U.S. patent application number 16/857464 was filed with the patent office on 2020-10-29 for hydrogel implants for lowering intraocular pressure.
The applicant listed for this patent is Ocular Therapeutix, Inc.. Invention is credited to Charles D. Blizzard, Ankita Desai, Arthur Driscoll, Michael Goldstein.
Application Number | 20200337990 16/857464 |
Document ID | / |
Family ID | 1000004798864 |
Filed Date | 2020-10-29 |
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United States Patent
Application |
20200337990 |
Kind Code |
A1 |
Goldstein; Michael ; et
al. |
October 29, 2020 |
HYDROGEL IMPLANTS FOR LOWERING INTRAOCULAR PRESSURE
Abstract
Provided herein are sustained release biodegradable ocular
hydrogel implants which are useful for lowering ocular pressure and
for treating related conditions.
Inventors: |
Goldstein; Michael;
(Cambridge, MA) ; Driscoll; Arthur; (Reading,
MA) ; Blizzard; Charles D.; (Nashua, NH) ;
Desai; Ankita; (Reading, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Ocular Therapeutix, Inc. |
Bedford |
MA |
US |
|
|
Family ID: |
1000004798864 |
Appl. No.: |
16/857464 |
Filed: |
April 24, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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62970828 |
Feb 6, 2020 |
|
|
|
62840134 |
Apr 29, 2019 |
|
|
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62838791 |
Apr 25, 2019 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/0024 20130101;
A61P 27/06 20180101; A61K 9/0051 20130101; A61K 31/215 20130101;
A61P 27/02 20180101 |
International
Class: |
A61K 9/00 20060101
A61K009/00; A61K 31/215 20060101 A61K031/215; A61P 27/06 20060101
A61P027/06; A61P 27/02 20060101 A61P027/02 |
Claims
1. A sustained release biodegradable intracameral hydrogel implant
comprising travoprost and a polymer network.
2. The hydrogel implant of claim 1, wherein the polymer network
comprises a plurality of polyethylene glycol (PEG) units.
3. The hydrogel implant of claim 1, wherein the polymer network
comprises a plurality of multi-arm PEG units having from 2 to 10
arms.
4. The hydrogel implant of claim 1, wherein the polymer network
comprises a plurality of multi-arm PEG units having from 4 to 10
arms.
5. The hydrogel implant of claim 1, wherein the polymer network
comprises a plurality of multi-arm PEG units having from 4 to 8
arms.
6. The hydrogel implant of claim 1, wherein the polymer network
comprises a plurality of multi-arm PEG units having 8 arms.
7. The hydrogel implant of claim 1, wherein the polymer network
comprises a plurality of multi-arm PEG units having 4 arms.
8. The hydrogel implant of claim 1, wherein the polymer network
comprises a plurality of multi-arm PEG units having the formula:
##STR00004## wherein n represents an ethylene oxide repeating unit
and the wavy lines represent the points of repeating units of the
polymer network.
9. The hydrogel implant of claim 1, wherein the polymer network is
formed by reacting a plurality of polyethylene glycol (PEG) units
selected from 4a20K PEG SAZ, 4a20K PEG SAP, 4a20K PEG SG, 4a20K PEG
SS, 8a20K PEG SAZ, 8a20K PEG SAP, 8a20K PEG SG, 8a20K PEG SS with
one or more PEG or Lysine based-amine groups selected from 4a20K
PEG NH2, 8a20K PEG NH2, and trilysine, or a salt thereof.
10. The hydrogel implant of claim 1, wherein the polymer network is
formed by reacting 8a15K PEG-SAZ with trilysine or a salt
thereof.
11. The hydrogel implant of claim 1, wherein the polymer network is
amorphous.
12. The hydrogel implant of claim 1, wherein the polymer network is
semi-crystalline.
13. The hydrogel implant of claim 1, wherein the travoprost is
homogenously dispersed within the polymer network.
14. The hydrogel implant of claim 1, wherein the travoprost is
delivered to the eye in a sustained manner for a period ranging
from about 2 to about 8 months.
15. The hydrogel implant of claim 1, wherein the travoprost is
delivered to the eye in a sustained manner for a period ranging
from about 3 to about 7 months.
16. The hydrogel implant of claim 1, wherein the travoprost is
delivered to the eye in a sustained manner for a period ranging
from about 4 to about 6 months.
17. The hydrogel implant of claim 1, wherein sustained release
occurs in the aqueous humor.
18. The hydrogel implant of claim 1, wherein the travoprost is
microencapsulated.
19. The hydrogel implant of claim 1, wherein the travoprost is
microencapsulated with poly(lactic-co-glycolic acid) (PLGA) or
poly(lactic acid) (PLA), or a combination thereof.
20. The hydrogel implant of claim 1, wherein the travoprost is
microencapsulated with PLA.
21. The hydrogel implant of claim 1, wherein the polymer networks
is conjugated to fluorescein.
22. The hydrogel implant of claim 1, wherein the implant is
designed for implantation near the corneal endothelial cells.
23. The hydrogel implant of claim 1, wherein the implant is
designed for implantation in the inferior iridocorneal angle.
24. A method of lowering ocular pressure in a subject in need
thereof comprising administering the hydrogel implant of claim 1 to
the eye of a subject.
25. A method of treating ocular hypertension in a subject in need
thereof comprising administering the hydrogel implant of claim 1 to
the eye of a subject.
26. A method of treating glaucoma in a subject in need thereof
comprising administering the hydrogel implant of claim 1 to the eye
of a subject.
27. The method of claim 23, wherein the glaucoma is open angle
glaucoma.
28. The method of claim 24, wherein essentially no endothelial
damage occurs following administration of a disclosed implant.
Description
RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional
Application No. 62/838,791, filed Apr. 25, 2019, U.S. Provisional
Application No. 62/840,134, filed Apr. 29, 2019, and U.S.
Provisional Application No. 62/970,828, filed Feb. 6, 2020, the
entire contents of each of which are incorporated herein by
reference.
BACKGROUND
[0002] Glaucoma is a group of eye disorders that lead to
progressive damage to the optic nerve. Glaucoma is the
second-leading cause of blindness in the United States and most
often occurs in people over age 40. Although there are many
theories on the cause of glaucoma, most associate the condition as
a result of prolonged increase in the fluid pressure inside the
eye. Indeed, lowering intraocular pressure (IOP) is a critical
factor for slowing progression for both glaucoma and ocular
hypertension. See e.g., Noecker R J, Ther Clin Risk Manag. 2006;
2(2):193-206.
[0003] Prostaglandin analogues such travoprost are commonly used as
the first line of therapy to effectively lower IOP. However,
limitations with the application of topical drops (difficulty with
handling the bottle, limited instillation accuracy, potential
washout of drops), poor adherence to regimen, and limited
bioavailability of topical applications are serious issues
affecting IOP control management.
SUMMARY
[0004] Provided herein are sustained release ocular hydrogel
implants comprising travoprost.
[0005] Preclinical studies of the disclosed implants demonstrated
acceptable safety profile, maintenance of drug levels in the
aqueous humor, and a sustained lowering of intraocular pressure.
See Example 1 and 2. In one aspect, e.g., a single dose of the
disclosed implants delivers sustained travoprost free acid levels
through 4 months with drug depleted by 5 months. See e.g., FIG. 5.
In addition, no statistically significant difference in central
corneal thickness (CCT) was observed over 4 and 7 months. See e.g.,
FIGS. 3 and 4.
[0006] No changes in endothelial cell counts or pachymetry from
baseline for certain subjects was observed through 9 months of
treatment. See e.g., FIG. 9.
BRIEF DESCRIPTION OF THE FIGURES
[0007] FIG. 1 shows fluorescein visualization of a disclosed
implant at 3 days in vivo in beagles residing in the inferior
iridocorneal angle using cobalt-blue light illumination through a
yellow filter.
[0008] FIG. 2 shows ultrasound images in beagles of a disclosed
implant residing in the iridocorneal angle at 1 month and 3 months
after injection.
[0009] FIG. 3 shows the central corneal thickness pre- and
post-administration of a disclosed implant in beagles demonstrating
no significant change over 7 months compared to baseline.
[0010] FIG. 4 shows the central corneal thickness pre- and
post-administration of a disclosed implant in beagle eyes
demonstrating no significant change over 4 months.
