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WO2009143011A1 - Compositions antivirales, procédés de fabrication et d’utilisation de ces compositions, et système de délivrance pulmonaire de ces compositions - Google Patents

Compositions antivirales, procédés de fabrication et d’utilisation de ces compositions, et système de délivrance pulmonaire de ces compositions Download PDF

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Publication number
WO2009143011A1
WO2009143011A1 PCT/US2009/044122 US2009044122W WO2009143011A1 WO 2009143011 A1 WO2009143011 A1 WO 2009143011A1 US 2009044122 W US2009044122 W US 2009044122W WO 2009143011 A1 WO2009143011 A1 WO 2009143011A1
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WIPO (PCT)
Prior art keywords
pharmaceutical composition
particles
antiviral
pharmaceutically acceptable
compositions
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PCT/US2009/044122
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English (en)
Inventor
Mei-Chang Kuo
Guy Lalonde
David Sahner
Blaine Bueche
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Novartis Ag
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Publication of WO2009143011A1 publication Critical patent/WO2009143011A1/fr

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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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • 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
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • 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
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles

Definitions

  • Antiviral Compositions Methods of Making and Using Such Compositions, and Systems for Pulmonary Delivery of Such Compositions
  • the present invention relates to pharmaceutical compositions comprising an antiviral active, powder compositions comprising antiviral actives, and compositions comprising combinations of two or more antiviral actives.
  • One or more embodiments of the present invention include methods of making and using such compositions, and methods and systems for pulmonary delivery of such compositions.
  • This invention relates to methods and compositions for treating viral infections, and has particular reference to the treatment of influenza.
  • Influenza more commonly known as the flu
  • the flu is an acute, viral infection that attacks mainly the upper respiratory tract-the nose, throat and bronchi and rarely also the lungs.
  • the flu is considered to be an infection of the respiratory tract, individuals suffering from the flu usually become acutely ill with high fever, chills, headache, weakness, loss of appetite and aching joints.
  • the typical length of time from when a person is exposed to influenza virus to when symptoms first occur ranges between one and five days, with an average of two days.
  • Adults can be infectious (i.e., shedding virus) starting the day before the onset of symptoms begin until approximately 5 days after the onset of illness.
  • Children can be infectious for longer periods of time.
  • Systemic symptoms include abrupt onset of fever (e.g. usually 100-103 0 F in an adult and possibly higher in children), chills, headaches, myalgia and malaise.
  • influenza infections are known to increase the susceptibility of an infected to particular bacterial infections caused by species of bacterial pathogens such as, pneumococcus, staphylococcus, mycoplasma, non-group H. influenza, and Moraxella catarrhalis.
  • Secondary bacterial infections such as, but not limited to, infections of the lower respiratory tract (e.g., pneumonia), middle ear infections (e.g., otitis media) and bacterial sinusitis are common complications of an infection with viral influenza.
  • the flu and its associated complications e.g.
  • Aerosolized medicaments are used to treat patients suffering from a variety of ailments. Medicaments can be delivered directly to the lungs by having the patient inhale the aerosol through a tube and/or mouthpiece coupled to an aerosol generator. By inhaling the aerosolized medicament, the patient can quickly, safely and efficiently receive a dose of medicament.
  • Aerosolized medicaments can be administered directly to the lungs to treat diseases and/or conditions of the lung, and to treat diseases or conditions having a systemic effect or component thereof.
  • Many medicaments cannot be administered orally, due to their sensitivity to metabolism and/or degradation and resulting inactivation in the gastrointestinal tract, thus pulmonary delivery avoids the need for intramuscular, subcutaneous or transdermal delivery and associated needles. Additionally or alternatively, it may be safer and/or more efficacious to deliver the medicament directly to the lungs and/or pulmonary system instead of other administration routes.
  • Pulmonary delivery by aerosol inhalation has received much attention as an attractive alternative to intravenous, intramuscular, and subcutaneous injection, since this approach eliminates the necessity for injection syringes and needles. Pulmonary delivery also limits irritation to the skin and body mucosa which are common side effects of transdermal ⁇ , iontophoretically, and intranasally delivered drugs, eliminates the need for nasal and skin penetration enhancers (typical components of intranasal and transdermal systems that often cause skin irritation/dermatitis), is economically attractive, is amenable to patient self-administration, and is often preferred by patients over other alternative modes of administration.
  • Pulmonary delivery may comprise aerosolized liquids, dispersions, or powder forms.
  • the compositions may be delivered via liquid nebulizers, metered dose (pressurized) inhalers or dry-powder inhalers.
  • Dry powder inhalers are known in the art as disclosed, for example, in U.S.
  • the present invention relates to antiviral pharmaceutical compositions, methods of making and using such compositions, and systems for pulmonary delivery of such compositions.
  • compositions comprising particles comprising antiviral actives (i.e. drugs, pharmaceuticals, compounds, chemicals, metals, biologies and combinations having antiviral activity, individually and collectively referred to as antivirals.)
  • antiviral actives i.e. drugs, pharmaceuticals, compounds, chemicals, metals, biologies and combinations having antiviral activity, individually and collectively referred to as antivirals.
  • the present invention relates to pharmaceutical compositions comprising particles comprising an effective amount of an antiviral and a pharmaceutically acceptable excipient, wherein the particles have a mass median aerodynamic diameter (MMAD) from about 1 ⁇ m to about 7 ⁇ m, and a bulk density of less than about 1.0 g/cm 3 .
  • MMAD mass median aerodynamic diameter
  • the present invention is directed to a pharmaceutical composition for pulmonary delivery comprising particles comprising at least one antiviral and a pharmaceutically acceptable excipient, wherein pulmonary distribution (i.e. to and throughout bronchi, bronchioles and alveoli) is very good.
  • the present invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising particles comprising one or more antivirals selected from the group consisting of a neuraminidase inhibitor, a hemagglutinin inhibitor, an M2 proton channel blocker, a nucleoside analog, peptide analogs, protease inhibitors, SiRNAs, antibodies, antibody fragments, antibody constructs and glycodendritic structures or polymers and any combination thereof.
  • the present invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising particles comprising one or more antivirals selected from the group consisting of a neuraminidase inhibitor, a hemagglutinin inhibitor, an M2 proton channel blocker, a nucleoside analog and any combination thereof.
  • the present invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising particles comprising two or more antivirals selected from the group consisting of a neuraminidase inhibitor, a hemagglutinin inhibitor and a M2 proton channel blocker.
  • the present invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising particles comprising an antiviral which is selected from the group consisting of a neuraminidase inhibitor, a hemagglutinin inhibitor, a M2 proton channel blocker, a nucleoside analog and combinations thereof, wherein the particles have a mass median aerodynamic diameter from about 1 ⁇ m to about 7 ⁇ m, and a bulk density of less than about 1.0 g/cm 3 .
  • the present invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising particles comprising an antiviral which is selected from the group consisting of a neuraminidase inhibitor, a hemagglutinin inhibitor, a M2 proton channel blocker, a nucleoside analog and combinations thereof, wherein the particles have a mass median aerodynamic diameter from about 1 ⁇ m to about 5 ⁇ m and a bulk density of less than about 1.0 g/cm 3 .
  • the present invention is directed to one of the aforementioned pharmaceutical composition comprising particles comprising about 10-99 wt% of antiviral which is selected from a neuraminidase inhibitor, a hemagglutinin inhibitor, a M2 proton channel blocker, a nucleoside analog and combinations thereof.
  • the present invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising particles comprising a neuraminidase inhibitor and a M2 proton channel blocker, wherein the particles have a mass median aerodynamic diameter from about 1 ⁇ m to about 7 ⁇ m and a bulk density of less than about 1.0 g/cm 3 .
  • the present invention is directed to a pharmaceutical composition comprising porous and/or holiow particles comprising an antiviral.
  • the present invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising particles as described above, wherein the composition is in the form of a powder.
  • the present invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising particles comprising at least one antiviral selected from the group consisting of a neuraminidase inhibitor, a hemagglutinin inhibitor, a M2 proton channel blocker and a nucleoside analog, and at least one excipient, wherein the particles have a mass median aerodynamic diameter from about 1 ⁇ m to about 7 ⁇ m and a bulk density of less than about 1.0 g/cm 3 , a particle size distribution of at least 50% of the particles having an aerodynamic diameter of less than about 3 microns.
  • the composition provides an emitted dose of active of at least about 50% of the antiviral.
  • the present invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising particles comprising zamanivir and an excipient selected from a phospholipid or a di- or tri-peptide comprising at least two leucines, wherein the particles have a mass median aerodynamic diameter from about 1 ⁇ m to about 7 ⁇ m and a bulk density of less than about 1.0 g/cm 3 , a particle size distribution of at least 50% having an aerodynamic diameter less than about 3 microns, and wherein the composition further provides an emitted dose of active of at least about 50%.
  • the present invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising particles comprising rimantadine and a pharmaceutically acceptable excipient selected from a phospholipid or a di- or tri-peptide comprising at least two leucines, wherein the particles have a mass median aerodynamic diameter from about 1 ⁇ m to about 7 ⁇ m and a bulk density of less than about 1.0 g/cm 3 , a particle size distribution of at least 50% having an aerodynamic diameter less than about 3 microns, and wherein the composition further provides an emitted dose of active of at least about 50%.
  • the present invention is directed to a unit dosage form, comprising a container containing a pharmaceutical composition comprising particles comprising an effective amount of antiviral and a pharmaceutically acceptable excipient, wherein the particles have a mass median aerodynamic diameter from about 1 ⁇ m to about 7 ⁇ m and a bulk density of less than about 1.0 g/cm 3 .
  • the present invention is directed to a unit dosage form, comprising a container containing a pharmaceutical composition comprising particles comprising an effective amount of antiviral and a di or tri- peptide containing at least two leucines, wherein the particles have a mass median aerodynamic diameter from about 1 ⁇ m to about 7 ⁇ m and a bulk density of less than about 1.0 g/cm 3 .
  • the present invention is directed to a unit dosage form, comprising a container containing a pharmaceutical composition comprising particles comprising an effective amount of antiviral and a phospholipid, wherein the particles have a mass median aerodynamic diameter from about 1 ⁇ m to about 7 ⁇ m and a bulk density of less than about 1.0 g/cm 3 .
  • the present invention is directed to a delivery system, comprising an inhaler and a pharmaceutical composition comprising particles comprising antiviral and a pharmaceutically acceptable excipient as set out above.
  • the present invention is directed to a method of making particles, comprising suspending an antiviral in a liquid to form a feedstock and removing the liquid therefrom to produce particles, wherein the particles comprise an antiviral and have a mass median aerodynamic diameter from about 1 ⁇ m to about 7 ⁇ m and a bulk density of less than about 1.0 g/cm 3 .
  • the present invention is directed to a method of making particles, comprising suspending an antiviral in a liquid to form a feedstock and spray drying the feedstock to produce spray-dried particles, wherein the particles comprise an antiviral and have a mass median aerodynamic diameter from about 1 ⁇ m to about 7 ⁇ m and a bulk density of less than about 1.0 g/cm 3 .
  • the present invention is directed to a method of treating a patient with a condition associated with a viral infection comprising administering an effective amount of a pharmaceutical composition comprising antiviral by inhalation to a patient, wherein the composition comprises particles comprising an antiviral a pharmaceutically acceptable excipient, such particles having a mass median aerodynamic diameter from about 1 ⁇ m to about 7 ⁇ m and a bulk density of less than about 1.0 g/cm 3 .
