Microsponges for colon targeted drug delivery system: An overview ...

[AJPTech.]

Asian J. Pharm. Tech. 2011; Vol. 1: Issue 4, Pg 87-93

ISSN- 2231–5705 (Print) www.asianpharmaonline.org ISSN- 2231–5713 (Online) 0974-3618 REVIEW ARTICLE

Microsponges for colon targeted drug delivery system: An overview Rajendra Jangde*

University Institute of Pharmacy, Pt. Ravishankar Shukla University, Raipur (C.G.) 492010 *Corresponding Author E-mail: [email protected]

ABSTRACT:

The drug delivery technology landscape has become highly competitive and rapidly evolving. More and more developments in delivery systems are being integrated to optimize the efficacy and cost-effectiveness of the therapy. Peptides, proteins and DNA-based therapeutics cannot be effectively delivered by conventional means. To control the delivery rate of active agents to a predetermined site in human body has been one of the biggest challenges faced by drug industry. Controlled release of drugs onto the epidermis with assurance that the drug remains primarily localized and does not enter the systemic circulation in significant amounts is an area of research that is successively done by the microsponge delivery system. When applied to the skin, the microsponge releases its active ingredient on a time mode and also in response to other stimuli (rubbing, temperature, pH, etc). Microsponge technology offers entrapment of ingredients and is believed to contribute towards reduced side effects, improved stability, increased elegance, and enhanced formulation flexibility. In addition, numerous studies have confirmed that microsponge systems are nonirritating, non-mutagenic, non-allergenic, and non-toxic. MDS technology is being used currently in cosmetics, overthe-counter (OTC) skin care, sunscreens and prescription products

KEYWORDS: Microsponge; transdermal delivery; proteins and peptides. 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 systems 2 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.

Received on 21.09.2011 Accepted on 05.10.2011 © Asian Pharma Press All Right Reserved Asian J. Pharm. Tech. 1(4): Oct. - Dec. 2011; Page 87-93

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.

87

[AJPTech.]


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.

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 reliable7. 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 4. Preparation of Microsponges: Drug loading in microsponges can take place in two ways, and abundantly available for colonic drug delivery 9. one-step process or by two-step process; based on physico2 APPROACHES TO DELIVERY THE INTACT chemical properties of drug to be loaded. If the drug is typically an inert non-polar material, will create the porous MOLECULE TO THE COLON: structure it is called porogen. Porogen drug, which neither 2.1 Coating with polymers: The intact molecule can be delivered to the colon without hinders the polymerization nor become activated by it and to free radicals is entrapped with one-step process absorbing at the upper part of the intestine by coating of the stable 14,15 . 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 fluid 11. 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.

Figure2: Reaction vessel for microsponge preparation by liquidliquid 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.

88

[AJPTech.]


Figure 3: Preparation of microsponges by quasi emulsion solvent diffusion method

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 35oC. 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 40oC 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

(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 m can impart gritty feeling and hence particles of sizes between 10 and 25 m 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

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

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 21.

89

[AJPTech.]


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.

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

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 Release mechanisms: By proper manipulation of the aforementioned equation 23. 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 Where D is the pore diameter ( m); the surface tension of ingredient from microsponges onto skin. mercury (485 dyn cm−1); the contact angle (130o); and P 2. Temperature change: Some entrapped actives can be too is the pressure (psia). viscous at room temperature to flow spontaneously from Total pore area (Atot) was calculated by using equation, 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 Where P is the pressure (psia); V the intrusion volume (mL microsponges and the outside system. g−1); Vtot is the total specific intrusion volume (mL g−1). Sustained release microsponges can also be developed. The average pore diameter (Dm) was calculated by using Various factors that are to be considered during equation, 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 Envelope (bulk) density ( se) of the microsponges was finally dispersed. Particle size, pore characteristics, resiliency and monomer calculated by using equation, 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 actives26 . Where Ws is the weight of the microsponge sample (g); Vp Formulation Considerations: the empty penetrometer (mL); VHg is the volume of Actives entrapped in MDS can then be incorporated into many products such as creams, lotions, powders and soaps. mercury (mL). When formulating the vehicle, certain considerations are taken into account in order to achieve desired product Polymer/ Monomer composition: characteristics. Factors such as microsphere size, drug loading, and polymer composition govern the drug release from 1. The solubility of actives in the vehicle must be limited. microspheres. Polymer composition of the MDS can affect Otherwise the vehicle will deplete the microsponges before partition coefficient of the entrapped drug between the the application. vehicle and the microsponge system and hence have direct

90

[AJPTech.]


