Microspheres (Drug Delivery System)


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20 June 2011 1 MICROSPHERES AISSMS college of Pharmacy, Pune Presented by Ms. Neeta T. Jare, M. Pharm. II Sem (Pharmaceutics) Under the guidance of Dr. M. R. Bhalekar


Contents 1. Definition 2. Advantages 3. Preparation methods 4. Loading of drug 5. Drug release kinetics 6. Materials/ polymers used 7. Evaluation 8. Applications 20 June 2011 2


20 June 2011 3 Definition Microspheres are characteristically free flowing powders consisting of proteins or synthetic polymers which are biodegradable in nature and ideally having a particle size less than 200 μm. Microspheres are used as carriers for delivering a therapeutic substance to the target site in a sustained / controlled release fashion .

What Are Microcapsules & Microspheres:

What Are Microcapsules & Microspheres A Microcapsule has a drug located centrally within the particle, where it is encapsulated within a polymeric membrane A Microsphere has its drug dispersed throughout the particle i.e. the internal structure is a matrix of drug and polymer 20 June 2011 4

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20 June 2011 5 A diagram representing a microsphere

Advantages :

20 June 2011 6 Advantages 1. Reliable means to deliver the drug to the target site with specificity and to maintain the desired concentration at the site of interest without unwanted effects. 2. Microspheres have the potential for the controlled release of drug. 3. Microspheres can achieve not only prolonged release, but also targeting of drugs to the tumor.

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20 June 2011 7 4. Studies on the macrophage uptake of microspheres have demonstrated their potential in targeting drugs to pathogens residing intracellularly. 5. Toxic drugs, which can cause side effects when administered in large quantities, or insoluble drugs, which may require large doses to promote absorption, can be administered with a lower frequency and smaller quantity. 6.Sensitive drugs like peptides & proteins are protected against chemical and enzymatic degradation when entrapped in microspheres.

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7. The use of microspheres for drug delivery is not limited to any specific illness, rather it can be widely applied to many situations where continuous and controlled drug administration is essential. 8. It provides protection to photosensitive drugs, also to the volatile substances. 20 June 2011 8


Limitations 1. Significant initial burst and unpredictable release in certain cases. 2. The phagocytosis of carriers, rapid clearance are common disadvantages of particulate system. 20 June 2011 9

Preparation methods:

20 June 2011 10 Preparation methods Preparation of microspheres should satisfy certain criteria: 1. The ability to incorporate reasonably high concentrations of the drug. 2. Stability of the preparation after synthesis with a clinically acceptable shelf life. 3. Controlled particle size and dispersibility in aqueous vehicles for injection. 4. Release of active agent with a good control over a wide time scale. 5. Biocompatibility with a controllable biodegradability 6. Susceptibility to chemical modification.

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20 June 2011 11 Methods mainly includes: 1. Single emulsion technique 2. Double emulsion technique 3. Polymerization techniques 4. Phase séparation coacervation technique 5. Spray drying and spray congealing 6. Solvent extraction 7. Ionic gelation

1. Single emulsion technique:

1. Single emulsion technique 20 June 2011 12 Aqueous solution of polymer Dispersion in organic phase like oil cross linking by heat cross linking by chemical cross linkers Microsphere Stirring, sonication Centrifugation, washing, separation

2. Double emulsion technique:

2. Double emulsion technique 20 June 2011 13 Aq. solution of polymer containing drug Dispersion in oil/ organic phase a Microspheres in solution Addition to aq. Solution of PVA Addition to large aq. Phase Microspheres homogenization 1 st emulsion Multiple emulsion hardening Separation, washing, drying

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It is best suited to water soluble drugs, peptides, proteins and the vaccines. This method can be used with both the natural as well as synthetic polymers. 20 June 2011 14

3. Polymerization techniques:

3. Polymerization techniques I. Normal polymerization II. Interfacial polymerization. Normal polymerization : It is carried out using different techniques as bulk, suspension, emulsion polymerization processes. 20 June 2011 15

