Chitosan nanoparticles for controlled delivery of brimonidine tartrate to the ocular membrane

Various efforts have been made to improve the bioavailability and to prolong the residence time of eye drops. Drug loaded polymeric nanoparticles offer several favorable biological properties. Thus, brimonidine tartrate (BT) loaded chitosan (CS) nanoparticles were prepared by inducing the ionic gelation upon addition of sodium tripolyphosphate (TPP). Nanoparticles were characterized by TEM, SEM, particle size, polydispersity index (PI), DSC, IR, entrapment efficiency which gave an insight of physicochemical interaction that influenced the CS nanoparticle formation and entrapment of BT. In vitro release of BT nanoparticle showed sustained release over the period of 4 h in saline phosphate buffer pH 7.4. Both placebo and BT loaded nanoparticles had a mean particle size range of about 270-370 nm with PI less than 0.5. DSC studies demonstrated structural interactions between BT, TPP and CS matrix. Entrapment efficiency of the CS nanoparticles ranged from 36-49% depending on the CS:TPP weight ratio. In vivo studies confirmed a significant sustained effect of BT nanoparticles compared to conventional eye drops. These results suggest that BT loaded CS nanoparticles could help to reduce dosage frequency by sustained drug release in the treatment of glaucoma.     

Chitosan nanoparticles for daptomycin delivery in ocular treatment of bacterial endophthalmitis

Abstract

Context: Chitosan nanoparticles were prepared to encapsulate daptomycin and proposed as a delivery system of this antibiotic to the eye for the treatment of bacterial endophthalmitis.

Objective: The aim of this study was to develop daptomycin-loaded nanoparticles to apply directly to the eye, as a possible non-invasive and less painful alternative for the treatment of endophthalmitis, increasing the effectiveness of treatment and reducing toxicity associated with systemic administration.

Materials and methods: Nanoparticles were obtained by ionotropic gelation between chitosan and sodium tripolyphosphate (TPP). Physicochemical and morphological characteristics of nanoparticles were evaluated, as well as determination of antimicrobial efficiency of encapsulated daptomycin and stability of the nanoparticles in the presence of lysozyme and mucin.

Results: Loaded nanoparticles presented mean particle sizes around 200?nm, low polydispersity index, and positive zeta potential. Morphological examination by scanning electron microscopy (SEM) confirmed their small size and round-shaped structure. Encapsulation efficiency ranged from 80 to 97%. Total in vitro release of daptomycin was obtained within 4?h. Determination of minimum inhibitory concentrations (MICs) showed that bacteria were still susceptible to daptomycin encapsulated into the nanoparticles. Incubation with lysozyme did not significantly affect the integrity of the nanoparticles, although mucin positively affected their mucoadhesive properties.

Discussion and conclusion: The obtained nanoparticles have suitable characteristics for ocular applications, arising as a promising solution for the topical administration of daptomycin to the eye.     

Application of lipid nanoparticles to ocular drug delivery

ABSTRACT

Introduction: Although eye drops are widely used as drug delivery systems for the anterior segment of the eye, they are also associated with poor drug bioavailability due to transient contact time and rapid washout by tearing. Moreover, effective drug delivery to the posterior segment of the eye is challenging, and alternative routes of administration (periocular and intravitreal) are generally needed, the blood–retinal barrier being the major obstacle to systemic drug delivery.

Areas covered: Nanotechnology, and especially lipid nanoparticles, can improve the therapeutic efficiency, compliance and safety of ocular drugs, administered via different routes, to both the anterior and posterior segment of the eye. This review highlights the main ocular barriers to drug delivery, as well as the most common eye diseases suitable for pharmacological treatment in which lipid nanoparticles have proved efficacious as alternative delivery systems.

Expert opinion: Lipid-based nanocarriers are among the most biocompatible and versatile means for ocular delivery. Mucoadhesion with consequent increase in pre-corneal retention time, and enhanced permeation due to cellular uptake by corneal epithelial cells, are the essential goals for topical lipid nanoparticle delivery. Gene delivery to the retina has shown very promising results after intravitreal administration of lipid nanoparticles as non-viral vectors.     

