theory in brief of sr/cr formulation

1. A
SEMINAR
ON
SUSTAINED RELEASE
DRUG DELIVERY
SYSTEM
presented by
BASHANT KUMAR SAH
M.Pharm (1st year, 1ST SEM)
Dept.of Pharmaceutics

2. Outer layer

3. INTRODUCTION
CONCEPT OF S.R.D.F.
DIFFERENCE BETWEEN C .R. AND S. R.
ADVANTAGES
DISADVANTAGES
CONTENTs

4. The history of controlled release technology is divided into three
time periods
From 1950 to 1970 was the period of sustain drug release
From 1970 to 1990 was involved in the determination of the
needs of the control drug delivery
Post 1990 modern era of controlled release technology
INTRODUCTION

5. Before initiating a discussion of sustained release dosage forms, it is
necessary to provide a short explanation of terminology used because there is
considerable confusion in this area. The general consensus is that controlled
release denotes systems, which can provide some control, whether this is of a
temporal or spatial nature, or both, of drug release in the body. In other
words, the systems attempts to control drug concentration in the target tissue
or cells. Thus, prolonged release or sustained release systems, which only
prolong therapeutic blood or tissue levels of the drug for an extended period
of time, cannot be considered as controlled release systems by this definition.
They are distinguished from rate-controlled drug delivery systems, which are
able to specify the release rate and duration in vivo precisely, on the basis of
simple in vitro tests. Drug targeting, on the other hand, can be considered as
a form of controlled release in that it exercises spatial control of drug release
within the body.
INTRODUCTION

6. In the conventional therapy aliquot quantities of drugs are
introduced into the system at specified intervals of time with the
result that there is considerable fluctuation in drug concentration
level as indicated in the figure.
HIGH
LOW
HIGH
LOW
INTRODUCTION

7. However, an ideal dosage regimen would be one, in which the concentration of the drug,
nearly coinciding with minimum effective concentration (M.E.C.), is maintained at a
constant level throughout the treatment period. Such a situation can be graphically
represented by the following figure
CONSTANT LEVEL
INTRODUCTION

8. “Drug Delivery system that are designed to achieve prolonged therapeutic
effect by continuously releasing medication over an extended period of time
after administration of single dose.”
The basic goal of therapy is to achieve steady state blood level that is
therapeutically effective and non toxic for an extended period of time.
The design of proper dosage regimen is an important element in
accomplishing this goal.

9. Concept of sustained release
formulation
The Concept of sustained release formulation can be divided in to two
considerations i.e. release rate & dose consideration
A) Release rate consideration :-
In conventional dosage form Kr>Ka in this the release of drug from dosage form is not
rate limiting step.

10. The above criteria i.e. (Kr>Ka) is in case of immediate release, where as in non immediate
(Kr<Ka) i.e. release is rate limiting step.
So that effort for developing S.R.F must be directed primarily altering the release rate. the
rate should be independent of drug removing in the dosage form over constant time.
The release rate should follow zero order kinetics
Kr = rate in = rate out = KeVd.Cd
Where
Ke = overall elimination (first order kinetics).
Vd = total volume of distribution.
Cd = desired drug concentration.

11. To achieve the therapeutic level & sustain for a given period of time for
the dosage form generally consist of 2 part
a) Initial (primary) dose b) maintenance dose
there for the total dose ‘W’ can be.
W = Di + Dm
In a system, the therapeutic dose release follows zero order process for
specified time period then,
W= Di + K0 r. Td
Td = time desired for sustained release from one dose.

12. If maintenance dose begins to release the drug
during dosing t=O then,
W = Di + K0 r Td – K0 r Tp
Tp = time of peak drug level.
However a constant drug can be obtained by
suitable combination of Di & Dm that release the
drug by first order process, then
W = Di + ( Ke Cd /Kr ) Vd

13. CONTROLLED RELEASE
1) Controlled drug delivery- which delivers the drug at a pre
determined rate for a specified period of time
2) Controlled release is perfectly zero order release that is
the drug release over time irrespective of concentration
SUSTAINED RELEASE
1) Sustain release dosage form- is defined as the type of
dosage form in which a portion i.e. (initial dose) of the
drug is released immediately, in order to achieve desired
therapeutic response more promptly, and the
remaining(maintanance dose) is then released slowly
there by achieving a therapeutic level which is
prolonged, but not maintained constant.
2) Sustained release implies slow release of the drug over
a time period. It may or may not be controlled release.
The difference between controlled release and sustained release,

