Eur J Drug Metab Pharmacokinet. 1998 Apr-Jun;23(2):103-8.
Effect of PEG 4000 on the dissolution rate of naproxen.

Velaz I, Sanchez M, Martin C, Martinez-Oharriz MC.

Dpto. de Quimica Seccion de Quimica-Fisica, Facultad de Ciencias, Universidad de Navarra, Pamplona, Spain.

Naproxen is a nonsteroidal anti-inflammatory drug characterized by its low wettability and poor water solubility. Solid dispersions naproxen:PEG 4000 have been prepared in order to improve the solubility and dissolution rate of the drug, since these factors can be the limiting steps for absorption and bioavailability of poorly soluble drugs. X-ray diffraction analysis, infrared spectroscopy and differential scanning calorimetry detected no physico-chemical interaction between the drug and the inert carrier PEG 4000. The phase diagram of the naproxen-PEG 4000 system produced by DSC and hot stage microscopy is reported. The intrinsic dissolution rate of naproxen is calculated. The dissolution kinetics of solid dispersions prepared by the solvent and melt methods are compared with those of free drug and physical mixture. The studies were carried out at 37 degrees C and pH 1.2 according to the dispersed amount method. The dissolution profiles obtained indicate that a significant dissolution enhancement occurs with solid dispersions in comparison with the physical mixture. In addition, the physical mixture showed a dissolution rate higher than the free drug. Dissolution rate constants were determined by fitting the experimental data to the cube root function, to get straight line plots.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9725465&dopt=Abstract Naproxen Naprosyn





J Auton Pharmacol. 1998 Feb;18(1):31-7.
Contribution of cAMP to the inhibitory effect of non-steroidal anti-inflammatory drugs in rat uterine smooth muscle.

Hidalgo A, Cantabrana B, Perez-Vallina JR.

Departamento de Medicina, Facultad de Medicina, Oviedo, Spain.

1. The effect of the non-steroidal anti-inflammatory drugs naproxen, mefenamic acid, phenylbutazone, piroxicam and tolmetin on the vanadate (0.3 mM)-induced tonic contraction, as well as the modifications of these effects by the G-protein inhibitor pertussis toxin, and the inhibitors of protein kinase A, Rp-cAMPS (Rp-Adenosine 3',5'-cyclic monophosphothioate triethylamine salt) and protein kinase C, H-7 [1(5-isoquinolynilsulfonyl)-2-methyl-piperazine], have been assayed to study the possible nature of intracellular mediators contributing to the inhibitory effects of NSAIDs in rat uterine smooth muscle incubated in medium lacking calcium plus EDTA. The effect of phorbol 12,13-dibutyrate on vanadate contraction and its modification with H-7 has also been examined. 2. Naproxen (6-600 microM), mefenamic acid (6-300 microM), phenylbutazone (6-300 microM), piroxicam (6-600 microM) and tolmetin (6-600 microM) produced concentration-dependent relaxation of vanadate-induced tonic contraction. The potency order, in accordance with their respective IC50 values was: phenylbutazone > or = mefenamic acid > or = naproxen > tolmetin > or = piroxicam. 3. The relaxant effects of naproxen, phenylbutazone, piroxicam and tolmetin were significantly antagonized with pertussis toxin (50 ng ml-1), Rp-cAMPS (100 microM) and H-7 (1 microM). However, the effect of mefenamic acid was unmodified by the three drugs. This suggests that the effect of mefenamic acid and other NSAIDs occur by different mechanisms. 4. Phorbol 12,13-dibutyrate relaxed the vanadate contraction but the maximal relaxation achieved (54.8 +/- 8.3%, n = 4) was lower than those induced with the NSAIDs. On the other hand, H-7 (1 microM) did not modify the relaxant effect of phorbol 12,13-dibutyrate. This suggests that H-7 behaves as a PKA, but not a PKC inhibitor, under the present experimental conditions. 5. The relaxation by naproxen, phenylbutazone, piroxicam and tolmetin is presumably produced by increasing cAMP because the effects of these are antagonized with Rp-cAMPS and H-7, and by pertussis-toxin-sensitive mechanisms.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9728323&dopt=Abstract Naproxen Naprosyn


