U.S. patent application number 15/772779 was filed with the patent office on 2019-08-01 for topical formulations and uses thereof.
This patent application is currently assigned to SUN PHARMA GLOBAL FZE. The applicant listed for this patent is SUN PHARMA GLOBAL FZE. Invention is credited to Sidney L. WEISS.
Application Number | 20190231885 15/772779 |
Document ID | / |
Family ID | 58695926 |
Filed Date | 2019-08-01 |
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United States Patent
Application |
20190231885 |
Kind Code |
A1 |
WEISS; Sidney L. |
August 1, 2019 |
TOPICAL FORMULATIONS AND USES THEREOF
Abstract
Provided herein include formulations for topical administration,
such as ophthalmic formulations, and methods of using such
formulations. In some aspects and embodiments the formulations may
include a polyoxyl lipid or fatty acid, and/or a polyalkoxylated
alcohol and may include nanomicelles. Also include methods of
treating or preventing diseases or conditions, such as ocular
diseases or conditions.
Inventors: |
WEISS; Sidney L.; (Randolph,
NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
SUN PHARMA GLOBAL FZE |
Sharjah |
|
AE |
|
|
Assignee: |
SUN PHARMA GLOBAL FZE
Sharjah
AE
|
Family ID: |
58695926 |
Appl. No.: |
15/772779 |
Filed: |
November 3, 2016 |
PCT Filed: |
November 3, 2016 |
PCT NO: |
PCT/US16/60391 |
371 Date: |
May 1, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
62253569 |
Nov 10, 2015 |
|
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|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 43/00 20180101;
A61K 31/425 20130101; A61K 9/1075 20130101; A61K 47/44 20130101;
A61K 47/10 20130101; A61K 9/0048 20130101; A61P 27/02 20180101 |
International
Class: |
A61K 47/44 20060101
A61K047/44; A61K 47/10 20060101 A61K047/10; A61K 9/00 20060101
A61K009/00; A61K 9/107 20060101 A61K009/107; A61K 31/425 20060101
A61K031/425 |
Claims
1. A formulation comprising a polyoxyl lipid or fatty acid and a
polyalkoxylated alcohol, wherein said formulation comprises mixed
nanomicelles, wherein said formulation does not include organic
solvents, and wherein said formulation does not contain any
pharmaceutically active agent that has received regulatory approval
for the specific treatment of an ocular condition.
2. The formulation of claim 1, wherein said polyoxyl lipid or fatty
acid is present in an amount equal to greater than 1% of said
formulation.
3. The formulation of claim 1, comprising 0.05-5% of one or more
polyoxyl lipid selected from the group consisting of HCO-40,
HCO-60, HCO-80, HCO-100, polyoxyl 40 stearate and polyoxyl 35
castor oil; and about 0.01-0.1% octoxynol-40.
4. The formulation of any of the preceding claims, wherein the
formulation does not include any active agent selected from the
group consisting of calcineurin inhibitors, mTOR inhibitors,
peptides, eicosanoids (e.g. prostacyclins and prostaglandins),
anti-inflammatory drugs (such as NSAIDS), autonomic drugs (e.g.
beta-blockers, alpha-blockers, beta-agonists, and alpha-agonists),
biologics, gene therapy agents (e.g. viral vectors),
anti-infectives (e.g. antifungals, antibiotics, and antivirals),
retinoids, RNAi, photo sensitizers, steroids (e.g., estrogens and
derivatives thereof, and corticosteriods), mixture drugs,
immuno-modulators, chemotherapeutic agents, G-coupled protein
receptor antagonists, receptor tyrosine kinase (RTK) inhibitors,
growth hormone inhibitors, integrin inhibitors, Sdf1/CXCR4 pathway
inhibitors, and nACh receptor antagonists, resolvins (or
resolvin-like compounds), lipoxins, and oxylipins.
5. The formulation of any of the preceding claims, wherein the
formulation does include a resolvin.
6. The formulation of any of the preceding claims, wherein
formulation does not include compound 1001.
7. The ophthalmic formulation of any of the preceding claims,
wherein the formulation does not include cyclosporine A,
voclosporin, ascomycin, tacrolimus, pimecrolimus, an analog
thereof, or a pharmaceutically acceptable salt thereof.
8. The formulation of any of the preceding claims, wherein the
formulation does not include cyclosporine A.
9. A method of treating or preventing an ocular disease or
condition, said method comprising topically administering a
formulation of any of the preceding claims.
10. A method of manufacturing an ophthalmic formulation comprising
liquefying/melting and mixing (a) a polyoxyl lipid or fatty acid,
(b) a polyalkoxylated alcohol and (c) optionally an active agent
and subsequently adding a buffer and a saline.
11. The formulation of claim 1, wherein said polyalkoxylated
alcohol is Octoxynol-40.
12. The formulation of claim 11, wherein the Octoxynol-40 is
present in an amount between 0.002 and 4% of the solution.
13. The formulation of claim 1, wherein said polyoxyl lipid
comprises one or more selected from the group consisting of HCO-40,
HCO-60, HCO-80, HCO-100, polyoxyl 40 stearate and polyoxyl 35
castor oil; and wherein said polyalkoxylated alcohol is
Octoxynol-40.
14. The formulation of claim 1, wherein said polyoxyl lipid
comprises one or more selected from the group consisting of HCO-40,
HCO-60, HCO-80, HCO-100, polyoxyl 40 stearate and polyoxyl 35
castor oil and is present in an amount between 0.5-2% of the
solution; and said polyalkoxylated alcohol is Octoxynol-40 and is
present in an amount between 0.002 and 4% of the solution.
15. The formulation of claim 1, wherein said polyoxyl lipid
comprises one or more selected from the group consisting of HCO-40,
HCO-60, HCO-80, HCO-100, polyoxyl 40 stearate and polyoxyl 35
castor oil and is present in an amount between 0.5-1.5% of the
solution; and said polyalkoxylated alcohol is Octoxynol-40 and is
present in an amount between 0.02 and 0.1% of the solution.
16. The formulation of claim 1, wherein said polyoxyl lipid
comprises one or more selected from the group consisting of HCO-40,
HCO-60, HCO-80, HCO-100, polyoxyl 40 stearate and polyoxyl 35
castor oil and is present in an amount between 0.5-5% of the
solution; said polyalkoxylated alcohol is Octoxynol-40 and is
present in an amount between 0.02 and 4% of the solution.
17. The formulation of claim 1, wherein said polyoxyl lipid
comprises one or more selected from the group consisting of HCO-40,
HCO-60, HCO-80, HCO-100, polyoxyl 40 stearate and polyoxyl 35
castor oil and is present in an amount between 0.5-1.5% of the
solution; and said polyalkoxylated alcohol is Octoxynol-40 and is
present in an amount between 0.02 and 0.1% of the solution.
Description
FIELD OF THE INVENTION
[0001] The present disclosure relates to the field of formulations
for topical administration, such as ophthalmic formulations, and
methods of using such formulations.
BACKGROUND OF THE INVENTION
[0002] The information provided herein and references cited are
provided solely to assist the understanding of the reader, and does
not constitute an admission that any of the references or
information is prior art to the present disclosure.
[0003] United States Patent Application Nos US2010/0310462 and
US2009/0092665 disclose drug delivery systems for ophthalmic use
that have nanomicelles that include vitamin E TPGS.
[0004] Travoprost involves a formulation for glaucoma or ocular
hypertension that includes HCO-40 and a prostaglandin analog as the
active ingredient. See
dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=338e7ff4-0d91-4208-a45d-bf-
a2be52334d on the world-wide web. The active ingredient is present
at 0.004%. The formulation includes propylene glycol and does not
include nanomicelles. HCO-40 is present in Travoprost at 0.5%. See
ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/huma-
n/000665/WC500038389.pdf on the world-wide web.
SUMMARY OF THE INVENTION
[0005] The present disclosure relates to topical formulations such
as formulations suitable for ophthalmic administration. In certain
aspects and embodiments, the formulations of the present disclosure
may include a polyoxyl lipid or fatty acid, and/or a
polyalkoxylated alcohol and may include nanomicelles. In certain
aspects and embodiments, the formulations of the present disclosure
are formulated in the absence of any pharmaceutically active agent,
i.e., without any non-lipid non-surfactant pharmaceutically active
agent that has received regulatory approval for the treatment of an
ocular condition. As used herein, the term "formulation" is not
meant to imply that the ingredients or components are in
combination with a pharmaceutically active agent, i.e., any
non-lipid non-surfactant active agent that has received regulatory
approval for the treatment of an ocular condition.
[0006] In certain aspects and embodiments as described herein, the
formulations as described herein may have certain surprising
features and advantages that could not have been predicted prior to
the present disclosure.
[0007] In some embodiments, the formulations of the present
disclosure are surprisingly stable at high temperatures, for
example, temperatures above about 40.degree. C. In some aspects and
embodiments the nanomicellular nature of some formulations
described herein allow for improved ocular tissue distribution. In
certain aspects and embodiments, formulations as described herein
are particularly suitable for anterior eye delivery, or posterior
eye delivery, or anterior and posterior eye delivery.
[0008] Accordingly, in a first aspect provided is a formulation
that includes a polyoxyl lipid or fatty acid and a polyalkoxylated
alcohol, and does not include an active agent. In some embodiments
the formulations include nanomicelles. In some embodiments the
polyoxyl lipid or fatty acid is a polyoxyl castor oil. In some
embodiments, the polyoxyl lipid or fatty acid is one or more
selected from HCO-40, HCO-60, HCO-80 or HCO-100. In some
embodiments the polyoxyl lipid or fatty acid (such as a polyoxyl
castor oil such as HCO-40, HCO-60, HCO-80 or HCO-100) is present
between 1 and 6%; or 2 and 6%; or 2 and 6%; or 3 and 6%; or 4 and
6%; or 2 and 5%; or 3 and 5%; or 3 and 5%; or 2 and 6%; or about
4%; or greater than 0.7%; or greater than 1%, or greater than 1.5%;
or greater than 2%; or greater than 3%; or greater than 4% by
weight of the formulation. In some embodiments the polyoxyl lipid
is HCO-60. In some embodiments the polyoxyl lipid is HCO-80. In
some embodiments the polyoxyl lipid is HCO-100. In some
embodiments, the formulation includes a polyalkoxylated alcohol
that is octoxynol-40. In some embodiments, the formulation includes
a polyalkoxylated alcohol (such as octoxynol-40) present between
0.002 and 4%; or between 0.005 and 3%; or 0.005 and 2%; or 0.005
and 1%; or 0.005 and 0.5%; or 0.005 and 0.1%; or 0.005 and 0.05%;
or 0.008 and 0.02%; or about 0.01% by weight of the
formulation.
[0009] As used herein, the term "polyoxyl lipid or fatty acid"
refers to mono- and diesters of lipids or fatty acids and
polyoxyethylene diols. Polyoxyl lipids or fatty acids may be
numbered ("n") according to the average polymer length of the
oxyethylene units (e.g., 40, 60, 80, 100) as is well understood in
the art. The term "n 40 polyoxyl lipid" means that the ployoxyl
lipid or fatty acid has an average oxyethylene polymer length equal
to or greater than 40 units. Stearate hydrogenated castor oil and
castor oil are common lipids/fatty acids commercially available as
polyoxyl lipids or fatty acid, however, it is understood that any
lipid or fatty acid could polyoxylated to become a polyoxyl lipid
or fatty acid as contemplated herein. Examples of polyoxyl lipid or
fatty acids include without limitation HCO-40, HCO-60, HCO-80,
HCO-100, polyoxyl 40 stearate, polyoxyl 35 castor oil.
[0010] As used herein, the term "micelle" or "nanomicelle" refers
to an aggregate (or cluster) of surfactant molecules. Micelles only
form when the concentration of surfactant is greater than the
critical micelle concentration (CMC). Surfactants are chemicals
that are amphipathic, which means that they contain both
hydrophobic and hydrophilic groups. Micelles can exist in different
shapes, including spherical, cylindrical, and discoidal. A micelle
comprising at least two different molecular species is a mixed
micelle. In some embodiments, ophthalmic compositions of the
present disclosure include an aqueous, clear, mixed micellar
solution.
[0011] In a second aspect, provided is a formulation, comprising a
n.gtoreq.40 polyoxyl lipid or fatty acid, and optionally, an active
agent. In some embodiments the formulations includes nanomicelles.
In some embodiments the polyoxyl lipid or fatty acid is a polyoxyl
castor oil. In some embodiments, the polyoxyl lipid or fatty acid
is one or more selected from HCO-40, HCO-60, HCO-80 or HCO-100. In
some embodiments the polyoxyl lipid or fatty acid (such as a
polyoxyl castor oil such as HCO-40, HCO-60, HCO-80 or HCO-100) is
present between 0.5 and 2%, or 0.7 and 2%, or 1 and 6%; or 2 and
6%; or 2 and 6%; or 3 and 6%; or 4 and 6%; or 2 and 5%; or 3 and
5%; or 3 and 5%; or 2 and 6%; or about 4%; or greater than 0.7%; or
greater than 1%, or greater than 1.5%; or greater than 2%; or
greater than 3%; or greater than 4% by weight of the formulation.
In some embodiments the polyoxyl lipid is HCO-60. In some
embodiments the polyoxyl lipid is HCO-80. In some embodiments the
polyoxyl lipid is HCO-100. In some embodiments, the formulation
further includes polyalkoxylated alcohol. In some embodiments, the
formulation further includes polyalkoxylated alcohol that is
octoxynol-40. In some embodiments, the formulation includes a
polyalkoxylated alcohol (such as octoxynol-40) present between
0.002 and 4%; or between 0.005 and 3%; or between 0.005 and 2%; or
between 0.005 and 1%; or between 0.005 and 0.5%; or between 0.005
and 0.1%; or between 0.005 and 0.05%; or between 0.008 and 0.02%;
or between 0.01 and 0.1%; or between 0.02 and 0.08%; or between
0.005 and 0.08%; or about 0.05%, or about 0.01% by weight of the
formulation.
[0012] In a third aspect, provided is a formulation, that includes
a polyoxyl lipid or fatty acid; and does not include an active
agent, wherein said polyoxyl lipid or fatty acid is present in an
amount equal to or greater than 1% of said formulation. In a
similar aspect, provided is a formulation that includes a polyoxyl
lipid or fatty acid, and does not include an active agent; wherein
said polyoxyl lipid or fatty acid is present in an amount equal to
or greater than 0.05% of said formulation. In some embodiments the
formulations includes nanomicelles. In some embodiments the
polyoxyl lipid or fatty acid is a polyoxyl castor oil. In some
embodiments, the polyoxyl lipid or fatty acid is one or more
selected from HCO-40, HCO-60, HCO-80 or HCO-100. In some
embodiments the polyoxyl lipid or fatty acid (such as a polyoxyl
castor oil such as HCO-60, HCO-80 or HCO-100) is present between
0.5 and 2%, or 0.7 and 2%, or between 1 and 6%; or 2 and 6%; or 2
and 6%; or 3 and 6%; or 4 and 6%; or 2 and 5%; or 3 and 5%; or 3
and 5%; or 2 and 6%; or about 4%; or greater than 1.5%; or greater
than 2%; or greater than 3%; or greater than 4% by weight of the
formulation. In some embodiments the polyoxyl lipid is HCO-40. In
some embodiments the polyoxyl lipid is HCO-60. In some embodiments
the polyoxyl lipid is HCO-80. In some embodiments the polyoxyl
lipid is HCO-100. In some embodiments, the formulation further
includes polyalkoxylated alcohol. In some embodiments, the
formulation further includes polyalkoxylated alcohol that is
octoxynol-40. In some embodiments, the formulation includes a
polyalkoxylated alcohol (such as octoxynol-40) present between
0.002 and 4%; or between 0.005 and 3%; or between 0.005 and 2%; or
between 0.005 and 1%; or between 0.005 and 0.5%; or between 0.005
and 0.1%; or between 0.005 and 0.05%; or between 0.008 and 0.02%;
or between 0.01 and 0.1%; or between 0.02 and 0.08%; or between
0.005 and 0.08%; or about 0.05%, or about 0.01% by weight of the
formulation.
[0013] In a fourth aspect, provided is a formulation that includes
a polyoxyl lipid or fatty acid, and does not include an active
agent; wherein said formulation comprises nanomicelles. In some
embodiments the polyoxyl lipid or fatty acid is a polyoxyl castor
oil. In some embodiments, the polyoxyl lipid or fatty acid is one
or more selected from HCO-40, HCO-60, HCO-80 or HCO-100. In some
embodiments the polyoxyl lipid or fatty acid (such as a polyoxyl
castor oil such as HCO-40, HCO-60, HCO-80 or HCO-100) is present
between 0.5 and 2%, or 0.7 and 2%, or between 1 and 6%; or 2 and
6%; or 2 and 6%; or 3 and 6%; or 4 and 6%; or 2 and 5%; or 3 and
5%; or 3 and 5%; or 2 and 6%; or about 4%; or greater than 0.7%; or
greater than 1%, or greater than 1.5%; or greater than 2%; or
greater than 3%; or greater than 4% by weight of the formulation.
In some embodiments the polyoxyl lipid is HCO-40. In some
embodiments the polyoxyl lipid is HCO-60. In some embodiments the
polyoxyl lipid is HCO-80. In some embodiments the polyoxyl lipid is
HCO-100. In some embodiments, the formulation further includes
polyalkoxylated alcohol. In some embodiments, the formulation
further includes polyalkoxylated alcohol that is octoxynol-40. In
some embodiments, the formulation includes a polyalkoxylated
alcohol (such as octoxynol-40) present between 0.002 and 4%; or
between 0.005 and 3%; or between 0.005 and 2%; or between 0.005 and
1%; or between 0.005 and 0.5%; or between 0.005 and 0.1%; or
between 0.005 and 0.05%; or between 0.008 and 0.02%; or between
0.01 and 0.1%; or between 0.02 and 0.08%; or between 0.005 and
0.08%; or about 0.05%, or about 0.01% by weight of the
formulation.
[0014] In a further aspect provided is a formulation, comprising
1-5% of one or more polyoxyl lipid selected from the group
consisting of HCO-40, HCO-60, HCO-80 and HCO-100; about 0.01%
octoxynol-40, and does not include an active agent.
[0015] In another aspect, provided is a formulation, comprising
1-5% of one or more polyoxyl lipid selected from the group
consisting of HCO-40, HCO-60, HCO-80 and HCO-100; about 0.01%
octoxynol-40, and does not include an active agent.
[0016] In yet another aspect, provided is a formulation comprising
1-5% of one or more polyoxyl lipid selected from the group
consisting of HCO-40, HCO-60, HCO-80 and HCO-100; about 0.01%
octoxynol-40, and does not include an active agent.
[0017] In one aspect, provided is a formulation comprising 1-5% of
one or more polyoxyl lipid selected from the group consisting of
HCO-40, HCO-60, HCO-80 and HCO-100; about 0.01% octoxynol-40, and
does not include an active agent.
[0018] In a further aspect provided is a formulation comprising
about 4% of HCO-60, about 0.01% octoxynol-40, and does not include
an active agent.
[0019] In another aspect provided is a formulation comprising
0.7-1.5% of one or more polyoxyl lipid selected from the group
consisting of HCO-40, HCO-60, HCO-80 and HCO-100; about 0.05%
octoxynol-40, and does not include an active agent.
[0020] In another aspect, provided is a formulation comprising
0.7-1.5% of one or more polyoxyl lipid selected from the group
consisting of HCO-40, HCO-60, HCO-80 and HCO-100; about 0.05%
octoxynol-40, and does not include an active agent.
[0021] In yet another aspect, provided is a formulation comprising
0.7-1.5% of one or more polyoxyl lipid selected from the group
consisting of HCO-40, HCO-60, HCO-80 and HCO-100; about 0.05%
octoxynol-40, and does not include an active agent.
[0022] In one aspect, provided is a formulation comprising 0.7-1.5%
of one or more polyoxyl lipid selected from the group consisting of
HCO-40, HCO-60, HCO-80 and HCO-100; about 0.05% octoxynol-40, and
does not include an active agent.
[0023] In a further aspect provided is a formulation comprising
about 1% of HCO-60, about 0.05% octoxynol-40, and does not include
an active agent.
[0024] In various embodiments of any of the aspects and embodiments
described herein, the formulation includes nanomicelles.
[0025] In some embodiments of the aspects and embodiments described
herein, the formulation includes a polyoxyl lipid or fatty acid. In
some embodiments the polyoxyl lipid or fatty acid is a polyoxyl
castor oil. In some embodiments, the polyoxyl lipid or fatty acid
is one or more selected from HCO-40, HCO-60, HCO-80 or HCO-100. In
some embodiments the polyoxyl lipid or fatty acid (such as a
polyoxyl castor oil such as HCO-60, HCO-80 or HCO-100) is present
between 0.5 and 2%, or 0.7 and 2%, or 1 and 6%; or 2 and 6%; or 2
and 6%; or 3 and 6%; or 4 and 6%; or 2 and 5%; or 3 and 5%; or 3
and 5%; or 2 and 6%; or about 4%; or greater than 0.7%; or greater
than 1%, or greater than 1.5%; or greater than 2%; or greater than
3%; or greater than 4% by weight of the formulation. In some
embodiments the polyoxyl lipid is HCO-40. In some embodiments the
polyoxyl lipid is HCO-60. In some embodiments the polyoxyl lipid is
HCO-80. In some embodiments the polyoxyl lipid is HCO-100.
[0026] In some embodiments of the aspects and embodiments disclosed
herein, the formulation includes a polyalkoxylated alcohol. In some
embodiments, the formulation includes a polyalkoxylated alcohol
that is octoxynol-40. In some embodiments, the formulation includes
a polyalkoxylated alcohol (such as octoxynol-40) present between
0.002 and 4%; or between 0.005 and 3%; or between 0.005 and 2%; or
between 0.005 and 1%; or between 0.005 and 0.5%; or between 0.005
and 0.1%; or between 0.005 and 0.05%; or between 0.008 and 0.02%;
or between 0.01 and 0.1%; or between 0.02 and 0.08%; or between
0.005 and 0.08%; or about 0.05%, or about 0.01% by weight of the
formulation.
[0027] In certain aspects and embodiments disclosed herein, the
formulations of the present disclosure are formulated in the
absence of any pharmaceutically active agent, i.e., any non-lipid
non-surfactant pharmaceutically active agent that has received
regulatory approval for the treatment of an ocular condition.
[0028] Exemplary active agents which are optionally excluded from
the formulations of the present disclosure include one or more
selected from the group consisting of calcineurin inhibitors, mTOR
inhibitors, peptides, eicosanoids (e.g. prostacyclins and
prostaglandins), anti-inflammatory drugs (such as NSAIDS),
autonomic drugs (e.g. beta-blockers, alpha-blockers, beta-agonists,
and alpha-agonists), biologics, gene therapy agents (e.g. viral
vectors), anti-infectives (e.g. antifungals, antibiotics, and
antivirals), retinoids, RNAi, photo sensitizers, steroids (e.g.,
estrogens and derivatives thereof, and corticosteroids), mixture
drugs, immuno-modulators, chemotherapeutic agents, G-coupled
protein receptor antagonists, receptor tyrosine kinase (RTK)
inhibitors, growth hormone inhibitors, integrin inhibitors,
Sdf1/CXCR4 pathway inhibitors, and nACh receptor antagonists,
resolvins (resolvin-like compounds), lipoxins, neuroprotectins,
maresins and oxylipins.
[0029] In some embodiments, the active ingredients which are
optionally excluded from the formulations of the present disclosure
include one or more selected from the group consisting of
cyclosporine A, voclosporin, ascomycin, tacrolimus, pimecrolimus,
an analog thereof, or a pharmaceutically acceptable salt thereof.
In one embodiment, the active agent is cyclosporine A. In one
embodiment, the active agent is voclosporin.
[0030] In some embodiments, the active ingredients which are
optionally excluded from the formulations of the present disclosure
include one or more selected from the group consisting of sirolimus
(rapamycin), temsirolimus, everolimus, an analog thereof, or a
pharmaceutically acceptable salt thereof.
[0031] In certain aspects and embodiments disclosed herein, the
active agents which are optionally excluded from the formulations
of the present disclosure include a resolvin or a resolvin-like
compound. As used herein a resolvin-like compound includes
resolvins and compounds with similar structures and/or features.
Resolvins and resolvin-like compounds include a compound of formula
A, a compound of any one of formulae 1-49, a compound of any one of
formulae I-IX, a lipoxin compound, an oxylipin compound, a prodrug
of any of the foregoing, or a pharmaceutically acceptable salt of
any of the foregoing. In some embodiments the active agent which is
optionally excluded from the formulations of the present disclosure
includes compounds selected from a compound of any one of Formulae
1 to 115.
[0032] In some embodiments of any of the aspects and embodiments
disclosed herein, the active agent which is optionally excluded
from the formulations of the present disclosure includes a compound
of formula I,
##STR00001##
and pharmaceutically acceptable salts thereof, wherein: [0033] the
stereochemistry of the carbon qq' to carbon rr' double bond is cis
or trans; [0034] the stereochemistry of the carbon ss' to carbon
tt' double bond is cis or trans; [0035] Re and Rf are independently
selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl,
acyl (e.g., alkoxyacyl, aminoacyl), aminocarbonyl, alkoxycarbonyl,
or silyl; [0036] E is a branched alkoxy such as isopropoxy,
isobutoxy, sec-butoxy, tert-butoxy, 3-methylbutoxy,
2,2-dimethylpropoxy, or 1,1,2-trimethylpropoxy; [0037] Rh and Ri
are independently selected from hydrogen, alkyl, alkenyl, alkynyl,
perfluoroalkyl, aryl or heteroaryl; [0038] R.sub.5 is selected from
i-iv as follows: i) CH.sub.2CH(R.sub.6)CH.sub.2, where R.sub.6 is
hydrogen, alkyl, alkenyl, alkynyl, perfluoroalkyl, aryl,
heteroaryl, fluoro, hydroxyl or alkoxy; ii)
CH.sub.2C(R.sub.6R.sub.7)CH.sub.2, where R.sub.6 and R.sub.7 are
each independently alkyl, alkenyl, alkynyl, perfluoroalkyl, aryl,
or fluoro, or R.sub.6 and R.sub.7 are connected together to form a
carbocyclic or heterocyclic ring; iii) CH.sub.2OCH.sub.2,
CH.sub.2C(O)CH.sub.2, or CH.sub.2CH.sub.2; or iv) R.sub.5 is a
carbocyclic, heterocyclic, aryl or heteroaryl ring; and [0039]
R.sub.8 and R.sub.9 are independently selected from hydrogen,
alkyl, alkenyl, alkynyl, perfluoroalkyl, alkoxy, aryl or
heteroaryl, or R.sub.8 and R.sub.9 are connected together to form a
carbocyclic or heterocyclic ring.
[0040] In certain embodiments, a compound of formula I which is
optionally excluded from the formulations of the present disclosure
is represented by formula II,
##STR00002##
and pharmaceutically acceptable salts thereof, wherein: the
stereochemistry of the carbon qq' to carbon rr' double bond is cis
or trans; the stereochemistry of the carbon ss' to carbon tt'
double bond is cis or trans; and Re, Rf, R.sub.5, and E are as
defined above.
[0041] In certain embodiments, a compound of formula I or II is
which is optionally excluded from the formulations of the present
disclosure is represented by formula III,
##STR00003##
and pharmaceutically acceptable salts thereof, wherein: Re, Rf, and
E are as defined above.
[0042] In some embodiments of any of the aspects disclosed herein,
the active agent which is optionally excluded from the formulations
of the present disclosure is a compound of formula I, wherein: Re,
Rf, Rh, Ri, R.sub.8 and R.sub.9 are hydrogen; E is branched alkoxy
(such as isopropyl); and R.sub.5 is CH.sub.2CH.sub.2CH.sub.2.
[0043] In some embodiments of any of the aspects disclosed herein,
the active agent which is optionally excluded from the formulations
of the present disclosure is a compound 1001 or a pharmaceutically
acceptable salt thereof.
[0044] The term "acyl" is art-recognized and refers to a group
represented by the general formula hydrocarbylC(O)--, preferably
alkylC(O)--.
[0045] The term "acylamino" is art-recognized and refers to an
amino group substituted with an acyl group and may be represented,
for example, by the formula hydrocarbylC(O)NH--.
[0046] The term "acyloxy" is art-recognized and refers to a group
represented by the general formula hydrocarbylC(O)O--, preferably
alkylC(O)O--.
[0047] The term "alkoxy" refers to an alkyl group, preferably a
lower alkyl group, having an oxygen attached thereto.
Representative alkoxy groups include methoxy, ethoxy, propoxy,
tert-butoxy and the like.
[0048] The term "alkoxyalkyl" refers to an alkyl group substituted
with an alkoxy group and may be represented by the general formula
alkyl-O-alkyl.
[0049] The term "alkenyl", as used herein, refers to an aliphatic
group containing at least one double bond and is intended to
include both "unsubstituted alkenyls" and "substituted alkenyls",
the latter of which refers to alkenyl moieties having substituents
replacing a hydrogen on one or more carbons of the alkenyl group.
Such substituents may occur on one or more carbons that are
included or not included in one or more double bonds. Moreover,
such substituents include all those contemplated for alkyl groups,
as discussed below, except where stability is prohibitive. For
example, substitution of alkenyl groups by one or more alkyl,
carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is
contemplated.
