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Inhalable Nanoparticles
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Inhalable Nanoparticles






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Inhalable Nanoparticles Inhalable Nanoparticles Presentation Transcript

  • Nanoparticle Delivery N i l D li  Oral O l  Intravenous  Nasal  Ophthalmic  Rectal/Vaginal  Trans Dermal  Pulmonary
  • Local delivery vs. systemic  Aerosol route of administration  Local effect (reduced systemic site effects) ( y )  Systemic (prevent Gi-tract or invasive administration)  Aerosol target  Treatment Organ  Absorption Organ p g
  • Lungs as Treatment organ  Asthma (Hardy and Chadwick, 2000)  Cystic fibrosis (Garcia-Contreras and Hickey, 2002)  Lung cancer (Rao et al 2003) al.,  Tuberculosis (Pandey and Khuller, 2005; Zahoor et al., 2005) h l )
  • NANOPARTICLES in Cancer Treatment  Nanoparticles are drug vehicles able to accumulate in tumor tissues or cells, while protecting the drug from premature inactivation during the transport… g p  Promising drug carriers… Brigger I, Dubernet C, Couvreur P. Nanoparticles in cancer therapy and diagnosis. Advanced Drug Delivery Reviews 2002;54(5):631-651.
  • Biological activity of the g y Nanoparticles H460 A549 100 100 Dox-NP Dox-NP Empty-NP py 80 xicity ( % ) 80 Empty-NP E t NP Dox otoxicity (%) Dox 60 60 40 40 Cytotox Cyto 20 20 0 0 0.625 0.315 0.156 0.078 0.039 0.019 0 625 0 315 0 156 0 078 0 039 0 019 0.625 0.315 0.156 0.078 0.039 0.019 0 625 0 315 0 156 0 078 0 039 0 019 Doxorubicin ( g/mL) Doxorubicin ( g/mL) Shirzad Azarmi, Xia Tao, Hua Chen, Zhaolin Wang, Warren. H. Finlay, Raimar Löb b R i Löbenberg, Wil Wilson. H. R H Roa; F Formulation and C t t i it of D l ti d Cytotoxicity f Doxorubicin Nanoparticles bi i N ti l Carried by Dry Powder Aerosol Particles Int J Pharm 2006
  • DEPOSITION MECHANISM General air flow through the respiratory tract Large particles will Impact in the upper respiratory tract (>5 um) Small particles will have no deposition because of Brownian diffusion ( um) (<1 u ) Sedimentation in the alveolar region (1-5 um) (1 5 www.becomehealthynow.com
  • Pulmonary Nanoparticle delivery  Solid colloidal particles < 1000 nm  But how can you deliver them to the lungs?  Suitable size is between 1000 and 5000 nm? We had to go back to the lab and do some experiments
  • THE CONCEPT Respirable aerosol particles containing nanoparticles The carrier particles deposit in the alveolar region The carrier dissolves The nanoparticles are released
  • THE CONCEPT evaporation of water Respirable lactose aerosol Suspension of particles lactose and containing nanoparticles nanoparticles Spray drying
  • CUTTING THROUGH THE PARTICLES Continuous matrix of carrier particles Confocal laser scanning microscopy Hollow carrier particles
  • Most Cited Paper
  • Active Release of Nanoparticles from the Carrier Particle  How to create forces which increase the disperse-ability of the nanoparticles? We had to go back to the lab and do some experiments
  • NEW SYSTEM OF CARRIER PARTICLES with Active Release Our approach:  The in situ generated gas pressure may h l to help t disperse the content of the carrier particle
  • Active Release of Nanoparticles from the Carrier Particle  How to how to avoid that the reaction is happening while spray drying? We had to go back to the lab and do some experiments
  • NEW SYSTEM OF CARRIER PARTICLES  Effervescent carrier particles: Lactose Sodium Carbonate FORMULATION Acid Citric Ammonia Evaporation Water
  • MAJOR PARAMETERS Machine parameters Pump Atomization •Pressure Temperatures •inlet Aspirator •outlet
  • MAJOR PARAMETERS Formulation parameters Solid concentration Excipients: E i i t • leucine • polyethylene glycol • ethanol • surfactants
  • RESULTS: Polyethylene glycol (PEG) and L-leucine PEG and L-leucine 50 w e ight fra ction % 40 30 20 10 0 5.6 4.3 3.4 2 1.1 0.51 cut points PEG and l-leucine both work as a lubricant L- leucine can decrease the aggregation of gg g spray dried particles
  • Fine Particle Fraction (FPF) Fine Particle Fraction 50 43.97 45 40 35.7 35 FPF (% 30 F 25 17.6 20 15 12.5 12.5 10 5 0 Tween 80 Ethanol 30% Lactose 1% Spray dryer L-leucine + and Jet mill PEG FPF means particle fraction that can be delivered to the lungs
  • Carrier particles with active release mechanism A B (A) green nanoparticles nanoparticles. (B) red carrier matrix (C) normal light (D) C D
