Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—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
• • 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
  • A61K31/16—Amides, e.g. hydroxamic acids
  • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
  • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
• • 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
  • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
• • 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
  • A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]

Definitions

• the invention relates to methods of administering inhalation particles and related formulations in dose-sparing amounts, wherein the inhalation particles comprise formoterol fumarate and budesonide.
• APIs active pharmaceutical ingredients
• other therapeutic agents to the respiratory tract via nasal and pulmonary delivery of inhalation particles is widely used for the treatment of a variety of diseases and conditions.
• Respiratory delivery is accomplished in many ways, such as but not limited to: (i) using an aerosol comprising inhalation particles surrounded by a liquid; (ii) using a multi-dose inhaler; (iii) via the delivery of fine dry powdered inhalation particles via a dry powder inhaler; or (iv) using a nebulizer to nebulize a liquid solution or suspension of the API.
• an API or other therapeutic agents to the respiratory tract offers several advantages, such as, but not limited to, avoidance of metabolism of the drug via the first pass metabolic mechanisms and an increased efficiency of delivery to respiratory tissues (as compared to traditional administration via the bloodstream).
• Such increased efficiency of delivery to respiratory issues is important in the case of inhaled products that comprise inhaled corticosteroids and long-acting beta agonists.
• Symbicort® inhaled formoterol fumarate & budesonide, available from Astra Zeneca
• Symbicort® inhaled formoterol fumarate & budesonide, available from Astra Zeneca
• Symbicort® inhaled formoterol fumarate & budesonide, available from Astra Zeneca
• formoterol fumarate and budesonide an inhaled product that combines formoterol fumarate and budesonide as a physical mixture of formoterol fumarate- containing particles and budesonide-containing particles.
• the very process of dispersion into an aerosol can partition such admixture blends of particles by impaction or sedimentation based on the effective aerodynamic diameter of each particle or their agglomerate.
• MMAD mass median aerodynamic diameter
• the mass median aerodynamic diameter (MMAD) of a particle of API in the blend is only slightly larger than the MMAD of the other particle of API in the blend, then well known aerodynamic effects will partition out the larger particle API, thereby increasing the fraction of the smaller particle API, in the resulting aerosol, causing a shift from the original fixed combination ratio.
• one of the two actives in the Symbicort admixture has a minimum efficacy dose of approximately 4 micrograms in adult asthmatics. At levels above about 12 micrograms systemic b2 agonist effects begin to occur. To overcome dose content inconsistency the label dose of Symbicort is 9 micrograms; this ensures enough drug is always delivered to be effective, but risks triggering adverse effects of systemic b2 agonism (BP elevation, heartrate elevation changes in potassium and glucose serum levels and shakes).
• systemic b2 agonism BP elevation, heartrate elevation changes in potassium and glucose serum levels and shakes.
• the invention relates to methods that comprise administering a dose- sparing amount of a formulation comprising inhalation particles to a subject by inhalation; wherein the inhalation particles comprise formoterol fumarate and budesonide, the formoterol fumarate and budesonide being in a distributed encapsulated morphology with respect to one another within said inhalation particles and the formoterol fumarate being in a predetermined mass ratio with regard to the budesonide within said inhalation particles.
• Figure 1 shows plasma budesonide concentrations as a function of time.
• Figure 2 shows the study design for Example 2.
• Figure 3 shows the mean plasma budesonide AUC240 characterized by emitted dose, as determined according to Example 2.
• the inventors have found, surprisingly, that the problems noted in the art can be addressed by providing methods, along with related compositions, that comprise administering a dose-sparing amount of a formulation comprising inhalation particles to a subject by inhalation; wherein the inhalation particles comprise formoterol fumarate and budesonide, the formoterol fumarate and budesonide being in a distributed encapsulated morphology with respect to one another within said inhalation particles and the formoterol fumarate being in a predetermined mass ratio with regard to the budesonide within said inhalation particles.
