutics, Inc. Method for producing protein microspheres
US5382437A (en) * 1993-10-25 1995-01-17 Hunter Research Corporation Frozen liquified gas composition and method for oral administration of drugs, biologicals, nutrients and foodstuffs
US5413797A (en) * 1992-03-12 1995-05-09 Alkermes Controlled Therapeutics, Inc. Controlled release ACTH containing microspheres
US5468598A (en) * 1994-04-18 1995-11-21 Eastman Kodak Company Solid particle dispersions for imaging systems
US5470583A (en) * 1992-12-11 1995-11-28 Eastman Kodak Company Method of preparing nanoparticle compositions containing charged phospholipids to reduce aggregation
US5500331A (en) * 1994-05-25 1996-03-19 Eastman Kodak Company Comminution with small particle milling media
US5510118A (en) * 1995-02-14 1996-04-23 Nanosystems Llc Process for preparing therapeutic compositions containing nanoparticles
US5513803A (en) * 1994-05-25 1996-05-07 Eastman Kodak Company Continuous media recirculation milling process
US5518187A (en) * 1992-11-25 1996-05-21 Nano Systems L.L.C. Method of grinding pharmaceutical substances
US5518738A (en) * 1995-02-09 1996-05-21 Nanosystem L.L.C. Nanoparticulate nsaid compositions
US5534270A (en) * 1995-02-09 1996-07-09 Nanosystems Llc Method of preparing stable drug nanoparticles
US5552160A (en) * 1991-01-25 1996-09-03 Nanosystems L.L.C. Surface modified NSAID nanoparticles
US5560932A (en) * 1995-01-10 1996-10-01 Nano Systems L.L.C. Microprecipitation of nanoparticulate pharmaceutical agents
US5565188A (en) * 1995-02-24 1996-10-15 Nanosystems L.L.C. Polyalkylene block copolymers as surface modifiers for nanoparticles
US5569448A (en) * 1995-01-24 1996-10-29 Nano Systems L.L.C. Sulfated nonionic block copolymer surfactants as stabilizer coatings for nanoparticle compositions
US5571536A (en) * 1995-02-06 1996-11-05 Nano Systems L.L.C. Formulations of compounds as nanoparticulate dispersions in digestible oils or fatty acids
US5580579A (en) * 1995-02-15 1996-12-03 Nano Systems L.L.C. Site-specific adhesion within the GI tract using nanoparticles stabilized by high molecular weight, linear poly (ethylene oxide) polymers
US5587143A (en) * 1994-06-28 1996-12-24 Nanosystems L.L.C. Butylene oxide-ethylene oxide block copolymer surfactants as stabilizer coatings for nanoparticle compositions
US5591456A (en) * 1995-02-10 1997-01-07 Nanosystems L.L.C. Milled naproxen with hydroxypropyl cellulose as a dispersion stabilizer
US5609998A (en) * 1994-12-29 1997-03-11 Eastman Kodak Company Process for dispersing concentrated aqueous slurries
US5611344A (en) * 1996-03-05 1997-03-18 Acusphere, Inc. Microencapsulated fluorinated gases for use as imaging agents
US5622938A (en) * 1995-02-09 1997-04-22 Nano Systems L.L.C. Sugar base surfactant for nanocrystals
US5622279A (en) * 1994-09-14 1997-04-22 Schutz; Udo Pallet container for transportation and storage of liquids
US5643605A (en) * 1993-10-25 1997-07-01 Genentech, Inc. Methods and compositions for microencapsulation of adjuvants
US5657931A (en) * 1994-04-18 1997-08-19 Eastman Kodak Company Stable aqueous solid particle dispersions
US5662883A (en) * 1995-01-10 1997-09-02 Nanosystems L.L.C. Microprecipitation of micro-nanoparticulate pharmaceutical agents
US5665331A (en) * 1995-01-10 1997-09-09 Nanosystems L.L.C. Co-microprecipitation of nanoparticulate pharmaceutical agents with crystal growth modifiers
US5676968A (en) * 1991-10-31 1997-10-14 Schering Aktiengesellschaft Transdermal therapeutic systems with crystallization inhibitors
