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David N Criddle - One of the best experts on this subject based on the ideXlab platform.
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comparative inhibitory effects of Niflumic Acid and novel synthetic derivatives on the rat isolated stomach fundus
Journal of Pharmacy and Pharmacology, 2010Co-Authors: David N Criddle, Ana Vanesca P Meireles, Liana B Macedo, Jose Henrique Lealcardoso, H C Scarparo, Mohammed JaffarAbstract:Novel derivatives of 2-[3-(trifluoromethyl)-analino]nicotinic Acid (Niflumic Acid) were synthesized. The compounds were compared for their inhibitory effects on 5-hydroxytryptamine (5-HT)- and KCI-induced contraction of the rat fundus. The aim was to assess structure-activity relationships regarding the selectivity and potency of these compounds. Niflumic Acid (1-100 microM) concentration-dependently inhibited 5-HT-induced tonic contractions with an IC50 value (concentration reducing the control contractile response by 50%, calculated from semi-log graphs) of 0.24 x 10(4) M (n = 9). In contrast, it was significantly less potent at inhibiting KCl-induced responses (IC50 = 1.49 x 10(4) M, n = 9). The methyl ester (NFAme) and amido (NFAm) analogues showed no selectivity between 5-HT- and KCl-induced contractions with IC50 values of 1.64 x 10(-4) M (n = 8) and 1.87 x 10(-4) M (n = 9) for 5-HT responses, and 2.61 x 10(-4) M (n = 8) and 2.55 x 10(-4) M (n = 7) for KCl-induced responses, respectively. Our results suggest that alteration of the carboxylic Acid moiety of Niflumic Acid reduces the selectivity and potency of its inhibitory action on 5-HT-induced contractile responses of the rat fundus, possibly via a reduced interaction with calcium-activated chloride channels.
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selective inhibitory effects of Niflumic Acid on 5 ht induced contraction of the rat isolated stomach fundus
British Journal of Pharmacology, 2000Co-Authors: H C Scarparo, Jose Henrique Lealcardoso, G C M Santos, David N CriddleAbstract:The effects of Niflumic Acid (NFA), an inhibitor of calcium-activated chloride currents I(Cl(Ca)), were compared with the actions of the voltage-dependent calcium channel (VDCC) blocker nifedipine on 5-hydroxtryptamine (5-HT)- and acetylcholine (ACh)-induced contractions of the rat isolated fundus. NFA (1 - 30 microM) elicited a concentration-dependent inhibition of contractions induced by 5-HT (10 microM) with a reduction to 15. 5+/-6.0% of the control value at 30 microM. 1 microM nifedipine reduced 5-HT-induced contraction to 15.2+/-4.9% of the control, an effect not greater in the additional presence of 30 microM NFA. In contrast, the contractile response to ACh (10 microM) was not inhibited by NFA in concentrations /=10 microM. Our results show that NFA can exert selective inhibitory effects on the chloride-dependent 5-HT-induced contractions of the rat fundus. The data support the hypothesis that activation of Cl((Ca)) channels leading to calcium entry via VDCCs is a mechanism utilized by 5-HT, but not by ACh, to elicit contraction of the rat fundus.
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comparative effects of Niflumic Acid and nifedipine on 5 hydroxytryptamine and acetylcholine induced contraction of the rat trachea
European Journal of Pharmacology, 2000Co-Authors: Maria C L Teixeira, Jose Henrique Lealcardoso, Roberta Ribeiro Coelho, David N CriddleAbstract:The effects of Niflumic Acid, an inhibitor of Ca(2+)-activated Cl(-) (Cl((Ca))) channels, were compared with those of the voltage-dependent Ca(2+) channel (VDCC) blocker nifedipine on 5-hydroxytryptamine (5-HT)- and acetylcholine-induced contractions of the rat isolated trachea. Niflumic Acid (3-100 microM) induced a concentration-dependent inhibition of 5-HT (10 microM)-induced contractions, with a reduction to 37.0+/-9.5% of the control at the highest concentration. One micromolar nifedipine, which completely blocked 60 mM KCl-induced contractions, reduced the response to 5-HT similarly to 39.2+/-11.5% of the control. The inhibition of the 5-HT response was not significantly different from that produced by the combined presence of nifedipine (1 microM) and Niflumic Acid (100 microM), suggesting that their effects were not additive. In contrast, neither Niflumic Acid (3-100 microM) nor nifedipine (1 microM) inhibited acetylcholine-induced contractions. The contraction to 5-HT (10 microM) in Cl(-)-free solution was decreased by more than approximately 85% of the control, whilst that of acetylcholine was reduced only by approximately 36%. Our data show that Niflumic Acid exerts selective inhibitory effects on 5-HT-induced contraction, and suggest that activation of Cl((Ca)) channels may be a mechanism whereby 5-HT (but not acetylcholine) induces Ca(2+) entry via VDCCs to elicit contraction.
