MICROSPHERE AS DRUG CARRIER: A REVIEW

ABOUT AUTHORS:
Madhuri D. Ghadage*¹, Gajanan H. Banapure^2
1Department of Pharmaceutics, SMBT College of Pharmacy, Dhamangaon, Nashik
²H. R. Patel Institute of Pharmaceutical Education and Research, Shirpur Dhule
*maadhuri.ghadge@gmail.com

ABSTRACT
The controlled release of drugs in slow and sustained manner is one of the major challenges in drug delivery system. Targeting of drug to the particular site is an important aspect of drug delivery system. Carrier technology offers an intelligent approach for drug delivery by coupling the drug to a carrier particle such as microsphere which modulates the release and absorption characteristics of the drug. These delivery systems offer numerous advantages over the conventional dosage forms including improved efficacy, reduced toxicity, and improved patient compliance. Microspheres received much attention not only for prolonged release, but also for targeting of anticancer drugs. In future microspheres will find the central place in novel drug delivery, particularly in diseased cell sorting, diagnostics, genetic materials, targeted and effective drug delivery. The current aim of this review is to study various aspects of the microparticulates drug delivery system including method of formulation, evaluation & characterization.

REFERENCE ID: PHARMATUTOR-ART-1799

INTRODUCTION
The development of new delivery systems for the controlled release of drugs is one of the most interesting fields of research in pharmaceutical sciences. A well designed controlled drug delivery system can overcome some of the problems of conventional therapy and enhance the therapeutic efficacy of a given drug. To obtain maximum therapeutic efficacy, it becomes necessary to deliver the agent to the target tissue in the optimal amount in the right period of time there by causing little toxicity and minimal side effects. There are various approaches in delivering a therapeutic substance to the target site in a sustained controlled release fashion. The process of targeting and site specific delivery with absolute accuracy can be achieved by attaching bioactive molecule to liposome, bioerodible polymer, implants, monoclonal antibodies and various particulate. One such approach is using microspheres as carriers for drugs. Microsphere can be used for the controlled release of drugs, vaccines, antibiotics, and hormones. For example, by taking advantage of the characteristics of microspheres, beyond the basic benefits, the microspheres could provide a larger surface area and possess an easier estimation of diffusion and mass transfer behavior.

Microspheres are defined as “Monolithic sphere or therapeutic agent distributed throughout the matrix either as a molecular dispersion of particles” (or) can be defined as structure made up of continuous phase of one or more miscible polymers in which drug particles are dispersed at the molecular or macroscopic level. Microspheres are small spherical particles, with diameters in the micrometer range (typically 1 μm to 1000 μm). Microspheres are sometimes referred to as microparticles. Biodegradable synthetic polymers and modified natural products such as starches, gums, proteins, fats and waxes. The natural polymers include albumin and gelatin, the synthetic polymer include poly lactic acid and polyglycolic acid. The solvents used to dissolve the polymeric materials chosen according to the polymer and drug solubility and stabilities, process safety and economic considerations.^{1, 2}

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. Polyethyleneandpolystyrenemicrospheres are two most common types of polymer microspheres. Polystyrenemicrospheresare typically used in biomedical applications due to their ability to facilitate procedures such as cell sorting and immune precipitation. Proteins and ligands adsorbed onto polystyrene readily and permanently, which makes polystyrene microspheres suitable for medicalresearch and biological laboratory experiments. Polyethylenemicrospheresare 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 coloured and fluorescent microspheres, makes them highly desirable for flow visualization and fluid flow analysis, microscopy techniques, health sciences, process trouble shooting and numerous research applications. Glassmicrospheresare primarily used as a filler and volumizer for weight reduction, retro-reflector for highway safety, additive for cosmetics and adhesives, with limited applications in medical technology. Ceramicmicrospheresare used primarily as grinding media. Microspheres vary widely in quality, sphericity, uniformity, and particle size and particle size distribution. The appropriate microsphere needs to be chosen for each unique application.

