INTRODUCTION:
In the modern era, sustained release dosage form is suppressing the use of conventional dosage form. The sustained release tablet provides uniform release of drug over a long period of time. Controlled release dosage form covers a wide range of prolonged action formulation which provides continuous release of their active ingredient at a predetermined rate and time. Sustained or controlled drug delivery system is to reduce the frequency of dosing [1] or to increase the effectiveness of drug by localization at the site of action, reducing dose required, providing continuous drug delivery, reduce incidence of adverse effect and maintain drug concentration in system.
Matrix tablets serve as an important tool for oral extended- release dosage forms. Hence, various problems like patient compliance, drug targeting, local side effects, frequent administration and fluctuations in blood concentration levels, associated with their counterparts, therefore the conventional dosage forms restricted [2,3]. A matrix tablet is the oral solid dosage form in which the drug or active ingredient is homogeneously dispersed throughout the hydrophilic or hydrophobic matrices which serve as release rate retardants.
Aspirin’s efficacy in preventing myocardial infarction is related to preventing thrombus formation by decreasing platelet aggregation. Aspirin (AS) is a non-steroidal anti-inflammatory drug (NSAID) that permanently inactivates the cyclooxygenase (COX)-mediated activities of prostaglandins through irreversible binding. There are two forms of COX: COX-1 and COX-2. COX-1 is responsible for the synthesis of thromboxane A2 in platelets and the production of prostacyclinine vascular walls. Thromboxane A2 is a vasoconstrictor and platelet aggregating [4,5] agent, while prostacycline acts as a vasodilator and platelet inhibitor. The major drawback of aspirin G.I. Mucosa ulceration can be avoided by providing the Effective enteric coating. In this study, an attempt was made to formulate aspirin delayed release tablets with the use of enteric polymer.
MATERIALS AND METHODS:
MATERIALS:
Aspirin was obtained from Hetero Drugs Pvt. Ltd. India. Starch, CAP, TiO2, HPMC, PEG400, lactose, talc and magnesium stearate was purchased from S.D. Fine Chemicals Ltd, Mumbai, India. All other solvents and reagents used were of analytical grade.
METHODS:
Preparation of controlled release (CR) tablets:
Sustained release tablets of AS using varying concentration of starch and synthetic (HPMC K100M) polymers were prepared by direct compression method. Other ingredients like lactose was used as diluent, magnesium stearate as lubricant and talc as glidant. All the excipients along with API weighed as shown in Table 1 and passed through sieve no.20. Then, all ingredients were mixed following geometric mixing excluding glidant and lubricant for 15 minutes. The powder blend was thoroughly mixed with talc and magnesium stearate and compressed into tablets on twelve station rotary punch tabletting machine (Karnavati, Rimek Mini Press- 2).
Table 1: Composition of CR tablets
|
Ingredients(mg) |
ASF1 |
ASF 2 |
ASF 3 |
|
Aspirin(AS) |
81 |
81 |
81 |
|
Lactose |
178 |
142 |
106 |
|
Starch |
6 |
12 |
18 |
|
HPMC K100M |
30 |
60 |
90 |
|
Magnesium Stearate |
3 |
3 |
3 |
|
Talc |
2 |
2 |
2 |
|
Total weight(mg) |
300 |
300 |
300 |
Coating of core tablets:
The coating solution was prepared taking required ingredients from table 2 and acetone was added quantity sufficient maintaining proper viscosity of solution. The coatings of tablets were performed by dip coating. Coated tablets were dried at 50şC for 12 h.
Table 2: Coating composition for CR tablets
|
Formulation code |
CAP (g) |
PEG 400 (g) |
TiO2 |
Acetone (ml) |
|
ASF1 |
6 |
2 |
1.5 |
300 |
|
ASF2 |
6 |
2 |
1.5 |
300 |
|
ASF3 |
6 |
2 |
1.5 |
300 |
Evaluation of CR matrix tablets:
Pre compression parameters of CR powder blend[6,7]:
Angle of repose:
The angle of repose of granules blend was determined by the fixed funnel method. The accurately weighed quantity of granules was taken in a funnel. The height of funnel was adjusted in such a way that the tip of the funnel just touched the apex of the heap of the granules. The granules are allowed to flow through the funnel freely onto the surface. The diameter of powder cone was measured and angle of repose was calculated using the following equation
Tan ϴ=h/r
ϴ= tan-1(h/r)
Where ϴ is the angle of repose, h is the height of cone in cm and r is the radius of the cone base in cm.
Bulk density (еb):
Bulk density was determined by pouring the granules into a graduated cylinder in bulk density apparatus (Sisco,India). The bulk volume (Vb) and mass (m) of the granules was determined. The bulk density was calculated by using the following formula.
еb=m/Vb
Tapped density (еt):
The measuring cylinder containing known mass (m) of granules blend was tapped 1000 times for a fixed time in bulk density apparatus (Sisco, India).The minimum volume occupied in the cylinder (Vt) and mass of the granules (m) was measured. The tapped density was measured by using the following formula.
