U.S. patent application number 11/351761 was filed with the patent office on 2006-11-16 for liquid formulations for treatment of diseases or conditions.
Invention is credited to Philippe JM Dor, Sidiq Farooq, Sreenivasu Mudumba, Thierry Nivaggioli, David A. Weber.
Application Number | 20060258698 11/351761 |
Document ID | / |
Family ID | 36793384 |
Filed Date | 2006-11-16 |
United States Patent
Application |
20060258698 |
Kind Code |
A1 |
Mudumba; Sreenivasu ; et
al. |
November 16, 2006 |
Liquid formulations for treatment of diseases or conditions
Abstract
Diseases and conditions associated with tissues of the body,
including but not limited to tissues in the eye, can be effectively
treated, prevented, inhibited, onset delayed, or regression caused
by administering therapeutic agents to those tissues. Described
herein are liquid formulations which deliver a variety of
therapeutic agents, including but not limited to rapamycin, to a
subject for an extended period of time; liquid formulations which
form a non-dispersed mass when placed in an aqueous medium of a
subject; non-dispersed mass-forming liquid formulations which form
a gel or gel-like substance in an aqueous medium; liquid
formulations, comprising a therapeutic agent and a plurality of
polymers; and methods for delivering therapeutic agents to a
subject for an extended period of time using the liquid
formulations. The liquid formulation may be placed in an aqueous
medium of a subject, including but not limited to via intraocular
or periocular administration, or placement proximate to a site of a
disease or condition to be treated in a subject. A method may be
used to administer rapamycin to treat or prevent angiogenesis,
choroidal neovascularization, or age-related macular degeneration,
or wet age-related macular degeneration in a subject. The liquid
formulations may comprise rapamycin or other therapeutic
agents.
Inventors: |
Mudumba; Sreenivasu; (Union
City, CA) ; Dor; Philippe JM; (Cupertino, CA)
; Nivaggioli; Thierry; (Atherton, CA) ; Weber;
David A.; (Danville, CA) ; Farooq; Sidiq;
(Newark, CA) |
Correspondence
Address: |
MORRISON & FOERSTER LLP
755 PAGE MILL RD
PALO ALTO
CA
94304-1018
US
|
Family ID: |
36793384 |
Appl. No.: |
11/351761 |
Filed: |
February 9, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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60664306 |
Mar 21, 2005 |
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60664040 |
Mar 21, 2005 |
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60651790 |
Feb 9, 2005 |
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Current U.S.
Class: |
514/291 |
Current CPC
Class: |
A61K 31/44 20130101;
A61P 37/06 20180101; A61K 9/0019 20130101; A61P 27/02 20180101;
A61K 31/4745 20130101; A61K 31/045 20130101; A61K 47/12 20130101;
A61K 9/0048 20130101; A61K 47/10 20130101; A61P 9/10 20180101; A61K
9/0046 20130101; A61K 31/436 20130101; A61P 27/08 20180101; A61K
47/44 20130101 |
Class at
Publication: |
514/291 |
International
Class: |
A61K 31/4745 20060101
A61K031/4745 |
Claims
1. A liquid formulation comprising a therapeutic agent, wherein the
liquid formulation when injected into the vitreous of a rabbit eye
delivers an amount of the therapeutic agent sufficient to achieve,
for a period of time of at least 30 days following administration
of the liquid formulation, an average concentration of therapeutic
agent in the retina choroid tissues of the rabbit eye equivalent to
a rapamycin concentration of at least 0.01 ng/mg.
2. A liquid formulation comprising a therapeutic agent, wherein the
liquid formulation when injected into the vitreous of a rabbit eye
delivers an amount of the therapeutic agent sufficient to achieve,
for a period of time of at least 30 days following administration
of the liquid formulation, an average concentration of therapeutic
agent in the vitreous of the rabbit eye equivalent to a rapamycin
concentration of at least 1000 ng/ml.
3. A liquid formulation comprising a therapeutic agent, wherein the
liquid formulation when injected between the sclera and conjunctiva
of a rabbit eye delivers an amount of the therapeutic agent
sufficient to achieve, for a period of time of at least 30 days
following administration of the liquid formulation, an average
concentration of therapeutic agent in the vitreous of the rabbit
eye equivalent to a rapamycin concentration of at least 0.01
ng/ml.
4. A liquid formulation comprising a therapeutic agent, wherein the
liquid formulation when injected between the sclera and conjunctiva
of a rabbit eye delivers an amount of the therapeutic agent
sufficient to achieve, for a period of time of at least 30 days
following administration of the liquid formulation, an average
concentration of therapeutic agent in the retina choroid tissues of
the rabbit eye equivalent to a rapamycin concentration of at least
0.001 ng/mg.
5. A liquid formulation comprising a therapeutic agent, wherein the
liquid formulation forms a non-dispersed mass when injected into
the vitreous of a rabbit eye.
6. The liquid formulation of claim 1, wherein the therapeutic agent
is selected from the group consisting of rapamycin, SDZ-RAD,
tacrolimus, everolimus, pimecrolimus, CCI-779, AP23841, ABT-578,
cyclophilins, FK506-binding proteins (FKBPs), TAFA-93, RAD-001,
temsirolimus, AP23573, 7-epi-rapamycin, 7-thiomethyl-rapamycin,
7-epi-trimethoxyphenyl-rapamycin, 7-epi-thiomethyl-rapamycin,
7-demethoxy-rapamycin, 32-demethoxy-rapamycin,
2-desmethyl-rapamycin, monoester derivatives of rapamycin, diester
derivatives of rapamycin, 27-oximes of rapamycin; 42-oxo analogs of
rapamycin; bicyclic rapamycins; rapamycin dimers; silyl ethers of
rapamycin; rapamycin arylsulfonates, rapamycin sulfamates,
monoesters at positions 31 and 42, diesters at positions 31 and 42,
30-demethoxy rapamycin, and pharmaceutically acceptable prodrugs,
analogs, salts and esters thereof.
7. The liquid formulation of claim 6, wherein the therapeutic agent
is selected from the group consisting of rapamycin, SDZ-RAD,
tacrolimus, everolimus, pimecrolimus, CCI-779, AP23841, ABT-578,
and pharmaceutically acceptable salts and esters thereof.
8. The liquid formulation of claim 2, wherein the therapeutic agent
is selected from the group consisting of rapamycin, SDZ-RAD,
tacrolimus, everolimus, pimecrolimus, CCI-779, AP23841, ABT-578,
cyclophilins, FK506-binding proteins (FKBPs), TAFA-93, RAD-001,
temsirolimus, AP23573, 7-epi-rapamycin, 7-thiomethyl-rapamycin,
7-epi-trimethoxyphenyl-rapamycin, 7-epi-thiomethyl-rapamycin,
7-demethoxy-rapamycin, 32-demethoxy-rapamycin,
2-desmethyl-rapamycin, monoester derivatives of rapamycin, diester
derivatives of rapamycin, 27-oximes of rapamycin; 42-oxo analogs of
rapamycin; bicyclic rapamycins; rapamycin dimers; silyl ethers of
rapamycin; rapamycin arylsulfonates, rapamycin sulfamates,
monoesters at positions 31 and 42, diesters at positions 31 and 42,
30-demethoxy rapamycin, and pharmaceutically acceptable prodrugs,
analogs, salts and esters thereof.
9. The liquid formulation of claim 8, wherein the therapeutic agent
is selected from the group consisting of rapamycin, SDZ-RAD,
tacrolimus, everolimus, pimecrolimus, CCI-779, AP23841, ABT-578,
and pharmaceutically acceptable salts and esters thereof.
10. The liquid formulation of claim 3, wherein the therapeutic
agent is selected from the group consisting of rapamycin, SDZ-RAD,
tacrolimus, everolimus, pimecrolimus, CCI-779, AP23841, ABT-578,
cyclophilins, FK506-binding proteins (FKBPs), TAFA-93, RAD-001,
temsirolimus, AP23573, 7-epi-rapamycin, 7-thiomethyl-rapamycin,
7-epi-trimethoxyphenyl-rapamycin, 7-epi-thiomethyl-rapamycin,
7-demethoxy-rapamycin, 32-demethoxy-rapamycin,
2-desmethyl-rapamycin, monoester derivatives of rapamycin, diester
derivatives of rapamycin, 27-oximes of rapamycin; 42-oxo analogs of
rapamycin; bicyclic rapamycins; rapamycin dimers; silyl ethers of
rapamycin; rapamycin arylsulfonates, rapamycin sulfamates,
monoesters at positions 31 and 42, diesters at positions 31 and 42,
30-demethoxy rapamycin, and pharmaceutically acceptable prodrugs,
analogs, salts and esters thereof.
11. The liquid formulation of claim 10, wherein the therapeutic
agent is selected from the group consisting of rapamycin, SDZ-RAD,
tacrolimus, everolimus, pimecrolimus, CCI-779, AP23841, ABT-578,
and pharmaceutically acceptable salts and esters thereof.
12. The liquid formulation of claim 4, wherein the therapeutic
agent is selected from the group consisting of rapamycin, SDZ-RAD,
tacrolimus, everolimus, pimecrolimus, CCI-779, AP23841, ABT-578,
cyclophilins, FK506-binding proteins (FKBPs), TAFA-93, RAD-001,
temsirolimus, AP23573, 7-epi-rapamycin, 7-thiomethyl-rapamycin,
7-epi-trimethoxyphenyl-rapamycin, 7-epi-thiomethyl-rapamycin,
7-demethoxy-rapamycin, 32-demethoxy-rapamycin,
2-desmethyl-rapamycin, monoester derivatives of rapamycin, diester
derivatives of rapamycin, 27-oximes of rapamycin; 42-oxo analogs of
rapamycin; bicyclic rapamycins; rapamycin dimers; silyl ethers of
rapamycin; rapamycin arylsulfonates, rapamycin sulfamates,
monoesters at positions 31 and 42, diesters at positions 31 and 42,
30-demethoxy rapamycin, and pharmaceutically acceptable prodrugs,
analogs, salts and esters thereof.
13. The liquid formulation of claim 12, wherein the therapeutic
agent is selected from the group consisting of rapamycin, SDZ-RAD,
tacrolimus, everolimus, pimecrolimus, CCI-779, AP23841, ABT-578,
and pharmaceutically acceptable salts and esters thereof.
14. The liquid formulation of claim 5, wherein the therapeutic
agent is selected from the group consisting of rapamycin, SDZ-RAD,
tacrolimus, everolimus, pimecrolimus, CCI-779, AP23841, ABT-578,
cyclophilins, FK506-binding proteins (FKBPs), TAFA-93, RAD-001,
temsirolimus AP23573, 7-epi-rapamycin, 7-thiomethyl-rapamycin,
7-epi-trimethoxyphenyl-rapamycin, 7-epi-thiomethyl-rapamycin,
7-demethoxy-rapamycin, 32-demethoxy-rapamycin,
2-desmethyl-rapamycin, monoester derivatives of rapamycin, diester
derivatives of rapamycin, 27-oximes of rapamycin; 42-oxo analogs of
rapamycin; bicyclic rapamycins; rapamycin dimers; silyl ethers of
rapamycin; rapamycin arylsulfonates, rapamycin sulfamates,
monoesters at positions 31 and 42, diesters at positions 31 and 42,
30-demethoxy rapamycin, and pharmaceutically acceptable prodrugs,
analogs, salts and esters thereof.
15. The liquid formulation of claim 14, wherein the therapeutic
agent is selected from the group consisting of rapamycin, SDZ-RAD,
tacrolimus, everolimus, pimecrolimus, CCI-779, AP23841, ABT-578,
and pharmaceutically acceptable salts and esters thereof.
16. A method for treating wet age-related macular degeneration in a
human subject, the method comprising administering to the human
subject by intraocular or periocular delivery a volume of the
liquid formulation of any of claims 7, 9, 11, 13, and 15 containing
an amount of rapamycin effective to treat wet age-related macular
degeneration in the human subject.
17. A method for preventing wet age-related macular degeneration in
a human subject, the method comprising administering to the human
subject by intraocular or periocular delivery a volume of the
liquid formulation of any of claims 7, 9, 11, 13, and 15 containing
an amount of rapamycin effective to prevent wet age-related macular
degeneration in the human subject.
18. The method of claim 16, wherein the liquid formulation further
comprises polyethylene glycol and wherein the volume of liquid
formulation is administered to the human subject by placement in
the vitreous and the volume of liquid formulation contains less
than 100 .mu.L of polyethylene glycol.
19. The method of claim 16, wherein the liquid formulation further
comprises polyethylene glycol and wherein the volume of liquid
formulation is administered to the human subject by placement
between the sclera and conjunctiva and the volume of liquid
formulation contains less than 150 .mu.L of polyethylene
glycol.
20. The method of claim 17, wherein the liquid formulation further
comprises polyethylene glycol and wherein the volume of liquid
formulation is administered to the human subject by placement
between the sclera and conjunctiva and the volume of liquid
formulation contains less than 150 .mu.L of polyethylene
glycol.
21. A method for treating wet age-related macular degeneration in a
human subject, the method comprising administering to the human
subject by intraocular or periocular delivery of a liquid
formulation comprising an effective amount of a therapeutic agent
selected from rapamycin, SDZ-RAD, tacrolimus, everolimus,
pimecrolimus, CCI-779, AP23841, ABT-578, and pharmaceutically
acceptable salts and esters thereof; and wherein the liquid
formulation has one or more characteristics selected from the group
consisting of (1) the liquid formulation when injected into the
vitreous of a rabbit eye delivers an amount of the therapeutic
agent sufficient to achieve, for a period of time of at least 30
days following administration of the liquid formulation, an average
concentration of therapeutic agent in the retina choroid tissues of
the rabbit eye equivalent to a rapamycin concentration of at least
0.01 ng/mg; (2) the liquid formulation when injected into the
vitreous of a rabbit eye delivers an amount of the therapeutic
agent sufficient to achieve, for a period of time of at least 30
days following administration of the liquid formulation, an average
concentration of therapeutic agent in the vitreous of the rabbit
eye equivalent to a rapamycin concentration of at least 1000 ng/ml;
(3) the liquid formulation when injected between the sclera and
conjunctiva of a rabbit eye delivers an amount of the therapeutic
agent sufficient to achieve, for a period of time of at least 30
days following administration of the liquid formulation, an average
concentration of therapeutic agent in the vitreous of the rabbit
eye equivalent to a rapamycin concentration of at least 0.01 ng/ml;
(4) the liquid formulation when injected between the sclera and
conjunctiva of a rabbit eye delivers an amount of the therapeutic
agent sufficient to achieve, for a period of time of at least 30
days following administration of the liquid formulation, an average
concentration of therapeutic agent in the retina choroid tissues of
the rabbit eye equivalent to a rapamycin concentration of at least
0.001 ng/mg; and (5) the liquid formulation forms a non-dispersed
mass when injected into the vitreous of a rabbit eye.
22. A method for preventing wet age-related macular degeneration in
a human subject, the method comprising administering to the human
subject by intraocular or periocular delivery of a liquid
formulation comprising an effective amount of a therapeutic agent
selected from rapamycin, SDZ-RAD, tacrolimus, everolimus,
pimecrolimus, CCI-779, AP23841, ABT-578, and pharmaceutically
acceptable salts and esters thereof; and wherein the liquid
formulation has one or more characteristic selected from the group
consisting of (1) the liquid formulation when injected into the
vitreous of a rabbit eye delivers an amount of the therapeutic
agent sufficient to achieve, for a period of time of at least 30
days following administration of the liquid formulation, an average
concentration of therapeutic agent in the retina choroid tissues of
the rabbit eye equivalent to a rapamycin concentration of at least
0.01 ng/mg; (2) the liquid formulation when injected into the
vitreous of a rabbit eye delivers an amount of the therapeutic
agent sufficient to achieve, for a period of time of at least 30
days following administration of the liquid formulation, an average
concentration of therapeutic agent in the vitreous of the rabbit
eye equivalent to a rapamycin concentration of at least 1000 ng/ml;
(3) the liquid formulation when injected between the sclera and
conjunctiva of a rabbit eye delivers an amount of the therapeutic
agent sufficient to achieve, for a period of time of at least 30
days following administration of the liquid formulation, an average
concentration of therapeutic agent in the vitreous of the rabbit
eye equivalent to a rapamycin concentration of at least 0.01 ng/ml;
(4) the liquid formulation when injected between the sclera and
conjunctiva of a rabbit eye delivers an amount of the therapeutic
agent sufficient to achieve, for a period of time of at least 30
days following administration of the liquid formulation, an average
concentration of therapeutic agent in the retina choroid tissues of
the rabbit eye equivalent to a rapamycin concentration of at least
0.001 ng/mg; and (5) the liquid formulation forms a non-dispersed
mass when injected into the vitreous of a rabbit eye.
23. The method of claim 22, wherein the human subject is identified
as being at heightened risk of developing wet age-related macular
degeneration in the eye to which the liquid formulation is
administered.
24. The method of claim 23, wherein the human subject has dry
age-related macular degeneration in at least one eye.
25. The method of claim 23, wherein the human subject has wet
age-related macular degeneration in one eye and the liquid
formulation is administered to the eye without wet age-related
macular degeneration.
26. A method for treating dry age-related macular degeneration in a
human subject, the method comprising administering to the human
subject by intraocular or periocular delivery of a liquid
formulation comprising an effective amount of a therapeutic agent
selected from rapamycin, SDZ-RAD, tacrolimus, everolimus,
pimecrolimus, CCI-779, AP23841, ABT-578, and pharmaceutically
acceptable salts and esters thereof; and wherein the liquid
formulation has one or more characteristic selected from the group
consisting of (1) the liquid formulation when injected into the
vitreous of a rabbit eye delivers an amount of the therapeutic
agent sufficient to achieve, for a period of time of at least 30
days following administration of the liquid formulation, an average
concentration of therapeutic agent in the retina choroid tissues of
the rabbit eye equivalent to a rapamycin concentration of at least
0.01 ng/mg; (2) the liquid formulation when injected into the
vitreous of a rabbit eye delivers an amount of the therapeutic
agent sufficient to achieve, for a period of time of at least 30
days following administration of the liquid formulation, an average
concentration of therapeutic agent in the vitreous of the rabbit
eye equivalent to a rapamycin concentration of at least 1000 ng/ml;
(3) the liquid formulation when injected between the sclera and
conjunctiva of a rabbit eye delivers an amount of the therapeutic
agent sufficient to achieve, for a period of time of at least 30
days following administration of the liquid formulation, an average
concentration of therapeutic agent in the vitreous of the rabbit
eye equivalent to a rapamycin concentration of at least 0.01 ng/ml;
(4) the liquid formulation when injected between the sclera and
conjunctiva of a rabbit eye delivers an amount of the therapeutic
agent sufficient to achieve, for a period of time of at least 30
days following administration of the liquid formulation, an average
concentration of therapeutic agent in the retina choroid tissues of
the rabbit eye equivalent to a rapamycin concentration of at least
0.001 ng/mg; and (5) the liquid formulation forms a non-dispersed
mass when injected into the vitreous of a rabbit eye.
27. A method for preventing wet age-related macular degeneration in
a human subject having dry age-related macular degeneration, the
method comprising administering to a human subject having dry
age-related macular degeneration a liquid formulation comprising an
effective amount of a therapeutic agent selected from rapamycin,
SDZ-RAD, tacrolimus, everolimus, pimecrolimus, CCI-779, AP23841,
ABT-578, and pharmaceutically acceptable salts and esters thereof;
wherein the liquid formulation is administered by intraocular or
periocular delivery; and wherein the liquid formulation has one or
more characteristic selected from the group consisting of (1) the
liquid formulation when injected into the vitreous of a rabbit eye
delivers an amount of the therapeutic agent sufficient to achieve,
for a period of time of at least 30 days following administration
of the liquid formulation, an average concentration of therapeutic
agent in the retina choroid tissues of the rabbit eye equivalent to
a rapamycin concentration of at least 0.01 ng/mg; (2) the liquid
formulation when injected into the vitreous of a rabbit eye
delivers an amount of the therapeutic agent sufficient to achieve,
for a period of time of at least 30 days following administration
of the liquid formulation, an average concentration of therapeutic
agent in the vitreous of the rabbit eye equivalent to a rapamycin
concentration of at least 1000 ng/ml; (3) the liquid formulation
when injected between the sclera and conjunctiva of a rabbit eye
delivers an amount of the therapeutic agent sufficient to achieve,
for a period of time of at least 30 days following administration
of the liquid formulation, an average concentration of therapeutic
agent in the vitreous of the rabbit eye equivalent to a rapamycin
concentration of at least 0.01 ng/ml; (4) the liquid formulation
when injected between the sclera and conjunctiva of a rabbit eye
delivers an amount of the therapeutic agent sufficient to achieve,
for a period of time of at least 30 days following administration
of the liquid formulation, an average concentration of therapeutic
agent in the retina choroid tissues of the rabbit eye equivalent to
a rapamycin concentration of at least 0.001 ng/mg; and (5) the
liquid formulation forms a non-dispersed mass when injected into
the vitreous of a rabbit eye.
Description
CROSS-REFERENCES TO RELATED APPLICATIONS
[0001] The present application is related to and claims priority
from U.S. Provisional Patent Application Ser. No. 60/664,040 titled
"Liquid Formulations For Treatment Of Diseases Or Conditions,"
filed Mar. 21, 2005, U.S. Provisional Patent Application Ser. No.
60/664,306 titled "In Situ Gelling Formulations And Liquid
Formulations For Treatment of Diseases Or Conditions," filed Mar.
21, 2005, U.S. Provisional Patent Application Ser. No. 60/651,790,
titled "Formulations For Ocular Treatment," filed Feb. 9, 2005,
each of which is incorporated herein by reference in its entirety
for all purposes.
FIELD
[0002] Described herein are liquid formulations for treatment,
prevention, inhibition, delaying onset of, or causing regression of
a disease or condition by delivery of therapeutic agents to a
subject, including but not limited to a human subject, including
but not limited to the treatment of age-related macular
degeneration ("AMD") by delivery of a liquid formulation comprising
a therapeutic agent, including but not limited to rapamycin
(sirolimus), to the eye of a subject, including but not limited to
a human subject. Nonlimiting examples of liquid formulations
include solutions, suspensions, and in situ gelling
formulations.
BACKGROUND
[0003] The retina of the eye contains the cones and rods that
detect light. In the center of the retina is the macula lutea,
which is about 1/3to 1/2 cm in diameter. The macula provides
detailed vision, particularly in the center (the fovea), because
the cones are higher in density. Blood vessels, ganglion cells,
inner nuclear layer and cells, and the plexiform layers are all
displaced to one side (rather than resting above the cones),
thereby allowing light a more direct path to the cones.
[0004] Under the retina are the choroid, comprising a collection of
blood vessels embedded within a fibrous tissue, and the deeply
pigmented epithelium, which overlays the choroid layer. The
choroidal blood vessels provide nutrition to the retina
(particularly its visual cells).
[0005] There are a variety of retinal disorders for which there is
currently no treatment or for which the current treatment is not
optimal. Retinal disorders such as uveitis (an inflammation of the
uveal tract: iris, ciliary body, and choroid), central retinal vein
occlusive diseases (CRVO), branch retinal venous occlusion (BRVO),
macular degeneration, macular edema, proliferative diabetic
retinopathy, and retinal detachment generally are all retinal
disorders that are difficult to treat with conventional
therapies.
[0006] Age-related macular degeneration (AMD) is the major cause of
severe visual loss in the United States for individuals over the
age of 60. AMD occurs in either an atrophic or less commonly an
exudative form. The atrophic form of AMD is also called "dry AMD,"
and the exudative form of AMD is also called "wet AMD."
[0007] In exudative AMD, blood vessels grow from the
choriocapillaris through defects in Bruch's membrane, and in some
cases the underlying retinal pigment epithelium. Organization of
serous or hemorrhagic exudates escaping from these vessels results
in fibrovascular scarring of the macular region with attendant
degeneration of the neuroretina, detachment and tears of the
retinal, pigment epithelium, vitreous hemorrhage and permanent loss
of central vision. This process is responsible for more than 80% of
cases of significant visual loss in subjects with AMD. Current or
forthcoming treatments include laser photocoagulation, photodynamic
therapy, treatment with VEGF antibody fragments, treatment with
pegylated aptamers, and treatment with certain small molecule
agents.
[0008] Several studies have recently described the use of laser
photocoagulation in the treatment of initial or recurrent
neovascular lesions associated with AMD (Macular Photocoagulation
Study Groups (1991) in Arch. Ophthal. 109:1220; Arch. Ophthal.
109:1232; Arch. Ophthal. 109:1242). Unfortunately, AMD subjects
with subfoveal lesions subjected to laser treatment experienced a
rather precipitous reduction in visual acuity (mean 3 lines) at 3
months follow-up. Moreover, at two years post-treatment treated
eyes had only marginally better visual acuity than their untreated
counterparts (means of 20/320 and 20/400, respectively). Another
drawback of the procedure is that vision after surgery is
immediately worse.
[0009] Photodynamic therapy (PDT) is a form of phototherapy, a term
encompassing all treatments that use light to produce a beneficial
reaction in a subject. Optimally, PDT destroys unwanted tissue
while sparing normal tissue. Typically, a compound called a
photosensitizer is administered to the subject. Usually, the
photosensitizer alone has little or no effect on the subject. When
light, often from a laser, is directed onto a tissue containing the
photosensitizer, the photosensitizer is activated and begins
destroying targeted tissue. Because the light provided to the
subject is confined to a particularly targeted area, PDT can be
used to selectively target abnormal tissue, thus sparing
surrounding healthy tissue. PDT is currently used to treat retinal
diseases such as AMD. PDT is currently the mainstay of treatment
for subfoveal choroidal neovascularization in subjects with AMD
(Photodynamic Therapy for Subfoveal Choroidal Neovascularization in
Age Related Macular Degeneration with Verteporfin (TAP Study Group)
Arch Ophthalmol. 1999 117:1329-1345.
[0010] Choroidal neovascularization (CNV) has proven to be
recalcitrant to treatment in most cases. Conventional laser
treatment can ablate CNV and help to preserve vision in selected
cases not involving the center of the retina, but this is limited
to only about 10% of the cases. Unfortunately, even with successful
conventional laser photocoagulation, the neovascularization recurs
in about 50-70% of eyes (50% over 3 years and >60% at 5 years).
(Macular Photocoagulation Study Group, Arch. Ophthalmol.
204:694-701 (1986)). In addition, many subjects who develop CNV are
not good candidates for laser therapy because the CNV is too large
for laser treatment, or the location cannot be determined so that
the physician cannot accurately aim the laser. Photodynamic
therapy, although utilized in up to 50% of new cases of subfoveal
CNV has only marginal benefits over natural history, and generally
delays progression of visual loss rather than improving vision
which is already decreased secondary to the subfoveal lesion. PDT
is neither preventive or definitive. Several PDT treatments are
usually required per subject and additionally, certain subtypes of
CNV fare less well than others.
[0011] Thus, there remains a long-felt need for methods,
compositions, and formulations that may be used to optimally
prevent or significantly inhibit choroidal neovascularization and
to prevent and treat wet AMD.
[0012] In addition to AMD, choroidal neovascularization is
associated with such retinal disorders as presumed ocular
histoplasmosis syndrome, myopic degeneration, angioid streaks,
idiopathic central serous chorioretinopathy, inflammatory
conditions of the retina and or choroid, and ocular trauma.
Angiogenic damage associated with neovascularization occurs in a
wide range of disorders including diabetic retinopathy, venous
occlusions, sickle cell retinopathy, retinopathy of prematurity,
retinal detachment, ocular ischemia and trauma.
[0013] Uveitis is another retinal disorder that has proven
difficult to treat using existing therapies. Uveitis is a general
term that indicates an inflammation of any component of the uveal
tract. The uveal tract of the eye consists of the iris, ciliary
body, and choroid. Inflammation of the overlying retina, called
retinitis, or of the optic nerve, called optic neuritis, may occur
with or without accompanying uveitis.
[0014] Uveitis is most commonly classified anatomically as
anterior, intermediate, posterior, or diffuse. Posterior uveitis
signifies any of a number of forms of retinitis, choroiditis, or
optic neuritis. Diffuse uveitis implies inflammation involving all
parts of the eye, including anterior, intermediate, and posterior
structures.
[0015] The symptoms and signs of uveitis' may be subtle, and vary
considerably depending on the site and severity of the
inflammation. Regarding posterior uveitis, the most common symptoms
include the presence of floaters and decreased vision. Cells in the
vitreous humor, white or yellow-white lesions in the retina and/or
underlying choroid, exudative retinal detachments, retinal
vasculitis, and optic nerve edema may also be present in a subject
suffering from posterior uveitis.
[0016] Ocular complications of uveitis may produce profound and
irreversible loss of vision, especially when unrecognized or
treated improperly. The most frequent complications of posterior
uveitis include retinal detachment; neovascularization of the
retina, optic nerve, or iris; and cystoid macular edema.
[0017] Macular edema (ME) can occur if the swelling, leaking, and
hard exudates noted in background diabetic retinopathy (BDR) occur
within the macula, the central 5% of the retina most critical to
vision. Background diabetic retinopathy (BDR) typically consists of
retinal microaneurisms that result from changes in the retinal
microcirculation. These microaneurisms are usually the earliest
visible change in retinopathy seen on exam with an ophthalmoscope
as scattered red spots in the retina where tiny, weakened blood
vessels have ballooned out. The ocular findings in background
diabetic retinopathy progress to cotton wool spots, intraretinal
hemorrhages, leakage of fluid from the retinal capillaries, and
retinal exudates. The increased vascular permeability is also
related to elevated levels of local growth factors such as vascular
endothelial growth factor. The macula is rich in cones, the nerve
endings that detect color and upon which daytime vision depends.
When increased retinal capillary permeability effects the macula,
blurring occurs in the middle or just to the side of the central
visual field, rather like looking through cellophane. Visual loss
may progress over a period of months, and can be very annoying
because of the inability to focus clearly. ME is a common cause of
severe visual impairment.
[0018] There have been many attempts to treat CNV and its related
diseases and conditions, as well as other conditions such as
macular edema and chronic inflammation, with pharmaceuticals. For
example, use of rapamycin to inhibit CNV and wet AMD has been
described in U.S. application Ser. No. 10/665,203, which is
incorporated herein by reference in its entirety. The use of
rapamycin to treat inflammatory diseases of the eye has been
described in U.S. Pat. No. 5,387,589, titled Method of Treating
Ocular Inflammation, with inventor Prassad Kulkarni, assigned to
University of Louisville Research Foundation, the contents of which
is incorporated herein in its entirety.
[0019] Particularly for chronic diseases, including those described
herein, there is a great need for long acting methods for
delivering therapeutic agents to the eye, such as to the posterior
segment to treat CNV in such diseases as AMD, macular edema,
proliferative retinopathies, and chronic inflammation. Formulations
with extended delivery of therapeutic agent are more comfortable
and convenient for a subject, due to a diminished frequency of
ocular injections of the therapeutic agent.
[0020] Direct delivery of therapeutic agents to the eye rather than
systemic administration may be advantageous because the therapeutic
agent concentration at the site of action is increased relative to
the therapeutic agent concentration in a subject's circulatory
system Additionally, therapeutic agents may have undesirable side
effects when delivered systemically to treat posterior segment
disease. Thus, localized drug delivery may promote efficacy while
decreasing side effects and systemic toxicity.
SUMMARY
[0021] The methods, compositions, and liquid formulations described
herein allow delivery of a therapeutic agent to a subject,
including but not limited to a human subject or to the eye of a
subject. Described herein are methods, compositions, and liquid
formulations for delivering a variety of therapeutic agents for
extended periods of time which can be used for the treatment,
prevention, inhibition, delaying onset of, or causing regression of
a number of conditions or diseases, including but not limited to
diseases or conditions of the eye. The liquid formulations include,
without limitation, solutions, suspensions, and in situ gelling
formulations.
[0022] Described herein are methods, compositions and liquid
formulations for administering to a human subject an amount of
rapamycin effective to treat, prevent, inhibit, delay onset of, or
cause regression of wet AMD.
[0023] As described in further detail in the Detailed Description
section, the methods, compositions and liquid formulations may also
be used for delivery to a subject, including but not limited to a
human subject or to the eye of a human subject of therapeutically
effective amounts of rapamycin for the treatment, prevention,
inhibition, delaying of the onset of, or causing the regression of
wet AMD. In some variations, the methods, compositions, and liquid
formulations are used to treat wet AMD. In some variations, the
methods, compositions, and liquid formulations are used to prevent
wet AMD. In some variations, the methods and formulations described
herein are used to prevent the transition from dry AMD to wet AMD.
The methods, compositions and liquid formulations may also be used
for delivery to a subject, including but not limited to a human
subject or to the eye of a subject of therapeutically effective
amount units of rapamycin for the treatment, prevention,
inhibition, delaying of the onset of, or causing the regression of
CNV. In some variations, the methods, compositions and liquid
formulations are used to treat CNV. The methods, compositions and
liquid formulations may also be used for delivery to a subject,
including but not limited to a human subject or to the eye of a
subject of therapeutically effective amounts of rapamycin for the
treatment, prevention, inhibition, delaying of the onset of, or
causing the regression of angiogenesis in the eye. In some
variations, the methods, compositions and liquid formulations are
used to treat angiogenesis. Other diseases and conditions that may
be treated, prevented, inhibited, have onset delayed, or caused to
regress using rapamycin are described in the Diseases and
Conditions section of the Detailed Description.
[0024] As described in further detail in the Detailed Description,
the methods, compositions and liquid formulations may also be used
for delivery to a subject, including but not limited to a human
subject or to the eye of a subject of therapeutically effective
amounts of therapeutic agents other than rapamycin for the
treatment, prevention, inhibition, delaying of the onset of, or
causing the regression of wet AMD. In some variations, the methods,
compositions and liquid formulations are used to treat wet AMD.
Therapeutic agents that may be used are described in detail in the
Therapeutic Agents section. Such therapeutic agents include but are
not limited to immunophilin binding compounds. Immunophilin binding
compounds that may be used include but are not limited to the limus
family of compounds described further in the Therapeutic Agents
section herein, including rapamycin, SDZ-RAD, tacrolimus,
everolimus, pimecrolimus, CCI-779, AP23841, ABT-578, derivatives,
analogs, prodrugs, salts and esters thereof. The methods,
compositions and liquid formulations may also be used for delivery
to a subject, including but not limited to a human subject or to
the eye of a subject of therapeutically effective amounts of
therapeutic agents for the treatment, prevention, inhibition,
delaying of the onset of, or causing the regression of CNV. In some
variations, the methods, compositions and liquid formulations are
used to treat CNV. The methods, compositions and liquid
formulations may also be used for delivery to a subject, including
but not limited to a human subject or to the eye of a subject of
therapeutically effective amounts of therapeutic agents for the
treatment, prevention, inhibition, delaying of the onset of, or
causing the regression of angiogenesis in the eye. In some
variations, the methods, compositions and liquid formulations are
used to treat angiogenesis. Other diseases and conditions that may
be treated, prevented, inhibited, have onset delayed, or caused to
regress using therapeutic agents other than rapamycin are described
in the Diseases and Conditions section of the Detailed
Description.
[0025] One liquid formulation described herein comprises a solution
that includes a therapeutic agent dissolved in a solvent.
Generally, any solvent that has the desired effect may be used in
which the therapeutic agent dissolves and which can be administered
to a subject, including but not limited to a human subject or an
eye of a subject. Generally, any concentration of therapeutic agent
that has the desired effect can be used. The formulation in some
variations is a solution which is unsaturated, a saturated or a
supersaturated solution. The solvent may be a pure solvent or may
be a mixture of liquid solvent components. In some variations the
solution formed is an in situ gelling formulation. Solvents and
types of solutions that may be used are well known to those versed
in such drug delivery technologies.
[0026] The liquid formulations described herein may form a
non-dispersed mass when placed into a rabbit eye, including but not
limited to the vitreous of a rabbit eye. In some variations the
non-dispersed mass comprises a gel. In some variations, the liquid
formulation comprises a therapeutic agent and a plurality of
polymers. In some variations one of the polymers is polyacrylate or
polymethacrylate. In some variations one of the polymers is
polyvinylpyrrolidone.
[0027] In some variations, the non-dispersed mass comprises a
depot. In some variations, the non-dispersed mass consists of a
depot.
[0028] For liquid formulations which form a non-dispersed mass, the
non-dispersed mass may generally be any geometry or shape. The
non-dispersed mass-forming liquid formulations may, for instance,
appear as a compact spherical mass when placed in the vitreous. In
some variations the liquid formulations described herein form a
milky or whitish colored semi-contiguous or semi-solid
non-dispersed mass relative to the medium in which it is placed,
when placed in the vitreous.
[0029] The liquid formulations may generally be administered in any
volume that has the desired effect. In one method a volume of a
liquid formulation is administered to the vitreous and the liquid
formulation is less than one half the volume of the vitreous.
[0030] Routes of administration that may be used to administer a
liquid formulation include but are not limited to (1) placement of
the liquid formulation by placement, including by injection, into a
medium, including but not limited to an aqueous medium in the body,
including but not limited to intraocular or periocular injection;
or (2) oral administration of the liquid formulation. The liquid
formulation may be administered systemically, including but not
limited to the following delivery routes: rectal, vaginal,
infusion, intramuscular, intraperitoneal, intraarterial,
intrathecal, intrabronchial, intracisternal, cutaneous,
subcutaneous, intradermal, transdermal, intravenous, intracervical,
intraabdominal, intracranial, intrapulmonary, intrathoracic,
intratracheal, nasal, buccal, sublingual, oral, parenteral, or
nebulised or aerosolized using aerosol propellants. In some
variations, the liquid formulation is administered
subconjunctivally. In some variations, the liquid formulation is
administered intravitreally.
[0031] The liquid formulations described herein may be delivered to
any medium of a subject, including but not limited to a human
subject, including but not limited to an aqueous medium of a
subject.
[0032] One liquid formulation described herein comprises a liquid
formulation of rapamycin or other therapeutic agent. The liquid
formulations may comprise a solution, suspension, an in situ
gelling formulation, or an emulsion. The droplets in the emulsion
may generally be of any size, including but not limited to up to
about 5,000 nm.
[0033] In some formulations described herein, the liquid
formulations may comprise a therapeutic agent including but not
limited to rapamycin, and one or more solubilizing agents or
solvents. In some variations, the solubilizing agent or solvent is
glycerin, DMSO, DMA, N-methylpyrrolidone, ethanol, benzyl alcohol,
isopropyl alcohol, polyethylene glycol of various molecular
weights, including but not limited to PEG 300 and PEG 400, or
propylene glycol or a mixture of one or more thereof.
[0034] In some formulations described herein, the liquid
formulation includes hyaluronic acid.
[0035] The liquid formulations described herein may deliver a
therapeutic agent or agents for an extended period of time. One
nonlimiting example of such an extended release delivery system is
a liquid formulation that delivers a therapeutic agent or agents to
a subject, including but not limited to a human subject or to the
eye of a subject in an amount sufficient to maintain an amount
effective to treat, prevent, inhibit, delay onset of, or cause
regression of a disease or condition in a subject for an extended
period of time. In some variations, the liquid formulation is used
to treat a disease or condition in a subject, including but not
limited to a human subject. In some variations, the liquid
formulation delivers the therapeutic agent for at least about one,
about two, about three, about six, about nine, or about twelve
months.
[0036] The liquid formulations described herein may deliver
rapamycin or other therapeutic agents for an extended period of
time. One nonlimiting example of such an extended release delivery
system is a liquid formulation that delivers rapamycin to a
subject, including but not limited to a human subject or to the eye
of a subject in an amount sufficient to maintain an amount
effective to treat, prevent, inhibit, delay onset of, or cause
regression of wet age-related macular degeneration for an extended
period of time. In some variations, the liquid formulation is used
to treat wet age-related macular degeneration for an extended
period of time. In some variations, the liquid formulation is used
to prevent wet age-related macular degeneration for an extended
period of time. In some variations, the liquid formulation is used
to prevent transition of dry AMD to wet AMD for an extended period
of time. In one nonlimiting example, the liquid formulation
delivers the rapamycin to the vitreous, sclera, retina, choroid,
macula, or other tissues of a subject, including but not limited to
a human subject in an amount sufficient to treat, prevent, inhibit,
delay onset of, or cause regression of wet age-related macular
degeneration for at least about three, about six, about nine, or
about twelve months. In some variations, the level of rapamycin is
sufficient to treat AMD. In some variations, the level of rapamycin
is sufficient to prevent onset of wet AMD.
[0037] Other extended periods of release are described in the
Detailed Description.
BRIEF DESCRIPTION OF THE DRAWINGS
[0038] FIGS. 1A-1C schematically depicts formation of a
non-dispersed mass, after injection of a liquid formulation into
the vitreous of an eye, as it is believed to occur in some
variations.
[0039] FIG. 2 depicts the level of rapamycin in the vitreous
(ng/ml), retina choroid (ng/mg), and sclera (ng/mg) of rabbit eyes
at 20, 40, 67, and 90 days after subconjunctival injection of a
1.256% solution of rapamycin in water, ethanol, and F127
(Lutrol).
[0040] FIG. 3 depicts the level of rapamycin in the vitreous
(ng/ml), retina choroid (ng/mg), and sclera (ng/mg) of rabbit eyes
at 14, 35, 62, and 85 days after subconjunctival injection of a 5%
solution of rapamycin in PEG 400 and ethanol. The level of
rapamycin present in the vitreous (ng/ml) is also shown at 2 days
after injection.
[0041] FIG. 4 depicts the level of rapamycin in the vitreous
(ng/ml), retina choroid (ng/mg), and sclera (ng/mg) of rabbit eyes
at 14, 35, 62, and 90 days after intravitreal injection of a 5%
solution of rapamycin in PEG 400 and ethanol. The level of
rapamycin present in the vitreous (ng/ml) is also shown at 2 days
after injection.
[0042] FIG. 5 depicts images of rabbit eyes 8 days after
intravitreal injection of 10 .mu.l (FIG. 4A), 20 .mu.l (FIG. 4B),
and 40 .mu.l (FIG. 4C) of a 6% rapamycin suspension in PEG400.
[0043] FIG. 6 depicts the level of rapamycin in the vitreous
(ng/ml), retina choroid tissues (ng/mg), and sclera (ng/mg) of
rabbit eyes at 7, 32, 45, and 90 days after subconjunctival
injection of a 4.2% solution of rapamycin in ethanol, PVP K90, PEG
400, and Eudragit RL 100.
[0044] FIG. 7 depicts the level of rapamycin in the vitreous
(ng/ml), retina choroid tissues (ng/mg), and sclera (ng/mg) of
rabbit eyes at 14, 42, 63, and 91 days after subconjunctival
injection of a 3% suspension of rapamycin in PEG 400.
[0045] FIG. 8 depicts the level of rapamycin in the vitreous
(ng/ml), retina choroid tissues (ng/mg) and sclera (ng/mg) of
rabbit eyes at 14, 42, 63, and 91 days after intravitreal injection
of a 3% suspension of rapamycin in PEG 400, and in the vitreous at
63 and 91 days after injection.
[0046] FIG. 9 depicts the level of rapamycin in the vitreous
(ng/ml), retina choroid tissues (ng/mg), and sclera (ng/mg) of
rabbit eyes at 14, 42, 63, and 91 days after subconjunctival
injection of a 2% solutin of rapamycin in ethanol and PEG 400.
[0047] FIG. 10 depicts the level of rapamycin in the retina choroid
tissues (ng/mg) and sclera (ng/mg) of rabbit eyes at 14, 42, 63,
and 91 days after intravitreal injection of a 2% solution of
rapamycin in ethanol and PEG 400.
[0048] FIG. 11 depicts the level of rapamycin in the vitreous
(ng/ml) of rabbit eyes at 63 and 91 days after intravitreal
injection of a 2% solution of rapamycin in ethanol and PEG 400.
[0049] FIG. 12 depicts the level of rapamycin in the vitreous
(ng/ml) of rabbit eyes at 5, 30, 60, 90, and 120 days after
subconjunctival injection of 20 .mu.l, 40 .mu.l, and 60 .mu.l doses
of a 2% solution of rapamycin in ethanol and PEG 400.
[0050] FIG. 13 depicts the level of rapamycin in the retina choroid
tissues (ng/mg) of rabbit eyes at 5, 30, 60, 90, and 120 days after
subconjunctival injection of 20 .mu.l, 40 .mu.l, and 60 .mu.l doses
of a 2% solution of rapamycin in ethanol and PEG 400.
[0051] FIG. 14 depicts the level of rapamycin in the vitreous
(ng/ml) of rabbit eyes at 5, 30, 60, 90, and 120 days after
intravitreal injection of 20 .mu.l and 40 .mu.l doses of a 2%
solution of rapamycin in ethanol and PEG 400 and of a 100 .mu.l
dose of a 0.4% rapamycin solution in ethanol and PEG 400.
[0052] FIG. 15 depicts the level of rapamycin in the retina choroid
tissues (ng/mg) of rabbit eyes at 5, 30, 60, 90, and 120 days after
intravitreal injection of 20 .mu.l and 40 .mu.l doses of a 2%
solution of rapamycin in ethanol and PEG 400 and of a 100 .mu.l
dose of a 0.4% rapamycin solution in ethanol and PEG 400.
[0053] FIG. 16 depicts the level of rapamycin in the vitreous
(ng/ml) of rabbit eyes at 5 and 14 days after subconjunctival
injection of a single 10 .mu.l dose, a single 60 .mu.l dose, two 30
.mu.l doses, and three 30 .mu.l doses of a 2% solution of rapamycin
in ethanol and PEG 400.
[0054] FIG. 17 depicts the level of rapamycin in the retina choroid
tissues (ng/mg) of rabbit eyes at 5 and 14 days after
subconjunctival injection of a single 10 .mu.l dose, a single 60
.mu.l dose, two 30 .mu.l doses, and three 30 .mu.l doses of a 2%
solution of rapamycin in ethanol and PEG 400.
