1. INTRODUCTION:

1.1 Microsponges:

Microsponges are porous, polymeric microspheres that are mostly used for prolonged topical administration. Microsponges are designed to deliver a pharmaceutically active ingredient efficiently at minimum dose and also to enhance stability, reduce side effects, and modify drug release proﬁles¹.These attributes have been successfully demonstrated in the FDA-approved Retin-A Micro® (0.1% or 0.04% tretinoin) and Carac (0.5% 5-ﬂurouracil) products for acne treatment and actinic keratoses, respectively. Many of conventional delivery systems require high concentrations of active agents to be incorporated for effective therapy because of their low efﬁciency as delivery systems² Thus, the need exists for delivery systems to maximize the period of time that an active ingredient is present, 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. Microsponges are prepared by several methods utilizing emulsion systems as well as by suspension polymerization in a liquid–liquid system. The most common emulsion system used is oil-in-water (o/w), with the microsponges being produced by the emulsion solvent diffusion (ESD) method ^3.

1.2 Colon targeted drug delivery:

Colon, as a site, offers distinct advantages on account of a near neutral pH, a much longer transit time, reduced digestive enzymatic activity and a much greater responsiveness to absorption enhancers ^{4, 5.} Colon specific drug delivery systems have been the focus of increasing interest due to the importance of this region of the gastrointestinal tract, not only for local but also for systemic therapy. Additionally, colonic delivery of drugs may be extremely useful when a delay in drug absorption is required from a therapeutic point of view, e.g. in case of diurnal asthma, angina pectoris and arthritis. Conventional oral dosage forms are ineffective in delivering drugs to the colon due to absorption and/or degradation of the active ingredient in the upper gastrointestinal tract. Several triggering mechanisms utilizing the gastrointestinal transit time of various formulations and the change in pH, bacterial concentration and pressure in the gastrointestinal tract have been reported to achieve colon specific drug delivery⁶.

Figure 1: View of Microsponge

Every system has advantage as well as shortcoming. Prodrugs, as being considered as a new chemical entity from regulatory perspective, the similarity in pH between the small intestine and the colon and also the highly variable retention times make the mentioned strategies less reliable^7. However, microflora-activated systems formulated making use of non-starch polysaccharides are highly promising because the polysaccharides remain undigested in the stomach and the small intestine and can only be degraded by the vast anaerobic microflora of the colon. Furthermore, this strategy exploiting the abrupt increase of the bacteria population (400 distinct species of bacteria) and corresponding enzyme activities will also accomplish greater site-specificity of initial drug release⁸. The polysaccharides are also inexpensive, naturally occurring and abundantly available for colonic drug delivery⁹.

2 APPROACHES TO DELIVERY THE INTACT MOLECULE TO THE COLON:

2.1 Coating with polymers:

The intact molecule can be delivered to the colon without absorbing at the upper part of the intestine by coating of the drug molecule with the suitable polymers, which degrade only in the colon. ¹⁰

2.2 Coating with pH-sensitive polymers:

The pH-dependent systems exploit the generally accepted view that pH of the human GIT increases progressively from the stomach (pH 1-2 which increases to 4 during digestion, small intestine (pH 6-7) at the site of digestion and it increases to 7-8 in the distal ileum. The coating of pH-sensitive polymers to the tablets, capsules or pellets provide delayed release and protect the active drug from gastric fluid¹¹.

2.3 Coating with biodegradable polymers:

The bioenvironment inside the human GIT is characterized by the presence of complex microflora especially the colon that is rich in microorganisms that are involved in the process of reduction of dietary component or other materials. Drugs that are coated with the polymers, which are showing degradability due to the influence of colonic microorganisms, can be exploited in designing drugs for colon targeting¹².

3. The Microsponge Delivery System:

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. Several predictable and reliable systems were developed for systemic drugs under the heading of transdermal delivery system (TDS) using the skin as portal of entry¹³.it improved the efficacy and safety of many drugs that may be better administered through skin. But TDS is not practical for delivery of materials whose final target is skin itself.

Most liquid or soluble ingredients can be entrapped in the particles. Actives that can be entrapped in microsponges must meet following requirements,

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

2. It should be water immiscible or at most only slightly soluble.

3. It should be inert to monomers.

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

Active following these criteria serves as porogen or pore forming agent. Such drugs can be entrapped while polymerization takes place by one-step process. While when the material is sensitive to the polymerization conditions, polymerization is performed using substitute porogen. The porogen is then removed and replaced by contact absorption assisted by solvents to enhance absorption rate.

4. Preparation of Microsponges:

Drug loading in microsponges can take place in two ways, one-step process or by two-step process; based on physico-chemical properties of drug to be loaded. If the drug is typically an inert non-polar material, will create the porous structure it is called porogen. Porogen drug, which neither hinders the polymerization nor become activated by it and stable to free radicals is entrapped with one-step process^1,

Figure2: Reaction vessel for microsponge preparation by liquid-liquid suspension polymerization

When the drug is sensitive to the polymerization conditions, two-step process is used. The polymerization is performed using substitute porogen and is replaced by the functional substance under mild experimental conditions.

