Long-Term Efficacy Following Intra-articular Injection of Carboxymethyl-chitosan, a New Product Class for Knee Osteoarthritis: Results from an Observational Study in Germany.

INTRODUCTION: Evaluate the real-world efficacy of a single intra-articular injection of carboxymethyl-chitosan (CM-chitosan), a new product class for knee osteoarthritis (OA). METHODS: This post-marketing study included adult patients with knee OA, who received a single injection of 60 mg CM-chitosan (currently marketed as KioMedinevsone) according to the instructions for use. Follow-up was performed at weeks 1, 12, 24, and 36. Efficacy was evaluated using a Visual Analog Scale (VAS) score for pain, the Knee injury and Osteoarthritis Outcome Score (KOOS), Patient's Global Assessment (PGA), and overall patient satisfaction. RESULTS: Forty-nine patients were included in the study. VAS pain score significantly decreased from a median of 49.0 mm at baseline to 24.0 mm at week 1 and to 18 mm at week 36. Pain improvement was stable since at week 36; 91.8% of patients confirmed pain reduction. All KOOS subscales (symptoms, pain, activities of daily living, sports and recreational activities, quality of life) improved significantly compared to baseline at all time points. KOOS pain improved progressively from a median of 58.3% at baseline (mean 56.2 ± 18.8%) to 86.1% (mean 74.1 ± 24%) at week 36 compared to baseline. Overall, more than 70% of patients reported a condition gain (PGA), matching well with the more than 75% of patients being satisfied with the treatment. At 6 months, 72.7% of the patients could be classified as responder according to the OMERACT-OARSI proposed set of responder criteria. CONCLUSION: CM-chitosan showed a rapid onset of pain relief after 1 week and with a duration of 9 months. In a real-world setting, treatment with CM-chitosan would appear to be a potentially effective option to reduce pain and improve physical function and global condition in patients with knee OA, opening new perspectives in patients who are considered as refractory to current symptomatic therapies and where the unmet need is high. TRIAL REGISTRATION NUMBER: NCT04757051 (ClinicalTrials.gov).

Optimisation of HPMC ophthalmic inserts with sustained release properties as a carrier for thermolabile therapeutics.

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°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® and no cytotoxic effects were observed.

Evaluation of a newly developed HPMC ophthalmic insert with sustained release properties as a carrier for thermolabile therapeutics.

A novel drug delivery system (DDS) with sustained release properties was developed to allow ocular protein delivery. The DDS developed is aimed at overcoming stability issues during preparation such as denaturation of proteins caused by shear forces applied or due to elevated temperatures and air entrapment potentially causing oxidation of the molecule. The rod-shaped HPMC inserts were loaded with lysozyme and several HPMC types were studied and compared. An aqueous colloidal HPMC solution (hydrogel) was prepared and subsequently dried at 150°C to dehydrate the polymer solution. This partially dehydrated polymer cylinder was loaded with an aqueous glycerol/lysozyme solution at 2°C. A 2(4) full factorial design was set up to evaluate the effect of the different preparation parameters on water uptake and release properties. As a result, four out of sixteen formulations revealed homogenous distribution for lysozyme in both duplicates. The change in water uptake over time was dependent on the type of HPMC polymer used but not between the chosen HPMC percentages. After 240min, 50% of lysozyme loaded was released depending on the chosen formulation. Lysozyme molecules exhibit slower release from a K100M matrix compared to E10M inserts, albeit the overall effect is relatively limited.

Development and characterization of mucoadhesive chitosan films for ophthalmic delivery of cyclosporine A.

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 2(4) 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.

Full factorial design, physicochemical characterisation and biological assessment of cyclosporine A loaded cationic nanoparticles.

Cyclosporine A loaded poly(lactide-co-glycolide) nanoparticles coated with chitosan were prepared using the o/w emulsification solvent evaporation method. A 2(3) full factorial design was used to investigate the effect of 3 preparation parameters on the particle size, polydispersity index, zeta potential and drug release. In vitro experiments were performed in order to evaluate the cytotoxicity and anti-inflammatory activity of the developed nanoparticles. Particle sizes varied from 156 nm to 314 nm, and polydispersity index values of 0.07-0.56 were obtained depending on the different preparation parameters. All nanoparticles showed positive zeta potential values. Nanoparticles prepared with the highest concentration chitosan retained a positive zeta potential after dispersion in simulated lachrymal fluid, which supports the possibility of an electrostatic interaction between these particles and the negatively charged mucus layer at the eye. The in vitro release profile of cyclosporine A from the chitosan-coated nanoparticles was strongly dependent on the release medium used. None of the cationic nanoparticle formulations showed significant cytotoxicity compared to the negative control using human epithelial cells (HaCaT). Cyclosporine A encapsulated in the various nanoparticle formulations remained anti-inflammatory active as significant suppression of interleukine-2 secretion in concanavalin A stimulated Jurkat T cells was observed.

Cytotoxicity of submicron emulsions and solid lipid nanoparticles for dermal application.

The cytotoxicity and physical properties of various submicron O/W emulsions and solid lipid nanoparticles for dermal applications were investigated. Droplet size and zetapotential of submicron emulsions depended on the composition of the cosurfactant blend used. The viability of J774 macrophages, mouse 3T3 fibroblasts and HaCaT keratinocytes was significantly reduced in the presence of stearylamine. Nanoparticles consisting of stearic acid or different kinds of adeps solidus could be manufactured when formulated with lecithin, sodium taurocholate, polysorbate 80 and stearylamine. Survival of macrophages was highly affected by stearic acid and stearylamine. In general a viability of more than 90% was observed when semi-synthetic glycerides or hard fat was employed to formulate nanoparticles.

Effects of roller compaction settings on the preparation of bioadhesive granules and ocular minitablets.

An experimental factorial design was employed to evaluate bioadhesive granules and bioerodible ocular minitablets (6 mg and Psi 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 microm) 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.

The influence of the use of viscosifying agents as dispersion media on the drug release properties from PLGA nanoparticles.

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 gamma-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.

Ocular bioerodible minitablets as strategy for the management of microbial keratitis.

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.

Mucoadhesive ocular insert based on thiolated poly(acrylic acid): development and in vivo evaluation in humans.

The aim of the study was to develop a mucoadhesive ocular insert for the controlled delivery of ophthalmic drugs and to evaluate its efficacy in vivo. The inserts tested were based either on unmodified or thiolated poly(acrylic acid). Water uptake and swelling behavior of the inserts as well as the drug release rates of the model drugs fluorescein and two diclofenac salts with different solubility properties were evaluated in vitro. Fluorescein was used as fluorescent tracer to study the drug release from the insert in humans. The mean fluorescein concentration in the cornea/tearfilm compartment as a function of time was determined after application of aqueous eye drops and inserts composed of unmodified and of thiolated poly(acrylic acid). The acceptability of the inserts by the volunteers was also evaluated. Inserts based on thiolated poly(acrylic acid) were not soluble and had good cohesive properties. A controlled release was achieved for the incorporated model drugs. The in vivo study showed that inserts based on thiolated poly(acrylic acid) provide a fluorescein concentration on the eye surface for more than 8 h, whereas the fluorescein concentration rapidly decreased after application of aqueous eye drops or inserts based on unmodified poly(acrylic acid). Moreover, these inserts were well accepted by the volunteers. The present study indicates that ocular inserts based on thiolated poly(acrylic acid) are promising new solid devices for ocular drug delivery.