Formulation and optimization of pH-sensitive nanocrystals for improved oral delivery.

The challenge of low water solubility in pharmaceutical science profoundly impacts drug absorption and therapeutic effectiveness. Nanocrystals (NC), consisting of drug molecules and stabilizing agents, offer a promising solution to enhance solubility and control release rates. In the pharmaceutical industry, top-down techniques are favored for their flexibility and cost-effectiveness. However, increased solubility can lead to premature drug dissolution in the stomach, which is problematic due to the acidic pH or enzymes. Researchers are exploring encapsulating agents that facilitate drug release at customized pH levels as a valuable strategy to address this. This study employed wet milling and spray drying techniques to create encapsulated NC for delivering the drug to the intestinal tract using the model drug ivermectin (IVM). Nanosuspensions (NS) were efficiently produced within 2 h using NanoDisp®, with a particle size of 198.4 ± 0.6 nm and a low polydispersity index (PDI) of 0.184, ensuring uniformity. Stability tests over 100 days at 4 °C and 25 °C demonstrated practical viability, with no precipitation or significant changes observed. Cytotoxicity evaluations indicated less harm to Caco-2 cells compared to the pure drug. Furthermore, the solubility of the NC increased by 47-fold in water and 4.8-fold in simulated intestinal fluid compared to the pure active compound. Finally, dissolution tests showed less than 10% release in acidic conditions and significant improvement in simulated intestinal conditions, promising enhanced drug solubility and bioavailability. This addresses a long-standing pharmaceutical challenge in a cost-effective and scalable manner.

Significant progress in improving Atorvastatin dissolution rate: Physicochemical characterization and stability assessment of self-dispersible Atorvastatin/Tween 80® nanocrystals formulated through wet milling and freeze-drying.

Atorvastatin (ATV) is a first-line drug for the treatment of hyperlipidemia. This drug presents biopharmaceutical problems, partly due to its low solubility and dissolution rate. In this work, nanocrystals of ATV stabilized with Tween 80® were designed by wet milling. A full factorial design was applied to optimize the process. Additionally, a cryoprotectant agent (maltodextrin, MTX) was identified, which allowed maintaining the properties of the nanocrystals after lyophilization. The storage stability of the nanocrystals was demonstrated for six months in different conditions. The obtained nanocrystal powder was characterized using SEM, EDXS, TEM, DSC, TGA, FT-IR, and XRD, showing the presence of irregular crystals with semi-amorphous characteristics, likely due to the particle collision process. Based on the reduction in particle size and the decrease in drug crystallinity, a significant increase in water and phosphate buffer (pH 6.8) solubility by 4 and 6 times, respectively, was observed. On the other hand, a noticeable increase in the dissolution rate was observed, with 90 % of the drug dissolved within 60 min of study, compared to 30 % of the drug dissolved within 12 h in the case of the untreated drug or the physical mixture of components. Based on these results, it can be concluded that the nano-milling of Atorvastatin stabilized with Tween 80® is a promising strategy for developing new formulations with improved biopharmaceutical properties of this widely used drug.

Design of a pilot plant-type pharmaceutical reactor to address the problem of interchangeability of generic semisolid formulations.

OBJECTIVE AND SIGNIFICANCE: This research aims to design and develop a pilot plant-type pharmaceutical reactor with a strong focus on its volumetric capacity and heat transfer capabilities. The primary goal is to replicate design and control strategies at the laboratory or pilot scale to analyze and produce generic semisolid formulations. METHODS: Computational fluid dynamics and heat transfer modeling, utilizing the finite volume method, were employed to determine the reactor's performance and particle trajectory during the mixing and stirring. This allowed for the establishment of optimal operational parameters and variables. Furthermore, prototypes were constructed at 1:2.5 and 1:15 scales to examine the reactor's morphology, ensure volumetric versatility, and conduct mixing, homogenization, and coloration tests using varying volumes. RESULTS AND CONCLUSIONS: The outcomes of this study yielded a versatile reactor suitable for processing pharmaceutical semisolids at both laboratory and pilot-scale volumes. Notably, the reactor demonstrated exceptional volumetric capacity within a single vessel while effectively facilitating heat transfer to its interior.

