Pharma Tips

The Micro Sponge Use as a Controlled Drug Delivery System

By: Pharma Tips | Views: 9174 | Date: 01-Jul-2010

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.

1. Introduction: 
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. New classes of pharmaceuticals, biopharmaceuticals (peptides, proteins and DNA-based therapeutics) are fueling the rapid evolution of drug delivery technology. These new drugs typically cannot be effectively delivered by conventional means. The benefits from targeted, localized delivery of therapeutic agents are other driving forces for the market. 
Drug delivery systems (DDS) that can precisely control the release rates or target drugs to a specific body site have had an enormous impact on the health care system. Carrier technology offers an intelligent approach for drug delivery by coupling the drug to a carrier particle such as microspheres, nanoparticles, liposomes, etc. Which modulates the release and absorption characteristics of the drug? Microspheres constitute an important part of these particulate DDS by virtue of their small size and efficient carrier characteristics. 1 
1.1 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 entry.2 It has 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. 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 has only recently been addressed with success. No efficient vehicles have been developed for controlled and localized delivery of drugs into the stratum corneum and underlying skin layers and not beyond the epidermis. Application of topical drugs suffers many problems such as ointments, which are often aesthetically unappealing,
greasiness, stickiness etc. that often results into lack of patient compliance. These vehicles require high concentrations of active agents for effective therapy because of their low efficiency of delivery system, resulting into irritation and allergic reactions in significant users. Other drawbacks of topical formulations are uncontrolled evaporation of active ingredient, unpleasant odour and potential incompatibility of drugs with the vehicles. Thus the need exists for system to maximize amount of time that an active ingredient is present either on skin surface or with in the epidermis, while minimizing its transdermal penetration into the body. The microsponge delivery system fulfills these requirements. A Microsponge® Delivery System (MDS) is “Patented, highly cross-linked,porous, polymeric microspheres polymeric system consisting of porous microspheres that can entrap wide range of actives and then release them onto the skin over a time and in response to trigger”. 3 It is a unique technology for the controlled release of topical agents and consists of microporous beads, typically 10-25 microns in diameter, loaded with active agent. When applied to the skin, the MDS releases its active ingredient on a time mode and also in response to other stimuli (rubbing, temperature, pH, etc). MDS technology is being used in cosmetics, over-the-counter (OTC) skin care, sunscreens and prescription products. Delivery system comprised of a polymeric bead having network of pores with an active ingredient held within was developed to provide controlled release of the active ingredients whose final target is skin itself.4 The
system was employed for the improvement of performance of topically applied drugs.5, 6, 7 The common methods of formulation remains same; the incorporation of the active substance at its maximum thermodynamic activity in an optimized vehicle and the reduction of the resistance to the diffusion of the stratum corneum. 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 with in microcapsules will be released. Liposomes suffer from lower payload, difficult formulation, limited chemical stability and microbial instability. While microsponge system in contrast to the above systems are stable over range of pH 1 to 11, temperature up to 130oC; compatible with most vehicles and ingredients; self sterilizing as average pore size is 0.25μm where bacteria cannot penetrate; higher payload (50 to 60%), still free flowing and can be cost effective. 
Most liquid or soluble ingredients can be entrapped in the particles. Actives that can be entrapped in microsponges must meet following requirements, It should be either fully miscible in monomer or capable of beingmade miscible by addition of small amount of a water immiscible solvent. 
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. 
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. Release can be controlled through diffusion or other triggers such as moisture, pH, friction, or temperature. This release technology is available for absorbent materials or to enhance product aesthetics. Microsponge delivery system can be incorporated into conventional dosage forms such as creams, lotions, gels, ointments, and powder and share a broad package of benefits. Systems can and improve its formulation flexibility. 

2. 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. 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.

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.

Figure 1: 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 8.

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 (PY). 9 

Figure 2: Preparation of microsponges by quasi emulsion solvent diffusion method 

3. Physical characterization of microsponges
3.1) Particle size determination 10 
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. 
3.2) 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 ultrastructure 11. 
3.3) 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.12

 3.4) 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 determinations. 
3.5) Characterization of pore structure

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. 13

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 equation.14


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).

