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Synthesis and Characterization of Nanocomposite Microparticles (nCmP) for the Treatment of Cystic Fibrosis-Related Infections

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Abstract

Purpose

Pulmonary antibiotic delivery is recommended as maintenance therapy for cystic fibrosis (CF) patients who experience chronic infections. However, abnormally thick and sticky mucus present in the respiratory tract of CF patients impairs mucus penetration and limits the efficacy of inhaled antibiotics. To overcome the obstacles of pulmonary antibiotic delivery, we have developed nanocomposite microparticles (nCmP) for the inhalation application of antibiotics in the form of dry powder aerosols.

Methods

Azithromycin-loaded and rapamycin-loaded polymeric nanoparticles (NP) were prepared via nanoprecipitation and nCmP were prepared by spray drying and the physicochemical characteristics were evaluated.

Results

The nanoparticles were 200 nm in diameter both before loading into and after redispersion from nCmP. The NP exhibited smooth, spherical morphology and the nCmP were corrugated spheres about 1 μm in diameter. Both drugs were successfully encapsulated into the NP and were released in a sustained manner. The NP were successfully loaded into nCmP with favorable encapsulation efficacy. All materials were stable at manufacturing and storage conditions and nCmP were in an amorphous state after spray drying. nCmP demonstrated desirable aerosol dispersion characteristics, allowing them to deposit into the deep lung regions for effective drug delivery.

Conclusions

The described nCmP have the potential to overcome mucus-limited pulmonary delivery of antibiotics.

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Abbreviations

Ac-Dex:

Acetalated dextran

AZI:

Azithromycin

CAC:

Cyclic-to-acyclic

CDCl3 :

Deuterated chloroform

CF:

Cystic fibrosis

CFTR:

Cystic fibrosis transmembrane conductance regulator

D2O:

Deuterium oxide

DCC:

N,N′-dicyclohexyl- carbodiimde

DCl:

Deuterium chloride

DMAP:

4-(dimethylamino) pyridine

ED:

Emitted dose

EE:

Encapsulation efficiency

FPD:

Fine particle dose

FPF:

Fine particles fraction

HPMC:

Hydroxypropyl methylcellulose

KF:

Karl Fischer

mPEG:

Poly(ethylene glycol) methyl ether

nCmP:

Nanocomposite microparticles

NGI:

Next Generation Impactor

NP:

Nanoparticles

PPTS:

P-toluenesulfonate

PXRD:

Powder X-ray diffraction

RAP:

Rapamycin

RF:

Respirable fraction

TEA:

2-methoxypropene (2-MOP), triethylamine

VP5k:

poly(ethylene glycol) vitamin E

References

  1. Bowenand S-J, Hull J. The basic science of cystic fibrosis. Paediatr Child Health. 2015;25:159–64.

    Article  Google Scholar 

  2. Bradbury NA. Cystic Fibrosis. In: Bradshaw RA, Stahl PD, Gilbert A, editors. Encyclopedia of Cell Biology, 1st ed. Waltham; 2015. p 283–293.

  3. Thursfieldand RM, Davies JC. Cystic Fibrosis: therapies targeting specific gene defects. Paediatr Respir Rev. 2012;13:215–9.

    Article  Google Scholar 

  4. Chuchalin A, Amelina E, Bianco F. Tobramycin for inhalation in cystic fibrosis: beyond respiratory improvements. Pulm Pharmacol Ther. 2009;22:526–32.

    Article  CAS  PubMed  Google Scholar 

  5. Milla CE. Nutrition and lung disease in cystic fibrosis. Clin Chest Med. 2007;28:319–30.

    Article  PubMed  Google Scholar 

  6. FibrosisFoundation C. Patient registry 2005 annual report. Maryland: Bethesda; 2005.

    Google Scholar 

  7. Heijerman H, Westerman E, Conway S, Touw D. Inhaled medication and inhalation devices for lung disease in patients with cystic fibrosis: a European consensus. J Cyst Fibros. 2009;8:295–315.

    Article  CAS  PubMed  Google Scholar 

  8. Rajan S, Saiman L. Pulmonary infections in patients with cystic fibrosis. Semin Respir Infect. 2002;17:47–56.

    Article  PubMed  Google Scholar 

  9. Regelmann WE, Elliott GR, Warwick WJ, Clawson CC. Reduction of sputum pseudomonas aeruginosa density by antibiotics improves lung function in cystic fibrosis more than Do bronchodilators and chest physiotherapy alone. Am Rev Respir Dis. 1990;141:914–21.

    Article  CAS  PubMed  Google Scholar 

  10. Wagner T, Soong G, Sokol S, Saiman L, Prince A. EFfects of azithromycin on clinical isolates of pseudomonas aeruginosa from cystic fibrosis patients. Chest. 2005;128:912–9.

