Transcript SUSTAINED RELEASE FORMULATIONS Prof. Dr. Basavaraj K. Nanjwade M. Pharm., Ph.

SUSTAINED RELEASE FORMULATIONS
Prof. Dr. Basavaraj K. Nanjwade M. Pharm., Ph. D
Department of Pharmaceutics
KLE University’s College of Pharmacy, Belgaum- 590010, Karnataka, India
Cell No: 0091 9742431000
E-mail: [email protected]
1
Introduction
Concept
Advantages and disadvantages
Physicochemical properties
Biological properties
2
The period between 1950 to 1970 is considered as
period of Sustained drug release.
The main AIM of preparing sustained release
formulation’s was intended to modify and improve the
drug performance by
 Increasing the duration of drug action.
 Decreasing the frequency of dosing.
 Decreasing the required dose employed.
 Providing uniform drug delivery.
3
DEFINITIONS: SRF’s describes the slow release of a drug
substance from a dosage form to maintain
therapeutic response for extended period (8-12hrs)of
time. Time depends on the dosage form. In oral form
it is in hours, and in parenteral’s it is in days and
months. Ex: Aspirin SR, Dextrim SR.
 Controlled release dosage form: In this the rate or
speed at which the drug is released is controlled.
Ex: Adalat CR (Nifidipine), Dynacirc CR (Isradipine.)
4
The
of SRDF’s is to obtain Zero order
release from the dosage form.
Zero order release is a release which is
independent of the amount of drug present in the
dosage form.
Usually SRDF’s do not follow zero order release
but they try to mimic zero order release by
releasing the drug in a slow first order fashion.
Pharmacological action is seen as long as the drug
is in therapeutic range, problems occur when drug
concentration is above/below therapeutic range.
5
ORAL
PARENTRALS
Pellets
Capsules
Solutions
Suspensions
suspensions Tablets
Slow
Repeat
release action
Mixed
Multilayer Porous Osmotic
release granules inert
system
granules
carrier
Ion
Slightly
exchange soluble
resin
salts
complexes
6
 Improved patient compliance:
 Less frequent dosing
 Allows whole day coverage.
 Decreased local and systemic side effects.
 Decreased GIT irritation.
 Decreased local inflammation.
 Better drug utilisation.
 Decreased total amount of drug used.
 Minimum drug accumulation on chronic dosing.
 Improved efficiency in treatment.
 Uniform blood and plasma concentration.
 Decreased fluctuation in drug level i.e uniform pharmacological
response.
 Increased bioavailability of some drugs
 Special effects: SR Aspirin gives symptomatic relief in Arthritis
after waking
 Economy
7
 DOSE DUMPING :Increase quantity of drug release causes
dumping of drug which in turn leads to toxicity.
 REDUCED POTENTIAL FOR ACCURATE DOSE
ADJUSTMENT: Administrating a fraction of drug is not possible.
 NEED FOR ADDITIONAL PATIENT EDUCATION:
“Do not Crush or Chew the dosage unit”.
“ Tablet residue may appear in stools”.
 STABILITY PROBLEMS: The complexity of SRF’s will lead to
stability problem.
 REDUCTION IN SYSTEMIC AVAILABILITY: Example
Theophylline, Procainamide and vitamin combinations.
8
 Retrieval of the drug is difficult in case of toxicity / poisoning /
hypersensitive reaction.
 Higher cost of the formulation.
 Half life: Drugs having shorter half life (less than one hour) and
drugs having longer half life (More than twelve hrs) cannot be
formulated as SRDF’s.
 If a dosage form contains more than 500mgs., of active
ingredient formulation of SRDF’s is difficult.
 If CRDF is required (With New polymers) cost of government
approval is very high.
9
 DRUG PROPERTIES: Stability, solubility, partition coefficient
and protein binding are to be considered.
 ROUTE OF DRUG DELIVERY: Area of the body where drugs
are applied or administered play a vital role.
 TARGET SITES: To minimize side effects, its desired to
maximize the fraction of dose applied.
 ACUTE OR CHRONIC DOSING: Cure, Control and length of
drug therapy must be considered.
 THE DISEASE: Pathological conditions play a significant role.
 THE PATIENT: Ambulatory/ bedridden, young or old, etc., must
be considered.
10
 AQUEOUS SOLUBILITY & pKa
 PARTITION COEFFICIENT
 DRUG STABILITY
 PROTEIN BINDING
 MOLECULAR SIZE & DIFFUSIVITY
 DOSE SIZE
11
AQUEOUS SOLUBILITY
For a drug to be absorbed, it must first dissolve in the
aqueous phase surrounding the site of administration.
 AqS of a drug influences its dissolution rate which in turn
establishes its concentration in solution.
 Dissolution
rate is related to AqS solubility as shown by
Noyes Whitney equation under sink condition( CGIT»C)
dc/ dt= KD ACS
dc/ dt- dissolution rate
KD - dissolution rate constant
A- Total surface area of drug particles.
CS- Aqueous saturation solubility.
12
 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.: Aspirin.
13
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)
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
14
FOR WEAK BASES:
St = So(1+[H ] \Ka) =So(1+pKa-pH)
St – Total solubility of both conjugate and free base form
of weak base.
So– 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.
15

