Low Urinary Free Cortisol as a Risk Factor for Patients with Variceal Bleeding.

Background and Objectives: Specificity and reliability issues of the current cortisol assessment methods lead to limitations on the accurate assessment of relative adrenal insufficiency. Although free cortisol provides a more accurate evaluation of adrenal cortisol production, the expense and time-consuming nature of these assays make them impractical for routine use. Research has, thus, focused on alternative methods, such as indirectly measuring free cortisol using Coolens' equation or directly assessing salivary cortisol concentration, which is considered a more favorable approach despite associated challenges like sampling issues and infection risks. The aim of this study was to explore correlations between 24 h urinary free cortisol (UFC), free plasma cortisol, serum total cortisol, and salivary cortisol as potential reliable indices of free cortisol in the setting of variceal bleeding. Additionally, we assessed the predictive value of UFC for 6-week mortality and 5-day treatment failure in patients with liver cirrhosis and variceal bleeding. Materials and Methods: A total of 40 outpatients with liver cirrhosis and variceal bleeding were enrolled. Free cortisol levels in serum, saliva, and urine were assessed using the electrochemiluminescence immunoassay method. For the measurement of plasma-free cortisol, a single quadrupole mass spectrometer was employed. The quantification of free cortisol was fulfilled by analyzing the signal response in the negative ESI-MS mode. Results: UFC was significantly correlated to free plasma cortisol. Negative correlations were demonstrated between UFC, the Child-Pugh (CP) score, and C reactive protein (CRP) levels. In the multivariate analysis, CP stage C was associated with 6-week mortality risk and portal vein thrombosis with 5-day treatment failure using Cox regression and binary logistic regression analyses, respectively. Patients who experienced rebleeding, infection, or death (or any combination of these events) presented with lower levels of UFC. Conclusions: This study suggests that low levels of UFC may impose a risk factor for patients with liver cirrhosis and variceal bleeding. The use of UFC as an index of adrenal cortisol production in variceal bleeding warrants further investigation.

In Vitro Permeability Study of Homotaurine Using a High-Performance Liquid Chromatography with Fluorescence Detection Pre-Column Derivatization Method.

Homotaurine (HOM) is considered a promising drug for the treatment of Alzheimer's and other neurodegenerative diseases. In the present work, a new high-performance liquid chromatography with fluorescence detection (HPLC-FLD) (λex. = 340 nm and λem. = 455 nm) method was developed and validated for the study of substance permeability in the central nervous system (CNS). Analysis was performed on a RP-C18 column with a binary gradient elution system consisting of methanol-potassium phosphate buffer solution (pH = 7.0, 0.02 M) as mobile phase. Samples of homotaurine and histidine (internal standard) were initially derivatized with ortho-phthalaldehyde (OPA) (0.01 M), N-acetylcysteine (0.01 M) and borate buffer (pH = 10.5; 0.05 M). To ensure the stability and efficiency of the reaction, the presence of different nucleophilic reagents, namely (a) 2-mercaptoethanol (2-ME), (b) N-acetylcysteine (NAC), (c) tiopronin (Thiola), (d) 3-mercaptopropionic acid (3-MPA) and (e) captopril, was investigated. The method was validated (R2 = 0.9999, intra-day repeatability %RSD < 3.22%, inter-day precision %RSD = 1.83%, limits of detection 5.75 ng/mL and limits of quantification 17.43 ng/mL, recovery of five different concentrations 99.75-101.58%) and successfully applied to investigate the in vitro permeability of homotaurine using Franz diffusion cells. The apparent permeability (Papp) of HOM was compared with that of memantine, which is considered a potential therapeutic drug for various CNSs. Our study demonstrates that homotaurine exhibits superior permeability through the simulated blood-brain barrier compared to memantine, offering promising insights for enhanced drug delivery strategies targeting neurological conditions.

In vitro and in silico computational methods for assessing vaginal permeability.

