Improvement of Bioavailability of Valsartan through Novel Transdermal Drug Delivery System

Valsartan is a potent and specific competitive angiotensin II antagonist which is used in the management of hypertension. It is well absorbed following oral administration, with rather poor bioavailability of about 25 %. Peak plasma concentration of valsartan occurs 2-4 hours after ingestion. Optimized VAL-SLN was prepared by preemulsion sonication method and sprays dried to improve the handling processing and stability. Solid state studies such as Infra Red Spectroscopy and Differential Scanning Calorimetry indicated absence of any chemical interaction between valsartan and the lipids. Prepared patches possess satisfactory physiochemical characteristics. The absorption of VAL-SLN patches (F-4) resulted in 2.02 fold increase in bioavailability as compared to oral capsule formulation. Results of pharmacokinetic studies indicated that the solid lipid nanoparticles can be successfully used as potential vehicles for enhancement of bioavailability of poorly soluble drugs. The aim of the study was to study the enhancement of bioavailability of valsartan from transdermally applied solid lipid nanoparticles.


INTRODUCTION
Tablets and injections have been the traditional way to take medications; new options are becoming increasingly popular. One highly successful alternative delivery method is the transdermal route. This route may offer several benefits, including more consistent symptom control and enhanced convenience. The transdermal route has vied with oral treatment as the most successful innovative research area in drug delivery. In the USA (the most important clinical market), out of 129 drug delivery candidate products under clinical evaluation, 51 are transdermal or dermal systems; 30 % of 77 candidate products in preclinical development represents such drug delivery. Few molecules that are under clinical development are listed in (Table 1) [1]. Valsartan is well absorbed following oral administration, with rather poor bioavailability of about 25 %. Peak plasma concentration of valsartan occurs 2-4 hours after ingestion. Drug is not significantly metabolised and is excreted mainly via the bile as unchanged drug. Valsartan also has pH dependent solubility whereby, it ranges from very slightly soluble in an acidic environment to soluble in a neutral environment of the GI tract. Permeability of valsartan is low and also pH dependent where it decreases as environmental pH increases from acidic to a neutral pH values in GI tract. As a result of these complex biopharmaceutical properties, development of a more releasable and bioavailable dosage form of valsartan with less inter -and intrasubject variability is challenging [2].
• Chemical structure of valsartan.

1.4) Fundamentals of skin permeations [3]
In old days the skin was supposed to be impermeable with exception to gases. However, in the last century the study indicated the permeability to lipid soluble drugs. Also it was recognized that various layers of skin are not equally permeable i.e. epidermis is less permeable than dermis. The transdermal permeation can be visualized as composite of a series in sequence as:

Pre-optimization studies for formulation of Preemulsion
Pre-optimization studies of pre-emulsion were done with different concentration of Compritol 888 ATO to determine optimum percent of Compritol 888 ATO. Then, different surfactants with different concentration were used for initial optimization of pre-emulsion with optimum lipid concentration ( Table  2).

Experimental design
The traditional approach to developing a formulation is to change 1 variable at a time. By this method it is difficult to develop an optimized formulation, as the method reveals nothing about the interactions among the variables. Hence, a Box-Behnken statistical design with 3 factors, 3 levels, and 15 runs was selected for the optimization study. The experimental design consists of a set of points lying at the midpoint of each edge and the replicated centre point of the multidimensional cube [4]. Independent and dependent variables are listed in (Table 3). The polynomial equation generated is given below. Y = K + aX 1 + bX 2 + cX 3 + dX 1 X 2 + e X 1 X 3 + f X 2 X 3 + g X 1 X1 + h X 2 X2 + i X 3

Preparation of Val-SLN dispersions
Val-SLN was prepared by using pre-emulsion probe sonication method. The ingredients used and their levels taken for further study on formulation optimization of valsartan loaded SLN (VAL-SLN) dispersions (Table 4).

Stability studies
Stability studies on the optimized formulated patches (F-4) were carried out as per ICH guidelines. Drug content were used to check the stability of the formulation after predetermined time. Samples were withdrawn at the end of 0, 30, 60 and 90 days and evaluated for Drug content.

Selection of lipid
Selection of lipid was done on the basis of maximum solubility of valsartan in different lipids and also on melting point of lipid as the type of drug-lipid matrix and drug release pattern will depend on it. Out of different lipids used, valsartan showed maximum solubility in Compritol ATO 888 (Fig. 2) 1  The particle size analysis of the nanoparticulate dispersion by laser diffraction using Malvern Mastersizer showed particle size in the range between 149.3nm to 473 nm. Particle size distribution curve of optimized sample O4 was 224.32 nm is shown below (Fig.3).

Fig. 3: Particle size distribution curve of Sample O4
Solid state study Drug content determination Drug content of optimized formulations were shown in following (Table 5) Data shows mean (n = 3) ± SD

CONCLUSION
Optimized VAL-SLN was prepared by pre-emulsion sonication method and sprays dried to improve the handling processing and stability. Transdermal patches incorporating valsartan loaded solid lipid nanoparticles (VAL-SLN) and plain valsartan were prepared by solvent evaporation method using polymer matrix containing ethyl cellulose (EC) and polyvinyl pyrrolidone (PVP) in different ratio, of which PVP:EC (3:2) was selected as relatively best ratio compare to other with respect to drug release study and used for further study. Prepared patches possess satisfactory physiochemical characteristics.
Results of pharmacokinetic studies indicated that the solid lipid nanoparticles can be successfully used as potential vehicles for enhancement of bioavailability of poorly soluble drugs.