The method by which a drug is delivered can have a significant effect on its efficacy. Some drugs have an optimum concentration range within which maximum benefit is derived, and concentrations above or below this range can be toxic or do not produce therapeutic benefit at all. On the other hand, the very slow progress in the efficacy of the treatment of severe diseases, has suggested a growing need for a multidisciplinary approach to the delivery of therapeutics to targets in tissues. From this, new ideas on controlling the pharmacokinetics, pharmacodynamics, non-specific toxicity, immunogenicity, biorecognition, and efficacy of drugs were generated. These new strategies of drug delivery systems (DDS) are based on interdisciplinary approaches that combine polymer science, pharmaceutics, bioconjugate chemistry, and molecular biology.
To minimize drug degradation and loss, to prevent harmful side-effects and to increase drug bioavailability and the fraction of the drug accumulated in the required zone, various drug delivery and drug targeting systems are currently under development. Among drug carriers one can name soluble polymers, microparticles made of insoluble or biodegradable natural and synthetic polymers, microcapsules, cells, cell ghosts, lipoproteins, liposomes, and micelles. The carriers can be made slowly degradable, stimuli-reactive (e.g., pH- or temperature-sensitive), and even targeted (e.g., by conjugating them with specific antibodies against certain characteristic components of the area of interest).
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Controlled drug release and subsequent biodegradation are important for developing successful formulations. Potential release mechanisms involve:
Desorption of surface-bound /adsorbed drugs
Diffusion through the carrier matrix
Diffusion through the carrier wall (nanocapsule)
Carrier matrix erosion
A combined erosion /diffusion process
The mode of delivery can be the difference between a drug's success and failure, as the choice of a drug is often influenced by the way the medicine is administered. Sustained (or continuous) release of a drug involves polymers that release the drug at a controlled rate due to diffusion out of the polymer or by degradation of the polymer over time. Pulsatile release is often the preferred method of drug delivery, as it closely mimics the way by which the body naturally produces hormones such as insulin. It is achieved by using drug-carrying polymers that respond to specific stimuli (e.g., exposure to light, changes in pH or temperature).
There are various departments of medicine like cancer, pulmonary, cardiology, radiology, gynecology, and oncology etc., numerous drugs are used and they are delivered by various types of drug delivery system. 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 one of the important aspect of drug delivery system. Microparticles have been proven to be useful in this manner for the delivery of various active pharmaceutical ingredients.
Microparticulate drug delivery system is one of the processes to provide the sustained and controlled delivery of drug to long period of time. They are small particles of solid or small droplets of liquids surrounded by walls of natural and synthetic polymer films of varying thickness and degree of permeability acting as a release rate controlling substance. These microparticles have a diameter upto the range of 0.1 Âµm to 200 Âµm . Microparticles have a much larger surface-to-volume ratio than at the macroscale, and thus their behavior can be quite different. Within the broad category of microparticles, "microspheres" specifically refers to spherical microparticles and the subcategory of "micro-capsules" applies to microparticles which have a core surrounded by a material which is distinctly different from that of the core. The core may be solid, liquid, or even gas [2-4].
Despite the specific and logical subcategories, many researchers use the terms interchangeably, which often leads to the confusion of the reader. It is usually assumed that a formulation described as a microsphere is comprised of a fairly homogeneous mixture of polymer and active agent, whereas microcapsules have at least one discrete domain of active agent and sometimes more. Some variations on microparticle structures are given in figure 1:
Initially, use of albumin microspheres in DDS was suggested by Kramer (1974). Java Krishna and Catha(1997) proposed the use of microspheres as sustained release vehicles. There are also reports about using hemoglobin as natural biodegradable carriers for drugs for microparticulate administration . Microparticles have been proved to be an ideal way of preparing sustained and controlled release dosage forms. They are also a beneficial way of delivering APIs which are pharmacologically active but are difficult to deliver due to limited solubility in water. In such drugs the attainment of high Cmax, Tmax, and area under the curve is problematic. Microsphere based formulations can be formulated to provide a constant drug concentration in the blood or to target drugs to specific cells or organs  .