[0050] The term "alkyl" refers to the radical of saturated
aliphatic groups, including straight-chain alkyl groups,
branched-chain alkyl groups, cycloalkyl (alicyclic) groups,
alkyl-substituted cycloalkyl groups, and cycloalkyl-substituted
alkyl groups. In preferred embodiments, a straight chain or
branched chain alkyl has 30 or fewer carbon atoms in its backbone
(e.g., C.sub.1-C.sub.30 for straight chains, C.sub.3-C.sub.30 for
branched chains), and more preferably 20 or fewer. Likewise,
preferred cycloalkyls have from 3-10 carbon atoms in their ring
structure, and more preferably have 5, 6 or 7 carbons in the ring
structure.
[0051] Moreover, the term "alkyl" (or "lower alkyl") as used
throughout the specification, examples, and claims is intended to
include both "unsubstituted alkyls" and "substituted alkyls", the
latter of which refers to alkyl moieties having substituents
replacing a hydrogen on one or more carbons of the hydrocarbon
backbone. Such substituents, if not otherwise specified, can
include, for example, a halogen, a hydroxyl, a carbonyl (such as a
carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl
(such as a thioester, a thioacetate, or a thioformate), an alkoxyl,
a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino,
an amido, an amidine, an imine, a cyano, a nitro, an azido, a
sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a
sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic
or heteroaromatic moiety. It will be understood by those skilled in
the art that the moieties substituted on the hydrocarbon chain can
themselves be substituted, if appropriate. For instance, the
substituents of a substituted alkyl may include substituted and
unsubstituted forms of amino, azido, imino, amido, phosphoryl
(including phosphonate and phosphinate), sulfonyl (including
sulfate, sulfonamido, sulfamoyl and sulfonate), and silyl groups,
as well as ethers, alkylthios, carbonyls (including ketones,
aldehydes, carboxylates, and esters), --CF.sub.3, --CN and the
like. Exemplary substituted alkyls are described below. Cycloalkyls
can be further substituted with alkyls, alkenyls, alkoxys,
alkylthios, aminoalkyls, carbonyl-substituted alkyls, --CF.sub.3,
--CN, and the like.
[0052] The term "C.sub.x-y" when used in conjunction with a
chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl,
or alkoxy is meant to include groups that contain from x to y
carbons in the chain. For example, the term "C.sub.x-yalkyl" refers
to substituted or unsubstituted saturated hydrocarbon groups,
including straight-chain alkyl and branched-chain alkyl groups that
contain from x to y carbons in the chain, including haloalkyl
groups such as trifluoromethyl and 2,2,2-tirfluoroethyl, etc.
C.sub.0 alkyl indicates a hydrogen where the group is in a terminal
position, a bond if internal. The terms "C.sub.2-yalkenyl" and
"C.sub.2-yalkynyl" refer to substituted or unsubstituted
unsaturated aliphatic groups analogous in length and possible
substitution to the alkyls described above, but that contain at
least one double or triple bond respectively.
[0053] The term "alkylamino", as used herein, refers to an amino
group substituted with at least one alkyl group.
[0054] The term "alkylthio", as used herein, refers to a thiol
group substituted with an alkyl group and may be represented by the
general formula alkylS--.
[0055] The term "alkynyl", as used herein, refers to an aliphatic
group containing at least one triple bond and is intended to
include both "unsubstituted alkynyls" and "substituted alkynyls",
the latter of which refers to alkynyl moieties having substituents
replacing a hydrogen on one or more carbons of the alkynyl group.
Such substituents may occur on one or more carbons that are
included or not included in one or more triple bonds. Moreover,
such substituents include all those contemplated for alkyl groups,
as discussed above, except where stability is prohibitive. For
example, substitution of alkynyl groups by one or more alkyl,
carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is
contemplated.
[0056] The term "amide", as used herein, refers to a group
##STR00004##
wherein each R.sup.10 independently represent a hydrogen or
hydrocarbyl group, or two R.sup.10 are taken together with the N
atom to which they are attached complete a heterocycle having from
4 to 8 atoms in the ring structure.
[0057] The terms "amine" and "amino" are art-recognized and refer
to both unsubstituted and substituted amines and salts thereof,
e.g., a moiety that can be represented by
##STR00005##
wherein each R.sup.10 independently represents a hydrogen or a
hydrocarbyl group, or two R.sup.10 are taken together with the N
atom to which they are attached complete a heterocycle having from
4 to 8 atoms in the ring structure.
[0058] The term "aminoalkyl", as used herein, refers to an alkyl
group substituted with an amino group.
[0059] The term "aralkyl", as used herein, refers to an alkyl group
substituted with an aryl group.
[0060] The term "aryl" as used herein include substituted or
unsubstituted single-ring aromatic groups in which each atom of the
ring is carbon. Preferably the ring is a 5- to 7-membered ring,
more preferably a 6-membered ring. The term "aryl" also includes
polycyclic ring systems having two or more cyclic rings in which
two or more carbons are common to two adjoining rings wherein at
least one of the rings is aromatic, e.g., the other cyclic rings
can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls,
heteroaryls, and/or heterocyclyls. Aryl groups include benzene,
naphthalene, phenanthrene, phenol, aniline, and the like.
[0061] The term "carbamate" is art-recognized and refers to a
group
##STR00006##
wherein R.sup.9 and R.sup.10 independently represent hydrogen or a
hydrocarbyl group, such as an alkyl group, or R.sup.9 and R.sup.10
taken together with the intervening atom(s) complete a heterocycle
having from 4 to 8 atoms in the ring structure.
[0062] The terms "carbocycle", "carbocyclyl", and "carbocyclic", as
used herein, refers to a non-aromatic saturated or unsaturated ring
in which each atom of the ring is carbon. Preferably a carbocycle
ring contains from 3 to 10 atoms, more preferably from 5 to 7
atoms.
[0063] The term "carbocyclylalkyl", as used herein, refers to an
alkyl group substituted with a carbocycle group.
[0064] The term "carbonate" is art-recognized and refers to a group
--OCO.sub.2--R.sup.10, wherein R.sup.10 represents a hydrocarbyl
group.
[0065] The term "carboxy", as used herein, refers to a group
represented by the formula --CO.sub.2H.
[0066] The term "ester", as used herein, refers to a group
--C(O)OR.sup.10 wherein R.sup.10 represents a hydrocarbyl
group.
[0067] The term "ether", as used herein, refers to a hydrocarbyl
group linked through an oxygen to another hydrocarbyl group.
Accordingly, an ether substituent of a hydrocarbyl group may be
hydrocarbyl-O--. Ethers may be either symmetrical or unsymmetrical.
Examples of ethers include, but are not limited to,
heterocycle-O-heterocycle and aryl-O-heterocycle. Ethers include
"alkoxyalkyl" groups, which may be represented by the general
formula alkyl-O-alkyl.
[0068] The terms "halo" and "halogen" as used herein means halogen
and includes chloro, fluoro, bromo, and iodo.
[0069] The terms "hetaralkyl" and "heteroaralkyl", as used herein,
refers to an alkyl group substituted with a hetaryl group.
[0070] The term "heteroalkyl", as used herein, refers to a
saturated or unsaturated chain of carbon atoms and at least one
heteroatom, wherein no two heteroatoms are adjacent.
[0071] The terms "heteroaryl" and "hetaryl" include substituted or
unsubstituted aromatic single ring structures, preferably 5- to
7-membered rings, more preferably 5- to 6-membered rings, whose
ring structures include at least one heteroatom, preferably one to
four heteroatoms, more preferably one or two heteroatoms. The terms
"heteroaryl" and "hetaryl" also include polycyclic ring systems
having two or more cyclic rings in which two or more carbons are
common to two adjoining rings wherein at least one of the rings is
heteroaromatic, e.g., the other cyclic rings can be cycloalkyls,
cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or
heterocyclyls. Heteroaryl groups include, for example, pyrrole,
furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine,
pyrazine, pyridazine, and pyrimidine, and the like.
[0072] The term "heteroatom" as used herein means an atom of any
element other than carbon or hydrogen. Preferred heteroatoms are
nitrogen, oxygen, and sulfur.
[0073] The terms "heterocyclyl", "heterocycle", and "heterocyclic"
refer to substituted or unsubstituted non-aromatic ring structures,
preferably 3- to 10-membered rings, more preferably 3- to
7-membered rings, whose ring structures include at least one
heteroatom, preferably one to four heteroatoms, more preferably one
or two heteroatoms. The terms "heterocyclyl" and "heterocyclic"
also include polycyclic ring systems having two or more cyclic
rings in which two or more carbons are common to two adjoining
rings wherein at least one of the rings is heterocyclic, e.g., the
other cyclic rings can be cycloalkyls, cycloalkenyls,
cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
Heterocyclyl groups include, for example, piperidine, piperazine,
pyrrolidine, morpholine, lactones, lactams, and the like.
[0074] The term "heterocyclylalkyl", as used herein, refers to an
alkyl group substituted with a heterocycle group.
[0075] The term "hydrocarbyl", as used herein, refers to a group
that is bonded through a carbon atom that does not have a .dbd.O or
.dbd.S substituent, and typically has at least one carbon-hydrogen
bond and a primarily carbon backbone, but may optionally include
heteroatoms. Thus, groups like methyl, ethoxyethyl, 2-pyridyl, and
trifluoromethyl are considered to be hydrocarbyl for the purposes
of this application, but substituents such as acetyl (which has a
.dbd.O substituent on the linking carbon) and ethoxy (which is
linked through oxygen, not carbon) are not. Hydrocarbyl groups
include, but are not limited to aryl, heteroaryl, carbocycle,
heterocycle, alkyl, alkenyl, alkynyl, and combinations thereof.
[0076] The term "hydroxyalkyl", as used herein, refers to an alkyl
group substituted with a hydroxy group.
[0077] The term "lower" when used in conjunction with a chemical
moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy
is meant to include groups where there are ten or fewer
non-hydrogen atoms in the substituent, preferably six or fewer. A
"lower alkyl", for example, refers to an alkyl group that contains
ten or fewer carbon atoms, preferably six or fewer. In certain
embodiments, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy
substituents defined herein are respectively lower acyl, lower
acyloxy, lower alkyl, lower alkenyl, lower alkynyl, or lower
alkoxy, whether they appear alone or in combination with other
substituents, such as in the recitations hydroxyalkyl and aralkyl
(in which case, for example, the atoms within the aryl group are
not counted when counting the carbon atoms in the alkyl
substituent).
[0078] The terms "polycyclyl", "polycycle", and "polycyclic" refer
to two or more rings (e.g., cycloalkyls, cycloalkenyls,
cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls) in which
two or more atoms are common to two adjoining rings, e.g., the
rings are "fused rings". Each of the rings of the polycycle can be
substituted or unsubstituted. In certain embodiments, each ring of
the polycycle contains from 3 to 10 atoms in the ring, preferably
from 5 to 7.
[0079] The term "silyl" refers to a silicon moiety with three
hydrocarbyl moieties attached thereto.
[0080] The term "substituted" refers to moieties having
substituents replacing a hydrogen on one or more carbons of the
backbone. It will be understood that "substitution" or "substituted
with" includes the implicit proviso that such substitution is in
accordance with permitted valence of the substituted atom and the
substituent, and that the substitution results in a stable
compound, e.g., which does not spontaneously undergo transformation
such as by rearrangement, cyclization, elimination, etc. As used
herein, the term "substituted" is contemplated to include all
permissible substituents of organic compounds. In a broad aspect,
the permissible substituents include acyclic and cyclic, branched
and unbranched, carbocyclic and heterocyclic, aromatic and
non-aromatic substituents of organic compounds. The permissible
substituents can be one or more and the same or different for
appropriate organic compounds. For purposes of the present
disclosure, the heteroatoms such as nitrogen may have hydrogen
substituents and/or any permissible substituents of organic
compounds described herein which satisfy the valences of the
heteroatoms. Substituents can include any substituents described
herein, for example, a halogen, a hydroxyl, a carbonyl (such as a
carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl
(such as a thioester, a thioacetate, or a thioformate), an alkoxyl,
a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino,
an amido, an amidine, an imine, a cyano, a nitro, an azido, a
sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a
sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic
or heteroaromatic moiety. It will be understood by those skilled in
the art that the moieties substituted on the hydrocarbon chain can
themselves be substituted, if appropriate. Unless specifically
stated as "unsubstituted," references to chemical moieties herein
are understood to include substituted variants. For example,
reference to an "aryl" group or moiety implicitly includes both
substituted and unsubstituted variants.
[0081] The term "sulfate" is art-recognized and refers to the group
--OSO.sub.3H, or a pharmaceutically acceptable salt thereof.
[0082] The term "sulfonamide" is art-recognized and refers to the
group represented by the general formulae
##STR00007##
[0083] wherein R.sup.9 and R.sup.10 independently represents
hydrogen or hydrocarbyl, such as alkyl, or R.sup.9 and R.sup.10
taken together with the intervening atom(s) complete a heterocycle
having from 4 to 8 atoms in the ring structure.
[0084] The term "sulfoxide" is art-recognized and refers to the
group --S(O)--R.sup.10, wherein R.sup.10 represents a
hydrocarbyl.
[0085] The term "sulfonate" is art-recognized and refers to the
group SO.sub.3H, or a pharmaceutically acceptable salt thereof.
[0086] The term "sulfone" is art-recognized and refers to the group
--S(O).sub.2--R.sup.10, wherein R.sup.10 represents a
hydrocarbyl.
[0087] The term "thioalkyl", as used herein, refers to an alkyl
group substituted with a thiol group.
[0088] The term "thioester", as used herein, refers to a group
--C(O)SR.sup.10 or --SC(O)R.sup.10 wherein R.sup.10 represents a
hydrocarbyl.
[0089] The term "thioether", as used herein, is equivalent to an
ether, wherein the oxygen is replaced with a sulfur.
[0090] The term "urea" is art-recognized and may be represented by
the general formula
##STR00008##
wherein R.sup.9 and R.sup.10 independently represent hydrogen or a
hydrocarbyl, such as alkyl, or either occurrence of R.sup.9 taken
together with R.sup.10 and the intervening atom(s) complete a
heterocycle having from 4 to 8 atoms in the ring structure.
[0091] "Protecting group" refers to a group of atoms that, when
attached to a reactive functional group in a molecule, mask, reduce
or prevent the reactivity of the functional group. Typically, a
protecting group may be selectively removed as desired during the
course of a synthesis. Examples of protecting groups can be found
in Greene and Wuts, Protective Groups in Organic Chemistry,
3.sup.rd Ed., 1999, John Wiley & Sons, NY and Harrison et al.,
Compendium of Synthetic Organic Methods, Vols. 1-8, 1971-1996, John
Wiley & Sons, NY. Representative nitrogen protecting groups
include, but are not limited to, formyl, acetyl, trifluoroacetyl,
benzyl, benzyloxycarbonyl ("CBZ"), tert-butoxycarbonyl ("Boc"),
trimethylsilyl ("TMS"), 2-trimethylsilyl-ethanesulfonyl ("TES"),
trityl and substituted trityl groups, allyloxycarbonyl,
9-fluorenylmethyloxycarbonyl ("FMOC"), nitro-veratryloxycarbonyl
("NVOC") and the like. Representative hydroxylprotecting groups
include, but are not limited to, those where the hydroxyl group is
either acylated (esterified) or alkylated such as benzyl and trityl
ethers, as well as alkyl ethers, tetrahydropyranyl ethers,
trialkylsilyl ethers (e.g., TMS or TIPS groups), glycol ethers,
such as ethylene glycol and propylene glycol derivatives and allyl
ethers.
[0092] The present disclosure further relates to treating or
preventing ocular diseases or disorders, for example by local
administration of the formulations as described herein.
[0093] A patient or subject to be treated by any of the
compositions or methods of the present disclosure can mean either a
human or a non-human animal. In an embodiment, the present
disclosure provides methods for the treatment of an ocular disease
in a human patient in need thereof. In an embodiment, the present
disclosure provides methods for the treatment of an inflammatory
ocular disease in a human patient in need thereof. In another
embodiment, the present disclosure provides methods for the
treatment of an ocular disease in a veterinary patient in need
thereof, including, but not limited to dogs, horses, cats, rabbits,
gerbils, hamsters, rodents, birds, aquatic mammals, cattle, pigs,
camelids, and other zoological animals.
[0094] In some embodiments of the compositions and methods
disclosed herein, the active agent, when present, may include a
combination of two or more different active ingredients. In some
embodiments the active agent, when present, may include two or more
active agents selected from the group consisting of a resolvin or
resolvin-like compound, a steroid (such as a corticosteroid),
cyclosporine A, and voclosporin. In some embodiments the active
agent, when present, may include a resolvin and cyclosporine A. In
some embodiments the active agent, when present, may include a
resolvin and a corticosteroid. In some embodiments the active
agent, when present, may include cyclosporine A and a
corticosteroid. In some embodiments, the active agent, when
present, may include a resolvin, cyclosporine A and a
corticosteroid. In some embodiments, the active agent, when
present, may include two or more active agents and one of said
active agents is an antibiotic, for example one or more antibiotics
selected from the group consisting of azythromycin, ciprofloxacin,
ofloxacin, gatifloxacin, levofloxacin, moxifloxacin, besifloxacin,
and levofloxacin. In some embodiments, the active agent, when
present, may include two or more active agents and one of the
active agents is an antibiotic, for example one or more antibiotics
selected from the group consisting of azythromycin, ciprofloxacin,
ofloxacin, gatifloxacin, levofloxacin, moxifloxacin, besifloxacin,
and levofloxacin; and a second of such agents is a resolvin such as
described herein (including without limitation compound 1001). In
some embodiments, the active agent, when present, may include two
or more active agents and one of said active agents is an
antiviral, for example one or more antivirals selected from the
group consisting of ganciclovir, trifluridine, acyclovir,
famciclovir, valacyclovir, penciclovir and cidofovir. In some
embodiments, the active agent, when present, may include two or
more active agents and one of the active agents is an antibiotic,
for example one or more antivirals selected from the group
consisting of ganciclovir, trifluridine, acyclovir, famciclovir,
valacyclovir, penciclovir and cidofovir; and a second of the active
agents is a resolvin such as described herein (including without
limitation compound 1001).
[0095] The term "treating" refers to: preventing a disease,
disorder or condition from occurring in a cell, a tissue, a system,
animal or human which may be predisposed to the disease, disorder
and/or condition but has not yet been diagnosed as having it;
stabilizing a disease, disorder or condition, i.e., arresting its
development; and/or relieving one or more symptoms of the disease,
disorder or condition, i.e., causing regression of the disease,
disorder and/or condition.
[0096] As used herein, a therapeutic that "prevents" a disorder or
condition refers to a compound that, in a statistical sample,
reduces the occurrence of the disorder or condition in the treated
sample relative to an untreated control sample, or delays the onset
or reduces the severity of one or more symptoms of the disorder or
condition relative to the untreated control sample.
[0097] As used herein, the terms "ocular disease," "ocular
condition," "eye disease," and "eye condition" refer to
diseases/conditions of the eye(s) that can be sight threatening,
lead to eye discomfort, and may signal systemic health
problems.
[0098] As used herein, the term "anterior segment disease" refers
to all disorders that affect the eye surface, anterior chamber,
iris and ciliary body and lens of the eye. The eye surface is
composed of the cornea, conjunctiva, eyelids, lacrimal and
meibomian glands, and the interconnecting nerves.
[0099] As used herein, the terms "posterior segment eye disease"
and "back-of-the-eye disease" refer to all disorders that affect
the posterior segment of the eye. A posterior eye disease is a
disease which primarily affects a posterior ocular site such as
choroid or sclera, vitreous, vitreous chamber, retina, optic nerve,
and blood vessels and nerves which vascularize or innervate a
posterior ocular site.
[0100] Accordingly, in one aspect, provided is a method treating or
preventing an ocular disease or condition, that includes locally
administering a formulation of any of the aspects or embodiments as
disclosed herein. In some embodiments, the ocular disease is an
anterior segment disease. In some embodiments, the ocular disease
is a posterior segment disease. In some embodiments, the ocular
disease is one or more selected from the group consisting of dry
eye syndrome, Sjogren's syndrome, uveitis, anterior uveitis
(iritis), chorioretinitis, posterior uveitis, conjunctivitis,
allergic conjunctivitis, keratitis, keratoconjunctivitis, vernal
keratoconjunctivitis (VKC), atopic keratoconjunctivitis, systemic
immune mediated diseases such as cicatrizing conjunctivitis and
other autoimmune disorders of the ocular surface, blepharitis,
scleritis, age-related macular degeneration (AMD), diabetic
retinopathy (DR), diabetic macular edema (DME), ocular
neovascularization, age-related macular degeneration (ARMD),
proliferative vitreoretinopathy (PVR), cytomegalovirus (CMV)
retinitis, optic neuritis, retrobulbar neuritis, and macular
pucker. In one embodiment, the ocular disease is dry eye. In one
embodiment, the ocular disease is allergic conjunctivitis. In one
embodiment the ocular disease is age-related macular degeneration
(AMD). In one embodiment the ocular disease is diabetic
retinopathy. In one aspect, a formulation of any of the aspects or
embodiments disclosed herein are used as artificial tears; for
example the formulations may be used to moisten and lubricate eyes.
The formulations provided herein may also, or alternatively, be
used to moisten contact lenses or to moisten eyes in the presence
of contact lenses. In certain embodiments the formulations provided
herein may be "over-the-counter"; ie offered directly to a consumer
without the need for a prescription from a health care
provider.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
Active Agents
[0101] In accordance with various aspects and embodiments of the
methods and compositions provided herein, the formulations of the
present disclosure are formulated in the absence of any
pharmaceutically active agent, i.e., any non-lipid non-surfactant
pharmaceutically active agent that has received regulatory approval
for the treatment of an ocular condition.
[0102] In some embodiments, active agents that may be specifically
excluded from various embodiments of the formulations herein may be
any agent capable of affecting a biological process, especially
agents that have received regulatory approval for the treatment of
an ocular condition. Active agents (the term active ingredient is
used herein interchangably with the term active agent) contemplated
for exclusion herein may include drugs, hormones, cytokines,
toxins, therapeutic agents, vitamins, and the like. In some
embodiments active agents contemplated for exclusion herein in
accordance with the aspects and embodiments disclosed herein are
agents capable of, or approved for, treating or preventing a
disease or condition, for example in some embodiments an active
agent is capable of, or approved for, treating or preventing an
ocular disease or condition.
[0103] The compositions of the present disclosure can be used as a
topically applied or locally injected drug delivery platform for
delivery of a variety of active agents including hydrophobic,
water-insoluble drugs. Active agents for which delivery may be
enhanced by compositions of the present disclosure, but which may
be excluded from compositions of the present disclosure, may
include calcineurin inhibitors or mTOR inhibitors, peptides,
eicosanoids (e.g. prostacyclins and prostaglandins),
anti-inflammatory drugs, autonomic drugs (e.g. beta-blockers,
alpha-blockers, beta-agonists, and alpha-agonists), biologics, gene
therapy agents (e.g. viral vectors), anti-infectives (e.g.
antifungals, antibiotics, and antivirals), retinoids, RNAi, photo
sensitizers, steroids (e.g., estrogens and derivatives thereof),
mixture drugs, immuno-modulators, chemotherapeutic agents,
G-coupled protein receptor antagonists, receptor tyrosine kinase
(RTK) inhibitors, growth hormone inhibitors, integrin inhibitors,
Sdf1/CXCR4 pathway inhibitors, and nACh receptor antagonists,
resolvins, lipoxins, oxylipins and the like. In some embodiments,
the active agent for which delivery may be enhanced by compositions
of the present disclosure, but which may be excluded from
compositions of the present disclosure, is a corticosteroid,
including prednisolone, hydrocortisone, triamcinolone and
budesonide. In certain embodiments the active ingredient for which
delivery may be enhanced by compositions of the present disclosure,
but which may be excluded from compositions of the present
disclosure, may be a non-steroidal anti-inflammatory drug (NSAID),
for example Cox-2 inhibitors such as celecoxib, ruboxistaurin and
nimesulide. In certain embodiments an active agent for which
delivery may be enhanced by compositions of the present disclosure,
but which may be excluded from compositions of the present
disclosure, may be an anti-growth factor molecule including, but
are not limited to, vascular endothelial growth factor (VEGF)
inhibitors such as, pegaptanib (macugen), ranibizumab (lucentis),
and bevacizumab (avastin). In some embodiments, the active agent
for which delivery may be enhanced by compositions of the present
disclosure, but which may be excluded from compositions of the
present disclosure, is an antibiotic, for example one or more
antibiotics selected from the group consisting of azythromycin,
ciprofloxacin, ofloxacin, gatifloxacin, levofloxacin, moxifloxacin,
besifloxacin, and levofloxacin. In some embodiments, the active
agent for which delivery may be enhanced by compositions of the
present disclosure, but which may be excluded from compositions of
the present disclosure, is an antiviral, for example one or more
antivirals selected from the group consisting of ganciclovir,
trifluridine, acyclovir, famciclovir, valacyclovir, penciclovir and
cidofovir.
[0104] In some embodiments, when compositions of the present
disclosure include an active agent, a combination of two active
agents may be used, including but not limited to a vascular
endothelial growth factor (VEGF) inhibitor and an antagonist of
platelet-derived growth factor (PDGF).
[0105] In some embodiments of any of the aspects and embodiments
disclosed herein, when compositions of the present disclosure
include an active agent, the following active agents may be
excluded from compositions of the present disclosure: calcineurin
inhibitors such as cyclosporine A, voclosporin, ascomycin,
tacrolimus, pimecrolimus, an analog thereof, or a pharmaceutically
acceptable salt thereof.
[0106] In some embodiments of any of the aspects and embodiments
disclosed herein, when compositions of the present disclosure
include an active agent, the following active agents may be
excluded from compositions of the present disclosure: a mTOR
inhibitor such as sirolimus (rapamycin), temsirolimus, everolimus,
an analog thereof, or a pharmaceutically acceptable salt
thereof.
Resolvins, Lipoxins and the Like
[0107] In some aspects and embodiments as described herein, when
compositions of the present disclosure include an active agent,
resolvins are excluded as the active agent. In certain aspects and
embodiments, when compositions of the present disclosure include an
active agent, compounds of formula A are excluded as the active
agent, compounds of any one of formulae 1-49 are excluded as the
active agent, compounds of any one of formulae I-IX are excluded as
the active agent, lipoxin compounds are excluded as the active
agent, oxylipin compounds are excluded as the active agent, prodrug
of any of the foregoing, or a pharmaceutically acceptable salt of
any of the foregoing are excluded as the active agent.
[0108] Compounds optionally excluded from use as active agents in
accordance with the aspects and embodiments of the present
disclosure, when compositions of the present disclosure include an
active agent, include those of Formula A,
##STR00009##
wherein: [0109] each of W' and Y' is a bond or a linker
independently selected from a ring containing up to 20 atoms or a
chain of up to 20 atoms, provided that W' and Y' can independently
include one or more nitrogen, oxygen, sulfur or phosphorous atoms,
further provided that W' and Y' can independently include one or
more substituents independently selected from hydrogen, alkyl,
alkenyl, alkynyl, aryl, heteroaryl, chloro, iodo, bromo, fluoro,
hydroxy, alkoxy, aryloxy, carboxy, amino, alkylamino, dialkylamino,
acylamino, carboxamido, cyano, oxo, thio, alkylthio, arylthio,
acylthio, alkylsulfonate, arylsulfonate, phosphoryl, or sulfonyl,
further provided that W' and Y' can independently contain one or
more fused carbocyclic, heterocyclic, aryl or heteroaryl rings, and
further provided that when o' is 0, and V.sub.1 is
##STR00010##
[0109] Y' is connected to V.sub.1 via a carbon atom; [0110] V.sub.1
is selected from
##STR00011##
[0110] wherein when q' is 0 and V.sub.3 is a bond, n' is 0 or 1;
otherwise n' is 1; [0111] V.sub.2 is selected from a bond,
##STR00012##
[0111] wherein: [0112] L' is selected from --C(R.sup.1003) wherein
each of R.sup.1003 and R.sup.1004 is independently selected from
hydrogen, alkyl, alkenyl, alkynyl, perfluoroalkyl, alkoxy, aryl or
heteroaryl, or R.sup.1003 and R.sup.1004 are connected together to
form a carbocyclic or heterocyclic ring; when V.sub.3 is
##STR00013##
[0112] L' is additionally selected from W'; and n' is 0 or 1;
[0113] V.sub.3 is selected from a bond or
##STR00014##
[0113] wherein: [0114] each R.sup.1001 and R.sup.1002 is
independently for each occurrence selected from hydrogen, alkyl,
alkenyl, alkynyl, aryl, heteroaryl, alkylaryl, alkoxy, or halo,
wherein said alkyl- or aryl-containing moiety is optionally
substituted with up to 3 independently selected substituents;
[0115] each of R.sup.a' and R.sup.b' is independently for each
occurrence selected from --OR' or --N(R).sub.2, or adjacent
R.sup.a' and R.sup.b' are taken together to form an epoxide ring
having a cis or trans configuration, wherein each R' is
independently selected from hydrogen, alkyl, alkenyl, alkynyl,
aryl, heteroaryl, acyl, silyl, alkoxyacyl, aminoacyl,
aminocarbonyl, alkoxycarbonyl, or a protecting group; [0116] or
when V.sub.1 is
##STR00015##
[0116] and V.sub.2 is
##STR00016##
[0117] R.sup.1003 are R.sup.b' both hydrogen; [0118] X' is selected
from --CN, --C(NH)N(R'')(R''), --C(S)-A', --C(S)R'', --C(O)-A',
--C(O)--R'', --C(O)--SR'', --C(O)--NH--S(O).sub.2--R'',
--S(O).sub.2-A', --S(O).sub.2--R'', S(O).sub.2N(R'')(R''),
--P(O).sub.2-A', --PO(OR'')-A', -tetrazole, alkyltetrazole, or
--CH.sub.2OH, wherein [0119] A' is selected from --OR'',
--N(R'')(R'') or --OM'; [0120] each R'' is independently selected
from hydrogen, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl
or a detectable label molecule, wherein any alkyl-, aryl- or
heteroaryl-containing moiety is optionally substituted with up to 3
independently selected substituents; and [0121] M' is a cation;
[0122] G' is selected from hydrogen, halo, hydroxy, alkyl, aryl,
arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, aryloxy, carboxy,
amino, alkylamino, dialkylamino, acylamino, carboxamido or a
detectable label molecule, wherein any alkyl-, aryl- or
heteroaryl-containing moiety is optionally substituted with up to 3
independently selected substituents; [0123] o' is 0, 1, 2, 3, 4, or
5; [0124] p' is 0, 1, 2, 3, 4, or 5; [0125] q' is 0, 1, or 2; and
[0126] o'+p'+q' is 1, 2, 3, 4, 5 or 6; wherein: [0127] if V.sub.2
is a bond, then q' is 0, and V.sub.3 is a bond; [0128] if V.sub.3
is
##STR00017##
[0128] then o' is 0, V.sub.1 is
##STR00018##
p' is 1 and V.sub.2 is
##STR00019## [0129] any acyclic double bond may be in a cis or a
trans configuration or is optionally replaced by a triple bond; and
[0130] either one
##STR00020##
[0130] portion of the compound, if present, is optionally replaced
by
##STR00021##
or one
##STR00022##
portion of the compound, if present, is optionally replaced by
##STR00023##
wherein Q' represents one or more substituents and each Q' is
independently selected from halo, alkyl, alkenyl, alkynyl,
cycloalkyl, aryl, heteroaryl, alkoxy, aryloxy, alkylcarbonyl,
arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, amino, hydroxy,
cyano, carboxyl, alkoxycarbonyloxy, aryloxycarbonyloxy or
aminocarbonyl.
