Contolled Relese Dosage Forms

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ORAL CONTROLLED RELEASE DRUGDELIVERY SYSTEMS


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The majority of oral controlled release systems rely on dissolution, diffusion, or a

combination of both mechanisms to generate slow release of drug to the

gastrointestinal milleu.

A. DISSOLUTION CONTROLLED RELEASE:Sustained release oral products employing dissolution as the rate-limiting step

are in principle the simplest to prepare.

1. Encapsulation dissolution control:These methods generally involve coating individual particles or granules of drug

with a slowly dissolving material.

The coated particles can be compressed directly into tablets as in Spacetabs orplaced in capsules as in the Spansule Products.

Since the time required for dissolution of the coat is a function of its thickness

and aqueous solubility, one can obtain repeat or sustained action by employing anarrow or a wide spectrum of coated particles of varying thicknesses respectively


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2. Matrix dissolution control:An alternative approach is to compress the drug with a slowly dissolving

carrier of some sort into a tablet form. Here, the rate of drug availability is

controlled by the rate of penetration of the dissolution fluid into the matrix.

This, in turn, can be controlled by porosity of the tablet matrix, the presence of

hydrophobic additives, and the wettability of the tablet and particles surface.

B. DIFFUSION CONTROLLED RELEASE:There are basically two types of diffusion controlled systems which have

been developed over the past two decades, reservoir devices and matrixdevices.


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1. Reservoir devices:In this system, a water-insoluble polymeric material encases a core of

drug.

Drug will partition into the membrane and exchange with the fluid

surrounding the particle or tablet.

Additional drug will enter the membrane, diffuse to the periphery, and

exchange with the surrounding media.


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2. Matrix devices:In this system, a solid drug is dispersed in an insoluble matrix.

The rate of drug release is dependent on the rate of drug diffusion but

not on the rate of solid dissolution.


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C. DIFFUSION AND DISSOLUTION CONTROLLED SYSTEMS:The main feature of this system is that the drug core is enclosed with a

partially soluble membrane.

Dissolution of part of the membrane allows for diffusion of the contained

drug through pores in the polymer coat.


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D. ION-EXCHANGE RESINS:Resins are water-insoluble materials containing anionic or cationic

groups in repeating positions on the resin chain.

The drug-charged resin is prepared by mixing the resin with drug

solution either by repeated exposure of the resin to the drug in a

chromatographic column or by keeping the resin in contact with the drug

solution for extended periods of time.

Polymer- coated drug-resin design Polymer- coated drug-resindispersion

Th d i i th h d t t i t i d d i d t f


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The drug-resin is then washed to remove contaminant ions and dried to form

particles or beads.

When a high concentration of an appropriately charged ion is in contact with

the ion-exchange group, the drug molecules is exchanged and diffuses out of the

resin to the bulk solution.

E. pH - INDEPENDENT FORMULATIONS:The granules are designed for the oral controlled release of basic or acidic

drugs at a rate that is independent of the PH in the GI tract.

They are prepared by mixing a basic or acidic drug with one or more

buffering agents, granulating with appropriate pharmaceutical excipients, andfinally, coating with a gastrointestinal fluid permeable film-forming polymer.

When the GI fluid permeates through the membrane, the buffering agents

adjust the fluid inside to a suitable constant pH, thereby rendering a constant rateof dru release.


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F. OSMOTICALLY CONTROLLED RELEASE:In this type of drug delivery systems, osmotic pressure is the driving

force that generates constant drug release.

This system is fabricated by applying a semipermeable membrane

around a core of an osmotically active drug or a core of an osmotically inactive

drug in combination with an osmotically active salt.

A delivery orifice is drilled in each system by laser or by a high speed

mechanical drill.

The elementary osmoticpump

Osmotic pressure-controlled drug deliverysystem with compartments separated by amovable partit ion


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G. ALTERED DENSITY FORMULATIONS:It is reasonable to expect that unless a delivery system remains in the

vicinity of the absorption site until most, if not all of its drug contents is

released, it would have limited utility.

