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

1. Oral Drug Delivery: A Mechanistic
Approach
Lecture 1
Gordon L Amidon
College of Pharmacy
University of Michigan
Ann Arbor, MI 48109

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. Modern Biopharmaceutics

4. Oral Absorption: Mechanism

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. Mechanism: Cell-Membrane Level

7. Predicting
Absorption

8. Delivery Technology

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. 19th Century Oral Delivery

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. 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. 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. 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. Routes of Administration

16. Dissolution In Vivo(?)

17. Oral Absorption

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

20. 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)

21. Cmax and AUC Criteria

23. ∫∫∫ ⋅∞=
t
A
effabs CdAdtPMtMF
0
)(/)(

24. Absorption vs. Systemic Availability
Absolute Bioavailability
is a commonly used term.
It is equivalent to the
much preferred term
Systemic Availability

25. Oral Drug Delivery: The Main Factors
• Permeability
• Metabolism
• Solubility
• Transit

26. 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
= ⋅
= ⋅
=

27. GI Tract: Mass Transport
/ / effj dM dt A P C= = ⋅

28. Modern Biopharmaceutics: A
Transport View
( / )1/
( / sec.)
j dM dt A
P C
P Permeability cm
≡
= ⋅∆
=

29. 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

30. Diffusion vs.
Pharmacokinetic Views
( / )1/dM dt A
P C= ⋅∆
( / )1/
a
dM dt V
k C= ⋅∆
/ak A V P= ⋅
Diffusion Pharmacokinetic

31. 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

32. Mass Transport
Mass

33. Diffusion and Convection
V
Diffusion + Convection
Reaction

36. Mass Transport
Diffusion (concentration gradient)
Convection (pressure gradient)
Reaction (Chemical or Enzymatic)

37. 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

39. Permeability Determination
In Vivo
Human, animal
In Situ
rat, rabbit
Excised Tissue
Rabbit, rat, human
Tissue Culture

40. Jejunal
perfusion
(10 cm)
Ports/
Probes
Cross-section
Human Permeabilities

41. Modern Biopharmaceutics