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Angiogenesis, the complex process of formation of new blood vessels from pre-existing blood vessels, which involves the participation of several pro- and anti-angiogenic factors, is implicated in many physiological and pathological conditions. Nanoparticle-based anti-angiogenic activity at the tumour tissue, harnessed by the Enhanced Permeability and Retention Effect (EPR effect), could potentially become a breakthrough therapy to halt tumour progression. Herein, we evaluate the anti-angiogenic effect of ZnWO4 nanoparticles (NPs). The nanoparticles were obtained by microwave-assisted hydrothermal synthesis (MAHS) at 120 °C for 60 min and were structurally characterised by X-ray diffraction (XRD) and micro-Raman (MR) spectroscopy. The mean size and polydispersity index were estimated by Zeta potential analysis. The XRD analysis revealed structural organisation at a long-range order, with an average crystallite size of around 3.67 nm, while MR revealed short-range order for ZnWO4. The anti-angiogeni...

Purpose To evaluate the safety and feasibility of a 25-gauge biodegradable implant containing 350 μg of dexamethasone (DDS-25) for the treatment of decreased vision due to macular edema associated with central or branch retinal vein occlusion. Methods Prospective, nonrandomized, open-label, Phase I clinical trial, including 10 patients with decreased vision (best-corrected early treatment diabetic retinopathy study visual acuity of 20/40 or worse) due to macular edema associated with central retinal vein occlusion (n = 4) or branch retinal vein occlusion (n = 6) for more than 4 months. Comprehensive ophthalmic evaluation, including best-corrected visual acuity, spectral domain optical coherence tomography (Spectralis Heidelberg Engineering) for determination of central subfield thickness, full-field electroretinography (ISCEV standard ERG), and fluorescein angiography, was performed at baseline, and 1, 4, 12, and 24 weeks after intravitreal DDS-25 insertion. Results Mean best-corrected visual acuity was 0.72 ± 0.1 logMAR (20/100) at baseline and improved by 7 early treatment diabetic retinopathy study letters to 0.58 ± 0.08 logMAR (20/80 + 1) at 24 weeks (P = 0.049), with 3 central retinal vein occlusion and 3 branch retinal vein occlusion patients improving between 1 and 4 early treatment diabetic retinopathy study lines. Significant central subfield thickness reduction was observed at 24 weeks compared with baseline (P = 0.011); mean ± standard error (range) central subfield thickness (μm) was 461.2 ± 41.3 (288-701) at baseline, and 439.6 ± 40.4 (259-631), 442.5 ± 44.6 (255-632), 354.6 ± 31.2 (228-537), and 316.5 ± 26.4 (226-441) at 1, 4, 12, and 24 weeks, respectively. No significant changes in electroretinography responses or area of retinal nonperfusion were observed during 24 weeks of follow-up. There was no significant change in mean intraocular pressure at any of the study visits compared with baseline. One patient had mild anterior chamber inflammation (1-5 cells) at one week after DDS-25 insertion. Conclusion In this Phase I study demonstrating the feasibility of intravitreal DDS-25 insertion for the treatment of decreased vision due to macular edema associated with retinal vein occlusion, no safety concerns were observed. A larger prospective randomized study with longer follow-up is warranted to confirm these findings.

Most of the pharmaceutical products are formulated as solid dosage form, which may present drug–excipient interactions that lead to changes in the chemical nature of the drug, such as solubility and bioavailability and may compromise its safety and effectiveness. Differential scanning calorimetry (DSC) is a widely used method for the rapid evaluation of the drug-excipient compatibility and the stability of the mixture formed; however, there is no consensus on the preparation methods of the drug–excipient mixtures. The aim of this study was to investigate the influence of the mixing method on the drug–excipient compatibility studies by means of DSC analysis, using tenofovir disoproxil fumarate as a drug model. Statistical analysis revealed significant differences in the heat of fusion of the drug in the mixtures prepared by several mixing methods. Vortex Mixer with a Pop-Off Cup used for 3 min proved to be very satisfactory for these studies. A polymorphic transition was observed in the mixture prepared with the mortar and pestle. Therefore, this method should be avoided since it may induce errors in the interpretation of DSC results. In this way, the mixing method used to prepare a mixture for studies of interactions between the API and the excipients in a pharmaceutical formulation has a great influence on the results and it must be chosen carefully.

Glaucoma is a heterogeneous group of multifactorial optic neuropathies and the leading cause of irreversible blindness and visual impairment. Epidemiological data has estimated that in 2020 there will be more than 80 million individuals affected by the disease worldwide. Nowadays, intraocular pressure (IOP) lowering is carried out mainly by pharmacotherapy, with different drugs. The study of ocular pharmacokinetics of antiglaucoma drugs, crucial for better understanding of ocular distribution, bioavailability, and pharmacodynamic parameters, can benefit the development of antiglaucoma drugs or formulations. Bioanalysis of drugs in ocular matrices is still underestimated, since it is challenging and rarely performed. Therefore, this review summarized the chromatographic methods employed for the quantification of several antiglaucoma drugs in different ocular matrices, discussing bioanalytical steps, such as sample preparation, separation, and detection. Animals and matrices as well as the challenges faced in ocular bioanalysis were also discussed. Ocular bioanalysis has been performed mainly in rabbits, the most adequate animal model for ocular studies. The matrix most used is aqueous humor, because it is cleaner and easier to sample. Sample preparation was carried out primarily employing classic techniques, such as liquid-liquid extraction, protein precipitation, and solid-phase extraction, with conventional solvents and sorbents. Chromatographic separation was achieved predominantly by reversed-phase liquid chromatography. Ultraviolet spectrophotometry and tandem mass spectrometry prevailed for detection, although other techniques, such as fluorimetry, have also been used. It was evidenced that more efforts must be directed towards miniaturized, eco-friendly, and non-terminal sampling for sample preparation. In its turn, ultra high-performance liquid chromatography and mass spectrometry should gain prominence in ocular bioanalysis for separation and detection, respectively, since it combines high separation capacity with selectivity and sensitivity, in addition to being an environmental friendly approach.

Retinal ischemia, one of the most common cause of visual loss, is associated with blood flow inadequacy and subsequent tissue injury. In this setting, some treatments that can counteract glutamate increase, arouse interest in ischemic pathogenesis. Ketamine, a potent N-methyl-d-aspartate (NMDA) receptor antagonist, provides a neuroprotective pathway via decreasing the excitotoxicity triggered by excess glutamatergic. Thus, the goal of this study was to evaluate the safety of intravitreal use of ketamine and their potential protective effects on retinal cells in retinal ischemia/reperfusion model. Initially, ketamine toxicity was evaluated by cytotoxicity assay and Hen's egg chorioallantoic membrane (HET-CAM) method. Afterward, some ketamine concentrations were tested in rat's eyes to verify the safety of the intravitreal use. To investigate the neuroprotective effect on retinal, a single intravitreal injection of ketamine in concentrations of 0.059 mmol.L−1 and 0.118 mmol.L−1 was performed one day before the retinal injury by ischemia/reperfusion model. After 7 and 15 days, the retina activity was evaluated by electroretinogram (ERG) records and, lastly, by morphological analyzes. Cytotoxicity assay reveals that the maximum ketamine concentration that could reach retinal pigmented epithelium cells is 0.353 mmol.L−1. HET-CAM assay showed that concentrations above 0.237 mmol.L−1 are irritants to the eye. Thus, Ketamine in concentrations of 0.0237 mmol.L−1, 0.118 mmol.L-1, and 0.059 mmol.L-1 were selected for in vivo toxicity test. ERG records reveal a tendency of b-wave amplitude to decrease as the luminous intensity increased, in the group receiving ketamine at 0.237 mmol.L−1. Therefore, ketamine in concentrations at 0.059 mmol.L−1 and 0.118 mmol.L-1 were chosen for the following tests. In the ischemia retinal degeneration model, pretreatment with ketamine was capable to promote a recovery of retinal electrophysiological function minimizing the ischemic effects. In histological analysis, the groups that received intravitreal ketamine showed a number of retinal cells significantly higher than the vehicle group. In TUNEL assay a reduction on TUNEL-positive cells was observed in all the layers for both concentrations which allow to affirm that ketamine contributes to reducing cell death in the retina. Transmission electron microscopy (TEM) reaffirms this finding. Ketamine intravitreal pretreatment showed reduced ultrastructural changes. Our findings demonstrate that ketamine is safe for intravitreal use in doses up to 0.118 mmol.L−1. They seem to be particularly efficient to protect the retina from ischemic injury.

