WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES

Shagufta et al. World Journal of Pharmacy and Pharmaceutical Sciences Volume 1, Issue 1, 125-145. Review Article ISSN 2278 4357

MICROSPHERES: A REVIEW
*Shagufta Khan, Tripti Tiwari, Neha Rao, Amit Joshi, Bal Krishna Dubey

T.I.T. College of Pharmacy, Anand Nagar, P.B. No. 24, Bhopal- 462021(M.P.), India

ABSTRACT
Article Received on 01 May 2012, Revised on 15 May 2012, Accepted on 22 May 2012

Controlled drug delivery technology is concerned with the systematic release of a pharmaceutical agent to maintain a therapeutic level of the drug in the body for a sustained period of time. This may be achieved by incorporating the therapeutic agent into a degradable polymer vehicle, releasing the agent continuously as the matrix erodes. .Microspheres are characteristically free flowing powders

*Correspondence for Author: * Shagufta Khan T.I.T. College of Pharmacy, Anand Nagar, P.B. No. 24, Bhopal- 462021(M.P.), India gr8nazli@yahoo.co.in

consisting of proteins or synthetic polymers having a particle size ranging from 1-1000 m. The range of Techniques for the preparation of microspheres offers a Variety of opportunities to control aspects of drug administration and enhance the therapeutic efficacy of a given drug. There are various approaches in delivering a therapeutic substance to the target site in a sustained controlled release fashion. One such approach is using microspheres as carriers for drugs also known as microparticles. It is the reliable means to deliver the drug to the target site with specificity, if modified, and to maintain the desired concentration at the site of interest. Microspheres

received much attention not only for prolonged release, but also for targeting of anticancer drugs. In future by combining various other strategies, microspheres will find the central place in novel drug delivery, particularly in diseased cell sorting, diagnostics, gene & genetic materials, safe, targeted and effective in vivo delivery and supplements as miniature versions of diseased organ and tissues in the body. Keywords: Microspheres, controlled release, target site, specificity, therapeutic efficacy, novel drug delivery.

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INTRODUCTION Microspheres are small spherical particles, with diameters in the micrometer range (typically 1 m to 1000 m). Microspheres are sometimes referred to as microparticles. Microspheres can be manufactured from various natural and synthetic materials. Glass microspheres, polymer microspheres and ceramic microspheres are commercially available. Solid and hollow microspheres vary widely in density and, therefore, are used for different applications. Hollow microspheres are typically used as additives to lower the density of a material. Solid microspheres have numerous applications depending on what material they are constructed of and what size they are. Polyethylene and polystyrene microspheres are two most common types of polymermicrospheres.Polystyrene microspheres are typically used inbiomedical applications due to their ability to facilitate procedures such as cell sorting and immuno precipitation. Proteins and ligands adsorb onto polystyrene readily and permanently, which makes polystyrene microspheres suitable for medical research and biological laboratory

experiments. Polyethylene microspheres are commonly used as permanent or temporary filler. Lower melting temperature enables polyethylene microspheres to create porous structures in ceramics and other materials. High sphericity of polyethylene microspheres, as well as availability of colored and fluorescent microspheres, makes them highly desirable for flow visualization and fluid flow analysis, microscopy techniques, health sciences, process troubleshooting and numerous research applications. Charged polyethylene microspheres are also used in electronic paper digital displays. Glass microspheres are primarily used as filler for weight reduction, retro-reflector for highway safety, additive for cosmetics and adhesives, with limited applications in medical technology. Ceramic microspheres are used primarily as grinding media. Microspheres vary widely in quality, sphericity, uniformity of particle and particle size distribution. The appropriate microsphere needs to be chosen for each unique application5[1] The term microcapsule is defined as a spherical particle with size varying from 50nm to 2nm containing a core substance. Alternate terminology for the microsphere is microbeads and beads are used alternatively.

