Extended-Release Dosage Form Consider: Drug Therapeutic indication DRUG CANDIDATES FOR EXTENDED- RELEASE PRODUCTS To 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 solubility Maintain adequate residence time in g.i.t
Poor candidates: Poorly absorbed drugs Drugs 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 safety
Therapeutic Index most widely used measure of the margin TD50/ED50 Very potent drugs = narrow/very small therapeutic index Larger 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 fluids b) Controlling drug diffusion rates from dosage forms c) Chemical reaction/interaction between the drug substance of its pharmaceutical barrier & site-specific biologic fluids COATED BEADS, GRANULES, & MICROSPHERES
Drug distributed onto: Beads Pellets Granules 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: Ethylcellulose plasticizer
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 alcohol Ethylcellulose Polyvinyl 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 stirred 4. Addition of a solution of a 2 nd 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 material Wall 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