Biomedical Engineering Reference
In-Depth Information
Each part has a unique and
important contribution
Extraliposome
medium
Lipid bilayer hydrophobic
part [rigid LO]
Intraliposome
precipitated drug
Hydrated and charge
hindered headgroups
by PEG
Head group attached
Flexible highly
hydrated polymer
Intraliposome
aqueous phase
Intraliposome
aqueous phase
Figure 12.7 A cartoon of Doxil ® = pegylated nano (<100 nm) unilamellar
liposome. It is based on cryo-TEM, SAXS, WAXS, DLS, compressibility, and
doxorubicin absorbance and fluorescence (Lasic et al., 1992, 1995; Haran et
al., 1993; Tirosh et al., 1998). See also Color Insert.
A calculation based on the lipid molar concentration of the
components and on liposome size reveals that 1 mL of the Doxil
dispersion contains 2.3 × 10 14 liposomes and each liposome contains
~10,000 molecules of doxorubicin, above 95% of which is in the
crystalline phase.
12.4.8 Doxil-Related I.P.
It is important to note that Doxil ® is based on two families of patents.
One family covers the eff ect of adding the lipopolymer PEG-DSPE as
a liposome lipid component on liposome circulation time (Woodle et
al., 1991; US patent 5,013,556).
The second patent family is on the transmembrane-driven remote
loading of amphipathic weak bases such as doxorubicin (Barenholz
and Haran, 1993, 1994, US patents 5,192,549 and 5,316,771).
Namely, there is no direct patent on Doxil!
It took seven and a half years from the submission of these two
families of patent applications in 1988/1989 till Doxil approval in
November 1995. As remote loading patents were extended till March
9, 2010, Doxil enjoyed 14 years of patent protection.
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