Chapter 9 Solid Oral Modified-Release Dosage Forms and Drug Delivery Systems

The Rationale for Extended-Release Pharmaceuticals

Some drugs are inherently long lasting and require only once-a-day oral dosing to sustain
adequate drug blood levels and the desired therapeutic effect. These drugs are formulated in the
conventional manner in immediate-release dosage (IR) forms. However, many other drugs are
not inherently long lasting and require multiple daily dosing to achieve the desired therapeutic
results.
Multiple daily dosing is: 1. inconvenient for the patient, 2. can result in missed doses, made-up
doses, and, 3. noncompliance with the regimen. When conventional immediate-release dosage
forms are taken on schedule and more than once daily, they cause sequential therapeutic blood
level peaks and valleys (troughs) associated with the taking of each dose (See diagram below).
However, when doses are not administered on schedule, the resulting peaks and valleys reflect
less than optimum drug therapy. For example, if doses are administered too frequently, minimum
toxic concentrations of drug may be reached, with toxic side effects resulting. If doses are
missed, periods of subtherapeutic drug blood levels or those below the minimum effective
concentration may result, with no benefit to the patient.

Hypothetical drug blood level–time curves for a conventional solid dosage form and a multiple-
action product. (MEC, minimum effective concentration; MTC, minimum toxic concentration)
Extended-release tablets and capsules are commonly taken only once or twice daily, compared
with counterpart conventional forms that may have to be taken three or four times daily to
achieve the same therapeutic effect. Typically, extended-release products provide an immediate
release of drug that promptly produces the desired therapeutic effect, followed by gradual release
of additional amounts of drug to maintain this effect over a predetermined period (see diagram
below). The sustained plasma drug levels provided by extended-release products oftentimes
eliminate the need for night dosing, which benefits not only the patient but the caregiver as well.

For non-oral rate-controlled drug delivery systems, the drug-release pattern ranges in duration
from 24 hours for most transdermal patches to 3 months for the estradiol vaginal ring insert.

Hypothetical drug blood level–time curves for a conventional solid dosage form and a
controlled-release product. (MEC, minimum effective concentration; MTC, minimum toxic
concentration

Terminology
Many terms (and abbreviations), such as:
1) Sustained release (SR), 2) sustained action (SA), 3) prolonged action (PA), 4) controlled
release (CR), 5) extended release (ER), 6) timed release (TR), and 7) long acting (LA), have
been used by manufacturers to describe product types and features.
Although these terms often have been used interchangeably, individual products bearing these
descriptions may differ in design and performance and must be examined individually to
ascertain their respective features. For the most part, these terms are used to describe orally
administered dosage forms, whereas the term rate-controlled delivery is applied to certain types
of drug delivery systems in which the rate of delivery is controlled by features of the device
rather than by physiologic or environmental conditions like gastrointestinal pH or drug transit
time through the gastrointestinal tract.
Modified Release
In recent years, modified release has come into general use to describe dosage forms having
drug-release features based on time, course, and/or location that are designed to accomplish
therapeutic or convenience objectives not offered by conventional or immediate-release forms.
The US Pharmacopeia (USP) differentiates modified-release forms as extended release and
delayed release.
Extended Release
Extended-release dosage form is one that allows a reduction in dosing frequency from that
necessitated by a conventional dosage form, such as a solution or an immediate-release dosage
form.
Delayed Release
A delayed-release dosage form is designed to release the drug at a time other than promptly after
administration. The delay may be time based or based on the influence of environmental
conditions, like gastrointestinal pH.
• Protect a drug destroyed by gastric fluids
• Reduce gastric distress caused by drugs particularly irritating to the stomach
• Facilitate GI transit for drugs that are better absorbed from the intestines
• Enteric coatings: time, pH, or enzyme dependent

Repeat Action
Repeat-action forms usually contain two single doses of medication, one for immediate release
and the second for delayed release. Two-layer tablets, for example, may be prepared with one
layer of drug for immediate release with the second layer designed to release drug later either as
a second dose or in an extended-release manner.
Targeted Release
Targeted release describes drug release directed toward isolating or concentrating a drug in a
body region, tissue, or site for absorption or for drug action.

Extended-Release Oral Dosage Forms

Not all drugs are suited for formulation into extended-release products, and not all medical
conditions require treatment with such a product. The drug and the therapeutic indication must
be considered jointly in determining whether or not to develop an extended-release dosage form.
Drug Candidates for Extended-Release Products
To be a successful extended-release product, the drug must be released from the dosage form at a
predetermined rate, dissolved in the gastrointestinal fluids, maintained at sufficient
gastrointestinal residence time, and absorbed at a rate that will replace the amount of drug being
metabolized and excreted.
Candidate for ER
Drugs best suited for incorporation into an extended-release product have the following
characteristics:
1. They exhibit neither 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.
2. Drugs with very short half-lives, that is, less than 2 hours, are poor candidates for ER because
of the large quantities of drug required for such a formulation.
3. Drugs that act by affecting enzyme systems may be longer acting than indicated by their
quantitative half-lives because of residual effects and recovery of the diminished biosystem.
They are uniformly absorbed from the gastrointestinal tract.
4. Drugs prepared in extended-release forms 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.
5. They are administered in relatively small doses. Drugs with large single doses frequently are
not suitable for ER 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.
6. They possess a good margin of safety. For very potent drugs, the therapeutic index may be
narrow or very small. The larger the therapeutic index, the safer the drug.
7. Drugs that are administered in very small doses or possess very narrow therapeutic indices are
poor candidates for formulation into extended-release formulations because of technologic
limitations of precise control over release rates and the risk of dose dumping because of a
product defect. Patient misuse (e.g., chewing dosage unit) also could result in toxic drug levels.
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.

