Dry powder insufflation of crystalline and amorphous voriconazole formulations produced by thin film freezing to mice

Beinborn, Nicole A.; Du, Ju; Wiederhold, Nathan P.; Williams, Robert O.

doi:10.1016/j.ejpb.2012.04.019

Cited by 58 publications

(33 citation statements)

References 35 publications

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“…Each reconstituted formulation freshly prepared (raw material, recrystallized MBZ and RDM 1:1; 1:2.5, and 1:5) was administered at a dose of 5 mg/kg. Following the procedures described by Torrado et al18 and Beinborn et al19 after drug administration, six mice per formulation were euthanized by 15% urethane solution at each of the predetermined time points (0.25, 0.5, 0.75, 1.5, 3, 6, and 24 hours). Whole blood (approximately 1.5 mL) was collected by cardiac puncture into heparinized vials and centrifuged at 9,000 rpm for 15 minutes to obtain plasma.…”

Section: Methodsmentioning

confidence: 99%

Enhanced bioavailability and anthelmintic efficacy of mebendazole in redispersible microparticles with low-substituted hydroxypropylcellulose

Torre-Iglesias¹,

García-Rodríguez²,

Pena-Fernandez³

et al. 2014

DDDT

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BackgroundMebendazole (MBZ) is an extremely insoluble and therefore poorly absorbed drug and the variable clinical results may correlate with blood concentrations. The necessity of a prolonged high dose treatment of this drug increases the risk of adverse effects.MethodsIn the present study we prepared redispersible microparticles (RDM) containing MBZ, an oral, poorly water-soluble drug, in different proportions of low-substituted hydroxypropylcellulose (L-HPC). We investigated the microparticulate structures that emerge spontaneously upon dispersion of an RDM in aqueous medium and elucidated their influence on dissolution, and also on their oral bioavailability and therapeutic efficiency using a murine model of infection with the nematode parasite Trichinella spiralis.ResultsElevated percentages of dissolved drug were obtained with RDM at 1:2.5 and 1:5 ratios of MBZ: L-HPC. Thermal analysis showed an amorphization of MBZ in the RDM by the absence of a clear MBZ melting peak in formulations. The rapid dissolution behavior could be due to the decreased drug crystallinity, the fast dissolution time of carriers as L-HPC, together with its superior dispersibility and excellent wetting properties. RDM-1:2.5 and RDM-1:5 resulted in increased maximum plasma concentration and area(s) under the curve (AUC)0-∞ values. Likewise, after oral administration of the RDM-1:2.5 and RDM-1:5 the AUC0-∞ were 2.67- and 2.97-fold higher, respectively, compared to those of pure MBZ. Therapeutic activity, assessed on the Trichinella spiralis life cycle, showed that RDM-1:5 was the most effective in reducing the number of parasites (4.56-fold) as compared to pure MBZ, on the encysted stage.ConclusionThe MBZ: L-HPC RDM might be an effective way of improving oral bioavailability and therapeutic activity using low doses of MBZ (5 mg/kg), which implies a low degree of toxicity for humans.

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Section: Methodsmentioning

confidence: 99%

Enhanced bioavailability and anthelmintic efficacy of mebendazole in redispersible microparticles with low-substituted hydroxypropylcellulose

Torre-Iglesias¹,

García-Rodríguez²,

Pena-Fernandez³

et al. 2014

DDDT

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“…Additional formulations are currently being investigated worldwide, including a sustained release tablet for IFI [41], liposomal [42] and nanostructured lipid [43] formulations intended for ocular delivery , and an inhaled dry powder formulation of voriconazole that would allow more direct treatment of invasive pulmonary aspergillosis although no human safety or efficacy data is available at this time [44][45][46].…”

Section: Voriconazole Formulationsmentioning

confidence: 98%

Pharmacodynamic studies of voriconazole: informing the clinical management of invasive fungal infections

Job

Olson

Constance

et al. 2016

Expert Review of Anti-infective Therapy

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The objective of this review is to summarize the pharmacodynamic properties of voriconazole and to provide considerations for potential optimal dosing strategies. Studies have demonstrated superior clinical response when an AUC/MIC >25 or Cmin/MIC >1 is attained in adult patients, correlating to a trough concentration range as narrow as 2-4.5 mg/L; however, these targets are poorly established in the pediatric population. Topics in this discussion include voriconazole use in multiple age groups, predisposing patient factors for IFI, and considerations for clinicians managing IFI. Expert commentary: The relationship between voriconazole dosing and exposure is not well defined due to the large inter- and intra-subject variability. Development of comprehensive decision support tools for individualizing dosing, particularly in children who require higher dosing, will help to increase the probability of achieving therapeutic efficacy and decrease sub-therapeutic dosing and adverse events.

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“…Crystalline form, by virtue of its lower surface area as well as poor aerodynamics had better residence in the lung tissues, whereas, the amorphous form had a faster partitioning from the lungs through the alveolar blood partition and easily passed into the plasma providing poor localized effect to the lungs [95].…”

Section: Influence Of Polymorphic Transformation On Drug Pharmacokinementioning

confidence: 99%

Understanding pharmaceutical polymorphic transformations II: crystallization variables and influence on dosage forms

Sood

Sapra

Bhandari

et al. 2015

Therapeutic Delivery

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Excipients or formulation variables have often been exploited to improve stability, modify release, or improve physicochemical properties of dosage forms. In pharmaceutical field, it is generally expected that excipients work at macromolecular level where they might influence the crystal structure of a solid. These polymers/colloidal particles may modify the rate and direction of crystal growth. It has also been observed, that different polymorphic crystals exhibit different colors on exposure to same colorant, predominantly due to difference in surface pH of different crystal lattices. Apart from physicochemical affect, crystal habit also influences pharmacokinetic parameters of the dosage form. Crystals with smaller size or lower lattice energy have shown to exhibit higher bioavailability with faster rate of release.

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Dry powder insufflation of crystalline and amorphous voriconazole formulations produced by thin film freezing to mice

Cited by 58 publications

References 35 publications

Enhanced bioavailability and anthelmintic efficacy of mebendazole in redispersible microparticles with low-substituted hydroxypropylcellulose

Enhanced bioavailability and anthelmintic efficacy of mebendazole in redispersible microparticles with low-substituted hydroxypropylcellulose

Pharmacodynamic studies of voriconazole: informing the clinical management of invasive fungal infections

Understanding pharmaceutical polymorphic transformations II: crystallization variables and influence on dosage forms

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