Oral sustained and controlled release dosage forms Dr GS SANAP

SUSTAINED AND CONTROLLED
RELEASE DOSAGE FORMS
Presented by:
Dr Gajanan S. Sanap
M. Pharm.,Ph.D
DEPARTMENT OF PHARMACEUTICS,
Ideal College of Pharmacy and Research,
Kalyan -421 306

WHAT IS DRUG DELIVERY SYSTEMS?
 Drug delivery systems refer to the technology
utilized to present the drug to the desired body site
for drug release and absorption.
 Newer discoveries and advancements in
technology has lead to various new techniques of
delivering the drugs for maximum patient
compliance at minimal dose and side effects.

In the conventional therapy aliquot quantities of drugs are
introduced into the system at specified intervals of time with the
result that there is considerable fluctuation in drug
concentration level as indicated in the figure.
HIGH
LOW
HIGH
LOW

However, an ideal dosage regimen would be one, in which the
concentration of the drug, nearly coinciding with minimum
effective concentration (M.E.C.), is maintained at a constant level
throughout the treatment period. Such a situation can be graphically
represented by the following figure
CONSTANT LEVEL

IDEAL DRUG DELIVERY SYSTEM
First, it should deliver drug at a rate dictated by the needs of the
body over the period of the treatment.
Second it should channel the active entity solely to the site of
action.
This is achieved by development of new various modified drug
release dosage forms, like-

SUSTAINED RELEASE DRUG DELIVERY: Any of the dosage form that
maintains the therapeutic blood or tissue levels of drug by continuous release of
medication for a prolonged period of time, after administration of a single dose. In
case of injectable dosage forms it may vary from days to months.
SITE SPECIFIC AND RECEPTOR TARGETING : Targeting a drug directly to
a certain biological location .For site specific release the target is the adjacent to or in
the diseased organ or tissue, for receptor release the target is the particular drug
receptor within an organ or tissue.
CONTROLLED RELEASE DRUG DELIVERY :Delivery of the drug at a
predetermined rate and /or to a location according to the needs of the body and
disease states for a definite period of time.
MaximumSafe Conc. (MSC)
MinimumEffective
Conc. (MEC)
Time
Plasma
conc.of
drug
A: Conventional dosage form
B: Prolonged release DDS
C: Sustained release DDS
A
B
C

Contd..
REPEAT ACTION DOSAGE FORM: contain 2 or 3 full doses which are
so designed that the doses are released sequentially one after the other.
OTHER NOVEL(NEW) DOSAGE FORMS:
includes- Microspheres, Nanoparticles,, Trans-dermal delivery
systems, Ocular drug delivery, Nasal drug delivery, Implants etc.
TIMED RELEASE OR DELAYED RELEASE: These are the systems that use
repetitive, intermittent dosing of a drug from one or more immediate release units
incorporated into a single dosage form or an enteric delayed release systems e.g.
Repeat action tablets and capsules and enteric coated tablets where time release is
achieved by barrier coating, or wherein the release of the drug is intentionally
delayed until it reaches the intestinal environment.

What is a sustained release dosage form???
“Drug Delivery systems that are designed to achieve
prolonged therapeutic effect by continuously
releasing medication over an extended period of time
after administration of single dose.”
Basic goal of the therapy
to achieve steady state blood level that is
therapeutically effective & non toxic for an
extended period of time.
Also referred to as prolonged-release
(PR), slow release (SR), sustained
action (SA), prolonged action (PA) or
extended-release (ER).

Comparison of Drug Release Profile

Objectives of drug delivery
• Temporal drug delivery:
controlling the rate or specific time
of drug delivery to the target tissue.
• Spatial drug delivery:
targeting a drug to a specific organ
or tissue.

The difference between controlled release
and sustained release
Sustained release dosage form
Sustain release dosage form- is defined
as the type of dosage form in which a
portion i.e. (initial dose) of the drug is
released immediately, in order to achieve
desired therapeutic response more
promptly, and the
remaining(maintanance dose) is then
released slowly there by achieving a
therapeutic level which is prolonged, but
not maintained constant.
Constitutes dosage form that provides
medication over extended period of time
SRDF generally do not attain zero order
release kinetics
Usually do not contain mechanisms to
promote localization of the drug at active
site.
Controlled release dosage form
which delivers the drug at a pre
determined rate for a specified period of
time
Constitutes dosage form that maintains
constant drug levels in blood or tissue
Maintains constant drug levels in the
blood target tissue usually by releasing
the drug in a zero order pattern.
Controlled dosage forms contain
methods to promote localization of the
drug at active site.
zero order release that is the drug
release over time irrespective of
concentration.
Sustained release implies slow release
of the drug over a time period.
It may or may not be controlled release.

Advantages
Reduction in blood level fluctuations of drug, thus better management of the disease.
Reduction in dosing frequency.
Enhanced patient convenience and compliance.
Reduction in adverse effects(both systemic and local), esp. of potent drugs, in
sensitive patients.
Reduction in health care costs.
Improved efficiency of treatment.
Reduces nursing and hospitalizing time.
Maximum bioavailability with a minimum dose.
 Minimize drug accumulation with chronic dosing.
 Cure or control condition more promptly.
 Make use of special effects, e.g. Treatment of Arthritis.
 Constant blood levels achieve desired effect and this effect is maintained for an
intended period of time.
 Drug susceptible to enzymatic inactivation or by bacterial decomposition can be
protected by encapsulation in polymer system suitable for SR.

Disadvantages
 Administration of sustained release medication dose not permit prompt termination
of therapy. Immediate changes in the drug if needed during therapy when significant
adverse effects are noted cannot be accommodated.
The physician has less flexibility in adjusting dosage regimen, as it is fixed by
dosage form design.
Sustained release dosage forms are designed for normal population i.e. on basis of
average biologic half-life. Consequently, disease states that alter drug disposition,
significant patient variation, and so forth are not accommodated.
More costly process and equipment are involved in manufacturing many sustained
release dosage forms.
Dose dumping
Unpredictable and poor in vitro and in vivo relationship.
Effective drug release time period is influenced and limited by GI residence time.
Need additional patient education.(such as not to chew or crush the dosage form
before swallowing)
Drugs having very short half life or very long half life are poor candidates for
sustained release dosage forms. For Ex: diazepam.
Delayed onset of action, hence sometimes not useful in acute conditions.

Rationality in designing S.R.Dosage form.
The basic objective in dosage form design is to optimize the
delivery of medication to achieve the control of therapeutic effect in
the face of uncertain fluctuation in the vivo environment in which
drug release take place.
This is usually concerned with maximum drug availability by
attempting to attain a maximum rate and extent of drug absorption
however, control of drug action through formulation also implies
controlling bioavailability to reduce drug absorption rates.

Plasma concentration v/s time curve

INTRODUCTION :
‘Targeted drug delivery system is a special form of drug
delivery system where the medicament is selectively
targeted or delivered only to its site of action or
absorption and not to the non-target organs or tissues or
cells.’
• It is a method of delivering medication to a patient in a
manner that increases the concentration of the medication
in some parts of the body relative to others.
• Targeted drug delivery seeks to concentrate the medication
in the tissues of interest while reducing the relative
concentration of the medication in the remaining tissues.
• This improves efficacy and reduce side effects.
TARGETED DRUG DELIVERY SYSTEM

THE DRUG MAY BE DELIVERED :
• To the capillary bed of the active sites.
• To the specific type of cell (or) even an intracellular region.
Ex: Tumour cells but not to normal cells.
• To a specific organ (or) tissues by complexion with the
carrier that recognizes the target.
OBJECTIVE :
• To achieve a desired pharmacological response at a selected
sites without undesirable interaction at other sites, there by
the drug have a specific action with minimum side effects &
better therapeutic index.
• Ex- In cancer chemotherapy and enzyme replacement
therapy.

REASON FOR DRUG TARGETING :
• In the treatment or prevention or diseases.
• Pharmaceutical drug instability in conventional dosage form
solubility ,biopharmaceutical low absorption, high-membrane
bounding, biological instability, pharmacokinetic /
pharmacodynamic short half life, large volume of distribution,
low specificity, clinical, low therapeutic index.

IDEAL CHARACTERISTICS :
• It should be nontoxic, biocompatible, biodegradable,
and physicochemical stable invivo and invitro.
• Restrict drug distribution to target cells or tissues or
organs and should have uniform capillary distribution.
• Controllable and predicate rate of drug release.
• Drug release does not effect the drug action.
• Therapeutic amount of drug release.
• Minimal drug leakage during transit.
• Carriers used must be bio-degradable or readily
eliminated from the body without any problem and no
carrier induced modulation of diseased state.
• The preparation of the delivery system should be easy or
reasonably simple, reproductive and cost effective.

ADVANTAGES :
• Drug administration protocols may be simplified.
• Toxicity is reduced by delivering a drug to its target site,
there by reducing harmful systemic effects.
• Drug can be administered in a smaller dose to produce the
desire effect.
• Avoidance of hepatic first pass metabolism.
• Enhancement of the absorption of target molecules such as
peptides and particulates.
• Dose is less compared to conventional drug delivery system.
• No peak and valley plasma concentration.
• Selective targeting to infections cells that compare to normal
cells.

DISADVANTAGES :
• Rapid clearance of targeted systems.
• Immune reactions against intravenous administered carrier
systems.
• Insufficient localization of targeted systems into tumour cells.
• Diffusion and redistribution of released drugs.
• Requires highly sophisticated technology for the formulation.
• Requires skill for manufacturing storage, administration.
• Drug deposition at the target site may produce toxicity
symptoms.
•Difficult to maintain stability of dosage form.
E.g.: Resealed erythrocytes have to be stored at 40 C.
• Drug loading is usually law. E.g. As in micelles. Therefore it
is difficult to predict /fix the dosage regimen.

Multiparticulate Drug Delivery Systems
 Pharmaceutical invention and research are increasingly
focusing on delivery systems which enhance desirable
therapeutic objectives while minimising side effects.
 Recent trends indicate that multiparticulate drug delivery
systems are especially suitable for achieving controlled or
delayed release oral formulations with low risk of dose
dumping, flexibility of blending to attain different release
patterns as well as reproducible and short gastric residence
time.
 The release of drug from microparticles depends on a
variety of factors including the carrier used to form the
multiparticles and the amount of drug contained in them.
 Consequently, multiparticulate drug delivery systems
provide tremendous opportunities for designing new
controlled and delayed release oral formulations, thus
extending the frontier of future pharmaceutical development.

 Multi-particulate drug delivery systems are mainly oral
dosage forms consisting of a multiplicity of small discrete
units, each exhibiting some desired characteristics.
 In these systems, the dosage of the drug substances is
divided on a plurality of subunit, typically consisting of
thousands of spherical particles with diameter of 0.05-
2.00mm.
 Thus multiparticulate dosage forms are pharmaceutical
formulations in which the active substance is present as a
number of small independent subunits.
 To deliver the recommended total dose, these subunits are
filled into a sachet and encapsulated or compressed into a
tablet.

