factors effecting drug absorption and dissolution

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Factors Impacting Drug Dissolution and Absorption: Current State of Science : 

Advisory Committee for Pharmaceutical Science May 3, 2005 Factors Impacting Drug Dissolution and Absorption: Current State of Science Lawrence X. Yu, Ph. D. Director for Science Office of Generic Drugs Food and Drug Administration

Presentation Outline : 

Presentation Outline In Vitro Dissolution Testing Limits to Oral Drug Absorption Challenges to Regulatory Evaluation

Oral Drug Absorption : 

Oral Drug Absorption Gastric Emptying Transit Permeation Dissolution Metabolism

What Does Dissolution Measure? : 

What Does Dissolution Measure? Solid drug particle stagnant layer (h) with a concentration = Cs bulk solution with a concentration = Ct = Xd/V Bulk Solvent

Quality Control: Pharmaceutical Solid Polymorphism : 

Quality Control: Pharmaceutical Solid Polymorphism Form II Form I

In Vivo Bioequivalence: IVIVC : 

In Vivo Bioequivalence: IVIVC Dissolution Profiles Fraction Absorption Profiles

Presentation Outline : 

Presentation Outline In Vitro Dissolution Testing Limits to Oral Drug Absorption Challenges to Regulatory Evaluation

Slide 8: 

What Affects Dissolution? Drug Substance Factors

In Vivo and In Vitro Relationship: Scientific Issues : 

In Vivo and In Vitro Relationship: Scientific Issues Limits to oral drug absorption Dissolution-limited Solubility-limited Permeability-limited

Quantitative Estimation of Absorption : 

Quantitative Estimation of Absorption

Limits to Oral Drug Absorption(Yu, Pharm. Res. 16:1884-1888 (1999)) : 

Limits to Oral Drug Absorption(Yu, Pharm. Res. 16:1884-1888 (1999))

CAT Model: Extent of Intestinal Drug Absorption (Permeability-limited)(Yu et al. Int. J. Pharm. 186:119-125 (1999)) : 

CAT Model: Extent of Intestinal Drug Absorption (Permeability-limited)(Yu et al. Int. J. Pharm. 186:119-125 (1999))

Digoxin: Dissolution-limited (Yu, Pharm. Res. 16:1884-1888 (1999)) : 

Digoxin: Dissolution-limited (Yu, Pharm. Res. 16:1884-1888 (1999))

Griseofulvin: Solubility-limited(Yu, Pharm. Res. 16:1884-1888 (1999)) : 

Griseofulvin: Solubility-limited(Yu, Pharm. Res. 16:1884-1888 (1999))

Applications of Predictive Absorption Model in Drug Discovery : 

Applications of Predictive Absorption Model in Drug Discovery

Slide 16: 

What Affects Dissolution? Dosage Form Factors

Plasma Concentration Profile of a Drug from an Oral Solution : 

Plasma Concentration Profile of a Drug from an Oral Solution 0 2 4 6 8 10 12 14 0 2 4 6 8 10 12 Plasma Conc time (hr) Oral Solution Data Oral Solution Simulation

Slide 18: 

Dissolution Profile from a Drug from A Solid Oral Dosage Form

Slide 19: 

Plasma Concentration Profile of a Drug from a Solid Oral Dosage Form

Slide 20: 

Dissolution Profile of a Drug with Different Protective Coating

PK Profile of a Drug with Different Protective Coating : 

PK Profile of a Drug with Different Protective Coating 0 0.01 0.02 0.03 0.04 0.05 0 5 10 15 20 Plasma Conc time (hr) Measured Slow Medium Fast

Presentation Outline : 

Presentation Outline In Vitro Dissolution Testing Limits to Oral Drug Absorption Challenges to Regulatory Evaluation

Dissolution and Limits to Oral Absorption : 

Dissolution and Limits to Oral Absorption When dissolution is rapid and, therefore, not the rate determining step, drug levels in blood/plasma may not reflect dissolution differences Dissolution-limited absorption IVIVC possible for IR/ER products In vivo fraction absorption profile is not always possible; Deconvolution-based IVIVC methods Solubility-limited absorption Permeability-limited absorption Convolution-based IVIVC methods

Dissolution Profile Comparison : 

Dissolution Profile Comparison f2= ‘Similarity’ Factor. Values are scaled between 0-100. f2 values greater than 50 (50-100) reflect a 10% or less, ‘overall’ or ‘global’ difference between the two curves.

In Vitro and In Vivo : 

In Vitro and In Vivo Dissolution testing is “non-discriminating” Dissolution - limited absorption Others Dissolution testing is “over discriminating” Solubility - limited absorption Permeability - limited absorption “f2 values greater than 50 (50-100) ensure sameness or equivalence of the two curves and, thus, of the performance of the test (post -change) and reference (pre-change) products.”

Role of Dissolution Testing : 

Role of Dissolution Testing A quality control tool to monitor batch-to-batch consistency of the drug release from a product An in vitro surrogate for product performance that can guide formulation development and ascertain the need for bioequivalence tests Are these goals consistent?

Hydrodynamic Conditions : 

Hydrodynamic Conditions Current Paddle Speeds Result in Re: Re = 4688 (50 RPM) Re = 9375 (100 RPM) Some evidence that current speeds are correlated with in vivo dissolution Slower laminar flows would lead to much more reproducible hydrodynamics, but may not correlate with in vivo hydrodynamics. A. Scholz, E. Kostewicz, B. Abrahamsson and J. B. Dressman Can the USP paddle method be used to represent in-vivo hydrodynamics? Journal of Pharmacy and Pharmacology 55 (2003) 443-451

Medium : 

Medium Product Specific Medium Allows full dissolution for all products in a finite time and dissolution volume Universal/Biorelevant Media A true in vivo correlation should use the same media for all products

Role of Dissolution : 

Role of Dissolution Should the roles be separated? Is single point acceptance criterion relevant for either role? Do the multiple roles impede the reduction of variability?

Dissolution for Quality Control : 

Dissolution for Quality Control A product specific quality control test The hydrodynamics and medium for this test are chosen for reproducibility and detection of product changes The design of this test is not constrained by a desire to mimic in vivo conditions.

Dissolution for In Vivo Performance : 

Dissolution for In Vivo Performance A biorelevant dissolution test All products should undergo dissolution testing in the same device and same media (corresponding to stomach and intestine under fed and fasted conditions) that gives the best possibility to correlate with in vivo dissolution The biorelevant dissolution test is a one-time test to provide a baseline for product performance Any biowaivers should rely on the biorelevant dissolution testing Biorelevant dissolution testing as a quality control test

Summary : 

Summary In Vitro Dissolution Testing - Over discriminating/Non-discriminating dissolution - Not sufficient to assure bioequivalence/bioavailability Limits to Oral Drug Absorption - Dissolution/Solubility/Permeability-limited absorption Challenges to Regulatory Evaluation Dissolution Profile Comparison Role of Dissolution Testing

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