• the inventors have found that dosing consistency may be increased by combining formoterol fumarate and budesonide into a single particle, minimizing dose partitioning during aerosol generation and during inhalation delivery. Therefore the dose of formoterol can be reduced from that of the Symbicort, 9 micrograms is reduced to 5.4 micrograms, and the dose of the budesonide can be reduced from 80 micrograms to 52 micrograms in the instant invention whilst maintaining equivalent efficacy to Symbicort as measured by the pharmacodynamic standard, FEV1 and by pharmacokinetics. Thus a dose sparing amount is achieved.
• inhalation particles that contain only one API or inhalation particles that contain a combination of APIs where the APIs are commingled with one another as admixtures or physical blends.
• certain useful properties of inhalation particles containing one or more APIs cannot be exploited.
• it would be beneficial when using a combination of APIs to provide an inhalation particle that contained an essentially pure kernel or central unified portion of a first API that is coated or substantially coated with a second API (of course, the first API could also coat or substantially coat a central unified portion of the second API).
• first and second APIs Such particles are referred to in the art as core/shell, encapsulated or coated.
• the second API could protect the first API from degradation or instability by forming a protective coating around the first API. In such a case a first API that was prone to degradation or instability could be protected from such by the second API.
• a single, discrete inhalation particle comprising two or more APIs would be advantageous in order to control the delivery of the first and/or second APIs or to control the pharmacological availability of the first and/or second APIs.
• Such a composition of an inhalation particle and formulations comprising such inhalation particles have not been previously known in the art.
• a single, discrete inhalation particle comprising two or more APIs would be advantageous since the delivery of both drugs would be directed to a single target cell, maximizing the potential synergy of both APIs and controlling the ratio of delivery of each API to a given cell.
• the presence of the first and the second API in each discrete inhalation particle promotes the coincidental delivery of the first and second API.
• coincidental delivery means that the first and second APIs are delivered to the same cell at the same time. The coincidental delivery of the first and second APIs offers therapeutic advantages not previously known in the art.
• glucocorticoid receptor GR
• beta-agonists making it more receptive to the inhaled corticosteroid
• beta-agonists making it more receptive to the inhaled corticosteroid
• the beta-agonists make it more receptive to the inhaled corticosteroid
• the increased translocation of the inhaled corticosteroid-glucocorticoid receptor complex into the cell nucleus (where the complex exerts biological activity) by the beta-agonists activation or 'priming' of the glucocorticoid receptor (GR) by the beta-agonists making it more receptive to the inhaled corticosteroid
• the increased translocation of the inhaled corticosteroid-glucocorticoid receptor complex into the cell nucleus (where the complex exerts biological activity) by the beta-agonists are two mechanisms to explain this therapeutic advantage.
• the delivery of each drug to the same cell and/or the order of delivery cannot be controlled. Therefore, it is difficult to ensure that each cell in need of treatment receives each drug.
• the inhalation particles of the present disclosure solve this problem. Furthermore, by selecting the desired morphology and the first and second API, not only can the coincidental delivery of the first and second APIs be ensured, the order of release of the first and second APIs can be controlled and determined to achieve maximum therapeutic benefit.
• Example 1 illustrates a formulation that could be useful in the practice of the present invention when administered in dose sparing amounts.
• Example 2 shows that the recited formulations can be administered in dose sparing amounts.
• a pharmacodynamic measure the FEV1 (Forced Expiratory Volume in 1 second), was determined for MAP0005 formulation (2 puffs and 6 puffs) and Symbicort (2 puffs) in a crossover PK/PD trial.
• the FEV1 response is a direct measure of the clinical efficacy of the formoterol fumarate active contained in both of these combination products.
• MAP0005 (2 puffs) dose contained 104 micrograms of budesonide combined with 5.4 micrgrams of formoterol fumarate.
• Symbicort (2 puffs ) dose contained 160 micrograms of budesonide and 9.0 micrograms of formoterol fumarate.
• FIG. 1a First Treatment Day
• Symbicort 80 ug Budesonide/4.5 ug Formoterol Fumarate
• vs MAP0005 52 ug Budesonide/2.7 ug Formoterol Fu ma rate
• a particle includes a plurality of such particles
• a reference to “a carrier” is a reference to one or more carriers and equivalents thereof, and so forth.
