RESUMEN
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.
Asunto(s)
Itraconazol , Nanopartículas , Solubilidad , Suspensiones , Agua , Nanopartículas/química , Itraconazol/química , Itraconazol/administración & dosificación , Agua/química , Composición de Medicamentos/métodos , Albúminas/química , Estabilidad de Medicamentos , Tecnología Farmacéutica/métodos , Tamaño de la Partícula , Química Farmacéutica/métodosRESUMEN
Commercial topical formulations containing itraconazole (poorly water soluble), for mycotic infections, have poor penetration to infection sites beneath the nails and skin thereby necessitating oral administration. To improve penetration, colloidal solutions of itraconazole (G1-G4) containing Poloxamer 188, tween 80, ethanol, and propylene glycol were prepared and incorporated into HFA-134-containing sprays. Formulations were characterized using particle size, drug content, and Fourier-transform infrared spectroscopy (FTIR). In vitro permeation studies were performed using Franz diffusion cells for 8 h. Antimycotic activity on Candida albicans and Trichophyton rubrum was performed using broth micro-dilution and flow cytometry, while cytotoxicity was tested on HaCaT cell lines. Particle size ranged from 39.35-116.80 nm. FTIR and drug content revealed that G1 was the most stable formulation (optimized formulation). In vitro release over 2 h was 45% for G1 and 34% for the cream. There was a twofold increase in skin permeation, fivefold intradermal retention, and a sevenfold increase in nail penetration of G1 over the cream. Minimum fungicidal concentrations (MFC) against C. albicans were 0.156 and 0.313 µg/mL for G1 and cream, respectively. The formulations showed optimum killing kinetics after 48 h. MFC values against T. rubrum were 0.312 and 0.625 µg/mL for the G1 and cream, respectively. Transmission electron microscopy revealed organelle destruction and cell leakage for G1 in both organisms and penetration of keratin layers to destroy T. rubrum. Cytotoxicity evaluation of G1 showed relative safety for skin cells. The G1 formulation showed superior skin permeation, nail penetration, and fungicidal activity compared with the cream formulation.
Asunto(s)
Antifúngicos , Candida albicans , Coloides , Itraconazol , Antifúngicos/farmacología , Antifúngicos/administración & dosificación , Candida albicans/efectos de los fármacos , Itraconazol/farmacología , Itraconazol/administración & dosificación , Itraconazol/química , Humanos , Animales , Trichophyton/efectos de los fármacos , Pruebas de Sensibilidad Microbiana/métodos , Química Farmacéutica/métodos , Tamaño de la Partícula , Piel/metabolismo , Piel/efectos de los fármacos , Piel/microbiología , Absorción Cutánea/efectos de los fármacos , Línea Celular , Células HaCaT , Uñas/efectos de los fármacos , Uñas/microbiología , Uñas/metabolismo , ArthrodermataceaeRESUMEN
This study presents a novel approach by utilizing poly(vinylpyrrolidone)s (PVPs) with various topologies as potential matrices for the liquid crystalline (LC) active pharmaceutical ingredient itraconazole (ITZ). We examined amorphous solid dispersions (ASDs) composed of ITZ and (i) self-synthesized linear PVP, (ii) self-synthesized star-shaped PVP, and (iii) commercial linear PVP K30. Differential scanning calorimetry, X-ray diffraction, and broad-band dielectric spectroscopy were employed to get a comprehensive insight into the thermal and structural properties, as well as global and local molecular dynamics of ITZ-PVP systems. The primary objective was to assess the influence of PVPs' topology and the composition of ASD on the LC ordering, changes in the temperature of transitions between mesophases, the rate of their restoration, and finally the solubility of ITZ in the prepared ASDs. Our research clearly showed that regardless of the PVP type, both LC transitions, from smectic (Sm) to nematic (N) and from N to isotropic (I) phases, are effectively suppressed. Moreover, a significant difference in the miscibility of different PVPs with the investigated API was found. This phenomenon also affected the solubility of API, which was the greatest, up to 100 µg/mL in the case of starPVP 85:15 w/w mixture in comparison to neat crystalline API (5 µg/mL). Obtained data emphasize the crucial role of the polymer's topology in designing new pharmaceutical formulations.
