Preparation and Characterization of a Novel Preparation of Itraconazole Nanoparticles with Improved Dissolution and Bioavailability (original) (raw)
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Iraqi Journal of Pharmaceutical Sciences ( P-ISSN: 1683 - 3597 , E-ISSN : 2521 - 3512), 2019
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 nanosuspe...
Asian Journal of Pharmaceutical and Clinical Research, 2018
Objective: The objective of this study was to prepare and evaluate itraconazole (ITZ) nanosuspensionsusing polymer Eudragit RL-100 and stabilizer Tween-80 by nanoprecipitation method. Materials and Methods: Itraconazole is a potent broad-spectrum Biopharmaceutical Classification System Class II triazole antifungal drug. Nanosuspensions were prepared using solvent displacement/nanoprecipitation method with the help of Eudragit RL-100 as rate-controlled polymer in different ratios and using Tween-80 as stabilizer. The nanosuspension preparation was optimized for particle size by investigating two factors that are solvent:anti-solvent ratio and surfactant concentration, at three levels. The prepared nanosuspensions were evaluated and characterized for particle size, drug excipient compatibility, percentage yield, drug entrapment efficiency, surface morphology, zeta potential, saturation solubility, solid state, and in vitro drug release studies. Results: The nanosuspensions of itraconazole were successfully prepared using solvent displacement/nanoprecipitation method. The two factors solvent: anti-solvent ratio and surfactant concentration influenced the particle size of the nanosuspensions prepared. The Fourier-transform infrared spectroscopy studies confirmed that drug and excipients are compatible, and the X-ray powdered diffraction and differential scanning calorimetry results indicated that the nanoprecipitation method led to the amorphization of itraconazole. Itraconazolenanosuspensions increased the saturation solubility to an extent of 4 times. Itraconazole nanosuspensions completely dissolved in the dissolution medium within 10 s and 72% drug release within 5 min, while the pure drug was dissolved only up to 20% in 15 min and nanosuspensions showed increased dissolution rate of 3 folds, the active drug. Conclusions: Stable itraconazole nanosuspensions were successfully prepared and these nanosuspensions demonstrated dramatic improvement in dissolution rate of the active drug.
Formulation and Stability Testing of Itraconazole Crystalline Nanoparticles
AAPS PharmSciTech, 2011
Itraconazole (ITZ) crystalline nanoparticles were prepared using relatively simple, low-cost sonoprecipitation technique, in which both the solvent and antisolvent were organic in nature. The effect of stabilizer type (hydroxypropyl methylcellulose, hydroxypropyl cellulose, Inutec SP1®, and pluronic F127), drying method (oven and freeze drying) and matrix former used (Avicel PH101, and Aerosil®200) on the dissolution performance as a key characteristic of nanocrystals was evaluated. In 10 min, all of the prepared nanocrystals showed 3.77−8.59 times improvement in percent drug dissolved compared to pure ITZ. Concerning the effect of stabilizer type, the following rank order can be given: pluronic F127≥ hydroxypropyl cellulose≥hydroxypropyl methylcellulose (HPMC)>inutec SP1. Freeze-dried ITZ nanocrystals containing Avicel PH 101 showed better dissolution rate compared to other nanocrystals. The chemical structure of itraconazole nanocrystals was not changed as revealed by Fourier transform infrared. Stability study of selected nanocrystals (F5, F7, and F8) revealed physical and chemical stability of F7 and F8, while a decrease in dissolution rate of F5 was observed (although being chemically stable) when stored under high relative humidity conditions. Although inutec is less potent than pluronic F127 and HPMC regarding their effect on dissolution rate enhancement, it is equipotent to pluronic F127 in preserving the rapid drug dissolution.
International Journal of Pharmaceutics, 2008
A nebulized dispersion of amorphous, high surface area, nanostructured aggregates of itraconazole (ITZ):mannitol:lecithin (1:0.5:0.2, w/w) yielded improved bioavailability in mice. The ultra-rapid freezing (URF) technique used to produce the nanoparticles was found to molecularly disperse the ITZ with the excipients as a solid solution. Upon addition to water, ITZ formed a colloidal dispersion suitable for nebulization, which demonstrated optimal aerodynamic properties for deep lung delivery and high lung and systemic levels when dosed to mice. The ITZ nanoparticles produced supersaturation levels 27 times the crystalline solubility upon dissolution in simulated lung fluid. A dissolution/permeation model indicated that the absorption of 3 m ITZ particles is limited by the dissolution rate (BCS Class II behavior), while absorption is permeation-limited for more rapidly dissolving 230 nm particles. The predicted absorption half-life for 230 nm amorphous ITZ particles was only 15 min, as a result of the small particle size and high supersaturation, in general agreement with the in vivo results. Thus, bioavailability may be enhanced, by decreasing the particle size to accelerate dissolution and increasing permeation with (1) an amorphous morphology to raise the drug solubility, and (2) permeability enhancers.
