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Stabilization of Interferon alpha-2b in a Topical Cream
The authors describe a proprietary process for producing a stable, topical interferon alpha-2b formulation that can deliver large drug molecules into the skin or mucosa.
Formulation screening and lead-formulation selection
Applying the principles previously described led to the development of 39 formulations (i.e., 21Q series). The goal was to
improve product stability without compromising physicochemical properties or in vitro skin delivery of IFNα-2b.
Two trial formulations selected from the 21Q series were screened in an in vitro Bronaugh-type (flow-through) diffusion cell model to evaluate IFNα-2b absorption into excised human breast skin. The skin
in the diffusion cells was kept at 32 °C and perfused at 37 °C with phosphate-buffered saline containing 5 mM L-methionine
and 100 µg/mL bovine serum albumin. IFNα-2b absorption from infinite doses of cream was similar for formulations Q25A and
Q25C as measured in the skin samples using AVA (9).
Three types of toxicology studies were initially conducted using formulation Q25A: skin-sensitization studies in guinea pigs,
repeat-dose dermal irritation studies in rabbits, and vaginal irritation studies in rabbits. Formulation Q25A was nonsensitizing
in guinea pigs, transiently irritating in the dermal repeated-dose study in rabbits (approximately the first 10 days of the
30-day study), and minimally irritating in the vaginal irritation study. Dermal irritation scores improved dramatically following
a slight procedural modification and the quantitative reduction of a single excipient in the formulation to create formulation
Q25C.
Figure 2: Reverse-phase high-performance liquid chromatogram of Interferon alpha-2b (IFNα-2b) Cream after 15 months at 2–8
°C demonstrating the absence of Component A. EU is emission unit.
IFN = IFNα-2b.
Formulation Q25C was found to be chemically stable with no loss of potency for at least nine months when packaged in polypropylene
tubes and stored at 2–8 °C. Almost negligible amounts of Component A were formed after 15 months (see Figure 2). Based on
the stability, in vitro skin absorption, and toxicology data. Formulation Q25C was selected as the lead formulation for clinical development.
Lead formulation composition, preparation, and stability
The composition of Interferon alpha-2b Cream (Q25C) included the following excipients: benzalkonium chloride, butylated hydroxytoluene,
cetyl alcohol, cholesterol, edetate disodium dihydrate, glycine, glycerol monostearate, L-methionine, methylparaben, olive
oil (super-refined), polyethylene glycol (PEG 40), castor oil (hydrogenated), phospholipid, propylene glycol, propylparaben,
purified water, and phosphate buffer.
The method of preparation is summarized in Figure 3. All steps after the addition of IFNα-2b are performed under nitrogen.
The product is purged with an inert gas before filling into polypropylene tubes.
Praveen Kumar, M. Pharm. and PhD, is vice-president of topical drug product development at Helix BioPharma, 301111 Research Drive, Innovation Place, Saskatoon, Saskatchewan, Canada S7N 3R2, tel. 306.934.7471 ext 230, fax 306.934.7453.
Articles by Praveen Kumar
Ravinderjit Batta
Ravinderjit Batta, M. Pharm., is group leader of formulation development at Helix BioPharma.
Articles by Ravinderjit Batta
Kim Gaspar, PhD, is manager of quality assurance at Helix BioPharma.
Articles by Kim Gaspar
John Docherty
John Docherty, M. Sc., is president and chief operating officer at Helix BioPharma.
Articles by John Docherty
Marianna Foldvari
Marianna Foldvari, D. Pharm. Sci. and PhD, is Canada research chair in bionanotechnology and nanomedicine and associate director of research and graduate studies at the School of Pharmacy, University of Waterloo, Ontario, Canada.
Articles by Marianna Foldvari
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