Bottom-up production of injectable itraconazole suspensions using membrane technology.

Bottom-up production of active pharmaceutical ingredient (API) crystal suspensions offers advantages in surface property control and operational ease over top-down methods. However, downstream separation and concentration pose challenges. This proof-of-concept study explores membrane diafiltration as a comprehensive solution for downstream processing of API crystal suspensions produced via anti-solvent crystallization. It involves switching the residual solvent (N-methyl-2-pyrrolidone, NMP) with water, adjusting the excipient (d-α-Tocopherol polyethylene glycol 1000 succinate, TPGS) quantity, and enhancing API loading (solid concentration) in itraconazole crystal suspensions. NMP concentration was decreased from 9 wt% to below 0.05 wt% (in compliance with European Medicine Agency guidelines), while the TPGS concentration was decreased from 0.475 wt% to 0.07 wt%. This reduced the TPGS-to-itraconazole ratio from 1:2 to less than 1:50 and raised the itraconazole loading from 1 wt% to 35.6 wt%. Importantly, these changes did not adversely affect the itraconazole crystal stability in suspension. This study presents membrane diafiltration as a one-step solution to address downstream challenges in bottom-up API crystal suspension production. These findings contribute to optimizing pharmaceutical manufacturing processes and hold promise for advancing the development of long-acting API crystal suspensions via bottom-up production techniques at a commercial scale.

Comprehensive evaluation of polymer types and ratios in Spray-Dried Dispersions: Compaction, Dissolution, and physical stability.

Amorphous solid dispersion (ASD) is a well-established strategy for enhancing the solubility and bioavailability of poorly soluble drugs. A significant portion of ASD products are in tablet form. However, the influence of common polymers and drug loading on the manufacturability of ASD tablets remains underexplored. This study focuses on investigating spray-dried ASDs from a tableting perspective by evaluating their physiochemical and mechanical properties. Itraconazole (ITZ) and indomethacin (IND), at the drug loadings ranging from 10% to 50%, were prepared with two polymers, hydroxypropyl methylcellulose acetate succinate (HPMCAS) and polyvinylpyrrolidone (PVP), serving as representative systems. Our findings revealed that increasing the drug loading resulted in a decreased surface area in ITZ-HPMCAS, IND-HPMCAS, and IND-PVP ASDs. However, this trend was not observed in ITZ-PVP dispersions, possibly due to the morphological disparities. Compaction results demonstrated that tabletability improved with decreasing drug loadings, except for ITZ-PVP dispersions. A partial least square analysis underscored particle surface area as the key factor influencing the tensile strength of ASD tablets. Additionally, our study disclosed that ITZ-PVP ASDs exhibited the worst release profiles and stability performance. The comprehensive journey from characterizing ASD particles to analyzing their compaction behavior and investigating drug release and physical stability offered profound insights into the attributes crucial for the downstream processing of amorphous pharmaceuticals.

Development of long-acting injectable suspensions by continuous antisolvent crystallization: An integrated bottom-up process.

Our present work elucidated the operational feasibility of direct generation and stabilization of long-acting injectable (LAI) suspensions of a practically insoluble drug, itraconazole (ITZ), by combining continuous liquid antisolvent crystallization with downstream processing (i.e., centrifugal filtration and reconstitution). A novel microchannel reactor-based bottom-up crystallization setup was assembled and optimized for the continuous production of micro-suspension. Based upon the solvent screening and solubility study, N-methyl pyrrolidone (NMP) was selected as the optimal solvent and an impinging jet Y-shaped microchannel reactor (MCR) was selected as the fluidic device to provide a reproducible homogenous mixing environment. Operating parameters such as solvent to antisolvent ratio (S/AS), total jet liquid flow rates (TFRs), ITZ feed solution concentration and the maturation time in spiral tubing were tailored to 1:9 v/v, 50 mL/min, 10 g/100 g solution, and 96 h, respectively. Vitamin E TPGS (0.5% w/w) was found to be the most suitable excipient to stabilize ITZ particles amongst 14 commonly used stabilizers screened. The effect of scaling up from 25 mL to 15 L was evaluated effectively with in situ monitoring of particle size distribution (PSD) and solid-state form. Thereafter, the suspension was subjected to centrifugal filtration to remove excess solvent and increase ITZ solid fraction. As an alternative, an even more concentrated wet pellet was reconstituted with an aqueous solution of 0.5% w/w Vitamin E TPGS as resuspending agent. The ITZ LAI suspension (of 300 mg/mL solid concentration) has the optimal PSD with a D10 of 1.1 ± 0.3 µm, a D50 of 3.53 ± 0.4 µm and a D90 of 6.5 ± 0.8 µm, corroborated by scanning electron microscopy (SEM), as remained stable after 548 days of storage at 25 °C. Finally, in vitro release methods using Dialyzer, dialysis membrane sac were investigated for evaluation of dissolution of ITZ LAI suspensions. The framework presented in this manuscript provides a useful guidance for development of LAI suspensions by an integrated bottom-up approach using ITZ as model API.

