Design and Characterization of Ocular Inserts Loaded with Dexamethasone for the Treatment of Inflammatory Ophthalmic Disease.

The short precorneal residence time of ophthalmic drops is associated with their low absorption; therefore, the development of ocular inserts capable of prolonging and controlling the ophthalmic release of drugs is an interesting option in the design and development of these drugs. A surface response design was developed, specifically the Central Composite Design (CCD), to produce ophthalmic films loaded with Dexamethasone (DEX) by the solvent evaporation method having experimental levels of different concentrations of previously selected polymers (PVP K-30 and Eudragit RS100.). Once optimization of the formulation was obtained, the in vivo test was continued. The optimal formulation obtained a thickness of 0.265 ± 0.095 mm, pH of 7.11 ± 0.04, tensile strength of 15.50 ± 3.94 gF, humidity (%) of 22.54 ± 1.7, mucoadhesion strength of 16.89 ± 3.46 gF, chemical content (%) of 98.19 ± 1.124, release of (%) 13,510.71, and swelling of 0.0403 ± 0.023 g; furthermore, in the in vivo testing the number and residence time of PMN cells were lower compared to the Ophthalmic Drops. The present study confirms the potential use of polymeric systems using PVPK30 and ERS100 as a new strategy of controlled release of ophthalmic drugs by controlling and prolonging the release of DEX at the affected site by decreasing the systemic effects of the drug.

Synergistic Effect of Retinoic Acid and Lactoferrin in the Maintenance of Gut Homeostasis.

Lactoferrin (LF) is a glycoprotein that binds to iron ions (Fe2+) and other metallic ions, such as Mg2+, Zn2+, and Cu2+, and has antibacterial and immunomodulatory properties. The antibacterial properties of LF are due to its ability to sequester iron. The immunomodulatory capability of LF promotes homeostasis in the enteric environment, acting directly on the beneficial microbiota. LF can modulate antigen-presenting cell (APC) biology, including migration and cell activation. Nonetheless, some gut microbiota strains produce toxic metabolites, and APCs are responsible for initiating the process that inhibits the inflammatory response against them. Thus, eliminating harmful strains lowers the risk of inducing chronic inflammation, and consequently, metabolic disease, which can progress to type 2 diabetes mellitus (T2DM). LF and retinoic acid (RA) exhibit immunomodulatory properties such as decreasing cytokine production, thus modifying the inflammatory response. Their activities have been observed both in vitro and in vivo. The combined, simultaneous effect of these molecules has not been studied; however, the synergistic effect of LF and RA may be employed for enhancing the secretion of humoral factors, such as IgA. We speculate that the combination of LF and RA could be a potential prophylactic alternative for the treatment of metabolic dysregulations such as T2DM. The present review focuses on the importance of a healthy diet for a balanced gut and describes how probiotics and prebiotics with immunomodulatory activity as well as inductors of differentiation and cell proliferation could be acquired directly from the diet or indirectly through the oral administration of formulations aimed to maintain gut health or restore a eubiotic state in an intestinal environment that has been dysregulated by external factors such as stress and a high-fat diet.

Ceftriaxone-Loaded Polymeric Microneedles, Dressings, and Microfibers for Wound Treatment.

The objective of this study was to create polymeric dressings, microfibers, and microneedles (MN) loaded with ceftriaxone, using PMVA (Poly (Methyl vinyl ether-alt-maleic acid), Kollicoat® 100P, and Kollicoat® Protect as polymers to treat diabetic wounds and accelerate their recovery. These formulations were optimized through a series of experiments and were subsequently subjected to physicochemical tests. The results of the characterization of the dressings, microfibers, and microneedles (PMVA and 100P) were, respectively, a bioadhesion of 281.34, 720, 720, 2487, and 510.5 gf; a post-humectation bioadhesion of 186.34, 831.5, 2380, and 630.5 gf, tear strength of 2200, 1233, 1562, and 385 gf, erythema of 358, 8.4, 227, and 188; transepidermal water loss (TEWL) of 2.6, 4.7, 1.9, and 5.2 g/h·m2; hydration of 76.1, 89.9, 73.5, and 83.5%; pH of 4.85, 5.40, 5.85, and 4.85; and drug release (Peppas kinetics release) of n: 0.53, n: 0.62, n: 0.62, and n: 0.66). In vitro studies were performed on Franz-type diffusion cells and indicated flux of 57.1, 145.4, 718.7, and 2.7 µg/cm2; permeation coefficient (Kp) of 13.2, 19.56, 42, and 0.00015 cm2/h; and time lag (tL) of 6.29, 17.61, 27. 49, and 22.3 h, respectively, in wounded skin. There was no passage of ceftriaxone from dressings and microfibers to healthy skin, but that was not the case for PMVA/100P and Kollicoat® 100P microneedles, which exhibited flux of 194 and 0.4 µg/cm2, Kp of 11.3 and 0.00002 cm2/h, and tL of 5.2 and 9.7 h, respectively. The healing time of the formulations in vivo (tests carried out using diabetic Wistar rats) was under 14 days. In summary, polymeric dressings, microfibers, and microneedles loaded with ceftriaxone were developed. These formulations have the potential to address the challenges associated with chronic wounds, such as diabetic foot, improving the outcomes.

