Sustained release dosage form

Sustained release dosage form

1. SUSTAINED RELEASE
DOSAGE FORMS

Presented by:
Sujit R. Patel,
1
st
M. pharm.
DEPARTMENT OF PHARMACEUTICS,
Maratha Mandal’s College OF PHARMACY,
Belgaum - 590 010.
February 11, 2013 1M.M.C.P.

2. INTRODUCTION
Drug delivery systems refer to the technology
utilized to present the drug to the desired body site
for drug release and absorption.
Newer discoveries and advancements in
technology has lead to various new techniques of
delivering the drugs for maximum patient
compliance at minimal dose and side effects.

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3. IDEAL DRUG DELIVERY SYSTEM
First, it should deliver drug at a rate dictated by the needs
of the body over the period of the treatment.
Second it should channel the active entity solely to the site
of action.
This is achieved by development of new various modified
drug release dosage forms, like-

 Control release dosage forms
 Time release dosage forms
 Sustained release dosage forms
 Site specific or targeted drug delivery systems etc
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4. SUSTAINED RELEASE DRUG DELIVERY : Any of the dosage form that
maintains the therapeutic blood or tissue levels of drug by continuous release
of medication for a prolonged period of time, after administration of a single
dose. In case of injectable dosage forms it may vary from days to months.
SITE SPECIFIC AND RECEPTOR TARGETINGSITE SPECIFIC AND RECEPTOR TARGETING : : Targeting a drug
directly to a certain biological location .For site specific release the target is
the adjacent to or in the diseased organ or tissue, for receptor release the
target is the particular drug receptor within an organ or tissue.
CONTROLLED RELEASE DRUG DELIVERY :Delivery of the drug at a
predetermined rate and /or to a location according to the needs of the body
and disease states for a definite period of time.
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5. Contd..
REPEAT ACTION DOSAGE FORMREPEAT ACTION DOSAGE FORM : contain 2 or 3 full doses which
are so designed that the doses are released sequentially one after the other.
OTHER NOVEL(NEW) DOSAGE FORMS:OTHER NOVEL(NEW) DOSAGE FORMS:
includes- Microspheres, Nanoparticles,, Trans-dermal delivery
systems, Ocular drug delivery, Nasal drug delivery, Implants etc.
TIMED RELEASE OR DELAYED RELEASETIMED RELEASE OR DELAYED RELEASE : : These are the
systems that use repetitive, intermittent dosing of a drug from one or
more immediate release units incorporated into a single dosage form or
an enteric delayed release systems e.g. Repeat action tablets and
capsules and enteric coated tablets where time release is achieved by
barrier coating, or wherein the release of the drug is intentionally
delayed until it reaches the intestinal environment.
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6. Sustained release
dosage forms
(SRDF’S)
time
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7. INTRODUCTION
Sustained release describes the release of
drug substance from a dosage form or
delivery system over an extended period of
time.
Also referred to as prolonged-release (PR),
slow release (SR), sustained action (SA),
prolonged action (PA) or extended-release
(ER).
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8. COMPARISION OF DRUG RELEASE
PROFILES
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9. Differences between sustained and
controlled drug delivery system
Sustained release Sustained release
dosage formdosage form
•Constitutes dosage form that Constitutes dosage form that
provides medication over provides medication over
extended period of timeextended period of time
•SRDF generally do not SRDF generally do not
attain zero order release attain zero order release
kinetics kinetics
•Usually do not contain Usually do not contain
mechanisms to promote mechanisms to promote
localization of the drug at localization of the drug at
active site. active site.
Controlled release Controlled release
dosage formdosage form
•Constitutes dosage form that Constitutes dosage form that
maintains constant drug levels in maintains constant drug levels in
blood or tissue blood or tissue
•Maintains constant drug levels in Maintains constant drug levels in
the blood target tissue usually by the blood target tissue usually by
releasing the drug in a zero order releasing the drug in a zero order
