Fawaz

Physicochemical characterization and dissolution of norfloxacin/cyclodextrin inclusion compounds and PEG solid dispersions

Abstract Increase in the poor water solubility and dissolution rate of norfloxacin was studied. Two systems were used: solid dispersion with PEG 6000 prepared using the fusion method and inclusion complexes with cyclodextrins (β-cyclodextrin and HP-β-cyclodextrin) obtained by freeze-drying. IR spectrophotometry, X-ray diffractometry, and differential scanning calorimetry showed differences between norfloxacin/cyclodextrin complexes and their corresponding physical mixtures, but not between norfloxacin/PEG 6000 solid dispersions and their corresponding physical mixtures. The solubility and dissolution rate of norfloxacin were significantly increased with PEG solid dispersions and cyclodextrin complexes as well as with norfloxacin-CD physical mixtures. However, enhancement was not statistically different either among various cyclodextrin complexes, or between solid dispersions and cyclodextrin complexes.

Influence of Poly(DL-Lactide) Nanocapsules on the Biliary Clearance and Enterohepatic Circulation of Indomethacin in the Rabbit

Following intravenous administration, the uptake of colloidal drug carriers by cells of the mononuclear phagocyte system, mainly the Kuppfer cells, may concentrate an encapsulated drug close to the liver parenchymal cells and facilitate its biliary excretion and enterohepatic circulation. To test this hypothesis indomethacin was administered (10 mg/kg) in four groups of 10 rabbits each by intravenous infusion at a constant rate over 2 hr, either in its free form (aqueous solution) or as nanocapsules prepared from preformed poly(DL-lactide). Unchanged drug was assayed in plasma of the two control (sham-operated) groups and in both plasma and bile of the two bile-cannulated groups. Pharmacokinetic analysis led to the conclusion that the uptake of nanocapsules by liver macrophages reduces the concentration of the drug by enhancing its total clearance. This enhancement was due to an increase in biliary clearance, as a result of parallel increases in bile concentration and biliary excretion of the drug. It was also demonstrated that nanocapsules enhance the enterohepatic circulation of indomethacin.

Bioavailability of norfloxacin from PEG 6000 solid dispersion and cyclodextrin inclusion complexes in rabbits

Abstract A comparative bioavailability study was carried out in rabbits on pure powder of norfloxacin and its formulations: aqueous solution, polyethyleneglycol 6000 solid dispersions (PEG 6000 SD), beta-cyclodextrin (β-CD) and hydroxy-propyl-beta cyclodextrin (HP-β-CD) complexes. Norfloxacin plasma concentrations were measured by HPLC method with a fluorimetric detection. Estimation of t 1 2 and ke proved that PEG 6000 SD and CD complexes did not modify the elimination characteristics of norfloxacin. Data from plasma concentration profiles indicated that absorption of norfloxacin from of SD and inclusion complexes was markedly accelerated when compared with powder of pure drug. The extent of absorption was significantly smaller with powder of norfloxacin than with its formulations. Bioavailability was improved and significantly higher with CD and complexes SD than with powder, but the improvement was lower than expected.

Ciproflexacin-loaded polyisobutylcyanoacrylate nanoparticles: Preparation and characterization

Abstract Experimental conditions for attachment of ciprofloxacin hydrochloride to poly(isobutylcyanoacrylate) (PIBCA) nanoparticles (NP) and release of drug were studied. Attachment of the drug was performed by the incorporative and adsorptive processes. The pH, and to a lesser degree the drug concentration in the reaction medium, were shown to be important factors in controlling the size of NP only in the incorporative process. The diameter of NP increased when the initial drug concentration was higher than 1.2 mg/ml. Ciproflaxacin content of NP was influenced by the drug concentration in the polymerization and incubation media. The binding capacity in the adsorptive process was not influenced by the pH. In contrast, the entrapment of ciprofloxacin in the NP by incorporation was greatly influenced by the pH in the range 1.5-4. Thin layer chromatography (TLC) of NP prepared by incorporation showed new products suggesting interactions between ciprofloxacin and isobutylcyanoacrylate. Ciprofloxacin release from nanoparticles prepared by the incorporating process was found to be slower as compared to nanoparticles produced by adsorptive process from which the drug release was practically complete within 1 h in absence of esterases in the release medium. Drug release from the two types of NP was accelerated in the presence of esterases in the release medium.