Absolute (skeletal) density (ρsa) of microsponges was calculated by using equation,


Where Vse is the volume of the penetrometer minus the volume of the mercury (mL).

Finally, the percent porosity of the sample was found from equation,


Pore morphology can be characterized from the intrusion–extrusion profiles of mercury in the microsponges as described by Orr. 15

3.6) Compatibility studies 
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). 16, 17, 18 For DSC approximately 5 mg 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. 
Polymer/ Monomer composition 
Factors such as microsphere size, drug loading, and polymer composition govern the drug release from microspheres. 19, 20 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.
3.7) Resiliency 
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. Hence resiliency of microsponges will be studied and optimized as per the requirement by considering release as a function of cross-linking with time. 

4. Release evaluations 
4.1) Dissolution tests
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 analysed by suitable analytical method at various intervals. 
4.2) Release mechanisms 21
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 triggers. 
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
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. 
4.3) Safety considerations 22, 23
Safety substantiation of microsponges can be confirmed by skin irritation studies in
rabbits; eye irritation studies in rabbits; oral toxicity studies in rats; mutagenicity in bacteria and allergenicity in guinea pigs. 

5. 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. 24 
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 
Examples of improved formulation flexibility
Improved thermal, physical, and chemical stability 
Incorporation of immiscibles 
Liquids can be converted in to powders improving material processing 
Flexibility to develop novel product forms 

6. 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. 
The system can have following applications 25, 
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. 

6.1) The Microsponge as Programmable Topical Delivery
The Microsponge systems are based on microscopic, polymer-based microspheres that can bind, suspend or entrap a wide variety of substances and then be incorporated into a formulated product, such as a gel, cream, liquid or powder. A single Microsponge is as tiny as a particle of talcum powder, measuring less than one-thousandth of an inch in diameter. Like a true sponge, each microsphere consists of a myriad of interconnecting voids within a non-collapsible structure that can accept a wide variety of substances.
The outer surface is typically porous, allowing the controlled flow of substances into and out of the sphere. Several primary characteristics, or parameters, of the Microsponge system can be defined during the production phase to obtain spheres that are tailored to specific product applications and vehicle compatibility.  Microsponge systems are made of biologically inert polymers. Extensive safety studies have demonstrated that the polymers are non-irritating, non-mutagenic, non-allergenic, non-toxic and non-biodegradable. As a result, the human body cannot convert them into other substances or break them down. Furthermore, although they are microscopic in size, these systems are too large to pass through the stratum corneum when incorporated into topical products. Benzoyl peroxide (BPO) is commonly used in topical formulations for the treatment of acne, with skin irritation as a common side effect. 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. Therefore, microspongic delivery of Benzoyl peroxide was developed 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 26 and by suspension polymerization of styrene and divinyl benzene.27, 28 The prepared microsponges were dispersed in gel base and microspongic gels are evaluated for anti-bacterial and skin irritancy. The entrapped system released the drug at slower rate than the system containing free BPO. Topical delivery system with reduced irritancy were successfully developed.29 Hydroquinone (HQ) bleaching creams are considered the gold standard for treating hyperpigmentation. A new formulation of HQ 4% with retinol 0.15% entrapped in microsponge reservoirs was developed to release HQ gradually to prolong exposure to treatment and to minimize skin irritation. The safety and efficacy of this product were evaluated in a 12-week open-label study. A total of 28 patients were enrolled, and 25 completed the study. Study end points included disease severity, pigmentation intensity, lesion area, and colorimetry assessments. Adverse events also were recorded. Patients applied the microentrapped HQ 4% formulation to the full face twice daily (morning and evening). A broad-spectrum sunscreen was applied once in the morning, 15 minutes after application of the test product. Patients were evaluated at baseline and at 4, 8, and 12 weeks. The microentrapped HQ 4%/retinol 0.15% formulation produced improvement at all study end points. Improvement in disease severity and pigmentation intensity was statistically significant at weeks 4, 8, and 12 compared with baseline (P<0.001). Lesion area and colorimetry measurements also were significantly improved at each visit (P<0.001). Microentrapped HQ 4% was well tolerated, with only one patient discontinuing because of an allergic reaction, which was not considered serious. In this open-label study, microentrapped HQ 4% with retinol 0.15% was safe and effective.12 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 of fluconazole with an appropriate drug release profile and to bring remarkable decrease in frequently appearing irritation was attempted. Microsponges were prepared by liquid-liquid suspension polymerization of styrene and methyl methacrylate. Compatibility studies were carried out using TLC-FTIR, DSC and XRD. The prepared microsponges were evaluated for polymer composition, particle size (microscopy), surface topography (SEM), pore diameter, drug content (HPLC) and drug release. Microsponges were dispersed in gel prepared by using carbopol 940 and evaluated for drug release using Franz diffusion cell. Free flowing powder with size distribution (30 to 107 μm) was obtained. 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 release.31 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 MDS.32 