14. Disadvantages of Conventional Drug Delivery System
1. Inconvenient
2. Difficult to monitor
3. Careful calculation necessary to prevent overdosing
4. Large amounts of drug can be “lost” when they don’t get to the target organ
5. Drug goes to non-target cells and can cause damage
6. Expensive (using more drug than necessary).5

15. Advantages of sustained release dosage forms
1. Reduction in frequency of intakes.
2. Reduce side effects.
3. Uniform release of drug over time.
4. Better patient compliance.
Disadvantages of sustained release drug delivery
1. Increased cost.
2. Toxicity due to dose dumping.
3. Unpredictable and often poor in vitro-in vivo correlation.
4. Risk of side effects or toxicity upon fast release of contained drug (mechanical failure,
chewing or masticating, alcohol intake).
5. Increased potential for first- pass clearance.

16. FACTORS AFFECTING THE FORMULATION OF ORAL SR DDS
There are two major factors that affect the release rate from the DDS. They are:
1. Physicochemical factors
2. Biological factors.
1 PHYSICOCHEMICAL FACTORS
a. Aqueous solubility
b. Partition coefficient (P [O/W])
c. Drug pKa and ionization at physiological pH
d. Drug stability
e. Molecular weight and diffusivity
f. Protein binding
g. Dose size.
e. Margin of safety/therapeutic index
f. Side effect
g. Disease state
BIOLOGICAL FACTORS
a. Absorption
b. Distribution
c. Metabolism
d. Biological half-life/duration of action h.patient:

17. AQUEOUS SOLUBILITY
Drugs must be in solution before they can be absorbed.
Most of the drugs are weak acids or weak bases. Drugs with low water solubility
will be difficult to incorporate into SR mechanism.
for ex. Digoxin, warfarin,griseofulvin, salicylamide whose action can be
prolonged by making it less soluble which may results in incomplete bioavilability.
For a drug with high solubility and rapid dissolution rate, it is often quite
difficult to retard its dissolution rate.
A drug of high water solubility can dissolve in water or GI fluid readily and
tends to release its dosage form in a burst and thus is absorbed quickly leading to a
sharp increase in the blood drug concentration compared to less soluble drug .
some drugs solubility at one site and absorption at another.
for Ex. Tetracyclin dissolves much in stomach than in intestine although it is
best absorbed in intestine which is poor candidates for SR formulation

18. Some antibiotics have high aqueous solubilty but very slow
dissolution rates which shows active SR/CR by incorporation in
matrix system but have limited bioavilability
Aqueous solubility also limits the loading efficiency of
drugs into a variety of carrierslike liposomes,erythrocytes,and
other microparticles, followed by leaking from these.

19. PARTITION COEFFICIENT AND MOLECULAR SIZE
Definition.
The partition coefficient is defined as the fraction of drug in an oil phase to that of an adjacent
aqueous phase.
Partition coefficient and mol. Size influences not only the permeation of the drug across
the biological membranes but also diffusion across the rate controlling membrane or matrix
between the time when a drug is administered, and when it is eliminated from the body, it must
diffuse through a variety of biological membranes that act primarily as lipid-like barriers.
A major criterion in evaluation of the ability of a drug to penetrate these lipid
membranes (i.e., its membrane permeability) in its apparent oil or water partition coefficient
defined as,
K=Co/Cw
Where,
Co = Equilibrium concentration of all forms of the drug in an organic phase at equilibrium,
Cw = Equilibrium concentration of all forms in an aqueous phase.
low o/w partion coefficients and high mol.size cannot peneterate the membranes.
HANSCH AND DUNN shows that for many body tissues like skin, GI, eye, the optimum n-
octanol/water PC. At which maximum flux occurs is approximately 1000

20. The relation between diffusivity and molecular size is shown by following equation
Log D = -Sv logV+Kv = -Sm logM + Km
D- diffusivity
M- molecular wt.
V- molecular volume
Sv,Sm,Kv,and Km are constants in particular medium.