Considering the many biological activities of nitric oxide (NO), some lines of research focused on the modulation of these activities through the provision of this mediator by designing and synthesizing compounds coupled with an NO donor group. Thus, the objectives of the present study were to carry out an electrochemical investigation of the nitrooxy compound 4-((nitrooxy) methyl)-3-nitrobenzoic acid (1) and evaluate its activities and putative mechanisms in experimental models of pain and inflammation. Voltammetric studies performed in aprotic medium (mimetic of membranes) showed important electrochemical reduction mechanisms: nitroaromatic reduction, self-protonation, and finally reductive elimination, which leads to nitrate release. Systemic administration of the nitrooxy compound (1) inhibited the nociceptive response induced by heat and the tactile hypersensitivity and paw edema induced by carrageenan in mice. The activities in the models of inflammatory pain and edema were associated with reduced neutrophil recruitment and production of inflammatory cytokines, such as interleukin (IL)-1β, IL-6, tumor necrosis factor-α and CXCL-1, and increased production of IL-10. Concluding, electrochemical analysis revealed unequivocally that electron transfer at the nitro group of the nitrooxy compound (1) results in the cleavage of the organic nitrate, potentially resulting in the generation of NO. This electrochemical mechanism may be compared to a biochemical electron-transfer mediated nitrate release that, by appropriate in vivo bioreduction (enzymatic or not) would lead to NO production. Compound (1) exhibits activities in models of inflammatory pain and edema that may be due to reduced recruitment of neutrophils and production of inflammatory cytokines and increased production of IL-10. These results reinforce the interest in the investigation of NO donor compounds as candidates for analgesic and anti-inflammatory drugs.

Age-related macular degeneration (AMD) is a degenerative ocular disease that affects the central retina. It is considered the main cause of blindness and loss of vision worldwide. Angiogenic factors are associated with AMD, which has led to the use of antiangiogenic drugs, such as bevacizumab, to treat the disease using frequent intravitreal injections. In the present study, biodegradable core shell nanofibers containing bevacizumab were prepared by the coaxial electrospinning technique. It is thought that the shell could control the release of the drug, while the core would protect and store the drug. Poly(caprolactone) (PCL) and gelatin were used to form the shell of the nanofibers, while poly(vinyl alcohol) (PVA) and bevacizumab comprised the core. The nanofibers were characterized using microscopy techniques, thermal analysis, and FTIR. The results showed that core-shell nanofibers were produced as designed. Bevacizumab activity was evaluated using a chicken embryo chorioallantoic membrane (CAM) assay. An enzyme-linked immunosorbent assay was used to quantify the amount of the drug released from the different nanofibers in vitro. The toxicity of the nanofibers was evaluated in human retinal pigment epithelial (ARPE) cells. The CAM results demonstrated that bevacizumab maintained its antiangiogenic activity when incorporated into the nanofibers. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) tests revealed that the nanofibers showed no cellular toxicity, even in the presence of bevacizumab. The core-shell structure of the nanofibers reduced the release rate of bevacizumab compared with PVA nanofibers. The bevacizumab-loaded biodegradable nanofibers presented interesting properties that would potentially constitute an alternative therapy to intravitreal injections to treat AMD.

A reversed-phase high-performance liquid chromatographic (HPLC) method was developed and validated for the determination of encapsulation efficiency of zidovudine in nanoparticules. The method was carried out in isocratic mode using 0.040M sodium acetate: methanol: acetonitrile: glacial acetic acid (880:100:20:2) as mobile phase, a C8 column at 25ºC and UV detection at 240 nm. The method was linear (r2 ˃ 0.99) over the range of 25.0-150.0 μg/mL, precise (RSD ˂ 5%), accurate (recovery = 100.5%), robust and selective. The validated HPLC-UV method can be successfully applied to determine the rate of zidovudine in nanoparticules.

Despite advances in the development of new therapeutic agents and diagnostic imaging techniques, the 5-year survival of osteosarcoma, the most common type of bone cancer, remains practically unaltered for the last three decades at around 60%. Nanoparticle-based carriers have emerged as new class of drug delivery systems that could potentially overcome conventional chemotherapy limitations, by promoting a better drug biodistribution profile by allowing a preferential accumulation of the drug in the desired tissue, while minimising non-targeted tissue toxicity, thus resulting in an improved overall therapeutic effectiveness. Hydroxyapatite nanoparticles (HANP) are known to be biocompatible and non-immunogenic and have shown to be preferentially accumulated in bone tissues being considered a promising carrier to bone tissues. Herein, we successfully synthesised mesoporous hydroxyapatite nanoparticles with mean size of 285.32 ± 10.29 nm and superficial area of 103.5 m2/g, containing significant quanti...

Bacterial keratitis is an ocular infection that can lead to severe visual disability. Staphylococcus aureus is a major pathogen of the eye. We recently demonstrated the strong antimicrobial activity of LyeTxI-b, a synthetic peptide derived from a Lycosa erithrognatha toxin. Herein, we evaluated a topical formulation (eye drops) containing LyeTxI-b to treat resistant bacterial keratitis. Keratitis was induced with intrastromal injection of 4 &times, 105 cells (4 &micro, L) in New Zealand female white rabbits. Minimum inhibitory concentration (MIC) and biofilm viability were determined. LyeTxI-b ocular toxicity was evaluated through chorioallantoic membrane and Draize tests. One drop of the formulation (LyeTxI-b 28.9 &micro, mol/L +0.5% CMC in 0.9% NaCl) was instilled into each eye four times a day, for a week. Slit-lamp biomicroscopy analysis, corneal histopathological studies and cellular infiltrate quantification through myeloperoxidase (MPO) and N-acetylglucosaminidase (NAG) detection were performed. LyeTxI-b was very effective in the treatment of keratitis, with no signs of ocular toxicity. Planktonic bacteria MIC was 3.6 &micro, mol/L and LyeTxI-b treatment reduced biofilm viability in 90%. LyeTxI-b eliminated bacteria and reduced inflammatory cellular activity in the eyes. Healthy and treated animals showed similar NAG and MPO levels. LyeTxI-b is a potent new drug to treat resistant bacterial keratitis, showing effective antimicrobial and anti-inflammatory activity.

