Urinary excretion of ciprofloxacin after administration of extended release tablets in healthy volunteers. Swellable drug-polyelectrolyte matrix versus bilayer tablets.

This paper builds on a previous paper in which new ciprofloxacin extended-release tablets were developed based on a ciprofloxacin-based swellable drug polyelectrolyte matrix (SDPM-CIP). The matrix contains a molecular dispersion of ciprofloxacin ionically bonded to the acidic groups of carbomer, forming the polyelectrolyte-drug complex CB-CIP. This formulation showed that the release profile of the ciprofloxacin bilayer tablets currently commercialised can be achieved with a simpler strategy. Thus, since ciprofloxacin urine concentrations are associated with the clinical cure of urinary tract infections, the goal of this work was to compare the urinary excretion of SDPM-CIP tablets with those of the CIPRO XR® bilayer tablets. A batch of SDPM-CIP tablets was manufactured by the wet granulation method and the CB-CIP ionic complex was obtained in situ. Fasted healthy volunteers received a single oral dose of 500 mg ciprofloxacin of either formulation in a randomised crossover study. Urinary concentrations were assessed by HPLC at intervals up to 36 h. Pharmacokinetic parameters (rate of urinary excretion, maximum urine excretion rate, tmax, area under the curve, amount and percentage of the ciprofloxacin dose excreted in urine) showed no statistical differences between both formulations at any of the time intervals of collection. The processing conditions to obtain SDPM-CIP tablets are easy to scale up since they involve technology currently employed in the pharmaceutical industry and the process is less challenging to implement. In addition, SDPM-CIP tablets met pharmacopoeial quality specifications.

Enhanced bacterial uptake and bactericidal properties of ofloxacin loaded on bioadhesive hydrogels against Pseudomonas aeruginosa.

Carbomer hydrogels 971pNf, 934pNf and 940Nf loaded with ofloxacin were characterized and their antimicrobial properties evaluated. bactericidal profiles show improved efficacy and prolonged activity exhibited by ofloxacin-containing hydrogels against Pseudomonas aeruginosa. Analysis of bactericidal index (BI) values after a short time of drug exposure confirms the higher potency of hydrogels compared with that of ofloxacin. Increased BI values observed after 24 h indicate prolonged action against the microorganisms evaluated. The bacterial uptake of ofloxacin from hydrogels was higher than that obtained with a solution of free ofloxacin in both fluoroquinolone-sensitive and -resistant P. aeruginosa. The improved uptake in fluoroquinolone-resistant isolates was correlated with the viscosity of hydrogels. The performance of hydrogels seems to be related to their bioadhesive properties that allow prolonged contact time and the release of an effective amount of drug close to bacterial cells. Hence, hydrogels could be used in the development of more effective formulations for topical administration of antibiotics. Improved performance of an old antibiotic can preserve the use of new generation fluoroquinolones.

Benzenesulfonamide analogs of fluoroquinolones. Antibacterial activity and QSAR studies.

The structure-activity relationships (SAR) of new antibacterial benzenesulfonamidefluoroquinolones (BSFQs), coming from derivatization of N4-piperazinyl of ciprofloxacin (CIP) were studied. The behavior of the new BSFQ series was similar to the previously norfloxacin (NOR) analogs reported, making possible a quantitative structure-activity relationships (QSAR) analysis of the complete set of BSFQs. The presence of the benzenesulfonylamido (BS) groups shifted the activity of classic antimicrobial fluoroquinolones from being more active against Gram-negative to Gram-positive strains. QSAR studies through Hansch analysis showed a linear correlation of the activity with electronic and steric parameters. Small electron-donor groups would increase the in vitro activity against Gram-positive bacteria. Hydrophobic properties played a minor role when activity is measured as minimum inhibitory concentration (MIC). QSAR analysis also reinforces previous biological findings about the presence of new interactions with target topoisomerases.

Release kinetics and up-take studies of model fluoroquinolones from carbomer hydrogels.

Hydrogels of carbomer (C) loaded with model slightly soluble fluoroquinolone antimicrobials (AMFQ), norfloxacin (I) and ciprofloxacin (II) were prepared to evaluate their physical and delivery properties. Thus, dispersions of 0.25% of C loaded with 0.2-0.5 mol equivalents of AMFQ and 0.2-0.5 mol equivalents of NaOH yielded pseudoplastic hydrogels with a high negative electrokinetic potential and good physical stability. Concentration of AMFQ in the hydrogels was, respectively, 7.2 and 34 times higher than I and II aqueous solubility, indicating a high increase in aqueous compatibility. Release of AMFQ in bicompartimetal Franz type cell occurred by zero order kinetics. Delivery rate constant (k(0)) was five to six times higher as water was replaced by NaCl solution as receptor medium. Release in agar dishes revealed that, even under high dilution, delivery remains modulated. Intestinal absorption flux coefficient in everted rat intestine (k(U)) were measured with reference solutions (RS) of free AMFQ (k(U)(RS) II>k(U)(RS) I) and with hydrogels (H), in which the pattern was reversed since k(U)(H) I>k(U)(H) II. As expected k(U)(H) II was 0.55 times lower than k(U)(RS) II. However, k(U)(H) I was 1.37 times higher than its reference, which cannot be explained from the analysis of k(0) and k(U)(RS) alone. Hydrogels C-AMFQ behave as a reservoir of AMFQ able to deliver it at a constant rate and would be useful to design topical and or systemic dosage forms.

