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WO2011050206A2 - Compositions et procédés pour le traitement de troubles sino-nasaux - Google Patents

Compositions et procédés pour le traitement de troubles sino-nasaux Download PDF

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Publication number
WO2011050206A2
WO2011050206A2 PCT/US2010/053616 US2010053616W WO2011050206A2 WO 2011050206 A2 WO2011050206 A2 WO 2011050206A2 US 2010053616 W US2010053616 W US 2010053616W WO 2011050206 A2 WO2011050206 A2 WO 2011050206A2
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WO
WIPO (PCT)
Prior art keywords
sinonasal
formulation
composition
active agent
nasal
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2010/053616
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English (en)
Other versions
WO2011050206A3 (fr
Inventor
Jay Lichter
Carl Lebel
Fabrice Piu
Jeffrey P. Harris
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Otonomy Inc
University of California Berkeley
University of California San Diego UCSD
Original Assignee
Otonomy Inc
University of California Berkeley
University of California San Diego UCSD
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Publication date
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Publication of WO2011050206A2 publication Critical patent/WO2011050206A2/fr
Publication of WO2011050206A3 publication Critical patent/WO2011050206A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0043—Nose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the nasal cavity, sinonasal caity and nasopharynx form a functional unit.
  • Humans have four pairs of sinusoidal cavities placed symmetrically on opposite sides of the head.
  • the nasal cavity is divided into the olfactory region and respiratory region placed behind the nose in the middle of the face.
  • the nasopharynx includes the respiratory passage above and behind the soft palate.
  • Certain sinonasal, nasal, and nasopharynx conditions are associated with infection and/or inflammation and/or allergic response and/or deformities in sinonasal, nasal, and nasopharynx cavities or structures.
  • Described herein are methods for providing sustained release of desired agents to, or in the vicinity of, at least one structure or region of the sinusoidal, nasal, and/or
  • nasopharynx cavities, structures or passages are administered to, or in the vicinity of, the sinusoidal and/or nasal and/or nasopharynx regions.
  • Administration of sustained release compositions and formulations described herein into, or in the vicinity of, the sinusoidal and/or nasal and/or nasopharynx regions allows for treatment of sinusoidal, nasal, and/or nasopharyngeal disorders, including, and not limited to, sinonasal polyposis, allergic fungal sinusitis, chronic sinusitis, reduction of post-surgical complications associated with sinonasal surgery (e.g., inferior turbinate removal, polypectomy), nasal polyps, and nasopharyngeal cancers.
  • the methods of treatment described herein reduce recurrence of a sinonasal condition and/or complications after surgery for a sinonasal condition.
  • the methods of treatment described herein reduce recurrence of a nasal condition (e.g., a polyp) and/or complications after surgery for a nasal condition.
  • the methods of treatment described herein reduce the frequency of dose administration thereby increasing patient comfort and/or compliance.
  • the sustained release formulations e.g., intrasinusoidal and/or nasal formulations
  • the sustained release formulations described herein that are suitable for use in the methods described herein, comprise an anti-inflammatory agent, or an antibiotic, or an antifungal, or an antiviral, or a chemotherapeutic agent, or an antiangiogenesis agent, or a growth factor, or a combination thereof.
  • the methods described herein comprise the use of sustained release intrasinusoidal and/or nasal and/or nasopharyngeal formulations in combination with surgical procedures such as sinoplasty, ballon rhinoplasty,
  • kits for providing sustained release of an active agent into one or more sinonasal cavities of a human comprising administering to one or more sinonasal cavities, or in the vicinity of one or more sinonasal cavities of the human in need thereof a pharmaceutical composition comprising:
  • composition provides sustained release of the one or more active agents into or in the vicinity of one or more sinonasal cavities for a period of at least 3 days.
  • the composition provides sustained release of the one or more active agents into or in the vicinity of one or more sinonasal cavities for a period of at least 5 days. In some embodiments of the methods, the composition provides sustained release of the one or more active agents into or in the vicinity of one or more sinonasal cavities for a period of at least 7 days. In some embodiments of the methods, the composition provides sustained release of the one or more active agents into or in the vicinity of one or more sinonasal cavities for a period of at least 10 days. In some embodiments of the methods, the composition provides sustained release of the one or more active agents into or in the vicinity of one or more sinonasal cavities for a period of at least 14 days.
  • the pharmaceutical composition is a thermoreversible gel.
  • thermoreversible gel has a gelation temperature of less than about 42 °C. In some embodiments of the methods, the
  • thermoreversible gel has a gelation temperature between about 5 °C and about 37 °C.
  • the composition is a liquid at the time of administation and wherein the liquid is suitable for administration via a narrow gauge needle or cannula or catheter.
  • the composition is administered as a nasal spray.
  • the one or more active agents comprises multiparticulates.
  • the one or more active agents is essentially in the form of micronized particles.
  • the one or more active agents in a sinonasal formulation described herein is an anti-inflammatory agent as described herein. In some embodiments of the methods, the one or more active agents in a sinonasal formulation described herein is an immunomodulating agent as described herein. In some embodiments of the methods, the one or more active agents in a sinonasal formulation described herein is an antimicrobial agent (e.g., antibiotic, antiviral or antifungal agent) as described herein.
  • an antimicrobial agent e.g., antibiotic, antiviral or antifungal agent
  • the one or more active agents in a sinonasal formulation described herein is a cytotoxic agent (e.g., microtubule stabilizer, antimetabolite, chemotherapeutic) as described herein.
  • the one or more active agents in a sinonasal formulation described herein is a mitochondrial modulator as described herein.
  • the one or more active agents in a sinonasal formulation described herein is an estrogen receptor modulator as described herein.
  • the one or more active agents in a sinonasal formulation described herein is a growth factor as described herein.
  • the one or more active agents in a sinonasal formulation described herein is a neurotrophic factor as described herein.
  • the one or more active agents in a sinonasal formulation described herein is an apoptosis modulator (e.g., JNK modulator, JAK modulator, AKT modulator, PI3 kinase modulator, NF-KB modulator, p38 modulator, Src modulator and the like) as described herein.
  • the one or more active agents in a sinonasal formulation described herein is a antihistamine as described herein.
  • the one or more active agents in a sinonasal formulation described herein is a
  • the one or more active agents in a sinonasal formulation described herein is an acetylcholine esterase inhibitor as described herein. In some embodiments of the methods, the one or more active agents in a sinonasal formulation described herein is a dopamine modulator as described herein. In some embodiments of the methods, the one or more active agents in a sinonasal formulation described herein is a monoamine oxidase inhibitor as described herein.
  • the one or more active agents in a sinonasal formulation described herein is an ion channel modulator (e.g., NMDA receptor modulator, ENaC receptor modulator, calcium channel modulator, potassium channel modulator, sodium channel modulator and the like) as described herein.
  • the one or more active agents in a sinonasal formulation described herein is a metabotropic glutamate receptor modulator as described herein.
  • the one or more active agents in a sinonasal formulation described herein is an anti-angiogenesi agent as described herein.
  • the one or more active agents in a sinonasal formulation described herein is an immunosuppressant as described herein. In some embodiments of the methods, the one or more active agents in a sinonasal formulation described herein is an antisense agent as described herein. In some
  • the one or more active agents in a sinonasal formulation described herein is a modulator of sinonasal epithelial cells as described herein. In some embodiments of the methods, the one or more active agents in a sinonasal formulation described herein is a modulator or keratin synthesis as described herein. In some embodiments of the methods, the one or more active agents in a sinonasal formulation described herein is an agent that modulates eosinophils and/or cytokines as described herein.
  • the one or more active agents is a
  • the amount of corticosteroid in the composition is between about 0.01 to about 25% by weight of the composition.
  • the corticosteroid is 21-acetoxypregnenolone, alclometasone, algestone, amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clobetasone, clocortolone, cloprednol, corticosterone, cortisone, cortivazol, deflazacort, desonide, desoximetasone, dexamethasone, diflorasone, diflucortolone, difluprednate, enoxolone, fluazacort, flucloronide, flumethasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocortolone, fluorometholone, fluperolone acetate, fluprednidene acetate, flupred
  • the corticosteroid is dexamethasone, prednisolone, methylprednisolone, triamcinolone, or a salt or prodrug thereof, or a combination thereof. In some embodiments of the methods, the corticosteroid is
  • the dexamethasone is dexamethasone sodium phosphate or dexamethasone acetate.
  • the composition comprises multiparticulate corticosteroid.
  • the multiparticulate corticosteroid is essentially micronized corticosteroid.
  • the composition provides an in vivo sustained release of a therapeutically effective amount of corticosteroid for a period of at least 5 days. In some embodiments of the methods, the composition provides an in vivo sustained release of a therapeutically effective amount of corticosteroid for a period of at least 7 days.
  • the one or more active agents is an antimicrobial agent.
  • the antimicrobial agent is an antibiotic.
  • the amount of antibiotic in the first or more active agents is an antimicrobial agent.
