DEVELOPMENT, CHARACTERISATION AND INVITRO EVALUATION OF BUCCOADHESIVE BILAYERED TABLETS FOR THE TREATMENT OF HYPERTENSION

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ABOUT AUTHORS:
Kavitha Reddy Jupally*, A.Pavani, R. Raja Reddy, Habibuddin.
Department of Pharmaceutics, Malla Reddy Pharmacy College,
Maisammaguda (via- Hakimpet), secunderabad, Telangana, India.
kavithareddy0811@gmail.com

ABSTRACT
Ramipril is a prodrug belonging to the class of angiotensin-converting enzyme (ACE) inhibitor, which undergoes extensive hepatic first pass metabolism. The aim of the present study is to develop buccoadhesive bilayered tablet of ramipril  to achieve the greater therapeutic efficacy, to increase the bioavailability, to overcome the first pass hepatic metabolism of the drug. A UV spectrophotometric method has been employed for the estimation of Ramipril at 219 nm. Buccal tablets of Ramipril were prepared by direct compression method using ethyl cellulose as a polymer. The precompression parameters like bulk density, tapped density, carr’s index and angle of repose were determined. The post compression parameters like hardness, thickness, friability, weight variation, in vitro dissolution, FTIR studies were carried out to check if any interactions had occurred, results were promising. The optimized formulation was selected based on results and percentage drug release was found to be 92.95 and followed First order, peppas model with Fickian release mechanism.

REFERENCE ID: PHARMATUTOR-ART-2299

INTRODUCTION^[1,2,3,4]
In recent years, there has been a growing interest in the use of delivery of therapeutic agents through various transmucosal routes to provide a therapeutic amount of drug to the proper site in body to achieve and maintain the desired concentration. Drug delivery via buccal mucosa by using bioadhesive polymers  offers a novel route of drug administration. It provides direct entry of drug molecules into systemic circulation, thus avoiding hepatic first pass effect.  The ease of administration and ability to terminate drug delivery when required makes it a potential and attractive route of drug delivery. Buccoadhesive drug delivery system prolong the residence time of the dosage form at the site of absorption and facilitate an intimate contact of the dosage form with the absorption surface and thus contribute to improved therapeutic efficacy of the drug ^[5,6]. Ramipril is an ACE inhibitor which undergoes extensive hepatic first pass metabolism (80%), with an oral bioavailability of 28% and half life of 2-4hrs^[7].  The present study is carried out in order to increase the bioavailability and to decrease the hepatic metabolism of the drug Ramipril.

MATERIALS AND METHODLOGY
Ramipril was obtained as a gift sample from Dr. Reddy’s Laboratories, Hyderabad. Ethyl cellulose was obtained from Colorcon Asia Pvt. Ltd., Goa. Other excipients were procured from  SD Fine Chemicals.

SCANNING OF THE DRUG FOR THE DETERMINATION OF λmax^[8]:
10mg of Ramipril was weighed and dissolved in 100 ml phosphate buffer pH 6.8. Standard solution having concentration of 10 μg/ml was prepared. The absorption maxima of the standard solution was scanned between 200-400 nm on UV Spectrophotometer against blank. The absorption maxima was found to be 219nm.

STANDARD CALIBRATION CURVE OF RAMIPRIL^[8]
The calibration curve for Ramipril was prepared in phosphate buffer pH 6.8. Accurately weighed sample of 50 mg of Ramipril was dissolved in 100 ml of phosphate buffer pH 6.8. 1 ml of each of this solution was diluted to 100 ml with phosphate buffer pH 6.8. The resulting stock solution was of 5μg/ml. From this stock solution, serial dilutions 5-25 μg/ml of Ramipril concentration were made using phosphate buffer pH 6.8. The prepared solutions of Ramipril were analyzed by UV spectrophotometer by measuring the absorbance at 219 nm against phosphate buffer pH 6.8 as blank.

FORMULATION OF BUCCOADHESIVE BILAYERED TABLETS OF RAMIPRIL^[9,10,11]
Buccoadhesive bilayered tablets are prepared in 3 stages:

STAGE 1: PREPARATION OF IMMEDIATE RELEASE LAYER
Weigh accurate  quantity of Ramipril , polymers (preferred polymer and their different concentrations) and lubricant (2% w/w) were blended homogeneously for 15 minutes by trituration using glass mortar and pestle. The mixture was used for compression of core layer. The composition of the core tablets is tabulated in table no 1.

STAGE 2: PREPARATION OF SUSTAINED LAYER
Weigh accurate  quantity of Ramipril , polymers (preferred polymer and their different concentrations) and lubricant (2% w/w). Small quantity of methanol is added to Ethyl cellulose to dissolve ethyl cellulose. To this mixture other ingredients are added except Magnesium stearate and talc and dough is made. This dough is passed through sieve #44 to get granules. These granules are further dried in a oven at a temperature of 40^ºC.  Magnesium stearate  and talc is added to the granules. The mixture was used for compression of backing layer. The composition of the core tablets is tabulated in Table 2.

STAGE 3: COMPRESSION ^[12,13]
Core layer and backing layer were sequentially compressed by indigenously developed and standardised dies and punches on tablet compression machine. An accurately weighed 25 mg drug-polymers mixture was compressed initially. The upper punch was removed and backing layer composition 25 mg was added over the core layer and again compressed.