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Inhibitory action of Niflumic Acid on noradrenaline- and 5-hydroxytryptamine-induced pressor responses in the isolated mesenteric vascular bed of the rat
British Journal of Pharmacology, 1997Co-Authors: David N Criddle, Iain A Greenwood, R. Soares De Moura, W A LargeAbstract:The effects of Niflumic Acid, an inhibitor of calcium-activated chloride currents, were compared with the actions of the calcium channel blocker nifedipine on noradrenaline- and 5-hydroxytryptamine (5-HT)-induced pressor responses of the rat perfused isolated mesenteric vascular bed. Bolus injections of noradrenaline (1 and 10 nmol) increased the perfusion pressure in a dose-dependent manner. Nifedipine (1 μm) inhibited the increase in pressure produced by 1 nmol noradrenaline by 31±5%. Niflumic Acid (10 and 30 μm) also inhibited the noradrenaline-induced increase in perfusion pressure and 30 μm Niflumic Acid reduced the pressor response to 1 nmol noradrenaline by 34±6%. The increases in perfusion elicited by 5-HT (0.3 and 3 nmol) were reduced by Niflumic Acid (10 and 30 μm) in a concentration-dependent manner and 30 μm Niflumic Acid inhibited responses to 0.3 and 3 nmol 5-HT by, respectively, 49±8% and 50±7%. Nifedipine (1 μm) decreased the pressor response to 3 nmol 5-HT by 44±9%. In the presence of a combination of 30 μm Niflumic Acid and 1 μm nifedipine the inhibition of the pressor effects of noradrenaline (10 nmol) and 5-HT (3 nmol) was not significantly greater than with Niflumic Acid (30 μm) alone. Thus the effects of Niflumic Acid and nifedipine were not additive. In Ca-free conditions the transient contractions induced by 5-HT (3 nmol) were not reduced by 30 μm Niflumic Acid, suggesting that this agent does not inhibit calcium release from the intracellular store or the binding of 5-HT to its receptor. Niflumic Acid 30 μm did not inhibit the pressor responses induced by KCl (20 and 60 μmol) which were markedly reduced by 1 μm nifedipine. In addition, 1 μm levcromakalim decreased pressor responses produced by 20 μmol KCl. These data suggest that Niflumic Acid does not block directly calcium channels or activate potassium channels. It is concluded that Niflumic Acid selectively reduces a component of noradrenaline- and 5-HT-induced pressor responses by inhibiting a mechanism which leads to the opening of voltage-gated calcium channels. Our data suggest that the Ca2+-activated chloride conductance may play a pivotal role in the activation of voltage-gated calcium channels in agonist-induced constriction of resistance blood vessels. British Journal of Pharmacology (1997) 120, 813–818; doi:10.1038/sj.bjp.0700981
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effect of Niflumic Acid on noradrenaline induced contractions of the rat aorta
British Journal of Pharmacology, 1996Co-Authors: David N Criddle, Soares R De Moura, Iain A Greenwood, W A LargeAbstract:1. The effects of Niflumic Acid, an inhibitor of calcium-activated chloride channels, were compared with the actions of the calcium channel antagonist nifedipine on noradrenaline-evoked contractions in isolated preparations of the rat aorta. 2. The cumulative concentration-effect curve to noradrenaline (NA) was depressed by both nifedipine and Niflumic Acid in a reversible and concentration-dependent manner. The degree of inhibition of the maximal contractile response to NA (1 microM) produced by 10 microM Niflumic Acid (38%) was similar to the effect of 1 microM nifedipine (39%). 3. Contractions to brief applications (30 s) of 1 microM NA were inhibited by 55% and 62% respectively by 10 microM Niflumic Acid and 1 microM nifedipine. 4. In the presence of 0.1 microM nifedipine, Niflumic Acid (10 microM) produced no further inhibition of the NA-evoked contractions. Thus, the actions of Niflumic Acid and nifedipine were not additive. 5. In Ca-free conditions the transient contraction induced by 1 microM NA was not inhibited by Niflumic Acid (10 microM) and therefore this agent does not reduce the amount of calcium released from the intracellular store or reduce the sensitivity of the contractile apparatus to calcium. 6. Niflumic Acid 10 microM did not inhibit the contractions produced by KCl (up to 120 mM) which were totally blocked by nifedipine. Contractions induced by 25 mM KCl were completely inhibited by 1 microM levcromakalim but were unaffected by Niflumic Acid. 7. It was concluded that Niflumic Acid produces selective inhibition of a component of NA-evoked contraction which is probably mediated by voltage-gated calcium channels. These data are consistent with a model in which NA stimulates a calcium-activated chloride conductance which leads to the opening of voltage-gated calcium channels to produce contraction.
