Transcript mucoadhesion, floating drug delivery systems

Drug targeting is the ability of the drug to
accumulate in the target organ or tissue
selectively and quantitatively, independent of
the site and methods of its administration.
Drug targeting
The main problems currently associated with
systemic drug administration are:
1. Even bio-distribution of drug throughout the body;
2. The lack of drug specific affinity toward a pathological site;
3.
The necessity of a large total dose of a drug;
4.
Non-specific toxicity and other adverse side-effects.
Drug Targeting May solve Many Of These Problems.
Drug Targeting
Advantages of drug targeting:
1. Drug administration protocols may be simplified;
2. Drug quantity may be greatly reduced as well as the
cost of therapy;
3.
Drug concentration in the required sites can be
sharply increased without negative effects on nontarget compartments.
Strategy for drug targeting
The concept of drug targeting allow the development of
drugs which are potent and non-toxic and targeted drug to
its particular site of action through:
Use Cell-specific enzymes and ligands
Development of prodrug-based technologies
Use of smart polymeric systems
 A prodrug is a pharmacologically inactive compound
which undergo chemical or enzymatic metabolism to
give the active compound.
 Most chemically designed prodrugs consist of two
components, which are the active drug chemically
linked to a pharmacologically inert moiety .
 After administration or absorption of the prodrug,
the active drug is usually released by either chemical
or enzymatic hydrolytic or reductive processes.
 The prodrug must be sufficiently stable to withstand
the
pharmaceutical
formulation
while
permitting
chemical or enzymatic cleavage at the appropriate
time or site.
Factors for optimizing site-specific drug delivery:
1. The prodrug must be readily transported to the
site
of
action,
rapid
uptake
and
essentially
perfusion rate limited.
2. Once at the site, the prodrug must be selectively
cleaved
to
the
active
drug
relative
to
its
conversion at other sites.
3. Once selectively generated at the site of action,
the active drug must be retained by the tissue.
Prodrug
used
to
solve
a
wide
range
of
pharmaceutical problems including:
Un palatability
gastric irritation
pain on injection
insolubility
instability.
poor drug adsorption and drug distribution
by increasing the lipophilicity of the drug molecule.
Advantages
Overcome
biological & pharmaceutical barriers which
separate the site of administration from the site of
action of drug.
 Enhance efficacy of drug. eg,
methoxy
methyl
ester
of
the administration of the
hetacillin
(derivative
of
ampicillin) gaiv more distribution of ampicillin in the
tissues than occurs on administration of ampicillin itself.
Prodrugs
are decreases toxic side-effects by restricting
the action of a drug to a specific target site in the body.
SITE-SPECIFIC ENZYME-BASED
DELIVERY SYSTEMS
Are prodrug designed to ensure the release of the active
drug only at its site of action by utilizing enzyme or
chemical activity of a particular cell.
For example, the prodrug cyclophosphamide is initially
activated
by
hepatic
cell
hydroxycyclophosphamide
converted
to
the
enzymes
which
alkylating
is
to
then
cytotoxic
mustard in the hepatic target cells.
generate
4-
specifically
phosphoramide
can used for site-specific delivery to tumor cells.

 As
the
blood
supply
to
large
solid
tumors
is
disorganized, the internal regions are often nonvasculated and the cells termed hypoxic cell ( poor O2)
 The
absence
of
molecular
oxygen
enhances
the
reductase activity in hypoxic tissues providing means of
targeting the internal regions of solid tumors using a
selective chemical prodrug-delivery system.
 For
example,
the
2-nitro-imidazole
compound
selectively cytotoxic to cultured hypoxic cells.
is
SITE-SPECIFIC REDOX-BASED
DRUG DELIVERY SYSTEMS
Use
of
lipophilic
impenetrability
of
prodrugs
some
barriers
overcome
as
the
blood-brain
barrier to highly polar drugs, however the increased
lipid solubility may enhance uptake in other tissues
with a result in increase drug toxicity.
These problems overcome by utilizing a drug delivery
system which "trapping" a prodrug in the brain by oxidizing
the prodrug to a less membrane permeable derivative.
This approach used to enhance the CNS penetration of a
non-polar prodrug which crosses the blood-brain barrier but
is then rapidly oxidized to the active form and trapped in
the CNS.
Dihydropyridine-pyridinium
salt
redox
systems
of
phenylethylamine and dopamine illustrate this technology.
Dihydropyridine-pyridinium salt redox system for sitespecific delivery to the brain.
The 1,4 dihydro-prodrug is delivered directly to the brain,
where it is oxidized and trapped as the prodrug of
quaternary ammonium salt.
