Microsponges

 

D.M. Shinkar1* , Bhushan S Bhamare1, R.B. Saudagar2

1Department of Pharmaceutics, R.G. Sapkal College of Pharmacy, Anjaneri, Nashik

2Department of Pharmaceutical Chemistry, R.G. Sapkal College of Pharmacy, Anjaneri, Nashik

*Corresponding Author E-mail: bhushanbhamare29@gmail.com, dattashinkar@gmail.com

 

 

Received on 04.04.2016       Accepted on 20.04.2016     

© Asian Pharma Press All Right Reserved

Asian J. Res. Pharm. Sci. 2016; 6(2): 77-84

DOI: 10.5958/2231-5659.2016.00011.4

 

 

ABSTRACT:

The drug delivery technology landscape has become highly competitive and rapidly evolving. More and more developments in delivery systems are being integrated to optimize the efficacy and cost-effectiveness of the therapy. Peptides, proteins and DNA-based therapeutics cannot be effectively delivered by conventional means. To control the delivery rate of active agents to a predetermined site in human body has been one of the biggest challenges faced by drug industry. Controlled release of drugs onto the epidermis with assurance that the drug remains primarily localized and does not enter the systemic circulation in significant amounts is an area of research that is successively done by the Microsponge delivery system.  This review covers the advantages of Microsponges, their formulation and applications in pharmaceutical field.

 

KEYWORDS: Microsponge, Controlled release, Topical drug delivery, Oral drug delivery, Liquid-liquid suspension polymerization

 


INTRODUCTION:

The area of drug delivery technology is evolving rapidly and becoming highly competitive day by day. The developments in the delivery systems are being utilized to optimize the efficacy and the cost effectiveness of the therapy. The challenges faced by drug development industry are:

• Sustained release technology for reducing irritation of a wide range of APIs and other skin care actives thereby increasing patient/client compliance and results.

• Enhanced formulation stability ensuring long term product efficacy and extended shelf life.

• Superior skin feel and exceptional product esthetics1.

 

Several predictable and reliable systems were developed for systemic drugs under the heading of transdermal delivery system (TDS) using the skin as portal of entry. It has improved the efficacy and safety of many drugs. But TDS is not practical for delivery of materials whose final target is skin itself. Thus the need exists for system to maximize amount of time that an active ingredient is present either on skin surface or within the epidermis, while minimizing its transdermal penetration in the  body 2.

 

The Microsponge delivery system fulfills these requirements. Microsponge deli-very systems are uniform, spherical polymer particles. Their high degree of cross-linking results in particles that are insoluble, inert and of  sufficient strength to stand up to the high shear commonly used in manufacturing of creams, lotions, and powders. Their characteristic feature is the capacity to adsorb or “load” a high degree of active materials into the particle and on to its surface. Its large capacity for entrapment of actives, up to three times its weight, differentiates micro-sponge products from other types of dermatological delivery systems. While the active payload is protected in the formulation by the Microsponge particle, it is delivered to skin via controlled diffusion. This sustained release of actives to skin over time is an extremely valuable tool to extend the efficacy and lessen the irritation commonly associated with powerful therapeutic agents such as Retinoid or Benzoyl Peroxide. Micro-sponge polymers possess the versatility to load a wide range of actives providing the benefits of enhanced product efficacy, mildness, tolerability, and extended wear to a wide range of skin therapies 3.

 

ADVANTAGES:

·        Advanced oil control, absorb up to 6 times its weight without drying

·        Extended release

·        Reduced irritation formulas

·        Allows novel product form

·        Improved product aesthetics

·        Extended release, continuous action up to 12 hours

·        Reduced irritation, better tolerance means broader consumer acceptance

·        Improved product aesthetics, gives product an elegant feel

·        Improves stability, thermal, physical and chemical stability

·        Allows incorporation of immiscible products.

·        Improves material processing eg. liquid can be converted to powders

·        Allows for novel product forms.

·        Improves efficacy in treatment.