 Multiparticulates are discrete particles that make up a
multiple unit system. They provide many advantages over
single-unit systems because of their small size.
 Multiparticulates are less dependent on gastric empyting,
resulting in less inter and intra-subject variability in
gastrointestinal transit time. They are also better distributed
and less likely to cause local Irritation.
 Recently much emphasis is being laid on the development of
multiparticulate dosage forms in preference to single unit
systems because of their potential benefits such as increased
bioavailability, reduced risk of systemic toxicity, reduced risk
of local irritation and predictable gastric emptying.

 There are many reasons for formulating a drug as a
multiparticulate system for example, to facilitate disintegration
in the stomach, or to provide a convenient, fast disintegrating
tablet that dissolves in water before swallowing which can aid
compliance in older patients and children.
 Multiparticulate systems show better reproducible
pharmacokinetic behavior than conventional (monolithic)
formulations.
 After disintegration which occurs within a few minutes often
even within seconds, the individual subunit particles pass
rapidly through the GI tract.
 If these subunits have diameters of less than 2mm, they are
able to leave the stomach continuously, even if the pylorus is
closed.
 These results in lower intra and inter individual variability in
plasma levels and bioavailability.

MECHANISM OF DRUG RELEASE FROM MULTI-
PARTICULATES
 Diffusion :-
On contact with aqueous fluids in the gastrointestinal tract
(GIT), water diffuses into the interior of the particle. Drug
dissolution occurs and the drug solutions diffuse across the
release coat to the exterior.
 Erosion :-
Some coatings can be designed to erode gradually with time,
thereby releasing the drug contained within the particle.
 Osmosis :-
In allowing water to enter under the right circumstances, an
osmotic pressure can be built up within the interior of the
particle. The drug is forced out of the particle into the
exterior through the coating.

PELLETS
o WHAT IS PELLETS:-
o Traditionally, the word "pellet" has been used to
describe the variety of systematically produced,
geometrically defined agglomerates obtained from
diverse starting materials utilizing different
processing conditions.
o These products may be fertilizers, Animal feeds,
Iron Ores or Pharmaceutical Dosage forms.
o Pellets are small spherical free flowing units with
improved flow properties and flexibility in
formulation development and manufacture.

PELLETS
 Their size and shape allow their administration
as injections and also for oral drug delivery.
 Pellets range in size, typically, between 0.5 – 1.5
mm, though other sizes could be prepared.
 Pellets are for pharmaceutical purposes and are
produced primarily for the purpose of oral
controlled-release dosage forms having gastro
resistant or sustained-release properties or the
capability of site-specific drug delivery.

PELLETS
 For such purposes, coated pellets are administered
in the form of hard gelatin capsules or
disintegrating tablets that quickly liberate their
contents of pellets in the stomach.
 As drug-delivery systems become more
sophisticated, the role of pellets in the design and
development of dosage forms is increasing.
 Formulation of drugs in multiple-unit dosage forms,
such as coated pellets filled in capsules or
compressed into tablets, offers flexibility as to
target-release properties.

WHY PELLETS?
 Excellent Stability.
 Dust free Round pellets.
 Good flow behavior.
 Easy to dose.
 Compact structure.
 Very Low hygroscopicity.
 High bulk density.
 Dense, uniform surface.
PELLETIZATION

 Narrow grain size distribution.
 Low abrasion.
 High active ingredient content possible.
 Optimum starting shape for subsequent
coating.
 Controlled-release applications.
 Drug absorption.
 The risks of the local damage to the GI-
tract mucosal.
WHY PELLETS?

ADVANTAGES OF PELLETS
 They can be divided in to desired dosage strength
without process or formulation changes.
 When pellets containing the active ingredient are in
the form of suspension, capsules, or disintegrating
tablets, they offer significant therapeutic
advantages over single unit dosage forms.
 They can also be blended to deliver incompatible
bioactive agents.
 They can also be used to provide different release
profile at the same or different sites in the
gastrointestinal tract.

ADVANTAGES OF PELLETS
 Pellets offer high degree of flexibility in the
design and development of oral dosage form like
suspension, sachet, tablet and capsule.
 Pellets disperse freely in GI tract, maximize drug
absorption, and minimize local irritation of the
mucosa by certain irritant drugs.
 Improved flow characteristics: Spheres have
excellent flow properties which can be used in
automated processes or in processes where exact
dosing is required, e.g. tabletting, moulding
operations, capsule filling, and packaging.

Disadvantages of Pellets
 Dosing by volume rather than number and
splitting into single dose units as required.
 Involves capsule filling which can increase
the costs or tabletting which destroy film
coatings on the pellets.
 The size of pellets varies from formulation
to formulation but usually lies between 1 to
2mm.

PELLETIZATION
DEFINITION OF PELLETIZATION
 Pelletization is an agglomeration process,
that converts fine powder blend of drug(s)
and Excipients into small, free flowing,
spherical units, referred to as pellets.

PELLETIZATION
 Pelletization is referred to as a size
enlargement process and if the final
agglomerates are spherical with a size of
0.5-2.0 mm and low intra-agglomerate
porosity (about 10%), they are called
pellets.

PELLETIZATION TECHNIQUES
 Powder layering Solution/Suspension
layering.
 Extrusion–Spheronization.
 Spherical agglomeration or balling Spray
congealing/ drying.
 Cryopelletization and,
 Melt Spheronization.

Extrusion Spheronization
 Compared to single-unit dosage forms, oral
multiparticulate drug-delivery systems (e.g. pellets,
granules) offer biopharmaceutical advantages in
terms of a more even and predictable distribution
and transportation in the gastro-intestinal tract.
 There are different pelletizations and granulation
techniques available to prepare drug loaded
spherical particles or granules.
 Extrusion Spheronization is one of them and
utilized in formulation of beads and pellets.

 Limitations related to bioavailability and site specific
drug delivery can be over come by this technique.
 Today this technology has gained attention because
of its simple and fast processing.
 Extrusion spheronization is widely utilized in
formulation of sustained release, controlled release
delivery system.
 The main objective of the extrusion spheronization is
to produce pellets/spheroids of uniform size with
high drug loading capacity.

 The extrusion-spheronization process is commonly
used in the pharmaceutical industry to make
uniformly sized spheroids.
 It is especially useful for making dense granules
for controlled-release solid dosage oral forms with
a minimum amount of excipients.
 Extrusion/spheronization begins with extrusion
process in which the wet metered mass is placed
into the extruder where it is continuously formed
into cylindrical rods of uniform size and shape.

 Amount of granulating fluid and uniform dispersion
of fluid plays an important role in preparation of
wet mass as optimum plasticity and cohesiveness
directly affect the final production of pellets.
 Once the extrudates are prepared, they are then
taken to spheroniser where it is spheronized or
rotated at higher speed by friction plate that
breaks the rod shaped particles into smaller
particles and round them to form spheres.

 The size of the spheroids mainly depends on
the diameter of circular die that modifies
the diameter of cylindrical rods produced in
extrusion stage.

 The extrusion-spheronization process can be
broken down into the following steps:
1. Dry mixing of the active ingredients and
excipients to achieve a homogenious powder.
2. Wet massing, with binder added to the dry
mixture
3. Extrusion into a spaghetti-like extrudate.
4. Spheronization to from the extrudate in to
spheroids of uniform size.
5. Drying.
6. Dry sizing, or sifting (optional) to achieve the
desired size distribution
7. Coating (optional).

 The extrusion-spheronization process can be
broken down.

 Product features
• Dust free
• High spherocity
• Free flowing
• Compact structure
• Low hygroscopicity
• High bulk density
• Low abrasion
• Narrow particle size distribution
• Smooth surface

MELT EXTRUSION
 Melt extrusion is one of the most widely applied
processing technologies in the plastic, rubber and
food industry. Today this technology has found its
place in the array of pharmaceutical manufacturing
operations.
 Melt extrusion process are currently applied in the
pharmaceutical field for the manufacture of a
variety of dosage forms and formulations such as
granules, pellets, tablets, suppositories, implants,
stents, transdermal systems and ophthalmic inserts.

MELT EXTRUSION
Advantages:
 Neither solvent nor water used in this process.
 Fewer processing steps needed thus time consuming drying
steps eliminated.
 There are no requirements on the compressibility of active
ingredients and the entire procedure simple, continuous and
efficient.
 Uniform dispersion of fine particle occurs.
 Good stability at varying pH and moisture levels.
 Safe application in humans due to their non-swellable and
water insoluble nature

MELT EXTRUSION
Disadvantages:
 Requires high energy input.
 The melt technique is that the process
cannot be applied to heat-sensitive materials
owing to the elevated temperatures involved.
 Lower-melting-point binder risks situations
where melting or softening of the binder
occurs during handling and storage of the
agglomerates

MELT EXTRUSION
Applications in the pharmaceutical industry:
 In pharmaceutical industry the melt extrusion has
been used for various purposes, such as
 1. Improving the dissolution rate and bioavailability
of the drug by forming a solid dispersion or solid
solution.
 2. Controlling or modifying the release of the drug.
 3. Masking the bitter taste of an active drug

MELT EXTRUSION
 Melt extrusion technology has proven to be a suitable
method for the production of controlled release
reservoir systems consisting of polyethylene vinyl
acetate (PVA) co-polymers.
 Based on this technology, two controlled release
systems Implanon® and Nuvaring® have been
developed.
 A melt extrusion process for manufacturing matrix
drug delivery system was reported by Sprockel and co-
workers. In 1994 Follonier and co-workers investigated
hot-melt extrusion technology to produce sustained-
release pellets.

MELT EXTRUSION
Process and Equipment:
 Hot-melt extrusion equipment consists of an
extruder, auxiliary equipment for the extruder, down
stream processing equipment, and other monitoring
tools used for performance and product quality
evaluation.
 The extruder is typically composed of a feeding
hopper, barrels, single or twin screws, and the die and
screw– driving unit

MELT EXTRUSION
Figure: Micro-18 Twin screw co-rotating Leistritz extruder

MELT EXTRUSION
 The auxiliary equipment for the extruder mainly
consists of a heating/cooling device for the barrels,
a conveyer belt to cool down the product and a
solvent delivery pump.
 The monitoring devices on the equipment include
temperature gauges, a screw-speed controller, an
extrusion torque monitor and pressure gauges.
 The monitoring devices on the equipment include
temperature gauges, a screw-speed controller, an
extrusion torque monitor and pressure gauges.

MELT EXTRUSION
 The theoretical approach to understanding the melt
extrusion process is therefore, generally presented
by dividing the process of flow into four sections:
1) Feeding of the extruder.
2) Conveying of mass (mixing and reduction of
particle size).
3) Flow through the die.
4) Exit from the die and down-stream processing.