  • composition is between about 0.01 to about 20% by weight of the composition
  • the antibiotic is amikacin, gentamicin, kanamycin, neomycin, netilmicin, streptomycin, tobramycin, paromycin, geldanamycin, herbimycin, loracarbef, ertapenem, doripenem, imipenem, meropenem, cefaclor, cefamandole, cefotoxin, cefprozil, cefuroxime, cefixime, cefdinir, cefditoren, cefpodoxime, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefepime, ceftobirprole, vancomycin, azithromycin, clarithromycin, dirithromycin, erythromycin, roxithromycin, troleandomycin, telithromycin, spectinomycin, aztreonam, amoxicillin, ampicillin, azociling, carb
  • the composition comprises multiparticulate antibiotic.
  • the multiparticulate antibiotic is essentially micronized antibiotic.
  • the antibiotic agent is ciprofloxacin, amoxicillin, amoxicillin+clavulanic acid, moxifloxacin or ofloxacin, or salt or solvate thereof. In some embodiments of the methods, the antibiotic agent is ciprofloxacin or ciprofloxacin hydrate.
  • the composition provides an in vivo sustained release of a therapeutically effective amount of antibiotic agent for a period of at least 5 days. In some embodiments of the methods, the composition provides an in vivo sustained release of a therapeutically effective amount of antibiotic agent for a period of at least 7 days.
  • the one or more active agents is a
  • the composition is an aspetic mixture of sterile active agent and a sterile solution comprising a copolymer of polyoxy ethylene and polyoxypropylene.
  • the composition comprises between about 14.0% and about 27% of a copolymer of polyoxyethylene and polyoxypropylene. In some embodiments of the methods, the composition comprises between about 14.5% and about 25% of a copolymer of polyoxyethylene and polyoxypropylene. In some embodiments of the methods, the composition comprises between about 14.5% and about 21% of a copolymer of polyoxyethylene and polyoxypropylene. In some embodiments of the methods, the composition comprises between about 15% and about 18% of a copolymer of polyoxyethylene and polyoxypropylene. In some of such embodiments, the formulation further comprises a viscosity enhancing agent as described herein. In some other embodiments of the methods, the composition comprises between about 25% and about 50% of a copolymer of polyoxyethylene and polyoxypropylene.
  • the copolymer of polyoxyethylene and polyoxypropylene is Poloxamer 407 (also known as PF-127, Pol-407, Pluronic-127).
  • the composition further comprises a mucoadhesive.
  • the composition has a pH of between about 3.0 and about 12.0. In some embodiments of the methods, the composition has a pH of between about 5.0 and about 9.0. In some embodiments of the methods, the composition has a pH of between about 7.0 and about 8.0.
  • composition provides sustained release of the one or more active agents into or in the vicinity of one or more sinonasal cavities for a period of at least 3 days.
  • the one or more active agents is selected from a corticosteroid, an antibiotic, or a combination thereof.
  • the composition is administered in an ethmoid, maxillary, frontal or sphenoid sinusoidal cavity, or any combination thereof.
  • the composition is administered in an ethmoid, maxillary, frontal or sphenoid sinusoidal cavity, or any combination thereof.
  • composition is administered into a polyp. In some embodiments of the methods described above, the composition is administered in the vicinity of a polyp. In some embodiments of the methods described above, the composition is administered in a nasal cavity. [0032] Further provided herein are methods for preventing or reducing occurrence of post- surgery complications, comprising administration in one or more sinonasal cavities or in the vicinity of one or more sinonasal cavities of an individual in need thereof, a composition comprising
  • composition provides sustained release of the one or more active agents into or in the vicinity of one or more sinonasal cavities for a period of at least 3 days.
  • the one or more active agents is selected from a corticosteroid, an antibiotic, or a combination thereof.
  • the surgery is inferior turbinate removal, or removal of sinonasal polyps or balloon rhinoplasty.
  • the surgery is removal of polyps.
  • the composition is administered at the site of the polyps after removal of the polyps.
  • the method prevents or reduces recurrence of sinonasal polyps after surgical removal of the sinonasal polyps.
  • a method for treatment of chronic sinusitis, sinonasal polyps, or allergic fungal sinusitis comprising administration in one or more sinonasal cavities, or in the vicinity of one or more sinonasal cavities, of an individual in need thereof a composition comprising comprising a thermoreversible polymer and a corticosteroid, wherein the composition provides sustained release of a corticosteroid into or in the vicinity of one or more sinonasal cavities for a period of at least 3 days, at least 5 days, or atleast 7 days.
  • the composition further comprises an antimicrobial agent.
  • the antimicrobial agent is an antibiotic.
  • compositions comprising comprising a thermoreversible polymer and a corticosteroid, wherein the composition provides sustained release of a corticosteroid into or in the vicinity of one or more sinonasal cavities for a period of at least 3 days, at least 5 days, or at least 7 days.
  • the composition further comprises an antimicrobial agent.
  • the antimicrobial agent is an antibiotic.
  • a method for treating sinonasal cancers comprising administration in one or more sinonasal cavities, or in the vicinity of one or more sinonasal cavities, of an individual in need thereof a composition comprising comprising a thermoreversible polymer and a corticosteroid, wherein the composition provides sustained release of a corticosteroid into or in the vicinity of one or more sinonasal cavities for a period of at least 3 days, at least 5 days or at least 7 days.
  • the composition further comprises an antimicrobial agent.
  • the antimicrobial agent is an antibiotic.
  • a method for determination of release of an active agent from a sustained release sinonasal formulation in an individual in need thereof comprising analysis of nasal lavage or sinusoidal lavage of the individual and detecting the presence of active agent in the nasal lavage or sinusoidal lavage.
  • the presence of an active agent in the nasal or sinusoidal lavage is determined using any suitable technique (e.g, UV spectrometry, HPLC, Mass Spectrometry or NMR analysis).
  • tissue exposure of an active agent is determined using any suitable technique (e.g, UV spectrometry, HPLC, Mass Spectrometry or NMR analysis).
  • any composition described above is substantially free of additional preservatives. In some embodiments, any composition described above is substantially free of additional tonicity agents. In some embodiments, any composition described above has any individual product related impurity of no more than 1%. In some embodiments, any composition described above has total product related impurities of no more than 2%.
  • the dexamethasone, or salt or prodrug or solvate thereof is present in an amount from about 0.05% to about 40% by weight of the formulation. In some embodiments of any composition described above, the dexamethasone, or salt or prodrug or solvate thereof, is present in an amount from about 0.1% to about 30% by weight of the formulation. In some embodiments of any composition described above, the dexamethasone, or salt or prodrug or solvate thereof, is present in an amount from about 0.2% to about 20% by weight of the formulation.
  • the ciprofloxacin, or salt or solvate thereof is present in an amount from about 0.05% to about 40% by weight of the formulation. In some embodiments of any composition described above, the ciprofloxacin, or salt or solvate thereof, is present in an amount from about 0.1% to about 30% by weight of the
  • the ciprofloxacin, or salt or solvate thereof is present in an amount from about 0.2% to about 20% by weight of the formulation.
  • Figure 1 is an illustrative comparison of non- sustained release and sustained release formulations.
  • Figure 2 are illustrative predicted tunable releases of an agent from four compositions.
  • Figure 3 is an illustration of in vitro mean dissolution time with increasing concentrations of steroid drug in sustained release formulations.
  • Figure 4 is an illustration of in vitro mean dissolution time of high versus low solubility drug substances and solution versus gel formulations.
  • kits for providing sustained release of an active agent into, or in the vicinity of, a sinonasal cavity of a human are also provided herein, in some embodiments, are methods for providing sustained release of an active agent into, or in the vicinity of, a nasal or nasopharyngeal region of a human.
  • sustained release of an active agent into the sinusoidal cavity of a human are methods for providing sustained release of an active agent into the sinusoidal cavity of a human.
  • intrasinusoidal formulations described herein are administered in the sinus cavity and/or in the vicinity of the sinus cavity.
  • Current treatment regimens for sinusodial conditions include nasal sprays and/or nasal irrigation for topical drug administration into the paranasal sinuses.
  • nasal sprays and/or nasal irrigation are not effective in delivering a solution in the paranasal sinuses and/or the sinusoidal cavities.
  • the solutions drain out of the nasal passages.
  • sustained release of active agents in the paranasal cavities comprising administration of sustained release formulations in a sinonasal cavity or in the vicinity of a sinonasal cavity of an individual in need thereof.
  • the sustained release formulations described herein gel upon contact with sinonasal surfaces and adhere to surfaces in sinonasal cavities or to surfaces in the vicinity of sinonasal cavities thereby providing a depot for extended release of an active agent from an administered formulation.
  • the methods and/or formulations described herein prolong residence time of an active agent in a sinonasal region or in the vicinity of a site of sinonasal inflammation and/or infection.
  • nasal cavities There is also considerable anatomical variation in the nasal cavities amongst individuals.
  • Current treatment regimens for nasal disorders include nasal sprays and/or nasal irrigation for topical drug administration into the nasal cavity.
  • nasal sprays and/or nasal irrigation are not effective in retaining a medicament in a nasal cavity.
  • nasal formulations that gel upon contact with a nasal surface.
  • the sustained release nasal formulations described herein adhere to the surfaces of nasal regions and do not drain out of the nasal passages, thereby providing sustained release of an active agent in the affected region.