Chitosan Nanoparticles as Oral Drug Carriers.

The use of nanoparticles as drug delivery systems has increased in importance in the last decades. Despite the disadvantages of difficulty swallowing, gastric irritation, low solubility, and poor bioavailability, oral administration stands out as the most widely used route for therapeutic treatments, though it may not always be the most effective route. The effect of the first hepatic pass is one of the primary challenges that drugs must overcome to carry out their therapeutic effect. For these reasons, controlled-release systems based on nanoparticles synthesized from biodegradable natural polymers have been reported to be very efficient in enhancing oral delivery in multiple studies. Chitosan has been shown to have an extensive variability of properties and roles in the pharmaceutical and health fields; of its most important properties are the ability to encapsulate and transport drugs within the body and enhance the drug interaction with the target cells, which improves the efficacy of the encapsulated drugs. The physicochemical properties of chitosan give it the ability to form nanoparticles through multiple mechanisms, which will be addressed in this article. The present review article focuses on highlighting the applications of chitosan nanoparticles for oral drug delivery.

Development, Characterization, Optimization, and In Vivo Evaluation of Methacrylic Acid-Ethyl Acrylate Copolymer Nanoparticles Loaded with Glibenclamide in Diabetic Rats for Oral Administration.

The methacrylic acid-ethyl acrylate copolymer nanoparticles were prepared using the solvent displacement method. The independent variables were the drug/polymer ratio, surfactant concentration, Polioxyl 40 hydrogenated castor oil, the added water volume, time, and stirring speed, while size, PDI, zeta potential, and encapsulation efficiency were the response variables analyzed. A design of screening experiments was carried out to subsequently perform the optimization of the nanoparticle preparation process. The optimal formulation was characterized through the dependent variables size, PDI, zeta potential, encapsulation efficiency and drug release profiles. In vivo tests were performed in Wistar rats previously induced with diabetes by administration of streptozotocin. Once hyperglycemia was determined in rats, a suspension of nanoparticles loaded with glibenclamide was administered to them while the other group was administered with tablets of glibenclamide. The optimal nanoparticle formulation obtained a size of 18.98 +/- 9.14 nm with a PDI of 0.37085 +/- 0.014 and a zeta potential of -13.7125 +/- 1.82 mV; the encapsulation efficiency was of 44.5%. The in vivo model demonstrated a significant effect (p < 0.05) between the group administered with nanoparticles loaded with glibenclamide and the group administered with tablets compared to the group of untreated individuals.

Microneedles as Enhancer of Drug Absorption Through the Skin and Applications in Medicine and Cosmetology.

The microneedles technology has found applications in many health-related fields. For example, their application in drugs and vaccines delivery as well, as the determination of biomarkers, has been reported. They also have a place in the dermatology and cosmetic areas such as the treatment of wounds from burns, scars, acne, depigmentation, and alopecia will be shown. Microneedles are used in therapeutic applications and are manufactured using materials such as metal (steel, titanium, nickel), polymer (oly-glycolic acid (PGA), poly-lactide-co-glycolide acid (PLGA), poly-L-lactic acid (PLA), chitosan), glass, silicon, ceramic, carbohydrates (trehalose, sucrose, mannitol). Examples of application of microneedles and their advantages and disadvantages are discussed. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

[Urinary tract lymphoepithelial carcinoma. Report of two cases and bibliographic review.] / Carcinoma linfoepitelial del tracto urinario. Presentación de dos casos y revision de la literatura.

