Solid Dispersions Of Itraconazole Research Articles

Exploring novel carrier for improving bioavailability of Itraconazole: Solid dispersion through hot-melt extrusion

Kollicoat® Smartseal (Methyl methacrylate and diethylaminoethyl methacrylate copolymer dispersion) which is used for taste masking and moisture protection, has shown the ability for forming solid dispersion. The present study aimed to check its feasibility for improvement of pharmacokinetics when studied in-vivo in comparison to model high melting point drug-like Itraconazole. Hot-melt extrusion (HME) is a very well commercially accepted technology for solubility enhancement. However, there are limited polymers that can be utilized due to narrow processing window, low thermoplastic behavior or impart stability to the formed amorphous solid dispersion. Thus, having a carrier, which can address all these concerns, will give the industry an additional choice of the carrier for the development of formulations. Thus, the authors have tried to address this issue and demonstrated the ability of the novel carrier to be exploited into HME technology. Solid dispersions of Itraconazole were prepared, characterized, and tested for in-vivo performance in rats. The results indicated that the carrier exhibited good thermoplastic behavior over a temperature range of 120 °C–220 °C. Itraconazole had a plasticizing effect on the carrier. The in-vitro results indicated 20 fold improved solubility over plain Itraconazole. The results of thermal analysis fosters the possibility of the formation of solid solution which converts into an amorphous form. Kollicoat® Smartseal has shown high potential as a carrier to be used in HME for solubility enhancement of highly insoluble drugs like Itraconazole. It offered no processing challenges and the in-vivo results are in good agreement with in-vitro studies.

Formulation and evaluation of sustained released buccoadhesive tablets of Itraconazole

The aim of present research was to report the buccoadhesive tablet of itraconazole to provide localized delivery of drug for the treatment of oral thrush and maintain the drug concentration in the mouth for prolonged period of time thereby improving the oral bioavailability of drug. Buccoadhesive tablet is a sustained release of itraconazole for easy permeation across buccal mucosa and provide a local delivery concentration that may or may not be sufficient to maintain MIC to kill the microorganism. Solid dispersion of itraconazole was prepared by solvent evaporation technique using silica gel act as adsorbent and drug was soluble in chloroform to obtain a slurry or uniform mixture. The buccoadhesive tablet was prepared by direct compression method using different polymers such as Carbopol(C934P), HPMC K4M, Eudragit E100. Five formulations of different concentrations were prepared. Itraconazole strength were kept constant at 30mg and target was fixed at 120mg. After examine the moisture content, bulk density, tapped density, Angle of repose of powder blend get the result were found to be prescribed limit and indicated good flow property. Then the tablets were evaluated for hardness, thickness, weight variation, drug content, friability, swelling index, In-vitro drug release.

Amorphization of itraconazole by inorganic pharmaceutical excipients: comparison of excipients and processing methods

The aim of this study was to investigate the effects of solid carriers and processing routes on the properties of amorphous solid dispersions of itraconazole. Three solid carriers with a range of surface properties were studied, (1) a mesoporous silicate, magnesium aluminum silicate (Neusilin US2), (2) a nonporous silicate of corresponding composition (Veegum) and (3) a non-silicate, inorganic excipient, calcium phosphate dibasic anhydrous (A-TAB). The drug was incorporated via either solvent-deposition or ball milling. Both the maximum drug deposited by solvent-based method that produced an amorphous composite and the time for complete amorphization by co-milling was determined by X-ray powder diffraction (XRPD). Changes in the drug and excipients were monitored by nitrogen adsorption and wettability of the powder. The ability of the excipients to amorphize the drug and enhance its dissolution was related to the powder characteristics. Neusilin provided the fastest amorphization time in the mill and highest drug loading by solvent-deposition, compared with the other two excipients. Solvent-deposition provided greater dissolution enhancement than milling, due to the reduction in Neusilin porosity during high energy milling.This study confirms that substrates as well as the processing routes have notable influence on the drug deposition, amorphization, physical stability and drug in vitro release.

Preparation and characterization of various solid dispersion formulations of itraconazole to enhance the drug dissolution profile

This study investigated various solid dispersions of itraconazole with different carrier blends to enhance its dissolution. HPMC E5, HPMC E15, PEG 20000 and TPGS 1000 were used to construct 20 % drug containing solid matrices by spray drying method. The formulations were analyzed in terms of dissolution profile, x-ray diffraction (XRD) and/or differential scanning calorimetry (DSC) pattern once immediately after preparation and again after storage for three months at accelerated conditions. The results showed that different excipients could put their effects on the dissolution behavior of the drug mainly through affecting the solid states of the resultant mixtures. In this regard, presence of high portions of HPMC in the resultant matrices was the most promising approach for improving the dissolution rate of itraconazole. The dissolution behavior of the drug after storage was directly related to its relative crystal growth during this period, since the more generated semicrystalline structures showed slower dissolution rates.