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Fig1. MICROSPHERES [2] Types of polymer used in preparation of microspheres Classification: 1] Synthetic polymer A] Non biodegradable: Acrolein Glycidyl methacrylate Epoxy polymer PMMA

B] Biodegradable: Polyanhydides Lactides and glycolides and their copolymer. Polyalkyl cyno acrylates

2] Natural Materials A] Proteins Albumins Gelatins Collagens

B] Carbohydrates Chitosan Carrageenan Starch 127

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Agaose

C] Chemically modified carbohydrate Poly (acryl) dextran Poly (acryl) starch DEAE cellulose [3]

TYPES OF MICROSPHERES Bioadhesive microspheres Adhesion can be defined as sticking of drug to the membrane by using the sticking property of the water soluble polymers. Adhesion of drug delivery device to the mucosal membrane such as buccal, ocular, rectal, nasal etc can be termed as bio adhesion. These kinds of microspheres exhibit a prolonged residence time at the site of application and causes intimate contact with the absorption site and produces better therapeutic action. Magnetic microspheres This kind of delivery system is very much important which localises the drug to the disease site. In this larger amount of freely circulating drug can be replaced by smaller amount of magnetically targeted drug. Magnetic carriers receive magnetic responses to a magnetic field from incorporated materials that are used for magnetic microspheres are chitosan, dextran etc.The different type are Therapeutic magnetic microspheres: Are used to deliver chemotherapeutic agent to liver tumour. Drugs like proteins and peptides can also be targeted through this system.6 Diagnostic microspheres: Can be used for imaging liver metastases and also can be used to distinguish bowel loops from other abdominal structures by forming nano size particlessupramagnetic iron oxides. Floating microspheres In floating types the bulk density is less than the gastric fluid and so remains buoyant in stomach without affecting gastric emptying rate. The drug is released slowly at the desired rate, if the system is floating on gasteric contentand increases gastric residence and increases fluctuation in plasma concentration. Moreover it also reduces chances of striking and dose dumping. One another way it produces prolonged therapeutic effect and therefore reduces dosing frequencies. Drug (ketoprofen)given through this form.

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Radioactive microspheres Radio emobilisation therapy microspheres sized 10-30 nm are of larger than capillaries and gets tapped in first capillary bed when they come across. They are injected to the arteries that lead to tumour of interest. So all these conditions radcioactive microspheres deliver high radiation dose to the targeted areas without damaging the normal surrounding tissues.It differs from drug delivery system, as radio activity is not released from microspheres but acts from within a radioisotope typical distance and the different kinds of radioactive microsphers are emitters, emitters, emitters. Polymeric microspheres The diffent types of polymeric microspheres can be classified as followsand they are biodegradable polymeric microspheres and Synthetic polymeric microspheres. Biodegradable polymeric microspheres Natural polymers such as starch are used with the concept that they are biodegradable, biocompatible, and also bio adhesive in nature. Biodegradable polymers prolongs the residence time when contact with mucous membrane due to its high degree of swelling property with aqueous medium , results gel formation. The rate and extent of drug release is controlled by concentration of polymer and the release pattern in a sustained manner. The main drawback is, in clinical use drug loading efficiency of biodegradable microspheres is complex and is difficult to control the drug release. However they provide wide range of application in microsphere based treatment. Synthetic polymeric microspheres The interest of synthetic polymeric microspheres are widely used in clinical application, moreover that also used as bulking agent, fillers, embolic particles, drug delivery vehicles etc and proved to be safe and biocompatible.11But the main disadvantage of these kind of microspheres, are tend to migrate away from injection site and lead to potential risk, embolismand further organ damage.[4] PREPARATION OF MICROSPHERES The preparation of microspheres should satisfy certain criteria. They are: (i) The ability to incorporate reasonably concentrations of the drug, (ii) Stability of the preparation after synthesis with a clinically acceptable shelf-life, (iii) Controllable particle size and dispensability in aqueous vehicles for injection, www.wjpps.com 129