AAPS PharmSciTech, 2013
The present research work explores formulation design, critical scale-up considerations and bioequivalence studies of soluble itraconazole (ITZ) in a tablet form using disordered drug delivery approach. Disordered system of ITZ with a lower viscosity grade of hydroxypropyl methyl cellulose (Pharmacoat 603) was developed for the first time and extensively characterised at three different stages, namely development of glass system, pellet coating and tablet compression using advanced analytical techniques. Complete molecular embedment of ITZ resulting in amorphisation was observed and found to be sustained until end of the real-time and accelerated stability studies. Developed formulation exhibited comparative in vitro dissolution profile (similarity factor >70) with reference product (Sporanox, Janssen Pharmaceutica) in simulated gastric fluid without enzymes. Formulation was scaled up in three batches (50,000 tablets/batch) with detailed validation of critical process parameters using process capability index method. Critical scale-up considerations like control of residual solvent content, effect of pellet size on dissolution, process variables in pellet coating, compressibility of coated pellets and cushioning effect required for desired compressibility were thoroughly discussed. Bioequivalence study of single dose of test and reference product in seven healthy human volunteers under fed condition exhibited significant bioequivalence with results (AUC last and AUC ∞) lying between 90% confidence interval. With increase in number of subjects to 24, a significant effect on pharmacokinetic parameters of both reference as well as developed ITZ tablets was observed.
Formulation of itraconazole nanococrystals and evaluation of their bioavailability in dogs
European Journal of Pharmaceutics and Biopharmaceutics, 2014
The aim of the study was to increase the bioavailability of itraconazole (ITRA) using nanosized cocrystals prepared via wet milling of ITRA in combination with dicarboxylic acids. Wet milling was used in order to create a nanosuspension of ITRA in combination with dicarboxylic acids. After spraydrying and bead layering, solid state was characterized by MDSC, XRD, Raman and FT-IR. The release profiles and bioavailability of the nanococrystalline suspension, the spray-dried and bead layered formulation were evaluated. A monodispers nanosuspension (549 ± 51 nm) of ITRA was developed using adipic acid and Tween®80. Solid state characterization indicated the formation of nanococrystals by hydrogen bounds between the triazole group of ITRA and the carboxyl group of adipic acid. A bioavailability study was performed in dogs. The faster drug release from the nanocrystal-based formulation was reflected in the in-vivo results since T max of mean profile after administration of the formulations was observed 3h after administration, while T max of mean profile after administration of the reference formulation was observed only 6h after administration. This fast release of ITRA was obtained by a dual concept: manufacturing of nanosized cocrystals of ITRA and adipic acid via wet milling. Formation of stable nanosized cocrystals via this approach seems a good alternative for amorphous systems to increase the solubility and obtain a fast drug release of BCS class II drugs.
