CHAPTER 9 - solid oral modified-release dosage forms and drug delivery systems

ROUTES OF ADMINISTRATION Oral Ocular Parenteral Subdermal Vaginal * Extended-release tablets and capsules are commonly taken only once or twice daily. ADVANTAGES: 1) Less fluctuation in drug blood vessels 2) Frequency reduction in dosing 3) Enhanced convenience and compliance 4) Reduction in overall health care costs DISADVANTAGES 1) Loss of flexibility in adjusting the drug dose/regimen 2) Risk of sudden and total drug release 3) Dose dumping due to a failure of technology TERMINOLOGY MODIFIED RELEASE - Dosage forms having drug release features based on time, course, and location - Designed to accomplish therapeutic or convenience objectives not offered by conventional or immediate-release forms. EXTENDED RELEASE - One that allows reduction in dosing frequency from that necessitated by a conventional dosage form, such as a solution or an immediate-release dosage form. DELAYED RELEASE - Is designed to release the drug at a time other than promptly after administration REPEAT ACTION - Contain two single doses of medication, one for immediate release and second for delayed release TARGETED RELEASE - Describes drug release directed toward isolating or concentrating a drug in body region, tissue, or site for absorption or for drug action

DRUG CANDIDATES FOR EXTENDED RELEASE PRODUCTS 1) They exhibit neither very slow nor very fast rates of absorption and excretion 2) They are uniformly absorbed from the gastrointestinal tract 3) They are administered in relatively small doses 4) They possess a good margin of safety 5) They are used in the treatment of chronic rather that acute conditions EXTENDED-RELEASE TECHNOLOGY FOR ORAL DOSAGE FORMS Extended drug action is achieved by: - affecting the rate at which the drug is released from the dosage form - slowing the transit time of the dosage form through the gastrointestinal tract Rate of drug release from solid dosage forms may be modified by the technologies, which are based on: a) Modifying drug dissolution by controlling access of biologic fluids to the drug through the use of barrier coatings b) Controlling drug diffusion rates from dosage forms c) Chemical Reaction or Interaction between a drug substance or its pharmaceutical barrier and specific biologic fluids. COATED BEADS, GRANULES and MICROSPHERES - Using conventional pan coating or air suspension coating, a solution of the drug substance is placed on small inert nonpareil seeds or beads made of sugar and starch or on microcrystalline cellulose spheres. - Nonpareil seeds: range of 424 to 850m - Microcrystalline cellulose spheres: 170 to 600m - Microcrystalline spheres are more durable that sugarbased cores during production MULTITABLET SYSTEM - Small spheroid tablets 3 to 4mm diameter - May be prepared to have varying drug release characteristics. MICROENCAPSULATED DRUG Microencapsulation - Is a process by which solids, liquids or even gases may be enclosed in microscopic particles by formation of thin coatings of wall material substance. Coacervate: droplets of gelatin concentrates

HYDROPHILIC MATRIX SYSTEM - Embedding Drug in slowly eroding system - The drug is combined and made into granules with an excipient material that slowly erodes in body fluids, progressively releasing the drug for absorption - Hydrophilic cellulose polymers: excipient base EMBEDDING DRUG IN INERT PLASTIC MATRIX - The drug I granulated with an inert plastic material such as polyethylene, polyvinyl acetate, or polymethacrylate. - Granulation is compressed into tablets - The drug is slowly released from the inert plastic matrix by diffusion. COMPLEX FORMATION - Some drug substances, when chemically combined with certain other chemical agents, form complexes that may be only slowly soluble in body fluids, depending on the pH of the environment. - This dissolution rate provides the extended release of drug. ION EXCHANGE RESINS - A solution of a cationic drug may be passed through a column containing an ion exchange resin, forming a complex by the replacement of hydrogen atoms. - The resin-drug complex is washed and may be tableted, encapsulated or suspended in a aqueous vehicle OSMOTIC PUMP OROS - the pioneer oral osmotic pump drug delivery system - developed by Alza The system is composed of a core tablet surrounded a semi-permeable membrane coating having a 0.4mm diameter hole produced by laser beam. The core tablet has 2 layers 1) Active layer: drug 2) Push layer: polymeric osmotic agent Drug release rate may be altered by changing: 1) Surface area 2) Thickness / composition 3) Diameter of the drug release orifice Drug release rate is NOT AFFECTED by: 1) Gastrointestinal acidity 2) Alkalinity 3) Fed conditions/ Gastrointestinal motility

REPEAT-ACTION TABLETS - Are prepared so that an initial dose of drug is released immediately and a second dose follow. - Are best suited for: Treatment of chronic conditions requiring repeat dosing - Should have low dosage and fairly rapid rates for absorption as excretion. DELAYED-RELEASE ORAL DOSAGE FORMS - The release of the drug from an oral dosage form may be intentionally delayed until it reaches the intestines for several reasons: 1) To protect a drug destroyed by gastric fluids 2) To reduce gastric distress caused by drugs particularly irritating to the stomach 3) To facilitate gastrointestinal transit for drugs that are better absorbed from the intestines ENTERIC COATING - Capsules and tablets specially coated remain intact in the stomach and to yield their ingredients in the intestines. Properties: 1) pH dependent 2) Breaking down in the less acidic environment of the intestines 3) Time dependent 4) Eroding by moisture over time 5) Enzyme dependent (hydrolysis-catalyzing) USP REQUIREMENTS & FDA GUIDANCE DRUG RELEASE - Based on drug dissolution from the dosage unit against elapsed test time UNIFORMITY OF DOSAGE UNITS - Weight variation & content uniformity IN VITRO-VIVO DISSOLUTION - In vitro-in vivo correlations (IVIVC) is important throughout the product development, clinical evaluation, submission of an application for FDA approval for marketing. Criteria: 1) USP dissolution apparatus type I or type II 2) An aqueous medium with a pH not exceeding 6.8 is preferred as the medium for dissolution studies 3) The dissolution profiles of at least 12 individual dosage units from each lot should be determined. 4) In vivo studies, human subjects are used in the fasted state unless the drug is not well tolerated 5) Crossover studies are preferred

LABELING - Requirements are specific to the monograph CLINICAL CONSIDERATIONS IN THE USE OF ORAL MODIFIED-RELEASE DOSAGE FORMS 1) Patients should be advised of the dose & dose frequency of modified drug release products and instructed NOT to use them INTERCHANGEABLY or CONCOMITANTLY with immediate release form of drugs. 2) Patients stabilized on a modified-release product should NOT be changed to an immediate release product without consideration if any existing blood level concentrations of the drug 3) Patients should be advised that modified-release tablets and capsules should NOT BE CRUSHED or CHEWED, since such action compromised their drug release features 4) Patients and caregivers should be advised that nonerodible plastic matrix shells and osmotic tablet REMAIN INTACT throughout gastrointestinal transit and the empty shell or ghosts from osmotic tablets may be seen in the stool.