Design of Regioselective Bilayer Floating Tablets of Propranolol Hydrochloride and Lovastatin for Biphasic Release Profile

ABSTRACT

The purpose of the study was to design bilayer floating tablets of Propranolol hydrochloride and Lovastatin to give immediate release of Lovastatin and controlled release of Propranolol hydrochloride. Bilayer floating tablets comprised of two layers, immediate release layer and controlled release layer. Direct compression method was employed for formulation of the bilayer tablets. Short term accelerated stability studies were carried out on the prepared tablets. All the formulations floated for more than 12h. More than 90% Lovastatin was released within 30 min. from the formulations. HPMC K4M and Xanthan gum retarded the release of Propranolol hydrochloride from the controlled release layer for 12h. After stability studies, apparent degradation of both the drugs were found but the drug content was found to be within the range. Diffusion exponent (n) was determined for all the formulations (0.53-7). Based on coefficient of correlation(R), the release of Propranolol hydrochloride was found to follow mixed release pattern of Hixson-Crowell, Korsmeyer-Peppas and matrix, except formulation F6 and F9, which followed zero order release pattern. Statistical analysis revealed that there was no significant difference in in vitro release pattern of the drugs before and after stability studies.

Key words: Lovastatin, Propranolol hydrochloride, floating, bi- layer tablets.

INTRODUCTION

Hypertension and hypercholesterolemia frequently coexist and may require concomitant drug treatment. The efficacy and safety profile of Lovastatin given in the presence of antihypertensive medication was evaluated using patient subgroups identified in the Expanded Clinical Evaluation of Lovastatin study.[1-3] The treatment of hypertension co-existing with hyperlipidemia is always subjected to various kinds of drugs, like, angiotensine converting enzyme inhibitors, calcium channel blockers, b-blockers etc. Control over the blood pressure was effectively achieved in combination therapy than individual therapy. In U.S., ever large clinical trials were conducted namely Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trials (ALLHAT). Several studies suggest that hypertension & hyperlipidemia may have additive or perhaps synergistic effects. Various clinical trials conducted suggest combination therapy for the treatment of hypertension & hyperlipidemia.[4-7] In the present study, we have attempted to combine Lovastatin and Propranalol hydrochloride by formulating into a bilayer tablet. Many approaches are currently utilized to design gastroretentive dosage forms[8,9].These include, low density floating dosage forms ¹⁰ ; high density dosage forms which remain at the bottom of the stomach, bioadhesive systems¹¹ ; swelling sytems ¹² ; hydrodynamically balanced systems¹³.Gastric retention of the drugs provide advantages such as (i) delivery of the drugs with narrow absorption windows in the small intestinal region; (ii) longer residence time in the stomach could be advantageous for local action in the upper part of small intestine¹³. Various dosage forms have been designed for gastric retention; these include, floating tablets ¹⁴ ; floating beads ¹⁵ ; pellets ¹⁶ ; floating granules ¹⁷ ; floating microspheres ¹⁸. The current investigation employs development of floating bilayer tablet for different release pattern of Lovastatin and Propranolol hydrochloride using gas generating agent. Propranolol hydrochloride, a non-selective beta adrenergic blocking agent has been widely used in the treatment of angina pectoris, hypertension and many other cardiovascular disorders. The drug is water soluble and has half life of 3.4 h. It’s bioavailability is 5-50% ¹⁹.Therefore, it was chosen as a drug for preparation of gastro-retentive formulation. Lovastatin, a HMG Co-A reductase inhibitor is widely used in the treatment of hyperlipidemia. The drug has very short half life of 1.1-1.7h with very less bioavailability 5-50% [20, 21]. The bilayer tablet comprised of immediate release layer of Lovastatin and controlled release layer of Propranolol hydrochloride. The release kinetics of Propranolol hydrochloride was analyzed using different mathematical models. Accelerated stability studies were carried out on the prepared tablets ²². At the end of stability studies, tablets were evaluated for in vitro drug release, floating characteristics, drug content and other physicochemical parameters.

MATERIALS AND METHODS

Propranolol hydrochloride was procured from CIPLA Ltd., (Mumbai, India).Lovastatin was a generous gift from Panacea Biotech (Chandigarh, India). HPMC K4M and Xanthan gum(XG) were obtained as gift samples from Panacea Biotech (Chandigarh, India).Sodium starch glycolate(SSG), was procured from Okasa Pharma Ltd., (Satara, India).Tablettose 80 was received as a gift sample from Wockhardt Ltd.,(Aurangabad, India).Other materials were purchased from commercial sources:Magnesium stearate(Loba chemicals, Mumbai, India), di-calcium phosphate(S.D.Fine chemicals,Mumbai,India), Sodium bi carbonate(Research lab, Mumbai, India).

Method

Preparation of Bilayer Floating Tablets

Bilayer floating tablets were prepared by direct compression method employing sodium starch glycolate as superdisintegrant, HPMC K4M and XG as rate controlling polymers, sodium bicarbonate as gas generating agent. The optimum concentrations of above ingredients were developed under experimental conditions and on the basis of trial preparation of the tablets. Preparation of bilayer floating tablets had two steps: i) preparation of controlled release layer

The ingredients (Table 1) were accurately weighed and were added into the blender in ascending order. The powder mix was blended for 20 min. so as to have uniform distribution of drug in the formulation. 300 mg of the powder mix was weighed accurately and fed into the die of single punch machinery (Cadmach, Ahemedabad, India.) and compressed at 1.5 N compression force using 10 mm concave punches. ii) preparation of immediate release layer

The ingredients (Table 1) were accurately weighed and were added into the blender in ascending order. The powder mix was blended for 20 min. so as to have uniform distribution of drug in the formulation. 100 mg of the powder mix was weighed accurately and fed onto the controlled release layer and compressed at 3 N compression pressure using 10 mm concave punches.

