Stabilization of Interferon alpha-2b in a Topical Cream - Pharmaceutical Technology

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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.

Pharmaceutical Technology
Volume 33, Issue 7, pp. 80-86

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 g/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.

Figure 3: Interferon (IFN) alpha-2b Cream manufacturing flow chart.
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.


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