·        Cure or control confirm more promptly.

·        Improve control of condition.

·        Improve bioavailability of same drugs 4.

 

APPLICATIONS OF MICROSPONGE SYSTEMS:

Microsponge delivery systems are used to enhance the safety, effectiveness and aesthetic quality of topical prescription, over-the-counter and personal care products. Products under development or in the market place utilize the Topical Microsponge systems in three primary

ways:

1. As reservoirs releasing active ingredients over an extended period of time,

2. As receptacles for absorbing undesirable substances, such as excess skin oils, or

3. As closed containers holding ingredients away from the skin for superficial action.

 

Releasing of active ingredients from conventional topical formulations over an extended period of time is quite difficult. Cosmetics and skin care preparations are intended to work only on the outer layers of the skin. 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 overmedication, 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. Microsponges are porous, polymeric microspheres that are used mostly for topical and recently for oral administration. 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.

 

(і)Topical drug delivery using microsponge technology:

Benzoyl peroxide (BPO) is commonly used in topical formulations for the treatment of acne and athletes foot. Skin irritation is a common side effect, and it has been shown that controlled release of BPO from a delivery system to the skin could reduce the side effect while reducing percutaneous absorption. Benzoyl peroxide micro particles were prepared using an emulsion solvent diffusion method by adding an organic internal phase containing benzoyl peroxide, ethyl cellulose and dichloromethane into a stirred aqueous phase containing polyvinyl  alcohol 5.

 

Disorders of hyper pigmentation such as melasma and post inflammatory hyper pigmentation (PIH) are common, particularly among people with darker skin types. Hydroquinone (HQ) bleaching creams are considered the gold standard for treating hyper pigmentation. Recently, a new formulation of HQ 4% with retinol 0.15% entrapped in Microsponge reservoirs was developed for the treatment of melasma and PIH. Microsponges were used to release HQ gradually to prolong exposure to treatment and to minimize skin irritation6. Microsponges containing mupirocin were prepared by an emulsion solvent diffusion method. The optimized Microsponges were incorporated into an emulgel base. Drug release through cellulose dialysis membrane showed diffusion controlled release pattern and drug deposition studies using rat abdominal skin exhibited significant retention of active in skin from Microsponge based formulations by 24 h. The optimized formulations were stable and nonirritant to skin as demonstrated by Draize patch test. Microsponges-based emulgel formulations showed prolonged efficacy in mouse surgical wound model infected with S. aureus. Mupirocin was stable in topical emulgel formulations and showed enhanced retention in the skin indicating better potential of the delivery system for treatment of primary and secondary skin infections, such as impetigo, eczema, and atopic dermatitis7. Fluconazole is an active agent against yeasts, yeast-like fungi and dimorphic fungi, with possible drawback of itching in topical therapy. Microspongic drug delivery system using fluconazole with an appropriate drug release profile and to bring remarkable decrease in frequently appearing irritation. Microsponges were prepared by liquid-liquid suspension polymerization of styrene and methyl methacrylate. Microsponges were dispersed in gel prepared by using carbopol 940 and evaluated for drug release using Franz diffusion cell. The average drug release from the gels containing microspongic fluconazole was 67.81 % in 12 h. Drug release from the gels containing Microsponge loaded fluconazole and marketed formulations has followed zero order kinetics (r = 0.973, 0.988 respectively). Drug diffusion study reveals extended drug release, in comparison with marketed formulations containing un-entrapped fluconazole. Microspongic system for topical delivery of fluconazole was observed potential in extending the release8. Carac contains 0.5% fluorouracil incorporated into a patented porous Microsponge System. The particles are dispersed in a cream and hold the active ingredient until applied to the skin. Carac cream is the newest topical treatment for multiple actinic or solar keratoses. Carac provides sufferers with options for shorter duration of therapy (1, 2 or 4 weeks), once-a-day dosing, and more rapid recovery time from irritation9. An MDS system for retinoic acid was developed and tested for drug release and anti-acne efficacy. Statistically significant greater reductions in inflammatory and non-inflammatory lesions were obtained with entrapped tretinoin in the MDS10.