Materials used⁴
Microspheres used usually are polymers. They are classified into two types.
1. Synthetic Polymers
2. Natural polymers

Synthetic polymers are divided into two types.

i. Non-biodegradable polymers

• Poly methyl methacrylate (PMMA)
  
• Acrolein
  
• Glycidyl methacrylate
  
• Epoxy polymers
  

ii. Biodegradable polymers^{3, 4}

• Lactides, Glycolides & their co polymers
  
• Poly alkyl cyano Acrylates
  
• Poly anhydrides
  

Natural polymers obtained from different sources like proteins, carbohydrates and chemically modified carbohydrates.^{6, 10}

A] Proteins:

• Albumin
  
• Gelatin⁷
  
• Collagen
  

B] Carbohydrates:

• Agarose
  
• Carrageenan
  
• Chitosan⁹
  
• Starch
  

C] Chemically modified carbohydrates:

• Poly dextran
  
• Poly starch.
  

TYPES OF MICROSPHERE^{11, 12, 13}
1. Bioadhesive microspheres^14,15,16
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.

2. Magnetic microspheres¹⁷
This kind of delivery system is very much important which localizes 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 types are therapeutic magnetic microspheres and diagnostic microspheres.

i. Therapeutic magnetic microspheres
It is used to deliver chemotherapeutic agent to liver tumor. Drugs like proteins and peptides can also be targeted through this system.

ii. Diagnostic microspheres
It can be used for imaging liver metastases and also can be used to distinguish bowel loops from other abdominal structures by forming nano size particles supramagnetic iron oxides.

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3. Floating microspheres^18,19
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 gastric content and 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.

4. Polymeric microspheres²⁰
The different types of polymeric microspheres can be classified as follows and they are biodegradable polymeric microspheres and synthetic polymeric microspheres.

i. Biodegradable polymeric microspheres²¹
Natural polymers such as starch are used with the concept that they are biodegradable, biocompatible, and also bioadhesive 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.

ii. 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. But the main disadvantage of these kinds of microspheres, are tend to migrate away from injection site and lead to potential risk, embolism and further organ damage.

ADVANTAGES²²
1. Microspheres provide constant and prolonged therapeutic effect.
Reduces the dosing frequency and thereby improve the patient compliance.
3. They could be injected into the body due to the spherical shape and smaller size.
4. Better drug utilization will improve the bioavailability and reduce the incidence or intensity of adverse effects.
5. Microsphere morphology all ows a controllable variability in degradation and drug release.

LIMITATION²²
Some of the disadvantages were found to be as follows
1. The modified release from the formulations.
2. The release rate of the controlled release dosage form may vary from a variety of factors like food and the rate of transit though gut.
3. Differences in the release rate from one dose to another.
4. Controlled release formulations generally contarin a higher drug load and thus any loss of integrity of the release characteristics of the dosage form may lead to potential toxicity.
5. Dosage forms of this kind should not be crushed or chewed.

METHOD OF PREPARATION^{22, 23}
1. Solvent evaporation method,
· Single emulsion technique
· Double emulsion technique.
2. Emulsion cross linking method
3. Coacervation phase separation method.
4. Spray drying and spray congealing method.
5. Solvent extraction method
6. Ionic gelation method
7. Polymerization method.

1. Solvent Evaporation Method^{24, 25}
· 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 glutaraldehyde, formaldehyde, terephthalate chloride, diacidchloride, etc. Crosslinking by heat is affected 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.

· 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.(Examples: hydrophilic drugs like LHRH agonist, vaccines.

2. Emulsion cross linking method¹³
In this method drug was dissolved in aqueous gelatin solution which was previously heated for 1 hr at 40⁰C. The solution was added drop wise to liquid paraffin while stirring the mixture at 1500 rpm for 10 min at 35⁰C, results in w/o emulsion then further stirring is done for 10 min at 15⁰C. Thus the produced microspheres were washed respectively three times with acetone and isopropyl alcohol which then air dried and dispersed in 5mL of aqueous glutaraldehyde saturated toluene solution at room temperature for 3 hrs for cross linking and then was treated with 100mL of 10mm glyciene solution containing 0.1%w/v of tween 80 at 37⁰C for 10 min to block unreacted glutaraldehyde.

