Thermosensitive Injectable Hydrogels for Intra-Articular Delivery of Etanercept for the Treatment of Osteoarthritis.

The intra-articular administration of drugs has attracted great interest in recent decades for the treatment of osteoarthritis. The use of modified drugs has also attracted interest in recent years because their intra-articular administration has demonstrated encouraging results. The objective of this work was to prepare injectable-thermosensitive hydrogels for the intra-articular administration of Etanercept (ETA), an inhibitor of tumor necrosis factor-α. Hydrogels were prepared from the physical mixture of chitosan and Pluronic F127 with ß-glycerolphosphate (BGP). Adding ß-glycerolphosphate to the system reduced the gelation time and also modified the morphology of the resulting material. In vitro studies were carried out to determine the cytocompatibility of the prepared hydrogels for the human chondrocyte line C28/I2. The in vitro release study showed that the incorporation of BGP into the system markedly modified the release of ETA. In the in vivo studies, it was verified that the hydrogels remained inside the implantation site in the joint until the end of the study. Furthermore, ETA was highly concentrated in the blood of the study mice 48 h after the loaded material was injected. Histological investigation of osteoarthritic knees showed that the material promotes cartilage recovery in osteoarthritic mice. The results demonstrate the potential of ETA-loaded injectable hydrogels for the localized treatment of joints.

Dexamethasone: Insights into Pharmacological Aspects, Therapeutic Mechanisms, and Delivery Systems.

Dexamethasone (DEX) has been widely used to treat a variety of diseases, including autoimmune diseases, allergies, ocular disorders, cancer, and, more recently, COVID-19. However, DEX usage is often restricted in the clinic due to its poor water solubility. When administered through a systemic route, it can elicit severe side effects, such as hypertension, peptic ulcers, hyperglycemia, and hydro-electrolytic disorders. There is currently much interest in developing efficient DEX-loaded nanoformulations that ameliorate adverse disease effects inhibiting advancements in scientific research. Various nanoparticles have been developed to selectively deliver drugs without destroying healthy cells or organs in recent years. In the present review, we have summarized some of the most attractive applications of DEX-loaded delivery systems, including liposomes, polymers, hydrogels, nanofibers, silica, calcium phosphate, and hydroxyapatite. This review provides our readers with a broad spectrum of nanomedicine approaches to deliver DEX safely.

Chitosan/Pluronic F127 Thermosensitive Hydrogel as an Injectable Dexamethasone Delivery Carrier.

Intra-articular administration of anti-inflammatory drugs is a strategy that allows localized action on damaged articular cartilage and reduces the side effects associated with systemic drug administration. The objective of this work is to prepare injectable thermosensitive hydrogels for the long-term application of dexamethasone. The hydrogels were prepared by mixing chitosan (CS) and Pluronic-F127 (PF) physically. In addition, tripolyphosphate (TPP) was used as a crosslinking agent. Chitosan added to the mix increased the gel time compared to the pluronic gel alone. The incorporation of TPP into the material modified the morphology of the hydrogels formed. Subsequently, MTS and Live/Dead® experiments were performed to investigate the toxicity of hydrogels against human chondrocytes. The in vitro releases of dexamethasone (DMT) from CS-PF and CS-PF-TPP gels had an initial burst and took more time than that from the PF hydrogel. In vivo studies showed that hydrogels retained the fluorescent compound longer in the joint than when administered in PBS alone. These results suggest that the CS-PF and CS-PF-TPP hydrogels loaded with DMT could be a promising drug delivery platform for the treatment of osteoarthritis.

Synthesis and Evaluation of AlgNa-g-Poly(QCL-co-HEMA) Hydrogels as Platform for Chondrocyte Proliferation and Controlled Release of Betamethasone.

