team 1 final presentation: "zero-order implantable drug delivery
TRANSCRIPT
Zero-order implantable drug delivery microchip
Capstone Final Presentation: May 11, 2012
Steven Ramiro, Schuyler Fearins, Ben Shefter, Doug Trigg,
Alex Sposito, Maureen Perry, Daniel Rowley, and Eric Feldman
Outline 1. Introduction to the Project 2. Literature Review 3. Modeling 4. Simulations 5. Design 6. Prototyping & Fabrication 7. Testing 8. Results 9. Conclusion 10. Path Forward 11. Video
Introduction to our Project
Motivation
http://cheed.nus.edu.sg/~chewch/NEW/drug_highlights.htm
• Gliomas account for 80% of brain tumors
– 13,000 deaths per year in US – 18,000 new diagnoses
• Treatment
– Implant Gliadel wafers – Burst release, non linear
release profile • Develop implantable drug
delivery device that can provide a linear release profile
Intellectual Merit
• Developed a model relating dissolution, diffusion, and degradation kinetics in hemispherical DDS
• Understanding the relation of
variables and their effect on release profile
• Proof of concept of customizable
drug delivery systems
http://www.setyoufreenews.com/2011/11/25/implantable-microchips-and-cyborgs-are-no-longer-conspiracy-theories/
Impact • Controlled and localized drug
release
• Reduce patient non-compliance • Multiple medicines delivered
with one chip
• Help patients with brain cancer recovery and immunotherapy
• Prevent lethal mixing of different drugs
http://topnews.com.sg/images/medications_0.jpg
Ethical and Environmental Issues
Consumer Health Impact: • Active agent release rate • Chip degradation rate • Biocompatibility of microchip • Predictability of drug release
Environmental Impact: • Processing can be scaled, low energy
consumption and waste - minimal impact • Chip degrades in body - minimal impact • No toxic or harmful chemicals used during
processing - minimal impact
MSE Aspects • Biocompatibility - implantable (chip design), hydrolysis, inflammatory response
• Kinetics - drug dissolution and diffusion, chip degradation, system level interactions, boundary conditions
• Chemistry - solvent compatibility, CNC lubricant, adhesive choice, hydrolysis solution mixing, drug concentration
• Polymers - degradation rate
• Mechanical Properties - material strength, elastic deformation
• Processing - polymer processing, mold processing, drug processing, process flow for entire chip
• Experimentation - solution mixing, drug concentration
• Characterization – UV/Vis Spectroscopy, optical microscopy
Literature Review
Previous Work • Microchip Devices
o Gliadel Wafers for brain cancer o 7.7mg Carmustine (BCNU) in one week o Non-linear release profile
• Controlling Release o Polymer material o Drug loading o Porosity o Size of microspheres
• Geometric Control of Release o Hemispheres (Narasimhan 1997) o Linear release profile o Limitations (critical assumption, PVAc)
• PLGA Release Mechanism (Fredenburg (2011)
o Diffusion through water filled pores o Diffusion through polymer o Erosion o Osmotic Pumping
Domb 1998 Fleming, 2002
Non-linear release profile
Narasimhan 1997
Fredenberg 2011
Technical Approach
Previous Work
Probabilistic Model
Design
Deterministic Model
Modeling
Diffusion Model
Higuchi et al:
"Rate of release of medicaments from ointment bases containing drug in suspension”
Siepmann 2011
Diffusion Model
Higuchi et al: Evaluate over small
times and small changes in h
Higuchi's variation of Fick's 1st Law
Equation for changes in h
Combine to get a change in mass/area independent of h
Higuchi's 3rd Assumption: c(ini) >> c(s)
Diffusion Model
• Build upon the work done by Higuchi and Bechard and McMullen, "Solute Release from a Porous Polymer Matrix: Inwardly Tapered Disc with a Central Releasing Hole"
• Revised the equations done by Bechard and Mcmullen to work for three monolithic geometries
• Fixed boundary conditions on the system to model release in radial coordinates
"Theoretical analysis of inward hemispheric release above and below drug solubility"
Siegel et al:
Siegel 2000
Diffusion Model
Siegel et al: Ø Concentration profile in radial coordinates:
Ø Mass balance for hemispherical and hemisphere-like monolithes:
Ø Final equation relating changes in radius to changes in time:
Ø Limiting/Boundary Equations:
Ø Final equation relating changes in radius to changes in radius:
Degradation Model
Mechanisms:
• Hydrolysis
• Autocatalysis
http://www.pla-drugcarrier.com/guideline/
Pores and Erosion Model
Gopferich, 2002
Erosion Model
Derivation arrived from Fitzgerald 1993
Complete Deterministic Model
*He et al. suggests that the mechanisms can be combined as: !!!!
= !"##$%"&' + !" ∗ !"#$%#&!
Data obtained from He 2005
Deterministic Model Results
*variable D = bi-phasic *constant D = linear
*A presoak can enable a pseudo zero order release with a R2 = 0.956
*constant τ = pseudo linear R2 = 0.99 *constant D = linear R2 = 1
Variation of Parameters
*If we assume a constant D - by changing the orifice size (left Figure) and the well size (right Figure) we can control the time of release.
