INTRODUCTION:

Microsponges are polymeric delivery systems composed of porous microspheres. They are tiny sponge-like spherical particles with a large porous surface. Moreover, they may enhance stability, reduce side effects and modify drug release favorably. Microsponge technology has many favourable characteristics, which make it a versatile drug delivery vehicle. Microsponge Systems are based on microscopic, polymer-based microspheres that can suspend or entrap a wide variety of substances, and can then be incorporated into a formulated product such as a gel, cream, liquid or powder. MDS can provide increased efficacy for topically active agents with enhanced safety, extended product stability and improved aesthetic properties in an efficient manner^{[1, 2, 3]}.

To control the delivery rate of active agents to a predetermined site in the human body has been one of the biggest challenges faced by Pharmaceutical scientists. Several predictable and reliable systems have been developed for systemic delivery of 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 that may be better administered through skin. But TDS is not practicable for delivery of materials whose final target is skin itself. 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 a challenging area of research^[^4]. Microsponges consist of non-collapsible structures with porous surface through which active ingredients are released in controlled manner. Depending upon the size, the total pore length may range up to 10 ft. and pore volume up to 1 ml/g. When applied to the skin, the microsponge drug delivery system (MDS) releases its active ingredient on a time mode and also in response to other stimuli such as rubbing, temperature, and pH Microsponges have the capacity to adsorb or load a high degree of active materials into the particle or onto its surface. Its large capacity for entrapment of actives up to 3 times its weight differentiates microsponges from other types of dermatological delivery systems. Mostly microsponge is use for transdermal drug delivery system ^{[5, 6]}.

Figure 1: View of microsponge^[^5]

Advantages microsponge delivery system (MDS)^[^6]:

· Microsponges can absorb oil up to 6 times its weight without drying.

· It provides continuous action up to 12 hours i.e. extended release.

· Improved product elegancy.

· Lessen the irritation and better tolerance leads to improved patient compliance.

· They have better thermal, physical and chemical stability.

· These are non-irritating, non-mutagenic, non allergenic and non-toxic.

· MDS allows the incorporation of immiscible products.

· They have superior formulation flexibility.

· In contrast to other technologies like microencapsulation and liposomes, MDS has wide range of chemical stability, higher payload and are easy to formulate.

· Liquids can be converted in to powders improving material processing.

· It has flexibility to develop novel product forms.

· MDS can improve bioavailability of same drugs.

· It can also improve efficacy in treatment.

Salient features of microsponges^[^7]:

· MDS are stable over range of pH 1 to 11.

· These are stable at the temperature up to 130˚C.

· These are compatible with the majority of vehicles and ingredients.

· Self sterilizing as their average pore size is 0.25μm where bacteria cannot penetrate.

· These systems have higher payload up to 50 to 60%.

· These are free flowing and can be cost effective.

Characteristics of actives moieties that is entrapped into microsponges:

1. Active ingredients that are entrapped in microsponge can then be incorporated into many products such as creams, gels, powders, lotions and soaps.

2. Certain considerations are taken into account while, formulating the vehicle in order to achieve desired product characteristics.

3. It should be either fully miscible in monomer as well as capable of being made miscible by addition of small amount of a water immiscible solvent.

4. It should be inert to monomers and should not increase the viscosity of the mixture during formulation.

5. It should be water immiscible or nearly only slightly soluble.

6. It should not collapse spherical structure of the microsponges.

7. It should be stable in contact with polymerization catalyst and also in conditions of polymerization.

8. The solubility of actives in the vehicle must be limited.

9. If not, the vehicles will deplete the microsponges before the application.

10. Not more than 10 to 12% w/w microsponges must be incorporated into the vehicle in order to avoid cosmetic problems.

11. Payload and polymer design of the microsponges for the active must be optimized for required release rate for given period of time ^{[8, 9]}

Method of Preaparation of Microsponges:

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 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:

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^[^9]. 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.^[^10]

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.

