DRUG%20DELIVERY%20AND%20TARGETING

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DRUG DELIVERY AND TARGETING
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Drug Delivery and Targeting Systems

• It is dosage form or device that serve as drug
  carrier to deliver the drug into targeted site
  upon application using suitable rout of
  administration.
• Drug delivery and targeting systems are referred
  to as
• "controlled release
  "monolithic"
• "sustained release" "smart
• "zero-order
  "stealth
• "membrane-controlled "reservoir"

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Terminology of Drug Delivery and Targeting Systems

• Prolonged/sustained release
• The delivery system prolongs therapeutic levels
  of the drug in blood or tissue for an extended
  period of time.
• Zero-order release
• The drug release does not vary with time thus
  the delivery system maintains a (relatively)
  constant effective drug level in the body for
  prolonged periods.

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• Variable release
• The delivery system provides drug input at a
  variable rate, to match, for example, endogenous
  circadian rhythms, or to mimic natural
  biorhythms.
• Bio-responsive release
• The system modulates drug release in response to
  a biological stimulus (e.g. blood glucose levels
  triggering the release of insulin from a drug
  delivery device).
• Modulated/self-regulated release
• The system delivers the necessary amount of drug
  under the control of the patient.

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• Rate-controlled release
• The system delivers the drug at some
  predetermined rate, either systemically or
  locally, for a specific period of time.
• Targeted-drug delivery
• The delivery system achieves site-specific drug
  delivery independent on site and rout of
  administration
• Temporal-drug delivery
• The control of delivery to produce an effect in
  a desired time-related manner.

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• Spatial-drug delivery
• The delivery of a drug to a specific region of
  the body (dependant on both route of
  administration and drug distribution).
• Bioavailability
• The rate and extent at which a drug is taken up
  into the body.

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Advantages of controlled-release system

• Improve patient compliance.
• Use of less total drug.
• Fewer local or systemic side effects.
• Minimal drug accumulation with long-term dosage.
• Fewer problems with potentiation or loss of drug
  activity with long-term use.

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1. Improved treatment efficiency.
2. More rapid control of the patient's condition.
3. Less fluctuation in drug-blood level.
4. Improved bioavailability for some drugs.
5. Improved ability to provide special effects
   (e.g., morning relief of arthritis by bedtime
   dosing).
6. Reduced cost.

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RATE-CONTROLLED RELEASE IN DRUG DELIVERY AND
TARGETING

• There are a number of mechanisms by which drug
  release rate is controlled
• Diffusion-controlled release mechanisms
• Dissolution-controlled release mechanisms
• Osmosis-controlled release mechanisms
• Mechanical-controlled release mechanisms
• Bio-responsive controlled release mechanisms

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DRUG TARGETING SYSTEMS

• Advantages of Drug targeting delivery
• improve Drug safety, minimized toxic
  side-effects caused by drug action at non-target
  sites .
• improve Drug efficacy, as the drug is
  concentrated at the site of action rather than
  being dispersed throughout the body.
• improve Patient compliance, as increased safety
  and efficacy make therapy more acceptable .

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STRATIGES TO ACHIVE DRUG TARGETING SYSTEMS

• local administration of drug with conventional
  dosage forms.
• Targeting the skin by apply the drug as
  ointment, lotion, or cream.
• Direct injection of an anti-inflammatory agent
  into a joint.
• oral delivery, targeting the drug to the small
  intestine, colon, or gut lymphatics. By using
  enteric coatings, prodrugs , osmotic pumps,
  colloidal carriers and hydrogels .

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• By parenteral administration.
• are most advanced , delivering drug to specific
• targets sites , protect drugs from degradation
• premature elimination.
• include the use of carriers as
• Soluble carriers as monoclonal antibodies,
  dextrans , soluble synthetic polymers.
• Particulate carriers, such as liposomes, micro-
  and nano- particles, microspheres.
• Target-specific recognition moieties, such as
  monoclonal antibodies, carbohydrates lectins .

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Pharmaceutical carriers
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DOSAGE FORMS FOR ADVANCED DRUG DELIVERY AND
TARGETING

• Are available, in a wide range of sizes, from the
  molecular level to large devices.

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Molecular

• Drugs attached to water-soluble carriers, such as
  monoclonal antibodies, carbohydrates, lectins and
  immuno-toxins.
• Such systems achieve site-specific drug delivery
  following parenteral administration.
• Release of the attached drug molecules at the
  target site achieved by enzymatic or hydrolytic
  cleavage.
• Larger complexes include drug conjugates with
  soluble natural or synthetic polymers.