4.1 Liquid-liquid suspension polymerization:

Microsponges are conveniently prepared by liquid-liquid suspension polymerization. Polymerization of styrene or methyl methacrylate is carried out in round bottom flask. A solution of non-polar drug is made in the monomer, to which aqueous phase, usually containing surfactant and dispersant to promote suspension is added. Polymerization is effected, once suspension with the discrete droplets of the desired size is established; by activating the monomers either by catalysis or increased temperature ^16.

4.2 Quasi-emulsion solvent diffusion:

As explained in Figure 2 the microsponges can also be prepared by quasi-emulsion solvent diffusion method using the different polymer amounts. The processing flow chart is presented in Fig. 1a. To prepare the inner phase, Eudragit RS 100 was dissolved in ethyl alcohol. Then, drug can be then added to solution and dissolved under ultrasonication at 35^oC. The inner phase was poured into the PVA 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 and weighed to determine production yield^.¹⁷

5. Evaluation parameters of microsponges:

• Particle size (Microscopy)

• Morphology and Surface topography

• Characterization of pore structure

• Loading efficiency and production yield

• Characterization of pore structure

• Compatibility studies

• Resiliency

• Drug release study

Particle size determination:

Free-flowing powders with fine aesthetic attributes are possible to obtain by controlling the size of particles during polymerization. Particle size analysis of loaded and unloaded microsponges can be performed by laser light diffractometry or any other suitable method. The values (d50) 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 30 μm can impart gritty feeling and hence particles of sizes between 10 and 25 μm are preferred to use in final topical formulation ^18.

Morphology and Surface topography of microsponges:

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 ultrastructure¹⁹.

Determination of loading efficiency and production yield:

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

The production yield of the microparticles can be determined by calculating accurately the initial weight of the raw materials and the last weight of the microsponge obtained^{. 20}

Determination of true density:

The true density of microparticles and BPO was measured using an ultra-pycnometer under helium gas and was calculated from a mean of repeated determinations²¹.

Characterization of pore structure:

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^.
22.

Porosity parameters of microsponges such as intrusion–extrusion isotherms pore size distribution, total pore surface area, average pore diameters, shape and morphology of the pores, bulk and apparent density can be determined by using mercury intrusion porosimetry. Incremental intrusion volumes can be plotted against pore diameters that represented pore size distributions. The pore diameter of microsponges can be calculated by using Washburn equation²³.

Where D is the pore diameter (μm); γ the surface tension of mercury (485 dyn cm−1); θ the contact angle (130o); and P is the pressure (psia).

Total pore area (Atot) was calculated by using equation,

Where P is the pressure (psia); V the intrusion volume (mL g−1); Vtot is the total specific intrusion volume (mL g−1).

The average pore diameter (Dm) was calculated by using equation,

Envelope (bulk) density (ρse) of the microsponges was calculated by using equation,

Where Ws is the weight of the microsponge sample (g); Vp the empty penetrometer (mL); VHg is the volume of mercury (mL).

Polymer/ Monomer composition:

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. Release rate and total amount of drug released from the system composed of methyl methacrylate ethylene glycol dimethacrylate is slower than styrene divinyl benzene system.

Selection of monomer is dictated both by characteristics of active ingredient ultimately to be entrapped and by the vehicle into which it will be dispersed. Polymers with varying electrical charges or degrees of hydrophobicity or lipophilicity may be prepared to provide flexibility in the release of active ingredients. Various monomer combinations will be screened for their suitability with the drugs by studying their drug release profile. ²⁴

Release mechanisms:

By proper manipulation of the aforementioned programmable parameters, microsponges can be designed to release given amount of active ingredients over time in response to one or more external triggers²⁵.

1. Pressure: Rubbing/ pressure applied can release active ingredient from microsponges onto skin.

2. Temperature change: Some entrapped actives can be too viscous at room temperature to flow spontaneously from microsponges onto the skin. Increased in skin temperature can result in an increased flow rate and hence release.

3. Solubility: Microsponges loaded with water-soluble ingredients like anti-prespirants and antiseptics will release the ingredient in the presence of water. The release can also be activated by diffusion taking into consideration the partition coefficient of the ingredient between the microsponges and the outside system.

Sustained release microsponges can also be developed. Various factors that are to be considered during development of such formulations includes,

1. Physical and chemical properties of entrapped actives.

2. Physical properties of microsponge system like pore diameter, pore volume, resiliency etc.

3. Properties of vehicle in which the microsponges are finally dispersed.

Particle size, pore characteristics, resiliency and monomer compositions can be considered as programmable parameters and microsponges can be designed to release given amount of actives in response to one or more external triggers like; pressure, temperature and solubility of actives^{26 .}

Formulation Considerations:

Actives entrapped in MDS can then be incorporated into many products such as creams, lotions, powders and soaps. When formulating the vehicle, certain considerations are taken into account in order to achieve desired product characteristics.

1. The solubility of actives in the vehicle must be limited. Otherwise the vehicle will deplete the microsponges before the application.

2. To avoid cosmetic problems; not more than 10 to 12% w/w microsponges must be incorporated into the vehicle.

3. Polymer design and payload of the microsponges for the active must be optimized for required release rate for given time period.