To this end, several approaches have been developed to prolong the

residence time of drug delivery systems in the GI tract.

One such approach is the bioadhesion approach, which is based on the

adherence of bioadhesive polymers to the mucin / epithelial surface of the GI

tract.

The other approach is to alter the formulations density by using either

high or low density pellets.


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1. High density approach:In this approach, the density of the pellets must exceed that of normal

stomach content and should therefore be at least 1.4.

In preparing such formulations, drug can be coated on a heavy core or

mixed with heavy inert materials such as barium sulfate, titanium dioxide, iron

powder, and zinc oxide.

The weighed pellet can then be covered with a diffusion controlled

membrane.


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2. Low-density approach:Globular shells which have an apparent density lower than that of gastric

fluid can be used as carrier of drug for sustained release purposes.

Polystyrol, poprice, and even popcorn are all candidates as carriers. The

surface of these empty shells is undercoated with sugar or with a polymeric

material such as methacrylic polymer and cellulose acetate phthalate.

Drug delivery system with flotationchamber


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The undercoated shell is then coated by a mixture of drug with polymers

such as ethyl cellulose and hydroxy propyl cellulose.

The final product floats on the gastric fluid for a prolonged period, while

slowly releasing drug.

TYPES OF TABLETS:1. MATRIX TABLETS:There are three types of matrix tablets

1. Hydrophilic matrices 2. Plastic matrices

3. Fatwax matrices


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2. ION-EXCHANGE RESIN TABLETS:The tablets are commonly developed by embedding the drug molecules

in the ion-exchange resin matrix and then this core is coated with a semipermeable coating material such as ethyl cellulose.

The most widely used and safe ion exchange resin is divinyl benzene

sulphonate.

Drugs that were prepared using cationic exchange resins include

codeine, ephedrine.


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3. FILM COATED TABLETS:Simple coating of the tablets by the polymers can control the dissolution

rate of drug from the tablets.

Various polymers such as H.P.M.C, E.C & Eudragit polymers have been

used for the polymeric film coating of the tablets. These polymer coatings act

as diffusion controlling membranes.

The selection of coating material will decide the dissolution rate of the

drug molecules.

Plasticizers also accelerate the drug release.


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4. FLOATING TABLETS:Floating tablets can be used for local action in the proximal G.I.T.

Poorly soluble and unstable as well as poorly absorbable drugs are suitable

for floating dosage units.

These systems are retained in the stomach for prolonged time due to their

floating property.

Floating dosage forms have been developed to float over G.I fluids &to

release the drug over a desired period of time.

Increased G.I time is the consequent property of floating tablets.

Drugs suitable to be formulated as floating tablets

--morphine

--captopril

--diazepam


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5. ENTERIC COATED &DELAYED RELEASE TABLETS:The materials used for enteric coating are acid impermeable polymers.

An ideal enteric coating should dissolve at a pH slightly lower than 7.

Various solvents such as alcohol, acetone, and methylene chloride have been

used to dissolve the enteric coating polymers.

Ex: 1. Aspirin given as enteric coated tablets prevents gastric irritation.

2. Erythromycin degrades in gastric pH. Hence, it is given as prodrug/enteric

coated formulation. The enteric coating formulation needs higher pH 6.5-7.0 for

disintegration of coating, which delays the release of erythromycin beyond the

absorption site.

Here, efficacy of formulation depends on selection of suitable polymer.


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6. OSMATIC TABLETS:The osmotic tablets are comprised of a drug contained in a rigid, semi

permeable membrane in which an aperture is created by a mechanical drill or laser

beam.

These systems are suitable for the soluble drugs such as indomethacin &

metoprolol.

Semi permeable polymers such as cellulose acetate & polyurethane are

commonly used for osmotic tablet formulations.

