CONTROLLED RELEASE

FORMULATIONS
 “Ideal” Drug Delivery System

• Inert
• Biocompatible
• Mechanically strong
• Comfortable for the patient
• Capable of achieving high drug loading
• Safe from accidental release
• Simple to administer and remove
• Easy to fabricate and sterilize
• Free of leachable impurities
• Sustained release:
– any dosage form that provides medication over an
extended time
• timed release, prolonged release etc

• Controlled release:
Controlled drug delivery is one which delivers the drug at a
predetermined rate, for locally or systemically, for a specified
period of time
Advantages of Controlled Drug Delivery

• Eliminate over or under dosing

• Maintain drug levels in desired range
• Need for less dosing
• Increased patient compliance
• Prevention of side effects
 Potential Limitations
• Delay in onset of drug action
• Possibility of dose dumping in the case of a poor
formulation strategy
• Increased potential for first pass metabolism
• Greater dependence on GI residence time of dosage
form
• Possibility of less accurate dose adjustment in some
cases
• Not all drugs are suitable for formulating into ER
dosage form
 Examples
Pills, capsules and injectable drug carriers(that often
have an additional release function), forms of controlled
release medicines include gels, implants
and transdermal patches.
 Design of Controlled Drug Delivery
• Biopharmaceutic Characteristics of the Drug
Molecular weight, Aqueous solubility, Partition coefficient,
Drug Pka and Ionization, Route of administration, Drug
stability etc

• Pharmacokinetic Characteristics of the Drug

Absorption rate, Elimination Half-Life, Rate of metabolism
etc.

• Pharmacodynamic Characteristics of the Drug

Therapeutic Range, Therapeutic index, Plasma
concentration response relationship
 Examples of Controlled Drug Delivery
Formulations

• Depends on the formulation and the application, the time of

release can be quite varied
• Procardia XL - 24 hours
• Lupron Depot - 1 month
• Norplant - 5 years
 Terminology
• The following terms have been applied to “extended”
or “controlled” drug delivery systems:
– Controlled-release (CR)
– Extended release (ER)
– Sustained-release (SR)
– Timed-release (TR)
– Long-acting (LA)
– Prolonged-action (PA), and
– Sustained-action (SA)
 Current Polymers used in Controlled
Drug Delivery

These polymers became usable in controlled delivery due to

their inert physical characteristics and being free of leachable
impurities

– Poly 2-hydroxy ethyl methacrylate

– Polyvinyl alcohol
– Polyacrylic acid
– Polyethylene glycol
– Polymethacrylic acid
 Controlled release society (CRS)
• The CRS is the worldwide society for delivery science and
technologies. CRS serves more than 1,600 members from
more than 50 countries. Two-thirds of CRS membership is
represented by industry and one-third represents academia and
government. CRS is affiliated with the
Journal of Controlled Release and Drug Delivery and
Translational Research scientific journals.
 Novel drug delivery systems
• Dissolution controlled Systems
• Dissolution systems must have the system dissolved slowly in
order for the drug to have sustained release properties which can
be achieved by using appropriate salts and/or derivatives as well
as coating the drug with a dissolving material.
• It is used for drug compounds with high solubility in water.When
the drug is covered with some slow dissolving coat, it will
eventually release the drug. Instead of diffusion, the drug release
depends on the solubility and thickness of the coating. Because of
this mechanism, the dissolution will be the rate limiting factor
here for drug release.Dissolution systems can be broken down to
subcategories called reservoir devices and matrix devices.
A. The reservoir device coats the drug with an appropriate
material which will dissolve slowly. It can also be used
to administer beads as a group with varying thickness,
making the drug release in multiple times creating a SR.
B. The matrix device has the drug in a matrix and the
matrix is dissolved instead of a coating. It can come
either as drug impregnated spheres or drug impregnated
tablets.
 Diffusion Systems

