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Custom-Shaped Bio-Microparticles for Precision Drug Delivery

Custom-Shaped Bio-Microparticles for Precision Drug Delivery. Young Bin Choy, Ph.D. Department of Biomedical Engineering Seoul National University College of Medicine 28 Yeongondong , Chongnogu , Seoul, Rep. of Korea. Outline. Motivations

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Custom-Shaped Bio-Microparticles for Precision Drug Delivery

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  1. Custom-Shaped Bio-Microparticles for Precision Drug Delivery Young Bin Choy, Ph.D. Department of Biomedical Engineering Seoul National University College of Medicine 28 Yeongondong, Chongnogu, Seoul, Rep. of Korea

  2. Outline Motivations Disease cure with high controllability and high patients’ compliance Huge market place in drug delivery devices Custom shaped microparticles Precision Drug Therapy Targeted Drug Delivery

  3. Motivations Cure for diseases via drug therapy with controlled means Patients’ compliance and convenience Small in size: minimal invasiveness Small incision for administration Small vesicles for drug delivery Small number of treatments Big on precision: high effectiveness Accurate control on drug delivery Accurate targeting for enhanced treatment Global market Medicinal devices (drug delivery): > $500 billion (~ 750조 원) Korean Government Budget in the year of 2008 = 257조 원!! Drug Delivery: Global Industry Guide, (Datamonitor, USA, Nov, 2006)

  4. Drug Delivery Devices Drug can cure or alleviate the diseases or pains. Standard drug dosing Quick Burst Drug degradation Frequent dosing Drug delivery devices Lower burst effect Sustained drug release Protection of the drug • Standard drug dosing • Drug dosing via medicinal devices Multiple doses Single dose Drug concentration Side effects Therapeutic window Time

  5. Biomaterial-Based Microparticles • Small in size • Simplicity of administration • Local targeting • Versatility • Numerous drug delivery scenarios 5

  6. Conventional Fabrication Methods Chemical reaction Phase separation Interfacial polymerization Mechanical agitation Sonication/homogenization Spray drying Fluidized bed Almost No Physical Control!! 6

  7. Importance in Physical Control “………A clearer picture is emerging that physical attributes such as size, shape and mechanical properties form essential building blocks of biology, just as chemistry and molecular recognition do……….” 7

  8. Precision Microparticles Accurate control on size, drug distribution and biomaterial decomposition Engineered geometry Modified surface chemistry

  9. Single Nozzle Drop Generation Nozzle walls • Rayleigh’s equation - rd: radius of the drop- rj: jet radius- vj: jet velocity- f : excitation frequency.  Critical Limitation: Minimum achievable drop size = Twice the nozzle opening.

  10. Precision Microparticle Fabrication Precision Particle Fabrication (PPF) method Mechanical, hydrodynamic and ELECTRIC forces Generation of drops smaller than nozzle orifice Surfactant free fabrication  nontoxic and suitable for biomedical applications Nozzle walls Thinner inner stream Carrier stream Drop separation by Coulombic repulsion

  11. Generation of Uniform Droplets Increasing acoustic frequencyand/or increasing carrier stream flow rate Increasing amount of electric charge on drop

  12. Schematic of Apparatus Power Supply Computer Interface PolymerSolution Acoustic Excitation Monitor Computer Carrier stream Stroboscope Optical Lens Camera Collection Bath Control line Electric connection

  13. Electronic Control onMicroparticle Fabrication

  14. Monodisperse Microparticles of Various Biomaterials Chitosan Hetastarch Gelatin (Type 1) Gelatin (Type 2) 15 μm 17 μm 25 μm 20 μm 30 μm 30 μm 30 μm 15 μm 20 μm 30 μm 40 μm 30 μm 28 μm 45 μm 50 μm 40 μm

  15. Densely PackedPrecision Microparticles Chitosan 20 μm 28 μm 15 μm 5 μm Hetastarch 17 μm 30 μm 45 μm 10 μm

  16. Additional Controls on Precision Microparticles C1 C2 C3 C4 C5 C6 Day 1 Day 2 50 μm 50 μm Day 3 Day 6 Day 9 N/A N/A Day 12 N/A N/A N/A

  17. Various Drug Release Profiles from Precision Microparticles Choy et. al, Uniform ethyl cellulose microspheres of controlled sizes and polymer viscosities and their drug release profiles,Journal of Applied Polymer Science, 112(2), 850-857, 2008 Choy, et. al, Uniform chitosan microspheres for potential application to colon-specific drug delivery, Macromolecular Bioscience, 8(12), 1173-1181, 2008 Choy, et. al, Monodisperse gelatin microspheres as a drug delivery vehicle: release profile and effect of cross-linking density, Macromolecular Bioscience, 8(8), 758-765, 2008 Choy, et. al, Uniform biodegradable hydrogel microspheres fabricated by a surfactant-free electric-field-assisted method, Macromolecular Bioscience, 7(4), 423-428, 2007

  18. Fabrication of Uniform Bio-Microparticles Selected as a cover paper!!

  19. Controlled Drug Release from Precision Microparticles • Highlight of Student Posters in31st Annual Meeting & Exposition of the Controlled Release Society, Honolulu, HI, USA Felodipine release Nifedipine release Nifedipine and felodipine release from ethyl cellulose microspheres with uniform size and size distribution, Abstract & Poster, 2004, 31st Annual Meeting & Exposition of the Controlled Release Society, Honolulu, HI, USA

  20. Precision Microparticles for Tissue Engineering BMP-2 TGF-β1 • Dual growth factor delivery • Schematic representations of the two designs of experimental devices • Variation in the placement of the precision microparticles affecting the release profiles Black and white confocal microscopy images of the gelatin microspheres contained within layers of gelatin sheets. Dotted line indicates microsphere region. [Contributed by Prof. Jamison’s group at UIUC].