 

(іі)Oral drug delivery using microsponge technology

In oral drug delivery the Microsponge system increase the rate of solubilization of poorly water soluble drugs by entrapping them in the Microsponge system’s pores. As these pores are very small the drug is in effect reduced to microscopic particles and the significant increase in the surface area thus greatly increase the rate of solubilization. Controlled oral delivery of ibuprofen Microsponges is achieved with an acrylic polymer, eudragit RS, by changing their intraparticle density. The release of ketoprofen incorporated into modified release ketoprofen Microsponge 200 mg tablets and Profenid Retard 200 mg was studied in vitro and in vivo. The formulation containing ketoprofen Microsponges yielded good modified release tablets. An in vivo study was designed to evaluate the pharmacokinetic parameters and to compare them with the commercially available ketoprofen retard tablets containing the same amount of the active drug. Commercial ketoprofen retard tablets showed a more rapid absorption rate than modified release tablets and peak levels were reached within almost 3.6 h after administration. However, the new modified release tablets showed a slower absorption rate and peak levels were reached 8 h after administration11. A 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. This approach opens up entirely new opportunities for MDS by colon specific targeting of drugs. Paracetamol loaded eudragit based Microsponges were prepared using quasiemulsion solvent diffusion method, then the colon specific tablets were prepared by compressing the Microsponges followed by coating with pectin: hydroxypropylmethyl cellulose (HPMC) mixture. In vitro release studies exhibited that compression coated colon specific tablet formulations started releasing the drug at 6th hour corresponding to the arrival time at proximal colon12. Dicyclomine loaded, Eudragit based microsponges were prepared using a quasiemulsion solvent diffusion method. Kinetic analysis showed that the main mechanism of drug release was by Higuchi matrix controlled diffusion. Drug release was biphasic with an initial burst effect with 16 – 30 % of the drug was released in the first hour. Cumulative release for the Microsponges over 8 hours ranged from 59 - 86 %13. 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. The colon specific formulations were prepared by compression coating and also pore plugging of Microsponges with pectin: hydroxypropylmethyl cellulose (HPMC) mixture followed by tab letting. Mechanically strong tablets prepared for colon specific drug delivery were obtained owing to the plastic deformation of sponge-like structure of Microsponges. In vitro studies exhibited that compression coated colon specific tablet formulations started to release the drug at the 8th hour corresponding to the proximal colon arrival time due to the addition of enzyme, following a modified release pattern while the drug release from the colon specific formulations prepared by pore plugging the Microsponges showed an increase at the 8th hour which was the time point that the enzyme addition made14.

 

(ііі)Bone tissue engineering using Microsponge technology:

3D biodegradable porous scaffold plays a very important role in articular cartilage tissue engineering. The hybrid structure of 3D scaffolds was developed that combined the advantages of natural type I collagen and synthetic PLGA knitted mesh. The mechanically strong PLGA mesh served as a skeleton while the collagen microsponges facilitated cell seeding and tissue formation. The scaffolds were divided into 3 groups:

 

(1) THIN:

collagen Microsponge formed in interstices of PLGA mesh;

 

(2) SEMI:

collagen Microsponge formed on one side of PLGA mesh; (3) SANDWICH: collagen sponge formed on both sides of PLGA mesh. Bovine chondrocytes were cultured in these scaffolds and transplanted subcutaneously into nude mice for 2, 4, and 8 weeks. All three groups of transplants showed homogeneous cell distribution, natural chondrocyte morphology, and abundant cartilaginous ECM deposition. Production of GAGs per DNA and the expression of type II collagen and aggre can mRNA were much higher in the SEMI and SANDWICH groups than in the THIN group. When compared to native articular cartilage, the mechanical strength of the engineered cartilage reached 54.8%, 49.3% in Young's modulus and 68.8%, 62.7% in stiffness, respectively, in SEMI and SANDWICH. These scaffolds could be used for the tissue engineering of articular cartilage with adjustable thickness. The design of the hybrid structures provides a strategy for the preparation of 3D porous scaffolds 15.