[0131] In certain embodiments, V.sub.1 is selected from
##STR00024##
[0132] In certain embodiments, V.sub.2 is selected from a bond,
##STR00025##
[0133] In certain embodiments, when q' is 0 and V.sub.3 is a bond,
n' is 0 or 1; otherwise n' is 1.
[0134] In certain embodiments, p' is 0, 1, 2, 3, or 5.
[0135] In certain embodiments, q' is 0 or 1.
[0136] In certain embodiments, if V.sub.1 is
##STR00026##
then o' is 0 or 1, p' is 1 or 2, o'+p' is 1 or 2, V.sub.2 is
##STR00027##
and V.sub.3 is a bond.
[0137] In certain embodiments, if V.sub.1 is
##STR00028##
then o' is 3, 4 or 5, p' is 0, 1 or 2, o'+p' is 4 or 5, and V.sub.2
is a bond.
[0138] In certain embodiments, if V.sub.2 is a bond, then o' is 0,
3, 4 or 5; p' is 0, 1, 2 or 5, o'+p' is 4 or 5, q' is 0, and
V.sub.3 is a bond.
[0139] In certain embodiments, each of W' and Y' is independently
selected from a bond or lower alkyl or heteroalkyl optionally
substituted with one or more substituents independently selected
from alkenyl, alkynyl, aryl, chloro, iodo, bromo, fluoro, hydroxy,
amino, or oxo.
[0140] In certain embodiments, the compound of formula A is other
than a compound of formulae 48, 48a, 48b, 48c, or 48d.
[0141] In certain embodiments of Formula A, when o' is 2, V.sub.1
is
##STR00029##
p' is 1, V.sub.2 is
##STR00030##
q' is 1, and V.sub.3 is a bond, at least one occurrence of
R.sup.1001 is other than hydrogen.
[0142] Compounds optionally excluded from use as active agents of
the disclosure include those of Formula 1,
##STR00031##
wherein: [0143] Carbons a' and b' are connected by a double bond or
a triple bond; [0144] Carbons c' and d' are connected by a double
bond or a triple bond; [0145] Re, Rf, and Rg are independently
selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl,
acyl (e.g., alkoxyacyl, aminoacyl), aminocarbonyl, alkoxycarbonyl,
or silyl; [0146] Rh, Ri and Rj are independently selected from
hydrogen, alkyl, alkenyl, alkynyl, perfluoroalkyl, aryl or
heteroaryl; [0147] I is selected from --C(O)-E, --SO.sub.2-E,
--PO(OR)-E, where E is hydroxy, alkoxy, aryloxy, amino, alkylamino,
dialkylamino, or arylamino; and R is hydrogen or alkyl; [0148] J, L
and H are linkers independently selected from a ring containing up
to 20 atoms or a chain of up to 20 atoms, provided that J, L and H
can independently include one or more nitrogen, oxygen, sulfur or
phosphorous atoms, and further provided that J, L and H can
independently include one or more substituents selected from
hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, chloro, iodo,
bromo, fluoro, hydroxy, alkoxy, aryloxy, carboxy, amino,
alkylamino, dialkylamino, acylamino, carboxamido, cyano, oxo, thio,
alkylthio, arylthio, acylthio, alkylsulfonate, arylsulfonate,
phosphoryl, and sulfonyl, and further provided that J, L and H can
also contain one or more fused carbocyclic, heterocyclic, aryl or
heteroaryl rings, and provided that linker J is connected to the
adjacent C(R)OR group via a carbon atom; [0149] G is selected from
hydrogen, alkyl, perfluoroalkyl, alkenyl, alkynyl, aryl,
heteroaryl, chloro, iodo, bromo, fluoro, hydroxy, alkoxy, aryloxy,
carboxy, amino, alkylamino, dialkylamino, acylamino, or
carboxamido; [0150] or pharmaceutically acceptable salts
thereof.
[0151] In certain embodiments, a pharmaceutically acceptable salt
of the compound is formed by derivatizing E, wherein E is --OM,
where M is a cation selected from ammonium, tetra-alkyl ammonium,
Na, K, Mg, and Zn.
[0152] In certain embodiments, when compositions of the present
disclosure include an active agent, a compound of formula 1,
represented by formula 2 is optionally excluded from such
compositions:
##STR00032##
wherein: E, Re, Rf, and Rg are as defined above.
[0153] In certain embodiments, when compositions of the present
disclosure include an active agent, a pharmaceutically acceptable
salt of the compound formed by derivatizing E, wherein E is --OM,
where M is a cation selected from ammonium, tetra-alkyl ammonium,
Na, K, Mg, and Zn is optionally excluded from such
compositions.
[0154] Exemplary compounds of formula 2 optionally excluded from
such compositions include compound 2a,
##STR00033##
[0155] In certain embodiments, when compositions of the present
disclosure include an active agent, a compound of formula 1,
represented by formula 3, is optionally excluded from such
compositions
##STR00034##
wherein: E, Re, Rf, and Rg are as defined above.
[0156] In certain embodiments, when compositions of the present
disclosure include an active agent, a pharmaceutically acceptable
salt of the compound formed by derivatizing E, wherein E is --OM,
where M is a cation selected from ammonium, tetra-alkyl ammonium,
Na, K, Mg, and Zn is optionally excluded from such
compositions.
[0157] Exemplary compounds of formula 3 optionally excluded from
such compositions include compound 3a,
##STR00035##
and compound 3b,
##STR00036##
[0158] Further exemplary compounds of formula 1 optionally excluded
from such compositions include Compound X,
##STR00037##
and pharmaceutically acceptable salts and esters thereof.
[0159] Other compounds optionally excluded for use as active
ingredients in such compositions, when compositions of the present
disclosure include an active agent, include those of Formula 4,
##STR00038##
wherein: [0160] A is H or --OP.sub.4; [0161] P.sub.1, P.sub.2 and
P.sub.4 each individually is a protecting group or hydrogen atom;
[0162] R.sub.1 and R.sub.2 each individually is a substituted or
unsubstituted, branched or unbranched alkyl, alkenyl, or alkynyl
group, substituted or unsubstituted aryl group, substituted or
unsubstituted, branched or unbranched alkylaryl group, halogen
atom, hydrogen atom; [0163] Z is --C(O)OR.sup.d,
--C(O)NR.sup.cR.sup.c, --C(O)H, --C(NH)NR.sup.cR.sup.c, --C(S)H,
--C(S)OR.sup.d, --C(S)NR.sup.cR.sup.c, --CN, preferably a
carboxylic acid, ester, amide, thioester, thiocarboxamide or a
nitrile; [0164] each R.sup.a, if present, is independently selected
from hydrogen, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl,
(C3-C8) cycloalkyl, cyclohexyl, (C4-C11) cycloalkylalkyl, (C5-C10)
aryl, phenyl, (C6-C16) arylalkyl, benzyl, 2-6 membered heteroalkyl,
3-8 membered heterocyclyl, morpholinyl, piperazinyl,
homopiperazinyl, piperidinyl, 4-11 membered heterocyclylalkyl, 5-10
membered heteroaryl and 6-16 membered heteroarylalkyl; [0165] each
R.sup.b, if present, is a suitable group independently selected
from .dbd.O, --OR.sup.d, (C1-C3) haloalkyloxy, --OCF.sub.3, .dbd.S,
--SR.sup.d, .dbd.NR.sup.d, .dbd.NOR.sup.d, --NR.sup.cR.sup.c,
halogen, --CF.sub.3, --CN, --NC, --OCN, --SCN, --NO, --NO.sub.2,
.dbd.N.sub.2, --N.sub.3, --S(O)R.sup.d, --S(O).sub.2R.sup.d,
--S(O).sub.2OR.sup.d, --S(O)NR.sup.cR.sup.c,
--S(O).sub.2NR.sup.cR.sup.c, --OS(O)R.sup.d, --OS(O).sub.2R.sup.d,
--OS(O).sub.2OR.sup.d, --OS(O).sub.2NR.sup.cR.sup.c, --C(O)R.sup.d,
--C(O)OR.sup.d, --C(O)NR.sup.cR.sup.c, --C(NH)NR.sup.cR.sup.c,
--C(NR.sup.a)NR.sup.cR.sup.c, --C(NOH)R.sup.a,
--C(NOH)NR.sup.cR.sup.c, --OC(O)R.sup.d, --OC(O)OR.sup.d,
--OC(O)NR.sup.cR.sup.c, --OC(NH)NR.sup.cR.sup.c,
--OC(NR.sup.a)NR.sup.cR.sup.c, --[NHC(O)].sub.nR.sup.d, --[NR.sup.a
C(O)]--[NHC(O)].sub.nOR.sup.d, --[NR.sup.a C(O)].sub.nOR.sup.d,
[NHC(O)].sub.nNR.sup.cR.sup.c, --[NR.sup.a
C(O)].sub.nNR.sup.cR.sup.c, --[NHC(NH)].sub.nNR.sup.cR.sup.c and
--[NR.sup.a C(NR.sup.a)].sub.nNR.sup.cR.sup.c; [0166] each R.sup.c,
if present, is independently a protecting group or R.sup.a, or,
alternatively, two R.sup.c taken together with the nitrogen atom to
they are bonded form a 5 to 8-membered heterocyclyl or heteroaryl
which optionally including one or more additional heteroatoms and
optionally substituted with one or more of the same or different
R.sup.a or suitable R.sup.b groups; [0167] each n independently is
an integer from 0 to 3; [0168] each R.sup.d independently is a
protecting group or R.sup.a; [0169] or pharmaceutically acceptable
salts thereof.
[0170] Exemplary compounds of formula 4 optionally excluded from
such compositions include compound 4a,
##STR00039##
compound 4b,
##STR00040##
and pharmaceutically acceptable salts and esters thereof.
[0171] Other compounds optionally excluded for use as active agents
in such compositions, when compositions of the present disclosure
include an active agent, include those of Formula 5,
##STR00041##
or pharmaceutically acceptable salts thereof, wherein: the
stereochemistry of the carbon ii' to carbon jj' bond is cis or
trans; P.sub.3 is a protecting group or hydrogen atom; and P.sub.1,
P.sub.2, R.sub.1 and Z are as defined above in formula 4.
[0172] In certain embodiments, the stereochemistry of the carbon
ii' to carbon jj' bond is trans.
[0173] Exemplary compounds of formula 5 optionally excluded from
such compositions include compound 5a,
##STR00042##
compound 5b,
##STR00043##
and pharmaceutically acceptable salts and esters thereof.
[0174] Other compounds optionally excluded for use as active agents
in such compositions, when compositions of the present disclosure
include an active agent, include those of Formula 6,
##STR00044##
or pharmaceutically acceptable salts thereof, wherein: [0175] the
stereochemistry of the carbon gg' to carbon hh' bond is cis or
trans; [0176] each X represents hydrogen or taken together both X
groups represent one substituted or unsubstituted methylene, an
oxygen atom, a substituted or unsubstituted N atom, or a sulfur
atom such that a three-membered ring is formed; and [0177] P.sub.1,
P.sub.2, P.sub.3, R.sub.1 and Z are as defined above.
[0178] In certain embodiments, the stereochemistry of the carbon
gg' to carbon hh' bond is trans.
[0179] Exemplary compounds of formula 6 is optionally excluded from
such compositions include compound 6a,
##STR00045##
compound 6b,
##STR00046##
and pharmaceutically acceptable salts and esters thereof.
[0180] Other compounds optionally excluded for use as active agents
in such compositions, when compositions of the present disclosure
include an active agent, include those of Formula 7,
##STR00047##
or pharmaceutically acceptable salts thereof, wherein: [0181]
Carbons e' and f' are connected by a double bond or a triple bond,
and when carbon e' is connected to carbon f' through a double bond
the stereochemistry is cis or trans; [0182] Carbons g' and h' are
connected by a double bond or a triple bond and when carbon g' is
connected to carbon h' through a double bond the stereochemistry is
cis or trans; [0183] m is 0 or 1; [0184] T' is hydrogen, (C1-C6)
alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C5-C14) aryl, (C6-C16)
arylalkyl, 5-14 membered heteroaryl, 6-16 membered heteroarylalkyl,
or --CH.dbd.CHCH.sub.2CH.sub.3; [0185] T is --(CH.sub.2).sub.q-- or
--(CH.sub.2).sub.q--O--, where q is an integer from 0 to 6; [0186]
Z' is (C1-C6) alkylene optionally substituted with 1, 2, 3, 4, 5 or
6 of the same or different halogen atoms,
--(CH.sub.2).sub.p--O--CH.sub.2-- or
--(CH.sub.2).sub.m--S--CH.sub.2--, where p is an integer from 0 to
4; [0187] R.sub.11, R.sub.12 and R.sub.13 each individually is
substituted or unsubstituted, branched or unbranched alkyl,
alkenyl, or alkynyl group, substituted or unsubstituted aryl group,
substituted or unsubstituted, branched or unbranched alkylaryl
group, C.sub.1-4alkoxy, halogen atom, --CH.sub.2R.sub.14,
--CHR.sub.14R.sub.14, --CR.sub.14R.sub.14R.sub.14, or a hydrogen
atom; [0188] R.sub.14 is independently for each occurrence selected
from --CN, --NO.sub.2 or halogen; and [0189] P.sub.1, P.sub.2,
P.sub.3, and Z are as defined above.
[0190] In certain embodiments, carbons e' and f' are connected by a
cis double bond.
[0191] In certain embodiments, carbons g' and h' are connected by a
double bond.
[0192] In certain embodiments, carbons e' and f' are connected by a
cis double bond and carbons g' and h' are connected by a double
bond.
[0193] Exemplary compounds of formula 7 optionally excluded from
such compositions include compound 7a,
##STR00048##
compound 7b,
##STR00049##
and pharmaceutically acceptable salts and esters thereof.
[0194] Other compounds optionally excluded for use as active agents
in such compositions, when compositions of the present disclosure
include an active agent, include those of Formula 8,
##STR00050##
or pharmaceutically acceptable salts thereof, wherein: [0195] the
stereochemistry of the carbon i' to carbon j' bond is cis or trans;
[0196] m is 0 or 1; [0197] D' is CH.sub.3, --CH.dbd.CHCH.sub.2U or
--CH.dbd.CHCH.sub.2CH.sub.2A; [0198] U is a branched or unbranched,
substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl,
aryl, alkoxy, aryloxy, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl,
aryloxycarbonyl, alkoxycarbonyloxy, and aryloxycarbonyloxy group;
[0199] A is H or --OP.sub.4; [0200] P.sub.1, P.sub.2, P.sub.4,
R.sub.1, R.sub.2 and Z are as defined above.
[0201] In certain embodiments, the stereochemistry of the carbon i'
to carbon j' bond is cis.
[0202] Exemplary compounds of formula 8 optionally excluded from
such compositions include compound 8a,
##STR00051##
compound 8b,
##STR00052##
compound 8c,
##STR00053##
and pharmaceutically acceptable salts and esters thereof.
[0203] Other compounds optionally excluded for use as active agents
in such compositions, when compositions of the present disclosure
include an active agent, include those of Formula 9,
##STR00054##
or pharmaceutically acceptable salts thereof, wherein: [0204]
Carbons k' and l' are connected by a double bond or a triple bond,
and when carbon k' is connected to carbon l' through a double bond
the stereochemistry is cis or trans; [0205] the stereochemistry of
the carbon m' to carbon n' double bond is cis or trans; [0206] m is
0 or 1; [0207] D is --CH.sub.3 or --CH.dbd.CHCH.sub.2CH.sub.3;
[0208] P.sub.1, P.sub.2, P.sub.3, R.sub.1, X, and Z are as defined
above.
[0209] In certain embodiments, the stereochemistry of the carbon m'
to carbon n' double bond is cis.
[0210] In certain embodiments, carbons k' and l' are connected by a
cis double bond.
[0211] In certain embodiments, the stereochemistry of the carbon m'
to carbon n' double bond is cis and carbons k' and l' are connected
by a cis double bond.
[0212] Exemplary compounds of formula 9 optionally excluded from
such compositions include compound 9a,
##STR00055##
compound 9b,
##STR00056##
and pharmaceutically acceptable salts and esters thereof.
[0213] Other compounds optionally excluded for use as active agents
in such compositions, when compositions of the present disclosure
include an active agent, include those of Formula 10,
##STR00057##
or pharmaceutically acceptable salts thereof, wherein: [0214]
P.sub.1, P.sub.2, P.sub.3, R.sub.1 and Z are as defined above; and
[0215] Q represents one or more substituents and each Q
individually, if present, is a halogen atom or a branched or
unbranched, substituted or unsubstituted alkyl, alkenyl, alkynyl,
cycloalkyl, aryl, alkoxy, aryloxy, alkylcarbonyl, arylcarbonyl,
alkoxycarbonyl, aryloxycarbonyl, amino, hydroxy, cyano, carboxyl,
alkoxycarbonyloxy, aryloxycarbonyloxy or aminocarbonyl group.
[0216] Other compounds optionally excluded for use as active agents
in such compositions, when compositions of the present disclosure
include an active agent, include those of Formula 11,
##STR00058##
or pharmaceutically acceptable salts thereof, wherein: P.sub.1,
P.sub.2, P.sub.3, R.sub.1, and Z are as defined above.
[0217] Other compounds optionally excluded for use as active agents
in such compositions, when compositions of the present disclosure
include an active agent, include those of Formula 12,
##STR00059##
or pharmaceutically acceptable salts thereof, wherein P.sub.1,
P.sub.2, P.sub.3, Q, R.sub.1, and Z are as defined above.
[0218] Other compounds optionally excluded for use as active agents
in such compositions, when compositions of the present disclosure
include an active agent, include those of Formula 13,
##STR00060##
or pharmaceutically acceptable salts thereof, wherein: P.sub.1,
P.sub.2, R.sub.1, R.sub.2, U, and Z are as defined above.
[0219] Other compounds optionally excluded for use as active agents
in such compositions, when compositions of the present disclosure
include an active agent, include those of Formula 14,
##STR00061##
or pharmaceutically acceptable salts thereof, wherein: P.sub.1,
P.sub.2, R.sub.1, R.sub.2, Q, and Z are as defined above.
[0220] Other compounds optionally excluded for use as active agents
in such compositions, when compositions of the present disclosure
include an active agent, include those of Formula 15,
##STR00062##
or pharmaceutically acceptable salts thereof, wherein: P.sub.1,
P.sub.2, and Z are as defined above.
[0221] Other compounds optionally excluded for use as active agents
in such compositions, when compositions of the present disclosure
include an active agent, include those of Formula 16,
##STR00063##
or pharmaceutically acceptable salts thereof, wherein: P.sub.1 and
Z are as defined above.
[0222] Other compounds optionally excluded for use as active agents
in such compositions, when compositions of the present disclosure
include an active agent, include those of Formula 17,
##STR00064##
or pharmaceutically acceptable salts thereof, wherein: [0223]
Carbons o' and p' are connected by a single or a double bond (e.g.,
a cis or trans double bond); [0224] Carbons q' and r' are connected
by a single or a double bond (e.g., a cis or trans double bond);
and [0225] P.sub.1, P.sub.2, and Z are as defined above.
[0226] Other compounds optionally excluded for use as active agents
in such compositions, when compositions of the present disclosure
include an active agent, include those of Formula 18,
##STR00065##
or pharmaceutically acceptable salts thereof, wherein: the
stereochemistry of the carbon s' to carbon t' double bond is cis or
trans; the stereochemistry of the carbon u' to carbon v' double
bond is cis or trans; and P.sub.1, P.sub.2, R.sub.1, R.sub.2, and Z
are as defined above.
[0227] Other compounds optionally excluded for use as active agents
in such compositions, when compositions of the present disclosure
include an active agent, include those of Formula 19,
##STR00066##
or pharmaceutically acceptable salts thereof, wherein: Carbons w'
and x' are connected by a single or a double bond; Carbons y' and
z' are connected by a single or a double bond; and P.sub.1,
P.sub.2, and Z are as defined above.
[0228] In certain embodiments of formulae 4 to 19, each R.sup.b, if
present, is a suitable group independently selected from .dbd.O,
--OR.sup.d, (C1-C3) haloalkyloxy, --OCF.sub.3, .dbd.S, --SR.sup.d,
.dbd.NR.sup.d, .dbd.NOR.sup.d, --NR.sup.cR.sup.c, halogen,
--CF.sub.3, --CN, --NC, --OCN, --SCN, --NO, --NO.sub.2,
.dbd.N.sub.2, --N.sub.3, --S(O)R.sup.d, --S(O).sub.2R.sup.d,
--S(O).sub.2OR.sup.d, --S(O)NR.sup.cR.sup.c,
--S(O).sub.2NR.sup.cR.sup.c, --OS(O)R.sup.d, --OS(O).sub.2R.sup.d,
--OS(O).sub.2OR.sup.d, --OS(O).sub.2NR.sup.cR.sup.c, --C(O)R.sup.d,
--C(O)OR.sup.d, --C(O)NR.sup.cR.sup.c, --C(NH)NR.sup.cR.sup.c,
--C(NR.sup.a)NR.sup.cR.sup.c, --C(NOH)R.sup.a,
--C(NOH)NR.sup.cR.sup.c, --OC(O)R.sup.d, --OC(O)OR.sup.d,
--OC(O)NR.sup.cR.sup.c, --OC(NH)NR.sup.cR.sup.c,
--OC(NR.sup.a)NR.sup.cR.sup.c, --[NHC(O)].sub.nR.sup.d, --[NR.sup.a
C(O)].sub.nR.sup.d, --[NHC(O)].sub.nOR.sup.d,
[NHC(O)].sub.nNR.sup.cR.sup.c, --[NR.sup.a
C(O)].sub.nNR.sup.cR.sup.c, --[NHC(NH)].sub.nNR.sup.cR.sup.c and
--[NR.sup.a C(NR.sup.a)].sub.nNR.sup.cR.sup.c.
[0229] Other compounds optionally excluded for use as active agents
in such compounds, when compositions of the present disclosure
include an active agent, include those of Formula 20,
##STR00067## ##STR00068##
or pharmaceutically acceptable salts of any of the above, wherein
each P is individually selected from H or a protecting group; and R
is H, C.sub.1-6alkyl (e.g., methyl, ethyl, glycerol),
C.sub.2-6alkenyl or C.sub.2-6alkynyl.
[0230] Exemplary compounds of formula 21 is optionally excluded
from such compositions include compound 21a,
##STR00069##
and pharmaceutically acceptable salts and esters thereof.
[0231] Other compounds optionally excluded for use as active agents
in such compositions, when compositions of the present disclosure
include an active agent, include those of Formula 29,
##STR00070##
and pharmaceutically acceptable salts, hydrates and solvates
thereof, wherein: [0232] D.sub.1-E.sub.1 and F.sub.1-G.sub.1 are
independently are cis or trans --C.dbd.C-- or --C.ident.C--; [0233]
R.sub.101, R.sub.102 and R.sub.103 are independently selected from
hydrogen, (C1-C4) straight-chained or branched alkyl, (C2-C4)
alkenyl, (C2-C4) alkynyl, (C1-C4) alkoxy, --CH.sub.2R.sub.104,
--CHR.sub.104R.sub.104 and --CR.sub.104R.sub.104R.sub.104; [0234]
each R.sub.104 is independently selected from CN, --NO.sub.2 and
halogen; [0235] W.sub.1 is selected from --R.sub.105, --OR.sub.105,
--SR.sub.105 and --NR.sub.105R.sub.105; [0236] each R.sub.105 is
independently selected from hydrogen, (C1-C6) alkyl, (C2-C6)
alkenyl or (C2-C6) alkynyl optionally substituted with one or more
of the same or different R groups, (C5-C14) aryl optionally
substituted with one or more of the same or different R groups,
phenyl optionally substituted with one or more of the same or
different R groups, (C6-C16) arylalkyl optionally substituted with
one or more of the same or different R groups, 5-14 membered
heteroaryl optionally substituted with one or more of the same or
different R groups, 6-16 membered heteroarylalkyl optionally
substituted with one or more of the same or different R groups and
a detectable label molecule; [0237] A.sub.1 is selected from
(C1-C6) alkylene optionally substituted with 1, 2, 3, 4, 5 or 6 of
the same or different halogen atoms,
--(CH.sub.2).sub.m--O--CH.sub.2-- and
--(CH.sub.2).sub.m--S--CH.sub.2--, where m is an integer from 0 to
4; [0238] X.sub.1 is selected from --(CH.sub.2).sub.n-- and
--(CH.sub.2).sub.n--O--, where n is an integer from 0 to 6; [0239]
Y.sub.1 is selected from hydrogen, (C1-C6) alkyl, (C2-C6) alkenyl,
or (C2-C6) alkynyl, optionally substituted with one or more of the
same or different R.sub.100 groups, (C5-C14) aryl optionally
substituted with one or more of the same or different R.sub.100
groups, phenyl, optionally substituted with one or more of the same
or different R.sub.100 groups, (C6-C16) arylalkyl optionally
substituted with one or more of the same or different R.sub.100
groups, 5-14 membered heteroaryl optionally substituted with one or
more of the same or different R.sub.100 groups, 6-16 membered
heteroarylalkyl optionally substituted with one or more of the same
or different R.sub.100 groups and a detectable label molecule;
[0240] each R.sub.100 is independently selected from an
electronegative group, .dbd.O, --OR.sup.a1, (C1-C3) haloalkyloxy,
.dbd.S, --SR.sup.a1, .dbd.NR.sup.a1, .dbd.NONR.sup.a1,
--NR.sup.c1R.sup.c1, halogen, --CF.sub.3, --CN, --NC, --OCN, --SCN,
--NO, --NO.sub.2, .dbd.N.sub.2, --N.sub.3, --S(O)R.sup.a1,
--S(O).sub.2R.sup.a1, --S(O).sub.2OR.sup.a1,
--S(O).sub.2NR.sup.c1R.sup.c1, --OS(O)R.sup.a1,
--OS(O).sub.2R.sup.a1, --OS(O).sub.2OR.sup.a1,
--OS(O).sub.2NR.sup.c1R.sup.c1, --C(O)R.sup.a1, --C(O)OR.sup.a1,
--C(O)NR.sup.c1R.sup.c1, --C(NH)NR.sup.c1R.sup.c1, --OC(O)R.sup.a1,
--OC(O)OR.sup.a1, --OC(O)NR.sup.c1R.sup.c1,
--OC(NH)NR.sup.c1R.sup.c1, --NHC(O)R.sup.a1, --NHC(O)OR.sup.a1,
--NHC(O)NR.sup.c1R.sup.c1 and --NHC(NH)NR.sup.c1R.sup.c1; [0241]
each R.sup.a1 is independently selected from hydrogen, (C1-C4)
alkyl, (C2-C4) alkenyl or (C2-C4) alkynyl; and [0242] each R.sup.c1
is independently an R.sup.a1 or, alternatively, R.sup.c1R.sup.c1
taken together with the nitrogen atom to which it is bonded forms a
5 or 6 membered ring.
[0243] In certain embodiments of Formula 29, when X.sub.1--Y.sub.1
is --CH.sub.2CH.sub.3, then at least one of R.sub.101, R.sub.102 or
R.sub.103 is other than hydrogen.
