MICROSPHERES

Submitted to: Submitted by:Mr. Santosh Kumar Singh P. Swetha. Sugunan M.Pharm, Pharmceutics, 2nd sem.

CONTENTIntroductionAdvantagesPolymer used for preparationGeneral method of preparationRelease of drug from

microspheresCharacterization of microspheresApplications

INTRODUCTIONMicrospheres 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.

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

Microcapsule

Micromatrix

Types of Microspheres

ADVANTAGESPotential 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

aqueous media,

• Production of SR, CR, and targeted medications.

PHARMACEUTICAL APPLICATIONS

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

Microencapsulated KCl is used to prevent gastrointestinal complications associated with potassium chloride.

Microspheres have also found potential applications as injection, or inhalation products.

Most encapsulation processes are expensive and require significant capital investment for equipment.

An additional expense is due to the fact that most microencapsulation processes are patent protected.

.

OTHER APPLICATIONS Microcapsules are also extensively used as diagnostics, for

example, temperature-sensitive microcapsules for thermographic detection of tumors.

In the biotechnology industry microencapsulated microbial cells are being used for the production of recombinant proteins and peptides.

Encapsulation of microbial cells can also increase the cell-loading capacity and the rate of production in bioreactors.

A feline breast tumor line, which was difficult to grow in conventional culture, has been successfully grown in microcapsules.

Microencapsulated activated charcoal has been used for hemoperfusion.

Paramedical uses of microcapsules include bandages with microencapsulated anti-infective substances.

Synthetic Polymers

Non-biodegradablePMMAAcroleinEpoxy polymers

BiodegradableLactides and Glycolides copolymersPolyalkyl cyanoacrylatesPolyanhydrides

Natural MaterialsProteins

AlbuminsGelatinCollagen

CarbohydratesStarch agaroseCarrageenanChitosan

Chemically modified carbohydrates

Poly (acryl) dextranPoly(acryl)starch DEAE cellulose

POLYMERS USED IN THE MICROSPHERE PREPARATION

Prerequisites for Ideal Microparticulate Carriers

• Longer duration of action

• Control of content release

• Increase of therapeutic efficacy

• Protection of drug

• Reduction of toxicity

• Biocompatibility

• Sterilizability

• Relative stability

• Water solubility or dispersibility

• Bioresorbability

• Targetability

• Polyvalent

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

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

SIMPLE EMULSION BASED METHOD

Aq.Solution/suspension of polymer

Dispersion in organic phase (Oil/Chloroform)

Microspheres in organic phase Microspheres in organic phase

MICROSPHERES

Stirring, Sonication

CROSS LINKING

Chemical cross linking (Glutaraldehyde/Formaldehyde/ Butanol)

Heat denaturation

Centrifugation, Washing, Separation

DOUBLE EMULSION BASED METHODAq.Solution of protein/polymer

First emulsion (W/O)

MICROSPHERES

Dispersion in oil/organic phaseHomogenization

Separation, Washing, Drying

Addition of aq. Solution of PVA

Addition to large aq. PhaseDenaturation/hardening

Multiple emulsion

Microspheres in solution

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 polymer around the oily droplets.

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 medium during particle formation.

Once the microcapsules are formed, acetone is eliminated under reduced pressure.

INTERFACIAL DEPOSITION TECHNIQUE

A)NORMAL POLYMERIZATION

Normal Polymerization is done by bulk, suspension, pption,emulsion and

polymerization process.1. Bulk polymerization:

Monomer Bioactive material Initiator Heated to initiate polymerization Initiator accelerate rate of reaction Polymer(Block) Moulded/fragmented

Microspheres

B)SUSPENSION POLYMERIZATION

Monomer Bioactive material Initiator

Dispersion in water & stabilizer

Droplet

Vigorous ,Aggitation Polymerization by Heat

Hardened microspheres

Separation & Drying

MICROSPHERES

C)EMULSION POLYMERISATIONMonomer/ Aq.Solution of NaOH,

Bioactive material Initiator, Surfactant , Stabilizer

Dispersion with vigorous stirring

Micellar sol. Of Polymer in aqueous medium

Polymerization

Microspheres formation

MICROSPHERES

When two reactive monomers are

dissolved in immiscible solvents, the monomers diffuse to the oil-water 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 after polymerization completed.

