Development of Sustained Release Baricitinib Loaded Lipid-Polymer Hybrid Nanoparticles with Improved Oral Bioavailability.

Baricitinib (BTB) is an orally administered Janus kinase inhibitor, therapeutically used for the treatment of rheumatoid arthritis. Recently it has also been approved for the treatment of COVID-19 infection. In this study, four different BTB-loaded lipids (stearin)-polymer (Poly(d,l-lactide-co-glycolide)) hybrid nanoparticles (B-PLN1 to B-PLN4) were prepared by the single-step nanoprecipitation method. Next, they were characterised in terms of physicochemical properties such as particle size, zeta potential (ζP), polydispersity index (PDI), entrapment efficiency (EE) and drug loading (DL). Based on preliminary evaluation, the B-PLN4 was regarded as the optimised formulation with particle size (272 ± 7.6 nm), PDI (0.225), ζP (-36.5 ± 3.1 mV), %EE (71.6 ± 1.5%) and %DL (2.87 ± 0.42%). This formulation (B-PLN4) was further assessed concerning morphology, in vitro release, and in vivo pharmacokinetic studies in rats. The in vitro release profile exhibited a sustained release pattern well-fitted by the Korsmeyer-Peppas kinetic model (R2 = 0.879). The in vivo pharmacokinetic data showed an enhancement (2.92 times more) in bioavailability in comparison to the normal suspension of pure BTB. These data concluded that the formulated lipid-polymer hybrid nanoparticles could be a promising drug delivery option to enhance the bioavailability of BTB. Overall, this study provides a scientific basis for future studies on the entrapment efficiency of lipid-polymer hybrid systems as promising carriers for overcoming pharmacokinetic limitations.

Toward an Improved Electrocatalytic Determination of Immunomodulator COVID Medication Baricitinib Using Multiwalled Carbon Nanotube Nickel Hybrid.

The study presents a first electrochemical method for the determination of the immunomodulator drug Baricitinib (BARI), crucial in managing COVID-19 patients requiring oxygen support. A unique electrode was developed by modifying graphite carbon nickel nanoparticles (NiNPs) with functionalized multiwalled carbon nanotubes (f.MWCNTs), resulting in nanohybrids tailored for highly sensitive BARI detection. Comparative analysis revealed the superior electrocatalytic performance of the nanohybrid-modified electrode over unmodified counterparts and other modifications, attributed to synergistic interactions between f.MWCNTs and nickel nanoparticles. Under optimized conditions, the sensors exhibited linear detection within a concentration range from 4.00 × 10-8 to 5.56 × 10-5 M, with a remarkably low detection limit of 9.65 × 10-9 M. Notably, the modified electrode displayed minimal interference from common substances and demonstrated high precision in detecting BARI in plasma and medicinal formulations, underscoring its clinical relevance and potential impact on COVID-19 treatment strategies.

Design and characterization of nanocrystal formulations containing ezetimibe.

Ezetimibe is a lipid-lowering compound that selectively inhibits the absorption of cholesterol and related phytosterols from the intestine. As ezetimibe is almost insoluble in water, its bioavailability is too low to be detected. Thus, the objective of this study was to improve the solubility and dissolution rate of ezetimibe by preparing drug nanocrystals utilizing ball milling, high speed homogenization techniques. Pluronic F127 was chosen as a surface modifier to stabilize the nanocrystal formulations. Nanocrystal formulations of ezetimibe were prepared by using ball milling and high speed homogenization techniques. Additionally, the physicochemical characteristics of ezetimibe and nanocrystal formulations were determined by Fourier transform infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), X-ray analysis and particle size analysis. Tablets were prepared containing ezetimibe nanocrystals formed by high speed homogenization (ultrasonic) and ball milling according to the results of particle size measurements and in vitro dissolution rates of the nanocrystal formulations. As a result of these experiments, it was found that the dissolution rate of the nanocrystal formulations increased and although tablet formulations which did not contain any solubilizing agent like sodium lauryl sulfate (SDS), the dissolution profile of these formulations were found similar to the commercial product.

