Luana Perioli

Intercalation compounds of hydrotalcite-like anionic clays with antiinflammatory agents — I. Intercalation and in vitro release of ibuprofen

Hydrotalcite-like compounds are layered solids having positively charged layers and interlayer charge-compensating anions. The synthetic Mg0.67Al0.33(OH)2 Cl0.33.0.6H2O, which is biocompatible, has been used to intercalate a model drug, ibuprofen, in order to prepare a modified release formulation. The intercalation compound was prepared via ion-exchange starting from the chloride form of hydrotalcite and its composition, determined both by elemental microanalysis and thermogravimetric analysis, was Mg0.67Al0.33(OH)2IBU0.33.0.47H2O, drug content 50% (w/w). As a consequence of the intercalation, the interlayer distance of the host increased from 0.78 nm (interlayer distance of chloride form) to 2.17 nm. The result of dissolution tests at pH 7.5 showed that the in vitro drug release was modified if compared with that obtained with comparative formulations. The mechanism of modified drug release has been interpreted on the basis of the ion exchange process of the ibuprofen anion intercalated in the lamellar host and phosphates contained in the intestinal fluid buffer.

Intercalation compounds of hydrotalcite-like anionic clays with anti-inflammatory agents, II: Uptake of diclofenac for a controlled release formulation

The purpose of this study was to investigate whether hydrotalcite is able to intercalate diclofenac, a nonsteroidal anti-inflammatory drug, and release it in a controlled manner. Layered Mg−Al hydrotalcite in the chloride form was used as a host, and the intercalation compound was prepared by Cl−/diclofenac anionic exchange. Drug release from the intercalation compound was performed in vitro in simulated intestinal fluid at pH 7.5 according to USP 24 and in a pH 7.0 solution designed to mimic the ionic conditions of the small intestine. Results from the intercalation process show that hydrotalcite is able to intercalate diclofenac with a simple procedure and with a good drug loading (55% wt/wt). The in vitro drug release was remarkably lower than that from the corresponding physical mixture at both pH 7.5 and pH 7.0. In the latter case, the release was not complete at 24 hours. The kinetic analysis shows the importance of the diffusion through the particle in controlling the drug release rate. The obtained results show that hydrotalcite may be used to prepare modified release formulations.

Ketoprofen poly(lactide-co-glycolide) physical interaction

The aim of this work was to provide an understanding of the interaction occurring between ketoprofen and poly(lacticco-glycodic acid) (PLGA) that leads to polymer plasticization. Experimental glass transition temperature (Tg) values were fitted with the theoretical ones predicted by the Fox and Gordon-Taylor/Kelley-Bueche equations. PLGA films containing different amounts of ketoprofen (KET) were prepared by solvent casting and characterized by scanning electron microscopy, differential scanning calorimetry, and Fourier transform infrared spectroscopy (FTIR). Differential scanning calorimetry evidenced that KET acted as a plasticizer in a similar biphasic way in both end-capped and uncapped PLGA. At KET contents of 20% to 35%, depending on the investigated polymer, the Tg was around 23°C. Higher KET amounts did not lower further the Tg, and the excess of drug was found to crystallize into the polymeric matrix. Experimental Tgs deviated negatively from the predicted ones probably because of hydrogen bonding. The FTIR spectra of the films, loaded with different amounts of KET, showed a shift to higher wavenumbers for the peaks at 1697 and 1655 cm−1 confirming the presence of some interactions, probably hydrogen bonds between the ketoprofen carboxylic group and the PLGA carbonyl groups along the polymer backbone. The hydrogen bonding between KET and PLGA is probably responsible for KET plasticizing effect. KET behaving as a lubricant may disrupt polymer chain-chain interactions, removing additional barriers to bond rotation and chain mobility.

Mucoadhesive bilayered tablets for buccal sustained release of flurbiprofen

The aim of this work was the design of sustained-release mucoadhesive bilayered tablets, using mixtures of mucoadhesive polymers and an inorganic matrix (hydrotalcite), for the topical administration of flurbiprofen in the oral cavity. The first layer, responsible for the tablet retention on the mucosa, was prepared by compression of a cellulose derivative and polyacrylic derivative blend. The second layer, responsible for buccal drug delivery, was obtained by compression of a mixture of the same (first layer) mucoadhesive polymers and hydrotalcite containing flurbiprofen. Nonmedicated tablets were evaluated in terms of swelling, mucosal adhesion, and organoleptic characteristics; in vitro and in vivo release studies of flurbiprofen-loaded tablets were performed as well.The best results were obtained from the tablets containing 20 mg of flurbiprofen, which allowed a good anti-inflammatory sustained release in the buccal cavity for 12 hours, ensuring efficacious salivary concentrations, and led to no irritation. This mucoadhesive formulation offers many advantages over buccal lozenges because it allows for reduction in daily administrations and daily drug dosage and is suitable for the treatment of irritation, pain, and discomfort associated with gingivitis, sore throats, laryngopharyngitis, cold, and periodontal surgery. Moreover, it adheres well to the gum and is simple to apply, which means that patient compliance is improved.

Novel composite microparticles for protein stabilization and delivery

The aim of this work was to develop a novel composite alginate/poly(lactic-co-glycolic) acid microparticulate system for protein stabilization and delivery using bovine insulin as model drug. Alginate particles, prepared by ionic gelation, were embedded into PLGA microparticles using the solvent diffusion evaporation technique. Actual loading was determined by micro-BCA protein assay for total insulin and by reversed phase-high performance liquid chromatography for soluble insulin. Insulin loaded composite microparticles showed reproducible encapsulation efficiency with a higher soluble insulin content when compared to conventional microparticles. Bovine insulin in vitro release studies and adsorption behavior were investigated in 10 mM glycine buffer (pH 2.8) at 37 degrees C. The stability of bovine insulin, solubilized in the above mentioned buffer, was studied as well. In this case, bovine insulin showed to be instable at the investigated conditions and 55% of insulin was lost after 7 days. However, composite microparticle release, characterized by a low burst effect, lasted up to 4 months. Moreover, no significant peptide adsorption on blank PLGA or blank composite microparticles was observed while, a strong interaction between alginate particles and bovine insulin was detected.