Description of the S-Apple mixed rotation and transposition flap: preliminary note / Descrição do retalho misto de rotação e transposição S-Apple: nota prévia

Introduction: The flaps, whose function is to reduce or redirect tension during a closure, are classified based on their primary movement: transposition, advancement, and rotation, each with its characteristics, indications, and peculiarities. Combining the qualities of the transposition flaps with those of rotation, which make up the S-Apple flap, makes it more versatile and with better aesthetic results than the bilobed flap, which denotes the archetype for the appearance of the S-Apple. Method: Having the rotation and transposition flaps as an archetype, four flaps are made in the S-Apple flap, which are rotated and transposed to close the defect. This is excised in a circular format for the oncological safety of margins. The "S" of the flap is traced at a 30º angle in relation to the defect. The arm dimension must be the same diameter as the defect, with the flaps transposed as in a z-plasty, and the flap rotated to cover the defect, resulting from the exeresis of the lesion. Results: No necrosis, infection, dehiscence, recurrences, trapdoor scars, or rotation point elevation were observed. The scars were classified as satisfactory and extremely satisfactory. Conclusion: The S-Apple flap proved versatile and easy to mark with excellent aesthetic and functional results.

Introdução: Os retalhos, com função de reduzir ou redirecionar a tensão durante um fechamento, são classificados com base em seu movimento primário: transposição, avanço e rotação, cada um com suas características, indicações e peculiaridades. O arregimentar das qualidades dos retalhos de transposição com os de rotação, que compõem o retalho S-Apple, tornam-no mais versátil e com melhores resultados estéticos em relação ao retalho bilobado, que denota o arquétipo para o surgimento do S-Apple. Método: Tendo como arquétipo os retalhos de rotação e transposição, no retalho S-Apple são confeccionados quatro retalhos, que são rotacionados e transpostos para fechamento do defeito. Este é excisado em formato circular para segurança oncológica de margens. O "S" do retalho é traçado em um ângulo de 30º em relação ao defeito. A dimensão do braço deve ser do mesmo diâmetro do defeito, sendo os retalhos transpostos como em uma zetaplastia e o retalho rotacionado para cobrir o defeito, resultante da exérese da lesão. Resultados: Não foram observadas necroses, infecção, deiscências, recidivas, cicatrizes em alçapão e elevação em ponto de rotação. As cicatrizes foram classificadas como satisfatórias e extremamente satisfatórias. Conclusão: O retalho S-Apple se mostrou um retalho versátil de fácil marcação com excelentes resultados estéticos e funcionais.

3D-Printed Gastroretentive Tablets Loaded with Niclosamide Nanocrystals by the Melting Solidification Printing Process (MESO-PP).

Niclosamide (NICLO) is a recognized antiparasitic drug being repositioned for Helicobacter pylori. The present work aimed to formulate NICLO nanocrystals (NICLO-NCRs) to produce a higher dissolution rate of the active ingredient and to incorporate these nanosystems into a floating solid dosage form to release them into the stomach slowly. For this purpose, NICLO-NCRs were produced by wet-milling and included in a floating Gelucire l3D printed tablet by semi-solid extrusion, applying the Melting solidification printing process (MESO-PP) methodology. The results obtained in TGA, DSC, XRD and FT-IR analysis showed no physicochemical interactions or modifications in the crystallinity of NICLO-NCR after inclusion in Gelucire 50/13 ink. This method allowed the incorporation of NICLO-NCRs in a concentration of up to 25% w/w. It achieved a controlled release of NCRs in a simulated gastric medium. Moreover, the presence of NICLO-NCRs after redispersion of the printlets was observed by STEM. Additionally, no effects on the cell viability of the NCRs were demonstrated in the GES-1 cell line. Finally, gastroretention was demonstrated for 180 min in dogs. These findings show the potential of the MESO-PP technique in obtaining slow-release gastro-retentive oral solid dosage forms loaded with nanocrystals of a poorly soluble drug, an ideal system for treating gastric pathologies such as H. pylori.

Humoral response to different SARS-CoV-2 vaccines in orthotopic liver transplant recipients.

