RECENT ADVANCEMENTS: MICROSPONGE DRUG DELIVERY SYSTEM; A REVIEW

About Authors:
Deepak Sharma*, Arunabha Banik, S k Gupta
Department of Pharmaceutical Technology,
MIET,Meerut
*thakraan.southcarolina@gmail.com

ABSTRACT
The Microspongesdelivery system are extremely small, inert,indestructibleclusters of even tinierspherical particles of microscopic sizepatented polymeric delivery systems consisting of porous microspheres that can entrap a wide range of active ingredients such as emollients, fragrances, essential oils, sunscreens, and anti-infective, anti-fungal, and anti-inflammatory agents and are very well tolerated, and highly efficacious, novel productsthat do not pass through the skin, capable of holding four times their weight in skin secretionsand can absorb skin secretions. Like a true sponge, each microspheres consists of a myriad of interconnecting voids within a non-collapsible structure with a large porous surface. The size of the microsponges can be varied usually from 5-300µm in diameter, depending upon the degree of smoothness or after-feel required for the end formula. Although the microsponge size may vary, a typical 25µm sphere can have up to 250000 pores and an internal pore structure equivalent to 10ft in length providing a total pore volume of about 1ml/g. This results in a large reservoir within each microsponge, which can be loaded with up to its own weight in active agent. The microsponge particles themselves are too large to be absorbed into the skin and this adds a measure of safety to these microsponge materials. Another safety concern is the potential bacterial contamination of the materials entrapped in the microsponge. Because the size of the pore diameter is smaller than bacteria, ranging from 0.007 to 0.2µm, bacteria cannot penetrate into the tunnel structure of the microsponges.The microsponge system can prevent excessive accumulation of ingredients within the epidermis and the dermis. Potentially, the microsponge system can reduce significantly the irritation of effective drugs without reducing their efficacy.

Reference Id: PHARMATUTOR-ART-1374

INTRODUCTION:
A Microsponge drugdelivery system (MDDS) is a patented, highly cross-linked, porous, polymeric microspheres polymeric system (10-25 µ) consisting of porous microspheresparticles consisting of a myriad of inter connecting voids within non-collapsible structures with a large porous surfacethat can entrap wide range of actives (cosmetics, over-the-counter (OTC) skin care, sunscreens and prescription products)and then release them onto the skin over a time and in response to trigger. A typical 25µm sphere can have up to 250000 pores and an internal pore structure equivalent to 10ft in length providing a total pore volume of about 1ml/g[1]. Microsponge do not pass through the skin (capable of holding four times their weight in skin secretions). Rather, they collect in the tiny nooks and crannies of skin and slowly release the entrapped drug, as the skin needs it. The microsponge system can prevent excessive accumulation of ingredients within the epidermis and the dermis. These products are typically presented to the consumer in conventional forms like creams, gels or lotions and they contain relatively high concentration of active ingredients .[2] Microsponges are polymeric delivery systems consisting of porous microspheres that can entrap a wide range of active ingredients such as emollients, fragrances, essential oils, sunscreens, and anti-infective, anti-fungal, and anti-inflammatory agents.

The MDS has advantages over other technologies like microencapsulation and liposomes. Microcapsules cannot usually control the release rate of actives. Once the wall is ruptured the actives contained within microcapsules will be released. Liposome suffer from lower payload, difficult formulation, limited chemical stability and microbial instability.

HISTORY OF MICROSPONGE:
The microsponge technology was developed by Won in 1987 and the original patents were assigned to Advanced Polymer Systems, Inc. This Company developed a large number of variations of the technique and applied those to cosmetic as well as OTC and prescription pharmaceutical products. At the present time, this interesting technology has been licensed to Cardinal Health, Inc., for use in topical products.[3]

