Development and Characterization of Potential Ocular Mucoadhesive Nano Lipid Carriers Using Full Factorial Design.

Generally, topically applied eye drops have low bioavailability due to short residence time and low penetration of the drug. The aim of the present study was to incorporate dexamethasone (DXM) into nano lipid carriers (NLC), which contain mucoadhesive polymer, in order to increase the bioavailability of the drug. A 23 factorial experimental design was applied, in which the three factors were the polymer, the DXM, and the emulsifier concentrations. The samples were analyzed for particle size, zeta potential, polydispersity index, and Span value. The significant factors were identified. The biocompatibility of the formulations was evaluated with human corneal toxicity tests and immunoassay analysis. The possible increase in bioavailability was analyzed by means of mucoadhesivity, in vitro drug diffusion, and different penetration tests, such as in vitro cornea PAMPA model, human corneal cell penetration, and ex vivo porcine corneal penetration using Raman mapping. The results indicated that DXM can be incorporated in stable mucoadhesive NLC systems, which are non-toxic and do not have any harmful effect on cell junctions. Mucoadhesive NLCs can create a depot on the surface of the cornea, which can predict improved bioavailability.

Comparison of hydrophilic ophthalmic media on silicone oil emulsification.

The aim of this study was to investigate whether and how the biological media which are in contact with silicone oil play a role in the silicone emulsification process. Commercially available Oxane 1300 silicone oil and potential hydrophilic phases of the emulsions in the eye (porcine aqueous humor, porcine vitreous and balanced salt solution) were investigated separately and in a mixture or emulsions by means of surface tension, rheological, zeta potential measurements and microscopic investigation. The surface tension of biological media (vitreous and aqueous humor) was significantly lower than that of non-biological media, especially in the case of aqueous humor, which indicates a remarkable emulsification tendency with these phases. The biological media are able to form both oil-in-water and water-in-oil emulsions, which can be observed in the clinical practice as well. It was established that the vitreous has a more expressed emulsification ability compared with the aqueous humor because smaller and more stable droplets can form with silicon oil when the vitreous is still there. It can be concluded that the vitreous has a higher impact on emulsification than the aqueous medium, which can predict that the vitreous remaining after vitrectomy has a key role in emulsion formation in the eye with silicone oil endotamponade.

Design and Optimization of Nanostructured Lipid Carrier Containing Dexamethasone for Ophthalmic Use.

The aim of this study was to perform a preformulation study of dexamethasone (DXM)-loaded nanostructured lipid carriers (NLCs) for ocular use. Lipid screening was applied to find the most suitable solid and liquid lipids and surfactant for the NLC formulation. The visual observation was proved with XRD measurements for the establishment of the soluble state of DXM. Thermoanalytical measurements indicated that the most relevant depression of the crystallinity index could be ensured when using a 7:3 solid lipid:oil ratio. In order to optimize the NLC composition, a 23 full factorial experimental design was used. It was established that each independent factor (lipid, DXM, and surfactant concentration) had a significant effect on the particle size while in the case of entrapment efficiency, the DXM and surfactant concentrations were significant. Lower surfactant and lipid concentrations could be beneficial because the stability and the entrapment efficacy of NLCs were more favorable. The toxicity tests on human cornea cells indicated good ophthalmic tolerability of NLCs. The in vitro drug release study predicted a higher concentration of the solute DXM on the eye surface while the Raman mapping penetration study on the porcine cornea showed a high concentration of nanocarriers in the hydrophylic stroma layer.

Mucoadhesive Cyclodextrin-Modified Thiolated Poly(aspartic acid) as a Potential Ophthalmic Drug Delivery System.