[0011] FIG. 5 shows the pharmacokinetics of travoprost released
from a disclosed implant in vivo (rabbits) and in vitro over 5
months.
[0012] FIG. 6 shows in vitro release testing of an inventive
implant over 147 days.
[0013] FIG. 7 shows the pharmacokinetics for travoprost free acid
in the aqueous humor of beagle dogs following low and high dose
administration of an inventive implant.
[0014] FIG. 8 shows a comparison of travoprost free acid in the
aqueous humor of beagle dogs compared to the theoretical maximal
concentration from in vitro release testing.
[0015] FIG. 9 shows the effect of selected concentrations of
travoprost in beagles with primary open angle glaucoma on IOP.
[0016] FIG. 10 shows the effect of selected concentrations of
travoprost on pupil diameter in beagles with primary open angle
glaucoma.
[0017] FIG. 11 shows pre- and post-dose inventive implant
administration IOP change relative to baseline for each test group
over the study duration.
[0018] FIG. 12 shows the study design for primary open angle
glaucoma or ocular hypertension trials using inventive implant.
[0019] FIG. 13A shows the mean IOP Change from Baseline, Cohort 1
from the study design for primary open angle glaucoma or ocular
hypertension with measurements taken at 8AM.
[0020] FIG. 13B compares the mean IOP Change from Baseline of
different loading concentrations of travoprost from the study
design for primary open angle glaucoma or ocular hypertension.
[0021] FIG. 14 shows implant resorption over a clinical study in
human eyes (top, left to right) Days 1, 14, 28, and (bottom) Month
4, 5, 6.
[0022] FIG. 15 illustrates the endothelial cell count over time for
subjects administered inventive implant.
DETAILED DESCRIPTION
[0023] Provided herein are sustained release biodegradable hydrogel
implants comprising travoprost and a polymer network.
[0024] Also provided herein are methods, uses, and medicament
formulations for lowering ocular pressure in a subject, comprising
administering to the eye of the subject a disclosed hydrogel
implant.
[0025] Also provided herein are methods, uses, and medicament
formulations for treating ocular hypertension in a subject,
comprising administering to the eye of the subject a disclosed
hydrogel implant.
[0026] Also provided herein are methods, uses, and medicament
formulations for treating glaucoma in a subject, comprising
administering to the eye of the subject a disclosed hydrogel
implant.
1. Definitions
[0027] The term "biodegradable" refers to a material, such as the
disclosed hydrogel implants, which degrades in vivo. Degradation of
the material occurs over time and may occur concurrently with, or
subsequent to, release of travoprost. In one aspect,
"biodegradable" means that complete dissolution of the implant
occurs, i.e., there is no residual hydrogel implant matter in the
eye. In an alternative aspect, degradation may occur independently
of travoprost release such that e.g., residual travoprost remains
following degradation.
[0028] The term "polymer network" refers to a group of polymers
comprising multiple branch structures (also referred to as "arms")
cross-linked to other polymer chains. The polymer chains may be of
the same or different chemical structures, e.g., as in
complementary or non-complementary repeating units.
[0029] Nomenclature for synthetic precursors used to generate the
disclosed polymer networks are referenced using the number of arms
followed by the MW of the PEG and then the reactive group (e.g.,
electrophile or nucleophile). For example 4a20K PEG SAZ refers to a
20,000 Da PEG with 4 arms with a succinimidylazelate end group,
4a20K PEG SAP refers to a 20,000 Da PEG with 4 arms with a
succinimidyladipate end group, 4a20K PEG SG refers to a 20,000 Da
PEG with 4 arms with a succinimidylglutarate end group, 4a20K PEG
SS refers to a 20,000 Da PEG with 4 arms with a
succinimidylsuccinate end group, etc. Similarly, 4a20K PEG NH2
means a 20,000 Da PEG with 4 arms with an amine end group, 8a20K
PEG NH2 means a 20,000 Da PEG with 8 arms with an amine end group,
etc.
[0030] The term "semi-crystalline" refers to a polymer or polymer
network which possesses some crystalline character, i.e., exhibits
crystalline properties in thermal analysis, X-ray scattering or
electron scattering experiments. In some aspects,
"semi-crystalline" polymers or networks of polymers have a highly
ordered molecular structure with sharp melt points. In some
aspects, "semi-crystalline" polymers or networks of polymers do not
gradually soften with a temperature increase and instead remain
solid until a given quantity of heat is absorbed and then rapidly
change into a rubber or liquid.
[0031] As used herein, "homogenously dispersed" means the
component, such as the travoprost, is uniformly dispersed
throughout the hydrogel or polymer network.
[0032] The term "treat", "treating", or "treatment" are used
interchangeably and refer to reversing, alleviating, delaying the
onset of, or inhibiting the progress of a disclosed condition
(e.g., ocular hypertension or glaucoma), or one or more symptoms
thereof, as described herein. In other aspects, treatment may be
administered in the absence of symptoms. For example, treatment may
be administered to a susceptible individual prior to the onset of
symptoms (e.g., in light of a history of symptoms and/or in light
of exposure to a particular organism, or other susceptibility
factors), i.e., prophylactic treatment. Treatment may also be
continued after symptoms have resolved, for example to delay their
recurrence.
[0033] The terms "subject" and "patient" may be used
interchangeably, and means a mammal in need of treatment, e.g.,
companion animals (e.g., dogs, cats, and the like), farm animals
(e.g., cows, pigs, horses, sheep, goats and the like) and
laboratory animals (e.g., rats, mice, guinea pigs and the like).
Typically, the subject is a human in need of treatment.
[0034] It will be understood that the specific dosage and treatment
regimen for any particular patient will depend upon a variety of
factors, including the activity of the specific protein employed,
the age, body weight, general health, sex, diet, time of
administration, rate of excretion, the judgment of the treating
physician and the severity of the particular condition being
treated.
2. Implants
[0035] As part of a first embodiment, provided herein is a
sustained release biodegradable intracameral hydrogel implant
comprising travoprost and a polymer network.
[0036] As part of a second embodiment, the polymer network of the
disclosed hydrogel implant (e.g., as in the first embodiment)
comprises a plurality of polyethylene glycol (PEG) units.
[0037] As part of a third embodiment, the plurality of polyethylene
glycol (PEG) units included in the disclosed implants are
cross-linked to form a polymer network comprising a plurality of
multi-arm PEG units having at least 2 arms, wherein the remaining
features of the implants are described herein e.g., as in the first
or second embodiment. Alternatively, as part of a third embodiment,
the polymer network of the disclosed implants comprise a plurality
of multi-arm PEG units having from 2 to 10 arms, wherein the
remaining features of the implants are described herein e.g., as in
the first or second embodiment. In another alternative, as part of
a third embodiment, the polymer network of the disclosed implants
comprise a plurality of multi-arm PEG units having from 4 to 8
arms, wherein the remaining features of the implants are described
herein e.g., as in the first or second embodiment. In another
alternative, as part of a third embodiment, the polymer network of
the disclosed implants comprise a plurality of 4-arm PEG units,
wherein the remaining features of the implants are described herein
e.g., as in the first or second embodiment. In another alternative,
as part of a third embodiment, the polymer network of the disclosed
implants comprise a plurality of 8-arm PEG units, wherein the
remaining features of the implants are described herein e.g., as in
the first or second embodiment.
[0038] As part of a fourth embodiment, the polymer network of the
disclosed implants comprises a plurality of PEG units having a
number average molecular weight (Mn) ranging from about 5 KDa to
about 50 KDa, wherein the remaining features of the implants are
described herein e.g., as in the first through third embodiments.
Alternatively, as part of a fourth embodiment, the polymer network
of the disclosed implants comprise a plurality of PEG units having
a number average molecular weight (Mn) ranging from about 5 KDa to
about 40 KDa, wherein the remaining features of the implants are
described herein e.g., as in the first through third embodiments.
