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AAPS PharmSciTech

, Volume 19, Issue 5, pp 2434–2448 | Cite as

Spray-Dried Proliposome Microparticles for High-Performance Aerosol Delivery Using a Monodose Powder Inhaler

  • Huner K. Omer
  • Nozad R. Hussein
  • Amina Ferraz
  • Mohammad Najlah
  • Waqar Ahmed
  • Kevin M. G. Taylor
  • Abdelbary M. A. Elhissi
Research Article
  • 134 Downloads

Abstract

Proliposome formulations containing salbutamol sulphate (SS) were developed using spray drying, and the effects of carrier type (lactose monohydrate (LMH) or mannitol) and lipid to carrier ratio were evaluated. The lipid phase comprised soy phosphatidylcholine (SPC) and cholesterol (1:1), and the ratios of lipid to carrier were 1:2, 1:4, 1:6, 1:8 or 1:10 w/w. X-ray powder diffraction (XRPD) revealed an interaction between the components of the proliposome particles, and scanning electron microscopy (SEM) showed that mannitol-based proliposomes were uniformly sized and spherical, whilst LMH-based proliposomes were irregular and relatively large. Using a two-stage impinger (TSI), fine particle fraction (FPF) values of the proliposomes were higher for mannitol-based formulations, reaching 52.6%, which was attributed to the better flow properties when mannitol was used as carrier. Following hydration of proliposomes, transmission electron microscopy (TEM) demonstrated that vesicles generated from mannitol-based formulations were oligolamellar, whilst LMH-based proliposomes generated ‘worm-like’ structures and vesicle clusters. Vesicle size decreased upon increasing carrier to lipid ratio, and the zeta potential values were negative. Drug entrapment efficiency (EE) was higher for liposomes generated from LMH-based proliposomes, reaching 37.76% when 1:2 lipid to carrier ratio was used. The in vitro drug release profile was similar for both carriers when 1:6 lipid to carrier ratio was used. This study showed that spray drying can produce inhalable proliposome microparticles that can generate liposomes upon contact with an aqueous phase, and the FPF of proliposomes and the EE offered by liposomes were formulation-dependent.

KEY WORDS

aerosol morphology particle size powder pulmonary 

Notes

Acknowledgements

We thank MIAT, Italy for supplying us with the Monodose dry powder inhaler device. We also thank Mr. David McCarthy, Microscopy unit, UCL-School of Pharmacy for the TEM images and Lipoid, Switzerland for supplying us with SPC (Lipoid S-100).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Supplementary material

12249_2018_1058_MOESM1_ESM.pdf (197 kb)
ESM 1 (PDF 196 kb)

