Formulation Of Celecoxib Research Articles

English

The purpose of this study was to assess bioequivalence of two marketed formulations of celecoxib capsules in healthy human male volunteers. The study was conducted according to a single dose, randomized sequence, open label, two-period and crossover design. Both test and reference formulations comprised labeled dose of 200 mg celecoxib and were administered to each subject after an overnight fasting on two treatment days separated by one week of washout period. After drug administration, blood samples were collected at predetermined time points for a period of 48 h. Plasma separated from blood was analyzed for celecoxib concentrations using validated reverse phase-high performance liquid chromatographic (RP-HPLC) method. Various pharmacokinetic parameters including Cmax, Tmax, AUC0-t, AUC0-∞, T1/2 and Kel were determined from the plasma concentration for both formulations. Cmax, AUC0-t and AUC0-∞, were evaluated for bioequivalence after log-transformation of data. The 90% confidence intervals for the ratio of Cmax (93.26 to 100.70%), AUC0-t (87.00 to 117.50%) and AUC0-∞ (86.49 to 118.56%), values for the test and reference products were within the acceptance range of 80 to 125%, proposed by Food and Drug Administration (FDA) and European Medicines Evaluation Agency (EMEA). Based on these statistical inferences, it was concluded that two formulations of celecoxib are bioequivalent in their rate and extent of absorption. Key words: Celecoxib, pharmacokinetics, bioequivalence, healthy human male volunteers.

Effect of liposomal celecoxib on proliferation of colon cancer cell and inhibition of DMBA-induced tumor in rat model.

Celecoxib, a selective cyclooxygenase-2 inhibitor, has shown potential anticancerous activity against majority of solid tumors especially on patients with colon cancer. However, associations of serious side effects limit the usage of celecoxib in colon cancer treatment. To address this issue and provide an alternative strategy to increase the efficacy of celecoxib, liposomal formulation of celecoxib was prepared and characterized. Anticancer activity of liposomal celecoxib on colon cancer cell HCT 15 was evaluated in vitro. Furthermore, tumor inhibition efficiency by liposomal celecoxib was studied on 7,12-dimethyl benz(a)anthracene (DMBA)-induced tumor in rat model. In order to elucidate the antioxidant activity of celecoxib-loaded liposomes, antioxidant superoxide dismutase (SOD) generation and lipid peroxide (LPx) formation in both liver and kidney tissues were examined. Characterization of the formed unilamellar liposomes revealed the formation of homogeneous suspension of neutral (empty) or anionic (celecoxib-loaded) liposomes with a well-defined spherical shape which have a mean size of 103.5 nm (empty liposome) and 169 nm (liposomal celecoxib). High-performance liquid chromatography (HPLC) analysis and hemolytic assay demonstrated 46% of celecoxib entrapment efficiency and significantly low hemolysis, respectively. Liposomal celecoxib exhibited dose-dependent cytotoxicity and apoptotic activity against HCT 15 cells which are comparable to free celecoxib. In vivo study demonstrated inhibition of tumor growth. Biochemical analysis of the liposomal celecoxib-treated group significantly inhibited the LPx formation (oxygen-free radicals) and increased the activity of SOD. Our results present the potential of inhibiting colon cancer in vitro and DMBA-induced tumor in rat model in vivo by liposomal celecoxib.

Application of a Biphasic Test for Characterization of In Vitro Drug Release of Immediate Release Formulations of Celecoxib and Its Relevance to In Vivo Absorption

A biphasic in vitro test method was used to examine release profiles of a poorly soluble model drug, celecoxib (CEB), from its immediate release formulations. Three formulations of CEB were investigated in this study, including a commercial Celebrex capsule, a solution formulation (containing cosolvent and surfactant) and a supersaturatable self-emulsifying drug delivery system (S-SEDDS). The biphasic test system consisted of an aqueous buffer and a water-immiscible organic solvent (e.g., octanol) with the use of both USP II and IV apparatuses. The aqueous phase provided a nonsink dissolution medium for CEB, while the octanol phase acted as a sink for CEB partitioning. For comparison, CEB concentration-time profiles of these formulations in the aqueous medium under either a sink condition or a nonsink condition were also explored. CEB release profiles of these formulations observed in the aqueous medium from either the sink condition test, the nonsink condition test, or the biphasic test have little relevance to the pharmacokinetic observations (e.g., AUC, C(max)) in human subjects. In contrast, a rank order correlation among the three CEB formulations is obtained between the in vitro AUC values of CEB from the octanol phase up to t = 2 h and the in vivo mean AUC (or C(max)) values. As the biphasic test permits a rapid removal of drug from the aqueous phase by partitioning into the organic phase, the amount of drug in the organic phase represents the amount of drug accumulated in systemic circulation in vivo. This hypothesis provides the scientific rationale for the rank order relationship among these CEB formulations between their CEB concentrations in the organic phase and the relative AUC or C(max). In addition, the biphasic test method permits differentiation and discrimination of key attributes among the three different CEB formulations. This work demonstrates that the biphasic in vitro test method appears to be useful as a tool in evaluating performance of formulations of poorly water-soluble drugs and to provide potential for establishing an in vitro-in vivo relationship.