[0055] FIG. 18 depicts the level of rapamycin in the vitreous
(ng/ml) of rabbit eyes at 5, 14, and 30 days after subconjunctival
injection of a single 10 .mu.l dose, a single 30 .mu.l dose, and
three 30 .mu.l doses of a 3% suspension of rapamycin in PEG
400.
[0056] FIG. 19 depicts the level of rapamycin in the retina choroid
tissues (ng/mg) of rabbit eyes at 5, 14, and 30 days after
subconjunctival injection of a single 10 .mu.l dose, a single 30
.mu.l dose, and three 30 .mu.l doses of a 3% suspension of
rapamycin in PEG 400.
[0057] FIG. 20 depicts the level of rapamycin in the retina choroid
tissues (ng/mg) of rabbit eyes at 5, 30, and 90 days after
intravitreal injection of 10 .mu.l of a 0.2% solution of rapamycin
in ethanol and PEG 400, of 10 .mu.l of a 0.6% solution of rapamycin
in ethanol and PEG 400, and of 10 .mu.l of a 2% solution of
rapamycin in ethanol and PEG 400.
[0058] FIG. 21 depicts the level of rapamycin in the vitreous
(ng/ml) of rabbit eyes at 5, 30, and 90 days after intravitreal
injection of 10 .mu.l of a 0.2% solution of rapamycin in ethanol
and PEG 400, of 10 .mu.l of a 0.6% solution of rapamycin in ethanol
and PEG 400, and of 10 .mu.l of a 2% solution of rapamycin in
ethanol and PEG 400.
[0059] FIG. 22 depicts the level of rapamycin in the aqueous humor
(ng/ml) of rabbit eyes, the cornea (ng/mg), and the retina choroid
tissues (ng/mg) at 1, 4, 7, 11, 14, 21, 28, 35, 54, and 56 days
after subconjunctival injection of 40 .mu.l of a 2% solution of
rapamycin in ethanol and PEG 400.
DETAILED DESCRIPTION
[0060] Described herein are compositions, liquid formulations and
methods relating to delivery of therapeutic agents to a subject,
including but not limited to a human subject or to the eye of a
subject. These compositions, liquid formulations, and methods may
be used for the treatment, prevention, inhibition, delaying onset
of, or causing regression of diseases and conditions of the eye
including but not limited to diseases or conditions of the
posterior segment, including but not limited to choroidal
neovascularization; macular degeneration; age-related macular
degeneration, including wet AMD and dry AMD; retinal angiogenesis;
chronic uveitis; and other retinoproliferative conditions. In some
variations, the compositions, liquid formulations, and methods are
used for the treatment of the aforementioned diseases or conditions
of the eye.
[0061] Herein are described (1) the therapeutic agents that may be
delivered to a subject, including but not limited to a human
subject or an eye of a subject using the compositions, liquid
formulations, and methods described herein, (2) the diseases and
conditions that may be treated, prevented, inhibited, onset
delayed, or regression caused by delivery of the therapeutic
agents, (3) liquid formulations that may be used to deliver the
therapeutic agents, (4) routes of administration for delivery of
the liquid formulations, (5) extended delivery of therapeutic
agents including but not limited to rapamycin, and (6) description
of the treatment of CNV and wet AMD by delivery of rapamycin to a
subject, including but not limited to a human subject or to the eye
of a subject for an extended period of time using the described
compositions and liquid formulations.
[0062] The term "about," as used herein, generally refers to the
level of accuracy that is obtained when the methods described
herein, such as the methods in the examples, are used. However, by
"about" a certain amount of a component of a formulation is meant
90-110% of the amount stated.
Therapeutic Agents
[0063] Most generally, any compounds and compositions currently
known or yet to be discovered that are useful in treating,
preventing, inhibiting, delaying the onset of, or causing the
regression of the diseases and conditions described herein may be
therapeutic agents for use in the compositions, liquid
formulations, and methods described herein.
[0064] Therapeutic agents that may be used include compounds that
act by binding members of the immunophilin family of cellular
proteins. Such compounds are known as "immunophilin binding
compounds." Immunophilin binding compounds include but are not
limited to the "limus" family of compounds. Examples of limus
compounds that may be used include but are not limited to
cyclophilins and FK506-binding proteins (FKBPs), including
sirolimus (rapamycin) and its water soluble analog SDZ-RAD
(Novartis), TAFA-93 (Isotechnika), tacrolimus, everolimus, RAD-001
(Novartis), pimecrolimus, temsirolimus, CCI-779 (Wyeth), AP23841
(Ariad), AP23573 (Ariad), and ABT-578 (Abbott Laboratories). Limus
compound analogs and derivatives that may be used include but are
not limited to the compounds described in U.S. Pat. Nos. 5,527,907;
6,376,517; and 6,329,386 and U.S. patent application Ser. No.
09/950,307, each of which is incorporated herein by reference in
their entirety. Therapeutic agents also include analogs, prodrugs,
salts and esters of limus compounds.
[0065] The terms rapamycin, rapa, and sirolimus are used
interchangeably herein.
[0066] Other rapamycin derivatives that may be used include,
without limitation, 7-epi-rapamycin, 7-thiomethyl-rapamycin,
7-epi-trimethoxyphenyl-rapamycin, 7-epi-thiomethyl-rapamycin,
7-demethoxy-rapamycin, 32-demethoxy-rapamycin,
2-desmethyl-rapamycin, mono- and di-ester derivatives of rapamycin,
27-oximes of rapamycin; 42-oxo analog of rapamycin; bicyclic
rapamycins; rapamycin dimers; silyl ethers of rapamycin; rapamycin
arylsulfonates and sulfamates, mono-esters and di-esters at
positions 31 and 42, 30-demethoxy rapamycin, and other derivatives
described in Vezina et al., "Rapamycin (AY-22,989), A New
Antifungal Antibiotic. I. Taxonomy Of The Producing Streptomycete
And Isolation Of The Active Principle" J. Antibiot. (Tokyo)
28:721-726 (1975); Sehgal et al., "Rapamycin (AY-22,989), A New
Antifungal Antibiotic. II. Fermentation, Isolation And
Characterization" J. Antibiot. (Tokyo) 28:727-732 (1975); Sehgal et
al., "Demethoxyrapamycin (AY-24,668), A New Antifungal Antibiotic"
J. Antibiot. (Tokyo) 36:351-354 (1983); and Paiva et al.,
"Incorporation Of Acetate, Propionate, And Methionine Into
Rapamycin By Streptomycetes hygroscopicus" J Nat Prod 54:167-177
(1991), WO 92/05179, EP 467606, Caufield et al., "Hydrogenated
Rapamycin Derivatives" U.S. Pat. No. 5,023,262; Kao et al.,
"Bicyclic Rapamycins" U.S. Pat. No. 5,120,725; Kao et al.,
"Rapamycin Dimers" U.S. Pat. No. 5,120,727; Failli et al., "Silyl
Ethers Of Rapamycin" U.S. Pat. No. 5,120,842; Failli et al.,
"Rapamycin 42-Sulfonates And 42-(N-carboalkoxy) Sulfamates Useful
As Immunosuppressive Agents" U.S. Pat. No. 5,177,203; Nicolaou et
al., "Total Synthesis Of Rapamycin" J. Am. Chem. Soc. 115:
4419-4420 (1993); Romo et al, "Total Synthesis Of (-) Rapamycin
Using An Evans-Tishchenko Fragment Coupling" J. Am. Chem. Soc.
115:7906-7907 (1993); and Hayward et al, "Total Synthesis Of
Rapamycin Via A Novel Titanium-Mediated Aldol Macrocyclization
Reaction" J. Am. Chem. Soc., 115:9345-9346 (1993), each of which is
incorporated herein by reference in its entirety.
[0067] The limus family of compounds may be used in the
compositions, liquid formulations and methods for the treatment,
prevention, inhibition, delaying the onset of, or causing the
regression of angiogenesis-mediated diseases and conditions of the
eye, including choroidal neovascularization. The limus family of
compounds may be used to prevent, treat, inhibit, delay the onset
of, or cause regression of AMD, including wet AMD. Rapamycin and
rapamycin derivatives and analogs may be used to prevent, treat,
inhibit, delay the onset of, or cause regression of
angiogenesis-mediated diseases and conditions of the eye, including
choroidal neovascularization. Rapamycin may be used to prevent,
treat, inhibit, delay the onset of, or cause regression of AMD,
including wet AMD. In some variations, a member of the limus family
of compounds or rapamycin is used to treat wet AMD or angiogenesis
mediated diseases and conditions of the eye including choroidal
neovascularization.
[0068] Other therapeutic agents that may be used include those
disclosed in the following patents and publications, the contents
of each of which is incorporated herein by reference in its
entirety: PCT publication WO 2004/027027, published Apr. 1, 2004,
titled Method of inhibiting choroidal neovascularization, assigned
to Trustees of the University of Pennsylvania; U.S. Pat. No.
5,387,589, issued Feb. 7, 1995, titled Method of Treating Ocular
Inflammation, with inventor Prassad Kulkarni, assigned to
University of Louisville Research Foundation; U.S. Pat. No.
6,376,517, issued Apr. 23, 2003, titled Pipecolic acid derivatives
for vision and memory disorders, assigned to GPI NIL Holdings, Inc;
PCT publication WO 2004/028477, published Apr. 8, 2004, titled
Method subretinal administration of therapeutics including
steroids: method for localizing pharmadynamic action at the choroid
and retina; and related methods for treatment and or prevention of
retinal diseases, assigned to Innorx, Inc; U.S. Pat. No. 6,416,777,
issued Jul. 9, 2002, titled Ophthalmic drug delivery device,
assigned to Alcon Universal Ltd; U.S. Pat. No. 6,713,081, issued
Mar. 30, 2004, titled Ocular therapeutic agent delivery device and
methods for making and using such devices, assigned to Department
of Health and Human Services; U.S. Pat. No. 5,100,899, issued Mar.
31, 1992, titled Methods of inhibiting transplant rejection in
mammals using rapamycin and derivatives and prodrugs thereof.
[0069] Other therapeutic agents that may be used include
pyrrolidine, dithiocarbamate (NF.kappa.B inhibitor); squalamine;
TPN 470 analogue and fumagillin; PKC (protein kinase C) inhibitors;
Tie-1 and Tie-2 kinase inhibitors; inhibitors of VEGF receptor
kinase; proteosome inhibitors such as Velcade.TM. (bortezomib, for
injection; ranibuzumab (Lucentis.TM.) and other antibodies directed
to the same target; pegaptanib (Macugen.TM.); vitronectin receptor
antagonists, such as cyclic peptide antagonists of vitronectin
receptor-type integrins; .alpha.-v/.beta.-3 integrin antagonists;
.alpha.-v/.beta.-1 integrin antagonists; thiazolidinediones such as
rosiglitazone or troglitazone; interferon, including
.gamma.-interferon or interferon targeted to CNV by use of dextran
and metal coordination; pigment epithelium derived factor (PEDF);
endostatin; angiostatin; tumistatin; canstatin; anecortave acetate;
acetonide; triamcinolone; tetrathiomolybdate; RNA silencing or RNA
interference (RNAi) of angiogenic factors, including ribozymes that
target VEGF expression; Accutane.TM. (13-cis retinoic acid); ACE
inhibitors, including but not limited to quinopril, captopril, and
perindozril; inhibitors of mTOR (mammalian target of rapamycin);
3-aminothalidomide; pentoxifylline; 2-methoxyestradiol;
colchicines; AMG-1470; cyclooxygenase inhibitors such as nepafenac,
rofecoxib, diclofenac, rofecoxib, NS398, celecoxib, vioxx, and
(E)-2-alkyl-2(4-methanesulfonylphenyl)-1-phenylethene; t-RNA
synthase modulator; metalloprotease 13 inhibitor;
acetylcholinesterase inhibitor; potassium channel blockers;
endorepellin; purine analog of 6-thioguanine; cyclic peroxide
ANO-2; (recombinant) arginine deiminase;
epigallocatechin-3-gallate; cerivastatin; analogues of suramin;
VEGF trap molecules; apoptosis inhibiting agents; Visudyne.TM.,
snET2 and other photo sensitizers, which may be used with
photodynamic therapy (PDT); inhibitors of hepatocyte growth factor
(antibodies to the growth factor or its receptors, small molecular
inhibitors of the c-met tyrosine kinase, truncated versions of HGF
e.g. NK4).
[0070] Other therapeutic agents that may be used include
anti-inflammatory agents, including, but not limited to
nonsteroidal anti-inflammatory agents and steroidal
anti-inflammatory agents. In some variations, active agents that
may be used in the liquid formulations are ace-inhibitors,
endogenous cytokines, agents that influence basement membrane,
agents that influence the growth of endothelial cells, adrenergic
agonists or blockers, cholinergic agonists or blockers, aldose
reductase inhibitors, analgesics, anesthetics, antiallergics,
antibacterials, antihypertensives, pressors, antiprotozoal agents,
antiviral agents, antifungal agents, anti-infective agents,
antitumor agents, antimetabolites, and antiangiogenic agents.
[0071] Steroidal therapeutic agents that may be used include but
are not limited to 21-acetoxypregnenolone, alclometasone,
algestone, amcinonide, beclomethasone, betamethasone, budesonide,
chloroprednisone, clobetasol, clobetasone, clocortolone,
cloprednol, corticosterone, cortisone, cortivazol, deflazacort,
desonide, desoximetasone, dexamethasone, diflorasone,
diflucortolone, difluprednate, enoxolone, fluazacort, flucloronide,
flumethasone, flunisolide, fluocinolone acetonide, fluocinonide,
fluocortin butyl, fluocortolone, fluorometholone, fluperolone
acetate, fluprednidene acetate, fluprednisolone, flurandrenolide,
fluticasone propionate, formocortal, halcinonide, halobetasol
propionate, halometasone, halopredone acetate, hydrocortamate,
hydrocortisone, loteprednol etabonate, mazipredone, medrysone,
meprednisone, methylprednisolone, mometasone furoate,
paramethasone, prednicarbate, prednisolone, prednisolone
25-diethylamino-acetate, prednisolone sodium phosphate, prednisone,
prednival, prednylidene, rimexolone, tixocortol, triamcinolone,
triamcinolone acetonide, triamcinolone benetonide, triamcinolone
hexacetonide, and any of their derivatives.
[0072] In some variations, cortisone, dexamethasone, fluocinolone,
hydrocortisone, methylprednisolone, prednisolone, prednisone, and
triamcinolone, or their derivatives, may be used. The liquid
formulation may include a combination of two or more steroidal
therapeutic agents.
[0073] In one nonlimiting example, the steroidal therapeutic agents
may constitute from about 0.05% to about 50% by weight of the
liquid formulation. In another nonlimiting example, the steroid
constitutes from about 0.05% to about 10%, between about 10% to
about 20%; between about 30% to about 40%; or between about 40% to
about 50% by weight of the liquid formulation.
[0074] Other nonlimiting examples of therapeutic agents that may be
used include but are not limited to anaesthetics, analgesics, cell
transport/mobility impending agents such as colchicines,
vincristine, cytochalasin B and related compounds; carbonic
anhydrase inhibitors such as acetazolamide, methazolamide,
dichlorphenamide, diamox and neuroprotectants such as nimodipine
and related compounds; antibiotics such as tetracycline,
chlortetracycline, bacitracin, neomycin, polymyxin, gramicidin,
cephalexin, oxytetracycline, chloramphenicol, rifampicin,
ciprofloxacin, aminosides, gentamycin, erythromycin and penicillin,
quinolone, ceftazidime, vancomycine imipeneme; antifungals such as
amphotericin B, fluconazole, ketoconazole and miconazole;
antibacterials such as sulfonamides, sulfadiazine, sulfacetamide,
sulfamethizole and sulfisoxazole, nitrofurazone and sodium
propionate; antivirals, such as idoxuridine, trifluorothymidine,
trifluorouridine, acyclovir, ganciclovir, cidofovir, interferon,
DDI, AZT, foscamet, vidarabine, irbavirin, protease inhibitors and
anti-cytomegalovirus agents; antiallergenics such as sodium
cromoglycate, antazoline, methapyriline, chlorpheniramine,
cetirizine, pyrilamine and prophenpyridamine; synthetic
gluocorticoids and mineralocorticoids and more generally hormones
forms derivating from the cholesterol metabolism (DHEA,
progesterone, estrogens); non-steroidal anti-inflammatories such as
salicylate, indomethacin, ibuprofen, diclofenac, flurbiprofen,
piroxicam and COX2 inhibitors; antineoplastics such as carmustine,
cisplatin, fluorouracil; adriamycin, asparaginase, azacitidine,
azathioprine, bleomycin, busulfan, carboplatin, carmustine,
chlorambucil, cyclophosphamide, cyclosporine, cytarabine,
dacarbazine, dactinomycin, daunorubicin, doxorubicin, estramustine,
etoposide, etretinate, filgrastin, floxuridine, fludarabine,
fluorouracil, florxymesterone, flutamide, goserelin, hydroxyurea,
ifosfamide, leuprolide, levamisole, limustine, nitrogen mustard,
melphalan, mercaptopurine, methotrexate, mitomycin, mitotane,
pentostatin, pipobroman, plicamycin, procarbazine, sargramostin,
streptozocin, tamoxifen, taxol, teniposide, thioguanine, uracil
mustard, vinblastine, vincristine and vindesine; immunological
drugs such as vaccines and immune stimulants; insulin, calcitonin,
parathyroid hormone and peptide and vasopressin hypothalamus
releasing factor; beta adrenergic blockers such as timolol,
levobunolol and betaxolol; cytokines, interleukines and growth
factors epidermal growth factor, fibroblast growth factor, platelet
derived growth factor, transforming growth factor beta, ciliary
neurotrophic growth factor, glial derived neurotrophic factor, NGF,
EPO, PLGF, brain nerve growth factor (BNGF), vascular endothelial
growth factor (VEGF) and monoclonal antibodies or fragments thereof
directed against such growth factors; anti-inflammatories such as
hydrocortisone, dexamethasone, fluocinolone, prednisone,
prednisolone, methylprednisolone, fluorometholone, betamethasone
and triamcino lone; decongestants such as phenylephrine,
naphazoline and tetrahydrazoline; miotics and anti-cholinesterases
such as pilocarpine, carbachol, di-isopropyl fluorophosphate,
phospholine iodine and demecarium bromide; mydriatics such as
atropine sulphate, cyclopentolate, homatropine, scopolamine,
tropicamide, eucatropine; sympathomimetics such as epinephrine and
vasoconstrictors and vasodilators, anticlotting agents such as
heparin, antifibrinogen, fibrinolysin, anticlotting activase,
antidiabetic agents include acetohexamide, chlorpropamide,
glipizide, glyburide, tolazamide, tolbutamide, insulin and aldose
reductase inhibitors, hormones, peptides, nucleic acids,
saccharides, lipids, glycolipids, glycoproteins and other
macromolecules include endocrine hormones such as pituitary,
insulin, insulin-related growth factor, thyroid, growth hormones;
heat shock proteins; immunological response modifiers such as
muramyl dipeptide, cyclosporins, interferons (including alpha-,
beta- and gamma-interferons), interleukin-2, cytokines, FK506 (an
epoxy-pyrido-oxaazcyclotricosine-tetrone, also known as
Tacrolimus), tumor necrosis factor, pentostatin, thymopentin,
transforming factor beta2, erythropoetin; antineogenesis proteins
(e.g. anti VEGF, interferons), antibodies (monoclonal, polyclonal,
humanized, etc.) or antibodies fragments, oligoaptamers, aptamers
and gene fragments (oligonucleotides, plasmids, ribozymes, small
interference RNA (SiRNA), nucleic acid fragments, peptides),
immunomodulators such as endoxan, thalidomide, tamoxifene;
antithrombolytic and vasodilator agents such as rtPA, urokinase,
plasmin; nitric oxide donors, nucleic acids, dexamethasone,
cyclosporin A, azathioprine, brequinar, gusperimus,
6-mercaptopurine, mizoribine, rapamycin, tacrolimus (FK-506), folic
acid analogs (e.g., denopterin, edatrexate, methotrexate,
piritrexim, pteropterin, Tomudex.RTM., trimetrexate), purine
analogs (e.g., cladribine, fludarabine, 6-mercaptopurine,
thiamiprine, thiaguanine), pyrimidine analogs (e.g., ancitabine,
azacitidine, 6-azauridine, carmofur, cytarabine, doxifluridine,
emitefur, enocitabine, floxuridine, fluorouracil, gemcitabine,
tegafur) fluocinol one, triaminolone, anecortave acetate,
fluorometholone, medrysone, and prednislone. In some variations the
immunosuppressive agent is dexamethasone. In some variations the
immunosuppressive agent is cyclosporin A.
[0075] In some variations the formulation comprises a combination
of one or more therapeutic agents.
[0076] Other nonlimiting examples of therapeutic agents that may be
used in the formulations described herein include antibacterial
antibiotics, aminoglycosides (e.g., amikacin, apramycin, arbekacin,
bambermycins, butirosin, dibekacin, dihydrostreptomycin,
fortimicin(s), gentamicin, isepamicin, kanamycin, micronomicin,
neomycin, neomycin undecylenate, netilmicin, paromomycin,
ribostamycin, sisomicin, spectinomycin, streptomycin, tobramycin,
trospectomycin), amphenicols (e.g., azidamfenicol, chloramphenicol,
florfenicol, thiamphenicol), ansamycins (e.g., rifamide, rifampin,
rifamycin sv, rifapentine, rifaximin), P-lactams (e.g.,
carbacephems (e.g., loracarbef), carbapenems (e.g., biapenem,
imipenem, meropenem, panipenem), cephalosporins (e.g., cefaclor,
cefadroxil, cefamandole, cefatrizine, cefazedone, cefazolin,
cefcapene pivoxil, cefclidin, cefdinir, cefditoren, cefepime,
cefetamet, cefixime, cefinenoxime, cefodizime, cefonicid,
cefoperazone, ceforamide, cefotaxime, cefotiam, cefozopran,
cefpimizole, cefpiramide, cefpirome, cefpodoxime proxetil,
cefprozil, cefroxadine, cefsulodin, ceftazidime, cefteram,
ceftezole, ceftibuten, ceftizoxime, ceftriaxone, cefuroxime,
cefuzonam, cephacetrile sodium, cephalexin, cephaloglycin,
cephaloridine, cephalosporin, cephalothin, cephapirin sodium,
cephradine, pivcefalexin), cephamycins (e.g., cefbuperazone,
cefinetazole, cefminox, cefotetan, cefoxitin), monobactams (e.g.,
aztreonam, carumonam, tigemonam), oxacephems, flomoxef,
moxalactam), penicillins (e.g., amdinocillin, amdinocillin pivoxil,
amoxicillin, ampicillin, apalcillin, aspoxicillin, azidocillin,
azlocillin, bacampicillin, benzylpenicillinic acid,
benzylpenicillin sodium, carbenicillin, carindacillin,
clometocillin, cloxacillin, cyclacillin, dicloxacillin, epicillin,
fenbenicillin, floxacillin, hetacillin, lenampicillin,
metampicillin, methicillin sodium, mezlocillin, nafcillin sodium,
oxacillin, penamecillin, penethamate hydriodide, penicillin g
benethamine, penicillin g benzathine, penicillin g benzhydrylamine,
penicillin g calcium, penicillin g hydrabamine, penicillin g
potassium, penicillin g procaine, penicillin n, penicillin o,
penicillin v, penicillin v benzathine, penicillin v hydrabamine,
penimepicycline, phenethicillin potassium, piperacillin,
pivampicillin, propicillin, quinacillin, sulbenicillin,
sultamicillin, talampicillin, temocillin, ticarcillin), ritipenem,
lincosamides (e.g., clindamycin, lincomycin), macrolides (e.g.,
azithromycin, carbomycin, clarithromycin, dirithromycin,
erythromycin, erythromycin acistrate, erythromycin estolate,
erythromycin glucoheptonate, erythromycin lactobionate,
erythromycin propionate, erythromycin stearate, josamycin,
leucomycins, midecamycins, miokamycin, oleandomycin, primycin,
rokitamycin, rosaramicin, roxithromycin, spiramycin,
troleandomycin), polypeptides (e.g., amphomycin, bacitracin,
capreomycin, colistin, enduracidin, enviomycin, fusaftiungine,
gramicidin s, gramicidin(s), mikamycin, polymyxin, pristinamycin,
ristocetin, teicoplanin, thiostrepton, tuberactinomycin,
tyrocidine, tyrothricin, vancomycin, viomycin, virginiamycin, zinc
bacitracin), tetracyclines (e.g., apicycline, chlortetracycline,
clomocycline, demeclocycline, doxycycline, guamecycline,
lymecycline, meclocycline, methacycline, minocycline,
oxytetracycline, penimepicycline, pipacycline, rolitetracycline,
sancycline, tetracycline), and others (e.g., cycloserine,
mupirocin, tuberin); synthetic antibacterials,
2.4-Diaminopyiimidines (e.g., brodimoprim, tetroxoprim,
trimethoprim), nitrofurans (e.g., furaltadone, furazolium chloride,
nifuradene, nifuratel, nifurfoline, nifurpirinol, nifurprazine,
nifurtoinol, nitrofurantoin), quinolones and analogs (e.g.,
cinoxacin, ciprofloxacin, clinafloxacin, difloxacin, enoxacin,
fleroxacin, flumequine, grepafloxacin, lomefloxacin, miloxacin,
nadifloxacin, nalidixic acid, norfloxacin, ofloxacin, oxolinic
acid, pazufloxacin, pefloxacin, pipemidic acid, piromidic acid,
rosoxacin, rufloxacin, sparfloxacin, temafloxacin, tosufloxacin,
trovafloxacin), sulfonamides (e.g., acetyl sulfamethoxypyrazine,
benzylsulfamide, chloramine-b, chloramine-t, dichloramine t,
n2-formylsulfisomidine, n4-.beta.-d-glucosylsulfanilamide,
mafenide, 4'-(methylsulfamoyl)sulfanilanilide, noprylsulfamide,
phthalylsulfacetamide, phthalylsulfathiazole, salazosulfadimidine,
succinylsulfathiazole, sulfabenzamide, sulfacetamide,
sulfachlorpyridazine, sulfachrysoidine, sulfacytine, sulfadiazine,
sulfadicramide, sulfadimethoxine, sulfadoxine, sulfaethidole,
sulfaguanidine, sulfaguanol, sulfalene, sulfaloxic acid,
sulfamerazine, sulfameter, sulfamethazine, sulfamethizole,
sulfamethomidine, sulfamethoxazole, sulfamethoxypyridazine,
sulfametrole, sulfamidochrysoidine, sulfamoxole, sulfanilamide,
4-sulfanilamidosalicylic acid, n4-sulfanilylsulfanilamide,
sulfanilylurea, n-sulfanilyl-3,4-xylamide, sulfanitran,
sulfaperine, sulfaphenazole, sulfaproxyline, sulfapyrazine,
sulfapyridine, sulfasomizole, sulfasymazine, sulfathiazole,
sulfathiourea, sulfatolamide, sulfisomidine, sulfisoxazole)
sulfones (e.g., acedapsone, acediasulfone, acetosulfone sodium,
dapsone, diathymosulfone, glucosulfone sodium, solasulfone,
succisulfone, sulfanilic acid, p-sulfanilylbenzylamine, sulfoxone
sodium, thiazolsulfone), and others (e.g., clofoctol, hexedine,
methenamine, methenamine anhydromethylene-citrate, methenamine
hippurate, methenamine mandelate, methenamine sulfosalicylate,
nitroxoline, taurolidine, xibomol), antifungal antibiotics,
polyenes (e.g., amphotericin b, candicidin, dermosiatin, filipin,
fungichromin, hachimycin, hamycin, lucensomycin, mepartricin,
natamycin, nystatin, pecilocin, perimycin), azaserine,
griseofulvin, oligomycins, neomycin undecylenate, pyrroInitrin,
siccanin, tubercidin, viridin, synthetic antifungals, allylamines
(e.g., butenafine, naftifine, terbinafine), imidazoles (e.g.,
bifonazole, butoconazole, chlordantoin, chlormidazole, cloconazole,
clotrimazole, econazole, enilconazole, fenticonazole, flutrimazole,
isoconazole, ketoconazole, lanoconazole, miconazole, omoconazole,
oxiconazole nitrate, sertaconazole, sulconazole, tioconazole),
thiocarbamates (e.g., tolciclate, tolindate, tolnaftate), triazoles
(e.g., fluconazole, itraconazole, saperconazole, terconazole),
acrisorcin, amorolfine, biphenamine, bromosalicylchloranilide,
buclosamide, calcium propionate, chlorphenesin, ciclopirox,
cloxyquin, coparaffinate, diamthazole dihydrochloride, exalamide,
flucytosine, halethazole, hexetidine, loflucarban, nifuratel,
potassium iodide, propionic acid, pyrithione, salicylanilide,
sodium propionate, sulbentine, tenonitrozole, triacetin, ujothion,
undecylenic acid, zinc propionate, antineoplastics, antibiotics and
analogs (e.g., aclacinomycins, actinomycin f1, anthramycin,
azaserine, bleomycins, cactinomycin, carubicin, carzinophilin,
chromomycins, dactinomycin, daunorubicin,
6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, idarubicin,
menogaril, mitomycins, mycophenolic acid, nogalamycin,
olivomycines, peplomycin, pirarubicin, plicamycin, porfiromycin,
puromycin, streptonigrin, streptozocin, tubercidin, zinostatin,
zorubicin), antimetabolites (e.g. folic acid analogs (e.g.,
denopterin, edatrexate, methotrexate, piritrexim, pteropterin,
Tomudex.RTM., trimetrexate), purine analogs (e.g., cladribine,
fludarabine, 6-mercaptopurine, thiamiprine, thioguanine),
pyrimidine analogs (e.g., ancitabine, azacitidine, 6-azauridine,
carmofur, cytarabine, doxifluridine, emitefur, enocitabine,
floxuridine, fluorouracil, gemcitabine, tagafur), antiinflammatory
agents, steroidal antiinflammatory agents, acetoxypregnenolone,
alclometasone, algestone, amcinonide, beclomethasone,
betamethasone, budesonide, chloroprednisone, clobetasol,
clobetasone, clocortolone, cloprednol, corticosterone, cortisone,
cortivazol, deflazacort, desonide, desoximetasone, dexamethasone,
diflorasone, diflucortolone, difluprednate, enoxolone, fluazacort,
flucloronide, flumethasone, flunisolide, fluocinolone acetonide,
fluocinonide, fluocortin butyl, fluocortolone, fluorometholone,
fluperolone acetate, fluprednidene acetate, fluprednisolone,
flurandrenolide, fluticasone propionate, formocortal, halcinonide,
halobetasol propionate, halometasone, halopredone acetate,
hydrocortamate, hydrocortisone, loteprednol etabonate, mazipredone,
medrysone, meprednisone, methylprednisolone, mometasone furoate,
paramethasone, prednicarbate, prednisolone, prednisolone
25-diethylamino-acetate, prednisolone sodium phosphate, prednisone,
prednival, prednylidene, rimexolone, tixocortol, triamcinolone,
triamcinolone acetonide, triamcinolone benetonide, and
triamcinolone hexacetonide, non-steroidal antiinflammatory agents,
aminoarylcarboxylic acid derivatives (e.g., enfenamic acid,
etofenamate, flufenamic acid, isonixin, meclofenamic acid,
mefenamic acid, niflumic acid, talniflumate, terofenamate,
tolfenamic acid), arylacetic acid derivatives (e.g., aceclofenac,
acemetacin, alclofenac, amfenac, amtolmetin guacil, bromfenac,
bufexamac, cimnetacin, clopirac, diclofenac sodium, etodolac,
felbinac, fenclozic acid, fentiazac, glucametacin, ibufenac,
indomethacin, isofezolac, isoxepac, lonazolac, metiazinic acid,
mofezolac, oxametacine, pirazolac, proglumetacin, sulindac,
tiaramide, tolmetin, tropesin, zomepirac), arylbutyric acid
derivatives (e.g., burnadizon, butibufen, fenbufen, xenbucin),
arylcarboxylic acids (e.g., clidanac, ketorolac, tinoridine),
arylpropionic acid derivatives (e.g., alminoprofen, benoxaprofen,
bermoprofen, bucloxic acid, carprofen, fenoprofen, flunoxaprofen,
flurbiprofen, ibuprofen, ibuproxam, indoprofen, ketoprofen,
loxoprofen, naproxen, oxaprozin, piketoprolen, pirprofen,
pranoprofen, protizinic acid, suprofen, tiaprofenic acid,
ximoprofen, zaltoprofen), pyrazoles (e.g., difenamizole,
epirizole), pyrazolones (e.g., apazone, benzpiperylon, feprazone,
mofebutazone, morazone, oxyphenbutazone, phenylbutazone,
pipebuzone, propyphenazone, ramifenazone, suxibuzone,
thiazolinobutazone), salicylic acid derivatives (e.g.,
acetaminosalol, aspirin, benorylate, bromosaligenin, calcium
acetylsalicylate, diflunisal, etersalate, fendosal, gentisic acid,
glycol salicylate, imidazole salicylate, lysine acetylsalicylate,
mesalamine, morpholine salicylate, 1-naphthyl salicylate,
olsalazine, parsalmide, phenyl acetylsalicylate, phenyl salicylate,
salacetamide, salicylamide o-acetic acid, salicylsulfuric acid,
salsalate, sulfasalazine), thiazinecarboxamides (e.g., ampiroxicam,
droxicam, isoxicam, lomoxicam, piroxicam, tenoxicam),
.epsilon.-acetamidocaproic acid, s-adenosylmethionine,
3-amino-4-hydroxybutyric acid, amixetrine, bendazac, benzydamine,
a-bisabolol, bucolome, difenpiramide, ditazol, emorfazone,
fepradinol, guaiazulene, nabuinetone, nimesulide, oxaceprol,
paranyline, perisoxal, proquazone, superoxide dismutase, tenidap,
and zileuton.
[0077] The therapeutic agents may also be used in combination with
other therapeutic agents and therapies, including but not limited
to agents and therapies useful for the treatment, prevention,
inhibition, delaying onset of, or causing regression of
angiogenesis or neovascularization, particularly CNV. In some
variations the additional agent or therapy is used to treat
regression of angiogenesis or neovascularization, particularly CNV.
Non-limiting examples of such additional agents and therapies
include pyrrolidine, dithiocarbamate (NF.kappa.B inhibitor);
squalamine; TPN 470 analogue and fumagillin; PKC (protein kinase C)
inhibitors; Tie-1 and Tie-2 kinase inhibitors; inhibitors of VEGF
receptor kinase; proteosome inhibitors such as Velcade.TM.
(bortezomib, for injection; ranibuzumab (Lucentis.TM.) and other
antibodies directed to the same target; pegaptanib (Macugen.TM.);
vitronectin receptor antagonists, such as cyclic peptide
antagonists of vitronectin receptor-type integrins;
.alpha.-v/.beta.-3 integrin antagonists; .alpha.-v/.beta.-1
integrin antagonists; thiazolidinediones such as rosiglitazone or
troglitazone; interferon, including .gamma.-interferon or
interferon targeted to CNV by use of dextran and metal
coordination; pigment epithelium derived factor (PEDF); endostatin;
angiostatin; tumistatin; canstatin; anecortave acetate; acetonide;
triamcinolone; tetrathiomolybdate; RNA silencing or RNA
interference (RNAi) of angiogenic factors, including ribozymes that
target VEGF expression; Accutane.TM. (13-cis retinoic acid); ACE
inhibitors, including but not limited to quinopril, captopril, and
perindozril; inhibitors of mTOR (mammalian target of rapamycin);
3-aminothalidomide; pentoxifylline; 2-methoxyestradiol;
colchicines; AMG-1470; cyclooxygenase inhibitors such as nepafenac,
rofecoxib, diclofenac, rofecoxib, NS398, celecoxib, vioxx, and
(E)-2-alkyl-2(4-methanesulfonylphenyl)-1-phenylethene; t-RNA
synthase modulator; metalloprotease 13 inhibitor;
acetylcholinesterase inhibitor; potassium channel blockers;
endorepellin; purine analog of 6-thioguanine; cyclic peroxide
ANO-2; (recombinant) arginine deiminase;
epigallocatechin-3-gallate; cerivastatin; analogues of suramin;
VEGF trap molecules; inhibitors of hepatocyte growth factor
(antibodies to the growth factor or its receptors, small molecular
inhibitors of the c-met tyrosine kinase, truncated versions of HGF
e.g. NK4); apoptosis inhibiting agents; Visudyne.TM., snET2 and
other photo sensitizers with photodynamic therapy (PDT); and laser
photocoagulation.
Diseases and Conditions that may be Treated, Prevented, Inhibited,
Onset Delayed, or Regression Caused
[0078] Herein are described diseases and conditions that may be
treated, prevented, inhibited, onset delayed, or regression caused
using the therapeutic agents and the formulations, liquid
formulations, and methods described herein. In some variations, the
diseases or conditions are treated using the therapeutic agents and
the formulations, liquid formulations, and methods described
herein. Unless the context indicates otherwise, it is envisioned
that the subjects on whom all of the methods of treatment may be
performed include, but are not limited to, human subjects.
[0079] Generally, any diseases or condition of the eye susceptible
to treatment, prevention, inhibition, delaying the onset of, or
causing the regression of using the therapeutic agents and the
formulations, liquid formulations and methods described herein may
be treated, prevented, inhibited, onset delayed, or regression
caused treated or prevented. Examples of diseases or conditions of
the eye include, but are not limited to, diseases or conditions
associated with neovascularization including retinal and/or
choroidal neovascularization.
[0080] Diseases or conditions associated with retinal and/or
choroidal neovascularization that can be treated, prevented
inhibited, have onset delayed, or be caused to regress using the
formulations, liquid formulations, and methods described herein
include, but are not limited to, diabetic retinopathy, macular
degeneration, wet and dry AMD, retinopathy of prematurity
(retrolental fibroplasia), infections causing a retinitis or
choroiditis, presumed ocular histoplasmosis, myopic degeneration,
angioid streaks, and ocular trauma. Other non-limiting examples of
diseases and conditions of the eye that may be treated, prevented
inhibited, have onset delayed, or be caused to regress using the
formulations, liquid formulations, and methods described herein
include, but are not limited to, pseudoxanthoma elasticum, vein
occlusion, artery occlusion, carotid obstructive disease, Sickle
Cell anemia, Eales disease, myopia, chronic retinal detachment,
hyperviscosity syndromes, toxoplasmosis, trauma, polypoidal
choroidal vasculopathy, post-laser complications, complications of
idiopathic central serous chorioretinopathy, complications of
choroidal inflammatory conditions, rubeosis, diseases associated
with rubeosis (neovascularization of the angle), neovascular
glaucoma, uveitis and chronic uveitis, macular edema, proliferative
retinopathies and diseases or conditions caused by the abnormal
proliferation of fibrovascular or fibrous tissue, including all
forms of proliferative vitreoretinopathy (including post-operative
proliferative vitreoretinopathy), whether or not associated with
diabetes.
[0081] In some variations, the formulations and pharmaceutical
formulations described herein are used to prevent or delay onset of
a disease or condition of the eye where the subject, including but
not limited to a human subject, is at heightened risk of developing
the disease or condition of the eye. A subject with a heightened
risk of developing a disease or condition is a subject with one or
more indications that the disease or condition is likely to develop
in the particular subject. In some variations the subject with a
heightened risk of developing wet AMD is a subject with dry AMD in
at least one eye. In some variations the subject with a heightened
risk of developing wet AMD in a fellow eye is a subject with wet
AMD in the other eye. In some variations, the formulations and
pharmaceutical formulations described herein are used to prevent or
delay onset of CNV in a subject at heightened risk of developing
CNV, including but not limited to prevention or delaying onset of
CNV in the fellow eye of a subject, including but not limited to a
human subject with AMD in one eye. In some variations, the
formulations and pharmaceutical formulations described herein are
used to prevent or delay onset of CNV in the fellow eye of a
subject with wet AMD in one eye. In some variations, the
formulations and pharmaceutical formulations comprise a limus
compound, including but not limited to rapamycin. In some
variations the formulations and pharmaceutical formulations are
administered periocularly, including without limitation
subconjunctivally, to a human subject with vision of 20/40 or
better. In some variations, the formulations and pharmaceutical
formulations are administered periocularly, including without
limitation subconjunctivally, to the eye of a human subject where
the eye to which the formulation is administered has vision of
20/40 or better.
[0082] In some variations, the formulations and pharmaceutical
formulations described herein are used to treat, prevent, or delay
onset of AMD. In some variations, the formulations and
pharmaceutical formulations described herein are used to treat,
prevent, or delay onset of dry AMD. In some variations, subjects
including but not limited to human subjects with non-central
geographic atrophy are administered a formulation or pharmaceutical
formulations described herein to treat, prevent, or delay onset of
central geographic atrophy. In some variations, the formulations
and pharmaceutical formulations comprise a limus compound,
including but not limited to rapamycin. In some variations the
formulations and pharmaceutical formulations are administered
periocularly, including without limitation subconjunctivally, to a
human subject with vision of 20/40 or better. In some variations,
the formulations and pharmaceutical formulations described herein
are administered and the subject, including but not limited to a
human subject is also treated with a second therapy for treating
the disease or disorder. In some variations, the formulations and
pharmaceutical formulations described herein are used to treat,
prevent, or delay onset of wet or dry AMD and the subject,
including but not limited to a human subject is also treated with
laser therapy such as photodynamic laser therapy, either before,
during, or after treatment with the formulations or pharmaceutical
formulations described herein.
[0083] In some variations, the formulations and pharmaceutical
formulations described herein are used to treat one or more of
uveitis, allergic conjunctivitis, macular edema, glaucoma, or dry
eye.
[0084] In some variations, a formulations or pharmaceutical
formulation comprises a limus compound such as rapamycin, and is
administered to treat, prevent, or delay onset of dry eye. In some
variations, a formulations or pharmaceutical formulation comprises
a limus compound such as rapamycin, and is administered to treat,
prevent, or delay onset of allergic conjunctivitis.
[0085] In some variations, the formulations and pharmaceutical
formulations described herein are used to treat glaucoma. In some
variations, the formulations and pharmaceutical formulations
described herein for treating glaucoma comprise a limus compound
such as rapamycin, and are used as a surgical adjuvant to prevent,
reduce or delay surgical complications. In some variations, the
formulations and pharmaceutical formulations described herein for
treating glaucoma comprise a limus compound such as rapamycin, and
are used to improve or prolong surgical implant success. In some
variations, the formulations and pharmaceutical formulations
described herein for treating glaucoma comprise a limus compound
such as rapamycin, and are used to improve or prolong success of an
argon laser trabeculectomy or other glaucoma-related surgery. In
some variations, the formulations and pharmaceutical formulations
described herein have a neuroprotective effect and are used to
treat glaucoma.
[0086] In some variations, the formulations and pharmaceutical
formulations described herein are used to treat retinitis
pigmentosa. In some variations, the formulations and pharmaceutical
formulations described herein for treating glaucoma comprise a
limus compound such as rapamycin, and are used to treat, prevent,
or delay onset of retinitis pigmentosa. In some variations, the
formulations and pharmaceutical formulations described herein have
a neuroprotective effect and are used to treat retinitis
pigmentosa.
[0087] In some variations, the formulations and pharmaceutical
formulations described herein are used to treat one or more of
central retinal vein occlusive diseases (CRVO), branch retinal
venous occlusion (BRVO), retinal vascular diseases and conditions,
macular edema, diabetic macular edema, iris neovascularization,
diabetic retinopathy, or corneal graft rejection. In some
variations, a formulations or pharmaceutical formulation comprises
a limus compound such as rapamycin, and is administered to treat,
prevent, or delay onset of one or more of these diseases or
conditions. In some variations the formulations and pharmaceutical
formulations are administered subconjunctivally to an eye with
vision of 20/40 or better.
[0088] When used to treat, prevent, inhibit, delay the onset of, or
cause regressions of uveitis, the formulations and pharmaceutical
formulations described herein may be administered by a variety of
routes as is known in the art, including but not limited to by
ocular or oral administration. Other routes of administration are
known and are routine in the art. In some variations, the
formulations described herein comprise rapamycin and are used to
treat uveitis.
[0089] One disease that may be treated, prevented, inhibited, have
onset delayed, or be caused to regress using the formulation,
liquid formulations and methods described herein is the wet form of
AMD. In some variations wet AMD is treated using the formulations,
liquid formulations and methods described herein. The wet form of
AMD is characterized by blood vessels growing from their normal
location in the choroid into an undesirable position under the
retina. Leakage and bleeding from these new blood vessels results
in vision loss and possibly blindness.
[0090] The formulations, liquid formulation's, and methods
described herein may also be used to prevent or slow the transition
from the dry form of AMD (wherein the retinal pigment epithelium or
RPE degenerates and leads to photoreceptor cell death and the
formation of yellow deposits called drusen under the retina) to the
wet form of AMD.
[0091] "Macular degeneration" is characterized by the excessive
buildup of fibrous deposits in the macula and retina and the
atrophy of the retinal pigment epithelium. As used herein, an eye
"afflicted" with macular degeneration is understood to mean that
the eye exhibits at least one detectable physical characteristic
associated with the disease of macular degeneration. The
administration of rapamycin appears to limit and regress
angiogenesis, such as choroidal neovascularization in age-related
macular degeneration (AMD), which may occur without treatment. As
used herein, the term "angiogenesis" means the generation of new
blood vessels ("neovascularization") into a tissue or organ. An
"angiogenesis-mediated disease or condition" of the eye or retina
is one in which new blood vessels are generated in a pathogenic
manner in the eye or retina, resulting in dimunition or loss of
vision or other problem, e.g., choroidal neovascularization
associated with AMD.
