Microsponge Drug Delivery System

Microsponge as a Topical Drug Delivery System

1. MICROSPONGE DRUG DELIVERY SYSTEM PRESENTED BY Karad B. B. M Pharm- I Sem GUIDED BY Mrs. Barhate A.N. SVPM’S College of Pharmacy, Malegaon ( BkII ) Tal.Baramati, Dist. Pune 2015-2016 1

2. CONTENTS Introduction Need of microsponge delivery system Methods of preparation Characteristics of microsponges Release mechanism Advantages & limitations Applications Evaluation Parameters Marketed formulations References 2

3. Introduction 1,5,12 MICROSPONGE: “Microsponges are polymeric delivery systems composed of porous microspheres. They are tiny sponge-like spherical particles with a large porous surface.” Microsponge is recent novel technique for control release and target specific drug delivery system. They are desire to deliver API efficiently at the minimum dose and also to enhance stability, reduce side effect and modify drug release. Typically in 5-25 µ m in diameter. 3

4. Microsponge as Topical drug delivery The human skin is a large and complex organ that protects internal tissue from environmental exposure. As the interface between the organism and the external world, the skin is susceptible to injuries from the environment or from other organisms. Topical drug delivery systems are formulated either to give local effect or to enter in to the systemic circulation, where skin serves as the portal of entry to the drug and various formulations made available in the market are creams, gels, lotions, ointments etc. Skin 4

5. Main drawbacks of topical preparations for local action are they may readily absorbed and hence, less duration of action and decreased activity. Similarly topical preparations for systemic action have drawback like drug doesn’t reaches the systemic circulation in sufficient amounts. To overcome this problems MDS technique plays imp. Role. A Microsponge Delivery System (MDS) is patented, highly cross-linked, porous, polymeric microspheres that can entrap wide range of actives and then release them with desired rate. This system is applicable for the improvement of performance of topically applied drugs. When microsponge delivery system applied to the skin, the release of drug can be controlled through diffusion or other variety of triggers, including rubbing, moisture, pH, friction, a nd skin temperature. Thus the microsponge should remain maximum time at the skin and below the epidermis and release the medicament slowly. 5

6. Typical view of Microsponges Fig.Highly porous nature of Microsponge Fig.Retinol entrapped in Microsponge 6

7. NEED FOR MICROSPONGE DELIVERY SYSTEM Microsponges consist of non-collapsible structures with porous surface through which active ingredients are released in a controlled manner. Their characteristic feature is the capacity to adsorb or “ load ” a high degree of active materials into the particle and on to its surface. To prevent excessive accumulation of ingredients within the epidermis and the dermis. Controlled release of drug on to epidermis does not enter the systemic circulation in significant amounts. 7

8. METHODS OF MICROSPONGE PREPARATION 1,4,6,11,23 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. Following techniques are commonly used Liquid-liquid suspension polymerization Quasi-emulsion solvent diffusion 8

9. Preparation of microsponge Drug loading in microsponge One step process Two step process Liquid -liquid suspension polymerisation Quasi emulsion solvent diffusion Based on physico-chemical properties of drug to be loaded 9

10. Liquid-liquid suspension polymerization Microsponges are prepared by suspension polymerization process in liquid-liquid systems (one-step process). In their preparation, the monomers are first dissolved along with active ingredients in a suitable solvent solution of monomer and are then dispersed in the aqueous phase, which consist of additives (surfactant, suspending agents, etc. to aid in formation of suspension). Once the suspension is established with distinct droplets of the preferred size then, polymerization is initiated by increasing temperature as well as irradiation. After polymerization process is complete, the liquid is removed which is permeate within preformed microsponges then, incorporates the variety of active substances like anti fungal, anti acne, anti inflammatory etc. which act as a topical carriers. 10

11. 1. LIQUID-LIQUID SUSPENSION POLYMERIZATION Fig .:- Reaction vessel for microsponge preparation by liquid-liquid Suspension Polymerization 11

