Marta Espina

Role of hydroxypropyl-β-cyclodextrin on freeze-dried and gamma-irradiated PLGA and PLGA-PEG diblock copolymer nanospheres for ophthalmic flurbiprofen delivery.

Poly(D,L-lactide-co-glycolide) and poly(D,L-lactide-co-glycolide) with poly(ethylene glycol) nanospheres (NSs) incorporating flurbiprofen (FB) were freeze-dried with several cryoprotective agents and sterilized by γ-irradiation. Only when 5.0% (w/v) hydroxypropyl-β-cyclodextrin (HPβCD) was used, a complete resuspension by manual shaking and almost identical particle size of the NSs was obtained after freeze-drying. In vitro drug release and ex vivo corneal permeation of NSs with and without HPβCD were evaluated. The presence of HPβCD resulted in a reduction of burst effect, providing a more sustained release of the drug. A significant decrease in the FB transcorneal permeation of NSs containing HPβCD was obtained, related to the slower diffusion of FB observed in the in vitro results. The uptake mechanism of the NSs was examined by confocal microscopy, suggesting that NSs penetrate corneal epithelium through a transcellular pathway. Ocular tolerance was assessed in vitro and in vivo by the Eytex™ and Draize test, respectively. Long-term stability studies revealed that γ-irradiated NSs stored as freeze-dried powders maintained their initial characteristics. Stability studies of the resuspended NSs after 3 months of storage in the aqueous form showed that NSs were stable at 4°C, while formulations stored at 25°C and 40°C increased their initial particle size.

Flurbiprofen-loaded nanospheres: analysis of the matrix structure by thermal methods

We report the preparation and evaluation of flurbiprofen loaded-poly-epsilon-caprolactone nanospheres obtained by solvent displacement method. Characterization by thermal methods, infrared spectroscopy and X-ray diffraction analysis can reveal the dispersion state of the drug inside the nanospheres. Such information predicts the stability of the particles and the drug release behaviour. The study has indicated the presence of a molecular dispersed system. In addition, construction of a phase diagram has allowed us to determine the drug/polymer ratios at which flurbiprofen has the highest entrapment efficiency.

Stability and in vitro drug release of flurbiprofen-loaded poly-ε-caprolactone nanospheres

The effects of temperature and two different initial pH (2.67 and 7.00) on poly-e-caprolactone (PeCL) nanospheres loaded with flurbiprofen (FB) (aqueous suspensions) were studied to investigate their influence on the stability and physicochemical characteristics of these drug delivery systems. The drug release behavior was also studied. Release of the associated FB occurred very fast on high dilution in a buffered medium. The stability of the polymeric system depends on the temperature and the initial pH value; it is more degradable with the particles stored at 40°C with an initial pH value of 2.67.

Flurbiprofen PLGA-PEG nanospheres: role of hydroxy-β-cyclodextrin on ex vivo human skin permeation and in vivo topical anti-inflammatory efficacy.

In this study, flurbiprofen (FB) loaded poly(d,l-lactide-co-glycolide) (PLGA) and PLGA with poly(ethylene glycol) (PLGA-PEG) nanospheres (NSs) with and without hydroxypropyl-β-cyclodextrin (HPβCD) were developed as skin controlled delivery systems. X-ray diffraction was used to determine the physical state of the entrapped drug. Results showed that the drug in PLGA NSs was present in the form of a molecular dispersion (dissolved state) in the polymers, whereas in PLGA-PEG NSs, the drug was present in both molecular dispersion and crystalline forms. Furthermore, HPβCD provided solubilization of the free FB present on the surface of the PLGA-PEG NSs and a complete amorphosization of the drug was obtained. Optical analyses using TurbiscanLab(®) demonstrated that HPβCD provided an efficient steric stability of the NSs, preventing particle aggregation. The ex vivo permeation profiles of the NSs and conventional FB solution were evaluated using human skin. Results demonstrated that only PLGA-PEG NSs showed slight permeation improvement. However, after 24h, the FB retained in the skin was about 9-fold higher with NSs compared with the control solution, attributed to the reservoir effect of NSs acting as a depot, sustaining the drug and limiting its systemic absorption. In vivo performance of NSs was evaluated by assessing anti-inflammatory efficacy in TPA-induced mouse ear edema. Topically applied NSs significantly decreased in vivo inflammation compared to the control solution and the anti-inflammatory efficacy of HPβCD NSs was stronger than NSs without HPβCD. In vivo skin irritation evaluated by the in vivo Draize test showed no irritation of the formulations tested.

Lipid nanoparticles (SLN, NLC): Overcoming the anatomical and physiological barriers of the eye - Part II - Ocular drug-loaded lipid nanoparticles.

&NA; In the recent decades, various controlled delivery systems have been introduced with the aim to improve solubility, stability and bioavailability of poorly absorbed drugs. Among all, lipid nanoparticles gather interesting properties as drug or gene delivery carriers. These systems, composed either of solid lipids (SLN) or of solid and liquid lipids (NLC) stabilized with surfactants, combine the advantages of other colloidal particles such as polymeric nanoparticles, fat emulsions and liposomes avoiding their main disadvantages. Lipid nanoparticles represent an interesting approach for eye drug delivery as they can improve the corneal absorption of drugs enhancing their bioavailability. The Generally Recognized as Safe status of formulation excipients, the scaling‐up facilities and the possibility of sterilization, make them suitable for industrial production. In this review, the latest findings, potential applications, and challenges related to the use of lipid nanoparticles for ocular drug delivery are comprehensively discussed. Graphical abstract Figure. No caption available.