  • the present invention is directed to a method of treating viral infections by pulmonary administration of a pharmaceutical composition as set out above comprising an antiviral combination, wherein an effective dose of the antiviral combination is at least about ten times lower than an effective dose of the same antiviral delivered orally.
  • the present invention is directed to a kit comprising a pharmaceutical composition comprising particles comprising an effective amount of antiviral and a pharmaceutically acceptable excipient, wherein the particles have a mass median aerodynamic diameter from about 1 ⁇ m to about 7 ⁇ m and a bulk density of less than about 1.0 g/cm 3 , and a delivery device for the composition.
  • Figs 1A-1E show a passive inhaler device.
  • Figs 2A-2D are photomicrographs showing particles made with varying amounts of antiviral and excipient, in accordance with one or more embodiments of the present invention.
  • Fig 3 is a graph showing particle size and particle size distribution for particles made in accordance with one or more embodiments of the present invention.
  • Fig 4 is a bar graph showing emitted dose showing particles made with varying amounts of antiviral and excipient, in accordance with one or more embodiments of the present invention
  • Figs 5A-5B are graphs showing emptying profiles of amorphous drug particles made with varying amounts of antiviral and excipient, in accordance with one or more embodiments of the present invention.
  • Fig 6 is a bar graph of drug delivered (as lung dose) for particles made with varying amounts of antiviral and excipient, in accordance with one or more embodiments of the present invention
  • a phospholipid includes a single phospholipid as well as two or more phospholipids in combination or admixture unless the context clearly dictates otherwise.
  • an active agent when referring to an active agent, the term encompasses not only the specified molecular entity, but also its pharmaceutically acceptable, pharmacologically active analogs, including, but not limited to, salts, esters, amides, hydrazides, N-alkyl derivatives, N-acyl derivatives, prodrugs, conjugates, active metabolites, and other such derivatives, analogs, and related compounds. Therefore, as used herein, the term “antiviral” refers to antivirals per se or derivatives, analogs, or related compounds noted above, as long as such antivirals derivatives, analogs, or related compounds exhibit antiviral activity.
  • treating and “treatment” refer to reduction in severity and/or frequency of symptoms, elimination of symptoms and/or underlying cause, reduction in likelihood of the occurrence of symptoms and/or underlying cause, and improvement or remediation of damage.
  • treating a patient with an active agent as provided herein includes prevention of a particular condition, disease or disorder in a susceptible individual as well as treatment of a clinically symptomatic individual.
  • effective amount refers to an amount covering both therapeutically effective amounts and prophylactically effective amounts.
  • therapeutically effective amount refers to an amount that is effective to achieve the desired therapeutic result.
  • a therapeutically effective amount of a given active agent will typically vary with respect to factors such as the type and severity of the disorder or disease being treated and the age, gender, and weight of the patient.
  • prophylactically effective amount refers to an amount that is effective to achieve the desired prophylactic result. Because a prophylactic dose is administered in patients prior to onset of disease, the prophylactically effective amount typically is tess than the therapeutically effective amount.
  • the term "respiratory infections” includes, but is not limited to upper respiratory tract infections such as sinusitis, pharyngitis, and influenza, and lower respiratory tract infections such as tuberculosis, bronchiectasis (both the cystic fibrosis and non-cystic fibrosis indications), bronchitis (both acute bronchitis and acute exacerbation of chronic bronchitis), and pneumonia (including various types of complications that arise from viral and bacterial infections including hospital-acquired and community-acquired infections).
  • upper respiratory tract infections such as sinusitis, pharyngitis, and influenza
  • lower respiratory tract infections such as tuberculosis, bronchiectasis (both the cystic fibrosis and non-cystic fibrosis indications), bronchitis (both acute bronchitis and acute exacerbation of chronic bronchitis), and pneumonia (including various types of complications that arise from viral and bacterial infections including hospital
  • MMD mass median diameter
  • powder samples are added directly to the feeder funnel of the Sympatec RODOS dry powder dispersion unit. This can be achieved manually or by agitating mechanically from the end of a VIBRI vibratory feeder element.
  • Samples are dispersed to primary particles via application of pressurized air (2 to 3 bar), with vacuum depression (suction) maximized for a given dispersion pressure.
  • Dispersed particles are probed with a 632.8 nm laser beam that intersects the dispersed particles' trajectory at right angles.
  • Laser light scattered from the ensemble of particles is imaged onto a concentric array of photomultiplier detector elements using a reverse-Fourier lens assembly. Scattered light is acquired in time-slices of 5 ms.
  • Particle size distributions are back-calculated from the scattered light spatial/intensity distribution using a proprietary algorithm.
  • geometric diameter refers to the diameter of a single particle, as determined by microscopy, unless the context indicates otherwise.
  • MMAD mass median aerodynamic diameter
  • the “aerodynamic diameter” is the diameter of a unit density sphere having the same settling velocity, generally in air, as a powder and is therefore a useful way to characterize an aerosolized powder or other dispersed particle or particle formulation in terms of its settling behavior.
  • the aerodynamic diameter encompasses particle or particle shape, density, and physical size of the particle or particle.
  • MMAD refers to the median of the aerodynamic particle or particle size distribution of an aerosolized powder determined by cascade impaction, unless the context indicates otherwise.
  • the term "emitted dose” or "ED" refers to an indication of the delivery of dry powder from an inhaler device after an actuation or dispersion event from a powder unit or reservoir.
  • ED is defined as the ratio of the dose delivered by an inhaler device to the nominal dose (i.e., the mass of powder per unit dose placed into a suitable inhaler device prior to firing).
  • the ED is an experimentally determined amount, and may be determined using an in vitro device set up which mimics patient dosing.
  • a nominal dose of dry powder (as defined herein) is placed into a suitable inhaler device, for example, a Turbospin® DPI device (PH&T, Italy), described in U.S. Patent Nos. 4,069,819 and 4,995,385, which are incorporated herein by reference in their entireties.
  • the inhaler device is actuated, dispersing the powder.
  • the resulting aerosol cloud is then drawn from the device by vacuum (30 L/min) for 2.5 seconds after actuation, where it is captured on a tared glass fiber filter (Gelman, 47 mm diameter) attached to the device mouthpiece.
  • the amount of powder that reaches the filter constitutes the delivered dose.
  • passive dry powder inhaler refers to an inhalation device that relies upon a patient's inspiratory effort to disperse and aerosolize a pharmaceutical composition contained within the device in a reservoir or in a unit dose form and does not include inhaler devices which comprise a means for providing energy, such as pressurized gas and vibrating or rotating elements, to disperse and aerosolize the drug composition.
  • active dry powder inhaler refers to an inhalation device that does not rely solely on a patient's inspiratory effort to disperse and aerosolize a pharmaceutical composition contained within the device in a reservoir or in a unit dose form and does include inhaler devices that comprise a means for providing energy to disperse and aerosolize the drug composition, such as pressurized gas and vibrating or rotating elements.
  • compositions including antivirals may include various forms and amounts of antivirals.
  • the antiviral may be present in an amount from, in weight percentage (wt%) at least about 0.01 , or 0.5 or 1 or 2 or 5 or 10 or 20 or 30 or 40 or 50 or 60 or 70 or 80 or 90 or 95 or 98 or 99 wt%, or in a range of any combination of the stated amounts.
  • the pharmaceutical composition according to one or more embodiments of the invention may comprise one or more antiviral and, optionally, one or more other active ingredients and/or pharmaceutically acceptable excipients.
  • the pharmaceutical composition may comprise neat particles of antiviral, may comprise neat particles of antiviral together with other particles, and/or may comprise particles comprising antiviral and one or more active ingredients and/or one or more pharmaceutically acceptable excipients.
  • the particles may be as a dry powder, or may be suspended or dispersed in a liquid.
  • compositions according to one or more embodiments of the invention may comprise one or more antiviral and, optionally, one or more other active ingredients and/or pharmaceutically acceptable excipients.
  • the pharmaceutical composition according to one or more embodiments of the invention may, if desired, contain a combination of antiviral and one or more other active ingredients.
  • other active agents include, but are not limited to, agents that may be delivered to or through the lungs or nasal passages.
  • the other active agent(s) may be long-acting agents and/or active agents that are active against pulmonary and/or nasal infections such as antifungals and/or antibiotics.
  • the present invention comprises a particulate formulation comprising at least one antiviral. In one or more embodiments, the present invention comprises a formulation comprising at least two antivirals. In one or more embodiments, the present invention comprises a formulation comprising at least two antivirals wherein the antivirals are of different classes. In one or more embodiments, the present invention comprises a formulation comprising at least three antivirals wherein the antivirals are of different classes.
  • Antivirals may be classified by a variety of schemes. One such scheme is based upon the target inhibited within the viral life cycle stage. In this classification scheme, antivirals may be conveniently divided into three classes, by approximate functional mode
  • a very early stage of viral infection is viral entry, when the virus attaches to and enters the host cell.
  • the virus must first bind to a specific receptor molecule on the surface of the host cell. Viruses that have a lipid envelope must also fuse their envelope with the target cell, or with a vesicle that transports them into the cell, before they can uncoat.
  • This stage of viral replication can be inhibited by using agents which mimic the virus-associated protein (VAP) and bind to the cellular receptors.
  • VAP virus-associated protein
  • This may include VAP anti-idiotypic antibodies, anti-receptor antibodies, and natural ligands of the receptor and anti-receptor antibodies.
  • Agents which mimic the receptor and bind to the VAP also exist, such as anti-VAP antibodies, receptor anti-idiotypic antibodies, extraneous receptor and synthetic receptor mimics.
  • One entry-blocker is pleconaril, which works against rhinoviruses, by blocking a pocket on the surface of the virus that controls the uncoating process.
  • Hemagglutinin is an antigenic glycoprotein found on the surface of the influenza viruses (as well as many other bacteria and viruses). It is responsible for binding the virus to the cell that is being infected. HA binds to the monosaccharide sialic acid which is present on the surface of its target cells. This causes the viral particles to stick to the cell's surface. The cell membrane then engulfs the virus and the portion of the membrane that encloses it pinches off to form a new membrane-bound compartment within the cell (an endosome), which contains the engulfed virus. The cell then attempts to begin digesting the contents of the endosome by acidifying its interior and transforming it into a lysosome.
  • a second approach is to target the processes that synthesize virus components after a virus invades a cell.
  • One way of doing this is to develop nucleotide or nucleoside analogues that look like the building blocks of RNA or DNA, but deactivate the enzymes that synthesize the RNA or DNA once the analogue is incorporated.
  • Examples include acyclovir and zidovudine, which are effective against herpes virus infections.
  • lamivudine approved to treat hepatitis B, which uses reverse transcriptase as part of its replication process.
  • Inhibitors have been developed that do not look like nucleosides, but can still block reverse transcriptase.
  • mRNA messenger RNA
  • Antisense molecules are segments of DNA or RNA designed as mirror images to critical sections of viral genomes, and the binding of these antisense segments to these target sections blocks the operation of those genomes.
  • a phospho roth bate antisense drug named fomivirsen is used to treat opportunistic eye infections in AIDS patients caused by cytomegalovirus.
