Name: Pharmaceutical Dosage Chapter 9: Modified-Release Dosage Forms and Drug Delivery Systems Modified Release Dosage

Forms y With drug release features based on time, course, and/or location to accomplish therapeutic or convenient objectives (not offered by conventional or immediate-release forms) y Differentiated into:  Extended-release  Delayed release Extended Release y Allows a reduction in dosing frequency from that necessitated by a conventional dosage forms, such as a solution or an immediate-release dosage form U.S. Food and Drug Administration (FDA) y Tablets and capsules  Taken once or twice daily  Provides immediate release of drug:  Provides promptly desired therapeutic effect  Followed by gradual and continual release of additional amounts of drug maintaining effect over predetermined period of time Delayed Release y Release the drug at a time other than promptly after administration y Delay is time based or based on the influence of environmental conditions, like gastrointestinal pH Examples of Proprietary Modified-Release Oral Dosage Forms y Delayed release  Prilosec (Omeprazole)  Enteric coated granules of Omeprazole placed in capsules  Omeprazole is acid labile and is degraded by gastric acid.  Use: treatment of duodenal ulcer Repeat Action y Contain two single doses of medication:  One: for immediate release  Second: for delayed release y Example: two layer tablets:  One layer of drug for immediate release  Second layer to release drug later as a second dose or in an extended-release manner Targeted Release y Release towards isolating or concentrating a drug in body region, tissue, or site for absorption or for drug action Advantages of Extended-Release Dosage Forms over Conventional Forms y Less fluctuation in drug blood vessels y Frequency reduction in dosing y Enhanced convenience and compliance y Reduction in adverse side effects y Reduction in overall health care costs Disadvantages of Extended-Release Dosage Form y Loss of flexibility in adjusting the drug dose and/or dosage regimen y Risk of sudden and total drug release or dose dumping due to failure of technology Characteristics of Drugs Suited for Incorporation into an ExtendedRelease y Exhibit neither very slow nor very fast rates of absorption and secretion y Uniformly absorbed from the gastrointestinal tract y Administered in small doses

y Good margin of safety y For the treatment of chronic conditions Mechanisms by which Extended Drug Actions are Achieved y Affecting the rate at which the drug is released by slowing the transit time of the dosage form through the gastrointestinal tract

Challenges in Oral Drug Activity y Gastric retention of a highly swellable, gastroretentive drug delivery system Three Ways the Rate of Drug Release from the Solid Dosage Forms be Modified y Modifying drug dissolution: controlling access of biologic fluids by use of barrier coating y Controlling drug diffusion reaction rates from dosage forms y Chemical reaction or interaction between the drug substance or its pharmaceutical barrier and site-specific biologic fluid Controlled Release is Achieved by Constructing a Tablet of Two Basic Components y A core of hydroxypropyl methylcellulose (HPMC) matrix that contains the active drugs y One or two additional barrier layers that control the surface area diffusion of drug or drugs out of the core Different Technologies Employed in the Modification of Drug Release Rate y 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 (425 ± 850 um) or beads made of sugar and starch  Microcrystalline cellulose sphere (170 to 600 um) o More durable during production than sugar-based cores  Ex: Theo-Dur Sprinkle, Spansules, Sequels y Multitablet system  Small spheroid compressing tablets 3 to 4mm in diameter  Prepared to having varying drug release characteristics  Placed in gelatin capsule shells to provide the desired pattern of drug release  Each capsule may contain 8 to 10 minitablets  Some uncoated for immediate release and others coated for extended drug release y Osmotic pump  Oros System (Alza): pioneer oral osmotic pump drug delivery system  Composed of: o Core tablet:  Semipermeable membrane coating (0.4mm diameter hole produced by laser beam)  Two layers: active layer (drug) and push layer (polymeric osmotic agent)  Principle: osmotic pressure  Examples: o Elementary osmotic pump o OROS Push±Pull o L-OROS


