INTRODUCTION:

Aceclofenac is a non-steroidal anti-inflammatory drug (NSAIDS). It has anti-inflammatory and analgesic properties and is used for the relief of pain and inflammation in rheumatoid arthritis, osteoarthritis and ankylosing spondylitis. Paracetamol is an analgesic and antipyretic drug used worldwide for management of pain and fever [1]. Both the drugs have short biological half life (3-4 h) and dosing frequency is more than one per day makes them ideal drugs for their sustained release formulation. Tablets containing 100 mg of aceclofenac and 500 mg of paracetamol have been approved worldwide for relief from various diseases related with pain and inflammation such as acute pain in osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, low back pain, dental pain, fracture, painful pharyngitis and tonsillitis.

The successful treatment of severe pain in arthritis can be maintained by effective drug concentration in the blood for extended period of time. The sustained release tablets dissolve slowly and delivering the drugs for long period of time to achieve this objective.

The literature survey revealed that the formulation and evaluation of aceclofenac sustained release matrix tablets was reported using hydrophilic polymer by wet granulation technique up to 24 h [2, 3]. Aceclofenac Sustained release matrix tablets of aceclofenac was prepared and evaluated using natural polymers such as xanthan gum, guar gum and chitosan by direct compression technique for drug release up to 12 h [4-6]. Sustained release microspheres of aceclofenac encapsulated with biodegradable polymer rosin, from which drug release was controlled for about 24 h has also been reported [7]. Some clinical studies were conducted on paracetamol for effectiveness of sustained and immediate release tablets and found that analgesic efficacy and safety profiles were similar after receiving the single oral dose of IR paracetamol and SR paracetamol in the control of pain [8, 9]. Report on development and optimization of microspheres consisting aceclofenac and paracetamol, both as SR form with in-vitro drug release up to 8 hrs is also available [10]. Formulation and evaluation of bilayer tablets containing aceclofenac and paracetamol, both as IR form gave in-vitro drug release within 1 h has also been reported [11]. The aceclofenac controlled release and paracetamol immediate release bilayer tablet has been reported in which one layer consisted of IR aceclofenac and paracetamol, and another layer was SR aceclofenac [12]. The authors are reported in our previously published work the formulation and in-vitro evaluation of a bilayer matrix tablet containing aceclofenac as sustained release and paracetamol as immediate release [13]. The objective of the presented research work is to formulate and evaluate sustained release matrix tablets containing aceclofenac and paracetamol by wet granulation method.

MATERIALS AND METHODS:

MATERIALS:

Aceclofenac and paracetamol were kindly supplied as gift sample by Moraceae Pharmaceuticals Ltd. (Uttarakhand, India). HPMC K4M, HPMC K15M, HPMC K100, HPMC K100M, polyvinyl pyrrolidone (PVP), talc and magnesium stearate were purchased from S.D. Fine Chemicals Ltd., Mumbai, India. HPLC grade acetonitrile, methanol, and ammonium acetate were purchased from Fluka analytical, Sigma-Aldrich Corporation, St. Louis, MO, USA. All other chemicals and reagents were of analytical grade.

METHODS:

Preparation and Compression of Tablets:

Granules for tablet formulation were prepared by wet granulation method. Both drugs were mixed with the HPMC K4 100 and PVP polymer at different ratios in a planetary mixer for 5 min. The powders were granulated with isopropyl alcohol, sieved using a mesh 20 screen, and dried at 30 ºC for 1 h. The dried granules were again sized by a mesh 20 screen and mixed with talc and magnesium stearate for 2 min. The final weight of each trial formulation was kept at 575 mg. Granules were compressed into 920 mg tablets to an average hardness of 7 Kg/cm2 on a 16-station double rotary tablet punching machine (Cadmach, Mumbai, India). The composition of different formulations is given in Table 1.

Evaluation of Physical Properties of Tablets:

The tablets were characterized for weight variation, friability, hardness and thickness test. The weight variation of the tablets was evaluated on 20 tablets using an electronic balance (Shimadzu). Friability was determined using 10 tablets in a Roche friabilator for 5 min rotated at the speed of 25 rpm. The hardness of tablets was evaluated on 10 tablets by using Mosanto hardness tester. The thickness of tablets was measured on 10 tablets by Vernier caliper.