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

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 watersoluble 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 6. Examples of enhanced product performance: • Oil control: Microsponge can absorb oil up to 6 times the rate of solubilization. An added benefit is that the time it its weight without drying. takes the Microsponge system to traverse the small and • Extended release large intestine is significantly increased thus maximizing • Reduced irritation and hence improved patient the amount of drug that is absorbed 29. compliance • Improved product elegancy 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 8. Applications of microsponge systems: Microsponges are porous, polymeric microspheres that are successful open up new fields of opportunity in systemic used mostly for topical and recently for oral administration. drug delivery arenas. It offers the formulator a range of alternatives to develop drug and cosmetic products. Microsponges are designed to Kawashima et al. have described methods for the deliver a pharmaceutical active ingredient efficiently at the preparation of hollow microspheres ('microballoons') with minimum dose and also to enhance stability, reduce side the drug dispersed in the sphere's shell, and also highly effects and modify drug release. porous matrix-type microspheres (‘microsponge’). The microsponges were prepared by dissolving the drug and polymer in ethanol. On addition to water, the ethanol Table 1-The system can have following applications 28 diffused from the emulsion droplets to leave a highly Sr. Active agents Applications porous particle. Variation of the ratios of drug and polymer No. in the ethanol solution gave control over the porosity of the 1. Sunscreens Long lasting product efficacy, with particle, and the drug release properties were fitted to the improved protection against sunburns and sun related injuries even at elevated Higuchi model. An approach to evaluate the loading concentration and with reduced irritancy capacity of these Microsponge® delivery systems has been and sensitization. developed utilizing the relative inter-particulate friction 2. Anti-acne Maintained efficacy with decreased skin sensing capability of the Hausner ratio (tap density/apparent e.g. Benzoyl irritation and sensitization. density) and comparing it to a more conventional peroxide 3. Anti-inflammatory Long lasting activity with reduction of flowability test 30. e.g. hydrocortisone 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 Rubefacients

Improved stabilization against oxidation with improved efficacy and aesthetic appeal. Prolonged activity with reduced irritancy greasiness and odour.

8.

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.

91

[AJPTech.]

Asian J. Pharm. Tech. 2011; Vol. 1: Issue 4, Pg 87-93 Table2: marketed formulation of microsponges34 S.N. Drug Formulation 1. Mesalamine Eudragit-S coated tablets(dissolves at pH 7) 2. Mesalamine Eudragit-L coated tablets(dissolves at pH 6) 3. Mesalamine Eudragit-L coated tablets 4.

Budesonide

Eudragit-L coated beads 9 mg/day

5-Fluorouracil (5-FU): 5-FU is an effective chemotherapeutic agent for treating actinic keratosis, a precancerous, 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.

Trade name Asacol Salofac

Dose 0.8 -2.4 g/day 1.0-4.0 g/day

Claversal Mesazal Calitoflak Entocort

1.0-2.0 g/day 9 mg/day

10. Benefits of Microsponge Technology 35 • 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.

92

[AJPTech.]


12. REFERENCES: 1.

2.

3. 4. 5.

6. 7.

8. 9. 10.

11.

12. 13.

14. 15. 16.

17. 18. 19. 20. 21. 22.

