Transcript 12_Controlled drug release

Controlled drug release
Dr Mohammad Issa
1
Frequency of dosing and therapeutic
index


Therapeutic index (TI) is described as the ratio of
the maximum drug conc in the blood that can be
tolerated to the minimum drug conc needed to
produce a satisfactory clinical response. In some
cases these ranges are narrow, resulting in small
therapeutic index
We seek to maintain drug conc in blood within the
Therapeutic range during therapy. This requires
not only the selection of an appropriate daily
dose, the drug must also be given with sufficient
frequency so as to minimize the range of blood
conc that are produced. The ratio of max to
minimum drug conc at steady state should not
exceed the therapeutic index of the drug.
2
Frequency of dosing and therapeutic
index

For drugs that are absorbed and
distributed rapidly, the following
relation apply
 ln(TI) 

τ  t 1  
2
 ln(2) 
where τ is the dosing intervals,
t 1 is the half life, and TI is the therapeut ic index
2
3
Frequency of dosing and therapeutic
index


A drug with the TI of 2, t1/2 of 3 hrs
must be given no less frequently
than every 3 hours
A drug with similar half life but a
therapeutic index of 4 may be given
every 6 hours
4
Absorption rate and frequency of
dosing



Dosing regimen for rapidly absorbed drugs are a
function of the pharmacodynamics and
pharmacokinetics of the drug molecule, they must
be based on the therapeutic index and half life of
the drug
Reducing the absorption rate of a drug by
controlling the rate of drug release in the dosage
form, can dramatically affect drug conc at steady
state
For a given formula, the slower the release of the
drug, the smaller is the ratio of maximum to
minimum drug con at steady state. Under these
conditions, we can give larger doses at less
frequent intervals and still stay within the
5
therapeutic conc of the drug
Absorption rate and frequency of
dosing



Prolonged release medication offer obvious
advantages for drugs with short half lives and
narrow therapeutic indices. As they permit the
drug to be given at more reasonable intervals
within the day (improve patient compliance)
They also minimize the peak to trough drug conc
ratio, which may be useful for many drugs.
For example: potassium depleting
hydrocholrthiazides: their potassium depleting
effect disappears when the fluctuations in blood
levels decrease. Nephrotoxicity of gentamicin is
reduced when steady state conc are reached and
maintained in a narrow range.
6
Zero order release



Continuous, constant rate IV infusion leads to
constant blood levels. Under these conditions
blood levels are invariant with time, there are
no peaks and troughs
Provided that the constant drug conc is within
the therapeutic range, this is an ideal
situation for many drugs
The only way to achieve constant blood levels
is to administer the drug at a constant (zeroorder) rate over the entire dosing interval.
7
Zero order release


Fluctuations in blood levels do occur as a
result of transient changes in clearance or
in the delivery rate, but they are usually
small
Constant rate release is not limited to
infusion, today there are dosage forms
oral, ocular, intravaginal, IM that release
the drug in a zero order or near zero
order fashion.
8
Oral prolonged release medications


Most prolonged release medications are
intended for oral use. A prolonged release
unit usually contains more drug than a
conventional dosage unit, but it intended
to be given less frequently
A drug that is usually administered at a
dose of 250 mg 4 times daily, may be
given at a dose of 500 mg twice daily, or
1 gm once daily
9
Oral prolonged release medications

The ultimate criteria of for evaluating
such dosage forms are:
the amount of drug intended to be absorbed
is indeed absorbed in a predictable and
consistent manner
2. the steady state ratio of maximum to
minimum drug conc is no greater or
optimally less than that produced by the
more frequently administered conventional
dosage forms
1.
10
Potential advantages oral prolonged
release medications
1.
Improved control of the maintenance therapuetic
level of the drug which permit:



improved treatment of many chronic illnesses
where symptoms breakthrough occurs if plasma
levels went down (asthma, depression)
maintenance of the therapeutic action during night
(management of pain)
reduction in the incidence and severity of side
effects caused by increased plasma levels
2.
improved patient compliance
3.
reduction of the incidence and severity of
gastrointestinal side effects caused by irritant
drugs administered in a conventional dosage
form
11
Potential limitations oral prolonged
release medications
1.
variable physiological factors (gastric
emptying, gastric and intestinal transit rate,
food) which often influence drug bioavailability
of conventional dosage form may also interfere
with the precision of control of release of the
SR dosage forms
2.
the rate of transit of the sustained release oral
dosage form along the GI limits the maximum
period of time for which the therapeutic
response is maintained
3.
Sustained release dosage forms which tend to
remain intact, may become lodged at some sit
of the GI--- slow release, high localized conc
of drug, local irritation
12
Potential limitations oral prolonged
release medications
4.
Reduced potential for accurate dosage
adjustment: fine dose adjustment is difficult.
5.
Dose dumping: uncontrolled rapid release of the
drug material due to failure of the formulation
which result in abnormal high blood levels of
circulating drug
13
Controlling drug release


All sustained release formulations employ a
chemical or physical barrier to provide slow
release of the drug
Use of drug derivatives with reduced
solubility or dissolution rate: increase
particle size, less soluble complexes and
salts, ion exchange resins to bind the drug,
use of coating, embedding the drug in a
wax, fat, or inert matrices.
14
Subdivided vs. single unit




Most peroral dosage forms can be characterized as
being subdivided or single unit.
Subdivided: hard gelatin capsule containing
numerous beads in which the drug is entrapped,.
Often several kinds of beads (pellets) are found in
a capsule, some releasing the drug rapidly and
other more slowly
Single unit: remain more or less intact throughout
the GIT, releasing the drug slowly as it passes
through
It is judged that subdivided dosage forms are
potentially safer than intact or single unit dosage
form
15
16