Genetic variations of CYP3A4 on the metabolism of itraconazole in vitro.

Itraconazole is a triazole anti-infective drug that has been proven to prevent and treat a variety of fungal and viral infections and has been considered to be a potential therapeutic remedy for COVID-19 treatment. In this study, we aimed to completely evaluate the impacts of Cytochrome P450 3A4 (CYP3A4) variant proteins and drug interactions on the metabolism of itraconazole in recombinant insect microsomes, and to characterize the potential mechanism of substrate selectivity. Incubations with itraconazole (0.2-15 µM) in the presence/absence of lopinavir or darunavir were assessed by CYP3A4 variants, and the metabolite hydroxyitraconazole concentrations were measured by UPLC-MS/MS. Our data showed that when compared with CYP3A4.1, 4 variants (CYP3A4.9, .10, .28 and .34) displayed no significant differences, and 3 variants (CYP3A4.14, .15 and .19) exhibited increased intrinsic clearance (CLint), whereas the remaining 17 variant proteins showed decreased enzyme activities for the catalysis of itraconazole. Moreover, the inhibitory effects of lopinavir and darunavir on itraconazole metabolism varied in different degrees. Furthermore, different changed trend of the kinetic parameters in ten variants (CYP3A4.5, .9, .10, .16, .19, .24, .28, .29, .31, and .33) were observed, especially CYP3A4.5 and CYP3A4.16, and this may be related to the metabolic site-heme iron atom distance. In the present study, we functionally analyzed the effects of 25 CYP3A4 protein variants on itraconazole metabolism for the first time, and provided comprehensive data on itraconazole metabolism in vitro. This may help to better assess the metabolism and elimination of itraconazole in clinic to improve the safety and efficacy of its clinical treatment and also provide new possibilities for the treatment of COVID-19.

Fabrication and optimization of itraconazole-loaded zein-based nanoparticles in coated capsules as a promising colon-targeting approach pursuing opportunistic fungal infections.

Itraconazole (ITZ), a broad-spectrum antifungal drug, was formulated into colon-targeting system aiming to treat opportunistic colonic fungal infections that commonly infect chronic inflammatory bowel diseases (IBD) patients due to immunosuppressive therapy. Antisolvent precipitation technique was employed to formulate ITZ-loaded zein nanoparticles (ITZ-ZNPs) using various zein: drug and aqueous:organic phase ratios. Central composite face-centered design (CCFD) was used for statistical analysis and optimization. The optimized formulation was composed of 5.5:1 zein:drug ratio and 9.5:1 aqueous:organic phase ratio with its observed particle size, polydispersity index, zeta potential, and entrapment efficiency of 208 ± 4.29 nm, 0.35 ± 0.04, 35.7 ± 1.65 mV, and 66.78 ± 3.89%, respectively. ITZ-ZNPs were imaged by TEM that revealed spherical core-shell structure, and DSC proved ITZ transformation from crystalline to amorphous form. FT-IR showed coupling of zein NH group with ITZ carbonyl group without affecting ITZ antifungal activity as confirmed by antifungal activity test that showed enhanced activity of ITZ-ZNPs over the pure drug. Histopathological examination and cytotoxicity tests ensured biosafety and tolerance of ITZ-ZNPs to the colon tissue. The optimized formulation was then loaded into Eudragit S100-coated capsules and both in vitro release and in vivo X-ray imaging confirmed the success of such coated capsules in protecting ITZ from the release in stomach and intestine while targeting ITZ to the colon. The study proved that ITZ-ZNPs is promising and safe nanoparticulate system that can protect ITZ throughout the GIT and targeting its release to the colon with effectual focused local action for the treatment of colon fungal infections.