  • Morpholino oligos have been used to experimentally suppress many viral types including caliciviruses, flaviviruses (including WNV, Dengue and HCV), and corona viruses.
  • ribozymes are enzymes that will cut apart viral RNA or DNA at selected sites.
  • a ribozyme antivirals exist or are under development to treat hepatitis C and HIV.
  • viruses include a protease that cuts viral protein chains apart so they can be assembled into their final configuration. Protease inhibitors can thus attack the virus at the assembly phase of its life-cycle.
  • the class of M2 channel blockers includes amantadine and rimantadine.
  • Zanamivir (Relenza), oseltamivir (Tamiflu) and Peramivir have been introduced to treat influenza by preventing the release of viral particles by blocking the neuraminidase enzyme (neuraminidase inhibitors) that is found on the surface of flu viruses.
  • Zanamivir may be formulated for as a powder for inhalation.
  • a commercially-available inhalation powder of Zanamivir (Relenza) is formulated with lactose, yielding relatively large particles.
  • Neuraminidase is a glycoside hydrolase enzyme (EC 3.2.1.18). It is frequently found as an antigenic glycoprotein and is best known as one of the enzymes found on the surface of the Influenza virus. Some variants of the influenza neuraminidase confer more virulence to the virus than others. At least four neuraminidases in the human genome have been described. Neuraminidase has functions that aid in the efficiency of virus release from cells. Neuraminidase cleaves terminal sialic acid residues from carbohydrate moieties on the surfaces of infected cells. This promotes the release of progeny viruses from infected cells. Neuraminidase also cleaves sialic acid residues from viral proteins, preventing aggregation of viruses. Administration of chemical inhibitors of neuraminidase is a treatment that limits the severity and spread of viral infections.
  • Antivirals may also be classified by chemical type, such as: nucleoside analogs; peptide anologs, neuraminic acid mimetics, proteins, triazoles, tricyclic amines, small cyclic molecules and kinase inhibitors, for example.
  • SiRNA small interfering RNAs
  • SiRNA small interfering RNAs
  • antivirals include, but are not limited to, acyclovir, gangcyclovir, azidothymidine, cytidine arabinoside, ribavirin, rifampacin, iododeoxyuridine, poscamet, and trifluridine.
  • the present invention comprises one or more antivirals formulated for inhalation in the form of particles to have a MMAD particle size of less than about 7 microns, such as less than about 6 or 5 or 4 or 3 or 2 microns.
  • the antiviral composition comprises a powder which can be administered using an inhaler device.
  • the antiviral composition comprises particles which are sufficiently small to provide good lung distribution, through the lower airways and alveoli. Such distribution not only aids in therapeutic effect, but helps to mitigate, reduce or eliminate toxicity associated with uneven distribution of drug. Moreover, the specified small particle size helps to mitigate, reduce or eliminate bronchospasm.
  • the antiviral composition comprises particles comprising at least two different antiviral actives and an excipient matrix such that the individual particles comprise predominantly all three components. In one or more embodiments, the antiviral composition comprises particles comprising a single antiviral active and an excipient matrix such that the individual particles comprise predominantly only two components. In one or more embodiments, the antiviral composition comprises a mixture of first and second particles, wherein the first particle comprises a first antiviral active and an excipient matrix, and the second particle comprises a second antiviral active and an excipient matrix, and wherein the excipient may be the same or different, and the first and second particles may be of substantially similar physical characteristics, or may differ in one or more physical characteristics.
  • the antiviral formulation of the present invention when administered by inhalation, affords a beneficial ratio of lung C max to serum C max .
  • a lung concentration is sufficiently high to provide therapeutic effectiveness, while a serum concentration is sufficiently low to eliminate or minimize side effects, unwanted effects, adverse reactions and/or toxicity.
  • a ratio of lung C m a x to serum C max is at least about 2000:1.
  • the agents may be provided in combination in a single species of pharmaceutical composition or individually in separate species of pharmaceutical compositions. Further, the pharmaceutical composition may be combined with one or more other active or bioactive agents that provide the desired dispersion stability or powder dispersibility.
  • the amount of active agent ⁇ s), e.g., antiviral, in the pharmaceutical composition may vary.
  • the amount of active agent(s) is typically at least about 0.5 wt%, such as at least about 1 wt%, at least about 2 wt%, at least about 5 wt%, at least about 10 wt%, at least about 20 wt%, at least about 30 wt%, at least about 40 wt%, at least about 50 wt%, at least about 60 wt%, at least about 70 wt%, or at least about 80 wt%, of the total amount of the pharmaceutical composition.
  • the amount of active agent(s) generally varies between about 0.1 wt% to 100 wt%, such as about 1 wt% to about 95 wt%, about 2 wt% to about 90 wt%, about 30 wt% to about 80 wt%, about 40 wt% to about 70 wt%, about 50 wt% to about 60 wt%, about 1 wt% to about 20 wt%, about 2 wt% to about 10 wt%, about 5 wt% to about 50 wt%, or about 4 wt% to about 20 wt%.
  • the pharmaceutical composition may include one or more pharmaceutically acceptable excipients.
  • pharmaceutically acceptable excipients include, but are not limited to, lipids, metal ions, surfactants, amino acids, carbohydrates, buffers, salts, polymers, and the like, and combinations thereof.
  • lipids include, but are not limited to, phospholipids, glycolipids, ganglioside GM1 , sphingomyelin, phosphatide acid, cardiolipin; lipids bearing polymer chains such as polyethylene glycol, chitin, hyaluronic acid, or polyvinylpyrrolidone; lipids bearing sulfonated mono-, di-, and polysaccharides; fatty acids such as palmitic acid, stearic acid, and oleic acid; cholesterol, cholesterol esters, and cholesterol hemisuccinate.
  • the phospholipid comprises a saturated phospholipid, such as one or more phosphatidylcholines.
  • exemplary acyl chain lengths are 16:0 and 18:0 (i.e., palmitoyl and stearoyl).
  • the phospholipid content may be determined by the active agent activity, the mode of delivery, and other factors.
  • Phospholipids from both natural and synthetic sources may be used in varying amounts. When phospholipids are present, the amount is typically sufficient to coat the active agent(s) with at least a single molecular layer of phospholipid. In general, the phospholipid content ranges from about 5 wt% to about 99.9 wt%, such as about 20 wt% to about 80 wt%.
  • compatible phospholipids comprise those that have a gel to liquid crystal phase transition greater than about 40 0 C, such as greater than about 60 0 C, or greater than about 80 0 C.
  • the incorporated phospholipids may be relatively long chain ⁇ e.g., C 16 -C 22 ) saturated lipids.
  • Exemplary phospholipids useful in the disclosed stabilized preparations include, but are not limited to, phosphoglycerides such as dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, diarachidoylphosphatidylcholine, dibehenoylphosphatidylcholine, dimyristoylphosphatidylcholine, diphosphatidyl glycerols, short-chain phosphatidylcholines, hydrogenated phosphatidylcholine, E-100-3 (available from Lipoid KG, Ludwigshafen, Germany), long-chain saturated phosphatidylethanolamines, long- chain saturated phosphatidylserines, long-chain saturated phosphatidylglycerols, long- chain saturated phosphatidylinositols, phosphatidic acid, phosphatidylinositol, and sphingomyelin.
  • phosphoglycerides such as
  • metal ions include, but are not limited to, divalent cations, including calcium, magnesium, zinc, iron, and the like.
  • the pharmaceutical composition may also comprise a polyvalent cation, as disclosed in WO 01/85136 and WO 01/85137, which are incorporated herein by reference in their entireties.
  • the polyvalent cation may be present in an amount effective to increase the melting temperature (T m ) of the phospholipid such that the pharmaceutical composition exhibits a T m which is greater than its storage temperature (T s ) by at least about 20 0 C, or 25°C or 30 0 C or 35°C or 40 0 C or 45 0 C or more.
  • the molar ratio of polyvalent cation to phospholipid may be at least about 0.05:1, such as about 0.05:1 to about 2.0: 1 or about 0.25: 1 to about 1.0: 1.
  • An example of the molar ratio of polyvalent cation:phospholipid is about 0.50:1.
  • the polyvalent cation is calcium, it may be in the form of calcium chloride. Although metal ion, such as calcium, is often included with phospholipid, none is required.
  • One or more embodiments of the pharmaceutical composition may include one or more surfactants.
  • one or more surfactants may be in the liquid phase with one or more being associated with solid particles or particles of the composition.
  • associated with it is meant that the pharmaceutical compositions may incorporate, sorb, adsorb, absorb, be coated with, or be formed by the surfactant.
  • Surfactants include, but are not limited to, fluorinated and nonfluorinated compounds, such as saturated and unsaturated lipids, nonionic detergents, nonionic block copolymers, ionic surfactants, and combinations thereof. It should be emphasized that, in addition to the aforementioned surfactants, suitable fluorinated surfactants are compatible with the teachings herein and may be used to provide the desired preparations.
  • nonionic detergents include, but are not limited to, sorbitan esters including sorbitan trioleate (SpanTM 85), sorbitan sesquioleate, sorbitan monooleate, sorbitan monolaurate, polyoxyethylene (20) sorbitan monolaurate, and polyoxyethylene (20) sorbitan monooleate, oleyl polyoxyethylene (2) ether, stearyf polyoxyethylene (2) ether, lauryl polyoxyethylene (4) ether, glycerol esters, and sucrose esters.
  • sorbitan esters including sorbitan trioleate (SpanTM 85), sorbitan sesquioleate, sorbitan monooleate, sorbitan monolaurate, polyoxyethylene (20) sorbitan monolaurate, and polyoxyethylene (20) sorbitan monooleate, oleyl polyoxyethylene (2) ether, stearyf polyoxyethylene (2) ether, lauryl polyoxyethylene (4) ether, glycerol esters
  • block copolymers include, but are not limited to, diblock and triblock copolymers of polyoxyethylene and polyoxypropylene, including poloxamer 188 (PluronicTM F-68), poloxamer 407 (PluronicTM F-127), and poloxamer 338.
  • ionic surfactants include, but are not limited to, sodium sulfosuccinate, and fatty acid soaps.
  • amino acids include, but are not limited to, hydrophobic amino acids.
  • Use of amino acids as pharmaceutically acceptable excipients is known in the art as disclosed in WO 95/31479, WO 96/32096, and WO 96/32149, which are incorporated herein by reference.
  • Hydrophobic amino acids and lipids are capable of providing a particle surface of low surface energy. Magnesium stearate may also be used as an excipient to reduce surface energy.
  • Examples of carbohydrates include, but are not limited to, monosaccharides, disaccharides, and polysaccharides.
  • monosaccharides such as dextrose (anhydrous and monohydrate), galactose, mannitol, D-mannose, sorbitol, sorbose and the like; disaccharides such as lactose, maltose, sucrose, trehalose, and the like; trisaccharides such as raffinose and the like; and other carbohydrates such as starches (hydroxyethylstarch), cyclodextrins and maltodextrins.
  • buffers include, but are not limited to, tris, citrate, acetate, phosphate, TES and MES.
  • acids include, but are not limited to, organic acids such as carboxylic acids, in particular mono and di- carboxylic acids. .
  • salts include, but are not limited to, sodium chloride, salts of carboxylic acids, (e.g., sodium citrate, sodium ascorbate, magnesium gluconate, sodium gluconate, tromethamine hydrochloride, etc.), ammonium carbonate, ammonium acetate, ammonium chloride, and the like.
