Custom-Shaped Bio-Microparticles for Precision Drug
Delivery
Young Bin Choy, Ph.D.
Department of Biomedical EngineeringSeoul 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 (~ 750 조 원 ) Korean Government Budget in the year of 2008 = 257 조 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
Dru
g c
on
cen
trat
ion
Side effects
Therapeutic window
Multiple doses
- Standard drug dosing
Time
Single dose
- Drug dosing via medicinal devices
5
Biomaterial-Based Microparticles
Small in size Simplicity of
administration Local targeting
Versatility Numerous drug
delivery scenarios
6
Conventional Fabrication Methods
Chemical reaction Phase separation Interfacial polymerization
Mechanical agitation Sonication/homogenization Spray drying Fluidized bed
Almost No Physical Control!!
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……….”
8
Precision Microparticles
Accurate control on size, drug distribution and biomaterial decomposition
Engineered geometry
Modified surface chemistry
9
Single Nozzle Drop Generation
Nozzle walls
fv /
Critical Limitation: Minimum achievable drop size = Twice the nozzle opening.
Rayleigh’s equation
- rd: radius of the drop- rj: jet radius- vj: jet velocity- f : excitation frequency.
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 rateIncreasing amount of electric charge on drop
Schematic of Apparatus
Computer
Interface
Computer
Control line
Electric connection
Power Supply
Camera
Stroboscope
Monitor
CollectionBath
Optical Lens
Carrier stream
PolymerSolution
AcousticExcitation
13
Electronic Control onMicroparticle Fabrication
14
Monodisperse Microparticles of Various Biomaterials
15 μm
20 μm
28 μm
15 μm
Chitosan
17 μm
30 μm
45 μm
30 μm
Hetastarch
25 μm
40 μm
50 μm
30 μm
Gelatin (Type 1)
20 μm
30 μm
40 μm
30 μm
Gelatin (Type 2)
15
Densely PackedPrecision Microparticles
5 μm
15 μm 20 μm 28 μm
Chitosan
17 μm 30 μm 45 μm
10 μm
Hetastarch
16
Additional Controls on Precision Microparticles
50 μm 50 μm
N/A N/A
N/AN/AN/A
Day 1
Day 2
Day 3
Day 6
Day 9
Day 12
C1 C2 C3 C4 C5 C6
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, 2008Choy, et. al, Uniform chitosan microspheres for potential application to colon-specific drug delivery, Macromolecular Bioscience, 8(12), 1173-1181, 2008Choy, et. al, Monodisperse gelatin microspheres as a drug delivery vehicle: release profile and effect of cross-linking density, Macromolecular Bioscience, 8(8), 758-765, 2008Choy, 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
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
Felodipine release Nifedipine release
Highlight of Student Posters in31st Annual Meeting & Exposition of the Controlled Release Society, Honolulu, HI, USA
Precision Microparticles for Tissue Engineering
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].
Dual growth factor de-livery
Schematic representa-tions of the two de-signs of experimental devices
Variation in the place-ment of the precision microparticles affect-ing the release profiles
TGF-β1 BMP-2
21
10 μm
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
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
10 μm
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
Tablet Dosage Form
3 mm
Tablet
3 mm
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.
In Vivo Mucoadhesion Test
0
10
20
30
40
50
60
10 min 30 min 60 min
Re
ma
inin
g p
art
icle
s (
%)
PLG MS suspensionPLG MS tabletPLG MD suspensionPLG MD tabletPLG/PEG MS suspensionPLG/PEG MS tabletPLG/PEG MD suspensionPLG/PEG MD tablet
**
*
Choy et. al, Mucoadhesive microparticles for ophthalmic drug delivery, Journal of Physics and Chemistry of Solids, 69(5-6), 1533-1536, 2008.Choy et. al, Mucoadhesive microdiscs 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 LC SF IF CN LC SF IFCN LC SF IF CN LC SF IF
PLG MS suspension PLG MS tabletPLG MD suspension PLG MD tablet
10 min
30 min
1 hr
CN LC SF IF CN LC SF IFCN LC SF IF
PLG/PEG MS suspension PLG/PEG MS tabletPLG/PEG MD suspension
CN LC SF IF
PLG/PEG MD tablet
10 min
30 min
1 hr
CN LC SF IF
PLG/PEG MD Tablet
10 min
30 min
1 hr
CN: Cornea; LC: Lacrimal caruncle; SF: Superior fornix; IF: Inferior fornix
Choy et. al, Mucoadhesive microparticles for ophthalmic drug delivery, Journal of Physics and Chemistry of Solids, 69(5-6), 1533-1536, 2008.Choy et. al, Mucoadhesive microdiscs engineered for ophthalmic drug delivery: effect of particle geometry and tablet formulation, Investigative Ophthalmology & Visual Science, 49(11), 4808-4815, 2008.
Some In Vivo ResultsPupil constriction after Pilocarpine delivery
40
60
80
100
0 60 120 180 240 300
Time (min)
Per
cen
tag
e (%
)
PH solution
PVA tablet
PLG MP
PLGPEG MP
Some In Vivo Results
N/A N/A
N/A N/A
N/AN/A
PH solution
PLG MP
PVA tablet
PLGPEG MP
0 12030 18060 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.