3. Coacervation phase separation method²⁶
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 the polymer solution itself, if hydrophobic. Phase separation is then accomplished by changing the solution conditions.

4. Spray drying and spray congealing^27,28
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 as dichloromethane, 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 μm. 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 mononitrat and sulphaethylthiadizole 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.

5. Solvent extraction
Solvent evaporation method is used for the preparation of microparticles, involves removal of the organic phase by extraction of the organic solvent. The method involves water miscible organic solvents such as isopropanol. Organic phase is removed by extraction with water. This process decreases the hardening time for the microspheres. One variation of the process involves direct addition of the drug or protein to polymer organic solution. The rate of solvent removal by extraction method depends on the temperature of water, ratio of emulsion volume to the water and the solubility profile of the polymer.

6. Ionic gelation method^29,30
Ionotropic gelation is based on the ability of polyelectrolytes to cross link in the presence of counter ions to form hydrogels. Since, the use of alginates, gellan gum, chitosan, and pectin for the encapsulation of drug. These anions forms meshwork structure by combining with the polyvalent cations and induce gelation by binding mainly to the anion blocks. The hydrogel beads are produced by dropping a drug-loaded polymeric solution into the aqueous solution of polyvalent cations. The cations diffuses into the drug-loaded polymeric drops, forming a three dimensional lattice of ionically crossed linked moiety.

Loading of drug³¹
The active components are loaded over the microsphere principally using two methods, i.e. during the preparation of the microsphere or after the formation of the microsphere by incubating them with drug/ protein. The active components can be loaded by means of the physical entrapment, chemical linkage and surface adsorption. The entrapment largely depends on the method of preparation and nature of the drug or polymer. Maximum loading can be achieved by incorporating drug during the time of preparation but it may get affected by many other process variables such as method of preparation, presence of additives (e.g. cross linking agent, surfactant stabilizers, etc.) heat of polymerization, agitation intensity, etc.

The loading is carried out in pre-formed microspheres by incubating them with high concentration of the drug in a suitable solvent. The drug in these microsphere is loaded via penetration or diffusion of the through the pores in the microsphere as well as adsorption on their surface. The solvent is then removed, leaving drug-loaded microsphere.

Drug release kinetics^{32, 33}
Release of the active constituent is an important consideration in case of microspheres. The release profile from the microspheres depends on the nature of the polymer used in the preparation as well as on the nature of the active drug. Much theoretically possible mechanism may be considered for the release of drug from the microparticulates.
1. Liberation due to polymer erosion or degradation,
2. Self diffusion through the pore,
3. Release from the surface of the polymer,
4. Pulsed delivery initiated by the application of an oscillation or sonic field.

The release of drug from both biodegradable as well as non-biodegradable microsphere(s) is influenced by structure or micro-morphology of the carrier and the properties of the polymer itself. The drugs could be released through the microspheres by any of the three methods, first is the osmotically driven burst mechanism, second by pore diffusion mechanism, and third by erosion or the degradation of the polymer. In osmotically driven burst mechanism, water diffuse into the core through biodegradable or non-biodegradable coating, creating sufficient pressure that ruptures the membrane. The burst effect is mainly controlled by three factors the macromolecule/polymer ratio, particle size of the dispersed macromolecule and the particle size of the microspheres. The pore diffusion method is named so because as penetrating water front continue to diffuse towards the core. The polymer erosion, i.e. loss of polymer is accompanied by accumulation of the monomer in the release medium. The erosion of the polymer begins with the changes in the microstructure of the carrier as water penetrates within it leading to the plasticization of the matrix. Drug release from the non-biodegradable type of polymers can be understood by considering the geometry of the carrier. The geometry of the carrier, i.e. whether it is reservoir type where the drug is present as core, or matrix type in which drug is dispersed throughout the carrier, governs overall release profile of the drug or active ingredients.

CHARECTERIZATION/ EVALUATION OF MICROSPHERES^{34,35,36,37,38}
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.

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 surface degradation of the biodegradable microspheres.

Attenuated total reflectance Fourier Transfom-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 behavior or ion absorption nature of the microspheres.