Quasi-emulsion solvent diffusion

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 35⁰C 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 2hr^[^11]. Then, the mixture was filtered to separate the microsponges. The product (microsponges) was washed and dried in an airheated oven at 40°C for 12hr ^[12].

Drug Release Mechanism

Microsponges can be intended to release given amount of active ingredients over time in response to one or more following external triggers i.e. pressure, temperature change and solubility etc which are described as follows:

Temperature change: At room temperature, few entrapped active ingredients can be too viscous to flow suddenly from microsponges onto the skin. With increase in skin temperature, flow rate is also increased and therefore release is also enhanced ^{[14] .}

Pressure: Rubbing or pressure applied can release the active ingredient from microsponges onto skin¹⁴.

Solubility: Microsponges loaded with water miscible ingredients like antiseptics and anti-perspirants will release the ingredient in the presence of water. The release can also be activated by diffusion but taking into consideration, the partition coefficient of the ingredient between the microsponges and the external system ^[14].

Characterization of Microsponges

Particle size analysis: Particle size determination of loaded as well as blank microsponges can be carried out by laser light diffractometry or any other appropriate method. Values can be expressed for all the formulations in terms of mean size range. It can be studied by plotting cumulative % drug release from microsponges of different particle size against time to study effect of particle size on drug release. Particles having sizes bigger than 30 μm can impart grittiness and thus particles having sizes between 10 and 25 μm are favored to be use in final topical formulation ^{[15] .}

Determination of entrapment efficiency and production yield: The entrapment efficiency (%) of the microsponges can be calculated according to the following equation16: Entrapment efficiency (%) = [Actual drug content/Theoretical drug content] X 100 The production yield of the microsponges can be obtained by calculating accurately the initial weight of the raw materials and the last weight of the microsponge obtained. Production yield = [Practical mass of microsponges/Theoretical mass (polymer + drug)] X 100 ^[16] .ON OF

Morphology and surface topography of microsponges:

The internal and external morphology and surface topography can be studied by scanning electron microscopy (SEM). Prepared microsponges can be coated with gold–palladium under an argon atmosphere at room temperature and then SEM images of microsponges were recorded at the required magnification. SEM of a fractured microsponge particle can also be taken to illustrate its ultra structure ^{[17] .}

Characterization of pore structure:

Pore volume and pore diameter are critical in controlling the intensity as well as duration of effectiveness of the active ingredient. Pore diameter can also affects the passage of active ingredients from microsponges into the vehicle in which the material is dispersed. The effect of pore diameter as well as volume with rate of drug release from microsponges can be studied by mercury intrusion porosimetry. Porosity parameters of microsponges such as intrusion–extrusion isotherms, total pore surface area, pore size distribution, average pore diameters, shape and morphology of the pores, bulk and apparent density can also be determined by using mercury intrusion porosimetry ^{[17] .}

Determination of true density:

The true density of microsponges was measured by an ultra-pycnometer under helium gas and was calculated from a mean of repeated determinations ^{[18] .}

Polymer/ Monomer composition:

Various factors such as microsphere size, polymer composition and drug loading govern the drug release from microspheres. Polymer composition can also influence the partition coefficient of the entrapped drug between the microsponge system and the vehicle and thus have direct affect on the rate of release of entrapped drug. Drug release from microsponge systems of different polymer compositions can be studied by plotting cumulative % drug release against time. The choice of monomer is dictated both by the vehicle into which it will be dispersed and characteristics of active ingredient to be entrapped. Polymers with varying degrees of hydrophobicity or lipophilicity or electrical charges may be prepared to give flexibility in the release of active ingredients. A variety of probable monomer combinations will be screened for their appropriateness with drugs by studying their drug release profile^[^18]

Resiliency:

Viscoelastic properties (resiliency) of microsponges can be tailored to create bead lets which is softer or firmer according to the requirements of the final formulation. Increased crosslinking tends to slow down the release rate. Therefore, resiliency of microsponges will be performed and optimized as per the prerequisite by considering release as a function of crosslinking with time^[^19] .

