Method and a tobramycin aerosol formulation for treatment prevention and containment of tuberculosis

• US 6,083,922 A
• Filed: 04/02/1997
• Issued: 07/04/2000
• Est. Priority Date: 04/02/1996
• Status: Expired due to Term

• Current Assignee: Chiron Corporation (Bayer AG)
• Original Assignee: PathoGenesis Corporation (Bayer AG)
• Inventors: Montgomery, Alan Bruce
• Primary Examiner(s): Peselev, Elli
• Application Number:
  US08/825,725
• Time in Patent Office: 1,189 Days
• Field of Search: 514/38, 514/924, 424/43
• US Class Current: 514/38
• CPC Class Codes: A61K 31/7036 having at least one amino group directly attached to the carbocyclic ring, e.g. streptomycin, gentamycin, amikacin, validamycin, fortimicins
• CPC Class Codes: A61K 9/0078 for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 31/06 for tuberculosis

Abstract

A method for treatment, prevention and containment of acute and chronic tuberculosis using a preservative-free concentrated tobramycin aerosol formulation delivering tobramycin to the lung endobronchial space including alveoli in an aerosol having mass medium average diameter predominantly between 1 to 5μ. The method comprises administration of tobramycin in concentration one to ten thousand times higher than the minimal inhibitory concentration of Mycobacterium tuberculosis. A method for containment of and decreasing infectivity periods of tuberculosis patients to shorter periods of time.

Claims

1. A method for treatment and containment of infectivity of pulmonary tuberculosis by providing a patient in need of such treatment an aerosol formulation comprising aerosolized tobramycin, said method comprising a step:

(a) administering to the patient a nebulized aerosol formulation consisting essentially of from about 40 to about 800 mg tobramycin dissolved in full strength or diluted saline adjusted to pH between 5.5 and 7.0 using a nebulizer producing an aerosolized tobramycin of particles sizes of which a mass medium average diameter is predominantly between 1 and 5μ

once or twice daily at least until a count of Mycobacterium tuberculosis decreases to less than 10³.

2. The method of claim 1 wherein the formulation is consisting essentially of from about 80 to about 300 mg of tobramycin dissolved in about 3 to about 5 mL of the full strength or diluted saline adjusted to pH between about 5.5 and 6.5.

3. The method of claim 2 wherein said formulation is consisting essentially of 300 mg of tobramycin administered by a jet nebulizer able to produce aerosol particle sizes predominantly between about 1 and about 5 microns.

4. The method of claim 1 suitable for therapy of pulmonary tuberculosis wherein the treatment comprises administration of aerosolized tobramycin in concentration from about 100 to about 400 mg twice daily for at least five days or more.

5. The method of claim 4 wherein the treatment comprises administration about 200 to about 300 mg of aerosolized tobramycin per one treatment.

6. The method of claim 5 wherein the treatment comprises administration of aerosolized tobramycin in concentration of about 300 mg.

11. The method of claim 4 wherein the treatment further comprises administration of a concentrated tobramycin solution consisting essentially of 100 to 600 mg of tobramycin by spray or smear.

7. A method for containment of infectivity of pulmonary tuberculosis in a patient infected with Mycobacterium tuberculosis by providing said patient a tobramycin aerosol formulation, said method comprising steps:

(a) administering to said patient a nebulized tobramycin aerosol formulation consisting essentially of from about 40 to about 800 mg tobramycin dissolved in the full strength or diluted saline adjusted to pH between 5.5 and 7.0 using a nebulizer producing an aerosolized tobramycin of particles sizes of which a mass medium average diameter is predominantly between 1 and 5μ

, said formulation administered once or twice daily;

(b) continuing such treatment until inhibition of at least 95% of susceptible Mycobacterium tuberculosis in endobronchial space of lower lungs, upper lung, alveoli, larynx and pharynx of said patient is achieved or until a count of Mycobacterium tuberculosis decreases to less than 10³.

8. The method of claim 7 wherein the tobramycin formulation is consisting essentially of from about 80 to about 300 mg of tobramycin dissolved in about 1 to about 5 mL of normal or diluted saline.

