ENHANCEMENT OF ORAL BIOAVAILABILITY OF VALSARTAN BY USING SOLID SELF EMULSIFYING DRUG DELIVERY SYSTEM

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1 141 P a g e International Standard Serial Number (ISSN): International Journal of Universal Pharmacy and Bio Sciences 3(3): May-June 2014 INTERNATIONAL JOURNAL OF UNIVERSAL PHARMACY AND BIO SCIENCES IMPACT FACTOR 1.89*** Pharmaceutical Sciences ICV 5.13*** RESEARCH ARTICLE!!! ENHANCEMENT OF ORAL BIOAVAILABILITY OF VALSARTAN BY USING SOLID SELF EMULSIFYING DRUG DELIVERY SYSTEM Patel KB.*, Patel BK Department of Pharmaceutics, Shri Satsangi Saketdham, Ram Ashram Group of Institutions, Gujrat Technological University, Vadasma,Gujrat. KEYWORDS: Valsartan, S-SEDDS, Silysia, Pseudo ternary phase diagram. For Correspondence: Patel KB.* Address: Department of Pharmaceutics, Shri Satsangi Saketdham, Ram Ashram Group of Institutions, Gujrat Technological University, Vadasma,Gujrat. patelkb1990@gmail.com ABSTRACT Valsartan is an angiotensin-receptor blocker antihypertensive agent. It is a lipophilic (log p 5.27), poorly water soluble drug with absolute bioavailability of 25%. The aim of the present investigation was to develop a self-emulsifying drug delivery system (SEDDS) to enhance the solubility and that may enhance the oral bioavailability of poorly water soluble Valsartan. The solubility of Valsartan was determined in various vehicles like oils, surfactants and co-surfactants. Pseudoternary phase diagrams were constructed by CHEMIX software to identify the efficient self-emulsifying region. Prepared SEDDS was evaluated for viscosity, droplet size, zeta potential and in vitro dissolution. The optimized SEDDS formulation formulated using Capmul MCM C8 (10%), Tween 20 (45%) and Propylene glycol (45%) with 40 mg0f Valsartan. Formulation A1 was shown, droplet size (29.53 nm), polydispersity index (0.310), viscosity ( cp) and infinite dilution capability. The developed liquid SEDDS was converted into Solid SEDDS (S-SEDDS) formulations by using adsorption carriers i.e. Silysia. The developed S-SEDDS formulation of Valsartan was evaluated for flow properties, drug content, FTIR, SEM, and in-vitro dissolution study. Results of in-vitro dissolution showed that there was enhancement of dissolution rate of Valsartan as compared with that of plain Valsartan. From the results study concluded that, Silysia can be used to develop S-SMEDDS by adsorption technique to enhance dissolution rate of poorly water soluble drug such as Valsartan.

2 142 P a g e International Standard Serial Number (ISSN): INTRODUCTION: Lipid-based formulation approaches, particularly the self-emulsifying drug delivery system (SEDDS), are well known for their potential as alternative strategies for delivery of hydrophobic drugs 1 which are associated with poor water solubility and low oral bioavailability 2. Conventional SEDDS are usually prepared in a liquid dosage form that can be administered in soft gelatin capsules, which have some disadvantages particularly in the manufacturing process and incompatibility problems with the shells of soft gelatin. Solid SEDDS have recently been described and they surmount the disadvantages of liquid SEDDS as well as exhibited more commercial potential and patient acceptability 3. Many techniques are offered to convert convention-al liquid SEDDS to solid such as adsorptions to solid carriers, spray drying, spray cooling, melt extrusion, nanoparticles technology, supercritical fluid based methods, etc. 4 Valsartan is (S)-3- ethyl-2- N-{[2'-(2H-1,2,3,4-tetrazol-5-yl) biphenyl l-4-yl] methyl} pentanamido) butanoic acid with log P value It belongs to class II drug in BCS classification. Valsartan is angiotensin-receptor blocker antihypertensive agent, that may be used to treat a variety of cardiac conditions including hypertension, diabetic nephropathy and heart failure. The solubility of Valsartan in aqueous medium is very low. Absolute bioavailability of the TEL is 25% that results into poor bioavailability after oral administration. Hence it is necessary to increasing aqueous solubility and dissolution of Valsartan. Figure 1: structure of Valsartan MATERIALS AND METHODS Materials Valsartan was gifted from Cadila Healthcare Pvt. Ltd, Ahmedabad, Capmul MCM C8,Captex 355, Acconon MC8 were gifted from Abitec corporation,usa. Silysia gifted from Fuji chemicals, Japan.