Table 1. Composition of SR Tablets of Aceclofenac and Paracetamol

Ingredients (mg)	Formulation Code
Ingredients (mg)	F1	F2	F3
Aceclofenac	100	100	100
Paracetamol	500	500	500
HPMC K 100	100	150	200
Polyvinyl Pyrrolidone	200	150	100
Talc	10	10	10
Magnesium Stearate	10	10	10
Total weight	920	920	920

Drug Content Studies:

Twenty tablets were weighed accurately and powdered. Powder equivalent to 100 mg of aceclofenac and 500 mg of paracetamol was taken and transferred to a 50 mL volumetric flask. The powder was dissolved with approximately 25 mL of methanol and ultrasonicated for 10 min. The final volume was made up with methanol. This solution was filtered through a 0.45 mm nylon membrane filter to remove all the excipients. The resultant filtrate was further diluted with methanol: water (50:50, v/v) to give a sample solution containing 100 ng/mL of aceclofenac and 500 ng/mL of paracetamol. The solutions were filtered through a 0.20 mm nylon syringe filter and injected into the UPLC-PDA system for analysis. The amount of aceclofenac and paracetamol in tablets were determined by calibration equations obtained from the respective calibration curve.

UPLC Conditions:

UPLC was performed with a Waters Acquity UPLC system equipped with a binary solvent manager, an auto-sampler, column manager and a tunable PDA detector. Chromatographic separation was performed on a Waters Acquity UPLC BEH C18 (100.0×2.1 mm, 1.7 mm) column. The detection was carried out at 275 nm. The mobile phase for UPLC analysis consisted of acetonitrile-2 mM ammonium acetate (50:50, v/v) which was filtered through 0.45 mm membrane filter and degassed by sonication. For isocratic elution, the flow rate of the mobile phase was kept at 0.25 mL/min and 10 mL of sample solution was injected in each run. The total chromatographic run time was 2.0 min.

Validation of the Method:

The developed method was validated according to ICH validation guidelines [14]. For the determination of linearity and range different standard concentrations each of aceclofenac and paracetamol in the range of 1-1000 ng/mL was prepared separately in methanol: water (50:50, v/v). The solutions were filtered through a 0.20 mm nylon syringe filter and injected into the UPLC-PDA system for analysis. Linearity was described by slope, intercept, and correlation coefficient obtained from regression equations. The other validation parameters were also evaluated such as limit of detection (LOD) and limit of quantitation (LOQ), precision, and accuracy.

Drug Release Studies:

Drug release studies from the tablets were carried out using USP paddle apparatus, Veego VDR-8DR (Veego Instruments, Mumbai, India). The dissolution medium consisted hydrochloric acid buffer of pH 1.2 (0.1N) with 1% w/v sodium lauryl sulfate (SLS) as solubiliser maintained at 37 ºC with a rotation speed of 100 rpm. Each dissolution test was performed on total number of 8 tablets. A single tablet was added to the dissolution medium in each vessel. 5 mL of samples were taken at different time intervals initially every 10 min and continue for every one hour. An equivalent amount of fresh medium was added to the dissolution medium. The samples were filtered through 0.45 mm nylon membrane filter to remove all the excipients. The filtrates were further diluted with methanol: water (50:50, v/v) to get the sample solution containing required concentration of both the drugs and injected into the UPLC system for analysis. The amount of drugs dissolved in different time intervals were calculated from the corresponding peak areas.

RESULTS AND DISCUSSION:

Physical Properties of Tablets:

Both the drugs are insoluble in water, hence HPMC was used to enhance the solubility and also bulking agents to extend the bulk of the drugs. PVP was used as binding agent for both the layers. SSG used as superdisintegrants for fast disintegration of IR layer. Talc and magnesium stearate were used as lubricant. The tablets of different formulations were subjected to various evaluation tests such as weight variation, thickness, hardness, friability, and drug content studies. The results of evaluation tests are given Table 2. All the formulations showed uniform thickness. The tablets passed all the tests in accordance with the specification limits of United States Pharmacopoeia (USP, 2002) such as weight variation, thickness, hardness, friability (less than 1%) and drug content studies (more than 98 %) [15, 16].

Drug Content Studies:

The validated method was applied for the determination of aceclofenac and paracetamol in prepared tablets containing 100 mg of aceclofenac and 500 mg of paracetamol. The aceclofenac content from tablets was 98.15–99.75% and paracetamol content was 97.92–98.54% indicated that method was suitable for analysis of aceclofenac and paracetamol in tablets without any interference from excipients.