Rita Ambrus - One of the best experts on this subject based on the ideXlab platform.
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electrospun nanofiber based Niflumic Acid capsules with superior physicochemical properties
Journal of Pharmaceutical and Biomedical Analysis, 2019Co-Authors: Norbert Radacsi, Piroska Szaborevesz, Konstantinos P Giapis, George Ovari, Rita AmbrusAbstract:The aim of this study was to assess whether nanofibrous drug mats have potential as delivery systems for poorly water-soluble drugs. Amorphous nanofiber mats from a model poorly water-soluble active pharmaceutical ingredient (API), Niflumic Acid, together with the polymer excipient, polyvinyl pyrrolidine, were prepared by nozzle-free electrospinning. This technique offers a scalable way for drug formulation, and by increasing the surface area of the drug, the dissolution rate and therefore bioavailability of the API can be improved. In this study, both the amount of the dissolved active ingredient and the dissolution kinetics has been improved significantly when the nanofibrous mats were used in the drug formulation. A 15-fold increase in the dissolved amount of the produced amorphous Niflumic Acid nanofiber was observed compared to the dissolved amount of the raw drug within the first 15 minutes. Capsule formulation was made by mixing the electrospun nanofibers with a microcrystalline cellulose filler agent. When comparing the dissolution rate of the capsule formulation on the market with the nanofibrous capsules, a 14-fold increase was observed in the dissolved drug amount within the first 15 minutes.
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analysis of Niflumic Acid prepared by rapid microwave assisted evaporation
Journal of Pharmaceutical and Biomedical Analysis, 2014Co-Authors: Norbert Radacsi, Georgios D Stefanidis, Piroska Szaborevesz, Rita AmbrusAbstract:Evaporative crystallization is widely applied in several industrial processes, including the pharmaceutical industry. Microwave irradiation can significantly speed up solvent evaporation in these crystallization processes, resulting in reduced particle size due to rapid crystallization. A single-mode microwave setup was used for evaporative crystallization of the model active pharmaceutical ingredient, Niflumic Acid, and the polymer, polyvinylpirrolidone (PVP). Production of crystals by microwave irradiation offers a modern way for drug formulation, and by reducing the particle size the dissolution rate and bioavailability of the active pharmaceutical ingredient can be enhanced. In this study, a 2.5-fold increase in the dissolution rate of the produced Niflumic Acid crystals was observed compared to the dissolution rate of the original drug in 120min. When Niflumic Acid was produced together with the PVP in the microwave system, an amorphous solid dispersion was created with particles in the nano-size range, which showed a 5-fold increase in dissolution rate in 120min compared to the dissolution of the crystalline Niflumic Acid samples created by the microwave irradiation in the absence of PVP.
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nanonization of Niflumic Acid by co grinding
Advances in Nanoparticles, 2013Co-Authors: Timea Szunyogh, Rita Ambrus, Piroska SzaboreveszAbstract:The aim of this study was to produce Niflumic Acid nanoparticles without using an organic solvent, in order to achieve an increased rate of dissolution of the final products. Co-grinding with excipients was used to decrease the particle size. Poloxamer 188 (P) and mannitol (M) applied as co-grinding materials stabilized the system, preventing aggregation of the nanocrystals. The morphology and particle size distribution of the products were visualized by using scanning electron microscopy and laser diffraction. The crystalline states of the samples were investigated by differential scanning calorimetry and X-ray powder diffraction. The rate of dissolution of Niflumic Acid was measured with a paddle method from simulated media. It was concluded that the particles produced were in the nanometer range (the mean particle size was ~250 nm) and the nanoparticles maintained their crystallinity during the process. The rate of dissolution of the coground sample was significantly improved.
