Controlled Drug Delivery

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Controlled Drug Delivery
Spatial and temporal control over drug
concentration
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Usual Gold Standard in Controlled Release

• Zero Order Release

Toxic Level
Drug Concentration in Plasma
Minimum effective concentration
Time
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• Zero order delivery ineffective when
• Minimum effective concentration changes with time
• Insulin (required level depends on glycemia)
• Addictive drugs, e.g. heroin, cocaine, etc.
• Down regulation of hormone receptors
• Other drugs (e.g. nitroglycerin)

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NONTRADITIONAL DRUG DELIVERY
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Gonadotropin Hormone Releasing Hormone (GnRH)

• Hypogonadotropic Hypogonadism
• Failure of episodic GnRH secretion
• Males Failure to reach puberty
• Females Failure to sustain reproductive cycle
• Treatment Rhythmic, pulsatile delivery of GnRH

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VALUE OF RHYTHMIC DELIVERY
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OTHER HORMONES
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DEVICE DESIGN
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SIMPLE(ST) TOY MODEL
Glucose Permeability
(Area A)
(G)
(rapid step)
(h)
(Volume V)

ASSUMPTIONS Instantaneous conversion of glucose
to H Instantaneous phase transition of
membrane Constant permability to H
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TOY MODEL BEHAVIOR
Time (t)
hss,L
hLH
h
hss,H
hHL
CONDITION FOR OSCILLATION
Pulse Width
Interpulse Interval
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Prototype Device
Glucose pH7.4
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pH Oscillations with Corresponding r-GnRH Flux
into Donor Cell
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Effect of Changing MAA Doping
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What is a hydrogel?
Hydrogels are 3-D crosslinked hydrophilic polymer
networks.
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Discrete Hydrogel Volume Phase Transition (DVPT)

• Discrete
• First-order phase transition
• Volume
• Swells or collapses
• Polyelectrolytes
• Ionizable groups
• Induced by changes in temperature, pH, organic
  solvents, light, and salt

• ??

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Hydrogel Volume Phase Transition
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Swelling ForcesElasticity of Matrix

• Entropic
• unperturbed state is most likely

• Modulus
• due to cross-link density

Modified from T. Tanaka, Sci. Am., 1981, Vol. 244
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Swelling ForcesPolymer-solvent Mixing

• Polymer-solvent mixing entropy
• mixed state more probable
• Polymer-solvent interaction
• Polymer prefers polymer
• Solvent prefers solvent
• Chi parameter quantifies preferences

Modified from T. Tanaka, Sci. Am., 1981, Vol. 244
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Swelling Forces--Ionic

• Ion-solvent mixing
• Mixed state more probable
• Ideal, dilute solution
• Donnan Partitioning
• Negative charge on membrane
• Positive ions drawn in to neutralize membrane

P. Flory, Principles of Polymer Chemistry, 1965
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Hydrogen Ion Dissociation, Charge Density on
Hydrogel
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Matrix Stress vs. Swelling Ratio

• Ionization ? environmental sensitivity
• Bistability

Collapsed equilibrium
Curve shifts with pH
Swollen equilibrium
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More Advanced Toy Model
Swelling of Hydrogel
H Concentration in Hydrogel
Glucose Transport/H Production
Dissociation
Electroneutrality
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SWELLING HYSTERESIS
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HOPF BIFURCATIONSPREDICTED OSCILLATIONS
b
a
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Acknowledgments

• John P. Baker
• Jean-Christophe Leroux
• Gauri Misra
• Anish Dhanarajan
• Jon Urban
• Yuandong Gu
• NSF, NIH