targeted drug delivery systems
TRANSCRIPT
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A presentation bySUBODH S SATHEESH
MPHARM, PHARMACEUTICS
Targeted drug delivery systems
DRUG TARGETING
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• It is a special form of drug delivery system where the pharmacologically active agent or 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.
• 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 complexing with the
carrier that recognizes the target.
Introduction
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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.
Need for targeted drug delivery
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• Biochemically inert (non-toxic) • Non-immunogenic. • Both physically and chemically stable in vivo and in vitro. • 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
Ideal characters
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PhysicalChemicalbiological
Types of drug targeting
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Soluble synthetic polymersMicrospheresNanoparticlesLiposomesPolymeric micelles
Physical methods
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substances that dissolve, disperse or swell in watermodify the physical properties of aqueous systems in the
form of gellation, thickening or emulsificationthe polymer chains contain hydrophilic groups The hydrophilic groups may be nonionic, anionic, cationic
or amphoteric
Soluble synthetic polymers
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Poly dispersity index (PDI)PEG have low PDIReactions catalyzed by anionic polymerization result in
PEGs with low PDIEnhances physical and chemical properties of drugPEG helps in reducing the aggregation of red blood cells PEG-drug conjugates have reduced protein
immunogenicity, increased residence time in the body, reduced enzymatic degradation.
Poly ethylene glycol
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Polyvinyl alcoholPolymerisation of vinyl acetate to
polyvinyl acetatePVA hydrogels have
pharmaceutical and biomedical applications
Nontoxic, noncarcinogenic, nonadhesive
PVA used for contact lenses, the lining for artificial hearts, and drug- delivery applications
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Polyvinyl pyrolidinePVP gives gives harder
granulates with good flowability, higher binding and low friability
Enhances bioavailabilitygood hydrophilization
properties, universal solubility and ability to form water soluble complexes
PVP and polyvinyl pyrrolidone-vinyl acetate (PVP-VA) copolymer improves the bioavailability of many poorly water soluble drugs
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Polyacrylic acida super adsorbent, in water
treatmentit exists as a liquid at pH 5 and
as a gel at pH 7Polyacrylic acid based
polymers are mainly used for oral and mucosal contact applications
used as thickening, suspending and emulsion stabilizing agent in low viscosity systems for topical applications
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Polymeric micelles
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A di-block structure with a hydrophilic shell and a hydrophobic core.
The hydrophobic core generally consists of a biodegradable polymer it act as a reservoir for an insoluble drug.
Non- or poorly biodegradable polymers can be used, as long as they are not toxic to cells and can be renally secreted
Nature of the cell responsible for micellar stabilisation
Polymeric micelles
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Polymeric micelles are mostly small (10–100 nm) in size and drugs can be incorporated by chemical conjugation or physical entrapment
PMs present a great potential for compounds that are hydrophobic and exhibit poor bioavailability
Block copolymers can be diblock copolymers or triblock copolymers
protection of the loaded drug from the harsh environment of the GI tract
release of the loaded drug in a controlled manner at target sites
Polymeric micelles
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unfavorable interactions of the hydrophobic segments of the lipid molecule with the solvent
Liposomes consist of an aqueous core surrounded by a lipid bilayer, much like a membrane, separating the inner aqueous core from the bulk outside
Lipos and somaLiposomes have been used to improve the therapeutic index
by modifying drug absorptionLiposomal actions depend upon size, composition, loading
efficiency and stability, as well as their biological interaction with the cell membranes.
liposomes
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Multi-lamellar vesicles(MLV)Uni-lamellar vesicles Small unilamellar vesicles SUV Large unilamellar vesicles(LUV)
classification
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Passive loading techniques Active loading technique. Passive loading techniques Mechanical dispersion method.Solvent dispersion method. Detergent removal method
Preparation of liposomes
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Sonication. French pressure cell: extrusion. Freeze-thawed liposomes. Lipid film hydration by hand shaking, non-hand. shaking
or freeze drying. Micro-emulsification. Membrane extrusiogn.
