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MICROPARTICLES: AN APPROACH FOR BETTERMENT OF DRUG DELIVERY SYSTEM Abhay N. Padalkar1*, Sadhana R.Shahi1, Mahesh W. Thube1
1

Abhay Padalkar

Government College of Pharmacy, Aurangabad-431005, M.S, India Email:abhaypadalkar1@gmail.com

ABSTRACT Recent drug discovery using advanced techniques such as genomics, combinatorial chemistry, high throughput screening and in silico three dimensional drug design has yielded drug candidates with low water solubility and thus an inherently low mucosal permeability which makes the development of pharmaceutical formulations difficult. To overcome these, particulate systems like microparticles have been used as a physical approach to alter and improve the pharmacokinetic and pharmacodynamics properties of various types of drug molecules. They have been used in vivo to protect the drug entity in the systemic circulation, restrict access of the drug to the chosen sites and to deliver the drug at a controlled and sustained rate to the site of action. Various polymers have been used in the formulation of microparticles for drug delivery research to increase therapeutic benefit, while minimizing side effects. The review embraces various aspects of microparticle formulations, characterization, effect of their characteristics and their applications in delivery of drug molecules and therapeutic genes.

Key Words: microparticles, absorption, low solubility INTRODUCTION Microparticles are defined as particulate dispersions or solid particles with a size in the range of 1-1000 m. The drug is dissolved, entrapped, encapsulated or attached to a microparticle matrix. Depending upon the method of preparation, microparticles, microspheres or microcapsules can be obtained. Microcapsules are systems in which the drug is confined to a cavity surrounded by a unique polymer membrane, while microspheres are matrix systems in which the drug is physically and uniformly dispersed. In recent years, biodegradable polymeric microparticles, particularly those coated with hydrophilic polymer such as poly (ethylene glycol) (PEG) known as long-circulating particles, have been used as potential drug delivery devices because

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of their ability to circulate for a prolonged period time target a particular organ, as carriers of DNA in gene therapy, and their ability to deliver proteins, peptides and genes1-3. Microparticles offers easy administration to deliver macromolecules by a variety of routes and effectively control the release of drugs over the periods ranging from few hours to months, because of effective protection of encapsulated drug against degradation (e.g. enzymatic)4. Controlled drug delivery systems could be extremely useful in providing the optimal therapy for a given drug molecule. Each drug has a characteristic minimum effective concentration, below which no therapeutic effect is observed and a characteristic minimum toxic concentration above which undesired side effects occur (as shown in Figure 1). The range in between is called the therapeutic range or therapeutic window. (Refer Fig. No. 01) Depending upon the type of drug and physiological factors, this therapeutic window could be narrow. The optimum effect of many medical treatments is obtained by maintaining the drug concentration in the therapeutic range over a sustained period of time. This is especially true for highly potent drugs, such as anti-cancer drugs. Administration of the entire drug dose at once using conventional pharmaceutical dosage (e.g. tablets, bolus injection), the whole amount is rapidly released into the stomach, absorbed into the blood stream and distributed throughout the human body. As a result, the rate at which the drug reaches its site of action is often high. Depending on the therapeutic range and administered dose, the risk of toxic side effects can be considerable. As no continuous drug supply is provided and as the human body eliminates the active agent, the concentration decreases again. The result is a fluctuating

concentration of the drug levels in the plasma and the therapeutic range is attained during only very short time periods. The idea behind a controlled drug delivery system is to incorporate the drug within a polymeric carrier that controls the release rate of the drug. Various processes, such as diffusion, erosion, and/or swelling can be involved in the control of the overall drug release rate, resulting in a broad spectrum of possible release profiles. For example, a continuous drug supply can be provided, compensating for the clearance of the drug from the human body, thus resulting in constant drug concentration at the site of action over a prolonged period. The present review details the latest development of microparticulate drug delivery systems, surface modification issues, drug loading strategies, release control and potential applications of microparticles. The advantages of using microparticulate drug delivery system include following, 1. Particle size and surface characteristics of microparticles can be easily manipulated to achieve both passive and active drug targeting after parenteral administration. 2. They control and sustain release of the drug during the transportation and at the site of localization, altering organ distribution of the drug and subsequent clearance of the drug so as to achieve increase in drug therapeutic efficacy and reduction in side effects. 3. Controlled release and particle degradation characteristics can be readily modulated by the choice of matrix constituents. Drug loading is relatively high and drugs can be incorporated into the systems without any chemical reaction; this is an important factor for preserving the drug activity.

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4. Site-specific targeting can be achieved by attaching targeting ligands to surface of particles or use of magnetic guidance. 5. The system can be used for various routes of administration including oral, nasal, parenteral, intra-ocular etc. In spite of these advantages, microparticles do have limitations. For example, their small size and large surface area can lead to particle aggregation, making physical handling of microparticles difficult in liquid and dry forms. In addition, small particles size and large surface area readily result in limited drug loading and burst release. These practical problems have to be overcome before microparticles can be used clinically or made commercially available. Fabrication of microparticles Within the broad category of micro particles (Figure 2), microspheres specifically refer to spherical microparticles and microcapsules 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. A microparticle usually refers to a homogeneous mixture of the polymer and active agent, whereas microcapsules have at least one discrete domain of active agent. (Refer Fig. No. 02) A number of techniques to fabricated drugloaded biodegradable Poly (lactide-coglycolide) microdevices have been reported5. The method employed to encapsulate the drug in the polymeric device must meet the following requirements6: I. The stability and biological activity of the drug must not be affected by the processing parameters employed in the fabrication of drug-loaded microparticles.

