microencapsulation ndds roll no.01
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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
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 [email protected] www.harperintl.com. www.pharmacy2011foru.blogspot.com