1. INTRODUCTION:

Over the past few decades colloidal systems have been explored as potential delivery systems, because of their compartmentalized hydrophobic and hydrophilic domains, where both polar and non-polar molecules could be encapsulated and stabilized. Self micro emulsifying drug delivery systems (SMEDDS) are micro emulsion pre concentrates (or) anhydrous forms of micro emulsions. These systems are anhydrous isotropic mixtures of oil, surfactants and drug, which when introduced into aqueous phase under conditions of gentle agitation, spontaneously form o/w microemulsions (usually globule size less than 200nm)^1,2. SMEDDS can also contain co emulsifier (or) co surfactant in order to facilitate micro emulsification or improve the drug. incorporation in SMEDDS. In the body, the agitation required for formation of micro emulsions is provided by digestive motility of the GI tract^3,4.

Atorvastatin is an anticholesteremic agent, hydroxy methylglutaryl-CoA reductase inhibitor. However, the low solubility and poor dissolution of this drug affects its rate of absorption, resulting in a low and variable oral bioavailability⁵. Hence it becomes necessary to develop Atorvastatin novel SMEDDS formulations with enhanced solubility and bioavailability.

2. MATERIALS AND METHODS:

Materials: Atorvastatin was gift sample from Bright labs Hyderabad, Transcutol was a generous gift sample from Gattefosse France, Cremophore RH 40 was a gift sample from BASF corp Germany, Tween 80, sunflower oil and PEG 400 was purchased from S.Dfine chemicals ltd, Mumbai.

3. METHODS :

3.1. Solubility study of Atorvastatin in various excipients:

The solubility of Atorvastatin in various oil, surfactant, co-surfactant was determined. Solubility studies were conducted by placing an excess amount of drug in each vehicle in a 2ml Microtube(Axygen MCT 200) containing 1.5ml of the vehicle⁶. Then the mixture was vortexed and kept for 48hrs at 25˚C in a Orbital shaking incubator (Remi electrotechnik ltd.) to facilitate the solubilization⁷. The samples were centrifuged at 3000rpm for 15min to remove the undissolved drug. The supernatant was taken and the concentration of drug in each vehicle were quantified by UV-spectrophotometer.

3.2. Construction of Pseudo-ternary phase diagrams:

The pseudo-ternary phase diagrams of oil, surfactant co surfactant and water were developed using surfactant titration method: The mixtures of oil and water at certain weight ratios were titrated with surfactant: co surfactant mix in a drop wise manner^8,9. Three types of surfactant phases were prepared: cremophore RH40+ PEG 400(1:1,1:2,2:1.). For each phase diagram at a specific ratio of surfactant/co surfactant transparent and homogenous mixture of oil and water was formed under the mixing by cyclomixer. Then, visually observed for phase clarity and flow ability¹⁰. After the identification of micro emulsion region in the phase diagrams, the micro-emulsion formulations were selected at desired component ratios, in order to form the micro emulsion.

3.3. Formulation design of SMEDDS containing Atorvastatin:

The formulations were prepared by initially dissolving the formulation amount of Atorvastatin in co-surfactant at 45˚C in an isothermal water bath. Oil was then added and mixture was cooled to ambient temperature, then surfactant was added and the final mixture was sonicated until a clear solution was obtained¹¹. The formulation was equilibrated at ambient temperature for at least 48 hours and examined for signs of turbidity (or) phase separation.

Table no 1: Formulation table of Atorvastatin SMEDDS

F	% cremophore	% of PEG400	% of sunflower oil	Drug (mg)
SA1	47.5	47.5	5	10
SA2	63.33	31.66	5	10
SA3	45	45	10	10
SA4	60	30	10	10

3.4. Characterization for Atorvastatin SMEDDS:

FTIR studies, droplet size analysis, zeta potential analysis, invitro release study, SEM and thermo dynamic stability studies were carried out same as that of microemulsion formulations¹².

3.5. Determination of self emulsification time:

The primary means of self micro emulsification assessment is visual evaluation. The efficiency of self micro emulsification could be estimated by using magnetic stirrer with 100 rpm, water and 0.1N Hcl solution as medium¹³. Temperature was maintained at 37±0.5˚C. Fill the beaker with 100ml of medium and pour the SMEDDS formulation into the medium and the contents being mixed gently at 100rpm and determining the time required to form microemulsion upon dilution of SMEDDS with water.

