FORMULATION AND EVALUATION OF MICROSPONGE DRUG DELIVERY SYSTEM

Mahajan Aniruddha G et al. IRJP 2011, 2 (10), 64-69

INTERNATIONAL RESEARCH JOURNAL OF PHARMACY, 2(10), 2011

INTERNATIONAL RESEARCH JOURNAL OF PHARMACY ISSN 2230 – 8407 Available online www.irjponline.com Research Article

FORMULATION AND EVALUATION OF MICROSPONGE DRUG DELIVERY SYSTEM

USING INDOMETHACIN Mahajan Aniruddha G*1, Jagtap Leena S2, Chaudhari Atul L, Swami Sima P, Mali Prabha R2

1Cognizant Technology Solutions India Pvt. Ltd., Powai, Mumbai, India 2Padmashree Dr. D Y Patil Institute of Pharmacy, Akurdi, Pune, India

Article Received on: 14/08/11 Revised on: 22/09/11 Approved for publication: 18/10/11

*Email: [email protected] ABSTRACT In the present study controlled release formulation of Indomethacin microsponges were prepared by using Eudragit RS 100, pH independent release retardant polymer and PVA, stabilizer or emulsifier. Microsponges were prepared by Quasi emulsion solvent diffusion method by changing drug polymer ratio (3:1, 4:1, 5:1) and process was optimized. Microsponges were evaluated by micromeritic properties, drug content, encapsulation efficiency, and particle size. Characterization of Indomethacin microsponges were done by FT-IR spectroscopy, Differential scanning calorimetry, X-ray diffractometry and Scanning electron microscopy for pure drug, polymer, physical mixture and formulation. In-vitro dissolution study indicated that the release of Indomethacin varied according to the concentration of matrix forming polymer. Therefore, Indomethacin microsponges prepared in thus study are promising as being more useful than conventional formulation in therapy. Keywords: Microsponge, Quasi-emulsion solvent diffusion method, DSC, XRD, FTIR and SEM INTRODUCTION Microsponges are porous microspheres having myriad of interconnected voids of particle size ranging from 5-150 µm. Microsponge Drug Delivery System is a unique technology which provides controlled release of active ingredients1,2. It offers numerous advantages over other technologies like reduced side effects, improved stability, increased elegance and enhanced formulation flexibility3,4. Microsponges are porous, polymeric microspheres that are used mostly for topical and recently for oral administration. They can be incorporated into conventional dosage forms such as creams, lotions, gels, ointment, tablet and powder and share a broad package of benefits & thus provides formulation flexibility5,6,7. Non-steroidal anti-inflammatory drugs (NSAIDs) are used as an analgesic and anti-inflammatory agents in various disorders e.g. rheumatoid arthritis, spondylitis, acute gout etc. These are nonselective inhibitor of COX І and COX ІІ enzymes that participate in prostaglandin synthesis from arachidonic acid8,9,10. In case of disease state like arthritis, conventional oral dosage forms are ineffective in delivering the drugs to lower GI tract due to absorption or degradation of drug in upper GI tract and from the therapeutic point of view it is beneficial to increase the residence time of drug to get maximum absorption11,12. Among the NSAID’s, Indomethacin is the drug having short biological half life (2 to 3 hours), degradation in the upper part of GIT and posses side effect like GI irritation. Also the usual dosage regimen is 25 to 100 mg, three times a day13,14,15. From the literature study, it was evident that modified release dosage form of indomethacin was required to be formulated to minimize the side effects like GI irritation and protect the drug from first pass effect i.e. presystemic degradation of drug in liver16,17,18. Hence, in the present work an attempt was made to develop controlled release microsponges using synthetic polymer to

minimize frequent dosing, prolong the pharmacological effect and thus improve patient compliance19,20. MATERIALS & METHODS Indomethacin was obtained as a gift sample from Themis laboratories Mumbai. Eudragit RS 100 was purchased from Degussa laboratories. PVA was obtained from Colorcon Goa. Method of Preparation of Microsponges The microsponges were prepared by Quasi-emulsion solvent diffusion method. The method consists of two steps. In first step inner phase was prepared and in second step outer phase was prepared. Inner phase was prepared by dissolving the Eudragit RS 100 in ethanol. Then the drug Indomethacin was added to solution and dissolved under ultrasonication at 35 0C for 15 minutes. Outer phase was prepared by dissolving PVA in distilled water and the process was carried out at room temperature. Then Inner phase was then poured into outer phase at room temperature. After emulsification, the mixture was continuously stirred at 500 rpm for two hours. After the formation of microsponges the mixture is filtered to separate the microsponges. The product was washed and dried in oven at 400C Initially preliminary batches were prepared by using drug polymer ratio (3:1, 4:1, 5:1) and process was optimized as shown in Table No.1. In order to study the effect of PVA the microsponges are prepared by changing the concentration Table no. 2 gives the detail of the formulated batches. Once the formulation was prepared characterization of microsponges were done by determining drug loading and encapsulation efficiency as shown in Table No. 3 and Table No. 4, FTIR, DSC, XRD, SEM and In-vitro study. RESULTS Evaluation of drug content The Indomethacin content in the microsponges was estimated by procedure given in (USP 30 NF 25, 2007) and calculation was done by using formula

