formulation and evaluation of microsponge drug delivery system using ...

Mahajan Aniruddha G et al. IRJP 2011, 2 (10), 64-69 INTERNATIONAL RESEARCH JOURNAL OF PHARMACY

ISSN 2230 – 8407 Research Article

Available online www.irjponline.com

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 1

Cognizant Technology Solutions India Pvt. Ltd., Powai, Mumbai, India 2 Padmashree 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 Theoretical drug content

and

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

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

Mahajan Aniruddha G et al. IRJP 2011, 2 (10), 64-69 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 O ) radiation and a crystal monochrometer, K 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: 196201. [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: 103117. [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.


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


Mahajan Aniruddha G et al. IRJP 2011, 2 (10), 64-69 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 Time ( USP 30 Test 3 Requirement ) Batch No.

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

100

Cumulative % Release

90 80 70 60 50 40 30 20 10 0 0

1

2

3

4

5

6

7

8

9

10

11

12

13

Time (hrs) F1

F2

F3

F4

F5

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


Mahajan Aniruddha G et al. IRJP 2011, 2 (10), 64-69 Microsponge Batches F6,F7,F8,F9,F10 100 Cumulative % Release

90 80 70 60 50 40 30 20 10 0 0

1

2

3

4

5

6

7

8

9

10

11

12

13

Tim e (hrs)

F6

F7

F8

F9

F10

Fig. No. 2. Dissolution profile of batches F6, F7, F8, F9 and F10 Microsponge Batches F11,F12,F13,F14,F15 Cumulative % Drug Release

100 90 80 70 60 50 40 30 20 10 0 0

1

2

3

4

5

6

7

8

9

10

11

12

13

Tim e (hrs)

F11

F12

F13

F14

F15

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


Mahajan Aniruddha G et al. IRJP 2011, 2 (10), 64-69 DSC mW 0.00

-10.00

Onset

157.53C

Endset

177.65C

Transition

-1.70mW -0.34mW/mg

Mid Point

152.13C

Peak

160.99C

Onset

157.53C

Endset

164.60C

Heat

-589.18mJ -117.84J/g

-20.00

-30.00

200.00

100.00 Temp [C]

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
