FABRICATION DEVELOPMENT AND PERMEATION STUDIES OF ANTIHYPERTENSIVE DRUG NEBIVOLOL HYDROCHLORIDE TRANSDERMAL PATCHES

Article Info: Received 18 May 2019; Accepted 15 June. 2019 DOI: https://doi.org/10.32553/jbpr.v8i3.617 Address for Correspondence: Syed Imran, PG Department of Pharmaceutics, SJM College of Pharmacy, SJMIT Campus, NH4, Chitradurga, Karnataka, India-577502 Conflict of interest statement: No conflict of interest ABSTRACT: Nebivolol Hydrochloride is selective Beta blocker having a unique character which distinguishes it from other beta blockers. It increases the release of nitric oxide which causes vasodilation which in turn improves the arterial compliance and decreases the peripheral vascular resistance. The objective of present investigation is to design, evaluate the physical parameters and to carry out the permeation studies of Nebivolol Hydrochloride antihypertensive Transdermal patch by employing suitable polymers such as Eudragit RL100, and Eudragit RS100. The drug and polymer compatibility study has been studied by FTIR and DSC studies. The prepared Nebivolol transdermal patches were subjected various evaluation parameters like weight variation, drug content, moisture content, moisture uptake, thickness uniformity, invitro diffusion study, after performing all evaluation tests, it is confirmed that formulation F2 is the optimized formulation and it shows better invitro diffusion compared to other formulations.


INTRODUCTION
Transdermal drug delivery is type of drug delivery which comes under the category of controlled drug delivery system. In which the main aim is to deliver the drug through the skin in to the systemic circulation at a predetermined rate 2 . This type of drug delivery helps to overcome from many problems like plasma drug fluctuations, multidose therapy, hepatic first pass metabolism etc. 3 Drugs which are administered through conventional dosage form produces more fluctuations in plasma drug concentration and leads to undesirable toxicity and poor effectiveness. 4 In the olden days humans have applied various agents like cosmetics and therapeutic agents to the skin for long term drug delivery. However nowadays the skin becomes one of the important routes for the drug delivery. 5 Nebivolol Hydrochloride is a beta blocker Antihypertensive drug. Beta blockers produce their action by acting selectively or non-selectively on beta receptors. Nebivolol may be considered both depending on its concentration in the body. Nebivolol at 10mg or below is selective beta 1 blocker whereas at higher concentration it loses its selectivity and acts on both beta 1 and beta 2 . Nebivolol also possess vasoactive factors. It produces vasodilation by releasing endothelial nitric oxide.

METHOD FOR THE ESTIMATION OF NEBIVOLOL HYDROCHLORIDE 6
A spectroscopic method based on the measurement of absorbance at 282 nm

Materials:
Nebivolol Hydrochloride is a gift sample from Aarti Pharma.
Standard Solution: 7, 8 10 mg of nebivolol was dissolved in 10ml methanol in 100 ml of volumetric flask.

Procedure:
The Standard solution of Nebivolol was subsequently diluted with 7.4 ph. buffer series of dilutions containing 2, 4, 6, 8, & 10μg in 1 ml solution. The absorbance of these solution was measured in UV-Spectrophotometer at 282 nm using 7.4 ph. buffer as blank. The concentration of Nebivolol and the corresponding are given in table.
The absorbance was plotted against concentration of Nebivolol Hydrochloride.

Estimation of Nebivolol HCl
Nebivolol Hydrochloride Concentration (μg/ml) The transdermal patches are prepared by solvent evaporation method. The polymers (Eudragit RS100 and Eudragit RL 100) are accurately weighed and dissolved in 10 ml of solvent and known volume of plasticizer and permeation enhancer were added and mixed thoroughly to get the homogenous dispersion. Then 100mg of drug was dissolved in the solution and mixed for 10 min. The resultant solution was poured in to Petri dish. And kept evaporation for 24hrs and dried films were removed and cut in to suitable sizes and stored in the desiccators. Table 1:

Evaluation of Transdermal Patches
Film thickness 11 : The thickness of the film can be determined by using micrometre, electronic Vernier callipers, dial gauge, or screw gauge. Thickness is measured at five different points of on the film. And average of five readings is considered.

Folding endurance 12, 13:
Folding endurance of the patches can be determined by continuous and repeatedly folding of the film at the same place till it will break. The number of times that it will take to break gives the folding endurance value of the patch.

Percentage moisture uptake 14, 15
A weighed film is kept in desiccator at room temperature for 24 hrs then it is taken out and exposed to 84% relative humidity (a saturated solution of potassium chloride) in a dessicator until a constant weight for the film is obtained. The percentage moisture uptake is calculated by using the following formula.
Weight uniformity 16,17 Weight uniformity of the patches can be determined by randomly selecting about ten patches. A specified area of the patch is cut at different parts of the patch and weighed by using digital balance. Then calculate the overage weight and standard deviation value from the individual weights. These determinations are performed for each formulation.

Tensile strength 18, 19
Tensile strength of the patch is determined by using a modified pully system. In this method weight of the pulley is gradually increased in order to increase the pulling force until the patch breaks.
The force required to break the patch gives the tensile strength value. Tensile strength of the patch is calculated as kg/cm 2 .

Drug content: 20, 21
In determination of drug content, a small portion of the film (1x1 or 2x2) is cut and then put this in 100ml of buffer (pH 7.4 or 6.8 or as prescribed) and shaken continuously for 24 hrs then the whole solution is ultrasonicated for 15min. After filtration the drug is estimated spectrophotometrically and drug content is determined.
Percentage of moisture content 22 Invitro drug release studies:

a) Invitro Drug Release
The fabricated film was placed on the semi permeable membrane and attached to the modified diffusion cell such that the cell's drug releasing surface towards the receptor compartment which was filled with phosphate buffer solution of pH 7.4 at 37 ± 1 0 C. The elution medium was stirred magnetically. The aliquots (5ml) were withdrawn at predetermined time intervals and replaced. with same volume of phosphate buffer of pH 7.4. The samples were analysed for drug content using UV spectrophotometer at 282 nm.

b) Kinetics of drug release
To examine the drug release kinetics and mechanism, the cumulative release data were fitted to models representing Zero order (Q v/s t), first order ( Log(Q 0 -Q) v/s t) , Higuchi's square root of time (Q v/s ) and KorsemeyerPeppas double log plot (log Q v/s log t) respectively, where Q is the cumulative percentage of drug released at time t and (Q 0 -Q) is the cumulative percentage of drug remaining after time t.

Conclusion
Based on all these factors the transdermal drug delivery system F2-is having greater % drug release. Formulation F5-having less drug release capacity than other formulations. The formulation F2-shows better extended release up to 12 hrs when compared to other formulations. So it was concluded that the formulation F2-prepared by using Eudragit RS 100 is better formulation for control release of drug up to 12 hrs of time. However, the in vitro drug release of the best formulation F2 follows Korsmeyer's peppas model and the mechanism of diffusion. Results of the present study encouraged that the Nebivolol HCl with Eudragit transdermal patch can be used as controlled drug delivery system and frequency of administration can be minimized.