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Bulk polymerisation Suspension polymerization Monomer + Bioactive material+ Initiator Polymerization Polymer block Microspheres Monomer + Bioactive material+ Initiator Dispersed in water containing stabilizer Droplets are formed Microspheres (>100mm) Mould /Mechanical fragmentation Vigorous agitation Polymerization Microspheres in suspension 20 June 2011 16

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20 June 2011 17 Monomer+ drug a Aq. solution of Initiator + Surfactant + Stabilizer Micellar solutions of polymer in aq. medium Microspheres formation microspheres polymerization Dispersion with vigorous stirring Separation, Washing, Drying Emulsion polymerization

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Interfacial polymerization : 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. 20 June 2011 18

4. Phase separation coacervation technique:

4. Phase separation coacervation technique 20 June 2011 19 Aq./organic solution of polymer Drug dispersed or dissolved in polymer solution Polymer rich globules Microspheres in aq./organic phase Microspheres Drug addition Phase separation Separation, Drying

5. Spray drying & Spray congealing :

5. Spray drying & Spray congealing These methods are based on the drying of the mist of the polymer and drug in the air. Depending upon the removal of the solvent by drying or cooling of the solution, the two processes are named spray drying and spray congealing respectively. 20 June 2011 20

6. Solvent evaporation & Solvent extraction:

6. Solvent evaporation & Solvent extraction Solvent evaporation method is used for the preparation of microparticles, involves removal of the organic phase by evaporation/extraction of the organic solvent. The solvent evaporation is carried out by stirring or by using reduced pressure, so that organic phase evaporates out. In case of solvent extraction, organic phase is removed by extraction with large quantity of water. 20 June 2011 21

7. Ionic-gelation technique:

7. Ionic-gelation technique 20 June 2011 22 Polymer+ drug in aq. solution Dispersion in continuous phase Formation of droplets Addition to ionic solution Continuous stirring Emulsion formation Microspheres Ionic gelation

Loading of drug:

Loading of drug The active components are loaded over the microspheres principally using two methods, During the preparation of the microspheres After the formation of the microspheres by incubating them with the drug/protein. The active component can be loaded by means of the physical entrapment, chemical linkage or surface adsorption . 20 June 2011 23

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Maximum loading can be achieved by incorporating the drug during the time of preparation but it may get affected by many other process variables such as Presence of additives (e.g. cross linking agent, surfactant or stabilizers) Heat of polymerization(maximum loading is achieved at lower and higher temperature) Agitation intensity (high speed of agitation is required for high loading) 20 June 2011 24

Drug release kinetics:

Drug release kinetics Release of the active constituent is an important consideration in case of microspheres The release profile from the microspheres depends on the nature of the polymer used in the preparation as well as on the nature of the active drug . 20 June 2011 25

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The drugs could be released through the microspheres by any of the three methods, By the osmotically driven burst mechanism, By pore diffusion mechanism, By erosion or the degradation of the polymer. 20 June 2011 26

Materials/ polymers used :

20 June 2011 27 Materials/ polymers used Materials used usually are polymers. They are classified into two types: 1. Synthetic Polymers 2. Natural polymers 1. Synthetic polymers are divided into two types. a. Non-biodegradable polymers e.g. Poly methyl methacrylate (PMMA) Acrolein Glycidyl methacrylate Epoxy polymers

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b. Biodegradable polymers e.g. Lactides, Glycolides & their co polymers Poly alkyl cyano acrylates Poly anhydrides 2. Natural polymers obtained from different sources like Proteins: Albumin, Gelatin, and Collagen Carbohydrates: Agarose, Carrageenan, Chitosan,Starch Chemically modified carbohydrates: Poly dextran, Poly starch. 20 June 2011 28

Evaluation parameters:

Evaluation parameters 1. Particle size and shape The most widely used procedures to visualize microparticles are conventional light microscopy (LM) and scanning electron microscopy (SEM). Both can be used to determine the shape and outer structure of microparticles. 20 June 2011 29

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20 June 2011 30 SEM image of microspheres

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2. Electron spectroscopy for chemical analysis The surface chemistry of the microspheres can be determined using the electron spectroscopy for chemical analysis. It provides means for determination of the atomic composition of the surface. It is used to determine the surface degradation of the microspheres. . 20 June 2011 31

