Increased Bioavailability Via Multiple Routes

2013 Aegis Therapeutics LLC
2013 Aegis Therapeutics, LLC

16870 W. Bernardo Drive,
Suite 390
San Diego, CA 92127
Phone: 858-618-1400
Facsimile: 858-618-1441
www.aegisthera.com
Novel Formulations for
Non-Invasive Delivery of Peptides
and Small molecule Drugs
Intravail
/ProTek
Technologies - Based on
Alkylsaccharides (sugar + alkyl chain - various linkages)

2
Typical linkages:
glycosidic
thioglycosidic
amide linkage
ureide
ester
Typical oligosaccharides:
maltose
maltotriose
maltotetraose
sucrose
trehalose
sucrose
trehalulose
turanose
maltulose
leucrose
palatinose
isomaltose
maltitol
Typical alkyl chain lengths:
10-18 carbons
O
O
O
CH
2
OH
OH
OH
OH
OH
OH
O
CH
2
OH
(CH
2
)
n
CH
3
n
O
O
O
OH
OH
OH
OH
OH
CH
2
OH
COCH
2
O
(CH
2
)
n
H
3
C
HOCH
2
n
General Intravail /ProTek Characteristics
Safe, odorless, tasteless, non-toxic, non-mutagenic, and non-irritating
Synthetic pure chemical entities prepared under GMP
Provides unmatched bioavailability - comparable to subcutaneous
injection, via the intranasal and other mucosal membrane
administration routes (up to ~30KDa MW)
Allows controlled transient mucosal permeation by both paracellular
(tight-junction) and transcellular routes
Soluble in water or oils compatible with routine liquid formulation
and dispensing processes for ease of scale-up and production
Shown to be highly effective (orally) for BCS Class III/IV small
peptides and small molecules
Shown to greatly increase oral bioavailability in tablets, oils (i.e., soft-
gel compatible), and flash-dissolve oral (Zydis
-like) formats

3
Multiple Modes of Transmucosal Delivery
for Macromolecular Drugs
4
Nasal

Oral (gastrointestinal)

Oral cavity (buccal, sublingual)
Flash dissolve Edible films
Metered spray pumps
Gelcaps Tablets
Diazepam 0.28kDa B/A=96%
OB-3 ~1kDa B/A=363%

Intravail Provides Intranasal
Bioavailability Comparable to Injection
5
Paracellular Absorption: Reduction in TEER
*

(Normal Human Tracheal/Bronchial Epithelial Cell Derived Mucociliary Tissue)
6
0
20
40
60
80
100
120
T
y
p
e

A
,

0
.
1
%
T
y
p
e

A
,

0
.
2
%
T
y
p
e

B
,

0
.
1
%
T
y
p
e

B
,

0
.
2
%
T
y
p
e

C
,

0
.
1
%
T
y
p
e

C
,

0
.
2
%
N
o
n
-
I
n
t
r
.
X

,

0
.
1
%
N
o
n
-
I
n
t
r
.
X
,

0
.
2
%
N
o
n
-
I
n
t
r
.
Y
,

0
.
1
%
N
o
n
-
I
n
t
r
.
Y
,

0
.
2
%
P
B
S
%

T
E
E
R

D
e
c
r
e
a
s
e
Non-Intravail
Alkylsaccharides
Intravail Excipients
*1h. exposure
C
14
M C
12
M C
12
S C
8
G C
7
G
PBS 0.1% 0.2% 0.1% 0.2% 0.1% 0.2% 0.1% 0.2% 0.1% 0.2%

*Adapted from: Chen,S.-C., Eiting,K.T.,Li, A.A.W., Lamharzi, N. and Quay, S.C. (2005), 45
th
American
Society for Cell Biology Meeting, December 10-14, 2005, San Francisco (late abstract) Peptide Drug
Permeation Enhancement By Select Classes of Lipids

Key: MMaltoside, S Sucrose ester, G Glucoside
Intravail

Interacts With Nasal Mucosa Not Drug
7
Calcitonin
0 20 40 60 80 100120
0
10
20
30
40
50
S
e
r
u
m

S
o
m
a
t
r
o
p
i
n

(
n
g
/
m
L
)
Time (minutes)
Somatropin
0 40 80 120
0
50
100
150
200
250
300
350
0 minutes
60 minutes
120 minutes
P
l
a
s
m
a

C
a
l
c
i
t
o
n
i
n

(
p
g
/
m
L
)
Time (minutes)
Rat Model Data
Time between
Intravail & API
Arnold, Fyrberg, Meezan, Pillion (2010) J Pharm Sci. 99(4):1912-20.
3-Way Human Crossover Study Intravail