OBJECTIVE: Vaginal administration is an important alternative to the oral route for both topical and systemic use. Therefore, the development of reliable in silico methods for the study of drugs permeability is becoming popular in order to avoid time-consuming and costly experiments. METHODS: In the current study, Franz cells and appropriate HPLC or ESI-Q/MS analytical methods were used to experimentally measure the apparent permeability coefficient (Papp) of 108 compounds (drugs and non-drugs). Papp values were then correlate with 75 molecular descriptors (physicochemical, structural, and pharmacokinetic) by developing two Quantitative Structure Permeability Relationship (QSPR) models, a Partial Least Square (PLS) and a Support Vector Machine (SVM). Both were validated by internal, external and cross-validation. RESULTS: Based on the calculated statistical parameters (PLS model A: R2 = 0.673 and Q2 = 0.594, PLS model B: R2 = 0.902 and Q2 = 0.631, SVM: R2 = 0.708 and Q2 = 0.758). SVM presents higher predictability while PLS adequately interprets the theory of permeability. CONCLUSIONS: The most important parameters for vaginal permeability were found to be the relative PSA, logP, logD, water solubility and fraction unbound (FU). Respectively, the combination of both models could be a useful tool for understanding and predicting the vaginal permeability of drug candidates.

Analytical quality by design approach for the determination of imidazole in sildenafil API and its formulations using zwitterionic HILIC stationary phase.

Herein, the development of a HILIC method for the determination of imidazole (Imp E) in sildenafil citrate API and its final formulations is reported. The main goal of this study was to develop a robust, application-specific HPLC method according to the Analytical Quality by Design principles for the analysis of the above impurity. After the risk assessment study, the high-risk method parameters were sequentially screened and optimized by using 2-level fractional factorial and Box-Behnken designs. The mathematical models were combined with the Monte-Carlo simulations to identify the Method Operable Design Region. The method was thoroughly validated between 25 % and 150 % of the target concentration limit of the imidazole using the total-error concept. The relative bias varied between 1.6 % and 5.6 % and the RSD values were lower than 5.8 % for repeatability and intermediate precision. The limit of detection and the lower limit of quantification were satisfactory and found to be 0.025 and 0.125 µg mL-1 imidazole, respectively. The applicability of the proposed approach has been demonstrated in the analysis of several sildenafil citrate API batches and final products.

Urinary free cortisol is a reliable index of adrenal cortisol production in patients with liver cirrhosis.

BACKGROUND: The measurement of total and free cortisol has been studied as a clinical index of adrenal cortisol production in patients with liver cirrhosis. Correlations between free plasma and salivary cortisol have previously been reported in stable cirrhotic patients. Urinary free cortisol constitutes an index of adrenal cortisol production; however, it has never been used in assessing adrenal function in patients with liver cirrhosis. AIMS: The aim of this observational study was to determine associations between urinary free cortisol, serum total, salivary, measured and calculated plasma free cortisol levels in cirrhotics, determining which of them can be used as an indirect index of free cortisol levels. Moreover, we investigated the potential use of 24 h urinary free cortisol as a prognostic factor for mortality. METHODS: Seventy-eight outpatients with liver cirrhosis were included. Serum, salivary and urinary free cortisol were measured using the electrochemiluminenscence immunoassay. Plasma free cortisol determination was conducted using a single quadrupole mass spectrometer. The quantification of free cortisol was achieved by determining the signal response on negative ESI-MS mode. RESULTS: Twenty-four hour urinary free cortisol levels correlated with free cortisol determined by mass spectrometer, total cortisol and calculated free cortisol levels. Patients with low levels of urinary free cortisol presented a significantly higher mortality rate compared to those with high levels. The factors associated with death risk were determined by Cox regression. In the multivariate analysis, two models were applied; in the first model, CP score, PVT and urinary free cortisol were found to be significantly related to patients' survival, whereas in the second, MELD score, ascites and urinary free cortisol were independently related to survival. CONCLUSIONS: This study suggests that 24 h urinary free cortisol could be considered as a potential index of adrenal cortisol production in patients with liver cirrhosis and it potentially detects patients with a high mortality risk.

Development and validation of HPLC-DAD and LC-(ESI)/MS methods for the determination of sulfasalazine, mesalazine and hydrocortisone 21-acetate in tablets and rectal suppositories: In vitro and ex vivo permeability studies.