The nanoparticle suspension is then purified to remove various stabilizers and surfactants employed for polymerization by ultracentrifugation and re-suspending the particles in an isotonic surfactant-free medium.

This technique has been reported for making polybutylcyanoacrylate or poly (alkylcyanoacrylate) nanoparticles.

INTERFACIAL POLYMERIZATION TECHNIQUE

PHASE SEPARATION METHODAqueous/Organic Solution of polymer

Drug dispersed or dissolved in polymer solution

MICROSPHERES

Drug

Separation, Washing, Drying

Phase seperation induced by various means

Hardening

Polymer rich globules

Microspheres in aq./organic phase

E) SPRAY DRYING

Polymer dissolve in volatile organic solvent (acetone, dichloromethane)

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

Leads to formation of Microspheres

Microspheres separated from hot air by cyclone separator, Trace of solvent are removed by vacuum drying

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

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 tertiaryStructure is induced leading (when a certain degree of desolvation is obtained), to the formation of protein aggregates.

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 aggregates that are too large will be formed.

Nanospheres are obtained by subsequent crosslinking of these aggregates with glutaraldehyde.

PREPARATION OF MICROSPHERES BY DESOLVATION OF ALBUMIN

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 polymer precipitation in the form of spherical nanospheres

SALTING-OUT PROCESS

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.

PREPARATION OF MICROSPHERES BY THERMAL DENATURATION OF ALBUMIN

Release pattern of drug from microspheresNaltroxone (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 resulting in sustained release of medication with the elimination of water and carbon dioxide as degradation product of polymer matrix.

CHARACTERIZATION OF MICROSPHERES

CHARACTERIZATION OF MICROSPHERES

YIELD VALUES AND LOADING EFFICIENCY:

Yield value = 100 x Obtained wgt. Of microspheres

Theoretical wgt to be prepared

Loading = 100 x actual amt. of drug obtained by extraction

effeciency theoretical wgt. of drug added in preparation

MICROSPHERE MORPHOLOGY:In this the prepared loaded microsphere is analyzed by scanning electronic microscope(SEM)after palladium/gold coating of the samples on an aluminium strip.

MICROSPHERE SIZE DISTRIBUTION: Mean size is determined by methods like Laser diffractometry method.

BULK 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.

SURFACE CHEMISTRY BY ELECTRON SPECTROSCOPY: Done for chemical analysis. Provides means of determination of atomic composition of the surface.

RELEASE STUDY: Carried out in phosphate saline buffer Ph 7.4. Two methods-

1. 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.

DEGREE OF HYDRATION: Measured to evaluate water uptake by the system as a first step in biodegradation.

RECENT ADVANCEMENT SWINE FLU INFLUENZA DNA VACCINE ENCAPSULATED IN PLGA MICROSPHEREDNA 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.

PLGA microspheres containing DNA vaccine can be used to achieved prolonged released of plasmid DNA.

s-PLLA/IBUPROFIN MICROSPHERES(2010)

These are star shaped poly(L- lactide)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

s-PLLA/IBU microspheres is high and release of ibuprofen

from microspheres is slow and effective.

APPLICATIONSVaccine delivery – Improved antigenecity, Ag

release, Stabilization of AgDrug targeting

◦ Ocular: gelation with increased residence time

◦ Intranasal: protein and peptide delivery◦ Oral

Magnetic microspheres ImmunomicrospheresChemoembolization ImagingMicrospongesSurface modified microspheres

REFERENCES

www.google.comwww.wikipedia.comwww.autorsteam.comwww.informahealthcare.comwww.en.cnki.com.cnwww.pharmainfo.net