WO2006033713A2

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Publication number: WO2006033713A2
Application number: PCT/US2005/028102
Authority: WO
Inventors: Johnny Lai; Allan Wagman; Pete Challoner; Ribhi Shawar; Andy Towell; Rahul Tak; Kay Huh
Original assignee: Chiron Corporation
Priority date: 2004-08-09
Filing date: 2005-08-09
Publication date: 2006-03-30
Also published as: WO2006033713A3

Abstract

The present invention relates to dry power inhaled formulations containing ciprofloxacin for increased efficacy and decreased toxicity in treating microbial infections.

Description

METHODS FOR CIPROFLOXACIN INHALATION

FIELD OF THE INVENTION

[0001] The present invention relates to dry powder inhaled formulations containing ciprofloxacin for increased efficacy and decreased toxicity in treating microbial infections.

BACKGROUND OF THE INVENTION

[0002] 1 -cyclopropyl-ό-fluoro- 1 ,4-dihydro-4-oxo-7-( 1 -piperazinyl)-3 -quinoline carboxylic acid (also known as ciprofloxacin) belongs to the fluoroquinolone class of antibiotics, which are known to possess a broad antibacterial spectrum against both Gram positive and Gram negative bacteria, in particular against Enterobacteriaceae. (See e.g., U.S. Pat. Nos. 4,284,629, 4,499, 091, 4,704,459, 4,668,784, 4,670,444, 5,286,754, and 5,840,333).

[0003] Use of fluoroquinolones as antimicrobial agents has distinct advantages over the use of other antibiotics (e.g., penicillins, cephalosporins, aminoglycosides, sulphonamides and tetracyclines) in that fluoroquinolones have not been shown to induce the same bacterial tolerance or resistance as said antibiotics. Specifically, ciprofloxacin has been shown to have low toxicity to humans, although systemic accumulation due to higher doses required for certain modes of administration, such as intravenous administration, can be problematic.

[0004] Delivering concentrations of fluoroquinolines substantially above the MIC to the site of an infection is expected to improve treatment of an infection by improving antibacterial activity as observed in in vitro and clinical research. Zhanel, G., et at A critical review of the fluoroquinolones: Focus on respiratory tract infections, Drugs 2002, 62(1), 13-59.

[0005] Fluoroquinolones kill bacteria in a concentration-dependent manner, therefore higher concentrations of fluoroquinolones lead to improved antibacterial activity in vitro and in vivo. The rate and extent of bactericidal activity increases proportionately as the drug concentration is increased, even at concentrations well above the MIC of the target bacteria. In human studies, larger C_max/MIC or AUCo_to24/MIC (AUIC₂₄) ratios correlate well with positive clinical outcomes and i microbiological eradication. Hyatt, J. et al. The importance of pharmacokinetic/pharmacodynamic surrogate markers to outcome: Focus on antibacterial agents, Clinical Pharmacokinetics 1995, 28(2), 143-60.

[0006] Higher concentrations of fluoroquinolones above the MIC (termed the mutant prevention concentration (MPC)) can reduce the possibility for selection of antibacterial-resistance mutations in vitro, and may prevent mutant selection. Zhao, X, et al. Restricting the selection of antibiotic-resistant mutants: A general strategy derived from fluoroquinolone, Clinical Infectious Diseases 2001, 33(Suppl. 3), S147-S156 andDrlica, K. The future of fluoroquinolones, Annals of Medicine (Helsinki) 2000, 32(9), 585-587. The antibiotic activity of fluoroquinolones is derived from inhibition of two independent bacterial enzymes, topoisomerase IV and DNA gyrase. Genetic resistance mutations can occur in either topoisomerase IV or DNA gyrase, resulting in low to moderate loss of fluoroquinolone susceptibility. Bacterial resistance selection is much more likely when bacteria are exposed to suboptimal or sub-MIC levels of drug. Mutations in both targets can occur which result in bacteria that are highly resistant to fluoroquinolones. However, simultaneous acquisition of multiple resistance mutations is a rare genetic event. Studies indicate that bacterial fluoroquinolone resistance mutations typically occur in a stepwise manner. The MPC is set at the concentration (typically 2-10 fold above the MIC), which will inhibit the growth of most or all susceptible and moderately resistant bacteria, those with a single-step mutation. Treating bacteria at high concentrations, such as, at or above the MPC, rapidly reduces the number of bacterial cells, both susceptible and moderately resistant. Due to the infrequency of fluoroquinolone chromosomal resistance mutations (10^'7 to 10^"10 for fluoroquinolones in S. pneumoniae), statistically there are too few growing cells to quickly select for resistance mutations as observed during in vitro experiments. Blondeau, J. et al. Mutant prevention concentrations of fluoroquinolones for clinical isolates of Streptococcus pneumoniae, Antimicrobial Agents and Chemotherapy 2001, 45(2), 433-438.

[0007] Although administering doses of fluoroquinolones to humans at or above the MPC has not been specifically investigated in clinical trials, treatment of an infection at or above the MPC is expected to reduce the propensity for development of antibacterial resistance during acute or chronic treatment of infections. Clinical reports indicate that higher doses of fluoroquinolones do result in improved treatment outcomes and suppression of bacterial resistance. For example, in a recent clinical study of critically ill patients with nosocomial lower respiratory tract infections caused by Gram-negative bacilli (e.g. P. aeruginosa), data indicates that treatment using ciprofloxacin at C_max/MIC ratios of 10:1 and AUIC₂₄ ratios of 100- 125 maximizes bacterial eradication, thereby preventing the emergence of resistant bacteria during treatment. Forrest A. et al. Pharmacodynamics of intravenous ciprofloxacin in seriously ill patients, Antimicrobial Agents Chemother. 1993, 37(5), 1073-81.

[0008] While high dose fluoroquinolone treatment regiments lead to improved clinical outcomes, the mode of administration (either IV or PO) leads to high systemic exposure and increased incidence of adverse side effects. Delivering high concentrations of fluoroquinolones to a local site of infection should provide a benefit in treatment outcome while reducing toxic side effects if this mode of administration lowers systemic exposure in patients.

[0009] The lungs act as a portal to the body by means of uptake of materials by cells of the lung, such as alveolar macrophages. As a result antiinfective agents, such as antibacterial and antiviral agents, can be administered through the lung portal. Such systematic treatment can avoid hepatic first pass inactivation and allow for lower doses with fewer side effects. Inhalation can specifically be used to treat pulmonary infections, and more particularly intracellular infections that involve uptake, persistence and transport of the bacteria by the pulmonary macrophages of the lungs. The administration of ciprofloxacin for treatment of infection by inhalation is particularly attractive for several reasons. Firstly, inhalation is a more localized administration method and can therefore be more effective in terms of timing and concentration of drag reaching the infection while avoiding undesired toxicity due to systemic exposure. Further, inhalation can be easier to use. In some instances ciprofloxacin can even be self-administered by inhalation, which tends to improve patient compliance and reduce costs.