Rutoside decreases human macrophage-derived inflammatory mediators and improves clinical signs in adjuvant-induced arthritis.

BackgroundDietary flavonols may play an important role in the adjunct therapy of chronic inflammation. The availability of therapeutic formulations of pentahydroxyflavone glycoside, rutoside (RU), led us to investigate the ability of this molecule to modulate the release of various proinflammatory mediators from human activated macrophages in vitro and to ameliorate arthritic markers in a rat model.MethodsRU was added simultaneously to human macrophages during their activation. Cells were then analyzed for inflammation-related gene expression using a specific array, and cell supernatants were collected to measure inflammatory mediators. RU was also injected into adjuvant-induced arthritic rats, and disease progression and body weight were evaluated until 50 days after injection. Sera and peritoneal macrophages were also collected to quantify the RU effect on various inflammatory markers.ResultsRU inhibited inflammation-related gene expression in activated human macrophages and the release of nitric oxide, tumor necrosis factor-alpha, interleukin (IL)-1, and IL-6 from these cells. In a rat model, RU inhibited clinical signs of chronic arthritis, correlating with decreased levels of inflammatory cytokines detected in rat sera and macrophage supernatants.ConclusionThus, RU may have clinical value in reducing inflammatory manifestations in human arthritis and other inflammatory diseases.

Ciprofloxacin-loaded polyisobutylcyanoacrylate nanoparticles: pharmacokinetics and in vitro antimicrobial activity

Abstract The disposition of ciprofloxacin in free form and loaded PIBCA/NP has been studied after intravenous infusion to the rabbit. Data from plasma concentration profiles revealed that pharmacokinetic parameters of ciprofloxacin associated with the colloidal carrier were greatly modified. Thus, ciprofloxacin-loaded PIBCA/NP led to increased AUC, t1/2 and Vd, and to a decreased Cl as compared with drug in solution. This could be due not only to the colloidal drug carrier but also to the pharmacokinetics of ciprofloxacin itself. Studies of efficacy against Mycobacterium avium complex in human macrophages proved that ciprofloxacin-loaded PIBCA/NP was more effective than free drug. The cytotoxicity of the polymeric material was observed at concentrations higher than 80 μg of PIBCA per ml with drastic reduction of viable macrophages. This may explain why the efficacy of ciprofloxacin associated with nanoparticles was much lower than expected.

The initial pharmaceutical development of an artesunate/amodiaquine oral formulation for the treatment of malaria: a public-private partnership

BackgroundArtemisinin-based combination therapy is currently recommended worldwide for the treatment of uncomplicated malaria. Fixed-dose combinations are preferred as they favour compliance. This paper reports on the initial phases of the pharmaceutical development of an artesunate-amodiaquine (ASAQ) bilayer co-formulation tablet, undertaken following pre-formulation studies by a network of scientists and industrials from institutions of both industrialized and low income countries.MethodsPharmaceutical development was performed by a research laboratory at the University Bordeaux Segalen, School of Pharmacy, for feasibility and early stability studies of various drug formulations, further transferred to a company specialized in pharmaceutical development, and then provided to another company for clinical batch manufacturing. The work was conducted by a regional public-private not-for-profit network (TropiVal) within a larger Public Private partnership (the FACT project), set up by WHO/TDR, Médecins Sans Frontières and the Drugs for Neglected Disease initiative (DNDi).ResultsThe main pharmaceutical goal was to combine in a solid oral form two incompatible active principles while preventing artesunate degradation under tropical conditions. Several options were attempted and failed to provide satisfactory stability results: incorporating artesunate in the external phase of the tablets, adding a pH regulator, alcoholic wet granulation, dry granulation, addition of an hydrophobic agent, tablet manufacturing in controlled conditions. However, long-term stability could be achieved, in experimental batches under GMP conditions, by physical separation of artesunate and amodiaquine in a bilayer co-formulation tablet in alu-alu blisters. Conduction of the workplan was monitored by DNDi.ConclusionsCollaborations between research and industrial groups greatly accelerated the process of development of the bi-layered ASAQ tablet. Lack of public funding was the main obstacle hampering the development process, and no intellectual property right was claimed. This approach resulted in a rapid technology transfer to the drug company Sanofi-Aventis, finalizing the process of development, registration and WHO pre-qualification of the fixed-dose co-formulation together with DNDi. The bi-layered tablet is made available under the names of Coarsucam® and Artesunate amodiaquine Winthrop®, Sanofi-Aventis. The issue related to the difficulty of public institutions to valorise their participation in such initiative by lack of priority and funding of applied research is discussed.

