Uy, Alyssa V. 2BPh CHAPTER 9 - Solid Oral Modified-Release Dosage Form and Drug Delivery
Frequency reduction in dosing – extended-release products frequently deliver more than less
Systems
often than conventional form DepoFoam Drug Delivery System INTRODUCTION
Describes solid oral dosage forms and drug delivery system that
taking a dose, also it provides greater convenience with day and
release features
night administration
Modified release products provide either delayed release or
release their medication within the intestinal tract
Reduction in adverse side effects
– because of fewer blood level peaks outside therapeutic range and into toxic range, adverse side effects are less frequent
Most delayed release products are enteric-coated tablets or capsules designed to pass through the stomach unaltered, later to
– with less frequency in dosing, a patient is less apt to neglect
virtue of formulation and product design have modified drug
extended release of drug
Enhanced convenience and compliance
Reduction in overall health care costs – overall cost of treatment may be less because of enhanced
therapeutic benefit, fewer side effects, and reduced time for
Enteric coatings are used either to protect a substance from
health care personnel to dispense and administer drugs and
destruction by gastric fluids or to irritating drugs
monitor patients DISADVANTAGE OF ETENDED-RELEASE DOSAGE FORMS OVER CONVENTIONAL FORMS
loss of flexibility in adjusting the drug dose and/or dosage regimen
risk of sudden and total drug release
dose dumping due to failure in technology
TERMINOLOGY
Extended release products are designed to release their medication in a
1.
Sustained Release (SR) – Melatonex
2.
Sustained Action (SA) – Drixoral
3.
Extended Release (ER) – NOX3
4.
Long Acting (LA) – Theraflu
5.
Prolong Action (PA) –
6.
Controlled Release (CR) – Melatonin
7.
Timed Release (TR) – Vit-Min 100
Products bearing these descriptions differ in design and
controlled manner at a predetermined rate, duration, and location to achieve and maintain optimum therapeutic blood levels of drug RATIONAL FOR EXTENDED RELEASE PHARMACEUTICALS PHARMACEUTICALS
Extended release tablets & capsules = take once or twice daily Conventional forms = 3 to 4 times daily to achieve same TE
For non oral rate-controlled DDSs = 24 hours for most transdermal patches to months to years
–
Ex.: Lovenorgestrel subdermal implants (Norplat System)
MULTIPLE DAILY DOSING
performance and must be examined individually to ascertain their
inconvenient for the patient and can result in missed doses,
respective features
made-up doses, and noncompliance with the regimen
when doses are not administered on schedule, the resulting peaks and valleys reflect the optimum drug therapy
Rate-Controlled delivery
applied to certain types of drug delivery systems in which the rate of delivery is controlled by features of service rather than by
ADVANTAGES OF EXTENDED-RELEASE DOSAGE FORMS OVER
physiologic or environmental conditions like gastrointestinal pH or
CONVENTIONAL FORMS
drug transit time through the gastrointestinal tract
Reduction in drug blood levels fluctuation – controlling the rate of release eliminatedpeaks and valleys of
blood levels
Modified release
has come into general use to describe dosage forms having drug release features based on time course and/or location that are
Page 1 of 6
designed to accomplish therapeutic or convenience objectives not offered by conventional or immediate-release forms
5.
They are used in the treatment of chronic rather than acute conditions drugs for acute conditions require greater adjustment of the dosage by the physician than that provided by extended-release
Extended-release
products
dosage forms of this type are the ones that allow a reduction in dosing frequency form that necessitated by a conventional dosage
BASIS OF DRUG RELEASE modifying drug dissolution by controlling excess of biologic fluids to the drug through the use of
forms, such as solution or an immediate-release drug dosage form
barrier coatings Delayed release
releases the drug at a time other than promptly after
controlling drug diffusion rate from dosage forms
chemical reaction or interaction between the drug substance or its pharmaceutical barrier and site-specific biologic fluids
administration. The delay may be time base or base on the influence of environmental conditions such as gastrointestinal pH
BASIS OF DRUG RELEASE Repeat action
to the drug through the use of barrier coatings
two single doses of medication; one for immediate release; another one for modified release
controlling drug diffusion rate from dosage forms
chemical reaction or interaction between the drug substance or its pharmaceutical barrier and site-specific biologic fluids
Targeted release
modifying drug dissolution by controlling excess of biologic fluids
drug release directed toward isolating or concentrating a drug in a body region, tissue or site of absorption or for drug action
MICROSPHERES COATED BEADS, GRANULES AND MICROSPHERES
using conventional pan coating or air suspension coating, a solution of the drug substance is placed on small intact nonparent
Extended Release Oral Dosage Forms (Successful ER Product) Release from dosage forms at a predetermine rate
seeds or beads made of sugar and stand or on microcrystalline
2.