[0092] The formulations and liquid formulations described herein,
including but not limited to rapamycin-containing formulations and
liquid formulations, may also be used to treat, prevent, inhibit,
delay the onset of, or cause regression of various immune-related
diseases and conditions, including but not limited to organ
transplant rejection in a host, graft vs. host disease, autoimmune
diseases, diseases of inflammation, hyperproliferative vascular
disorders, solid tumors, and fungal infections. In some variations,
the formulations and liquid formulations described herein,
including but not limited to rapamycin-containing formulations and
liquid formulations, are used to treat various immune-related
diseases and conditions, including but not limited to organ
transplant rejection in a host, graft vs. host disease, autoimmune
diseases, diseases of inflammation, hyperproliferative vascular
disorders, solid tumors, and fungal infections. The formulations
and liquid formulations described herein, including but not limited
to rapamycin-containing formulations and liquid formulations, may
be used as immunosuppressants. The formulations and liquid
formulations described herein, including but not limited to
rapamycin-containing formulations and liquid formulations, may be
used to treat, prevent, inhibit, or delay the onset of rejection of
transplanted organs or tissues including but not limited to
transplanted heart, liver, kidney, spleen, lung, small bowel,
pancreas, and bone marrow. In some variations, the formulations and
liquid formulations described herein are used to treat the onset of
rejection of transplanted organs or tissues including but not
limited to transplanted heart, liver, kidney, spleen, lung, small
bowel, pancreas, and bone marrow. When used to treat, prevent,
inhibit, delay the onset of, or cause regressions of immune-related
diseases, including but not limited to transplant rejection, the
formulations and liquid formulations described herein may be
administered by a variety of routes as is known in the art,
including but not limited to by oral administration.
[0093] Systemic administration may be achieved by oral
administration of the liquid formulation. Other systemic routes of
administration are known and are routine in the art. Some examples
thereof are listed in the Detailed Description section.
[0094] As used herein, to "inhibit" a disease or condition by
administration of a therapeutic agent means that the progress of at
least one detectable physical characteristic or symptom of the
disease or condition is slowed or stopped following administration
of the therapeutic agent as compared to the progress of the disease
or condition without administration of the therapeutic agent.
[0095] As used herein, to "prevent" a disease or condition by
administration of a therapeutic agent means that the detectable
physical characteristics or symptom of the disease or condition do
not develop following administration of the therapeutic agent.
[0096] As used herein, to "delay onset of" a disease or condition
by administration of a therapeutic agent means that at least one
detectable physical characteristic or symptom of the disease or
condition develops later in time following administration of the
therapeutic agent as compared to the progress of the disease or
condition without administration of the therapeutic agent.
[0097] As used herein, to "treat" a disease or condition by
administration of a therapeutic agent means that the progress of at
least one detectable physical characteristic or symptom of the
disease or condition is slowed, stopped, or reversed following
administration of the therapeutic agent as compared to the progress
of the disease or condition without administration of the
therapeutic agent.
[0098] As used herein, to "cause regression of" a disease or
condition by administration of a therapeutic agent means that the
progress of at least one detectable physical characteristic or
symptom of the disease or condition is reversed to some extent
following administration of the therapeutic agent.
[0099] A subject, including but not limited to a human subject,
having a predisposition for or in need of prevention may be
identified by the skilled practitioner by established methods and
criteria in the field given the teachings herein. The skilled
practitioner may also readily diagnose individuals as in need of
inhibition or treatment based upon established criteria in the
field for identifying angiogenesis ahd/or neovascularization given
the teachings herein.
[0100] As used herein, a "subject" is generally any animal that may
benefit from administration of the therapeutic agents described
herein. In some variations the therapeutic agents are administered
to a mammalian subject. In some variations the therapeutic agents
are administered to a human subject. In some variations the
therapeutic agents may be administered to a veterinary animal
subject. In some variations the therapeutic agents may be
administered to a model experimental animal subject.
[0101] Other diseases and conditions that may be treated,
prevented, inhibited, have the onset delayed, or be caused to
regress using the methods described herein include those disclosed
in the following patents and publications, the contents of each of
which is incorporated herein in its entirety: PCT publication WO
2004/027027, published Apr. 1, 2004, titled Method of inhibiting
choroidal neovascularization, assigned to Trustees of the
University of Pennsylvania; U.S. Pat. No. 5,387,589, issued Feb. 7,
1995, titled Method of Treating Ocular Inflammation, with inventor
Prassad Kulkarni, assigned to University of Louisville Research
Foundation; U.S. Pat. No. 6,376,517, issued Apr. 23, 2003, titled
Pipecolic acid derivatives for vision and memory disorders,
assigned to GPI NIL Holdings, Inc; PCT publication WO 2004/028477,
published Apr. 8, 2004, titled Method subretinal administration of
therapeutics including steroids: method for localizing
pharmadynamic action at the choroid and retina; and related methods
for treatment and or prevention of retinal diseases, assigned to
Innorx, Inc; U.S. Pat. No. 6,416,777, issued Jul. 9, 2002, titled
Ophthalmic drug delivery device, assigned to Alcon Universal Ltd;
U.S. Pat. No. 6,713,081, issued Mar. 30, 2004, titled Ocular
therapeutic agent delivery device and methods for making and using
such devices, assigned to Department of Health and Human Services;
and U.S. Pat. No. 5,536,729, issued Jul. 16, 1996, titled Rapamycin
Formulations for Oral Administration, assigned to American Home
Products Corp., and U.S. Pat. App. Nos. 60/503,840 and
10/945,682.
Liquid Formulations
[0102] The liquid formulations described herein contain a
therapeutic agent and may generally be any liquid formulation,
including but not limited to solutions, suspensions, and emulsions.
In some variations the liquid formulations form a non-dispersed
mass relative to a surrounding medium when placed in the vitreous
of a rabbit eye.
[0103] When a certain volume of a liquid formulation is
administered, it is understood that there is some imprecision in
the accuracy of various devices that may be used to administer the
liquid formulation. Where a certain volume is specified, it is
understood that this is the target volume. However, certain devices
such as insulin syringes are inaccurate to greater than 10%, and
sometimes inaccurate to greater than 20% or more. Hamilton HPLC
type syringes are generally considered precise to within 100, and
are recommended for volumes below 10 .mu.l are to be injected.
[0104] In some variations, a volume of a liquid formulation
described herein is administered to the vitreous of a rabbit eye or
a subject's, including but not limiting a human subject's eye that
is less than about 500 .mu.l, less than about 400 .mu.l, less than
about 300 .mu.l, less than about200 .mu.l, less than about 100
.mu.l, less than about 90 .mu.l, less than about 80 .mu.l, less
than about 70 .mu.l, less than about 60 .mu.l, less than about 50
.mu.l, less than about 40 .mu.l, less than about 30 .mu.l, less
than about 20 .mu.l, less than about 10 .mu.l, less than about 5
.mu.l, less than about 3 .mu.l, or less than about 1 .mu.l. In some
variations, a volume of a liquid formulation described herein is
administered to the vitreous of a rabbit eye or subject's,
including but not limited to a human subject's eye that is less
than about 20 .mu.l. In some variations, a volume of a liquid
formulation described herein is administered to the vitreous that
is less than about 10 .mu.l. In some variations, a volume of a
liquid formulation described herein is administered to the vitreous
of a rabbit eye or a subject's, including but not limited to a
human subject's eye that is between about 0.1 .mu.l and about 200
.mu.l, between about 50 .mu.l and about 200 .mu.l, between about 50
.mu.l and about 150 .mu.l, between about 0.1 .mu.l and about 100
.mu.l, between about 0.1 .mu.l and about 50 .mu.l, between about 1
.mu.l and about 40 .mu.l, between about 1 .mu.l and about 30 .mu.l,
between about 1 .mu.l and about 20 .mu.l, between about 1 .mu.l and
about 10 .mu.l, or between about 1 .mu.l and about 5 .mu.l. In some
variations, a volume of a liquid formulation described herein is
administered to the vitreous of a rabbit eye or a subject's,
including but not limited to a human subject's eye that is between
about 1 .mu.l and about 10 .mu.l. In some variations, a volume of a
liquid formulation described herein is administered to the vitreous
of a rabbit eye or a subject's, including but not limited to a
human subject's eye that is between about 1 .mu.l and about 5
.mu.l. In some variations, a volume of a liquid formulation
described herein is administered to the vitreous of a rabbit eye or
a subject's eye that is between about 1 .mu.l and about 5 .mu.l. In
some variations, a volume of a liquid formulation described herein
is administered to the vitreous of a rabbit eye or a subject's,
including but not limited to a human subject's eye that is between
about 0.1 .mu.l and about 200 .mu.l.
[0105] In some variations, a total volume of a liquid formulation
described herein is subconjunctivally administered to a rabbit eye
or a subject's, including but not limited to a human subject's eye
that is less than about 1000 .mu.l, less than about 900 .mu.l, less
than about 800 .mu.l, less than about 700 .mu.l, less than about
600 .mu.l, less than about 50011, less than about 400 .mu.l, less
than about 300 .mu.l, less than about 200 .mu.l, less than about
100 .mu.l, less than about 90 .mu.l, less than about 80 .mu.l, less
than about 70 .mu.l, less than about 60 .mu.l, less than about 50
.mu.l, less than about 40 .mu.l, less than about 30 .mu.l, less
than about 20 .mu.l, less than about 10 .mu.l, less than about 5
.mu.l, less than about 3 .mu.l, or less than about 1 .mu.l. In some
variations, a volume of a liquid formulation described herein is
subconjunctivally administered to a rabbit eye or a subject's,
including but not limited to a human suibject's eye that is less
than about 20 .mu.l. In some variations, a volume of a liquid
formulation described herein is subconjunctivally administered to a
rabbit eye or a subject's, including but not limited to a human
subject's eye that is less than about 10 .mu.l. In some variations,
a volume of a liquid formulation described herein is
subconjunctivally administered to a rabbit eye or a subject's,
including but not limited to a human subject's eye that is between
about 0.1 .mu.l and about 200 .mu.l, between about 50 .mu.l and
about 200 .mu.l, between about 200 .mu.l and about 300 .mu.l,
between about 300 .mu.l and about 400 .mu.l, between about 400
.mu.l and about 500 .mu.l, between about 600 .mu.l and about 700
.mu.l, between about 700 .mu.l and about 800 .mu.l, between about
800 .mu.l and about 900 .mu.l, between about 900 .mu.l and about
1000 .mu.l, between about 50 .mu.l and about 1501 .mu.l, between
about 0.1 .mu.l and about 100 .mu.l, between about 0.1 .mu.l and
about 50 .mu.l, between about 1 .mu.l and about 40 .mu.l, between
about 1 .mu.l and about 30 .mu.l, between about 1 .mu.l and about
20 .mu.l, between about 1 .mu.l and about 10 .mu.l, or between
about 1 .mu.l and about 5 .mu.l. In some variations, a volume of a
liquid formulation described herein is subconjunctivally
administered to a rabbit eye or a subject's, including but not
limited to a human subject's eye that is between about 1 .mu.l and
about 10 .mu.l. In some variations, a volume of a liquid
formulation described herein is subconjunctivally administered to a
rabbit eye or a subject's, including but not limited to a human
subject's eye that is between about 1 .mu.l and about 5 .mu.l. In
some variations, a volume of a liquid formulation described herein
is administered to subconjunctivally administered to a rabbit eye
or a subject's, including but not limited to a human subject's eye
that is between about 1 .mu.l and about 5 .mu.l. In some
variations, a volume of a liquid formulation described herein is
administered to subconjunctivally administered to a rabbit eye or a
subject's, including but not limited to a human subject's eye that
is between about 0.1 .mu.l and about 200 .mu.l.
[0106] In some variations the liquid formulations described herein
are administered in multiple subconjunctival locations within a
period of time, including without limitation within an hour of one
another. Without being bound by theory, it is thought that such
multiple administrations, such as multiple injections, allow for a
greater total dose to be administered subconjunctivally than a
single dose due to a potentially limited ability of the local
ocular tissues to absorb larger volumes.
[0107] One liquid formulation described herein is an in situ
gelling formulation. In situ gelling formulations, as described
herein, comprise a therapeutic agent and a plurality of polymers
which give a formulation that forms a gel or a gel-like substance
when placed in an aqueous medium, including but not limited to an
aqueous medium of the eye.
[0108] In some variations of the liquid formulations described
herein, the therapeutic agent is a solution or suspension of
rapamycin in a liquid medium. Liquid media include but are not
limited to solvents, including but not limited to those in the
Solubilization of Therapeutic Agents section.
[0109] The liquid formulations described herein may comprise a
solubilizing agent component. In some variations the solubilizing
agent component is a surfactant. Note that there is some overlap
between components that may be solvents and solubilizing agents,
and therefore the same component may in some systems be used as
either a solvent or a solubilizing agent. A liquid formulation that
comprises a therapeutic agent and a component that may be
considered either a solvent or a solubilizing agent or surfactant
will be considered a solvent if it is playing the role of a
solvent; if the component is not playing the role of the solvent,
the component may be considered a solubilizing agent or
surfactant.
[0110] Liquid formulations may optionally further comprise
stabilizers, excipients, gelling agents, adjuvants, antioxidants,
and/or other components as described herein.
[0111] In some variations all components in the liquid formulation,
other than the therapeutic agent, are liquid at room
temperature.
[0112] In some variations, the liquid formulation comprises a
release modifying agent. In some variations, the release modifying
agent is a film-forming polymer component. The film-forming polymer
component may comprise one or more film-forming polymers. Any
film-forming polymer may be used in the excipient component. In
some variations, the film-forming polymer component comprises a
water insoluble film forming polymer. In some variations, the
release modifying agent component comprises an acrylic polymer,
including but not limited to polymethacrylate, including but not
limited to Eudragit RL.
[0113] Described herein are compositions and liquid formulations
for delivery of the therapeutic agents described in the Therapeutic
Agents section. Delivery of therapeutic agents using the
compositions and liquid formulations described herein may be used
to treat, prevent, inhibit, delay the onset of, or cause the
regression of the diseases and conditions described in the Diseases
and Conditions section. The compositions and liquid formulations
described herein may comprise any of the therapeutic agents
described in the Therapeutic Agents section, including but not
limited to rapamycin. The compositions and liquid formulations
described herein may comprise one or more than one therapeutic
agent. Other compositions and liquid formulations in addition to
those explicitly described herein may be used.
[0114] When the therapeutic agent is rapamycin, the compositions
and liquid formulations may be used to maintain an amount of
rapamycin in the vitreous effective to treat wet AMD. In one
nonlimiting example, it is believed that a liquid formulation
delivering rapamycin to maintain a concentration of rapamycin of
about 10 pg/ml to about 2 .mu.g/ml in the vitreous over a period of
time may be used for the treatment of wet AMD. When the rapamycin
is in a liquid formulation that forms a non-dispersed mass, the
stated concentration of rapamycin represents the amount that is
effectively treating the disease or condition of the eye, and not
merely present in the form of the non-dispersed mass. In another
nonlimiting example, it is believed that a delivery system
delivering rapamycin to maintain a concentration of rapamycin of
about 0.01 pg/mg to about 10 ng/mg in the retina choroid tissues
over a period of time may be used for treatment of wet AMD. Other
therapeutically effective amounts of therapeutic agent are also
possible, and can be readily determined by one of skill in the art
given the teachings herein.
[0115] When the therapeutic agent is rapamycin, the compositions
and liquid formulations described herein may be used to deliver a
dose of rapamycin to a subject, including but not limited to a
human subject or to the eye of a subject. In one nonlimiting
example, it is believed that a liquid formulation containing a dose
of about 20 .mu.g to about 4 mg may be used for the treatment of
wet AMD.
[0116] In some variations the therapeutic agent in the liquid
formulation comprises between about 0.01 to about 30% of the total
weight of the composition; between about 0.05 to about 15%; between
about 0.1 to about 10%; between about 1 to about 5%; or between
about 5 to about 15%; between about 8 to about 10%; between about
0.01 to about 1%; between about 0.05 to about 5%; between about 0.1
to about 0.2%; between about 0.2 to about 0.3%; between about 0.3
to about 0.4%; between about 0.4 to about 0.5%; between about 0.5
to about 0.6%; between about 0.6 to about 0.7%; between about 0.7
to about 1%; between about 1 to about 5%; between about 5 to about
10%; between about 15 to about 30%, between about 20 to about 30%;
or between about 25 to about 30%.
[0117] Those of skill in the art, based on the teachings herein can
determine what amount or concentration of a given therapeutic agent
is equivalent to an amount or concentration of rapamycin by, for
example, administering the therapeutic agent at various amounts or
concentrations to a disease model system, such as an in vivo or in
vivo model system, and comparing the results in the model system
relative to the results of various amounts or concentrations of
rapamycin. Those of skill in the art, based on the teachings herein
can also determine what amount or concentration of a given
therapeutic agent is equivalent to an amount or concentration of
rapamycin by reviewing the scientific literature for experiments
performed comparing rapamycin to other therapeutic agents. It is
understood that even the same therapeutic agent may have a
different equivalent level of rapamycin when, for example, a
different disease or disorder is being evaluated, or a different
type of formulation is used. Nonlimiting examples of scientific
references with comparative studies of rapamycin and other
therapeutic agents on ocular disease are Ohia et al., Effects of
steroids and immunosuppressive drugs on endotoxin-uveitis in
rabbits, J. Ocul. Pharmacol. 8(4):295-307 (1992); Kulkarni,
Steroidal and nonsteroidal drugs in endotoxin-induced uveitis, J.
Ocul. Pharmacol. 10(1):329-34 (1994); Hafizi et al., Differential
effects of rapamycin, cyclosporine A, and FK506 on human coronary
artery smooth muscle cell proliferation and signaling, Vascul
Pharmacol. 41(4-5):167-76 (2004); and US 2005/0187241.
[0118] For example, in a model for wet AMD, if a therapeutic agent
is found to be approximately 10-fold less potent or efficacious
than rapamycin in the treatment of wet AMD, a concentration of 10
ng/ml of the therapeutic agent would be equivalent to a 1 ng/ml
concentration of rapamycin. Or if a therapeutic agent is found to
be approximately 10-fold less potent or efficacious than rapamycin
in the treatment of wet AMD, a 10-fold amount of the therapeutic
agent would be administered relative to the amount of
rapamycin.
[0119] The solvent component may comprise, for instance, between
about 0.01 to about 99.9% of the total weight of the composition;
between about 0.1 to about 99%; between about 25 to about 55%;
between about 30 to about 50%; or between about 35 to about 45%;
between about 0.1 to about 10%; between about 10 to about 20%;
between about 20 to about 30%; between about 30 to about 40%;
between about 40 to about 45%; between about 40 to about 45%;
between about 45 to about 50%; between about 50 to about 60%;
between about 50 to about 70%; between about 70 to about 80%;
between about 80 to about 90%; or between about 90 to about
100%.
[0120] The solubilizing agent component may comprise, for instance,
between about 0.01 to about 30% of the total weight of the
composition; between about 0.1 to about 20%; between about 2.5 to
about 15%; between about 10 to about 15%; or between about 5 to
about 10%; between about 8 to about 12%; between about 10 to about
20%; between about 20 to about 30%.
[0121] In some variations, the liquid formulations described herein
have a viscosity of between 40% and 120% centipoise. In some
variations the liquid formulations described herein have a
viscosity of between 60% and 80% centipoise.
[0122] In some variations the liquid formulations described herein
comprise a therapeutic agent and a solvent component. The solvent
component may comprise a single solvent or a combination of
solvents. The therapeutic agent component may comprise a single
therapeutic agent or a combination of therapeutic agents. In some
variations, the solvent is glycerin, dimethylsulfoxide,
N-methylpyrrolidone, dimethyl acetamide (DMA), dimethyl formamide,
glycerol formal, ethoxy diglycol, triethylene glycol dimethyl
ether, triacetin, diacetin, corn oil, acetyl triethyl citrate
(ATC), ethyl lactate, polyglycolated capryl glycerides
butyrolactone, dimethyl isosorbide, benzyl alcohol, ethanol,
isopropyl alcohol, polyethylene glycol of various molecular
weights, including but not limited to PEG 300 and PEG 400, or
propylene glycol, or a mixture of one or more thereof.
[0123] In some variations the liquid formulations described herein
are solutions, and comprise a therapeutic agent and a solvent
component. In some variations the solvent component comprises
ethanol. In some variations the solvent component comprises ethanol
and a polyethylene glycol, including but not limited to a liquid
polyethylene glycol, including but not limited to one or more of
PEG 300 or PEG 400.
[0124] In some variations the liquid formulations described herein
contain no greater than about 250 .mu.l of polyethylene glycol. In
some variations the liquid formulations described herein contain no
greater than about 250 .mu.l, no greater than about 200 .mu.l, no
greater than about 150 .mu.l, no greater than about 125 .mu.l, no
greater than about 100 .mu.l, no greater than about 75 .mu.l, no
greater than about 50 .mu.l, no greater than about 25 .mu.l, no
greater than about 20 .mu.l, no greater than about 15 .mu.l, no
greater than about 10 .mu.l, no greater than about 7.5 .mu.l, no
greater than about 5 .mu.l, no greater than about 2.5 .mu.l, no
greater than about 1.0 .mu.l, or no greater than about 0.5 .mu.l of
polyethylene glycol. Formulations containing polyethylene glycol
may contain, for example, PEG 300 or PEG 400.
[0125] In some variations, the liquid formulations described herein
are suspensions, and comprise a therapeutic agent and a diluent
component. In some variations, the diluent component comprises one
or more components listed herein as solvents or solubilizing
agents, wherein the resulting mixture is a suspension.
[0126] In some variations the liquid formulation is partly a
solution and partly a suspension.
[0127] In some variations the liquid formulation is an in situ
gelling formulation, and comprises a therapeutic agent and a
polymer component, wherein the polymer component may comprise a
plurality of polymers. In some variations, the liquid formulation
comprises a polymethacrylate polymer. In some variations, the
liquid formulation comprises a polyvinylpyrrolidone polymer.
[0128] Some variations of liquid formulations include a therapeutic
agent or agents such as but not limited to rapamycin between about
0.01% and about 20% by weight of the total, a solvent between about
5% and about 15% by weight of the total, a solubilizing agent
including but not limited to a surfactant between about 5% and
about 15% by weight of the total, with water as the primary
remaining component. In some variations the formulations further
comprise stabilizing agents, excipients, adjuvants, or
antioxidants, between about 0 and about 40% by weight of the
total.
[0129] In some variations, a liquid formulation comprises up to
about 5% therapeutic agent, including but not limited to rapamycin,
per weight of the total; and up to about 99.9% of a solvent
component, by weight of the total. In some variations the liquid
formulation comprises up to about 5% therapeutic agent, including
but not limited to rapamycin, per weight of the total; and up to
about 99.9% of a diluent component.
[0130] In some variations, a liquid formulation may comprise up to
about 5% therapeutic agent, including but not limited to rapamycin,
per weight of the total; up to about 10% solvent by weight of the
total; and up to about 85% of a solubilizing component, by weight
of the total. In some variations the solubilizing component is an
aqueous solution of a surfactant.
[0131] A plurality of polymers component may comprise, for
instance, between about 0.01 to about 30% of the total weight of
the composition; between about 0.1 to about 20%; between about 2.5
to about 15%; between about 10 to about 15%; between about 3 to
about 5%; between about 5 to about 10%; between about 8 to about
12%; between about 10 to about 20%; or between about 20 to about
30%.
[0132] Some variations of liquid formulations includes a
therapeutic agent or agents such as but not limited to rapamycin
between about 0.01% and about 20% by weight of the total, a solvent
component between about 60% and about 98% by weight of the total,
and a plurality of polymers, whose combined percentage is between
about 0.1% and about 15% by weight of the total. In some variations
the formulations further comprise stabilizing agents, excipients,
adjuvants, or antioxidants, between about 0 and about 40% by weight
of the total.
[0133] In some variations, a liquid formulation may comprise about
4% therapeutic agent, including but not limited to rapamycin, per
weight of the total; about 91% solvent by weight of the total; and
about 5% polymeric component, per weight of the total.
[0134] Some examples and variations of liquid formulations
described herein were prepared and are listed in Table 1. Depending
on their type, the listed formulations are denoted one or more of
solutions ("S"), suspensions ("SP"), emulsions ("E") or in situ
gelling ("ISG"). Median particle size is listed for some of the
suspensions. As described herein, some liquid formulations form a
non-dispersed mass after, for example, injection into an aqueous
environment such as the vitreous of an eye. For those formulations
injected into the vitreous of a rabbit eye, the right-hand column
of Table 1 indicates whether or not a non-dispersed mass (NDM)
formed after a specified volume was injected into the vitreous of
the rabbit eye.
[0135] The following references, each of which is incorporated
herein by reference in its entirety, show one or more formulations,
including but not limited to rapamycin formulations, and which
describe use of rapamycin at various doses and other therapeutic
agents for treating various diseases or conditions: U.S.
60/651,790, filed Feb. 9, 2005, titled FORMULATIONS FOR OCULAR
TREATMENT, attorney docket number 57796-30002.00; U.S. 60/664,040,
filed Feb. 9, 2005, attorney docket number 57796-30004.00, titled
LIQUID FORMULATIONS FOR TREATMENT OF DISEASES OR CONDITIONS; U.S.
60/664,119, filed Mar. 21, 2005, attorney docket number
57796-30005.00, titled DRUG DELIVERY SYSTEMS FOR TREATMENT OF
DISEASES OR CONDITIONS; U.S. 60/664,306, filed Mar. 21, 2005,
attorney docket number 57796-30006.00 titled IN SITU GELLING
FORMULATIONS AND LIQUID FORMULATIONS FOR TREATMENT OF DISEASES OR
CONDITIONS; US ______, filed Feb. 9, 2006, titled FORMULATIONS FOR
OCULAR TREATMENT, attorney docket number 57796-20002.00; ______,
filed Feb. 9, 2006, attorney docket number 57796-20004.00, titled
LIQUID FORMULATIONS FOR TREATMENT OF DISEASES OR CONDITIONS; US
2005/0187241, and US 2005/0064010.
Liquid Formulations which Form a Non-Dispersed Mass
[0136] One class of liquid formulations described herein forms a
non-dispersed mass when placed in an aqueous medium. As used
herein, a "non-dispersed mass" refers to the structure formed or
shape assumed when the liquid formulation is placed into an
environment, relative to the environment in which it is placed.
Generally, a non-dispersed mass of a liquid formulation is anything
other than a homogeneous distribution of the liquid formulation in
the surrounding medium. The non-dispersed mass may, for instance,
be indicated by visually inspecting the administered liquid
formulation and characterizing its appearance relative to the
surrounding medium.
[0137] In some variations, the aqueous medium is water. In some
variations, the water is deionized, distilled, sterile, or tap
water, including but not limited to tap water available at the
place of business of MacuSight in Union City, Calif.
[0138] In some variations, the aqueous medium is an aqueous medium
of a subject. In some variations the aqueous medium is an aqueous
medium of the eye of a subject, including but not limited to the
vitreous of an eye of a subject. In some variations the subject is
a human subject. In some variations the subject is a rabbit.
[0139] In some variations the liquid formulation forms a
non-dispersed mass when exposed to a certain temperature or range
of temperatures, including but not limited to about room
temperature, about ambient temperature, about 30.degree. C., about
37.degree. C., or about the temperature of the aqueous medium of
the subject.
[0140] In some variations the liquid formulation forms a
non-dispersed mass when exposed to a certain pH or range of pH,
including but not limited to a pH between about 6 and about 8.
[0141] In some variations, the non-dispersed mass comprises a gel
or gel-like substance.
[0142] In some variations, the non-dispersed mass comprises a
polymer matrix. In some variations, the non-dispersed mass
comprises a polymer matrix in which a therapeutic agent is
dispersed.
[0143] The liquid formulations described herein may generally be of
any geometry or shape after administration to a subject or the eye
of a subject, including but not limited to a human subject. In some
variations, the non-dispersed mass is between about 0.1 and about 5
mm. In some variations, the non-dispersed mass is between about 1
and about 3 mm. The non-dispersed mass-forming liquid formulations
may, for instance, appear as a compact spherical mass when
administered to the vitreous. In some instances, the liquid
formulation may appear as a non-dispersed mass relative to the
surrounding medium, wherein the non-dispersed mass is less clearly
defined and the geometry is more amorphous than spherical.
[0144] The non-dispersed mass-forming liquid formulations described
herein may form a non-dispersed mass immediately upon placement in
the medium or the non-dispersed mass may form some period of time
after placement of the liquid formulation. In some variations the
non-dispersed mass forms over the course of about 1, about 2, about
3, about 4, about 5, about 6, or about 7 days. In some variations
the non-dispersed mass forms over the course of about 1 week, about
2 weeks, or about 3 weeks.
[0145] In some variations, the liquid formulations described herein
that form a non-dispersed mass appear as a milky or whitish colored
semi-contiguous or semi-solid non-dispersed mass relative to the
medium in which it is placed.
[0146] One liquid formulation described herein forms a
non-dispersed mass which has the form of a solid depot when the
formulation is injected into any or all of water, the vitreous of a
rabbit eye, or between the sclera and the conjunctiva of a rabbit
eye. One liquid formulation described herein forms a non-dispersed
mass which has the form of a semi-solid when the formulation is
injected into any or all of water, the vitreous of a rabbit eye, or
between the sclera and the conjunctiva of a rabbit eye. One liquid
formulation described herein forms a non-dispersed mass which has
the form of a polymeric matrix when the formulation is injected
into any or all of water, the vitreous of a rabbit eye, or between
the sclera and the conjunctiva of a rabbit eye. One liquid
formulation described herein forms a non-dispersed mass which has
the form of a gel, a hydrogel, or a gel-like substance when the
formulation is injected into any or all of water, the vitreous of a
rabbit eye, or between the sclera and the conjunctiva of a rabbit
eye.
[0147] In some variations described herein the liquid formulation
forms a non-dispersed mass relative to a surrounding medium where
the surrounding medium is aqueous. An "aqueous medium" or "aqueous
environment" is one that contains at least about 50% water.
Examples of aqueous media include but are not limited to water, the
vitreous, extracellular fluid, conjunctiva, sclera, between the
sclera and the conjunctiva, aqueous humor, gastric fluid, and any
tissue or body fluid comprised of at least about 50% of water.
Aqueous media include but are not limited to gel structures,
including but not limited to those of the conjunctiva and
sclera.
[0148] In some variations, the liquid formulations described herein
form a non-dispersed mass when a test volume of the liquid
formulation is placed in the vitreous of a rabbit eye. In some
variations the test volume administered to a rabbit eye, and the
test volume is equal to the volume of the liquid formulation
administered to a subject's, including but not limited to a human
subject's eye.
[0149] In some variations, the test volume administered to a rabbit
eye is equal to the volume administered to the subject's eye
multiplied by a scale factor, and the scale factor is equal to the
average volume of a rabbit eye divided by the average volume of a
subject eye. The "average volume" of an eye, as used herein, refers
to the average volume of an eye of a member of similar age of the
species under consideration generally, as opposed to the average
volume of any particular individual's eye.
[0150] In some variations, the test volume administered to the
rabbit eye is between about 10 .mu.l and about 50 .mu.l. In some
variations, the test volume administered to the rabbit eye is
between about 1 .mu.l and about 30 .mu.l. In some variations, the
test volume administered to the rabbit eye is between about 50
.mu.l and about 100 .mu.l. In some variations, the test volume
administered to the rabbit eye is between about 25 .mu.l and about
75 .mu.l. In some variations, the test volume administered to the
rabbit eye is about 30 .mu.l.
[0151] In some variations, the liquid formulation that forms a
non-dispersed mass when placed in the medium may comprises a
therapeutic agent or agents with a concentration of between about
0.01% and about 10% by weight of the total, and a solvent between
about 10% and about 99% by weight of the total. In some variations
the formulation further comprises a solubilizing agent including
but not limited to a surfactant. In some variations the liquid
formulation further comprises a stabilizing agent, excipient,
adjuvant, or antioxidant, etc., between about 0 and about 40% by
weight of the total. In some variations, the therapeutic agent is
about 5% by weight of the total, and the solvent component is about
95% by weight of the total.
[0152] Whether a liquid formulation exhibits a non-dispersed mass
relative to a surrounding medium when present in a subject,
including but not limited to a human subject or the eye of a
subject may be determined by, for instance, mixing a therapeutic
agent with a solvent, administering it to the vitreous of an eye of
a subject, including but not limited to a human subject, and
comparing the liquid formulation to the surrounding medium.
[0153] One liquid formulation that may be used for treating,
preventing, inhibiting, delaying the onset of, or causing the
regression of the diseases and conditions of a subject, including
but not limited to a human subject, is a liquid formulation that
forms a non-dispersed mass when placed into the vitreous of a
rabbit eye. When used for treating, preventing, inhibiting,
delaying the onset of, or causing the regression of the disease or
condition of the subject, the liquid formulation is administered to
the subject. The liquid formulation may or may not form a
non-dispersed mass in the subject. One liquid formulation described
herein forms a non-dispersed mass when administered to a subject
and forms a non-dispersed mass when administered to a rabbit
eye.
[0154] Without being bound by theory, it is believed that the low
solubility of rapamycin in the vitreous contributes to the
formation of a non-dispersed mass by some rapamycin-containing
liquid formulations described herein. The vitreous is a clear gel
composed almost entirely of water (up to 99%). Without being bound
by theory, it is believed that as rapamycin in an injected
formulation contacts the vitreous, the rapamycin precipitates.
[0155] Without being bound by theory, factors believed to affect
the formation of and geometry of a non-dispersed mass include the
concentration of rapamycin in the formulation, the viscosity of the
formulation, ethanol content of the formulation, and the volume of
injection. It is believed that maintaining a higher local
concentration of rapamycin after injection of the formulation
favors formation of a non-dispersed mass, as opposed to a lower
local concentration of rapamycin after injection of the
formulation. As volume is increased for a given dose, formation of
a non-dispersed mass may become less favorable. Formation of a
non-dispersed mass may become more favorable as rapamycin
concentration is increased and/or as viscosity is increased.
Ethanol content affects both the solubility of the rapamycin in the
formulation and the viscosity of the formulation.
[0156] In one comparison, 100 .mu.l of a solution of 0.4%
rapamycin, 4.0% ethanol, and 95.6% PEG 400 (a 400 .mu.g dose) did
not form a non-dispersed mass after injection into a rabbit eye. In
contrast, 20 .mu.l of a solution of 2.00% rapamycin, 4.0% ethanol,
and 94% PEG 400 (also a 400 .mu.g dose) formed a compact spherical
non-dispersed mass after injection into a rabbit eye.
[0157] Without being bound by theory, in the latter example, it is
hypothesized that formation of the non-dispersed mass occurred as
depicted in FIGS. 1A-1C and described as follows. Upon injection,
due to its viscosity the liquid formulation formed a spherical
globule 100 within the vitreous 110. Ethanol then diffused out of
this globule, resulting in localized precipitation 120 of the
rapamycin within the globule. Eventually, the polyethylene glycol
also diffused out of the globule to leave a solid, compact
non-dispersed mass of rapamycin 130.
[0158] In some variations, the non-dispersed masses described
herein consists of at least about 20%, at least about 30%, at least
about 40%, at least about 50%, at least about 60%, at least about
70%, at least about 80%, at least about 90%, or at least about 95%
by volume of therapeutic agent when injected into the vitreous of a
rabbit eye.
[0159] In some variations, upon formation a non-dispersed mass
comprising rapamycin, for example, delivers the drug continuously
at approximately a constant rate for an extended period of time.
Without being bound by theory, it is believed that delivery of
rapamycin from a non-dispersed mass in the vitreous depends on
dissolution of the rapamycin in the vitreous, which depends in turn
on clearance of the drug from the vitreous to other tissues.
Without being bound by theory, this release process is believed to
maintain a steady-state concentration of rapamycin in the
vitreous.
[0160] In some variations, formation of a non-dispersed mass
reduces the toxicity of the injected liquid formulation compared to
an equivalent dose that did not form a non-dispersed mass. In
variations in which a liquid formulation injected into the vitreous
does not form a non-dispersed mass, the drug (e.g., rapamycin)
appears to disperse in the vitreous body. In some variations this
may interfere with vision.
[0161] In some variations, liquid formulations that are suspensions
form a non-dispersed mass upon injection into the vitreous.
Formation of a non-dispersed mass from an injected suspension may
become more favorable as the suspension particle size
increases.
[0162] In some variations, it is believed that the liquid
formulations will form a visually observable non-dispersed mass
when injected into the eye of a subject, including but not limited
to a human subject.
[0163] In some variations, liquid formulations are believed to form
non-dispersed masses when injected subconjunctivally. In some
variations it is believed that when subconjunctivally administered
the liquid formulation forms a depot in the scleral tissue. That
is, it is believed that the therapeutic agent is absorbed into the
sclera proximate to the injection site and forms a local
concentration of drug in the sclera.
In Situ Gelling Formulations
[0164] Described herein are non-dispersed mass-forming liquid
formulations which form a gel or gel-like substance when placed in
an aqueous medium. In some variations, the non-dispersed mass
comprises a gel; in some variations the gel is a hydrogel.
[0165] An "in situ gelling formulation," as used herein, refers to
a liquid formulation which forms a gel-like non-dispersed mass when
the liquid formulation is placed in an aqueous medium, including
but not limited to aqueous media that are water, the vitreous of a
rabbit eye, and between the sclera and the conjunctiva of a rabbit
eye. In some variations, an in situ gelling formulation forms a
gel-like non-dispersed mass when placed in tap water.
[0166] In some variations, the in situ gelling formulation is a
suspension prior to placement in an aqueous medium, and forms a gel
in situ upon placement in an aqueous medium. In some variations,
the in situ gelling formulation is a solution prior to placement in
an aqueous medium, and forms a gel in situ upon placement in an
aqueous medium. In some variations, the in situ gelling formulation
is an emulsion prior to placement in an aqueous medium, and forms a
gel in situ upon placement in an aqueous medium. In some variations
a gel-like non-dispersed mass forms after placement of the in situ
gelling formulation into an aqueous medium, including but not
limited to any or all of water, the vitreous, or between the sclera
and the conjunctiva of an eye. In some variations, the in situ gel
is formed of a polymer matrix. In some variations a therapeutic
agent is dispersed in the polymer matrix.
[0167] Described herein are in situ gelling formulations which may
be used for treating, preventing, inhibiting, delaying the onset
of, or causing the regression of the diseases and conditions of a
subject including but not limited to a human subject. When used for
treating, preventing, inhibiting, delaying the onset of, or causing
the regression of the disease or condition of the subject, the in
situ gelling formulation is administered to the subject. One liquid
formulation described herein comprises an in situ gelling
formulation which forms a non-dispersed mass when administered to a
subject and forms a non-dispersed mass when administered to a
rabbit eye.
[0168] In some variations, the in situ gelling formulation
comprises one or more polymers. Described herein are various types
of polymers, including polymers which are solvents, polymers which
are solubilizing agents, polymers which are release modifying
agents, polymers which are stabilizing agents, etc. In some
variations, any combination of polymers is used wherein the
polymers when combined with the therapeutic agent form any or all
of a non-dispersed mass, a gel, a hydrogel, or polymeric matrix
when placed in an aqueous medium, including but not limited to any
or all of water, the vitreous, or between the sclera and the
conjunctiva.
[0169] In some variations, the in situ gelling formulation delivers
extended release of therapeutic agents to a subject when
administered to the subject.
[0170] In some variations, the liquid formulation comprises a
therapeutic agent and a plurality of polymers, wherein one of the
polymers is a polymethacrylate. Polymethacrylates are known by
various names and are available in various preparations, including
but not limited to polymeric methacrylates, methacrylic acid-ethyl
acrylate copolymer (1:1), methacrylic acid-ethyl acrylate copolymer
(1:1) dispersion 30 percent, methacrylic acid-methyl methacrylate
copolymer (1:1), methacrylic acid-methyl methacrylate copolymer
(1:2), acidum methacrylicum et ethylis acrylas polymerisatum 1:1,
acidum methacrylicum et ethylis acrylas polymerisatum 1:1 dispersio
30 per centum, acidum methacrylicum et methylis methacrylas
polymerisatum 1:1, acidum methacrylicum et methylis methacrylas
polymerisatum 1:2, USPNF: ammonio methacrylate copolymer,
methacrylic acid copolymer, methacrylic acid copolymer
dispersion.
[0171] In some variations, one of the polymers is
polyvinylpyrrolidone. Polyvinylpyrrolidone is known by various
names and is available in various preparations, including but not
limited to povidone, povidonum, kollidon; plasdone;
poly[1-(2-oxo-1-pyrrolidinyl)ethylene]; polyvidone; PVP;
1-vinyl-2-pyrrolidinone polymer, and 1-Ethenyl-2-pyrrolidinone
homopolymer.
[0172] One liquid formulation described herein comprises a
therapeutic agent and a solvent component. The solvent component
may comprise a single solvent or a combination of solvents.
[0173] In some variations, the solvent is glycerin,
dimethylsulfoxide, N-methylpyrrolidone, ethanol, isopropyl alcohol,
polyethylene glycol of various molecular weights, including but not
limited to PEG 300 and PEG 400, or propylene glycol, or a mixture
of one or more thereof.
[0174] In some variations, the solvent is polyethylene glycol.
Polyethylene glycol is known by various names and is available in
various preparations, including but not limited to macrogels,
macrogel 400, macrogel 1500, macrogel 4000, macrogel 6000, macrogel
20000, macrogola, breox PEG; carbowax; carbowax sentry; Hodag PEG;
Lipo; Lipoxol; Lutrol E; PEG; Pluriol E; polyoxyethylene glycol,
and .alpha.-Hydro-.omega.-hydroxy-poly(oxy-1,2-ethanediyl).
Compositions and Liquid Formulations for Delivery of Therapeutic
Agents
[0175] The compositions and liquid formulations described herein
may be used to deliver amounts of the therapeutic agents effective
for treating, preventing, inhibiting, delaying on set of, or
causing the regression of the diseases and conditions described in
the Diseases and Conditions section. In some variations the
compositions and liquid formulations described herein deliver one
or more therapeutic agents over an extended period of time.
[0176] An "effective amount," which is also referred to herein as a
"therapeutically effective amount," of a therapeutic agent for
administration as described herein is that amount of the
therapeutic agent that provides the therapeutic effect sought when
administered to the subject, including but not limited to a human
subject. The achieving of different therapeutic effects may require
different effective amounts of therapeutic agent. For example, the
therapeutically effective amount of a therapeutic agent used for
preventing a disease or condition may be different from the
therapeutically effective amount used for treating, inhibiting,
delaying the onset of, or causing the regression of the disease or
condition. In addition, the therapeutically effective amount may
depend on the age, weight, and other health conditions of the
subject as is well know to those versed in the disease or condition
being addressed. Thus, the therapeutically effective amount may not
be the same in every subject to which the therapeutic agent is
administered.
[0177] An effective amount of a therapeutic agent for treating,
preventing, inhibiting, delaying the onset of, or causing the
regression of a specific disease or condition is also referred to
herein as the amount of therapeutic agent effective to treat,
prevent, inhibit, delay the onset of, or cause the regression of
the disease or condition.
[0178] To determine whether a level of therapeutic agent is a
"therapeutically effective amount" to treat, prevent, inhibit,
delay on set of, or cause the regression of the diseases and
conditions described in the Diseases and Conditions section, liquid
formulations may be administered in animal models for the diseases
or conditions of interest, and the effects may be observed. In
addition, dose ranging human clinical trials may be conducted to
determine the therapeutically effective amount of a therapeutic
agent.
[0179] Generally, the therapeutic agent may be formulated in any
composition or liquid formulation capable of delivery of a
therapeutically effective amount of the therapeutic agent to a
subject or to the eye of a subject for the required delivery
period. Compositions include liquid formulations.
Solubilization of Therapeutic Agents
[0180] One composition or liquid formulation that may be used is a
composition or liquid formulation in which the therapeutic agent is
dissolved in a solvent component. Generally, any solvent which has
the desired effect may be used in which the therapeutic agent
dissolves. In some variations the solvent is aqueous. In some
variations the solvent is non-aqueous. An "aqueous solvent" is a
solvent that contains at least about 50% water.
[0181] Generally, any concentration of solubilized therapeutic
agent that has the desired effect can be used. The solvent
component may be a single solvent or may be a mixture of solvents.
The solvent component may be a single solvent or may be a mixture
of solvents. Solvents and types of solutions are well known to
those versed in such drug delivery technologies. See for example,
Remington: The Science and Practice of Pharmacy, Twentieth Edition,
Lippincott Williams & Wilkins; 20th edition (Dec. 15, 2000);
Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems,
Eighth Edition, Lippincott Williams & Wilkins (August 2004);
Handbook Of Pharmaceutical Excipients 2003, American Pharmaceutical
Association, Washington, D.C., USA and Pharmaceutical Press,
London, UK; and Strickley, solubilizing Excipients in Oral and
Injectable Formulations, Pharmaceutical Research, Vol. 21, No. 2,
February 2004.
[0182] As noted previously, some solvents may also serve as
solubilizing agents.
[0183] Solvents that may be used include but are not limited to
DMSO, ethanol, methanol, isopropyl alcohol; castor oil, propylene
glycol, glycerin, polysorbate 80, benzyl alcohol, dimethyl
acetamide (DMA), dimethyl formamide (DMF), triacetin, diacetin,
corn oil, acetyl triethyl citrate (ATC), ethyl lactate, glycerol
formal, ethoxy diglycol (Transcutol, Gattefosse), tryethylene
glycol dimethyl ether (Triglyme), dimethyl isosorbide (DMI),
.gamma.-butyrolactone, N-Methyl-2-pyrrolidinone (NMP), polyethylene
glycol of various molecular weights, including but not limited to
PEG 300 and PEG 400, and polyglycolated capryl glyceride (Labrasol,
Gattefosse), combinations of any one or more of the foregoing, or
analogs or derivatives of any one or more of the foregoing.
[0184] In some variations, the solvent is a polyethylene glycol.