Asunto(s)
Rastreo Diferencial de Calorimetría , Itraconazol , Cristales Líquidos , Povidona , Solubilidad , Difracción de Rayos X , Itraconazol/química , Cristales Líquidos/química , Povidona/química , Rastreo Diferencial de Calorimetría/métodos , Difracción de Rayos X/métodos , Polímeros/química , Antifúngicos/química , Composición de Medicamentos/métodos , Cristalización , Química Farmacéutica/métodosRESUMEN
OBJECTIVES: 1) Identify processes limiting the arrival of itraconazole at the intestinal epithelium when Sporanox® amorphous solid dispersion (ASD) pellets are transferred from the stomach through the upper small intestine, after a high-calorie, high-fat meal. 2) Evaluate whether itraconazole concentrations in the colloidal phase of aqueous contents of the upper small intestine are useful for the assessment of dose effects in the fed state and food effects on plasma levels. METHODS: Itraconazole concentrations, apparent viscosity, and solubilization capacity were measured in aspirates from the upper gastrointestinal lumen collected during a recently performed clinical study in healthy adults. Published itraconazole concentrations in plasma, after a high-calorie high-fat meal and Sporanox® ASD pellets, and in contents of the upper small intestine of healthy adults, after administration of Sporanox® ASD pellets in the fasted state, were used to achieve the second objective. RESULTS: When Sporanox® ASD pellets (up to 200 mg) are transferred from the stomach through the upper small intestine, after a high-calorie, high-fat meal, itraconazole concentrations in the colloidal phase or the micellar phase of aqueous contents of the upper small intestine are unsaturated, in most cases. During the first 3 h post-dosing after a high-calorie, high-fat meal, the impact of dose (200 mg vs. 100 mg) on itraconazole concentrations in the colloidal phase of aqueous contents of the upper small intestine seems to underestimate the impact of dose on plasma levels. When Sporanox® ASD pellets are administered after a high-calorie, high-fat meal at the 200 mg dose level, itraconazole concentrations in the colloidal phase of aqueous contents of the upper small intestine are, on average, lower than those achieved in fasted state. CONCLUSIONS: When Sporanox® ASD pellets are transferred from the stomach to the upper small intestine after a high-calorie, high-fat meal, itraconazole's arrival at the intestinal epithelium seems to be limited by its arrival at the colloidal phase of aqueous contents of the upper small intestine. The impact of dose (100 mg vs. 200 mg) on plasma levels after a high-calorie, high-fat meal and during the gastrointestinal transfer of Sporanox® pellets requires consideration of pre-systemic itraconazole metabolism. At the 200 mg dose level, after taking into consideration differences in the volume of the contents of the upper small intestine between the fasted and the fed state during the gastrointestinal transfer of Sporanox® ASD pellets, itraconazole concentrations in the colloidal phase of aqueous contents of the upper small intestine suggest a mild negative food effect on average plasma levels; published clinical data are inconclusive.
Asunto(s)
Itraconazol , Itraconazol/farmacocinética , Itraconazol/administración & dosificación , Itraconazol/sangre , Itraconazol/química , Administración Oral , Humanos , Adulto , Antifúngicos/farmacocinética , Antifúngicos/administración & dosificación , Antifúngicos/sangre , Masculino , Absorción Intestinal , Solubilidad , Interacciones Alimento-Droga , Dieta Alta en Grasa , Intestino Delgado/metabolismo , Viscosidad , Femenino , Adulto JovenRESUMEN
It is desirable to predict positive food effect of oral formulations due to food mediated dissolution enhancement of lipophilic drugs. The objective was to assess the ability of in vitro lipolysis to anticipate a positive food effect. Tested formulations included rivaroxaban and itraconazole, where some formulations, but not all, exhibit a positive food effect in vivo in humans. Amorphous solid dispersion formulations of ritonavir, which exhibit a negative food effect in vivo in humans, were also studied. Fe-lipolysis and Fa-lipolysis media representing fed and fasted intestinal conditions were used. Results show frequent agreement between in vitro lipolysis predictions and in vivo human outcomes. For rivaroxaban, food effect of unformulated active pharmaceutical ingredient (API) and products were correctly predicted where 2.5 mg and 10 mg strengths did not show any food effect; however, 20 mg did show a positive food effect. For itraconazole, all four products were correctly predicted, with Sporanox, Sempera, and generic capsules having a food effect, but Tolsura not having a positive food effect. For ritonavir, lipolysis predicted a positive food effect for API and Norvir tablet and powder, but Norvir products have negative food effect in vivo in humans. Overall, the lipolysis model showed favorable predictability and merits additional evaluation.