INTRODUCTION
 Microspheres are characteristically free flowing
powders consisting of proteins or synthetic polymers
which are biodegradable in nature and ideally having
a particle size less than 200 μm.
Spherical particle with size
varying from 50 nm to 2 mm.
Microcapsule Micromatrix
Types of Microspheres
MICROSPHERES

ADVANTAGES
Potential use of microspheres in the pharmaceutical industry
• Taste and odor masking
• Conversion of oils and other liquids to solids for ease of handling
• Protection of drugs against the environment (moisture, light etc.)
• Separation of incompatible materials (other drugs or excipients)
• Improvement of flow of powders
• Aid in dispersion of water-insoluble substances in aqueous media,
• Production of SR, CR, and targeted medications.

PHARMACEUTICAL
APPLICATIONS
 Microencapsulated products currently on the market, such
as aspirin, theophylline & its derivatives, vitamins,
pancrelipase, antihypertensive, potassium chloride,
progesterone, and contraceptive hormone combinations.
 Microencapsulated KCl is used to prevent gastrointestinal
complications associated with potassium chloride.
 Microspheres have also found potential applications as
injection, or inhalation products.
 Most encapsulation processes are expensive and require
significant capital investment for equipment.
 An additional expense is due to the fact that most
microencapsulation processes are patent protected.

.
OTHER APPLICATIONS
 Microcapsules are also extensively used as diagnostics, for
example, temperature-sensitive microcapsules for thermographic
detection of tumors.
 In the biotechnology industry microencapsulated microbial cells
are being used for the production of recombinant proteins and
peptides.
 Encapsulation of microbial cells can also increase the cell-loading
capacity and the rate of production in bioreactors.
 A feline breast tumor line, which was difficult to grow in
conventional culture, has been successfully grown in
microcapsules.
 Microencapsulated activated charcoal has been used for
hemoperfusion.
 Paramedical uses of microcapsules include bandages with
microencapsulated anti-infective substances.

Synthetic Polymers
Non-biodegradable
PMMA
Acrolein
Epoxy polymers
Biodegradable
Lactides and Glycolides
copolymers
Polyalkyl cyanoacrylates
Polyanhydrides
Natural Materials
Proteins
Albumins
Gelatin
Collagen
Carbohydrates
Starch agarose
Carrageenan
Chitosan
Chemically modified carbohydrates
Poly (acryl) dextran
Poly(acryl)starch
DEAE cellulose
POLYMERS USED IN THE MICROSPHERE
PREPARATION

Prerequisites for Ideal
Microparticulate Carriers
• Longer duration of action
• Control of content release
• Increase of therapeutic efficacy
• Protection of drug
• Reduction of toxicity
• Biocompatibility
• Sterilizability
• Relative stability
• Water solubility or dispersibility
• Bioresorbability
• Targetability
• Polyvalent

GENERAL METHODS OF
PREPARATION
• Single Emulsion techniques
• Double emulsion techniques
• Polymerization techniques
- Normal polymerization
- Interfacial polymerization
• Coacervation phase separation techniques
• Spray drying and spray congealing
• Solvent extraction

SIMPLE EMULSION BASED METHOD
Aq.Solution/suspension of polymer
Dispersion in organic phase
(Oil/Chloroform)
Microspheres in organic phase Microspheres in organic phase
MICROSPHERES
Stirring, Sonication
CROSS LINKING
Chemical cross linking
(Glutaraldehyde/Formalde
hyde/ Butanol)
Heat denaturation
Centrifugation, Washing, Separation

DOUBLE EMULSION BASED METHOD
Aq.Solution of protein/polymer
First emulsion (W/O)
MICROSPHERES
Dispersion in oil/organic phase
Homogenization
Separation, Washing, Drying
Addition of aq. Solution of PVA
Addition to large aq. Phase
Denaturation/hardening
Multiple emulsion
Microspheres in solution

Release pattern of drug from
microspheres
 Naltroxone (vivitrol TM) microspheres (PLA-PLGA)
the first approved alcohol dependence medication in
USA:
MECHANISM: The release pattern of naltroxone as a
result of:
absorbing water and swelling immediately after
injection where the near surface drug is released first
-as water absorption continues hydrolysis starts and
after several days physical erosion begins.
-further drug diffuse to the surrounding resulting in
sustained release of medication with the elimination
of water and carbon dioxide as degradation product
of polymer matrix.

CHARACTERIZATION OF MICROSPHERES

GASTRO RETENTIVE DRUG
DELIVERY SYSTEM

Introduction
Conventional oral drug delivery system (DDS) is
complicated by limited gastric residence time
(GRT).
Rapid GI transit can prevent complete drug
release in absorption zone & reduce the efficacy
of the administered dose since the majority of
drugs are absorbed in stomach or the upper part of
small intestine.

To overcome these limitations, various
approaches have been proposed to increase
gastric residence of drug delivery systems in
the upper part of GIT includes gastro retentive
drug delivery system (GRDDS).
Among the GRDDS, floating drug delivery
system (FDDS) have been the most commonly
used.

 Gastro-retentive delivery is one of the site
specific delivery of the drugs at stomach. It is
obtained by retaining dosage form into
stomach and drug is being released at
sustained manner to specific site either in
stomach or intestine.
What is GRDDS??????

Differ from Conventional Release…
Conventional Release GRDDS
Absorption
window

Advantages…
 Delivery of drugs with narrow absorption window in
the small intestine region.
 Longer residence time in the stomach could be
advantageous for local action in stomach, for
example treatment of peptic ulcer disease.
 Bio-availability can be improved.

 Reduced Frequency of Dosing with improved
patient compliance
 Minimize the Fluctuation of drug
concentrations
 Site specific drug delivery
 Enhances the Pharmacological effects

Candidates for GRDDS
 Drugs acting locally in the stomach E.g. Antacids
 Drugs that are principally absorbed in the stomach
 Drugs that are poorly soluble at the alkaline pH
 Drugs with a narrow window of absorption E.g.
Furosemide
 Drugs absorbed readily from the GI tract
 Drugs that degrade in the colon
 Drugs with variable Bioavailability
 Drugs with less half life

Non -
Effervescent
System
Effervescent
System
High density
systems
Swellable/
Expandable
systems Muco-
adhesive
systems
Low-density
systems
(Floating
drug
delivery)
Gastro Retentive Technologies

A) Low Density Approach
(Floating Drug Delivery)
 Retained in stomach
 Useful for poorly water
soluble OR unstable in intestinal
Fluid
 Bulk density : Less than
gastric fluid, so remain buoyant
in the stomach without affecting
gastric emptying rate for
prolonged period of time
 So drug release slowly at the
desired rate from system

Drugs those are...
 Primarily absorbed in the stomach
 Poorly soluble at an alkaline pH
 Narrow window of absorption
 Degrade in colon
Advantages of Low Density Approach OR
Floating Drug Delivery

 When there is a vigorous intestinal movement
and a short transit time as might occur in
certain type of diarrhoea, poor absorption is
expected. Under such circumstances it may be
advantageous to keep the drug in floating
condition in stomach to get a relatively better
response.

 Not feasible for those drugs that have
solubility OR stability problem in GIT
Require high level of fluid in stomach
 The drugs that may irritate the stomach lining
OR are unstable in acidic environment
 The dosage form should be administered with
a full glass of water (200-250 ml)
Disadvantages of Low Density Approach
OR
Floating Drug Delivery

B) Swellable System
Also called ‘ PLUG SYSTEM’
Size of the formulation more
than Pyloric sphincter
It should expand for gastric
retention Should be
Collapsed after lag time

 The Dosage form must maintain a size larger
than pyloric sphincter
 The Dosage form must resist premature
gastric emptying
Disadvantages of Swelling System

C) Bio/Muco Adhesive System
Here, the drug is incorporated with bio/
Muco-adhesive agents, enabling the
Device to adhere to the stomach walls,
Thus resisting gastric emptying.
However, the mucus on the walls of
the Stomach is in a state of constant
renewal, Resulting in unpredictable
adherence.
Thus, this approach is not widely used.

Chitosan
Polyacrylic acid
Carbopol 934P, 971P, 980
Sodium alginate
HPMC K4M, K15M, K100M
Hydroxypropylcellulose (HPC)
Cholestyramine
Bio/Muco Adhesive Polymers

Rapid removal of mucus.
We are not sure weather the DF will adhere to
the mucus or epithelial cell layer
DF may adhere to esophagus resulting in drug
induced injuries
Problem of Muco-adhesive System

D) High Density Approch
Density should be more then
stomach content i.e. 3 g/cm3
Capable to withstand with
peristaltic movement of
stomach
Prepared by coating or mixing
drug with heavy inert material

Diluents such as…
 barium sulphate (density = 4.9),
 zinc oxide,
 titanium dioxide,
 iron powder
must be used to manufacture such high-density
formulations.

 Higher amount of drug require
The dosage form must stand with peristaltic
movement of stomach
Problem with High Density
Approch

 It is not recommended for drugs which are
unstable at gastric/acidic pH, insoluble or very
low soluble drugs and drugs which causes
gastric irritation.
 For floating, high level of fluid is required in
GIT. Also sleeping condition is favorable for
the better results of GRDDS.
Limitation of GRDDS

 Bioadhesive systems, cannot prevail longer due to
high turn-over rate of mucus layer and presence of
soluble mucin
 For swelling systems, it is necessary that the
formulation should not exit before the appropriate
swelling
 For High density systems, High amount of drug is
require
Limitation of GRDDS

TRANSDERMAL DRUG
DELIVERY SYSTEM (TDDS)

When one hears the words transdermal drug delivery, what comes to
mind? More than likely one thinks about a simple patch that one stick
onto skin like an adhesive bandage such as nicotine patch.
 The NDDS may involve a new dosage form e.g., from thrice a day
dosage to once a day dosage form or developing a patch form in
place of injections.
 Throughout the past 2 decades, the transdermal patch has become a
proven technology that offers a variety of significant clinical
benefits over other dosage forms.
 Because transdermal drug delivery offers controlled release of the
drug into the patient, it enables a steady blood-level profile,
resulting in reduced systemic side effects and, sometimes, improved
efficacy over other dosage forms
History of TDDS

Transdermal drug delivery system was first introduced more than 20
years ago.
The technology generated tremendous excitement and interest amongst
major pharmaceutical companies in the 1980s and 90s.

First transdermal patch was approved in 1981 to prevent the nausea
and vomiting associated with motion sickness, the FDA has approved,
throughout the past 22 years, more than 35 transdermal patch products,
spanning 13 molecules.
 1970-- Alza Research (US) began first development of the modern
transdermal
 1980-- Scopolamine first transdermal reached US
 2002– Many Rx and non-RX products in US market.
 Transdermals deliver drugs from a few hours up to
7 days.

 Transdermal delivery represents an attractive alternative to oral
delivery of drugs and is poised to provide an alternative to
hypodermic injection too.
 For thousands of years, people have placed substances on the skin
for therapeutic effects.
Definition:
Transdermal drug delivery is defined as a self contained discrete
dosage form, which when applied to the intact skin, will deliver the
drug at a controlled rate to the systemic circulation.
Or
Transdermal drug delivery systems (patches) are dosage forms
designed to deliver a therapeutically effective amount of drug across
a patient’s skin also defined as Medicated adhesive patch that is
placed on the skin to deliver a specific dose of Medication through
the skin and into the blood stream.

