Preparation and Characterization of Self Emulsifying Drug Delivery System (SEDDS)

S.M. Sarode¹*, M.A. Chaudhari², M.K. Kale² and G. Vidyasagar²

¹Veerayatan Institute of Pharmacy, Bhuj, Gujarat

²K.Y.D.S.C.T’s College of Pharmacy, Sakegaon (M.S.)

ABSTRACT:

A mixture of oil and surfactant (especially non-ionic) forms clear and transparent isotropic solution known as self-emulsifying system (SES). Lovastatin is HMG-CoA enzyme inhibitor. This enzyme is needed by the body to make cholesterol. Lovastatin causes cholesterol to be lost from LDL, but also reduces the concentration of circulating LDL (low density lipoprotein) particles. Animals studies demonstrated that lovastatin crosses the blood-brain and placental barriers. Elderly patients or those with renal insufficiency may have higher plasma concentrations of lovastatin after administration and may require a lower dose. SEDDS is prepared and filled in hard gelatin capsules. In vitro dissolution indicates that the release of lovastatin from SEDDS varied according to the type and ratio of the oil and surfactants. It was concluded that there was an increase in both the solubility and dissolution rate of drug in SEDDS form as compared to marketed tablet.

KEYWORDS: SEDDS, enzymes

INTRODUCTION:

Approximately 40% of new drug candidates exhibit low solubility in water, which leads to poor oral bioavailability, high inter and intra-subject variability and lack of dose proportionality. Thus to overcome these problems, various formulation strategies^1-4 are explored which include modification of the physicochemical properties, such as salt formation and particle size reduction of compound, complexation with cyclodextrins, solid dispersion, nanoparticles, lipids etc^1,16.

As compared to other routes, oral delivery is preferred for administration of drugs in chronic therapy and most of the potent drugs, which are administered orally, are lipophilic in nature, exhibiting low oral bioavailability due to their poor aqueous solubility properties. To solve this problem, efforts are going on to enhance the oral bioavailability of lipophilic drugs in order to increase their clinical efficacy. In recent years, much attention has been focused on lipid based formulations to improve the oral bioavailability of poorly water soluble drugs. In lipid base formulationsthe most popular approach is the incorporation of drug into lipid vehicles such as oils, surfactant dispersions, self-emulsifying formulations, emulsions and liposome. A mixture of oil and surfactant (especially non-ionic) forms clear and transparent isotropic solution known as self-emulsifying system (SES).Microemulsion preconcentrate, also known as self-microemulsifying drug delivery system (SMEDDS), upon dilution with aqueous media, accompanied by gentle agitation, spontaneously forms clear isotropic solutions or microemulsions. Compared to ready-to-use microemulsions, it has improved physical stability profile upon long-term storage, and can be filled directly into soft or hard gelatin capsules for convenient oral delivery^2,4,15.

MATERIAL AND METHODS:

Lovastatin was obtained from Artemis Biotech Ltd, Mumbai.Captex, Labrafill were obtained from colorcon, and Goa.Reagents was obtained from Loba Chemicals Ltd, Mumbai.

Procedure: The oil and surfactant were weighed as per its percentage in glass vial, and lovastatin (40 mg) was added in this mixture and mixed with glass rod for ½ h, and then sonicated the vial in sonicator for 2 h. The prepared SEDDS (600 µl) was filled in hard gelatin capsule shell size' 0 ' with the help of micropipette^3,14.

Evaluation of SEDDS:

Drug content:

Prepared SEDDS containing lovastatin equivalent to 40 mg was added in 10 ml volumetric flask (VF) containing acetonitrile and mixed it well with shaking or inverting the VF for two to three times. 0.1 ml of this solution was diluted with 10 ml fresh acetonitrile and drug content was determined using UV -spectrophotometer at 238.20 nm^5,17.

Ternary Phase Diagram of SEDDS:

In order to find out the concentration range of components for the existing range of microemulsions, pseudo-ternary phase diagrams were constructed using H₂O titration method. Three phase diagrams were prepared with the

1) CAMPUL PG8 + TWEEN 80

2) CAMPUL PG8 + CREMOPHOR EL

3) CAMPUL PG8 + TWEEN 80: CREMOPHOR EL (1:1)

Phase separation study:

Each SEDDS (0.05 ml) was added to glass test tube containing five of 0.1 N HCL and Distilled water. After inverting the test tube for 3-4 times, each mixture was stored for a period of 2 h and phase separation was observed visually^6,12,13.