Comparative assessment of solubility enhancement of itroconazole by solid dispersion and co-crystallization technique: Investigation of simultaneous effect of media composition on drug dissolution.

Solubility of the drug is an important property of the drug as it affects the release, absorption, dissolution rate and ultimately bioavailability of the drug. Hence, the poorly aqueous soluble drug, need to be processed, to enhance its solubility and dissolution. The Biopharmaceutical System of Classification (BCS) II drugs are poorly soluble and have high permeability. Though their good ability to permeate through the membrane make them clinically useful but the problem associated with the solubility restrict their clinical use. Therefore, there is need to improve the solubility of such drug molecules to get effective pharmacological action. Itraconazole (ITZ) is an antifungal agent used in the treatment of fungal infections having poor aqueous solubility as belonging to BCS class II. The present study was aim to enhance the solubility of ITZ by solid dispersion and co-crystallization techniques. Investigation of simultaneous effect of media composition on drug dissolution was also the objective of this work. The ITZ-SD and ITZ-CCs were prepared from ITZ and other excipients like PEG 4000, oxalic acid, fumaric and malic acid by solvent evaporation, kneading technique, slurry conversion and solvent drop grinding methods. The prepared ITZ-SD, ITZ-OA-CCs, ITZ-FA-CCs and ITZ-MA-CCs were evaluated for FTIR, DSC, PXRD, % yield, micromeritic properties. The optimized ITZ-SD and ITZ-CCs were used to compress a tablet and subject to post-compression parameters. The results of FTIR and DSC showed the absence of interaction between the drug and excipients. The PXRD pattern demonstrated the formation of crystalline structures with 6 folds increased in solubility during saturation solubility analysis. In vitro dissolution was carried out in dissolution media with different pH which shows the maximum release from ITZ-SD and ITZ-CCs in pH 6.8. This also revealed the highly pH dependent solubility and dissolution behavior of the weakly basic BCS class II drug (ITZ) with pKa value of 3.7. The overall results in this study indicated the potential of solid dispersion and co-crystals for enhancement of solubility of the poorly water-soluble drugs.

Effect of Shear Strain on the Supercooled Itraconazole.

This article investigated the effect of shear strain on the nematic itraconazole (ITR) from both elastic and plastic deformation regions. The rheo-dielectric technique was used for this purpose. It has been demonstrated that shear strain can change the sample color, liquid crystal alignment as well as its dielectric and thermal properties. The observed modifications depend on the shear strain value. One can distinguish four regions regarding the slope of ITR stress-strain dependence and caused changes. Proper alignment changes (obtained after the shearing procedure) can additionally affect the further recrystallization of ITR to other than the initial, i.e., second polymorphic form.

Itraconazole-loaded microemulsions: formulation, characterization, and dermal delivery using shed snakeskin as the model membrane.

Microemulsions (MEs) were developed for dermal delivery of 1% w/w itraconazole (ITZ). Solubility of ITZ in various oils was investigated and clove oil was selected as oil phase. Pseudoternary phase diagrams were constructed by titration method. The system containing clove oil as oil phase, Tween®80 as surfactant, and 1:1 mixture of water and polyethylene glycol 400 as aqueous phase provided the largest ME region. It was selected for the formulation development of ITZ-loaded MEs. Physicochemical stability was evaluated at 4 °C, room temperature (25 °C), and 45 °C for three months. In vitro permeation and retention studies were assessed using shed snakeskin as a model membrane. Antifungal activity was investigated by agar diffusion method. Results indicated that incorporation of ITZ in the selected MEs did not affect physical properties. Physicochemical data after storage periods revealed that the most suitable storage temperature was 4 °C. Skin permeation and retention data indicated that water-in-oil (w/o) ITZ-loaded MEs had superior dermal delivery of ITZ than oil-in-water (o/w) ITZ-loaded ME and ITZ-oily solution. Moreover, w/o ITZ-loaded MEs showed larger inhibition zones against C. albicans and T. rubrum than a commercial gel. Therefore, w/o ITZ-loaded MEs possibly provided effective dermal delivery and antifungal activity to treat superficial fungal infections.

