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CHAPTER 9 - Solid Oral Modified-Release Dosage Form and Drug Delivery

Systems

INTRODUCTION

Describes solid oral dosage forms and drug delivery system that

virtue of formulation and product design have modified drug

release features

Modified release products provide either delayed release or

extended release of drug

Most delayed release products are enteric-coated tablets or

capsules designed to pass through the stomach unaltered, later to

release their medication within the intestinal tract

Enteric coatings are used either to protect a substance from

destruction by gastric fluids or to irritating drugs

Extended release products are designed to release their medication in a

controlled manner at a predetermined rate, duration, and location to

achieve and maintain optimum therapeutic blood levels of drug

RATIONAL FOR EXTENDED RELEASE 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

inconvenient for the patient and can result in missed doses,

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

ADVANTAGES OF EXTENDED-RELEASE DOSAGE FORMS OVER

CONVENTIONAL FORMS

Reduction in drug blood levels fluctuation

– controlling the rate of release eliminatedpeaks and valleys of

blood levels

Frequency reduction in dosing

– extended-release products frequently deliver more than less

often than conventional form DepoFoam Drug Delivery System

Enhanced convenience and compliance

– with less frequency in dosing, a patient is less apt to neglect

taking a dose, also it provides greater convenience with day and

night administration

Reduction in adverse side effects

– because of fewer blood level peaks outside therapeutic range

and into toxic range, adverse side effects are less frequent

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

health care personnel to dispense and administer drugs and

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

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

performance and must be examined individually to ascertain their

respective features

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

physiologic or environmental conditions like gastrointestinal pH or

drug transit time through the gastrointestinal tract

Modified release

has come into general use to describe dosage forms having drug

release features based on time course and/or location that are

Uy, Alyssa V.

2BPh

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designed to accomplish therapeutic or convenience objectives not

offered by conventional or immediate-release forms

Extended-release

dosage forms of this type are the ones that allow a reduction in

dosing frequency form that necessitated by a conventional dosage

forms, such as solution or an immediate-release drug dosage form

Delayed release

releases the drug at a time other than promptly after

administration. The delay may be time base or base on the

influence of environmental conditions such as gastrointestinal pH

Repeat action

two single doses of medication; one for immediate release;

another one for modified release

Targeted release

drug release directed toward isolating or concentrating a drug in a

body region, tissue or site of absorption or for drug action

Extended Release Oral Dosage Forms (Successful ER Product)

1. Release from dosage forms at a predetermine rate

2. Dissolve in GT

3. Maintain sufficient Gastrointestinal residence time

4. Be absorbed at a rate that will replace the amount of drug being

metabolized and excreted

CHARACTERISTICS OF EXTENDED-RELEASE PRODUCTS

1. They exhibit very slow nor very fast rates of absorption and excretion

drugs with slow rates of absorption and excretion are usually

inherently long-acting, and it is not necessary to prepare them in

extended-release forms

drug with very short half-lives, less than 2 hours, are poor

candidates for extended release

drugs that act by affecting enzyme systems may be loner acting

than indicated by their quantitative half-lives because of their

residual effects and recovery of the diminished biosystem

2. They are uniformly absorbed from the gastrointestinal tract they must have good aqueous solubility and maintain adequate

residence time in the gastrointestinal tract

drugs absorbed poorly or at varying and unpredictable rates are

not good candidates for extended-release products

3. They are administered in relatively small doses

drugs with large single doses frequently are not suitable for

extended release because the tablet or capsule needed to

maintain a sustained therapeutic blood level of the drug would be

too large for the patient to swallow easily

4. They possess a good margin of safety

the most widely used measure of the margin of a drug’s safety is

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

narrow therapeutic indices are poor candidates for formulations

because of technologic limitations of precise control over release

rates and the risk of dose dumping due to a product defect

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

products

BASIS OF DRUG RELEASE modifying drug dissolution by

controlling excess of biologic fluids to the drug through the use of

barrier coatings

controlling drug diffusion rate from dosage forms

chemical reaction or interaction between the drug substance or

its pharmaceutical barrier and site-specific biologic fluids

BASIS OF DRUG RELEASE

modifying drug dissolution by controlling excess of biologic fluids

to the drug through the use of barrier coatings

controlling drug diffusion rate from dosage forms

chemical reaction or interaction between the drug substance or

its pharmaceutical barrier and site-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 intact nonparent

