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
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system

Definitions

• the present invention is directed to a method of treating respiratory disorders by delivering antibiotic to the lung alveoli.
• Known aerosol drug delivery systems include, for example, a unit dose dry-powder inhaler, a dry powder pulmonary device, a pressurized metered dose inhaler, a metered-dose inhaler, a nebulizer, and the like.
• these systems have not been applied to delivery of antibiotics to the lungs to treat cystic fibrosis.
• Some aerosol devices are capable of delivering the smaller droplet sizes needed for deep lung penetration.
• One commercially available example is the SWIRLER ® aerosol drug delivery system which is described at amici-inc.com, and in U.S. Patents No. 5,603,314, 5,630,409, 5,611 ,332 and 6,230,703, which patents are incorporated by reference herein.
• the SWIRLER ® aerosol drug delivery system is an aerosol inhalation device that provides an aerosol mist to a patient.
• This device includes a nebulizer having a liquid reservoir containing the liquid to be inhaled, a gas inlet for receiving pressurized gas, and an aerosol outlet.
• An important feature of the device is a gas swirling or flow control means which creates a swirling action to the gas forming the aerosol; this produces a greater shear force and smaller particle sizes.
• the swirling gas creates a vacuum as it exits the outlet and this vacuum draws liquid form the reservoir, producing an aerosol.
• the device is capable of producing aerosol particles less than one micrometer in size.
• ZOSYN® is an injectable antibacterial combination product consisting of the semi- synthetic antibiotic piperacillin sodium and the (beta)-lactamase inhibitor tazobactam sodium for intravenous administration.
• the product is disclosed in U.S. Patent Nos. 4,562,073, 4,477,452, 4,534,977, and 6,207,661.
• Piperacillin sodium is derived from D(-)-(alpha)-aminobenzyl-penicillin.
• the chemical name of piperacillin sodium is sodium (2 S ,5 R ,6 R )-6-[( R )-2-(4-ethyl-2,3-dioxo-1- piperazine-carboxamido ⁇ -phenylacetamidol-S.S-dimethyl ⁇ -oxo ⁇ -thia-i- azabicyclo[3.2.0]heptane-2-carboxylate.
• the chemical formula is C 2 3 H 2 ⁇ N s NaO 7 S and the molecular weight is 539.5.
• the product is disclosed in U.S. Patent No. 4,562,073.
• Tazobactam sodium a derivative of the penicillin nucleus, is a penicillanic acid sulfone. Its chemical name is sodium (2 S ,3 S ,5 R )-3-methyl-7-oxo-3-(1 H -1,2,3- triazol-1 -ylmethyl)-4-thia-1 -azabicyclo ⁇ .Olheptane ⁇ -carboxylate ⁇ -dioxide.
• the chemical formula is C 10 H n N 4 NaO 5 S and the molecular weight is 322.3.
• the product is disclosed in U.S. Patent No. 4,958,020.
• TYGACIL® is a first in class glycylcycline antibacterial disclosed in U.S. patent number 5,494,903.
• the chemical name of tigecycline is (4S,4aS,5aR,12aS)- 9-[2-(teAt-butylamino)acetamido3-4,7-bis(dimethylamino)-1,4,4a,5,5a I 6,11,12a- octahydro-3, 10, 12, 12a-tetrahydroxy-1 , 11 -dioxo-2-naphthacenecarboxamide.
• the empirical formula is 0 29 H 39 N 5 O 8 and the molecular weight is 585.65.
• Tigecycline has an expanded spectrum of activity against gram positives, gram negatives, anaerobes, and atypicals including resistant pathogens, and allows for flat dosing.
• the product is disclosed in U.S. Patent Nos. 5,494,903, 5,299,900, and 5,284,963.
• the present invention relates to a method of treating respiratory disorders comprising administering an antibiotic aerosol to a mammal via an aerosol drug delivery system wherein the aerosol drug delivery system produces an antibiotic particle size of at least about 90%, preferably at least about 95%, of the particles in the aerosol of about 1-3 microns or less, thereby allowing the antibiotic aerosol to reach the alveoli of the lung.
• the antibiotic is delivered at a particle size of less than 1.1 microns.
• the method above is used for treating a respiratory disorder such as, but not limited to, cystic fibrosis.