In another alternative, as part of a fourth embodiment, the polymer
network of the disclosed implants comprise a plurality of PEG units
having a number average molecular weight (Mn) ranging from about 5
KDa to about 30 KDa, wherein the remaining features of the implants
are described herein e.g., as in the first through third
embodiments. In another alternative, as part of a fourth
embodiment, the polymer network of the disclosed implants comprise
a plurality of PEG units having a number average molecular weight
(Mn) ranging from about 10 KDa to about 50 KDa, wherein the
remaining features of the implants are described herein e.g., as in
the first through third embodiments. In another alternative, as
part of a fourth embodiment, the polymer network of the disclosed
implants comprise a plurality of PEG units having a number average
molecular weight (Mn) ranging from about 10 KDa to about 40 KDa,
wherein the remaining features of the implants are described herein
e.g., as in the first through third embodiments. In another
alternative, as part of a fourth embodiment, the polymer network of
the disclosed implants comprise a plurality of PEG units having a
number average molecular weight (Mn) ranging from about 10 KDa to
about 30 KDa, wherein the remaining features of the implants are
described herein e.g., as in the first through third embodiments.
In another alternative, as part of a fourth embodiment, the polymer
network of the disclosed implants comprise a plurality of PEG units
having a number average molecular weight (Mn) ranging from about 10
KDa to about 20 KDa, wherein the remaining features of the implants
are described herein e.g., as in the first through third
embodiments. In another alternative, as part of a fourth
embodiment, the polymer network of the disclosed implants comprise
a plurality of PEG units having a number average molecular weight
(Mn) ranging from about 30 KDa to about 50 KDa, wherein the
remaining features of the implants are described herein e.g., as in
the first through third embodiments. In another alternative, as
part of a fourth embodiment, the polymer network of the disclosed
implants comprise a plurality of PEG units having a number average
molecular weight (Mn) ranging from about 35 KDa to about 45 KDa,
wherein the remaining features of the implants are described herein
e.g., as in the first through third embodiments. In another
alternative, as part of a fourth embodiment, the polymer network of
the disclosed implants comprise a plurality of PEG units having a
number average molecular weight (Mn) ranging from about 15 KDa to
about 30 KDa, wherein the remaining features of the implants are
described herein e.g., as in the first through third embodiments.
In another alternative, as part of a fourth embodiment, the polymer
network of the disclosed implants comprise a plurality of PEG units
having a number average molecular weight (Mn) ranging from about 15
KDa to about 25 KDa, wherein the remaining features of the implants
are described herein e.g., as in the first through third
embodiments. In another alternative, as part of a fourth
embodiment, the polymer network of the disclosed implants comprise
a plurality of PEG units having a number average molecular weight
(Mn) of at least about 5 KDa, wherein the remaining features of the
implants are described herein e.g., as in the first through third
embodiments. In another alternative, as part of a fourth
embodiment, the polymer network of the disclosed implants comprise
a plurality of PEG units having a number average molecular weight
(Mn) of at least about 10 KDa, wherein the remaining features of
the implants are described herein e.g., as in the first through
third embodiments. In another alternative, as part of a fourth
embodiment, the polymer network of the disclosed implants comprise
a plurality of PEG units having a number average molecular weight
(Mn) of at least 15 about KDa, wherein the remaining features of
the implants are described herein e.g., as in the first through
third embodiments. In another alternative, as part of a fourth
embodiment, the polymer network of the disclosed implants comprise
a plurality of PEG units having a number average molecular weight
(Mn) of at least 20 about KDa, wherein the remaining features of
the implants are described herein e.g., as in the first through
third embodiments. In another alternative, as part of a fourth
embodiment, the polymer network of the disclosed implants comprise
a plurality of PEG units having a number average molecular weight
(Mn) of at least 30 about KDa, wherein the remaining features of
the implants are described herein e.g., as in the first through
third embodiments. In another alternative, as part of a fourth
embodiment, the polymer network of the disclosed implants comprise
a plurality of PEG units having a number average molecular weight
(Mn) of at least 40 about KDa, wherein the remaining features of
the implants are described herein e.g., as in the first through
third embodiments. In another alternative, as part of a fourth
embodiment, the polymer network of the disclosed implants comprise
a plurality of PEG units having a number average molecular weight
(Mn) of about 10 KDa, wherein the remaining features of the
implants are described herein e.g., as in the first through third
embodiments. In another alternative, as part of a fourth
embodiment, the polymer network of the disclosed implants comprise
a plurality of PEG units having a number average molecular weight
(Mn) of about 15 KDa, wherein the remaining features of the
implants are described herein e.g., as in the first through third
embodiments. In another alternative, as part of a fourth
embodiment, the polymer network of the disclosed implants comprise
a plurality of PEG units having a number average molecular weight
(Mn) of about 20 KDa, wherein the remaining features of the
implants are described herein e.g., as in the first through third
embodiments. In another alternative, as part of a fourth
embodiment, the polymer network of the disclosed implants comprise
a plurality of PEG units having a number average molecular weight
(Mn) of about 40 KDa, wherein the remaining features of the
implants are described herein e.g., as in the first through third
embodiments.
[0039] In a fifth embodiment, the polymer network of the disclosed
implants comprise a plurality of PEG units crosslinked by a
hydrolyzable linker, wherein the remaining features of the
disclosed implants are described herein e.g., as in the first
through fourth embodiments. Alternatively, as part of a fifth
embodiment, the polymer network of the disclosed implants comprise
a plurality of PEG units crosslinked by a hydrolyzable linker
having the formula:
##STR00001##
wherein m is an integer from 1 to 9 and wherein the remaining
features of the implants are described herein e.g., as in the first
through fourth embodiments. In another alternative, as part of a
fifth embodiment, the polymer network of the disclosed implants
comprise a plurality of PEG units crosslinked by a hydrolyzable
linker having the formula:
##STR00002##
wherein m is an integer from 2 to 6 and wherein the remaining
features of the implants are described herein e.g., as in the first
through fourth embodiments. In another alternative, as part of a
fifth embodiment, the polymer network of the disclosed implants
comprise a plurality of PEG units having the formula:
##STR00003##
wherein n represents an ethylene oxide repeating unit and the wavy
lines represent the points of repeating units of the polymer
network, wherein the remaining features of the implants are
described herein e.g., as in the first through fourth embodiments.
In another alternative, as part of a fifth embodiment, the polymer
network of the disclosed implants comprise a plurality of PEG units
having the formula set forth above, but with an 8-arm PEG scaffold,
wherein the remaining features of the implants are described herein
e.g., as in the first through fourth embodiments.
[0040] In a sixth embodiment, the polymer network of the disclosed
hydrogel implant is formed by reacting a plurality of polyethylene
glycol (PEG) units comprising groups which are susceptible to
nucleophilic attack with one or more nucleophilic groups to form
the polymer network, wherein the remaining features of the hydrogel
are described herein e.g., as in the first through fifth
embodiments. Examples of suitable groups which are susceptible to
nucleophilic attack include, but art not limited to activated
esters (e.g., thioesters, succinimidyl esters, benzotriazolyl
esters, esters of acrylic acids, and the like). Examples of
suitable nucleophilic groups include, but art not limited to,
amines and thiols.
[0041] In a seventh embodiment, the polymer network of the
disclosed hydrogel implant is formed by reacting a plurality of
polyethylene glycol (PEG) units, each having a molecule weight as
described above in the fourth embodiment and which comprise groups
which are susceptible to nucleophilic attack, with one or more
nucleophilic groups to form the polymer network, wherein the
remaining features of the hydrogel are described herein e.g., as in
the first through sixth embodiments. Alternatively, as part of a
seventh embodiment, the polymer network of the disclosed hydrogel
implant is formed by reacting a plurality of polyethylene glycol
(PEG) units, each having a molecule weight as described above in
the fourth embodiment and which comprise a succinimidyl ester
group, with one or more nucleophilic groups to form the polymer
network, wherein the remaining features of the hydrogel are
described herein e.g., as in the first through sixth embodiments.
In another alternative, as part of a seventh embodiment, the
polymer network of the disclosed hydrogel implant is formed by
reacting a plurality of polyethylene glycol (PEG) units selected
from 4a20K PEG SAZ, 4a20K PEG SAP, 4a20K PEG SG, 4a20K PEG SS,
8a20K PEG SAZ, 8a20K PEG SAP, 8a20K PEG SG, 8a20K PEG SS, wherein
the remaining features of the hydrogel are described herein e.g.,
as in the first through sixth embodiments.
