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Recent Advances in BCS and Drug Product (BioPredictive) Dissolution Gordon L Amidon College of Pharmacy Charles Walgreen Jr. Professor of Pharmacy University.

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Presentation on theme: "Recent Advances in BCS and Drug Product (BioPredictive) Dissolution Gordon L Amidon College of Pharmacy Charles Walgreen Jr. Professor of Pharmacy University."— Presentation transcript:

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(F abs ) vs. Systemic Availability (F sys )

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 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. Bioavailability (21 CFR 320)* * 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 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. Bioavailability (21 CFR 320)* * 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! Label Product “BE”

14 BE: Transport (Absorptive) View

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

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% Fabs

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

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 IHigh >85% Dissolution in 15 min; 30 min, f2., pH = 6.8. II-ALowHigh 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-BHighLowHigh>85% Dissolution in 15 min., pH = 1.2. II-CLow High 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%. IIIHigh Low>85% Dissolution in 15 min., pH = 1.2, 4.5, 6.8. IV-ALowHighLow 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-BHighLow >85% Dissolution in 15 min., pH = 1.2. IV-CLow 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%.

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

33 Human In Vivo Buffer: Bicarbonate J.G. Hardman, et al., eds., Goodman and Gilman’s The pharmacological basis for therapeutics, 10 th ed., Chapter 39, p1038. N.W. Tietz, et al., eds., Clinical guide to laboratory tests., 3 rd 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). 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

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 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: Fasted State Simulated Small Intestinal Fluids (FaSSIF 1 ) Fasted State Simulated Small Intestinal Fluids (FaSSIF 1 ) 29 mM NaH 2 PO4 29 mM NaH 2 PO4 q.s. to pH 6.5 with NaOH q.s. to pH 6.5 with NaOH 3 mM Na taurocholate 3 mM Na taurocholate 0.75 mM lecithin 0.75 mM lecithin 106 mM NaCl 106 mM NaCl Other buffers covering pH Other buffers covering pH Simulated gastric fluids (SGF): pH 1.2 HCl Simulated gastric fluids (SGF): pH 1.2 HCl FeSSIF (Fed State Simulated Small Intestine fluids) pH 5.0 acetate buffer FeSSIF (Fed State Simulated Small Intestine fluids) pH 5.0 acetate buffer pH 7.5 phosphate buffer pH 7.5 phosphate buffer Buffer choice of analytical chemists with addition of SLS, Tween, and CTAB. Buffer choice of analytical chemists with addition of SLS, Tween, and CTAB.

37 Equilibrium (?) In the Intestine Bicarbonate Equilibrium H 2 CO 3 HCO 3 − + H + K a1 = 2.5×10 −4 ; pK a1 = 3.60 at 25 °C. HCO 3 − CO 3 2− + H + K a2 = 5.61×10 −11 ; pK a2 = at 25 °C Gas Phase Equilibrium –CO 2 (gas) = CO 2 (dissolved) where k H =29.76 atm/(mol/L) at 25°C (Henry constant)Henry constant CO 2(aq) + H 2 O = H 2 CO 3 (aq) Then of course we have CO 2 transport in the Intestine Transporters, Exchangers, intracellular equilibrium PCO2 (Intestine)~200 mmHg CO 2 (aq) + H 2 O = H 2 CO 3 CO 2 (g)

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

39 Bicarbonate Buffer: Reactions and Rates

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

41 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 cm 2 /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 ) 地獄の辺土 ( 天国と地獄の間 ) 天獄 地獄

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49 Predicting Absorption

50 Time Dependent Absorption

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

52 Predicting Absorption(F abs ) vs. Systemic Availability (F sys )

53 Predicting Absorption

54 Transport View Of Oral Absorption

55


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