POTENTIAL ADVANTAGES OF MICROSPONGE DRUG DELIVERY SYSTEM: [4]
v  Microsponge formulations are stable over range of pH 1 to 11.
v  Microsponge formulations are stable at the temperature up to 130^oC.
v  Microsponge formulations arecompatible with most vehicles andingredients.
Microsponge formulations are self sterilizing as their average pore sizeis 0.25μm where bacteria cannotpenetrate.
v  Microsponge formulations havehigher payload (50 to 60%), still free flowing and can be costeffective.
v  Microcapsules cannot usually control the release rate of actives. Once the wall is ruptured the actives contained within microcapsules will be released. Whether MDS can do it.[5]
v  Liposome suffer from lower pay load, difficult formulation, limited chemical stability and microbial instability. Whether MDS have wide range of chemical stability and easy to formulation.[6]
v  Microsponges are microscopic spheres capable of absorbing skin secretions, therefore reducing oiliness and shine from the skin.

APPLICATION OF MICROSPONGE
Microsponges are porous, polymeric microspheres that are used mostly for topical and recently for oral administration. It offers the formulator a range of alternatives to develop drug and cosmetic products. Microsponges are designed to deliver a pharmaceutical active ingredient efficiently at the minimum dose and also to enhance stability, reduce side effects and modify drug release.[6]

The Microsponge for Oral Delivery: [7]
The Microsponge system offers the potential to hold active ingredients in a protected environment and provide controlled delivery of oral medication to the lower gastrointestinal (GI) tract, where it will be released upon exposure to specific enzymes in the colon.

Bioerodible Systems based on new polymers for the delivery of small and large molecule drugs, including proteins and peptides, can also be developed which, if successful open up new fields of opportunity in systemic drug delivery arenas.[8]

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Kawashima et al. have described methods for the preparation of hollow microspheres ('microballoons') with the drug dispersed in the sphere's shell, and also highly porous matrix-type microspheres (‘microsponge’). The microsponges were prepared by dissolving the drug and polymer in ethanol. On addition to water, the ethanol diffused from the emulsion droplets to leave a highly porous particle. Variation of the ratios of drug and polymer in the ethanol solution gave control over the porosity of the particle, and the drug release properties were fitted to the Higuchi model. [9]

To determine if coated microsponges are viable for the slow release of chlorpheniramine maleate (CPM), cellulose (Cellurofine) microparticles were loaded with CPM and coated with Eudragit RS to form powder coated microsponges.

Ketoprofen microsponges were prepared by quasi-emulsion solvent diffusion method with Eudragit RS 100 and afterwards tablets of microsponges were prepared by direct compression method.. .Colon specific drug delivery system containing flurbiprofen (FLB) microsponges comprised of  Eudragit RS100 were prepared by quasi-emulsion solvent diffusion methodMechanically strong tablets prepared for colon specific drug delivery were obtained owing to the plastic deformation of sponge-like structure of microsponges.[10]

Bone-substitute compounds
were obtained by mixing pre-polymerised powders of polymethylmethacrylate and liquid methylmethacrylate monomer with two aqueous dispersions of a-tricalcium phosphate (a-TCP) grains and calcium-deficient hydroxyapatite (CDHA) powders. The final composites appeared to be porous. The total open porosity was a function of the amount of water added. The water, which was the pore-forming agent, vapourised after the polymerisation process, leaving behind empty spaces in the polymeric matrix. The inorganic powders placed inside the polymeric matrix were shown to act as local microsponges. Formation of new trabecular bone was observed inside the pores where the inorganic powders had been placed. The material produced shows a good level of biocompatibility, good osteointegration rate and osteogenetic properties. [11]

The Microsponge in Delivery of biopharmaceuticals
The MDS is employed for the delivery of biopharmaceuticals and in tissue engineering also. Newton D. W. has overviewed tissue targeted biopharmaceuticals deliverythroughmicrosponge   storage and release of endogenous growth factors by the extracellular matrix (ECM) are important biological events that control tissue homeostasis and regeneration. bFGF spontaneously interacts with type I collagen solution and sponges under in vitro and in vivo physiological conditions, and is protected from the proteolytic environment by the collagen. bFGF incorporated in a collagen sponge sheet was sustained released in the mouse sub-cutis according to the biodegradation of the sponge matrix, and exhibited local angiogenic activity in a dose-dependent manner. Intra-muscular injection of collagen microsponges incorporating bFGF induced a significant increase in the blood flow in the murine ischemic hind limb, which could never have been attained by bolus injection of bFGF.[12]