    Article  CAS  PubMed  Google Scholar 

  11. Southernand KW, Barker PM. Azithromycin for cystic fibrosis. Eur Respir J. 2004;24:834–8.

    Article  Google Scholar 

  12. Saiman L, Marshall BC, Mayer-Hamblett N, et al. Azithromycin in patients with cystic fibrosis chronically infected with pseudomonas aeruginosa: A randomized controlled trial. JAMA. 2003;290:1749–56.

    Article  CAS  PubMed  Google Scholar 

  13. Wilms EB, Touw DJ, Heijerman HGM, van der Ent CK. Azithromycin maintenance therapy in patients with cystic fibrosis: A dose advice based on a review of pharmacokinetics, efficacy, and side effects. Pediatr Pulmonol. 2012;47:658–65.

    Article  PubMed  Google Scholar 

  14. Piscitalle SC, Danziger LH, Rodvold KA. Clarithromycin and azithromycin: new macrolide antibiotics. Clin Pharmacol. 1992;11:137–52.

    Google Scholar 

  15. Zhao M, You Y, Ren Y, Zhang Y, Tang X. Formulation, characteristics and aerosolization performance of azithromycin DPI prepared by spray-drying. Powder Technol. 2008;187:214–21.

    Article  CAS  Google Scholar 

  16. Abdulrahman BA, Khweek AA, Akhter A, Caution K, Kotrange S, Abdelaziz DHA, et al. Autophagy stimulation by rapamycin suppresses lung inflammation and infection by Burkholderia cenocepacia in a model of cystic fibrosis. Autophagy. 2011;7:1359–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Chen Y-C, Lo C-L, Lin Y-F, Hsiue G-H. Rapamycin encapsulated in dual-responsive micelles for cancer therapy. Biomaterials. 2013;34:1115–27.

    Article  CAS  PubMed  Google Scholar 

  18. Broaders KE, Cohen JA, Beaudette TT, Bachelder EM, Frechet JMJ. Acetalated dextran is a chemically and biologically tunable material for particulate immunotherapy. Proc Natl Acad Sci U S A. 2009;106:5497–502.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Cook RO, Pannu RK, Kellaway IW. Novel sustained release microspheres for pulmonary drug delivery. J Control Release. 2005;104:79–90.

    Article  CAS  PubMed  Google Scholar 

  20. Kauffman KJ, Kanthamneni N, Meenach SA, Pierson BC, Bachelder EM, Ainslie KM. Optimization of rapamycin-loaded acetalated dextran microparticles for immunosuppression. Int J Pharm. 2012;422:356–63.

    Article  CAS  PubMed  Google Scholar 

  21. Broaders KE, Cohen JA, Beaudette TT, Bachelder EM, Fréchet JMJ. Acetalated dextran is a chemically and biologically tunable material for particulate immunotherapy. Proc Natl Acad Sci. 2009;106:5497–502.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Bachelder EM, Beaudette TT, Broaders KE, Dashe J, Fréchet JMJ. Acetal-derivatized dextran: an acid-responsive biodegradable material for therapeutic applications. J Am Chem Soc. 2008;130:10494–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Sham JOH, Zhang Y, Finlay WH, Roa WH, Löbenberg R. Formulation and characterization of spray-dried powders containing nanoparticles for aerosol delivery to the lung. Int J Pharm. 2004;269:457–67.

    Article  CAS  PubMed  Google Scholar 

  24. Ong HX, Traini D, Ballerin G, Morgan L, Buddle L, Scalia S, et al. Combined inhaled salbutamol and mannitol therapy for mucus hyper-secretion in pulmonary diseases. AAPS J. 2014;16:269–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Jensen DMK, Cun D, Maltesen MJ, Frokjaer S, Nielsen HM, Foged C. Spray drying of siRNA-containing PLGA nanoparticles intended for inhalation. J Control Release. 2010;142:138–45.

    Article  PubMed  Google Scholar 

  26. Littringer EM, Mescher A, Schroettner H, Achelis L, Walzel P, Urbanetz NA. Spray dried mannitol carrier particles with tailored surface properties – The influence of carrier surface roughness and shape. Eur J Pharm Biopharm. 2012;82:194–204.

    Article  CAS  PubMed  Google Scholar 

  27. Cooney GF, Lum BL, Tomaselli M, Fiel SB. Absolute bioavailability and absorption characteristics of aerosolized tobramycin in adults with cystic fibrosis. J Clin Pharmacol. 1994;34:255–9.

    Article  CAS  PubMed  Google Scholar 

  28. Hoppentocht M, Hagedoorn P, Frijlink HW, de Boer AH. Developments and strategies for inhaled antibiotic drugs in tuberculosis therapy: A critical evaluation. Eur J Pharm Biopharm. 2014;86:23–30.

