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Aim: Benznidazole (BNZ), a class-II drug, is the primary treatment for Chagas disease, but its low aqueous solubility presents challenges in formulation and efficacy. Nanosuspensions (NS) could potentially address these issues.Methods: BNZ-NS were prepared using a simple, organic solvents-free nano-milling approach. Physicochemical characterizations were conducted on both NS and lyophilized solid-state BNZ-nanocrystals (NC).Results: BNZ-NS exhibited particle size <500 nm, an acceptable polydispersity index (0.23), high Z-potential, and physical stability for at least 90 days. BNZ-NC showed tenfold higher solubility than pure BNZ. Dissolution assays revealed rapid BNZ-NS dissolution. BNZ-NC demonstrated biocompatibility on an eukaryotic cell and enhanced BNZ efficacy against trypomastigotes of Trypanosoma cruzi.Conclusion: BNZ-NS offers a promising alternative, overcoming limitations associated with BNZ for optimized pharmacotherapy.

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Assuntos

RESUMO

3D printing technology is revolutionizing pharmaceuticals, offering tailored solutions for solid dosage forms. This innovation is particularly significant for conditions like Chagas disease, which require weight-dependent treatments. In this work, a formulation of benznidazole (BNZ), the primary treatment for this infection, was developed to be utilized with the Melting Solidification Printing Process (MESO-PP) 3D printing technique. Considering the limited aqueous solubility of BNZ, an interpolyelectrolyte complex (IPEC), composed of chitosan and pectin, was integrated to improve its dissolution profile. The formulations, also called inks in this context, with and without IPEC were integrally characterized and compared. The printing process was studied, the release of BNZ from 3D-prints (3DP) was exhaustively analyzed and a physiologically based pharmacokinetic model (PKPB) was developed to forecast their pharmacokinetic performance. 3DP were successfully achieved loading 25, 50 and 100 mg of BNZ. The presence of the IPEC in the ink caused a decrease in the crystalline domain of BNZ and facilitated the printing process, reaching a print success rate of 83.3 %. Interestingly, 3DP-IPEC showed accelerated release dissolution profiles, releasing over 85 % of BNZ in 90 min, while 3DP took up to 48 h for doses above 25 mg. The PBPK model demonstrated that 3DP-IPEC tablets would present high bioavailability (0.92), higher than 3DP (0.36) and similar to the commercial product. This breakthrough holds immense potential for improving treatment outcomes for neglected diseases.

Assuntos

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Increasing the solubility of drugs is a recurrent objective of pharmaceutical research, and one of the most widespread strategies today is the formulation of nanocrystals (NCs). Beyond the many advantages of formulating NCs, their incorporation into solid dosage forms remains a challenge that limits their use. In this work, we set out to load Atorvastatin NCs (ATV-NCs) in a delivery device by combining 3D scaffolds with an "in situ" loading method such as freeze-drying. When comparing two infill patterns for the scaffolds at two different percentages, the one with the highest NCs load was chosen (Gyroid 20 % infill pattern, 13.8 ± 0.5 mg). Colloidal stability studies of NCs suggest instability in acidic media, and therefore, the system is postulated for use as a sublingual device, potentially bypassing stomach and hepatic first-pass effects. An ad hoc dissolution device was developed to mimic the release of actives. The nanometric size and properties acquired in the process were maintained, mainly in the dissolution rate and speed, achieving 100 % dissolution of the content in 180 s. Based on these results, the proof of concept represents an innovative approach to converting NCs suspensions into solid dosage forms.

Assuntos

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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.

Assuntos

RESUMO

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.

Assuntos

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The aims of this study were: To evaluate the surface hardness of simulated dentin caries lesions treated with either silver nanoclusters (AgNCls) synthesized in polymethacrylic acid (PMAA) or 38% silver diammine fluoride (SDF), as well as observe the penetration of the treatment solutions into the simulated caries lesions. Dentin blocks 4 mm thick obtained from caries-free third molars were sectioned and then simulated caries lesions on the occlusal dentin surfaces were created. Each specimen (n = 8) was divided into four sections: (A) treated with 20% AgNCls/PMAA; (B) treated with SDF 38% (FAgamin, Tedequim, Cordoba, Argentina); (C) sound tooth protected by nail-varnish during artificial caries generation (positive control); and (D) artificial caries lesion without surface treatment (negative control). AgNCls/PMAA or SDF were applied on the simulated lesions with a microbrush for 10 s, then excess removed. The surface hardness was measured by means of Vickers indentation test. To trace the depth of penetration, up to 400 µm, of silver ions, elemental composition of the samples was observed using EDX, coupled with SEM, and measured every 50 µm from the surface towards the pulp chamber. Laser Induced Breakdown Spectroscopy (LIBS) was also employed to trace silver ion penetration; the atomic silver line 328.06 nm was used with a 60 µm laser spot size to a depth of 240 µm. Student's-t test identified significant differences between treatment groups for each depth and the Bonferroni test was used for statistical analysis of all groups (p < 0.05). Mean surface hardness values obtained were 111.2 MPa, 72.3 MPa, 103.3 MPa and 50.5 MPa for groups A, B, C and D respectively. There was a significant difference between groups A and C compared with groups B and D, the group treated with AgNCls/PMAA achieved the highest surface hardness, similar or higher than the sound dentin control. A constant presence of silver was observed throughout the depth of the sample for group A, while group B showed a peak concentration of silver at the surface with a significant drop beyond 50 µm. The 20% AgNCls/PMAA solution applied to simulated dentin caries lesions achieved the recovery of surface hardness equivalent to sound dentin with the penetration of silver ions throughout the depth of the lesion.