[0010] A method of preparing ciprofloxacin-loaded bovine serum albumin microspheres is disclosed in J. Microencapsul. 2001 Nov-Dec; 18(6):825-9. It is suggested that these microspheres could be administered through a dry powder inhaler and result in attenuated dissolution profiles due to the slow degradation of the microspheres. The postulated advantage for a low dissolution rate was to overcome the unfavorable pharmacokinetic profile in the lower respiratory tract, typically associated with oral or IV modes of administration. No in vivo trials were ever reported to test their theory, however the lower dissolution profile could actually be problematic in that much of the particulate may be cleared from the lungs prior to release of ciprofloxacin, subsequently being released in downstream tissue regions outside of the lungs. It would be preferable to formulate a composition that delivers targeted highly concentrated quantities of ciprofloxacin to the site of infection.

[0011] Therefore, a goal of the immediate invention is to administer high, localized doses of ciprofloxacin while avoiding systemic exposures that lead to toxic events, such as gastrointestinal disturbances, CNS effects (dizziness and headache), cardiovascular effects (prolongation of QTc interval), phototoxicity, injection site reaction and arthropathy in pediatric patients. Aggressive treatment of respiratory infections by pulmonary delivery of ciprofloxacin should have a much improved safety profile.

[0012] The present invention overcomes the disadvantages of conventional modes of ciprofloxacin administration by dry powder inhalation and offers new advantages that can enhance its therapeutic index.

BRIEF DESCRIPTION OF THE DRAWINGS

[0013] Figure 1: PK study findings with lung and plasma concentration versus time of ciprofloxacin dry powder inhalation and IV administration, demonstrating that dry powder inhalation results in five times the lung-to-plasma AUC ratio of ciprofloxacin compared to a human equivalent IV dose of 25 mg/kg (data shown in Table 1). The plasma levels and AUC were approximately 2.5 times lower by dry powder inhalation than by IV.

[0014] Figure 2: The liquid aerosol inhalation PK results with lung and plasma concentration versus time of ciprofloxacin liquid aerosol and dry powder inhalation, demonstrating that one can achieve a higher lung deposition per dosing time (30 minutes) using the dry powder formulation (1.3 mg/kg) than with a liquid aerosol (0.67 mg/kg).

[0015] Figure 3: Efficacy studies of ciprofloxacin intravenous treatment of rats with infection established using E. coli embedded in agarose beads through IV administration. The x-axis corresponds to dosage of Ciprofloxacin. [0016] Figure 4: Efficacy studies of ciprofloxacin liquid aerosol exposure to rats for 30 minutes with infection established using E. coli embedded in agarose beads through IV administration. The x-axis corresponds to dosage of Ciprofloxacin.

[0017] Figure 5: Efficacy studies of ciprofloxacin dry powder aerosol exposure to rats with infection established using E. coli embedded in agarose beads through IV administration. The x-axis corresponds to dosage of Ciprofloxacin.

[0018] Figure 6: Efficacy studies of ciprofloxacin intravenous treatment of rats with infection established using E. coli embedded in agarose beads through IT administration. The x-axis corresponds to dosage of Ciprofloxacin.

[0019] Figure 7: Efficacy studies of ciprofloxacin dry powder aerosol exposure of rats with infection established using E. coli embedded in agarose beads through IT administration. The x-axis corresponds to dosage of Ciprofloxacin.

SUMMARY OF THE INVENTION

[0020] The present invention provides for dry powder inhaled ciprofloxacin compositions suitable for drug delivery. The composition may be delivered alone or with other salts and/or excipients. The compositions and methods of administration described herein have superior properties beyond existing methods know in the art. [0021] One embodiment of the invention provides a dispersible dry powder antimicrobial composition comprising 55.0 - 99.9 % by weight of l-cyclopropyl-6- fluoro-l,4-dihydro-4-oxo-7-(l-piperizinyl)-3-quinolinecarboxylic acid; or a pharmaceutically acceptable salt thereof.

[0022] A further embodiment of the invention provides a method of treating a patient with a microbial infection comprising: providing a dispersible dry powder composition comprising l-cyclopropyl-6- fluoro-l,4-dihydro-4-oxo-7-(l-piperizinyl)-3-quinolinecarboxylic acid, or a pharmaceutically acceptable salt thereof; loading said composition into a dry powder inhaler; inhaling the composition from said dry powder inhaler, wherein upon inhalation said patient is treated for the microbial infection.

[0023] Another embodiment of the invention provides a method of administering 1- cyclopropyl-6-fluoro-l,4-dihydro-4-oxo-7-(l-piperizinyl)-3-quinolinecarboxylic acid; or a pharmaceutically acceptable salt thereof, comprising: a) providing a dispersible dry powder composition comprising 1-cyclopropyl- 6-fluoro-l,4-dihydro-4-oxo-7-(l-piperizinyl)-3-quinolinecarboxylic acid, or a pharmaceutically acceptable salt thereof; b) administering said dry powder composition to a patient by inhalation from a dry powder inhaler; and c) obtaining a dry powder AUC value corresponding to said concentrations of 1 -cyclopropyl-ό-fluoro- 1 ,4-dihydro-4-oxo-7-( 1 -piperizinyl)-3 - quinolinecarboxylic acid in said plasma.

[0024] Another embodiment of the invention provides a method of treating a patient having an endobronchial infection comprising administering a therapeutically effective amount of inhaled dry powder composition comprising, 1 -cyclopropyl-ό- fluoro- l,4-dihydro-4-oxo-7-(l-piperizinyl)-3-quinolinecarboxyric acid, or a pharmaceutically acceptable salt or excipient thereof.

[0025] Another embodiment of the invention provides a method of administering 1- cyclopropyl-6-fluoro-l,4-dihydro-4-oxo-7-(l-piperizinyl)-3-quinolinecarboxylic acid; or a pharmaceutically acceptable salt thereof, comprising: a) providing a dispersible dry powder composition comprising l-cyclopropyl-6- fluoro-l,4-dihydro-4-oxo-7-(l-piperizinyl)-3-quinolinecarboxyric acid, or a pharmaceutically acceptable salt thereof; b) administering said dry powder composition to a subject by inhalation from a dry powder inhaler; and c) monitoring concentrations of l-cyclopropyl-6-fluoro-l,4-dihydro-4-oxo-7-(l- piperizinyl)-3-quinolinecarboxylic acid, or a pharmaceutically acceptable salt thereof in lungs and human plasma of said subject to produce a lung concentration value, a plasma concentration value, and a ratio of lung concentration to plasma concentration, wherein the ratio of lung concentration to plasma concentration is greater than 1.2.

[0026] Another embodiment provides a dispersible dry powder antimicrobial composition comprising l-cyclopropyl-6-fluoro-l,4-dihydro-4-oxo-7-(l- piperizinyl)-3-quinolinecarboxylic acid; or a pharmaceutically acceptable salt thereof, having an AUC₂₄ZMIC ratio less than about 10.

[0027] Additionally, methods of preparation and manufacture of a dispersible dry powder antimicrobial composition comprising l-cyclopropyl-6-fluoro-l,4-dihydro- 4-oxo-7-(l-piperizinyl)-3-quinolinecarboxylic acid; or a pharmaceutically acceptable salt or excipient thereof are provided.

[0028] Further embodiments of the invention include those described in the detailed description.

DETAILED DESCRIPTION

[0036] A further embodiment of the invention provides a method of treating a patient with a microbial infection comprising: providing a dispersible dry powder composition comprising l-cyclopropyl-6- fluoro-l,4-dihydro-4-oxo-7-(l-piperizinyl)-3-quinolinecarboxylic acid, or a pharmaceutically acceptable salt thereof; loading said composition into a dry powder inhaler; inhaling the composition from said dry powder inhaler, wherein upon inhalation said patient is treated for the microbial infection.