When Interactions Between Bile Salts and Cyclodextrin Cause a Negative Food Effect: Dynamic Dissolution/Permeation Studies with Itraconazole (Sporanox®) and Biomimetic Media.

The marketed oral solution of itraconazole (Sporanox®) contains 40% (259.2 mM) of 2-hydroxypropyl-ß-cyclodextrin (HP-ß-CD). The obvious role of HP-ß-CD is to solubilize itraconazole and to overcome its poor aqueous solubility that restricts its absorption. In this study, we investigated the biorelevance of in vitro experiments by the influence of biomimetic media (containing bile salts and phospholipids) on the predicted itraconazole absorption from the commercial HP-ß-CD-based Sporanox® solution. We performed phase-solubility studies of itraconazole and dynamic 2-step-dissolution/permeation studies using a biomimetic artificial barrier, Sporanox® solution, and fasted state simulated intestinal fluid (FaSSIF_V1). Both FaSSIF_V1 and HP-ß-CD increased the apparent solubility of itraconazole when used individually. In combination, their solubility-enhancing effects were not additive probably due to the competition of bile salts with itraconazole for the hydrophobic cavity of HP-ß-CD. Our combined dissolution/permeation experiments indicated the occurrence of a transient supersaturation from Sporanox® upon two-step dissolution. Through systematic variation of bile salt concentrations in the biomimetic media, it was observed that the extent and the duration of supersaturation depend on the concentrations of bile salts: supersaturation was rather stable in the absence of bile salts and phospholipids. The higher the bile salt concentration, the faster the collapse of the transient supersaturation occurred, an effect which is nicely mirrored by reduced in vitro permeation across the barrier. This is an indication of a negative food effect, which in fact correlates well with what earlier had been observed in clinical studies for Sporanox® solution. In essence, we could demonstrate that in vitro two-stage dissolution/permeation experiments using an artificial barrier and selected biomimetic media may predict the negative effects of the latter on cyclodextrin-based drug formulations like Sporanox® Oral Solution and, at the same time, provide a deeper mechanistic insight.

Fused deposition modeling 3D printing of solid oral dosage forms containing amorphous solid dispersions: How to elucidate drug dissolution mechanisms through surface spectral analysis techniques?

Many active principles belong to the second class of the Biopharmaceutics Classification System due to their low aqueous solubility. Elaboration of new solid oral forms by hot-melt extrusion and fused deposition modeling appears as a promising tool to increase the dissolution rate of these drugs. Indeed, hot-melt extrusion allows the amorphisation of drugs and forms with complex geometries are built by 3D printing. Therefore, the goal of this work is to enhance the dissolution rate of poorly soluble drugs using hot-melt extrusion coupled with fused deposition modeling. Four formulations containing Affinisol® 15LV, Kollidon® VA64 and a challenging amount of itraconazole (25 % (wt.)) were successfully printed into forms of 20, 50 and 80 % infill densities. Differential scanning calorimetry analysis has shown that itraconazole remained amorphous during 52 weeks. The drug release rate was highly improved compared to itraconazole in a crystalline form. The dissolution rate was influenced by the infill density and the polymer composition of printed forms which could modify respectively the surface to volume ratio and the distribution of the components in the printed forms. One formulation printed with 20 % infill density even had a solubility profile similar to that of Sporanox®, the commercialized drug product in Belgium.

Combination of co-crystal and nanocrystal techniques to improve the solubility and dissolution rate of poorly soluble drugs.