The quaternary ammonium salt is slowly cleaved by
chemical/enzymatic
action
with
the
biologically active phenylethylamine .
release
of
the
SITE-SPECIFIC ANTIBODYDIRECTED ENZYME PRODRUG
THERAPY
(ADEPT)
It is also possible
to target drugs
to specific cells th
 use specific cell surface ligands – prodrug
that use
antibody-directed enzyme for cleavage to active drug.
 The approach has been used to target drugs to tumor
cells by employing an enzyme, not normally present in
the extracellular fluid or on cell membranes, conjugated
only to an tumor antibody which localizes in the tumor
via an antibody-antigen interaction on administration.
Following clearance of any unbound antibody conjugate
1
enzyme from the systemic circulation, a prodrug which is
specifically
activated
by
the
enzyme
conjugate,
is
administered.
2
The bound enzyme-antibody conjugate ensures that the
prodrug is only converted to the cytotoxic parent compound
at the tumor site thereby reducing systemic toxicity.
Example:
using cytosine deaminase to generate 5-fluorouracil from
the 5-fluorocytosine prodrug at tumor sites increases the
delivery to the tumor by 17 fold compared to that achieved
on administration of 5-fluorouracil alone.
Gastrointestinal tract
TARGETING SYSTEMS
stomach TARGETING SYSTEMS
Orally administered controlled release dosage forms are
subjected to 2 complications:
1- short gastric residence time
2- irregular gastric emptying rate.
Gastric emptying of dosage forms is valuable asset for
dosage forms, which need to be residence in the stomach
for a longer period of time.
Advantages of Prolonged gastric retention
improves bioavailability of drug
reduces drug waste
improves solubility for drugs that are less soluble in a high pH
environment.
It has a local drug delivery to the stomach and proximal small
intestines.
The controlled gastric retention of solid dosage forms may be
achieved by the mechanisms of :
mucoadhesion
sedimentation,
,floating
drug
expansion,
delivery
modified
systems
shape
(FDDS),
systems,
simultaneous administration of pharmacological agents that
delay gastric emptying.
Factors affecting gastric residence time of solid dosage
forms :
 Size and shape of dosage unit
 Tetrahedron-
and ring-shaped dosage have a better
gastric residence time as compared with other shapes.

Dosage forms having a diameter of more than 7.5 mm
show a better gastric residence
 Several
formulation parameters can affect the gastric
residence time.
 The
density of a dosage form also affects the gastric
emptying rate.
A buoyant (floating) dosage form
having a density of less than that of the gastric fluids and it
is floats. Since it is away from the pyloric sphincter, the
dosage unit is retained in the stomach for a prolonged
period.
Applications of Floating Drug Delivery Systems
Floating drug delivery offers several applications:
For drugs having poor bioavailability because of the narrow
absorption window in the upper part of the gastrointestinal
tract.
 It retains the dosage form at the site of absorption and thus
enhances the bioavailability.
Sustained Drug Delivery
 HBS systems remain in the stomach for long periods and
hence can release the drug over a prolonged period of time.
 These systems have a bulk density of <1 as a result of
which they can float on the gastric contents.
 These systems are relatively large in size and passing
from the pyloric sphincter is prohibited.
Site-Specific Drug Delivery
These systems are particularly advantageous for drugs that
are specifically absorbed from stomach or the proximal part of
the small intestine, eg, riboflavin and furosemide.
By targeting drugs to the stomach, desired therapeutic levels
achieved and drug waste could be reduced
FDDS serves as an excellent drug delivery system for the
eradication of Helicobacter pylori ,which causes chronic
gastritis and peptic ulcers. The treatment requires high drug
concentrations within the gastric mucosa.
Absorption Enhancement
Drugs that have poor bioavailability because of sitespecific
absorption
gastrointestinal
tract
from
are
the
upper
potential
part
candidates
of
to
the
be
formulated as floating drug delivery systems, thereby
maximizing their absorption.
As increase in the bioavailability of floating dosage forms
of enteric-coated LASIX-long product (42.9%) could be
achieved as compared with commercially LASIX tablets
(33.4%)
On comparison of floating & nonfloating dosage units,
The
floating dosage units remained floating on the gastric
contents throughout their residence in the gastrointestinal
tract,
Floating units away from the gastro-duodenal junction were
protected from the peristaltic waves during digestive phase
While the non floating dosage units sink and remained in the
lower part of the stomach, And stayed close to the pylorus
and were subjected to propelling and retropelling waves of
the digestive phase .
Intragastric residence
positions of floating and
nonfloating units
Design Floating Dosage Forms
Single-Unit Floating Dosage Forms:
The
globular
shells
with
popcorn,
poprice,
and
polystyrol have been used as drug carriers, having lower
density than that of gastric fluid
used for drug
controlled release.

Sugar
polymeric
materials
such
as
methacrylic
polymer and cellulose acetate phthalate have been used
to coat these shells.
 These are coated with a polymer mixture.