[0042] In an eighth embodiment, the polymer network of the
disclosed hydrogel implant is formed by reacting a plurality of
polyethylene glycol (PEG) units comprising groups which are
susceptible to nucleophilic attack with one or more amine groups to
form the polymer network, wherein the remaining features of the
hydrogel are described herein e.g., as in the first through seventh
embodiments. Alternatively, as part of a sixteenth embodiment, the
polymer network of the disclosed hydrogel implant is formed by
reacting a plurality of polyethylene glycol (PEG) units comprising
groups which are susceptible to nucleophilic attack with one or
more PEG or Lysine based-amine groups to form the polymer network,
wherein the remaining features of the hydrogel are described herein
e.g., as in the first through seventh embodiments. In another
alternative, as part of a sixteenth embodiment, the polymer network
of the disclosed hydrogel implant is formed by reacting a plurality
of polyethylene glycol (PEG) units comprising groups which are
susceptible to nucleophilic attack with one or more PEG or Lysine
based-amine groups selected from 4a20K PEG NH2, 8a20K PEG NH2, and
trilysine, or salts thereof, wherein the remaining features of the
hydrogel are described herein e.g., as in the first through seventh
embodiments.
[0043] As part of a ninth embodiment, the polymer network of the
disclosed implants are amorphous (e.g., under aqueous conditions
such as in vivo), wherein the remaining features of the implants
are described herein e.g., as in the first through eighth
embodiments. Alternatively, as part of a ninth embodiment, the
polymer network of the disclosed implants are semi-crystalline
(e.g., in the absence of water), wherein the remaining features of
the compositions are described herein e.g., as in the first through
eighth embodiments.
[0044] As part of a tenth embodiment, the travoprost of the
disclosed implants is homogenously dispersed within the polymer
network, wherein the remaining features of the implants are
described herein e.g., as in the first through ninth
embodiments.
[0045] As part of an eleventh embodiment, the travoprost is
delivered to the eye in a sustained manner for a period ranging
from about 1 month to about 1 year, wherein the remaining features
of the implants are described herein e.g., as in the first through
tenth embodiments. Alternatively, as part of an eleventh
embodiment, the travoprost is delivered to the eye in a sustained
manner for a period ranging from about 1 month to about 11 months,
wherein the remaining features of the implants are described herein
e.g., as in the first through tenth embodiments. In another
alternative, as part of an eleventh embodiment, the travoprost is
delivered to the eye in a sustained manner for a period ranging
from about 1 month to about 10 months, wherein the remaining
features of the implants are described herein e.g., as in the first
through tenth embodiments. In another alternative, as part of an
eleventh embodiment, the travoprost is delivered to the eye in a
sustained manner for a period ranging from about 1 month to about 9
months, wherein the remaining features of the implants are
described herein e.g., as in the first through tenth embodiments.
In another alternative, as part of an eleventh embodiment, the
travoprost is delivered to the eye in a sustained manner for a
period ranging from about 1 month to about 8 months, wherein the
remaining features of the implants are described herein e.g., as in
the first through tenth embodiments. In another alternative, as
part of an eleventh embodiment, the travoprost is delivered to the
eye in a sustained manner for a period ranging from about 2 month
to about 8 months, wherein the remaining features of the implants
are described herein e.g., as in the first through tenth
embodiments. In another alternative, as part of an eleventh
embodiment, the travoprost is delivered to the eye in a sustained
manner for a period ranging from about 3 month to about 7 months,
wherein the remaining features of the implants are described herein
e.g., as in the first through tenth embodiments. In another
alternative, as part of an eleventh embodiment, the travoprost is
delivered to the eye in a sustained manner for a period ranging
from about 4 month to about 6 months, wherein the remaining
features of the implants are described herein e.g., as in the first
through tenth embodiments. In another alternative, as part of an
eleventh embodiment, the travoprost is delivered to the eye in a
sustained manner for a period of about 1 month, wherein the
remaining features of the implants are described herein e.g., as in
the first through tenth embodiments. In another alternative, as
part of an eleventh embodiment, the travoprost is delivered to the
eye in a sustained manner for a period of about 2 months, wherein
the remaining features of the implants are described herein e.g.,
as in the first through tenth embodiments. In another alternative,
as part of an eleventh embodiment, the travoprost is delivered to
the eye in a sustained manner for a period of about 3 months,
wherein the remaining features of the implants are described herein
e.g., as in the first through tenth embodiments. In another
alternative, as part of an eleventh embodiment, the travoprost is
delivered to the eye in a sustained manner for a period of about 4
months, wherein the remaining features of the implants are
described herein e.g., as in the first through tenth embodiments.
In another alternative, as part of an eleventh embodiment, the
travoprost is delivered to the eye in a sustained manner for a
period of about 5 months, wherein the remaining features of the
implants are described herein e.g., as in the first through tenth
embodiments. In another alternative, as part of an eleventh
embodiment, the travoprost is delivered to the eye in a sustained
manner for a period of about 6 months, wherein the remaining
features of the implants are described herein e.g., as in the first
through tenth embodiments.
[0046] As part of a twelfth embodiment, sustained release of the
travoprost occurs in the aqueous humor, wherein the remaining
features of the implants are described herein e.g., as in the first
through eleventh embodiments.
[0047] As part of a twelfth embodiment, travoprost in the disclosed
implants is microencapsulated, wherein the remaining features of
the implants are described herein e.g., as in the first through
eleventh embodiments. Alternatively, as part of a twelfth
embodiment, travoprost in the disclosed implants is
microencapsulated with poly(lactic-co-glycolic acid) (PLGA) or
poly(lactic acid) (PLA), or a combination thereof, wherein the
remaining features of the implants are described herein e.g., as in
the first through eleventh embodiments. In another alternative, as
part of a twelfth embodiment, travoprost in the disclosed implants
is microencapsulated with PLA, wherein the remaining features of
the implants are described herein e.g., as in the first through
eleventh embodiments.
[0048] As part of an thirteenth embodiment, the polymer network of
the disclosed hydrogel implants is conjugated to fluorescein,
wherein the remaining features of the implants are described herein
e.g., as in the first through twelfth embodiments.
[0049] As part of a fourteenth embodiment, the disclosed implants
are designed for implantation near the corneal endothelial cells,
wherein the remaining features of the implants are described herein
e.g., as in the first through thirteenth embodiments.
[0050] As part of a fifteenth embodiment, the disclosed implants
are designed for implantation in the inferior iridocorneal angle,
wherein the remaining features of the implants are described herein
e.g., as in the first through fourteenth embodiments.
[0051] As part of a sixteenth embodiment, the disclosed implants
comprise 5 .mu.g, 15 .mu.g or 26 .mu.g of travoprost, wherein the
remaining features of the implants are described herein e.g., as in
the first through fifteenth embodiments. Alternatively, as part of
a the disclosed implants comprise 5 .mu.g, 15 .mu.g or 26 .mu.g of
travoprost; and comprises a polymer networks formed by reacting a
plurality of polyethylene glycol (PEG) units comprising groups
which are susceptible to nucleophilic attack with one or more PEG
or Lysine based-amine groups selected from 4a20K PEG NH2, 8a20K PEG
NH2, and trilysine, wherein the remaining features of the hydrogel
are described herein e.g., as in the first through seventh
embodiments.
[0052] As part of a seventeenth embodiment, the disclosed implants
are fully degraded following complete release of travoprost,
wherein the remaining features of the implants are described herein
e.g., as in the first through fifteenth embodiments. Alternatively,
as part of a seventeenth embodiment, the hydrogel implant is fully
degraded after about 12 months, after about 11 months, after about
10 months, after about 9 months, after about 8 months, after about
6 months, after about 5 months, after about 4 months, after about 3
months, after about 2 months, after about 1 month (i.e., after
about 30 days) following complete release of travoprost, wherein
the remaining features of the implants are described herein e.g.,
as in the first through fifteenth embodiments. Alternatively, as
part of a seventeenth embodiment, the hydrogel implant is fully
degraded following at least 90% (e.g., at least 91%, at least 92%,
at least 93%, at least 94%, at least 95%, at least 96%, at least
97%, at least 98%, or at least 99%) release of travoprost, wherein
the remaining features of the implants are described herein e.g.,
as in the first through fifteenth embodiments.
[0053] Methods and Uses
[0054] The disclosed implants are useful in lowering ocular
pressure. Thus, provided herein are methods of lowering ocular
pressure in a subject in need thereof comprising administering a
hydrogel implant described herein. Also disclosed in the use of a
disclosed implant for lowering ocular pressure in a subject.
Further provided is the use of a disclosed implant in the
manufacture of a medicament for lowering ocular pressure.