Actual drug content Encapsulation efficiency (%) = ----------------------------------------× 100 and Theoretical drug content Weight of drug

Drug Loading (%) = ---------------------------------------- × 100 Weight of microsponges



In-Vitro Release study Accurately weighted quantity of microsponges equivalent to 40 mg of Indomethacin were taken in muslin cloth and was kept in basket. During dissolution study, 10 ml aliquot was withdrawn at different time intervals of 1, 2, 3---12 hrs and same was replaced with equal volume of fresh medium. The withdrawn sample was filtered through Whatman filter paper No.42 and absorbances were measured at 318nm (USP 30 NF25, 2007). The experiment was performed in triplicate. FT –IR Study To know the interaction between drug and polymer FT-IR spectrum obtained using KBr pellets technique and was compared with the spectrum available in official book. X-Ray Diffractometry Study The X-Ray powder diffraction patterns was obtained by x-ray diffractometer with Cu K O) radiation and a crystal monochrometer, voltage : 45 mv and current 20 amp. The diffraction patterns run at 5-100 C / min in terms of 2 crystal and physical state characterization of Indomethacin. Differential Scanning Calorimetry For the structural, crystal and physical state characterization of Indomethacin, the DSC study was performed for pure drug, polymer and formulations. All accurately weighed samples were placed in a sealed aluminium pans before heating under nitrogen flow (20 ml/min) at a scanning rate of 10 0C per min from 25 to 300 0C. An empty aluminium pan was used as a reference. Scanning Electron Microscopy This study was performed using Scanning Electron Microscopy (SEM).The microsponges were coated with platinum by ion sputtering using autofine coater.The microsponges were kept on the sample holder and the scanning electron micrographs were taken. DISSCUSION The primary benefit of controlled release preparation compared to conventional dosage forms is that more uniform maintenance of blood plasma level of active agent which is helpful to avoid undesirable peaks and troughs achieved with multiple immediate release preparations. Therefore, in this study controlled release formulation of Indomethacin was prepared. The drug polymer ratio showed significant effect on the encapsulation efficiency of microsponges. The decreased concentration of polymer showed the decreased drug encapsulation efficiency of microsponges. In-vitro dissolution study indicated that the release of indomethacin varied according to the concentration of matrix forming polymer. The release of indomethacin increased with decreasing concentration of Eudragit RS 100. The release of drug from formulations containing varying concentration of Eudragit RS 100 was inversely proportional i.e. 0.666< 0.500< 0.400 (gm). Higher release rate was found from microsponges prepared from the lower concentration of Eudragit RS 100 in 12 hours study. The effect of PVA on drug release from microsponge formulations showed a slight decrease in release with increased concentration. Characterization of Indomethacin microsponges were done by FT-IR spectroscopy, DSC, X-ray diffractometry and scanning electron microscopy for pure drug, polymer, physical mixture and formulation. The results of FT-IR study revealed that there was no chemical interaction between drug and polymer or formation of any decomposition product in the final formulation. From the thermograms of DSC study obtained, it was observed that there was no interaction between pure drug and polymer as well as

