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  • II. Technological approaches to improve the dissolution behavior of nateglinide, a lipophilic insoluble drug: co-milling.

II. Technological approaches to improve the dissolution behavior of nateglinide, a lipophilic insoluble drug: co-milling.

International journal of pharmaceutics (2013-07-23)
Lauretta Maggi, Giovanna Bruni, Mariarosa Maietta, Andrea Canobbio, Andrea Cardini, Ubaldo Conte
ABSTRACT

Nateglinide is an oral antidiabetic agent that should be administered 10-30 min before the meal, but it shows low and pH-dependent solubility that may reduce its oral bioavailability. To improve nateglinide dissolution rate, the active was co-milled with three different super-disintegrants or with some hydrophilic excipients, in 1:1, 1:2, and 1:4 drug to carrier ratio (w:w). The three super-disintegrants were crosslinked polyvinylpyrrolidone (PVPC), sodium starch glycolate (SSG) and crosslinked carboxymethyl cellulose (CMCC). The three hydrophilic excipient were amorphous silica (AS), mannitol (M) and Poloxamer (PO). A strong enhancement of drug dissolution rate was obtained from the nateglinide:super-disintegrant co-milled systems in 1:4 ratio, which can be explained by a combination of several factors: an increase in wettability, due to the hydrophilic nature of the carriers, a possible reduction of particle size and a more intimate dispersion of the drug onto the carrier, as a result of the mechanical treatment.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Polyvinylpyrrolidone, average mol wt 40,000
Sigma-Aldrich
Polyvinylpyrrolidone, suitable for plant cell culture, average mol wt 10,000
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Polyvinylpyrrolidone, powder, BioXtra, suitable for mouse embryo cell culture
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Polyvinylpyrrolidone, for molecular biology, nucleic acid hybridization tested, mol wt 360,000
Sigma-Aldrich
Carboxymethylcellulose sodium salt, High viscosity
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Carboxymethylcellulose sodium salt, low viscosity
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Carboxymethylcellulose sodium salt, Medium viscosity
Sigma-Aldrich
Nateglinide, ≥98% (HPLC), solid
Sigma-Aldrich
Polyvinylpyrrolidone, K 30
Sigma-Aldrich
Polyvinylpyrrolidone, powder, average Mw ~29,000
Sigma-Aldrich
Polyvinylpyrrolidone, powder, average Mw ~55,000
Sigma-Aldrich
Polyvinylpyrrolidone, average Mw ~1,300,000 by LS
Sigma-Aldrich
Polyvinylpyrrolidone, K 90
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Polyvinylpyrrolidone solution, K 60, 45% in H2O
Sigma-Aldrich
Polyvinylpyrrolidone, mol wt (number average molecular weight Mn 360)
Sigma-Aldrich
Polyvinylpyrrolidone, K 25, tested according to Ph. Eur.
Sigma-Aldrich
Polyvinylpyrrolidone, average mol wt 10,000
N-[(cis-4-Isopropylcyclohexyl)carbonyl]-D-phenylalanine, European Pharmacopoeia (EP) Reference Standard
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Sodium carboxymethyl cellulose, average Mw ~250,000, degree of substitution 0.9
Sigma-Aldrich
Sodium carboxymethyl cellulose, average Mw ~250,000, degree of substitution 1.2
Sigma-Aldrich
D-Mannitol, suitable for plant cell culture
Sigma-Aldrich
D-Mannitol, meets EP, FCC, USP testing specifications
Sigma-Aldrich
D-Mannitol, BioXtra, ≥98% (HPLC)
Sigma-Aldrich
D-Mannitol, ≥98%
Sigma-Aldrich
Carboxymethylcellulose sodium, meets USP testing specifications, Medium viscosity
Sigma-Aldrich
D-Mannitol, ACS reagent
Sigma-Aldrich
Povidone, meets USP testing specifications
Sigma-Aldrich
D-Mannitol, tested according to Ph. Eur.
Sigma-Aldrich
Kollidon® 25
Supelco
Mannitol, Pharmaceutical Secondary Standard; Certified Reference Material