Chitosan nanoparticles as a new delivery system for the anti-Alzheimer drug tacrine

Tacrine-loaded chitosan nanoparticles were prepared by spontaneous emulsification. The particle size and zeta potential was determined by scanning probe microscopy and Zetasizer, respectively. The prepared particles showed good drug-loading capacity. The in vitro release studies showed that after the initial burst, all the drug-loaded batches provided a continuous and slow release of the drug. Coating of nanoparticles with Polysorbate 80 slightly reduced the drug release from the nanoparticles. Release kinetics studies showed that the release of drug from nanoparticles was diffusion-controlled, and the mechanism of drug release was Fickian. The biodistribution of these particles after intravenous injection in rats showed that of nanoparticles coated with 1% Polysorbate 80 altered the biodistribution pattern of nanoparticles.From the Clinical EditorIn this paper, chitosan nanoparticles are investigated in a pre-clinical study as an optimized delivery system for tacrin, a drug with potential significance in Alzheimer's disease. The preparation showed optimal pharmacokinetic characteristics in a rat model.     

Chitosan nanoparticles for drug delivery to the eye

The purpose of this review is to provide the reader with an overview of the advances made in ocular delivery of bioactive molecules by means of chitosan-based nanosystems, and their potential relevance in clinical use. The studies described clearly emphasise that chitosan-based nanostructures are versatile systems that can be tailor-made according to required compositions, surface characteristics and particle size. Such parameters, which are known to influence their in vivo performance, can be modulated by adjusting the formulation conditions of the nanotechnologies responsible for their formation, by incorporating additional materials in the preparation steps, and/or by using synthetically modified chitosan. Moreover, this review illustrates how the advances achieved in the understanding of the interaction of nanosystems with the ocular structures should result in the coming years, logically, into challenging innovations in ocular nanomedicines with significant impact on clinical practice.     

Chitosan nanoparticles as a novel delivery system for ammonium glycyrrhizinate

The ammonium glycyrrhizinate-loaded chitosan nanoparticles were prepared by ionic gelation of chitosan with tripolyphosphate anions (TPP). The particle size and zeta potential of nanoparticles were determined, respectively, by dynamic light scattering (DLS) and a zeta potential analyzer. The effects, including chitosan molecular weight, chitosan concentration, ammonium glycyrrhizinate concentration and polyethylene glycol (PEG) on the physicochemical properties of the nanoparticles were studied. These nanoparticles have ammonium glycyrrhizinate loading efficiency. The encapsulation efficiency decreased with the increase of ammonium glycyrrhizinate concentration and chitosan concentration. The introduction of PEG can decrease significantly the positive charge of particle surface. These studies showed that chitosan can complex TPP to form stable cationic nanoparticles for subsequent ammonium glycyrrhizinate loading.     

Albumin nanoparticles for the intravitreal delivery of anticytomegaloviral drugs

Albumin nanoparticles (NP) were proved to be effective and safe carriers for delivering anticytomegaloviral compounds in the vitreous. NP improved the antiviral activity of both ganciclovir and the phosphodiester oligonucleotide analog to formivirsen. NP appeared to be fusogenic carriers able to target the nucleus of cells. In addition, these drug carriers were well tolerated when administered by the intravitreal route and did not induce autoimmune reactions.     

Microrobots: a new era in ocular drug delivery

Introduction: Ocular microrobots have the potential to change the way in which we treat a variety of diseases at the anterior and the posterior segments of the eye. Wireless manipulation and positioning of drug delivery magnetic millimeter and submillimeter platforms into the eye constitute a potential route for minimally invasive targeted therapy. However, the field is still in its infancy and faces challenges related to the fabrication, control an interaction with complex biological environments.

Areas covered: This review briefly introduces the complex anatomy and physiology of the eye, which renders limitations to the current treatments of ocular diseases. The topical administration of eye drops, intravitreal injections and drug delivery implants is briefly mentioned together with their drawbacks. The authors also analyze the minimally invasive microrobotic approach as an alternative method and report the recent advancements in the fabrication, control, manipulation and drug delivery.