Hydrogels obtained from combining different polymers are an interesting strategy for developing controlled release system platforms and tissue engineering scaffolds. In this study, the applicability of sodium alginate-g-(QCL-co-HEMA) hydrogels for these biomedical applications was evaluated. Hydrogels were synthesized by free-radical polymerization using a different concentration of the components. The hydrogels were characterized by Fourier transform-infrared spectroscopy, scanning electron microscopy, and a swelling degree. Betamethasone release as well as the in vitro cytocompatibility with chondrocytes and fibroblast cells were also evaluated. Scanning electron microscopy confirmed the porous surface morphology of the hydrogels in all cases. The swelling percent was determined at a different pH and was observed to be pH-sensitive. The controlled release behavior of betamethasone from the matrices was investigated in PBS media (pH = 7.4) and the drug was released in a controlled manner for up to 8 h. Human chondrocytes and fibroblasts were cultured on the hydrogels. The MTS assay showed that almost all hydrogels are cytocompatibles and an increase of proliferation in both cell types after one week of incubation was observed by the Live/Dead® assay. These results demonstrate that these hydrogels are attractive materials for pharmaceutical and biomedical applications due to their characteristics, their release kinetics, and biocompatibility.

Doxorubicin Loaded Poloxamer Thermosensitive Hydrogels: Chemical, Pharmacological and Biological Evaluation.

(1) Background: doxorubicin is a potent chemotherapeutic agent, but it has limitations regarding its side effects and therapy resistance. Hydrogels potentially deal with these problems, but several characterizations need to be optimized to better understand how hydrogel assisted chemotherapy works. Poloxamer 407 (P407) hydrogels were mixed with doxorubicin and physico-chemical, biological, and pharmacological characterizations were considered. (2) Methods: hydrogels were prepared by mixing P407 in PBS at 4 °C. Doxorubicin was added upon solutions became clear. Time-to-gelation, hydrogel morphology, and micelles were studied first. The effects of P407-doxorubicin were evaluated on MC-38 colon cancer cells. Furthermore, doxorubicin release was assessed and contrasted with non-invasive in vivo whole body fluorescence imaging. (3) Results: 25% P407 had favorable gelation properties with pore sizes of 30-180 µm. P407 micelles were approximately 5 nm in size. Doxorubicin was fully released in vitro from 25% P407 hydrogel within 120 h. Furthermore, P407 micelles strongly enhanced the anti-neoplastic effects of doxorubicin on MC-38 cells. In vivo fluorescence imaging revealed that hydrogels retained fluorescence signals at the injection site for 168 h. (4) Conclusions: non-invasive imaging showed how P407 gels retained drug at the injection site. Doxorubicin P407 micelles strongly enhanced the anti-tumor effects.

Thermosensitive hydrogels as sustained drug delivery system for CTLA-4 checkpoint blocking antibodies.

Thermosensitive poloxamer 407 (P407) hydrogels were evaluated as slow release system for optimizing CTLA-4 therapy. Slow release reduces systemic antibody levels and potentially mitigates the side effects of CTLA-4 therapy. The 25% P407 hydrogel is injectable at room temperature and depots are established quickly after subcutaneous injection. Scanning electron microscopy revealed the porous structure of the hydrogel, average pore surface was 1335 µm2. Release studies were optimized using the human IgG antibody. IgG was easily incorporated in the hydrogel by simple mixing and no antibodies were lost during preparation. In vitro, hydrogels showed low burst release within the first 24 h. Total IgG load was gradually released within 120 h. In vitro cytotoxicity assays showed that P407 is not cytotoxic and induces no immune activation by itself. In vivo, P407 hydrogels significantly reduced serum IgG levels, were biocompatible and were broken down 1 week after injection. Finally, local hydrogel delivery of anti-CTLA-4 antibodies near established tumors effectively slowed down tumor growth, whilst significantly reduced serum anti-CTLA-4 levels. Altogether, P407 hydrogels represent promising delivery systems for the optimization of CTLA-4 blocking therapy.

Targeting Polymeric Nanobiomaterials as a Platform for Cartilage Tissue Engineering.

Articular cartilage is a connective tissue structure that is found in anatomical areas that are important for the movement of the human body. Osteoarthritis is the ailment that most often affects the articular cartilage. Due to its poor intrinsic healing capacity, damage to the articular cartilage is highly detrimental and at present the reconstructive options for its repair are limited. Tissue engineering and the science of nanobiomaterials are two lines of research that together can contribute to the restoration of damaged tissue. The science of nanobiomaterials focuses on the development of different nanoscale structures that can be used as carriers of drugs / cells to treat and repair damaged tissues such as articular cartilage. This review article is an overview of the composition of articular cartilage, the causes and treatments of osteoarthritis, with a special emphasis on nanomaterials as carriers of drugs and cells, which reduce inflammation, promote the activation of biochemical factors and ultimately contribute to the total restoration of articular cartilage.

