MICROSPHERESMICROSPHERESPresented by,

Hinglajia Hetal RatilalM.Pharm- Pharmaceutics, Sem-II14024671001SKPCPER, Ganpat University, Kherwa

Guided by,Dr. R. P. Patel

INTRODUCTION• The oral route is considered as the most promising route of drug delivery. Conventional

drug delivery system achieves as well as maintains the drug concentration within the

therapeutically effective range needed for treatment, only when taken several times a

day.

• This results in a significant fluctuation in drug levels. A well defined controlled drug

delivery system can overcome some of the problems of conventional therapy and

enhance the therapeutic efficacy of a given drug..

• There are various approaches in delivering a therapeutic susbstance to the target site

in sustained controlled release fashion using microspheres as carrier for drug

• Administration of drugs in the form of microspheres usually improves the treatment by

providing the localization of the active substances at the site of action & by prolonging

the release of drugs.

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 aqueous media, and Production of SR, CR, and targeted medications.

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

DEFINITION OF MICROSPHERES

• Microparticles or microspheres are defined as small, insoluble, free flowing spherical particles consisting of a polymer matrix and drug. and sized from about 50 nm to about 2 mm.

• The term Nano spheres is often applied to the smaller spheres (sized 10 to 500 nm) to distinguish them from larger microspheres

• Ideally, microspheres are completely spherical and homogeneous in size

• Microspheres are made from polymeric , waxy or protective materials that is biodegradable synthetic polymers and modified natural products.

• Microspheres are manufactured in both solid and hollow form. Hollow microspheres are used as additives to lower the density of a material.

• Solid biodegradable microspheres incorporating a drug dispersed or dissolved throughout particle matrix have the potential for controlled release of the drug.

• These carriers received much attention not only for prolonged release but also for the targeting anti cancer drugs to the tumour.

TYPES OF MICROSPHERES• Microcapsule: consisting of an encapsulated core particle. Entrapped

substance completely surrounded by a distinct capsule wall.

• Micromatrix: Consisting of homogenous dispersion of active ingredient in particle.

Microcapsule Micromatrix

Types of Microspheres

POLYMERS USED IN THE MICROSPHERE PREPARATION

Synthetic Polymers Non-biodegradable

• PMMA - Poly(methyl methacrylate)• 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

ADVANTAGES

• Controlled release for longer period of time (like 1-3 months).• Frequency is reduced and hence patient compliance is

increased.• Constant release and hence no peaks and troughs in

concentration of drug.• Low dose and hence toxic effect is less.• Targeting the tissue is possible.• Other organ toxicity is less.• No distribution through out the body (no dilution effect)

DISADVANTAGES

• Intended mainly for parenteral route which causes pain.• Forms a depot in tissue or muscle for longer period and

hence may produce pain when muscle activities are done.

• Once administered, it is difficult to take back the dose.• Polymer may produce toxic effects.• High cost.

MECHANISMS OF DRUG RELEASE

• Degradation controlled monolithic system.

• Diffusion controlled monolithic system.

• Erodible poly agent system.

DEGRADATION CONTROLLED MONOLITHIC SYSTEM.

• The drug is dissolved in the matrix is in degradation controlled monolithic microspheres system, the dissolved and is released only on degradation of the matrix.

• The diffusion of the drug is slow compared with the degradation of the matrix.

• When degradation as by homogeneous bulk mechanism, drug release is show initially and increase rapidly when repaid bulk degradation starts.

• Drug release from such type of device in independent of the geometry of the device if the degradation is by homogeneous mechanism, degradation is confined to the surface. Hence rate of release is affected by the geometry of the device.

DIFFUSION CONTROLLED MONOLITHIC SYSTEM.

• Here the active is released by diffusion prior to or concurrent with the degradation of the

polymer matrix.

• Degeneration of the polymer matrix affects the rate of release and to be taker into

account.

• Rate of release also depends on whether the polymer degrades by homogeneous or

heterogeneous mechanism.

ERODIBLE POLY AGENT SYSTEM.

• In this case the active agent is chemically attach to matrix & the rate of

biodegradation of matrix is slow compared to the rate of hydrolysis of drug-polymer

bond.

• Assuming that the rate of diffusion of active agent from the matrix to the surrounding

is rapid, the rate limiting step is the rate of cleavage of bond attaching drug to

polymer matrix.