Mechanical dispersion method
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Drying down lipids from organic solvent. Dispersing the lipid in aqueous media. Purifying the resultant liposome. Analyzing the final product.
Basic steps in liposome production
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sonication
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Probe sonication The tip of a sonicator is directly
engrossed into the liposome dispersion.
The energy input into lipid dispersion is very high in this method.
the vessel must be engrossed into a water/ice bath.
Throughout the sonication up to 1 h, more than 5% of the lipids can be deesterified.
the probe sonicator, titanium will slough off and pollute the solution.
The liposome dispersion in a cylinder is placed into a bath sonicator.
Controlling the temperature of the lipid dispersion is usually easy
The material being sonicated can be protected in a sterile vessel, dissimilar the probe units, or under an inert atmosphere .
SonicationBath sonictaion
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French pressure cell involves the extrusion of MLV through a small orifice .
The proteins do not seem to be significantly pretentious during the procedure as they are in sonication .
The method involves gentle handling of unstable materials.
The resulting liposomes are rather larger than sonicated SUVs.
high temperature is difficult to attain, and the working volumes are comparatively small
French pressure cell
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Ether injection A solution of lipids dissolved in
diethyl ether or ether-methanol mixture
It is gradually injected to an aqueous solution of the material to be encapsulated.
The consequent removal of ether under vacuum leads to the creation of liposomes.
The main disadvantages are that the population is heterogeneous (70 to 200 nm) and the exposure of compounds high temperature.
A lipid solution of ethanol is rapidly injected to a huge excess of buffer.
The MLVs are formed. The disadvantages of the method
are that the population is heterogeneous
liposomes are very dilute, the removal all ethanol is difficult because it forms into azeotrope with water.
Solvent dispersion methodEthanol injection
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Detergent removal method
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dialysis The detergents at their critical
micelle concentrations (CMC) have been used to solubilize lipids.
the micelles become increasingly better-off in phospholipid and lastly combine to form LUVs.
The dialysis can be performed in dialysis bags engrossed in large detergent free buffers
detergent adsorbers eliminate detergents with a very low CMC, which are not entirely depleted.
Aqueous mixed micellar solution of detergent and phospholipids are mixed with buffer
micellar size and the polydispersity increase
system is diluted beyond the mixed micellar phase boundary
spontaneous transition from poly-dispersed micelles to vesicles occurs
Detergent removal methoddilution
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completely biodegradable and nontoxicbiologically inert and nonantigenicbiocompatible and can be bioadhsiveThey can be used for delivering hydrophilic substancesEncapsulated drug is protected from degradation
Advantages of liposomes
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Liposomes above a certain size range can block capillariesThe lipid components of liposomes may induce metabolic
changes and cause toxicitySterility should be maintained in each step of production
and ingredients used should of highest purity
Disadvantages
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Treatment of cancerIntracellular parasitic diseasesMetal toxicityDiabetesCosmetics and dermatologyRadiopharmaceutical carriers
Applications
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Microspheres are small spherical particles, with diameters in the micrometer range typically 1 μm to 1000 μm
Glass microspheres, polymer microspheres and ceramic microspheres
Polyethylene and polystyrene microspheresPolystyrene microspheres are typically used in biomedical
applicationPolyethylene microspheres are commonly used as permanent
or temporary fillerMicrospheres vary widely in quality, sphericity, uniformity of
particle and particle size distribution
microspheres
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Spray dryingSolvent evaporationEmulsion techniquesPolymerisation techniquesSolvent extraction
Methods of preparation
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Spray drying polymer is first dissolved in a suitable
solvent like dichloromethane, Acetone The drug in the solid form is then
dispersed in the polymer solution under high-speed homogenization.
This dispersion is then atomized in a stream of hot air.
The atomization leads to the formation of the small droplets
solvent evaporate instantaneously leading the formation of the microspheres in a size range 1-100μm.