Entrapment Efficiency³⁹
The entrapment 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.

Encapsulation efficiency was calculated using the following formula,

E = Qp / Qt X 100

Where,
E = percentage of encapsulation of microspheres
Qp = quantity of drug encapsulated in microspheres
Qt = quantity of the drug added for encapsulation

Angle of repose
Angle of repose was determined by using funnel method. The accurately weighed microspheres were taken in a funnel and then height of funnel was adjusted in such as way that the tip of funnel just touches the apex of heap of blends. The blends were allowed to flow through funnel freely on to surface. The diameter of powder cone was measured and angle of repose was calculated by using following equation.
tanθ = h/r

Where
θ - Angle of repose,
h - Height of pile,
r - Radius of base.

X-ray diffraction
Change in crystallinity of drug can be determined by this technique. Microparticles and its individual components were analysed by the help of D & discover (Bruker, Germany). Scanning range angle between 8 ⁰C - 70 ⁰C.Scan speed – 4 ⁰/min
Scintillation detector
Primary silt=1mm
Secondary silt=0.6 mm.

Thermal analysis
Thermal analysis of microcapsule and its component can be done by using-

Differential scanning calorimetry (DSC) Thermo gravimetric analysis (TGA)

Differential thermometric analysis (DTA) Accurately the sample was weighed and heated on alumina pan at constant rate of 10⁰ C/min under nitrogen flow of 40 ml/min.

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UV-FTTR (Fourier transform infra red)
The drug polymer interaction and also degradation of drug while processing for microencapsulation can be determined by FTIR.

Stability studies
By placing the microspheres in screw capped glass container and stored them at following conditions:
1. Ambient humid condition
2. Room temperature (27±2⁰C)
3. Oven temperature (40±2⁰C)
4. Refrigerator (5 ⁰C -8⁰C).

It was carried out of a 60 days and the drug content of the microsphere was analyzed.

Zeta potential
The polyelectrolyte shell was prepared by incorporating chitosan of different molecular weight into the W2 phase and the resulting particles were determined by zeta potential measurement.

Invitromethods^{40, 41, 42}
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 invitroand invivotechniques have been reported. Invitrodrug release studies have been employed as a quality control procedure in pharmaceutical production, in product development etc. Sensitive and reproducible release data derived from physicochemically and hydro dynamically defined conditions are necessary. The influence of technologically defined conditions and difficulty in simulating invivoconditions has led to development of a number of invitrorelease methods for buccal formulations; however no standard invitro 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
Standard USP or BP dissolution apparatus have been used to study invitrorelease profiles using rotating elements, paddle and basket. Dissolution medium used for the study varied from 100-500 ml and speed of rotation from 50-100 rpm.

Invivomethods⁴³
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 penetrate 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 invivostudies 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 invivo (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 multicomponent 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.

Invitro-Invivocorrelations
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 “invitro-invivocorrelations”. Such correlations allow one to develop product specifications with bioavailability.

APPLICATION
1.      Microspheres in vaccine delivery^44,45
The prerequisite of a vaccine is protection against the micro organism or its toxic product. An ideal vaccine must fulfill the requirement of efficacy, safety, convenience in application and cost. The aspect of safety and minimization of adverse reaction is a complex issue. The aspect of safety and the degree of the production of antibody responses are closely related to mode of application. Biodegradable delivery systems for vaccines that are given by parenteral route may overcome the shortcoming of the conventional vaccines49. The interest in parenteral (subcutaneous, intramuscular, intradermal) carrier lies since they offer specific advantages including:

• Improved antigenicity by adjuvant action
  
• Modulation of antigen release
  
• Stabilization of antigen.
  

2.      Targeting using microparticulate carriers^46,47
The concept of targeting, i.e. site specific drug delivery is a well established dogma, which is gaining full attention. The therapeutic efficacy of the drug relies on its access and specific interaction with its candidate receptors. The ability to leave the pool in reproducible, efficient and specific manner is center to drug action mediated by use of a carrier system. Placement of the particles indiscrete anatomical compartment leads to their retention either because of the physical properties of the environment or biophysical interaction of the particles with the cellular content of the target tissue.