6.2) 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 absorbed. 
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. 33, 34 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 test.35  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. These microsponges were dispersed in wax matrix granules and compared with microparticles with wax matrix only. The dissolution profile of CPM consisted of a fast release phase and slow release phase. The dissolution rates for fast and slow release phases of powder coated microsponge-wax matrix granules were 8.92 and 0117 per h, respectively and were lower than those of the uncoated granules. In dogs, the powder-coated granules demonstrated lower Cmax and longer Tmax  than CPM alone following oral administration.36 Ketoprofen was used as a model drug for systemic drug delivery of microsponges in the study. 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. Different pressure values were applied
to the tablet powder mass in order to determine the optimum pressure value for compression of the tablets. Results indicated that compressibility was much improved over the physical mixture of the drug and polymer; due to the plastic deformation of sponge-like structure microsponges produce mechanically strong tablets. 37 

Colon specific drug delivery system containing flurbiprofen (FLB) microsponges was designed. Microsponges containing FLB and Eudragit RS100 were prepared by
quasi-emulsion solvent diffusion method. Additionally, FLB was entrapped into a commercial Microsponge® 5640 system using entrapment method. The microsponges were spherical in shape, between 30.7 and 94.5μm in diameter and showed high porosity values (61–72%). 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 made. 38, 39  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. The water capacity of these microsponges can be determined by a centrifugation step carried out on aqueous dispersion of a-TCP and/or CDHA powders that occur before any reaction with the organic compound. The relationship between the total open porosity of the composites and the amount of water trapped inside the inorganic agglomerates proved to be almost linear. The effect of the chemical composition of the powder on the total open porosity is not too great, provided that the two kinds of pellets are prepared with the same amount of water. Both the permeability and shape of the pores proved to be a function of the total open porosity. An increase of the latter parameter produces an increase in permeability and a decrease in tortuosity. Osteoconductivity and osteoinductivity of the final composites were tested in vivo by implantation in rabbits. 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.42 