• Diffusion systems rate release is dependent on the rate at

which the drug dissolves through a barrier which is usually a
type of polymer. Diffusion systems can be divided into two
subcategories:
1.reservoir devices
2. matrix devices
• Reservoir devices coat the drug with polymers and in order for
the reservoir devices to have sustained release effects, the
polymer must not dissolve and let the drug be released through
diffusion
• Matrix devices forms a matrix (drug(s) mixed with a gelling
agent) where the drug is dissolved/dispersed..The drug is
usually dispersed within a polymer and then released by
undergoing diffusion.
 Characteristics of Matrix Diffusion Systems

• Advantages
– easier to produce than reservoir devices
– can deliver high molecular-weight compounds
• Disadvantages
– cannot obtain zero-order release
– removal of remaining matrix is necessary for implanted
systems
 Osmotic Systems

• osmotic pressure provides the driving force to generate

controlled release of drug.

• Consider a semipermeable membrane that is permeable to

water, but not to drug. When this device is exposed to water or
any body fluid, water will flow into the tablet owing to the
osmotic pressure difference.
 Types of Osmotically Controlled
Systems
• Type A contains a osmotic core with drug

• Type B contains the drug solution in a flexible bag, with the

osmotic core surrounding
 Ion-exchange Resin

• In the ion-exchange method, the resins are cross-linked water-

insoluble polymers that contain ionisable functional groups
that form a repeating pattern of polymers, creating a polymer
chain.
• The drug is attached to the resin and is released when an
appropriate interaction of ions and ion exchange groups occur.
The area and length of the drug release and number of cross-
link polymers dictate the rate at which the drug is released,
determining the SR effect.
 Characteristics of Osmotically
Controlled Devices
• Advantages
– Zero-order release is obtainable
– reformulation is not required for different drugs
– release of drug is independent of environment of the
system

• Disadvantages
– systems can be very expensive
– quality control is more extensive
 pH sensitive drug delivery system
• Controlled drug delivery systems, which are
intended to deliver drugs at predetermined rates
for predefined periods of time, have been used
to overcome the shortcomings of conventional
drug formulations. Although, significant progress
has been made in the controlled drug delivery
area, more advances are yet to be made for
treating many clinical disorders, such as diabetes
and rhythmic heart disorders.
DISEASES TARGETING pH SENSITIVE DRUG
DELIVERY
• Anti-ulcer therapy
• Anti-inflammatory therapy
• Anti-asthma therapy
• Cardiovascular therapy
• Chemotherapy
• Colonic drug therapy
Methodologies for pH sensitive hydrogels