PURPOSE: Solubility and dissolution rate are essential for the oral absorption and bioavailability of poorly soluble drugs. The aim of this study was to prepare nano-co-crystals by combination of nanocrystal and co-crystal technologies, and investigate its effect, in situ, on increased kinetic solubility and dissolution rate. METHODS: Co-crystals of itraconazole-fumaric acid, itraconazole-succinic acid, indomethacin-saccharin and indomethacin-nicotinamide were prepared and nano-sized by wet milling. The particle size and solid state of the co-crystals were characterized by optical microscope, LD, PCS, DSC and XRPD before and after milling. RESULTS: 300-450 nm sized nano-co-crystals with a stable physical solid state were successfully prepared. Nano-co-crystals exhibited a lower crystallinity reduction than nanocrystals after wet milling. The particle size effect on the kinetic solubility of co-crystals was analysed for macro-, micro- and nano-co-crystals with in situ kinetic solubility studies. The maximum kinetic solubility of nano-co-crystals increased with excess conditions until a plateau. The highest increase was obtained with itraconazole-succinic acid nano-co-crystals with a kinetic solubility of 263.5 ± 3.9 µg/mL which was 51.5 and 6.6 times higher than the solubility of raw itraconazole and itraconazole-succinic acid co-crystal. CONCLUSIONS: The synergistic effect of nanocrystals and co-crystals with regard to increased kinetic solubility and dissolution rate was proven. The combination of the advantages of nanocrystals and co-crystals is a promising formulation strategy to increase both the solubility and dissolution rate of poorly soluble drugs.

Incorporation of itraconazole nano-co-crystals into multiparticulate oral dosage forms.

Limited research has been performed on the downstream processing of nano-co-crystal suspensions into solid oral dosage forms. The objectives of this study were to evaluate the impact of three downstream processes (wet granulation, spray granulation and bead layering) on the performance of itraconazole-succinic acid (ITZ-SUC) nano-co-crystal suspension. An optimized ITZ-SUC nano-co-crystal suspension mixed with HPMC E5 was utilized for the downstream processing. The suspension was converted in the solid state either by wet or spray granulation (with microcrystalline cellulose or lactose as substrates) or by layering onto microcrystalline cellulose and sugar beads. The multiparticulate solid dosage forms were characterized by optical microscopy, differential scanning calorimeter (DSC), X-ray powder diffraction (XRPD) and in situ dissolution studies. Spray granulation and bead layering resulted in less particle aggregation, a faster dissolution rate, and higher kinetic solubility when compared to wet granulation. ITZ-SUC nano-co-crystals spray granulated with lactose resulted in higher kinetic solubility profiles compared to microcrystalline cellulose granules. The type of bead core had no impact on the dissolution behavior. A slower dissolution and decreased kinetic solubility were observed with increasing drug loading for sprayed granules when microcrystalline cellulose was used as substrate. All dosage forms were stable under accelerated storage conditions (40 °C/75% RH) when blistered. Nano-co-crystals incorporated in granules were less stable than layered beads under non-blistered condition. Nano-co-crystals layered sugar beads are an interesting alternative to amorphous solid dispersion; a comparable kinetic solubility but a faster drug release were achieved. This study identified bead layering as a superior downstream process approach for incorporating ITZ-SUC nano-co-crystals into an oral solid dosage form without compromising drug dissolution.

Insight from high-pressure dielectric studies into molecular dynamics of the itraconazole-glycerol mixture in smectic and isotropic phases.

We present here the results of high-pressure broadband dielectric spectroscopy (BDS) measurements for a mixture of liquid-crystalline drug itraconazole (ITZ) and glycerol (GLY) at a critical concentration of 5% w/w in which the nematic order is eliminated. In the investigated system, smectic-A to isotropic phase transition leaves a clear fingerprint on the dielectric response, allowing for a phase diagram creation using BDS data. By following the α-relaxation dynamics under different thermodynamic conditions, we provide insights into the effect of pressure on temperature and the phenomenology of smectic-A to the isotropic phase transition. Additional measurements of specific volume as a function of pressure and temperature provide us with a deeper insight into material properties that could be analyzed comprehensively via the equation of state. We proved the validity of the density scaling concept, showing that the mixture's complexity does not exclude thermodynamic scaling of dynamic properties related to the α-process in the smectic-A phase. The low value of scaling exponent γ = 2.00 ± 0.02 and a high ratio of the activation energy at constant volume, EV, to the activation enthalpy at constant pressure, HP, indicate that temperature is a dominant variable controlling α-relaxation dynamics in the ordered smectic-A phase of the ITZ-GLY mixture.

