Biomedical Engineering Reference
In-Depth Information
pharmaceuticals are in clinical use. The most successful examples
are
•
PEGASYS:
Pegylated interferon alpha for use in the treatment
of chronic hepatitis C and hepatitis B (Hoff mann-La Roche)
•
Pegintron:
Pegylated interferon alpha for use in the treatment
of chronic hepatitis C and hepatitis B (Schering-Plough/
Enzon)
•
Oncaspar:
Pegylated L-asparaginase for the treatment of acute
lymphoblastic leukemia in patients who are hypersensitive to
the native unmodified form of L-asparaginase (Enzon). This
drug was recently approved as a first-line treatment
•
Neulasta:
Pegylated recombinant methionyl human
granulocyte colony-stimulating factor for severe cancer-
chemotherapy-induced neutropenia (Amgen)
Many other pegylated peptides and proteins are now in clinical
trials or under development.
The success of pegylated proteins was the driving force for
the successful development of Doxil
®
as the first FDA-approved
liposomal drug and nano-drug (November 17, 1995). In lipids, PEG
chains of >350 to 15,000 were tried (equivalent to 8 to 334 ethylene
oxide units) and various considerations, such as the metabolism of
the pegylated lipids and the rate of secretion via the kidneys were
used in the decision which PEG length to select for lipid pegylation.
12.4.5
Selection of Pegylated Nanoliposomes as the
Basis of Doxil
Each of the laboratories working on long circulating liposomes
described above has its publications and patents on its unique
liposome formulations. In the early 1990s, it became evident that
for various scientific and practical reasons (availability, cost, species
specificity, etc.) described elsewhere (Woodle, 1993; Allen, 1995),
the GM1-ganglioside-based formulation was excluded. At LTI, HPI
and PEG-DSPE remained in the race. In order for LTI to decide
which of the two lipids will be the one to use in evaluating the novel
formulation in human, we performed in 1991 a critical comparative
PK experiment in Beagle dogs (Gabizon et al., 1993). Dog is a preferred
animal due to its much larger plasma volume (~500 mL), which
resembles much better that of human beings in studying the eff ect
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