3 143 P a g e International Standard Serial Number (ISSN): Labrafil M 2125CS, Plurol olique were gifted from Gattefosse, Mumbai. All other chemicals used were of analytical grade and used as received. METHODS Solubility studies The most important criterion for the screening of components for SMEDDS is the solubility of poorly soluble drug in oils, surfactants and co surfactants. Since the aim of this study is to develop an oral formulation, therefore, solubility of drug in oils is more important as the ability of SEDDS to maintain the drug in solubilised form is greatly influenced by the solubility of the drug in oil phase. The solubility of Valsartan in various oils, surfactant, and co surfactant was determined by adding an excess amount of drug in 2mL of selected oils, surfactant, co surfactants. The mixture was then kept at 25±1.0 0C in an isothermal shaker for 72 hr to reach equilibrium. The equilibrated samples were removed from shaker and centrifuged at 3000 rpm for 15 min. The supernatant was taken and filtered through a 0.45 μm membrane filter. The concentration of Valsartan was determined in oils by using UV spectrophotometer at 250 nm 5. Pseudo ternary phase diagram On the basis of the solubility study of drug, oil, surfactants, co-surfactants and aqueous phase were used for construction of phase diagram. Oil, surfactant, and co-surfactant are grouped in four different combinations for phase studies. Surfactant and co-surfactant (Smix) in each group were mixed in different weight ratio (1:1, 1:2, 2:1,). These Smix ratios are chosen in increasing concentration of surfactant with respect to co-surfactant and in increasing concentration of co surfactant with respect to surfactant for detail study of the phase diagram for formulation of micro emulsion. For each phase diagram, oil, and specific Smix ratio are mixed thoroughly in different weight ratio from 1:9 to 9:1 (1:9, 2:8, 3:7, 4:6, 5:5, 6:4,7:3, 8:2, 9:1) in different glass vials. Different combination of oils and Smix were made so those maximum ratios were covered for the study to delineate the boundaries of phase precisely formed in the phase diagrams. Pseudo-ternary phase diagram was developed using aqueous titration method. Slow titration with aqueous phase is done to each weight ratio of oil and Smix and visual observation is carried out for transparent and easily flow able o/w micro emulsion. The physical state of the micro emulsion was marked on a pseudo-three-component phase diagram with one axis representing aqueous phase, the other representing oil and the third representing a mixture of surfactant and cosurfactant at fixed weight ratios (Smix ratio) 6.

4 144 P a g e International Standard Serial Number (ISSN): Preparation of Valsartan SMEDDS A series of SEDDS formulations were prepared using various oil, Surfactant and Cosurfactant as shown in Table 1. In all the formulations, the level of Valsartan was kept constant (i.e.40 mg). The amount of SEDDS should be such that it should solubilize the drug (single dose) completely. The Valsartan (40 mg) was added in the mixture. Then the components were mixed by gentle stirring and mixing, and heated at 37 C.The mixture was stored at room temperature until used. So, prepared SEDDS was the concentrate of oil, surfactant, co-surfactant and drug 7 Table 1: Formulation of Liquid SEDDS Formulation Code Composition Valsartan (mg) Capmul MCM C8 (%v/v) Tween 20 (%v/v) A A A A Propylene Glycol (%v/v) Evaluation tests Viscosity 8, 9, 10, 11 The viscosities were measured to determine rheological properties of formulations. Brookfield viscometer at 30 C used to serve this purpose. The results are as shown in Table no 5 Determination of Self emulsification time The emulsification time of SEDDS was determined according to USP 22, dissolution apparatus 2.1 ml of each formulation added drop wise to 500 ml purified water at 37 C. Gentle agitation was provided by a standard stainless steel dissolution paddle rotating at 50 rpm/min. Emulsification time was assessed visually. The result were shown in Table no 7 Particle size distribution (PSD) and ζ-potential analysis One gram of SMEDDS was dispersed in 100 ml distilled water and 0.1 mol/l HCl, at 37 ± 0.5 C. The resultant emulsions were prepared by gentle agitation for 10 min using a magnetic stirrer. In addition, the PSD and ζ-potential of the final microemulsion were determined using, Malvern zetasizer. The result were shown in Table no 9