Embedding drug in slowly eroding or hydrophilic matrix system  Drug substance and excipient material (hydrophilic cellulose polymers): granules slowly erodes in body fluids releasing the drug adsorption  Uncombined granules (without excipient) and drug excipient granules: immediate effect (uncombined granules) and extended action (drug excipient granules)  Example: Oramorph SR y Ion exchange resins  Solution of a cationic drug passed through a column containing:  On exchange resin: forming a complex by the replacement of hydrogen atoms  Resin-drug complex: washed and tableted, encapsulated or suspended in an aqueous vehicle  Release drug depend on: pH and electrolyte concentration on GIT  Example: Hydroxcodone polistirex & chlorpeniramine politirex suspension (Tussionex Perinkinetic ER Suspension [Medeval]) and Phentermine resin capsules (Ionamin capsules) (Pharmanex)  Incorporates: Polymer barrier coating bead technology  Initial dose from uncoated portion and remainder from coated beads y Complex formation  Drug substance and chemical agents: complexes slowly soluble in body fluids (provides the extended release) depending on the environmental pH  Salts of tannic acid (tannates): Rynatan (Wallace) y Microencapsulated drug  Microencapsulation: solids, liquids or gases enclosed in microscopic particles by formation of thins coatings of wall material around the substance  Example: Bayer time release aspirin  Coacervation: most common method of microencapsulation (hydrophilic substance and colloidal drug dispersion)  Advantage: administered drug dose: subdivided into small units spread over a large area of the GIT (enhance absorption by diminishing local drug concentrate) y Embedding drug in inert plastic matrix system  Drug substance and inert plastic material (polyethylene, polyvinyl acetate or polymetacrylate): granulated and compressed into tablets (released from the inert plastic matrix)  Example: Gradumet (Abbott)  Principle: diffusion Examples of Proprietary Modified-Release Oral Dosage Forms y Extended-release  Coated particles and beads  Compazine Spansule Capsule o Coated pellets in capsule formulated to release initial dose promptly with additional drug for prolonged release o Use: antinausea, antivomiting  Osmotic

Glucotrol XL Tablets o Controlled-release GITS osmotic system o Ingredients: polyethylene oxide, hydroxypropyl cellulose, cellulose acetate o Use: antihyperglycemic  Concerta o Tri-layer example using OROS Push-Pull Osmotic System o This medicine treats attention deficit hyperactivity disorder (ADHD)  Hydrophilic or eroding matrix  Oramorph SR Tablets o Sustained-release hydrophilic matrix system, based on polymer hydroxypropyl methylcellulose o Use: analgesic for severe pain  Ion Exchange Resins  Ionamin Capsules  Inert Matrix  Procanbid Tablets o Extended-release tablets with a core tablet of a nonerodible wax matrix coated with cellulose polymers o Use: antiarrhythmic Delayed Release Oral Dosage Form y Enteric coated capsules and tablets (delayed release features)  Remain intact in the stomach to yield their ingredients in the intestine Reasons Drug Remain Intact until it Reaches the Intestine y To protect a drug destroyed by gastric fluids y To reduce gastric distress caused by drug particularly irritating to the stomach y To facilitate GIT for drugs that is better absorbed from the intestine Repeat Action Tablets y Prepared for initial dose of drug is released immediately second dose follows later y 2 layers or coatings (separated by a slowly permeable barrier coating)  Outer shell or coating: immediate release dose in tablet¶s inner core (second dose) Controlled release is achieved by constructing a tablet of two components: y A core of hydroxypropyl methylcellulose (HPMC) matrix that contains the active drugs y One or two additional barrier layer that control the surface area diffusion of drug or drugs out of the core Drug Release Test (USP) y For extended release and delayed release articles based on drug dissolution from the dosage unit against elapsed test time USP of Dosage Unit y Demonstrated by either of two methods: weight variation or content uniformity Development of IVIVC Model y Assessing IVIVC is important throughout product development and clinical evaluation y Application for FDA approval: marketing and proposed approval for any proposed formulation or manufacturing y To develop formulations with different release rates or single release rate 


