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Oral Drug Delivery 2010: A Mechanistic Approach, as Presented by Dr. Gordon Amidon

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Lecture #1 from the Drug Delivery Foundation's Oral Drug Delivery Conference 2010: http://www.ddfint.org/previous-events/2017/4/22/odd2010-strategies-for-oral-drug-delivery

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Oral Drug Delivery 2010: A Mechanistic Approach, as Presented by Dr. Gordon Amidon

  1. 1. Oral Drug Delivery: A Mechanistic Approach Lecture 1 Gordon L Amidon College of Pharmacy University of Michigan Ann Arbor, MI 48109
  2. 2. Organizers Gordon L. Amidon (Ann Arbor, Michigan, USA) Peter Langguth (Mainz, Germany) Hans Lennernäs (Uppsala, Sweden) James Polli (Baltimore, MD, USA) Shinji Yamashita (Osaka, Japan) Oral Drug Delivery: 2010 • GI Physiology: A Mechanistic Approach • Methods For Evaluation • Intestinal and Hepatic Transport and Metabolism • Poorly Soluble Drugs • From Discovery to Regulation
  3. 3. Modern Biopharmaceutics
  4. 4. Oral Absorption: Mechanism
  5. 5. van Helmont, J. B., Oriatrike or Physick Refined, transl. J. Chandler, London, 1662 Beaumont, W., Experiments and Ovservations on the Gastric Juice and the Physiology of Digestion, Plattsburg, Va. 1833 Early GI History
  6. 6. Mechanism: Cell-Membrane Level
  7. 7. Predicting Absorption
  8. 8. Delivery Technology
  9. 9. Oral Drug Delivery: Significant Products • DilantinTM ; 1946 • Digoxin,1930; • Griseofulvin, 1939, 1962 • Levodopa-Carbidopa • ContacTM • PlendilTM , Extended-Release • PrilosecTM , Delayed-Release • Procardia-XLTM • Oral Polio Vaccine
  10. 10. 19th Century Oral Delivery
  11. 11. Upjohn’s Friable Pills Early Example of Drug Delivery Circa 1880 Recognized Disintegration as Important “Selling’ Point! Tablets Invented circa 1840 Built Company Image
  12. 12. Dissolution Technology • Early recognition 18951 • 1970 USP-NF Joint Panel “Official Apparatus” -1945 British Pharmacopeia (Disintegration Test) 1980 USP ‘policy’ -1980 72 USP Monographs 1. “A Trreatise on Pharmacy,” Gaspari, C. , Philadelphia, 1895 2. 2. L.T. Grady,(Retiured Director of USP Drug Standards) (http://www.layloff.net/)
  13. 13. Regulation of Dissolution: 1965 NF “For the purposes of this test, disintegration does not imply complete solution of the tablet or even of it’s active constituent”
  14. 14. Biopharmaceutics and Drug Regulation • 1938 F D & C Act of 1938 (safety) – Use of Diethylene Glycol in Sulfanilamide IV Drug • 1962 Amendments (Kefauver-Harris or Drug Efficacy Amendment) • 1974 Office of Technology Assessment: Drug Bioequivalence • 1984 Drug Price Competition and Patent Term Restoration Act (Hatch-Waxman Act [Public Law 98-417]) • 1989 Generic Drug Scandal – Bribery and ‘clerical’ error • 1990 FDA Office of Generic Drugs (Products)
  15. 15. Routes of Administration
  16. 16. Dissolution In Vivo(?)
  17. 17. Oral Absorption
  18. 18. Biopharmaceutics Factors • Physiological – Membrane Properties (Permeability), pH, Fluid Contents, Solubilizers (Bile Salts), Membrane Transporters, Metabolism, PK Properties • Transit Time ( Residence Time): Motility – Fasted & Fed States • Physical Chemical – Solubility, Vehicle (Solvent, Solubilizers), Particle Size, Residence Transit ( Residence Time), Time • Formulation and Process – Excipients, Controlled Release, Solubilizers
  19. 19. Bioavailability: Code Of Federal Regulations (CFR) CFR 21.320.1 ( Definitions) Bioavailability means the rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action. (CFR = Code of Federal Regulations)
  20. 20. Cmax and AUC Criteria
  21. 21. ∫∫∫ ⋅∞= t A effabs CdAdtPMtMF 0 )(/)(
  22. 22. Absorption vs. Systemic Availability Absolute Bioavailability is a commonly used term. It is equivalent to the much preferred term Systemic Availability
  23. 23. Oral Drug Delivery: The Main Factors • Permeability • Metabolism • Solubility • Transit
  24. 24. Classical Biopharmaceutics / ( / )1/ ( ) ( 1/sec b (Textbook Version) -C ) (More) Correct Version) a a l a dC dt k C dM dt V k t C k = ⋅ = ⋅ =
  25. 25. GI Tract: Mass Transport / / effj dM dt A P C= = ⋅
  26. 26. Modern Biopharmaceutics: A Transport View ( / )1/ ( / sec.) j dM dt A P C P Permeability cm ≡ = ⋅∆ =
  27. 27. Diffusion vs.Pharmacokinetic Views ( / )1/ /sec. j dM dt A P C P cm = = ⋅∆ = / ( / )1/ 1/sec a a a dC dt k C dM dt V k C k = ⋅ = = ⋅∆ = Diffusion Pharmacokinetic
  28. 28. Diffusion vs. Pharmacokinetic Views ( / )1/dM dt A P C= ⋅∆ ( / )1/ a dM dt V k C= ⋅∆ /ak A V P= ⋅ Diffusion Pharmacokinetic
  29. 29. Relationship between ka and P ( ) ( ) / ( ) ( )ak t A t V t P t= ⋅ The complexity is in the time dependence of surface area (A), (fluid) volume and (position dependence of) permeability along the GIT
  30. 30. Mass Transport Mass
  31. 31. Diffusion and Convection V Diffusion + Convection Reaction
  32. 32. Mass Transport Diffusion (concentration gradient) Convection (pressure gradient) Reaction (Chemical or Enzymatic)
  33. 33. Macroscopic Mass Balance dM/dt =A J = A Peff C Rate of Mass In Rate of Mass Out (Q*Cin) (Q*Cout) L 2R Rate of Mass Absorbed
  34. 34. Permeability Determination In Vivo Human, animal In Situ rat, rabbit Excised Tissue Rabbit, rat, human Tissue Culture
  35. 35. Jejunal perfusion (10 cm) Ports/ Probes Cross-section Human Permeabilities
  36. 36. Modern Biopharmaceutics

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