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Pharmaceutical Research

, Volume 29, Issue 10, pp 2845–2859 | Cite as

New Respirable and Fast Dissolving Itraconazole Dry Powder Composition for the Treatment of Invasive Pulmonary Aspergillosis

  • Christophe DuretEmail author
  • Nathalie Wauthoz
  • Thami Sebti
  • Francis Vanderbist
  • Karim Amighi
Research Paper

ABSTRACT

Purpose

Novel itraconazole (ITZ)-based dry powders for inhalation (DPI) were optimized for aerodynamic and dissolution properties and contained excipients that are acceptable for inhalation.

Methods

The DPI were produced by spray drying solutions. The drug content, crystallinity state, and morphological evaluation of the dry powders were determined by high performance liquid chromatography, powder X-ray diffraction, differential scanning calorimetry, and scanning electron microscopy, respectively. A particle size analysis was conducted using laser light scattering. The aerodynamic behaviors of the powders were characterized by impaction tests. ITZ dissolution rates were evaluated using a dissolution method adapted to inhaled products.

Results

The DPI presented very high fine particle fractions that ranged from 46.9% to 67.0% of the nominal dose. The formulations showed very fast dissolution rates compared to unformulated crystalline ITZ with the possibility of modulating the dissolution rate by varying the quantity of phospholipids (PL) incorporated. ITZ remained amorphous while the mannitol was crystalline. The α, β and δ-mannitol polymorph ratios varied depending on the formulation compositions.

Conclusion

This formulation strategy could be an attractive alternative for treating invasive pulmonary aspergillosis. The ITZ and PL content are key characteristics because of their influence on the dissolution rate and aerosol performance.

KEY WORDS

dry powder for inhalation (DPI) invasive aspergillosis itraconazole mannitol polymorphism 

ABBREVIATIONS

API

active pharmaceutical ingredient

CI

Carr’s index

dae

aerodynamic diameter

DPI(s)