5 145 P a g e International Standard Serial Number (ISSN): % Transmittance Measurement The percent transmittance of various formulations was measured at 257 nm using UV spectrophotometer keeping methanol as a blank. The results are as shown in Table no 8. Polydispersibility Index The procedure is same as for particle size distribution. In vitro Drug release Studies The in vitro drug release of Valsartan from the optimized SEDDS was performed using USP dissolution Apparatus II. Hard gelatin capsules, size 2 filled with preconcentrate (equivalent to 40mg Valsartan) were put into each of 900 ml 0.1 N HCL, at 37 ± 0.5 C with a 50 rpm rotating speed. Samples (10ml) were withdrawn at regular time intervals (5, 10, 20, 30, 40, 50 and 60 min) and filtered using a 0.45 μm filter. An equal volume of the dissolution medium was added to maintain the volume constant. The drug content of the samples was assayed using UV visible spectrophotometric method. All measurements were done in triplicate. The results are as shown in figure Solid Self Micro emulsifying Delivery System (S-SMEDDS) of Valsartan Based upon the above results liquid SEDDS is optimized which are further converted to Solid SEDDS (Tablet) by adsorbing it on to adsorbent carriers like Silysia 350 FCP formulations was prepared. In-vitro dissolution study of Solid SMEDDS In vitro drug release studies from Solid SMEDDS were performed using USP Type II dissolution apparatus with number of paddle rotations set to 50 rpm. The dissolution medium consisted of 900 ml of 0.1N HCL maintained at 37 ±0.5 C. Solid SMEDDS containing 40 mg of Valsartan tablet was introduced into the dissolution medium. At predetermined time intervals 10 ml of aliquot was withdrawn, filtered using 0.45μm syringe filter and an equivalent volume of fresh dissolution medium was immediately added. The amount of drug released was estimated by measuring absorbance at 250 nm using a UV spectrophotometer. 13, 14 Morphology of SMEDDS It is done by SEM study to check crystalline structures characteristic of Valsartan are not seen in Solid SEDDS micrographs suggesting that the drug is present in a completely dissolved state in the Solid SEDDS.

6 Concentration mg/ml 146 P a g e International Standard Serial Number (ISSN): RESULTS AND DISCUSSION Solubility studies The solubility of the drug was tested in different oils phases and maximum solubility was determined in capmul MCM C ± 0.78 mg/ml and was selected as oily phase for SEDDS formulation. Table 2: Solubility of Valsartan in Different Oil SN oils Solubility (mg/ml) 1 Castor oil ± Olive oil ± Labrafil M2125 CS ± Captex 355 NP/NF ± Capmul MCM C ± Cotton seed oil 0.563± castor oil olive oil Labrafil M2125 CS Captex 355 NP/NF Capmul MCM C8 Cotton Seed Oil oils Figure 2: solubility of Valsartan in oils The solubility of the drug was tested in different surfactant and co-surfactant and maximum solubility determined ± 0.88 mg/g of tween-20 as a surfactant phase and ± 1.77mg/g of Propylene glycol as a co-surfactant phase. It was selected as surfactant and co-surfactant for SEDDS formulation. Table 3: Solubility of Valsartan in Different Surfactant SN Surfactant Solubility (mg/ml) 1 Plurol Olique ± Acconon MC8-2EP/NF ± Tween ± Tween ± 1.12

