Controlled Release Oral

Drug Delivery System

2
Contents
Overview of Digestive system
Introduction
Advantages
Disadvantages
Mechanisms
1.Dissolution
2.Diffusion
3.Combination of Dissolution & Diffusion
4.Osmotic pressure controlled system
References
3
Digestive System
4
Concept
Controlled drug delivery is one which
delivers the drug at a predetermined rate,
for locally or systemically, for a specified
period of time.
Continuous oral delivery of drugs at
predictable & reproducible kinetics for
predetermined period throughout the
course of GIT.
S
Plasma concentration time profile
6
Challenges in Oral
Drug Delivery
Development of drug delivery system
Delivering a drug at therapeutically effective rate to
desirable site.
Modulation of GI transit time
%ransportation of drug to target site.
Minimization of first pass elimination
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Advantages
Total dose is low.
Reduced GI side effects.
Reduced dosing frequency.
Better patient acceptance and compliance.
Less fluctuation at plasma drug levels.
More uniform drug effect
Improved efficacy/safety ratio.
8
Disadvantages
ose dumping.
Reduced potential for accurate dose adjustment.
Need of additional patient education.
Stability problem.
Controlledrelease drug delivery systems (CrDDSs) can be classified
as follows
1. Ratepreprogrammed drug delivery
systems.
2. Activationmodulated drug delivery
systems.
3. Feedbackregulated drug delivery
systems.
4. Sitetargeting drug delivery systems.
RATEPREPROCRANNED DRUC
DEL!vERY SYSTENS
!n this group of CrDDSs, the release of drug molecules from the
delivery systems has been preprogrammed at a specific rate
profile. This is accomplished by system design, which controls
the molecular diffusion of drug molecules in and/or across the
barrier medium within or surrounding the delivery system. Fick's
laws of diffusion are often followed. These CrDDSs can further
be classified as follows:
1. Polymer membrane permeationcontrolled drug delivery
systems.
2. Polymer matrix diffusioncontrolled drug delivery systems.
3. Polymer (membrane/matrix) hybridtype drug delivery systems.
4. Nicroreservoir partitioncontrolled drug delivery systems.
Polymer Nembrane PermeationControlled
Drug Delivery Systems
!n this type of CrDDS, a drug formulation is
either totally or partially encapsulated in a
drug reservoir compartment whose drug
releasing surface is covered by a rate
controlling polymeric membrane. The drug
reservoir can be drug solid particles, a
dispersion of drug solid particles, or a
concentrated drug solution in a liquid or
solidtype dispersing medium.
The release oI drug Irom this type oI CrDDSs should be at a
constant rate (Q/t), which is deIined by the Iollowing
general equation.
Where Km/r and Ka/m are, respectively, the partition
coeIIicients Ior the interIacial partitioning oI drug
molecules Irom the reservoir to the membrane and
Irom the membrane to the aqueous diIIusion layer;
Dm, and Dd are, respectively, the diIIusion coeIIicients in the
rate-controlling membrane with a thickness oI h
m
, and in
the aqueous diIIusion layer with a thickness oI h
d
.
For microporous membrane, the porosity, and tortuosity oI
the pores in the membrane should be included in the
estimation oI D
m
and h
m
CR is the drug concentration in
the reservoir compartment.
Rate controlling factors.
The release of drug molecules from this
type of CrDDS is controlled at a
preprogrammed rate by modulating the
partition coefficient and the diffusivity
of drug molecule and the rate
controlling membrane and the thickness
of the membrane. Several CrDDSs of
this type have been successfully
marketed for therapeutical uses
!n this controlledrelease ocular insert, the drug reservoir
is a thin disc of pilocarpine-alginate complex sandwiched between
two transparent discs of microporous
membrane fabricated from ethylene-vinyl
acetate copolymer. Ocusert system
31/12/2003 Nepal Pharmaceutical Ltd., Nepal
2. Progestasert 2. Progestasert
PIatform
Progesterone in reservoir
with BaSO
4
and siIicone oiI
Rate-controIIing poIymeric
membrane and entry portaI
Therapeutic program: 65g/day
progesterone for one year
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Mechanism aspects of Oral drug
delivery formulation
1.Dissolution : 1.Mutrix
.Incupsolution
2.Diffusion : 1.Mutrix
.Reservoir
3.Combination of both dissolution & diffusion.