Why transdermal drug delivery?
• Continuous IV administration at a constant rate of
infusion is a superior mode of drug delivery
• IV administration avoids hepatic first-pass metabolism
and maintain constant therapeutic drug levels in the
body
• TDD can closely duplicate continuous IV fusion.
Hence it is helpful in delivering drugs that undergo
significant first pass metabolism and/or have narrow
therapeutic index

Principles of diffusion through membranes
Homogenous
membrane
Aqueous
pores
Cellulose
fibres
(1) Diffusion - random molecular motion. Must have concentration gradient.

Donor Receptor
Cd
C1
C2
Cr
h
D
C0
Donor
solution
K

POTENTIAL BENEFITS OF TRANSDERMAL DRUG
DELIVERY (ADVANTAGES)
• Easy to use.
• Avoid GIT absorption problems for drugs.
• Avoids FP hepatic metabolism of drugs.
• More improved and convenient patient compliance.
• Rapid termination in case of toxicity is possible.
• Self medication is possible.
• Reduces frequency of dosing.
• Maintains therapeutic level for 1 to 7 days.
• Controlled delivery resulting in more reliable and predictable
blood levels.

DISADVANTAGES
• Daily dose of more than 10mg is not possible.
• Local irritation is a major problem.
• Drug requiring high blood levels are unsuitable.
• Drug with long half life can not be formulated in TDDS.
• Uncomfortable to wear.
• May not be economical.
• Barrier function changes from person to person and within the
same person.
• Heat, cold, sweating (perspiring) and showering prevent the
patch from sticking to the surface of the skin for more than one
day. A new patch has to be applied daily.

LIMITATIONS OF TDD
 Limited skin permeability
 Significant lag time
 Cannot be used for large molecule (>500 Dalton)
 Restricted to potent drug
 Skin irritation and allergic response
 Tolerance inducing drugs or those (e.g., hormones) requiring
chronopharmacological management are not suitable candidates.
• Skin structure poses a barrier on the mw of the drug (< 500 Da)
• Usually reserved for drugs which are extremely potent (thus
requiring a dosage of only a few mg).
– The largest daily dose of a drug from a patch is the nicotine
patch, with delivers a daily dose of only 21 mg.

Consideration of TDS development
 Bioactivity of drug
 Skin characteristics
 Formulation
 Adhesion
 System design
Factors influence the permeation of drugs
 Skin structure and its properties.
 The penetrating molecule and its physical-chemical
relationship to skin and the delivery platform
 The platform or delivery system carrying the penetrant
 The combination of skin, penetrant and delivery system

1. Must be non-ionic
2. Low molecular weight (less than 500 Daltons)
3. Lipophilicity (Log Ko/w: 1-3)
4. Low melting point (less than 200 degree C)
5. Dose is less than 50 mg per day, and ideally less t
han 10 mg per day.
IDEAL DRUG CANDIDATE FOR TDD

BASIC COMPONENTS OF TDDS

Polymer matrix
 The drug
 Permeation enhancers
 Other excipients
1.Polymer matrix
Ideal polymer
 MWT, and chemical functionality of the polymer should not affect
the diffusivity of drug and its release
 Stable
 non reactive
 easily manufactured
 easily fabricated into desired product
 Inexpensive
 degaradation product must be non toxic or non antagonistic to the host
 Should retain its mechanical properties when the large amount of drug is
loaded in to it.

Polymers used in TDDS
 Natural polymers
 Cellulose derivatives
 Zein
 Gelatin
 Shellac
 Waxes
 Proteins
 Gums
 Natural rubbers
 starch
 Synthetic elastomers
--polybutadiene
--hydrin rubber
--polysiloxone
--silicone rubber
--nitrile
--
--acrylonitrile
--butyl rubber
--styrene butadiene rubber
--neoprine etc.
Synthetic polymers
PVA,PVC,PE,PP,Poly amide,Poly
acrylate,Polyurea,PVP,PMMA,Epoxy etc.

2. Suitable drug candidate
 Physico chemical properties of drug
 Should have MW less than 1000 daltons(800-1000)
 Should have affinity for both lipophilic and hydrophilic phases
 Should have low melting pont
 Biological properties of drug
 Should be potent(less than 20mg)
 Half life should be short
 Must not induce a cutaneous irritant or allergic response
 Drugs which degrade in the GI tract or inactivated by hepatic first
pass effect are suitable candidate
 Tolerance to the drug must not develop
 Drugs which has to be administered for a longer period of time can
be formulated
 Drugs which cause adverse effects to non target tissues can also be
formulated

3.PERMEATION ENHANCERS
(to enhance stratum corneum permeability)
 Solvents
Increases penetration by swelling the polar pathway transport or fluidising lipids
Eg.water,ethanol,methanol,DMS,homologs of methyl sulphoxide,dimethyl acetamide,and
DMF,2-pyrrolidone,N-methyl,2-pyrrolidone,laurocapram,PG,glycerol,silicone fluids,isopr
opyl palmitate.
 Surfactants
Enhances the polar pathway transport of hydrophilic drugs
 Anionic surfactants
Dioctyl sulpho succinate,SLS,deco decylmethyl sulphoxide etc.
 Non ionic surfactants
Pluronic F127,Pluronic F68,etc.
 Bile salts
Sodium taurocholate,sodium deoxy cholate,sodium tauroglycocholate.
 Binary systems
Propylene glucol-oleic acid and 1,4-butane diol-linoleic acid
 Miscellaneous
Urea-hydrating and keratolytic agent,N,N-dimethyl-m-toluamide,calcium thioglycolate,ant
i cholinergic agents
 Potential permetion enhancers
Euclyptol,di-o-methyl-ß-cyclodextrin and soyabean casein

Permeability Coefficient Is the Critical Predictor
of Transdermal Delivery
Transport = Flux = (mg/cm
2
/sec) = P x A x (Cd – Cr)
Permeability Coefficient = P = D x K (cm/sec)
h
Where A = Surface area of patch
D = Diffusivity of drug in membrane (skin)
K = Partition coefficient (patch/skin)
C = Concentration in donor or receptor
(patch or skin)
h = Thickness of membrane (skin)

General terms
Backing - The material, i.e. film, foam, nonwoven, etc.
, used as the outermost layer of the transdermal or
medical system to protect the product during the
wear period.
Membrane - A material placed between the drug
formulation and the final layer of adhesive. The diffusion
properties of the membrane are used to control
availability of the drug and/or excipients to the skin.

Liner - The film, removed and discarded prior to p
atch application, that protects the transdermal syst
em by covering the adhesive side.
Laminate - Two or more materials combined in lay
ers to form a single substrate.
Occlusive - Refers to a material’s ability to limit dif
fusion. Generally used in characterization of backin
gs with respect to moisture vapor and oxygen diffu
sion. An occlusive backing would have very low dif
fusion rates.

4.OTHER EXCIPIENTS Adhesives
 pressure sensitive polymeric adhesive .
 Serves to adhere the components of the patch together along with adhering
the patch to the skin.
Ideal properties
 Should not irritate or sensitize the skin or affect normal functions of the skin
 Should adhere to the skin aggressively
 Should be easily removed
 Should not leave an un washable residue on the skin
 Should have an intimate contact with the skin
 Should be compatible with the drug,excipients and permeation enhancers
 Permeation of drug should not be affected
THREE MAJOR FAMILIES OF PSAS:
1. Rubber-based PSAs,
2. Acrylic PSAs in the form of acrylic solutions,
3. Emulsion polymers or hot melts, and silicon PSAs

BACKING FILMS /membrane
ROLE OF FILM :
1. To protect the active layer and safeguard the stability of the
system,
2. To affect skin permeation and tolerance, depending on
occlusion or breathability.
3. It must also be flexible, comfortable and must present good
affinity with the adhesive, as well as excellent printability.
Ideal properties
Flexible and provide good bond to the drug reservoir
Prevent drug from leaving the dosage form
Should be impermeable
E.g. metallic plastic laminate, plastic backing with absorbent pad and
occlusive base plate, adhesive foam pad with occlusive base plate.
MOST COMMON MATERIALS USED : polypropylene,
polyethylene (both high and low density), aran, polyesters,
PVC,and nylon.

RELEASE LINERS
ROLE OF FILM :
1. To protect the system as long as it is in the package.
2. Play a crucial role in the stability of the product .
3. An incorrect release liner does not permit the easy release of the
patch, and can interfere with the active(s) or other components,
thereby reducing its shelf life.
MOST COMMON FILMS USED :
 paper-based,
 plastic film-based and
 composite films.
TWO MAJOR CLASSES OF ANTI-ADHERENT COATING :
 silicones and fluoro-polymers.

 A release liner is a film covered with an anti-adherent coating.
 To protect the system as long as it is in the package, and it is
removed just before the adhesion of the TDDS to the skin.
 During storage the patch is covered by a protective liner that is
removed & discharged immediately before the application of the
patch to the skin.
 It is there fore regarded as a part of primary packing material rather
than a part of dosage form for delivering the drug.

MICROPOROUS OR SEMI-PERMEABLE MEMBRANES or rate
controlling mambrne
The function depends on the design of the specific system, the size
of the active component and the need to have a rate-limiting factor
in order to satisfy the release and absorption characteristics of the
system.
ROLE OF THE MEMBRANES
 To limit the flow of the semi-solid content from the liquid reservoir,
and/or to act as a rate-limiting membrane for both liquid reservoir and
matrix systems.
TWO TYPES OF POROUS MEMBRANES
I Ethylene Vinyl Acetate Membranes (EVA)
II Microporous Polyethylene Membranes

POUCHING MATERIALS
ROLE :
1. Stability and integrity of the product
THREE MAIN LAYERS IN THE COMPOSITE
MATERIALS USED FOR POUCHES:
1. Internal plastic heat sealable layer,
2. Aluminium foil layer
3. External printable layer.

Classification of TDDS/Approaches
1. Polymer membrane permeation-controlled.
2. Polymer matrix diffusion- controlled
3. Drug reservoir gradient-controlled
4. Micro reservoir dissolution-controlled

Formulation of TDDS
1.Membrane-moderated or Permeation controlled TDDS (Reservoir
type)
• Drug reservoir (homogenous dispersion of drug with polymeric matrix
or suspension of drug in un leachable viscous liquid medium such as
silicone fluid) is encapsulated within drug impermeable metallic plastic
laminate and a rate controlling polymeric membrane (ethylene vinyl
acetate co polymer)
• The cross sectional view of this system is shown in the following Fig.1

RESERVOIR SYSTEM ( MEMBRANE MODERATED TDDS )
TransdermScop® (Scopolamine) for 3 days protection of motion sickness
The drug reservoir is encapsulated in a shallow compartment moulded from a
drug impermeable metallic – plastic lamination whilst the drug delivery side is
covered by controlling polymeric membrane.

