Targeted drug delivery systems

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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


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


• 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


PhysicalChemicalbiological

Types of drug targeting


Soluble synthetic polymersMicrospheresNanoparticlesLiposomesPolymeric micelles

Physical methods


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


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


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


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


Polymeric micelles


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


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


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


Multi-lamellar vesicles(MLV)Uni-lamellar vesicles Small unilamellar vesicles SUV Large unilamellar vesicles(LUV)

classification


Passive loading techniques Active loading technique. Passive loading techniques Mechanical dispersion method.Solvent dispersion method. Detergent removal method

Preparation of liposomes


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


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


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


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


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


Detergent removal method


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


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


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


Treatment of cancerIntracellular parasitic diseasesMetal toxicityDiabetesCosmetics and dermatologyRadiopharmaceutical carriers

Applications


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


Spray dryingSolvent evaporationEmulsion techniquesPolymerisation techniquesSolvent extraction

Methods of preparation


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.


Solvent evaporation


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


Solvent extraction


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


Normal polymerisationInterfacial polymerisation

Polymerisation techniques


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


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


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


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


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


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


Thanks to all

Targeted drug delivery systems

Science

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