Controlled Release Oral Drug Delivery System

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Contents

Overview of Digestive system Introduction Advantages Disadvantages

Mechanisms 1.Dissolution 2.Diffusion 3.Combination of Dissolution & Diffusion 4.Osmotic pressure controlled system References

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Digestive System

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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.

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Plasma concentration time profile

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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

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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.

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Disadvantages

Dose dumping.

Reduced potential for accurate dose adjustment.

Need of additional patient education.

Stability problem.

Controlled-release drug delivery systems (CrDDSs) can be classified as follows

1. Rate-preprogrammed drug delivery systems.

2. Activation-modulated drug delivery systems.

3. Feedback-regulated drug delivery systems.

4. Site-targeting drug delivery systems.

RATE-PREPROGRAMMED DRUGDELIVERY SYSTEMS

In 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 permeation-controlled drug delivery

systems.2. Polymer matrix diffusion-controlled drug delivery systems.3. Polymer (membrane/matrix) hybrid-type drug delivery

systems.4. Microreservoir partition-controlled drug delivery systems.

Polymer Membrane Permeation-ControlledDrug Delivery Systems

In 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 solid-type dispersing medium.

The release of drug from this type of CrDDSs should be at a constant rate (Q/t), which is defined by the following general equation.

Where Km/r and Ka/m are, respectively, the partition coefficients for the interfacial partitioning of drug molecules from the reservoir to the membrane and

from the membrane to the aqueous diffusion layer; Dm, and Dd are, respectively, the diffusion coefficients in the

rate-controlling membrane with a thickness of hm, and in the aqueous diffusion layer with a thickness of hd.

For microporous membrane, the porosity, and tortuosity of the pores in the membrane should be included in the estimation of Dm and hm 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

In this controlled-release ocular insert, the drug reservoiris a thin disc of pilocarpine–alginate complex sandwiched between two transparent discs of microporousmembrane fabricated from ethylene–vinylacetate copolymer. Ocusert system

31/12/2009Nepal Pharmaceutical Ltd.,

Nepal

2. Progestasert2. Progestasert

Platform

Progesterone in reservoirwith BaSO4 and silicone oil

Rate-controlling polymericmembrane and entry portal

Therapeutic program: 65µg/dayprogesterone for one year 27

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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

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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.

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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.

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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

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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

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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.

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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

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Matrix system

Rate controlling step:

Diffusion of dissolved drug in matrix.

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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.

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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

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

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Osmotic Pressure Controlled Drug Delivery System

Definition

Procedure

Diagram

Modifications

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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 pressureIt 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

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,

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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.

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Osmotic Pressure Controlled System

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Osmotic Pressure Controlled System

Modifications

- Immediate release system.- Osmotically active compartment system

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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.

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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

Delivery orifice

Osmotically active compartment

Drug 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 ) Dospan tablet ( Merrell Dow ) Chronotab tablet ( Schering ) Plateau capsule ( Marion ) Tempule capsule ( Armour )

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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)

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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.

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Recent 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)

ELEMENTARY OSMOTIC PUMP

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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 DRSULAR ER

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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

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