Name:  Good margin of safety

Pharmaceutical Dosage  For the treatment of chronic conditions

Chapter 9: Modified-Release Dosage Forms and Drug Delivery Mechanisms by which Extended Drug Actions are Achieved
Systems  Affecting the rate at which the drug is released by slowing
Modified Release Dosage Forms the transit time of the dosage form through the
 With drug release features based on time, course, and/or gastrointestinal tract
location to accomplish therapeutic or convenient objectives
(not offered by conventional or immediate-release forms) Challenges in Oral Drug Activity
 Differentiated into:  Gastric retention of a highly swellable, gastroretentive drug
 Extended-release delivery system
 Delayed release Three Ways the Rate of Drug Release from the Solid Dosage Forms
Extended Release be Modified
 Allows a reduction in dosing frequency from that  Modifying drug dissolution: controlling access of biologic
necessitated by a conventional dosage forms, such as a fluids by use of barrier coating
solution or an immediate-release dosage form U.S. Food  Controlling drug diffusion reaction rates from dosage forms
and Drug Administration (FDA)  Chemical reaction or interaction between the drug
 Tablets and capsules substance or its pharmaceutical barrier and site-specific
 Taken once or twice daily biologic fluid
 Provides immediate release of drug: Controlled Release is Achieved by Constructing a Tablet of Two
 Provides promptly desired therapeutic effect Basic Components
 Followed by gradual and continual release  A core of hydroxypropyl methylcellulose (HPMC) matrix
of additional amounts of drug maintaining that contains the active drugs
effect over predetermined period of time  One or two additional barrier layers that control the surface
Delayed Release area diffusion of drug or drugs out of the core
 Release the drug at a time other than promptly after Different Technologies Employed in the Modification of Drug
administration Release Rate
 Delay is time based or based on the influence of  Coated beads, granules and microspheres
environmental conditions, like gastrointestinal pH  Using conventional pan coating or air suspension
Examples of Proprietary Modified-Release Oral Dosage Forms coating, a solution of the drug substance is placed
 Delayed release on:
 Prilosec (Omeprazole)  Small inert nonpareil seeds (425 – 850
 Enteric coated granules of Omeprazole um) or beads made of sugar and starch
placed in capsules  Microcrystalline cellulose sphere (170
 Omeprazole is acid labile and is to 600 um)
degraded by gastric acid. o More durable during production
 Use: treatment of duodenal ulcer than sugar-based cores
Repeat Action  Ex: Theo-Dur Sprinkle, Spansules, Sequels
 Contain two single doses of medication:  Multitablet system
 One: for immediate release  Small spheroid compressing tablets 3 to 4mm in
 Second: for delayed release diameter
 Example: two layer tablets:  Prepared to having varying drug release
 One layer of drug for immediate release characteristics
 Second layer to release drug later as a second dose or  Placed in gelatin capsule shells to provide the
in an extended-release manner desired pattern of drug release
Targeted Release  Each capsule may contain 8 to 10
 Release towards isolating or concentrating a drug in body minitablets
region, tissue, or site for absorption or for drug action  Some uncoated for immediate release
Advantages of Extended-Release Dosage Forms over Conventional and others coated for extended drug
Forms release
 Less fluctuation in drug blood vessels  Osmotic pump
 Frequency reduction in dosing  Oros System (Alza): pioneer oral osmotic pump
 Enhanced convenience and compliance drug delivery system
 Reduction in adverse side effects  Composed of:
 Reduction in overall health care costs o Core tablet:
Disadvantages of Extended-Release Dosage Form  Semipermeable membrane
 Loss of flexibility in adjusting the drug dose and/or dosage coating (0.4mm diameter
regimen hole produced by laser beam)
 Risk of sudden and total drug release or dose dumping due  Two layers: active layer
to failure of technology (drug) and push layer
Characteristics of Drugs Suited for Incorporation into an Extended- (polymeric osmotic agent)
Release  Principle: osmotic pressure
 Exhibit neither very slow nor very fast rates of absorption  Examples:
and secretion o Elementary osmotic pump
 Uniformly absorbed from the gastrointestinal tract o OROS Push–Pull
 Administered in small doses o L-OROS

1
  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
 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 &  Inert Matrix
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
 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)
 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)
 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
 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
 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
 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
 To protect a drug destroyed by gastric fluids
 To reduce gastric distress caused by drug particularly
irritating to the stomach
 To facilitate GIT for drugs that is better absorbed from the
intestine
Repeat Action Tablets
 Prepared for initial dose of drug is released immediately
second dose follows later
 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:
 A core of hydroxypropyl methylcellulose (HPMC) matrix
that contains the active drugs
 One or two additional barrier layer that control the surface
area diffusion of drug or drugs out of the core
Drug Release Test (USP)
 For extended release and delayed release articles based on
drug dissolution from the dosage unit against elapsed test
time
USP of Dosage Unit
 Demonstrated by either of two methods: weight variation or
content uniformity
Development of IVIVC Model
 Assessing IVIVC is important throughout product
development and clinical evaluation
 Application for FDA approval: marketing and proposed
approval for any proposed formulation or manufacturing
2
  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
 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
 Bio relevant
 Flexible
 Compliant
 Easily configured
VK 7000/7010 Dissolution Apparatus
 Reliable and robust
 1L, 2L, and 4L apparatus
 Meets all current USP, JP, and EP requirements
VK 7025 Dissolution Apparatus
 Standard Dosage Delivery Module (DDM) can be
programmed to automatically deliver simultaneous or
sequential dosages into vessels using either instantaneous
or delayed starts
 AutoTemp In-vessel Temperature Sensing System
 Optional AutoSpindle Control
IVIVC Model Development
 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
 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
 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
 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)
 Ocular drug product
 Parental system
 Vaginal inserts
 Subdermal implants
Non-oral Modified Release Systems
 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
 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
 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
3
 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
 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, Wyeth-
Ayerst)
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
 Delayed release
 Aspirin delayed-release tablets
 Dirithromycin delayed-release tablets
 Doxycycline hyclate delayed-release capsules
 Erythromycin delayed-release capsules
 Oxtriphylline delayed-release tablets
 Extended release
 Aspirin extended-release tablets
 Diltiazem extended-release capsules
 Disopyramide phosphate extended-release
capsules
 Ferrous fumarate and docusate sodium extended-
release tablets
 Indomethacin extended-release capsules
 Isosorbide dinitrate extended-release tablets and
capsules
 Lithium carbonate extended-release tablets
 Oxtriphylline extended-release tablets
 Phenylpropanolamine hydrochloride extended-
release 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
 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 (Astra-
Merck)
 Enteric coated granules of omeprazole
placed in capsule
 Omeprazole is acid labile and is degraded by
gastric acid
 Use: treatment of duodenal ulcer
 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)
4
  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 GITS a osmotic system
 Ingredients include polyethylene oxide,
hydropropyl cellulose, cellulose acetate
 Use: antihyerglycemic
 Covera-HS (verapamil HCL) Tablets (Searle)
 A COER b osmotic system
 Use: antihypertensive, antianginal