Formulation and evaluation of s-(-)-amlodipine besylate and nebivolol hydrochloride tablets.

The objective of the present study was to develop a tablet formulation of S-(-)-amlodipine besylate chiral separation drug and nebivolol hydrochloride for better management of hypertension, while reducing or avoiding undesirable adverse effects, which are often associated with administration of a racemic mixture of amlodipine. The composition containing the optically pure S-(-)- isomer of amlodipine 2.5 mg has calcium channel blocking activity and, nebivolol hydrochloride 5 mg has beta-receptor blocking activity.The study was also carried out to design a suitable dissolution medium for S-(-) - amlodipine besylate and nebivolol hydrochloride. Amlodipine besylate and nebivolol hydrochloride had maximum solubility in pH 1.2 and thus pH 1.2 was selected as the most suitable media for S-(-) - amlodipine besylate and nebivolol hydrochloride dissolution studies. The RSD below 2% indicated insignificant batch-to-batch variation. The accelerated stability study of the optimized formulation was performed as the ICH guidelines. The results indicated no change in optical rotation of S-(-) - amlodipine besylate. Hence, combination of two drugs can be formulated into the tablet by wet granulation technique having satisfactory release profile.

INTRODUCTION

High blood pressure is estimated to cause 7.1 million deaths, about 13 percent of the global fatality total. It is believed this number will grow to approximately 11 million by the year 2020. Heart disease is the leading cause of death in the U.S., accounting for nearly 740,000 deaths each year. Cardiovascular disease is also the leading cause of death in Europe, accounting for over 4 million deaths each year. Hypertension is the leading risk factor for cardiovascular and renal disease, increasing the risk of myocardial infarction, stroke, congestive heart failure, ruptured aortic aneurysm, and renal disease. It is clearly understandable that a more rational approach to diagnosing and treating high blood pressure could have a substantial impact on population morbidity and mortality, especially considering the current lack of success[1].

NEED OF COMBINATION THERAPY

Combination drug therapy are available for many chonic conditions and have been advocated to improve adherence, reduced side effects, reduced cost and decrease confusion for patients who require multiple medications. Combination drug therapy is recommended for treatment of hypertension to allow medications of different mechanism of action to complement each other and together effectively lower blood pressure at lower than maximum doses of each.

The Seventh Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC 7) offers combination drugs an advantage to clinicians designing complex drug regimen needed to improve outcomes in older persons with chonic conditions. Combination drugs offer the additional benefits of fewer pills for older adults who may have swallowing difficulties. The increased use of fixed dose combination therapy may make it easier for patients to remember to take pills and get them to goal quicker and with less trouble. This should improve the rates of blood pressure control and ultimately accelerate the reduction in cardiovascular disease to hypertension[2].

Since no systematic studies on design and development of S-(-)- amlodipine besylate and nebivolol hydrochloride tablet or in vitro are available in literature, we propose to develop a suitable formulation and dissolution medium to characterize in vitro release profile of S-(-)- amlodipine besylate and nebivolol hydrochloride tablet. Thus may reduce undesirable adverse effects with improved patient compliance and acceptance.

The improved dissolution profile and insignificant batch-to-batch variation of the formulated formulation was indicated by RSD below 2%.

Amlodipine is a dihydropyridine calcium antagonist (calcium ion antagonist or slow channel Mocker) that inhibits the trap membrane influx of calcium ions into vascular smooth muscle and cardiac muscle[34]. The (-) isomer has been reported to be more active than the (+) isomer[56].

S (-) amilodipine besiate is a potent drug for the treatment of hypertension while avoiding the concomitant liability of adverse effects associated with the administration of the racemic mixture of amlodipine. The S(-) isomer of amlodipine is also useful for the treatment of angina and such other conditions as may be related to the activity of S (-) amlodipine as a calcium channel antagonist without the concomitant liability of adverse effects associated with the racemic mixture of amlodipine[78].

Nebivolol is a racemate of two enantiomers, SR RR-nebivolol (d-or d-nebivolol) and RSSS-nebivolol (or 1-nebivolol). It combines two pharmacological activities:

It is a competitive & selective B1- receptor antagonist which is attributable to the d-enantiomers

It has mild vasodilating properties, possible due to an interaction with the L-arginine/ nitric oxide pathway.

It is also devoid of alpha-adrenergic antagonism at therapeutic doses[9].

MATERIALS AND METHOD

Materials

Amlodipine besylate was generously supplied as a gift sample by M/S Pravin Laboratories (P) Ltd, (Moje-Jolwa,Gujarat), Nebivolol Hydrochloride, M/s Cadila Pharmaceuticals (Ankleshwar, Gujarat). Lactose, M/ S Dynamix India (Baramati, M.S.), Starch, M/ S Tirupati Starch and Chemicals Ltd (Dhar, M.P.), and Microcrystalline cellulose (MCC) JRS Pharma (Rosenberg, Germany), All other chemicals were of analytical reagent grade and were used as received.

Formulations of S-(-) - Amlodipine besylate and Nebivolol Hydrochloride Tablet

The granules of microcrystalline cellulose-starch and lactose-starch were prepared in the ratio as shown in (Table 1). To arrive at an optimal formulation, preliminary data on various derived characters and physical characters of tablets were generated (Table 2). The granules were lubricated with magnesium stearate (0.5%) and talc (1%), and compressed using a Cadmach make double rotary single punch, with oval shaped punches. The drugs S-(-) - amlodipine besylate and nebivolol hydrochloride were added at the lubrication stage. The tablets had an average weight of 125 mg and each tablet contained 2.5 mg of S-(-)-amlodipine besylate and 5.0 mg nebivolol hydrochloride.