  • carboxylic acids e.g., sodium citrate, sodium ascorbate, magnesium gluconate, sodium gluconate, tromethamine hydrochloride, etc.
  • ammonium carbonate e.g., sodium citrate, sodium ascorbate, magnesium gluconate, sodium gluconate, tromethamine hydrochloride, etc.
  • the excipients may be glass forming excipients providing an amorphous glass, e.g., with a glass transition temperature that is at least 20 0 C greater than the storage temperature.
  • Glass forming systems are disclosed in U.S. Patent Nos. 6,258,341; 5,098,893; 5,928,469; and 6,071 ,428, which are incorporated herein by reference.
  • the pharmaceutical composition of one or more embodiments of the present invention may also include a biocompatible, such as biodegradable polymer, copolymer, or blend or other combination thereof.
  • useful polymers comprise polylactides, polylactide-glycolides, cyclodextrins, polyacrylates, methylcellulose, carboxymethylcellulose, polyvinyl alcohols, polyanhydrides, polylactams, polyvinyl pyrrolidones, polysaccharides (dextrans, starches, chitin, chitosan, etc.), hyaluronic acid, proteins, (albumin, collagen, gelatin, etc.).
  • the delivery efficiency of the composition and/or the stability of the dispersions may be tailored to optimize the effectiveness of the active agent(s).
  • compositions may be desirable to add other pharmaceutically acceptable excipients to the pharmaceutical composition to improve particle rigidity, production yield, emitted dose and deposition, shelf-life, and patient acceptance.
  • pharmaceutically acceptable excipients include, but are not limited to: coloring agents, taste masking agents, buffers, hygroscopic agents, antioxidants, and chemical stabilizers.
  • various pharmaceutically acceptable excipients may be used to provide structure and form to the particle compositions (e.g., latex particles).
  • the rigidifying components can be removed using a post-production technique such as selective solvent extraction.
  • compositions may also include mixtures of pharmaceutically acceptable excipients.
  • excipients include, but are not limited to, (a) distearoylphosphatidylcholine to calcium chloride (e.g., in a 2:1 molar ratio); (b) core-shell particles comprised of a shell of trileucine, and a core comprised of glass forming excipients, including sodium citrate and trehalose.
  • the present invention may comprise one or more antivirals combined with one or more antibiotics, such as an antifungal and/or antbiotic.
  • antifungals include, but are not limited to, azoles (e.g., imidazoles, itraconazole, pozaconazole), micafungin, caspafungin, salicylic acid, oxiconazole nitrate, ciclopirox olamine, ketoconazole, miconazole nitrate, and butoconazofe nitrate.
  • antibiotics include, but are not limited to, penicillin and drugs of the penicillin family of antimicrobial drugs, including but not limited to penicillin-G, penicillin-V, phenethicillin, ampicillin, amoxacillin, cyclacillin, bacampicillin, hetacillin, cloxacillin, dicloxacillin, methicillin, nafcillin, oxacillin, azlocillin, carbenicillin, mezlocillin, piperacillin, ticaricillin, and imipenim; cephalosporin and drugs of the cephalosporin family, including but not limited to cefadroxil, cefazolin, caphalexn, cephalothin, cephapirin, cephradine, cefaclor, cefamandole, cefonicid, cefoxin, cefuroxime, ceforanide, cefotetan, cefinetazole, cefoperazone, cefotaxime
  • compositions of one or more embodiments of the present invention may take various forms, such as dry powders, capsules, tablets, reconstituted powders, suspensions, or dispersions comprising a non-aqueous phase, such as propellants (e.g., chlorofluorocarbon, hydrofluoroalkane).
  • a non-aqueous phase such as propellants (e.g., chlorofluorocarbon, hydrofluoroalkane).
  • the moisture content of dry powder may be less than about 15 wt%, such as less than about 10 wt%, less than about 5 wt%, less than about 2 wt%, less than about 1 wt%, or less than about 0.5 wt%.
  • propellants e.g., chlorofluorocarbon, hydrofluoroalkane
  • the moisture content of dry powder may be less than about 15 wt%, such as less than about 10 wt%, less than about 5 wt%, less than about 2 wt%
  • compositions of antiviral incorporated in a matrix material with little, if any, unincorporated antiviral.
  • at least about 40 wt%, at least about 50 wt%, at least about 60 wt%, at least about 70%, at least about 80%, at least about 90 wt%, at least about 95 wt%, or at least about 99 wt%, of the composition may comprise particles including both antiviral and matrix material.
  • the particle size (such as a mass median diameter, and/or a geometric diameter, and or aerodynamic diameter) of the particles is particularly advantageous for the particle size (such as a mass median diameter, and/or a geometric diameter, and or aerodynamic diameter) of the particles to be below 3.0 microns, preferably below 2.5 microns, and more preferably below about 2.0 microns, in order to provide highly dispersible, homogenous compositions of active agent incorporated into the matrix material. Accordingly, a preferred embodiment is directed to homogeneous compositions of active agent incorporated in a matrix material without any unincorporated active agents particles.
  • a heterogeneous composition may be desirable in order to provide a desired pharmacokinetic profile of the antiviral to be administered, and in these cases, a large antiviral particle (e.g., mass median diameter of about 3 ⁇ m to about 10 ⁇ m, or larger) may be used.
  • a large antiviral particle e.g., mass median diameter of about 3 ⁇ m to about 10 ⁇ m, or larger
  • the pharmaceutical composition comprises an antiviral incorporated into a phospholipid matrix.
  • the pharmaceutical composition may comprise phospholipid matrices that incorporate the active agent and that are in the form of particles that are hollow and/or porous microstructures, as described in the aforementioned WO 99/16419, WO 99/16420, WO 99/16422, WO 01/85136, and WO 01/85137, US 20040156792; and US 20050214224, all of which are incorporated herein by reference in their entireties.
  • the hollow and/or porous microstructures are useful in delivering the antiviral to the lungs because the density, size, and aerodynamic qualities of the hollow and/or porous microstructures facilitate transport into the deep lungs during a user's inhalation.
  • the phospholipid-based hollow and/or porous microstructures reduce the attraction forces between particles, making the pharmaceutical composition easier to deagglomerate during aerosolization and improving the flow properties of the pharmaceutical composition making it easier to process.
  • the pharmaceutical composition is composed of hollow and/or porous microstructures having a bulk density less than about 1.0 g/cm 3 , less than about 0.8 g/cm 3 , less than about 0.5 g/cm 3 , less than about 0.3 g/cm 3 , less than about 0.2 g/cm 3 , or less than about 0.1 g/cm 3 .
  • small porous particles of the present invention may have a bulk density ranging from 0.01 g/cm 3 to 0.4 g/cm 3 , such as from 0.03 g/cm 3 to 0.25 g/cm 3 .
  • Particle density can be controlled by controlling the drying rate and surface composition of spray-dried particles, or by inclusion of a specific pore forming agent in the formulation.
  • Preferred pore-forming agents are medium chain fluorocarbons such as perfluorooctyl bromide (PFOB), perfluorodecalin (PFD), and perfluorooctyl ethane (PFOE).
  • PFOB perfluorooctyl bromide
  • PFD perfluorodecalin
  • PFOE perfluorooctyl ethane
  • the minimum powder mass that can be filled into a unit dose container is reduced, which eliminates the need for carrier particles. That is, the relatively low density of the powders of one or more embodiments of the present invention provides for the reproducible administration of relatively low dose pharmaceutical compounds. Moreover, the elimination of carrier particles will potentially reduce throat deposition and any "gag" effect or coughing, since large carrier particles, e.g., lactose particles, will impact the throat and upper airways due to their size.
  • the pharmaceutical composition is in dry powder form and is contained within a unit dose receptacle which may be inserted into or near the aerosolization apparatus to aerosolize the unit dose of the pharmaceutical composition.
  • This version is useful in that the dry powder form may be stably stored in its unit dose receptacle for a long period of time.
  • the pharmaceutical compositions of one or more embodiments of the present invention may be stable for at least about 2 years. In some versions, no refrigeration may be required to obtain stability. In other versions, reduced temperatures, e.g., at 2-8 0 C, may be used to prolong stable storage. In many versions, the storage stability allows aerosolization with an external power source.
  • compositions disclosed herein may comprise a structural matrix that exhibits, defines or comprises voids, pores, defects, hollows, spaces, interstitial spaces, apertures, perforations or holes.
  • the absolute shape (as opposed to the morphology) of the perforated microstructure is generally not critical and any overall configuration that provides the desired characteristics is contemplated as being within the scope of the invention. Accordingly, some embodiments comprise approximately spherical shapes. However, non-spherical shapes, or amorphous shapes, such as collapsed, deformed or fractured spherical-shaped particles are also within the scope of the invention.
  • the antiviral is incorporated in a matrix that forms a discrete particle
  • the pharmaceutical composition comprises a plurality of the discrete particles.
  • the discrete particles may be sized so that they are effectively administered and/or so that they are available where needed.
  • the particles are of a size that allows the particles to be aerosolized and delivered to a user's respiratory tract during the user's inhalation.
  • the pharmaceutical composition comprises particles having a mass median diameter less than about 20 ⁇ m, such as less than about 10 ⁇ m, less than about 7 ⁇ m, or less than about 5 ⁇ m, and may, e.g., range from 1 ⁇ m to 10 ⁇ m, such as from 1 ⁇ m to 5 ⁇ m.
  • the particles may have a mass median aerodynamic diameter (MMAD) ranging from about 1 ⁇ m to about 6 ⁇ m, such as about 1.5 ⁇ m to about 5 ⁇ m, or about 2 ⁇ m to about 4 ⁇ m.
  • MMAD mass median aerodynamic diameter
  • the particle size and/or size distribution are selected to maximize and/or optimize the number and/or mass of particles that will reach the deep lung.
  • the particle size and/or size distribution are additionally or alternatively selected to minimize or optimize the number and/or mass of particles that may be exhaled.
  • the matrix material may comprise a hydrophobic or a partially hydrophobic material.
  • the matrix material may comprise a lipid, such as a phospholipid, and/or a hydrophobic amino acid, such as leucine or tri-leucine.
  • phospholipid matrices are described in WO 99/16419, WO 99/16420, WO 99/16422, WO 01/85136, and WO 01/85137 and in U.S. Patent Nos. 5,874,064; 5,855,913; 5,985,309; and 6,503,480, and in U.S. Application Publication No. 20040156792, all of which are incorporated herein by reference in their entireties.
  • hydrophobic amino acid matrices examples include hydrophobic amino acid matrices, and in U.S. Application Publication No. 20020177562, each of which are incorporated herein by reference in their entireties.
  • the pharmaceutical composition may also comprise a polyvalent cation, as disclosed in WO 01/85136 and WO 01/85137, which are incorporated herein by reference in their entireties.
  • release kinetics of the active agent(s) containing composition is controlled.
  • the compositions of the present invention provide immediate release of the active agent(s).
  • the compositions of other embodiments of the present invention may be provided as non-homogeneous mixtures of active agent incorporated into a matrix material and unincorporated active agent in order to provide desirable release rates of antifungal agent.
  • active agents formulated using the emulsion-based manufacturing process of one or more embodiments of the present invention have utility in immediate release applications when administered to the respiratory tract. Rapid release is facilitated by: (a) the high specific surface area of the low density porous powders and; (c) the low surface energy of the particles.
