Impact of Drug-Polymer Interaction in Amorphous Solid Dispersion Aiming for the Supersaturation of Poorly Soluble Drug in Biorelevant Medium.

The aim of this study was to investigate the influence of the production method and the polymeric carrier on the ability to generate and maintain the supersaturation of a poorly soluble drug in biorelevant medium. The amorphous solid dispersion of sulfamethoxazole, an antibacterial drug, was produced using two different polymers by spray-drying or hot melt extrusion methods. When Eudragit EPO was used, supersaturation was maintained up to 24 h for both techniques at all drug-polymer proportions. However, when Soluplus was employed in hot melt extrusion, a smaller amount of drug was dissolved when compared to the amorphous drug. The proportion of 3:7 drug-Eudragit EPO (w/w) produced by spray-drying presented a higher amount of drug dissolved in supersaturation studies and it was able to maintain the physical stability under different storage conditions throughout the 90-day evaluation. Supersaturation generation and system stability were found to be related to more effective chemical interaction between the polymer and the drug provided by the production method, as revealed by the 1D ROESY NMR experiment. Investigation of drug-polymer interaction is critical in supersaturating drug delivery systems to avoid crystallization of the drug and to predict the effectiveness of the system. Chemical compounds studied in this article: Sulfamethoxazole (PubChem CID: 4539) and Methacrylate copolymer - Eudragit EPO (PubChem CID: 65358).

Supersaturating drug delivery system of fixed drug combination: sulfamethoxazole and trimethoprim.

Background: The drug supersaturation in the intestinal lumen for few hours could result in high bioavailability. The goal of this study was the development of a supersaturating drug delivery system containing sulfamethoxazole and trimethoprim at fixed dose combination (sulfamethoxazole:trimethoprim 5:1 w/w). Methods: The amorphous solid dispersions were formed at three different proportions containing 30, 50 and 70% of Eudragit EPO in the formulation. Results: The supersaturation state is formed by the amorphous drugs produced by spray drying technique, and the maintenance of this state is due to the chemical interactions between the drugs and the polymer selected, which was observed in the fluorescence interaction studies realized between the drugs and the polymer. The Formulation containing 70% of the polymer was able to produce and maintain the supersaturated state of both drugs for 24 h. Solid state characterization demonstrated the amorphization of the drugs in the solid dispersion and indicated the hydrogen bond formation responsible for the improvement in the apparent solubility. This formulation presented an improved antibacterial activity when compared to the combination of the drugs. Conclusion: For the first time, a supersaturating drug delivery system was developed to the complementary antibacterial drugs. This ternary formulation is a powerful alternative to improve oral absorption of recognized safety drugs, reducing the dose and consequently the antibiotic resistance emergence.

Intestinal permeability determinants of norfloxacin in Ussing chamber model.

Recently, many efforts are taken to identify the intestinal uptake and efflux transporters since they are responsible for the absorption of many drugs as their interactions. Norfloxacin (NFX) is a fluoroquinolone that presents low solubility and low permeability, and as a consequence, low bioavailability. In this context, the aim of this study is evaluate for the first time the intestinal permeability mechanisms of NFX by Ussing chamber model. The low permeation of NFX at low temperature, where the efflux pumps are not active, reveals that NFX permeation is transporter-dependent. The permeation study at different level of intestine demonstrated that NFX passage is in the decrescent order: ileum > jejunum > duodenum > colon, probably attributed to transporters that are expressed differently along the intestinal tract. NFX intestinal flow was evaluated in the presence of many inhibitors and substrates to identify the uptake and efflux transporters implicate in NFX permeability mechanism. It could be observed that BCRP and MRPs are involved in the NFX efflux and PEPT1, PMAT and OCT in the NFX uptake transport. Furthermore, this work revealed that NFX has itself an affinity for OCTN and OATP, demonstrating that NFX could inhibit these transporters and influence the absorption of other drugs. The updated description of NFX intestinal permeability factors could contribute to the development of rational pharmaceutical formulations that could circumvent the efflux problems and consequently improve NFX biopharmaceutical properties and avoid drug-drug interactions.

Cyclodextrin based nanosponge of norfloxacin: Intestinal permeation enhancement and improved antibacterial activity.

Nanosponges are a novel class of hyperbranched cyclodextrin-based nanostructures that exhibits remarkable potential as a drug host system for the improvement in biopharmaceutical properties. This work aims the development of cyclodextrin-based nanosponge of norfloxacin to improve its physicochemical characteristics. ß-cyclodextrin was used as base and diphenyl carbonate as crosslinker agent at different proportions to produce nanosponges that were evaluated by in vitro and in vivo techniques. The proportion cyclodextrin:crosslinker 1:2 M/M was chosen due to its higher encapsulation efficiency (80%), revealing an average diameter size of 40 nm with zeta potential of -19 mV. Norfloxacin-loaded nanosponges exhibited higher passage of norfloxacin in comparison to norfloxacin drug alone by Ussing chamber method. The nanosponge formulation also revealed a mucoadhesive property that could increase norfloxacin absorption thus improving its antibiotic activity in an in vivo sepsis model. Therefore, nanosponges may be suitable carrier of norfloxacin to maximize and facilitate oral absorption.

Liquid chromatographic determination of lumiracoxib in pharmaceutical formulations.

