U.S. patent application number 17/254617 was filed with the patent office on 2021-04-29 for sustained-release drug delivery systems comprising an intraocular pressure lowering agent, a cnp compound, an npr-b compound, a tie-2 agonist, or neurotrophic agent for use for treating glaucoma or ocular hypertension.
The applicant listed for this patent is Cella Therapeutics, LLC. Invention is credited to Lukas Scheibler, Rhett M. Schiffman.
Application Number | 20210121534 17/254617 |
Document ID | / |
Family ID | 1000005348178 |
Filed Date | 2021-04-29 |
![](/patent/app/20210121534/US20210121534A1-20210429\US20210121534A1-2021042)
United States Patent
Application |
20210121534 |
Kind Code |
A1 |
Schiffman; Rhett M. ; et
al. |
April 29, 2021 |
SUSTAINED-RELEASE DRUG DELIVERY SYSTEMS COMPRISING AN INTRAOCULAR
PRESSURE LOWERING AGENT, A CNP COMPOUND, AN NPR-B COMPOUND, A TIE-2
AGONIST, OR NEUROTROPHIC AGENT FOR USE FOR TREATING GLAUCOMA OR
OCULAR HYPERTENSION
Abstract
This disclosure relates to a drug delivery system comprising an
intraocular pressure lowering agent, a neurotrophic agent, such as
a CNTF compound, a C-type Natriuretic Peptide (CNP) compound, a
Tie-2 agonist, a Natriuretic Peptide Receptor-B (NPR-B) compound,
or an apoptosis signaling fragment inhibitor (FAS) or FAS-ligand
(FASL) inhibitor, including any combination of these compounds and
a sustained delivery component. Methods of treating a glaucoma or
related conditions, medicaments, kits, uses and methods of
manufacturing are also described.
Inventors: |
Schiffman; Rhett M.; (Laguna
Beach, CA) ; Scheibler; Lukas; (Laguna Beach,
CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Cella Therapeutics, LLC |
Miami |
FL |
US |
|
|
Family ID: |
1000005348178 |
Appl. No.: |
17/254617 |
Filed: |
June 18, 2019 |
PCT Filed: |
June 18, 2019 |
PCT NO: |
PCT/US2019/037774 |
371 Date: |
December 21, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
62687172 |
Jun 19, 2018 |
|
|
|
62726029 |
Aug 31, 2018 |
|
|
|
62747060 |
Oct 17, 2018 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 38/1796 20130101;
A61K 47/55 20170801; A61K 47/6425 20170801; A61K 45/06 20130101;
A61K 31/165 20130101; A61K 38/22 20130101; A61K 47/64 20170801 |
International
Class: |
A61K 38/22 20060101
A61K038/22; A61K 38/17 20060101 A61K038/17; A61K 47/64 20060101
A61K047/64; A61K 31/165 20060101 A61K031/165; A61K 45/06 20060101
A61K045/06; A61K 47/55 20060101 A61K047/55 |
Claims
1. A drug delivery system comprising: a first active pharmaceutical
ingredient (API) and a sustained delivery component, wherein the
first API is an intraocular pressure lowering agent, a neurotrophic
agent, a C-type Natriuretic Peptide (CNP), a Natriuretic Peptide
Receptor-B (NPR-B), an apoptosis signaling fragment (FAS) inhibitor
or a FAS-ligand (FASL) inhibitor, or a combination thereof.
2. The drug delivery system of claim 1, further comprising a second
API, wherein the first API is the intraocular pressure lowering
agent and the second API is the neurotrophic agent.
3. The drug delivery system of claim 1, further comprising a second
API, wherein the first API is the intraocular pressure lowering
agent and the second API is the CNP.
4. The drug delivery system of claim 1, further comprising a second
API, wherein the first API is the intraocular pressure lowering
agent and the second API is the NPR-B.
5. The drug delivery system of claim 1, further comprising a second
API, wherein the first API is the intraocular pressure lowering
agent and the second API is the FAS inhibitor or the FASL
inhibitor.
6. The drug delivery system of claim 1, further comprising a second
API, wherein the first API is the neurotrophic agent and the second
API is the CNP.
7. The drug delivery system of claim 1, further comprising a second
API, wherein the first API is the neurotrophic agent and the second
API is the NRP-B.
8. The drug delivery system of claim 1, further comprising a second
API, wherein the first API is the neurotrophic agent and the second
API is the FAS inhibitor or the FASL inhibitor.
9. The drug delivery system of claim 1, further comprising a second
API, wherein the first API is the CNP and the second API is the
NRP-B.
10. The drug delivery system of claim 1, further comprising a
second API, wherein the first API is the CNP and the second API is
the FAS inhibitor or the FASL inhibitor.
11. The drug delivery system of claim 1, further comprising a
second API, wherein the first API is the NRP-B and the second API
is the FAS inhibitor or the FASL inhibitor.
12. The drug delivery system of claim 1, further comprising a
second API, wherein the first API and the second API are not
covalently bonded to one another.
13. The drug delivery system of claim 1, further comprising a
second API, wherein the first API is covalently bonded to the
second API.
14. The drug delivery system of claim 1, wherein the first API is
covalently bonded to the sustained delivery component.
15. The drug delivery system of claim 1, further comprising a
second API, wherein the second API is covalently bonded to the
sustained delivery component.
16. The drug delivery system of claim 1, having about 100 .mu.g to
about 1 mg of the first API.
17. The drug delivery system of claim 1, further comprising a
second API, having about 100 .mu.g to about 1 mg of the second
API.
18. The drug delivery system of claim 1, wherein the implant has a
weight of about 300 .mu.g to about 10 mg.
19. A method of treating a glaucoma comprising administering a drug
delivery system of claim 1, to a mammal in suffering from glaucoma
or ocular hypertension.
20. The method of claim 19, wherein the drug delivery system is
injected into an eye of the mammal, and wherein the mammal is a
human being.
21.-26. (canceled)
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of United States
Provisional Application Nos. 62/687,172, filed Jun. 19, 2018,
62/726,029, filed Aug. 31, 2018, and 62/747,060, filed Oct. 17,
2018, which are incorporated by reference herein in their entirety.
Application C4019.10002WO01, filed Jun. 18, 2019, is also
incorporated by reference herein in its entirety. A PCT application
being concurrently filed on Jun. 18, 2019 under docket number
C4019.10002WO01, with inventors Rhett M. Schiffman and Lukas
Scheibler, is also incorporated by reference herein in its
entirety.
SEQUENCE LISTING
[0002] The instant application contains a Sequence Listing which
has been submitted electronically in ASCII format and is hereby
incorporated by reference in its entirety. Said ASCII copy, created
on Jun. 17, 2019, is named V3563_10001 WO01_SL.txt and is 4,008
bytes in size.
SUMMARY
[0003] This disclosure relates to a drug delivery system comprising
an intraocular pressure lowering agent, a neurotrophic agent, such
as a CNTF compound, a C-type Natriuretic Peptide (CNP) compound, a
Tie-2 agonist, a Natriuretic Peptide Receptor-B (NPR-B) compound,
or an apoptosis signaling fragment inhibitor (FAS) or FAS-ligand
(FASL) inhibitor, including any combination of these compounds and
a sustained delivery component. This type of drug delivery system
can be used to treat a glaucoma or ocular hypertension.
[0004] Some embodiments include a drug delivery system comprising:
a first active pharmaceutical ingredient (API) and a sustained
delivery component, wherein the first API is an intraocular
pressure lowering agent, a neurotrophic agent, a C-type Natriuretic
Peptide (CNP), a Natriuretic Peptide Receptor-B (NPR-B), an
apoptosis signaling fragment (FAS) inhibitor or a FAS-ligand (FASL)
inhibitor, or a combination thereof.
[0005] Some embodiments include a method of treating a glaucoma
comprising administering a drug delivery system of described herein
to a mammal in suffering from glaucoma or ocular hypertension.
[0006] Some embodiments include use of an intraocular pressure
lowering agent, a neurotrophic agent, a CNP, a NPR-B, a FAS
inhibitor or a FASL inhibitor, or a combination thereof, in the
manufacture of a drug delivery system described herein for the
treatment of glaucoma or ocular hypertension.
[0007] Some embodiments include a kit comprising a drug delivery
system described herein and a label with instructions for use of
the drug delivery system for the treatment of a glaucoma.
DETAILED DESCRIPTION
[0008] With respect to a drug delivery system comprising an
intraocular pressure lowering agent, a neurotrophic agent, such as
a CNTF compound, a CNP compound, a NPR-B compound, or a FAS or FASL
inhibitor (referred to herein as "subject drug delivery system"),
and a sustained delivery component, any suitable prostaglandin
receptor agonist, prostanoid receptor agonist, or any suitable
prostaglandin compound, including any prostaglandin acid form (e.g.
the acid obtained by hydrolyzing prostaglandin esters), any
prostaglandin salt form, or any prostaglandin ester prodrug, may be
used. Examples include bimatoprost (amide) or the bimatoprost acid,
i.e. the carboxylic acid obtained when the amide group is
hydrolyzed, travoprost, travoprost acid, latanoprost, latanoprost
acid, latanoprostene, tafluprost, tafluprost acid, etc., a
prostaglandin EP2 agonist, a prostaglandin EP3 agonist, or a
combination thereof.
[0009] Any suitable amount of a prostaglandin compound, such as
bimatoprost, bimatoprost acid, travoprost, travoprost acid,
latanoprost, latanoprost acid, latanoprostene, tafluprost,
tafluprost acid, etc., a prostaglandin EP2 agonist, or a
prostaglandin EP3 agonist, may be used in the drug delivery system.
For example, a drug delivery system may contain about 0.01-1 .mu.g,
about 1-2 .mu.g, about 2-3 .mu.g, about 3-4 .mu.g, about 4-5 .mu.g,
about 5-6 .mu.g, about 6-7 .mu.g, about 7-8 .mu.g, about 8-9 .mu.g,
about 9-10 .mu.g, about 0.01-3 .mu.g, about 3-6 .mu.g, about 6-10
.mu.g, about 0.01-10 .mu.g, about 10-20 .mu.g, about 20-30 .mu.g,
about 30-40 .mu.g, about 40-50 .mu.g, about 50-60 .mu.g, about
60-70 .mu.g, about 70-80 .mu.g, about 80-90 .mu.g, about 90-100
.mu.g, about 0.010-30 .mu.g, about 30-60 .mu.g, about 60-100 .mu.g,
about 0.01-100 .mu.g, about 0.010-100 .mu.g, about 100-200 .mu.g,
about 200-300 .mu.g, about 300-400 .mu.g, about 400-500 .mu.g,
about 500-600 .mu.g, about 600-700 .mu.g, about 700-800 .mu.g,
about 800-900 .mu.g, about 900-1,000 .mu.g, about 0.01-300 .mu.g,
about 300-600 .mu.g, about 600-1,000 .mu.g, about 0.01-1 mg, about
0.1-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg,
about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10
mg, about 0.01-3 mg, about 3-6 mg, about 6-10 mg, or about 0.01-10
mg of one of these compounds. These amounts may also apply to a
situation where the drug is present in a covalently bonded form,
such as to another drug or to the sustained delivery component. For
example, a compound of Formula 1 or Formula 3 may be said to
contain 1 mg of the prostaglandin compound even though the
prostaglandin is covalently bound to other parts of the drug
delivery system.
[0010] Use of the amounts given above for a prostaglandin compound,
such as bimatoprost, bimatoprost acid, travoprost, travoprost acid,
latanoprost, latanoprost acid, latanoprostene, tafluprost,
tafluprost acid, etc., a prostaglandin EP2 agonist, or a
prostaglandin EP3 agonist, in a drug delivery system, may provide a
drug delivery system that provides therapeutic levels of the
prostaglandin compound for about 1-4 weeks, about 1-3 months, about
3-6 months, about 6-9 months, about 9-12 months, about 12-18
months, about 18-24 months, about 2-5 years, about 5-10 years, or
longer.
##STR00001##
[0011] In some embodiments, the prostaglandin receptor agonist,
prostanoid receptor agonist, or prostaglandin compound is
bimatoprost (amide) or the bimatoprost acid. In some embodiments,
the prostaglandin receptor agonist or prostaglandin compound is
travoprost. In some embodiments, the prostaglandin receptor agonist
or prostaglandin compound is travoprost acid. In some embodiments,
the prostaglandin receptor agonist or prostaglandin compound is
latanoprost. In some embodiments, the prostaglandin receptor
agonist or prostaglandin compound is latanoprost acid. In some
embodiments, the prostaglandin receptor agonist or prostaglandin
compound is latanoprostene. In some embodiments, the prostaglandin
receptor agonist or prostaglandin compound is tafluprost. In some
embodiments, the prostaglandin receptor agonist or prostaglandin
compound is tafluprost acid. In some embodiments, the prostaglandin
receptor agonist or prostaglandin compound is a prostaglandin EP2
receptor agonist. In some embodiments, the prostaglandin receptor
agonist or prostaglandin compound is a prostaglandin EP3 receptor
agonist.
[0012] Some subject drug delivery systems may include an
intraocular pressure lowering agent, such as a beta blocker, an
alpha agonist, a carbonic anhydrase inhibitor, a Rho Kinase
inhibitor, a cannabinoid receptor agonist, etc. Some subject drug
delivery systems may include two or more intraocular pressure
lowering agents, such as a prostaglandin compound, a prostaglandin
receptor agonist, or a prostanoid receptor agonist; a beta blocker;
an alpha agonist; a carbonic anhydrase inhibitor; a cannabinoid
receptor agonist; a Rho kinase inhibitor; etc. Some subject drug
delivery systems contain two or more of: a prostaglandin receptor
agonist (or a prostaglandin compound or prostanoid receptor
agonist), a beta blocker, an alpha agonist, a carbonic anhydrase
inhibitor, a cannabinoid receptor agonist, a Rho kinase inhibitor,
etc.
[0013] With respect to a subject drug delivery system, any suitable
beta blocker, or any suitable beta adrenergic antagonist, may be
used. Examples include timolol, betaxolol, levobunolol,
metipranolol, etc., or a combination thereof. In some embodiments,
the beta blocker is timolol. In some embodiments, the beta blocker
is betaxolol. In some embodiments, the beta blocker is levobunolol.
In some embodiments, the beta blocker is metipranolol.
[0014] Any suitable amount of a beta blocker or a beta adrenergic
antagonist, such as timolol, betaxolol, levobunolol, or
metipranolol, may be used in the drug delivery system. For example,
a drug delivery system may contain about 0.01-1 .mu.g, about 1-2
.mu.g, about 2-3 .mu.g, about 3-4 .mu.g, about 4-5 .mu.g, about 5-6
.mu.g, about 6-7 .mu.g, about 7-8 .mu.g, about 8-9 .mu.g, about
9-10 .mu.g, about 0.01-3 .mu.g, about 3-6 .mu.g, about 6-10 .mu.g,
about 0.01-10 .mu.g, about 10-20 .mu.g, about 20-30 .mu.g, about
30-40 .mu.g, about 40-50 .mu.g, about 50-60 .mu.g, about 60-70
.mu.g, about 70-80 .mu.g, about 80-90 .mu.g, about 90-100 .mu.g,
about 0.01-30 .mu.g, about 30-60 .mu.g, about 60-100 .mu.g, about
0.01-100 .mu.g, about 0.01-100 .mu.g, about 100-200 .mu.g, about
200-300 .mu.g, about 300-400 .mu.g, about 400-500 .mu.g, about
500-600 .mu.g, about 600-700 .mu.g, about 700-800 .mu.g, about
800-900 .mu.g, about 900-1,000 .mu.g, about 0.01-300 .mu.g, about
300-600 .mu.g, about 600-1,000 .mu.g, about 0.01-1 mg, about 0.1-1
mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about
5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg,
about 0.01-3 mg, about 3-6 mg, about 6-10 mg, or about 0.01-10 mg
of one of these compounds. These amounts may also apply to a
situation where the drug is present in a covalently bonded form,
such as to another drug or to the sustained delivery component.
[0015] Use of the amounts given above for a beta blocker or a beta
adrenergic antagonist, such as timolol, betaxolol, levobunolol, or
metipranolol, in a drug delivery system, may provide a drug
delivery system that provides therapeutic levels of the beta
blocker or the beta adrenergic antagonist for about 1-4 weeks,
about 1-3 months, about 3-6 months, about 6-9 months, about 9-12
months, about 12-18 months, about 18-24 months, about 2-5 years,
about 5-10 years, or longer.
[0016] With respect to a subject drug delivery system, any suitable
alpha agonist, or alpha adrenergic agonist, may be used. Examples
include brimonidine, apraclonidine, etc., or a combination thereof.
In some embodiments, the alpha agonist is brimonidine. In some
embodiments, the alpha agonist is apraclonidine.
[0017] Any suitable amount of an alpha agonist or an alpha
adrenergic agonist such as brimonidine, apraclonidine, etc., may be
used in the drug delivery system. For example, a drug delivery
system may contain about 0.01-1 .mu.g, about 1-2 .mu.g, about 2-3
.mu.g, about 3-4 .mu.g, about 4-5 .mu.g, about 5-6 .mu.g, about 6-7
.mu.g, about 7-8 .mu.g, about 8-9 .mu.g, about 9-10 .mu.g, about
0.01-3 .mu.g, about 3-6 .mu.g, about 6-10 .mu.g, about 0.01-10
.mu.g, about 10-20 .mu.g, about 20-30 .mu.g, about 30-40 .mu.g,
about 40-50 .mu.g, about 50-60 .mu.g, about 60-70 .mu.g, about
70-80 .mu.g, about 80-90 .mu.g, about 90-100 .mu.g, about 0.01-30
.mu.g, about 30-60 .mu.g, about 60-100 .mu.g, about 0.01-100 .mu.g,
about 0.1-100 .mu.g, about 100-200 .mu.g, about 200-300 .mu.g,
about 300-400 .mu.g, about 400-500 .mu.g, about 500-600 .mu.g,
about 600-700 .mu.g, about 700-800 .mu.g, about 800-900 .mu.g,
about 900-1,000 .mu.g, about 0.01-300 .mu.g, about 300-600 .mu.g,
about 600-1,000 .mu.g, about 0.01-1 mg, about 0.1-1 mg, about 1-2
mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about
6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 0.01-3 mg,
about 3-6 mg, about 6-10 mg, or about 0.01-10 mg of one of these
compounds. These amounts may also apply to a situation where the
drug is present in a covalently bonded form, such as to another
drug or to the sustained delivery component.
[0018] Use of the amounts given above for an alpha agonist or an
alpha adrenergic agonist such as brimonidine, apraclonidine, etc.,
in a drug delivery system, may provide a drug delivery system that
provides therapeutic levels of the alpha agonist or the alpha
adrenergic agonist for about 1-4 weeks, about 1-3 months, about 3-6
months, about 6-9 months, about 9-12 months, about 12-18 months,
about 18-24 months, about 2-5 years, about 5-10 years, or
longer.
[0019] With respect to a subject drug delivery system, any suitable
carbonic anhydrase inhibitor may be used. Examples include
brinzolamide, acetazolamide, dorzolamide, methazolamide, etc., or a
combination thereof. In some embodiments, the carbonic anhydrase
inhibitor is brinzolamide. In some embodiments, the carbonic
anhydrase inhibitor is acetazolamide. In some embodiments, the
carbonic anhydrase inhibitor is dorzolamide. In some embodiments,
the carbonic anhydrase inhibitor is methazolamide.