7 Concentration mg/ml Concentration mg/ml 147 P a g e International Standard Serial Number (ISSN): plurol olique Acconon MC 8 Tween 20 Tween 80 Surfactants Figure 3: solubility of Valsartan in Surfactant Table 4: Solubility of Valsartan in Different Co-surfactant SN Co-surfactants Solubility (mg/ml) 1 PEG ± Propylene Glycol ± PEG ± Transcutol P 14.23± PEG 400 Propylene Glycol PEG 200 Transcutol P Co-surfactants Figure 4: solubility of Valsartan in Co-surfactant Pseudoternary phase diagram Constructing phase diagrams is time consuming, particularly when the aim is to accurately delineate a phase boundary. Care was taken to ensure that observations are not made on metastable systems, although the free energy required to form a microemulsion is very low, the formation is thermodynamically spontaneous. The relationship between the phase behavior of a mixture and its composition can be captured with the aid of a phase diagram. Capmul (oil), Tween20 (surfactants) and Propylene glycol (co-surfactant) were put in different groups based on the ratio of surfactant to cosurfactant (1:1,1:2,2:1) under test to study the phase diagrams in detail.

8 148 P a g e International Standard Serial Number (ISSN): From the trial has shown that the emulsifying effect is good if the ratio of the surfactant to the cosurfactant is higher than 1:2 but stability properties are inferior at this ratio. Fixing the surfactant/cosurfactant ratio at 1:1 is a better choice from the stability point of view 15. Evaluation of liquid SEDDS Viscosity Figure 5: Pseudoternary phase diagram The viscosity of developed formulation A1-A4 shown in Table 5. It was observed that the viscosity of all the formulations is less than cp. Formulation, A1 has the maximum viscosity cp. Thus, it shows that SEDDS forms o/w microemulsion water remains as external phase and viscosity of SEDDS is near to water. This reveals that formulation A1 is very clear, transparent and low viscous liquid Table 5: Viscosity of SEDDS SN Formulation Code Viscosity (cp) 1 A A A A Drug Content Irrespective of difference in composition, the drug content of formulations A1 to A4 was found in range %. Table 6: % Drug content of SEDDS formulation SN Formulation code % Drug content* 1 A ± A ± A ± A ± 0.28

9 149 P a g e International Standard Serial Number (ISSN): Visual assessment of self emulsification The results of rate of emulsification are shown in Table 7. Self emulsification of SEDDS that depend upon concentration of surfactant. Higher concentration of surfactant that decreasing size of oil globules and that easily dispersed in water. So the formulation A1 shows lower the self emulsification time (12 sec) Table 7: Self emulsification time of SEDDS formulations SN Formulation Code Self emulsification Time (sec)* 1 A1 12±2 2 A2 21±2 3 A3 15±3 4 A4 24±2 % Transmittance The clarity of microemulsions was checked by transparency, measured in terms of transmittance (%T). SMEDDS forms o/w microemulsion since water is external phase Formulation A1 has % transmittance value greater than 99%.These results indicate the high clarity of microemulsion. In case of other systems %T values were about 97% suggesting less clarity of microemulsions. This may be due to greater particle size of the formulation. Due to higher particle size, oil globules may reduce the transparency of microemulsion and thereby values of %T. The results of %T are as shown in table 8 Table 8: %Transmittance of SEDDS Formulation Formulation code % Transmittance* A ±0.04 A ±0.01 A ±0.02 A ±0.02 Droplet Size Determination The droplet size of the emulsion is a crucial factor in self- emulsification performance because it determines the rate and extent of drug release as well as absorption. Average droplet size was found in water, which range from nm indicating all the particles were in the nanometer range (Table 6.15). Polydispersity index (PDI) (<0.5) indicates a homogenous dispersion, while a PDI (>0.5) indicates a higher heterogeneous dispersion. With increase of Smix proportion there was a decrease in droplet size and that may enhance the rate of emulsification which was confirmed by lower emulsification time of the

10 150 P a g e International Standard Serial Number (ISSN): formulation with higher Smix concentrations. The Formulation A1 show smaller particle size and lower PDI that indicates its containg homogenous dispersed emulsion. Table 9: Droplet size and poly dispersity index of SEDDS Formulation Formulation code Droplet size in water (nm) PDI* A A A A Figure 6 : Droplet Size Distribution of Batch A1 Figure 7 : Droplet Size Distribution of Batch A2 Figure 8 : Droplet Size Distribution of Batch A3 Figure 9 : Droplet Size Distribution of Batch A4