US5716642A (en) * 1995-01-10 1998-02-10 Nano Systems L.L.C. Microprecipitation of nanoparticulate pharmaceutical agents using surface active material derived from similar pharmaceutical agents
US5718919A (en) * 1995-02-24 1998-02-17 Nanosystems L.L.C. Nanoparticles containing the R(-)enantiomer of ibuprofen
US5747001A (en) * 1995-02-24 1998-05-05 Nanosystems, L.L.C. Aerosols containing beclomethazone nanoparticle dispersions
US5759520A (en) * 1994-07-21 1998-06-02 Tillotts Pharma Ag Aqueous foamable composition
US5762961A (en) * 1996-02-09 1998-06-09 Quadrant Holdings Cambridge Ltd. Rapidly soluble oral solid dosage forms, methods of making same, and compositions thereof
US5919434A (en) * 1993-09-03 1999-07-06 Nycomed Imaging As Polymeric surfactant-encapsulated microbubbles and their use in ultrasound imaging
US5976574A (en) * 1996-12-31 1999-11-02 Inhale Therapeutic Systems Processes for spray drying hydrophobic drugs in organic solvent suspensions
US5985285A (en) * 1995-03-13 1999-11-16 The Secretary Of State For Defence In Her Britanic Majesty's Government Of The United Kingdom Of Great Britain And Northern Ireland Vaccines for plague
US20010018072A1 (en) * 1997-05-13 2001-08-30 Imarx Therapeutics, Inc. Solid matrix therapeutic compositions
US6565885B1 (en) * 1997-09-29 2003-05-20 Inhale Therapeutic Systems, Inc. Methods of spray drying pharmaceutical compositions
US6800297B2 (en) * 2000-06-15 2004-10-05 Acusphere, Inc. Porous COX-2 inhibitor matrices and methods of manufacture thereof
US6946117B1 (en) * 1997-09-29 2005-09-20 Nektar Therapeutics Stabilized preparations for use in nebulizers

Family Cites Families (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1265615A (en) 1970-09-10 1972-03-01
IL82245A (en) 1986-04-25 1990-07-26 Basf Ag Preparation of spray-dried granules of active ingredients
US5064640A (en) * 1986-12-02 1991-11-12 Purdue Research Foundation Anticariogenic compositions
US20030035845A1 (en) * 1992-06-11 2003-02-20 Zale Stephen E. Composition for sustained release of non-aggregated erythropoietin
US5916596A (en) 1993-02-22 1999-06-29 Vivorx Pharmaceuticals, Inc. Protein stabilized pharmacologically active agents, methods for the preparation thereof and methods for the use thereof
US5439686A (en) 1993-02-22 1995-08-08 Vivorx Pharmaceuticals, Inc. Methods for in vivo delivery of substantially water insoluble pharmacologically active agents and compositions useful therefor
US6096331A (en) 1993-02-22 2000-08-01 Vivorx Pharmaceuticals, Inc. Methods and compositions useful for administration of chemotherapeutic agents
EP0655237A1 (en) 1993-11-27 1995-05-31 Hoechst Aktiengesellschaft Medicinal aerosol formulation
US5478858A (en) * 1993-12-17 1995-12-26 The Procter & Gamble Company 5-(2-imidazolinylamino) benzimidazole compounds useful as alpha-2 adrenoceptor agonists
US5795978A (en) * 1995-11-15 1998-08-18 Henkel Kommanditgesellschaft Auf Aktien Emulsifiers
US5662279A (en) 1995-12-05 1997-09-02 Eastman Kodak Company Process for milling and media separation
US5763445A (en) * 1996-03-08 1998-06-09 Adolor Corporation Kappa agonist compounds pharmaceutical formulations and method of prevention and treatment of pruritus therewith
US5855913A (en) 1997-01-16 1999-01-05 Massachusetts Instite Of Technology Particles incorporating surfactants for pulmonary drug delivery
JP3884484B2 (en) 1997-01-16 2007-02-21 マサチューセッツ インスティチュート オブ テクノロジー Preparation of particles for inhalation
US6423345B2 (en) 1998-04-30 2002-07-23 Acusphere, Inc. Matrices formed of polymer and hydrophobic compounds for use in drug delivery