• administering means dosing a pharmacologically active material, such as formoterol fumarate and/or budesonide, to a subject in a manner that is pharmacologically useful.
• a pharmacologically active material such as formoterol fumarate and/or budesonide
• Distributed encapsulated means that the formoterol fumarate is partially encapsulated by the budesonide.
• Distributed means that the formoterol fumarate exists in a plurality of independent, noninterconnected phase domains distributed within a continuous matrix of budesonide.
• partially means that certain domains of the formoterol fumarate are completely encapsulated by the budesonide and certain domains of the formoterol fumarate are exposed on the surface of the inhalation particle.
• the formoterol fumarate has a surface area exposed at the surface of the inhalation particle of greater than 10% but less than or equal to 50% of the total exterior surface area of the inhalation particle and the budesonide covers and/or protects from 89.9% to 50% of the formoterol fumarate.
• the formoterol fumarate has a surface area exposed at the surface of the inhalation particle of greater than 10% but less than or equal to 90% of the total exterior surface area of the inhalation particle and the budesonide covers and/or protects from 89.9% to 10% of the formoterol fumarate.
• the formoterol fumarate has a surface area exposed at the surface of the inhalation particle of greater than 10% but less than or equal to 99% of the total exterior surface area of the inhalation particle and the budesonide covers and/or protects from 89.9% to 1% of the formoterol fumarate.
• Surface coverage or exposure can be measured using exponential dilution titration HLPC spectroscopy.
• the formoterol fumarate is present in a volume percentage in the inhalation particles of between 0.1 and 36% by volume.
• Dose-sparing amount means an amount (e.g. specified number of mass units) of formoterol fumarate and budesonide that provides a desired therapeutic outcome wherein the dose-sparing amount is an amount which is numerically less than would be required to provide substantially the same therapeutic outcome (such as FEV1) if administered separately.
• dose-sparing amount is an amount which is numerically less than would be required to provide substantially the same therapeutic outcome (such as FEV1) if administered separately.
• “separately” means that the formoterol fumarate and budesonide are administered in separate particles that are physically blended.
• Formulation means an inventive composition that comprises inhalation particles and additional pharmaceutically active or inactive ingredients.
• additional pharmaceutically active or inactive ingredients may comprise one or more propellants such as hydrofluoralkanes, chlorofluoroalkes, alkanes, carbon dioxide, or blends thereof; a carrier; a stabilizer; an excipient; a preservative; a suspending agent; a chelating agent; a complexing agent; a diluent; a co-solvent or a combination of any of the foregoing.
• “Inhalation” means delivery of a drug, such as formoterol fumarate and budesonide particles, to the lung via inhalation through the mouth or nose.
• “Inhalation Device” means inhalation particles that comprise formoterol fumarate and budesonide in a device suitable for administration to a subject by inhalation.
• preferred inhalation devices comprise pressurized metered dose inhalers, breath actuated pressurized metered dose inhalers, dry powder inhalers, nebulizers including vibrating mesh, ultrasonic and jet nebulizers, or soft mist inhalers.
• Inhalation particles means particles that comprises pharmacologically active ingredients and are suitable for administration by inhalation.
• inhalation particles comprise formoterol fumarate and budesonide.
• Subject means an animal, including mammals such as humans and primates, that is the object of treatment or observation.
• the inhalation particles of the present disclosure may be created using methods including, but are not limited to, the use of supercritical fluid (SCF) precipitation or sub- supercritical (i.e., near supercritical) precipitation techniques and solution precipitation techniques.
• SCF techniques include, as but not limited to, rapid expansion (RES), solution enhanced diffusion (SEDS), gas-anti solvent (GAS), supercritical antisolvent (SAS), precipitation from gas-saturated solution (PGSS), precipitation with compressed antisolvent (PCA), and aerosol solvent extraction system (ASES).