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Nano- and Micro-particles

• Nanoparticles are solid colloidal particles,
  generally less than 200 nm.
• Such systems include us of drug carrier polymer
  poly (alkyl- cyanoacrylate)
• Nanoparticles used for parenteral drug targeting
  delivery.

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• Liposomes , vesicular structures based on one or
  more lipid bilayer(s) encapsulating an aqueous
  core represent highly versatile carriers.

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• Microparticles are colloidal particles in the, in
  the size range 0.2-100 µm.
• Include use of Synthetic polymers, such as poly
  (lactide-co-glycolide) as drug carrier.
• Include use of Natural polymers, such as albumin,
  gelatin , starch, used as micro-particulate drug
  carriers.

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Macrodevices

• are widely used in many applications, including
• Parenteral drug delivery mechanical pumps,
  implantable devices.
• Oral drug delivery solid dosage forms such as
  tablets and capsules which incorporate controlled
  release/ targeting technologies.
• Buccal drug delivery buccal adhesive patches and
  films.

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• Transdermal drug delivery transdermal patches,
  iontophoretic devices.
• Nasal drug delivery nasal sprays and drops.
• Pulmonary drug delivery metered-dose inhalers,
  dry-powder inhalers, nebulizers.
• Vaginal drug delivery vaginal rings, creams,
  sponges.
• Ophthalmic drug delivery ophthalmic drops and
  sprays.

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Properties of an "ideal" Drug Delivery dosage
form

• Good Patient acceptability and compliance
• Parenteral delivery This is painful for the
  patient, and requiring the intervention of
  medical professionals.
• The oral route, involves swallowing a tablet,
  liquid or capsule, thus a much more convenient
  and attractive route for drug delivery.

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• Transdermal patches are also well accepted by
  patients and convenient.
• Nebulizers, pessaries and suppositories, have
  more limited patient compliance.

• 2) Reproducibility
• The dosage form should allow accurate and
  reproducible drug delivery, particularly for
  drugs with a narrow therapeutic index.

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• 3) Ease of termination
• The dosage form should be easily removed either
  at the end of an application period, or in the
  case of toxicity.
• Transdermal adhesive patches and buccal tablet
  are easily removed
• Non-biodegradable polymeric implants and osmotic
  pumps must be surgically take back at the end of
  treatment.

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• 4)Biocompatibility and absence of adverse effects
  
• The drug delivery system should be non-toxic and
  non-immunogenic .
• Dosage forms containing penetration enhancers has
  a harmful effects on epithelial tissue as well
  as the increased epithelial permeability may
  allow the entrance of potentially toxic agents.

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• 5) Large effective area of contact
• For drugs absorbed via passive mechanisms,
  increasing the area of contact of the drug with
  the absorbing surface will increase the amount
  absorbed.
• The dosage form can influence the size of the
  area over which the drug is absorped . For
  example, increasing the size of a transdermal
  patch increases transdermal bioavailability.

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• 6) Prolonged contact time
• Ideally, the dosage form should facilitate a
  prolonged contact time between the drug and the
  absorbing surface, thereby facilitating
  absorption.
• Drug delivery to epithelial sites is often
  limited by a variety of physiological clearance
  mechanisms at the site of administration as
  mucociliary clearance and intestinal motility.
• Bioadhesive materials (sometimes also termed
  mucocadhesive) adhere to biological substrates
  such as mucus or tissue and increase the
  effective contact time.

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Properties of an "ideal" route of administration

• maximize the amount of drug entering the systemic
  circulation from the site of administration, the
  delivery site should possess certain properties

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1) Large surface area

• A large surface area are facilitates absorption.
• Due to the presence of the villi and the
  microvilli, the available surface area of the
  small intestine of the gastrointestinal tract is
  very large, which is important for oral drug
  delivery.
• The surface area of the lungs is broad making
  this region a promising alternative route to the
  parenteral and oral routes for systemic drug
  delivery.

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2) Low metabolic activity

• Degradative enzymes may deactivate the drug,
  prior to absorption.
• Poor drug bioavailability may thus be expected
  from an absorption site in which enzyme activity
  is high, such as the gastrointestinal tract.
  Furthermore, drugs which are orally absorbed must
  first pass through the intestinal wall and the
  liver, prior to reaching the systemic
  circulation. These" first-pass" effects can
  result in a significant loss of drug activity.