  • the particle matrix so that extended release of the active agent(s) is effected. This may be particularly desirable when the active agent(s) is rapidly cleared from the lungs or when sustained release is desired.
  • the nature of the phase behavior of phospholipid molecules is influenced by the nature of their chemical structure and/or preparation methods in spray- drying feedstock and drying conditions and other composition components utilized.
  • the active agent(s) are encapsulated within multiple bilayers and are released over an extended time.
  • spray-drying of a feedstock comprised of emulsion droplets and dispersed or dissolved active agent(s) in accordance with the teachings herein leads to a phospholipid matrix with less long-range order, thereby facilitating rapid release. While not being bound to any particular theory, it is believed that this is due in part to the fact that the active agent(s) are never formally encapsulated in the phospholipid, and the fact that the phospholipid is initially present on the surface of the emulsion droplets as a monolayer (not a bilayer as in the case of liposomes).
  • the spray-dried particles prepared by the emulsion-based manufacturing process of one or more embodiments of the present invention often have a high degree of disorder.
  • the spray-dried particles typically have low surface energies, where values as low as 20 mN/m have been observed for spray-dried DSPC particles (determined by inverse gas chromatography).
  • SAXS Small angle X- ray scattering
  • a matrix having a high gel to liquid crystal phase transition temperature is not sufficient in itself to achieve sustained release of the active agent(s). Having sufficient order for the bilayer structures is also important for achieving sustained release.
  • an emulsion-system of high porosity (high surface area), and minimal interaction between the drug substance and phospholipid may be used.
  • the pharmaceutical composition formation process may also include the additions of other composition components (e.g., small polymers such as Pluronic F-68; carbohydrates, salts, hydrotropes) to break the bilayer structure are also contemplated.
  • incorporation of the phospholipid in bilayer form may be used, especially if the active agent is encapsulated therein.
  • T m of the phospholipid may provide benefit via incorporation of divalent counterions or cholesterol.
  • increasing the interaction between the phospholipid and drug substance via the formation of ion-pairs negatively charged active + steaylamine, positively charged active + phosphatidylglycerol
  • the active is amphiphilic, surfactant/surfactant interactions may also slow active dissolution.
  • divalent counterions e.g., calcium or magnesium ions
  • long-chain saturated phosphatidylcholines results in an interaction between the negatively charged phosphate portion of the zwitterionic headgroup and the positively charged metal ion. This results in a displacement of water of hydration and a condensation of the packing of the phospholipid lipid headgroup and acyl chains. Further, this results in an increase in the Tm of the phospholipid.
  • the decrease in headgroup hydration can have profound effects on the spreading properties of spray-dried phospholipid particles on contact with water.
  • compositions of the invention may comprise one or more di- or tripeptides containing two or more leucine residues.
  • di-leucyl- containing dipeptides e.g., dileucine
  • tripeptides are superior in their ability to increase the dispersibility of powdered compositions, and, as demonstrated in the Examples, are better than leucine in improving aerosol performance.
  • Di-leucyl containing tripeptides for use in the invention are tripeptides having the formula, X-Y-Z, where at least X and Y or X and Z are furcyl residues (i.e., the leucyl residues can be adjacent to each other (at the 1 and 2 positions), or can form the ends of the trimer (occupying positions 1 and 3).
  • the remaining amino acid contained in the trimer can be any amino acid as defined in section I above.
  • Suitable are amino acids such as glycine (gly), alanine (ala), valine (val), leucine (leu), isoleucine (ile), methionine (met), proline (pro), phenylalanine (phe), trytophan (trp), serine (ser), threonine (thr), cysteine (cys), tyrosine (tyr), asparagine (asp), glutamic acid (glu), lysine (lys), arginine (arg), histidine (his), norleucine (nor), and modified forms thereof.
  • the third amino acid component of the trimer is one of the following: leucine (leu), valine (val), isofeucine (isoleu), tryptophan (try) alanine (ala), methionine (met), phenylalanine (phe), tyrosine (tyr), histidine (his), and proline (pro).
  • trimers for use in the invention include but are not limited to the following: leu-leu-gly, leu- leu-ala, leu-leu-val, !eu-leu-leu, leu-leu-ile, leu-leu-met, leu-leu-pro, leu-leu-phe, leu-leu- trp, leu-leu-ser, leu-leu-thr, leu-leu-cys, leu-leu-tyr, leu-leu-asp, leu-leu-glu, leu-leu-lys, leu-leu-arg, leu-leu-his, leu-leu-nor, leu-gly-leu, leu-ala-leu, leu-val-leu, leu-ile-leu, leu- met-leu, leu-pro-leu, leu-phe-leu, leu-trp-
  • additional dispersibility-enhancing peptides for use in the invention are 4-mers and 5-mers containing two or more leucine residues.
  • the leucine residues may occupy any position within the peptide, and the remaining (i.e., non- leucyl) amino acids positions are occupied by any amino acid as described above, provided that the resulting 4-mer or 5-mer has a solubility in water of at least about 1 mg/ml.
  • the non-leucyl amino acids in a 4-mer or 5-mer are hydrophilic amino acids such as lysine, to thereby increase the solubility of the peptide in water.
  • di- and tripeptides having a glass transition temperature greater than about 40DC.
  • di- and tripeptides for use in the present invention are those peptides that are surface active.
  • Dileucine and trileucine are extremely effective, even when present in low concentrations, at significantly depressing the surface tension of water.
  • the noted Kuo et al patents show that dipeptides and tripeptides containing two or more leucines have a much greater surface activity than dipeptides and tripeptides composed of fewer than two leucyl residues. Due to their highly surface active nature, the di- and tripeptides of the invention, when contained in dry powder compositions, tend to concentrate on the surface (enriching the surface) of the powder particles, thereby imparting to the resulting particles high dispersivities.
  • the compositions of the invention will contain from about 1% to about 99% by weight di- or tripeptide, preferably from about 2% to about 75% by weight di- or tripeptide, and even more preferably from about 5% to about 50% by weight di- or tripeptide.
  • the optimal amount of di- or tripeptide is determined experimentally, i.e., by preparing compositions containing varying amounts of di- or tripeptide (ranging from low to high), examining the dispersibilities of the resulting compositions, and further exploring the range at which optimal aerosol performance is attained.
  • an optimal amount of trileucine appears to be around 22-25% by weight.
  • the pharmaceutical composition comprises low density particles achieved by co-spray-drying with a perfluorocarbon-in-water emulsion.
  • perfluorocarbons include, but are not limited to, perfluorohexane, perfluorooctyl bromide, perfluorooctyl ethane, perfluorodecalin, perfluorobutyi ethane.
  • the particle compositions will preferably be provided in a "dry" state. That is, in one or more embodiments, the particles will possess a moisture content that allows the powder to remain chemically and physically stable during storage at ambient or reduced temperature and remain dispersible. In this regard, there is little or no change in primary particle size, content, purity, and aerodynamic particle size distribution.
  • the moisture content of the particles is typically less than about 10 wt%, such as less than about 6 wt%, less than about 3 wt%, or less than about 1 wt%.
  • the moisture content is, at least in part, dictated by the composition and is controlled by the process conditions employed, e.g., inlet temperature, feed concentration, pump rate, and blowing agent type, concentration and post drying. Reduction in bound water leads to significant improvements in the dispersibility and flowability of phospholipid based powders, leading to the potential for highly efficient delivery of powdered lung surfactants or particle composition comprising active agent dispersed in the phospholipid.
  • the improved dispersibility allows simple passive DPI devices to be used to effectively deliver these powders.
  • compositions that may comprise, or may be partially or completely coated with, charged species that prolong residence time at the point of contact or enhance penetration through mucosae.
  • anionic charges are known to favor mucoadhesion while cationic charges may be used to associate the formed particle with negatively charged bioactive agents such as genetic material.
  • the charges may be imparted through the association or incorporation of polyanionic or polycationic materials such as polyacrylic acids, polylysine, polylactic acid, and chitosan.
  • These unit dose pharmaceutical compositions may be contained in a container.
  • containers include, but are not limited to, capsules, blisters, vials, ampoules, or container closure systems made of metal, polymer (e.g., plastic, elastomer), glass, or the like.
  • the container may be inserted into an aerosol ization device.
  • the container may be of a suitable shape, size, and material to contain the pharmaceutical composition and to provide the pharmaceutical composition in a usable condition.
  • the capsule or blister may comprise a wall which comprises a material that does not adversely react with the pharmaceutical composition.
  • the wall may comprise a material that allows the capsule to be opened to allow the pharmaceutical composition to be aerosolized.
  • the wall comprises one or more of gelatin, hydroxypropyl methylcellulose (HPMC), polyethyleneglycol-compounded HPMC, hydroxyproplycellulose, agar, aluminum foil, or the like.
  • the capsule may comprise telescopically adjoining sections, as described for example in U.S. Patent No.
  • the size of the capsule may be selected to adequately contain the dose of the pharmaceutical composition.
  • the sizes generally range from size 5 to size 000 with the outer diameters ranging from about 4.91 mm to 9.97 mm, the heights ranging from about 11.10 mm to about 26.14 mm, and the volumes ranging from about 0.13 mL to about 1.37 mL Suitable capsules are available commercially from, for example, Shionogi Qualicaps Co. in Nara, Japan and Capsugel in Greenwood, South Carolina.
  • a top portion may be placed over the bottom portion to form a capsule shape and to contain the powder within the capsule, as described in U.S. Patent Nos. 4,846,876 and 6,357,490, and in WO 00/07572, which are incorporated herein by reference in their entireties.
  • the capsule can optionally be banded.
  • the pharmaceutical composition comprising antiviral is aerosolizable so that it may be delivered to the lungs of a patient during the patient's inhalation.
  • the antiviral in the pharmaceutical composition is delivered directly to the site of infection. This is advantageous over systemic administration.
  • the active agent(s) often have renal or other toxicity, minimizing systemic exposure is typically preferred. Therefore, the amount of active agent(s) that may be delivered to the lungs is preferably limited to the minimum pharmacologically effective dose. By administering the active agent(s) directly to the lungs, a greater amount may be delivered to the site in need of the therapy while significantly reducing systemic exposure.
  • compositions of one or more embodiments of the present invention lack taste.
  • taste masking agents are optionally included within the composition, the compositions often lack taste even without a taste masking agent.
  • the particles, particles, and compositions of one or more embodiments of the present invention may be made by any of the various methods and techniques known and available to those skilled in the art.
  • the pharmaceutical composition may be produced using various known techniques.
  • the composition may be formed by spray drying, lyophilization, milling (e.g., wet milling, dry milling), and the like.
  • a liquid solution, suspension or dispersion of one or more antiviral actives, and optional excipient or excipients in an appropriate solvent may be made, and then converted to a powder form by a liquid or solvent removal process.
  • a liquid or solvent removal process may comprise a supercritical solvent extraction, spray-drying, or other solvent removal process.
  • the preparation to be spray-dried or feedstock can be any solution, coarse suspension, slurry, colloidal dispersion, or paste that may be atomized using the selected spray drying apparatus.
  • the feedstock may comprise a suspension as described above.
  • a dilute solution and/or one or more solvents may be utilized in the feedstock.
