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 μm. The addition of L-leucine resulted in minor changes to the MMAD (1.69 ± 0.35 μm) 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.
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Abbreviations
- 1599:
-
Spectinamide 1599
- API:
-
Active Pharmaceutical Ingredient
- APSD:
-
Aerodynamic particle size determination
- AUC:
-
Area under the curve
- Cmax :
-
Peak plasma concentration
- DI:
-
Deionized
- DPI:
-
Dry powder inhaler
- DSC:
-
Differential scanning calorimetry
- EMB:
-
Ethambutol
- FPFED :
-
Emitted dose fine particle fraction
- FPFN :
-
Nominal fine particle fraction
- GSD:
-
Geometric standard deviation
- HILIC:
-
Hydrophobic interatom liquid chromatography
- HIV:
-
Human immunodeficiency virus
- HPMC:
-
Hydroxypropylmethylcellulose
- INH:
-
Isoniazid
- KF:
-
Karl Fischer titration
- Leu:
-
L-leucine
- MDR:
-
Multiple drug-resistant
- MIC:
-
Minimum inhibitory concentration
- MMAD:
-
Mass median aerodynamic diameter
- Mtb :
-
Mycobacterium tuberculosis
- NGI:
-
Next generation impactor
- PK:
-
Pharmacokinetic
- PZA:
-
Pyrazinamide
- RH:
-
Relative Humidity
- RIF:
-
Rifampicin
- SEM:
-
Scanning electron microscopy
- TB:
-
Tuberculosis
- TGA:
-
Thermogravimetric analysis
- WHO:
-
World Health Organization
- XDR:
-
Extensively drug-resistant
- XRD:
-
X-ray diffraction
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Acknowledgments and Disclosures
The authors would like to acknowledge Jennifer Arab and Amanda Walz from Colorado State University for their technical contributions and Phillip Durham, now at UNC Eshelman School of Pharmacy (Chapel Hill, NC, USA), for his insightful discussions. XRD analysis was performed by Todd Ennis at RTI International and XPS analysis was completed by Mark Walters at the Shared Materials Instrumentation Facility (SMIF) at Duke University (Durham, NC, USA). This work was supported by NIH R01 AI120670, R01 AI090810, S10OD016226 and ALSAC, St. Jude Children’s Research Hospital. The authors declare that they have no conflict of interest.
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Stewart, I.E., Lukka, P.B., Liu, J. et al. Development and Characterization of a Dry Powder Formulation for Anti-Tuberculosis Drug Spectinamide 1599. Pharm Res 36, 136 (2019). https://doi.org/10.1007/s11095-019-2666-8
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DOI: https://doi.org/10.1007/s11095-019-2666-8