[0040] In a more particular embodiment of said method of treating a patient with a microbial infection, said step of inhaling the composition from said dry powder inhaler results in an emitted dose greater than 50%, or greater than 60%, or greater than 70%, or greater than 80%, or greater than 90%.

[0041] In a more particular embodiment of said method of treating a patient with a microbial infection, said dry powder inhaler has a resistance less than about 0.6 cm H₂O⁰⁵ZLPM, or less than about 0.5 CmH₂O °⁵ZLPM, or less than about 0.4 CmH₂O^α5/LPM, or less than about 0.2 cm H₂O⁰⁵ZLPM, or less than about 0.1 cm H₂O⁰⁵ZLPM, or less than about 0.08 CmH₂O⁰⁵ZLPM.

[0042] In a more particular embodiment of said method of treating a patient with a microbial infection, said dry powder inhaler has a flow rate between about 20 and about 90 LPM, or about 20 and about 80 LPM, or about 30 and about 80 LPM, or about 40 and about 80 LPM, or about 50 and about 80 LPM, or about 20 and about 70 LPM, or about 20 and about 60 LPM, or about 20 and about 50 LPM, or about 30 and about 70 LPM, or about 40 and about 60 LPM, or about 45 and about 60 LPM.

[0043] In a more particular embodiment of said method of treating a patient with a microbial infection, said dry powder inhaler is a passive dry powder inhaler.

[0044] Another embodiment provides a method of treating a patient suffering from an endobronchial infection comprising administering a compound of embodiment 1.

[0045] Another embodiment of the invention provides a method of administering 1- cyclopropyl-6-fluoro-l,4-dihydro-4-oxo-7-(l-piperizinyl)-3-quinolinecarboxylic acid; or a pharmaceutically acceptable salt thereof, comprising: a) providing a dispersible dry powder composition comprising 1-cyclopropyl- 6-fluoro-l,4-dihydro-4-oxo-7-(l-piperizinyl)-3-quinolinecarboxylic acid, or a pharmaceutically acceptable salt thereof; b) administering said dry powder composition to a patient by inhalation from a dry powder inhaler; c) obtaining a dry powder AUC value corresponding to said concentrations of l-cyclopropyl-6-fluoro-l,4-dihydro-4-oxo-7-(l-piperizinyl)-3- quinolinecarboxylic acid in said plasma. [0046] A more particular embodiment thereof comprises a step of comparing a dry powder AUC value with an IV AUC value obtained by intravenously administering an equivalent amount of l-cyclopropyl-6-fluoro-l,4-dihydro-4-oxo-7-(l- piperizinyl)-3-quinolinecarboxylic acid, wherein said dry powder AUC value is less than the IV AUC value.

[0047] In another embodiment said step of inhaling the composition from said dry powder inhaler results in an emitted dose greater than 70%.

[0048] In another embodiment said dry powder inhaler has a resistance less than about 0.4 CmH₂O⁰⁵/LPM.

[0049] In another embodiment said dry powder inhaler has a flow rate between about 30 and about 80 LPM.

[0050] In another embodiment said dry powder inhaler is a passive dry powder inhaler.

[0051] Another embodiment of the invention provides a method of treating a patient having an endobronchial infection comprising administering a therapeutically effective amount of an inhaled dry powder composition comprising, 1-cyclopropyl- 6-fluoro-l,4-dihydro-4-oxo-7-(l-piperizinyl)-3-quinolinecarboxylic acid, or a pharmaceutically acceptable salt or excipient thereof.

[0052] In another more particular embodiment, said inhaled dry powder composition yields a dry powder AUC value which is less than an IV AUC value obtained from intravenously administering l-cyclopropyl-6-fluoro-l,4-dihydro-4-oxo-7-(l- piperizinyl)-3-quinolinecarboxylic acid.

[0053] A more particular embodiment is provided wherein said composition is administered in a subtherapeutic blood concentration.

[0054] A more particular embodiment is provided wherein said composition comprises at least 55.0 % by weight l-cyclopropyl-β-fluoro-l^-dihydro^-oxo^-Cl- piperizinyl)-3-quinolinecarboxylic acid, or a pharmaceutically acceptable salt thereof.

[0055] A more particular embodiment is provided wherein said dry powder AUC value is less than³A the IV AUC value. A more particular embodiment is provided wherein said dry powder AUC value is less than Vz the IV AUC value. A more particular embodiment is provided wherein said dry powder AUC value is less than VA the IV AUC value.

[0056] In another embodiment said composition further comprises an excipient selected from the group consisting of hydrophobic amino acids, water soluble polypeptides, and phospholipids. In a more particular embodiment still, said excipient is leucine. [0057] In another embodiment said composition consists of particles having a geometric diameter and a mass median aerodynamic diameter less than 5.0 microns and a residual moisture content of less than 5.0 % by weight. [0058] In another embodiment the inhalation of the composition is from a dry powder inhaler and results in an emitted dose greater than 70%. [0059] In another embodiment (upon inhalation of ciprofloxacin) the resulting C_max in the patient is less than 2.5 ug/mL, or 1.25 ug/mL, or 0.75 ug/mL, or 0.25 ug/mL. [0060] In another embodiment (upon inhalation of ciprofloxacin) the resulting C_ss in the patient is less than 2.5 ug/mL, or 1.25 ug/mL, or 0.75 ug/mL, or 0.25 ug/mL. [0061] Another embodiment of the invention provides a method of administering 1- cyclopropyl-6-fluoro-l,4-dihydro-4-oxo-7-(l-ρiperizinyl)-3-quinolinecarboxylic acid; or a pharmaceutically acceptable salt thereof, comprising: a) providing a dispersible dry powder composition comprising l-cyclopropyl-6- fluoro-l,4-dihydro-4-oxo-7-(l-piperizinyl)-3-quinolinecarboxylic acid, or a pharmaceutically acceptable salt thereof; b) administering said dry powder composition to a subject by inhalation from a dry powder inhaler; wherein, the administration of the dispersible dry powder results in a ratio of lung concentration to plasma concentration that is greater than 1.2.

[0063] Another embodiment provides a dispersible dry powder antimicrobial composition comprising l-cyclopropyl-6-fluoro-l ,4-dihydro-4-oxo-7-(l- piperizinyl)-3-quinolinecarboxylic acid; or a pharmaceutically acceptable salt thereof, having a AUC₁₂ value below about 10 ug hr/ml when given in a dose of between 400 and 600 mg, or 300 and 600 mg, or 200 and 500 mg, or 300 and 400 mg, or 350 and 400mg, or 500 and 600 mg, or 400 and 500 mg, or 400 and 450 mg, or 200 and 300 mg, or 250 and 300mg, or 100 and 200mg, or 150 and 200mg, or 100 and 300 mg, or 50 and 100 mg.