Floating characteristics

Floating characteristics of the prepared formulation were determined by using USP 23 paddle apparatus ¹⁹ (Electrolab TDT-06P, Mumbai, India) at paddle speed of 50 rpm in 900 ml 0.1N HCl (pH 1.2) at 37±0.20C for 24 h. The time between introduction of tablet and its buoyancy on the simulated gastric fluid (floating lag time) and the time during which the dosage form remain buoyant (floating duration) were measured. Also, the integrity of the tablet during study was observed visually (matrix integrity).

Drug content

Propranolol HCl

Twenty tablets were accurately weighed and average weight was calculated. These tablets were ground to a fine powder. An accurately weighed tablet powder equivalent to 120 mg of Propranolol hydrochloride was dissolved in methanol and volume was made to 100 ml. The solution was filtered through Whatmann filter paper No.41. An aliquot of 1 ml was taken and diluted to 24 ml. Further, 1 ml from this diluted stock solution was taken and diluted to 10 ml. For the estimation of Propranolol hydrochloride from the sample solution absorbance of sample solution was recorded at 255nm and 287nm and the quantity of Propranolol hydrochloride in the sample solution was obtained from the calibration curve. The calibration curve for Propranolol hydrochloride was plotted using absorbance of 10 standard solution of Propranolol hydrochloride over a concentration range of 1mcg/ml to 10mcg/ml. Lovastatin has no absorbance at 255nm and 287nm.

Lovastatin

Twenty tablets were accurately weighed and average weight was calculated. These tablets were ground to a fine powder. An accurately weighed tablet powder equivalent to 50 mg of Lovastatin was dissolved in methanol and volume was made to 100 ml. The solution was filtered through Whatmann filter paper No.41. An aliquot of 1 ml was taken and diluted to 100 ml. For the estimation of Lovastatin from the sample solution a difference spectrophotometric method was developed and validated to eliminate interference of absorbance by Propranolol hydrochloride in the sample solution. The calibration curve for estimation of Lovastatin was obtained by plotting difference of absorbance at 247nm and 312nm of 10 mixed standard solution containing 1mcg/ml to 10 mcg/ml of Lovastatin against its concentration.

Drug release

The release of Propranolol hydrochloride and Lovastatin from different formulations was determined using USP 23 paddle apparatus2 ²³ (Electrolab TDT-06P, Mumbai, India) under sink conditions. The dissolution medium was 900 ml 0.1N HCl (pH 1.2) at 37±0.20C with a stirring speed of 50 rpm. For each formulation, the study was carried out in triplicate. The release data was analyzed to study release kinetics using zero order, Korsmeyer-Peppas and Higuchi equations [24, 25].

Hardness

Hardness of the prepared formulations was determined using Monsanto hardness tester (n=10) ²⁶.

Stability

To assess the drugs and formulations, short term stability studies were carried out. All the formulation samples, sealed in aluminium packaging coated inside with polyethylene, and various replicates were kept in humidity chamber maintained at 400C and 75% RH for 3 months. At the end of the studies, samples were analyzed for drug content, floating characteristics, hardness and in vitro dissolution studies. The study was carried out in triplicate.

DSC studies

Thermal analysis was carried out using Mettler Toledo 821e DSC (Switzerland). The tablet was ground to powder and 1-2 mg sample was hermetically sealed in an aluminum pan and heated at a constant rate of 100C/min, over a temperature range of 500C-5000C. Inert atmosphere was maintained by purging nitrogen gas at the flow rate of 20mL/min.

Assessment of Similarity factor

The similarity factor (f2 factor) was used to compare dissolution profiles of Propranolol hydrochloride. The in vitro dissolution release profile of the formulations before stability studies were considered as reference and in vitro dissolution release profile of the formulations after stability studies were considered as test. Similarity factor was calculated using PCP Disso software. The f2 factor is a logarithmic reciprocal square root transformation of the sum of squared error. The f2 factor is used to quantitate agreement between two dissolution profiles. Dissolution testing was conducted under exactly the same conditions. The values of f2 in between 50 to 100 shows similarity in dissolution profile with reference.

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Statistical Analysis

Analysis of variance (ANOVA) was performed to find out significant difference in drug released at 12h, floating lag time and drug content from all formulations. Student’s‘t’ test was applied to assess difference in the release pattern of the drug before and after stability studies.

RESULTS

Floating characteristics

All the formulations floated more than 12h with lag time of 16 min. During floating duration formulations maintained matrix integrity (Table 2). Swelling of the tablets was observed, which added the floating ability to the formulations. A 5% concentration of sodium bi carbonate was found to be optimum for low lag time and prolonged floating duration. Floating duration and lag time was found to be the functions of amount of polymers incorporated in the formulations

Drug content

Propranolol hydrochloride (99.36%-102%) and Lovastatin (95.9%-102.02%) content were found within the specifications. Additives in the formulations did not have any effect on the drug content (Table 2).

In vitro drug release

Lovastatin

Immediate release layer of bilayer floating tablet disintegrated liberating Lovastatin. All the formulations liberated more than 90% Lovastatin within 30 min. A 8% concentration of sodium starch glycolate was found to be optimum. Disintegration of the immediate release layer did not have any effect on the characteristics of the controlled release layer.

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