[0020] Any suitable amount of a carbonic anhydrase inhibitor such
as brinzolamide, acetazolamide, dorzolamide, methazolamide, etc.,
may be used in the drug delivery system. For example, a drug
delivery system may contain about 0.01-1 .mu.g, about 1-2 .mu.g,
about 2-3 .mu.g, about 3-4 .mu.g, about 4-5 .mu.g, about 5-6 .mu.g,
about 6-7 .mu.g, about 7-8 .mu.g, about 8-9 .mu.g, about 9-10
.mu.g, about 0.01-3 .mu.g, about 3-6 .mu.g, about 6-10 .mu.g, about
0.01-10 .mu.g, about 10-20 .mu.g, about 20-30 .mu.g, about 30-40
.mu.g, about 40-50 .mu.g, about 50-60 .mu.g, about 60-70 .mu.g,
about 70-80 .mu.g, about 80-90 .mu.g, about 90-100 .mu.g, about
0.01-30 .mu.g, about 30-60 .mu.g, about 60-100 .mu.g, about
0.01-100 .mu.g, about 0.1-100 .mu.g, about 100-200 .mu.g, about
200-300 .mu.g, about 300-400 .mu.g, about 400-500 .mu.g, about
500-600 .mu.g, about 600-700 .mu.g, about 700-800 .mu.g, about
800-900 .mu.g, about 900-1,000 .mu.g, about 0.01-300 .mu.g, about
300-600 .mu.g, about 600-1,000 .mu.g, about 0.01-1 mg, about 0.1-1
mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about
5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg,
about 0.01-3 mg, about 3-6 mg, about 6-10 mg, or about 0.01-10 mg
of one of these compounds. These amounts may also apply to a
situation where the drug is present in a covalently bonded form,
such as to another drug or to the sustained delivery component.
[0021] Use of the amounts given above for a carbonic anhydrase
inhibitor such as brinzolamide, acetazolamide, dorzolamide,
methazolamide, etc., in a drug delivery system, may provide a drug
delivery system that provides therapeutic levels of the carbonic
anhydrase inhibitor for about 1-4 weeks, about 1-3 months, about
3-6 months, about 6-9 months, about 9-12 months, about 12-18
months, about 18-24 months, about 2-5 years, about 5-10 years, or
longer.
[0022] With respect to a subject drug delivery system, any suitable
cholinergic may be used. Examples include pilocarpine, carbachol,
etc., or a combination thereof. In some embodiments, the
cholinergic may be pilocarpine. In some embodiments, the
cholinergic may be carbachol.
[0023] Any suitable amount of a cholinergic, such as pilocarpine,
carbachol, etc., may be used in the drug delivery system. For
example, a drug delivery system may contain about 0.01-1 .mu.g,
about 1-2 .mu.g, about 2-3 .mu.g, about 3-4 .mu.g, about 4-5 .mu.g,
about 5-6 .mu.g, about 6-7 .mu.g, about 7-8 .mu.g, about 8-9 .mu.g,
about 9-10 .mu.g, about 0.01-3 .mu.g, about 3-6 .mu.g, about 6-10
.mu.g, about 0.01-10 .mu.g, about 10-20 .mu.g, about 20-30 .mu.g,
about 30-40 .mu.g, about 40-50 .mu.g, about 50-60 .mu.g, about
60-70 .mu.g, about 70-80 .mu.g, about 80-90 .mu.g, about 90-100
.mu.g, about 0.01-30 .mu.g, about 30-60 .mu.g, about 60-100 .mu.g,
about 0.01-100 .mu.g, about 0.1-100 .mu.g, about 100-200 .mu.g,
about 200-300 .mu.g, about 300-400 .mu.g, about 400-500 .mu.g,
about 500-600 .mu.g, about 600-700 .mu.g, about 700-800 .mu.g,
about 800-900 .mu.g, about 900-1,000 .mu.g, about 0.01-300 .mu.g,
about 300-600 .mu.g, about 600-1,000 .mu.g, about 0.01-1 mg, about
0.1-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg,
about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10
mg, about 0.01-3 mg, about 3-6 mg, about 6-10 mg, or about 0.01-10
mg of one of these compounds. These amounts may also apply to a
situation where the drug is present in a covalently bonded form,
such as to another drug or to the sustained delivery component.
[0024] Use of the amounts given above for a cholinergic, such as
pilocarpine, carbachol, etc., in a drug delivery system, may
provide a drug delivery system that provides therapeutic levels of
the cholinergic for about 1-4 weeks, about 1-3 months, about 3-6
months, about 6-9 months, about 9-12 months, about 12-18 months,
about 18-24 months, about 2-5 years, about 5-10 years, or
longer.
[0025] With respect to a subject drug delivery system, any suitable
Rho kinase inhibitor, such as netarsudil, may be used. In some
embodiments, the Rho kinase inhibitor is netarsudil.
[0026] Any suitable amount of a Rho kinase inhibitor, such as
netarsudil, may be used in the drug delivery system. For example, a
drug delivery system may contain about 0.01-1 .mu.g, about 1-2
.mu.g, about 2-3 .mu.g, about 3-4 .mu.g, about 4-5 .mu.g, about 5-6
.mu.g, about 6-7 .mu.g, about 7-8 .mu.g, about 8-9 .mu.g, about
9-10 .mu.g, about 0.01-3 .mu.g, about 3-6 .mu.g, about 6-10 .mu.g,
about 0.01-10 .mu.g, about 10-20 .mu.g, about 20-30 .mu.g, about
30-40 .mu.g, about 40-50 .mu.g, about 50-60 .mu.g, about 60-70
.mu.g, about 70-80 .mu.g, about 80-90 .mu.g, about 90-100 .mu.g,
about 0.01-30 .mu.g, about 30-60 .mu.g, about 60-100 .mu.g, about
0.01-100 .mu.g, about 0.1-100 .mu.g, about 100-200 .mu.g, about
200-300 .mu.g, about 300-400 .mu.g, about 400-500 .mu.g, about
500-600 .mu.g, about 600-700 .mu.g, about 700-800 .mu.g, about
800-900 .mu.g, about 900-1,000 .mu.g, about 0.01-300 .mu.g, about
300-600 .mu.g, about 600-1,000 .mu.g, about 0.01-1 mg, about 0.1-1
mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about
5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg,
about 0.01-3 mg, about 3-6 mg, about 6-10 mg, or about 0.01-10 mg
of one of these compounds. These amounts may also apply to a
situation where the drug is present in a covalently bonded form,
such as to another drug or to the sustained delivery component.
[0027] Use of the amounts given above fora Rho kinase inhibitor,
such as netarsudil, in a drug delivery system, may provide a drug
delivery system that provides therapeutic levels of the Rho kinase
inhibitor for about 1-4 weeks, about 1-3 months, about 3-6 months,
about 6-9 months, about 9-12 months, about 12-18 months, about
18-24 months, about 2-5 years, about 5-10 years, or longer.
[0028] With respect to a subject drug delivery system, any suitable
Tie-2 agonist may be used, such as angiopoietin-1, angiopoietin-2,
angiopoietin-3, angiopoietin-4, etc.
[0029] Any suitable amount of a Tie-2 agonist, such as
angiopoietin-1, angiopoietin-2, angiopoietin-3, angiopoietin-4,
etc., may be used in the drug delivery system. For example, a drug
delivery system may contain about 0.01-1 .mu.g, about 1-2 .mu.g,
about 2-3 .mu.g, about 3-4 .mu.g, about 4-5 .mu.g, about 5-6 .mu.g,
about 6-7 .mu.g, about 7-8 .mu.g, about 8-9 .mu.g, about 9-10
.mu.g, about 0.01-3 .mu.g, about 3-6 .mu.g, about 6-10 .mu.g, about
0.01-10 .mu.g, about 10-20 .mu.g, about 20-30 .mu.g, about 30-40
.mu.g, about 40-50 .mu.g, about 50-60 .mu.g, about 60-70 .mu.g,
about 70-80 .mu.g, about 80-90 .mu.g, about 90-100 .mu.g, about
0.01-30 .mu.g, about 30-60 .mu.g, about 60-100 .mu.g, about
0.01-100 .mu.g, about 0.1-100 .mu.g, about 100-200 .mu.g, about
200-300 .mu.g, about 300-400 .mu.g, about 400-500 .mu.g, about
500-600 .mu.g, about 600-700 .mu.g, about 700-800 .mu.g, about
800-900 .mu.g, about 900-1,000 .mu.g, about 0.0100-300 .mu.g, about
300-600 .mu.g, about 600-1,000 .mu.g, about 0.01-1 mg, about 0.1-1
mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about
5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg,
about 0.01-3 mg, about 3-6 mg, about 6-10 mg, or about 0.01-10 mg
of one of these compounds. These amounts may also apply to a
situation where the drug is present in a covalently bonded form,
such as to another drug or to the sustained delivery component.
[0030] Use of the amounts given above for Tie-2 agonist, such as
angiopoietin-1, angiopoietin-2, angiopoietin-3, angiopoietin-4,
etc., in a drug delivery system, may provide a drug delivery system
that provides therapeutic levels of the Tie-2 agonist for about 1-4
weeks, about 1-3 months, about 3-6 months, about 6-9 months, about
9-12 months, about 12-18 months, about 18-24 months, about 2-5
years, about 5-10 years, or longer.
[0031] With respect to a subject drug delivery system, a
neurotrophic agent can include a CNTF compound or another
neurotrophic agent, a CNTF compound includes any compound having a
structure or activity similar to Ciliary neurotrophic factor
(CNTF), including CNTF, protein derivatives of CNTF, or a CNTF
peptide. Examples include CNTF, a peptide containing part of the
CNTF sequence, such as Peptide 6 (P6; Ac-VGDGGLFEKKL-NH2 (SEQ ID
NO: 1)) and Peptide 21 (P21; Ac-DGGL.sup.AG-NH2 (SEQ ID NO: 2)),
recombinant CNTF (rhCNTF), or a neurotrophic peptide identified in
U.S. Pat. No. 8,592,374, which is incorporated herein by reference
for its disclosure related to neurotrophic peptides, including
neurotrophic peptides having an adamantly group at the C- and/or
N-terminal end, or any other peptide having similar biological
activity to CNTF. Other neurotrophic agents include nerve growth
factor (NGF), Brain-derived neurotrophic factor (BDNF), glial
cell-derived neurotrophic factor (GDNF), etc.
[0032] Any suitable amount of a neurotrophic agent, such as a CNTF
compound, NGF, BDNF, GDNF, etc., may be used in the drug delivery
system. For example, a drug delivery system may contain about
0.01-1 .mu.g, about 1-2 .mu.g, about 2-3 .mu.g, about 3-4 .mu.g,
about 4-5 .mu.g, about 5-6 .mu.g, about 6-7 .mu.g, about 7-8 .mu.g,
about 8-9 .mu.g, about 9-10 .mu.g, about 0.01-3 .mu.g, about 3-6
.mu.g, about 6-10 .mu.g, about 0.01-10 .mu.g, about 10-20 .mu.g,
about 20-30 .mu.g, about 30-40 .mu.g, about 40-50 .mu.g, about
50-60 .mu.g, about 60-70 .mu.g, about 70-80 .mu.g, about 80-90
.mu.g, about 90-100 .mu.g, about 0.01-30 .mu.g, about 30-60 .mu.g,
about 60-100 .mu.g, about 0.01-100 .mu.g, about 0.1-100 .mu.g,
about 100-200 .mu.g, about 200-300 .mu.g, about 300-400 .mu.g,
about 400-500 .mu.g, about 500-600 .mu.g, about 600-700 .mu.g,
about 700-800 .mu.g, about 800-900 .mu.g, about 900-1,000 .mu.g,
about 0.01-300 .mu.g, about 300-600 .mu.g, about 600-1,000 .mu.g,
about 0.01-1 mg, about 0.1-1 mg, about 1-2 mg, about 2-3 mg, about
3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg,
about 8-9 mg, about 9-10 mg, about 0.01-3 mg, about 3-6 mg, about
6-10 mg, or about 0.01-10 mg of one of these compounds. These
amounts may also apply to a situation where the drug is present in
a covalently bonded form, such as to another drug or to the
sustained delivery component.
[0033] Use of the amounts given above for a neurotrophic agent,
such as a CNTF compound, NGF, BDNF, GDNF, etc., in a drug delivery
system, may provide a drug delivery system that provides
therapeutic levels of the neurotrophic agent for about 1-4 weeks,
about 1-3 months, about 3-6 months, about 6-9 months, about 9-12
months, about 12-18 months, about 18-24 months, about 2-5 years,
about 5-10 years, or longer.
[0034] With respect to a subject drug delivery system, a CNP
compound includes any compound having a structure or activity
similar to C-type Natriuretic Peptide, including natural C-type
Natriuretic Peptide.
[0035] Any suitable amount of a CNP compound, such as natural CNP,
may be used in the drug delivery system. For example, a drug
delivery system may contain about 0.01-1 .mu.g, about 1-2 .mu.g,
about 2-3 .mu.g, about 3-4 .mu.g, about 4-5 .mu.g, about 5-6 .mu.g,
about 6-7 .mu.g, about 7-8 .mu.g, about 8-9 .mu.g, about 9-10
.mu.g, about 0.01-3 .mu.g, about 3-6 .mu.g, about 6-10 .mu.g, about
0.01-10 .mu.g, about 10-20 .mu.g, about 20-30 .mu.g, about 30-40
.mu.g, about 40-50 .mu.g, about 50-60 .mu.g, about 60-70 .mu.g,
about 70-80 .mu.g, about 80-90 .mu.g, about 90-100 .mu.g, about
0.01-30 .mu.g, about 30-60 .mu.g, about 60-100 .mu.g, about
0.01-100 .mu.g, about 0.1-100 .mu.g, about 100-200 .mu.g, about
200-300 .mu.g, about 300-400 .mu.g, about 400-500 .mu.g, about
500-600 .mu.g, about 600-700 .mu.g, about 700-800 .mu.g, about
800-900 .mu.g, about 900-1,000 .mu.g, about 0.01-300 .mu.g, about
300-600 .mu.g, about 600-1,000 .mu.g, about 0.01-1 mg, about 0.1-1
mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about
5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg,
about 0.01-3 mg, about 3-6 mg, about 6-10 mg, or about 0.01-10 mg
of one of these compounds. These amounts may also apply to a
situation where the drug is present in a covalently bonded form,
such as to another drug or to the sustained delivery component.
[0036] Use of the amounts given above for a CNP compound, such as
natural CNP, in a drug delivery system, may provide a drug delivery
system that provides therapeutic levels of the CNP compound for
about 1-4 weeks, about 1-3 months, about 3-6 months, about 6-9
months, about 9-12 months, about 12-18 months, about 18-24 months,
about 2-5 years, about 5-10 years, or longer.
[0037] With respect to a subject drug delivery system, an NPR-B
compound includes any compound having a structure or activity
similar to Natriuretic Peptide Receptor-B, including natural
Natriuretic Peptide Receptor-B.
[0038] Any suitable amount of a NPR-B compound, such as natural
NPR-B, may be used in the drug delivery system. For example, a drug
delivery system may contain about 0.01-1 .mu.g, about 1-2 .mu.g,
about 2-3 .mu.g, about 3-4 .mu.g, about 4-5 .mu.g, about 5-6 .mu.g,
about 6-7 .mu.g, about 7-8 .mu.g, about 8-9 .mu.g, about 9-10
.mu.g, about 0.01-3 .mu.g, about 3-6 .mu.g, about 6-10 .mu.g, about
0.01-10 .mu.g, about 10-20 .mu.g, about 20-30 .mu.g, about 30-40
.mu.g, about 40-50 .mu.g, about 50-60 .mu.g, about 60-70 .mu.g,
about 70-80 .mu.g, about 80-90 .mu.g, about 90-100 .mu.g, about
0.01-30 .mu.g, about 30-60 .mu.g, about 60-100 .mu.g, about
0.01-100 .mu.g, about 0.1-100 .mu.g, about 100-200 .mu.g, about
200-300 .mu.g, about 300-400 .mu.g, about 400-500 .mu.g, about
500-600 .mu.g, about 600-700 .mu.g, about 700-800 .mu.g, about
800-900 .mu.g, about 900-1,000 .mu.g, about 0.01-300 .mu.g, about
300-600 .mu.g, about 600-1,000 .mu.g, about 0.01-1 mg, about 0.1-1
mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg, about
5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg,
about 0.01-3 mg, about 3-6 mg, about 6-10 mg, or about 0.01-10 mg
of one of these compounds. These amounts may also apply to a
situation where the drug is present in a covalently bonded form,
such as to another drug or to the sustained delivery component.
[0039] Use of the amounts given above for a NPR-B compound, such as
natural NPR-B, in a drug delivery system, may provide a drug
delivery system that provides therapeutic levels of the NPR-B
compound for about 1-4 weeks, about 1-3 months, about 3-6 months,
about 6-9 months, about 9-12 months, about 12-18 months, about
18-24 months, about 2-5 years, about 5-10 years, or longer.
[0040] Useful FAS or FASL inhibitors include bicyclol, FLIP; MET12
(HHIYLGAVNYIY (SEQ ID NO: 3), HHIYLGATNYIY (SEQ ID NO: 4), or
H.sup.60HIYLGATNYIY.sup.71 (SEQ ID NO: 4)), or a shorter fragment
thereof, such as a tetramer having a sequence YLGA (SEQ ID NO: 5),
or a fragment having a sequence homology of at least about 10%, at
least about 20%, at least about 30%, at least about 40%, at least
about 50%, at least about 60%, at least about 70%, at least about
80%, or at least about 90% sequence homology to MET12, including
compound having a sequence shown in Table 1 below, such as compound
1, compound 2, compound 3, compound 4, compound 5, compound 6,
compound 7, compound 8, compound 9, compound 10, or compound 11, ON
L1204 (e.g. a peptide comprising or consisting of a sequence
HHIYLGATNYIY (SEQ ID NO: 4)); other MET12 derivatives such as a
compound having a sequence: H.sup.60HIYLGATNYIY.sup.71-NH.sub.2
(SEQ ID NO: 4), FAS apoptotic inhibitory molecule [FAIM]; NOL3
[nucleolar protein 3 (apoptosis repressor with CARD domain [ARC]),
etc.]; DcR1; DcR2; or DcR3.
##STR00002##
TABLE-US-00001 TABLE 1 Compound Sequence SEQ ID NO: 1 YLGA 5 2
IYLGA 6 3 YLGAV 7 4 HIYLGA 8 5 IYLGAV 9 6 HIYLGAV 10 7 IYLGAVN 11 8
HHIYLGA 12 9 YLGAVNY 13 10 HHIYLGAV 14 11 YLGAVNYI 15
[0041] Any suitable amount of a FAS or FASL inhibitor, such as
bicyclol, FLIP, compound 1, compound 2, compound 3, compound 4,
compound 5, compound 6, compound 7, compound 8, compound 9,
compound 10, or compound 11, ONL1204,
H.sup.60HIYLGATNYIY.sup.71-NH.sub.2 (SEQ ID NO: 4), FAIM, NOL3,
DcR1, DcR2, DcR3, etc., may be used in the drug delivery system.
For example, a drug delivery system may contain about 0.01-1 .mu.g,
about 1-2 .mu.g, about 2-3 .mu.g, about 3-4 .mu.g, about 4-5 .mu.g,
about 5-6 .mu.g, about 6-7 .mu.g, about 7-8 .mu.g, about 8-9 .mu.g,
about 9-10 .mu.g, about 0.01-3 .mu.g, about 3-6 .mu.g, about 6-10
.mu.g, about 0.01-10 .mu.g, about 10-20 .mu.g, about 20-30 .mu.g,
about 30-40 .mu.g, about 40-50 .mu.g, about 50-60 .mu.g, about
60-70 .mu.g, about 70-80 .mu.g, about 80-90 .mu.g, about 90-100
.mu.g, about 0.01-30 .mu.g, about 30-60 .mu.g, about 60-100 .mu.g,
about 0.01-100 .mu.g, about 0.1-100 .mu.g, about 100-200 .mu.g,
about 200-300 .mu.g, about 300-400 .mu.g, about 400-500 .mu.g,
about 500-600 .mu.g, about 600-700 .mu.g, about 700-800 .mu.g,
about 800-900 .mu.g, about 900-1,000 .mu.g, about 0.0100-300 .mu.g,
about 300-600 .mu.g, about 600-1,000 .mu.g, about 0.01-1 mg, about
0.1-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg,
about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10
mg, about 0.01-3 mg, about 3-6 mg, about 6-10 mg, or about 0.01-10
mg of one of these compounds. These amounts may also apply to a
situation where the drug is present in a covalently bonded form,
such as to another drug or to the sustained delivery component.