• RES rapid expansion
• SEDS solution enhanced diffusion
• GAS gas-anti solvent
• SAS supercritical antisolvent
• PGSS gas-saturated solution
• PCA precipitation with compressed antisolvent
• NA aerosol solvent extraction system
• the inhalation particles may be fabricated by spray drying, lyophilization, volume exclusion, and any other conventional methods of particle reduction. These methods permit the formation of micron and sub-micron sized particles with differing morphologies depending on the method and parameters selected.
• the method used to produce the inhalation particles is a modified ASES system as developed by Eiffel Technologies Limited and as described in a Patent Application filed on July 15, 2005 and titled "Method of Particle Formation”.
• Inhalation particles produced through the use of these methods can be formulated into formulations.
• the inhalation particles may be formulated into formulations (such as suspensions) for nebulization by well established methods, such as jet nebulizers, ultrasonic nebulizers, and vibrating orifice nebulizers including Aerogen Aeroneb®, Omron MicroAire®, PARI EFIowTM, Boehngher Respimat®, Aradigm AERx®, and next generation nebulizers from Repironics, Ventaira, and Profile Therapeutics.
• the formulations can be packaged into nebulas by blow/fill/seal technology presented either as a unit container of a biphasic system.
• the inhalation particles may also be formulated into aerosol formulations using propellants.
• propellants include, but not limited to, hydrofluoroalkanes (HFA) such as the C1-C4 hydrofluorocarbons.
• HFA propellants include but are not limited to, 1 ,1 ,1 ,2,3,3,-heptafluoro-n-propane (HFA 227) and/or 1 ,1 ,1 ,2- tetrafluoroethane (HFA 134) or any mixture of both in any proportions.
• the mixture of HFA propellants is selected so that the density of the mixture is matched to the density of the inhalation particles in order to minimize settling or creaming of the inhalation particles.
• Carbon dioxide and alkanes such as pentane, isopentane, butane, isobutane, propane and ethane, can also be used as propellants or blended with the C 1-4 hydrofluoroalkane propellants discussed above.
• the formulation may (but is not required to) further comprise carriers, additives and/or diluents as is known in the art.
• the inhalation particles produced may be formulated into dry powder formulations, i.e. formulations suitable for use in dry powder inhalation devices.
• the particles can be used for pulmonary drug delivery by inhalation directly without added carriers, additives or diluents by packaging the inhalation particles into capsules, cartridges, blister packs or reservoirs of a dry powder inhaler (a variety of dry powder inhalers may be used as is known in the art).
• the inhalation particles may also comprise one or more carriers, additives or diluents to form loose agglomerates of the inhalation particles that are dispersed into individual inhalation particles by the action of the dry powder inhaler.
• the formulation may (but is not required to) further comprise carriers, additives and/or diluents as is known in the art.
• Carriers alone or in combination with other additives, commonly used include, but are not limited to, lactose, dextran, mannitol and glucose. Carriers may be used simply as bulking agents or to improve the dispersibility of the inhalation particles.
• the total amount of the formoterol fumarate and budesonide is typically about 0.1-99.9% (w/w), about 0.25- 75% (w/w), about 0.5-50% (w/w), about 0.75-25% (w/w) or about 1-10% (w/w), based on total weight of the formulation.
• Such formulations may be prepared by methods known in the art. Formulations as above comprising the inhalation particles described herein may be used for nasal and pulmonary inhalation an appropriate device. As stated above, the formulations may contain added carriers, additives and diluents.
• the carriers, additives and diluents can be added in the range of 0.0 to 99.9% (w/w) based on the total weight of the formulation.
• Additives include, but are not limited to, stabilizers, excipients preservatives, suspending agents, chelating agents, complexing agents and/or other components known to one or ordinary skill in the art.
• Such carriers, additives and diluents may be a pharmaceutically acceptable grade.
• Suitable excipients include, but are not limited to ionic and non-ionic surfactants, polymers, natural products and oligomers. Examples of certain suitable excipients that may be used are disclosed in US Patent Nos. 6,264,739, 5,145,684, 5,565,188 and 5,587,143.
• the excipient is an ionic or non-ionic surfactant.