SG73563A1 (en) * 1998-11-30 2000-06-20 Rahmonic Resources Pte Ltd Apparatus and method to measure three-dimensional data
US6040330A (en) * 1999-01-08 2000-03-21 Bionumerik Pharmaceuticals, Inc. Pharmaceutical formulations of taxanes
US6306425B1 (en) 1999-04-09 2001-10-23 Southern Research Institute Injectable naltrexone microsphere compositions and their use in reducing consumption of heroin and alcohol
US6610317B2 (en) * 1999-05-27 2003-08-26 Acusphere, Inc. Porous paclitaxel matrices and methods of manufacture thereof
US6395300B1 (en) * 1999-05-27 2002-05-28 Acusphere, Inc. Porous drug matrices and methods of manufacture thereof
US6743446B2 (en) * 1999-12-15 2004-06-01 The Ohio State University Research Foundation Methods for stabilizing biologically active agents encapsulated in biodegradable controlled-release polymers

Patent Citations (42)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4818542A (en) * 1983-11-14 1989-04-04 The University Of Kentucky Research Foundation Porous microspheres for drug delivery and methods for making same
US5271961A (en) * 1989-11-06 1993-12-21 Alkermes Controlled Therapeutics, Inc. Method for producing protein microspheres
US5552160A (en) * 1991-01-25 1996-09-03 Nanosystems L.L.C. Surface modified NSAID nanoparticles
US5676968A (en) * 1991-10-31 1997-10-14 Schering Aktiengesellschaft Transdermal therapeutic systems with crystallization inhibitors
US5413797A (en) * 1992-03-12 1995-05-09 Alkermes Controlled Therapeutics, Inc. Controlled release ACTH containing microspheres
US5518187A (en) * 1992-11-25 1996-05-21 Nano Systems L.L.C. Method of grinding pharmaceutical substances
US5470583A (en) * 1992-12-11 1995-11-28 Eastman Kodak Company Method of preparing nanoparticle compositions containing charged phospholipids to reduce aggregation
US5919434A (en) * 1993-09-03 1999-07-06 Nycomed Imaging As Polymeric surfactant-encapsulated microbubbles and their use in ultrasound imaging
US5382437A (en) * 1993-10-25 1995-01-17 Hunter Research Corporation Frozen liquified gas composition and method for oral administration of drugs, biologicals, nutrients and foodstuffs
US5643605A (en) * 1993-10-25 1997-07-01 Genentech, Inc. Methods and compositions for microencapsulation of adjuvants
US5468598A (en) * 1994-04-18 1995-11-21 Eastman Kodak Company Solid particle dispersions for imaging systems
US5657931A (en) * 1994-04-18 1997-08-19 Eastman Kodak Company Stable aqueous solid particle dispersions
US5500331A (en) * 1994-05-25 1996-03-19 Eastman Kodak Company Comminution with small particle milling media
US5513803A (en) * 1994-05-25 1996-05-07 Eastman Kodak Company Continuous media recirculation milling process
US5587143A (en) * 1994-06-28 1996-12-24 Nanosystems L.L.C. Butylene oxide-ethylene oxide block copolymer surfactants as stabilizer coatings for nanoparticle compositions
US5759520A (en) * 1994-07-21 1998-06-02 Tillotts Pharma Ag Aqueous foamable composition
US5622279A (en) * 1994-09-14 1997-04-22 Schutz; Udo Pallet container for transportation and storage of liquids
US5609998A (en) * 1994-12-29 1997-03-11 Eastman Kodak Company Process for dispersing concentrated aqueous slurries
US5560932A (en) * 1995-01-10 1996-10-01 Nano Systems L.L.C. Microprecipitation of nanoparticulate pharmaceutical agents
US5716642A (en) * 1995-01-10 1998-02-10 Nano Systems L.L.C. Microprecipitation of nanoparticulate pharmaceutical agents using surface active material derived from similar pharmaceutical agents