  • the feed stock will comprise a colloidal system such as an emulsion, reverse emulsion, microemulsion, multiple emulsion, particle dispersion, or slurry.
  • the antiviral and the matrix material are added to an aqueous feedstock to form a feedstock solution, suspension, or emulsion.
  • the feedstock is then spray dried to produce dried particles comprising the matrix material and the antiviral.
  • Suitable spray-drying processes are known in the art, for example as disclosed in WO 99/16419 and U.S. Patent Nos. 6,077,543; 6,051,256; 6,001 ,336; 5,985,248; and 5,976,574, which are incorporated herein by reference in their entireties.
  • the first step in particle production typically comprises feedstock preparation. If a phosphoiipids-based particle is intended to act as a carrier for the antiviral, the selected active agent(s) may be introduced into a liquid, such as water, to produce a concentrated suspension.
  • concentration of antiviral and optional active agents typically depends on the amount of agent required in the final powder and the performance of the delivery device employed, e.g., the fine particle dose for a metered dose inhaler (MDI) or a dry powder inhaler (DPI).
  • MDI metered dose inhaler
  • DPI dry powder inhaler
  • any additional active agent(s) may be incorporated in a single feedstock preparation and subjected to a solvent removal process (e.g. spray drying) to provide a single pharmaceutical composition species comprising a plurality of active agents.
  • a solvent removal process e.g. spray drying
  • individual active agents could be added to separate stocks and subjected to a solvent removal process (e.g. spray drying) separately to provide a plurality of pharmaceutical composition species with different compositions.
  • These individual species could be added to the suspension medium or dry powder dispensing compartment in any desired proportion and placed in the aerosol delivery system as described below.
  • Polyvalent cation may be combined with the antiviral suspension, combined with the phospholipid emulsion, or combined with an oN-in-water emulsion formed in a separate vessel.
  • the antiviral may also be dispersed directly in the emulsion.
  • polyvalent cation and phospholipid may be homogenized in hot distilled water (e.g., 70 0 C) using a suitable high shear mechanical mixer (e.g., Ultra-Turrax model T-25 mixer) at 8000 rpm for 2 to 5 min. Typically, 5 to 25 g of fluorocarbon is added dropwise to the dispersed surfactant solution while mixing. The resulting polyvalent cation-containing perfluorocarbon in water emulsion may then be processed using a high pressure homogenizer to reduce the particle size. Typically, the emulsion is processed for five discrete passes at 12,000 to 18,000 PSI and kept at about 50 0 C to about 80 0 C.
  • a suitable high shear mechanical mixer e.g., Ultra-Turrax model T-25 mixer
  • the dispersion stability and dispersibility of the spray dried pharmaceutical composition can be improved by using a blowing agent, as described in US 6565885, which is incorporated herein by reference in its entirety.
  • a blowing agent as described in US 6565885, which is incorporated herein by reference in its entirety.
  • This process forms an emulsion, optionally stabilized by an incorporated surfactant, typically comprising submicron droplets of water immiscible blowing agent dispersed in an aqueous continuous phase.
  • the blowing agent may be a fluorinated compound (e.g.
  • liquid blowing agents include non-fluorinated oils, chloroform, Freon® fluorocarbons, ethyl acetate, alcohols, hydrocarbons, nitrogen, and carbon dioxide gases.
  • the blowing agent may be emulsified with a phospholipid.
  • the pharmaceutical compositions may be formed using a blowing agent as described above, it will be appreciated that, in some instances, no additional blowing agent is required and an aqueous dispersion of the antiviral and/or pharmaceutically acceptable excipients and surfactant(s) are spray dried directly.
  • the pharmaceutical composition may possess certain physicochemical properties (e.g., elevated melting temperature, surface activity, etc.) that make it particularly suitable for use in such techniques.
  • cosurfactants such as poloxamer 188 or span 80 may be dispersed into this annex solution. Additionally, pharmaceutically acceptable excipients such as sugars and starches can also be added.
  • the feedstock(s) may then be fed into a spray dryer.
  • the feedstock is sprayed into a current of warm filtered air that evaporates the solvent and conveys the dried product to a collector.
  • the spent air is then exhausted with the solvent.
  • Commercial spray dryers manufactured by B ⁇ chi Ltd. or Niro Corp. may be modified for use to produce the pharmaceutical composition. Examples of spray drying methods and systems suitable for making the dry powders of one or more embodiments of the present invention are disclosed in U.S. Patent Nos. 6,077,543; 6,051 ,256; 6,001 ,336; 5,985,248; and 5,976,574, which are incorporated herein by reference in their entireties.
  • Exemplary settings are as follows: an air inlet temperature between about 60°C and about 170 0 C, such as between 80 0 C and 120 0 C; an air outlet between about 40 0 C to about 120 0 C, such as about 50 0 C and 70°C; a feed rate between about 3 mL/min to about 15 mL/min; an aspiration air flow of about 300 L/min; and an atomization air flow rate between about 25 L/min and about 50 L/min.
  • the solids content in the spray-drying feedstock will typically be in the range from 0.5 wt% to 10 wt%, such as 1.0 wt% to 5.0 wt%.
  • the settings will, of course, vary depending on the type of equipment used. In any event, the use of these and similar methods allow formation of aerodynamically light particles with diameters appropriate for aerosol deposition into the lung.
  • Hollow and/or porous microstructures may be formed by spray drying, as disclosed in WO 99/16419, which is incorporated herein by reference.
  • the spray-drying process can result in the formation of a pharmaceutical composition comprising particles having a relatively thin porous wall defining a large internal void.
  • the spray-drying process is also often advantageous over other processes in that the particles formed are less likely to rupture during processing or during deagglomeration.
  • compositions useful in one or more embodiments of the present invention may additionally or alternatively formed by lyophilization.
  • Lyophilization is a freeze-drying process in which water is sublimed from the composition after it is frozen.
  • the lyophilization process is often used because biologicals and pharmaceuticals that are relatively unstable in an aqueous solution may be dried without exposure to elevated temperatures, and then stored in a dry state where there are fewer stability problems.
  • such techniques are particularly compatible with the incorporation of peptides, proteins, genetic material and other natural and synthetic macromolecules in pharmaceutical compositions without compromising physiological activity.
  • Lyophilized cake containing a fine foam-like structure can be micronized using techniques known in the art to provide particles of the desired size.
  • a formulation comprising two or more antiviral actives may be produced by preparing individual feedstocks comprising a single antiviral active in an appropriate liquid. Each feedstock is then subjected to a liquid removal process with characteristics selected to yield particles of appropriate physical characteristics. For example, a feedstock may be spray-dried, supertically processed or other liquid removal process. The resulting particles may then be dry blended to produce a powder having a combination of two or more antiviral actives.
  • the liquid removal step and powder blending steps may occur simultaneously, for example, by spray drying two or more feedstocks with a multiple nozzle spray drier, leading to a common powder collector.
  • compositions of one or more embodiments of the present invention may be administered by known techniques, such as inhalation, oral, intramuscular, intravenous, intratracheal, intraperitoneal, subcutaneous, and transdermal.
  • pharmaceutical compositions of one or more embodiments of the invention are effective in the treatment, including adjunctive treatment, of viral diseases or conditions.
  • compositions when inhaled, penetrate into the nasal cavities and/or airways of the lungs to achieve effective antiviral concentrations.
  • compositions may include a bronchodilator, and/or other adjuncts intended to improve drug or delivery effectiveness, patient compliance or safety.
  • a pharmaceutical composition comprising antiviral is administered to the lungs of a patient in need thereof.
  • the patient may have been diagnosed with a viral infection or the patient may be determined to be susceptible to a viral infection.
  • compositions of one or more embodiments of the present invention can be used to treat and/or provide prophylaxis for a broad range of patients.
  • a suitable patient for receiving treatment and/or prophylaxis as described herein is any mammalian patient in need thereof, preferably such mammal is a human. Examples of patients include, but are not limited to, pediatric patients, adult patients, and geriatric patients.
  • an aerosolizeable pharmaceutical composition comprising antiviral is administered to the lungs and/or nasal cavity of a patient in a manner that results in an effective antiviral concentration.
  • the pharmaceutical composition comprising antiviral is administered so that a target concentration is maintained over a desired period of time. For example, it has been determined that an administration routine that maintains a target concentration of antiviral is effective in treating and/or providing prophylaxis.
  • the antiviral concentration is maintained at the target lung concentration for a period of at least about 1 week, or about 2 weeks, or about 3 weeks.
  • the dosage necessary and the frequency of dosing for maintaining the antiviral concentration within the target concentration depends on the composition and concentration of the antiviral within the composition. In each of the administration regimens, the dosages and frequencies are determined to give a lung antiviral concentration that is maintained within a certain target range.
  • the antiviral may be administered daily. In such versions, the daily dosage of antiviral may range from about 2 mg to about 75 mg, such as about 3 mg to about 50 mg, about 4 mg to about 25 mg, about 5 mg to about 20 mg, and about 7 mg to about 10 mg.
  • a unit dosage of antiviral may comprise from about 20 mg to about 60 mg, such as about 30 mg to about 40 mg.
  • a pharmaceutical formulation comprises at least 10 or 20 or 30 or 40 or 45 or 50 or 55 or 60 mg of antiviral.
  • a human dose of the pharmaceutical formulation comprises at least about 0.1 or 0.2 or 0.3 or 0.4 or 0.5 or 0.6 or 0.7 or 0.8 or 0.9 or 1.0 or 1.5 or 2.0 mg/Kg of antiviral.
  • the drug loading in the small porous particles of the present invention depends upon factors including: (a) the volume of the unit dose (blister or capsule); (b) the lung delivery efficiency achieved with the device; (c) factors related to the mechanism of device emptying.
  • pulmonary delivery efficiency for the powder formulations of the present invention with portable, passive dry powder inhalers will be 40%-80%. In such versions, this would suggest a powder loading of 125 to 250% of the target lung dose.
  • optimal performance of capsule-based devices e.g., the inhaler shown in Figs. 1A-1 E) depends at least in part, upon having sufficient mass in the capsule to facilitate proper capsule spinning and emptying characteristics.
  • a drug loading i.e. active drug as a percentage of powder composition
  • a higher drug loading can be achieved with a blister- based inhaler.
  • An example of such an inhaler is disclosed in international application published as WO2008/051621 , the disclosure of which is fully incorporated herein by reference.
  • This device comprises a smaller volume for loading powder.
  • the loading will typically range from 5 wt% to 90 wt%, such as 10 wt% to 80 wt%.
  • a drug loading will provide for delivery of between about 10 mg to 100 mg, such as between about 32 mg to 75 mg, of active in a single puff (i.e. a single inhalation) from a dry powder inhaler.
  • the reduction in administration time is anticipated to improve patient compliance.
  • the dose may be administered during a single inhalation or may be administered during several inhalations.
  • the fluctuations of lung antiviral concentration can be reduced by administering the pharmaceutical composition more often or may be increased by administering the pharmaceutical composition less often. Therefore, the pharmaceutical composition of one or more embodiments of the present invention may be administered from about three times daily to about once every two days.
  • the amount per dose of antiviral is be an amount that is effective, especially therapeutically-effective.
  • a dose ranges from about 0.01 mg/kg to about 5.0 mg/kg, such as about 0.4 mg/kg to about 4.0 mg/kg, or about 0.7 mg/kg to about 3.0 mg/kg.
