Modified Release Drug

Products and Targeted Drug

Delivery Systems

Reatul Karim
Lecturer, Dept. of Pharmacy
State University of Bangladesh
 What is drug release?

It is described in different ways-

1. Immediate release drug products refer to the
instantaneous availability of drug for absorption or
pharmacological action.
It allows the drug to dissolve in the GI contents with no
intention of delaying or prolonging the dissolution or
absorption of the drug.
1. Modified release dosage forms whose drug release
characteristics of time course and/or location are
chosen to accomplish therapeutic or convenience
objectives not offered by conventional dosage forms
such as a solution or an IR dosage form. It includes
both delayed and extended release drug products.

2
 Modified-Release Drug Products

The term modified-release drug product is used to

describe products that alter-
# the timing and/or
# the rate of release of the drug substance.

According to USP/NF
A modified-release dosage form is defined as one for
which the drug-release characteristics of time
course and/or location are chosen to accomplish
therapeutic or convenience objectives not offered by
conventional dosage forms such as solutions, ointments,
or promptly dissolving dosage forms as presently
recognized.

4
 Several types of modified-release drug products are recognized:
1. Extended-release drug products: A dosage form that
allows at least a twofold reduction in dosage frequency as
compared to that drug presented as an immediate-release
(conventional) dosage form. Examples of extended-release
dosage forms include controlled-release, sustained-release, and
long-acting drug products.
2. Delayed-release drug products: A dosage form that
releases a discrete portion or portions of drug at a time or at
times other than promptly after administration, although
one portion may be released promptly after administration.
Enteric-coated dosage forms are the most common delayed-
release products.
3. Targeted-release drug products: A dosage form that
releases drug at or near the intended physiologic site of
action. Targeted-release dosage forms may have either
immediate- or extended-release characteristics.
- 4. Pulsatile release products: involves the release of
finite amounts (or pulse) of drug at distinct time
intervals that are programmed into the drug products.

5
 A repeat-action tablet release one dose of drug initially,
followed by a second dose of drug at a later time.
A prolonged-action drug product is designed to release
the drug slowly over an extended period. Most prolonged-
release products extend the duration of action but do not
release drug at a constant rate.
Sustained-release drug product, a constant plasma drug
concentration is maintained with minimal fluctuations. A
prolonged-action tablet is similar to a first-order-release
product except that the peak is delayed differently. A
prolonged-action tablet typically results in peak and trough
drug levels in the body.

6
 The term controlled-release drug product was previously used
to describe various types of oral extended-release rate dosage
forms, including sustained-release, sustained-action, prolonged-
action, long-action, slow-release, and programmed drug delivery.
Other terms, such as ER, SR, XL, XR, and CD, are also used.

Fig: Drug dissolution rates of Fig: Simulated plasmadrug

three different extended-release concentrations resulting from
products in vitro. three different sustained-release
products.
 Kinetics of Extended-Release Dosage
Forms
The amount of drug required in an extended-release dosage form to
provide a sustained drug level in the body is determined by
- the pharmacokinetics of the drug,
- the desired therapeutic level of the drug, and
- the intended duration of action.
In general, the total dose required (Dtot) is the sum of the maintenance
dose (Dm) and the initial dose (DI) released immediately to provide a
therapeutic blood level.

In practice, Dm (mg) is released over a period of time and is equal to the

product of td (the duration of drug release) and the zero-order rate kr0
(mg/hr). Therefore, Equation 1 can be expressed as-
 2
Ideally, the maintenance dose (Dm) is released after DI has produced a
blood level equal to the therapeutic drug level (Cp). However, due to the
limits of formulations, Dm actually starts to release at t = 0. Therefore,
DI may be reduced from the calculated amount to avoid "topping."

