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Preparation and evaluation of high dispersion stable nanocrystal formulation of poorly water-soluble compounds by using povacoat.

Journal of pharmaceutical sciences (2014-09-12)
Kayo Yuminoki, Fuko Seko, Shota Horii, Haruka Takeuchi, Katsuya Teramoto, Yuichiro Nakada, Naofumi Hashimoto
ABSTRACT

In this study, we reported the application of Povacoat®, a hydrophilic polyvinylalcohol copolymer, as a dispersion stabilizer of nanoparticles of poorly water-soluble compounds. In addition, the influence of aggregation of the nanoparticles on their solubility and oral absorption was studied. Griseofulvin (GF) was used as a model compound with poor water solubility and was milled to nanoparticles by wet bead milling. The dispersion stability of GF milled with Povacoat® or the generally used polymers (polyvinylalcohol, hydroxypropylcellulose SSL, and polyvinylpyrrolidone K30) was compared. Milled GF suspended in Povacoat® aqueous solution with D-mannitol, added to improve the disintegration rate of freeze-dried GF, exhibited high dispersion stability without aggregation (D90 = ca. 0.220 μm), whereas milled GF suspended in aqueous solutions of the other polymers aggregated (D90 > 5 μm). Milled GF with Povacoat® showed improved aqueous solubility and bioavailability compared with the other polymers. The aggregation of nanoparticles had significant impact on the solubility and bioavailability of GF. Povacoat® also prevented the aggregation of the various milled poorly water-soluble compounds (hydrochlorothiazide and tolbutamide, etc.) more effectively than the other polymers. These results showed that Povacoat® could have wide applicability to the development of nanoformulations of poorly water-soluble compounds.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
D-Mannitol, ≥98%
Sigma-Aldrich
Indomethacin, 98.5-100.5% (in accordance with EP)
Supelco
Mannitol, Pharmaceutical Secondary Standard; Certified Reference Material
Sigma-Aldrich
D-Mannitol, ACS reagent
Sigma-Aldrich
D-Mannitol, meets EP, FCC, USP testing specifications
Supelco
Hydrochlorothiazide, Pharmaceutical Secondary Standard; Certified Reference Material
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Acyclovir, Pharmaceutical Secondary Standard; Certified Reference Material
Sigma-Aldrich
D-Mannitol, BioXtra, ≥98% (HPLC)
Sigma-Aldrich
D-Mannitol, suitable for plant cell culture
Supelco
Naproxen, Pharmaceutical Secondary Standard; Certified Reference Material
Supelco
Indomethacin, Pharmaceutical Secondary Standard; Certified Reference Material
Supelco
Tolbutamide, analytical standard
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Naproxen, meets USP testing specifications
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Phenytoin, Pharmaceutical Secondary Standard; Certified Reference Material
Mannitol, European Pharmacopoeia (EP) Reference Standard
USP
Mannitol, United States Pharmacopeia (USP) Reference Standard
Millipore
D-Mannitol, ACS reagent, suitable for microbiology, ≥99.0%
Sigma-Aldrich
Hydrochlorothiazide, crystalline
Sigma-Aldrich
D-Mannitol, BioUltra, ≥99.0% (sum of enantiomers, HPLC)
Sigma-Aldrich
Indomethacin, meets USP testing specifications
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Griseofulvin, from Penicillium griseofulvum, 97.0-102.0%
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Piroxicam, ≥98% (TLC)
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USP
Acyclovir, United States Pharmacopeia (USP) Reference Standard
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Sigma-Aldrich
(S)-(+)-6-Methoxy-α-methyl-2-naphthaleneacetic acid, 98%
USP
Hydrochlorothiazide, United States Pharmacopeia (USP) Reference Standard
Supelco
Griseofulvin, Pharmaceutical Secondary Standard; Certified Reference Material
Sigma-Aldrich
D-Mannitol, tested according to Ph. Eur.
Supelco
Naproxen, VETRANAL®, analytical standard