Transcript Controlled Release Oral Drug Delivery System Dr. Basavaraj K. Nanjwade M.Pharm., Ph.D Professor of Pharmaceutics Department of Pharmaceutics JN Medical College KEL University, Belgaum- 590010, Karnataka, India E-mail:

Controlled Release Oral
Drug Delivery System
Dr. Basavaraj K. Nanjwade
M.Pharm., Ph.D
Professor of Pharmaceutics
Department of Pharmaceutics
JN Medical College
KEL University, Belgaum- 590010, Karnataka, India
E-mail: [email protected]
Cell No: 00919742431000
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
Digestive System
31/12/2009
Nepal Pharmaceutical Ltd., Nepal
3
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.
31/12/2009
Nepal Pharmaceutical Ltd., Nepal
4
Plasma concentration time profile
31/12/2009
Nepal Pharmaceutical Ltd., Nepal
5
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
31/12/2009
Nepal Pharmaceutical Ltd., Nepal
6
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.
31/12/2009
Nepal Pharmaceutical Ltd., Nepal
7
Disadvantages

Dose dumping.

Reduced potential for accurate dose adjustment.

Need of additional patient education.

Stability problem.
31/12/2009
Nepal Pharmaceutical Ltd., Nepal
8
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
31/12/2009
Nepal Pharmaceutical Ltd., Nepal
9
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.
31/12/2009
Nepal Pharmaceutical Ltd., Nepal
10
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.
31/12/2009
Nepal Pharmaceutical Ltd., Nepal
11
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.
31/12/2009
Nepal Pharmaceutical Ltd., Nepal
Soluble drug
Slowly
dissolving
matrix
12
Encapsulation



Called as Coating dissolution
controlled system.
Soluble drug
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
31/12/2009
Nepal Pharmaceutical Ltd., Nepal
Slowly
dissolving
or erodible
coat
13
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.
31/12/2009
Nepal Pharmaceutical Ltd., Nepal
14
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
31/12/2009
Nepal Pharmaceutical Ltd., Nepal
15
Matrix system
Rate controlling
step:
Diffusion of dissolved
drug in matrix.
31/12/2009
Nepal Pharmaceutical Ltd., Nepal
16
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.
31/12/2009
Nepal Pharmaceutical Ltd., Nepal
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
31/12/2009
Nepal Pharmaceutical Ltd., Nepal
18
Reservoir System
Rate controlling
steps :
Polymeric content in
coating, thickness of
coating, hardness of
microcapsule.
31/12/2009
Nepal Pharmaceutical Ltd., Nepal
19
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.
31/12/2009
Nepal Pharmaceutical Ltd., Nepal
Insoluble
membrane
Entry of
dissolution
fluid
Drug
diffusion
Pore created by
dissolution of
soluble fraction of
membrane
20
Osmotic Pressure Controlled
Drug Delivery System

Definition

Procedure

Diagram

Modifications
31/12/2009
Nepal Pharmaceutical Ltd., Nepal
21
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.
31/12/2009
Nepal Pharmaceutical Ltd., Nepal
22
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,
31/12/2009
Nepal Pharmaceutical Ltd., Nepal
23
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.
31/12/2009
Nepal Pharmaceutical Ltd., Nepal
24
Osmotic Pressure Controlled
System
31/12/2009
Nepal Pharmaceutical Ltd., Nepal
25
Osmotic Pressure Controlled
System
31/12/2009
Nepal Pharmaceutical Ltd., Nepal
26
Modifications
- 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.
31/12/2009
Nepal Pharmaceutical Ltd., Nepal
28
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.
31/12/2009
Delivery orifice
Drug compartment
Osmotically active
compartment
Nepal Pharmaceutical Ltd., Nepal
Movable
partition
29
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 )
31/12/2009
Nepal Pharmaceutical Ltd., Nepal
30
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)
31/12/2009
Nepal Pharmaceutical Ltd., Nepal
31
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.
31/12/2009
Nepal Pharmaceutical Ltd., Nepal
32
Recent Trends : Extended release
formulation of Bupropion
31/12/2009
Nepal Pharmaceutical Ltd., Nepal
33
Recent Trends: OROS Technology
(ALZA corporation)
ELEMENTARY OSMOTIC PUMP





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)
31/12/2009
Nepal Pharmaceutical Ltd., Nepal
34
Recent trends: Geomatrix® (SKY Parma)
Products in market:
Cordicant -uno®
Madopar DR
SULAR ER
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
31/12/2009
Nepal Pharmaceutical Ltd., Nepal
35
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.
www.google.com
31/12/2009
Nepal Pharmaceutical Ltd., Nepal
36
Thank you for listening me………
31/12/2009
Nepal Pharmaceutical Ltd., Nepal
37