Equation 3 describes the total dose of drug needed, where tp

representing the time needed to reach peak drug concentration after the
initial dose.
For a drug that follows a one-compartment open model, the rate of
elimination (R) needed to maintain the drug at a therapeutic level (Cp) is-
4

Where kr0 must be equal to R in order to provide a stable blood level

of the drug.
 Equation 4 provides an estimation of the release rate (kr0) required in
the formulation. Equation 4 may also be written as-

Where ClT is the clearance of the drug. In designing an extended-release

product, DI would be the loading dose that would raise the drug
concentration in the body to Cp, and the total dose needed to maintain
therapeutic concentration in the body would be simply
6

For many sustained-release drug products, there is no built-in loading

dose (ie, DI=0). The dose needed to maintain a therapeutic concentration
for hours is-
7

where is the dosing interval.

 Examples of modified release
dosage forms
A) Oral dosage forms
# Extended release
Prolonged release
Sustained release
Controlled release
# Delayed release
Enteric coated release
B) Intramuscular dosage forms
# Depot injection
# Water immiscible injection (eg, oil)

11
C) Subcutaneous dosage forms
# Implants
D) Transdermal delivery systems
# Patches
# Creams etc.
E) Targeted delivery systems
# Enteric coated tablet

12
 Advantages of Extended-Release
Products
1. Reduction in drug blood level fluctuation: By controlling the
rate of drug release peaks and valleys of drug blood levels are
eliminated.
2. Frequency reduction in dosing: Extended release products
deliver frequently more than a single dose of medication and thus
they may be taken less often than conventional forms.
3. Enhanced patient convenience and compliance: With less
frequency of dose administration, a patient has a lass chance to
miss a dose.
4. Reduction in adverse/side effects: Because there are fewer
drug blood level peaks outside the drugs therapeutic range and
into the toxic range, adverse/side effects occur less frequently.
5. Reduction in overall health care cost: A single dose of
extended release product may cost less than an equivalent drug
dose given several times a day in rapid release tablets. For
patients under nursing care, the cost of nursing time required to
administer medication is decreased if only one drug dose is given
to the patient each day.

13
 Disadvantages of Extended-Release
Products
1. Withdrawal of dose: If the patient suffers from an adverse
drug reaction or accidentally becomes intoxicated, the removal
of drug from the system is more difficult with an extended-
release drug product.
2. Erratic drug absorption: Orally administered extended-
release drug products may yield erratic or variable drug
absorption as a result of various drug interactions with the
contents of the GI tract and changes in GI motility.
3. Not feasible in large doses: The formulation of extended-
release drug products may not be practical for drugs that are
usually given in large doses (e.g., 500 mg) in conventional
dosage forms. Because the extended-release drug product
generally contain two or more times the dose given at more
frequent intervals and size becomes too large for the patient to
swallow easily.

14
4. Dose dumping: The extended-release dosage form
contains the equivalent of two or more drug doses given in a
conventional dosage form, the failure of the extended-
release dosage form may lead to dose dumping.
5. Drugs absorbed in proximal intestine are not
compatible: Drugs that are efficiently absorbed only in the
proximal intestine should not be administered in a prolonged
release product just to avoid incomplete absorption.
6. Poor formulation: With delayed release or enteric drug
products, two possible problems may occur if the enteric
coating is poorly formulated. First, the enteric coating may
become degraded in the stomach, allowing for early release
of the drug, possibly causing irritation. Second, the enteric
coating may fail to dissolve at the proper site, and tablet
may be lost prior to drug release, resulting in incomplete
absorption.

15
7. Toxic metabolites may be formed: Microorganisms in
the lower bowel may enzymatically reduce a drug, leading
to metabolites that are not ordinarily seen after
administration of the drug in conventional dosage forms.
Bacterial metabolism may decrease bioavailability or result
in toxic metabolites.
8. Effect of food is still unpredictable: We can not still
predict the effect of food on the bioavialability of drugs
given in prolonged release dosage forms.