[0042] Use of the amounts given above for a FAS or FASL inhibitor,
such as bicyclol, FLIP, compound 1, compound 2, compound 3,
compound 4, compound 5, compound 6, compound 7, compound 8,
compound 9, compound 10, or compound 11, ONL1204,
H.sup.60HIYLGATNYIY.sup.71-NH.sub.2 (SEQ ID NO: 4), FAIM, NOL3,
DcR1, DcR2, DcR3, etc., in a drug delivery system, may provide a
drug delivery system that provides therapeutic levels of the NPR-B
compound for about 1-4 weeks, about 1-3 months, about 3-6 months,
about 6-9 months, about 9-12 months, about 12-18 months, about
18-24 months, about 2-5 years, about 5-10 years, or longer.
[0043] Table 2 below depicts drug combinations that are of
particular interest in a subject drug delivery system.
TABLE-US-00002 TABLE 2 Drug 1 Drug 2 PG beta blocker PG alpha
agonist PG carbonic anhydrase inhibitor PG Rho Kinase inhibitor
beta blocker alpha agonist beta blocker carbonic anhydrase
inhibitor beta blocker Rho Kinase inhibitor alpha agonist carbonic
anhydrase inhibitor alpha agonist Rho Kinase inhibitor carbonic
anhydrase inhibitor Rho Kinase inhibitor intraocular pressure
lowering agent neurotrophic agent intraocular pressure lowering
agent CNTF compound intraocular pressure lowering agent CNP
compound intraocular pressure lowering agent NPR-B compound CNTF
compound CNP compound CNTF compound NPR-B compound CNTF compound PG
CNTF compound beta blocker CNTF compound alpha agonist CNTF
compound carbonic anhydrase inhibitor CNTF compound Rho Kinase
inhibitor CNP compound NPR-B compound CNP compound PG CNP compound
beta blocker CNP compound alpha agonist CNP compound carbonic
anhydrase inhibitor CNP compound Rho Kinase inhibitor NPR-B
compound PG NPR-B compound beta blocker NPR-B compound alpha
agonist NPR-B compound carbonic anhydrase inhibitor NPR-B compound
Rho Kinase inhibitor Tie-2 agonist PG Tie-2 agonist beta blocker
Tie-2 agonist alpha agonist Tie-2 agonist carbonic anhydrase
inhibitor Tie-2 agonist Rho Kinase inhibitor Tie-2 agonist
cannabinoid receptor agonist Tie-2 agonist CNTF compound Tie-2
agonist CNP compound Tie-2 agonist NPR-B compound Cannabinoid
receptor agonist PG Cannabinoid receptor agonist beta blocker
Cannabinoid receptor agonist alpha agonist Cannabinoid receptor
agonist carbonic anhydrase inhibitor Cannabinoid receptor agonist
Rho Kinase inhibitor Cannabinoid receptor agonist CNTF compound
Cannabinoid receptor agonist CNP compound Cannabinoid receptor
agonist NPR-B compound Neurotrophic agent CNP compound Neurotrophic
agent NPR-B compound Neurotrophic agent PG Neurotrophic agent beta
blocker Neurotrophic agent alpha agonist Neurotrophic agent
carbonic anhydrase inhibitor Neurotrophic agent Rho Kinase
inhibitor FAS or FASL inhibitor PG FAS or FASL inhibitor beta
blocker FAS or FASL inhibitor alpha agonist FAS or FASL inhibitor
carbonic anhydrase inhibitor FAS or FASL inhibitor Rho Kinase
inhibitor FAS or FASL inhibitor cannabinoid receptor agonist FAS or
FASL inhibitor CNTF compound FAS or FASL inhibitor CNP compound FAS
or FASL inhibitor NPR-B compound FAS or FASL inhibitor Tie-2
agonist
PG: prostaglandin compound or prostaglandin receptor agonist,
including acid, salt, and ester or ester prodrug forms
[0044] Some drug delivery systems include a combination of
bimatoprost acid and bicyclol, which is either directly covalently
bonded, bonded with a linking group, or wherein both are bonded to
a polymer or to a silicon-based drug delivery particle.
[0045] With respect to a subject drug delivery system comprising a
prostaglandin receptor agonist or a prostaglandin compound and an
intraocular pressure lowering agent, in some embodiments, the
prostaglandin receptor agonist is covalently bound to the
intraocular pressure lowering agent. In some embodiments, the
prostaglandin receptor agonist is covalently bound to the
intraocular pressure lowering agent via a linking group.
[0046] For example, some compounds containing a prostaglandin
compound or a prostaglandin receptor agonist covalently bound to an
intraocular pressure lowering agent by a linking group are
represented by Formula 1 or 1A:
PG-L-IOP Formula 1
IOP-L-IOP Formula 1A
wherein PG-H or PG-OH is a prostaglandin receptor agonist, such as
a prostaglandin compound or prostaglandin receptor agonist recited
above; and each IOP-H or IOP-OH is independently an intraocular
pressure lowering agent, such as an intraocular pressure lowering
agent recited above.
[0047] With respect to a subject drug delivery system comprising
both the prostaglandin receptor agonist and the neurotrophic agent,
such as the CNTF compound, in some embodiments, the prostaglandin
receptor agonist and the neurotrophic agent, such as the CNTF
compound, are covalently bound to one another. In some embodiments,
the prostaglandin receptor agonist and the neurotrophic agent, such
as the CNTF compound, are covalently bound to one another via a
linking group.
[0048] Some subject drug delivery systems comprise both the
intraocular pressure lowering agent and the neurotrophic agent,
such as the CNTF compound. In some embodiments, the intraocular
pressure lowering agent and the neurotrophic agent, such as the
CNTF compound, are covalently bound to one another. In some
embodiments, the intraocular pressure lowering agent and the
neurotrophic agent, such as the CNTF compound, are covalently bound
to one another via a linking group.
[0049] Some subject drug delivery systems comprise both the
intraocular pressure lowering agent and the CNP compound. In some
embodiments, the intraocular pressure lowering agent and the CNP
compound are covalently bound to one another. In some embodiments,
the intraocular pressure lowering agent and the CNP compound are
covalently bound to one another via a linking group.
[0050] Some subject drug delivery systems comprise the intraocular
pressure lowering agent and the NPR-B compound. In some
embodiments, the intraocular pressure lowering agent and the NPR-B
compound are covalently bound to one another. In some embodiments,
the intraocular pressure lowering agent and the NPR-B compound are
covalently bound to one another via a linking group.
[0051] Some subject drug delivery systems comprise both the
neurotrophic agent, such as the CNTF compound, and the CNP
compound. In some embodiments, the neurotrophic agent, such as the
CNTF compound, and the CNP compound are covalently bound to one
another. In some embodiments, the neurotrophic agent, such as the
CNTF compound, and the CNP compound are covalently bound to one
another via a linking group.
[0052] Some subject drug delivery systems comprise both the
neurotrophic agent, such as the CNTF compound, and the NPR-B
compound. In some embodiments, the neurotrophic agent, such as the
CNTF compound, and the NPR-B compound are covalently bound to one
another. In some embodiments, the neurotrophic agent, such as the
CNTF compound, and the NPR-B compound are covalently bound to one
another via a linking group.
[0053] Some subject drug delivery systems comprise both and the CNP
compound and the NPR-B compound. In some embodiments, the CNP
compound and the NPR-B compound are covalently bound to one
another. In some embodiments, the CNP compound and the NPR-B
compound are covalently bound to one another via a linking
group.
[0054] For example, some compounds containing a prostaglandin
compound or a prostaglandin receptor covalently bound to a CNTF
compound by a linking group are represented by Formula 2:
PG-L-CNTF Formula 2
wherein PG-H or PG-OH is a prostaglandin receptor agonist, such as
a prostaglandin compound or prostaglandin receptor agonist recited
above; and CNTF-H or CNTF-OH is a CNTF compound, such as a CNTF
compound recited above.
[0055] Other covalently linked compounds include compounds
represented by Formula 2A, 2B, 2C, 2D, 2E, or 2F:
IOP-L-CNTF Formula 2A
IOP-L-CNP Formula 2B
IOP-L-NPRB Formula 2C
CNTF-L-CNP Formula 2D
CNTF-L-NPRB Formula 2E
CNP-L-NPRB Formula 2F
Wherein IOP-H is intraocular pressure lowering agent, such as an
intraocular pressure lowering agent recited above; CNTF-H or
CNTF-OH is a CNTF compound, such as a CNTF compound recited above;
CNP-H or CNP-OH is a CNP compound; and NPR-H or NPR-OH is a NPR-B
compound.
[0056] With respect to any relevant structural representation, such
as Formula 1, 2, 2A, 2B, 2C, 2D, 2E, 2F, 3, 4, 5, 3D, 4D, or 5D
(Formulas 3-5 and 3D-5D are depicted below), L is a linking group
represented by the empirical formula C.sub.aH.sub.bO.sub.cN.sub.d
or C.sub.aH.sub.bO.sub.c.
[0057] With respect to any L, a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,
11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. In some embodiments, a
is 1-5, 5-10, 10-15, 15-20, 1-10, or 10-20.
[0058] With respect to any L, b is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,
11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27,
28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, or 43.
In some embodiments, b is 1-10, 10-20, 20-30, 30-40, 40-43, 1-15,
15-30, or 30-43.
[0059] With respect to any L, c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or
10. In some embodiments, c is 0-2, 2-4, 4-6, 6-8, 8-10, 0-3, 3-6,
or 6-10.
[0060] With respect to any L, d is 0, 1, or 2. In some embodiments,
d is 0. In some embodiments, d is 1. In some embodiments, d is
2.
[0061] In some embodiments, L may be represented by Formula L-1,
L-2, L-3, L-4, L-5, L-6, L-7, or L-8:
##STR00003##
[0062] With respect to any relevant structural representation, such
as Formula L-1, L-2, L-3, L-4, L-5, L-6, L-7, or L-8, L1 may be
represented by the empirical formula C.sub.eH.sub.fO.sub.gN.sub.h
or C.sub.eH.sub.fO.sub.g.
[0063] With respect to any L.sup.1, e is 1, 2, 3, 4, 5, 6, 7, 8, 9,
10, 11, 12, 13, 14, 15, 16, 17, or 18. In some embodiments, e is
1-5, 5-10, 10-15, 15-18, 1-10, or 10-18.
[0064] With respect to any L.sup.1, f is 1, 2, 3, 4, 5, 6, 7, 8, 9,
10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26,
27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, or 38. In some
embodiments, f is 1-10, 10-20, 20-30, 30-38, 1-15, 15-30, or
30-38.
[0065] With respect to any L.sup.1, g is 0, 1, 2, 3, 4, 5, 6, 7, or
8. In some embodiments, g is 0-2, 2-4, 4-6, 6-8, 0-3, 3-6, or
6-8.
[0066] With respect to any L.sup.1, h is 0, 1, or 2. In some
embodiments, h is 0. In some embodiments, h is 1. In some
embodiments, h is 2.
[0067] With respect to any relevant structural representation, such
as Formula L-1, L-2, L-3, L-4, L-5, L-6, L-7, or L-8, in some
embodiments L1 may be:
--(CH.sub.2).sub.i--(OCH.sub.2CH.sub.2).sub.j--O--(CH.sub.2).sub.k--
[Formula L.sup.1-1],
--(CH.sub.2).sub.i--(OCH.sub.2CH.sub.2).sub.j--O--CONH--(CH.sub.2).sub.k-
-- [Formula L.sup.1-2],
--(C.sub.iH.sub.2i)--(OCH.sub.2CH.sub.2).sub.j--O--(C.sub.kH.sub.2k)--
[Formula L.sup.1-3],
--(C.sub.iH.sub.2i)--(OCH.sub.2CH.sub.2).sub.j--O--CONH--(C.sub.kH.sub.2-
k)-- [Formula L.sup.1-4],
--NH.sub.2(CH.sub.2).sub.i--(OCH.sub.2CH.sub.2).sub.j--O--(CH.sub.2).sub-
.k-- [Formula L.sup.1-5],
--NH.sub.2(CH.sub.2).sub.i--(OCH.sub.2CH.sub.2).sub.j--O--CONH--(CH.sub.-
2).sub.k-- [Formula L.sup.1-6],
--NH.sub.2(C.sub.iH.sub.2i)--(OCH.sub.2CH.sub.2).sub.j--O--(C.sub.kH.sub-
.2k)-- [Formula L.sup.1-7], or
--NH.sub.2(C.sub.iH.sub.2i)--(OCH.sub.2CH.sub.2).sub.j--O--CONH--(C.sub.-
kH.sub.2k)-- [Formula L.sup.1-8].
[0068] With respect to any relevant structural representation, such
as Formula L.sup.1-1, L.sup.1-2, 3, L.sup.1-4, L.sup.1-5,
L.sup.1-6, L.sup.1-7, or L.sup.1-8, i is 0, 1, 2, 3, or 4. In some
embodiments, i is 2.
[0069] With respect to any relevant structural representation, such
as Formula L.sup.1-1, L.sup.1-2, L.sup.1-3, L.sup.1-4, L.sup.1-5,
L.sup.1-6, L.sup.1-7, or L.sup.1-8, j is 0, 1, 2, 3, 4, or 5.
[0070] With respect to any relevant structural representation, such
as Formula L.sup.1-1, L.sup.1-2, L.sup.1-3, L.sup.1-4, L.sup.1-5,
L.sup.1-6, L.sup.1-7, or L.sup.1-8, k is 0, 1, 2, 3, or 4.
[0071] With respect to Formula L.sup.1-1, L.sup.1-2, L.sup.1-3,
L.sup.1-4, L.sup.1-5, L.sup.1-6, L.sup.1-7, or L.sup.1-8, any H
atom of an NH or an NH.sub.2 moiety may be replaced with a
substituent, such as C.sub.1-12 hydrocarbyl, C.sub.1-6 hydrocarbyl,
or C.sub.1-3 hydrocarbyl group, including phenyl, C.sub.1-12 alkyl,
C.sub.1-6 alkyl, C.sub.3-12 cycloalkyl, C.sub.3-6 cycloalkyl,
C.sub.1-3 alkyl, C.sub.2-12 alkenyl, C.sub.2-6 alkenyl, C.sub.3-12
cycloalkenyl, C.sub.3-6 cycloalkenyl, C.sub.2-3 alkenyl, C.sub.2-12
alkynyl, C.sub.2-6 alkynyl, C.sub.8-12 cycloalkynyl, C.sub.2-3
alkynyl, etc.
