Itraconazole Nanosuspension Research Articles

Development of a screening platform for the formulation of poorly water-soluble drugs as albumin-stabilized nanosuspensions using nab™ technology

The nanoparticle albumin bound™ (nab™) technology generally offers great potential for the formulation of poorly water-soluble drugs as albumin-stabilized nanosuspensions for intravenous use while avoiding solubilizers and cross-linking agents. The nab™ technology is a three-step process consisting of emulsification, high-pressure homogenization and solvent evaporation.Within this work, a screening approach was developed to predict whether active pharmaceutical ingredients are suitable for nab™ formulations. A design of experiments approach was used to investigate the effects of ultrasonic homogenization on an albumin-stabilized itraconazole nanosuspension. Based on this, a screening platform was developed, and subsequently evaluated and applied to a selection of poorly water-soluble drugs. The screening process to produce albumin-stabilized nanosuspensions consists of two process steps: Ultrasonic treatment, which combined emulsification and homogenization, followed by solvent evaporation. The results of the screening process were fully transferable to the standard three-step process of nab™ technology. In addition, based on drug screening, drug properties were highlighted that are important for the development of nab™ formulations.All in all, the nab™ technology is a promising but not universal formulation platform for poorly water-soluble drugs. Nevertheless, for some poorly soluble drugs it offers a valuable approach for the formulation of nanosuspensions for intravenous use.

Challenges of nanoparticle albumin bound (nab™) technology: Comparative study of Abraxane® with a newly developed albumin-stabilized itraconazole nanosuspension

Nanoparticle albumin bound™ (nab™) technology is an established delivery platform for development of albumin stabilized nanoparticles as drug delivery systems for poorly water-soluble drugs. By using albumin for particle stabilization, nab™ technology does not require solubilizers or emulsifiers for the formulation of poorly water-soluble drugs for intravenous use. Despite the great potential, however, to date only two products based on nab™ technology have been approved by the Food and Drug Administration: Abraxane® (nab™ paclitaxel) and Fyarro® (nab™ rapamycin).In this study, the commercially available product Abraxane® was characterized in comparison to an albumin stabilized nanosuspension for the poorly water-soluble drug itraconazole. The aim of this study was to identify critical product parameters of the nanosuspensions depending on the manufacturing process in order to assess the transferability of nab™ technology to other drugs. The colloidal properties, stabilizing protein composition and particle disintegration behavior were analyzed. In addition, studies were carried out on the impact of the key process step, the high-pressure homogenization, using a design of experiments (DoE) approach. A nanosuspension comprising spherical, stable drug nanoparticles stabilized by a large fraction of dissolved albumin around the nanoparticles were identified. During the manufacturing process, the drug core was coated with a layer of albumin, which was cross-linked to a certain level. The Abraxane® and itraconazole suspensions differed in the analyzed protein fraction, with stronger cross-linking at the particle surface for Abraxane®. Both active pharmaceutical ingredients were present in the amorphous state as nanoparticles. In vitro disintegration studies performed to mimic a strong dilution during intravenous application showed the disintegration of the nanoparticles. All in all, the analysis underlined the transferability of the nab™ technology to selected other poorly water-soluble drugs with the great advantage of eliminating solubilizers and emulsifiers for intravenous applications.

Gellan gum-based in situ gelling ophthalmic nanosuspension of Posaconazole.

