Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2001-11-28
2002-05-14
Henley, III, Raymond (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S037000, C514S039000, C514S041000
Reexamination Certificate
active
06387886
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to methods and compositions for the treatment of severe chronic bronchitis or bronchiectasis by endobronchial delivery of aminoglycoside antibiotic compounds, such as tobramycin. In particular, the invention concerns formulations including aminoglycoside powders or concentrated solutions having pH between 5.5 and 7.0. The formulations permit delivery of aminoglycoside antibiotic compounds to the lung endobronchial space of airways in dry powder form or as an aerosol having mass medium average diameter predominantly between 1 to 5&mgr;. The formulated and delivered efficacious amount of aminoglycoside antibiotic compound, such as tobramycin, is sufficient for treatment and prophylaxis of acute and chronic endobronchial infections, particularly those caused by the bacterium
Pseudomonas aeruginosa
. In other aspects, the invention relates to the endobronchial delivery of effective amounts of an aminoglycoside antibiotic, such as tobramycin, to patients with bronchiectasis with
P. aeruginosa
to cause substantially complete eradication of the organism. The novel formulations have small volume yet deliver effective doses of aminoglycoside antibiotic compounds to the site of the infection.
BACKGROUND OF THE INVENTION
Bronchiectasis is defined as irreversible abnormal dilatation of the airways. Bronchiectasis can be caused by either acquired or congenital mechanisms that disrupt the normal processes of airway clearance and/or host defense. These causes may include ciliary motility disorders and cystic fibrosis (CF), or processes that cause persistent damage, such as a bacterial or viral pneumonia. Defects in host defense such as agammaglobulinemia, or mechanical processes such as foreign bodies that cause post-obstructive infection can also result in bronchiectasis (Barker, A. F. et al., “Bronchiectasis: update of an orphan disease,”
Am Rev Respir Dis
; 137(4):969-78(1988)). Morbidity from bronchiectasis is caused by persistent airway infection. Treatment of infection may reduce morbidity. The microbiology of lung infections in CF has been well characterized, with
Staphylococcus aureus, Haemophilus influenzae
, and
Pseudomonas aeruginosa
colonizing in an age-related sequence.
P. aeruginosa
infects 60% of all patients with CF (Cystic Fibrosis Foundation,
Cystic Fibrosis Foundation Patient Registry, Annual Data Report
1992, (1993)). However, the microbiology of bronchiectasis in patients without CF has not been well-characterized. One retrospective study of bronchiectasis found the most frequently isolated organisms to be
P. aeruginosa
(30.9% of patients),
Haemophilus influenzae
(30.1%), mycobacteria (22.8%),
Mycobacterium avium
-
intracelluare
(17.1%), other Gram-negative bacilli (13%), and
Streptococcus pneumoniae
(10.6%) (Nicotra, M. B. et al., “Clinical, pathophysiologic, and microbiologic characterization of bronchiectasis in an aging cohort,”
Chest
108(4):955-61 (1995)).
Clinically, bronchiectasis is characterized by chronic airway infection, associated with intermittent exacerbations. Infection may manifest by expectoration of purulent sputum, fever, malaise, and weight loss. The density of
P. aeruginosa
in sputum in patients with exacerbations of bronchiectasis has been estimated at 10
7
cfu/mL (Currie D. C. et al., “Simple method of monitoring colonizing microbial load in chronic bronchial sepsis: pilot comparison of reduction in colonizing microbial load with antibiotics given intermittently and continuously,”
J Clin Pathol
40:830-836 (1987)). Exacerbations may be treated with oral or parenteral antibiotics, but the options for treatment of
P. aeruginosa
are limited. One common regimen, a 14-21 day course of parenteral aminoglycoside in combination with a third-generation cephalosporin, is widely used but has several disadvantages. The penetration of parenterally-administered aminoglycosides into bronchial secretions is poor and thus hill doses must be given in order to achieve high sputum concentrations (Pennington J. E., “Penetration of antibiotics into respiratory secretions,”
Rev Infect Dis
3(1):67-73 (1981)). High doses and multiple courses of therapy lead to high serum concentrations and increase the risk of serious adverse effects, such as ototoxicity and nephrotoxicity. Treatment of patients with bronchiectasis with
P. aeruginosa
seldom, if ever, eradicates the organisms—most of the treatment benefit from either oral or IV antibiotics just suppresses growth, with regrowth occurring after discontinuation of antibiotic therapy. Therefore, any method that can eradicate infection for any period of time would be useful, novel and an advance in the art.
