Invented by Jeffry Weers, Thomas Tarara, Novartis AG

The market for pulmonary administration of a fluoroquinolone has been growing steadily over the years. Fluoroquinolones are a class of antibiotics that are widely used to treat a variety of bacterial infections. They are known for their broad-spectrum activity and are effective against both gram-positive and gram-negative bacteria. The pulmonary administration of fluoroquinolones is a relatively new approach that has gained popularity in recent years. The pulmonary administration of fluoroquinolones involves the delivery of the drug directly to the lungs. This approach is particularly useful in the treatment of respiratory tract infections such as pneumonia, bronchitis, and tuberculosis. The use of pulmonary administration allows for a higher concentration of the drug to be delivered to the site of infection, which can result in faster and more effective treatment. The market for pulmonary administration of fluoroquinolones is driven by several factors. Firstly, the increasing prevalence of respiratory tract infections is a major driver of demand for this approach. Respiratory tract infections are a common cause of morbidity and mortality worldwide, and the use of pulmonary administration of fluoroquinolones can help to improve outcomes for patients. Secondly, the development of new and improved delivery systems for pulmonary administration has also contributed to the growth of this market. Advances in technology have led to the development of more efficient and effective delivery systems, such as nebulizers and inhalers, which have made it easier for patients to receive treatment. Thirdly, the increasing awareness among healthcare providers and patients about the benefits of pulmonary administration of fluoroquinolones has also contributed to the growth of this market. Healthcare providers are increasingly recognizing the advantages of this approach, such as its ability to deliver high concentrations of the drug to the site of infection, and its potential to reduce the risk of systemic side effects. In conclusion, the market for pulmonary administration of fluoroquinolones is expected to continue to grow in the coming years. The increasing prevalence of respiratory tract infections, the development of new and improved delivery systems, and the growing awareness among healthcare providers and patients about the benefits of this approach are all factors that are driving demand for this treatment option. As such, it is likely that we will see continued investment in research and development in this area, as well as increased adoption of this approach in clinical practice.

The Novartis AG invention works as follows

A composition for pulmonary administration consists of a fluoroquinolone-betaine such as ciprofloxacin, and an excipient. One version has particles with a mass median aerodynamic dimension of about 1 to 5 millimeters and a fluoroquinolone half-life in the lungs of at most 1.5 hours. This composition can be used to treat an endobronchial disease, such as Pseudomonas Aeruginosa. It is also useful for cystic Fibrosis.

Background for Pulmonary administration of a fluoroquinolone.

One or more embodiments include pharmaceutical compositions that contain one or more fluoroquinolones such as ciprofloxacin. One or more embodiments include powders containing the betaine form one or more fluoroquinolones such as ciprofloxacin. The present invention includes methods of making, using, and/or administering pharmaceutical compositions, dosage forms thereof, and devices, systems, and methods for the delivery of such compositions to the lungs.

This invention relates compositions and methods to treat bacterial infections and includes particular reference to cystic fibrosis and non-CF bronchiectasis and acute exacerbations of chronic obstructive pulmonary diseases.

Cystic Fibrosis is the most common genetic disease that causes life-threatening complications in the United States. It affects approximately 30,000 people in the United States, and an equal number in Western Europe. This autosomal recessive disorder is caused by a genetic defect in the CF transmembrane conducting regulator (CFTR), which codes for a protein that channels chloride. People with CF often have chronic endobronchial and sinusitis. They also suffer from obstructive hepatobiliary diseases, increased salt loss in sweat, malabsorption, and decreased fertility. Respiratory disease is a leading cause of death and accounts for 90% of all deaths in people with CF. The predictor of survival for CF patients is lung function, measured as forced expiratory volume at one second (FEV1%) The 2-year survival rate for a given population with CF decreases 2-fold for every 10% reduction in FEV1%. Persons with FEV1 lower than 30% have a 2-year survival rate below 50% (Kerem E.,?Predictions of Mortality in Patients With Cystic Fibrosis?,? N Engl J Med 326.1187-1191 (1992). Lung function loss rates vary between individuals and across time. Retrospective longitudinal studies show that rates of decline range from less than 2% FEV1% per year to more than 9% FEV1% per year. The overall rate of decline is strongly associated with the age of death.