The formulation and delivery of highly hydrophobic drugs in an optimized dosage form is challenging to formulation scientists. Posaconazole has shown promising action in case studies against fungal keratitis. Biological macromolecules like gellan gum would aid in enhancing the availability of such drugs by increasing the contact time of the formulation. Herein, we propose a transmucosal ocular delivery system of Posaconazole by developing a gellan gum–based in situ gelling nanosuspension. The HPLC method for Posaconazole was developed and validated as per ICH guidelines. The nanosuspension was prepared by microfluidization and optimized by Quality by Design. The gellan gum concentration selected was 0.4% w/v based on the viscosity and mucoadhesion measurements. A greater zone of inhibition of ~ 15 mm was observed for the prepared nanosuspension as compared to ~ 11 mm for the marketed itraconazole nanosuspension. A potential irritancy score of 0.85, considered to be non-irritant, was observed for the developed nanosuspension. Higher drug release of ~ 35% was noted for the nanosuspension compared to about ~ 10% for the coarse suspension. Ex vivo corneal retention studies on excised goat cornea demonstrated ~ 70% drug retention in the tissue.Graphical abstractGraphical abstract depicting the central hypothesis of the work. Supplementary informationThe online version contains supplementary material available at 10.1007/s13346-022-01155-0.

Formulation and Characterization of Itraconazole as Nanosuspension Dosage Form for Enhancement of Solubility

Abstract
 Itraconazole is a triazole antifungal given orally for the treatment of oropharyngeal and vulvovaginal candidiasis, for systemic infections including aspergillosis, candidiasis, and for the prophylaxis of fungal infections in immunocompromised patients.
 The study aimed to formulate a practical water-insoluble Itraconazole, with insufficient bioavailability as nanosuspension to increase aqueous solubility and improve its dissolution and oral bioavailability.
 Itraconazole nanosuspension was produced by a solvent-antisolvent nanoprecipitation method in the presence of different stabilisers (Poloxamer-188, HPMCE5) at different ratios with the drug alone or combination with surfactant(tween 80, SLS).
 The results exhibit that the particle sizes of all prepared itraconazole formulations were in the nano size. The best formula (F6) has a particle size. ( 42 ) nm and Zeta potential of (- 21.86 ) mV. In vitro cumulative release from the nanosuspension was (88 %) at (30) min when compared to the pure drug (13%) and lyophilized nanoparticles (98.2%) at (30)min. Effect of different parameters was investigated.
 Fourier transforms infrared spectroscopy(FTIR), Differential scanning calorimetry (DSC) and X-ray diffraction (XRD), Scanning electron microscope( SEM) was done for the optimized nanoparticles prepared by lyophilization technique
 Thus, Nanosuspension appears to be an encouraging approach to formulate Itraconazole nanosuspension with high solubility and dissolution rate.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Keywords: Itraconazole, Nanoprecipitation method, Nanosuspension

Impact of polymers on the aggregation of wet-milled itraconazole particles and their dissolution from spray-dried nanocomposites

We explore the impact of various polymers and their molecular weight on the stabilization of wet-milled suspensions of itraconazole (ITZ), a poorly soluble drug, and its dissolution from spray-dried suspensions. To this end, ITZ suspensions with SSL, SL, and L grades of hydroxypropyl cellulose (HPC) having molecular weights (MWs) of 40, 100, and 140 kg/mol, respectively, hydroxypropyl methyl cellulose (HPMC E3 with 10 kg/mol), polyvinylpyrrolidone (PVP K30 with 50 kg/mol), sodium dodecyl sulfate (SDS, surfactant), and HPC SL–SDS were wet media milled and spray-dried. Laser diffraction results show that 2.5% HPC SL–0.2% SDS led to the finest ITZ nanosuspension, whereas without SDS, only 4.5% HPC with SL/L grades ensured minimal aggregation. Rheological characterization reveals that aggregated suspensions exhibited pronounced pseudoplasticity, whereas stable suspensions exhibited near Newtonian behavior. Spray-drying yielded nanocomposites with 60–78% mean ITZ loading and acceptable content uniformity. Severe aggregation occurred during milling/drying when 4.5% polymers with MW ≤ 50 kg/mol were used; their nanocomposites exhibited incomplete redispersion due to slow matrix erosion and released ITZ slowly during dissolution test. Overall, high drug-loaded, surfactant-free ITZ nanocomposites that exhibited immediate release (>80% dissolved in 20 min) were prepared via spray-drying of wet-milled ITZ with 4.5% HPC SL/L.