BACKGROUND: The safety and efficacy data of the different types of available vaccines is still needed. The goal of the present analysis was to evaluate the humoral response to the COVID-19 vaccines in orthotopic liver transplant (OLT) recipients. METHODS: Participants were included from February to September 2021. No prioritized vaccination roll call applied for OLT patients. Controls were otherwise healthy people. Blood samples were drawn after 15 days of the complete vaccine doses. The samples were analyzed according to the manufacturer's instructions using the Liaison XL platform from DiaSorin (DiaSorin S.p.A., Italy), and SARS-COV-2 IgG II Quant (Abbott Diagnostics, IL, USA). RESULTS: A total of 187 participants (133 OLT, 54 controls, median age: 60 years, 58.8% women) were included for the analysis; 74.3% had at least one comorbidity. The serologic response in OLT patients was lower than in controls (median 549 AU/mL vs. 3450 AU/mL, respectively; p = 0.001). A positive humoral response was found in 133 OLT individuals: 89.2% with BNT162b2 (Pfizer-BioNTech), 60% ChAdOx1 nCOV-19 (Oxford-AstraZeneca), 76.9% with CoronaVac (Sinovac, Life Sciences, China), 55.6% Ad5-nCov (Cansino, Biologics), 68.2% Gam-COVID-Vac (Sputnik V) and 100% with mRNA-1273. In controls the serological response was 100%, except for Cansino (75%). In a multivariable model, personal history of COVID-19 and BNT162b2 inoculation were associated with the serologic response, while the use of prednisone (vs. other immunosuppressants) reduced this response. CONCLUSION: The serologic response to COVID-19 vaccines in OLT patients is lower than in healthy controls. The BNT162b2 vaccine was associated with a higher serologic response.

The Effect of Different Formulations of Praziquantel in Reducing Worms in the Prepatent Period of Schistosomiasis in Murine Models.

Schistosomiasis is a widely distributed parasitic disease and one of the most important neglected tropical diseases globally, for which Praziquantel® (PZQ) is the only available treatment. In this context, tests with new PZQ formulations become relevant for disease control. This study evaluated the effects of PZQ treatment in the prepatent phase of schistosomiasis using two formulations: nanoencapsulated (PZQ-NANO) and active pharmaceutical ingredient (PZQ-API). Five experimental groups were established, for which the following serological parameters were evaluated: ALT, AST, ALP, and TP. Animals treated with PZQ-API at 15 and 30 days post-infection showed decreased eggs per gram of feces (EPG) compared to untreated infected animals. The same animals showed reductions of 63.6 and 65.1%, respectively, at 60 days post-infection. Animals treated with PZQ-NANO experienced no significant changes in EPG at any time of observation. Animals treated with either PZQ-API or PZQ-NANO had higher ALT and AST levels in the patent period (60 and 90 days post-infection). Treatment with PZQ, either API or NANO, at 15 days post-infection reduced AST, ALT, and TP levels. It is concluded that prepatent treatment with PZQ-API can reduce the parasite load of infected animals and that treatment at 15 days post-infection can prevent increased serum levels of ALT, AST, and TP.

Design and optimization of pH-sensitive Eudragit nanoparticles for improved oral delivery of triclabendazole.

Design of Experiments (DoE) techniques were used to identify and optimize the parameters involved in the formulation of triclabendazole pH-sensitive Eudragit® nanoparticles (NPs). Using a Placket Burmann design, Eudragit® E, Eudragit® RS, and two stabilizers (PVP and PVA) were evaluated for NPs formulation by nanoprecipitation. Based on the screening results, Eudragit E 100® and PVP were selected as excipients, and their levels were studied and optimized using a central composite design, obtaining an optimum nanoparticulated system with a Size of 240 nm, a PDI of 0.420, and a ZP of 46.3 mV. Finally, a full characterization of the optimum system was carried out by XRD, DSC, equilibrium solubility, and dissolution rate in biorelevant mediums. As observed in XRD and DSC, the nanoencapsulation process produced a remarkable reduction in drug crystallinity that improved drug solubility and dissolution rate. Although more than 90% of TCBZ was dissolved in acidic mediums at 10 min, no increase in solubility or dissolution rate was observed in simulated saliva. Consequently, the development of pH-sensitive Eudragit® NPs would be a promising strategy in developing an immediate gastric release TCBZ formulation for oral delivery.