2. ADVANTAGES OF MICROSPHERES:
Always on Time
Marked to Standard
Recently, controlled release has become a very useful tool in pharmaceutical area, offering a wide range of actual and perceived advantages to the chronic diseases such as rheumatoid arthritis, osteoarthritis, and musculoskeletal disorders including degenerative joint conditions still demand long-term therapy. With the advent of Microparticles following advantages were noted in the dosage forms:
Effective delivery of agents which are insoluble or sparingly soluble in water.
The system provides the way for improving taste of an active agent.
It increases the relative bioavailability of drugs.
The formulation also provides targeting the drug to specific sites.
It reduces the dosage frequency and toxicity.
Microparticles can be used as carrier for drugs and vaccines and diagnostic agents.
They can also be used to produce amorphous drugs with desirable physical properties.
They also cause reduced local side effects.
Eg. GI irritation of drugs on oral ingestion.
They provide the sustained release formulation with lower dose of drug to maintain plasma concentration and improved patient compliance.
The pH triggered microparticles are used in immunization, transfection and gene therapy.
Parentral microparticles have the advantage of administering high concentration of water soluble drugs without severe osmotic effects at site of administration.
They also have an advantage of being stored in dry particle or suspension form with little or no loss of activity over an extended storage period.
They are useful in administration of effervescent dosage form of medicaments to individual unable to chew.
Eg. Debilitated patients having difficulty in swallowing solids and the elderly .
3. FORMULATION OF MICROSPHERE:
The coating material can be selected from a wide variety of natural and synthetic polymers depending on the core material to be encapsulated and the desired characteristics. The amount of coating material used ranges from 3% to 30% of the total weight, which corresponds to a dry film thickness of less than 1-200Âµm, depending on the surface to be coated.
Hydrophilic colloids: These are large molecules that are soluble or dispersible in aqueous solutions. Some examples of natural and synthetic hydrophilic colloids [10, 11, 12] are:
Agar acrylic polymers
Poly acryl methacrylate
Poly hydroxyl butyrate-co-valerate)
Cellulose acetate phthalate
Hydroxyl propyl cellulose
Hydroxyl propyl methyl cellulose
Hydroxyl propyl methyl cellulose phthalate
Sodium carboxy methyl cellulose
Poly dimethyl slioxin
Here the capsule wall presents a good barrier to oily and hydrophobic materials, but it is usually a poor barrier to hydrophilic substances.
Hydrophobic colloids: are required for the encapsulation of lipophobic drugs which need to cross the lipid barriers.
Soluble starch and its derivatives including amylodextrin, amylopectin and carboxy methyl starch are used as wall forming material in solid microsphere preparation.
Biocompatible colloids: Some examples biocompatible colloids are :
Poly ortho esters
PLGA is a water-insoluble polymer; strength, hydrophobicity, and pliability are the significant physical advantages . As a polymeric vehicle, biocompatibility, biodegradability, predictability of degradation, ease of fabrication and regulatory approval are features that make PLGA desirable for medical applications [14-17].
Bioavailability enhancers: Some examples are lysophatide, lysophosphatidyl choline.
Permeability modifier and membrane fluidity modifier: These include enamines like phenyl alanine enamine. Malonates like diethylene ox methylene malonate, salicylates, bile salts, fusidates etc.
Techniques of microsphere preparation:
Techniques of microsphere preparation
eg. In-situ polymerization
eg. Meltable dispersion
eg. pan coating
Chemical processes include the interfacial and in situ polymerization methods.
Physiochemical processes include phase separation- coacervation, complex emulsion, meltable dispersion and powder bed methods.
Mechanical processes include the air-suspension method, pan coating, and spray drying, spray congealing, micro-orifice system and rotary fluidization bed granulator method. Spheronization is sometimes included under the mechanical process[18, 19, 20].
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When preparing controlled release microspheres, the choice of optimal method has utmost importance for the efficient entrapment of the active substance. Various pharmaceutically acceptable techniques for the preparation of microparticles have been given. Some of the methods include:
Emulsion-solvent evaporation (o/w, w/o, w/o/w)
Phase separation (non solvent addition and solvent partitioning)
Superficial antisolvent precipitation technique
pH triggered microparticle
Condensed phase microparticles
Hydroxyl appetite (HAP) microspheres in sphere morphology
3.2.1. Emulsion-solvent evaporation:
The solvent evaporation method involves the emulsification of an organic solvent (usually methylene chloride) containing dissolved polymer and dissolved/dispersed
drug in an excess amount of aqueous continuous phase, with the aid of an agitator. The schematic
representation is given in Fig. 2.