[0244] In certain embodiments, a compound of Formula 29, as
represented by Formula 30, is optionally excluded from such
compositions,
##STR00071##
and pharmaceutically acceptable salts, hydrates and solvates
thereof, wherein: D.sub.1-E.sub.1 and F.sub.1-G.sub.1 are
independently are cis or trans --C.dbd.C-- or --C.ident.C--; and
R.sub.101, R.sub.102, R.sub.103, R.sub.104, W.sub.1, R.sub.105,
A.sub.1, X.sub.1, n, Y.sub.1, R.sub.100, R.sup.a1, and R.sup.c1 are
as defined above.
[0245] Other compounds optionally excluded for use as active agents
in such compositions, when compositions of the present disclosure
include an active agent, include those of Formulae 31 to 37
##STR00072##
[0246] and pharmaceutically acceptable salts, hydrates and solvates
thereof,
wherein: R.sub.106 is --OH, --OCH.sub.3, --OCH(CH.sub.3).sub.2 or
--NHCH.sub.2CH.sub.3; and
R.sub.107 is
##STR00073##
[0248] Other compounds optionally excluded for use as active agents
in such compositions, when compositions of the present disclosure
include an active agent, include those of Formula 38,
##STR00074##
wherein: [0249] Carbons aa' and bb' are connected by a double bond
or a triple bond; [0250] Carbons cc' and dd' are connected by a
double bond or a triple bond; [0251] Re, Rf, and Rg are
independently selected from hydrogen, alkyl, alkenyl, alkynyl,
aryl, heteroaryl, acyl (e.g., alkoxyacyl, aminoacyl),
aminocarbonyl, alkoxycarbonyl, or silyl; [0252] E is hydroxyl,
alkoxy, aryloxy, amino, alkylamino, dialkylamino, or arylamino;
[0253] Rh, Ri and Rj are independently selected from hydrogen,
alkyl, alkenyl, alkynyl, perfluoroalkyl, aryl or heteroaryl; [0254]
R.sub.4 is selected from hydrogen, alkyl, perfluoroalkyl, alkenyl,
alkynyl, aryl, heteroaryl, fluoro, hydroxyl, alkoxy, aryloxy;
[0255] R.sub.5 is selected from i-iv as follows: i)
CH.sub.2CH(R.sub.6)CH.sub.2, where R.sub.6 is hydrogen, alkyl,
alkenyl, alkynyl, perfluoroalkyl, aryl, heteroaryl, fluoro,
hydroxyl or alkoxy; ii) CH.sub.2C(R.sub.6R.sub.7)CH.sub.2, where
R.sub.6 and R.sub.7 are each independently alkyl, alkenyl, alkynyl,
perfluoroalkyl, aryl, or fluoro, or R.sub.6 and R.sub.7 are
connected together to form a carbocyclic or heterocyclic ring; iii)
CH.sub.2OCH.sub.2, CH.sub.2C(O)CH.sub.2, or CH.sub.2CH.sub.2; or
iv) R.sub.5 is a carbocyclic, heterocyclic, aryl or heteroaryl
ring; and [0256] R.sub.8 and R.sub.9 are independently selected
from hydrogen, alkyl, alkenyl, alkynyl, perfluoroalkyl, alkoxy,
aryl or heteroaryl, or R.sub.8 and R.sub.9 are connected together
to form a carbocyclic or heterocyclic ring; [0257] or
pharmaceutically acceptable salts thereof.
[0258] In certain embodiments R.sub.8 and R.sub.9 are hydrogen.
[0259] In certain embodiments, a pharmaceutically acceptable salt
of the compound formed by derivatizing E, wherein E is --OM, where
M is a cation selected from ammonium, tetra-alkyl ammonium, Na, K,
Mg, and Zn is optionally excluded from such compositions.
[0260] Other compounds optionally excluded for use as active agents
in such compositions, when compositions of the present disclosure
include an active agent, include those of Formulae 39-44,
##STR00075##
and pharmaceutically acceptable salts thereof, wherein: Re, Rf, E,
Ri, R.sub.5, R.sub.8 and R.sub.9 are as defined above.
[0261] Exemplary compounds of formulae 39, 41, and 43 include:
##STR00076##
and pharmaceutically acceptable salts and esters thereof.
[0262] In certain embodiments, when compositions of the present
disclosure include an active agent, a pharmaceutically acceptable
salt of the compound formed by derivatizing E, wherein E is --OM,
where M is a cation selected from ammonium, tetra-alkyl ammonium,
Na, K, Mg, and Zn is optionally excluded from such compositions.
Examples of such compounds include compound Z,
##STR00077##
[0263] Other compounds optionally excluded for use as active agents
in such compositions, when compositions of the present disclosure
include an active agent, include those of Formula 46,
##STR00078##
or a pharmaceutically acceptable salt or prodrug thereof, wherein:
[0264] each independently designates a double or triple bond;
[0265] R.sup.1, R.sup.2, and R.sup.3 are each independently OR,
OX', SR, SX.sup.2, N(R).sub.2, NHX.sup.3, NRC(O)R,
NRC(O)N(R).sub.2, C(O)OR, C(O)N(R).sub.2, SO.sub.2R, NRSO.sub.2R,
C(O)R, or SO.sub.2N(R).sub.2; [0266] each R is independently
selected from hydrogen or an optionally substituted group selected
from C.sub.1-6 aliphatic, a 3-8 membered saturated, partially
unsaturated, or aryl ring having 0-4 heteroatoms independently
selected from nitrogen, oxygen, or sulfur, or; [0267] two R on the
same nitrogen are taken together with the nitrogen to form a 5-8
membered heterocyclyl or heteroaryl ring having 1-3 heteroatoms
independently selected from nitrogen, oxygen, or sulfur; [0268]
each X.sup.1 is independently a suitable hydroxyl protecting group;
[0269] each X.sup.2 is independently a suitable thiol protecting
group; [0270] each X.sup.3 is independently a suitable amino
protecting group; and [0271] R.sup.4 is NRC(O)R, NRC(O)N(R).sub.2,
C(O)OR, C(O)N(R).sub.2, SO.sub.2R, NRSO.sub.2R, C(O)R, or
SO.sub.2N(R).sub.2.
[0272] Other compounds optionally excluded for use as active agents
in such compositions, when compositions of the present disclosure
include an active agent, include those of Formula 47,
##STR00079##
or a pharmaceutically acceptable salt or prodrug thereof, wherein:
[0273] the stereochemistry of the carbon kk' to carbon ll' double
bond is cis or trans; [0274] the stereochemistry of the carbon mm'
to carbon nn' double bond is cis or trans; [0275] the
stereochemistry of the carbon oo' to carbon pp' double bond is cis
or trans; [0276] Y' is a bond or a linker selected from a ring
containing up to 20 atoms or a chain of up to 20 atoms, provided
that Y' can include one or more nitrogen, oxygen, sulfur or
phosphorous atoms, further provided that Y' can include one or more
substituents independently selected from hydrogen, alkyl, alkenyl,
alkynyl, aryl, heteroaryl, chloro, iodo, bromo, fluoro, hydroxy,
alkoxy, aryloxy, carboxy, amino, alkylamino, dialkylamino,
acylamino, carboxamido, cyano, oxo, thio, alkylthio, arylthio,
acylthio, alkylsulfonate, arylsulfonate, phosphoryl, or sulfonyl,
further provided that Y' can contain one or more fused carbocyclic,
heterocyclic, aryl or heteroaryl rings; [0277] Z' is selected from
--CN, --C(NH)N(R'')(R''), --C(S)-A', --C(S)R'', --C(O)-A',
--C(O)--R'', --C(O)--SR'', --C(O)--NH--S(O).sub.2--R'',
--S(O).sub.2-A', --S(O).sub.2--R'', S(O).sub.2N(R'')(R''),
--P(O).sub.2-A', --PO(OR'')-A', -tetrazole, alkyltetrazole, or
--CH.sub.2OH, wherein [0278] A' is selected from --OR'',
--N(R'')(R'') or --OM'; [0279] each R'' is independently selected
from hydrogen, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl
or a detectable label molecule, wherein any alkyl-, aryl- or
heteroaryl-containing moiety is optionally substituted with up to 3
independently selected substituents; and [0280] M' is a cation.
[0281] In certain embodiments, a compound of formula 47 is
represented by formula 48,
##STR00080##
or pharmaceutically acceptable salts and esters thereof, wherein:
the stereochemistry of the carbon kk' to carbon ll' double bond is
cis or trans; the stereochemistry of the carbon mm' to carbon nn'
double bond is cis or trans; the stereochemistry of the carbon oo'
to carbon pp' double bond is cis or trans.
[0282] In certain embodiments, the stereochemistry of the carbon
kk' to carbon ll' double bond is trans.
[0283] In certain embodiments, the stereochemistry of the carbon
mm' to carbon nn' double bond trans.
[0284] In certain embodiments, the stereochemistry of the carbon
oo' to carbon pp' double bond is cis.
[0285] In certain embodiments, the stereochemistry of the carbon
kk' to carbon ll' double bond is trans, the stereochemistry of the
carbon mm' to carbon nn' double bond trans, and the stereochemistry
of the carbon oo' to carbon pp' double bond is cis.
[0286] In certain embodiments, a compound of formula 47 is
represented by compound 48a,
##STR00081##
compound 48b,
##STR00082##
compound 48c,
##STR00083##
or pharmaceutically acceptable salts and esters thereof.
[0287] In certain embodiments, a compound of formula 47 is
represented by formula 48d,
##STR00084##
or pharmaceutically acceptable salts and esters thereof, wherein:
the stereochemistry of the carbon kk' to carbon ll' double bond is
cis or trans; the stereochemistry of the carbon mm' to carbon nn'
double bond is cis or trans; the stereochemistry of the carbon oo'
to carbon pp' double bond is cis or trans.
[0288] In certain embodiments, the compound of formula 47 is other
than a compound of formula 48, 48a, 48b, 48c, or 48d.
[0289] Other compounds optionally excluded for use as active agents
in such compositions, when compositions of the present disclosure
include an active agent, include those of Formula 49,
##STR00085##
or a pharmaceutically acceptable salt or prodrug thereof, wherein:
[0290] Y' is a bond or a linker selected from a ring containing up
to 20 atoms or a chain of up to 20 atoms, provided that Y' can
include one or more nitrogen, oxygen, sulfur or phosphorous atoms,
further provided that Y' can include one or more substituents
independently selected from hydrogen, alkyl, alkenyl, alkynyl,
aryl, heteroaryl, chloro, iodo, bromo, fluoro, hydroxy, alkoxy,
aryloxy, carboxy, amino, alkylamino, dialkylamino, acylamino,
carboxamido, cyano, oxo, thio, alkylthio, arylthio, acylthio,
alkylsulfonate, arylsulfonate, phosphoryl, or sulfonyl, further
provided that Y' can contain one or more fused carbocyclic,
heterocyclic, aryl or heteroaryl rings; [0291] Z' is selected from
--CN, --C(NH)N(R'')(R''), --C(S)-A', --C(S)R'', --C(O)-A',
--C(O)--R'', --C(O)--SR'', --C(O)--NH--S(O).sub.2--R'',
--S(O).sub.2-A', --S(O).sub.2--R'', S(O).sub.2N(R'')(R''),
--P(O).sub.2-A', --PO(OR'')-A', -tetrazole, alkyltetrazole, or
--CH.sub.2OH, wherein [0292] A' is selected from --OR'',
--N(R'')(R'') or +OM'; [0293] each R'' is independently selected
from hydrogen, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl
or a detectable label molecule, wherein any alkyl-, aryl- or
heteroaryl-containing moiety is optionally substituted with up to 3
independently selected substituents; and [0294] M' is a cation; and
[0295] each of R.sup.a' and R.sup.b' is independently for each
occurrence selected from --OR', or adjacent R.sup.a' and R.sup.b'
are taken together to form an epoxide ring having a cis or trans
configuration, wherein each R' is independently selected from
hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, acyl, silyl,
alkoxyacyl, aminoacyl, aminocarbonyl, alkoxycarbonyl, or a
protecting group.
[0296] Exemplary compounds of formula 49 include compound 49a,
##STR00086##
compound 49b,
##STR00087##
or pharmaceutically acceptable salts and esters thereof.
[0297] The compounds above (e.g., compounds of formula A or
formulae 1 to 49) are known to be useful in the treatment or
prevention of inflammation or inflammatory disease. Examples of
such compounds are disclosed in the following patents and
applications: US 2003/0191184, WO 2004/014835, WO 2004/078143, U.S.
Pat. No. 6,670,396, US 2003/0236423, US 2005/0228047, US
2005/0238589 and US2005/0261255. These compounds are optionally
excluded for use in methods of the present disclosure.
[0298] Other compounds for which delivery may be enhanced by
compositions of the present disclosure, but which may be excluded
from compositions of the present disclosure, are compounds that are
chemically similar variants to any of the compounds of formula A or
formulae 1-49 set forth above. The term "chemically similar
variants" includes, but is not limited to, replacement of various
moieties with known biosteres; replacement of the end groups of one
of the compounds above with a corresponding end group of any other
compound above, modification of the orientation of any double bond
in a compound, the replacement of any double bond with a triple
bond in any compound, and the replacement of one or more
substituents present in one of the compounds above with a
corresponding substituent of any other compound.
[0299] Lipoxin compounds optionally excluded for use as active
agents, when compositions of the present disclosure include an
active agent, include those of formula 50:
##STR00088##
wherein: [0300] X is R.sub.301, OR.sub.301, or SR.sub.301; [0301]
R.sub.301 is [0302] (a) a hydrogen atom; [0303] (b) an alkyl of 1
to 8 carbons atoms, inclusive, which may be straight chain or
branched; [0304] (c) a cycloalkyl of 3 to 10 carbon atoms; [0305]
(d) an aralkyl of 7 to 12 carbon atoms; [0306] (e) phenyl; [0307]
(f) substituted phenyl
##STR00089##
[0307] wherein Z.sub.i, Z.sub.ii, Z.sub.iii, Z.sub.iv and Z.sub.v
are each independently selected from --NO.sub.2, --CN,
--C(.dbd.O)--R.sub.301, --SO.sub.3H, a hydrogen atom, halogen,
methyl, --OR.sub.x, wherein R.sub.x is 1 to 8 carbon atoms,
inclusive, which may be a straight chain or branched, and hydroxyl,
wherein when any of Z.sub.i, Z.sub.ii, Z.sub.iii, Z.sub.iv or
Z.sub.v is C(.dbd.O)--R.sub.301, said Z.sub.i, Z.sub.ii, Z.sub.iii,
Z.sub.iv or Z.sub.v is not substituted with another
C(.dbd.O)--R.sub.301. [0308] (g) a detectable label molecule; or
[0309] (h) a straight or branched chain alkenyl of 2 to 8 carbon
atoms, inclusive; [0310] Q.sub.1 is (C.dbd.O), SO.sub.2 or (CN),
provided when Q.sub.1 is CN, then X is absent; [0311] Q.sub.3 and
Q.sub.4 are each independently O, S or NH; [0312] one of R.sub.302
and R.sub.303 is a hydrogen atom and the other is: [0313] (a) H;
[0314] (b) an alkyl of 1 to 8 carbon atoms, inclusive, which may be
a straight chain or branched; [0315] (c) a cycloalkyl of 3 to 6
carbon atoms, inclusive; [0316] (d) an alkenyl of 2 to 8 carbon
atoms, inclusive, which may be straight chain or branched; or
[0317] (e) R.sub.kQ.sub.2R.sub.1 wherein Q.sub.2 is --O-- or --S--;
wherein R.sub.k is alkylene of 0 to 6 carbons atoms, inclusive,
which may be straight chain or branched and wherein R.sub.1 is
alkyl of 0 to 8 carbon atoms, inclusive, which may be straight
chain or branched, provided when R.sub.1 is 0, then R.sub.1 is a
hydrogen atom; [0318] R.sub.304 is [0319] (a) H; [0320] (b) an
alkyl of 1 to 6 carbon atoms, inclusive, which may be a straight
chain or branched; [0321] R.sub.305 is
##STR00090##
[0321] wherein Z.sub.i, Z.sub.ii, Z.sub.iii, Z.sub.iv and Z.sub.v
are defined as above; [0322] R.sub.306 is [0323] (a) H; [0324] (b)
an alkyl from 1 to 4 carbon atoms, inclusive, straight chain or
branched; [0325] wherein Y.sub.301 is --OH, methyl, --SH, an alkyl
of 2 to 4 carbon atoms, inclusive, straight chain or branched, an
alkoxy of 1 to 4 carbon atoms, inclusive, or (CH).sub.p(Z).sub.q,
where p+q=3, p=0 to 3, q=0 to 3 and Z is cyano, nitro or a halogen;
and [0326] T is O or S, and pharmaceutically acceptable salts
thereof.
[0327] Lipoxin compounds optionally excluded for use as active
agents in such compositions, when compositions of the present
disclosure include an active agent, include those of formulae 51,
52, 53 or 54:
##STR00091##
wherein: [0328] each R.sub.307 is independently selected from
hydrogen and straight, branched, cyclic, saturated, or unsaturated
alkyl having from 1 to 20 carbon atoms; [0329] R.sub.308,
R.sub.309, R.sub.310, R.sub.319, and R.sub.320 are independently
selected from: [0330] (a) hydrogen; [0331] (b) straight, branched,
cyclic, saturated, or unsaturated alkyl having from 1 to 20 carbon
atoms; [0332] (c) substituted alkyl having from 1 to 20 carbon
atoms, wherein the alkyl is substituted with one or more
substituents selected from halo, hydroxy, lower alkoxy, aryloxy,
amino, alkylamino, dialkylamino, acylamino, arylamino,
hydroxyamino, alkoxyamino, alkylthio, arylthio, carboxy,
carboxamido, carboalkoxy, aryl, and heteroaryl; [0333] (d)
substituted aryl or heteroaryl, wherein the aryl or heteroaryl is
substituted with one or more substituents selected from alkyl,
cycloalkyl, alkoxy, halo, aryl, heteroaryl, carboxyl, and
carboxamido; and [0334] (e) Z--Y, wherein: [0335] Z is selected
from a straight, branched, cyclic, saturated, or unsaturated alkyl
having from 1 to 20 carbon atoms; substituted lower alkyl, wherein
the alkyl is substituted with one or more substituents selected
from halo, hydroxy, lower alkoxy, aryloxy, amino, alkylamino,
dialkylamino, acylamino, arylamino, hydroxyamino, alkoxyamino,
alkylthio, arylthio, carboxy, carboxamido, carboalkoxy, aryl, and
heteroaryl; and substituted aryl or heteroaryl, wherein the aryl or
heteroaryl is substituted with one or more substituents selected
from alkyl, cycloalkyl, alkoxy, halo, aryl, heteroaryl, carboxyl,
and carboxamido; and [0336] Y is selected from hydrogen; alkyl;
cycloalkyl; carboxyl; carboxamido; aryl; heteroaryl; substituted
aryl or heteroaryl, wherein the aryl or heteroaryl is substituted
with one or more substituents selected from alkyl, cycloalkyl,
alkoxy, halo, aryl, heteroaryl, carboxyl, and carboxamido; and
[0337] R.sub.311 to R.sub.318 are independently selected from:
[0338] (a) hydrogen; [0339] (b) halo; [0340] (c) straight,
branched, cyclic, saturated, or unsaturated alkyl having from 1 to
20 carbon atoms; [0341] (d) substituted alkyl having from 1 to 20
carbon atoms, wherein the alkyl is substituted with one or more
substituents selected from halo, hydroxy, lower alkoxy, aryloxy,
amino, alkylamino, dialkylamino, acylamino, arylamino,
hydroxyamino, alkoxyamino, alkylthio, arylthio, carboxy,
carboxamido, carboalkoxy, aryl, and heteroaryl; [0342] (e)
substituted aryl or heteroaryl, wherein the aryl or heteroaryl is
substituted with one or more substituents selected from alkyl,
cycloalkyl, alkoxy, halo, aryl, heteroaryl, carboxyl, and
carboxamido; or [0343] R.sub.308 to R.sub.320 are independently a
bond that forms a carbon-carbon double bond, a carbon-carbon triple
bond, or a ring with the lipoxin backbone; or [0344] any two of
R.sub.307 to R.sub.320 are taken together with the atoms to which
they are bound and optionally to 1 to 6 oxygen atoms, 1 to 6
nitrogen atoms, or both 1 to 6 oxygen atoms and 1 to 6 nitrogen
atoms, to form a ring containing 3 to 20 atoms.
[0345] Lipoxin compounds optionally excluded for use as active
agents in such compositions, when compositions of the present
disclosure include an active agent, include those of formula
55:
##STR00092##
wherein: R.sub.401 is selected from:
##STR00093##
R.sub.402 is selected from:
##STR00094##
X.sub.10 is R.sub.411, OR.sub.411, or SR.sub.411;
R.sub.411 is
[0346] (a) a hydrogen atom; [0347] (b) an alkyl of 1 to 8 carbons
atoms, inclusive, which may be straight chain or branched; [0348]
(c) a cycloalkyl of 3 to 10 carbon atoms; [0349] (d) an aralkyl of
7 to 12 carbon atoms; [0350] (e) phenyl; [0351] (f) substituted
phenyl
##STR00095##
[0351] wherein Z.sub.i, Z.sub.ii, Z.sub.iii, Z.sub.iv and Z.sub.v
are each independently selected from --NO.sub.2, --CN,
--C(.dbd.O)--R.sub.411, --SO.sub.3H, a hydrogen atom, halogen,
methyl, --OR.sub.x, wherein R.sub.x is 1 to 8 carbon atoms,
inclusive, which may be a straight chain or branched, and hydroxyl;
wherein when any of Z.sub.i, Z.sub.ii, Z.sub.iii, Z.sub.iv or
Z.sub.v is C(.dbd.O)--R.sub.411, said Z.sub.i, Z.sub.ii, Z.sub.iii,
Z.sub.iv or Z.sub.v is not substituted with another
C(.dbd.O)--R.sub.411. [0352] (g) a detectable label molecule; or
[0353] (h) a straight or branched chain alkenyl of 2 to 8 carbon
atoms, inclusive; Q.sub.1 is (C.dbd.O), SO.sub.2 or (CN);
Q.sub.3 is O, S or NH;
[0354] one of R.sub.412 and R.sub.413 is a hydrogen atom and the
other is selected from: [0355] (a) H; [0356] (b) an alkyl of 1 to 8
carbon atoms, inclusive, which can be straight chain or branched;
[0357] (c) a cycloalkyl of 3 to 6 carbon atoms, inclusive; [0358]
(d) an alkenyl of 2 to 8 carbon atoms, inclusive, which can be
straight chain or branched; or [0359] (e) R.sub.431Q.sub.2R.sub.432
wherein Q.sub.2 is --O-- or --S--; wherein R.sub.431 is alkylene of
0 to 6 carbons atoms, inclusive, which can be straight chain or
branched and wherein R.sub.431 is alkyl of 0 to 8 carbon atoms,
inclusive, which can be straight chain or branched; R.sub.413a and
R.sub.413b are each independently: [0360] (a) H; [0361] (b) an
alkyl of 1 to 8 carbon atoms, inclusive, which can be straight
chain or branched; [0362] (c) a cycloalkyl of 3 to 6 carbon atoms,
inclusive; [0363] (d) an alkenyl of 2 to 8 carbon atoms, inclusive,
which can be straight chain or branched; or [0364] (e)
R.sub.431Q.sub.2R.sub.432 wherein R.sub.431, Q.sub.2, and R.sub.432
are as defined above;
R.sub.414 is
[0364] [0365] (a) H; [0366] (b) an alkyl of 1 to 6 carbon atoms,
inclusive, can be straight chain or branched;
R.sub.415 is
[0366] [0367] (a) an alkyl of 1 to 9 carbon atoms which can be
straight chain or branched; [0368] (b) --(CH.sub.2)--R.sub.i [0369]
wherein n=0 to 4 and R.sub.i is [0370] (i) a cycloalkyl of 3 to 10
carbon atoms, inclusive; [0371] (ii) a phenyl; or [0372] (iii)
substituted phenyl
##STR00096##
[0372] wherein Z.sub.i through Z.sub.v are as defined above; [0373]
(c) R.sub.431Q.sub.2R.sub.432, wherein R.sub.431, Q.sub.2, and
R.sub.432 are as defined above; [0374] (d)
C(R.sub.iii)(R.sub.iv)--R.sub.i, [0375] wherein R.sub.iii and
R.sub.iv are each independently: [0376] (i) a hydrogen atom; [0377]
(ii) (CH).sub.p(Z).sub.q, wherein Z, p, and q are as defined above;
[0378] (e) a haloalkyl of 1 to 8 carbon atoms, inclusive, and 1 to
6 halogen atoms, inclusive, straight chain or branched;
R.sub.416 is
[0378] [0379] (a) H; [0380] (b) an alkyl from 1 to 4 carbon atoms,
inclusive, straight chain or branched; [0381] (c) a halogen; one of
Y.sub.401 or Y.sub.402 is --OH, methyl, or --SH, and wherein the
other is selected from: [0382] (a) H; [0383] (b)
(CH).sub.p(Z).sub.q where p+q=3, p=0 to 3, q=0 to 3 and each Z,
independently, is cyano, nitro or a halogen; [0384] (c) an alkyl of
2 to 4 carbon atoms, inclusive, straight chain or branched; or
[0385] (d) an alkoxy of 1 to 4 carbon atoms, inclusive, or
Y.sub.401 and Y.sub.402 taken together are: [0386] (a) .dbd.NH; or
[0387] (b) .dbd.O; one of Y.sub.403 or Y.sub.404 is --OH, methyl,
or --SH, and wherein the other is selected from: [0388] (a) H;
[0389] (b) (CH).sub.p(Z).sub.q wherein Z, p, and q are as defined
above; [0390] (c) an alkyl of 2 to 4 carbon atoms, inclusive,
straight chain or branched; or [0391] (d) an alkoxy of 1 to 4
carbon atoms, inclusive, or Y.sub.401 and Y.sub.402 taken together
are: [0392] (a) .dbd.NH; or [0393] (b) .dbd.O; one of Y.sub.405 or
Y.sub.406 is --OH, methyl, or --SH, and wherein the other is
selected from: [0394] (a) H [0395] (b) (CH).sub.p(Z).sub.q wherein
Z, p, and q are as defined above; [0396] (c) an alkyl of 2 to 4
carbon atoms, inclusive, straight chain or branched; or [0397] (d)
an alkoxy of 1 to 4 carbon atoms, inclusive, or Y.sub.401 and
Y.sub.402 taken together are: [0398] (a) .dbd.NH; or [0399] (b)
.dbd.O;
R.sub.421 is
[0399] [0400] (a) H; or [0401] (b) alkyl of 1 to 8 carbon atoms;
R.sub.422 and R.sub.423 are each independently: [0402] (a) H;
[0403] (b) a hydroxyl, or a thiol; [0404] (c) a methyl or a
halomethyl; [0405] (d) a halogen; or [0406] (e) an alkoxy of 1 to 3
carbon atoms; R.sub.424 and R.sub.425 are each independently:
[0407] (a) H; [0408] (b) a hydroxyl, or a thiol; [0409] (c) a
methyl or a halomethyl; [0410] (d) a halogen; [0411] (e) an alkoxy
of 1 to 3 carbon atoms; or [0412] (f) an alkyl or haloalkyl of 2 to
4 carbon atoms inclusive, which can be straight chain or branched;
and
R.sub.426 is
[0412] [0413] (a) a substituted phenyl
##STR00097##
[0413] wherein Z.sub.i through Z.sub.v are as defined above; [0414]
(b) a substituted phenoxy
##STR00098##
[0414] wherein Z.sub.i through Z.sub.v are as defined above; or
[0415] (c)
##STR00099##
[0415] wherein Z.sub.i through Z.sub.v are as defined above.
[0416] Lipoxin compounds optionally excluded for use as active
agents in such compositions, when compositions of the present
disclosure include an active agent, include those of formula
56:
##STR00100##
wherein:
[0417] E is hydroxy, alkoxy, aryloxy, amino, alkylamino,
dialkylamino or --OM, where M is a cation selected from ammonium,
tetra-alkyl ammonium, and the cations of sodium, potassium,
magnesium and zinc;
[0418] W is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl,
halo, hydroxy, alkoxy, aryloxy, carboxy, amino, alkylamino,
dialkylamino, acylamino, carboxamido, or sulfonamide;
[0419] each of R.sub.501-R.sub.503 are independently selected from
hydrogen, alkyl, aryl, acyl or alkoxyacyl;
[0420] n is 0, 1 or 2;
[0421] m is 1 or 2; and
[0422] the two substituents on the phenyl ring are ortho, meta, or
para.