  • sustained release of an active agent into the nasopharynx of a human are administered in the nasopharynx and/or in the vicinity of the nasopharynx and provide sustained release of an active agent in the affected region.
  • the methods described herein comprise the use of sinusoidal and/or nasal and/or nasopharynx formulations that are manufactured with low bioburden or sterilized with stringent sterility requirements and are suitable for administration to the vulnerable environment in the sinonasal cavities.
  • the compositions described herein are substantially free of pyrogens and/or microbes.
  • a disadvantage of liquid formulations is their propensity to drain into nasal passages and cause rapid clearance of the formulation.
  • kits for providing sustained release of active agents in sinonasal cavities comprising administration of fomulations that comprise thermoreversible polymers that gel at about body temperature and remain in contact with the target sinonasal surfaces for extended periods of time.
  • Instrasinusoidal and/or nasi and/or nasopharyngeal formulations described herein avoid attenuation of therapeutic benefit due to drainage or leakage of active agents via the nasal passages.
  • the compositions are formulated with minimum excipients and thus reduce or eliminate irritation or toxicity in the environment of sinonasal cavities or regions.
  • the formulations comprise thermoreversible polymers that are biocompatible and/or otherwise non-toxic to the sinonasal environment.
  • the thermoreversible gel is biodegradable and/or bioeliminated (e.g., the copolymer is eliminated from the body by a biodegradation process, e.g., elimination in the urine, the feces or the like).
  • a formulation described herein comprises at least about 5.0% and not more than about 50% of a thermoreversible polymer (e.g., polyoxyethylene- polyoxypropylene triblock copolymer) by weight of the composition.
  • a thermoreversible polymer e.g., polyoxyethylene- polyoxypropylene triblock copolymer
  • a formulation described herein comprises at least about 5.0% and not more than about 40% of a thermoreversible polymer (e.g., polyoxyethylene-polyoxypropylene triblock copolymer) by weight of the composition. In some embodiments, a formulation described herein comprises at least about 10.0% and not more than about 35% of a thermoreversible polymer (e.g., polyoxyethylene-polyoxypropylene triblock copolymer) by weight of the composition. In some embodiments, a formulation described herein comprises at least about 10.0% and not more than about 30% of a thermoreversible polymer (e.g., polyoxyethylene-polyoxypropylene triblock copolymer) by weight of the composition. In some embodiments, a formulation described herein comprises at least about 10.0% and not more than about 25% of a thermoreversible polymer (e.g., polyoxyethylene - polyoxypropylene triblock copolymer) by weight of the composition. In some embodiments,
  • a formulation described herein comprises at least about 5% and not more than about 20% of a thermoreversible polymer (e.g., polyoxyethylene- polyoxypropylene triblock copolymer) by weight of the composition.
  • a thermoreversible polymer e.g., polyoxyethylene- polyoxypropylene triblock copolymer
  • a formulation described herein comprises at least about 10% and not more than about 20% of a thermoreversible polymer (e.g., polyoxyethylene -polyoxypropylene triblock copolymer) by weight of the composition. In some embodiments, a formulation described herein comprises at least about 10% and not more than about 18% of a thermoreversible polymer (e.g., polyoxyethylene -polyoxypropylene triblock copolymer) by weight of the composition. In some embodiments, a formulation described herein comprises at least about 10% and not more than about 16% of a thermoreversible polymer (e.g., polyoxyethylene -polyoxypropylene triblock copolymer) by weight of the composition. In some embodiments, a formulation described herein comprises at least about 10% and not more than about 15% of a thermoreversible polymer (e.g., polyoxyethylene - polyoxypropylene triblock copolymer) by weight of the composition. In some embodiments,
  • thermoreversible polymer comprising polyoxyethylene-polyoxypropylene triblock copolymers is purified P407. In some other embodiments, the thermoreversible polymer comprising polyoxyethylene-polyoxypropylene triblock copolymers is non-purified P407 (e.g., commercially purchased P407).
  • formulations described above have a gelation temperature between about 5 °C and about 42 °C and comprise between about 5% to about 40% of a thermoreversible polymer by weight of the composition. In some embodiments,
  • the about 5% to about 40% of a thermoreversible polymer comprises a polyoxyethylene-polyoxypropylene triblock copolymer and the formulation further comprises a gel temperature modulating agent.
  • a gel temperature modulating agent is selected from, for example,
  • the formulations comprise purified poloxamer.
  • a formulation comprising a purified poloxamer contains a lower poloxamer concentration compared to a formulation comprising non-purified poloxamer while retaining the ability to gel at a temperature between about 5 °C and about 42 °C.
  • a formulation comprising a purified poloxamer contains a lower poloxamer concentration compared to a formulation comprising non- purified poloxamer while retaining the ability to gel at a temperature between about 14 °C and about 42 °C.
  • a micronized dexamethasone formulation comprising between about 10% and about 12% of fractionated poloxamer 407 gels at a temperature between about 14 °C and about 42 °C
  • a micronized dexamethasone formulation comprising between about 14.5% and about 25% of un-purified poloxamer 407 also gels at a temperature between about 14 °C and about 42 °C.
  • purified poloxamer allows for use of a lower amount of the thermoreversible polymer while retaining the gel temperature and sustained release properties of the formulation.
  • a narrow gauge needle or cannula or catheter using normal finger pressure (e.g., by a physician using normal finger pressure on the plunger of the syringe, such that the needle of the syringe can accurately and stably deliver the
  • the formulations described herein are free or substantially free of additional thickening agents.
  • additional thickening agents include chitosan, or polyethylene glycol (PEG).
  • a formulation disclosed herein comprises less than about 5% by weight of chitosan.
  • a formulation disclosed herein comprises less than about 4% by weight of chitosan.
  • a formulation disclosed herein comprises less than about 3% by weight of chitosan.
  • a formulation disclosed herein comprises less than about 2% by weight of chitosan.
  • a formulation disclosed herein comprises less than about 1% by weight of chitosan.
  • a formulation disclosed herein comprises less than about 0.5% by weight of chitosan.
  • the formulations described herein are free or substantially free of additional preservatives and are suitable for administration in sinonasal cavities and/or nasopharyngeal sites.
  • Additional preservatives do not include trace amounts of antioxidants (e.g., Butylated hydroxytoluene (BHT)) that stabilize thermoreversible polymers, and which are typically provided commercially with thermoreversible polymers.
  • antioxidants e.g., Butylated hydroxytoluene (BHT)
  • BHT Butylated hydroxytoluene
  • additional preservatives include benzethonium chloride, benzalkonium chloride, and thiomersal.
  • a formulation disclosed herein comprises less than about 50 ppm of each of benzethonium chloride, benzalkonium chloride, and thiomersal.
  • a formulation disclosed herein comprises less than about 10 ppm of propylene glycol. In some embodiments, a formulation disclosed herein comprises less than about 5 ppm of propylene glycol. In some embodiments, a formulation disclosed herein comprises less than about 1 ppm of propylene glycol.
  • the formulations described herein are free or substantially free of additional moisture retention agents and are suitable for administration in sinonasal sites.
  • moisture retention agents include glycerin.
  • a formulation described herein is free or substantially free of glycerin.
  • a formulation disclosed herein comprises less than about 50 ppm of glycerin. In some embodiments, a formulation disclosed herein comprises less than about 25 ppm of glycerin. In some embodiments, a formulation disclosed herein comprises less than about 20 ppm of glycerin. In some embodiments, a formulation disclosed herein comprises less than about 10 ppm of glycerin. In some embodiments, a formulation disclosed herein comprises less than about 5 ppm of glycerin. In some embodiments, a formulation disclosed herein comprises less than about 1 ppm of glycerin.
  • the term means less than 1% by weight of the active agent and/or the polymer components are degradation products of the active agent and/or the polymer components.
  • the formulations described herein are free or substantially free of additional common solvents and are suitable for administration in sinonasal sites.
  • additional solvents include ethanol, propylene glycol, DMSO, N-Methyl-2 - pyrrolidone, and cyclohexane.
  • a formulation described herein is free or substantially free of ethanol, propylene glycol, DMSO, N-Methyl-2 -pyrrolidone, and cyclohexane.
  • the formulations described herein are free or substantially free of additional antiseptics that are commonly used to disinfect any component of a sinonasal preparation and that are potentially toxic.
  • additional antiseptics that are known to be toxic include acetic acid, iodine and merbromin.
  • a formulation disclosed herein is free or substantially free of acetic acid, iodine, merbromin, and chlorhexidene.
  • a formulation disclosed herein comprises less than about 50 ppm of each of acetic acid, iodine, merbromin, and chlorhexidene.
  • a formulation disclosed herein comprises less than about 25 ppm of each of acetic acid, iodine, merbromin, and chlorhexidene.
  • intrasinusoidal preparations require particularly low concentrations of several potentially-common contaminants that are known to be toxic.
  • Other dosage forms while seeking to limit the contamination attributable to these compounds, do not require the stringent precautions that intrasinusoidal preparations require.
  • the formulations described herein are free or substantially free of
  • a formulation disclosed herein is free or substantially free of arsenic, lead, mercury, and tin. In some embodiments, a formulation disclosed herein comprises less than about 50 ppm of each of arsenic, lead, mercury, and tin. In some embodiments, a formulation disclosed herein comprises less than about 25 ppm of each of arsenic, lead, mercury, and tin. In some embodiments, a formulation disclosed herein comprises less than about 20 ppm of each of arsenic, lead, mercury, and tin.