    Article  CAS  PubMed  Google Scholar 

  29. Stanojevic S, Waters V, Mathew JL, Taylor L, Ratjen F. Effectiveness of inhaled tobramycin in eradicating Pseudomonas aeruginosa in children with cystic fibrosis. J Cyst Fibros. 2014;13:172–8.

    Article  CAS  PubMed  Google Scholar 

  30. Geller DE, Pitlick WH, Nardella PA, Tracewell WG, Ramsey BW. PHarmacokinetics and bioavailability of aerosolized tobramycin in cystic fibrosis. Chest. 2002;122:219–26.

    Article  CAS  PubMed  Google Scholar 

  31. Dolovichand MB, Dhand R. Aerosol drug delivery: developments in device design and clinical use. Lancet. 2011;377:1032–45.

    Article  Google Scholar 

  32. Ibrahim BM, Tsifansky MD, Yang Y, Yeo Y. Challenges and advances in the development of inhalable drug formulations for cystic fibrosis lung disease. Expert Opin Drug Deliv. 2011;8:451–66.

    Article  CAS  PubMed  Google Scholar 

  33. Kuzmovand A, Minko T. Nanotechnology approaches for inhalation treatment of lung diseases. J Control Release. 2015;219:500–18.

    Article  Google Scholar 

  34. Daniels T, Mills N, Whitaker P. Nebuliser systems for drug delivery in cystic fibrosis. Cochrane Database Syst Rev. 2013. doi:10.1002/14651858.CD007639.pub2.

  35. Tang BC, Dawson M, Lai SK, Wang Y-Y, Suk JS, Yang M, et al. Biodegradable polymer nanoparticles that rapidly penetrate the human mucus barrier. Proc Natl Acad Sci. 2009;106(46):19268–73. doi:10.1073/pnas.0905998106.

  36. Stegemann S, Kopp S, Borchard G, Shah VP, Senel S, Dubey R, et al. Developing and advancing dry powder inhalation towards enhanced therapeutics. Eur J Pharm Sci. 2013;48:181–94.

    Article  CAS  PubMed  Google Scholar 

  37. Wattsand AB, Williams RO. Nanoparticles for pulmonary delivery. In: Smythand DCH, Hickey JA, editors. Controlled pulmonary drug delivery. New York: Springer; 2011. p. 335–66.

    Chapter  Google Scholar 

  38. Collnot E-M, Baldes C, Wempe MF, Hyatt J, Navarro L, Edgar KJ, et al. Influence of vitamin E TPGS poly(ethylene glycol) chain length on apical efflux transporters in Caco-2 cell monolayers. J Control Release. 2006;111:35–40.

    Article  CAS  PubMed  Google Scholar 

  39. Meenach SA, Anderson KW, Zach Hilt J, McGarry RC, Mansour HM. Characterization and aerosol dispersion performance of advanced spray-dried chemotherapeutic PEGylated phospholipid particles for dry powder inhalation delivery in lung cancer. Eur J Pharm Sci. 2013;49:699–711.

    Article  CAS  PubMed  Google Scholar 

  40. F. W. The ARLA Respiratory deposition calculator 2008.

  41. Mert O, Lai SK, Ensign L, Yang M, Wang Y-Y, Wood J, et al. A poly(ethylene glycol)-based surfactant for formulation of drug-loaded mucus penetrating particles. J Control Release. 2012;157:455–60.

    Article  CAS  PubMed  Google Scholar 

  42. Bootz A, Vogel V, Schubert D, Kreuter J. Comparison of scanning electron microscopy, dynamic light scattering and analytical ultracentrifugation for the sizing of poly(butyl cyanoacrylate) nanoparticles. Eur J Pharm Biopharm. 2004;57:369–75.

    Article  CAS  PubMed  Google Scholar 

  43. Meenach SA, Kim YJ, Kauffman KJ, Kanthamneni N, Bachelder EM, Ainslie KM. Synthesis, optimization, and characterization of camptothecin-loaded acetalated dextran porous microparticles for pulmonary delivery. Mol Pharm. 2012;9:290–8.

    Article  CAS  PubMed  Google Scholar 

  44. Wu X, Hayes D, Zwischenberger JB, Kuhn RJ, Mansour HM. Design and physicochemical characterization of advanced spray-dried tacrolimus multifunctional particles for inhalation. Drug Des Devel Ther. 2013;7:59–72.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Meenach SA, Vogt FG, Anderson KW, Hilt JZ, McGarry RC, Mansour HM. Design, physicochemical characterization, and optimization of organic solution advanced spray-dried inhalable dipalmitoylphosphatidylcholine (DPPC) and dipalmitoylphosphatidylethanolamine poly(ethylene glycol) (DPPE-PEG) microparticles and nanoparticles for targeted respiratory nanomedicine delivery as dry powder inhalation aerosols. Int J Nanomedicine. 2013;8:275–93.