Netal A, Bajaj A and Madan M, Development of Microsponges for Topical Delivery of Mupirocin, AAPS Pharm. Sci. Tech, 10(2), 2009:123-128. Jelvehgari M, Siahi-Shadbad MR and Azarmi S, Themicrosponge delivery system of benzoyl peroxide: Preparation, characterization and release studies. Int J Pharm 308 2006:124-13 Nacht S and Katz M. The microsponge: a novel topical programmable delivery system. Topical drug delivery formulations. New York: Marcel Dekker; 1990. pp. 299–325. Mine O, Erdal C and Ahmet A, Design and evaluation of colon specific drug delivery system containing flurbiprofen microsponges, Int. J.Pharm. 318, 2006:103–117. Edwards C.A., Anatomical and physiological basis: physiological factors influencing drug absorption. Colonic Drug Absorption and Metabolism. Marcel Dekker, New York, 1993: pp. 1–28 Yang L, Chu J S and Fix J A , Colon-specific drug delivery: new approaches and in vitro/in vivo evaluation. Int. J. Pharm. 235, 2002: 1–15. Kean WF, Antal EJ, Grace EM, Cauvier H, Rischke J and Buchanan WW. The pharmacokinetics of flurbiprofen in younger and elderly patients with rheumatoid arthritis. J. Clin. Pharmacology. 32, 1992: 41–48. Saraija S and Hota A , colon specific drug delivery system, Ind. pharma s 62, 2008:1-8. Khan M Z I , Dissolution testing for sustained or controlled release oral dosage forms and corrosion with in vivo date: challenges and opportunities. Int J Pharm, 140, 1996:141-143. Dressman J B , Amidon C, Reppas C and Shah V P , Dissolution testing as a prognostic tool for oral drug absorption: Immediate release dosage forms, Pharm Res, 15, 1998:11-22. Kimura Y, Makita Y, Kumagi T, Yamane T, Kiato H, Sasatani H and Kim S I, Degradation of azo-containg polyurethane by the action of intestinal flora: its metabolism and application as a drug delivery system. Polymer, 33, 1992:5294-5299. Chowdary K P R and Rao Y S, Mucoadhesive Microspheres for Controlled Drug Delivery, Biol. Pharm. Bull., 27(11)2004:1711724. Nacht S and Kantz M The Microsponge: A Novel Topical Programmable Delivery System. Chapter 15, In: Topical Drug Delivery Systems. Edited by David W. O. and Anfon H. A. Volume 42, 1992: pp 299-325 Weiss R, Drug Delivery in the Space Age, Consultant Pharmacist, 4 Jan. 19(23). 1989:15-17. Won R, United States Patent No. 5,145,675 Two step method for preparation of controlled release formulations.1992. Jelvehgari M, Siahi-Shadbad M R, Azarmi S, Gary P and Nokhodchi A, The microsponge delivery system of benzoyl peroxide: Preparation, characterization and release studies, Int. J. Pharm., 308, 2006:124–132. Martin A, Swarbrick J and Cammarrata A, Chapter 19, In: Physical Pharmacy- Physical Chemical Principles in Pharmaceutical Sciences. 3rd Ed. 1991 pp 527. Emanuele A D and Dinarvand R, Preparation, Characterization and Drug Release from Thermo responsive Microspheres, Int. J. Pharm, 1995, 237-242. Kilicarslan M and Baykara T. The effect of the drug/polymer ratio on the properties of Verapamil HCl loaded microspheres. Int. J. Pharm. 252, 2003: 99–109. Shah VP, Determination of In-vitro Release from Hydrocortisone Creams. Int. J. Pharm. 53, 1989: 53-59. Orr J C, Application of mercury penetration to material analysis. Powder Technol. 3, 1969:117–123. Jones DS and Pearce KJ. Investigation of the effects of some process variables on, microencapsulation of propranolol HCl by solvent evaporation method. Int. J. Pharm. 118.1995: 99-205.

23. 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. 16, 1990:2057-2075. 24. James J L, Shalita A, Diane T, Kenneth W, and Guy W, Topical Retinoids in Inflammatory Acne: A Retrospective, InvestigatorBlinded, Vehicle-Controlled, Photographic Assessment, Clin. Therapeutics, 27,2005:216-224. 25. Guoping C, Sato T, Ohgushi H, Takashi U, Tetsuya T and Junzo T, Culturing of skin fibroblasts in a thin PLGA–collagen hybrid mesh, Biomaterials, 26, 2005:2559–2566. 26. Franz T J, Percutaneous absorption. On the relevance of in vitro date. J. Invest. Dermatol., 45, 1975:498-503. 27. Khopade A J, Jain S and Jain NK, “The Microsponge”; Eastern Pharmacist, March 1996: 49-53. 28. D'souza J I , In-vitro Antibacterial and Skin Irritation Studies of Microsponges of Benzoyl Peroxide, Indian Drugs, 38(7) 2001: 12-14. 29. D’souza J I, Masvekar RR, Pattekari PP, Pudi SR and More H N, Microspongic Delivery Of Fluconazole For Topical Application, 1st Indo-Japanese International Conference On Advances In Pharmaceutical Research And Technology, Mumbai, India, NOV.2005:25-29. 30. Grimes P E, A microsponge formulation of hydroquinone 4% and retinol 0.15% in the treatment of melasma and post-inflammatory hyperpigmentation, Cutis. Dec; 74(6) 2004:362-844. 31. James J L, Shalita A, Diane T, Kenneth W, and Guy W, Topical Retinoids in Inflammatory Acne: A Retrospective, InvestigatorBlinded, Vehicle-Controlled, Photographic Assessment, Clin. Therapeutics, 27, 2005:216-224. 32. Chen G, Sato T, Ohgushi H, Takashi U, Tetsuya T and Tanaka J, Culturing of skin fibroblasts in a thin PLGA–collagen hybrid mesh, Biomaterials, 26, 2005: 2559–2566. 33. Khan M Z, Prebeg Z, and Kurjakovic N, A pH dependent colon targeted oral drug delivery system using methacrylic acid copolymers I. Manipulation of drug release using Eudragit L10055 and EudragitS100 combinations, J Control Rel, 58: 1999:215222. 34. Fatima L, Asghar A and Chandran S, Multiparticulate Formulation. Approach to Colon Specific Drug Delivery: Current Perspectives J Pharm Pharmaceut Sci. 9 (3): 2006; 327-338. 35. Embik and Nacht S. The microsponge delivery system (MDS).a topical delivery sys. with reduced irritancy incorporating multiple trigger mechanism for the releases of actives j.microencapsulation,308,1996:124-132.

93