The concentration of the emulsifier present in the aqueous phase affects the particle size and shape.
When the desired emulsion droplet size is formed, the stirring rate is reduced and evaporation of the organic solvent is realized under atmospheric or reduced pressure at an appropriate temperature. Subsequent evaporation of the dispersed phase solvent yields solid polymeric microparticles entrapping the drug. The solid microparticles are recovered from the suspension by filtration, centrifugation, or lyophilization .
Single-Emulsion Solvent Evaporation:
For emulsion solvent evaporation, there are basically two systems from which to choose: oil-in-water (o/w) or water-in-oil (w/o). Oil-in- water emulsion was [22, 23] to encapsulate progesterone. Afterward lipid-soluble drugs such as steroids , local anesthetics, bleomycin sulfate, doxorubicin, chlorpromazine, naltrexone, promethazine, were encapsulated successfully. In general, solvent evaporation method is particularly suitable for the microencapsulation of lipophilic drugs that can be either dispersed or dissolved in the dispersed phase of a volatile solvent. Sansdrap and Moes suggested that in order to obtain batches of microspheres with reproducible sizes, manufacturing factors such as emulsifier concentration, stirring rate, and organic phase volume should be under control.
Multiple-Emulsion Technique (w/o/w):
Multiple-emulsion or double-emulsion technique is appropriate for the efficient incorporation of watersoluble peptides, proteins, and other macromolecules . This method allows the encapsulation of water-soluble drugs with an external aqueous phase when compared to nonaqueous methods as the o/o solvent evaporation or organic phase separation. In brief, the polymers are dissolved in an organic solvent and emulsified into an aqueous drug solution to form a w/o emulsion. This primary emulsion is reemulsified into an aqueous solution containing an emulsifier to produce multiple w/o/w dispersion. The organic phase acts as a barrier between the two aqueous compartments, preventing the diffusion of the active material toward the external aqueous phase.
Microspheres manufactured by the (w/o/w method exhibit various morphologies such as porous or
nonporous external polymer shell layers  enclosing hollow, macro porous, or micro porous internal structures, depending on different parameters.
3.2.2. Phase Separation-Coacervation:
The term coacervation was suggested for the first time by two Dutch scientists . The word coacervation comes from the latin acervus, meaning aggregation, and the prefix co, signifying the preceding union of the colloidal particles. In this process, both the drug and the polymer should be insoluble in water, while a water-immiscible solvent is required for the polymer. A schematic representation of o/w emulsification- solvent evaporation technique is shown in Fig. 3.
Problems relating to the efficient incorporation of water-soluble active substances into biodegradable polymer matrices using simple o/w emulsification with solvent evaporation are originating to a great extent from the separation and/or removal of water-soluble material into the aqueous continuous phase . Using this method microparticle can be prepared using following steps with continuous with continued agitation:
1. The first step consists of formation of three immiscible chemical phases. In this the core material is dispersed in solution of coating polymer, the solvent for polymer being liquid manufacturing vehicle phase.
2. The second step consists of deposition of coating polymer on core material & absorption at interphase between core material & liquid vehicle phase.
3. And the final step comprises of rigidising the coating by thermal, cross linking or desolvation techniques to form microparticles. Phase separation-Coacervation can be obtained by temperature change, nonsolvent or salt addition, incompatible polymer addition, and polymer-polymer interaction. Drugs belonging to different pharmacological groups have been encapsulated. Antibiotics, Anti-inflammatory agents, analgesics, and antihypertensive are some of these groups.