Downstream drug product processing of itraconazole nanosuspension: Factors influencing tablet material properties and dissolution of compacted nanosuspension-layered sugar beads

There has been limited research done on the downstream processing of nanosuspensions into solid oral dosage forms. This paper demonstrates the bead layering process with a layering level at 150% and 240%, as well as the selection and justification of the outer phase excipients for tabletability and disintegrating properties. In a previous study, an itraconazole nanosuspension stabilised by SDS and HPMC E5 was layered onto sugar beads with coating polymer HPMC VLV. In the current study, compression studies with these layered beads utilising the small bead size at 150% or 240% layering levels with outer phase cushioning excipients MCC, copovidone or isomalt were performed. Other excipients such as co-compressed crospovidone-PEG 4000; DCP functioning as a disintegrant; and HPC as a binder was also added. Target output variables were achieved with a balance between an adequate tensile strength and fast dissolution rate with a release of 99.0% (±1.0% SD) within 10min, which is in accordance with the FDA guidance for dissolution testing. The results show that the compaction of nanosuspension-layered beads is a suitable process for processing an itraconazole nanosuspension into a solid dosage form such as a compacted tablet without compromising on drug release.

Downstream drug product processing of itraconazole nanosuspension: Factors influencing drug particle size and dissolution from nanosuspension-layered beads

There is more research required to broaden the knowledge on the downstream processing of nanosuspensions into solid oral dosage forms, especially for coated nanosuspensions onto beads as carriers. This study focuses on bead layering as one approach to solidify nanosuspensions. The aim was to systematically investigate the influence of type of coating polymer (HPMC VLV vs. copovidone), bead material and bead size (sugar vs. MCC, and small vs. large) and coating thickness (50%–150% layering level) on the properties of a dried itraconazole nanosuspension. A stable itraconazole nanosuspension with a mean particle size below 200nm was prepared and a ratio of itraconazole and coating polymer of around 1:1 was identified. XRD and DSC scans revealed that itraconazole remained mostly crystalline after the bead layering process. The fastest dissolution rate was achieved using the small bead size, sugar beads, HPMC VLV as film-forming polymer and lowest layering level, with the best formulation releasing 94.1% (±3.45% SD) within the first 5min. A deterioration of the release profile with increasing layering level was only observed for MCC beads and was more pronounced when copovidone was used as a coating polymer. It was observed that bead layering is a suitable method to process an itraconazole nanosuspension into a solid form without compromising release.

Activity and Safety of Inhaled Itraconazole Nanosuspension in a Model Pulmonary Aspergillus fumigatus Infection in Inoculated Young Quails.

Pulmonary aspergillosis is frequently reported in parrots, falcons, and other birds held in captivity. Inhalation is the main route of infection for Aspergillus fumigatus, resulting in both acute and chronic disease conditions. Itraconazole (ITRA) is an antifungal commonly used in birds, but its administration requires repeated oral dosing, and the safety margin is narrow. To investigate the efficacy of inhaled ITRA, six groups of ten young quails (Coturnix japonica) were inoculated intratracheally with 5 × 106 spores (3 groups) or 5 × 107 spores (3 groups). Animals were exposed to nebulized ITRA nanosuspension as 10 % suspension or 4 % suspension, once daily for 30 min, starting 2 h after inoculation for 6 days. Control groups were exposed to nebulized saline for the same period of time. Survival and clinical scores were evaluated, and animals were subjected to gross pathology. In control animals, aspergillosis resulted in systemic disease without pulmonary or air sac granulomas. Animals died from multiple organ failure. Inhalation of 10 % ITRA nanosuspension blocked lethality and prevented disease-related symptoms in the quails exposed to the low dose of spores, while the disease course in quails inoculated with the high-spore dose was retarded. Inhalation of 4 % ITRA nanosuspension was less effective. Both inhalations were well tolerated, and gross pathology did not reveal signs of local toxicity. The data indicate that inhaled administration of 10 % ITRA nanosuspension is capable of alleviating an acute A. fumigatus infection in quails. A lower ITRA concentration may be only active in chronic pulmonary aspergillosis.