US5665331A (en) * 1995-01-10 1997-09-09 Nanosystems L.L.C. Co-microprecipitation of nanoparticulate pharmaceutical agents with crystal growth modifiers
US5662883A (en) * 1995-01-10 1997-09-02 Nanosystems L.L.C. Microprecipitation of micro-nanoparticulate pharmaceutical agents
US5569448A (en) * 1995-01-24 1996-10-29 Nano Systems L.L.C. Sulfated nonionic block copolymer surfactants as stabilizer coatings for nanoparticle compositions
US5571536A (en) * 1995-02-06 1996-11-05 Nano Systems L.L.C. Formulations of compounds as nanoparticulate dispersions in digestible oils or fatty acids
US5518738A (en) * 1995-02-09 1996-05-21 Nanosystem L.L.C. Nanoparticulate nsaid compositions
US5534270A (en) * 1995-02-09 1996-07-09 Nanosystems Llc Method of preparing stable drug nanoparticles
US5622938A (en) * 1995-02-09 1997-04-22 Nano Systems L.L.C. Sugar base surfactant for nanocrystals
US5591456A (en) * 1995-02-10 1997-01-07 Nanosystems L.L.C. Milled naproxen with hydroxypropyl cellulose as a dispersion stabilizer
US5510118A (en) * 1995-02-14 1996-04-23 Nanosystems Llc Process for preparing therapeutic compositions containing nanoparticles
US5580579A (en) * 1995-02-15 1996-12-03 Nano Systems L.L.C. Site-specific adhesion within the GI tract using nanoparticles stabilized by high molecular weight, linear poly (ethylene oxide) polymers
US5565188A (en) * 1995-02-24 1996-10-15 Nanosystems L.L.C. Polyalkylene block copolymers as surface modifiers for nanoparticles
US5718919A (en) * 1995-02-24 1998-02-17 Nanosystems L.L.C. Nanoparticles containing the R(-)enantiomer of ibuprofen
US5747001A (en) * 1995-02-24 1998-05-05 Nanosystems, L.L.C. Aerosols containing beclomethazone nanoparticle dispersions
US5985285A (en) * 1995-03-13 1999-11-16 The Secretary Of State For Defence In Her Britanic Majesty's Government Of The United Kingdom Of Great Britain And Northern Ireland Vaccines for plague
US5762961A (en) * 1996-02-09 1998-06-09 Quadrant Holdings Cambridge Ltd. Rapidly soluble oral solid dosage forms, methods of making same, and compositions thereof
US5611344A (en) * 1996-03-05 1997-03-18 Acusphere, Inc. Microencapsulated fluorinated gases for use as imaging agents
US5976574A (en) * 1996-12-31 1999-11-02 Inhale Therapeutic Systems Processes for spray drying hydrophobic drugs in organic solvent suspensions
US6001336A (en) * 1996-12-31 1999-12-14 Inhale Therapeutic Systems Processes for spray drying aqueous suspensions of hydrophobic drugs and compositions thereof
US20010018072A1 (en) * 1997-05-13 2001-08-30 Imarx Therapeutics, Inc. Solid matrix therapeutic compositions
US6565885B1 (en) * 1997-09-29 2003-05-20 Inhale Therapeutic Systems, Inc. Methods of spray drying pharmaceutical compositions
US6946117B1 (en) * 1997-09-29 2005-09-20 Nektar Therapeutics Stabilized preparations for use in nebulizers
US6800297B2 (en) * 2000-06-15 2004-10-05 Acusphere, Inc. Porous COX-2 inhibitor matrices and methods of manufacture thereof

Cited By (132)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
USRE40493E1 (en) * 1999-05-27 2008-09-09 Acusphere, Inc. Porous paclitaxel matrices and methods of manufacture thereof
US8470347B2 (en) 2000-05-30 2013-06-25 AbbVie Deutschland GmbH and Co KG Self-emulsifying active substance formulation and use of this formulation
US20110008430A1 (en) * 2003-08-28 2011-01-13 Abbott Laboratories Solid Pharmaceutical Dosage Form
US8691878B2 (en) 2003-08-28 2014-04-08 Abbvie Inc. Solid pharmaceutical dosage form
