Skip to main content

Advertisement

SpringerLink
Log in

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

  • Research Paper
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1.
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

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

References

  1. WorldHealthOrganization. Tuberculosis Key Facts. WHO Press. Available from: http://www.who.int/en/news-room/fact-sheets/detail/tuberculosis. March 2019

  2. Sloan DJ, Davies GR, Khoo SH. Recent advances in tuberculosis: New drugs and treatment regimens. Curr Respir Med Rev 2013;9(3):200–10.

    Article  CAS  Google Scholar 

  3. Murray S, Mendel C, Spigelman MTB. Alliance regimen development for multidrug-resistant tuberculosis. Int. J. Tuberc. Lung Dis. 2016;20(12):S38–41.

    Article  Google Scholar 

  4. Misra A, Hickey AJ, Rossi C, Borchard G, Terada H, Makino K, et al. Inhaled drug therapy for treatment of tuberculosis. Tuberculosis. 2011;91(1):71–81.

    Article  CAS  Google Scholar 

  5. Hickey AJ, Durham PG, Dharmadhikari A, Nardell EA. Inhaled drug treatment for tuberculosis: Past progress and future prospects. J. Control. Release. 2016;240:127–34.

    Article  CAS  Google Scholar 

  6. Mitchison DA, Fourie PB. The near future: improving the activity of rifamycins and pyrazinamide. Tuberculosis (Edinb.). 2010;90(3):177–81.

    Article  CAS  Google Scholar 

  7. Muttil P, Wang C, Hickey AJ. Inhaled drug delivery for tuberculosis therapy. Pharm. Res. 2009;26(11):2401–16.

    Article  CAS  Google Scholar 

  8. Blasi P, Schoubben A, Giovagnoli S, Rossi C, Ricci M. Fighting tuberculosis: old drugs, new formulations. Expert Opin. Drug Deliv. 2009;6(9):977–93.

    Article  CAS  Google Scholar 

  9. Parumasivam T, Chang RY, Abdelghany S, Ye TT, Britton WJ, Chan HK. Dry powder inhalable formulations for anti-tubercular therapy. Adv. Drug Deliv. Rev. 2016;102:83–101.

    Article  CAS  Google Scholar 

  10. de Boer AH, Hagedoorn P, Hoppentocht M, Buttini F, Grasmeijer F, Frijlink HW. Dry powder inhalation: past, present and future. Expert Opin. Drug Deliv. 2017;14(4):499–512.

    Article  Google Scholar 

  11. Sou T, Meeusen EN, de Veer M, Morton DA, Kaminskas LM, McIntosh MP. New developments in dry powder pulmonary vaccine delivery. Trends Biotechnol. 2011;29(4):191–8.

    Article  CAS  Google Scholar 

  12. Garcia-Contreras L, Sung JC, Muttil P, Padilla D, Telko M, Verberkmoes JL, et al. Dry powder PA-824 aerosols for treatment of tuberculosis in guinea pigs. Antimicrob. Agents Chemother. 2010;54(4):1436–42.

    Article  CAS  Google Scholar 

  13. Suarez S, O’Hara P, Kazantseva M, Newcomer CE, Hopfer R, McMurray DN, et al. Airways delivery of rifampicin microparticles for the treatment of tuberculosis. J. Antimicrob. Chemother. 2001;48(3):431–4.

    Article  CAS  Google Scholar 

  14. Dharmadhikari AS, Kabadi M, Gerety B, Hickey AJ, Fourie PB, Nardell E. Phase I, single-dose, dose-escalating study of inhaled dry powder capreomycin: a new approach to therapy of drug-resistant tuberculosis. Antimicrob. Agents Chemother. 2013;57(6):2613–9.

    Article  CAS  Google Scholar 

  15. Lee RE, Hurdle JG, Liu J, Bruhn DF, Matt T, Scherman MS, et al. Spectinamides: a new class of semisynthetic antituberculosis agents that overcome native drug efflux. Nat. Med. 2014;20(2):152–8.