seeds or beads made of sugar and stand or on microcrystalline

cellulose sphere

Nonpareil seeds

425-850μm

Microcrystalline cellulose

More durable during production than sugar-based cores

170-600μm

Lipid materials used to coat granules

Beeswax

Carnauba wax

Glyceryl monostearate

Cetyl alcohol

Cellulosic material (ethyl cellulose)

Aqueous coating system eliminate the hazards and environmental

concerns associated with organic based solvent systems

The thicker the coat, the more resistant to penetration and the

more delayed will be the drug release and dissolution

Spansule

MULTITABLET SYSTEMS

small spheroidal compressed tablets 3 to 4 mm in diameter may

be prepared

each capsule contain 8 to 10 minitablets some uncoated for

immediate release and others coated for extended drug release

MICROENCAPSULATED DRUG

Microencapsulation

A process by which solid, liquid or even gases may be enclosed in

microscopic particles by formation of thin coatings of wall

material around the substance

Gelatin

A common wall forming material and synthetic polymers, such as

polyvinyl alcohol, ethyl cellulose, polyvinyl chloride and other

materials may be used

dissolving the wall material

encapsulated material is added to the mixture and the thoroughly

stirred

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a solution to second material is added, example of acacia

the final dry microcapsules are free-flowing discrete particles of

coated material

wall material constitute into 20% of the total particle weigh

ADVANTAGE OF MICROENCAPSULATION

administered dose of a drug is subdivided into small units that are

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

capsule is filled, which is gravity-fed from a stainless steel bin into

the machine’s hopper. An average of 6 million capsules a day can

be produced.

EMBEDDING DRUG SLOWLY ERODING OR HYDROPHILIC MATRIX SYSTEM

drug substance 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

commonly used as the excipient base in tablet matrix systems

EFFECTIVENESS OF THE HYDROPHILIC MATRIX IS BASED ON:

successive process of hydration on the polymer’s surface

gel formation on the polymer’s surface

tablet erosion

subsequent and continuous release of drug

Hydroxypropyl Methyl Cellulose (HPMC)

a free flowing powder; commonly used to provide the hydrophilic

matrix

A successful hydrophilic matrix system must contain the

following:

polymer must form a gelatinous layer rapidly enough to protect

the inner core of the tablet from disintegrating too rapidly after

ingestion

20% of HPMC results in satisfactory rates of release for an

extended-release tablet formation (e.g Oramorph SR Tablet)

Manufacturers may prepare two-layer tablets

one layer containing the uncombined drug for immediate release

the other layer having the drug encoded in a hydrophilic matrix

for extended release

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

shell containing drug for immediate release

EMBEDDING DRUG IN INERT PLASTIC MATRIX

Drug is granulated with an inert plastic material such as

polyethylene, polyvinyl acetate, o polymethacrylate and the

granulation is compressed into tablets

released from the inert plastic matrix by diffusion

retains its shape during leaching of he drug and during its passage

through the alimentary tract

Example: Gradumet

COMPLEX FORMATION

form complexes that may be slowly soluble in body fluids,

depending on the pH of the environment

slow dissolution rate (e.g. Rynatan)

salts of tannic acid, tannates, provide this quality in a variety of

proprietary products

ION EXCHANGE RESINS

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

release of the drug depends on the pH and electrolyte

concentration in the gastrointestinal tract

release is greater in the acidity of the stomach than in the less

acidic environment of the small intestine

hydrocodone polistirex (Tussionex) and chlorpheniramine

polistirex suspension and phentermine resin capsules

Mechanism of ion exchange resins:

In the stomach

1. drug resinate + HCl ↔ acidic resin + drug hydrochloride

2. resin salt + HCl ↔ resin chloride + acidic drug

In the intestine

1. drug resinate + NaCl ↔ sodium resinate + drug hydrochloride

2. resin salt + NaCl ↔ resin chloride + sodium salt of drug

release is extended over 12 hours by ionic exchange

OSMOTIC PUMP

the pioneer oral osmotic pump drug delivery system is the Oros

system developed by Alza

composed of a core tablet surrounded by a semipermeable

membrane coating having a 0.4mm diameter hole produced by

laser beam. Example: Acutrim

core tablet has two layers, one containing the drug and the other

containing a polymeric osmotic agent

Drug suspension or

solution

Osmotic drug core Deliver orifices

Delivery orifice

Water Water

Rate controlling Polymeric osmotic

Semipermeable Osmotic core membrane push compartment

membrane containing drug

A. Elementary OROS osmotic B. OROS Push-Pull Osmotic System

pump drug delivery system

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the system is designed such that only a few drops of water are

drawn into the tablet each hour

function of the tablet depends on the osmotic gradient between

the contents of the two-layer core and the fluid in the

gastrointestinal tract

Drug release rate may be altered by:

changing the surface area

thickness

composition of the membrane and/or diameter of the drug

release orifice

Release rate is not affected by:

gastrointestinal acidity or alkalinity

fed conditions

gastrointestinal motility

Gastrointestinal therapeutic system (GIT systems)

is employed in the manufacture of Glucotrol XL Extended release

tablets, and Procardia XL release tablets

the initial drug is released 4 to 5 hours after tablet ingestion

REPEAT-ACTION TABLETS

the initial dose of drug is released immediately and a second dose

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

DELAYED-RELEASE ORAL DOSAGE FORMS

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

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

fats

fatty acids

waxes

shellac

cellulose acetate phthalate

EXAMPLES OF 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

Diltiazem extended-release capsules

Disopyramide phosphate extended-release capsules

Isosorbide dinitrate extended-release tablets and capsules

Propanolol hydrochloride extended-release capsules

Theophylline extended-release capsules

USP Requirements and FDA Guidelines for Modified Release Dosage Forms

1. DRUG RELEASE

based on drug dissolution from the dosage unit against elapsed

test time (e.g. Aspirin Extended-release Tablets)

Aspirin dissolution rate:

2. UNIFORMITY OF DOSAGE UNITS

uniformity of dosage units may be demonstrated by either of two

methods, weight variations or content uniformity

3. IN VITRO-IN VIVO CORRELATIONS

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

and release time course and the entire in vivo

response time course

Ex.: the time course of plasma drug concentration or

amount of drug absorbed

Level B

Time (hours) Amount dissolved

1.0 2.0 4.0 8.0

15-40% 25-60% 35-75%

Not less than 70%

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predictive mathematical model of the relationship

between summary parameters that characterize in

vitro and in vivo time courses

Example: models that relate the mean in vivo

dissolution time to the mean in vitro dissolution time

Level C

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

formulation development when pilot formulations are

being selected

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

approaches

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

patients using a modified release product should not be changed

into immediate release without consideration to the blood

concentration

patients should not be changed to another extended-release

product unless there is assurance of equivalent bioavailability

different product can result in a marketed shift in the patient’s

drug blood level because of differences in drug release

characteristics

modified release tablets and capsules should not be crushed or

chewed

patients if fed through the nasogastric tube may receive modified-

release medications

nonerodible plastic matrix shells and osmotic tablets remain

intact throughout gastrointestinal transit and the empty shells or

ghosts from osmotic tablets may be seen in the stool

Propriety Modified-Release Oral Dosage Forms

Delayed-release

Extended-Release Coated Particles and Breads

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Extended-Release Inert Matrix

Extended Release Hydrophilic/Eroding Matrix

Extended-Release Microencapsulated Drug

Extended-Release Osmotic