The yield of microparticles should have the desired size range and the drug encapsulation efficiency should be high III. The particle quality and the drug release profile should be reproducible. 1) Solvent evaporation and extraction based processes i) Single emulsion process: The process involves oil-in-water (o/w) emulsification. The o/w emulsion system consists of an organic phase comprised of a volatile solvent with dissolved polymer and the drug to be encapsulated, emulsified in an aqueous phase containing a dissolved surfactant. A surfactant is included in the aqueous phase to prevent the organic droplets from coalescing once they are formed. The polymer-solventdrug solution is emulsified (with appropriate stirring and temperature conditions) to yield an o/w emulsion. The emulsionis created by using a propeller or magnetic bar for mixing the organic and aqueous phases. As seen in the figure 3, surfactants are used to stabilize the dispersed phase droplets formed during emulsification and inhibit coalescence. Surfactants are amphipathic in nature and will align themselves at the droplet surface promoting stability by lowering the free energy at the interface between the two phases. The surfactant also confers resistance to coalescence and microsphere flocculation. PVA is one of the widely used surfactants for producing the microparticles. Once the emulsion is formed, it is subjected to solvent removal by either evaporation or extraction process to solidify the polymer droplets. In the case of solvent removal by evaporation, the emulsion is maintained at a reduced pressure or at atmospheric pressure and the stir rate is reduced to enable the volatile

II.

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solvent to evaporate. The organic solvent leaches out of the droplet into the external aqueous phase before evaporating at the water air interface. In the case of extraction, the emulsion is transferred to a large quantity of water or other quench medium, into which the solvent associated with the oil droplets is diffused out. The rate of solvent removal by extraction depends on the temperature of quench medium, ratio of the emulsion volume to quench medium and the solubility characteristics of the polymer, the solvent and the dispersion medium. A high extraction result will result in formation of particles with a high porosity that could lead to undesirable drugrelease profiles7, 8. The solvent removal method by extraction is faster (generally <30 minutes) than the evaporation process and hence the microspheres made by this method are often more porous in comparison to those made by solvent evaporation method. (Refer Fig. No. 01) One of the disadvantages of the o/w emulsification process is the poor encapsulation efficiency with moderately water-soluble drugs. The drug diffuses out or partitions from the dispersed oil phase into the aqueous continuous phase and microcrystalline fragments of the hydrophilic drugs get deposited on to the microsphere surface9 and dispersed in the polymer matrix. The result in poor trapping of the hydrophilic drug and initial rapid release of the drug (burst effect)6. The oil/water emulsification process is thus widely used to encapsulate lipid-soluble drugs. In order to increase the encapsulation efficiency of water soluble drugs, an oil-in-oil emulsion method was developed10. In this method, the drug may be dissolved or suspended in the oil phase before being dispersed in another oil phase. A watermiscible organic solvent like acetonitrile is employed to solubilise the drug in which Polymer is also soluble. The solution is then dispersed in oil such as light mineral oil in the

presence of an oil soluble surfactant like sorbitan oleate (Span) to yield the o/o emulsion. Microparticles are finally obtained by evaporation or extraction of the organic solvent from the dispersed oil droplets and the oil is washed off by solvents like n-hexane6. ii) Double emulsion process: A double emulsion process is usually employed for drugs not soluble in an organic solvent. A solid-in-oil-in-water emulsion (s/o/w) process could be used to encapsulate a drug provided its form is of small size. The size of the drug crystal should be at least an order of magnitude smaller than the desired microparticle diameter in order to avoid large bursts associated with dissolution of larger crystals. Smaller crystals will be homogeneously distributed throughout the organic droplets created in emulsion. Hydrophilic drugs (cisplatin, doxorubicin) have been encapsulated using this method. The problem with encapsulating hydrophilic drugs is the loss of drug to the external aqueous phase during the formation of the microparticle. Along with the loss of drug to the external phase, the remaining drug may migrate to the surface of the droplet before solidifying. To minimize these problems, the organic droplets should be solidified into microparticles as quickly as possible following their formation11. This is achieved by using a viscous organic solution of polymer and drug and a large secondary volume of water that attracts the organic solvent into the aqueous phase immediately, thus leaving the microparticle with the encapsulated drug. The viscous dispersed phase minimizes the volume of organic solvent, facilitating its quick removal from the droplet and also makes it more difficult for the solid drug particles/crystal to migrate to its surface, resulting in a more homogeneous distribution of the drug within the particle.