3. Monoclonal antibodies mediated microspheres targeting⁴⁸
Monoclonal antibodies targeting microspheres are immune microspheres. This targeting is a method used to achieve selective targeting to the specific sites. Monoclonal antibodies are extremely specific molecules. This extreme specificity of monoclonal antibodies (Mabs) can be utilized to target microspheres loaded bioactive molecules to selected sites. Mabs can be directly attached to the microspheres by means of covalent coupling. The free aldehyde groups, amino groups or hydroxyl groups on the surface of the microspheres can be linked to the antibodies. The Mabs can be attached to microspheres by any of the following methods
1. Non specific adsorption
2. Specific adsorption
3. Direct coupling
4. Coupling via reagents

4.      Imaging
The microspheres have been extensively studied and used for the targeting purposes. Various cells, cell lines, tissues and organs can be imaged using radio labelled microspheres. The particle size range of microspheres is an important factor in determining the imaging of particular sites. The particles injected intravenously apart from the portal vein will become entrapped in the capillary bed of the lungs. This phenomenon is exploited for the scintigraphic imaging of the tumour masses in lungs using labeled human serum albumin microspheres.

5. Topical porous microspheres^49,50
Microsponges are porous microspheres having myriad of interconnected voids of particle size range 5-300 μm. These microsponges having capacity to entrap wide range of active ingredients such as emollients, fragrances, essential oils etc., are used as the topical carries system further, these porous microspheres with active ingredients can be incorporated into formulations such as creams, lotions and powders. Microsponges consist of non collapsible structures with porous surface through which active ingredients are released in a controlled manner.

6. Surface modified microspheres⁵¹
Different approaches have been utilized to change the surface properties of carriers to protect them against phagocytic clearance and to alter their body distribution patterns .The adsorption of the poloxamer on the surface of the polystyrene, polyester or poly methyl methacrylate microspheres renders them more hydrophilic and hence decrease their MPS uptake. Protein microspheres covalently modified by PEG derivatives show decreased immunogenicity and clearance. The most studied surface modifiers are:
1. Antibodies and their fragments

2. Proteins

3. Mono- oligo- and polysaccharides

4. Chelating compounds (EDTA, DTPA or Desferroxamine)

5. Synthetic soluble polymers such modifications are provided surface of microspheres in order to achieve the targeting to the discrete organs and to avoid rapid clearance from the body.

6. Microspheres for DNA Delivery^52,53
Microspheres have been recently used as a delivery vehicle for the transfer of plasmid DNA which leads to improve the transfer of plasmid DNA and their stability in the bio- environment. Truong-Le & Co workers (1998) developed a novel system for gene delivery based on the use of DNA-gelatin microspheres/ nanoparticles formed by salt induced complex coacervation of gelatin & plasmid DNA as shown in table

7. Microspheres for Lymph targeting⁵⁴
The major purpose of lymph targeting is to provide an effective anticancer chemotherapy to prevent the metastasis of tumor cells by accumulating the drug in the regional lymph node. Example:

• Poly alkyl cyanoacrylate microspheres bearing anticancer drugs for tumor of peritoneal cavity.
  
• Poly (lactide-co-glycolide) microspheres for the lymphatic of diagnostic agents.
  

Pharmaceutical Applications In Drug Delivery System
1. Ophthalmic Drug Delivery⁵⁵
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.

2. Gene delivery⁵⁶
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.

3. Oral drug delivery⁵⁷
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 the primary amine groups, make polymer a unique polymer for oral drug delivery applications.

4. Nasal drug delivery⁵⁸
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.

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5. Gastrointestinal drug delivery⁵⁹
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 controlled release 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.

6. Vaginal drug delivery⁶⁰
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.

7. Transdermal drug delivery⁶¹
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.

8. Colonic drug delivery^{62, 63}
Polymer has been used for the specific delivery of insulin to the colon. The chitosan capsules were coated with enteric coating (Hydroxyl 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.

