BIOLOGICAL FACTORS- Absorption
Absorption of drug need dissolution in fluid
before it reaches to systemic circulation.
T he rate, extent and uniformity in
absorption of drug are important factors
when formulating SR/CR system
absorption=dissolution
BIOLOGICAL FACTORS- Absorption
• The maximum half-life for absorption
should be approximately 3-4 hr
otherwise, the device will pass out of
potential absorptive region before drug
release is complete.
Drug absorbed by specialized transport
are poor candidates for SR/CR
preparations e.g. riboflavin
BIOLOGICAL FACTORS- Absorption
SR/CR-rate of release is much slower
than rate of absorption.
The rate limiting step in drug delivery
from a S R / C R system is its release from
a dosage form, rather than absorption.
kr <<< ka
Compounds that demonstrate lower absorption
rate constants will probably be poor
candidates for sustaining systems.
BIOLOGICA
L FACTORS
BIOLOGICAL FACTORS- Distribution
For design of SR/CR release
products, one must have
information of disposition of drug
Disposition means distribution and
metabolism
BIOLOGICAL FACTORS- Distribution
The distribution of drugs into tissues can
be important factor in the overall drug
elimination kinetics
Distribution lowers the
concentration of drug in plasma
BIOLOGICAL FACTORS- Distribution
2 parameters used to describe distribution
characteristics of a drug are its
i) apparent volume of distribution [Vd] and
ii) ratio of drug concentration in tissue to that in
plasma at the steady state [t/p] ratio.
in case of one compartment model
vd = dose/c0
where, c0= initial drug concentration immediately
after an iv bolus injection
BIOLOGICAL FACTORS- Distribution
In case of one compartment model
vd = dose/c0
where, c0= initial drug concentration immediately
after an iv bolus injection
In case of two compartment model
vss = (1+k12/k21)/v1
where:
v1 = volume of central compartment
k12= rate constant for distribution of drug from
central to peripheral k21= rate constant for
distribution of drug from peripheral to central vss=
estimation of extent of distribution in the body
BIOLOGICAL FACTORS- Distribution
The amount of drug in the body can be
calculated by t/p ratio as given bellow.
t/p = k12 (k21-β)
where, β = slow deposition constant
t= amount of drug in peripheral to central
compartment
BIOLOGICAL FACTORS- Metabolism
There are 2 areas of concern relative to
metabolism that significantly restrict SR/CR
formulation design.
1) if drug upon chronic administration is capable of
either inducing or inhibiting enzyme synthesis, it
will be poor candidate for SR/CR formulation
because of difficulty of maintaining uniform blood
levels of drugs.
2) If there is a variable drug level i n blood
due to a first-pass metabolism, this also will
BIOLOGICAL FACTORS- Metabolism
Drugs that are significantly metabolized before
absorption, either in liver or lumen of intestine,
can show decreased bio-availability from SR/CR
dosage forms.
Examples
Drugs undergoing intestinal metabolism:
nitroglycerin, levodopa
Drugs undergoing first pass metabolism: lidocaine,
phenacetin, propranolol
BIOLOGICAL FACTORS-Elimination
The usual goal of SR/CR product is to maintain
therapeutic blood level over an extended period
For this drug must enter the circulation at
approximately the same rate at which it is eliminated.
The elimination rate (KE) is quantitatively described
by the half-life (t1/2)
t1/2 = 0.693/KE =0.693 Vd/cls = 0.693 Vd
AUC/dose
since, cls = dose/auc
where, Vd= apparent volume of distribution, cls =
systemic clearance
AUC = area under curve
BIOLOGICAL FACTORS-elimination
Therapeutic compounds with short half life are
excellent candidates for S R - C R since these can
reduce dosing frequency.
Drugs with very short half-life (<2 hours) are poor
for SR/CR formulation because it requires large
release rates and large dose. e.g.: furosemide,
levodopa
compounds with long half-life more than 8
hours are also generally not used in sustaining
forms, since their effect is already sustained. e.g.;
digoxin, warfarin, phenytoin etc.
Continuous release system
These systems release the drug continuously for prolonged
period of time along the entire length of GIT with normal
transit time.
Different systems under this class are-
a) Dissolution controlled release system
b) Diffusion controlled release system
c) Dissolution and diffusion controlled release System
d) Ion exchange drug resin complexes
e) Slow dissolving salts and complexes
f) pH-dependent formulation
g) Osmotic pressure controlled release system
h) Hydrodynamic pressure controlled release system
21
24
DIFFUSION CONTROLLED
DRUG RELEASE Rate controlling
factors
Polymeric content
in
coating
Thickness of
coating
Hardness of
microcapsule
• Polymeric
content
• Diffusion of
dissolved drug
through the 26
matrix
Diffusion Controlled Drug
Release
Reservoir devices
Product Active ingrediant
Nico 400 capsule Nicotinic acid
Nitro Bid capsule Nitroglycerin
Measurin capsule Acetyl salicylic acid
Bronkodyl capsule Theophylline
Matrix devices
Product Active ingrediant
Ferro gradumet tablet Ferrous fumarate
Procan tablet Procainamide Hcl
Desoxyn tablet Methamphetamine Hcl
27
Dissolution Controlled
Drug Release
Rate Dissolution Solubility &
Controlling of dispersed thickness of
factors drug through coat
medium
37
Dissolution Controlled
Drug Release
Encapsulation dissolution control
Product Active ingrediant
Benzedrine Amphetamine sulpahte
Thorazine Chlorpheniramine Hcl
Diamox Acetazolamide
Ferro sequels Ferrous fumarate
Matrix dissolution control
Product Active ingredient
Quinidex Quinidine sulphate
Nicobid Nicotinic acid
Chlor trimeton Chlorpheniramine 39
maleate
Dissolution and Diffusion
Controlled
Drug Release
• Drug core is enclosed with a partially soluble
membrane. Dissolution of part of membrane
allows for diffusion of contained drug through
pores in the polymer coat. Rate controlling
factor
Fraction of
soluble
polymer in the
coat
50