12. The various steps in the preparation of microsponges are summarized as: Selection of monomer or combination of monomers. Formation of chain monomers as polymerization begins Formations of ladders as a result of cross linking between chain monomers Folding of monomer ladder to form spherical particles Agglomeration of microspheres, which give rise to formation of bunches of microspheres Binding of bunches to form microsponges. Fig. Steps in the preparation of microsponges 12

13. Quasi-emulsion solvent diffusion: Porous microspheres (microsponges) are also prepared by a quasi-emulsion solvent diffusion method (two-step process) using an internal phase containing polymer such as eudragit which is dissolved in ethyl alcohol. Then, the drug is slowly added to the polymer solution and dissolved under ultra-sonication at 35 º C and plasticizer such as triethylcitrate (TEC) is added in order to aid the plasticity. The inner phase is then poured into external phase containing polyvinyl alcohol and distilled water with continuous stirring for 2 hours. Then, the mixture is filtered to separate the microsponges. The product (microsponges) was washed and dried in an air- heated oven at 50°C for 24 hr. 13

14. 2 . QUASI-EMULSION SOLVENT DIFFUSION Fig.: Preparation of microsponges by quasi emulsion solvent diffusion method 14

15. CHARACTERISTICS OF MICROSPONGES 10,15,17 Microsponge formulations are stable over range of pH 1 to 11. It is stable at the temperature up to 130º c. They are compatible with most vehicles and ingredients. They are self sterilizing as their average pore size is 0.25 μ m where bacteria cannot penetrate. Microsponge formulations have high entrapment upto 50 to 60%. It is free flowing and can be cost effective reduced irritation and hence improved patient compliance. 15

16. Drug explored in Microsponge drug delivery system 1,17 Ibuprofen Fluconazole Benzoyl peroxide Ketoprofen Paracetamol Dicyclomine Flurbiprofen Ketoconazole Tretinoin Trolamine Retinol Salicylic acid 16

17. CHARACTERISTICS OF MATERIALS ENTRAPED IN MICROSPONGES 10,23,15,17 They should be completely miscible in monomer. They should be water immiscible or at most only slightly soluble. They should be inert to monomers. They should be stable in contact with polymerization catalyst and conditions of polymerization Mostly liquid or soluble ingredients can be entrapped In the microsponge . 17

18.   Release Mechanisms 2,4,17,6 Pressure Temperature change Solubility pH triggred system 18

19. Pressure: Rubbing/ pressure applied can release active ingredient from microsponges onto skin. The amount released depends upon various characteristics of the sponge. 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 . 19

20. Solubility: Microsponges loaded with water-soluble ingredients like anti- perspirants 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. pH triggered systems: Triggering the pH-based release of the active can be achieved by modifying the coating on the microsponge . 20

21. ADVANTAGES OF MICROSPONGE 1,2,5,15 Microsponge systems are non-irritating, non-mutagenic, non-allergenic and non-toxic. Improved formulation flexibility. Extended release of drug continuous upto 12 hours. Reduce irritation and improve patient complience . Microsponge drug delivery can improve bioavailability of drug. 21

22. ADVANTAGES OF MICROSPONGE They have better thermal, physical and chemical stability. Allows incorporation of immiscible product. Advance oil control. Easy to formulate. 22

23. LIMITATIONS 2,5 The preparation methods usually use organic solvents as porogens , which pose an environmental hazard, as some may be highly inflammable, posing a safety hazard. In some cases, the traces of residual monomers have been observed, which may be toxic and hazardous to health . 23

24. Sr.No . Active Agents Applications 1. Sunscreens Improved Protection Against Sunburns and Sun Related Injuries. 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-dandruffs: E.g. zinc pyrithione , selenium sulfide. Reduced Unpleasant Odour with Lowered Irritation with Extended Safety and Efficacy . Applications 2,3,11 24

25. Sr.No . Active Agent Applications 5. Antipruritics Extended and improved activity. 6. Skin depigmenting: E.g.hydroquinone. Improved stabilization against oxidation with improved efficacy and aesthetic agents . 7. Rubefacients Prolonged activity with reduced irritancy, greasiness and odour. 8. Anti- fungals Sustained release of active ingredients. Applications 25