[0055] Also provided are methods of treating ocular hypertension in
a subject in need thereof comprising administering a hydrogel
implant described herein. Also disclosed in the use of a disclosed
implant for treating ocular hypertension in a subject. Further
provided is the use of a disclosed implant in the manufacture of a
medicament for treating ocular hypertension.
[0056] Also provided are methods for treating glaucoma (open angle
glaucoma) in a subject in need thereof comprising administering a
hydrogel implant described herein. Also disclosed in the use of a
disclosed implant for treating glaucoma (open angle glaucoma) in a
subject. Further provided is the use of a disclosed implant in the
manufacture of a medicament for treating glaucoma (open angle
glaucoma).
EXEMPLIFICATION
[0057] The present invention will now be illustrated by the
following non-limiting examples.
[0058] Synthetic Methods
[0059] Intracameral Depot comprises travoprost as the active
pharmaceutical ingredient (API), polylactide (PLA) microparticles
which provide sustained delivery of the API and 8-arm polyethylene
glycol (PEG) based hydrogel conjugated with fluorescein which
serves as the inactive delivery platform.
TABLE-US-00001 Microparticle Encapsulation Step Manufacturing
Action 1 Prepare Polyvinyl Alcohol (PVA) stock solution in water. 2
Prepare dispersed phase (DP) by dissolving travoprost and PLA in
dichloromethane (DCM). 3 Prepare continuous phase (CP) by diluting
the PVA stock solution with water in a reactor and mix using an
overhead mixer. Prepare CP with DCM in a separate reactor if
required (for 4A, 7A, 9A, 5.5E PLA). 4 Inject the travoprost/PLA
solution (DP) at the inlet of the homogenizer through a cannula
positioned perpendicular to the flow of the continuous phase. After
homogenization, the nascent microparticles flow into the quench
reactor. 5 Mix the suspension in quench reactor for 16-24 hours to
allow evaporation of DCM and harden microparticles. 6 After
hardening, transfer microparticles from the outlet of the quench
reactor to the inlet of the sieve agitator using a peristaltic
pump. 7 Agitate microparticles on the sieve stack at a set rate
while/ washing with a continuous flow of water. Through this
process the microparticles are sieved to the specified size
fractions. 8 Aliquot the wet sieved microparticles into vials,
remove excess water from the vials and freeze dry. 9 Store dry
microparticles frozen until ready for depot fabrication.
TABLE-US-00002 Intracameral Implant Manufacturing Step
Manufacturing Action 1 Cut polyurethane tubing in appropriate
length pieces and insert dispensing tips to both ends of the tubing
pieces. 2 Formulate Trilysine Acetate (TLA)/NHS Fluorescein (FL)
solution and allow to react for 1-24 hours. 3 Formulate PEG
solution, microparticle suspension and aliquot appropriate amount
of TLA/FL solution in three different syringes to cast a single run
of depots. The OTX-TIC Intracameral Depot process is designed to
build four separate runs and pool them together in a single batch.
4 Combine content of three syringes (PEG/Microparticles/TLA-FL) and
inject through the dispensing tip into tubing pieces. Cap the
dispensing tips to close the tubing. Roll the tubing strands while
gel sets. Measure and record the gel time. Repeat for each run. 5
After gel has formed, place strands on drying fixtures and dry in
an incubator. 6 Remove the dry hydrogel strands from the drying
fixture and cut into 2.0 mm long implants. 7 Inspect each implant
under the microscope for the in-process visual, length and diameter
specifications. Discard any depots outside of the
specification.
TABLE-US-00003 Intracameral Depot Packaging and Yield Calculations
Step Manufacturing Action 1 Prepare syringe assemblies, package in
foil pouches and sterilize. 2 Attach a needle to the pre-sterilized
syringe assembly and poke a hole through the luer hub of the
needle. 3 Cut an appropriate size wire and feed it into the tip of
the needle. Ensure the wire is flush with the tip of the needle.
Withdraw the plunger and ensure the wire sits on top of the plunger
in upright position. Clip the syringe lock onto the plunger. 4
Insert a single implant into the needle. Insert a second piece of
wire into the tip of the wire. Place the protective cap on the
needle. 5 Place the syringe kit assembly in the foil pouch with the
needle cap oriented away from the opening of the foil pouch. Repeat
steps 2-5 for all syringe assemblies to be packaged. 6 Transfer
foil pouches into the glove box and allow foil pouches containing
depots in syringe assemblies to condition for 24-96 hours. 7 Seal
foil pouches and remove from the glove box. 8 Transfer the sealed
foil pouches in clearly labeled bags and store in a refrigerator
prior to sterilization. 9 Complete required yield calculations.
Example 1: Pharmacokinetic Release of Travoprost Using an Inventive
Hydrogel Implant
[0060] An intracameral implant comprising travoprost particles
formulated into a hydrogel matrix was injected into the anterior
chamber bilaterally (N=48) through a 27 gauge needle in 24 New
Zealand White rabbits on Day 0. In vivo drug release was assessed
by collecting aqueous humor samples from 6 eyes at Days 34 and 63,
and 12 eyes at Days 91, 126 and 153. Drug concentrations in the
aqueous humor were measured by LC/MS/MS. In vitro drug release was
assessed in physiologically representative conditions (PBS with a
surfactant (polyoxyl hydrogenated castor oil 40), pH 7.4,
37.degree. C.) at Days 28, 63, 92, 119, and 126, and analyzed by
UPLC/UV. Pharmacokinetic findings are shown below and in Table 1
and FIG. 5.
TABLE-US-00004 TABLE 1 In Vitro (PBS, pH 7.4, 37.degree. C.) In
Vivo (Rabbit AH) OS mean .+-. SD Travoprost Time OD Time travoprost
acid released (% of (months) (days) (ng/mL) Time (days) sustained
dose) 1 34 10.9 .+-. 4.9 28 25% 2 63 20.0 .+-. 8.8 63 52% 3 91 8.7
.+-. 3.5 92 79% 4 126 1.5 .+-. 2.2 119-126 100% 5 153 0.0 .+-. 0.0
NA NA Comparison with Maximum Travoprost free acid Concentration
from a single drop administration Travoprost Z at 1 hour 10.2 .+-.
3.0 NA NA
[0061] Aqueous humor sample in rabbits demonstrated elevated
travoprost free acid level post-injection through 3-4 months and an
absence at 5 months. The inventive implant released approximately
25% of the travoprost sustained dose in vitro each month for 4
months. The decrease in travoprost free acid concentration observed
at 4 months aligns with the decrease in in vitro release rate
observed at 4 months. The inventive implant drug concentrations of
10.9, 20.0, and 8.7 ng/mL at 1, 2, and 3 months are comparable to
or exceed the maximum travoprost free acid concentration of
10.2.+-.3.0 ng/mL from a single drop administration of Travoprost Z
(travoprost solution/drops Alcon laboratories) in rabbits at 1
hour, as reported in the literature (Travatan Z NDA 21-994). Longer
release durations (e.g., >6 months) are projected in humans
compared to rabbits due to lower anterior chamber temperatures and
reduced pH slowing hydrolysis of the biodegradable particles within
the inventive implant.
Example 2: Inventive Hydrogel Implants Effects on Central Corneal
Thickness
[0062] Studies were performed in beagle dogs to report central
corneal thickness (CCT). Inventive hydrogel implant, containing 18
.mu.g travoprost per implant and designed to degrade over time
providing sustained release of travoprost over 4-6 months, was
injected via a 27 gauge needle into the lower portion of the
anterior chamber on Day 0 (Table 2), where the implant resides in
the iridocorneal angle. Five individual pachymetry measurements
were obtained per eye and averaged together to report a mean CCT
and standard deviation per time point. Both implant treated eyes
were averaged per animal (Study 1: OD (n=6) and OS (n=6); Study 2:
OD (n=8) and OS (n=8)). Fluorescein visualization with a
cobalt-blue light illumination though a yellow filter was performed
at 3 days showing the implant residing in the inferior iridocorneal
angle (FIG. 1). Ultrasound images in beagles showing the implant
residing in the iridocorneal angle at 1 month and 3 months after
injection is shown in FIG. 2.