[0423] Lipoxin compounds optionally excluded for use as active
agents in such compositions, when compositions of the present
disclosure include an active agent, include those of formula
57:
##STR00101##
wherein:
[0424] I is selected from: --C(O)-E, --SO.sub.2-E, --PO(OR)-E,
where E is hydroxy, alkoxy, aryloxy, amino, alkylamino,
dialkylamino, or --OM, where M is a cation selected from ammonium,
tetra-alkyl ammonium, Na, K, Mg, and Zn; and R is hydroxyl or
alkoxy
[0425] J' and K' are linkers independently selected from a chain of
up to 20 atoms and a ring containing up to 20 atoms, provided that
J' and K' can independently include one or more nitrogen, oxygen,
sulfur or phosphorous atoms, and further provided that J' and K'
can independently include one or more substituents selected from
hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, chloro, iodo,
bromo, fluoro, hydroxy, alkoxy, aryloxy, carboxy, amino,
alkylamino, dialkylamino, acylamino, carboxamido, cyano, oxo, thio,
alkylthio, arylthio, acylthio, alkylsulfonate, arylsulfonate,
phosphoryl, and sulfonyl, and further provided that J' and K' can
also contain one or more fused carbocyclic, heterocyclic, aryl or
heteroaryl rings, and provided that linkers J' and K' are connected
to the adjacent C(R)OR group via a carbon atom or a C-heteroatom
bond where the heteroatom is oxygen, sulfur, phosphorous or
nitrogen;
[0426] G is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl,
heteroaryl, chloro, iodo, bromo, fluoro, hydroxy, alkoxy, aryloxy,
carboxy, amino, alkylamino, dialkylamino, acylamino, and
carboxamido.
[0427] Re, Rf and Rg, are independently selected from hydrogen,
alkyl, aryl, heteroaryl, acyl, silyl, alkoxyacyl and aminoacyl;
[0428] R.sub.601, R.sub.602 and R.sub.603 are independently
selected from hydrogen, alkyl, aryl and heteroaryl, provided that
R.sub.601, R.sub.602 and R.sub.603 can independently be connected
to linkers J' or K';
[0429] R.sub.604 and R.sub.605 are independently selected from
hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, fluoro, and
provided that R.sub.604 and R.sub.605 can be joined together to
form a carbocyclic, heterocyclic or aromatic ring, and further
provided that R.sub.604 and R.sub.605 can be replaced by a bond to
form a triple bond.
[0430] Other compounds optionally excluded for use as active agents
in such compositions, when compositions of the present disclosure
include an active agent, are the oxylipins described in
international applications WO 2006055965, WO 2007090162, and
WO2008103753, the compounds in which are incorporated herein by
reference. Examples of such compounds are those of formulae 58-115,
as shown in Table 1. These compounds include long chain omega-6
fatty acids, docosapentaenoic acid (DPAn-6) (compounds 58-73) and
docosatetraenoic acid (DTAn-6) (compounds 74-83), and the omega-3
counterpart of DPAn-6, docosapentaenoic acid (DPAn-3) (compounds
84-97). Further compounds are the docosanoids 98-115, the
.alpha.-linolenic acids (GLA) (compounds 116-122), and the
stearidonic acids (SDA) (compounds 123-132).
TABLE-US-00001 TABLE 1 10,17-Dihydroxy DPAn-6 (58) ##STR00102##
16,17-Dihydroxy DPAn-6 (59) ##STR00103## 4,5-Dihydroxy DPAn-6 (60)
##STR00104## 7,17-Dihydroxy DPAn-6 (61) ##STR00105## 7-Hydroxy
DPAn-6 (62) ##STR00106## 10-hydroxy DPAn-6 (63) ##STR00107##
13-Hydroxy DPAn-6 (64) ##STR00108## 17-hydroxy DPAn-6 (65)
##STR00109## 4,5,17-Trihydroxy DPAn-6 (66) ##STR00110##
7,16,17-Trihydroxy DPAn-6 (67) ##STR00111## 8-Hydroxy DPAn-6 (68)
##STR00112## 14-Hydroxy DPAn-6 (69) ##STR00113## 13,17-Dihydroxy
DPAn-6 (70) ##STR00114## 7,14-Dihydroxy DPAn-6 (71) ##STR00115##
8,14-Dihydroxy DPAn-6 (72) ##STR00116## 11-Hydroxy DPAn-6 (73)
##STR00117## 10,17-Dihydroxy-DTAn-6 (74) ##STR00118##
16,17-Dihydroxy-DTAn-6 (75) ##STR00119## 4,5-Dihydroxy-DTAn-6 (76)
##STR00120## 7,17-Dihydroxy-DTAn-6 (77) ##STR00121##
7-Hydroxy-DTAn-6 (78) ##STR00122## 10-Hydroxy-DTAn-6 (79)
##STR00123## 13-Hydroxy-DTAn-6 (80) ##STR00124## 17-Hydroxy-DTAn-6
(81) ##STR00125## 4,5,17-Trihydroxy-DTAn-6 (82) ##STR00126##
7,16,17-Trihydroxy-DTAn-6 (83) ##STR00127## 10,17-Dihydroxy DPAn-3
(84) ##STR00128## 10,20-Dihydroxy DPAn-3 (85) ##STR00129##
13,20-Dihydroxy DPAn-3 (86) ##STR00130## 16,17-Dihydroxy DPAn-3
(87) ##STR00131## 7,17-Dihydroxy DPAn-3 (88) ##STR00132## 7-Hydroxy
DPAn-3 (89) ##STR00133## 10-Hydroxy DPAn-3 (90) ##STR00134##
13-Hydroxy DPAn-3 (91) ##STR00135## 17-Hydroxy DPAn-3 (92)
##STR00136## 7,16,17-Trihydroxy DPAn-3 (93) ##STR00137## 16-Hydroxy
DPAn-3 (94) ##STR00138## 11-Hydroxy DPAn-3 (95) ##STR00139##
14-Hydroxy DPAn-3 (96) ##STR00140## 8,14-Dihydroxy DPAn-3 (97)
##STR00141## 10,11-Epoxy DHA (98) ##STR00142## 13,14-Dihydroxy DHA
(99) ##STR00143## 13,14-Epoxy DHA (100) ##STR00144## 19,20-Epoxy
DHA (101) ##STR00145## 7,8-Epoxy DHA (102) ##STR00146##
4,5-Epoxy-17-0H DPA (103) ##STR00147## 7,16,17-Trihydroxy DTAn-3
(104) ##STR00148## 16,17-Dihidroxy DTAn-3 (105) ##STR00149##
10,16,17-Trihydroxy DTRAn-6 (106) ##STR00150## 16,17-Dihydroxy
DTRAn-6 (107) ##STR00151## 7,16,17-Trihydroxy DTRAn-6 (108)
##STR00152## 15-epi-lipoxin A4 (109) ##STR00153## 16,17-epoxy DHA
(110) ##STR00154## 7,8-epoxy DPA (111) ##STR00155## 10,11 epoxy DPA
(112) ##STR00156## 19,20 epoxy DPA (113) ##STR00157## 7-hydroxy DHA
(114) ##STR00158## 13,14 epoxy DPA (115) ##STR00159## 6-hydroxy GLA
(116) ##STR00160## 10-hydroxy GLA (117) ##STR00161## 7-hydroxy GLA
(118) ##STR00162## 12-hydroxy GLA (119) ##STR00163## 9-hydroxy GLA
(120) ##STR00164## 13-hydroxy GLA (121) ##STR00165## 6,13 dihydroxy
GLA (122) ##STR00166## 6-hydroxy SDA (123) ##STR00167## 10-hydroxy
SDA (124) ##STR00168## 7-hydroxy SDA (125) ##STR00169## 12-hydroxy
SDA (126) ##STR00170## 9-hydroxy SDA (127) ##STR00171## 13-hydroxy
SDA (128) ##STR00172## 15-hydroxy SDA (129) ##STR00173## 16-hydroxy
SDA (130) ##STR00174## 6,13 dihydroxy SDA (131) ##STR00175## 6,16
dihydroxy SDA (132) ##STR00176##
[0431] Other oxylipin compounds that are optionally excluded for
use as active agents in such compositions, when compositions of the
present disclosure include an active agent, include analogs of the
compounds shown in Table 1. Such compounds include but are not
limited to those analogs wherein one or more double bonds are
replaced by triple bonds, those wherein one or more carboxy groups
are derivatized to form esters, amides or salts, those wherein the
hydroxyl-bearing carbons are further derivatized (with, for
example, a substituted or unsubstituted, branched or unbranched
alkyl, alkenyl, or alkynyl group, substituted or unsubstituted aryl
group, substituted or unsubstituted, branched or unbranched
alkylaryl group, halogen atom) to form tertiary alcohols (or
ethers, esters, or other derivatives thereof), those wherein one or
more hydroxyl groups are derivatized to form esters or protected
alcohols, or those having combinations of any of the foregoing
modifications.
[0432] Further oxylipin compounds optionally excluded for use as
active agents in such compositions, when compositions of the
present disclosure include an active agent, include the following:
isolated docosanoids of docosapentaenoic acid (DPAn-6);
monohydroxy, dihydroxy, and trihydroxy derivatives of DPAn-6;
isolated docosanoids of docosapentaenoic acid (DPAn-3);
monohydroxy, dihydroxy, and trihydroxy derivatives of DPAn-3;
isolated docosanoids of docosapentaenoic acid (DTAn-6); or
monohydroxy, dihydroxy, and trihydroxy derivatives of DTAn-6.
[0433] Other compounds optionally excluded for use as active agents
in such compositions, when compositions of the present disclosure
include an active agent, include compounds of formula I,
##STR00177##
and pharmaceutically acceptable salts thereof, wherein: [0434] the
stereochemistry of the carbon qq' to carbon rr' double bond is cis
or trans; [0435] the stereochemistry of the carbon ss' to carbon
tt' double bond is cis or trans; [0436] Re and Rf are independently
selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl,
acyl (e.g., alkoxyacyl, aminoacyl), aminocarbonyl, alkoxycarbonyl,
or silyl, preferably from hydrogen, acyl (e.g., alkoxyacyl,
aminoacyl), aminocarbonyl, and alkoxycarbonyl, most preferably
hydrogen; [0437] E is a branched alkoxy such as isopropoxy,
isobutoxyt, sec-butoxy, tert-butoxy, 3-methylbutoxy,
2,2-dimethylpropoxy, or 1,1,2-trimethylpropoxy, preferably
isopropoxy; [0438] Rh and Ri are independently selected from
hydrogen, alkyl, alkenyl, alkynyl, perfluoroalkyl, aryl or
heteroaryl, preferably hydrogen or alkyl, most preferably hydrogen;
[0439] R.sub.5 is selected from i-iv as follows: i)
CH.sub.2CH(R.sub.6)CH.sub.2, where R.sub.6 is hydrogen, alkyl,
alkenyl, alkynyl, perfluoroalkyl, aryl, heteroaryl, fluoro,
hydroxyl or alkoxy; ii) CH.sub.2C(R.sub.6R.sub.7)CH.sub.2, where
R.sub.6 and R.sub.7 are each independently alkyl, alkenyl, alkynyl,
perfluoroalkyl, aryl, or fluoro, or R.sub.6 and R.sub.7 are
connected together to form a carbocyclic or heterocyclic ring; iii)
CH.sub.2OCH.sub.2, CH.sub.2C(O)CH.sub.2, CH.sub.2, or
CH.sub.2CH.sub.2; or iv) R.sub.5 is a carbocyclic, heterocyclic,
aryl or heteroaryl ring, preferably (CH.sub.2).sub.3; and [0440]
R.sub.8 and R.sub.9 are independently selected from hydrogen,
alkyl, alkenyl, alkynyl, perfluoroalkyl, alkoxy, aryl or
heteroaryl, or R.sub.8 and R.sub.9 are connected together to form a
carbocyclic or heterocyclic ring, preferably from hydrogen and
alkyl, most preferably hydrogen.
[0441] For example, an active agent optionally excluded from such
compositions, when compositions of the present disclosure include
an active agent, may be a compound of formula Ia,
##STR00178##
and pharmaceutically acceptable salts thereof, wherein: [0442] Re
and Rf are independently selected from hydrogen, alkyl, alkenyl,
alkynyl, aryl, heteroaryl, acyl (e.g., alkoxyacyl, aminoacyl),
aminocarbonyl, alkoxycarbonyl, or silyl, preferably from hydrogen,
acyl (e.g., alkoxyacyl, aminoacyl), aminocarbonyl, and
alkoxycarbonyl, most preferably hydrogen; [0443] E is a branched
alkoxy such as isopropoxy, isobutoxyt, sec-butoxy, tert-butoxy,
3-methylbutoxy, 2,2-dimethylpropoxy, or 1,1,2-trimethylpropoxy,
preferably isopropoxy; [0444] Rh and Ri are independently selected
from hydrogen, alkyl, alkenyl, alkynyl, perfluoroalkyl, aryl or
heteroaryl, preferably hydrogen or alkyl, most preferably hydrogen;
[0445] R.sub.5 is selected from i-iv as follows: i)
CH.sub.2CH(R.sub.6)CH.sub.2, where R.sub.6 is hydrogen, alkyl,
alkenyl, alkynyl, perfluoroalkyl, aryl, heteroaryl, fluoro,
hydroxyl or alkoxy; ii) CH.sub.2C(R.sub.6R.sub.7)CH.sub.2, where
R.sub.6 and R.sub.7 are each independently alkyl, alkenyl, alkynyl,
perfluoroalkyl, aryl, or fluoro, or R.sub.6 and R.sub.7 are
connected together to form a carbocyclic or heterocyclic ring; iii)
CH.sub.2OCH.sub.2, CH.sub.2C(O)CH.sub.2, CH.sub.2, or
CH.sub.2CH.sub.2; or iv) R.sub.5 is a carbocyclic, heterocyclic,
aryl or heteroaryl ring, preferably (CH.sub.2).sub.3; and [0446]
R.sub.8 and R.sub.9 are independently selected from hydrogen,
alkyl, alkenyl, alkynyl, perfluoroalkyl, alkoxy, aryl or
heteroaryl, or R.sub.8 and R.sub.9 are connected together to form a
carbocyclic or heterocyclic ring, preferably from hydrogen and
alkyl, most preferably hydrogen.
[0447] In certain preferred embodiments of formula Ia, the
stereochemistry of the carbons bearing --ORf and --ORe are as shown
in formula Ia',
##STR00179##
[0448] In certain embodiments, a compound of formula I is
represented by formula II,
##STR00180##
and pharmaceutically acceptable salts thereof, wherein: the
stereochemistry of the carbon qq' to carbon rr' double bond is cis
or trans; the stereochemistry of the carbon ss' to carbon tt'
double bond is cis or trans; Re, Rf, R.sub.5, and E are as defined
above.
[0449] For example, an active agent optionally excluded from such
compositions, when compositions of the present disclosure include
an active agent, may be a compound of formula IIa,
##STR00181##
and pharmaceutically acceptable salts thereof, wherein: Re, Rf,
R.sub.5, and E are as defined above.
[0450] In certain embodiments, a compound of formula I or II is
represented by formula III,
##STR00182##
and pharmaceutically acceptable salts thereof, wherein: Re, Rf, and
E are as defined above.
[0451] In certain embodiments of Formulae I-III, when E represents
O--R, where R represents an alkyl group, preferably a lower alkyl
group, that is branched at the position bonded to the oxygen atom
is optionally excluded from such compositions. Exemplary such R
moieties include --CH(CH.sub.3).sub.2 (isopropyl),
--CH(CH.sub.2CH.sub.3).sub.2, --CH(CH.sub.3)(CH.sub.2CH.sub.3)
(sec-butyl), and --C(CH.sub.3).sub.3 (tert-butyl).
[0452] Exemplary compounds of formulae I, II, and III include
compound 1001
##STR00183##
and pharmaceutically acceptable salts thereof.
[0453] In some embodiments an active agent optionally excluded from
such compositions, when compositions of the present disclosure
include an active agent, may be a compound of formula IV,
##STR00184##
or a pharmaceutically acceptable salt thereof, wherein: [0454] X is
selected from --C.ident.C--, --C(R.sup.7).dbd.C(R.sup.7)--,
-(cyclopropyl)-, -(cyclobutyl)-, -(cyclopentyl)-, and
-(cyclohexyl)-; [0455] R.sup.1 is selected from --OR.sup.a,
--N(R.sup.a)--SO.sub.2--R.sup.c and --N(R.sup.a)(R.sup.b), wherein
each of R.sup.a and R.sup.b is independently selected from H,
C.sub.1-C.sub.6-alkyl, aryl, aralkyl, heteroaryl, and
heteroaralkyl, and R.sup.c is selected from C.sub.1-C.sub.6-alkyl,
aryl, aralkyl, heteroaryl, and heteroaralkyl; [0456] R.sup.2 is
selected from --CH.sub.2--, --C(O)--, --PO(OR)--, and tetrazole;
[0457] R is selected from hydrogen and alkyl; [0458] R.sup.3 is
selected from a carbocyclic ring, a heterocyclic ring,
--(CH.sub.2).sub.n--, CH.sub.2C(O)CH.sub.2, and
--CH.sub.2--O--CH.sub.2, wherein: [0459] n is an integer from 1 to
3; [0460] any hydrogen atom in R.sup.3 is optionally and
independently replaced by halo, (C.sub.1-C.sub.5)-alkyl,
perfluoroalkyl, aryl, heteroaryl, hydroxy, or
O--(C.sub.1-C.sub.5)-alkyl; and [0461] any two hydrogen atoms bound
to a common carbon atom in R.sup.3 are optionally taken together
with the carbon atom to which they are bound to form a carbocyclic
or heterocyclic ring; [0462] each of R.sup.4a and R.sup.4b is
independently selected from hydrogen, halo, --OH,
--O--(C.sub.1-C.sub.5)-alkyl, --O-aryl, O-heteroaryl,
--O--C(O)-aryl, --O--C(O)-heteroaryl,
--O--C(O)--O--(C.sub.1-C.sub.5)-alkyl, --O--C(O)--O-aryl,
--O--C(O)--O-heteroaryl, and --O--C(O)--N(R.sup.a)(R.sup.b),
wherein any alkyl, aryl or heteroaryl is optionally substituted
with up to 3 substituents independently selected from halo,
(C.sub.1-C.sub.5)-alkyl, O--(C.sub.1-C.sub.5)-alkyl, hydroxyl,
carboxyl, ester, alkoxycarbonyl, acyl, thioester, thioacyl,
thioether, amino, amido, acylamino, cyano, and nitro; [0463] each
of R.sup.5a and R.sup.5b is independently selected from hydrogen,
halo, (C.sub.1-C.sub.5)-alkyl, perfluoroalkyl, aryl, and
heteroaryl, preferably hydrogen, halo and (C.sub.1-C.sub.5)-alkyl;
[0464] R.sup.6 is selected from -phenyl, --(C.sub.1-C.sub.5)-alkyl,
--(C.sub.3-C.sub.7)-cycloalkyl,
--C.ident.C--(C.sub.3-C.sub.7)-cycloalkyl,
--C.ident.C--(C.sub.1-C.sub.5)-alkyl, and --O-phenyl, wherein
phenyl is optionally substituted with up to 3 substituents
independently selected from halo, (C.sub.1-C.sub.5)-alkyl,
O--(C.sub.1-C.sub.5)-alkyl, hydroxyl, carboxyl, ester,
alkoxycarbonyl, acyl, thioester, thioacyl, thioether, amino, amido,
acylamino, cyano, and nitro, [0465] and R.sup.6 is additionally
selected from --C.ident.CH when: [0466] a) X is
--C(R.sup.7).dbd.C(R.sup.7)-- or -(cyclopropyl)-; or [0467] b) each
of R.sup.4a and R.sup.5b is hydrogen or halo; or [0468] c) each of
R.sup.5a and R.sup.5b is halo; or [0469] d) R.sup.2 is
--CH.sub.2--; [0470] each R.sup.7 is independently selected from
hydrogen and (C.sub.1-C.sub.5)-alkyl, or two occurrences of R.sup.7
may optionally be taken together with the carbons to which they are
attached to form a 5- or 6-membered ring; [0471] each of R.sup.10a
and R.sup.10b is independently selected from hydrogen,
(C.sub.1-C.sub.5)-alkyl, perfluoroalkyl,
O--(C.sub.1-C.sub.5)-alkyl, aryl and heteroaryl, or [0472]
R.sup.10a and R.sup.10b are taken together with the carbon atom to
which they are bound to form a carbocyclic or heterocyclic ring;
[0473] and each double bond is independently in an E- or a
Z-configuration.
[0474] In certain embodiments, when R.sup.1 is --OM, M is a cation
selected from ammonium, tetra-alkyl ammonium, Na, K, Mg, and Zn, is
optionally excluded from such compositions.
[0475] In certain embodiments, R.sup.2 and R.sup.1 together are
##STR00185##
[0476] In certain embodiments, X is --C.ident.C--. In certain
embodiments, X is --C(R.sup.7).dbd.C(R.sup.7)--, -(cyclopropyl)-,
-(cyclobutyl)-, -(cyclopentyl)-, or -(cyclohexyl)-. In certain
embodiments, X is --C(R.sup.7).dbd.C(R.sup.7)--. In certain
embodiments, X is -(cyclopropyl)-, -(cyclobutyl)-, -(cyclopentyl)-,
or -(cyclohexyl)-. In certain embodiments, X is -(cyclopropyl)-. In
certain embodiments, X is --C.ident.C-- or
--C(R.sup.7).dbd.C(R.sup.7)--. In certain embodiments wherein X is
-(cyclopropyl)-, -(cyclobutyl)-, -(cyclopentyl)-, or
-(cyclohexyl)-, the olefin and the carbon bearing R.sup.4a are
attached to adjacent carbons on the -(cyclopropyl)-,
-(cyclobutyl)-, -(cyclopentyl)-, or -(cyclohexyl)- ring system.
[0477] In certain embodiments, R.sup.4b is hydrogen. In certain
embodiments, R.sup.4b is halo, --OH, --O--(C.sub.1-C.sub.5)-alkyl,
--O-aryl, O-heteroaryl, --O--C(O)--(C.sub.1-C.sub.5)-alkyl,
--O--C(O)-aryl, --O--C(O)-heteroaryl,
--O--C(O)--O--(C.sub.1-C.sub.5)-alkyl, --O--C(O)--O-aryl,
--O--C(O)--O-heteroaryl, or --O--C(O)--N(R.sup.a)(R.sup.b), wherein
any alkyl, aryl or heteroaryl is optionally substituted with up to
3 substituents independently selected from halo,
(C.sub.1-C.sub.5)-alkyl, O--(C.sub.1-C.sub.5)-alkyl, hydroxyl,
carboxyl, ester, alkoxycarbonyl, acyl, thioester, thioacyl,
thioether, amino, amido, acylamino, cyano, and nitro. In certain
embodiments, R.sup.4b is fluoro. In certain embodiments, R.sup.4b
is hydrogen, --OH, --O--(C.sub.1-C.sub.5)-alkyl, --O-aryl,
O-heteroaryl, --O--C(O)--(C.sub.1-C.sub.5)-alkyl, --O--C(O)-aryl,
--O--C(O)-heteroaryl, --O--C(O)--O--(C.sub.1-C.sub.5)-alkyl,
--O--C(O)--O-aryl, --O--C(O)--O-heteroaryl, or
--O--C(O)--N(R.sup.a)(R.sup.b), wherein any alkyl, aryl or
heteroaryl is optionally substituted with up to 3 substituents
independently selected from halo, (C.sub.1-C.sub.5)-alkyl,
O--(C.sub.1-C.sub.5)-alkyl, hydroxyl, carboxyl, ester,
alkoxycarbonyl, acyl, thioester, thioacyl, thioether, amino, amido,
acylamino, cyano, and nitro. In certain embodiments, Rob is
selected from --OH, --O--(C.sub.1-C.sub.5)-alkyl, O-aryl,
O-heteroaryl, --O--C(O)--(C.sub.1-C.sub.5)-alkyl, O--C(O)-aryl,
O--C(O)-heteroaryl, and --O--C(O)--N(R.sup.a)(R.sup.b). In certain
embodiments, R.sup.4b is hydrogen, halo,
--O--C(O)--O--(C.sub.1-C.sub.5)-alkyl, --O--C(O)--O-aryl, or
--O--C(O)--O-heteroaryl, wherein any alkyl, aryl or heteroaryl is
optionally substituted with up to 3 substituents independently
selected from halo, (C.sub.1-C.sub.5)-alkyl,
O--(C.sub.1-C.sub.5)-alkyl, hydroxyl, carboxyl, ester,
alkoxycarbonyl, acyl, thioester, thioacyl, thioether, amino, amido,
acylamino, cyano, and nitro. In certain embodiments, R.sup.4b is
selected from hydrogen, halo, --OH, or
--O--(C.sub.1-C.sub.5)-alkyl. In certain embodiments, R.sup.4b is
--O-aryl, O-heteroaryl, --O--C(O)--(C.sub.1-C.sub.5)-alkyl,
--O--C(O)-aryl, --O--C(O)-heteroaryl,
--O--C(O)--O--(C.sub.1-C.sub.5)-alkyl, --O--C(O)--O-aryl,
--O--C(O)--O-heteroaryl, or --O--C(O)--N(R.sup.a)(R.sup.b), wherein
any alkyl, aryl or heteroaryl is optionally substituted with up to
3 substituents independently selected from halo,
(C.sub.1-C.sub.5)-alkyl, O--(C.sub.1-C.sub.5)-alkyl, hydroxyl,
carboxyl, ester, alkoxycarbonyl, acyl, thioester, thioacyl,
thioether, amino, amido, acylamino, cyano, and nitro. In certain
embodiments, R.sup.4b is selected from --OH,
--O--(C.sub.1-C.sub.5)-alkyl, --O-aryl, O-heteroaryl,
--O--C(O)--(C.sub.1-C.sub.5)-alkyl, --O--C(O)-aryl,
--O--C(O)-heteroaryl, --O--C(O)--O--(C.sub.1-C.sub.5)-alkyl,
--O--C(O)--O-aryl, --O--C(O)--O-heteroaryl, and
--O--C(O)--N(R.sup.a)(R.sup.b), wherein any alkyl, aryl or
heteroaryl is optionally substituted with up to 3 substituents
independently selected from halo, (C.sub.1-C.sub.5)-alkyl,
O--(C.sub.1-C.sub.5)-alkyl, hydroxyl, carboxyl, ester,
alkoxycarbonyl, acyl, thioester, thioacyl, thioether, amino, amido,
acylamino, cyano, and nitro. In certain embodiments, R.sup.4b is
selected from hydrogen or halo.
[0478] In certain embodiments, R.sup.4b is in an (R) configuration.
In certain embodiments, R.sup.4b is in an (S) configuration.
[0479] In certain embodiments, R.sup.4a is hydrogen. In certain
embodiments, R.sup.4a is halo, --OH, --O--(C.sub.1-C.sub.5)-alkyl,
--O-aryl, O-heteroaryl, --O--C(O)--(C.sub.1-C.sub.5)-alkyl,
--O--C(O)-aryl, --O--C(O)-heteroaryl,
--O--C(O)--O--(C.sub.1-C.sub.5)-alkyl, --O--C(O)--O-aryl,
--O--C(O)--O-heteroaryl, or --O--C(O)--N(R.sup.a)(R.sup.b), wherein
any alkyl, aryl or heteroaryl is optionally substituted with up to
3 substituents independently selected from halo,
(C.sub.1-C.sub.5)-alkyl, O--(C.sub.1-C.sub.5)-alkyl, hydroxyl,
carboxyl, ester, alkoxycarbonyl, acyl, thioester, thioacyl,
thioether, amino, amido, acylamino, cyano, and nitro. In certain
embodiments, R.sup.4a is fluoro. In certain embodiments, R.sup.4a
is hydrogen, --OH, --O--(C.sub.1-C.sub.5)-alkyl, --O-aryl,
O-heteroaryl, --O--C(O)--(C.sub.1-C.sub.5)-alkyl, --O--C(O)-aryl,
--O--C(O)-heteroaryl, --O--C(O)--O--(C.sub.1-C.sub.5)-alkyl,
--O--C(O)--O-aryl, --O--C(O)--O-heteroaryl, or
--O--C(O)--N(R.sup.a)(R.sup.b), wherein any alkyl, aryl or
heteroaryl is optionally substituted with up to 3 substituents
independently selected from halo, (C.sub.1-C.sub.5)-alkyl,
O--(C.sub.1-C.sub.5)-alkyl, hydroxyl, carboxyl, ester,
alkoxycarbonyl, acyl, thioester, thioacyl, thioether, amino, amido,
acylamino, cyano, and nitro. In certain embodiments, R.sup.4a is
selected from --OH, --O--(C.sub.1-C.sub.5)-alkyl, O-aryl,
O-heteroaryl, --O--C(O)--(C.sub.1-C.sub.5)-alkyl, O--C(O)-aryl,
O--C(O)-heteroaryl, and --O--C(O)--N(R.sup.a)(R.sup.b). In certain
embodiments, R.sup.4a is hydrogen, halo,
--O--C(O)--O--(C.sub.1-C.sub.5)-alkyl, --O--C(O)--O-aryl, or
--O--C(O)--O-heteroaryl, wherein any alkyl, aryl or heteroaryl is
optionally substituted with up to 3 substituents independently
selected from halo, (C.sub.1-C.sub.5)-alkyl,
O--(C.sub.1-C.sub.5)-alkyl, hydroxyl, carboxyl, ester,
alkoxycarbonyl, acyl, thioester, thioacyl, thioether, amino, amido,
acylamino, cyano, and nitro. In certain embodiments, R.sup.4a is
selected from hydrogen, halo, --OH, or
--O--(C.sub.1-C.sub.5)-alkyl. In certain embodiments, R.sup.4a is
--O-aryl, O-heteroaryl, --O--C(O)--(C.sub.1-C.sub.5)-alkyl,
--O--C(O)-aryl, --O--C(O)-heteroaryl,
--O--C(O)--O--(C.sub.1-C.sub.5)-alkyl, --O--C(O)--O-aryl,
--O--C(O)--O-heteroaryl, or --O--C(O)--N(R.sup.a)(R.sup.b), wherein
any alkyl, aryl or heteroaryl is optionally substituted with up to
3 substituents independently selected from halo,
(C.sub.1-C.sub.5)-alkyl, O--(C.sub.1-C.sub.5)-alkyl, hydroxyl,
carboxyl, ester, alkoxycarbonyl, acyl, thioester, thioacyl,
thioether, amino, amido, acylamino, cyano, and nitro. In certain
embodiments, R.sup.4a is selected from --OH,
--O--(C.sub.1-C.sub.5)-alkyl, --O-aryl, O-heteroaryl,
--O--C(O)--(C.sub.1-C.sub.5)-alkyl, --O--C(O)-aryl,
--O--C(O)-heteroaryl, --O--C(O)--O--(C.sub.1-C.sub.5)-alkyl,
--O--C(O)--O-aryl, --O--C(O)--O-heteroaryl, and
--O--C(O)--N(R.sup.a)(R.sup.b), wherein any alkyl, aryl or
heteroaryl is optionally substituted with up to 3 substituents
independently selected from halo, (C.sub.1-C.sub.5)-alkyl,
O--(C.sub.1-C.sub.5)-alkyl, hydroxyl, carboxyl, ester,
alkoxycarbonyl, acyl, thioester, thioacyl, thioether, amino, amido,
acylamino, cyano, and nitro. In certain embodiments, R.sup.4a is
selected from hydrogen or halo.
