SUSTAINED RELEASE AND
CONTROLLED DOSAGE FORMS
Syllabus:
Concept and principles in the formulation of SR dosage
forms. Drug delivery rate from the dosage forms, formulation and manufacture of
sustained action dosage forms. In vitro-in vivo drug availability from the
formulations. Quality control tests.
INTRODUCTION
Most conventional drug products,
such as tablets and capsules are formulated to release the active drug
immediately after administration to obtain rapid and complete systemic drug
absorption.
The goal of any drug delivery
system is to provide a therapeutic amount of drug to the proper site in desired
concentration.
Controlled drug delivery systems
These systems deliver the drug at the absorption site at a
controlled rate.
Classification of controlled drug
delivery systems (DDS)
1. Extended release
dosage forms
A dosage form that
allows at least a two-fold reduction in dosage frequency as compared to an
immediate release (conventional) dosage form.
It contains (a)
Prolonged release DDS and (b) Sustained release dosage forms.
(a) Prolonged release DDS
After a single
dose the drug is released slowly and rate of absorption is slow. Onset of
action is delayed. Duration of action is greater than a conventional dosage
form.
(b) Sustained release DDS
·
Contains loading dose +
maintenance dose.
Contains loading dose +
maintenance dose.
·
Loading dose is immediately released to produce
quick onset of action.
·
Maintenance dose is released at a controlled
rate so that the plasma concentration remains constant above Minimum Effective
Concentration (MEC).
·
Plasma concentration comes down according to
first order elimination kinetics.
2. Delayed release dosage forms
On delayed
release dosage forms one or more immediate release units are incorporated into
a single dosage form.
e.g. repeat
action tablet, enteric coated tablet.
Advantages: These dosage forms produce
better patient compliance.
Disadvantages: Drug level is not uniform
within the therapeutic range.
3. Targeted release
dosage forms
This is a dosage form that releases
drug at or near the intended physiologic site of action.
Advantages of a controlled drug delivery system over a conventional dosage forms are:-
1.
Frequency of drug administration is reduced – patient
compliance is improved.
2.
In multiple dosing of conventional dosage forms the
blood level of drug shows oscillatory characteristic. In controlled release
dosage form the blood level is evenly maintained.
3.
The safety margin of high potency drugs can be
increased and thus side-effects or adverse effects can be minimized.
4.
Total amount of drug administered can be reduced
because of maximum utilization.
5.
Reduction in health care costs through improved
therapy, shorter treatment period, less frequency of dosing and reduction in
personnel time to dispense, administer and monitor patients.
Disadvantages of controlled release dosage forms :-
1.
Decrease systemic availability in comparison to
immediate release conventional dosage forms, this may be due to incomplete
release, increased first-pass metabolism, increased instability, insufficient
residence time for complete release site specific absorption, pH dependent
solubility etc.
2. Poor
in vitro-in vivo correlation.
3.
Possibility of dose dumping due to food, physiologic or
formulation variables or chewing or oral formulations by the patient and thus
increased risk of toxicity.
4.
Retrieval of drug is difficult in case of toxicity,
poisoning or hypersensitivity reactions.
5.
Reduced potential for dosage adjustment of drugs
normally administered in varying strength.
6.
Higher cost of formulation.
DESIGN OF CONTROLED DRUG DELIVERY SYSTEM (DDS)
The performance of a drug presented as a controlled release
system depends upon its:
1. Release
of drug from the dosage form.
2. Movement
of the drug within the body.
 |
The release depends on the fabrication of the dosage forms and the movement depends on the pharmacokinetics of the drug.
Desired characteristics of drug suitable for controlled DDS
A. Biopharmaceutical characteristics
1.
Molecular weight
of the drug: Less than 600 daltons are suitable for passive diffusion.
Larger molecules are not suitable e.g. peptides and proteins.
2.
Aqueous
solubility of the drug:
·
Good aqueous solubility, with pH independent
solubility serves as a good candidate for oral controled DDS. E.g.
pentoxifylline.
·
Drug with pH dependent aqueous solubility (e.g.
phenytoin) or drug soluble in nonaqueous solvents (e.g. steroids) is suitable
candidates for parenteral controlled DDS (e.g. intramuscular depot).
·
Poorly water-soluble drugs are not suitable
candidates because their dissolution is rate limited.
3.
Ionization and
pKa of the drug
·
Drug that remains is unionized state at
absorption site is a good candidate.
·
Drug that remains in ionized state (e.f.
hexamethonium) are poor candidates.
4.
Drug stability:
Drugs unstable in gastro-intestinal environment are poor candidates for oral
controlled DDS because bioavailability will be less.
5. Mechanism of absorption: Drugs absorbed
by carrier mediated transport and those absorbed through an “absorption window” are poor candidates
e.g. several B-vitamins.
6. Route of administration:
(a) Oral
route: Duration of action may be extended to 12 to 24 hours. Maximum 1000mg
can be given.
(b) Intramuscular
/ Subcutaneous route: Duration of action can be prolonged from 24hours to
12 months. Maximum 2ml or 2 gm can be administered through this route.
(c) Transdermal
route : 12 hours to several days. Very low dose drugs (e.g. nitroglycerine)
can be administered. Drugs with extensive first pass metabolism is suitable.
