1. Recent Advances in BCS and Drug Product (BioPredictive) Dissolution
Gordon L Amidon
College of Pharmacy
Charles Walgreen Jr. Professor of Pharmacy
University of Michigan
Ann Arbor, MI
Moscow, Oct 28, 2013

2. Major Considerations in Pharmaceutical Products
Must Insure Labeling
Must Insure Product Does What the Label States
Must Set Pharmaceutical Standards
Insure Therapeutic Interchangeability
World Market is Generic = Multi Source Products
Singular Fact: Patients Have (almost) No Choice

3. Oral Drug Product Performance

4. Predicting Absorption(Fabs) vs. Systemic Availability (Fsys)

5. Pharmaceutical Standards
Identity
Purity
Safety and Efficacy
Potency  Dose  Bioavailability
BIOEQUIVALENCE!

6. Bioequivalence: Orange Book
Bioequivalent Drug Products. This term describes pharmaceutical equivalent or alternative products that display comparable bioavailability when studied under similar experimental conditions. Section 505 (j)(8)(B) of the Act describes one set of conditions under which a test and reference listed drug5 shall be considered bioequivalent:
the rate and extent of absorption of the test drug do not show a significant difference from the rate and extent of absorption of the reference drug when administered at the same molar dose of the therapeutic ingredient under similar experimental conditions in either a single dose or multiple doses; or

7. Bioavailability (21 CFR 320)*
This term 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.
* Code of Federal Regulations (US Government)

8. Bioequivalence (BE): Today

9. Bioequivalence (BE) Paradigm (Oral)
Similar Plasma Levels  Similar Efficacy
Similar In Vivo Dissolution  Similar Plasma Levels
Similar In Vitro Dissolution  Similar In Vivo Dissolution

10. Bioavailability (21 CFR 320)*
This term 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.
* Code of Federal Regulations (US Government)

11. General BE Confidence Interval Test

12. Transport View of BE Science

13. BE connects the product in the bottle with the claims on the label!

14. BE: Transport (Absorptive) View

15. Transport Bioequivalence(BE)
If Two Drug Products, Same Drug, present the drug to the absorbing membrane the same way, (C[x,y,z,t]), they will be bioequivalent (BE)

16. Predicting Absorption

17. Absorption Rate Same Absorption Rate Same metabolism rate
Same Plasma Levels

18. Oral BE and Dissolution
Amidon et al., Clinical pharmacology and Therapeutics, 90, 467 (2011)

19. The Case for ‘Dissolution’ Bioperformance Dissolution
Phase III Clinically tested Product
In Vivo Dissolution of Phase III Product = Bioperformance Dissolution
In Vitro Dissolution?
Amidon, KS, et al. Clin. Pharmac. Therap., 90, 467, 2011

20. August 2000 FDA Guidance
G.L. Amidon et. al., Pharmaceutical Research, 12, 413 (1995).

21. Biopharmaceutical Classification
High Solubility
Low Solubility
Class 1
High Solubility
High Permeability
(Rapid Dissolution)
Class 2
Low Solubility
High Permeability
Permeability
High
Class 3
High Solubility
Low Permeability
Class 4
Low Solubility
Low Permeability
Permeability
Low
Amidon et al., Pharm Res 12: , 1995

22. BCS: Definitions High Permeability Fraction Absorbed>90% (85%)
Permeability is Surrogate (Human/Animal/Caco2)
High Solubility->Highest Dose Soluble 250 ml
pH (6.8), pKa

23. High Permeability Drug: Fabs>90%

24. High Solubility Drug Vs = Volume of Solution <250 ml,
FDA Glass of Water= 8 oz.
(240 ml)
Vs = Volume of Solution <250 ml,
pH=1-7.5 (6.8)
Highest Dose Strength
Do=Dose/250/C s <1

25. BCS of Worlds Drugs

26. Drug database of oral immediate-release (IR) drugs on 200 top-selling US, GB, ES, JP, and KR drug products
US: 113 oral IR drugs (56.5%)
GB: 102 oral drugs (51.0%)
ES: 106 oral drugs (53.0%)
JP: 113 oral drugs (56.5%)
KR: 87 oral drugs (43.5%)
Based on 200 top-selling drug products in 5 countries, and WHO Essential drugs (EML), drug databases of Combined List (346 drugs), Western List (147 drugs), Eastern List (163 drugs) was made and analyzed on molecular properties and BCS classification.

27. Comparison of the percentage of oral IR drugs of permeability class on the Combined, Western, Eastern, US, GB, ES, JP, KR, and WHO lists

28. Comparison of the percentage of oral IR drugs of solubility class in the Combined, Western, Eastern, US, GB, ES, JP, KR, and WHO lists

29. BCS Worlds Drugs

30. Bioperformance Dissolution (Definition)
An in vitro dissolution methodology that is predictive of in vivo dissolution
This methodology is not a QC methodology
It is not a regulatory methodology
It IS a drug product development methodology