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Another alternative to encapsulate hydrophilic drugs is to employ the water-in-oil-in water (w/o/w) emulsion process (Figure 4). An aqueous solution of the drug is added to an organic phase consisting of the polymer and organic solvent with vigorous stirring to form the first w/o emulsion. The emulsion is then dispersed in another aqueous phase containing more surfactant to form the w/o/w emulsion. A number of hydrophilic drugs like the peptide leuprolide acetate, a luteinizing hormonereleasing hormone agonist12, 13 vaccines14, 15, proteins/peptides16, 17, 18 and conventional molecules19, 20 have been successfully encapsulated by this method. The problem with this type of emulsion occurs when the inner emulsion is not sufficiently stabilized, resulting in loss of aqueous droplets containing drug to the external aqueous phase. The choice of surfactants that can be used to stabilize the inner emulsion is limited to materials that will dissolve in the organic solvent. Typically, the fatty acid esters of polyoxyethylene or sorbitan are used due to their high solubility in organic solvents and good biocompatibility.(Refer Fig. No. 04) 2) Phase separation: The process consists of decreasing the solubility of the encapsulating polymer by addition of a third component to the polymer solution 21, 6. The process yields two liquid phases: the polymer containing coacervate phase and the supernatant phase depleted in polymer. The drug which is dispersed /dissolved in the polymer solution is coated by the coacervate. Thus the coacervation process consists of the following three steps: i) phase separation of the coating polymer solution, ii) adsorption of the coacervate around the drug particles, and iii) solidification of the microspheres.

The polymer is first dissolved in an organic solution. The water-soluble drugs like peptides and proteins are dissolved in water and dispersed in the polymer solution (w/o emulsion). Hydrophobic drugs like steroids are either solubilized or dispersed in the polymer solution. An organic non-solvent is then added to the polymer-drug-solvent system with stirring, which gradually extracts the polymer solvent. As a result, the polymer is subjected to phase separation and it forms soft coacervate droplets that entrap the drug. The system is then transferred to a large quantity of another organic non-solvent to harden the microdroplets and form the final microspheres which are collected by washing, sieving, filtration, or centrifugation, and are finally dried22. The process is suitable to encapsulate bother water-soluble as well as water-insoluble drugs. However, the coacervation process is mainly used to encapsulate water-soluble drugs like peptides, proteins, and vaccines. The rate at which the first non-solvent is added should be such that the polymer solvent is extracted slowly, allowing sufficient time for the polymer to deposit and coat evenly on the drug particle surface during the coacervation process. The concentration of the polymer used is important as well, since too high a concentration would result in rapid phase separation and nonuniform coating of the drug particles. The coacervate droplets are extremely sticky and adhere to each other before the complete phase separation or hardening stages of this method. Adjusting the stirring rate, temperature, or the incorporation of an additive is known to rectify this problem22. Dichloromethane, acetonitrile, ethyl acetate, and toluene have been used as non-solvents in this process. The non-solvent affects both phase separation and the hardening stages of the coacervation process. The non-solvents should not dissolve the polymer or the drug and should be miscible with the polymer solvent23. The second non-solvent

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should be relatively volatile and should easily remove the first viscous nonsolvent by washing. Some of the oils used as the first non-solvent are silicone oil, vegetable oils, light liquid paraffin, low molecular weight liquid polybutadiene, and low molecular weight liquid methacrylic polymers. Examples of the second non-solvent include aliphatic hydrocarbons like hexane, heptane, and petroleum ether22. 3) Spray drying: Spray-drying is a widely used method in the pharmaceutical industry and has been investigated by several researchers as a method for formulating biodegradable microparticles24-27. It is rapid, convenient, easy to scale-up, involves mild conditions, and is less dependent on the solubility parameters of the drug and the polymer. The method typically uses drug dissolved or suspended in a polymer solution (either organic or aqueous solvent, depending on the polymer used). The solution/suspension is then fed into the spraydrying apparatus through the most important component is the nozzle and polymer/drug solution is mixed rapidly with air and forced through a small diameter orifice. Nebulization of the polymer/drug solution occurs at the nozzle25 and the resultant droplets are very quickly dried by evaporation (under high-pressure air) before collection. Significant advantages of using this technique include high encapsulation efficiencies and no residual surfactant on the surface of the microparticles. There is no external aqueous phase that can act as a sink for the drug and there is no surfactant present anywhere in the formulation. Parameters that affect the microparticles size and morphology are temperature, pressure (of the air used for drying), nozzle diameter, air/solution volume mixture, and polymer/drug concentrations.

Pack et al have reported a novel technique24 based on spray drying to generate microspheres with uniform size distribution (see Figure 5). The microsphere fabrication protocol is based on passing a solution containing the polymeric material (and the drug to be encapsulated) through a small nozzle to form a smooth cylindrical jet. A piezoelectric transducer, driven by a wave generator at a frequency tuned to match the flow rate and the desired drop size, vibrates the nozzle and breaks down the jet into a train of uniform droplets. An annular, non-solvent carrier-stream over the polymer solution provided further control over the droplet size and they have fabricated uniform spheres with average diameters from ~5 to > 500 m. (Refer Fig. No. 05 Microparticle preparation considerations 1. Stabilizer Stabilizer plays an important role in the formulation of microparticles. In the absence of an appropriate stabilizer, the high surface energy of micro-sized particles can induce agglomeration or aggregation of the drug crystals. The main functions of a stabilizer are t o wet the drug particles thoroughly, and to prevent Ostwalds ripening and agglomeration of microparticles in order to yield a physically stable formulation by providing steric or ionic barriers28. The type and amount of stabilizer has a pronounced effect on the physical stability and in-vivo behavior of microparticles. In some cases, a mixture of stabilizers is required to obtain stable microparticles. The drug-tostabilizer ratio in the formulation may vary from 1:20 to 20:1 and should be investigated for a specific case. Stabilizers that have been explored so far include cellulosics, poloxamers, polysorbates, lecithins and povidones29. Lecithin is the stabilizer of choice if one intends to -Formulation