• A thin layer of silicone or poly acrylate adhesive may be applied to the
external surface of the rate controlling membrane to achieve intimate
contact of the TDDS and the skin surface
• Release rate of this TDDS depends upon the polymer composition,
permeability co efficient and thickness of the rate controlling membrane
and adhesive
• The intrinsic rate of drug release from this TDDS is calculated by the
following formula.1
CR
dQ/dt= --------------------
1/Pm+1/Pa
CR-con.of drug in the reservoir compartment
Pm-permeability co efficient of rate controlling polymeric
membrane
Pa- permeability co efficient of adhesive

Drug mixed with polymer
solution
Drug suspended in
polymer solution
Volume controlled
injection pump system
Molding as TDDS using
primary packing material
Packing machinery using
secondary packing material
Transdermal therapeutic
system

Example of this system are
1.Nitro glycerin releasing TDDS (Transderm-Nitro/ciba,USA)for once a
day medication in angina pectoris
2.Scopolamine releasing TDDS (Transderm-Scop/ciba,USA)for 72
hrs.prophylaxis of motion sickness
3. Estradiol releasing TDDS (Estraderm/ciba)for treatment of menopausal
syndrome
4. Clonidine releasing TDDS (Catapres/Boehringer Ingelheim)for 7 day
therapy of hyper tension
5. Prostaglandin-derivatives TDDS

METHODS FOR PREPARATION
1.Membrane Permeation – Controlled Systems

• Ocular administration of drug is primarily associated
with the need to treat ophthalmic diseases.
•Eye is the most easily accessible site for topical
administration of a medication.
•Ideal ophthalmic drug delivery must be able to sustain
the drug release and to remain in the vicinity of front of
the eye for prolong period of time.
INTRODUCTION
OCUSERT

OCULAR ABSORPTION
Corneal Absorption
Depend upon physicochemical
properties of drug
Only access to small ionic &
lipophilic molecules
Outer Epithelium: rate limiting
barrier
Trans cellular transport:
transport between corneal
epithelium & stroma
e.g. pilocarpine
Non-Corneal
Absorption
Penetration across Sclera &
Conjunctiva into Intra
Ocular tissues
Non-Productive: because
penetrated drug is absorbed
by general circulation.
Minor pathway
Important for drug with low
corneal permeability
e.g. inulin

OCULAR DELIVERY
SYSTEMS
CONVENTIONAL VESICULAR
CONTROL
RELEASE
PARTICULATE
SOLUTION
SUSPENTION
EMULSION
OINTMENT
INSERT
GELS
IMPLANTS
HYDROGELS
DENDRIMERS
IONTOPORESIS
COLLAGEN SHIELD
POLYMERIC
SOLUTIONS
CONTACT LENSES
CYCLODEXRIN
MICROONEEDLE
MICROEMULSIONS
NANO SUSPENSION
ADVANCED
SCLERAL PLUGS
GENE DELIVERY
Si RNA
STEM CELL
ECT
MICROPARTICLE
S
NANOPARTICLES
LIPOSOMES
NIOSOMES
DISCOMES
PHARMACOSOME
S

Ocular inserts : OCULAR CONTROLLED DRUG
DELIVERY DEVICES
Definition-
Sterile preparations, with a solid or semisolid consistency
Main objective is to increase contact time between conjunctival tissue
and preparation
Inserted into the eye and worn under the upper or lower lid
Ensures a sustained and controlled release effect
Requirements for success-
COMFORT
EASE OF
HANDLI
NG
REPRODUCIBI
LITY OF
RELEASE
KINETICS
STERILITY
&
STABILITY
EASE
OF
MFG
NON-
INTERFERE
NCE WITH
VISION
LACK OF
TOXICITY
&
EXPULSIO
N

Improves BA
Prolonged drug release &
better efficacy
Over comes side effects of
pulsed dosing
Accurate dose & better
therapy
Circumvent the protective
barriers like drainage etc
Ophthalmic inserts resides in
their solidity
Patient discomfort
Movement around eye cause
abrasion
Inadvertent loss during sleep &
while rubbing eye
Difficult placement & removal
Interference with vision (in
elderly)
ADVANTAGES LIMITATIONS

Classification of
ocular inserts
Insoluble inserts
• Diffusion
based(Ocusert®)
• Osmotic based
• Soft(presoaked)
contact lenses
Bioerodible
inserts
e.g. Lacrisert®,
Minidisc.
Soluble inserts
e.g. SODI,
BioCor®-12,24,72.

. Ocular Inserts
I. Insoluble inserts:
• Insoluble insert is a multilayered structure consisting
of a drug containing core surrounded on each side by a
layer of copolymer membranes through which the drug
diffuses at a constant rate.
• The rate of drug diffusion is controlled by:
- The polymer composition
- The membrane thickness
- The solubility of the drug
e.g. The Ocusert® Pilo-20 and Pilo-40 Ocular system
- Designed to be placed in the inferior cul-de-sac between
the sclera and the eyelid and to release pilocarpine
continuously at a steady rate for 7 days for treatment of
glucoma.

Insoluble ophthalmic inserts
Diffusion controlled ocular inserts
These consists of a medicated core prepared out of a hydrogel polymer like
alginates, sandwiched between two sheets of transparent lipophilic, rate
controlling polymer.
The drug molecule penetrate through the rate controlling membranes at
zero order rate process.
dQ/dt = Dp Km (Cr-Ct)/δm
dQ/dt = Dp Km Cs/δm (Cr >> Ct sink condition)
eg ; ocusert pilo-20

Synthetic and semi- synthetic polymers-
Offer additional advantage of simple design & easily processed.
Soluble
synthetic
polymers
Cellulose derivatives- HPC, MC, HEC, HPMC, SOD. CMC
others- poly vinyl alcohol, ethylene vinyl acetate co
polymer
Additives Plasticizers- poly ethylene glycol, glycerine, propylene
glycol
complexing agent- PVP
Bioadhesives- poly acrylic acids, methyl hyroxy ethyl
cellulose
Soluble cellulose derivative inserts are composed of 30% of water.
Presence of water is unfavorable from stand point of stability of drug.
Insert can be sterilized by exposure to gamma radiation without the
cellulose component being altered.

The first soluble ophthalmic drug insert (SODI) developed was
of soluble co-polymer of acrylamide, N- vinyl pyrrolidone & ethyl
acetate.
It was in form of sterile thin films or wafers or oval shape,
weighing 15 – 16 mg.
A new type of ophthalmic insert incorporating a water-
soluble bio-adhesive component in its formulation has been
developed to decrease risk of expulsion & ensure prolonged
residence in eye, combined with the controlled release.
These inserts, named bio-adhesive ophthalmic drug inserts
(BODI)

II.Soluble Ocular inserts:
Lacrisert is a sterile ophthalmic insert use in the treatment of dry
Eye syndrome and is usually recommended for patients unable
to obtain symptomatic relief with artifical tear solutions.
The insert is composed of 5 mg of Hydroxypropyl cellulose
in a rod-shaped form about 1.27 mm diameter by about 3.5 mm
long.

II.Soluble Ocular inserts:
- Soluble inserts consists of all monolytic polymeric
devices that at the end of their release, the device
dissolve or erode.
Types
a) Based on natural polymers e.g. collagen.
b) Based on synthetic or semi synthetic polymers e.g.
Cellulose derivatives – Hydroxypropyl cellulose,
methylcellulose or Polyvinyl alcohol, ethylene vinyl
acetate copolymer.
- The system soften in 10-15 sec after introduction into
the upper conjunctival sac, gradually dissolves within
1h , while releasing the drug.
- Advantage: Being entirely soluble so that they do not need
to be removed from their site of application.

BIO ERODIBLE INSERTS
Main component of this type of inserts is the bio-erodible
polymers.
They undergoes hydrolysis of chemical bonds & hence dissolution.
Bio-erodible matrix controlling the release rate of the drug
ensures zero order release rate.
Eg., poly (ortho esters), poly (ortho carbonates)
Great advantage of these bio-erodible polymers is the possibility
of modulating their erosion rate by modifying their final structure
during synthesis.

Implantable silicone devices
Developed for the local delivery of an anti-neoplastic drug to
the intra-ocular site.
Composed of 2 sheets of silicone rubber glued to the edge with
adhesive to form a balloon like sac through which a silicone
tubing (0.3 mm dia) is inserted.
Such devices have significant potential for local controlled
delivery of anti- bacterial, anti-cancer, & anti-viral drugs to
anterior chamber of eye.

Other delivery devices
Ocufit® is a sustained release rod shape device made up of silicone
elastomer.
Lacrisert® is another cylindrical device, which is made of HPC and
used for treating dry- eye patients.
Mini disk ocular therapeutic systems (OTS)- It is a miniature
contact lens shaped, made of silicone based pre polymer. It requires
less time & less manual dexterity for insertion, when compared with
lacrisert®.
New ophthalmic delivery system (NODS)- It is a method for
delivering precise amounts of drugs to eye within a water soluble,
drug- loaded film.
When evaluated in humans, the NODS produced an 8 fold increase
in BA for pilocarpine with respect to std. eye drop formulations.

Preparation of ocular insert
Casting method
Polymer solution of diff composition
were prepared in boiling distilled water
Kept aside for 20-24 hrs to get clear solution
& then 10% w/w plasticizer was added &
stirred for 3 hrs
Weighed amounts of drug was added &
stirred for 4hrs to get uniform dispersion
Dispersion was degassed & casted on
glass substrate & dried at 500c for 18-20
hrs
Dried films are carefully removed & inserts
of required dimensions were punched out,
wrapped individually in Al. foil

Characterization of inserts
Uniformities of weight & thickness
Uniformities of drug content
Surface PH
In-vitro release studies (continuous flow through apparatus)
Ocular irritation test
In-vitro microbial studies

PACKAGING
Ophthalmic insert 5 mg supplied in packages of 60 sterile unit
dosage forms.
Each wrapped in an aluminum blister.
With two reusable applicators.
A plastic storage container to store the applicators for use.

How To Use
•To apply the system, wash hands first.
•Tilt your head back, gaze upward and pull down the
lower eyelid to make
a pouch.
•Place the system into the pouch.
•Blink a few times and roll your eye to move the insert into
place.
•Practice inserting and removing the system in the doctor s
office where
you can be shown the proper technique.
•Damaged or deformed systems should not be used or kept
in the eye.
•Replace with a new system.

Advantages
• Increasing contact time and thus improving
bioavailability.
• Providing a prolong drug release and thus a better
efficacy.
• Reduction of systemic side effects and thus reduced
adverse effects.
• Reduction of the number of administrations and thus
better patient compliance.