4.Osmotic pressure controlled system
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Dissolution Definition:
Solid substances solubilizes in a given
solvent.
Mass transfer from solid to liquid.
Rate determining step: iffusion from solid
to liquid.
Several theories to explain dissolution -
iffusion layer theory (imp)
Surface renewal theory
Limited solvation theory.
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oyes Whitney Equation
dc/dt = k.A (Cs - C )
dc/dt = /h A. (Cs - C)
dc/dt = issolution rate.
k= issolution rate constant (1
st
order).
= iffusion coefficient/diffusivity
Cs = Saturation/ maximum drug solubility.
C =Con. Of drug in bulk solution.
Cs-C=concentration gradient.
h =Thickness of diffusion layer.
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Matrix Type
Also called as Monolith dissolution
controlled system.
Controlled dissolution by:
1.Altering porosity of tablet.
2.ecreasing its wettebility.
3.issolving at slower rate.
First order drug release.
rug release determined by
dissolution rate of polymer.
Examples: imetane extencaps,
imetapp extentabs.
Soluble drug
Slowly
dissolving
matrix
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Encapsulation
Called as Coating dissolution
controlled system.
issolution rate of coat depends
upon stability & thickness of
coating.
Masks
colour,odour,taste,minimising GI
irritation.
One of the microencapsulation
method is used.
Examples: Ornade spansules,
Chlortrimeton Repetabs
Soluble drug
Slowly
dissolving
or erodible
coat
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Diffusion
Najor process for absorption.
No energy required.
Drug molecules diffuse from a region of higher concentration to
lower concentration until equilibrium is attainded.
Directly proportional to the concentration gradient across the
membrane.
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Matrix Diffusion Types
Rigid Matrix Diffusion
Materials used are insoluble plastics such as PVP & fatty
acids.
Swellable Matrix Diffusion
1. Also called as Glassy hydrogels.Popular for sustaining
the release of highly water soluble drugs.
2. Materials used are hydrophilic gums.
Examples : Natural- Guar gum,Tragacanth.
Semisynthetic -HPMC,CMC,Xanthum gum.
Synthetic -Polyacrilamides.
Examples: Glucotrol XL, Procardia XL
2S
Matrix system
Rate controlling
step:
iffusion of dissolved
drug in matrix.
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iguchi Equation
" = E/T (2A.E Cs)Cs.t)
1/2
Where ,
"=amt of drug release per unit surface area at time t.
=diffusion coefficient of drug in the release medium.
E=porosity of matrix.
Cs=solubility of drug in release medium.
T=tortuosity of matrix.
A=concentration of drug present in matrix per unit
volume.
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Reservoir System
Also called as Laminated matrix device.
Hollow system containing an inner core surrounded
in water insoluble membrane.
Polymer can be applied by coating or micro
encapsulation.
Rate controlling mechanism - partitioning into
membrane with subsequent release into surrounding
fluid by diffusion.
Commonly used polymers - HPC, ethyl cellulose &
polyvinyl acetate.
Examples: Nico-400, Nitro-Bid
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Reservoir System
Rate controlling
steps :
Polymeric content in
coating, thickness of
coating, hardness of
microcapsule.
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Dissolution & Diffusion
Controlled Release system
rug encased in a partially soluble
membrane.
Pores are created due to dissolution
of parts of membrane.
It permits entry of aqueous medium
into core & drug dissolution.
iffusion of dissolved drug out of
system.
Ex- Ethyl cellulose & PVP mixture
dissolves in water & create pores of
insoluble ethyl cellulose membrane.
Insoluble
membrane
Pore created by
dissolution of
soluble fraction of
membrane
Entry of
dissolution
fluid
rug
diffusion
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Osmotic Pressure Controlled
Drug Delivery System
efinition
Procedure
iagram
Modifications
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Osmosis
Novement of solvent from lower to higher concentration.
- The passage of solvent into a solution through
semipermeable membrane.
Semipermeable Membrane
Molecules are permitted only to one component
(Water).
