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Improved bioavailability of a water-insoluble drug by inhalation of drug-containing maltosyl-?-cyclodextrin microspheres using a four-fluid nozzle spray drier.

ABSTRACT: We previously developed a unique four-fluid nozzle spray drier that can produce water-soluble microspheres containing water-insoluble drug nanoparticles in one step without any common solvent between the water-insoluble drug and water-soluble carrier. In the present study, we focused on maltosyl-?-cyclodextrin (malt-?-CD) as a new water-soluble carrier and it was investigated whether drug/malt-?-CD microspheres could improve the bioavailability compared with our previously reported drug/mannitol (MAN) microspheres. The physicochemical properties of bare drug microparticles (ONO-2921, a model water-insoluble drug), drug/MAN microspheres, and drug/malt-?-CD microspheres were evaluated. In vitro aerosol performance, in vitro dissolution rate, and the blood concentration profiles after intratracheal administration were compared between these formulations. The mean diameter of both drug/MAN and drug/malt-?-CD microspheres was approximately 3-5 ?m and both exhibited high aerosol performance (>20% in stages 2-7), but drug/malt-?-CD microspheres had superior release properties. Drug/malt-?-CD microspheres dissolved in an aqueous phase within 2 min, while drug/MAN microspheres failed to dissolve in 30 min. Inhalation of drug/malt-?-CD microspheres enhanced the area under the curve of the blood concentration curve by 15.9-fold than that of bare drug microparticles and by 6.1-fold than that of drug/MAN microspheres. Absolute bioavailability (pulmonary/intravenous route) of drug/malt-?-CD microspheres was also much higher (42%) than that of drug/MAN microspheres (6.9%). These results indicate that drug/malt-?-CD microspheres prepared by our four-fluid nozzle spray drier can improve drug solubility and pulmonary delivery.

SUBMITTER: Ozeki T

PROVIDER: S-EPMC3513433 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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Improved bioavailability of a water-insoluble drug by inhalation of drug-containing maltosyl-β-cyclodextrin microspheres using a four-fluid nozzle spray drier.

Ozeki Tetsuya T Kano Yoshihito Y Takahashi Norimitsu N Tagami Tatsuaki T Okada Hiroaki H

AAPS PharmSciTech 20120901 4

We previously developed a unique four-fluid nozzle spray drier that can produce water-soluble microspheres containing water-insoluble drug nanoparticles in one step without any common solvent between the water-insoluble drug and water-soluble carrier. In the present study, we focused on maltosyl-β-cyclodextrin (malt-β-CD) as a new water-soluble carrier and it was investigated whether drug/malt-β-CD microspheres could improve the bioavailability compared with our previously reported drug/mannitol ...[more]

PMID: 22945234

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Project description:In a spray drying operation, a two-fluid nozzle (2FN) with a single channel is commonly used for atomizing the feed solution. However, the less commonly used three-fluid nozzle (3FN) has two separate channels, which allow spray drying of materials in two incompatible solution systems. Although amorphous solid dispersions (ASDs) prepared using a 3FN have been reported to deliver comparable drug dissolution performance relative to those prepared using a 2FN, few studies have systematically examined the effect of 3FN on the physical stability. Therefore, the goal of this work is to systematically study the physical stability of ASDs that are spray-dried using a 3FN compared to those prepared using the traditional 2FN. For the 2FN, a single solution of naproxen and polyvinylpyrrolidone (PVP) was prepared in a mixture of acetone and water at a 1:1 volume ratio because 2FN allows for only one solution inlet. For the 3FN, naproxen and PVP were dissolved individually in acetone and water, respectively, because 3FN allows simultaneous entry of two solutions. Upon storage of the formulated ASDs at different humidity levels (25%, 55% and 75% RH), naproxen crystallized more quickly from the 3FN ASDs as compared with the 2FN ASDs. 3FN ASDs crystallized after 5 days of storage at all conditions, whereas 2FN ASDs did not crystallize even at 55% RH for two months. This relatively higher crystallization tendency of 3FN ASDs was attributed to the inhomogeneity of drug and polymers as identified by the solid-state Nuclear Magnetic Resonance findings, specifically due to poor mixing of water- and acetone-based solutions at the 3FN nozzle. When only acetone was used as a solvent to prepare drug-polymer solutions for 3FN, the formulated ASD was found to be stable for >3 months of storage (at 75% RH), which suggests that instability of the 3FN ASD was due to the insufficient mixing of water and acetone solutions. This study provides insights into the effects of solvent and nozzle choices on the physical stability of spray-dried ASDs.

Dataset Information

Improved bioavailability of a water-insoluble drug by inhalation of drug-containing maltosyl-?-cyclodextrin microspheres using a four-fluid nozzle spray drier.

Publications

Improved bioavailability of a water-insoluble drug by inhalation of drug-containing maltosyl-β-cyclodextrin microspheres using a four-fluid nozzle spray drier.

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