9. The method of claim 7 wherein the tobramycin formulation is consisting essentially of from about 100 to about 200 mg of tobramycin dissolved in about 1 to about 5 mL of normal or diluted saline.

10. The method of claim 7 wherein tobramycin aerosol formulation is consisting essentially of from about 300 to about 600 mg of tobramycin dissolved in about 1 to about 5 mL of normal or diluted saline.

12. An aerosol formulation suitable for treatment of pulmonary infection, said formulation consisting essentially of from about 40 to about 800 mg of tobramycin dissolved in about 3 to about 7 mL of a normal or diluted saline adjusted to pH between about 5.5 and 7.0 and administered by aerosolization using a jet or ultrasonic nebulizer able to produce aerosol particle sizes predominantly between 1 and 5μ

.

13. The formulation of claim 12 wherein the saline is a quarter normal saline.

14. The formulation of claim 13 wherein the nebulizer is the jet nebulizer and wherein the pH of the formulation is adjusted to about 5.5 to about 6.0.

15. The formulation of claim 13 wherein the nebulizer is the ultrasonic nebulizer and wherein the pH of the formulation is adjusted to about 5.5 to about 6.0.

16. The formulation of claim 14 consisting essentially of from about 100 to about 400 mg of tobramycin dissolved in about 5 mL of quarter normal saline solution.

17. The formulation of claim 16 consisting essentially of about 300 mg of tobramycin.

18. A method for treatment of Mycobacterium tuberculosis infections comprising steps:

(a) administering to upper lung, lower lung and sputum of a patient infected with Mycobacterium tuberculosis twice a day an aerosol formulation consisting essentially of about 300 mg of tobramycin dissolved in about 5 mL of solution containing a quarter normal saline adjusted to pH between about 5.5 and 6.5 by nebulization using a jet or ultrasonic nebulizer able to produce predominantly aerosol particle size between 1 and 5μ

;

(b) periodically determining a count of Mycobacterium tuberculosis in the patient'"'"'s sputum; and

(c) continuing the treatment of step (a) until the count of Mycobacterium tuberculosis in sputum is lower than 10³ or until undetectable.

19. A method for prophylactic treatment of an individual exposed to a Mycobacterium tuberculosis infection and showing a determinable count of Mycobacterium tuberculosis but not experiencing tuberculosis symptoms, said method comprising steps:

(a) determining a presence of Mycobacterium tuberculosis in the sputum of individual exposed to the infection;

(b) administering to the individual exposed to the Mycobacterium tuberculosis infection a nebulized tobramycin formulation of consisting essentially of about 200 to about 300 mg of tobramycin, once or twice a day for at least five days,

wherein said tobramycin is dissolved in about 3 to 5 mL of normal or quarter normal saline adjusted to pH between about 5.5 and 6.5; and

wherein said formulation is administered by a jet or ultrasonic nebulizer producing an aerosol having a particle sizes predominantly between about 1 and about 5 microns,

said aerosol delivering a sufficient amount of tobramycin to upper airways, lower airways and sputum to eradicate the Mycobacterium tuberculosis; and

(c) determining an absence of Mycobacterium tuberculosis in sputum following the treatment.

20. A method for prophylactic treatment of an individual exposed to a Mycobacterium tuberculosis infection but not showing a detectable count of Mycobacterium tuberculosis, said method comprising steps:

(a) administering to the individual exposed to the Mycobacterium tuberculosis infection a nebulized tobramycin formulation consisting essentially of about 100 to about 200 mg of tobramycin, once or twice a day for at least five days,

wherein said tobramycin is dissolved in about 3 to 5 mL of normal or quarter normal saline adjusted to pH between about 5.5 and 6.5; and

wherein said formulation is administered by a jet or ultrasonic nebulizer producing an aerosol having a particle sizes predominantly between about 1 and about 5 microns,

said aerosol delivering a sufficient amount of tobramycin to upper airways, lower airways and sputum to eradicate the Mycobacterium tuberculosis; and

(b) confirming an absence of Mycobacterium tuberculosis in sputum following the treatment.