26. Evaluation parameters 1,4,6,18 Particle size (Microscopy ) Morphology and Surface topography Determination of true density Loading efficiency and production yield Characterization of pore structure Compatibility studies Resiliency (viscoelastic properties) Drug release study 26

27. Particle size analysis of loaded and unloaded microsponges can be performed by laser light diffractometer or any other suitable method. The values can be expressed for all formulations as mean size range. Cumulative percentage drug release from microsponges of different particle size must be plotted against time to study effect of particle size on drug release. Particles larger than 30μm can impart gritty feeling and hence particles of sizes between 10 and 25μm are preferred to use in final topical formulation . 1. Particle size determination : 27

28. 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 ultra structure. 2. Morphology and surface topography of microsponges : The true density of microparticles is measured using an ultra- pycnometer under helium gas and is calculated from a mean of repeated determinations . 3. Determination of true Density : 28

29. 4. Determination of loading efficiency and production yield : The loading efficiency (%) of the microsponges can be calculated according to the following equation: 100 The production yield of the microparticles can be determined by following equation: 100   29

30. 5. Characterization of pore structure : Mercury intrusion porosimetry can be employed to study effect of pore diameter and volume with rate of drug release from microsponges . 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 . 30

31. 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 ). 31

32. 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. In vitro release studies can be performed using United States Pharmacopeial (USP) dissolution apparatus equipped with a modified basket consisted of 5 μm stainless steel mesh at 37°C. The release medium is selected according to the type of formulation that is, topical or oral, while considering solubility of active ingredients to ensure sink conditions. 8.Invitro Drug Release study : 32

33. Examples of MDS with their formulation 6 33 MDS Drugs Disease treatment Gels Benzoyl peroxide Anti-acne Treatment Fluconazole Anti-fungal Diclofenac Sodium Anti Inflammation Terbinafine HCL Anti-fungal Lotions Benzoyl Peroxide Anti-acne Treatment Creams Hydroquinone and Retinol Melanoma Other Ibuprofen NSAID Mefenamic acid Rhumatoid arthritis

34. Marketed formulation of the MDS 1,3,11,18 Product Name Active Ingredient Treatment Manufacturer Retin -A-Micro 0.1% and 0.4% tretinoin in an aq. gel. Acne vulgaris Ortho-McNeil Pharmaceutical, Inc. Cerac Cream, 0.5% 0.5% flurouracil Actinic Keratoses (AK). Dermik Laboratories, Inc. Berwyn, PA 19312 USA Oil Control Lotion Natural antibiotics Acne-Prone, oily skin conditions. Fountain Cosmetics Ultra Guard Dimethicone Protect a baby’s skin from diaper rash. Scott Paper Company. Salicylic Peel 20 Salicylic Peel 30 Salicylic acid 20% Salicylic acid 30% Improve fine lines, pigmentation and acne concerns. Biophora . 34

35. Product Name Active Ingredient Treatment Manufacturer Lactrex ™ 12% Moisturizing Cream 12% lactic acid as the neutral ammonium salt, ammonium lactate. Long lasting moisturization . SDR Pharmaceuticals, Inc., Andover, NJ U.S.A. 07821. EpiQuin Micro Retinol and Hydroquinone Minimize skin irritation, Reduce age spot, sun spot etc. Skin Medica Inc. Line eliminator Dual Retinol Facial Treatment Retinol (vitamin A) Diminish wrinkle, appearance of fine lines etc. Avon Sportscream RS and XS Topical analgesic, anti-inflammatory and counterirritant. Management of Musculoskeletal conditions. Embil Pharmaceutical Co .Ltd . Micro peel plus / Acne peel Salicylic acid in forms of Microcrystals. Remove all dead cells doing no damage to skin . Biomedic . 35

36. Ultra guard Cerac cream EpiQuin Micro Neutrogena Shine stopper Oil control Dermalogica Oil control Murad Moisturizing cream Image Sunscreen Marketed Preparations 36