11 151 P a g e International Standard Serial Number (ISSN): Zeta potential (ζ) Determination ζ-potential can be defined as the difference in potential between surface of the tightly bound layer (shear plane) and the electro neutral region of an emulsion. It has got practical application in the stability of emulsion since, ζ-potential governs the degree of repulsion between adjacent, similarly charged, dispersed droplets. If the ζ-potential is reduced below a certain value (which is depends on a particular system being used), the attractive forces exceed the repulsive forces, and the particles come together leading to flocculation. The zeta potential of the formulations was from to In general, the zeta potential value of ±30 mv is sufficient for the stability of a microemulsion. All formulations, complies with the requirement of the zeta potential for stability. A1 shows higher value of the Zeta potential which indicates that form a stable emulsion. Table 10: Zeta Potential of SEDDS formulations SN Formulation code Zeta potential (mv) 1 A A A A In-vitro Drug release studies In vitro drug release studies were performed to compare the release of drug from four different SEDDS formulations (A1-A4) and plain drug are presented in Figure Dissolution studies were performed for the SEDDS formulations in 0.1 N HCL and the results were compared with the pure drug. There is no any significant difference in dissolution of four SEDDS formulation. As the emulsification time is below 25 s, about 85% percentage of the drug is released within 40 min in case of SEDDS (Table 6.17); while plain drug showed only 18.8% dissolution at the end of 40 min. The dissolution studies were conducted for 1 hr. to observe the variation or occurrence of precipitation over a time. The quantitative release of the Valsartan from the SEDDS is droplet size dependent. This suggests that larger interfacial area present in emulsions with smaller drops, promotes rapid drug release. Therefore release rate of the drug was increased by decreasing the microemulsions droplet size, suggesting that release rate of poorly water soluble drug like Valsartan could be controlled by judiciously selecting the mean droplet size in the carrier emulsion generated from SEDDS. The In-vitro dissolution studies indicates that formulation of Valsartan in the form of SEDDS formulation enhance the dissolution properties.

12 % Drug release--> 152 P a g e International Standard Serial Number (ISSN): Time (min) A1 A2 A3 A4 Valsartan Figure 10 : In-vitro drug release profile of A1 to A4 and Pure Valsartan in 0.1 N HCL EVALUATION OF SOLID SEDDS Morphology of Solid SMEDDS For converting a Liquid SEDDS into the solid state, a highy porous powder with good oil adsorbing capacity is required. Such powders can adsorb oil components of the Liquid SEDDS and convert them into a free flowing powder. Silysia has a highly porous structure which is capable of adsorbing upto three times its weight of oil. Scanning electron microscopy reveals the morphology of solid SEDDS. From the figure 11. Valsartan appeared to be made of irregular crystalline structures. Silysia appears to be spherical porous particles of size of approximately 100 μm. Micrographs of Solid SEDDS shows Liquid SEDDS adsorbed onto the surface of Silysia particles. Since the formulation process involved facilitating adsorption through physical mixing, partially covered Silysia are also visible in the field of vision. Crystalline structures characteristic of Valsartan are not seen in Solid SEDDS micrographs suggesting that the drug is present in a completely dissolved state in the Solid SEDDS (a) (b)

13 153 P a g e International Standard Serial Number (ISSN): Figure 11: Scanning Electron Microscopy images of (a) Valsartan b) Silysia (c) Solid SEDDS Micromeritics Properties From the Liquid SEDDS formulation A1 converted into solid form by using Adsorbent Silysia. The prepared powder evaluated for pre compression characteristic. The result was shown in Table 11. From the result that shows the this solid powder contains free flowing properties. (c) Table 11: Micromeritics Properties of Solid SEDDS SN Parameter Result 1 Angle of Repose ± Carr s Index 24.93± Hausner s Ratio 1.12± Type of flow Good Post compression parameter The prepared tablet was evaluated for the post compression characteristic. The result was shown in Table 12. Table 12: Post compression parameter of Solid SEDDS SN Parameter Result 1 Weight Variation 230± 5 mg 2 Thickness 4 mm 3 Diameter 9 mm 4 Hardness 1 kg/cm 2 5 Friability 0.04 %

