Nimesulide

Nimesulide is a selective Cyclooxygenase - 2 enzyme inhibitor useful in inflammatory conditions. It belongs to class 2 of Biopharmaceutical classification system (BCS), which has very low water solubility leading to low oral bioavailability. The objective of present study was to enhance the solubility and dissolution rate of poorly soluble model drug, nimesulide. For the same purpose, two approaches were used. First approach includes Electrospinning technique, and the second approach is co-grinding technique. In Electrospinning technique, the solution containing drug and polymer (PVP K-90) dissolved in an organic solvent was taken and made in to nanofibers of different drug- polymer ratios (1:1, 1:2, 1:3, 1:4, 1:5) using electro-spinning apparatus. In the co-grinding technique, mixtures with different ratios (1:1, 1:3, 1:5, 1:7, 1:9) of drug and carrier were prepared employing potato starch, lactose, microcrystalline cellulose, sodium starch glycolate and treated agar as carriers. Of the two approaches, nanofibers provided a better solubility enhancement when compared to co-grinding mixtures and pure drug. The optimized formulation (nanofibers) was characterized by Fourier transform infrared spectroscopy (FTIR), Scanning electron microscopy (SEM), Differential scanning calorimetry (DSC) and the in-vitro dissolution rate studies. The optimized nimesulide nanofiber formulation displayed nearly 50- fold faster dissolution compared to the pure drug and the optimized co-ground mixture. It has also shown two to three- fold greater anti-inflammatory activity in Wistar albino rats as compared to pure drug. Hence, nanofibers produced by electrospinning technique provided a scope for enhancing the solubility and dissolution rate by encapsulating poorly water soluble drugs within the polymeric matrix leading to potential bioavailability enhancement through the oral or topical routes.

A simultaneous estimation of RP-HPLC method was developed and validated for the estimation of Nimesulide, Cetrizine and Pseudo ephedrine HCl in tablet dosage form using C18 column (250mm 4.6mm, 5mm) with mobile phase consisting of Methanol: Water (65:35v/v) with a  flow rate of 1.0ml/min (UVdetection 220nm). Linearity was observed over the concentration range 0.1–5 µg/ml (R2=0.996) with regression equation y = 0.501x + 0.043 for Nimesulide and for Cetrizine 0.1–5 µg/mL (R2=0.994) with regression equation y = 0.4519x + 0.1656 and PseudoephidrineHcl 0.1–5 µg/mL (R2=0.997) with regression equation y = 0.3554x + 0.0088. The method was validated as per ICH guidelines.

The purpose of present work was to prepare a nimesulide-loaded liquid suppository using menthol and to study the effects of various penetration enhancers such as neem oil, tulsi oil and ethanol on the cumulative percentage release of nimesulide. The physicochemical properties such as gelation temperature and gel strength of various formulations composed of nimesulide, menthol and poloxamer 188 were investigated. The in vitro study of nimesulide delivered by the liquid suppositories composed of poloxamer 188, menthol and various concentrations of penetration enhancers were performed. The in vitro studies were performed using Keshary-Chein diffusion cell and Small wonder (Lyzer apparatus). The cumulative percentage release of nimesulide of each formulation were calculated and compared with the other formulations. The liquid suppository formulations containing neem oil 2% and tulsi oil 2% showed excellent release rate as compared to other formulations.

An accurate, simple, precise and sensitive HPLC method with UV detection was developed and validated to separate and detect ibuprofen in human plasma using Nimesulide as an internal standard. Ibuprofen and Nimesulide were extracted from human plasma using acetonitrile protein precipitation and HPLC analysis was performed using Waters 515 Series pumps combined with a Waters PDA 2998 series photo diode array detector (DAD). The column used was Agilent C18 column (150mm×4.6mm, particle size 5-micron Agilent, USA). Analysis was isocratic at 1.5 ml/min flow rate with ACN: Buffer (0.025M Potassium dihydrogen ortho phosphate) pH 4.5 (55:45, v/v) as mobile phase. The mobile phase was premixed, filtered through a 0.2 µm nylon membrane filter to remove any particulate matter and degassed by sonication before use. The elution was detected at 230 nm. Each solution was injected in triplicate, and the relative standard deviation (R.S.D.) was measured. The retention times of Ibuprofen 2.24 min and for I.S. 1.72 min respectively. The method was validated over the range of 0.5-8.0 μ/ml. The limit of detection was 0.06μg/ml and the limit of quantification was 0.193μg/ml for ibuprofen. Inter-day as well intra-day replicates of Ibuprofen, gave % R.S.D. below 2.07 and 2.001 respectively  The absolute recovery of ibuprofen was greater than 90% were achieved. This method of analysis for Ibuprofen determination using RP-HPLC was applied for determination of Ibuprofen in plasma.

  Solid dispersion is a widely accepted technique for enhancing the dissolution rate of poorly soluble BCS class II drugs. In the present study starch phosphate- a new modified starch, PVP and PEG 4000 were evaluated as a carriers in solid dispersions for enhancing the dissolution rate and efficiency of nimesulide, a BCS class II drug. Their individual and combined (interaction) effects in enhancing the dissolution rate and dissolution efficiency of nimesulide were evaluated in a 23- factorial study. Among the individual effects PEG 4000 gave highest enhancement in the dissolution rate of nimesulide (14.23 fold), followed by starch phosphate (11.34 fold). Addition of PVP and PEG 4000 to the solid dispersions in starch phosphate has further enhanced the dissolution rate upto 75.70 fold and dissolution efficiency upto 26.67 fold.   Key words: Solid dispersions, Nimesulide, Starch Phosphate, PVP, PEG 4000, Factorial Study.