There remains equilibrium between microsponge and vehicle and microsponge releases drug in response to the depletion of drug concentration in the vehicle. Drug concentration in the vehicle is depleted by absorption of the drug into skin. Hence continuous and steady release of actives onto the skin is accomplished with this system.

Drug release from the topical semisolid formulation can be studied by using Franz-type static diffusion cells.²⁷

6. Examples of enhanced product performance:

• Oil control: Microsponge can absorb oil up to 6 times its weight without drying.

• Extended release

• Reduced irritation and hence improved patient compliance

• Improved product elegancy

8. Applications of microsponge systems:

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.

Table 1-The system can have following applications²⁸

Sr. No.	Active agents	Applications
1.	Sunscreens	Long lasting product efficacy, with improved protection against sunburns and sun related injuries even at elevated concentration and with reduced irritancy and sensitization.
2.	Anti-acne e.g. Benzoyl peroxide	Maintained efficacy with decreased skin irritation and sensitization.
3.	Anti-inflammatory e.g. hydrocortisone	Long lasting activity with reduction of skin allergic response and dermatoses.
4.	Anti-fungals	Sustained release of actives.
5.	Anti-dandruffs e.g. zinc pyrithione, selenium sulfide	Reduced unpleasant odour with lowered irritation with extended safety and efficacy.
6.	Antipruritics	Extended and improved activity.
7.	Skin depigmenting agents e.g. hydroquinone	Improved stabilization against oxidation with improved efficacy and aesthetic appeal.
8.	Rubefacients	Prolonged activity with reduced irritancy greasiness and odour.

9. The Microsponge for Oral Delivery:

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 if successful should open up entirely new opportunities for MDS.

In oral applications, the Microsponge system has been shown to increase the rate of solubilization of poorly water-soluble drugs by entrapping such drugs in the Microsponge system's pores. Because these pores are very small, the drug is in effect reduced to microscopic particles and the significantly increased surface area thus greatly increases the rate of solubilization. An added benefit is that the time it takes the Microsponge system to traverse the small and large intestine is significantly increased thus maximizing the amount of drug that is absorbed²⁹.

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.

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. An approach to evaluate the loading capacity of these Microsponge® delivery systems has been developed utilizing the relative inter-particulate friction sensing capability of the Hausner ratio (tap density/apparent density) and comparing it to a more conventional flowability test³⁰.

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. Products under development or in the marketplace utilize the Topical Microsponge systems in three primary ways ³¹

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.

The resulting benefits include extended efficacy, reduced skin irritation, cosmetic elegance, formulation flexibility and improved product stability.

5-Fluorouracil (5-FU): 5-FU is an effective chemotherapeutic agent for treating actinic keratosis, a pre-cancerous, hardened-skin condition caused by excessive exposure to sunlight. 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 under the brand of Carac.

Tretinoin Photo-damage Treatment: Microsponge system product for the treatment of photo-damage, which contributes to the premature aging of skin and has been implicated in skin cancer.

Cosmaceutical Products Retinol: Retinol is a highly pure form of vitamin A which has demonstrated a remarkable ability for maintaining the skin's youthful appearance. However, it has been available only on a limited basis because it becomes unstable when mixed with other ingredients. Stabilized retinol in a formulation which is cosmetically elegant and which has a low potential for skin irritation were successfully developed and marketed.

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. The technology is currently employed in almost number of products sold by major cosmetic and toiletry companies worldwide. 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 qualities. APS developed microsphere precursors to the Microsponge for use as a testing standard for gauging the purity of municipal drinking water. Marketed nationwide, these microspheres are suspended in pure water to form an accurate, stable, reproducible turbidity standard for the calibration of turbid meters used to test water purity. The technology can have much broader applications than testing the turbidity of water and can even be used for the calibration of spectrophotometers and colorimeters.

10. Benefits of Microsponge Technology³⁵

• 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

11. SUMMARY AND CONCLUSION:

The MDS which was originally developed for topical delivery of drugs can also be used for controlled oral delivery of drugs using bioerodible polymers, especially for colon specific delivery. 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.

A Microsponge Delivery System can entrap wide range of actives and then release them onto the skin over a time and in response to trigger. 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. A Microsponge Delivery System can release its active ingredient on a time mode and also in response to other stimuli. Thus microsponge has got a lot of potential and is a very emerging field which is needed to be explored.

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Received on 21.09.2011 Accepted on 05.10.2011

Asian J. Pharm. Tech. 1(4): Oct. - Dec. 2011; Page 87-93

S.N.	Drug	Formulation	Trade name	Dose
1.	Mesalamine	Eudragit-S coated tablets(dissolves at pH 7)	Asacol	0.8 -2.4 g/day
2.	Mesalamine	Eudragit-L coated tablets(dissolves at pH 6)	Salofac	1.0-4.0 g/day
3.	Mesalamine	Eudragit-L coated tablets	Claversal Mesazal Calitoflak	1.0-2.0 g/day
4.	Budesonide	Eudragit-L coated beads 9 mg/day	Entocort	9 mg/day