Bevacizumab, a monoclonal anti-vascular endothelial growth factor antibody, has been suggested as a potential healing therapeutic following glaucoma surgery. Here, we aimed to improve the bioavailability of bevacizumab when used as an adjunct therapy to non-penetrating deep sclerectomy (DS) by using a bevacizumab-methylcellulose mixture (BMM). Ten previously non-operated eyes in ten patients diagnosed with primary open angle glaucoma underwent DS with a subconjunctival injection of 0.3 ml of BMM (bevacizumab 3.75 mg incorporated into 4% methylcellulose) at the surgical site. Bevacizumab release was evaluated in vitro using size-exclusion high performance liquid chromatography (HPLC). Intraocular pressure (IOP), bleb morphology, corneal endothelial cell count (CECC), and complications were evaluated at 6 months after surgery. Using HPLC, bevacizumab was detected in BMM for up to 72 h. Moreover, all surgical blebs remained expanded with hyaline material during the first week. A significant IOP reduction (mean ± SD= -10.3 ± 5.4 mmHg, P

Pensando em melhorar a qualidade de vida dos pacientes com doencas do humor vitreo, os oftalmologistas comecaram a utilizar recentemente implantes biodegradaveis com corticoide. Estes mesmos implantes podem ser uma alternativa no tratamento da RSC e, para isso, realizamos um estudo experimental em seios maxilares de coelhos. OBJETIVO: Avaliar histologicamente a mucosa de seio maxilar de coelhos apos a colocacao de implante biodegradavel de prednisolona. METODO: Dezoito coelhos foram divididos aleatoriamente em dois grupos: Grupo 1: no seio maxilar esquerdo foi inserido um implante biodegradavel com prednisolona; Grupo 2: No seio maxilar esquerdo foi inserido um implante biodegradavel sem medicacao. Os seios maxilares do lado direito serviram como controle. Apos 7, 14 e 28 dias foram escolhidos aleatoriamente tres coelhos de cada grupo e a resposta tecidual inflamatoria foi avaliada. RESULTADOS: Foi encontrada diferenca nao significativa de inflamacao na mucosa, quando comparamos o grupo de coelhos que receberam implantes com e sem medicacao com o grupo controle; ou quando comparamos o grupo que recebeu implante com prednisolona com o grupo que recebeu implante sem medicacao. CONCLUSAO: Nao foram observados sinais de toxicidade ou inflamacao na mucosa do seio maxilar do coelho a presenca do implante com ou sem prednisolona.

Bioactive glass nanoparticles-loaded poly(ɛ-caprolactone) nanofibers (BIOG PCL nanofibers) were synthesized and evaluated as substrates for ocular cells (ARPE-19). BIOG PCL nanofibers were characterized using SEM, FTIR, and DSC, and thein vitrodegradation profile was also investigated. Thein vitroocular biocompatibility of nanofibers was exploited in Müller glial cells (MIO-M1 cells) and in chorioallantoic membrane (CAM); and the proliferative capacity, cytotoxicity, and functionality were evaluated. Finally, ARPE-19 cells were seeded onto BIOG PCL nanofibers and they were investigated as supports forin vitrocell adhesion and proliferation. SEM images revealed the incorporation of BIOG nanoparticles into PCL nanofibers. Nanoparticles did not induce modifications in the chemical structure and semicrystalline nature of PCL in the nanofiber, as shown by FTIR and DSC. MIO-M1 cells exposed to BIOG PCL nanofibers showed viability, and they were able to proliferate and to express GFAP, indicating cellular functionality. Moreover, nanofibers were well tolerated by CAM. These findings suggested thein vitroocular biocompatibility and absence of toxicity of these nanofibers. Finally, the BIOG nanoparticles modulated the protein adsorption, and, subsequently, ARPE-19 cells adhered and proliferated onto the nanostructured supports, establishing cell-substrate interactions. In conclusion, the biodegradable and biocompatible BIOG PCL nanofibers supported the ARPE-19 cells.

The purpose of this study was to develop triamcinolone acetonide-loaded polyurethane implants (TA PU implants) for the local treatment of different pathologies including arthritis, ocular and neuroinflammatory disorders. The TA PU implants were characterized by FTIR, SAXS and WAXS. The in vitro and in vivo release of TA from the PU implants was evaluated. The efficacy of TA PU implants in suppressing inflammatory-angiogenesis in a murine sponge model was demonstrated. FTIR results revealed no chemical interactions between polymer and drug. SAXS results indicated that the incorporation of the drug did not disturb the polymer morphology. WAXS showed that the crystalline nature of the TA was preserved after incorporation into the PU. The TA released from the PU implants efficiently inhibited the inflammatory-angiogenesis induced by sponge discs in an experimental animal model. Finally, TA PU implants could be used as local drug delivery systems because of their controlled delivery of TA.

Cyclosporine-A-loaded PLGA implants were developed intended for ocular route. Implants were prepared using solvent extraction/ evaporation technique followed by casting of the cake into rods in a heated surface. XRD patterns showed that cyclosporine-A was completely incorporated into PLGA. FTIR and DSC results indicated alterations on drug molecular conformation aiming to reach the most stable thermodynamic conformation at polymer/drug interface. Implants provided controlled/sustained in vitro release of the drug. During the first 7 weeks, the drug release was controlled by the diffusion of the cyclosporine-A; and between 7-23 week period, the drug diffusion and degradation of PLGA controlled the drug release.

Implants are defined as controlled sustained release delivery systems of therapeutic agents incorporated or dispersed into a polymeric carrier. These systems can be implanted in specific organs and delivered by the therapeutic agents at the target site to treat various pathological processes. In the present study, the effects of dexamethasone-loaded polyurethane implants [PU ACT (dexamethasone acetate) implants] on inflammatory angiogenesis in a murine sponge model were investigated. PU ACT implants were inserted into nonbiocompatible sponges, used as a framework for fibrovascular tissue growth, and implanted into subcutaneous tissue located on the back of mice. After 7 days of implantation, the implant system was collected and processed for the assessment of hemoglobin (Hb; vascular index), myeloperoxidase (MPO), and N -acetyl-β- D -glucosaminidase (NAG; inflammatory enzymes activities) and collagen content. ACT released from the polymeric implants provided a significant decrease in the neovascularization in the sponge (Hb content). PU ACT implants provided no effects on neutrophil infiltration (MPO activity) but macrophage recruitment was affected by the glucocorticoid delivered by implants (NAG activity). ACT released from implants was able to reduce the collagen deposition. The qualitative histological findings corroborated with the measured biochemical parameters. These local drug delivery systems derived from polyurethane efficiently modulated the key components of inflammation, angiogenesis, and fibrosis induced by sponge discs in an experimental animal model.

