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Controlled Drug Delivery

Controlled Drug Delivery. Spatial and temporal control over drug concentration. Usual Gold Standard in Controlled Release. Zero Order Release . Toxic Level. Drug Concentration in Plasma. Minimum effective concentration. Time. Zero order delivery ineffective when…

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Controlled Drug Delivery

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  1. Controlled Drug Delivery • Spatial and temporal control over drug concentration

  2. Usual Gold Standard in Controlled Release • Zero Order Release Toxic Level Drug Concentration in Plasma Minimum effective concentration Time

  3. 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)

  4. “NONTRADITIONAL” DRUG DELIVERY

  5. 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

  6. VALUE OF RHYTHMIC DELIVERY

  7. OTHER HORMONES

  8. inhibition (Nuclear translocation) inhibition (Nuclear translocation)

  9. DEVICE DESIGN

  10. 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+

  11. TOY MODEL BEHAVIOR Time (t) hss,L hLH h hHL hss,H CONDITION FOR OSCILLATION: Pulse Width: Interpulse Interval:

  12. pH pH Stat Stat pH Meter Meter Recorder Recorder pH Donor Cell Donor Cell Solution Out Solution Out Glucose Glucose Solution In Solution In Glucose Receptor Glucose Donor Receptor Donor Oxidase Oxidase Cell Cell Cell Cell Magnetic stirrer Magnetic stirrer Prototype Device Glucose pH=7.4

  13. pH Oscillations with Corresponding r-GnRH Flux into Donor Cell

  14. DELIVERY RATE OBTAINED BY DECONVOLUTION

  15. Effect of Changing MAA Doping

  16. What is a hydrogel? Hydrogels are 3-D crosslinked hydrophilic polymer networks.

  17. 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 

  18. pH = 5.5 (> pKa of MAA) Na+ -COO- -COOH pH = 4.5 (< pKa of MAA) -COO- -COOH Na+ -COOH -COO- Na+ -COOH -COO- Na+ -COOH Na+ -COO- Hydrogel Volume Phase Transition

  19. 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

  20. 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

  21. 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

  22. Hydrogen Ion Dissociation, Charge Density on Hydrogel

  23. Matrix Stress vs. Swelling Ratio • Ionization  environmental sensitivity • Bistability Collapsedequilibrium Curve shifts with pH Swollen equilibrium

  24. More Advanced Toy Model Swelling of Hydrogel H+ Concentration in Hydrogel Glucose Transport/H+ Production Dissociation Electroneutrality

  25. SWELLING HYSTERESIS

  26. HOPF BIFURCATIONSPREDICTED OSCILLATIONS b a

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

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