 

A novel three-dimensional porous scaffold has been developed for bone tissue engineering by hybridizing synthetic poly (DL-lactic-co-glycolic acid) (PLGA), naturally derived collagen, and inorganic apatite. First, a porous PLGA sponge was prepared. Then, collagen Microsponges were formed in the pores of the PLGA sponge. Finally, apatite particulates were deposited on the surfaces of the collagen Microsponges in the pores of PLGA sponge. The PLGA-collagen sponge served as a template for apatite deposition, and the deposition was accomplished by alternate immersion of PLGA–collagen sponge in CaCl2 and Na2HPO4 aqueous solutions and centrifugation. The deposited particulates were small and scarce after one cycle of alternate immersion. Their number and size increased with the number of alternate immersion cycles. The surfaces of collagen Microsponges were completely covered with apatite after three cycles of alternate immersion. The porosity of the hybrid sponge decreased gradually as the number of alternate immersion increased. Energy dispersive spectroscopy analysis and X-ray diffraction spectra showed that the calcium to- phosphorus molar ratio of the deposited particulates and the level of crystallinity increased with the number of alternate immersion cycles, and became almost the same as that of hydroxyapatite after four cycles of alternate immersion. The deposition process was controllable. Use of the PLGA sponge as a mechanical skeleton facilitated formation of the PLGA–collagen– apatite hybrid sponge into desired shapes and collagen Microsponges facilitated the uniform deposition of apatite particulates throughout the sponge. The PLGA– collagen–apatite hybrid sponge would serve as a useful three-dimensional porous scaffold for bone tissue engineering16.

 

(іv)Cardiovascular engineering using microsponge technology:

Biodegradable materials with autologous cell seeding requires a complicated and invasive procedure that carries the risk of infection. To avoid these problems, a biodegradable graft material containing collagen Microsponge that would permit the regeneration of autologous vessel tissue has developed. The ability of this material to accelerate in situ cellularization with autologous endothelial and smooth muscle cells was tested with and without precellularization. Poly (lactic-co-glycolic acid) as a biodegradable scaffold was compounded with collagen microsponge to form a vascular patch material. These poly (lacticco- glycolic acid)-collagen patches with (n = 10) or without (n = 10) autologous vessel cellularization were used to patch the canine pulmonary artery trunk. Histologic and biochemical assessments were performed 2 and 6 months after the implantation. There was no thrombus formation in either group, and the poly (lactic-co-glycolic acid) scaffold was almost completely absorbed in both groups. Histologic results showed the formation of an endothelial cell monolayer, a parallel alignment of smooth muscle cells, and reconstructed vessel wall with elastin and collagen fibers. The cellular and extracellular components in the patch had increased to levels similar to those in native tissue at 6 months. This patch shows promise as a bioengineered material for promoting in situ cellularization and the regeneration of autologous tissue in cardiovascular surgery17.

 

(v)Reconstruction of vascular wall using microsponge technology:

The tissue-engineered patch was fabricated by compounding a collagen-Microsponge with a biodegradable polymeric scaffold composed of polyglycolic acid knitted mesh, reinforced on the outside with woven polylactic acid. Tissue-engineered patches without precellularization were grafted into the porcine descending aorta (n = 5), the porcine pulmonary arterial trunk(n = 8), or the canine right ventricular outflow tract (as the large graft model; n = 4). Histologic and biochemical assessments were performed 1, 2, and 6 months after the implantation. There was no thrombus formation in any animal. Two months after grafting, all the grafts showed good in situ cellularization by hematoxylin/eosin and immunostaining. The quantification of the cell population by polymerase chain reaction showed a large number of endothelial and smooth muscle cells 2 months after implantation. In the large graft model, the architecture of the patch was similar to that of native tissue 6 months after implantation and this patch can be used as a novel surgical material for the repair of the cardiovascular system18.

