Optimised formulation of tobramycin for aerosolization

• US 20050163722A1
• Filed: 03/18/2005
• Published: 07/28/2005
• Est. Priority Date: 07/02/2001
• Status: Active Grant

• Current Assignee: Chiesi Farmaceutici SPA (Valline Srl)
• Original Assignee: Chiesi Farmaceutici SPA (Valline Srl)
• Inventors: Garzia, Raffaella, Malvolti, Chiara
• Granted Patent: US 7,696,178 B2
• Time in Patent Office: Days
• US Class Current: 424/45
• 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 11/06 Antiasthmatics
• CPC Class Codes: A61P 11/08 Bronchodilators
• CPC Class Codes: A61P 11/12 Mucolytics
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 Antibacterial agents

Abstract

The invention provides a tobramycin formulation for delivery by aerosolization in the form of additive-free, isotonic solution whose pH has been optimised to ensure adequate shelf-life at room temperature. Said formulation can be advantageously used for the treatment and prophylaxis of acute and chronic endobronchial infections, in particular those caused by the bacterium Pseudomonas aeruginosa associated to lung diseases such as cystic fibrosis.

Claims

1. An aerosol formulation, comprising:

75 mg/ml of tobramycin dissolved in an aqueous solution containing 0.45% sodium chloride;

wherein the pH is between 4.0 and 5.5 and the osmolarity ranges between 250 and 450 mOsm/l.

2. The aerosol formulation according to claim 1, wherein the pH is 5.2 and the osmolarity is between 280 and 350 mOsm/l.

3. A process for the preparation of an aerosol formulation according to claim 1, comprising:

i) preparing an aqueous solution containing 0.45% w/v of sodium chloride;

ii) adjusting the pH with a concentrated strong acid;

iii) adding the active ingredient and mixing to complete dissolution;

iv) re-adjusting the pH to the desired value;

v) filling the solution in suitable container.

4. The process according to claim 3, wherein the solution is pre-sterilized by filtration.

5. The aerosol formulation according to claim 1, wherein said osmolarity is 280 to 350 mOsm/l.

6. The process according to claim 3, wherein the concentrated strong acid is sulfuric acid.

7. The process according to claim 3, wherein in step ii) the pH is adjusted to 4.0 to 5.5.

8. The process according to claim 3, wherein in step iv) the pH is re-adjusted to 4.0 to 5.5.

9. The process according to claim 3, wherein said container is a multidose vial.

10. The process according to claim 3, wherein said container is a pre-sterilized unit vial of 2 ml.

11. The process according to claim 3, wherein said container is a pre-sterilized unit vial of 4 ml.

12. The process according to claim 3, wherein said filling in step v) is carried out under an inert atmosphere.

13. The aerosol formulation according to claim 1, which is stable for at least 9 month at room temperature.