Production of advanced solid dispersions for enhanced bioavailability of itraconazole using KinetiSol® Dispersing

Objectives: To investigate the ability of KinetiSol® Dispersing to prepare amorphous solid dispersions of itraconazole using concentration-enhancing polymers. Methods: Concentration-enhancing nature of several cellulosic polymers (HPMC, hypromellose acetate succinate) was studied using a modified in vitro dissolution test. Solid dispersions were prepared by KinetiSol® Dispersing and characterized for solid-state properties using X-ray diffraction and differential scanning calorimetry. Potency and release characteristics were also assessed by high-performance liquid chromatography. Oral bioavailability of lead formulations was also assessed in animal models. Results: Screening studies demonstrated superior concentration-enhancing performance from the hypromellose acetate succinate polymer class. Data showed that stabilization was related to molecular weight and the degree of hydrophobic substitution on the polymer such that HF > MF ≈ LF, indicating that stabilization was achieved through a combination of steric hindrance and hydrophobic interaction, supplemented by the amphiphilic nature and ionization state of the polymer. Solid dispersions exhibited amorphous solid-state behavior and provided neutral media supersaturation using a surfactant-free pH change method. Rank-order behavior was such that LF > MF > HF. Addition of Carbopol 974P increased acidic media dissolution, while providing a lower magnitude of supersaturation in neutral media because of swelling of the high viscosity gel. In vivo results for both lead compositions displayed erratic absorption was attributed to the variability of gastrointestinal pH in the animals. Conclusions: These results showed that production of amorphous solid dispersions containing concentration-enhancing polymers through KinetiSol® Dispersing can provide improved oral bioavailability; however, additional formulation techniques must be developed to minimize variability associated with natural variations in subject gastrointestinal physiology.

A Novel Itraconazole Bioadhesive Film for Vaginal Delivery: Design, Optimization, and Physicodynamic Characterization

The purpose of this work was to design and optimize a novel vaginal drug delivery system for more effective treatment against vaginal candidiasis. Itraconazole was formulated in bioadhesive film formulations that could be retained in the vagina for prolonged intervals. The polymeric films were prepared by solvent evaporation and optimized for various physicodynamic and aesthetic properties. In addition, percentage drug retained on vaginal mucosa was evaluated using a simulated dynamic vaginal system as function of time. A polymeric film containing 100 mg itraconazole per unit (2.5 cm x 2.5 cm) have been developed using generally regarded as safe listed excipients. The pH of vaginal film was found to be slightly acidic (4.90 +/- 0.04) in simulated vaginal fluid and alkaline (7.04 +/- 0.07) in water. The little moisture content (7.66 +/- 0.51% w/w) was present in the film, which helps them to remain stable and kept them from being completely dry and brittle. The mechanical properties, tensile strength, and percentage elongation at break (9.64 N/mm(2) and 67.56% for ITRF(65)) reveal that the formulations were found to be soft and tough. The films (ITRF(65)) contained solid dispersion of itraconazole (2.5)/hydroxypropyl cellulose (1)/polyethylene glycol 400 (0.5), which was found to be the optimal composition for a novel bioadhesive vaginal formulation, as they showed good peelability, relatively good swelling index, and moderate tensile strength and retained vaginal mucosa up to 8 h. Also, the film did not markedly affect normal vaginal flora (lactobacillus) and was noncytotoxic as indicated by the negligible decrease in cell viability.

A Novel Intravaginal Delivery System for Itraconazole: In Vitro and In Vivo Evaluation

The purpose of the present study was to formulate and systematically evaluate in vitro, ex vivo and in vivo performances of itraconazole containing bioadhesive vaginal film. We introduce here a novel intravaginal delivery system for itraconazole based on solid dispersion of itraconazole and hydroxypropyl methylcellulose E15 that improve drug solubility and produce bioadhesive system in presence of other ingredients. Solid dispersions of itraconazole were prepared with hydroxypropyl methylcellulose by a spray drying method and characterized by X-ray diffraction and differential scanning calorimetry. The film was prepared using a solvent evaporation technique. In the in vitro antimicrobial study, it was found that solid dispersion containing formulation improves antimicrobial action of itraconazole. From the ex vivo retention study, it was found that the bioadhesive polymers hold the film upto 7 hours on the vaginal mucosa. In vivo antifungal activity tested against Candida albicans vaginitis in female rats, was found to significantly improve the therapeutic benefit of the drug. At 6 days post-dose, the c.f.u. of Candida albicans was more than 10(3) fold decreased in film treated groups without affecting the morphology of vaginal mucosa. These studies suggested that bioadhesive vaginal film is a novel approach for delivery of itraconazole as topical drug delivery system for treating vaginal candidiasis.