A stability-indicating reversed-phase liquid chromatography (LC) method was developed and validated for the determination of lumiracoxib in pharmaceutical formulations. The LC method was carried out on a Synergi fusion C(18) column (150 mmx4.6mm), maintained at 30 degrees C. The mobile phase was composed of phosphoric acid (25 mM; pH 3.0)/acetonitrile (40:60, v/v), run at a flow rate of 1.0mL/min, and detection at 272nm. The chromatographic separation was obtained within 10 min and it was linear in the concentration range of 10-100 microg/mL (r(2)=0.9999). Validation parameters such as the specificity, linearity, precision, accuracy, and robustness were evaluated, giving results within the acceptable range. Stress studies were carried out and no interference of the degradation products was detected. Moreover, the proposed method was successfully applied for the assay of lumiracoxib in pharmaceutical formulations.

Physico-chemical solid-state characterization of omeprazole sodium: thermal, spectroscopic and crystallinity studies.

The physical characterization of active pharmaceutical substances is crucial to the successful development of the final drug product. The different solid forms and variations in the degree of crystallinity can lead to significantly different physical and chemical properties, including color, morphology, stability, dissolution and bioavailability. In the case of omeprazole sodium (OMS), its chemical structures contain a specific number of water molecules (hydrate). The behavior of pharmaceutical hydrates has become the object of increasing attention over the past decade, primarily due to the potential impact of hydrates on the development process and dosage form performance. The present study was designed to characterize and evaluate the crystallinity of omeprazole sodium, dehydrated omeprazole sodium (DOMS) and omeprazole free base (OM) using a variety of techniques including thermal analysis (thermogravimetry/derivative thermogravimetry (TG/DTG) and differential scanning calorimetry (DSC)), diffuse reflectance infrared Fourier transform (DRIFT) spectroscopy, scanning electron microscopy (SEM) and X-ray powder diffraction (XRPD). Furthermore, an NMR spectroscopy study was also carried out to clarify the conformation and crystal structure.

Development and validation of an RP-HPLC method to quantitate acyclovir in cross-linked chitosan microspheres produced by spray drying.

An accurate, simple, reproducible, and sensitive liquid chromatographic method is developed and validated to quantitate acyclovir (ACV) in cross-linked chitosan microspheres produced by spray drying. The analysis is carried out using a reversed-phase C18 column with UV-vis detection at 254 nm. The mobile phase is diluted with pure water and acetonitrile (95:5 v/v) at a flow-rate of 0.8 mL/min. The parameters used in the validation process are: linearity, range, quantitation limit, detection limit, accuracy, specificity precision, and ruggedness. The retention time of acyclovir is approximately 3.5 min with symmetrical peaks. The linearity in the range of 1-10 microg/mL presents a correlation coefficient of 0.9999. The chitosan and the tripolyphosphate in the formulation do not interfere with the analysis, and the recovery is quantitative. Results are satisfactory, and the method proves to be suitable to quantitate ACV in cross-linked chitosan microspheres.

Development and validation of an HPLC method to quantify camptothecin in polymeric nanocapsule suspensions.

A simple, rapid, and sensitive reversed-phase column high-performance liquid chromatographic method was developed and validated to quantify camptothecin (CPT) in polymeric nanocapsule suspensions. The chromatographic separation was performed on a Supelcosil LC-18 column (15 cm x 4.6 mm id, 5 microm) using a mobile phase consisting of methanol-10 mM KH2PO4 (60 + 40, v/v; pH 2.8) at a flow rate of 1.0 mL/min and ultraviolet detection at 254 nm. The calibration graph was linear from 0.5 to 3.0 microg/mL with a correlation coefficient of 0.9979, and the limit of quantitation was 0.35 microg/mL. The assay recovery ranged from 97.3 to 105.0%. The intraday and interday relative standard deviation values were < 5.0%. The validation results confirmed that the developed method is specific, linear, accurate, and precise for its intended use. The current method was successfully applied to the evaluation of CPT entrapment efficiency and drug content in polymeric nanocapsule suspensions during the early stage of formulation development.

Physicochemical properties and dissolution studies of dexamethasone acetate-beta-cyclodextrin inclusion complexes produced by different methods.

Inclusion complexes between dexamethasone acetate (DMA), a poorly water soluble drug, and beta-cyclodextrin (betaCD) were obtained to improve the solubility and dissolution rate of this drug. Phase-solubility profile indicated that the solubility of DMA was significantly increased in the presence of betaCD (33-fold) and was classified as A(L)-type, indicating the 1:1 stoichiometric inclusion complexes. Solid complexes prepared by different methods (kneading, coevaporation, freeze drying) and physical mixture were characterized by differential scanning calorimetry, thermogravimetry, infrared absorption and optical microscopy. Preparation methods influenced the physicochemical properties of the products. The dissolution profiles of solid complexes were determined and compared with those DMA alone and their physical mixture, in three different mediums: simulated gastric fluid (pH 1.2), simulated intestinal fluid (pH 7.4) and distilled water. The dissolution studies showed that in all mediums DMA presented an incomplete dissolution even in four hours. In contrast, the complexes formed presented a higher dissolution rate in simulated gastric fluid (SGF pH 1.2), which indicate that these have different ionization characteristics. According to the results, the freeze-dried and kneaded products exhibited higher dissolution rates than the drug alone, in all the mediums.