Phase Separation- Coacervation
Simple Coacervation : Simple coacervation can be accomplished by the addition of chemical
compounds with a high affinity for water, such as salts and alcohols. In principle, simple coacervation can be brought about in any aqueous polymer solution when temperature, pH, solvent, and salt are properly chosen. This process depends primarily on the degree of hydration produced. The added substances cause two phases to be formed, one rich in colloid droplets and the other poor. Its principal requirement is the creation of an insufficiency of water in a part of the total system. Figure illustrates the preparation of microcapsules by simple Coacervation. The microencapsulation process can be explained by the following steps :
1. Dispersion of the core material in an aqueous solution of the polymer
2. Creation of insufficiency of water for the hydrophilic colloid and the deposition of the coacervate around the core
3. Gelation of the coacervate and hardening of the microcapsules
Complex Coacervation: This technique of complex coacervation was first described by Phares
and Sperandio . It involves neutralization of the charges on the colloids and depends primarily on pH. This is accomplished by mixing two colloids of opposite charges together. The encapsulation process in complex coacervation consists of four steps:
1. Preparation of a hydrophilic colloid solution
2. Addition of a second hydrophilic colloid solution of opposite charge to induce coacervation
3. Deposition around the core
4. Gelation of the coacervate and hardening of the microcapsules.
Organic Phase Separation Methods: Organic phase separation is the inverse of the aqueous phase separation process in that the wall-containing phase is hydrophobic in nature and the core material is water miscible. The principle is to enclose water-soluble material with a polymeric wall material in an organic solvent by adding a nonsolvent or a second polymeric material to induce phase separation. A schematic representation is given in Fig. 4.
3.2.3. Interfacial Polymerization Method:
Interfacial polymerization technique is one in which two monomers, one oil-soluble and the other water-soluble, are employed and a polymer is formed on the droplet surface. The method involve the reaction of monomeric units located at the interface existing between a core material substance & a continuous phase in which the core material is dispersed.
3.2.4. Spray drying:
Spray drying is used to protect sensitive substances from oxidation based on the atomization of a solution by compressed air and drying across a current of warm air . Microparticle formulation by spray drying is conducted by dispersing a core material in a coating solution, in which the coating substance is dissolved & in which the core material is insoluble, & then by atomizing the mixture into an air stream. The heated air causes removal of solvent from the coating solution thus causing formation of the microcapsule.
3.2.5. Gelatin Dispersion:
This is a specific embodiment of a more general approach in which the polymer filaments or monomer subunits used in forming the microparticles are mixed with a suspension of proteins, such as agar, gelatin, or albumin . One method employs alginate plus Ca +2 in producing the particles. The mixture is then dispersed under conditions effective to produce desired sized particles containing the mixture components. In the case of gelatin containing particles, the mixture may be cooled during the dispersion process to produce gelled particles having a desired size. The particles are then treated under polymerization and/or cross linking conditions, preferably under conditions that do not also lead to cross linking of gelatin molecules to the polymer structure. After microparticle formation, the gelatin molecules may be removed from the structure, with such in a decondensed form, e.g., by heating the material or enzymatic digestion.
3.2.6. Superficial antisolvent precipitation technique:
This technique is useful if the drug is insoluble in gas & gas is soluble in liquid. The drug is dissolved in polymeric solution of suitable solvent. Then the application of an antisolvent decreases the solubility of material the dissolved in solution leading to microparticle beads formation.
3.2.7. pH-triggered microparticle:
Microparticles that are designed to release their payload when exposed to acidic conditions are provided as a vehicle for drug delivery. Any therapeutic, diagnostic or prophylactic agent may be encapsulated in a lipid-protein-sugar or polymer matrix with a PH- triggering agent to form microparticles. Preferably the diameter of the pH triggered microparticles ranges from 50 nm to 10 micrometers. The matrix of the particles may be prepared using any known lipid (e.g., DPPC), protein (e.g., albumin), or sugar (e.g., lactose). The matrix of the particles may also be prepared using any synthetic polymers such as polyesters. The process of formulation include providing an agent & contacting with a PH triggering agent & component selected from lipid, proteins, sugars & spray drying th resultant mixture to create microparticles. Typically, the pH triggering agent is a chemical compound including polymers with a pKa less than 7. PH triggering agent used is poly (butyl methacrylateco-(2-dimethyl amino ethyl) methacrylate-co-methyl methacrylate) (1:2:1) i.e. Eudragit 110. The PH triggered microparticles release the encapsulated agent when exposed to an acidic environment such as in phagosome or endosome of a cell that has taken up particles thereby allowing for efficient delivery of agent intracellularly.