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develop a parenterally autoclavable microparticles. 2. Organic solvents

acceptable

and

4. Other additives Microparticles may contain additives such as buffers, salts, polyols, osmogent and cryoprotectant, depending on either the route of administration or the properties of the drug moiety. Effect of Characteristics of Microparticles on Drug Delivery 1. Particle size Particle size and size distribution are the most important characteristics of microparticle systems. Drug release is affected by particle size. Smaller particles have larger surface area, therefore, most of the drug associated would be at or near the particle surface, leading to fast drug release. Whereas, larger particles have large cores which allow more drug to be encapsulated and slowly diffuse out30. Smaller particles also have greater risk of aggregation of particles during storage and transportation of microparticle dispersion. It is always a challenge to formulate microparticles with the smallest size possible but maximum stability. Polymer degradation can also be affected by the particle size. For instance, the rate of polymer degradation was found to increase with increasing particle size in vitro31. It was thought that in smaller particles, degradation products of formed can diffuse out of the particles easily while in large particles, degradation products are more likely remained within the polymer matrix for a longer period to cause autocatalytic degradation of the polymer material. Therefore, it was hypothesized that larger particles will contribute to faster polymer degradation as well as the drug release. However, Panyam et al prepared particles with different size ranges and found that the polymer degradation rates in vitro were not substantially different for different size particles32.

Organic solvents may be required in the formulation of microparticles if they are to be prepared using an emulsion or microemulsion as a template. As these techniques are still in their infancy, elaborate information on formulation considerations is not available. The acceptability of the organic solvents in the pharmaceutical arena, their toxicity potential and the ease of their removal from the formulation need to be considered when formulating microparticles using emulsions or microemulsion as templates. The pharmaceutically acceptable and less hazardous water-miscible solvents, such as ethanol and isopropanol, and partially watermiscible solvents, such as ethyl acetate, ethyl formate, butyl lactate, triacetin, propylene carbonate and benzyl alcohol, are preferred in the formulation over the conventional hazardous solvents, such as dichloromethane. Additionally, partially watermiscible organic solvents can be used as the internal phase of the microemulsion when the microparticles are to be produced using a microemulsion as a template. 3. Co-surfactants The choice of co-surfactant is critical when using microemulsion to formulate microparticles. Since co-surfactants can greatly influence phase behavior, the effect of cosurfactant on uptake of the internal phase for selected microemulsion composition and on drug loading should be investigated. Although the literature describes the use of bile salts and dipotassium glycerrhizinate as co-surfactants, various solubilizers, such as Transcutol, glycofurol, ethanol and isopropanol, can be safely used as co-surfactants in the formulation of microemulsions.

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Currently, the fastest and most routine method of determining particle size is by photoncorrelation spectroscopy or dynamic light scattering. Photon-correlation spectroscopy requires the viscosity of the medium to be known and determines the diameter of the particle by Brownian motion and light scattering properties33. The results obtained by photoncorrelation spectroscopy are usually verified by scanning or transmission electron microscopy (SEM or TEM). When microparticles are administered intravenously, they are easily recognized by the body immune systems, and are then cleared by phagocytes from the circulation34. Apart from the size of microparticles, their surface hydrophobicity determines the amount of adsorbed blood components, mainly proteins (opsonins). This in turn influences the in vivo fate of microparticles binding of these opsonins onto the surface of microparticles called opsonization acts as a bridge between The microparticles and phagocytes35. association of a drug to conventional carriers leads to modification of the drug biodistribution profile, as it is mainly delivered to the mononuclear phagocytes system (MPS) such as liver, spleen, lungs and bone marrow. Indeed, once in the blood stream, surface nonmodified microparticles (conventional microparticles) are rapidly opsonized and massively cleared by the macrophages of MPS rich organs36. Generally, it is IgG, compliment C3 components that are used for recognition of foreign substances, especially foreign macromolecules. Hence, to increase the likelihood of the success in drug targeting by microparticles, it is necessary to minimize the opsonization and to prolong the circulation of microparticles in vivo. This can be achieved by a) Surface coating of microparticles with hydrophilic polymers/surfactants;

b) Formulation of microparticles with biodegradable copolymers with hydrophilic segments such as Polyethylene glycol (PEG), polyethylene oxide, polyoxamer, poloxamine and polysorbate 80 (Tween 80). Studies show that PEG conformation at the microparticle surface is of utmost importance for the opsonin repelling function of the PEG layer. PEG surfaces in brush-like and intermediate configurations reduced phagocytosis and complement activation whereas PEG surfaces in mushroom-like configuration were potent complement activators and favored phagocytosis. The zeta potential of a microparticle is commonly used to characterize the surface charge property of microparticles. It reflects the electrical Potential of particles and is influenced by the composition of the particle and the medium in which it is dispersed. Microparticles with a zeta potential above (+/-) 30 mV have been shown to be stable in suspension, as the surface charge prevents aggregation of the particles. The zeta potential can also be used to determine whether a charged active material is encapsulated within the centre of the microcapsule or adsorbed onto the surface37. 2. Drug loading Ideally, a successful micro particulate system should have a high drug-loading capacity thereby reduce the quantity of matrix materials for administration. Drug loading can be done by two methods: Incorporating at the time of microparticles production (incorporation method) Absorbing the drug after formation of microparticles by incubating the carrier with a concentrated drug solution (adsorption/absorption technique).