Spray drying of a poorly water-soluble drug nanosuspension for tablet preparation: formulation and process optimization with bioavailability evaluation

Spray drying experiments of an itraconazole nanosuspension were conducted to generate a dry nanocrystal powder which was subsequently formulated into a tablet formulation for direct compression. The nanosuspension was prepared by high pressure homogenization and characterized for particle-size distribution and surface morphology. A central composite statistical design approach was applied to identify the optimal drug-to-excipient ratio and spray drying temperature. It was demonstrated that the spray drying of a nanosuspension with a mannitol-to-drug mass ratio of 4.5 and at an inlet temperature of 120 °C resulted in a dry powder with the smallest increase in particle size as compared with that of the nanosuspension. X-ray diffraction results indicated that the crystalline structure of the drug was not altered during the spray-drying process. The tablet formulation was identified by determining the micromeritic properties such as flowability and compressibility of the powder mixtures composed of the spray dried nanocrystal powder and other commonly used direct compression excipients. The dissolution rate of the nanocrystal tablets was significantly enhanced and was found to be comparable to that of the marketed Sporanox®. No statistically significant difference in oral absorption between the nanocrystal tablets and Sporanox® capsules was found. In conclusion, the nanosuspension approach is feasible to improve the oral absorption of a BCS Class II drug in a tablet formulation and capable of achieving oral bioavailability equivalent to other well established oral absorption enhancement method.

Preparation and evaluation of chitosan–itraconazole co-precipitated nanosuspension for ocular delivery

The purpose of the present study was to prepare itraconazole-loaded chitosan nanosuspension and evaluate it for ocular delivery. Itraconazole-loaded chitosan nanosuspension was prepared by controlled co-precipitation of chitosan and itraconazole from aqueous acetate solution using a combination of pH change and non-solvent addition. The co-precipitated suspension was evaluated for particle size, zeta-potential, entrapment efficiency and solubility study. It was observed that co-precipitation of itraconazole and chitosan from chitosan–lysine system in the presence of Poloxamer-188 as stabiliser provided nanosuspension of the smallest particle size with a 12-fold increase in aqueous saturation solubility of itraconazole and the fastest in vitro release. Transmission electron micrographs of the nanosuspension showed ovoid-shaped particles. A comparative evaluation of the itraconazole (1%, w/v) nanosuspension with commercial itraconazole suspension (1%, w/v) revealed a significantly higher percentage cumulative permeation of itraconazole across the isolated goat cornea from the nanosuspension dosage form as compared to the commercial suspension (P < 0.01).

Increased dissolution and oral absorption of itraconazole/Soluplus extrudate compared with itraconazole nanosuspension

The purpose of this article was to compare the in vitro and in vivo profiles of itraconazole (ITZ) extrudates and nanosuspension separately prepared by two different methods. And it was proved truly to form nanocrystalline and amorphous ITZ characterized by differential scanning calorimetry (DSC), X-ray powder diffraction (XRD) analysis, Fourier transform infrared spectrum (FTIR), transmission electron microscope (TEM), and scanning electron microscope (SEM). The release of ITZ/Soluplus solid dispersions with amorphous ITZ was almost complete while only 40% release was obtained with ITZ nanocrystals. The amorphous state need not to cross over the crystal lattice energy upon dissolution while the crystalline need to overcome it. In the in vivo assay, the AUC(0–t) and Cmax of ITZ/Soluplus were 6.9- and 11.6-time higher than those of pure ITZ. The formulation of the extrudate had an AUC(0–t) and Cmax similar to those of ITZ and also OH-ITZ compared with the commercial capsule (Sporanox®). The relative bioavailability values with their 95% confidence limit were calculated to be 98.3% (92.5–104.1%) and 101.3% (97.9–104.1%), respectively. The results of this study showed increased dissolution and bioavailability of the solid dispersion of Soluplus-based carrier loading ITZ prepared by HME compared with the ITZ nanosuspension prepared by wet milling.

