Formulation and evaluation of aceclofenac mouth-dissolving tablet.

Aceclofenac has been shown to have potent analgesic and anti-inflammatory activities similar to indomethacin and diclofenac, and due to its preferential Cox-2 blockade, it has a better safety than conventional Non steroidal anti-inflammatory drug (NSAIDs) with respect to adverse effect on gastrointestinal and cardiovascular systems. Aceclofenac is superior from other NSAIDs as it has selectivity for Cox-2, a beneficial Cox inhibitor is well tolerated, has better Gastrointestinal (GI) tolerability and improved cardiovascular safety when compared with other selective Cox-2 inhibitor. To provide the patient with the most convenient mode of administration, there is need to develop a fast-disintegrating dosage form, particularly one that disintegrates and dissolves/disperses in saliva and can be administered without water, anywhere, any time. Such tablets are also called as "melt in mouth tablet." Direct compression, freeze drying, sublimation, spray drying, tablet molding, disintegrant addition, and use of sugar-based excipients are technologies available for mouth-dissolving tablet. Mouth-dissolving tablets of aceclofenac were prepared with two different techniques, wet granulation and direct compression, in which different formulations were prepared with varying concentration of excipients. These tablets were evaluated for their friability, hardness, wetting time, and disintegration time; the drug release profile was studied in buffer Phosphate buffered Saline (PBS) pH 7.4. Direct compression batch C3 gave far better dissolution than the wet granulation Batch F2, which released only 75.37% drug, and C3, which released 89.69% drug in 90 minutes.

INTRODUCTION

Many patients find it difficult to swallow tablets and hard gelatin capsules and thus do not comply with the prescription which results in noncompliance and ineffective therapy. Recent advances in novel drug delivery systems aim to enhance safety and efficacy of drug molecule by formulating a convenient dosage form for administration to achieve better patient compliance. Rapidly disintegrating tablet are appreciated by significant segment of the population, particularly pediatric, geriatric, unconscious, and bed-ridden patients who have difficulty swallowing conventional tablet and capsule.[12] To overcome this, dispersible tablets and fast-disintegrating tablets have been developed. Most commonly used methods to prepare these tablets are freeze drying/lyophilization, tablet moulding, and direct compression methods. Lyophilized tablets show a porous structure, which causes very quick penetration of saliva into the pores when placed in oral cavity, but it has disadvantage of high cost production process.[3-6]

Conventional aceclofenac tablet available in the market are not suitable for acute pain and inflammatory conditions where quick onset of action of drug is required. This is because of poor patient compliance, particularly by the geriatric and pediatrics patient who experience difficulty in swallowing, and by those who are bed ridden or who are traveling and do not have an easy access to water. Aceclofenac is superior from other NSAIDs as it has selectivity for Cox-2, a beneficial Cox inhibitor, well-tolerated, better GI tolerability, and improved cardiovascular safety than other selective Cox-2 inhibitors. It also shows increased matrix component synthesis and protection of chondrocytes against apoptosis. Aceclofenac has a faster and more potent effect than the other NSAIDs. Aceclofenac has a faster and more potent effect than the other NSAIDs. It efficiently interferes with neutrophils adhesion to endothelium and this effect may represent an additional relevant mechanism in its anti-inflammatory activity. Aceclofenac has an outstanding anti-inflammatory profile, involving a classical inhibition of prostaglandins E2, a decrease in the expression of several cytokines including interleukin and tumor necrosis factor. It also inhibits activated oxygen species production and influences cell adhesion. It is mainly used for osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, dental pain, postoperative pain, post-traumatic pain, low back pain, and gynecological pain. Thus, it can be concluded that aceclofenac may be a better option for the management of pain. The drug is official in British Pharmacopoeia. Aceclofenac is practically insoluble in water, and peak blood level reaches between 1 to 3 hours after oral administration.[7]

The rapidly disintegrating tablets in oral cavity can be swallowed with a small amount of water or saliva. The tablet manufactured by any of the above mention methods are composed of drug and other excipients which disintegrate in small amount of water or saliva in the oral cavity within 30 seconds. Hence, an attempt was made to improve the dissolution of aceclofenac through the formulation of mouth-dissolving tablets with appropriate mechanical strength, which would disintegrate in oral cavity, in less than 30 seconds, and would provide an immediate relief from pain due to its faster dissolution in gastrointestinal tract.

MATERIALS AND METHODS

PVP K-30, magnesium stearate, talcum, sodium lauryl sulfate, and aspartame were purchased from CDH (P) Ltd., New Delhi. Aceclofenac, Avicel PH 102, ac-di-sol were obtained as a gift sample from Alembic Pharmaceutical Pvt. Ltd, Vadodara. All other materials used were of pharmaceutical grade.