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Drug loading and entrapment efficiency very much depend on the solid-state drug solubility in matrix material or polymer (solid dissolution or dispersion), which is related to the polymer composition, the molecular weight, the drug polymer interaction and the presence of end functional groups (ester or carboxyl) . The PEG moiety has no or little effect on drug loading38. The macromolecule or protein shows greatest loading efficiency when it is loaded at or near its isoelectric point when it has minimum solubility and maximum adsorption. For small molecules, studies show the use of ionic interaction between the drug and matrix materials can be a very effective way to increase the drug loading. 3. Drug release To develop a successful micro particulate system, both drug release and polymer biodegradation are important consideration factors. In general, drug release rate depends on: (1) solubility of drug; (2) desorption of the surface bound/ adsorbed drug; (3) drug diffusion through the microparticle matrix; (4) microparticle matrix erosion/degradation; and (5) combination of erosion/diffusion process. Thus solubility, diffusion and biodegradation of the matrix materials govern the release process. In the case of microspheres, where the drug is uniformly distributed, the release occurs by diffusion or erosion of the matrix under sink conditions. If the diffusion of the drug is faster than matrix erosion, the mechanism of release is largely controlled by a diffusion process. The rapid initial release or burst is mainly attributed to weakly bound or adsorbed drug to the large surface of microparticles. It is evident that the method of incorporation has an effect on release profile. If the drug is loaded by incorporation method, the system has a relatively small burst effect and better sustained release characteristics. If the microparticle is coated by polymer, the release is then controlled by diffusion of the drug from the core

across the polymeric membrane. The membrane coating acts as a barrier to release, therefore, the solubility and diffusivity of drug in polymer membrane becomes determining factor in drug release. Furthermore release rate can also be affected by ionic interaction between the drug and addition of auxiliary ingredients. When the drug is involved in interaction with auxiliary ingredients to form a less water soluble complex, then the drug release can be very slow with almost no burst release effect; whereas if the addition of auxillary ingredients e.g., addition of ethylene oxide-propylene oxide block copolymer (PEO-PPO) to chitosan, reduces the interaction of the model drug bovine serum albumin (BSA) with the matrix material (chitosan) due to competitive electrostatic interaction of PEO-PPO with chitosan, then an increase in drug release could be observed20. Various methods which can be used to study the in vitro release of the drug are: (1) side-by-side diffusion cells with artificial or biological membranes; (2) dialysis bag diffusion technique; (3) reverse dialysis bag technique; (4) agitation followed by ultracentrifugation/centrifugation; (5) Ultrafiltration or centrifugal ultra-filtration techniques. Usually the release study is carried out by controlled agitation followed by centrifugation. Due to the time-consuming nature and technical difficulties encountered in the separation of microparticles from release media, the dialysis technique is generally preferred. Characterization of microparticles The essential characterization parameters for microparticles are as follows. 1) Mean particle size and particle size distribution: The mean particle size and the width of particle size distribution are important characterization parameters as they govern the saturation solubility, dissolution velocity, physical stability

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and even biological performance of microparticles. It has been indicated by that saturation solubility and dissolution velocity show considerable variation with the changing particle size of the drug.Photon correlation spectroscopy (PCS) can be used for rapid and accurate determination of the mean particle diameter of microparticles39. Moreover, PCS can even be used for determining the width of the particle size distribution (polydispersity index, PI). The PI is an important parameter that governs the physical stability of microparticles and should be as low as possible for the longterm stability of microparticles. A PI value of 0.10.25 indicates a fairly narrow size distribution whereas a PI value greater than 0.5 indicates a very broad distribution. No logarithmic normal distribution can definitely be attributed to such a high PI value. Although PCS is a versatile technique, because of its low measuring range (3nm to 3 m) it becomes difficult to determine the possibility of contamination of the microparticles by microparticulate drugs (having particle size greater than 3 m). Hence, in addition to PCS analysis, laser diffractometry (LD) analysis of microparticles should be carried out in order to detect as well as quantify the drug microparticles that might have been generated during the production process. Laser diffractometry yields a volume size distribution and can be used to measure particles ranging from 0.0580 m and in certain instruments particle sizes up to 2000 m can be measured. The typical LD characterization includes determination of diameter 50% LD (50) and diameter 99% LD (99) values, which indicate that either 50 or 99% of the particles are below the indicated size. The LD analysis becomes critical for microparticles that are meant for parenteral and pulmonary delivery. Even if the microparticles contains a small number of particles greater than 56 m, there could be a possibility of capillary blockade or emboli formation, as the size of the smallest blood

capillary is 56 m. It should be noted that the particle size data of a microparticles obtained by LD and PCS analysis are not identical as LD data are volume based and the PCS mean diameter is the light intensity weighted size. The PCS mean diameter and the 50 or 99% diameter from the LD analysis are likely to differ, with LD data generally exhibiting higher values. The microparticles can be suitably diluted with deionized water before carrying out PCS or LD analysis. For microparticles that are intended for intravenous administration, particle size analysis by the Coulter counter technique is essential in addition to PCS and LD analysis. Since the Coulter counter gives the absolute number of particles per volume unit for the different size classes, it is a more efficient and appropriate technique than LD analysis for quantifying the contamination of microparticles by microparticulate drugs. 2) Crystalline morphology: state and particle

The assessment of the crystalline state and particle morphology together helps in understanding the polymorphic or morphological changes that a drug might undergo when subjected to microsizing. Additionally, when microparticles are prepared drug particles in an amorphous state are likely to be generated. Hence, it is essential to investigate the extent of amorphous drug microparticles generated during the production of microparticles. The changes in the physical state of the drug particles as well as the extent of the amorphous fraction can be determined by X-ray diffraction analysis and can be supplemented by differential scanning calorimetric In order to get an actual idea of particle morphology, scanning electron microscopy is preferred40.

