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Oral Drug Delivery 2009: GI Motility and Transit, as Presented by Dr. Gordon Amidon

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Lecture #3 from the Drug Delivery Foundation's 2009 Oral Drug Delivery Conference: http://www.ddfint.org/previous-events/2017/5/22/odd2009-strategies-for-oral-drug-delivery

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Oral Drug Delivery 2009: GI Motility and Transit, as Presented by Dr. Gordon Amidon

  1. 1. GI Motility and Transit Lecture 3 Gordon L Amidon
  2. 2. Early History of GI Physiology and Digestion
  3. 3. The Process of Digestion as Chemistry 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.
  4. 4. William Beaumonts Experiments • Fort Mackinac Michigan • Experiments 1822-1831 on French Canadian Porter accidentally wounded at close range • Wound Healed to form ‘Valve’ to Stomach
  5. 5. Mouth Pharynx Stomach Small Intestine Esophagus Large Intestine Gastrointestinal Tract
  6. 6. STOMACH Secretion 1. Hydrogen ion 2. Pepsinogens 3. Mucus 4. Bicarbonate 5. Intrinsic factor 6. Water
  7. 7. STOMACH Motility: Gastric Emptying 1. Storage of ingested material (reservoir) 2. Mixing and size reduction of luminal contents (preparatory chamber) 3. Moving luminal contents from stomach to intestine (emptying regulator)
  8. 8. Fundus Body Antrum Orad Region: • fundus and upper body part • gastric reservoir • slow sustained contraction --- liquid emptying Caudad Region: • lower body part and antrum • mixing, grinding, emptying • peristaltic contractions and retropropulsion STOMACH Motility: Gastric Emptying
  9. 9. STOMACH Motility: Gastric Emptying Propulsion Evacuation Retropulsion Grinding
  10. 10. Gastric Emptying of Liquids • T1/2=7 min. • Calories = slower
  11. 11. Gastric Emptying: Solids
  12. 12. 1. Slow wave: Periodic oscillating membrane potential of smooth muscle cells. 2. Spike potential: Bursts of electrical oscillations corresponding to a contraction. Extracellular Reference Potential Contractile Excitation Threshold Potential Resting Membrane Potential (-50 to -70 mV) Contractions Neurochemical Excitation STOMACH Motility: Gastric Motor Activities
  13. 13. STOMACH Motility: Migrating Myoelectric Complex (MMC) Fasted State
  14. 14. STOMACH Motility: Migrating Myoelectric Complex (MMC) Fed State
  15. 15. STOMACH Motility: Gastric Emptying of Liquid 1. Phase of ingestion time 2. Volume 3. Osmolarity 4. pH 5. Caloric content 6. Viscosity Factors influencing rate of emptying
  16. 16. STOMACH Motility: Gastric Emptying of Solid 1. In Fasted State 2. In Fed State
  17. 17. SMALL INTESTINE Structure
  18. 18. SMALL INTESTINE Structure: Cell Types
  19. 19. SMALL INTESTINE Structure: Cell Types
  20. 20. SMALL INTESTINE Functions 1. Completion of digestion 2. Absorption of nutrients ---amplification of surface area 3. Excretion of waste products 4. Immunological response
  21. 21. SMALL INTESTINE Function: Amplification of Surface Area
  22. 22. SMALL INTESTINE Motility: Pattern 1. Propagated contraction (peristalsis) 2. Localized contraction (segmental) 1. Ileus 2. Spasm Normal Pattern Abnormal Pattern
  23. 23. SMALL INTESTINE Motility
  24. 24. Intestinal Transit of Dosage Forms • 3 hr Transit time Fasted and Fed
  25. 25. Intestinal pH
  26. 26. LARGE INTESTINE Structure
  27. 27. LARGE INTESTINE Structure: Special Features - Teniae Coli - Haustra (Haustration) - Bacteria - Enzymes
  28. 28. LARGE INTESTINE Functions 1. Absorption of water and electrolytes 2. Formation, storage and evacuation of feces
  29. 29. FLUID General mechanism of water absorption is passive diffusion across the epithelial membrane. Passive diffusion depends on osmotic and hydrostatic pressures. Concentrations of ions, therefore, greatly influences fluid absorption.
  30. 30. Motility probes Cross-section 4.8 mm (o.d.) Gastric Manometry: GASTRIC EMPTYING STUDY
  31. 31. Gastric Motility Chart Recording: Channel Channel 1 2 3 Channel 1 4 5 6 1 mV 190 Time (min) 180 GASTRIC EMPTYING STUDY
  32. 32. Profile of drug markers for 0.7 mm CAFF and 3.6 mm APAP pellets overlaid on corresponding antral motility with designated tInitial time points at 4000 cP viscous caloric meal. GASTRIC EMPTYING STUDY
  33. 33. GASTRIC EMPTYING STUDY Gastric emptying profile of caffeine (0.7mm) vs. acetaminophen (3.5mm) under different gastric conditions.
  34. 34. GI Motility and Transit • Fasted vs. Fed State • Fasted State MMC (~2 hours) • Transit Times
  35. 35. Gastric Emptying With Food
  36. 36. Gastric Emptying of Liquids: Fasted State as a Function of Motility and Volume
  37. 37. FDA Meal
  38. 38. Transit Times: Rule of ‘3’ • Gastric Emptying: 0.3 hr. • Intestinal Transit: 3 hours • Colon Transit: 30 hrs • Meal: 3 cal/min.
  39. 39. Particle Emptying Conclusions • Large 3.5 mm particles empty slower that small 0.7 mm particles • Gastric Motility empties large particles
  40. 40. All you need to know about transit! Rule of ‘3’ • 0.3 hr. Gastric emptying time (fasted) • 3 cal per min. food emptying (gastric) • 3 hrs. Small Intestine Transit (fasted and Fed) • 30 hrs Large Intestine transit time
  41. 41. Oral Drug Delivery Implictions • IR Dosage Forms: GE, in vivo solubilization, and Permeability most important • MR Dosage Forms: Transit depends on dosage form hence absorption depends on dosage form and site

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