pattern.pattern.
•Controlled dosage forms contain Controlled dosage forms contain
methods to promote localization methods to promote localization
of the drug at active site.of the drug at active site.
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10. Merits of SRDF
Reduction in blood level fluctuations of drug, thus
better management of the disease.
Reduction in dosing frequency.
Enhanced patient convenience and compliance.
Reduction in adverse effects(both systemic and local),
esp. of potent drugs, in sensitive patients.
Reduction in health care costs.
Improved efficiency of treatment.
Reduces nursing and hospitalizing time.
Maximum bioavailability with a minimum dose.
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11. Contd..
  Minimize drug accumulation with chronic dosing. 
  Cure or control condition more promptly.  
  Make use of special effects, e.g. Treatment of Arthritis.
  Constant blood levels achieve desired effect and this 
effect is maintained for an intended period of time.
  Drug susceptible to enzymatic inactivation or by bacterial 
decomposition can be protected by encapsulation in polymer 
system suitable for SR.
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12. Limits of SRDF
 Administration of sustained release medication dose not 
permit prompt termination of therapy. Immediate changes in 
the drug if needed during therapy when significant adverse 
effects are noted cannot be accommodated.
The physician has less flexibility in adjusting dosage regimen, 
as it is fixed by dosage form design.
Sustained release dosage forms are designed for normal 
population i.e. on basis of average biologic half-life. 
Consequently, disease states that alter drug disposition, 
significant patient variation, and so forth are not 
accommodated.
More costly process and equipment are involved in 
manufacturing many sustained release dosage forms. 
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13. Contd..
Dose dumping
Unpredictable and poor in vitro and in vivo relationship.
Effective drug release time period is influenced and limited by GI 
residence time.
Need additional patient education.(such as not to chew or crush the 
dosage form before swallowing)
Drugs having very short half life or very long half life are poor 
candidates for sustained release dosage forms. For Ex: diazepam.
Delayed onset of action, hence sometimes not useful in acute 
conditions
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14. Characteristics of Drugs
Unsuitable for Peroral SRDF
I.Those which are absorbed and excreted rapidly; short 
biological half life(<1 hr).  Ex- Penicillin G , Furosemide.
II.Those with long biologic half life(>12 hrs). Ex- 
Diazepam, Phenytoin. 
III.For those which require large doses(>1 gm)                    
Ex- Sulfonamides. 
IV.Extensive binding of drugs to plasma proteins will have 
long elimination half life and such drugs generally do not 
require to be formulated to SRDF.
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15. Contd..
V.Those with cumulative action and undesirable 
side effects. Ex-Phenobarbital
VI.Those with low therapeutic indices. ex- 
Digitoxin.
VII.Those requiring precise dosage titration for 
every individual. Ex- Warfarin, Digitoxin.
VIII.In general a very highly soluble drug or a highly 
insoluble drug are undesirable for formulation 
into SRDF product. 
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16. Materials Used in Coating of Sustained
Release Dosage Forms (Encapsulation)
Mixtures of waxes [bees wax, carnauba wax, etc] with glyceryl 
monostearate , stearic acid , glyceryl mono palmitate and cetyl 
alcohol.These provide coatings that are dissolved slowly or broken 
down in the GIT.
Shellac and zein – polymers that remain intact until the PH of the GI 
contents become less acidic
Ethyl cellulose , which provides a membrane around the dosage 
form and remains intact throughout the GIT. However, it does 
permit water to permeate the film, dissolve the drug , and diffuse out 
again. 
Acrylic resins , which behave similarly to ethyl cellulose as a 
diffusion controlled drug release coating material.
Cellulose acetate [di acetate and tri acetate] 
 Silicone elastomers.
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17. Polymers for Micro-encapsulation
Water-soluble resins
Water-insoluble resins
Waxes and lipids
    