Celecoxib-loaded liposomes: effect of cholesterol on encapsulation and in vitro release characteristics

CLX (celecoxib) is a highly hydrophobic non-steroidal anti-inflammatory drug with high plasma protein binding. We describe here the encapsulation of CLX in MLVs (multilamellar vesicles) composed of DSPC (1,2-distearoyl-sn-glycero-3-phosphocholine) and variable amounts of cholesterol. The effects of cholesterol content on liposome size, percentage drug loading and in vitro drug release profiles were investigated. Differential scanning calorimetry and FTIR (Fourier-transform infrared) spectroscopy were used to determine molecular interactions between CLX, cholesterol and DSPC. The phase transition temperature (Tm) of vesicles was reduced in a synergistic manner in the presence of both CLX and cholesterol. Encapsulation efficiency, loading and release of CLX decreased with increasing cholesterol content. FTIR results indicated that this decrease was due to a competition between CLX and cholesterol for the co-operativity region of the phospholipids. In the presence of cholesterol, CLX was pushed further into the hydrophobic core of the bilayer. However, MLVs prepared with DSPC only (without cholesterol) exhibited the lowest ability for drug retention after 72 h. Our results indicated that CLX, without the requirement of modifications to enhance solubilization, can be encapsulated and released from liposomal formulations. This method of drug delivery may be used to circumvent the low bioavailability and systemic side effects of oral CLX formulations.

Safety pharmacological studies on the amorphous formulation of Celecoxib

Safety pharmacological studies on the amorphous formulation of Celecoxib

Development and <i>In vitro</i> Evaluation of Oral Controlled Release Formulations of Celecoxib Using Optimization Techniques

The objective of this study was to develop controlled release matrix embedded formulations of celecoxib (CCX) as candidate drug using hydroxy propyl methyl cellulose (HPMC) and ethyl cellulose (EC), either alone or in combination, using optimization techniques like polynomial method and composite design. This would enable development of controlled release formulations with predictable and better release characteristics in lesser number of trials. Controlled release matrix tablets of CCX were prepared by wet granulation method. The in vitro release rate studies were carried out in USP dissolution apparatus (paddle method) in 900 ml of sodium phosphate buffer (pH 7.4) with 1% v/v tween-80. The in vitro drug release data was suitably transformed and used to develop mathematical models using first order polynomial equation and composite design techniques of optimization. In the formulations prepared using HPMC alone, the release rate decreased as the polymer proportion in the matrix base was increased. Whereas in case of formulations prepared using EC alone, only marginal difference was observed in the release rate upon increasing the polymer proportion. In case of formulations containing combination of HPMC and EC, the release of the drug was found to be dependent on the relative proportions of HPMC and EC used in the tablet matrix. The release of the drug from these formulations was extended up to 21 h indicating they can serve as once daily controlled release formulations for CCX. Mathematical analysis of the release kinetics indicates a near approximate Fickian release character for most of the designed formulations. Mathematical equation developed by transforming the in vitro release data using composite design model showed better correlation between observed and predicted t(50%) (time required for 50% of the drug release) when compared to first order polynomial equation model. The equation thus developed can be used to predict the release characteristics of the drug from matrix embedded formulations depending upon the proportion of HPMC and EC used in the formulation.

Rapid and sensitive spectrofluorimetric method for the estimation of celecoxib and flurbiprofen

In this study new, rapid and sensitive spectrofluorimetric methods for the quantitative estimation of celecoxib and flurbiprofen in pure form and in their pharmaceutical dosage forms were developed. The solvent systems, wavelengths of detection (excitation and emission) were optimized in order to maximize the sensitivity and minimize the cost of analysis for both the drugs. No extraction procedure was employed for analysis of these compounds in their formulation matrix, which reduced the time of sample preparation. The excitation and emission wavelengths were found to be 256 nm and 403 nm respectively for celecoxib in water and 250 nm and 314 nm respectively for flurbiprofen in 1:1 mixture of methanol and 0.1N sulphuric acid. The linear regression equations obtained by least square regression method for fluorescence intensity (FI) and concentration in ng/ml (conc) were FI=1.2874´conc+22.647, for celecoxib; and FI=27.7970´conc+46.049, for flurbiprofen. The limit of detection as per the error propagation theory was found to be 4.97 ng/ml and 0.99 ng/ml for celecoxib and flurbiprofen respectively. The developed methods were successfully employed with high degree of precision and accuracy for the estimation of total drug content in two commercial capsule formulations of celecoxib and two ophthalmic drops of flurbiprofen. The results of analysis were treated statistically, as per International Conference on Harmonization guidelines for validation of analytical procedures, and by recovery studies. It was concluded that developed methods are simple, accurate, sensitive, precise and reproducible and could be applied directly and easily to the pharmaceutical preparations of celecoxib and flurbiprofen.

