MICROSPHERES

Click to edit Master subtitle style

Submitted to: Mr. Santosh Kumar Singh Sugunan

Submitted by: P. Swetha. M.Pharm, Pharmceutics, 2nd sem.

3/19/12

CONTENT

Introduction used for preparation method of preparation

Advantages Polymer General Release

of drug from microspheres of microspheres

Characterization Applications
3/19/12

INTRODUCTION

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 m. Types of Microspheres

Microcapsule

Micromatrix

Spherical particle with size varying from 50 nm to 2 mm.

3/19/12

ADVANTAGES
Potential use of microspheres in the pharmaceutical industry

Taste and odor masking Conversion of oils and other liquids to solids for ease of handling

Protection of drugs against the environment (moisture, light etc.)

Separation of incompatible materials (other drugs or excipients)

Improvement of flow of powders Aid in dispersion of water-insoluble substances in

3/19/12

PHARMACEUTICAL APPLICATIONS
Microencapsulated

products currently on the market, such as aspirin, theophylline & its derivatives, vitamins, pancrelipase, antihypertensive, potassium chloride, progesterone, and contraceptive hormone 3/19/12 combinations.

OTHER APPLICATIONS

Microcapsule

s are also extensively

3/19/12

POLYMERS USED IN THE MICROSPHERE PREPARATION

Synthetic Polymers Non-biodegradable PMMA Acrolein Epoxy polymers Biodegradable Lactides and Glycolides copolymers Polyalkyl cyanoacrylates Polyanhydrides Natural Materials Proteins Albumins Gelatin Collagen Carbohydrates Starch agarose Carrageenan Chitosan Chemically modified carbohydrates Poly (acryl) dextran Poly(acryl)starch DEAE cellulose

3/19/12

Prerequisites for Ideal Microparticulate Carriers action Longer duration of

Control of content release Increase of therapeutic efficacy Protection of drug Reduction of toxicity Biocompatibility Sterilizability Relative stability Water solubility or dispersibility Bioresorbability3/19/12

MICROSPHERE MANUFACTURE
Most

important physicochemical characteristics

that may be controlled in microsphere manufacture are:

Particle size and distribution Polymer molecular weight Ratio of drug to polymer Total mass of drug and polymer
3/19/12

GENERAL METHODS OF PREPARATION

Single Emulsion techniques Double emulsion techniques Polymerization techniques - Normal polymerization - Interfacial polymerization

Coacervation phase separation techniques Spray drying and spray congealing Solvent extraction
3/19/12

SIMPLE EMULSION BASED METHOD

Aq.Solution/suspension of polymer

Dispersion in organic phase (Oil/Chloroform)

Stirring, Sonication
Chemical cross linking (Glutaraldehyde/For maldehyde/ Butanol)

Heat denaturati Microspheres in on

organic phase

CROSS LINKING

Microspheres in organic phase

MICROSPHE 3/19/12 RES

Centrifugation, Washing, Separation

DOUBLE EMULSION BASED METHOD Aq.Solution of

protein/polymer First emulsion (W/O) Multiple emulsion
Dispersion in oil/organic phase Homogenization

Addition of aq. Solution of PVA

Addition to large aq. Phase Denaturation/harden ing Microspheres in

solution

Separation, Washing, Drying

MICROSPHERE S
3/19/12

INTERFACIAL DEPOSITION TECHNIQUE First, the polymer is dissolved in

acetone, then a phospholipid mixture (e.g., Epikuron'") and benzyl benzoate are added to this solution. The resulting organic solution is poured into an aqueous phase containing a surfactant (e.g., poloxamer 188) under moderate stirring. Acetone diffuses immediately into the aqueous phase, inducing the deposition and the precipitation of the Once the microcapsules are formed, acetone is eliminated polymer around the oily droplets. under reduced pressure. Drugs intended to be encapsulated by this method must have a high solubility in the organic-oily phase, otherwise they diffuse from the oily solution and precipitate in the aqueous 3/19/12 medium during particle formation.

A)NORMAL POLYMERIZATION
Normal Polymerization is done by bulk, suspension, pption,emulsion and polymerization process.
1.

Bulk polymerization: Bioactive material

Monomer Initiator

Heated to initiate polymerization Initiator accelerate rate of reaction

3/19/12

B)SUSPENSION POLYMERIZATION
Monomer Bioactive material Initiator

Dispersion in water & stabilizer Droplet

Vigorous ,Aggitation Polymerization by Heat

Hardened microspheres
3/19/12

Separation & Drying

C)EMULSION POLYMERISATION
Monomer/ Bioactive material Aq.Solution of NaOH, Initiator, Surfactant , Stabilizer

Dispersion with vigorous stirring Micellar sol. Of Polymer in aqueous medium Polymerization Microspheres formation 3/19/12

INTERFACIAL POLYMERIZATION TECHNIQUE When two reactive

monomers are dissolved in immiscible solvents, the monomers diffuse to the oilwater interface where they react to form a polymeric membrane.

Drug is incorporated either by being dissolved in the polymerization medium or by adsorption onto the nanoparticles This technique has been reported for making after polymerization 3/19/12 polybutylcyanoacrylate or poly completed.

