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
  • A61K9/10—Dispersions; Emulsions
  • A61K9/12—Aerosols; Foams
• • 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
  • A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
• • 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
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
  • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
  • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

• This invention concerns novel and improved macrolide formulations, such as erythromycylamine formulations, for delivery by inhalation and to improved methods of treatment of susceptible acute or chronic endobronchial infections.
• the invention relates to formulations comprising at least one concentrated macrolide antibiotic in a physiologically acceptable liquid solution or dry powder form.
• the formulations are suitable for delivery of a macrolide antibiotic drug, such as erythromycylamine, to the lung endobronchial airway space of a liquid aerosol or dry powder aerosol form, wherein a substantial portion of the aerosolized droplets or particles of the formulation have a mass median aerodynamic diameter between 1 to
• Formulated and aerosol delivered efficacious amounts of the macrolides are effective for the treatment and/or prophylaxis of acute and chronic endobronchial infections, and pneumonia, particularly those caused by Streptococcus pneumoniae,
• this invention relates to new and improved unit dose formulations of macrolide antibiotics for delivery by aerosol inhalation.
• COPD chronic obstructive pulmonary disease
• Chronic . bronchitis is a pulmonary disease that is characterized by the inflammation and progressive destruction of lung tissue.
• the debilitation ofthe lungs in CB patients is associated with chronic cough, increased daily sputum production, and accumulation of purulent sputum produced as a result of chronic endobronchial infections caused by compromised pulmonary function.
• Acute exacerbation of chronic bronchitis (AECB) is often characterized by increasing cough, purulent sputum production, and clinical deterioration caused by Streptococcus pneumonia, H. influenzae, and Moraxella catarrhalis.
• Pneumonia may also result from infection by these organisms either de novo or as a complication of COPD.
• Erythromycylamine is a 14-membered ring macrolide belonging to the erythromycin family of antibiotics and possesses a similar in vitro antibiotic spectrum to erythromycin A, and like erythromycin A, is an effective treatment of typical and atypical pneumonias.
• Erythromycylamine has a C-9 amino function having the S- configuration in place of the C-9 carbonyl group found in erythromycin A.
• erythromycylamine has a prodrug, dirithromycin, which features a bridged acetal function between the C-9 amino and C-l 1 hydroxy groups (see Fig. 1).
• the cyclic acetal is rapidly hydrolysized in plasma by a nonenzymatic process (half- life of approximately 30 minutes). Dirithromycin has been shown to successfully treat exacerbations that occur in patients with CB (M.
• the particles When, for example, the mass median aerodynamic diameter (MMAD) is greater than 5 ⁇ m, the particles are typically deposited in the upper airways, decreasing the amount of antibiotic delivered to the site of infection in the lower respiratory tract.
• MMAD mass median aerodynamic diameter
• the size range of aerosolized particles needed to deliver the drug to the endobronchial space and peripheral lung, the sites ofthe infection is preferably between about 1 and 5 ⁇ m.
• nebulizers that aerosolize therapeutics, including aminoglycosides, produce a large number of aerosol particles having sizes less than 1 ⁇ m or greater than 5 ⁇ m.
• the majority of aerosolized antibiotic particles should not have a MMAD larger than 5 ⁇ m.
• the larger-sized particles are deposited in the upper airways, decreasing the amount of antibiotic delivered to the site of infection in the lower respiratory tract.
• nebulizers three types of available nebulizers, jet nebulizers, vibrating porous plate nebulizers and ultrasonic nebulizers, can produce and deliver aerosol particles with diameter sizes between 1 and 5 ⁇ m, a particle size that is preferable for treatment of bacterial infections of the lung. Therefore, it would be highly advantageous to provide a macrolide formulation that could be efficiently aerosolized in a jet, vibrating porous plate, and ultrasonic nebulizer.
• newer aerosol generating technologies are now available, including mechanical extrusion and both passive and energized dry powder inhalers that are useful for the delivery of therapeutic agents in dry powder form.
• antibiotics and particularly antibiotic solutions for intravenous administration, contain phenol or other preservatives to maintain potency and to minimize the production of degradation products.
• phenol and other preservatives when aerosolized, may induce bronchospasm, an unwanted occurrence in patients with lung diseases such as chronic bronchitis.
• erythromycylamine for inhalation in the form of a liquid or dry powder aerosol
• An additional advantage of aerosol delivery of erythromycylamine is its inherent high affinity for lung tissue and persistence in the plasma compartment (long plasma/tissue half-life). The combination of a high- concentration aerosol delivery, long plasma/tissue half-life and high lung affinity would allow for safer macrolide therapy, which is capable of eradicating or substantially reducing endobronchial infections after a single aerosol dose.
• macrolide antibiotic formulations such as erythromycylamine formulations, containing no preservatives, at a pH adjusted to levels that slow or prevent degradation, and are tolerable for a patient, and that provide adequate shelf life suitable for commercial distribution, storage and use.
• macrolide antibiotics such as erythromycylamine, erythromycin A, roxithromycin, azithromycin and clarithromycin
• human and non-human animal subjects suffering from or at risk for endobronchial infection such as an infection by bacterial Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, Moraxella catarrhalis and/or the atypical pathogens Legionella pneumonia, Chlamydia pneumoniae, and/or Mycoplasma pneumoniae
• a macrolide antibiotic such as erythromycylamine, erythromycin A, roxithromycin, azithromycin or clarithromycin, in a liquid solution or dry powder form suitable for aerosol generation.