Nanocrystal-based 3D-printed tablets: Semi-solid extrusion using melting solidification printing process (MESO-PP) for oral administration of poorly soluble drugs.

This is the first report on the inclusion of nanocrystals (NCs) within 3D-printed oral solid dosage forms -3D-printed tablets or printlets- produced by the Melting Solidification Printing Process (MESO-PP) 3D printing technique. This method allowed the incorporation of albendazole (ABZ) nanocrystals in a concentration of up to 50% w/w, something not achieved in conventional tablets. An ink of PEG 1500/propylenegycol was used as a carrier and no physicochemical interactions or crystallinity modifications were observed due to the inclusion of ABZ-NCs into the ink, as demonstrated by TGA, DSC, XRD and FT-IR. In particular, the relative crystallinity of the ink loaded with NCs was 97.8% similar to the physical mixture of the components. Moreover, the presence of NCs was observed in the surface and matrix of the printlets by SEM. In addition, the printlet NCs demonstrated to be more effective than NCs included in hard gelatin capsules in improving drug dissolution in HCl 0.1 N. The particle size, crystallinity and chemical stability of the nanocrystals was maintained before and after 180 days of storage. Thus, these findings exhibit relevant pharmaceutical potential for developing stable, fast-release, oral, solid dosage forms of poorly soluble drugs combining 3D printing and nanocrystals. Additionally, this technique could be applied for printing objects using different types of nanocrystals embedded in low melting temperature polymers.

Cyclodextrin-Modified Nanomaterials for Drug Delivery: Classification and Advances in Controlled Release and Bioavailability.

In drug delivery, one widely used way of overcoming the biopharmaceutical problems present in several active pharmaceutical ingredients, such as poor aqueous solubility, early instability, and low bioavailability, is the formation of inclusion compounds with cyclodextrins (CD). In recent years, the use of CD derivatives in combination with nanomaterials has shown to be a promising strategy for formulating new, optimized systems. The goals of this review are to give in-depth knowledge and critical appraisal of the main CD-modified or CD-based nanomaterials for drug delivery, such as lipid-based nanocarriers, natural and synthetic polymeric nanocarriers, nanosponges, graphene derivatives, mesoporous silica nanoparticles, plasmonic and magnetic nanoparticles, quantum dots and other miscellaneous systems such as nanovalves, metal-organic frameworks, Janus nanoparticles, and nanofibers. Special attention is given to nanosystems that achieve controlled drug release and increase their bioavailability during in vivo studies.

Bases genômicas do carcinoma basocelular não sindrômico: revisão da literatura / Genomic bases of non-syndromic basal cell carcinoma: literature review

RESUMO Introdução: As neoplasias cutâneas não melanoma representam o tipo mais frequente em ambos os sexos no mundo, sendo o carcinoma basocelular o mais prevalente, representando de 75 a 80% dos casos. No Brasil, o número de casos novos esperados para o triênio 2020-2022, será de 83.770 em homens e 93.160 em mulheres, correspondendo a um risco estimado de 80,12 casos novos para 100 mil homens e de 86,65 casos novos para 100 mil mulheres. Este dado demonstra a grande importância do conhecimento genômico na gênese do carcinoma basocelular esporádico. Objetivo: Descrever os principais genes e marcadores moleculares envolvidos na predisposição e na patogênese do carcinoma basocelular não sindrômico. Métodos: Revisão da literatura nas principais bases de dados NCBI-GTR, ClinVar, ClinGen, MedGen, OMIM e GeneReviews , utilizando como descritores: "BCC" e " basal cell carcinoma ". Critérios de inclusão: língua portuguesa ou inglesa, artigos sobre CBC esporádico. Resultados: Foram selecionados treze artigos para análise. A análise revelou uma robusta ligação da via hedgehog na gênese do carcinoma basocelular esporádico, com os principais genes envolvidos representados por PATCH1, PATCH2 e smoothened . As variantes com maior significância clínica foram SMO-M2, PTCH1 e PTCH2-∆22. A mutação mais encontrada fora a relacionada à ação do UVB, sendo representada pela substituição de C>T ou CC>TT no sítio das pirimidinas, tanto no PTCH, quanto no SMO. Conclusão: Extremamente importante aos profissionais que atuam no diagnóstico e tratamento do CBC, dentre os quais os cirurgiões plásticos, pois assim poderão melhor conduzir seus casos, com diagnósticos mais precisos e condutas de prevenção baseadas na suscetibilidade individual de cada paciente, bem como terapêuticas direcionadas e individualizadas com melhores taxas de sucesso.