EVALUATION PARAMETERS

PRECOMPRESSIONAL PARAMETERS ^[14,15,16]

1.Bulk density^[14]:-Bulk density was determined by pouring gently 20 gm of sample (Albendazole) through a glass funnel into 50 ml graduated cylinder. The volumes occupied by the samples were recorded. Bulk density was calculated as:

2.Tapped density^[14]:
Tapped density was determined by using Electro lab density tester. An accurately weighed sample of powder was carefully added to the cylinder with the aid of a funnel. Typically, the initial volume was noted, and the sample is then tapped (500, 750 or 1250 tapping) until no further reduction in volume is noted and taped density is calculated using following formula.

Tapped density= Wt. of sample in gm / Tapped volume

3. Carr’s index^[14]:
Based on the poured density and tapped density, the percentage compressibility of the granules was computed using the Carr’s compressibility index by the formula,

                              tapped density - poured density
Carr’s index (%) =  ----------------------------------  X  100
                                      tapped density

4.Hausner’s ratio:
Hausner’s ratio was calculated using the formula,

                            tapped density
Hausner’s ratio =  --------------------
                            poured density

5. Angle of Repose^[14]:
The angle of repose has been used to characterize the flow properties of solids. Angle of repose is a characteristic related to inter particulate friction or resistance to movement between particles. This is the maximum angle possible between surface of pile of powder or granules and the horizontal plane.

Tan q= h / r

q= Tan ^–1 h / r

Where,
q= angle of repose,
h = height,
r = radius.

A funnel was fixed at a height approximately of 2-4 cm over the platform. The loose powder was slowly passed along the wall of funnel, till the cone of the powder formed.Determine the angle of repose by measuring the height of the cone of powder and radius of the heap of powder.

POSTCOMPRESSION PARAMETERS ^[17]:
All the prepared matrix tablets were evaluated for the following official and unofficial parameters.

a)General appearance:
The mucoadhesive tablets morphological characterization includes size, shape, colour, presence or absence of odour, taste surface texture was determined.

b) Thickness:
Thickness of the prepared buccal tablets was tested using calibrated vernier calipers.
This test was done in triplicate and average was calculated.

c)Hardness:
The prepared buccoadhesive tablet hardness was measured using Monsanto hardness tester. The hardness was measured in terms of kg/cm².

d)Friability^[14,15]:
The friability of the tablets was determined using electrolab friabilator. It is expressed in percentage (%). Ten tablets were initially weighed and transferred into the friabilator. The friabilator was operated at 25rpm for 4min. After 4min the tablets were weighed again. The friability was then calculated using the formula,

                        intitial weight - final weight
Friability (%) =  -----------------------------
                                intitial weight

e)Weight variation test^[15,16,17]:
Ten tablets were randomly selected from each batch and individually weighed. The average weight and standard deviation of 10 tablets was calculated. The batch passes the test for weight variation test if not more than two of the individual tablet weights deviate from the average weight by more than the percentage shown in table 9 and none deviate by more than twice the percentage shown.

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Weight variation tolerance for uncoated tablets

f) Drug content^[15]:
Ten tablets were randomly taken and triturated using a glass mortar and pestle. An accurately weighed quantity of triturated powder equivalent to 10 mg of drug was taken into 100 ml volumetric flask and dissolved in phosphate buffer pH 6.8. 1 ml of above solution was withdrawn and made to 10 ml with phosphate buffer. Thus the corresponding concentration was determined using uv spectrophotometer at 219 nm.

g) In vitro drug release studies ^[14]:
USP type II rotating paddle method was used to study the drug release from the bilayered tablet. The dissolution medium consisted of 900 ml phosphate pH 6.8. The release study was performed at 37 ±0.50ºC, with a rotation speed of 50 rpm. The samples were analyzed after appropriate dilution using UV double beam spectrophotometer at 219nm.

h) Drug Release Kinetics: ^[18]
To analyse the drug release kinetics and mechanism, the data obtained were fitted into zero order, first order, Higuchi model and Kosmeyer peppas model. The criteria for selecting the most appropriate model were selected on the basis of correlation coefficient values.

RESULTS AND DISUSSION
The FTIR studies showed that there is no drug-polymer incompatability. The pure drug of Ramipril was scanned over a range of 200 to 400nm and λmax was observed at 219nm (Figure 3). The standard calibration curve of ramipril in Phosphate buffer pH 6.8 was obtained and R² was found to be 0.999 (figure 4).

The tablets were evaluated for postcompressional parameters general appearance, weight variation, friability, hardness and invitro dissolution study. The hardness, thickness and friability was found to be in the range of 4 to 4.03kg/cm², 2.00 ± 0.01 to 2.02±0.01  and 0.08 to 1.79%. (table 4). From the above results it is clear that the formulated tablets have good mechanical strength and mechanical resistance.

The drug content was found to be in the range of 90.01% to 99.25%. the invitro drug dissolution studies were performed in PH 6.8 phosphate buffer for 6hrs at 50rpm. All the formulations showed  more than 70% to 92.25% drug release. The drug release data was fitted into different kinetic models i.e Zero order, First order, Higuchi model, kosmeyer’s and peppas model. (Figure no: )  The interpretation of data was done based on the value of correlation coefficient. The drug release followed First order & kosmeyer’s and peppas model  indicating fickian drug release (Table 5)

TABLE 1: COMPOSITION OF IMMEDIATE RELEASE LAYER

TABLE 2: COMPOSITION OF SUSTAINED RELEASE LAYER

TABLE 3: PRECOMPRESSION EVALUATION OF POWDER BLEND OF ALL FORMULATIONS

TABLE 4: POST COMPRESSION EVALUATION OF PREPARED TABLETS