16
 Biopharmaceutic Factors

The major objective of an extended-release drug product

is to achieve a prolonged therapeutic effect while
minimizing unwanted side effects due to fluctuating
plasma drug levels. Ideally, the extended-release drug
product should-
-release the drug at a constant, or zero-order rate
-absorption should be at zero-order rate
But unfortunately, most extended-release drug products-
-release a drug by zero-order kinetics in vitro
-release do not follow zero-order drug rate in vivo.
This is due to unpredictable events happening in the
gastrointestinal tract.

17
 1) Stomach

In presence of food: In the presence of food, the stomach

is in the digestive phase. During the digestive phase, the
food particles or solids larger than 2 mm are retained in the
stomach and smaller particles are emptied. A drug may
remain for several hours in the stomach if it is administered
during the digestive phase.
Dissolution of drugs in the stomach may also be affected by
the presence or absence of food. For example, the
extended-release drug product Theo-24 was shown to
release drug at a higher rate in the presence of food.
In absence of food: In the absence of food, the stomach is
in the inter-digestive phase. The stomach rests for a period
of up to 30 to 40 minutes. If the drug is administered during
the inter-digestive phase, the drug may be swept along
rapidly into the small intestine.

18
 2) Small Intestine

The small intestine provides an enormous surface area

for drug absorption because of the presence of
microvilli. The small-intestine transit time of a solid
preparation has been concluded to be about 3 hours.
Lactulose hydrogen test is used to estimate transit
time.
The transit time for pellets has been studied in both
disintegrating and non-disintegrating forms. Most of the
insoluble pellets were released from the capsule within
15 minutes. Scattering of pellets were seen in the
stomach.
With the disintegrating pellets, there was more
scattering of the pellets along the GI tract.

19
 3) Large Intestine

It consists of the cecum, the ascending and descending

colons, and eventually ends at the rectum. Little fluid is
in the colon, and drug transit is slow. unabsorbed drug
that reaches this region may be metabolized by
bacteria. Drugs are absorbed rapidly when
administered as rectal preparations.
Several extended-release and delayed-release drug
products (such as mesalamine delayed-release tablets),
are formulated to take advantage of the physiologic
conditions of the GI tract. Enteric-coated beads have
been found to release drug over 8 hours when taken
with food.

20
 Dosage Form Selection
The selection of the drug and dosage form is important in
formulating a sustain release product.

Drug with low aqueous solubility

-should not be formulated into a non-disintegrating
tablet
-risk of incomplete drug release

It should be formulated, so that most of the drug is released

before it reaches the colon.

Erosion tablets are more reliable for these drugs because

the entire tablet eventually dissolves.

21
 drug that is highly water soluble in the acid pH in the stomach but
very insoluble at intestinal pH
-may be very difficult to formulate into an extended-release product
-too much coating protection may result in low bioavailability,
-a moderate extension of duration with enteric-coated beads may be
possible
-the risk of erratic performance is higher
-the osmotic type of controlled system may be more suitable

With most single-unit dosage forms,

-there is a risk of erratic performance
-selection of a pellet or bead dosage form minimize the risk of erratic
stomach emptying
-disintegrating tablets have the same advantages because they
break up into small particles

22
Some mechanisms of modified drug
release
Pharmaceutical modification: The rate of drug release
is reduced by increasing particle size or forming insoluble
crystals (e.g.: Tegretol Retard or Adalat Retard).

Coated pellets: Drug pellets are coated with a slowly

dissolving polymer of varying thickness for varied release.
The pellets can either be compressed into a tablet or put
in a gelatin capsule (e.g.: Fenbid, Slo-phyllin or Inderal-LA).

Insoluble matrix: The drug is dispersed within an

insoluble porous matrix. As fluid enters the matrix, the
drug is dissolved and diffuses out slowly (e.g.: Slow-K,
Imdur or Betaloc-SA).

23
 Eroding matrix: The drug is dispersed within a soluble matrix.
As the matrix is eroded, the drug is slowly released (e.g.: MST
Continus or Phyllocontin Continus).