6.3) The Micro sponge 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 delivery
through microsponges.40, 41  Storage and release of endogenous growth factors by the extracellular matrix (ECM) are important biological events that control tissue homeostasis and regeneration. The interaction between basic fibroblast growth factor (bFGF) and heparan sulfate proteoglycans has been extensively studied and used as a prototype model of such a system, while the lower affinity of fibrillar type I collagen for bFGF has generally been considered biologically insignificant. 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. These results suggest the significance and therapeutic utility of type I collagen as a reservoir of bFGF.43 Biodegradable materials with autologous cell seeding have attracted much interest as potential cardiovascular grafts. However, pretreatment of these materials requires a complicated and invasive procedure that carries the risk of infection. To avoid these problems, we sought to develop a biodegradable graft material
containing collagen microsponge that would permit the regeneration of autologous
vessel tissue. The ability of this material to accelerate in situ cellularization with autologous endothelial and smooth muscle cells was tested with and without pre-cellularization. Poly (lactic-co-glycolic acid) as a biodegradable scaffold 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. 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 extra-cellular components in the patch had increased to levels similar to those in native tissue at 6 months. The poly (lactic-co-glycolic acid) collagen microsponge patch with and without pre-cellularization showed good histologic findings and durability. This patch
shows promise as a bioengineered material for promoting in situ cellularization and the regeneration of autologous tissue in cardiovascular surgery.44 A thin biodegradable hybrid mesh of synthetic poly (DL-lactic-co-glycolic acid) (PLGA) and naturally derived collagen was used for three-dimensional culture of human skin fibroblasts. The hybrid mesh was constructed by forming web-like collagen microsponges in the openings of a PLGA knitted mesh. The behaviors of the fibroblasts on the hybrid mesh and PLGA knitted mesh were compared. The efficiency of cell seeding was much higher and the cells grew more quickly in the hybrid mesh than in the PLGA mesh. The fibroblasts in the PLGA mesh grew from the peripheral PLGA fibers toward the centers of the openings, while those in the hybrid mesh also grew from the collagen microsponges in the openings of the mesh resulting in a more homogenous growth. The proliferated cells and secreted extracellular matrices were more uniformly distributed in the hybrid
mesh than in the PLGA mesh. Histological staining of in vitro cultured fibroblast/mesh
implants indicated that the fibroblasts were distributed throughout the hybrid mesh and formed a uniform layer of dermal tissue having almost the same thickness as that of the hybrid mesh. However, the tissue formed in the PLGA mesh was thick adjacent to the PLGA fibers and thin in the center of the openings. Fibroblasts cultured in the hybrid mesh were implanted in the back of nude mouse. Dermal tissues were formed after 2 weeks and became epithelialized after 4 weeks. 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 hybrid mesh may be useful for skin tissue engineering. Human skin fibroblasts were cultured in a thin biodegradable mesh having a hybrid structure with web-like collagen microsponges formed in the openings of a PLGA knitted mesh. More fibroblasts adhered and proliferated more quickly in the hybrid mesh than in the PLGA knitted mesh. The collagen microsponges in the hybrid mesh facilitated cell seeding, uniform cell distribution and, therefore, the formation of homogenous dermis tissue. The PLGA knitted mesh served as a skeleton, reinforced the hybrid mesh, maintained the integrity
of the forming tissue, and resulted in easy handling. PLGA–collagen hybrid mesh could be a useful candidate as a porous scaffold for skin tissue engineering.45  To solve several problems with artificial grafts, a novel bioengineered material that can promote tissue regeneration without ex vivo cell seeding and that has sufficient durability to be used for artery reconstruction was developed. It was tested whether this biodegradable material could accelerate the in situ regeneration of autologous cardiovascular tissue, especially of the arterial wall, in various models of cardiovascular surgeries. 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. A tissue-engineered patch made of our biodegradable polymer and collagen-microsponge provided good in situ regeneration at both the venous and arterial wall, suggesting that this patch can be used as a novel surgical material for the repair of the cardiovascular system.46 

7. Patent information of Micro sponge Products
In September 1, 1987, Won; Richard (Palo Alto, CA) of Advanced Polymer Systems, Inc. (Redwood City, CA) 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).  September 8, 1992 , Won; Richard (Palo Alto, CA) of Advanced Polymer Systems, Inc. ( Redwood City , CA ) received US patent for developing Two-step method for preparation of controlled release formulations (United States Patent 5, 145, 675). Advanced Polymer Systems, Inc. and subsidiaries ("APS" or the "Company") is using its patented Microsponge(R) delivery systems and related proprietary technologies to enhance the safety, effectiveness and aesthetic quality of topical
prescription, over-the-counter ("OTC") and personal care products like tretinoin, 5-fluorouracil and Vitamin-A etc. As on July 23, 2006 , the Company has a total of 10 issued U.S. patents and an additional 92 issued foreign patents. 21 patent applications
are pending worldwide. Dean, Jr. et al received US patent no. 4863856 for 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.47  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

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;

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.

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.