PHASE SEPARATION METHOD Aqueous/Organic

Solution of polymer Drug Drug dispersed or dissolved in polymer solution Phase seperation induced by various
means

Polymer rich globules Hardenin

g

Microspheres in aq./organic phase

MICROSPHERE S
3/19/12

Separation, Washing, Drying

E) SPRAY DRYING
(acetone, dichloromethane)

Polymer dissolve in volatile organic solvent

Drug dispersed in polymer solution under high speed homogenization Atomized in a stream of hot air Due to solvent evaporation small droplet or fine mist form
3/19/12

F) SOLVENT EXTRACTION
Drug is dispersed in organic solvent

(water miscible organic solvent such as Isopropanol)

Polymer in organic solvent

Organic phase is removed by extraction with water . (This process decreasing hardening time for microspheres)

Hardened microspheres 3/19/12

PREPARATION OF MICROSPHERES BY DESOLVATION OF ALBUMIN

Gelatin and albumin nanospheres can be produced by the slow addition of a desolvating agent (neutral salt or alcohol) to the protein solution. Upon this addition, a progressive modification of the protein tertiary Structure is induced leading (when a certain degree of desolvation is obtained), to the Nanospheres are obtained by subsequent crosslinking formation of protein aggregates. of these aggregates with glutaraldehyde. To obtain small and monodispersed particles, it is important to maintain the system at a point just before coacervation is initiated. The addition of the desolvating agent is monitored by turbidimetry measurements of the system and must be stopped as soon as the turbidity increases, otherwise 3/19/12 aggregates that are too large will be formed.

SALTING-OUT PROCESS
An aqueous phase saturated with electrolytes (e.g., magnesium acetate, magnesium chloride) and containing PVA as a stabilizing and viscosity increasing agent is added under vigorous stirring to an acetone solution of polymer. In this system, the miscibility of both phases is prevented by the saturation of the aqueous phase with electrolytes, according to a salting-out phenomenon. The addition of the aqueous phase is continued until a phase inversion occurs and an o/w emulsion is formed. Then, a sufficient amount of pure water is added to disrupt the equilibrium between the two phases and to allow complete diffusion of acetone into water, leading to 3/19/12 polymer precipitation in the form of spherical nanospheres

PREPARATION OF MICROSPHERES BY THERMAL DENATURATION OF ALBUMIN

Once a high degree of dispersion is achieved, the emulsion is added dropwise. Immediate vaporization of the water contained in the droplets and to the irreversible denaturation of the albumin which coagulates in the form of solid nanospheres. The suspension is then allowed to cool down at room temperature or in an ice bath. Subsequently, the particles are submitted to several washings using large amounts of organic solvent (e.g., ether, ethanol, acetone) for complete removal of the oil.

3/19/12

Release pattern of drug from microspheres

Naltroxone (vivitrol TM) microspheres (PLA-PLGA) the first approved alcohol dependence medication in USA:

MECHANISM: The release pattern of naltroxone as a result of: absorbing water and swelling immediately after injection where the near surface drug is released first -as water absorption continues hydrolysis starts and after several days physical erosion begins. -further drug diffuse to the surrounding
3/19/12

CHARACTERIZATION OF MICROSPHERES

3/19/12

CHARACTERIZATION OF MICROSPHERES

YIELD VALUES AND LOADING EFFICIENCY:

Theoretical wgt to be prepared

Yield value = 100 x Obtained wgt. Of microspheres

Loading = 100 x actual amt. of drug obtained by extraction effeciency preparation theoretical wgt. of drug added in

MICROSPHERE

MORPHOLOGY:In this the prepared loaded microsphere is analyzed by scanning electronic 3/19/12 microscope(SEM)after palladium/gold

MICROSPHERE SIZE DISTRIBUTION: Mean size is determined by methods like Laser diffractometry method. DENSITY MEASUREMENT: By dipping method. MEASUREMENT OF GLASS TRANSITION TEMP (Tg) BY DSC: Tg is measured by DSC for the blank (unloaded) and the prepared loaded microspheres. CHEMISTRY BY ELECTRON SPECTROSCOPY: Done for chemical analysis. Provides means of determination of atomic composition of 3/19/12 the surface.

BULK

SURFACE

RELEASE

STUDY: Carried out in phosphate saline buffer Ph 7.4. Two methods1. Rotating paddle dissolution appratus. 2. Dialysis method.

ISOELECTRIC

POINT: Microelectrophoresis apparatus is used to measure electrophoretic mobility of microspheres from which isoelectric point can be determined. OF HYDRATION: Measured to evaluate water uptake by the system as 3/19/12

DEGREE

RECENT ADVANCEMENT
SWINE FLU INFLUENZA DNA VACCINE ENCAPSULATED IN PLGA MICROSPHERE DNA vaccine against Swine flu influenza encapsulated in poly(D,L)lactic co glycolic acid(PLGA) microspheres. Prepared by Emulsion evaporation method using PLGA as biodegradable matrix formic polymer.
3/19/12 PLGA microspheres containing DNA

s-PLLA/IBUPROFIN MICROSPHERES(2010)

These are star shaped poly(Llactide)loaded ibuprofen (s-PLLA/IBU) microspheres. Prepared using Solvent evaporation method IBU could combine with s-PLLA well and part of PLLA were degraded after releasing. The drug encapsulating efficiency of sPLLA/IBU
3/19/12 microspheres is high and release of

APPLICATION S

Vaccine delivery Improved antigenecity, Ag release, Stabilization of Ag targeting

Drug

Ocular: gelation with increased residence time Intranasal: protein and peptide delivery Oral microspheres

Magnetic

Immunomicrospheres Chemoembolization Imaging

3/19/12

REFERENCES
www.google.com www.wikipedia.com www.autorsteam.com www.informahealthcare.com www.en.cnki.com.cn www.pharmainfo.net

3/19/12

3/19/12