Osmotic pump: The drug and an osmotic agent are enclosed

by a semipermeable membrane. As water is drawn into the
tablet, dissolving drug is released in a controlled way through a
laser-drilled hole (e.g.: Volmax, Adalat LA).

pH sensitive coating: The formulation is coated with a

polymer of pH dependent solubility for site specific delivery. This
can either avoid drug release in the stomach (entric coating)
e.g.: Nu-Seals Aspirin or spacifically deliver drug to the colon
e.g.: Asacol.

24
 Types of Extended-Release Products
General approaches to manufacturing an extended-release
drug product include-
-the use of a matrix structure in which the drug is
suspended or dissolved,
-the use of a rate-controlling membrane through which
the drug diffuses, or
-a combination of both.
Most extended-release products release drug by a
combination of processes involving-
-dissolution,
-permeation, and
-diffusion.
The most important factor is water permeation, without
which none of the product controls the rate drug dissolution.
Once the drug is dissolved, the rate of drug diffusion may be
further controlled to a desirable rate.

25
 A) Drug Release from Matrix
A matrix is an inert solid vehicle in which a drug is
uniformly suspended. A matrix may be formed by
compressing or fusing the drug and the matrix material
together. The matrix protects the drug from rapid
dissolution. Most matrix materials are water insoluble. Drug
release using a matrix dosage form may be achieved using
tablets or small beads.
In figure A, the drug is coated with a soluble coating. Drug
release depends on the regulation of drug release by the
matrix material. If the matrix is porous, water penetration
will be rapid and the drug will diffuse out rapidly. A less
porous matrix may give a longer duration of release.
Figure B, represents a matrix enclosed by an insoluble
membrane. The drug release rate is regulated by the
permeability of the membrane as well as the matrix.

26
 Fig: Examples of three different types of modified matrix-release
mechanisms.

Figure C, represents a matrix tablet enclosed with a combined

film. The film becomes porous after dissolution of the soluble
part of the film. An example of this is the combined film formed
by ethylcellulose and methylcellulose.
 Some
B) Gum-Type Matrix Tablets
excipients have a remarkable ability to swell in the
presence of water and form a substance with a gel-like consistency.
The gel provides a natural barrier to drug diffusion from the tablet.
Because the gel-like material is quite viscous and may not disperse for
hours, this provides a sustained action of drug for hours.
A common gelling material is gelatin. Gelatin disperse rapidly after
the gel is formed. Drug excipients, such as-
-methylcellulose,
-gum tragacanth,
-Veegum, and
-alginic acid
form a viscous mass and provide a useful matrix for controlling drug
dissolution. Drug formulation with these excipients provides sustained
drug release for hours.
For example, diazepam has been formulated using methylcellulose
to provide sustained release. In this case hydrocolloid (gel) floated
in the stomach to give sustained release.
The most important consideration in this type of formulation is the
gelling strength of the gum material.

28
 C) Polymeric Matrix Tablets

The most important characteristic of this type of

preparation is that the prolonged release may last for
days or weeks rather than for a shorter duration.
Example: Gradumet (Abbott Laboratories), which is
marketed as an iron preparation. The plastic matrix
provides a rigid geometric surface for drug diffusion, so
that a relatively constant rate of drug release is
obtained.

29
 Polymers used
The use of the matrix tablet in implantation has been more
popular. The use of biodegradable polymeric material,
polylactic acid copolymer, which degrades to natural
lactic acid and eliminates the problem of retrieval after
implantation.
The number of polymers available for drug formulations is
increasing and includes-
polyacrylate
methacrylate
polyester
polyglycolide
polylactide
silicone
ethylenevinyl acetate copolymer (EVA)

30
 Of these, the hydrophilic polymers, such as polylactic acid and
polyglycolic acid, erode in water and release the drug
gradually over time.

A hydrophobic polymer such as EVA releases the drug over a

longer duration time of weeks or months. The rate of release may
be controlled by blending two polymers and increasing the
proportion of the more hydrophilic polymer, thus increasing the
rate of drug release.

The type of plasticizer and the degree of cross-linking provide

additional means for modifying the release rate of the drug.

