Tobramycin is an aminoglycoside antibiotic specifically active against Pseudomonas aeruginosa. It is indicated for the long-term management of chronic pulmonary infection due to Pseudomonas aeruginosa in cystic fibrosis (CF) patients aged 6 years and older.
Tobramycin may be administered parenterally for the treatment of chronic pulmonary infection. However, aminoglycoside penetration into the bronchial secretions is poor and to achieve a therapeutic concentration in sputum, high doses are required. Such high doses increase the risk of systemic toxicity.
To avoid the problem of toxicity via parenteral administration, tobramycin may also be administered via inhalation. The preferred approach for administration by inhalation for tobramycin is by nebulisation of an aqueous solution of the tobramycin. Typically, active ingredients are dissolved in saline for nebulisation. However, jet and ultrasonic nebulisers are highly sensitive to the osmolality of the formulation and hence careful control of the tonicity is required. Moreover, cystic fibrosis patients and other patients with chronic endobronchial infections are sensitive to hypo- or hypertonic aerosols.
Tobramycin is marketed in the EU as TOBI®. TOBI® is sold in the form of a 300 mg/5 mL nebuliser solution. One 5 mL nebule contains tobramycin 300 mg as a single dose. It is supplied for use via inhalation. TOBI® contains tobramycin, sodium chloride, water for injection, and sulfuric acid/sodium hydroxide for pH adjustment. The concentration of sodium chloride in the formulation is 2.25 mg/mL.
Further discussion of the formulation may be found in WO 96/12471. WO 96/12471 describes aminoglycoside formulations formulated in about 5 mL of water, wherein the solution contains about 0.225% w/v of sodium chloride. This document also explains the importance of carefully controlling the concentration of the sodium chloride in order to provide correct nebulisation and to avoid bronchospasm in patients sensitive to hypo- or hypertonic aerosols.
WO02/094217, WO 03/004005 and WO 2005/037256 also discuss the importance of carefully controlling the amount of sodium chloride present in the formulation.
A further difficulty in formulating tobramycin is that tobramycin formulations tend to be chemically unstable. TOBI® is supplied with special precautions for storage, namely that it should be stored at 2-8° C. in its original packaging and protected from sunlight. Some yellowing of the formulation also occurs.
WO 96/12471 is not specifically concerned with addressing the problem of storage stability. However, it does explain that the formulation should be treated by nitrogen sparging (see the paragraph bridging pages 15 and 16) in order to minimise hydrolysis and oxidative degradation.
However, there remains a need in the art for chemically stable tobramycin formulations which are capable of being administered by inhalation. The present invention addresses this and other problems with the prior art.
USPTO Backgrounds
USPTO Backgrounds