References

  1. 1.
    Taylor KM, Taylor G, Kellaway IW, Stevens J. The influence of liposomal encapsulation on sodium cromoglycate pharmacokinetics in man. Pharm Res. 1989;6:633–6.CrossRefPubMedGoogle Scholar
  2. 2.
    Zeng XM, Martin GP, Marriott C. The controlled delivery of drugs to the lung. Int J Pharm. 1995;124:149–64.CrossRefGoogle Scholar
  3. 3.
    Ehsan Z, Wetzel JD, Clancy JP. Nebulized liposomal amikacin for the treatment of Pseudomonas aeruginosa infection in cystic fibrosis patients. Expert Opin Investig Drugs. 2014;23:743–9.CrossRefPubMedGoogle Scholar
  4. 4.
    Lee W-H, Loo C-Y, Traini D, Young PM. Inhalation of nanoparticle-based drug for lung cancer treatment: advantages and challenges. Asian J Pharm Sci. 2015;10:481–9.CrossRefGoogle Scholar
  5. 5.
    Elhissi A. Liposomes for pulmonary drug delivery: the role of formulation and inhalation device design. Curr Pharm Des. 2017;23:362–72.PubMedGoogle Scholar
  6. 6.
    Saari M, Vidgren MT, Koskinen MO, Turjanmaa VMH, Nieminen MM. Pulmonary distribution and clearance of two beclomethasone formulations in healthy volunteers. Int J Pharm. 1999;181:1–9.CrossRefPubMedGoogle Scholar
  7. 7.
    Clancy JP, Dupont L, Konstan MW, Billings J, Fustik S, Goss CH, et al. Phase II studies of nebulised Arikace in CF patients with Pseudomonas aeruginosa infection. Thorax. 2013;68:818–25.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Rudokas M, Najlah M, Alhnan MA, Elhissi A. Liposome delivery systems for inhalation: a critical review highlighting formulation issues and anticancer applications. Med Princ Pract. 2016;25(Suppl 2):60–72.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Cipolla D, Blanchard J, Gonda I. Development of liposomal ciprofloxacin to treat lung infections. Pharmaceutics. 2016;8  https://doi.org/10.3390/pharmaceutics8010006.
  10. 10.
    Elhissi AM, Faizi M, Naji WF, Gill HS, Taylor KM. Physical stability and aerosol properties of liposomes delivered using an air-jet nebulizer and a novel micropump device with large mesh apertures. Int J Pharm. 2007;2334:62–70.CrossRefGoogle Scholar
  11. 11.
    Ghazanfari T, Elhissi AM, Ding Z, Taylor KM. The influence of fluid physicochemical properties on vibrating-mesh nebulization. Int J Pharm. 2007;339:103–11.CrossRefPubMedGoogle Scholar
  12. 12.
    Najlah M, Vali A, Taylor M, Arafat BT, Ahmed W, Phoenix DA, et al. A study of the effects of sodium halides on the performance of air-jet and vibrating-mesh nebulizers. Int J Pharm. 2013;456:520–7.CrossRefPubMedGoogle Scholar
  13. 13.
    Elhissi AMA, Karnam KK, Danesh-Azari M-R, Gill HS, Taylor KMG. Formulations generated from ethanol-based proliposomes for delivery via medical nebulizers. J Pharm Pharmacol 2006. 2006;58:887–94.Google Scholar
  14. 14.
    Schreier H, McNicol KJ, Ausborn M, Soucy DM, Derendorf H, Stecenko AA, et al. Pulmonary delivery of amikacin liposomes and acute liposome toxicity in the sheep. Int J Pharm. 1992;87:183–93.CrossRefGoogle Scholar
  15. 15.
    Mobley WC. The effect of jet-milling on lyophilized liposomes. Pharm Res. 1998;15:149–52.CrossRefPubMedGoogle Scholar
  16. 16.
    Lu D, Hickey AJ. Liposomal dry powders for pulmonary delivery of proteins. AAPS PharmSciTech. 2005;6:E641–8.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Radhakrishnan, R., Mihalko, P.J., Abra, R.M. Method and apparatus for administering dehydrated liposomes by inhalation. US patent No 4895719, 1990.Google Scholar
  18. 18.
    Lo YL, Tsai JC, Kuo JH. Liposomes and disaccharides as carriers in spray-dried powder formulations of superoxide dismutase. J Cont Rel. 2004;94:259–72.CrossRefGoogle Scholar