US8268349B2 (en) 2003-08-28 2012-09-18 Abbott Laboratories Solid pharmaceutical dosage form
US20110015216A1 (en) * 2003-08-28 2011-01-20 Abbott Laboratories Solid Pharmaceutical Dosage Form
US8309613B2 (en) 2003-08-28 2012-11-13 Abbvie Inc. Solid pharmaceutical dosage form
US8333990B2 (en) 2003-08-28 2012-12-18 Abbott Laboratories Solid pharmaceutical dosage form
US8377952B2 (en) 2003-08-28 2013-02-19 Abbott Laboratories Solid pharmaceutical dosage formulation
US8399015B2 (en) 2003-08-28 2013-03-19 Abbvie Inc. Solid pharmaceutical dosage form
US20050143404A1 (en) * 2003-08-28 2005-06-30 Joerg Rosenberg Solid pharmaceutical dosage formulation
US20080226721A1 (en) * 2004-01-28 2008-09-18 Andrew Ian Cooper Porous Bodies and Method of Production Thereof
US7985423B2 (en) 2004-01-28 2011-07-26 Iota Nanosolutions Limited Porous bodies and method of production thereof
US8481565B2 (en) 2004-12-27 2013-07-09 Eisai R&D Management Co., Ltd. Method for stabilizing anti-dementia drug
US20090208579A1 (en) * 2004-12-27 2009-08-20 Eisai R & D Management Co., Ltd. Matrix Type Sustained-Release Preparation Containing Basic Drug or Salt Thereof, and Method for Manufacturing the Same
US8507527B2 (en) 2004-12-27 2013-08-13 Eisai R & D Management Co., Ltd. Method for stabilizing anti-dementia drug
US20100152164A1 (en) * 2004-12-27 2010-06-17 Eisai R&D Management Co., Ltd. Method For Stabilizing Anti-Dementia Drug
US20080213368A1 (en) * 2004-12-27 2008-09-04 Eisai R & D Management Co., Ltd. Method for Stabilizing Anti-Dementia Drug
US20060280789A1 (en) * 2004-12-27 2006-12-14 Eisai Research Institute Sustained release formulations
US20060246003A1 (en) * 2004-12-27 2006-11-02 Eisai Co. Ltd. Composition containing anti-dementia drug
US20080262100A1 (en) * 2005-01-28 2008-10-23 Andrew Ian Cooper Method of Preparing Carrier Liquids
US11413296B2 (en) 2005-11-12 2022-08-16 The Regents Of The University Of California Viscous budesonide for the treatment of inflammatory diseases of the gastrointestinal tract
US20090304806A1 (en) * 2006-07-13 2009-12-10 David John Duncalf Pharmaceutical Compositions
US20100068282A1 (en) * 2006-07-13 2010-03-18 Unilever Plc Preparation of pharmaceutical compositions
US20090239749A1 (en) * 2006-07-13 2009-09-24 David John Duncalf Biocidal compositions
US8821932B2 (en) 2006-07-13 2014-09-02 David John Duncalf Pharmaceutical compositions
US8945626B2 (en) 2006-07-13 2015-02-03 Andrew James Elphick Preparation of pharmaceutical compositions
US20100015229A1 (en) * 2006-07-13 2010-01-21 David John Duncalf Pharmaceutical compositions
US20100015233A1 (en) * 2006-07-13 2010-01-21 David John Duncalf anti-parasitic compositions
US9060937B2 (en) 2006-07-13 2015-06-23 David John Duncalf Pharmaceutical compositions
US9458166B2 (en) 2007-03-12 2016-10-04 Nektar Therapeutics Oligomer-opioid agonist conjugates
US8575196B2 (en) 2007-03-12 2013-11-05 Nektar Therapeutics Oligomer-opioid agonist conjugates
US9827239B2 (en) 2007-03-12 2017-11-28 Nektar Therapeutics Oligomer-opioid agonist conjugates
US10512644B2 (en) 2007-03-12 2019-12-24 Inheris Pharmaceuticals, Inc. Oligomer-opioid agonist conjugates
US10307416B2 (en) 2007-03-12 2019-06-04 Nektar Therapeutics Oligomer-opioid agonist conjugates
US10143690B2 (en) 2007-03-12 2018-12-04 Nektar Therapeutics Oligomer-opioid agonist conjugates
US8946285B2 (en) 2007-03-12 2015-02-03 Nektar Therapeutics Oligomer-opioid agonist conjugates
US9233168B2 (en) 2007-03-12 2016-01-12 Nektar Therapeutics Oligomer-opioid agonist conjugates
