Naproxen formulation

Aabakken L, Bjornbeth BA, Hofstad B, Olaussen B, Larsen S, Osnes M. Comparison of the gastrointestinal side effects of naproxen formulated as plain tablets, enteric-coated tablets, or enteric-coated granules in capsules. Scand J Gastroenterol Suppl 1989 163 65-73. 

Palazzini E, Cristofori M, Babbini M. Bioavailability of a new conlrolled-release oral naproxen formulation given widi and without food. IntJ Clin Pharmacol Res (1992) 12,179-84. 

The system developed by personnel at Sanofl uses the Formulogic shell with specific preformulation data on the drug. The system recommends one first-pass clinical capsule formulation with as many subsequent formulations as desired to accommodate an experimental design [24]. An example of a formulation proposed for naproxen at a dose of 500 mg is shown in Table 28.2. In addition to the formulation the system provides advice on the milling of the drug, the process to be used for blending, and details of the capsule shell. 

Bioactive compounds from Blumea gariepina salicin, salicylic acid, tenoxicam, ketorolac, piroxicam, tolmetin, naproxen, flurbiprofin, diclofenac, and ibuprofen in pharmaceutical formulations and biological samples ... 

Slow release formulations are available for tried and tested substances, e.g. ketoprofen and naproxen, if increased duration of effect is needed. 

Naproxen is a naphthylpropionic acid derivative. It is the only NSAID presently marketed as a single enantiomer. Naproxen s free fraction is significantly higher in women than in men, but half-life is similar in both sexes (Table 36-1). Naproxen is effective for the usual rheumatologic indications and is available in a slow-release formulation, as an oral suspension, and over the counter. A topical preparation and an ophthalmic solution are also available. 

Furthermore, in human clinical trials, the time to onset of action of a nanoparticle oral suspension of naproxen reached signiLcant plasma lel Jar( less than 20 min, which was 12-fold fasterthan commercial formulations of larger particle size (Figure 17.11). 

FIGURE 17.11 ln uence of formulation on absorption of naproxen (500 mg) in humans (fed) mean plasma data from clinical trials = 23). Plasma levels of naproxen (mg/mL) are plotted as a function of time (h) where ( ) is Naproxen NanoCrys fedispersion, (0) is Naprox suspension, ancDO is Anapro tablet. 

Davis, S.S., et al. 1986. Gastrointestinal transit of controlled release naproxen tablet formulation. 

The sodium naproxen extended release formulation from Andrx Pharmaceuticals contains a portion of the drug for initial burst release and another portion in the form of a sustained release matrix. Plasma levels of the drug are detected within 30 minutes of dosing, with peak plasma levels occurring at about 5 hours after dosing. 

Flurbiprofen, 100 mg three times daily, is a well-established first-line NSAID providing there is no evidence of vascular closure or scleral destruction on biomicroscopy. Flurbiprofen should provide pain relief within 2 days and improvement in clinical signs within 1 week. Indomethacin SR fiarmulation, 75 mg twice daily, is a well-established second-choice drug when flurbiprofen is not effective but has also been used as first line. NSAIDs that have shown efficacy and are now available in over-the-counter formulations include naproxen, 500 mg twice daily, and ibuprofen, 600 mg four times daily. If a simplified dosing schedule is a consideration, then pirox-icam, 20 mg/day, may be considered. Once effective control is established, a lower maintenance dose may suffice until the scleritis enters remission. To reduce the risk of gastrointestinal side effects, patients should be instructed to take NSAIDs with food or antacids. 

Other drugs studied by Moore et al. include chlorine containing photosensitizers (178), the effect of surfactants on photosensitizers (179), photosensitization by malarial drugs (180), nalidic and oxolinic acids (181), 6-mercaptopurine (182), azathioprine and nitroimidazole (183), 7-methylbenz[c]acridine and related products (184), naproxen, ben-oxaprofen and indomethacin (185), mefloquine (186), sulfamethoxazole and trimethoprim (187), benzydamine (188), photodecomposition of hydrochlorthiazide (189), tetracycline (190), frusemide (191), 6-mercaptopurine (192), 7-methylbenz[c]acridine (193), metronidazole, misonidazole and azathioprine (194), misonidazole and metronidazole (195), benzydamine (196), components in drug formulations (197) and sulfamethoxazole (198,199). 