  19. 19.
    Chougule MB, Padhi BK, Misra A. Nano-liposomal dry powder inhaler amiloride hydrochloride. J Nanosci Nanotechnol. 2006;6:3001–9.CrossRefPubMedGoogle Scholar
  20. 20.
    Chougule M, Padhi B, Misra A. Development of spray dried liposomal dry powder inhaler of Dapsone. AAPS PharmSciTech. 2008;9:47–53.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Ourique AF, Chaves Pdos S, Souto GD, Pohlmann AR, Guterres SS, Beck RC. Redispersible liposomal-N-acetylcysteine powder for pulmonary administration: development, in vitro characterization and antioxidant activity. Eur J Pharm Sci. 2014;65:174–82.CrossRefPubMedGoogle Scholar
  22. 22.
    Payne NI, Timmins P, Ambrose CV, Ward MD, Ridgway F. Proliposomes: a novel solution to an old problem. J Pharm Sci. 1986;75:325–9.CrossRefPubMedGoogle Scholar
  23. 23.
    Payne NI, Browning I, Hynes CA. Characterization of proliposomes. J Pharm Sci. 1986;75:330–3.CrossRefPubMedGoogle Scholar
  24. 24.
    Desai TR, Wong JP, Hancock RE, Finlay WH. A novel approach to the pulmonary delivery of liposomes in dry powder form to eliminate the deleterious effects of milling. J Pharm Sci. 2002;91:482–91.CrossRefPubMedGoogle Scholar
  25. 25.
    Desai TR, Hancock REW, Finlay WH. Delivery of liposomes in dry powder form: aerodynamic dispersion properties. Eur J Pharm Sci. 2003;20:459–67.CrossRefPubMedGoogle Scholar
  26. 26.
    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
  27. 27.
    Rojanarat W, Changsan N, Tawithong E, Pinsuwan S, Chan H-K, Srichana T. Isoniazid proliposome powders for inhalation—preparation, characterization and cell culture studies. Int J Mol Sci. 2011;12:4414–34.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Rojanarat W, Nakpheng T, Thawithong E, Yanyium N, Srichana T. Inhaled pyrazinamide proliposome for targeting alveolar macrophages. Drug Delivery. 2012;19:334–45.CrossRefPubMedGoogle Scholar
  29. 29.
    Lawaczeck R, Kainosho M, Chan SI. The formation and annealing of structural defects in lipid bilayer vesicles. Biochim Biophys Acta. 1976;443:313–30.CrossRefPubMedGoogle Scholar
  30. 30.
    Cevher E, Orhan Z, Mülazimoğlu L, Sensoy D, Alper M, Yildiz A, et al. Characterization of biodegradable chitosan microspheres containing vancomycin and treatment of experimental osteomyelitis caused by methicillin-resistant Staphylococcus aureus with prepared microspheres. Int J Pharm. 2006;317:127–35.CrossRefPubMedGoogle Scholar
  31. 31.
    Hallworth GW, Westmoreland DG. The twin impinger: a simple device for assessing the delivery of drugs from metered dose pressurized aerosol inhalers. J Pharm Pharmacol. 1987;39:966–72.CrossRefPubMedGoogle Scholar
  32. 32.
    Maury M, Murphy K, Kumar S, Shi L, Lee G. Effects of process variables on the powder yield of spray-dried trehalose on a laboratory spray-dryer. Eur J Pharm Biopharm. 2005;59:565–73.CrossRefPubMedGoogle Scholar
  33. 33.
    Maa YF, Nguyen PA, Sit K, Hsu CC. Spray-drying performance of a bench-top spray dryer for protein aerosol powder preparation. Biotechnol Bioeng. 1998;60:301–9.CrossRefPubMedGoogle Scholar
  34. 34.
    Bhandari BR, Datta N, Howes T. Problems associated with spray drying of sugar-rich foods. Dry Technol. 1997;15:671–84.CrossRefGoogle Scholar
  35. 35.
    Bhandari B, Howes T. Implication of glass transition for the drying and stability of dried foods. J Food Eng. 1999;40:71–9.CrossRefGoogle Scholar
  36. 36.
    Abbas KA, Lasekan O, Khalil SK. The significance of glass transition temperature in processing of selected fried food products: a review. Modern Appl Sci. 2010;4:3–21.Google Scholar