  • a formulation disclosed herein comprises less than about 10 ppm of each of arsenic, lead, mercury, and tin. In some embodiments, a formulation disclosed herein comprises less than about 5 ppm of each of arsenic, lead, mercury, and tin. In some embodiments, a formulation disclosed herein comprises less than about 1 ppm of each of arsenic, lead, mercury, and tin.
  • active agent pharmaceutical compositions or formulations disclosed herein are optionally targeted to distinct regions of the targeted sinonasal cavities, including but not limited to the ethmoid, maxillary, frontal and/or sphenoid sinusoidal cavities and other anatomical or physiological structures located within the sinonasal cavities such as nasal cavities, nasal polyps, turbinates, site of surgical wound or the like.
  • thermosetting polymers are polymers that undergo a reversible temperature-dependent phase transtion (e.g., a liquid to gel transition, a gel to liquid transition, or the like).
  • thermoreversible polymers that form thermoreversible gels include and are not limited to poloxamers (e.g., Pluronics F68 ® , F88 ® , and F108 ® , F127 ® , or the like) or any other thermosetting polymer described herein.
  • Viscosity enhancing polymers are polymers that increase viscosity of a
  • a viscosity enhanging polymer is a thermosensitive polymer.
  • a thermosensitive polymer is not a thermoreversible polymer.
  • a thermosensitive polymer is a thermoreversible polymer.
  • Suitable viscosity-enhancing polymers that are thermosensitive polymers include and are not limited to, hydrogels (e.g., chitosan), gelatin, hyaluronic acid, acrylic acid based polymers (e.g., Carbopol®), MedGel®, cellulose based polymers (e.g.,
  • the resulting formulation is a thermoreversible gel, but it need not be thermoreversible; that is, depending on the amount of thermosensitive polymer in the formulation, the resulting gel may be thermoreversible or not thermoreversible.
  • the calculated polydispersity index is the weight average molecular weight divided by the number average molecular weight of polymeric chains (M w /M n ). It indicates the distribution of individual molecular masses in a batch of polymers.
  • “therapeutically effective amount” includes, for example, a prophylactically effective amount.
  • An “effective amount” of an active agent disclosed herein is an amount effective to achieve a desired pharmacologic effect or therapeutic improvement without undue adverse side effects. It is understood that “an effective amount” or “a therapeutically effective amount” varies, in some embodiments, from subject to subject, due to variation in metabolism of the compound administered, age, weight, general condition of the subject, the condition being treated, the severity of the condition being treated, and the judgment of the prescribing physician. It is also understood that "an effective amount” in an extended- release dosing format may differ from “an effective amount” in an immediate release dosign format based upon pharmacokinetic and pharmacodynamic considerations.
  • active agent refers to active agents that treat, or reduce or ameliorate severity of any sinonasal disorder described herein.
  • Suitable “active agents” may be, for example, antimicrobial agents (e.g., antibacterial agents (effective against bacteria), antiviral agents (effective against viruses), antifungal agents (effective against fungal infections), corticosteroids, or any other active agent described herein.
  • active agents may work by any suitable mechanism, including by being anti-inflammatory, antimicrobial, toxic, cytostatic and/or immunomodulatory agents.
  • a sinonasal cavity refers to any cavity or passage or structure in the paranasal sinuses, or the nasal region.
  • a sinonasal cavity is a maxillary, frontal, ethmoid or sphenoid sinus cavity.
  • a sinonsasal cavity is in the nose or the vicinity of the nose or a nasal passage.
  • a sinonasal cavity is in the nasopharynx region.
  • the mean residence time is the average time that molecules of an active agent reside in a sinonasal structure after administration of a dose.
  • the prodrug is designed to alter the metabolic stability or the transport characteristics of a drug, to mask side effects or toxicity, or to alter other characteristics or properties of a drug.
  • Compounds provided herein, in some embodiments, are derivatized into suitable prodrugs.
  • the term "subject” is used to mean an animal, preferably a mammal, including a human or non-human.
  • the terms patient and subject may be used
  • treat include alleviating, abating or ameliorating a disease or condition, for example sinusitis, symptoms, preventing additional symptoms, ameliorating or preventing the underlying metabolic causes of symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and/or therapeutically.
  • the sinonasal cavities are an anatomically complex region; drainage of secretions from the sinusal cavities occurs through narrow passages including the ostiomeatal complex and the sphenoethmoid recess.
  • the ostiomeatal unit is a final common pathway for drainage and ventilation of the frontal and maxillary sinuses and the anterior ethmoidal cells.
  • the ethmoid infundibulum, middle nasal meatus, ethmoid bulla and frontal recess are included in the ostiomeatal complex.
  • the sphenoethmoid recess is a bilateral slit-like recess high and posterior in the nasal cavity, between the anterior wall of the sphenoid sinus, the medial wall of the posterior ethmoid cells, and the posterosuperior part of the nasal septum.
  • the sphenoid sinus and posterior ethmoid cells drain into the sphenoethmoid recess. In some instances, obstruction of these recesses and/or ostia lead to a disturbance in the mucociliary clearance of the dependent sinuses and induce sinusal inflammation.
  • the nasal cavity is divided into the olfactory region and respiratory region with nasal chambers on either side of the median plane formed by the nasal septum.
  • the respiratory region is lined with respiratory epithelium.
  • the olfactory segment is lined with olfactory epitheulium which contains receptors for the sense of smell.
  • Olfactory mucosal cell types include: bipolar neurons, supporting cells, basal cells and Bowman's glands. Anosmia is a nasal condition that causes the loss of smell.
  • the nose Because of its prominent position, the nose is especially vulnerable to injury, including fractures. Infections, nose bleeds (epistaxis), and polyps also can affect the nose. The mucous membrane of the nose may become inflamed (rhinitis). Nasal cancers occur when malignant cells form in the tissues of the nasal cavity, e.g., B cell lymphomas.
  • Sinonasal conditions include, and are not limited to, chronic sinusitis, allergic fungal sinusitis, sinonasal polyposis, inferior turbinate removal, and/or any inflammation, swelling, infection, sinusoidal fullnes and congestion, inverted papillomas, recurrent respiratory papillomas, cancers of the nasopharynx, anosmia, epistaxis and the like.
  • Nasal polyps are teardrop-shaped, noncancerous growths on the lining of nasal passages or sinuses. Larger nasal polyps can block nasal passages or sinuses and cause breathing difficulties, and/or frequent sinus infections. Children with cystic fibrosis often develop nasal polyps. In some cases, medication lessens the size of nasal polyps and/or eliminates them. But surgery is sometimes necessary to remove them. Small or isolated polyps are removed in a polypectomy using a small mechanical suction device or a microdebrider. Larger polyps are removed using endoscopic sinus surgery. The surgeon inserts an endoscope into sinus cavities and removes polyps and other obstructions that prevent the drainage of fluids from sinuses.
  • corticosteroid nasal sprays are prescribed to prevent recurrence of polyps.
  • the benefits are temporary and nasal polyps often recur.
  • Nasal sprays and/or nasal irrigation are not effective in delivering a solution in the paranasal sinuses and/or the sinusoidal cavities.
  • the solutions drain out of the nasal passages.
  • the sinonasal compositions described herein are administered in combination with surgery for nasal polyps (e.g., polypectomy). In some embodiments, a sinonasal composition is administered before surgery for nasal polyps. In some embodiments, a sinonasal composition is administered before surgery for nasal polyps.
  • a sinonasal composition is administered during surgery for nasal polyps. In some embodiments, a sinonasal composition is administered after surgery for nasal polyps. In some embodiments, methods of treating nasal polyposis described herein prevent or reduce post-surgical complications (e.g., incidence of inflammation and/or infection after surgery, or recurrence of polyps after surgery). In some embodiments, a sinonasal formulation is administered at the base of a polyp. In some embodiemnts, a sinonasal formulation is administered at the site of a polyp after the polyp is removed.
  • Allergic fungal sinusitis is believed to represent an immune-mediated, allergic-type response to environmental fungi that are dispersed in the air. This condition results in thick fungal debris and sticky mucus that must be surgically removed in order to keep the inflammatory condition under control. There is extensive nasal polyposis and fungal debris can expand and erode towards the eyes or brain. Surgeons endoscopically remove polyps and fungal debris that are adjacent to the skull base and eye while preserving normal structures, such as the septum and middle turbinate. Medical treatment consists of oral (prednisone) and topical steroids and immunotherapy (allergy shots). In spite of aggressive treatment, recurrence is not uncommon. In some embodiments, the methods described herein reduce or prevent allergic-type immune response in the sinuses and/or reduce recurrence of AFS.
  • the inferior turbinates are the largest turbinates, and direct the majority of airflow direction, humidification, heating, and filtering of air inhaled through the nose.
  • the middle turbinates are smaller and project downwards over the openings of the maxillary and ethmoid sinuses.
  • the middle turbinates protect the sinuses from coming in direct contact with pressurized nasal airflow.