• the aerosol drug delivery system can be for example a unit dose dry-powder inhaler, a dry powder pulmonary device, a pressurized metered dose inhaler, a metered-dose inhaler, a nebulizer, or any suitable aerosol drug delivery system as described in Guidelines for the Diagnosis and Management of Asthma, National Asthma
• the antibiotic aerosol may comprise an antibiotic and a diluent.
• the diluent can be for example sterile water for Injection, 0.9% sodium chloride for injection, 5% dextrose for injection, 5% dextrose and 0.9% sodium chloride for injection, 5% dextrose in lactated Ringers for injection, 5% dextrose-0.45% sodium chloride-0.15% potassium chloride for injection and lactated Ringers for injection.
• the antibiotic aerosol comprises a particle size range of 600 particles of > 25 microns and not more than 6000 particles >10 microns.
• Antibiotics of the present invention include anti-infective agents known in the art, such as those found in the current Physician's Desk Reference published by Medical Economics Company (www.pdr.nett and hereby incorporated by reference, and include but are not limited to ZOSYN ®, Piperacillin, Tazobactam, and TYGACI L®.
• the antibiotic can be administered alone or in combination with other antibiotics. At least one of the antibiotics is administered in an aerosol medium composition. Additional antibiotics may be administered orally, or by intralesional, intraperitoneal, intramuscular or intravenous injection; infusion; liposome-mediated delivery; topical, nasal, anal, vaginal, sublingual, uretheral, transdermal, intrathecal, ocular or otic delivery.
• a compound of the invention is in the form of a unit dose.
• Suitable unit dose forms include tablets, capsules and powders in sachets or vials.
• Such unit dose forms may contain from 0.1 to 300 mg of a compound of the invention, and preferably from 2 to 100 mg.
• Still further preferred unit dosage forms contain 5 to 50 mg of a compound of the present invention.
• the effective amount will be known to one of skill in the art; it will also be dependent upon the form of the compound.
• One of skill in the art could routinely perform empirical activity tests to determine the bioactivity of the compound in bioassays and thus determine what dosage to administer.
• the present invention relates to an aerosol medium composition containing an antibiotic.
• the aerosol medium composition may comprise diluents such as sterile water for Injection, 0.9% sodium chloride for injection, 5% dextrose for injection, 5% dextrose and 0.9% sodium chloride for injection, 5% dextrose in lactated Ringers for injection, 5% dextrose-0.45% sodium chloride-0.15% potassium chloride for injection or lactated Ringers injection.
• the antibiotic is suspended in the aerosol medium at a particle size range that will meet the subvisible particulate testing acceptance criteria as per USP 788 viz. not more than 600 particles > 25 microns and not more than 6000 particlesMO microns.
• the aerosol drug delivery system described herein can be but is not limited to delivery in small, disposable, unit dose dry-powder inhalers (DPI's), dry powder pulmonary devices, pressurized metered dose inhalers (pMDI's), metered-dose inhaler (MDI) or a nebulizer.
• DPI's dry-powder inhalers
• pMDI's pressurized metered dose inhalers
• MDI metered-dose inhaler
• nebulizer nebulizer
• Piperacillin (2 g - 4g lyophilized powder per vial) and at least one intravenous diluent for example but not limited to sterile water for injection, 0.9% sodium chloride injection, 5% dextrose injection, 5% dextrose and 0.9% sodium chloride injection, 5% dextrose in Lactated Ringers injection, 5% dextrose-0.45% sodium chloride-0.15% potassium chloride injection or lactated Ringers injection will be administered using an aerosol drug delivery system at a particle size of 95% particles ranging from 1-3 microns, and preferably less than 1.1 microns, to ensure deep lung delivery to the alveolar region of the lungs.
• intravenous diluent for example but not limited to sterile water for injection, 0.9% sodium chloride injection, 5% dextrose injection, 5% dextrose and 0.9% sodium chloride injection, 5% dextrose in Lactated Ringers injection, 5% dextrose-0.45% sodium chloride-0.15% potassium chloride injection
