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A methodology was developed and optimised for the preparation of a new drug delivery system (DDS) with sustained release properties to allow ocular protein delivery and to limit destructive production steps during manufacturing. Elevated temperatures, shear forces and an oxidative environment should be avoided in order to prevent denaturation or oxidation of proteins. An aqueous HPMC solution was prepared using heat and casted into small semi-rod-shaped PVC blisters. The polymer solution was allowed to cool down and was partially dehydrated at room temperature. A drug solution containing glycerol, drug and water was subsequently added to rehydrate the partially dehydrated polymer matrix at a temperature of 2 degrees C. Several parameters of the production process were varied to determine their influence on the release kinetics from HPMC inserts from three different molecules of different molecular weight. This production method was further optimised in order to shorten the rehydration time from weeks to days, while eliminating heat and shear forces on the selected drug molecules sodium fluorescein, lysozyme and albumin. Slow release kinetics were achieved for sodium fluorescein and lysozyme as model drug molecules. The higher molecular weight of albumin prevented a good penetration into the insert during the rehydration process resulting in predominantly burst release. The biocompatibility of a viscous HPMC solution was evaluated on SV40-human corneal epithelial cells with PrestoBlue (R) and no cytotoxic effects were observed. (C) 2017 Elsevier B.V. All rights reserved.

Ocular chitosan films were prepared in order to prolong ocular delivery of cyclosporine A. The mucoadhesive films were prepared using the solvent casting evaporation method. A 24 full factorial design was used to evaluate the effect of 4 preparation parameters on the film thickness, swelling index and mechanical properties. Moreover, uniformity of content and in vitro drug release were investigated. Possible interactions between the film excipients were studied by FTIR analysis. In vitro experiments were performed in order to evaluate the cytotoxicity and anti-inflammatory activity of the chitosan films. Film thickness, water uptake, mechanical properties and in vitro release of cyclosporine A were dependent on film composition, especially on the amount of plasticizer. Lower drug release was measured from chitosan films containing a higher amount of plasticizer as glycerol decreased the swelling of chitosan films. FTIR spectra suggest a reorganization of hydrogen bonds between chitosan chains in the presence of glycerol and cyclodextrins. None of the film formulations showed significant cytotoxicity as compared to the negative control using human epithelial cells (HaCaT). Cyclosporine A dispersed in the various film formulations remained anti-inflammatorily active as significant suppression of interleukin-2 secretion in concanavalin A stimulated Jurkat T cells was measured. (C) 2014 Elsevier B.V. All rights reserved.

This paper describes the development of poly(D,L-lactide-co-glycolide) (PLGA) nanoparticles (NPs) and nanosuspensions with the polyene antibiotic amphotericin B (AmB). The nanoformulations were prepared using nanoprecipitation and were characterised with respect to size, zeta potential, morphology, drug crystallinity and content. Standard in vitro sensitivity tests were performed on MRC-5 cells, red blood cells, Leishmania infantum promastigotes and intracellular amastigotes and the fungal species Candida albicans, Aspergillus fumigatus and Trichophyton rubrum. The in vivo efficacy was assessed and compared to that of Fungizone® and AmBisome® in the acute A. fumigatus mouse model at a dose of 2.5 and 5.0 mg/kg AmB equivalents. The developed AmB nanoformulations were equivalently or more effective against the different Leishmania stages and axenic fungi in comparison with the free drug. The in vitro biological activity, and especially hemolytic activity, clearly depended on the preparation parameters of the different nanoformulations. Further, we demonstrated that the superior in vitro antifungal activity could be extrapolated to the in vivo situation. At equivalent dose, the optimal AmB-loaded PLGA NP was about two times and the AmB nanosuspension about four times more efficacious in reducing the total burden than AmBisome®. The developed AmB nanomedicines could represent potent and cost-effective alternatives to Fungizone® and AmBisome®.

