*Corresponding Author:
P. V. Swamy
Department of Pharmaceutics, H. K. E. Society’s College of Pharmacy, Sedam Road, Gulbarga - 585 105, India
E-mail: [email protected]
Date of Submission 21 August 2006
Date of Revision 5 July 2007
Date of Acceptance 18 December 2007
Indian J Pharm Sci, 2007, 69 (6): 836-840  

Abstract

In the present work, orodispersible tablets of meloxicam were designed with a view to enhance patient compliance. A combination of super-disintegrants i.e., sodium starch glycolate- croscarmellose sodium or sodium starch glycolate-crospovidone were used along with directly compressible mannitol to enhance mouth feel. The prepared batches of tablets were evaluated for hardness, friability, drug content uniformity, wetting time, water absorption ratio and in vitro dispersion time. Based on in vitro dispersion time (approximately 10 s), two formulations (one from each batch) were tested for in vitro drug release pattern (in pH 6.8 phosphate buffer), short-term stability (at 45º for 3 w) and drug-excipient interaction (IR spectroscopy). Among the two formulations, the formulation prepared by direct compression method using 2% w/w sodium starch glycolate and 1.5% w/w croscarmellose sodium was found to be a better formulation (t 50% = 22 min) based on the in vitro drug release characteristics compared to conventional commercial tablet formulation (t 50% = 68 min). Short-term stability studies on the formulations indicated that there are no significant changes in drug content and in vitro dispersion time (P<0.05).

Keywords

Orodispersible tablets, meloxicam, sodium starch glycolate, crospovidone, croscarmellose sodium

Many patients express difficulty in swallowing tablets and hard gelatin capsules, tending to non-compliance and ineffective therapy [1]. Recent advances in novel drug delivery systems (NDDS) aim to enhance safety and efficacy of drug molecules by formulating a convenient dosage form for administration and to achieve better patient compliance. One such approach is orodispersible tablet [1-4]. Advantages of this drug delivery system include administration without water, accuracy of dosage, easy portability, alternative to liquid dosage forms, ideal for pediatric and geriatric patients and rapid onset of action. Meloxicam is an oxicam or enol carboxamide derivative. It is a nonsteroidal antiinflammatory drug (NSAID) with highly selective cyclo-oxygenase-2 (COX-2) inhibitory action. It is used in the treatment of rheumatoid arthritis, osteoarthritis, dental pain, and in the management of acute post-operative pain [5,6]. It was selected as drug candidate, as it is not available in such dosage form. Aim of the present study was to develop such a NDDS for meloxicam by simple and cost-effective direct compression technique.

Meloxicam and super-disintegrants were gift samples from Sun Pharma, Mumbai and Wockhardt Research Centre, Aurangabad, respectively. Directly compressible mannitol (Pearlitol SD200) was a generous gift from Strides Arcolabs, Bangalore. Microcrystalline cellulose (Loba Chemie Pvt. Ltd., Mumbai), colloidal silicon dioxide (Yucca Enterprises, Mumbai), magnesium stearate (CDH, Mumbai) were used. All other chemicals used were of Analytical Reagent grade.

Orodispersible tablets of meloxicam were prepared by direct compression [7] according to the formulae given in Table 1. All the ingredients were passed through #60 mesh separately. Then the ingredients were weighed and mixed in geometrical order and tablets were compressed using 8 mm normal concave punches to get tablets of 200 mg weight on a 16-station rotary tablet machine (Cadmach). A batch of 60 tablets was prepared for all the designed formulations.

Ingredients (mg/tablet) Formulation code
DC0 DCC1 DCC2 DCC3 DCC4 DCC5 DCP1 DCP2 DCP3 DCP4 DCP5
Meloxicam 7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5
Sodium pstarchglycolate - 2 4 8 12 16 2 4 8 12 16
Cros-carmellose sodium - 2 3 4 5 6 - - - - -
Cros-povidone - - - - - - 6 6 8 8 8
Pearlitol SD 200 20 20 20 20 20 20 20 20 20 20 20
Aerosil 2 2 2 2 2 2 2 2 2 2 2
Magnesium stearate 1 1 1 1 1 1 1 1 1 1 1
Sodium saccharin 1 1 1 1 1 1 1 1 1 1 1
Flavour 4 4 4 4 4 4 4 4 4 4 4
Micro- crystalline                      
cellulose 164.5 160.5 157.5 152.5 147.5 142.5 156.5 154.5 148.5 144.5 140.5

Table 1: Composition of different batches of orodispersible tablets of meloxicam.