3.2.8. Condensed phase microparticles:
They are an alternative method for storing & administration of drugs at high concentration in condensed phase with sizes ranging between 0.05-50 microns. They consists of- - matrix of cross linked polyionic polymer filaments capable of swelling from a condensed phase to an expanded, decondensed phase or state, when the matrix is exposed to monovalent counter ions. - small molecules entrapped in microparticle matrix, with such in its condensed phase. - Polyvalent counter ions effective to retard the release of small molecules from the micro particles, when exposed to monovalent counter ions. The composition is useful in delivery of vehicle for reagents is unstable on storage, or where it is desirable to introduce reagent at a selected step in reaction The method of preparation include infusing the compound into polymer suspended in a decondensed phase typically containing 10-200 millimole concentration of monovalent counter ions leading to hydration & increase in size. After compound infusion into open particle matrices, multivalent counter ion mainly Calcium ion is added to fully condense the microparticle. This technique is used for small, water soluble drug molecules. They are having advantages that high concentration of water soluble rugs can be administered without severe osmotic effect at site of administration thus they are essentially nonosmotic until they decompose & release drug.
3.2.9. Hydroxyl appetite (HAP) microspheres in sphere morphology:
This was used to prepare microspheres with peculiar spheres in sphere morphology microspheres were prepared by o/w emulsion followed by solvent evaporation. At first o/w emulsion was prepared by dispersing the organic phase (Diclofenac sodium containing 5% w/w of EVA and appropriate amount of HAP) in aqueous phase of surfactant. The organic phase was dispersed in the form of tiny droplets which were surrounded by surfactant molecules this prevented the droplets from co solvencing and helped them to stay individual droplets .While stirring the DCM was slowly evaporated and the droplets solidify individual to become microspheres .
3.3.Mechanism and kinetics of drug release:
Major mechanisms of drug release from microspheres include diffusion, dissolution, osmosis and erosion.
Diffusion is the most commonly involved mechanism wherein the dissolution fluid penetrates the shell, dissolves the core and leak out through the interstitial channels or pores. Thus, the overall release depends on,
(a) The rate at which dissolution fluid penetrates the wall of microcapsules,
(b) the rate at which drug dissolves in the dissolution fluid, and
(c) the rate at which the dissolved drug leak out and disperse from the surface. The kinetics of such drug release obeys Higuchi's equation as below [28,29,30]:
Q = [D/J (2A - Îµ Cs) Cs t] Â½
Q is the amount of drug released per unit area of exposed surface in time t;
D is the diffusion coefficient of the solute in the solution;
A is the total amount of drug per unit volume;
CS is the solubility of drug in permeating dissolution fluid;
Îµ is the porosity of the wall of microcapsule;
J is the tortuosity of the capillary system in the wall.
The above equation can be simplified to
Q = vt
v is the apparent release rate.
Dissolution rate of polymer coat determines the release rate of drug from the microcapsule when the coat is soluble in the dissolution fluid. Thickness of coat and its solubility in the dissolution fluid influence the release rate [29, 31].
The polymer coat of microcapsule acts as semi permeable membrane and allows the creation of an osmotic pressure difference between the inside and the outside of the microcapsule and drives drug solution out of the microcapsule through small pores in the coat .
Erosion of coat due to pH and/or enzymatic hydrolysis causes drug release with certain coat materials like glyceryl monostearate, bee's wax and stearyl alcohol [29, 32].
Attempts to model drug release from microcapsules have become complicated due to great diversity in physical forms of microcapsules with regard to size, shape and arrangement of the core and coat materials.
The physiochemical properties of core materials such as solubility, diffusibility and partition coefficient, and of coating materials such as variable thickness, porosity, and inertness also makes modeling of drug release difficult.
However, based on various studies concerning the release characteristics, the following generalizations can be made:
Drug release rate from microcapsules conforming to reservoir type is of zero order.
Microcapsules of monolithic type and containing dissolved drug have release rates that are t1/2 dependant for the first half of the total drug release and thereafter decline exponentially.
However, if a monolithic microcapsule containing large excess of dissolved drug, the release rate is essentially t1/2 dependant throughout almost the entire drug release.
In monolithic capsules the path traveled by drug is not constant; the drug at the center travels a large distance than the drug at the surface. Therefore, the release rate generally decreases with time.