Kinetic solubility improvement and influence of polymers on controlled supersaturation of itraconazole-succinic acid nano-co-crystals.

Nano-co-crystals enhance the solubility and dissolution rate of poorly soluble drugs. The objective of this study was to obtain a better understanding of the dissolution process of nano-co-crystals and of the precipitation inhibition by various polymers. Itraconazole-succinic acid (ITZ-SUC) nano-co-crystal was chosen as model drug formulation to investigate the supersaturation and precipitation inhibition capabilities of various polymers (HPMC E5, HPMC E50, HPMCAS, HPC-SSL, PVPK30 and PVPVA64). The kinetic concentration-time profiles of nano-co-crystal were measured under non-sink conditions with in situ UV-VIS spectroscopy. HPMC E5 performed best by achieving the greatest extended supersaturation/precipitation inhibition. The precipitation inhibition capacity of HPMC E5 was proportional to its concentration. The maximum achievable supersaturation was proportional to the dissolution rate which can be modulated by the rate of supersaturation generation (i.e., addition rate or dose). Supersaturation could be prolonged significantly resulting in 2-5-fold increased area under the dissolution curves compared to nano-co-crystals alone. This effect was limited by a critical excess of undissolved particles with high specific surface area which acted as crystallization seeds resulting in faster precipitation. The study highlighted that a faster dissolution rate and the use of precipitation inhibitors were two key factors determining the extent and time of supersaturation of nano-co-crystals.

Preparation and functional evaluation of electrospun polymeric nanofibers as a new system for sustained topical ocular delivery of itraconazole.

Due to the rapid clearance of external agents from the surface of the cornea, conventional ocular formulations usually require frequent and long duration of administration to achieve a therapeutic level of the drug on the cornea which can be conquered using prolonged-release nanofibrous inserts. In the present study, for the first time, polymeric nanofibers of itraconazole (ITZ), a potent triazole antifungal agent, were prepared as ocular inserts to enhance the topical ocular delivery of the drug. Three different nanofibers were prepared by electrospinning using polyvinyl alcohol-cellulose acetate and polycaprolactone-polyethylene glycol 12 000 polymeric blends. Nanofibers indicated uniform structures with the mean diameter ranging between 137 and 180 nm. Differential scanning calorimetry and Fourier-transform infrared spectroscopy confirmed the amorphous state of the drug in the formulations and the no drug-polymer interaction. Appropriate stability, suitable flexibility, and 2.2-3.9 MPa tensile strength were observed. Formulations indicated antifungal efficacy against Candida albicans and Aspergillus fumigatus and cell viability >70% at different concentrations. Results of bioassay against Candida albicans exhibited prolonged in vitro release of 50-70% of ITZ for almost 55 days. The results suggested that the nanofibers could be considered suitable for prolonged delivery of the ITZ as an antifungal requiring frequent and long duration of administration.

Bioisosteric modification on benzylidene-carbonyl compounds improved the drug-likeness and maintained the antifungal activity against Sporothrix brasiliensis.