In-vitro release studies:

In-vitro release studies have been carried out using dissolution apparatus USP XXIII equipped with a modified basket consisted of 5μm stainless steel mesh. Dissolution rates were measured at 37°C under 150 rpm rotor speed. The dissolution medium is selected while considering solubility of active ingredients to ensure sink conditions. Sample aliquots were withdrawn from the dissolution medium and analyzed by suitable analytical method (UV spectrophotometer) at regular intervals of time ^[20].

Microsponge for topical delivery:

Benzoyl peroxide (BPO) is mainly used in the treatment of mild to moderate acne and athlete’s foot and the most common side effect associated with BPO is skin irritation and it has been shown that controlled release of BPO from a delivery system to the skin could lessen the side effect while reducing percutaneous absorption. Topical delivery system with reduced irritancy was successfully developed. It has been revealed that encapsulation and controlled release of BPO can lessen the side effect while, when administered to the skin it also reduces percutaneous absorption. The goal of the study was to design and formulate a suitable encapsulated form of BPO using microsponge technology and investigate the parameters affecting the morphology and other characteristics of the resulting products with the help of scanning electron microscopy (SEM). Benzoyl peroxide particles were prepared by an emulsion solvent diffusion method by including an organic internal phase containing benzoyl peroxide, dichloromethane and ethyl cellulose into a stirred aqueous phase containing polyvinyl alcohol (PVA)^[^21] .

Different concentrations of BPO microsponges were incorporated in lotion formulations and the drug release from these formulations were studied. The SEM micrographs of the BPO microsponges used for the measurement of their size and showed that they were porous and spherical. Results showed that the morphology and particle size of microsponges were affected by drug: polymer ratio, amount of emulsifier used and stirring rate. The results obtained also showed that with increase in the ratio of drug: polymer resulted in a reduction in the rate of release of BPO from the microsponges.

The release data showed that the highest and the lowest release rates were obtained from lotions containing plain BPO particles and BPO microsponges with the drug:polymer ratio (13:1) respectively. Kinetics studies showed that the release data followed peppas model but diffusion was the main mechanism of drug release from BPO microsponges. Amrutiya et al25 developed microsponge based topical delivery system of mupirocin by an emulsion solvent diffusion method and evaluated for sustained release and enhanced drug deposition in the skin.

The effect of formulation and process variables like stirring speed and internal phase volume on the physical characteristics of microsponges was analyzed on optimized drug/polymer ratio by 32 factorial design. The optimized microsponges were incorporated into an emulgel base. Several parameters were studied i.e. in-vitro drug release, ex-vivo drug deposition and in-vivo antibacterial activity of mupirocin-loaded formulations. Prepared microsponges were spherical and porous and found no interaction between drug and polymer molecules.

Microsponge for oral delivery:

In oral applications, the microsponge system has been shown to increase the rate of solubilisation of poorly water soluble drugs by entrapping such drugs 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 increases the rate of solubilisation. Controlled oral delivery of ibuprofen microsponges is achieved with an acrylic polymer, Eudragit RS, by changing their intraparticle density. Sustained release formulation of chlorpheniramine maleate, using powder-coated microsponges, is prepared by the dry impact blending method, for oral drug delivery.

Controlled oral delivery of Ketoprofen prepared by quasi-emulsion solvent diffusion method with Eudragit RS 100 and afterwards tablets of microsponges were prepared by the direct compression method. Results indicated that compressibility was much improved in the physical mixture of the drug and polymer; due to the plastic deformation of the sponge-like microsponge structure, producing mechanically strong tablets.

Colon-specific, controlled delivery of Flurbiprofen was conducted by using a commercial Microsponge 5640 system. In vitro studies exhibited that compression-coated colon-specific tablet formulations started to release the drug at the eighth hour, corresponding to the proximal colon arrival time, due to addition of the 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 eighth hour, which was the point of time when the enzyme addition was made^[^22,23] .