Controlled-release tablets and rectal suppositories of sulfasalazine (SLF) and hydrocortisone 21-acetate (HA) were prepared as recommended dosage forms for the treatment of acute episodes of ulcerative colitis, in patients who do not respond to monotherapy. A High-Performance Liquid Chromatography (HPLC) Diode-array method with a gradient elution mobile phase was developed to evaluate the production quality of both formulations (assay and dissolution profiles in gastric and intestinal fluids). Method's validation was carried out providing good linearity (r ≥ 0.9995), precision (RSD < 1.53%), recovery (96.9% - 103.7%) and limits of detection (LODSLF = 12 ng/mL, LODHA = 15 ng/mL). Experimental design and Plackett-Burman methodology was constructed to study the robustness of the analysis. In all composite substrates, a freezing lipid precipitation approach was used as purification step. The method was optimized by applying Central Composite design mode. The in-vitro/ex-vivo permeability studies of both formulations were evaluated by a Liquid Chromatography-Electron Spray Ionization Mass Spectrometry (LC-ESI/MS) +/- mode. The analysis of sulfamethazine (internal standard, SLM, m/z 279), HA (m/z 449, [M + HCOO]-), SLF (m/z 399) and its active metabolite mesalazine (MSL, m/z 154) was performed using a C18 column and gradient elution. The validation of the method met the requirements of the International Council for Harmonization (ICH) (r ≥ 0.9997, RSD ≤ 4.62%, Recovery > 95%, LODSLF = 1.28 ng/mL, LODHA = 1.07 ng/mL, LODMSL = 3.16 ng/mL). Based on the results, important conclusions were drawn concerning the role of excipients and SLF metabolism.

Salting-out homogeneous liquid-liquid microextraction for the determination of azole drugs in human urine: Validation using total error concept.

A salting-out homogeneous liquid-liquid microextraction was proposed for the quantification of four azole drugs in human urine prior to high-performance liquid chromatography analysis. The procedure involved the mixing of the sample with acetonitrile in appropriate volumes followed by the addition of sodium sulfate solution in order to facilitate phase separation. The parameters influencing the extraction performance were studied and optimized using a two-step experimental design. The analytical procedure was thoroughly validated using the accuracy profiles as a graphical decision-making tool. The ß-expectation tolerance intervals did not exceed the acceptance criteria of ±15% meaning that 95% of future results will be included in the defined bias limits. The limits of detection of the procedure were satisfactory, ranging between 0.01 and 0.03 µg/mL. The mean analytical bias in the spiking levels was satisfactory and ranged between -10.3 and 4.2% while the relative standard deviation was lower than 5.6%. Monte-Carlo simulations followed by capability analysis were employed to investigate the ruggedness of the sample preparation protocol. The developed method offers advantages compared to previously reported approaches for the same type of analysis including extraction efficiency and scaling down of the sample volume and extraction time.

Amoxicillin chewable tablets intended for pediatric use: formulation development, stability evaluation and taste assessment.

To cover the unpleasant taste of amoxicillin (250 mg), maize starch (baby food) and milk chocolate were co-formulated. The raw materials and the final formulations were characterized by means of Dynamic Light Scattering (DLS), Differential Scanning Calorimetry (DSC) and Fourier-Transform Infrared (FT-IR) spectroscopy. To evaluate the taste masking two different groups of volunteers were used, according to the Ethical Research Committee of the Aristotle University of Thessaloniki. The optimization of excipients' content in the tablet was determined by experimental design methodology (crossed D-optimal). Due to the matrix complexity, amoxicillin was extracted using liquid extraction and analyzed isocratically by HPLC. The developed chromatographic method was validated (%Recovery 98.7-101.3, %RSD = 1.3, LOD and LOQ 0.15 and 0.45 µg mL-1 respectively) according to the International Conference on Harmonization (ICH) guidelines. The physicochemical properties of the tablets were also examined demonstrating satisfactory quality characteristics (diameter: 15 mm, thickness: 6 mm, hardness <98 Newton, loss of mass <1.0%, disintegration time ∼25min). Additionally, dissolution (%Recovery >90) and in vitro digestion tests (%Recovery >95) were carried out. Stability experiments indicated that amoxicillin is stable in the prepared formulations for at least one year (%Recovery <91).

Fluorimetric Analysis of Five Amino Acids in Chocolate: Development and Validation.

Amino acids present ergogenic action, helping to increase, protect, and restore the muscular system of young athletes. Moreover, the encapsulation of five relevant amino acids in chocolate pellet form will appeal to them, facilitating their daily consumption. A reliable HPLC fluorimetric method was developed to detect and quantitatively determine L-Leucine, L-Isoleucine, L-Histidine, L-Valine, and ß-Alanine in chocolate using aniline as an internal standard. Experimental design methodology was used to investigate and optimize the clean-up procedure of the samples. Therefore, three extraction techniques (solid-phase extraction (by two different SPE cartridges) and liquid-solid extraction (LSE)) were compared and evaluated. The LOQ values in chocolate varied from 24 to 118 ng/g (recovery 89.7-95.6%, %RSD < 2.5). Amino acids were pre-column derivatized with o-phthalaldehyde (OPA), while derivatization parameters were thoroughly investigated by experimental design methodology. The analysis was performed by HPLC-fluorescence (emission: λ = 455 nm, excitation: λ = 340 nm) method using a C18 column and a mixture of phosphate buffer (pH = 2.8; 20 mM)-methanol as a mobile phase in gradient elution. The method was validated (r2 > 0.999, %RSD < 2, LOD: 10 ng mL-1 for histidine and leucine, 2 ng mL-1 for alanine and valine, and 4 ng mL-1 for Isoleucine) according to the International Conference on Harmonization guidelines.