Purpose The transplant of retinal pigment epithelium (RPE) cells on supports may well be an effective therapeutic approach to improve the visual results of patients with age-related macular degeneration. In this study, two biodegradable polyurethanes were investigated as supports for human RPE cells (ARPE-19). Methods Polyurethane aqueous dispersions based on poly(caprolactone) and/or poly(ethylene glycol) as soft segments, and isophorone diisocyanate and hydrazine as hard segments were prepared. Polyurethane films were produced by casting the dispersions and allowing them to dry at room temperature for one week. The ARPE-19 cells were seeded onto the polyurethane films and they were investigated as supports for in vitro adhesion, proliferation, and uniform distribution of differentiated ARPE-19 cells. Additionally, the in vivo ocular biocompatibility of the polyurethane films was evaluated. Results The RPE adhered to and proliferated onto the polyurethane supports, thus establishing cellPUD surface interactions. Upon confluence, the cells formed an organized monolayer, exhibited a polygonal appearance, and displayed actin filaments which ran along the upper cytoplasm. At 15 days of seeding, the occluding expression was confirmed between adjacent cells, representing the barrier functionality of epithelial cells on polymeric surfaces and the establishment of cell-cell interactions. Results from the in vivo study indicated that polyurethanes exhibited a high degree of short-term intraocular biocompatibility. Conclusions Biodegradable polyurethane films display the proper mechanical properties for an easy transscleral-driven subretinal implantation and can be considered as biocompatible supports for a functional ARPE-19 monolayer.

The treatment of diseases affecting the posterior segment of the eye is limited by the difficulty in transporting effective doses of drugs to the vitreous, retina, and choroid. Topically applied drugs are poorly absorbed due to the low permeability of the external ocular tissues and tearing. The blood-retina barrier limits drug diffusion from the systemic blood to the posterior segment, thus high doses of drug are needed to maintain therapeutic levels. In addition, systemic side effects are common. Intraocular injections could be an alternative, but the fast flowing blood supply in this region, associated with rapid clearance rates, causes drug concentration to quickly fall below therapeutic levels. To obtain therapeutic levels over longer time periods, polymeric sustained-drug release systems implanted within the vitreous are being studied for the treatment of vitreoretinal disorders. These systems are prepared using different kinds of biodegradable or non-biodegradable polymers. This review aims to demonstrate the main characteristics of these drug delivery implants and their potential for clinical application.O tratamento de doenças do segmento posterior do olho é limitado pela dificuldade no transporte de doses efetivas de fármacos para o vítreo, retina e coróide. Os fármacos aplicados topicamente são pouco absorvidos por causa da baixa permeabilidade dos tecidos oculares externos e ao lacrimejamento. Embora a administração sistêmica seja capaz de transportar fármacos para o segmento posterior do olho, as barreiras hemato-aquosa e hematorretiniana dificultam a absorção e, normalmente, são necessárias doses elevadas, as quais estão geralmente associadas a potenciais efeitos adversos. Injeções intravitreais são capazes de transportar fármacos para o segmento posterior do olho, mas é uma técnica invasiva, pouco tolerada pelos pacientes e apresenta riscos de infecções oculares e danos aos tecidos. Visando a obtenção de níveis terapêuticos adequados de fármacos no segmento posterior do bulbo do olho por longos períodos, sistemas de liberação poliméricos implantados diretamente no vítreo estão sendo investigados para o tratamento de várias doenças vítreo-retinianas. Esses implantes podem ser preparados a partir de diferentes polímeros biocompatíveis, biodegradáveis ou não-biodegradáveis. Nesta revisão, as principais características destes implantes transportadores de fármacos são descritas, expondo suas potencialidades de aplicação clínica.

OBJETIVO: O presente estudo objetivou o desenvolvimento e a avaliação de um sistema biodegradável de liberação de fármacos com característica de liberação prolongada, destinado à administração orbitária de acetato de prednisolona (AP). MÉTODOS: O sistema desenvolvido, na forma de microesferas (MEs) de poli-e-caprolactona (PCL) contendo o AP, foi obtido pelo método de evaporação de solvente. As MEs foram caracterizadas por microscopia eletrônica de varredura (MEV), calorimetria diferencial exploratória (DSC), avaliação do teor de encapsulação e pelo perfil de liberação in vitro. O perfil de liberação in vivo foi avaliado em coelhos após administração peribulbar de uma suspensão aquosa das MEs. A biocompatibilidade local do sistema foi verificada por meio de análise histopatológica da região de implantação. RESULTADOS: Após obtenção das MEs, a análise morfológica por MEV mostrou a viabilidade do método de obtenção do sistema. O teor de AP encapsulado foi de 43 ± 7% e pode ser considerado bastante satisfatório. A caracterização do sistema por DSC, além de confirmar a sua estabilidade, não indicou a existência de interação entre o fármaco e o polímero. O estudo de liberação in vitro indicou que o sistema apresenta perfil de liberação prolongada. O estudo in vivo confirmou o perfil de liberação prolongado do AP a partir das MEs, sugerindo, também, a viabilidade do sistema devido à ausência de toxicidade local. CONCLUSÃO: O conjunto dos resultados obtidos neste trabalho é relevante e credencia o sistema desenvolvido como uma possível alternativa ao tratamento de orbitopatias inflamatórias.PURPOSE: The present study aimed to evaluate an injectable extended-release formulation of prednisolone acetate (PA) for orbital administration. METHODS: Microspheres (MEs) of poly-e-caprolactone (PCL) containing PA were developed by the method of solvent evaporation. The MEs obtained were characterized by scanning electron microscopy (SEM), differential scanning calorimetry (DSC), encapsulation efficiency and in vitro release profile. The in vivo release profile was evaluated in rabbits after periocular injection of an aqueous suspension of MEs. The local biocompatibility of the system was verified by histopathologic analysis of the deployment region. RESULTS: After MEs preparation, morphological analysis by SEM showed the feasibility of the employed method. The content of PA encapsulated was 43 ± 7% and can be considered as satisfactory. The system characterization by DSC technique, in addition to confirm the system stability, did not indicate the existence of interaction between the drug and the polymer. The in vitro release study showed the prolonged-release features of the developed system. Preliminary in vivo study showed the absence of local toxicity and confirmed the prolonged release profile of PA from MEs, suggesting the viability of the developed system for the treatment of orbital inflammatory diseases. CONCLUSION: The results obtained in this work are relevant and accredit the system developed as a possible alternative to the treatment of inflammatory orbitopathy.