Formulation and drying of miconazole and itraconazole nanosuspensions

Miconazole and itraconazole possess adequate membrane permeability, but only slight water solubility, which limits their bioavailability and antifungal effect. To increase their dissolution rate, the compounds were nanoground by media milling to produce nanosuspensions with mean particle size of approximately 210 nm and stabilized with sodium dodecylsulfate (SDS) in combinations with either cellulose ethers (HPC or HPMC) or poloxamers. During storage for 3 months at 25 °C, HPC/SDS stabilized more efficiently miconazole nanoparticles, while poloxamer 407/SDS performed better with itraconazole nanosuspensions. The stabilizing efficiency of the excipients was explained by physical-chemical drug-excipients interactions. The HPC/SDS-stabilized nanosuspensions were spray-dried or freeze-dried with and without the matrix formers mannitol or microcrystalline cellulose (MCC). In absence of matrix former, itraconazole particles agglomerated more extensively than miconazole particles, resulting in a low dissolution rate. Dissolution of the spray- or freeze-dried miconazole nanosuspension was enhanced in presence of mannitol or MCC (drug substance:excipient ratio of 1:1, w/w), as compared to the coarse drug suspension (twice the amount dissolved after 10 and 20 min). Spray-drying itraconazole nanosuspension in presence of mannitol or MCC also yielded fast dissolution (60% dissolved in less than 10 min as compared to 30-45 min with the coarse suspension). Freeze-dried itraconazole nanosuspensions did generally not dissolve substantially faster than freeze-dried coarse suspension. In conclusion, we were able to process miconazole and itraconazole successfully and under similar conditions into dry nanoparticulate drug products with enhanced in vitro performance.

Inhalable highly concentrated itraconazole nanosuspension for the treatment of bronchopulmonary aspergillosis

Cystic fibrosis (CF) patients are suffering from multiple often chronic endobronchial infection. The stiff mucus in these patients represents a compartment, which cannot easily be reached by systemic treatment. While bacterial infections are now successfully treated with repeated inhalation of antibiotics such as tobramycine, 57% of CF patients are colonized by Aspergillus species. About 10–20% of colonized patients develop symptoms of allergic bronchopulmonary aspergillosis (ABPA). While current standard of treatment of ABPA in CF patients is to suppress the allergy related symptoms by administration of glucocorticoids, itraconazole (ITRA), administered orally at high doses, can alleviate the symptoms of ABPA. However, no inhalable formulation of ITRA is available to enable local treatment of aspergillosis. The aim of this study was to describe an aqueous nanosuspension of ITRA and to characterize the pharmacokinetics after single dose inhalation. Using wet-milling with organic milling beads, a stable nanosuspension with particle size in the range of 200nm and an ITRA concentration of 20% (v/w) could be obtained, using polysorbate 80 at a concentration of 14% relative to ITRA. The suspension was stable if stored at 8°C for 3months without particle growth and could be nebulized using standard nebulizer technologies including mesh technology and pressured air nebulizers. A 10% suspension was well tolerated upon repeated dose inhalation once daily for 7days at a predicted dose of 45mg/kg in rats. A single dose inhalation at a predicted dose of 22.5mg/kg resulted in maximum lung tissue concentration of 21.4μg/g tissue with a terminal half-life of 25.4h. Serum concentrations were lower, with a maximum concentration of 104ng/ml at 4h after dosing and a terminal half-life of 10.5h.The data indicate that ITRA nanosuspension represents an interesting formulation for inhaled administration in CF patients suffering from ABPA. High and long lasting lung tissue concentrations well above the minimal inhibitory concentration of Aspergillus species enable once daily administration with minimal systemic exposure.