3.4. Factors affecting drug release rates:
The microsphere fabrication method is a governing factor in the encapsulation and release of therapeutics. In addition, a complicated array of factors including the type of polymer, the polymer molecular weight, the copolymer composition, the nature of any excipients added to the microsphere formulation (e.g., for stabilization of the therapeutics), and the microsphere size can have a strong impact on the delivery rates.
First, the type of polymer used in microsphere fabrication and the way in which the polymer degrades obviously affect drug release rates. Depending on the rate of hydrolysis of their functional groups, polymers can be broadly categorized into two types: surface eroding and bulk-eroding .
Bulk-eroding polymers, such as PLG, readily allow permeation of water into the polymer matrix and degrade throughout the microsphere matrix. In contrast, surface-eroding polymers, such as polyanhydrides, are composed of relatively hydrophobic monomers linked by labile bonds. In this way, they are able to resist the penetration of water into the polymer bulk, while degrading quickly into oligomers and monomers at the polymer/water interface via hydrolysis. Bulk-eroding polymer microspheres are often characterized by a "burst" of drug-as much as 50% of the total drug load released during the first few hours of incubation, followed by a slow, diffusion-controlled release and sometimes a third phase in which the remaining drug is released quickly as a result of severe degradation of the polymer matrix. In microspheres composed of surface-eroding polymers, drug is released primarily at the surface as the polymer breaks down around it. Erosion of such polymers usually proceeds at a constant velocity. If the drug of interest is homogeneously dispersed throughout a microsphere, the largest rate of release will occur at the beginning [35, 36]. As time proceeds, the surface area of the sphere and the release rate decrease asymptotically.
Polymer molecular weight can affect polymer degradation and drug release rates. As one might expect, an increase in molecular weight decreases diffusivity and therefore drug release rate . In addition, a major mechanism for release of many drugs is diffusion through water-filled pores, formed as polymer degradation generates soluble monomers and oligomers that can diffuse out of the particle. These small products are formed more quickly upon degradation of lower molecular weight polymers. The decrease in release rates with increasing polymer molecular weight appears to hold for small molecules, peptides, and proteins. However, molecular weight typically has little effect on release rates from surface-eroding polyanhydride microspheres.
The co-monomer ratios in many copolymers can also affect release rates. Most often, increasing the content of the more rapidly degrading monomer increases the release rate. Similarly, when drug release is controlled by polymer erosion, release rate typically increases with higher concentration of the smaller and/or more soluble monomer . However, the effect of the copolymer composition can be complicated by differences in the polymer phase behavior or the thermodynamics of the encapsulated drug.
A variety of excipients may be added to microsphere formulations to stabilize the drug during fabrication and/or release and may impact drug release through several different mechanisms [35,37]. For example, to improve the encapsulation of bovine serum albumin (BSA) in microspheres of poly(Îµ-caprolactone) (PCL) and 65:35 PLG,Yang et al. included poly(vinyl alcohol) (PVA) in the BSA solution to stabilize the primary emulsion resulting in a more uniform BSA distribution in the microspheres . Increasing concentrations of PVA decreased the initial burst of protein and the overall release rates. Jain et al. encapsulated myoglobin in PLG microspheres in the presence of a stabilizer, mannitol . They report that mannitol increased the release rate and the final amount of drug released by increasing the initial porosity of the PLG matrix, leading to faster formation of the pore network within the sphere due to polymer erosion.
Clearly, microsphere size will strongly affect the rate of drug release. As size decreases, the surface area-to-volume ratio of the particle increases. Thus, for a given rate of drug diffusion through the microsphere, the rate of flux of drug out of the microsphere, per mass of formulation, will increase with decreasing particle size. In addition, water penetration into smaller particles may be quicker due to the shorter distance from the surface to the center of the particle. Also, while the decrease in surface area with particle size may lead to decreased rate of erosion of poorly water-permeable polymers like polyanhydrides, because surface area-to-volume ratio increases with decreasing particle size, drug release rates (per mass of polymer) will be faster for smaller polyanhydride microspheres.
4. TYPES OF MICROSPHERES:
4.1. 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.
4.2. 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[24,25]. The different types 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.