  • the pharmaceutical composition may be delivered to the lungs of a patient in the form of a dry powder.
  • the pharmaceutical composition comprises a dry powder that may be effectively delivered to the deep lungs or to another target site.
  • This pharmaceutical composition is in the form of a dry powder comprising particles or particles having a size selected to permit penetration into the alveoli of the lungs.
  • a unit dose such as powder doses of 5 mg or 10 mg or greater of antiviral to the lung in a single inhalation.
  • the above described dry powder particles allow for powder doses of about 5 mg or greater, in some embodiments greater than about 10 mg, and in some embodiments greater than about 25 mg, to be delivered in a single inhalation and in an advantageous manner.
  • a dosage may be delivered over two or more inhalations.
  • a 10 mg powder dosage may be delivered by providing two unit doses of 5 mg each, and the two unit doses may be separately inhaled.
  • the dispersions or powder pharmaceutical compositions may be administered using an aerosolization device.
  • the aerosolization device may be a nebulizer, a metered dose inhaler, a liquid dose instillation device, or a dry powder inhaler.
  • the powder pharmaceutical composition may be delivered by a nebulizer as described in WO 99/16420, by a metered dose inhaler as described in WO 99/16422, by a liquid dose instillation apparatus as described in WO 99/16421 , and by a dry powder inhaler as described in U.S. Patent Application No. 09/888,311 filed on June 22, 2001, in WO 99/16419, in WO 02/83220, in U.S. Patent No.
  • an inhaler may comprise a canister containing the particles or particles and propellant, and wherein the inhaler comprises a metering valve in communication with an interior of the canister.
  • the propellant may be a hydrofluoroalkane.
  • Suitable passive dry powder inhalers include both capsule-based inhalers and blister-based inhalers.
  • Suitable capsule-based inhalers include: devices by Nektar Therapeutics disclosed in U.S. Application Nos.
  • Suitable blister-based inhalers include: the Diskus (GSK), the device of Nektar Therapeutics disclosed in WO 2008/051621, which is incorporated herein by reference, Gyrohaler (Vectura), E-Flex, Microdrug, Diskhaler (GSK). Also contemplated are active dry powder inhalers including: the inhalation device described in U.S. Patent No. 6,257,233, Aspirair (Vectura), and Microdose inhaler (Microdose).
  • the pharmaceutical composition of one or more embodiments of the present invention typically has improved emitted dose efficiency. Accordingly, high doses of the pharmaceutical composition may be delivered using a variety of aerosol ization devices and techniques.
  • the emitted dose (ED) of these powders may be greater than about 30%, such as greater than about 40%, or 45%, or 50%, or 55% or 60%, or 65% or 70% or 75% or 80% or 85% or 90% or 95%.
  • FIG. 1A An example of a dry powder aerosol ization apparatus particularly useful in aerosolizing a pharmaceutical composition 100 according to one or more embodiments of the present invention is shown schematically in Fig. 1A.
  • the aerosolization apparatus 200 comprises a housing 205 defining a chamber 210 having one or more air inlets 215 and one or more air outlets 220.
  • the chamber 210 is sized to receive a capsule 225 which contains an aerosolizable pharmaceutical composition comprising antiviral.
  • a puncturing mechanism 230 comprises a puncture member 235 that is moveable within the chamber 210.
  • Near or adjacent the outlet 220 is an end section 240 that may be sized and shaped to be received in a user's mouth or nose so that the user may inhale through an opening 245 in the end section 240 that is in communication with the outlet 220.
  • the dry powder aerosolization apparatus 200 utilizes air flowing through the chamber 210 to aerosolize the pharmaceutical composition in the capsule 225.
  • Figs. 1A-1E illustrate the operation of a version of an aerosolization apparatus 200 where air flowing through the inlet 215 is used to aerosolize the pharmaceutical composition and the aerosolized pharmaceutical composition flows through the outlet 220 so that it may be delivered to the user through the opening 245 in the end section 240.
  • the dry powder aerosolization apparatus 200 is shown in its initial condition in Fig. 1A.
  • the capsule 225 is positioned within the chamber 210 and the pharmaceutical composition is contained within the capsule 225.
  • the pharmaceutical composition in the capsule 225 is exposed to allow it to be aerosolized.
  • the puncture mechanism 230 is advanced within the chamber 210 by applying a force 250 to the puncture mechanism 230.
  • a force 250 For example, a user may press against a surface 255 of the puncturing mechanism 230 to cause the puncturing mechanism 230 to slide within the housing 205 so that the puncture member 235 contacts the capsule 225 in the chamber 210, as shown in Fig. 1B.
  • the puncture member 235 is advanced into and through the wall of the capsule 225, as shown in Fig, 1 C.
  • the puncture member may comprise one or more sharpened tips 252 to facilitate the advancement through the wall of the capsule 225.
  • the puncturing mechanism 230 is then retracted to the position shown in Fig. 1 D, leaving an opening 260 through the wall of the capsule 225 to expose the pharmaceutical composition in the capsule 225.
  • Air or other gas then flows through an inlet 215, as shown by arrows 265 in Fig. 1E.
  • the flow of air causes the pharmaceutical composition to be aerosolized.
  • the aerosolized pharmaceutical composition is delivered to the user's respiratory tract.
  • the air flow 265 may be caused by the user's inhalation 270.
  • compressed air or other gas may be ejected into the inlet 215 to cause the aerosolizing air flow 265.
  • the chamber 210 comprises a longitudinal axis that lies generally in the inhalation direction, and the capsule 225 is insertable lengthwise into the chamber 210 so that the capsule's longitudinal axis may be parallel to the longitudinal axis of the chamber 210.
  • the chamber 210 is sized to receive a capsule 225 containing a pharmaceutical composition in a manner which allows the capsule to move within the chamber 210.
  • the inlets 215 comprise a plurality of tangentially oriented slots.
  • the capsule 225 rotates within the chamber 210 in a manner where the longitudinal axis of the capsule is remains at an angle less than 80 degrees, and preferably less than 45 degrees from the longitudinal axis of the chamber.
  • the movement of the capsule 225 in the chamber 210 may be caused by the width of the chamber 210 being less than the length of the capsule 225.
  • the chamber 210 comprises a tapered section that terminates at an edge. During the flow of swirling air in the chamber 210, the forward end of the capsule 225 contacts and rests on the partition and a sidewall of the capsule 225 contacts the edge and slides and/or rotates along the edge. This motion of the capsule is particularly effective in forcing a large amount of the pharmaceutical composition through one or more openings 260 in the rear of the capsule 225.
  • the dry powder aerosolization apparatus 200 may be configured differently than as shown in Figs. 1A-1E.
  • the chamber 210 may be sized and shaped to receive the capsule 225 so that the capsule 225 is orthogonal to the inhalation direction, as described in U.S. Patent No. 3,991 ,761, which is incorporated herein by reference in its entirety.
  • the puncturing mechanism 230 may puncture both ends of the capsule 225.
  • the chamber may receive the capsule 225 in a manner where air flows through the capsule 225 as described for example in U.S. Patent Nos. 4,338,931 and 5,619,985.
  • the aerosolization of the pharmaceutical composition may be accomplished by pressurized gas flowing through the inlets, as described for example in U.S. Patent Nos. 5,458,135; 5,785,049; and 6,257,233, or propellant, as described in WO 00/72904 and U.S. Patent No. 4,114,615, which are incorporated herein by reference.
  • These types of dry powder inhalers are generally referred to as active dry powder inhalers.
  • a blister-based inhaler device can achieve a high drug loading loading.
  • a specific example of such a device is that disclosed in the WO 2008/051621. This device typically operates with a smaller volume for loading powder.
  • the loading will typically range from 5 wt% to 50 wt%, such as 4 wt% to 20 wt%.
  • the loading will typically range from about 0.7 to 8 mg per blister, such as from about 4 to 6 mg per blister.
  • such drug loading and device will provide for delivery of up to about 4 mg (of antiviral active) in a single puff (or inhalation) from a dry powder inhaler.
  • the pharmaceutical composition disclosed herein may also be administered to the pulmonary and/or nasal air passages of a patient via aerosolization, such as with a metered dose inhaler.
  • aerosolization such as with a metered dose inhaler.
  • the use of such stabilized preparations provides for superior dose reproducibility and improved lung deposition as disclosed in WO 99/16422, which is incorporated herein by reference in its entirety.
  • MDIs are well known in the art and could be employed for administration of the antiviral. Breath activated MDIs, as well as those comprising other types of improvements which have been, or will be, developed are also compatible with the pharmaceutical composition of one or more embodiments of the present invention.
  • Nebulizers are known in the art and can be employed for administration of the antiviral dosage forms herein by making a dispersion or aerosol thereof. Breath activated nebulizers, as well as those comprising other types of improvements which have been, or will be, developed are also compatible with dispersions, which are contemplated as being with in the scope of one or more embodiments of the present invention. Along with the aforementioned embodiments, the dispersions of one or more embodiments of the present invention may also be used in conjunction with nebulizers as disclosed in WO 99/16420, which is incorporated herein by reference in its entirety, in order to provide an aerosolized medicament that may be administered to the pulmonary and/or nasal air passages of a patient in need thereof.
  • the stabilized dispersions, suspensions or solutions of one or more embodiments of the present invention may be used in conjunction with liquid dose instillation or LDI techniques as disclosed in, for example, WO 99/16421 , which is incorporated herein by reference in its entirety.
  • Liquid dose instillation involves the direct administration of a stabilized dispersion to the lung.
  • direct pulmonary and/or nasal administration of bioactive compounds is particularly effective in the treatment of disorders especially where poor vascular circulation of diseased portions of a lung reduces the effectiveness of intravenous drug delivery.
  • the stabilized dispersions are preferably used in conjunction with partial liquid ventilation or total liquid ventilation.
  • one or more embodiments of the present invention may further comprise introducing a therapeutically beneficial amount of a physiologically acceptable gas (such as nitric oxide or oxygen) into the pharmaceutical microdispersion prior to, during or following administration.
  • a physiologically acceptable gas such as nitric oxide or oxygen
  • the time for dosing is typically short. For a single capsule (e.g., 5 mg powder dose), the total dosing time is normally less than about 1 minute. A two capsule close (e.g., 10 mg powder) usually takes about 1 min. A five capsule dose (e.g., 25 mg powder) may take about 3.5 min to administer. Thus, the time for dosing may be less than about 5 min, such as less than about 4 min, less than about 3 min, less than about 2 min, or less than about 1 min.
  • the pharmaceutical composition may comprise a liquid form and may be aerosolized using an aerosol generator nebulizer.
  • aerosol generator nebulizers include, but are not limited to, the Aeroneb®Go or Aeroneb®Pro nebulizers, available from Stamford Ltd, of Galway, Ireland.
  • the nebulizer i.e., aerosol generator
  • the nebulizer thus may be of the type, for example, where a vibratable member is vibrated at ultrasonic frequencies to produce liquid droplets.
  • the ultrasonic frequency of vibration comprises at least about 45 kHz.
  • Some specific, non-limiting examples of technologies for producing fine liquid droplets is by supplying liquid to an aperture plate having a plurality of tapered apertures and vibrating the aperture plate to eject liquid droplets through the apertures. Such techniques are described generally in U.S. Patent Nos. 5,164,740; 5,938,117; 5,586,550; 5,758,637, 6,014,970, and 6,085,740, the complete disclosures of which are incorporated by reference.