Injection moulded controlled release amorphous solid dispersions: Synchronized drug and polymer release for robust performance.

A study has been carried out to investigate controlled release performance of caplet shaped injection moulded (IM) amorphous solid dispersion (ASD) tablets based on the model drug AZD0837 and polyethylene oxide (PEO). The physical/chemical storage stability and release robustness of the IM tablets were characterized and compared to that of conventional extended release (ER) hydrophilic matrix tablets of the same raw materials and compositions manufactured via direct compression (DC). To gain an improved understanding of the release mechanisms, the dissolution of both the polymer and the drug were studied. Under conditions where the amount of dissolution media was limited, the controlled release ASD IM tablets demonstrated complete and synchronized release of both PEO and AZD0837 whereas the release of AZD0837 was found to be slower and incomplete from conventional direct compressed ER hydrophilic matrix tablets. The results clearly indicated that AZD0837 remained amorphous throughout the dissolution process and was maintained in a supersaturated state and hence kept stable with the aid of the polymeric carrier when released in a synchronized manner. In addition, it was found that the IM tablets were robust to variation in hydrodynamics of the dissolution environment and PEO molecular weight.

Preparation and physicochemical characterization of surfactant based solid dispersions of ezetimibe.

Solid dispersions of the poorly water-soluble drug ezetimibe were prepared with a surfactant, Pluronic 188 in different ratios and characterized by FTIR, XRD, DSC and dissolution studies. The melting method was employed to prepare the solid dispersions whereas a physical mixture (1:3) was prepared by co-grinding the individual components in a mortar. Physical studies demonstrated a significant reduction in crystallinity with a possibility of presence of amorphous character of drug in the solid dispersions of ezetimibe. Among all binary systems studied, the 1:3 proportion of ezetimibe: Pluronic 188 showed fastest dissolution rate (DE90: 73.38% +/- 3.95) suggesting optimum ratio of the surfactant used.

Monocyclic ß-lactams loaded on hydroxyapatite: new biomaterials with enhanced antibacterial activity against resistant strains.

The development of biomaterials able to act against a wide range of bacteria, including antibiotic resistant bacteria, is of great importance since bacterial colonization is one of the main causes of implant failure. In this work, we explored the possibility to functionalize hydroxyapatite (HA) nanocrystals with some monocyclic N-thio-substituted ß-lactams. To this aim, a series of non-polar azetidinones have been synthesized and characterized. The amount of azetidinones loaded on HA could be properly controlled on changing the polarity of the loading solution and it can reach values up to 17 wt%. Data on cumulative release in aqueous solution show different trends which can be related to the lipophilicity of the molecules and can be modulated by suitable groups on the azetidinone. The examined ß-lactams-HA composites display good antibacterial activity against reference Gram-positive and Gram-negative bacteria. However, the results of citotoxicity and antibacterial tests indicate that HA loaded with 4-acetoxy-1-(methylthio)-azetidin-2-one displays the best performance. In fact, this material strongly inhibited the bacterial growth of both methicillin resistant and methicillin susceptible clinical isolates of S. aureus from surgical bone biopsies, showing to be a very good candidate as a new functional biomaterial with enhanced antibacterial activity.

The polymer-supported and combinatorial synthesis of beta-lactam compounds: an update.

Solid-phase organic synthesis (SPOS) has become an effective synthetic tool for the preparation of combinatorial libraries of non-oligomeric small molecules. Owing to their high efficacy and extremely safe toxicological profile, beta-lactam antibiotics are the first choice for bacterial infectious diseases. Moreover, beta-lactam compounds have also showed other biological activities that include inhibition of prostate specific antigen, thrombin, human cytomegalovirus protein, human leukocyte elastase and cholesterol absorption. Thus, the application of combinatorial and related methodologies to the chemistry of the beta-lactam ring has been recognized as a very attractive challenge by different research groups around the world. This review covers the solid-phase and combinatorial chemistry related to mono-and multicyclic beta-lactam compounds that has been reported in the literature from 1999 to 2004.

