Drug – bio-affecting and body treating compositions – Effervescent or pressurized fluid containing – Organic pressurized fluid
Reexamination Certificate
2001-12-20
2003-12-09
Hartley, Michael G. (Department: 1616)
Drug, bio-affecting and body treating compositions
Effervescent or pressurized fluid containing
Organic pressurized fluid
C424S046000, C424S489000, C514S002600, C128S203140
Reexamination Certificate
active
06660249
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The current invention concerns a novel, safe, nonirritating and physiologically compatible inhalable aztreonam formulation suitable for treatment of pulmonary bacterial infections caused by gram negative bacteria, such as
Escherichia coli,
Enterobacteria species,
Klebsiella pneumoniae, K. oxytoca, Proteus mirabilis, Pseudomonas aeruginosa, Serratia marcescens, Haemophilus influenzae, Burkholderia cepacia, Stenotrophomonas maltophilia, Alcaligenes xylosoxidans.
In particular, the invention concerns the inhalable formulation comprising aztreonam or a pharmaceutically acceptable salt thereof suitable for treatment and prophylaxis of acute and chronic pulmonary bacterial infections, particularly those caused by gram-negative bacteria
Burkholderia cepacia, Stenotrophomonas maltophlia, Alcaligenes xylosoxidans,
and multidrug resistant
Pseudomonas aeruginosa
which are resistant to treatment with other antibiotics. The inhalable formulation is delivered as an aerosol or as an inhalable dry powder. For aerosolization, about 1 to about 250 mg of aztreonam is dissolved in about 1 to about 5 ml of saline or other aqueous solution having a pH between 4.5 and 7.5, delivered to the lung endobronchial space in an aerosol having mass medium average diameter particles predominantly between 1 to 5&mgr; using a nebulizer able to atomize the aztreonam solution into particles of required sizes. The aerosol formulation has a small volume yet delivers a therapeutically efficacious dose of aztreonam to the site of the infection in amounts sufficient to treat bacterial pulmonary infections. A combination of the novel formulation with the atomizing nebulizer permits about 50% delivery of the administered dose of aztreonam into airways. For delivery of dry inhalable powder, aztreonam is milled or spray dried to particle sizes between about 1 and 5&mgr;. The dry powder formulation or a reconstituted aztreonam solid for aerosolization have a long shelf-life and storage stability.
2. Background and Related Disclosures
A wide variety of gram-negative bacteria cause severe pulmonary infections. Many of these bacteria are or become resistant to commonly used or specialty antibiotics and require treatment with new types of antibiotics. The pulmonary infections caused by gram-negative bacteria are particularly dangerous to patients who have decreased immunoprotective responses, such as for example cystic fibrosis and HIV patients, patients with bronchiectasis or those on mechanical ventilation.
Therefore, the bacterial respiratory infections caused by organisms resistant to antibiotics continues to be a major problem, particularly in immunocompromised or hospitalized patients, as well as in patients assisted by mechanical ventilation, as described in
Principles and Practice of Infectious Diseases,
Eds. Mandel, G. L., Bennett, J. E., and Dolin, R., Churchill Livingstone Inc., New York, N.Y., (1995).
Currently accepted therapy for severe bacterial respiratory tract infections, particularly for treatment of pneumonia in patients with underlying illnesses, includes treatment with various intravenous antibacterial agents, often used in two or three way combination. Most of these agents are not suitable, available or FDA approved for either oral or aerosol dosing. In some cases the efficacious systemic intravenous or oral dose, if oral delivery is possible, requires doses which are borderline or outright toxic thus often preventing a use of perfectly good antibiotic for treatment of the pulmonary infections.
Thus it would be desirable to have available other modes of delivery routes of these antibiotics enabling a targeted delivery of smaller amounts of the antibiotic to endobronchial space of airways for treatment of these bacterial infections rather than administering the antibiotic systemically in large amounts.