37. Patel A, Upadhyay P. Microsponges As The Versatile Tool For Topical Route: A Review. Int J Pharm Sci. Res . 2012;3(9 ): 2926-2937. Kale S, Shalini R. Microsponge : Comprehensive Review of Application. Int J Pharm Bio Sci. 2013;3(1 ):214-226. Shaha V, Jain H. Microsponge Drug Delivery: A Review. Int J Res Pharm Sci. 2010;1(2):212-218. Patel EK, Oswal RJ. Nanosponge And Micro Sponges: A Novel Drug Delivery System. Int J Res . Pharm Chem . 2012;2(2):237-243. Hussain H, Juyal D. Microsponges: An Overview. Ind J Novel Drug Delivery 2014;6(3 ):198-207 . Sinkar NB, Gondkar SB, Saudagar RB. Microsponge A Innovative Strategy For Drug Delivery System, Current Status And Future Prospects-A Review. Int J Inst Pharm Life Sci. 2015;5(3 ):226-242 . References 37

38. Arora N, Agarwal S, Murthy RS. Latest Technology Advances In Cosmaceuticals . Int J Pharm Sci. Drug Res. 2012;4(3):168-182. Hussain H, Dhyani A, Juyal D. Formulation And Evaluation of Gel-Loaded Microsponges Of Diclofenac Sodium For Topical Delivery. The Pharma Innovation J. 2014;3(10):58-63. Mahajan A, Jagtap L, Chaudhari A. Formulation And Evaluation of Microsponge Drug Delivery System Using Indomethacin. Int Res J Pharm. 2011;2(10 ): 64-69. Saroj Kumar Pradhan . Microsponges As The Versatile Tool For Drug Delivery System: A Review. Int J Res Pharm Chem . 2011;1(2 ); 243-258. Yerram C, Shaik F, Rubia Y. Microsponges: A Novel Drug Delivery System For Controlled Delivery of Topical Drugs. Int J Pharm Res. 2012;2(2 ):79-86 . Pandey P , Jain V, Mahajan SC. A Review: Microsponge Drug Delivery System. Int J Bio Pharm . 2013;4(3):225-230 . 38

39. Charde MS, Ghanawat PB. Microsponge A Novel New Drug Delivery System: A Review. Int J Adv Pharm. 2013;2(6 ):64-70 . Aloorkar NH, Kulkarni AS. Microsponge As Innovative Drug Delivery System. Int J Pharm Sci. 2012;5(1 ):1597-1606 . Makwana R, Patel H, Patel V. Microsponge For Topical Drug Delivery System. Int J Pharm Tech . 2014 ; 5(4): 2839-2851. Kumar R, Sharma SK. Microsponge Drug Delivery Systems For Novel Topical Drug Delivery. Int J Pharm Sci Letters. 2014; 4(3):384-390 . Jadhav N, Patel V, Mungekar S. Microsponge Delivery System: An Updated Review, Current Status And Future Prospects. J Sci Innovative Res. 2013;2(6 ):1097-1110 . Ravi R, Senthilkumar Sk. Microsponges Drug Delivery System: A Review. Int J Pharm Rev Res . 2013;3(1 ):6-11. 39

40. Jangde R. Microsponges For Colon Targeted Drug Delivery System: An Overview. Asian J Pharm Tech. 2011;1(4 ): 87-93. Ravi R, Senthil Kumar SK, Parthiban S. Formulation And Evaluation of The Microsponges Gel For An Anti Acne Agent For The Treatment of Acne. Ind J Pharm Sci Res . 2013; 3(1): 32-38. D’souza J, More HN. Topical Anti-Inflammatory Gels of Fluocinolone Acetonide Entrapped In Eudragit Based Microsponge Delivery System. Res J Pharm Tech. 2008;1(4 ): 502-506. Bhowmik D, Gopinath H. Recent Advances In Novel Topical Drug Delivery System. The Pharma Innovation. 2012;1(9 ): 12-31. Osmani RA, Aloorkar NH, Ingale DJ. Microsponges Based Novel Drug Delivery System For Augmented Arthritis Therapy. Saudi Pharm J 2015. Karthika R, Elango K . Formulation And Evaluation of Lornoxicam Microsponge Tablets For The Treatment of Arthritis. Int J Pharm Innovations 2013; 3(2):29-40 . 40