31
 Limitations

For certain patients with reduced GI motility caused

by disease, polymeric matrix tablets should be
avoided, because accumulation or obstruction of the
GI tract by matrix tablet has been reported.
For oral drug delivery, incomplete drug release from
the matrix dosage form may occur.
Another problem is that drug release rates may be
affected by the amount of drug loaded.

32
 D) Pellet-Type Sustained-Release
Productsdrug product is also often
The pellet type of sustained-release
referred to as a bead-type dosage form. The beads are
prepared by coating drug powder onto preformed cores called
nonpareil seeds. Preparation of the cores is tedious.
The drug-coated beads generally provide a rapid-release carrier
for the drug depending on the coating solution used. Coatings
may be aqueous or non-aqueous. Aqueous coatings are
preferred. Non-aqueous coatings may leave residual solvents in
the product.
Cores are coated by either sprayed pan coating or by air-
suspension coating. Once the drug beads are prepared, they
may be further coated with a protective coating to allow a
sustained or prolonged release of the drug.
Some products take advantage of bead blending to provide two
doses of drug in one formulation. For example, a blend of rapid-
release beads with some pH-sensitive enteric-coated material
may provide a second dose of drug release when the drug
reaches the intestine. The pellet dosage form can be prepared
as a capsule or tablet.
33
Fig: Incidence of Adverse Effects of Sustained-Release Theophylline
Pellet versus Theophylline Solution

34
 Example

Dextroamphetamine sulfate timed-release pellets

(Dexedrine Spansule) is an early example of a beaded
dosage form. Another older product is a pellet-type
extended-release product of theophylline (Gyrocap).
If theophylline is administered as a solution, a high drug
concentration may be reached in the body due to rapid
drug absorption. Some side effects may be attributed to
the high concentration of theophylline. Pellet dosage
form allows drug to be absorbed gradually, therefore
reducing the incidence of side effects by preventing a
high Cmax.
A second example involves the drug bitolterol mesylate
(Tornalate). The incidence of tachycardia was reduced
using an extended-release bead preparation, whereas
the bronchodilation effect was not reduced.

35
 Advantages

Formulation of a drug into pellet form may reduce

gastric irritation, because the drug is released slowly
over a period of time.
A major advantage of the pellet dosage form is that the
pellets are less affected by the effect of stomach
emptying. Because numerous pellets are within a
capsule, some pellets will gradually reach the small
intestine.
Enteric-coated tablets may be delayed for hours by the
presence of food in the stomach, whereas enteric-
coated pellets are relatively unaffected by the
presence of food.

36
 E) Prolonged-Action Tablets
An approach to prolong the action of a drug is to reduce the
aqueous solubility of the drug, so that the drug dissolves
slowly over a period of several hours. The solubility of a drug
is dependent on the salt form used.
In general, the base or acid form of the drug is usually
much less soluble than the corresponding salt. For
example, sodium phenobarbital is more water soluble than
phenobarbital, the acid form of the drug.
Diphenhydramine hydrochloride is more soluble than the
base form, diphenhydramine.
In cases where it is inconvenient to prepare a less soluble
form of the drug, the drug may be granulated with an
excipient to slow dissolution of the drug.

37
 Stearic acid, castor wax, high-molecular-weight
polyethylene glycol (Carbowax), glyceryl monosterate,
white wax, and spermaceti oil are useful ingredients in
providing an oily barrier to slow water penetration and the
dissolution of the tablet.
Many lubricants used in tableting may also be used as
lipophilic agents to slow dissolution. For example,
magnesium stearate and hydrogenated vegetable oil
(Sterotex) are used to cause sustained drug release
preparation of a drug.

Limitations
There is the difficulty in maintaining a reproducible drug
release from patient to patient, because oily materials
may be subjected to digestion, temperature, and
mechanical stress, which may affect the release rate of
the drug.
38
 F) Ion-Exchange Products

Ion-exchange preparations usually involve an insoluble

resin capable of reacting with either an anionic or
cationic drug.
An anionic resin is negatively charged so that a
positively charged cationic drug may react with the
resin to form an insoluble non-absorbable resin
drug complex. Upon exposure in the GI tract, cations
in the gut, such as potassium and sodium, may
displace the drug from the resin, releasing the drug.