Table 1

Formulation of S-(-) - amlodipine besylate and nebivolol hydrochloride by wet granulation techniques

Table 2

Effect of diluents on derived properties of S-(-) - amlodipine besylate and nebivolol hydrochloride granules

Flow ability

Bulk and Tapped Density (Hausner's Ratio and Carr's Compressional Index): The density parameters were determined using 10.0 g of each material in a 25 mL graduated cylinder (n = 3) (Electro lab Tap density tester USP: ETD-1020). The values were used to calculate Hausner's Ratio and Carr's Compressional Index[1011].

The flow properties of the sample were evaluated by the dynamic flow determination. The analysis was performed 3 times with 10.0 g of each sample[12].

All the flow parameters were reported in table 2.

Evaluation

The tablets of S-(-)- amlodipine besylate and nebivolol hydrochloride was prepared by wet granulation technique and evaluated for preformulation and post formulation parameters, such as hardness, friability, disintegration, content uniformity and in vitro release profile (Table 3 and 4).

Table 3

Evaluation of Tablets

Table 4

Content and dissolution profile of S-(-) - amlodipine besylate and nebivolol hydrochloride tablet

Solubility Study of S-(-) - Amlodipine besylate and Nebivolol Hydrochloride

Maximal solubility of S-(-) - amlodipine besylate and nebivolol hydrochloride in various physiological pH (pH 1.2, pH 4.0, pH 6.8 Phosphate buffer, pH 7.4 Phosphate buffer), was studied. Excess amount of S-(-)- amlodipine besylate and nebivolol hydrochloride, respectively, was taken in 10 ml of the above media, in boiling test tube, and dissolved in triplicates by sonication. The maximal solubility of S-(-)-amlodipine besylate and nebivolol hydrochloride in each medium, was determined at different time intervals (0, 15 and 60 min) after filtering the content of each test tube by Whatman filter paper, the S-(-)- amlodipine besylate and nebivolol hydrochloride content was determined spectrophotmetrically at 239 nm and 281 nm respectively.

In vitro Dissolution Study of S-(-)-Amlodipine besylate and Nebivolol Hydrochloride Tablet

The optimized formulation WMS 3 [Wet granulation microcrystalline cellulose: starch blend (50:50)], was selected and for in vitro dissolution study in USP XXIV dissolution apparatus type II at 37 ± 0.5°C and at 75 RPM, using 500 ml of dissolution media pH 1.2. The dissolution profile was compared with that of marketed preparation. The results recorded in Table 4.

Content uniformity

Content uniformity of the optimized batches was also studied, using HPLC, Shimadzu (model: LC-2010HT). The results noted in Table 4.

Stability Studies

The selected formulation (WMS 3) was studied for accelerated stability studies as per the ICH guidelines[13]. The optical rotation of S-(-) - amlodipine besylate in the formulation was measured using Polarimeter, Perkin Elmer (model: 341).

RESULT AND DISCUSSION

The studies revealed that S-(-) amlodipine besylate and nebivolol hydrochloride has very poor flow property, and a very good compressibility. The various flow parameters determined were reported in table 2. Microcrystalline cellulose: starch blend gave the satisfactory Carr's index (15.90), Hausner's ratio (1.189) and angle of repose (27°). The blend appeared to be the better alternative as it had better compressibility and flow property as compared to lactose: starch blend. The formulated batches hardness, friability and disintegration were reported in table: 3; the values showed satisfactory results. Results revealed that 5% starch paste gave optimized results, in terms of hardness and friability.

Experiments with solubility study of S-(--)-amlodipine besylate and nebivolol hydrochloride in various physiological pH. The results obtained from the solubility studies revealed that S-(-) - amlodipine besylate and nebivolol hydrochloride is soluble in pH 1.2. Hence pH 1.2 was the ideal dissolution media, to study in vitro release profile of S-(-) - amlodipine besylate and nebivolol hydrochloride. The optimized batch of S-(-) - amlodipine besylate and nebivolol hydrochloride tablet formulation WMS 3 was studied for the content uniformity and in vitro release profile in the above media and the results were reported in table 4.

The results indicated improved dissolution profile of the formulated S-(-)-amlodipine besylate and nebivolol hydrochloride tablet (WMS 3) as compared with the available marketed preparations. The content uniformity was found to be NLT 85% and NMT 115%. The results for content uniformity followed the general pharmacopoeia) specification. The accelerated stability studies as per ICH guidelines revealed no change in optical rotation of S-(-) - amlodipine besylate. Hence the formulated batch passes the stability study conditions.

CONCLUSION

The formulation and dissolution profile of formulation WMS 3 was encouraging. The trial conducted with consecutive three batches revealed RSD below 2%, indicative of insignificant batch-to-batch variation. The formulation showed improved dissolution as compared to the marketed preparation. Thus the formulation of S-(-) amlodipine besylate and nebivolol hydrochloride uses microcrystalline cellulose: starch blend would be cost effective and dissolution media pH 1.2 would the ideal media for conducting dissolution studies.