[0072] In some embodiments, H-L-H, HO-L-H, HO-L-OH, H.sub.2N-L-H,
or H.sub.2N-L-NH.sub.2, or HO-L-NH.sub.2 is one or more of the
following:
##STR00004##
[0073] In some embodiments; a drug delivery system comprises one of
the following drug combinations; including salts; free acids; or
free based of the drugs; either covalently linked (such as by a
linking group L, including groups represented by Formula L-1, L-2,
L-3, L-4, L-5, L-6, L-7, or L-8 or not covalently linked:
bimatoprost or bimatoprost acid and travoprost or travoprost acid;
bimatoprost or bimatoprost acid and latanoprost or latanoprost
acid; bimatoprost or bimatoprost acid and latanoprostene;
bimatoprost or bimatoprost acid and tafluprost or tafluprost acid;
bimatoprost or bimatoprost acid and timolol; bimatoprost or
bimatoprost acid and betaxolol; bimatoprost or bimatoprost acid and
levobunolol; bimatoprost or bimatoprost acid and metipranolol;
bimatoprost or bimatoprost acid and brimonidine; bimatoprost or
bimatoprost acid and apraclonidine; bimatoprost or bimatoprost acid
and brinzolamide; bimatoprost or bimatoprost acid and
acetazolamide; bimatoprost or bimatoprost acid and dorzolamide;
bimatoprost or bimatoprost acid and methazolamide; bimatoprost or
bimatoprost acid and pilocarpine; bimatoprost or bimatoprost acid
and carbachol; bimatoprost or bimatoprost acid and netarsudil;
bimatoprost or bimatoprost acid and angiopoietin-1; bimatoprost or
bimatoprost acid and angiopoietin-2; bimatoprost or bimatoprost
acid and angiopoietin-3; bimatoprost or bimatoprost acid and
angiopoietin-4; bimatoprost or bimatoprost acid and CNTF;
bimatoprost or bimatoprost acid and Peptide 6; bimatoprost or
bimatoprost acid and Peptide 21; bimatoprost or bimatoprost acid
and recombinant CNTF; bimatoprost or bimatoprost acid and NGF;
bimatoprost or bimatoprost acid and BDNF; bimatoprost or
bimatoprost acid and GDNF; bimatoprost or bimatoprost acid and
C-type Natriuretic Peptide; bimatoprost or bimatoprost acid and
natural C-type Natriuretic Peptide; bimatoprost or bimatoprost acid
and Natriuretic Peptide Receptor-B; bimatoprost or bimatoprost acid
and bicyclol; bimatoprost or bimatoprost acid and FLIP; bimatoprost
or bimatoprost acid and MET12; bimatoprost or bimatoprost acid and
compound 1 from Table 1; bimatoprost or bimatoprost acid and
compound 2 from Table 1; bimatoprost or bimatoprost acid and
compound 3 from Table 1; bimatoprost or bimatoprost acid and
compound 4 from Table 1; bimatoprost or bimatoprost acid and
compound 5 from Table 1; bimatoprost or bimatoprost acid and
compound 6 from Table 1; bimatoprost or bimatoprost acid and
compound 7 from Table 1; bimatoprost or bimatoprost acid and
compound 8 from Table 1; bimatoprost or bimatoprost acid and
compound 9 from Table 1; bimatoprost or bimatoprost acid and
compound 10 from Table 1; bimatoprost or bimatoprost acid and
compound 11 from Table 1; bimatoprost or bimatoprost acid and
H.sup.60HIYLGATNYIY.sup.71-NH.sub.2 (SEQ ID NO: 4); bimatoprost or
bimatoprost acid and FAIM; bimatoprost or bimatoprost acid and
NOL3; bimatoprost or bimatoprost acid and DcR1; bimatoprost or
bimatoprost acid and DcR2; bimatoprost or bimatoprost acid and
DcR3; travoprost or travoprost acid and latanoprost or latanoprost
acid; travoprost or travoprost acid and latanoprostene; travoprost
or travoprost acid and tafluprost or tafluprost acid; travoprost or
travoprost acid and timolol; travoprost or travoprost acid and
betaxolol; travoprost or travoprost acid and levobunolol;
travoprost or travoprost acid and metipranolol; travoprost or
travoprost acid and brimonidine; travoprost or travoprost acid and
apraclonidine; travoprost or travoprost acid and brinzolamide;
travoprost or travoprost acid and acetazolamide; travoprost or
travoprost acid and dorzolamide; travoprost or travoprost acid and
methazolamide; travoprost or travoprost acid and pilocarpine;
travoprost or travoprost acid and carbachol; travoprost or
travoprost acid and netarsudil; travoprost or travoprost acid and
angiopoietin-1; travoprost or travoprost acid and angiopoietin-2;
travoprost or travoprost acid and angiopoietin-3; travoprost or
travoprost acid and a ngiopoietin-4; travoprost or travoprost acid
and CNTF; travoprost or travoprost acid and Peptide 6; travoprost
or travoprost acid and Peptide 21; travoprost or travoprost acid
and recombinant CNTF; travoprost or travoprost acid and NGF;
travoprost or travoprost acid and BDNF; travoprost or travoprost
acid and GDNF; travoprost or travoprost acid and C-type Natriuretic
Peptide; travoprost or travoprost acid and natural C-type
Natriuretic Peptide; travoprost or travoprost acid and Natriuretic
Peptide Receptor-B; travoprost or travoprost acid and bicyclol;
travoprost or travoprost acid and FLIP; travoprost or travoprost
acid and MET12; travoprost or travoprost acid and compound 1 from
Table 1; travoprost or travoprost acid and compound 2 from Table 1;
travoprost or travoprost acid and compound 3 from Table 1;
travoprost or travoprost acid and compound 4 from Table 1;
travoprost or travoprost acid and compound 5 from Table 1;
travoprost or travoprost acid and compound 6 from Table 1;
travoprost or travoprost acid and compound 7 from Table 1;
travoprost or travoprost acid and compound 8 from Table 1;
travoprost or travoprost acid and compound 9 from Table 1;
travoprost or travoprost acid and compound 10 from Table 1;
travoprost or travoprost acid and compound 11 from Table 1;
travoprost or travoprost acid and
H.sup.60HIYLGATNYIY.sup.71-NH.sub.2 (SEQ ID NO: 4); travoprost or
travoprost acid and FAIM; travoprost or travoprost acid and NOL3;
travoprost or travoprost acid and DcR1; travoprost or travoprost
acid and DcR2; travoprost or travoprost acid and DcR3; latanoprost
or latanoprost acid and latanoprostene; latanoprost or latanoprost
acid and tafluprost or tafluprost acid; latanoprost or latanoprost
acid and timolol; latanoprost or latanoprost acid and betaxolol;
latanoprost or latanoprost acid and levobunolol; latanoprost or
latanoprost acid and metipranolol; latanoprost or latanoprost acid
and brimonidine; latanoprost or latanoprost acid and apraclonidine;
latanoprost or latanoprost acid and brinzolamide; latanoprost or
latanoprost acid and acetazolamide; latanoprost or latanoprost acid
and dorzolamide; latanoprost or latanoprost acid and methazolamide;
latanoprost or latanoprost acid and pilocarpine; latanoprost or
latanoprost acid and carbachol; latanoprost or latanoprost acid and
netarsudil; latanoprost or latanoprost acid and angiopoietin-1;
latanoprost or latanoprost acid and angiopoietin-2; latanoprost or
latanoprost acid and angiopoietin-3; latanoprost or latanoprost
acid and angiopoietin-4; latanoprost or latanoprost acid and CNTF;
latanoprost or latanoprost acid and Peptide 6; latanoprost or
latanoprost acid and Peptide 21; latanoprost or latanoprost acid
and recombinant CNTF; latanoprost or latanoprost acid and NGF;
latanoprost or latanoprost acid and BDNF; latanoprost or
latanoprost acid and GDNF; latanoprost or latanoprost acid and
C-type Natriuretic Peptide; latanoprost or latanoprost acid and
natural C-type Natriuretic Peptide; latanoprost or latanoprost acid
and Natriuretic Peptide Receptor-B; latanoprost or latanoprost acid
and bicyclol; latanoprost or latanoprost acid and FLIP; latanoprost
or latanoprost acid and MET12; latanoprost or latanoprost acid and
compound 1 from Table 1; latanoprost or latanoprost acid and
compound 2 from Table 1; latanoprost or latanoprost acid and
compound 3 from Table 1; latanoprost or latanoprost acid and
compound 4 from Table 1; latanoprost or latanoprost acid and
compound 5 from Table 1; latanoprost or latanoprost acid and
compound 6 from Table 1; latanoprost or latanoprost acid and
compound 7 from Table 1; latanoprost or latanoprost acid and
compound 8 from Table 1; latanoprost or latanoprost acid and
compound 9 from Table 1; latanoprost or latanoprost acid and
compound 10 from Table 1; latanoprost or latanoprost acid and
compound 11 from Table 1; latanoprost or latanoprost acid and
H.sup.60HIYLGATNYIY.sup.71-NH.sub.2 (SEQ ID NO: 4); latanoprost or
latanoprost acid and FAIM; latanoprost or latanoprost acid and
NOL3; latanoprost or latanoprost acid and DcR1; latanoprost or
latanoprost acid and DcR2; latanoprost or latanoprost acid and
DcR3; latanoprostene and tafluprost or tafluprost acid;
latanoprostene and timolol; latanoprostene and betaxolol;
latanoprostene and levobunolol; latanoprostene and metipranolol;
latanoprostene and brimonidine; latanoprostene and apraclonidine;
latanoprostene and brinzolamide; latanoprostene and acetazolamide;
latanoprostene and dorzolamide; latanoprostene and methazolamide;
latanoprostene and pilocarpine; latanoprostene and carbachol;
latanoprostene and netarsudil; latanoprostene and angiopoietin-1;
latanoprostene and a ngiopoietin-2; latanoprostene and
angiopoietin-3; latanoprostene and angiopoietin-4; latanoprostene
and CNTF; latanoprostene and Peptide 6; latanoprostene and Peptide
21; latanoprostene and recombinant CNTF; latanoprostene and NGF;
latanoprostene and BDNF; latanoprostene and GDNF; latanoprostene
and C-type Natriuretic Peptide; latanoprostene and natural C-type
Natriuretic Peptide; latanoprostene and Natriuretic Peptide
Receptor-B; latanoprostene and bicyclol; latanoprostene and FLIP;
latanoprostene and MET12; latanoprostene and compound 1 from Table
1; latanoprostene and compound 2 from Table 1; latanoprostene and
compound 3 from Table 1; latanoprostene and compound 4 from Table
1; latanoprostene and compound 5 from Table 1; latanoprostene and
compound 6 from Table 1; latanoprostene and compound 7 from Table
1; latanoprostene and compound 8 from Table 1; latanoprostene and
compound 9 from Table 1; latanoprostene and compound 10 from Table
1; latanoprostene and compound 11 from Table 1; latanoprostene and
H.sup.60HIYLGATNYIY.sup.71-NH.sub.2 (SEQ ID NO: 4); latanoprostene
and FAIM; latanoprostene and NOL3; latanoprostene and DcR1;
latanoprostene and DcR2; latanoprostene and DcR3; tafluprost or
tafluprost acid and timolol; tafluprost or tafluprost acid and
betaxolol; tafluprost or tafluprost acid and levobunolol;
tafluprost or tafluprost acid and metipranolol; tafluprost or
tafluprost acid and brimonidine; tafluprost or tafluprost acid and
apraclonidine; tafluprost or tafluprost acid and brinzolamide;
tafluprost or tafluprost acid and acetazolamide; tafluprost or
tafluprost acid and dorzolamide; tafluprost or tafluprost acid and
methazolamide; tafluprost or tafluprost acid and pilocarpine;
tafluprost or tafluprost acid and carbachol; tafluprost or
tafluprost acid and netarsudil; tafluprost or tafluprost acid and
angiopoietin-1; tafluprost or tafluprost acid and angiopoietin-2;
tafluprost or tafluprost acid and angiopoietin-3; tafluprost or
tafluprost acid and angiopoietin-4; tafluprost or tafluprost acid
and CNTF; tafluprost or tafluprost acid and Peptide 6; tafluprost
or tafluprost acid and Peptide 21; tafluprost or tafluprost acid
and recombinant CNTF; tafluprost or tafluprost acid and NGF;
tafluprost or tafluprost acid and BDNF; tafluprost or tafluprost
acid and GDNF; tafluprost or tafluprost acid and C-type Natriuretic
Peptide; tafluprost or tafluprost acid and natural C-type
Natriuretic Peptide; tafluprost or tafluprost acid and Natriuretic
Peptide Receptor-B; tafluprost or tafluprost acid and bicyclol;
tafluprost or tafluprost acid and FLIP; tafluprost or tafluprost
acid and MET12; tafluprost or tafluprost acid and compound 1 from
Table 1; tafluprost or tafluprost acid and compound 2 from Table 1;
tafluprost or tafluprost acid and compound 3 from Table 1;
tafluprost or tafluprost acid and compound 4 from Table 1;
tafluprost or tafluprost acid and compound 5 from Table 1;
tafluprost or tafluprost acid and compound 6 from Table 1;
tafluprost or tafluprost acid and compound 7 from Table 1;
tafluprost or tafluprost acid and compound 8 from Table 1;
tafluprost or tafluprost acid and compound 9 from Table 1;
tafluprost or tafluprost acid and compound 10 from Table 1;
tafluprost or tafluprost acid and compound 11 from Table 1;
tafluprost or tafluprost acid and
H.sup.60HIYLGATNYIY.sup.71-NH.sub.2 (SEQ ID NO: 4); tafluprost or
tafluprost acid and FAIM; tafluprost or tafluprost acid and NOL3;
tafluprost or tafluprost acid and DcR1; tafluprost or tafluprost
acid and DcR2; tafluprost or tafluprost acid and DcR3; timolol and
betaxolol; timolol and levobunolol; timolol and metipranolol;
timolol and brimonidine; timolol and apraclonidine; timolol and
brinzolamide; timolol and acetazolamide; timolol and dorzolamide;
timolol and methazolamide; timolol and pilocarpine; timolol and
carbachol; timolol and netarsudil; timolol and angiopoietin-1;
timolol and angiopoietin-2; timolol and angiopoietin-3; timolol and
angiopoietin-4; timolol and CNTF; timolol and Peptide 6; timolol
and Peptide 21; timolol and recombinant CNTF; timolol and NGF;
timolol and BDNF; timolol and GDNF; timolol and C-type Natriuretic
Peptide; timolol and natural C-type Natriuretic Peptide; timolol
and Natriuretic Peptide Receptor-B; timolol and bicyclol; timolol
and FLIP; timolol and MET12; timolol and compound 1 from Table 1;
timolol and compound 2 from Table 1; timolol and compound 3 from
Table 1; timolol and compound 4 from Table 1; timolol and compound
5 from Table 1; timolol and compound 6 from Table 1; timolol and
compound 7 from Table 1; timolol and compound 8 from Table 1;
timolol and compound 9 from Table 1; timolol and compound 10 from
Table 1; timolol and compound 11 from Table 1; timolol and
H.sup.60HIYLGATNYIY.sup.71-NH.sub.2 (SEQ ID NO: 4); timolol and
FAIM; timolol and NOL3; timolol and DcR1; timolol and DcR2; timolol
and DcR3; betaxolol and levobunolol; betaxolol and metipranolol;
betaxolol and brimonidine; betaxolol and apraclonidine; betaxolol
and brinzolamide; betaxolol and acetazolamide; betaxolol and
dorzolamide; betaxolol and methazolamide; betaxolol and
pilocarpine; betaxolol and carbachol; betaxolol and netarsudil;
betaxolol and angiopoietin-1; betaxolol and angiopoietin-2;
betaxolol and angiopoietin-3; betaxolol and angiopoietin-4;
betaxolol and CNTF; betaxolol and Peptide 6; betaxolol and Peptide
21; betaxolol and recombinant CNTF; betaxolol and NGF; betaxolol
and BDNF; betaxolol and GDNF; betaxolol and C-type Natriuretic
Peptide; betaxolol and natural C-type Natriuretic Peptide;
betaxolol and Natriuretic Peptide Receptor-B; betaxolol and
bicyclol; betaxolol and FLIP; betaxolol and MET12; betaxolol and
compound 1 from Table 1; betaxolol and compound 2 from Table 1;
betaxolol and compound 3 from Table 1; betaxolol and compound 4
from Table 1; betaxolol and compound 5 from Table 1; betaxolol and
compound 6 from Table 1; betaxolol and compound 7 from Table 1;
betaxolol and compound 8 from Table 1; betaxolol and compound 9
from Table 1; betaxolol and compound 10 from Table 1; betaxolol and
compound 11 from Table 1; betaxolol and
H.sup.60HIYLGATNYIY.sup.71-NH.sub.2 (SEQ ID NO: 4); betaxolol and
FAIM; betaxolol and NOL3; betaxolol and DcR1; betaxolol and DcR2;
betaxolol and DcR3; levobunolol and metipranolol; levobunolol and
brimonidine; levobunolol and apraclonidine; levobunolol and
brinzolamide; levobunolol and acetazolamide; levobunolol and
dorzolamide; levobunolol and methazolamide; levobunolol and
pilocarpine; levobunolol and carbachol; levobunolol and netarsudil;
levobunolol and angiopoietin-1; levobunolol and angiopoietin-2;
levobunolol and angiopoietin-3; levobunolol and angiopoietin-4;
levobunolol and CNTF; levobunolol and Peptide 6; levobunolol and
Peptide 21; levobunolol and recombinant CNTF; levobunolol and NGF;
levobunolol and BDNF; levobunolol and GDNF; levobunolol and C-type
Natriuretic Peptide; levobunolol and natural C-type Natriuretic
Peptide; levobunolol and Natriuretic Peptide Receptor-B;
levobunolol and bicyclol; levobunolol and FLIP; levobunolol and
MET12; levobunolol and compound 1 from Table 1; levobunolol and
compound 2 from Table 1; levobunolol and compound 3 from Table 1;
levobunolol and compound 4 from Table 1; levobunolol and compound 5
from Table 1; levobunolol and compound 6 from Table 1; levobunolol
and compound 7 from Table 1; levobunolol and compound 8 from Table
1; levobunolol and compound 9 from Table 1; levobunolol and
compound 10 from Table 1; levobunolol and compound 11 from Table 1;
levobunolol and H
.sup.60HIYLGATNYIY.sup.71-NH.sub.2 (SEQ ID NO: 4); levobunolol and
FAIM; levobunolol and NOL3; levobunolol and DcR1; levobunolol and
DcR2; levobunolol and DcR3; metipranolol and brimonidine;
metipranolol and apraclonidine; metipranolol and brinzolamide;
metipranolol and acetazolamide; metipranolol and dorzolamide;
metipranolol and methazolamide; metipranolol and pilocarpine;
metipranolol and carbachol; metipranolol and netarsudil;
metipranolol and angiopoietin-1; metipranolol and angiopoietin-2;
metipranolol and angiopoietin-3; metipranolol and angiopoietin-4;
metipranolol and CNTF; metipranolol and Peptide 6; metipranolol and
Peptide 21; metipranolol and recombinant CNTF; metipranolol and
NGF; metipranolol and BDNF; metipranolol and GDNF; metipranolol and
C-type Natriuretic Peptide; metipranolol and natural C-type
Natriuretic Peptide; metipranolol and Natriuretic Peptide
Receptor-B; metipranolol and bicyclol; metipranolol and FLIP;
metipranolol and MET12; metipranolol and compound 1 from Table 1;
metipranolol and compound 2 from Table 1; metipranolol and compound
3 from Table 1; metipranolol and compound 4 from Table 1;
metipranolol and compound 5 from Table 1; metipranolol and compound
6 from Table 1; metipranolol and compound 7 from Table 1;
metipranolol and compound 8 from Table 1; metipranolol and compound
9 from Table 1; metipranolol and compound 10 from Table 1;
metipranolol and compound 11 from Table 1; metipranolol and
H.sup.60HIYLGATNYIY.sup.71-NH.sub.2 (SEQ ID NO: 4); metipranolol
and FAIM; metipranolol and NOL3; metipranolol and DcR1;