 

METHODS OF PREPARATION OF MICROSPONGES [19-23]

Initially, drug loading in Microsponges is mainly take place in two ways depending upon the physicochemical properties of drug to be loaded. If the drug is typically an inert non-polar material which will generate the porous structure then, it is known as porogen. A Porogen drug neither hinders the polymerization process nor become activated by it and also it is stable to free radicals is entrapped with one-step process (liquid-liquid suspension polymerization). Microsponges are suitably prepared by the following methods:

 

a) Liquid-liquid suspension polymerization:

Microsponges are prepared by suspension polymerization process in liquid-liquid systems (one-step process). Firstly, the monomers are dissolved along with active ingredients (non-polar drug) in an appropriate solvent solution of monomer, which are then dispersed in the aqueous phase with agitation. Aqueous phase typically consist of additives such as surfactants and dispersants (suspending agents) etc in order to facilitate the formation of suspension. Once the suspension is established with distinct droplets of the preferred size then, polymerization is initiated by the addition of catalyst or by increasing temperature as well as irradiation. The polymerization method leads to the development of a reservoir type of system that opens at the surface through pores. During the polymerization, an inert liquid immiscible with water however completely miscible with monomer is used to form the pore network in some cases. Once the polymerization process is complete, the liquid is removed leaving the Microsponges which is permeate within preformed Microsponges then, incorporates the variety of active substances like anti fungal, rubefacients, anti acne, anti inflammatory etc and act as a topical carriers. In some cases, solvent can be used for efficient and faster inclusion of the functional substances. If the drug is susceptible to the condition of polymerization then, two-step process is used and the polymerization is performed by means of alternate porogen and it is replaced by the functional substance under mild conditions. The various steps involved in the preparation of Microsponges are summarized as follows:

 

Step 1: Selection of monomer as well as combination of monomers.

Step 2: Formation of chain monomers as polymerization starts.

Step 3: Formations of ladders as a result of cross-linking between chain monomers.

Step 4: Folding of monomer ladder to form spherical particles.

Step 5: Agglomeration of microspheres leads to the production of bunches of microspheres.

Step 6:Binding of bunches to produce Microsponges.

 

a) Quasi-Emulsion Solvent Diffusion Method:

Porous microspheres (Microsponges) were also prepared by a quasi-emulsion solvent diffusion method (two-step process) using an internal phase containing polymer such as Eudragit RS 100 which is dissolved in ethyl alcohol. Then, the drug is slowly added to the polymer solution and dissolved under ultrasonication at 35oC and plasticizer such as triethylcitrate (TEC) was added in order to aid the plasticity. The inner phase is then poured into external phase containing polyvinyl alcohol and distilled water with continuous stirring for 2 hours11. Then, the mixture was filtered to separate the Microsponges. The product (Microsponges) was washed and dried in an air heated oven at 40°C for 12 hrs.

 

PHYSICAL CHARACTERIZATION OF MICROSPONGES:

(i) Particle size determination24

Particle size analysis of loaded and unloaded Microsponges can be performed by laser light diffractometry or any other suitable method. The values can be expressed for all formulations as mean size range. Cumulative percentage drug release from Microsponges of different particle size will be plotted against time to study effect of particle size on drug release. Particles larger than 30μm can impart gritty feeling and hence particles of sizes between 10 and 25μm are preferred to use in final topical formulation.

 

(ii) Morphology and surface topography of microsponges:25

For morphology and surface topography, prepared Microsponges can be coated with gold–palladium under an argon atmosphere at room temperature and then the surface morphology of the Microsponges can be studied by scanning electron microscopy (SEM). SEM of a fractured Microsponge particle can also be taken to illustrate its ultra structure.

 

(iii) Determination of loading efficiency and production yield:26

The loading efficiency (%) of the Microsponges can be calculated according to the following equation:

 

Loading efficiency =

Actual Drug Content in Microsponges X 100…….. (1)

 

Theoretical Drug Content:

The production yield of the micro particles can be determined by calculating accurately the initial weight of the raw materials and the last weight of the Microsponge obtained.

