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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.
Dissolution in body fluids
Transported by fluids
Escape unwanted distribution
Endure metabolic attack (1st.pass effect)
Penetrate in adequate conc. into sites of action
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.
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);
♦ SOLUTION: drug in liquid form (acidic x basic medium).
iii) Factors affecting rate of dissolution:
Surface area: inversely proportional to particle size (micronized
powders) Teixeira 1 University of Wyoming PHCY 6100 (b)
Crystal or amorphous forms
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
Fick’s first law: rate of transport across a membrane is proportional
to the difference in drug conc. on both sides of the membrane.
driven by concentration gradient
lipid-soluble substances (high partition coefficient =oil/water
Filtration: small water-soluble molecules pass through pores or
Degree of ionization: non-ionized are more permeable; depends on
pH of solution and dissociation constant (pKa) of drug.
♦ Specialized transport mechanisms
Active: lipid-insoluble and large molecules; against concentration
gradient, carriers, saturation, specificity, competition, inhibition
Facilitated diffusion: similar to active but driven by concentration
vii) Routes of drug administration
viii) Bioavailability (F): rate and extent of absorption and availability at site of
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.
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
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
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
v) Prodrug: needs metabolization to become active (Enalapril -Vasotec®
vi) Factors influencing metabolism
♦ Species; interindividual variations
♦ disease states: hepatitis
♦ other drugs: pesticides, alcohol, nicotine, etc
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.
- Fall '10