Celecoxib Nanoformulations with Enhanced Solubility, Dissolution Rate, and Oral Bioavailability: Experimental Approaches over In Vitro/In Vivo Evaluation.

Celecoxib (CXB) is a Biopharmaceutical Classification System (BCS) Class II molecule with high permeability that is practically insoluble in water. Because of the poor water solubility, there is a wide range of absorption and limited bioavailability following oral administration. These unfavorable properties can be improved using dry co-milling technology, which is an industrial applicable technology. The purpose of this study was to develop and optimize CXB nanoformulations prepared by dry co-milling technology, with a quality by design approach to maintain enhanced solubility, dissolution rate, and oral bioavailability. The resulting co-milled CXB composition using povidone (PVP), mannitol (MAN) and sodium lauryl sulfate (SLS) showed the maximum solubility and dissolution rate in physiologically relevant media. Potential risk factors were determined with an Ishikawa diagram, important risk factors were selected with Plackett-Burman experimental design, and CXB compositions were optimized with Central Composite design (CCD) and Bayesian optimization (BO). Physical characterization, intrinsic dissolution rate, solubility, and stability experiments were used to evaluate the optimized co-milled CXB compositions. Dissolution and permeability studies were carried out for the resulting CXB nanoformulation. Oral pharmacokinetic studies of the CXB nanoformulation and reference product were performed in rats. The results of in vitro and in vivo studies show that the CXB nanoformulations have enhanced solubility (over 4.8-fold (8.6 ± 1.06 µg/mL vs. 1.8 ± 0.33 µg/mL) in water when compared with celecoxib pure powder), and dissolution rate (at least 85% of celecoxib is dissolved in 20 min), and improved oral pharmacokinetic profile (the relative bioavailability was 145.2%, compared to that of Celebrex®, and faster tmax 3.80 ± 2.28 h vs. 6.00 ± 3.67 h, indicating a more rapid absorption rate).

Design of Besifloxacin HCl-Loaded Nanostructured Lipid Carriers: In Vitro and Ex Vivo Evaluation.

Objective: In the treatment of severe cases of bacterial keratitis, conventional eye drops containing antibiotics should be applied daily and very frequently. The aim of this study is to develop low-dose high-effect formulations with the prepared nanostructured lipid carrier (NLC) formulations to reduce antibiotic resistance and increase patient compliance. Methods: NLC formulations were loaded with besifloxacin HCl (BHL) and the besifloxacin HCl: sulfobutyl ether beta-cyclodextrin (SBE-CD) complex. Positive charge was gained with chitosan, and corneal permeation and resolubility were increased with SBE-CD. In vitro characterization studies, permeability studies, and cytotoxicity and ex vivo transport studies were carried out. Results: In this study, it was found that SBE-CD increased BHL's solubility by 8-fold based on phase solubility studies. The optimized NLCs were small in size (13.63-16.09 nm) with a low polydispersity index (0.107-0.181) and adequate BHL drug loading efficiency. In vitro release studies showed that formulations were released approximately for 8 h and at levels over the minimum inhibitory concentration of Pseudomonas aeruginosa and Staphylococcus aureus. NLC formulations had a better corneal permeation rate than the marketed product during 6 h of ex vivo studies. Conclusions: According to in vitro and ex vivo data, it was determined that the most favorable NLC formulation was the formulation containing BHL/SBE-CD that was covered with chitosan. It has the highest drug loading capacity and one of the highest ex vivo corneal passage levels, along with desired drug release. The formulation containing BHL/SBE-CD and chitosan can be a potential alternative for the treatment of bacterial keratitis.

Dry powders for the inhalation of ciprofloxacin or levofloxacin combined with a mucolytic agent for cystic fibrosis patients.

OBJECTIVE: This study aimed to design and characterize an inhalable dry powder of ciprofloxacin or levofloxacin combined with the mucolytics acetylcysteine and dornase alfa for the management of pulmonary infections in patients with cystic fibrosis. METHODS: Ball milling, homogenization in isopropyl alcohol and spray drying processes were used to prepare dry powders for inhalation. Physico-chemical characteristics of the dry powders were assessed via thermogravimetric analysis, differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FT-IR), X-ray diffractometry and scanning electron microscopy. The particle size distribution, dissolution rate and permeability across Calu-3 cell monolayers were analyzed. The aerodynamic parameters of dry powders were determined using the Andersen cascade impactor (ACI). RESULTS: After the micronization process, the particle sizes of the raw materials significantly decreased. X-ray and DSC results indicated that although ciprofloxacin showed no changes in its crystal structure, the structure of levofloxacin became amorphous after the micronization process. FT-IR spectra exhibited the characteristic peaks for ciprofloxacin and levofloxacin in all formulations. The dissolution rates of micro-homogenized and spray-dried ciprofloxacin were higher than that of untreated ciprofloxacin. ACI results showed that all formulations had a mass median aerodynamic diameter less than 5 µm; however, levofloxacin microparticles showed higher respirability than ciprofloxacin powders did. The permeability of levofloxacin was higher than those of the ciprofloxacin formulations. CONCLUSION: Together, our study showed that these methods could suitably characterize antibiotic and mucolytic-containing dry powder inhalers.