Dataset Information

Development and Characterization of a Dry Powder Formulation for Anti-Tuberculosis Drug Spectinamide 1599.

ABSTRACT:

Purpose

Human tuberculosis (TB) is a global health problem that causes nearly 2 million deaths per year. Anti-TB therapy exists, but it needs to be administered as a cocktail of antibiotics for six months. This lengthy therapy results in low patient compliance and is the main reason attributable to the emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains of Mycobacterium tuberculosis.

Methods

One alternative approach is to combine anti-TB multidrug therapy with inhalational TB therapy. The aim of this work was to develop and characterize dry powder formulations of spectinamide 1599 and ensure in vitro and in vivo delivered dose reproducibility using custom dosators.

Results

Amorphous dry powders of spectinamide 1599 were successfully spray dried with mass median aerodynamic diameter (MMAD)?=?2.32?±?0.05 ?m. The addition of L-leucine resulted in minor changes to the MMAD (1.69?±?0.35 ?m) but significantly improved the inhalable portion of spectinamide 1599 while maintaining amorphous qualities. Additionally, we were able to demonstrate reproducibility of dry powder administration in vitro and in vivo in mice.

Conclusions

The corresponding systemic drug exposure data indicates dose-dependent exposure in vivo in mice after dry powder intrapulmonary aerosol delivery in the dose range 15.4 - 32.8 mg/kg.

SUBMITTER: Stewart IE

PROVIDER: S-EPMC7851762 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Publications

Development and Characterization of a Dry Powder Formulation for Anti-Tuberculosis Drug Spectinamide 1599.

Stewart Ian E IE Lukka Pradeep B PB Liu Jiuyu J Meibohm Bernd B Gonzalez-Juarrero Mercedes M Braunstein Miriam S MS Lee Richard E RE Hickey Anthony J AJ

Pharmaceutical research 20190718 9

<h4>Purpose</h4>Human tuberculosis (TB) is a global health problem that causes nearly 2 million deaths per year. Anti-TB therapy exists, but it needs to be administered as a cocktail of antibiotics for six months. This lengthy therapy results in low patient compliance and is the main reason attributable to the emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains of Mycobacterium tuberculosis.<h4>Methods</h4>One alternative approach is to combine anti-TB multidrug t ...[more]

PMID: 31321552

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Project description:BackgroundOral and intravenous formulations of ciprofloxacin have established efficacy and safety profiles in respiratory infections. A dry powder for inhalation (DPI) that uses Novartis' PulmoSphere™ technology has been developed to deliver high concentrations of ciprofloxacin to the lung with low systemic exposure using a portable and convenient passive dry powder inhaler (Novartis' T-326 inhaler).ObjectivesThe primary objective was to investigate the safety and tolerability of ciprofloxacin DPI in healthy male subjects, with a secondary objective to investigate the pharmacokinetics of ciprofloxacin after ciprofloxacin DPI administration.MethodsThis was a phase I, single-dose, single-site, randomized, single-blind, placebo-controlled, crossover study conducted in the hospital setting. Subjects were followed up for safety for approximately 2 weeks. Six healthy male subjects, aged 27-42 years with no history of pulmonary disease, repeated bronchitis or respiratory allergies were enrolled. In randomized order and separated by a 1-week washout period, subjects inhaled a single dose of ciprofloxacin DPI 32.5 mg or placebo from the T-326 inhaler. Primary safety parameters included vital signs, electrocardiogram, laboratory tests, adverse events and lung function (total specific resistance, thoracic gas volume and forced expiratory volume in 1 s). Plasma concentration-time data were used to calculate pharmacokinetic parameters.ResultsCiprofloxacin DPI was well tolerated with no clinically relevant adverse effects on lung function. Estimates of lung deposition derived from physiology-based pharmacokinetic modelling suggest that approximately 40 % of the total dose of ciprofloxacin DPI reached the trachea/bronchi and alveolar space. Systemic ciprofloxacin was detected soon after inhalation [peak concentration in plasma (C(max)) 56.42 μg/L, median time to C max 0.625 h], but total systemic exposure was minimal (area under the plasma concentration-time curve 354.4 μg·h/L). Terminal elimination half-life (9.5 h), apparent total clearance from plasma after non-intravenous administration (91.7 L/h) and apparent volume of distribution (1,262 L) data suggest that elimination from the respiratory tract was prolonged.ConclusionsIn healthy subjects, ciprofloxacin DPI was well tolerated, delivered ciprofloxacin to the lungs and resulted in minimal systemic exposure, allowing further investigation of its clinical use for the management of specific, chronic infections in pulmonary diseases.

Dataset Information

Development and Characterization of a Dry Powder Formulation for Anti-Tuberculosis Drug Spectinamide 1599.

Purpose

Methods

Results

Conclusions

Publications

Development and Characterization of a Dry Powder Formulation for Anti-Tuberculosis Drug Spectinamide 1599.

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