Dispersed Systems:
 Dispersed systems consist of particulate matter (dispersed phase),
distributed throughout a continuous phase (dispersion medium).
 They are classified according to the particle diameter of the
dispersed material:
1- Molecular dispersions (less than 1 nm)
- Particles invisible in electron microscope
- Pass through semipermeable membranes and filter paper
- Particles do not settle down on standing
- Undergo rapid diffusion
- E.g. ordinary ions, glucose

Dispersed Systems:
2- Colloidal dispersions (1 nm - o.5 um)
- Particles not resolved by ordinary microscope, can be detected by
electron microscope.
- Pass through filter paper but not pass through semipermeable
membrane.
- Particles made to settle by centrifugation
- Diffuse very slowly
- E.g. colloidal silver sols, naural and synthetic polymers
3- Coarse dispersions (> 0.5 um)
- Particles are visible under ordinary microscope
- Do not pass through filter paper or semipermeable membrane.
- Particles settle down under gravity
- Do not diffuse
- E.g. emulsions, suspensions, red blood cells

DEFINITION:
“ Nanoparticles are sub-nanosized colloidal structures
composed of synthetic or semi-synthetic polymers.”
 Size range : 10–1000 nm
 The drug is dissolved, entrapped, encapsulated or attached
to a nanoparticle matrix.
Based On Method Of Preparation:
Nanocapsules:- Nanocapsules are systems in which the
drug is confined to a cavity surrounded by a unique
polymer membrane.
Nanospheres:- Nanospheres are matrix systems in which
the drug is physically and uniformly dispersed.

Nanoparticulate drug-delivery systems

Nanoparticles
Nanospheres Nanoencapsules
Solid core spherical
particle , in which drug
embedded within
matrix or adsorbed on
the surface .
Drug is encapsulated
Within central
volume surrounded
by embryonic
polymeric sheath

Classificaton Of Nanoparticles:
 Solid Lipid Nanoparticles
 Polymeric Nanoparticles
 Ceramic Nanoparticles
 Hydrogel Nanoparticles
 Copolymerized Peptide Nanoparticles
 Nanocrystals and Nanosuspensions
 Nanotubes And Nanowires
 Functionalized Nanocarriers
 Nanospheres
 Nanocapsules

Advantages Of Nanoparticles:
• Nano particle can be administered by parenteral, oral,
nasal,occular routes.
• By attaching specific ligands on to their surfaces,nano particles
can be used for directing the drugs to specific target cells.
• Improves stability and therapeutics index and reduce toxic
affects.
• Both active & passive drug targetting can be achieved by
manipulating the particel size and surface characteristics of
nano particles

Disadvantages Of Nanoparticles
 Small size & large surface area can lead to particle
aggregation .
 Physical handling of nano particles is difficult in liquid
and dry forms.
 Limited drug loading.
 Toxic metabolites may form.

The selection of matrix materials is dependent on
many factors including
(a) size of nanoparticles required
(b) inherent properties of the drug, e.g., aqueous solubility
and stability;
(c) surface characteristics such as charge and permeability;
(d) degree of biodegradability, biocompatibility and toxicity;
(e) Drug release profile desired; and
(f) Antigenicity of the final product.

Polymers For Nanoparticles
 Natural hydrophilic polymers
• Proteins: - Gelatin, albumin, lectins, legumin.
• Polysaccharides: - alginate, dextran, chitosan,
agarose.
 Synthetic hydrophobic polymers
• Pre-polymerized polymers: - Poly (e-caprolactone)
(PECL),Poly (Lactic acid)(PLA), Polystyrene
• Polymerized in process polymers: - Poly (isobutyl
cyanoacrylates) (PICA), Poly (butyl cyano acrylates)

Equipments for Nanoparticles
• Homogenizer
• Ultra Sonicator
• Mills
• Spray Milling
• Supercritical Fluid Technology
• Electrospray
• Ultracentrifugation
• Nanofiltration

Preparation of polymeric Nanoparticles
Dispersion
polymerization
(DP)
Emulsion
polymerization
(EP) Solvent
evaporation
method
Solvent
Displacement
method
EP in aqueous
Continuous
phase
EP in an organic
continuous
phase
Salting out
tech.
Polymerization Preformed
polymer
Super critical
fluid tech.

DISPERSION POLYMERIZATION:
lsolation of nanospheres
Oligomers aggregate &
precipitates
Further, By chemical initiation
(ammonium or potassium per oxo disulphate)
(Acrylamide or Methyl methacrylate) Monomer is dissolved
in an aqueous medium
Heated to above 65 C

INTERFACIAL POLYMER CONDENSATION:
o/w
emulsion.
Ploymer
phase
Core phase +
drug
Nanocapsul
es.
(30-300nm)
Non-solvent which
precipitate polymer from
either of the phases

INTERFACIAL COMPLEXATION:
nanoparticles.
Reverse micellePolyelectrolyte.
Competing
polyelectrolyte
Polymer complexation

SOLVENT EVAPORATION METHOD:
Organic phase
solvent, drug,
polymer.
Aqueous phase
distilled water,
stabilizer.
o/w emulsion
Nanoparticles.
Sonication,
homogenization
Solvent extraction, solvent
evaporation.

Double emulsion solvent evaporation method:
Organic phase
solvent, drug,
polymer.
Aqueous phase
distilled water,
Stabilizer.
w/o
emulsion
stabilized
at 4oc
w/o/w
emulsion.
Nanoparti
cles.
Sonication, homogenization
Aqueous phase with stabilizer
Solvent extraction, solvent evaporation

SOLVENT DISPLACEMENT METHOD:
Distilled water,
polaxamer 188
Distilled water,
polaxamer 188
Organic
solvent,
polymer,
drug
Polar
solvent, oil,
polymer,
drug.
Nanosphe
res.
Nanocaps
ules.
Magnetic stirring

SALTING OUT:
Nanopartic
le.
Distilled
water, PVA,
MgCl2
Organic
solvent, drug,
polymer.
o/w
emulsion.
Mechanical stirring
Distilled water

Characterization of nanoparticles
Parameter Characterization method
Particle size and size distribution
Charge determination Laser Doppler Anemometry
Zeta potentiometer
Chemical analysis of surface
Static secondary ion mass spectrometry
Sorptometer
Carrier drug interaction Differential scanning calorimetry
photon correlation spectroscopy
Laser diffractometry
Transmission electron microscopy
Scanning electron microscopy
Atomic force microscopy
Drug stability
Bioassay of drug extracted from nanoparticles
Chemical analysis of drug

What are Liposomes?
• They are simply vesicles or ‘bags’ in which an
aqueous volume is entirely enclosed by a membrane
composed of lipid (fat) molecules, usually
phospholipids.
LIPOSOMES

These vesicles can encapsulate water-soluble drugs in
their aqueous spaces and lipid soluble drug within
the membrane itself.
• Structurally, liposomes are bilayered vesicles in
which an aqueous volume is entirely enclosed by a
membranous lipid bilayer mainly composed
of natural or synthetic phospholipids.

Advantages of liposome :
• Provides selective passive targeting to tumor tissues
• Increased efficacy and therapeutic index
• Increased stability via encapsulation
• Reduction in toxicity of the encapsulated agent.
• Improved pharmacokinetic effects
• Used as carriers for controlled and sustained drug
delivery
• Can be made into variety of sizes.

Disadvantages of liposome :
• Leakage of encapsulated drug during storage.
• Uptake of liposomes by the reticuloendothelial system
• Batch to batch variation
• Difficult in large scale manufacturing and sterilization
• Once administered, liposomes can not be removed
• Possibility of dumping, due to faulty administration

Mechanism of liposome formation
• In order to understand why liposomes are formed when
phospholipids are hydrated, it requires a basic
understanding of physiochemical features of
phospholipids.
• Phospholipids are amphipathic molecules (having affinity
for both aqueous and polar moieties) as they have a
hydrophobic tail is composed of two fatty acids
containing 10-24 carbon atoms and 0-6 double bonds in
each chain.

• In aqueous medium the phospholipids molecules are
oriented in such a way that the polar portion of the
molecule remains in contact with the polar environment
and at the same shields the non-polar part.
• They align themselves closely in planer bilayer sheets to
minimize the interaction between the bulky aqueous
phase and long hydrocarbon fatty acyl chains.
• This alignment requires input of sufficient amount of
energy (in the form of shaking, sonication,
homogenization, heating, etc).

• Interactions are completely eliminated when these
sheets fold over themselves to form closed, sealed
and continuous bilayer vesicles.

Classification of liposome's
1) Based on structural parameters
MLV, OLV,UV,SUV,MUV,LUV,GUV,MV.
2) Based on method of liposome preparation
REV, MLV-REV, SPLV, FATMLV, VET, DRV.
3) Based on the composition and application
CL, RSVE, LCL ,pH sensitive liposome, cationic
liposome , immuno- liposomes .

Materials used in preparation of
liposomes
A) Phospholipids :
• It is the major component of the biological membrane.
• Two types of phospholipids are used natural and synthetic
phospholipids.
• The most common natural phospholipid is the phospatidylcholine
(PC) is the amphipathic molecule and also known as lecithin.
• It is originated from animal (hen egg) and vegetable (soya bean).

B. Steroids :
• Cholesterol is generally used steroid in the formulation
of liposomes.
• It improves the fluidity of the bilayer membrane and
reduces the permeability of bilayer membrane in the
presence of biological fluids such as blood / plasma.
• Cholesterol appears to reduce the interactions with
blood proteins.

TECHNIQUES OF LIPOSOMES PREPARATION
(A) physical dispersion
a) Hand-shaken multilamellar vesicles (MLVs)
b) Non-shaking vesicles
c) Pro-liposomes
d) Freeze drying
(B) Processing of lipids hydrated by physical means
a) Micro emulsification liposomes (MEL)
b) Sonicated unilamellar vesicles (SUVs)
c) French pressure cell liposomes
d) Membrane extrusion liposomes
e) Dried-reconstituted vesicles (DRVs)
f) Freeze thaw sonication (FTS)
g) pH induced vesiculation
h) Calcium induced fusion

Surface charge Free-flow electrophoresis
Electrical surface potential and
surface pH
Zeta potential measurements & pH sensitive
probes
Percent of free drug/
percent capture
Drug release Diffusion cell/ dialysis
Vesicle shape and surface
morphology
Mean vesicle size and size
distribution
Dynamic light scattering, zetasizer,
Photon correlation spectroscopy, laser light
scattering, gel permeation and gel exclusion
Mini column centrifugation, ion-exchange
chromatography, radiolabelling
Transmission electron microscopy,
Freeze-fracture electron microscopy
Physical Characterization

Phopholipid peroxidation UV absorbance, Iodometric and GLC
Phospholipid hydrolysis,
Cholesterol auto-oxidation
HPLC and TLC
Osmolarity
Phospholipid concentration
Cholesterol concentration Cholesterol oxidase assay and HPLC
Osmometer
Barlett assay, stewart assay, HPLC
Chemical Characterization

Animal toxicity Monitoring survival rates, histology and
pathology
Sterility
Pyrogenicity Limulus Amebocyte Lysate (LAL) test
Aerobic or anaerobic cultures
Biological Characterization

Stability
• Physical stability :
Once liposome are formed, they behave similar to the
other colloidal particles suspended in water.
Neutral particles tend to aggregate or flocculate and
sediment with increase in size on storage. Adding
charged lipids such as stearyl amine, diactyl phosphate
and phosphatidyl serine can control the aggregation.
The addition of charged lipids causes repulsion and
prevents major changes in the overall size of liposome.