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3) Saturation velocity:

solubility

and

dissolution

The determination of the saturation solubility and dissolution velocity is very important as these two parameters together help to anticipate any change in the in-vivo performance (blood profiles, plasma peaks and bioavailability) of the drug. As microparticles are known to improve the saturation solubility of the drug, the determination of the saturation solubility rather than an increase in saturation solubility remains an important investigational parameter. The saturation solubility of the drug in different physiological buffers as well as at different temperatures should be assessed using methods described in the literature. The investigation of the dissolution velocity of microparticles reflects the advantages that can be achieved over conventional formulations, especially when designing the sustainedrelease dosage forms based on microparticulate drugs. The dissolution velocity of drug microparticles in various physiological buffers should be determined according to methods reported in the pharmacopoeia. 4) In-vivo biological performance: The establishment of an in-vitro/in-vivo correlation and the monitoring of then-vivo performance of the drug is an essential part of the study, irrespective of the route and the delivery system employed. It is of the utmost importance in the case of intravenously injected microparticles since then-vivo behavior of the drug depends on the organ distribution, which in turn depends on its surface properties, such as surface hydrophobicity and interactions with plasma proteins41. In fact, the qualitative and quantitative composition of the protein absorption pattern observed after the intravenous injection of microparticles is recognized as the essential factor for organ distribution. Hence, suitable techniques have to be used in order to evaluate the surface

properties and protein interactions to get an idea of in-vivo behavior. Techniques such as hydrophobic interaction chromatography can be used to determine surface hydrophobicity, whereas 2-D PAGE can be employed for the quantitative and qualitative measurement of protein adsorption after intravenous injection of drug microparticles in animals. Applications delivery of microparticles in drug

1) Oral drug delivery The oral route is the preferred route for drug delivery because of its numerous well-known advantages. The efficacy or performance of the orally administered drug generally depends on its solubility and absorption through the gastrointestinal tract. Hence, a drug candidate that exhibits poor aqueous solubility and/or dissolution-rate limited absorption is believed to possess low and/or highly variable oral bioavailability. Owing to low oral bioavailability, such a drug candidate would have to be administered in a larger excess than actually required if it were completely bio-available in order to achieve a therapeutically active concentration, thus making the therapy costly. Orally administered antibiotics such as atovaquone and bupravaquone reflect this problem very well. Microsizing of such drugs can lead to a dramatic increase in their oral absorption and subsequently bioavailability. The amelioration in oral bioavailability can be attributed to the adhesiveness of the drug microparticles, increased surface area (due to reduction in particle size by 1050-fold), and increased saturation solubility, leading to an increased concentration gradient between the gastrointestinal tract lumen and blood, and increased dissolution velocity. The enhancement in bioavailability will lead to a subsequent reduction in drug dose, rendering

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the therapy cost-effective and obliterating any undue drug dumping in the body. Microparticles are also advantageous in achieving quick onset of action for drugs that are completely but slowly absorbed, i.e. those having high tmax values. This is illustrated by the study carried out for naproxen, a nonsteroidal anti-inflammatory drug. A dosage form with fast onset of action would be highly desirable for naproxen. A study involving a comparison of the pharmacokinetic profiles of naproxen in the form of microparticles, suspension (Naprosyn) and tablet (Anaprox) forms revealed that the time required to achieve Cmax was reduced by approximately 50% for the microparticles compared to the suspension and tablet. Additionally, naproxen microparticles resulted in a 2.54.5-fold increase in the AUCs during the first hour of the study. Apart from improving oral absorption, microparticles offer the following advantages: Improved dose proportionality Reduced fed/fasted state variability Reduced inter-subject variability.

Numerous drug candidates that are poorly water-soluble are required to be taken over a prolonged period of time for effective medication. However, many of them cannot be formulated into sustained-release dosage forms because of the risk of dose dumping and poor in-vivo performance. 2) Parenteral drug delivery The parenteral route is an invasive route. Parenteral administration of drugs is critical and often associated with the problems such as the limited number of acceptable excipients, restrictions on the quantities of excipients approved for parenteral use, the stringent

requirements of the aseptic production process, safety issues, patient noncompliance and biological problems such as allergic reactions and thrombophlebitis. Despite all these limitations, the parenteral route still retains its value because of its special advantages, such as quick onset of action in case of emergency, reduction in dose of the drug and the ability to target the drug quickly to the desired site of action, especially in the case of severe infections. The parenteral route is often employed as an alternative when the drug is either not absorbed through the gastrointestinal tract or undergoes extensive first-pass metabolism. For administration by the parenteral route, the drug either has to be solubilized or have particle/globule size below 5 _m to avoid the capillary blockade. The current approaches for parenteral delivery include salt formation, solubilization using co-solvents, micellar solutions, complexation with cyclodextrins and recently liposomes. However, there are limitations on the use of these approaches because of limitations on their solubilization capacity and parenteral acceptability. In this regard, liposomes are much more tolerable and versatile in terms of parenteral delivery. However, they often suffer from problems such as physical instability, high manufacturing cost and difficulties in scale-up. 3) Ocular drug delivery Micro suspensions can prove to be a boon for drugs that exhibit poor solubility in lachrymal fluids. For delivery of such drugs, approaches such as suspensions and ointments have been recommended. Although suspensions offer advantages such as prolonged residence time in a cul-de-sac (which is desirable for most ocular diseases for effective treatment) and avoidance of the high tonicity created by watersoluble drugs, their actual performance depends on the intrinsic solubility of the drug in lachrymal fluids. Thus, the intrinsic dissolution