ABSTRACT Introduction: Non-melanoma skin neoplasms represent the most frequent type in both sexes globally, with basal cell carcinoma being the most prevalent, representing 75 to 80% of cases. In Brazil, the number of new cases expected for the triennium 2020-2022 will be 83,770 in men and 93,160 in women, corresponding to an estimated risk of 80.12 new cases for 100,000 men and 86.65 new cases for 100,000 women. This data demonstrates the great importance of genomic knowledge in the genesis of sporadic basal cell carcinoma. Objective: To describe the main genes and molecular markers involved in the predisposition and pathogenesis of non-syndromic basal cell carcinoma. Methods: Literature review in the main databases NCBI-GTR, ClinVar, ClinGen, MedGen, OMIM and GeneReviews , using as descriptors: "BCC" and " basal cell carcinoma ". Inclusion criteria: Portuguese or EnGLIsh language, articles on sporadic BCC. Results: Thirteen articles were selected for analysis. The analysis revealed a robust hedgehog pathway link in the genesis of sporadic basal cell carcinoma, with the main genes involved represented by PATCH1, PATCH2 and smoothened . The variants with the highest clinical significance were SMO-M2, PTCH1 and PTCH2-∆22. The mutation most found was related to the action of UVB, being represented by the substitution of C>T or CC>TT at the pyrimidine site, both in PTCH and in SMO. Conclusion: Extremely important to professionals working in the diagnosis and treatment of BCC, including plastic surgeons, as this way they can better conduct their cases, with more accurate diagnoses and prevention approaches based on the individual susceptibility of each patient, as well as targeted therapies and individualized with better success rates.

The First Genetic Map for a Psoraleoid Legume (Bituminaria bituminosa) Reveals Highly Conserved Synteny with Phaseoloid Legumes.

We present the first genetic map of tedera (Bituminaria bituminosa (L.) C.H. Stirton), a drought-tolerant forage legume from the Canary Islands with useful pharmaceutical properties. It is also the first genetic map for any species in the tribe Psoraleeae (Fabaceae). The map comprises 2042 genotyping-by-sequencing (GBS) markers distributed across 10 linkage groups, consistent with the haploid chromosome count for this species (n = 10). Sequence tags from the markers were used to find homologous matches in the genome sequences of the closely related species in the Phaseoleae tribe: soybean, common bean, and cowpea. No tedera linkage groups align in their entirety to chromosomes in any of these phaseoloid species, but there are long stretches of collinearity that could be used in tedera research for gene discovery purposes using the better-resourced phaseoloid species. Using Ks analysis of a tedera transcriptome against five legume genomes provides an estimated divergence time of 17.4 million years between tedera and soybean. Genomic information and resources developed here will be invaluable for breeding tedera varieties for forage and pharmaceutical purposes.

COVID-19 and a novel initiative to improve safety by 3D printing personal protective equipment parts from computed tomography.

BACKGROUND: Powered air-purifying respirators are in short supply and can break down with extended use. Replacement parts can become hard to acquire. The aim of this study was to create an innovative quality improvement proof of concept using rapid prototyping. METHODS: Here we report three cases of 3D printed powered air-purifying respirator parts. 3D printing was performed on all parts using fused deposition modeling with standard polylactic acid, in the same way that presurgical models would be created. Measurements using an electronic caliper as well as CT scans were used to compare an original part to its corresponding 3D printed parts for accuracy. RESULTS: Electronic caliper and computed tomography measurements both showed accuracy consistant with current published norms. CONCLUSIONS: Ultimately, there will be questions surrounding intellectual property, effectiveness and potential long-term safety for these types of 3D printed parts. Future research should look into the addition of specific nanoparticles from the position of cost, efficacy, safety and improved accuracy.