Considering the emergence of antifungal resistance on Sporothrix brasiliensis, we aimed to assess new benzylidene-carbonyl compounds against feline-borne S. brasiliensis isolates. The compounds were designed as bioisosteres from previously reported benzylidene-ketones generating the p-coumaric (1), cinnamic (2), p-methoxycinnamic (3) and caffeic acid (4) analogues. The corresponding compounds were tested against feline isolates of S. brasiliensis with sensitivity (n = 4) and resistance (n = 5) to itraconazole (ITZ), following the M38-A2 protocol (CLSI, Reference method for broth dilution antifungal susceptibility testing of filamentous fungi M38-A2 Guideline, 2008). Eleven analogues showed activity against all fungal strains with minimum inhibitory concentrations (MIC) ≤1 mg/ml (1a-d, 2e, 3b, 3e, 4, 4a and 5e) and fungicidal concentrations (MFC) ≤1 mg/ml (1b, 1d, 3e and 4a), whereas 3 was the less active with both MIC and MFC values above 1 mg/ml. Compound 3e (4-methoxy-N-butylcinnamamide) was the most potent (MICrange 0.08-0.16 mg/ml; MFCrange 0.32-0.64 mg/ml) from the set, suggesting a different role of the substituents in ester and amide derivatives. The designed compounds proved to be important prototypes with improved drug-likeness to achieve compounds with higher activity against ITZ-resistant S. brasiliensis.

Insights into the Release Mechanisms of ITZ:HPMCAS Amorphous Solid Dispersions: The Role of Drug-Rich Colloids.

Understanding the dissolution mechanisms of amorphous solid dispersions (ASDs) and being able to link enhanced drug exposure with process parameters are key when formulating poorly soluble compounds. Thus, in this study, ASDs composed by itraconazole (ITZ) and hydroxypropylmethylcellulose acetate succinate (HPMCAS) were formulated with different polymer grades and drug loads (DLs) and processed by spray drying with different atomization ratios and outlet temperatures. Their in vitro performance and the ability to form drug-rich colloids were then evaluated by a physiologically relevant dissolution method. In gastric media, drug release followed a diffusion-controlled mechanism and drug-rich colloids were not formed since the solubility of the amorphous API at pH 1.6 was not exceeded. After changing to intestinal media, the API followed a polymer dissolution-controlled release, where the polymer rapidly dissolved, promoting the immediate release of API and thus leading to liquid-liquid phase separation (LLPS) and consequent formation of drug-rich colloids. However, the release of API and polymer was not congruent, so API surface enrichment occurred, which limited the further dissolution of the polymer, leading to a drug-controlled release. ASDs formulated with M-grade showed the highest ability to maintain supersaturation and the lowest tendency for AAPS due to its good balance between acetyl and succinoyl groups, and thus strong interactions with both the hydrophobic drug and the aqueous dissolution medium. The ability to form colloids increased for low DL (15%) and high specific surface area due to the high amount of polymer released until the occurrence of API surface enrichment. Even though congruent release was not observed, all ASDs formed drug-rich colloids that were stable in the solution until the end of the dissolution study (4 h), maintaining the same size distribution (ca. 300 nm). Drug-rich colloids can, in vivo, act as a drug reservoir replenishing the drug while it permeates. Designing ASDs that are prone to form colloids can overcome the solubility constraints of Biopharmaceutics Classification System (BCS) II and IV drugs, posing as a reliable formulation strategy.

ZnO, TiO2 and Ag nanoparticles impact against some species of pathogenic bacteria and yeast.

The economic approaches for manufacturing the nanoparticles with physical and chemical effects and limited resistance to antibiotics have been progressed recently due to the rise of microbial resistance to antibiotics. This research aimed to study the antimicrobial efficacy of silver nanoparticles Ag, ZnO, and Tio2 nanoparticles against Salmonella typhimurium and Brucella abortus and Candida albicans. Two isolates of Salmonella and two isolates of Brucella abortus were isolated from food spastically meat and blood specimens, respectively. Candida albicans were isolated from the patient's mouth with oral candidiasis (oral thrush) and confirmed diagnosis by API 20C test. The antimicrobial susceptibility of Salmonella typhimurium and B. abortus isolates were performed against nine different antibiotics. Silver nanoparticles consisting of AgNPs size (90) nm, ZnO NPs size (20, 50) nm as well as TiO2 NPs size (10, 50) nm, were used. UV-Visible spectrophotometer was used to characterize silver nanoparticles. The highest resistance of Candida albicans was seen for fluconazole, Clotrimazole and Itraconazole. The results of the Minimum Inhibitory Concentration (MIC) of nanoparticles against Salmonella typhimurium showed the average MIC of Tio2-10nm and Tio2-50nm were 5000 and 2500 µg\ml for S1 and S2 isolates, respectively. The isolated Brucella abortus (B1 and B2) showed sensitivity to NPs with different MIC. The average MIC for Ag-90nm was 5000 and 2500 µg/ml for B1 and B2 isolates, respectively. The findings suggest NP solution has fungicidal and bactericidal impacts on the tested microorganisms so they can be suitable for multiple applications of the biomedical field such as developing new antimicrobial agents.