PASS assisted search and evaluation of some azetidin-2-ones as C.N.S. active agents.

PURPOSE: The present study evaluates some azetidin-2-ones derivatives for their central nervous system (CNS) modulating activities. The compounds were chosen from a series (5a-o) which were previously synthesized and evaluated for hypolipidemic and antihyperglycemic activity based on the predictions made by the computer software "Prediction of Activity Spectra for Substances (PASS)". MATERIAL AND METHODS: The test compounds were predicted to have a variety of biological activities but those with the best potential for CNS modulating activity were selected for evaluation of a particular CNS activity as 5a for anti-anxiety, 5b, 5n and 5j for nootropic activity and compound 5c anti-catatonic and anti-dyskinetic activities. Test compound 5a was evaluated for anti-anxiety activity in mirrored chamber model and for pentobarbitone induced sleep potentiation in mice. Test compounds 5b, 5n and 5j were evaluated for nootropic activity in mice by examining the effect on transfer latency on elevated plus maze (EPM) in mice and compound 5c was tested for anti-catatonic activity in perphenazine-induced catatonia and anti-dyskinetic effects in reserpine induced orofacial dyskinesia in rats, respectively. RESULTS AND DISCUSSION: The test compound 5a showed significant anxiolytic activity in the mirror chamber paradigm and showed potentiation of the pentobarbitone-induced hypnosis, which was comparable to diazepam. The nootropic activity of compounds 5b, 5n and 5j were found to be significant in elevated and maze test. The test compound 5c significantly prevented the perphenazine-induced catalepsy in a dose dependent manner. Potentiation of anti-catatonic effect of sub-effective dose of L-dopa and reversal of sulpiride-induced catalepsy was also observed by compound 5c. It indicated that the test compound might be showing anticatatonic effect by dopaminergic stimulation probably through D2 dopaminergic receptors. Compound 5c significantly reduced the vacuous chewing movements, tongue protrusions and jaw tremors induced by reserpine. It further supports the dopaminergic agonism by the test compound as reserpine induces oral dyskinetic features by depleting catecholamine (dopamine and nor- epinephrine). CONCLUSION: It was concluded that azetidinones possess considerable CNS activities and can be further explored to find additional CNS active compounds.

Catalysts with mixed ligands on immobilized supports. Electronic and steric advantages.

[reaction: see text] Immobilized dirhodium(II) catalysts having mixed chiral ligands enhance reactivity (AH = azetidinone) and influence stereoselectivity in cyclopropanation and carbon-hydrogen insertion reactions.

Practical syntheses of N-substituted 3-hydroxyazetidines and 4-hydroxypiperidines by hydroxylation with Sphingomonas sp. HXN-200.

[reaction: see text] Hydroxylation of N-substituted azetidines 11 and 12 and piperidines 15-19 with Sphingomonas sp. HXN-200 gave 91-98% of the corresponding 3-hydroxyazetidines 13 and 14 and 4-hydroxypiperidines 20-24, respectively, with high activity and excellent regioselectivity. High yields and high product concentrations (2 g/L) were achieved with frozen/thawed cells as biocatalyst. For the first time, rehydrated lyophilized cells were successfully used for the biohydroxylation.

Spectroscopic identification of an amorphous-to-crystalline drug transition in a solid dispersion SCH 48461 capsule formulation.

Changes in the dissolution of a solid dispersion capsule formulation composed of amorphous SCH 48461 in a polyethylene glycol 8000 matrix were investigated. SCH 48461 [(3R,4S)-1,4-bis(4-methoxyphenyl)-3-(3-phenylpropyl)-2-azetidinone] is a potent cholesterol absorption inhibitor with low water solubility and low melting point. Several capsule lots placed under controlled storage conditions exhibited a slowing of dissolution as a function of time with large inter-lot and intra-lot dissolution variations. Capsule contents were analyzed by attenuated total reflectance infrared (ATR-IR) microspectroscopy and solid-state cross-polarization, magic angle spinning (CPMAS) 13C-nuclear magnetic resonance (NMR) spectrometry. ATR-IR microspectroscopic analysis showed large IR spectral differences between the lots including the presence of a crystalline drug fraction in lots which exhibited incomplete dissolution. Solid-state CPMAS 13C-NMR analysis confirmed the presence of a crystalline drug fraction in the problematic capsule lots. Both ATR-IR and CPMAS 13C-NMR spectral results produced a rank ordering of the crystalline drug fraction present in the capsule lots that correspond to the dissolution results.

