María Verónica Ramírez-Rigo

Enhanced intestinal permeability and oral bioavailability of enalapril maleate upon complexation with the cationic polymethacrylate Eudragit E100.

The low bioavailability of enalapril maleate associated to its instability in solid state motivated the development of a polyelectrolyte-drug complex between enalapril maleate and the cationic polymethacrylate Eudragit E100. The solid complexes were characterized by DSC-TG, FT-IR and X-ray diffraction. Their aqueous dispersions were evaluated for drug delivery in bicompartimental Franz cells and electrokinetic potentials. Stability in solid state was also evaluated using an HPLC-UV stability indicating method. Absorption of enalapril maleate was assessed thorough the rat everted gut sac model. In addition, urinary recovery after oral administration in rats was used as an indicator of systemic exposition. The solid materials are stable amorphous solids in which both moieties of enalapril maleate are ionically bonded to the polymer. Their aqueous dispersions exhibited controlled release over more than 7h in physiologic saline solution, being ionic exchange the fundamental mechanism that modified the extent and rate of drug release. Intestinal permeation of enalapril maleate was 1.7 times higher in the presence of the cationic polymer. This increase can be related with the capacity to adhere the mucosa due to the positive zeta potential of the complexes. As a consequence bioavailability was significantly improved (1.39 times) after oral administration of the complexes. In addition, no signs of chemical decomposition were observed after a 14months period. The results indicated that the products are new chemical entities that improve unfavorable properties of a useful drug.

New alginic acid-atenolol microparticles for inhalatory drug targeting.

The inhalatory route allows drug delivery for local or systemic treatments in a noninvasively way. The current tendency of inhalable systems is oriented to dry powder inhalers due to their advantages in terms of stability and efficiency. In this work, microparticles of atenolol (AT, basic antihypertensive drug) and alginic acid (AA, acid biocompatible polyelectrolyte) were obtained by spray drying. Several formulations, varying the relative composition AT/AA and the total solid content of the atomized dispersions, were tested. The powders were characterized by: Fourier Transform Infrared Spectroscopy, Differential Scanning Calorimetry and Powder X-ray Diffraction, while also the following properties were measured: drug load efficiency, flow properties, particles size and density, moisture content, hygroscopicity and morphology. The ionic interaction between AA and AT was demonstrated, then the new chemical entity could improve the drug targeting to the respiratory membrane and increase its time residence due to the mucoadhesive properties of the AA polymeric chains. Powders exhibited high load efficiencies, low moisture contents, adequate mean aerodynamic diameters and high cumulative fraction of respirable particles (lower than 10 μm).

Valeriana officinalis Dry Plant Extract for Direct Compression: Preparation and Characterization

Valeriana officinalis L. (Valerianaceae) is one of the most widely used plants for the treatment of anxiety and insomnia. Usually dry plant extracts, including V. officinalis, are hygroscopic materials with poor physico-mechanical properties that can be directly compressed. A V. officinalis dry extract with moderate hygroscocity is suitable for direct compression, and was obtained by using a simple and economical technique. The V. officinalis fluid extract was oven-dried with colloidal silicon dioxide as a drying adjuvant. The addition of colloidal silicon dioxide resulted in a dry plant extract with good physico-mechanical properties for direct compression and lower hygroscopicity than the dry extract without the carrier. The dry plant extract glass transition temperature was considerably above room temperature (about 72 °C). The colloidal silicon dioxide also produced an antiplasticizing effect, improving the powder’s physical stability. The pharmaceutical performance of the prepared V. officinalis dry extract was studied through the design of tablets. The manufactured tablets showed good compactability, friability, hardness, and disintegration time. Those containing a disintegrant (Avicel PH 101) exhibited the best pharmaceutical performance, having the lowest disintegration time of around 40 seconds.

Very fast dissolving acid carboxymethylcellulose-rifampicin matrix: Development and solid-state characterization

&NA; One of the main obstacles to the successful treatment of tuberculosis is the poor and variable oral bioavailability of rifampicin (RIF), which is mainly due to its low hydrophilicity and dissolution rate. The aim of this work was to obtain a hydrophilic new material that allows a very fast dissolution rate of RIF and therefore is potentially useful in the development of oral solid dosage forms. The acid form of carboxymethylcellulose (CMC) was co‐processed with RIF by solvent impregnation to obtain CMC‐RIF powder, which was characterized by polarized optical microscopy, powder x‐ray diffraction, DSC‐TGA, hot stage microscopy, 13C and 15N solid‐state NMR and FT‐IR spectroscopy. In addition, the CMC‐RIF matrices were subjected to water uptake and dissolution studies to assess hydrophilicity and release kinetics. CMC‐RIF is a crystalline solid dispersion. Solid‐state characterization indicated that no ionic interaction occurred between the components, but RIF crystallized as a zwitterion over the surface of CMC, which drastically increased the hydrophilicity of the solid. The CMC‐RIF matrices significantly improved the water uptake of RIF and disintegrated in a very short period immediately releasing RIF. As CMC improves the hydrophilicity and delivery properties of RIF, CMC‐RIF is very useful in the design of oral solid dosage forms with very fast dissolution of RIF, either alone or in combination with other antitubercular drugs. Graphical abstract Figure. No caption available.