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biorelevant solubility of poorly soluble drugs rivaroxaban furosemide papaverine and Niflumic Acid
Journal of Pharmaceutical and Biomedical Analysis, 2013Co-Authors: Krisztina Takacsnovak, Rita Ambrus, Vera Szőke, Gergely Volgyi, Peter Horvath, Piroska SzaboreveszAbstract:Abstract In this work the biorelevant solubility of four drugs representing different Acid–base property, wide range of lipohilicity and low aqueous solubility was studied. The equilibrium solubility of rivaroxaban (non-ionizable), furosemide (Acid), papaverine (base) and Niflumic Acid (ampholyte) was determined in simulated gastric fluid (SGF pH 1.2), in simulated intestinal fluid fasted state (FaSSIF pH 6.5) and fed state (FeSSIF pH 5.0) and their corresponding blank buffers at a temperature of 37 °C using saturation shake-flask method. The concentration was measured by optimized HPLC analysis. The solubilizing effect of bile Acid/lipid micelles as additive components of biorelevent media (BRM) is expressed with the solubility ratio (SR: SBRM/Sblank buffer) and the food effect was estimated from SFeSSIF/SFaSSIF coefficient. It was revealed that ionization plays primarily role in solubility of compounds which undergo ionization in BRM. The solubilizing effect in FaSSIF was marginal for the neutral compound (rivaroxaban) and for molecules are anionic at pH 6.5 (furosemide and Niflumic Acid). The higher concentration of solubilizing agents in FeSSIF improved the solubility of papaverine carrying positive charge and Niflumic Acid being partially zwitterionic at pH 5.0.
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analysis of submicron sized Niflumic Acid crystals prepared by electrospray crystallization
Journal of Pharmaceutical and Biomedical Analysis, 2013Co-Authors: Rita Ambrus, Norbert Radacsi, Timea Szunyogh, Joop H. Ter Horst, Antoine E D M Van Der Heijden, Piroska SzaboreveszAbstract:Interest in submicron-sized drug particles has emerged from both laboratory and industrial perspectives in the last decade. Production of crystals in the nano size scale offers a novel way to particles for drug formulation solving formulation problems of drugs with low solubility in class II of the Biopharmaceutical Classification System. In this work Niflumic Acid nanoparticles with a size range of 200-800. nm were produced by the novel crystallization method, electrospray crystallization. Their properties were compared to those from evaporative and anti-solvent crystallizations, using the same organic solvent, acetone. There is a remarkable difference in the product crystal size depending on the applied methods. The size and morphology were analyzed by scanning electron microscopy and laser diffraction. The structure of the samples was investigated using differential scanning calorimetry, Fourier-transformed infrared spectroscopy and X-ray powder diffraction. The particles produced using electrospray crystallization process were probably changing from amorphous to crystalline state after the procedure. © 2012 Elsevier B.V.
Norbert Radacsi - One of the best experts on this subject based on the ideXlab platform.
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electrospun nanofiber based Niflumic Acid capsules with superior physicochemical properties
Journal of Pharmaceutical and Biomedical Analysis, 2019Co-Authors: Norbert Radacsi, Piroska Szaborevesz, Konstantinos P Giapis, George Ovari, Rita AmbrusAbstract:The aim of this study was to assess whether nanofibrous drug mats have potential as delivery systems for poorly water-soluble drugs. Amorphous nanofiber mats from a model poorly water-soluble active pharmaceutical ingredient (API), Niflumic Acid, together with the polymer excipient, polyvinyl pyrrolidine, were prepared by nozzle-free electrospinning. This technique offers a scalable way for drug formulation, and by increasing the surface area of the drug, the dissolution rate and therefore bioavailability of the API can be improved. In this study, both the amount of the dissolved active ingredient and the dissolution kinetics has been improved significantly when the nanofibrous mats were used in the drug formulation. A 15-fold increase in the dissolved amount of the produced amorphous Niflumic Acid nanofiber was observed compared to the dissolved amount of the raw drug within the first 15 minutes. Capsule formulation was made by mixing the electrospun nanofibers with a microcrystalline cellulose filler agent. When comparing the dissolution rate of the capsule formulation on the market with the nanofibrous capsules, a 14-fold increase was observed in the dissolved drug amount within the first 15 minutes.
