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(12) Patent Application Publication (10) Pub. No.: US 2003/0133925A1 Shawar (43) Pub US 2003O133925A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2003/0133925A1 Shawar (43) Pub. Date: Jul. 17, 2003 (54) MONOBACTAM COMPOSITIONS AND Related U.S. Application Data METHODS OF USE THEREOF (60) Provisional application No. 60/325,933, filed on Sep. (76) Inventor: Ribhi M. Shawar, Bellevue, WA (US) 28, 2001. Publication Classification Correspondence Address: Chiron Corporation (51) Int. Cl." ......................... A61K 38/47; A61K 31/56; Intellectual E. ert A61K 31/498; A61K 31/198 P.O. BOX 8097 perty (52) U.S. Cl. ................ 424/94.61; 514/210.15; 514/171; ww 514/562 Emeryville, CA 94662-8097 (US) f (57) ABSTRACT (21) Appl. No.: 10/256,341 Methods, compounds and compositions are provided for inhibiting the growth of pathogenic microbes in vitro and of treatment of pathogenic bacterial infections in Vivo using an (22) Filed: Sep. 26, 2002 antibacterial monobactam compound and a mucolytic agent. Patent Application Publication Jul. 17, 2003 Sheet 1 of 4 US 2003/0133925A1 PA-1806 Time-Kill Assay vs. P. aeruginosa ATCC #27853 1.OE+09 1.OE-08 - 1.OE+07 - 1.OE-06 - s 1.0E+05 1.OE-04 1.OE+03 - 1.OE-02 1.OE-01 -- - O 4. 8 12 16 20 24 Time (hours) -0- Growth Control --PA-1806/0.5 pg/mL -A-PA-1806. 1 g/ml --PA-1806/2ug/mL --PA-180614 uglml - - - - - - LOO = 20 CFU/mL Fig. 1 Patent Application Publication Jul. 17, 2003 Sheet 2 of 4 US 2003/0133925 A1 PA-1806 Time-Kill Assay vs. B. cepacia Clinical isolate 1.OE-09 1.OE-08 1.OE+07 - 1.OE--06 1.OE-05 1.OE-04 1.OE-03 - 1.OE-02 - Time (hours) -0- Growth Control -HPA-1806/1 uglml -A-PA-1806. 8 g/mL - - - - - - LOO" = 20 CFU/mL. Fig. 2 Patent Application Publication Jul. 17, 2003 Sheet 3 of 4 US 2003/0133925 A1 PA-18062%. Mucin Time-Kill Assay vs. P. aeruginosa ATCC #27853 1.0E+09 - 1.OE+08 1.OE+07 - 1.0E06 - - S S 1.0E+05 - C) 1.0+04 1.0E+03 - 1.OE-02 - 1.0E+01 T I I f I O 4. 8 12 16 20 24 Time (hours) -0-Growth Control, No Mucin -- Growth Control, Mucin -A-PA-1806. 2 g/mL, No Mucin --PA-180674 uglmL, No Mucin --PA-1806/8 uglmL, Mucin -O-PA-1806/ 64 g/mL, Mucin --PA-1806f 128 g/mL, Mucin - - - - - - OO = 20 CFUm Fig. 3 Patent Application Publication Jul. 17, 2003 Sheet 4 of 4 US 2003/0133925 A1 Tobramycin 2% Mucin Time-Kill Assay vs. P. aeruginosa ATCC #27853 1.OE-- 11 1.OE 10 1.OE-09 1.OE-08 1.O-OS 1.OE-05 1.OE-04 1.0--03 1.OE--O2 1.OE-00 O 4. 8 12 16 2O 24 Time (hours) -0- Growth Control, No Mucin -a- Growth Control, Mucin -A-Tobramycin? 0.5 g/mL, No Mucin -se-Tobramycin/ 12.5 g/mL, Mucin -e-Tobtamycin/ 25 ug/mL, Mucin -o-Tobramycin f 50 g/mL, Mucin - Fig. 4 US 2003/O133925 A1 Jul. 17, 2003 MONOBACTAM COMPOSITIONS AND METHODS cin in this environment. It is estimated that 5 to 10 times OF USE THEREOF higher concentrations of tobramycin are required in the Sputum to overcome these inhibitory effects (Levy J. et al., CROSS-REFERENCE TO RELATED “Bioactivity of gentamicin in purulent Sputum from patients APPLICATIONS with cystic fibrosis or bronchiectasis: comparison with activ 0001. This application is related to provisional applica ity in serum.J Infect Dis 148(6):1069-76 (1983); Mendel tion Serial No. 60/325,933, filed Sep. 28, 2001, from which man, P. M., et al., “Aminoglycoside penetration, inactiva application priority is claimed under 35 USCS119(e)(1) and tion, and efficacy in cystic fibrosis Sputum, Am. Rev. Respir. which application is incorporated herein by reference in its Dis. 132:761-765 (1985)). entirety. 0006 A preservative-free, stable, and convenient formu FIELD OF THE INVENTION lation of tobramycin (TOBIOR tobramycin solution for inha lation; 60 mg/mL tobramycin in 5 mL of 4 normal saline) 0002 The present invention relates to methods of treating for administration via jet nebulizer was developed by Patho bacterial infections with monobactam compounds, Such as Genesis Corporation, Seattle, Wash. (now Chiron Corpora PA-1806, and with a mucolytic agent, and to new compo tion). The combination of a 5 mL BID TOBI dose (300 mg Sitions for the treatment of bacterial infections. tobramycin) and the PARI LC PLUS/Pulmo Aide compres Sor delivery system was approved under NDA 50-753, BACKGROUND OF THE INVENTION December 1997, for the management of P. aeruginosa in CF 0.003 Progressive pulmonary disease is the cause of patients, and remains the industry Standard for this purpose. death in over 90% of cystic fibrosis (CF) patients (Koch, C. The aerosol administration of a 5 ml dose of a formulation et al., “Pathogenesis of cystic fibrosis,'Lancet containing 300 mg of tobramycin in quarter normal Saline 341 (8852):1065-9 (1993); Konstan M. W. et al., “Infection for the Suppression of P. aeruginosa in the endobronchial and inflammation of the lung in cystic fibrosis,” Davis PB, space of a patient is disclosed in U.S. Pat. No. 5,508,269, the ed., Lung Biology in Health and Disease, Vol. 64. New York, disclosure of which is incorporated herein in its entirety by N.Y.: Dekker: 