The polymer of choice can be either ethyl cellulose or
hydroxy propyl cellulose depending on the type of release
desired.
Finally, the product floats on the gastric fluid while
releasing the drug gradually over a prolonged period.
A buoyant dosage form can also be obtained by using a
fluid-filled system that floats in the stomach. As Hydro
dynamically balanced systems (HBS)
Design Floating Dosage Forms
multiple-Unit Floating Dosage Forms:
This systems are classified depending on formulation :
 Effervescent
 Non-effervescent systems.
Effervescent Floating Dosage Forms
a) matrix types systems
prepared with the swellable polymers such as
methylcellulose and chitosan and various effervescent
compounds eg, sodium bicarbonate, tartaric acid, and citric
acid.
They are formulated in a way that when in contact with the
acidic gastric contents, CO2
is liberated and entrapped in
swollen hydrocolloids, which provides buoyancy to the
dosage forms.
Sublayers membrane
polyvinyl acetate & purified
shellac
Effervescent Layer
inner & outer sublayer
sodium bicarbonate &
tartaric acid
Conventional sustained
release pill
Swelable membrane
layer
methylcellulose &
chitosan
(A)Multiple-unit oral floating drug delivery system.
(B)Working principle of effervescent floating drug delivery system .
The effervescent layer containing sodium bicarbonate and
tartaric acid was divided into 2 sublayers to avoid direct
contact between the 2 agents.
These sublayers were surrounded by a swellable polymer
membrane containing polyvinyl acetate and purified shellac.
 When this system was immersed in the buffer at 370C, it
settled down and the solution permeated into the effervescent
layer through the outer swellable membrane. CO
2
was
generated by the neutralization reaction between the 2
effervescent agents, producing swollen pills with a density less
than 1.0 g/mL.
It was found that the system had good floating ability
independent of pH and viscosity.
b) ion exchange resin floating system
Use resin that was loaded with bicarbonate by mixing the
resine beads with 1 M sodium bicarbonate solution.
The loaded resine beads were then surrounded by a
semipermeable membrane to avoid sudden loss of CO2
Effervescent floating drug
delivery system
based on ion exchange resin
Upon coming in contact with gastric contents an exchange of
chloride and bicarbonate ions took place that resulted in CO2
generation thereby carrying beads toward the top of gastric
contents and producing a floating layer of resin beads.
The gastric residence time was prolonged considerably (24
hours) compared with uncoated beads (1 to 3 hours).
Effervescent floating drug
delivery system
based on ion exchange resin
Non-Effervescent Floating Dosage Forms
Non-effervescent floating dosage forms use a gel forming
hydrocolloids of swellable cellulose type , polysaccharides,
and matrix-forming polymers like polycarbonate, polyacrylate,
poly methacrylate , and polystyrene and bioadhesion polymers
like chitosan and carbopols.
The formulation method includes:
a simple mixing the drug and the gel-forming hydrocolloid.
Working principle of non effervescent floating drug delivery
system:
After oral administration in contact with gastric fluids this
dosage form swells and attains a bulk density of < 1.
The air entrapped within the swollen matrix imparts
buoyancy to the dosage form. The formed swollen gel-like
structure acts as a reservoir and allows sustained release of
drug.
Intragastric floating drug delivery device.
The system composed of a drug reservoir encapsulated in a
microporous compartment having pores on top and bottom
surfaces. The peripheral walls of the reservoir compartment
were completely sealed to prevent any physical contact of the
undissolved drug with walls of the stomach.
Tablets of 2 kg/cm2 and 4 kg/cm2 hardness after immersion
into the floating media floated immediately for 3 to 4 minutes
and then came to the surface. And remained floating for 24
hours. The tablet with 8 kg/cm2 hardness showed no floating
capability.
intestinal TARGETING SYSTEMS
Small intestinal transit time is an important parameter for
drugs that are incompletely absorbed.
Intestinal target solid dosage forms (enteric coated tablets) is
intended to:
Prevent destruction of the drug by gastric juices.
To prevent irritation of the stomach lining by the drug.
To promote drug absorption
Colon TARGETING SYSTEMS
 Colon-specific diseases are inefficiently treated by oral
therapy, because most orally administered drugs are absorbed
before arriving in the colon.
 Advantages of Colon-specific drug delivery systems include:

used for the local treatment of colonic disorders such as
Crohn`s
disease,
ulcerative
colitis
and
irritable
bowel
syndrome
 deliver drugs to the lower gastrointestinal tract without
releasing them in the upper GI-tract, with expected decrease
in the side-effects of the drugs.
 colon is a preferable site for the absorption of liable
compounds such as peptides and proteins, because the
hydrolytic enzyme activities of the colon are lower than
that of the small intestine thus improve the bioavailability
of such drugs.