The generality of TiO -induced photo-oxidation for drug sample solutions was examined by evaluating drug products containing acetaminophen, naproxen, and pseudoephedrine hydrochloride. All formulations were dissolved in their corresponding assay method diluents (Table 14) and placed in clear volumetric flasks. 

Naprelan (naproxen sodium) as a once daily formulation. 

An example of a formulation generated by this system, for the non-steroidal anti-inflammatory drug naproxen, is given in Table 6. This example, as well as others, was considered acceptable by experienced formulators for manufacture and initial stability evaluation. 

Table 6 An example of a hard gelatin capsule formulation for the anti-inflammatory drug naproxen as generated by the system described by Bateman et al.

The 2-arylpropionic acid ( profen ) non-steroidal anti-inflammatory drugs, each of which contains a single chiral center, are formulated as racemic (50 50) mixtures of the S(+)- and R(-)-enantiomers, with the exception of naproxen, which is formulated as the S(- -)-enantiomer. Based on inhibition of cyclooxygenase activity, the S(- -)-enantiomer is the eutomer (more potent enantiomer). These drugs differ markedly in both pharmacodynamic activity and pharmacokinetic behavior and, in addition, enantiomer pharmacokinetics of each drug varies among animal species. After intravenous administration of racemic keto-profen to horses, sheep, and 20-week-old calves and measurement of individual enantiomers in plasma, significant differences between the enantiomers were found in systemic clearance in horses and in both systemic clearance and volume of distribution in sheep... 

The suspension and modified-release tablets produce the usual pattern of adverse effects (SEDA-15,101), although an enteric-coated formulation of naproxen in patients... 

Even rectal and enteric-coated formulations can cause adverse reactions in the upper gastrointestinal tract. In one double-blind, crossover trial, plain naproxen caused fewer gastrointestinal adverse effects than enteric-coated phenylbutazone (Butacote) (24). 

A number of differential scanning calorimetry studies have investigated the compatibility of stearic acid with drugs. Although such laboratory studies have suggested incompatibilities, e.g. with naproxen, they may not necessarily be applicable to formulated products. 

Nuguru KS, Giambattislo D, Al-Ghazawi AK. Evaluation and characterization of spray-dried mannitol as an excipient for direct copression formulations of naproxen sodium. AAPS Pharm Sci 2001 3 Abstract available from http //www.aapspharmsci.CH g/... 

Research was undertaken to develop a controlled release tablet of naproxen using ethylcellulose and both methods of wet granulation and solid dispersion were compared for effectiveness. Naproxen level was kept constant at 16% while ethylcellulose content was varied from 6% to 28% in the formulations. While both methods were successful at producing formulations with drug release profiles of at least 12 hours, the amount of ethylcellulose required to prepare such formulations was 33% less using the solid dispersion method. While none of the formulations released 100% of the drug, a cumulative 88% of naproxen was released from the solid dispersion formulation, compared with 84% from the wet granulation formulation (50). 

For certain substances it is generally accepted that in conventional orcil pharmaceutical formulations they do not cause bioequivalence problems. That is why the MEB does not consider it necessary to perform and submit bioequivalence research for the following 19 substances amoxicilline, dextromethorfan, diazepam, doxycycline, potassiumfenoxymethylpenicillin, flunarizine, indometacine, isosorbide-5-mononitrate, lorazepam, lormetazepam, metoprolol, naproxen, nitrazepam, oxprenolol, paracetamol, pindolol, piroxicam, salbutamol, temazepam. According to the MEB there is enough evidence present in literature to prove that there is no problem with the bioequivalence. 

The 2-arylpropionic acid NSAIDs (the profens ) possess a chiral centre at the carbon atom a to the carboxyl function, and it is known that the activity of these drugs resides in the S(+) [szrasferj-enantiomers while the R(-) [rectus]-enantiomers either have low activity or are inactive (Shen, 1981). The NSAIDs of this subclass are formulated as racemic mixtures containing equal quantities of the two enantiomers, with the exception of naproxen which is commercially... 

Charles, B.G. Mogg, G.A.G Comparative in vitro and in vivo bioavailabDity of naproxen from tablet and caplet formulations. Biopharm.Drug Dispos., 1994, 15, 121-128... 

Cumulative Postsurgical Adhesion Pilot Data with HA/Naproxen Sodium Formulations and Placebos... 

---