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18. Water-soluble resins
Gelatin
Povidone (PVP)
CMC
HEC
MC
PVA
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19. Water-insoluble resins
Ethyl cellulose
Polyamide (Nylon)
Polyethylene
Cellulose nitrate
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20. Waxes and lipids
Paraffin
Carnauba
Beeswax
Stearic acid
Stearyl alcohol
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21. Physicochemical Properties of Drug
Candidate:–
DoseDose
sizesize
DoseDose
sizesize
Molecular size Molecular size
and diffusivityand diffusivity
Molecular size Molecular size
and diffusivityand diffusivity
Protein bindingProtein binding Protein bindingProtein binding
Drug Drug
stabilitystability
Drug Drug
stabilitystability
Partition Partition
coefficientcoefficient
Partition Partition
coefficientcoefficient
Aqueous Aqueous
solubility and pka solubility and pka
Aqueous Aqueous
solubility and pka solubility and pka
Physicochemical Physicochemical
propertiesproperties
Physicochemical Physicochemical
propertiesproperties
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22. Physicochemical properties:–
1)Aqueous solubility & PKaː–

Aqueous solubility–
ː
A drug with good aqueous solubility,
especially if pH independent, serves as a
good candidates
Drug to be absorbed it first must dissolve in
the aqueous phase surrounding the site of
administration and then partition into
absorbing membrane.
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23. Contd..
Noyes Whitney Equation
dc = K
D
AC
s
dt
where ,dc/dt= dissolution rate.
KD = Dissoltion rate constant.
A = total surface area of drug.
Cs = aqueous saturation solubility.
Drugs with low aqueous solubility have low dissolution rate and have oral bioavailability problems.
E.g.: Tetracycline.
 Drugs with high aqueous solubility are undesirable to formulate SRDF’s.
E.g.: Paraacetamol
.
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24. PKa–
ː
The aqueous solubility of weak acids & weak
bases is governed by the pKa of the compound
and pH of the medium.
FOR WEAK ACID
St = So(1+Ka\[H ] =So(1+10pH-pKa)
where, St – Total solubility of the weak acid
So – Solubility of the un-ionized form
Ka – Acid dissociation constant
H - Hydrogen ion concentration
Weakly acidic drug exist as unionized form in
the stomach absorption is favored by acidic
medium.
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25. FOR WEAK BASES
S
t
= S
o
(1+[H ] \Ka) =S
o
(1+pKa-pH)
Where, St

– Total solubility of both
conjugate and free base form of weak base.
S
o
– Solubility of the free base.
Weakly basic drug exists as ionized form in the
stomach hence absorption of this type is poor in
this medium .
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26. 2) Partition coefficient–
ː

Between the time a drug is administered and is
eliminated from the body, it must diffuse through
a variety of biological membranes.
•Oil/Water partition coefficient plays a major role
in evaluating the drug penetration.
K=Co/Cs
where, Co= Equilibrium concentration in organic phase.
Cs= Equilibrium concentration in aqueous phase.
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27.  According to ‘Hanch correlation’ a parabolic relationship
between the log of its partition coefficient has with that of the
log of its activity or ability to be absorbed.
Drugs with extremely high partition coefficient are very
oil soluble and penetrates in to various membranes very
easily.
Log K
L
o
g

a
c
t
i
v
i
t
y
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28. Contd……..
There is an optimum partition coefficient for a drug in which it
permeates membrane effectively and shows greater activity.
Partition coefficient with higher or lower than the optimum are
poorer candidates for the formulation
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29. Contd……..
Values of partition coefficient below optimum result in the
decreased lipid solubility and remain localized in the first aqueous
phase it contacts.
Values larger than the optimum , result in poor aqueous
solubility but enhanced lipid solubility and the drug will not
partition out of the lipid membrane once it gets in.
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30. 3) Drug stability–
ː

Solid state undergoes degradation at much slower rate than
in the suspension or solution etc..
 Drugs stable in stomach gets released in stomach and which
are unstable gets released in intestine.
 Drugs with stability problems in any particular area of G.I.T
are less suitable for the formulation.
 Drugs may be protected from enzymatic degradation by
incorporation in to a polymeric matrix.
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31. 4) Protein binding–
ː

Drug binding to plasma proteins (albumins) & resulting retention of
the drug in the vascular space.
Drug -protein complex can serve as a reservoir in vascular
space.
Main forces for binding are Vander Waal forces, hydrogen
bonding , electrostatic forces.
Charged compounds has greater tendency to bind proteins
than uncharged ones.
Extensive binding of plasma proteins results in longer half-life
of elimination for the drug.
E.x..95% binding in Amitriptyline , diazepam , diazepoxide.
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32. 5) Molecular size & diffusivity–
ː

The ability of a drug to diffuse through
membranes is called diffusivity which is a
function of molecular weight.
In most polymers it is possible to relate log
D to some function of molecular size as,
Log D = - Sv log v + Kv = - S
M
log M + Km
where,V – Molecular volume.
M – Molecular weight.
Sv, Sm, Kv & Km are constants.

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33. The value of D is related to the size and shape
of the cavities, as well as the drugs.
The drugs with high molecular weight show
very slow kinetics.
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34. 6) Dose size–
ː

For those drugs requiring large conventional doses, the
volume of sustained dose may be too large to be practical.

The compounds that require large dose are given in
multiple amounts or formulated into liquid systems.
 The greater the dose size,greater the fluctuation.
 So the dose should have proper size.
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35. Name Marketer Dosage form Indication
Carbotrol
Glucotrol Xl
Adderall XR
Procardia Xl
Ortho Evra
Dura gesic
Shri Us
Pfizer
Shri US
Pfizer
Ortho – Mcneil
Janssen
Oral capsule
Oral TabletOral Tablet
Oral Capsule Oral Capsule
Oral TabletOral Tablet
Trans Dermal PatchTrans Dermal Patch
Trans Dermal PatchTrans Dermal Patch
Epilepsy
Hyperglycaemia
ADHD
Angina / Hypertension
Contraceptive
Chronic pain
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36. REFERENCE–
ː
1) Remington’s pharmaceutical sciences.
2) Sustained and controlled release systems.
-James W Robinson.
3) Theory and Practice of Industrial
Pharmacy.
-Lachmann and Liebermann.
4) Biopharmaceutics And Pharmacokinetics A
Treatise. - D.M. Brahmankar.
5) www.google.com
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