Recubrimiento de microesferas de quitosana-ibuprofeno con un complejo interpolimérico pH dependiente / Coating of chitosan-Ibuprofen microspheres with a pH-depending interpolymer complex

INTRODUCCIÓN: el efecto irritante sobre la mucosa gástrica que producen los antiinflamatorios no esteroideos es una de sus principales reacciones adversas. La encapsulación de estos en matrices poliméricas con propiedades entéricas constituye una alternativa tecnológica para solucionar dicho problema. OBJETIVO: obtener micropartículas de quitosana cargadas con ibuprofeno recubiertas con un complejo interpolimérico pH dependiente a base de poli(ácido acrílico)/poli(N-vinil-2-pirrolidona) MÉTODOS: se prepararon micropartículas de quitosana cargadas con ibuprofeno mediante secado por aspersión y se determinó el rendimiento del proceso y la eficiencia de encapsulación. Las micropartículas se recubrieron con un complejo interpolimérico pH dependiente de poli(ácido acrílico)/poli(N-vinil-2-pirrolidona), empleando la técnica de emulsión/evaporación del disolvente. Mediante espectroscopia infrarroja de transformada de Fourier, se comprobó la formación del complejo, y la evaluación morfológica se realizó por microscopia electrónica de barrido. Los estudios de liberación se realizaron en fluido gástrico e intestinal simulados (FGS pH= 1,2; FIS pH= 6,8). RESULTADOS: en el proceso de obtención de las micropartículas de quitosana y quitosana-ibuprofeno hubo un rendimiento de 69 ± 1 por ciento y 54,4 ± 0,8 por ciento respectivamente. La eficiencia de encapsulación resultó de 46,8 ± 0,7 por ciento. Las micropartículas recubiertas presentaron una superficie rugosa. La formación del complejo se confirmó a través de los cambios observados en la posición de las bandas de absorción de los grupos funcionales involucrados en la formación del enlace por puente de hidrógeno. La liberación de ibuprofeno en FGS resultó del 40 por ciento para las micropartículas sin recubrimiento, mientras que fue despreciable en el caso de las micropartículas recubiertas durante el intervalo de tiempo estudiado. CONCLUSIONES: los resultados muestran las potencialidades del complejo interpolimérico poli(ácido acrílico)/poli(N-vinil-2-pirrolidona) como cubierta pH dependiente, con vistas a obtener un recubrimiento de tipo entérico que reduzca los efectos adversos sobre la mucosa gástrica de fármacos como los antiinflamatorios no esteroideos(AU)

INTRODUCTION: the irritating effect on the gastric mucosa caused by non-steroidal anti-inflammatory drugs is one of the main adverse reactions. Their encapsulation in polymer matrices with enteric properties is a technological alternative to solve the problem. OBJECTIVE: to obtain ibuprofen-loaded chitosan microparticles coated with a pH dependent interpolymer complex based on poly(acrylic acid)/poly(N-vinyl-2-pyrrolidone). METHODS: Ibuprofen-loaded chitosan microparticles were prepared through the spray drying technique; the yield and the efficiency of encapsulation were evaluated. Microparticles were coated with a pH-dependent interpolymer complex based on poly(acrylic acid)/poly(N-vinyl-2-pyrrolidone) using the emulsion/solvent evaporation technique. The complex formation was verified by Fourier transform infrared spectroscopy and the morphological evaluation was made with the electronic scanning microscopy. Release studies used simulated gastric (SGF, pH= 1.2) and intestinal (SIF, pH= 6.8) fluids. RESULTS: in the process of obtaining the chitosan and chitosan-ibuprofen microparticles, the yield rates amounted to 69 ± 1 percent and 54.4 ± 0.8 percent respectively were obtained. The encapsulation efficiency was 46.8 ± 0.7 percent he coated microparticles presented rough surface. Complex formation was confirmed by changes in the position of the absorption bands of the functional groups involved in hydrogen bonding. The release of ibuprofen from uncoated microparticles in simulated gastrointestinal fluid reached 40 percent whereas it was neglectable in the coated microparticles during the study interval. CONCLUSIONS: the results show the potential of poly(acrylic acid)/poly(N-vinyl-2-pyrrolidone) interpolymer complex as pH dependent cover for use as enteric coating to reduce the side effects on the gastric mucosa of medications such as non-steroidal anti-inflammatory drugs(AU).