A etapa principal na ativação e ligação da insulina ao seu receptor é a dissociação dos hexâmeros do hormônio, normalmente presente nas preparações farmacêuticas, para a forma monomérica bioativa. A utilização de diferentes ciclodextrinas (CDs) como adjuvantes em formulações contendo insulina vem sendo explorada e os estudos realizados demonstram que estas substâncias podem aumentar a absorção da insulina principalmente por diminuírem sua capacidade de formar dímeros e hexâmeros em meio aquoso. No presente trabalho, complexos de insulina:hidroxipropil-beta-ciclodextrina (INS:HP-beta-CD) e insulina:dimetil-beta-ciclodextrina (INS:DM-beta-CD) foram caracterizados utilizando técnicas de titulação calorimétrica isotérmica e espalhamento dinâmico de luz. Por meio da titulação calorimétrica foram determinados os parâmetros termodinâmicos de interação entre a insulina e as CDs utilizadas, sugerindo que o mecanismo de complexação ocorre com aumento de entropia para ambos os sistemas. Os experimentos de espalhamento dinâmico de luz não indicaram diminuição do diâmetro hidrodinâmico das espécies moleculares de insulina após a complexação com as CDs. Os complexos INS:HP-beta-CD e INS:DM-beta-CD foram encapsulados em microesferas (MEs) de PLGA 50:50. A caracterização das MEs obtidas revelou aumento considerável na taxa de encapsulamento de insulina quando complexada com as CDs sem que ocorresse diferença significativa no diâmetro das partículas em função da complexação.The main stage in the linking and activation of the specific receptors by the insulin is the dissociation of this peptide hexamers, normally present in pharmaceutical formulations, in the monomeric active form. Because of this, the use of different cyclodextrins as adjuvants in the formulations containing insulin has been explored and the realized studies have demonstrated that the cyclodextrins can increase the absorption of the insulin mainly by reducing the ability of insulin oligomerization in aqueous media. In this work, complexes of INS:HP-beta-CD and INS:DM-beta-CD have been characterized by the use of isothermal calorimetry titration (ICT) and dynamic scattering of light. By means of ICT, the thermodynamic parameters of interaction between insulin and the cyclodextrins have been determined, and it was observed that the complexation occurs with an increase of entropy for both systems. The experiments of dynamic scattering of light have not showed reduction in the size of insulin particles, which could indicate the dissociation of insulin hexamers after the complexation with cyclodextrins. Then, the INS: HP-beta-CD and INS:DM-beta-CD complexes were encapsulated in PLGA microspheres. These systems were characterized and it was not observed any significant difference in the microspheres diameter, but a considerable increase in the hormone loading after the complexation with HP-beta-CD and DM-beta-CD was shown.

As doenças do segmento posterior do olho são responsáveis pela maioria dos casos de cegueira irreversível no mundo inteiro. Este cenário estimula o desenvolvimento de novas modalidades de tratamento para estas doenças. O sucesso no tratamento visa, essencialmente, o transporte de doses efetivas de drogas diretamente para os locais a serem tratados. Devido às dificuldades encontradas no transporte de drogas para o segmento posterior do olho, pesquisas têm sido realizadas no sentido de desenvolver sistemas de administração intra-oculares que permitam liberar concentrações terapêuticas das drogas por período prolongado. Tais sistemas podem proporcionar inúmeras vantagens, como: aumentar a biodisponibilidade e a concentração local da droga, atingir especificamente um tipo de tecido ou célula, reduzir a freqüência de injeções intra-oculares. Tais vantagens podem aumentar o conforto do paciente e reduzir as complicações observadas com a utilização das injeções intra-oculares. Diferentes sistemas de transporte de drogas têm sido desenvolvidos com as finalidades acima descritas. Estes sistemas podem ser compostos por polímeros biodegradáveis ou não-biodegradáveis ou serem formulações lipídicas. Os sistemas de transporte de drogas são representados, principalmente, pelas micro e nanopartículas e pelos implantes, sendo eles compostos por diferentes polímeros; pelos lipossomos, que são compostos por lípides e emulsionantes; e pela iontoforese, que se baseia na aplicação de corrente elétrica. Nesta revisão, as principais características dos diferentes sistemas de transporte de drogas serão descritas, expondo suas potencialidades de aplicação clínica.The diseases of the posterior segment of the eye are responsible for most cases of irreversible blindness worldwide. These conditions stimulate the development of new modalities of treatment for vitreoretinal diseases. The success in the treatment aims, mainly, the delivery of effective doses of pharmacological agents directly to the target sites. Because of the difficulties in delivering drugs to the posterior segment of the eye, the development of intraocular delivery systems that allow the delivery of therapeutic concentrations of drugs for long periods are being studied. These systems offer many advantages, such as increase in drug bioavailability, obtaining constant and sustained drug release, to achievement of elevated local concentrations of drugs without systemic side effects, targeting one specific tissue or cell type, reducing the frequency of intraocular injections. These advantages can increase the comfort of the patient and reduce the complications observed with intraocular injections. Several drug delivery systems are being developed with the above described purposes. These systems may be prepared with biodegradable or non-biodegradable polymers or they may be lipid formulations. The drug delivery systems are represented, mainly, by micro- e nanoparticles and implants, composed of different polymers; by liposomes, which are made of lipids and surfactants; and by iontophoresis, that is based on the application of an electric current. In this review, the main characteristics of the different drug delivery systems will be shown, with their potentialities of clinical application.

The diseases of the posterior segment of the eye are responsible for most cases of irreversible blindness worldwide. These conditions stimulate the development of new modalities of treatment for vitreoretinal diseases. The success in the treatment aims, mainly, the delivery of effective doses of pharmacological agents directly to the target sites. Because of the difficulties in delivering drugs to the posterior segment of the eye, the development of intraocular delivery systems that allow the delivery of therapeutic concentrations of drugs for long periods are being studied. These systems offer many advantages, such as increase in drug bioavailability, obtaining constant and sustained drug release, to achievement of elevated local concentrations of drugs without systemic side effects, targeting one specific tissue or cell type, reducing the frequency of intraocular injections. These advantages can increase the comfort of the patient and reduce the complications observed with intraocular injections. Several drug delivery systems are being developed with the above described purposes. These systems may be prepared with biodegradable or non-biodegradable polymers or they may be lipid formulations. The drug delivery systems are represented, mainly, by micro- e nanoparticles and implants, composed of different polymers; by liposomes, which are made of lipids and surfactants; and by iontophoresis, that is based on the application of an electric current. In this review, the main characteristics of the different drug delivery systems will be shown, with their potentialities of clinical application.

O metodo mais comum de administracao de drogas no olho e por meio de colirios. Entretanto, por este metodo, nao e possivel atingir a concentracao terapeutica nos fluidos e tecidos posteriores do olho. A administracao sistemica apresenta reduzido acesso ao segmento posterior do olho devido a presenca das barreiras oculares. Injecoes subconjuntivais e retrobulbares nao sao capazes de proporcionar niveis adequados da droga, e a injecao intravitrea e metodo invasivo, inconveniente e que apre-senta riscos de perfuracao do bulbo ocular ou descolamento da retina. A iontoforese, no entanto, apresenta-se como alternativa para o transporte de doses terapeuticas de drogas para o segmento posterior do olho. A iontoforese e uma tecnica que consiste na administracao de drogas para o organismo atraves dos tecidos, utilizando um campo eletrico. O eletrodo ativo, que se encontra em contato com a droga, e colocado no local a ser tratado, e um segundo eletrodo, com a finalidade de fechar o circuito eletrico, e colocado em outro local do organismo. O campo eletrico facilita o transporte da droga, que deve se encontrar, preferencialmente, na forma ionizada. A iontoforese pode ser considerada como um metodo seguro e nao invasivo de transporte de drogas para locais especificos do olho. Aplicada experimentalmente para o tratamento de doencas oculares, esta tecnica tem evoluido muito nos ultimos anos e, atualmente, testes clinicos de fase III encontram-se em andamento.