 

Production Yield=

Practical mass of Microsponges X 100……… (2)

 

Theoritical mass (Polymer+drug)

 

(iv) Determination of true density:27

The true density of micro particles is measured using an ultra-pycnometer under helium gas and is calculated from a mean of repeated determinations.

 

(v) Characterization of pore structure:28, 29

Pore volume and diameter are vital in controlling the intensity and duration of effectiveness of the active ingredient. Pore diameter also affects the migration of active ingredients from Microsponges into the vehicle in which the material is dispersed. Mercury intrusion porosimetry can be employed to study effect of pore diameter and volume with rate of drug release from Microsponges. Porosity parameters of Microsponges such as intrusion–extrusion isotherms, pore size distribution, total pore surface area, average pore diameters, interstitial void volume, percent porosity, percent porosity filled, shape and morphology of the pores, bulk and apparent density can be determined by using mercury intrusion porosimetry.

 

(vi) Compatibility studies:30-32

Compatibility of drug with reaction adjuncts can be studied by thin layer chromatography (TLC) and Fourier Transform Infra-red spectroscopy (FT-IR). Effect of polymerization on crystallinity of the drug can be studied by powder X-ray diffraction (XRD) and Differential Scanning Colorimetry (DSC). For DSC approximately 5mg samples can be accurately weighed into aluminum pans and sealed and can be run at a heating rate of 15oC/min over a temperature range 25–430oC in atmosphere of nitrogen.

 

(vii) Polymer/monomer composition:33

Factors such as microsphere size, drug loading, and polymer composition govern the drug release from microspheres. Polymer composition of the MDS can affect partition coefficient of the entrapped drug between the vehicle and the Microsponge system and hence have direct influence on the release rate of entrapped drug. Release of drug from Microsponge systems of different polymer compositions can be studied by plotting cumulative % drug release against time.

 

(viii) Resiliency (viscoelastic properties) :28

Resiliency (viscoelastic properties) of Microsponges can be modified to produce beadlets that is softer or firmer according to the needs of the final formulation. Increased cross-linking tends to slow down the rate of release.

 

(ix) Dissolution studies:

Dissolution profile of microsponges can be studied by use of dissolution apparatus USP XXIII with a modified basket consisted of 5μm stainless steel mesh. The speed of the rotation is 150 rpm. The dissolution medium is selected while considering solubility of actives to ensure sink conditions. Samples from the dissolution medium can be analyzed by suitable analytical method at various intervals.

 

(x) Kinetics of release:

To determine the drug release mechanism and to compare the release profile differences among Microsponges, the drug released amount versus time was used. The release data were analyzed with the following mathematical models:

 

Q = k1 tn or logQ = log k 1 + n log t …. (3)

 

Where Q is the amount of the released at time (h), n is a diffusion exponent which indicates the release mechanism, and k 1 is a constant characteristic of the drug– polymer interaction. From the slope and intercept of the plot of log Q versus log t, kinetic parameters n and k 1 were calculated. For comparison purposes, the data was also subjected to Eq. (4), which may be considered a simple, Higuchi type equation.

 

Q = k 2 t0.5 + C…. (4)

 

Eq. (4), for release data dependent on the square root of time, would give a straight line release profile, with k 2 presented as a root time dissolution rate constant and C as a constant.

 

MARKETED FORMULATIONS OF MICROSPONGE:34

Marketed formulation using the MDS includes Dermatological products which can absorb large amounts of excess of skin oil, 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, and unique tactile qualitie.

