Biopharmaceutics of Solid Oral Dosage Forms PDF

PR5217: Biopharmaceutics of Solid Oral Dosage Forms Associate Professor Matthias G. Wacker, PhD Department of Pharmacy | Faculty of Science [email protected] © Copyright National University of Singapore. All Rights Reserved. © Copyright Nation...

PR5217: Biopharmaceutics of Solid Oral Dosage Forms Associate Professor Matthias G. Wacker, PhD Department of Pharmacy | Faculty of Science [email protected] © Copyright National University of Singapore. All Rights Reserved. © Copyright National University of Singapore. All Rights Reserved.  Written Questions in PR5217 © Copyright National University of Singapore. All Rights Reserved.  Learning Outcomes Understand the reasons for dissolution testing in the context of solid oral dosage forms. Learn about procedures, methods, and standards that apply to dissolution testing of medicines. Get to know the challenges and applications of dissolution testing at various stages of drug development and testing. © Copyright National University of Singapore. All Rights Reserved.  Fundamentals © Copyright National University of Singapore. All Rights Reserved.  Biopharmaceutics Biopharmaceutics is the study of parameters with influence on rate and amount of drugs reaching the site of action. For many drugs, the availability in systemic circulation is assumed to reflect the availability at the target site. Biopharmaceutical characterization of oral drug formulations often includes: Solubility and Permeability (as part of the BCS classification) Dissolution Testing In vitro-in vivo correlation © Copyright National University of Singapore. All Rights Reserved.  Absorption from the GI tract The gastrointestinal (GI) tract is a cascade of different compartments with different residence times Passage times In the GI tract Esophagus 10 sec Stomach 0.1-5 h Small intestine 1.5-2 h Colon 1-24 h © Copyright National University of Singapore. All Rights Reserved. Source: Vertzoni et al. 2019, Eur J Pharm Sci (https://doi.org/10.1016/j.ejps.2019.04.013)  A Short History Lesson 1897 1951 1971 1980s © Copyright National University of Singapore. All Rights Reserved.  Noyes-Whitney Noyes and Whitney investigated influences on the dissolution rate of solids. Dissolution rate depends on surface area, hydrodynamics, and concentration gradient. 𝑑𝑀 𝐷 ∗ 𝐴 A − = ∗ (𝑐𝑆 − 𝑐𝑋 ) 𝑑𝑡 ℎ cS Solubility © Copyright National University of Singapore. All Rights Reserved.  Dissolution vs. Solubility Mainly the solubility limits the amount of monomolecular drug available in the GI tract Solubility Drug concentration Dissolution rate 0 45 90 135 180 225 270 315 Time [min] © Copyright National University of Singapore. All Rights Reserved.  Absorption from the GI tract Interindividual difference of the human gastrointestinal tract considerably contributes to the variability in clinical trials. © Copyright National University of Singapore. All Rights Reserved. Source: Vertzoni et al. 2019, Eur J Pharm Sci (https://doi.org/10.1016/j.ejps.2019.04.013)  GI tract Vertzoni et al. 2019, Eur J Pharm Sci (https://doi.org/10.1016/j.ejps.2019.04.013); © Copyright National University of Singapore. All Rights Reserved. Source: Flynn and Roberts 2015, Michigan Publishing (ISBN 9781607853466)  1.2 6.8 © Copyright National University of Singapore. All Rights Reserved. Source: https://www.scientificanimations.com/digestive-system/  Permeability Following FDA guidelines permeability of compounds is determined based on the absorption observed in human clinical trials or suitable in vitro/ex vivo/in vivo methods. Parallel Artificial Membrane Permeability Assay CaCo2 Cell Assay Rat perfusion (PAMPA) model Wang et al. 2012, Int J Nanomedicine (http://dx.doi.org/10.2147/IJN.S33014) Ponmozhi et al. 2021, Micromachines (https://doi.org/10.3390/mi12030294); © Copyright National University of Singapore. All Rights Reserved. Source: Robinson et al. 2018, bioRxiv (https://doi.org/10.1101/355552)  Influences of Dosage Forms Drug dissolution and dosage form determine together at which rate and quantity the drug reaches the intestinal membrane. Drug permeability determines how much of this drug molecule is absorbed into systematic circulation. Formulation Tablet Drug Absorption Distribution Metabolism Elimination disintegration dissolution Drug molecule © Copyright National University of Singapore. All Rights Reserved.  Biopharmaceutical Classification System Solubility and permeability are the main parameters of influence. Classification of compounds by these criteria provides an estimate of expected absorption. © Copyright National University of Singapore. All Rights Reserved. Source: Lubrizol Life Sciences (https://lubrizolcdmo.com/technical-briefs/biopharmaceutical-classification-system)  Summary Biopharmaceutics of oral dosage forms includes all processes that may affect bioavailability. Dissolution and permeability have a major influence on absorption of oral dosage forms. Dissolution and permeability were defined as major criteria to assess their performance. Physiological parameters such as gastric emptying or other influences may alter the processes we assume predictable. © Copyright National University of Singapore. All Rights Reserved.  