O tratamento de doenças oculares que acometem o vítreo e a retina tem sido um problema devido à dificuldade de penetração das drogas no segmento posterior do bulbo ocular. A administração de colírios apresenta efeito terapêutico mínimo nessa região do olho, que, geralmente, é mantido com a administração de doses freqüentes do medicamento. Uma alternativa seria a injeção intra-ocular; entretanto, a rápida circulação sangüínea nesses locais promove uma redução da meia-vida das drogas, diminuindo, rapidamente, suas concentrações a níveis subterapêuticos. Visando a obtenção de níveis terapêuticos adequados de drogas no segmento posterior do bulbo ocular por longos períodos, sistemas de liberação poliméricos implantados intravítreo estão sendo investigados para o tratamento de várias doenças vítreo-retinianas. Esses implantes são preparados a partir de diferentes polímeros, os quais podem ser biodegradáveis ou não biodegradáveis. Os polímeros derivados dos ácidos lático e glicólico têm se revelados bastante promissores devido, principalmente, às suas características de biocompatibilidade e biodegradabilidade. De acordo com os estudos realizados até o momento, os implantes podem se apresentar na forma de bastão, de discos ou de membranas e ser obtidos pelos métodos de moldagem, de extrusão ou de preparação de filmes. O presente artigo objetiva uma revisão de literatura abordando o tema e os principais estudos relacionados com a utilização de implantes poliméricos como sistemas transportadores de drogas para aplicação intra-ocular.

O tratamento de doenças oculares que acometem o vítreo e a retina tem sido um problema devido à dificuldade de penetração das drogas no segmento posterior do bulbo ocular. A administração de colírios apresenta efeito terapêutico mínimo nessa região do olho, que, geralmente, é mantido com a administração de doses freqüentes do medicamento. Uma alternativa seria a injeção intra-ocular; entretanto, a rápida circulação sangüínea nesses locais promove uma redução da meia-vida das drogas, diminuindo, rapidamente, suas concentrações a níveis subterapêuticos. Visando a obtenção de níveis terapêuticos adequados de drogas no segmento posterior do bulbo ocular por longos períodos, sistemas de liberação poliméricos implantados intravítreo estão sendo investigados para o tratamento de várias doenças vítreo-retinianas. Esses implantes são preparados a partir de diferentes polímeros, os quais podem ser biodegradáveis ou não biodegradáveis. Os polímeros derivados dos ácidos lático e glicólico têm se revelados bastante promissores devido, principalmente, às suas características de biocompatibilidade e biodegradabilidade. De acordo com os estudos realizados até o momento, os implantes podem se apresentar na forma de bastão, de discos ou de membranas e ser obtidos pelos métodos de moldagem, de extrusão ou de preparação de filmes. O presente artigo objetiva uma revisão de literatura abordando o tema e os principais estudos relacionados com a utilização de implantes poliméricos como sistemas transportadores de drogas para aplicação intra-ocular.The treatment of vitreoretinal disorders has been problematic because it is difficult to gain access to the posterior segment of the eye. Topical instillation of eye drops has little therapeutic effect on posterior structures which cannot be maintained without frequent administration. Intraocular injections could be an alternative, but the fast flowing blood supply in this region, associated with the rapid clearance rates, causes the drug concentration to fall rapidly below therapeutic levels. In order to obtain therapeutic levels over longer time periods, polymeric sustained-drug release systems, implanted into the vitreous, are being studied for the treatment of vitreoretinal disorders. These systems are prepared using different kinds of polymers that can be biodegradable or nonbiodegradable. The polymers derived from lactic and glycolic acids have been the most promising for drug delivery systems because of their biocompatibility and biodegradation. According to previous studies, the polymers can be manufactured in the form of rods, discs or membranes, using the following methods: molding, extrusion or preparation of films. In this review, we present the technology and some preliminary studies of biodegradable implants in relation to intraocular drug delivery systems.

As formas farmacêuticas oftálmicas convencionais são relativamente simples: drogas solúveis em água são formuladas em solução aquosa e drogas pouco solúveis em suspensão ou pomada. Entretanto, essas formulações apresentam como inconvenientes baixa biodisponibilidade corneal, absorção sistêmica devida à drenagem nasolacrimal e reduzida eficácia no segmento posterior do olho. Assim, o desenvolvimento de novos sistemas de liberação de drogas de administração oftálmica tem sido um dos principais temas de pesquisa em tecnologia farmacêutica nos últimos anos. Entre as alternativas avaliadas, destacam-se principalmente as microemulsões. Estas formas farmacêuticas que são dispersões de água e óleo, estabilizadas por um emulsionante e por um co-emulsionante, transparentes, termodinamicamente estáveis, apresentam partículas de tamanho menor que 1,0 mm e, portanto, passíveis de serem esterilizadas por filtração. Além disso, as microemulsões apresentam baixa viscosidade, possuem grande capacidade para o transporte de drogas, demonstram comprovada propriedade promotora de absorção para as drogas veiculadas e são facilmente obtidas, sem a necessidade de utilização de equipamentos sofisticados e de componentes de custo proibitivo. O presente artigo objetiva revisão de literatura abordando o tema e os principais estudos relacionados com a utilização de microemulsões como sistemas de liberação de drogas oftálmicas.The conventional ophthalmic dosage forms are relatively simple: usually, water-soluble drugs are delivered in aqueous solution and water-insoluble drugs are prepared as suspensions or ointments. However, these delivery systems currently used present very low corneal bioavailability, systemic exposure because of nasolacrimal drainage and lack of efficiency in the posterior segment of ocular tissue. Recent research efforts have focused on the development of new ophthalmic drug delivery systems. As a result of these efforts, microemulsions are promising dosage forms for ocular use. These delivery systems are dispersions of water and oil that require surfactant and co-surfactant agents in order to stabilize the interfacial area. The microemulsions have a transparent appearance, thermodynamic stability and small droplet size of the dispersed fase (

In this work we describe the development and characterization of a new formulation of insulin (INS). Insulin was complexed with cyclodextrins (CD) in order to improve its solubility and stability being available as a dry powder, after encapsulation into poly (D,L-lactic-co-glycolic acid) (PLGA) microspheres. The complex INS : CD was encapsulated into microspheres in order to obtain particles with an average diameter between 2 and 6 microm. This system was able to induce significant reduction of the plasma glucose level in two rodent models, normal mice and diabetic rats, after intratracheal administration.

PURPOSE: To evaluate the tissue response of the mucosa of the tympanic cavity of guinea pigs, when receiving biodegradable implant. METHODS: A total of 20 male guinea pigs were divided into 2 groups. After paracentesis in both ears, a biodegradable polymer of poly lactic-co-glycolic acid was implanted in only one middle ear. Histological analysis using neutrophil exudate and vascular neoformation (acute inflammation) and fibroblast proliferation and mononuclear inflammatory cells (chronic inflammation) as parameters was performed after 10 and 30 days of survival (groups 1 and 2, respectively). RESULTS: Four ears in group 1 and 7 in group 2 had an increase of neutrophil exudate. Vascular neoformation occurred in ears with or without the implant, in both groups. Fibroblast proliferation and mononuclear inflammatory cells (lymphocytes and macrophages) increased in ears with implant in group 2. CONCLUSION: The tissue response by histological analysis of the mucosa of the tympanic cavity of guinea pigs, when receiving biodegradable implant, showed no statistically significant difference between ears with or without the implant.

Dexamethasone-loaded poly(lactide-co-glycolide) (PLGA) devices are commonly used as model systems for controlled release. In this study, PLGA nanoparticles containing dexamethasone acetate were prepared by a nanoprecipitation technique in the absence of organochlorine solvents and were characterized by their mean size, f potential, scanning electron microscopy, and differential scanning calorimetry to develop a controlled release system. The analytical method for the quantification of dexamethasone acetate by high-performance liquid chromatography was validated. The results show that it was possible to prepare particles at a nanometric size because the average diameter of the drug-loaded PLGA particles was 540 6 4 nm with a polydispersity index of 0.07 6 0.01 and a f poten- tial of 22.5 6 0.3 mV. These values remained stable for at least 7 months. The drug encapsulation efficiency was 48%. In vitro tests showed that about 25% of the drug was released in 48 h. V C 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014, 131, 41199.