• Tazobactam (0.25 g - 0.50 g lyophilized powder per vial) and at least one intravenous diluent, for example but not limited to sterile water for injection, 0.9% sodium chloride injection, 5% dextrose injection, 5% dextrose and 0.9% sodium chloride injection, 5% dextrose in Lactated Ringers injection, 5% dextrose-0.45% sodium chl ⁇ ride-0.15% potassium chloride injection or lactated Ringers injection will be administered using an aerosol drug delivery system at a particle size of 95% particles ranging from 1-3 microns, and preferably less than 1.1 microns, to ensure deep lung delivery to the alveolar region of the lungs.
• intravenous diluent for example but not limited to sterile water for injection, 0.9% sodium chloride injection, 5% dextrose injection, 5% dextrose and 0.9% sodium chloride injection, 5% dextrose in Lactated Ringers injection, 5% dextrose-0.45%
• ZOSYN® (2-4 g piperacillin plus 250-500mg tazobactam) and at least one intravenous diluent, for example but not limited to sterile water for injection, 0.9% sodium chloride injection, 5% dextrose injection, 5% dextrose and 0.9% sodium chloride injection, 5% dextrose in Lactated Ringers injection, 5% dextrose-0.45% sodium chtoride-0.15% potassium chloride injection or lactated Ringers injection will be administered using an aerosol drug delivery system at a particle size of 95% particles ranging from 1-3 microns, and preferably less than 1.1 microns, to ensure deep lung delivery to the alveolar region of the lungs.
• intravenous diluent for example but not limited to sterile water for injection, 0.9% sodium chloride injection, 5% dextrose injection, 5% dextrose and 0.9% sodium chloride injection, 5% dextrose in Lactated Ringers injection, 5% dextrose-0.45% sodium
• Tygacil 50mg lyophilized powder per 5ml_ vial
• at least one intravenous diluent for example but not limited to sterile water for injection, 0.9% sodium chloride injection, 5% dextrose injection, 5% dextrose and 0.9% sodium chloride injection, 5% dextrose in Lactated Ringers injection, .5% dextrose-0.45% sodium chloride-0.15% potassium chloride injection or lactated Ringers injection will be administered using an aerosol drug delivery system at a particle size of 95% particles ranging from 1-3 microns, and preferably less than 1.1 microns, to ensure deep lung delivery to the alveolar region of the lungs.
• Tygacil ® 2 nd Generation product was used to conduct the study. Sterile Water for injection and 0.9 % Normal Saline were used at diluents.
• Tygacil ® is a sterile, lyophilized powder for intravenous infusion, containing 53 mg of the Tigecycline active ingredient.
• the product is supplied in a single dose; Type I, clear, glass vial, sealed under a blanket of nitrogen with a gray butyl rubber stopper and a snap-off aluminum crimp seal.
• Tigecycline for Injection is an orange powder or cake.
• Tygacil ® was reconstituted using 100 ml of 0.9 % Sodium Chloride (Normal Saline) or Sterile Water for Injection USP.
• the Tigecycline powder was allowed to dissolve in the diluents. A clear yellow to orange solution was obtained.
• the solution was then transferred into the SW IRLER ® device. Oxygen was supplied to the SW IRLER ® via an NG tube to aerosolize the solution.
• An oxygen air pressure regulator was used to set.the air pressure to 15 CFM.
• a Malvern MXS, S/N 6196 was used to measure the particle size of the droplets. Results show a high percentage (90%) of the particles are less than 1.1 micron which is the desired size for deep lung delivery. Data are reported in Table 2 below:
• Table 2 Particle Size distribution of Tygacil ® reconstituted with Normal Saline or Sterile Water for Injection and administered through a SWIRLER ® for Deep Lung Delivery

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Cited By (8)

Citations (5)

• 2007
  • 2007-06-01 PE PE2007000682A patent/PE20080329A1/es not_active Application Discontinuation
  • 2007-06-01 WO PCT/US2007/013071 patent/WO2007145868A1/en active Application Filing
  • 2007-06-05 TW TW096120125A patent/TW200815002A/zh unknown
  • 2007-06-07 AR ARP070102453A patent/AR061262A1/es unknown

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