Disposition and protective effect against irritation after intravenous and rectal administration of indomethacin loaded nanocapsules to rabbits

Abstract Indomethacin loaded poly(D,L-lactide) nanocapsules (PLA-NCs) were investigated after intravenous and rectal administration to rabbits. A rebound of indomethacin plasma concentrations attributed to enterohepatic circulation of indomethacin was observed with all preparations. Following i.v. infusions, results showed that PLA-NCs altered the pharmacokinetics of indomethacin in ways that accelerate the extravascular distribution by enhancing the capture of the colloidal carrier by the liver and, at the same time, modifying the elimination rate of indomethacin. After rectal administration of indomethacin formulations, drug plasma concentration profiles revealed that absorption was more complete and more progressive with nanocapsules than with solution. T max had nearly the same value for all formulations, and bioavailability of indomethacin by this route was increased by nanoencapsulation. The terminal half-life of indomethacin was significantly lower when the drug was given by the rectal route either in solution by PLA-NCs, as compared to suppository. PLA-NCs exhibited a protective effect against the rectal irritability of indomethacin which can be attributed to the reduction of direct contact of free indomethacin with rectal mucosa.

Improvement of norfloxacin oral bioavailability by EDTA and sodium caprate

The EDTA and sodium caprate (Na caprate) effects on the oral bioavailability of norfloxacin were tested. It was found that absorption kinetic of norfloxacin was markedly accelerated when mixed with EDTA or Na caprate in a ratio of 1:1. When mixed with the absorption enhancers in a ratio of 1:5, only Na caprate improved norfloxacin bioavailability significantly. In vitro dissolution tests demonstrated that EDTA and Na caprate increased norfloxacin dissolution kinetic. However, the correlation between bioavailability and in vitro dissolution improvement was not clearly established. So, we can conclude that the solubilizing property of EDTA and Na caprate did not take a prominent part in norfloxacin absorption.

Investigation of porous graphitic carbon at high-temperature liquid chromatography with evaporative light scattering detection for the analysis of the drug combination artesunate—Azithromycin for the treatment of severe malaria

Artesunate combined therapies represent the best option for the treatment of malaria and require the development of new methods of analysis. Retention, selectivity and detection with high-temperature liquid chromatography-porous graphitic carbon-evaporative light scattering detection was studied for artesunate and azithromycin separation. Organic solvent, concentration of organic modifiers, temperature and flow rate were all relevant parameters to optimize this separation. The behaviour of artesunate in the tested conditions appeared close to a neutral compound. In CH(3)OH, only azithromycin retention was dramatically altered depending on the [triethylamine]/[formic acid] ratio and on the temperature, whereas in CH(3)CN, azithromycin, artesunate, artemisinin and dihydroartemisinin retentions decreased with the temperature increase whatever the organic modifier ratio. The best efficiency was obtained with CH(3)CN. 25% variation of the concentration values of the organic modifiers did not significantly influenced the retention. The sensitivity of ELSD increased with the flow rate decrease. Peak area and S/N ratio dramatically decreased with the flow rate increase by 10- and 5-fold for artesunate and azithromycin, respectively. Non-linear calibration curves were obtained for both artesunate and azithromycin.