Formulation approaches to improving the delivery of an antiviral drug with activity against seasonal flu.

Formulation approaches to improving the delivery of an antiviral drug with activity against seasonal flu.

Pharmaceutical development and technology (2013-11-14)

Srinivasa M Sammeta, Li Wang, Shravan K Mutyam, Kathleen O'Loughlin, Carol E Green, Milton H Werner, Terence Kelly, Gita N Shankar

PMID24218989

ABSTRACT

The main objective of the present study was to develop formulations of noscapine hydrochloride hydrate with enhanced solubility and bioavailability using co-solvent- and cyclodextrin-based approaches. Different combinations of co-solvents, which were selected on the basis of high-throughput solubility screening, were subjected to in vitro intestinal drug permeability studies conducted with Ussing chambers. Vitamin E tocopherol polyethylene glycol succinate and propylene glycol based co-solvent formulations provided the maximum permeability coefficient for the drug. Inclusion complexes of the drug were prepared using hydroxypropyl-β-cyclodextrin and sulphobutylether cyclodextrins. Pharmacokinetic studies were carried out in male Sprague-Dawley rats for the selected formulations. The relative bioavailabilities of the drug with the co-solvent- and cyclodextrin-based formulations were found to be similar.

MATERIALS

Product Number

Brand

Product Description

32900

Supelco

Benalaxyl-M, PESTANAL^®, analytical standard

03-2910

Sigma-Aldrich

Boric acid, SAJ first grade, ≥99.5%

258024

Sigma-Aldrich

α-Tocopherol, ≥95.5%

16033

Sigma-Aldrich

1,2-Propanediol, meets analytical specification of Ph. Eur., BP, USP, ≥99.5%

82281

Sigma-Aldrich

1,2-Propanediol, tested according to Ph. Eur.

T3634

Sigma-Aldrich

(+)-α-Tocopherol, from vegetable oil, Type V, ~1000 IU/g

T1539

Sigma-Aldrich

(+)-α-Tocopherol, Type VI, from vegetable oil, liquid (≥0.88M based on potency, density and molecular wt.), BioReagent, suitable for insect cell culture, ≥1000 IU/g

N9007

Supelco

Noscapine hydrochloride hydrate, analytical standard

B2645

Sigma-Aldrich

Boric acid, tablet, 1 g boric acid per tablet

T1550000

α-Tocopherol, European Pharmacopoeia (EP) Reference Standard

82280

Sigma-Aldrich

1,2-Propanediol, puriss. p.a., ACS reagent, ≥99.5% (GC)

12279

Supelco

1,2-Propanediol, analytical standard

398039

Sigma-Aldrich

1,2-Propanediol, ACS reagent, ≥99.5%

G7893

Sigma-Aldrich

Glycerol, ACS reagent, ≥99.5%

G5516

Sigma-Aldrich

Glycerol, for molecular biology, ≥99.0%

134368

Sigma-Aldrich

1,2-Propanediol, ReagentPlus^®, 99%

49779

Sigma-Aldrich

Glycerol, tested according to Ph. Eur., anhydrous

1295607

USP

Glycerin, United States Pharmacopeia (USP) Reference Standard

71642

Sigma-Aldrich

Sodium phosphate dibasic, purum p.a., anhydrous, ≥98.0% (T)

S0876

Sigma-Aldrich

Sodium phosphate dibasic, ReagentPlus^®, ≥99.0%

S9763

Sigma-Aldrich

Sodium phosphate dibasic, ACS reagent, ≥99.0%

255793

Sigma-Aldrich

Sodium phosphate dibasic, 99.95% trace metals basis

71636

Sigma-Aldrich

Sodium phosphate dibasic, BioUltra, for molecular biology, ≥99.5% (T)

S7907

Sigma-Aldrich

Sodium phosphate dibasic, BioXtra, ≥99.0%

S3264

Sigma-Aldrich

Sodium phosphate dibasic, for molecular biology, ≥98.5% (titration)

04276

Sigma-Aldrich

Sodium phosphate dibasic, puriss., meets analytical specification of Ph. Eur., BP, USP, FCC, E 339, anhydrous, 98-100.5% (calc. to the dried substance)

71640

Sigma-Aldrich

Sodium phosphate dibasic, puriss. p.a., ACS reagent, anhydrous, ≥99.0% (T)

S5136

Sigma-Aldrich

Sodium phosphate dibasic, BioReagent, suitable for cell culture, suitable for insect cell culture, ≥99.0%

W252506

Sigma-Aldrich

Glycerol, FCC, FG

G2289

Sigma-Aldrich

Glycerin, meets USP testing specifications