US9233167B2 (en) 2007-03-12 2016-01-12 Nektar Therapeutics Oligomer-opioid agonist conjugates
US8952032B2 (en) 2007-03-12 2015-02-10 Nektar Therapeutics Oligomer-opioid agonist conjugates
US8569343B2 (en) 2007-03-12 2013-10-29 Nektar Therapeutics Oligomer-opioid agonist conjugates
US9512135B2 (en) 2007-03-12 2016-12-06 Nektar Therapeutics Oligomer-opioid agonist conjugates
US20090169622A1 (en) * 2007-12-27 2009-07-02 Roxane Laboratories, Inc. Delayed-release oral pharmaceutical composition for treatment of colonic disorders
US20100081628A1 (en) * 2008-06-11 2010-04-01 Pharmasset, Inc. Nucleoside cyclicphosphates
US8759510B2 (en) 2008-06-11 2014-06-24 Gilead Pharmasset Llc Nucleoside cyclicphosphates
US8173621B2 (en) 2008-06-11 2012-05-08 Gilead Pharmasset Llc Nucleoside cyclicphosphates
US20110237614A1 (en) * 2008-09-16 2011-09-29 Nektar Therapeutics Pegylated Opioids with Low Potential for Abuse
EP2349336A4 (en) * 2008-10-28 2013-10-23 Agency Science Tech & Res Mesoporous material excipients for poorly aqueous soluble ingredients
EP2349336A1 (en) * 2008-10-28 2011-08-03 Agency For Science, Technology And Research Mesoporous material excipients for poorly aqueous soluble ingredients
US8778401B2 (en) 2008-10-28 2014-07-15 Agency For Science, Technology And Research Mesoporous material excipients for poorly aqueous soluble ingredients
EP2671888A1 (en) 2008-12-23 2013-12-11 Gilead Pharmasset LLC 3',5'-cyclic nucleoside phosphate analogues
US8716262B2 (en) 2008-12-23 2014-05-06 Gilead Pharmasset Llc Nucleoside phosphoramidates
US8716263B2 (en) 2008-12-23 2014-05-06 Gilead Pharmasset Llc Synthesis of purine nucleosides
EP3222628A1 (en) 2008-12-23 2017-09-27 Gilead Pharmasset LLC Nucleoside phosphoramidates
US9045520B2 (en) 2008-12-23 2015-06-02 Gilead Pharmasset Llc Synthesis of purine nucleosides
US8551973B2 (en) 2008-12-23 2013-10-08 Gilead Pharmasset Llc Nucleoside analogs
US8957045B2 (en) 2008-12-23 2015-02-17 Gilead Pharmasset Llc Nucleoside phosphoramidates
WO2010075549A2 (en) 2008-12-23 2010-07-01 Pharmasset, Inc. Nucleoside phosphoramidates
WO2010075554A1 (en) 2008-12-23 2010-07-01 Pharmasset, Inc. Synthesis of purine nucleosides
WO2010075517A2 (en) 2008-12-23 2010-07-01 Pharmasset, Inc. Nucleoside analogs
WO2010135569A1 (en) 2009-05-20 2010-11-25 Pharmasset, Inc. N- [ (2 ' r) -2 ' -deoxy-2 ' -fluoro-2 ' -methyl-p-phenyl-5 ' -uridylyl] -l-alanine 1-methylethyl ester and process for its production
EP2913337A1 (en) 2009-05-20 2015-09-02 Gilead Pharmasset LLC N-[(2'r)-2'-deoxy-2'-fluoro-2'-methyl-p-phenyl-5'-uridylyl]-l-alanine 1-methylethyl ester and process for its production
EP2910562A1 (en) 2009-05-20 2015-08-26 Gilead Pharmasset LLC N-[(2'r)-2'-deoxy-2 '-fluoro-2'-methyl-p-phenyl-5 '-uridylyl]-l-alanine 1-methylethyl ester in crystalline form
EP3321275A1 (en) 2009-05-20 2018-05-16 Gilead Pharmasset LLC Crystalline form of sofosbuvir
EP2610264A2 (en) 2009-05-20 2013-07-03 Gilead Pharmasset LLC N-[(2'r)-2'-deoxy-2'-fluoro-2'-methyl-p-phenyl-5'-uridylyl]-l-alanine 1-methylethyl ester and process for its production
US20110097401A1 (en) * 2009-06-12 2011-04-28 Meritage Pharma, Inc. Methods for treating gastrointestinal disorders
WO2010144865A2 (en) 2009-06-12 2010-12-16 Meritage Pharma, Inc. Methods for treating gastrointestinal disorders
WO2011123672A1 (en) 2010-03-31 2011-10-06 Pharmasset, Inc. Purine nucleoside phosphoramidate
EP3290428A1 (en) 2010-03-31 2018-03-07 Gilead Pharmasset LLC Tablet comprising crystalline (s)-isopropyl 2-(((s)-(((2r,3r,4r,5r)-5-(2,4-dioxo-3,4-dihydropyrimidin-1 (2h)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate
US8563530B2 (en) 2010-03-31 2013-10-22 Gilead Pharmassel LLC Purine nucleoside phosphoramidate
US8859756B2 (en) 2010-03-31 2014-10-14 Gilead Pharmasset Llc Stereoselective synthesis of phosphorus containing actives
WO2011123645A2 (en) 2010-03-31 2011-10-06 Pharmasset, Inc. Nucleoside phosphoramidates
WO2011123668A2 (en) 2010-03-31 2011-10-06 Pharmasset, Inc. Stereoselective synthesis of phosphorus containing actives
EP2609923A2 (en) 2010-03-31 2013-07-03 Gilead Pharmasset LLC Nucleoside Phosphoramidates
EP2752422A1 (en) 2010-03-31 2014-07-09 Gilead Pharmasset LLC Stereoselective synthesis of phosphorus containing actives
WO2011141721A3 (en) * 2010-05-14 2012-02-02 Iota Nanosolutions Limited Compositions
WO2012075140A1 (en) 2010-11-30 2012-06-07 Pharmasset, Inc. Compounds
US8841275B2 (en) 2010-11-30 2014-09-23 Gilead Pharmasset Llc 2′-spiro-nucleosides and derivatives thereof useful for treating hepatitis C virus and dengue virus infections
EP3042910A2 (en) 2010-11-30 2016-07-13 Gilead Pharmasset LLC 2'-spiro-nucleosides for use in the therapy of hepatitis c
US9394331B2 (en) 2010-11-30 2016-07-19 Gilead Pharmasset Llc 2′-spiro-nucleosides and derivatives thereof useful for treating hepatitis C virus and dengue virus infections
US8987237B2 (en) 2011-11-23 2015-03-24 Therapeuticsmd, Inc. Natural combination hormone replacement formulations and therapies
US8633178B2 (en) 2011-11-23 2014-01-21 Therapeuticsmd, Inc. Natural combination hormone replacement formulations and therapies
US10675288B2 (en) 2011-11-23 2020-06-09 Therapeuticsmd, Inc. Natural combination hormone replacement formulations and therapies
US9248136B2 (en) 2011-11-23 2016-02-02 Therapeuticsmd, Inc. Transdermal hormone replacement therapies
US8846649B2 (en) 2011-11-23 2014-09-30 Therapeuticsmd, Inc. Natural combination hormone replacement formulations and therapies
US11103516B2 (en) 2011-11-23 2021-08-31 Therapeuticsmd, Inc. Natural combination hormone replacement formulations and therapies
US8846648B2 (en) 2011-11-23 2014-09-30 Therapeuticsmd, Inc. Natural combination hormone replacement formulations and therapies
US11793819B2 (en) 2011-11-23 2023-10-24 Therapeuticsmd, Inc. Natural combination hormone replacement formulations and therapies
US11529360B2 (en) 2012-06-18 2022-12-20 Therapeuticsmd, Inc. Natural combination hormone replacement formulations and therapies
US9301920B2 (en) 2012-06-18 2016-04-05 Therapeuticsmd, Inc. Natural combination hormone replacement formulations and therapies
US8933059B2 (en) 2012-06-18 2015-01-13 Therapeuticsmd, Inc. Natural combination hormone replacement formulations and therapies
US10639375B2 (en) 2012-06-18 2020-05-05 Therapeuticsmd, Inc. Progesterone formulations
US8987238B2 (en) 2012-06-18 2015-03-24 Therapeuticsmd, Inc. Natural combination hormone replacement formulations and therapies
US11166963B2 (en) 2012-06-18 2021-11-09 Therapeuticsmd, Inc. Natural combination hormone replacement formulations and therapies
US9006222B2 (en) 2012-06-18 2015-04-14 Therapeuticsmd, Inc. Natural combination hormone replacement formulations and therapies
US10052386B2 (en) 2012-06-18 2018-08-21 Therapeuticsmd, Inc. Progesterone formulations
US11110099B2 (en) 2012-06-18 2021-09-07 Therapeuticsmd, Inc. Natural combination hormone replacement formulations and therapies
US10471148B2 (en) 2012-06-18 2019-11-12 Therapeuticsmd, Inc. Progesterone formulations having a desirable PK profile