Thiolated poly(aspartic acid) is known as a good mucoadhesive polymer in aqueous ophthalmic formulations. In this paper, cyclodextrin-modified thiolated poly(aspartic acid) was synthesized for the incorporation of prednisolone, a lipophilic ophthalmic drug, in an aqueous in situ gellable mucoadhesive solution. This polymer combines the advantages of cyclodextrins and thiolated polymers. The formation of the cyclodextrin-drug complex in the gels was analyzed by X-ray powder diffraction. The ocular applicability of the polymer was characterized by means of physicochemical, rheological and drug diffusion tests. It was established that the chemical bonding of the cyclodextrin molecule did not affect the complexation of prednisolone, while the polymer solution preserved its in situ gellable and good mucoadhesive characteristics. The chemical immobilization of cyclodextrin modified the diffusion profile of prednisolone and prolonged drug release was observed. The combination of free and immobilized cyclodextrins provided the best release profile because the free complex can diffuse rapidly, while the bonded complex ensures a prolonged action.

[Case report on choroidal effusion after oral acetazolamide administration: an unusual manifestation of a well-known idiosyncratic effect?] / Acetazolamid orális alkalmazása mellett jelentkezo chorioidealeválás két esete: ismert idioszinkráziás hatás szokatlan megjelenési formája?

Sulpha drugs are widely employed in medicine for various diseases and disorders. During the last several decades, numerous papers had been published on supra ciliary and posterior choroidal effusion likely presenting as an idiosyncratic effect of these drugs especially of acetazolamide. In each publication, the effusion was associated with either an acute angle-closure glaucoma or transitory myopia or both of these as leading symptoms. In the current publication, authors report on two cases where the acetazolamide-induced choroidal effusion was an accidental finding without either a myopic shift in refraction or an acute elevation in intraocular pressure. To our best knowledge, ours is the first report in the literature describing this unusual, "silent" form of a sulpha drug-induced choroidal effusion. Since the choroidal involvement may vary in size and location, and is not necessarily associated with acute glaucoma and myopia, one can assume that a considerable amount of acetazolamide-related ocular side-effects will not be discovered. The above case report aims to draw the attention of other specialities to the need for ophthalmic examination for their patients taking sulpha drugs with acute visual deterioration. Orv Hetil. 2017; 158(50): 1998-2002.

Cationic Thiolated Poly(aspartamide) Polymer as a Potential Excipient for Artificial Tear Formulations.

Dry eye disease is a relatively common ocular problem, which causes eye discomfort and visual disorders leading to a decrease in the quality of life. The aim of this study was to find a possible excipient for eye drop formulations, which is able to stabilize the tear film. A cationic thiolated polyaspartamide polymer, poly[(N-mercaptoethylaspartamide)-co-(N-(N',N'-dimethylaminoethyl)aspartamide)] (ThioPASP-DME), was used as a potential vehicle. Besides satisfying the basic requirements, the chemical structure of ThioPASP-DME is similar to those of ocular mucins as it is a protein-like polymer bearing a considerable number of thiol groups. The solution of the polymer is therefore able to mimic the physiological properties of the mucins and it can interact with the mucus layer via disulphide bond formation. The resultant mucoadhesion provides a prolonged residence time and ensures protective effect for the corneal/conjunctival epithelium. ThioPASP-DME also has an antioxidant effect due to the presence of the thiol groups. The applicability of ThioPASP-DME as a potential excipient in eye drops was determined by means of ocular compatibility tests and through examinations of the interactions with the mucosal surface. The results indicate that ThioPASP-DME can serve as a potential eye drop excipient for the therapy of dry eye disease.

Comparative study of nanosized cross-linked sodium-, linear sodium- and zinc-hyaluronate as potential ocular mucoadhesive drug delivery systems.

Hyaluronic acid (HA) and its derivatives play important roles in many fields of therapy, such as arthritis treatment, plastic surgery, dermatology, otology, ophthalmology, etc. With a view to increase the beneficial properties of HA in ocular drug delivery, many types of chemical structural modifications have been performed. In the course of our research work, we characterized nanosized cross-linked - (CLNaHA), linear sodium hyaluronate (NaHA) and zinc-hyaluronate (ZnHA), as potential ocular drug delivery systems. The aim was to determine the influence of the structure on biocompatibility, mucoadhesion and drug release. The structure was characterized by means of rheology. The cytotoxicity of the samples was determined on rabbit corneal epithelial cells (RCE) by the MTT test. Mucoadhesion measurements were made by a rheological method in vitro and by tensile tests in vitro and ex vivo. The release of sodium diclofenac, a frequently used non-steroidal anti-inflammatory drug with low bioavailability, from the gels was determined with a vertical Franz diffusion cell. The results demonstrated that all three derivatives have adequate mucoadhesive properties and their rapid drug release profiles are beneficial in ocular therapy. Thanks to these properties, the bioavailability of the ophthalmic preparations can be increased, especially with the application of CLNaHA.