The objective of this study was to enhance the encapsulation of the antileishmanial saponin aescin in poly(D,L-lactide-co-glycolide) (PLGA) nanoparticles (NPs). We prepared the NPs by the O/W and W/O/W combined emulsification solvent evaporation/salting-out technique and investigated the influence of organic phase composition on the NPs size, zeta potential and entrapment efficiency (EE%) using mixture designs. The obtained NPs were monodispersed with Zave

Colloidal carriers are known to improve the therapeutic index of the conventional drugs in the treatment of visceral leishmaniasis (VL) by decreasing their toxicity whilst maintaining or increasing therapeutic efficacy. This paper describes the development of poly(d,l-lactide-co-glycolide) (PLGA) nanoparticles (NPs) for the antileishmanial saponin β-aescin. NPs were prepared by the W/O/W emulsification solvent evaporation technique and the influence of five preparation parameters on the NPs' size (Z(ave)), zeta potential and entrapment efficiency (EE%) was investigated using a 2(5-2) fractional factorial design. Cytotoxicity of aescin, aescin-loaded and blank PLGA NPs was evaluated in J774 macrophages and non-phagocytic MRC-5 cells, whereas antileishmanial activity was determined in the Leishmania infantum ex vivo model. The developed PLGA NPs were monodispersed with Z(ave)

Pilocarpine loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles were prepared by solvent evaporation method and coated with various mucoadhesive polymers, in particular chitosan, sodium alginate and poloxamers. The size of chitosan-coated nanoparticles was larger than the size of all the other particles obtained. Their surface charge was changed from negative (−22.8 mV) to positive (+61.0 mV). The interaction between mucin and chitosan-coated nanoparticles took place up to six hours according to turbidimetric study. The positive charge of chitosan-coated nanoparticles decreased significantly six hours after incubation in mucin dispersion, which was attributed to their electrostatic interaction. The coating with chitosan could be considered useful approach aiming to prolong nanoparticle residence time after local ocular application.

In the present update on mucoadhesive ocular dosage forms, the tremendous advances in the biochemistry of mucins, the development of new polymers, the use of drug complexes and other technological advances are discussed. This review focusses on recent literature regarding mucoadhesive liquid (viscous solutions, particulate systems), semi-solid (hydrogel, in situ gelling system) and solid dosage forms, with special attention to in vivo studies. Gel-forming minitablets and inserts made of thiomers show an interesting potential for future applications in the treatment of ocular diseases.

An experimental factorial design was employed to evaluate bioadhesive granules and bioerodible ocular minitablets (6 mg and O 2 mm). The purpose of this study was to compare minitablets prepared using roller compacted granules with an optimised minitablet formulation, manufactured on laboratory scale by direct compression. The formulation consisted of drum dried waxy maize starch, Carbopol® 974P, and ciprofloxacin in a ratio of 90.5/5/3 (w/w/w). Three roller compactor parameters were varied, i.e. the roller speed, the horizontal screw speed and the compaction force, while the vertical screw speed was kept constant. Afterwards, the ribbons were milled to obtain granules suitable for compression. The friability, the flow properties, the bulk material characteristics (apparent and tap density and porosity) and the particle size distributions of two granule sieve fractions (90–125 and 125–355 μm) were investigated. The roller speed and the compaction force have the largest influence on the granule characteristics, followed by the horizontal screw speed. The physical properties of non- and gamma-irradiated minitablets were determined. From the tablet strength, friability and dissolution results, a low compaction force and a high roller speed were shown to be preferable to prepare granules which can be further tabletted into adequate ocular minitablets.

