title: Rehydrated sterically stabilized phospholipid nanomicelles of budesonide for nebulization: physicochemical characterization and in vitro, in vivo evaluations.
abstract: BACKGROUND
  Inhaled corticosteroids provide unique systems for local treatment of asthma or chronic obstructive pulmonary disease. However, the use of poorly soluble drugs for nebulization has been inadequate, and many patients rely on large doses to achieve optimal control of their disease. Theoretically, nanotechnology with a sustained-release formulation may provide a favorable therapeutic index. The aim of this study was to determine the feasibility of using sterically stabilized phospholipid nanomicelles of budesonide for pulmonary delivery via nebulization.
  
  
  METHODS
  PEG(5000)-DSPE polymeric micelles containing budesonide (BUD-SSMs) were prepared by the coprecipitation and reconstitution method, and the physicochemical and pharmacodynamic characteristics of BUD-SSMs were investigated.
  
  
  RESULTS
  The optimal concentration of solubilized budesonide at 5 mM PEG(5000)-DSPE was 605.71 ± 6.38 μg/mL, with a single-sized peak population determined by photon correlation spectroscopy and a particle size distribution of 21.51 ± 1.5 nm. The zeta potential of BUD-SSMs was -28.43 ± 1.98 mV. The percent entrapment efficiency, percent yield, and percent drug loading of the lyophilized formulations were 100.13% ± 1.09%, 97.98% ± 1.95%, and 2.01% ± 0.02%, respectively. Budesonide was found to be amorphous by differential scanning calorimetry, and had no chemical interaction with PEGylated polymer according to Fourier transform infrared spectroscopy. Transmission electron microscopic images of BUD-SSMs revealed spherical nanoparticles. BUD-SSMs exhibited prolonged dissolution behavior compared with Pulmicort Respules (P < 0.05). Aerodynamic characteristics indicated significantly higher deposition in the lungs compared with Pulmicort Respules. The mass median aerodynamic, geometric standard deviation, percent emitted dose, and the fine particle fraction were 2.83 ± 0.08 μm, 2.33 ± 0.04 μm, 59.13% ± 0.19%, and 52.31% ± 0.25%, respectively. Intratracheal administration of BUD-SSMs 23 hours before challenge (1 mg/kg) in an asthmatic/chronic obstructive pulmonary disease rat model led to a significant reduction in inflammatory cell counts (76.94 ± 5.11) in bronchoalveolar lavage fluid compared with administration of Pulmicort Respules (25.06 ± 6.91).
  
