er oral df final

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Extended-Release Dosage FormConsider:DrugTherapeutic indication

DRUG CANDIDATES FOR EXTENDED-RELEASE PRODUCTSTo be successful, drug must be: Released from dosage form at predetermined rate

Dissolve in gastrointestinal fluids

Maintained at sufficient gastrointestinal residence time

Be absorbed at a rate that will replace the amount of drug being metabolized & excretedCharacteristics of Extended-Release Products:Exhibit neither very slow nor very fast rates of absorption & excretion Not necessary:Drug w/ slow rates of absorption & excretionPoor candidates:Drugs w/ short half lives, less than 2 hoursDrugs that act by affecting enzyme systems

Characteristics of Extended-Release Products:Uniformly absorbed from g.i.t Drug must have:Good aqueous solubilityMaintain adequate residence time in g.i.t

Poor candidates:Poorly absorbed drugsDrugs at varying & unpredictable ratesCharacteristics of Extended-Release Products:Administered in relatively small doses

Not suitable:Drugs w/ large single dosesCharacteristics of Extended-Release Products:Posses a good margin of safety

Therapeutic Index most widely used measure of the marginTD50/ED50Very potent drugs = narrow/very small therapeutic indexLarger therapeutic index = Safer drug

Poor candidate:Drugs administered in small doses/ possess very narrow therapeutic indicesCharacteristics of Extended-Release Products:Used in the treatment of chronic rather than acute condition

Cause:Drugs for acute condition = greater adjustment of the dosage by physician


Affecting the rate (drug release from dosage form)Slowing the transit time of dosage form through g.i.tEXTENDED-RELEASE TECHNOLOGY FOR ORAL DOSAGE FORMSTechnologies modify rate of drug release from solid dosage forms

Based on:Modifying drug dissolution by controlling access of biologic fluidsControlling drug diffusion rates from dosage formsChemical reaction/interaction between the drug substance of its pharmaceutical barrier & site-specific biologic fluidsCOATED BEADS, GRANULES, & MICROSPHERESDrug distributed onto:BeadsPelletsGranules Other particulate systems

Commercial ExamplesToprol-XL (metoprolol succinate) tabs. (Astra);

Indocin SR (indomethacin capsules (Merck);

COATED BEADS, GRANULES, & MICROSPHERESConventional pan coating / air suspension coating - a solution of drug substance is placed on small inert nonpareil seeds/ beads made of sugar & starch or on microcrystalline cellulose spheres

Nonpareil seeds 425 to 850 um

Microcrystalline cellulose spheres- 170-600 um- more durable during production than sugar-based cores

COATED BEADS, GRANULES, & MICROSPHERESLarge dosestarting granules may be composed of drugs itself

Uncoated granulesimmediate drug release

Varying Coated Granules Lipid materials like beeswax, carnauba wax, glyceryl monostrearate, or cetyl alcohol or a cellulosic material like ethylcellulose

Careful blending of granules w/ different coating thicknesses Provide desired drug-released characteristics

COATED BEADS, GRANULES, & MICROSPHERESColored coatingDistinguish granules/beads of different coating thickness

Place in capsules/ formed into tabletsProperly blended granules

COATED BEADS, GRANULES, & MICROSPHERESVarious commercial aqueous coating systems use:Ethylcelluloseplasticizer

Surelease [Colorcon]Aquacoat [FMC Corporation]Aqueous coating systems eliminates hazards & environmental concerns

COATED BEADS, GRANULES, & MICROSPHERESThicker coatmore resistant to penetrationmore delayed drug release & dissolutionCoated beads1mm in diameterCombined to have 3 or 4 release groups among the more than 100 beads contained in the dosing unit

Provide desired different rates of sustained or extended release & targeting of the coated beads to desired segement of g.i.t

Spansule (SmithKline Beecham) capsuleMULTITABLET SYSTEMPreparation of small spheroid compressed tablets 3-4mm in diameter To have varying drug release characteristics

Then, may be placed in gelatin capsule shellsTo provide the desired pattern of drug release

Each capsule- 8-10 minitablets- Some uncoated = immediate release- Some coated = extended drug release

MICROENCAPSULATED DRUGMicroencapsulationA process by which solids, liquids, or even gases may be enclosed in microscopic particles by formation of thin coating of wall material around the substance

Late 1930sCleaner substitute for carbon paper & carbon ribbons

1950s- Ultimate development of reproduction paper & ribbons that contained dyes in tiny gelatin capsules released on impact by typewriter key or the pressure of a pen/pencil

Stimulus for development of a host of microencapsulated materials. Including drugs

MICROENCAPSULATED DRUGGelatinCommon wall forming material, and synthetic polymer such as:Polyvinyl alcoholEthylcellulosePolyvinyl chloride

MICROENCAPSULATED DRUGTypical encapsulation process:Dissolve the wall materialGelatin in waterAddition of material to be encapsulated Two-phase mixture thoroughly stirredAddition of a solution of a 2nd material to the desired particle size of the material to be encapsulatedUsually Acacia Additive material concentrates the gelatin (polymer) into tiny liquid dropletsDroplets(coacervate) - Form a film/coat around the particles of the substance to be encapsulated - Consequence of low interfacial tension of residual water/solvent in the wall material- To have continuous tight film coating

MICROENCAPSULATED DRUGFinal Dry Microcapsules:Free flowing discrete particles of coated materialWall material 2% to 20% of total particle weight

To obtain different rates of drug release:Change ratio of core to wall, the polymer used for coating, and method of microencapsulation

MICROENCAPSULATED DRUGAdvantage:Administered dose of drug is subdivided into small units that are spread over a large area of the g.i.t

Enhance absorption by diminishing local drug concentration

Potassium Chloride (Micro-K Extencaps, A.H. Robins)