US9012434B2 (en) 2012-06-18 2015-04-21 Therapeuticsmd, Inc. Natural combination hormone replacement formulations and therapies
US11865179B2 (en) 2012-06-18 2024-01-09 Therapeuticsmd, Inc. Progesterone formulations having a desirable PK profile
US11033626B2 (en) 2012-06-18 2021-06-15 Therapeuticsmd, Inc. Progesterone formulations having a desirable pk profile
US10806740B2 (en) 2012-06-18 2020-10-20 Therapeuticsmd, Inc. Natural combination hormone replacement formulations and therapies
US9289382B2 (en) 2012-06-18 2016-03-22 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US11116717B2 (en) 2012-12-21 2021-09-14 Therapeuticsmd, Inc. Soluble estradiol capsule for vaginal insertion
US11497709B2 (en) 2012-12-21 2022-11-15 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US10568891B2 (en) 2012-12-21 2020-02-25 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US10537581B2 (en) 2012-12-21 2020-01-21 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US9180091B2 (en) 2012-12-21 2015-11-10 Therapeuticsmd, Inc. Soluble estradiol capsule for vaginal insertion
US10806697B2 (en) 2012-12-21 2020-10-20 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US10835487B2 (en) 2012-12-21 2020-11-17 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US10888516B2 (en) 2012-12-21 2021-01-12 Therapeuticsmd, Inc. Soluble estradiol capsule for vaginal insertion
US11622933B2 (en) 2012-12-21 2023-04-11 Therapeuticsmd, Inc. Soluble estradiol capsule for vaginal insertion
US11246875B2 (en) 2012-12-21 2022-02-15 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US11065197B2 (en) 2012-12-21 2021-07-20 Therapeuticsmd, Inc. Soluble estradiol capsule for vaginal insertion
US11241445B2 (en) 2012-12-21 2022-02-08 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US10471072B2 (en) 2012-12-21 2019-11-12 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US11266661B2 (en) 2012-12-21 2022-03-08 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US11351182B2 (en) 2012-12-21 2022-06-07 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US11123283B2 (en) 2012-12-21 2021-09-21 Therapeuticsmd, Inc. Soluble estradiol capsule for vaginal insertion
US11304959B2 (en) 2012-12-21 2022-04-19 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US11103513B2 (en) 2014-05-22 2021-08-31 TherapeuticsMD Natural combination hormone replacement formulations and therapies
US10206932B2 (en) 2014-05-22 2019-02-19 Therapeuticsmd, Inc. Natural combination hormone replacement formulations and therapies
US10258630B2 (en) 2014-10-22 2019-04-16 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US10668082B2 (en) 2014-10-22 2020-06-02 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US10398708B2 (en) 2014-10-22 2019-09-03 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US10806770B2 (en) 2014-10-31 2020-10-20 Monash University Powder formulation
US10328087B2 (en) 2015-07-23 2019-06-25 Therapeuticsmd, Inc. Formulations for solubilizing hormones
US10912783B2 (en) 2015-07-23 2021-02-09 Therapeuticsmd, Inc. Formulations for solubilizing hormones
US10286077B2 (en) 2016-04-01 2019-05-14 Therapeuticsmd, Inc. Steroid hormone compositions in medium chain oils
US10532059B2 (en) 2016-04-01 2020-01-14 Therapeuticsmd, Inc. Steroid hormone pharmaceutical composition
US9931349B2 (en) 2016-04-01 2018-04-03 Therapeuticsmd, Inc. Steroid hormone pharmaceutical composition
US11633405B2 (en) 2020-02-07 2023-04-25 Therapeuticsmd, Inc. Steroid hormone pharmaceutical formulations

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