• Typical surfactants include, but are not limited to, oleates, stearates, myristates, alkylethers, alklyaryl ethers and sorbates and any combination of the foregoing.
• the surfactant is a polyoxyethylene sorbitan fatty acid ester, such as Tween 20 or Tween 80, sorbitan monooleate (SPAN-80) or isopropyl myristate.
• Suitable excipients include polyvinylprrolidine, polyethylene glycol, microcrystalline cellulose, cellulose, cellulose acetate, cyclosdextrin, hydroxypropyl beta cyclodextrin, lecithin, magnesium stearate, lactose, mannitol, trehalose and the like and any combination of the foregoing.
• the formulations may also comprise polar solvents in small amounts to aid in the solubilization of the surfactants, when used. Suitable polar compounds include C2-6 alcohols and polyols, such as ethanol, isopropanol, polypropylene glycol and any combination of the foregoing.
• lactose In the event the inhalation particles are to be formulated for use with a dry powder inhaler, lactose, dextran, mannitol and glucose or other suitable compounds may be used.
• Suitable preservatives include, but are not limited to, chlorobutanol and benzalkonium chloride and any combination of the foregoing.
• Suitable chelating agents include, but are not limited to, EDTA and EGTA and any combination of the foregoing.
• the formulations described above may comprise additional components as well, such as, but not limited to, suspending agents and other components commonly used and known in the art.
• the size of an inhalation particle determines the depth of penetration into the lung.
• the depth of penetration is important for achieving the desired therapeutic benefit.
• the inhalation particles have a particle size defined as the median mass aerodynamic diameter (MMAD) of less than about 10 microns MMAD, preferably less than about 7.0 microns MMAD 1 less than about 5.8 microns MMAD, preferably less than about 3 microns in diameter or preferably less than about 1.5 microns MMAD.
• MMAD median mass aerodynamic diameter
• at least 80%, at least 90% or at least 95% of the inhalation particles in a given formulation have an average particle size less than 7.0 microns MMAD.
• At least 80%, at least 90% or at least 95% of the inhalation particles in a given formulation have an average particle size less than 5.8 microns MMAD.
• the inhalation particles have a particle size greater than about 0.1 microns MMAD, greater than about 1.0 microns MMAD 1 or greater than about 1.2 microns MMAD, in certain embodiments, at least 80%, at least 90% or at least 95% of the inhalation particles in a given formulation have an average particle size greater than 0.1 microns MMAD. In further embodiments, at least 80%, at least 90% or at least 95% of the inhalation particles in a given formulation have an average particle size less than 1.2 microns MMAD.
• At least 90% of the inhalation particles have a particle size greater than 0.1 microns MMAD and less than 10 microns MMAD; preferably at least 90% of the particles have a particle size greater than 0.1 microns in diameter and less than 5.8 microns MMAD.
• MMAD - is a measure reported in a compendial methods for characterizing aerosol particle size distributions. It is determined by means known and standard in the art such as a cascade impactor, such as an Anderson Cascade lmpactor also known as an "Apparatus 1" per USP 601. It is generally known that stages 3-6 detect inhalation particles having a size between about 1.2 and 6.5 microns and that stages 3-8 detect inhalation particles having a size between about 0.26 and 6.5 microns. Inhalation particle sizes between about 1.2 and 6.5 microns or between about 0.26 and 6.5 microns are known as the effective particle size range or the fine particle fraction.
• the mass ratio of the formoterol fumarate to the budesonide can be varied. In one embodiment the mass ratio of the formoterol fumarate to budesonide ranges from 50:1 to 1 :500. In another embodiment, the mass ratio of the formoterol fumarate to budesonide is from 5:1 to 1:100. In a further embodiment the mass ratio of the formoterol fumarate to budesonide ranges from 1 :1 to 1 :250. In still another embodiment the mass ratio of the formoterol fumarate to budesonide ranges from 1:1 to 1 :80. In another embodiment, the mass ratio of the formoterol fumarate to budesonide ranges from 1 :15 to 1 :18. In yet another embodiment, the mass ratio of the formoterol fumarate to budesonide is about 1 :16.9.