Simulation
Monte Carlo Simulation • Attempts to simulate dissolution, diffusion, and
degradation in a probabilistic manner
• Kinetic model based on a defined unit area, mass, and rates in which an event happens
• The Rules: 1. A cell touching a wet cell has a probability of becoming
wet 2. When a polymer becomes wet its life begins reducing 3. Any polymer with lifetime less than 0 turns into water 4. Drug has a probability of dissolving into water 5. Drug has a probability of diffusing through the water or
matrix
Validation System was validated using a
1-D diffusion equation:
Porter et al.
x position
drug conc (#/row)
x position
drug conc (#/row)
Simulation
R = 1000 um
Simulations: Results
Design
Design Goals 1. Design a completely biodegradable and
implantable drug delivery microchip device that can deliver 7 mg of active agent to patients over one week
2. Develop probabilistic and deterministic models to assist our design and predict the release profile of a single hemispherical well
3. Obtain a "zero order" release profile up through
at least 85% release with R-squared = 0.98
Design Concept 1. Microchip contains seven hemispherical
wells loaded with 50:50 Ibuprofen:PLGA 5.6kDa.
2. Upon immersion in water or bodily fluids, water diffuses inward through the top orifice, and the hydrolysis reaction of the polymer backbone begins.
3. Hydrolysis leads to increased porosity. Active agent diffuses through water filled pores to facilitate release.
4. Entire device biodegrades and is resorbed by body after several months.
Materials
Ibuprofen 5.6 kDa PLGA
Cyanoacrylate
115 kDa PLA
• Chip Material – biocompatibility, slow hydrolysis, processable
• Active Agent – similar MW Carmustine, well characterized, known parameters
• Well Material – biocompatible, faster hydrolysis (lower MW), compatible with Ibuprofen • Adhesive – biocompatibility, bonds polyesters, no solvents
chemical structure diagrams were taken from wikipedia.com
Design Parameters Part Size Note Material
Diameter of chip
1.3 cm
To be similar in size to gliadel wafers. Easily implantable.
PLA 115kDa
Thickness of chip 0.3 cm Structural integrity PLA 115kDa
Radius of well 0.15 cm Allows for maximal loading of chip
Number of wells 7 Allows for maximal loading of chip
Drug loading
50% w/w Allows for loading well above solubility limit, allows maximal drug release
Ibuprofen in PLGA 5.6 kDa
Drug concentration
0.756 g/mL Calculated with 50% drug loading. Solubility of Ibuprofen in PBS 7.4 = .0075 g/mL (Klose 2011)
Ibuprofen
Mass of drug in one well
0.00427 g Ibuprofen
Total mass of drug in chip
14.96 mg Compare to 7- 8 mg BCNU per Gliadel Wafer Ibuprofen
Thickness of top membrane
0.2 cm
PLA 115kDa
Radius of inner orifice 0.01 cm
Design
Prototype & Fabrication
Fabrication Process Process: 1. Hot pressed PLA
bottom wafer
2. Milled hemispherical wells in top wafer
3. Pressed Ibu/PLGA composite into top wafer and planarized
4. Hot pressed PLA top wafer
5. Planarized top wafer and milled channels
6. Applied cyanoacrylate adhesive to bond top and bottom wafers
Bottom PLA Wafer Top PLA Wafer
Fabrication Facilities
http://www.promarkind.com/cnc%20machining.html
http://www.mech.uq.edu.au/ultracomp/composites/facilities/
http://www.avac.com/ovens.php
Prototype
Budget Item Qty Company Cost
Ibuprofen 1 g Sigma-Aldrich $53.81
115 kDa PLA 10 g SurModics $55.00
5.6 kDa PLGA 10 g SurModics $55.00
62 kDa PLGA 10 g SurModics $55.00
Shipping Costs 1 SurModics $30.81
Glassware 1 UMD Chm Store $37.63
Mold Machining 1 Physics Machine Shop $50.00
3 mm ball-end end mill 1 McMaster-Carr $70.51
Medical Adhesive 20 g McMaster-Carr $17.35
TOTAL: $425.11
Testing
Testing
In-vitro studies: 1. Chip placed in orbital shaker,
37ºC @ 80rpm in 100mL flask PBS 7.4pH
2. Samples tested via UV/Vis Spectroscopy every 8 hours
A = log10II0
!
"#
$
%&= εdc
http://en.wikipedia.org/wiki/Beer%E2%80%93Lambert_law
Beer-Lambert Law:
Results
In Vitro Results Cumulative Mass Released
• Near zero order release profile over seven days • R-squared = 0.95 • 35% Released • Total Release = 5.62 mg ibuprofen
Comparison to Gliadel Wafers Fraction Released
• In vitro release data for Gliadel Wafer reproduced from Domb et al. 1998
Comparison to Gliadel Wafers Cumulative Mass Released
• In vitro release data for Gliadel Wafer reproduced from Domb et al. 1998
Results vs. Simulations
Summary 1. Design a completely biodegradable and implantable drug
delivery microchip device that can deliver 7 mg of active agent to patients over one week Ø Biodegradable, implantable, 5.5 mg of active agent to
patients over one week 2. Develop probabilistic and deterministic models to assist
our design and predict the release profile of a single hemispherical well Ø Developed probabilistic and deterministic models
3. Obtain a "zero order" release profile up through at least 85% release with R-squared = 0.98 Ø Zero order 35% release with R-squared = 0.95
Path Forward • Run the drug release to complete release • Test additional microchips to obtain a
statistically relevant data • Perform a control test • Further development of our DDS o Add caps to the wells o Different types of drugs in each well o Wells on both sides o Optimizing well size
• In vivo studies
Video
Acknowledgements
Dr. Phaneuf Dr. Seog Dr. Al-Sheikhly Dr. Wuttig Dr. Devoe Barney Woodard
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