DRUG%20TARGETING

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DRUG TARGETING
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DRUG TARGETING
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.
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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.
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Drug Targeting

• Advantages of drug targeting
• Drug administration protocols may be simplified
• 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
  non-target compartments.

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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
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Strategy for Site-Specific drug Delivery
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• 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 .

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• 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.

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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.

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• 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.

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Advantages

• Overcome biological pharmaceutical barriers
  which separate the site of administration from
  the site of action of drug.
• Enhance efficacy of drug. eg, the administration
  of the methoxy methyl ester of 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.

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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 enzymes to generate
4-hydroxycyclophosphamide which is then
specifically converted to the alkylating
cytotoxic phosphoramide mustard in the hepatic
target cells.
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• can used for site-specific delivery to
  tumor cells.
• As the blood supply to large solid tumors is
  disorganized, the internal regions are often
  non-vasculated 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 is
  selectively cytotoxic to cultured hypoxic cells.

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SITE-SPECIFIC REDOX-BASED DRUG DELIVERY SYSTEMS
Use of lipophilic prodrugs overcome the
impenetrability of some barriers as 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.
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• 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.

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• Dihydropyridine-pyridinium salt redox system for
  site-specific 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 release of the
  biologically active phenylethylamine .

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SITE-SPECIFIC ANTIBODY-DIRECTED 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.

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Following clearance of any unbound antibody
conjugate enzyme from the systemic circulation, a
prodrug which is specifically activated by the
enzyme conjugate, is administered. 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.
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DRUG TARGETING USING DRUG DESIGN POLYMERIC
SYSTEMS
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Gastrointestinal tract TARGETING SYSTEMS
TARGETING SYSTEMS stomach
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.
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• 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, floating drug delivery systems
  (FDDS), sedimentation, expansion, modified shape
  systems, simultaneous administration of
  pharmacological agents that delay gastric
  emptying.

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• 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.

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• 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.

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• 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.

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• 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 lt1 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.

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• 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.

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• Absorption Enhancement
• Drugs that have poor bioavailability because of
  site-specific absorption from the upper part of
  the gastrointestinal tract are potential
  candidates to 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)

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• 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.

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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.

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• 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)

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Design Floating Dosage Forms

• multiple-Unit Floating Dosage Forms
• This systems are classified depending on
  formulation
• Effervescent
• Non-effervescent systems.

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• 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.

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Sublayers membrane
polyvinyl acetate purified shellac
sodium bicarbonate tartaric acid
methylcellulose chitosan

1. Multiple-unit oral floating drug delivery system.
   
2. Working principle of effervescent floating drug
   delivery system.

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• 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.

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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
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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).
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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.
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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 lt 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.
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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.
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TARGETING SYSTEMS intestinal

• 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

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TARGETING SYSTEMS Colon

• 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 Crohns 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.

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• 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.

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• 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,

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• 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 in diet,
  environmental conditions, and state of disease.

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• 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.

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• 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.

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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
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Schematics of conceptual design of CODESTM
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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.

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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.

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• 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 Parkinsons disease, Alzheimers
  disease or pain.

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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.
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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.
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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
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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.