  • the aerosol generator comprises a vibrating mesh type, wherein vibrational energy is supplied via a piezoelectric element in communication (directly or indirectly) with the mesh element.
  • the aerosolization element may be constructed of a variety of materials, comprising metals, which may be electroformed to create apertures as the element is formed, as described, for example, in U.S. patent No. 6,235,177 assigned to the present assignee and incorporated by reference herein in its entirety.
  • Palladium is believed to be of particular usefulness in producing an electroformed, multi-apertured aerosolization element, as well as in operation thereof to aerosolize liquids.
  • Other metals that can be used are palladium alloys, such as PdNi, with, for example, 80 percent palladium and 20% nickel. Other metals and materials may be used without departing from the present invention.
  • the aerosol generator comprises a tube core design, as described in WO 2006/127181, assigned to the same assignee as the invention herein, and incorporated by reference herein in its entirety for all purposes.
  • Feed stock preparation All feedstock component ratios, including liquids were based upon mass. Trileucine was dissolved in the specified mass of water/ethanol. Zanamivir and rimantadine were added and the solution was adjusted to pH 6.5 - 6.6. The compositions of all feed stocks are shown in Table 1 below.
  • Spray Drying Powders were spray dried on a Buchi Spray dryer using a standard Buchi nozzle, and nitrogen as the atomization and drying gas. Feed stock feed rate was 5.0 ml/min. Atomization pressures were 20 and 40 psi and outlet temperature was 7O 0 C.
  • Figs 2B-2C Yields of the spray-dried feed stocks were 67% to 71 %.
  • the powders containing trileucine had similar "dimpled" or "raisin-like" morphologies, as shown in Figs 2B-2C.
  • Fig 2A shows formulation 5976- 56, which lacks trileucine.
  • Figs 2B, 2C and 2D show the -59, -61 and -67 formulations, respectively.
  • the powder lacking trileucine contained more spherical particles, which posses less favorable aerodynamic properties.
  • a graph of particle size distributions for Sample 5976-67 ⁇ 25% trileucine, 9% zanamivir and 66% rimantadine) is shown in Fig 3.
  • Table 2 shows median particles sizes (in microns) for Sample No. 5976-67. In the Table, particles sizes are given as below the 10, 16, 50, 84 and 90% distribution ranges.
  • Trileucine appears to result in good aerosol performance.
  • the emitted dose for Sample No. 5976-59 (30% trileucine) and No. 5976-67 (25% trileucine) were above 90% with %SD of 2% and capsule retentions of 1% and 2% respectively.
  • the ED was still 83% with %SD of 6 and capsule retention of 6%.
  • Figs 5A-5B show aerosol pulse measurement of two powders, wherein Fig 5 A refers to Sample No. 5976-67, exiting an inhaler device mouthpiece, demonstrating times required to complete emptying formulations of the present invention. It can be seen that peak flow rates reach about 60L/min, thus a 2L volume is emptied in less than about 2 to 2.5 seconds.
  • aqueous feedstock formulation of rimantadine was prepared by dissolving 80% rimandadine and 20% trileucine in a sufficient amount of a 95% water, 5% ethanol solution to yield a 2% solids level. All feedstock component ratios, including liquids, were based upon mass. The solution was adjusted to pH 6.5. Ethanol was used to decrease the solubility of the trileucine and to cause early shell formation.
  • the feedstock was spray dried on a Buchi Spray dryer using a standard Buchi nozzle, and nitrogen as the atomization and drying gas.
  • Feed stock feed rate was 5.0 ml/min
  • Atomization pressures were 20 and 40psi
  • outlet temperature was 6O 0 C or 72 0 C.
  • the feedstock formulation was divided into two lots: one was spray dried and at 60 0 C (lot 11/60) and the other at 72°C (lot 11/72) outlet temperatures.
  • the spray-dried powders were transferred into a glovebox with a relative humidity less than 5% and placed into unit dosage forms (capsules or blisters) suitable for use in a dry powder inhaler device as described herein, for example, as described in U.S. Patent No. 4995305.
  • An aqueous feedstock formulation of zanamivir is prepared by dissolving 80% zanamivir and 20% trileucine in a sufficient amount of a 95% water, 5% ethanol solution to yield a 2% solids level. The solution is adjusted to pH 6.5. Ethanol is used to decrease the solubility of the trileucine and to cause early shell formation. All feedstock component ratios, including liquids, are based upon mass.
  • the feedstock is spray dried on a Buchi Spray dryer using a standard Buchi nozzle, and nitrogen as the atomization and drying gas.
  • Feed stock feed rate is 5.0 ml/min
  • Atomization pressures are 20 and 40 psi
  • outlet temperature is 7O 0 C.
  • the powders are transferred into a glovebox with a relative humidity less than 5% and placed into unit dosage forms (capsules or blisters) suitable for use in a dry powder inhaler device as described herein, for example, as described in U.S. Patent No. 4995305.

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Abstract

La présente invention concerne une composition pharmaceutique qui comprend des particules comprenant un principe actif antiviral, les particules ayant un diamètre aérodynamique médian en masse d’environ 1 µm à environ 7 µm et une densité apparente inférieure à environ 1,0 g/cm3. Une composition pharmaceutique comprend une poudre comprenant une quantité efficace d’antiviral et d’excipient pharmaceutiquement acceptable, la poudre comprenant des particules ayant un diamètre aérodynamique médian en masse d’environ 1 µm à environ 7 µm, et une densité apparente inférieure à environ 1,0 g/cm3. La présente invention concerne également des compositions pharmaceutiques comprenant des combinaisons de deux principes actifs antiviraux ou plus. La présente invention concerne en outre des formes posologiques unitaires, des procédés de fabrication et d’utilisation de ces compositions, ainsi que des procédés et des systèmes de délivrance pulmonaire de ces compositions.
PCT/US2009/044122 2008-05-20 2009-05-15 Compositions antivirales, procédés de fabrication et d’utilisation de ces compositions, et système de délivrance pulmonaire de ces compositions WO2009143011A1 (fr)

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WO2013016754A1 (fr) * 2011-08-01 2013-02-07 Monash University Procédé et formulation pour inhalation
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CN103446078A (zh) * 2013-08-26 2013-12-18 陈永奇 含有奥司他韦羧酸胍基类似体和/或其乙酯制剂的给药方法
WO2016106050A1 (fr) * 2014-12-26 2016-06-30 Emory University N4-hydroxycytidine, ses dérivés et utilisations anti-virales
WO2017085692A1 (fr) 2015-11-18 2017-05-26 Glaxosmithkline Intellectual Property (No.2) Limited Compositions pharmaceutiques à base de ribavirine
WO2017156380A1 (fr) * 2016-03-10 2017-09-14 Emory University N4-hydroxycytidine et dérivés et leurs utilisations anti-virales
CN111358773A (zh) * 2020-04-10 2020-07-03 广州南鑫药业有限公司 一种帕拉米韦干粉吸入剂及其制备方法
US10806770B2 (en) 2014-10-31 2020-10-20 Monash University Powder formulation
US20210386697A1 (en) * 2019-02-25 2021-12-16 Guangzhou Nanxin Pharmaceutical Co., Ltd. Peramivir solution type inhalant and preparation method therefor
US11331331B2 (en) 2017-12-07 2022-05-17 Emory University N4-hydroxycytidine and derivatives and anti-viral uses related thereto
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US12186361B2 (en) 2011-08-01 2025-01-07 Monash University Method and formulation for inhalation
AU2011374218B2 (en) * 2011-08-01 2017-05-11 Monash University Method and formulation for inhalation
WO2013016754A1 (fr) * 2011-08-01 2013-02-07 Monash University Procédé et formulation pour inhalation
CN103446051A (zh) * 2013-08-26 2013-12-18 陈永奇 含有帕拉米韦和/或其衍生物制剂的给药方法
CN103446078A (zh) * 2013-08-26 2013-12-18 陈永奇 含有奥司他韦羧酸胍基类似体和/或其乙酯制剂的给药方法
WO2015027848A1 (fr) * 2013-08-26 2015-03-05 Chen Yongqi Méthode pour administrer une formulation comportant du peramivir et/ou un dérivé correspondant
WO2015027847A3 (fr) * 2013-08-26 2015-04-23 陈永奇 Procédé d'administration d'une préparation contenant des analogues de guanidino de carboxylate d'oseltamivir et/ou leurs esters éthyliques
US10806770B2 (en) 2014-10-31 2020-10-20 Monash University Powder formulation
IL252997B (en) * 2014-12-26 2021-01-31 Univ Emory N4-hydroxycytidine and derivatives and anti-viral uses related thereto
WO2016106050A1 (fr) * 2014-12-26 2016-06-30 Emory University N4-hydroxycytidine, ses dérivés et utilisations anti-virales
US11628181B2 (en) 2014-12-26 2023-04-18 Emory University N4-hydroxycytidine and derivatives and anti-viral uses related thereto
WO2017085692A1 (fr) 2015-11-18 2017-05-26 Glaxosmithkline Intellectual Property (No.2) Limited Compositions pharmaceutiques à base de ribavirine
WO2017156380A1 (fr) * 2016-03-10 2017-09-14 Emory University N4-hydroxycytidine et dérivés et leurs utilisations anti-virales
US10874683B2 (en) 2016-03-10 2020-12-29 Emory University N4-hydroxycytidine and derivatives and anti-viral uses related thereto
US11331331B2 (en) 2017-12-07 2022-05-17 Emory University N4-hydroxycytidine and derivatives and anti-viral uses related thereto
US11903959B2 (en) 2017-12-07 2024-02-20 Emory University N4-hydroxycytidine and derivatives and anti-viral uses related thereto
EP3932400A4 (fr) * 2019-02-25 2022-09-21 Guangzhou Nanxin Pharmaceutical Co., Ltd. Inhalant de type solution de péramivir et son procédé de préparation
US12226384B2 (en) * 2019-02-25 2025-02-18 Guangzhou Nanxin Pharmaceutical Co., Ltd. Peramivir solution type inhalant and preparation method therefor
US20210386697A1 (en) * 2019-02-25 2021-12-16 Guangzhou Nanxin Pharmaceutical Co., Ltd. Peramivir solution type inhalant and preparation method therefor
CN111358773B (zh) * 2020-04-10 2021-03-30 广州南鑫药业有限公司 一种帕拉米韦干粉吸入剂及其制备方法
EP4134074A4 (fr) * 2020-04-10 2024-04-10 Guangzhou Nucien Pharmaceutical Co., Ltd. Produit d'inhalation de poudre sèche de peramivir et sa méthode de préparation
WO2021203914A1 (fr) * 2020-04-10 2021-10-14 广州南鑫药业有限公司 Produit d'inhalation de poudre sèche de peramivir et sa méthode de préparation
CN111358773A (zh) * 2020-04-10 2020-07-03 广州南鑫药业有限公司 一种帕拉米韦干粉吸入剂及其制备方法
WO2022162635A1 (fr) * 2021-02-01 2022-08-04 Plumestars S.R.L. Nouvelles compositions antivirales et leur utilisation en thérapie et dans le traitement d'infections virales
IT202100002003A1 (it) * 2021-02-01 2022-08-01 Plumestars S R L Nuove composizioni antivirali e loro utilizzo in terapia e nel trattamento di infezioni virali

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