metipranolol and DcR2; metipranolol and DcR3; brimonidine and
apraclonidine; brimonidine and brinzolamide; brimonidine and
acetazolamide; brimonidine and dorzolamide; brimonidine and
methazolamide; brimonidine and pilocarpine; brimonidine and
carbachol; brimonidine and netarsudil; brimonidine and
angiopoietin-1; brimonidine and angiopoietin-2; brimonidine and
angiopoietin-3; brimonidine and angiopoietin-4; brimonidine and
CNTF; brimonidine and Peptide 6; brimonidine and Peptide 21;
brimonidine and recombinant CNTF; brimonidine and NGF; brimonidine
and BDNF; brimonidine and GDNF; brimonidine and C-type Natriuretic
Peptide; brimonidine and natural C-type Natriuretic Peptide;
brimonidine and Natriuretic Peptide Receptor-B; brimonidine and
bicyclol; brimonidine and FLIP; brimonidine and MET12; brimonidine
and compound 1 from Table 1; brimonidine and compound 2 from Table
1; brimonidine and compound 3 from Table 1; brimonidine and
compound 4 from Table 1; brimonidine and compound 5 from Table 1;
brimonidine and compound 6 from Table 1; brimonidine and compound 7
from Table 1; brimonidine and compound 8 from Table 1; brimonidine
and compound 9 from Table 1; brimonidine and compound 10 from Table
1; brimonidine and compound 11 from Table 1; brimonidine and
H.sup.60HIYLGATNYIY.sup.71-NH.sub.2 (SEQ ID NO: 4); brimonidine and
FAIM; brimonidine and NOL3; brimonidine and DcR1; brimonidine and
DcR2; brimonidine and DcR3; apraclonidine and brinzolamide;
apraclonidine and acetazolamide; apraclonidine and dorzolamide;
apraclonidine and methazolamide; apraclonidine and pilocarpine;
apraclonidine and carbachol; apraclonidine and netarsudil;
apraclonidine and angiopoietin-1; apraclonidine and angiopoietin-2;
apraclonidine and angiopoietin-3; apraclonidine and angiopoietin-4;
apraclonidine and CNTF; apraclonidine and Peptide 6; apraclonidine
and Peptide 21; apraclonidine and recombinant CNTF; apraclonidine
and NGF; apraclonidine and BDNF; apraclonidine and GDNF;
apraclonidine and C-type Natriuretic Peptide; apraclonidine and
natural C-type Natriuretic Peptide; apraclonidine and Natriuretic
Peptide Receptor-B; apraclonidine and bicyclol; apraclonidine and
FLIP; apraclonidine and MET12; apraclonidine and compound 1 from
Table 1; apraclonidine and compound 2 from Table 1; apraclonidine
and compound 3 from Table 1; apraclonidine and compound 4 from
Table 1; apraclonidine and compound 5 from Table 1; apraclonidine
and compound 6 from Table 1; apraclonidine and compound 7 from
Table 1; apraclonidine and compound 8 from Table 1; apraclonidine
and compound 9 from Table 1; apraclonidine and compound 10 from
Table 1; apraclonidine and compound 11 from Table 1; apraclonidine
and H.sup.60HIYLGATNYIY.sup.71-NH.sub.2 (SEQ ID NO: 4);
apraclonidine and FAIM; apraclonidine and NOL3; apraclonidine and
DcR1; apraclonidine and DcR2; apraclonidine and DcR3; brinzolamide
and acetazolamide; brinzolamide and dorzolamide; brinzolamide and
methazolamide; brinzolamide and pilocarpine; brinzolamide and
carbachol; brinzolamide and netarsudil; brinzolamide and
angiopoietin-1; brinzolamide and angiopoietin-2; brinzolamide and
angiopoietin-3; brinzolamide and angiopoietin-4; brinzolamide and
CNTF; brinzolamide and Peptide 6; brinzolamide and Peptide 21;
brinzolamide and recombinant CNTF; brinzolamide and NGF;
brinzolamide and BDNF; brinzolamide and GDNF; brinzolamide and
C-type Natriuretic Peptide; brinzolamide and natural C-type
Natriuretic Peptide; brinzolamide and Natriuretic Peptide
Receptor-B; brinzolamide and bicyclol; brinzolamide and FLIP;
brinzolamide and MET12; brinzolamide and compound 1 from Table 1;
brinzolamide and compound 2 from Table 1; brinzolamide and compound
3 from Table 1; brinzolamide and compound 4 from Table 1;
brinzolamide and compound 5 from Table 1; brinzolamide and compound
6 from Table 1; brinzolamide and compound 7 from Table 1;
brinzolamide and compound 8 from Table 1; brinzolamide and compound
9 from Table 1; brinzolamide and compound 10 from Table 1;
brinzolamide and compound 11 from Table 1; brinzolamide and
H.sup.60HIYLGATNYIY.sup.71-NH.sub.2 (SEQ ID NO: 4); brinzolamide
and FAIM; brinzolamide and NOL3; brinzolamide and DcR1;
brinzolamide and DcR2; brinzolamide and DcR3; acetazolamide and
dorzolamide; acetazolamide and methazolamide; acetazolamide and
pilocarpine; acetazolamide and carbachol; acetazolamide and
netarsudil; acetazolamide and angiopoietin-1; acetazolamide and a
ngiopoietin-2; acetazolamide and angiopoietin-3; acetazolamide and
angiopoietin-4; acetazolamide and CNTF; acetazolamide and Peptide
6; acetazolamide and Peptide 21; acetazolamide and recombinant
CNTF; acetazolamide and NGF; acetazolamide and BDNF; acetazolamide
and GDNF; acetazolamide and C-type Natriuretic Peptide;
acetazolamide and natural C-type Natriuretic Peptide; acetazolamide
and Natriuretic Peptide Receptor-B; acetazolamide and bicyclol;
acetazolamide and FLIP; acetazolamide and MET12; acetazolamide and
compound 1 from Table 1; acetazolamide and compound 2 from Table 1;
acetazolamide and compound 3 from Table 1; acetazolamide and
compound 4 from Table 1; acetazolamide and compound 5 from Table 1;
acetazolamide and compound 6 from Table 1; acetazolamide and
compound 7 from Table 1; acetazolamide and compound 8 from Table 1;
acetazolamide and compound 9 from Table 1; acetazolamide and
compound 10 from Table 1; acetazolamide and compound 11 from Table
1; acetazolamide and H.sup.60HIYLGATNYIY.sup.71-NH.sub.2 (SEQ ID
NO: 4); acetazolamide and FAIM; acetazolamide and NOL3;
acetazolamide and DcR1; acetazolamide and DcR2; acetazolamide and
DcR3; dorzolamide and methazolamide; dorzolamide and pilocarpine;
dorzolamide and carbachol; dorzolamide and netarsudil; dorzolamide
and angiopoietin-1; dorzolamide and angiopoietin-2; dorzolamide and
angiopoietin-3; dorzolamide and angiopoietin-4; dorzolamide and
CNTF; dorzolamide and Peptide 6; dorzolamide and Peptide 21;
dorzolamide and recombinant CNTF; dorzolamide and NGF; dorzolamide
and BDNF; dorzolamide and GDNF; dorzolamide and C-type Natriuretic
Peptide; dorzolamide and natural C-type Natriuretic Peptide;
dorzolamide and Natriuretic Peptide Receptor-B; dorzolamide and
bicyclol; dorzolamide and FLIP; dorzolamide and MET12; dorzolamide
and compound 1 from Table 1; dorzolamide and compound 2 from Table
1; dorzolamide and compound 3 from Table 1; dorzolamide and
compound 4 from Table 1; dorzolamide and compound 5 from Table 1;
dorzolamide and compound 6 from Table 1; dorzolamide and compound 7
from Table 1; dorzolamide and compound 8 from Table 1; dorzolamide
and compound 9 from Table 1; dorzolamide and compound 10 from Table
1; dorzolamide and compound 11 from Table 1; dorzolamide and
H.sup.60HIYLGATNYIY.sup.71-NH.sub.2 (SEQ ID NO: 4); dorzolamide and
FAIM; dorzolamide and NOL3; dorzolamide and DcR1; dorzolamide and
DcR2; dorzolamide and DcR3; methazolamide and pilocarpine;
methazolamide and carbachol; methazolamide and netarsudil;
methazolamide and angiopoietin-1; methazolamide and angiopoietin-2;
methazolamide and angiopoietin-3; methazolamide and angiopoietin-4;
methazolamide and CNTF; methazolamide and Peptide 6; methazolamide
and Peptide 21; methazolamide and recombinant CNTF; methazolamide
and NGF; methazolamide and BDNF; methazolamide and GDNF;
methazolamide and C-type Natriuretic Peptide; methazolamide and
natural C-type Natriuretic Peptide; Peptide Receptor-B;
methazolamide and Natriuretic Peptide Receptor-B; methazolamide and
bicyclol; methazolamide and FLIP; methazolamide and MET12;
methazolamide and compound 1 from Table 1; methazolamide and
compound 2 from Table 1; methazolamide and compound 3 from Table 1;
methazolamide and compound 4 from Table 1; methazolamide and
compound 5 from Table 1; methazolamide and compound 6 from Table 1;
methazolamide and compound 7 from Table 1; methazolamide and
compound 8 from Table 1; methazolamide and compound 9 from Table 1;
methazolamide and compound 10 from Table 1; methazolamide and
compound 11 from Table 1; methazolamide and
H.sup.60HIYLGATNYIY.sup.71-NH.sub.2 (SEQ ID NO: 4); methazolamide
and FAIM; methazolamide and NOL3; methazolamide and DcR1;
methazolamide and DcR2; methazolamide and DcR3; pilocarpine and
carbachol; pilocarpine and netarsudil; pilocarpine and
angiopoietin-1; pilocarpine and angiopoietin-2; pilocarpine and
angiopoietin-3; pilocarpine and angiopoietin-4; pilocarpine and
CNTF; pilocarpine and Peptide 6; pilocarpine and Peptide 21;
pilocarpine and recombinant CNTF; pilocarpine and NGF; pilocarpine
and BDNF; pilocarpine and GDNF; pilocarpine and C-type Natriuretic
Peptide; pilocarpine and natural C-type Natriuretic Peptide;
pilocarpine and Natriuretic Peptide Receptor-B; pilocarpine and
bicyclol; pilocarpine and FLIP; pilocarpine and MET12; pilocarpine
and compound 1 from Table 1; pilocarpine and compound 2 from Table
1; pilocarpine and compound 3 from Table 1; pilocarpine and
compound 4 from Table 1; pilocarpine and compound 5 from Table 1;
pilocarpine and compound 6 from Table 1; pilocarpine and compound 7
from Table 1; pilocarpine and compound 8 from Table 1; pilocarpine
and compound 9 from Table 1; pilocarpine and compound 10 from Table
1; pilocarpine and compound 11 from Table 1; pilocarpine and
H.sup.60HIYLGATNYIY.sup.71-NH.sub.2 (SEQ ID NO: 4); pilocarpine and
FAIM; pilocarpine and NOL3; pilocarpine and DcR1; pilocarpine and
DcR2; pilocarpine and DcR3; carbachol and netarsudil; carbachol and
angiopoietin-1; carbachol and angiopoietin-2; carbachol and
angiopoietin-3; carbachol and angiopoietin-4; carbachol and CNTF;
carbachol and Peptide 6; carbachol and Peptide 21; carbachol and
recombinant CNTF; carbachol and NGF; carbachol and BDNF; carbachol
and GDNF; carbachol and C-type Natriuretic Peptide; carbachol and
natural C-type Natriuretic Peptide; carbachol and Natriuretic
Peptide Receptor-B; carbachol and bicyclol; carbachol and FLIP;
carbachol and MET12; carbachol and compound 1 from Table 1;
carbachol and compound 2 from Table 1; carbachol and compound 3
from Table 1; carbachol and compound 4 from Table 1; carbachol and
compound 5 from Table 1; carbachol and compound 6 from Table 1;
carbachol and compound 7 from Table 1; carbachol and compound 8
from Table 1; carbachol and compound 9 from Table 1; carbachol and
compound 10 from Table 1; carbachol and compound 11 from Table 1;
carbachol and H.sup.60HIYLGATNYIY.sup.71-NH.sub.2 (SEQ ID NO: 4);
carbachol and FAIM; carbachol and NOL3; carbachol and DcR1;
carbachol and DcR2; carbachol and DcR3; netarsudil and
angiopoietin-1; netarsudil and angiopoietin-2; netarsudil and
angiopoietin-3; netarsudil and angiopoietin-4; netarsudil and CNTF;
netarsudil and Peptide 6; netarsudil and Peptide 21; netarsudil and
recombinant CNTF; netarsudil and NGF; netarsudil and BDNF;
netarsudil and GDNF; netarsudil and C-type Natriuretic Peptide;
netarsudil and natural C-type Natriuretic Peptide; netarsudil and
Natriuretic Peptide Receptor-B; netarsudil and bicyclol; netarsudil
and FLIP; netarsudil and MET12; netarsudil and compound 1 from
Table 1; netarsudil and compound 2 from Table 1; netarsudil and
compound 3 from Table 1; netarsudil and compound 4 from Table 1;
netarsudil and compound 5 from Table 1; netarsudil and compound 6
from Table 1; netarsudil and compound 7 from Table 1; netarsudil
and compound 8 from Table 1; netarsudil and compound 9 from Table
1; netarsudil and compound 10 from Table 1; netarsudil and compound
11 from Table 1; netarsudil and H.sup.60HIYLGATNYIY.sup.71-NH.sub.2
(SEQ ID NO: 4); netarsudil and FAIM; netarsudil and NOL3;
netarsudil and DcR1; netarsudil and DcR2; netarsudil and DcR3;
angiopoietin-1 and angiopoietin-2; angiopoietin-1 and
angiopoietin-3; angiopoietin-1 and angiopoietin-4; angiopoietin-1
and CNTF; angiopoietin-1 and Peptide 6; angiopoietin-1 and Peptide
21; angiopoietin-1 and recombinant CNTF; angiopoietin-1 and NGF;
angiopoietin-1 and BDNF; angiopoietin-1 and GDNF; angiopoietin-1
and C-type Natriuretic Peptide; angiopoietin-1 and natural C-type
Natriuretic Peptide; angiopoietin-1 and Natriuretic Peptide
Receptor-B; angiopoietin-1 and bicyclol; angiopoietin-1 and FLIP;
angiopoietin-1 and MET12; angiopoietin-1 and compound 1 from Table
1; angiopoietin-1 and compound 2 from Table 1; angiopoietin-1 and
compound 3 from Table 1; angiopoietin-1 and compound 4 from Table
1; angiopoietin-1 and compound 5 from Table 1; a ngiopoietin-1 and
compound 6 from Table 1; a ngiopoietin-1 and compound 7 from Table
1; angiopoietin-1 and compound 8 from Table 1; angiopoietin-1 and
compound 9 from Table 1; angiopoietin-1 and compound 10 from Table
1; angiopoietin-1 and compound 11 from Table 1; angiopoietin-1 and
H.sup.60HIYLGATNYIY.sup.71-NH.sub.2 (SEQ ID NO: 4); angiopoietin-1
and FAIM; angiopoietin-1 and NOL3; angiopoietin-1 and DcR1;
angiopoietin-1 and DcR2; angiopoietin-1 and DcR3; angiopoietin-2
and angiopoietin-3; angiopoietin-2 and angiopoietin-4;
angiopoietin-2 and CNTF; angiopoietin-2 and Peptide 6;
angiopoietin-2 and Peptide 21; angiopoietin-2 and recombinant CNTF;
angiopoietin-2 and NGF; angiopoietin-2 and BDNF; angiopoietin-2 and
GDNF; angiopoietin-2 and C-type Natriuretic Peptide; angiopoietin-2
and natural C-type Natriuretic Peptide; angiopoietin-2 and
Natriuretic Peptide Receptor-B; angiopoietin-2 and bicyclol;
angiopoietin-2 and FLIP; angiopoietin-2 and MET12; angiopoietin-2
and compound 1 from Table 1; angiopoietin-2 and compound 2 from
Table 1; angiopoietin-2 and compound 3 from Table 1; angiopoietin-2
and compound 4 from Table 1; angiopoietin-2 and compound 5 from
Table 1; angiopoietin-2 and compound 6 from Table 1; angiopoietin-2
and compound 7 from Table 1; angiopoietin-2 and compound 8 from
Table 1; angiopoietin-2 and compound 9 from Table 1; angiopoietin-2
and compound 10 from Table 1; angiopoietin-2 and compound 11 from
Table 1; angiopoietin-2 and H
.sup.60HIYLGATNYIY.sup.71-NH.sub.2 (SEQ ID NO: 4); angiopoietin-2
and FAIM; angiopoietin-2 and NOL3; angiopoietin-2 and DcR1;
angiopoietin-2 and DcR2; angiopoietin-2 and DcR3; angiopoietin-3
and angiopoietin-4; angiopoietin-3 and CNTF; angiopoietin-3 and
Peptide 6; angiopoietin-3 and Peptide 21; angiopoietin-3 and
recombinant CNTF; angiopoietin-3 and NGF; angiopoietin-3 and BDNF;
angiopoietin-3 and GDNF; angiopoietin-3 and C-type Natriuretic
Peptide; angiopoietin-3 and natural C-type Natriuretic Peptide;
angiopoietin-3 and Natriuretic Peptide Receptor-B; angiopoietin-3
and bicyclol; angiopoietin-3 and FLIP; angiopoietin-3 and MET12;
angiopoietin-3 and compound 1 from Table 1; angiopoietin-3 and
compound 2 from Table 1; angiopoietin-3 and compound 3 from Table
1; angiopoietin-3 and compound 4 from Table 1; angiopoietin-3 and
compound 5 from Table 1; angiopoietin-3 and compound 6 from Table
1; angiopoietin-3 and compound 7 from Table 1; angiopoietin-3 and
compound 8 from Table 1; angiopoietin-3 and compound 9 from Table
1; a ngiopoietin-3 and compound 10 from Table 1; angiopoietin-3 and
compound 11 from Table 1; angiopoietin-3 and
H.sup.60HIYLGATNYIY.sup.71-NH.sub.2 (SEQ ID NO: 4); angiopoietin-3
and FAIM; angiopoietin-3 and NOL3; angiopoietin-3 and DcR1;
angiopoietin-3 and DcR2; angiopoietin-3 and DcR3; angiopoietin-4
and CNTF; angiopoietin-4 and Peptide 6; angiopoietin-4 and Peptide
21; angiopoietin-4 and recombinant CNTF; angiopoietin-4 and NGF;
angiopoietin-4 and BDNF; angiopoietin-4 and GDNF; angiopoietin-4
and C-type Natriuretic Peptide; angiopoietin-4 and natural C-type
Natriuretic Peptide; angiopoietin-4 and Natriuretic Peptide
Receptor-B; angiopoietin-4 and bicyclol; angiopoietin-4 and FLIP;
angiopoietin-4 and MET12; angiopoietin-4 and compound 1 from Table
1; angiopoietin-4 and compound 2 from Table 1; angiopoietin-4 and
compound 3 from Table 1; angiopoietin-4 and compound 4 from Table
1; angiopoietin-4 and compound 5 from Table 1; angiopoietin-4 and
compound 6 from Table 1; angiopoietin-4 and compound 7 from Table
1; angiopoietin-4 and compound 8 from Table 1; angiopoietin-4 and
compound 9 from Table 1; angiopoietin-4 and compound 10 from Table
1; angiopoietin-4 and compound 11 from Table 1; angiopoietin-4 and
H.sup.60HIYLGATNYIY.sup.71-NH.sub.2 (SEQ ID NO: 4); angiopoietin-4
and FAIM; angiopoietin-4 and NOL3; angiopoietin-4 and DcR1;
angiopoietin-4 and DcR2; angiopoietin-4 and DcR3; CNTF and Peptide
6; CNTF and Peptide 21; CNTF and recombinant CNTF; CNTF and NGF;
CNTF and BDNF; CNTF and GDNF; CNTF and C-type Natriuretic Peptide;
CNTF and natural C-type Natriuretic Peptide; CNTF and Natriuretic
Peptide Receptor-B; CNTF and bicyclol; CNTF and FLIP; CNTF and
MET12; CNTF and compound 1 from Table 1; CNTF and compound 2 from
Table 1; CNTF and compound 3 from Table 1; CNTF and compound 4 from
Table 1; CNTF and compound 5 from Table 1; CNTF and compound 6 from
Table 1; CNTF and compound 7 from Table 1; CNTF and compound 8 from
Table 1; CNTF and compound 9 from Table 1; CNTF and compound 10
from Table 1; CNTF and compound 11 from Table 1; CNTF and
H.sup.60HIYLGATNYIY.sup.71-NH.sub.2 (SEQ ID NO: 4); CNTF and FAIM;
CNTF and NOL3; CNTF and DcR1; CNTF and DcR2; CNTF and DcR3; Peptide
6 and Peptide 21; Peptide 6 and recombinant Peptide 6; Peptide 6
and NGF; Peptide 6 and BDNF; Peptide 6 and GDNF; Peptide 6 and
C-type Natriuretic Peptide; Peptide 6 and natural C-type
Natriuretic Peptide; Peptide 6 and Natriuretic Peptide Receptor-B;
Peptide 6 and bicyclol; Peptide 6 and FLIP; Peptide 6 and MET12;
Peptide 6 and compound 1 from Table 1; Peptide 6 and compound 2
from Table 1; Peptide 6 and compound 3 from Table 1; Peptide 6 and
compound 4 from Table 1; Peptide 6 and compound 5 from Table 1;
Peptide 6 and compound 6 from Table 1; Peptide 6 and compound 7
from Table 1; Peptide 6 and compound 8 from Table 1; Peptide 6 and
compound 9 from Table 1; Peptide 6 and compound 10 from Table 1;
Peptide 6 and compound 11 from Table 1; Peptide 6 and
H.sup.60HIYLGATNYIY.sup.71-NH.sub.2 (SEQ ID NO: 4); Peptide 6 and