crystalline nature of drug remains thermally stable up to the final formulation which was also supported by XRD study while SEM study revealed that the microsponges observed was discrete and spherical. With this kind of formulation, the undesirable side effects and presystemic metabolism of the drug can be eliminated and a sustained effect can be obtained. Therefore, Indomethacin microsponges prepared in thus study are promising as being more useful than conventional formulation in therapy. Finally it can be concluded that the objective of this study is achieved. FUTURE PROSPECTUS In future microsponges can be used to prepare suitable dosage form and its in-vivo absorption studies in animals/ humans can be carried out to know the bioavailability from sustained release formulation. REFERENCES [1] Jain NK. Advances in controlled and novel drug delivery. New Delhi: CBS Publishers and Distributors; 2003: 89-91. [2] Kydonius AF, Controlled release technologies: Methods, Theory and Applications, Boca Raton: CRC; 1980 Press,: 21-49. [3] Nacht S, Katz M. The microsponge ; a programmable delivery system. In Osborne , DW, Aman AH , Topical drug delivery formulations. New York: Marcel Dekker; 1990 : 299-325. [4] Embil K, Nacht S. The microsponge delivery system (MDS): a topical delivery system with reduced irritancy incorporating multiple triggering mechanisms for release of actives. J. Microencapsul 1994; 13:575-588. [5] Kim W, Hwang S, Park J, Park H. Preparation and characterization of drug loaded polymethacrylate microspheres by an emulsion solvent evaporation method. J. Microencapsul200; 6: 811-822. [6] Kawashima Y, Niwa T, Hand T, Takeuchi H, Iwamoto T. Control of prolonged drug release and compression properties of ibuprofen microspheres with acrylic polymer by changing their intra-particle porosity. Chem. Pharm Bull 1992; 40: 196-201. [7] Dashora K, Saraf S. Effect of processing variables on micro particulate system of nimesulide. Chinese J. Pharm 2006;58: 67-74. [8] Jelvehgari M, Shadbad M, Azarmi S, Martin J. The microsponge delivery system of benzoyl peroxide: preparation characterization and release studies. Int J Pharm 2006; 308: 124-132. [9] Tiyaboonchi W, Ritthidej C. Development of indomethacin sustained release microcapsules using chitosan carboxymethyl cellulose complex coacervation. J Sci Tech 2003; 25: 245-354. [10] James W. Pharmaceutical preformulation: the physicochemical properties of drug substances. In: Aulton ME. (Ed.), Pharmaceutics The Science of Dosage Form Design. Edinburgh: Churchill Livingstone 2002: 133-135. [11] Schroder K, Schmid K, Lobenberg R.Influence of bulk and tapped density on the determination of thermal nature of powders and blends. AAPS Pharm Sci Tech 2007; 8:3: 78. [12] Conors K. A Textbook of Pharmaceutical Analysis. New York: Wiley Interscience Publication; 1982 : 173-178. [13] Comoglu T, Gonul N, Baykara T. Preparation and in vitro evaluation of modified release ketoprofen microsponges. IL Farmaco2002;58: 101-106. [14] Perumal D. Microencapsulation of ibuprofen and Eudragit RS 100 by the emulsion solvent diffusion technique. Int. J Pharm 2001;218: 1-11. [15] Perumal D, Danger C, Alock R, Hurbans N, Moonpanar K. Effect of formulation variables on in vitro drug release and micromeritic properties of modified release ibuprofen microspheres. J Microencapsul 1999;16: 475-487. [16] Orlu M, Cevher E, Araman A. Design and evaluation of colon specific drug delivery system containing flurbiprofen microsponges. Int J Pharm 2006; 318: 103-117. [17] Nokhodchi A, Jelvehgari M, Siahi M, Mozafari M. Factors affecting the morphology of benzoyl peroxide microsponges. Micron 2007;38: 834-840. [18] Nokhodchi A.The effect of type and concentration of vehicles on the dissolution rate of a poorly soluble drug indomethacin. J Pharm Sci. 2005; 8: 18-25 [19] Pan X, Julian T, Augsburger L. Quantitative measurement of indomethacin crystallinity using differential scanning calorimetry and X-ray powder diffractometry. AAPS Pharm Sci Tech 2006; 7: 11. [20] Akhavein N, Khan F, Uddin, N, Lai Y. In vito release of indomethacin from crosslinked albumin microspheres. Int J Pharm 2004; 209: 167-174.



Table No. 1 Optimum values for microsponge formulation

Specifications Optimum Values

Drug: Polymer ratio 3:1, 4:1 and 5:1

Amount of drug (g) 2

PVA (mg) 30-70

Inner phase solvent Ethyl alcohol

Amount of inner phase solvent (ml) 10 ml

Amount of water in outer phase (ml) 200 ml

Temperature of inner phase (0C) 37

Stirrer type Three blade

Stirring rate (rpm) 500

Stirring time (min) 60

Table No. 2 Batches prepared on basis of preliminary batches of microsponges

Batch Code Drug (g) Eudragit RS 100 (g) PVA (mg) Ethanol (ml) Distilled water

(ml)

F1 2 0.666 30 10 200

F2 2 0.666 40 10 200

F3 2 0.666 50 10 200

F4 2 0.666 60 10 200

F5 2 0.666 70 10 200

F6 2 0.500 30 10 200

F7 2 0.500 40 10 200

F8 2 0.500 50 10 200

F9 2 0.500 60 10 200

F10 2 0.500 70 10 200

F11 2 0.400 30 10 200

F12 2 0.400 40 10 200

F13 2 0.400 50 10 200

F14 2 0.400 60 10 200

F15 2 0.400 70 10 200



Table No. 3 Actual drug content, encapsulation efficiency and yield of microsponges