• one aspect of the current invention relates to concentrated formulations suitable for efficacious delivery by inhalation of a macrolide antibiotic drug, such as erythromycylamine, erythromycin A, roxithromycin, azithromycin or clarithromycin, into the endobronchial space of a subject suffering from or at risk for a bacterial pulmonary infection.
• a macrolide antibiotic drug such as erythromycylamine, erythromycin A, roxithromycin, azithromycin or clarithromycin
• Another aspect of the invention provides formulations suitable for efficacious delivery of a macrolide antibiotic drug, such as erythromycylamine, erythromycin A, roxithromycin, azithromycin or clarithromycin, into the endobronchial space of a subject suffering from bacterial Streptococcus pneumoniae, Haemophilus in ⁇ uenzae, Staphylococcus aureus, Moraxella catarrhalis and/or the atypical pathogens Legionella pneumonia, Chlamydia pneumoniae, and/or Mycoplasma pneumoniae pulmonary infection.
• a macrolide antibiotic drug such as erythromycylamine, erythromycin A, roxithromycin, azithromycin or clarithromycin
• Another aspect of the current invention provides formulations suitable for efficacious delivery of a macrolide antibiotic drug, such as erythromycylamine, erythromycin A, roxithromycin, azithromycin or clarithromycin, into endobronchial space of a subject to prevent or substantially reduce the risk of pulmonary infection in at-risk patients caused by Stretococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, Moraxella catarrhalis and/or the atypical pathogens Legionella pneumonia, Chlamydia pneumoniae, and or Mycoplasma pneumoniae.
• a macrolide antibiotic drug such as erythromycylamine, erythromycin A, roxithromycin, azithromycin or clarithromycin
• Still another aspect of the current invention provides liquid formulations comprising the equivalent of 50 to 750 mg of a macrolide antibiotic drug, such as erythromycylamine, erythromycin A, roxithromycin, azithromycin or clarithromycin, in 0.5 to 5 ml of a physiologically acceptable carrier, such as saline diluted into a quarter normal saline strength wherein said formulation has a physiologically tolerated osmolarity, salinity, and pH and is suitable for delivery to a subject in concentrated form by aerosol inhalation.
• a macrolide antibiotic drug such as erythromycylamine, erythromycin A, roxithromycin, azithromycin or clarithromycin
• Still another aspect ofthe current invention provides dry powder formulations comprising the equivalent of 25 to 250 mg of a macrolide antibiotic drag, such as erythromycylamine, erythromycin A, roxithromycin, azithromycin or clarithromycin, in a physiologically acceptable dry powder carrier for delivery to a subject in concentrated form by aerosol inhalation, wherein the dry powder formulations comprise about 50 to 90% by weight ofthe macrolide antibiotic drug.
• a macrolide antibiotic drag such as erythromycylamine, erythromycin A, roxithromycin, azithromycin or clarithromycin
• Still another aspect ofthe current invention provides methods for the treatment of pulmonary infections caused by susceptible bacteria by administering to a subject requiring such treatment by inhalation an aerosol formulation comprising an antibacterially effective amount of a macrolide antibiotic drug, such as erythromycylamine, erythromycin A, roxithromycin, azithromycin or clarithromycin, formulated in a physiologically compatible liquid solution or dry powder form, wherein the mass median aerodynamic diameter (MMAD) of particles in the aerosol formulation is predominantly between 1 and 5 ⁇ m.
• a macrolide antibiotic drug such as erythromycylamine, erythromycin A, roxithromycin, azithromycin or clarithromycin
• the present invention provides unit dose formulations and devices adapted for use in connection with a high efficiency inhalation system, the unit dose device comprising a container designed to hold and store the relatively small volumes of the macrolide antibiotic formulations of the invention, and to deliver the formulations to an inhalation device for delivery to a subject in aerosol form.
• a unit dose device of the invention comprises a sealed container, such as an ampoule, containing less than about 2.0 ml of a liquid macrolide antibiotic formulation comprising from about 50 to about 150 mg/ml of a macrolide antibiotic in a physiologically acceptable liquid carrier.
• a unit dose device ofthe invention comprises a sealed container, such as an ampoule, containing a dry powder macrolide antibiotic formulation comprising from about 20 to about 250 mg of a macrolide antibiotic in a physiologically acceptable dry powder carrier.
• the sealed unit dose containers ofthe invention are preferably adapted to deliver the macrolide antibiotic formulation to a high efficiency inhalation device for aerosolization and inhalation by a subject.
• FIGURE 1 illustrates the chemical structure of erythromycylamine and dirithromycin
• FIGURE 2 is a graphical representation of the stability of erythromycylamine hydrochloride in aqueous solution at 60, 100, and 150 mg/mL and pH 5.0, 6.0, and 7.0, at 4 degrees centigrade, as described in Example 4;
• FIGURE 3 is a graphical representation of the stability of erythromycylamine hydrochloride in aqueous solution at 60, 100, and 150 mg/mL and pH 5.0, 6.0, and 7.0, at 25 degrees centigrade, as described in Example 4;
• FIGURE 4 is a graphical representation of the stability of erythromycylamine hydrochloride in aqueous solution at 60, 100, and 150 mg/mL and pH 5.0, 6.0, and 7.0, at 40 degrees centigrade, as described in Example 4;
• FIGURE 5 is a graphical representation of the stability of erythromycylamine hydrochloride in aqueous solution at 60, 100, and 150 mg/mL and pH 5.0, 6.0, and 7.0, at 60 degrees centigrade, as described in Example 4;
• FIGURE 6 is a graphical representation ofthe stability of erythromycylamine sulfate in aqueous solution at 60, 100, and 150 mg/mL and pH 5.0, 6.0, and 7.0, at 60 degrees centigrade, as described in Example 4;
• FIGURE 7 is a graphical representation of the stability of erythromycylamine acetate in aqueous solution at 60, 100, and 150 mg/mL and pH 5.0, 6.0, and 7.0, at 60 degrees centigrade, as described in Example 4;
• FIGURE 12 illustrates the mean plasma and whole lung concentrations of erythromycylamine following a single dose, 30 minute inhalation administration of a 60 mg/mL sulfate solution in dogs, as described in Example 9.