Thiolated poly(aspartic acid) as potential in situ gelling, ocular mucoadhesive drug delivery system.

The ophthalmic formulations on the market suffer from poor bioavailability, and it would therefore be useful to design a new formulation which is able to prolong the residence time and reduce the administration frequency. Polymer matrices which exhibit strong mucoadhesion are promising platforms in ocular drug delivery from the aspect of improved bioavailability. In the present study, an in situ gelling, mucoadhesive drug delivery system was fabricated from thiolated poly(aspartic acid) (ThioPASP). The thiol groups of ThioPASP are able to form disulphide linkages with the mucin glycoproteins and prolong the residence time on the eye. The effects of the thiol groups on the structure, swelling behaviour and mucoadhesive character of the gel and on the drug release profile were determined. The gel structure was characterized by means of rheology. The ThioPASP gel was demonstrated by rheology, tensile test and 'wash away' measurements to display strong mucoadhesion. The drug release from the ThioPASP gel was studied on a vertical Franz diffusion cell: a burst release of sodium diclofenac occurred in the first hour, followed by sustained release of the encapsulated drug for up to 24h. The results proved the importance of the presence of the thiol groups and suggested that a ThioPASP formulation can be useful as an in situ gelling, ocular dosage form.

Sublethal dose of 4-hydroxynonenal reduces intracellular calcium in surviving motor neurons in vivo.

4-Hydroxynonenal (4-HNE), a major lipid peroxidation product, induces oxidative stress, acts as an autonomous effector of cell death in motor neuron hybrid cell cultures, and is elevated in the cerebrospinal fluid (CSF) of patients with amyotrophic lateral sclerosis (ALS). Elevation of the total intracellular calcium has also been demonstrated in motor axon terminals of ALS patients as well as in spinal motor neurons of animal models of familial and sporadic ALS. Since the association of intracellular calcium and oxidative stress has been suggested in ALS, the in vivo effect of intrathecally administered 4-HNE on the motor neuronal calcium level was examined in the spinal cord of rats. After 12 days of treatment, total intracellular calcium was assayed by electron microscopic histochemistry using the oxalate-pyroantimonate method. Morphology of spinal motor neurons was characterized by light and electron microscopy. In rats, 4-HNE treatment induced a mild impairment of gait, elevation of 4-HNE in the CSF, loss of spinal motor neurons, and reduction of total calcium in the surviving, structurally intact motor neurons. 4-HNE could only cause a lesion if glutathione synthesis was concomitantly inhibited in the animals. The results suggest that upstream components of the oxidative injury in relation to lipid peroxidation are necessary to compromise the glutathione system in ALS, allowing an increase of 4-HNE in the CSF, which further aggravates the primary oxidative lesion. The reduced intracellular calcium in the surviving motor neurons with no morphological features of degeneration may reflect an impaired ionic homeostasis, which may indicate a residual damage of an incomplete degenerative process.

The expression of PARP, NF-kappa B and parvalbumin is increased in Parkinson disease.

Immunohistochemical techniques revealed a significant increase of poly(ADP-ribose) polymerase (PARP)-containing nuclei in the dopaminergic neurons of the substantia nigra (SN) in Parkinson disease and in diffuse Lewy body disease as compared with a group of patients with other neurodegenerative diseases and normal controls. The nuclear translocation of nuclear factor kappa B (NF-kappa B) was also noted in the same cells. The over-activation of PARP and the transcriptional activation of NF-kappa B can contribute to the pathomechanism of the disease specific lesion of the neurons in the SN. However, in another subgroup of dopaminergic cells of the SN an increased parvalbumin content was detected reflecting a natural protective mechanism against the putative increase of intracellular calcium caused by excitotoxic injury and oxidative stress.