Sildenafil 4.0-Integrated Synthetic Chemistry, Formulation and Analytical Strategies Effecting Immense Therapeutic and Societal Impact in the Fourth Industrial Era.

Sildenafil is a potent selective, reversible inhibitor of phosphodiesterase type 5 (PDE5) approved for the treatment of erectile dysfunction and pulmonary arterial hypertension. Whilst twenty years have passed since its original approval by the US Food and Drug Administration (USFDA), sildenafil enters the fourth industrial era catalyzing the treatment advances against erectile dysfunction and pulmonary hypertension. The plethora of detailed clinical data accumulated and the two sildenafil analogues marketed, namely tadalafil and vardenafil, signify the relevant therapeutic and commercial achievements. The pharmacokinetic and pharmacodynamic behavior of the drug appears complex, interdependent and of critical importance whereas the treatment of special population cohorts is considered. The diversity of the available formulation strategies and their compatible administration routes, extend from tablets to bolus suspensions and from per os to intravenous, respectively, inheriting the associated strengths and weaknesses. In this comprehensive review, we attempt to elucidate the multi-disciplinary elements spanning the knowledge fields of chemical synthesis, physicochemical properties, pharmacology, clinical applications, biopharmaceutical profile, formulation approaches for different routes of administration and analytical strategies, currently employed to guide the development of sildenafil-based compositions.

mRNA Therapeutic Modalities Design, Formulation and Manufacturing under Pharma 4.0 Principles.

In the quest for a formidable weapon against the SARS-CoV-2 pandemic, mRNA therapeutics have stolen the spotlight. mRNA vaccines are a prime example of the benefits of mRNA approaches towards a broad array of clinical entities and druggable targets. Amongst these benefits is the rapid cycle "from design to production" of an mRNA product compared to their peptide counterparts, the mutability of the production line should another target be chosen, the side-stepping of safety issues posed by DNA therapeutics being permanently integrated into the transfected cell's genome and the controlled precision over the translated peptides. Furthermore, mRNA applications are versatile: apart from vaccines it can be used as a replacement therapy, even to create chimeric antigen receptor T-cells or reprogram somatic cells. Still, the sudden global demand for mRNA has highlighted the shortcomings in its industrial production as well as its formulation, efficacy and applicability. Continuous, smart mRNA manufacturing 4.0 technologies have been recently proposed to address such challenges. In this work, we examine the lab and upscaled production of mRNA therapeutics, the mRNA modifications proposed that increase its efficacy and lower its immunogenicity, the vectors available for delivery and the stability considerations concerning long-term storage.

Recent Trends in Pharmaceutical Analytical Chemistry.

Modern analytical chemistry plays a vital role in pharmaceutical sciences [...].

Development and Characterization of Inkjet Printed Edible Films for Buccal Delivery of B-Complex Vitamins.

Buccal films containing two vitamins, i.e., thiamine hydrochloride (THCl) and nicotinic acid (NA), were fabricated via two-dimensional (2D) inkjet printing. For the preparation of buccal films, solubility studies and rheological evaluations were conducted in distilled water and propylene-glycol (PG) as main solvent and viscosity/surface tension modifier, respectively. The increased solubility in the solvents' mixture indicated that manufacturing of several doses of the THCl and NA is achievable. Various doses were deposited onto sugar-sheet substrates, by increasing the number of printing passes. The physiochemical characterization (SEM, DSC, FTIR) revealed that inkjet printing does not affect the solid state of the matrix. Water uptake studies were conducted, to compare the different vitamin-loaded formulations. The in vitro release studies indicated the burst release of both vitamins within 10 min, a preferable feature for buccal administration. The in vitro permeation studies indicated that higher concentrations of the vitamins onto the sugar sheet improved the in vitro permeation performance of printed formulations.

Self-Nanoemulsifying Drug Delivery Systems (SNEDDS) Containing Rice Bran Oil for Enhanced Fenofibrate Oral Delivery: In Vitro Digestion, Ex Vivo Permeability, and In Vivo Bioavailability Studies.