[0064] Another embodiment provides a dispersible dry powder antimicrobial composition comprising l-cyclopropyl-6-fluoro-l,4-dihydro-4-oxo-7-(l- piperizinyl)~3-quinolinecarboxylic acid; or a pharmaceutically acceptable salt thereof, having a AUC₁₂ value below about 5 ug hr/ml when given in a dose of between 400 and 600 mg, or 300 and 600 mg, or 200 and 500 mg, or 300 and 400 mg, or 350 and 400mg, or 500 and 600 mg, or 400 and 500 mg, or 400 and 450 mg, or 200 and 300 mg, or 250 and 300mg, or 100 and 200mg, or 150 and 200mg, or 100 and 300 mg, or 50 and 100 mg.

[0065] In a more particular embodiment thereof, the AUC₁₂ is below 25, or 24, or 23, or 22, or 21, or 20, or 19, or 18, or 17, or 16, or 15, or 14, or 13, or 12, or 11, or 10, or 9, or 8, or 7, or 6, or 5, or 4, or 3, or 2, or 1, or 0.5, or 0.25, or 0.125 ug hr/ml.

[0066] Another embodiment provides a dispersible dry powder antimicrobial composition comprising l-cyclopropyl-6-fluoro- 1 ,4-dihydro-4-oxo-7-(l- piperizinyl)-3-quinolinecarboxylic acid; or a pharmaceutically acceptable salt thereof, having a AUC₂₄ value below about 20 ug hr/ml when given in a dose of between 400 and 600 mg, or 300 and 600 mg, or 300 and 500 mg, or 300 and 400 mg, or 350 and 400mg, or 500 and 600 mg, or 400 and 500 mg, or 400 and 450 mg, or 200 and 300 mg, or 250 and 300mg, or 100 and 200mg, or 150 and 200mg, or 100 and 300 mg, or 50 and 100 mg. [0067] In a more particular embodiment thereof, the AUC₂₄ is below 35, or 30, or 25, or 24, or 23, or 22, or 21, or 20, or 19, or 18, or 17, or 16, or 15, or 14, or 13, or 12, or 11, or 10, or 9, or 8, or 7, or 6, or 5, or 3, or 2, or 1 ug hr/ml.

[0068] Another embodiment provides a dispersible dry powder antimicrobial composition comprising l-cyclopropyl-6-fluoro- 1 ,4-dihydro-4-oxo-7-(l- piperizinyl)-3-quinolinecarboxylic acid; or a pharmaceutically acceptable salt thereof, having an AUC₂₄/MIC ratio less than about 1. In a more particular embodiment said MIC corresponds to inhibition of bacteria selected from the group consisting of P. aeruginosa, E. coli, S. pneumoniae, S. aureus, and H. influenzae.

[0069] Another embodiment provides a dispersible dry powder antimicrobial composition comprising l-cyclopropyl-6-fluoro-l ,4-dihydro-4-oxo-7-(l- piperizinyl)-3-quinolinecarboxylic acid; or a pharmaceutically acceptable salt thereof, having an AUCa₄ZMIC ratio less than about 2.5. In a more particular embodiment said MIC corresponds to inhibition of bacteria selected from the group consisting of P. aeruginosa, E. coli, S. pneumoniae, S. aureus, and H. influenzae.

[0070] Another embodiment provides a dispersible dry powder antimicrobial composition comprising l-cyclopropyl-6-fluoro-l,4-dihydro-4-oxo-7-(l- piperizinyl)-3-quinolinecarboxylic acid; or a pharmaceutically acceptable salt thereof, having an AUC₂₄/MIC ratio less than about 5. In a more particular embodiment said MIC corresponds to inhibition of bacteria selected from the group consisting of P. aeruginosa, E. coli, S. pneumoniae, S. aureus, and H. influenzae.

[0071] Another embodiment provides a dispersible dry powder antimicrobial composition comprising l-cyclopropyl-6-fϊuoro-l,4-dihydro-4-oxo-7-(l- piperizinyl)-3-quinolinecarboxylic acid; or a pharmaceutically acceptable salt thereof, having an AUC₂₄/MIC ratio less than about 10. In a more particular embodiment said MIC corresponds to inhibition of bacteria selected from the group consisting of P. aeruginosa, E. coli, S. pneumoniae, S. aureus, and H. influenzae.

[0072] Another embodiment provides a dispersible dry powder antimicrobial composition comprising l-cyclopropyl-ό-fluoro-l ,4-dihydro-4-oxo-7-(l- piperizinyl)-3-quinolinecarboxylic acid; or a pharmaceutically acceptable salt thereof, having an AUC₂₄/MIC ratio less than about 25. In a more particular embodiment said MIC corresponds to inhibition of bacteria selected from the group consisting of P. aeruginosa, E. coli, S. pneumoniae, S. aureus, and H. influenzae. [0073] Another embodiment provides a dispersible dry powder antimicrobial composition comprising l-cyclopropyl-6-fluoro-l,4-dihydro-4-oxo-7-(l- piperizinyl)-3-quinolinecarboxylic acid; or a pharmaceutically acceptable salt thereof, having an AUC₂VMIC ratio less than about 50. In a more particular embodiment said MIC corresponds to inhibition of bacteria selected from the group consisting of P. aeruginosa, E. coli, S. pneumoniae, S. aureus, and H. influenzae.

[0074] Another embodiment provides a dispersible dry powder antimicrobial composition comprising l-cyclopropyl-6-fluoro-l ,4-dihydro-4-oxo-7-(l- piperizinyl)-3-quinolinecarboxylic acid; or a pharmaceutically acceptable salt thereof, having an AUC₂₄ZMIC ratio less than about 125. In a more particular embodiment said MIC corresponds to inhibition of bacteria selected from the group consisting of P. aeruginosa, E. coli, S. pneumoniae, S. aureus, and H. influenzae.

[0075] Another embodiment provides a dispersible dry powder antimicrobial composition comprising l-cyclopropyl-6-fluoro-l ,4-dihydro-4-oxo-7-(l- piperizinyl)-3-quinolinecarboxylic acid; or a pharmaceutically acceptable salt thereof, having an AUC₂₄ZMIC ratio less than about 200. In a more particular embodiment said MIC corresponds to inhibition of bacteria selected from the group consisting of P. aeruginosa, E. coli, S. pneumoniae, S. aureus, and H. influenzae.

[0076] Another embodiment of the invention provides a method of treating a patient suffering from anthrax exposure comprising administering a dry powder composition comprising at least 55.0 % by weight of l-cyclopropyl-6-fluoro-l,4- dihydro-4-oxo-7-(l-piperizinyl)-3-quinolinecarboxylic acid; or a pharmaceutically acceptable salt thereof.

[0077] Another embodiment of the invention provides a method of treating a patient comprising administering l-cyclopropyl-6-fluoro-l ,4-dihydro-4-oxo-7-(l- piperizinyl)-3-quinolinecarboxylic acid, a pharmaceutically acceptable salt, or excipient thereof, in a subtherapeutic blood concentration.

[0078] It is contemplated that the invention encompasses all possible combinations of the embodiments described herein. Further, it is contemplated that any of the compositions or methods of the invention may be used to treat a patient suffering from anthrax exposure.