Marketed Formulation Using the MDS
Microsponge delivery systems are used to enhance the safety, effectiveness and aesthetic quality of topical prescription, over-the-counter ("OTC") and personal care products. The resulting benefits include extended efficacy, reduced skin irritation, cosmetic elegance, formulation flexibility and improved product stability.[13]

The fundamental appeal of the Microsponge technology stems from the difficulty experienced with conventional topical formulations in releasing active ingredients over an extended period of time. Cosmetics and skin care preparations are intended to work only on the outer layers of the skin. Yet, the typical active ingredient in conventional products is present in a relatively high concentration and, when applied to the skin, may be rapidly absorbed. The common result is over-medication, followed by a period of under-medication until the next application. Rashes and more serious side effects can occur when the active ingredients rapidly penetrate below the skin's surface. Microsponge technology is designed to allow a prolonged rate of release of the active ingredients, thereby offering potential reduction in the side effects while maintaining the therapeutic efficacy.
Ethical dermatology products have been developed or are under development includes,
Tretinoin Acne Medication: 
In February 1997, the FDA approved for the first ethical pharmaceutical product based on patented Microsponge technology; Retin-A-Micro^(TM), which has been licensed to Ortho-McNeil Pharmaceutical Corporation. The Company believes its patented approach to drug delivery reduces the potentially irritating side effects of tretinoin. [14]

5-Fluorouracil (5-FU): 
5-FU is an effective chemotherapeutic agent for treating actinic keratosis. However, patient compliance with the treatment regimen is poor, due to significant, adverse side effects. Microsponge-enhanced topical formulation that potentially offers a less irritating solution for treating actinic keratosis is sold.[15]

Personal Care and OTC Products: 
MDS is ideal for skin and personal care products. They can retain several times their weight in liquids, respond to a variety of release stimuli, and absorb large amounts of excess skin oil, all while retaining an elegant feel on the skin's surface. Among these products are skin cleansers, conditioners, oil control lotions, moisturizers, deodorants, razors, lipstick, makeup, powders, and eye shadows; which offers several advantages, including improved physical and chemical stability, greater available concentrations, controlled release of the active ingredients, reduced skin irritation and sensitization.

List of marketed products using microsponge drug delivery system:[16]

DRUGS &POLYMERS EXPLORED IN MICROSPONGES:[17]

PROPERTIES OF ACTIVE MOIETY FOR THE ENTRAPMENT INTO A MICROSPONGE:[18]
1.      It should be water immiscible or at most only slightly soluble.
2.      It should be inert to monomers.
3.      It should be stable in contact with polymerization catalyst and conditions of polymerization

Methods of Preparation of Microsponges:[19]
Microsponges are conveniently prepared by the following methods:
1. Liquid-Liquid Suspension Polymerization^:
In general, a solution is made comprising the monomers and the functional or the active ingredients which is immiscible with water. This phase is then suspended with agitation in an aqueous phase, usually containing additives such as surfactants, and dispersants to promote suspension. Once the suspension is established with discrete droplets of the desired size, polymerization is effected by activating the monomers either by catalysis, increased temperature or irradiation. As the polymerization process continues, a spherical structure is produced containing thousands of microsponges bunched together like grapes, forming interconnecting reservoirs.

Once the polymerization is complete the solid particles that results from the process are recovered from the suspension. The particles are then washed and processed until they are substantially ready for use. The microsponge products can be made using styrene and divinylbenzene or methylmethacrylate and ethylene glycol dimethacrylate as starting materials.