Lipid-based drug delivery systems (LbDDS), such as self-nanoemulsifying drug delivery systems (SNEDDS), constitute a prominent formulation approach for enhancing the aqueous solubility and oral bioavailability of poorly water-soluble compounds. Utilization of biorefinery wastes, such as oil from rice bran, may prove advantageous to both improving drug solubilization and absorption and to achieving sustainable agri-food waste valorization. Here, we assessed the effect of four SNEDDS compositions differing in the oil (rice bran oil and corn oil) and surfactant type (Kolliphor RH40 and EL) on the oral bioavailability of fenofibrate, a BCS class II compound. Prior to the in vivo oral administration of the SNEDDS in rats, drug solubilization was tested in vitro using the static digestion model, followed by the ex vivo permeability study of the predigested SNEDDS using the non-everted gut sac model. No significant variation was observed in the solubilization capacity within the different SNEDDS formulations. On the other hand, the ex vivo permeability data of the predigested SNEDDS correlated well with the in vivo bioavailability data designating the superiority of rice bran oil with Kolliphor EL as the surfactant, to enhance the oral absorption of fenofibrate. Results indicated that valorization of agro-industrial waste such as rice bran oil may prove useful in enhancing the oral performance of LbDDS in the case of fenofibrate, while at the same time maximizing the use of agricultural by-products via the creation of new sustainable value chains in the pharmaceutical field.

UHPLC-fluorescence method for the determination of trace levels of hydrazine in allopurinol and its formulations: Validation using total-error concept.

The present approach poses an interesting way to quantify residues of the genotoxic impurity hydrazine in allopurinol and its pharmaceutical formulations using ultra high performance liquid chromatography coupled to fluorescence detection. Hydrazine was pre-column derivatized through a unique chemistry with o-phthalaldehyde under acidic conditions. Using highly acidic mobile phase the derivative exhibits a strong fluorescence intensity. Derivatization and chromatographic parameters were thoroughly investigated. The validation of the developed method has been carried out in the range of 10 to 200% of the target concentration limit of the analyte using the accuracy profiles as a graphical decision-making tool. The ß-expectation tolerance intervals did not exceed the acceptance criteria of ±20% which means that 95% of future results will be included in the defined bias limits. The variation of the relative bias ranged between -6.0 and 0.5% and the RSD values for repeatability and intermediate precision were lower than 6.9% in all cases. The limit of detection (LOD) and the lower limit of quantification (LLOQ) were satisfactory and found to be 0.3 ng mL-1 (corresponding to 0.03 µg g-1 in solid sample). Experimental designs were constructed to study the robustness of the instrumental method and the derivatization procedure. The developed method has been successfully applied for the analysis of hydrazine in allopurinol API batches and tablets indicating that this methodology could be adopted from QC laboratories.

Solid Dosage Forms of Dexamethasone Sodium Phosphate Intended for Pediatric Use: Formulation and Stability Studies.

Undesirable taste has always been a key issue for oral dosage forms. The aim of the present study was to co-formulate dexamethasone sodium phosphate (DSP), in common pediatric oral forms, using sweet preserves and/or different types of chocolate as excipients. An array of different kinds of chocolate were co-formulated with DSP and were further characterized by means of dynamic light scattering (DLS), x-ray diffraction (XRD), differential scanning calorimetry (DSC) and Fourier-transform infrared (FT-IR) spectroscopy. For the assay of active pharmaceutical ingredient (API), the chocolate samples were pre-treated by means of liquid extraction and analyzed using an high-performance liquid chromatographic (HPLC) method with a strong anion exchange column and a phosphate buffer (17 mM, pH = 3)/acetonitrile, 50:50 v/v as mobile phase. The developed chromatographic method was validated based on the International Conference on Harmonization (ICH) guidelines (%Mean Recovery = 99.4% and %Relative Standard Deviation, RSD = 0.43%). Furthermore, dissolution and in vitro digestion tests of chocolate formulations were evaluated. The DSP was found to be stable for at least 1 year in prepared preparations.

Partial Least Square Model (PLS) as a Tool to Predict the Diffusion of Steroids Across Artificial Membranes.