dry powder(s) for inhalation

ED

emitted dose

FDA

Food and Drug Administration

FPD

fine particle dose

FPF

fine particle fraction

IA

invasive aspergillosis

IC

immunocompromised

ICDD

International Center for Diffraction Data

ITZ

itraconazole

IV

intravenous

MIC

minimal inhibitory concentration

MsLI

multi-stage liquid impactor

MTDSC

modulated temperature differential scanning calorimetry

NGI

next generation impactor

PL

phospholipids

PSD

particle size distribution

PXRD

powder X-ray diffraction

RIR

reference intensity ratio

RPM

round per minute

SD

spray dried

SEM

scanning electron microscopy

TGA

thermogravimetric analysis

References

  1. 1.
    Mcneil MM, Nash SL, Hajjeh RA, Phelan MA, Conn LA, Plikaytis BD, Warnock DW. Trends in mortality due to invasive mycotic diseases in the United States, 1980–1997. Clin Infect Dis. 2001;33:641–7.PubMedCrossRefGoogle Scholar
  2. 2.
    Denning DW. Invasive aspergillosis. Clin Infect Dis. 1998;26:781–803.PubMedCrossRefGoogle Scholar
  3. 3.
    Hope WW. Invasion of the alveolar-capillary barrier by Aspergillus spp.: therapeutic and diagnostic implications for immunocompromised patients with invasive pulmonary aspergillosis. Med Mycol. 2009;47 Suppl 1:S291–8.PubMedCrossRefGoogle Scholar
  4. 4.
    Hope WW, Billaud EM, Lestner J, Denning DW. Therapeutic drug monitoring for triazoles. Curr Opin Infect Dis. 2008;21:580–6.PubMedCrossRefGoogle Scholar
  5. 5.
    Coronel B, Levron JC, Dorez D, Van Devenne A, Archimbaud E, Mercatello A. Itraconazole lung concentrations in haematological patients. Mycoses. 2000;43:125–7.PubMedCrossRefGoogle Scholar
  6. 6.
    Hoeben BJ, Burgess DS, McConville JT, Najvar LK, Talbert RL, Peters JI, Wiederhold NP, Frei BL, Graybill JR, Bocanegra R, Overhoff KA, Sinswat P, Johnston KP, Williams RO. In vivo efficacy of aerosolized nanostructured itraconazole formulations for prevention of invasive pulmonary aspergillosis. Antimicrob Agents Chemother. 2006;50:1552–4.PubMedCrossRefGoogle Scholar
  7. 7.
    Alvarez CA, Wiederhold NP, McConville JT, Peters JI, Najvar LK, Graybill JR, Coalson JJ, Talbert RL, Burgess DS, Bocanegra R, Johnston KP, Williams RO. Aerosolized nanostructured itraconazole as prophylaxis against invasive pulmonary aspergillosis. J Infect. 2007;55:68–74.PubMedCrossRefGoogle Scholar
  8. 8.
    Chan HK. Dry powder aerosol delivery systems: current and future research directions. J Aerosol Med. 2006;19:21–7.PubMedCrossRefGoogle Scholar
  9. 9.
    Amidon GL, Lennernas H, Shah VP, Crison JR. A theoretical basis for A biopharmaceutic drug classification—the correlation of in-vitro drug product dissolution and in-vivo bioavailability. Pharm Res. 1995;12:413–20.PubMedCrossRefGoogle Scholar
  10. 10.
    Yang W, Tam J, Miller DA, Zhou J, McConville JT, Johnston KP, Williams RO. High bioavailability from nebulized itraconazole nanoparticle dispersions with biocompatible stabilizers. Int J Pharm. 2008;361:177–88.PubMedCrossRefGoogle Scholar
  11. 11.
    Tran CL, Buchanan D, Cullen RT, Searl A, Jones AD, Donaldson K. Inhalation of poorly soluble particles. II. Influence of particle surface area on inflammation and clearance. Inhal Toxicol. 2000;12:1113–26.PubMedCrossRefGoogle Scholar
  12. 12.
    Jones RM, Neef N. Interpretation and prediction of inhaled drug particle accumulation in the lung and its associated toxicity. Xenobiotica. 2012;42:86–93.PubMedCrossRefGoogle Scholar
  13. 13.
    Bindu MB, Kusum B, Banji D. Novel strategies for poorly water soluble drugs. Int J Pharm Sci Rev Res. 2010;4:76–84.Google Scholar
  14. 14.
    Pilcer G, Amighi K. Formulation strategy and use of excipients in pulmonary drug delivery. Int J Pharm. 2010;392:1–19.PubMedCrossRefGoogle Scholar
  15. 15.
    Duret C, Wauthoz N, Sebti T, Vanderbist F, Amighi K. Solid dispersions of itraconazole for inhalation with enhanced dissolution, solubility and dispersion properties. Int J Pharm. 2012;428(1–2):103–13.PubMedCrossRefGoogle Scholar
  16. 16.