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2. Quasi-Emulsion Solvent Diffusion^:
To prepare the inner organic phase, Eudragit RS 100 is dissolved in ethyl alcohol. Then, the drug is added to solution and dissolved under ultrasonication at 35^o C. The inner phase is poured into the polyvinyl alcohol solution in water (outer phase). Following 60 min of stirring, the mixture is filtered to separate the microsponges. The microsponges are dried in an air-heated oven at 40 ^oC for 12 h.

Ingredients can be entrapped in microsponge polymers either at the time of synthesis or if too labile to withstand polymerization conditions, they can be post-loaded after the microsphere structure has been pre-formed. In general, the latter process is the preferred mode since many cosmetic ingredients, and most pharmaceutical ones, would decompose at the temperatures employed for polymerization.

Patent information of Microsponge Products:
Won; Richard et al, 1987 of Advanced Polymer Systems, Inc. received US patent for developing method for delivering an active ingredient by controlled time release utilizing a novel delivery vehicle which can be prepared by a process utilizing the active ingredient as a porogen (United States Patent 4,690,825).Delivery vehicles comprised of a polymeric bead having a network of pores with an active ingredient held within the network are provided for use in a method to provide controlled release of the active ingredient. The network of pores is substantially non-collapsible upon removal of the active ingredient and the delivery vehicles are polymerized by a process in which the active ingredient also comprises the porogen during formation of the network of pores,[20]

Won; Richard et al September 8, 1992,of Advanced Polymer Systems, Inc. received US patent for developing Two-step method for preparation of controlled release formulations (United States Patent 5,145,675).Active substances intended for topical application are incorporated in novel formulations in which they are retained as impregnants inside the pores of porous solid particles or microspheres. The pores form a continuous network open to the exterior of the particles, permitting outward diffusion of the impregnants at a controlled rate depending on the pore size. The impregnated particles are prepared by impregnation of preformed particles with the active substance.[21]

Dean, Jr. et al received US patent no. 4863856for the development of weighted collagen microsponges having a highly cross-linked collagen matrix are described suitable for use in culturing organisms in motive reactor systems. The microsponges have an open to the surface pore structure, pore sizes and volumes suitable for immobilizing a variety of bioactive materials.[22]

LITERATURE REVIEW :
Ø  Kawashima,TashiyakiNiwa, Hirofumi Takeuchi., have prepared controlled release microspheres of Ibuprofen with acrylic polymers by a novel Quasi-Emulsion Solvent-Diffusion technique and the microspheres obtained had a matrix or sponge like texture and the drug release from the microspheres could be controlled by the type and the concentration of the polymer[23]

Ø  Perumul D has worked on the microencapsulation of ibuprofen. The microspheres were prepared by the emulsion solvent diffusion technique using Eudragit RS 100 as the retardant material. The influence of various process variables like the presence/absence of baffles in the reaction vessel, agitation rate and drying time of microspheres, polymer and drug content on the microencapsulation efficiency, in vitro drug release and micromeritic properties were analyzed. By increasing the agitation speed the particle size decreased. By drying the microspheres at 40+ 0.50C for 24hrs gave particles with less moisture content and free flowing nature. The release studies show that microencapsulation with Eudragit RS 100 gave controlled release of the drug. And 9.1% Eudragit RS 100 released the drug more rapidly, while those with 33.3% Eudragit RS 100 exhibited slower drug release profile[24]

Ø  Gonul N, T Comoglu, T Baykara., have worked on the effect of pressure and direct compression on tableting of microsponges. In this study ketoprofen was used as a model drug for systemic delivery. The ketoprofen microsponges were prepared by quasi emulsion solvent diffusion technique using Eudragit RS 100 as the polymer. The microsponges possess a unique compression property due to their matrix or sponge like structure which differed from conventional microcapsules or physical mixtures. The in vitro release rate studies show that the tablets prepared with microsponges exhibited typical drug release profiles characterized by Higuchi-matrix model. By applying pressure more than 3800 kg/cm2 the drug release was higher compared to the lower pressures which was because of the structural deformation of microsponges[25]