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rate of the drug in lachrymal fluid governs its release and ocular bioavailability. However, the intrinsic dissolution rate of the drug will vary because of the constant inflow and outflow of lachrymal fluids. Hence, suspensions may fail to give consistent performance. However, micro suspensions, by their inherent ability to improve the saturation solubility of the drug, represent an ideal approach for ocular delivery of hydrophobic drugs. Moreover, the microparticulate nature of the drug allows its prolonged residence in the cul-de-sac, giving sustained release of the drug.

Conclusion The microparticles drug delivery system is a physical approach to alter and improve the pharmacokinetic and pharmacodynamics properties of various types of drug molecules. They have been used in vivo to protect the drug entity in the systemic circulation, restrict access of the drug to the chosen sites and to deliver the drug at a controlled and sustained rate to the site of action with enhanced therapeutic benefit, while minimizing side effects. The review embracing various aspects of microparticle formulations, characterization, effect of their characteristics and their applications in cell specific delivery of drug molecules and therapeutic genes will give the researchers and academicians a better insight of microparticulate drug delivery arena for better management of life threatening diseases. REFERENCES 1. Langer R, Folkman J. Polymers for the Sustained Release of Proteins andOther Macromolecules. Nature, 263, 1976, 797-800. 2. Putney SD, Burke PA, Improving Protein Therapeutics with Sustained release

Formulations, Nature Biotechnology, 16, 1998, 153-157. 3. Moore, J, The Drug Delivery Outlook to 2005. Business Insights Ltd. 1999. 4. Siepmann, J, Microparticles used as drug delivery systems, Progress in Colloidand Polymer Science, 133, 2006, 15. 5. Jain RA, The manufacturing techniques of various drug loaded biodegradablepoly(lactide-/co/-glycolide) (PLGA) devices. Biomaterials, 21(23), 2000, 2475-2490. 6. Jalil R and Nixon JR, Biodegradable poly(lactic acid) and poly(lactide-coglycolide) microcapsules: problems associated with preparative techniques and release properties, Journal of Microencapsulation, 7(3), 1990, 297325. 7. Jeyanthi R, Effect of solvent removal technique on the matrix characteristics ofpolylactide/glycolide microspheres for peptide delivery, Journal of Controlled Release, 38(2, 3), 1996, 235. 8. Arshady R, Preparation of biodegradable microspheres and microcapsules: 2.Polyactides and related polyesters, Journal of Controlled Release, 17(1), 1991, 1-22. 9. Cavalier M, Benoit JP, Thies C, The formation and characterization ofhydrocortisone-loaded poly((+/-)-lactide) microspheres, Journal of Pharmacy and Pharmacology, 38(4), 1986, 249-253. 10. Tsai DC, et al, Preparation and in vitro evaluation of polylactic acidmitomycinC microcapsules, Journal of Microencapsulation, 3(3), 1986, 181. 11. Thies C, Dunbrow M(ed.), Formation of degradable drug-loaded microparticles by inliquid drying processes, In: Microcapsules and Nanoparticles in Medicine and Pharmacy, CRC: Boca Raton, 1992, 47-71. 12. Toguchi H, Formulation study of leuprorelin acetate to improve clinical performance. Clinical Therapeutics, 14, 1992, 121.

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13. Okada H, et al, Preparation of threemonth depot injectable microspheres of leuprorelin acetate using biodegradable polymers, Pharmaceutical Research, 11(8), 1994, 1143. 14. Singh M, Biodegradable delivery system for a birth controls vaccine: immunogenicity studies in rats and monkeys, Pharmaceutical Research, 2(11), 1991, 1796. 15. O'Hagan DT, et al, Controlled release microparticles for vaccine development, Vaccine, 9(10), 1991, 768. 16. Cleland JL, and Jones A, Stable formulations of recombinant human growth hormone and interferon- for microencapsulation in biodegradable microspheres, Pharmaceutical Research, 13(10), 1996, 1464-1475. 17. Crotts G and Park TG, Protein delivery from poly(lactic-co-glycolic acid) biodegradable microspheres: release kinetics and stability issues. Journal of Microencapsulation, 15(6), 1998, 699-705. 18. Yan C, et al, Characterization and morphological analysis of protein-loaded poly (lactide-co-glycolide) microparticles prepared by water-in-oil-in-water emulsion technique. Journal of Controlled Release, 32(3), 1994, 231-241. 19. Mandal TK and Tenjarla S, Preparation of biodegradable microcapsules of zidovudine using solvent evaporation: Effect of the modification of aqueous phase, International Journal of Pharmaceutics, 137(2), 1996, 187197. 20. Ghaderi R, Sturesson C, and Carlfors J, Effect of preparative parameters on the characteristics of poly ,-lactide-coglycolide)microspheres made by the double emulsion method, International Journal of Pharmaceutics, 141(1-2), 1996, 205-216. 21. Lewis DH, Chasin M, (ed.) Controlled release of bioactive agents from lactide/glycolide polymers, in Biodegradable

