Lecture 4 & 5 CH 7 2023 Final.pdf

Drug Absorption • Process of the movement of drug from the site of administration into the extracellular compartment of the body. • GI tract is an important factor in oral absorption. • Passive non-ionic diffusion is the most common mechanism of absorption. – Absorption is influenced by 4 facto...

Drug Absorption • Process of the movement of drug from the site of administration into the extracellular compartment of the body. • GI tract is an important factor in oral absorption. • Passive non-ionic diffusion is the most common mechanism of absorption. – Absorption is influenced by 4 factors 1. 2. 3. 4. molecular size, shape, degree of ionization, and lipid solubility. 3 Factors Affecting Oral Drug Absorption 1. Disintegration – For oral solid dosage forms (SDFs), the drug product must disintegrate (break) into small particles to allow drug release. – USP, has an official guidelines • Applies to most SDFs with the exception of troches, chewable tablets, and modified release DFs. • USP, chapter <701> 4 https://onlinelibrary.wiley.com/doi/full/10.1002/jps.24511 https://www.google.com/search?rls=en&sxsrf=ACYBGNQjLA2qW 2R6OoGeEldjIavIprZhYA:1578867390648&q=usp+disintegration+ diagram&tbm=isch&source=univ&client=safari&sa=X&ved=2ahU KEwje6t2vi__mAhUHd98KHbybBfwQ4216BAgJECM&biw=1389& bih=731#imgrc=Y1jc0J3i7t_NtM: Disintegration Apparatus 5 Factors Affecting Oral Drug Absorption, cont’d 2. Dissolution and Solubility – Dissolution is the process where the drug dissolves in a solvent. – For pharmaceutical development (USP), solubility is determined by dissolving a known quantity of a drug in 250mL buffer (pH 1.0-8.0). – Rate of dissolution is often directly related to the rate of absorption. 7 Factors Affecting Oral Drug Absorption − Dissolution testing • Apparatus • Described in USP, chapter <711> • Most common are Apparatus 1 and Apparatus 2 • Dissolution medium • pH range of 1.2 – 6.8 (dependent on area of absorption from the GI tract) • Temperature of 37oC + 0.5oC • Agitation • Most commonly between 50 – 100 rpm 8 Factors Affecting Oral Drug Absorption 3. Permeability is …… – An indirect measurement of absorption. – A direct measurement of the rate of mass transfer across the human intestinal membrane. – An in vitro test using human and non-human systems. • Testing can sometimes be used to obtain a waiver of in vivo bioavailability for bioequivalence studies. – If data shows that the intestinal membrane is not a factor inhibiting bioavailability » Drug readily crosses the the intestinal membrane and isn’t a rate limiting factor 9 Factors Affecting Oral Drug Absorption 4. Rate-Limiting Steps in Drug Absorption – Slowest step = the rate-limiting step – Generally, tablet disintegration is the fastest step. • Dissolution is often the rate limiting step for low water soluble (hydrophobic) drugs. • Permeability is often the rate limiting step for high water soluble (hydrophilic) drugs. 10 • Solutions • Suspensions Dosage Forms – Exhibit the most rapid absorption of all oral dosage forms. – Rate limiting step is typically gastric emptying. • Solutions are already dissolved so dissolution is not a rate limiting step – Requires dissolution even though it is a liquid dosage form. • Drug particles are suspended in a vehicle – Formulation considerations include particle size, viscosity, and wetting agents. 12 Solid Dosage Forms Capsules Tablets Efficient dosage form distinguished by a shell that holds the drug formulation. • Shell must release the drug particles before absorption can take place. Can be formulated as controlled-release to alter absorption kinetics. Must first break into granules/large pieces and then into drug particles. Can be formulated as controlled-release to alter absorption kinetics. 13 Controlled-Release -vs- Immediate Release Products Plasma Concentration Time-curves 14 Bioavailability • Indicates the fractional extent to which a dose of drug reaches the site of action. • For oral products, bioavailability depends on the drugs dissolution and absorption • Can be altered by the drugs stability in gastric fluids, formulation components, and first-pass effect (hepatic metabolism). 15 Bioavailability • Three indices of bioavailability include: 1) Cmax 2) tmax 3) AUC 16 Bioequivalence • Used to describe the bioavailability of same drug in two different formulations. • Important for comparing generic products with the name-brand product. – Testing typically involves in vivo human PK studies to evaluate the rate and extent of absorption. 17 Questions to Answer 1. What is drug absorption? 2. What are the factors affecting oral drug absorption – Disintegration, dissolution (testing), solubility, permeability, rate-limiting steps 3. What are the dosage forms discussed – solutions, suspensions, caps, tabs 4. Controlled-release vs immediate release products – How do the plasma conc. time-curves differ? 5. What are drug bioavailability and bioequivalence? – How do they differ – Bioavailability indices 6. Biopharmaceutics Classification System (BCS) – Solubility – Permeability 18