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Microwave-Assisted Evaporative Crystallization of Niflumic Acid for Particle Size Reduction
2016Co-Authors: Norbert Radacsi, Joop H. Ter Horst, Georgios D StefanidisAbstract:Microwave irradiation can significantly speed up solvent evaporation in crystallization processes, resulting in rapid crystallization and reduced particle size. A single-mode microwave setup was used for evaporative crystallization of the model pharmaceutical compound, Niflumic Acid. Production of crystals by microwave irradiation offers a novel way to particles for drug formulation solving formulation problems of drugs with low solubility and permeability in class II of the Biopharmaceutics Classification System. In this work, Niflumic Acid was produced using microwave irradiation and conventional heating. The final product size, as measured by a particle size analyzer, was reduced when increasing the evaporation rate using microwave irradiation. X-ray diffraction proved that the crystal form after microwave-assisted crystallization remained unchanged
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analysis of Niflumic Acid prepared by rapid microwave assisted evaporation
Journal of Pharmaceutical and Biomedical Analysis, 2014Co-Authors: Norbert Radacsi, Georgios D Stefanidis, Piroska Szaborevesz, Rita AmbrusAbstract:Evaporative crystallization is widely applied in several industrial processes, including the pharmaceutical industry. Microwave irradiation can significantly speed up solvent evaporation in these crystallization processes, resulting in reduced particle size due to rapid crystallization. A single-mode microwave setup was used for evaporative crystallization of the model active pharmaceutical ingredient, Niflumic Acid, and the polymer, polyvinylpirrolidone (PVP). Production of crystals by microwave irradiation offers a modern way for drug formulation, and by reducing the particle size the dissolution rate and bioavailability of the active pharmaceutical ingredient can be enhanced. In this study, a 2.5-fold increase in the dissolution rate of the produced Niflumic Acid crystals was observed compared to the dissolution rate of the original drug in 120min. When Niflumic Acid was produced together with the PVP in the microwave system, an amorphous solid dispersion was created with particles in the nano-size range, which showed a 5-fold increase in dissolution rate in 120min compared to the dissolution of the crystalline Niflumic Acid samples created by the microwave irradiation in the absence of PVP.
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analysis of submicron sized Niflumic Acid crystals prepared by electrospray crystallization
Journal of Pharmaceutical and Biomedical Analysis, 2013Co-Authors: Rita Ambrus, Norbert Radacsi, Timea Szunyogh, Joop H. Ter Horst, Antoine E D M Van Der Heijden, Piroska SzaboreveszAbstract:Interest in submicron-sized drug particles has emerged from both laboratory and industrial perspectives in the last decade. Production of crystals in the nano size scale offers a novel way to particles for drug formulation solving formulation problems of drugs with low solubility in class II of the Biopharmaceutical Classification System. In this work Niflumic Acid nanoparticles with a size range of 200-800. nm were produced by the novel crystallization method, electrospray crystallization. Their properties were compared to those from evaporative and anti-solvent crystallizations, using the same organic solvent, acetone. There is a remarkable difference in the product crystal size depending on the applied methods. The size and morphology were analyzed by scanning electron microscopy and laser diffraction. The structure of the samples was investigated using differential scanning calorimetry, Fourier-transformed infrared spectroscopy and X-ray powder diffraction. The particles produced using electrospray crystallization process were probably changing from amorphous to crystalline state after the procedure. © 2012 Elsevier B.V.
Piroska Szaborevesz - One of the best experts on this subject based on the ideXlab platform.
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electrospun nanofiber based Niflumic Acid capsules with superior physicochemical properties
Journal of Pharmaceutical and Biomedical Analysis, 2019Co-Authors: Norbert Radacsi, Piroska Szaborevesz, Konstantinos P Giapis, George Ovari, Rita AmbrusAbstract:The aim of this study was to assess whether nanofibrous drug mats have potential as delivery systems for poorly water-soluble drugs. Amorphous nanofiber mats from a model poorly water-soluble active pharmaceutical ingredient (API), Niflumic Acid, together with the polymer excipient, polyvinyl pyrrolidine, were prepared by nozzle-free electrospinning. This technique offers a scalable way for drug formulation, and by increasing the surface area of the drug, the dissolution rate and therefore bioavailability of the API can be improved. In this study, both the amount of the dissolved active ingredient and the dissolution kinetics has been improved significantly when the nanofibrous mats were used in the drug formulation. A 15-fold increase in the dissolved amount of the produced amorphous Niflumic Acid nanofiber was observed compared to the dissolved amount of the raw drug within the first 15 minutes. Capsule formulation was made by mixing the electrospun nanofibers with a microcrystalline cellulose filler agent. When comparing the dissolution rate of the capsule formulation on the market with the nanofibrous capsules, a 14-fold increase was observed in the dissolved drug amount within the first 15 minutes.