CONCLUSION
It has been observed that microspheres are better choice of drug delivery system than many other types of drug delivery system because it is having the advantage of target specificity and better patient compliance. Its applications are enormous as they are not only used for delivering drugs but also for imaging tumors, detecting bimolecular interaction etc. In future by combining various other strategies, microspheres will find the central place in novel drug delivery.

REFERENCES
1.Chein YW. Oral Drug Delivery Systems: In Novel drug delivery systems. Vol.50, Marcel Dekker, Inc., New York. 139- 177(1992).
2.Jain NK. Controlled and Novel drug delivery, 4th Edition, CBS Publishers New Delhi, India; 236-237.
3.K. Lalla and K. Sapna, Biodegradable microspheres of poly(dl-lactic acid) containing piroxicam as a model drug for controlled release via the parenteral route. J. Microencapsul, 10(4): 449–460, (1993).
4.P.M. Dandagi, VS. Mastiholimath, M.B. Patil, M.K. Gupta, Biodegradable microparticulate system of captopril. International Journal of Pharmaceutics, 307: 83-88, (2006).
5.Chinna Gangadhar B, Shyam Sunder R., Vimal Kumar Varma. M., Sleeva Raju M., Sai Kiran M, Formulation and Evaluation of Indomethacin Microspheres using natural and synthetic polymers as Controlled Release Dosage Forms. International Journal of Drug Discovery, 2(1): 8-16, (2010).
6.Rana mazumder, lila K. Nath, Anwarul, Haque, Tarasankar Maity, Prasant K. Choudhary, Bhupendra Shreshta, Formulation and in vitro evaluation of natural polymers based microsphere for colonic drug delivery, International journal of pharmacy and pharmaceutical sciences, 2(1): 211-219, (2010).
7.Kavitha K, Chintagunta Pavanveena, Anil Kumar S. N., Tamizh Mani T, Formulation and evaluation of trimetazine hydrochloride loaded gelatin microsphere. International Journal of Pharmacy and Pharmaceutical Sciences, 2(3):67-70, (2010).
8.Lorenzo-Lamosa ML. Design of microencapsulated chitosan microspheres for colon drug delivery. J Control Release , 52(1- 2): 109-118, (1998).
9.Sudha Mani T and Naveen Kumar K, At preparation and evaluation of ethyl cellulose microspheres of ibuprofen for sustained drug delivery. International Journal Of Pharma Research And Development, 2(8):120-121, (2010).
10.Bunty Chanu Irom, K. Kavitha, M. Rupeshkumar1, SD. Jagadeesh Singh, Natural Polymeric Microsphere for Drug Delivery: A Review. International Journal Of Pharmaceutical Research And Development, 4(07):31-37, (2012).
11.Imran Abdul Kayyum Tadwee*, Sadhana Shahi, M. Thube, Ankit S. Review on Microspheres. International Journal of Pharmaceutical Research Allied Sciences, 1(1):24-33, (2012).
12.Saravana Kumar K., Jayachandra Reddy P., Chandra Sekhar K.B., A Review on Microsphere for Novel drug delivery System. Journal of Pharmacy Research, 5(1):420-424, (2012).
13.Kataria Sahil, Middha Akanksha, Sandhu Premjeet, Ajay Bilandi and Bhawana Kapoor, Microsphere: A Review, International Journal of Research In Pharmacy and Chemistry, 1(4):1184-1198, (2011).
14.Sipai Altaf Bhai. M. Vandana yadav, Mamatha. Y, Prasanth V. V., Mucoadhesive Microsphere An overview. American journal of Pharmtech Research, 2(1):237-258, (2012).
15.Shiv Shankar Hardenia, Ankit Jian, Ritesh Patel, Anu Kaushal, Formulation and evaluation of mucoadhesive microsphere of ciprofloxacin. Journal of Advanced Pharmacy Education and research,1(4): 214-224, (2011).