    Article  CAS  Google Scholar 

  16. Robertson GT, Scherman MS, Bruhn DF, Liu J, Hastings C, McNeil MR, et al. Spectinamides are effective partner agents for the treatment of tuberculosis in multiple mouse infection models. J. Antimicrob. Chemother. 2017;72(3):770–7.

    CAS  PubMed  Google Scholar 

  17. Rathi C, Lukka PB, Wagh S, Lee RE, Lenaerts AJ, Braunstein M, et al. Comparative pharmacokinetics of spectinamide 1599 after subcutaneous and intrapulmonary aerosol administration in mice. Tuberculosis. 2019;114:119–22.

    Article  CAS  Google Scholar 

  18. Liu J, Bruhn DF, Lee RB, Zheng Z, Janusic T, Scherbakov D, et al. Structure-Activity Relationships of Spectinamide Antituberculosis Agents: A Dissection of Ribosomal Inhibition and Native Efflux Avoidance Contributions. ACS Infect Dis 2017;3(1):72–88.

    Article  CAS  Google Scholar 

  19. U.S.P. Convention, U.S. Pharmacopeia National Formulary 2011: USP 34 NF 292011.

  20. Durham PG, Zhang Y, German N, Mortensen N, Dhillon J, Mitchison DA, et al. Spray Dried Aerosol Particles of Pyrazinoic Acid Salts for Tuberculosis Therapy. Mol. Pharm. 2015;12(8):2574–81.

    Article  CAS  Google Scholar 

  21. Srichana T, Martin GP, Marriott C. Dry powder inhalers: the influence of device resistance and powder formulation on drug and lactose deposition in vitro. Eur. J. Pharm. Sci. 1998;7(1):73–80.

    Article  CAS  Google Scholar 

  22. Durham PG, Hanif SN, Contreras LG, Young EF, Braunstein MS, Hickey AJ. Disposable dosators for pulmonary insufflation of therapeutic agents to small animals. JoVE. 2017(121):e55356.

  23. Mager H, Goller G. Resampling methods in sparse sampling situations in preclinical pharmacokinetic studies. J. Pharm. Sci. 1998;87(3):372–8.

    Article  CAS  Google Scholar 

  24. Vehring R. Pharmaceutical particle engineering via spray drying. Pharm. Res. 2008;25(5):999–1022.

    Article  CAS  Google Scholar 

  25. Vehring R, Foss WR, Lechuga-Ballesteros D. Particle formation in spray drying. J. Aerosol Sci. 2007;38(7):728–46.

    Article  CAS  Google Scholar 

  26. Wolfenden R, Andersson L, Cullis PM, Southgate CCB. Affinities of amino acid side chains for solvent water. Biochemistry. 1981;20(4):849–55.

    Article  CAS  Google Scholar 

  27. Gliński J, Chavepeyer G, Platten J-K. Surface properties of aqueous solutions of l-leucine. Biophys. Chem. 2000;84(2):99–103.

    Article  Google Scholar 

  28. Seville PC, Learoyd TP, Li HY, Williamson IJ, Birchall JC. Amino acid-modified spray-dried powders with enhanced aerosolisation properties for pulmonary drug delivery. Powder Technol. 2007;178(1):40–50.

    Article  CAS  Google Scholar 

  29. Chew NY, Chan HK. Use of solid corrugated particles to enhance powder aerosol performance. Pharm. Res. 2001;18(11):1570–7.

    Article  CAS  Google Scholar 

  30. Peng T, Lin S, Niu B, Wang X, Huang Y, Zhang X, et al. Influence of physical properties of carrier on the performance of dry powder inhalers. Acta Pharm Sin B. 2016;6(4):308–18.

    Article  Google Scholar 

  31. Weiler C, Egen M, Trunk M, Langguth P. Force control and powder dispersibility of spray dried particles for inhalation. J. Pharm. Sci. 2010;99(1):303–16.

    Article  CAS  Google Scholar 

  32. Boraey MA, Hoe S, Sharif H, Miller DP, Lechuga-Ballesteros D, Vehring R. Improvement of the dispersibility of spray-dried budesonide powders using leucine in an ethanol–water cosolvent system. Powder Technol. 2013;236:171–8.