• pH-sensitive hydrogels
All the pH-sensitive polymers contain pendant
acidic (e.g. carboxylic and sulfonic acids) or basic
(e.g., ammonium salts) groups that either accept
or release protons in response to changes in
environmental pH.
• Properties of pH-sensitive hydrogels
Hydrogels made of crosslinked polyelectrolytes display
big differences in swelling properties depending on the
pH of the environment. The pendant acidic or basic
groups on polyelectrolytes undergo ionization just like
acidic or basic groups of monoacids or monobases.
Ionization on polyelectrolytes, however, is more
difficult due to electrostatic effects exerted by other
adjacent ionized groups. This tends to make the
apparent dissociation constant (K a) different from that
of the corresponding monoacid or monobase.
• Other applications
pH-sensitive hydrogels have also been used in making
biosensors and permeation switches
pH-sensitive liposomes: The concept of pH-sensitive
liposomes emerged from the observation that certain
enveloped viruses infect cells following acidification
of the endosomal lumen to infect cells and from the
knowledge that some pathological tissues (tumors,
inflamed and infected tissue) have a more acidic
environment compared to normal tissues. Although,
pH-sensitive liposomes are stable at physiological pH,
they destabilize under acidic conditions, leading to
the release of their aqueous contents
• pH sensitive microspheres: The pH of the human
gastrointestinal tract was shown to increase
progressively from the stomach (pH 2-3), small
intestine (pH 6.5- 7) to the colon (7.0-7.8). Recent
studies using sensitive and reliable equipment
have given more exact data showing that the pH
values in the stomach range from 1.2 to 5.0, while
the pH values in the duodenum, jejunum and
ileum and colon are 6.6±0.5, 7.4±0.4, 7.5±0.4 and
7.0±0.7, respectively
• pH sensitive nanoparticles:
Particles in the size range 40-120 nm were
translocated both transcellularly and
paracellularly. In addition to the potential for
enhancing drug bioavailability via particle
uptake mechanisms, particulate oral delivery
systems can protect labile macromolecules from
stomach acid and from the first-pass metabolism
in the gastrointestinal tract
 Gastro retentive drug delivery system
(GRDDS)
• It is one of the site specific drug delivery
system for delivery of drug at stomach
• It is obtained by retaining dosage form into
the stomach and drug is being released at
targetted site in controlled manner
 APPROPRIATE CANDIDATE DRUGS FOR
GRDDS
• Drugs acting locally in the stomach.
E.g. Antacids and drugs for H. Pylori viz.,
Misoprostol.
• Drugs that are primarily absorbed in the stomach.
E.g. Amoxicillin
• Drugs that is poorly soluble at alkaline pH.
E.g. Furosamide, Diazepam, Verapamil, etc.
• Drugs with a narrow absorption window.
E.g. Cyclosporine, , Levodopa, Methotrexate etc.
• Drugs which are absorbed rapidly from the GI
tract.
E.g. Metronidazole, tetracycline.
• Drugs that degrade in the colon.
E.g. Ranitidine, Metformin.
• Drugs that disturb normal colonic microbes
E.g. antibiotics against Helicobacter pylori.
 ADVANTAGES
• Enhanced bioavailability
• Sustained drug delivery/reduced frequency of
Dosing
• Targeted therapy for local ailments in the
upper GIT
• Reduced fluctuations of drug concentration
• Improved selectivity in receptor activation
• Reduced counter-activity of the body
 LIMITATIONS
• The drug substances that are unstable in the
acidic environment of the stomach are not
suitable candidates to be incorporated in the
systems.
• These systems require a high level of fluid in
the stomach for drug delivery to float and
work efficiently.
• Not suitable for drugs that have solubility or
stability problem in GIT.
• Drugs which are irritant to gastric mucosa are
also not suitable.
• These systems do not offer significant
advantages over the conventional dosage
forms for drugs, which are absorbed
throughout GIT.
 APPROACHES FOR PROLONGING THE
GASTRIC RESIDENCE TIME
• High-density systems.
(HDS)
• Floating systems. (FS)

• Swelling and expanding

systems. (SS)
• Mucoadhesive &
Bioadhesive systems. (AS)
 FLOATING DRUG DELIVERY
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. They Include:
Hydrodynamically balanced systems (HBS)
Gas-generating systems
Volatile liquid/ vacuum containing systems
Raft-forming systems
Low-density systems
HYDRODYNAMICALLY BALANCED SYSYTEMS

 Prepared by incorporating a high level(20-

75%w/w) gel-forming hydrocolloids. E.g.:-
Hydoxyethylcellulose,
hydroxypropylcellulose, HPMC & Sod. CMC
into the formulation and then compressing
these granules into a tablets or capsules.
It maintains the bulk density less than 1.
 RAFT FORMING
• This system is used for delivery of antacids and
drug delivery for treatment of gastrointestinal
infections and disorders.
• The mechanism involved in this system
includes the formation of a viscous cohesive
gel in contact with gastric fluids, forming a
continuous layer called raft.
 GAS GENERATING SYSTEMS
• Carbonates or bicarbonates, which react with
gastric acid or any other acid (e.g., citric or
tartaric) present in the formulation to produce
CO2 , are usually incorporated in the dosage
form, thus reducing the density of the system
and making it float on the media.