Thickening mucus is a sign of CF. It’s thought that thickened mucus may be due to impaired epithelial ion transportation, which impairs lung host defenses. This makes patients more susceptible to early endobronchial infection with Staphylococcus aureus and Haemophilus influenzae. CF patients are more likely to have P. aeruginosa in their sputum by the time they reach adolescence. Endobronchial infections can cause persistent inflammation in the airway, especially with P.aeruginosa. This leads to progressive obstructive diseases such as diffuse bronchiectasis. Winnie, G. B. and others, Respiratory Tract Colonization With Pseudomonas Aeruginosa in Cystic Fibrosis. Correlations Between Pulmonary Function And AxAi -Pseudomonas. Pediatr Pulmonol 10 :92-100 (1991). Evidence of a link between chronic endobronchial P.aeruginosa infection, lung inflammation and loss of lung function and death is supported by the significantly lower survival rate associated with chronic P.aeruginosa infections (Henry R. L. et. al.,?Mucoid Pseudomonas Aeruginosa is an indicator of poor survival in Cystic Fibrosis?,?). Pediatr Pulmonol 12, 158-61 (1992), and the strong association between childhood mortality and early chronic P.aeruginosa infection (Demko and colleagues,?Gender Differences In Cystic Fibrosis: Pseudomonas Aeruginosa Infection. J Clin Epidemiol 48:1041-1049 (1995)).

P. aeruginosa has been treated in CF patients with various therapies. These treatments aim to suppress or reduce bacterial loads in the lungs, as well as suppress inflammation. These therapies are not without their limitations. However, they have been shown to decrease the rate of decline in lung function in patients with bacterial infections.

P. aeruginosa endobronchial infection was treated with parenteral antipseudomonal drugs for 14-21 days, usually including an aminoglycoside. These agents were unable to move efficiently from the bloodstream into lung tissue and secretions, resulting in low therapeutic concentrations at the target area. Due to repeated exposure to parenteral amylosides, resistant strains developed. These isolates were more likely to produce mucus and other virulence factors. It was necessary to obtain sufficient drug concentrations at the site of infection by parenteral administration. These levels should be comparable to those associated with nephrotoxicity, vestibuletoxicity, and ototoxicity (?American Academy of Otolaryngology). Guide for the evaluation and treatment of hearing impairment, JAMA 241 (19):2055-9 (1979); Brummett R. E., Drug-induced ototoxicity. Drugs 19:412-28 (1980 )).

Inhalation of antibiotics such as aminoglycosides is an attractive option. It delivers high concentrations directly to the area of infection in the endobronchial spaces while minimizing systemic Bioavailability.

Tobramycin should not be used in CF patients. IV injections of systemic tobramycin can cause serious side effects, including kidney and ototoxicity. There may be issues with the preparation or administration of nebulized liquids. Also, there could be an increase in resistance to P. aeruginosa (i.e., an increase in the minimal inhibitory concentration value, MIC) during treatment. To avoid resistance, the treatment must be continued for one month with one month off. This will allow the pathogens to repopulate despite the possibility of deterioration of pulmonary function. The long-term effects of inhaled aminoglycosides upon kidney function are not known. It takes approximately 15-20 minutes to administer the 5 mL dose. Additional time is required for setting up and cleaning the nebulizer. Other disadvantages of nebulization include cost, efficiency, reproducibility, risk for bacterial contamination, lack of portability (need to transport bulky compressors, gas cylinders, or power sources) and inefficiency.

To reduce the harmful cycles of infection, obstruction, and inflammation in the CF lungs, there are many other therapies that can be used in addition to the inhaled antibiotics like the TOBI product. Chronic treatment of CF patients can include aggressive airway clearance therapy, inhaled bronchodilators and mucolytics like recombinant Human Dornase Alpha. This creates a significant burden. Many CF patients receive therapy for more than four hours each day. It is not surprising that CF patients have difficulty adhering to their treatment regimens. This can vary depending on the specific treatment. Any regimen that reduces the administration time and allows for easy administration (e.g. device portability and ease-of-use) can be beneficial. This could improve patient compliance and outcome. Alternative inhaled antibiotic formulations that can be administered in the TOBI-off-period could offer a treatment option that does not require the repopulation or loss of pulmonary function.

Ciprofloxacin, a synthetic fluorinated carboxyquinolone, has a wide spectrum of activity. Ciprofloxacin inhibits the synthesis of bacterial deoxyribonucleic acids (DNA) by selectively acting on DNA gyrase, topoisomerase IV. These enzymes are essential for DNA replication, repair, transcription and topology control. Ciprofloxacin has shown good in-vitro activity against many pathogens that can cause respiratory infections including Mycobacterium tuberculosis and Mycobacterium intracellulare. Ciprofloxacin, which is considered to be one of the most effective fluoroquinolones against P.aeruginosa is also highly bactericidal. Clinically, ciprofloxacin has been administered intravenous and oral to treat respiratory tract infections.