PARTITION COEFFICIENT
 Between the time of drug administration & elimination it diffuse
through several membranes ( Lipid barrier’s)
 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.
 Drugs with extremely high partition coefficient are very oil
soluble and penetrates in to various membranes very easily.
16
Contd………..
Log activity
 The relationship between tissue penetration and partition
coefficient for the drug is known as Hansch Correlation.
Log K
The activity of the drug is a function of its ability to cross
membranes
and
interact
with
receptors.
The
more
effectively the drug crosses the membrane the greater is the
activity
17
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
Unionized water soluble are highly absorbed from the intestine
and lipid soluble drugs are absorbed from the tissue.
18
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.
19
 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.
20
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
21
E.x..95% binding in Amitriptyline , diazepam , diazepoxide.
The ability of the drug to diffuse through a
membrane is called diffusivity (Diffusion coefficient).
It is the function of its molecular size (molecular
weight).
In most polymers it is possible to relate log D
to some function of molecular size as,
Log D = -Svlog V + Kv = -Smlog M+ Km
22
Contd...,
V – Molecular volume.
M – Molecular weight.
Sv, Sm, Kv & Km are constants
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.
23
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.
 For oral route the volume of product is limited by patients.
For IM,IV or SC routes its tolerated.
24
ABSORPTION
DISTRIBUTION
METABOLISM
ELIMINATION & HALF LIFE
SIDE EFFECTS & MARGIN OF SAFETY
ROLE OF DISEASED STATE
ROLE OF CIRCADIAN RHYTHM
25
The release of a drug from a dosage form is important than
its absorption.
The reason of poor absorption are poor water solubility, low
partition coefficient, acid hydrolysis and metabolism.
For SRDF’s rate of release is much slower than the rate
of absorption.
Transit time of drug is between 9-12hrs.
Maximum absorption half-life should be 3-4hr.
26
Continued..
 Low density pellets, capsules or tablets are formulated which
float on top of gastric juice and delay their transfer out of
stomach e.g. PABA
 GI retention for drugs with poor absorption can be increased
by enhancers.
 Bioadhesive materials is made which has high affinity to the
mucin coat.
 A drug that is slowly absorbed is poor candidate for SRDF
eg.,Gentamycin, Hexamethonium
27
Distribution of drugs in to vascular & extra vascular spaces is an
important factor.
Apparent volume of distribution & drug concentration in tissue to
that of plasma at steady state are important parameters for
distribution. It is called T\P ratio.
Calculation of this distribution is mainly based on one
compartment pharmacokinetic models.
It is given by..
V= Dose\Co
Co–Initial concentration immediately after i.v bolus injection
28
 For two compartment models, the total volume of distribution
is given by the apparent volume of the distribution at steady state
Vss = (1+K12\K21)V1
Where.
V1 - Volume of the central compartment
K12-Rate constant for distribution of the drug
from central compartment to peripheral
K21 - Peripheral to the central compartment
blood or plasma to the total volume.
29
Metabolic conversion of drug to another chemical form.
Factors associated with metabolism are;
Ability of drug to induce or inhibit enzyme synthesis. This
results in fluctuating drug blood level with chronic dosing.
Fluctuating drug blood level due to intestinal metabolism or
through a hepatic first pass effect. Ex.., intestinal metabolism
upon oral dosing are hydralazine , salicylamide , nitroglycerine.
30
Rate of elimination of the drug is described quantitatively by its
biological half life i.e.. T1/2.
The half life of the drug is related to its apparent volume of
distribution and its systemic clearance.
t1/2 = 0.693V/CLs = 0.693 AUC/dose
31
Contd...
A drug with shorter half life requires frequent dosing.
Drugs with half life 2hr should not be used ,since such system
requires unexpectedly large release rate and large doses.
E.x.., Ampicillin , Cephalosporin
Drugs with half life greater than 8 hrs should not be used,
formulation of such drugs is unnecessary.
E.x.., Diazepam, Digitoxin , Digoxin
32
SRDF is useful in minimizing the side effects of the drug.
Slow release potassium – SR of potassium to prevent gastric
irritation. Timed release of aspirin – to prevent gastric irritation.
Measure of margin of safety of the drug is THERAPEUTIC INDEX(TI).
TI = TD50\ED50
TD50 = median toxic dose
ED50 = median effective dose.
For potent drugs TI value is small. Larger the value of TI safer the
drug.
Drugs with small value of TI are poor candidates for the formulation.
A drug is considered to be relatively safe if TI exceeds 10.
Some drugs of TI less than 10 are Digitoxin, Digoxin and
Phenobarbitone.
33
Different methods used are..
 BASED ON DRUG MODIFICATION.
 BASED ON DOSAGE FORM MODIFICATION.
34

