Chp 5. Dosage Form Design - Biopharmaceutical And Pharmacokinetic Considerations PDF

Chp 5: Dosage Form Design: Biopharmaceutical and Pharmacokinetic Considerations Dosage Form Design: Biopharmaceutical and Pharmacokinetic Considerations • Principles of drug absorption • Dissolution and drug absorption • Bioavailability and bioequivalence • Routes of drug admin...

Chp 5: Dosage Form Design: Biopharmaceutical and Pharmacokinetic Considerations Dosage Form Design: Biopharmaceutical and Pharmacokinetic Considerations • Principles of drug absorption • Dissolution and drug absorption • Bioavailability and bioequivalence • Routes of drug administration • Fate of drug after absorption • Pharmacokinetic principles Principles of Drug Absorption • Passive diffusion • Specialized transport mechanisms 1. Passive Diffusion • The passage of (drug) molecules through a membrane that does not actively participate in the process. • Passive absorption. • Fick first law. • Absorption process is driven by concentration gradient of drug across the membrane. 2. Specialized Transport Mechanisms • Active transport – A process using a “carrier” with the additional feature of the drug being moved across the membrane against a concentration gradient; from lower concentration to higher concentration • Facilitated diffusion – A specialized transport using the “carrier,” but the drug is not moved against a concent ration gradient Dissolution and Drug Absorption 1. Surface Area • Particle size has an effect on dissolution rate and solubility. As show n in the Noyes - Whitney equation: dC /dT = kS(C s − C t) • W here dC/dT is the rate of dissolution (concentration wit h respect to time), K i s the dissolution rate constant, S is th e surface area of the particles, Cs is the concentration of the drug in the immediate proximity of the dissolving particle, that is, the solubility of the drug, Ct is the concentration of the d rug in the bulk fluid. 2. Crystal or Amorphous Drug Form • Crystalline – Lowest energy state – Ordered • Amorphous – Metastable state – Gradually revert back to crystalline state over time – Stable and unstable polymorphs 3. Salt Forms • Solubility – Salts are generally more soluble. • Dissolution – Salts generally dissolve faster. • Sodium and potassium salts of weak organic acids • Hydrochloride salts of weak organic bases 4. Other Factors • State of hydration – Can affect solubility – Can affect absor ption – . • Complex formation – Can affect solubility – Can affect absorption • Adsorption of drug Bioavailability and Bioequivalence Describes the rate and extent to which an active drug ingredient or therapeutic moiety is absorbed from a drug product and becomes available at the site of action 1. Blood, Serum, or Plasma Concentration –Time Curve Serum concentration –time curve showing peak height concentration, time of peak concentration, and AUC 3. Parameters for Assessment and Comparison of Bioavailability • Peak height • Time of peak • Area under the serum concentration –time curve 4. Bioequivalence of Drug Products • Same drug in different dosage forms may have di fferent bioavailability characteristics and different clinical effectiveness. • Dissolution correlated with pharmacokinetic data can be used to assist in determining the existence of significant bioavailability and bioinequivalence problems. 5. A Generic Drug Must: • Contain the same active ingredient(s) • Be identical in strength, dosage form, and route of administration • Have the same indications and precautions for use and other labeling instructions • Be bioequivalent • Meet same batch -to-batch requirements for identity, strength, purity, and quality • 6. Equivalents • Pharmaceutical equivalents – Drug products that contain identical amounts of the identical active drug ingredient • Pharmaceutical alternatives – Drug products that contain the identical therapeutic moiety or its precursor but not necessarily in the same amount or dosage form or as the same salt or ester • Bioequivalent drug products – Pharmaceutical equivalents or pharmaceutical alternatives whose rate and extent of absorption do not show a significant differe nce Routes of Drug Administration 1. Oral Route • Dosage forms applicable – Tablets, capsules – Suspensions, solutions, emulsions – Others – Absorption 2. Rectal Route • Suppositories • Enemas 3. Parenteral Route • Dosage forms applicable – Solutions, suspensions, emulsions, pellets • Subcutaneous injections • Intramuscular injections • Intravenous injections • Intradermal injections 4. Epicutaneous Route • Topical • Transdermal 5. Ocular, Otic, and Nasal Routes Ocular – Solutions, suspensions Otic – Solutions, suspensions, powders Nasal – Solutions, suspensions, sprays, drops 6. Other Routes • Oral inhalation • Vaginal • Urethral Fate of Drug After Absorption 1. Drug Metabolism or Biotransformation • Metabolism or biotransformation involves chemical changes to drugs within the body. • Results in one or more compounds that are more water soluble, more ionized, less capable of binding to proteins of the plasma and tissues, less capable of being stored in fat tissue, and less able to penetrate cell membranes • Consequently, more easily excr eted • Also called detoxification or inactivation 2. Excretion of Drugs • Kidney (urine) • Feces • Lungs • Sweat • Saliva • Milk • Reabsorption of some drugs Pharmacokinetic Principles 1. Half -Life 2. Concept of Clearance 3. Dosage Regimen Considerations Empirical approach • entails administration of a drug in a certain quantity, noting the therapeutic response and modifying the amount and interval of dosage accordingly Kinetic approach • based on the assumption that the therapeutic and toxic effects of a drug are related to the amount of drug in the body or to the plasma (or serum) concentration of drug at the receptor site Frequency of administration