FORMULATION AND EVALUATION OF MICROSPHERES

PRESENTED BY

DADHICHI K THAKKAR M.PHARM SEMISTER -I Guided by :-Dr UPENDRA PATEL

DEPARTMENT OF PHARMACUETICAL TECHNOLOGY ARIHANT COLLEGE OF PHARMACY GUJARAT TECHNICAL UNIVERSITY..

CONTENTS
       INTRODUCTION CLASSIFICATION OF POLYMERS. METHODS OF PREPARATION. CHARACTERIZATION. APPLICATIONS. CONCLUSION. REFERENCES

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

Contd.,
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.

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 nanospheres 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.

 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.

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.

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

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

Types of Microspheres
Microcapsule: consisting of an encapsulated core particle. Entrapped substance completely surrounded by a distinct capsule wall.
Types of Microspheres

Microcapsule

Micromatrix

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

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
Stirring, Sonication

Dispersion in organic phase (Oil/Chloroform)

Chemical cross linking (Glutaraldehyde/Formald ehyde/Butanol

Heat denaturation

CROSS LINKING

Microspheres in organic phase

Microspheres in organic phase

Centrifugation, Washing, Separation

MICROSPHERES

DOUBLE EMULSION BASED METHOD

Aq.Solution of protein/polymer
Dispersion in oil/organic phase Homogenization

First emulsion (W/O)

Addition of aq. Solution of PVA

Multiple emulsion
Addition to large aq. Phase Denaturation/hardening

Microspheres in solution
Separation, Washing, Drying

MICROSPHERES

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 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

Drug dispersed or dissolved in polymer solution

Polymer rich globules

Hardening

Microspheres in aq./organic phase

Separation, Washing, Drying

MICROSPHERES

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.

The BRACE-Process
 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 50m and 5000m nonabrading, therefore dust-free free flowing, porous, large surface area,soft or rigid

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 liquidmolten

materials, solutions, dispersions, sols, or suspensions can be used to manufacture perfectly spherical Microspheres.

DRUG LOADING
During the preparation of microspheres or after the formation of microspheres by incubating. Loading into preformed microspheres has an advantage of removing all impurities from microsphere preparation before the drug is incorporated. High loading can be achieved by insitu loading.

ROUTE OF ADMINISTRATION
 ORAL DELIVERY  PARENTERAL DELIVERY

CHARACTERIZATION
       PARTICLE SIZE. PARTICLE SHAPE. DENSITY DETERMINATION. ISOELECTRIC POINT. CAPTURE EFFICIENCY. RELEASE STUDIES. ANGLE OF CONTACT.

PARTICLE SIZE AND SHAPE

Particle size and distribution can be determined by
conventional light microscopy  scanning electron microscopy Confocal laser scanning microscopy Confocal fluorescence microscopy Laser light scattering and multisize coulter counter


PARTICLE SIZE

PARTICLE SHAPE

DENSITY DETERMINATION
Measured by psychnometer. using a Multivolume

ISOELECTRIC POINT
The microelectrophoresis is an apparatus used to measure the electophoretic mobility of microspheres from which isoelectric point can be determined.

CAPTURE EFFICIENCY

RELEASE STUDIES
Rotating paddle apparatus Dialysis method

ANGLE OF CONTACT
Determine wetting microparticulate carrier. property of

APPLICATIONS
 MICROSPHERES IN VACCINE DELIVERY. Eg ; Diphtheria toxoid , Tetanus toxoid.     TARGETED DRUG DELIVERY. Eg ; ocular, eye (cornea).etc CONTROLLED RELEASE. Eg ; luprodine (prostate cancer). CHEMOEMBOLIZATION. Gene delivery

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.

 Modified release microspheres of indomethacin were prepared by the emulsion solvent diffusion technique using a synthetic polymer, Acrycoat s100. Microspheres of diltiazem hydrochloride were formulated using combination of polyethylene glycol 6000 and Eudragit RS 100 and Eudragit RS 100 alone by solvent evaporation and non-solvent addition methods with an aim to prolong its release

Cancer research
One useful discovery made from the research of microspheres is a way to fight cancer on a molecular level. According to Wake Oncologists, "SIR-Spheres microspheres are radioactive polymer spheres that emit beta radiation. Physicians insert a catheter through the groin into the hepatic artery and deliver millions of microspheres directly to the tumor site. The SIR-Spheres microspheres target the liver tumors and spare healthy liver tissue. Approximately 55 physicians in the United States use Sirtexs SIR-Spheres microspheres in more than 60 medical centers.

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 , 3rd edition volume-4 .  www.koboproducts.com  www.brace.com  www.wikipedia.org  info@polysciences.com  www.harperintl.com.  www.pharmacy2011foru.blogspot.com

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