Formulation, In Vitro Characterization and Stability Studies of Self M

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Formulation, In Vitro Characterization and Stability Studies of Self Microemulsifying Drug Delivery Systems of Domperidone:

Formulation, In Vitro Characterization and Stability Studies of Self Microemulsifying Drug Delivery Systems of Domperidone 1 PRESENTED BY :- Bansi Zalavadia International Journal Of Innovative Pharmaceutical Research,2010,1(4). Mts.V.B.Manvar college of pharmacy,Dumiyani Sudhanshu Sharma and Preeti K. Suresh* GuidED BY :- Dr. h. m. tank mr. sandip patel

CONTENT:

CONTENT Abstract Keywords Introduction Material and method Evaluation Result and discussion Conclusion Acknowledgements References 2

ABSTRACT:

ABSTRACT Self-micro emulsifying drug delivery system (SMEDDS) is a novel and versatile approach for overcoming the formulation difficulties of drugs with poor aqueous solubility. The aim of the present study was to develop and evaluate the performance of SMEDDS for improving the oral delivery of domperidone . 3

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The solubility of drug was determined in various oils, surfactants and cosurfactants for selection of components of formulations. Phase behaviour of the selected components was investigated by construction of ternary phase diagrams. The SMEDDS were characterised for robustness to dilution, globule size, and zeta potential. 4

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The average globule size was in the range of 146-230 nm. The zeta potential of all the formulations was less then -30, indicating good stability. It was concluded that SMEDDS prepared with oleic acid, tween 80 and PEG 400 and surfactant co-surfactant ratio (3:1) is a promising approach to improve the solubility and dissolution rate of domperidone . 5

KEYWORDS:

KEYWORDS Domperidone , Self microemulsifying drug delivery systems, Phase behaviour , Oleic acid, Tween 80, PEG 400. 6

INTRODUCTION:

INTRODUCTION Self microemulsifying drug delivery systems(SMEDDS) are isotropic mixtures of an oil, surfactant, cosurfactant and drug. The basic principle of this system is its ability to form fine oil-in water (o/w ) microemulsions following dilution by aqueous phases which is provided by gentle agitation of the digestive motility of the stomach and intestine in vivo. 7

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The spontaneous formation of an emulsion upon drug release in the GI tract advantageously presents the drug in a dissolved form and the small droplet size provides a large interfacial surface area for drug absorption. ADVANTAGES:- Better physico -chemical stability, E nhanced oral bioavailability enabling reduction in dose. Consistent temporal profiles of drug absorption. Ability to increase Cmax , AUC, and reduced tmax . 8

MATERIALS:

MATERIALS Domperidone (S.K Kant Lab ( Vapi , India ). Oleic acid,Tween 80, PEG 400, propylene glycol, Span 80 and castor oil ( Loba Chemie Pvt. Ltd .( Mumbai, India ). 9

Table:1 Composition of various SMEDDS formulations of Domperidone:

Table:1 Composition of various SMEDDS formulations of Domperidone Formulation Oil (Oleic acid) (mg) Surfactant ( Tween 80) (mg) Cosurfactant (PEG 400) (mg) Drug ( Domperidone ) (mg) Formulation 1 S/CO-(1:1 ) 492 64 64 20 Formulation 2 S/CO-(2:1) 428 128 64 20 Formulation 3 S/CO-(3:1) 364 192 64 20 Formulation 4 S/CO-(4:1) 300 256 64 20 Formulation 5 S/CO-(5:1) 236 320 64 20 10

PREPARATION:

PREPARATION 11 Domperidone dissolve in oleic acid in glass vials PEG 400 & Tween 80 Mixture 40°C 30 min Resulant mixture Stored until further use

EVALUTION PARAMETER:

EVALUTION PARAMETER Solubility study Screening of oils Construction of pseudoternary phase diagrams Robustness to dilution Zeta potential Globule size analysis Determination of emulsification time Stability study Drug loading efficiency In vitro dissolution profile 12

1) SOLUBILITY STUDY Table.2 Solubility profile of Domperidone in various oils and surfactants:

1) SOLUBILITY STUDY Table.2 Solubility profile of Domperidone in various oils and surfactants Sr. no. Oil/Surfactant Solubility (mg/ml) 1 Oleic acid 27.24 2 Castor oil 9.10 3 Olive oil 18.20 4 Soya oil 16.30 5 Tween 80 12.61 6 Span 80 Insoluble 7 Propylene glycol 7.21 8 PEG 400 14.10 13