Marketed formulation using the MDS includes Ethical Dermatological products (APS defined ethical dermatology products as prescription and non-prescription drugs that are promoted primarily through the medical profession for the prevention and treatment of skin problems or diseases). Several ethical dermatology products approved by US FDA, OTC and personal care products are sold in the United States. Results from various human clinical studies reaffirmed that the technology offers the potential to reduce the drug side effects, maintain the therapeutic efficacy and potentially increase patient compliance with the treatment regimen.

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. This product was launched in March 1997. However, skin irritation among sensitive individuals can limit patient compliance with the prescribed therapy. The Company believes its patented approach to drug delivery reduces the potentially irritating side effects of tretinoin. Ortho Dermatological began marketing this product in March 1997.

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.

Cosmeceutical 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.

Product name




0.1% and 0.04% tretinoin entrapped in MDS for topical treatment of acne vulgaris. This formulation uses patented methyl methacrylate/ glycol dimethacrylate cross-polymer porous microspheres (MICROSPONGE® System) to enable inclusion of the active ingredient, tretinoin, in an aqueous gel.

Ortho-McNeil Pharmaceutical, Inc.

Carac Cream, 0.5%

Carac Cream contains 0.5% fluorouracil, with 0.35% being incorporated into a patented porous microsphere (Microsponge) composed of methyl methacrylate / glycol dimethacrylate cross-polymer and dimethicone. Carac is a once-a-day topical prescription product for the treatment of actinic keratoses (AK), a common pre-cancerous skin condition caused by over-exposure to the sun. The product has a number of advantages over existing topical therapies, including less irritation with shorter duration of therapy and reduced dosage frequency.

Dermik Laboratories, Inc.
Berwyn , PA 19312 USA

Line Eliminator Dual Retinol Facial Treatment

Lightweight cream with a retinol (pure Vitamin A) in MDS, delivers both immediate and time released wrinkle-fighting action.


Retinol cream

The retinol molecule is kept in the microsponge system to protect the potency of the vitamin A. This helps to maximize retinol dosage while reducing the possibility of irritation. Retinol is a topical vitamin A derivative which helps maintain healthy skin, hair and mucous membranes.


Retinol 15 Nightcream

A nighttime treatment cream with Microsponge technology using a stabilized formula of pure retinol, Vitamin A. Continued use of Retinol 15 will result in the visible diminishment of fine lines and wrinkles, a noticeable improvement in the skin discolorations due to aging, and enhanced skin smoothness.


EpiQuin Micro

The Microsponge ® system uses microscopic reservoirs that entrap hydroquinone and retinol. The microsponges release these ingredients into the skin gradually throughout the day. This provides the skin with continuous exposure to hydroquinone and retinol over time, which may minimize skin irritation. 49

SkinMedica Inc

Sportscream RS and XS

Topical analgesic-anti-inflammatory and counterirritant actives in a Microsponge® Delivery System (MDS) for the management of musculoskeletal conditions. 48

Embil Pharmaceutical Co. Ltd.

Salicylic Peel 20

Deep BHA peeling agent for (professional use only): Salicylic acid 20%, Microsponge Technology, Excellent exfoliation and stimulation of the skin for more resistant skin types or for faster results. Will dramatically improve fine lines, pigmentation, and acne concerns.


Salicylic Peel 30

Deeper BHA peeling agent for (professional use only): Salicylic acid 30%, Microsponge Technology, Most powerful exfoliation and stimulation of the skin. For more resistant skin types or for faster results. Will dramatically improve fine lines, pigmentation, and acne concerns.

Micro Peel Plus

The MicroPeel ® Plus procedure stimulates cell turnover through the application of salicylic acid in the form of microcrystals using Microsponge ® technology. These microcrystals target the exact areas on the skin that need improvement. The MicroPeel ® Plus aggressively outperforms other superficial chemical peels by freeing the skin of all dead cells while doing no damage to the skin.