One of the most challenging goals in modern pharmaceutical research is to develop models that can predict drugs' behavior, particularly permeability in human tissues. Since the permeability is closely related to the molecular properties, numerous characteristics are necessary in order to develop a reliable predictive tool. The present study attempts to decode the permeability by correlating the apparent permeability coefficient (Papp) of 33 steroids with their properties (physicochemical and structural). The Papp of the molecules was determined by in vitro experiments and the results were plotted as Y variable on a Partial Least Squares (PLS) model, while 37 pharmacokinetic and structural properties were used as X descriptors. The developed model was subjected to internal validation and it tends to be robust with good predictive potential (R2Y = 0.902, RMSEE = 0.00265379, Q2Y = 0.722, RMSEP = 0.0077). Based on the results specific properties (logS, logP, logD, PSA and VDss) were proved to be more important than others in terms of drugs Papp. The models can be utilized to predict the permeability of a new candidate drug avoiding needless animal experiments, as well as time and material consuming experiments.

Modern pediatric formulations of the soft candies in the form of a jelly: determination of metoclopramide content and dissolution.

In pediatrics, it is crucial to ameliorate the unpleasant taste of oral pharmaceutical formulations in order to facilitate patient compliance. Scientists' attempt to develop modern products for children is included among the new trends in pharmaceutical technology. Designing the preparation procedures and selecting the age-appropriate dosage form should be based on a benefit-risk approach, taking into account safety, efficacy, ease of use and accessibility to the patient. Part of this process should examine the necessity for taste masking, considering organoleptic and physicochemical properties of the active pharmaceutical ingredient. This research describes the incorporation of metoclopramide hydrochloride in the form of a soft candy (jelly) containing pomegranate juice. The low cost excipients and the ease of preparation are such characteristics that qualify the proposed technique as one of the alternative methods for modern drug formulations. At the same time, metoclopramide is quantitatively determined by developing a reverse phase HPLC method. The method is accurate (%RSD = 2.63, %mean recovery = 100.75) and can be used for routine analysis. The stability of metoclopramide was satisfactory after 6 months of storage (recovery 103.43%). Dissolution of the drug exceeded 92%. The proposed formulation enclosing metoclopramide in a jelly is modern, palatable and can be administered to children.

Fabrication of an osmotic 3D printed solid dosage form for controlled release of active pharmaceutical ingredients.

In pharmaceutical formulations, pharmacokinetic behavior of the Active Pharmaceutical Ingredients (API's) is significantly affected by their dissolution profiles. In this project, we attempted to create personalized dosage forms with osmotic properties that exhibit different API release patterns via Fused Deposition Modelling (FDM) 3D printing. Specifically, cellulose acetate was employed to create an external shell of an osmotically active core containing Diltiazem (DIL) as model drug. By removing parts of the shell (upper surface, linear lateral segments) were created dosage forms that modify their shape at specific time frames under the effect of the gradually induced osmotic pressure. Hot-Melt Extrusion (HME) was employed to fabricate two different 3DP feeding filaments, for the creation of either the shell or the osmotic core (dual-extrusion printing). Printed formulations and filaments were characterized by means of (TGA, XRD, DSC) and inspected using microscopy (optical and electron). The mechanical properties of the filaments were assessed by means of micro- and macro mechanical testing, whereas micro-Computed Tomography (µCT) was employed to investigate the volumetric changes occurring during the hydration process. XRD indicated the amorphization of DIL inside HME filaments and printed dosage forms, whereas the incorporated NaCl (osmogen) retained its crystallinity. Mechanical properties' testing confirmed the printability of produced filaments. Dissolution tests revealed that all formulations exhibited sustained release differing at the initiation time of the API dissolution (0, 120 and 360 min for the three different formulations). Finally, µCT uncovered the key structural changes associated with distinct phases of the release profile. The above results demonstrate the successful utilization of an FDM 3D printer in order to create osmotic 3D printed formulations exhibiting sustained and/or delayed release, that can be easily personalized containing API doses corresponding to each patient's specific needs.

Examining barbiturate scaffold for the synthesis of new agents with biological interest.

Aim: Barbiturates have a long history of being used as drugs presenting wide varieties of biological activities (antimicrobial, anti-urease and antioxidant). Reactive oxygen species are associated with inflammation implicated in cancer, atherosclerosis and autoimmune diseases. Multitarget agents represent a powerful approach to the therapy of complicated inflammatory diseases. Results: A novel series of barbiturates has been synthesized and evaluated in several in vitro assays. Compound 16b (lipoxygenases inhibitor, 55.0 µM) was found to be a cyclooxygenase-2 inhibitor (27.5 µM). Compound 8b was profiled as a drug-like candidate. Conclusion: The barbiturate core represents a new scaffold for lipoxygenases inhibition, and the undertaken derivatives show promise as multiple-target agents to combat inflammatory diseases.