• a dry powder inhaler In a dry powder inhaler (DPI), the dose to be administered is stored in the form of a non-pressurized dry powder and, on actuation of the inhaler, the particles of the powder are inhaled by the subject. Similar to pressurized metered dose inhalers (pMDIs), a compressed gas may be used to dispense the powder. Alternatively, when the DPI is breath-actuated, the powder may be packaged in various forms, such as a loose powder, cake or pressed shape in a reservoir. Examples of these types of DPIs include the TurbohalerTM inhaler (Astrazeneca, Wilmington, DE) and Clickhaler® inhaler (Innovata, Ruddington, Nottingham, UK).
• the powder When a doctor blade or shutter slides across the powder, cake or shape, the powder is culled into a flowpath whereby the patient can inhale the powder in a single breath.
• Other powders are packaged as blisters, gelcaps, tabules, or other preformed vessels that may be pierced, crushed, or otherwise unsealed to release the powder into a flowpath for subsequent inhalation.
• DiskusTM inhaler Gaxo, Greenford, Middlesex, UK
• EasyHaler® Orion, Expoo, Fl
• NovohalerTM inhalers Still others release the powder into a chamber or capsule and use mechanical or electrical agitators to keep the drug suspended for a short period until the patient inhales. Examples of this are the Exubera® inhaler (Pfizer, New York, NY), Qdose inhaler (Microdose, Monmouth Junction, NJ), and Spiros® inhaler (Dura, San Diego, CA).
• pMDIs generally have two components: a canister in which the drug particles are stored under pressure in a suspension or solution form, and a receptacle used to hold and actuate the canister.
• the canister may contain multiple doses of the formulation, although it is possible to have single dose canisters as well.
• the canister may include a valve, typically a metering valve, from which the contents of the canister may be discharged. Aerosolized drug is dispensed from the pMDI by applying a force on the canister to push it into the receptacle, thereby opening the valve and causing the drug particles to be conveyed from the valve through the receptacle outlet. Upon discharge from the canister, the drug particles are atomized, forming an aerosol.
• pMDIs generally use propellants to pressurize the contents of the canister and to propel the drug particles out of the receptacle outlet.
• the composition is provided in liquid form, and resides within the canister along with the propellant.
• the propellant may take a variety of forms.
• the propellant may be a compressed gas or a liquefied gas.
• Chlorofluorocarbons (CFC) were once commonly used as liquid propellants, but have now been banned. They have been replaced by the now widely accepted hydrofluroralkane (HFA) propellants.
• a manual discharge of aerosolized drug must be coordinated with inhalation, so that the drug particles are entrained within the inspiratory air flow and conveyed to the lungs.
• a breath-actuated trigger such as that included in the Tempo® inhaler (MAP Pharmaceuticals, Mountain View, CA) may be employed that simultaneously discharges a dose of drug upon sensing inhalation, in other words, the device automatically discharges the drug aerosol when the user begins to inhale.
• Tempo® inhaler MAP Pharmaceuticals, Mountain View, CA
• baMDIs breath-actuated pressurized metered dose inhalers
• Nebulizers are liquid aerosol generators that convert bulk liquids, usually aqueous- based compositions, into mists or clouds of small droplets, having diameters less than 5 microns mass median aerodynamic diameter (MMAD) 1 which can be inhaled into the lower respiratory tract. This process is called atomization.
• the bulk liquid contains particles of the therapeutic agent(s) or a solution of the therapeutic agent(s), and any necessary excipients.
• the droplets carry the therapeutic agent(s) into the nose, upper airways or deep lungs when the aerosol cloud is inhaled.
• Pneumatic (jet) nebulizers use a pressurized gas supply as a driving force for liquid atomization.
• Compressed gas is delivered through a nozzle or jet to create a low pressure field which entrains a surrounding bulk liquid and shears it into a thin film or filaments.
• the film or filaments are unstable and break up into small droplets that are carried by the compressed gas flow into the inspiratory breath.