Expert opinion: Although microrobotics is a young field, a significant amount of work has been developed to face different challenges related to the minimally invasive manipulation of microdevices in the eye. Current research is already at the state of in vivo testing for systems and their biocompatibility. It is expected that the general concepts acquired will soon be applied for specific interventions, especially for posterior eye pathologies.     

Development of gatifloxacin-loaded cationic polymeric nanoparticles for ocular drug delivery

The present investigation aimed at improving the ocular bioavailability of gatifloxacin by prolonging its residence time in the eye and reducing problems associated with the drug re-crystallization after application through incorporation into cationic polymeric nanoparticles. Gatifloxacin-loaded nanoparticles were prepared via the nanoprecipitation and double emulsion techniques. A 50:50 Eudragit® RL and RS mixture was used as cationic polymer with other formulation parameters varied. Prepared nanoparticles were evaluated for size, zeta potential, and drug loading. An optimized formulation was selected and further characterized for in vitro drug release, cytotoxicity, and antimicrobial activity. The double emulsion method produced larger nanoparticles than the nanoprecipitation method (410?nm and 68?nm, respectively). Surfactant choice also affected particle size and zeta potential with Tween 80 producing smaller-sized particles with higher zeta potential than PVA. However, the zeta potential was positive at all experimental conditions investigated. The optimal formulation produced by double emulsion technique and has achieved 46% drug loading. This formulation had optimal physicochemical properties with acceptable cytotoxicity results, and very prolonged release rate. The particles antimicrobial activities of the selected formulation have been tested against Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus and showed prolonged antimicrobial effect for gatifloxacin.     

Chitosan nanoparticles as a dual growth factor delivery system for tissue engineering applications

The effect of stabilizer type (small molecule vs. polymeric) and the amount of micellar solubilized drug on Ostwald ripening of nanosuspensions was investigated. Indomethacin nanosuspensions were prepared with small molecule stabilizers (sodium lauryl sulfate (SLS) and Dowfax 2A1 (DF)) and a polymeric stabilizer (hydroxypropyl methyl cellulose (HPMC)). Two different drug:stabilizer ratios were used to evaluate the effect of micellar solubilized drug. The Ostwald ripening potential of nanosuspensions was evaluated by subjecting them to various stress conditions (temperature (15, 25, 35 and 45°C), thermal cycling, and mechanical shaking) for three months. The mean particle size increased in all SLS and DF formulations stored under different stress conditions. No effect of micellar solubilized drug on the Ostwald ripening rate was observed. In the case of HPMC formulations only those stored at higher temperatures (35 or 45°C) exhibited an increase in mean particle size. The increase in size in the HPMC formulation stored at 45°C was attributed to dehydration of the HPMC chains and subsequent loss of protection of the nanoparticles. The cube of the mean particle diameter versus time plot was determined to be non-linear for all formulations exhibiting Ostwald ripening. Therefore, according to the Lifshitz, Slyozov and Wagner theory the process was not diffusion controlled. The most probable mechanism for Ostwald ripening was surface nucleation controlled.     

Ion-activated in situ gelling systems for antisense oligodeoxynucleotide delivery to the ocular surface

Ion-activated in situ gelling systems are able to cross-link with the cations present in the tear fluid, forming a gel on the ocular surface and prolonging corneal contact time. Corneal scrape wounding offers an exceptional model to investigate the efficacy of these formulations for connexin43 (Cx43) antisense oligodeoxynucleotide (AsODN) delivery used to improve wound repair. Systems based on gellan gum and carrageenan have previously been found advantageous in terms of their physicochemical properties, in vitro and in vivo release profiles and precorneal retention. The present study describes AsODN penetration into corneal tissue after wounding and determines the formulations' delivery efficacy by evaluating wound size, tissue inflammation and connexin levels. No difference was shown between the penetration patterns of the formulations, with most of the AsODN accumulating in the epithelium close to the wound leading edge and the stroma underlying the wound. However, significant differences were seen in the delivery efficacy, with gellan gum and carrageenan based systems resulting in the lowest connexin levels and subsequently in the greatest reduction in wound size, the least stromal edema and hypercellularity. This demonstrates their potential use as delivery vehicles for AsODNs to the ocular surface.     