    Article  CAS  Google Scholar 

  33. Sou T, Kaminskas LM, Nguyen T-H, Carlberg R, McIntosh MP, Morton DAV. The effect of amino acid excipients on morphology and solid-state properties of multi-component spray-dried formulations for pulmonary delivery of biomacromolecules. Eur. J. Pharm. Biopharm. 2013;83(2):234–43.

    Article  CAS  Google Scholar 

  34. Simon A, Amaro MI, Cabral LM, Healy AM, de Sousa VP. Development of a novel dry powder inhalation formulation for the delivery of rivastigmine hydrogen tartrate. Int. J. Pharm. 2016;501(1–2):124–38.

    Article  CAS  Google Scholar 

  35. Feng AL, Boraey MA, Gwin MA, Finlay PR, Kuehl PJ, Vehring R. Mechanistic models facilitate efficient development of leucine containing microparticles for pulmonary drug delivery. Int. J. Pharm. 2011;409(1):156–63.

    Article  CAS  Google Scholar 

  36. Li L, Sun S, Parumasivam T, Denman JA, Gengenbach T, Tang P, et al. L-Leucine as an excipient against moisture on in vitro aerosolization performances of highly hygroscopic spray-dried powders. European journal of pharmaceutics and biopharmaceutics: official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik eV. 2016;102:132–41.

    Article  CAS  Google Scholar 

  37. Mangal S, Meiser F, Tan G, Gengenbach T, Denman J, Rowles MR, et al. Relationship between surface concentration of l-leucine and bulk powder properties in spray dried formulations. Eur. J. Pharm. Biopharm. 2015;94:160–9.

    Article  CAS  Google Scholar 

  38. Kaewjan K, Srichana T. Nano spray-dried pyrazinamide-l-leucine dry powders, physical properties and feasibility used as dry powder aerosols. Pharm. Dev. Technol. 2016;21(1):68–75.

    Article  CAS  Google Scholar 

  39. Chang Y-X, Yang J-J, Pan R-L, Chang Q, Liao Y-H. Anti-hygroscopic effect of leucine on spray-dried herbal extract powders. Powder Technol. 2014;266:388–95.

    Article  CAS  Google Scholar 

  40. Telko MJ, Hickey AJ. Dry powder inhaler formulation. Respir. Care. 2005;50(9):1209–27.

    PubMed  Google Scholar 

  41. Tseng H-C, Lee C-Y, Weng W-L, Shiah IM. Solubilities of amino acids in water at various pH values under 298.15 K. Fluid Phase Equilibria. 2009;285(1):90–5.

    Article  CAS  Google Scholar 

  42. Shetty N, Park H, Zemlyanov D, Mangal S, Bhujbal S, Zhou Q. Influence of excipients on physical and aerosolization stability of spray dried high-dose powder formulations for inhalation. Int. J. Pharm. 2018;544(1):222–34.

    Article  CAS  Google Scholar 

  43. Eedara BB, Rangnekar B, Doyle C, Cavallaro A, Das SC. The influence of surface active l-leucine and 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine (DPPC) in the improvement of aerosolization of pyrazinamide and moxifloxacin co-spray dried powders. Int. J. Pharm. 2018;542(1–2):72–81.

    Article  CAS  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

  1. Engineered Systems, RTI International, Durham, North Carolina, USA

    Ian E. Stewart & Anthony J. Hickey

  2. Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee, USA

    Pradeep B. Lukka & Bernd Meibohm

  3. Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA

    Jiuyu Liu & Richard E. Lee

  4. Mycobacteria Research Laboratories, Department of Microbiology, Colorado State University, Fort Collins, Colorado, USA

    Mercedes Gonzalez-Juarrero

  5. Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA

    Miriam S. Braunstein

Authors
  1. Ian E. Stewart
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Pradeep B. Lukka
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jiuyu Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Bernd Meibohm
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mercedes Gonzalez-Juarrero
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Miriam S. Braunstein
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Richard E. Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Anthony J. Hickey
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Anthony J. Hickey.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

ESM 1

(DOCX 1262 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s11095-019-2666-8

Key Words

Search

Navigation