• Baffles inserted into the droplet plume screen out the larger droplets and return them to the bulk liquid reservoir. Examples include PARI LC Plus®, Sprint®, Devilbiss PulmoAide®, and Boehringer lngelheim Respimat®.
• Electromechanical nebulizers use electrically generated mechanical force to atomize liquids.
• the electromechanical driving force is applied by vibrating the bulk liquid at ultrasonic frequencies, or by forcing the bulk liquid through small holes in a thin film.
• the forces generate thin liquid films or filament streams which break up into small droplets to form a slow moving aerosol stream which can be entrained in an inspiratory flow.
• ultrasonic nebulizers in which the bulk liquid is coupled to a vibrator oscillating at frequencies in the ultrasonic range.
• the coupling is achieved by placing the liquid in direct contact with the vibrator such as a plate or ring in a holding cup, or by placing large droplets on a solid vibrating projector (a horn).
• the vibrations generate circular standing films which break up into droplets at their edges to atomize the liquid. Examples include DuroMist®, Drive Medical Beetle Neb®, Octive Tech Densylogic®, and John Bunn Nano-Sonic®.
• an electromechanical nebulizer is a mesh nebulizer, in which the bulk liquid is driven through a mesh or membrane with small holes ranging from 2 to 8 microns in diameter, to generate thin filaments which immediately break up into small droplets.
• the liquid is forced through the mesh by applying pressure with a solenoid piston driver (AERx®), or by sandwiching the liquid between a piezoelectrically vibrated plate and the mesh, which results in a oscillatory pumping action (EFIow®, AerovectRx, TouchSprayTM).
• AERx® solenoid piston driver
• EFIow® AerovectRx, TouchSprayTM
• the mesh vibrates back and forth through a standing column of the liquid to pump it through the holes (AeroNeb®). Examples include the AeroNeb Go®, Pro®; PARI EFIow®; Omron 22UE®; and Aradigm AERx®.
• kits comprise one or more of an administration device (e.g., inhalers, etc) and one or a plurality of doses or a reservoir or cache configured to deliver multiple doses of the composition as described above.
• the dosage form is loaded with an inventive formulation.
• the kit can additionally comprise a carrier or diluent, a case, and instructions for employing the appropriate administration device.
• an inhaler device is included.
• the inhaler device is loaded with a reservoir containing an inventive formulation.
• the kit comprises one or more unit doses of the inventive formulation.
• the inhaler device is a baMDI such the TEMPOTM Inhaler.
• Formulations according to the invention may be administered according to the invention by oral inhalation using inhalation devices such as those discussed elsewhere herein. Dosing frequency may be determined based on the indication being treated and the individual nature of the subject. In embodiments, the inventive inhalation particles or inventive formulations may be administered three times/day, twice/day, or once/day.
• dose ranges may comprise:
• Example 1 Inhalation Particles and Formulation (Prophetic)
• Inhalation particles comprising formoterol fumarate as the formoterol fumarate and budesonide as the budesonide are produced using a modified ASES system as developed by Eiffel Technologies Limited and as described in Australian Patent Application filed on July 15, 2005 and titled "Method of Particle Formation".
• the resultant inhalation particles have a formoterol to budesonide mass ratio of 1 :16.9.
• the inhalation particles are in the form of unagglomerated, discrete, fine, white, easily-dispersible powder comprising mainly torroidal- shaped particles of less than 5 micron in diameter when viewed under SEM.
• the inhalation particles, in their dry powder, neat form have an average emitted dose of 79.2% by mass, an average fine particle fraction of 70.6% by mass (as a percentage of the emitted dose), and an average fine particle fraction of 55.8% by mass (as a percentage of the loaded dose).
• Each subject was medically screened for inclusion (Visit 1a) and then returned 0 to 4 days later for spirometry and testing for airway reversibility to an inhaled bronchodilator and clinical laboratory investigations (Visit 1b), prior to being deemed eligible for inclusion in the study.
• Subjects then returned 2 to 14 days after Visit 1b and were randomized if still eligible (Visit 2) to one of 6 dosing sequences, received their first treatment, and were observed for a minimum of 4 hours.