TABLE-US-00005 TABLE 2 Pachy- Pachy- metry metry Duration Treatment
on Day 0 Time- Device Study (months) N OD OS points Used 1 7 12
Inventive Implant Baseline & Ultrasound months Pachymeter 0.5,
1-7 2 4 8 Untreated Vehicle Baseline & Ultrasound (no Control
months Pachymeter implant) (no drug) 0.5, 1-7 16 Inventive
Implant
[0063] Administration into the anterior chamber of beagle eyes
demonstrated no statistically significant differences in CCT
(one-way ANOVA with post-hoc tukey test P.gtoreq.0.05) over 7
months (FIG. 3). Baseline CCT was 596.+-..mu.m. It was also found
that there was no statistically significant difference
(P.gtoreq.0.05) in CCT measured in implanted eyes over 4 months
when compared to either untreated or vehicle control eyes in
beagles (FIG. 4).
Example 3--Pharmacokinetics
[0064] a. Pharmacokinetics in Dogs Administered Inventive
(Travoprost) Implant--PK Study
[0065] The purpose of the study was to inject the inventive
hydrogel implant containing either 5 .mu.g, 15 .mu.g or 26 .mu.g of
the active ingredient travoprost into the anterior chamber of
beagle dogs and collect aqueous humor and plasma samples over time
to assess the travoprost and travoprost free acid pharmacokinetic
profile using the same batch of hydrogel test articles containing
18 .mu.g of travoprost per implant that was assessed in the 120-day
Intracameral Ocular Toxicity Study in Beagle Dogs. A secondary
assessment for pharmacodynamic evaluation measured the intraocular
pressure and pupil diameter over the study duration. A safety
evaluation included daily clinical observations and daily ocular
irritation assessments over the study duration.
[0066] Drug levels of travoprost (prodrug ester) and travoprost
free acid (active) in plasma and aqueous humor (AH) released from
inventive hydrogel were determined in beagles over 4 months to
generate pharmacokinetic profiles. For aqueous humor (via
paracentesis) and plasma sampling the 12 animals were divided into
4 groups with 3 animals (n=6 eyes) per group in the following
manner: Group 1 (Pre-Dose; Weeks 2, 10); Group 2 (1 hour Post Dose;
Weeks 4. 12); Group 3 (4 hours Post Dose; Weeks 6, 14); and Group 4
(1 Day Post Dose; Weeks 8, 16). Sample analysis was performed using
a validated LC-MS/MS assay method.
[0067] All travoprost (LOQ=0.5 ng/mL) and travoprost free acid
(LOQ=0.25 ng/mL) plasma values were reported to be below the limit
of quantitation (LOQ). This result below the LOQ in plasma was
anticipated since the travoprost sustained release dose from the
implant is primarily delivered over a period of 4-months into the
systemic system. Additionally it was shown previously that plasma
concentrations below the LOQ (LOQ=0.01 ng/mL) are generally
observed following topical ocular dosing of TRAVATAN (travoprost
ophthalmic solution) 0.004%, with no demonstration of
accumulation.
[0068] Travoprost and travoprost free acid concentrations were
measured in beagle AH that were collected pre-dose and post-dose (1
and 4 hours, and at 2, 4, 6, 8, 10, 12, 14 and 16 weeks) to
determine pharmacokinetics of drug levels in AH. The LOQ for this
method is 0.05 ng/mL and values less than the LOQ are reported as
zero. Test results are presented in Table 3. The T.sub.max for
travoprost occurs 1 hour post dose with a reported mean C.sub.max
of 68.7 ng/mL. The T.sub.max for travoprost free acid occurs 4
hours post dose with a reported mean C.sub.max of 16.7 ng/mL. The
TFA levels in beagles were an average of 1.4 ng/mL (range 0.3 to
4.2 ng/mL) for the 18 .mu.g dosage strength from Days 1 to 112.
TABLE-US-00006 TABLE 3 Ocular Pharmacokinetic/Toxicokinetic Study
Summary for Travoprost and Travoprost Free Acid in the Aqueous
Humor of Beagle Dogs Following Intracameral Administration of
OTX-TIC Travoprost Travoprost Free Acid (ng/mL) (ng/mL) Mean
Standard Mean Standard Time (n = 6 eyes) Deviation (n = 6 eyes)
Deviation Pre-dose 0.0 0.0 0.0 0.0 1 hour 68.7 39.8 6.5 5.0 4 hours
26.1 23.8 16.7 13.1 1 day 13.5 10.0 2.3 2.7 14 days 0.6 0.7 0.8 0.9
28 days 0.1 0.2 4.2 1.7 42 days 0.1 0.1 1.1 0.4 56 days 0.0 0.0 0.3
0.3 70 days 0.0 0.1 2.0 2.1 84 days 0.0 0.0 1.3 1.2 98 days 0.0 0.0
0.3 0.2 112 days 0.0 0.0 0.3 0.4 T.sub.max 1 hour n.a. 4 hours n.a.
C.sub.max 68.7 39.8 16.7 13.1
[0069] The T.sub.max aligns with the in vitro burst release from
inventive implant, which occurs within 1 day of dissolution testing
in release media. Steady state drug release (zero-order kinetics)
from inventive implant is observed from Day 1 through 4 months
during dissolution testing in release media, as seen in FIG. 6. The
in vitro release of the test articles studied was performed in
biorelevant conditions that utilized a dissolution media of
1.times. PBS, 0.5% polyoxyl 40 hydrogenated castor oil, 0.01%
sodium fluoride, pH 7.2-7.4 performed at 37.degree. C. The polyoxyl
40 hydrogenated castor oil is added as a nonionic surfactant to aid
travoprost solubility to ensure sink conditions and it is used for
this purpose to aid solubility in commercial Travatan.RTM. eye drop
formulations. Because of the duration of the release test, sodium
fluoride is added as a bacteriostatic agent to the release media.
The basis of travoprost release from inventive implant is the
degradation of the PLA microparticles to lower molecular weights by
ester hydrolysis in the presence of water and the subsequent
release of the entrapped travoprost from within the
microparticles.
[0070] b. Pharmacokinetics in Dogs Administered Inventive
(Travoprost) Implant--Dose Response PK/PD/Persistence/Tolerability
Study
[0071] The purpose of this study was to investigate aqueous humor
pharmacokinetics, pharmacodynamics (intraocular pressure "IOP" and
pupil diameter "PD"), implant persistence, implant location with
imaging, and eye tolerability after a single anterior chamber
(intracameral) injection of inventive implant comprising travoprost
in male beagle dogs over a 7-month period at two dosage strengths.
Inventive implant containing 14 .mu.g or 41 .mu.g travoprost per
implant was administered via intracameral injection in 12
normotensive beagles (n=6 beagles/12 eyes per dosage strength).
This section will discuss the pharmacokinetic portion of this
study.
[0072] Drug levels of travoprost (prodrug ester) and travoprost
free acid (active) in aqueous humor (AH) released from inventive
implant were determined in beagles over the study duration to
generate pharmacokinetic profiles. For aqueous humor sampling via
paracentesis the 12 animals were divided into 4 groups with 3
animals (n=6 eyes) per group in the following manner: Low
Dose--Group 1 (Days 29, 92, 148, 211 OU eyes); Low Dose--Group 2
(Pre-Dose OD eyes, Days 59, 120, 183 OU eyes); High Dose--Group 3
(Days 29, 92, 148, 211 OU eyes); and High Dose--Group 4 (Pre-Dose
OD eyes, Days 59, 120, 183 OU eyes). Sample analysis was performed
using a validated LC-MS/MS assay method. The LOQ for this method is
0.050 ng/mL and values less than the LOQ are reported as zero.
[0073] Travoprost and travoprost free acid (TFA) concentrations
were measured as <LOQ for all pre-dose AH samples. The
travoprost ester form in the AH was <LOQ for all study
timepoints and only TFA levels above the LOQ were observed. It has
been demonstrated that travoprost released from a sustained
released intracameral depot converts to the active travoprost free
acid form in the aqueous humor within the anterior chamber of
normotensive beagle eyes. The mean TFA results for both dosage
strengths are presented in FIG. 7. Results demonstrate an average
TFA concentration with standard deviations in the beagle AH of
1.1.+-.0.2 ng/mL for the low dosage strength and 3.0.+-.0.8 ng/mL
for the high dosage strength through 120 days. Following 120 days
the values drop to 0.1 ng/mL for both dosage strengths and then are
below the LOQ for the remainder of the study.