• FIGURE 13 illustrates the mean lung concentrations of erythromycylamine in individual lung lobes following a single dose, 30 minute inhalation administration of a 60 mg/mL sulfate solution in dogs as described in Example 9.
• Erythromycylamine and dirithromycin are macrolides having a chemical structure depicted in FIG. 1.
• Dirithromycin, a prodrug of erythromycylamine, is a broad-spectrum macrolide antibiotic used for treatment of AECB and pneumonia.
• Macrolide antibiotics useful in the present invention include, for example, erythromycylamine, dirithromycin (a prodrug of erythromycylamine), erythromycin A, clarithromycin (6-O-methyl erythromycin), azithromycin, and roxithromycin.
• Other newer macrolides such as the ketolides (for example, ABT-773 (39 th ICAAC (1999), September 26-29, abstracts F-2133-2141, and HMR-3647 (Drugs of the Future, 23, 591 (1998), 38 th ICAAC (1998), September 24-27, abstract A-49), and anhydrolides (see, J. Med.
• the macrolide antibiotic used in the aerosol formulations described herein is erythromycylamine or dirithromycin. Erythromycylamine and dirithromycin have the chemical structures depicted in FIG. 1.
• methods are provided for the treatment of a subject in need of treatment, such as a subject suffering from an endobronchial infection, comprising administering to the subject by inhalation an antibacterially effective amount of a macrolide antibiotic formulation.
• This aspect of the invention is particularly suitable for formulation of concentrated macrolides, such as erythromycylamine, for aerosolization by small volume, breath actuated, high output rate and high efficiency inhalers to produce a macrolide aerosol particle size between 1 and 5 ⁇ m desirable for efficacious delivery of the macrolide into the endobronchial space to treat susceptible microbial infections.
• the formulations preferably contain minimal yet efficacious amounts of the macrolide formulated in small volumes of a physiologically acceptable solution. For example, an aqueous solution having a salinity adjusted to permit generation of macrolide aerosol particles that are well-tolerated by patients but prevent the development of secondary undesirable side effects such as bronchospasm and cough.
• a quarter normal saline solution is useful for this purpose.
• substantially smaller volumes of macrolide than the conventional administration regime are administered in substantially shorter periods of time, thereby reducing the costs of administration and drug waste, and significantly enhancing the likelihood of patient compliance.
• methods are provided for the treatment of a subject in need of treatment, such as a subject suffering from a susceptible endobronchial infection, comprising administering to the subject for inhalation a dose of a nebulized aerosol formulation comprising from about 50 to about 750 mg of a macrolide and a pharmaceutically acceptable carrier.
• the aerosol formulations administered in the practice of the invention may be liquid formulations comprising from about 50 to about 150 mg/ml of a macrolide antibiotic, preferably from about 70 to about 130 mg/ml of a macrolide antibiotic, and more preferably from about 90 to about 110 mg/ml of a macrolide antibiotic.
• small volumes of aerosol formulation are administered to the subject.
• a dose of less than about 2.0 ml of a nebulized liquid aerosol formulation is administered to the subject.
• a dose of less than about 1.5 ml of a nebulized aerosol formulation is administered to the subject.
• a dose of less than about 1.0 ml of a nebulized aerosol formulation is administered to the subject.
• the macrolide compounds ofthe invention may be formulated for aerosol delivery as a dry powder.
• the term "powder” means a composition that consists of finely dispersed solid particles that are free flowing and capable of being readily dispersed in an inhalation device and subsequently inhaled by a subject so that the particles reach the lungs to permit penetration and deposition in the peripheral airways.
• powder formulations of the invention are said to be "respirable.”
• the average powder particle size is less than about 10 ⁇ m in diameter with a relatively uniform spheroidal shape. More preferably the diameter is less than about 7.5 ⁇ m and most preferably less than about 5.0 ⁇ m.
• the particle size distribution is between about 0.1 ⁇ m and about 5 ⁇ m in diameter, particularly about 1 ⁇ m to about 5 ⁇ m.
• Dry powder formulations of the invention have a moisture content such that the particles are readily dispersible in an inhalation device to form an aerosol. This moisture content will generally be below about 10% by weight (% w) water, usually below about 5% w water and preferably less than about 3% w water.
• Dry powder formulations ofthe invention generally comprise a therapeutically effective amount of a macrolide compound of the invention together with a pharmaceutically acceptable carrier.
• the dry powder formulations of the invention may comprise from about 25 to about 250 mg of a macrolide antibiotic, preferably from about 50 to about 200 mg of a macrolide antibiotic, and more preferably from about 75 to about 150 mg of a macrolide antibiotic.
• the dry powder formulations may comprise from about 50% to about 90% by weight ofthe macrolide antibiotic, preferably from about 60% to about 88% by weight ofthe macrolide antibiotic, and more preferably from about 75% to about 85% by weight of the macrolide antibiotic.