OBJECTIVE: We report two cases of patients diagnosed with lymphoepithelioma-like carcinomas of the urinary tract. We review the literature of this rare entity. The objective is to clarify the clinical and therapeutic characteristics. METHODS: We present a retrospective review of medical records of two patients diagnosed with lymphoepithelioma-like carcinomas, one in the renal pelvis and the other in the bladder. We review the epidemiology, diagnosis and therapeutic alternatives. RESULTS: Case 1: A 74-year-old women with past medical history of left radical nephrectomy and retroperitoneal lymphadenectomy six years before for renal pelvis carcinoma type pure lymphoepithelioma-like, stage pT4R0pN1cM0. She received adjuvant chemotherapy with Cisplatin and Gemcitabine. Five years later, she presented tumor recurrence in the left ureteral meatus, this lesion was resected. The pathology reported a high-grade urothelial carcinoma with marked lymphoid component, stage pT1. At follow-up, one year after the last recurrence, the patient was asymptomatic. In tomography control, no local or distant recurrences were objectified. Case 2: A 82-year-old men with diagnosis of muscleinvasive bladder cancer. The tumor caused right obstructive uropathy without extracapsular, regional or remote extension. We performed a radical cystoprostatectomy with bilateral pelvic lymphadenectomy and urinary diversión type cutaneous transureterostomy. The pathology reported a urothelial bladder carcinoma type mixed lymphoepithelioma-like, stage pT4aR1pN2cM0. At six months follow-up, the patient had liver and spleen lesions and retroperitoneal adenopathic nodes, all suggestive of metastases. He is currently receiving symptomatic treatment of their disease. CONCLUSIONS: We emphasize the clinical importance involved in the diagnosis of this entity. The diagnosis influence the aggressiveness of treatment and disease-specific survival. Therefore, concomitant transitional cell carcinoma defines the prognosis. The role of immunohistochemical staining is fundamental, allowing us to confirm the presence of the epithelial component.

Carcinoma linfoepitelial del tracto urinario. Presentación de dos casos y revisión de la literatura / Urinary tract lymphoepithelial carcinoma. Report of two cases and bibliographic review

OBJETIVO: Presentar dos casos de pacientes diagnosticados de carcinomas linfoepiteliales del tracto urinario. Realizamos una revisión de la literatura de esta infrecuente entidad, con el fin de aclarar las características clínicas y terapéuticas. MÉTODOS: Revisión retrospectiva de la historia clínica de dos pacientes diagnosticados de carcinomas linfoepiteliales, uno en pelvis renal y el otro en vejiga. RESULTADOS: Caso 1: Mujer de 74 años. Se le realiza una nefrectomía radical izquierda y linfadenectomía retroperitoneal por carcinoma de pelvis renal tipo linfoepitelioma like puro, estadio pT4R0pN1cM0. Recibe quimioterapia adyuvante. A los cinco años presenta recidiva tumoral en el meato ureteral izquierdo que se reseca; es informado como carcinoma uroterial de alto grado, con marcado componente linfoide, estadio pT1. Al año de seguimiento de la recidiva la paciente se encuentra asintomática y sin recaída local ni a distancia. Caso 2: Varón de 82 años diagnosticado de carcinoma vesical infiltrante. Se le realiza una cistoprostatectomía radical con linfadenectomía pélvica y derivación urinaria. El resultado es un carcinoma urotelial de vejiga tipo linfoepitelioma- like puro, estadio pT4aR1pN2cM0. A los seis meses se objetiva la aparición de metástasis de órganos sólidos y ganglionares. Actualmente se encuentra con tratamiento sintomático de su enfermedad. CONCLUSIONES: Destacar la importancia clínica que implica el diagnóstico de esta entidad, ya que puede influir en el tratamiento y la supervivencia específica de la enfermedad, siendo el carcinoma uroterial concomitante el que marque el pronóstico. El papel que desempeñan las tinciones inmunohistoquímicas es fundamental, ya que nos permiten confirmar la presencia del componente epitelial