Transillumination of Calot's Triangle on Laparoscopic Cholecystectomy: A Feasible Approach to Achieve a Critical View of Safety.

Background Laparoscopic cholecystectomy is currently one of the most commonly performed procedures globally. Morbidity of laparoscopic cholecystectomy is low; however, bile duct injury is still a feared complication. Despite worldwide efforts, the global incidence of bile duct injury remains higher for laparoscopic cholecystectomy compared with open cholecystectomy. Despite the general belief that the learning curve and lack of laparoscopic skills represent the most common causes of bile duct injuries, the principal cause is the misidentification of biliary anatomy. The aim of our study is to determine if laparoscopic transillumination is a feasible approach to bile and vascular structures visualization during laparoscopic cholecystectomy because the only other method for real-time visualization is fluorescent cholangiography, which can be cost-prohibitive and requires specialized equipment and training. Materials and methods We performed a retrospective comparison of outcomes between the transillumination approach in 10 patients receiving laparoscopic cholecystectomy (group A) and a control group of 50 conventional laparoscopic cholecystectomy patients (group B). We compared demographic data, type of surgery, operative time, bleeding, intraoperative and postoperative complications, and hospital stay. We used a conventional four-port positioning for laparoscopic cholecystectomy, and a 5-mm/30° scope was used as a light source and placed behind the area identified as Calot's triangle. Results Group A consisted of 10 patients (9 women, 1 man), with a mean age of 50.7 (± 17.4) years. The mean body mass index (BMI) in group A was 26.8 (± 0.65) kg/m2. In group A, three of the cholecystectomies were conducted as emergency procedures. Group B consisted of 50 patients (40 women, 10 men), with a mean age of 49.7 (±15.2) years. The mean BMI in group B was 27.5 (±4.5) kg/m2, and two cholecystectomies were emergency procedures. In comparing the transillumination approach with conventional cholecystectomy, we found no statistical differences in operative time, bleeding, complications, or mean hospital stay. Conclusions Laparoscopic transillumination is a feasible method for real-time visualization of Calot's triangle structures. Our initial experience with transillumination did not provide better outcomes than conventional cholecystectomy.

Nanodelivery of nitazoxanide: impact on the metabolism of Taenia crassiceps cysticerci intracranially inoculated in mice.

Aim: To formulate nanocapsules and nanoemulsions of nitazoxanide (NTZ) and evaluate the metabolic effect on Taenia crassiceps cysticerci inoculated intracranially into mice. Materials & methods: NTZ nanosystems were formulated through solvent diffusion methodology. These nanoformulations were administered perorally and their impact on glycolysis, the tricarboxylic acid cycle and fatty acid metabolism in T. crassiceps cysticerci was investigated. Results: Gluconeogenesis and protein catabolism were significantly increased by the nanoformulations when compared with the control group and the NTZ-treated group. All the other metabolic pathways were inhibited by the nanoformulation treatments. Conclusion: The remarkable metabolic modifications that occur in this in vivo model through the application of these developed nanosystems confirm their capability to deliver NTZ into targeted tissues.

Improving the Dissolution of Triclabendazole from Stable Crystalline Solid Dispersions Formulated for Oral Delivery.

Triclabendazole belongs to the class II/IV of the Biopharmaceuticals Classification System, and its low aqueous solubility represents a major drawback during the development of effective dosage forms. Therefore, the goal of this study was to elucidate whether polymeric solid dispersions would represent a suitable approach to overcome such disadvantage. Due to the lack of information on triclabendazole release, four different dissolution media were evaluated to analyze drug dissolution rate. The polymeric solid dispersions were characterized by X-ray diffraction and Fourier transform infrared spectroscopy. The selected final formulations were further stored for 24 months, and their physical stability was evaluated by means of X-ray diffraction and drug dissolution assays. Drug solubility studies indicated that poloxamer 407 (P407) solubilized a higher amount of drug than polyethylene glycol 6000. Drug-to-carrier ratio, nature of the selected carriers, and the type of dissolution media were important factors for increasing dissolution. By infrared spectroscopy, there were no specific interactions between the drug and polymers. The physicochemical characterization of the systems showed a detectable evidence of drug amorphization by increasing the carrier ratio. Micromeritic studies indicated that raw triclabendazole, physical mixtures, and reference formulation showed poor flow properties, in contrast to the triclabendazole:P407 solid dispersion sample. Both the crystalline properties and dissolution rate of selected samples were very similar after 24 months at room temperature. Thus, considering physical stability and dissolution studies, the development of the solid dispersion is a very suitable methodology to improve triclabendazole dissolution and, potentially, its biopharmaceutical performance.