еt = m/Vt
Compressibility index (Carr’s Index):
The compressibility index determines the flow property characterstics of granules developed by Carr. The percentage compressibility of granules is a direct measure of the potential powder arch and stability. The Carr’s index can be calculated by the following formula.
et - eb
% Carr’s Index (C.I) = ---------------- X 100
eb
Where et is the tapped density of granules and eb is bulk density of granules
Hausner’s ratio:
Hausner’s ratio is used for the determination of flow properties of granules. The ratio can be calculated by the taking the ratio of tapped density to the ratio of bulk density.
Matematically Hausner’s ratio (H.R)= et/eb
The scale of flowability is mentioned in table 3.
Table 3: Scale of flowability determined by different methods [8]
|
Flow property |
Angle of repose |
Compressibility index |
Hausner’s ratio |
|
Excellent |
25-30 |
|
1.00-1.11 |
|
Good |
31-35 |
11-15 |
1.12-1.18 |
|
Fair |
36-40 |
16-20 |
1.19-1.25 |
|
Passable |
41-45 |
21-25 |
1.26-1.34 |
|
Poor |
46-55 |
26-31 |
1.35-1.45 |
|
Very poor |
56-65 |
32-37 |
1.46-1.59 |
|
Very very poor |
|
|
|
Post compression parameters of CR tablets [9,10]
Thickness:
The thickness of individual tablets is measured by using vernier caliper which gives the accurate measurement of thickness. It provides information of variation of thickness between tablets. Generally the unit for thickness measurement is mm.The limit of the thickness deviation of each tablet is ± 5%.
Hardness:
The hardness of a tablet is associated with the resistance of the solid specimen towards fracturing and attrition. The hardness of tablets can be determined by using Monsanto hardness tester and measured in terms of kg/cm2.
Friability:
Friability of tablets was performed in a Roche friabilator. Ten tablets were initially weighed (WI) together and then placed in the chamber. The friabilator was operated for 100 revolutions and the tablets were subjected to the combined effects of abrasion and shock because the Plastic chamber carrying the tablets drops them at a distance of six inches with every revolution. The tablets are then dusted and reweighed finally (WF).The percentage of friability was calculated using the following equation.
WF
% Friability (F) = (1- -------- ) 
100
WI
Where, WI and WF are the weight of the tablets before (initially weight) and after (final weight) the test respectively.
Weight Variation:
The weight variation test was done by weighing 20 tablets individually (Shimadzu digital balance), calculating the average weight and comparing the individual tablet weights to the average. The percentage weight deviation was calculated and then compared with USP specifications.
Drug Content:
Drug content for tablet was done by the assay method. Ten tablets were weighed and powdered. The powder weight equivalent to 100 mg of drug was dissolved in 100ml of phosphate buffer pH 6.8 using magnetic stirrer (Ricon, Hyderabad, India) in a volumetric flask for 24 h. It gives 1000µg/ml concentration of primary stock solution. The primary stock solution was filtered through Whatman filter paper No.1.From this primary stock solution 1ml of solution is withdrawn and diluted up to 25 ml with phosphate buffer pH 6.8 solutions to get 40µg/ml concentration of secondary stock solution. From this secondary stock solution 4ml was withdrawn and diluted upto 20ml getting desired concentration 8µg/ml. From the desired concentration the drug content of formulations were calculated using calibrated standard curve equation.
Diameter of tablet:
The diameter of individual tablets is measured by using vernier caliper which gives the accurate measurement of diameter. It provides information of variation of diameter between osmotic pump tablets. Generally the unit for thickness measurement is mm.
In vitro dissolution studies:
The in vitro dissolution studies were carried out using USP apparatus type II (Tab Machines, Mumbai, India) at 100 rpm. The dissolution medium consisted 0.1N HCl for 2 hours after 2 hours medium is replaced with phosphate buffer pH 6.8 for remaining h (900 mL), maintained at 37°C±0.5°C. The drug release at different time intervals was measured by UV-visible spectrophotometer (Systronics UV spectrophotometer-117, Mumbai, India) at 265 nm for 0.1N HCl and 280 nm for 6.8 phosphate buffer and calculated the drug release using calibration curve of AS.
Accelerated stability studies:
The packed tablets in air tight container were placed in stability chambers(Thermo lab Scientific equipment Pvt.Ltd.,Mumbai,India) maintained at 40±20C/75±5% RH conditions for accelerated testing) for 3 months[11]. Tablets were periodically removed and evaluated for physical characteristics, drug content, in‐vitro drug release etc
RESULTS AND DISCUSSION:
Pre-compression parameters of CR formulations:
All the compressible excipients for various batches were evaluated for angle of repose, bulk density, tapped density, Carr’s index and Hausner’s ratio. It is observed all the parameters fall within specified limit. It is shown it table 4.
In vitro drug release study:
The in vitro drug release was carried out in phosphate buffer of pH 6.8. The initial drug release was depending upon the water penetration in to the polymeric matrix. The % in vitro drug release from formulations ASF1, ASF2 and ASF3 at the end of 10 h was found to be 81.37±1.14, 88.01±1.19, and 96.14±1.17 % respectively. The optimized formulation profile was given by ASF3 contained 30w/w% concentration of HPMC K100M act as hydrophilic rate retardant
Stability studies:
From short term stability studies of optimized formulation ASF3, it was confirmed that there was no significance changes in physical appearance, weight variation, %friability, drug content and % drug release. It is shown in table 6.