FAIM; Peptide 6 and NOL3; Peptide 6 and DcR1; Peptide 6 and DcR2;
Peptide 6 and DcR3; Peptide 21 and recombinant Peptide 21; Peptide
21 and NGF; Peptide 21 and BDNF; Peptide 21 and GDNF; Peptide 21
and C-type Natriuretic Peptide; Peptide 21 and natural C-type
Natriuretic Peptide; Peptide 21 and Natriuretic Peptide Receptor-B;
Peptide 21 and bicyclol; Peptide 21 and FLIP; Peptide 21 and MET12;
Peptide 21 and compound 1 from Table 1; Peptide 21 and compound 2
from Table 1; Peptide 21 and compound 3 from Table 1; Peptide 21
and compound 4 from Table 1; Peptide 21 and compound 5 from Table
1; Peptide 21 and compound 6 from Table 1; Peptide 21 and compound
7 from Table 1; Peptide 21 and compound 8 from Table 1; Peptide 21
and compound 9 from Table 1; Peptide 21 and compound 10 from Table
1; Peptide 21 and compound 11 from Table 1; Peptide 21 and
H.sup.60HIYLGATNYIY.sup.71-NH.sub.2 (SEQ ID NO: 4); Peptide 21 and
FAIM; Peptide 21 and NOL3; Peptide 21 and DcR1; Peptide 21 and
DcR2; Peptide 21 and DcR3; recombinant Peptide 21 and NGF;
recombinant Peptide 21 and BDNF; recombinant Peptide 21 and GDNF;
recombinant Peptide 21 and C-type Natriuretic Peptide; recombinant
Peptide 21 and natural C-type Natriuretic Peptide; recombinant
Peptide 21 and Natriuretic Peptide Receptor-B; recombinant Peptide
21 and bicyclol; recombinant Peptide 21 and FLIP; recombinant
Peptide 21 and MET12; recombinant Peptide 21 and compound 1 from
Table 1; recombinant Peptide 21 and compound 2 from Table 1;
recombinant Peptide 21 and compound 3 from Table 1; recombinant
Peptide 21 and compound 4 from Table 1; recombinant Peptide 21 and
compound 5 from Table 1; recombinant Peptide 21 and compound 6 from
Table 1; recombinant Peptide 21 and compound 7 from Table 1;
recombinant Peptide 21 and compound 8 from Table 1; recombinant
Peptide 21 and compound 9 from Table 1; recombinant Peptide 21 and
compound 10 from Table 1; recombinant Peptide 21 and compound 11
from Table 1; recombinant Peptide 21 and
H.sup.60HIYLGATNYIY.sup.71-NH.sub.2 (SEQ ID NO: 4); recombinant
Peptide 21 and FAIM; recombinant Peptide 21 and NOL3; recombinant
Peptide 21 and DcR1; recombinant Peptide 21 and DcR2; recombinant
Peptide 21 and DcR3; NGF and BDNF; NGF and GDNF; NGF and C-type
Natriuretic Peptide; NGF and natural C-type Natriuretic Peptide;
NGF and Natriuretic Peptide Receptor-B; NGF and bicyclol; NGF and
FLIP; NGF and MET12; NGF and compound 1 from Table 1; NGF and
compound 2 from Table 1; NGF and compound 3 from Table 1; NGF and
compound 4 from Table 1; NGF and compound 5 from Table 1; NGF and
compound 6 from Table 1; NGF and compound 7 from Table 1; NGF and
compound 8 from Table 1; NGF and compound 9 from Table 1; NGF and
compound 10 from Table 1; NGF and compound 11 from Table 1; NGF and
H.sup.60HIYLGATNYIY.sup.71-NH.sub.2 (SEQ ID NO: 4); NGF and FAIM;
NGF and NOL3; NGF and DcR1; NGF and DcR2; NGF and DcR3; BDNF and
GDNF; BDNF and C-type Natriuretic Peptide; BDNF and natural C-type
Natriuretic Peptide; BDNF and Natriuretic Peptide Receptor-B; BDNF
and bicyclol; BDNF and FLIP; BDNF and MET12; BDNF and compound 1
from Table 1; BDNF and compound 2 from Table 1; BDNF and compound 3
from Table 1; BDNF and compound 4 from Table 1; BDNF and compound 5
from Table 1; BDNF and compound 6 from Table 1; BDNF and compound 7
from Table 1; BDNF and compound 8 from Table 1; BDNF and compound 9
from Table 1; BDNF and compound 10 from Table 1; BDNF and compound
11 from Table 1; BDNF and H.sup.60HIYLGATNYIY.sup.71-NH.sub.2 (SEQ
ID NO: 4); BDNF and FAIM; BDNF and NOL3; BDNF and DcR1; BDNF and
DcR2; BDNF and DcR3; GDNF and C-type Natriuretic Peptide; GDNF and
natural C-type Natriuretic Peptide; GDNF and Natriuretic Peptide
Receptor-B; GDNF and bicyclol; GDNF and FLIP; GDNF and MET12; GDNF
and compound 1 from Table 1; GDNF and compound 2 from Table 1; GDNF
and compound 3 from Table 1; GDNF and compound 4 from Table 1; GDNF
and compound 5 from Table 1; GDNF and compound 6 from Table 1; GDNF
and compound 7 from Table 1; GDNF and compound 8 from Table 1; GDNF
and compound 9 from Table 1; GDNF and compound 10 from Table 1;
GDNF and compound 11 from Table 1; GDNF and
H.sup.60HIYLGATNYIY.sup.71-NH.sub.2 (SEQ ID NO: 4); GDNF and FAIM;
GDNF and NOL3; GDNF and DcR1; GDNF and DcR2; GDNF and DcR3; C-type
Natriuretic Peptide and natural C-type Natriuretic Peptide; C-type
Natriuretic Peptide and Natriuretic Peptide Receptor-B; C-type
Natriuretic Peptide and bicyclol; C-type Natriuretic Peptide and
FLIP; C-type Natriuretic Peptide and MET12; C-type Natriuretic
Peptide and compound 1 from Table 1; C-type Natriuretic Peptide and
compound 2 from Table 1; C-type Natriuretic Peptide and compound 3
from Table 1; C-type Natriuretic Peptide and compound 4 from Table
1; C-type Natriuretic Peptide and compound 5 from Table 1; C-type
Natriuretic Peptide and compound 6 from Table 1; C-type Natriuretic
Peptide and compound 7 from Table 1; C-type Natriuretic Peptide and
compound 8 from Table 1; C-type Natriuretic Peptide and compound 9
from Table 1; C-type Natriuretic Peptide and compound 10 from Table
1; C-type Natriuretic Peptide and compound 11 from Table 1; C-type
Natriuretic Peptide and H.sup.60HIYLGATNYIY.sup.71-NH.sub.2 (SEQ ID
NO: 4); C-type Natriuretic Peptide and FAIM; C-type Natriuretic
Peptide and NOL3; C-type Natriuretic Peptide and DcR1; C-type
Natriuretic Peptide and DcR2; C-type Natriuretic Peptide and DcR3;
natural C-type Natriuretic Peptide and Natriuretic Peptide
Receptor-B; natural C-type Natriuretic Peptide and bicyclol;
natural C-type Natriuretic Peptide and FLIP; natural C-type
Natriuretic Peptide and MET12; natural C-type Natriuretic Peptide
and compound 1 from Table 1; natural C-type Natriuretic Peptide and
compound 2 from Table 1; natural C-type Natriuretic Peptide and
compound 3 from Table 1; natural C-type Natriuretic Peptide and
compound 4 from Table 1; natural C-type Natriuretic Peptide and
compound 5 from Table 1; natural C-type Natriuretic Peptide and
compound 6 from Table 1; natural C-type Natriuretic Peptide and
compound 7 from Table 1; natural C-type Natriuretic Peptide and
compound 8 from Table 1; natural C-type Natriuretic Peptide and
compound 9 from Table 1; natural C-type Natriuretic Peptide and
compound 10 from Table 1; natural C-type Natriuretic Peptide and
compound 11 from Table 1; natural C-type Natriuretic Peptide and
H.sup.60HIYLGATNYIY.sup.71-NH.sub.2 (SEQ ID NO: 4); natural C-type
Natriuretic Peptide and FAIM; natural C-type Natriuretic Peptide
and NOL3; natural C-type Natriuretic Peptide and DcR1; natural
C-type Natriuretic Peptide and DcR2; natural C-type Natriuretic
Peptide and DcR3; Natriuretic Peptide Receptor-B and bicyclol;
Natriuretic Peptide Receptor-B and FLIP; Natriuretic Peptide
Receptor-B and MET12; Natriuretic Peptide Receptor-B and compound 1
from Table 1; Natriuretic Peptide Receptor-B and compound 2 from
Table 1; Natriuretic Peptide Receptor-B and compound 3 from Table
1; Natriuretic Peptide Receptor-B and compound 4 from Table 1;
Natriuretic Peptide Receptor-B and compound 5 from Table 1;
Natriuretic Peptide Receptor-B and compound 6 from Table 1;
Natriuretic Peptide Receptor-B and compound 7 from Table 1;
Natriuretic Peptide Receptor-B and compound 8 from Table 1;
Natriuretic Peptide Receptor-B and compound 9 from Table 1;
Natriuretic Peptide Receptor-B and compound 10 from Table 1;
Natriuretic Peptide Receptor-B and compound 11 from Table 1;
Natriuretic Peptide Receptor-B and
H.sup.60HIYLGATNYIY.sup.71-NH.sub.2 (SEQ ID NO: 4); Natriuretic
Peptide Receptor-B and FAIM; Natriuretic Peptide Receptor-B and
NOL3; Natriuretic Peptide Receptor-B and DcR1; Natriuretic Peptide
Receptor-B and DcR2; Natriuretic Peptide Receptor-B and DcR3;
bicyclol and FLIP; bicyclol and MET12; bicyclol and compound 1 from
Table 1; bicyclol and compound 2 from Table 1; bicyclol and
compound 3 from Table 1; bicyclol and compound 4 from Table 1;
bicyclol and compound 5 from Table 1; bicyclol and compound 6 from
Table 1; bicyclol and compound 7 from Table 1; bicyclol and
compound 8 from Table 1; bicyclol and compound 9 from Table 1;
bicyclol and compound 10 from Table 1; bicyclol and compound 11
from Table 1; bicyclol and H.sup.60HIYLGATNYIY.sup.71-NH.sub.2 (SEQ
ID NO: 4); bicyclol and FAIM; bicyclol and NOL3; bicyclol and DcR1;
bicyclol and DcR2; bicyclol and DcR3; FLIP and MET12; FLIP and
compound 1 from Table 1; FLIP and compound 2 from Table 1; FLIP and
compound 3 from Table 1; FLIP and compound 4 from Table 1; FLIP and
compound 5 from Table 1; FLIP and compound 6 from Table 1; FLIP and
compound 7 from Table 1; FLIP and compound 8 from Table 1; FLIP and
compound 9 from Table 1; FLIP and compound 10 from Table 1; FLIP
and compound 11 from Table 1; FLIP and
H.sup.60HIYLGATNYIY.sup.71-NH.sub.2 (SEQ ID NO: 4); FLIP and FAIM;
FLIP and NOL3; FLIP and DcR1; FLIP and DcR2; FLIP and DcR3; MET12
and compound 1 from Table 1; MET12 and compound 2 from Table 1;
MET12 and compound 3 from Table 1; MET12 and compound 4 from Table
1; MET12 and compound 5 from Table 1; MET12 and compound 6 from
Table 1; MET12 and compound 7 from Table 1; MET12 and compound 8
from Table 1; MET12 and compound 9 from Table 1; MET12 and compound
10 from Table 1; MET12 and compound 11 from Table 1; MET12 and
H.sup.60HIYLGATNYIY.sup.71-NH.sub.2 (SEQ ID NO: 4); MET12 and FAIM;
MET12 and NOL3; MET12 and DcR1; MET12 and DcR2; MET12 and DcR3;
compound 1 from Table 1 and compound 2 from Table 1; compound 1
from Table 1 and compound 3 from Table 1; compound 1 from Table 1
and compound 4 from Table 1; compound 1 from Table 1 and compound 5
from Table 1; compound 1 from Table 1 and compound 6 from Table 1;
compound 1 from Table 1 and compound 7 from Table 1; compound 1
from Table 1 and compound 8 from Table 1; compound 1 from Table 1
and compound 9 from Table 1; compound 1 from Table 1 and compound
10 from Table 1; compound 1 from Table 1 and compound 11 from Table
1; compound 1 from Table 1 and H.sup.60HIYLGATNYIY.sup.71-NH.sub.2
(SEQ ID NO: 4); compound 1 from Table 1 and FAIM; compound 1 from
Table 1 and NOL3; compound 1 from Table 1 and DcR1; compound 1 from
Table 1 and DcR2; compound 1 from Table 1 and DcR3; compound 2 from
Table 1 and compound 3 from Table 1; compound 2 from Table 1 and
compound 4 from Table 1; compound 2 from Table 1 and compound 5
from Table 1; compound 2 from Table 1 and compound 6 from Table 1;
compound 2 from Table 1 and compound 7 from Table 1; compound 2
from Table 1 and compound 8 from Table 1; compound 2 from Table 1
and compound 9 from Table 1; compound 2 from Table 1 and compound
10 from Table 1; compound 2 from Table 1 and compound 11 from Table
1; compound 2 from Table 1 and H.sup.60HIYLGATNYIY.sup.71-NH.sub.2
(SEQ ID NO: 4); compound 2 from Table 1 and FAIM; compound 2 from
Table 1 and NOL3; compound 2 from Table 1 and DcR1; compound 2 from
Table 1 and DcR2; compound 2 from Table 1 and DcR3; compound 3 from
Table 1 and compound 4 from Table 1; compound 3 from Table 1 and
compound 5 from Table 1; compound 3 from Table 1 and compound 6
from Table 1; compound 3 from Table 1 and compound 7 from Table 1;
compound 3 from Table 1 and compound 8 from Table 1; compound 3
from Table 1 and compound 9 from Table 1; compound 3 from Table 1
and compound 10 from Table 1; compound 3 from Table 1 and compound
11 from Table 1; compound 3 from Table 1 and H
.sup.60HIYLGATNYIY.sup.71-NH.sub.2 (SEQ ID NO: 4); compound 3 from
Table 1 and FAIM; compound 3 from Table 1 and NOL3; compound 3 from
Table 1 and DcR1; compound 3 from Table 1 and DcR2; compound 3 from
Table 1 and DcR3; compound 4 from Table 1 and compound 5 from Table
1; compound 4 from Table 1 and compound 6 from Table 1; compound 4
from Table 1 and compound 7 from Table 1; compound 4 from Table 1
and compound 8 from Table 1; compound 4 from Table 1 and compound 9
from Table 1; compound 4 from Table 1 and compound 10 from Table 1;
compound 4 from Table 1 and compound 11 from Table 1; compound 4
from Table 1 and H.sup.60HIYLGATNYIY.sup.71-NH.sub.2 (SEQ ID NO:
4); compound 4 from Table 1 and FAIM; compound 4 from Table 1 and
NOL3; compound 4 from Table 1 and DcR1; compound 4 from Table 1 and
DcR2; compound 4 from Table 1 and DcR3; compound 5 from Table 1 and
compound 6 from Table 1; compound 5 from Table 1 and compound 7
from Table 1; compound 5 from Table 1 and compound 8 from Table 1;
compound 5 from Table 1 and compound 9 from Table 1; compound 5
from Table 1 and compound 10 from Table 1; compound 5 from Table 1
and compound 11 from Table 1; compound 5 from Table 1 and
H.sup.60HIYLGATNYIY.sup.71-NH.sub.2 (SEQ ID NO: 4); compound 5 from
Table 1 and FAIM; compound 5 from Table 1 and NOL3; compound 5 from
Table 1 and DcR1; compound 5 from Table 1 and DcR2; compound 5 from
Table 1 and DcR3; compound 6 from Table 1 and compound 7 from Table
1; compound 6 from Table 1 and compound 8 from Table 1; compound 6
from Table 1 and compound 9 from Table 1; compound 6 from Table 1
and compound 10 from Table 1; compound 6 from Table 1 and compound
11 from Table 1; compound 6 from Table 1 and
H.sup.60HIYLGATNYIY.sup.71-NH.sub.2 (SEQ ID NO: 4); compound 6 from
Table 1 and FAIM; compound 6 from Table 1 and NOL3; compound 6 from
Table 1 and DcR1; compound 6 from Table 1 and DcR2; compound 6 from
Table 1 and DcR3; compound 7 from Table 1 and compound 8 from Table
1; compound 7 from Table 1 and compound 9 from Table 1; compound 7
from Table 1 and compound 10 from Table 1; compound 7 from Table 1
and compound 11 from Table 1; compound 7 from Table 1 and
H.sup.60HIYLGATNYIY.sup.71-NH.sub.2 (SEQ ID NO: 4); compound 7 from
Table 1 and FAIM; compound 7 from Table 1 and NOL3; compound 7 from
Table 1 and DcR1; compound 7 from Table 1 and DcR2; compound 7 from
Table 1 and DcR3; compound 8 from Table 1 and compound 9 from Table
1; compound 8 from Table 1 and compound 10 from Table 1; compound 8
from Table 1 and compound 11 from Table 1; compound 8 from Table 1
and H.sup.60HIYLGATNYIY.sup.71-NH.sub.2 (SEQ ID NO: 4); compound 8
from Table 1 and FAIM; compound 8 from Table 1 and NOL3; compound 8
from Table 1 and DcR1; compound 8 from Table 1 and DcR2; compound 8
from Table 1 and DcR3; compound 9 from Table 1 and compound 10 from
Table 1; compound 9 from Table 1 and compound 11 from Table 1;
compound 9 from Table 1 and H.sup.60HIYLGATNYIY.sup.71-NH.sub.2
(SEQ ID NO: 4); compound 9 from Table 1 and FAIM; compound 9 from
Table 1 and NOL3; compound 9 from Table 1 and DcR1; compound 9 from
Table 1 and DcR2; compound 9 from Table 1 and DcR3; compound 10
from Table 1 and compound 11 from Table 1; compound 10 from Table 1
and H.sup.60HIYLGATNYIY.sup.71-NH.sub.2 (SEQ ID NO: 4); compound 10
from Table 1 and FAIM; compound 10 from Table 1 and NOL3; compound
10 from Table 1 and DcR1; compound 10 from Table 1 and DcR2;
compound 10 from Table 1 and DcR3; compound 11 from Table 1 and
H.sup.60HIYLGATNYIY.sup.71-NH.sub.2 (SEQ ID NO: 4); compound 11
from Table 1 and FAIM; compound 11 from Table 1 and NOL3; compound
11 from Table 1 and DcR1; compound 11 from Table 1 and DcR2;
compound 11 from Table 1 and DcR3;
H.sup.60HIYLGATNYIY.sup.71-NH.sub.2 (SEQ ID NO: 4) and FAIM;
H.sup.60HIYLGATNYIY.sup.71-NH.sub.2 (SEQ ID NO: 4) and NOL3;
H.sup.60HIYLGATNYIY.sup.71-NH.sub.2 (SEQ ID NO: 4) and DcR1;
H.sup.60HIYLGATNYIY.sup.71-NH.sub.2 (SEQ ID NO: 4) and DcR2;
H.sup.60HIYLGATNYIY.sup.71-NH.sub.2 (SEQ ID NO: 4) and DcR3; FAIM
and NOL3; FAIM and DcR1; FAIM and DcR2; FAIM and DcR3; NOL3 and
DcR1; NOL3 and DcR2; NOL3 and DcR3; and DcR1 and DcR2; DcR1 and
DcR3; DcR2 and DcR3.
[0074] Some covalently linked combinations are represented by the
following structural formulas:
P6-Met12 Formula C-1.
P6-Met12-P6 Formula C-2.
Met12-P6-Met12 Formula C-3.
P6-GGG-Met12 Formula C-4.
Met12-GGG-P6 Formula C-5.
P6-GGG-Met12-GGG-P6 Formula C-6.
Met12-GGG-P6-GGG-Met12 Formula C-7.
P6-(N-AEAc).sub.x-Met12 Formula C-8.
Met12-(N-AEEAc).sub.x-P6 Formula C-9.
Met12-(N-AEEAc).sub.x-P6-(N-AEEAc).sub.y-Met12 Formula C-10.
P6-(N-AEEAc).sub.x-Met12-(N-AEEAc).sub.y-P6 Formula C-11.
P6-(N-dPEG12).sub.x-Met12 Formula C-12.
P21-Met12 Formula C-13.
P21-Met12-P21 Formula C-14.
Met12-P21-Met12 Formula C-15.
P21-GGG-Met12 Formula C-16.
Met12-GGG-P21 Formula C-17.
P21-GGG-Met12-GGG-P21 Formula C-18.
Met12-GGG-P21-GGG-Met12 Formula C-19.
P21-(N-AEAc).sub.x-Met12 Formula C-20.
Met12-(N-AEEAc).sub.x-P21 Formula C-21.
Met12-(N-AEEAc).sub.x-P21-(N-AEEAc).sub.y-Met12 Formula C-22.
P21-(N-AEEAc).sub.x-Met12-(N-AEEAc).sub.y-P21 Formula C-23.
P21-(N-dPEG12).sub.x-Met12 Formula C-24.
P6-(O-AEAc).sub.x-Met12 Formula C-25.
Met12-(O-AEEAc).sub.x-P6 Formula C-26.
Met12-(O-AEEAc).sub.x-P6-(O-AEEAc).sub.y-Met12 Formula C-27.
P6-(O-AEEAc).sub.x-Met12-(O-AEEAc).sub.y-P6 Formula C-28.
P6-(O-dPEG12).sub.x-Met12 Formula C-29.
P21-(O-AEAc).sub.x-Met12 Formula C-30.
Met12-(O-AEEAc).sub.x-P21 Formula C-31.
Met12-(O-AEEAc).sub.x-P21-(O-AEEAc).sub.y-Met12 Formula C-32.
P21-(O-AEEAc).sub.x-Met12-(O-AEEAc).sub.y-P21 Formula C-33.
P21-(O-dPEG12).sub.x-Met12 Formula C-34.
P6-Met12-BC Formula C-35.
P6-Met12-P6-BC Formula C-36.
Met12-P6-Met12-BC Formula C-37.
P6-GGG-Met12-BC Formula C-38.
Met12-GGG-P6-BC Formula C-39.
P6-GGG-Met12-GGG-P6-BC Formula C-40.
Met12-GGG-P6-GGG-Met12-BC Formula C-41.
P6-(N-AEAc).sub.x-Met12-BC Formula C-42.
Met12-(N-AEEAc).sub.x-P6-BC Formula C-43.
Met12-(N-AEEAc).sub.x-P6-(N-AEEAc).sub.y-Met12-BC Formula C-44.
P6-(N-AEEAc).sub.x-Met12-(N-AEEAc).sub.y-P6-BC Formula C-45.
P6-(N-dPEG12).sub.x-Met12-BC Formula C-46.
P21-Met12-BC Formula C-47.
P21-Met12-P21-BC Formula C-48.
Met12-P21-Met12-BC Formula C-49.
P21-GGG-Met12-BC Formula C-50.
Met12-GGG-P21-BC Formula C-51.
P21-GGG-Met12-GGG-P21-BC Formula C-52.
Met12-GGG-P21-GGG-Met12-BC Formula C-53.
P21-(N-AEAc).sub.x-Met12-BC Formula C-54.
Met12-(N-AEEAc).sub.x-P21-BC Formula C-55.
Met12-(N-AEEAc).sub.x-P21-(N-AEEAc).sub.y-Met12-BC Formula
C-56.
P21-(N-AEEAc).sub.x-Met12-(N-AEEAc).sub.y-P21-BC Formula C-57.
P21-(N-dPEG12).sub.x-Met12-BC Formula C-58.