Oil free matte block spf20

Shield skin from damaging UV rays and control oil production with this invisible sunscreen. Microsponge technology absorbs oil, maintaining an all-day matte finish and preventing shine without any powdery residue. Oil free formula contains soothing Green Tea to help calm inflammation caused by breakouts. Contains no artificial fragrance or color. Cornstarch and Vinyl Dimethicone/ Methicone Silsesquioxane Cross-polymer act as microsponges to absorb excess surface oils on skin.


Oil Control Lotion

A feature-light lotion with technically advanced microsponges that absorb oil on the skin's surface during the day, for a matte finish. Eliminate shine for hours with this feature-weight lotion, formulated with oil-absorbing Microsponge technology and hydrating botanicals. The naturally- antibiotic Skin Response Complexe soothes inflammation and tightness to promote healing. Acne-Prone, oily skin conditions.

Fountain Cosmetics

Lactrex™ 12% Moisturizing Cream

Lactrex™ 12% Moisturizing Cream contains 12% lactic acid as the neutral ammonium salt, ammonium lactate. Microsponge® technology has been included for comfortable application and long lasting moisturization. Lactrex™ also contains water and glycerin, a natural humectant, to soften and help moisturize dry, flaky, cracked skin.

SDR Pharmaceuticals, Inc., Andover , NJ , U.S.A. 07821

Dermalogica Oil Control Lotion

Exclusive skin response complex soothes and purifies, provides effective skin hydration, without adding excess oil; eliminate shine for hours with Dermalogica Oil Control Lotion. Oil Control Lotion is a feather-light lotion, formulated with oil absorbing Microsponge technology and hydrating botanicals. The naturally antiseptic Skin Response Complex helps soothe and purify the skin.

John and Ginger Dermalogica Skin Care Products

Aramis fragrances

24 Hour High Performance Antiperspirant Spray Sustained release of fragrance in the microsponge. The microsponge comes in the form of an ultra light powder, and because it is micro in size, it can absorb fragrance oil easily while maintaining a free-flowing powder characteristic where release is controlled due to moisture and temperature.

Aramis Inc .

Ultra Guard

Microsponge system that contains dimethicone to help protect a baby's skin from diaper rash.

Scott Paper Company

Table 2: List of marketed products using microsponge drug delivery system

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 turbidimeters 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.

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. 