• Suitable pharmaceutically acceptable carriers include carriers that can be taken into the lungs of a patient with no significant adverse toxicological effects on the lungs, including, for example, stabilizers, bulking agents, buffers, salts and the like.
• a sufficient amount of the pharmaceutically acceptable carrier is employed to obtain desired stability, dispersibility, consistency and bulking characteristics to ensure a uniform pulmonary delivery of the composition to a subject in need thereof.
• the actual amount of pharmaceutically acceptable carrier employed may be from about 0.05% w to about 99.95% w. More preferably, from about 5% w to about 95% w of the pharmaceutically acceptable carrier will be used. Most preferably, from about 10% w to about 90% w ofthe pharmaceutically acceptable carrier will be used.
• compositions useful as carriers in this invention include stabilizers such as human serum albumin (HSA), bulking agents such as carbohydrates, amino acids and polypeptides; pH adjusters or buffers; salts such as sodium chloride; and the like. These carriers may be in a crystalline or amorphous form or may be a mixture of the two.
• Preferred bulking agents include compatible carbohydrates, polypeptides, amino acids or combinations thereof.
• Suitable carbohydrates include monosaccharides such as galactose, D-mannose, sorbose, and the like; disaccharides, such as lactose, trehalose, and the like; cyclodextrins, such as 2-hydroxypropyl- ⁇ -cyclodextrin; and polysaccharides, such as raffinose, maltodextrins, dextrans, and the like; alditols, such as mannitol, xylitol, and the like.
• a preferred group of carbohydrates includes lactose, threhalose, raffinose maltodextrins, and mannitol.
• Suitable polypeptides include aspartame.
• Amino acids include alanine and glycine, with glycine being preferred.
• Additives which may be included as minor components of the dry powder formulations of the invention, may be included for conformational stability during spray drying and for improving dispersibility of the powder. These additives include hydrophobic amino acids such tryptophan, tyrosine, leucine, phenylalanine, and the like.
• Suitable pH adjusters or buffers include organic salts prepared from organic acids and bases, such as sodium citrate, sodium ascorbate, and the like; sodium citrate is preferred.
• the present invention relates to concentrated macrolide formulations, such as a concentrated erythromycylamine formulation, suitable for efficacious delivery ofthe macrolide by aerosolization into endobronchial space.
• the invention is suitable for formulation of concentrated erythromycylamine for aerosolization by jet, vibrating porous plate, ultrasonic or dry powder nebulizers to produce erythromycylamine aerosol particle size between 1 and 5 ⁇ m preferable for efficacious delivery of erythromycylamine into the endobronchial space to treat Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus Moraxella catarrhalis and Legionella pneumonia, Chlamydia pneumoniae, and Mycoplasma pneumoniae infections.
• the formulations preferably contain minimal, yet efficacious amounts of erythromycylamine formulated in a relatively small volume of physiologically acceptable solution having a salinity, or a dry powder, adjusted to permit generation of an erythromycylamine aerosol that is well-tolerated by patients but preventing the development of secondary undesirable side effects such as bronchospasm and cough.
• the aerosol formulation is nebulized predominantly into particle sizes which can be delivered to the terminal and respiratory bronchioles where the Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, and Moraxella catarrhalis and the atypical bacteria Legionella pneumonia, Chlamydia pneumoniae, and Mycoplasma pneumoniae or other susceptible bacteria reside in patients with chronic bronchitis and pneumonia. Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, Moraxella catarrhalis, Legionella pneumonia, Chlamydia pneumoniae, and Mycoplasma pneumoniae are present throughout the airways including the bronchi, bronchioli and lung parenchema.
• the present invention provides a formulation that is delivered throughout the endobronchial tree to the terminal bronchioles and eventually to the parenchymal tissue. Aerosolized erythromycylamine formulation is formulated for efficacious delivery of erythromycylamine to the lung endobronchial space.
• a specific jet, vibrating porous plate or ultrasonic nebulizer is selected to allow the formation of an erythromycylarnine aerosol particles with a mass median aerodynamic diameter predominantly between 1 to 5 ⁇ m.
• the formulated and delivered amount of erythromycylamine is efficacious for treatment and/or prophylaxis of endobronchial infections, particularly those caused by the bacteria Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, and Moraxella catarrhalis and the atypical pneumonias Legionella pneumonia, Chlamydia pneumoniae, and Mycoplasma pneumoniae.
• the formulation has salinity adjusted to permit generation of erythromycylamine aerosol well tolerated by patients. Further, the formulation has suitable osmolarity.
• the formulation has a small aerosolizable volume and is able to deliver an effective dose of erythromycylamine to the site of the infection.
• the aerosolized formulation does not impair negatively the function of the airways by causing undesirable side effects.
• the antibiotic formulation may be administered with the use of an inhalation device having a relatively high rate of aerosol output, high emitted dose efficiency, and emission limited to periods of actual inhalation by the patient.
• inhalation devices useful for use in the practice ofthe present invention will typically exhibit a rate of aerosol output of not less that about 5 ⁇ l/sec, more preferably not less than about 6.5 ⁇ l/sec, and most preferably not less than about 8 ⁇ l/sec.
• conventional air-jet nebulizers have a relatively low emitted dose efficiency and typically release about 55% (or less) of the nominal dose as aerosol
• inhalation devices useful for use in the practice of the present invention will typically release at least about 75%, more preferably at least about 80% and most preferably at least about 85% of the loaded dose as aerosol for inhalation by the subject.