21. DRUG PKA AND IONIZATION AT PHYSIOLOGICAL PH
Drugs existing largely in an ionized form are poor candidates for oral
SR DDS.
Absorption of the unionized drugs is well whereas permeation of
ionized drug is negligible because the absorption rate of the ionized
drug is 3-4 times less than that of the unionized drug.
The pKa range for an acidic drug whose ionization is pH
sensitive is around 3.0-7.5 and pKa range for a basic drug whose
ionization is pH sensitive is around 7.0-11.0 are ideal for optimum
positive absorption. Drug shall be unionized at the site to an extent
0.1-5.0%

22. DRUG STABILITY
Drugs undergo both acid/base hydrolysis and enzymatic
degradation when administered oral route.
Drugs that are unstable in gastric pH can be developed as
slow release dosage form and drug release can be delayed until
the dosage form reaches the intestine.
Drugs that undergo gut wall metabolism and show instability in the small intestine are not
suitable for SR system.
In such case, the drug can be modified chemically to form prodrugs, which may possess
different physicochemical properties or a different route of administration should be chosen
for ex CR of Nitroglycerin.

23. PROTEIN BINDING
It is well-known that many drugs bind to plasma proteins with
concomitant influence on the duration of drug action.
Since blood proteins are for the most part re-circulated and
not eliminated, drug protein binding can serve as the depot for
drug producing a prolonged release profile, especially if a high
degree of drug binding occurs.
The drug interaction and the period of binding with mucin-like
protein also influence the rate and extent of oral absorption

24. DOSE SIZE
For orally administered systems, there is an upper limit to the
bulk size of the dose to be administered.
In general, a single dose of 0.5-1.0 g is considered maximal
for a conventional dosage form.
This also holds for sustained-release dosage forms. Those
compounds that require large dosing size can sometimes be
given in multiple amounts or formulated into liquid system.
Another consideration is the margin of safety involved in
the administration of large amounts of a drug with narrow
therapeutic range

25. Biological factors,
ABSORPTION
The constant blood or tissue concentration of drug can
be obtained from the oral SR systems through uniform
and consistent release as well as absorption of the drug.
Apparently the release of the drug from
the system is the rate limiting step, where rapid
absorption relative to the drug release is always
expected, i.e., Kr << Ka

26. If we assume the transit time of dosage forms in the absorptive areas of GI tract
is about 8-12 hrs, the maximum half-life for absorption should be approximately
3-4 hrs. Otherwise, the dosage form will pass out of absorptive regions before
drug release is complete. Therefore, the compounds with lower absorption rate
constants are poor candidates. Some possible reasons for the low extent of
absorption are poor water solubility, small partition co-efficient, protein binding,
acid hydrolysis and metabolism or site specific or dose-dependent absorption.
Drugs with the high apparent volume of distribution, which influence the rate of
elimination of the drugs, are a poor candidate for oral SR DDS.
A drug which extensively metabolizes is not suitable for SR DDS.
A drug capable of inducing metabolism, inhibiting metabolism, metabolized at
the site of absorption or first-pass effect is the poor candidate for SR delivery, as
it could be difficult to maintain constant blood level. Drugs that are metabolized
before absorption, either in the lumen or the tissues of the intestine, can show
decreased bioavailability from the sustained releasing systems

27. for ex. Pilocarpine is usually absorbed across the cornea to the extent of about 1% from an
applied dose, the extensive loss due to the drainage and absorbtion into non targeted tissue
however despite the low fraction of dose absorbed, a controlled released product was prepared
which shows low bioavailability.
certain drugs absorbtion can be varied due to uneven absorbtive surface of GI tract examples
of such drugs are dicoumarol , hexamethonium , decamethonium , aminoglycosides (
gentamycin and kanamycin )
drugs like riboflavin is absorbed by an active transport hence it is poor candidates for CR
formulation.
IRON doesnot absorbed uniformily along the lenth of GI tract ( high at upper part of
duodenum )hence its CR formulation is doubt. As absorbtion is not uniform.