Linfoma anaplásico de grandes células relacionado ao implante mamário: revisão sistemática da literatura / Breast implant-associated anaplastic large-cell lymphoma: a systematic literature review

O linfoma anaplásico de grandes células associado ao implante de mama (Breast Implant Associated Anaplastic Large Cell Lymphoma - BIA-ALCL) é uma doença maligna recentemente descoberta, rara e possivelmente associada aos implantes mamários texturizados. Essa revisão da literatura teve como objetivo trazer novas atualizações acerca da epidemiologia, fisiopatologia e fatores de risco para desenvolvimento do BIAALCL. Foi realizado o levantamento de dados do período de dezembro de 2018 a fevereiro de 2019, através das bases de dados PUBMED, LILACS e Scielo sendo selecionados 10 artigos publicados entre 2016 e 2018. Foi encontrada uma incidência variando entre 2,8:100.000 a 1:3 milhões de pacientes com implantes mamários. Os dados coletados corroboram para a teoria de que não há uma relação direta de causa e efeito entre os implantes mamários, mormente os texturizados, e o desenvolvimento do BIA-ALCL, podendo esses ser considerados somente como fatores de risco e não agentes causadores. A teoria fisiopatológica mais aceita é a de que os implantes mamários com maior área de superfície levariam a formação de maior biofilme por maior adesão bacteriana gerando inflamação crônica mais proeminente, levando ao gatilho para a transformação maligna das células T. As informações explicitadas nessa revisão devem auxiliar na ampliação de estudos acerca da doença e criação de políticas públicas para a prevenção e diagnóstico precoce de tal enfermidade. Pelos dados encontrados há necessidade de que cirurgiões plásticos realizem acompanhamento mais próximo de seus pacientes, assim como orientem os pacientes antes das cirurgias sobre a existência da doença.

Breast implant-associated anaplastic large-cell lymphoma (BIA-ALCL) is a newly discovered and rare cancer possibly associated with textured breast implants. This literature review investigates its epidemiology, pathophysiology, and risk factors. PubMed, LILACS, and SciELO databases were searched from December 2018 to February 2019, and 10 articles published between 2016 and 2018 were selected. The incidence of BIA-ALCL ranged from 2.8:100,000 to 1:3 million breast implants. The obtained data corroborate the hypothesis that there is no direct cause and effect relationship between breast implants, especially textured implants, and BIA-ALCL, and these implants can be considered risk factors but not causative factors. The most accepted hypothesis on disease pathophysiology is that breast implants with larger surface areas may promote bacterial adhesion and biofilm formation, leading to severe chronic inflammation, triggering the malignant transformation of T cells. This review provides knowledge on BIA-ALCL and helps develop and implement public policies for disease prevention and timely diagnosis. The data highlight that long-term follow up is necessary and that surgeons should advise patients of the potential risk of developing BIA-ALCL before performing the implant surgery.

Chitosan-based nanodelivery systems applied to the development of novel triclabendazole formulations.