• conventional air-jet nebulizers typically continually release aerosolized drug throughout the delivery period, without regard to whether the subject is inhaling, exhaling or in a static portion of the breathing cycle, thereby wasting a substantial portion of the loaded drag dose.
• preferred inhalation devices for use in the present invention will be breath actuated, and restricted to delivery of aerosolized particles ofthe macrolide formulation to the period of actual inhalation by the subject.
• a representative inhalation device meeting the above criteria and suitable for use in the practice of the invention is the Aerodose TM inhaler, available from Aerogen, Inc., Sunnyvale, California.
• the Aerodose TM inhaler generates an aerosol using a porous membrane driven by a piezoelectric oscillator. Aerosol delivery is breath actuated, and restricted to the inhalation phase of the breath cycle, i.e., aerosolization does not occur during the exhalation phase ofthe breath cycle.
• the airflow path design allows normal inhale-exhale breathing, compared to breath-hold inhalers. Additionally, the Aerodose TM inhaler is a hand-held, self-contained, and easily transported inhaler. Although piezoelectric oscillator aerosol generators, such as the Aerodose TM inhaler, are presently preferred for use in the practice of the invention, other inhaler or nebulizer devices may be employed that meet the above performance criteria and are capable of delivering the small dosage volumes of the invention with a relative high effective deposition rate in a comparatively short period of time.
• unit dose formulations and devices are provided for administration of a macrolide antibiotic formulation to a subject with an inhaler, in accordance with the methods of the invention as described supra.
• Preferred unit dose devices comprise a container designed to hold and store the relatively small volumes ofthe macrolide antibiotic formulations ofthe invention, and to deliver the formulations to an inhalation device for delivery to a patient in aerosol form.
• unit dose containers ofthe invention comprise a plastic ampoule filled with a macrolide antibiotic formulation ofthe invention, and sealed under sterile conditions.
• the unit dose ampoule is provided with a twist-off tab or other easy opening device for opening of the ampoule and delivery of the macrolide antibiotic formulation to the inhalation device.
• Ampoules for containing drug formulations are well known to those skilled in the art (see, for example, U.S. Patent Nos. 5,409,125, 5,379,898, 5,213,860, 5,046,627, 4,995,519, 4,979,630, 4,951,822, 4,502,616 and 3,993,223, the disclosures of which are incorporated herein by this reference).
• the unit dose containers of the invention may be designed to be inserted directly into an inhalation device of the invention for delivery of the contained macrolide antibiotic formulation to the inhalation device and ultimately to the subject.
• a unit dose device comprising a sealed container containing less than about 5.0 ml, preferably less than about 3.0 ml and most preferably less than about 2.0 ml of a liquid macrolide antibiotic formulation comprising from about 50 to about 150 mg/ml of a macrolide antibiotic in a physiologically acceptable carrier, the sealed container being adapted to deliver the macrolide antibiotic formulation to an inhalation device for aerosolization.
• Suitable macrolide antibiotics for use in connection with this aspect of the invention include those macrolide antibiotics described in detail, supra.
• the macrolide antibiotic employed in the unit dose devices of the invention is erythromycylamine.
• the unit dose devices of the invention may contain a liquid macrolide antibiotic formulation comprising from about 70 to about 130 mg/ml of macrolide antibiotic. In yet other aspects of the invention, the unit dose devices of the invention may contain a liquid macrolide antibiotic formulation comprising from about 90 to about 110 mg/ml of macrolide antibiotic.
• the physiologically acceptable carrier may comprise a physiological saline solution such as a solution of one quarter strength of normal saline, having a salinity adjusted to permit generation of erythromycylamine aerosol well-tolerated by patients but to prevent substantially the development of secondary undesirable side effects such as bronchospasm and cough.
• a physiological saline solution such as a solution of one quarter strength of normal saline, having a salinity adjusted to permit generation of erythromycylamine aerosol well-tolerated by patients but to prevent substantially the development of secondary undesirable side effects such as bronchospasm and cough.
• dry powder formulations ofthe invention are placed within a suitable unit dose receptacle in an amount sufficient to provide a subject with a macrolide antibiotic compound of the invention for a unit dosage treatment by dry powder inhalation.
• Preferred dry powder unit dosage receptacles fit within a suitable inhalation device to allow for the aerosolization of the macrolide- based dry powder composition by dispersion into a gas stream to form an aerosol and then capturing the aerosol so produced in a chamber having a mouthpiece attached for subsequent inhalation by a subject in need of treatment.
• Such a dosage receptacle includes any container enclosing the formulations known in the art such as gelatin or plastic capsules with a removable portion that allows a stream of gas (e.g., air) to be directed into the container to disperse the dry powder formulation.
• a stream of gas e.g., air
• Such containers are exemplified by those shown in U.S. Patent Nos. 4,227,522, 4,192,309, and 4,105,027.
• Suitable containers also include those used in conjunction with Glaxo's Nentolin Rotohaler brand powder inhaler or Fison's Spinhaler brand powder inhaler.
• Another suitable unit-dose container which provides a superior moisture barrier is formed from an aluminum foil plastic laminate.
• the macrolide powder is filled by weight or by volume into the depression in the formable foil and hermetically sealed with a covering foil-plastic laminate.
• a container for use with a powder inhalation device is described in U.S. Pat. No. 4,778,054 and is used with Glaxo's Diskhaler.RTM. (U.S. Patent Nos. 4,627,432, 4,811,731; and 5,035,237). All of these references are incorporated herein by reference.
