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

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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

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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)

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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

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Biomaterial-Based Microparticles

Small in size Simplicity of

administration Local targeting

Versatility Numerous drug

delivery scenarios

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Conventional Fabrication Methods

Chemical reaction Phase separation Interfacial polymerization

Mechanical agitation Sonication/homogenization Spray drying Fluidized bed

Almost No Physical Control!!

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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……….”

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Precision Microparticles

Accurate control on size, drug distribution and biomaterial decomposition

Engineered geometry

Modified surface chemistry

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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.

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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

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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

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Electronic Control onMicroparticle Fabrication

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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)

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Densely PackedPrecision Microparticles

5 μm

15 μm 20 μm 28 μm

Chitosan

17 μm 30 μm 45 μm

10 μm

Hetastarch

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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

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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

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Fabrication of Uniform Bio-Microparticles

Selected as a cover paper!!

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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

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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.

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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)

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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.

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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

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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.

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Thank YouFor Your

Attention

Email: ybchoy@snu.ac.kr