  21. Engineered Microparticles for Ophthalmic Drug Delivery Current problems with conventional topical treatments Rapid clearance mechanism of tear low retention time of drug at the preocular surface Inconvenient administration schedules 10 μm 10 μm • EngineeredMicroparticles • Wall material: Poly(lactic-co-glycolic acid) • Mucoadhesion promoter: PEG • Size: 1 ~ 10 µm to avoid eye irritation and for safe clearance through lacrimal canals • Geometry: disc shape • Formulation: rapidly dissolving tablet

  22. Dosage Form Design • Microparticle suspension • HBSS • 5 mg/ml • Tablet embedded with microparticles • 20 mg Mannitol; 0.5 mg microparticles • Maximum dimension < 3 mm • ~ 21 ul volume • Tested formulations • PLG MS suspension • PLGPEG MS suspension • PLG MD suspension • PLGPEG MD suspension • PLG MS tablet • PLGPEG MS tablet • PLG MD tablet • PLGPEG MD tablet

  23. Tablet Dosage Form Tablet 3 mm 3 mm

  24. In Vivo Mucoadhesion Test • New Zealand White rabbits • Suspension • 100 ul of 5 mg/ml suspension (0.5 mg microparticles) • 4 consecutive administrations of 25 ul suspension with 1 min intervals in between • Tablet • 20 mg & 20 ul Mannitol (0.5 mg microparticles) • Lower cul-de-sac • Eye closed manually for 5 min • Remaining microparticles were extracted and measured at scheduled intervals.

  25. In Vivo Mucoadhesion Test ** * Choy et. al, Mucoadhesivemicroparticles for ophthalmic drug delivery, Journal of Physics and Chemistry of Solids,69(5-6), 1533-1536,2008. Choy et. al, Mucoadhesivemicrodiscs engineered for ophthalmic drug delivery: effect of particle geometry and tablet formulation, Investigative Ophthalmology & Visual Science, 49(11), 4808-4815, 2008.

  26. In Vivo Images ofRemaining Microparticles CN CN LC LC SF SF IF IF CN: Cornea; LC: Lacrimalcaruncle; SF: Superior fornix; IF: Inferior fornix PLG MS suspension PLG MD suspension PLG MS tablet PLG MD tablet CN LC SF IF CN LC SF IF CN LC SF IF 10 min 30 min 1 hr PLG/PEG MS suspension PLG/PEG MS tablet PLG/PEG MD tablet PLG/PEG MD Tablet PLG/PEG MD suspension CN LC SF IF CN LC SF IF CN CN LC LC SF SF IF IF 10 min 10 min 30 min 30 min 1 hr 1 hr Choy et. al, Mucoadhesivemicroparticles for ophthalmic drug delivery, Journal of Physics and Chemistry of Solids,69(5-6), 1533-1536,2008. Choy et. al, Mucoadhesivemicrodiscs engineered for ophthalmic drug delivery: effect of particle geometry and tablet formulation, Investigative Ophthalmology & Visual Science, 49(11), 4808-4815, 2008. 26

  27. Some In Vivo Results Pupil constriction after Pilocarpine delivery

  28. Some In Vivo Results N/A N/A PH solution PVA tablet N/A N/A N/A N/A PLG MP PLGPEG MP 0 30 60 120 180 240 330 Time (min)

  29. Summary Uniform bio-microparticles were successfully engineered with a novel nontoxic method. Due to precise control on microparticle designs, drug delivery could be also accurately tailored. Bio-microparticles engineered with a combined entity of mucoadhesion, disc shape and dry dosage form were a promising vehicle for ophthalmic applications in sustained drug delivery.

  30. Acknowledgement Funding Sources Georgia Institute of Technology The National Institute of Health The National Eye Institute UIUC Critical Research Initiative funds of the University of Illinois Korean Ministry of Commerce, Industry and Energy

  31. Acknowledgement Felice Cheng, Jin Keun Park, Ravindra Kumar, Changwook Kim, Huichan Seo, Sangho Lim, Dr. Seung Jae Hong, and Profs. Hyungsoo Choi, and Kyekyoon (Kevin) Kim and all other members in Thin Film and Charged Particle Research Laboratory at University of Illinois at Urbana, Champaign. Dr. Cory Berkland, and Profs. Russell Jamison, Bruce Wheeler, Daniel Pack, and Brian Cunningham at University of Illinois at Urbana, Champaign. Drs. Abby Morgan and Aylin Sendemir-Urkmez in Prof. Jamison’s group at University of Illinois at Urbana, Champaign. Summer Rhodes and Professor Jennifer Lewis at University of Illinois at Urbana, Champaign. Yeu Chun Kim, Samirkumar Patel, Chetsi Patel, Prof. Mark Prausnitz, and all other members in Laboratory for Drug Delivery at Georgia Institute of Technology. Glenn Holly, and Profs. Bernard McCarey and Henry Edelhauser in the Emory Eye Center at Emory University.

  32. Thank You For Your Attention Email: ybchoy@snu.ac.kr

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