BASED ON DRUG MODIFICATION:
COMPLEX FORMATION
DRUG-ADSORBATE PREPARATION .
PRO DRUG SYNTHESIS.
ION EXCHANGE RESINS.
35

Complex formation:
The rate of dissolution of solid complex in biological fluids
and rate of dissociation of complex in the solution are considered
and they depend upon pH and composition of gastric and
intestinal fluids.
Drug-adsorbate preparation:
In this product is insoluble. Drug availability is determined
by rate of disabsorption.
Pro drug synthesis:
They are inactive and need enzymatic hydrolysis for
regeneration. Solubility, absorption rate of prodrug must be lower
than parent drug.
36

Ion exchange resins:
They are water insoluble, cross linked polymers
containing salt forming groups. The drug is bound to the resin
by using chromatographic column or by prolonged contact.
Drug release from this complex depends on pH &
property of resin. Drug that is attached to the resin is released
by exchanging with the ions present in the GIT.
Resin+ -Drug- +X-
Resin+- X- + Drug-
Example: Biphetamine.
37

BASED ON DOSAGE FORM MODIFICATION.
 Microencapsulation:
It’s a process in which tiny particles are surrounded by
uniform coating (microcapsule) or held in a matrix of polymer
(microsphere.) Spray drying is used which involves rapid
evaporation of the solvent from the drug surface.
 Barrier coating:
In this one quarter of the granules are in non sustained
form for sudden drug release, remaining part are coated for
sustained release. Both these granules are filled in hard gelatin
capsule or compressed in a tablet, and the release mechanism is
by diffusion. Coating material used are fats, waxes.
38
 Matrix embedding: Drug is dispersed in a matrix of retardant
material which may be encapsulated or compressed in a tablet.
39
Name
Marketer
Dosage form
Indication
Carbotrol
Shri Us
Oral capsule
Epilepsy
Glucotrol Xl
Pfizer
Oral Tablet
Hyperglycaemia
Adderall XR
Shri US
Oral Capsule
ADHD
Procardia Xl
Pfizer
Oral Tablet
Angina / Hypertension
Ortho Evra
Ortho – Mcneil
Trans Dermal Patch
Contraceptive
Dura gesic
Janssen
Trans Dermal Patch
Chronic pain
40
1) Text book of Sustained release dosage form by Y.S.Robinson,
Decker Series.
2) Controlled release dosage form by Y.W.Chien.
3) Ansel’s Pharmaceutical Dosage forms and Drug delivery
Systems.
4) Tutorial Pharmacy by Cooper and Gunns.
5) Remington’s Pharmaceutical Sciences
6) Text book of Pharmaceutics by Bentley and Drivers.
7) www.google.co.in (CRDF design- google book result- cherngjukin).
8) Text book of Pharmaceutical Sciences by Aulton.
41
42
43