Tablet Coatings

• Protect ingredients from light, air, moisture, etc.

• Mask an objectionable taste or odor

• Improve the appearance of the dosage form

• Modify the release rate of the drug

Enteric Coatings

• Do not disintegrate in the stomach but do disintegrate in the intestinal fluids.

– Control the site of drug release

– Protect activity of the drug from the gastric pH

– Prevent nausea or gastric irritation

Advantages of Extended-Release Dosage Forms over Conventional Forms

Advantage Explanation
1.Less fluctuation
Controlling rate of release eliminates peaks and valleys of blood
in drug blood
levels.
levels

2.Frequency Extended-release products frequently deliver more than a single

reduction in dose, hence may be taken less often than conventional forms.
dosing

3.Enhanced With less frequency of dosing, a patient is less apt to neglect taking a
convenience and dose; also greater convenience with day and night administration.
compliance

4.Reduction in Because of fewer blood level peaks outside therapeutic range and
adverse side into toxic range, adverse side effects are less frequent.
effects
5. Reduction in Although initial cost of extended-release dosage forms may be
overall health greater than for conventional forms, overall cost of treatment may be
care costs less because of enhanced therapeutic benefit, fewer side effects, and
Advantage Explanation
reduced time for health care personnel to dispense and administer
drugs and monitor patients.

Multitablet System
Small spheroid compressed tablets 3 to 4 mm in diameter may be prepared to have varying drug-
release characteristics. They then may be 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:
Microencapsulated Drug
Microencapsulation is a process by which solids or liquids may be enclosed in microscopic
particles by formation of thin coatings of wall material around the substance.
Advantages of microencapsulation is that the administered dose of a drug is subdivided into
small units that are spread over a large area of the gastrointestinal tract, which may enhance
absorption by diminishing local drug concentration.
Reasons for Microencapsulation
• Environmental protection

• Gastric irritation reduction

• Liquid–solid conversion

• Odor/taste masking

• Separation of incompatibilities

• Sustained release

• Targeting

Mechanism of action of drug release from Pump delivery system

The pioneer oral osmotic pump drug delivery system is the OROS system developed by Alza.
The system is composed of a core tablet surrounded by a semipermeable membrane coating
having a 0.4-mm-diameter hole produced by laser beam. The core tablet has two layers, one
containing the drug (the active layer) and the other containing a polymeric osmotic agent (the
push layer). The system operates on the principle of osmotic pressure.
A: Elementary OROS (oral release osmotic system) osmotic pump drug delivery system. B:
Push–pull osmotic system.

1. When the tablet is swallowed, the semipermeable membrane permits water to enter from the
patient's stomach into the core tablet, dissolving or suspending the drug.
2. As pressure increases in the osmotic layer, it pumps the drug solution out of the delivery
orifice on the side of the tablet.
3. Only the drug solution (not the undissolved drug) is capable of passing through the hole in the
tablet. The system is designed such that only a few drops of water are drawn into the tablet each
hour.
4. The rate of inflow of water and the function of the tablet depend on an osmotic gradient
between the contents of the two-layer core and the fluid in the gastrointestinal tract. Drug
delivery is essentially constant as long as the osmotic gradient remains constant.
5. The drug-release rate may be altered by changing the surface area, thickness or composition of
the membrane, and/or diameter of the drug-release orifice.
6. The drug-release rate is not affected by gastrointestinal acidity, alkalinity, fed conditions, or
gastrointestinal motility. The biologically inert components of the tablet remain intact during
gastrointestinal transit and are eliminated in the feces as an insoluble shell.
This type of osmotic system, termed the gastrointestinal therapeutic system (GITS [Pfizer]), is
employed in the manufacture of Glucotrol XL ER tablets and Procardia XL ER tablets.

Clinical Considerations for patients taking ER

• Patients should be advised of:
− Dose and dosing frequency
− Do not use them interchangeably with IR
− Do not crush or chew
− Nasogastric (NG) and percutaneous endoscopic gastrostomy (PEG) tube patients
− Non-erodible plastic matrix shells and osmotic tablets remain intact in the stool.
1. Patients should be advised of the dose and dosing frequency of modified drug-release products
and instructed not to use them interchangeably or concomitantly with immediate-release forms of
the same drug.
2. Patients stabilized on a modified-release product should not be changed to an immediate-
release product without consideration of any existing blood level concentrations of the drug.
3. Patients should be advised that modified-release tablets should not be crushed or chewed,
because such action compromises their drug-release features.
4. Patients being fed by enteral nutrition through a nasogastric tube may receive conventional or
modified-release medication. For example, coated pellets from inside capsules simply may be
mixed with water and poured down the feeding tube.
5. Patients and caregivers should be advised that non-erodible 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. The patient should be assured of the normalcy of this
event and that drug absorption has taken place.