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Microsphere preparation for naproxen slow release was investigated using two newly prepared biodegradable polyorganophosphazenes, derivatized at the phosphorus atoms with phenylalanine ethyl ester and imidazole at molar ratios of 71/29 and 80/20. The polymers were prepared by substitution of the chloride atoms of polydichlorophosphazene with a phenylalanine ethyl ester-imidazole mixture followed, after 7 or 48 h reaction, by the addition of excess imidazole. Three methods of microsphere preparation have been considered: spray-drying, emulsion/solvent evaporation and emulsion/solvent evaporation-extraction. Microparticles obtained by spray-drying were found to possess a narrow distribution size with a mean diameter of 2-5 microm. Their internal structure consisted of a porous or empty core depending upon the solvent used for the preparation. Furthermore the microspheres prepared with this technique rapidly released the entrapped naproxen independently of the used polymer, the drug loading or the preparation process. On the other hand microspheres prepared by solvent evaporation or solvent evaporation-extraction showed a distribution size ranging between 10 and 100 microm. By the appropriate choice of pH and solvent composition of the external phase, naproxen could be entrapped, in these microspheres, with a yield higher of 80%. The polymer composition dictates the in vitro release rate of naproxen from the particles, which was faster when the microspheres were prepared with the polymer at higher imidazole content. In vivo experiments, carried out by subcutaneous implantation in rats of microspheres prepared by solvent evaporation, demonstrated that a constant level of naproxen in plasma could be maintained up to 400 h at a suitable concentration for antinflammatory activity.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9743444&dopt=Abstract Naproxen Naprosyn





J Clin Pharm Ther. 1998 Feb;23(1):57-65.
Naproxen incorporated lipid emulsions. I. Formulation and stability studies.

Nasirideen S, Kas HS, Oner F, Alpar R, Hincal AA.

Pharmacy Faculty, Pharmaceutical Technology Department, Hacettepe University, Ankara, Turkey.

BACKGROUND: Intravenous lipid emulsions stabilized with phospholipids have been an attractive alternative as vehicles for drug delivery, particularly for the parenteral administration of drugs with solubility problems. METHODS: Naproxen (a poorly aqueous soluble non-steroidal anti-inflammatory agent) emulsions were formulated with different types of emulsifiers (soybean lecithin, synperonic PEF-127 and a 50:50 mixture of these). The stability of the various emulsion systems was evaluated at different temperatures (4, 25 and 40 degrees C) for a period of 6 months by measuring changes in pH, droplet size, viscosity and percentage oil separation. The percentage of naproxen incorporation and the degree of haemolysis induced by the different types of emulsion systems was also determined. RESULTS: The emulsifier type showed a pronounced effect on the physicochemical properties of the emulsion systems, whereas storage temperature and time did not. Irrespective of emulsifier type, storage temperature and time, the percentage incorporation of naproxen in emulsions was between 80 and 100%. The degree of haemolysis induced by other emulsion components (dimethylsulfoxide (DMSO) and naproxen solution in DMSO) was about 10 times higher than that induced by emulsion systems. CONCLUSION: Choice of emulsifier is the most important factor in the stability of the naproxen emulsions.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9756113&dopt=Abstract Naproxen Naprosyn


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The kinetic behaviour of a naproxen human serum albumin conjugate (Nap23-HSA) was investigated in rats and in isolated perfused rat livers (IPRL), as compared to its active metabolite naproxen-lysine (Nap-lysine) and free naproxen. Through covalently linking the anti-inflammatory drug naproxen to HSA, this drug can be selectively delivered to non parenchymal cells of the liver. Liver endothelial and Kupffer cells play an important role in the pathogenesis of inflammatory liver diseases. Targeting naproxen to these cells might increase its efficacy and reduce the side effects. The altered kinetic properties of Nap23-HSA, after i.v. injection of 22 mg x kg(-1), as compared to an equimolar amount of the uncoupled drug, were demonstrated in vivo by a decrease in the steady state volume of distribution (41 +/- 5 vs. 134 +/- 19 ml x kg(-1)), a decrease in its clearance (0.48 +/- 0.05 vs. 0.63 +/- 0.1 ml x min(-1) x kg(-1)), a shorter plasma half life (60 +/- 11 vs. 152 +/- 44 min) and a sustained biliary excretion. Liver targeting of Nap23-HSA was clearly demonstrated: drug content of the liver 180 min after injection was about 30 times higher for Nap23-HSA as compared to naproxen itself. The IPRL experiments showed that the Vmax of hepatic removal of the conjugate was 40 microg x min(-1) x g liver(-1). With doses below receptor saturation a rapid removal of the conjugate (t1/2 = 6 min) from the perfusion medium was found. In conclusion, this study demonstrates the saturable uptake of Nap23-HSA and its lysosomal degradation in both in vivo and IPRL experiments. Covalently linked naproxen is released as Nap-lysine. This active metabolite accumulates in Kupffer and endothelial cells in which it reaches therapeutic concentrations. Release from these cells leads to rapid uptake by hepatocytes and carrier mediated excretion into bile. Levels of Nap-lysine in bile and plasma reflect the slowest step in its generation: the proteolytic release in endothelial and Kupffer cells.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9771615&dopt=Abstract Naproxen Naprosyn





