Chitosan/hydroxyethyl cellulose inserts for sustained-release of dorzolamide for glaucoma treatment: In vitro and in vivo evaluation.

Eye drops containing hydrophilic drugs are commonly used to reduce intraocular pressure (IOP) in glaucoma patients, but compliance to the treatement is commonly reduced by frequent dosing and eventual systemic side effects. Sustained-release drug delivery systems, such as ocular inserts, can reduce dosing, limit systemic exposure, reduce side effects, and, then, improve patient adherence to therapy. Here, we developed and evaluated chitosan/hydroxyethyl cellulose-based ocular inserts for sustained release of dorzolamide, a hydrophilic drug. Dorzolamide inserts (DI) were produced by solvent/casting method and characterized by various physicochemical techniques. Pharmacokinetics studies were performed using scintigraphic images and ex vivo biodistribution. The effectiveness of inserts was tested in glaucomatous rats. Characterization studies showed that the drug strongly interacted with the polymeric matrix, but in vitro results showed that DI took only 3 h to release 75% of dorzolamide entraped. However, scintigraphic images and ex vivo biodistribution studies revealed that more than 50% of 99mTc-dorzolamide remained in the eye after 18 h of DI administration, while only about 30% of the drug remained in the eye after drops instilation. DI exerted significant hypotensive effect for two weeks, after single administration, while IOP values remained high in placebo and untreated groups. Eye drops were effective only during the treatment period. Only DI treatment prevented retinal ganglion cells death. Altogether, these findings evidenced the potential application of polymeric-based inserts for sustained release of dorzolamide in glaucoma management.

Physics, chemistry, and Hirshfeld surface analyses of gamma-irradiated thalidomide to evaluate behavior under sterilization doses.

Thalidomide was indicated as a sedative and antiemetic and prescribed for pregnant women. Its tragic teratogenic effects culminated in withdrawal from the market. Since the discovery of its anti-angiogenic and anti-inflammatory actions, thalidomide has been used in the treatment of leprosy and multiple myeloma, which justify studies of its stability. We investigated the effects of irradiation of thalidomide up to 100 kGy (fourfold the usual sterilizing dose for pharmaceutics). The ß polymorph of thalidomide was obtained in an isothermal experiment at 270 °C. All samples underwent gamma irradiation for specific times. At different doses, decomposition of the pharmaceutical was not observed up to 100 kGy. The observed effect was angle turning between the phthalimide and glutarimide rings modulated by repulsion towards the carbonyl group, leading to a stable energetic configuration, as measured by the equilibrium in the torsion angle after irradiation. The thalidomide molecule has a center of symmetry, so a full turn starting from 57.3° will lead to an identical molecule. Further irradiation will start the process again. Samples irradiated at 30 and 100 kGy have more compact unit cells and a lower volume, which leads to an increase in the intermolecular hydrogen interaction within the unit cell, resulting in higher thermal stability for polymorph α.

Physicochemical characterization, the Hirshfeld surface, and biological evaluation of two meloxicam compounding pharmacy samples.

Meloxicam (MLX) is an anti-inflammatory drug susceptible to variations and crystalline transitions. In compounding pharmacies, the complete crystallographic evaluation of the raw material is not a routine procedure. We performed a complete crystallographic characterization of aleatory raw MLX samples from compounding pharmacies. X-ray diffraction indicated the presence of two crystalline forms in one sample. DSC experiments suggested that crystallization, or a crystal transition, occurred differently between samples. The FTIR and 1H NMR spectra showed characteristic assignments. 13C solid-state NMR spectroscopy indicated the presence of more than one phase in a sample from pharmacy B. The Hirshfeld surface analysis, with electrostatic potential projection, allowed complete assignment of the UV spectra in ethanol solution. The polymorph I of meloxicam was more active than polymorph III in an experimental model of acute inflammation in mice. Our results highlighted the need for complete crystallographic characterization and the separation of freely used raw materials in compounding pharmacies, as a routine procedure, to ensure the desired dose/effect.

Anti-Toxoplasma activity and impact evaluation of lyophilization, hot molding process, and gamma-irradiation techniques on CLH-PLGA intravitreal implants.