• Chemical stability :
Phospholipids, especially those derived from natural
sources, are subject to two major degradative reaction
A. Lipid peroxidation : most phospolipid liposomes
contain unsaturated acyl chains as part of their
molecular structure and susceptible to oxidative
degradation. It can be minimized by the use of animal
derived lipids like egg PC, which has less saturated
lipids, use of light resistant containers, use of
antioxidants are useful in minimizing oxidation.

B. Lipid hydrolysis :
hydrolysis in phospholipids results in the formation of
free fatty acids and lyso-lecithin. Selecting a good source
of lipid, temperature, pH, and minimizing oxidation.
• Biological stability :
liposome's release entrapped molecules rapidly when
incubated with blood or plasma. This instability is
attributed to the transfer of bilayer lipids to albumin and
high density liposome.

 APPLICATION OF LIPOSOMES
 Liposomes as drug/protein delivery vehicles
 Controlled and sustained drug release in situ.
 Enhanced drug solubilization
 Altered pharmacokinetics and biodistribution
 Enzyme replacement therapy and lysosomal storage
disorders
 Liposomes in antimicrobial, antifungal and antiviral therapy
 Liposomal drugs
 Liposomal biological response modifiers
 Liposomes in tumour therapy
 Carrier of small cytotoxic molecules
 Vehicle for macomolecules as cytokines o genes

 Liposomes in gene delivery
 Gene and antisense therapy
 Genetic vaccination
 Liposomes in immunology
 Immonoadjuvant
 Immunomodulator
 Immunodiagnosis
 Liposomes as artificial blood surrogates
 Liposomes as radiophamaceutical and radiodiagnostic cariers
 Liposomes in cosmetics an dermatology
 Liposomes in enzyme immobilization and bioreactor
technology

Some liposomal formulation of Amphotericin B
System Target disease Brand name Product
Liposomes
(i.v)
Systemic fungal
infection,
Visceral
leishmaniasis
AmBisome NeXstar, USA
Liposomes
(i.v)
Systemic fungal
infection
Amphocil SEQUUS,
USA
Liposomes
(i.v)
Systemic fungal
infection
ABELECT The Liposome
company,
USA

Liposomes in gene therapy:
Type of
vector
Advantages Disadvantages
Viral
vector
 Relative high transfection
efficiency
 Immunogenicity, presence of
contaminants and safety
 Vector restricted size limitation
for recombinant gene
 Unfavourable p’ceutical issue-
large scale production, GMP,
stability and cost
Non-
viral
 Favourable p’ceutical issue-
large scale production, GMP,
stability and cost
 Plasmid independent structure
 Low immunogenicity
 Opportunity for
chemical/physical
manipulation
 Relative low transfection
efficiency

Limitations of liposome technology
• 1. Stability
• 2. Sterilization
• 3. Encapsulation efficiency
• 4. Active targeting
• 5. Gene therapy
• 6. Lysosomal degradation

INTRODUCTION
Surfactant
Oil Phase
Water Phase
Co-Surfactant
What is Micro Emulsion?

Microemulsion
• Microemulsions are thermodynamically stable dispersions of oil and
water stabilized by a surfactant and, in many cases, also a
cosurfactant.
• Microemulsions can have characteristic properties such as ultralow
interfacial tension, large interfacial area and capacity to solubilize
both aqueous and oil-soluble compounds.
Theories of Microemulsion Formation
1. Interfacial or mixed film theories.
2. Solubilization theories.
3. Thermodynamic treatments.

Interfacial/Mixed Film Theories:
• They considered that the spontaneous formation of microemulsion
droplets was due to the formation of a complex film at the oil-water
interface by the surfactant and co-surfactant.
• This caused a reduction in oil-water interfacial tension to very low values
(from close to zero to negative)
• equation. γi = γo/w -πi
Where,
γ o/w = Oil-water interfacial tension without the film present
πi = Spreading pressure
γi =Interfacial tension

Mechanism of curvature of a duplex film:
• The interfacial film should be curved to form small droplets to explain
both the stability of the system and bending of the interface.
• A flat duplex film would be under stress because of the difference in
tension and spreading of pressure on either side of it.
• Reduction of this tension gradient by equalizing the two surface tensions
is the driving force for the film curvature.
• It is generally easier to expand the oil side of an interface than the water
side and hence W/O microemulsion can be formed easily than O/W
microemulsion.

Solubilization Theories:-
• Illustrated the relationship between reverse micelles and W/O
microemulsion with the help of phase diagrams.
• The inverse micelle region of ternary system i.e. water, pentanol and
sodium dodecyl sulphate (SDS) is composed of water solubilized reverse
micelles of SDS in pentanol.
• Addition of O-xylene up to 50% gives rise to transparent W/O region
containing a maximum of 28% water with 5 % pentanol and 6% surfactant
(i.e. microemulsions).
• These four component systems could be prepared by adding hydrocarbon
directly to the inverse micellar phase by titration.

Thermodynamic theory
• The process of formation of oil droplets from a bulk oil phase is
accompanied by an increase in the interfacial area ∆A, and hence an
interfacial energy ∆G .
• The entropy of dispersion of the droplets is equal to T ∆ S and hence the
free energy of formation of the system is given by the expression.
∆Gf = γ ∆a - T ∆S
Where,
∆Gf = free energy of formation
∆A = change in interfacial area of microemulsion
∆ S = change in entropy of the system
T = temperature
γ = surface tension of oil water interphase

• When the interfacial tension is made sufficiently low that the interfacial
energy becomes comparable to or even lower than the entropy of
dispersion.
• The dominant favorable entropic contribution is very large dispersion
entropy arising from the mixing of one phase in the other in the form of
large number of small droplets.
• The free energy of formation of the system becomes zero or negative.
• This explains the thermodynamic stability of micro emulsions.
• The co-surfactant along with surfactant lower the interfacial tension to a
very small even transient negative value .

Constituents of Microemulsion
Oil phase :-
Isopropyl Myristate
Oleic acid
Olive oil
Mineral oil
Medium chain triglyceride
Soybean oil
Captex 355
Isopropyl palmitate
Sunflower Oil
Safflower Oil
Surfactants :-
Tween 80
Tween 40
Labrafil M1944CS
Polyoxyethylene-35-ricinoleate
Brij 58
Span 80
Cremophor EL
Labrasol
Cremophor RH
Lecithin
Cosurfactant/Stabilizer :-
Propylene glycol
Ethylene glycol
Ethanol
1-butanol
Isopropyl alcohol
PEG 600
Glycerol
PEG 400

Oil Component
• As compare to long chain alkanes, short chain oil penetrate the tail group
region to a greater extent and resulting in increased negative curvature (and
reduced effective HLB).
• Following are the different oil are mainly used for the formulation of
microemulsion:
1. Saturated fatty acid-lauric acid, myristic acid,capric acid
2. Unsaturated fatty acid-oleic acid, linoleic acid,linolenic acid
3. Fatty acid ester-ethyl or methyl esters of lauric, myristic and oleic acid.
• The main criterion for the selection of oil is that the drug should have high
solubility in it.
• This will minimize the volume of the formulation to deliver the therapeutic
dose of the drug in an encapsulated form.

Surfactants
• It is to lower the interfacial tension which will ultimately facilitates
dispersion process and provide a flexible around the droplets.
• Generally, low HLB (3-6) surfactants are suitable for w/o microemulsion,
whereas high HLB (8-18) are suitable for o/w microemulsion.
They allow the interfacial film sufficient flexible to take up different
curvatures required to form microemulsion over a wide range of
composition.
1. Short to medium chain length alcohols (C3-C8) reduce the interfacial
tension and increase the fluidity of the interface.
Co surfactants

1. Surfactant having HLB greater than 20 often require the presence of
cosurfactant to reduce their effective HLB to a value within the range
required for microemulsion formulation.
a) by reducing the interfacial tension
• b) By increasing the flexibility and fluidity of the interface by positioning
itself between the surfactant tails which alters the solvent properties of both
the dispersed and continuous microemulsion phases;
• c) by lowering overall viscosity.
• d) by being often soluble in both organic and aqueous phases, co-
surfactants help solubilise poorlysoluble compounds (e.g., peptides, vitames

Types of micro emulsion
• O/W Microemulsion
• W/O Microemulsion
• Bi continuous Microemulsion

Phase Behaviour
• For four or more components
pseudo ternary phase diagrams are
used to study the phase behaviour.
• In this diagram a corner represent a
binary mixture of two components
such as water/drug, oil/drug or
surfactant/co-surfactant.

• With high oil concentration surfactant forms reverse micelles capable of
solubilizing water molecules in their hydrophilic interior.
• Continued addition of water in this system may result in the formation
of W/O micro emulsion in which water exists as droplets surrounded
and stabilized by interfacial layer of the surfactant / co-surfactant
mixture.
• Finally, as amount of water increases, this lamellar structure will break
down and water will form a continuous phase containing droplets of oil
stabilized by a surfactant / co-surfactant (O/W microemulsions)

Preparation of Microemulsion
• Following are the different methods are used for the
preparation of microemulsion:
1. Phase titration method
2. Phase inversion method

• 1)dilution of an oil-surfactant mixture with water.(w/o)
• 2) dilution of a water-surfactant mixture with oil.(o/w)
• 3) mixing all components at once. In some systems, the order of
ingredient addition may determine whether a microemulsion forms or not.
•e.g.(w/o)
soybean oil, ethoxylated mono- and di-glycerides as surfactants and a
mixture of sucrose and ethanol as the aqueous phase.
Transparent microemulsions resulted from dilution of the oil-surfactant
mixtures with water along several regions in the pseudo-ternary phase
diagram.
Phase titration method

Phase inversion method :
Phase Inversion Temperature (PIT), i.e., the temperature range in which an
o/w microemulsion inverts to a w/o type or vice versa.
• using non-ionic surfactants, polyoxyethylene are very susceptible to
temperature since surfactant solubility (in oil or water) strongly depends on
temperature.
With increasing temperature, the polyoxyethylene group becomes
dehydrated, altering the critical packing parameter which results in phase
inversion.
• For ionic surfactants, increasing temperatures increase the electrostatic
repulsion between the surfactant headgroups thus causing reversal of film
curvature.
Hence the effect of temperature is opposite to the effect seen with non-ionic
surfactants.