Clin Sci (Lond). 1998 Nov;95(5):603-9.
Renal targeting of a non-steroidal anti-inflammatory drug: effects on renal prostaglandin synthesis in the rat.

Haas M, Moolenaar F, Meijer DK, de Jong PE, de Zeeuw D.

Department of Internal Medicine, Division of Nephrology, Groningen Institute for Drug Studies, University Hospital, Hanzeplein 1, NL-9713 GZ Groningen, The Netherlands.

1.Renal specific targeting of the non-steroidal anti-inflammatory drug naproxen was obtained by coupling to the low-molecular-mass protein lysozyme. A previous study showed that conjugation to lysozyme resulted in a 70-fold increase of naproxen accumulation in the kidney with a subsequent renal release of the active metabolite naproxen-lysine.2.In the present study we questioned whether naproxen-lysozyme is active in the rat kidney, inhibiting the urinary excretion of prostaglandin E2 and renal sodium and water excretion in salt-restricted baseline conditions as well as during frusemide treatment.3.A high dose of free naproxen (10 mg.day-1. kg-1) did not affect prostaglandin E2 excretion in baseline conditions (naproxen, 11+/-1 ng/8 h; vehicle, 13+/-4 ng/8 h), whereas sodium and water excretion were, respectively, 3.0 and 1.6 times lower in the naproxen group (P<0.05). Naproxen completely prevented the frusemide-induced increase (3-fold) in prostaglandin E2 excretion (naproxen 6.6+/-1.1 ng/8 h, vehicle 40+/-12 ng/8 h, P<0. 005). Frusemide-stimulated natriuresis and diuresis were, respectively, 1.6 (P<0.05) and 1.8 times (P<0.005) lower in the naproxen group.4.A dose of 2 mg.day-1.kg-1 lysozyme-conjugated naproxen did not affect prostaglandin E2 excretion in baseline conditions (conjugate, 18+/-2 ng/8 h; vehicle, 24+/-5 ng/8 h). The conjugate also had no effect on sodium and water excretion. However, the naproxen conjugate completely prevented the frusemide-induced increase (2-fold) in prostaglandin E2 excretion (conjugate, 16+/-3 ng/8 h; vehicle, 48+/-13 ng/8 h, P<0.05). Surprisingly, frusemide-induced natriuresis and diuresis were not affected by the conjugate.5.In conclusion, a renal specific delivery of the non-steroidal anti-inflammatory drug naproxen using lysozyme results in an inhibitory effect on renal prostaglandin E2 synthesis but does not affect the excretion of sodium and water, in contrast to free naproxen.

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Analyst. 1998 Jul;123(7):1571-4.
Determination of naproxen with chemiluminescence detection.

Campiglio A.

Department of Pharmaceutical Chemistry, University of Pavia, Italy.

A rapid chemiluminescence method is described for the determination of naproxen, based on the chemiluminescence reaction with cerium(IV) in sulfuric acid medium. The optimum conditions for the chemiluminescence emission were investigated. With the integrated chemiluminescence intensity for 15 s after CeIV injection as a quantitative parameter, naproxen can be determined over the concentration range 100-1000 ng ml-1 with a detection limit of 15 ng ml-1 and with RSDs (n = 10) of 0.9% and 1.5% at levels of 1000 and 100 ng ml-1, respectively. The method was applied to the determination of naproxen in pharmaceutical preparations.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9830168&dopt=Abstract Naproxen Naprosyn