Formulation and Evaluation of Aerosolized Celecoxib for the Treatment of Lung Cancer

We examined the effect of aerosolized celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, on the in vitro cytotoxicity and apoptotic response of docetaxel against the human lung carcinoma cell lines A549 and H460. A metered dose inhaler (MDI) formulation of celecoxib was prepared and evaluated for its medication delivery and aerodynamic properties. The in vitro cytotoxicity of the aerosolized celecoxib-MDI alone or in combination with docetaxel was assessed using a six-stage viable impactor by a previously established method. The induction of apoptosis was evaluated by morphologic examination (acridine orange and Hoechst staining) and DNA fragmentation. Furthermore, in an attempt to identify molecular targets involved in the anticancer mechanisms of celecoxib and docetaxel, we examined their effect on the expression of an array of markers involved in the COX-2 dependent and independent pathways. The celecoxib-MDI had a medication delivery of 231.3 microg/shot, mass median aerodynamic diameter (MMAD) of 1.4 microm (GSD = 1.9), and respirable fraction of 50.7%. The celecoxib-MDI (2 shots) in combination with docetaxel had cell kills as high as 81.3% and 67.7% in A549 and H460 cells, respectively. Hoechst and acridine orange staining showed an enhanced induction of apoptosis in A549 and H460 cells exposed to aerosolized celecoxib with docetaxel, which was further confirmed by DNA fragmentation. Western blot analysis showed a significant reduction in cPLA2 expression in both A549 and H460 cells treated with the combination of celecoxib with docetaxel. In the COX-2 independent pathway, there was a significant increase in the expression of PPAR-gamma and p53, whereas pro-caspase-3 expression was significantly decreased, which may contribute to the enhanced apoptotic response observed with the combination treatment. Our results suggest that aerosolized celecoxib significantly enhances the in vitro cytotoxicity and apoptotic response of docetaxel against A549 and H460 cells, and this enhanced activity is mediated via alterations in expression of various molecular targets involved in apoptosis.

Celecoxib Incorporated Chitosan Microspheres: In Vitro and In Vivo Evaluation

Recently, considerable interest has been focussed on the use of biodegradable polymers for specialized applications such as controlled release of drug formulations; meanwhile, microsphere drug delivery systems using various kinds of biodegradable polymers have been studied extensively during the past two decades. In the present investigation, it was aimed to prepare microsphere formulations of celecoxib using a natural polymer, chitosan as a carrier for intra-articular administration to extend the retention of the drug in the knee joint. Microsphere formulations were evaluated in vitro for particle size, entrapment efficiency, surface morphology and in vitro drug release. For in vivo studies, 99mTechnetium- labeled glutathione was used as a radiopharmaceutical to demonstrate arthritic lesions by gamma scintigraphy. Evaluation of arthritic lesions post therapy in rats showed a significant difference (P<0.05) in the group treated with celecoxib solution compared to the group treated with celecoxib loaded chitosan microspheres.

Determination of celecoxib in pharmaceutical formulations using UV spectrophotometry and liquid chromatography

A new UV spectrophotometric method (UV method) and a reversed phase liquid chromatographic method (LC method) for the quantitative estimation of celecoxib, a selective COX-2 inhibitor, in pure form and in solid dosage form were developed in the present study. The linear regression equations obtained by least square regression method, were Abs=4.949×10 −2 · Conc. (in μg/ml)+1.110×10 −2 for the UV method and Area under the curve=5.340×10 1 · Conc. (in ng/ml)+3.144×10 2 for the LC method, respectively. The detection limit, as per the error propagation theory, was found to be 0.26 μg/ml and 25 ng/ml, respectively, for the UV and LC methods. The developed methods were employed with a high degree of precision and accuracy for the estimation of total drug content in three commercial capsule formulations of celecoxib. The results of analysis were treated statistically, as per International Conference on Harmonisation (ICH) guidelines for validation of analytical procedures, and by recovery studies. The results were found to be accurate, reproducible and free from interference and better than the earlier reported methods.