  • the superior turbinates are the smallest structures and serve to protect the olfactory bulb.
  • kits that comprise administration of sinonasal compositions described herein in the sinonasal cavities before, during and/or after surgery for sectioning and/or repositioning of swollen and/or otherwise deformed turbinates.
  • the sinonasal compositions described herein are administered in combination with sinonasal surgery (e.g., inferior turbinate removal).
  • sinonasal surgery e.g., inferior turbinate removal
  • a sinonasal composition is administered before sinonasal surgery (e.g., inferior turbinate removal). In some embodiments, a sinonasal composition is administered during sinonasal surgery (e.g., inferior turbinate removal). In some embodiments, a sinonasal composition is administered after sinonasal surgery (e.g., inferior turbinate removal). In some embodiments, methods of treating sinonasal conditions described herein prevent or reduce post-surgical complications (e.g., incidence of inflammation and/or infection after surgery). In some embodiments, methods described herein reduce and/or prevent recurrence of turbinate swelling after surgery and/or reduce post-surgical complications such as inflammation and/or infection.
  • post-surgical complications e.g., incidence of inflammation and/or infection after surgery. In some embodiments, methods described herein reduce and/or prevent recurrence of turbinate swelling after surgery and/or reduce post-surgical complications such as inflammation and/or infection.
  • Epistaxis is the occurrence of hemorrhage from the nose. Contemplated within the scope of embodiments presented herein is the use of sustained release formulations (e.g., formulations comprising antiangiogenic agents) for treatment of expistaxis.
  • sustained release formulations e.g., formulations comprising antiangiogenic agents
  • Anosmia is a temporary or permanent loss of ability to perceive odors.
  • composition provides sustained release of the one or more active agents into or in the vicinity of one or more sinonasal cavities for a period of at least 3 days.
  • the neurodegenerative disorder is any disorder associated with, for example, aging and/or genetic predisposition and/or exposure to toxic substances.
  • the neurodegenerative disorder is Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic Lateral Sclerosis, and the like.
  • sinonasal administration of a composition described herein allows administration of the active agents into the brain while avoiding the blood brain barrier.
  • such a route of adminstration reduces or eliminates side-effects associated with penetration into the brain when using other modes of adminstration.
  • such a route of adminstration allows for presence of higher levels of an active agent in the brain by reducing or avoiding the BBB-mediated efflux of the active agent from the brain.
  • the active agent in a comosition described herein is an antiviral agent.
  • the antiviral agents include but are not limited to acyclovir, famciclovir and valacyclovir.
  • Corticosteroids including any agents that act at glucorticoid receptors
  • other antiinflammatory steroids are compatible with the formulations disclosed herein.
  • One advantage of the use of a formulation described herein is the greatly reduced systemic exposure to anti-inflammatory glucocorticoid steroids.
  • TACE inhibitors include and are not limited to Nitroarginine analog A, GW3333, TMI-1, BMS-561392, DPC-3333, TMI-2, BMS-566394, TMI-005, apratastat, GW4459, W-3646, IK-682, GI-5402, GI-245402, BB-2983, DPC-A38088, DPH-067517, Pv-618, CH-138 or the like.
  • Interleukin inhibitors include and are not limited to WS-4 (an antibody against IL-8), SB 265610 (N-(2-Bromophenyl)-N'-(7-cyano-lH-benzotriazol-4-yl)urea); SB 225002 (N-(2-Bromophenyl)-N'-(2-hydroxy-4-nitrophenyl)urea); SB203580 (4-(4- Fluorophenyl)-2-(4-methylsulfinyl phenyl)-5-(4-pyridyl) lH-imidazole); SB272844 (GlaxoSmithKline); SB517785 (Glaxo SmithKline); SB656933 (GlaxoSmithKline);
  • progesterone receptor modulators include and are not limited to RU-486 ((1 lb, 17 b)-l l-[4-(Dimethylamino)phenyl]-17-hydroxy-17-(l-propyn yl)-estra-4,9-dien-3- one); CDB-2914 (17a-acetoxy-l ip-[4-N,N-dimethylaminophenyl]-19-norpregna-4,9-diene- 3,20-dione); CDB-4124 (17a-acetoxy-21-methoxy-l ip-[4-N,N-dimethylaminophenyl]-19- norpregna-4,9- diene-3,20-dione); CDB-4453 (17a-acetoxy-21-methoxy-l 1 ⁇ -[4- ⁇ - methylaminophenyl]-19-norpregna-4,9-diene-3,20-dione); RTI 3021-022 (
  • prostaglandins and/or analogs thereof include and are not limited to naturally occurring prostaglandins, Prostaglandin analogues, such as latanoprost, travoprost, unoprostone, minprostin F2 alpha and bimtoprost, SQ29548, JB004/A or the like.
  • Examples of adenosine receptor modulators include and are not limited to ATL313 (4-(3-(6-amino-9-(5-cyclopropylcarbamoyl-3,4-dihydroxytetrahydrofuran-2-yl)-9H-purin- 2-yl)prop-2-ynyl)piperidine-l-carboxylic acid methyl ester); GW328267X ((2R,3R,4S,5R)- 2- ⁇ 6-amino-2-[(l-benzyl-2-hydroxyethyl)amino]-9H-purin-9-yl ⁇ -5-(2-ethyl-2H-tetrazol-5- yl)tetrahydrofuran-3,4-diol); CGS 21680 hydrochloride (4-[2-[[6-Amino-9-(N-ethyl-b-D- ribofuranuronamidosyl)-9H -purin-2-
  • some embodiments of the methods and compositions described herein incorporate the use of cytotoxic agents for treatment of sinonasal and/or nasopharyngeal conditions including and not limited to cancers.
  • antimetabolites and other anticancer agents such as methotrexate (RHEUMATREX®, Amethopterin) cyclophosphamide (CYTOXAN®), thalidomide (THALIDOMID®), acridine carboxamide, actimid®, actinomycin, 17-N-allylamino-17- demethoxygeldanamycin, aminopterin, amsacrine, anthracycline, antineoplastic, antineoplaston, 5-azacytidine, azathioprine, BL22, bendamustine, biricodar, bleomycin, bortezomib, bryostatin, busulfan, calyculin, camptothecin, capecitabine, carboplatin, chlorambucil, cisplatin, cladribine, clofarabine, cytarabine, dacarbazine, dasatinib, daunorubicin, decitabine, dich
  • cytotoxic agents are described in, for example, U.S. Appl. No. 12/493,611, which agents are incorporated herein by reference.
  • an active agent suitable for use in formulations and methods desribed herein is a mitochondrial modulator.
  • mitochondrial modulators include glibenclamide, 5 -hydroxy decanoate, pinacidil, diazoxide, benzodiazepines (e.g., chlordiazepoxide, diazepam, or the like), and non-benzodiazepines (e.g., Zolpidem, zaleplon and eszopiclone or the like).
  • motochondrial modulators alter the mitochondrial oxidation state and include ion channel modulators described herein.
  • Contemplated for use with the formulations disclosed herein are agents which modulate epithelial cell growth. Accordingly, some embodiments of the methods and compositions described herein incorporate the use of growth factors and/or modulators of growth factors for treatment of sinonasal conditions associated with aberrant growth in sinonasal cavities.
  • JAK (Janus Kinase) modulators [00159] Contemplated for use with the formulations disclosed herein are agents that fully or partially inhibit JAK kinases.
  • the anti-apoptotic agent is VX-680, TG101348, TG101209, INCB018424, XL019, CEP-701, AT9283, or combinations thereof.
  • the NF- kB transcription factor agonist, partial agonist, and/or positive allosteric modulator is Pam 3 Cys ((S)-(2,3-bis(palmitoyloxy)-(2RS)-propyl)-N-palmitoyl-(R)-Cys-(S)-Ser(S)-Lys4- OH, trihydrochloride); Actl (NF-kB activator 1); Acetyl- 11-keto-b-Boswellic Acid;
  • Contemplated for use with the formulations disclosed herein are agents which reduce or ameliorate symptoms or effects as a result of wheal and flare in sinonasal passages. Accordingly, some embodiments of the methods and compositions described herein incorporate the use of antihistamines for treatment of sinonasal conditions.
  • the agent that modulates ion channel activity in sinonasal epithelia is a modulator of ENaC channels.
  • the epithelial sodium channel (ENaC, sodium channel non-neuronal 1 (SCNN1) or amiloride sensitive sodium channel (ASSC)) is a membrane-bound ion-channel that is permeable for Li + -ions, protons and Na + -ions.
  • ENaC is located in the apical membrane of polarized epithelial cells and is involved in transepithelial Na + -ion transport. Na + /K+-ATPase is also involved in Na + transport and ion homeostasis.
  • modulators of the activity of ENaC include, by way of example, the mineralcorticoid aldosterone, triamterene, and amiloride.
  • benzenesulfonamide HC1 CGS- 12066A (7-Trifluoromethyl-4-(4-methyl- 1 - piperazinyl)pyrrolo-[l,2-a]quinoxaline); dofetilide; sotalol; apamin; amiodarone; azimilide; bretylium; clofilium; tedisamil; ibutilide; sematilide; nifekalant; tamulustoxin and combinations thereof.