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(iv) Release of active agent with good control over a wide time scale, (v) Biocompatibility with a controllable biodegradability, and (vi) Susceptibility to chemical modification.[5] METHODS USE OF PREPARATION OF MICROSPHERES 1. Solvent evaporation method, a) Single emulsion technique. b) Double emulsion technique. 2. Coacervation phase separation method. 3. Spray drying and spray congealing method. 4. Polymerization method. 1. Solvent Evaporation Method a) Single emulsion technique The microparticulate carriers of natural polymers, i.e. those of proteins & carbohydrates are prepared by single emulsion technique. The natural polymers are dissolved/ dispersed in aqueous medium followed by dispersion in the non aqueous medium. Ex: oil. In the 2nd step, cross linking of the dispersed globule is carried out either by means of heat or by using chemical cross linkers. The chemical cross linking agents used gluteraldehyde, formaldehyde, terephthalate chloride, diacidchloride, etc. Crosslinking by heat is effected by adding the dispersion to previously heated oil. Heat denaturation is not suitable for the thermolabile drugs while the chemical cross-linking suffers disadvantage of excessive exposure of active ingredient to chemicals if added at the time of preparation. (Fig.2) b) Double emulsion technique Involves the formation of the multiple emulsions or the double emulsion of type w/o/w & is best suited to the water soluble drugs, peptides, proteins & the vaccines. The aqueous protein solution is dispersed in a lipophilic organic continuous phase which is generally consisted of polymer solution that eventually encapsulates protein contained in dispersed aqueous phase. The primary emulsion is then subjected to the homogenization before addition to aqueous solution of PVA .this results in formation of double emulsion which is then subjected to solvent removal by solvent evaporation maintaining the emulsion at reduced pressure or by stirring so that organic phase evaporates out.(Fig.3) Examples: hydrophilic drugs like LHRH agonist, vaccines. www.wjpps.com 130

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2. Coacervation phase separation method Specially designed for preparing the reservoir type of the system, i.e., to encapsulate water soluble drugs e.g. peptides, proteins, matrix type particularly, when the drug is hydrophobic in nature e.g., steroids. In matrix type device, the drug or the protein is soluble in the polymer phase. The process is based on the principle of decreasing the solubility of the polymer in the organic phase to affect the formation of the polymer rich phase called the coacervates. The coacervation can be brought about by addition of the third component to the system which results in the formation of the two phases, one i.e. supernatant, depleted of the polymer. In this technique, the polymer is first dissolved in a suitable solvent & then drug is dispersed by making its aqueous solution, if hydrophilic or dissolved in t he polymer solution itself, if hydrophobic. Phase separation is then accomplished by changing the solution conditions. (Fig.4) 3. Spray drying and spray congealing: These methods are based on the drying of the mist of the polymer and drug in the air. Depending upon the removal of the solvent or cooling of the solution, the two processes are named spray drying and spray congealing respectively. The polymer is first dissolved in a suitable volatile organic solvent such asdichloromethane, acetone, etc. The drug in the solid form is then dispersed in the polymer solution under high speed homogenization. This dispersion is then atomized in a stream of hot air. The atomization leads to the formation of the small droplets or the fine mist from which the solvent evaporates instantaneously leading the formation of the microspheres in a size range 1- 100 m. Microparticles are separated from the hot air by means of the cyclone separator while the traces of solvent are removed by vacuum drying. One of the major advantages of the process is feasibility of operation under aseptic conditions. The spray drying process is used to encapsulate various penicillins. Thiamine mononitrate and sulpha ethylthiadizole are encapsulated in a mixture of mono- and diglycerides of stearic acid and palmitic acid using spray congealing. Very rapid solvent evaporation, however leads to the formation of porous microparticles. (Fig.5) 4. Polymerization method I. Normal polymerization II. Interfacial polymerization. Normal polymerization Proceeds using techniques like bulk, suspension precipitation, emulsion & micellar polymerization processes. In bulk polymerization, a monomer along with initiator is heated to 131 www.wjpps.com