Osmotic pressure
It is the hydrostatic pressure produced by a solution
in a space divided by a semipermeable membrane
due to difference in concentration of solutes.
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Osmotic Pressure Controlled
System
Provides zero order release
rug may be osmotically active, or combined with an
osmotically active salt (e.g., NaCl).
Semipermeable membrane usually made from cellulose
acetate.
More suitable for hydrophilic drug.
Examples: Glucotrol XL, Procardia XL,
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Equation
("/t) z = Pw Am/ hm (s-e )
("/t)= Rate of zero order drug release.
Pw, Am & hm= water permeability, effective surface
area & thickness of semipermeable membrane.
s= osmotic pressure of saturated solution of
osmotically active drug or salt in system.
e = osmotic pressure of GI fluid.
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Osmotic Pressure Controlled
System
3S
Osmotic Pressure Controlled
System
Modifications
- Immediate release system.
- Osmotically active compartment system
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Immediate Release System
Activation of system is done.
ividing a dose into two parts.
One third immediate release.
Two third controlled release.
Encapsulated into semipermeable
membrane.
e.g. : Phenyl propanolamine.
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Osmotically active system
Two compartments
separated by movable
partition.
Osmotically active
compartment absorbs
water from GIT.
Creates osmotic
pressure.
Partition moves
upward & then drug
releases.
Ex: Nifedipine.
Movable
partition
elivery orifice
Osmotically active
compartment
rug compartment
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Some Popular Brand names used
for OCDDS
Spansule capsule ( SK & F )
Sequal capsule (Lederle )
Extentab tablets ( Robins )
Timespan tablet ( Roche )
ospan tablet ( Merrell ow )
Chronotab tablet ( Schering )
Plateau capsule ( Marion )
Tempule capsule ( Armour )
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&ome Examples of OCDD&
Propranolol (Inderal LA)
Methyiphenidate HCl (RitalinSR)
Iron (Slow-Fe)
GITS-Prazosin (Minipress)
Morphine sulfate (Roxanol SR)
econgestant & antihistamine (Resaid SR, Novafed SR
ristan)
Pseudoephedrine HCI (Sudafed SA)
Potassium (Micro-K, Slow-K, Klotrix)
Antitussive combinations (Rescap, Ornade Spansules)
Chlorpheniramine maleate (ChlorTrimeton)
econgestant, antihistamine and anticholinergic (allergy,
Supres)
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%ecent Trends : Extended release
formulation of Bupropion
Bupropion is used in the treatment of major depressive
disorder.
Conventional formulation has to be administered 3 times
daily
Initially 150 mg ER formulation was introduced for bid
regimen
Later on 300 mg ER formulation was introduced for once
daily regimen
For ER formulation provide similar Cmax and AUC values
as compared to immediate release formulation at steady
state.
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%ecent Trends : Extended release
formulation of Bupropion
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Recent Trends: OROS Technology
(ALZA corporation)
Single layer tablet: Drug
core (water soluble drug
with or without excipients)
Semipermeable membrane
with a drilled orifice
Water imbibition by the core
because of osmotic action
results in drug dissolution,
which is released at a
controlled rate through the
orifice
Not suitable for water insoluble drugs.
Examples: Sudafed 24
hours (Pseudoephedrine), volmax (Salbutamol)
ELEMETARY OSMOTIC PUMP
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Recent trends: Ceomatrix (SKY Parma)
This technology Controls amount,
timing and location of release in
body.
-Formulation with predictable and
reproducible drug release profile.
-Controls rate of drug diffusion
throughout release process,
ensuring 100% release Products
Products in market:
Cordicant -uno
Madopar R
SULAR ER
4S
References
ovel drug delivery system , volume 50,
Y.W.Chien
The theory & practice of industrial pharmacy,
Leon Lachman , erbert A.Lieberman,
Joseph L.Kanig,3 rd edition.
The Eastern pharmacist, november 1993.
Sustained release drugs, V R.Gudsoorkar & D.Rambhau
page 27-32
Biopharmaceuitics & pharmacokinetics,
D M.Brahmankar & Sunil B. Jaiswal.
www.google.com
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