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analysis of Niflumic Acid prepared by rapid microwave assisted evaporation
Journal of Pharmaceutical and Biomedical Analysis, 2014Co-Authors: Norbert Radacsi, Georgios D Stefanidis, Piroska Szaborevesz, Rita AmbrusAbstract:Evaporative crystallization is widely applied in several industrial processes, including the pharmaceutical industry. Microwave irradiation can significantly speed up solvent evaporation in these crystallization processes, resulting in reduced particle size due to rapid crystallization. A single-mode microwave setup was used for evaporative crystallization of the model active pharmaceutical ingredient, Niflumic Acid, and the polymer, polyvinylpirrolidone (PVP). Production of crystals by microwave irradiation offers a modern way for drug formulation, and by reducing the particle size the dissolution rate and bioavailability of the active pharmaceutical ingredient can be enhanced. In this study, a 2.5-fold increase in the dissolution rate of the produced Niflumic Acid crystals was observed compared to the dissolution rate of the original drug in 120min. When Niflumic Acid was produced together with the PVP in the microwave system, an amorphous solid dispersion was created with particles in the nano-size range, which showed a 5-fold increase in dissolution rate in 120min compared to the dissolution of the crystalline Niflumic Acid samples created by the microwave irradiation in the absence of PVP.
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nanonization of Niflumic Acid by co grinding
Advances in Nanoparticles, 2013Co-Authors: Timea Szunyogh, Rita Ambrus, Piroska SzaboreveszAbstract:The aim of this study was to produce Niflumic Acid nanoparticles without using an organic solvent, in order to achieve an increased rate of dissolution of the final products. Co-grinding with excipients was used to decrease the particle size. Poloxamer 188 (P) and mannitol (M) applied as co-grinding materials stabilized the system, preventing aggregation of the nanocrystals. The morphology and particle size distribution of the products were visualized by using scanning electron microscopy and laser diffraction. The crystalline states of the samples were investigated by differential scanning calorimetry and X-ray powder diffraction. The rate of dissolution of Niflumic Acid was measured with a paddle method from simulated media. It was concluded that the particles produced were in the nanometer range (the mean particle size was ~250 nm) and the nanoparticles maintained their crystallinity during the process. The rate of dissolution of the coground sample was significantly improved.
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biorelevant solubility of poorly soluble drugs rivaroxaban furosemide papaverine and Niflumic Acid
Journal of Pharmaceutical and Biomedical Analysis, 2013Co-Authors: Krisztina Takacsnovak, Rita Ambrus, Vera Szőke, Gergely Volgyi, Peter Horvath, Piroska SzaboreveszAbstract:Abstract In this work the biorelevant solubility of four drugs representing different Acid–base property, wide range of lipohilicity and low aqueous solubility was studied. The equilibrium solubility of rivaroxaban (non-ionizable), furosemide (Acid), papaverine (base) and Niflumic Acid (ampholyte) was determined in simulated gastric fluid (SGF pH 1.2), in simulated intestinal fluid fasted state (FaSSIF pH 6.5) and fed state (FeSSIF pH 5.0) and their corresponding blank buffers at a temperature of 37 °C using saturation shake-flask method. The concentration was measured by optimized HPLC analysis. The solubilizing effect of bile Acid/lipid micelles as additive components of biorelevent media (BRM) is expressed with the solubility ratio (SR: SBRM/Sblank buffer) and the food effect was estimated from SFeSSIF/SFaSSIF coefficient. It was revealed that ionization plays primarily role in solubility of compounds which undergo ionization in BRM. The solubilizing effect in FaSSIF was marginal for the neutral compound (rivaroxaban) and for molecules are anionic at pH 6.5 (furosemide and Niflumic Acid). The higher concentration of solubilizing agents in FeSSIF improved the solubility of papaverine carrying positive charge and Niflumic Acid being partially zwitterionic at pH 5.0.