Recubrimiento de microesferas de quitosana-ibuprofeno con un complejo interpolimérico pH dependiente / Coating of chitosan-Ibuprofen microspheres with a pH-depending interpolymer complex

Introducción: el efecto irritante sobre la mucosa gástrica que producen los antiinflamatorios no esteroideos es una de sus principales reacciones adversas. La encapsulación de estos en matrices poliméricas con propiedades entéricas constituye una alternativa tecnológica para solucionar dicho problema. Objetivo: obtener micropartículas de quitosana cargadas con ibuprofeno recubiertas con un complejo interpolimérico pH dependiente a base de poli(ácido acrílico)/poli(N-vinil-2-pirrolidona). Métodos: se prepararon micropartículas de quitosana cargadas con ibuprofeno mediante secado por aspersión y se determinó el rendimiento del proceso y la eficiencia de encapsulación. Las micropartículas se recubrieron con un complejo interpolimérico pH dependiente de poli(ácido acrílico)/poli(N-vinil-2-pirrolidona), empleando la técnica de emulsión/evaporación del disolvente. Mediante espectroscopia infrarroja de transformada de Fourier, se comprobó la formación del complejo, y la evaluación morfológica se realizó por microscopia electrónica de barrido. Los estudios de liberación se realizaron en fluido gástrico e intestinal simulados (FGS pH= 1,2; FIS pH= 6,8). Resultados: en el proceso de obtención de las micropartículas de quitosana y quitosana-ibuprofeno hubo un rendimiento de 69 ± 1 por ciento y 54,4 ± 0,8 por ciento respectivamente. La eficiencia de encapsulación resultó de 46,8 ± 0,7 por ciento. Las micropartículas recubiertas presentaron una superficie rugosa. La formación del complejo se confirmó a través de los cambios observados en la posición de las bandas de absorción de los grupos funcionales involucrados en la formación del enlace por puente de hidrógeno. La liberación de ibuprofeno en FGS resultó del 40 por ciento para las micropartículas sin recubrimiento, mientras que fue despreciable en el caso de las micropartículas recubiertas durante el intervalo de tiempo estudiado. Conclusiones: los resultados muestran las potencialidades del complejo interpolimérico...

Introduction: the irritating effect on the gastric mucosa caused by non-steroidal anti-inflammatory drugs is one of the main adverse reactions. Their encapsulation in polymer matrices with enteric properties is a technological alternative to solve the problem. Objective: to obtain ibuprofen-loaded chitosan microparticles coated with a pH dependent interpolymer complex based on poly(acrylic acid)/poly(N-vinyl-2-pyrrolidone). Methods: Ibuprofen-loaded chitosan microparticles were prepared through the spray drying technique; the yield and the efficiency of encapsulation were evaluated. Microparticles were coated with a pH-dependent interpolymer complex based on poly(acrylic acid)/poly(N-vinyl-2-pyrrolidone) using the emulsion/solvent evaporation technique. The complex formation was verified by Fourier transform infrared spectroscopy and the morphological evaluation was made with the electronic scanning microscopy. Release studies used simulated gastric (SGF, pH= 1.2) and intestinal (SIF, pH= 6.8) fluids. Results: in the process of obtaining the chitosan and chitosan-ibuprofen microparticles, the yield rates amounted to 69 ± 1 percent and 54.4 ± 0.8 percent respectively were obtained. The encapsulation efficiency was 46.8 ± 0.7 percent. The coated microparticles presented rough surface. Complex formation was confirmed by changes in the position of the absorption bands of the functional groups involved in hydrogen bonding. The release of ibuprofen from uncoated microparticles in simulated gastrointestinal fluid reached 40 percent whereas it was neglectable in the coated microparticles during the study interval. Conclusions: the results show the potential of poly(acrylic acid)/poly(N-vinyl-2-pyrrolidone) interpolymer complex as pH dependent cover for use as enteric coating to reduce the side effects on the gastric mucosa of medications such as non-steroidal anti-inflammatory drugs(AU)