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2.Kydonieus A. F. and Berner B., Transdermal Delivery of Drugs, CRC Press, Boca Raton; 1987. 
3.Nacht S. and Kantz M., A Novel Topical Programmable Delivery System, Topical Drug Delivery Systems, (1992); 15(42): 299-325. 
4.Won R., 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. Sep, United States Patent No. 4,690,825, 1987. 
5.Embil, K., and Nacht, S., a topical delivery system with reduced irritancy incorporating multiple triggering mechanisms for the release of actives. J. Microencapsul, 1996; 13: 575–588. 
6.L. Delattre and I. Delneuville, Biopharmaceutical aspects of the formulation of dermatological vehicles, Journal of the European Academy of Dermatology and Venereology, 1995; 5: 1-70. 
7.Weiss R., Drug Delivery in the Space Age, Consultant Pharmacist, 1989; 15-23. 
8.Won R., Two step method for preparation of controlled release formulations, United States Patent No. 5,145,675, 1992,
9.M. Jelvehgari, M.R. Siahi-Shadbad, S. Azarmi, Gary P. Martin, and Ali Nokhodchi The microsponge delivery system of benzoyl peroxide: Preparation, characterization and release studies, International Journal of Pharmaceutics, 2006; 308: 124–132. 
10.Martin A., Swarbrick J. and Cammarrata A., , In: Physical Pharmacy- Physical Chemical Principles in Pharmaceutical Sciences, 1991; 3rd Ed: 527. 
11.Emanuele A. D., Dinarvand R., Preparation, Characterization and Drug Release from Thermo responsive Microspheres, International Journal of Pharmaceutics, 1995; 237-242. 
12.Kilicarslan, M., and Baykara, T., The effect of the drug/polymer ratio on the properties of Verapamil HCl loaded microspheres. Int. J. Pharm., 2003; 252: 99–109. 
13.Poresizer Model No. 9310, Micromeritics Instrument Corp., Nor-cross , Georgia . 
14.Washburn, E.W., Note on a method of determining the distribution of pore sizes in a porous material. Proc. Natl. Acad. Sci., 1921; U.S.A. 7: 115–116. 
15.Orr Jr., Application of mercury penetration to material analysis. Powder
Technol., 1969; 3: 117–123. 
16.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. 
17.Bodmeier R, Chen H. Preparation and characterization of microspheres containing the anti-inflammatory agents, indomethacin, ibu-profen, and ketoprofen. J. Control. Release., 1989; 10: 167-175. 
18.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. 
19.Wakiyama N, Juni K,and Nakano M. Preparation and evaluation in vitro of polylactic acid microspheres containing local anesthetic. Chem. Pharm. Bull. ( Tokyo ). 1981; 29: 3363-3368. 
20.Barkai A, Pathak V, and 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. 
21.Shah V.P., Determination of In-vitro Release from Hydrocortisone Creams. International Journal of Pharmaceutics, 1989; 53: 53-59. 
22.Sato T, Kanke M, Schroeder G, and Deluca P. Porous biodegradable microspheres for controlled drug delivery. I: Assessment of processing conditions and solvent removal techniques. Pharm Res., 1988; 5: 21-30. 
23.Draize J.H., Woodard J & Calvary H.O.,xMethods for the Study of Irritation
& Toxicity of Substances Applied Topically to the Skin & Mucous Membranes. Journal of Pharmacology & Experimental Therapeutics., 1989; 82: 377-389. 
24.Franz T. J., Percutaneous absorption. On the relevance of in vitro date. J. Invest. Dermatol., 1975; 45, 498-503. 
25.Khopade A. J., Jain Sanjay, Jain N.K., March  “The Microsponge”; Eastern Pharmacist, 1996, 49-53. 
26.Yazici, E.; Kas, H. S.; Hincal, A. A., Microsponges, Farmasotik Bilimler Dergisi (Turkey), 1994; V19(3): 121-128. 
27.Wester R., Patel R., Natch S., Leyden J., Melendres J., Maibach H., Controlled release of benzoyl peroxide from a porous microsphere polymeric system can reduce topical irritancy, J. Am. Acad. Derm., 1991; 24: 720-726. 
28.John I. D'souza, Jagdish K. Saboji, Suresh G. Killedar, Harinath N. More “Design and Evaluation of Benzoyl Peroxide Microsponges to Enhance Therapeutic Efficacy in Acne Treatment”, Accepted for presentation in 20th FAPA Congress, Bangkok , Thailand, 2004 . 
29.D'souza J. I. et al, In-vitro Antibacterial and Skin Irritation Studies of Microsponges of Benzoyl Peroxide, Indian Drugs, 2001; 38(7). 
30.Fincham J. E., Karnik K. A., Patient Counseling and Derm Therapy, US Pharmacist, 1994; 56-57, 61-62, 66, 71-72, 74, 77-78, 81-82. 