  • an immunosuppresant is an agent that acts at glucocorticoid receptors (e.g., any glucocorticoid described herein, including and not limited to Hydrocortisone, Cortisone, Prednisone, Prednisolone,
  • Methylprednisolone Dexamethasone, Betamethasone, Triamcinolone, Beclometasone,
  • a 20-25 bp siRNA molecule with sequences complementary to a target is generated (e.g. by PCR).
  • a 20-25 bp siRNA molecule with sequences complementary to a target is generated.
  • the 20-25 bp siRNA molecule has 2-5 bp overhangs on the 3' end of each strand, and a 5' phosphate terminus and a 3' hydroxyl terminus.
  • the 20-25 bp siRNA molecule has blunt ends.
  • a formulation described herein comprises an antibiotic in combination with dexamethasone. In certain embodiments, a formulation described herein comprises an antibiotic in combination with methylprednisolone or prednisolone. In certain embodiments, a formulation described herein comprises ciprofloxacin in combination with dexamethasone. In certain embodiments, a formulation described herein comprises moxifloxacin in combination with dexamethasone. In certain embodiments, a formulation described herein comprises ofloxacin in combination with dexamethasone. In certain embodiments, a formulation described herein comprises ciprofloxacin in combination with methylprednisolone or prednisolone or triamcinolone.
  • any controlled release formulation described herein has less than about 100 colony forming units, less than about 60 colony forming units, less than about 50 colony forming units, less than about 40 colony forming units, or less than about 30 colony forming units of microbial agents per gram of formulation.
  • the sterile formulations described herein are substantially free of microbes.
  • An additional aspect of the sterilization process is the removal of by-products from the killing of microorganisms.
  • the process of depyrogenation removes such pyrogens from the sample.
  • endotoxin units One EU is equivalent to 100 picograms of E. coli LPS. Humans can develop a response to as little as 5 EU/kg of body weight.
  • sinonasal compositions described herein contain lower endotoxin levels (e.g.
  • a hemolysis index of 1 indicates that the "practical osmolality" experienced by the RBCs is suitable for sinonasal administration.
  • the RBCs are intact in media with a suitable practical osmolality ( Figure 5).
  • the osmolality of the poloxamer solution was also measured by freezing point depression method or vapor pressure methods.
  • the practical osmolality of the formulation is measured using commercially available osmometers and the value is confirmed by the hemolysis assay.
  • the pH of a formulation described herein is between about 3.0, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, or 7.0 and about 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 1 1.0, or 12.0. In some embodiments, the pH of a formulation described herein is between about 3.0 and about 12.0. In some embodiments, the pH of a formulation described herein is between about 3.0 and about 10.0. In some embodiments, the pH of a formulation described herein is between about 3.5 and about 8.5. In some embodiments, the pH of a formulation described herein is between about 4.0 and about 8.0. In some embodiments, the pH of a formulation described herein is between about 4.5 and about 8.0.
  • Micronization is a process of reducing the average diameter of particles of a solid material.
  • the average diameter of particles in a micronized solid is from about 0.5 ⁇ to about 500 ⁇ .
  • the average diameter of particles in a micronized solid is from about 1 ⁇ to about 200 ⁇ .
  • the average diameter of particles in a micronized solid is from about 2 ⁇ to about 100 ⁇ .
  • the average diameter of particles in a micronized solid is from about 3 ⁇ to about 50 ⁇ .
  • the use of multiparticulates of active agent allows for extended and/or sustained release of the active agent from any formulation described herein compared to a formulation comprising non-multiparticulate or a water-soluble active agent.
  • an oligonucleotide anionic drug e.g., alicaforsen
  • a protein e.g., insulin
  • a zinc salt thereof is rendered insoluble or less soluble in biological and/or aqueous fluids by formation of a zinc salt thereof.
  • modifying the solubility of the active agent can also have an effect on the properties of the thermoreversible gel.
  • amitriptyline is water soluble (greater than 100 mg/mL) and increases the gelation temperature of a poloxamer formulation. Reducing the solubility of amitriptyline (e.g., by formation of a prodrug) allows for tuning of the gelation temperature of a poloxamer formulation.
  • An active agent that has been rendered less soluble or insoluble in aqueous and/or biological media has a water solubility of less than 10 mg/mL, less than Img/mL or less than O. lmg/mL.
  • the release profile of an active agent and/or any salts thereof is compared using in vitro and in vivo procedures described herein.
  • Yet another approach to tune the release profile of an active agent from a formulation described herein is to complex a salt or free base of an active agent with a polyelectrolyte (e.g., poly(sodium styrene sulfonate), polyacrylic acid, polyamines or the like).
  • a polyelectrolyte e.g., poly(sodium styrene sulfonate), polyacrylic acid, polyamines or the like.
  • the ionic interactions between the polyelectrolyte and the salt or free base of the active agent modify the dissolution characteristics of the active agent in biological and/or aqueous fluids.
  • solubility of genetic material in biological and/or aqueous media is modified by addition of cationic polymers and/or formation of cationic micelles.
  • the release profile of an active agent and a complex thereof is compared using in vitro and in vivo procedures described herein.
  • microparticulates or micronized active agent that is substantially free of thermoreversible polymer components provides intermediate sustained release of active agent.
  • a formulation comprising microparticulates or micronized active agent and a thermoreversible polymer provides an extended sustained release of active agent.
  • immediate release of an active agent refers to substantially complete release of an active agent from the formulation in less than about 5 hours.
  • sustained release refers to extended release of an active agent from a formulation such as, for example, a sustained release of active agent over at least 2, 3, 5, 7, 14, 21, 28 days, or at least 1, 2, 3, 4, 5 or 6 months or 1 year.
  • intrasinusoidal and/or nasal and/or nasophamygeal formulations provided herein provide sustained release of an active agent (e.g., a corticosteroid, an antibiotic) for a period of at least 3 weeks. In some embodiments, intrasinusoidal and/or nasal and/or nasophamygeal formulations provided herein provide sustained release of an active agent (e.g., a corticosteroid, an antibiotic) for a period of at least 4 weeks.
  • an active agent e.g., a corticosteroid, an antibiotic
  • intrasinusoidal and/or nasal and/or nasophamygeal formulations provided herein provide sustained release of an active agent (e.g., a corticosteroid, an antibiotic) for a period of at least 8 weeks. In some embodiments, intrasinusoidal and/or nasal and/or nasophamygeal formulations provided herein provide sustained release of an active agent (e.g., a corticosteroid, an antibiotic) for a period of at least 3 months.
  • an active agent e.g., a corticosteroid, an antibiotic
  • intrasinusoidal and/or nasal and/or nasophamygeal formulations provided herein provide sustained release of an active agent (e.g., a corticosteroid, an antibiotic) for a period of at least 6 months. In some embodiments, intrasinusoidal and/or nasal and/or nasophamygeal formulations provided herein provide sustained release of an active agent (e.g., a corticosteroid, an antibiotic) for a period of at least 7 months.
  • an active agent e.g., a corticosteroid, an antibiotic
  • a sinonasal formulation described herein comprises between about 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or 55% and about 0.5%, 1%, 5%, 10%, 15%, 20% 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75% 80% or 89% of a viscosity enhancing polymer.
  • a viscosity enhancing polymer is a thermosensitive polymer.
  • a viscosity enhancing polymer is a pH sensitive polymer.
  • a viscosity enhancing polymer is sensitive to concentration of ions (e.g., in some instances, alginates gel in presence of Ca +2 ions).
  • Poloxamer is a synthetic block polymer of ethylene oxide and propylene oxide.
  • Poloxamer 407 also known as PF-127, P407, Pluronic-127 is a theroreversible polymer composed of polyoxyethylene-polyoxypropylene copolymers.
  • Other poloxamers include 124, 188 (F-68 grade), 237 (F-87 grade), and 338 (F-108 grade).
  • Aqueous solutions of poloxamers are stable in the presence of acids, alkalis, and metal ions.
  • PF-127 or P407 is a commercially available polyoxyethylene-polyoxypropylene triblock copolymer, with an average molar mass of 13,000.
  • Poloxamers are available in several types, and with varying molecular weights ranging from about 2000 to about 15000.
  • the a-hydro-co-hydroxypoly(oxyethylene) a poly(oxypropylene) b poly(oxyethylene) a block copolymers comprise varying ratios of a b as shown below:
  • the thermoreversible gel comprises a PEG-PLGA- PEG triblock copolymer (Jeong etal, Nature (1997), 388:860-2; Jeong etal, J. Control. Release (2000), 63: 155-63; Jeong etal, Adv. Drug Delivery Rev. (2002), 54:37-51).
  • the polymer exhibits sol-gel behavior over a concentration of about 5% w/w to about 40% w/w.
  • the lactide/glycolide molar ratio in the PLGA copolymer ranges from about 1 : 1 to about 20: 1.
  • the resulting coploymers are soluble in water and form a free-flowing liquid at room temperature, but form a gel at body temperature.
  • thermoreversible polymers are useful depending upon the particular active agent, other pharmaceutical agent or excipients/additives used, and as such are considered to fall within the scope of the present disclosure.