    Weers JG, Tarara TE, Clark AR. Design of fine particles for pulmonary drug delivery. Expert Opin Drug Deliv. 2007;4(3):297–313.PubMedCrossRefGoogle Scholar
  17. 17.
    Shah B, Kakumanu VK, Bansal AK. Analytical techniques for quantification of amorphous/crystalline phases in pharmaceutical solids. J Pharm Sci. 2006;95:1641–65.PubMedCrossRefGoogle Scholar
  18. 18.
    Chung FH. Quantitative interpretation of X-ray diffraction patterns of mixtures. II. Adiabatic principle of X-ray diffraction analysis of mixtures. J App Cryst. 1974;7:526–31.CrossRefGoogle Scholar
  19. 19.
    Wandt MA, Rodgers AL. Quantitative X-ray diffraction analysis of urinary calculi by use of the internal-standard method and reference intensity ratios. Clin Chem. 1988;34:289–93.PubMedGoogle Scholar
  20. 20.
    Galunin E, Vidal M, Alba MD. The effect of polymorphic structure on the structural and chemical stability of yttrium disilicates. Am Mineral. 2011;96:1512–20.CrossRefGoogle Scholar
  21. 21.
    Morris G, Kokki MH, Anderson K, Richardson MD. Sampling of Aspergillus spores in air. J Hosp Infect. 2000;44:81–92.PubMedCrossRefGoogle Scholar
  22. 22.
    Shah VP, Tsong Y, Sathe P, Liu JP. In vitro dissolution profile comparison–statistics and analysis of the similarity factor, f2. Pharm Res. 1998;15:889–96.PubMedCrossRefGoogle Scholar
  23. 23.
    Weiler C, Egen M, Trunk M, Langguth P. Force control and powder dispersibility of spray dried particles for inhalation. J Pharm Sci. 2010;99:303–16.PubMedCrossRefGoogle Scholar
  24. 24.
    Miao S, Roos YH. Crystallization kinetics and x-ray diffraction of crystals formed in amorphous lactose, trehalose, and lactose/trehalose mixtures. J Food Sci. 2005;70:E350–8.CrossRefGoogle Scholar
  25. 25.
    Hulse WL, Forbes RT, Bonner MC, Getrost M. The characterization and comparison of spray-dried mannitol samples. Drug Dev Ind Pharm. 2009;35:712–8.PubMedCrossRefGoogle Scholar
  26. 26.
    Elversson J, Millqvist-Fureby A. Particle size and density in spray drying—effects of carbohydrate properties. J Pharm Sci. 2005;94:2049–60.PubMedCrossRefGoogle Scholar
  27. 27.
    Sebti T, Amighi K. Preparation and in vitro evaluation of lipidic carriers and fillers for inhalation. Eur J Pharm Biopharm. 2006;63:51–8.PubMedCrossRefGoogle Scholar
  28. 28.
    Kaialy W, Martin GP, Ticehurst MD, Momin MN, Nokhodchi A. The enhanced aerosol performance of salbutamol from dry powders containing engineered mannitol as excipient. Int J Pharm. 2010;392:178–88.PubMedCrossRefGoogle Scholar
  29. 29.
    Burger A, Henck JO, Hetz S, Rollinger JM, Weissnicht AA, Stottner H. Energy/temperature diagram and compression behavior of the polymorphs of D-mannitol. J Pharm Sci. 2000;89:457–68.PubMedCrossRefGoogle Scholar
  30. 30.
    Hulse WL, Forbes RT, Bonner MC, Getrost M. Influence of protein on mannitol polymorphic form produced during co-spray drying. Int J Pharm. 2009;382:67–72.PubMedCrossRefGoogle Scholar
  31. 31.
    Ostwald W. Studien uber die bildung und Umwandlung fester Korper. Z Phys Chem. 1897;22:289.Google Scholar
  32. 32.
    Khoshkhoo S, Anwart J. Crystallization of polymorphs: the effect of solvent. J Phys D: Appl Phys. 1993;26:890–3.CrossRefGoogle Scholar
  33. 33.
    Yoshinari T, Forbes RT, York P, Kawashima Y. Moisture induced polymorphic transition of mannitol and its morphological transformation. Int J Pharm. 2002;247:69–77.PubMedCrossRefGoogle Scholar
  34. 34.
    Alves GP, Santana MHA. Phospholipid dry powders produced by spray drying processing: structural, thermodynamic and physical properties. Powder Technol. 2004;145:139–48.CrossRefGoogle Scholar
  35. 35.
    Iida K, Hayakawa Y, Okamoto H, Danjo K, Leuenberger H. Evaluation of flow properties of dry powder inhalation of salbutamol sulfate with lactose carrier. Chem Pharm Bull. 2001;49:1326–30.PubMedCrossRefGoogle Scholar
  36. 36.
    Larhrib H, Martin GP, Marriott C, Prime D. The influence of carrier and drug morphology on drug delivery from dry powder formulations. Int J Pharm. 2003;257:283–96.PubMedCrossRefGoogle Scholar