  37. 37.
    Truong V. Glass transition temperature and spray drying of sugar-rich foods: modelling and stickiness. LAP LAMBERT Academic Publishing, Saarbrücken, 2014.Google Scholar
  38. 38.
    Roos Y. Melting and glass transitions of low molecular weight carbohydrates. Carbohydr Res. 1993;238:39–48.CrossRefGoogle Scholar
  39. 39.
    Roos Y, Karel M. Plasticizing effect of water on thermal behavior and crystallization of amorphous food models. J Food Sci. 1991;56:38–43.CrossRefGoogle Scholar
  40. 40.
    Imtiaz-Ul-Islam M, Langrish TAG. Comparing the crystallization of sucrose and lactose in spray dryers. Food Bioprod Process. 2009;87:87–95.CrossRefGoogle Scholar
  41. 41.
    Yu, L., Mishra, D.S., Rigsbee, D.R., 1998. Determination of the glass properties of D-mannitol using sorbitol as an impurity. J Pharm Sci, 87:774–777.Google Scholar
  42. 42.
    Telang C, Suryanarayanan R, Yu L. Crystallization of D-mannitol in binary mixtures with NaCl: phase diagram and polymorphism. Pharm Res. 2003;20:1939–45.CrossRefPubMedGoogle Scholar
  43. 43.
    Yoshinari T, Forbes RT, York P, Kawashima Y. Crystallisation of amorphous mannitol is retarded using boric acid. Int J Pharm. 2003;258:109–20.CrossRefPubMedGoogle Scholar
  44. 44.
    Shiga H, Joreau H, Neoh TL, Furuta T, Yoshii H. Encapsulation of alcohol dehydrogenase in mannitol by spray drying. Pharmaceutics. 2014;6:185–94.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Chan H-K. Dry powder aerosol delivery systems: current and future research directions. J Aerosol Med. 2006;19:21–7.CrossRefPubMedGoogle Scholar
  46. 46.
    Byron PR. Prediction of drug residence times in regions of the human respiratory tract following aerosol inhalation. J Pharm Sci. 1986;75:433–8.CrossRefPubMedGoogle Scholar
  47. 47.
    Dozan T, Benkovic´ M, Bauman I. Sucrose particle size reduction—determination of critical particle diameters causing flowability difficulties. J Hyg Eng Des. 2014;8:3–10.Google Scholar
  48. 48.
    Wang, J., Shi, Q., Huang, Z., Gu, Y., Musango, L., Yang, Y., 2015. Experimental investigation of particle size effect on agglomeration behaviors in gas–solid fluidized beds. Ind Eng Chem Res, 54:12177–12186.Google Scholar
  49. 49.
    Pilcer G, Wauthoz N, Amighi K. Lactose characteristics and the generation of the aerosol. Adv Drug Del Rev. 2012;64:233–56.CrossRefGoogle Scholar
  50. 50.
    Kou X, Chan LW, Steckel H, Heng PWS. Physico-chemical aspects of lactose for inhalation. Adv Drug Del Rev. 2012;64:220–32.CrossRefGoogle Scholar
  51. 51.
    Daniher DI, Zhu J. Dry powder platform for pulmonary drug delivery. Particuology. 2008;6:225–38.CrossRefGoogle Scholar
  52. 52.
    Scichilone N, Spatafora M, Battaglia S, Arrigo R, Benfante A, Bellia V. Lung penetration and patient adherence considerations in the management of asthma: role of extra-fine formulations. J Asthma Allergy. 2013;6:11–21.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    de Boer AH, Gjaltema D, Hagedoorn P, Frijlink HW. Can “extrafine” dry powder aerosols improve lung deposition? Eur J Pharm Biopharm. 2015;96:143–51.CrossRefPubMedGoogle Scholar
  54. 54.
    Merchant Z, Buckton G, Taylor KM, Stapleton P, Saleem IY, Zariwala MG, et al. Pulmonary delivery of nano-antimicrobial therapeutics to treat chronic pulmonary infections. Curr Pharm Des. 2016;22:2577–98.CrossRefPubMedGoogle Scholar
  55. 55.
    Harjunen P, Lehto V-P, Martimo K, Suihko E, Lankinen T, Paronen P, et al. Lactose modifications enhance its drug performance in the novel multiple dose Taifun DPI. Eur J Pharm Sci. 2002;16:313–21.CrossRefPubMedGoogle Scholar
