Download ERT 420 BIOPHARMACEUTICAL ENGINEERING

ERT 420
BIOPHARMACEUTICAL
ENGINEERING
Semester 1
Academic Session 2012/2013
HUZAIRY HASSAN
School Of Bioprocess Engineering
Universiti Malaysia Perlis
DRUG BIOAVAILABILTY &
BIOEQUIVALENCE
Drug Absorption & Bioavailability
Absorption is the rate and extent at which drugs reach the
systemic circulation from the site of administration.
Distribution of drugs includes all the processes involved
from the time when the drugs reaches the circulation to the
time when it (or drug metabolite) leaves the body.
Metabolism involves all biochemical processes resulted in a
chemical change to the drug compound including both the
metabolism in the gut wall, the liver, and blood circulation.
Excretion is the process in which the drug is eliminated from
the systemic circulation into bile, urine, feces, sweat, and
air.
Bioavailability (BA): rate and extent to which API or
active moiety is absorbed from a drug product and
becomes available at the site of action.
Bioavailablity, F ;
F = Fa x Fg x Fh
* Fraction of drug absorbed
Fraction that escapes first
pass hepatic metabolism
Fraction that escapes metabolism in GI tract
Oral drug absorption process occurs mainly in small
intestinal regions, including passive transcellular
diffusion, carrier-mediated transport processes,
paracellular transport, and endocytosis.
In general,
Lipophilic compounds- absorbed by passive diffusion
Hydrophilic compounds- absorbed through carriermediated process
Some small hydrophilic compounds – may be
transported through paracellular junction
Types of Intestinal Membrane Transport
IMT includes paracellular and transcellular transports.
Passage of solute
without passage
through the
epithelium cells
Can be divided into
passive diffusion,
endocytosis, and
carrier-mediated
transport.
Transcellular Transport
1) Passive Diffusion
- hydrophobic molecules can pass through the lipid
bilayers by random molecular motions.
- mass transfer of molecules depends on the
concentration gradient on the 2 sides of membrane.
- governed by Fick’s first law of diffusion.
J= flux (amount of material flowing through a unit cross section)
M = drug mass (g, mol)
A = surface area (cm2)
t = time (s)
D = diffusion coefficient (diffusivity, cm2s-1)
C1 = drug concentration at membrane wall in intestinal lumen (mol L-1)
C2 = drug concentration at membrane wall in blood side (mol L-1)
h = membrane thickness (cm)
Assumptions:
-
Steady state flux
The transfer of drugs reaches to steady state very fast
Steady state follows sink conditions: both side of membrane
are well stirred and homogeneous.
Define partition coefficient, K
K = C1 / Cd = C2 / C r
Cd : drug concentration in the GI lumen
Cr : drug concentration in the blood
2) Carrier-mediated Transport
- Intestinal epithelial cell membranes are highly polarized.
- Apical membrane faces the external lumen with many
microvilli to increase membrane surface area.
- Many membrane transporters are located in this side
facilitating absorption for most nutrients and many drugs,
while basolateral membrane is toward blood.
Carrier-mediated transport
Facilitated Diffusion
Active transport
- Involve carrier protein
- Transported against electrical /
- does not need energy
- depends on solutes conc.
gradient (similar to passive),
but has higher transport rate
chemical conc. gradient.
- Involves membrane bound protein
molecule that binds reversibly to
the solute at specific site
- The complex changes in
conformation that translocates
the solute to the other side of
membrane.
3) Endocytosis
- A process in which a substance or compound gain entry
into a cell without passing through the lipid cell
membrane.
- 3 types: Pinocytosis, Phagocytosis, and receptormediated.
- In each types, endocytosis results in formation of
intracellular vesicle by which the drug molecules are
transported into the cells.
Paracellular Transport
- Refers to transport solutes in between cells, without
passage through the epithelial cells themselves.
- Knowing that intercellular junctions between epithelial
cells of capillaries are “leaky”, allowing paracellular
transport of small molecules.
- is passive transport, follows drug concentration
gradient, does not require energy.