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analysis of submicron sized Niflumic Acid crystals prepared by electrospray crystallization
Journal of Pharmaceutical and Biomedical Analysis, 2013Co-Authors: Rita Ambrus, Norbert Radacsi, Timea Szunyogh, Joop H. Ter Horst, Antoine E D M Van Der Heijden, Piroska SzaboreveszAbstract:Interest in submicron-sized drug particles has emerged from both laboratory and industrial perspectives in the last decade. Production of crystals in the nano size scale offers a novel way to particles for drug formulation solving formulation problems of drugs with low solubility in class II of the Biopharmaceutical Classification System. In this work Niflumic Acid nanoparticles with a size range of 200-800. nm were produced by the novel crystallization method, electrospray crystallization. Their properties were compared to those from evaporative and anti-solvent crystallizations, using the same organic solvent, acetone. There is a remarkable difference in the product crystal size depending on the applied methods. The size and morphology were analyzed by scanning electron microscopy and laser diffraction. The structure of the samples was investigated using differential scanning calorimetry, Fourier-transformed infrared spectroscopy and X-ray powder diffraction. The particles produced using electrospray crystallization process were probably changing from amorphous to crystalline state after the procedure. © 2012 Elsevier B.V.
Hidetaka Kamimura - One of the best experts on this subject based on the ideXlab platform.
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identification of human udp glucuronosyltransferase responsible for the glucuronidation of Niflumic Acid in human liver
Pharmaceutical Research, 2006Co-Authors: Yuji Mano, Takashi Usui, Hidetaka KamimuraAbstract:To assess the uridine diphosphate (UDP)-glucuronosyltransferase (UGT) isozymes involved in the glucuronidation of Niflumic Acid in human liver. The glucuronidation activity of Niflumic Acid was determined in liver microsomes and recombinant UGT isozymes by incubation of Niflumic Acid with UDP-glucuronic Acid (UDPGA). Incubation of Niflumic Acid with liver microsomes and UDPGA produced one peak, which was identified as a glucuronide from mass spectrometric analysis. A study involving a panel of recombinant human UGT isozymes showed that glucuronidation activity was highest in UGT1A1 among the isozymes investigated. The glucuronidation in human liver microsomes (HLMs) followed Michaelis-Menten kinetics with a Km value of 16 μM, which is similar to that found with recombinant UGT1A1. The glucuronidation activity of Niflumic Acid in microsomes from eight human livers significantly correlated with UGT1A1-catalyzed estradiol 3β-glucuronidation activity (r=0.78, p<0.05). β-Estradiol inhibited Niflumic Acid glucuronidation with an IC50 of 25 μM in HLMs, comparable to that for UGT1A1. These findings indicate that UGT1A1 is the main isozyme involved in the glucuronidation of Niflumic Acid in the human liver.
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in vitro inhibitory effects of non steroidal anti inflammatory drugs on 4 methylumbelliferone glucuronidation in recombinant human udp glucuronosyltransferase 1a9 potent inhibition by Niflumic Acid
Biopharmaceutics & Drug Disposition, 2006Co-Authors: Yuji Mano, Takashi Usui, Hidetaka KamimuraAbstract:The inhibitory potencies of non-steroidal anti-inflammatory drugs (NSAIDs) on UDP-glucuronosyltransferase (UGT) 1A9 activity were investigated in recombinant human UGT1A9 using 4-methylumbelliferone (4-MU) as a substrate for glucuronidation. 4-MU glucuronidation (4-MUG) showed Michaelis-Menten kinetics with a Km value of 6.7 µM. The inhibitory effects of the following seven NSAIDs were investigated: acetaminophen, diclofenac, diflunisal, indomethacin, ketoprofen, naproxen and Niflumic Acid. Niflumic Acid had the most potent inhibitory effect on 4-MUG with an IC50 value of 0.0341 µM. The IC50 values of diflunisal, diclofenac and indomethacin were 1.31, 24.2, and 34.1 µM, respectively, while acetaminophen, ketoprofen and naproxen showed less potent inhibition. Niflumic Acid, diflunisal, diclofenac and indomethacin inhibited 4-MUG competitively with Ki values of 0.0275, 0.710, 53.3 and 69.9 µM, respectively, being similar to each IC50 value. In conclusion, of the seven NSAIDs investigated, Niflumic Acid was the most potent inhibitor of recombinant UGT1A9 via 4-MUG in a competitive manner. Copyright © 2005 John Wiley & Sons, Ltd.