Chitosan and a modified chitosan as agents to improve performances of mucoadhesive vaginal gels.

New mucoadhesive formulations were designed and studied in order to improve local vaginal therapy by increasing formulation retention prolonging thus drug-mucosa contact time. Some gels were prepared using hydroxyethylcellulose (HEC) alone or mixed with chitosan (CS) or its derivative 5-methyl-pyrrolidinone-chitosan (MPCS) and were loaded with the antibacterial metronidazole (MET) (0.75%). All formulations showed pseudoplastic flow and viscosity increase was observed proportionally to chitosan content (CS>MPCS). Prepared gels showed better extrusion properties (yield stress) than market formulation Zidoval. Mucoadhesion force studies permitted to point out that: (i) CS decreases mucoadhesion force; (ii) MPCS addition increases the mucoadhesion force at high percentage; (iii) all gels containing chitosan showed better mucoadhesive performances than Zidoval. Gels containing MPCS showed higher and faster drug release than those containing CS. All the preparations were able to release higher drug amounts if compared to market formulation. In conclusion MPCS improved gel characteristics in terms of mucoadhesion force, rheological behaviour and drug release pointing out that this modified chitosan is very suitable to obtain manageable and more acceptable vaginal formulation.

FG90 chitosan as a new polymer for metronidazole mucoadhesive tablets for vaginal administration.

Topical administration of the antibacterial metronidazole (MET) represents the most common therapy in the treatment of bacterial vaginosis (BV). The formulations generally available for BV therapy are creams, gels, vaginal lavages and vaginal suppositories. In this study, a new dosage form, containing MET, was developed with the aim to realize vaginal mucoadhesive tablets by including bioadhesive polymers as chitosan (FG90C), polyvinylpyrrolidone (PVPK90) and polycarbophil (PCPAA1), blended in different ratios. All formulations were characterized by studies of DSC, friability, hardness, hydration, mucoadhesion, in vitro release and antibacterial activity. All polymer mixtures employed were used to prepare tablets with the compactness and hardness so as allow the application on vaginal mucosa. FG90C performances improved in particular when mixed to PVPK90 (1:1 ratio). This kind of delivery system is suitable for formulating MET for topical application representing a good alternative to traditional dosage forms for vaginal topical administration.

Synthesis of some new 1,4-benzothiazine and 1,5-benzothiazepine tricyclic derivatives with structural analogy with TIBO and their screening for anti-HIV activity#

Abstract Several new tricyclic derivatives with structural analogy to TIBO were prepared starting from properly substituted 1,4-benzothiazines and 1,5-benzothiazepine. All synthesized compounds were submitted to screenings for in vitro anti-HIV-1 activity. Only two compounds showed moderate activity.

Use of SBA-15 for furosemide oral delivery enhancement

The objective of this research was to realize a new oral solid dosage form in order to improve the release of furosemide (FURO) in its preferential absorption region. In fact FURO is a drug labeled in class IV of the Biopharmaceutical Classification System (BCS) characterized by low and variable bioavailability due to both low solubility and low permeability and because of its weakly acid nature is preferentially absorbed in the stomach whereas its solubility is hampered. FURO was included in the mesoporous silica material SBA-15 obtaining an inorganic-organic compound fully characterized by: thermogravimetric analysis (TGA), X-ray Powder Diffraction (XRPD), Differential Scanning Calorimetry (DSC), Fourier Transform Infrared Spectroscopy (FT-IR) and nitrogen adsorption-desorption analysis and then submitted to in vitro dissolution. The results showed a remarkable dissolution rate improvement in comparison to the crystalline drug and to the marketed product Lasix®. The inclusion product was also submitted to physical stability studies that revealed the matrix ability to prevent re-organization in crystal nucleus of the drug molecules.

Effect of gliclazide immobilization into layered double hydroxide on drug release.

This paper deals with a new hydrotalcite-like compound used as a matrix to improve dissolution rate of the poorly water-soluble drug gliclazide and to administer at the same time micro- and oligo-elements useful to improve insulin performance. Gliclazide is a second-generation sulfonylurea compound used in the treatment of type II diabetes mellitus. As a consequence of the poor water solubility, its absorption is limited. Thus, a new hydrotalcite-like compound containing Zinc and Chromium, micronutrients directly involved in the physiology of insulin and in the carbohydrate, lipid and protein metabolism, was synthesized. The gliclazide-hydrotalcite-like clay nanohybrid was prepared via ion-exchange in its nitrate form and was characterized by inductively coupled plasma-optical emission spectrometry and thermogravimetric analysis. The drug loading resulted in 42.9% (w/w). As a consequence of the intercalation, the interlayer distance of the host increased from 0.89 nm (interlayer distance of nitrate form) to 1.5 nm. The intercalation product was submitted to solubility measurements and in vitro dissolution test. A remarkable improvement of the apparent solubility and dissolution rate in comparison to the crystalline drug was observed in acid fluids (pH 1.2 and 3). The presence of chromium and zinc cations was also found in the medium. These results showed that the hybrid nanostructure could represent a promising system to improve drug dissolution rate and to release cations involved in the performance of insulin.