2) Screening of oils:

2) Screening of oils 13 Oil + surfactant (1:1) Mixture 1 ml of mixture + 5 ml of water Agitation Observed under microscope Turbid solution obtained

Table.3 Emulsification based screening of oils:

Table.3 Emulsification based screening of oils Oils used Emulsification Oleic acid Emulsifies Castor oil Emulsifies Olive oil Emulsifies Soyabean oil Emulsifies 15

3) CONSTRUCTION OF PSEUDOTERNARY PHASE DIAGRAMS:

3) CONSTRUCTION OF PSEUDOTERNARY PHASE DIAGRAMS Method : water titration method at ambient temp . Oleic acid + tween 80 + propylene glycol 400 Drug Water was added drop by drop During the titration, the samples were agitated gently in order to reach equilibrium The phase boundary was determined by observing the changes in the sample appearance from turbid to transparent or from transparent to turbid. 16

Fig.1 Ternary Phase Diagram of Oleic Acid–Tween 80+PEG 400–Water System:

Fig.1 Ternary Phase Diagram of Oleic Acid– Tween 80+PEG 400–Water System 17

4) ROBUSTNESS TO DILUTION:

4) ROBUSTNESS TO DILUTION 18 Table.4 Robustness to dilution of various SMEDDS (+ Phase separation, ++ Drug Precipitation, - No phase separation, -- No precipitation) Formulation Phase Separation Drug Precipitation 0.1 N HCL Phosphate Buffer (pH 6.8) 0.1 N HCL Phosphate Buffer (pH 6.8) F-1 - - -- -- F-2 - - -- -- F-3 - - -- -- F-4 - - -- -- F-5 - - -- --

5) ZETA POTENTIAL:

5) ZETA POTENTIAL 19 Zeta potential is used to identify the charge of the droplets. Determined by - Zeta-meter Temp.- 25°C Scattering angle – 173° Table.5 zeta potential of various SMEDDS Formulation Zeta Potential (mV) F-1 -40.9 F-2 -31.0 F-3 -58.2 F-4 -45.3 F-5 -42.0

6) GLOBULE SIZE:

6) GLOBULE SIZE Determined by- dynamic light scattering (DLS) At temp.-25°C Scattering angle - 173° Measure size range between - 6 nm to 0.6 μm . Table.6 Globule size of various SMEDDS 20 Formulation Average Globule size (nm) F-1 164.8 F-2 162.6 F-3 146.8 F-4 175.8 F-5 230.4

7) DETERMINATION OF EMULSIFICATION TIME:

7) DETERMINATION OF EMULSIFICATION TIME Formulations were graded for self emulsification time according to the visual assessment. Table.7 Visual assessment criteria of various SMEDDS 21 Grade Time required for microemulsion formation Appearance A within 1 min. Clear or slightly bluish B within 1 min bluish white C within 2 min similar in appearance to milk D Longer than 2 min Dull, slightly oily appearance E Longer than 2 min Poor or minimal emulsification ,large oil droplets present on the surface

Table.8 Visual assessment of various SMEDDS:

Table.8 Visual assessment of various SMEDDS 22 Formulation Grade based on visual observation Time of emulsification in (Min: Sec) F-1 A 00:25 F-2 A 00:35 F-3 A 00:40 F-4 B 00:55 F-5 B 00:60

8) STABILITY STUDY:

8) STABILITY STUDY The physical stability evaluated by visual inspection. Phase separation Drug precipitation Performed at 4°C, 25°C and 45°C for 15 days. Table.9 Stability profile of various SMEDDS following storage at 4°C 23 Formulation After 5 (days) After 15 (days) F-1 -, -- -,-- F-2 -, -- -, -- F-3 -,-- -,-- F-4 -,-- -,-- F-5 -,-- -,-- (+ Phase separation, + + Drug precipitation, - No phase separation, -- No precipitation)