• In vitro studies in rats using labeled drug polymer conjugate showed that a fairly

constant release is obtained during the time of observation which was 5 months

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• Emulsification-solvent evaporation method• Spray drying and spray congealing• Brace process

SINGLE 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/ButanolHeat denaturation

Centrifugation, Washing, Separation

Aq.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

DOUBLE EMULSION BASED METHOD

INTERFACIAL POLYMERIZATION TECHNIQUE

INTERFACIAL POLYMERIZATION TECHNIQUE• 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 that envelopes dispersed phase.

• 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.

PHASE SEPARATION METHOD

Aqueous/Organic.Solution of polymer

Drug dispersed or dissolved in polymer solution

MICROSPHERES

Drug

Separation, Washing, Drying

Hardening

Polymer rich globules

Microspheres in aq./organic phase

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

EMULSIFICATION-SOLVENT EVAPORATION

METHOD

SPRAY DRYING AND SPRAY CONGEALING METHOD

• These methods are based on drying of the mist of polymer and drug in air. Depending on the removal of solvent or cooling the solution are named as “drying” and “congealing”, respectively.

• The polymer dissolved in a suitable volatile organic solvent (dichloromethane,acetone,etc)

• The drug in the solid form is then dissolved in polymer solution under high speed homogenization.

• This dispersion is atomized in a stream of hot air.

• This leads to formation of small droplets from which solvent evaporates leading to the formation of microspheres.

• These are then separated from hot air by means of cyclone separator.

• Spray congealing involves the formation of microspheres by solidifying the melted mass of drug and polymer in the form of minute particles.

Ultra Spherical Microspheres..

Microspheres with a monodisperse grain size distribution and the smallest divergence are manufactured by BRACE.

• Perfectly spherical Microspheres

• Monodisperse grain size, narrow size distribution with diameters

between 50µm and 5000µm

• Nonabrading, therefore dust-free

• Free flowing, porous, large surface area,soft or rigid

The BRACE-Process

THE BRACE-PROCESS A liquid is gently pumped through a vibrating nozzle system

whereupon exiting the fluid stream breaks up into uniform droplets.

The surface tension of these droplets moulds them into perfect spheres in which gelation is induced during a short period of free fall.

Solidification can be induced in a gaseous and/or liquid medium through cooling, drying, or chemical reaction.

There are no constraints on the type of liquid—molten materials, solutions, dispersions, sols, or suspensions can be used to manufacture perfectly spherical Microspheres.

CONCLUSION

The concept of microsphere drug delivery systems offers certain advantages over the conventional drug delivery systems such as controlled and sustained delivery. Apart from that microspheres also allow drug targeting to various systems such as ocular , intranasal , oral and IV route .

Novel technologies like magnetic microspheres, immunomicrospheres offer great advantages and uses than conventional technologies.

Further more in future by combining various other strategies, microspheres will find the central place in novel drug delivery, particularly in diseased cellsorting ,diagnostics, gene and genetic materials, safe,targated and effective invivo delivery which may have implications in gene therapy.

This area of novel drug delivery has innumerable applications and there is a need for more research to be done in this area.

REFERENCES S.P.Vyas., R.K.Khar, International Journal for Targeted & Controlled Drug Delivery Novel Carrier Systems.,

First Edition :2002.,Reprint :2007 page no:417,453.

Review: Radioactive Microspheres for Medical Applications.

International journal of Pharmaceutics 282 (2004) 1-18,Review polymer microspheres for controlled drug release.

N.K.Jain ,Controlled and novel drug delivery edited by reprint 2007 pg.no.236-255.

Donald L.Wise, Handbook of pharmaceutical controlled release technology.

James Swarbrick, James C.Boylan ,Encyclopedia of pharmaceutical technology Editors, volume-10.

Patrick B.Deasy, Microencapsulation and related drug delivery processes edited by.

James Swarbrick, Encyclopedia of pharmaceutical technology , 3 rd edition volume-4 .

www.koboproducts.com

www.brace.com

www.wikipedia.org

info@polysciences.com

www.harperintl.com.

www.pharmacy2011foru.blogspot.com

Donald L.Wise, Handbook of pharmaceutical controlled release technology. James Swarbrick, James C.Boylan ,Encyclopedia of pharmaceutical technology

Editors, volume-10. Patrick B.Deasy, Microencapsulation and related drug delivery processes edited by. James Swarbrick, Encyclopedia of pharmaceutical technology , 3rd edition volume-4

. www.koboproducts.com www.brace.com www.wikipedia.org info@polysciences.com www.harperintl.com. www.pharmacy2011foru.blogspot.com