Polyethylene glycol is known by various names and is available in
various preparations, including but not limited to macrogels,
macrogel 400, macrogel 1500, macrogel 4000, macrogel 6000, macrogel
20000, macrogola, breox PEG; carbowax; carbowax sentry; Hodag PEG;
Lipo; Lipoxol; Lutrol E; PEG; Pluriol E; polyoxyethylene glycol,
and .alpha.-Hydro-.omega.-hydroxy-poly(oxy-1,2-ethanediyl).
[0185] In some variations the polyethylene glycol is a liquid PEG,
and is one or more of PEG 300 or PEG 400.
[0186] Other solvents include an amount of a C.sub.6-C.sub.24 fatty
acid sufficient to solubilize a therapeutic agent.
[0187] Phospholipid solvents may also be used, such as lecithin,
phosphatidylcholine, or a mixture of various diglycerides of
stearic, palmitic, and oleic acids, linked to the choline ester of
phosphoric acid; hydrogenated soy phosphatidylcholine (HSPC),
distearoylphosphatidylglycerol (DSPG),
L-.alpha.-dimyristoylphosphatidylcholine (DMPC),
L-.alpha.-dimyristoylphosphatidylglycerol (DMPG).
[0188] Further examples of solvents include, for example,
components such as alcohols, propylene glycol, polyethylene glycol
of various molecular weights, propylene glycol esters, propylene
glycol esterified with fatty acids such as oleic, stearic, palmic,
capric, linoleic, etc; medium chain mono-, di-, or triglycerides,
long chain fatty acids, naturally occurring oils, and a mixture
thereof. The oily components for the solvent system include
commercially available oils as well as naturally occurring oils.
The oils may further be vegetable oils or mineral oils. The oils
can be characterized as non-surface active oils, which typically
have no hydrophile lipophile balance value. Commercially available
substances comprising medium chain triglycerides include, but are
not limited to, Captex 100, Captex 300, Captex 355, Miglyol 810,
Miglyol 812, Miglyol 818, Miglyol 829, and Dynacerin 660. Propylene
glycol ester compositions that are commercially available encompass
Captex 200 and Miglyol 840, and the like. The commercial product,
Capmul MCM, comprises one of many possible medium chain mixtures
comprising monoglycerides and diglycerides.
[0189] Other solvents include naturally occurring oils such as
peppermint oil, and seed oils. Exemplary natural oils include oleic
acid, castor oil, safflower seed oil, soybean oil, olive oil,
sunflower seed oil, sesame oil, and peanut oil. Soy fatty acids may
also be used. Examples of fully saturated non-aqueous solvents
include, but are not limited to, esters of medium to long chain
fatty acids (such as fatty acid triglycerides with a chain length
of about C.sub.6 to about C.sub.24). Hydrogenated soybean oil and
other vegetable oils may also be used. Mixtures of fatty acids may
be split from the natural oil (for example coconut oil, palm kernel
oil, babassu oil, or the like) and refined. In some embodiments,
medium chain (about C.sub.8 to about C.sub.12) triglycerides, such
as caprilyic/capric triglycerides derived from coconut oil or palm
seed oil, may be used. Medium chain mono- and diglycerides may also
be used. Other fully saturated non-aqueous solvents include, but
are not limited to, saturated coconut oil (which typically includes
a mixture of lauric, myristic, palmitic, capric and caproic acids),
including those sold under the Miglyol.TM. trademark from Huls and
bearing trade designations 810, 812, 829 and 840). Also noted are
the NeoBee.TM. products sold by Drew Chemicals. Non-aqueous
solvents include isopropyl myristate. Examples of synthetic oils
include triglycerides and propylene glycol diesters of saturated or
unsaturated fatty acids having 6 to 24 carbon atoms such as, for
example hexanoic acid, octanoic (caprylic), nonanoic (pelargonic),
decanoic (capric), undecanoic, lauric, tridecanoic, tetradecanoic
(myristic), pentadecanoic, hexadecanoic (palmitic), heptadecanoic,
octadecanoic (stearic), nonadecanoic, heptadecanoic, eicosanoic,
heneicosanoic, docosanoic and lignoceric acids, and the like.
Examples of unsaturated carboxylic acids include oleic, linoleic
and linolenic acids, and the like. The non-aqueous solvent can
comprise the mono-, di- and triglyceryl esters of fatty acids or
mixed glycerides and/or propylene glycol mono- or diesters wherein
at least one molecule of glycerol has been esterified with fatty
acids of varying carbon atom length. A non-limiting example of a
"non-oil" useful as a solvent is polyethylene glycol.
[0190] Exemplary vegetable oils include cottonseed oil, corn oil,
sesame oil, soybean oil, olive oil, fractionated coconut oil,
peanut oil, sunflower oil, safflower oil, almond oil, avocado oil,
palm oil, palm kernel oil, babassu oil, beechnut oil, linseed oil,
rape oil and the like. Mono-, di-, and triglycerides of vegetable
oils, including but not limited to corn, may also be used.
[0191] Polyvinyl pyrrolidone (PVP) cross-linked or not, may also be
used as a solvent. Further solvents include but are not limited to
C.sub.6-C.sub.24 fatty acids, oleic acid, Imwitor 742, Capmul, F68,
F68 (Lutrol), PLURONICS including but not limited to PLURONICS
F108, F127, and F68, Poloxamers, Jeffamines), Tetronics, F127;
cyclodextrins such as .alpha.-cyclodextrin, .beta.-cyclodextrin,
hydroxypropyl-.beta.-cyclodextrin,
sulfobutylether-.beta.-cyclodextrin (Captisol); CMC, polysorbitan
20, Cavitron, polyethylene glycol of various molecular weights
including but not limited to PEG 300 and PEG 400.
[0192] Beeswax and d-.alpha.-tocopherol (Vitamin E) may also be
used as solvents.
[0193] Solvents for use in the liquid formulations can be
determined by a variety of methods known in the art, including but
not limited to (1) theoretically estimating their solubility
parameter values and choosing the ones that match with the
therapeutic agent, using standard equations in the field; and (2)
experimentally determining the saturation solubility of therapeutic
agent in the solvents, and choosing the ones that exhibit the
desired solubility.
Solubilization of Rapamycin
[0194] Where the therapeutic agent is rapamycin, solvents that may
be used for making solutions or suspensions of rapamycin include
but are not limited to any solvent described herein, including but
not limited to any one or more of DMSO, glycerin, ethanol,
methanol, isopropyl alcohol; castor oil, propylene glycol,
polyvinylpropylene, glycerin, polysorbate 80, benzyl alcohol,
dimethyl acetamide (DMA), dimethyl formamide (DMF), glycerol
formal, ethoxy diglycol (Transcutol, Gattefosse), tryethylene
glycol dimethyl ether (Triglyme), dimethyl isosorbide (DMI),
.gamma.-butyrolactone, N-Methyl-2-pyrrolidinone (NMP), polyethylene
glycol of various molecular weights, including but not limited to
PEG 300 and PEG 400, and polyglycolated capryl glyceride (Labrasol,
Gattefosse).
[0195] Further solvents include but are not limited to
C.sub.6-C.sub.24 fatty acids, oleic acid, Imwitor 742, Capmul, F68,
F68 (Lutrol), PLURONICS including but not limited to PLURONICS
F108, F127, and F68, Poloxamers, Jeffamines), Tetronics, F127,
beta-cyclodextrin, CMC, polysorbitan 20, Cavitron, softigen 767,
captisol, and sesame oil.
[0196] Other methods that may be used to dissolve rapamycin are
described in Solubilization of Rapamycin, P. Simamora et al. Int'l
J Pharma 213 (2001) 25-29, the contents of which is incorporated
herein in its entirety.
[0197] As a nonlimiting example, rapamycin can be dissolved in 5%
DMSO or methanol in a balanced salt solution. The rapamycin
solution can be unsaturated, a saturated or a supersaturated
solution of rapamycin. The rapamycin solution can be in contact
with solid rapamycin. In one nonlimiting example, rapamycin can be
dissolved in a concentration of up to about 400 mg/ml. Rapamycin
can also, for example, be dissolved in propylene glycol esterified
with fatty acids such as oleic, stearic, palmic, capric, linoleic,
etc.
[0198] Many other solvents are possible. Those of ordinary skill in
the art will find it routine to identify solvents for rapamycin
given the teachings herein.
Solubilizing Agents
[0199] Generally, any solubilizing agent or combination of
solubilizing agents may be used in the liquid formulations
described herein.
[0200] In some variations, the solubilizing agent is a surfactant
or combination of surfactants. Many surfactants are possible.
Combinations of surfactants, including combinations of various
types of surfactants, may also be used. For instance, surfactants
which are nonionic, anionic (i.e. soaps, sulfonates), cationic
(i.e. CTAB), zwitterionic, polymeric or amphoteric may be used.
[0201] Surfactants that can be used may be determined by mixing a
therapeutic agent of interest with a putative solvent and a
putative surfactant, and observing the characteristics of the
formulation after exposure to a medium.
[0202] Examples of surfactants include but are not limited to fatty
acid esters or amides or ether analogues, or hydrophilic
derivatives thereof; monoesters or diesters, or hydrophilic
derivatives thereof; or mixtures thereof; monoglycerides or
diglycerides, or hydrophilic derivatives thereof; or mixtures
thereof; mixtures having enriched mono- or/and diglycerides, or
hydrophilic derivatives thereof; surfactants with a partially
derivatized with a hydrophilic moiety; monoesters or diesters or
multiple-esters of other alcohols, polyols, saccharides or
oligosaccharides or polysaccharides, oxyalkylene oligomers or
polymers or block polymers or hydrophilic derivatives thereof, or
the amide analogues thereof; fatty acid derivatives of amines,
polyamines, polyimines, aminoalcohols, aminosugars,
hydroxyalkylamines, hydroxypolyimines, peptides, polypeptides, or
the ether analogues thereof.
[0203] Hydrophilic Lipophilic Balance ("HLB") is an expression of
the relative simultaneous attraction of a surfactant for water and
oil (or for the two phases of the emulsion system being
considered).
[0204] Surfactants are characterized according to the balance
between the hydrophilic and lipophilic portions of their molecules.
The hydrophilic-lipophilic balance (HLB) number indicates the
polarity of the molecule in an arbitrary range of 1-40, with the
most commonly used emulsifiers having a value between 1-20. The HLB
increases with increasing hydrophilicity.
[0205] Surfactants that may be used include but are not limited to
those with an HLB greater than 10, 11, 12, 13 or 14. Examples of
surfactants include polyoxyethylene products of hydrogenated
vegetable oils, polyethoxylated castor oils or polyethoxylated
hydrogenated castor oil, polyoxyethylene-sorbitan-fatty acid
esters, polyoxyethylene castor oil derivatives and the like, for
example, Nikkol HCO-50, Nikkol HCO-35, Nikkol HCO-40, Nikkol HCO-60
(from Nikko Chemicals Co. Ltd.); Cremophor (from BASF) such as
Cremophor RH40, Cremophor RH60, Cremophor EL, TWEENs (from ICI
Chemicals) e.g., TWEEN 20, TWEEN 21, TWEEN 40, TWEEN 60, TWEEN 80,
TWEEN 81, Cremophor RH 410, Cremophor RH 455 and the like.
[0206] The surfactant component may be selected from compounds
having at least one ether formed from at least about 1 to 100
ethylene oxide units and at least one fatty alcohol chain having
from at least about 12 to 22 carbon atoms; compounds having at
least one ester formed from at least about 1 to 100 ethylene oxide
units and at least one fatty acid chain having from at least about
12 to 22 carbon atoms; compounds having at least one ether, ester
or amide formed from at least about 1 to 100 ethylene oxide units
and at least one vitamin or vitamin derivative; and combinations
thereof consisting of no more than two surfactants.
[0207] Other examples of surfactants include Lumulse GRH-40, TGPS,
Polysorbate-80 (TWEEN-80), Polysorbate-20 (TWEEN-20),
polyoxyethylene (20) sorbitan mono-oleate), glyceryl glycol esters,
polyethylene glycol esters, polyglycokzed glycerides, and the like,
or mixtures thereof; polyethylene sorbitan fatty acid esters,
polyoxyethylene glycerol esters, such as Tagat TO, Tagat L, Tagat
I, tagat I2 and Tagat 0 (commercially available from Goldschmidt
Chemical Co., Essen, Germany); ethylene glycol esters, such as
glycol stearate and distearate; propylene glycol esters, such as
propylene glycol myristate; glyceryl esters of fatty acids, such as
glyceryl stearates and monostearates; sorbitan esters, such as
spans and TWEENs; polyglyceryl esters, such as polyglyceryl
4-oleate; fatty alcohol ethoxylates, such as Brij type emulsifiers;
ethoxylated propoxylated block copolymers, such as poloxamers;
polyethylene glycol esters of fatty acids, such as PEG 300 linoleic
glycerides or Labrafil 2125 CS, PEG 300 oleic glycerides or
Labrafil M 1944 CS, PEG 400 caprylic/capric glycerides or Labrasol,
and PEG 300 caprylic/capric glycerides or Softigen 767; cremophors,
such as Cremophor E, polyoxyl 35 castor oil or Cremophor EL,
Cremophor EL-P, Cremophor RH 4OP, polyoxyl 40 hydrogenated castor
oil, Cremophor RH40; polyoxyl 60 hydrogenated castor oil or
Cremophor RH 60, glycerol monocaprylate/caprate, such as Campmul CM
10; polyoxyethylated fatty acids (PEGstearates, PED-laurates,
Brij.RTM.), polyoxylated glycerides of fatty acid, polyoxylated
glycerol fatty acid esters i.e. Solutol HS-15; PEG-ethers
(Mirj.RTM.), sorbitan derivatives (TWEENs), sorbitan monooleate or
Span 20, aromatic compounds (Tritons.RTM.), PEG-glycerides
(PECEOL.TM.),PEG-PPG (polypropylene glycol) copolymers (PLURONICS
including but not limited to PLURONICS F108, F127, and F68,
Poloxamers, Jeffamines), Tetronics, Polyglycerines,
PEG-tocopherols, PEG-LICOL 6-oleate; propylene glycol derivatives,
sugar and polysaccharide alkyl and acyl derivatives (octylsucrose,
sucrose stearate, laurolydextran etc.) and/or a mixture thereof;
surfactants based on an oleate or laureate ester of a polyalcohol
copolymerized with ethylene oxide; Labrasol Gelucire 44/14;
polyoxytheylene stearates; saturated polyglycolyzedglycerides; or
poloxamers; all of which are commercially available.
Polyoxyethylene sorbitan fatty acid esters can include
polysorbates, for example, polysorbate 20, polysorbate 40,
polysorbate 60, and polysorbate 80. Polyoxyethylene stearates can
include polyoxyl 6 stearate, polyoxyl 8 stearate, polyoxyl 12
stearate and polyoxyl 20 stearate. Saturated polyglycolyzed
glycerides are, for example, GELUCIRE 44/14 or GELUCIRE.TM. 50/13
(Gattefosse, Westwood, N.J., U.S.A.). Poloxamers used herein
include poloxamer. 124 and poloxamer 188.
[0208] Surfactants include d-.alpha.-tocopheryl polyethylene glycol
1000 succinate (TPGS), polyoxyl 8 stearate (PEG 400 monostearate),
polyoxyl 40 stearate (PEG 1750 monostearate) and peppermint
oil.
[0209] In some variations, surfactants having an HLB lower than 10
are used. Such surfactants may optionally be used in combination
with other surfactants as co-surfactants. Examples of some
surfactants, mixtures, and other equivalent compositions having an
HLB less than or equal to 10 are propylene glycols, glyceryl fatty
acids, glyceryl fatty acid esters, polyethylene glycol esters,
glyceryl glycol esters, polyglycolyzed glycerides and polyoxyethyl
steryl ethers. Propylene glycol esters or partial esters form the
composition of commercial products, such as Lauroglycol FCC, which
contains propylene glycol laureate. The commercially available
excipient Maisine 35-1 comprises long chain fatty acids, for
example glyceryl linoleate. Products, such as Acconon E, which
comprise polyoxyethylene stearyl ethers, may also be used. Labrafil
M 1944 CS is one example of a surfactant wherein the composition
contains a mixture of glyceryl glycol esters and polyethylene
glycol esters.
Solubilizing Agents for Rapamycin
[0210] Many solubilizing agents may be used for rapamycin,
including but not limited to those in the solubilizing agents
section above.
[0211] In some variations the solubilizing agent is a surfactant.
Nonlimiting examples of surfactants that may be used for rapamycin
include but are not limited to surfactants with an HLB greater than
10, 11, 12, 13 or 14. One nonlimiting example is Cremophor EL. In
some variations, the surfactant may be a polymeric surfactant
including but not limited to PLURONICS F108, F127, and F68, and
Tetronics. As noted herein, some solvents may also serve as
surfactants. Those of ordinary skill in the art will find it
routine to identify which solubilizing agents and surfactants may
be used for rapamycin given the teachings herein.
Viscosity Modifying Agents
[0212] The liquid formulations described herein may be administered
with or further comprise a viscosity modifying agent.
[0213] One exemplary viscosity modifying agent that may be used is
hyaluronic acid. Hyaluronic acid is a glycosaminoglycan. It is made
of a repetitive sequence of glucuronic acid and glucosamine.
Hyaluronic acid is present in many tissues and organs of the body,
and contributes to the viscosity and consistency of such tissues
and organs. Hyaluronic acid is present in the eye, including the
vitreous of the eye, and along with collagen contributes to the
viscosity thereof. The liquid formulations described herein may
further comprise or be administered with hyaluronic acid.
[0214] Other nonlimiting examples of viscosity modifying agents
include polyalkylene oxides, glycerol, carboxymethyl cellulose,
sodium alginate, chitosan, dextran, dextran sulfate and collagen.
These viscosity modifying agents can be chemically modified.
[0215] Other viscosity modifying agents that may be used include
but are not limited to carrageenan, cellulose gel, colloidal
silicon dioxide, gelatin, propylene carbonate, carbonic acid,
alginic acid, agar, carboxyvinyl polymers or carbomers and
polyacrylamides, acacia, ester gum, guar gum, gum arabic, ghatti,
gum karaya, tragacanth, terra, pectin, tamarind seed, larch
arabinogalactan, alginates, locust bean, xanthan gum, starch,
veegum, tragacanth, polyvinyl alcohol, gellan gum, hydrocolloid
blends, and povidone. Other viscosity modifying agents known in the
art can also be used, including but not limited to sodium
carboxymethyl cellulose, algin, carageenans, galactomannans,
hydropropyl methyl cellulose, hydroxypropyl cellulose, polyethylene
glycol, polyvinylpyrrolidone, sodium carboxymethyl chitin, sodium
carboxymethyl dextran, sodium carboxymethyl starch, xanthan gum,
and zein.
Other Components of Liquid Formulations
[0216] The formulations described herein may further comprise
various other components such as stabilizers, for example.
Stabilizers that may be used in the formulations described herein
include but are not limited to agents that will (1) improve the
compatibility of excipients with the encapsulating materials such
as gelatin, (2) improve the stability (e.g. prevent crystal growth
of a therapeutic agent such as rapamycin) of a therapeutic agent
such as rapamycin and/or rapamycin derivatives, and/or (3) improve
formulation stability. Note that there is overlap between
components that are stabilizers and those that are solvents,
solubilizing agents or surfactants, and the same component can
carry out more than one role.
[0217] Stabilizers may be selected from fatty acids, fatty
alcohols, alcohols, long chain fatty acid esters, long chain
ethers, hydrophilic derivatives of fatty acids,
polyvinylpyrrolidones, polyvinylethers, polyvinyl alcohols,
hydrocarbons, hydrophobic polymers, moisture-absorbing polymers,
and combinations thereof. Amide analogues of the above stabilizers
can also be used. The chosen stabilizer may change the
hydrophobicity of the formulation (e.g. oleic acid, waxes), or
improve the mixing of various components in the formulation (e.g.
ethanol), control the moisture level in the formula (e.g. PVP),
control the mobility of the phase (substances with melting points
higher than room temperature such as long chain fatty acids,
alcohols, esters, ethers, amides etc. or mixtures thereof; waxes),
and/or improve the compatibility of the formula with encapsulating
materials (e.g. oleic acid or wax). Some of these stabilizers may
be used as solvents/co-solvents (e.g. ethanol). Stabilizers may be
present in sufficient amount to inhibit the therapeutic agent's
(such as rapamycin's) crystallization.
[0218] Examples of stabilizers include, but are not limited to,
saturated, monoenoic, polyenoic, branched, ring-containing,
acetylenic, dicarboxylic and functional-group-containing fatty
acids such as oleic acid, caprylic acid, capric acid, caproic acid,
lauric acid, myristic acid, palmitic acid, stearic acid, behenic
acid, linoleic acid, linolenic acid, eicosapentaenoic acid (EPA),
DHA; fatty alcohols such as stearyl alcohol, cetyl alcohol, ceteryl
alcohol; other alcohols such as ethanol, isopropyl alcohol,
butanol; long chain fatty acid esters, ethers or amides such as
glyceryl stearate, cetyl stearate, oleyl ethers, stearyl ethers,
cetyl ethers, oleyl amides, stearyl amides; hydrophilic derivatives
of fatty acids such as polyglyceryl fatty acids, polyethylene
glycol fatty acid esters;polyvinylpyrrolidones, polyvinylalcohols
(PVAs), waxes, docosahexaenoic acid and de-hydroabietic acid
etc.
[0219] The formulations described may further contain a gelling
agent that alters the texture of the final formulation through
formation of a gel.
[0220] The therapeutic agents for use as described herein, such as
rapamycin, may be subjected to conventional pharmaceutical
operations, such as sterilization and compositions containing the
therapeutic agent may also contain conventional adjuvants, such as
preservatives, stabilizers, wetting agents, emulsifiers, buffers
etc. The therapeutic agents may also be formulated with
pharmaceutically acceptable excipients for clinical use to produce
a pharmaceutical composition. Formulations for ocular
administration may be presented as a solution, suspension,
particles of solid material, a discrete mass of solid material,
incorporated within a polymer matrix, liquid formulations or in any
other form for ocular administration. The therapeutic agents may be
used to prepare a medicament to treat, prevent, inhibit, delay
onset, or cause regression of any of the conditions described
herein. In some variations, the therapeutic agents may be used to
prepare a medicament to treat any of the conditions described
herein.
[0221] A composition containing a therapeutic agent such as
rapamycin may contain one or more adjuvants appropriate for the
indicated route of administration. Adjuvants with which the
therapeutic agent may be admixed with include but are not limited
to lactose, sucrose, starch powder, cellulose esters of alkanoic
acids, stearic acid, talc, magnesium stearate, magnesium oxide,
sodium and calcium salts of phosphoric and sulphuric acids, acacia,
gelatin, sodium alginate, polyvinylpyrrolidine, and/or polyvinyl
alcohol. When asolubilized formulation is required the therapeutic
agent may be in a solvent including but not limited to polyethylene
glycol of various molecular weights, propylene glycol,
carboxymethyl cellulose colloidal solutions, methanol, ethanol,
DMSO, corn oil, peanut oil, cottonseed oil, sesame oil, tragacanth
gum, and/or various buffers. Other adjuvants and modes of
administration are well known in the pharmaceutical art and may be
used in the practice of the methods, compositions and liquid
formulations described herein. The carrier or diluent may include
time delay material, such as glyceryl monostearate or glyceryl
distearate alone or with a wax, or other materials well known in
the art. The formulations for use as described herein may also
include gel formulations, erodible and non-erodible polymers,
microspheres, and liposomes.
[0222] Other adjuvants and excipients that may be used include but
are not limited to C.sub.8-C.sub.10 fatty acid esters such as
softigen 767, polysorbate 80, PLURONICS, Tetronics, Miglyol, and
Transcutol.
[0223] Additives and diluents normally utilized in the
pharmaceutical arts can optionally be added to the pharmaceutical
composition and the liquid formulation. These include thickening,
granulating, dispersing, flavoring, sweetening, coloring, and
stabilizing agents, including pH stabilizers, other excipients,
anti-oxidants (e.g., tocopherol, BHA, BHT, TBHQ, tocopherol
acetate, ascorbyl palmitate, ascorbic acid propyl gallate, and the
like), preservatives (e.g., parabens), and the like. Exemplary
preservatives include, but are not limited to, benzylalcohol,
ethylalcohol, benzalkonium chloride, phenol, chlorobutanol, and the
like. Some useful antioxidants provide oxygen or peroxide
inhibiting agents for the formulation and include, but are not
limited to, butylated hydroxytoluene, butylhydroxyanisole, propyl
gallate, ascorbic acid palmitate, .alpha.-tocopherol, and the like.
Thickening agents, such as lecithin, hydroxypropylcellulose,
aluminum stearate, and the like, may improve the texture of the
formulation.
[0224] In some variations, the therapeutic agent is rapamycin, and
the rapamycin is formulated as rapamune in solid or liquid form. In
some variations, the rapamune is formulated as an oral dosage.
[0225] In addition, a viscous polymer may be added to the
suspension, assisting the localization and ease of placement and
handling. In some uses of the liquid formulation, a pocket in the
sclera may be surgically formed to receive an injection of the
liquid formulations. The hydrogel structure of the sclera can act
as a rate-controlling membrane. Particles of therapeutic agent
substance for forming a suspension can be produced by known methods
including but not limited to via ball milling, for example by using
ceramic beads. For example, a Cole Parmer ball mill such as Labmill
8000 may be used with 0.8 mm YTZ ceramic beads available from Tosoh
or Norstone Inc.
[0226] The formulations may conveniently be presented in unit
dosage form and may be prepared by conventional pharmaceutical
techniques. Such techniques include the step of bringing into
association the therapeutic agent and the pharmaceutical carrier(s)
or excipient(s). The formulations may be prepared by uniformly and
intimately bringing into associate the active ingredient with
liquid carriers or finely divided solid carriers or both, and then,
if necessary, shaping the product.
[0227] In some variations, the formulations described herein are
provided in one Or more unit dose forms, wherein the unit dose form
contains an amount of a liquid formulation described herein that is
effective to treat or prevent the disease or condition for which it
is being administered. In some variations, the formulations
described herein are provided in one or more unit dose forms,
wherein the unit dose form contains an amount of a liquid rapamycin
formulation described herein that is effective to treat or prevent
the disease or condition for which it is being administered.
[0228] In some embodiments, the unit dose form is prepared in the
concentration at which it will be administered. In some variations,
the unit dose form is diluted prior to administration to a subject.
In some variations, a liquid formulation described herein is
diluted in an aqueous medium prior to administration to a subject.
In some variations the aqueous medium is an isotonic medium. In
some variations, a liquid formulation described herein is diluted
in an non-aqueous medium prior to administration to a subject.
[0229] In a further aspect, provided herein are kits comprising one
or more unit dose forms as described herein. In some embodiments,
the kit comprises one or more of packaging and instructions for use
to treat one or more diseases or conditions. In some embodiments,
the kit comprises a diluent which is not in physical contact with
the formulation or pharmaceutical formulation. In some embodiments,
the kit comprises any of one or more unit dose forms described
herein in one or more sealed vessels. In some embodiments, the kit
comprises any of one or more sterile unit dose forms.
[0230] In some variations, the unit dose form is in a container,
including but not limited to a sterile sealed container. In some
variations the container is a vial, ampule, or low volume
applicator, including but not limited to a syringe. In some
variations, a low-volume applicator is pre-filled with rapamycin
for treatment of an ophthalmic disease or condition, including but
not limited to a limus compound for treatment of age-related
macular degeneration. Described herein is a pre-filled low-volume
applicator pre-filled with a formulation comprising a therapeutic
agent, including but not limited to rapamycin. In some variations a
low-volume applicator is pre-filled with a solution comprising a
therapeutic agent, including but not limited to rapamycin and a
polyethylene glycol, and optionally further comprises one or more
additional components including but not limited to ethanol. In some
variations a pre-filled low-volume applicator is pre-filled with a
solution comprising about 2% rapamycin, about 94% PEG-400, about 4%
ethanol.
[0231] Described herein are kits comprising one or more containers.
In some variations a kit comprises one or more low-volume
applicators is pre-filled with a formulation described herein
comprising a therapeutic agent, including but not limited to
formulations comprising rapamycin, formulations comprising
rapamycin and a polyethylene glycol, and optionally further
comprises one or more additional components including but not
limited to ethanol, and formulations in liquid form comprising
about 2% rapamycin, about 94% PEG-400, about 4% ethanol. In some
variations the kit comprises one or more containers, including but
not limited to pre-filled low-volume applicators, with instructions
for its use. In a further variation a kit comprises one or more
low-volume applicators pre-filled with rapamycin, with instructions
for its use in treating a disease or condition of the eye. In some
variations, the containers described herein are in a secondary
packaging.
Routes of Administration
[0232] The compositions, methods, and liquid formulations described
herein deliver one or more therapeutic agents to a subject,
including but not limited to a human subject.
[0233] In some variations, the compositions, methods, and liquid
formulations described herein deliver one or more therapeutic
agents to an aqueous medium of a human subject.
[0234] In some variations, the compositions, methods, and liquid
formulations described herein deliver one or more therapeutic
agents to an aqueous medium in or proximal to an area where a
disease or condition is to be treated, prevented, inhibited, onset
delayed, or regression caused.
[0235] In some variations, the compositions, methods, and liquid
formulations described herein deliver one or more therapeutic
agents to an eye of a subject, including the macula and the retina
choroid tissues, in an amount and for a duration effective to
treat, prevent, inhibit, delay the onset of, or cause the
regression of the diseases and conditions described in the Diseases
and Conditions section.
[0236] "Retina choroid" and "retina choroid tissues," as used
herein, are synonymous and refer to the combined retina and choroid
tissues of the eye.
[0237] As a non-limiting example, the compositions, liquid
formulations, and methods described in herein may be administered
to the vitreous, aqueous humor, sclera, conjunctiva, between the
sclera and conjunctiva, the retina choroid tissues, macula, or
other area in or proximate to the eye of a subject, either by
direct administration to these tissues or by periocular routes, in
amounts and for a duration effective to treat, prevent, inhibit,
delay the onset of, or cause the regression of CNV and wet AMD. The
effective amounts and durations may be different for each of
treating, preventing, inhibiting, delaying the onset of, or causing
the regression of CNV and wet AMD, and for each of the different
sites of delivery.
[0238] Intravitreal administration is more invasive than some other
types of ocular procedures. Because of the potential risks of
adverse effects, intravitreal administration may not be optimal for
treatment of relatively healthy eyes. By contrast, periocular
administration, such as subconjunctival administration, is much
less invasive than intravitreal administration. When a therapeutic
agent is delivered by a periocular route, it may be possible to
treat patients with healthier eyes than could be treated using
intravitreal administration. In some variations, subconjunctival
injection is used to prevent or delay onset of a disease or
condition of the eye, where the eye of the subject has visual
acuity of 20/40 or better.
[0239] "Subconjunctival" placement or injection, as used herein,
refers to placement or injection between the sclera and
conjunctiva. Subconjunctival is sometimes referred to herein as
"sub-conj" administration.
[0240] Routes of administration that may be used to administer a
liquid formulation include but are not limited to placement of the
liquid formulation, for example by injection, into an aqueous
medium in the subject, including but not limited to placement,
including but not limited to by injection, into the eye of a
subject, including but not limited to a human subject. The liquid
formulation may be administered systemically, including but not
limited to the following delivery routes: rectal, vaginal,
infusion, intramuscular, intraperitoneal, intraarterial,
intrathecal, intrabronchial, intracisternal, cutaneous,
subcutaneous, intradermal, transdermal, intravenous, intracervical,
intraabdominal, intracranial, intraocular, intrapulmonary,
intrathoracic, intratracheal, nasal, buccal, sublingual, oral,
parenteral, or nebulised or aerosolized using aerosol
propellants.
[0241] Compositions and liquid formulations comprising therapeutic
agent can be administered directly to the eye using a variety of
procedures, including but not limited to procedures in which (1)
the therapeutic agent is administered by injection using a syringe
and hypodermic needle, (2) a specially designed device is used to
inject the therapeutic agent, (3) prior to injection of the
therapeutic agent, a pocket is surgically formed within the sclera
to serve as a receptacle for the therapeutic agent or therapeutic
agent composition. For example, in one administration procedure a
surgeon forms a pocket within the sclera of the eye followed by
injection of a solution or liquid formulation comprising the
therapeutic agent into the pocket.
[0242] Other administration procedures include, but are not limited
to procedures in which (1) a formulation of the therapeutic agent,
is injected through a specially designed curved cannula to place
the therapeutic agent directly against a portion of the eye, (2) a
compressed form of the therapeutic agent is placed directly against
a portion of the eye, (3) the therapeutic agent is inserted into
the sclera by a specially designed injector or inserter, (4) the
liquid formulation comprising the therapeutic agent is incorporated
within a polymer, (5) a surgeon makes a small conjunctival incision
through which to pass a suture and any therapeutic agent delivery
structure so as to secure the structure adjacent to the sclera, (6)
a needle is used for injection directly into the vitreous of an
eye, or into any other site described.
[0243] The liquid formulations described herein may be used
directly, for example, by injection, as an elixir, for topical
administration including but not limited to via eye drops, or in
hard or soft gelatin or starch capsules. The capsules may be banded
to prevent leakage.
Delivery by Injection
[0244] One method that may be used to deliver the compositions and
liquid formulations described herein is delivery by injection. In
this method compositions and liquid formulations may be injected
into a subject, including but not limited to a human subject, or
into a position in or proximate to an eye of the subject for
delivery to a subject or to the eye of a subject. Injection
includes but is not limited to intraocular and periocular
injection. Nonlimiting examples of positions that are in or
proximate to an eye of a subject are as follows.
[0245] Injection of therapeutic agent into the vitreous may provide
a high local concentration of therapeutic agent in the vitreous and
retina. Further, it has been found that in the vitreous the
clearance half-lives of drugs increases with molecular weight.
[0246] Intracameral injection, or injection into the anterior
chamber of they eye, may also be used. In one example, up to about
100 .mu.l may be injected intracamerally.
[0247] Periocular routes of delivery may deliver therapeutic agent
to the retina without some of the risks of intravitreal delivery.
Periocular routes include but are not limited to subconjunctival,
subtenon, retrobulbar, peribulbar and posterior juxtascleral
delivery. A "periocular" route of administration means placement
near or around the eye. For a description of exemplary periocular
routes for retinal drug delivery, see Periocular routes for retinal
drug delivery, Raghava et al. (2004), Expert Opin. Drug Deliv.
1(1):99-114, which is incorporated herein by reference in its
entirety.
[0248] In some variations the liquid formulations described herein
are administered intraocularly. Intraocular administration includes
placement or injection within the eye, including in the
vitreous.
[0249] Subconjunctival injection may be by injection of therapeutic
agent underneath the conjunctiva, or between the sclera and
conjunctiva. In one example, up to about 500 .mu.l may be injected
subconjunctivally. As one nonlimiting example, a needle of up to
about 25 to about 30 gauge and about 30 mm long may be used. Local
pressure to the subconjunctival site of therapeutic agent
administration may elevate delivery of the therapeutic agent to the
posterior segment by reducing local choroidal blood flow.
[0250] Subtenon injection may be by injection of therapeutic agent
into the tenon's capsule around the upper portion of the eye and
into the "belly" of the superior rectus muscle. In one example, up
to about 4 ml may be injected subtenon. As one nonlimiting example,
a blunt-tipped cannula about 2.5 cm long may be used.
[0251] Retrobulbar injection refers to injection into the conical
compartment of the four rectus muscles and their intermuscular
septa, behind the globe of the eye. In one example, up to about 5
ml may be injected retrobulbarly. As one nonlimiting example, a
blunt needle of about 25- or about 27-gauge may be used.
[0252] Peribulbar injection may be at a location external to the
confines of the four rectus muscles and their intramuscular septa,
i.e., outside of the muscle cone. A volume of, for example, up to
about 10 ml may be injected peribulbarly. As one nonlimiting
example, a blunt-tipped cannula about 1.25 inches long and about
25-gauge may be used.
[0253] Posterior juxtascleral deliver refers to placement of a
therapeutic agent near and above the macula, in direct contact with
the outer surface of the sclera, and without puncturing the
eyeball. In one example, up to about 500 ml may be injected
posterior juxtasclerally. As one nonlimiting example, a
blunt-tipped curved cannula, specially designed at 56.degree., is
used to place the therapeutic agent in an incision in the
sclera.
[0254] In some variations the liquid formulations described herein
are injected intraocularly. Intraocular injection includes
injection within the eye.
[0255] Sites to which the compositions and liquid formulations may
be administered include but are not limited to the vitreous,
aqueous humor, sclera, conjunctiva, between the sclera and
conjunctiva, the retina choroid tissues, macula, or other area in
or proximate to the eye of a subject. Methods that may be used for
placement of the compositions and liquid formulations include but
are not limited to injection.
[0256] In one method that may be used, the therapeutic agent is
dissolved in an solvent or solvent mixture and then injected into
or proximate to the vitreous, aqueous humor, sclera, conjunctiva,
between the sclera and conjunctiva, the retina choroid tissues,
macula, other area in or proximate to the eye of a subject, or
other medium of a subject, according to any of the procedures
mentioned above. In one such method that may be used, the
therapeutic agent is rapamycin in a liquid formulation.
[0257] When the therapeutic agent is rapamycin, the compositions
and liquid formulations may be used to deliver or maintain an
amount of rapamycin in tissues of the eye, including without
limitation retina, choroid, or the Vitreous, which amount is
effective to treat AMD. In one nonlimiting example, it is believed
that a liquid formulation delivering rapamycin in an amount capable
of providing a concentration of rapamycin of about 0.1 pg/ml to
about 2 .mu.g/ml in the vitreous may be used for treatment of wet
AMD. In some nonlimiting examples, it is believed that a liquid
formulation delivering a concentration of rapamycin of about 0.1
.mu.g/mg to about 1 .mu.g/mg in the retina choroid tissues may be
used for treatment of wet AMD. Other effective concentrations are
readily ascertainable by those of skill in the art based on the
teachings described herein.
Method of preparing Liquid Formulations
[0258] One nonlimiting method that may be used for preparing the
liquid formulations described herein, including but not limited to
liquid formulations comprising rapamycin, is by mixing a solvent
and a therapeutic agent together at room temperature or at slightly
elevated temperature until a solution or suspension is obtained,
with optional use of a sonicator, and then cooling the formulation.
Other components including but not limited to those described above
may then be mixed with the formulation. Other preparation methods
that may be used are described herein including in the examples,
and those of skill in the art will be able to select other
preparation methods based on the teachings herein.
Extended Delivery of Therapeutic Agents
[0259] Described herein are compositions and liquid formulations
showing in vivo delivery or clearance profiles with one or more of
the following characteristics. The delivery or clearance profiles
are for clearance of the therapeutic agent in vivo after injection
of the composition or liquid formulations subconjunctivally or into
the vitreous of a rabbit eye. In some variations, the delivery or
clearance profiles are for clearance of rapamycin in vivo after
injection of the composition or liquid formulations
subconjunctivally or into the vitreous of a rabbit eye. The volume
of the rabbit vitreous is approximately 30-40% of the volume of the
human vitreous. The amount of therapeutic agent is measured using
techniques as described in Example 2, but without limitation to the
formulation and therapeutic agent described in Example 2.
[0260] In some variations, the therapeutic agents with the in vivo
delivery or clearance profiles described herein include but are not
limited to those described in the Therapeutic Agents section. In
some variations the therapeutic agent is rapamycin. In some
variations, the liquid formulations described herein are used to
deliver therapeutic agents in a concentration equivalent to
rapamycin. The liquid formulations described herein may comprise
any therapeutic agent including but not limited to those in the
Therapeutic Agents section, in a concentration equivalent to
rapamycin including but not limited to those concentrations
described herein including in the examples.
[0261] "Average percentage in vivo" level means that an average
concentration of therapeutic agent is obtained across multiple
rabbit eyes for a given timepoint, and the average concentration of
therapeutic agent at one timepoint is divided by the average
concentration of therapeutic agent at another timepoint. In some
variations of the average percentage in vivo levels, the
therapeutic agent is rapamycin.
[0262] The average concentration of a therapeutic agent in the
tissue of a rabbit eye at a given time after administration of a
formulation containing the therapeutic agent may be measured
according to the following method. Where volumes below 1011 are to
be injected, a Hamilton syringe is used.
[0263] The liquid formulations are stored at a temperature of
2-8.degree. C. prior to use.
[0264] The experimental animals are specific pathogen free (SPF)
New Zealand White rabbits. A mixed population of about 50% male,
about 50% female is used. The rabbits are at least 12 weeks of age,
usually at least 14 weeks of age, at the time of dosing. The
rabbits each weigh at least 2.2 kg, usually at least 2.5 kg, at the
time of dosing. Prior to the study, the animals are quarantined for
at least one week and examined for general health parameters. Any
unhealthy animals are not used in the study. At least 6 eyes are
measured and averaged for a given timepoint.
[0265] Housing and sanitation are performed according to standard
procedures used in the industry. The animals are provided
approximately 150 grams of Teklad Certified Hi-Fiber Rabbit Diet
daily, and are provided tap water ad libitum. No contaminants are
known to exist in the water and no additional analysis outside that
provided by the local water district is performed. Environmental
Conditions are monitored.
[0266] Each animal undergoes a pie-treatment ophthalmic examination
(slit lamp and ophthalmoscopy), performed by a board certified
veterinary ophthalmologist. Ocular findings are scored according to
the McDonald and Shadduck scoring system as described in
Dermatoxicology, F. N. Marzulli and H. I. Maibach, 1977 "Eye
Irritation," T. O. McDonald and J. A. Shadduck (pages 579-582).
Observations are recorded using a standardized data collection
sheet. Acceptance criteria for placement on study are as follows:
scores of .ltoreq.1 for conjunctival congestion and swelling;
scores of 0 for all other observation variables.
[0267] Gentamicin ophthalmic drops are placed into both eyes of
each animal twice daily on the day prior to dosing, on the day of
dosing (Day 1), and on the day after dosing (Day 2). Dosing is
performed in two phases, the first including one set of animals and
the second including the other animals. Animals are randomized
separately into masked treatment groups prior to each phase of
dosing according to modified Latin squares. Animals are fasted at
least 8 hours prior to injection. The start time of the fast and
time of injection are recorded.
[0268] Animals are weighed and anesthetized with an intravenous
injection of a ketamine/xylazine cocktail (87 mg/mL ketamine, 13
mg/mL xylazine) at a volume of 0.1-0.2 mL/kg. Both eyes of each
animal are prepared for injection as follows: approximately five
minutes prior to injection, eyes are moistened with an ophthalmic
Betadine solution. After five minutes, the Betadine is washed out
of the eyes with sterile saline. Proparacaine hydrochloride 0.5%
(1-2 drops) is delivered to each eye. For eyes to be intravitreally
injected, 1% Tropicamide (1 drop) is delivered to each eye.
[0269] On Day 1, both eyes of each animal receive an injection of
test or control article. Animals in selected groups are dosed a
second time on Day 90.+-.1. Dosing is subconjunctival or
intravitreal. Actual treatments, injection locations, and dose
volumes are masked and revealed at the end of the study.
[0270] Subconjunctival injections are given using an insulin
syringe and 30 gauge.times.1/2-inch needle. The bulbar conjunctiva
in the dorsotemporal quadrant is elevated using forceps. Test
article is injected into the subconjunctival space.
[0271] Intravitreal injections are given using an Insulin syringe
and 30 gauge.times.1/2-inch needle. For each injection, the needle
is introduced through the ventral-nasal quadrant of the eye,
approximately 2-3 mm posterior to the limbus, with the bevel of the
needle directed downward and posteriorly to avoid the lens. Test
article is injected in a single bolus in the vitreous near the
retina.
[0272] Animals are observed for mortality/morbidity twice daily. An
animal determined to be moribund is euthanized with an intravenous
injection of commercial euthanasia solution. Both eyes are removed
and stored frozen at -70.degree. C. for possible future evaluation.
If an animal is found dead prior to onset of rigor mortis, both
eyes are removed and stored frozen at -70.degree. C. for possible
future evaluation. Animals found after the onset of rigor mortis
are not necropsied.
[0273] Animals are weighed at randomization, on Day 1 prior to
dosing, and prior to euthanasia.
[0274] Ophthalmic observations (slit lamp and indirect
ophthalmoscopy) are performed on all animals on Days 5.+-.1,
30.+-.1, 60.+-.1, 90.+-.1, and at later dates in some variations.
Observations are performed by a board certified veterinary
ophthalmologist. For animals to be dosed on Day 90.+-.1, ophthalmic
observations are performed prior to dosing. Ocular findings are
scored according to the McDonald and Shadduck scoring system as
described in Dermatoxicology, F. N. Marzulli and H. I. Maibach,
1977 "Eye Irritation", T. O. McDonald and J. A. Shadduck (pages
579-582), and observations are recorded using a standardized data
collection sheet.
[0275] Whole blood samples (1-3 mL per sample) are collected from
each animal prior to necropsy in vacutainer tubes containing EDTA.
Each tube is filled at least 2/3 full and thoroughly mixed for at
least 30 seconds. Tubes are stored frozen until shipped on dry
ice.
[0276] Animals are euthanized with an intravenous injection of
commercial euthanasia solution. Euthanasia is performed according
to standard procedures used in the industry.
[0277] For treatment groups dosed intravitreally or
subconjunctivally with placebo, all eyes from each of these groups
are placed into Davidsons solution for approximately 24 hours.
Following the 24-hour period, the eyes are transferred to 70%
ethanol; these globes are submitted for masked histopathological
evaluation by a board certified veterinary pathologist. The time
that eyes are placed into Davidsons and the time of removal are
recorded.
[0278] For treatment groups dosed intravitreally or
subconjunctivally with test article, some eyes from each of these
groups are frozen at -70.degree. C. and submitted for
pharmacokinetic analysis. The remaining eyes from each of these
groups are placed into Davidsons solution for approximately 24
hours. Following the 24-hour period, the eyes are transferred to
70% ethanol; these globes are submitted for masked
histopathological evaluation by a board certified veterinary
pathologist. The time that eyes are placed into Davidsons and the
time of removal are recorded.