  • Carrier particles with active release mechanism After the sample wasas The green exposed to Nanoparticles humidity are actively distributed in the gas bubble The red carrier matrix dissolves The gas bubble is about 30 m
  • RESULTS: Influence of the formulation on the size of nanoparticles 350 Effervescent Dry Powder 300 for Respiratory Drug Delivery; 250 * Leticia Ely, Wilson Roa, Warren H. Finlay, Raimar 200 nm Löbenberg; Eur Pharm Bi h E J Ph Biopharm 150 2007 100 50 0 re r re te r fo te fo Af Be Af Be nt e nt ce os e ce os es ct es ct La rv rv La fe fe Ef Ef
  • Publication
  • Nanotoxicology of Inhalable Nanoparticles IS it safe to use inhalable nanoparticles?
  • Lung surfactant  Lung surfactant are a mixture of about 80% phospholipids,  5-10 proteins and  5-10% cholesterol containing compounds g p  Major co po e ts o t e p osp o p ds a e ajo components of the phospholipids are phosphatidylcholine PC and dipalmitoyl phosphatidylcholine DPPC.
  • Lung surfactant Function:  Reduction of Surface Tension  Gas Exchange
  • Surface pressure versus molecular area isotherms dipalmitoyl phosphatidylcholine DPPC DPPC nanoparticles 313 nm 187 nm
  • Surface pressure versus molecular area isotherms The study concluded 3 that: th t The high surface 2 pressure values obtained from 1 187 nm NP the isotherms of the binary 1 2 230 nm NP mixtures indicates the notion 3 DPPC that their size dependent incorporation does not destabilize the monolayer film. The study results demonstrated that pulmonary nanoparticle delivery is a possible route of administration. Biophysical investigation of nanoparticle interactions with lung surfactant model systems; Diana Stuart, Raimar Löbenberg, Tabitha Ku, Shirzad Azarmi, Leticia Ely, Wilson Roa and Elmar J. Prenner J Biomed Nanotech Vol 2 p1-8 2006
  • Spray freeze-drying Nitrogen Gas Peristaltic Doxorubicin pump Particles deposit in the nanoparticles alveolar region. The lactose carrier dissolves and nanoparticles are ti l released. Carrier Powder Liquid Nitrogen Freeze Drying 72 hr 300-400 mL 1-5 µm µ Density: ~ 0.1 g/cm3
  • Project/Animal Identification: Score Morbidity Appearance Normal 0 General lack of grooming g g 1 Scores Coat staring, ocular or nasal discharge 2 Piloerection, hunched up 3 Body Weight Normal < 5% 0 body wt. drop 6-15% 1 body wt. drop 16-25% 2 25 Body weight 14 body wt. drop 26-35% 3 body wt. drop > 35% y p 4 Morbidity M bidit score 12 Food Intake 20 Normal 0 10 B o d y w e ig h t (g ) M o rb i d i ty s c o r e food intake drop 10-33% 1 15 8 food intake drop 34-75% p 2 food intake drop > 75% 3 10 6 Clinical Signs Normal resp. rate and hydration 0 4 Slight changes g g 1 5 Resp. rates up or down 30%, measurable dehydration 2 2 Resp. rates changes 50% or very low, severe dehydration 3 0 0 Behavior 1 8 15 22 29 36 43 50 Normal 0 Minor inactivity or exaggerated responses 1 Time (day) Moderate change in expected behavior, isolated or listless 2 Reacts violently, or very weak and precomatose 3 Total
  • Study design  Female 4-5 weeks old BALB/c nude mice  NCl-H460 injection  Small lung metastatic nodules develop in 15 days  Treatment over 4 weeks with T k ih  Free Drug  Inhalable NPs  Blank NPs  No treatment
  • Expectation  The cancer will spread throughout the body  The animals will die because of cancer in other organs  The Lungs might show less cancer compared to other tissues due to the p treatment
  • Summary of what accomplished and performed Assessing the efficacy of DOX-loaded effervescent inhalable NPs in vivo 100% 90% 80% 70% rvival % 60% 50% Surv 40% 30% Effervescent NPs Normal NPs 20% DOX-NP IV 10% Dox solution IV Control 0% 0 20 40 60 80 100 120 140
  • Summary  Inhalable nanoparticles with active release mechanism were successfully synthesized  In vitro results demonstrate that nanoparticles do not compromise the biological function of the lung surfactant film  In vitro cell culture test show that doxorubicin bound to nanoparticles is more effective against lung cancer cells than free doxorubicin  In vivo studies demonstrate that the survival of mice can be improved if doxorubicin loaded nanoparticles are administered via the pulmonary route of administration
  • Conclusions  New dry powder technology is available to deliver NP or drugs to the lungs  Improved pulmonary drug delivery for cytotoxic molecules is possible using nanoparticles  Drug d li D delivery i th k t i is the key to improve (l (lung cancer) treatments.