Parameters
Studied
Techniques Used
Phase Behaviour Phase contrast microscopy and freeze fracture
TEM
Size and Shape Transmission Electron Microscopy (TEM),
SEM,DLS
Rheology Brookfield Viscometer
Conductivity Conductivity Meter
Zeta Potential Zetasizer
pH pH Meter
Drug Release
Studies
Franz Diffusion Cells
Physical Stability
Study
Ultracentrifuge
EVALUATION

• Advantages Of Microemulsion Over Other Dosage Forms
– Increase the rate of absorption
– Eliminates variability in absorption
– Helps solublize lipophilic drug
– Provides a aqueous dosage form for water insoluble drugs
– Increases bioavailability
– Various routes like tropical, oral and intravenous can be used to
deliver the product
– Rapid and efficient penetration of the drug moiety
– Helpful in taste masking
– Provides protection from hydrolysis and oxidation as drug in oil
phase in O/W microemulsion is not exposed to attack by water
and air.
– Liquid dosage form increases patient compliance.
– Less amount of energy requirement.

– Aesthetically appealing products can be formulated as trans-
parent o/w or w/o dispersions called microemulsions.
– These versatile systems are currently of great technological and
scientific interest to the researchers because of their potential to
incorporate a wide range of drug molecules (hydrophilic and
hydrophobic) due to the presence of both lipophilic and hydrophilic
domains.
– These adaptable delivery systems provide protection against
oxidation, enzymatic hydrolysis and improve the solubilization of
lipophilic drugs and hence enhance their bioavailability. In addition
to oral and intravenous delivery, they are amenable for sustained
and targeted delivery through ophthalmic, dental, pulmonary,
vaginal and topical routes.
– Microemulsions are experiencing a very active development as
reflected by the numerous publications and patents being granted
on these systems.

Application of microemulsion in delivery of drug
• Oral delivery
– Microemulsions have the potential to enhance the solubilization
of poorly soluble drugs (particularly BCS class II or class IV) and
overcome the dissolution related bioavailability problems.
– These systems have been protecting the incorporated drugs
against oxidation, enzymatic degradation and enhance
membrane permeability.
– Presently, Sandimmune Neoral(R) (Cyclosporine A),
Fortovase(R) (Saquinavir), Norvir(R) (Ritonavir) etc. are the
commercially available microemulsion formulations.
– Microemulsion formulation can be potentially useful to improve
the oral bioavailability of poorly water soluble drugs by
enhancing their solubility in gastrointestinal fluid.

• Parenteral delivery
– The formulation of parenteral dosage form of lipophilic and
hydrophilic drugs has proven to be difficult.
– O/w microemulsions are beneficial in the parenteral delivery of
sparingly soluble drugs where the administration of suspension
is not required.
– They provide a means of obtaining relatively high concentration
of these drugs which usually requires frequent administration.
– Other advantages are that they exhibit a higher physical stability
in plasma than liposome’s or other vehicles and the internal oil
phase is more resistant against drug leaching.
– Several sparingly soluble drugs have been formulated into o/w
microemulsion for parenteral delivery.

• Topical delivery
– Topical administration of drugs can have advantages over
other methods for several reasons, one of which is the
avoidance of hepatic first-pass metabolism of the drug and
related toxicity effects.
– Another is the direct delivery and targetability of the drug
to affected areas of the skin or eyes.
– Now a day, there have been a number of studies in the
area of drug penetration into the skin.
– They are able to incorporate both hydrophilic (5-
flurouracil, apomorphine hydrochloride, diphenhydramine
hydrochloride, tetracaine hydrochloride, methotrexate)
and lipophilic drugs (estradiol, finasteride, ketoprofen,
meloxicam, felodipine, triptolide) and enhance their
permeation.

• Ophthalmic delivery
– Low corneal bioavailability and lack of efficiency in the posterior
segment of ocular tissue are some of the serious problem of
conventional systems.
– Recent research has been focused on the development of new
and more effective delivery systems.
– Microemulsions have emerged as a promising dosage form for
ocular use.
– Chloramphenicol, an antibiotic used in the treatment of
trachoma and keratitis, in the common eye drops hydrolyzes
easily.
– Fialho et al. studied microemulsion based dexamethasone eye
drops which showed better tolerability and higher
bioavailability. The formulation showed greater penetration in
the eye which allowed the possibility of decreasing dosing
frequency and thereby improve patient compliance.

Iontophoreis
 Introduction of ions into the body using
direct electrical current
 Transports ions across a membrane or into a
tissue
 It is a painless, sterile, noninvasive
technique
 Demonstrated to have a positive effect on
the healing process

Iontophoresis vs Phonophoresis
 Both techniques deliver chemicals to
biologic tissues
 Phonophoresis uses acoustic energy
(ultrasound) to drive molecules into tissues
 Iontophoresis uses electrical current to
transport ions into tissues

Pharmacokinetics of Ion Transfer
 Iontophoresis delivers medication at a
constant rate so that the effective plasma
concentration remains within a therapeutic
window for an extended period of time
 Therapeutic window – range between the
minimum plasma concentration of a drug
necessary for a therapeutic effect and the
maximum effective plasma concentration
(above which adverse effects may occur)

 Iontophoresis facilitates the delivery of charged
and high molecular weight compounds through
the skin
– Overcomes the resistive properties of the skin
 Iontophoresis decreases absorption lag time while
increasing delivery rate
– Much better than passive skin application
 Iontophoresis reduces the development of
tolerance to drug
– Does so by providing both a spiked and
sustained release of the drug

 Rate at which a medication may be delivered is determined by…
 1). The concentration of the ion
 2). The pH of the solution
 3). Molecular size of the solute
 4). Current density
 5). Duration of the treatment
 Mechanisms of drug absorption via iontophoresis is similar to the
administration of drugs via other methods
 Advantages of taking medication via iontophoresis relative to oral
medications
 Concentrated in a specific area
 Does not have to be absorbed within the GI tract
 Safer than administering a drug via injection

Movement of Ions In Solution
 Ionization - soluable compounds (acids,
alkaloids, salts) dissolve into ions that are
suspended in solutions
 Resulting solutions are called electrolytes
 Electrophoresis - movement of ions in
electrolyte solutions according to the
electrically charged currents acting on them

 Cathode (positive pole) = negative electrode
 Highest concentration of electrons in tissues
 Repels positively charged ions
 Attracts negatively charged ions
 Accumulation of negatively charged ions in a
small area creates an acidic reaction
 Recall from Ch. 8 – this is desired for the first 72 hours of the
healing process (or with infection) because it results in
hardening of the tissues and decreased nerve irritability

 Anode (negative pole) = positive electrode
 Lower concentration of electrons in tissues
 Repels negatively charged ions
 Attracts positively charged ions
 Accumulation of positively charged ions in a
small area creates an alkaline reaction
 Recall from Ch. 8 – this is desired after 72 hours post injury
and results in softening of the tissues and increased nerve
irritability

 With iontophoresis…
– Positively charged ions are driven into tissues from
positive pole
– Negatively charged ions are driven into tissues from
negative pole
 The pole that is driving ions into tissue is called
the active electrode
– The other pole is called the inactive electrode
 Knowing correct ion polarity is essential to
administering an effective iontophoresis treatment

Movement of Ions In Tissue
 Force which acts to move ions through the
tissues is determined by…
 1). Strength of the electrical field
 2). Electrical impedance of tissues
 Skin and fat = high impedance*, poor conductors
 Sweat glands = low impedance; therefore, sweat
ducts is the primary path by which ions move
through the skin
* Skin impedance decreases during an iontophoresis treatment due to increased
blood flow between the electrodes

 Strength of the electrical field is determined
by the current density
 Difference in current density between the
active and inactive electrodes establishes a
gradient of potential difference
 Produces ion migration within the electrical field
 Ions move according to their electrochemical
gradient
 Concentration gradient
 Electrical gradient

 Current density may be altered by…
 1). Increasing or decreasing current intensity
– Higher current intensity is necessary in areas where
skin and fat layers are thick
– Increases risk of burns around negative electrode
 2). Changing the size of the electrode
– Increasing the size of the electrode will decrease
current density under that electrode
– Negative pole e-stim pad should be larger (2x)
because an alkaline reaction (+ ions) is more likely
to produce tissue damage than an acidic reaction
(- ions)

 The quantity of ions transferred into the
tissues via iontophoresis is directly
proportional to…
 1). Current density at the active electrode
 2). Duration of the current flow
 3). Concentration of ions in solution

 Once the medication (ions) passes through
the skin, the ions recombine with existing
ions and free radicals in the blood
– Increased blood flow between electrodes
 Form new compounds necessary for
favorable therapeutic effects

Iontophoresis Generators
 Produce continuous
DC*
 Assures
unidirectional
flow of ions
*One study has shown that
drugs can be delivered using AC
Iontophoresis Techniques

Iontophoresis
Generator
 Intensity: 3 to 5 mA
 Unit adjusts to
normal variations in
tissue impedance
 Reduces the
likelihood of burns
 Automatic
shutdown

Iontophoresis
Generator
 Adjustable Timer
 Up to 25 min

Iontophoresis
Generator
 Lead wires
 Active electrode
 Inactive electrode

Current Intensity
 Low amperage currents appear to be more
effective as a driving force than currents with
higher intensities
– Higher intensity currents tend to reduce effective
penetration
 Recommended current intensity: 3-5 mA
 Maximum current intensity may be determined
by the size (surface area) of the active electrode
– Current intensity may be set so that the current density
under the active electrode falls between 0.1 - 0.5
mA/cm2

Current Intensity
 Increase intensity slowly until patient reports
tingling or prickly sensation
 If pain or a burning sensation occurs,
intensity is too great and should be decreased
 When terminating treatment, intensity should
be slowly decreased to zero before electrodes
are disconnected

Treatment Time
 Treatment Time: ranges between 10-20 min.
 Patient should be comfortable with no
reported or visible signs of pain or burning
 Check skin every 3-5 minutes for signs of skin
irritation
 Decrease intensity during treatment to
accommodate for decrease in skin impedance
– This avoids pain or burning

Dosage of Medication
 Dosage is expressed in milliampere-minutes
(mA-min)
 Total drug dose delivered (mA-min) =
current X treatment time
 Typical iontophoresis drug dose is 40 mA-
min

Traditional Electrodes
 Older electrodes made of tin, copper, lead,
aluminum, or platinum backed by rubber
 Completely covered by sponge, towel, or
gauze which contacts skin
 Absorbent material is soaked with ionized
solution (medication)
 If medicated ointment is used, it should be
rubbed into the skin and covered by some
absorbent material

Commercial Electrodes
 Sold with most iontophoresis systems
 Electrodes have a small chamber covered by a
semipermiable membrane into which ionized
solution may be injected
 The electrode self adheres to the skin

Electrode Preparation
 Shave and clean skin
prior to attaching the
electrodes to ensure
maximum contact
 Do not excessively
abrade the skin during
cleaning
 Damaged skin has lower
resistance to current
– Increased risk of burns

Oral sustained and controlled release dosage forms Dr GS SANAP

Oral sustained and controlled release dosage forms Dr GS SANAP

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