219-76 (1993)). Pseudomonas aeruginosa is this reference. the most significant pathogen in CF lung disease. Over 80% 0007 Another factor tending to inhibit the effectiveness of CF patients eventually become colonized with P. aerugi of aeroSolized antibiotic agents in the treatment of CF noSa (Fitzsimmons S. C., “The changing epidemiology of patients is the presence of an abnormally high level of cystic fibrosis,'J Pediatr 122(1): 1-9 (1993)). The standard mucous secretions. N-acetylcysteine is an aerosolized muco therapy for P. aeruginosa endobronchial infections is 14 to lytic agent often used as adjunctive therapy for pulmonary 21 days of parenteral antipseudomonal antibiotics, typically complications of cystic fibrosis (CF) in combination with including an aminoglycoside. However, parenteral ami Vigorous chest physiotherapy. The Viscosity of mucous noglycosides, as highly polar agents, penetrate poorly into Secretions in the lungs is dependent upon the concentrations the endobronchial Space. To obtain adequate drug concen of mucoprotein, the presence of disulfide bonds between trations at the Site of infection with parenteral administra these macromolecules and DNA. N-acetylcysteine acts to tion, Serum levels approaching those associated with split the sulfide bonds in the macromolecules thereby nephro-, vestibul-, and oto-toxicity are required (“American decreasing Viscosity, allowing for removal by normal chest Academy of Otolaryngology. Guide for the evaluation of physiology. The action of N-acetylcysteine is pH depen hearing handicap,'JAMA 241 (19):2055-9 (1979); Brummett dent-mucolytic action is significant at ranges of pH 7-9. R. E., “Drug-induced ototoxicity."Drugs 19:412-28 (1980)). 0008 An additional factor that contributes to viscous 0004) Aerosolized administration of aminoglycosides mucus in CF patients is extracellular DNA. Bacterial cell offers an attractive alternative, delivering high concentra death and subsequent cell lysis releases DNA into the tions of antibiotic directly to the site of infection in the extracellular environment. This high extracellular DNA con endobronchial Space while minimizing Systemic bioavail tent works to further thicken airway Secretions. (Duplantier ability (Touw D. J. et al., “Inhalation of antibiotics in cystic D, McWaters D S. Cystic fibrosis: progress against a child fibrosis,'Eur Respir J 8:1594-604 (1995); Rosenfeld M. et hood killer. US Pharm 1992; 17:34-52). Recombinant al., “AeroSolized antibiotics for bacterial lower airway infec human DNase has been demonstrated to reduce the viscosity tions: principles, efficacy, and pitfalls,'Clinical Pulmonary of Sputum in CF patients by hydrolyzing the extracellular Medicine 4(2):101-12 (1997)). DNA. DNase is a highly purified solution of recombinant 0005 Tobramycin is commonly prescribed for the treat human deoxyribonuclease I (rhDNase), an enzyme that ment of Serious infections with P. aeruginosa. It is an selectively cleaves DNA. (Kastrup E K, et al. (eds) Respi aminoglycoside antibiotic produced by the actinomycete, ratory inhalant products. In Drug Facts and Comparisons, Streptomyces tenebrarius. Low concentrations of tobramy 1998. St. Louis, Facts and Comparisons. pp 1141-1163.) cin (<4 ug/mL) are effective in inhibiting the growth of Studies have demonstrated that daily administration of many Gram-negative bacteria and under certain conditions recombinant human DNase resulted in improvement in may be bactericidal (Neu, H. C., “Tobramycin: an overview, pulmonary function, as assessed by FEV1, above baseline. 'J Infect Dis 134, Suppl: S3-19 (1976)). Tobramycin is Recombinant human DNase use also resulted in Significant poorly absorbed acroSS mucosal Surfaces, conventionally reduction in the number of patients experiencing respiratory necessitating parenteral administration. Tobramycin activity tract infections that required the use of parenteral antibiotics. is inhibited by purulent Sputum: high concentrations of (Ranasinha C, et al., Efficacy and Safety of Short-term divalent cations, acidic conditions, increased ionic Strength administration of aerosolized recombinant human DNase I and macromolecules that bind the drug all inhibit tobramy in adults with stable stage cystic fibrosis. Lancet 1993; US 2003/O133925 A1 Jul. 17, 2003 342: 199-202.; Genentech. PULMOZYME(R) package insert. BRIEF DESCRIPTION OF THE DRAWINGS San Francisco, Calif., December,1993). 0013 The foregoing aspects and many of the attendant 0009. Although the some of the current conventional advantages of this invention will become more readily delivery Systems and antibacterials have been shown to be appreciated as the Same become better understood by ref clinically efficacious, there is a need for new and improved erence to the following detailed description, when taken in methods, compositions and devices for the delivery of conjunction with the accompanying drawings, wherein: antibiotic compounds to a patient by inhalation to reduce 0014 FIG.
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