Additionally, chronically ill patients are often affected with infections caused by bacteria which are largely resistant to commonly used antibiotics or, upon extended use of certain antibiotic, often develop strong resistance to such antibiotic. For example, chronic pulmonary colonization with
Pseudomonas aeruginosa
in patients with cystic fibrosis is a principal cause of their high mortality. When established, the chronic pulmonary infection is very difficult, if not impossible, to eradicate. More than 60% of cystic fibrosis patients are colonized with
Pseudomonas aeruginosa
bacterium strains which are largely resistant to regular and specialty antibiotics, such as piperacillin, ticarcillin, meropenem, netilmicin and only little sensitive to azlocillin, ciprofloxacin, timentin and ceftazidime. Many strains have also been shown to develop resistance to tobramycin and to colistin, if used continuously.
Often, after prolonged antibiotic therapy, a superinfection with organisms intrinsically resistant to oral, intravenous or inhaled antibiotics develops in patients with cystic fibrosis and other chronic pulmonary infections. The four most common drug resistant organisms are
Burkholderia cepacia, Stenotrophomonas maltophilia, Alcaligenes xylosoxidans,
and multidrug resistant
Pseudomonas aeruginosa.
Cystic fibrosis patients infected with
Burkholderia cepacia
have an increased rate of mortality compared to those patients with
Pseudomonas aeruginosa
infections. In some cystic fibrosis patients,
Burkholderia cepacia
can cause a rapid fatality, as described, for example in
Am. J. Respir. Crit. Care Med.,
160: 5, 1572-7 (1999).
The high level of antibiotic resistance demonstrated by most strains of
Burkholderia cepacia
severely limits therapeutic options for its treatment (
Clinics Chest Med.,
19:473-86 (September 1998)). Furthermore, unlike
Pseudomonas aeruginosa, Burkholderia cepacia
can cause epidemic spread among cystic fibrosis patients and therefore any patient infected with
Burkholderia cepacia
is usually isolated from other patients. This causes both additional expenses connected with caring for these patients and may also be psychologically devastating to the patient. Furthermore, most lung transplant centers will not perform a lung transplant on patients infected with
Burkholderia cepacia
(
Clinics Chest Med.,
19:473-86 (September 1998)). Therefore, the
Burkholderia cepacia
infection is often viewed as a death sentence by patients with cystic fibrosis.
Burkholderia cepacia
is usually resistant to the parenteral delivery of various antibiotics, including aztreonam, with showing only 5% of isolates to be sensitive to such treatment (
Antimicrob. Agents Chemother.,
34: 3, 487-8 (March 1990)). Thus it would be advantageous to have available treatment for
Burkholderia cepacia
infections.
Other gram-negative bacteria intrinsically resistant to tobramycin can also complicate the care of a cystic fibrosis patient. These bacteria include
Stenotrophomonas maltophilia
and
Alcaligenes xylosoxidans.
Antibiotic therapy of these infections is usually also ineffective or leads to rapid emergence of drug resistance. Therefore, the successful treatment of all these infections requires that samples of these isolates are sent to a laboratory for complex antibiotic synergy determination of proper therapy for each individual patient (
Ped. Pulmon., S
17: 118-119 (1998)). It would, therefore, be also advantageous to provide a therapy for these rare but hard to treat bacterial infections.
Similarly, the development of
P. aeruginosa
infection with strains which are resistant to, that is which have a high minimal inhibitory concentration (MIC) to a majority of antibiotics including tobramycin, predicts declining lung function and also may disqualify the patient from consideration for lung transplant (
Clinics Chest Med.,
19:535-554 (September 1998)).
Existing antibiotic treatments for
Burkholderia cepacia, Stenotrophomonas maltophilia, Alcaligenes xylosoxidans,
and multidrug resistant
Pseudomonas aeruginosa
pulmonary infections are either ineffective, or lead to rapid emergence of drug resistance.
From the brief description a
Haghighatian Mina
Hartley Michael G.
Salus Pharma, Inc.
Verny Hana
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