3.6. Visual observation, phase separation and stability study of emulsion ^14,15:

Each formulation of SMEDDS containing Atorvastatin was taken in a small beaker and was diluted with 200ml of distilled water at 37˚C,check visual appearance and the diluted preparation was vortexed for 1min, and then the mixtures was stored for a period of 24 hrs, and observe phase separation and precipitation visually. Mixtures exhibiting a negligible phase separation during the 2 hour period were used for subsequent studies. It gives the information about stability and viability of the formed microemulsion.

3.7. Cloud point measurement ^16,17:

Dilute the formulation with 50 ml of water in beaker and placed on a water bath with gradually increasing the temperature until the diluted formulation turned to cloudy. It gives the information about the stability of the microemulsion at body temperature.

Fig no 3: Drug excipient compatibility studies

Characterization of Atorvastatin SMEDDS:

Table no 2:Phase separation and Visibility grade

Formulation code	Visibility grade	Phase separation	Precipitation	Cloud point
SA1	I	×	××	74±6.52
SA2	I	×	××	73±5.15
SA3	I	×	××	80±4.64
SA4	I	×	××	76±5.8

Table no 3: Emulsification time

Formulation code	0.1N HCl		Distilled Water
Formulation code	Emulsification time (secs)	Tendency for emulsification	Emulsification time (secs)	Tendency for emulsification
SA1	67 ±0.5	Good	73 ±0.6	Good
SA2	56 ±0.3	Good	61 ±0.4	Good
SA3	82 ±0.1	Good	92 ±0.09	Good
SA4	71 ±0.7	Good	84 ±0.2	Good

Table no 4: Droplet size analysis

Formulation code	Droplet size (nm)	Zeta potential in mV
SA1	251 ±0.5	-8.6
SA2	242 ±0.7	-12.1
SA3	122 ±0.1	-15.2
SA4	178 ±0.6	-10.8

Fig no 4: Dissolution of SMEDDS in 6.8 pH phosphate buffer

The solubility of Atorvastatin in various vehicles is presented. PEG400 and cremophore RH40 provided higher solubility than other vehicles and sunflower oil and isopropyl myristate as oil was selected, for the optimal novel SMEDDS formulation resulting in improved drug loading capabilities. The phase study revealed that the maximum proportion of oil was incorporated in microemulsion systems when the surfactant/cosurfactant ratio was 1:2.

The dissolution studies for all the stable SMEDDS formulations were determined in USP dissolution medium pH 6.8. at the end of one hour, the dissolution of the SA3 microemulsion formulation was significantly greater than that of other formulations. It suggests that Atorvastatin dissolved perfectly in SMEDDS formulation, and could be released due to its small droplet size which permits a faster rate of drug release into the aqueous phase. In the study of formulations shown a good spontaneity of emulsification and good stability without any signs of drug or excipient precipitation and self emulsification time of various formulations. In this study, cloud points of all formulations were very high about 80˚C. In all the formulations cloudiness was reversible after minutes. Results contented the stability of all SMEDDS formulations towards separation in the GIT temperature¹⁸.

The formulation was found to be stable for 3months; there was no significant change in the drug content, or particle size of the resultant emulsion. It was also seen that the formulation was compatible with the hard gelatin capsule shells, as there was no sign of capsule shell deformation^19,20. Furthermore, the formulation was found to show no phase separation, drug precipitation, or capsule leaks. Thus, these studies confirmed the stability of the developed formulations.

Fig no 5: TEM and SEM micrograph of Atorvastatin SMEDDS

Table no 5: Stability studies:

Formulation code

Sampling point

Droplet size (nm)

% drug content

SA3

0 days

45 days

3 months

122 ±0.1

121.1 ±0.3

120.5 ±0.5

99.67 ±0.2

98.23 ±0.4

97.12 ±0.6

SA4

0 days

45 days

3 months

178 ±0.7

176.2 ±0.2

174.9 ±0.5

99.33 ±0.2

98.45 ±0.5

97.12 ±0.8

5.CONCLUSION:

Novel emulsion formulations, SMEDDS are a promising approach for the formulation of Atorvastatin. The oral delivery of hydrophobic drugs can be made possible by SMEDDS, which have been shown to substantially improve oral bioavailability with future development of this technology. These novel emulsions will continue to enable novel applications in drug delivery and solve problems associated with the delivery of poorly soluble drugs.

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Received on 01.04.2016 Modified on 22.04.2016

Research J. Pharm. and Tech. 2016; 9(7):789-793.

DOI: 10.5958/0974-360X.2016.00151.7