[0480] In certain embodiments, R.sup.4a is in an (S) configuration.
In certain embodiments, R.sup.4a is in an (R) configuration.
[0481] In certain embodiments wherein R.sup.4a is --OH, R.sup.5a is
selected from hydrogen or (C.sub.1-C.sub.5)-alkyl. In certain
embodiments wherein R.sup.4a is selected from --OH,
--O--(C.sub.1-C.sub.5)-alkyl, --O-aryl, O-heteroaryl,
--O--C(O)--(C.sub.1-C.sub.5)-alkyl, --O--C(O)-aryl,
--O--C(O)-heteroaryl, --O--C(O)--O--(C.sub.1-C.sub.5)-alkyl,
--O--C(O)--O-aryl, --O--C(O)--O-heteroaryl, and
--O--C(O)--N(R.sup.a)(R.sup.b), R.sup.5a is selected from hydrogen
or (C.sub.1-C.sub.5)-alkyl. In certain embodiments, R.sup.5a is
fluoro. In certain embodiments, R.sup.5a is selected from hydrogen
and (C.sub.1-C.sub.5)-alkyl.
[0482] In certain embodiments wherein R.sup.4b is --OH, R.sup.5b is
selected from hydrogen or (C.sub.1-C.sub.5)-alkyl. In certain
embodiments wherein R.sup.4b is selected from --OH,
--O--(C.sub.1-C.sub.5)-alkyl, --O-aryl, O-heteroaryl,
--O--C(O)--(C.sub.1-C.sub.5)-alkyl, --O--C(O)-aryl,
--O--C(O)-heteroaryl, --O--C(O)--O--(C.sub.1-C.sub.5)-alkyl,
--O--C(O)--O-aryl, --O--C(O)--O-heteroaryl, and
--O--C(O)--N(R.sup.a)(R.sup.b), R.sup.5b is selected from hydrogen
or (C.sub.1-C.sub.5)-alkyl. In certain embodiments, R.sup.5b is
fluoro. In certain embodiments, R.sup.5b is selected from hydrogen
and (C.sub.1-C.sub.5)-alkyl.
[0483] In certain embodiments, R.sup.2 is --CH.sub.2--. In certain
embodiments, R.sup.2 is --C(O)--.
[0484] In certain embodiments, R.sup.a is selected from H and
C.sub.1-C.sub.6-alkyl. In certain embodiments, R.sup.a is selected
from aryl, aralkyl, heteroaryl, and heteroaralkyl.
[0485] In certain embodiments, R.sup.b is selected from H and
C.sub.1-C.sub.6-alkyl. In certain embodiments, R.sup.b is selected
from aryl, aralkyl, heteroaryl, and heteroaralkyl.
[0486] In certain embodiments, R.sup.c is C.sub.1-C.sub.6-alkyl,
aryl, or heteroaryl. In certain embodiments, R.sup.c is selected
from aryl, aralkyl, heteroaryl, and heteroaralkyl.
[0487] In certain embodiments wherein R.sup.3 is selected from a
carbocyclic ring, a heterocyclic ring, --(CH.sub.2).sub.n--, and
CH.sub.2C(O)CH.sub.2, any hydrogen atom in R.sup.3 is optionally
and independently replaced by halo, (C.sub.1-C.sub.5)-alkyl,
perfluoroalkyl, aryl, heteroaryl, hydroxy, or
O--(C.sub.1-C.sub.5)-alkyl. In certain embodiments wherein R.sup.3
is --CH.sub.2--O--CH.sub.2, any hydrogen atom in R.sup.3 is
optionally and independently replaced by halo,
(C.sub.1-C.sub.5)-alkyl, perfluoroalkyl, aryl, heteroaryl, or
O--(C.sub.1-C.sub.5)-alkyl. In certain embodiments, R.sup.3 is
selected from --(CH.sub.2).sub.n-- and --CH.sub.2--O--CH.sub.2,
wherein n is an integer from 1 to 3, and up to two hydrogen atoms
in R.sup.3 are optionally and independently replaced by
(C.sub.1-C.sub.5)-alkyl. In certain embodiments, R.sup.3 is
selected from a carbocyclic ring, a heterocyclic ring, and
CH.sub.2C(O)CH.sub.2, wherein n is an integer from 1 to 3; any
hydrogen atom in R.sup.3 is optionally and independently replaced
by halo, (C.sub.1-C.sub.5)-alkyl, perfluoroalkyl, aryl, heteroaryl,
hydroxy, or O--(C.sub.1-C.sub.5)-alkyl; and any two hydrogen atoms
bound to a common carbon atom in R.sup.3 are optionally taken
together with the carbon atom to which they are bound to form a
carbocyclic or heterocyclic ring.
[0488] In certain embodiments, R.sup.10a is hydrogen. In certain
embodiments, R.sup.10a is selected from (C.sub.1-C.sub.5)-alkyl,
perfluoroalkyl, O--(C.sub.1-C.sub.5)-alkyl, aryl and heteroaryl, or
R.sup.10a is taken together with R.sup.10b and the carbon atom to
which they are bound to form a carbocyclic or heterocyclic
ring.
[0489] In certain embodiments, R.sup.10b is hydrogen. In certain
embodiments, R.sup.10b is selected from (C.sub.1-C.sub.5)-alkyl,
perfluoroalkyl, O--(C.sub.1-C.sub.5)-alkyl, aryl and heteroaryl, or
R.sup.10b is taken together with R.sup.10a and the carbon atom to
which they are bound to form a carbocyclic or heterocyclic
ring.
[0490] In certain embodiments, R.sup.1 is --OR.sup.a. In certain
embodiments, R.sup.1 is selected from
--N(R.sup.a)--SO.sub.2--R.sup.c and --N(R.sup.a)(R.sup.b). In
certain embodiments, R.sup.1 is --N(R.sup.a)--SO.sub.2--R.sup.c. In
certain embodiments, R.sup.1 is selected from --OR.sup.a and
--N(R.sup.a)(R.sup.b). In certain embodiments, R.sup.1 is
--N(R.sup.a)(R.sup.b). In certain embodiments, R.sup.1 is selected
from --OR.sup.a, and --N(R.sup.a)--SO.sub.2--R.sup.c.
[0491] In certain embodiments, R.sup.7 is hydrogen. In certain
embodiments, R.sup.7 is (C.sub.1-C.sub.5)-alkyl or two occurrences
of R.sup.7 may optionally be taken together with the carbons to
which they are attached to form a 5- or 6-membered ring.
[0492] In certain embodiments, X is --C.ident.C-- and R.sup.4b is
hydrogen.
[0493] In certain embodiments, X is --C.ident.C-- and R.sup.4a is
hydrogen.
[0494] In certain embodiments, X is --C.ident.C--, R.sup.4a is
fluoro, and R.sup.5a is fluoro.
[0495] In certain embodiments, X is --C.ident.C--, R.sup.4b is
fluoro, and R.sup.5b is fluoro.
[0496] In certain embodiments, X is --C.ident.C--, and each of
R.sup.4a and R.sup.4b is independently selected from --OH,
--O--(C.sub.1-C.sub.5)-alkyl, O-aryl, O-heteroaryl,
--O--C(O)--(C.sub.1-C.sub.5)-alkyl, O--C(O)-aryl,
O--C(O)-heteroaryl, and --O--C(O)--N(R.sup.a)(R.sup.b).
[0497] In certain embodiments, X is --C.ident.C-- and R.sup.2 is
--CH.sub.2--.
[0498] In certain embodiments, X is -(cyclopropyl)-,
-(cyclobutyl)-, -(cyclopentyl)-, and -(cyclohexyl)-. In certain
embodiments, X is -(cyclopropyl)-.
[0499] In certain embodiments, X is
--C(R.sup.7).dbd.C(R.sup.7)--.
[0500] In certain embodiments, each of R.sup.a and R.sup.b is
independently selected from H and C.sub.1-C.sub.6-alkyl; R.sup.c is
C.sub.1-C.sub.6-alkyl; R.sup.3 is selected from
--(CH.sub.2).sub.n-- and --CH.sub.2--O--CH.sub.2, wherein n is an
integer from 1 to 3, and up to two hydrogen atoms in R.sup.3 are
optionally and independently replaced by (C.sub.1-C.sub.5)-alkyl;
each of R.sup.4a and R.sup.4b is independently selected from
hydrogen, halo, --OH, --O--(C.sub.1-C.sub.5)-alkyl; and each of
R.sup.10a and R.sup.10b is hydrogen.
[0501] In certain embodiments, each double bond is in an
E-configuration. In certain embodiments, each double bond is in a
Z-configuration. In certain embodiments, one double bond is in an
E-configuration and one double bond is in a Z-configuration.
[0502] In certain embodiments, any combination of the foregoing is
contemplated herein. Those skilled in the art will recognize that
all specific combinations of the individual possible residues of
the variable regions of the compounds as disclosed herein, e.g.,
R.sup.1, R.sup.2, R.sup.3, R.sup.4a, R.sup.4b, R.sup.5a, R.sup.5b,
R.sup.6, R.sup.7, R.sup.10a, R.sup.10b, R.sup.a, R.sup.b, R.sup.c,
n and X, are within the scope of the present disclosure. As an
example, any of the various particular recited embodiments for
R.sup.4a may be combined with any of the various particular recited
embodiments of X.
[0503] In certain embodiments, the compound optionally excluded
from such compositions is selected from any one of:
##STR00186## ##STR00187## ##STR00188## ##STR00189## ##STR00190##
##STR00191## ##STR00192##
[0504] In some embodiments an active agent is optionally excluded
from such compositions, when compositions of the present disclosure
include an active agent, may be a compound of the formula V,
##STR00193##
or formula VI,
##STR00194##
or a pharmaceutically acceptable salt of either of the foregoing,
wherein: [0505] R.sup.1 is selected from --OR.sup.a,
--N(R.sup.a)--SO.sub.2--R.sup.c and --N(R.sup.a)(R.sup.b), wherein
each of R.sup.a and R.sup.b is independently selected from H,
C.sub.1-C.sub.6-alkyl, aryl, aralkyl, heteroaryl, and
heteroaralkyl, and R.sup.c is selected from C.sub.1-C.sub.6-alkyl,
aryl, aralkyl, heteroaryl, and heteroaralkyl; [0506] R.sup.2 is
selected from --C(O)--, --SO.sub.2--, --PO(OR)--, and tetrazole;
[0507] R is selected from hydrogen and alkyl; [0508] R.sup.3 is
selected from --(CH.sub.2).sub.n-- and --CH.sub.2--O--CH.sub.2,
wherein n is an integer from 1 to 3; and optionally up to two
hydrogen atoms in R.sup.3 are independently replaced by halo,
(C.sub.1-C.sub.5)-alkyl, or O--(C.sub.1-C.sub.5)-alkyl; [0509] each
of R.sup.5a and R.sup.5b is independently selected from hydrogen,
(C.sub.1-C.sub.5)-alkyl, perfluoroalkyl, aryl, and heteroaryl,
preferably hydrogen and (C.sub.1-C.sub.5)-alkyl; [0510] R.sup.6 is
selected from --C.ident.CH, -phenyl, --(C.sub.1-C.sub.5)-alkyl,
--(C.sub.3-C.sub.7)-cycloalkyl, --C.ident.C-phenyl,
--C.ident.C--(C.sub.3-C.sub.7)-cycloalkyl,
--C.ident.C--(C.sub.1-C.sub.5)-alkyl, and --O-phenyl, wherein
phenyl is optionally substituted with up to 3 substituents
independently selected from halo, (C.sub.1-C.sub.5)-alkyl,
O--(C.sub.1-C.sub.5)-alkyl, hydroxyl, carboxyl, ester,
alkoxycarbonyl, acyl, thioester, thioacyl, thioether, amino, amido,
acylamino, cyano, and nitro; [0511] each of R.sup.8 and R.sup.9 are
independently selected from hydrogen, --(C.sub.1-C.sub.5)-alkyl,
-aryl, -heteroaryl, --C(O)--(C.sub.1-C.sub.5)-alkyl, --C(O)-aryl,
--C(O)-heteroaryl, --C(O)--O--(C.sub.1-C.sub.5)-alkyl,
--C(O)--O-aryl, --C(O)--O-heteroaryl, and
--C(O)--N(R.sup.a)(R.sup.b), wherein any alkyl, aryl or heteroaryl
is optionally substituted with up to 3 substituents independently
selected from halo, (C.sub.1-C.sub.5)-alkyl,
O--(C.sub.1-C.sub.5)-alkyl, hydroxyl, carboxyl, ester,
alkoxycarbonyl, acyl, thioester, thioacyl, thioether, amino, amido,
acylamino, cyano, and nitro; [0512] each of R.sup.10a and R.sup.10b
is independently selected from hydrogen, (C.sub.1-C.sub.5)-alkyl,
perfluoroalkyl, O--(C.sub.1-C.sub.5)-alkyl, aryl and heteroaryl, or
[0513] R.sup.10a and R.sup.10b are taken together with the carbon
atom to which they are bound to form a carbocyclic or heterocyclic
ring; and [0514] wherein each double bond is independently in an E-
or a Z-configuration.
[0515] In certain embodiments, when R.sup.1 is --OM, and M is a
cation selected from ammonium, tetra-alkyl ammonium, Na, K, Mg, and
Zn is optionally excluded from such compositions.
[0516] In certain embodiments, R.sup.2 and R.sup.1 together are
##STR00195##
[0517] In certain embodiments, R.sup.2 is --C(O)--. In certain
embodiments, R.sup.1 is +OR.sup.a, wherein R.sup.a is hydrogen or
C.sub.1-C.sub.6-alkyl. In certain embodiments, R.sup.3 is
--(CH.sub.2).sub.n--, wherein n is 3. In certain embodiments,
R.sup.6 is --C.ident.CH. In certain embodiments, R.sup.5a is
hydrogen. In certain embodiments, R.sup.5b is hydrogen. In certain
embodiments, R.sup.10a is hydrogen. In certain embodiments,
R.sup.10b is hydrogen. In certain embodiments, R.sup.2 is --C(O)--,
R.sup.1 is +OR.sup.a, wherein R.sup.a is C.sub.1-C.sub.6-alkyl,
R.sup.3 is --(CH.sub.2).sub.n--, wherein n is 3, R.sup.6 is
--C.ident.CH, R.sup.5a is hydrogen, R.sup.5b is hydrogen, R.sup.10a
is hydrogen, and R.sup.10b is hydrogen.
[0518] In certain embodiments, the compound is selected from any
one of is optionally excluded from such compositions:
##STR00196##
[0519] In some embodiments an active agent optionally excluded from
such compositions, when compositions of the present disclosure
include an active agent, may be a compound of formula VII,
##STR00197##
and pharmaceutically acceptable salts thereof, wherein: [0520] Re
and Rf are independently selected from hydrogen, alkyl, alkenyl,
alkynyl, aryl, heteroaryl, acyl (e.g., alkoxyacyl, aminoacyl),
aminocarbonyl, alkoxycarbonyl, or silyl; [0521] E is a hydroxyl,
alkoxy, aryloxy, amino, alkylamino, dialkylamino, or arylamino;
[0522] Rh and Ri are independently selected from hydrogen, alkyl,
alkenyl, alkynyl, perfluoroalkyl, aryl or heteroaryl; [0523]
R.sub.5 is selected from i-iv as follows: i)
CH.sub.2CH(R.sub.6)CH.sub.2, where R.sub.6 is hydrogen, alkyl,
alkenyl, alkynyl, perfluoroalkyl, aryl, heteroaryl, fluoro,
hydroxyl or alkoxy; ii) CH.sub.2C(R.sub.6R.sub.7)CH.sub.2, where
R.sub.6 and R.sub.7 are each independently alkyl, alkenyl, alkynyl,
perfluoroalkyl, aryl, or fluoro, or R.sub.6 and R.sub.7 are
connected together to form a carbocyclic or heterocyclic ring; iii)
CH.sub.2OCH.sub.2, CH.sub.2C(O)CH.sub.2, or CH.sub.2CH.sub.2; or
iv) R.sub.5 is a carbocyclic, heterocyclic, aryl or heteroaryl
ring; and [0524] R.sub.8 and R.sub.9 are independently selected
from hydrogen, alkyl, alkenyl, alkynyl, perfluoroalkyl, alkoxy,
aryl or heteroaryl, or R.sub.8 and R.sub.9 are connected together
to form a carbocyclic or heterocyclic ring.
[0525] In certain embodiments, a compound of formula VII is
represented by formula VIII,
##STR00198##
and pharmaceutically acceptable salts thereof, wherein: Re, Rf,
R.sub.5, and E are as defined above.
[0526] In certain embodiments, a compound of formula VII or VIII is
represented by formula IX,
##STR00199##
and pharmaceutically acceptable salts thereof, wherein: Re, Rf, and
E are as defined above.
Ocular Diseases
[0527] In various aspects and embodiments the formulations as
disclosed herein may be used to treat or prevent an ocular disease
or disorder. Ocular diseases and disorders contemplated herein
include anterior segment diseases and posterior segment diseases.
Exemplary ocular diseases that may in certain embodiments be
treated with formulations as disclosed herein include the
following.
[0528] Dry eye syndrome (DES, Chronic dry eye, Keratitis sicca;
Xerophthalmia; Keratoconjunctivitis sicca) can be defined as a
condition that includes a variety of disorders that result in a
loss of, or altered composition of, the natural tear film, which
maintains the surface of the eye. Without this tear film, vision is
impaired and patients may suffer severe ocular discomfort. DES can
be caused by excessive tear evaporation or by a reduction of tear
production in the lacrimal gland, which is the site of tear
production. Though the exact causes of this condition are unknown,
there is evidence supporting the link between reduced tear
production and inflammation of one or more components of the
lacrimal apparatus. Currently available medications for DES are
leaving substantial room for more effective and better tolerated
products.
[0529] DES may also be a manifestation of Sjogren's syndrome which
is an autoimmune disorder in which the glands that produce tears
and saliva are destroyed. This leads to dry mouth, decreased
tearing, and other dry mucous membranes.
[0530] Noninfectious uveitis is a chronic inflammatory, putative
Th1/Th17-mediated autoimmune disease associated with substantial
visual morbidity and is potentially blinding. Blindness from
uveitis usually does not occur from a single inflammatory episode;
rather, cumulative damage results from recurrent episodes of
inflammation. The inflammatory sequalae resulting in vision loss
may include one or more of cystoid macular edema, cataracts,
vitreous debris, glaucoma, macular pathology (scarring and
atrophy), optic neuropathy, and retinal detachment.
[0531] Anterior uveitis (iritis) occurs in the front of the eye and
is the most common form of uveitis. Par planitis is an inflammation
of the pars plana, a narrow area between the iris and the choroid.
This condition occurs more frequently in young men, but is usually
not associated with another disease. Posterior uveitis
(chondroitis) affects primarily the choroid; the back portion of
the uveal tract. If the retina is also involved, it is called
chorioretinitis. Posterior uveitis may occur in association with an
autoimmune disease, or follow a systemic infection. In posterior
uveitis, inflammation can last from months to years and may cause
permanent vision damage, even with treatment.
[0532] Uveitis can cause vision impairment, ocular pain, and loss
of vision. It is estimated that about 10% of new cases of blindness
in the U.S. are caused by uveitis. Approximately 300,000 people
suffer from uveitis in the U.S. alone, the majority of whom are
affected by anterior uveitis. The only therapeutic class approved
by the FDA for treatment of uveitis is corticosteroids, which are
noted for multiple side effects, such as hypertension,
hyperglycemia, and hypercholesterolemia, and in the eye, glaucoma
and cataract formation.
[0533] Conjunctivitis (pink eye) describes a group of diseases that
cause swelling, itching, burning, and redness of the conjunctiva,
the protective membrane that lines the eyelids and covers exposed
areas of the sclera, or white of the eye.
[0534] Keratitis is an inflammation of the cornea (clear portion in
the front of the eye). Keratitis can be caused by an infection
(bacterial, fungal, viral, parasite, etc.) or a non-infectious
agent (e.g., certain types of auto-immune diseases are associated
with a variety of non-infectious keratitises).
[0535] Keratoconjunctivitis refers to an inflammation of the cornea
and conjunctiva.
[0536] Vernal keratoconjunctivitis (VKC) is a recurrent ocular
inflammatory disease characterized by hard, elevated, cobblestone
like bumps on the upper eyelid. There may also be swellings and
thickening of the conjunctiva. The conjunctiva is the outermost
membrane which lines the eyelids as well as the exposed parts of
the eye, except for the cornea.
[0537] Atopic keratoconjunctivitis is the result of a condition
called atopy. Atopy is a genetic condition whereby the immune
system produces higher than normal antibodies in response to a
given allergen.
[0538] Systemic immune mediated diseases such as cicatrizing
conjunctivitis and other autoimmune disorders of the ocular surface
represent a clinically heterogeneous group of conditions where
acute and chronic autoreactive mechanisms can cause significant
damage to the eye. When severe and affecting the epithelium and
substantia propria of the conjunctiva, cicatrization can ensue,
leading to significant mechanical alterations as a result of the
fibrosis. These conditions, though generally infrequent, can be the
cause of profound pathology and visual disability.
[0539] Blepharitis is a common condition that causes inflammation
of the eyelids.
[0540] Scleritis is a serious inflammatory disease that affects the
white outer coating of the eye, known as the sclera.
[0541] Age-related macular degeneration (AMD) is a disease
associated with aging that gradually destroys sharp, central
vision. AMD affects the macula, which is located at the center of
the retina. AMD occurs in two forms: wet and dry. Wet AMD occurs
when abnormal blood vessels behind the retina start to grow under
the macula. These new blood vessels tend to be very fragile and
often leak blood and fluid. The blood and fluid raise the macula
from its normal place at the back of the eye. Damage to the macula
occurs rapidly. Dry AMD occurs when the light-sensitive cells in
the macula slowly break down, gradually blurring central vision in
the affected eye.
[0542] Diabetes can affect the eye in a number of ways. Diabetic
retinopathy (DR) is a complication of diabetes that results from
damage to the blood vessels of the light-sensitive tissue at the
back of the eye (the retina). At first, diabetic retinopathy may
cause no symptoms or only mild vision problems. Eventually,
however, diabetic retinopathy can result in blindness. Diabetic
macular edema (DME) is the swelling of the retina in diabetes
mellitus due to leaking of fluid from blood vessels within the
macula.
[0543] Ocular neovascularization is the abnormal or excessive
formation of blood vessels in the eye. Ocular neovascularization
has been shown in diabetic retinopathy and age-related macular
degeneration (AMD).
[0544] Proliferative vitreoretinopathy (PVR) is scar tissue
formation within the eye. "Proliferative" because cells proliferate
and "vitreoretinopathy" because the problems involve the vitreous
and retina. In PVR scar tissue forms in sheets on the retina which
contract. This marked contraction pulls the retina toward the
center of the eye and detaches and distorts the retina severely.
PVR can occur both posteriorly and anteriorly with folding of the
retina both anteriorly and circumferentially.
[0545] The cytomegalovirus (CMV) is related to the herpes virus and
is present in almost everyone. When a person's immune system is
suppressed because of disease (HIV), organ or bone marrow
transplant, or chemotherapy, the CMV virus can cause damage and
disease to the eye and the rest of the body. CMV affects the eye in
about 30% of the cases by causing damage to the retina. This is
called CMV retinitis.
[0546] Optic neuritis occurs when the optic nerve becomes inflamed
and the myelin sheath becomes damaged or is destroyed. Nerve damage
that occurs in the section of the optic nerve located behind the
eye, is called retrobulbar neuritis, which is another term
sometimes used for optic neuritis.
[0547] Also known as macular pucker, epiretinal membrane is a
scar-tissue like membrane that forms over the macula. It typically
progresses slowly and affects central vision by causing blurring
and distortion. As it progresses, the pulling of the membrane on
the macula may cause swelling.
[0548] In an embodiment, the compositions can be used for
preventing transplant rejection of, for example, corneal allografts
following transplantation. It is well known that in inflammation
T-lymphocytes play a critical role in mediating rejection of
foreign tissues. Prevention of rejection is of paramount importance
in maintaining the health of transplanted corneas. Rejection may
occur in any of the layers comprising the cornea, for example, the
corneal epithelium, the corneal stroma or the corneal endothelium.
The functioning of the cornea can be compromised following
endothelial rejection. The endothelial layer serves to maintain the
cornea in a compact state, acting as a pump by removing water from
the corneal stroma. If the function of the endothelial layer is
compromised, disorientation of collagen fibers can ensue, and
transparency of the cornea can be lost. Human endothelial cells are
non-replicative, and as a consequence, donor cell loss in the
setting of rejection is irreversible and may lead to diminished
graft function and survival. Thus, the goal of either prevention or
treatment of rejection in corneal transplant recipients is to
minimize endothelial cell loss. The compositions of the present
disclosure can be used for the prevention of rejection following
corneal allograft transplantation.
Additional Formulation Ingredients
[0549] The compositions of the present disclosure may also contain
other components such as, but not limited to, additives, adjuvants,
buffers, tonicity agents, bioadhesive polymers, and preservatives.
In any of the compositions of this disclosure for topical
administration to the eye, the mixtures are preferably formulated
at about pH 5 to about pH 8. This pH range may be achieved by the
addition of buffers to the composition as described in the
examples. In an embodiment, the pH range in the composition in a
formulation is about pH 6.6 to about pH 7.0. It should be
appreciated that the compositions of the present disclosure may be
buffered by any common buffer system such as phosphate, borate,
acetate, citrate, carbonate and borate-polyol complexes, with the
pH and osmolality adjusted in accordance with well-known techniques
to proper physiological values. The mixed micellar compositions of
the present disclosure are stable in buffered aqueous solution.
That is, there is no adverse interaction between the buffer and any
other component that would cause the compositions to be
unstable.
[0550] Tonicity agents include, for example, mannitol, sodium
chloride, xylitol, etc. These tonicity agents may be used to adjust
the osmolality of the compositions. In one aspect, the osmolality
of the formulation is adjusted to be in the range of about 250 to
about 350 mOsmol/kg. In a preferred aspect, the osmolality of the
formulation is adjusted to between about 280 to about 300
mOsmol/kg.
[0551] An additive such as a sugar, a glycerol, and other sugar
alcohols, can be included in the compositions of the present
disclosure. Pharmaceutical additives can be added to increase the
efficacy or potency of other ingredients in the composition. For
example, a pharmaceutical additive can be added to a composition of
the present disclosure to improve the stability of the calcineurin
inhibitor or mTOR inhibitor, to adjust the osmolality of the
composition, to adjust the viscosity of the composition, or for
another reason, such as effecting drug delivery. Non-limiting
examples of pharmaceutical additives of the present disclosure
include sugars, such as, trehalose, mannose, D-galactose, and
lactose. In an embodiment, the sugars can be incorporated into a
composition prior to hydrating the thin film (i.e., internally). In
another embodiment, the sugars can be incorporated into a
composition during the hydration step (i.e., externally) (see
Example 17). In an embodiment, an aqueous, clear, mixed micellar
solution of the present disclosure includes additives such as
sugars.
[0552] In an embodiment, compositions of the present disclosure
further comprise one or more bioadhesive polymers. Bioadhesion
refers to the ability of certain synthetic and biological
macromolecules and hydrocolloids to adhere to biological tissues.
Bioadhesion is a complex phenomenon, depending in part upon the
properties of polymers, biological tissue, and the surrounding
environment. Several factors have been found to contribute to a
polymer's bioadhesive capacity: the presence of functional groups
able to form hydrogen bridges (--OH, COOH), the presence and
strength of anionic charges, sufficient elasticity for the
polymeric chains to interpenetrate the mucous layer, and high
molecular weight. Bioadhesion systems have been used in dentistry,
orthopedics, ophthalmology, and in surgical applications. However,
there has recently emerged significant interest in the use of
bioadhesive materials in other areas such as soft tissue-based
artificial replacements, and controlled release systems for local
release of bioactive agents. Such applications include systems for
release of drugs in the buccal or nasal cavity, and for intestinal
or rectal administration.