Microsponges for biopharmaceuticals delivery:

The microsponge delivery system (MDS) is employed for both in the delivery of biopharmaceuticals as well as in tissue engineering. Biodegradable materials with autologous cell seeding had gaining much interest as potential cardiovascular grafts. Though, pretreatment of biodegradable materials require an invasive and complicated procedure that carries the risk of infection. The main aim of the study is to develop a biodegradable graft material containing collagen microsponge that would allow the regeneration of autologous vessel tissue in order to avoid these problems. The capability of this material to hasten in situ cellularization with autologous endothelial and smooth muscle cells was tested with and without precellularization^[^24].

Poly (lactic-co-glycolic acid) has been used as a biodegradable scaffold which was compounded with collagen microsponge to form a vascular patch material. The poly (lactic-co-glycolic acid)–collagen patches with or without autologous vessel cellularization were used to patch the canine pulmonary artery trunk. Biochemical and histologic assessments were performed 2 and 6 months after the implantation^[^25] .

The results showed that there was no thrombus formation in either group but the poly (lactic-co-glycolic acid) scaffold was approximately completely absorbed in both groups. Histologic results showed the formation of an endothelial cell monolayer, parallel alignment of smooth muscle cells, and reconstructed vessel wall with elastin and collagen fibers.

The cellular and extra-cellular components in the patch had enlarged to levels analogous to those in native tissue at 6 months. The study concluded that poly (lactic-coglycolic acid) collagen microsponge patch with and without pre-cellularization showed good histologic result and durability^[^26] .

Future Prospects

MDS holds a promising future in various pharmaceutical applications in the coming years as they have unique properties like enhanced product performance and elegancy, extended release, reduced irritation, improved physical, chemical, and thermal stability so flexible to develope novel product forms. MDS which is originally developed for topical delivery of drugs like anti-acne, anti-inflammatory, anti-fungal, anti-dandruffs, antipruritics, rubefacients etc. The real challenge of microsponge delivery system in future is gaining for the advance core/shell delivery of the drug loaded microsponges for oral peptide delivery by varying ratio of polymers. Now a day it can also be used for controlled oral delivery of drugs using bioerodible polymers for colon specific delivery and also used for biopharmaceutical delivery as well as in tissue engineering. New classes of pharmaceuticals, biopharmaceuticals (peptides, proteins and DNA-based therapeutics) are fueling the rapid evolution of drug delivery technology.

CONCLUSION:

MDS has become highly competitive and rapidly evolving technology and more and more research are carrying out to optimize cost-effectiveness and efficacy of the therapy. It is a unique technology for the controlled release of topical agents and consists of microporous beads loaded with active agent and also use for oral as well as biopharmaceutical drug delivery. Microsponge delivery systems that can precisely control the release rates or target drugs to a specific body site have a vast impact on the health care system. A microsponge delivery system can release its active ingredient on a time mode and also in response to other stimuli. Therefore, microsponge has got a lot of potential and is a very emerging field which is needed to be explored. Microsponges constitute a significant part by virtue of their small size and efficient carrier characteristics.

REFERENCES:

1. Shivani Nanda, Mandeep Kaur, Nikhil Sood, Sahil Nagpal, Microsponge drug delivery System: an overview, World Journal of Pharmacy and Pharmaceutical Sciences, Volume 2, Issue 3, 1032-1043.

2. Aity, S., et al., Microsponges: A novel strategy for drug delivery system. J Adv Pharm Technol Res, 2010. 1(3): p. 90-283.

3. Chadawar, V. and J. Shaji, Microsponge delivery system. Curr Drug Deliv, 2007. 4(2): p. 9-123.

4. N.H. Aloorkar, A.S. Kulkarni, D.J. Ingale and R.A. Patil, Microsponges as Innovative Drug Delivery Systems, International Journal of pharmaceutical Sciences and Nonotechnology, Volume 5, Issue 1, April – June 2012.