Comparative study of new benzenesulphonamide fluoroquinolones structurally related to ciprofloxacin against selected ciprofloxacin-susceptible and -resistant Gram-positive cocci.

The in vitro activities of benzenesulphonamide fluoroquinolones (BSFQs) I-III, new fluoroquinolones with a p-substituted benzenesulphonyl moiety attached to the C(7) piperazinyl ring of ciprofloxacin, were assessed in comparison with those of N-sulfanilylpiperazinyl fluoroquinolone (NSFQ)-105 and ciprofloxacin for 133 Gram-positive clinical isolates. NSFQ-105 and BSFQ-I were the most active drugs. They were 16- to 64-fold more active than ciprofloxacin against Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis, including ciprofloxacin-resistant strains, and Streptococcus pneumoniae (eight- to 32-fold). A high degree of correlation was found between the MICs of the new compounds and ciprofloxacin for Staphylococcus spp. and E. faecalis. Staphylococci and enterococci exhibit cross-resistance to BSFQs and ciprofloxacin.

Engineering the specificity of antibacterial fluoroquinolones: benzenesulfonamide modifications at C-7 of ciprofloxacin change its primary target in Streptococcus pneumoniae from topoisomerase IV to gyrase.

We have examined the antipneumococcal mechanisms of a series of novel fluoroquinolones that are identical to ciprofloxacin except for the addition of a benzenesulfonylamido group to the C-7 piperazinyl ring. A number of these derivatives displayed enhanced activity against Streptococcus pneumoniae strain 7785, including compound NSFQ-105, bearing a 4-(4-aminophenylsulfonyl)-1-piperazinyl group at C-7, which exhibited an MIC of 0.06 to 0.125 microg/ml compared with a ciprofloxacin MIC of 1 microg/ml. Several complementary approaches established that unlike the case for ciprofloxacin (which targets topoisomerase IV), the increased potency of NSFQ-105 was associated with a target preference for gyrase: (i) parC mutants of strain 7785 that were resistant to ciprofloxacin remained susceptible to NSFQ-105, whereas by contrast, mutants bearing a quinolone resistance mutation in gyrA were four- to eightfold more resistant to NSFQ-105 (MIC of 0.5 microg/ml) but susceptible to ciprofloxacin; (ii) NSFQ-105 selected first-step gyrA mutants (MICs of 0.5 microg/ml) encoding Ser-81-to-Phe or -Tyr mutations, whereas ciprofloxacin selects parC mutants; and (iii) NSFQ-105 was at least eightfold more effective than ciprofloxacin at inhibiting DNA supercoiling by S. pneumoniae gyrase in vitro but was fourfold less active against topoisomerase IV. These data show unequivocally that the C-7 substituent determines not only the potency but also the target preference of fluoroquinolones. The importance of the C-7 substituent in drug-enzyme contacts demonstrated here supports one key postulate of the Shen model of quinolone action.

Formulation of a neutral solution of ciprofloxacin upon complexation with aluminum.

Clear solutions of 0.5 and 1.0% ciprofloxacin (CF) of pH 7.2 were prepared by the addition of aluminum chloride hexahydrate (AlCl3.6H2O) in the molar proportion CF:AlCl3.6H2O (3:1). Minimum inhibitory concentrations (MIC) of these solutions were the same as an equimolar solution of CF.HCl. Solutions exhibited good physical, chemical and microbiological stability and satisfactorily overcame an ocular irritation test on rabbits.

Mode of action of sulfanilyl fluoroquinolones.

The mode of action of sulfanilyl fluoroquinolones (NSFQs) was investigated with NSFQ-104, NSFQ-105, and some structurally related compounds. Evidence arising from interactions with p-aminobenzoic acid and trimethoprim suggested that a sulfonamidelike mechanism of action makes little or no contribution to the in vitro activity of NSFQs. NSFQ-105 showed an activity that inhibits gyrase-catalyzed DNA supercoiling that is similar to the activity of other fluoroquinolones. Also, NSFQ-105 uptake was decreased by the presence of Mg2+ and increased by a lower pH. These results indicate that NSFQs having only one ionizable group could exhibit more favorable kinetics of access to the bacterial cell than zwitterionic fluoroquinolones.

In-vitro activity of new sulphanilil fluoroquinolones against Staphylococcus aureus.

Two new quinolones, NSFQ-104 and NSFQ-105, derivatives of ciprofloxacin and norfloxacin with a 4-(4-aminophenylsulphonyl)-1-piperazinyl at position 7 showed better in-vitro activity against strains of methicillin-susceptible and methicillin-resistant Staphylococcus aureus than ciprofloxacin or norfloxacin. Their in-vitro activity was enhanced at pH 5.5.