Asunto(s)
Interacciones Alimento-Droga , Itraconazol , Lipólisis , Ritonavir , Rivaroxabán , Solubilidad , Itraconazol/química , Lipólisis/efectos de los fármacos , Ritonavir/química , Humanos , Rivaroxabán/química , Rivaroxabán/administración & dosificación , Agua/química , Administración Oral , Modelos Biológicos , ComprimidosRESUMEN
A series of new metal complexes, [Cu(ITZ)2Cl2] â 5H2O (1), [Cu(NO3)2(ITZ)2] â 3H2O â C4H10O (2) and [Cu(ITZ)2)(PPh3)2]NO3 â 5H2O (3) were synthesized by a reaction of itraconazole (ITZ) with the respective copper salts under reflux. The metal complexes were characterized by elemental analyses, molar conductivity, 1H and 13C{1H} nuclear magnetic resonance, UV-Vis, infrared and EPR spectroscopies. The antifungal activity of these metal complexes was evaluated against the main sporotrichosis agents: Sporothrix brasiliensis, Sporothrix schenkii, and Sporothrix globosa. All three new compounds inhibited the growth of S. brasiliensis and S. schenckii at lower concentrations than the free azole, with complex 2 able to kill all species at 4â µM and induce more pronounced alterations in fungal cells. Complexes 2 and 3 exhibited higher selectivity and no mutagenic effect at the concentration that inhibited fungal growth and affected fungal cells. The strategy of coordinating itraconazole (ITZ) to copper was successful, since the corresponding metal complexes were more effective than the parent drug. Particularly, the promising antifungal activity of the Cu-ITZ complexes makes them potential candidates for the development of an alternative drug to treat mycoses.
Asunto(s)
Antifúngicos , Complejos de Coordinación , Cobre , Itraconazol , Pruebas de Sensibilidad Microbiana , Sporothrix , Cobre/química , Cobre/farmacología , Itraconazol/farmacología , Itraconazol/química , Sporothrix/efectos de los fármacos , Antifúngicos/farmacología , Antifúngicos/química , Antifúngicos/síntesis química , Complejos de Coordinación/farmacología , Complejos de Coordinación/química , Complejos de Coordinación/síntesis química , Relación Estructura-Actividad , Estructura Molecular , Relación Dosis-Respuesta a DrogaRESUMEN
The aim of this study was to develop cholic-acid-stabilized itraconazole nanosuspensions (ITZ-Nanos) with the objective of enhancing drug dissolution and oral absorption. A laboratory-scale microprecipitation-high-pressure homogenization method was employed for the preparation of the ITZ-Nanos, while dynamic light scattering, transmission electron microscope analysis, X-ray diffraction, differential scanning calorimetry, and high-performance liquid chromatography analysis were utilized to evaluate their physicochemical properties. The absorption and bioavailability of the ITZ-Nanos were assessed using Caco-2 cells and rats, with Sporanox® pellets as a comparison. Prior to lyophilization, the particle size of the ITZ-Nanos measured approximately 225.7 nm. Both X-ray diffraction and differential scanning calorimetry confirmed that the ITZ remained crystalline within the nanocrystals. Compared to the pellets, the ITZ-Nanos exhibited significantly higher levels of supersaturation dissolution and demonstrated enhanced drug uptake by the Caco-2 cells. The AUC(0-t) value for the ITZ-Nanos in rats was 1.33-fold higher than that observed for the pellets. These findings suggest that cholic acid holds promise as a stabilizer for ITZ nanocrystals, as well as potentially other nanocrystals.