[0279] Frozen samples submitted for pharmacokinetic analysis are
dissected with disposable instruments. One set of instruments is
used per eye, and then discarded. The samples are thawed at room
temperature for 1 to 2 minutes to ensure that the frost around the
tissue has been removed. The sclera is dissected into 4 quadrants,
and the vitreous is removed. If a non-dispersed mass (NDM) is
clearly visible within the vitreous, the vitreous is separated into
two sections. The section with the NDM is approximately two-thirds
of the vitreous. The section without the NDM is the portion of the
vitreous that is the most distant from the NDM. The aqueous humor,
lens, iris, and cornea are separated. The retina choroid tissue is
removed using a forceps and collected for analysis. The conjunctiva
is separated from the sclera.
[0280] The various tissue types are collected into separate
individual pre-weighed vials which are then capped and weighed. The
vials of tissue are stored at -80.degree. C. until analyzed.
[0281] The sirolimus content of the retina choroid, sclera,
vitreous humor, and whole anti-coagulated blood is determined by
high-pressure liquid chromatography/tandem mass spectroscopy
(HPLC/MS/MS) using 32-O-desmethoxyrapamycin as an internal
standard. Where an NDM was observed in the vitreous, the section of
the vitreous containing the NDM and the section of the vitreous not
containing the NDM are analyzed separately.
[0282] The average concentration of a therapeutic agent over a
period of time means for representative timepoints over the period
of time the average concentration at each time point. For example,
if the time period is 30 days, the average concentration may be
measured at 5 day intervals: for the average concentration at day
5, the average of a number of measurements of concentration at day
5 would be calculated; for the average concentration at day 10, the
average of a number of measurements of the concentration at day 10
would be calculated, etc.
[0283] In some variations, the liquid formulations described herein
may have in vivo delivery to the vitreous profiles with the
following described characteristics, where the delivery profiles
are for delivery of therapeutic agent in vivo after injection of
the liquid formulation between the sclera and the conjunctiva of a
rabbit eye. One nonlimiting variation of in vivo delivery to the
vitreous profiles is shown in FIG. 2.
[0284] At day 40 after injection, the average percentage in vivo
vitreal level may be between about 70% and about 100%, and more
usually between about 80% and about 90%, relative to the level
present at day 20 after injection. At day 40 after injection, the
average percentage in vivo vitreal level may be greater than about
70%, and more usually greater than about 80%, relative to the level
present at day 20 after injection.
[0285] At day 67 after-injection, the average percentage in vivo
vitreal level may be between about 75% and about 115%, and more
usually between about 85% and about 105%, relative to the level
present at day 20 after injection. At day 67 after injection, the
average percentage in vivo vitreal level may be greater than about
75%, and more usually greater than about 85%, relative to the level
present at day 20 after injection.
[0286] At day 90 after injection, the average percentage in vivo
vitreal level may be between about 20% and about 50%, and more
usually between about 30% and about 40%, relative to the level
present at day 2' after injection. At day 90 after injection, the
average percentage in vivo vitreal level may be greater than about
20%, and more usually greater than about 30%, relative to the level
present at day 20 after injection.
[0287] In some variations, the average percentage in vivo vitreal
level has the following characteristics relative to the level
present at day 20 after injection: at 40 days after injection it is
less than about 100%; at 67 days after injection it is less than
about 115%; and 90 days after injection it is less than about
50%.
[0288] In some variations, the liquid formulation when injected
between the sclera and conjunctiva of a rabbit eye delivers
therapeutic agent giving an average concentration of therapeutic
agent in the vitreous of the rabbit eye of at least about 0.01
ng/mL for at least about 30, at least about 60, or at least about
90 days after administration of the liquid formulation to the
rabbit eyes. In some variations, the liquid formulation when
injected between the sclera and conjunctiva of a rabbit eye
delivers therapeutic agent giving an average concentration of
therapeutic agent in the vitreous of the rabbit eye of at least
about 0.1 ng/mL for at least about 30, at least about 60, or at
least about 90 days after administration of the liquid formulation
to the rabbit eyes. In some variations, the liquid formulation when
injected between the sclera and conjunctiva of a rabbit eye
delivers therapeutic agent giving an average concentration of
therapeutic agent in the vitreous of the rabbit eye of at least
about 1 ng/mL for at least about 30, at least about 60, or at least
about 90 days after administration of the liquid formulation to the
rabbit eyes.
[0289] In some variations, the liquid formulations described herein
may have in vivo delivery to the retina choroid profiles with the
following described characteristics, where the delivery profiles
are for delivery of therapeutic agent in vivo after injection of
the liquid formulation between the sclera and the conjunctiva of a
rabbit eye.
[0290] At day 40 after injection, the average percentage in vivo
retina choroid level may be between about 350% and about 410%, and
more usually between about 360% and about 400%, relative to the
level present at day 20 after injection. At day 40 after injection,
the average percentage in vivo retina choroid level may be greater
than about 350%, and more usually greater than about 360%, relative
to the level present at day 20 after injection.
[0291] At day 67 after injection, the average percentage in vivo
retina choroid level may be between about 125% and about 165%, and
more usually between about 135% and about 155%, relative to the
level present at day 20 after injection. At day 67 after injection,
the average percentage in vivo retina choroid level may be greater
than about 125%, and more usually greater than about 135%, relative
to the level present at day 20 after injection.
[0292] At day 90 after injection, the average percentage in vivo
retina choroid level may be between about 10% and about 50%, and
more usually between about 20% and about 40%, relative to the level
present at day 20 after injection. At day 90 after injection, the
average percentage in vivo retina choroid level may be greater than
about 10%, and more usually greater than about 20%, relative to the
level present at day 20 after injection.
[0293] In some variations, the average percentage in vivo retina
choroid level has the following characteristics relative to the
level present at day 20 after injection: at 40 days after injection
it is less than about 410%; at 67 days after injection it is less
than about 165%; and 90 days after injection it is less than about
0.50%.
[0294] In some variations, the liquid formulation when injected
between the sclera and conjunctiva of a rabbit eye delivers
therapeutic agent giving an average concentration of therapeutic
agent in the retina choroid tissues of the rabbit eye of at least
about 0.001 ng/mg for at least about 30, at least about 60, or at
least about 90 days after administration of the liquid formulation
to the rabbit eyes. In some variations, the liquid formulation when
injected between the sclera and conjunctiva of a rabbit eye
delivers therapeutic agent giving an average concentration of
therapeutic agent in the retina choroid tissues of the rabbit eye
of at least about 0.01 ng/mg for at least about 30, at least about
60, or at least about 90 days after administration of the liquid
formulation to the rabbit eyes.
[0295] In some variations, the level of therapeutic agent present
in the retina choroid first increases, then peaks and decreases.
The peak may, for instance, occur at about day 40 after
injection.
[0296] In some variations, the liquid formulations described herein
may have in vivo clearance from the sclera profiles with the
following described characteristics, where the clearance profiles
are for clearance of therapeutic agent in vivo after injection of
the liquid formulation between the sclera and the conjunctiva of a
rabbit eye. Where injection is between the sclera and the
conjunctiva, the scleral level is thought to include the injected
liquid formulation.
[0297] At day 40 after injection, the average percentage in vivo
scleral level may be between about 150% and about 230%, and more
usually between about 170% and about 210%, relative to the level
present at day 20 after injection. At day 40 after injection, the
average percentage in vivo scleral level may be greater than about
150%, and more usually greater than about 170%, relative to the
level: present at day 20 after injection.
[0298] At day 67 after injection, the average percentage in vivo
scleral level may be between about 30% and about 70%, and more
usually between about 40% and about 60%, relative to the level
present at day 20 after injection. At day 67 after injection, the
average percentage in vivo scleral level may be greater than about
30%, and more usually greater than about 40%, relative to the level
present at day 20 after injection.
[0299] At day 90 after injection, the average percentage in vivo
scleral level may be between about 110% and about 160%, and more
usually between about 125% and about 145%, relative to the level
present at day 20 after injection. At day 90 after injection, the
average percentage in vivo scleral level may be greater than about
110%, and more usually greater than about 125%, relative to the
level present at day 20 after injection.
[0300] In some variations, the average percentage in vivo scleral
level has the following characteristics relative to the level
present at day 20 after injection: at 40 days after injection it is
less than about 230%; at 67 days after injection it is less than
about 70%; and 90 days after injection it is less than about
160%.
[0301] In some variations, the level of therapeutic agent present
in the sclera first increases, then peaks and decreases. The peak
may, for instance, occur at about day 40 after injection.
[0302] In some variations, the liquid formulations described herein
may have in vivo delivery to the vitreous profiles with the
following described characteristics, where the delivery profiles
are for delivery of therapeutic agent in vivo after injection of
the liquid formulation between the sclera and the conjunctiva of a
rabbit eye.
[0303] At day 14 after injection, the average percentage in vivo
vitreal level may be between about 1350% and about 1650%, and more
usually between about 1450% and about 1550%, relative to the level
present at day 2 after injection. At day 14 after injection, the
average percentage in vivo vitreal level may be greater than about
1350%, and more usually greater than about 1450%, relative to the
level present at day 2 after injection.
[0304] At day 35 after injection, the average percentage in vivo
vitreal level may be between about 200% and about 300%, and more
usually between about 225% and about 275%, relative to the level
present at day 2 after injection. At day 35 after injection, the
average percentage in vivo vitreal level may be greater than about
200%, and more usually greater than about 225%, relative to the
level present at day 2 after injection.
[0305] At day 62 after injection, the average percentage in vivo
vitreal level may be between about 100% and about 160%, and more
usually between about 115% and about 145%, relative to the level
present at day 2 after injection. At day 62 after injection, the
average percentage in vivo vitreal level may be greater than about
100%, and more usually greater than about 115%, relative to the
level present at day 2 after injection.
[0306] At day 85 after injection, the average percentage in vivo
vitreal level may be between about 5% and about 30%, and more
usually between about 10% and about 25%, relative to the level
present at day 2 after injection. At day 85 after injection, the
average percentage in vivo vitreal level may be greater than about
5%, and more usually greater than about 10%, relative to the level
present at day 2 after injection.
[0307] In some variations, the average percentage in vivo vitreal
level has the following characteristics relative to the level
present at day 2 after injection: at 14 days after injection it is
less than about 1600%; at 35 days after injection it is less than
about 300%; at 62 days after injection it is less than about 160%
and 85 days after injection it is less than about 30%.
[0308] In some variations, the liquid formulation when injected
between the sclera and conjunctiva of a rabbit eye delivers
therapeutic agent giving an average concentration of therapeutic
agent in the vitreous of the rabbit eye of at least about 0.01
ng/mL for at least about 30, at least about 60, or at least about
85 days after administration of the liquid formulation to the
rabbit eyes. In some variations, the liquid formulation when
injected between the sclera and conjunctiva of a rabbit eye
delivers therapeutic agent giving an average concentration of
therapeutic agent in the vitreous of the rabbit eye of at least
about 0.1 ng/mL for at least about 30, at least about 60, or at
least about 85 days after administration of the liquid formulation
to the rabbit eyes. In some variations, the liquid formulation when
injected between the sclera and conjunctiva of a rabbit eye
delivers therapeutic agent giving an average concentration of
therapeutic agent in the vitreous of the rabbit eye of at least
about 1 ng/mL for at least about 30, or at least about 60 days
after administration of the liquid formulation to the rabbit
eyes.
[0309] In some variations, the level of therapeutic agent present
in the vitreous first increases, then peaks and decreases. The peak
may, for instance, occur at about day 14 after injection.
[0310] In some variations, the liquid formulations described herein
may have in vivo delivery to the retina choroid profiles with the
following described characteristics, where the delivery profiles
are for delivery of therapeutic agent in vivo after injection of
the liquid formulation between the sclera and the conjunctiva of a
rabbit eye.
[0311] At day 35 after injection, the average percentage in vivo
retina choroid level may be between about 320% and about 400%, and
more usually between about 340% and about 380%, relative to the
level present at day 14 after injection. At day 35 after injection,
the average percentage in vivo retina choroid level may be greater
than about 320%, and more usually greater than about 340%, relative
to the level present at day 14 after injection.
[0312] At day 62 after injection, the average percentage in vivo
retina choroid level may be between about 3% and about 25%, and
more usually between about 6% and about 20%, relative to the level
present at day 14 after injection. At day 62 after injection, the
average percentage in vivo retina choroid level may be greater than
about 3%, and more usually greater than about 6%, relative to the
level present at day 14 after injection.
[0313] At day 85 after injection, the average percentage in vivo
retina choroid level may be between about 0.1% and about 6%, and
more usually between about 0.5% and about 4%, relative to the level
present at day 14 after injection. At day 85 after injection, the
average percentage in vivo retina choroid level may be greater than
about 0.1%, and more usually greater than about 0.5%, relative to
the level present at day 14 after injection.
[0314] In some variations, the average percentage in vivo retina
choroid level has the following characteristics relative to the
level present at day 14 after injection: at 35 days after injection
it is less than about 400%; at 62 days after injection it is less
than about 25%; and 85 days after injection it is less than about
6%.
[0315] In some variations, the liquid formulation when injected
between the sclera and conjunctiva of a rabbit eye delivers
therapeutic agent giving an average concentration of therapeutic
agent in the retina choroid tissues of the rabbit eye of at least
about 0.001 ng/mg for at least about 30, at least about 60, or at
least about 85 days after administration of the liquid formulation
to the rabbit eyes. In some variations, the liquid formulation when
injected between the sclera and conjunctiva of a rabbit eye
delivers therapeutic agent giving an average concentration of
therapeutic agent in the retina choroid tissues of the rabbit eye
of at least about 0.01 ng/mg for at least about 30, at least about
60, or at least about 85 days after administration of the liquid
formulation to the rabbit eyes.
[0316] In some variations, the liquid formulations described herein
may have in vivo clearance from the sclera profiles with the
following described characteristics, where the clearance profiles
are for clearance of therapeutic agent in vivo after injection of
the liquid formulation between the sclera and the conjunctiva of a
rabbit eye. For injection between the sclera and conjunctiva, the
scleral level is thought to include the injected liquid
formulation.
[0317] At day 35 after injection, the average percentage in vivo
scleral level may be between about 0.1% and about 0.7%, and more
usually between about 0.2% and about 0.6%, relative to the level
present at day 14 after injection. At day 35 after injection, the
average percentage in vivo scleral level may be greater than about
0.1%, and more usually greater than about 0.2%, relative to the
level present at day 14 after injection.
[0318] At day 62 after injection, the average percentage in vivo
scleral level may be between about 0.05% and about 0.35%, and more
usually between about 0.07% and about 0.3%, relative to the level
present at day 14 after injection. At day 62 after injection, the
average percentage in vivo scleral level may be greater than about
0.05%, and more usually greater than about 0.07%, relative to the
level present at day 14 after injection.
[0319] At day 85 after injection, the average percentage in vivo
scleral level may be between about 0.1% and about 0.9%, and more
usually between about 0.3% and about 0.7%, relative to the level
present at day 14 after injection. At day 85 after injection, the
average percentage in vivo scleral level may be greater than about
0.1%, and more usually greater than about 0.3%, relative to the
level present at day 14 after injection.
[0320] In some variations, the average percentage in vivo scleral
level has the following characteristics relative to the level
present at day 14 after injection: at 35 days after injection it is
less than about 0.7%; at 62 days after injection it is less than
about 0.35%; and 85 days after injection it is less than about
0.9%.
[0321] In some variations, the liquid formulations described herein
may have in vivo clearance from the vitreous profiles with the
following described characteristics, where the clearance profiles
are for clearance of therapeutic agent in vivo after injection of
the liquid formulation into the vitreous of a rabbit eye. Where
injection is into the vitreous, the measured vitreous level is
thought to include the injected formulation.
[0322] At day 35 after injection, the average percentage in vivo
vitreal level may be between about 1% and about 40%, and more
usually between about 1% and about 10%, relative to the level
present at day 14 after injection. At day 35 after injection, the
average percentage in vivo vitreal level may be greater than about
1% relative to the level present at day 14 after injection.
[0323] At day 62 after injection, the average percentage in vivo
vitreal level may be between about 1% and about 40%, and more
usually between about 5% and about 25%, relative to the level
present at day 14 after injection. At day 62 after injection, the
average percentage in vivo vitreal level may be greater than about
1% relative to the level present at day 14 after injection, and
more usually greater than about 5% relative to the level present at
day 14 after injection.
[0324] At day 90 after injection, the average percentage in vivo
vitreal level may be between about 1% and about 40%, and more
usually between about 10% and about 30%, relative to the level
present at day 14 after injection. At day 90 after injection, the
average percentage in vivo vitreal level may be greater than about
1% relative to the level present at day 14 after injection, and
more usually greater than about 10% relative to the level present
at day 14 after injection.
[0325] In some variations, the level of therapeutic agent present
in the vitreous first increases, then peaks and decreases. The peak
may, for instance, occur at about day 14 after injection.
[0326] In some variations, the liquid formulations described herein
may have in vivo delivery to the retina choroid profiles with the
following described characteristics, where the delivery profiles
are for delivery of therapeutic agent in vivo after injection of
the liquid formulation into the vitreous of a rabbit eye.
[0327] At day 35 after injection, the average percentage in vivo
retina choroid level may be between about 3400% and about 5100%,
and more usually between about 3750% and about 4750%, relative to
the level present at day 14 after injection. At day 35 after
injection, the average percentage in vivo retina choroid level may
be greater than about 3400%, and more usually greater than about
3750%, relative to the level present at day 14 after injection.
[0328] At day 62 after injection, the average percentage in vivo
retina choroid level may be between about 0.1% and about 5%, and
more usually between about 1% and about 3%, relative to the level
present at day 14 after injection. At day 62 after injection, the
average percentage in vivo retina choroid level may be greater than
about 0.1%, and more usually greater than about 1%, relative to the
level present at day 14 after injection.
[0329] At day 90 after injection, the average percentage in vivo
retina choroid level may be between about 10% and about 50%, and
more usually between about 20% and about 40%, relative to the level
present at day 14 after injection. At day 90 after injection, the
average percentage in vivo retina choroid level may be greater than
about 10%, and more usually greater than about 20%, relative to the
level present at day 14 after injection.
[0330] In some variations, the average percentage in vivo retina
choroid level has the following characteristics relative to the
level present at day 14 after injection: at 35 days after injection
it is less than about 5100%; at 62 days after injection it is less
than about 5%; and 90 days after injection it is less than about
50%.
[0331] In some variations, the liquid formulations described herein
may have in vivo delivery to the sclera profiles with the following
described characteristics, where the delivery profiles are for
delivery of therapeutic agent in vivo after injection of the liquid
formulation into the vitreous of a rabbit eye.
[0332] At day 35 after injection, the average percentage in vivo
scleral level may be between about 1700% and about 2600%, and more
usually between about 1900% and about 2400%, relative to the level
present at day 14 after injection. At day 35 after injection, the
average percentage in vivo scleral level may be greater than about
1700%, and more usually greater than about 1900%, relative to the
level present at day 14 after injection.
[0333] At day 62 after injection, the average percentage in vivo
scleral level may be between about 120% and about 180%, and more
usually between about 140% and about 160%, relative to the level
present at day 14 after injection. At day 62 after injection, the
average percentage in vivo scleral level may be greater than about
120%, and more usually greater than about 140%, relative to the
level present at day 14 after injection.
[0334] At day 90 after injection, the average percentage in vivo
scleral level may be between about 95% and about 155%, and more
usually between about 115% and about 135%, relative to the level
present at day 14 after injection. At day 90 after injection, the
average percentage in vivo scleral level may be greater than about
95%, and more usually greater than about 115%, relative to the
level present at day 14 after injection.
[0335] In some variations, the average percentage in vivo scleral
level has the following characteristics relative to the level
present at day 14 after injection: at 35 days after injection it is
less than about 2600%; at 62 days after injection it is less than
about 180%; and 90 days after injection it is less than about
155%.
[0336] In some variations, the liquid formulation when injected
into the vitreous of a rabbit eye delivers therapeutic agent giving
an average concentration of therapeutic agent in the sclera of the
rabbit eye of at least about 0.001 ng/mg for at least about 30, at
least about 60, or at least about 90 days after administration of
the liquid formulation to the rabbit eyes. In some variations, the
liquid formulation when injected into the vitreous of a rabbit eye
delivers therapeutic agent giving an average concentration of
therapeutic agent in the sclera of the rabbit eye of at least about
0.01 ng/mg for at least about 30, at least about 60, or at least
about 90 days after administration of the liquid formulation to the
rabbit eyes. In some variations, the liquid formulation when
injected into the vitreous of a rabbit eye delivers therapeutic
agent giving an average concentration of therapeutic agent in the
sclera of the rabbit eye of at least about 0.1 ng/mg for at least
about 30, at least about 60, or at least about 90 days after
administration of the liquid formulation to the rabbit eyes.
[0337] In some variations, the level of therapeutic agent present
in the vitreous first increases, then peaks and decreases. The peak
may, for instance, occur at about day 35 after injection.
[0338] In some variations, in situ gelling liquid formulations
described herein may have in vivo delivery to the vitreous profiles
with the following described characteristics, where the delivery
profiles are for delivery of therapeutic agent in vivo after
injection of the liquid formulation between the sclera and the
conjunctiva of a rabbit eye.
[0339] At day 32 after injection, the average percentage in vivo
vitreal level may be between about 25% and about 85%, and more
usually between about 45% and about 65%, relative to the level
present at day 7 after injection. At day 40 after injection, the
average percentage in vivo vitreal level may be greater than about
25%, and more usually greater than about 45%, relative to the level
present at day 7 after injection.
[0340] At day 45 after injection, the average percentage in vivo
vitreal level may be between about 2% and about 50%, and more
usually between about 8% and about 20%, relative to the level
present at day 7 after injection. At day 67 after injection, the
average percentage in vivo vitreal level may be greater than about
2%, and more usually greater than about 5%, relative to the level
present at day 7 after injection.
[0341] At day 90 after injection, the average percentage in vivo
vitreal level may be between about 40% and about 100%, and more
usually between about 60% and about 80%, relative to the level
present at day 7 after injection. At day 90 after injection, the
average percentage in vivo vitreal level may be greater than about
40%, and more usually greater than about 60%, relative to the level
present at day 7 after injection.
[0342] In some variations, the average percentage in vivo vitreal
level has the following characteristics relative to the level
present at day 7 after injection: at 32 days after injection it is
less than about 80%; at 45 days after injection it is less than
about 30%; and 90 days after injection it is less than about
100%.
[0343] In some variations, the liquid formulation when injected
between the sclera and conjunctiva of a rabbit eye delivers
therapeutic agent giving an average concentration of therapeutic
agent in the vitreous of the rabbit eye of at least about 0.1 pg/mL
for at least about 30, at least about 60, or at least about 90 days
after administration of the liquid formulation to the rabbit eye.
In some variations, the liquid formulation when injected between
the sclera and conjunctiva of a rabbit eye delivers therapeutic
agent giving an average concentration of therapeutic agent in the
vitreous of the rabbit eye of at least about 0.01 ng/mL for at
least about 30, at least about 60, or at least about 90 days after
administration of the liquid formulation to the rabbit eye. In some
variations, the liquid formulation when injected between the sclera
and conjunctiva of a rabbit eye delivers therapeutic agent giving
an average concentration of therapeutic agent in the vitreous of
the rabbit eye of at least about 0.1 ng/mL for at least about 30,
at least about 60, or at least about 90 days after administration
of the liquid formulation to the rabbit eye. In some variations,
the liquid formulation when injected between the sclera and
conjunctiva of a rabbit eye delivers therapeutic agent giving an
average concentration of therapeutic agent in the vitreous of the
rabbit eye of at least about 1 ng/mL for at least about 30, at
least about 60, or at least about 90 days after administration of
the liquid formulation to the rabbit eye. In some variations, the
liquid formulation when injected between the sclera and conjunctiva
of a rabbit eye delivers therapeutic agent giving an average
concentration of therapeutic agent in the vitreous of the rabbit
eye of at least about 10 ng/mL for at least about 30, at least
about 60, or at least about 90 days after administration of the
liquid formulation to the rabbit eye.
[0344] In some variations, the liquid formulation when injected
between the sclera and conjunctiva of a rabbit eye delivers
therapeutic agent giving an average concentration of therapeutic
agent in the vitreous of the rabbit eye of at least 0.001 ng/mL for
at least 30, at least 60, at least 90, or at least 120 days after
administration of the liquid formulation to the rabbit eyes. In
some variations, the liquid formulation when injected between the
sclera and conjunctiva of a rabbit eye delivers therapeutic agent
giving an average concentration of therapeutic agent in the
vitreous of the rabbit eye of at least 0.01 ng/mL for at least 30,
at least 60, at least 90, or at least 120 days after administration
of the liquid formulation to the rabbit eyes. In some variations,
the liquid formulation when injected between the sclera and
conjunctiva of a rabbit eye delivers therapeutic agent giving an
average concentration of therapeutic agent in the vitreous of the
rabbit eye of at least 0.1 ng/mL for at least 30, at least 60, at
least 90, or at least 120 days after administration of the liquid
formulation to the rabbit eyes. In some variations, the liquid
formulation when injected between the sclera and conjunctiva of a
rabbit eye delivers therapeutic agent giving an average
concentration of therapeutic agent in the vitreous of the rabbit
eye of at least 0.5 ng/mL for at least 30, at least 60, at least
90, or at least 120 days after administration of the liquid
formulation to the rabbit eyes.
[0345] In some variations, the liquid formulation when injected
between the sclera and conjunctiva of a rabbit eye delivers
therapeutic agent giving an average concentration of therapeutic
agent in the vitreous of the rabbit eye of between 0.001 ng/mL and
10.0 ng/mL for at least 30, at least 60, at least 90, or at least
120 days after administration of the liquid formulation to the
rabbit eyes. In some variations, the liquid formulation when
injected between the sclera and conjunctiva of a rabbit eye
delivers therapeutic agent giving an average concentration of
therapeutic agent in the vitreous of the rabbit eye of between 0.01
ng/mL and 10 ng/mL for at least 30, at least 60, at least 90, or at
least 120 days after administration of the liquid formulation to
the rabbit eyes. In some variations, the liquid formulation when
injected between the sclera and conjunctiva of a rabbit eye
delivers therapeutic agent giving an average concentration of
therapeutic agent in the vitreous of the rabbit eye of between 0.1
ng/mL and 10 ng/mL for at least 30, at least 60, at least 90, or at
least 120 days after administration of the liquid formulation to
the rabbit eyes.
[0346] In some variations, the liquid formulation when injected
between the sclera and conjunctiva of a rabbit eye delivers
therapeutic agent giving an average concentration of therapeutic
agent in the vitreous of the rabbit eye of between 0.5 ng/mL and
10.0 ng/mL for at least 30, at least 60, at least 90, or at least
120 days after administration of the liquid formulation to the
rabbit eyes.
[0347] In some variations, the liquid formulation when injected
between the sclera and conjunctiva of a rabbit eye delivers
therapeutic agent giving a ratio of a maximum average concentration
of therapeutic agent in the vitreous of a rabbit eye to a minimum
average concentration of therapeutic agent in the vitreous of a
rabbit eye less than 100 for days 30 to at least 60, at least 90,
or at least 120 days after administration of the liquid formulation
to the rabbit eyes. In some variations, the liquid formulation when
injected between the sclera and conjunctiva of a rabbit eye
delivers therapeutic agent giving a ratio of a maximum average
concentration of therapeutic agent in the vitreous of a rabbit eye
to a minimum average concentration of therapeutic agent in the
vitreous of a rabbit eye less than 50 for days 30 to at least 60,
at least 90, or at least 120 days after administration of the
liquid formulation to the rabbit eyes. In some variations, the
liquid formulation when injected between the sclera and conjunctiva
of a rabbit eye delivers therapeutic agent giving a ratio of a
maximum average concentration of therapeutic agent in the vitreous
of a rabbit eye to a minimum average concentration of therapeutic
agent in the vitreous of a rabbit eye less than 10 for days 30 to
at least 60, at least 90, or at least 120 days after administration
of the liquid formulation to the rabbit eyes. In some variations,
the liquid formulation when injected between the sclera and
conjunctiva of a rabbit eye delivers therapeutic agent giving a
ratio of a maximum average concentration of therapeutic agent in
the vitreous of a rabbit eye to a minimum average concentration of
therapeutic agent in the vitreous of a rabbit eye less than 5 for
days 30 to at least 60, at least 90, or at least 120 days after
administration of the liquid formulation to the rabbit eyes.
[0348] "Approximately constant," as used herein, means that the
average level does not vary by more than one order of magnitude
over the extended period of time, i.e., the difference between the
maximum and minimum is less than a 10-fold difference for
measurements of the average concentration at times in the relevant
period of time.
[0349] In some variations, the liquid formulation when injected
between the sclera and conjunctiva of a rabbit eye delivers
therapeutic agent giving an average concentration of therapeutic
agent in the vitreous of a rabbit eye that is approximately
constant at a value greater than 0.001 ng/mL for days 30 to at
least 60, at least 90, or at least 120 days after administration of
the solution to the rabbit eyes. In some variations, the liquid
formulation when injected between the sclera and conjunctiva of a
rabbit eye delivers therapeutic agent giving an average
concentration of therapeutic agent in the vitreous of a rabbit eye
that is approximately constant at a value greater than 0.01 ng/mL
for days 30 to at least 60, at least 90, or at least 120 days after
administration of the liquid formulation to the rabbit eyes. In
some variations, the liquid formulation when injected between the
sclera and conjunctiva of a rabbit eye delivers therapeutic agent
giving an average concentration of therapeutic agent in the
vitreous of a rabbit eye that is approximately constant at a value
greater than 0.1 ng/mL for days 30 to at least 60, at least 90, or
at least 120 days after administration of the liquid formulation to
the rabbit eyes. In some variations, the liquid formulation when
injected between the sclera and conjunctiva of a rabbit eye
delivers therapeutic agent giving an average concentration of
therapeutic agent in the vitreous of a rabbit eye that is
approximately constant at a value of 1.0 ng/mL for days 36 to at
least 60, at least 90, or at least 120 days after administration of
the liquid formulation to the rabbit eyes.
[0350] In some variations, the liquid formulation when injected
between the sclera and conjunctiva of a rabbit eye delivers
therapeutic agent giving an average concentration of therapeutic
agent in the retina choroid tissues of the rabbit eye of at least
0.001 ng/mg for at least 30, at least 60, at least 90, or at least
120 days after administration of the liquid formulation to the
rabbit eyes. In some variations, the liquid formulation when
injected between the sclera and conjunctiva of a rabbit eye
delivers therapeutic agent giving an average concentration of
therapeutic agent in the retina choroid tissues of the rabbit eye
of at least 0.005 ng/mg for at least 30, at least 66, at least 90,
or at least 120 days after administration of the liquid formulation
to the rabbit eyes. In some variations, the liquid formulation when
injected between the sclera and conjunctiva of a rabbit eye
delivers therapeutic agent giving an average concentration of
therapeutic agent in the retina choroid tissues of the rabbit eye
of at least 0.01 ng/mg for at least 30, at least 60, at least 90,
or at least 120 days after administration of the liquid formulation
to the rabbit eyes.
[0351] In some variations, the liquid formulation when injected
between the sclera and conjunctiva of a rabbit eye delivers
therapeutic agent giving an average concentration of therapeutic
agent in the retina choroid tissues of the rabbit eye of between
0.001 ng/mg and 1.0 ng/mg for at least 30, at least 60, at least
90, or at least 120 days after administration of the liquid
formulation to the rabbit eyes. In some variations, the liquid
formulation when injected between the sclera and conjunctiva of a
rabbit eye delivers therapeutic agent giving an average
concentration of therapeutic agent in the retina choroid tissues of
the rabbit eye of between 0.001 ng/mg and 0.50 ng/mg for at least
30, at least 60, at least 90, or at least 120 days after
administration of the liquid formulation to the rabbit eyes. In
some variations, the liquid formulation when injected between the
sclera and conjunctiva of a rabbit eye delivers therapeutic agent
giving an average concentration of therapeutic agent in the retina
choroid tissues of the rabbit eye of between 0.001 ng/mg and 0.15
ng/mg for at least 30, at least 66, at least 90, or at least 120
days after administration of the liquid formulation to the rabbit
eyes. In some variations, the liquid formulation when injected
between the sclera and conjunctiva of a rabbit eye delivers
therapeutic agent giving an average concentration of therapeutic
agent in the retina choroid tissues of the rabbit eye of between
0.001 ng/mg and 0.1 ng/mg for at least 30, at least 60, at least
90, or at least 120 days after administration of the liquid
formulation to the rabbit eyes.
[0352] In some variations, the liquid formulation when injected
between the sclera and conjunctiva of a rabbit eye delivers
therapeutic agent giving an average concentration of therapeutic
agent in the retina choroid tissues of the rabbit eye of between
0.005 ng/mg and 1.0 ng/mg for at least 30, at least 60, at least
90, or at least 120 days after administration of the liquid
formulation to the rabbit eyes. In some variations, the liquid
formulation when injected between the sclera and conjunctiva of a
rabbit eye delivers therapeutic agent giving an average
concentration of therapeutic agent in the retina choroid tissues of
the rabbit eye of between 0.005 ng/mg and 0.50 ng/mg for at least
30, at least 60, at least 90, or at least 120 days after
administration of the liquid formulation to the rabbit eyes. In
some variations, the liquid formulation when injected between the
sclera and conjunctiva of a rabbit eye delivers therapeutic agent
giving an average concentration of therapeutic agent in the retina
choroid tissues of the rabbit eye of between 0.005 ng/mg and 0.15
ng/mg for at least 30, at least 60, at least 90, or at least 120
days after administration of the liquid formulation to the rabbit
eyes. In some variations, the liquid formulation when injected
between the sclera and conjunctiva of a rabbit eye delivers
therapeutic agent giving an average concentration of therapeutic
agent in the retina choroid tissues of the rabbit eye of between
0.005 ng/mg and 0.1 ng/mg for at least 30, at least 60, at least
90, or at least 120 days after administration of the liquid
formulation to the rabbit eyes.
[0353] In some variations, the liquid formulation when injected
between the sclera and conjunctiva of a rabbit eye delivers
therapeutic agent giving an average concentration of therapeutic
agent in the retina choroid tissues of the rabbit eye of between
0.01 ng/mg and 1.0 ng/mg for at least 30, at least 60, at least 90,
or at least 120 days after administration of the liquid formulation
to the rabbit eyes. In some variations, the liquid formulation when
injected between the sclera and conjunctiva of a rabbit eye
delivers therapeutic agent giving an average concentration of
therapeutic agent in the retina choroid tissues of the rabbit eye
of between 0.01 ng/mg and 0.50 ng/mg for at least 30, at least 60,
at least 90, or at least 120 days after administration of the
liquid formulation to the rabbit eyes. In some variations, the
liquid formulation when injected between the sclera and conjunctiva
of a rabbit eye delivers therapeutic agent giving an average
concentration of therapeutic agent in the retina choroid tissues of
the rabbit eye of between 0.01 ng/mg and 0.15 ng/mg for at least
30, at least 60, at least 90, or at least 120 days after
administration of the liquid formulation to the rabbit eyes. In
some variations, the liquid formulation when injected between the
sclera and conjunctiva of a rabbit eye delivers therapeutic agent
giving an average concentration of therapeutic agent in the retina
choroid tissues of the rabbit eye of between 0.01 ng/mg and 0.1
ng/mg for at least 30, at least 60, at least 90, or at least 120
days after administration of the liquid formulation to the rabbit
eyes.
[0354] In some variations, the liquid formulation when injected
between the sclera and conjunctiva of a rabbit eye delivers
therapeutic agent giving a ratio of a maximum average concentration
of therapeutic agent in the retina choroid tissues of a rabbit eye
to a minimum average concentration of therapeutic agent in the
retina choroid tissues of a rabbit eye less than 100 for days 30 to
at least 60, at least 90, or at least 120 days after administration
of the liquid formulation to the rabbit eyes. In some variations,
the liquid formulation when injected between the sclera and
conjunctiva of a rabbit eye delivers therapeutic agent giving a
ratio of a maximum average concentration of therapeutic agent in
the retina choroid tissues of a rabbit eye to a minimum average
concentration of therapeutic agent in the retina choroid tissues of
a rabbit eye less than 50 for days 30 to at least 60, at least 90,
or at least 120 days after administration of the liquid formulation
to the rabbit eyes. In some variations, the liquid formulation when
injected between the sclera and conjunctiva of a rabbit eye
delivers therapeutic agent giving a ratio of a maximum average
concentration of therapeutic agent in the retina choroid tissues of
a rabbit eye to a minimum average concentration of therapeutic
agent in the retina choroid tissues of a rabbit eye less than 10
for days 30 to at least 60, at least 90, or at least 120 days after
administration of the liquid formulation to the rabbit eyes. In
some variations, the liquid formulation when injected between the
sclera and conjunctiva of a rabbit eye delivers therapeutic agent
giving a ratio of a maximum average concentration of therapeutic
agent in the retina choroid tissues of a rabbit eye to a minimum
average concentration of therapeutic agent in the retina choroid
tissues of a rabbit eye less than 5 for days 30 to at least 60, at
least 90, or at least 120 days after administration of the liquid
formulation to the rabbit eyes.
[0355] In some variations, the liquid formulation when injected
between the sclera and conjunctiva of a rabbit eye delivers
therapeutic agent giving an average concentration of therapeutic
agent in the retina choroid tissues of a rabbit eye that is
approximately constant at a value greater than 0.001 ng/mg for days
30 to at least 60, at least 90, or at least 120 days after
administration of the liquid formulation to the rabbit eyes. In
some variations, the liquid formulation when injected between the
sclera and conjunctiva of a rabbit eye delivers therapeutic agent
giving an average concentration of therapeutic agent in the retina
choroid tissues of a rabbit eye that is approximately constant at a
value greater than 0.005 ng/mg for days 30 to at least 60, at least
90, or at least 120 days after administration of the liquid
formulation to the rabbit eyes. In some variations, the liquid
formulation when injected between the sclera and conjunctiva of a
rabbit eye delivers therapeutic agent giving an average
concentration of therapeutic agent in the retina choroid tissues of
a rabbit eye that is approximately constant at a value greater than
0.01 ng/mg for days 30 to at least 60, at least 90, or at least 120
days after administration of the liquid formulation to the rabbit
eyes.
[0356] In some variations, the liquid formulation when injected
into the vitreous of a rabbit eye delivers therapeutic agent giving
an average concentration of therapeutic agent in the vitreous of
the rabbit eye of at least 100 ng/mL for at least 30, at least 60,
at least 90, or at least 120 days after administration of the
liquid formulation to the rabbit eyes. In some variations, the
liquid formulation when injected into the vitreous of a rabbit eye
delivers therapeutic agent giving an average concentration of
therapeutic agent in the vitreous of the rabbit eye of at least
1000 ng/mL for at least 30, at least 60, at least 90, or at least
120 days after administration of the liquid formulation to the
rabbit eyes. In some variations, the liquid formulation when
injected into the vitreous of a rabbit eye delivers therapeutic
agent giving an average concentration of therapeutic agent in the
vitreous of the rabbit eye of at least 10,000 ng/mL for at least
30, at least 60, at least 90, or at least 120 days after
administration of the liquid formulation to the rabbit eyes.
[0357] In some variations, the liquid formulation when injected
into the vitreous of a rabbit eye delivers therapeutic agent giving
an average concentration of therapeutic agent in the vitreous of
the rabbit eye between 100 ng/mL and 100,000 ng/mL for day 30 to at
least 60, at least 90, or at least 120 days after administration of
the liquid formulation to the rabbit eyes. In some variations, the
liquid formulation when injected into the vitreous of a rabbit eye
delivers therapeutic agent giving an average concentration of
therapeutic agent in the vitreous of the rabbit eye between 100
ng/mL and 50,000 ng/mL for day 30 to at least 60, at least 90, or
at least 120 days after administration of the liquid formulation to
the rabbit eyes.
[0358] In some variations, the liquid formulation when injected
into the vitreous of a rabbit eye delivers therapeutic agent giving
an average concentration of therapeutic agent in the vitreous of
the rabbit eye between 1000 ng/mL and 100,000 ng/mL for day 30 to
at least 60, at least 90, or at least 120 days after administration
of the liquid formulation to the rabbit eyes. In some variations,
the liquid formulation when injected into the vitreous of a rabbit
eye delivers therapeutic agent giving an average concentration of
therapeutic agent in the vitreous of the rabbit eye between 1000
ng/mL and 50,000 ng/mL for day 30 to at least 60, at least 90, or
at least 120 days after administration of the liquid formulation to
the rabbit eyes.
[0359] In some variations, the liquid formulation when injected
into the vitreous of a rabbit eye delivers therapeutic agent giving
a ratio of a maximum average concentration of therapeutic agent in
the vitreous of the rabbit eye to a minimum average concentration
of therapeutic agent in the vitreous of the rabbit eye less than
100 for days 30 to at least 60, at least 90, or at least 120 days
after administration of the liquid formulation to the rabbit eyes.
In some variations, the liquid formulation when injected into the
vitreous of a rabbit eye delivers therapeutic agent giving a ratio
of a maximum average concentration of therapeutic agent in the
vitreous of the rabbit eye to a minimum average concentration of
therapeutic agent in the vitreous of the rabbit eye less than 50
for days 30 to at least 60, at least 90, or at least 120 days after
administration of the liquid formulation to the rabbit eyes. In
some variations, the liquid formulation when injected into the
vitreous of a rabbit eye delivers therapeutic agent giving a ratio
of a maximum average concentration of therapeutic agent in the
vitreous of the rabbit eye to a minimum average concentration of
therapeutic agent in the vitreous of the rabbit eye less than 10
for days 30 to at least 60, at least 90, or at least 120 days after
administration of the liquid formulation to the rabbit eyes.
[0360] In some variations, the liquid formulation when injected
into the vitreous of a rabbit eye delivers therapeutic agent giving
an average concentration of therapeutic agent in the vitreous of
the rabbit eye that is approximately constant at a value greater
than 100 ng/mL for days 30 to at least 60, at least 90, or at least
120 days after administration of the liquid formulation to the
rabbit eyes. In some variations, the liquid formulation when
injected into the vitreous of a rabbit eye delivers therapeutic
agent giving an average concentration of therapeutic agent in the
vitreous of the rabbit eye that is approximately constant at a
value greater than 1000 ng/mL for days 30 to at least 60, at least
90, or at least 120 days after administration of the liquid
formulation to the rabbit eyes. In some variations, the liquid
formulation when injected into the vitreous of a rabbit eye
delivers therapeutic agent giving an average concentration of
therapeutic agent in the vitreous of the rabbit eye that is
approximately constant at a value greater than 10,000 ng/mL for
days 30 to at least 60, at least 90, or at least 120 days after
administration of the liquid formulation to the rabbit eyes.
[0361] In some variations, the liquid formulation when injected
into the vitreous of a rabbit eye delivers therapeutic agent giving
an average concentration of therapeutic agent in the retina choroid
tissues of the rabbit eye of at least 0.001 ng/mg for at least 30,
at least 60, at least 90, or at least 120 days after administration
of the liquid formulation to the rabbit eyes. In some variations,
the liquid formulation when injected into the vitreous of a rabbit
eye delivers therapeutic agent giving an average concentration of
therapeutic agent in the retina choroid tissues of the rabbit eye
of at least 0.01 ng/mg for at least 30, at least 60, at least 90,
or at least 120 days after administration of the liquid formulation
to the rabbit eyes. In some variations, the liquid formulation when
injected into the vitreous of a rabbit eye delivers therapeutic
agent giving an average concentration of therapeutic agent in the
retina choroid tissues of the rabbit eye of at least 0.05 ng/mg for
at least 30, at least 60, at least 90, or at least 120 days after
administration of the liquid formulation to the rabbit eyes. In
some variations, the liquid formulation when injected into the
vitreous of a rabbit eye delivers therapeutic agent giving an
average concentration of therapeutic agent in the retina choroid
tissues of the rabbit eye of at least 0.10 ng/mg for at least 30,
at least 60, at least 90, or at least 120 days after administration
of the liquid formulation to the rabbit eyes.
[0362] In some variations, the liquid formulation when injected
into the vitreous of a rabbit eye delivers therapeutic agent giving
an average concentration of therapeutic agent in the retina choroid
tissues of the rabbit eye between 0.001 ng/mg and 10.00 ng/mg for
at least 30, at least 60, at least 90, or at least 120 days after
administration of the liquid formulation to the rabbit eyes. In
some variations, the liquid formulation when injected into the
vitreous of a rabbit eye delivers therapeutic agent giving an
average concentration of therapeutic agent in the retina choroid
tissues of the rabbit eye between 0.001 ng/mg and 5.00 ng/mg for at
least 30, at least 60, at least 90, or at least 120 days after
administration of the liquid formulation to the rabbit eyes. In
some variations, the liquid formulation when injected into the
vitreous of a rabbit eye delivers therapeutic agent giving an
average concentration of therapeutic agent in the retina choroid
tissues of the rabbit eye between 0.001 ng/mg and 1.00 ng/mg for at
least 30, at least 60, at least 90, or at least 120 days after
administration of the liquid formulation to the rabbit eyes.
[0363] In some variations, the liquid formulation when injected
into the vitreous of a rabbit eye delivers therapeutic agent giving
an average concentration of therapeutic agent in the retina choroid
tissues of the rabbit eye between 0.01 ng/mg and 10.00 ng/mg for at
least 30, at least 60, at least 90, or at least 120 days after
administration of the liquid formulation to the rabbit eyes. In
some variations, the liquid formulation when injected into the
vitreous of a rabbit eye delivers therapeutic agent giving an
average concentration of therapeutic agent in the retina choroid
tissues of the rabbit eye between 0.01 ng/mg and 5.00 ng/mg for at
least 30, at least 60, at least 90, or at least 120 days after
administration of the liquid formulation to the rabbit eyes. In
some variations, the liquid formulation when injected into the
vitreous of a rabbit eye delivers therapeutic agent giving an
average concentration of therapeutic agent in the retina choroid
tissues of the rabbit eye between 0.01 ng/mg and 1.00 ng/mg for at
least 30, at least 60, at least 90, or at least 120 days after
administration of the liquid formulation to the rabbit eyes.