• a unit dose device comprising a sealed container containing a dry powder formulation comprising from about 25 to about 250 mg of a macrolide antibiotic, preferably from about 50 to about 200 mg of a macrolide antibiotic, and more preferably from about 75 to about 150 mg of a macrolide antibiotic in a physiologically acceptable dry powder carrier, the sealed container being adapted to deliver the macrolide antibiotic formulation to an inhalation device for aerosolization.
• the dry powder formulations may comprise from about 50% to about 90% by weight ofthe macrolide antibiotic, preferably from about 60% to about 88% by weight of the macrolide antibiotic, and more preferably from about 75% to about 85% by weight of the macrolide antibiotic.
• Liquid and dry powder formulations according to the invention contain from about 50 to about 750 mg, preferably from about 75 to about 600 mg, and most preferably from about 100 to about 500 mg of a macrolide antibiotic drug, such as erythromycylamine acetate, per dose.
• Presently preferred liquid aerosol erythromycylamine formulations according to the invention comprise from about 90 to about 110 mg of erythromycylamine sulfate per 1 mL of quarter normal saline. This corresponds to a representative efficacious amount of erythromycylamine to suppress bacterial infections of AECB.
• the erythromycylamine acetate, hydrochloride, and sulfate formulation containing 60-100 mg of erythromycylamine per ml of quarter normal saline has an osmolarity in the range of 130-400 mOsm/kg. This is within the safe range of aerosols administered to a chronic bronchitis patient (Table 1). TABLE 1
• the pH of the formulation is equally important for aerosol delivery. As noted previously, when the aerosol is either acidic or basic, it can cause bronchospasm and cough. The safe range of pH is relative; some patients will tolerate a mildly acidic aerosol that in others will cause bronchospasm. Any aerosol with a pH of less than 4.5 usually will induce bronchospasm in a susceptible individual; aerosols with a pH between 4.5 and 5.0 will occasionally cause this problem. An aerosol with a pH between 5.0 and 7.0 is considered to be safe. Any aerosol having pH greater than 10.0 is to be avoided since irritation resulting in bronchospasm may occur. The optimum pH for the aerosol formulation was determined to be between pH 5.0 and 7.0.
• liquid formulations of the invention are preferably nebulized predominantly into particle sizes allowing a delivery ofthe drag into the terminal and respiratory bronchioles and lower airways where the bacteria reside.
• aerosol particles having a mass median aerodynamic diameter predominantly between 1 to 5 ⁇ m is necessary.
• the formulated and delivered amount of erythromycylamine for treatment and prophylaxis of endobronchial infections particularly those caused by the bacteria Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, Moraxella catarrhalis, Legionella pneumonia, Chlamydia pneumoniae, and Mycoplasma pneumoniae, must effectively target the endobronchial surface.
• Delivered doses of the formulations preferably have the smallest practical aerosolizable volume able to deliver an effective dose of erythromycylamine to the site of the infection.
• Preferred formulations additionally provide conditions that do not adversely affect the functionality of the airways. Consequently, preferred formulations contain a sufficient amount of the drug formulated under conditions that allow its efficacious delivery, while avoiding undesirable reactions.
• the new formulations according to the invention meet all these requirements.
• erythromycylamine is formulated in a dosage form intended for inhalation therapy by patients with chronic bronchitis and pneumonia. Since the patients reside throughout the world, it is desirable that the formulation has reasonably long shelf life. Storage conditions and formulation stability thus become important.
• the pH of the solution is important.
• the formulation is typically stored in a one- to two-milliliter low-density polyethylene (LDPE) vials.
• LDPE low-density polyethylene
• the vials are aseptically filled using a blow-fill-seal process.
• the vials are sealed in foil overpouches.
• Aerosolization devices such as a jet, vibrating porous plate or ultrasonic nebulizers, useful in the practice of the invention are generally able to nebulize the formulation of the invention into aerosol particles predominantly in the range from 1- 5 ⁇ m. Predominantly in this application means that at least 70% but preferably more than 90% of all generated aerosol particles are within 1-5 ⁇ m range.
• Nebulizers such as jet, ultrasonic, vibrating porous plate, and energized dry powder inhalers, that can produce and deliver particles between the 1 and 5 ⁇ m particle size that is optimal for treatment of Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, Moraxella catarrhalis Legionella pneumonia, Chlamydia pneumoniae, and Mycoplasma pneumoniae infections, are currently available or can be produced using known methods and materials.
• a jet nebulizer works by air pressure to break a liquid solution into aerosol droplets.
• Vibrating porous plate nebulizers work by using a sonic vacuum produced by a rapidly vibrating porous plate to extrude a solvent droplet through a porous plate.
• An ultrasonic nebulizer works by a piezoelectric crystal that shears a liquid into small aerosol droplets.
• erythromycylamine can be efficiently nebulized by these three nebulizers, as these devices are sensitive to the pH and ionic strength ofthe formulation.
• nebulizers useful in the present invention include, for example, AeroNeb and AeroDose vibrating
• Erythromycylamine was very effective by both intravenous and aerosol administration. At the lowest dose tested (10 mg/kg per day) intravenous erythromycylamine reduced the lung burden of S. pneumonia to below the limits of detection (10 CFU/gram of lung) as shown in Example 7. Aerosol was also very effective (see Figure 10) with only detectable recovery of S. pneumonia at 5 mg/ml aerosol solution (calculated dose 0.13 mg/kg per day). In addition, erythromyclamine was very effective when administered as a single aerosol dose at concentrations greater than those required for single daily doses for 3 days.
• a single dose of 0.13 mg/kg was less effective (less than 2 orders of magnitude reduction in CFU/gram) compared with 0.13 mg/kg for three consecutive days (5 orders of magnitude reduction).