Dissolve in GT
cellulose sphere
3.
Maintain sufficient Gastrointestinal residence time
4.
Be absorbed at a rate that will replace the amount of drug being
1.
Nonpareil seeds
425- 850μm
metabolized and excreted Microcrystalline cellulose CHARACTERISTICS CHARACTERISTICS OF EXTENDED-RELEASE PRODUCTS 1.
They exhibit very slow nor very fast rates of absorption and excretion
More durable during production than sugar-based cores
170- 600μm
drugs with slow rates of absorption and excretion are usually inherently long-acting, and it is not necessary to prepare them in
Lipid materials used to coat granules
extended-release forms
Beeswax
drug with very short half-lives, less than 2 hours, are poor
Carnauba wax
Glyceryl monostearate
drugs that act by affecting enzyme systems may be loner acting
Cetyl alcohol
than indicated by their quantitative half-lives because of their
Cellulosic material (ethyl cellulose)
residual effects and recovery of the diminished biosystem
Aqueous coating system eliminate the hazards and environmental
They are uniformly absorbed from the gastrointestinal tract they must have good aqueous solubility and maintain adequate
The thicker the coat, the more resistant to penetration and the
Spansule
candidates for extended release
concerns associated with organic based solvent systems 2.
residence time in the gastrointestinal tract
drugs absorbed poorly or at varying and unpredictable rates are not good candidates for extended-release products
more delayed will be the drug release and dissolution
MULTITABLET SYSTEMS
small spheroidal compressed tablets 3 to 4 mm in diameter may be prepared
3.
They are administered in relatively small doses drugs with large single doses frequently are not suitable for
each capsule contain 8 to 10 minitablets some uncoated for immediate release and others coated for extended drug release
extended release because the tablet or capsule needed to maintain a sustained therapeutic blood level of the drug would be
MICROENCAPSULATED MICROENCAPSULATED DRUG
too large for the patient to swallow easily
Microencapsulation
4.
They possess a good margin of safety the most widely used measure of the margin of a drug’s safety is
microscopic particles by formation of thin coatings of wall material around the substance
its therapeutic index, that is, the median toxic dose divided by the median affective dose
the larger the therapeutic index, the safer the drug
drugs that are administered in very small doses or possess very
Gelatin
rates and the risk of dose dumping due to a product defect
A common wall forming material and synthetic polymers, such as polyvinyl alcohol, ethyl cellulose, polyvinyl chloride and other
narrow therapeutic indices are poor candidates for formulations because of technologic limitations of precise control over release
A process by which solid, liquid or even gases may be enclosed in
materials may be used
dissolving the wall material
encapsulated material is added to the mixture and the thoroughly stirred
Page 2 of 6
a solution to second material is added, example of acacia
retains its shape during leaching of he drug and during its passage
Example: Gradumet
the final dry microcapsules are free-flowing discrete particles of coated material
through the alimentary tract
wall material constitute into 20% of the total particle weigh COMPLEX FORMATION
form complexes that may be slowly soluble in body fluids, depending on the pH of the environment
ADVANTAGE OF MICROENCAPSULATION MICROENCAPSULATION
administered dose of a drug is subdivided into small units that are
slow dissolution rate (e.g. Rynatan)
spread over a large area of the gastrointestinal tracts, which may enhance absorption by diminishing local drug concentration (e.g.
Micro-K ExtenCaps) >Encapsulation. All of the single and combination capsules are produced here. The empty gelatin capsules are placed in hoppers and free-flowing to the machine. The bottom portion of the
ION EXCHANGE RESINS
solution of a cationic drug may be passed through a column containing an ion exchange resin, forming a complex by the
capsule is filled, which is gravity-fed from a stainless steel bin into
replacement of hydrogen atoms
the machine’s hopper. An average of 6 million capsules a day can
be produced.