Infections caused by dermatophytes, mainly Trichophyton rubrum,are often vulnerable to relapses upon cessation of antifungal therapy, reinforcing the need of new antifungals. Aldimines have potential biological activities, but there are few reports on their antifungal profile. The aim of this study was to evaluate the antifungal activity of 2-(benzylideneamino)phenol (3A3) and 4-(benzylideneamino)phenol (3A4) against dermatophytes. We determined the minimum inhibitory concentration, minimum fungicidal concentration, time-kill curves and fractional inhibitory concentration of the combination of 3A3, 3A4 and itraconazole against a set of isolates of T. rubrum and T. interdigitale. 3A3 was tested in a murine model of dermatophytoses caused by T. rubrum, and the effect on phagocytosis was assessed. The MIC values ranged from 8 to 32 μg/mL for 3A3 and from 64 to 256 μg/mL for 3A4. The interaction between 3A3 and 3A4 with itraconazole proved to be synergistic and indifferent, respectively. 3A3 was as efficient as itraconazole in reducing the fungal burden on the skin of mice, being this effect associated with the influx of neutrophil and macrophage. Also, 3A3 was able to increase the internalization of conidia by macrophages. Altogether, our data encourage future clinical studies with 3A3 to treat dermatophytoses.

Objective The objective of the study is to evaluate the physical properties, in vitro release profile, and antibacterial efficiency of chitosan films prepared with ofloxacin. Procedure Mucoadhesive films were prepared by means of a casting and solvent evaporation technique performed in a 2 wt% acetic acid solution and distilled water. Physical properties were characterized by release and swelling studies, differential scanning calorimetry (DSC) analysis, and attenuated total reflectance Fourier transformed infrared spectroscopy (ATR-FTIR) analysis. The in vitro evaluation of the films was performed by inhibiting Staphylococcus aureus and Pseudomonas aeruginosa through activity studies. Results Circular ofloxacin-loaded chitosan-developed films with 0.3 mg of drug weighed 7 mg were 110 μm thick and 5 mm in diameter. The DSC curve of ofloxacin-loaded chitosan films suggests an amorphous dispersion of ofloxacin within these films. ATR-FTIR analysis showed that ofloxacin is indeed present in the matrix film. The drug was released in vitro over a 1-h period. No statistical difference could be observed between the ofloxacin-loaded chitosan films and sterile disk soaked for 1 min in 0.3% commercial ofloxacin ophthalmic solution for S. aureus and P. aeruginosa (P = 0.1686, P = 0.1172, respectively).The films presented a significantly larger mean bacterial inhibition zone of S. aureus than did the commercial ciprofloxacin control disk (P = 0.0002) and a significantly larger mean bacterial kill zone of P. aeruginosa than did the commercial enrofloxacin control disk (P

OBJETIVO: Este trabalho objetivou o desenvolvimento de um sistema mucoadesivo de liberação de ciclosporina A (CsA) para o tratamento de ceratoconjuntivite seca (CCS). MÉTODOS: O sistema mucoadesivo foi preparado na forma de filme utilizando o polímero quitosana e CsA (25%p/v). Foram administrados no saco conjuntival do olho direito de coelhos normais (n=6) e a aferição da produção de lágrimas foi realizada diariamente antes e após a aplicação, de forma bilateral, durante sete dias, por meio do teste lacrimal de Schirmer. Avaliação oftalmológica foi realizada diariamente durante todo o estudo e seguido da análise histológica. RESULTADOS: Os valores médios de produção de lágrimas foram alterados de 9,88 ± 0,37 mm/min para 16,02 ± 0,38 mm/min antes e após a administração do sistema respectivamente, significando um aumento de aproximadamente 60%. Todos os coelhos apresentaram hiperemia da conjuntiva palpebral e lacrimejamento. A hiperemia permaneceu durante 48 h após administração dos sistemas com resolução espontânea e o lacrimejamento foi diagnosticado até o final do experimento. Não foram observados outros sinais de reações indesejáveis. Nenhuma alteração histológica foi observada na mucosa conjuntival bulbar e palpebral à histopatologia. CONCLUSÃO: Os sistemas desenvolvidos são aparentemente seguros e eficientes criando expectativa para o tratamento da CCS. Novos estudos são necessários para avaliar a concentração de CsA liberada, assim como aceitabilidade e toxicidade dos sistemas em tratamentos mais prolongados. PURPOSE: The present work aimed to present the development of a conjunctival mucosa system for the controlled delivery of cyclosporine A (CsA) in the treatment of keratoconjunctivitis sicca (KCS). METHODS: The conjunctival mucosa system was prepared in the form of films containing chitosan as the polymer and CsA as the drug (25%w/v). The films were applied to the conjunctival sac of one eye from normal rabbits (n=6), and the evaluation of lachrymal production was performed daily, before and after application, for seven days. Clinical examination was executed daily on the eyes of each animal during the entire period of study. Histological analyses were carried out at the end of the study. RESULTS: The average amount of lachrymal production changed from 9.88 ± 0.37 mm/min to 16.02 ± 0.38 mm/min, respectively, before and after applying the systems, which indicates an increase of approximately 60%. All rabbits presented hyperemia in the palpebral conjunctiva and tearing. Hyperemia continued for 48h after the application of the systems with spontaneous resolution, and tearing was diagnosed throughout the entire study. No other sign of undesirable reactions could be observed. Moreover, no histological changes could be identified in the bulbar and palpebral conjunctival mucosa. CONCLUSION: The developed systems proved to be safe and efficient in this pilot study and present a promising future for the treatment of KCS. Other studies are warranted to evaluate the released concentration of CsA as well as the feasibility and toxicity of these systems in a more prolonged treatment.

Chitosan, a cationic polysaccharide biopolymer with mucoadhesive properties, presents a promising future in the prolonged ocular delivery of drugs. The present study compared the efficacy and safety of chitosan-coated timolol maleate (TM) mucoadhesive film, using a 0.5% TM commercial ophthalmic solution in a rabbit model. In addition, this study investigates the maximum release time of these implants in vivo.The mucoadhesive films were prepared by means of a casting and solvent evaporation technique performed in a 2 wt% acetic acid solution and distilled water. Physical properties were characterized by release and swelling studies, differential scanning calorimetry, and attenuated total reflectance fourier transformed infrared spectroscopy (ATR-FTIR). The developed formulations were evaluated for their pharmacodynamics in ocular normotensive albino rabbits, in which the intraocular pressure (IOP) was measured by means of applanation tonometer on alternative days (13 h) for 11 weeks. For 15 days, 0.5% TM commercial ophthalmic solution was administered twice a day (n=5) and compared to chitosan-coated TM (n=5). In the control group (n=5), saline was used twice a day. The maximum TM release time from chitosan films were also recorded. After euthanasia, the right eyes were removed from the 3 groups for histological analyses.In an in vitro study, TM was released over a 4-week period, in which 85% of the drug was released over the first 2 weeks. However, the film's release of TM lowered the in vivo IOP levels over a 10-week period. No significant difference in the lowering of IOP in rabbits treated with 0.5% TM commercial ophthalmic solution, as compared to those that received the films (P0.05), could be observed. No signs of ocular discomfort or irritations could be identified upon ophthalmic examination by slit-lamp biomicroscopy. Ophthalmic structures that came in direct contact with the films revealed no alterations within the histopathological studies. Moreover, the animals showed no signs of ocular discomfort during the experimental assays.These findings suggest that the TM-loaded chitosan film is safe and efficient and presents a promising future as an ocular drug delivery system in the treatment and prevention of glaucoma.