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• Drug delivery via other routes (nasal, buccal
  etc.) avoid intestinal first-pass effects, as
  metabolic activity at these sites is often lower
  than in the gastrointestinal tract, these routes
  are highly attractive alternatives for the
  systemic delivery of enzymatically labile drugs.

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3) Contact time

• The length of time the drug is in contact with
  the absorbing tissue will influence the amount of
  drug which crosses the mucosa.
• Materials administered to different sites of the
  body are removed from the site of administration
  by a variety of natural clearance mechanisms.

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• For example, intestinal motility moves material
  in the stomach or small intestine towards the
  large intestine.
• In the buccal cavity, the administered dosage
  form is washed daily with 0.5-2 liters of saliva.
  
• In the nasal cavity and the upper and central
  lungs, an efficient selfcleansing mechanism
  referred to as the "mucociliary escalator" is in
  place to remove any foreign material.
• In the eye, materials are diluted by tears and
  removed via the lachrymal drainage system.

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4) Blood supply

• Adequate blood flow from the absorption site is
  required to carry the drug to the site of action
  post-absorption.

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5) Accessibility

• Certain absorption sites, for example the
  alveolar region of the lungs, are not readily
  accessible and thus may require quite complex
  delivery devices to ensure the drug reaches the
  absorption site.
• Delivery efficiency to such sites may also
  therefore be low.
• In contrast, other sites, such as the skin,
  are highly accessible.

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6) Lack of variability

• Lack of variability is essential to ensure
  reproducible drug delivery.
• This is important principle for the delivery of
  highly potent drugs with a narrow therapeutic
  window.
• Due to such factors as extremes of pH, enzyme
  activity, intestinal motility, presence of food/
  fluid etc., the gastrointestinal tract can be a
  highly variable absorption site.

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• Diseases such as the common cold and hay fever
  are alter the physiological conditions of the
  nose, contributing to the variability of this
  site.
• The presence of disease can also compromise the
  reproducibility of drug delivery in the lungs.
• Cyclic changes in the female menstrual cycle mean
  that large fluctuations in vaginal
  bioavailability.

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7) Permeability

• A more permeable epithelium obviously facilitates
  greater absorption.
• Some epithelia are relatively more permeable than
  others.
• For example, the skin is an extremely impermeable
  barrier, whereas the permeability of the lung
  membranes towards many compounds is much higher
  than the skin and is also higher than that of the
  small intestine and other mucosal routes.
• The vaginal epithelium is relatively permeable,
  particularly at certain stages of the menstrual
  cycle.

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STRATEGIES TO INCREASE DRUG ABSORPTION

• a) Manipulation of the Drug
• The physicochemical properties of a drug which
  influence drug absorption include
• lipid solubility and partition coefficient.
• pKa.
• molecular weight and volume.
• aqueous solubility.
• chemical stability.

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• These properties can be manipulated to achieve
  more favorable absorption characteristics for a
  drug
• For example, various lipidization strategies can
  be employed to increase the lipophilicity of the
  drug and thereby increase its membrane-penetrating
  ability and absorption via transcellular passive
  diffusion.
• The hydrogen-bonding tendency of a drug molecule
  can be minimized by substitution, esterification
  or alkylation of existing groups on the
  molecules, which will decrease the drug's aqueous
  solubility and favoring partitioning of the drug
  into lipidic membranes.

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• Drug solubility may be enhanced by the use of
  amorphous or anhydrous forms, or the use of the
  corresponding salt form of a lipophilic drug.
• Low molecular weight analogues of an active
  moiety can be developed, to facilitate
  trans-membrane transport. By prepare derivatives
  which are substrates of natural transport
  carriers like peptides.

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• b) Manipulation of the formulation
• Various formulation additives may be included in
  the dosage form in order to maximize drug
  absorption.
• 1. Penetration enhancers
• Penetration enhancers are substances that
  facilitate absorption of solutes across
  biological membranes.

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• 2. Mucoadhesives
• Mucoadhesives, which are generally hydrophilic
  polymers, may be included in a dosage form to
  increase drug bioavailability.
• These agents are believed to act by
• Increasing the contact time of the drug at the
  absorbing surface.
• Increasing the local drug concentration at the
  site of adhesion/absorption.
• Protecting the drug from dilution and possible
  degradation.

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• 3. Enzyme inhibitors
• Enzyme inhibitors in a formulation may help to
  overcome the enzymatic activity of the epithelial
  barrier.
• The use of protease inhibitors facilitates the
  absorption of therapeutic peptides and proteins.