  • other commercially-available glycerin-based gels, glycerin-derived compounds, conjugated, or crosslinked gels, matrices, hydrogels, and polymers, as well as gelatins and their derivatives, alginates, and alginate-based gels, and even various native and synthetic hydrogel and hydrogel-derived compounds are all expected to be useful in the
  • any active composition described herein comprises purified thermoreversible polymer. In some embodiments, any active composition described herein comprises fractionated a purified thermoreversible polymer composed of polyoxyethylene- polyoxypropylene copolymers. In some of such embodiments, the thermoreversible polymer is a poloxamer.
  • formulations comprising purified poly(oxyethylene)/poly(oxypropylene) triblock polymers that are substantially free of the poly(oxyethylene) homopolymers and/or poly(oxypropylene)/poly(oxyethylene) diblock byproducts, thereby narrowing the molecular weight distribution of block copolymers, (i.e., providing low polydispersity).
  • thermoreversible polymer has a gelation temperature above 42 °C
  • addition of a gel temperature decreasing agent e.g., P188, P388, cyclodextrin, carboxymethyl cellulose, hyaluronic acid, Carbopol®
  • a gel temperature decreasing agent e.g., P188, P388, cyclodextrin, carboxymethyl cellulose, hyaluronic acid, Carbopol®
  • a pharmaceutical formulation described herein is a liquid at about room temperature.
  • the pharmaceutical formulation is characterized by a phase transition between about room temperature and about body temperature (including an individual with a serious fever, e.g., up to about 42 °C).
  • the phase transition occurs between at least about 1 °C below body temperature and body temperature, between at least about 2 °C below body temperature and body temperature, between at least about 3 °C below body temperture and body
  • a formulation described herein has a gelation temperature of between about 15 °C, 16 °C, 17 °C, 18 °C, 19 °C, or 20 °C, and about 25 °C, 28 °C, 30 °C , 33 °C, 35 °C , 37 °C , 40 °C or 42 °C. In some embodiments, a formulation described herein has a gelation temperature of between about 5 °C and about 42 °C. . In some embodiments, a formulation described herein has a gelation temperature of between about 5 °C and about 35 °C. .
  • thermoreversible polymer sufficient to provide a viscosity of between about 50,000 and about 1,000,000 centipoise.
  • a formulation described herein contains a thermoreversible polymer sufficient to provide a viscosity of between about 150,000 and about 1,000,000 centipoise.
  • a formulation described herein contains a thermosetting polymer sufficient to provide a viscosity of between about 50,000 and about 600,000 centipoise.
  • a formulation described herein contains a thermoreversible polymer sufficient to provide a viscosity of between about 100,000 and about 500,000 centipoise.
  • the buffer used is tris(hydroxymethyl)aminomethane, bicarbonate, carbonate or phosphate at slightly basic pH.
  • the buffer is a sodium bicarbonate buffer having a pH of about 6.5 to about 8.5, or about 7.0 to about 8.0.
  • the buffer is a sodium phosphate dibasic buffer having a pH of about 6.0 to about 9.0.
  • the solvent in a formulation described herein, is water.
  • a formulation described herein comprises a mixture of solvents (e.g., a mixture of water and an alcohol, or the like).
  • the solvent in a formulation described herein the solvent is a mixture of ethanol and water.
  • a formulation described herein further comprises additional sinonasal cavity-compatible excipients.
  • additional excipients include agents for imaging and/or visualization as described herein.
  • Other additional excipients include mucoadhesives, e.g., hyaluronic acid, (including and not limited to Hyalastine®,
  • a compositon disclosed herein is administered to an individual in need thereof once. In some embodiments, a compositon disclosed herein is administered to an individual in need thereof more than once.
  • a composition is administered to an individual in need thereof depends on the discretion of a medical professional, the disorder, the severity of the disorder, and the individuals's response to the formulation.
  • a formulation described herein is administered as prophylactically, therapeutically or as a chronic treatment over an extended perior of time.
  • the administration of the active agent compounds may be given continuously; alternatively, the dose of drug being administered may be temporarily reduced or temporarily suspended for a certain length of time (i.e., a "drug holiday").
  • intrasinusoidal and/or nasal and/or nasopharnygeal formulations described herein are manufactured as ready to use single component solutions that are administered to an individual in need thereof.
  • intrasinusoidal and/or nasal and/or nasopharnygeal formulations described herein are manufactured as multi-component kits comprising dry-heat sterilized multiparticulate (e.g., micronized, nanoparticles, non-sized particles) active agent powder, a medium for reconstitution of the dry powder (e.g., sterile water or buffer or saline) and/or a solution comprising the thermoreversible polymer and a buffer.
  • the dry powder is reconstituted with the sterile medium and/or the solution comprising the thermoreversible polymer and buffer just prior to administration of the sinonasal formulation to an individual in need thereof.
  • a 10-g batch of gel formulation containing 2.0% micronized dexamethasone is prepared. 13.8 mg of sodium phosphate dibasic dihydrate USP (Fisher Scientific.) + 3.1 mg of sodium phosphate monobasic monohydrate USP (Fisher Scientific.) + 74 mg of sodium chloride USP (Fisher Scientific.) is dissolved with 8.2g of sterile filtered DI water and the pH is adjusted to 7.4 with 1 M NaOH. The buffer solution is chilled down and 1.6 g of poloxamer 407 (BASF Corp., containing approximately 100 ppm of BHT) is sprinkled into the chilled PBS solution while mixing, solution is mixed until all the poloxamer is dissolved.
  • poloxamer 407 BASF Corp., containing approximately 100 ppm of BHT
  • the poloxamer is sterile filtered using a 33mm PVDF 0.22 ⁇ sterile syringe filter (Millipore Corp.) and delivered to 2 mL sterile glass vials (Wheaton) in an aseptic environment, the vials are closed with sterile butyl rubber stoppers (Kimble) and crimped sealed with 13 mm Al seals (Kimble).
  • poloxamer 407 BASF Corp., containing approximately 100 ppm of BHT
  • a chilled PBS solution while mixing, solution is mixed until all the poloxamer is dissolved.
  • the poloxamer is sterile filtered using a 33mm PVDF 0.22 ⁇ sterile syringe filter (Millipore Corp.) and delivered to 2 mL sterile glass vials (Wheaton) in an aseptic environment, the vials are closed with sterile butyl rubber stoppers (Kimble) and crimped sealed with 13 mm Al seals (Kimble).
  • micronized AM-101 is placed in separate clean depyrogenated vials, the vials are closed with sterile butyl rubber stoppers (Kimble) and crimped sealed with 13 mm Al seals (Kimble), vials are dry heat sterilized (Fisher Scientific Isotemp oven) at 140°C.
  • 1 mL of the cold poloxamer solution is delivered to a vial containing 20 mg of sterile micronized AM-101 using a 21G needle (Becton Dickinson) attached to a 1 mL sterile syringe (Becton Dickinson), suspension mixed well by shaking to ensure homogeneity of the suspension.
  • the suspension is withdrawn with the 21G syinge and the needle is switched to a 27 G needle for administration.
  • a solution containing poloxamers is prepared as described above in Example 1 and is sterile filtered using a 33mm PVDF 0.22 ⁇ sterile syringe filter (Millipore Corp.) and delivered to 2 mL sterile glass vials (Wheaton) in an aseptic environment.
  • the vials are closed with sterile butyl rubber stoppers (Kimble) and crimped sealed with 13 mm Al seals (Kimble).
  • a solution of poloxamer and PEG is prepared as described above and sterile filtered using a 33mm PVDF 0.22 ⁇ sterile syringe filter (Millipore Corp.) and delivered to 2 mL sterile glass vials (Wheaton) in an aseptic environment.
  • the vials are closed with sterile butyl rubber stoppers (Kimble) and crimped sealed with 13 mm Al seals (Kimble).
  • HPLC analysis was performed using an Agilent 1200 equipped with a Luna CI 8(2) 3 ⁇ , lOOA, 250x4.6 mm column) using a 30-95 of solvent B ( solvent A 35%
  • micronized/coated/liposomal particles (or salt or prodrug thereof) is used for all experiments.
  • the lower phase is drained a second time and the solution returned to near its original weight by the addition of water/iso-propanol solution and sodium chloride as described earlier.
  • the resulting solution is centrifuged, the lower phase is drained and discarded.
  • the upper phase from the third extraction is dried then extracted with chloroform.
  • the chloroform layer is then evaporated in vacuo. The residue is dried under vacuum.
  • Method B Poloxamer 407 from BASF Corporation, Mount Olive, N. J., is dissolved in deionized water. The solution is maintained close to freezing, then ammonium sulfate is added. The solution is equilibrated at 2° C. and after two distinct phases are formed, the lower phase is discarded, and the upper phase is collected and weighed. Deionized water is added and the solution is equilibrated to 2°C. followed by addition of ammonium sulfate with stirring. After the salt is dissolved, the solution is maintained at approximately 2° C. until two phases formed. The upper phase is isolated and diluted with deionized water. The solution is chilled to about 2° C. and ammonium sulfate is added.
  • Tgel measurements were performed using a Brookfield viscometer RVDV-II+P with a CP-51 spindle rotated at 0.08 rpm (shear rate of 0.31 s "1 ) equipped with a temperature control unit (temperature ramped from 15-37°C at 1.6 °C/min).
