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.

Proteins perform essential biological functions in living cells and are composed of individual amino acids connected by peptide bonds. With the advent of recombinant deoxyribonucleic acid technology, cost-effective production of protein-based drugs such as hormones, cytokines, and vaccines is possible. Formulation of therapeutic proteins provides different challenges compared with small molecule-based products. The main problems encountered during protein formulation include aggregation, thermal denaturation, oxidation, deamidation, and peptide-bond hydrolysis, all of which can lead to loss of protein potency.

There are very few marketed topical products containing protein-derived drugs. Regranex gel (becaplermin, Johnson & Johnson, New Brunswick, NJ), which contains platelet-derived growth factor, is one example. Other protein-derived drugs could provide benefit to localized topical therapeutic targets if such topical formulations could be developed.

Table I: Some commercially available interferon products.
Interferon alpha-2b (IFNα-2b) is a recombinant 19 kDa protein that possesses antiproliferative, immunomodulatory, and antiviral effects (1). IFNα-2b is active against a variety of human papillomavirus (HPV)-induced lesions, particularly cutaneous lesions such as genital warts (i.e., condyloma acuminata). IFNα-2b is also used clinically to treat hairy-cell leukemia, malignant melanoma, follicular lymphoma, AIDS-related Kaposi's sarcoma, chronic hepatitis C, and chronic hepatitis B (2). In addition, it has therapeutic potential against human hyperproliferative and viral diseases such as low-grade squamous intraepithelial lesions (LSIL) (3). All currently approved interferon products such as Intron A (Schering-Plough, Kenilworth, NJ) are injectables (see Table I). To date, no successful topical dosage form has been developed for clinical delivery of IFNα-2b via the skin or mucosa.

Microencapsulation technology for interferon

Biphasix (Helix BioPharma, Aurora, Ontario, Canada) is a microencapsulation platform technology for noninvasive delivery of drugs into or through the skin and mucosa (i.e., dermal or mucosal delivery) in a painless manner. Biphasix is a complex system in which microvesicles, consisting of lipid bilayers, entrap the oil and aqueous phases as a stabilized emulsion. Biphasix technology allows the formulation of hydrophilic and lipophilic drugs of any size, including small molecules and macromolecules (4, 5).

Using Biphasix technology, Helix BioPharma developed a specialized cream containing encapsulated IFNα-2b known as Interferon alpha-2b Cream (2 MIU/g). The IFNα-2b is entrapped in specialized liposomes, which are microscopic vesicles composed of a single phospholipid bilayer or multiple concentric lipid bilayers. The initial therapeutic focus was for the vaginal administration of the cream in patients with cervical LSIL.

Development of Interferon alpha-2b Cream

Interferon alpha-2b Cream was developed with the following objectives:
• Retain the chemical and biological stability of IFNα-2b in the product
• Enhance the ability to transport IFNα-2b into the skin or mucosal layers
• Improve patient compliance through ease of application and emollient properties.