[0364] In some variations, the liquid formulation when injected
into the vitreous of a rabbit eye delivers therapeutic agent giving
an average concentration of therapeutic agent in the retina choroid
tissues of the rabbit eye between 0.05 ng/mg and 10.00 ng/mg for at
least 30, at least 60, at least 90, or at least 120 days after
administration of the liquid formulation to the rabbit eyes. In
some variations, the liquid formulation when injected into the
vitreous of a rabbit eye delivers therapeutic agent giving an
average concentration of therapeutic agent in the retina choroid
tissues of the rabbit eye between 0.05 ng/mg and 5.00 ng/mg for at
least 30, at least 60, at least 90, or at least 120 days after
administration of the liquid formulation to the rabbit eyes. In
some variations, the liquid formulation when injected into the
vitreous of a rabbit eye delivers therapeutic agent giving an
average concentration of therapeutic agent in the retina choroid
tissues of the rabbit eye between 0.05 ng/mg and 1.00 ng/mg for at
least 30, at least 60, at least 90, or at least 120 days after
administration of the liquid formulation to the rabbit eyes.
[0365] In some variations, the liquid formulation when injected
into the vitreous of a rabbit eye delivers therapeutic agent giving
an average concentration of therapeutic agent in the retina choroid
tissues of the rabbit eye between 0.10 ng/mg and 10.00 ng/mg for at
least 30, at least 60, at least 90, or at least 120 days after
administration of the liquid formulation to the rabbit eyes. In
some variations, the liquid formulation when injected into the
vitreous of a rabbit eye delivers therapeutic agent giving an
average concentration of therapeutic agent in the retina choroid
tissues of the rabbit eye between 0.10 ng/mg and 5.00 ng/mg for at
least 30, at least 60, at least 90, or at least 120 days after
administration of the liquid formulation to the rabbit eyes. In
some variations, the liquid formulation when injected into the
vitreous of a rabbit eye delivers therapeutic agent giving an
average concentration of therapeutic agent in the retina choroid
tissues of the rabbit eye between 0.10 ng/mg and 1.00 ng/mg for at
least 30, at least 60, at least 90, or at least 120 days after
administration of the liquid formulation to the rabbit eyes.
[0366] In some variations, the liquid formulation when injected
into the vitreous of a rabbit eye delivers therapeutic agent giving
a ratio of a maximum average concentration of therapeutic agent in
the retina choroid tissues of the rabbit eye to a minimum average
concentration of therapeutic agent in the retina choroid tissues of
the rabbit eye less than 100 for days 30 to at least 60, at least
90, or at least 120 days after administration of the liquid
formulation to the rabbit eyes. In some variations, the liquid
formulation when injected into the vitreous of a rabbit eye
delivers therapeutic agent giving a ratio of a maximum average
concentration of therapeutic agent in the retina choroid tissues of
the rabbit eye to a minimum average concentration of therapeutic
agent in the retina choroid tissues of the rabbit eye less than 50
for days 30 to at least 60, at least 90, or at least 120 days after
administration of the liquid formulation to the rabbit eyes.
[0367] In some variations, in situ gelling liquid formulations
described herein may have in vivo delivery to the retina choroid
tissue profiles with the following described characteristics, where
the delivery profiles are for delivery of therapeutic agent in vivo
after injection of the liquid formulation between the sclera and
the conjunctiva of a rabbit eye.
[0368] At day 32 after injection, the percentage in vivo vitreal
level may be between about 20% and about 80%, and more usually
between about 40% and about 60%, relative to the level present at
day 7 after injection. At day 40 after injection, the percentage in
vivo vitreal level may be greater than about 20%, and more usually
greater than about 40%, relative to the level present at day 7
after injection.
[0369] At day 45 after injection, the percentage in vivo vitreal
level may be between about 15% and about 55%, and more usually
between about 25% and about 45%, relative to the level present at
day 7 after injection. At day 67 after injection, the percentage in
vivo vitreal level may be greater than about 15%, and more usually
greater than about 25%, relative to the level present at day 7
after injection.
[0370] At day 90 after injection, the percentage in vivo vitreal
level may be between about 60% and about 100%, and more usually
between about 70% and about 90%, relative to the level present at
day 7 after injection. At day 90 after injection, the percentage in
vivo vitreal level may be greater than about 60%, and more usually
greater than about 70%, relative to the level present at day 7
after injection.
[0371] In some variations, the percentage in vivo vitreal level has
the following characteristics relative to the level present at day
7 after injection: at 32 days after injection it is less than about
80%; at 45 days after injection it is less than about 60%; and 90
days after injection it is less than about 100%.
[0372] In some variations, the liquid formulation when injected
between the sclera and conjunctiva of a rabbit eye delivers
therapeutic agent giving an average concentration of therapeutic
agent in the retina choroid tissues of the rabbit eye of at least
about 0.1 pg/mg for at least about 30, at least about 60, or at
least about 90 days after administration of the liquid formulation
to the rabbit eye. In some variations, the liquid formulation when
injected between the sclera and conjunctiva of a rabbit eye
delivers therapeutic agent giving an average concentration of
therapeutic agent in the vitreous of the rabbit eye of at least
about 0.01 ng/mg for at least about 30, at least about 60, or at
least about 90 days after administration of the liquid formulation
to the rabbit eye. In some variations, the liquid formulation when
injected between the sclera and conjunctiva of a rabbit eye
delivers therapeutic agent giving an average concentration of
therapeutic agent in the vitreous of the rabbit eye of at least
about 0.1 ng/mg for at least about 30, at least about 60, or at
least about 90 days after administration of the liquid formulation
to the rabbit eye. In some variations, the liquid formulation when
injected between the sclera and conjunctiva of a rabbit eye
delivers therapeutic agent giving an average concentration of
therapeutic agent in the vitreous of the rabbit eye of at least
about 1 ng/mL for at least about 30, at least about 60, or at least
about 90 days after administration of the liquid formulation to the
rabbit eye.
[0373] In some variations, the ratio of the base ten logarithms of
the average levels of a therapeutic agent in two or more of the
retina choroid tissues, the sclera, and the vitreous is
approximately constant over an extended period of time after
placement of the in situ gelling formulation in or proximate to the
eye. In some variations, the ratio of the base ten logarithms of
the average levels of a therapeutic agent in two or more of the
retina choroid tissues, the sclera, and the vitreous is
approximately constant over an extended period of time after
placement of the in situ gelling formulation between the sclera and
the conjunctiva of an eye. In some variations, the ratio of the
base ten logarithms of the average levels of a therapeutic agent in
the vitreous and the sclera is approximately constant over an
extended period of time after placement of the in situ gelling
formulation between the sclera and the conjunctiva of an eye.
[0374] In some variations, the ratio of the base ten logarithms of
the average levels of a therapeutic agent in the vitreous and the
retina choroid tissues is approximately constant over an extended
period of time. Put another way, as the level of therapeutic agent
in the vitreous rises, the level of therapeutic agent in the retina
choroid tissues rises to a similar degree when considered on the
logarithmic scale, and vice versa.
[0375] In some variations, the ratio of the base ten logarithms of
the average levels of a therapeutic agent in the vitreous versus
the retina choroid tissues is approximately constant over an
extended period of time of about 7, about 30, about 60, or about 90
days. In some variations, the ratio of the average level of
therapeutic agent in the vitreous relative to the level of
therapeutic agent in the retina choroid tissues after placement of
the in situ gelling formulation between the sclera and the
conjunctiva of an eye is constant at about 37:1 at day 7, about
40:1 at day 32, about 10:1 at day 45, and about 34:1 at day 90.
[0376] In some variations, the ratio of the average level of
therapeutic agent in the vitreous relative to the level of
therapeutic agent in the retina choroid tissues is constant at
about 40:1 over a period of about 7, about 32, about 45, or about
90 days.
[0377] In some variations, the average level of the therapeutic
agent in any or all of the retina choroid tissues, the sclera, and
the vitreous is approximately constant over an extended period of
time after placement of the in situ gelling formulation in or
proximate to the eye.
[0378] In some variations, after placement of an in situ gelling
formulation between the sclera and the conjunctiva, the average
level of therapeutic agent in the vitreous is approximately
constant at about 8.1 ng/ml. In some variations, after placement of
an in situ gelling formulation between the sclera and the
conjunctiva, the average level of therapeutic agent in the retina
choroid tissues is approximately constant at about 0.25 ng/mg. In
some variations, after placement of an in situ gelling formulation
between the sclera and the conjunctiva, the average level of
therapeutic agent in the sclera is approximately constant at about
1930 ng/mg.
[0379] In some variations, the in situ gelling formulation when
injected between the sclera and conjunctiva of a rabbit eye
maintains an average level of therapeutic agent in the vitreous
that is approximately constant at about 0.1 pg/mL for at least
about 30, at least about 60, or at least about 90 days after
administration of the liquid formulation to the rabbit eye. In some
variations, the in situ gelling formulation when injected between
the sclera and conjunctiva of a rabbit eye maintains an average
level of therapeutic agent in the vitreous that is approximately
constant at about 0.001 ng/mL for at least about 30, at least about
60, or at least about 90 days after administration of the liquid
formulation to the rabbit eye. In some variations, the in situ
gelling formulation when injected between the sclera and
conjunctiva of a rabbit eye maintains an average level of
therapeutic agent in the vitreous that is approximately constant at
about 0.01 ng/mL for at least about 30, at least about 60, or at
least about 90 days after administration of the liquid formulation
to the rabbit eye. In some variations, the in situ gelling
formulation when injected between the sclera and conjunctiva of a
rabbit eye maintains an average level of therapeutic agent in the
vitreous that is approximately constant at about 0.1 ng/mL for at
least about 30, at least about 60, or at least about 90 days after
administration of the liquid formulation to the rabbit eye. In some
variations, the in situ gelling formulation when injected between
the sclera and conjunctiva of a rabbit eye maintains an average
level of therapeutic agent in the vitreous that is approximately
constant at about 1 ng/mL for at least about 30, at least about 60,
or at least about 90 days after administration of the liquid
formulation to the rabbit eye. In some variations, the in situ
gelling formulation when injected between the sclera and
conjunctiva of a rabbit eye maintains an average level of
therapeutic agent in the vitreous that is approximately constant at
about 10 ng/mL for at least about 30, at least about 60, or at
least about 90 days after administration of the liquid formulation
to the rabbit eye. In some variations, the in situ gelling
formulation when injected between the sclera and conjunctiva of a
rabbit eye maintains an average level of therapeutic agent in the
vitreous that is approximately constant at about 100 ng/mL for at
least about 30, at least about 60, or at least about 90 days after
administration of the liquid formulation to the rabbit eye.
[0380] In some variations, the in situ gelling formulation when
injected between the sclera and conjunctiva of a rabbit eye
maintains an average level of therapeutic agent in the retina
choroid tissues that is approximately constant at about 0.1 pg/mg
for at least about 30, at least about 60, or at least about 90 days
after administration of the liquid formulation to the rabbit eye.
In some variations, the in situ gelling formulation when injected
between the sclera and conjunctiva of a rabbit eye maintains an
average level of therapeutic agent in the retina choroid tissues
that is approximately constant at about 0.001 ng/mg for at least
about 30, at least about 60, or at least about 90 days after
administration of the liquid formulation to the rabbit eye. In some
variations, the in situ gelling formulation when injected between
the sclera and conjunctiva of a rabbit eye maintains an average
level of therapeutic agent in the retina choroid tissues that is
approximately constant at about 0.01 ng/mg for at least about 30,
at least about 60, or at least about 90 days after administration
of the liquid formulation to the rabbit eye. In some variations,
the in situ gelling formulation when injected between the sclera
and conjunctiva of a rabbit eye maintains an average level of
therapeutic agent in the retina choroid tissues that is
approximately constant at about 0.1 ng/mg for at least about 30, at
least about 60, or at least about 90 days after administration of
the liquid formulation to the rabbit eye. In some variations, the
in situ gelling formulation when injected between the sclera and
conjunctiva of a rabbit eye maintains an average level of
therapeutic agent in the retina choroid tissues that is
approximately constant at about 1 ng/mg for at least about 30, at
least about 60, or at least about 90 days after administration of
the liquid formulation to the rabbit eye. In some variations, the
in situ gelling formulation when injected between the sclera and
conjunctiva of a rabbit eye maintains an average level of
therapeutic agent in the retina choroid tissues that is
approximately constant at about 10 ng/mg for at least about 30, at
least about 60, or at least about 90 days after administration of
the liquid formulation to the rabbit eye.
[0381] In some variations, the in situ gelling formulation when
injected between the sclera and conjunctiva of a rabbit eye
maintains an average level of therapeutic agent in the sclera that
is approximately constant at about 0.1 pg/mg for at least about 30,
at least about 60, or at least about 90 days after administration
of the liquid formulation to the rabbit eye. In some variations,
the in situ gelling formulation when injected between the sclera
and conjunctiva of a rabbit eye maintains an average level of
therapeutic agent in the sclera that is approximately constant at
about 0.001 ng/mg for at least about 30, at least about 60, or at
least about 90 days after administration of the liquid formulation
to the rabbit eye. In some variations, the in situ gelling
formulation when injected between the sclera and conjunctiva of a
rabbit eye maintains an average level of therapeutic agent in the
sclera that is approximately constant at about 0.01 ng/mg for at
least about 30, at least about 60, or at least about 90 days after
administration of the liquid formulation to the rabbit eye. In some
variations, the in situ gelling formulation when injected between
the sclera and conjunctiva of a rabbit eye maintains an average
level of therapeutic agent in the sclera that is approximately
constant at about 0.1 ng/mg for at least about 30, at least about
60, or at least about 90 days after administration of the liquid
formulation to the rabbit eye. In some variations, the in situ
gelling formulation when injected between the sclera and
conjunctiva of a rabbit eye maintains an average level of
therapeutic agent in the sclera that is approximately constant at
about 1 ng/mg for at least about 30, at least about 60, or at least
about 90 days after administration of the liquid formulation to the
rabbit eye. In some variations, the in situ gelling formulation
when injected between the sclera and conjunctiva of a rabbit eye
maintains an average level of therapeutic agent in the sclera that
is approximately constant at about 10 ng/mg for at least about 30,
at least about 60, or at least about 90 days after administration
of the liquid formulation to the rabbit eye. In some variations,
the in situ gelling formulation when injected between the sclera
and conjunctiva of a rabbit eye maintains an average level of
therapeutic agent in the sclera that is approximately constant at
about 100 ng/mg for at least about 30, at least about 60, or at
least about 90 days after administration of the liquid formulation
to the rabbit eye. In some variations, the in situ gelling
formulation when injected between the sclera and conjunctiva of a
rabbit eye maintains an average level of therapeutic agent in the
sclera that is approximately constant at about 1 .mu.g/mg for at
least about 30, at least about 60, or at least about 90 days after
administration of the liquid formulation to the rabbit eye. In some
variations, the in situ gelling formulation when injected between
the sclera and conjunctiva of a rabbit eye maintains an average
level of therapeutic agent in the sclera that is approximately
constant at about 10 .mu.g/mg for at least about 30, at least about
60, or at least about 90 days after administration of the liquid
formulation to the rabbit eye.
[0382] For treatment, prevention, inhibition, delaying the onset
of, or causing the regression of certain diseases or conditions, it
may be desirable to maintain delivery of a therapeutically
effective amount of the therapeutic agent for an extended period of
time. Depending on the disease or condition being treated,
prevented, inhibited, having onset delayed, or being caused to
regress this extended period of time may be at least about 1 week,
at least about 2 weeks, at least about 3 weeks, at least about 1
month, at least about 3 months, at least about 6 months, at least
about 9 months, or at least about 1 year. Generally, however, any
extended period of delivery may be possible. A therapeutically
effective amount of agent may be delivered for an extended period
by a liquid formulation or composition that maintains for the
extended period a concentration of agent in a subject or an eye of
a subject sufficient to deliver a therapeutically effective amount
of agent for the extended time.
[0383] Delivery of a therapeutically effective amount of the
therapeutic agent for an extended period may be achieved via
placement of one composition or liquid formulation or may be
achieved by application of two or more doses of composition or
liquid formulations. As a non-limiting example of such multiple
applications, maintenance of the therapeutic amount of rapamycin
for 3 months for treatment, prevention, inhibition, delay of onset,
or cause of regression of wet AMD may be achieved by application of
one liquid formulation or composition delivering a therapeutic
amount for 3 months or by sequential application of a plurality of
liquid formulations or compositions. The optimal dosage regime will
depend on the therapeutic amount of the therapeutic agent needing
to be delivered, and the period over which it need be delivered.
Those versed in such extended therapeutic agent delivery dosing
will understand how to identify dosing regimes that may be used
based on the teachings provided herein.
[0384] When using certain therapeutic agents or for the treatment,
prevention, inhibition, delaying the onset of, or causing the
regression of certain diseases, it may be desirable for delivery of
the therapeutic agent not to commence immediately upon placement of
the liquid formulation or composition into the eye region, but for
delivery to commence after some delay. For example, but in no way
limiting, such delayed release may be useful where the therapeutic
agent inhibits or delays wound healing and delayed release is
desirable to allow healing of any wounds occurring upon placement
of the liquid formulation or composition. Depending on the
therapeutic agent being delivered and/or the diseases and
conditions being treated, prevented, inhibited, onset delayed, and
regression caused this period of delay before delivery of the
therapeutic agent commences may be about 1 hour, about 6 hours,
about 12 hours, about 18 hours, about 1 day, about 2 days, about 3
days, about 4 days, about 5 days, about 6 days, about 7 days, about
8 days, about 9 days, about 10 days, about 111 days, about 12 days,
about 13 days, about 14 days, about 21 days, about 28 days, about
35 days, or about 42 days. Other delay periods may be possible.
Delayed release formulations that may be used are known to people
versed in the technology.
Intravitreal and Subconjunctival Delivery of Rapamycin for
Treatment, Prevention, Inhibition, Delay of Onset, or cause of
Regression of AMD
[0385] In one method described herein, a liquid formulation
comprising rapamycin is delivered subconjunctivally or to the
vitreous of an eye to prevent, treat, inhibit, delay onset of, or
cause regression of angiogenesis in the eye, including but not
limited to treating CNV as observed, for example, in AMD. In some
variations, the liquid formulation is used to treat angiogenesis in
the eye, including but not limited to treating CNV as observed, for
example, in AMD. Rapamycin has been shown to inhibit CNV in rat and
mice models, as described in U.S. application Ser. No. 10/665,203,
which is incorporated herein by reference in its entirety.
Rapamycin has been observed to inhibit Matrigel.TM. and
laser-induced CNV when administered systemically and subretinally.
Also, periocular injection of rapamycin inhibits laser-induced
CNV.
[0386] Other therapeutic agents that may be delivered to the eye,
particularly the vitreous of an eye, for treatment, prevention,
inhibition, delaying onset, or causing regression of angiogenesis
in the eye (such as CNV) are members of the limus family of
compounds other than rapamycin including but not limited to
everolimus and tacrolimus (FK-506).
[0387] As described herein, the dosage of the therapeutic agent
will depend on the condition being addressed, whether the condition
is to be treated, prevented, inhibited, have onset delayed, or be
caused to regress, the particular therapeutic agent, and other
clinical factors such as weight and condition of the subject and
the route of administration of the therapeutic agent. It is to be
understood that the methods, liquid formulations, and compositions
described herein have application for both human and veterinary
use, as well as uses in other possible animals. As described
herein, tissue concentrations of therapeutic agents expressed in
units of mass per volume generally refer to tissues that are
primarily aqueous such as the vitreous, for example. Tissue
concentrations of therapeutic agents expressed in unit of mass per
mass generally refer to other tissues such as the sclera or retina
choroid tissues, for example.
[0388] One concentration of rapamycin that may be used in the
methods described herein is one that provides about 0.01 pg/ml or
pg/mg or more of rapamycin at the tissue level. Another
concentration that may be used is one that provides about 0.1 pg/ml
or ng/mg or more at the tissue level. Another concentration that
may be used is one that provides about 1 pg/ml or ng/mg or more at
the tissue level. Another concentration that may be used is one
that provides about 0.01 ng/ml or ng/mg, or more at the tissue
level. Another concentration that may be used is one that provides
about 0.1 ng/ml or ng/mg or more at the tissue level. Another
concentration that may be used is one that provides about 0.5 ng/ml
or ng/mg or more at the tissue level. Another concentration that
may be used is one that provides about 1 ng/ml or more at the
tissue level. Another concentration that may be used is one that
provides about 2 ng/ml or more at the tissue level. Another
concentration that may be used is one that provides about 3 ng/ml
or more at the tissue level. Another concentration that may be used
is one that provides about 5 ng/ml or more at the tissue level.
Another concentration that may be used is one that provides about
10 ng/ml or more at the tissue level. Another concentration that
may be used is one that provides about 15 ng/ml or more at the
tissue level. Another concentration that may be used is one that
provides about 20 ng/ml or more at the tissue level. Another
concentration that may be used is one that provides about 30 ng/ml
or more at the tissue level. Another concentration that may be used
is one that provides about 50 ng/ml or more at the tissue level.
One of ordinary skill in the art would know how to arrive at an
appropriate concentration depending on the route and duration of
administration utilized, given the teachings herein.
[0389] Generally, the amount of rapamycin administered in a liquid
formulation is an amount sufficient to treat, prevent, inhibit,
delay the onset, or cause regression of the disease or condition of
the eye for the required amount of time. In some variations the
amount of rapamycin administered in the liquid formulation is an
amount sufficient to treat the disease or condition of the eye for
the required amount of time.
[0390] In some variations, a total amount of rapamycin less than
about 5 mg is administered subconjunctivally. In some variations, a
total amount of rapamycin less than about 5.0 mg is administered
subconjunctivally. In some variations, a total amount of rapamycin
less than about 4.5 mg is administered subconjunctivally. In some
variations, a total amount of rapamycin less than about 4.0 mg is
administered subconjunctivally. In some variations, a total amount
of rapamycin less than about 3.5 mg is administered
subconjunctivally. In some variations, a total amount of rapamycin
less than about 3.0 mg is administered subconjunctivally. In some
variations, a total amount of rapamycin less than about 2.5 mg is
administered subconjunctivally. In some variations, a total amount
of rapamycin less than about 2 mg is administered
subconjunctivally. In some variations, a total amount of rapamycin
less than about 1.2 mg is administered subconjunctivally. In some
variations, a total amount of rapamycin less than about 1.0 mg is
administered subconjunctivally. In some variations, a total amount
of rapamycin less than about 0.8 mg is administered
subconjunctivally. In some variations, a total amount of rapamycin
less than about 0.6 mg is administered subconjunctivally. In some
variations, a total amount of rapamycin less than about 0.4 mg is
administered subconjunctivally. In some variations, a volume of a
formulation is administered that contains an amount of rapamycin
described herein.
[0391] In some variations, a liquid formulation containing a
concentration of rapamycin by weight of the total of between about
0.5% and about 6% is subconjunctivally administered to a human
subject by administering between about 0.1 .mu.l and about 200
.mu.l of a liquid formulation described herein. In some variations,
a liquid formulation containing a concentration of rapamycin by
weight of the total of between about 0.5% and about 4% is
subconjunctivally administered to a human subject by administering
between about 1 .mu.l and about 50 .mu.l of a liquid formulation
described herein. In some variations, a liquid formulation
containing a concentration of rapamycin by weight of the total of
between about 1.5% and about 3.5% is subconjunctivally administered
to a human subject by administering between about 1 .mu.l and about
15 .mu.l of a liquid formulation described herein. In some
variations, a liquid formulation containing a concentration of
rapamycin by weight of the total of about 2% is subconjunctivally
administered to a human subject by administering between about 1
.mu.l and about 15 .mu.l of a liquid formulation described
herein.
[0392] In some variations, a liquid formulation containing an
amount of rapamycin of between about 0.2 .mu.g and about 4 mg is
subconjunctivally administered to a human subject by administering
between about 0.1 .mu.l and about 200 .mu.l of a liquid formulation
described herein. In some variations, a liquid formulation
containing an amount of rapamycin of between about 20 .mu.g and
about 2 mg is subconjunctivally administered to a human subject by
administering between about 1 .mu.l and about 100 .mu.l of a liquid
formulation described herein. In some variations, a liquid
formulation containing an amount of rapamycin of between about 20
.mu.g and about 1 mg is subconjunctivally administered to a human
subject by administering between about 1 .mu.l and about 50 .mu.l
of a liquid formulation described herein. In some variations, a
liquid formulation containing an amount of rapamycin of between
about 20 .mu.g and about 500 .mu.g is subconjunctivally
administered to a human subject by administering between about 1
.mu.l and about 25 .mu.l of a liquid formulation described herein.
In some variations, a liquid formulation containing an amount of
rapamycin of between about 20 .mu.g and about 300 .mu.g is
subconjunctivally administered to a human subject by administering
between about 1 .mu.l and about 15 .mu.l of a liquid formulation
described herein.
[0393] In some variations, a total amount of rapamycin less than
about 200 .mu.g is administered intravitreally. In some variations,
a total amount of rapamycin less than about 200 .mu.g is
administered intravitreally. In some variations, a total amount of
rapamycin less than about 300 .mu.g is administered intravitreally.
In some variations, a total amount of rapamycin less than about 400
.mu.g is administered intravitreally. In some variations, a total
amount of rapamycin less than about 500 .mu.g is administered
intravitreally. In some variations, a total amount of rapamycin
less than about 600 .mu.g is administered intravitreally. In some
variations, a total amount of rapamycin less than about 800 .mu.g
is administered intravitreally. In some variations, a total amount
of rapamycin less than about 1 mg is administered intravitreally.
In some variations, a total amount of rapamycin less than about 2
mg is administered intravitreally. In some variations, a total
amount of rapamycin less than about 2.5 mg is administered
intravitreally. In some variations, a total amount of rapamycin
less than about 3 mg is administered intravitreally. In some
variations, a total amount of rapamycin less than about 3.5 mg is
administered intravitreally. In some variations, a total amount of
rapamycin less than about 4 mg is administered intravitreally. In
some variations, a volume of a formulation is administered that
contains an amount of rapamycin described herein.
[0394] In some variations, a liquid formulation containing a
concentration of rapamycin by weight of the total of between about
0.5% and about 6% is intravitreally administered to a human subject
by administering between about 0.1 .mu.l and about 200 .mu.l of a
liquid formulation described herein. In some variations, a liquid
formulation containing a concentration of rapamycin by weight of
the total of between about 0.5% and about 4% is intravitreally
administered to a human subject by administering between about 1
.mu.l and about 50 .mu.l of a liquid formulation described herein.
In some variations, a liquid formulation containing a concentration
of rapamycin by weight of the total of between about 1.5% and about
3.5% is intravitreally administered to a human subject by
administering between about 1 .mu.l and about 15 .mu.l of a liquid
formulation described herein. In some variations, a liquid
formulation containing a concentration of rapamycin by weight of
the total of about 2% is intravitreally administered to a human
subject by administering between about 1 .mu.l and about 1 .mu.l of
a liquid formulation described herein.
[0395] In some variations, a liquid formulation containing an
amount of rapamycin of between about 0.2 .mu.g and about 4 mg is
intravitreally administered to a human subject by administering
between about 0.1 .mu.l and about 200 .mu.l of a liquid formulation
described herein. In some variations, a liquid formulation
containing an amount of rapamycin of between about 1 .mu.g and
about 2 mg is intravitreally administered to a human subject by
administering between about 1 .mu.l and about 100 .mu.l of a liquid
formulation described herein. In some variations, a liquid
formulation containing an amount of rapamycin of between about 20
.mu.g and about 1 mg is intravitreally administered to a human
subject by administering between about 1 .mu.l and about 50 .mu.l
of a liquid formulation described herein. In some variations, a
liquid formulation containing an amount of rapamycin of between
about 20 .mu.g and about 500 .mu.g is intravitreally administered
to a human subject by administering between about 1 .mu.l and about
25 .mu.l of a liquid formulation described herein. In some
variations, a liquid formulation containing an amount of rapamycin
of between about 20 .mu.g and about 300 .mu.g is intravitreally
administered to a human subject by administering between about 1
.mu.l and about 15 .mu.l of a liquid formulation described
herein.
[0396] In some variations a liquid formulation as described herein
containing an amount of rapamycin of between about 1 .mu.g and
about 5 mg is administered to a human subject for treatment of wet
AMD. In some variations a liquid formulation as described herein
containing an amount of rapamycin of between about 20 .mu.g and
about 4 mg is administered to a human subject for treatment of wet
AMD. In some variations a liquid formulation as described herein
containing an amount of rapamycin of between about 20 .mu.g and
about 1.2 mg is administered to a human subject for treatment of
wet AMD. In some variations an amount of rapamycin of between about
10 .mu.g and about 0.5 mg is administered to a human subject for
treatment of wet AMD. In some variations an amount of rapamycin of
between about 10 .mu.g and 90 .mu.g is administered to a human
subject for treatment of wet AMD. In some variations an amount of
rapamycin of between about 60 .mu.g and about 120 .mu.g is
administered to a human subject for treatment of wet AMD. In some
variations an amount of rapamycin of between about 100 .mu.g and
about 400 .mu.g is administered to a human subject for treatment of
wet AMD. In some variations an amount of rapamycin of between about
400 .mu.g and about 1 mg is administered to a human subject for
treatment of wet AMD. In some variations an amount of rapamycin of
between about 1 mg and about 5 mg is administered to a human
subject for treatment of wet AMD. In some variations, an amount of
rapamycin of between about 3 mg and about 7 mg is administered to a
human subject for treatment of wet AMD. In some variations, an
amount of rapamycin of between about 5 mg and about 10 mg is
administered to a human subject for treatment of wet AMD.
[0397] In some variations a liquid formulation as described herein
containing an amount of rapamycin of between about 1 .mu.g and
about 5 mg is administered to a human subject for prevention of wet
AMD. In some variations a liquid formulation as described herein
containing an amount of rapamycin of between about 20 .mu.g and
about 4 mg is administered to a human subject for prevention of wet
AMD. In some variations a liquid formulation as described herein
containing an amount of rapamycin of between about 20 .mu.g and
about 1.2 mg is administered to a human subject for prevention of
wet AMD. In some variations an amount of rapamycin of between about
10 .mu.g and about 0.5 mg is administered to a human subject for
prevention of wet AMD. In some variations an amount of rapamycin of
between about 10 .mu.g and 90 .mu.g is administered to a human
subject for prevention of wet AMD. In some variations an amount of
rapamycin of between about 60 .mu.g and about 120 .mu.g is
administered to a human subject for prevention of wet AMD. In some
variations an amount of rapamycin of between about 100 .mu.g and
about 400 .mu.g is administered to a human subject for prevention
of wet AMD. In some variations an amount of rapamycin of between
about 400 .mu.g and about 1 mg is administered to a human subject
for prevention of wet AMD. In some variations an amount of
rapamycin of between about 1 mg and about 5 mg is administered to a
human subject for prevention of wet AMD. In some variations, an
amount of rapamycin of between about 3 mg and about 7 mg is
administered to a human subject for prevention of wet AMD. In some
variations, an amount of rapamycin of between about 5 mg and about
10 mg is administered to a human subject for prevention of wet
AMD.
[0398] In some variations a liquid formulation as described herein
containing an amount of rapamycin of between about 1 .mu.g and
about 5 mg is administered to a human subject for treatment of dry
AMD. In some variations a liquid formulation as described herein
containing an amount of rapamycin of between about 20 .mu.g and
about 4 mg is administered to a human subject for treatment of dry
AMD. In some variations a liquid formulation as described herein
containing an amount of rapamycin of between about 20 .mu.g and
about 1.2 mg is administered to a human subject for treatment of
dry AMD. In some variations an amount of rapamycin of between about
10 .mu.g and about 0.5 mg is administered to a human subject for
treatment of dry AMD. In some variations an amount of rapamycin of
between about 10 .mu.g and 90 .mu.g is administered to a human
subject for treatment of dry AMD. In some variations an amount of
rapamycin of between about 60 .mu.g and about 120 .mu.g is
administered to a human subject for treatment of dry AMD. In some
variations an amount of rapamycin of between about 100 .mu.g and
about 400 .mu.g is administered to a human subject for treatment of
dry AMD. In some variations an amount of rapamycin of between about
400 .mu.g and about 1 mg is administered to a human subject for
treatment of dry AMD. In some variations an amount of rapamycin of
between about 1 mg and about 5 mg is administered to a human
subject for treatment of dry AMD. In some variations, an amount of
rapamycin of between about 3 mg and about 7 mg is administered to a
human subject for treatment of dry AMD. In some variations, an
amount of rapamycin of between about 5 mg and about 10 mg is
administered to a human subject for treatment of dry AMD.
[0399] In some variations, a liquid formulation as described herein
containing an amount of rapamycin of between about 1 .mu.g and
about 5 mg is administered to a human subject for treatment of
angiogenesis, including but not limited to choroidal
neovascularization. In some variations, an amount of rapamycin of
between about 20 .mu.g and about 4 mg is administered to the human
subject; between about 20 .mu.g and about 1.2 mg; between about 10
.mu.g and about 0.5 mg is administered to a human subject for
treatment of wet AMD, between about 10 .mu.g and 90 .mu.g, between
about 60 .mu.g and 120 .mu.g is administered to the human subject;
between about 100 .mu.g and 400 .mu.g, between about 400 .mu.g and
1 mg is administered to the human subject; in some variations, an
amount of rapamycin of between about 1 mg and 5 mg is administered
to the human subject; in some variations, an amount of rapamycin of
between about 3 mg and 7 mg is administered to the human subject;
in some variations, an amount of rapamycin of between about 5 mg
and 10 mg is administered to the human subject for treatment of
angiogenesis, including but not limited to choroidal
neovascularization.
[0400] In one method, a liquid formulation as described herein
contains an amount of a therapeutic agent equivalent to an amount
of rapamycin.
[0401] In one method, a liquid formulation as described herein
containing an amount of a therapeutic agent equivalent to an amount
of rapamycin of between about 1 .mu.g and about 5 mg is
administered to a human subject for treatment of wet AMD. In some
variations, an amount of a therapeutic agent equivalent to an
amount of rapamycin of between about 1 .mu.g and about 5 mg is
administered to the human subject; between about 20 .mu.g and about
1.2 mg; between about 10 .mu.g and about 0.5 mg is administered to
a human subject for treatment of wet AMD, between about 10 .mu.g
and 90 .mu.g, between about 60 .mu.g and 120 .mu.g is administered
to the human subject; between about 100 .mu.g and 400 .mu.g,
between about 400 .mu.g and 1 mg is administered to the human
subject is administered to the human subject; in some variations,
an amount of a therapeutic agent equivalent to an amount of
rapamycin of between about 1 mg and 5 mg is administered to the
human subject; in some variations, an amount of a therapeutic agent
equivalent to an amount of rapamycin of between about 3 mg and 7 mg
is administered to the human subject; in some variations, an amount
of a therapeutic agent equivalent to an amount of rapamycin of
between about 5 mg and 10 mg is administered to the human
subject.
[0402] In some variations, a liquid formulation as described herein
containing an amount of a therapeutic agent equivalent to an amount
of rapamycin of between about 1 .mu.g and about 5 mg is
administered to a human subject for treatment of dry AMD. In some
variations, an amount of a therapeutic agent equivalent to an
amount of rapamycin of between about 20 .mu.g and about 4 mg is
administered to the human subject; between about 20 .mu.g and about
1.2 mg; between about 10 .mu.g and about 0.5 mg is administered to
a human subject for treatment of wet AMD, between about 10 .mu.g
and 90 .mu.g, between about 60 .mu.g and 120 .mu.g is administered
to the human subject; between about 100 .mu.g and 400 .mu.g,
between about 400 .mu.g and 1 mg is administered to the human
subject; in some variations, an amount of a therapeutic agent
equivalent to an amount of rapamycin of between about 400 .mu.g and
1 mg is administered to the human subject; in some variations, an
amount of a therapeutic agent equivalent to an amount of rapamycin
of between about 1 mg and 5 mg is administered to the human
subject; in some variations, an amount of a therapeutic agent
equivalent to an amount of rapamycin of between about 3 mg and 7 mg
is administered to the human subject; in some variations, an amount
of a therapeutic agent equivalent to an amount of rapamycin of
between about 5 mg and 10 mg is administered to the human subject
to treat dry AMD.
[0403] In some variations, a liquid formulation as described herein
containing an amount of a therapeutic agent equivalent to an amount
of rapamycin of between about 1 .mu.g and about 5 mg is
administered to a human subject for prevention of wet AMD. In some
variations, an amount of a therapeutic agent equivalent to an
amount of rapamycin of between about 20 .mu.g and about 4 mg is
administered to the human subject; between about 20 .mu.g and about
1.2 mg; between about 10 .mu.g and about 0.5 mg is administered to
a human subject for prevention of wet AMD, between about 10 .mu.g
and 90 .mu.g, between about 60 .mu.g and 120 .mu.g is administered
to the human subject; between about 100 .mu.g and 400 .mu.g,
between about 400 .mu.g and 1 mg is administered to the human
subject; in some variations, an amount of a therapeutic agent
equivalent to an amount of rapamycin of between about 400 .mu.g and
1 mg is administered to the human subject; in some variations, an
amount of a therapeutic agent equivalent to an amount of rapamycin
of between about 1 mg and 5 mg is administered to the human
subject; in some variations, an amount of a therapeutic agent
equivalent to an amount of rapamycin of between about 3 mg and 7 mg
is administered to the human subject; in some variations, an amount
of a therapeutic agent equivalent to an amount of rapamycin of
between about 5 mg and 10 mg is administered to the human subject
to prevent wet AMD.
[0404] In some variations, any one or more of the formulations
described herein are administered intravitreally every 3 or more
months, every 6 or more months, every 9 or more months, or every 12
or more months, or longer, to treat one or more of choroidal
neovascularization, wet AMD, dry AMD, to prevent wet AMD, or to
prevent progression of dry AMD to wet AMD. In some variations, any
one or more of the formulations described herein are administered
subconjunctivally every 3 or more months, every 6 or more months,
every 9 or more months, or every 12 or more months, or longer, to
treat one or more of choroidal neovascularization, wet AMD, dry
AMD, or to prevent wet AMD.
[0405] In some variations, any one or more of the rapamycin
formulations described herein are administered intravitreally every
3 or more months, every 6 or more months, every 9 or more months,
or every 12 or more months, or longer, to treat one or more of
choroidal neovascularization, wet AMD, dry AMD, to prevent wet AMD,
or to prevent progression of dry AMD to wet AMD. In some
variations, any one or more of the rapamycin formulations described
herein are administered subconjunctivally every 3 or more months,
every 6 or more months, every 9 or more months, or every 12 or more
months, or longer, to treat one or more of choroidal
neovascularization, wet AMD, dry AMD, or to prevent wet AMD. In
some variations, the effect of the rapamycin persists beyond the
period during which it is present in the ocular tissues.
[0406] Delivery of the therapeutic agents described herein may, for
example, be delivered at a dosage range between about 1 ng/day and
about 100 .mu.g/day, or at dosages higher or lower than this range,
depending on the route and duration of administration. In some
variations of liquid formulation or composition used in the methods
described herein, the therapeutic agents are delivered at a dosage
range of between about 0.1 .mu.g/day and about 10 .mu.g/day. In
some variations of liquid formulation or composition used in the
methods described herein, the therapeutic agents are delivered at a
dosage range of between about 1 .mu.g/day and about 5 .mu.g/day.
Dosages of various therapeutic agents for treatment, prevention,
inhibition, delay of onset, or cause of regression of various
diseases and conditions described herein can be refined by the use
of clinical trials.
[0407] The liquid formulations, including but not limited to
solutions, suspensions, emulsions and situ gelling formulations,
and compositions described herein may be used for delivery to the
eye, as one nonlimiting example by ocular or periocular
administration, of therapeutically effective amounts of rapamycin
for extended periods of time to treat, prevent, inhibit, delay the
onset of, or cause regression of CNV, and thus may be used to
treat, prevent, inhibit, delay the onset of, or cause regression of
wet AMD, or transition of dry AMD to wet AMD. It is believed that
by changing certain characteristics of the liquid formulations
described herein, including but not limited to the components of
the liquid formulations, the location in the eye to which the
liquid formulation is delivered, including without limitation
subconjunctival or intravitreal placement, the liquid formulations
may be used to deliver therapeutically effective amounts of
rapamycin to the eye for a variety of extended time periods
including delivery of therapeutic amounts for greater than about 1
week, for greater than about 2 weeks, for greater than about 3
weeks, for greater than about 1 month, for greater than about 3
months, for greater than about 6 months, for greater than about 9
months, for greater than about 1 year.
[0408] When a therapeutically effective amount of rapamycin is
administered to a subject suffering from wet AMD, the rapamycin may
treat, inhibit, or cause regression of the wet AMD. Different
therapeutically effective amounts may be required for treatment,
inhibition or causing regression. A subject suffering from wet AMD
may have CNV lesions, and it is believed that administration of a
therapeutically effective amount of rapamycin may have a variety of
effects, including but not limited to causing regression of the CNV
lesions, stabilizing the CNV lesion, and preventing progression of
an active CNV lesion.
[0409] When a therapeutically effective amount of rapamycin is
administered to a subject suffering from dry AMD, it is believed
that the rapamycin may prevent or slow the progression of dry AMD
to wet AMD.
EXAMPLES
[0410] Unless the context indicates otherwise, the error bars in
the charts show one standard deviation. Where ethanol is used, it
is 200 proof ethanol from Gold Shield Distributors, Hayward, Calif.
Where rapamycin is used, it is from LC laboratories, Woburn, Mass.,
or Chunghwa Chemical Synthesis & Biotech Co., LTD (CCSB),
Taipei Hsien, Taiwan, ROC. Where PEG 400 is used, it is from The
Dow Chemical Company, New Milford, Conn. Some of the graphs use the
expression "uL" or "ug" to refer to .mu.L or .mu.g, respectively.
Where a volume of 10 .mu.L or less is administered, Hamilton HPLC
syringes were used.
Example 1
Preparation and Characterization of a Rapamycin-Containing
Solution
[0411] 1.256% rapamycin (percentage of the total weight) was
dissolved in 9.676% ethanol (percentage of the total weight). An
aqueous solution of 15% F 127 (Lutrol) in sterile water was slowly
added under continuous agitation. The final concentration was
approximately 78.57% sterile water (percentage of the total weight)
and approximately 10.50% F 127 (Lutrol) (percentage of the total
weight). This solution is listed as formulation #32 in Table 1. The
solution was placed at 2.degree. C. until use.
Example 2
Subconjunctival Injection of a Rapamycin-Containing Solution
[0412] 50 .mu.l of the solution described in Example 1 was injected
between the sclera and the conjunctiva of the eye of New Zealand
white rabbits.
[0413] FIG. 2 depicts the average concentration of rapamycin
present in the vitreous (ng/ml), retina choroid (ng/mg), and sclera
(ng/mg) on a logarithmic scale at 20, 40, 67, and 90 days after
injection.
[0414] The analysis was by liquid chromatography mass spectroscopy
(LCMS) using an internal standard.
[0415] At each timepoint, the average concentration of rapamycin
was calculated by adding the concentrations of rapamycin obtained
for each eye from each rabbit, and dividing the total by the number
of eyes analyzed. In this experiment, each timepoint represents the
average of either two eyes of each of two rabbits (four eyes at
that timepoint) or the average of two eyes of one rabbits (two eyes
at that timepoint).
[0416] The full vitreous was homogenized and analyzed. The average
concentration of the vitreous was calculated by dividing the mass
of rapamycin measured by the volume of vitreous analyzed. The
sample did not include the site of administration; thus, this
measurement indicated the level of rapamycin delivered to the
vitreous via the solution.
[0417] The average level of rapamycin in the vitreous at 20, 40,
67, and 90 days after subconjunctival injection was about 4.425,
3.800, 4.100, and 1.500 ng/ml, respectively.
[0418] The full retina choroid was homogenized and analyzed. The
average concentration of the retina choroid was calculated by
dividing the mass of rapamycin measured by the mass of retina
choroid analyzed. The sample did not include the site of
administration; thus, this measurement indicated the level of
rapamycin delivered to the retina choroid via the solution.
[0419] The average level of rapamycin in the retina choroid at 20,
40, 67, and 90 days after subconjunctival injection was about
0.055, 0.209, 0.080, and 0.017 ng/mg, respectively.
[0420] The sclera was analyzed in the same way as the retina
choroid. The scleral sample included the site of injection; thus,
this measurement indicated clearance of rapamycin from the
sclera.
[0421] The average level of rapamycin in the sclera at 20, 40, 67,
and 90 days after subconjunctival injection was about 0.141, 0.271,
0.067, and 0.192 ng/mg, respectively.
Example 3
Preparation and Characterization of a Rapamycin-Containing
Solution
[0422] 5.233% rapamycin (per weight of the total of the formulation
after all components were added) was dissolved in 0.4177 g of EtOH;
the quantity of EtOH was reduced by forced evaporation (heat) to
0.1296 g (6.344%, w/w). PEG 400 was added under continuous
agitation. Final concentrations as a percentage of the total weight
were approximately: rapamycin 5.233%, ethanol 6.344%, and PEG 400
88.424%. When contacted with the vitreous, the formulation formed a
non-dispersed mass relative to the surrounding medium. This
solution is listed as formulation #34 in Table 1.
Example 4
Subconjunctival Injection of a Rapamycin-Containing Solution
[0423] 25 .mu.l of the solution described in Example 3 were
injected between the sclera and the conjunctiva of the eye of New
Zealand white rabbits.
