DoseFormDesign-Part2-outline

DoseFormDesign-Part2-outline - University of Wyoming PHCY...

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Unformatted text preview: University of Wyoming PHCY 6100 DOSAGE FORM DESIGN Part 2: Biopharmaceutical and pharmacokinetic considerations 1) Biopharmaceutics: relationship between physical, chemical and biological characteristics of drugs, dosage forms and drug action. DRUG ↓ Dissolution in body fluids ↓ Transported by fluids ↓ Traverse membranes ↓ Escape unwanted distribution ↓ Endure metabolic attack (1st.pass effect) ↓ Penetrate in adequate conc. into sites of action ↓ Interact specifically ↓ Cause alteration of cellular function 2) ADME Studies a) Absorption, Distribution, Metabolism, Elimination b) Pharmacokinetics: studies the time course of drug concentration in the blood and tissues _rate and extent. c) ABSORPTION i) Dissolution of drug in fluids and entrance into the circulation. ii) Dissolution & absorption_ Ex: solid dosage form ♦ DISINTEGRATION: tablet/capsule into granules ♦ DEAGGREGATION: granules into fine particles ♦ WETTING: fine particles get wet ♦ DISSOLUTION: fine particles diffuse in liquid (diffusion layer: saturated layer of drug solution that envelops the surface of the solid drug particle); rate-limiting step. ♦ SOLUTION: drug in liquid form (acidic x basic medium). iii) Factors affecting rate of dissolution: (a) Surface area: inversely proportional to particle size (micronized powders) Teixeira 1 University of Wyoming PHCY 6100 (b) Crystal or amorphous forms (c) Salt forms: increased dissolution iv) Other factors: state of hydration (ampicillin); GI tract pH, foodstuffs and other drugs (tetracycline complexation with cations). v) Biologic membranes (=barriers): bimolecular lipoid layer + protein layers on both sides; water-filled pores or channels. ♦ Several layers of cells: skin ♦ Single layer of cells: intestinal epithelium ♦ Less than one cell thick: memb. of a single cell vi) Processes of transport ♦ Passive diffusion (a) Fick’s first law: rate of transport across a membrane is proportional to the difference in drug conc. on both sides of the membrane. (b) driven by concentration gradient (c) lipid-soluble substances (high partition coefficient =oil/water solubility) (d) Filtration: small water-soluble molecules pass through pores or channels (e) Degree of ionization: non-ionized are more permeable; depends on pH of solution and dissociation constant (pKa) of drug. ♦ Specialized transport mechanisms (a) Active: lipid-insoluble and large molecules; against concentration gradient, carriers, saturation, specificity, competition, inhibition (b) Facilitated diffusion: similar to active but driven by concentration gradient. vii) Routes of drug administration viii) Bioavailability (F): rate and extent of absorption and availability at site of action. ix) Bioequivalence: comparison of bioavailabilities of different formulations, drug products, or batches of the same drug product. x) Serum concentration-time curve xi) Parameters for assessment and comparison of bioavailability ♦ Cmax : maximum drug concentration in the blood (peak height) ♦ Tmax : time of the maximum concentration (time of peak) ♦ AUC : area under the blood concentration time curve Teixeira 2 University of Wyoming PHCY 6100 xii) Bioequivalent drug products: generic bio-equivalence to brand ♦ FDA= rate + extent of absorption do not show significant difference from that of the pioneer drug, at same molar dose of active ingredient and same experimental conditions. ♦ Orange Book: approved drug products with therapeutic equivalence evaluations, published and updated by FDA. d) DISTRIBUTION i) Fate of drug after absorption ii) Depends on binding to plasma proteins: albumin, globulins. iii) Unbound drug = ACTIVE iv) Bound = INACTIVE v) Unbound drug is free to leave the circulation for tissues and cellular sites. vi) Bound drug (reservoir, depot) is neither metabolized norfiltered through the renal glomeruli. vii) Serum albumin is about 20% lower in elderly: phenytoin dosage adjustment. viii) Affinity to specific components of certain cells ix) Drug displacement: Warfarin x Naproxen e) METABOLISM (Biotransformation, Detoxification) i) Drug chemical changes and formation of less toxic and more readily excreted compounds. ii) Cytochrome P450 (liver) iii) Oxidases, reductases, esterases (hydrolysis of esters and amides; blood, gut, liver), glucuronide conjugation (liver) iv) Metabolites: more water soluble, more ionized, less toxic; sometimes more active… v) Prodrug: needs metabolization to become active (Enalapril -Vasotec® =enalaprilat) vi) Factors influencing metabolism ♦ Species; interindividual variations ♦ age ♦ diet ♦ disease states: hepatitis ♦ other drugs: pesticides, alcohol, nicotine, etc f) EXCRETION: i) Termination of drug’s activity and presence in the body. ii) Kidneys, bile and feces (GI), lungs, sweat glands, saliva, and breast milk. Teixeira 3 University of Wyoming PHCY 6100 3) Pharmacokinetic principles a) Determination of drug concentration at active site: compartmental analysis b) Volume of distribution (Vd): volume of the compartment into which the total amount of drug is distributed. c) Half-life (T1/2): time required for a drug’s blood concentration to decrease by half; determination of dosage regimen; affected by hepatic metabolism, renal excretion, nicotine, protein binding (drug displacement). d) Clearance (Cl): removal of drug from the body. i) Hepatic clearance (Clh) ii) Renal clearance (Clr) iii) Total body clearance (ClB): fraction of total volume of distribution that can be cleared per unit of time. 4) Dosage regimen a) How much and how often b) Empirical x kinetic approach Teixeira 4 ...
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This note was uploaded on 10/15/2010 for the course PHCY 6100 taught by Professor Teixeira during the Fall '10 term at Wyoming.

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