[0079] The formulations described herein may be delivered using any suitable dry powder inhaler (DPI), i.e., an inhaler device that utilizes the patient's inhaled breath as a vehicle to transport the dry powder drug to the lungs. Preferred is the T-326 Dry Powder Inhaler (T-326 Inhaler, Nektar Therapeutics, San Carlos, CA). The T- 326 Inhaler is a hand-held, manually operated, breath-activated, dry powder inhaler which uses no stored power sources or electronics. The T-326 inhaler has a flow resistance of approximately 0.09 cm H₂O⁰⁵/LPM or about 8 cm H₂O at 30 LPM (a pneumotachometer has a flow resistance of approximately 1 cm at the 30 LPM).

[0080] Further inhalers include Inhale Therapeutic Systems' dry powder inhalation devices as described in Patton, J. S., et al., U.S. Pat. No. 5, 458,135 (1995) Smith, A. E., et al., U.S. Pat. No. 5,740,794 (1998); and in Smith, A. E., et. al., U.S. Pat. No. 5,785,049 (1998), herein incorporated by reference. When administered using a device of this type, the powder is contained in a receptacle having a puncturable lid or other access surface, preferably a blister package or cartridge, where the receptacle may contain a single dosage unit or multiple dosage units. Convenient methods for filling large numbers of cavities (i.e., unit dose packages) with metered doses of dry powder medicament are described, e.g., in Parks, D. J., et al., WO 97/41031 (1997) incorporated herein by reference.

[0081] Also suitable for delivering the powders described herein are dry powder inhalers of the type described, for example, in Cocozza, S., et al. , U.S. Pat. No. 3,906,950 (1974), and in Cocozza, S., et al., U.S. Pat. No. 4,013,075 (1997), incorporated herein by reference, wherein a premeasured dose of dry powder for delivery to a subject is contained within a hard gelatin capsule.

[0082] Other dry powder dispersion devices for pulmonarily administering dry powders include those described, for example, in Newell, R. E., et al, European Patent No. EP 129985 (1988); in Hodson, P. D., et al., European Patent No. EP 472598 (1996); in Cocozza, S., et al., European Patent No. EP 467172 (1994), and in Lloyd, L. J. et al., U.S. Pat. No. 5,522,385 (1996), incorporated herein by reference. Also suitable for delivering the dry powders of the invention are inhalation devices such as the Astra- Draco "TURBUHALER". This type of device is described in detail in Virtanen, R., U.S. Pat. No. 4,668,281 (1987); in Wetterlin, K., et al U.S. Pat. No. 4,667,668 (1987); and in Wetterlin, K., et al. U.S. Pat. No. 4, 805,811 (1989), all of which are incorporated herein by reference. Other suitable devices include dry powder inhalers such as the Rotahaler® (Glaxo), Discus® (Glaxo), Spiros® inhaler (Dura Pharmaceuticals), and the Spinhaler® (Fisons). Also suitable are devices which employ the use of a piston to provide air for either entraining powdered medicament, lifting medicament from a carrier screen by passing air through the screen, or mixing air with powder medicament in a mixing chamber with subsequent introduction of the powder to the patient through the mouthpiece of the device, such as described in Mulhauser, P., et al, U.S. Pat. No. 5,388, 572 (1997), incorporated herein by reference.

[0083] Dry powders may also be delivered using a pressurized, metered dose inhaler (MDI), e.g., the Ventolin® metered dose inhaler, containing a solution or suspension of drug in a pharmaceutically inert liquid propellant, e.g., a chlorofluorocarbon or fluorocarbon, as described in Laube, et al., U.S. Pat. No. 5,320,094 (1994), and in Rubsamen, R. M., et al, U.S. Pat. No. 5,672,581 (1994), both incorporated herein by reference. Alternatively, the powders described herein may be dissolved or suspended in a solvent, e.g., water, ethanol, or saline, and administered by nebulization. Nebulizers for delivering an aerosolized solution include the AERx® (Aradigm), the Ultravent® (Mallinkrodt), and the Acorn H® (Marquest Medical Products).

[0084] Prior to use, dry powders are generally stored under ambient conditions, and preferably are stored at temperatures at or below about 25° C, and relative humidities (RH) ranging from about 30 to 60%. More preferred relative humidity conditions, e.g., less than about 30%, may be achieved by the incorporation of a desiccating agent in the secondary packaging of the dosage form.

[0085] Clinical Pharmacology obtained from Physicians Desk Reference, 58^th Ed. (2004) 845, which is incorporated by reference:

Definitions:

AUC Area under the curve

AUC_n Area under the curve, wherein n is the time period in hours, such as

24

AUC/MIC or AUIC Area under the curve inhibitory concentration cm H₂O °^'5 /LPM Unit of resistance to flow; the square root of pressure drop divided by flow rate.

C_max Maximum concentration

C_ss Steady state concentration DPI Dry Powder Inhaler

ED Emitted Dose

FEV₁ Forced Expiratory Volume in 1 second

FVC Forced Vital Capacity

GCP Good Clinical Practice

HCl Hydrochloride salt (derived from hydrochloric acid)

IT Intratracheal (as a mode of administration)

IV Intravenous (as a mode of administration)

LPM Liters per minute

MBC Minimum Bactericidal Concentration

MIC Minimum Inhibitory Concentration

MMAD Mass median aerodynamic diameter

PK Pharmacokinetic

SAE Serious Adverse Event

SCFM Standard cubic feet per minute

SEM Scanning electron microscopy

TPI Tobramycin Powder for Inhalation

[0086] The term "effective amount" is an amount necessary or sufficient to realize a desired biological effect. For example, an effective amount of a compound to treat an infectious disorder may be an amount necessary to cause an antigen specific immune response upon exposure to an infectious agent. The effective amount may vary, depending, for example, upon the condition treated, weight of the subject and severity of the disease. One of skill in the art can readily determine the effective amount empirically without undue experimentation.

[0087] As used herein "treatment" or "treated," as in being "treated for the microbial infection" refers to an amount sufficient to palliate, ameliorate, stabilize, reverse, slow or delay progression of a condition such as a microbial infection, and/or symptoms associated therewith.

[0088] A "subject" or "patient" is meant to describe a human or vertebrate animal including a dog, cat, pocket pet, marmoset, horse, cow, pig, sheep, goat, elephant, giraffe, chicken, lion, monkey, owl, rat, squirrel, slender loris, mouse, or other vertebrate animal commonly found in a zoo, such as, for example the San Diego Zoo.

[0089] A "pocket pet" refers to a group of vertebrate animals capable of fitting into a commodious coat pocket such as, for example, hamsters, chinchillas, ferrets, rats, guinea pigs, gerbils, rabbits and sugar gliders. [0090] The compositions of the present invention can be used in the form of salts as in "pharmaceutically acceptable salts" suitable for attachment to ciprofloxacin. A "pharmaceutically acceptable salt" includes a salt with an inorganic base, organic base, inorganic acid, organic acid, or basic or acidic amino acid. As salts of inorganic bases, the invention includes, for example, alkali metals such as sodium or potassium; alkaline earth metals such as calcium and magnesium or aluminum; and ammonia. As salts of organic bases, the invention includes, for example, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, and triethanolamine. As salts of inorganic acids, the instant invention includes, for example, hydrochloric acid, hydroboric acid, nitric acid, sulfuric acid, and phosphoric acid. As salts of organic acids, the instant invention includes, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid. As salts of basic amino acids, the instant invention includes, for example, arginine, lysine and ornithine. Acidic amino acids include, for example, aspartic acid and glutamic acid.