[0553] In an embodiment, a composition of the present disclosure
includes at least one bioadhesive polymer. The bioadhesive polymer
can enhance the viscosity of the composition and thereby increase
residence time in the eye. Bioadhesive polymers of the present
disclosure include, for example, carboxylic polymers like
Carbopol.RTM. (carbomers), Noveon.RTM. (polycarbophils), cellulose
derivatives including alkyl and hydroxyalkyl cellulose like
methylcellulose, hydroxypropylcellulose, carboxymethylcellulose,
gums like locust beam, xanthan, agarose, karaya, guar, and other
polymers including but not limited to polyvinyl alcohol, polyvinyl
pyrollidone, polyethylene glycol, Pluronic.RTM. (Poloxamers),
tragacanth, and hyaluronic acid; phase-transition polymers for
providing sustained and controlled delivery of enclosed medicaments
to the eye (e.g., alginic acid, carrageenans (e.g., Eucheuma),
xanthan and locust bean gum mixtures, pectins, cellulose acetate
phthalate, alkylhydroxyalkyl cellulose and derivatives thereof,
hydroxyalkylated polyacrylic acids and derivatives thereof,
poloxamers and their derivatives, etc. Physical characteristics in
these polymers can be mediated by changes in environmental factors
such as ionic strength, pH, or temperature alone or in combination
with other factors. In an embodiment, the optional one or more
bioadhesive polymers is present in the composition from about 0.01
wt % to about 10 wt %/volume, preferably from about 0.1 to about 5
wt %/volume. In an embodiment, the compositions of the present
disclosure further comprise at least one hydrophilic polymer
excipient selected from, for example, PVP-K-30, PVP-K-90, HPMC,
HEC, and polycarbophil. In an embodiment, the polymer excipient is
selected from PVP-K-90, PVP-K-30 or HPMC. In an embodiment, the
polymer excipient is selected from PVP-K-90 or PVP-K-30.
[0554] In an embodiment, if a preservative is desired, the
compositions may optionally be preserved with any of many
well-known preservatives, including benzyl alcohol with/without
EDTA, benzalkonium chloride, chlorhexidine, Cosmocil.RTM. CQ, or
Dowicil.RTM. 200. In certain embodiments, it may be desirable for a
formulation as described herein to not include any preservatives.
In this regard, preservatives may in some embodiments not be
necessary or desirable in formulations included in single use
containers. In other embodiments it may be advantageous to include
preservatives, such as in certain embodiments in which the
formulations are included in a multiuse container.
[0555] The ophthalmic compositions can be administered topically to
the eye as biocompatible, aqueous, clear mixed micellar solutions.
The compositions have the drugs incorporated and/or encapsulated in
micelles which are dispersed in an aqueous medium.
Non-Limiting List of Exemplary Embodiments
[0556] In addition to the aspects and embodiments described and
provided elsewhere in this disclosure, the following non-limiting
list of particular embodiments are specifically contemplated.
1. A formulation comprising a polyoxyl lipid or fatty acid and a
polyalkoxylated alcohol, [0557] wherein said formulation comprises
mixed nanomicelles, [0558] wherein said formulation does not
include organic solvents, and [0559] wherein said formulation does
not contain any pharmaceutically active agent that has received
regulatory approval for the specific treatment of an ocular
condition. 2. The formulation of embodiment 1, wherein said
polyoxyl lipid or fatty acid is present in an amount equal to or
greater than 1% of said formulation. 3. The formulation of
embodiment 1, comprising 1-5% of one or more polyoxyl lipid
selected from the group consisting of HCO-40, HCO-60, HCO-80 and
HCO-100; and about 0.01-0.1% octoxynol-40. 4. The formulation of
embodiment 1, comprising 1.5-4% of one or more polyoxyl lipids
selected from the group consisting of HCO-40, HCO-60, HCO-80 and
HCO-100; and about 0.01-0.1% octoxynol-40. 5. The formulation of
embodiment 1, comprising about 4% of one or more polyoxyl lipids
selected from the group consisting of HCO-40, HCO-60, HCO-80 and
HCO-100; and about 0.01-0.1% octoxynol-40. 6. The formulation of
embodiment 1, comprising about 4% of HCO-60 and about 0.01-0.1%
octoxynol-40. 7. The formulation of embodiment 1, comprising 1-5%
of one or more polyoxyl lipid selected from the group consisting of
HCO-40, HCO-60, HCO-80 and HCO-100; and about 0.01% octoxynol-40.
8. The formulation of embodiment 1, comprising 1.5-4% of one or
more polyoxl lipid selected from the group consisting of HCO-40,
HCO-60, HCO-80 and HCO-100; and about 0.01% octoxynol-40. 9. The
formulation of embodiment 1, comprising 1.5-4% of polyoxl lipids or
fatty acids; and about 0.01% octoxynol-40. 10. The formulation of
embodiment 1, comprising about 4% of one or more polyoxyl lipid
selected from the group consisting of HCO-40, HCO-60, HCO-80 and
HCO-100; and about 0.01% octoxynol-40. 11. The formulation of
embodiment 1, comprising about 4% of HCO-60 and about 0.01%
octoxynol-40. 12. The formulation of any of the preceding
embodiments, wherein said polyoxyl lipid or fatty acid is between
0.5 and 6% by weight of said formulation. 13. The formulation of
any of the preceding embodiments, wherein said polyoxyl lipid or
fatty acid is between 0.5 and 2% by weight of said formulation. 14.
The formulation of any of the preceding embodiments, wherein said
polyoxyl lipid or fatty acid is between 0.5 and 3% by weight of
said formulation. 15. The formulation of any of the preceding
embodiments, wherein said polyoxyl lipid or fatty acid is between
0.5 and 4% by weight of said formulation. 16. The formulation of
any of the preceding embodiments, wherein said polyoxyl lipid or
fatty acid is between 0.5 and 5% by weight of said formulation. 17.
The formulation of any of the preceding embodiments, wherein said
polyoxyl lipid or fatty acid is between 1 and 6% by weight of said
formulation. 18. The formulation of any of the preceding
embodiments, wherein said polyoxyl lipid or fatty acid is between 1
and 2% by weight of said formulation. 19. The formulation of any of
the preceding embodiments, wherein said polyoxyl lipid or fatty
acid is between 1 and 3% by weight of said formulation. 20. The
formulation of any of the preceding embodiments, wherein said
polyoxyl lipid or fatty acid is between 1 and 4% by weight of said
formulation. 21. The formulation of any of the preceding
embodiments, wherein said polyoxyl lipid or fatty acid is between 1
and 5% by weight of said formulation. 22. The formulation of any of
the preceding embodiments, wherein said polyoxyl lipid or fatty
acid is between 1 and 6% by weight of said formulation. 23. The
formulation of any of the preceding embodiments, wherein said
polyoxyl lipid or fatty acid is between 2 and 6% by weight of said
formulation. 24. The formulation of any of the preceding
embodiments, wherein said polyoxyl lipid or fatty acid is between 3
and 6% by weight of said formulation. 25. The formulation of any of
the preceding embodiments, wherein said polyoxyl lipid or fatty
acid is between 4 and 6% by weight of said formulation. 26. The
formulation of any of the preceding embodiments, wherein said
polyoxyl lipid or fatty acid is between 2 and 5% by weight of said
formulation. 27. The formulation of any of the preceding
embodiments, wherein said polyoxyl lipid or fatty acid is between 3
and 5% by weight of said formulation. 28. The formulation of any of
the preceding embodiments, wherein said polyoxyl lipid or fatty
acid is about 4% by weight of said formulation. 29. The formulation
of any of the preceding embodiments, wherein said polyoxyl lipid or
fatty acid is greater than about 0.7% by weight of said
formulation. 30. The formulation of any of the preceding
embodiments, wherein said polyoxyl lipid or fatty acid is greater
than about 1% by weight of said formulation. 31. The formulation of
any of the preceding embodiments, wherein said polyoxyl lipid or
fatty acid is greater than about 1.5% by weight of said
formulation. 32. The formulation of any of the preceding
embodiments, wherein said polyoxyl lipid or fatty acid is greater
than about 2% by weight of said formulation. 33. The formulation of
any of the preceding embodiments, wherein said polyoxyl lipid or
fatty acid is greater than about 3% by weight of said formulation.
34. The formulation of any of the preceding embodiments, wherein
said polyalkoxylated alcohol if present is between 0.002 and 4% by
weight of said formulation. 35. The formulation of any of the
preceding embodiments, wherein said polyalkoxylated alcohol if
present is between 0.005 and 3% by weight of said formulation. 36.
The formulation of any of the preceding embodiments, wherein said
polyalkoxylated alcohol if present is between 0.005 and 2% by
weight of said formulation. 37. The formulation of any of the
preceding embodiments, wherein said polyalkoxylated alcohol if
present is between 0.005 and 1% by weight of said formulation. 38.
The formulation of any of the preceding embodiments, wherein said
polyalkoxylated alcohol if present is between 0.005 and 0.5% by
weight of said formulation. 39. The formulation of any of the
preceding embodiments, wherein said polyalkoxylated alcohol if
present is between 0.005 and 0.1% by weight of said formulation.
40. The formulation of any of the preceding embodiments, wherein
said polyalkoxylated alcohol if present is between 0.005 and 0.05%
by weight of said formulation. 41. The formulation of any of the
preceding embodiments, wherein said polyalkoxylated alcohol if
present is between 0.008 and 0.02% by weight of said formulation.
42. The formulation of any of the preceding embodiments, wherein
said polyalkoxylated alcohol if present is about 0.01% by weight of
said formulation. 43. The formulation of any of the preceding
embodiments, wherein said formulation does not include a resolvin
or a resolvin-like compound. 44. The formulation of any of the
preceding embodiments, wherein said formulation does not include a
resolvin. 45. The formulation of any of the preceding embodiments,
wherein said polyoxyl lipid or fatty acid is a polyoxyl castor oil.
46. The formulation of any of the preceding embodiments, wherein
said polyoxyl lipid or fatty acid is one or more selected from
HCO-60, HCO-80 or HCO-100. 47. The formulation of any of the
preceding embodiments, wherein said polyoxyl lipid or fatty acid is
HCO-60. 48. The formulation of any of the preceding embodiments,
wherein said polyalkoxylated alcohol, if present is octoxynol-40.
49. The formulation of any of the preceding embodiments, wherein
said formulation does not contain any active agents selected from
the group consisting of calcineurin inhibitors, mTOR inhibitors,
peptides, eicosanoids (e.g. prostacyclins and prostaglandins),
anti-inflammatory drugs (such as NSAIDS), autonomic drugs (e.g.
beta-blockers, alpha-blockers, beta-agonists, and alpha-agonists),
biologics, gene therapy agents (e.g. viral vectors),
anti-infectives (e.g. antifungals, antibiotics, and antivirals),
retinoids, RNAi, photo sensitizers, steroids (e.g., estrogens and
derivatives thereof, and corticosteriods), mixture drugs,
immuno-modulators, chemotherapeutic agents, G-coupled protein
receptor antagonists, receptor tyrosine kinase (RTK) inhibitors,
growth hormone inhibitors, integrin inhibitors, Sdf1/CXCR4 pathway
inhibitors, and nACh receptor antagonists, resolvins (or
resolvin-like compounds), lipoxins, and oxylipins. 50. The
formulation of any of the preceding embodiments, wherein said
formulation does not contain any active agents selected from the
group consisting of cyclosporine A, voclosporin, ascomycin,
tacrolimus, pimecrolimus, an analog thereof, or a pharmaceutically
acceptable salt thereof. 51. The formulation of any of the
preceding embodiments, wherein said formulation does not contain
cyclosporine A. 52. The formulation of any of the preceding
embodiments, wherein said formulation does not contain voclosporin.
53. The formulation of any of the preceding embodiments, wherein
said formulation does not contain any active agents selected from
the group consisting of sirolimus (rapamycin), temsirolimus,
everolimus, an analog thereof, or a pharmaceutically acceptable
salt thereof. 54. The formulation of any of the preceding
embodiments, wherein said formulation does not contain a compound
of formula A, a compound of any one of formulae 1-49, formulae
I-IX, a lipoxin compound, an oxylipin compound, a prodrug of any of
the foregoing, or a pharmaceutically acceptable salt of any of the
foregoing. 55. The formulation of any of the preceding embodiments,
wherein said formulation does not contain a compound of formula A,
a compound of any one of formulae 1-49, formulae I-IX, a lipoxin
compound, an oxylipin compound, a prodrug of any of the foregoing,
or a pharmaceutically acceptable salt of any of the foregoing. 56.
The formulation of any of the preceding embodiments, wherein said
formulation does not contain a combination of two different active
agents. 57. The formulation of any of the preceding embodiments,
wherein the formulation does not contain two or more active agents
selected from the group consisting of a resolvin or resolvin-like
compound, a steroid (such as a corticosteroid), cyclosporine A, and
voclosporin. 58. The formulation of any of the preceding
embodiments, wherein the formulation does not contain a resolvin
and a corticosteroid. 59. The formulation of any of the preceding
embodiments, wherein the formulation does not contain cyclosporine
A and a corticosteroid. 60. The formulation of any of the preceding
embodiments, wherein the formulation does not contain a resolvin,
cyclosporine A and a corticosteroid. 61. The formulation of any of
the preceding embodiments, wherein said formulation does not
contain a compound of formula I,
[0559] ##STR00200## [0560] or a pharmaceutically acceptable salt
thereof, wherein: [0561] Re and Rf are independently selected from
hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, acyl (e.g.,
alkoxyacyl, aminoacyl), aminocarbonyl, alkoxycarbonyl, or silyl;
[0562] E is a branched alkoxy; [0563] Rh and Ri are independently
selected from hydrogen, alkyl, alkenyl, alkynyl, perfluoroalkyl,
aryl or heteroaryl; [0564] R.sub.5 is selected from i-iv as
follows: i) CH.sub.2CH(R.sub.6)CH.sub.2, where R.sub.6 is hydrogen,
alkyl, alkenyl, alkynyl, perfluoroalkyl, aryl, heteroaryl, fluoro,
hydroxyl or alkoxy; ii) CH.sub.2C(R.sub.6R.sub.7)CH.sub.2, where
R.sub.6 and R.sub.7 are each independently alkyl, alkenyl, alkynyl,
perfluoroalkyl, aryl, or fluoro, or R.sub.6 and R.sub.7 are
connected together to form a carbocyclic or heterocyclic ring; iii)
CH.sub.2OCH.sub.2, CH.sub.2C(O)CH.sub.2, or CH.sub.2CH.sub.2; or
iv) R.sub.5 is a carbocyclic, heterocyclic, aryl or heteroaryl
ring; and [0565] R.sub.8 and R.sub.9 are independently selected
from hydrogen, alkyl, alkenyl, alkynyl, perfluoroalkyl, alkoxy,
aryl or heteroaryl, or R.sub.8 and R.sub.9 are connected together
to form a carbocyclic or heterocyclic ring. 62. The formulation of
any of the preceding embodiments, wherein said formulation does not
contain a compound of formula I, wherein [0566] Re, Rf, Rh, Ri,
R.sub.8 and R.sub.9 are hydrogen; [0567] E is branched alkoxy (such
as isopropyl); and [0568] R.sub.5 is CH.sub.2CH.sub.2CH.sub.2. 63.
The formulation of any of the preceding embodiments, wherein said
resolvin, if present, is a compound of Formula I. 64. The
formulation of any of the preceding embodiments, wherein said
resolvin, if present, is compound 1001. 65. The formulation of any
of the preceding embodiments, wherein said formulation further
comprises a preservative. 66. The formulation of any of the
preceding embodiments, wherein said formulation further comprises
one or more preservatives selected from the group consisting of
benzyl alcohol with/without EDTA, benzalkonium chloride,
chlorhexidine, Cosmocil.RTM. CQ, and Dowicil.RTM. 200. 67. The
formulation of any of the preceding embodiments, wherein said
formulation does not include preservatives. 68. The formulation of
any of the preceding embodiments, wherein said formulation does not
include benzyl alcohol with/without EDTA, benzalkonium chloride,
chlorhexidine, Cosmocil.RTM. CQ, or Dowicil.RTM. 200. 69. A method
of treating or preventing an ocular disease or condition, said
method comprising topically administering a formulation of any of
the preceding embodiments. 70. A method of treating or preventing
an ocular disease or condition, said method comprising topically
administering a formulation of any of the preceding embodiments;
wherein said disease is an anterior segment disease. 71. A method
of treating or preventing an ocular disease or condition, said
method comprising topically administering a formulation of any of
the preceding embodiments; wherein said disease is an posterior
segment disease. 72. A method of treating or preventing an ocular
disease or condition, said method comprising topically
administering a formulation of any of the preceding embodiments;
wherein said disease is one or more selected from the group
consisting of dry eye syndrome, Sjogren's syndrome, uveitis,
anterior uveitis (iritis), chorioretinitis, posterior uveitis,
conjunctivitis, allergic conjunctivitis, keratitis,
keratoconjunctivitis, vernal keratoconjunctivitis (VKC), atopic
keratoconjunctivitis, systemic immune mediated diseases such as
cicatrizing conjunctivitis and other autoimmune disorders of the
ocular surface, blepharitis, scleritis, age-related macular
degeneration (AMD), diabetic retinopathy (DR), diabetic macular
edema (DME), ocular neovascularization, age-related macular
degeneration (ARMD), proliferative vitreoretinopathy (PVR),
cytomegalovirus (CMV) retinitis, optic neuritis, retrobulbar
neuritis, and macular pucker. 73. A method of treating or
preventing an ocular disease or condition, said method comprising
topically administering a formulation of any of the preceding
embodiments; wherein said disease is dry eye syndrome. 74. A method
of treating or preventing an ocular disease or condition, said
method comprising topically administering a formulation of any of
the preceding embodiments; wherein said disease is allergic
conjunctivitis. 75. A method of treating or preventing an ocular
disease or condition, said method comprising topically
administering a formulation of any of the preceding embodiments;
wherein said disease is age-related macular degeneration (AMD).
[0569] The following examples are provided to further illustrate
aspects of the present disclosure. These examples are non-limiting
and should not be construed as limiting any aspect of the present
disclosure.
Example 1
Preparation of Mixed Nanomicellar Formulation Using Dialysis
Method
[0570] Mixed nanomicellar formulation of an active compound is
prepared by dialysis method with varying ratio of polymers and the
drug. Experimental design software, JMP 9.0 is used to design the
experiments and analyze the results. Accurately weighted quantities
of two polymers namely polyoxyl hydrogenated castor-60 (HCO-60) and
octoxynol-40 (Oc-40) are dissolved in 300 microliter volume of
propylene glycol. Eighty microliter (or 80 mg of active compound in
PG) of propylene glycol containing active compound is added to this
polymer mixture and vortex mixed to get a clear homogenous
solution. The volume of the mixture is made up (500 microliters)
with propylene glycol. The solution is vortex mixed to get a
homogenous solution. A volume of 500 microliter distilled deionized
water is added to this mixture to obtain a total volume of 1000
microliter (1 milliliter). Addition of water to the drug polymer
mixture in organic solvent should spontaneously generate micelles
thereby entrapping the pharmaceutical active agent in the
hydrophobic core of mixed nanomicelles.
[0571] The mixture is transferred to a dialysis bag (molecular
weight cut off 1000) and transferred to a beaker containing one
liter of distilled deionized water. Beaker and the contents are
protected from sunlight by covering with aluminum foil and are kept
under slow constant stirring at room temperature. Dialysis of the
mixture is carried over a period of 24 h to remove the water
soluble organic solvent, propylene glycol, from the mixture. Water
in the dialysis chamber is changed at predetermined time points: 1
h, 2 h, 4 h, 6 h, 12 h and 24 h. At the end of dialysis (24 h), the
contents of the dialysis bag are carefully transferred to a 15-mL
centrifuge tube and formulations are subjected to sonication in
water bath (time range from 0 min to 5 min). The final volume is
made up with 2.times. phosphate buffer saline and adjusted pH of
the formulation to 6.5.+-.0.1. The resultant formulation is
filtered with 0.22 micrometer nylon filter to remove any foreign
particulate matter.
[0572] The prepared formulations are subjected to various tests
such as entrapment efficiency, loading efficiency, mixed
nanomicellar size and polydispersity index.
[0573] Mixed Nanomicellar Size and Polydispersity Index:
[0574] The formulation size and polydispersity index are determined
with Zetasizer, Malvern Instruments, NJ. In brief, approximately 1
mL of each formulation is transferred to a cuvette and placed in
the instrument. A laser beam of light is used to determine the
mixed nanomicellar size. The results of the size are summarized in
Table 2.
[0575] Entrapment Efficiency:
[0576] To determine the entrapment efficiency of the formulation,
all the prepared formulations are subjected to entrapment
efficiency test. Briefly, formulations are vortex mixed for
homogeneity and 1 mL is transferred to a fresh (1.5 mL) eppendorf
tube. Each formulation is lyophilized to obtain a solid at the
bottom of eppendorf tube. The obtained solid is suspended in 1 mL
of organic solvent (diethyl ether) to generate reverse micelles and
release the drug into the external organic solvent. The organic
solvent is evaporated overnight in speed vacuum. The resultant
reversed micelles are resuspended in 1 mL of 2-propanol (dilution
factor was taken into account) and further diluted to determine the
concentration of active compound entrapped in each micellar
preparation with HPLC. The entrapment efficiency of the formulation
is calculated with the following formula (wherein MNF=Mixed
Nanomicellar Formulation):
Entrapment efficiency=(amount of drug quantified in MNF/Amount of
drug added in the MNF).times.100
[0577] Drug Quantification by an HPLC Method:
[0578] In vitro analysis of active compound is performed by a
reversed phase high performance liquid chromatography (RP-HPLC)
method with a Shimadzu HPLC pump (Shimadzu, Shimadzu Scientific
instruments, Columbia, Md.), Alcott autosampler (model 718 AL),
Shimadzu UV/Visible detector (Shimadzu, SPD-20A/20AV, USA), ODS
column (5 .mu.m, 150.times.4.6 mm) thermostated at 40.degree..+-.1
C and Hewlett Packard HPLC integrator (Hewlett Packard, Palo Alto,
Calif.). The mobile phase is comprised of methanol (MeOH), water
and trifluoroacetic acid (TFA) (70:30:0.05% v/v) which is set at a
flow rate of 0.5 mL/min. Detection wavelength is set at 272 nm. The
sample tray temperature is maintained at 4.degree. C. Calibration
curve (0.5 to 5 .mu.g/mL) for active compound is prepared by making
appropriate dilutions from the stock solution in 2-propanol. An
injection volume of 10 .mu.l is injected into the HPLC column for
analysis. All the standards and samples prepared are stored at
4.degree. C. before and during the analysis.
Example 2
Preparation of Mixed Nanomicellar Formulation Using Ethyl Acetate
Solvent Evaporation Method
[0579] Mixed nanomicellar formulation encapsulating active compound
is prepared by solvent evaporation method in two steps: 1)
Preparation of basic formulation and 2) rehydration. In step one,
active compound, HCO-60 and octoxynol-40 are dissolved separately
in 0.3 mL of ethyl acetate. These three solutions are mixed
together in 15-mL centrifuge tube. The resultant mixture is
vortexed to obtain a homogenous solution. Ethyl acetate solvent is
removed with speed vacuum to obtain a solid thin film. The residue
is kept overnight under high vacuum at room temperature to remove
residual organic solvent.
[0580] In step two, the resultant thin film is hydrated with 1 mL
of double distilled deionized water by vortexing the solution. The
rehydrated formulation is suspended in 2.times. phosphate buffer
solution, (pH 6.5). It is filtered through 0.2 .mu.m nylon filter
membrane to remove the unentrapped drug aggregates and other
foreign particulates. The entrapment of active compound is
determined by RP-HPLC following disruption of the micelles and
solubilization of 1001 in the diluent (2-propanol) as described
below.
[0581] The prepared formulations are subjected to various tests
such as entrapment efficiency, loading efficiency, mixed
nanomicellar size and polydispersity index according to the methods
described in Example 1.
[0582] Weight percent of drug loaded into MNF is determined
following the method for entrapment efficiency. Size and
polydispersity index of the formulations is determined with Malvern
zetasizer as described above. The results obtained are summarized
in Table 2 below. The formulations appear clear and have small size
and narrow size distribution.
TABLE-US-00002 TABLE 2 Characterization of the mixed nanomicellar
formulation encapsulating compound 1001 with solvent evaporation
method Active Active (loaded HCO- (initially in mixed Mixed 60
Octoxynol- added) micelles) nanomicellar Polydispersity (wt %) 40
(wt %) wt % wt % size (nm) Index Result 4 0.01 0.035 0.033 24.90
0.442 Clear/transparent solution before and after filtration 4 0.01
0.070 0.065 25.01 0.414 Clear/transparent solution before and after
filtration 4 0.01 0.095 0.084 24.79 0.415 Clear/transparent
solution before and after filtration 4 0.01 0.120 0.11 18.28 0.320
Pale yellow color transparent solution before and after filtration
4 0.01 0.250 0.26 18.37 0.331 Yellow color solution before and
after filtration 4 0.01 0.300 0.32 18.29 0.345 Yellow color 4 0.01
0.400 0.45 18.2 0.333 solution before and after filtration
Example 3
Preparation of Mixed Nanomicellar Formulation Using Melt Method
[0583] Two hundred milligrams of hydrogenated castor oil-60
(HCO-60) (4 wt %) is weighed and transferred to a 10 mL round
bottom flask (RBF). The neck of the round bottom flask is closed
with aluminum foil, sealed with parafilm and transferred to a water
bath set at 40.degree. C. The round bottom flask is left overnight
in a water bath to liquefy/melt the HCO-60. On the next day, ten
micro liters of octoxynol-40 is diluted 100 fold and allowed to
equilibrate at 40.degree. C. for 1 h in a water bath. Similarly,
active compound (as a neat oil) is allowed to equilibrate at
40.degree. C. in the water bath for 1 h. To the HCO-60 melt, 50
.mu.L of 100 fold diluted octoxynol-40 (0.01 wt %) is added at
40.degree. C. To the above mixture, .about.20 .mu.L of active
compound at 40.degree. C. is added and stirred. To this mixture
distilled deionized water, approx. 2 mL, equilibrated at 40 C is
slowly added and stirred. The neck of the round bottom flask is
closed with aluminum foil and sealed with parafilm. The solution is
stirred in a water bath set at 40.degree. C. overnight protected
from light (covering with aluminum foil). On the next day, the
above obtained solution at 40.degree. C. is removed from the water
bath and allowed to cool to room temperature and observed for
clarity. Two milliliters phosphate buffer (2.times.) is added to
the above prepared solution (phosphate buffer was previously
prepared and the pH was adjusted to 5.5). The volume of the
formulation is made up to 5 mL with the 2.times. phosphate buffer
saline. The prepared formulation is filtered with 0.2 .mu.m nylon
filter and stored at 4.degree. C.
[0584] The prepared formulations are subjected to various tests
such as entrapment efficiency, loading efficiency, mixed
nanomicellar size and polydispersity index according to the methods
described in Example 1.
Example 4
Preparation of Mixed Nanomicellar Formulation Using Second Melt
Method
[0585] The preparation of MNF encapsulating active compound (as a
neat oil) can be divided into two steps. An example for the
development of 3.0 wt % HCO-40 or HCO-60 MNF encapsulating 0.4%
active compound is described below. In step 1, HCO-40 or HCO-60,
150 mg, is thermostated at 40.degree. C. in a water bath to melt
and result in a clear thick viscous liquid. To this melt polymer,
active compound (.about.20 mg), thermostated at 40.degree. C., is
added and mixed for homogenous distribution. The mixture is allowed
to reach room temperature, which results in a pale yellow color
viscous liquid with HCO-40 and waxy solid with HCO-60. Further, to
solidify the viscous liquid of HCO-40, the mixture is stored at
4.degree. C. (in refrigerator).
[0586] In step 2, the pellet and/or viscous liquid is allowed to
reach room temperature under natural conditions. The pellet and/or
viscous liquid is thermostated in a water bath at 40.degree. C. and
resuspended in 2.0 mL of distilled water (thermostated at
40.degree. C.) under constant stirring. This results in spontaneous
development of a clear aqueous solution of 0.4% active compound
MNF. This aqueous solution is allowed to reach room temperature,
under natural conditions. The pH of the solution is adjusted to 5.5
and the volume is made up with 2.times. phosphate buffer saline (pH
5.5) containing octoxynol-40 (0.01 wt %) and PVP-K-90 (1.2 wt %).
The formulation is filtered through 0.2 .mu.m nylon filter to
remove any foreign material and obtain a clear homogenous aqueous
active-containing formulation.
[0587] .sup.1H NMR Qualitative Studies:
[0588] To determine the absence of free drug in the outer aqueous
environment, qualitative studies are conducted. Qualitative proton
nuclear magnetic resonance (NMR) studies are conducted with Varian
400 MHz NMR. Deuterated chloroform and water as solvent systems are
used to resuspend the formulation and NMR studies are
performed.