Ø  Mandal T K, L.A. Bostanian, R.A. Graves, S.R. Chapman.have developed a method for the preparation of porous biodegradable controlled release formulation of poly(lactide/glycolide) (PLGA) containing pentamidine. Scanning electron microscopy pictures showed that these micro particles are highly porous and spherical in shape. Irrespective of the oil (corn or mineral) used in the preparation; the microparticles were all smaller than 90 mm. A change in the drug/polymer ratio did not change the particle size. The efficiency of encapsulation was higher than 58%. In the presence of corn oil, the efficiency of encapsulation was between 60 and 66%, whereas in the presence of mineral oil, the efficiency of encapsulation was between 58 and 74%. The rate of drug release from these microparticles was very high. This significantly high rate of drug release from PLGA microparticles was due to the porous surface morphology [26].

Ø  Beruto T D, Rodolfo Botter, Milena Fini., has worked on the effect of water in inorganic microsponges of calcium phosphates on the porosity and permeability of composites made with polymethylmethacrylate. The inorganic powder was placed inside the polymeric matrix by polymerization technique in the aqueous mixture of the required powders. These polymeric matrix obtained was porous and act as local microsponges. The total open porosity was a function of the amount of water present, which vaporized after polymerization, leaving behind the empty spaces in the polymeric matrix. A linear relationship exists between the composites and amount of water inside the inorganic agglomerates[27]

Ø  Comoglu T, N Gonul, T Baykara., has prepared Microsponges containing ketoprofen and Eudragit RS 100 by quasi-emulsion solvent diffusion method. The effects of different mixing speeds, drug/polymer ratios, solvent/polymer ratios on the physical characteristics of the microsponges as well as the in vitro release rate of the drug from the microsponges were investigated. All the factors studied had an influence on the physical characteristics of the microsponges.[28]

Ø  Baykar T, M Kilicarslan., has worked on the effect of the drug/polymer ratio on the properties of the verapamil HCl loaded microspheres. The microspheres were prepared by solvent evaporation technique using the Eudragit RS 100 as polymer. The results show that the drug release profile could be slowed down by increasing polymer amount in the formulations and the particle size, surface characteristics of microspheres and dissolution of drug could be modified through the variation of drug/polymer [28].

Ø  Sato Y, Y Kawashima, H Takeuchi, H Yamamoto., have prepared hollow microspheres by emulsion solvent diffusion method utilizing enteric acrylic polymers co-dissolved with drug in a mixture of dichloromethane and ethanol. The in vitro release studies of five different drugs which differ in aqueous solubility’s were done. The results show that the aspirin, salicylic acid and ethoxybenzamide followed higuchi equation whereas indomethacin and riboflavin release profiles does not follow the higuchi equation it was because of increased amount of riboflavin loading than the solubility of it in the mixture of Dichloromethane and ethanol. The drug release profiles show a initial burst release as the insoluble riboflavin crystals were released preferentially at the initial stages of the release studies.[29]

Ø  Dortunc B, S. Haznedar., has worked on the preparation and in vitro evaluation of Eudragit (RS RL) microspheres containing acetozolamide. Microspheres were prepared by solvent evaporation technique using acetone/liquid paraffin system. The influence of formulation factors (stirring speed, polymer/drug ratio, type of polymer, ratio of combination of polymer) on particle size, encapsulation efficiency and in vitro release characteristics of the microspheres were investigated. Mean particle size changed by changing the polymer/drug ratio or the stirring speed of the system. Although the acetozolamide release rates from Eudragit RS microspheres were very slow and incomplete for all formulations they were fast from Eudragit RL microspheres. The combination of RS and RL polymers resulted in the slowed down release rates and was suitable for peroral administration.[30]

Ø  Bogataj M, Rojnik TM, Frlan R, Bukovec P., have studied the effect of various preparation temperatures (10, 25, 35, 400C) in solvent evaporation process on Eudragit RS microsphere properties (particle size and morphology, drug content and release kinetics and drug crystal state). At 100C particles of irregular shape are formed, where as higher temperatures gradually improve the sphericity of microspheres. The results also showed that temperature has no effect on either Ketoprofen microencapsulation efficiency or on its crystal state.[31]