Pharmacokinetic characteristics
1. Absorption rate: The rate of release( Kr) << Rate
of absorption (Ka.)
2. Elimination half life: 
– excellent candidate for controlled release
DDS
– excellent candidate for controlled release
DDS
– good
candidate for controlled release DDS
long t1/2. – not suitable for controlled release
DDS
3. Rate of metabolism: Drug that is rapidly metabolized in the liver
are not good candidate for oral controlled release DDS they are better given by
parenteral controlled release formulation.
Pharmacodynamic characteristics
1. Therapeutic range: Therapeutics range of a drug is wide ® good
candidate for controlled DDS
2. Plasma concentration – Response relation
ship: Drugs such as reserpine whose pharmacological activity is independent
of its plasma concentration are poor candidate for controlled DDS.
Calculation of amount
of drug required for designing a sustained release dosage form
The amount of drug required in a
sustained release dosage form to provide a sustained drug level (CSS)
in the body is determined by
·
the pharmacokinetic parameters of the drug (Vd,
KE, CL),
·
the desired therapeutic concentration of the
drug (CSS)and
·
the intended duration of action (T).
Total dose (Dtot ) required = Initial dose or loading dose (Di) +
Maintenance dose (Dm)
Dtot =
Di + Dm
Calculation
of initial dose
At the desired therapeutic
concentration (CSS) the body contains( CSS x Vd
) amount of drug.
If Di amount of drug is administered
as loading dose then (FxDi ) amount of drug will be absorbed in the body where
F is the oral bioavailability of drug
Therefore, F Di = CSS x Vd. or, 
Calculation
of maintenance dose
The Di dose will raise the plasma
concentration of the drug to CSS and will reach the peak. After CSS
is reached the elimination rate from the body will be maximum and the
elimination rate will be KE x Vd x CSS. An
ideal maintenance dose will supply drug at a rate in which the drug is
eliminated from the body.
Therefore, the rate of delivery from
the maintenance dose = elimination rate (Routput)
i.e. Routput = KE x Vd x CSS.
= CL x
CSS. where the
clearance value of the drug, CL = KE x Vd.
If the intended duration of action =
T then the amount of drug required for maintenance dose Dm can be
calculated from the equation:
FxDm = Routput x T or, 
Therefore, 
Drug
release pattern from various oral dosage forms
EVALUATION OF SUSTAINED RELEASE
DOSAGE FORMS
In vitro tests
Objective
of evaluation
1. In-vitro tests are required to guide the
researchers during the developmental stage, prior to clinical testing.
2. In vitro testing is necessary to ensure
batch to batch uniformity in the production of an already developed sustained
release product.
Test using USP dissolution rate
test apparatus
In vitro tests include release studies
from the dosage forms in a dissolution medium. It may be either simulated
gastric fluid (pH 1.2) or simulated intestinal fluid (pH 7.2) or may be pH in
between gastric and intestinal. USP dissolution rate test apparatus 1 (rotating
basket type) or apparatus 2 (paddle type) may be taken. Simulated gastric or
intestinal fluid is taken in the round bottom beaker. Samples are taken at
known intervals and is replaced with fresh medium, amount of drug released from
the SR dosage form is potted against time.
Test using
rotating bottle assembly
Samples are tested
in 90ml bottles containing 60 ml dissolution medium, which are rotated at 40rpm
in water bath of 370C. Time to time samples are withdrawn.
Test using
Sartorius device
Sartorius device
includes a semi-permeable membrane (dialysis membrane) separating the
dissolution chamber and simulated plasma chamber. Samples are withdrawn from
plasma chamber. Thus amount absorbed is plotted against time.
Stability tests
Most SR dosage
forms are complex and the special ingredients used in them may produce
stability problem. So the stability testing program includes storage of
formulation under both normal (shelf) and exaggerated (accelerated) conditions
of temperature, humidity, light etc.
Physical
stability, chemical stability and release profile is checked after a time
interval at each set of conditions.
In
vivo tests
Objectives
1. To
determine the fraction of drug absorbed (should be ideally ³ 80%
of conventional release dosage form).
2. To
check for the occurrence of dose dumping.
3. To
determine the influence of food on drug absorption.
4. To
determine the duration of action
5. To
determine the Cmax / Cmin ratios at steady state.
6. To
determine the percent fluctuation calculated from equation: 100(Cmax
– Cmin) / Css.
A single dose is sufficient to assess
the first three objectives but the subsequent ones can only be evaluate from a
multiple dose study. The reference standard is a solution or suspension of the
drug or currently marketed controlled dosage forms.
ORAL CONTROLLED RELEASE SYSTEMS
A. Continuous
controlled release systems
1. Dissolution controlled release
systems
(a) Matrix
(or monolith) systems
(b) Encapsulation
/ Coating systems
2. Diffusion
controlled release systems
(a) Matrix
systems
(b) Reservoir
systems
3. Dissolution and
diffusion controlled release systems
4. Ion-exchange
resin – Drug complexes
5. Slow dissolving
salts and complexes
6. pH independent
formulation
7. Osmotic pressure
controlled systems
8. Hydrodynamic
pressure controlled system.
B. Delayed transit
and then continuous release systems
1. Altered
density systems
2. Mucoadhesive
systems
3. Size-based
system
C. Delayed release
systems
1. Intestinal
release systems
2. Colonic
release systems