Tobramycin is commonly prescribed for the treatment of serious infections with
P. aeruginosa
. It is an aminoglycoside antibiotic produced by the actinomycete,
Streptomyces tenebrarius
. Low concentrations of tobramycin (<4 &mgr;g/mL) are effective in inhibiting the growth of many Gram-negative bacteria and under certain conditions may be bactericidal (Neu. H. C., “Tobramycin: an overview,”
J Infect Dis
134, Suppl: S3-19 (1976)). Tobramycin is poorly absorbed across mucosal surfaces, necessitating parenteral administration. Tobramycin activity is inhibited by purulent sputum: high concentrations of divalent cations, acidic conditions, increased ionic strength and macromolecules that bind the drug all inhibit tobramycin in this environment. It is estimated that 5-10× higher concentrations of tobramycin are required in the sputum to overcome these inhibitory effects (Ledy J. et al., “Bioactivity of gentamicin in purulent sputum from patients with cystic fibrosis or bronchiectasis: comparison with activity in serum,”
J Infect Dis
148(6):1069-76 (1983)).
Delivery of the poorly absorbed antibiotic tobramycin to the airway by the aerosol route of cystic fibrosis (CF) patients has been documented using the aerosol route. Much of this work has been done toward treatment of chronic lung infections with
P. aeruginosa
in cystic fibrosis (CF) patients. A multicenter, double blind, placebo-controlled, crossover trial of 600 mg tid of aerosolized tobramycin for endobronchial infections due to
P. aeruginosa in
71 CF patients demonstrated a significant reduction in sputum density of this pathogen as well as improved spirometry in the treatment group. Emergence of
P. aeruginosa
strains highly resistant to tobramycin (defined as MIC >128 &mgr;g/mL) was comparable in the placebo and treatment groups. The presence in the sputum of Gram-negative organisms other than
P. aeruginosa
intrinsically resistant to tobramycin occurred with equal frequency during administration of tobramycin or placebo (Ramsey B. et al., “Response to Letter to the Editor: Aerosolized tobramycin in patients with cystic fibrosis,”
N Engl J Med
329:1660 (1993)).
Although this regimen was found to be both safe and efficacious, it is costly and inconvenient. A survey of the MICs for
P. aeruginosa
isolates from initial sputum cultures for patients at the Children's Hospital CF Center, Seattle, Wash., in 1993 found that 90% of isolates had MICs <16 &mgr;g/mL and 98% of all isolates had MICs ≦128 &mgr;g/mL. This survey suggested that achieving a sputum tobramycin concentration of 128 &mgr;g/mL should treat the endobronchial infection in CF patients (Levy J. et al., “Bioactivity of gentamicin in purulent sputum from patients with cystic fibrosis or bronchiectasis: comparison with activity in serum,”
J Infect Dis
148(6):1069-76 (1983)).
A randomized, cross-over study compared the ability of several nebulizers to deliver tobramycin by measuring peak sputum tobramycin concentrations in samples collected ten minutes after completion of the aerosol dose. This study used a new formulation. TOBI®, PathoGenesis Corporation, Seattle, Wash., containing 60 mg/mL, tobramycin in 5 mL one quarter (¼) normal saline. The Pari® LC jet nebulizer, Pari Respiratory Equipment, Inc., Richmond, Va., delivered a mean peak sputum tobramycin concentration of 678.8 &mgr;g/g (s.d. 66
Baker William R.
Montgomery Alan B.
Blackburn Robert P.
Chiron Corporation
Henley III Raymond
Lentini David P.
Shelton Dennis K.
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