5. Anderson D.L., Cheng C.H., Nacht S (1994). Flow Characteristics of Loosely Compacted Macroporous Microsponge(R) Polymeric Systems. Powder Technol78: 15-18.

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

7. Aritomi H, Yamasaki Y, Yamada K, Honda H, Koshi M, Development of sustained release formulation of chlorpheniramine maleate using powder coated microsponges prepared by dry impact blending method, J Pharm Sci Tech, 56 , 1996, 49-56.

8. Neelam Jain, Pramod Kumar Sharma, Arunabha Banik, Recent advances on microsponge delivery system, International Journal of Pharmaceutical Sciences Review and Research, Volume 8, Issue 2, May – June 2011.

9. Kawashima Y, Niwa T, Takeuchi H, Hino T, Itoh Y, Control of prolonged drug release and compression properties of ibuprofen microsponges with acrylic polymer, eudragit RS, by changing their intraparticle density, Chem Pharm Bull, 40, 1992, 196-201.

10. Hainey P, Huxham IM, Rowatt B, Sherrington DC, Synthesis and ultrastructural studies, of styrenedivinylbenzene polyhipe polymers, Macromolecules, 24, 1991, 117-121.

11. http://www.pharmainfo.net/files/images/stories/article_images/ReactionVessel For MicrosongePreparation.jpg

12. Shah VP, Elkins J, Lam S, Skelly JP, Determination of in vitro drug release from hydrocortisone creams, Int J Pharm, 53, 1989, 53-59.

13. http://www.pharmainfo.net/files/images/stories/article_images/Preparation of Microsponges.jpg.

14. Khopade AJ, Jain S, Jain NK, The microsponge, Eastern Pharmacist, 1996, 49-53.

15. Martin AN, Swarbrick J, Cammarrata A, Physical pharmacy: Physical chemical principles in pharmaceutical sciences, 3rd Edn, Lea & Febiger (Philadelphia) publisher, 1983, 664.

16. Kilicarslan M, Baykara T, The effect of the drug/polymer ratio on the properties of verapamil Hcl loaded microspheres, Int J Pharm, 252, 2003, 99–109.

17. Emanuele AD, Dinarvand R, Preparation, characterization and drug release from thermo- responsive microspheres, Int J Pharm, 118, 1995, 237-242.

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

19. D’souza JI, The microsponge drug delivery system: For delivering an active ingredient by controlled time release, Pharmainfo.net, 6, 2008, 62.

20. D’souza JI, In-vitro antibacterial and skin irritation studies of microsponges of benzoyl peroxide, Indian Drugs, 38, 2001, 361-362.

21. D'souza JI, Jagdish K, Saboji, Suresh G, Killedar, Harinath N, Design and evaluation of benzoyl peroxide microsponges to enhance therapeutic efficacy in acne treatment, Accepted for presentation in 20th FAPA congress, Bangkok, 2004.

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

23. Park W H, Lee S J and Moon H I. Antimalarial Activity of a New Stilbene Glycoside from Parthenocissus tricuspidata in Mice. Antimicrobial Agents and Chemotherapy. 52(9) (2008): 3451–3453.

24. 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, 128, 2004, 472-479.

25. Kanematsu A, Marui A, Yamamoto S, Ozeki M, Hirano Y, Yamamoto M, Ogawa O, Komeda M, Tabata Y, Type I collagen can function as a reservoir of basic fibroblast growth factor, J Control Release, 99, 2004, 281-292.

26. Chen G, Sato T, Ohgusi H, Ushida T, Tateishi T, Tanaka J, Culturing of skin fibroblasts in a thin PLGA–collagen hybrid mesh, Biomaterials, 26, 2005, 2559-2566.

Received on 24.02.2016 Accepted on 17.03.2016

Asian J. Pharm. Tech. 2016; Vol. 6: Issue 1, Jan. - Mar., Pg 51-57

DOI: 10.5958/2231-5713.2016.00008.8