28. DISTRIBUTION
The distribution of drug molecules into the tissue and cells can be the primary factor in
particularly drug elimination kinetics.
Since it not only lowers the concentration of circulating drug, but it also can be rate limiting in
its equilibrium with blood and extravascular tissue.
The distribution includes the binding of the drug to the tissues and blood proteins.
Protein-bound drugs molecules are considered as inactive and unable to permeate biological
membranes, and a high degree of protein binding provides prolonged therapeutic action. The
apparent volume of distribution is one of the important parameters of the drugs that describes
the magnitude of distribution as well as protein binding within the body
the total apparent volume of distribution for a drug at steady state can be calculated as
Vd ss = [(K 12 +K 21)/K21]Vp
Vd – apparent volume of distribution ,k12 is constant for dd from central to peripheral
compartment
k21 is constant for dd from peripheral to central
Vp is the volume of central compartment

29. Drugs and its volume of distribution(Vdss)
• Drugs
• Amoxicillin
• Cefazolin
• Digoxin
• Furosemide
• Vdss
• 22
• 9
• 500
• 5

30. METABOLISM
Metabolism of the drug is either an inactivation of an active drug or conversion of an inactive
drug to an active metabolite.
Metabolism of the drug occurs in a variety of tissues, which are containing more enzymes.
Drugs that are significantly metabolized before absorption, either in the lumen or tissue of the
intestine, can show decreased bioavailability from slower-releasing dosage forms.
Drugs that are capable of either inducing or inhibiting enzyme synthesis, they are the
poor candidate for SR delivery system due to difficulty in maintaining uniform blood levels.
Drugs possessing variation in bioavailability due to the first-pass effect or intestinal
metabolism are not suitable for SR DDS
for ex isosorbide 2,5- dinitrate
for ex. Hydralyzin is metabolized by intestinal wall or in tha liver during absorbtion although
it is well absorbed
for ex. BROCADOPA the SR form of std. drug levodopa has no advantages
upon std. levodopa. As it is metabolized by gut wall flora.

31. BIOLOGICAL HALF-LIFE/DURATION OF ACTION
The usual goal of an oral sustained-release product is to maintain therapeutic blood levels over
an extended period.
The duration of action significantly influences the design of oral SR delivery system and it is
dependent on the biological half-life.
Factors influencing the biological half-life of a drug include its elimination, metabolism and
distribution patterns.
Drugs with short half-lives required frequent dosing to minimize fluctuations in the blood
levels. SR dosage forms would appear very desirable for such drugs.
For a given steady state drug concentration, the zero-order rate of release of a drug from its
dosage form is directly proportional to its rate of elimination.
In general, drugs with half-lives shorter than 2 hrs are poor candidates for sustained-release
preparations. For ex propranolol t1/2= 4hrs, procainamide T1/2 = 3 hrs are in boarderline for
prolonged release product
Compounds with long half-lives, more than 8 hrs, are also generally not used in sustaining
forms, since there effect is already sustained

32. MARGIN OF SAFETY/THERAPEUTIC INDEX
Margin of safety of a drug can be described by considering therapeutic
index, which is the ration of median toxic dose and median effective
dose.
Therapeutic index = TD50/ED50
A drug is considered to be relatively safe with therapeutic index more
than 10 i.e., larger the ratio the more safely is the drug.
Margin of the safety of the drugs determined on the basis of
therapeutic index is the range of plasma concentration in which the drug
is considered to the safe and therapeutically effective. The drugs with
narrow therapeutic indices the release pattern should be more precise
to maintain the plasma concentration within the narrow therapeutic and
safety range. The unfavorable therapeutic index of a drug can be

33. SIDE EFFECT
The side effects of the some drugs are mainly developed due to
fluctuation in the plasma concentrations.
The incidences of side effects can be minimized by controlling
the concentration within therapeutic range at any given time.
The SR drug delivery is the most widely used to incidences of the
GI (local) side effects rather than a systemic side effect of the
drug. The drug properties which induce local or systemic side
effect can be circumvented or modified by their incorporation in
a suitable oral SR delivery system that employs a specific
controlled release mechanism for ex DIGITOXIN,PHENOBARBIT.

34. DISEASE STATE
Disease state and circadian rhythm are not drug properties, but they are
equally important as drug properties in considering a drug for SR. For
example:-
• Aspirin is a drug of choice for rheumatoid arthritis though it is not
suitable for SR dosage form. Still, aspirin SR dosage form could be
advantageous to maintain therapeutic concentrations, particularly
throughout the night, thus alleviating morning stiffness.
• Asthma attacks are commonly occurring before bedtime, due to a low
cortisol level. The highest cortisol level occurred between 12 midnight
and 4 a.m. These variations entail for the design an oral SR delivery in
accordance to circadian rhythm

35. Thank u
ref. w.y chien.