salts of tannic acid, tannates, provide this quality in a variety of proprietary products
release of the drug depends on the pH and electrolyte concentration in the gastrointestinal tract
EMBEDDING DRUG SLOWLY ERODING OR HYDROPHILIC MATRIX SYSTEM
acidic environment of the small intestine
drug substance is combined and made into granules with an excipient material that slowly erodes in body fluids, progressively
commonly used as the excipient base in tablet matrix systems
EFFECTIVENESS OF THE HYDROPHILIC MATRIX IS BASED ON:
hydrocodone polistirex (Tussionex) and chlorpheniramine polistirex suspension and phentermine resin capsules
releasing the drug for absorption Hydrophilic cellulose polymers
release is greater in the acidity of the stomach than in the less
Mechanism of ion exchange resins: In the stomach 1. drug resinate + HCl ↔ acidic resin + drug hydrochloride 2. resin salt + HCl ↔ resin chloride + acidic drug
successive process of hydration on the polymer’s surface
In the intestine
gel formation on the polymer’s surface
1. drug resinate + NaCl ↔ sodium resinate + drug hydrochloride
tablet erosion
2. resin salt + NaCl ↔ resin chlor ide + sodium salt of drug
subsequent and continuous release of drug
release is extended over 12 hours by ionic exchange
Hydroxypropyl Methyl Cellulose (HPMC)
a free flowing powder; commonly used to provide the hydrophilic matrix
Drug suspension or solution
A successful hydrophilic matrix system must contain the following:
Osmoti Osmotic c drug core core
Delive Deliverr orif orific ices es
polymer must form a gelatinous layer rapidly enough to protect the inner core of the tablet from disintegrating too rapidly after ingestion
Delivery orifice
20% of HPMC results in satisfactory rates of release for an extended-release tablet formation (e.g Oramorph SR Tablet)
Wat er
Manufacturers may prepare two-layer tablets
one layer containing the uncombined drug for immediate release
Semipermeab le
the other layer having the drug encoded in a hydrophilic matrix for extended release
membrane
Os mot ic c ore
Wat er
Rat e controlling
Polymeric osmotic
membr ane
p u sh compart ment
containing dru g
A . El em em en en ta tar y OR OROS os os mo mo ti ti c
B . OROS Pu Pu sh sh -P -P ul ul l Os mo mo ti ti c Sy s stt e em m
pump drug delivery s ystem
they may also prepare a three-layer tablets
outer layers containing the drug for immediate release
some commercial tablets are prepared with an inner core containing the extended-release portion of the drug and an outer
OSMOTIC PUMP
shell containing drug for immediate release
system developed by Alza
Drug is granulated with an inert plastic material such as polyethylene, polyvinyl acetate, o polymethacrylate and the granulation is compressed into tablets
composed of a core tablet surrounded by a semipermeable membrane coating having a 0.4mm diameter hole produced by
EMBEDDING DRUG IN INERT PLASTIC MATRIX
the pioneer oral osmotic pump drug delivery system is the Oros
laser beam. Example: Acutrim
core tablet has two layers, one containing the drug and the other containing a polymeric osmotic agent
released from the inert plastic matrix by diffusion
Page 3 of 6
the system is designed such that only a few drops of water are
EXAMPLES OF MODIFIED-RELEASE TABLETS AND CAPSULES OFFICIAL IN THE
drawn into the tablet each hour
USP
function of the tablet depends on the osmotic gradient between the contents of the two-layer core and the fluid in the
Delayed release Aspirin delayed-release tablets
gastrointestinal tract
Dirithromycin delayed-release tablets Doxycycline hyclate delayed-release capsules
Drug release rate may be altered by:
changing the surface area
Erythromycin delayed-release capsules
thickness
Oxtriphylline delayed-release tablets
composition of the membrane and/or diameter of the drug release orifice Extended release Diltiazem extended-release capsules Disopyramide phosphate extended-release capsules
Release rate is not affected by:
gastrointestinal acidity or alkalinity
Isosorbide dinitrate extended-release tablets and capsules
fed conditions
Propanolol hydrochloride extended-release capsules
gastrointestinal motility
Theophylline extended-release capsules
Gastrointestinal therapeutic system (GIT systems)
is employed in the manufacture of Glucotrol XL Extended release
USP Requirements and FDA Guidelines for Modified Release Dosage Forms 1. DRUG RELEASE
tablets, and Procardia XL release tablets
based on drug dissolution from the dosage unit against elapsed test time (e.g. Aspirin Extended-release Tablets)
the initial drug is released 4 to 5 hours after tablet ingestion
Aspirin dissolution rate: rate :
REPEAT-ACTION TABLETS
the initial dose of drug is released immediately and a second dose
Time (hours) 1.0 2.0 4.0 8.0
follows later
released 4 to 6 hours after administration
Example: Repetabs
they are best suited for treatment of chronic conditions requiring repeated dosing
low dosage and fairly rapid rates of absorption and excretion
2. UNIFORMITY OF DOSAGE DOSAGE UNITS
release of a drug that may be intentionally delayed until it reaches the intestines for several reasons
protect a drug destroyed by gastric fluids reduce gastric distress caused by drugs of particularly irritating to
3.