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3. Attenuated total reflectance Fourier Transform-Infrared Spectroscopy: FT-IR is used to determine the degradation of the polymeric matrix of the carrier system. The surface of the microspheres is investigated measuring attenuated total reflectance (ATR). The ATR-FTIR provides information about the surface composition of the microspheres. 20 June 2011 32

Slide 33:

4. Density determination: The density of the microspheres can be measured by using a multi volume pycnometer. The porosity of microspheres is further obtained by using density. It is further utilized mainly in preparation of tablets. 5. Entrapment efficiency: The entrapment efficiency of the microspheres or the percent entrapment can be determined by allowing washed microspheres to lyse. 20 June 2011 33

Slide 34:

The lysate is then subjected to the determination of active constituents. The percent entrapment efficiency is calculated by equation: % Entrapment = Actual content/Theoretical content x100 6. Release studies : Release studies for microspheres are carried out using rotating paddle apparatus or by using dialysis method. Samples are withdrawn at time intervals and analyzed by UV-spectrometer 20 June 2011 34


Applications 1. Microspheres in vaccine delivery Biodegradable delivery systems for vaccines that are given by parenteral route may overcome the shortcoming of the conventional vaccines. The use of parenteral carrier offer specific advantages including: 1. Improved antigenicity 2. Modulation of antigen release 3. Stabilization of antigen. 20 June 2011 35

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2. Targeting using microparticulate carriers Drug targeting is done to sites like ocular, intranasal, oral. As the therapeutic efficacy of the drug relies on its access and specific interaction with its candidate receptors, the targeting is done by use of carriers. Such targeted delivery of an entrapped drug reduces side-effects. 20 June 2011 36

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3. Monoclonal antibodies mediated microspheres targeting Monoclonal antibodies targeting microspheres are immunomicrospheres. This targeting is a method used to achieve selective targeting to the specific sites. As Monoclonal antibodies are extremely specific molecules, this extreme specificity of monoclonal antibodies can be utilized to target these microspheres to selected sites. Mabs can be directly attached to the microspheres by means of covalent coupling, physical adsorption. 20 June 2011 37

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4. Imaging The microspheres are used for the targeting purposes. Various cells, cell lines, tissues and organs can be imaged using radio labeled microspheres. The particle size range of microspheres is an important factor in determining the imaging of particular sites. Eg. the particles injected intravenously will become entrapped in the capillary bed of the lungs. This is used in imaging of the tumor masses in lungs using labeled human serum albumin microspheres. 20 June 2011 38

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5. Topical porous microspheres Microsponges are porous microspheres having interconnected voids of particle size range 5-300 μm. Microsponges consist of non collapsible structures with porous surface through which active ingredients are released in a controlled manner. These porous microspheres with active ingredients can be incorporated into formulations such as creams, lotions and powders. 20 June 2011 39

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6. Surface modified microspheres Different approaches have been utilized to change the surface properties of carriers to protect them against phagocytic clearance and to alter their body distribution patterns. Such modifications are provided on surface of microspheres in order to achieve the targeting to the discrete organs and to avoid rapid clearance from the body. eg. Mucoadhesive microsphere Application of mucoadhesive microspheres to mucosal tissues causes localized effect, prolong release of drug. 20 June 2011 40


References: 1. Vyas & Khar, Targeted and Controlled drug delivery, Novel carrier systems, CBS publishers 1 st ed., pp.417-454 2. S. Freiberg, Polymer microspheres for controlled drug release, Int. J. of Pharm. 282,(2004),1–18 3. N.K.Jain, Biodegradable polymeric microspheres as drug carriers, pp.236-250. 4. M. Alagusundaram, M. Chetty,Microspheres as a novel drug delivery system , Int. J. ChemTech , vol.1,pp.526-232 20 June 2011 41


References: 5. Jaspreet V., Tambwekar K., Garg V.,Bioadhesive microspheres as a controlled drug delivery system, Int. J. Pharm. 255, (2003), 13–32 6. http://biophotonics.illinois.edu/gallery/protein micros.jpg, accessed on april,2010 7. www.hindavi.com/journals/int/2009/html, accessed on april,2010 8. www.microspheres-nanospheres.com, on april,2010 20 June 2011 42