16.Nalini M. Anandea, Sunil K. Jain a,∗, Narendra K. Jain, Con-A conjugated mucoadhesive microspheres for the colonic delivery of diloxanide furoate. International Journal of Pharmaceutics, 359:182-189, (2008).
17.Guojun Liu, Husheng Yang, Jiayun Zhou, Preparation of magnetic microsphere from water-in-oil emulsion stabilized by block copolymer dispersant,. Biomacromolecules , 6:1280-1288, (2005).
18.P. Dutta, J.Struti, Ch. Niranajan patra, M.E. Bhaoji rao, Floating Microsphere: Recents Trends in the Development of Gastroretentive Floating Drug Delivery System. International Journal of Pharmaceutical Science and nanotechnology, 4(1):1293-1306, (2011).
19.Y. Kawashima, T. Niwa, H. Takeuchi, T. Hino, Y. Ito, Preparation of multiple unit hollow microspheres (microbal loons) with acrylic resin containing tranilast and their drug release characteristics (in vitro) and floating behavior (in vivo). J. Control. Release, 16:279-290, (1991).
20.Alexander K. Andrianov, Lendon G. Payne, Polymeric carriers for oral uptake of microparticulates. Advanced Drug Delivery Reviews, 34:155-170, (1998).
21.I. Genta , P. Perugini , F. Pavanetto , K. Maculotti , T. Modena , B. Casado , A. Lupib, P. Iadarolab, B. Contia Enzyme loaded biodegradable microspheres in vitro ex vivo evaluation. Journal of Controlled Release 77: 287-295, (2001).
22.Vyas SP, Khar RK. Targeted and Controlled drug delivery., 7th Edition; Vallabh Prakashan, New Delhi India , 420-445.
23.Ming Li, Olivier Rouaud, Denis Poncelet, Microencapsulation by solvent evaporation: State of the art for process engineering approach. International Journal of Pharmaceutics, 363:26-39, (2008).
24.P.B. O’Donnell and J.W. Mc Ginity. Preparation of microspheres by the solvent evaporation technique. Adv. Drug Del. Rev, 28:25-42, (1997).
25.Piush Khare and Sanjay K. Jain, Influence of Rheology of Dispersion Media in the Preparation of Polymeric Microspheres through Emulsification Method. AAPS PharmSciTech. 10(4):1295-1300, (2009).
26.Aristi R., Bachtsi, Costas Kiparissides, Synthesis and release studies of oil-containing poly (vinyl alcohol) microsphere prepared by coacervation,. Journal of Controlled release, 38:49-58, (1995).
27.P. He, S.S. Davis, and L. Illum. Chitosan microspheres prepared by spray drying. Int J Pharma, 187:53–65, (1999).
28.Chang-Moon Lee, Dong-moon kim, Hyun-Chul Lee, ki- Young Lee, pectin Microsphere for Oral Colon Delivery: Preparation Using Spray Drying method and Vitro Release of Indomethacin. Biotechnology and Bioprocess Engineering, 9:191-195, (2004).
29.Amit k. Pandey, Niharika Choudhary, Vineet K. Rai, Harinath Driwedi, Koshy M. Kymanil, Shubhini A. Saraf, Fabrication and evaluation of tinidazole microbeads for colon targeting. Asian Pacific Journal of tropical disease, s197-s201, (2012).
30.Singh Ajay, Kumar pradeep, malik Anuj, Bharali Kumar Rajib, M.d. Alam-imtiyaz, Design, development and in vitro evaluation of metadoxine microbeads: ionic gelation method, The Pharma Research, 5(1):62-69, (2011).
31.Forni F, Vandelli MA, Cameroni R. Influence of drug loading level on drug release and dynamic swelling of crosslinked gelatin microspheres. J Microencapsul , 29–39, (1992).
32.T.W. Wong, H.Y. Lee, L.W. Chan, P.W.S. Heng Drug release properties of pectinate microspheres prepared by emulsification method. International Journal of Pharmaceutics , 242:233–237, (2002).
33.I. ORIENTI, K. AIEDEH, E. GIANASI, V. BERTASI and V. Zecchit, Indomethacin loaded chitosan microspheres. Correlation between the erosion process and release kinetics. J. Microencapsul, 13(4), 463-472, (1996).
