The human interferon alphas are a family of proteins comprising at least 24 subspecies, Zoon K. C, Interferon 9:1-12 (1987), Gresser I., ed. Academic Press, New York. They were originally described as agents capable of inducing an anti-viral state in cells but are known as pleitropic lymphokines affecting many functions of the immune system, Opdenakker, et al., Expermentia 45: 513-520 (1989). Apart from their in vitro biological activities, the human interferon alphas are currently used for several indications, e.g., hairy cell leukemia, Kaposi Sarcoma, venereal warts, hepatitis B and hepatitis C.
Presently, interferon is administered to patients by injection. Injection suffers from several drawbacks including pain and poor patient compliance. An alternative mode of administration of interferon or PEG-interferon would be beneficial.
Macromolecules have limited modes of administration. Transdermal or oral delivery is difficult because of their sheer size which usually has a molecular weight greater than 7,000 KDa, and instability in the gastrointestinal environment. In general, protein drugs are administered either by subcutaneous or intravenous injection usually in hospital or clinical settings. Proteins having a molecular weight less than 30,000 have serum half-lives duration of hours when injected subcutaneously or intravenously and characteristically show a “burst” (rapid blood serum clearance rate) profile when blood levels are measured over time. There is increasing awareness that drug release patterns (continuous versus pulsatile) significantly affect therapeutic responses.
Pulmonary delivery of a crystalline interferon alpha has been described previously (U.S. Pat. No. 5,972,331). The patent describes a method for preparing a crystalline interferon alpha suitable for aerosol formulation either for systemic or topical (inhaled) drug delivery.
There remains a need in the art for high quality, highly ordered interferon crystals that are particularly useful for pulmonary delivery or delivery in a sustained release formulation. A Zn2+ mediated interferon alpha 2b dimeric crystal was produced previously (see Radhakrishnan et al., Structure. 4(12):1453-63 (1996); see also U.S. Pat. No. 5,441,734 to Reichert et al.); however, interferon structural data gained from the prior art crystals, was only to a 2.7 Å or 2.9 Å resolution.
Due to the ongoing strong scientific interest in understanding interferon and its properties, there is also an interest in obtaining crystals which are of superior quality and particularly useful for interferon structural determination.
USPTO Backgrounds
USPTO Backgrounds