[0091] The pharmaceutical compositions containing the compounds described herein can include additives such as "excipients." Suitable pharmaceutically acceptable excipients include processing agents and drug delivery modifiers and enhancers, such as, for example, calcium phosphate, magnesium stearate, talc, monosaccharides, disaccharides, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, dextrose, hydroxypropyl-β-cyclodextrin, polyvinylpyrrolidinone, low melting waxes, ion exchange resins, surfactants, and the like, as well as combinations of any two or more thereof. Preferred excipients of the instant invention include amino acids (preferably hydrophobic, such as leucine), water soluble polypeptides, sugars, and phospholipids. Preferred phospholipids for use as excipients include dipalmitoylphosphatidylcholine, disteroylphosphatidylcholine, diarachidoylphosphatidylcholine dibehenoylphosphatidylcholine, diphosphatidyl glycerol, short-chain phosphatidylcholines, long-chain saturated phosphatidylethanolamines, long-chain saturated phosphatidylserines, long-chain saturated phosphatidylglycerols, and long- chain saturated phosphatidylinositols.

[0092] Other suitable pharmaceutically acceptable excipients are described in

"Remington's Pharmaceutical Sciences," Mack Pub. Co., New Jersey (1991), and PCT applications WO 95/31479, WO 96/32096, and WO 96/32149, which are incorporated herein by reference.

[0093] A "subtherapeutic blood concentration" refers to a measurable concentration of ciprofloxacin in the blood stream or plasma that is less than an amount required to eradicate a bacterial infection through direct administration to the blood stream (i.e. intravenously). Since the current invention involves inhalation of ciprofloxacin, thereby targeting lung infections much more precisely without substantial dispersal of ciprofloxacin outside the lungs, a subtherapeutic blood concentration (involving a blood sample taken from outside the lungs) is actually very desirable. In one embodiment the ciprofloxacin blood concentration (C_max) in the blood is less than 2.5 ug/mL, or 1.25 ug/mL, or 0.75 ug/mL, or 0.25 ug/mL. In another embodiment the ciprofloxacin blood concentration (C_ss) in the blood is less than 2.5 ug/mL, or 1.25 ug/mL, or 0.75 ug/mL, or 0.25 ug/mL.

[0094] As used herein, the term "dry powder" refers to a composition that contains finely dispersed, or "dispersible" solid particles that are capable of (i) being readily dispersed in or by means of an inhalation device and (ii) inhaled by a subject so that a portion of the particles reach the lungs. Such a powder is considered to be "respirable" or suitable for pulmonary delivery. Suitable agents to enhance dispersion, which are disclosed in PCT applications WO 95/31479, WO 96/32096, and WO 96/32149, are hereby incorporated in their entirety by reference.

[0095] As used herein, "passive dry powder inhaler" refers to an inhalation device which relies upon the patient's inspiratory effort to disperse and aerosolize a drug formulation contained within the device and does not include inhaler devices which comprise a means for providing energy to disperse and aerosolize the drug formulation, such as pressurized gas and vibrating or rotating elements.

[0096] A dry powder typically contains less than about 15% moisture or "residual moisture content by weight," preferably less than 10% moisture, and more preferably contains less than 5% moisture.

[0097] "AUC" as used herein, means area under the plasma concentration-time curve, as calculated by the trapezoidal rule over a time period, such as a 24-hour interval (AUC₂₄), for the formulations.

[0098] The trapezoidal rule is expressed mathematically as follows (3):^b Δx f{s)ds N -TT- (Z(Jo) + 2Z(Ji) + 2Z(s₂) +^{■ ■ ■} + 2Z(J_n-I ) + Z(*n )) ■ (3)

/ [0099] "AUC₂₄/MIC" ratios describe interactions of a αrug with specific targets in a respective pathogen by occupying a specific number of critical binding sites. The ratio has been shown to effectively predict the therapeutic response of micro¬ organisms to antimicrobials, such as ciprofloxacin. Zhanel, G., et al. Drugs 2002, 62(1), 29.

[00100] As used herein, the term "emitted dose" or "ED" refers to the delivery of dry powder from a suitable inhaler device after a firing or dispersion event from a powder unit, capsule, or reservoir. ED is defined as the ratio of the dose delivered by an inhaler device to the nominal dose (i.e., the mass of powder per unit dose placed into a suitable inhaler device prior to firing). The ED is an experimentally- determined amount and is typically determined using an in-vitro device set up which mimics patient dosing.

[00101] To determine an ED value (further described in the Examples section), a nominal dose of dry powder (as defined above) is placed into a suitable passive dry powder inhaler. The resulting aerosol cloud is then drawn by vacuum from the device. The amount of powder that is released from the device constitutes the delivered dose. For example, for a 5 mg, dry powder containing capsule placed into an inhalation device, if dispersion of the powder results in 4 mg of powder as described above, then the ED for the dry powder composition is: 4 mg (delivered dose)/5 mg (nominal dose) x 100 = 80%.

[00102] As used herein, the term "geometric diameter" is a measure of geometric particle size and is determined using, for example, a Malvern Spraytec laser diffraction analyzer.

[00103] As used herein the term "mass median aerodynamic diameter" or "MMAD" is a measure of the aerodynamic size of a dispersed particle. The aerodynamic diameter is used to describe an aerosolized powder in terms of its settling behavior and is the diameter of a unit density sphere having the same settling velocity generally in air as the particle. The aerodynamic diameter encompasses particle shape density and physical size of a particle. As used herein mass median aerodynamic diameter or MMAD refers to the midpoint or median of the aerodynamic particle size distribution of an aerosolized powder determined by Anderson cascade impaction described in the Examples section.

[00104] As used herein "antimicrobial" refers to a composition, namely ciprofloxacin, that is harmful to microbes, or capable of destroying or inhibiting the growth of microorganisms. Microbes as described herein, include pathogenic bacteria, fungi, protozoans, microscopic algae, and viruses; alternatively, reference to a "microbial infection" involves infection with at least on of the following: bacteria, fungi, protozoans, microscopic algae, and/or viruses.

[00105] The term "dispersible dry powder antimicrobial composition" refers to a composition capable of (i) being readily dispersed in or by means of an inhalation device and (ii) inhaled by a subject so that a portion of the particles reach the lungs, which is harmful to microbes, or capable of destroying or inhibiting the growth of microorganisms, such as, pathogenic bacteria, fungi, protozoans, microscopic algae, and viruses.

[00106] The term "l-cyclopropyl-6-fluoro-l,4-dihydro-4-oxo-7-(l-piperizinyl)-3- quinolinecarboxylic acid" refers to ciprofloxacin.

[00107] The invention is described in greater detail by way of specific examples. The following examples are offered for illustrative purposes, and are not intended to limit the invention in any manner. Those of skill in the art will readily recognize a variety of noncritical parameters which can be changed or modified to yield essentially the same results.

EXAMPLES

Example 1.

[00108] Formulation: Dry powder compositions containing ciprofloxacin were prepared by mixing ciprofloxacin hydrochloride and excipient(s) (if used) with a liquid medium to form a solution. The pH of the solution was adjusted as appropriate to facilitate solubilization and/or stabilization of the components in the solution.

Example 2.