OBJECTIVE: We report two cases of patients diagnosed with lymphoepithelioma-like carcinomas of the urinary tract. We review the literature of this rare entity. The objective is to clarify the clinical and therapeutic characteristics. METHODS: We present a retrospective review of medical records of two patients diagnosed with lymphoepitheliomalike carcinomas, one in the renal pelvis and the other in the bladder. We review the epidemiology, diagnosis and therapeutic alternatives. RESULTS: Case 1: A 74-year-old women with past medical history of left radical nephrectomy and retroperitoneal lymphadenectomy six years before for renal pelvis carcinoma type pure lymphoepithelioma-like, stage pT4R0pN1cM0. She received adjuvant chemotherapy with Cisplatin and Gemcitabine. Five years later, she presented tumor recurrence in the left ureteral meatus, this lesion was resected. The pathology reported a high-grade urothelial carcinoma with marked lymphoid component, stage pT1. At follow-up, one year after the last recurrence, the patient was asymptomatic. In tomography control, no local or distant recurrences were objectified Case 2: A 82-year-old men with diagnosis of muscleinvasive bladder cancer. The tumor caused right obstructive uropathy without extracapsular, regional or remote extension. We performed a radical cystoprostatectomy with bilateral pelvic lymphadenectomy and urinary diversión type cutaneous transureterostomy. The pathology reported a urothelial bladder carcinoma type mixed lymphoepithelioma-like, stage pT4aR1pN2cM0. At six months follow-up, the patient had liver and spleen lesions and retroperitoneal adenopathic nodes, all suggestive of metastases. He is currently receiving symptomatic treatment of their disease. CONCLUSIONS: We emphasize the clinical importance involved in the diagnosis of this entity. The diagnosis influence the aggressiveness of treatment and disease-specific survival. Therefore, concomitant transitional cell carcinoma defines the prognosis. The role of immunohistochemical staining is fundamental, allowing us to confirm the presence of the epithelial component

Polymeric nanospheres as strategy to increase the amount of triclosan retained in the skin: passive diffusion vs. iontophoresis.

The aim of this study was to evaluate the passive and iontophoretic permeation of triclosan in human skin using a triclosan solution and triclosan-loaded cationic nanospheres in order to determine which of the two strategies is more effective in allowing the deposition of triclosan within the skin. Triclosan-loaded nanospheres were prepared by the emulsification-solvent displacement technique using aminoalkyl methacrylate (Eudragit® RL 100) as polymer matrix. Nanospheres of 261.0 ± 15.1 nm with a positive surface charge (Ψz = 26.0 ± 3.2 mV) were obtained. Drug loading was 62.0 ± 1.7%. Results demonstrated that the amount of triclosan retained within the skin was significantly greater (8.5-fold) when this was encapsulated into cationic nanospheres and administered by passive diffusion than when the triclosan solution was employed. The amount of triclosan retained within the skin when the cationic nanospheres were administered by iontophoresis was 3.1-fold greater than when the triclosan solution was administered by passive diffusion. Iontophoresis proved to be effective in enhancing the passage of triclosan in solution throughout the skin, whereas the triclosan nanospheres could achieve a local effect by forming a controlled release dermal depot.

Targeting nicotine addiction: the possibility of a therapeutic vaccine.

Cigarette smoking is the primary cause of lung cancer, cardiovascular diseases, reproductive disorders, and delayed wound healing all over the world. The goals of smoking cessation are both to reduce health risks and to improve quality of life. The development of novel and more effective medications for smoking cessation is crucial in the treatment of nicotine dependence. Currently, first-line smoking cessation therapies include nicotine replacement products and bupropion. The partial nicotinic receptor agonist, varenicline, has recently been approved by the US Food and Drug Administration (FDA) for smoking cessation. Clonidine and nortriptyline have demonstrated some efficacy, but side effects may limit their use to second-line treatment products. Other therapeutic drugs that are under development include rimonabant, mecamylamine, monoamine oxidase inhibitors, and dopamine D3 receptor antagonists. Nicotine vaccines are among newer products seeking approval from the FDA. Antidrug vaccines are irreversible, provide protection over years and need booster injections far beyond the critical phase of acute withdrawal symptoms. Interacting with the drug in the blood rather than with a receptor in the brain, the vaccines are free of side effects due to central interaction. For drugs like nicotine, which interacts with different types of receptors in many organs, this is a further advantage. Three anti-nicotine vaccines are today in an advanced stage of clinical evaluation. Results show that the efficiency of the vaccines is directly related to the antibody levels, a fact which will help to optimize the vaccine effect. The vaccines are expected to appear on the market between 2011 and 2012.

Preparation and characterization of triclosan nanoparticles intended to be used for the treatment of acne.