Performance Testing © Copyright National University of Singapore. All Rights Reserved.  What are the Learning Outcomes? Which apparatuses and instruments are used for in vitro performance testing? Why are there so many standards in performance testing? What are the applications of performance assays? How does a typical “dissolution profile” look like? © Copyright National University of Singapore. All Rights Reserved.  Dissolution Testing Disintegration and dissolution are the most important influences of oral dosage forms on the pharmacokinetics of drugs. “…in vitro dissolution may be relevant to the prediction of in vivo performance. Based on this general consideration, in vitro dissolution tests […] are used to (1) assess the lot-to-lot quality of a drug product; (2) guide development of new formulations and (3) ensure continuing product quality and performance […].” © Copyright National University of Singapore. All Rights Reserved.  Applications of Dissolution Testing Routine quality control of every batch of a drug product. Comparability testing after scale-up and post-approval changes (SUPACs). Evaluate bioequivalence in a biowaiver application. Discriminate between candidates in formulation development. Predict the in vivo performance of the drug product. © Copyright National University of Singapore. All Rights Reserved.  Pharmacopeial Standards Pharmacopeial standards set a framework for quality testing and requirements of medicines © Copyright National University of Singapore. All Rights Reserved. Source: Wiggins and Albanese 2019, www.biopharminternational.com  Pharmacopeial Standards United States Pharmacopeia, European Pharmacopeia, and Japanese Pharmacopeia have been partially harmonized. © Copyright National University of Singapore. All Rights Reserved.  Pharmacopeial Dissolution Testing © Copyright National University of Singapore. All Rights Reserved.  Dissolution Test Amount corresponding to a single dose administration is tested (e.g. 1 cup of oral suspension, tablet or capsule). Exact dimensions of the instrument (e.g. vessel, dimensions of the stirrer) are outlined by the pharmacopeia. Temperature is kept constant at 37 °C ± 0.5 °C. Kinetic measurement of the release/dissolution. © Copyright National University of Singapore. All Rights Reserved.  Dissolution vs. Solubility Mainly the solubility limits the amount of monomolecular drug available in the GI tract Solubility Drug concentration Dissolution rate 0 45 90 135 180 225 270 315 Time [min] © Copyright National University of Singapore. All Rights Reserved.  USP dissolution apparatus 1 and 2 First method ever introduced to the USP Robust in routine applications Preferred for capsules Evaporation of the medium is significant Tablets/capsules 50-100 rpm © Copyright National University of Singapore. All Rights Reserved. Source: Pharma Test Apparatebau AG  USP Dissolution Apparatus 1 and 2 © Copyright National University of Singapore. All Rights Reserved. Source: United States Pharmacopeia (Access time 03-2019), Pharma Test Apparatebau AG  Apparatus 2: Paddle Robust standard method Evaporation of the medium is significant Tablets/capsules 50-75 rpm Suspensions 25-50 rpm Gold standard for immediate release (IR) dosage forms © Copyright National University of Singapore. All Rights Reserved. Source: Pharma Test Apparatebau AG  Apparatus 3: Reciprocating cylinder Mostly solid modified- release (MR) dosage forms. Dosage forms are dipped into the medium at a defined rate. Easy medium change from one row to Intestinal fluid another. Colonic fluid Gastric fluid © Copyright National University of Singapore. All Rights Reserved. Source: United States Pharmacopeia (Access time 03-2019), Erweka AG (Heusenstamm, Germany)  Apparatus 4: Flow-through cell Cell is perfused with release medium. Flexible medium composition and volume. Poor reproducibility compared to “paddle” or “basket”. © Copyright National University of Singapore. All Rights Reserved. Source: United States Pharmacopeia (Access time 03-2019), www.sotax.com  Release Testing with Paddle Apparatus © Copyright National University of Singapore. All Rights Reserved. Source: Pharma Test Apparatebau AG  Dissolution Result 120 Plateau 100 Cumulative drug release [%] 80 Release 60 40 20 0 0 45 90 135 180 225 270 315 Time [min] © Copyright National University of Singapore. All Rights Reserved. © Copyright National University of Singapore. All Rights Reserved.  Summary Each apparatus has specific advantages and disadvantages and qualifies for particular drug products. Robustness, evaporation and medium change are very common issues in method development. A typical dissolution profile is characterized by different phases and gives the fraction of the dose that has been dissolved. © Copyright National University of Singapore. All Rights Reserved.  Challenges and Applications © Copyright National University of Singapore. All Rights Reserved.  Learning Outcomes What is are mechanism of release and performance? How do you develop a performance assay for oral dosage forms? What is a “biowaiver“ and how are physiological complexity and practical issues in assay design considered? © Copyright National University of Singapore. All Rights Reserved.  