Factors Influence Drug Absorption
 Drug solubility
 GI Membrane permeability
 Dissolution of Solid Dosage
Forms
**Case Study**
1) Membrane permeability
-
Passive permeability (P) of molecules across a
membrane:
K: Partition coefficient (measure of substance solubility in
lipid)
D: Diffusion coefficient (depends on MW or size of molecule)
h: thickness of cell membrane
 Therefore, P is related to membrane and drug properties. For
specific drug, the passive membrane permeability should be
a constant Pm and independent to drug concentration.
- Active Permeability for absorption:
Jmax: Maximum drug flux
Km: Drug affinity to carrier
 Active permeability is dependent to drug concentration.
Therefore, Total Effective Permeability:
2) Solubility
- The drug molecules have to be dissolved in the solution
for the absorption to occur in intestinal tract.
- Low oil/water partition coefficient, K indicates high
solubility in water and high K indicates high solubility in
lipid.
- But, drug with high lipid solubility possesses high
membrane permeability.
- Ionization:
* For weak basic drugs, more unionized form would be
predominant in intestine at high pH (5-8) favors
absorption.
* For weak acid drugs, more ionized form in intestine.
* Ionized form is more water soluble than unionized.
* Unionized form is easier for absorption by passive diffusion.
3) Dissolution of solid dosage forms
- For the drugs in solid dosage form, they must be
dissolved in GI tract before absorption can take place.
- For drugs with low solubility and high dose, the
dissolution will be slow, and the dissolution rate will be
rate-limiting step for absorption.
- Factors that affect dissolution will control the whole
absorption process.
BIOEQUIVALENCE
Federal regulations (21 CFR, 2006) define
Bioequivalence as:
The absence of a significant difference in the rate and
extent to which the active ingredient or active moiety in
pharmaceutical equivalents or pharmaceutical
alternatives becomes available at the site of drug action
when administered at the same molar dose under similar
conditions in an appropriately designed study.
Equivalence: Relationship in terms of bioavailability,
therapeutic response, or a set of established standards of
one drug product to another.
Bioequivalent drug products:
describes pharmaceutical equivalent or pharmaceutical
alternatives products that display comparable
bioavailability when studied under similar experimental
conditions.
- For systemically absorbed drugs, the test and reference
listed drug, RLD (brand-name) shall be considered
bioequivalent if:
a) the rate & extent of absorption of the test drug do not
show significant difference from the rate & extent of
absorption of the reference drug when administered at
the same molar dose under similar experimental
conditions in either single or multiple doses;
b) the difference from the reference drug in the rate of drug
absorption is intentional, is reflected in its proposed
labeling, is not essential to the attainment of effective
body drug concentrations on chronic use.
Bioequivalent drug products may
contain different inactive ingredients,
provided the manufacturer identifies
the differences and provides
information that the differences do
not affect the safety or efficacy of the
product.
Pharmaceutical Alternatives (PA):
- Drug products that contain the same therapeutic moiety
but as different salts, esters, or complexes.
- Ex: tetracycline phosphate or tetracycline hydrochloride
equivalent to 250 mg tetracycline base.
- Different dosage forms and strength within a product line
by a single manufacturer (ex: extended-release dosage
form and a standard immediate-release dosage form of
the same active ingredient).
- * FDA considers a tablet and capsule containing the
same active ingredient in the same dosage strength as
PA.
Pharmaceutical Equivalents (PE):
- Drug products in identical dosage forms that contain the
same active ingredient (s), i.e., the same salt or ester,
same dosage form, use the same route of administration,
are identical strength or concentration
(ex: chlordiazepoxide hydrochloride, 5-mg capsules),
but, may differ in characteristics such as shape,
scoring configuration, release mechanism, packaging,
excipients ( including color, flavors, preservatives),
expiration time, and within certain limit, labeling.
 When applicable, PE must meet the same content
uniformity, disintegration time, and/or dissolution rates.
Biopharmaceutical Classification System
• According to BCS, drug substances are
classified as :
Class I : High Solubility – High Permeability
Class II : Low Solubility – High Permeability
Class III: High Solubility – Low Permeability
Class IV: Low Solubility – Low Permeability
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