Ø  Orlu M, ErdalCevher ,AhmetAraman., have studied the design and evaluation of colon specific drug delivery system containing Flurbiprofenmicrosponges. Microsponges containing Flurbiprofen(FLB) and Eudragit RS 100 were prepared by quasi-emulsion solvent diffusion method. Additionally, FLB was entrapped into a commercial Microsponge® 5640 system using entrapment method. Afterwards, the effects of drug: polymer ratio, inner phase solvent amount, stirring time and speed and stirrer type on the physical characteristics of microsponges were investigated. The thermal behaviour, surface morphology, particle size and pore structure of microsponges were examined. The colon specific formulations were prepared by compression coating and also pore plugging of microsponges with pectin: hydroxypropylmethyl cellulose (HPMC) mixture followed by tabletting. It was concluded that both the microsponges prepared by quasi-emulsion solvent diffusion method and Microsponge® 5640 can be used successfully in the systems designed for colon specific drug delivery.[32]

Ø  Yan Gao, Fu-de Cui, Ying Guan, Lei Yang, Yong-sheng Wang.,have prepared microspheres of Roxithromycin with Eudragit S100 and silica by the emulsion solvent diffusion method to mask the bitter taste of the antibiotic. The effect of different polymers and drug–polymer ratios on the taste masking and the characteristics of the microspheres were investigated. It was found that Eudragit S100 was the best for masking the unpleasant taste of roxithromycin among the six kinds of polymers investigated. The influence of other formulation factors, i.e. dichloromethane–acetone ratios and silica–polymer ratios on the properties of the microspheres were also examined. In conclusion, the results of the present study will be helpful for the preparation of oral forms of roxithromycin with an acceptable taste.[33]

Ø  Chen G, T Sato, H Ohgushi, T Ushida, T Tateishia., have worked on the culturing of skin fibroblast in a thin PLGA-collagen hybrid mesh. The hybrid mesh was constructed by forming web-like collagen microsponges in the openings of a PLGA knitted mesh. The results indicate that the web-like collagen microsponges formed in the openings of the PLGA Knitted mesh increased the efficiency of cell seeding, improved cell distribution, and therefore facilitated rapid formation of dermal tissue having a uniform thickness. PLGA- collagen microsponges are useful in the skin tissue engineering[34].

Ø  Cevher E, Mine Orlu, AhmetAraman., have worked on the design and evaluation of colon specific drug delivery system containing Flurbiprofen microsponges. Flurbiprofen (FLB) microsponges were prepared by quasi emulsion solvent diffusion technique using Eudragit RS 100 as polymer. The effects of drug/polymer ratio, inner phase volume, stirring time and rate, on physical properties of the microsponges were determined. The results show that the microsponges were of spherical shape with spherical and cylindrical hole like pores. The plastic properties of microsponges allow direct compression of the microsponges to obtain mechanically strong tablets than the physical mixture of drug and polymer. The in vitro release profile shows that the drug release from the microsponges was faster when compared to the rigid microparticles due to more porous internal structure of the microsponges.[35]

Ø  Jelvehgari M, Siahi-Shadbad MR, Azarmi S, Martin GP., have worked on the preparation characterization and release studies of Benzyle peroxide microsponges. The effect of drug/polymer ratio on topography, particle size and size distribution and porosity were analyzed. According to the results, the topographical study shows that the microparticles obtained were spherical and contain interconnected pores (appearing like a sponge); with increase in drug/polymer concentration the porosity and the mean particle size of the sponges decreased. The drug release studies were done by formulating BPO microsponges as a cream. The release shows that as the drug/polymer ratio increases the release of drug from BPO microsponge cream was reduced because of decreased internal porosity of the microsponges with increase in drug/polymer.[36]