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initiate polymerization. Initiator is added to accelerate the rate of reaction. Drug is added during process of polymerization. The polymer so obtained is fragmented to microspheres. Suspension polymerization Suspension polymerization is also called as bead/pearl polymerization. Carried out by heating the monomer or mixture of monomers with active principles(drug) as droplets dispersion in a continuous phase. The droplets may also contain an initiator & other additives. The emulsion polymerization, differs from the suspension polymerization as due to presence of initiator in the aqueous phase, which later on diffuses to the surface of the micelles or the emulsion globules. The suspension & emulsion polymerization can be carried out at lower temperature, since continuous external phase is normally water through which heat can easily dissipate. The 2 processes also lead to the formation of higher mol. wt polymer at relatively faster rate. Interfacial polymerization Involves reaction of various monomers at the interface between the 2 immiscible liquid phases to form a film of polymer that essentially envelopes the dispersed phase. In this 2 reacting monomers are employed one of which is dissolved in the continuous phase while the other being dispersed in the continuous phase. Monomer present in either phases diffuse rapidly 7 polymerize rapidly at the interface. If the polymer is soluble in the droplet it will lead to the formation of monolithic type of the carrier on the other hand if polymer is insoluble in the monomer droplet, the formed carrier is of capsular(reservoir) type. The degree of polymerization can be controlled by the reactivity of monomer chosen, their concentration, the composition of the vehicle of either phases & by the temperature of the system. The particle size can be controlled by controlling the droplets or globule size of the disperse phase. The polymerization reaction can be controlled by maintaining the concentration of the monomers, which can be achieved by the addition of an excess of the continuous phase. (Fig.6)

Figure 2: Processing scheme for microspheres-preparation by single emulsion technique www.wjpps.com 132

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Figure 3: Processing scheme for microspheres-preparation by double emulsion technique

Figure 4: Coacervation phase separation method

Figure 5: Spray drying and spray congealing

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Figure 6: Polymerization method

PHYSICOCHEMICAL EVALUATION CHARACTERIZATION The characterization of the microparticulate carrier is an important phenomenon, which helps to design a suitable carrier for the proteins, drug or antigen delivery. These microspheres have different microstructures. These microstructures determine the release and the stability of the carrier. Particle size and shape The most widely used procedures to visualize microparticles are conventional light microscopy (LM) and scanning electron microscopy (SEM). Both can be used to determine the shape and outer structure of microparticles. LM provides a control over coating parameters in case of double walled microspheres. The microspheres structures can be visualized before and after coating and the change can be measured microscopically. SEM provides higher resolution in contrast to the LM17. SEM allows investigations of the microspheres surfaces and after particles are cross-sectioned, it can also be used for the investigation of double walled systems. Conflocal fluorescence microscopy1 is used for the structure characterization of multiple walled microspheres. Laser light scattering and multi size coulter counter other than instrumental methods, which can be used for the characterization of size, shape and morphology of the microspheres. www.wjpps.com 134

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Electron spectroscopy for chemical analysis The surface chemistry of the microspheres can be determined using the electron spectroscopy for chemical analysis (ESCA). ESCA provides a means for the determination of the atomic composition of the surface. The spectra obtained using ECSA can be used to determine the surfacial degradation of the biodegradable microspheres. Attenuated total reflectance FourierTransfom-Infrared Spectroscopy FT-IR is used to determine the degradation of the polymeric matrix of the carrier system. The surface of the microspheres is investigated measuring alternated total reflectance (ATR). The IR beam passing through the ATR cell reflected many times through the sample to provide IR spectra mainly of surface material. The ATRFTIR provides information about the surface composition of the microspheres depending upon manufacturing procedures and conditions. Density determination The density of the microspheres can be measured by using a multi volume pychnometer. Accurately weighed sample in a cup is placed into the multi volume pychnometer. Helium is introduced at a constant pressure in the chamber and allowed to expand. This expansion results in a decrease in pressure within the chamber. Two consecutive readings of reduction in pressure at different initial pressure are noted. From two pressure readings the volume and hence the density of the microsphere carrier is determined. Isoelectric point The micro electrophoresis is an apparatus used to measure the electrophoretic mobility of microspheres from which the isoelectric point can be determined. The mean velocity at different Ph values ranging from 3-10 is calculated by measuring the time of particle movement over a distance of 1 mm. By using this data the electrical mobility of the particle can be determined. The electrophoretic mobility can be related to surface contained charge, ionisable behaviour or ion absorption nature of the microspheres. Capture efficiency The capture efficiency of the microspheres or the percent entrapment can be determined by allowing washed microspheres to lyse. The lysate is then subjected to the determination of active constituents as per monograph requirement. The percent encapsulation efficiency is calculated using following equation: % Entrapment = Actual content/Theoretical content x 100. www.wjpps.com 135