Twenty tablets were selected at random and weighed individually. The individual weights were compared with the average weight for determination of weight variation [8]. Hardness and friability of the tablets were determined by using Monsanto Hardness Tester and Roche friabilator respectively. For content uniformity test, ten tablets were weighed and powdered. The powder equivalent to 7.5 mg of meloxicam was extracted into methanol and liquid was filtered. The meloxicam content was determined by measuring the absorbance at 363.2 nm after appropriate dilution with methanol. The drug content was calculated using the standard calibration curve. The mean percent drug content was calculated as an average of three determinations [9]. For determination of wetting time and water absorption ratio [10], a piece of tissue paper folded twice was placed in a small Petri dish (internal diameter of 5 cm) containing 6 ml of water. A tablet was placed on the paper and the time required for complete wetting was measured. The wetted tablet was then weighed. Water absorption ratio ‘R’ was determined using the equation, R=100(Wb- Wa)/Wa, where, Wa is the weight of the tablet before water absorption and Wb is the weight of the tablet after water absorption. For determination of in vitro dispersion time, one tablet was placed in a beaker containing 10 ml of pH 6.8 phosphate buffer at 37±0.5º and the time required for complete dispersion was determined [11]. IR spectra of meloxicam and its formulations were obtained by KBr pellet method using Perkin-Elmer FTIR series (model-1615) spectrophotometer in order to rule out drug-carrier interactions.

In vitro dissolution of meloxicam orodispersible tablets was studied in USP XXIII type-II dissolution apparatus (Electrolab, Model-TDT 06N) employing a paddle stirrer at 50 rpm using 900 ml of pH 6.8 phosphate buffer at 37±0.5° as dissolution medium [12]. One tablet was used in each test. Aliquots of dissolution medium were withdrawn at specified intervals of time and analyzed for drug content by measuring the absorbance at 363 nm. The volume withdrawn at each time interval was replaced with fresh quantity of dissolution medium. Cumulative percent of meloxicam released was calculated and plotted against time. Short-term stability studies on the promising formulations (DCC2 and DCP2) were carried out by storing the tablets at 45±1° over a 3 w period. At intervals of one week, the tablets were visually examined for any physical changes, changes in drug content and in vitro dispersion time.

Orodispersible tablets of meloxicam were prepared by direct compression method employing combination of two super-disintegrants at a time (Table 1). Sodium starch glycolate (SSG), croscarmellose sodium (CCS) and crospovidone (CP) were used as super-disintegrants while microcrystalline cellulose (MCC) and directly compressible mannitol (Pearlitol SD200) were used as diluent and sweetening agent respectively. A total of ten formulations and a control formulation DC0 (without super-disintegrants) were designed. Preliminary studies with tablets containing only one super-disintegrant, viz., SSG (5% w/w) or CCS (3% w/w) or CP (4% w/w) displayed in vitro dispersion time of 67, 60 and 71 s, respectively. Hence it was decided to use a combination of two super-disintegrants so that orodispersible tablets with in vitro dispersion time of less than 15 s may be developed.

As the material was free flowing (angle of repose values <30° and Carr’s index <15), tablets obtained were of uniform weight (due to uniform die fill), with acceptable variation as per IP specifications i.e., below 7.5%. Drug content was found to be in the range of 97-101%, which is within acceptable limits. Hardness of the tablets was found to be 3.3 to 4 kg/ cm2. Friability below 1% was an indication of good mechanical resistance of the tablets. Water absorption ratio and wetting time, which are important criteria for understanding the capacity of disintegrants to swell in presence of little amount of water, were found to be in the range of 71 to 78% and 5 to 7 s respectively. Formulations DCC2 and DCP2 were found to be promising and displayed an in vitro dispersion time of approximately 10 s, which facilitates their faster dispersion in the mouth.

Among the tablet formulations employing various combinations of SSG (1-8% w/w) and CCS (1-3% w/w) as super-disintegrants, the formulation DCC2 containing 2% w/w SSG and 1.5% w/w CCS was found to be promising, and has shown an in vitro dispersion time of 10 s, wetting time of 5s and water absorption ratio of 76% when compared to the control formulation (DCo) which shows 125 s, 24 s and 69.4% values, respectively for the above parameters (Table 2). Further increase in the amount of super-disintegrants increases the in vitro dispersion time (up to 44 s for formulation DCC5), which can be attributed to the gelling effect of SSG at higher concentration [13,14].