[0074] A comparison between the travoprost concentrations released
in vitro was made to the concentrations measured in vivo in the
beagle AH over the study duration. The amount of travoprost
released from the test articles in vitro was converted to daily
concentrations by determining the daily amount of travoprost mass
released between sampling points in vitro divided by the aqueous
humor daily flow rate in beagles (8.5 mL/day). For a comparable in
vitro and in vivo hydrolytic degradation rate the in vitro value
approximates the theoretical maximal concentration of cumulative
travoprost and/or TFA in the beagle AH. This is plotted on the
right side y-axis in FIG. 8 and compared to the PK profiles
previously presented in FIG. 6 for the low- and high dose
formulations. Results demonstrate an approximate 10-fold difference
in concentration for both dosage strengths between the in vivo TFA
levels and the in vitro cumulative travoprost levels over the study
duration. This is an early demonstration of an in vitro/in vivo
relationship, showing an approximate bioavailability of 10% in an
animal model that is maintained over the study duration at two
different dosage strengths. The remaining 90% of released
travoprost most likely passes directly into outflow pathways due to
close proximity in the inferior angle. A dose relationship is
established since the 3.times. difference in TFA concentrations in
the AH correlates with the 3.times. difference in dose between the
low (14 .mu.g) and high (41 .mu.g) strengths assessed in this
study.
Example 4--Pharmacology
[0075] a. Repeat Low Dose Administration in Lasered Hypertensive
Cynomolgus Monkeys
[0076] A Travatan.RTM. eye drop is a 25 uL drop size at 40 ug/mL or
1 ug per drop and it is administered once per day. A single and
twice a day dose of 0.3 .mu.g travoprost has been demonstrated to
reduce IOP by 19-26% and 19%-30% in lasered hypertensive cynomolgus
monkeys, respectively. A single dose of 0.1 .mu.g travoprost did
not significantly lower IOP, however continued twice a day dosing
at 0.1 .mu.g resulted in significant lowering of IOP after doses 4
and 5 (Travatan NDA 021257 Pharmacology Review). This IOP reduction
observed in the monkey with more frequent low dose delivery of
travoprost augments the basis for efficacy via sustained drug
delivery from the inventive (travoprost) implant.
[0077] b. IOP Reduction and Effects on Pupil Diameter in Dogs with
Travatan.RTM. Eye Drops
[0078] A pharmacodynamic study performed in twelve glaucomatous
beagles evaluated the changes in intraocular pressure (IOP) and
pupil diameter (PD) after instillations of 0.033, 0.0033, 0.001,
0.00033, and 0.0001% travoprost in multiple single-dose studies.
Concentrations of 0.00033, 0.001, and 0.0033% travoprost
significantly lowered IOP (see FIG. 9) and PD (see FIG. 10), but
the 0.0001% concentration provided limited IOP changes, although PD
changes were still significant. This suggests travoprost is
effective in the dog to lower IOP and reduce pupil size at
concentrations starting between 0.0001 and 0.00033% (1/12 the
commercially available concentration). However, only the
.gtoreq.0.001% travoprost dosage strength maintained IOP reduction
for 24 hours and no dosage strength maintained pupil constriction
for 24 hours.
[0079] c. IOP Reduction in Dogs with a Travoprost Intracameral
Implant
[0080] A pharmacodynamic study of a biodegradable travoprost
sustained release implant that was administered via intracameral
injection in 3 beagle dogs (n=6 eyes) was reported in the
literature (Robeson, RiLee, et al. "A 12-Month Study of the ENV515
(Travoprost) Intracameral Implant on Intraocular Pressure in Beagle
Dogs." Investigative Ophthalmology & Visual Science 58.8
(2017): 1072-1072). An IOP reduction was observed for 7-months with
an average treatment effect of a 38% decrease in IOP from baseline.
No dosing information was reported in this study.
[0081] d. IOP Reduction and Effects on Pupil Diameter in Dogs with
Inventive (Travoprost) Implant--PK Study
[0082] The purpose of the study was to inject inventive implant
into the anterior chamber of beagle dogs and collect aqueous humor
and plasma samples over time to assess the travoprost and
travoprost free acid pharmacokinetic profile using the same batch
of inventive implant test articles containing 18 .mu.g of
travoprost per implant that was assessed in the 120-day
Intracameral Ocular Toxicity Study in Beagle Dogs. A secondary
assessment for pharmacodynamic evaluation measured the intraocular
pressure and pupil diameter over the study duration is discussed in
this section. A safety evaluation included daily clinical
observations and daily ocular irritation assessments over the study
duration.
[0083] Inventive implant containing 18 .mu.g travoprost per implant
was administered via intracameral injection into both eyes of 12
normotensive beagles (n=24 eyes). Intraocular pressure was measured
using a TonoVet.RTM. tonometer and pupil diameter was measured
using a standard commercial ruler with both measurements done pre-
and monthly post-dose administration.
[0084] The IOP measurements taken pre- and post-administration of
inventive implant are presented in Table 4. All animals received
the same inventive implant test article and were divided into four
groups for pharmacokinetic sampling purposes. Results demonstrate a
mean baseline of IOP of 19 mmHg followed by an IOP reduction to 11
mmHg (-42%) at 1 month, 13 mmHg (-32%) at 2-months, 12 mmHg (-37%)
at 3-months and 15 mmHg (-21%) at 4 months demonstrating the
intended primary pharmacodynamic response of IOP reduction post
administration over the study duration.
TABLE-US-00007 TABLE 4 Pre- and Post-Inventive Implant
Administration Intraocular Pressure Measurements over the Study
Duration. Month Number Relative to Start Date Animal Pre-Dose Month
1 Month 2 Month 3 Month 4 Group # # R L R L R L R L R L Group 1
1101 21 16 7 8 11 11 12 11 19 17 1102 25 21 7 11 13 14 12 13 15 17
1103 17 17 10 13 13 11 11 12 11 12 Group 2 2101 19 12 10 11 12 13
14 13 13 13 2102 21 17 11 11 14 16 12 12 15 14 2103 22 20 12 14 13
11 12 11 15 14 Group 3 3101 19 21 11 10 13 16 13 12 15 15 3102 21
19 10 13 12 14 11 11 17 17 3003 18 17 10 10 11 10 12 13 13 16 Group
4 4101 21 18 11 11 12 10 11 10 14 12 4102 21 18 12 14 12 17 12 15
13 13 4004 21 19 12 9 14 11 14 12 17 14 Mean 19 11 13 12 15 STDEV 3
2 2 1 2
[0085] Travoprost is a miotic agent in beagles demonstrating strong
pupil constriction after administration of inventive implant. Pupil
diameter measurements taken pre- and post-administration of
inventive implant over the study duration are presented in Table 5.
Results demonstrate sustained pupil constriction following
inventive implant administration demonstrating a secondary
pharmacodynamic response in beagles over the 4-month study
duration.
TABLE-US-00008 TABLE 5 Pre- and Post-Inventive Implant
Administration Pupil Diameter Measurements over the Study Duration.
Month Number Relative to Start Date Group Animal Pre-Dose Month 1
Month 2 Month 3 Month 4 # # R L R L R L R L R L Group 1 1101 8 8 1
1 1 1 1 1 5 2 1102 7 7 3 2 <1 1 1 1 2 2 1103 8 8 3 2 6 5 4 5 4 3
Group 2 2101 7 7 1 1 <1 1 1 1 1 1 2102 9 9 2 2 3 4 2 3 4 4 2103
9 8 1 1 3 2 2 2 2 2 Group 3 3101 7 8 3 2 3 4 3 3 2 2 3102 8 7 5 3 5
3 4 3 1.5 1.5 3003 9 9 4 3 3 3 5 3 1 1 Group 4 4101 8 8 3 3 3 3 3 3
1 1.5 4102 9 8 4 <1 3 2 3 2 1 2 4004 8 8 3 2 4 2 3 3 4 2 Mean 8
2 3 3 2 STDEV 1 1 1 1 1
[0086] e. Reduction and Effects on Pupil Diameter in Dogs with
Inventive (Travoprost) Implant--Hydrogel
Persistence/PD/Tolerability Study
[0087] The purpose of this study was to investigate
pharmacodynamics (intraocular pressure "IOP" and pupil diameter
"PD"), implant persistence, and eye tolerability after a single
anterior chamber (intracameral) injection of inventive (travoprost)
implant in male beagle dogs over a 7-month period formulated with
two different persisting hydrogel formulations. Inventive implant
containing 15 .mu.g travoprost per implant formulated with either a
two month persisting hydrogel (Group 1, 8-arm 15K succinimidyl
glutarate) or a four month persisting hydrogel (Group 2, 8-arm 15K
succinimidyl azelate) was administered via intracameral injection
in 12 normotensive beagles (n=6 beagles/12 eyes per group). The
Group 2 hydrogel formulation composition was the same as tested in
Cohorts A (15 .mu.g travoprost dose) and B (26 .mu.g travoprost
dose) in the Phase 1 clinical study. A solid polylactide implant
(no travoprost) was administered via intracameral injection in 3
normotensive beagles (n=6 eyes) and served as a control arm in the
study (Group 3). This section will discuss the IOP (primary) and
pupil diameter (secondary) pharmacodynamic responses.
