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

PHR1020

Supelco

Glycerin, Pharmaceutical Secondary Standard; Certified Reference Material

T1550000

α-Tocopherol, European Pharmacopoeia (EP) Reference Standard

609765

Sigma-Aldrich

Sodium hydroxide-¹⁶O solution, 20 wt. % in H₂¹⁶O, 99.9 atom % ¹⁶O

W252506

Sigma-Aldrich

Glycerol, FCC, FG

258024

Sigma-Aldrich

α-Tocopherol, ≥95.5%

32900

Supelco

Benalaxyl-M, PESTANAL^®, analytical standard

82281

Sigma-Aldrich

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

71642

Sigma-Aldrich

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

49779

Sigma-Aldrich

Glycerol, tested according to Ph. Eur., anhydrous

339067

Sigma-Aldrich

Boric acid, 99.97% trace metals basis

82280

Sigma-Aldrich

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

398039

Sigma-Aldrich

1,2-Propanediol, ACS reagent, ≥99.5%

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

S0876

Sigma-Aldrich

Sodium phosphate dibasic, ReagentPlus^®, ≥99.0%

B2645

Sigma-Aldrich

Boric acid, tablet, 1 g boric acid per tablet

G6279

Sigma-Aldrich

Glycerol, BioXtra, ≥99% (GC)

G9012

Sigma-Aldrich

Glycerol, ≥99.5%

S7907

Sigma-Aldrich

Sodium phosphate dibasic, BioXtra, ≥99.0%

N9007

Supelco

Noscapine hydrochloride hydrate, analytical standard

B7660

Sigma-Aldrich

Boric acid, BioXtra, ≥99.5%

T3634

Sigma-Aldrich

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

12279

Supelco

1,2-Propanediol, analytical standard

16033

Sigma-Aldrich

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

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)

S9763

Sigma-Aldrich

Sodium phosphate dibasic, ACS reagent, ≥99.0%

G7893

Sigma-Aldrich

Glycerol, ACS reagent, ≥99.5%

77067

Supelco

Glycerol, analytical standard

RDD038

Sigma-Aldrich

Sodium phosphate dibasic, BioReagent, suitable for cell culture, suitable for insect cell culture, ≥99.0%, free-flowing, Redi-Dri^™

202878

Sigma-Aldrich

Boric acid, 99.999% trace metals basis