[00109] Spray Drying Preparation: The ciprofloxacin solutions are spray dried, for example, with Buchi 190 Mini Spray Dryers, having nozzles and cyclones that were designed to generate and catch very fine particles. (For formulations utilizing organic solvents, a modified Buchi 190 Mini Spray Dryer can be used that supplies nitrogen as the gas source and is equipped with an oxygen sensor and other safety equipment to minimize the possibility of explosion.) The solution feed rate is 5 ml/minute; and maintained at room temperature, inlet temperature range is 120 - 131°C and is adjusted to obtain an outlet temperature of approximately 80°C, the drying gas flow rate is about 18 SCFM, and the atomizing air is supplied at 0.5 to 1.5 SCFM, typically at a pressure of about 100 PSI.

Example 3.

[00110] Characterization: Each powder was characterized in terms of moisture content, emitted dose (ED), and mass median aerodynamic diameter (MMAD). ED is a measure of efficiency for the powder package/device combination. MMAD refers to a measure of the particle size of the aerosolized powder. For these experiments, ciprofloxacin hydrochloride powders (56-84 % (w/w) ciprofloxacin) were formulated and manufactured (spray dried) with leucine as an excipient. FJPLC analysis demonstrated that the ciprofloxacin remained stable through the spray drying process (percent areas greater than 98%). The residual water content of these formulations was 2.5-4.2% (w/w) as determined by Karl Fisher titration. The stability of these formulations was demonstrated by comparing initial HPLC results to a four-month time point for samples stored at desiccated room temperature. There was no detectable degradation of the ciprofloxacin in these formulations.

[00111] Morphology is determined by scanning electron microscopy (SEM).

[00112] To determine the ED, the spray-dried powders are first filled into capsules. The test can be performed by connecting a vacuum system to the mouthpiece of a passive dry powder inhaler. The vacuum system is set to have a flow rate of 60 liters/minute. A capsule containing, for example, 5 mg of the formulation to be evaluated is loaded into a device. The device is pumped which pierces the capsule and the aerosol cloud is then drawn out of the device chamber by vacuum. The difference in weight of the capsule is determined. Emitted dose is calculated as this weight, multiplied by one hundred, divided by the fill weight in the capsule. A higher number is a better result than a lower number.

[00113] MMAD can be determined with an Andersen cascade impactor. In a cascade impactor the aerosolized powder (which is aerosolized using an inhaler device as described in U.S. Patent No. 5,740,794) enters the impactor via an air stream, and encounters a series of stages that separate particles by their aerodynamic diameter (the smallest particles pass farthest down the impactor). The amount of powder collected on each stage is determined gravimetrically, and the mass median aerodynamic diameter is then calculated. Example 4.

[00114] Rat PK Studies: Rat studies were conducted to compare the lung and plasma pharmacokinetics (PK) after ciprofloxacin nose-only exposure of either ciprofloxacin dry powder and ciprofloxacin liquid aerosol to intravenous (IV) administration of ciprofloxacin liquid formation.

[00115] The pharmacokinetic parameters were determined by non-compartmental analysis using WinNonlin® software.

[00116] The pharmacokinetic study results are listed in Table 1 and shown in Figure 1 and 2. The results demonstrate that dry powder inhalation results in five times the lung-to-plasma AUC ratio of ciprofloxacin compared to a human equivalent IV dose of 25 mg/kg (Table 1). The plasma levels and AUC were approximately 2.5 times lower by dry powder inhalation than by IV (Table 1). This indicates a potential for delivery of much higher dose by aerosol without the associated high drug systemic levels. In addition, the liquid aerosol inhalation PK results (Figure 2) show that one can achieve a higher lung deposition per dosing time (30 minutes) using the dry powder formulation (1.3 mg/kg) than with a liquid aerosol (0.67 mg/kg).

Table 1. Summary of Calculated Pharmacokinetic Parameters.

A - Values for drug concentration at the time of the first IV plasma sample. These values are not true C max and t max, but are provided for purposes of easy comparison.

[00117] Efficacy studies of nose-only exposure of rats to ciprofloxacin liquid aerosol, ciprofloxacin (71% (w/w)) dry powder, and IV administration of ciprofloxacin liquid formation in rats were performed. The lung infection was established using E. coli ATCC# 25922 embedded in agarose beads through the either IV or intratracheal (IT) administration. Ciprofloxacin was dosed twice daily in all studies.

[00118] The results of the efficacy study using the IV lung infection model are listed in Tables 2-4 and shown in Figures 3-5. These results suggest that the use of inhalation as a viable delivery route for efficacious doses of ciprofloxacin. See Results Summary below for a discussion of the findings.

Table 2.

Results for Ciprofloxacin Intravenous Treatment (Rat IV E.coli Lung Infection Model)

[00119] Pulmonary Deposited Dose for Tables 3-6 were calculated based on gravimetric measurement of filters collected at the nose port and an assumption that 10% of the measured dose are delivered to the lungs. Data for Table 3 was collected by exposing rats for 30 minutes at 3 different solution concentrations (1, 5 and 10 mg/ml) for the liquid aerosol studies to achieve pulmonary deposited doses of 0.04, 0.18, and 0.31 mg/kg, respectively.

Table 3.

Results for Ciprofloxacin Liquid Aerosol Exposure (Rat IV E.coli Lung Infection Model)

[00120] The dry powder aerosol doses depicted in Table 4 data, were adjusted by varying the length of the exposure time at similar aerosol concentrations. Table 4.

Results for Ciprofloxacin Dry Powder Aerosol Exposure (Rat IV E.coli Lung Infection Model)

[00121] The IT lung infection model allows examination of the efficacy of the ciprofloxacin dry power on a highly localized infection. In addition, the resulting infection via the IT route is considered a robust infections and difficult to treat. The results of this efficacy study using the IT lung infection model are listed in Tables 5 and 6 and shown in Figure 6 and 7.

Table 5. Results for Ciprofloxacin Intravenous Treatment

(Rat IT E.coli Lung Infection Model)

Table 6.

Results for Ciprofloxacin Dry Powder Aerosol Exposure (Rat IT E.coli Lung Infection Model)

Results Summary:

[00122] As depicted in Figure 1, a lung concentration (by Cmax or AUC) that is twice that of the human equivalent IV dose of 25 mg/kg can be achieved with a dry powder inhalation dose of 1.3 mg/kg. Thus a higher lung concentration of drug can be achieved with a single dose of dry powder inhaled ciprofloxacin than can be achieved with a single human equivalent IV dose.

[00123] It is likely that lower activity of inhaled ciprofloxacin compared to intravenous administration of ciprofloxacin in the rat IV lung infection models, depicted in Figures 3-5, is because inhaled ciprofloxacin failed to reach intravascular concentrations at specific IV-induced intracellular locations inhabited by populations of E.coli. Animals infected by IV administration of E.coli develop regions of infected lung tissue beyond the alveoli, on the circulatory side of the lungs, that is difficult treat by inhalation. Fortunately, human populations with lung infections represent a small population of patients. Since the identification of resultant bacterial populations were performed indiscriminately on the entire lung of the infected animal, it was not possible to see what areas of the lungs were still infected after treatment with respective inhaled and intravenous ciprofloxacin regimens.

