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Gallium formulation for the treatment and prevention of infe

作者:ihpa.net 发布时间:2017-10-13

STATEMENT CONCERNING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

Certain aspects of the invention disclosed herein were made with United States government support under NIH R41AI072866-01. The United States government may have certain rights in the invention.

FIELD OF THE INVENTION

The invention encompasses a method to formulate gallium for use as an anti-infective for treatment of gram-negative and gram-positive bacteria, viruses, fungi, and protozoa. In particular, the methods describe liquid and dry powder formulations containing gallium in a pharmaceutically acceptable salt or complex thereof, delivered as a liquid or dry powder aerosol.

BACKGROUND OF THE INVENTION

Approximately 100 antibiotics are in use today, 15 in phase 2 or 3 clinical studies, 13 of which are against multi drug-resistant gram-positive and 2 against extended spectrum β-lactamase producing gram-negative bacteria. Heavy antibiotic use and communal spread of bacteria have greatly increased antibiotic resistance, and this problem is continually increasing in severity. The bacterium Pseudomonas aeruginosa (Pa) is a prime example: 30% of clinical isolates from intensive care unit (ICU) or nursing home patients are now resistant to 3 or more drugs, and a similar situation exists for other organisms. Another reason why conventional antibiotics generally work poorly in chronic infections is that the infecting organisms live in biofilms, which are surface-associated bacterial communities encased in a complex biopolymeric matrix. Physiological changes inherent to biofilm growth make bacteria far more resistant to killing by the immune system and antibiotics than cells in the free-living (planktonic) state. Examples of biofilm infections include the airway infections in cystic fibrosis (CF) patients, chronic wound and sinus infections, endocarditis, and medical device infections, among others.

The prominence of Pa infection and its impact on the lungs of CF patients is well documented (Fick (1989) Chest 96:158-164; Hoiby (1993) Annu Rev. Med. 44:1-10). Existing therapies, such as aminoglycoside antibiotics, eventually have little or no impact on disease progression and ultimately, 80-95% of CF patients succumb to respiratory failure due to chronic Pa infection and airway inflammation. Despite recent advances in disease management, the lungs of CF patients are particularly susceptible to chronic bacterial infections. Moreover, current therapies to control Pa infections in CF patients are inconvenient and with modest impact on mortality. There is a consensus that because Pa resides in the lung at the tissue-air interface, the most effective route of antibiotics drug delivery is locally by direct inhalation. The current standard of care to treat Pa infection in CF patients is twice-daily treatment of tobramycin solution administered by oral inhalation for alternating 28-day on-off cycles. The drug administration involves nebulizer priming, followed by approximately half an hour of inhalation at each dosing. Given that CF patients are increasingly burdened with multiple treatment regimens on an average day, the quality of life has become an important factor in the development of new drug therapies; for example, nearly three hours of the day are spent dealing with inhalation therapy (i.e. saline solution, antibiotic and DNase treatment) (Geller, D. E., et al (2007) Pediatric Pulmonology 42:307-313).

Inhaled tobramycin solution represents a significant advancement in treating pulmonary infection in CF patients. Further improvements have been enabled by recent advances in powder engineering, allowing for additional reduction in dose level as well as dosing time. For example, inhalation of tobramycin dry powder produced serum tobramycin PK profiles comparable to those obtained via nebulization, with a significant reduction in dose and shorter administration time. Four capsules of 28 mg (total tobramycin dose 112 mg) produced comparable systemic exposure to 300 mg inhaled nebulized solution, in less than one-third the administration time (Geller, D. E., et al (2007) Pediatric Pulmonology 42:307-313). In addition, tobramycin dry powder increased the local lung exposure, increasing efficacy, and reduced systemic exposure, thereby reducing systemic side effects. The data demonstrated that recent technological improvements in particle engineering and in inhalation devices have enabled a fast, safe, and efficacious delivery of high payload of powder even to the already susceptible CF patients' lungs. However, despite the delivery advances which achieved higher local tobramycin concentrations and delayed the onset of bacterial resistance development, the occurrence of Pa-resistant strains continues (Plasencia, V., et al (2007) Antimicrobial Agents Chemotherapy 51:2574-2581). Therefore, there is not only a need for new classes of safe and efficacious anti-infective agents, but ones that can be delivered locally to the lung with simple and convenient administration experience.

The effectiveness of gallium against Pa has stimulated interests in developing this drug candidate for CF lung infections. For many years, gallium has been used for the treatment of several human and animal disorders, including hypocalcaemia and osteoporosis (Warell et al., U.S. Pat. No. 4,529,593; Bockman et al., U.S. Pat. No. 4,704,277; Bradley et al., U.S. Pat. No. 5,196,412; Bradley et al., U.S. Pat. No. 5,281,578), cancer (Adamson et al. (1975) Cancer Chemothe. Rept 59:599-610; Foster et al. (1986) Cancer Treat Rep 70:1311-1319; Chitambar et al. (1997) Am. J. Clin. Oncol. 20:173-178), wound healing and tissue repair (Bockman et al., U.S. Pat. No. 5,556,645; Bockman et al., U.S. Pat. No. 6,287,606), as well as both intracellular and extracellular infections (Schlesinger et al., U.S. Pat. No. 5,997,912; Schlesinger et al., U.S. Pat. No. 6,203,822; Bernstein, et al., International Patent Application Publication no. WO 03/053347; Perl, U.S. 2008/0241275). These patent documents, and any U.S. counterparts, are expressly incorporated herein by reference. Gallium was shown to be both bacterial growth inhibiting as well as bactericidal as the minimum inhibitory concentration (MIC90) and bactericidal concentration (MBC) of gallium against Pa are both approximately 0.7 μg/mL (Kaneko et al. (2007) J. Clin. Invest. 117:877-888). Gallium nitrate has demonstrated strong bactericidal activity against many gram-negative and gram-positive bacteria. The effectiveness of gallium nitrate against a variety of bacteria found to chronically colonize the lungs of CF patients, such as Pseudomonas aeruginosa, Burkholderia cepacia, and methicillin-resistant Staphylococcus aureus (MRSA), makes it a promising drug candidate for treatment in CF.

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