Interferon formulation

Lactide/glycoUde polymers have been investigated for delivery of several other macromolecules. Synthetic double-stranded RNA, poly-isosinic acid/polycytidylic acid, a potent inducer of interferon, was formulated in a 53 47 copolymer of DL-lactide-co-glycoUde. The microspheres were evaluated in mice challenged with Right Valley fever virus. More than 16 days protection was afforded versus only 3 days for controls (137). 

Pegylated interferon is interferon that is attached to a polyethylene glycol molecule that increases the half-life of the drug, thus allowing once-weekly dosing versus thrice-weekly administration required for the unmodified formulation. Pegylated interferon is well tolerated and is superior in efficacy to unmodified interferon for the treatment of chronic hepatitis B.26... 

Neutropenia associated with interferon or pegylated interferon therapy is defined as an absolute neutrophil count (ANC) of less than 1000 cells/mm3 in rare cases, an ANC less than 500 cells/mm3 maybe observed. The neutropenia is more common and in some cases more severe with pegylated interferon than with unmodified interferon. Neutropenia usually occurs within the first 2 weeks after initiating either formulation of interferon, with the WBC count stabilizing by week four or six. The neutropenia is reversible upon discontinuing therapy. Granulocyte colony-stimulating factor has been used as an adjunctive therapy for interferon-induced neutropenia in hepatitis patients.44... 

Discuss the pros and cons of interferon-a therapy for melanoma, and formulate a monitoring plan for patients receiving interferon-a. 

J. L. Cleland and A. J. Jones, Stable formulations of recombinant human growth hormone and interferon-y for microencapsulation in biodegradable microspheres, Phar. Res, 13(10), 1464 (1996). 

Rebif is produced via recombinant DNA technology in a CHO cell line. It displays an identical amino acid sequence to that of native human IFN-P-la and, like the native product, is glycosylated. After cell culture the interferon is purified using a series of chromatographic steps (affinity, ion-exchange, gel-filtration and reverse-phase liquid chromatography). It is formulated as a sterile solution in pre-filled syringes and contains mannitol, HSA, sodium acetate, acetic acid and sodium hydroxide as excipients. It is administered subcutaneously three times weekly. 

Braun and Alsenz6 used an ELISA to detect aggregates in interferon-alpha (IFN-a) formulations. They analyzed IFN-a formulations for possible aggregate formation because all marketed interferons are reported to induce antibodies to some extent. Because of its stabilizing effects, human serum albumin (HSA) is used in the formulation of marketed IFN-a at a great excess over IFN-a itself. HSA can also interact with other proteins. Braun and Alsenz developed an ELISA for the detection of both IFN-a-IFN-a and HSA-IFN-a aggregates. A MAb was used for the capture and detection of the IFN-a and a polyclonal for the detection of HSA. The assay is shown schematically in Figure 11.4. 

Braun, A. and J. Alsenz (1997). Development and use of enzyme-linked immunosorbent assays (ELISA) for the detection of protein aggregates in interferon-alpha (IFN-alpha) formulations. Pharm Res 14(10) 1394-1400. 

Hypersensitivity to natural or recombinant interferon beta, albumin human, or any other component of the formulation. 

Like the p-interferons, glatiramer reduces the frequency of relapse. A high-dose formulation of interferon-P-la, Rebif, has recently been approved in the United... 

Dosage form Avonex is formulated as a sterile, lyophilized powder for injection after reconstitution with supplied diluent or sterile water for injection. Each 1.0ml of reconstituted Avonex contains 30 pg of interferon beta-la. 

Dosage form Rebif is formulated as a sterile solution in a graduated prelilled syringe. Each 0.5 ml of Rebif contains interferon beta-la, either 44pg or 22pg, and excipients. 

Hofer, C., et al. 1999. Formulation of interleukin-2 and interferon-alpha containing ultradeformable carriers for potential transdermal application. Anticancer Res 19 1505. 

Therapeutic formulations contain a recombinant form of IFN-a (either interferon alfa-2a or interferon alfa-2b). These are available as powders for reconstitution or as prefilled injection pens. The drug is administered by subcutaneous injection (or intravenous for reconstituted powder formulations) and intramuscular injection. The dosage is usually stated as units per millilitre (refer to BNF for various preparations and dosages). Powder formulations of interferon alfa-2b also contain glycine, sodium phosphate (mono- and dibasic) and human albumin prefilled pens contain sodium chloride, edetate disodium, polysorbate 80 and m-cresol as a preservative. 

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