Disadvantages
colon is not suitable site for drug absorption as the small
intestine, because the water content in the colon is much
lower and the colonic surface area for drug absorption is
narrow in comparison with the small intestine.
Methodologies For Colon Site-Specific Drug Release:
 pH-sensitive delivery systems
Methods based on pH-Sensitive Polymer Coated Drug Delivery
to the Colon such as enteric coated dosage forms
However failure of pH-dependent system may be expected
due to:
 inter and intra subject variation of GI pH
pH
variation due to pathological conditions and diet
composition.
such
methods release the drug in the upper small intestine
after gastric emptying,
 Delayed Release Drug delivery to Colon (Time Controlled
Release System) (TCRS) :
In (TCRS) the location of drug release depends on the transit
time in GIT. such as sustained release dosage forms.
Disadvantages
Due
to the large variation in the gastric emptying time due
amount of food intake and peristalsis in the stomach thus in
this approach the colon arrival time of dosage forms cannot be
accurately predicted, resulting in poor colonical availability.
The
approach
is
affected
by
the
changes
environmental conditions, and state of disease.
in
diet,
 Colon microflora triggered system (CODESTM)
is considered as a preferable design of colon-specific drug
delivery systems, since the immediate increase of the
bacterial population and corresponding enzymes activities in
the colon represent a non-continuous event independent of
GI transit time.
Some synthetic polymers containing an aromatic azo group,
which are degraded by the azoreducatase in the large
bowel , can be used as coating materials for drug to form
polymeric prodrug with azo linkage between the polymer
and drug .
However, they have demonstrated some toxicity in contrast
to polysaccharides which are non toxic.
The colon contains over 400 distinct species of bacteria. The
primary sources of carbon and energy for these bacteria is the
fermentation of polysaccharides present in dietary residues.
Thus colon-specific drug delivery system is designed
depending on the bacterial degradation of polysaccharides.
Colon microflora triggered system (CODESTM)
The system consists of a traditional tablet core containing
lactulose , which is over coated with and acid soluble material,
and then subsequently overcoated with an enteric material,
Eudragit L
Schematics of conceptual design of CODESTM
During the passage of CODESTM through the GIT:
CODESTM
remain intact in the stomach due to the enteric
coat.
In small intestine, where the pH is above 6, the enteric coat
will dissolve and acid soluble polymer coating becomes only
slightly permeable and swellable.
Upon
entry into the colon, the polysaccharide (HPMC)
around the core tablet will dissolve and drug diffuse through
the coating. Where The bacteria will enzymatically degrade
the lactulos into organic acid.
 This
lowers the pH surrounding the system sufficiently to
affect the dissolution of the acid-soluble coating and
subsequent drug release.
brain TARGETING SYSTEMS
Targeting the brain via nasal administration shown a direct
route of transport from the olfactory region to the central
nervous system (CNS) without prior absorption to the
circulating blood.
Advantages :
That the olfactory receptor cells are in contact with the
nasal cavity and the CNS thus provides a target route of
drug entry to the brain
Therapeutically rapid specific targeting of drugs to the
brain would be beneficial for the treatment of Parkinson’s
disease, Alzheimer’s disease or pain.
tumor TARGETING SYSTEMS
One of the major difficulties in cancer therapy is to
achieve good specificity of antineoplastic agents for their
intended site of action in the body.
As a result of their toxicity towards healthy tissues, many
anticancer drugs are often administered at doses that are
subtherapeutic.
Thus, tumor targeting systems are used to altering the
pharmacokinetic and bio-distribution profiles of these
drugs.
This can be achieved by:
1) Encapsulating antineoplastic drugs in nanoparticles
as liposomes and polymeric micelles.
These nanoparticles systems enhance drug accumulation at
the tumor site and reduce distribution to healthy tissues. In
this method drug carriers achieve this selectivity by the
enhanced permeation and retention (EPR) depending on
difference in capillary structure between healthy and
cancerous tissues.
Neoplastic tissues generally have porous vasculature
and poor lymphatic drainage allowing for enhanced
permeation of nanoparticles across the endothelium
and greater retention within the tumor
2) Use of Tumor Selective Bioadhesive Peptides
as Drug Carriers
By the use of isopeptide-AcAASIK(L)VAVSADR-NH2 coated
drug to which the attachment of blood cells is weaker than
to peptide-AcAASIKVAVSADR-NH2
The isopeptide linkage in AcAASIK(L)VAVSADR-NH2 is
enzymatically cleaved by proteases in tumors to give the
bioadhesive
peptide
AcAASIKVAVSADR-NH2
thus
bioadhesion becomes active only at the tumor site.
Thus isopeptide AcAASIK(L)VAVSADR-NH2, can act as
prodrug
form
for
the
bioadhesive
peptide
AcAASIKVAVSADR-NH2 that act as anticancer drug carrier
for tumor targeting.