P6-(O-AEAc).sub.x-Met12-BC Formula C-59.
Met12-(O-AEEAc).sub.x-P6-BC Formula C-60.
Met12-(O-AEEAc).sub.x-P6-(O-AEEAc).sub.y-Met12-BC Formula C-61.
P6-(O-AEEAc).sub.x-Met12-(O-AEEAc).sub.y-P6-BC Formula C-62.
P6-(O-dPEG12).sub.x-Met12-BC Formula C-63.
P21-(O-AEAc).sub.x-Met12-BC Formula C-64.
Met12-(O-AEEAc).sub.x-P21-BC Formula C-65.
Met12-(O-AEEAc).sub.x-P21-(O-AEEAc).sub.y-Met12-BC Formula
C-66.
P21-(O-AEEAc).sub.x-Met12-(O-AEEAc).sub.y-P21-BC Formula C-67.
P21-(O-dPEG12).sub.x-Met12-BC Formula C-68.
BC-P6-Met12 Formula C-69.
BC-P6-Met12-P6 Formula C-70.
BC-Met12-P6-Met12 Formula C-71.
BC-P6-GGG-Met12 Formula C-72.
BC-Met12-GGG-P6 Formula C-73.
BC-P6-GGG-Met12-GGG-P6 Formula C-74.
BC-Met12-GGG-P6-GGG-Met12 Formula C-75.
BC-P6-(N-AEAc).sub.x-Met12 Formula C-76.
BC-Met12-(N-AEEAc).sub.x-P6 Formula C-77.
BC-Met12-(N-AEEAc).sub.x-P6-(N-AEEAc).sub.y-Met12 Formula C-78.
BC-P6-(N-AEEAc).sub.x-Met12-(N-AEEAc).sub.y-P6 Formula C-79.
BC-P6-(N-dPEG12).sub.x-Met12 Formula C-80.
BC-P21-Met12 Formula C-81.
BC-P21-Met12-P21 Formula C-82.
BC-Met12-P21-Met12 Formula C-83.
BC-P21-GGG-Met12 Formula C-84.
BC-Met12-GGG-P21 Formula C-85.
BC-P21-GGG-Met12-GGG-P21 Formula C-86.
BC-Met12-GGG-P21-GGG-Met12 Formula C-87.
BC-P21-(N-AEAc).sub.x-Met12 Formula C-88.
BC-Met12-(N-AEEAc).sub.x-P21 Formula C-89.
BC-Met12-(N-AEEAc).sub.x-P21-(N-AEEAc).sub.y-Met12 Formula
C-90.
BC-P21-(N-AEEAc).sub.x-Met12-(N-AEEAc).sub.y-P21 Formula C-91.
BC-P21-(N-dPEG12).sub.x-Met12 Formula C-92.
BC-P6(O-AEAc).sub.x-Met12 Formula C-93.
BC-Met12(O-AEEAc).sub.x-P6 Formula C-94.
BC-Met12(O-AEEAc).sub.x-P6(O-AEEAc).sub.y-Met12 Formula C-95.
BC-P6(O-AEEAc).sub.x-Met12(O-AEEAc).sub.y-P6 Formula C-96.
BC-P6(O-dPEG12).sub.x-Met12 Formula C-97.
BC-P21(O-AEAc).sub.x-Met12 Formula C-98.
BC-Met12(O-AEEAc).sub.x-P21 Formula C-99.
BC-Met12(O-AEEAc).sub.x-P21(O-AEEAc).sub.y-Met12 Formula C-100.
BC-P21(O-AEEAc).sub.x-Met12(O-AEEAc).sub.y-P21 Formula C-101.
BC-P21(O-dPEG12).sub.x-Met12 Formula C-102.
[0075] For structural formulas C-1 to C-102 above, x is 1, 2, 3, 4,
5, 6, 7, 8, 9, or 10; and y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
Bonding can occur at either end, or in any position, of Met12, P6,
P21, or BC. P6, Met12, GGG, N-AEEAc, N-dPEG12, etc., represent the
corresponding compound with the structure modified to accommodate
the bonding represented. For example,
[0076] P6 is Ac-VGDGGLFEKKL-NH.sub.2 (SEQ ID NO: 1).
[0077] Met12 is
##STR00005##
[0078] One potential structure for P6-Met12 (P6 and Met12 disclosed
as SEQ ID NOS 1 and 3, respectively) is:
##STR00006##
[0079] Some covalent linked compounds for use in a drug delivery
system include:
##STR00007##
[0080] With respect to any relevant structural representation, such
as Formula C103 or C104, z is 0-10,000, 0-1,000, 1,000-2,000,
2,000-3,000, 3,000-4,000, 4,000-5,000, 5,000-6,000, 6,000-7,000,
8,000-9,000, 9,000-10,000, 0-5,000, or 5,000-10,000.
[0081] With respect to any relevant structural representation, such
as Formula C104, Y is N or O.
[0082] With respect to any relevant structural representation, such
as Formula C104, A.sup.1 is P6, P21, or a group derived from
C1-C34, e.g. with the relevant atoms removed to accommodate the
bonding, as explained above.
[0083] With respect to any relevant structural representation, such
as Formula C104, A.sup.2 is OCH.sub.2CH.sub.2O-- or
NHCH.sub.2CH.sub.2N--.
[0084] A sustained delivery component is the portion of the drug
delivery system that allows the drug to remain in the body for a
sustained period of time, e.g. long beyond the time that it takes
for the drug to be metabolized or passed out of the body.
Typically, a sustained delivery component is an implant, such as a
solid implant, that works by encapsulating or otherwise entrapping
the drug into the implant. If the implant is biodegradable or
bioerodible, the drug may be released as the implant biodegrades or
bioerodes. The implant may also be porous so that, over a period of
time, drug may diffuse out of the implant. Biodegradable or
bioerodible implants may be porous or non-porous. Typically,
non-biodegradable or non-bioerodible implants are porous, and the
drug is released by diffusion. However, other mechanisms may
operate, such as an osmotic pump.
[0085] The drug may be physically trapped in the sustained delivery
component and/or may be covalently bonded to a molecule that is
part of the sustained delivery component.
[0086] Typical examples of biodegradable materials for porous or
non-porous biodegradable implants generally include, silica-based
materials, or organic biodegradable materials, such as polymers
comprising poly (D,L-lactic acid) (PLA) and poly
(D,L-lactic-co-glycolic acid)(PLGA), polyesteramide (PEA, DSM
chemical), and polycaprolactone (PCL); hydrogels, such as polyvinyl
alcohols (PVA), PEG amines, PEG-N-hydroxysuccinamide esters (like
Ocular Therapeutix) and the like; collagen based materials (e.g.
Euclid systems); or a combination thereof.
[0087] There are a number of suitable silica based sustained
delivery components.
[0088] One type of silica based sustained delivery component
includes a silica hydrogel composite obtainable by mixing silica
particles, comprising an encapsulated drug, with a silica sol,
wherein obtained hydrogel composite is shear-thinning. This type of
delivery system is an injectable, all-silica-based
microparticle-silica hydrogel controlled release system which
reduces the burst remarkably with different types of encapsulated
therapeutic and biologically active agents. Detailed descriptions
of this type of silica based sustained delivery component, and how
they are made, are found in U.S. Pat. No. 9,949,922, issued on Apr.
24, 2018 to Jokinen, et al., which is incorporated by reference
herein in its entirety.
[0089] Another type of silica based sustained delivery component
includes flowing silica compositions and gels comprising a drug
which are obtainable by method for producing a flowing silica
composition including a sol-gel transfer, where redispersion is
carried out. The redispersion includes adding, after having reached
gel point of the sol-gel transfer, liquid into the gel formed by
the sol-gel transfer, and the addition being made within a
sufficiently short time period after reaching the gel point, to
result, after mixing of the gel and the liquid, in a rheologically
homogenous flowing silica composition, which is and remains
injectable as such, or by short stirring <30 s, through a thin
22G needle. These flowing and injectable sustained delivery silica
compositions may increase the stability and preserve the activity
of encapsulated therapeutic agents. Detailed descriptions of this
type of silica based sustained delivery component, and how it is
made, is found in United States Patent Application No. 20140057996,
published Feb. 27, 2014 by Jokinen, et al., which is incorporated
by reference herein in its entirety.
[0090] Another type of silica based sustained delivery component
comprises a composition comprising a bioerodible porous
silicon-based carrier material wherein the carrier material carries
a drug and at least one amorphous sugar, optionally further
comprising a crystallization inhibitor. These delivery systems
comprise loading biomolecules into the pores of the silica carrier
material, thus stabilizing the biomolecules. However, these systems
may also be used for small molecule therapeutic compounds. Detailed
descriptions of this type of silica based sustained delivery
component, and how it is made, is found in U.S. Pat. No. 9,603,801,
issued on Mar. 28, 2017 to Barnett, et al., which is incorporated
by reference herein in its entirety.
[0091] Another type of silica based sustained delivery component
includes bioerodible devices, such as implants for delivering drugs
in a controlled manner. The devices comprise a porous silicon-based
carrier material impregnated or loaded with the drug. These
particular silicon carrier materials comprise at least one large
molecule therapeutic agent disposed in the pores of the carrier
material. It is believed that the loading of large therapeutic
molecule into the pores of the carrier material stabilizes the
large molecules. In many embodiments, the large molecule is a
protein and the pores have an average size between about 15 nm to
about 40 nm, and the protein has a molecular weight from about
100,000 amu to about 200,000 amu. However, these systems may also
be used for small molecule therapeutic compounds. Detailed
descriptions of this type of silica based sustained delivery
component, and how it is made, is found in U.S. Pat. No. 9,808,421,
issued on Nov. 7, 2017, to Ashton et al., U.S. Pat. No. 9,333,173
issued on May 10, 2016 to Ashton et al., and United States Patent
Publication No. 20140271764 published on Sep. 28, 2014 by Ashton,
et al., all of which are incorporated by reference herein in its
entirety.
[0092] The sustained delivery component may have any suitable mass,
such as about 10 .mu.g-100 mg, about 10-20 .mu.g, about 20-30
.mu.g, about 30-40 .mu.g, about 40-50 .mu.g, about 50-60 .mu.g,
about 60-70 .mu.g, about 70-80 .mu.g, about 80-90 .mu.g, about
90-100 .mu.g, about 100-200 .mu.g, about 200-300 .mu.g, about
300-400 .mu.g, about 400-500 .mu.g, about 500-600 .mu.g, about
600-700 .mu.g, about 700-800 .mu.g, about 800-900 .mu.g, about
900-1,000 .mu.g, about 1-2 mg, about 2-3 mg, about 3-4 mg, about
4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg,
about 9-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg,
about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg,
about 80-90 mg, about 90-100 mg, about 100-200 mg, about 200-300
mg, about 300-400 mg, about 400-500 mg, about 500-600 mg, about
600-700 mg, about 700-800 mg, about 800-900 mg, about 900-1,000 mg,
about 1-2 g, about 2-3 g, about 3-4 g, about 4-5 g, about 5-6 g,
about 6-7 g, about 7-8 g, about 8-9 g, about 9-10 g, about 10-20 g,
about 20-30 g, about 30-40 g, about 40-50 g, about 50-60 g, about
60-70 g, about 70-80 g, about 80-90 g, about 90-100 g, about
100-200 g, about 200-300 g, about 300-400 g, about 400-500 g, about
500-600 g, about 600-700 g, about 700-800 g, about 800-900 g, about
900-1,000 g, about 10-100 .mu.g, about 100-1,000 .mu.g, about 1-10
mg, about 10-100 mg, about 100-1,000 mg, about 1-10 g, about 10-100
g, or about 100-1,000 g. Ranges above which are about 1 g or less,
or 100 mg or less, may be of interest for drug delivery systems
delivered onto or into the eye.
[0093] The sustained delivery component may be any suitable
percentage of the implant, such as about 1-99 wt %, about 1-10 wt
%, about 10-20 wt %, about 20-30 wt %, about 30-40 wt %, about
40-50 wt %, about 50-60 wt %, about 60-70 wt %, about 70-80 wt %,
about 80-90 wt %, about 90-99 wt %, about 1-30 wt %, about 30-65 wt
%, about 65-99 wt %, about 1-50 wt %, or about 50-99 wt %.
[0094] The drug delivery system may be of any suitable size, such
as about 10 .mu.g-100 mg, about 10-20 .mu.g, about 20-30 .mu.g,
about 30-40 .mu.g, about 40-50 .mu.g, about 50-60 .mu.g, about
60-70 .mu.g, about 70-80 .mu.g, about 80-90 .mu.g, about 90-100
.mu.g, about 100-200 .mu.g, about 200-300 .mu.g, about 300-400
.mu.g, about 400-500 .mu.g, about 500-600 .mu.g, about 600-700
.mu.g, about 700-800 .mu.g, about 800-900 .mu.g, about 900-1,000
.mu.g, about 1-2 mg, about 2-3 mg, about 3-4 mg, about 4-5 mg,
about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10
mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg,
about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg,
about 90-100 mg, about 100-200 mg, about 200-300 mg, about 300-400
mg, about 400-500 mg, about 500-600 mg, about 600-700 mg, about
700-800 mg, about 800-900 mg, about 900-1,000 mg, about 1-2 g,
about 2-3 g, about 3-4 g, about 4-5 g, about 5-6 g, about 6-7 g,
about 7-8 g, about 8-9 g, about 9-10 g, about 10-20 g, about 20-30
g, about 30-40 g, about 40-50 g, about 50-60 g, about 60-70 g,
about 70-80 g, about 80-90 g, about 90-100 g, about 100-200 g,
about 200-300 g, about 300-400 g, about 400-500 g, about 500-600 g,
about 600-700 g, about 700-800 g, about 800-900 g, about 900-1,000
g, about 10-100 .mu.g, about 100-1,000 .mu.g, about 1-10 mg, about
10-100 mg, about 100-1,000 mg, about 1-10 g, about 10-100 g, or
about 100-1,000 g. Ranges above which are about 1 g or less, or 100
mg or less, may be of interest for drug delivery systems delivered
onto or into the eye.
[0095] Typical examples of non-biodegradable or non-bioerodible
materials for implants include silicones or PVA as semipermeable
membranes (like Psivida).
[0096] Other potential sustained delivery components could be based
upon cell-based approaches like encapsulated cell technology; and
reservoir type approaches (forsight4; Replenish).
[0097] The prostaglandin compound or prostaglandin receptor
agonist, the intraocular pressure lowering agent, and/or the
neurotrophic agent, such as the CNTF compound, may, or may not, be
covalently attached to the sustained delivery component.
[0098] In some embodiments, the prostaglandin compound or
prostaglandin receptor agonist is covalently attached to the
sustained delivery component. In some embodiments, the
prostaglandin compound or prostaglandin receptor agonist is not
covalently attached to the sustained delivery component.
[0099] In some embodiments, the intraocular pressure lowering agent
is covalently attached to the sustained delivery component. In some
embodiments, the intraocular pressure lowering agent is not
covalently attached to the sustained delivery component.
[0100] In some embodiments, the neurotrophic agent, such as the
CNTF compound, is covalently attached to the sustained delivery
component. In some embodiments, the neurotrophic agent, such as the
CNTF compound, is not covalently attached to the sustained delivery
component.
[0101] For example, a prostaglandin compound or prostaglandin
receptor agonist may be covalently attached to the sustained
delivery component using a compound represented by a formula:
##STR00008##
wherein PG-H is a prostaglandin compound or prostaglandin receptor
agonist, such as a prostaglandin compound or prostaglandin receptor
agonist recited above.
[0102] Compounds of Formula 3 may be further represented by Formula
3A and 3B:
##STR00009##
wherein Prg-CO.sub.2H is a prostaglandin agonist and n is 1, 2, 3,
4, 5, 6, 7, 8, 9, 10, etc.
[0103] An intraocular pressure lowering agent may be covalently
attached to the sustained delivery component using a compound
represented by a formula:
##STR00010##
wherein IOP-H is an intraocular pressure lowering agent, such as an
intraocular pressure lowering agent recited above.
[0104] A CNTF compound or another neurotrophic agent may be
covalently attached to the sustained delivery component using a
compound represented by a formula:
##STR00011##
wherein CNTF-H is a CNTF compound or another neurotrophic agent,
such as a CNTF compound or another neurotrophic agent recited
above.
[0105] A CNP compound may be covalently attached to the sustained
delivery component using a compound represented by a formula:
##STR00012##
wherein CNP-H is a CNP compound.
[0106] An NPR-B compound may be covalently attached to the
sustained delivery component using a compound represented by a
formula:
##STR00013##
wherein NPRB-H is a NRP-B compound.
[0107] With respect to any relevant structural representation, such
as Formula 3, 3A, 3B, 4, 5, 6, or 7, or the compounds depicted
below, R.sup.1 is independently H or C.sub.1-6 alkyl, such as
CH.sub.3, C.sub.2 alkyl, C.sub.3 alkyl, C.sub.4 alkyl, C.sub.5
alkyl, or C.sub.6 alkyl.
[0108] With respect to any relevant structural representation, such
as Formula 3, 3A, 3B, 4, 5, 6, or 7, or the compounds depicted
below, R.sup.2 is independently H or C.sub.1-6 alkyl, such as
CH.sub.3, C.sub.2 alkyl, C.sub.3 alkyl, C.sub.4 alkyl, C.sub.5
alkyl, or C.sub.6 alkyl.
[0109] With respect to any relevant structural representation, such
as Formula 3, 3A, 3B, 4, 5, 6, or 7, or the compounds depicted
below, and R.sup.3 is independently H or C.sub.1-6 alkyl, such as
CH.sub.3, C.sub.2 alkyl, C.sub.3 alkyl, C.sub.4 alkyl, C.sub.5
alkyl, or C.sub.6 alkyl.
[0110] The compounds are examples of compounds of Formula 3, 3A or
3B:
##STR00014##
In the body, the ester bond can hydrolyze to release the
compound:
##STR00015##
The table below shows three compounds that are examples of
compounds of Formula 4, and the three compounds that can be
released in the body by hydrolysis of the ester or amide group:
TABLE-US-00003 Compound of Formula 4 Compound released in body
##STR00016## ##STR00017## ##STR00018## ##STR00019## ##STR00020##
##STR00021##
In the table above, any Si(OH).sub.3 group may be replaced with
SiOR.sup.1O R.sup.2O R.sup.3. An example of a compound of Formula 5
is: VGDGGLFEKKL-PEG-Si(OH).sub.3 ("VGDGGLFEKKL" disclosed as SEQ ID
NO: 1) or VGDGGLFEKKL-PEG-SiOR.sup.1O R.sup.2O R.sup.3
("VGDGGLFEKKL" disclosed as SEQ ID NO: 1) wherein PEG is a
polyethylene glycol chain (e.g. (OCH.sub.2CH.sub.2).sub.n--, where
n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc.). In the body, the ester
bond can hydrolyze to release VGDGGLFEKKL (SEQ ID NO: 1).
[0111] The SiOR.sup.1O R.sup.2O R.sup.3 group of Formulas 3, 3A,
3B, 4, 5, 6, or 7 may be covalently bonded to the silica of a
silica based drug delivery system, e.g. to form compounds
represented by Formulas 3D, 3AD, 3BD, 4D, or 5D, wherein D is a
sustained delivery component comprising the Si of the SiOR.sup.1O
R.sup.2O R.sup.3 of Formula 3, 3A, 3B, 4, 5, 6, or 7.
##STR00022##
[0112] Some drug delivery systems may be comprise a polymer
represented by a formula:
##STR00023##
wherein each X is independently
##STR00024##
[0113] A subject drug delivery system may be administered to a
mammal, such as a human, by any suitable method, such as by
injection or surgical implantation into any part of the body, oral
administration, or topical application to the eye or skin. In some
embodiments, an implant is injected or otherwise implanted in or
around an eye, including but not limited to: the anterior chamber,
the vitreous, the posterior chamber, the subconjunctival space, the
suprachoroidal space, or subtenon's space.