If dissolution is independent of condition Obtain in vitro dissolution profiles and in vivo plasma concentration profiles  Using appropriate mathematical approaches: estimate the in vivo absorption or dissolution time course for each formulation and subject Varian Biodis Dissolution Apparatus y Varian¶s BIO-DIS III Extended Release Testing Station for USP Apparatus 3 is ideal for extended release products or any dosage form requiring release profiling at multiple pH levels y Bio relevant y Flexible y Compliant y Easily configured VK 7000/7010 Dissolution Apparatus y Reliable and robust y 1L, 2L, and 4L apparatus y Meets all current USP, JP, and EP requirements VK 7025 Dissolution Apparatus y Standard Dosage Delivery Module (DDM) can be programmed to automatically deliver simultaneous or sequential dosages into vessels using either instantaneous or delayed starts y AutoTemp In-vessel Temperature Sensing System y Optional AutoSpindle Control IVIVC Model Development y Level A  Mathematical model for the relationship between the entire in vitro in vivo dissolution and release time course  E.g. time course of plasma drug concentration of amount of drug absorbed y Level B  Mathematical model of the relationship between summary parameters that characterize the in vitro in vivo time course  E.g. models that relate the mean in vitro dissolution time to the mean in vivo dissolution time  Mean in vitro dissolution time to the mean residence time in vivo, or the vitro dissolution rate constant y Level C  Mathematical model of the relationship between the amounts dissolved in vitro at particular time and a summary parameter that characterizes the in vivo time course Clinical Considerations in the Use of Oral Modifies-Release Dosage Forms y Patients should be advised of:  Dose and dosing frequency and instructed not to use them interchangeably or concomitantly with immediate release forms of the same drug  Modified release product should not be changed to an immediate-release product without consideration of any existing blood level concentrations of the drug  Modified release tablets and capsules should not be crushed or chewed (compromises drug release features)  Nonerodible plastic matrix shells and osmotic tablet remain intact throughout GIT transit and the empty shells or ghosts from osmotic tablet may be seen in the stool Extended Drug Action Achieved (Other Routes than Oral Administration) y Ocular drug product 

y Parental system y Vaginal inserts y Subdermal implants Non-oral Modified Release Systems y Ocular Drug Product  Problem associated with ophthalmic solutions: rapid loss of administered drug due to the blinking of the eye & flushing effect of lacrimal fluids  Extended periods of therapy achieved: formulations increase in contact time between the medication and the corneal surface by use of agents that increase viscosity of solutions by ophthalmic suspensions where drug particles slowly dissolve by slowly dissipating ophthalmic ointments or by the use of ophthalmic inserts  Preparations designed to extend drug action which utilize viscosity increasing agents to increase corneal contact time:  Pilocarpine HS Gel (Pilocarpine, Alcon) o Employs Carbopol 940 9synthetic HMW cross linked polymer of acrylic acid  Timoptic XF (Timolol maleate, Merck) o Employs Gelrite (gellan gum) forming a gel upon contact with precorneal tear film  Ophthalmic inserts: innovative achievement in the delivery of medication to the eye  Occusert System (Alza) o Elliptical, flexible and with drug containing core surrounded on each side by a layer of hydrophobic ethylene or vinyl acetate copolymer membranes through which drug diffuses at a constant rate  Lacrisert (Merck) o Rod-shaped, water soluble form of hydroxypropyl cellulose, soften and slowly dissolve, thickening the precorneal tear film & prolonging the tear film breakup y Parenteral system  Extended rates of drug action following injection may be achieved in a number of ways:  Use of crystal or amorphous drug forms having prolonged dissolution characteristics o Slowly dissolving chemical complexes of the drug entity; solutions or suspensions of drug in slowly absorbed carriers or vehicles (as oleaginous) o Increased particle size of drug in suspension o Injection of slowly eroding microspheres of the drug o Slow IV infusion using controlled drug infusion pumps y Vaginal Insert  Cervidil vaginal insert (Forest Pharmaceutical)  Rectangular polymeric pouch containing dinoprostone (Prostaglandin E2) in a cross-linked polyethylene oxide or urethane polymer releasing the drug at a predetermined controlled release rate for induction of labor  Crinone gel (Wyeth-Ayerst)