Test   Average weight* (mg) ± SD Hardness* (kg/cm2) ± SD Friability (%) Percent drug content* ± SD Wetting time* (s) ± SD Water absorption ratio*(%) ± SD In vitro Dispersion time* (s) ± SD
DC0 197 ± 0.002 4.0 ± 0.246 0.48 101.33 ± 0.577 24 ± 0.486 89.4 ± 0.214 125 ± 0.432
DCC1 196 ± 0.001 3.5 ± 0.313 0.83 99.03 ± 0.776 5 ± 0.416 77.3 ± 0.654 14 ± 0.645
DCC2 197 ± 0.002 3.5 ± 0.224 0.69 98.66 ± 0.231 5 ± 0.315 76.4 ± 0.586 10 ± 0.326
DCC3 198 ± 0.002 3.4 ± 0.456 0.75 97.66 ± 0.471 7 ± 0.409 76.4 ± 0.209 25 ± 0.212
DCC4 199 ± 0.002 3.5 ± 0.283 0.73 97.33 ± 0.618 6 ± 0.416 74.3 ± 0.224 38 ± 0.224
DCC5 201 ± 0.002 3.3 ± 0.336 0.84 99.36 ± 0.980 5 ± 0.454 71.6 ± 0.287 44 ± 0.326
DCP1 200 ± 0.001 3.5 ± 0.244 0.61 102.13 ± 0.659 7 ± 0.456 75.6 ± 0.324 26 ± 0.414
DCP2 199 ± 0.002 3.3 ± 0.215 0.63 99.00 ± 0.374 7 ± 0.533 74.6 ± 0.313 11 ± 0.218
DCP3 200 ± 0.002 3.4 ± 0.218 0.56 98.36 ± 0.679 6 ± 0.493 76.1 ± 0.354 18 ± 0.216
DCP4 201 ± 0.001 3.5 ± 0.248 0.59 97.96 ± 0.124 5 ± 0.416 77.0 ± 0.246 26 ± 0.242
DCP5 201 ± 0.002 3.5 ± 0.212 0.59 98.32 ± 0.840 5 ± 0.224 78.2 ± 0.315 29 ± 0.284

Table 2: Evaluation of orodispersible tablets

Among the tablet formulations employing various combinations of SSG (1-8% w/w) and CP (3-4% w/w) as super-disintegrants, the formulation DCP2 containing 2% w/w SSG and 3% w/w CP was found to be promising, and has displayed an in vitro dispersion time of 11 s, wetting time of 7 s and water absorption ratio of 75% when compared to the control formulation (DCo), which shows 125 s, 24 s and 69.4% values, respectively, for the above parameters (Table 2). Further increase in the amount of super-disintegrants increases the in vitro dispersion time (up to 29 s for formulation DCP5) due to the same reasoning as stated above.

In vitro dissolution studies on the promising formulations (DCC2 and DCP2), the control (DCo) and commercial formulation (CF) along with the pure drug (meloxicam) were carried out in pH 6.8 phosphate buffer, and the various dissolution parameter values viz., percent drug dissolved in 10 min (D10), dissolution efficiency at 30 min (DE30 min)15, t50% and t70% are shown in Table 3, and the dissolution profiles depicted in fig. 1. This data reveals that overall, the formulation DCC2 has shown three-fold faster drug release (t50%=22 min) when compared to the marketed conventional tablet formulation of meloxicam (t50%=68 min) and released 12 times more drug than the control formulation in 10 min.

Formulation code D10 (%) DE30 min (%) t50% (min) t70% (min)
MX 5.46 5.23 >120 >120
DC0 2.9 2.63 >120 >120
DCC2 34.17 36.9 22 53
DCP2 23.06 21.1 69 > 120
CF 18.53 20.9 68 > 120

Table 3: in vitro dissolution parameters in ph 6.8 phosphate buffer.

Figure

Figure 1: In vitro cumulative percent drug release vs time profiles of promising meloxicam formulations

Plot showing cumulative percent drug release in pH 6.8 phosphate buffer from meloxicam (pure drug) (─♦─); control tablet DC0 (─▲─); orodispersible tablet DCC2 (─■─); orodispersible tablet DCP2 (─x─); conventional commercial tablet formulation CF (─O─)

IR spectroscopy indicated that the drug is compatible with all the excipients. The IR spectrum of DCC2 showed all the characteristic peaks of meloxicam pure drug, thus confirming that no interaction of drug occurred with the components of the formulation. Short-term stability studies of the above formulation indicated that there were no significant changes in drug content and in vitro dispersion time at the end of a 3 w period (P<0.05).

References