PEGylated PLGA nanospheres optimized by design of experiments for ocular administration of dexibuprofen—in vitro, ex vivo and in vivo characterization

Dexibuprofen-loaded PEGylated PLGA nanospheres have been developed to improve the biopharmaceutical profile of the anti-inflammatory drug for ocular administration. Dexibuprofen is the active enantiomer of ibuprofen and therefore lower doses may be applied to achieve the same therapeutic level. According to this, two batches of nanospheres of different drug concentrations, 0.5 and 1.0mg/ml respectively, have been developed (the latter corresponding to the therapeutic ibuprofen concentration for inflammatory eye diseases). Both batches were composed of negatively charged nanospheres (--14.1 and --15.9mV), with a mean particle size below 200nm, and a high encapsulation efficiency (99%). X-ray, FTIR, and DSC analyses confirmed that the drug was dispersed inside the matrix of the nanospheres. While the in vitro release profile was sustained up to 12h, the ex vivo corneal and scleral permeation profile demonstrated higher drug retention and permeation in the corneal tissue rather than in the sclera. These results were also confirmed by the quantification of dexibuprofen in ocular tissues after the in vivo administration of drug-loaded nanospheres. Cell viability studies confirmed that PEGylated-PLGA nanospheres were less cytotoxic than free dexibuprofen in the majority of the tested concentrations. Ocular in vitro (HET-CAM test) and in vivo (Draize test) tolerance assays demonstrated the non-irritant character of both nanosphere batches. In vivo anti-inflammatory effects were evaluated in albino rabbits before and after inflammation induction. Both batches confirmed to be effective to treat and prevent ocular inflammation.

Tear pH, air pollution, and contact lenses

ABSTRACT We analyzed the tear pH of a random sample of 100 subjects, divided into 3 groups according to the stability of their precorneal tear film (normal eyes, borderline; and dry eyes). The average pH value obtained was 7.52. The pH for borderline and dry eyes was higher than for normal eyes. The purpose of this study was to determine the influence of air pollution, specifically sulfur dioxide (SO2), on the tear pH. We found that air pollution affected the lacrimal pH, which decreased when the atmospheric SO2 increased. Finally, we studied the effect of soft contact lens wear on tear pH after 7 days of contact lens adaptation by assessing the tear pH decrease. We took into account the influence of the sex and age of subjects on the results obtained.

Cyclophosphamide-loaded nanospheres: analysis of the matrix structure by thermal and spectroscopic methods

This study reports on the preparation and evaluation of cyclophosphamide loaded-polyalkylcyanoacrylate nanospheres obtained by emulsion polymerization. Characterization by differential scanning calorimetry, infrared spectroscopy and X-ray diffraction can reveal state dispersion of the drug inside the nanospheres. Such information predicts the stability of the particles and the drug release behaviour. The study has indicated the prescence of a molecular dispersed system. The drug release behaviour was also studied.

Design and elaboration of freeze-dried PLGA nanoparticles for the transcorneal permeation of carprofen: Ocular anti-inflammatory applications

This work aimed the design and development of poly(lactic-co-glycolic) acid (PLGA) nanoparticles (NPs) for the ocular delivery of Carprofen (CP) by a central rotatable composite design 2(3)+ star. NPs showed adequate size for ocular administration (189.50 ± 1.67 nm), low polydispersity (0.01 ± 0.01), negative charge surface (-22.80 ± 0.66 mV) and optimal entrapment efficiency (74.70 ± 0.95%). Physicochemical analysis confirmed that CP was dispersed inside the NPs. The drug release followed a first order kinetic model providing greater sustained CP release after lyophilization. Ex vivo permeation analysis through isolated rabbit cornea revealed that a sufficient amount of CP was retained in the tissue avoiding excessive permeation and thus, potential systemic levels. Ex vivo ocular tolerance results showed no signs of ocular irritancy, which was also confirmed by in vivo Draize test. In vivo ocular anti-inflammatory efficacy test confirmed an optimal efficacy of NPs and its potential application in eye surgery.

New potential strategies for Alzheimer's disease prevention: pegylated biodegradable dexibuprofen nanospheres administration to APPswe/PS1dE9

Dexibuprofen loaded pegylated poly(lactic-co-glycolic) nanospheres prepared by solvent diffusion method were designed to increase Dexibuprofen brain delivery reducing systemic side effects. Nanospheres exhibited a mean particle size around 200 nm (195.4 nm), monomodal population and negative surface charge. Drug loaded nanospheres showed a sustained release profile, allowing to modify the posology in vivo. Nanospheres were non-toxic neither in brain endothelial cells nor astrocytes and do not cause blood-brain barrier disruption. Nanospheres were able to partially cross the cells barrier and release the drug after co-culture in vitro experiments, increasing Dexibuprofen permeation coefficient. Behavioral tests performed in APPswe/PS1dE9 mice (mice model of familial Alzheimers disease) showed that nanospheres reduce memory impairment more efficiently than the free drug. Developed nanospheres decrease brain inflammation leading to β-amyloid plaques reduction. According to these results, chronical oral Dexibuprofen pegylated poly(lactic-co-glycolic) nanosystems could constitute a suitable strategy for the prevention of neurodegeneration.