[00124] It is generally accepted that an IT lung infection model is more robust and preferable to IV in that IT more closely resembles the mode of infection for a human, namely aspirations of bacteria, which results in infection of the airway regions of the lung. The instant invention is geared more toward the treatment of airway infections, which is representative of the IT infection model. Superior results using inhalation as a mode of delivery for the IT infection model, highlights the effectiveness of inhaled ciprofloxacin in localized and targeted regions. As a result, the concentration of ciprofloxacin reaching the site of infection is much higher, while the concentration of^v systemic ciproflaxicin inducing toxicity and bacterial resistance is much lower.

[00125] These efficacy studies demonstrate the ability to deliver an efficacious dose of ciprofloxacin to the lungs using a dry powder aerosol and that this delivery results in a superior effect than IV administration of ciprofloxacin.

[00126] All of the above captioned citations are fully incorporated by reference as if set forth herein.

scope of the above disclosure.

Claims

1. A dispersible dry powder antimicrobial composition comprising at least 55.0 % by weight of l-cyclopropyl-6-fluoro-l,4-dihydro-4-oxo~7-(l-piperizinyl)-3- quinolinecarboxylic acid; or a pharmaceutically acceptable salt thereof.

2. The composition according to claim 1 further comprising an excipient.

3. The composition according to claim 2 wherein said excipient is selected from the group consisting of hydrophobic amino acids, water soluble polypeptides, and phospholipids.

4. The composition according to claim 2 wherein said excipient is a hydrophobic amino acid selected from the group consisting of alanine, isoleucine, leucine, methionine, phenylalanine, proline, tryptophan, and valine.

5. The composition according to claim 2 wherein said excipient is leucine.

6. The composition as in claim 1 or claim 5, in which said pharmaceutically acceptable salt is HCl.

7. The composition according to claim 1 wherein the residual moisture content is less than 5.0 % by weight.

8. The composition according to claim 1 wherein said composition comprises particles having a geometric diameter less than 5.0 microns.

9. The composition as in claim 1 or claim 5, in which said composition comprises particles having a geometric diameter between about 2.0 and about 3.5 microns.

10. The composition according to claim 1 wherein said composition comprises particles having a mass median aerodynamic diameter less than 5.0 microns.

11. The composition as in claim 1 or claim 5, in which said composition comprises particles having a mass median aerodynamic diameter between about 2.1 and about 3.1 microns.

12. The composition according to claim 1 comprising 65.0 - 85.0 % by weight of 1- cyclopropyl-6-fluoro- 1 ,4-dihydro-4-oxo-7-( 1 -piperizinyl)-3-qumolinecarboxylic acid; or a pharmaceutically acceptable salt thereof.

13. The composition according to claim 1 comprising an emitted dose greater than 70%.

14. A method of treating a patient suffering from an endobronchial infection comprising administering a compound of claim 1.

15. A method of treating a patient suffering from anthrax comprising administering a compound of claim 1.

16. A method of treating a patient having an endobronchial infection comprising administering a therapeutically effective amount of an inhaled dry powder composition comprising, 1 -cyclopropyl-6-fluoro-l ,4-dihydro-4-oxo-7-(l-piperizinyl)-3- quinolinecarboxylic acid; or a pharmaceutically acceptable salt or excipient thereof.

17. The method according to claim 16 wherein said inhaled dry powder composition yields a dry powder AUC value which is less than an IV AUC value obtained from intravenously administering l-cyclopropyl-6-fluoro-l,4-dihydro-4-oxo-7-(l- piperizinyl)-3-quinolinecarboxylic acid.

18. The method according to claim 16 wherein said composition is administered in a subtherapeutic blood concentration.

19. The method according to claim 16 wherein said composition comprises at least 55.0 % by weight l-cyclopropyl-6-fluoro-l,4-dihydro-4-oxo-7-(l-piperizinyl)-3- quinolinecarboxylic acid; or a pharmaceutically acceptable salt thereof.

20. The method according to claim 17 wherein said dry powder AUC value is less than Vi the IV AUC value.

21. The method as in any one of claims 16-20 wherein said composition further comprises an excipient selected from the group consisting of hydrophobic amino acids, water soluble polypeptides, and phospholipids.

22. The method according to claim 21 wherein said excipient is leucine.

23. The method as in any one of claims 16-20 wherein said composition consists of particles having a geometric diameter and a mass median aerodynamic diameter less than 5.0 microns and a residual moisture content of less than 5.0 % by weight.

24. The method as in any one claims 16-20 wherein the inhalation of the composition is from a dry powder inhaler and results in an emitted dose greater than 70%.

25. The method as in any of claims 16-20 wherein the resulting C_max in the patient is less than 2.5 ug/mL.

26. The method as in any of claims 16-20 wherein the resulting C_max in the patient is less than 0.75 ug/mL.

27. The method as in any of claims 16-20 wherein the resulting C_ss in the patient is less than 1.25 ug/mL.

28. A method of administering l-cyclopropyl-6-fluoro-l,4-dihydro-4-oxo-7-(l- piperizinyl)-3-quinolinecarboxylic acid; or a pharmaceutically acceptable salt thereof, comprising: a) providing a dispersible dry powder composition comprising l-cyclopropyl-6- fluoro-l,4-dihydro-4-oxo-7-(l-piperizinyl)-3-quinolinecarboxylic acid, or a pharmaceutically acceptable salt thereof; b) administering said dry powder composition to a subject by inhalation from a dry powder inhaler; wherein the administration of the dispersible dry powder results in a ratio of lung concentration to plasma concentration that is greater than 1.2.

29. The method according to claim 28 wherein the ratio of lung concentration to plasma concentration is greater than 2.

30. The method according to claim 28 wherein the ratio of lung concentration to plasma concentration is greater than 5.

31. The method according to claim 28 wherein the ratio of lung concentration to plasma concentration is greater than 10.

32. A dispersible dry powder antimicrobial composition comprising l-cyclopropyl-6- fluoro-l,4-dihydro-4-oxo-7-(l-piperizinyl)-3-quinolinecarboxylic acid; or a pharmaceutically acceptable salt thereof, having a AUC₁₂ value below about 10 ug hr/ml when administered by inhalation in a dose between 200 and 500 mg.

33. The method according to claim 32 wherein the AUC₁₂ is below 5 ug hr/ml.

34. A dispersible dry powder antimicrobial composition comprising l-cyclopropyl-6- fluoro-l^-dihydro^-oxo-T-Cl-piperiziny^-S-quinolinecarboxylic acid; or a pharmaceutically acceptable salt thereof, having an AUC₂₄VMIC ratio less than about 10, when administered by inhalation.

35. The composition according to claim 34 having an AUC₂₄ZMIC ratio less than about 25.

36. The composition according to claim 34 having an AUC₂₄/MIC ratio less than about 50.

37. The composition according to claim 34 having an AUC₂₄/MIC ratio less than about 125.

38. The composition as in any of claims 34-37 wherein said MIC corresponds to inhibition of bacteria selected from the group consisting of P. aeruginosa, E. coli, S. pneumoniae, S. aureus, and H. influenzae.

39. A method of treating a patient comprising administering l-cyclopropyl-6-fluoro- l,4-dihydro-4-oxo-7-(l-piperizinyl)-3-qumolinecarboxylic acid, a pharmaceutically acceptable salt, or excipient thereof, in a subtherapeutic blood concentration.