 

CONCLUSION:

Ease manufacturing, simple ingredients and wide range actives can be entrapped along with a programmable release make Microsponges extremely attractive. MDS is originally developed for topical delivery of drugs like anti-acne, anti-inflammatory, anti-fungal, anti-dandruffs, antipruritics, rubefacients etc. Now days it can also be used for tissue engineering and controlled oral delivery of drugs using bio erodible polymers, especially for colon specific delivery. Microsponge delivery systems that can precisely control the release rates or target drugs to a specific body site have an enormous impact on the health care system. MDS holds a promising future in various pharmaceutical applications in the coming years by virtue of their unique properties like small size, efficient carrier characteristics enhanced product performance and elegancy, extended release, reduced irritation, improved thermal, physical, and chemical stability so flexible to develop novel product forms. New classes of pharmaceuticals, biopharmaceuticals (peptides, proteins and DNA-based therapeutics) are fueling the rapid evolution of drug delivery technology. Thus MDS is a very emerging field which is needed to be explored.

 

REFERENCES:

1.       Kirti Deshmukh, Sushilkumar S Poddar. Solid porous microsphere: emerging trend in pharmaceutical technology. Int J Pharm Bio Sci, 2(1), 2011, 364-377.

2.       Patel SB, Patel HJ and Seth AK. Microsponge drug delivery system: an overview. J Global Pharm Tech, 2(8), 2010, 1-9.

3.       Viral Shaha, Hitesh Jain, Jethva Krishna1, Pramit Patel. Microsponge drug delivery: A Review. Int. J. Res. Pharm. Sci, 1(2), 2010, 212-218.

4.       Patidar K, Soni M, Saxena C, Soni P, Sharma DK. Microspongea versatile vesicular approach for transdermal drug delivery system. J Global Pharm Tec, 2(3), 2010, 154-164.

1.       5 Jelvehgari M, Siahi-Shadbad MR, Azarmi S, Gary P, Martin, Nokhodchi A. The Microsponge delivery system of benzoyl peroxide: Preparation, characterization and release studies. International Journal of Pharmaceutics 2006;308:124-132.

5.       Khopade AJ, Jain Sanjay, Jain NK. “The Microsponge”. Eastern Pharmacist 1996:49-53.

6.       Fincham JE, Karnik KA. Patient Counseling and Derm Therapy. US Pharm. 1994;19:56-57,61-62,71-72,74,77-78,81-82.

7.       Amrutiya N, Bajaj A, Madan M. AAPS Pharm. Sci. Tech. Vol. 10, No. 2, June 2009:402 09.

8.       Grimes PE. A Microsponge formulation of hydroquinone 4% and retinol 0.15% in the treatment of melasma and post-inflammatory hyperpigmentation 2004;74(6):362- 368.

9.       D’souza JI, Harinath NM. Topical Anti-Inflammatory Gels of Fluocinolone Acetonide Entrapped in Eudragit Based Microsponge Delivery System. Research J. Pharm. and Tech 2008;1(4):502-506.

10.     James J, Leyden , Alan S, Diane T, Kenneth W, Guy W. Topical Retinoids in Inflammatory Acne: Retrospective, Investigator-Blinded, Vehicle-Controlled, Photographic Assessment, Clinical Therapeutics 2005;27:216-224.

11.     Comoglu T, Savaşer A, Ozkan Y, Gönül N, Baykara T. Enhancement of ketoprofen bioavailability by formation of microsponge tablets. Pharmazie. 2007;62(1):51-4.

12.     Jain V, Singh R. Development and characterization of eudragit RS 100 loaded microsponges and its colonic delivery using natural polysaccharides. Acta Poloniae Pharmaceutica - Drug Research, 2010; 67:407-415.

13.     Jain V, Singh R. Dicyclomine-loaded Eudragit®-based Microsponge with Potential for Colonic Delivery: Preparation and Characterization. Tropical Journal of Pharmaceutical

2.       Research. 2010;9(1):67-72.

14.     Orlu M, Cevher E, Araman A. Design and evaluation of colon specific drug delivery system containing flurbiprofen microsponges. Int. J. Pharm. 2006; 318:103-117.

15.     Dai W, Kawazoe N, Lin X, Dong J, Chen G. The influence of structural design of PLGA/collagen hybrid scaffolds in cartilage tissue engineering. Biomaterials 2010; 31(8):2141-2152.