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 particles supramagnetic iron oxides.
4.3. 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 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. Drug (ketoprofen) given through this form .
4.4. Radioactive microspheres:
Radio emobilisation therapy microspheres sized 10-30 nm are of larger than capillaries and gets tapped in first capillary bed when they comeacross. 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 Î± emitters, Î² emitters, Î³ emitters .
4.5. Polymeric microspheres:
The diffent types of polymeric microspheres can be classified as follows:
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 biocompatibl. But the main disadvantage of these kind of microspheres, are tend to migrate away from injection site and lead to potential risk, embolism and further organ damage .
5. EVALUATION OF MICROPARTICLES:
The various evaluation techniques for microparticle preparation are as follows[38, 39]:
1. Particle shape & size determination. It can be done by microscopy, sieve analysis, laser light scattering, coulter counter method, photon correlation spectroscopy.
Crystallinity can be evaluated by differential scanning calorimetery analysis.
Shape & surface morphology can be studied by freeze fracture microscopy & freezes etch electron microscopy.
Laser diffractometer & light microscope is also used to measure the size range of the
Size analysis of all the batches of prepared microparticles can be carried out using a set of standard sieves ranging from 10-100 meshes. The microparticles are passed through the set of sieves and the amount retained on each sieve is weighed. The arithmetic average diameter is determined by dividing the total weight size by 100.
2. Bulk & tap density of microparticles is also evaluated. Porosity, specific area can also be evaluated by Mercury or Helium intrusion potensiometry. Flow properties of microparticles can be evaluated by determining the angle of repose by fixed funnel & free standing cone method & the compressibility index by tapped density method.
3. The Thermal Properties are detected by:
Differential Scanning Calorimetry Thermo gravimetric analysis.
In Differential scanning calorimetry or DSC the amount of heat required to increase the temperature of a sample and reference is measured as a function of temperature. Both the sample and reference are maintained at nearly the same temperature throughout the experiment. Generally, the temperature program for a DSC analysis is designed such that the sample holder temperature increases linearly as a function of time. The reference sample should have a well-defined heat capacity over the range of temperatures to be scanned.
Thermogravimetric analysis or thermal gravimetric analysis (TGA) is a type of testing that is performed on samples to determine changes in weight in relation to change in temperature. Analysis is carried out by raising the temperature gradually and plotting weight (percentage) against temperature. The temperature in many testing methods routinely reaches 1000Â°C or greater, but the oven is so greatly insulated that an operator would not be aware of any change in temperature even if standing directly in front of the device. After the data are obtained, curve smoothing and other operations may be done such as to find the exact points of inflection.
4. Electrostatic interaction is detected by rheological & FTIR assays (Fourier Transform Infra red
spectroscopy) using potassium bromide pellets.
5. Peptide entrapment & entrapment efficacy can be evaluated by HPLC.
6. APPLICATIONS OF MICROSPHERES:
Some of the applications of microspheres can be described in detail as given below [40, 41]:
Prolonged release dosage forms. The microencapsulated drug can be administered, as microencapsulation is perhaps most useful for the preparation of tablets, capsules or parenteral dosage forms.
Microspheres can be used to prepare enteric-coated dosage forms, so that the medicament will be selectively absorbed in the intestine rather than the stomach.
It can be used to mask the taste of bitter drugs.
From the mechanical point of view, microencapsulation has been used to aid in the addition of oily medicines to tableted dosage forms. This has been used to overcome problems inherent in producing tablets from otherwise tacky granulations and in direct compression to tablets.
It has been used to protect drugs from environmental hazards such as humidity, light, oxygen or heat. Microsphere does not yet provide a perfect barrier for materials, which degrade in the presence of oxygen, moisture or heat, however a great degree of protection against these elements can be provided.
The separations of incompatible substances, for example, pharmaceutical eutectics have been achieved by encapsulation. This is a case where direct contact of materials brings about liquid formation. The stability enhancement of incompatible aspirin- chlorpheniramine maleate mixture was accomplished by micro-encapsulating both of them before mixing.
Microspheres can be used to decrease the volatility. An encapsulated volatile substance can be stored for longer times without substantial evaporation.