In the present study, the influence of freeze-drying with several cryoprotective agents and gamma (γ)-irradiation sterilization on the physicochemical characteristics of ciprofloxacin HCl-loaded poly(D,L-lactide-co-glycolide) (PLGA) nanoparticles was evaluated. Nanoparticles were prepared by W/O/W emulsification solvent evaporation followed by high-pressure homogenization. They were freeze-dried in the presence of 5.0% (w/v) mannitol, trehalose or glucose, with 5.0% (w/v) or 15.0% (w/v) dextran as cryoprotectants. The nanoparticles were irradiated at a dose of 25 kGy using a 60Co source. The following physicochemical properties of the formulations were investigated: the ratio of particle size before (initial) and after freeze-drying, the ease of reconstitution of the nanoparticle suspensions and the drug-release profiles of irradiated and non-irradiated nanoparticles. The anti-bacterial activity against Pseudomonas aeruginosa was measured. The freeze-drying process induced a significant increase in particle size when no cryoprotectant was employed. Similar results were observed when cryoprotectants were added to the formulation. Only when mannitol was used was no significant size increase measured. Moreover, for formulations with dextran, reconstitution after freeze-drying was difficult by manual agitation and particle size could not be determined because of aggregation. After γ-sterilization no significant difference in mean particle size was observed, but reconstitution was more difficult and drug release was influenced negatively. Ciprofloxacin HCl incorporated in the nanoparticles was still effective against the micro-organism selected after freeze-drying and γ-sterilization.

PURPOSE Evaluation in volunteers of ciprofloxacin-containing ocular gelling minitablets with prolonged release properties. METHODS The irritation potential of ciprofloxacin-containing bioadhesive powder mixtures, used to prepare ocular bioerodible minitablets, was evaluated with a slug mucosal-irritation test. The tear pharmacokinetic profiles of ciprofloxacin were determined in six healthy volunteers after topical administration of a minitablet and a single eye drop in the lower fornix. The drug concentrations in the tear samples collected were measured by using a validated HPLC METHOD: Each volunteer was asked to give an evaluation of the preparations applied by answering a standard questionnaire. RESULTS The results of the mucosal-irritation test demonstrated the nonirritating properties of the bioadhesive powder mixtures. The ocular minitablet, applied in the fornix was in general well tolerated by the healthy volunteers. The mean tear concentration of ciprofloxacin was 33.0, 135.2, and 33.7 microg/g at 30, 300, and 480 minutes after application of the minitablet. Mean tear levels of 84.7, 45.6, and 8.4 microg/g were obtained at 5, 30, and 60 minutes after application of an eye drop. CONCLUSIONS Due to their prolonged drug release properties, the ocular minitablets containing ciprofloxacin can be considered as a promising drug delivery system to be used in the treatment of ulcerative bacterial keratitis.

Poly(lactide-co-glycolide) nanoparticles incorporating ciprofloxacin HCl were prepared by means of a W/O/W emulsification solvent evaporation method. The physicochemical properties of these particles were evaluated by measuring particle size, zeta potential and drug loading efficiency. Gamma-sterilised nanoparticles were dispersed in different isoviscous polymer solutions, commonly used as vehicles in eye drops. The influence of γ-irradiation of the viscosifying agents on the drug release properties of the dispersed nanoparticles was evaluated with respect to release in mannitol solution. The viscosity of the polymer solutions prepared was measured by flow rheometry and thereby the influence of temperature and sterilisation by autoclaving on viscosity was examined. Before and after freeze-drying and subsequent sterilisation by gamma-irradiation, the polymer solutions were also characterised by dynamic stress sweep and dynamic frequency sweep oscillation measurements to deduce possible structural changes. A possible relationship between the differences in ciprofloxacin release from the nanoparticles suspended in the various media and the network structure or rheological behaviour of the polymers was investigated.

Ophthalmic solutions are available for multidose or single-dose administration in a wide variety of glass and plastic dropper bottles which deliver drops with a volume between 25 and 70 microl. From a biopharmaceutical and economic point of view, however, smaller volumes of 5 to 15 microl should be instilled. In this review, the technical, pharmaceutical, and therapeutic aspects of eye drop formation and delivery are presented. The different types of containers are described and the determinants of eye drop size are discussed, such as the design and physical characteristics of the dropper tip and bottle, the physico-chemical properties of the solution, and the manner in which the patient dispenses the drops. Preferred and alternative instillation techniques and aids to facilitate the administration of eye drops by elderly patients are described.