IN VITRO-IN VIVO CORRELATIONS CORRELATIONS
the stomach
to facilitate gastrointestinal transit for drugs that are absorbed from the intestines
Examples: Enteric Coated Enseals – Lilly; Ecotrin SmithKline
PROPERTIES OF AN ENTERIC COATING TABLETS/CAPSULES
pH dependent
breaks down in the less acidic environment of the intestine
time dependent
erodes by moisture over time during gastrointestinal transit
enzyme dependent
deteriorating as a result of hydrolysis-catalyzing action of intestinal enzyme
AGENTS USED FOR ENTERIC COATING OF CAPSULES AND TABLETS
uniformity of dosage units may be demonstrated by either of two methods, weight variations or content uniformity
DELAYED-RELEASE ORAL DOSAGE FORMS
Amount dissolved 15-40% 25-60% 35-75% Not less than 70%
critical to the development of oral extended-release products important throughout product dev ’t, clinical evaluation submission of an application for FDA approval for marketing, & during post approval for any proposed formulation or manufacturing changes it provides guidance to sponsors of new drug applications and abbreviated new drug applications and abbreviated new drug applications for extended release of oral products
IVIVC provides methods of:
developing an IVIVC and evaluating its predictability
using an IVIVC to establish dissolution specifications
applying an IVIVC as a surrogate for in vitro-in vivo bioequivalence during the approval process or during post approval for certain formulation or manufacturing changes
3 Categories of IVIVCs include in the document Level A the relationship between the entire in vitro dissolution
fats
and release time course and the entire in vivo
fatty acids
response time course
waxes
shellac
cellulose acetate phthalate
Ex.: the time course of plasma drug concentration or amount of drug absorbed
Level B
Page 4 of 6
predictive mathematical model of the relationship
patients using a modified release product should not be changed
between summary parameters that characterize in
into immediate release without consideration to the blood
vitro and in vivo time courses
concentration
Example: models that relate the mean in vivo
patients should not be changed to another extended-release product unless there is assurance of equivalent bioavailability
dissolution time to the mean in vitro dissolution time
different product can result in a marketed shift in t he patient’s drug blood level because of differences in drug release
Level C
characteristics a predictive mathematical model of the relationship
between the amount dissolved in vitro at a particular time and a summary parameter that characterizes the
time in vivo time course or area under the curve
the level of IVIVCs may be useful in the early stages of
modified release tablets and capsules should not be crushed or chewed patients if fed through the nasogastric tube may receive modifiedrelease medications
nonerodible plastic matrix shells and osmotic tablets remain
formulation development when pilot formulations are
intact throughout gastrointestinal transit and the empty shells or
being selected
ghosts from osmotic tablets may be seen in the stool
MOST COMMON PROCESS FOR DEVELOPING IVIVC MODEL (LEVEL A)
develop formulations with different release rates or a single release rate if dissolution is independent of condition
obtain in vitro dissolution profiles and in vivo plasma concentration profiles for these formulations
estimate the in vivo absorption or dissolution time course for each formulation and subject using appropriate mathematical Propriety Modified-Release Oral Dosage Forms
approaches
Delayed-release
Extended-Release Coated Particles and Breads
CRITERIA IN DEVELOPMENT APPLICABLE TO THE DEVELOPMENT OF IVIVCS ARE THE FOLLOWING
in determining in vitro dissolution, USP dissolution apparatus; type I (basket) or type II (paddle) is preferred, although type III (reciprocating cylinder) or type IV (flow-through cell) may be applicable in some substances
aqueous medium with a pH not exceeding 6.8 is preferred as the medium for dissolution studies. For poorly soluble drugs, a surfactant may be added
the dissolution profiles of at least 12 individual dosage units from each lot should be determined
for vivo studies, human subjects are used in the fasted state unless the drug is not well tolerated, in which case the studies may be conducted in the fed state. Acceptable data sets have been shown to be generated with use of 6 to 36 human subjects
crossover studies are preferred, but parallel studies or cross-study analysis may be acceptable using a common reference treatment product, such as an intravenous solution, an aqueous oral solution, or an immediate-release product
LABELING
they must be specific for the monograph article aspirin delayed-release tablets must state that the tablets are enteric coated
capsules must indicate whether the product is intended for dosage every 12 to 24 hours and state which in vitro drug release test the product complies CLINICAL CONSIDERATIONS
not to be used interchangeably
or concomitantly with immediate-release forms of the same drug
Page 5 of 6
Extended-Release Inert Matrix
Extended Release Hydrophilic/Eroding Hydrophilic/Eroding Matrix
Extended-Release Microencapsulated Drug
Extended-Release Osmotic
Page 6 of 6
