EXTENDED-RELEASE ORAL DOSAGE FORMS Presented by:Zelica Trina Santos
Extended-Release Dosage Form
Consider: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 & excreted
Characteristics of Extended-Release Products:
• Exhibit neither very slow nor very fast rates of absorption & excretion
Not necessary:
Drug w/ slow rates of absorption & excretion
Poor candidates: Drugs w/ short half lives, less than 2 hours Drugs 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 rates
Characteristics of Extended-Release Products:
• Administered in relatively small doses
Not suitable:Drugs w/ large single doses
Characteristics of Extended-Release Products:
• Posses a good margin of safetyTherapeutic 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 indices
Characteristics 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
EXTENDED-RELEASE TECHNOLOGY FOR ORAL DOSAGE FORMS
• Extended drug action achieved by:
Affecting the rate (drug release from dosage form)Slowing the transit time of dosage form through g.i.t
EXTENDED-RELEASE TECHNOLOGY FOR ORAL DOSAGE FORMS• Technologies
– modify rate of drug release from solid dosage forms
Based on:a) Modifying drug dissolution by controlling access of
biologic fluidsb) Controlling drug diffusion rates from dosage formsc) Chemical reaction/interaction between the drug
substance of its pharmaceutical barrier & site-specific biologic fluids
COATED BEADS, GRANULES, & MICROSPHERES
• Drug distributed onto:BeadsPelletsGranules Other particulate
systems
Commercial Examples• Toprol-XL® (metoprolol succinate) tabs. (Astra);
• Indocin SR ® (indomethacin capsules (Merck);
COATED BEADS, GRANULES, & MICROSPHERES
• Conventional 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, & MICROSPHERES• Large dose
• starting granules may be composed of drugs itself
• Uncoated granules• immediate 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, & MICROSPHERES
• Colored coating• Distinguish granules/beads of different coating thickness
• Place in capsules/ formed into tablets• Properly blended granules
COATED BEADS, GRANULES, & MICROSPHERES• Various commercial aqueous coating systems use:
Ethylcelluloseplasticizer
Surelease [Colorcon] Aquacoat [FMC Corporation]
“Aqueous coating systems eliminates hazards & environmental concerns”
COATED BEADS, GRANULES, & MICROSPHERES• Thicker coat
• more resistant to penetration• more delayed drug release & dissolution
• Coated beads• 1mm in diameter• Combined 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) capsule
MULTITABLET SYSTEM• Preparation of small spheroid compressed tablets 3-4mm
in diameter • To have varying drug release characteristics
• Then, may be placed in gelatin capsule shells- To provide the desired pattern of drug release
• Each capsule- 8-10 minitablets- Some uncoated = immediate release- Some coated = extended drug release
MICROENCAPSULATED DRUG• Microencapsulation
- A 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 1930s- Cleaner 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 DRUG• Gelatin
Common wall forming material, and synthetic polymer such as:Polyvinyl alcoholEthylcellulosePolyvinyl chloride
MICROENCAPSULATED DRUG• Typical encapsulation process:
1. Dissolve the wall material Gelatin in water
2. Addition of material to be encapsulated 3. Two-phase mixture thoroughly stirred4. Addition of a solution of a 2nd material to the desired particle
size of the material to be encapsulated Usually Acacia Additive material – concentrates the gelatin (polymer) into tiny
liquid droplets Droplets(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 DRUG• Final 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 DRUG• Advantage:
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)