Ø  Nokhodchi A, Jelvehgari M, Siahi MR, Mozafari MR., have worked on the factors affecting the morphology of BPO microsponges. BPO microsponges were prepared using an emulsion solvent diffusion method by adding an organic internal phase containing BPO, ethyl cellulose and dichloromethane (DCM) into a stirred aqueous phase containing polyvinyl alcohol (PVA) with stirring for about 8hrs until complete diffusion of DCM. The results show that the microsponges obtained by this technique were predominantly of spherical shape and contain orifices with sponge like appearance. The effect of drug/polymer ratios on morphology, particle size and size distribution were determined; with increase in drug/polymer concentration the porosity and the mean particle size of the sponges decreased. The prepared microsponges were formulated as lotions and the drug release was performed. The data show that an increase in drug/polymer ratio resulted in a reduction in the release rate of drug from BPO microsponge lotions, due to decreased internal porosity of the microsponges.[37]

Ø  Wester RC, Patel R, Nacht S, Leydan J, Malendres J., have revealed that the controlled release of BPO from a porous microsphere polymeric system can reduce topical irritancy. This controlled release of BPO to skin can alter the dose relation that exists between efficacy and skin irritation. Corresponding studies showed reduced skin irritation in cumulative irritancy studies in rabbits and human beings, whereas in - vivo human antimicrobial efficacy studies showed that application of the formulations containing entrapped BPO significantly reduced counts of Propioni bacterium acnes (p less than 0.001) and aerobic bacteria (p less than 0.001) and the free fatty acid/triglyceride ratio in skin lipids. These findings support the hypothesis that, at least for this drug, controlled topical delivery can enhance safety without sacrificing efficacy.[38]

Ø  NetalAmrutiya, Amrita Bajaj and MadhuMadan., have worked on development of microsponges for topical delivery of Mupirocin and they prepared microsponges containing Mupirocin by an emulsion solvent diffusion method. The effect of formulation and process variables such as internal phase volume and stirring speed on the physical characteristics of microsponges were examined on optimized drug/polymer ratio by 32 factorial design. The optimized microsponges were incorporated into an emulgel base. In vitro drug release, ex vivo drug deposition, and in vivo antibacterial activity of mupirocin-loaded formulations were studied. And they have concluded that, the formulations showed enhanced retention of drug in skin, indicating better potential of delivery system as compared with marketed mupirocin ointment and conventional Mupirocinemulgel.[39]

Ø  FerhanSevgi, AysuYurdasiper, BuketKaynarsoy, EzgiTurunç., have worked on formulation, in vitro release and in situ studies in rats of mefenamic acid microparticles and they prepared mefenamic acid loaded Chitosan and alginate beads by Ionotropic gelation process and microsponges containing mefenamic acid and Eudragit RS100 by quasi emulsion solvent diffusion method and they investigated the in vitro characteristics of mefenamic acid microparticles as well as their effects on DNA damage.[40]

Ø  Vikas Jain, Ranjit Singh., have worked on development and characterization of Eudragit RS 100 loaded microsponges and its colonic delivery using natural Polysaccharides. Paracetamol loaded Eudragit based microsponges were prepared using quasi-emulsion solvent diffusion method. The compatibility of the drug with various formulation components was established. Process parameters were analyzed in order to optimize the formulation. Shape and surface morphology of the microsponges were examined using scanning electron microscopy. The colon specific formulations were prepared by compression coating of microsponges with pectin:hydroxypropylmethylcellulose (HPMC) mixture followed by tabletting. The in vitro dissolution studies were done on all formulations and the results were evaluated kinetically and statically. And concluded that the prepared microsponges exhibited characteristics of an ideal delivery system for colon targeting. The unique compressibility of microsponges offers a new alternative for producing mechanically strong tablets. Further colon specific tablets based on microsponges could provide effective local action as microsponges may selectively be taken up by the macrophages present in colon.[41]