Viscosity determination of SEDDS:

Twenty gram of each of formulation was weighed and transferred to beaker and the viscosity of formulation was determined with the help of Brookfield Viscometer DV -E model, spindle no 6, at 10 rpm for 5 min.

Turbidimetric Evaluation of SEDDS:

Nepheloturbidimetric evaluation was done to monitor the growth of emulsification. SEDDS (0.5 ml) with and without drug (to observe the effect of drug loading in formulation on the turbidity) was added to 0.1 N hydrochloric acid (150 ml) under continuous stirring (50 rpm) on magnetic plate at ambient temperature and the increase in turbidity was measured using a turbidimeter¹⁸.

In Vitro Dissolution Study of SEDDS:

Dissolution study was carried out using USP Type II apparatus (paddle method) at 50 rpm, and at 37± 0.5°C, two dissolution medium was used for study^19,20.

A) Dissolution study in 0.1 N HCl (1.2 pH):

Prepared SEDDS capsule was placed in 900 ml of dissolution medium (0.1 N HCl) and after every 5 min interval 10 ml of aliquot was withdrawn and filtered through Whatman Filter paper (no. 40). Study was carried out for 60 min. Amount of drug release was determined using UV - spectrophotometer at 238.80 nm. Same procedure was applied for marketed tablets (M). All the experiments were repeated in triplicate^7,8.

B) Dissolution study in 7.0 pH phosphate buffer:

Prepared SEDDS capsule was placed in 900 ml of dissolution medium i.e. 7.0 pH phosphate buffer and after every 5 min interval 10 ml of aliquot was withdrawn and filtered through Whatman Filter paper (no.40). Study was carried out for 60 min. Amount of drug release was determined using UV- spectrophotometer at 238.60 nm. Same procedure was applied for marketed tablet (M). All the experiments were done in triplicate^9,10.

Particle size and Poly-Dispersity Index Determination of SEDDS:

Particle size distribution of resultant emulsion was determined by Photon Correlation Spectroscopy using a (Malvern Particle Size Analyser, Nano ZS, DTS Ver: 5.03), Malvern Instruments Ltd, Worcestershire, UK. Samples were diluted appropriately with the 0.1 N HCl for the measurement. The time-average intensity of light scattered by the sample at an angle of 90° was collected by averaging the individual readings of count rate obtained over a few minutes¹¹.

RESULTS AND DISCUSSION:

Drug content:

All the formulation complies with 100 ± 10% limit (Table 1). Hence all these formulations were considered for further study.

Ternary Phase Diagram of SEDDS:

From ternary phase diagram it was observed that there was formation of more microemulsion region in all the three types of SEDDS without any significant difference.

Hence it was not possible to find out the best SEDDS, which gives more microemulsion region, from ternary phase diagram construction (Fig. 1, 2 and 3). Hence all the formulation was selected for further study.

Phase separation study:

Phase separation study showed that all the formulations except CC1, CC2, CT1, CT2, CCT1 and CCT2 subjected for this study were stable as no signs of phase separation within 2 h was observed, which implies formation of stable emulsion. Since formulation CC1, CC2, CT1, CT2, CCT1 and CCT2 showed phase separation, hence all these formulations were not subjected to further evaluation.

Table 1: Drug content of SEDDS *(n=3), FC: Formulation Code

FC	*% Drug content Mean ± S.D**	FC	*% Drug content Mean ± S.D**	FC	*% Drug content Mean ± S.D**
CC1	91.20 ± 0.862	CT1	90.62 ± 0.735	CCT1	92.66 ± 0.254
CC2	93.44 ± 0.183	CT2	94.17 ± 0.650	CCT2	93.09 ± 0.827
CC3	96.14 ± 0.678	CT3	97.49 ± 1.598	CCT3	95.44 ± 0.183
CC4	97.87 ± 0.480	CT4	91.89 ± 0.226	CCT4	98.26 ± 0.636
CC5	98.91 ± 1.173	CT5	95.33 ± 0.579	CCT5	99.49 ± 1.385
CC6	99.11 ± 0.848	CT6	99.18 ± 0.412	CCT6	99.61 ± 0.410
CC7	100.19 ± 0.537	CT7	99.61 ± 0.933	CCT7	99.15 ± 1.923
CC8	99.84 ± 0.905	CT8	100.84 ± 0.098	CCT8	100.01 ± 0.707
CC9	97.60 ± 0.113	CT9	99.76 ± 1.01	CCT9	100.50 ± 0.144