Quality Control Dissolution testing enables a comparison of two batches with regards to their quality. Rather than a prediction of the physiological situation, the test is detecting changes. QC assumes that changes in quality often translate into a different therapeutic performance. © Copyright National University of Singapore. All Rights Reserved.  Dissolution Media Media utilized in quality control Water Buffer systems Solubilizers European Pharmacopeia and USP, e.g. Simulated Gastric Fluid (SGF) pH = 1.2 Simulated Intestinal fluid (SIF) pH = 6.8 © Copyright National University of Singapore. All Rights Reserved. © Copyright National University of Singapore. All Rights Reserved.  Deaeration Insufficient deaeration can strongly limit reproducibility. The air-liquid interface produces additional sheer stress but also reduces the surface area available for dissolution. © Copyright National University of Singapore. All Rights Reserved. Source: Gao et al. 2006, J Pharm Sci (https://doi.org/10.1002/jps.20622)  Sink Conditions Dissolution rate (dissolution phase) can only be measured accurately if the drug dissolves and does not reach its solubility limit too fast (plateau phase). Sink conditions are introduced to account enable accurate discrimination by rate rather than solubility differences. Under sink conditions the solubility in the dissolution vessel is at least 5-10 times higher than required to dissolve the tested dose. © Copyright National University of Singapore. All Rights Reserved.  Typical QC dissolution test According to the WHO recommendation for highly soluble drugs (BCS classes I and II), quality control of tablets should be done with: Simulated intestinal fluid, pH 6.8 500 mL medium, 37 °C 75 rpm 7.5, 15, 30, 60 und 90 min © Copyright National University of Singapore. All Rights Reserved. Source: Pharma Test Apparatebau AG  Quality Control Specs One-point specification for immediate release (IR) dosage forms IR dosage forms About 80 percent 120 within 45 min 100 (Quick release) Release [%] 80 60 40 20 0 0 45 90 135 180 225 270 315 Time [min] © Copyright National University of Singapore. All Rights Reserved.  Quality Control Specs Three-point specification for modified release (MR) dosage forms MR dosage forms About 20-30 percent 120 (identify "dose dumping") 100 Release [%] About 50 percent 80 (defining the profile) 60 40 About 80 percent 20 (confirm complete release) 0 0 45 90 135 180 225 270 315 Time [min] © Copyright National University of Singapore. All Rights Reserved.  Biowaiver Two products with almost the same pharmacokinetic profiles are considered "equally bioavailable," i.e. if AUC and cMax are almost identical. If a drug is highly permeable bioavailability mostly depends on the dissolution rate. For biowaivers the bioequivalence can be examined in vitro instead of conducting a clinical trial. © Copyright National University of Singapore. All Rights Reserved.  Biowaiver © Copyright National University of Singapore. All Rights Reserved. Source: Dr. Anita Nair, Merck KGaA/Germany (https://www.youtube.com/watch?v=429k_h3D7qw)  Biopredictive Testing Biopredictive test methods mimic the conditions in the gastrointestinal tract sufficiently (e.g., by fluids that simulate the stomach content) to predict pharmacokinetics: © Copyright National University of Singapore. All Rights Reserved. Source: Modified from Villa Nova et al. 2022, Expert Opin. Drug Deliv. (https://doi.org/10.1080/17425247.2022.2081682)  Tablet © Copyright National University of Singapore. All Rights Reserved. Source: Modified from Jung and Thurn et al. 2021, Eur J Pharm Biopharm (https://doi.org/10.1016/j.ejpb.2021.01.007)  Dissolution In Vitro Experiment Non-dissolved fraction affected by gastric emptying Dissolution in the stomach Dissolution in the intestine © Copyright National University of Singapore. All Rights Reserved. Source: Jung and Thurn et al. 2021, Eur J Pharm Biopharm (https://doi.org/10.1016/j.ejpb.2021.01.007)  Gastric Emptying Computer Model Simulation mass transport of non-dissolved Pharmacokinetics drug © Copyright National University of Singapore. All Rights Reserved. Source: Nothnagel and Jung et al. 2018, Eur. J. Pharm. Biopharm. (https://doi.org/10.1016/j.ejpb.2018.11.012)  Dissolution Food effects with pediatric breakfast Drug A Drug B (Strongly accelerated dissolution) (Moderately accelerated dissolution) © Copyright National University of Singapore. All Rights Reserved.  Mimicking Physiology In Vitro © Copyright National University of Singapore. All Rights Reserved. Source: Dickinson et al. 2012, AAPS Journal (http://dx.doi.org/10.1208/s12248-012-9333-x)  Summary Biopharmaceutical characterization facilitates reliable and efficient delivery of drugs. Performance testing has many applications and follows strict national and international standards. Specifications are based on the type of the drug product. Biowaiver is a way to approve generic drug products using in vitro instead of clinical testing. Biopredictive assays are meant to predict pharmacokinetics and mimic physiology more closely. © Copyright National University of Singapore. All Rights Reserved.  Questions in PR5217 Answers provided twice a week © Copyright National University of Singapore. All Rights Reserved.