  56. 56.
    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.CrossRefPubMedGoogle Scholar
  57. 57.
    Zhang Q, Yang H, Yan W. Effect of ethanol on the crystallinity and acid sites of MFI zeolite nanosheets. RSC Adv. 2014;4:56938–44.CrossRefGoogle Scholar
  58. 58.
    Ebrahimi A, Saffari M, Langrish T. Developing a new production process for high-porosity lactose particles with high degrees of crystallinity. Powder Technol. 2015;272:45–53.CrossRefGoogle Scholar
  59. 59.
    Sebhatu T, Angberg M, Ahlneck C. Assessment of the degree of disorder in crystalline solids by isothermal microcalorimetry. Int J Pharm. 1994;104:135–44.CrossRefGoogle Scholar
  60. 60.
    Hancock BC, Zografi G. Characteristics and significance of the amorphous state in pharmaceutical systems. J Pharm Sci. 1997;86:1–12.CrossRefPubMedGoogle Scholar
  61. 61.
    Bennett RC, Brough C, Miller DA, O’Donnell KP, Keen JM, Hughey JR, et al. Preparation of amorphous solid dispersions by rotary evaporation and KinetiSol dispersing: approaches to enhance solubility of a poorly water-soluble gum extract. Drug Dev Ind Pharm. 2015;41:382–97.CrossRefPubMedGoogle Scholar
  62. 62.
    Shin GH, Li J, Cho JH, Kim JT, Park HJ. Enhancement of curcumin solubility by phase change from crystalline to amorphous in Cur-TPGS nanosuspension. J Food Sci. 2016;81:N494–501.CrossRefPubMedGoogle Scholar
  63. 63.
    White GW, Cakebread SH. The glassy state in certain sugar-containing food products. Int J Food Sci Tech Res. 1966;1:73–82.CrossRefGoogle Scholar
  64. 64.
    Pia Fäldt BB. The surface composition of spray-dried protein-lactose powders. Colloids Surf Physicochem Eng Asp. 1994;90:183–90.CrossRefGoogle Scholar
  65. 65.
    Darcy P, Buckton G. The influence of heating/drying on the crystallisation of amorphous lactose after structural collapse. Int J Pharm. 1997;158:157–64.CrossRefGoogle Scholar
  66. 66.
    Wu L, Miao X, Shan Z, Huang Y, Li L, Pan X, et al. Studies on the spray dried lactose as carrier for dry powder inhalation. Asian J Pharm Sci. 2014;9:336–41.CrossRefGoogle Scholar
  67. 67.
    Amdadul Haque M, Chen J, Aldred P, Adhikari B. Denaturation and physical characteristics of spray dried whey protein isolate powders produced in the presence and absence of lactose, trehalose and polysorbate-80. Dry Technol. 2015;33:1243–54.CrossRefGoogle Scholar
  68. 68.
    Kawashima Y, Serigano T, Hino T, Yamamoto H, Takeuchi H. Effect of surface morphology of carrier lactose on dry powder inhalation property of pranlukast hydrate. Int J Pharm. 1998;172:179–88.CrossRefGoogle Scholar
  69. 69.
    Pilcer G, Amighi K. Formulation strategy and use of excipients in pulmonary drug delivery. Int J Pharm. 2010;392:1–19.CrossRefPubMedGoogle Scholar
  70. 70.
    Hupfeld S, Holsaeter AM, Skar M, Frantzen CB, Brandl M. Liposome size analysis by dynamic/static light scattering upon size exclusion-/field flow-fractionation. J Nanosci Nanotechnol. 2006;6:3025–31.CrossRefPubMedGoogle Scholar
  71. 71.
    Abra RM, Mihalko PJ, Schreier H. The effect of lipid composition upon the encapsulation and in vitro leakage of metaproterenol sulfate from 0.2μm diameter, extruded, multilamellar liposomes. J Cont Rel. 1990;14:71–8.CrossRefGoogle Scholar
  72. 72.
    Betageri GV, Parsons DL. Drug encapsulation and release from multilamellar and unilamellar liposomes. Int J Pharm. 1992;81:235–41.CrossRefGoogle Scholar
  73. 73.
    Laouini A, Jaafar-Maalej C, Limayem-Blouza I, Sfar S, Charcosset C, Fessi H. Preparation, characterization and applications of liposomes: state of the art. J Colloid Sci Biotechnol. 2012;1:147–68.CrossRefGoogle Scholar
