Enhanced Bioavailability of Itraconazole in Hydroxypropylβ-Cyclodextrin Solution versus Capsules in Healthy Volunteers

Barone, Joseph A.; Moskovitz, Bruce L.; Guarnieri, Joseph A.; Hassell, Alan E.; Colaizzi, John L.; Bierman, Robert; Jessen, Lois

doi:10.1128/aac.42.7.1862

Cited by 197 publications

(100 citation statements)

References 30 publications

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“…Because it has relatively low bioavailability after oral administration, especially when given in capsule form (Barone et al 1998;Heykant et al 1989), gastric acidity is required for drug dissolution and adequate absorption with capsule formulations. Decreased absorption has been observed in the fasting state and in patients with low gastric acidity (Barone et al 1993).…”

Section: Introductionmentioning

confidence: 98%

Development of self emulsifying drug delivery system of itraconazole for oral delivery: formulation and pharmacokinetic consideration

Chudasama

Shah

Patel

et al. 2015

Journal of Pharmaceutical Investigation

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Poorly water-soluble drug, itraconazole (ITZ) offers a challenge in developing a drug product with adequate bioavailability. The potential for lipidic self-emulsifying drug delivery system to improve the oral bioavailability of ITZ was investigated in fasted rats. A series of ITZ SEDDS were prepared in three groups based on oil:S/CoS mixture ratios (1:9, 1:6 and 1:4) using Capryol 90 (oil), a mixture of Labrasol and Tween 20 (-surfactants) and Transcutol P (co-surfactant). The multicomponent delivery systems were optimized by evaluating their ability to self-emulsify when introduced in simulated gastric fluid, without pepsin, under gentle agitation and by determination of droplet size and visual observation. Three formulations (F5, F21 and F27), one from each group were selected based on droplet size and visual observation. The effect of oil and surfactants content on mean globule size of resulting emulsions was studied. It was clear that oil to surfactant and co-surfactant ratio has the main impact on the droplet size of the emulsion formed after dilution. However, the relation between droplet size and in vivo absorption of ITZ was futile. The order of AUC was 1:4 [ 1:6 [ 1.9 for oil:S/CoS mixture ratios. Following an oral administration of developed SEDDS and marketed capsule to rats, a 1.7, 2.0 and 2.33-fold increase in bioavailability was observed for F5, F21 and F27 respectively, compared with marketed capsule. The results from this study demonstrate the potential use of SEDDS to provide an effective way of improving oral absorption of lipophilic drugs.

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Section: Introductionmentioning

confidence: 98%

Development of self emulsifying drug delivery system of itraconazole for oral delivery: formulation and pharmacokinetic consideration

Chudasama

Shah

Patel

et al. 2015

Journal of Pharmaceutical Investigation

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show abstract

“…In addition, the drug has limited or no activity against Fusarium species, Zygomycetes, and some Scedosporium species (i.e., S. prolificans, S. apiospermum) [72,131,132]. Other limitations include a high risk for drug interactions and the erratic pharmacokinetic profile of the capsule formulation [133,134].…”

Section: Itraconazolementioning

confidence: 97%

Aspergillus to Zygomycetes: Causes, Risk Factors, Prevention, and Treatment of Invasive Fungal Infections

Cornely

2008

Infection

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Invasive fungal infections (IFIs) are an important cause of morbidity and mortality, particularly in patients with underlying risk factors (e.g., neutropenia, cancer chemotherapy, transplantation, AIDS). Although Candida species remain a relevant cause of IFI, other organisms (particularly moulds) have become increasingly prevalent. In particular, Aspergillus species are the leading cause of mould infections although other moulds including Fusarium species and Zygomycetes are increasing in frequency, and are associated with a high mortality rate. Options available for the prevention and treatment of these infections include standard and liposomal formulations of amphotericin B, but toxicity concerns limit their use; fluconazole is effective for the prevention and treatment of candidiasis but its inactivity against moulds and increasing resistance are limiting factors. Newer azoles, particularly voriconazole and posaconazole, have an enhanced spectrum of activity that includes Candida species, Aspergillus species, Cryptococcus species, dimorphic fungi, Fusarium species, and, for posaconazole, Zygomycetes. Recent data suggest that these agents are highly effective in a variety of clinical settings. Echinocandins have good activity against Candida species and Aspergillus species but their spectrum generally does not include Fusarium species, Cryptococcus species, Trichosporon species, Zygomycetes, and dematiaceous moulds. While these agents are unlikely to exhibit crossresistance with polyenes or azoles, they must be administered intravenously. Knowledge of the pathogenesis of IFIs and the activity, efficacy, and limitations of available treatment options will allow the selection of an appropriate antifungal agent for individual patients.

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“…The increased solubility of cyclodextrin inclusion complexes of a drug can increase its dissolution rate, so that increased oral bioavailability is achieved for agents that are otherwise non-absorbable [15]. For example, the bioavailability of itraconazole and its metabolite hydroxyl-itraconazole could be enhanced by 30-37% following oral administration of cyclodextrin inclusion complexes compared with the conventional capsule [16]. Thus, natamycin could hypothetically be absorbed from the gastrointestinal tract following oral administration of a soluble natamycin-cyclodextrin inclusion complex; absorbed natamycin could hypothetically expose organ systems relevant for toxicological examinations to higher drug concentrations than studied previously.…”

Section: Dietary Exposure To Natamycin Following Consumption Of Natammentioning

confidence: 97%

Does use of the polyene natamycin as a food preservative jeopardise the clinical efficacy of amphotericin B? A word of concern

Dalhoff¹,

Levy

2015

International Journal of Antimicrobial Agents

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Natamycin is a poorly soluble, polyene macrolide antifungal agent used in the food industry for the surface treatment of cheese and sausages. This use is not of safety concern. However, highly soluble natamycin-cyclodextrin inclusion complexes have been developed for the protection of beverages. This practice leads to high drug exposures exceeding the safety level. Apart from the definition of an acceptable daily dietary exposure to natamycin, its effect on the faecal flora as a reservoir for resistance has to be examined. Consumption of food to which natamycin has been added and mixed homogeneously, such as yoghurt, and in particular the addition of cyclodextrin inclusion complexes to beverages and wine generates high faecal natamycin concentrations resulting in high drug exposures of faecal Candida spp. Development of natamycin resistance has been observed in Candida spp. colonising the intestinal tract of patients following natamycin treatment of fungal infections. Horizontal gene transfer among different Candida spp. and within Aspergillus fumigatus spreads resistance. Therefore, it cannot be denied that use of natamycin for preservation of yoghurt and beverages may foster development of resistance to polyenes in Candida spp.

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Enhanced Bioavailability of Itraconazole in Hydroxypropylβ-Cyclodextrin Solution versus Capsules in Healthy Volunteers

Cited by 197 publications

References 30 publications

Development of self emulsifying drug delivery system of itraconazole for oral delivery: formulation and pharmacokinetic consideration

Development of self emulsifying drug delivery system of itraconazole for oral delivery: formulation and pharmacokinetic consideration

Aspergillus to Zygomycetes: Causes, Risk Factors, Prevention, and Treatment of Invasive Fungal Infections

Does use of the polyene natamycin as a food preservative jeopardise the clinical efficacy of amphotericin B? A word of concern

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