OBJETIVO: O presente estudo objetivou o desenvolvimento e a avaliação de um sistema biodegradável de liberação de fármacos com característica de liberação prolongada, destinado à administração orbitária de acetato de prednisolona (AP). MÉTODOS: O sistema desenvolvido, na forma de microesferas (MEs) de poli-e-caprolactona (PCL) contendo o AP, foi obtido pelo método de evaporação de solvente. As MEs foram caracterizadas por microscopia eletrônica de varredura (MEV), calorimetria diferencial exploratória (DSC), avaliação do teor de encapsulação e pelo perfil de liberação in vitro. O perfil de liberação in vivo foi avaliado em coelhos após administração peribulbar de uma suspensão aquosa das MEs. A biocompatibilidade local do sistema foi verificada por meio de análise histopatológica da região de implantação. RESULTADOS: Após obtenção das MEs, a análise morfológica por MEV mostrou a viabilidade do método de obtenção do sistema. O teor de AP encapsulado foi de 43 ± 7% e pode ser considerado bastante satisfatório. A caracterização do sistema por DSC, além de confirmar a sua estabilidade, não indicou a existência de interação entre o fármaco e o polímero. O estudo de liberação in vitro indicou que o sistema apresenta perfil de liberação prolongada. O estudo in vivo confirmou o perfil de liberação prolongado do AP a partir das MEs, sugerindo, também, a viabilidade do sistema devido à ausência de toxicidade local. CONCLUSÃO: O conjunto dos resultados obtidos neste trabalho é relevante e credencia o sistema desenvolvido como uma possível alternativa ao tratamento de orbitopatias inflamatórias. PURPOSE: The present study aimed to evaluate an injectable extended-release formulation of prednisolone acetate (PA) for orbital administration. METHODS: Microspheres (MEs) of poly-e-caprolactone (PCL) containing PA were developed by the method of solvent evaporation. The MEs obtained were characterized by scanning electron microscopy (SEM), differential scanning calorimetry (DSC), encapsulation efficiency and in vitro release profile. The in vivo release profile was evaluated in rabbits after periocular injection of an aqueous suspension of MEs. The local biocompatibility of the system was verified by histopathologic analysis of the deployment region. RESULTS: After MEs preparation, morphological analysis by SEM showed the feasibility of the employed method. The content of PA encapsulated was 43 ± 7% and can be considered as satisfactory. The system characterization by DSC technique, in addition to confirm the system stability, did not indicate the existence of interaction between the drug and the polymer. The in vitro release study showed the prolonged-release features of the developed system. Preliminary in vivo study showed the absence of local toxicity and confirmed the prolonged release profile of PA from MEs, suggesting the viability of the developed system for the treatment of orbital inflammatory diseases. CONCLUSION: The results obtained in this work are relevant and accredit the system developed as a possible alternative to the treatment of inflammatory orbitopathy.

A etapa principal na ativação e ligação da insulina ao seu receptor é a dissociação dos hexâmeros do hormônio, normalmente presente nas preparações farmacêuticas, para a forma monomérica bioativa. A utilização de diferentes ciclodextrinas (CDs) como adjuvantes em formulações contendo insulina vem sendo explorada e os estudos realizados demonstram que estas substâncias podem aumentar a absorção da insulina principalmente por diminuírem sua capacidade de formar dímeros e hexâmeros em meio aquoso. No presente trabalho, complexos de insulina:hidroxipropil-beta-ciclodextrina (INS:HP-beta-CD) e insulina:dimetil-beta-ciclodextrina (INS:DM-beta-CD) foram caracterizados utilizando técnicas de titulação calorimétrica isotérmica e espalhamento dinâmico de luz. Por meio da titulação calorimétrica foram determinados os parâmetros termodinâmicos de interação entre a insulina e as CDs utilizadas, sugerindo que o mecanismo de complexação ocorre com aumento de entropia para ambos os sistemas. Os experimentos de espalhamento dinâmico de luz não indicaram diminuição do diâmetro hidrodinâmico das espécies moleculares de insulina após a complexação com as CDs. Os complexos INS:HP-beta-CD e INS:DM-beta-CD foram encapsulados em microesferas (MEs) de PLGA 50:50. A caracterização das MEs obtidas revelou aumento considerável na taxa de encapsulamento de insulina quando complexada com as CDs sem que ocorresse diferença significativa no diâmetro das partículas em função da complexação. The main stage in the linking and activation of the specific receptors by the insulin is the dissociation of this peptide hexamers, normally present in pharmaceutical formulations, in the monomeric active form. Because of this, the use of different cyclodextrins as adjuvants in the formulations containing insulin has been explored and the realized studies have demonstrated that the cyclodextrins can increase the absorption of the insulin mainly by reducing the ability of insulin oligomerization in aqueous media. In this work, complexes of INS:HP-beta-CD and INS:DM-beta-CD have been characterized by the use of isothermal calorimetry titration (ICT) and dynamic scattering of light. By means of ICT, the thermodynamic parameters of interaction between insulin and the cyclodextrins have been determined, and it was observed that the complexation occurs with an increase of entropy for both systems. The experiments of dynamic scattering of light have not showed reduction in the size of insulin particles, which could indicate the dissociation of insulin hexamers after the complexation with cyclodextrins. Then, the INS: HP-beta-CD and INS:DM-beta-CD complexes were encapsulated in PLGA microspheres. These systems were characterized and it was not observed any significant difference in the microspheres diameter, but a considerable increase in the hormone loading after the complexation with HP-beta-CD and DM-beta-CD was shown.

The diseases of the posterior segment of the eye are responsible for most cases of irreversible blindness worldwide. These conditions stimulate the development of new modalities of treatment for vitreoretinal diseases. The success in the treatment aims, mainly, the delivery of effective doses of pharmacological agents directly to the target sites. Because of the difficulties in delivering drugs to the posterior segment of the eye, the development of intraocular delivery systems that allow the delivery of therapeutic concentrations of drugs for long periods are being studied. These systems offer many advantages, such as increase in drug bioavailability, obtaining constant and sustained drug release, to achievement of elevated local concentrations of drugs without systemic side effects, targeting one specific tissue or cell type, reducing the frequency of intraocular injections. These advantages can increase the comfort of the patient and reduce the complications observed with intraocular injections. Several drug delivery systems are being developed with the above described purposes. These systems may be prepared with biodegradable or non-biodegradable polymers or they may be lipid formulations. The drug delivery systems are represented, mainly, by micro- e nanoparticles and implants, composed of different polymers; by liposomes, which are made of lipids and surfactants; and by iontophoresis, that is based on the application of an electric current. In this review, the main characteristics of the different drug delivery systems will be shown, with their potentialities of clinical application.