  
  CONCLUSIONS
  The BUD-SSMs system might be advantageous for asthma or chronic obstructive pulmonary disease and other inflammatory airway diseases.
authors.affiliation: School of Pharmaceutical Sciences, Universiti Sains Malaysia, Penang, Malaysia. mohanad_pharm@yahoo.com
authors.forename: Mohanad Naji
authors.initials: MN
authors.lastname: Sahib
authors.forename: Yusrida
authors.initials: Y
authors.lastname: Darwis
authors.forename: Kok Khiang
authors.initials: KK
authors.lastname: Peh
authors.forename: Shaymaa Abdalwahed
authors.initials: SA
authors.lastname: Abdulameer
authors.forename: Yvonne Tze Fung
authors.initials: YT
authors.lastname: Tan
mesh_terms: D000280:Administration, Inhalation; D000336:Aerosols; D000704:Analysis of Variance; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D019819:Budesonide / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D002152:Calorimetry, Differential Scanning; D004337:Drug Carriers / Q000008:administration & dosage / Q000737:chemistry*; D005240:Feasibility Studies; D008214:Lymphocytes / Q000187:drug effects; D008297:Male; D008823:Micelles; D046529:Microscopy, Electron, Transmission; D009330:Nebulizers and Vaporizers; D010316:Particle Size; D010714:Phosphatidylethanolamines / Q000008:administration & dosage / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D017550:Spectroscopy, Fourier Transform Infrared
chemical_list: D000336:Aerosols; D000893:Anti-Inflammatory Agents; D004337:Drug Carriers; D008823:Micelles; D010714:Phosphatidylethanolamines; C038089:1,2-distearoylphosphatidylethanolamine; D011092:Polyethylene Glycols; D019819:Budesonide
references.citation: J Control Release. 2005 May 5;104(1):79-90
references.pmid: 15866336
references.citation: Eur J Pharm Biopharm. 1999 Sep;48(2):101-11
references.pmid: 10469928
references.citation: Pharm Res. 2002 Feb;19(2):189-94
references.pmid: 11883646
references.citation: J Control Release. 2005 Feb 2;102(2):373-81
references.pmid: 15653158
references.citation: Pulm Pharmacol Ther. 2005;18(2):151-3
references.pmid: 15649857
references.citation: Eur J Pharm Biopharm. 2007 Nov;67(3):655-66
references.pmid: 17540552
references.citation: J Control Release. 2003 Jan 17;86(2-3):323-38
references.pmid: 12526828
references.citation: J Control Release. 2003 Jan 9;86(1):131-44
references.pmid: 12490379
references.citation: J Control Release. 2003 Apr 29;89(2):199-212
references.pmid: 12711444
references.citation: AAPS PharmSciTech. 2007 Dec 21;8(4):E110
references.pmid: 18181531
references.citation: J Control Release. 2007 Jul 31;120(3):131-48
references.pmid: 17582642
references.citation: Int J Pharm. 2003 Apr 14;255(1-2):175-87
references.pmid: 12672613
references.citation: J Pharm Sci. 1997 Jun;86(6):690-700
references.pmid: 9188051
references.citation: J Biopharm Stat. 1997 May;7(2):241-58
references.pmid: 9136067
references.citation: Chest. 2006 Jul;130(1 Suppl):54S-64S
references.pmid: 16840368
references.citation: Nanomedicine. 2005 Mar;1(1):77-84
references.pmid: 17292061
references.citation: AAPS J. 2010 Sep;12(3):263-71
references.pmid: 20373062
references.citation: J Pharm Sci. 2003 Jun;92(6):1216-33
references.pmid: 12761811
references.citation: Acta Pol Pharm. 2010 May-Jun;67(3):217-23
references.pmid: 20524422
references.citation: J Control Release. 2009 Sep 15;138(3):214-23
references.pmid: 19376167
references.citation: AAPS PharmSciTech. 2010 Jun;11(2):663-71
references.pmid: 20405256
references.citation: J Drug Target. 2003 Jan;11(1):61-74
references.pmid: 12852442
references.citation: Thorax. 2001 Dec;56(12):972-7
references.pmid: 11713362
references.citation: Eur J Pharm Sci. 2001 May;13(2):123-33
references.pmid: 11297896
references.citation: Int J Pharm. 2001 Sep 11;226(1-2):107-25
references.pmid: 11532575
references.citation: Med Res Rev. 2009 Jan;29(1):196-212
references.pmid: 18958847
references.citation: Curr Drug Deliv. 2009 Jan;6(1):62-8
references.pmid: 19418957
references.citation: Eur J Pharm Biopharm. 2006 Nov;64(3):261-8
references.pmid: 16884896
references.citation: Int J Pharm. 2009 Feb 9;367(1-2):79-85
references.pmid: 18929631
references.citation: J Aerosol Med. 2000 Spring;13(1):43-55
references.pmid: 10947323
references.citation: Int J Pharm. 2010 Aug 16;395(1-2):132-41
references.pmid: 20580794
references.citation: Eur J Pharm Biopharm. 2007 Jan;65(1):47-56
references.pmid: 16962749
references.citation: J Control Release. 2005 Dec 5;109(1-3):169-88
references.pmid: 16289422
references.citation: Int J Pharm. 2000 Nov 19;209(1-2):57-67
references.pmid: 11084246
references.citation: Eur J Pharm Sci. 2007 Jun;31(2):73-84
references.pmid: 17408932
references.citation: Drug Discov Ther. 2010 Feb;4(1):26-32
references.pmid: 22491149
references.citation: J Control Release. 2001 Oct 19;76(3):239-54
references.pmid: 11578739
references.citation: J Control Release. 2004 Apr 16;96(1):135-48
references.pmid: 15063036
references.citation: Nanomedicine. 2009 Jun;5(2):178-83
references.pmid: 19071064
references.citation: Colloids Surf B Biointerfaces. 2010 Nov 1;81(1):313-20
references.pmid: 20674292
references.citation: Eur J Pharm Biopharm. 1999 Nov;48(3):207-15
references.pmid: 10612031
references.citation: J Control Release. 2002 Apr 23;80(1-3):207-18
references.pmid: 11943399
references.citation: Allergy. 1995 Apr;50(4):349-58
references.pmid: 7573819
references.citation: Int J Nanomedicine. 2010 Aug 09;5:463-71
references.pmid: 20957168
references.citation: Biomaterials. 2002 Nov;23(22):4425-33
references.pmid: 12219833
references.citation: Biomaterials. 1997 Sep;18(17):1153-61
references.pmid: 9259512
references.citation: Int J Pharm. 2007 Feb 1;329(1-2):158-65
references.pmid: 17008034
references.citation: J Control Release. 2009 Aug 19;138(1):16-23
references.pmid: 19376169
references.citation: J Aerosol Med. 2003 Summer;16(2):153-66
references.pmid: 12823909
references.citation: Int J Pharm. 2008 May 22;356(1-2):345-50
references.pmid: 18289811
references.citation: Cancer Res. 1980 Dec;40(12):4460-6
references.pmid: 7002293
references.citation: Eur J Pharm Sci. 2005 Jul-Aug;25(4-5):427-37
references.pmid: 15893461
references.citation: J Appl Physiol (1985). 1994 Feb;76(2):584-8
references.pmid: 8175567
references.citation: Eur J Pharm Biopharm. 2011 Oct;79(2):276-84
references.pmid: 21575719
references.citation: J Control Release. 2006 Dec 1;116(3):322-9
references.pmid: 17109985
references.citation: Am J Respir Crit Care Med. 2000 Oct;162(4 Pt 1):1455-61
references.pmid: 11029361
references.citation: Int J Nanomedicine. 2008;3(1):1-19
references.pmid: 18488412
references.citation: Int J Pharm. 2008 May 22;356(1-2):239-47
references.pmid: 18358652
references.citation: Pulm Pharmacol Ther. 2008;21(1):98-104
references.pmid: 17331766
references.citation: Int J Pharm. 2001 Feb 19;214(1-2):93-8
references.pmid: 11282244
references.citation: J Control Release. 2001 Jun 15;73(2-3):137-72
references.pmid: 11516494
references.citation: Lab Anim. 1981 Apr;15(2):163-70
references.pmid: 7278122