Synergistic Enhancement of Itraconazole Dissolution by Ternary System Formation with Pluronic F68 and Hydroxypropylmethylcellulose

Pluronic F68 is a surfactant which can inhibit CYP3A4, an enzyme responsible for hepatic metabolism of many drugs including itraconazole. This study investigated the effect of incorporation of Pluronic F68 as a ternary component in solid dispersions of itraconazole with hydroxypropyl-methylcellulose (HPMC) on the dissolution rate of itraconazole. Binary solid dispersions with HPMC, reduced the drug crystallinity, increased the equilibrium solubility but showed slow dissolution. Binary dispersions with Pluronic produced eutectic systems but the increase in solubility and dissolution was lower than that of HPMC systems. Ternary system comprising optimum proportions of drug with Pluronic and HPMC enhanced the dissolution rate showing dissolution efficiency comparable to that obtained with the marketed product of itraconazole. The study thus presented a system capable of increasing the dissolution rate of itraconazole with a potential for increased oral bioavailability by inhibiting its pre-systemic metabolism as well.

Development of trilayered mucoadhesive tablet of itraconazole with zero-order release

Itraconazole is practically insoluble in water; large interindividual and intraindividual variations of its oral bioavailability are reported. A mucoadhesive drug delivery system is useful to prolong the retention time of a dosage form in the stomach,thereby improving the oral bioavailability of the drug. Solid dispersion of itraconazole with Eudragit E100 was prepared by spray-drying method to improve dissolution. Trilayered mucoadhesive tablet was prepared, with inner core containing solid dispersion of the drug and with carbopol and HPMC sandwiched between two layers of hydrophilic mucoadhesive polymer mixture of carbopol and Hydroxypropyl methyl cellulose (HPMC). Amounts of Carbopol 934P (CP) and Methocel K4M (HPMC) were varied in the outer coat around the solid dispersion. The drug-release pattern for all the formulation combinations was found to be nonfickian, approaching zero-order kinetics. Suitable combination of two polymers provided adequate bioadhesive strength and sustained-release profile with zero-order kinetics.

Development and optimization of solid dispersion containing pellets of itraconazole prepared by high shear pelletization

This study investigated the solid dispersion containing pellets of itraconazole for enhanced drug dissolution rate. The influence of process parameters used during high shear pelletization on the pellet properties including pellet size and dissolution rate was also studied. Solid dispersions of itraconazole were prepared with Eudragit ® E100, a hydrophilic polymer, by a simple fusion method followed by powdered and characterized by differential scanning calorimetry and X-ray powder diffraction. Solid dispersions containing pellets were consequently prepared using a lab-scale high shear mixer. In order to improve the product quality, a central composite design was applied to optimize the critical process variables, such as impeller speed and kneading time, and the results were modeled statistically. Itraconazole was presented as an amorphous state in the solid dispersion prepared at a drug to polymer ratio of 1:2. Both studied parameters had great effect on the responses. Powdered solid dispersion and pellets prepared using the optimal parameter settings showed approximately 30- and 70-fold increases in dissolution rate over the pure drug, respectively. Solid dispersion prepared by simple fusion method could be an option for itraconazole solubility enhancement. Pelletization process in high shear mixer can be optimized effectively by central composite design.

Solid dispersions of itraconazole and enteric polymers made by ultra-rapid freezing

The primary objective of the study is to investigate the influence of composition parameters including drug:polymer ratio and polymer type, and particle structure of enteric solid dispersions on the release of ITZ under sink and supersaturated dissolution conditions. Modulated differential scanning calorimetry (MDSC) was utilized to define the level of ITZ miscibility with each polymer. The compositions were completely miscible at 60% ITZ for both polymers and as high as 70% in HP-55. High potency composition glass transition temperatures ( T g) correlated with predicted T g's from the Gordon–Taylor equation, however, recrystallization exotherms revealed pure amorphous regions indicating that phase separation occurred during particle formation. Furthermore, in vitro studies including X-ray powder diffraction (XRD), scanning electron microscopy (SEM), surface area analysis (BET), and dissolution were performed to determine differences between low potency (completely miscible) and high potency (partially miscible) compositions. Dissolution studies on low potency ITZ compositions revealed that miscibility plays an active role in ITZ release under sink conditions, and square root diffusion through the enteric polymer is observed. Supersaturated dissolution profiles revealed high potency compositions had maximum saturation levels ( C/ C e q max ) between 10.6- and 8-times equilibrium solubility, but had higher cumulative extents of supersaturation, compared to low potency compositions which had C/ C e q max values of 15–19.6. However, these low potency compositions rapidly precipitated leading to significantly lower AUCs ( p < 0.05). The change in the miscibility of the solid dispersion had a pronounced effect of drug release (sink) while differences in potency influenced supersaturated dissolution profiles.

