Engineered PLGA nano- and micro-carriers for pulmonary delivery: challenges and promises.

OBJECTIVES: The aim of this review is to summarize the current state-of-the-art in poly(lactic-co-glycolic acid) (PLGA) carriers for inhalation. It presents the rational of use, the potential and the recent advances in developing PLGA microparticles and nanoparticles for pulmonary delivery. The most promising particle engineering strategies are discussed, highlighting the advantages along with the major challenges for researchers working in this field. KEY FINDINGS: Biodegradable polymer carriers, such as PLGA particles, may permit effective protection and long-term delivery of the inhaled drug and, when adequately engineered, its efficient transport to the target. The carrier can be designed for inhalation on the basis of several strategies through the adequate combination of available particle technologies and excipients. In so doing, the properties of PLGA particles can be finely tuned at micro-size and nano-size level to fulfill specific therapeutic needs. This means not only to realize optimal in vitro/in vivo lung deposition of the formulation, which is still crucial, but also to control the fate of the drug in the lung after particle landing. SUMMARY: Although many challenges still exist, PLGA carriers may be highly beneficial and present a new scenario for patients suffering from chronic lung diseases and for pharmaceutical companies working to develop novel inhaled products.

Injectable thermally responsive mucoadhesive gel for sustained protein delivery.

Poloxamer thermoresponsive gels are widely explored in controlled drug delivery. Nevertheless, these gels possess inadequate mechanical properties, poor bioadhesiveness, and high permeability to water. To overcome these issues, we blended mucoadhesive hyaluronic acid (HA) with poloxamer analogs. This study aimed to investigate the features affecting the microscopic properties of the gels, which determine their macroscopic properties and capability to control/sustain protein release. Results showed that HA hampers water-poloxamer interactions, thus, strongly influencing physicochemical properties of poloxamer gels. This leads to gels with improved mechanical properties in which the diffusion kinetics of macromolecular active molecules are drastically slowed down. Poloxamer-HA gels can sustain the delivery of proteins, such as insulin, and may allow the modulation of its release kinetics by modifying HA content within the gels in the administration sites in which the active molecule release mechanism is mainly governed by its diffusion.

Bioactivation of collagen matrices through sustained VEGF release from PLGA microspheres.

The success of any tissue engineering implant relies upon prompt vascularization of the cellular construct and, hence, on the ability of the scaffold to broadcast specific activation of host endothelium and guide vessel ingrowth. Vascular endothelial growth factor (VEGF) is a potent angiogenic stimulator, and if released in a controlled manner it may enhance and guide scaffold vascularization. Therefore, the aim of this work was to realize a scaffold with integrated depots able to release VEGF in a controlled rate and assess the ability of this scaffold to promote angiogenesis. VEGF-loaded poly(lactide-co-glycolide) (PLGA) microspheres were produced and included in a collagen scaffold. The release of VEGF from microspheres was tailored to be sustained over several weeks and occurred at a rate of approximately 0.6 ng/day per mg of microspheres. It was found that collagen scaffolds bioactivated with VEGF-loaded microspheres strongly enhanced endothelial cell activation and vascular sprouting both in vitro and in vivo as compared with a collagen scaffold bioactivated with free VEGF. This report demonstrates that by finely tuning VEGF release rate within a polymeric scaffold, sprouting of angiogenic vessels can be guided within the scaffolds interstices as well as broadcasted from the host tissues.

A novel poloxamers/hyaluronic acid in situ forming hydrogel for drug delivery: rheological, mucoadhesive and in vitro release properties.

The influence of hyaluronic acid (HA) on the gelation properties of poloxamers blends has been studied with the aim of engineering thermosensitive and mucoadhesive polymeric platforms for drug delivery. The gelation temperature (T(gel)), viscoelastic properties and mucoadhesive force of the systems were investigated and optimised by means of rheological analyses. Poloxamers micellar diameter was evaluated by photon correlation spectroscopy (PCS). Moreover in order to explore the feasibility of these platforms for drug delivery, the optimised systems were loaded with acyclovir and its release properties studied in vitro. By formulating poloxamers/HA platforms, at specific concentrations, it was possible to obtain a thermoreversible gel with a T(gel) close to body temperature. The addition of HA did not hamper the self assembling process of poloxamers just delaying the gelation temperature of few Celsius degrees. Furthermore, HA presence led to a strong increase of the poloxamer rheological properties thus indicating possible HA interactions with micelles through secondary bonds, such as hydrogen ones, which reinforce the gel structure. These interactions could also explain PCS results which show, in systems containing HA, aggregates with hydrodynamic diameters much higher than those of poloxamer micelles. Mucoadhesion experiments showed a rheological synergism between poloxamers/HA gels and mucin dispersion which led to a change of the flow behaviour from a quite Newtonian one of the separate solutions to a pseudoplastic one of their mixture. In vitro release experiments indicated that the optimised platform was able to prolong and control acyclovir release for more than 6h.

Pharmacokinetics of cetirizine in tear fluid after a single oral dose.

BACKGROUND: Antihistamines (histamine H(1) receptor antagonists) are effective and convenient drugs for the treatment of allergic conjunctivitis. Because of the short duration of action generally observed for drugs administered topically to the eye, the oral route is often preferred. However, the presence of a selective barrier between blood and ocular tissues, the so-called blood-ocular barrier, does not allow a priori assessment of the most suitable dosage for ocular therapy. OBJECTIVE: To investigate the tear concentrations of cetirizine, a second-generation antihistamine, over time following oral administration, and to study the relationship between plasma and tear fluid concentrations. DESIGN AND PARTICIPANTS: Pharmacokinetic study of a single oral dose of cetirizine 10mg in 40 patients treated for allergic conjunctivitis. METHODS: Patients received a single oral dose of cetirizine. Samples of blood and tear fluid were taken according to predefined sampling schedules and the concentrations of cetirizine were determined by a new high performance liquid chromatography method. RESULTS: Concentration-time profiles for cetirizine in serum and tear fluid were similar, although the mean maximum concentration in tear fluid was reached later than in serum (90 and 30 min, respectively). However, at 60 and 120 min the cetirizine concentration in tear fluid was 98 and 92% of the mean maximum concentration, respectively, showing a plateau region and indicating that the disposition rate for the tear fluid compartment was very similar to that for the blood compartment. CONCLUSION: Oral administration of cetirizine yields therapeutically effective concentrations of the drug at the anterior surface of the eye.