Chapter 5 Dosage Form Design:Biopharmaceutical and Pharmacokinetic Considerations
Biopharmaceutic ConsiderationsBiopharmaceutics is the area of the study embracing therelationship between physical, chemical and biological sciencesas they apply to drug and to drug action ADMEBioavailability - describe the rate and extent to which an activedrug ingredient or therapeutic moiety is absorbed from adrug product and becomes available at the site of the drugaction.Bioequivalence - refers to the comparison of bioavailabilities ofdifferent formulations, drug products, or batches of the samedrug product.
Bioavailability Data are used todetermine:1. The amount or proportion of drug absorbedfrom a formulation or dosage form2. The rate at which the drug was absorbed3. The duration of the drug’s presence in thebiologic fluid or tissue; and, when correlatedwith patient response4. The relationship between drug blood levelsand clinical efficacy and toxicity
Terms Used To define The Type or Level Of“Equivalency” Between Drug ProductsPharmaceutical Equivalents -are drug products that containidentical amounts of the identical active ingredient. Example: thesame salt or ester of the same therapeutic moietyPharmaceutical Alternatives - are drug products that contain theidentical therapeutic moiety, or its precursor, but not necessarily inthe same amount or dosage form or as the same salt or ester.Bioequivalent Drug Products - are pharmaceutical equivalents or pharmaceutical alternatives whose rate and extent of absorption do not show a significant difference when administered at the same molar dose of the therapeutic moiety under similar experimental conditions, either single dose or multiple dose.
Therapeutic Equivalent - has been used to indicatepharmaceutical equivalent which, when administeredto the same individuals in the same dosage regimens, willprovide essentially the same therapeutic effect. The most common experimental plan to comparethe bioavailability of two drug products is the simplecrossover design study. (12 to 14 individuals, males between 18 to 40years, same height and weight)
How A Drug Passes Through The Body1. Absorption = The site at which a drug entersthe body affects its rates of absorption a. Skin c. Digestive Tract b. Lungs d. Bloodstream2. Distribution = Most drugs enter thebloodstream; many are then distributed tocells of various organs a. Bone e. Glands b. Nerves f. Heart c. Muscles g. Cells d. Brain h. Other organs
3. Metabolism = A drug is partially brokendown, usually in the liver, before or afterdistribution a. Liver4. Elimination = Finally, a drug is eliminated,mainly via kidneys, but also in stools andtears or through breathing a. Breast milk c. Tears b. Saliva d. Sweat
APPROVAL REQUIREMENTS FOR GENERIC DRUG PRODUCTS1. Contain the same active ingredients as the pioneer drug (inert ingredient may vary)2. Be identical in strength, dosage form, and route ofadministration3. Have the same indications and precautions for use andother labeling instructions4. Be bioequivalent5. Meet the same batch to batch requirements for identity, strength, purity, and quality6. Be manufactured under the same strict standards ofFDA’s CGMP regulations as required for pioneerproducts.
Some Factors Which Can influence TheBioavailability Of Orally Administered DrugsI. Drug Substance PhysiochemicalPropertiesII. Pharmaceutical Ingredients andDosage Form CharacteristicsIII. Physiologic Factors and PatientCharacteristics
Some Factors Which Can influence The Bioavailability OfOrally Administered DrugsI. Drug Substance Physiochemical Properties A. Particle Size B. Crystalline or Amorphous Form C. Salt Form D. Hydration E. Lipid/Water Solubility F. pH and pKa
Some Factors Which Can influence The Bioavailability Of Orally Administered DrugsII. Pharmaceutic Ingredients and Dosage Form Characteristics A. Pharmaceutical Ingredients1. Fillers 7. Surface Active Agents2. Binders 8. Flavoring Agents7. Coatings 9. Coloring Agents8. Disintegrating Agents 10. Preservative Agents• Lubricants 11. Stabilizing Agents• Suspending Agents
Some Factors Which Can influence The Bioavailability Of OrallyAdministered Drugs B. Disintegration Rate (Tablets) C. Dissolution Time of Drug in Dosage Form D. Product Age and storage ConditionsIII. Physiologic Factors and Patient Characteristics A. Gastric Emptying Time B. Intestinal Transit Time C. Gastrointestinal Abnormality or Pathologic Condition D. Gastric Contents 1. Food 2. Other Drugs 3. Fluid E. Gastrointestinal pH F. Drug Metabolism (gut and during first passage through liver)
Examples Of Drugs That Undergo Significant Liver Metabolism andExhibit Low Bioavailability when Administered by First-pass Routes Drug Class Examples Analgesics Aspirin, meperidine, Pentazocine Propoxyphene Antianginal Nitroglycerin Antiarrhythmics Lidocaine Beta-adrenergic Labetolol, Metoprolol, Propranolol blockers Calcium channel Verapamil blockers Sympathomimetic Isoproterenol amines Tricyclic Desipramine, Imipramine, antidepressants Nortriptyline
Several Examples of Biotransformationsoccurring within the body are as follows:1. Acetaminophen Conjugation Acetaminophen glucuronide (active) (inactive)2. Amoxapine Oxidation 8-hydroxy-amoxaphine (active) (inactive)3. Procainamide Hydrolysis p-Aminobenzoic acid (active) (inactive)4. Nitroglycerin reduction 1-2 and 1-3 dinitroglycerol (active) (inactive)
Some compound under full, partial nobiotransformation1. Lisinopril (zestril) - does not go metabolism,excreted unchanged2. Verapamil (Calan) - 12 metanolites, the mostprevalent is norverapamil3. Diltiazem (Cardizem) - partially metabolizedto desacetyldiltiazem4. Indomethacin (Indocin) - metabolized in partto desmethyl, desbenzoyl, anddesmethylbenzoyl5. Propoxypehene napsylate (Darvon N) -metabolized to norpropoxyphene
Routes Of Drug Administration TERM SITEoral mouthperoral (per os, p.o.) gastrointestinal tract via mouthsublingual under the tongueparenteral other than GIT (by injection) intravenous vein intraarterial artery intracardiac heart intraspinal/intrathecal spine intraosseous bone intraarticular joint intrasynovial joint-fluid area intracutaneous/intradermal skin subcutaneous beneath the skin intramuscular muscle
Routes Of Drug Administration TERM SITEepicutaneous (topical) skin surfacetransdermal skin surfaceconjunctival conjunctivaintraocular eyeintranasal noseaural earintrarespiratory lungrectal rectumvaginal vaginaurethral urethra
Factors That Determine A Dosage RegimenActivity, Toxicity PharmacokneticsMinimum therapeutic dose AbsorptionToxic Dose DistributionTherapeutic index MetabolismSide effects Dosage Excretion RegimenDose-response relationship Clinical Factors Other FactorsClinical State of patient Management of TherapyAge, weight, urine pH Multiple drug therapy Tolerance-dependenceCondition being treated Convenience of regimen Pharmacogenetics- idiosyncrasyExistence of other disease states Compliance of patient Drug interactions