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Angle of contact The angle of contact is measured to determine the wetting property of a micro particulate carrier. It determines the nature of microspheres in terms of hydrophilicity or hydrophobicity. This thermodynamic property is specific to solid and affected by the presence of the adsorbed component. The angle of contact is measured at the solid/air/water interface. The advancing and receding angle of contact are measured by placing a droplet in a circular cell mounted above objective of inverted microscope. Contact angle is measured at 200C within a minute of deposition of microspheres. In vitro methods There is a need for experimental methods which allow the release characteristics and permeability of a drug through membrane to be determined. For this purpose, a number of in vitro and in vivo techniques have been reported. In vitro drug release studies have been employed as a quality control procedure in pharmaceutical production, in product development etc. Sensitive and reproducible release data derived from physico chemically and hydro dynamically defined conditions are necessary. The influence of technologically defined conditions and difficulty in simulating in vivo conditions has led to development of a number of in vitro release methods for buccal formulations; however no standard in vitro method has yet been developed. Different workers have used apparatus of varying designs and under varying conditions, depending on the shape and application of the dosage form developed. Interface diffusion system This method is developed by Dearden & Tomlinson. It consists of four compartments. The compartment A represents the oral cavity, and initially contained an appropriate concentration of drug in a buffer. The compartment B representing the buccal membrane, contained 1-octanol, and compartment C representing body fluids, contained 0.2 M HCl. The compartment D representing protein binding also contained 1-octanol. Before use, the aqueous phase and 1-octanol were saturated with each other. Samples were withdrawn and returned to compartment A with a syringe. Dissolution apparatus

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Standard USP or BP dissolution apparatus have been used to study in vitro release profiles using both rotating elements, paddle and baske. Dissolution medium used for the study varied from 100- 500 ml and speed of rotation from 50-100 rpm. In vivo methods Methods for studying the permeability of intact mucosa comprise of techniques that exploit the biological response of the organism locally or systemically and those that involve direct local measurement of uptake or accumulation of penetrants at the surface. Some of the earliest and simple studies of mucosal permeability utilized the systemic pharmacological effects produced by drugs after application to the oral mucosa. However the most widely used methods include in vivo studies using animal models, buccal absorption tests, and perfusion chambers for studying drug permeability. Animal models Animal models are used mainly for the screening of the series of compounds, investigating the mechanisms and usefulness of permeation enhancers or evaluating a set of formulations. A number of animal models have been reported in the literature, however, very few in vivo (animal). Animal models such as the dog, rats, rabbits, cat, hamster, pigs, and sheep have been reported. In general, the procedure involves anesthetizing the animal followed by administration of the dosage form. In case of rats, the oesophagus is ligated to prevent absorption pathways other than oral mucosa. At different time intervals, the blood is withdrawn and analyzed. Buccal absorption test The buccal absorption test was developed by Beckett & Triggs in 1967. It is a simple and reliable method for measuring the extent of drug loss of the human oral cavity for single and multi component mixtures of drugs. The test has been successfully used to investigate the relative importance of drug structure, contact time, initial drug concentration and Ph of the solution while the drug is held in the oral cavity. In vitro-In vivo correlations Correlations between in vitro dissolution rates and the rate and extent of availability as determined by blood concentration and or urinary excretion of drug or metabolites are referred to as in vitro-in vivo correlations1. Such correlations allow one to develop product specifications with bioavailability.