[0424] FIG. 3 depicts the level of rapamycin present in the
vitreous (ng/ml), retina choroid (ng/mg), and sclera (ng/mg) on a
logarithmic scale at 14, 35, 62, and 85 days after injection. The
level of rapamycin present in the vitreous (ng/ml) is also shown at
2 days after injection.
[0425] The vitreous was homogenized and analyzed as described in
Example 2, except on day 2 a single eye of each of three rabbits
was analyzed; at day 14 two eyes from each of two rabbits were
analyzed; at day 35 two eyes from a single rabbit were analyzed; at
day 62 two eyes from a single rabbit were analyzed; and at day 85
one eye from a single rabbit plus two eyes from a second rabbit
were analyzed.
[0426] The vitreous sample did not include the site of
administration; thus, this measurement indicated the level of
rapamycin delivered to the vitreous via the solution. The average
level of rapamycin in the vitreous at 2, 14, 35, 62, and 85 days
after subconjunctival injection was about 3.57, 53.65, 9.00, 4.700,
and 0.600 ng/ml, respectively.
[0427] The retina choroid was homogenized and analyzed as described
in Example 2, with the samples taken on the days as described for
the vitreous above. No day 2 analysis was done. The retina choroid
sample did not include the site of administration; thus, this
measurement indicated the level of rapamycin delivered to the
retina choroid via the solution. The average level of rapamycin in
the retina choroid at 14, 35, 62, and 85 days after subconjunctival
injection was about 0.4815, 1.725, 0.057, and 0.009 ng/mg,
respectively.
[0428] The scleral sample was analyzed as described in Example 2,
and the samples were taken on the days as described for the retina
choroid as above. The scleral sample included the site of
injection; thus, this measurement indicated clearance of rapamycin
from the sclera. The average level of rapamycin in the sclera at
14, 35, 62, and 85 days after subconjunctival injection was about
34.5815, 0.135, 0.042, and 0.163666667 ng/mg, respectively.
Example 5
Intravitreal Injection of a Rapamycin-Containing Solution
[0429] 25 .mu.l of the solution described in Example 3 was injected
into the vitreous of the eye of New Zealand white rabbits. FIG. 4
depicts the level of rapamycin present in the vitreous (ng/ml),
retina choroid (ng/mg), and sclera (ng/mg) on a logarithmic scale
at 14, 35, 62, and 90 days after injection. The level o present in
the vitreous (ng/ml) is also shown at 2 days after injection.
[0430] The vitreous was homogenized and analyzed as described in
Example 2, except on day 2 approximately 1 .mu.l of a single eye of
each of three rabbits was analyzed; at day 14 two eyes from each of
two rabbits were analyzed; at day 35 two eyes from a single rabbit
were analyzed; at day 62 two eyes from a single rabbit were
analyzed; and at day 90 two eyes from each of two rabbits were
analyzed.
[0431] Excepting the day 2 sample, the vitreous samples included
the site of administration. An effort was made to avoid the
administered solution where possible. However, the accuracy of the
measured levels of rapamycin was potentially affected by sampling
errors due to inadvertent inclusion of the administered
solution.
[0432] The average level of rapamycin in the vitreous at 2, 14, 35,
62, and 90 days after intravitreal injection was about 11.4,
136538, 2850.3, 21820.35, and 27142.75 ng/ml, respectively.
[0433] The retina choroid was homogenized and analyzed as described
in Example 2, with the samples taken on the days described for the
vitreous above. No day 2 analysis was done. The retina choroid
sample did not include the site of administration; thus, this
measurement indicated the level of rapamycin delivered to the
retina choroid via the solution. The average level of rapamycin in
the retina choroid at 14, 35, 62, and 90 days after intravitreal
injection was about 5.78975, 244.485, 0.105, and 1.782 ng/mg,
respectively.
[0434] The scleral sample was analyzed as described in Example 2,
and the samples were taken on the days as described for the retina
choroid above. The scleral sample did not include the site of
injection; thus, this measurement indicated level of rapamycin
delivered to the sclera. The average level of rapamycin in the
sclera at 14, 35, 62, and 90 days after intravitreal injection was
about 0.5695, 12.34, 0.8505, and 0.71175 ng/mg, respectively.
Example 6
Preparation and Characterization of a Rapamycin-Containing
Suspension
[0435] 6% rapamycin (percentage of the total weight) was dispersed
in 94% PEG400 (percentage of the total weight). This suspension is
listed as formulation #55 in Table 1.
Example 7
Intravitreal Injection of a Rapamycin-Containing Suspension
[0436] The solution prepared in Example 6 was injected
intravitreally into the eyes of New Zealand white rabbits. FIG. 5
depicts images of rabbit eyes after intravitreal injection of 10
.mu.L (FIG. 5A), 20 .mu.l (FIG. 5B), and 40 .mu.l (FIG. 5C) of a 6%
rapamycin suspension in PEG400. This resulted in an injected dose
of about 0.6, about 1.2, and about 2.4 mg. The images were focused
on the administered suspension. These images show that the
suspension forms a non-dispersed mass relative to the surrounding
vitreal medium.
Example 8
Preparation and Characterization of a Rapamycin-Containing In Situ
Gelling Formulation
[0437] A liquid formulation of 4.2% rapamycin (obtained from LC
laboratories in Woburn, Mass., and Chunghwa Chemical Synthesis
& BioTech. Co, Ltd in Taiwan), 4.3% ethanol (obtained from Gold
Shield Chemical in Hayward, Calif.), 2.2% PVP K90 (obtained from
BASF), 87.1% PEG 400 (obtained from DOW Chemical), and 2.2%
Eudragit RL 100 (obtained from Rohm Pharma Polymers), where all
percentages are by weight of the total.
[0438] Eudragit RL 100 was dissolved in ethanol. Sonication and
heat may be required at this step. Ethanol--Eudragit was added to
PEG 400. PVP was slowly added to the Eudragit-Ethanol-PEG solution,
and a uniformly mixed solution was obtained. Vigorous mixing may be
required for this step.
[0439] Rapamycin was added to and dissolved in the
Eudragit-ethanol-PEG-PVP mix. Heat and sonication may be used. The
formulation was mixed thoroughly (using a vortex or mixer) to
achieve uniformity. This formulation is listed as #37 in Table
1.
[0440] When placed in deionized water or tap water, the liquid
formulation formed a non-dispersed mass. The non-dispersed mass
appeared as a gel-like substance.
Example 9
Subconjunctival Injection of a Rapamycin-Containing Non-Dispersed
Mass-Forming Formulation
[0441] 50 .mu.l of the solution described in Example 8 was injected
between the sclera and the conjunctiva of the eye of New Zealand
white rabbits.
[0442] FIG. 6 depicts the average concentration of rapamycin
present in the vitreous (ng/ml), retina choroid tissues (ng/mg),
and sclera (ng/mg) on a logarithmic scale at 7, 32, 45, and 90 days
after injection of the in situ gelling formulation.
[0443] The analysis was by LCMS (liquid chromatography--mass
spectroscopy).
[0444] Where more than a single eye was analyzed, the average
concentration of rapamycin was calculated by adding the
concentrations of rapamycin obtained for each eye from each rabbit,
and dividing the total by the number of eyes analyzed. In this
experiment, the vitreous day 7 and the sclera day 7, 32, and 45
timepoints represent a single eye, as opposed to an average level.
The remaining day 7, 32, and 45 timepoints represent the average of
two eyes of one rabbit, and the day 90 timepoint represents the
average of two eyes of each of two rabbits (four eyes total).
[0445] The full vitreous was homogenized and analyzed. The average
concentration of the vitreous was calculated by dividing the mass
of rapamycin measured by the volume of vitreous analyzed. The
sample did not include the site of administration; thus, this
measurement indicated the level of rapamycin delivered to the
vitreous via the in situ gelling formulation.
[0446] The average level of rapamycin in the vitreous at 7, 32, 45,
and 90 days after subconjunctival injection was about 13.9, about
7.4, about 1.35, and about 9.9 ng/ml, respectively.
[0447] The full retina choroid tissues were homogenized and
analyzed. The average concentration of the retina choroid tissues
was calculated by dividing the mass of rapamycin measured by the
mass of retina choroid tissues analyzed. The sample did not include
the site of administration; thus, this measurement indicated the
level of rapamycin delivered to the retina choroid tissues via the
in situ gelling formulation.
[0448] The average level of rapamycin in the retina choroid tissues
at 7, 32, 45, and 90 days after subconjunctival injection was about
0.376, about 0.1875, about 0.136, and about 0.29 ng/mg,
respectively.
[0449] The sclera was analyzed in the same way as the retina
choroid tissues. The scleral sample may have included the injected
liquid formulation; thus, this measurement was indicative of
clearance of rapamycin from the sclera.
[0450] The average level of rapamycin in the sclera at 7, 32, 45,
and 90 days after subconjunctival injection was about 2033, about
1653, about 3626, and about 420.5 ng/mg, respectively.
Example 10
Preparation and Characterization of a Rapamycin-Containing
Suspension
[0451] A rapamycin containing suspension was formed by dispersing
150.5 mg of rapamycin (3.004% by weight) in 4860.3 mg of PEG 400
(96.996% by weight). This formulation is listed as #49 in Table 1.
150.5 mg rapamycin (3.004% by weight) and 4860.3 mg of PEG 400
(96.996% by weight) were placed in an amber vial. High Wear
Resistant Zirconia Grinding Media (beads) of 3 mm diameter were
added, up to three quarters of the total volume. The vial was
sealed and placed in a Cole-Parmer milling apparatus for 48 hrs.
The particle size median for rapamycin was 2.8386 mm and the mean
was 3.1275 mm. The formulation was kept at 4 C until use. Volumes
of 20 .mu.l and 40 .mu.l each formed a non-dispersed mass when
placed in the vitreous of a rabbit eye.
Example 11
Subconjunctival Injection of a Rapamycin-Containing Suspension
[0452] 40 .mu.l of the suspension described in Example 10 were
injected between the sclera and the conjunctiva of the eye of New
Zealand white rabbits. FIG. 7 depicts the level of rapamycin in the
vitreous (ng/ml), retina choroid (ng/mg), and the sclera (ng/mg) on
a logarithmic scale at 14, 42, 63, and 91 days after injection.
[0453] The vitreous was homogenized and analyzed as described in
Example 2. Two eyes from each of two rabbits were analyzed at each
time point except for day 91, on which two eyes from one rabbit
were analyzed. The vitreous sample did not include the site of
administration, so this measurement indicated the level of
rapamycin delivered to the vitreous. The average level of rapamycin
in the vitreous at 14, 42, 63, and 91 days after subconjunctival
injection was about 4.031, 23.11, 53.27, and 13.94 ng/ml,
respectively.
[0454] The retina choroid was homogenized and analyzed as described
in Example 2, with the samples taken as described for the vitreous
above. The retina choroid did not include the site of
administration, so this measurement indicated the level of
rapamycin delivered to the retina choroid. The average level of
rapamycin in the retina choroid at 14, 42, 63, and 91 days after
subconjunctival injection was about 0.1577, 4.965, 0.385, and 0.05
ng/mg, respectively.
[0455] The scleral sample was homogenized and analyzed as described
in Example 2, with the samples taken as described for the vitreous
above. The scleral sample included the site of injection. The
average level of rapamycin in the sclera at 14, 42, 63, and 91 days
after subconjunctival injection was about 1283, 476.3, 854.2, and
168.5 ng/mg, respectively.
Example 12
Intravitreal Injection of a Rapamycin-Containing Suspension
[0456] 20 .mu.l of the suspension described in Example 10 were
injected into the vitreous of the eye of New Zealand white rabbits.
The injected suspension formed a non-dispersed mass relative to the
surrounding medium. FIG. 8 depicts the level of rapamycin in the
retina choroid (ng/mg) and the sclera (ng/mg) on a logarithmic
scale at 14, 42, 63, and 91 days after injection and in the
vitreous (ng/ml) at 63 and 91 days after injection.
[0457] The vitreous was homogenized and, analyzed as described in
Example 2. Two eyes from each of two rabbits were analyzed at each
time point. The vitreous sample may have included the site of
administration. The average level of rapamycin in the vitreous at
63 and 91 days after intravitreal injection was about 381,600 and
150,400 ng/ml, respectively.
[0458] The retina choroid was homogenized and analyzed as described
in Example 2. Two eyes from each of two rabbits were analyzed at
each time point. The retina choroid did not include the site of
administration, so this measurement indicated the level of
rapamycin delivered to the retina choroid. The average level of
rapamycin in the retina choroid at 14, 42, 63, and 91 days after
intravitreal injection was about 2.588, 4.249, 21.42, and 0.922
ng/mg, respectively.
[0459] The scleral sample was homogenized and analyzed as described
in Example 2, with the samples taken as described for the retina
choroid above. The scleral sample did not include the site of
injection, so this measurement indicated the level of rapamycin
delivered to the sclera. The average level of rapamycin in the
sclera at 14, 42, 63, and 91 days after intravitreal injection was
about 0.7327, 6.053, 1.373, and 17.49 ng/mg, respectively.
Example 13
Preparation and Characterization of a Rapamycin-Containing
Solution
[0460] A rapamycin containing solution was formed by placing 116.6
mg of rapamycin in ethanol and storing the mixture at 4.degree. C.
for 6 hours. This solution was then mixed with 4647.5 mg of PEG 400
to give a solution having final concentrations by weight of 2.29%
rapamycin, 6.05% ethanol, and 91.66% PEG 400. This solution is
listed as formulation #51 in Table 1. A volume of 30 .mu.l formed a
non-dispersed mass when placed in the vitreous of rabbit eyes.
Example 14
Subconjunctival Injection of a Rapamycin-Containing Solution
[0461] 40 .mu.l of the solution described in Example 13 were
injected between the sclera and the conjunctiva of the eye of New
Zealand white rabbits. FIG. 9 depicts the level of rapamycin in the
vitreous (ng/ml), retina choroid (ng/mg), and the sclera (ng/mg) on
a linear scale at 14, 42, 63, and 91 days after injection.
[0462] The vitreous was homogenized and analyzed as described in
Example 2. Two eyes from each of two rabbits were analyzed at each
time point except for day 91, on which two eyes from one rabbit
were analyzed. The vitreous sample did not include the site of
administration, so this measurement indicated the level of
rapamycin delivered to the vitreous. The average level of rapamycin
in the vitreous at 14, 42, 63, and 91 days after subconjunctival
injection was about 1.804, 1.854, 1.785, and 1.255 ng/ml,
respectively.
[0463] The retina choroid was homogenized and analyzed as described
in Example 2, with the samples taken as described for the vitreous
above. The retina choroid did not include the site of
administration, so this measurement indicated the level of
rapamycin delivered to the retina choroid. The average level of
rapamycin in the retina choroid at 14, 42, 63, and 91 days after
subconjunctival injection was about 1.221, 4.697, 0.1075, and 0.02
ng/mg, respectively.
[0464] The scleral sample was homogenized and analyzed as described
in Example 2, with the samples taken as described for the vitreous
above. The scleral sample included the site of injection. The
average level of rapamycin in the sclera at 14, 42, 63, and 91 days
after subconjunctival injection was about 1.987, 1.884, 0.56, and
10.84 ng/mg, respectively.
Example 15
Intravitreal Injection of a Rapamycin-Containing Solution
[0465] 30 .mu.l of the solution described in Example 13 were
injected into the vitreous of the eye of New Zealand white rabbits.
The injected solution formed a non-dispersed mass relative to the
surrounding medium. FIG. 10 depicts the level of rapamycin in the
retina choroid (ng/mg) and the sclera (ng/mg) on a linear scale at
14, 42, 63, and 91 days after injection.
[0466] The retina choroid was homogenized and analyzed as described
in Example 2. Two eyes from each of two rabbits were analyzed at
each time point. The retina choroid did not include the site of
administration, so this measurement indicated the level of
rapamycin delivered to the retina choroid. The average level of
rapamycin in the retina choroid at 14, 42, 63, and 91 days after
intravitreal injection was about 5.515, 5.388, 0.3833, and 11.52
ng/mg, respectively.
[0467] The scleral sample was homogenized and analyzed as described
in Example 2, with the samples taken as described for the retina
choroid above. The scleral sample did not include the site of
injection, so this measurement indicated the level of rapamycin
delivered to the sclera. The average level of rapamycin in the
sclera at 14, 42, 63, and 91 days after intravitreal injection was
about 1.077, 0.9239, 0.0975, and 2.0825 ng/mg, respectively.
[0468] FIG. 11 depicts the level of rapamycin in the vitreous
(ng/ml) on a linear scale at 63 and 91 days after injection. The
vitreous was homogenized and analyzed as described in Example 2.
Two eyes from each of two rabbits were analyzed at each time point.
The vitreous sample may have included the site of administration.
The average level of rapamycin in the vitreous at 63 and 91 days
after intravitreal injection was about 299,900 and 196,600 ng/ml,
respectively.
Example 16
Preparation and Characterization of a Rapamycin-Containing
Solution
[0469] About 320 g of ethanol was sparged with N.sub.2 for about 10
minutes, and then about 40 g of sirolimus was added to the ethanol.
The mixture was sonicated for about 20 minutes, by the end of which
all of the sirolimus had gone into solution to form a sirolimus
stock solution. A diluent solvent was prepared by sonicating about
1880 g of PEG 400 for about 60 minutes, and then sparging the
solvent with Nitrogen for about 10 minutes.
[0470] The sirolimus stock solution and the PEG 400 were then
rotated at about room temperature in a rotary evaporator for about
10 minutes to mix the stock solution with the diluent solvent.
After mixing, the solution was sparged with nitrogen for about 10
minutes and blanketed with nitrogen for about 5 minutes. After the
solution was sparged and filled with nitrogen, about 240 g of
excess ethanol was evaporated from the solution by increasing the
solution temperature, maintaining a temperature that did not exceed
40.degree. C. for an extended period of time and continuing to
rotate the solution for about 2.5 hours.
[0471] The resulting solution comprised about 40 g of sirolimus
(about 2% by weight), about 80 g of ethanol (about 4% by weight),
and about 1880 g of PEG 400 (about 94% by weight). This solution
was sparged with nitrogen for about 10 minutes and blanketed with
nitrogen for about 5 minutes. The solution was then filtered
through a 0.2 micron filter. HPLC vials were filled with 2 ml each
of the filtered solution to leave a head space in each container of
about 400 .mu.l. This head space was filled with nitrogen gas and
capped.
Example 17
Preparation and Characterization of a Rapamycin-Containing
Solution
[0472] Rapamycin, ethanol and PEG 400 were placed in a container to
give final concentrations by weight of about 2.00% rapamycin, about
4.00% ethanol, and about 94.00% PEG 400. The mixture was capped and
sonicated for 1-2 hours. The sonication generated heat, with
temperatures of up to about 40 or 50.degree. C. This solution is
listed as formulation #100 in Table 1. Volumes of 1 .mu.l, 3 .mu.l,
20 .mu.l, and 40 .mu.l formed a non-dispersed mass in the vitreous
of rabbit eyes.
Example 18
Subconjunctival Injection of a Rapamycin-Containing Solution
[0473] 20 .mu.l of the solution described in Example 17 were
injected between the sclera and the conjunctiva of the eye of New
Zealand white rabbits. FIG. 12 depicts the level of rapamycin in
the vitreous on a logarithmic scale at 5, 30, 60, 90, and 120 days
after injection. FIG. 13 depicts the level of rapamycin in the
retina choroid on a logarithmic scale at the same time points. For
comparison, FIG. 12 and FIG. 13 also depict results of similar
studies, performed with 40 .mu.l and 60 .mu.l injections, described
below in Example 19 and Example 20.
[0474] In FIGS. 12-15, discussed in this and following examples,
some outlier points have been omitted. Individual data points fro'm
the same study at the same time point were compared to each other.
When the arithmetic mean of the data points was lower than their
standard deviation, the data points that were higher or lower by an
order of magnitude were considered as outliers.
[0475] The vitreous was homogenized and analyzed as described in
Example 2. Between two and five rabbit eyes were analyzed at each
time point. The vitreous sample did not include the site of
administration, so this measurement indicated the level of
rapamycin delivered to the vitreous. The average level of rapamycin
in the vitreous at 5, 30, 60, 90, and 120 days after
subconjunctival injection was about 1.81, 0.45, 0.39, 1.85, and
1.49 ng/ml, respectively.
[0476] The retina choroid was homogenized and analyzed as described
in Example 2, with the samples taken as described for the vitreous
above. The retina choroid did not include the site of
administration, so this measurement indicated the level of
rapamycin delivered to the retina choroid. The average level of
rapamycin in the retina choroid at 5, 30, 60, 90, and 120 days
after subconjunctival injection was about 0.14, 0.03, 0.02, 0.02,
and 0.01 ng/mg, respectively.
Example 19
Subconjunctival Injection of a Rapamycin-Containing Solution
[0477] 40 .mu.l of the solution described in Example 17 were
injected between the sclera and the conjunctiva of the eye of New
Zealand white rabbits. FIG. 12 depicts the level of rapamycin in
the vitreous on a logarithmic scale at 5, 30, 60, 90, and 120 days
after injection. FIG. 13 depicts the level of rapamycin in the
retina choroid on a logarithmic scale at the same time points.
[0478] The vitreous was homogenized and analyzed as described in
Example 2. Between two and five rabbit eyes were analyzed at each
time point. The vitreous sample did not include the site of
administration, so this measurement indicated the level of
rapamycin delivered to the vitreous. The average level of rapamycin
in the vitreous at 5, 30, 60, 90, and 120 days after
subconjunctival injection was about 2.39, 0.65, 0.54, 2.07, and
1.92 ng/ml, respectively.
[0479] The retina choroid was homogenized and analyzed as described
in Example 2, with the samples taken as described for the vitreous
above. The retina choroid did not include the site of
administration, so this measurement indicated the level of
rapamycin delivered to the retina choroid. The average level of
rapamycin in the retina choroid at 5, 30, 60, 90, and 120 days
after subconjunctival injection was about 0.47, 0.04, 0.01, 0.05,
and 0.0 ng/mg, respectively.
Example 20
Subconjunctival Injection of a Rapamycin-Containing Solution
[0480] 60 .mu.l of the solution described in Example 17 were
injected between the sclera and the conjunctiva of the eye of New
Zealand white rabbits. FIG. 12 depicts the level of rapamycin in
the vitreous on a logarithmic scale at 5, 30, 60, 90, and 120 days
after injection. FIG. 13 depicts the level of rapamycin in the
retina choroid on a logarithmic scale at the same time points.
[0481] The vitreous was homogenized and analyzed as described in
Example 2. Between two and five rabbit eyes were analyzed at each
time point. The vitreous sample did not include the site of
administration, so this measurement indicated the level of
rapamycin delivered to the vitreous. The average level of rapamycin
in the vitreous at 5, 30, 60, 90, and 120 days after
subconjunctival injection was about 8.65, 0.29, 0.18, 2.00, 1.41
ng/ml, respectively.
[0482] The retina choroid was homogenized and analyzed as described
in Example 2, with the samples taken as described for the vitreous
above. The retina choroid did not include the site of
administration, so this measurement indicated the level of
rapamycin delivered to the retina choroid. The average level of
rapamycin in the retina choroid at 5, 30, 60, 90, and 120 days
after subconjunctival injection was about 0.63, 0.02, 0.02, 0.06,
and 0.01 ng/mg, respectively.
Example 21
Intravitreal Injection of a Rapamycin-Containing Solution
[0483] 20 .mu.l of the solution described in Example 17 were
injected into the vitreous of the eye of New Zealand white rabbits.
The injected solution formed a non-dispersed mass relative to the
surrounding medium FIG. 14 depicts the level of rapamycin in the
vitreous on a logarithmic scale 5, 30, 60, 90, and 120 days after
injection. FIG. 15 depicts the level of rapamycin in the retina
choroid on a logarithmic scale at the same time points. For
comparison, FIG. 14 and FIG. 15 also depict results of other
studies described below in Example 22 and Example 24.
[0484] The vitreous was homogenized and analyzed as described in
Example 2. Between two and five rabbit eyes were analyzed at each
time point. The vitreous sample may have included the site of
administration. The average level of rapamycin in the vitreous at
5, 30, 60, 90, and 120 days after intravitreal injection was about
162,100; 18,780; 57,830; 94,040; and 13,150 ng/ml,
respectively.
[0485] The retina choroid was homogenized and analyzed as described
in Example 2, with the samples taken as described for the vitreous
above. The retina choroid did not include the site of
administration, so this measurement indicated the level of
rapamycin delivered to the retina choroid. The average level of
rapamycin in the retina choroid at 5, 30, 60, 90, and 120 days
after intravitreal injection was about 2.84, 2.26, 0.17, 0.22, and
0.05 ng/mg, respectively.
Example 22
Intravitreal Injection of a Rapamycin-Containing Solution
[0486] 40 .mu.l of the solution described in Example 17 were
injected into the vitreous of the eye of New Zealand white rabbits.
The injected solution formed a non-dispersed mass relative to the
surrounding medium. FIG. 14 depicts the level of rapamycin in the
vitreous on a logarithmic scale 5, 30, 60, 90, and 120 days after
injection. FIG. 15 depicts the level of rapamycin in the retina
choroid on a logarithmic scale at the same time points.
[0487] The vitreous was homogenized and analyzed as described in
Example 2. Between two and five rabbit eyes were analyzed at each
time point. The vitreous sample may have included the site of
administration. The average level of rapamycin in the vitreous at
5, 30, 60, 90, and 120 days after intravitreal injection was about
415,600; 4,830; 74,510; 301,300; and 7,854 ng/ml respectively.
[0488] The retina choroid was homogenized and analyzed as described
in Example 2, with the samples taken as described for the vitreous
above. The retina choroid did not include the site of
administration, so this measurement indicated the level of
rapamycin delivered to the retina choroid. The average level of
rapamycin in the retina choroid at 5, 30, 60, 90, and 120 days
after intravitreal injection was about 5.36, 0.23, 1.27, 1.08, and
0.08 ng/mg, respectively.
Example 23
Preparation and Characterization of a Rapamycin-Containing
Solution
[0489] Rapamycin, ethanol and PEG 400' were added to a container to
give final concentrations by weight of about 0.4% rapamycin, 4.0%
ethanol, and 95.6% PEG 400. The mixture was sonicated for 1-2
hours. Sonication resulted in elevated temperatures of up to about
40 to 50.degree. C. This solution is listed as formulation #99 in
Table 1.
Example 24
Intravitreal Injection of a Rapamycin-Containing Solution
[0490] 100 .mu.l of the solution described in Example 23 were
injected into the vitreous of the eye of New Zealand white rabbits.
The injected solution did not form a non-dispersed mass relative to
the surrounding medium. FIG. 14 depicts the level of rapamycin in
the vitreous on a logarithmic scale at 5, 30, 60, 90, and 120 days
after injection. FIG. 15 depicts the level of rapamycin in the
retina choroid on a logarithmic scale at the same time points.
[0491] The vitreous was homogenized and analyzed as described in
Example 2. Between two and five rabbit eyes were analyzed at each
time point. The vitreous sample may have included the site of
administration. The average level of rapamycin in the vitreous at
5, 30, 60, 90, and 120 days after intravitreal injection was about
151,000; 14,890; 4,743; and 1620 ng/ml respectively.
[0492] The retina choroid was homogenized and analyzed as described
in Example 2, with the samples taken as described for the vitreous
above. The retina choroid did not include the site of
administration, so this measurement indicated the level of
rapamycin delivered to the retina choroid. The average level of
rapamycin in the retina choroid at 5, 30, 60, 90, and 120 days
after intravitreal injection was about 1.21, 1.84, 0.04, 0.71, and
0.0 ng/mg, respectively.
Example 25
Preparation and Characterization of a Rapamycin-Containing
Solution
[0493] A rapamycin containing solution was formed by placing 102.4
mg of rapamycin in ethanol, adding 4719.3 mg of PEG 400, and
vortexing. The resulting solution had final concentrations by
weight of 2.036% rapamycin, 4.154%% ethanol, and 93.81% PEG 400.
This solution is listed as formulation #139 in Table 1.
Example 26
Subconjunctival Injection of a Rapamycin-Containing Solution
[0494] 10 .mu.l of the solution described in Example 25 were
injected as a single dose between the sclera and the conjunctiva of
the eye of New Zealand white rabbits. FIG. 16 depicts the level of
rapamycin in the vitreous on a logarithmic scale at 5 and 14 days
after injection. FIG. 17 depicts the level of rapamycin in the
retina choroid on a logarithmic scale at the same time points. For
comparison, FIG. 16 and FIG. 17 also depict results of other
studies described below in Examples 27-29.
[0495] The vitreous was homogenized and analyzed as described in
Example 2. Four rabbit eyes were analyzed at each time point. The
vitreous sample did not include the site of administration, so this
measurement indicated the level of rapamycin delivered to the
vitreous. The average level of rapamycin in the vitreous at 5 and
14 days after subconjunctival injection was about 2.45 and 20.13
ng/ml, respectively.
[0496] The retina choroid was homogenized and analyzed as described
in Example 2, with the samples taken as described for the vitreous
above. The retina choroid did not include the site of
administration, so this measurement indicated the level of
rapamycin delivered to the retina choroid. The average level of
rapamycin in the retina choroid at 5 and 14 days after
subconjunctival injection was about 0.13 and 0.19 ng/mg,
respectively.
Example 27
Subconjunctival Injection of a Rapamycin-Containing Solution
[0497] 60 .mu.l of the solution described in Example 25 were
injected as a single dose between the sclera and the conjunctiva of
the eye of New Zealand white rabbits. FIG. 16 depicts the level of
rapamycin in the vitreous on a logarithmic scale at 5 and 14 days
after injection. FIG. 17 depicts the level of rapamycin in the
retina choroid on a logarithmic scale at the same time points.
[0498] The vitreous was homogenized and analyzed as described in
Example 2. Four rabbit eyes were analyzed at each time point. The
vitreous sample did not include the site of administration, so this
measurement indicated the level of rapamycin delivered to the
vitreous. The average level of rapamycin in the vitreous at 5 and
14 days after subconjunctival injection was about 17.98 and 87.03
ng/ml, respectively.
[0499] The retina choroid was homogenized and analyzed as described
in Example 2, with the samples taken as described for the vitreous
above. The retina choroid did not include the site of
administration, so this measurement indicated the level of
rapamycin delivered to the retina choroid. The average level of
rapamycin in the retina choroid at 5 and 14 days after
subconjunctival injection was about 0.27 and 0.21 ng/mg,
respectively.
Example 28
Subconjunctival Injection of a Rapamycin-Containing Solution
[0500] 60 .mu.l of the solution described in Example 25 were
injected as two 30 .mu.l doses at two sites between the sclera and
the conjunctiva of the eye of New Zealand white rabbits. FIG. 16
depicts the level of rapamycin in the vitreous on a logarithmic
scale at 5 and 14 days after injection. FIG. 17 depicts the level
of rapamycin in the retina choroid on a logarithmic scale at the
same time points.
[0501] The vitreous was homogenized and analyzed as described in
Example 2. Four rabbit eyes were analyzed at each time point. The
vitreous sample did not include the site of administration, so this
measurement indicated the level of rapamycin delivered to the
vitreous. The average level of rapamycin in the vitreous at 5 and
14 days after subconjunctival injection was about 502.2 and 31.80
ng/ml, respectively.
[0502] The retina choroid was homogenized and analyzed as described
in Example 2, with the samples taken as described for the vitreous
above. The retina choroid did not include the site of
administration, so this measurement indicated the level of
rapamycin delivered to the retina choroid. The average level of
rapamycin in the retina choroid at 5 and 14 days after
subconjunctival injection was about 0.8,0 and 0.0.15 ng/mg,
respectively.
Example 29
Subconjunctival Injection of a Rapamycin-Containing Solution
[0503] 90 .mu.l of the solution described in Example 25 were
injected as three 30 .mu.l doses at three sites between the sclera
and the conjunctiva of the eye of New Zealand white rabbits. FIG.
16 depicts the level of rapamycin in the vitreous on a logarithmic
scale at 5 and 14 days after injection. FIG. 17 depicts the level
of rapamycin in the retina choroid on a logarithmic scale at the
same time points.
[0504] The vitreous was homogenized and analyzed as described in
Example 2. Four rabbit eyes were analyzed at each time point. The
vitreous sample did not include the site of administration, so this
measurement indicated the level of rapamycin delivered to the
vitreous. The average level of rapamycin in the vitreous at 5 and
14 days after subconjunctival injection was about 39.05 and 13.63
ng/ml, respectively.
[0505] The retina choroid was homogenized and analyzed as described
in Example 2, with the samples taken as described for the vitreous
above. The retina choroid did not include the site of
administration, so this measurement indicated the level of
rapamycin delivered to the retina choroid. The average level of
rapamycin in the retina choroid at 5 and 14 days after
subconjunctival injection was about 0.83 and 0.10 ng/mg,
respectively.
Example 30
Preparation and characterization of a Rapamycin-Containing
Suspension
[0506] A rapamycin containing suspension was formed by placing
201.6 mg of rapamycin (3.000% by weight) in 6518.8 mg of PEG 400
(97.000% by weight) and vortexing. The resulting particle size was
not quantified but it was large, estimated at about 10 .mu.m. This
suspension is listed as formulation #147 in Table 1.
Example 31
Subconjunctival Injection of a Rapamycin-Containing Suspension
[0507] 10 .mu.l of the suspension described in Example 30 were
injected as a single dose between the sclera and the conjunctiva of
the eye of New Zealand white rabbits. FIG. 18 depicts the level of
rapamycin in the vitreous on a logarithmic scale at 5, 14, and 30
days after injection. FIG. 19 depicts the level of rapamycin in the
retina choroid on a logarithmic scale at the same time points. For
comparison, FIG. 18 and FIG. 19 also depict results of other
studies described below in Example 32 and Example 33.
[0508] The vitreous was homogenized and analyzed as described in
Example 2. Four rabbit eyes were analyzed at each time point. The
vitreous sample did not include the site of administration, so this
measurement indicated the level of rapamycin delivered to the
vitreous. The average level of rapamycin in the vitreous at 5, 14,
and 30 days after subconjunctival injection was about 2.68, 0.90,
and 5.43 ng/ml, respectively.
[0509] The retina choroid was homogenized and analyzed as described
in Example 2, with the samples taken as described for the vitreous
above. The retina choroid did not include the site of
administration, so this measurement indicated the level of
rapamycin delivered to the retina choroid. The average level of
rapamycin in the retina choroid at 5, 14, and 30 days after
subconjunctival injection was about 0.20, 0.06, and 1.23 ng/mg,
respectively.
Example 32
Subconjunctival Injection of a Rapamycin-Containing Suspension
[0510] 30 .mu.l of the solution described in Example 30 were
injected as a single dose between the sclera and the conjunctiva of
the eye of New Zealand white rabbits. FIG. 18 depicts the level of
rapamycin in the vitreous on a logarithmic scale at 5, 14, and 30
days after injection. FIG. 19 depicts the level of rapamycin in the
retina choroid on a logarithmic scale at the same time points.
[0511] The vitreous was homogenized and analyzed as described in
Example 2. Four rabbit eyes were analyzed at each time point. The
vitreous sample did not include the site of administration, so this
measurement indicated the level of rapamycin delivered to the
vitreous. The average level of rapamycin in the vitreous at 5, 14,
and 30 days after subconjunctival injection was about 84.55, 11.23,
and 66.35 ng/ml, respectively.
[0512] The retina choroid was homogenized and analyzed as described
in Example 2, with the samples taken as described for the vitreous
above. The retina choroid did not include the site of
administration, so this measurement indicated the level of
rapamycin delivered to the retina choroid. The average level of
rapamycin in the retina choroid at 5, 14, and 30 days after
subconjunctival injection was about 1.09, 0.19, and 1.02 ng/mg,
respectively.
Example 33
Subconjunctival Injection of a Rapamycin-Containing Suspension
[0513] 90 .mu.l of the solution described in Example 30 were
injected as three 30 .mu.l doses at three sites between the sclera
and the conjunctiva of the eye of New Zealand white rabbits. FIG.
18 depicts the level of rapamycin in the vitreous on a logarithmic
scale at 5, 14, and 30 days after injection. FIG. 19 depicts the
level of rapamycin in the retina choroid on a logarithmic scale at
the same time points.
[0514] The vitreous was homogenized and analyzed as described in
Example 2. Four rabbit eyes were analyzed at each time point. The
vitreous sample did not include the site of administration, so this
measurement indicated the level of rapamycin delivered to the
vitreous. The average level of rapamycin in the vitreous at 5, 14,
and 30 days after subconjunctival injection was about 29.95, 15.30,
and 49.20 ng/ml, respectively.
[0515] The retina choroid was homogenized and analyzed as described
in Example 2, with the samples taken as described for the vitreous
above. The retina choroid did not include the site of
administration, so this measurement indicated the level of
rapamycin delivered to the retina choroid. The average level of
rapamycin in the retina choroid at 5, 14, and 30 days after
subconjunctival injection was about 0.55, 1.31, and 5.74 ng/mg,
respectively.
Example 34
Preparation and Characterization of a Rapamycin-Containing
Solution
[0516] 10.3 mg of rapamycin was placed in ethanol, 4995.8 mg of PEG
400 was added, and the mixture was vortexed to give a solution
having final concentrations by weight of 0.205% rapamycin, 0.544%
ethanol, and 99.251% PEG 400. This solution is listed as
formulation # 140 in Table 1. A volume of 10 .mu.l of this solution
formed a non-dispersed mass when placed in the vitreous of a rabbit
eye.
Example 35
Intravitreal Injection of a Rapamycin-Containing Solution
[0517] 10 .mu.l of the solution described in Example 34 were
injected into the vitreous of the eye of New Zealand white rabbits.
The injected solution formed a non-dispersed mass relative to the
surrounding medium. FIG. 20 depicts the level of rapamycin in the
retina choroid on a logarithmic scale at 5 and 30 days after
injection. FIG. 21 depicts the level of rapamycin in the vitreous
on a logarithmic scale at the same timepoints. For comparison, FIG.
20 and FIG. 21 also depict results of other studies described below
in Example 37 and Example 39.
[0518] The vitreous was homogenized and analyzed as described in
Example 2. Five rabbit eyes were analyzed at each time point. The
vitreous sample may have included the site of administration. The
average level of rapamycin in the vitreous at 5 and 30 days after
intravitreal injection was about 12.02 and 6.92 ng/ml,
respectively.
[0519] The retina choroid was homogenized and analyzed as described
in Example 2, with the samples taken as described for the vitreous
above. The retina choroid did not include the site of
administration, so this measurement indicated the level of
rapamycin delivered to the retina choroid. The average level of
rapamycin in the retina choroid at 5 and 30 days after intravitreal
injection was about 0.08 and 0.02 ng/mg, respectively.
Example 36
Preparation and Characterization of a Rapamycin-Containing
Solution
[0520] 31.5 mg of rapamycin was placed in ethanol, 4918.9 mg of PEG
400 was added, and the solution was vortexed. Final concentrations
by weight were 0.6238% rapamycin, 1.337% ethanol, and 98.035% PEG
400. This solution is listed as formulation #142 in Table 1. The
formulation was stored at 4.degree. C. until use. A volume of 1011
of this solution formed a non-dispersed mass when placed in the
vitreous of a rabbit eye.
Example 37
Intravitreal Injection of a Rapamycin-Containing Solution
[0521] 10 .mu.l of the solution described in Example 36 were
injected into the vitreous of the eye of New Zealand white rabbits.
The injected solution formed a non-dispersed mass relative to the
surrounding medium. FIG. 20 depicts the level of rapamycin in the
retina choroid on a logarithmic scale at 5 and 30 days after
injection. FIG. 21 depicts the level of rapamycin in the vitreous
on a logarithmic scale at the same timepoints.
[0522] The vitreous was homogenized and analyzed as described in
Example 2. Five rabbit eyes were analyzed at each time point. The
vitreous sample may have included the site of administration. The
average level of rapamycin in the vitreous at 5 and 30 days after
intravitreal injection was about 87.46 and 44.34 ng/ml,
respectively.
[0523] The retina choroid was homogenized and analyzed as described
in Example 2, with the samples taken as described for the vitreous
above. The retina choroid did not include the site of
administration, so this measurement indicated the level of
rapamycin delivered to the retina choroid. The average level of
rapamycin in the retina choroid at 5 and 30 days after intravitreal
injection was about 1.40 and 0.01 ng/mg, respectively.
Example 38
Preparation and Characterization of a Rapamycin-Containing
Solution
[0524] 103.5 mg of rapamycin was placed in ethanol, 4720.8 mg of
PEG 400 was added, and the mixture was vortexed to give a solution
having final concentrations by weight of 2.057% rapamycin, 4.116%
ethanol, and 93.827% PEG 400. This solution is listed as
formulation #144 in Table 1. A volume of 10 .mu.l of this solution
formed a non-dispersed mass in the vitreous of a rabbit eye.
Example 39
Intravitreal Injection of a Rapamycin-Containing Solution
[0525] 10 .mu.l of the solution described in Example 38 were
injected into the vitreous of the eye of New Zealand white rabbits.
The injected solution formed a non-dispersed mass relative to the
surrounding medium. FIG. 20 depicts the level of rapamycin in the
retina choroid on a logarithmic scale at 5, 30, and 90 days after
injection. FIG. 21 depicts the level of rapamycin in the vitreous
on a logarithmic scale at the same timepoints.
[0526] The vitreous was homogenized and analyzed as described in
Example 2. Four rabbit eyes were analyzed at each time point. The
vitreous sample may have included the site of administration. The
average level of rapamycin in the vitreous at 5, 30, and 90 days
after intravitreal injection was about 120,500; 55,160; and 0.55
ng/ml, respectively.
[0527] The retina choroid was homogenized and analyzed as described
in Example 2, with the samples taken as described for the vitreous
above except that five rabbit eyes were analyzed at the 5 and 30
day time points. The retina choroid did not include the site of
administration, so this measurement indicated the level of
rapamycin delivered to the retina choroid. The average level of
rapamycin in the retina choroid at 5, 30, and 90 days after
intravitreal injection was about 4.75, 0.17, and 0.01 ng/mg,
respectively.
Example 40
Subconjunctival Injection of a Rapamycin-Containing Solution
[0528] 40 .mu.l of the solution described in Example 17 were
injected between the sclera and the conjunctiva of the eye of New
Zealand white rabbits. FIG. 22 depicts on a logarithmic scale the
level of rapamycin in the aqueous humor (ng/ml) at 1, 4, 7, 11, 14,
21, 28, 35, 54, and 56 days after injection, and the levels of
rapamycin in the cornea (ng/mg) and the retina choroid (ng/mg) at
4, 14, 21, and 35 days after injection. The retina choroid level is
labeled as "R/Choroid" in FIG. 22.
[0529] The aqueous humor was homogenized and then analyzed by
liquid chromatography and mass spectroscopy. Four rabbit eyes were
analyzed for each time point. The aqueous humor did not include the
site of injection, so this measurement indicated the level of
rapamycin delivered to the aqueous humor. The average level of
rapamycin in the aqueous humor at 1, 4, 7, 11, 14, 21, 28, 35, 54,
and 56 days after injection was about 0.875, 1.0, 7.0, 0.725, 0.5,
0.525, 0.0, 0.125, 0.014, and 0.0485 ng/ml, respectively.
[0530] The cornea was homogenized and then analyzed by liquid
chromatography and mass spectroscopy. The cornea did not include
the site of injection, so this measurement indicated the level of
rapamycin delivered to the cornea. Four rabbit eyes were analyzed
for each time point. The average level of rapamycin in the cornea
at 4, 14, 21, and 35 days after injection was about 0.3225, 0.1,
0.0275, and 0.0125 ng/mg, respectively.
[0531] The retina choroid was homogenized and analyzed as described
in Example 2, with the samples taken as described for the vitreous
above. The retina choroid did not include the site of
administration, so this measurement indicated the level of
rapamycin delivered to the retina choroid. The average level of
rapamycin in the retina choroid at 4, 14, 21, and 35 days after
injection was about 11.61, 0.2, 0.0275, and 2.655 ng/mg,
respectively.
Example 41
Intravitreal Injection of a Rapamycin-Containing Solution
[0532] 1.0 .mu.l of the solution described in Example 17 was
injected into the vitreous of the eye of New Zealand white rabbits.
The injected solution formed a non-dispersed mass relative to the
surrounding medium. Table 2 reports the average level of rapamycin
in the aqueous humor one day after injection. For comparison, Table
2 also reports results of studies described in Examples 42-45
below.
[0533] The aqueous humor was homogenized and analyzed as described
in Example 40. Two rabbit eyes were analyzed. The aqueous humor did
not include the site of injection, so this measurement indicated
the level of rapamycin delivered to the aqueous humor. The average
level of rapamycin in the aqueous humor at 1 day after injection
was about 0.438 ng/ml with a standard deviation of about 0.141
ng/ml.
Example 42
Intravitreal Injection of a Rapamycin-Containing Solution
[0534] 3.0 .mu.l of the solution described in Example 17 were
injected into the vitreous of the eye of New Zealand white rabbits.
The injected solution formed a non-dispersed mass relative to the
surrounding medium. Table 2 reports the average level of rapamycin
in the aqueous humor one day after injection.
[0535] The aqueous humor was homogenized and analyzed as described
in Example 40. Two rabbit eyes were analyzed. The aqueous humor did
not include the site of injection, so this measurement indicated
the level of rapamycin delivered to the aqueous humor. The average
level of rapamycin in the aqueous humor at 1 day after injection
was about 0.355 ng/ml with a standard deviation of about 0.234
mg/ml.
Example 43
Subconjunctival Injection of a Rapamycin-Containing Solution
[0536] 3.0 .mu.l of the solution described in Example 17 were
injected between the sclera and the conjunctiva of the eye of New
Zealand white rabbits. The injected solution formed a non-dispersed
mass relative to the surrounding medium. Table 2 reports the
average level of rapamycin in the aqueous humor one day after
injection.