Ø  Yoon Yeo, Yan Yang, Nimisha Bajaj, PeishengXu., have worked on development of highly porous large PLGA microparticles for pulmonary drug delivery. They introduced a new process of making highly-porous large polymeric microparticles for local drug delivery to the lungs by inhalation. Poly(lactic-co-glycolic acid) (PLGA) microparticles (average diameter, 10–20 mm) were prepared by the double-emulsion method, in which PLGA was dissolved in dichloromethane. Freshly-prepared Ammonium bicarbonate solution (1% or 1.5%) was added to the polymer solution, and the mixture was sonicated in ice bath. The sonicated mixture was added to 1% polyvinyl alcohol (PVA) solution while it was being homogenized at a rate of 2000–6000 rpm for 1 min, then poured into water, and stirred overnight at room temperature to remove dichloromethane. The particles were collected by centrifugation at 4000 rpm for 5 min, washed 3 times with distilled water, and filtered through a wet-sieve and dried. [42]

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NEED AND OBJECTIVE:
Clotrimazoleis effectively used for treatment of primary and secondary skin infections andindicated for the topical treatment of candidiasis due to Candida albicansand tineaversicolor due to Malassezia furfur and in various dermal infections such as tineapedis, tineacruris, and tineacorporis due to Trichophytonrubrum, Trichophytonmentagrophytes, Epidermophytonfluoccosum, and Microsporumcanis.

Many of conventional delivery systems require high concentration of active agents to be incorporated for effective therapy because of their low efficiency as delivery systems. Due to unique structure of clotrimazole, itis slowly metabolized by the skin. Thus it has a potential to control the release and improves the efficiency of formulation and decrease the frequency of application.So,the existing delivery systemcan be maximized the retention time of an active ingredient either on the skin surface or within the epidermis while minimizing its transdermal penetration into the body. The microsponge-based polymeric microspheres uniquely fulfill such requirements.[44, 45]

Microsponges has aroused increasing interest to be incorporated intopical preparations (such as creams, lotions and ointments)because it offers entrapment of ingredients and  can prevent excessive release and accumulation of ingredients within the epidermis and dermiswhich is believed to contribute towards improved localization, prolonged residence of drug at the site of action, lesser side effects, decreased percutaneous absorption, improved stability and reduced skin irritancy as compared to conventional formulations that can easily release their active ingredients upon application. Thus producing highly concentrated layer of active ingredients and is rapidly absorbed.[46,47]

FUTURE IMPACT :
MDS holds a promising future invarious pharmaceutical applications in the coming years by virtue of their uniqueproperties like small size, efficient carrier characteristics enhanced productperformance and elegancy, extendedrelease, reduced irritation, improvedthermal, physical, and chemical stability soft exible to develop novel product form .It provides a wide range of formulating advantages. Liquids can be transformed into free flowing powders. Formulations can be developed with otherwise incompatible ingredients with prolonged stability without use of preservatives. Safety of the irritating and sensitizing drugs can be increased and programmed release can control the amount of drug release to the targeted site.[48]New classes of pharmaceuticals,biopharmaceuticals (peptides, proteins andDNA-based therapeutics) are fueling therapid evolution of drug deliverytechnology. Thus MDS is a very emerging field which is needed to be explored.They can also be used for tissue engineering and controlled oral delivery of drugs using biodegradable polymers. It provides a wide range of formulating advantages. Formulations can be developed with otherwise incompatible ingredients, with prolonged stability, without the use of preservatives[49]. Therefore, microsponges will be an ideal drug delivery system related to formulations like the transdermal delivery system. As it requires vehicles at a higher concentration in order to dissolve the API for effective therapy, it causes irritation and hypersensitivity reactions in significant users. Another demerit of topical formulations is uncontrolled evaporation of the cactive ingredient, unpleasant odor, and the potential incompatibility of drugs with the vehicles. [50]Conventional formulations of topical drugs are intended to work on the outer layers of the skin. Typically, such products release their active ingredients upon application, producing a highly concentrated layer of an active ingredient that is rapidly absorbed. Thus, the need exists for a system to maximize the amount of time that an active ingredient is present either on the skin surface or within the epidermis.

REFERENCES:
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