Validation of the Method:

The retention time (Rt) was found to be 1.50 min for aceclofenac, and 0.61 min for paracetamol with the total chromatographic run time of 2 min for each compound, as shown in Figure 1. For aceclofenac and paracetamol calibration curves were linear over the concentration range of 1-1000 ng/ml with correlation coefficient was more than 0.999. The limit of detection of both the drugs was 1 ng/mL. The obtained results indicated higher sensitivity of the method. The RSD less than 2% was obtained for both the drugs by evaluation of intraday, interday and different analysts precision suggested an excellent precision of the method. Hence the method was suitable for drug content studies and in-vitro studies without interference from excipients. The low analysis time is an advantage in fast dissolution study.

Figure: 1. UPLC-PDA chromatogram obtained from mixed standards of Aceclofenac (Rt 1.50 min) and Paracetamol (Rt 0.61 min).

Table 2. Physical properties of the optimized tablets

Formulation Code	Weight Variation (%)^b	Thickness (mm)^a	Hardness (Kg/cm²)^a	Friability (% w/w)^a
F1	1.25 ± 0.42	7.01 ± 0.01	7.10 ± 0.12	0.25 ± 0.35
F2	1.77 ± 0.15	7.11 ± 0.02	7.20 ± 0.13	0.45 ± 0.15
F3	1.50 ± 0.22	7.00 ± 0.03	7.00 ± 0.22	0.35 ± 0.25

^aValues are represented as M ± SE, (n=10); ^bValues are represented as M ± SE, (n=20)

Drug Release Studies:

Drug release studies were carried out by validated UPLC-PDA method. Both the drugs are water insoluble. Hydrophilic matrix tablet is the simplest method for formulating an extended release tablet. The HPMC hydrophilic polymer has been widely used because of its global acceptance, excellent stability within wide pH range, pH-independent drug release and suitability of various drugs. HPMC is water swellable polymer and increases the size of the tablet thereby retains in the stomach for the long time and provide the extended action [17-19]. HPMC has the greater solubility for water insoluble drugs, hence it was selected as hydrophilic polymer for both the drugs in tablets. Different grades of HPMC are available in the market such as HPMC K4M, HPMC K15M, and HPMC K100. The HPMC K100 has the highest viscosity and thus provides the slower rate of polymer hydration, hence it was selected for formulation of sustained release layer. From the study it was found that when the content of HPMC K 100 polymer increases in the tablet matrix, it dissolve slowly in the medium resulting sustained release of drugs over the extended period of time. PVP is highly water absorbable polymer and it increases the water absorption in the HPMC network and produces the synergistic increase in the viscosity. The enhanced viscosity of whole matrix is occurred due to the interaction between the PVP and hydroxyl groups of HPMC, resulted in complex formation between two polymers leading to more sustained release of drug. The in-vitro release profile of aceclofenac and paracetamol from matrix tablets from formulation (F3) is shown in Figure 2. Formulation F3 was found to release the drugs in sustained manner up to 6 h. Hence formulation F3 was selected the optimum formulation and compared with the marketed combination tablets. Higuchi’s model of drug diffusion was applied to understand the mechanism of drug release from matrix tablets, which is given by equation (Q = k_Ht^1/2). Where, Q is the amount of the drug release at time t, and k_H is the Higuchi’s diffusion constant. A graph was plotted between amount of drug released and square root of time. If the release of drug is diffusion controlled, then obtained graph will be linear [20-22]. The kinetic parameters for drug release from the tablets (F1 to F3) showed high linearity (R²: 0.994-0.999) for both the drugs.

Figure: 2. In-vitro release profile from formulated (F3) tablets (bars represent ± SD [n=3]).

CONCLUSION:

Both the drugs are slightly soluble in water and have almost similar half life (3-4h). Hence they are formulated as sustained release matrix tablets. Sustained release matrix tablets containing aceclofenac and paracetamol have been prepared and evaluated. HPMC K100 was used as matrix forming hydrophilic polymer along with PVP binder for both the drugs. In-vitro drug release from prepared tablets showed better sustained release effect when compared with marketed combination tablets. Tablets thus formulated provided sustained release of aceclofenac and paracetamol over the period of 6 h.

ACKNOWLEDGEMENT:

The authors are grateful to the Moraceae Pharmaceuticals Ltd., Uttarakhand, India, for providing gift samples of aceclofenac and paracetamol.

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Received on 23.05.2017 Modified on 22.06.2017

Res. J. Pharm. Dosage Form. & Tech. 2017; 9(2): 48-52.

DOI: 10.5958/0975-4377.2017.00010.6