Rational for Controlled Drug
• Just as cars are useless without roads,
drugs are useless without an effective
• The active ingredient in a medicine is
only part of the arsenal against
• The drug must somehow get to the
right place at the right time. That's
where drug delivery comes in.
• Drug delivery companies work to
devise new dosage forms for
medications. Historically, this has
meant product life-cycle management,
a process in which a pharmaceutical
company looks for ways to set apart a
product reaching the end of its patent
lifetime from the inevitable generic
competition. For example, a company
might tinker with a drug that patients
must take multiple times a day and
reduce that to a single dose.
Nowadays, the competition is so intense
in the pharmaceutical marketplace that
companies look to drug delivery as a way
to gain a competitive advantage. The
value that drug delivery adds can be
improved safety, efficacy, convenience,
and patient compliance.
• As a result of biotechnology
development, many people believe that
proteins are going to comprise an
increasing proportion of the new-drug
• Many existing peptide and protein
drugs are coming off patent, fueling the
interest in developing new dosage
• There is the equivalent of a generic industry
that will likely be developed for peptides and
proteins, analogous to [what evolved with]
• The race is on to develop alternatives to
injection for macromolecules. The main
methods being explored are pulmonary
(inhalation) and oral formulations. In
addition, transdermal and extended-release
injectable formulations are being targeted.
THIS IS ACHIEVED BY
• Better control of plasma drug levels and
less frequent dosing.
• For Linear one compartment PK drugs:
Dose interval ( < )דּt1/2 (Ln TI)/Ln 2
TI is therapeutic index = Cmax/Cmin or
For non-linear multi-compartment PK drugs:
t1/2 is replaced by 0.693*MRT
The dosing interval may be
increased by :
• Modifying the drug molecule to
decrease the rate of elimination.
• Modifying the release rate of a
dosage form to decrease the rate of
Factors influencing the design and
performance of a controlled release
1. Drug properties: physico-chemical
(stability- solubility- partition
2. Route of administration
3. Target sites
4. Acute or chronic therapy
5. The pateint
Advantages of Controlled drug
1. achieve more effective therapies while
eliminating the potential for both under-
2. the maintenance of drug levels within a
3. the need for fewer administrations,
optimal use of the drug in question, and
increased patient compliance.
Disadvantages of controlled drug
1. the possible toxicity or nonbiocompatibility of
the materials used.
2. undesirable by-products of degradation.
3. the chance of patient discomfort from the
delivery device for instance if any surgery
required to implant or remove the system.
4. the higher cost of controlled-release systems
compared with traditional pharmaceutical
Oral Controlled Release
Major challenges to an oral controlled
• Unpredectable gastric emptying time.
• High variations in Gastric emptying due
to factors such as age, race, sex, and
• Limited contact time at the site of
Oral Platform Drug Delivery
• Matrix based on hydrophillic
• Osmotic pumps.
• Diffussion controlled vesicle
Matrix based on hydrophillic
• Drug and excipients are mixed with polymers
such as Hydroxypropyl methylcellulose
(HPMC) and Hydroxypropyl cellulose (HPC).
• Tableted by conventional compression.
• Release from the tablet takes place by
combination of :
- water diffuses into the tablet, swells the
polymer and dissolves the drug.
- drug may diffuse out to be absorbed
Critical factors in Matrix based tablets
• The rate of drug out-diffusion should be
slower than the rate of polymer swelling.
• Tablet porosity affects the water
• Food may alter the rate of drug diffusion
as a result of increased mechanical stress
• In this type of drug
delivery, a core of
pure drug is coated
with a permeable
Very rapid gelling and nearly complete hydration of OCAS delivery system in the upper GI tract ensures drug release
throughout the entire GI tract,
including the colon where water is poorly available. Reprinted from European Urology Supplements, 4(2), Michel MC,
Korstanje C, KrauwinkelW, Kuipers M,
The pharmacokinetic profile of tamsulosin oral controlled absorption system (OCAS1), pp 15–24, 2005, with permission
from European Association of
• Is considered a special type of the previous type in which the
semipermeable membrane :
- allow the water to diffuse in.
- prevent the drug to diffuse out.
Drilling a hole in the outer membrane that allows the passage only
of the dissolved drug.
Diffussion controlled vesicle (DCV(
• The principal of this system is :
- The drug core is coated with a
suspension of a water soluble pore
former in a solution of impenetratable
- This process creates a macroporous
membrane that controls the diffusion of
Bioavailability of Deltiazem DCV Drug
delivery compared with oral solution
Potential drug candidates for gastro-
retentive drug delivery systems:
a. Weakly basic drugs that are poorly soluble in
intestinal pHs and have better dissolution in the
acidic medium of stomach.
b. Drugs that have absorption windows in the upper
part of the small intestine. They will gradually
empty in solution form to the site of absorption.
c. All drugs that are intended for local action on the
gastro-duodenal wall e.g. therapeutic agents of
Drugs that are unsuitable for gastro-retentive
drug delivery system:
a. Enteric coated systems.
b. Drugs intended for selective release in the colon e.g. 5-
aminosalicylic acid and corticosteroids.
c. Drugs that have very limited acid solubility e.g.
d. Drugs that suffer instability in the gastric environment
Approaches for prolonging the
gastric residence time:
• High-density systems.
• Floating systems.
• Swelling and expanding systems.
• The use of passage delaying excipients.
• Superporous hydrogels.
• Mucoadhesive & Bioadhesive systems.
• Magnetic systems
• Gastric contents have a density close to water
( 1.004 g cm− 3). When the patient is upright
small high-density pellets sink to the bottom of the
stomach where they become entrapped in the folds
of the antrum and withstand the peristaltic waves
of the stomach wall.
• A density close to 2.5 g cm−3 seems necessary for
significant prolongation of gastric residence time.
• Barium sulphate, zinc oxide, iron powder,and
titanium dioxide are examples for excipients used.
• These have a bulk density lower than the
gastric content. They remain buoyant in the
stomach for a prolonged period of time, with
the potential for continuous release of drug.
– Hydrodynamically balanced systems
– Gas-generating systems
– Raft-forming systems
– Low-density systems
Schematic localization of an intragastric floating system
and a high-density system in the stomach.
Hydrodynamically balanced systems:
Schematic diagram shows the mode of action for HBSTM
Schematic illustration of the barrier formed by a raft-
Different geometric forms of unfoldable systems proposed by
Caldwell et al. From Caldwell et al. (1988).
On the left, superporous hydrogel in its dry (a) and water-swollen
(b) state. On the right, schematic illustration of the transit of
superporous hydrogel. From Gutierrez-Rocca, (2003).
Mucoadhesive or bioadhesive systems
• The basis of mucoadhesion is that a dosage form can
stick to the mucosal surface by different
• Examples for Materials commonly used for
bioadhesion are poly(acrylic acid) (Carbopol®,
polycarbophil), chitosan, Gantrez® (Polymethyl vinyl
ether/maleic anhydride copolymers), cholestyramine,
tragacanth, sodium alginate.
• the rapid turnover of mucus in the gastrointestinal
tract is the main problem