39
 Disadvantage

The amount of cationanion in the GI tract is not

easily controllable and varies among individuals,
making it difficult to provide a consistent mechanism or
rate of drug release.
Resins may provide a potential means of interaction
with nutrients and other drugs.

40
 Advantage
Ion exchange may be used in extended-release liquid
preparations
the technique provides some protection for very bitter
or irritating drugs
Ion exchange has been combined with a coating to
obtain a more effective sustained-release product.
A general mechanism for the formulation of cationic drugs
is-
 G) Core Tablets
A core tablet is a tablet within a tablet. The core is
usually used for the slow-drug-release component, and
the outside shell contains a rapid-release dose of drug.
Formulation of a core tablet requires two granulations.
The core granulation is usually compressed lightly to
form a loose core and then transferred to a second die
cavity, where a second granulation containing additional
ingredients is compressed further to form the final tablet.

42
 The core material may be surrounded by hydrophobic
excipients so that the drug leaches out over a prolonged
period of time. This type of preparation is sometimes called a
slow-erosion core tablet, because the core generally
contains either no disintegrant or insufficient disintegrant to
fragment the tablet.
The success of core tablets depends very much on the
nature of the drug and the excipients used. This
preparation is very much hardness dependent in its
release rate.
Core tablets are occasionally used to avoid incompatibility
in preparations containing two physically incompatible
ingredients. For example, buffered aspirin has been
formulated into a core and shell to avoid a yellowing
discoloration of the two ingredients upon aging.

43
 H) Microencapsulation

Microencapsulation is a process of encapsulating

microscopic drug particles with a special coating
material.
Example
Aspirin has been microencapsulated with ethyl
cellulose, making the drug superior in its flow
characteristics; when compressed into a tablet, the
drug releases more gradually compared to a simple
compressed tablet.

44
 Techniques

Many techniques are used in microencapsulating a drug.

One process used in microencapsulating
acetaminophen involves suspending the drug in an
aqueous solution while stirring.
The coating material, ethyl cellulose, is dissolved in
cyclohexane is evaporated by heat, the ethylcellulose
coats the micro particles of the acetaminophen.
The microencapsulated particles have a slower
dissolution rate because the ethyl cellulose is not
water soluble and provides a barrier for diffusion of drug.
The amount of coating material deposited on the
acetaminophen determines the rate of drug dissolution.
The coating also serves as a means of reducing the
bitter taste of the drug.

45
 I) Osmotic Extended-Release
Products
The osmotic pump represents a newer concept in
extended-release preparations. Drug delivery is
controlled by the use of an osmotically controlled
device that promotes a constant amount of water
into the system, either by dissolving and releasing a
constant amount of drug per unit time.

46
 Mechanism

Drug is released via a single laser-drilled hole in the

tablet. One preparation consists of an outside layer of
semipermeable membrane filled with a mixture
of drug and osmotic agent. When the device is
placed in water, osmotic pressure generated by the
osmotic agent within the core causes water to move
into the device, which forces the dissolved drug to
move out of the drug delivery orifice.

47
 Example
A similar osmotic product available for implantation is the
osmotic minipump.
Another osmotic oral drug product is the "pushpull"
system called Gastrointestinal Therapeutic System
(GITS). The system consists of a semipermeable
membrane and a two-layer core of osmotic ingredient
and active drug. As water enters the system, the osmotic
pressure builds up from the inner layer, pushing the drug
out through a laser-drilled orifice in the drug layer. An
example of GITS uses acetazolamide for the treatment of
ocular hypertension in glaucoma.
Fig: Cross-sectional diagram of gastrointestinal therapeutic system.