31.D’souza J. I., Masvekar R.R., Pattekari P.P., Pudi S.R., More H. N., Microspongic
Delivery Of Fluconazole For Topical Application, 1st Indo-Japanese International Conference On Advances In Pharmaceutical Research And Technology, Mumbai, India, 2005; 25-29.
32.Grimes P. E., A microsponge formulation of hydroquinone 4% and retinol 0.15% in the treatment of melasma and post-inflammatory hyperpigmentation, Cutis. 2004; 74(6): 362-368. 
33.James J. Leyden , Alan Shalita, Diane Thiboutot, Kenneth Washenik, and Guy Webster, Topical Retinoids in Inflammatory Acne: A Retrospective, Investigator-Blinded, Vehicle-Controlled, Photographic Assessment, Clin. Therapeutics, 2005; 27: 216-224. 
34.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., 1992; 40 (1): 196-201. 
35.Kawashima Y., Niwa T., Takeuchi H., Hino T., Itoh Y., Hollow Mocrospheres for use as a Floating Controlled Drug delviery System in the Stomach., J. Pharm. Sci., 1992; 82 (2): 135-140. 
36.Dale L. Anderson, Chung-Heng Cheng and Sergio Nacht, Flow characteristics of loosely compacted macroporous microsponge® polymeric systems, Powder Technology, 1994;  78(1): 15-18. 
37.Aritomi H., Yamasaki Y., Yamada K., Honda H. and Koshi M., Development of sustained release formulation of chlorpheniramine maleate using powder coated
microsponges prepared by dry impact blending method, Journal of Pharmaceutical Sciences and Technology, 1996; 56(1): 49-56. 
38.Tansel C¸ omog˘lu, Nurs¸in Go¨nu¨, and Tamer Baykara Preparation and in vitro
evaluation of modified release ketoprofen microsponges, Il Farmaco, 2003; 58: 101-106. 
39.Mine Orlu, Erdal Cevher, Ahmet Araman Design and evaluation of colon specific drug delivery system containing flurbiprofen microsponges, International Journal of Pharmaceutics, 2006; 318: 103–117. 
40.Tansel C¸ omoglu, Nurs¸in Go¨nu¨ l , Tamer Baykara, The effects of pressure and direct compression on tabletting of microsponges, International Journal of Pharmaceutics, 2002; 242: 191–195. 
41.Newton D. W., Biotechnology Frontier: Targeted Drug Delivery, US Pharmacist,
1991; 16: 38-39, 43-44, 46-48, 50-51. 
42.Chen G, Ushida T, Tateishi T. A Biodegradable Hybrid Sponge Nested With Collagen Microsponges, J Biomed Mater Res, 2000; 51:273–9. 
43.Dario T. Berutoa, Rodolfo Bottera, Milena Fini, The effect of water in inorganic
microsponges of calcium phosphates on the porosity and permeability of
composites made with polymethylmethacrylate, Biomaterials, 2002; 23: 2509–2517. 
44.Akihiro Kanematsua,b, Akira Maruic, Shingo Yamamotob, Makoto Ozekia, Yoshiaki Hiranod, Masaya Yamamotoa, Osamu Ogawab, Masashi Komedac, Yasuhiko Tabata, Type I collagen can function as a reservoir of basic fibroblast growth factor, Journal of Controlled Release, 2004; 99: 281–292. 
45.Shigemitsu Iwai MD, Yoshiki Sawa MD, Hajime Ichikawa MD, Satoshi Taketani MD, Eiichiro Uchimura PhD, Guoping Chen PhD, Masayuki Hara PhD, Jun MiyakePhD and Hikaru Matsuda MD, Biodegradable polymer with collagen microsponge serves as a new bioengineered cardiovascular prosthesis, Journal of Thoracic and Cardiovascular Surgery, 2004; 128(3): 472-479. 
46.Guoping Chen, Takashi Sato, Hajime Ohgushi, Takashi Ushida, Tetsuya Tateishi, Junzo Tanaka, Culturing of skin fibroblasts in a thin PLGA–collagen hybrid mesh, Biomaterials, 2005; 26: 2559–2566. 
47.Dean, Jr., Robert C.; Silver, Frederick H.; Berg, Richard A.; Phillips, Philip G.;
Runstadler, Jr., Peter W.; Maffia, Gennaro J., United States Patent 4863856, Weighted collagen microsponge for immobilizing bioactive materials, 1989. 
48.Koral Embil V. P., OTC External Analgesic Cream / Topical Analgesic-Anti-inflammatory, Counterirritant utilizing the Microsponge Delivery System (MDS) for controlled release of actives, UK Patent Application No: 0101058.6, 2000 . 
49.Grimee P. E., Meraz M., A new microentrapped 4% hydroquinone formulation for treatment of hyperpigmentation, 60th Annual meeting of American Academy of Dermatology, February 2002; 22-27.
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52.Yazici, E.; Kas, H. S.; Hincal, A. A., Microsponges, Farmasotik Bilimler Dergisi (Turkey), 1994; 19(3): 121-128. 
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