• Subjects returned for their second treatment 2 to 10 days later (Visit 3) and were observed again for a minimum of 4 hours.
• Subjects returned for their third and final treatment 2 to 10 days later (Visit 4) and were again observed for a minimum of 4 hours.
• the study design is shown generally in Figure 2.
• Oral corticosteroid use was not permitted for 4 weeks prior to and throughout the study. All oral, inhaled, topical (dermal, intranasal or rectal) or systemic glucocorticosteroids that contained the active pharmaceutical ingredient budesonide were excluded at study enrollment and throughout the study duration for any given subject.
• Inhaled corticosteroid use was not permitted for at least 12 hours, short- acting ⁇ 2-agonists for 4 hours, oral and long-acting ⁇ 2-agonists for 12 hours, anticholinergics for 12 hours, and slow release theophyllines for 48 hours prior to spirometry assessment (Visit 1 b) to determine if subjects met inclusion criteria.
• Disodium cromoglycate and inhaled corticosteroids use other than budesonide, were permitted, provided doses remained constant for 4 weeks prior to study, through the end of study. If the subject was taking budesonide at the time of screening, it was substituted with an alternative inhaled corticosteroid for the course of the study as directed by the study investigator. Subjects who had budesonide substituted with an alternative inhaled corticosteroid were required to wait a minimum of 7 days before receiving their first treatment.
• the primary outcome of this study was the plasma budesonide concentration pre- and post-treatment.
• the pharmacokinetics of budesonide was evaluated for 240 minutes post-dose and the following estimates were performed:
• the objective of this proof of concept study was to determine the pharmacokinetic profile of the budesonide component of MAP's novel inhaled combination formulation of formoterol particles coated with budesonide, as well as to evaluate the consistency of budesonide delivery in subjects with asthma when administered by the Tempo® inhaler.
• MAP6 - 6 inhalations of inventive formulation using TEMPO® inhaler (312 ⁇ g bud, 16.2 ⁇ g form emitted dose);
• MAP2 - 2 inhalations of inventive formulation using TEMPO® inhaler (104 ⁇ g bud, 5.4 ⁇ g form emitted dose);
• S2 - 2 inhalations of Symbicort® using Turbuhaler® DPI 160 ⁇ g bud, 9.0 ⁇ g form emitted dose
• the mean AUC240 was lower in subjects receiving 2 inhalations of inventive formulation (35804 min * pg/ml_) than subjects receiving 6 inhalations of inventive formulation (92274 min*pg/ml_) or 2 inhalations of Symbicort® (62221 min*pg/ml_).
• a ratio of 3.0 would be expected for MAP6 inhalations compared to MAP2. Over the 4 hour pharmacokinetic sampling, the observed ratio was 2.63. In post-hoc analysis for AUCinf, the ratio was calculated at 2.85, showing tendency towards dose proportionality.
• Figure 3 shows the mean plasma budesonide AUC240 by emitted dose (error bars expressed as SD).
• MAP6 - 6 inhalations of inventive formulation using Tempo inhaler (312 ⁇ g bud, 16.2 ⁇ g form emitted dose)
• MAP 2 - 2 inhalations of inventive formulation using Tempo inhaler (104 ⁇ g bud, 5.4 ⁇ g form emitted dose)
• S2 - 2 inhalations of Symbicort using Turbuhaler DPI 160 ⁇ g bud, 9.0 ⁇ g form emitted dose
• Budesonide AUC was dose proportional for the two doses of the inventive formulation.
• MAP6 - 6 inhalations of inventive formulation using Tempo inhaler (312 ⁇ g bud, 16.2 ⁇ g form emitted dose);
• MAP2 - 2 inhalations of inventive formulation using TEMPO® inhaler (104 ⁇ g bud, 5.4 ⁇ g form emitted dose);
• S2 - 2 inhalations of Symbicort® using Turbuhaler® DPI 160 ⁇ g bud, 9.0 ⁇ g form emitted dose).

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