Viscosity of SEDDS:

F C	Viscosity (cp)	F C	Viscosity (cp)	FC	Viscosity (cp)
CC3	476	CT3	171	CCT3	328
CC4	589	CT4	261	CCT4	486
CC5	754	CT5	343	CCT5	616
CC6	893	CT6	582	CCT6	738
CC7	942	CT7	747	CCT7	876
CC8	1061	CT8	812	CCT8	912
CC9	1281	CT9	936	CCT9	1033

From viscosity determination it was observed that as the concentration of surfactant increased, viscosity of formulation also gets increased (Table 2). The order of viscosity of prepared SEDDS batches is as follow CC > CCT > CT .

Fig.1 Ternary phase diagram of CAMPUL PG8 (Oil) and CREMOPHOR EL (Surfactant).

Fig.2 Ternary phase diagram of CAMPUL PG8 (Oil) and TWEEN 80 (Surfactant)

Turbidimetric evaluation of SEDDS:

Turbidimetric data of SEDDS showed, as the concentration of surfactants increased in SEDDS, turbidity of the resultant microemulsion get decreased which implies there is formation of transparent and clear microemulsion which have very low droplets size (Fig 4).

Table 2: Viscosity of prepared SEDDS formulation.

F C: Formulation code (cp: centi poise)

Fig.3 Ternary phase diagram of CAMPUL PG8 (Oil) and 1:1 Ratio of TWEEN 80 & CREMOPHOR EL (Surfactant)

Dissolution study of SEDDS:

In vitro dissolution indicates that the release of lovastatin from SEDDS varied according to the type and ratio of the oil and surfactants. The release of lovastatin from SEDDS become faster and increased with increase in concentration of surfactant in formulation

Dissolution study of SEDDS in 0.1 N HCL (1.2 pH):

Fig.4 Turbidity profile of formulation CCT3 to CCT9 with and without drug in 0.1 N HCL

When in vitro dissolution study of marketed tablet of lovastatin (40 mg) was compared with SEDDS of lovastatin (40 mg) in 0.1 N HCl, marketed tablet showed only 43.51 % drug release in 60 min while all the SEDDS formulation showed almost complete drug release within 60 min or less (Fig 5).

Fig.5 In vitro release profiles of formulation CCT6 to CCT9 compared with marketed tablet in 0.1 N HCl

Dissolution study of SEDDS in 7.0 pH phosphate buffer:

When in-vitro dissolution study of marketed tablet of lovastatin (40 mg) was compared with SEDDS of lovastatin (40 mg) in 7.0 pH phosphate buffer, marketed tablet showed 79.67 % ± 1.032 drug release in 60 min, while SEDDS containing more than 80 % of surfactant shows fastest release of drug within 30 min as compared to marketed tablet(Fig 6).

Fig.6 In vitro release profiles of formulation CCT6 to CCT9 compared with marketed tablet in 7.0 pH phosphate buffer

Particle size analysis of SEDDS:

From particle size analysis it was observed that particle size of SEDDS of CC, CT and CCT formulations were decreased with respect to increased concentration of surfactant (Fig 7).

Fig.7 Particle size distribution of formulations

CONCLUSION:

From the entire study it was concluded that there was an increase in both the solubility and dissolution rate of drug in SEDDS form as compared to marketed tablet. The significant increase in solubility and dissolution was observed in formulation CC9, CT9 and CCT9. The other SEDDS also showed increased in dissolution rate as compared to marketed tablet.

From the stability study it was concluded that the stable formulation could be developed by incorporating lovastatin in CAMPUL PG8 as Oil (10 %) and CREMOPHORE EL as surfactant (90 %), CAMPUL PG8 as Oil (10 %) and TWEEN 80 as surfactant (90 %) and CAMPUL PG8 as Oil (10 %) and TWEEN 80: CREMOPHORE EL 1:1 as surfactant (90 %) in the form of SEDDS with lowest droplet size (i.e. 13.38, 14.17 and 15.21 nm) and poly-dispersity index (i.e. 0.158, 0.207 and 0.174 resp), which may definitely improve the oral bioavailability, reduce the gastric irritation and dose of drug.

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Received on 14.05.2010

Accepted on 04.06.2010

Research Journal of Pharmaceutical Dosage Forms and Technology. 2(4): July-August 2010, 290-294