Micro particles are separated from the hot air by means of the cyclone separator
trace of solvent is removed by vacuum drying.
Rapid and gives porous microparticles.
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Solvent evaporation
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microcapsule coating is dispersed in a volatile solvent which is immiscible with the liquid manufacturing vehicle phase
A core material to be microencapsulated is dissolved or dispersed in the coating polymer solution
With agitation the core material mixture is dispersed in the liquid manufacturing vehicle phase gives appropriate size microcapsule
core material is dissolved in the coating polymer solution, matrix – type microcapsules are formed
Solvent evaporation
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Solvent extraction
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It involves removal of the organic phase by extraction of the organic solvent.
The method involves water miscible organic solvents such as isopropanol.
Organic phase is removed by extraction with water. It decreases the hardening time for then microspheres. direct addition of the drug or protein to polymer organic
solution. The rate of solvent removal by extraction method depends on
the temperature of water, ratio of emulsion volume to the water and the solubility profile of the polymer.
Solvent extraction
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Normal polymerisationInterfacial polymerisation
Polymerisation techniques
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Bulk, suspension, precipitation, emulsion and micellar polymerization Processes
. In bulk, a monomer or a mixture of monomers along with the initiator or catalyst is usually heated to initiate polymerization
Suspension polymerisation is carried out by heating the monomer or mixture of monomers as droplets dispersion in a continuous aqueous phase.
Emulsion polymerization differs from suspension polymerization as due to the presence initiator in the aqueous phase, which later on diffuses to the surface of micelles
Normal Polymerisation
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It involves the reaction of various monomers at the interface between the two immiscible liquid phases to form a film of polymer that essentially envelops the dispersed phase
This process is based on the principle of decreasing the solubility of the polymer in organic phase to affect the formation of polymer rich phase called the coacervates.
The drug particles are dispersed in a solution of the polymer and an incompatible polymer is added to the system which makes first polymer to phase separate and engulf the drug particles
Poly lactic acid (PLA) microspheres have been prepared by this method by using butadiene as incompatible polymer.
Interfacial polymerisation
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The micro particulate carriers of natural polymers of proteins and carbohydrates are prepared by single emulsion technique.
The natural polymers are dissolved or dispersed in aqueous medium followed by dispersion in non-aqueous medium like oil.
cross linking of the dispersed globule is carried out. The cross linking can be achieved either by means of heat or by using the chemical
cross linkers. The chemical cross linking agents used are glutaraldehyde, formaldehyde, acid
chloride etc. Chemical cross linking has disadvantage of excessive exposure of active ingredient
to chemicals. The nature of the surfactants used to stabilize the emulsion phases can greatly
influence the size, size distribution, surface morphology, loading, drug release, and bio performance of the final multiparticulate product.
Single emulsion technique
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It involves the formation of the multiple emulsions or the double emulsion of type w/o/w and is best suited to water soluble drugs, peptides, proteins and the vaccines.
The aqueous protein solution is dispersed in a lipophilic organic continuous phase.
The continuous phase is generally consisted of the polymer solution that eventually encapsulates of the protein contained in dispersed aqueous phase.
The primary emulsion is subjected then to the homogenization or the sonication
The emulsion is then subjected to solvent removal either by solvent evaporation or by solvent extraction
Double emulsion technique
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They are used in vaccine deliveryMagnetic microspheres help in delivery of high
concentrations of therapeutic agentsThey are also used in imaging.Used as topical carriers of substances like antipyretic,
anti-inflammatory, antifungal etc
Applications
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Ijpr carriers in drug targeting page 1-51Intechophenonline.com targeted drug delivery system1-34Hindawi.com polymeric micelles a promising drug
delivery system 1-16Researchgate.com targeted drug delivery systems page 27-
43Pubs.rsc.org drug targeting page 1-28S Bharath Pharmaceutical technology concepts and
applications 2013edition page 189-226.
References
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Thanks to all