  • Ciprofloxacin chromatographic purity is shown in the table below.
  • Example 26 Treatment of sinusitis in an animal model
  • the maxillary sinus ostium of white rabbits is obstructed with a pledget through an antrostomy created in the anterior face of the maxilla.
  • the sinus is inoculated with
  • a reduction in bacterial counts in the nasal lavage, purulence and inflammation in the treatment group indicates an effective therapeutic outcome.
  • Exclusion Criteria Extensive previous sinonasal surgery in target ostia; cystic fibrosis; extensive sinonasal osteoneogenesis; sinonasal tumors or obstructive lesions;
  • Nasal polyps are defined as discreet polyps visible in the middle meatus area.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Inorganic Chemistry (AREA)
  • Otolaryngology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
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Abstract

L'invention concerne des compositions et des procédés pour le traitement de maladies ou de troubles sino-nasaux et/ou rhino-pharyngiens avec des compositions et formulations d'agents actifs administrées localement à un individu atteint d'une maladie ou d'un trouble sino-nasal ou rhino-pharyngien, par application directe de ces compositions et formulations sur ou par perfusion dans la ou les structures sino-nasales ciblées.
PCT/US2010/053616 2009-10-21 2010-10-21 Compositions et procédés pour le traitement de troubles sino-nasaux Ceased WO2011050206A2 (fr)

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US25378209P 2009-10-21 2009-10-21
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US25537909P 2009-10-27 2009-10-27
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US25578009P 2009-10-28 2009-10-28
US25578309P 2009-10-28 2009-10-28
US61/255,780 2009-10-28
US61/255,783 2009-10-28
US29713810P 2010-01-21 2010-01-21
US29717010P 2010-01-21 2010-01-21
US61/297,170 2010-01-21
US61/297,138 2010-01-21
US36428710P 2010-07-14 2010-07-14
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DE202013000748U1 (de) 2013-01-24 2013-02-19 Merz Pharma Gmbh & Co. Kgaa Sprühbare flüssige Zubereitung zur insbesondere nasalen Anwendung mit erhöhter lokaler Verweilzeit
WO2013176622A1 (fr) * 2012-05-21 2013-11-28 Agency For Science, Technology And Research (A*Star) Formulation de poudre sèche
DE102013001151A1 (de) 2013-01-24 2014-07-24 Merz Pharma Gmbh & Co. Kgaa Sprühbare flüssige Zubereitung zur insbesondere nasalen Anwendung mit erhöhter lokaler Verweilzeit
EP2759290A1 (fr) 2013-01-24 2014-07-30 Merz Pharma GmbH & Co. KGaA Composition liquide pulverisable en particulier pour application nasale avec un delai locale retentissant augmente
AU2012211514B2 (en) * 2006-10-24 2014-07-31 Aradigm Corporation Concentrated, inhalable ciprofloxacin formulation
US20140371305A1 (en) * 2013-06-14 2014-12-18 Professional Compounding Centers Of America Mupirocin Antibiotic Composition
CN104341405A (zh) * 2014-09-25 2015-02-11 武汉大学 一种具有抑制Aβ聚集活性的化合物的制备方法与用途
US9028864B2 (en) 2006-10-24 2015-05-12 Aradigm Corporation Concentrated, inhalable antibiotic formulation
US9402845B2 (en) 2005-12-08 2016-08-02 Insmed Incorporated Lipid-based compositions of antiinfectives for treating pulmonary infections and methods of use thereof
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WO2017105356A1 (fr) 2015-12-18 2017-06-22 Ak-Kim Kimya Sanayi Ve Ticaret Anonim Sirketi Module de membrane à fibres creuses
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US9987227B2 (en) 2013-10-22 2018-06-05 Aradigm Corporation Inhaled surfactant-modified liposomal formulations providing both an immediate and sustained release profile
US10064882B2 (en) 2007-05-07 2018-09-04 Insmed Incorporated Methods of treating pulmonary disorders with liposomal amikacin formulations
US10124066B2 (en) 2012-11-29 2018-11-13 Insmed Incorporated Stabilized vancomycin formulations
US10238675B2 (en) 2014-05-15 2019-03-26 Insmed Incorporated Methods for treating pulmonary non-tuberculous mycobacterial infections
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US11510916B2 (en) 2013-07-22 2022-11-29 Novel Drug Solutions Llc Pharmaceutical compositions for intraocular administration and methods for fabricating thereof
US11571386B2 (en) 2018-03-30 2023-02-07 Insmed Incorporated Methods for continuous manufacture of liposomal drug products
US12396981B2 (en) 2023-03-09 2025-08-26 William Shulman Methods of using DMT

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US20220135653A1 (en) * 2020-11-05 2022-05-05 Bravado Pharmaceuticals, LLC Intranasal Antiviral Therapy for Mucosal Protection Against Virus Infections
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GB9310412D0 (en) * 1993-05-20 1993-07-07 Danbiosyst Uk Nasal nicotine system

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US10328071B2 (en) 2005-12-08 2019-06-25 Insmed Incorporated Lipid-based compositions of antiinfectives for treating pulmonary infections and methods of use thereof
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US9028864B2 (en) 2006-10-24 2015-05-12 Aradigm Corporation Concentrated, inhalable antibiotic formulation
US11026941B2 (en) 2006-10-24 2021-06-08 Grifols, S.A. Concentrated, inhalable ciprofloxacin formulation
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US9545401B2 (en) 2006-10-24 2017-01-17 Aradigm Corporation Concentrated, inhalable ciprofloxacin formulation
US10064882B2 (en) 2007-05-07 2018-09-04 Insmed Incorporated Methods of treating pulmonary disorders with liposomal amikacin formulations
US9707228B2 (en) 2012-05-21 2017-07-18 Agency For Science, Technology And Research Dry powder formulation
WO2013176622A1 (fr) * 2012-05-21 2013-11-28 Agency For Science, Technology And Research (A*Star) Formulation de poudre sèche
US10471149B2 (en) 2012-11-29 2019-11-12 Insmed Incorporated Stabilized vancomycin formulations
US10124066B2 (en) 2012-11-29 2018-11-13 Insmed Incorporated Stabilized vancomycin formulations
DE202013000748U1 (de) 2013-01-24 2013-02-19 Merz Pharma Gmbh & Co. Kgaa Sprühbare flüssige Zubereitung zur insbesondere nasalen Anwendung mit erhöhter lokaler Verweilzeit
EP2759290A1 (fr) 2013-01-24 2014-07-30 Merz Pharma GmbH & Co. KGaA Composition liquide pulverisable en particulier pour application nasale avec un delai locale retentissant augmente
DE102013001151A1 (de) 2013-01-24 2014-07-24 Merz Pharma Gmbh & Co. Kgaa Sprühbare flüssige Zubereitung zur insbesondere nasalen Anwendung mit erhöhter lokaler Verweilzeit
US20140371305A1 (en) * 2013-06-14 2014-12-18 Professional Compounding Centers Of America Mupirocin Antibiotic Composition
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US11439590B2 (en) 2013-07-22 2022-09-13 Novel Drug Solutions Llc Pharmaceutical ophthalmic compositions for intraocular administration and methods for fabricating thereof
US11510916B2 (en) 2013-07-22 2022-11-29 Novel Drug Solutions Llc Pharmaceutical compositions for intraocular administration and methods for fabricating thereof
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US11395830B2 (en) 2014-05-15 2022-07-26 Insmed Incorporated Methods for treating pulmonary non-tuberculous mycobacterial infections
US12016873B2 (en) 2014-05-15 2024-06-25 Insmed Incorporated Methods for treating pulmonary non-tuberculous mycobacterial infections
US10398719B2 (en) 2014-05-15 2019-09-03 Insmed Incorporated Methods for treating pulmonary non-tuberculous mycobacterial infections
CN104341405A (zh) * 2014-09-25 2015-02-11 武汉大学 一种具有抑制Aβ聚集活性的化合物的制备方法与用途
WO2017105356A1 (fr) 2015-12-18 2017-06-22 Ak-Kim Kimya Sanayi Ve Ticaret Anonim Sirketi Module de membrane à fibres creuses
CN105902543A (zh) * 2016-04-28 2016-08-31 华北制药股份有限公司 一种高纯度美洛西林钠制剂及其制备方法
WO2018035534A1 (fr) * 2016-08-19 2018-02-22 Gerbe Labs Inc. Polythérapie antifongique
US11571386B2 (en) 2018-03-30 2023-02-07 Insmed Incorporated Methods for continuous manufacture of liposomal drug products
US12290600B2 (en) 2018-03-30 2025-05-06 Insmed Incorporated Methods for continuous manufacture of liposomal drug products
CN110141559A (zh) * 2019-06-18 2019-08-20 浦易（上海）生物技术有限公司 一种用于鼻粘膜的含药缓释微粒及其应用
WO2021207305A1 (fr) * 2020-04-08 2021-10-14 Nostrum Pharmaceuticals, Llc Compositions et procédés utilisant l'interféron destinés au traitement d'infections virales
US12396981B2 (en) 2023-03-09 2025-08-26 William Shulman Methods of using DMT

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