Lornoxicam Essay

Clinically, non-steroidal anti-inflammatory drugs (NSAIDs) are the most frequently prescribed class of drugs for inflammatory disorders (1). Lornoxicam is a novel NSAID drug. It has an equipotent COX isoenzyme inhibitory effect and subsequently reduces the production of prostaglandins, thromboxane, and leukotrienes (2). It is prescribed for mild to moderate pain and inflammation in osteoarthritis and rheumatoid arthritis (3). It is prescribed for the treatment of osteoarthritis due to its analgesic, anti-inflammatory effect and to promote the repair of damaged joints (4).
It is classified as Class II drug with low solubility and high permeability properties. Due to its very poor solubility in acidic pH of the stomach, it remains in the stomach wall for a long period, aggravating its potential side effects (peptic ulcers and gastric irritation) (5).
Immediate release (IR) oral dosage forms, i.e., tablets and capsules, are designed to disintegrate in the stomach followed by their dissolution in the fluids of the gastrointestinal
tract (6) with no special rate controlling features, giving relatively rapid drug absorption and onset of pharmacodynamic effects. For IR oral dosage forms containing poorly soluble drugs, drug absorption may be gradual due to slow dissolution in the gastrointestinal tract, resulting in a delayed onset time.

IR tablets are prepared by various techniques, mainly, direct compression, granulation (wet, dry or melt) followed by compression and hot melt extrusion using suitable diluents and superdisintegrant (6-9).
The aim of our work is to prepare lornoxicam IR liquitablets using liquid and solid release modulators (wetting agent "Tween 80", solubilizers "PEG 400/PEG 4000" and microenvironment pH modifiers "Tris/NaHCO3") in order to improve dissolution, absorption and bioavailability of lornoxicam and to reduce potential gastric side effects.
Tablets containing liquid dissolution modulators (Liquitablets) are often prepared using direct compression technique with the aid of suitable carrier and coating materials. In our work, according to our knowledge, it is the first time to prepare liquitablets using blister molding method. Blister molding technique is a simple, easily scalable and requires no special equipment compared to the conventional
methods.
The effect of the two different manufacturing methods; blister molding and direct compression, on the fast release characteristics (rapid disintegration and dissolution) was studied. Also, the tablets were characterized for weight variation, drug content, mechanical strength and solid state of the drug. Finally, selected formula was evaluated for anti-inflammatory activity and potential gastric side effects in rats.

Materials and methods
Materials
Lornoxicam: gift sample from Eva Pharma, Cairo, Egypt. Maltodextrin: Fluka Analytical Biochemika, Sigma–Aldrich Co., France. Avicel PH 102: FMC Co., Pennsylvania, USA. Tris (hydroxymethyl aminomethane): MP Biomedicals LLC, Germany. Pluronic F-127: Sigma-Aldrich, Inc., Germany. Polyvinylpyrrolidone K30 (PVP K30) and polyvinylpyrrolidone K90 (PVP K90): BASF, Germany. Tween 80®, polyethylene glycol 400 (PEG 400), polyethylene glycol 4000 (PEG 4000), Gelatin, sodium bicarbonate, sodium chloride, hydrochloric acid and methanol: Adwic, El-Nasr Pharmaceutical Chemicals Co., Egypt. Aeroperl®300: Pharma, Degussa, USA. Histamine and formaldehyde: Sigma-Aldrich Co., USA and Yeast (food grade). Lornoxicam 4 mg tablets (Global Napi Pharmaceuticals, 6th of October, Egypt).
Solubility studies
Lornoxicam (20 mg) was added to 3 ml of each solvent in screw capped glass vials, after vortex-mixing for 1 min, vials were shaken at 25±0.5 °C for 24 h in a thermostatically controlled shaking water bath (Model 1083, GLF Corp., Burgwedel, Germany). Samples from each mixture were centrifuged. An aliquot of the supernatant was collected and filtered, diluted with methanol and the amount of lornoxicam was determined at 375 nm (Shimadzu UV-1601 UV-Vis double beam spectrophotometer, Koyo, Japan).
Differential scanning calorimetry (DSC)
DSC patterns of samples of pure drug, excipients, and physical mixtures were determined using the DSC instrument (Shimadzu, Model TA–50, ESI, Kyoto, Japan). Temperature range was 20–400°C and the heating rate was 10oC/min.
Infrared spectroscopy (IR)
The infrared spectra of the samples of pure drug, PEG 4000, tris and physical mixtures were recorded over a wave number range of 4000 cm-1 to 500 cm-1 (Genesis ΙΙ, TM, Mattson Instruments, USA).
Preparation of blister-molded IR liquitablets (BMIR)
Homogenized mixture containing the drug and Tween 80 (wetting agent) was prepared using a magnetic stirrer (DAIHAN Scientific Co., South Korea). Aqueous solution containing the binder (PVP K30, PVP K90, Pluronic F-127 or gelatin) and one solubilizer (PEG 400 or PEG 4000) was prepared and added to the mixture. pH-modifier, when applicable (sodium bicarbonate or tris) was added to the mixture. Finally the carrier (maltodextrin and/or avicel PH 102) was added after completely dissolving or uniformly dispersing the drug. One gram of the mixture (under continuous stirring) was filled with a syringe into tablet polyvinylchloride blister packs to give 4 mg lornoxicam tablets. The blisters were placed in the desiccator overnight then placed in oven at 40 °C till dryness (10). The composition of all the prepared tablets is shown in Table 1.
Preparation of direct compression IR liquitablets (DCIR)
All ingredients were sieved through Sieve number 20 (size 810 μm), weighed separately and mixed geometrically. Aeroperl® was added to the resultant powder blends that were compressed into D1 and D2 liquitablets using single punch (9 mm and 8 mm respectively) tableting machine (Royal Artist, Bombay, India). The force of compression was adjusted so that the hardness is 6 ± 0.5 kg. The composition of the prepared tablets is shown in Table 1.
Tablets characterization
Weight variation
Ten tablets from each formula were weighed individually and the average weight was calculated.
Tablet intactness and friability
The blister molded tablet friability was expressed in terms of percentage pushed through the PVC blister intact (11), whereas directly compressed tablets were tested according to the BP specifications using a tablet friability tester (FAB-2, Logan Instruments Corp., NJ, USA).
Drug content determination