polymers as drug delivery systems, Marcel Dekker: New York, 1990, 1-41. 22. Wu XS, Wise D (ed.) Preparation, characteriztion, and drug delivery applications of microspheres based on biodegradable lactic/glycolic acid polymers, in Encyclopedic handbook of biomaterials and bioengineering, Marcel Dekker: New York, 1995, 1-41. 23. Csernus VJ, Szende B, Schally AV, Release of peptides from sustained delivery systems (microcapsules and microparticles) in vivo. A histological and immunohistochemical study, International Journal of peptide and protein research, 1990, 35(6), 557-65. 24. Berkland C, Kim KK, Pack DW, Fabrication of PLG microspheres with precisely controlled and monodisperse size distributions, Journal of Controlled Release, 2001, 73(1), 5974. 25. Giunchedi, P., Spray-drying as a preparation method of microparticulate drug delivery systems: An overview. S.T.P. Pharma Sciences, 1995, 5(4), 276. 26. Bodmeier, R. and H. Chen, Preparation of biodegradable poly(+/-)lactide microparticles using a spray-drying technique. Journal of Pharmacy and Pharmacology, 40(11), 1988. 754-757. 27. Gander, B., Quality improvement of spray-dried, protein-loaded D,L-PLA microspheres by appropriate polymer solvent selection. Journal of Microencapsulation, 12(1), 1995. 83-97. 28. Rawlins, E. A. (1982) Solutions. In: Rawlins, E. A. (ed.) Bentleys textbook of pharmaceutics. 8th edn, Bailliere Tindall, London, 6. 29. Liversidge, G. G., Cundy, K. C., Bishop, J. F., Czekai, D. A. (1992) Surface modified drug nanoparticles. US Patent 5,145,684 30. Redhead HM, Davis SS, Illum L. Drug delivery in poly(lactide-co-glycolide) nanoparticles surface modified with poloxamer 407 and poloxamine 908: in vitro

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characterisation and in vivo evaluation. J Control Release, 70, 2001, 353-363. 31. Dunne M, Corrigan OI, Ramtoola Z. Influence of particle size and dissolution conditions on the degradation properties of polylactide-co-glycolide particles. Biomaterials 21, 2000, 1659-1668. 32. Panyam J, Dali MM, Sahoo S K, Ma W, Chakravarthi SS, Amidon GL, Levy RJ, Labhasetwar V. Polymer degradation and in vitro release of a model protein from poly(,lactide-co-glycolide) nano- and microparticles. J Control Release, 92, 2003, 173-187. 33. Swarbrick J, Boylan J. Encyclopedia of pharmaceutical technology. 2nd ed.; Marcel Dekker: New York, 2002. 34. Muller RH, Wallis KH. Surface modification of i.v. injectable biodegradable nanoparticles with poloxamer polymers and poloxamine 908. Int. J. Pharm., 89, 1993, 2531. 35. Brigger I, Dubernet C, Couvreur P. Nanoparticles in cancer therapy and diagnosis. Adv. Drug Deliv. Rev. 54, 2002, 631-651. 36. Grislain L, Couvreur P, Lenaerts V, Roland M, Deprez-Decampeneere D, Speiser P. Pharmacokinetics and distribution of a

biodegradable drug-carrier.Int. J. Pharm. 15, 1983, 335-345. 37. Olivier JC. Drug transport to brain with targeted nanoparticles. NeuroRx, 2, 2005, 108119. 38. Peracchia M, Gref R, Minamitake Y, Domb A, Lotan N, Langer R. PEG-coated nanospheres from amphiphilic diblock and multiblock copolymers: investigation of their drug encapsulation and release characteristics. J Control Release, 46, 1997, 223231 39. Mu ller, R. H., Peters, K. (1998) Nanosuspensions for the formulation of poorly soluble drugs I: Preparation by a sizereduction technique. Int. J. Pharm. 160, 1998, 229237. 40. Mu ller, R. H., Bo hm, B. H. L. (1998) Nanosuspensions. In: Mu ller, R. H., Benita, S., Bo hm, B. H. L. (eds) Emulsions and nanosuspensions for the formulation of poorly soluble drugs. Medpharm Scientific Publishers, Stuttgart, 149174. 41. Blunk, T., Hochstrasser, D. F., Sanchez, J. C., Mu ller, B. W. (1993) Colloidal carriers for intravenous drug targeting: Plasma protein adsorption patterns on surface-modified latex particles evaluated by two-dimensional polyacrylamide gel electrophoresis. Electrophoresis 14: 13821387.

FIGURES Figure 1: Concentration(c) vs. Time (t) profiles for conventional and controlled release drug delivery devices

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Figure 2: Different categories of microparticles.

Figure 3: Encapsulation using oil-in-water emulsion technique

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Figure 4: Schematic of w/o/w in-liquid drying process for microparticle preparation

Figure 5: Spray-drying apparatus A) Schematic drawing of apparatus for fabricating microspheres portraying acoustic excitation with carrier stream B) Schematic drawing indicating the variables used for acoustic excitation theory development.

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