Development of a Mucoadhesive Vehicle Based on Lyophilized Liposomes for Drug Delivery through the Sublingual Mucosa.

A pharmaceutical vehicle based on lyophilized liposomes is proposed for the buccal administration of drugs aimed at systemic delivery through the sublingual mucosa. Liposomes made of egg phosphatidylcholine and cholesterol (7/3 molar ratio) were prepared and lyophilized in the presence of different additive mixtures with mucoadhesive and taste-masking properties. Palatability was assayed on healthy volunteers. The lyophilization cycle was optimized, and the lyophilized product was compressed to obtain round and capsule-shaped tables that were evaluated in healthy volunteers. Tablets were also assayed regarding weight and thickness uniformities, swelling index and liposome release. The results proved that lyophilized liposomes in unidirectional round tablets have palatability, small size, comfortability and buccal retention adequate for sublingual administration. In contact with water fluids, the tablets swelled, and rehydrated liposomes were released at a slower rate than permeation efficiency determined using a biomimetic membrane. Permeability efficiency values of 0.72 ± 0.34 µg/cm2/min and 4.18 ± 0.95 µg/cm2/min were obtained for the liposomes with and without additives, respectively. Altogether, the results point to the vehicle proposed as a liposomal formulation suitable for systemic drug delivery through the sublingual mucosa.

Lyoprotective Effects of Mannitol and Lactose Compared to Sucrose and Trehalose: Sildenafil Citrate Liposomes as a Case Study.

The lyoprotective effects of mannitol and lactose have been evaluated in the production of sildenafil citrate liposomes. Liposomes were prepared by mixing the components under ultrasonic agitation, followed by a transmembrane pH gradient for remote drug loading. Mannitol and lactose, as compared to sucrose and trehalose, were used as the stabilizing agents, and different freeze-drying cycles were assayed. The remaining moisture and the thermal characteristics of the lyophilized samples were analyzed. Size, entrapment efficiency, biocompatibility, and cell internalization of original and rehydrated liposomes were compared. The type of additive did not affect the biocompatibility or cell internalization, but did influence other liposome attributes, including the thermal characteristics and the remaining moisture of the lyophilized samples. A cut-off of 5% (w/w) remaining moisture was an indicator of primary drying completion-information useful for scaling up and transfer from laboratory to large-scale production. Lactose increased the glass transition temperature to over 70 °C, producing lyoprotective effects similar to those obtained with sucrose. Based on these results, formulations containing liposomes lyophilized with lactose meet the FDA's requirements and can be used as a biocompatible and biodegradable vehicle for the pulmonary delivery of therapeutic doses of sildenafil citrate.

Xanthan Gum-Konjac Glucomannan Blend Hydrogel for Wound Healing.

Hydrogels are considered to be the most ideal materials for the production of wound dressings since they display a three-dimensional structure that mimics the native extracellular matrix of skin as well as a high-water content, which confers a moist environment at the wound site. Until now, different polymers have been used, alone or blended, for the production of hydrogels aimed for this biomedical application. From the best of our knowledge, the application of a xanthan gum-konjac glucomannan blend has not been used for the production of wound dressings. Herein, a thermo-reversible hydrogel composed of xanthan gum-konjac glucomannan (at different concentrations (1% and 2% w/v) and ratios (50/50 and 60/40)) was produced and characterized. The obtained data emphasize the excellent physicochemical and biological properties of the produced hydrogels, which are suitable for their future application as wound dressings.

Lyophilized tablets for focal delivery of fluconazole and itraconazole through vaginal mucosa, rational design and in vitro evaluation.

The present work deals with the rational design and in vitro evaluation of vaginal tablets for focal delivery of fluconazole (FLZ) and itraconazol (ITZ). Drug loaded liposomes with and without d-alpha-tocopheryl polyethylene glycol 1000 succinate (vit E TPGS) were prepared by direct sonication of the components and mixed with albumin to obtain albusomes. Tablets were obtained by direct compression of the lyophilized cake. The influence of vit E TPGS on size, zeta potential and entrapment efficiency (EE%) of liposomes and albusomes was evaluated. Tablet swelling and drug release were studied by in vitro assays. Vit E TPGS neither affected the zeta potential nor the EE% of liposomes and albusomes, but affected the liposomes size and the tablet disintegration time. A rapid erosion was observed for the tablets with the highest content of vitamin, while a slow swelling for those lacking the vitamin (swelling index = 57.76 ±â€¯13.51%). A faster drug release profile was obtained for the former compared to the latter. The in vitro assay showed that FLZ diffused and solved in the vaginal fluid simulant while ITZ remained into the albusomes, which slowly released ITZ-albumin complex and ITZ-loaded liposomes, both suitable carriers for drug transport to deeper vaginal endothelium.