[0088] Intraocular pressure (IOP) was measured using a TonoVet.RTM.
tonometer and pupil diameter was measured using an embossed
pictorial scale on a penlight with both measurements done pre- and
monthly post-dose administration. IOP results for each study group
are reported in Table 6 and graphically represented as mean IOP
change relative to baseline in FIG. 11. Pupil diameter results for
each study group are reported in Table 7.
TABLE-US-00009 TABLE 6 Pre- and Post-Dose OTX-TIC Administration
IOP Measurements for Each Test Group over the Study Duration. Group
1 2 OTX-TIC OTX-TIC Two-month Four-month Persisting Persisting 3
Hydrogel Hydrogel Control Mean SD Mean SD Mean SD Time (mmHg)
(mmHg) (mmHg) (mmHg) (mmHg) (mmHg) Pre-Dose Baseline 1 23.2 2.9
23.8 3.9 21.4 2.3 Baseline 2 22.9 3.3 24.1 3.6 21.6 2.5 Baseline 3
23.8 2.5 24.8 4.2 20.3 1.7 Mean Baseline 23.3 2.9 24.2 3.9 21.1 2.3
Post-Dose 0.5 Months 16.6 2.0 16.0 2.8 19.7 2.9 1 Month 15.1 1.5
16.7 4.0 16.0 1.8 1.5 Months 19.9 4.9 21.0 3.2 21.3 2.1 2 Months
15.4 2.5 18.2 2.8 18.2 1.7 3 Months 17.6 2.1 20.2 4.3 19.0 1.5 4
Months 18.6 2.2 19.7 3.6 19.1 1.9 5 Months 20.6 3.3 23.4 4.4 19.4
2.8 6 Months 21.4 2.7 24.2 4.1 20.5 2.5 7 Months 22.0 2.8 26.1 4.6
22.5 1.3 SD denotes standard deviation
TABLE-US-00010 TABLE 7 Pre- and Post-Dose OTX-TIC Administration
Pupil Diameter Measurements for Each Test Group over the Study
Duration. Group 1 2 OTX-TIC OTX-TIC Two-month Four-month Persisting
Persisting 3 Hydrogel Hydrogel Control Mean SD Mean SD Mean SD Time
(mmHg) (mmHg) (mmHg) (mmHg) (mmHg) (mmHg) Baseline 7.3 0.5 7.0 0.6
6.0 0.0 (pre-dose) 0.5 Months 1.7 0.7 1.2 0.4 6.0 0.9 1 Month 2.4
0.7 2.3 0.8 7.0 0.0 1.5 Months 2.7 0.7 2.7 0.8 7.7 1.8 2 Months 2.8
0.7 1.5 0.7 6.7 0.5 3 Months 2.4 1.0 2.0 0.9 6.7 0.5 4 Months 3.3
1.7 2.5 1.4 6.3 0.5 5 Months 4.6 1.3 3.0 1.5 6.3 1.0 6 Months 5.5
0.5 5.2 1.0 6.7 0.8 7 Months 5.5 0.5 5.3 0.8 6.3 0.5 SD denotes
standard deviation
[0089] In this study, the median visual persistence of the Group 1
implant was 2 months and the Group 2 implant was 4 months. The
Group 2 duration is consistent with a median persistence finding of
4 months in a previous beagle study.
[0090] IOP results demonstrate that the 2-month persisting hydrogel
implant (Group 1) created a similar decrease in IOP compared to the
4-month persisting hydrogel implant (Group 2) through 4 months, and
statistically the mean difference from baseline IOP results were
within one-standard deviation between the two formulations, see
Table 6 and FIG. 11. Importantly, the IOP decrease at 3 months
between the present hydrogel (Group 2) or absent hydrogel (Group 1)
made no difference on the IOP reduction from baseline, whereby the
Group 1 hydrogel had been absent for 1 month in most eyes
indicating that travoprost release from the microparticles was
still regulating IOP reduction in the anterior chamber of the
beagle eye. Both travoprost containing hydrogel formulations
demonstrated a greater decrease in IOP compared to the control
article (Group 3).
[0091] The pupil diameter (PD) measurements taken pre- and
post-administration of inventive implant over the study duration
for each group are presented in Table 7. Following administration
through four months both inventive implant formulations (Groups 1
& 2) demonstrated a pronounced reduction in pupil diameter
(.gtoreq.4.0 mm) relative to baseline and Group 3 demonstrated no
reduction in pupil diameter compared to baseline. By 6 and 7 months
the pupil diameter returned to near baseline values for Groups 1
and 2.
Example 5: Safety, Tolerability and Efficacy of Inventive
(Travoprost) Implant in Subjects with Primary Open-Angle Glaucoma
or Ocular Hypertension
[0092] A 4-month low dose (15 .mu.g) or high dose (26 .mu.g) of
travoprost encapsulated in microparticles (4A/7A/9A/5.5E) was
formulated in a 12% inventive hydrogel comprising a polymer matrix
formed from 8a15K PEG-SAZ and trilysine with the 12% being the PEG
weight dived by the fluid weight times 100 and was injected via 27G
needle into the anterior chamber of 10 subjects over 7 months; one
eye per patient treated. See FIG. 12. Patient population was
controlled ocular hypertension or primary open-angle glaucoma;
open, normal anterior chamber angles on gonioscopy.
[0093] Primary outcomes were as follows. Diurnal IOP (8 AM, 10 AM,
4 PM) at Baseline, Day 14, Day 42, Day 85, Month 4 and Month 6.
Intraocular pressure at 8 AM at Day 1, Day 3, Day 7 and Day 28.
Safety evaluations, including adverse event reporting, ocular
comfort, global tolerance, BCVA, endothelial cell counts, and
pachymetry.
[0094] Mean IOP values were decreased in patients receiving both
OTX-TIC and topical travoprost as early as two days following
administration (FIGS. 13A and 13B). In patients receiving OTX-TIC,
mean IOP was decreased approximately 5-11 mmHg from Day 3 through
Month 9. Mean IOP values remained decreased from baseline values
through the study period (Month 7) and beyond (Month 9) in two of
two patients.
[0095] Upon injection, implant hydrated quickly and resided in the
iridocorneal angle. The implant was visualized in all subjects at
all visits through 7 months (FIG. 14). The implant was not observed
to move at slit lamp; in one subject, there was slight rotation
noted at the Day 14 visit as compared to the Day 7 visit. Implant
biodegraded in 2 of 2 subjects by Month 7.
[0096] Safety results: Adverse events reported included iritis
(n=2) and peripheral anterior synechiae (n=3); all were graded by
the investigator as mild or moderate. Patients received topical
rescue therapy at the discretion of the investigator as IOP
returned to baseline levels. 1 patient was rescued at Month 3.5.
Topical brimonidine/timolol given; both eyes required treatment. No
changes in endothelial cell counts or pachymetry from baseline for
5/5 subjects through Month 3; 3/3 subjects through Month 6; 2/2
subjects through Month 9 (FIG. 15). Additional studies were
performed using 15 .mu.g and 5 .mu.g travoprost encapsulated in
microparticles (4A/7A/9A and 4A/7A, respectively) in 12% for 15
.mu.g and 15% for 5 .mu.g hydrogels comprising a polymer matrix
formed from 8a15K PEG-SG and trilysine.
[0097] While we have described a number of embodiments of this, it
is apparent that our basic examples may be altered to provide other
embodiments that utilize the compounds and methods of this
disclosure. Therefore, it will be appreciated that the scope of
this disclosure is to be defined by the appended claims rather than
by the specific embodiments that have been represented by way of
example.
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