31. Bioperformance Dissolution Sub-Classification Proposal
BCS Class
Drug Solubility pH 1.2
Drug Solubility pH 6.8
Drug Permeability
Preferred Procedure I
High
>85% Dissolution in 15 min; 30 min, f2., pH = 6.8.
II-A
Low
15 min at pH=1.2, then 85% Dissolution in 30 min., pH = 6.8; F2>50; 5 points minimum; not more than one point > 85%.
II-B
>85% Dissolution in 15 min., pH = 1.2.
II-C
15 min at pH=1.2; then 85% Dissolution in 30 min., pH = 6.8 plus surfactant*; F2>50; 5 points minimum, not more than one point > 85%.
III
>85% Dissolution in 15 min., pH = 1.2, 4.5, 6.8.
IV-A
15 min. at pH = 1.2; then 85% Dissolution in 30 min., pH = 6.8,; F2>50; 5 points minimum.; not more than one point > 85%.
IV-B
IV-C

32. Bioperformance Dissolution: One Consideration
GI Physiology pH
Buffer
Transit
Fasted/Fed

33. Human In Vivo Buffer: Bicarbonate
Stomach
10mM
4-21mM,
Average= 15mM
30mM
70mM
Human GI Bicarbonate
Pharmaceutical
buffers
pH 1.2, 0.1N HCl
1. USP
2. FaSSIF
3. Others
J.G. Hardman, et al., eds., Goodman and Gilman’s The pharmacological basis for therapeutics, 10th ed., Chapter 39, p1038.
N.W. Tietz, et al., eds., Clinical guide to laboratory tests., 3rd ed., p 84.
W. G. Karr, et al., Intubation Studies Of The Human Small Intestine. Iv. Chemical Characteristics Of The Intestinal Contents In The Fasting State And As Influenced By The Administration Of Acids, Of Alkalies And Of Water. J Clin Invest 14: (1935).

34. A Pharmaceutical Product with CO2

35. CO2 in the Environment

36. Pharmaceutical Buffers
United State Pharmacopeias (USP) buffer
50 mM pH 6.8 phosphate buffer
Fasted State Simulated Small Intestinal Fluids (FaSSIF1)
29 mM NaH2PO4
q.s. to pH 6.5 with NaOH
3 mM Na taurocholate
0.75 mM lecithin
106 mM NaCl
Other buffers covering pH
Simulated gastric fluids (SGF): pH 1.2 HCl
FeSSIF (Fed State Simulated Small Intestine fluids) pH 5.0 acetate buffer
pH 7.5 phosphate buffer
Buffer choice of analytical chemists with addition of SLS, Tween, and CTAB.
1: Vertzoni M. et al., Dissolution media simulating the intralumenal composition of the small intestine: physiological issues and practical aspects. J. Pharmacy & Pharmacology, 2004, 56:

37. Equilibrium (?) In the Intestine
CO2 (g)
Bicarbonate Equilibrium
H2CO3 HCO3− + H Ka1 = 2.5×10−4 ; pKa1 = 3.60 at 25 °C.
HCO3− CO32− + H Ka2 = 5.61×10−11 ; pKa2 = at 25 °C
Gas Phase Equilibrium
CO2(gas) = CO2(dissolved)
where kH=29.76 atm/(mol/L) at 25°C (Henry constant)
  CO2(aq) + H2O = H2CO3 (aq)
Then of course we have CO2 transport in the Intestine Transporters, Exchangers, intracellular equilibrium
PCO2 (Intestine)~200 mmHg
CO2 (aq) + H2O = H2CO3

38. Bicarbonate Buffer Physiological Relevance
GI Lumen
Bicarbonate is secreted by the cells throughout the GI tract.
Bicarbonate in the lumen of the GI tract modulates luminal pH.
GI Epithelial Cell
Blood

39. Bicarbonate Buffer: Reactions and Rates

40. Film Model Flux and Flux using Cussler’s Reaction Enhancement Factor
Flux with Reaction Enhancement Factor
EL Cussler, “Diffusion and Mass Transport”, 2009, Wiley

41. Predicted and Experimental Flux in Bicarbonate Buffer at pH 6
Predicted and Experimental Flux in Bicarbonate Buffer at pH 6.5: Ibuprofen Solubility=3.3x10-4 M, pKa=4.43, Diffusion Coefficient =7.93x10-6 cm2/s

42. BABE 1960-Present Mainly Empirical: Cmax and AUC
Regulatory Dominated
Little Biopharmaceutical Mechanism
ADME very complex-> Empirical
Pharmacokinetics Dominated the Science
Analytical and Computational Technology
Regulatory Standards from the ~1970’s
BA & BE

43. Bioequivalence (BE) Today: Oral
Historically a Relative Bioavailability (BA) Based View
Misses the underlying scientific issues
IN Vivo Dissolution
BE Testing is Same Drug
Once Absorbed PK is the Same
The Science of BE is at the Absorption Site
For Oral Dosage Form in the GI Tract
The Question is: What is the Best BE Test

44. BioPredictive Dissolution (BPD)
BCS Class I, IIa, III
Rapid Dissolution
BCS Class IIb,c
More Complex
Modified Release
-Move Complex

45.  煉獄(苦行)
 天獄
 地獄の辺土(天国と地獄の間)
 地獄

49. Predicting Absorption

50. Time Dependent Absorption

51. Diffusion vs. Pharmacokinetic Views of Absorption: A Simpler Well Mixed View
Software e.g. GastroPlus®

52. Predicting Absorption(Fabs) vs. Systemic Availability (Fsys)

53. Predicting Absorption

54. Transport View Of Oral Absorption