Microencapsulation has also been used to decrease potential danger of handling of toxic or noxious substances. The toxicity occurred due to handling of fumigants, herbicides, insecticides and pesticides have been advantageously decreased after microencapsulation.
The hygroscopic properties of many core materials may be reduced by microencapsulation.
Many drugs have been microencapsulated to reduce gastric irritation.
Microencapsulation method has also been proposed to prepare intrauterine contraceptive device.
In the fabrication of multilayered tablet formulations for controlled release of medicament contained in medial layers of tableted particles.
7. RECENT ADVANCES:
The preparation method determines the type and the size of microparticle and influence the ability of the interaction among the components used in microparticle formulations. Microparticles-containing drugs are employed for various purposes including -but not restricted to- controlled drug delivery, masking the taste and odor of drugs, protection of the drugs from degradation, and protection of the body from the toxic effects of the drugs. Polymeric carriers being essentially multi-disciplinary are commonly utilized in microparticle fabrication and they can be of an erodible or a non-erodible type.
The use of various gel forming proteins (collagen and gelatin) and polysaccharides (agar, calcium alginate, and carrageenan) introduced a milder, biocompatable immobilization or isolation system. Obeidat and Price  employed a one step method for the preparation of microspheres having enteric and controlled release characteristics in one embodiment and swelling and controlled properties in another using the nonaqueous solvent evaporation method. Microspheres were especially useful for delivery of moderately non-polar active ingredients but can be formulated to deliver very soluble polar compounds.
Wen and Anderson prepared double wall microspheres using two biodegradable polymers by the o/w emulsification solvent extraction process. Futo et al.used a relatively large molecular weight (11,000 to about 27,000) lactic acid polymer or its salt to produce microspheres with prolonged release over a long period of time with a suppressed initial excessive release of a watersoluble LHRH derivative via single or double emulsion.
Rickey et al. provided a novel method for the preparation of biodegradable and biocompatible microparticles containing a biologically active agent such as risperidone, or testosterone dissolved in a blend of at least two substantially non-toxic solvents, free of halogenated hydrocarbons such as benzyl alcohol and ethyl acetate. The blend was dispersed in an aqueous solution to form droplets. The resulting emulsion was then added to an aqueous extraction medium. One of the solvents in the solvent blend would be extracted in the quench step (aqueous solution) more quickly than the other solvent. Owing to the high boiling point of the left solvent (benzyl alcohol) which is not easily removed by evaporation in air or other conventional evaporative means, some of the more rapidly extracted solvent can be added to the quench extraction medium prior to addition of the emulsion. Thus, when the emulsion is added to the quench liquid, extraction of the more rapidly extracted solvent is retarded and more of the second, more slowly extracted solvent is removed. A method for encapsulating vitamins, food supplements, oil soluble substances at high loading (70 wt %) by the solvent o/w emulsion extraction technique is provided by Kvitnitsky et al. Since evaporating the solvent from the dispersion is not applicable for delicate and sensitive compounds and it is not effective, because diffusion of solvent through a hard polymer wall is very slow, water at 10-30 times higher than the whole quantity of the organic solvent is added to the emulsion for extracting the solvent .
Encapsulation of nucleotides and growth hormone using simple or double emulsification methods was achieved by Johnson et al.respectively. Similar to synthetic polymers, such as poly (lactic acid) or polyorthoesters, proteins have also been used to form microparticles or microspheres for drug delivery. Most are cross-linked in solution using glutaraldehyde, or hardened at elevated temperatures. Unfortunately, there are problems with significant loss of biological activity of incorporated materials and lack of controlled size and in vivo degradation rates .
Microfabricated system offers potential advantages over conventional drug delivery systems. Microspheres and microcapsules are established as unique carrier systems for many pharmaceuticals and can be tailored to adhere to targeted tissue systems. Hence, micro-capsules and microspheres can be used not only for controlled release but also for targeted delivery of drugs to a specific site in the body. Although significant advances have been made in the field of microencapsulation, there are still many challenges ahead in this field. Of particular importance are the development of cheaper biopolymers for the microencapsulation technology and the development of universally acceptable evaluation methods especially for bioadhesive microspheres. Therefore, the development of safe and efficient particular systems will require, in the future, indepth investigations of both the biological and technological aspects of these systems.