Development and characterization of microemulsion containing antihypertensive agent using factorial design.

Microemulsion which act as a carrier for drug having poor water solubility, were formulated by the use of excipients having safety of administration and solubility of drug component. The phase study was carried out using isopropyl myristate, cremophor-el, propylene glycol and water with different ratios of components. Microemulsion region was chosen on basis of area covered. The % oil and % surfactant were selected as the independent factors and particle size and viscosity were selected as the dependent factors for the 2(2) Full Factorial Design. The optimized formulation showed the overcoming of the dissolution barrier helping in the formulation and administration.

Microemulsion as a carrier has been proved to be useful, specifically for agents having poor water solubility, as O/W microemulsion.[1] Antihypertensive agent Felodipine (FLD) (Dihydro-pyridine class calcium channel blocker) is absorbed throughout the gastro-intestinal tract. FLD is having very poor water solubility (0.8 μg/ml). So, solubility is the major barrier for the formulation development. Microemulsion can be used as drug carrier in which drug is incorporated into droplet structure (size 10 nm to 200 nm), leading to dissolution rate enhancement.[2]

Materials and Methods

All the ingredients of the formulation were chosen on the safety and solubility basis. The FLD was obtained as gift sample from Cipla Ltd (Mumbai). Isopropyl myristate, cremophor el, PEG 400, castor oil, tween 80, tween 20 were purchased from the Himedia Ltd. (Mumbai), and propylene glycol was purchased from Merck Inc. (Mumbai). All other ingredients were purchased of AR grade.

Ingredients were subjected to the solubility study. For this study excess of FLD was added into various components and then was subjected to the vortexing for 15 minutes and mixing for the 48 hours, after that the spectrophotometric determination was carried out. After quantification, the major components chosen were isopropyl myristate (IPM) (as Oil), cremophor-el (CEL) (as Surfactant) and propylene glycol (PG) (as Cosurfactant).

The phase study was carried out using IPM: CEL: PG: WATER with different ratios of the CEL: PG. From the phase diagram the microemulsion region was selected which had the greatest area covering the phase diagram. The 22 factorial design was applied for the screening of the microemulsion using the independent factors as amount of oil and surfactant and the dependent factors as particle size (PSA) and viscosity. The selected microemulsion was subjected to the various characterizations like DLS, pH, conductivity, transparency, viscosity etc. The stability of the microemulsion at room temperature, at 2°C and against centrifugal force was checked for the 1 month period.

Results and Discussion

Solubility study was carried out and IPM was selected as oil (25 mg/ml). The other components chosen were CEL, PG as surfactant and cosurfactant. Phase study shows the CEL: PG (3:1) ratio as a widest microemulsion region containing composition. From the 22 factorial design (Design Expert 8.0.7.1, Stat-Ease Inc., Minnesota, USA) the analysis of the PSA [Figure 1] and viscosity [Figure 2] as the factorial model could be plotted as below.

Figure 1

Contour and 3D surface plot for PSA as dependent factor

Figure 2

Contour and 3D surface plot for viscosity as dependent factor

Selected formulation was having 97.3nm z-average size(Malvern Zetasizer ns 90), p. 5.6 (Elico pH meter), conductivity 65 μS/ cm(EC-TDS Analyzer), transparency as % transmittance measurement which was 99.1% at 620 nm (UV 1800 Shimadzu) and viscosity was 70 cPs (Brookfield Viscometer-LVT). Microemulsion formulation showed in-vitro release up to 98% in 1 hour. Microemulsion formulation showed 5000-10000 times enhancement of solubility in comparison to the absolute solubility.

Conclusion

The formulated microemulsion succeeded in achieving the dissolution barrier of the FLD. Thus it aid in the formulation and administration of the FLD leading to improved compliance and dosage delivery.