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ADVANTAGES 1. Reliable means to deliver the drug to the,target site with specificity, if modified, and to maintain the desired concentration at the site of interest without untoward effects. 2. Solid biodegradable microspheres have the potential throughout the particle matrix for the controlled release of drug. 3. Microspheres received much attention not only for prolonged release, but also for targeting of anticancer drugs to the tumour. 4. The size, surface charge and surface hydrophilicity of microspheres have been found to be important in determining the fate of particles in vivo. 5. Studies on the macrophage uptake of microspheres have demonstrated their potential in targeting drugs to pathogens residing intracellularly. 6. Blood flow determination: Relatively large microspheres (10-15 m in diameter) are useful for regional blood flow studies in tissues and organs. In most cases the microspheres are injected at desired locations in the circulatory system and eventually lodge in the capillaries. The microspheres and fluorescent dyes they contain are first extracted from the tissue sample, and then fluorescence is quantitated on a spectrofluorometer or fluorescence microplate reader. Traditionally, this type of study has been carriedout using radiolabelled microspheres; however fluorescent microspheres have been shown to be superior in chronic blood flow measurements.[6] RELEASE OF THERAPEUTIC AGENTS Several mechanisms may be responsible for the overall release of a therapeutic agent dispersed in a degradable polymer matrix Erosion of the polymer; Diffusion of the drug particles through the matrix; Dissolution of the drug in the surrounding medium.[7] APPLICATIONS New applications for microspheres are discovered every day, below are just a few:

Assay - Coated microspheres provide measuring tool in biology and drug research Buoyancy - Hollow microspheres are used to decrease material density in plastics (glass and polymer)

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Ceramics - Used to create porous ceramics used for filters (microspheres melt out during firing, Polyethylene Microspheres)

Cosmetics - Opaque microspheres used to hide wrinkles and give color, Clear microspheres provide "smooth ball bearing" texture during application (Polyethylene Microspheres)

Drug delivery - As miniature time release drug capsule made of, for example, polymers. A similar use is as outer shells of microbubble contrast agents used in contrast-enhanced ultrasound.

Electronic paper - Dual Functional microspheres used in Gyricon electronic paper Personal Care - Added to Scrubs as an exfoliating agent (Polyethylene Microspheres) Spacers - Used in LCD screens to provide a precision spacing between glass panels (glass)

Standards - monodispere microspheres are used to calibrate particle sieves, and particle counting apparatus.

Retroreflective - added on top of paint used on roads and signs to increase night visibility of road stripes and signs (glass)

Thickening Agent - Added to paints and epoxies to modify viscosity and buoyancy

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 micropheres directly to the tumor site. The SIRSpheres microspheres target the liver tumors and spare healthy liver tissue.Cancer microsphere technology is the latest trend in cancer therapy. It helps the pharmacist to formulate the product with maximum therapeutic value and minimum or negligible range side effects. A major disadvantage of anticancer drugs is their lack of selectivity for tumor tissue alone, which causes severe side effects and results in low cure rates. Thus, it is very difficult to target abnormal cells by the conventional method of the drug delivery system. Microsphere technology is probably the only method that can be used for site-specific action, without causing significant side effects on normal cells.[8] Recent Applications of Controlled Release Microspheres Controlled-ReleaseVaccines www.wjpps.com 139

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Vaccination has been highly successful for controlling or even eradicating many important types of infectious diseases, and new or improved vaccines are being heavily investigated for AIDS , hepatitis B, anthrax, and SARS.Afrequent problem is the need for repeated administrationsusually KYEKYOON KEVIN KIM AND DANIEL W. PACK injectionsto ensure long-lasting immunity. For example, the current anthrax vaccine requires a series of boosters at 2 and 4 weeks, and at 6, 12, and 18 months following the first inoculation; and the Recombivax HBr_ vaccine for hepatitis Brequired for most healthcare workers in the U.S.is administered in three injections at 0, 1, and 6 months. The need for multiple injections poses a serious problem for patients in developing countries with limited access to medical care, where awareness is lacking, or for transient populations. Stabilization of Encapsulated Protein Therapeutics A major problem with protein encapsulation in polymer particles is loss of protein bioactivity. Damage to proteins can occur during fabrication of the particlesvia shear stresses or other physical forces,through contact with organic solvents, and by loss of water (e.g., upon lyophilization) as well as during incubation and release in the warm, moist, in vivo environment. Two types of damage occur most often: (i) covalent or non-covalent intermolecular aggregation and (ii) denaturation. Several studies have investigated the