Preparation and Evaluation of Tablets

The wet granulation and direct compression technique were selected for developing a novel mouth-dissolving formulation. In wet granulation, all materials were passed through a 40 mesh. Aceclofenac, Ac-Di-Sol, Avicel PH 102, and sodium lauryl sulfate were mixed properly. Alcoholic solution of PVPK30 was added to mixture in quantity just enough to bind the mass; granulation was done by passing the wet mass through a 14 mess. Granules were dried at 60°C for 30 minutes, then pass through 20 mesh, and granules were used for further processing. Granules were mixed with extragranular fraction of the lubricant/glidant and require proportion of fines (10%). The resulting mass then compressed into tablet using single punch tablet machine. For optimization, batch A1, A2, A3, A4 were prepared and evaluated. A1 shows better disintegration, further to improve the friability value and disintegration time, the batch A1 passed through different mesh size #22, #24, #30 and batch F1, F2, F3 were prepared (tablet weight, 280 mg).

In direct compression technique, batches were prepared using Avicel PH102 as diluent to obtain tablet of good quality. Excipients used were the same and were added in the similar proportion as in the batches made by wet granulation. All the materials were passed through 40 mesh prior to mixing. The drug was properly mixed with superdisintegrant (croscarmellose sodium), and then with the diluent Avicel PH102. The mixture was mixed with talc, aspartame, sodium lauryl sulfate, and magnesium stearate. The material was then subjected to compression using single punch tablet machine. Batch C3 was prepared to check the consistency of the formulation; three validation trials (batch D1, D2, D3) were performed.

Evaluation of tablets

Compressed tablets were then evaluated for hardness, wetting time, disintegration, friability, and drug content. Hardness was measured by Monsanto type hardness tester. One tablet was placed in each tube of disintegration apparatus (model DT-2D scientific), and the test was carried out using distilled water as a disintegrating media at 37±2°C. Friability was determined in friabilator (Roche friabilator) by taking ten tablets.[89] For drug content analysis, a tablet contained 100 mg of aceclofenac, was pulverized and taken into a 100 ml volumetric flask, and dissolved in 100 ml of methanol. One milliliter of the filtrate was diluted to obtain the concentration of solution 50 mg/ml, and assayed for drug content using a double-beam UV/Vis spectrophotometer (Shimadzu 1700) at 276 nm. All the dispersions contained 95±5% of the drug.

In vitro dissolution study of tablets

The dissolution study of tablet was conducted using USP dissolution apparatus II in 900 ml of PBS pH 7.4 maintained at 37 ± 0.5°C at a speed of 50 rpm.[10] One milliliter of samples was withdrawn at time intervals of 5, 10, 15, 20, 30, 60, and 90 minutes, filtered through a 0.45-μ membrane filter, diluted, and assayed at 276 nm, using a UV/Vis double-beam spectrophotometer. The volume of dissolution fluid was adjusted to 900 ml by replacing each 1 ml aliquot withdrawn with 1 ml of PBS pH 7.4. The cumulative % release of aceclofenac in tablet sample was determined by using standard curve.

RESULTS AND DISCUSSION

To develop wet granulation formulation, first of all, experimental series was designed by selecting additives according to requirement of formulation to overcome the hydrophobic property of aceclofenac and to form a mouth-dissolving tablet which disintegrates in fraction of seconds. For optimization of tablet properties as set standards of disintegration time (<30 s), crushing strength (1-6 kg/cm2), and friability (<0.9%). In this process, four types of tablet formulations were developed (batches A1, A2, A3, and A4) and for selection of checkpoint formulation batches F1, F2, F3 were prepared. result of batch F1 and F2, but F1 shows capping problem which may be due to relatively more fines, whereas batch F2 does not show such problem. Evaluation parameters of checkpoint batch F2 which gives best results are as follows: crushing strength – 3.6 kg/cm2, (%) friability – 0.32, wetting time – 123 seconds; disintegration time – 142 seconds, cumulative percentage release – 75.37% [Tables 1 and 2].

Table 1

Design layout and evaluation of different formulations prepared with avicel by wet granulation

Table 2

Prepared A1 formulation passed through the different mess size

The batch F2 formula had taken for optimization of second set of formulation which was prepared by direct compression method2; the batches D1, D2, and D3 had been validated to check the consistency of the results obtained from the selected batch C3 [Tables 3 and 4].

Table 3

Evaluation of formulation after direct compression

Table 4

To check the consistency of formulation C3, three validation trials [D1-D3] evaluation

The next step comparison of selected batches on the basis of method adopted was done. Comparison showed that formulation C3 (hardness – 3.8 kg/cm2, friability [%] – 0.24, wetting time – 13 seconds, disintegration time – 16 seconds, cumulative percent release – 89.69%) prepared by direct compression was the best one [Table 5 and Figure 1].

Table 5

Comparative dissolution profile of formulation F1, F2, F3, and C3

Figure 1

Graphical representation of comparative dissolution profile of batch F1, F2, F3, and C3. F1: Wet granulation; F2: Wet granulation; F3: Wet granulation; C3: Direct compression

In short, the aim of this work was achieved by selection of formulation C3, as mouth-dissolving tablets and the direct compression method is the best one respectively.

CONCLUSION

The study and results revealed that the method of preparation of formulation significantly affect the disintegration time, percentage friability, and release of drug. Present study underlines the importance of process variables. It is thus concluded that by adopting a systematic formulation approach, an optimum point can be reached in the shortest time with minimum efforts and direct compression technique would be an effective alternative approach compared with wet granulation technique.