[0537] The aqueous humor was homogenized and analyzed as described
in Example 40. Two rabbit eyes were analyzed. The aqueous humor did
not include the site of injection, so this measurement indicated
the level of rapamycin delivered to the aqueous humor. The average
level of rapamycin in the aqueous humor at 1 day after injection
was about 0.338 ng/ml with a standard deviation of about 0.122
ng/ml.
Example 44
Anterior Chamber administration of a Rapamycin-Containing
Solution
[0538] 5.0 .mu.l of the solution described in Example 17 were
injected into the anterior chamber of the eye of New Zealand white
rabbits by injection into the front-end of the eye. The aqueous
humor was withdrawn using a syringe. Table 2 reports the average
level of rapamycin in the aqueous humor 14 days after
injection.
[0539] The aqueous humor was homogenized and analyzed as described
in Example 40. Two rabbit eyes were analyzed. The aqueous humor did
not include the site of injection, so this measurement indicated
the level of rapamycin delivered to the aqueous humor. The average
level of rapamycin in the aqueous humor at 14 days after injection
was about 0.166 ng/ml with a standard deviation of about 0.183
ng/ml.
Example 45
Anterior Chamber Administration of a Rapamycin-Containing
Solution
[0540] 10 .mu.l of the solution described in Example 17 were
injected into the anterior chamber of the eye of New Zealand white
rabbits. Table 2 reports the average level of rapamycin in the
aqueous humor 14 days after injection.
[0541] The aqueous humor was homogenized and analyzed as described
in Example 40. Two rabbit eyes were analyzed. The aqueous humor did
not include the site of injection, so this measurement indicated
the level of rapamycin delivered to the aqueous humor. The average
level of rapamycin in the aqueous humor at 14 days after injection
was about 0.004 ng/ml with a standard deviation of about 0.006
ng/ml.
[0542] All references cited herein, including patents, patent
applications, and publications, are hereby incorporated by
reference in their entireties, whether previously specifically
incorporated or not. TABLE-US-00001 TABLE 1 Liquid Formulations
Formation Median of NDM, Form. Formulation particle Injection #
Composition (mg), % (w/w) Type size volume 1 DMSO = 2000 mg (20%) S
Water = 8000 mg (80%) 2 F68 = 1000 mg (10%) S Water = 9000 mg (90%)
3 F68 = 3000 mg (30%) S Water = 7000 mg (70%) 4 F127 = 1000 mg
(10%) S Water = 9000 mg (90%) 5 F127 = 1500 mg (15%) S Water = 8500
mg (85%) 6 Beta-cyclodextrin = 250 mg (2.5%) S Water = 9750 mg
(97.5%) 7 Rapa = 10.2 mg (0.101%) S No, 50 .mu.L Pluronic, F68 =
1010 mg (9.99%) Water = 9090 mg (89.909%) 8 Rapa = 10.2 mg (0.102%)
S No, 50 .mu.L Pluronic, F68 = 3000 mg (29.969%) Water = 7000 mg
(69.929%) 9 Rapa = 10.5 mg (0.104%) S No, 50 .mu.L Pluronic, F127 =
1010 mg (9.99%) Water = 9090 mg (89.907%) 10 Rapa = 10.5 mg
(0.105%) S No, 50 .mu.L Pluronic, F127 = 1500 mg (14.984%) Water =
8925 mg (84.9%) 11 Rapa = 10.7 mg (0.105%) S No, 50 .mu.L
Beta-cyclodextrin = 255 mg (2.497%) Water = 9945 mg (97.398%) 12
Rapa = 6.4 mg (0.0999%) SP CMC = 48 mg (0.7493%) Polysorbitan 20 =
2.56 mg (0.04%) Water = 6349.44 mg (99.111%) 13 Rapa = 6.5 mg
(0.0999%) S DMSO = 325 mg (4.995%) Water = 6175 mg (94.905%) 14
Rapa = 13.5 mg (0.0999%) SP CMC = 101.25 mg (0.7493%) Polysorbitan
20 = 5.4 mg (0.04%) Water = 13393.35 mg (99.112%) 15 Rapa = 11.0 mg
(0.2%) S EtOH = 5500 mg (99.8%) 16 Rapa = 6.6 mg (0.1%) S EtOH =
1054.6 mg (15.933%) F127 = 833.64 mg (12.595%) Water = 4723.96 mg
(71.372%) 17 Rapa = 5 mg (0.1%) S Cavitron = 0.25 g (5%) Ethanol,
95% = 57 mg (1.1%) Sterile water = 4.753 g (93.8%) 18 Rapa = 5 mg
(0.1%) S Ethanol, 95% = 150 mg (2.9%) PEG400 = 1.0 g (19.4%)
Sterile water = 4.01 g (77.6%) 19 Rapa = 5 mg (0.1%) S Yes, 50
.mu.L Ethanol, 95% = 152 mg (3.2%) PEG400 = 1.5227 g (30.2%)
Sterile water = 3.3592 g (66.67%) 20 Rapa = 6.6 mg (0.1%) S EtOH =
505.1 mg (7.618%) F127 = 917.8 mg (13.843%) Water = 5200.6 mg
(78.44%) 21 Rapa = 6.6 mg (0.1%) S No, 50 .mu.L EtOH = 536 mg
(7.5%) Pluronic, F127 = 983.75 mg (14.0%) Water = 5574.56 mg
(78.4%) 22 Rapa = 5.2 mg (0.1023%) S EtOH = 56.6 mg (1.127%)
Captisol = 2008.9 mg (39.5%) Water = 3013.3 mg (59.3%) 23 Rapa =
6.9 mg (0.201%) S EtOH = 3418.0 mg (99.799%) 24 Rapa = 9.1 mg
(0.491%) S EtOH = 90.9 mg (4.908%) F127 = 262.8 mg (14.191%) Water
= 1489.1 mg (80.409%) 25 Rapa = 0 mg (0%) S EtOH = 310.2 mg
(5.144%) F127 = 858.1 mg (14.228%) Water = 4862.6 mg (80.628%) 26
Rapa = 0 mg (0%) S EtOH = 613.1 mg (10.19%) F127 = 810.6 mg
(13.471%) Water = 4593.6 mg (76.339%) 27 Rapa = 53.5 mg (1.095%) S
Yes, 50 .mu.L EtOH = 414.8 mg (8.488%) F127 = 662.8 mg (13.563%)
Water = 3755.7 mg (76.854%) 28 Rapa = 0.3 g (10%) ISG, SP PVP K90 =
0.35 g (12%) Eudragit RS30D = 2.35 g (78%) 29 Rapa = 0.2154 g
(7.31%) ISG, SP PVP K90 = 0.25 g (8.5%) Eudragit RS30D = 2.48 g
(84.19%) 30 Rapa = 53.9 mg (1.103%) S No, 50 .mu.L EtOH = 413.6 mg
(8.463%) Sterile water = 3843.5 mg (78.647%) F127 (Lutrol) = 576.0
mg (11.786%) 31 Rapa = 0 mg (0%) S EtOH = 411.9 mg (8.513%) Sterile
Water = 3849.3 mg (79.554%) F127(Lutrol) = 577.4 mg (11.933%) 32
Rapa = 54.1 mg (1.256%) S EtOH = 416.8 mg (9.676%) Sterile Water =
3836.3 mg (78.569%) F127(Lutrol) = 577.5 mg (10.499%) 33 Rapa =
80.7 g (1.964%) S EtOH = 65.0 mg (0.158%) PEG400 = 4021.8 mg
(97.878%) 34 Rapa = 106.9 g (5.233%) S Yes, 25 .mu.L EtOH = 129.6
mg (6.344%) PEG400 = 1806.5 mg (88.424%) 35 Rapa = 0 mg (0%) ISG,
SP PVP K90 = 0.204 g (2.3%) Ethanol, 100% = 0.4 g (4.5%) Eudragit
RL100 = 0.201 g (2.3%) PEG 400 = 8.00 g (90.9%) 36 Rapa = 0 mg (0%)
ISG, SP PVP K90 = 0.2 g (2.2%) Ethanol, 100% = 0.4 g (4.4%) PVAP =
0.4 g (4.4%) PEG 400 = 8.00 g (88.9%) 37 Rapa = 106.1 mg (4.2%)
ISG, SP PVP K90 = 55.2 mg (2.2%) Ethanol, 100% = 108 mg (4.3%)
Eudragit RL100 = 55 mg (2.2%) PEG 400 = 2.2 g (87.1%) 38 Rapa =
399.6 mg (9.965%) S Yes, 20 .mu.L F68(Lutrol) = 40.6 mg (1.012%)
Sterile Water = 3569.7 mg (89.022%) 39 Rapa = 53.8 mg (1.1%) S EtOH
= 415.2 mg (8.489%) Sterile Water = 3844.2 mg (78.594%) F127 =
578.0 mg (11.817%) 40 Rapa = 208.1 mg (3.148%) S Yes, 20 .mu.L
PEG400 = 6403.4 mg (96.852%) 41 Rapa = 200.4 mg (5.148%) SP
F68(Lutrol) = 20.8 mg (0.534%) PEG400 = 3569.3 mg (91.697%) EtOH
(95%) = 102 mg (2.62%) 42 Rapa = 200.4 g (5.259%) SP PEG400 =
3561.4 mg (93.46%) Tween 80 = 48.8 mg(1.281%) 43 Rapa = 30.9 mg
(1.03%) S No, 50 .mu.L PEG 400 = 2.9624 g (98.97%) 44 Rapa = 61 mg
(1.96%) S Yes, 50 .mu.L Ethanol, 100% = 0.1860 g (6%) PEG 400 =
2.8588 g (92.04%) 45 Rapa = 90.7 mg (3.02%) S Yes, 50 .mu.L
Ethanol, 100% = 0.2722 g (9.06%) PEG 400 = 2.6423 g (87.94%) 46
Rapa = 101.6 mg (4.997%) S EtOH = 331.6 mg (16.308%) PEG400 =
1600.1 mg (78.695%) 47 Rapa = 120.9 g (3.189%) SP F68(Lutrol) =
42.4 mg (1.118%) Sterile Water = 3627.7 mg (95.692%) 48 Rapa =
100.1 g (1.999%) S EtOH = 305.1 mg (6.092%) PEG400 = 4602.9 mg
(91.909%) 49 Rapa = 150.5 mg (3.004%) SP Yes, 20 .mu.L, 40 .mu.L
PEG400 = 4860.3 mg (96.996%) 50 Rapa = 153.4 mg (3.055%) SP No, 20
.mu.L F68(Pluronic) = 50.6 mg (1.008%) Sterile Water = 4816.6 mg
(95.937%) 51 Rapa = 116.6 mg (2.29%) S Yes, 30 .mu.L EtOH = 306.6
mg (6.05%) PEG400 = 4647.5 mg (91.66%) 52 Rapa = 150.4 mg (2.994%)
SP F68 Lutrol = 15.4 mg (0.306%) Sterile water = 4859.1 mg (96.7%)
53 Rapa = 306.5 mg (6.088%) SP PEG 400 = 4727.7 mg (93.912%) 54
Rapa = 309.3 mg (6.146%) SP PEG 400 = 4723.3 mg (93.854%) 55 Rapa =
303.3 mg (6.061%) SP PEG 400 = 4700.6 mg (93.939%) 56 Rapa = 305.4
mg (6.088%) SP PEG 400 = 4711.0 mg (93.912%) 57 Rapa = 306.9 mg
(6.098%) SP PEG 400 = 4725.5 mg (93.902%) 58 Rapa = 302.5 mg
(6.021%) SP PEG 400 = 4721.6 mg (93.979%) 59 Rapa = 304.5 mg
(6.053%) SP PEG 400 = 4726.4 mg (93.947%) 60 Dexamethasone = 251.4
mg SP (5.011%) PEG 400 = 4765.2 mg (94.989%) 61 Dexamethasone =
252.4 mg (5%) SP PEG 400 = 4600 mg (92%) EtOH = 150 mg (3%) 62 Rapa
= 32.2 mg (0.641%) S PEG 400 = 4677.9 mg (93.096%) EtOH = 314.7 mg
(6.263%) 63 Rapa = 32.3 mg (0.6%) S PEG 400 = 5516.3 mg (93.1%)
EtOH = 314.7 mg (6.263%) 64 Rapa = 54.4 mg (1.007%) S PEG 400 =
4638.9 mg (92.702%) EtOH = 314.8 mg (6.291%) 65 Rapa = 50.8 mg
(1.013%) S PEG 400 = 4963.2 mg (98.987%) 66 Rapa = 52.1 mg (1.035%)
S PEG 400 = 4868.6 mg (96.718%) EtOH = 113.1 mg (2.247%) 67 Rapa =
50.5 mg (1.009%) S Yes, 20 .mu.L PEG 400 = 4752.8 mg (94.953%) No,
40 .mu.L, 100 .mu.L EtOH = 202.1 mg (4.038%) 68 Rapa = 101.8 mg
(2.030%) S PEG 400 = 4712.4 mg (93.970%) EtOH = 200.6 mg (4.000%)
69 Rapa = 102.1 mg (2.036%) S PEG 400 = 4605.5 mg (91.847%) EtOH =
306.7 mg (6.117%) 70 Rapa = 101.6 mg (2.025%) S PEG 400 = 4510.6 mg
(89.892%) EtOH = 405.6 mg (8.083%) 71 Rapa = 75.9 mg (3.019%) SP
PEG 400 = 2438.4 mg (96.981%) 72 Rapa = 50.9 mg (2.034%) S PEG 400
= 2350.1 mg (93.914%) EtOH = 101.4 mg (4.052%) 73 Rapa = 12.5 mg
(0.620%) SP PEG 400 = 2004.8 mg (99.380%) 74 Rapa = 1.20949 g
(2.0152%) S EtOH = 2.401 g (4.000%) PEG 400 = 56.407 g (93.9848%)
75 Rapa = 16.0 mg g (0.795%) S No, 50 .mu.L EtOH = 80.0 mg (3.976%)
PEG 400 = 1916.0 mg (95.2298%) 76 Rapa = 8.1 mg (0.400%) SP PEG 400
= 2014.5 mg (99.600%) 77 Rapa = 8.6 mg (0.428%) S PEG 400 = 2002.5
mg (99.572%) 78 Rapa = 8.2 mg (0.410%) S PEG 400 = 1992.0 mg
(99.590%) 79 Rapa = 8.7 mg (0.433%) S PEG 400 = 1998.8 mg (99.567%)
80 Rapa = 8.6 mg (0.427%) S PEG 400 = 2003.2 mg (99.573%)
81 Rapa = 8.6 mg (0.428%) S PEG 400 = 1999.3 mg (99.572%) 82 Rapa =
9.0 mg (0.448%) S PEG 400 = 2000.8 mg (99.552%) 83 Rapa = 8.0 mg
(0.397%) S PEG 400 = 2008.8 mg (99.603%) 84 Rapa = 8.5 mg (0.422%)
S PEG 400 = 2006.8 mg (99.578%) 85 Rapa = 8.0 mg (0.399%) S PEG 400
= 1998.2 mg (99.601%) 86 Rapa = 8.5 mg (0.422%) S PEG 400 = 2004.3
mg (99.578%) 87 Rapa = 8.6 mg (0.428%) S PEG 400 = 2002.5 mg
(99.572%) 88 Rapa = 0.7 g (1.983%) S EtOH = 1.4 g (3.966%) PEG 400
= 33.2 g (94.051%) 89 Rapa = 0 g (0%) S EtOH = 0.574 g (1.995%) PEG
400 = 28.2 g (98.005%) 90 Rapa = 1.95 g (1.950%) S EtOH = 4.05 g
(4.050%) PEG 400 = 94.00 g (94000.%) 91 Rapa = 0.0107 g (0.534%) S
No, 80 .mu.L EtOH = 0.0805 g (4.019%) PEG 400 = 1.912 g (95.447%)
92 Rapa = 0.0081 g (0.403%) S No, 100 .mu.L EtOH = 0.0804 g
(4.003%) PEG 400 = 1.920 g (95.594%) 93 Rapa = 1.992 g (2%) S EtOH
= 3.9419 (4%) PEG 400 = 93.95 g (94%) 94 Rapa = 0.405 g (0.4%) S
EtOH = 4.24 g (4%) PEG 400 = 95.6 (95.6%) 95 PEG 400 = 96 g (96%) S
EtOH = 3.9027 (4%) 96 Rapa = 0.4020 g (0.402%) S EtOH = 3.970 g
(3.971%) PEG 400 = 95.600 g (95.627%) 97 Rapa = 2.000 g (1.990%) S
EtOH = 4.000 g (3.980%) PEG 400 = 94.500 g (94.030%) 98 PEG 400 =
96 g (96%) S EtOH = 3.92 g (4%) 99 Rapa = 0.4036 g (0.4%) S No, 100
.mu.L EtOH = 3.9054 g (4%) PEG 400 = 95.6 (95.6%) 100 Rapa = 2.0025
g (2%) S Yes, 1 .mu.L, 3 .mu.L, 20 .mu.L, EtOH = 3.98 g (4%) 40
.mu.L PEG 400 = 94.00 g (94%) 101 Rapa = 9.5 mg (0.472%) S EtOH =
90.3 mg (4.485%) PEG 600 = 1913.5 mg (95.043%) 102 Rapa = 44.6 mg
(2.21%) S EtOH = 86.1.0 mg (4.26%) PEG 600 = 1891.1 mg (93.53%) 103
Rapa = 1.97 g (2%) S EtOH = 4.10 g (4%) PEG 400 = 94.15 g (94%) 104
Rapa = 1.95 g (2%) S EtOH = 4.00 g (4%) PEG 400 = 94.0 g (94%) 105
Rapa = 8.00 g (2%) S PEG 400 = 376.0 g EtOH = 16.0 g (4%) 106 Rapa
= 6.00 g (2%) S PEG 400 = 282.0 g (94%) EtOH = 12.0 g (4%) 107 Rapa
= 8.9 mg (0.4434%) S EtOH = 80.3 mg (4.0006%) PEG 300 = 1918.0 mg
(95.556%) 108 Rapa = 40.8 mg (2.00886%) S EtOH = 110.0 mg
(5.41605%) PEG 300 = 1880.2 mg (92.57509%) 109 Rapa = 9.9 mg
(0.488%) S EtOH = 86.7 mg (4.277%) PEG 400/300(50/50) = 1930.3 mg
(95.235%) 110 Dexamethasone = 142.5 mg SP 0.3305 .mu.m Yes, 30
.mu.L (4.994%) PEG 400 = 2710.7 mg (95.006%) 111 Dexamethasone =
134.3 mg SP >10 .mu.m (4.891%) PEG 400 = 2611.4 mg (95.109%) 112
Triamcinolone = 139.2 mg (5.087%) SP 3.98 .mu.m Yes, 30 .mu.L PEG
400 = 2597.4 mg (94.913%) 113 Triamcinolone = 135.3 mg (5.089%) SP
>10 .mu.m PEG 400 = 2523.5 mg (94.911%) 114 EtOH = 206.4 mg
(4.121%) S No, 30 .mu.L PEG 400 = 4801.6 mg (95.879%) 115 Rapa =
43.0 mg (2.144%) SP 61.4390 .mu.m PEG 400 = 1962.3 mg (97.8567%)
116 Rapa = 40.0 mg (2.001%) SP 3.7128 .mu.m PEG 400 = 1959.1 mg
(97.999%) 117 Rapa = 42.9 mg (2.142%) SP 2.7313 .mu.m PEG 400 =
1959.7 mg (97.858%) 118 Rapa = 100.8 mg (2.013%) SP 4.1063 .mu.m
PEG 400 = 4906.0 mg (97.987%) 119 Rapa = 20.9 mg (0.42%) S EtOH =
209.1 mg (4.17%) PEG 400 = 4784.9 mg (95.41%) 120 Rapa = 20.6 mg
(0.41%) S EtOH = 211.5 mg (4.22%) Benz. Chl = 19.1 mg (0.38%) PEG
400 = 4762.0 mg (94.99%) 121 Rapa = 20.1 mg (0.40%) S EtOH = 211.5
mg (4.22%) Benz. Chl = 2.3 mg (0.05%) PEG 400 = 4782.3 mg (95.34%)
122 Rapa = 8.0 g (2%) S EtOH = 16.0 g (4%) PEG 400 = 376.0 g (94%)
123 Rapa = 351.3 mg (2.006%) S EtOH = 2353.1 mg (4.093%) PEG 400 =
16448.2 mg (93.901%) 124 Rapa = 2.2035 g (2%) S EtOH = 4.45 g (4%)
PEG 400 = 103.7 g (94%( 125 Rapa = 515.5 mg (2.021%) SP 18.1453
.mu.m PEG 400 = 24,993.8 mg (97.979%) 126 Rapa = 0.3 g (2%) S EtOH
= 0.6 g (4%) PEG 400 = 14.1 g (94%) BHT = 0.0002 (0.002%) 127 Rapa
= 0.3 g (2%) S EtOH = 0.6 g (4%) PEG 400 = 14.1 g (94%) BHT =
0.00037 (0.004%) 128 Rapa = 0.3 g (2%) S EtOH = 0.6 g (4%) PEG 400
= 14.1 g (94%) BHT = 0.0081 (0.05%) 129 Rapa = 243.2 mg (1.869%) S
EtOH = 4.88.4 mg (3.753%) PEG 400 = 12283.3 mg (94.378%) 130 Rapa =
0.404 g (2%) S EtOH = 0.8 g (4%) PEG 400 = 18.8 g (94%) BHT =
0.00051 (0.002%) 131 Rapa = 0.6024 g (2%) S EtOH = 1.2 g (4%) PEG
400 = 28.25 g (94%) 132 Rapa = 2.001 g (2%) S EtOH = 4.05 g (4%)
PEG 400 = 94.45 g (94%) 133 Rapa = 0.5155 g (2.057%) S EtOH =
1.0198 g (4.070%) PEG 400 = 23.5225 g (93.873%) 134 PEG 400 = 9.6 g
(96%) S EtOH = 0.4 g (4%) 135 Rapa = 0.610 g (2%) S EtOH = 1.2 g
(4%) PEG 400 = 28.2 g (94%) 136 Rapa = 24.6 mg (1.193%) S EtOH =
91.1 mg (4.418%) Tyloxapol = 219.6 mg (10.649%) BSS = 1726.8 mg
(83.740%) 137 Rapa = 100.0 mg (1.993%) SP PEG 400 = 4916.9 mg
(98.007%) 138 Rapa = 201.6 mg (4.005%) SP PEG 400 = 4831.5 mg
(95.995%) 139 Rapa = 102.4 mg (2.036%) S EtOH = 209.0 mg (4.154%)
PEG 400 = 4719.3 mg (93.810%) 140 Rapa = 10.3 mg (0.205%) S Yes, 10
.mu.L EtOH = 27.4 mg (0.544%) PEG 400 = 4995.8 mg (99.251%) 141
Rapa = 10.6 mg (0.211%) S No, 10 .mu.L EtOH = 208.4 mg (4.150%) PEG
400 = 4802.3 mg (95.639%) 142 Rapa = 31.5 mg (0.628%) S Yes, 10
.mu.L EtOH = 67.1 mg (1.337%) PEG 400 = 4918.9 mg (98.035%) 143
Rapa = 30.8 mg (0.613%) S No, 10 .mu.L, 100 .mu.L EtOH = 204.5 mg
(4.073%) PEG 400 = 4786.1 mg (95.314%) 144 Rapa = 103.5 mg (2.057%)
S Yes, 10 .mu.L EtOH = 207.1 mg (4.116%) PEG 400 = 4720.8 mg
(93.827%) 145 Rapa = 283.0 mg (2.020%) S EtOH = 566.1 mg (4.041%)
PEG 400 = 13,160.8 mg (93.939%) 146 Rapa = 280.1 mg (1.998%) S EtOH
= 565.2 mg (4.033%) PEG 400 = 13,171.7 mg (93.969%) 147 Rapa =
201.6 mg (3.000%) SP PEG 400 = 6518.8 mg (97.000%) 148 Rapa = 31.9
mg (1.019%) S Benzyl Alcohol = 1021.9 mg (20.070%) Sesame Oil =
4017.9 mg (78.911%) 149 Rapa = 51.5 mg (1.03%) S Benzyl Alcohol =
259.9 mg (5.19%) Sesame Oil = 4694.3 mg (93.78%) 150 Rapa = 5.96 g
(2%) S EtOH = 12.0 g (4%) PEG 400 = 282.0 g (94%) 151 Rapa = 54.5
mg (1.07%) S Benzyl Alcohol = 1014.3 mg (19.95%) Olive Oil = 4014.8
mg (78.98%) 152 Rapa = 0 mg (0.00%) S Benzyl Alcohol = 269.4 mg
(5.421%) Tyloxapol = 608.2 mg (12.238%) Sesame Oil = 4092.2 mg
(82.341%) 153 Rapa = 76.3 mg (1.75%) S Benzyl Alcohol = 307.0 mg
(7.06%) Tyloxapol = 607.8 mg (13.97%) Sesame Oil = 3000.5 mg
(68.97%) Span 80 = 63.1 mg (1.45%) EtOH = 295.5 mg (6.79%) 154
Form. # 150 = 200 g (99.998) S BHT = 0.004 g (0.002%) 155 Rapa =
51.0 mg (0.87%) S EtOH = 642.3 mg (10.93%) Benzyl Alcohol = 431.8
mg (7.34%) Sesame Oil = 4753.7 mg (80.86%) 156 Rapa = 51.4 mg
(1.03%) S Benzyl Alcohol = 518.4 mg (10.34%) Olive Oil = 4444.7 mg
(88.64%) 157 Rapa = 8.1 g (2%) S EtOH = 16.0 g (4%) PEG 400 = 376.0
g (94%) 158 Form. # 157 = 225.00 g (99.998%) S BHT = 0.0045 g
(0.002%) 159 Rapa = 8.1 g (2%) S EtOH = 16.0 g (4%) PEG 400 = 376 g
(94%) 160 Form. # 159 = 112.0 g (99.998%) S BHT = 0.00224 g
(0.002%) 161 Form. # 159 = 112.0 g (99.998%) S BHT = 0.0019 g
(0.002%) 162 Rapa = 55.4 mg (1.10%) S EtOH = 112.7 mg (2.25%)
Benzyl Alcohol = 157.8 mg (3.15%) Cotton Seed Oil = 4688.0 mg
(93.50%) 163 Rapa = 5.005 g (1%) S EtOH = 10.0 g (2%) PEG 400 =
485.5 g (97%) 164 PEG 400 = 9.82 g (98%) S EtOH = 0.235 g (2%) 165
Form. # 163 = 100.25 g (99.998%) S BHT = 0.0026 g (0.002%) 166 Rapa
= 203.1 mg (2.025%) SP 2.8651 .mu.m F68 = 30.3 mg (0.303%) Sterile
Water = 9792.6 mg (97.672%) 167 Rapa = 201.4 mg (2.0005%) SP 1.0984
.mu.m Tween 20 = 43.9 mg (0.436%) Sterile Water = 9822.8
mg.(97.564%) 168 EtOH = 0.8301 g (4.144%) S
PEG 400 = 19.2014 g (95.856%) 169 Form. # 168 = 300 .mu.l S 170
Form. # 168 = 250 .mu.l S Form. # 154 = 50 .mu.l 171 Form. # 168 =
200 .mu.l S Form. # 154 = 100 .mu.l 172 Form. # 168 = 150 .mu.l S
Form. # 154 = 150 .mu.l 173 Form. # 154 = 300 .mu.l S 174 Rapa =
102.2 mg (2.041%) SP 0.4165 .mu.m F68 = 16.0 mg (0.32%) Sterile
Water = 4889.0 mg (97.639%) 175 Rapa = 101.1 mg (2.010%) SP 0.5294
.mu.m Tween 20 = 27.7 mg (0.551%) Sterile Water = 4901.0 mg
(97.439%) 176 BSS+ = 0 .mu.l S Sterile Water = 0 .mu.l Form. # 154
= 1000 .mu.l 177 BSS+ = 200 .mu.l SP Sterile Water = 0 .mu.l Form.
# 154 = 800 .mu.l 178 BSS+ = 400 .mu.l SP Form. # 154 = 600 .mu.l
179 BSS+ = 500 .mu.l SP Form. # 154 = 500 .mu.l 180 BSS+ = 600
.mu.l SP Form. # 154 = 400 .mu.l 181 BSS+ = 800 .mu.l SP Form. #
154 = 200 .mu.l 182 Sterile Water = 200 .mu.l SP Form. # 154 = 800
.mu.l 183 Sterile Water = 400 .mu.l SP Form. # 154 = 600 .mu.l 184
Sterile Water = 500 .mu.l SP Form. # 154 = 500 .mu.l 185 Sterile
Water = 600 .mu.l SP Form. # 154 = 400 .mu.l 186 Sterile Water =
800 .mu.l SP Form. # 154 = 200 .mu.l 187 BSS+ = 2536.9 mg (49.98%)
SP 60.2075 .mu.m Form. # 154 = 2538.7 mg (50.02%) 188 Sterile Water
= 2515.6 mg (49.84%) SP 617.5157 .mu.m Form. # 154 = 2532.2 mg
(50.16%) 189 F68 = 12.6 mg (0.25%) SP 70.6089 .mu.m Sterile Water =
2524.7 mg (49.79%) Form. # 154 = 2533.1 mg (49.96%) 190 Rapa =
2.0225 g (2%) S EtOH = 3.65 g (4%) PEG 400 = 94.0 g (94%) BHT =
0.002 g (0.002%) 191 F68 = 12.1 mg SP Sterile Water = 2558.9 mg
Form. # 154 = 2556.4 mg 192 F68 = 19.8 mg SP Sterile Water = 2564.1
mg Form. # 154 = 25557.5 mg 193 F68 = 25.3 mg SP Sterile Water =
2575.1 mg Form. # 154 = 2572.9 mg 194 F68 = 32.4 mg SP Sterile
Water = 2572.1 mg Form. # 154 = 2562.1 mg 195 F68 = 38.3 mg SP
Sterile Water = 2563.2 mg Form. # 154 = 2573.5 mg 196 F68 = 43.6 mg
SP Sterile Water = 2541.1 mg Form. # 154 = 2556.0 mg 197 F68 = 51.2
mg SP Sterile Water = 2594.5 mg Form. # 154 = 2594.1 mg 198 PEG 400
= 1920 g (96%) S EtOH = 80 g (4%) 199 Form. # 168 = 1000 .mu.l S
200 Form. # 168 = 200 .mu.l S Form. # 154 = 800 .mu.l 201 Form. #
168 = 400 .mu.l S Form. # 154 = 600 .mu.l 202 Form. # 168 = 500
.mu.l S Form. # 154 = 500 .mu.l 203 Form. # 168 = 600 .mu.l S Form.
# 154 = 400 .mu.l 204 Form. # 168 = 800 .mu.l S Form. # 154 = 200
.mu.l 205 PEG 400 = 200 .mu.l S Form. # 154 = 800 .mu.l 206 PEG 400
= 400 .mu.l S Form. # 154 = 600 .mu.l 207 PEG 400 = 500 .mu.l S
Form. # 154 = 500 .mu.l 208 PEG 400 = 600 .mu.l S Form. # 154 = 400
.mu.l 209 PEG 400 = 800 .mu.l S Form. # 154 = 200 .mu.l 210 Phosal
50PG = 6735.0 mg (99.002%) S Tween 80 = 67.9 mg (0.998%) 211 Rapa =
2.0047 g (2%) S EtOH = 4.00 g (4%) PEG 400 = 94.05 g (94%) 212
Phosal 50PG = 20.0662 g (98.999%) S Tween 80 = 0.2029 g (1.001%)
213 Form. # 154 = 100 .mu.l S Form. # 168 = 900 .mu.l 214 Form. #
154 = 100 .mu.l S Form. # 168 = 900 .mu.l 215 Form. # 154 = 100
.mu.l S Form. # 168 = 900 .mu.l 216 Form. # 154 = 100 .mu.l S PEG
400 = 900 .mu.l 217 Form. # 154 = 100 .mu.l S PEG 400 = 900 .mu.l
218 Form. # 154 = 100 .mu.l S PEG 400 = 900 .mu.l 219 Form. # 154 =
100 .mu.l SP BSS+ = 900 .mu.l 220 Form. # 154 = 100 .mu.l SP BSS+ =
900 .mu.l 221 Form. # 154 = 100 .mu.l SP BSS+ = 900 .mu.l 222 Form.
# 154 = 1000 .mu.l S 223 Form. # 154 = 1000 .mu.l S 224 Form. # 154
= 100 .mu.l S Form. # 168 = 900 .mu.l 225 Form. # 154 = 100 .mu.l S
Form. # 168 = 900 .mu.l 226 Form. # 154 = 100 .mu.l S Form. # 168 =
900 .mu.l 227 Form. # 154 = 100 .mu.l S PEG 400 = 900 .mu.l 228
Form. # 154 = 100 .mu.l S PEG 400 = 900 .mu.l 229 Form. # 154 = 100
.mu.l S PEG 400 = 900 .mu.l 230 Form. # 154 = 100 .mu.l SP BSS+ =
900 .mu.l 231 Form. # 154 = 100 .mu.l SP BSS+ = 900 .mu.l 232 Form.
# 154 = 100 .mu.l SP BSS+ = 900 .mu.l 233 Form. # 154 = 200 .mu.l S
Form. # 168 = 800 .mu.l 234 Form. # 154 = 200 .mu.l S Form. # 168 =
800 .mu.l 235 Form. # 154 = 200 .mu.l S Form. # 168 = 800 .mu.l 236
Form. # 154 = 200 .mu.l S Form. # 168 = 800 .mu.l 237 Form. # 154 =
200 .mu.l S PEG 400 = 800 .mu.l 238 Form. # 154 = 200 .mu.l S PEG
400 = 800 .mu.l 239 Form. # 154 = 200 .mu.l SP BSS+ = 800 .mu.l 240
Form. # 154 = 200 .mu.l SP BSS+ = 800 .mu.l 241 Form. # 154 = 200
.mu.l SP BSS+ = 800 .mu.l 242 Form. # 154 = 100 .mu.l S No, 10
.mu.L Form. # 168 = 900 .mu.l 243 Form. # 154 = 100 .mu.l S Yes, 10
.mu.L PEG 400 = 900 .mu.l 244 Form. # 154 = 100 .mu.l SP Yes, 10
.mu.L BSS+ = 900 .mu.l 245 Form. # 154 = 100 .mu.l SP
BSS+/CMC(0.5%) = 900 .mu.l 246 Form. # 154 = 400 .mu.l S No, 10
.mu.L Form. # 168 = 900 .mu.l 247 Form. # 154 = 400 .mu.l S Yes, 10
.mu.L PEG 400 = 900 .mu.l 248 Form. # 154 = 400 .mu.l SP Yes, 10
.mu.L BSS+ = 900 .mu.l 249 Form. # 154 = 400 .mu.l SP
BSS+/CMC(0.5%) = 900 .mu.l 250 Form. # 154 = 100 .mu.l SP
BSS+/CMC(0.5%) = 900 .mu.l 251 Form. # 154 = 100 .mu.l SP
BSS+/CMC(0.5%) = 900 .mu.l 252 Form. # 154 = 100 .mu.l SP
BSS+/CMC(0.5%) = 900 .mu.l 253 Form. # 154 = 200 .mu.l SP
BSS+/CMC(0.5%) = 800 .mu.l 254 Form. # 154 = 200 .mu.l SP
BSS+/CMC(0.5%) = 800 .mu.l 255 Form. # 154 = 200 .mu.l SP
BSS+/CMC(0.5%) = 800 .mu.l 256 Form. # 154 = 400 .mu.l SP
BSS+/CMC(0.5%) = 900 .mu.l 257 Form. # 154 = 400 .mu.l SP
BSS+/CMC(0.5%) = 900 .mu.l 258 Form. # 154 = 400 .mu.l SP
BSS+/CMC(0.5%) = 900 .mu.l 259 EtOH = 17.1 mg (0.57%) S PEG 400 =
2997.3 mg (99.43%) 260 EtOH = 40.8 mg (1.35%) S PEG 400 = 2980.2 mg
(98.65%) 261 EtOH = 47.1 mg (1.57%) S PEG 400 = 2950.1 mg (98.43%)
262 Rapa = 2.0032 g (2%) S EtOH = 3.92 g (4%) PEG 400 = 94.00 g
(94%) 263 Triamcinolone acetomide = 80.8 mg SP (4.04%) PEG 400 =
1920.8 mg (95.96%) 264 NFF-0007 filled in glove box S 265 PEG 400 =
9.598 g (96%) S EtOH = 0.4052 (4%) 266 Triamcinolone acetomide =
42.2 mg SP (4.123%) PEG 400 = 981.3 mg (95.877%) 267 Phosal 50PG =
20.0783 g S (99.00835%) Tween 80 = 0.2011 g (0.99165%) 268 PEG 400
= 96.1 g (96%) S EtOH = 4.00 g (4%) 269 Rapa = 0.4001 g (2%) S EtOH
= 0.80 g (4%) PEG 400 = 18.8 g (94%) 270 Sterile Water = 9955.8 mg
(99.27%) S CMC High visc. = 47.8 mg (0.48%) Tween 80 = 25.4 mg
(0.25%) 271 Sterile Water = 9947.5 mg (99.00%) S CMC Medium visc. =
75 mg (0.75%) Tween 80 = 25.1 mg (0.25%) 272 Rapa = 41 mg (2.01%)
SP Form. # 270 = 2000 mg (97.99%) 273 Rapa = 40.2 mg (1.97%) SP
MSF-03-172-07E = 2000 mg (98.03%) 274 NMP (Pharmasolve .RTM..sup.)
= 1280.5 mg S (65.89%) PLGA 75/25 = 662.9 mg (34.11%) 275 NMP
(Pharmasolve .RTM..sup.) = 1573.3 mg S (80.50%) PLGA 75/25 = 381.0
mg (19.50%) 276 NMP (Pharmasolve .RTM..sup.) = 1009.7 mg S Yes, 10
.mu.L 49.8%) PLGA 75/25 = 1001.6 mg (50.20%) 277 Sterile Water =
14934.0 mg (99.25%) S CMC Medium visc. = 112.4 mg (0.75%) 278
Propylene Glycol = 1893.7 mg S Yes, 10 .mu.L (93.85%) EtOH = 83.8
mg (4.16%) Rapa = 40.2 mg (1.99%) 279 Propylene Glycol = 1946.2 mg
S Yes, 10 .mu.L (95.68%) Benzyl Alcohol = 47.1 mg (2.31%) Rapa =
40.8 mg (2.01%) 280 PEG 300 = 1894.1 mg (93.74%) S Yes, 10 .mu.L
EtOH = 40.1 mg (1.98%) Rapa = 86.4 mg (4.28%) 281 PEG 300 = 1925.5
mg (95.88%) S Yes, 10 .mu.L, 30 .mu.L
EtOH = 39.8 mg (1.98%) Rapa = 43.0 mg (2.14%) 282 Rapa = 100.6 mg
(2.01%) SP Yes, 10 .mu.L, 30 .mu.L MSF-03-176-02 = 4910.8 mg
(97.99%) 283 Rapa = 11.5 mg (0.57%) S PEG 300 = 2012.5 mg (99.43%)
284 Rapa = 10.3 mg (0.51%) S PEG 400 = 2017.2 mg (99.49%) 285 Rapa
= 9.8 mg (0.486%) S PEG 600 = 2005.9 mg (99.51%) 286 Tacrolimus =
42.7 mg (2.11%) S EtOH = 46.0 mg (2.27%) PG = 1938.7 mg (95.62%)
287 Tacrolimus = 40.7 mg (2.01%) S EtOH = 43.0 mg (2.12%) PEG 300 =
1942.1 mg (95.87%) 288 Tacrolimus = 40.3 mg (1.99%) S EtOH = 43.8
mg (2.16%) PEG 400 = 1942.3 mg (95.85%) 289 Tacrolimus = 40.8 mg
(2.03%) S EtOH = 44.5 mg (2.21%) PEG 600 = 1924.0 mg (95.76%) 290
Rapa = 61.0 mg (3.17%) S NMP = 1226.54 mg (63.80%) PLGA 75/25 =
634.96 mg (33.03%) 291 Rapa = 100.2 mg (5.13%) S NMP = 1492.95 mg
mg (76.37%) PLGA 75/25 = 361.65 mg (18.50%) 292 Rapa = 62.9 mg
(3.04%) S NMP = 1103.8 g mg (53.40%) PLGA 75/25 = 900.2 mg (43.56%)
293 Rapa = 62.4 mg (3.00%) S NMP = 1205.1 mg mg (58.11%) PLGA 75/25
= 806.4 mg (38.89%) 294 Sterile Water + 1% CMC Med. = 4909.1 mg SP
(97.99%) Rapa = 100.5 mg (2.01%) 295 Sterile Water + 1% CMC high. =
4903.8 mg SP (97.96%) Rapa = 101.9 mg (2.04%) 296 Rapa = 40.5 mg
(2.03%) S NMP = 1958.7 mg (97.97%) 297 Rapa = 20.5 mg (2.0%) SP DMA
= 41.4 mg (4.0%) PVP = 35.0 mg (3.4%) H2O = 934.7 mg (90.6%) 298
Rapa = 10.6 mg (2.0%) S DMA = 10.6 mg (2.0%) PEG 400 = 506.1 mg
(96%) 299 Rapa = 5.2 mg (2.0%) SP 1% DMA in PEG 400 = 257.4 mg
(98%) 300 Rapa = 20.0 mg (2.0%) S DMA = 7.8 mg (0.8%) PEG 400 = 974
mg (97.2%) 301 Rapa = 20.1 mg (1.3%) S DMA = 19.5 mg (1.3%) PEG 400
= 1449.6 mg (97.3%) 302 Rapa = 20.0 mg (2.0%) SP PVP = 10.8 mg
(1.1%) PEG 400 = 994.5 mg (97.0%) 303 Rapa = 20.4 mg (2.0%) SP PVP
= 24.5 mg (2.4%) PEG 400 = 990.7 mg (95.7%) 304 Rapa = 25.5 mg
(2.4%) SP PVP = 51.9 mg (4.8%) PEG 400 = 1000.6 mg (92.8%) 305 Rapa
= 22.5 mg (2.3%) S BA = 27.5 mg (2.7%) PEG 400 = 950.7 mg (95.0%)
306 Rapa = 30.2 mg (2.3%) SP PVP = 240.9 mg (18.6%) PEG 400 =
1021.2 mg (79.0%) 307 Rapa = 8.7 mg (3.1%) SP 1% PVP in H2O = 273
mg (96.9%) 308 Rapa = 12.6 mg (2.53%) SP 5% PVP in H2O = 501.6 mg
(97.5%) 309 Rapa = 20.3 mg (3.8%) SP 10% PVP in H2O = 513.9 mg
(96.2%) 310 Rapa = 100.5 mg (2.0%) S Yes, 10 .mu.L DMA = 67.8 mg
(1.4%) PEG 400 = 4838.3 mg (96.6%) 311 Rapa = 96.8 mg (1.9%) S Yes,
10 .mu.L BA = 157.5 mg (3.2%) PEG 400 = 4748.7 mg (94.9%) 312 Rapa
= 105.8 mg (2.1%) S DMA = 5.63 mg (0.1%) PEG 400 = 4888.9 mg
(97.8%) 313 Rapa = 20.2 mg (2.0%) SP PVP = 99.2 mg (9.9%) H2O =
882.3 mg (88.1%) 314 Rapa = 100.3 mg (2.0%) SP PVP = 251.4 mg
(5.0%) H2O = 4662.8 mg (93.0%) 315 Rapa = 20.3 mg (2.0%) S DMA =
983.9 mg (98%) 316 Triamcinolone = 22.8 mg (2.0%) S Yes, 10 .mu.L
DMA = 12.0 mg (1.1%) PEG 400 = 1104.5 mg (96.9%) 317 Triamcinolone
= 1.0 mg (0.1%) S EtOH = 49.30 mg (4.0%) PEG 400 = 1191.9 mg
(96.0%) 318 Triamcinolone = 18.7 mg (0.9%) S PEG 400 = 959.8 mg
(99.1%) 319 Triamcinolone = 25.5 mg (1.3%) S EtOH = 83.0 mg (4.1%)
PEG 400 = 1905.6 mg (94.6%) 320 Dexamethasone = 20.4 mg (1.2%) S
EtOH = 71.7 mg (4.1%) PEG 400 = 1737.6 mg (98.8%) 321 Dexamethasone
= 27.5 mg (2.0%) S Yes, 10 .mu.L DMA = 5.6 mg (0.4%) PEG 400 =
1347.3 mg (97.6%) 322 Rapa = 9.1 mg (0.152%) E EtOH = 90.9 mg
(1.514%) F127 = 262.8 mg (4.378%) Water = 1489.1 mg (24.804%)
Sesame oil = 4151.5 mg (69.152%) 323 Rapa = 24.4 mg (0.625%) E
Phosal 50PG = 203.1 mg (5.201%) EtOH = 166.8 mg (4.272%) Labrafac
CC = 1502.8 mg (38.486%) Sesame oil = 2007.7 mg (51.416%) 324 Form.
# 174 with 2 mm beads SP 0.4929 .mu.m 325 Form. # 175 with 2 mm
beads SP 0.4804 .mu.m
[0543] TABLE-US-00002 TABLE 2 Aqueous Humor Rapa Concentration
Standard Injection of 2% Rapa-PEG- Mean deviation EtOH Solution
Rapa concentration (ng/mL) (ng/mL) 1.0 .mu.L intravitreal 0.438 (1
day after injection) 0.141 3.0 .mu.L intravitreal 0.355 (1 day
after injection) 0.234 3.0 .mu.L sub-conj 0.338 (1 day after
injection) 0.122 5.0 .mu.L into anterior chamber 0.167 (14 days
after injection) 0.183 10.0 .mu.L into anterior chamber 0.004 (14
days after injection) 0.006
* * * * *