Presentation on theme: "Recent Advances in BCS and Drug Product (BioPredictive) Dissolution"— Presentation transcript:
1 Recent Advances in BCS and Drug Product (BioPredictive) Dissolution Gordon L AmidonCollege of PharmacyCharles Walgreen Jr. Professor of PharmacyUniversity of MichiganAnn Arbor, MIMoscow, Oct 28, 2013
2 Major Considerations in Pharmaceutical Products Must Insure LabelingMust Insure Product Does What the Label StatesMust Set Pharmaceutical StandardsInsure Therapeutic InterchangeabilityWorld Market is Generic = Multi Source ProductsSingular Fact: Patients Have (almost) No Choice
4 Predicting Absorption(Fabs) vs. Systemic Availability (Fsys)
5 Pharmaceutical Standards IdentityPuritySafety and EfficacyPotency Dose BioavailabilityBIOEQUIVALENCE!
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)
9 Bioequivalence (BE) Paradigm (Oral) Similar Plasma Levels Similar EfficacySimilar In Vivo Dissolution Similar Plasma LevelsSimilar 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)
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 ProductIn Vivo Dissolution of Phase III Product = Bioperformance DissolutionIn Vitro Dissolution?Amidon, KS, et al. Clin. Pharmac. Therap., 90, 467, 2011
20 August 2000 FDA GuidanceG.L. Amidon et. al., Pharmaceutical Research, 12, 413 (1995).
21 Biopharmaceutical Classification High SolubilityLow SolubilityClass 1High SolubilityHigh Permeability(Rapid Dissolution)Class 2Low SolubilityHigh PermeabilityPermeabilityHighClass 3High SolubilityLow PermeabilityClass 4Low SolubilityLow PermeabilityPermeabilityLowAmidon 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 mlpH (6.8), pKa
26 Drug database of oral immediate-release (IR) drugs on 200 top-selling US, GB, ES, JP, and KR drug productsUS: 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
30 Bioperformance Dissolution (Definition) An in vitro dissolution methodology that is predictive of in vivo dissolutionThis methodology is not a QC methodologyIt is not a regulatory methodologyIt IS a drug product development methodology
31 Bioperformance Dissolution Sub-Classification Proposal BCS ClassDrug Solubility pH 1.2Drug Solubility pH 6.8Drug PermeabilityPreferred ProcedureIHigh>85% Dissolution in 15 min; 30 min, f2., pH = 6.8.II-ALow15 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-C15 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-A15 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-BIV-C
32 Bioperformance Dissolution: One Consideration GI PhysiologypHBufferTransitFasted/Fed
33 Human In Vivo Buffer: Bicarbonate Stomach10mM4-21mM,Average= 15mM30mM70mMHuman GI BicarbonatePharmaceuticalbufferspH 1.2, 0.1N HCl1. USP2. FaSSIF3. OthersJ.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).
36 Pharmaceutical Buffers United State Pharmacopeias (USP) buffer50 mM pH 6.8 phosphate bufferFasted State Simulated Small Intestinal Fluids (FaSSIF1)29 mM NaH2PO4q.s. to pH 6.5 with NaOH3 mM Na taurocholate0.75 mM lecithin106 mM NaClOther buffers covering pHSimulated gastric fluids (SGF): pH 1.2 HClFeSSIF (Fed State Simulated Small Intestine fluids) pH 5.0 acetate bufferpH 7.5 phosphate bufferBuffer 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 EquilibriumH2CO3 HCO3− + H Ka1 = 2.5×10−4 ; pKa1 = 3.60 at 25 °C.HCO3− CO32− + H Ka2 = 5.61×10−11 ; pKa2 = at 25 °CGas Phase EquilibriumCO2(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 equilibriumPCO2 (Intestine)~200 mmHgCO2 (aq) + H2O = H2CO3
38 Bicarbonate Buffer Physiological Relevance GI LumenBicarbonate is secreted by the cells throughout the GI tract.Bicarbonate in the lumen of the GI tract modulates luminal pH.GI Epithelial CellBlood
40 Film Model Flux and Flux using Cussler’s Reaction Enhancement Factor Flux with Reaction Enhancement FactorEL 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 DominatedLittle Biopharmaceutical MechanismADME very complex-> EmpiricalPharmacokinetics Dominated the ScienceAnalytical and Computational TechnologyRegulatory Standards from the ~1970’sBA & BE
43 Bioequivalence (BE) Today: Oral Historically a Relative Bioavailability (BA) Based ViewMisses the underlying scientific issuesIN Vivo DissolutionBE Testing is Same DrugOnce Absorbed PK is the SameThe Science of BE is at the Absorption SiteFor Oral Dosage Form in the GI TractThe Question is: What is the Best BE Test
44 BioPredictive Dissolution (BPD) BCS Class I, IIa, IIIRapid DissolutionBCS Class IIb,cMore ComplexModified Release-Move Complex