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Table.11 Stability profile of various SMEDDS following storage at 45°C 24 Formulation After 5 (days) After 15 (days) F-1 -, -- -,-- F-2 -,-- -,-- F-3 -,-- -,-- F-4 -,-- -,-- F-5 -,-- -,-- Formulation After 5 (days) After 15 (days) F-1 -,-- +,++ F-2 -,-- +,++ F-3 -,-- +,++ F-4 -,-- +,++ F-5 -,-- +,++ Table.10 Stability profile of various SMEDDS following storage at 25°C

9) DRUG LOADING EFFICIENCY:

9) DRUG LOADING EFFICIENCY 50 mg formulation Table.12 Drug content of various SMEDDS 100 ml volume made up with phosphate buffer (pH 6.8) The resultant solution was analysed spectroscopically 25 Formulation % Drug content F-1 93.70 F-2 92.40 F-3 89.50 F-4 94.80 F-5 95.85

10) IN VITRO DISSOLUTION PROFILE:

10) IN VITRO DISSOLUTION PROFILE Apparatus :- USP XXIV rotating paddle apparatus Temperature :- 37±0.5°C. Rotating speed :- 100 rpm Volume :- 900 ml of 0.1N HCl and Phosphate buffer (pH 6.8). 26

Fig.2 Cumulative % drug release from various Self microemulsifying formulations:

Fig.2 Cumulative % drug release from various Self microemulsifying formulations 27

RESULT AND DISCUSION:

RESULT AND DISCUSION Solubility studies of drug in oil indicated that it was more soluble in oleic acid, Tween 80, propylene glycol 400. The screening studies indicated that all the oils used were able to emulsify. Ternary phase diagrams of F-3 illustrated microemulsion region and therefore, surfactant/co-surfactant ratio (3/1) was selected as optimum for SMEDDS. 28

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Robustness to dilution study was not indicate any signs of phase separation or drug precipitation. The globule size dependent on concentration of surfactant/co-surfactant ratio. The average diameters of vesicles were in nano size range. Zeta potentials of all the formulations were less then –30, indicating good stability. Increase in surfactant concentration the time of emulsification increases. Drug content of the formulation increased with increase of droplet size. Drug content of the F-3 formulation was very low as compared to other formulations 29

CONCLUSION:

CONCLUSION F-3 formulation showed promising results. Concentration of surfactant co-surfactant was optimum in F-3 formulation.(3:1) Time of emulsification was within 1 min. However, the drug content of the f-3 formulation was very low as compared to other formulations. The droplet size decreases surface area increases greater dissolution higher drug release Thus, it can be a logical conclusion that SMEDDS formulations possess promising future in effective delivery of poorly water soluble drug. 30

ACKNOWLEDGEMENT:

ACKNOWLEDGEMENT The authors are grateful to the Director, University Institute of Pharmacy, Pt. Ravishankar Shukla University, Raipur for providing the necessary infrastructural facilities to carry out the study. 31

REFERENCES:

REFERENCES Amidon GL, Lennernas H, Shah VP, Crison JR. A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm. Res, 1995;12:413-420. Ammar HO, Salama HA, Ghorab M, Mahmoud AA. Implication of inclusion complexation of glimepiride in cyclodextrinpolymersystems on its dissolution, stability and therapeutic efficacy. Int. J. Pharm , 2006;320:53-57. Chen Y, Li G, Wu X, Chen Z, Hang J, Qin B, Chen S, Wang R. Self- Microemulsifying Drug Delivery System (SMEDDS) of Vinpocetine : Formulation Development and in Vivo Assessment. Biol Pharm Bull, 2008;31:118-125 32

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4) Charman SA, Charman WN, Rogge MC, Wilson TD, Dutko FJ, Pouton CW. Self-emulsifying drug delivery systems: formulation and biopharmaceutical evaluation of an investigational lipophilic compound. Pharm. Res, 1992;9:87-93. 5) Hong JY, Kim JK, Song YK, Park JS, Kim CKA. New self-emulsifying formulation of itraconazole with improved dissolution and oral absorption. J. Control Release, 2006;110:332-338. 6) Gershanik T, Benita S. Positively-charged self-emulsifying oil formulation for improving oral bioavailability of progesterone. Pharm. Dev. Technol , 1996;1:147-157. 7) Borhade V, Nair H, Hegde D. Design and Evaluation of Self Microemulsifying Drug Delivery System (SMEDDS) of Tacrolimus . AAPS Pharm Sci Tech, 2008;9:1. 33

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34 Thank you

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