Development of a Carrier-Free Dry Powder Ofloxacin Formulation With Enhanced Aerosolization Properties.

Tuberculosis (TB) is a serious infectious disease that affects more than new 10 million patients each year. Many of these cases are resistant to first-line drugs so second-line ones, like fluoroquinolones, need to be incorporated into the therapeutic. Ofloxacin (OF) is a fluoroquinolone which demonstrates high antibiotic activity against the bacteria that causes TB (M. tuberculosis). In this work, ionic complexes, composed by hyaluronic acid (HA) and OF, with different neutralization degrees, were prepared and processed by spray drying (SD) to obtain powders for inhalatory administration. Combining a formulation with high neutralization degree, high SD atomization air flowrate and the use of a high-performance collection cyclone, very good process yields were obtained. Carrier-free formulations with a loading of 0.39-0.46 gOF/gpowder showed excellent emitted, fine particle, and respirable fractions for capsule loadings of 25 and 100 mg. The ionic complexes demonstrated higher mucoadhesion than pure OF and HA. The best formulation did not affect CALU-3 cell viability up to a dose 6.5 times higher than the MIC90 reported to treat multi-drug resistant TB.

Carrier free indomethacin microparticles for dry powder inhalation.

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 µm 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 µm and the GSD lower than 3. The respirable fraction for particles with aerodynamic diameters smaller than 5 µm was around 29% while for particles with aerodynamic diameters smaller than 3 µm 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.

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%.

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).