Biomedical Engineering Reference
In-Depth Information
initial stages upon polymer injection [95]. Burst effect can be tolerable
for some drugs, but for insulin this phenomenon can easily lead to
dangerously low blood sugar.
In the mid-1990s, Eli Lilly and Novo Nordisk separately reported on the
development of fatty-acid-acylated insulins as soluble prolonged-acting
drugs [96-100]. The epsilon-amino group of LysB29, N
e
, was used as a
handle for insulin derivatization. Insulin has three amino groups, but N
e
is
significantly more basic than the two N
a
-terminals [101,102]. N
e
is hence
more nucleophilic than N
a
above pH values where N
e
is deprotonated, and
N
e
can therefore be selectively acylated at pH
>
10 (Figure 7.6).
pKa 8.6
pKa 11.2
NH
2
NH
2
S
S
I
V
E
Q
C
C
T
S
I
C
S
L
Y
Q
L
E
N
Y
C
N
OH
Ph
S
O
S
S
S
H
2
N
V
N
Q
H
L
C
G
S
H
L
V
E
A
L
Y
L
V
CG
E
R
G
F
F
Y
T
P N
OH
O
O
pKa 6.8
acylation reagents,
pH > 10
O
R
NH
NH
2
S
S
I
V
E
Q
C
C
T
S
I
C
S
L
Y
Q
L
E
N
Y
C
N
OH
Ph
O
S
S
S
S
H
2
N
V
N
Q
H
L
C
G
S
H
L
V
E
A
L
Y
L
V
CG
E
R
G
F
F
Y
T
P N
OH
O
O
Figure 7.6 Lysine-N
e
selective acylation at pH
>
10. With kind permission from
Springer Science and Business Media
The Eli Lilly compound was B29N
e
-palmityl human insulin (hexa-
decanoyl, C16) and the Novo Nordisk compound was B29N
e
-myristyl
desB30 human insulin (tetradecanoyl, C14). The Eli Lilly compound
W99-S-32 was not fully developed, apparently because of too low
potency in humans. The low potency may be related to the high
hydrophobicity of the compound, which in turn could lead to high
unspecific clearance. The Novo Nordisk compound NN304, alias
insulin detemir
, alias
Levemir
, was also found to be of relatively low
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