[0114] A subject drug delivery system may extend the amount of time
that the drug remains in the body. For example, a drug delivery
system may provide therapeutic levels of the drug for at least
about 2 weeks, at least about 4 weeks, at least about 6 weeks, at
least about 8 weeks, at least about 3 months, at least about 4
months, at least about 5 months, at least about 6 months, at least
about 7 months, at least about 8 months, at least about 9 months,
at least about 10 months, at least about 11 months, at least about
1 year, at least about 1.5 years, at least about 2 years, at least
about 3 years, at least about 4 years, about 1-6 months, about 6-12
months, about 12-18 months, about 18-24 months, about 24-36 months,
up to about 2 years, up to about 3 years, up to about 4 years, up
to about 5 years, or up to about 10 years. The drug delivery system
may be injected, implanted, or changed at a time in any of the
ranges above.
[0115] In some embodiments, a subject drug delivery system may be
administered to a mammal, such as a human being, to treat a
glaucoma, such as Primary Open-Angle Glaucoma (POAG), Acute Primary
Angle Close Glaucoma (APACG), Chronic Angle Closure Glaucoma,
Pigmentary Glaucoma, Pseudoexfoliation Glaucoma, Normal Tension
Glaucoma, Pediatric Glaucoma, a secondary glaucoma, etc., or a
combination thereof.
EXAMPLES
[0116] The following examples are intended to be illustrative of
the embodiments of the disclosure, but are not intended to limit
the scope or underlying principles in any way.
Example 1: Solid Phase Synthesis of a PG-L-CNTF Featuring an Amide
Linkage
[0117] Using methods known in the art, peptide 6 is linked to a
resin at the NH.sub.2 terminus, is protected with BOC groups and
t-Bu ester groups, and linked to NH.sub.2-terminated-PEG at the
carboxylic acid terminus to provide
Resin-L-K(Boc)-K(Boc)-E(tBu)-F-L-G-G-D(tBu)-G-V-CO.sub.2(CH.sub.2--CH.sub-
.2--O).sub.n--CH.sub.2--CH.sub.2--NH.sub.2. The nature of the
starting materials, and the order of reactions may be modified to
improve efficiency and selectivity, and all reactions are conducted
using methods known in the art. Bimatoprost free acid, having its
three hydroxyl groups protected with t-butyl groups (or other
alkyl- or silyl-protecting groups, as appropriate), is prepared by
methods known in the art. The free amine of the protected peptide 6
compound and the free acid of the protected prostaglandin compound
may be coupled by any appropriate peptide coupling method known in
the art. Following the coupling reaction, the protected amide can
be fully deprotected using TFA or other acid-catalyzed methods know
in the art to release the Peptide 6-Linker-Bimatoprost amide
derivative. Different orthogonal protecting group strategies may be
employed as necessary, as known in the art, to optimize the
efficiency of the overall procedure.
Example 2: Solid Phase Synthesis of a PG-L-CNTF Featuring an Ester
Linkage
[0118] Using methods known in the art, peptide 6 is linked to a
resin at the NH.sub.2 terminus, is protected with CBz groups on the
free amine groups and benzyl groups on the free acid groups, and is
coupled to polyethylene glycol at the carboxylic acid terminus to
provide
Resin-L-K(Cbz)-K(Cbz)-E(Bn)-F-L-G-G-D(Bn)-G-V-CO.sub.2(CH.sub.2--CH.sub.2-
--O).sub.n--CH.sub.2--CH.sub.2--OH. The nature of the starting
materials and the order of reactions may be modified to improve
selectivity, and all reactions are conducted using methods known in
the art. Bimatoprost free acid, having its three hydroxyl groups
protected with benzyl groups (or other hydrogenation-labile
protecting groups, as appropriate), is prepared by methods known in
the art. The free alcohol terminus of the protected peptide 6
compound and the free acid of the protected prostaglandin compound
may be coupled by any appropriate ester coupling method known in
the art. Following the coupling reaction, the protected ester can
be fully deprotected using hydrogenation methods or other
debenzylation methods known in the art to release the Peptide
6-Linker-Bimatoprost ester derivative. Different orthogonal
protecting group strategies may be employed as necessary, as known
in the art, to optimize the efficiency of the overall
procedure.
[0119] The following embodiments are specifically contemplated by
the inventors:
Embodiment 1. A drug delivery system comprising an intraocular
pressure lowering agent, a neurotrophic agent, a C-type Natriuretic
Peptide (CNP), a Natriuretic Peptide Receptor-B (NPR-B), or an
apoptosis signaling fragment inhibitor (FAS) or FAS-ligand (FASL)
inhibitor, and a sustained delivery component. Embodiment 2. The
drug delivery system of Embodiment 1, comprising the intraocular
pressure lowering agent. Embodiment 3. The drug delivery system of
Embodiment 2, wherein the intraocular pressure lowering agent is a
prostaglandin compound. Embodiment 4. The drug delivery system of
Embodiment 2 or 3, further comprising a second intraocular pressure
lowering agent. Embodiment 5. The drug delivery system of
Embodiment 2, 3, or 4, wherein the intraocular pressure lowering
agent comprises a beta blocker. Embodiment 6. The drug delivery
system of Embodiment 2, 3, 4, or 5, wherein the intraocular
pressure lowering agent comprises timolol. Embodiment 7. The drug
delivery system of Embodiment 2, 3, 4, 5, or 6, wherein the
intraocular pressure lowering agent comprises betaxolol. Embodiment
8. The drug delivery system of Embodiment 2, 3, 4, 5, 6, or 7,
wherein the intraocular pressure lowering agent comprises
levobunolol. Embodiment 9. The drug delivery system of Embodiment
2, 3, 4, 5, 6, 7, or 8, wherein the intraocular pressure lowering
agent comprises metipranolol. Embodiment 10. The drug delivery
system of Embodiment 2, 3, 4, 5, 6, 7, 8, or 9, wherein the
intraocular pressure lowering agent comprises an alpha adrenergic
agonist. Embodiment 11. The drug delivery system of Embodiment 2,
3, 4, 5, 6, 7, 8, 9, or 10, wherein the intraocular pressure
lowering agent comprises brimonidine. Embodiment 12. The drug
delivery system of Embodiment 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11, or
10, wherein the intraocular pressure lowering agent comprises
apraclonidine. Embodiment 13. The drug delivery system of
Embodiment 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, wherein the
intraocular pressure lowering agent comprises a carbonic anhydrase
inhibitor. Embodiment 14. The drug delivery system of Embodiment 2,
3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13, wherein the intraocular
pressure lowering agent comprises brinzolamide. Embodiment 15. The
drug delivery system of Embodiment 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,
12, 13, or 14, wherein the intraocular pressure lowering agent
comprises acetazolamide. Embodiment 16. The drug delivery system of
Embodiment 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15,
wherein the intraocular pressure lowering agent comprises
dorzolamide. Embodiment 17. The drug delivery system of Embodiment
2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16, wherein the
intraocular pressure lowering agent comprises methazolamide.
Embodiment 18. The drug delivery system of Embodiment 2, 3, 4, 5,
6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17, wherein the
intraocular pressure lowering agent comprises a cholinergic.
Embodiment 19. The drug delivery system of Embodiment 2, 3, 4, 5,
6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18, wherein the
intraocular pressure lowering agent comprises pilocarpine.
Embodiment 20. The drug delivery system of Embodiment 2, 3, 4, 5,
6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19, wherein the
intraocular pressure lowering agent comprises carbachol. Embodiment
21. The drug delivery system of Embodiment 2, 3, 4, 5, 6, 7, 8, 9,
10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20, wherein the
intraocular pressure lowering agent comprises a Rho Kinase (ROCK)
inhibitor. Embodiment 22. The drug delivery system of Embodiment 2,
3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or
21, wherein the intraocular pressure lowering agent comprises
netarsudil. Embodiment 23. The drug delivery system of Embodiment
1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,
20, 21, or 22, comprising the neurotrophic agent. Embodiment 24.
The drug delivery system of Embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9,
10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23,
comprising both the prostaglandin receptor agonist and the
neurotrophic agent. Embodiment 25. The drug delivery system of
Embodiment 24, wherein the prostaglandin receptor agonist and the
neurotrophic agent are covalently bound to one another. Embodiment
26. The drug delivery system of Embodiment 25, wherein the
prostaglandin receptor agonist and the neurotrophic agent are
covalently bound to one another via a linking group. Embodiment 27.
The drug delivery system of Embodiment 3, 4, 5, 6, 7, 8, 9, 10, 11,
12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or 26,
wherein the prostaglandin receptor agonist comprises bimatoprost.
Embodiment 28. The drug delivery system of Embodiment 3, 4, 5, 6,
7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23,
24, 25, or 26, wherein the prostaglandin receptor agonist comprises
travoprost. Embodiment 29. The drug delivery system of Embodiment
3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20,
21, 22, 23, 24, 25, or 26, wherein the prostaglandin receptor
agonist comprises latanoprost. Embodiment 30. The drug delivery
system of Embodiment 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,
16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or 26, wherein the
prostaglandin receptor agonist comprises latanoprostene. Embodiment
31. The drug delivery system of Embodiment 3, 4, 5, 6, 7, 8, 9, 10,
11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or 26,
wherein the prostaglandin receptor agonist comprises tafluprost.
Embodiment 32. The drug delivery system of Embodiment 3, 4, 5, 6,
7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23,
24, 25, or 26, wherein the prostaglandin receptor agonist comprises
a prostaglandin EP2 receptor agonist. Embodiment 33. The drug
delivery system of Embodiment 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,
14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or 26, wherein the
prostaglandin receptor agonist comprises a prostaglandin EP3
receptor agonist. Embodiment 34. The drug delivery system of
Embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,
17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, or
33, wherein the neurotrophic agent comprises CNTF Peptide 6.
Embodiment 35. The drug delivery system of Embodiment 1, 2, 3, 4,
5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,
23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, or 34, wherein the
neurotrophic agent comprises CNTF Peptide 21. Embodiment 36. The
drug delivery system of Embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,
11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27,
28, 29, 30, 31, 32, 33, 34, or 35, comprising the CNP compound.
Embodiment 37. The drug delivery system of Embodiment 1, 2, 3, 4,
5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,
23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36,
comprising the NPR-B compound. Embodiment 38. The drug delivery
system of Embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,
15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31,
32, 33, 34, 35, 36, or 37, comprising both the intraocular pressure
lowering agent and the neurotrophic agent. Embodiment 39. The drug
delivery system of Embodiment 38, wherein the intraocular pressure
lowering agent and the neurotrophic agent are covalently bound to
one another. Embodiment 40. The drug delivery system of Embodiment
39, wherein the intraocular pressure lowering agent and the
neurotrophic agent are covalently bound to one another via a
linking group. Embodiment 41. The drug delivery system of
Embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,
17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33,
34, 35, 36, 37, 38, 39, or 40, comprising both the intraocular
pressure lowering agent and the CNP compound. Embodiment 42. The
drug delivery system of Embodiment 41, wherein the intraocular
pressure lowering agent and the CNP compound are covalently bound
to one another. Embodiment 43. The drug delivery system of
Embodiment 42, wherein the intraocular pressure lowering agent and
the CNP compound are covalently bound to one another via a linking
group. Embodiment 44. The drug delivery system of Embodiment 1, 2,
3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20,
21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37,
38, 39, 40, 41, 42, or 43, comprising both the intraocular pressure
lowering agent and the NPR-B compound. Embodiment 45. The drug
delivery system of Embodiment 44, wherein the intraocular pressure
lowering agent and the NPR-B compound are covalently bound to one
another. Embodiment 46. The drug delivery system of Embodiment 45,
wherein the intraocular pressure lowering agent and the NPR-B
compound are covalently bound to one another via a linking group.
Embodiment 47. The drug delivery system of Embodiment 1, 2, 3, 4,
5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,
23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39,
40, 41, 42, 43, 44, 45, or 46, comprising both the neurotrophic
agent and the CNP compound. Embodiment 48. The drug delivery system
of Embodiment 47, wherein the neurotrophic agent and the CNP
compound are covalently bound to one another. Embodiment 49. The
drug delivery system of Embodiment 48 wherein the neurotrophic
agent and the CNP compound are covalently bound to one another via
a linking group. Embodiment 50. The drug delivery system of
Embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,
17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33,
34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, or 49,
comprising both the neurotrophic agent and the NPR-B compound.
Embodiment 51. The drug delivery system of Embodiment 50, wherein
the neurotrophic agent and the NPR-B compound are covalently bound
to one another. Embodiment 52. The drug delivery system of
Embodiment 51, wherein the neurotrophic agent and the NPR-B
compound are covalently bound to one another via a linking group.
Embodiment 53. The drug delivery system of Embodiment 1, 2, 3, 4,
5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,
23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39,
40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52, comprising
both the CNP compound and the NPR-B compound. Embodiment 54. The
drug delivery system of Embodiment 53, wherein the CNP compound and
the NPR-B compound are covalently bound to one another. Embodiment
55. The drug delivery system of Embodiment 54, wherein the CNP
compound and the NPR-B compound are covalently bound to one another
via a linking group. Embodiment 56. The drug delivery system of
Embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,
17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33,
34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50,
51, 52, 53, 54, or 55, wherein the neurotrophic agent is a CNTF
compound. Embodiment 57. The drug delivery system of Embodiment 1,
2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20,
21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37,
38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54,
55, or 56, wherein the sustained delivery component is silica
based. Embodiment 58. The drug delivery system of Embodiment 1, 2,
3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20,
21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37,
38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54,
55, or 56, wherein the sustained delivery component is porous.
Embodiment 59. The drug delivery system of Embodiment 1, 2, 3, 4,
5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,
23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39,
40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, or
56, wherein the sustained delivery component is non-porous.
Embodiment 60. The drug delivery system of Embodiment 1, 2, 3, 4,
5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,
23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39,
40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, or
56, wherein the sustained delivery component is of the type
described in U.S. Pat. No. 9,949,922, issued on Apr. 24, 2018 to
Jokinen, et al. Embodiment 61. The drug delivery system of
Embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,
17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33,
34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50,
51, 52, 53, 54, 55, or 56, wherein the sustained delivery component
is of the type described in United States Patent Application
Publication No. 20140057996, published Feb. 27, 2014 by Jokinen, et
al. Embodiment 62. The drug delivery system of Embodiment 1, 2, 3,
4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21,
22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38,
39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55,
or 56, wherein the sustained delivery component is of the type
described in U.S. Pat. No. 9,603,801, issued on Mar. 28, 2017 to
Barnett, et al., Embodiment 63. The drug delivery system of
Embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,
17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33,
34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50,
51, 52, 53, 54, 55, or 56, wherein the sustained delivery component
is of the type described in U.S. Pat. No. 9,808,421, issued on Nov.
7, 2017, to Ashton et al. Embodiment 64. The drug delivery system
of Embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,
16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32,
33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49,
50, 51, 52, 53, 54, 55, or 56, wherein the sustained delivery
component is of the type described in U.S. Pat. No. 9,333,173
issued on May 10, 2016 to Ashton et al. Embodiment 65. The drug
delivery system of Embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,
12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28,
29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45,
46, 47, 48, 49, 50, 51, 52, 53, 54, 55, or 56, wherein the
sustained delivery component is of the type described in United
States Patent Publication No. 20140271764 published on Sep. 28,
2014 by Ashton, et al. Embodiment 66. The drug delivery system of
Embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,
17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33,
34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50,
51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, or 65,
wherein the prostaglandin receptor agonist is covalently attached
to the sustained delivery component. Embodiment 67. The drug
delivery system of Embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,
12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28,
29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45,
46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62,
63, 64, 65, or 66, wherein the neurotrophic agent is covalently
attached to the sustained delivery component. Embodiment 68. The
drug delivery system of Embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,
11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27,
28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44,
45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61,
62, 63, 64, 65, or 67, wherein the prostaglandin receptor agonist
is not covalently attached to the sustained delivery component.
Embodiment 69. The drug delivery system of Embodiment 1, 2, 3, 4,
5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,
23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39,
40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56,
57, 58, 59, 60, 61, 62, 63, 64, 65, 66, or 68 wherein the
neurotrophic agent is not covalently attached to the sustained
delivery component. Embodiment 70. A method of treating a glaucoma
or ocular hypertension comprising administering a drug delivery
system of Embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,
15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31,
32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48,
49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65,
66, 67, 68, or 69 to a mammal suffering from glaucoma or ocular
hypertension. Embodiment 71. The method of Embodiment 70, wherein
the drug delivery system is administered by intravitreal injection
into an affected eye of the mammal. Embodiment 72. The method of
Embodiment 70, wherein the drug delivery system is implanted into
the anterior chamber, the subconjunctival space, the suprachoroidal
space, or the subtenon's space of an affected eye of the mammal.
Embodiment 73. The method of Embodiment 70, 71, or 72, wherein the
glaucoma comprises Primary Open-Angle Glaucoma (POAG). Embodiment
74. The method of Embodiment 70, 71, or 72, wherein the glaucoma
comprises Acute Primary Angle Close Glaucoma (APACG). Embodiment
75. The method of Embodiment 70, 71, or 72, wherein the glaucoma
comprises Chronic Angle Closure Glaucoma. Embodiment 76. The method
of Embodiment 70, 71, or 72, wherein the glaucoma comprises
Pigmentary Glaucoma. Embodiment 77. The method of Embodiment 70,
71, or 72, wherein the glaucoma comprises Pseudoexfoliation
Glaucoma. Embodiment 78. The method of Embodiment 70, 71, or 72,
wherein the glaucoma comprises Normal Tension Glaucoma. Embodiment
79. The method of Embodiment 70, 71, or 72, wherein the glaucoma
comprises Pediatric Glaucoma. Embodiment 80. The method of
Embodiment 70, 71, or 72, wherein
the glaucoma comprises a secondary glaucoma.
Sequence CWU 1
1
15111PRTArtificial Sequencesource/note="Description of Artificial
Sequence Synthetic peptide" 1Val Gly Asp Gly Gly Leu Phe Glu Lys
Lys Leu1 5 1025PRTArtificial Sequencesource/note="Description of
Artificial Sequence Synthetic peptide" 2Asp Gly Gly Leu Gly1
5312PRTArtificial Sequencesource/note="Description of Artificial
Sequence Synthetic peptide" 3His His Ile Tyr Leu Gly Ala Val Asn
Tyr Ile Tyr1 5 10412PRTArtificial Sequencesource/note="Description
of Artificial Sequence Synthetic peptide" 4His His Ile Tyr Leu Gly
Ala Thr Asn Tyr Ile Tyr1 5 1054PRTArtificial
Sequencesource/note="Description of Artificial Sequence Synthetic
peptide" 5Tyr Leu Gly Ala165PRTArtificial
Sequencesource/note="Description of Artificial Sequence Synthetic
peptide" 6Ile Tyr Leu Gly Ala1 575PRTArtificial
Sequencesource/note="Description of Artificial Sequence Synthetic
peptide" 7Tyr Leu Gly Ala Val1 586PRTArtificial
Sequencesource/note="Description of Artificial Sequence Synthetic
peptide" 8His Ile Tyr Leu Gly Ala1 596PRTArtificial
Sequencesource/note="Description of Artificial Sequence Synthetic
peptide" 9Ile Tyr Leu Gly Ala Val1 5107PRTArtificial
Sequencesource/note="Description of Artificial Sequence Synthetic
peptide" 10His Ile Tyr Leu Gly Ala Val1 5117PRTArtificial
Sequencesource/note="Description of Artificial Sequence Synthetic
peptide" 11Ile Tyr Leu Gly Ala Val Asn1 5127PRTArtificial
Sequencesource/note="Description of Artificial Sequence Synthetic
peptide" 12His His Ile Tyr Leu Gly Ala1 5137PRTArtificial
Sequencesource/note="Description of Artificial Sequence Synthetic
peptide" 13Tyr Leu Gly Ala Val Asn Tyr1 5148PRTArtificial
Sequencesource/note="Description of Artificial Sequence Synthetic
peptide" 14His His Ile Tyr Leu Gly Ala Val1 5158PRTArtificial
Sequencesource/note="Description of Artificial Sequence Synthetic
peptide" 15Tyr Leu Gly Ala Val Asn Tyr Ile1 5
* * * * *