Biological effects of cyclosporin A: a new antilymphocytic agent.

The fungus metabolite cyclosporin A is a small peptide acting as a novel antilymphocytic agent. It strongly depressed appearance of both direct and indirect plaque-forming cells and produced a clear dose-dependent inhibition of haemagglutinin formation in mice upon oral administration. Skin graft rejection in mice and graft-versus-host disease in mice and rats were considerably delayed by cycloporin A which also prevented the occurrence of paralysis in rats with experimental allergic encephalomyelitis. This compound was not only highly effective in preventing development of Freund's adjuvant arthritis, but in addition improved the symptoms in rats with established arthritis, although it is inactive in acute inflammation. This new agent contrasts with other immunosuppressives and cytostatic drugs in its weak myelotoxicity. Experimental evidence suggests that cyclosporin A, rather than being cytostatic or lympholytic, affects an early stage of mitogenic triggering of the immunocompetent lymphoid cell.     

Chitosan glutamate nanoparticles for protein delivery: development and effect on prolidase stability

PURPOSE: To evaluate the feasibility of exploiting ultrasonication coupled with ionotropic gelation in order to prepare tripolyphosphate (TPP)-chitosan glutamate nanoparticles suitable for the delivery of the enzyme prolidase. METHODS: All the parameters for the preparation of TPP-chitosan nanoparticles in terms of components weight ratio, ultrasonication conditions and time-saving nanoparticles recovery conditions were optimized. The best formulation was loaded with the prolidase. All the nanoparticles were characterized in terms of morphology, size, polydispersity, zeta-potential, yield of the process and encapsulation efficiency. The in-vitro activity of the prolidase was assessed by capillary electrophoresis (CE). RESULTS AND CONCLUSIONS: A TPP to chitosan weight ratio of 0.2:1 combined with one ultrasonication cycle (4 min using the probe-type sonifier at 75% power) obtained well-formed nanoparticles of spherical shape, mean size of approximately 365 nm (polydispersity index 0.3) and a + 17.94 mV zeta potential. A satisfactory prolidase encapsulation efficiency (43%) was obtained with a yield of the preparation process of approximately 55%. In vitro study of activity of prolidase, as free enzyme or released from chitosan nanoparticles, highlighted the ability of chitosan to stabilize the enzyme during all the steps of the preparation process and to modulate the enzyme activity up to 48 h.     

Chitosan glutamate nanoparticles for protein delivery: Development and effect on prolidase stability

Purpose: To evaluate the feasibility of exploiting ultrasonication coupled with ionotropic gelation in order to prepare tripolyphosphate (TPP)-chitosan glutamate nanoparticles suitable for the delivery of the enzyme prolidase.

Methods: All the parameters for the preparation of TPP-chitosan nanoparticles in terms of components weight ratio, ultrasonication conditions and time-saving nanoparticles recovery conditions were optimized. The best formulation was loaded with the prolidase. All the nanoparticles were characterized in terms of morphology, size, polydispersity, zeta-potential, yield of the process and encapsulation efficiency. The in-vitro activity of the prolidase was assessed by capillary electrophoresis (CE).

Results and conclusions: A TPP to chitosan weight ratio of 0.2:1 combined with one ultrasonication cycle (4?min using the probe-type sonifier at 75% power) obtained well-formed nanoparticles of spherical shape, mean size of ～ 365?nm (polydispersity index 0.3) and a?+?17.94?mV zeta potential. A satisfactory prolidase encapsulation efficiency (43%) was obtained with a yield of the preparation process of ～55%. In vitro study of activity of prolidase, as free enzyme or released from chitosan nanoparticles, highlighted the ability of chitosan to stabilize the enzyme during all the steps of the preparation process and to modulate the enzyme activity up to 48?h.     