• a single dose of 0.67 mg/kg achieved almost complete clearance of the organism from lung tissue, an effect similar to the multiple dose efficacy indicating that at this concentration, the second and third doses added little value (see Figure 11).
• the pharmacokinetic evaluation of aerosolized erythromycylamine suggests, and the efficacy data indicates, that equivalent lung concentrations to multiple daily IN, oral, or aerosol doses can be achieved by a single aerosol dose and that the single dose would be about 3-5 fold greater than required for similar effectiveness as three daily doses.
• One aspect of the utility of this invention is that small volume, high concentration formulations of macrolide antibiotics, such as erythromycylamine, can be used with suitable nebulizers to deliver an efficacious dose of erythromycylamine to the endobronchial space in people with chronic bronchitis, bronchiectasis, and pneumonia caused by macrolide susceptible bacteria or other infections.
• the formulation is safe and very cost effective.
• the formulations may be kept in a nitrogen environment, with pH controlled for tolerance, to provide adequate shelf life for commercial distribution.
• sample 40 microliters for a 150 mg/mL solution, 50 microliters for a 100 mg/mL, or 100 microliters for a 60 mg/mL solution
• a 20 mL scintillation vial 10 mL of the diluent were added to the vial and mixed thoroughly.
• Standard Preparation Standards were prepared in duplicate and used for a maximum of three days. Ery-amine free base (30 mg) was transferred to a tared 50 mL volumetric flask and exact weight was recorded. Sample diluent (45 mL) is added and sonicated briefly to dissolve. The standard was cooled and diluted to volume with diluent.
• a 200 ⁇ L solution of erythromycylamine sulfate (25 mg/kg) was delivered to male Sprague-Dawley rats (Simonsen Laboratories, 1180 C Day Road, Gilroy, CA 95020) by intravenous administration via the lateral tail vein.
• Animals were anesthetized with 1-4% isoflurane and lung and blood samples were collected from 3 rats at 0.083, 0.25, 0.5 1, 2, 4, 6, 8 and 24 hours post dosing.
• the blood samples were collected via cardiac puncture using heparin as an anticoagulant.
• Lungs were removed surgically following blood sampling, and the bronchi and trachea were removed and discarded. The remaining lung tissue was processed as described below.
• Plasma samples 100 ⁇ g were spiked with oleandomycin (internal standard, 1 ⁇ g/mL) before extraction. Plasma samples (100 ⁇ L) were deproteinated with 3.3% trichloroacetic acid (TCA). Samples were centrifuged (10,000 rpm, 10 min.) and the supernatant was transferred to HPLC centrifilter for centrifiltration (10,000 rpm, 10 min).
• a stainless steel analytical column (Zorbax SB-C18, 2.1 mm ID x 150.0 mm, 5 ⁇ m with a Phenomenex cartridge guard column) was used as the stationary phase. The column temperature was 50° C. Quantification of the erytfiromycylamine was performed using a HP 1100 LC/MSD API- Electrospray System.
• Data acquisition was set in the selective ion monitoring mode.
• the method was linear (r>0.9990) in the concentration range of 0.01 to 50 ⁇ g/ml.
• the absolute recovery was 95.0 ⁇ 2.19%.
• Lung samples were homogenized with Dl water. Oleandomycin was added to the samples as an internal standard. The homogenate was deproteinated with 0.9 M TCA. Samples were centrifuged at 10,000 rpm for 10 minutes and the supernatant was transferred to HPLC centrifilters for centrifiltration.
• a stainless steel analytical column (Zorbax SB-C18, 2.1 mm ID x 150.0 mm, 5 ⁇ m with a Phenomenex cartridge guard column) was used as the stationary phase. The column temperature was 50° C. Quantification of the erythromycylamine was performed using a HP 1100 LC/MSD API-Electrospray System. Data acquisition was set in the selective ion monitoring mode. The linearity (r>0.9990) of the assay ranged from 0.1 to 200 ⁇ g/g. The extraction efficiency was 93.8 + 2.54%.
• Pharmacokinetic parameters area under the curve (AUC) and mean residence time (MRT), were estimated based on the statistical moment theory using WinNonlinTM Professional Version 2.0 software (Pharsight Corporation). The peak concentration (C ⁇ was not estimated but observed.
• Rats were exposed once to either 30 or 60 mg/mL solution of erythromycylamine sulfate via inhalation in a 32-port nose-only rodent exposure system (Battelle, Richland, WA) for 30 minutes.
• the Battelle system nose-only rodent exposure system is based on the Cannon Flow-Past Nose only system (Am. Ind Hyg Assoc J 1983 Dec;44(12)923-8) and is made up of four stackable stain-less steel tiers with a total of 32 ports.
• the system includes inlet and exhaust flow monitoring and control, aerosol data was collected using the NORES version 1.1.4 software provided by Battelle.
• Erythromycylamine solutions were aerosolized using the PARI LC STARTM nebulizer.
• Mean aerosol concentrations were determined by gravimetric analysis of filter samples taken at 10 and 20 minutes following the start of exposure. The mean aerosol concentrations were 0.54 ⁇ 0.06 and 1.36 ⁇ 0.30 mg/L, respectively, for 30 and 60 mg/mL solutions.
• Lung and blood samples were collected from 3 rats at 0.083, 0.25, 0.5 1, 2, 4, 8 and 24 hours post dosing as described above.
• the sample collection and handling procedures for the inhalation study were same as for the intravenous study.