Batch No. Actual Drug Loading (%)

Theoretical Loading (%)

Encapsulation Efficiency (%) Yield (%)

F1 74.58±0.01 81.63 90.53±0.01 81.90±2.68

F2 74.82±0.02 81.96 91.28±0.02 82.74±2.71

F3 73.87±0.02 82.30 90.43±0.01 82.04±3.38

F4 74.64±0.01 82.64 89.10±0.01 81.38±2.96

F5 74.17±0.02 82.98 89.38±0.02 82.14±3.31

F6 73.43±0.01 78.43 93.54±0.02 79.40±2.49

F7 73.22±0.02 78.74 91.82±0.02 80.07±3.12

F8 73.63±0.02 79.05 93.15±0.03 79.78±1.97

F9 72.14±0.01 79.36 90.90±0.01 78.34±2.73

F10 72.84±0.03 79.68 91.41±0.02 78.64±1.89

F11 69.94±0.01 73.63 94.98±0.03 79.08±2.83

F12 68.90±0.02 73.90 93.20±0.02 81.03±2.14

F13 69.75±0.02 74.18 94.02±0.01 80.86±2.67

F14 69.08±0.01 74.46 92.77±0.02 79.74±2.34

F15 68.12±0.01 74.73 91.15±0.02 78.69±1.83

Table No. 4 Cumulative percent drug release of batches F1 to F15

Batch No.

Time ( USP 30 Test 3 Requirement )

1 Hour (15-40)

2 hour (35-55)

4 Hour (55-75)

6 Hour (65-85) 8 Hour 12 Hour

F1 25.103 37.829 52.431 65.308 74.600 88.698

F2 24.991 37.491 52.197 65.070 74.134 88.227

F3 24.879 37.602 51.860 64.841 73.896 87.746

F4 24.879 37.602 51.521 63.701 72.730 86.306

F5 24.991 37.491 51.294 63.355 72.376 85.941

F6 27.234 39.983 56.891 70.415 80.041 93.673

F7 27.234 39.647 56.545 70.172 78.220 93.385

F8 27.010 39.644 56.314 69.820 77.750 92.879

F9 26.561 39.291 55.629 68.564 77.135 92.381

F10 26.337 38.852 55.284 68.323 76.779 91.653

F11 27.907 40.776 57.930 71.143 81.577 95.533

F12 27.907 40.663 57.703 70.910 81.338 95.170

F13 27.408 40.210 57.355 70.215 80.515 94.878

F14 27.682 40.325 57.246 70.444 80.752 94.565

F15 27.570 40.099 57.016 69.871 80.280 94.074

Microsponge Batches F1,F2,F3,F4,F5

0102030405060708090

100

0 1 2 3 4 5 6 7 8 9 10 11 12 13

Time (hrs)

Cum

ulat

ive

% R

elea

se

F1 F2 F3 F4 F5

Fig. No.1. Dissolution profile of batches F1, F2, F3, F4 and F5




0102030405060708090

100

0 1 2 3 4 5 6 7 8 9 10 11 12 13Time (hrs)

Cum

ulat

ive

% R

elea

se

F6 F7 F8 F9 F10

Fig. No. 2. Dissolution profile of batches F6, F7, F8, F9 and F10

Fig. No. 3. Dissolution profile of batches F11, F12, F13, F14 and 15

Fig. No.4. FT-IR spectra of microsponge formulation (F11)

Fig.No.5. XRD Spectrum of microsponge formulation


010

2030

4050

6070

8090

100

0 1 2 3 4 5 6 7 8 9 10 11 12 13Time (hrs)

Cum

ulat

ive

% D

rug

Rel

ease

F11 F12 F13 F14 F15



100.00 200.00Temp [C]

-30.00

-20.00

-10.00

0.00

mWDSC

157.53COnset

164.60CEndset

160.99CPeak

-589.18mJ-117.84J/g

Heat

157.53COnset

177.65CEndset

152.13CMid Point

-1.70mW-0.34mW/mg

Transition

Fig.No.6. DSC thermogram of microsponge formulation

Fig.No.7 SEM photograph of Indomethacin microsponges

Source of support: Nil, Conflict of interest: None Declared

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FORMULATION AND EVALUATION OF MICROSPONGE DRUG DELIVERY SYSTEM