14 % Drug release--> 154 P a g e International Standard Serial Number (ISSN): Drug Content The drug content of Solid SEDDS shown in Table 13. Table 13: % Drug content of Solid SEDDS SN % Drug content Avg In-vitro drug release profile Dissolution studies were performed for the solid SEDDS formulation in 0.1 N HCL and the results were compared with the pure drug. As the emulsification time is below 25 s, about 85% percentage of the drug is released within 40 min in case of SEDDS; while plain drug showed only 18.8% dissolution at the end of 40 min. The dissolution studies were conducted for 1 hr. to observe the variation or occurrence of precipitation over a time. In the present investigation drug release profile of solid SEDDS showed that the formulation had higher drug release profile than the pure Valsartan powder, ensuring that the solid SEDDS preserved the improvement of in vitro dissolution. (Fig. 12) Time (min)---> solid SEDDS Valsartan Figure 12 : In-vitro drug release profile of pure Valsartan and solid SEDDS in 0.1 N HCL CONCLUSION In SEDDS formulation consist of oil, surfactant and co-surfactant. Oil, surfactant and co surfactant were selected on the basis of solubility and emulsification ability. Capmul oil, Tween-20 and PG were selected on the basis of solubility and emulsification ability for the SEDDS formulation. Valsartan was formulated as a SEDDS in an attempt to increase its solubility. An optimized formulation of SEDDS containing Valsartan was developed through the construction of pseudo-ternary phase diagram, in-vitro dissolution study, particle size analysis and zeta potential and other evaluation study. Optimized liquid SEDDS having particle size (29.53nm), zeta potential (-27.52), in-vitro dissolution study (99.41).

15 155 P a g e International Standard Serial Number (ISSN): Optimized liquid SEDDS was converted to S SEDDS by using adsorbents Silysia and showed highest drug release (99.16). S-SEDDS provided significant increase in the solubility compared to a marketed formulation SEDDS appeared to be an interesting approach to improve problems associated with oral delivery of Valsartan. Valsartan S-SEDDS formulation was superior to commercial formulation with respect to in vitro dissolution profile. Thus, S-SEDDS can be regarded as novel and commercially feasible alternative to current Valsartan formulations. ACKNOWLEDGEMENT: The authors are thankful to Department of Pharmaceutics, SRI Campus, Vadasma for providing support during this research work. We are also thankful to Gattefosse (Mumbai), Abitech corporation (USA) and) for providing gift samples. REFERENCES 1. Pouton CW.(2000) Lipid formulations for oral administration of drugs: non-emulsifying, selfemulsifying and self-microemulsifying drug delivery systems. Eur J Pharm Sci, 11, S93-S Constantinides PP. (1995) Lipid microemulsions for improving drug dissolution and oral absorption: physical and biopharmaceutical aspects. Pharm Res., 12, Akhter S., Hossain Md. I.(2012) Dissolution enhancement of Capmul PG8 and Cremophor EL based Ibuprofen Self Emulsifying Drug Delivery System (SEDDS) using Re-sponse surface methodology. International Current Pharmaceutical Journal, 1(6), Katteboina S, Chandrasekhar PVSR., Balaji S,(2009) Approaches for the development of solid selfemulsifying drug delivery systems and dosage forms. Asian Journal of Pharmaceutical Sciences2009, 4 (4), Patel M, Patel M, Patel N and Bhandari A.(2011) Formulation and Assessment of Lipid Based Formulation of Olmesartan Medoxomil. Int J of Drug Dev & Res. 3 (3), Sheikh S, Shakeel F, Talegaonkar S, Ahmad FJ, Khar RK and Ali M(2007). Development and bioavailability assessment of ramipril nanoemulsion formulation. Eur J Pharm Biopharm, 66, Kang BK, Lee JS, ChonSK, Jeong SY, Yuk SH, Khang G, Lee HB, Cho SH.(2004) Development of selfmicroemulsifying drug delivery systems (SMEDDS) for oral bioavailability enhancement of simvastatin in beagle dogs. International Journal ofpharmaceutics, 274:

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