mechanisms of damage. Protein stability can be enhanced by the addition of excipients to prevent aggregation and stabilize the folded protein structure or through judicious choice of polymer employed for fabrication of the devices. DNA Encapsulation Gene therapy holds tremendous potential for treating genetic diseases and acquired diseases including cancer, and as vaccines. A major barrier to development of gene-based pharmaceuticals is safe and efficient DNA delivery. Much research has focused on development of gene delivery vectors including viruses, liposomes, and polymers. However, parenteral administration of naked plasmid DNA (pDNA) leads to gene expression , and controlled release ofpDNA from polymeric matrices, microparticle and nanoparticles has been reported recently. In particular, encapsulation and controlled release of pDNA from biodegradable microspheres may provide a number of advantages including protection from nuclease degradation, access to alternative routes of administration (e.g., nasal, pulmonary, oral, and mucosal), passive targeting to professional antigen-presenting cells, and prolonged gene expression.[9] www.wjpps.com 140

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Pharmaceutical Applications In Drug Delivery System Ophthalmic Drug Delivery Polymer exhibits favorable biological behavior such as bioadhesion, permeability-enhancing properties, and interesting physico-chemical characteristics, which make it a unique material for the design of ocular drug delivery vehicles. Due to their elastic properties, polymer hydro gels offer better acceptability, with respect to solid or semisolid formulation, for ophthalmic delivery, such as suspensions or ointments, ophthalmic chitosan gels improve adhesion to the mucin, which coats the conjunctiva and the corneal surface of the eye, and increase precorneal drug residence times, showing down drug elimination by the lachrymal flow. Gene delivery Gene delivery systems include viral vectors, cationic liposomes, polycation complexes, and microencapsulated systems. Viral vectors are advantageous for gene delivery because they are highly efficient and have a wide range of cell targets. However, when used in vivo they cause immune responses and oncogenic effects. To overcome the limitations of viral vectors, non-viral delivery systems are considered for gene therapy. Non-viral delivery system has advantages such as ease of preparation, cell/tissue targeting, low immune response, unrestricted plasmid size, and large-scale reproducible production. Polymer has been used as a carrier of DNA for gene delivery applications. Intratumoral and local drug delivery Intratumoral and local drug delivery strategies have gained momentum recently as a promising modality in cancer therapy. In order to deliver paclitaxel at the tumor site in therapeutically relevant concentration, polymer films were fabricated. Paclitaxel could be loaded at 31% (w/w) in films, which were translucent and flexible. polymer films containing paclitaxels were obtained by casting method with high loading efficiencies and the chemical integrity of molecule was unaltered during preparation according to study. Oral drug delivery The potential of polymer films containing diazepam as an oral drug delivery was investigated in rabbits. The results indicated that a film composed of a 1:0.5 drug-polymer mixture might be an effective dosage form that is equivalent to the commercial tablet dosage forms. The ability of polymer to form films may permit its use in the formulation of film dosage forms, as an alternative to pharmaceutical tablets. The pH sensitivity, coupled with the reactivity of