Albumin micro/nanoparticles entrapping liposomes for itraconazole green formulation.

Itraconazole-loaded micro/nanoparticles containing albumin and liposomes were prepared by a technological process that avoids the use of organic solvents and crosslinker agents. The particles were characterized, lyophilized and formulated as tablets. Dynamic light scattering was used to determine the hydrodynamic diameter and zeta potential of the particles; optical and scanning-electron microscopy was used to evaluate their morphology. Spherical shaped particles of different sizes and zeta potential were obtained. An exponential relationship between the zeta potential and the albumin/cationic lipid molar ratio was established. Drug entrapment efficiency values were in the range of 51-68%, with no statistical differences among albumin feeding concentrations. Mannitol was used as lyophilization additive and the freeze-dried cake was directly compressed into tablets, suitable for vaginal administration. The results from the in vitro drug delivery assay show the influence of albumin on the itraconazole delivery profile; a rapid release was observed for particles with higher albumin amount compared to those with lower protein content. According to the results of this study, albumin particles entrapping liposomes prove to be a green pharmaceutical vehicle with a high potential for delivery of hydrophobic and highly albumin-bound drugs.

Development and In Vitro Evaluation of a Novel Drug Delivery System (Albumin Microspheres Containing Liposomes) Applied to Vancomycin.

A pharmaceutical vehicle based on the encapsulation of liposomes with unmodified albumin has been designed, formulated, and in vitro characterized. Microscopy was used to investigate particle morphology and dynamic light scattering to determine the size and zeta potential. Vancomycin was selected as a model drug for water-soluble and moderately albumin-bound products. The results indicated that regardless of the zeta potential of the liposomes these can be trapped within albumin microspheres. The zeta potential, drug entrapment efficacy, and drug delivery profile of the resulting microspheres were found to depend on the liposome composition and the conditions of flocculation. The protein concentration was observed to influence drug entrapment efficiency (from 13.17 ± 5.0% to 61.27 ± 4.54%), as did the zeta potential of the microspheres, which was also seen to depend on the initial charge of the liposomes. The relationship between the microsphere zeta potential or entrapment efficacy and the protein concentration used for flocculation was established. Regarding drug delivery, differences between microspheres prepared from cationic or anionic liposomes were observed. The combination of liposome versatility together with the drug-binding ability of albumin provides to a vehicle with multiple choices for theranostic delivery.

Disposition of linezolid in the isolated rat lung after systemic and pulmonary drug delivery.

OBJECTIVES: To characterize the distribution of linezolid in lung when it accesses this organ from the systemic circulation and when administered through the pulmonary route and to evaluate the influence of the 'respiratory mode' in the pulmonary distribution for both routes. METHODS: The study was conducted with 24 Wistar rats divided into four groups treated with linezolid under different experimental conditions. After the animals had been subjected to a tracheotomy followed by mechanical ventilation, the lungs were isolated. After a 5 min stabilization period, the antibiotic was administered through the systemic or the pulmonary route and samples of efferent fluid (EF) were collected using a previously programmed fraction collector. Samples of bronchoalveolar fluid (BALF) and of lung tissue were also taken at the end of each experiment. The concentrations of linezolid in the samples were determined using an HPLC technique with UV detection. RESULTS: The administration of linezolid through the inhalatory route significantly increased the levels of the drug in lung tissue and BALF with lung tissue/EF partition coefficients of 8.33 +/- 2.51 as compared with 1.90 +/- 0.78 for systemic administration. Also, the decrease in respiratory rate together with the increase in tidal volume favoured the process of linezolid distribution in pulmonary tissues and fluids. CONCLUSIONS: Administration through the pulmonary route affords and excellent method for passively vectoring linezolid to the pulmonary fluids and tissues and the respiratory mode seems to affect the disposition of the antibiotic in this tissue for both administration routes.

Pulmonary versus systemic delivery of antibiotics: comparison of vancomycin dispositions in the isolated rat lung.

Vancomycin dispositions in the respiratory system were compared after systemic and inhalatory administration under two respiratory conditions using the isolated-lung model. Inhalatory delivery led to much higher drug levels in pulmonary tissue and fluids. The respiratory pattern affects vancomycin disposition in the pulmonary system regardless of the administration route.