Asunto(s)
Itraconazol , Nanopartículas , Solubilidad , Tensoactivos , Itraconazol/química , Itraconazol/farmacocinética , Itraconazol/administración & dosificación , Nanopartículas/química , Humanos , Células CACO-2 , Animales , Ratas , Administración Oral , Tensoactivos/química , Masculino , Disponibilidad Biológica , Tamaño de la Partícula , Difracción de Rayos X , Rastreo Diferencial de Calorimetría , Ácido Cólico/químicaRESUMEN
Chitosan has received much more attention as a functional biopolymer with applications in pharmaceuticals, agricultural, drug delivery systems and cosmetics. The objectives of present investigation were to carry out modification of chitosan for enhancement of aqueous solubility, which will impart increased solubility and dissolution rate of poorly soluble drug itraconazole (ITZ) and also evaluate the modified chitosan for soyabean seed germination studies. The modification of chitosan was accomplished through the antisolvent precipitation method; employing five carboxylic acids. The resulting products were assessed for changes in molecular weight, degree of deacetylation, solubility and solid state characterization. Subsequently, the modified chitosan was complexed with itraconazole using the co-grinding technique. The prepared formulations were evaluated for solubility, FTIR (Fourier-transform infrared spectroscopy), PXRD (Powder X-ray diffraction), in-vitro dissolution studies. Furthermore the effect of modified chitosan has been evaluated on soybean seed germination. Results demonstrated that, modified chitosan improves self and solubility of itraconazole by six folds. As there was increased degree of deacetylation of chitosan leads to improvement in solubility. The results of FTIR showed the slight shifting of peaks in co-grind formulations of itraconazole. Formulations showed reduction in crystallinity of drug which leads to enhancement in dissolution rate as compared to pure itraconazole. Retention of property of seed germination was observed with modified chitosan at optimum concentration of 3 % w/v, with benefit of enhanced aqueous solubility of chitosan. This positive result paves the way for the advancement of pharmaceutical and agrochemical products employing derivatives of chitosan.
Asunto(s)
Agroquímicos , Quitosano , Itraconazol , Solubilidad , Quitosano/química , Agroquímicos/química , Agroquímicos/farmacología , Itraconazol/química , Itraconazol/farmacología , Glycine max/química , Germinación/efectos de los fármacos , Semillas/química , Semillas/efectos de los fármacos , Fenómenos Químicos , Espectroscopía Infrarroja por Transformada de Fourier , Peso Molecular , Difracción de Rayos XRESUMEN
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.
Asunto(s)
Itraconazol , Agua , Itraconazol/química , Solventes/química , Propiedades de Superficie , Tecnología , Suspensiones , Solubilidad , Tamaño de la PartículaRESUMEN
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.
Asunto(s)
Itraconazol , Polímeros , Polímeros/química , Solubilidad , Liberación de Fármacos , Itraconazol/química , Povidona/química , Composición de Medicamentos/métodosRESUMEN
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.
Asunto(s)
Química Farmacéutica , Itraconazol , Cristalización , Química Farmacéutica/métodos , Itraconazol/química , Solventes/química , Solubilidad , Vitamina E , Tamaño de la Partícula , SuspensionesRESUMEN
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.
Asunto(s)
COVID-19 , Itraconazol , Humanos , Itraconazol/farmacología , Itraconazol/química , Itraconazol/metabolismo , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Lopinavir , Darunavir , Tratamiento Farmacológico de COVID-19 , Cromatografía Liquida , Espectrometría de Masas en Tándem , Interacciones Farmacológicas , Variación GenéticaRESUMEN
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.
Asunto(s)
Micosis , Nanopartículas , Zeína , Humanos , Itraconazol/química , Antifúngicos/química , Espectroscopía Infrarroja por Transformada de Fourier , Nanopartículas/química , Colon , Tamaño de la PartículaRESUMEN
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.
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Excipientes , Itraconazol , Solubilidad , Liberación de Fármacos , Cristalización , Itraconazol/química , SolventesRESUMEN
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.
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Itraconazol , Itraconazol/químicaRESUMEN
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.
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Ciclodextrinas , Itraconazol , Itraconazol/química , Ciclodextrinas/química , Solubilidad , 2-Hidroxipropil-beta-Ciclodextrina/química , Ácidos y Sales Biliares , BiomiméticaRESUMEN
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.
Asunto(s)
Antifúngicos , Itraconazol , Itraconazol/farmacología , Itraconazol/química , Antifúngicos/farmacología , Antifúngicos/química , Aceite de Clavo/metabolismo , Aceite de Clavo/farmacología , Piel/metabolismo , Tensoactivos/química , Agua/química , Emulsiones/químicaRESUMEN
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.
Asunto(s)
Itraconazol , Povidona , Composición de Medicamentos/métodos , Liberación de Fármacos , Itraconazol/química , Polímeros/química , Povidona/química , Impresión Tridimensional , SolubilidadRESUMEN
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.
Asunto(s)
Itraconazol , Nanopartículas , Composición de Medicamentos/métodos , Itraconazol/química , Lactosa , Nanopartículas/química , Tamaño de la Partícula , Solubilidad , SuspensionesRESUMEN
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.