Development of PLGA-based itraconazole injectable nanospheres for sustained release

Abstract

Purpose Itraconazole (ITZ) is a synthetic triazole antifungal agent, which is widely used for treatment and prevention of fungal infections. The purpose of this study is to develop ITZ-loaded poly(lactic-co-glycolic acid) (PLGA) nanospheres (PLGA-ITZ-NS) as a new sustained-release formulation for intravenous ITZ administration. Materials and methods PLGA-ITZ-NS were prepared by a nanoprecipitation method and optimized by modifying the surfactant poloxamer 188 concentration and PLGA:ITZ ratio. Their physicochemical properties, including size, zeta potential, external morphology and encapsulation efficiency, were characterized by dynamic light scattering (DLS), scanning electron microscopy (SEM) and high performance liquid chromatography (HPLC). The effect of the different selected lyoprotectants with various concentrations on NS particles size and surface charge were also assessed. Rapid and sensitive HPLC and liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods were developed to determine ITZ concentrations in formulation and in rat plasma, respectively. Pharmacokinetics of the optimum PLGA-ITZ-NS formulation was compared with the former commercial Sporanox® injection formulation using rats as the animal model. Noncompartmental pharmacokinetic parameters were obtained by WinNonlin® software. Results Optimal PLGA-ITZ-NS had a mean particle size of about 200 nm with a high homogeneity (polydispersity index ≈0.2), favorable zeta potential (approximately −20 to −30 mV) and encapsulation efficiency (72%). In addition, 2% w/v sucrose was selected as a lyoprotectant for NS freeze-drying. The newly developed LC-MS/MS assay was validated and found to be accurate and precise. The in vivo study showed that the NS formulation has a similar systemic bioavailability to Sporanox® while providing a sustained plasma level (> 100 ng/mL) for up to 24 hours after intravenous administration. Conclusion Our newly developed PLGA-ITZ-NS has shown great sustained release and comparable bioavailability with Sporanox®, therefore having the potential to be an alternative injectable formulation of ITZ.

Development, Optimization, and Characterization of PEGylated Nanoemulsion of Prostaglandin E1 for Long Circulation

“…A large PDI value indicates that the particles have a broad size distribution and are substantially different in size. The ununiform particle size can cause pharmacokinetic parameters to be irregular and can affect the therapeutic efficiency of a drug formulation (39). PDI value of PGE1-PEG2000(1%)-NE was below 0.2, this indicated that the particle size distribution of PGE1-PEG2000(1%)-NE was homogeneous.…”

Porous silicon oxide–PLGA composite microspheres for sustained ocular delivery of daunorubicin

“…The drug release profile may also depend on the nature of the pSiO 2 particles within the PLGA microspheres [38–40]. A relatively large drug-containing pSiO 2 particle will have a smaller surface area and tend to degrade and leach drug more slowly than multiple smaller pSiO 2 particles, and this is observed in the data.…”

Nanoprecipitation: Applications for Entrapping Active Molecules of Interest in Pharmaceutics

“…Concerning the administration of carriers by the intravenous route, pharmacokinetic advantages were also evidenced compared to the free drug administration. As reported by Bian et al [22] and Han et al [27], even if a fraction of the polymeric nanoparticles are quickly removed by the reticuloendothelial system during the first 4 h after the administration, the remaining particles into the systemic circulation allow a sustained drug delivery for more than 20 h achieving AUC 0-t values from 2 to 10 times higher than free drug. As intended, pegylation of polymeric nanoparticles extends the elimination half-life by $100 h and increases in 84% the AUC regarding the free drug [27].…”

“…Some of the research works undertaken during the last years have proposed the vectorization in nanoparticles, via nanoprecipitation, of hydrophobic active molecules, mainly exhibiting logP values higher than 3. They include antineoplastics (e.g., doxorubicin [4], paclitaxel [5,6], docetaxel [7,8], methotrexate [9], triptolide [6], cucurbitacin [10], and sorafenib [11]), antiretrovirals (e.g., efavirenz [12] and nevirapine [13]), immune suppressants (mycophenolate [14]), anti-inflammatories (clobetasol [15], fluticasone propionate [16], dexamethasone [17,18], and diclofenac [19]), antimicrobial and antifungal agents (polymyxin B [20], amphotericin B [21], itraconazole [22], and linezolid [23]), antihyperlipidemics (fenofibrate [24,25]), anesthetics (tetracaine [26] and ketamine [27]), antihypertensives (nimodipine [28] and atenolol [29]), vitamins or their precursors (β-carotene [30] and vitamin E [31]), and antioxidants (quercetin [14,32]). Likewise, although in a much smaller number, hydrophilic active molecules such alendronate [33], N-acetylcysteine [34], and calcein [35], have been investigated.…”