34.Gheorghe Fundueanu a, Elisabetta Esposito b, Doina Mihai a, Adrian Carpov a, Jacques Desbrieres c, Marguerite Rinaudo c, Claudio Nastruzzi , Preparation and characterization of Ca-alginate microspheres by a new emulsification method, International Journal of Pharmaceutics, 170:11-21, (1998).
35.Alagusundaram M, Madhu Sudana chetty, and Umashankar C. Microspheres as a Novel drug delivery system. International J of chem. Tech res, 526-534, (2009).
36.Bozdag, S. Calis, H.S. Kas, M.T. Ercan, I. Peksoy, and A.A. Kincal. In vitro evaluation and intra-articular administration of biodegradable microspheres containing naproxen sodium. J. Microencap, 18(4):443-456, (2001).
37.Parmar Harshad, Bakliwal, Different Method Of Evaluation Of Mucoadhesive Microsphere. International Journal of Applied Biology and Pharmaceutical Technology, 1(3):1164-1165, (2010).
38.Harshad Parmar, Sunil Bakliwal, Nayan Gujarathi, Bhushan Rane, Sunil Pawar, Different methods of formulation of evaluation of mucoadhesive microsphere. International Journal of Applied Biology and Pharmaceutical Technology, 1(3):1157-1167, (2010).
39.Atmaram Pawar, Anil, R. Gadhe, Prabakaran Venkatachalam, Praveen Sher, Kakasaheb R. Mahadik, Effect of core and surface cross linking on the entrapment of metronidazole in pectin beads. Acta Pharma, 58:75-85, (2005).
40.S.Y. Lin, K.S. Chen, H.H. Teng, M.J. Li, In vitro degradation and dissolution behaviours of microspheres prepared by three low molecular weight polyesters. J. Microencapsul, 17(5):577-586, (2000).
41.Jat RC1, Jain Suman, Dubey Subodh, Jain Vinay, Bhardwaj Sudhir, Jain Amit, Preparation and evaluation of colon targeting microspheres. Journal of Pharmacy Research, 3(3):596-599, (2010).
42.S.K. Mehta, Gurpreet Kuar, Anil Verma, Fabrication of plant protein microsphere for encapsulation, stabilization and in vitro release of multiple anti-tuberculosis drugs. Colloids and surfaces A: Physicochemical and Engineering Aspects, 375:219-230 (2011).
43.Hitendra S. Mahajan ?, Bhushankumar V. Tatiya, Pankaj P. Nerkar, Ondansetron loaded pectin based microspheres for nasal administration: In vitro and in vivo studies. Powder Technology, 221:168–176, (2012).
44.Saravana Kumar A, NM Ramaswamy, Chitosan microsphere as potential vaccine delivery systems. International Journal of drug delivery, 3(1):43-50, (2011).
45.A Saravanakumar, Sunita Minz, Madhulika Pradhan, Pavani Sure, Atul N Chandu, Umesh Mishra, Polylactic Acid microsphere as a potential vaccine delivery system for the Tetanus toxoid: preparation and in vitro dissolution study. Research j Pharm and tech, 1(4):453-459, (2008).
46.Libo yang, james S. Chu, Joseph A. Fix, Colon-specific drug delivery: new approaches and in vitro/in vivo evaluation. International journal of Pharmaceutics, 235:1-15, (2002).
47.Alf Lamprecht, Hiromitsu Yamamoto, Hirofumi Takeuchi, Yoshiaki Kawashima, Microsphere design for the colonic delivery of 5-fluorouracil. Journal of Controlled Release, 90:313–322, (2003).
48.Illum L, Jones PD, Attachment of monoclonal antibodies to microspheres. Methods Enzymol, 112:67-84, (1985).
49.Kirti Deshmukh, Solid porous microsphere: emerging trend in pharmaceutical technology, International journal of pharma and biosciences, 2(1):364-377, (2011).
50.Wester RC, Patel R, Nacht S, Leyden J, Melendres J, Maibach H., Controlled release of benzoyl peroxide from a porous microsphere polymeric system can reduce topical irritancy. J Am Acad Dermatol, 1991, 24(5.1):720-726, (199