    PubMed  PubMed Central  Google Scholar 

  46. Wu X, Zhang W, Hayes D, Mansour HM. Physicochemical characterization and aerosol dispersion performance of organic solution advanced spray-dried cyclosporine A multifunctional particles for dry powder inhalation aerosol delivery. Int J Nanomedicine. 2013;8:1269–83.

    PubMed  PubMed Central  Google Scholar 

  47. Liand X, Mansour HM. Physicochemical characterization and water vapor sorption of organic solution advanced spray-dried inhalable trehalose microparticles and nanoparticles for targeted Dry powder pulmonary inhalation delivery. AAPS PharmSciTech. 2011;12:1420–30.

    Article  Google Scholar 

  48. Hickey AJ, Mansour HM, Telko MJ, Xu Z, Smyth HDC, Mulder T, et al. Physical characterization of component particles included in dry powder inhalers. I. Strategy review and static characteristics. J Pharm Sci. 2007;96:1282–301.

    Article  CAS  PubMed  Google Scholar 

  49. Chew NYK, Chan H-K. The Role of particle properties in pharmaceutical powder inhalation formulations. J Aerosol Med. 2002;15:325–30.

    Article  CAS  PubMed  Google Scholar 

  50. Mohammadi G, Valizadeh H, Barzegar-Jalali M, Lotfipour F, Adibkia K, Milani M, et al. Development of azithromycin–PLGA nanoparticles: physicochemical characterization and antibacterial effect against salmonella typhi. Colloids Surf B: Biointerfaces. 2010;80:34–9.

    Article  CAS  PubMed  Google Scholar 

  51. Kaialyand W, Nokhodchi A. Dry powder inhalers: physicochemical and aerosolization properties of several size-fractions of a promising alterative carrier, freeze-dried mannitol. Eur J Pharm Sci. 2015;68:56–67.

    Article  Google Scholar 

  52. Zhang Z, Xu L, Chen H, Li X. Rapamycin-loaded poly(ε-caprolactone)-poly(ethylene glycol)-poly(ε-caprolactone) nanoparticles: preparation, characterization and potential application in corneal transplantation. J Pharm Pharmacol. 2014;66:557–63.

    Article  CAS  PubMed  Google Scholar 

  53. Li X, Chang S, Du G, Li Y, Gong J, Yang M, et al. Encapsulation of azithromycin into polymeric microspheres by reduced pressure-solvent evaporation method. Int J Pharm. 2012;433:79–88.

    Article  CAS  PubMed  Google Scholar 

  54. Ungaro F, De Rosa G, Miro A, Quaglia F, La Rotonda MI. Cyclodextrins in the production of large porous particles: development of dry powders for the sustained release of insulin to the lungs. Eur J Pharm Sci. 2006;28:423–32.

    Article  CAS  PubMed  Google Scholar 

  55. Suarez S, Hickey AJ. Drug properties affecting aerosol behavior. Respir Care. 2000;45:652–66.

    CAS  PubMed  Google Scholar 

  56. Hickey AJ, Heidi M. Delivery of Drugs by the Pulmonary Route. In: Florence AT, Siepmann J. editors. Modern Pharmaceutics: Applications and Advances, 5th ed. New York: Informa Healthcare; 2009. p 191–219.

  57. Hickey AJ, Mansour HM. Formulation challenges of powders for the delivery of small molecular weight molecules as aerosols. In: Rathbone MJ, Hadgraft J, Roberts MS, Lane ME, editors. Modified-release drug delivery technology, 2nd ed. New York: Informa Healthcare; 2008. p. 573–602.

  58. Edwards DA. The macrotransport of aerosol particles in the lung: aerosol deposition phenomena. J Aerosol Sci. 1995;26:293–317.

    Article  CAS  Google Scholar 

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Acknowledgments And Disclosures

The authors gratefully acknowledge financial support from an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health under grant number P20GM103430. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors thank RI-INBRE for HPLC access and RIN2 for SEM, DLS, PXRD, and DSC access.

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Authors and Affiliations

  1. Department of Chemical Engineering, University of Rhode Island, 202 Crawford Hall, 16 Greenhouse Road, Kingston, RI, 02881, USA

    Zimeng Wang & Samantha A. Meenach

  2. Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, RI, 02881, USA

    Samantha A. Meenach

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  1. Zimeng Wang
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  2. Samantha A. Meenach
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Correspondence to Samantha A. Meenach.

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Wang, Z., Meenach, S.A. Synthesis and Characterization of Nanocomposite Microparticles (nCmP) for the Treatment of Cystic Fibrosis-Related Infections. Pharm Res 33, 1862–1872 (2016). https://doi.org/10.1007/s11095-016-1921-5

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  • DOI: https://doi.org/10.1007/s11095-016-1921-5

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