Determination of L-glutamate and L-glutamine in pharmaceutical formulations by amperometric L-glutamate oxidase based enzyme sensors.

An amperometric biosensor for the direct determination of L-glutamate was developed by chemical bonding of L-glutamate oxidase (GAO) on a carboxylic Nylon membrane with polyazetidine prepolymer (PAP), and using a hydrogen peroxide electrode as indicating sensor. The biosensor is specific for L-glutamate and the peculiar analytical properties (linearity range, reproducibility, accuracy) were experimentally determined. Furthermore, the same basic biosensor was also modified to be used and characterized for the direct determination of L-glutamine. This L-glutamine biosensor was obtained by coimmobilizing, on two separate membranes, glutamic acid oxidase and glutaminase (GMN) on the same biosensor. The two sensors were then used for the determination of glutamate and L-glutamine contained in pharmaceutical formulations and the results were compared with those obtained by other analytical methods.

Multifunctional poly(Vinyl Amine)s bearing Azetidinium groups: one pot preparation in water and antimicrobial properties.

A simple, robust one pot procedure for the preparation of waterborne multifunctional poly(vinyl amine)s (PVAms) is presented. By post-polymerization modification of PVAm with a bifunctional coupler and functional couplers cationic, reactive azetidinium groups, and alkyl chains are introduced in the side chains of PVAms. The structure-activity relations (effect of hydrophobic and cationic modifications) of these antimicrobial polymers are studied; the minimum inhibitory concentration (MIC) against both (Gram positive and Gram negative bacteria) of the library of multifunctional poly(vinyl amine)s are determined to identify the candidates with the highest efficacy. Furthermore, the hemolytic activity-the effective concentration at which 50 and 10% of red blood cells are killed (HC50 and HC10 )-of selected polymers is determined. The ability of the polymers prepared to differentiate between microorganisms (Gram positive and Gram negative bacteria) and mammalian cells (red blood cells) is understood by comparing MIC and HC values. Finally, as an example, the best polymer is used to prepare an antimicrobial surface.

Development of optimized supersaturable self-nanoemulsifying systems of ezetimibe: effect of polymers and efflux transporters.

OBJECTIVES: To develop an optimized supersaturable self-nanoemulsifying drug delivery system (S-SNEDDS) in order to control drug precipitation along with surmounting poor aqueous solubility and P-glycoprotein (P-gp) and multidrug resistance protein 2 (MRP2) efflux activity. METHODS: Long-term stability of a previously reported formulation (OPT-LCT) consisting of Maisine 35-1 and Labrasol indicated rapid precipitation of ezetimibe. In vitro supersaturation test was carried out for selection of apt polymeric precipitation inhibitor (PPI). Following incorporation of the selected PPI, the precipitates from various formulations were differentiated employing optical microscopy, differential scanning calorimetry (DSC) and X-ray diffraction techniques. The S-SNEDDS was evaluated for globule size distribution. Also, lipid-lowering activity of S-SNEDDS was compared in relation to marketed product and optimized-long chain triglyceride. Subsequently, in situ perfusion studies were carried out for calculating various permeability and absorptivity parameters with specific focus on P-gp and MRP2 inhibition. RESULTS: Supersaturation test facilitated the selection of HPMC E5LV as the best PPI. The precipitates from the S-SNEDDS were identified as amorphous while crystalline ezetimibe precipitates were found when HPMC was absent in the formulation. Owing to heterogeneous distribution, globule size analysis was not practicable. Plasma lipid estimations showed that S-SNEDDS had considerable influence in increasing the high-density lipid levels. The single-pass intestinal perfusion parameters, namely fraction absorbed and effective permeability demonstrated significant improvement in rate and extent of absorption from S-SNEDDS. Co-administration of itraconazole and indomethacin as P-gp and MRP2 inhibitors, respectively revealed the potential of S-SNEDDS in reducing the efflux activities. CONCLUSIONS: The studies revealed that the systemic exposure of ezetimibe following oral administration can be substantially improved using S-SNEDDS.