Poly(lactide-co-glycolide) nanoparticles loaded with pilocarpine hydrochloride were prepared by the high-pressure emulsification-solvent evaporation method. The nanoparticles were produced using polyvinylalcohol (PVA), carbomer (Carbopol 980) or poloxamer (Lutrol F-68) as stabilizers during emulsification. The influence of pressure and number of cycles on the nanoparticle properties was investigated. For comparison, nanoparicles without high-pressure treatment of the emulsion were made. The nanoparticle size, drug loading and release properties depended strongly on the homogenization pressure and number of cycles applied. Nanoparticles obtained without high pressure homogenization showed larger size and high values of polydispersity index, especially when carbopol and poloxamer were used as emulsifiers. Drug loading and encapsulation efficiency of all samples also decreased with pressure. The low drug loading could be due to two reasons. First, the high pressure promoted drug diffusion out of protoparticles during emulsification either by size reduction or shear forces. Secondly, the characteristics of the outer water phase of the emulsion also influenced the nanoparticle drug loading. This was proven by the different drug loadings measured when nanoparticles were made with PVA, carbopol or poloxamer at equal pressures applied. The main factor influencing the release properties of nanoparticles was the pressure used during emulsification. Faster drug release was observed from nanoparticles obtained after high-pressure emulsification compared to those prepared without homogenization of the emulsion.

We report the synthesis and physicochemical evaluation of a series of cationic polymethacrylates as vectors for gene delivery. Two different types of polymer have been synthesized: The first is a series of polymers containing tertiary amine, pyridine, imidazole and acid groups; the second is a series of polyamines containing poly(ethylene oxide) (PEO) blocks or grafts. The ability of the different polymers to condense DNA has been studied by agarose gel electrophoresis; all polymers are able to condense DNA, their ability to do so being dependent on their chemical composition and molecular weight. The particle size of the different polymer-DNA complexes formed has been measured by dynamic light scattering: complexes have a particle size of around 50nm. A clear effect of the chemical composition of the polymers on the zeta potential of their complexes with DNA is evident.

The present study investigated the influence of the rheological behaviour, the viscoelasticity and surface tension of various viscolysers on the weight of drops dispensed from a commercially available flexible dropper bottle. Furthermore, the effect of the concentration and molecular weight of some viscolysers and the angle at which the dropper bottle is held, were studied. Up to a value of 25 mPa·s, the viscosity and the rheological behaviour of the solution had no significant influence on the drop weight under conditions simulating patient manipulation. The lower the dynamic surface tension of the solution, however, the lower the weight of drops delivered. The dispensing angle (90 or 45°) of the dropper bottle, on the other hand, had an impact on the weight of drops dispensed.

The influence of the physicochemical properties of various penetration enhancers on the weight of drops dispensed from flexible plastic dropper bottles was examined. Two dropper tips with a different design were compared and the dropper bottle was held in the upright position (90 degrees angle) or at a 45 degrees angle. These two angles were chosen to simulate the manipulation of an eye dropper bottle by the patient. The surface tension of the penetration enhancer solutions was determined using the dynamic drop volume method. The dynamic surface tension values ranged from 65 to 30 mN/m. The lower the surface tension of the solution, the lower the weight of the drop delivered. Both the design of the dropper tip and the manipulation technique of the dropper bottle had a moderate to important influence on the drop weight. The relationship between the surface tension of the penetration enhancer solution instilled and the comfort of the patient was evaluated by an acceptability test based on answering a questionnaire. Penetration enhancers can be used to reduce the drop size of conventional ophthalmic solutions on condition that they do not elicit local irritation.