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the primary amine groups, make polymer a unique polymer for oral drug delivery applications. Nasal drug delivery The nasal mucosa presents an ideal site for bioadhesive drug delivery systems. Polymer based drug delivery systems, such as micro spheres, liposomes and gels have been demonstrated to have good bioadhesive characteristics and swell easily when in contact with the nasal mucosa increasing the bioavailability and residence time of the drugs to the nasal route. Various polymer salts such as chitosan lactate, chitosan aspartate, chitosan glutamate and chitosan hydrochloride are good candidates for nasal sustained release of vancomycin hydrochloride. Buccal drug delivery Polymer is an excellent polymer to be used for buccal delivery because it has muco/bioadhesive properties and can act as an absorption enhancer. Buccal tablets basedon chitosan microspheres contain chlorhexidine diacetate gives prolonged release of the drug in the buccal cavity improving the antimicrobial activity of the drug. polymer microparticles with no drug incorporated have antimicrobial activity due to the polymer. The buccal bilayered devices (bilaminated films, palavered tablets) using a mixture of drugs (nifedipine and propranolol hydrochloride) and chitosan, with or without anionic crosslinking polymers (polycarbophil, sodium alginate, gellan gum) has promising potential for use in controlled delivery in the oral cavity. Gastrointestinal drug delivery Polymer granules having internal cavities prepared by de acidification when added to acidic and neutral media are found buoyant and provided a controlled release of the drug prednisolone. Floating hollow microcapsules of melatonin showed gastroretentive controlledrelease delivery system. Release of the drug from these microcapsules is greatly retarded with release lasting for 1.75 to 6.7 hours in simulated gastric fluid. Most of the mucoadhesive microcapsules are retained in the stomach for more than 10 hours e.g., Metoclopramide and glipizide loaded chitosan microspheres. Peroral drug delivery As polymer and most of its derivatives has a mucoadhesive property, a presystemic metabolism of peptides can be strongly reduced leading to a strongly improved

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bioavailability of many perorally given peptide drugs, such as insulin, calcitonin, and buserelin. Unmodified chitosan has a permeation-enhancing effect for peptide drugs. Vaginal drug delivery Polymer, modified by the introduction of thioglycolic acid to the primary amino groups of the polymer, embeds clotrimazole, an imidazole derivative, is widely used for the treatment of mycotic infections of the genitourinary tract.

Transdermal drug delivery Polymer has good film-forming properties. The drug release from the devices is affected by the membrane thickness and cross-linking of the film. Chitosan-alginate polyelectrolyte complex has been prepared in-situ in beads and microspheres for potential applications in packaging, controlled release systems and wound dressings. Colonic drug delivery Polymer has been used for the specific delivery of insulin to the colon. The chitosan capsules were coated with enteric coating (Hydroxy propyl methyl cellulose phthalate) and contained, apart from insulin, various additional absorption enhancer and enzyme inhibitor. It was found that capsules specifically disintegrated in the colonic region. It was suggested that this disintegration was due to either the lower pH in the ascending colon as compared to the terminal ileum or to the presence bacterial enzyme, which can degrade the polymer.[1] Diagnostic uses of radioactive microspheres Gated blood pool study Thrombus imaging in deep vein thrombosis Blood flow measurements Investigation of biodistribution and fate of (drug-loaded) microspheres Lung scintigraphy Diagnostic radioembolization Liver and spleen imaging Bone marrow imaging Infection localization Tumor imaging www.wjpps.com 143

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Gastrointestinal transit studies Local restenosis prevention in coronary arteries [10] Magnetically targeted drug delivery systems In targeted drug delivery, drugs are directed to cells that need therapy or repair, such as in cancer treatment. Effective treatments of cancer involve either surgery, radiation, immunotherapy, chemotherapy or a combination of these choices. Tumour targeting, Magnetic delivery of chemotherapeutic drugs to liver tumors, Locoregional Cancer Treatment with Magnetic Drug Targeting, Magnetically induced Hyperthermia for treatment of cancer, Magnetic targeting of radioactivity [2] REFERENCES 1 Kataria Sahil, Middha Akanksha, Sandhu Premjeet, Ajay Bilandi And Bhawana Kapoor Microsphere: A Review International Journal Of Research In Pharmacy And Chemistry 2011;1(4):1184-1198. 2 Salim Md,Shukla V.K., Bhardwaj V., Garg V.K., And Sharma P.K. Magnetic Microspheres As A Magnetically Targeted Drug Delivery System Journal Of Global Pharma Technology 2010;2(3): 36-46. 3 Tadwee Kayyum Abdul Imran, Shahi Sadhana, M. Thube, S Ankit, Review On Microspheres, International Journal Of Pharmaceutical Research & Allied

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