The Pharmacokinetic Effect of Itraconazole and Voriconazole on Ripretinib in Beagle Dogs by UPLC-MS/MS Technique.

BACKGROUND: A new UPLC-MS/MS technique for the determination of ripretinib in beagle dog plasma was developed, and the pharmacokinetic effects of voriconazole and itraconazole on ripretinib in beagle dogs were studied. METHODS: After extraction with ethyl acetate under alkaline conditions, ripretinib was detected using avapritinib as the internal standard (IS). The mobile phases were 0.1% formic acid-acetonitrile. The scanning method was multi-reaction monitoring using ESI+ source, and the ion pairs for ripretinib and IS were m/z 509.93→416.85 and 499.1→482.09, respectively. This animal experiment adopted a three period self-control experimental design. In the first period, ripretinib was orally administered to six beagle dogs at a dose of 5 mg/kg. In the second period, the same six beagle dogs were orally given itraconazole at a dose of 7 mg/kg, after 30 min, ripretinib was orally given. In the third period, voriconazole at a dose of 7 mg/kg was given orally, and then ripretinib was orally given. At different time points, the blood samples were collected. The concentration of ripretinib was detected, and the pharmacokinetic parameters of ripretinib were calculated. RESULTS: Ripretinib had a good linear relationship in the range of 1-1000 ng/mL. The precision, accuracy, recovery, matrix effect and stability met the requirements of the guiding principles. After erdafitinib combined with itraconazole, the Cmax and AUC0→t of ripretinib increased by 38.35% and 36.36%, respectively, and the t1/2 was prolonged to 7.53 h. After ripretinib combined with voriconazole, the Cmax and AUC0→t of ripretinib increased by 37.44% and 25.52%, respectively, and the t1/2 was prolonged to 7.33 h. CONCLUSION: A new and reliable UPLC-MS/MS technique was fully optimized and developed to detect the concentration of ripretinib in beagle dog plasma. Itraconazole and voriconazole could inhibit the metabolism of ripretinib in beagle dogs and increase the plasma exposure of ripretinib.

Fabrication and characterization of itraconazole loaded anisotropic solid lipid-mannitol microstructures for enhanced antifungal activity.

Anisotropic microparticles containing flower like morphologies have recently attracted significant attention due to their potentially varied application range. Aim of the present work was to build an anisotropic drug delivery system (ASLMMSs) for the encapsulation and enhancement of antifungal activity of a hydrophobic antifungal drug i.e. itraconazole (IRL) with the combination of lipophilic (lipids) as well as hydrophilic (mannitol) materials. Encapsulation efficiency (EE) due to glyceryl monosteatrate (G.ASLMMSs) was 89.02%, whereas Precirol ATO5 formulation (P.ASLMMSs) showed 96.98% EE. FTIR analysis discovered the hydrogen bonding and Vander Waal's forces between lipids and mannitol, while evaluation of XRD data revealed the detailed structural and microstructural characterization indicating the crystallinity of final formulations. Observation under SEM revealed that the final formulations grew in the form of flower like morphologies. These flower-like structures were more obvious for P.ASLMMSs. The increment in dissolution rate (>80% in 6h) could be attributed to the mannitol. Dilutions of Itraconazole loaded anisotropic solid lipid mannitol microstructures (ASLMMSs) in water at concentration range of (500µg/mL, 250µg/mL, 125µg/mL and 75µg/mL) exhibited increased antifungal activity, while free IRL dilution in water showed no zone of inhibition. Both formulations, specifically P.ASLMMSs could signify a promising drug delivery system for lipophilic antifungal drugs.