Intraocular delivery systems have been developed to treat many eye diseases, especially those affecting the posterior segment of the eye. However, ocular toxoplasmosis, the leading cause of infectious posterior uveitis in the world, still lacks an effective treatment. Therefore, our group developed an intravitreal polymeric implant to release clindamycin, a potent anti-Toxoplasma antibiotic. In this work, we used different techniques such as differential scanning calorimetry, thermogravimetry, X-ray diffraction, scanning electron microscopy, and fourier-transform infrared spectroscopy to investigate drug/polymer properties while manufacturing the delivery system. We showed that the lyophilization, hot molding process, and sterilization by gamma irradiation did not change drug/polymer physical-chemistry properties. The drug was found to be homogeneously dispersed into the poly lactic-co-glycolic acid (PLGA) chains and the profile release was characterized by an initial burst followed by prolonged release. The drug profile release was not modified after gamma irradiation and non-covalent interaction was found between the drug and the PLGA. We also observed the preservation of the drug activity by showing the potent anti-Toxoplasma effect of the implant, after 24-72 h in contact with cells infected by the parasite, which highlights this system as an alternative to treat toxoplasmic retinochoroiditis.

Influence of different light sources on the conversion of composite resins.

AIMS: The purpose of this paper was to evaluate the influence of different light curing units on the conversion of four composite resins with different compositions (Durafill VS - Heraeus-Kulzer, Tetric Ceram - Ivoclar/Vivadent, Filtek Supreme XT - 3M ESPE e Aelite LS Packable - Bisco), using differential scanning calorimetry. MATERIALS AND METHODS: A stainless steel matrix was used to prepare 48 cylindrical composite test samples (n=6), measuring 3 mm in diameter and 1 mm in thickness. The samples were photoactivated using a halogen lamp (Optilux 500 - Demetron/Kerr) and three different generations of light-emitting diodes (LEDs) (LEC-470 I - MMOptics, Radii Plus - SDI and Ultra-Lume LED 5 - Ultradent). After removal of the matrix, each sample was weighed and hermetically sealed in an aluminum pan and analyzed. The amount of heat liberated by thermopolymerisation of residual monomers after photoactivation was measured in Joules/gram (J/g). The data were submitted to Analysis of Variance (ANOVA) test (P ≤ 0.002) and the Tukey test (P < 0.05). RESULTS: The Ultra-Lume LED 5 was superior on degree of conversion for all resins. The Radii Plus was equal to the Ultra-Lume LED 5, except for the resin Tetric Ceram , were the Optilux 500 was superior. The LEC-470 I was inferior for the conversion of all resins. CONCLUSION: The study proves the importance of the compatibility of the different photoinitiators in resin composites with the different light sources.

In vitro release and characterization of chitosan films as dexamethasone carrier.

Chitosan, a biodegradable and biocompatible polysaccharide, is a potentially useful material in various fields. We produced mono and bilayer chitosan films containing dexamethasone as a drug carrier for controlled release. The chitosan drug-loaded films were produced by a casting/solvent evaporation technique using 2 wt% acetic acid solution and distilled water and they were dried at room temperature. These films were characterized by release and swelling studies, DSC and ATR-FTIR. The total profile for water absorption was similar for the types of films developed. ATR-FTIR analysis showed little change in the band position of the O--H and N--H stretching from dexamethasone and chitosan, respectively. DSC analysis from bilayer film indicates that the dexamethasone peak was shifted from 256 to 240 degrees C. These results suggested an interaction between hydroxyl and amino groups of chitosan and hydroxyl groups of dexamethasone. In the drug release studies it was observed 89.6% release from the monolayer film in 8h and 84% from the bilayer film in 4 weeks. These results suggested that the chitosan sheet prepared in this study is a promising delivery carrier for dexamethasone.

New insight on the investigation of the role of water in the solid-state structures of potassium croconate, K(2)C(5)O(5).2H(2)O, and its anhydrate.

This work presents a comparative study of dihydrated and anhydrous forms of potassium croconate crystals by vibrational spectroscopy, X-ray powder diffraction, and thermogravimetry. These compounds have different colors (dihydrated is orange, and dehydrated is yellow) due to the presence of coordinated water molecules. X-ray diffraction patterns show that the unit cell of the yellow compound is smaller than that of the orange analogue, suggesting that the croconate ion layers are more closely bonded in this salt. The loss of water is reversible due to the potassium cation size which is intermediate between small (Li+ and Na+) and large (Rb+ and Cs+) alkaline metal ions. However, the hydrated compound (orange) is more stable, and with a small quantity of water the yellow compound is quickly converted to the orange compound. A diagnostic feature of the Raman spectrum for the orange (hydrated) and yellow (anhydrous) analogues is the singlet at 1240 cm(-1) in the former, assigned to a nu(CC) + delta(CCC) + nu(CO) + beta(CO) mode of E'2 symmetry, which splits in the yellow form to a doublet at 1256 and 1232 cm(-1).