Increases Calcitonin Bioavailability >5-fold

0
10
20
30
40
50
60
0
0
.
2
5
0
.
5
0
.
7
51
1
.
2
5
1
.
5
1
.
7
52
2
.
2
5
2
.
5
2
.
7
53
3
.
2
5
3
.
5
3
.
7
54
Time (hrs)
C
a
l
c
i
t
o
n
i
n

n
g
/
m
L
Injection Nasal-No Intravail Nasal + Intravail
Average Intravail
bioavailability ~37%
No Intravail
control ~ 6.6%
P
l
a
s
m
a

C
o
n
c
e
n
t
r
a
t
i
o
n

8
Mean Plasma Drug Concentration vs. S.C. Injection in 10 Healthy Females
Maggio, Meezan, Ghambeer, and Pillion (2010) Drug Del Tech. 2010;10:5863.
Multiple Modes of Transmucosal Delivery
for Macromolecular Drugs
9
Nasal

Oral (gastrointestinal)

Oral cavity (buccal, sublingual)
Flash dissolve Edible films
Metered spray pumps
Gelcaps Tablets
[D-Leu-4]OB3 First Orally Active Weight Loss &
Anti-Diabetic Peptide
Patented (7-mer peptide) leptin derived fragment
Reduces weight gain & food intake in mouse obesity
models
Normalizes blood glucose in mouse diabetes/obesity
models
Increases osteocalcin may prevent/reverse bone loss
associated with weight loss & osteoporosis
High oral bioavailability (56% w. Intravail
)
High nasal bioavailability (100% w. Intravail
) for
rapid onset
Multiple issued patents*

* Dr. Patricia Grasso et al., Albany Medical College
10
Time
0 20 40 60 80 100 120
S
e
r
u
m

P
e
p
t
i
d
e

C
o
n
c
.

(
n
g
/
m
L
)
0
2000
4000
6000
8000
10000
Oral Delivery of [D-leu-4]OB3 Anti-Obesity Peptide
in Rodents (~1kD MW)

552,710 ng*min/mL
137,585 ng/mL/min
With Intravail
No Intravail
Lee et al. Regulatory Peptides 160 (2010) 129132
11
Oral OB-3 Administration - Body Weight
Gain and Serum Glucose in ob/ob Mice
12
Novakovic, Grasso, et al. Diabetes Obes Metab. (2010) 12(6):532-9.
0
1
2
3
4
5
6
7
0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190
Ti me ( mi nut es)
O
c
t
r
e
o
t
i
d
e

a
c
e
t
a
t
e

(
n
g
/
m
l
)
A
Uptake of 30ug Octreotide
in PBS s.c.
0
10
20
30
40
50
60
0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190
Time (minutes)
O
c
t
r
e
o
t
i
d
e

a
c
e
t
a
t
e

(
n
g
/
m
l
)
1
2 1
B
AUC (ng/ml/min)
AUC1 353.03
AUC2 901.04
AUC (ng/ml/min) 311.63

1254.08
Oral Bioavailability with Intravail

Exceeds That of S.C. Injected Octreotide
Oral Uptake of 30ug Octreotide
in Intravail
Maggio & Grasso Regulatory Peptides 167 (2011) 233238
13
Human Clinical Data
Nasal sumatriptan
Six human trials to date
Tmax reduced to 8 min. from 60-120 min. for Imitrex
Therapeutic drug levels equivalent to Imitrex achieved in 2-3 min.. (i.e., 20X 30X
faster)
Licensee a Top-10 multinational generics company

Nasal diazepam
Nasal spray designed as an alternative to the Diastat rectal gel
Bioequivalent to Diastat
96% absolute bioavailability
Licensee Neurelis Inc. (San Diego)

Nasal PTH 1-34 (~4000 Da)
Nasal spray
Three phase 1 trials completed: single dose/7 day b.i.d, and 6 weeks b.i.d.
Approximately 30% nasal bioavailability compared to Forteo injection

Oral endocrine peptide (~1000 Da)
Formatted as a 3 sec. flash dissolve (Zydis) wafer
14 patient feasibility study completed
Intravail
Summary
Unmatched intranasal bioavailability (up to ~30kD)
Unmatched oral bioavailability for certain peptides
Rapid onset of action
Greater patient convenience and compliance
Elimination of needle stick injuries/infections
Avoidance of gastric hydrolysis & first pass effect
Compatible with off-the-shelf metered nasal spray
devices & oral tablet/capsule/flash-dissolve formats
15
16870 West Bernardo Drive, Suite 390
San Diego, CA 92127
Phone: 858-618-1400
Facsimile: 858-618-1441
www.aegisthera.com
Edward T. Maggio, Ph.D., Chief Executive Officer
emaggio@aegisthera.com
Ralph R. Barry, Chief Business Officer & CFO
rbarry@aegisthera.com
Contact Information:

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2013 Aegis Therapeutics LLC

2013 Aegis Therapeutics, LLC

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