controlled oral.pptx

Contents
 Overview of Digestive system
 Introduction
 Advantages
 Disadvantages
 Mechanisms
1.Dissolution
2.Diffusion
3.Combination of Dissolution & Diffusion
4.Osmotic pressure controlled system
 References
31/12/2009 Nepal Pharmaceutical Ltd., Nepal 2

 Patient comfort and compliance
 Therapeutic advantage
 Reduction in adverse side effects and improvement in
tolerability
 Reduction in healthcare cost
 Maximum utilization of drug enabling reduction in total
amount of dose administered
WHY CONTROLLED RELEASE

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.

Plasma concentration time profile

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
Transportation of drug to target site.
 Minimization of first pass elimination

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.

Disadvantages
 Dose dumping.
 Reduced potential for accurate dose adjustment.
 Need of additional patient education.
 Stability problem.

Mechanism aspects of Oral drug
delivery formulation
1.Dissolution : 1.Matrix
2.Encapsulation
2.Diffusion : 1.Matrix
2.Reservoir
3.Combination of both dissolution & diffusion.
4.Osmotic pressure controlled system

Dissolution Definition:
 Solid substances solubilizes in a given
solvent.
 Mass transfer from solid to liquid.
 Rate determining step: Diffusion from solid
to liquid.
 Several theories to explain dissolution –
Diffusion layer theory (imp)
Surface renewal theory
Limited solvation theory.

Noyes Whitney Equation
dc/dt = kD.A (Cs – C )
dc/dt = D/h A. (Cs – C)
dc/dt = Dissolution rate.
k= Dissolution rate constant (1st order).
D = Diffusion coefficient/diffusivity
Cs = Saturation/ maximum drug solubility.
C =Con. Of drug in bulk solution.
Cs-C=concentration gradient.
h =Thickness of diffusion layer.

Matrix Type
 Also called as Monolith dissolution
controlled system.
 Controlled dissolution by:
1.Altering porosity of tablet.
2.Decreasing its wettebility.
3.Dissolving at slower rate.
 First order drug release.
 Drug release determined by dissolution
rate of polymer.
 Examples: Dimetane extencaps,
Dimetapp extentabs.
Soluble drug
Slowly
dissolving
matrix

Encapsulation
 Called as Coating dissolution
controlled system.
 Dissolution 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

Diffusion
 Major 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.

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

Matrix system
Rate controlling
step:
Diffusion of dissolved
drug in matrix.

Higuchi Equation
Q = DE/T (2A.E Cs)Cs.t)1/2
Where ,
Q=amt of drug release per unit surface area at time t.
D=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.
17

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
18

Reservoir System Rate controlling
steps :
Polymeric content in
coating, thickness of
coating, hardness of
microcapsule.

Dissolution & Diffusion Controlled
Release system
 Drug 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.
 Diffusion 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
Drug
diffusion

Osmotic Pressure Controlled Drug
Delivery System
 Definition
 Procedure
 Diagram
 Modifications

Osmosis
- Movement 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.

Osmotic Pressure Controlled
System
 Provides zero order release
 Drug 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,

Equation
(Q/t) z = Pw Am/ hm (πs-πe )
(Q/t)= Rate of zero order drug release.
Pw, Am & hm= water permeability, effective surface
area & thickness of semipermeable membrane.
πs= osmotic pressure of saturated solution of
osmotically active drug or salt in system.
πe = osmotic pressure of GI fluid.

System

- Immediate release system.
- Osmotically active compartment system

Immediate Release System
 Activation of system is done.
 Dividing a dose into two parts.
 One third immediate release.
 Two third controlled release.
 Encapsulated into semipermeable
membrane.
e.g. : Phenyl propanolamine.

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
Delivery orifice
Osmotically active
compartment
Drug compartment

Some Popular Brand names used
for OCDDS
 Spansule capsule ( SK & F )
 Sequal capsule (Lederle )
 Extentab tablets ( Robins )
 Timespan tablet ( Roche )
 Dospan tablet ( Merrell Dow )
 Chronotab tablet ( Schering )
 Plateau capsule ( Marion )
 Tempule capsule ( Armour )

Some Examples of OCDDS
 Propranolol (Inderal LA)
 Methyiphenidate HCl (RitalinSR)
 Iron (Slow-Fe)
 GITS-Prazosin (Minipress)
 Morphine sulfate (Roxanol SR)
 Decongestant & antihistamine (Resaid SR, Novafed SR
Dristan)
 Pseudoephedrine HCI (Sudafed SA)
 Potassium (Micro-K, Slow-K, Klotrix)
 Antitussive combinations (Rescap, Ornade Spansules)
 Chlorpheniramine maleate (ChlorTrimeton)
 Decongestant, antihistamine and anticholinergic (Dallergy,
Supres)

Recent 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.

Recent Trends : Extended release formulation of
Bupropion

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)
ELEMENTARY OSMOTIC PUMP

Recent trends: Geomatrix® (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 DR
SULAR ER

Coating technology using various polymers for coating
tablets and granules
Matrix systems made of swellable or nonswellable
polymers
Slowly eroding devices
Osmotically controlled devices.
CURRENTLY MARKECONTROLLED-
RELEASE SYSTEMSTED ORAL

Oral CR
60%
Implant
10%
Inhalation
27%
Transdermal
8%
All Other
2%
US Drug Delivery Market
“Drug delivery market dominated by oral delivery systems”
Source: IMS America - Drug delivery based products

Particulate systems
Chronopharmacokinetic systems
Targeted drug delivery
Mucoadhesive delivery
THE FUTURE

Thank you for listening me………

References
 Novel drug delivery system , volume 50,
Y.W.Chien
 The theory & practice of industrial pharmacy,
Leon Lachman , Herbert 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.
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