16.     Chen G, Ushida T, Tateishi T. Poly (DL-lactic-co-glycolic acid) sponge hybridized with collagen microsponges and deposited apatite particulates. Journal of Biomedical Materials Research 2001;57(1):8-14.

17.     Iwai S, Sawa Y, Ichikawa H, Taketani S, Uchimura E, Chen G, Hara M, Miyake J, Matsuda H. Biodegradable polymer with collagen microsponge serves as a new bioengineered cardiovascular prosthesis. J. Thorac. Cardiovasc. Surg. 2004; 128(3):472-479.

18.     Mahajan Aniruddha G, Jag tap Leena S, Chaudhari atul L, Swami sima P, Mali Prabha R. Formulation and evaluation of microsponge drug delivery system using Indomethacin. IRJP, 2(10), 2011, 64-69.

19.     Jelvehgari M, Siahi-Shadbad MR, Azarmi S, Gary P Martin, Ali Nokhodchi. The microsponge delivery system of benzoyl peroxide: Preparation, characterization and release studies. Int J Pharm, 308, 2006, 124–132

20.     Tansel C¸ Omog˘Lu, Nursin Gonu, Tamer Baykara. Preparation and in vitro evaluation of modified release ketoprofen Microsponges. Il Farmaco, 58, 2003, 101-106.

21.     Saboji J. K, Manvi FV, Gadad AP. & Patel BD. Formulation and evaluation of ketoconazole Microsponge gel by quassi emulsion solvent diffusion. Journal of Cell and Tissue Research, 11(1), 2011, 2691-2696.

22.     Neelam Jain, Pramod Kumar Sharma, Arunabha Banik. Recent advances on microsponge delivery system. Int J Pharm Sci Review and Res, 8 (2), 2011, 13-23.

23.     Chadawar V, Shaji J. Microsponge delivery system. Current Drug

3.       Delivery 2007; 4:123-129.

24.     Martin A, Swarbrick J, Cammarrata A. In: Physical Pharmacy- Physical Chemical Principles in Pharmaceutical Sciences. 1991; 3:527.

25.     Kilicarslan, M., Baykara, T. The effect of the drug/polymer ratio on the properties of Verapamil HCl loaded microspheres. Int. J. Pharm. 2003; 252:99–109.

26.     Emanuele AD, Dinarvand R. Preparation, Characterization and Drug Release from Thermo responsive Microspheres. International Journal of Pharmaceutics 1995:237-42.

27.     Barkai A, Pathak V, Benita S. Polyacrylate (Eudragit retard) microspheres for oral controlled release of nifedipine. I. Formulation design and process optimization. Drug Dev. Ind. Pharm. 1990; 16:2057- 2075.

28.     D’ souza JI. The Microsponge Drug Delivery System: For Delivering an Active Ingredient by Controlled Time Release. Pharma.info.net 2008;6(3):62.

29.     Nacht S, Kantz M. The Microsponge: A Novel Topical Programmable Delivery System 1992; 42:299-325.

4.       Jones DS, Pearce KJ. Investigation of the effects of some process variables on, microencapsulation of propranolol HCl by solvent evaporation method. Int J Pharm 1995; 118:99-205.

30.     Kawashima Y, Niwa T, Takeuchi H, Hino T, Itoh Y, Furuyama S. Characterization of polymorphs of tranilast anhydrate and tranilast monohydrate when crystallized by two solvent change spherical crystallization techniques. J. Pharm. Sci. 1991; 81:472-478.

31.     Bodmeier R, Chen H. Preparation and characterization of microspheres containing the anti-inflammatory agents, indomethacin, ibuprofen, and ketoprofen. J. Control Release s1989; 10:165-75.

32.     Iwai S, Sawa Y, Taketani S, Torikai K, Hirakawa K, Matsuda H. Novel tissue-engineered biodegradable material for reconstruction of vascular wall. Ann. Thorac. Surg. 2005; 80(5): 1821-1827