Triclabendazole is a poorly-water soluble (0.24 µg/mL) compound classified into the Class II/IV of the Biopharmaceutical Classification System. It is the drug of choice to treat fascioliasis, a neglected parasitic disease worldwide disseminated. Triclabendazole is registered as veterinary medicine and it is only available for human treatment as 250 mg tablets. Thus, the aim of this work was to develop novel drug delivery systems based on nanotechnology approaches. The chitosan-based nanocapsules and nanoemulsions of triclabendazole were fully characterized regarding their particle size distribution, polydispersity index and zeta potential, in-vitro release and stability in biological media. Cytotoxicity evaluation and cellular uptake studies using CaCo-2 cell line were also investigated. The results indicated an average hydrodynamic size around ~160 nm were found for unloaded nanoemulsions which were slightly increased up to ~190 nm for loaded one. In contrast, the average hydrodynamic size of the nanocapsules increased from ~160 nm up to ~400 nm when loaded with triclabendazole. The stability studies upon 30 days storage at 4, 25 and 37°C showed that average size of nanoemulsions was not modified with varying amounts of loaded TCBZ while an opposite result was seen in case of loaded nanocapsules. In addition, a slight reduction of zeta potential values over time was observed in both triclabendazole nanosystems. Release of TCBZ from nanoformulations over 6 h in simulated gastric fluid was 9 to 16-fold higher than with untreated TCBZ dispersion. In phosphate buffer saline solution there was no drug release for neither nanocapsules nor nanoemulsions. Cell viabilities studies indicated that at certain concentrations, drug encapsulation can lower its cytotoxic effects when compared to untreated drug. Confocal laser scanning microscopy study has shown that nanocapsules strongly interacted with Caco-2 cells in vitro which could increase the passage time of triclabendazole after oral administration. The results of this study constitute the first step towards the development of nanoformulations intended for the oral delivery of anti-parasitic drugs of enhanced bioavailability.

Choosing Appropriate Solvents for ASD Preparation.

Amorphous solid dispersions (ASDs) are often used for formulating poorly water-soluble active pharmaceutical ingredients (APIs). In an ASD, the amorphous API is embedded in a suitable matrix excipient in order to stabilize the amorphous state and control the dissolution performance. ASDs can be prepared by commonly dissolving the API and the polymer in a suitable organic solvent which is evaporated afterward (e.g., via spray drying) aiming at a homogeneous API distribution in the polymer matrix. Sometimes, unexpected solvent influences on the heterogeneity of the dry ASD are observed. Thermodynamic predictions using the Perturbed-Chain Statistical Associating Fluid Theory combined with experimental investigations via Raman spectroscopy, differential scanning calorimetry, and microscopy performed in this work revealed the amorphous phase separation (APS) between the solvent and the polymer as causing the ASD heterogeneities. It will be shown that thermodynamic modeling allows for identifying appropriate solvents that will neither show APS with the polymeric excipient nor at any time of the drying process of ASD formulations.

Solving the Delivery Problems of Triclabendazole Using Cyclodextrins.

Triclabendazole is the first-line drug of choice to treat and control fasciolasis, a neglected parasitic human disease. It is a class II/IV compound according to the Biopharmaceutics Classification System. Thus, the aim of this study was to improve aqueous solubility and dissolution rate of triclabendazole complexed with 2-hydroxylpropyl-ß-cyclodextrin (HP-ß-CD) and methyl-ß-cyclodextrin (Me-ß-CD) at 1:1 and 1:2 M ratio. The impact of storage on the solubility, dissolution profile, and solid-state properties of such complexes was also investigated. Drug-carrier interactions were characterized by infrared spectroscopy, differential scanning calorimetry, X-ray diffractometry, and scanning electron microscopy. The solubility of triclabendazole improved up to 256- and 341-fold using HP-ß-CD and Me-ß-CD, respectively. In particular, the drug complexed with Me-ß-CD showed a positive deviation from linearity, suggesting that its solubility increases with an increasing concentration of Me-ß-CD concentration in a nonlinear manner. The drug dissolution was found to be improved through complex formation with HP-ß-CD and Me-ß-CD. In particular, the 1:2 M ratio complexes exhibited higher dissolution than the corresponding 1:1 M ratio complexes. The physicochemical characterization of the systems showed strong evidence of amorphous phases and/or of the formation of an inclusion complex. Stored at 25 °C, 60% RH for 24 months, drug complexed with ß-cyclodextrins (CDs) at 1:2 M ratio remained amorphous. Based on these findings, it is postulated that the formation of triclabendazole-CD inclusion complexes produced significant enhancement in both the dissolution and solid-state properties of the drug, which may lead to the development of triclabendazole novel formulations with improved biopharmaceutical characteristics.