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.
(COURTESY OF THE AUTHORS)
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.
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
Table I: Some commercially available interferon products.
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.