• Bioanalytical assay procedures for the inhalation study were the same as for the intravenous study.
• the calculated deposited dose in the lung was approximately 0.70 or 1.77 mg/kg following an inhalation dose of 30 or 60 mg/mL erythromycylamine solution for 30 minutes, respectively.
• the pulmonary dose in the lung was calculated as follows:
• LDD MAC x MV x DE x FLD ⁇ MBW
• Erythromycylamine solutions are prepared in sterile saline. Antibiotic was administered either by intravenous injection into the tail vein or by aerosol exposure. The aerosol exposure was accomplished by nose-only exposure using the In-Tox Aerosol Exposure System (model No. 04-1100). This system is a closed aerosol delivery system designed to expose rodents that are confined in plastic tubes, open to the system at one end (nose port) and sealed at the other to maintain system integrity. The aerosol is generated by a Pari LC Star TM air-jet nebulizer at a flow of approximately 6.5 liters per minute. Vacuum is set at 9 liters per minute such that the total flow through the system with diluter air is 7.5 liters per minute.
• Example 7 Male Sprague-Dawley rats were infected and exposed to aerosol treatment as described in Example 7. The single treatment was initiated 24 hours after infection with aerosol administered at the doses indicated for 30 minutes. No further treatment was undertaken and animals were observed until surgery. On day four after infection (day 3 after dosing), the animals were sacrificed and their lungs were surgically removed. After removal, the lungs are homogenized, diluted and quantitatively plated onto blood agar. The plates are incubated for 24 hours and colonies of S. pneumoniae are counted to determine bacteria load. The results after a single dose administration are shown in Figure 11. Further results are shown in Table 6: Table 6
• the dogs were removed from their pen in the dog holding area and transferred to the dosing laboratory. During dosing the animals were either restrained by an animal attendant or in a sling/harness system. Inhalation dosing was undertaken using a closed facemask connected to a nebulizer that was suitably characterized prior to commencement of dosing.
• the dosing apparatus incorporates a facemask and mouthpiece attached to flexible tubing, which was connected to the nebulizer device.
• the mouthpiece was located inside the animal's mouth, on top of the tongue, and the facemask sealed around the dog's snout by means of a rubber sleeve.
• An exhaust valve from the mask was connected to an extract system.
• Lung samples were collected from 2 dogs at 2, 24, 48, 72, 96 and 120 hours post-dosing. Lungs were removed surgically from the dogs, and each lobe (right caudal, left caudal, right cranial, left cranial, right middle and accessory), was separated for assay. Plasma samples were collected from all surviving animals at 2, 24, 48, 72, 96 and 120 hours post. Erythromycylamine concentrations in plasma and the lung (per gram of lung tissue) were determined using a LC-MS method.
• Plasma samples (100 ⁇ g) were spiked with oleandomycin (internal standard, 1 ⁇ g/mL) before extraction. Plasma samples (100 ⁇ L) were deproteinated with 3.3% trichloroacetic acid (TCA). Samples were centrifuged (10,000 rpm, 10 min.) and the supernatant was transferred to HPLC centrifilter for centrifiltration (10,000 rpm, 10 min).
• oleandomycin internal standard, 1 ⁇ g/mL
• TCA trichloroacetic acid
• a stainless steel analytical column (Zorbax SB-C18, 2.1 mm ID x 150.0 mm, 5 ⁇ m with a Phenomenex cartridge guard column) was used as the stationary phase. The column temperature was 50°C. Quantification of erythromycylamine was performed using a HP 1100 LC/MSD API-Electrospray System. Data acquisition was set in the selective ion monitoring mode. The method was linear (r>0.9990) in the concentration range of 0.01 to 50 ⁇ g/ml. The absolute recovery was greater than 90%.
• a stainless steel analytical column (Zorbax SB-C18, 2.1 mm ID x 150.0 mm, 5 ⁇ m with a Phenomenex cartridge guard column) was used as the stationary phase.
• the column temperature was 50° C.
• Quantification of the erythromycylamine was performed using a HP 1100 LC/MSD API-Electrospray System. Data acquisition was set in the selective ion monitoring mode.
• the linearity (r>0.99) of the assay ranged from 2 to 100 ⁇ g/g for lung.
• the extraction efficiency was greater than 90%.
• Pharmacokinetic parameters area under the curve (AUC) and mean residence time (MRT) and half-life (T 1/2 ) were estimated based on the statistical moment theory using WinNonlinTM Professional Version 3.1 software (Pharsight Corporation). The peak concentration (C max ) was not estimated but observed.
• a solution of erythromycylamine sulfate (100 mg/mL) in quarter normal saline at pH 7.0 is prepared in accordance with the general procedure ofthe foregoing examples.
• a 1.0 mL dose ofthe solution is administered by aerosol inhalation in less than 10 minutes to a human subject suffering from acute exacerbation of chronic bronchitis (AECB) using an AeroGen Aerodose TM inhaler.
• AECB acute exacerbation of chronic bronchitis
• AeroGen Aerodose TM AeroGen Aerodose
• a dry powder formulation of erythromycylamine sulfate (100 mg) and a dry powder carrier (equal parts of lactose, 2-hydroxypropyl- ⁇ -cyclodextrin, mannitol and aspartame; ⁇ total weight 25mg) is prepared.
• the formulation is administered by aerosol inhalation in less than 2 minutes to a human subject suffering from acute exacerbation of chronic bronchitis (AECB) using a Glaxo Ventolin Rotohale TM inhaler. A reduction in the bacteria associated with AECB and symptoms of AECB is observed.

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