Despite its success, ciprofloxacin has limitations in clinical use for lung infections. Its poor solubility at physiological pH, bitter taste and rapid renal clearance are just some of the factors that limit the drug?s clinical utility. To administer 500 mg intravenously, it must be dilute to 2 mg/ml, and infused slowly to prevent precipitation at injection site. Ciprofloxacin intravenously and orally has unfavorable profiles in the lower respiratory tract. It can be administered intravenously, orally, with a short elimination half-life, a low area below the concentration-time curve, and a low elimination rate of 1.0 to 1.5 hours.

Patients in need of ciprofloxacin, such as CF patients, COPD and anthraz patients would likely inhale high bactericidal levels in their airways. Sub-inhibitory levels of ciprofloxacin can affect the virulence and quorum sensing of P. aeruginosa, as well as reduce the risk of chronic airway infections for CF patients. A decrease in the airway bacteria load and possibly a slowing of re-infection could result in improved lung function and a better long-term prognosis. Inhaling ciprofloxacin can also be used to treat renal insufficiency that may have been caused by treatment with aminoglycosides.

However, effective pulmonary delivery has been difficult. The potential for rapid clearance of antiinfectives like ciprofloxacin from the lungs is a challenge. Following intratracheal administration, soluble ciprofloxacin hydrochloride is rapidly absorbed from the lungs into the systemic circulation with a half-life of just 0.2 hr (Wong J P, Cherwonogroszky J W, DiNinno V L et al: Liposome-encapsulated ciprofloxacin for the prevention and treatment of infectious diseases caused by intracellular pathogens. In: “Liposomes for Biomedical Applications?” (Florence A T and Gregoriadis, eds.) Harwood Academic Press Amsterdam 1995, p. 105-120. This time frame is too short for effective treatment of endobronchial P. Aeruginosa infections and poses a significant challenge in formulation development.

Researchers have looked into encapsulation with controlled release carriers such as liposomes to help overcome rapid clearance of ciprofloxacin chloride from the lungs. Wong and colleagues demonstrated significant increases in lung residence times after using liposomal Ciprofloxacin. This led to effective treatment of Francicella Tularensis in rodent models. There are two limitations to liposomal delivery via nebulization of ciprofloxacin: (1) extended administration times because of low drug loadings, and (2) limits on acceptable dispersion concentrations for nebulization (viscosity constraint); (2) limited control over the release kinetics. A standard jet nebulizer used in the Wong study. These nebulizers usually have a flow rate between 0.1 and 0.2 ml/min. The flow rate at a drug content of 10-40 mg/ml was between 1 and 8 mg/min. With a 10% delivery efficiency, the flow rate would deliver only 0.1 to 0.8%?g/min to the lungs. This model does not allow for lung doses exceeding 10 mg.

The use of polymeric carriers to prolong the ciprofloxacin hydrochloride’s lung residence time has not been incorporated into clinical practice.” There are still concerns about the slow clearance from the lungs of polymeric carriers.

Ciprofloxacin is highly soluble at pH values lower than pK1 (6.0), and higher than pK2 (8.8). The pH range of 6.0 to 8.8 is where the compound is zwitterionic and practically insoluble. Solubility at pH 7 is 60?g/ml. Studies have shown that the zwitterionic ciprofloxacin-betaine has a longer residence time in the lungs (Endermann, Labischinski, Labischinski, Ladel C, et al. Treatment of bacterial diseases. US Patent Appl US 2004/0254194A Endermann and colleagues do not instruct the patient how to administer ciprofloxacin.

Additionally, the need for therapeutic doses of antiinfectives in the lungs (>10 mg) is a major challenge. Aerosol delivery is dominated by asthma therapeutics, such as bronchodilators or corticosteroids. FIG. 1 Asthma drugs are very potent, with delivered lung doses less than 100 micrograms (?g. Also see Clark A, Weers J, Challoner PH: High-dose inhaled powder delivery: difficulties and techniques. In:?Respiratory drug delivery IX? (R N Dalby and P R Byron; J Peart, J D Suman and J D Suman, Eds.) Davis Healthcare Intl Publishing River Grove, Ill. 2004 pp 281-288

The existing treatments suffer from many deficiencies. There is still a need to find more efficient and convenient ways to administer antibiotic aerosols. The present invention addresses one or more of these requirements.

The invention addresses these needs.

In one aspect, the invention provides a pharmaceutical formulation for the delivery of a fluoroquinolone to the lungs. It is such a formulation that it can be delivered directly to the lungs.

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