  74. 74.
    Debbage P. Targeted drugs and nanomedicine: present and future. Curr Pharm Des. 2009;15:153–72.CrossRefPubMedGoogle Scholar
  75. 75.
    Gabizon A, Price DC, Huberty J, Bresalier RS, Papahadjopoulos D. Effect of liposome composition and other factors on the targeting of liposomes to experimental tumors: biodistribution and imaging studies. Cancer Res. 1990;50:6371–8.PubMedGoogle Scholar
  76. 76.
    Straubinger RM, Hong K, Friend DS, Papahadjopoulos D. Endocytosis of liposomes and intracellular fate of encapsulated molecules: encounter with a low pH compartment after internalization in coated vesicles. Cell. 1983;32:1069–79.CrossRefPubMedGoogle Scholar
  77. 77.
    Elhissi AMA, Ahmed W, McCarthy D, Taylor KMG. A study of size, microscopic morphology, and dispersion mechanism of structures generated on hydration of proliposomes. J Disp Sci Tech. 2012;33:1121–6.CrossRefGoogle Scholar
  78. 78.
    Gupta PK, Hickey AJ. Contemporary approaches in aerosolized drug delivery to the lung. J Cont Rel. 1991;17:127–47.CrossRefGoogle Scholar
  79. 79.
    Carr R. Evaluating flow properties of solids. Chem Eng. 1965;72:163–8.Google Scholar
  80. 80.
    Elkordy AA, Forbes RT, Barry BW. Integrity of crystalline lysozyme exceeds that of a spray-dried form. Int J Pharm. 2002;247:79–90.CrossRefPubMedGoogle Scholar
  81. 81.
    Al-Nimry SS, Alkhamis KA. Effect of moisture content of chitin-calcium silicate on rate of degradation of cefotaxime sodium. AAPS PharmSciTech. 2018;19:1337–43.PubMedGoogle Scholar
  82. 82.
    Saleem IY, Diez F, Jones BE, Kayali N, Polo L. Investigation on the aerosol performance of dry powder inhalation hypromellose capsules with different lubricant levels. Int J Pharm. 2015;492:258–63.CrossRefPubMedGoogle Scholar
  83. 83.
    de Boer AH, Chan HK, Price R. A critical view on lactose-based drug formulation and device studies for dry powder inhalation: which are relevant and what interactions to expect? Adv Drug Del Rev. 2012;64:257–74.CrossRefGoogle Scholar
  84. 84.
    Yoshida H, Kuwana A, Shibata H, Izutsu KI, Goda Y. Comparison of aerodynamic particle size distribution between a next generation impactor and a cascade impactor at a range of flow rates. AAPS PharmSciTech. 2017;18:646–53.CrossRefPubMedGoogle Scholar
  85. 85.
    Abadelah M, Chrystyn H, Bagherisadeghi G, Abdalla G, Larhrib H. Study of the emitted dose after two separate inhalations at different inhalation flow rates and volumes and an assessment of aerodynamic characteristics of indacaterol Onbrez Breezhaler® 150 and 300 μg. AAPS PharmSciTech. 2018;19:251–61.CrossRefPubMedGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2018

Authors and Affiliations

  • Huner K. Omer
    • 1
    • 2
  • Nozad R. Hussein
    • 1
    • 2
  • Amina Ferraz
    • 1
  • Mohammad Najlah
    • 3
  • Waqar Ahmed
    • 4
  • Kevin M. G. Taylor
    • 5
  • Abdelbary M. A. Elhissi
    • 6
    • 7
  1. 1.Institute of Nanotechnology and Bioengineering, School of Pharmacy and Biomedical SciencesUniversity of Central LancashirePrestonUK
  2. 2.College of PharmacyHawler Medical UniversityErbilIraq
  3. 3.Faculty of Medical ScienceAnglia Ruskin UniversityChelmsfordUK
  4. 4.Nanoscience Research Group, School of Mathematics and Physics, College of ScienceUniversity of LincolnLincolnUK
  5. 5.School of PharmacyUCLLondonUK
  6. 6.Research Planning and Development, Office of Vice President for Research and Graduate StudiesQatar UniversityDohaQatar
  7. 7.College of PharmacyQatar UniversityDohaQatar

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