  37. 37.
    Zhang Y, Wang XL, Lin X, Liu XL, Tian B, Tang X. High azithromycin loading powders for inhalation and their in vivo evaluation in rats. Int J Pharm. 2010;395:205–14.PubMedCrossRefGoogle Scholar
  38. 38.
    Bosquillon C, Rouxhet PG, Ahimou F, Simon D, Culot C, Preat V, Vanbever R. Aerosolization properties, surface composition and physical state of spray-dried protein powders. J Control Release. 2004;99:357–67.PubMedCrossRefGoogle Scholar
  39. 39.
    Glasmacher A, Hahn C, Leutner C, Molitor E, Wardelmann E, Losem C, Sauerbruch T, Marklein G, Schmidt-Wolf IG. Breakthrough invasive fungal infections in neutropenic patients after prophylaxis with itraconazole. Mycoses. 1999;42:443–51.PubMedCrossRefGoogle Scholar
  40. 40.
    Berenguer J, Ali NM, Allende MC, Lee J, Garrett K, Battaglia S, Piscitelli SC, Rinaldi MG, Pizzo PA, Walsh TJ. Itraconazole for experimental pulmonary aspergillosis: comparison with amphotericin B, interaction with cyclosporin A, and correlation between therapeutic response and itraconazole concentrations in plasma. Antimicrob Agents Chemother. 1994;38:1303–8.PubMedCrossRefGoogle Scholar
  41. 41.
    Pfaller MA, Messer SA, Hollis RJ, Jones RN. Antifungal activities of posaconazole, ravuconazole, and voriconazole compared to those of itraconazole and amphotericin B against 239 clinical isolates of Aspergillus spp. and other filamentous fungi: Report from SENTRY Antimicrobial Surveillance Program, 2000. Antimicrob Agents Chemother. 2002;46:1032–7.PubMedCrossRefGoogle Scholar
  42. 42.
    Osaki T, Hanagiri T, Nakanishi R, Yoshino I, Taga S, Yasumoto K. Bronchial arterial infusion is an effective therapeutic modality for centrally located early-stage lung cancer: results of a pilot study. Chest. 1999;115:1424–8.PubMedCrossRefGoogle Scholar
  43. 43.
    Lee YY, Wu JX, Yang M, Young PM, van Den BF, Rantanen J. Particle size dependence of polymorphism in spray-dried mannitol. Eur J Pharm Sci. 2011;44:41–8.PubMedCrossRefGoogle Scholar
  44. 44.
    Snelders E, van der Lee HA, Kuijpers J, Rijs AJ, Varga J, Samson RA, Mellado E, Donders AR, Melchers WJ, Verweij PE. Emergence of azole resistance in Aspergillus fumigatus and spread of a single resistance mechanism. PLoS Med. 2008;5:e219.PubMedCrossRefGoogle Scholar
  45. 45.
    Mortensen KL, Johansen HK, Fuursted K, Knudsen JD, Gahrn-Hansen B, Jensen RH, Howard SJ, Arendrup MC. A prospective survey of Aspergillus spp. in respiratory tract samples: prevalence, clinical impact and antifungal susceptibility. Eur J Clin Microbiol Infect Dis. 2011;30:1355–63.PubMedCrossRefGoogle Scholar
  46. 46.
    Verweij PE, Howard SJ, Melchers WJ, Denning DW. Azole-resistance in Aspergillus: proposed nomenclature and breakpoints. Drug Resist Updat. 2009;12:141–7.PubMedCrossRefGoogle Scholar
  47. 47.
    Misra R, Malik A, Singhal S. Comparison of the activities of amphotericin B, itraconazole, and voriconazole against clinical and environmental isolates of Aspergillus species. Indian J Pathol Microbiol. 2011;54:112–6.PubMedCrossRefGoogle Scholar
  48. 48.
    Wauthoz N, Deleuze P, Saumet A, Duret C, Kiss R, Amighi K. Temozolomide-based dry powder formulations for lung tumor-related inhalation treatment. Pharm Res. 2011;28:762–75.PubMedCrossRefGoogle Scholar
  49. 49.
    Six K, Verreck G, Peeters J, Brewster M, Van den Mooter G. Increased physical stability and improved dissolution properties of itraconazole, a class II drug, by solid dispersions that combine fast- and slow-dissolving polymers. J Pharm Sci. 2004;93:124–31.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Christophe Duret
    • 1
    Email author
  • Nathalie Wauthoz
    • 1
  • Thami Sebti
    • 2
  • Francis Vanderbist
    • 2
  • Karim Amighi
    • 1
  1. 1.Laboratoire de Pharmacie Galénique et de BiopharmacieUniversité Libre de BruxellesBrusselsBelgium
  2. 2.Laboratoires SMB S.A.BrusselsBelgium

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