7. MUCOADHESIVE TABLETS:They are developed for administration of drug to the oral cavity.

Buccal & sublingual mucosa offer for mucoadhesion.

Drug can be applied locally and removed.

Synthetic polymers including cellulose derivatives & polyacrylic acid are usedfor re aration of bioadhesive tablets.


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8. SWELLABLE TABLETS:The dosage forms can be developed in a size, which can be swallowed &

when they reach the stomach fluid swell quickly & attain considerably large

size.

In addition to swelling, gel forming property of the polymer can retain

the drug molecules within the dosage form thereby sustaining the release of

drug from the formulation.

9. MULTIPLE UNIT TABLETS:They contain subunits that are homogenous or heterogenous

They are prepared by combining the immediate release portion &

controlled release portion.


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10. MICROCAPSULES & MICROSPHERES:The mechanism of drug release is either dissolution or diffusion of the

drug & the formulation are either microencapsulated or matrix

Various methods including interfacial polymerization,

coacervation/phase separation are used to prepare micro particles.

The coating material should be selected depending on the material to

be coated & the release characteristics desired.


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EVALUATIONDISSOLUTION RATE - ASSESSMENT:

DEMONSTRATION OF SAFETY AND EFFICACY OF CONTROLLEDRELEASE DRUGS:

1. For drugs that have been approved by the FDA as safe and effectivein conventional dosage forms, the Food and Drug Administration has takenthe position that controlled clinical studies may be required to demonstrate

the safety and efficacy of the drugs (already approved for use in conventional

forms) in the controlled release formulations. In any case, bioavailability data

for the drug (s) in the controlled release formulation are required.

2. For drugs that have been previously approved as safe and effectivein controlled release dosage forms, data are required to establish

bioavailability comparability to an approved controlled release drug product.

Single dose bioavailability studies are acceptable for determining the


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3. Single dose bioavailability studies are acceptable for determining thefraction of the amount absorbed, lack of dose dumping, lack of food effects.

etc. Pharmacokinetic studies, performed under study state conditions, are

acceptable to demonstrate comparability to an approved immediate release

drug product, occupancy time with in a therapeutic window, percent

fluctuation, etc, and are acceptable for supporting dosage administration

labeling.

4. The optimum single dose study would be a three way cross overcomparing a rapidly available dosage form and the controlled release dosage

form under fasting conditions with the controlled release form administered

immediately after the ingestion of high fat meal. If significant differences are

found in AUC and peak concentrations as a function of the meal, it is necessaryto define the cause of the food effect.

With drugs having a narrow therapeutic index, it might be necessary to

carry out more extensive plasma concentration measurements in patients to

determine the potential for unusual drug release patterns.


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1. Biopharmaceutical considerations:The invitro test was desirable for the purposes of

A. Providing necessary process control and stability determinations of therelevant release characteristics.

B. Facilitating certain regulatory determinations and judgments, concerningminor formulation changes, site of manufacturing change, etc.

The key elements for the dissolution are:

1. Reproducibility of the method.

1. Proper choice of media.

2. Maintenance of sink conditions

3. Control of solution hydrodynamics.

4. Dissolution rate as a function of pH ranging from pH 1 to pH 8,

5. Selection of the most discriminating variables as the basis for the dissolutiontest and specification.


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The dissolution procedure should establish:

1. Lack of dose dumping indicated by a narrow limit on the onehour dissolution specification.

2. Controlled release characteristics by employing additionalsampling windows overtime.

3. Complete drug release indicated by a 75 80 % minimum releasespecifications at the last sampling interval.

4. Dosage form pH dependence / independence indicated by percentdissolution in water, appropriate buffer, gastric and simulated intestinal fluid.


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Invivo bioavailabil ity data:

A. General:

B. Specific types of in vivo studies:

1. Fasted single dose studies:

2. Post prandial study:

3. Multiple dose study state studies:

Contolled Relese Dosage Forms

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