Cubic liquid crystalline nanoparticles: optimization and evaluation for ocular delivery of tropicamide

The purpose of this study was to investigate the potential of cubic liquid crystalline nanoparticles for ocular delivery of tropicamide. Ultrasound-assisted fragmentation of cubic liquid crystalline bulk phases resulted in cubic liquid crystalline nanoparticles employing Pluronic F127 as dispersant. The effects of process variables such as sonication time, sonication amplitude, sonication depth, and pre-mixing time on particle size and polydispersity index was investigated using central composite design. The morphology of tropicamide-loaded nanoparticles was found to be nearly cubical in shape by transmission electron microscopy observation. Further, small angle X-ray scattering experiment confirmed the presence of D and P phase cubic structures in coexistence. The optimized tropicamide-loaded cubic nanoparticles showed in vitro corneal permeation of tropicamide across isolated porcine cornea comparable to its commercial preparation, Tropicacyl®. Ocular tolerance was evaluated by Hen’s egg–chorioallantoic membrane test and histological studies. The results of in vivo mydriatic response study demonstrated a remarkably higher area under mydriatic response curve (AUC_0→1440?min) values of cubic nanoparticles over Tropicacyl® indicating better therapeutic value of cubic nanoparticles. Furthermore, tropicamide-loaded cubic nanoparticles exhibited prolonged mydriatic effect on rabbits as compared to commercial conventional aqueous ophthalmic solution.     

Systems approach to vaginal delivery of drugs IV: methodology for determination of membrane surface pH.

A physical model including a diffusional layer in series with the membrane was developed for studying the possible differences between the pH at the membrane surface and that in the bulk solution. Both the membrane-secreted substances (acids and bases) and buffer constituents in the bulk solutions are assumed to contribute to the surface pH. Equations derived for this situation, together with experimental determinations of the acidic dissociation constant of the secreted material, the total secretion flux, the flux of total secreted acidic species, and the diffusion layer thickness, allow estimates to be made of the pH at the membrane surface. With the rabbit vagina, the membrane surface pH was close to that of the bulk solution in most cases. These results were supported by the fact that the absorption of 1-alkanoic acids in pH 2.2 phosphate buffers was relatively constant over the buffer concentration range of 0.003-0.1 M phosphate.     

Piroxicam nanoparticles for ocular delivery: physicochemical characterization and implementation in endotoxin-induced uveitis

To investigate the anti-inflammatory impacts of piroxicam nanosuspension, in the current investigation, piroxicam:Eudragit RS100 nanoformulations were used to control inflammatory symptoms in the rabbits with endotoxin-induced uveitis (EIU). The nanoparticles of piroxicam:Eudragit RS100 was formulated using the solvent evaporation/extraction technique. The morphological and physicochemical characteristics of nanoparticles were studied using particle size analysis, X-ray crystallography, differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FT-IR) and scanning electron microscopy (SEM). Drug release profiles were examined by fitting the data to the most common kinetic models. Selected nanosuspensions were used to assess the anti-inflammatory impacts of piroxicam nanoparticles in the rabbits with EIU. The major symptoms of EIU (i.e. inflammation and leukocytes numbers in the aqueous humor) were examined. All the prepared piroxicam formulations using Eudragit RS100 resulted in a nano-range size particles and displayed spherical smooth morphology with positively charged surface, however, the formulated particles of drug alone using same methodology failed to manifest such characteristics. The Eudragit RS100 containing nanoparticles displayed lower crystallinity than piroxicam with no chemical interactions between the drug and polymer molecules. Kinetically, the release profiles of piroxicam from nanoparticles appeared to fit best with the Weibull model and diffusion was the superior phenomenon. The in vivo examinations revealed that the inflammation can be inhibited by the drug:polymer nanosuspension more significantly than the microsuspension of drug alone in the rabbits with EIU. Upon these findings, we propose that the piroxicam:Eudragit RS100 nanosuspensions may be considered as an improved ocular delivery system for locally inhibition of inflammation.