The frequency of side effects experienced by patients

using GITS was considerably less than that with
conventional tablets.
 A newer osmotic delivery system is the L-Oros Softcap
(Alza), which claims to enhance bioavailability of poorly
soluble drug by formulating the drug in a soft gelatin
core and then providing extended drug delivery through an
orifice drilled into an osmotic driven shell.

Fig: Configuration of L-OROS SOFTCAP

 The soft gelatin capsule is surrounded by the barrier layer,
the expanding osmotic layer, and the release-rate-
controlling membrane.
When the system is administered, water permeates
through the rate-controlling membrane and activates the
osmotic engine. As the engine expands, hydrostatic
pressure inside the system builds up, thereby forcing the
liquid formulation to break through the hydrated gelatin
capsule shell at the delivery orifice and be pumped out
of the system. At the end of the operation, liquid drug fill is
squeezed out, and the gelatin capsule shell becomes
flattened. The osmotic layer, located between the inner
layer and the rate-controlling membrane, is the driving force
for pumping the liquid formulation out of the system.

51
 J) Transdermal Drug Delivery
Systems
A transdermal drug delivery system (or patch) is a drug-
dosage form intended for delivering a dose of medication
across the skin for systemic drug absorption.
Drug diffusion is controlled by a semipermeable
membrane next to the reservoir layer. In general, the
patch contains several parts:
(1) a backing or support layer,
(2) a drug layer (reservoir containing the dose),
(3) a release-controlling layer (usually a semipermeable
film),
(4) a pressure-sensitive adhesive (PSA), and
(5) a protective strip, which must be removed before
application.

52
 Example

Nitroglycerin is commonly administered by transdermal

delivery. Transdermal delivery systems of nitroglycerin
may provide hours of protection against angina

Fig: The four basic configurations for transdermal drug delivery systems.
 Criteria

The drug must be highly potent so that only a small

systemic drug dose is needed
The size of the patch should not be greater than 50
cm2
The drug include a small molecular weight (<500
Da)
The drug should have high lipid solubility
The elimination half-life should not be too short, to
avoid having to apply the patch more frequently than
once a day.

54
 The solubility of drug in the skin rather than the
concentration of drug in the patch layer is the most important
factor controlling the rate of drug absorption through the skin.
The amount of drug absorbed transdermally is related to-
# the amount of drug in the patch
# the size of the patch and
# the method of manufacture
Alzone, a permeation enhancer, is a solvent that increases
the absorption of many drugs through the skin. This solvent is
relatively non-toxic.
For ionic drugs, absorption may be enhanced transdermally by
iontophoresis, a method in which an electric field is
maintained across the epidermal layer with special
miniature electrodes.
Limitation
An important limitation of transdermal preparation is the
amount of drug that is needed in the transdermal patch to
be absorbed systemically to provide the optimum therapeutic
response.
55
 Considerations in the Evaluation of Modified-Release
Products
The two important requirements for preparing extended-
release products are-
(1)demonstration of safety and efficacy and
(2) demonstration of controlled drug release.

Bioavailability Data Requirements for MRD

The bioavailability data requirements are specified in the

Code of Federal Regulations. The important points are as
follows:
1. The product should demonstrate sustained release, as
claimed, without dose dumping
2. The drug should show steady-state levels comparable to
those reached using a conventional dosage form given in
multiple doses, and which was demonstrated to be effective.

56
3. The drug product should show consistent pharmacokinetic
performance between individual dosage units.
4. The product should allow for the maximum amount of drug
to be absorbed while maintaining minimum patient-to-
patient variation.
5. The demonstration of steady-state drug levels after the
recommended doses are given should be within the
effective plasma drug levels for the drug.
6. An in-vitro method and data that demonstrate the
reproducible extended-release nature of the product
should be developed. The in-vitro method usually consists of a
suitable dissolution procedure that provides a meaningful
in-vitroin-vivo correlation.
7. In-vivo pharmacokinetic data consist of single and
multiple dosing comparing the extended-release product to
a reference standard.

57
Thank you

58