Formulation and Characterization of Polysaccharide Microparticles for Pulmonary Delivery of Sodium Cromoglycate

ABSTRACTSodium cromoglycate (SC) is an antiasthmatic and antiallergenic drug commonly used for chronic inhalation therapy; however, many daily intakes are required due to the fast drug clearance from airways. For these reasons, SC polymeric particles for inhalatory administration with adequate aerosolization and mucoadhesive properties were designed to prolong the drug residence time in the site of action. Sodium carboxymethylcellulose (CMCNa), sodium hyaluronate, and sodium alginate were selected to co-process SC by spray drying. The influence of these polysaccharides on the spray drying process and powder quality was evaluated (among others, morphology, size, moisture content, hygroscopicity, flowability, densities, liquid sorption, and stability). In vitro aerosolization, drug release, and mucoadhesion performance were also studied. Particularly, a novel method to comparatively evaluate the interaction between formulations and mucin solution (mucoadhesion test) was proposed as a rapid methodology to measure adhesion properties of inhalable particles, being the results as indicative of clearance probability. Among all the studied formulations, the powder based on SC and CMCNa exhibited the best mucoadhesion and aerosolization performance, the highest process yield and adequate moisture content, hygroscopicity, and stability. SC-CMCNa formulation arose as a promising inhalatory system to reduce the daily intakes and to increase the patient compliance.

Impact of feed counterion addition and cyclone type on aerodynamic behavior of alginic-atenolol microparticles produced by spray drying

The inhalatory route has emerged as an interesting non-invasive alternative for drug delivery. This allows both pulmonary (local) and systemic treatments (via alveolar absorption). Further advantages in terms of stability, dose and patient preference have often lead researchers to focus on dry powder inhaler delivery systems. Atenolol is an antihypertensive drug with low oral bioavailability and gastrointestinal side effects. Because atenolol possesses adequate permeation across human epithelial membranes, it has been proposed as a good candidate for inhalatory administration. In a previous work, atenolol was combined with alginic acid (AA) and microparticles were developed using spray-drying (SD) technology. Different AA/atenolol ratios, total feed solid content and operative variables were previously explored. In order to improve particle quality for inhalatory administration and the SD yield, in this work the AA acid groups not neutralized by atenolol were kept either free or neutralized to pH∼7 and two different SD cyclones were used. Particle morphology, flow properties, moisture uptake and in vitro aerosolization behavior at different pressure drops were studied. When the AA acid groups were neutralized, particle size decreased as a consequence of the lower feed viscosity. The SD yield and in vitro particle deposition significantly increased when a high performance cyclone was employed, and even when lactose carrier particles were not used. Although the in vitro particle deposition decreased when the storage relative humidity increased, the developed SD powders showed adequate characteristics to be administered by inhalatory route up to storage relative humidities of about 60%.

Thermodynamic and Rheological Properties of Polyelectrolyte Systems

The chapter provides a treatment of the interaction between acidic or basic polyelctrolytes (PE) and ionizable organic molecules (selected model drugs) in aqueous environments, in terms of acid-base reactions. The electrostatic attraction between the ionized pending groups of the PE and the organic ions yields a high proportion of counterionic condensation with affinity constants in the range of 103 to 105. The high proportion of counterionic condensation in PE-drug aqueous dispersions determines many of the particular properties of these systems such as the effects of addition of electrolytes and non-electrolytes, the kinetic of drug release under different conditions, the raise of compatibility of low solubility drugs, the increase of chemical stability and the rheological behavior. The aqueous systems of acidic PE are characterized by their building viscosity capacity. Flow curves of PE-drug systems reflex the behavior of model PE-Na systems. However, complexes of a set of model drugs under similar conditions exhibit a wide range of viscosities. The determination of the kinetic of water sorption of PE-drug complexes in solid state provides valuable complementary information related to their swelling capacity. Rheology of PE-drug aqueous dispersions as well as their swelling capacity are relevant properties in the fields of mucoadhesivity and drug release.

Carrier free indomethacin microparticles for dry powder inhalation

Graphical abstract Figure. No Caption available. Abstract The present studies were designed to evaluate inhalatory microparticles carrying indomethacin (IN) for potential local (specific and non‐specific bronchial inflammatory asthma responses) and systemic treatments (joint inflammation, rheumatoid arthritis and osteoarthritis pain) by optimizing microparticle properties, characterizing their lung deposition, drug release, evaluating cytotoxicity and also pharmacological effect in vitro. The acidic groups of IN were complexed with the cationic groups of the polyelectrolyte polylysine in order to increase the drug water compatibility. The polylysine/indomethacin ratio was fixed and the pH was adjusted in different formulations. Microparticles were obtained by spray drying using a relatively high atomization air flowrate (742 L/min) and a high‐performance cyclone in order to optimize the production of microparticles with adequate attributes for inhalatory delivery. The produced microparticles exhibited high process yield and IN loading, volumetric mean diameters smaller than 5 &mgr;m and narrow particle size distributions. According to demonstrated aerosolization performance, the powders were suitable for inhalatory indomethacin local and systemic treatments. Emitted fraction was higher than 90%, the MMAD was around 3 &mgr;m and the GSD lower than 3. The respirable fraction for particles with aerodynamic diameters smaller than 5 &mgr;m was around 29% while for particles with aerodynamic diameters smaller than 3 &mgr;m the value was around 17%. The addition of lactose as carrier worsened the aerodynamic performance of the microparticles. The developed powdered systems got wet and dissolved quickly and presented higher release rates respect to pure IN in simulated lung physiological conditions. Furthermore, the assays performed in RAW 264.7 cell line showed that the microparticles exhibited the same anti‐inflammatory capability as the pure drug. The developed particles did not affect the RAW 264.7 cell viability. In conclusion, a promising powder formulation for DPIs has been developed to treat, locally and systemically, inflammatory diseases.