Bioadhesive vaginal gel containing micronized progesterone and the polymer polycarbophil in an oil in water emulsion system  Used to assist in reproduction  Estradiol vaginal ring (Estring Pharmacia & Upjohn)  Unique method of administering estradiol  Core of ring contains a reservoir of estradiol which releases immediately and at a continuous rate of 75ug per 24 hours over 90 days  For treatment of urogenital symptoms associated with postmenopausal atrophy of vagina, inserted into the upper 1/3 of the vaginal vault and worn continuously y Subdermal implant  Inserted under the skin by special injectors or by surgical incision termed implants  Provides continuous long-term through the slow release of medication  Examples:  Goserelin acetate (Zoladex Implant, Zeneca) o Treatment of advanced prostatic cancer o Biodegradable product for subcutaneous injection with continuous medication release over a 4-12 week period  Levonorgestrel (Norplant System, WyethAyerst) o Provides 5-year protection from pregnancy after subcutaneous insertion o Sterile flexible closed capsule made of silicone rubber tubing (silastic), a dimethylsiloxane or methylvinylsiloxane copolymer, containing synthetic progestin levonorgestrel o Insertion pattern facilitates removal of the expended capsules; following term of use, capsules are surgically removed and replaced with fresh capsules Table 9.2 Modified Release Tablets and Capsules Official in the USP y Delayed release  Aspirin delayed-release tablets  Dirithromycin delayed-release tablets  Doxycycline hyclate delayed-release capsules  Erythromycin delayed-release capsules  Oxtriphylline delayed-release tablets y Extended release  Aspirin extended-release tablets  Diltiazem extended-release capsules  Disopyramide phosphate extended-release capsules  Ferrous fumarate and docusate sodium extendedrelease tablets  Indomethacin extended-release capsules  Isosorbide dinitrate extended-release tablets and capsules  Lithium carbonate extended-release tablets  Oxtriphylline extended-release tablets  Phenylpropanolamine hydrochloride extendedrelease capsules  Potassium chloride extended-release tablets  Procainamide hydrochloride extended-release tablets 

Propanolol hydrochloride extended-release capsules  Quinidine gluconate extended-release tablets  Theophylline extended-release capsules Table 9.3 Proprietary Modified-Release Oral Dosage Forms y Delayed release  E-Mycin (erythromycin) Delayed Release Tablets (Knoll)  Tablets enteric coated with cellulose acetate phthalate, carnauba wax and cellulose polymers  Use: antibiotic  Asacol (mesalamine) Delayed Release Tablets (Procter and Gamble)  Tablets coated with Eudragit S(methylacrylic acid copolymer B), a resin that bypasses the stomach dissolves in the ileum and beyond  Use: treat ulcerative colitis  Prilosec (omeprazole) Delayed release capsule (AstraMerck)  Enteric coated granules of omeprazole placed in capsule  Omeprazole is acid labile and is degraded by gastric acid  Use: treatment of duodenal ulcer y Extended-release coated particles and beads  Toprol-XL (metoprolol succinate) Tablets (Astra)  Drug pellets coated with cellulose polymers compressed into tablets  Use: treatment of hypertension  Indocin SR (indomethacin) Capsules (Merck)  Coated pellets for sustained release  Formulation includes polyvinyl acetate-crotonic acid copolymer and hydroxypropyl methylcellulose  Use: analgesic, anti-inflammatory  Compazine (prochlorperazine) Spansule Capsule (SmithKline Beecham)  Coated pellets in capsule formulated to release initial dose promptly with additional drug for prolonged release  Use: antinausea, antivomiting


Extended-release inert matrix  Desoxyn (methamphetamine HCL) Gradumet Tablets (Abbott)  Drug impregnated in an inert, porous, plastic matrix  Drug leaches out as it passes slowly through the GI tract  Expended matrix is excreted in stool  Use: attention deficit disorder  Procanbid (procainamide HCl) Tablets (Parke-Davis)  Extended-release tablets with a core tablet of a nonerodible wax matrix coated with cellulose polymers.  Use: antiarrhythmic Extended-release hydrophilic or eroding matrix  Quinidex (quinidine sulfate) Tablets (Robins)  Extended-release provided by hydrophilic matrix that swells and solely erodes.  Use: antiarrythmic  Oramorph SR (morphine sulfate) Tablets (Roxane)




Sustained-release hydrophilic matrix system based on polymer hydroxypropyl methylcellulose  Use: analgesic for severe pain Extended-release microencapsulated  K-Dur Microburst Release System (potassium chloride) Tablets (Key)  Immediately dispersing drug microencapsulated with ethylcellulose and hydroxypropyl cellulose  Use: potassium depletion Extended-release osmotic  Glucotrol XL (glipizide) Tablets (Pfizer)  Controlled-release osmotic system  Ingredients include polyethylene oxide, hydropropyl cellulose, cellulose acetate  Use: antihyerglycemic  Covera-HS (verapamil HCL) Tablets (Searle)   A osmotic system Use: antihypertensive, antianginal 


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