Assuntos

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We describe the case of a mother in the second trimester of pregnancy with severe paraquat poisoning who ended her pregnancy at term and a healthy newborn. Management was initiated after 34 h of paraquat administration with the HA-230 hemoadsorption cartridge, followed by continuous venovenous hemodiafiltration for 120 h, in addition to cyclophosphamide and methylprednisolone. There was no evidence of adverse effects associated with treatment or extracorporeal therapy, and maternal and fetal well-being was maintained during the 26 days of hospitalization and at the end of pregnancy. This case treated with hemoadsorption and hemodiafiltration for paraquat poisoning during pregnancy is one of the few procedures reported in the literature and can be used as a guide for the management of subsequent cases.

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In the context of addressing antimicrobial drug resistance in periocular infections, Tea Tree Oil (TTO) has emerged as a promising therapeutic option. This study aimed to assess the efficacy of TTO against bacterial strains isolated from ocular infections, with a particular focus on its ability to inhibit biofilm formation. Additionally, we designed and analyzed microcapsules containing TTO to overcome certain unfavorable physicochemical properties and enhance its inherent biological attributes. The quality of TTO was confirmed through rigorous analysis using GC-MS and UV-Vis techniques. Our agar diffusion assay demonstrated the effectiveness of Tea Tree Oil (TTO) against ocular bacterial strains, including Corynebacterium spp., coagulase-negative Staphylococcus spp., and Staphylococcus aureus, as well as a reference strain of Staphylococcus aureus (ATCC 25923). Notably, the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) for all tested microorganisms were found to be 0.2% and 0.4%, respectively, with the exception of Corynebacterium spp., which exhibited resistance to TTO. Furthermore, TTO exhibited a substantial reduction in biofilm biomass, ranging from 30% to 70%, as determined by the MTT method. Through the spray-drying technique, we successfully prepared two TTO-containing formulations with high encapsulation yields (80-85%), microencapsulation efficiency (90-95%), and embedding rates (approximately 40%). These formulations yielded microcapsules with diameters of 6-12 µm, as determined by laser scattering particle size distribution analysis, and exhibited regular, spherical morphologies under scanning electron microscopy. Importantly, UV-Vis analysis post-encapsulation confirmed the presence of TTO within the capsules, with preserved antioxidant and antimicrobial activities. In summary, our findings underscore the substantial therapeutic potential of TTO and its microcapsules for treating ocular infections.

RESUMO

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.

RESUMO

Domperidone (DOM) is a drug commonly used to treat nausea and vomiting, as well as gastrointestinal disorders. However, its low solubility and extensive metabolism pose significant administration challenges. In this study, we aimed to improve DOM solubility and avoid its metabolism by developing nanocrystals (NC) of DOM through a 3D printing technology-melting solidification printing process (MESO-PP)-to be delivered via a solid dosage form (SDF) that can be administered sublingually. We obtained DOM-NCs using the wet milling process and designed an ultra-rapid release ink (composed of PEG 1500, propylene glycol, sodium starch glycolate, croscarmellose sodium, and sodium citrate) for the 3D printing process. The results demonstrated an increase in the saturation solubility of DOM in both water and simulated saliva without any physicochemical changes in the ink as observed by DSC, TGA, DRX, and FT-IR. The combination of nanotechnology and 3D printing technology enabled us to produce a rapidly disintegrating SDF with an improved drug-release profile. This study demonstrates the potential of developing sublingual dosage forms for drugs with low aqueous solubility using nanotechnology and 3D printing technology, providing a feasible solution to the challenges associated with the administration of drugs with low solubility and extensive metabolism in pharmacology.