Nanonization of Itraconazole by High Pressure Homogenization: Stabilizer Optimization and Effect of Particle Size on Oral Absorption

This study was performed to optimize stabilizer systems used in itraconazole (ITZ) nanosuspensions to achieve the greatest extent of size reduction and investigate the effect of particle size on the in vitro dissolution and oral absorption of ITZ. The nanosuspensions were prepared by high pressure homogenization and characterized for particle size, zeta potential, and surface morphology. A central composite method was applied to identify a multiple stabilizer system of Lutrol F127 and sodium lauryl sulfate for optimal particle size reduction. By using the optimized system, an ITZ nanosuspension was prepared that showed the particle size results in good agreement with the values predicted by the model. The nanosuspension was physically stable at 25°C for 1 week. The crystalline form of ITZ was not altered. The ITZ dissolution rate is directly correlated to its particle size, and a smaller particle size yields a faster dissolution rate. Pharmacokinetics study was performed using four ITZ suspensions with various particle sizes in rats (n = 3). A significant increase in both maximal plasma concentration of drug and area under the drug concentration-time curve (AUC) was shown when the particle size was reduced from micrometer to nanometer. However, the AUC was not significantly affected by further reduction of the particle size within the nano-size range.

Nanosuspension Formulation of Itraconazole Eliminates the Negative Inotropic Effect of SPORANOX® in Dogs

Previously, it was observed that a nanosuspension formulation of itraconazole was more efficacious and yet less acutely toxic in rats as compared with the conventional solution formulation, SPORANOX (itraconazole) Injection. The present study compares the two formulations with respect to specifically myocardial contractility in conscious dogs. Motivation for doing so is highlighted by the black-box warning in the package insert for SPORANOX (itraconazole) Injection, which warns of negative inotropic effects. Conscious dogs, instrumented with a high-fidelity pressure transducer in the left ventricle, were placed in a sling for dosing and cardiac monitoring. Test and control articles were administered intravenously via a peripheral vein, and left ventricular parameters were measured continuously through 60 min from the start of dosing. As expected, SPORANOX (itraconazole) Injection caused a significant reduction in myocardial contractility as determined by the contractility index. In contrast, the itraconazole nanosuspension administered at twice the dose and at twice the rate of infusion did not result in significant changes in myocardial contractility. A novel formulation technology applied to itraconazole completely prevented the negative inotropic effect observed in conscious dogs as compared with SPORANOX (itraconazole) Injection.

Itraconazole IV nanosuspension enhances efficacy through altered pharmacokinetics in the rat

The goal of this research was to evaluate an intravenous itraconazole nanosuspension dosage form, relative to a solution formulation, in the rat. Itraconazole was formulated as a nanosuspension by a tandem process of microcrystallization followed by homogenization. Acute toxicity, pharmacokinetics, and distribution were studied in the rat, and compared with a solution formulation of itraconazole. Efficacy was studied in an immunocompromised rat model, challenged with a lethal dose of either itraconazole-sensitive or itraconazole-resistant C. albicans. Itraconazole nanosuspension was tolerated at significantly higher doses compared with a solution formulation. Pharmacokinetics of the nanosuspension were altered relative to the solution formulation. C max was reduced and t 1/2 was much prolonged. This occurred due to distribution of the nanosuspension to organs of the monocyte phagocytic system (MPS), followed by sustained release from this IV depot. The higher dosing of the drug, enabled in the case of the nanosuspension, led to higher kidney drug levels and reduced colony counts. Survival was also shown to be superior relative to the solution formulation. Thus, formulation of itraconazole as a nanosuspension enhances efficacy of this antifungal agent relative to a solution formulation, because of altered pharmacokinetics, leading to increased tolerability, permitting higher dosing and resultant tissue drug levels.