Thermal Properties of Hot-Stage Extrudates of Itraconazole and Eudragit E100: Phase separation and polymorphism

Solid dispersions of itraconazole and eudragit E100 were prepared by hot-stage extrusion. Analysis of the physical structure revealed the existence of different phases, depending on the manufacturing condition. Extrudates prepared at 453 K existed as a molecular dispersion of itraconazole in eudragit E100 when the drug concentration did not exceed ca. 13% mass/mass. At higher concentrations, a second phase consisting of pure glassy itraconazole emerged. In other dispersions prepared at 413 K, the second phase consisted of pure crystalline itraconazole. The difference can be attributed to the relation of the process-temperature to the melting point. Heating of both dispersions induced cold crystallization. Extrudates prepared at 453 K showed comparable behavior before and after milling, with the exception that unmilled dispersions with a drug load of ≥60% mass/mass recrystallized upon heating into a polymorphic modification of itraconazole (Tm=431 K). Upon further heating the polymorph recrystallized to the stable crystalline form (Tm=441 K).

Investigation of Dissolution Enhancement of Itraconazole by Solid Dispersion in Superdisintegrants

Solid dispersions of itraconazole (ITR) in lactose, microcrystalline cellulose (MCC), and three superdisintegrants (Primogel, Kollidon CL, and Ac-Di-Sol) and their formulation into tablets were investigated with an objective of enhancing the dissolution rate of ITR from tablet formulations. X-ray diffraction (XRD) and differential scanning calorimetry (DSC) were used to characterize the dispersions. A marked enhancement in the dissolution rate of ITR was observed with all the excipients. The order for the excipients to enhance the dissolution rate was Ac-Di-Sol > Kollidon CL > Primogel > MCC > lactose. Solid dispersions in superdisintegrants gave much higher rates of dissolution than the dispersions in other excipients. Ac-Di-Sol gave the most improvement (28-fold) in the dissolution rate of ITR at a 1:1 drug: excipient ratio. Solid dispersions in superdisintegrants could be formulated into tablets. These tablets, apart from fulfilling all official and other specifications, exhibited higher rates of dissolution and dissolution efficiency (DE) values. XRD indicated the presence of ITR in amorphous form in the dispersions. DSC indicated a weak interaction between ITR and the excipients. Micronization and conversion of the drug into the amorphous form and the fast disintegrating and dispersing action of the superdisintegrants contribute to the enhancement of the dissolution rate of ITR from its solid dispersions in superdisintegrants and their corresponding tablet formulations.

Bioavailability of Itraconazole in Rats and Rabbits After Administration of Tablets Containing Solid Dispersion Particles

A tablet dosage form containing solid dispersions of itraconazole (Asd tablets) was prepared by using the spray-drying and wet granulation methods. The dissolution rate of itraconazole from Asd tablets was fast, with more than 90% released within 10 min, compared to less than 20% for a marketed product, Sporanox® capsules. The oral absorption of itraconazole from Asd tablets was determined in rats and rabbits and was compared with that for Sporanox capsules. In the rat, there was no difference between the Asd tablets and Sporanox capsules in the mean area under the curve (AUC) (3089.5 ± 4332.8 ng · hr/ml and 3653.9 ± 2348.9 ng · hr/ml, respectively) and Cmax (295.0 ± 344.5 and 390.5 ± 169.4 ng/ml, respectively). Also, in the rabbit, no difference was found between the two products in the mean AUC (AUMC; 19357.9 ± 5117.5 ng · hr/ml and 23382.2 ± 6236.5 ng · hr/ml, respectively) and Cmax (766.4 ± 276.5 and 1127.5 ± 577.9 ng/ml, respectively). Despite the rapid in vitro release characteristics of itraconazole from the Asd tablets, the in vivo absorption of itraconazole was comparable to that of Sporanox capsules, with no difference in Tmax in both animal species. Serum levels of the major active metabolite hydroxyitraconazole were also measured. Itraconazole was rapidly converted to hydroxyitraconazole in both rats and rabbits, but there were species-specific differences in their pharmacokinetics. It is concluded that, in addition to drug solubility and dissolution characteristics, other formulation factors such as the physical state of the drug and the granulation process, may also need to be considered in the prediction of the in vivo absorption of itraconazole based on in vitro data.