8/3/2019 The Micro Sponge Delivery System http://slidepdf.com/reader/full/the-micro-sponge-delivery-system 1/19 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 130 o C; 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, 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.
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
Pharmaceutical Considerations of Microsponges
Physical characterization of microsponges
Particle size determination 10
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 (d 50) 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.
Morphology and Surface topography of microsponges
For morphology and surface topography, prepared microsponges can be coated with gold–palladiumunder 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.
Determination of loading efficiency and production yield
The loading efficiency (%) of the microsponges can be calculated according to the following 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
Compatibility studies
Compatibility of drug with reaction adjuncts can be studied by thin layer chromatography (TLC) andFourier 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 andtotal 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.
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.
Release evaluations
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.
Overview of research work publishedThe 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 havedemonstrated 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. Themicroentrapped 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
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 pressurevalue 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 specificformulations 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
The Microsponge in Delivery of biopharmaceuticals
The MDS is employed for the delivery of biopharmaceuticals and in tissue engineering also. Newton D.
W. has overviewed tissue targeted biopharmaceuticals 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 potentialcardiovascular 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 andcollagen 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 inthe 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 microspongesformed 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
Patent information of Microsponge 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 careproducts 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 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.