[0589] Results:
[0590] Compound added to HCO-40 or HCO-60 at 40.degree. C. can be
used to entrap active compound. At higher temperatures the polymer
and the drug mixture remain in a viscous liquid state. When allowed
to reach room temperature, under natural conditions, HCO-60 mixture
solidifies and develops a waxy solid. This waxy solid when
thermostated at 40.degree. C., helps in resuspending the
formulation in distilled water to spontaneously develop active
compound-containing MNF. Similar observation and results are
obtained with HCO-40 viscous liquid. The viscosity of the mixture
appears to be improved at lower temperatures (4.degree. C.).
Therefore, it appears to stick to the walls of the container as
thick viscous liquid. Upon allowing to reach back to room
temperature the viscosity appears to be reduced and the mixture
retains its flow back.
[0591] The waxy solid developed with HCO-60 and active compound
mixture may be helpful to protect the drug and prevent drug
degradation with a surface blanket of an inert gas. The other
polymer (HCO-40) did not result in development of waxy solid at
room temperature or at low refrigerated conditions (4.degree. C.)
when used up to approx. 3.0 wt %.
[0592] Qualitative proton NMR studies show that resuspending the
formulation in the aqueous phase (D.sub.2O) spontaneously generates
mixed nanomicelles and no free drug peaks are evident in the
aqueous solution. If the drug is not entrapped in the core of mixed
nanomicelles then the oil would be floating at the surface as a
separate oil phase. While on the other hand, resuspending the same
formulation in organic solvent such as deuterated chloroform
(CDCl.sub.3) shows distinct peaks corresponding to drug along with
polymer peaks. This indicates that the drug is not encapsulated in
the micelle core and is freely available when present in organic
solvent.
[0593] The results obtained for physical appearance of the mixture,
different phases, at different temperatures and appearance of final
formulation are summarized in Tables 3a-3c.
TABLE-US-00003 TABLE 3a Physical appearance at Final formulation
HCO- room (make up with 2X 60 (wt Active temperature Resuspended in
buffer containing %) (wt %) (25.degree. C.) water 0.01% Oc-40) 1.0
4 Pale yellow half Emulsion Emulsion solid and half viscous liquid
2.0 4 Pale yellow Forms pale Pale yellow clear viscous solid
emulsion solution (with waxy and viscous liquid) 2.25 4 Pale yellow
waxy Forms pale Pale yellow clear solid emulsion solution 2.5 4
Pale yellow waxy Forms very pale Pale yellow clear solid emulsion
solution 2.75 4 Pale yellow waxy Forms very pale Clear solution
solid emulsion 3.0 4 Pale yellow waxy Clear solution Clear solution
solid 3.5 4 Pale yellow waxy Clear solution Clear solution solid
4.0 4 Pale yellow waxy Clear solution Clear solution solid Physical
appearance of melt mixture of HCO-60 and Active Compound at
25.degree. C. resuspending in water at 40.degree. C. and final
formulation of mixed nanomicellar formulation encapsulating active
compound (HCO-60 is melted and active compound is added to melt,
then allowed to cool to room temperature and the physical
appearance is noted)
TABLE-US-00004 TABLE 3b Mixture physical appearnce at HCO-40 Active
room temperature Resuspend in Final (wt %) (wt %) (25.degree. C.)
water formulation 0.5 4 Viscous yellow Emulsion Emulsion liquid
0.75 4 Viscous yellow Emulsion Emulsion liquid 1.0 4 Viscous yellow
Emulsion Emulsion liquid 1.25 4 Viscous yellow Emulsion Emulsion
liquid 1.5 4 Viscous yellow Emulsion Emulsion liquid 1.75 4 Viscous
yellow Emulsion Emulsion liquid 2.0 4 Viscous yellow Emulsion
Emulsion liquid 2.25 4 Viscous yellow Emulsion Emulsion liquid 2.5
4 Viscous yellow Yellow solution Yellow color liquid solution 2.75
4 Viscous yellow Pale yellow Pale yellow color liquid solution
solution 3.0 4 Viscous yellow Clear solution Clear solution liquid
4.0 4 Viscous yellow Clear solution Clear solution liquid Physical
appearance of melt mixture of HCO-40 and Active Compound at
25.degree. C. resuspending in water and final formulation of mixed
nanomicellar formulation encapsulating active compound (HCO-40 is
melted and active compound is added to melt at 40.degree. C., then
allowed to cool to room temperature and the physical appearance is
noted)
TABLE-US-00005 TABLE 3c Physical appearance of HCO-40 and active
compound melt mixture at 25.degree. C. and 4.degree. C., mixture
resuspended in water at 40.degree. C. and final formulation.
(HCO-40 is melted and active compound is added to melt at
40.degree. C., then allowed to cool to room temperature, placed at
4.degree. C. and brought back to room temperature. Physical
appearance of mixture is noted at all temperatures) Mixture Mixture
physical physical appearance at appearance at Allow to HCO- room
room reach room 40 Active temperature temperature temperature
Resuspend Final (wt %) (wt %) (25.degree. C.) (4.degree. C.)
(25.degree. C.) in water formulation 0.5 4 Viscous yellow Viscous
liquid Viscous liquid Emulsion Emulsion liquid 0.75 4 Viscous
yellow Viscous liquid Viscous liquid Emulsion Emulsion liquid 1.0 4
Viscous yellow Viscous liquid Viscous liquid Emulsion Emulsion
liquid 1.25 4 Viscous yellow Viscous liquid Viscous liquid Emulsion
Emulsion liquid 1.5 4 Viscous yellow Yellow waxy Viscous liquid
Emulsion Emulsion liquid solid 1.75 4 Viscous yellow Yellow waxy
Viscous liquid Emulsion Emulsion liquid solid 2.0 4 Viscous yellow
Yellow waxy Viscous liquid Emulsion Emulsion liquid solid 2.25 4
Viscous yellow Yellow waxy Viscous liquid Emulsion Emulsion liquid
solid 2.5 4 Viscous yellow Yellow waxy Viscous liquid Yellow Yellow
color liquid solid solution solution 2.75 4 Viscous yellow Pale
yellow Viscous liquid Pale yellow Very pale liquid waxy solid
solution yellow color solution 3.0 4 Viscous yellow Pale yellow
solid Viscous liquid Clear Clear solution liquid (half solid half
solution viscous liquid) 4.0 4 Viscous yellow Pale yellow Pale
yellow Clear Clear solution liquid waxy solid waxy solid
solution
[0594] Conclusions.
[0595] These studies show that the polymer HCO-60 can be used to
entrap active compound with Hot Melt method. HCO-40 does not
develop waxy solid at higher weight percent (3.0%) under the
conditions of this study. On the other hand, HCO-60 develops waxy
solid at 2.0 wt %. This method has unique advantages of being an
easy and fast method that avoids the use of organic solvent in the
preparation of MNF. Also, the method of preparation is easy and
fast. The waxy solid developed in stage 1 may be helpful in
preventing the drug degradation and help the drug to stay in waxy
solid state at room temperatures with a blanket of inert gas.
Qualitative proton NMR studies show that drug is not freely
available when resuspended in aqueous solution. On the other hand,
when the same formulation is resuspended in organic solvent,
CDCl.sub.3, drug peaks are clearly evident indicating the presence
of drug in the outer organic solvent environment due to the
formation.
Example 5
Preparation of Mixed Nanomicellar Formulation
[0596] MNF formulation of active agent is prepared by solvent
evaporation method in two steps: 1. Preparation of basic
formulation and 2. rehydration. In step one, active agent, HCO-40
and octoxynol-40 are dissolved separately in 0.5 mL of ethanol
aliquots. These three solutions are mixed together in a round
bottom flask. The resultant mixture is stirred to obtain a
homogenous solution. Ethanol solvent is removed by high speed
vacuum evaporation overnight to obtain a solid thin film.
[0597] In step two, the resultant thin film is hydrated with 2.0 mL
of double distilled deionized water and resuspended with stirring
overnight. The rehydrated formulation is pH adjusted and the volume
is made up with 2.times. phosphate buffer solution, (pH 6.8).
Further the formulation is filtered through 0.2 .mu.m nylon filter
membrane to remove the unentrapped drug aggregates and other
foreign particulates.
[0598] Different polymer weight percent combination than are used
for the preceding examples are used to develop aqueous MNF
entrapping 0.2 wt % active agent. Formulations are characterized
for their appearance, size and polydispersity indices. The
formulations are found to be clear and have very small size with
narrow polydispersity index. The results are summarized in tables
4a and 4b.
TABLE-US-00006 TABLE 4a Mixed nanomicellar formulations at lower
polymer concentrations. Octoxynol-40 Visual Polydispersity HCO-40
wt % wt % appearance Size (nm) index 0.5 0.1 Emulsion N.D N.D 0.75
0.1 Emulsion N.D N.D 1 0.1 Emulsion N.D N.D 1.25 0.1 Emulsion N.D
N.D 1.5 0.1 Emulsion N.D N.D 1.75 0.1 Clear solution N.D N.D 2.00
0.1 Clear solution 14.86 0.062 0.5 0.5 Emulsion 36.14 0.884 0.75
0.5 Emulsion N.D N.D 1 0.5 Emulsion N.D N.D 1.25 0.5 Emulsion N.D
N.D 1.5 0.5 Emulsion N.D N.D 1.75 0.5 Clear solution 14.81 0.075
2.00 0.5 Clear solution 21.27 0.295 N.D.--Not Determined.
TABLE-US-00007 TABLE 4b Mixed nanmicellar formulations at higher
polymer concentrations. HCO-40 Octocynol- Visual Polydispersity wt
% 40 wt % appearance Size (nm) index 0.5 1.0025 Clear solution 12.9
0.069 0.5 2 Clear solution 18.1 0.069 2.5 0.005 Clear solution
15.65 0.064 2.5 1.0025 Clear solution 14.56 0.096 2.5 1.0025 Clear
solution 14.81 0.078 2.5 1.0025 Clear solution 14.80 0.098 2.5
1.0025 Clear solution 14.45 0.102 2.5 2 Clear solution 13.92 0.108
4.5 0.005 Clear solution 20.59 0.271 4.5 1.0025 Clear solution
15.08 0.087 4.5 2 Clear solution 15.37 0.079
[0599] Water Method.
[0600] MNF formulation of active agent is prepared by the water
method. One mL of double distilled deionized water is heated to
60.degree. C. in a round bottom flask. This heated water is kept
under stirring. HCO-40 is added to the heated water and allowed to
dissolve under constant stirring. Octoxynol-40 is then added to
this mixture and allowed to dissolve. In a separate container,
phosphates, sodium chloride and CsA are blended by hand shaking for
a few minutes. Under stirring conditions, the phosphates/CsA/sodium
chloride blend is added to the solution of HCO-40 and octoxynol-40
to disperse the drug. This mixture is allowed to cool to room
temperature while stirring and check for complete dissolution of
drug. PVP K 90 solution is separately prepared using the remaining
1 mL double distilled deionized water. This PVP K 90 solution is
added to the solution of polymer/surfactant/drug/phosphate/sodium
chloride. Water is added to make up the final volume. Then the
formulation is filtered through 0.2 .mu.m nylon membrane to remove
the drug aggregates and other foreign particulates.
Example 6
Local Tolerability in Rabbits of Formulations
[0601] Healthy young adult New Zealand albino rabbits (3-4 Kg) are
used for the study of the local tolerability of formulations as
described herein, for example a formulation of Examples 1-5. One
drop (approximately 30muL) of saline is placed in one eye and a
drop of formulation is placed in the other eye of the rabbit. Both
eyes of each animal are examined by a veterinary ophthalmologist
using a hand-held slit lamp and indirect ophthalmoscope. Both
control and test eyes are graded according to conjunctival
congestion, swelling, and discharge, aqueous flare, iris light
reflex and involvement, corneal cloudiness severity and area,
pannus, fluorescein examination and lens opacity using the
Hackett/McDonald scoring system (see, for example, Hackett, R. B.
and McDonald, T. O. Ophthalmic Toxicology and Assessing Ocular
Irritation. Dermatoxicology, 5.sup.th Edition. Ed. F. N. Marzulli
and H. I. Maibach. Washington, D.C.: Hemisphere Publishing
Corporation. 1996; 299-305 and 557-566.). In the fluorescein
examination, approximately one drop of 0.9% sodium chloride, USP,
is applied to the end of a fluorescein impregnated strip and then
applied to the superior sclera of the left and right eyes (one
fluorescein impregnated strip is used for each animal). After an
approximate 15 second exposure, the fluorescein dye is gently
rinsed from each eye with 0.9% sodium chloride, USP. The eyes are
then examined using a slit lamp with a cobalt blue filtered light
source. For the lenticular examination approximately one drop of a
short-acting mydriatic solution is instilled onto each eye in order
to dilate the pupil. After acceptable dilation has occurred, the
lens of each eye is examined using a slit-lamp biomicroscope.
[0602] The crystalline lens is observed with the aid of the
slit-lamp biomicroscope, and the location of lenticular opacity is
discerned by direct and retro illumination. The location of
lenticular opacities are arbitrarily divided into the following
lenticular regions beginning with the anterior capsule: Anterior
subcapsular, Anterior cortical Nuclear Posterior cortical,
Posterior subcapsular, Posterior capsular. The lens is evaluated
routinely during ocular evaluations and graded as either 0 (normal)
or 1 (abnormal). The presence of lenticular opacities are described
and the location noted.
Example 7
Ocular Tissue Distribution of Formulations of 0.05 wt %, 0.2 wt %
and 0.5 wt % in Mixed Micellar Formulations of the Present
Disclosure
[0603] The temporal distribution and potential accumulation with
repeat dosing, gender difference, and potential melanin binding of
(ophthalmic solution) of the present disclosure (for example the
formulations of Examples 1-5) after ocular application is assessed
by determining concentration of active ingredients in ocular
tissues, tears, and blood in New Zealand White (NZW) and Dutch
Belted (DB) rabbits.
[0604] NZW rabbits are used in a single dose (SD) and 7-day repeat
dose (RD) studies. DB rabbits will be used in a single dose study).
Animals are either untreated (controls) or given a single or a
daily topical ocular dose for 7 days (0.05 wt %, 0.2 wt % or 0.5 wt
% in a mixed micellar formulation to one or both eyes). Blood and
ocular tissue concentrations are assessed.
[0605] The concentration of drug is in tissues in the front of the
eye (cornea, conjunctiva, sclera) and at the back of the eye
(retina, optic nerve) but minimal in the middle of the eye (aqueous
and vitreous humor), suggesting transport of the drug by a
mechanism other than passive transport through the eye. The high
drug levels achieved at the back of the eye make topical
administration of the compositions of the present disclosure
feasible for the treatment of diseases of the back-of-the-eye
(e.g., retinal, diseases involving optic nerve such as glaucoma).
Very high levels, especially in target tissues such as lachrymal
gland, will be shown with the compositions of the present
disclosure.
Example 8
Use of Mixed Nanomicellar Formulations for Treating Dry Eye
[0606] Mixed nanomicellar formulations according to Examples 1-5
are administered to a patient having dry eye at a concentration of
between 0.05% and 0.2% b.i.d. over a period of 1 month to 1 year or
more.
Example 9
Use of Mixed Nanomicellar Formulations for Treating Diabetic
Retinopathy
[0607] Mixed nanomicellar formulations according to Examples 1-5
are administered to a patient having proliferative diabetic
retinopathy at a concentration of between 0.2 wt % to 0.5 wt %
b.i.d. over a period of 1 month to 1 year or more.
Example 10
Tolerance and Ocular Tissue Distribution of Mixed Nanomicellar
Formulations
[0608] A study was conducted in rabbits to test the tolerance and
ocular tissue distribution of a nanomicellar formulation of active
agent against its placebo and balanced saline solution (BSS).
Healthy New Zealand female white rabbits (2-3 kg) are used for this
study. Study drug is prepared having 0.1% active agent essentially
as described in the examples herein. The below table shows the
formulation composition of the formulation and the Placebo.
TABLE-US-00008 TABLE 5 Formulation Composition: 0.1%
Active-containing Components formulation Placebo Cyclosporine 0.1%
0 Hydrogenated castor oil-40 1.0% 1.0% Octoxynol-40 0.05% 0.05%
Sodium chloride 0.10% 0.10% PVP-K90 0.60% 0.60% Disodium EDTA 0.05%
0.05% Benzalkonium chloride 0.003% 0.003% Sodium Phosphate buffer
~0.4% ~0.4% pH 7 7
[0609] One drop (approximately 35 .mu.L) of study drug is applied
o.d. 4.times./day at two hour intervals for 5 days. One drop of BSS
is applied to the contralateral eye.
[0610] The tolerance parameters evaluated are: physical examination
(acclimation study release); viability (daily); clinical
observations (daily); Hackett-McDonald Ocular Irritation scores
(pre-dose baseline data for each rabbit and then a pre-dose [prior
to first daily dose] each day and then 30 min after last dose
daily, intraocular pressure (IOP) pre-dose baseline data for each
rabbit and then 30 minutes after the evening examinations each day,
electroretinography (ERG) pre-dose-(pre-study) baseline data for
each rabbit and then one hour after the last treatment, and ocular
histopathology at euthanasia.
[0611] Mean cumulative Hackett-McDonald ocular irritation scores
demonstrate very minimal scores for both BSS-treated left eyes and
cyclosporine treated right eyes throughout the study, both for
pre-treatment and post-treatment examination times. Mean cumulative
inflammatory scores of less than 2 are observed in eyes treated
with the TA, placebo, and BSS. These clinical scores represent mild
conjunctival hyperemia (redness) and swelling. However, there are
no significant differences in mean cumulative Hackett-McDonald
ocular irritation scores between the groups, suggesting no
difference in irritation from topical application of 0.1% CsA in
HCO-40, the HCO-40 placebo, and BSS.
[0612] No changes in IOP are noted in eyes treated with BSS,
HCO-40, or active agent. No toxicologic changes in retinal function
are noted on ERG after 5 days of treatment with the test articles.
No toxicologic or inflammatory changes are observed histologically
in the anterior (conjunctiva/cornea/iris) or posterior segments
(vitreous/retina) of the eye of any groups.
[0613] Samples of selected ocular tissues (aqueous humor, vitreous
humor, conjunctiva, cornea, iris-ciliary body, lens,
retina/choroid, and sclera) are collected 1 hour following the last
dose on Day 5 from all two rabbits that received 0.1% active agent
with HCO-40 (OD), and BSS (OS), and from one rabbit (No. 21) that
received placebo HCO-40 formulation (OD) and BSS (OS). The samples
are assayed for active agent by liquid chromatography-tandem mass
spectrometry (LC-MS/MS). The internal standard is d.sub.4-active
agent. The established analytical ranges for active agent are
0.100-100 ng/mL for whole blood, and 2.00-2000 ng/mL for aqueous
humor and vitreous humor. The analytical ranges for the solid
tissues are 0.125-30 ng (low range) and 1.00-2500 ng (high range).
The results of the solid tissue analyses are converted to ng/g by
correcting for the amount of tissue analyzed.
[0614] Concentrations of active agent in ocular tissues collected 1
hour following the last dose on Day-5 are summarized in Table 6.
Following repeated administration of the 0.1% active agent-HCO-40
formulation, the highest average active agent concentrations in the
treated eye are observed in cornea (7805 ng/g), followed by
conjunctiva (2125 ng/g), sclera (720 ng/g), iris-ciliary body (204
ng/g), and aqueous humor (134 ng/mL). The lowest active agent
concentrations are observed in the lens (68.6 ng/g), retina/choroid
(54 ng/g), and vitreous humor (.about.8 ng/mL). Active agent
concentrations in the collateral eye treated with BSS are quite low
suggesting minimal systemic transfer of drug.
[0615] The ocular tissue concentrations for the 0.1% active agent
formulation observed in this study are generally higher than the
C.sub.max values following repeat dose administration (bid for 7
days) of an Allergan 0.2% 3H cyclosporine A formulation to rabbits
(see Acheampong A A, Shackleton M, Tang-Liu D, Ding S, Stern M E,
Decker R Distribution of cyclosporin A in ocular tissues after
topical administration to albino rabbits and beagle dogs; Current
Eye Research 18(2); 1999; pp 91-103).
TABLE-US-00009 TABLE 6 Nanomicellar Allergane Matrix 0.1% CsA 0.2%
CsA Aqueous Humor 134.5 ng/mL 19.3 ng-eq/mL Vitreous Humor 8.37
ng/mL 0.810 ng-eq/mL Selera 720.5 ng/g 35.2 ng-eq/g Conjunctiva
2125 ng/g ND ng-eq/g Cornea 7805 ng/g 6011 ng-eq/g Iris-Ciliary
Body 204 ng/g 109 ng-eq/g Lens 68.6 ng/g 39.6 ng-eq/g
Retina/Choroid 53.7 ng/g 4.62 ng-eq/g
Example 11
Tolerance and Ocular Tissue Distribution of Active Compound Mixed
Nanomicellar Formulations
[0616] A study is conducted in rabbits to test the tolerance and
ocular tissue distribution of two nanomicellar formulations of
active compound against matching placebos (Table 7a and 7b) and
balanced saline solution (BSS). Healthy New Zealand female white
rabbits (2-3 kg) are used for this study. One drop (approximately
35 .mu.L) of study drug is applied o.d. 4.times./day at two hour
intervals for 5 days. One drop of BSS is applied to the
contralateral eye.
[0617] The tolerance parameters evaluated are: physical examination
(acclimation study release); viability (daily); clinical
observations (daily); Hackett-McDonald Ocular Irritation scores
(pre-dose baseline data for each rabbit and then a pre-dose [prior
to first daily dose] each day and then 30 min after last dose
daily, intraocular pressure (IOP) pre-dose baseline data for each
rabbit and then 30 minutes after the evening examinations each day,
electroretinography (ERG) pre-dose-(pre-study) baseline data for
each rabbit and then one hour after the last treatment, and ocular
histopathology at euthanasia.
TABLE-US-00010 TABLE 7 Formulation Composition: RX-10045 0.15%
RX-10045 (0.1% in HCO-40 Placebo Components percentage percentage
RX-10045 0.1% 0 Hydrogenated Castor 1.0% 1.0% Oil-40 Octoxynol-40
0.05% 0.05% Sodium chloride 0.10% 0.10% PVP-K90 0.60% 0.60%
Disodium EDTA 0.05% 0.05% Benzalkonium 0.003% 0.003% chloride
Sodium Phosphate ~0.4% ~0.4% buffer pH 5.5 5.5
TABLE-US-00011 TABLE 7b Formulation Composition: RX-10045 0.1%
RX-10045 (0.15%) in HCO-60 Placebo Components percentage Percentage
RX-10045 0.15% 0 Hydrogenated Castor 1.0% 1.0% Oil-40 Octoxynol-40
0.05% 0.05% Sodium chloride 0.10% 0.10% PVP-K90 0.60% 0.60%
Disodium EDTA 0.05% 0.05% Benzalkonium 0.003% 0.003% chloride
Sodium Phosphate ~0.4% ~0.4% buffer pH 5.5 5.5
[0618] Cumulative Hackett-McDonald ocular irritation scores
demonstrate very minimal mean values for both BSS-treated left eyes
and test-article treated right eyes throughout the study, both for
pre-treatment and post-treatment examination times. There are no
significant differences in mean cumulative Hackett-McDonald ocular
irritation scores between the groups (Table 8). The observed ocular
irritation is interpreted as minimal and transient in all
groups.
TABLE-US-00012 TABLE 8 Hackett-McDonald Composite Scores (mean .+-.
s.d.) HCO-40 RX-10045 HCO-60 RX-10045 Placebo.sup.a 0.1%.sup.b
Placebo.sup.a 0.1%.sup.b Day 1 Predose 0.0-0.0 0.0-0.0 0.0-0.0
0.0-0.0 Day 1 Postdose 1.7-1.5 0.5-0.1 0.0-0.0 0.5-0.1 Day 2
Predose 0.0-0.0 0.0-0.0 0.0-0.0 1.0-1.2 Day 2 Postdose 2.0-0.0
0.0-0.0 0.7-1.1 0.5-1.0 Day 3 Predose 0.0-0.0 0.0-0.0 0.0-0.0
0.5-1.0 Day 3 Postdose 1.3-1.2 0.0-0.0 0.0-0.0 1.0-1.2 Day 4
Predose 1.3-1.2 0.0-0.0 0.3-0.6 0.5-1.0 Day 4 Postdose 1.3-1.2
0.0-0.0 0.7-1.2 0.8-1.0 Day 5 Predose 0.0-0.0 0.5-1.0 1.0-1.0
0.0-0.0 Day 5 Postdose 1.2-2.3 0.0-0.0 0.3-0.6 0.8-1.1
[0619] No changes in IOP are noted in eyes treated with BSS or test
articles. No toxicologic changes in retinal function are noted on
ERG after 5 days of treatment with the test articles. No
toxicologic or inflammatory changes are observed histologically in
the anterior (conjunctiva/cornea/iris) or posterior segments
(vitreous/retina) of the eye of any groups.
[0620] Selected ocular fluids/tissues (aqueous humor, vitreous
humor, conjunctiva, cornea, iris-ciliary body, lens,
retina/choroid, and sclera) collected from two rabbits each in the
active agent (0.15% in HCO-60, 0.1% in HCO-40) treatment groups,
and from one rabbit in each of the matching placebo groups, are
assayed for active compound by liquid chromatography-tandem mass
spectrometry (LC-MS/MS). Warfarin-d.sub.5 and 5-HDA are used as
internal standards for the analysis of RX-10045 and its active
metabolite, RX-10008, respectively, in aqueous humor and vitreous
humor. For the other ocular tissues (solid tissues), warfarin-d5
and phenyl acetic acid-d5 (PAA-d.sub.5) are used as the internal
standards for compound 1001 and RX-10008, respectively. The
analytical range for the solid tissues is 0.125-100 ng. The results
of the solid tissue analyses are converted to ng/g by correcting
for the amount of tissue analyzed.
[0621] Only sporadic, relatively low, concentrations of the
compound 1001 ester prodrug are observed in the sclera and
conjunctiva. Compound 1001 is either not detected or is below the
quantitation limit of the assay in the majority of ocular tissues.
These data suggest that RX-10045 is rapidly hydrolyzed to its
active metabolite, RX-10008.
[0622] A summary of the parent compound (RX-10008) tissue
concentrations is presented in Table 9. The highest concentrations
of RX-10008 are found in the cornea, followed by the iris-ciliary
body, conjunctiva, and sclera. There are also relatively high
concentrations of RX-10008 in the aqueous humor. Lower amounts are
found in the retina/choroid and lens. The lowest levels of RX-10008
are found in the vitreous humor.
TABLE-US-00013 Comparison of mean (n = 2) RX-10008 ocular tissue
concentrations following topical ocular administration of RX-10045
(0.15% in HCO-60, 0.1% in HCO-40) formulations to the eye four
times a day at 2 hour intervals for five days to New Zealand White
Rabbits Treatment Group 5 Treatment Group 4 0.1% RX-10045 0.15%
TX-10045 in HCO-40 in HCO-60 RX-10008 (ng/g or ug/mL) Selera
990.sup.a 701 Cornea 15700.sup.a 9650.sup.a Conjunctiva 1132 879
Lens 136 164 Iris-Ciliary Body 2725 2655 Retiua/Choroid 410 323
Vitreous Humor 18 15.7 Aquesous Humor >2000 >2000 .sup.an =
1
[0623] The invention illustratively described herein may be
practiced in the absence of any element or elements, limitation or
limitations which is not specifically disclosed herein. The terms
and expressions which have been employed are used as terms of
description and not of limitation, and there is no intention that
in the use of such terms and expressions of excluding any
equivalents of the features shown and described or portions
thereof, but it is recognized that various modifications are
possible within the scope of the invention claimed. Thus, it should
be understood that although the present invention has been
specifically disclosed by preferred embodiments and optional
features, modification and variation of the concepts herein
disclosed may be resorted to by those skilled in the art, and that
such modifications and variations are considered to be within the
scope of this invention as defined by the appended claims.
[0624] The contents of the articles, patents, and patent
applications, and all other documents and electronically available
information mentioned or cited herein, are hereby incorporated by
reference in their entirety to the same extent as if each
individual publication was specifically and individually indicated
to be incorporated by reference. Applicants reserve the right to
physically incorporate into this application any and all materials
and information from any such articles, patents, patent
applications, or other documents.
[0625] The inventions illustratively described herein may suitably
be practiced in the absence of any element or elements, limitation
or limitations, not specifically disclosed herein. Thus, for
example, the terms "comprising", "including," containing", etc.
shall be read expansively and without limitation. Additionally, the
terms and expressions employed herein have been used as terms of
description and not of limitation, and there is no intention in the
use of such terms and expressions of excluding any equivalents of
the features shown and described or portions thereof, but it is
recognized that various modifications are possible within the scope
of the invention claimed. Thus, it should be understood that
although the present invention has been specifically disclosed by
preferred embodiments and optional features, modification and
variation of the inventions embodied therein herein disclosed may
be resorted to by those skilled in the art, and that such
modifications and variations are considered to be within the scope
of this invention.
[0626] The invention has been described broadly and generically
herein. Each of the narrower species and subgeneric groupings
falling within the generic disclosure also form part of the
invention. This includes the generic description of the invention
with a proviso or negative limitation removing any subject matter
from the genus, regardless of whether or not the excised material
is specifically recited herein.
[0627] In addition, where features or aspects of the invention are
described in terms of Markush groups, those skilled in the art will
recognize that the invention is also thereby described in terms of
any individual member or subgroup of members of the Markush
group.
[0628] Other embodiments are set forth within the following
claims.
* * * * *