Enhancement of solubility of poorly water soluble anti hypertensive drug by nanosizing approach.

The objective of this research study was to optimize formulation and process variables affecting characteristic of nanosuspension in bead milling process. In this study, the practically water-insoluble telmisartan was nanoground by using top down method i.e. media milling method. Here the media used is ZnO(2) beads. A variety of surface active agents were tested for their stabilizing effects. Formulation factors evaluated were ratio of polymer to drug, whereas process parameters were milling time and concentration of ZnO(2) beads. Different concentration of stabilizers such as poloxamer 188, poloxamer 407, HPMC E 15, PVP K30 and combination of stabilizers were used for preparation of telmisartan nanosuspension. Responses measured in this study include particle size measurement, particle size distribution and zeta potential.

Water solubility has always been a key obstacle in pharmaceutical formulation, affecting formulation stability and drug bioavailability. Approaches for achieving complete dissolution often have disadvantages associated with the large quantities of required excipients. Nanosuspension, consisting essentially of pure anti hypertensive drug telmisartan with minimum amount of stabilizers was formulated for rapid dissolution, thus achieving pharmacokinetic properties similar to those of a solution.[12] Telmisartan is practically insoluble in water, has a high melting point (261 – 263°c) and has a high log P value (7.7). Given these features, nanosuspension can be considered as an attractive formulation approach. Poloxamer 188, poloxamer 407, HPMC E 15, PVP K 30, poloxamer 188/poloxamer 407, poloxamer 188/HPMC E15 and poloxamer 188/HPMC E15-stabilized nanosuspension were produced on a laboratory scale using media milling. Zirconium oxide beads are used as milling media in research study.[3]

Materials and Methods

Telmisartan was kindly provided by Sunij Pharama Pvt Ltd (Ahmedabad, Gujarat). Poloxamer 188 (Zydus Cadila Healthcare Ltd, Bavala, Gujarat) and Poloxamer 407 (Torrent Pharmaceuticals Ltd., Bhat, Gujarat) were commercially obtained. HPMC E15 and PVP K30 used were of laboratory grade. Zirconium oxide beads were kindly provided by Sun Pharma (Baroda, Gujarat). All other chemicals and solvents were of analytical reagent grade and deionized- distilled water was throughout the study.

Method

Nanosuspension was prepared using media milling. In 20 ml vial, solution of stabilizer was prepared in 10 ml water. 20 mg telmisartan was to prepare suspension. To this suspension, 15 gm of zirconium beads (Ø 0.8 mm) were added as a milling agent. Add a magnetic bead in to this vial and placed on the magnetic stirrer at 700 rpm for 18 hr. After milling, the vials were removed from the magnetic stirrer and the nanosuspension was separated from zirconium beads by decanting the suspension followed by washing of the beads with water.

Results and Discussion

Prepared nanosuspension was evaluated for particle size measurement, zeta potential, dissolution study and morphological characterization. The milling process resulted in, particle size in the range of 200 nm-600 nm, polydispersity index in the range of 0.3 to 0.7 and zeta potential in the range of –6mV to 10mV. An observation shows higher dissolution rates in nanosized product compared to untreated physical mixture. For the nanosuspension, have excellent disintegration and high surface area of the telmisartan nanoparticles give rise to a dissolution profile showing complete dissolution within minutes.

Conclusion

Media milling proved to be successful for the laboratory scale production of telmisartan nanosuspension. The process yielded nanosuspension with a mean particle size 450±35 nm, a mean polydispersity index 0.4±0.1 and zeta potential -6.0±0.5 mV. It is possible to transform the liquid nanosuspension formulation to solid powder. So the final product formulation should be the lyophilised nanopowder for getting the better stability during storage.