  • Articles  Formulation and in vivo evaluation of effervescent inhalable carrier particles for pulmonary delivery of nanoparticles. Azarmi S. Lobenberg R. Roa WH. Tai S. Finlay WH. Drug Development & Industrial Pharmacy. 34(9):943-7, 2008 Sep.  Targeted delivery of nanoparticles for the treatment of lung diseases Shirzad Azarmi, Wilson H. Roa and Raimar Löbenberg, Advanced Drug Delivery Reviews, 0(8):863-75, 2008 May 22.  Nanoparticles: characteristics, Mechanisms of Action and Toxicity in Pulmonary Drug Delivery – A Review S Gill R Löbenberg T Ku S Azarmi W Roa and EJ Penner Gill, Löbenberg, Azarmi, J Biomed Nanotechnology 2007  Effervescent Dry Powder Aerosols for Respiratory Drug Delivery Leticia Ely, Warren H Finlay, Wilson H Roa, Raimar Löbenberg Eur J Pharm Biopharm 2007 (65) 346-353  Biophysical investigation of nanoparticle interactions with lung surfactant model systems Diana Stuart, Raimar Löbenberg, Tabitha Ku, Shirzad Azarmi, Leticia Ely, Wilson Roa and Elmar J. Prenner J Biomed Nanotechnology Volume 2, Numbers 3-4, October/December 2006, pp. 245-252(8)  Formulation and Cytotoxicity of Doxorubicin Nanoparticles Carried by Dry Powder Aerosol Particles Shirzad Azarmi, Xia Tao, Hua Chen, Zhaolin Wang, Warren. H. Finlay, Raimar Löbenberg, Wilson. H. Roa Int J Pharm 2006 319 (1-2), pp. 155-161 (ranked # 23 for the journal in Jul – Sep 2006 )  Optimization of a two step desolvation method for preparing gelatin nanoparticles and cell uptake studies in 143B two-step osteosarcoma cancer cells Azarmi S, Huang Y, Chen H, McQuarrie S, Abrams D, Roa W, Finlay WH, Miller GG, Löbenberg R JPPS 9 (1): 124-132 2006  Dry Powder Inhalation Aerosols Containing Nanoparticulate Doxorubicin L.G. Sweeney, H. Chen, Z. Wang, R. Löbenberg, W. Roa, W.H. Finlay y g g y Eur J Pharm Sci 305 (1-2): 180-185 NOV 23 2005  Formulation and Characterization of Spray-Dried Powders Containing Nanoparticles for Aerosol Delivery to the Lung, Jeffrey O.-H. Sham, Yu Zhang, Warren H. Finlay, Wilson H. Roa, and Raimar Löbenberg Int. J. Pharm. Vol 269, (2), Pages 457-467 ranked Top 25 in 2004
  • Acknowledgements  Dr. Finlay D Fi l  Dr. Roa  Dr. Chacra  Dr. Prenner  Dr. Shirzad Azarmi  Dr. Dr Xia Tao  Dr. Chuching Tai  Yuan Huang  Leticia Ely L ti i El  Kamal Al-Hallak  NSERC, AHFMR, CIHR, ACB