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


Figure 4: Interferon alpha-2b content (%) over 12 months at 2–8 °C in three exhibit lots (4L8358, 4L8368, and 4L8403) of Interferon alpha-2b Cream.
Samples were stored in polypropylene tubes at 2–8 °C for long-term stability studies and tested for physical appearance, microscopy, pH, viscosity, preservative concentration, IFNα-2b content, and total chromatographic impurities, IFNα-2b potency and microbial load. Stability was evaluated in terms of changes in IFNα-2b content using the RP-HPLC method (see Figure 4) and the AVA.

Lead formulation improvement

Stability data collected for 12 months show that lead formulation remains within the predefined limits for IFNα-2b (80–120% of expected) under refrigerated conditions. Studies are underway to collect stability data for up to 24 months. Either IFNα-2b in the product also degrades via pathways other than oxidation, or degradation products were formed in very small amounts that were below the detection limit of the assay. Additional studies to further improve the stability of IFNα-2b are in progress.

Conclusion

IFNα-2b, which is used in a range of therapeutic indications, was stabilized in a specialized lipid vesicle-based topical Biphasix cream. L-methionine stabilized IFNα-2b throughout the shelf life of the Interferon alpha-2b Cream product by preventing auto-oxidation and the formation of a biologically active methioninesulfoxide derivative of IFNα-2b. A sensitive RP-HPLC method using a fluorescence detector was successfully developed to distinguish IFNα-2b from its oxidative variant. The precise mechanism by which L-methionine protects IFNα-2b in the topical Biphasix cream has not yet been elucidated. The Interferon alpha-2b Cream product has been used in Phase II human trials for treating LSIL, and Phase II studies are in progress to investigate its potential as a treatment for anogenital warts, another HPV-related disorder. The Biphasix technology provides an efficient drug-delivery system for formulating macromolecules into a topical formulation for delivery into or across the skin.

Praveen Kumar,* M. Pharm. and PhD, is vice-president of topical drug product development, Ravinderjit Batta, M. Pharm., is group leader of formulation development, Geriene LaBine, M. Sc., is head of quality control, Jinghui Shen, B. Eng., is an analytical chemist, Kim Gaspar, PhD, is manager of quality assurance, and John Docherty, M. Sc., is president and chief operating officer, all with Helix BioPharma, 301–111 Research Drive, Innovation Place, Saskatoon, Saskatchewan, Canada S7N 3R2, tel. 306.934.7471 ext 230, fax 306.934.7453,
. 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.

*To whom all correspondence should be addressed.




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References

1. "Interferon-α" in Human Cytokines: Handbook for Basic and Clinical Research, B.B. Aggarwal, and J.U. Gutterman, Eds. (Blackwell Scientific Publications, Cambridge, MA, 1992), pp. 13–15.

2 C.E. Samuel, "Antiviral Actions of Interferons," Clin. Microbiol. Rev. 14 (4), 778–809 (2001).

3. R. Cirelli and K. Tyring, "Interferons in Human Papillomavirus Infections," Antiviral Res. 24 (2–3), 191–204 (1994).

4. M.J. King et al., "Transdermal Delivery of Insulin from a Novel Biphasic Lipid System in Diabetic Rats," Diabetes Technol. Ther. 4 (4), 479–488 (2002).

5. M. Foldvari et al., "Biphasic Vesicles as a Topical Delivery System for Interferon Alpha," submitted for publication.

6. M. Cindric et al., "Evaluation of Recombinant HumanInterferon a-2b Structure and Stability by In-gel Tryptic Digestion, H/D Exchange and Mass Spectroscopy," J. Pharm. Biomed. Anal. 40 (3), 781–787 (2006).

7. G. Giltlin et al., "Isolation and Characterization of a MonomeThioninesulfoxide Variant of Interferon a-2b," Pharm. Res. 13 (5), 762–769 (1996).

8. K.H. Buchheit, A. Daas, and K.H. Jönsson, "Collaborative Study for Establishment of an HPLC Method for Batch Consistency Control of Recombinant Interferon-alfa-2," Pharmeuropa Spec. Issue Biol. 2002 (1), 7–21 (2002).

9. K.J. Gaspar et al., "In Vitro Absorption of Interferon Alpha-2b From a Topical Biphasix Formulation," manuscript in preparation.


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