This work focuses on the preparation and characterization of nanoparticles containing triclosan. Additionally, in vitro percutaneous permeation of triclosan through pig ear skin was performed, and comparisons were made with two commercial formulations: An o/w emulsion and a solution, intended for the treatment of acne. The nanoparticle suspensions were prepared by the emulsification-diffusion by solvent displacement method, using Eudragit® E 100 as polymer. All batches showed a size smaller than 300 nm and a positive Zeta potential, high enough (20-40 mV) to ensure a good physical stability. Differential scanning calorimetry (DSC), transmission electron microscopy (TEM), and scanning electron microscopy (SEM) studies suggested that triclosan was molecularly dispersed in the nanoparticle batches containing up to 31% of triclosan, with good encapsulation efficiency (95.9%). The results of the in vitro permeation studies showed the following order for the permeability coefficients: Solution>cream≈nanoparticles; while for the amount retained in the skin, the order was as follows: cream>nanoparticles≈solution. Nanoparticles, being free of surfactants or other potentially irritant agents, can be a good option for the delivery of triclosan to the skin, representing a good alternative for the treatment of acne.

The use of iontophoresis in the administration of nicotine and new non-nicotine drugs through the skin for smoking cessation.

Cigarette smoking is the primary cause of lung cancer, cardiovascular diseases, reproductive disorders and delayed wound healing all over the world; as such, the goals of smoking cessation are both to reduce health risks and to improve quality of life. The development of novel and more effective medications for smoking cessation is crucial in the treatment of nicotine dependence. Currently, first-line smoking cessation therapies include nicotine replacement products and bupropion. The partial nicotinic receptor agonist, varenicline, has recently been approved by the FDA for smoking cessation. A newer product seeking approval by the FDA is nicotine vaccine. Clonidine and nortriptyline have demonstrated some efficacy, but side effects may limit their use to second-line treatment products. Other therapeutic drugs that are under development include rimonabant, mecamylamine, monoamine oxidase inhibitors, and dopamine D3 receptor antagonists. In order to increase the range of drugs available for transdermal delivery a number of chemical and physical enhancement techniques have been developed in an attempt to compromise skin barrier function in a reversible manner without concomitant skin irritation. The controlled delivery afforded by constant current iontophoresis, which involves the application of a small electrical potential sets it apart from other technologies. The amount of compound delivered is directly proportional to the quantity of charge passed; it depends on the applied current, the duration of current application and the area of the skin surface in contact with the active electrode compartment. For these reasons, iontophoresis will provide smokers with an additional option to assist in achieving smoking cessation.

The use of sonophoresis in the administration of drugs throughout the skin.

Transdermal drug delivery offers an attractive alternative to the conventional drug delivery methods of oral administration and injection. However, the stratum corneum acts as a barrier that limits the penetration of substances through the skin. Application of ultrasound to the skin increases its permeability (sonophoresis) and enables the delivery of various substances into and through the skin. Ultrasound has been used extensively for medical diagnostics and to a certain extent in medical therapy (physiotherapy, ultrasonic surgery, hyperthermia). Nevertheless, it has only recently become popular as a technique to enhance drug release from drug delivery systems. A number of studies suggest the use of ultrasound as an external mean of delivering drugs at increased rates and at desired times. This review presents the main findings in the field of sonophoresis, namely transdermal drug delivery and transdermal monitoring. Particular attention is paid to proposed enhancement mechanisms and trends in the field of topical and transdermal delivery.

Nanoparticle infiltration to prepare solvent-free controlled drug delivery systems.

The purpose of this work was to propose a drug delivery system based on a biodegradable porous membrane, whose surface is covered by a nanoparticle film, thus achieving a controlled drug release rate. Furthermore, due to the fact that the assembly of the system is performed in aqueous medium, contact with organic solvents is avoided. The method is performed in two steps: (i) preparation of biodegradable porous membranes (by a solvent casting and particulate leaching technique) and biodegradable nanoparticles (by the emulsification-diffusion method), extensively eliminating the solvent in both of them; (ii) infiltration into membranes of an aqueous solution of a model drug (carbamazepine) and a nanoparticle dispersion. In both cases, poly(DL-lactic-co-glycolic acid) (PLGA 50:50) was used as a biodegradable polymer. Carbamazepine adsorbed onto biodegradable porous membranes shows an immediate release behavior (95% released in <15 min). Infiltration of different amounts of nanoparticles (50, 100, 400 and 600 mg of nanoparticles/0.625 g of membrane) into biodegradable porous membranes shows a Fickian diffusion according to Peppas model, and fits Higuchi's model. This behavior was attributed to the diffusional barrier constituted by the nanoparticle film. As expected, the carbamazepine release rate was dependent on the amount of infiltrated/adsorbed nanoparticles into biodegradable porous membrane. DSC studies show molecular dispersion of the drug throughout the membrane.