European Journal of Pharmaceutical Sciences, 2014
To investigate the performance of a solid-state self-nanoemulsifying system with no precipitation in gas-31 tric and intestinal fluid, itraconazole (ITZ) was selected as a model drug because of its practically insol-32 uble nature in intestinal fluid. A self-nanoemulsifying ITZ solid dispersion (SNESD) system was prepared 33 as follows: (1) establishment of self-nanoemulsifying composition via the hot melting method, (2) solid-34 ification with fumed silicon dioxide (Aerosil 300) via adsorption to prepare SNESD and (3) preparation of 35 a directly compressible tablet containing SNESD. This SNESD was easily formulated in the form of a dis-36 solving tablet and provided a favourable nanoemulsifying microenvironment with no precipitation in the 37 testing media. The SNESD and SNESD-loaded tablet displayed highly enhanced dissolution via nanomisa-38 tion (266.8 nm and 258.3 nm at 60 min and 120 min, respectively), whereas the drug alone or a reference 39 ITZ Sporanox Ò capsule displayed very low dissolution and precipitated immediately in intestinal fluid. 40 Drug precipitation in intestinal fluid may affect the in vivo performance of poorly soluble weakly basic 41 drugs and was estimated according to the crystal growth theory. The superdisintegrant and surfactant 42 in the formulation of the tablet were very crucial to the dissolution of the SNESD-loaded tablet. The drug 43 contents and dissolution rates of the SNESD-loaded tablets were also stable during storage in terms of 44 dissolution and drug content. The SNESD-loaded tablet displayed significantly increased oral bioavailabil-45 ity in healthy human volunteers compared with the reference Sporanox Ò capsule. The current solid-state 46 SNESD-loaded tablet could provide an alternative to liquid-based emulsifying preparations for various 47 65
Molecular pharmaceutics
The successful formulation of itraconazole and odanacatib into nanoparticle form with diameters of 145 and 350 nm, respectively, using rapid, block copolymer-directed precipitation is presented. These are the smallest stable nanoparticles that have been reported for these compounds. The difference in size of the nanoparticles for the two compounds is explained by the difference in nucleation rate and its dependence on supersaturation. The conditions for stability after formation are presented: storage at 5 degrees C and removal of residual processing solvent. These requirements are explained in terms of solute solubility and its dependence on both temperature and solvent concentration. The theory of Ostwald ripening provides the framework for understanding the differences in stability observed for the two compounds. The dynamics of the hydrophobic polymer block plays a major role in long-term stability as demonstrated by the behavior of nanoparticles stabilized by poloxamer vs polys...
Self-Solidifying and Self-Nanoemulsifying Drug Delivery System of Itraconazole
Indian journal of science and technology, 2023
Objective: To improve solubility, dissolution, and permeability of BCS class II drug Itraconazole (ITZ) using a self solidifying self nano emulsifying drug delivery system (SNEDDS). Method: The solubility of ITZ was assessed in oils, surfactants, co-surfactants, and buffers. Surfactants, co-surfactants, and combination of surfactants (S-comb) were selected on the basis of emulsification efficacy test. The ability to solidify self emulsifying mixture was assessed and solid SNEDDSS was developed and optimised. Finding: Solubility of ITZ was found maximum in 0.1N HCl (0.120 ± 0.07mg/mL) followed by SGF (0.089 ± 0.01mg/mL). Out of 20 oils screened, Peceol showed highest solubility. Among all surfactants and co-surfactants studied, Labrafil M 1944 CS (LM 1944) showed highest potential to solubilize ITZ (14.91 mg/g). The globule size of the optimised formulation was found to be 40.11 nm with PDI of 0.144. Zeta potential study revealed the stability of the SNEDDS. Drug content of solid SNEDDS of ITZ was found within the range of 98.11% to 102.51%, which was found in the acceptable limit. It was observed that ITZ solid SNEDDS (S-SNEDDS) showed a promising improvement in the in vitro dissolution profile compared to the plain ITZ and marketed product in all three-dissolution media. Nearly 3-fold enhancement of permeability of ITZ was attributed by uniformly dispersed globules with nano size. Analytical characterization demonstrated that the drug and excipients are compatible with amorphous characteristics of the ITZ. Novelty: The developed self solidifying SNEDDS of ITZ showed enhanced solubility, dissolution, and permeability in comparison to the pure drugs (ITZ). Self solidifying SNEDDS would be a novel approach to overcome the limitations associated with liquid dosage forms.
Journal of Pharmacy and Pharmacology, 2017
Objectives The aim of this study was to develop high payload itraconazole-incorporated lipid nanoparticles (HINP) with modulated release property using a binary mixture core of solid and liquid lipid for oral and parenteral administration. Methods High payload itraconazole-incorporated lipid nanoparticles were prepared by hot high-pressure homogenization method using tristearin (TS) as a solid lipid, triolein (TO) as a liquid lipid and egg phosphatidylcholine/Tween 80/DSPE-PEG2000 as a surfactants mixture. To investigate the effects of liquid lipid in lipid core on itraconazole (ITZ) dissolution and release, TS/TO ratio was varied as 100/0, 90/10 and 80/20 (mg/mg). Key findings All HINP formulations showed particle size around 300 nm and polydispersity index below 0.3. The incorporation efficiencies of HINP formulations were above 80%, and more than 40 mg of ITZ was incorporated into each HINP formulation. In-vitro dissolution and release rate of ITZ from HINP increased as the amoun...