Inhibition of intestinal cholesterol absorption with ezetimibe increases components of reverse cholesterol transport in humans.

OBJECTIVE: Reverse cholesterol transport (RCT) can be defined as a pathway of flux of cholesterol from peripheral tissues to the liver for potential excretion into feces. This prospective, placebo-controlled, double-blind crossover study assessed the effect of ezetimibe on several RCT parameters in hyperlipidemic patients. METHODS: Following 7 weeks of treatment (ezetimibe 10 mg/day or placebo), 26 patients received 24-h continuous IV infusions of [3,4-(13)C2]-cholesterol, then took heavy water ((2)H2O) by mouth. Cholesterol excretion was measured by quantification of neutral/acid sterols in stool and blood samples during 7 days post-infusion with continued treatment. Plasma de novo cholesterol synthesis was assessed by (2)H-labeling from (2)H2O. RESULTS: Ezetimibe significantly reduced levels of low-density lipoprotein cholesterol (22%, P < 0.001) without significant changes in triglycerides and high-density lipoprotein cholesterol and significantly increased the flux of plasma-derived cholesterol into fecal neutral sterols by 52% (P = 0.04) without change in flux into fecal bile acids. Total fecal neutral sterol output increased by 23% (P = 0.02). Plasma de novo cholesterol synthesis increased by 57% (P < 0.001). The fractional clearance rate (FCR) of plasma cholesteryl-ester trended higher (7%; P = 0.055) with a reduction in absolute cholesteryl-ester production rate (9%, P < 0.01). Whole-body free cholesterol efflux rate from extra-hepatic tissues into plasma was not measurably changed by ezetimibe. CONCLUSION: Ezetimibe treatment approximately doubled the flux of plasma-derived cholesterol into fecal neutral sterols, in association with increases in total fecal neutral sterol excretion, FCR of plasma cholesterol ester, and plasma de novo cholesterol synthesis. These effects are consistent with increased cholesterol transport through the plasma compartment and excretion from the body, in response to ezetimibe treatment in hyperlipidemic humans. Clintrials.gov: NCT00701727.

Synthesis from D-altrose of (5R,6R,7R,8S)-5,7-dihydroxy-8-hydroxymethylconidine and 2,4-dideoxy-2,4-imino-D-glucitol, azetidine analogues of swainsonine and 1,4-dideoxy-1,4-imino-D-mannitol.

Ring closure of a 3,5-di-O-triflate derived from D-altrose with benzylamine allowed the formation of both monocyclic and bicyclic azetidine analogues of swainsonine.

Polyazetidine-coated microelectrodes: electrochemical and diffusion characterization of different redox substrates.

The present paper reports on the diffusion characteristics and electron transfer properties of a membrane obtained from polyazetidine prepolymer (PAP) consisting of repeating units of 1-(aminomethyl)-1-{2-[(6-oxyhexane)amino]ethyl}-3-hydroxyazetidinium chloride studied in the presence of seven simple redox electroactive molecules: ABTS, catechol, dopamine, ferrocenecarboxylic acid, ferricyanide, ferrocyanide, and the osmium complex bis(2,2-bipyridyl)-4-aminomethylpyridine chloride hexafluorophosphate (Os[(bpy)(2) 4-AMP Cl](+)). Using water as medium, the apparent diffusion coefficients (D(app)), the concentrations of the compounds in the membrane, and the heterogeneous rate constants (k(s)) were calculated as a function of temperature, and the influence thereof on these parameters was evaluated. Even if D(app) and k(s) values in the presence of PAP are smaller than in solution, this decrease is small enough to indicate that the PAP membrane shows excellent diffusion and electron-exchange properties with respect to other commonly used membranes reported in the literature.