U.S. patent application number 14/014860 was filed with the patent office on 2014-02-06 for alpha-2 agonist polymeric drug delivery systems.
This patent application is currently assigned to Allergan, Inc.. The applicant listed for this patent is Allergan, Inc.. Invention is credited to Wendy M. Blanda, James A. Burke, James N. Chang, Patrick M. Hughes, Werhner C. Orilla, Lon T. Spada.
Application Number | 20140038972 14/014860 |
Document ID | / |
Family ID | 37108740 |
Filed Date | 2014-02-06 |
United States Patent
Application |
20140038972 |
Kind Code |
A1 |
Chang; James N. ; et
al. |
February 6, 2014 |
ALPHA-2 AGONIST POLYMERIC DRUG DELIVERY SYSTEMS
Abstract
Biocompatible intraocular implants include an alpha-2 adrenergic
receptor agonist and a polymer associated with the alpha-2
adrenergic receptor agonist to facilitate release of the alpha-2
adrenergic receptor agonist into an eye for an extended period of
time. The alpha-2 adrenergic receptor agonist may be associated
with a biodegradable polymer matrix, such as a matrix of a two
biodegradable polymers. The implants can be placed in an eye to
treat one or more ocular conditions, such as an ocular vasculopathy
or glaucoma, including reduction of an elevated intraocular
pressure.
Inventors: |
Chang; James N.; (Newport
Beach, CA) ; Spada; Lon T.; (Walnut, CA) ;
Blanda; Wendy M.; (Tustin, CA) ; Orilla; Werhner
C.; (Anaheim, CA) ; Burke; James A.; (Santa
Ana, CA) ; Hughes; Patrick M.; (Aliso Viejo,
CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Allergan, Inc. |
Irvine |
CA |
US |
|
|
Assignee: |
Allergan, Inc.
Irvine
CA
|
Family ID: |
37108740 |
Appl. No.: |
14/014860 |
Filed: |
August 30, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11394765 |
Mar 31, 2006 |
8529927 |
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14014860 |
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11119021 |
Apr 29, 2005 |
8293741 |
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11394765 |
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10836911 |
Apr 30, 2004 |
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11119021 |
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Current U.S.
Class: |
514/249 |
Current CPC
Class: |
A61L 27/26 20130101;
A61L 2430/16 20130101; A61L 27/54 20130101; A61L 27/58 20130101;
Y02A 50/30 20180101; Y02A 50/401 20180101; A61K 31/498 20130101;
A61L 27/18 20130101; A61L 2300/604 20130101; A61K 9/0051 20130101;
A61L 27/18 20130101; C08L 67/04 20130101 |
Class at
Publication: |
514/249 |
International
Class: |
A61K 9/00 20060101
A61K009/00; A61K 31/498 20060101 A61K031/498 |
Claims
1. A biodegradable intraocular implant comprising brimonidine free
base in an amount in the range of 1 wt % to 50 wt %, and a
biodegradable polymer, wherein the biodegradable polymer comprises
an ester end-capped biodegradable polymer and an acid end-capped
biodegradable polymer.
2. The implant of claim 1, wherein the implant comprises from about
10% to about 91% ester end-capped biodegradable polymer, from about
5 wt % to about 40 wt % acid end-capped biodegradable polymer, and
from about 4 wt % to about 50 wt % brimonidine free base.
3. The implant of claim 2, wherein the implant comprises from about
25% to about 80% ester end-capped biodegradable polymer, from about
10 wt % to about 40 wt % acid end-capped biodegradable polymer, and
about 10 wt % to about 35 wt % brimonidine free base.
4. The implant of claim 2, wherein the implant comprises about 88
wt % ester end-capped biodegradable polymer, about 10 wt % acid
end-capped biodegradable polymer, and about 12 wt % brimonidine
free base.
5. The implant of claim 2, wherein the implant comprises from about
53 wt % to about 73% ester end-capped biodegradable polymer, from
about 15 wt % to about 35 wt % acid end-capped biodegradable
polymer, and from about 9 wt % to about 12 wt % brimonidine free
base.
6. The implant of claim 2, wherein the biodegradable polymer
comprises more than one ester end-capped biodegradable polymer.
7. The implant of claim 2, wherein the biodegradable polymer
comprises more than one acid end-capped biodegradable polymer.
8. The implant of claim 2, wherein the implant has no or a nominal
lag time after ocular implantation or insertion of the implant
before release of a therapeutically effective amount of the
brimonidine free base from the implant occurs.
9. The implant of claim 1 which does not include any pore forming
additives, release rate modulators or release rate modifiers.
10. The implant of claim 1, wherein the implant can exhibit a
sustained release of the brimonidine free base from the
biodegradable polymeric matrix over a period of at least 115
days.
11. The implant of claim 1, wherein the implant exhibits a
substantially linear release of the brimonidine free base from the
biodegradable polymeric matrix of the implant over a period of time
of from about 20 days to about 50 days.
12. A process for making a biodegradable intraocular implant
comprising: (a) mixing a brimonidine free base and a biodegradable
polymer, wherein the biodegradable polymer comprises an ester
end-capped biodegradable polymer and an acid end-capped
biodegradable polymer; (b) heating the mixture, and; (c) extruding
the heated mixture, to thereby make a biodegradable intraocular
implant.
13. A biodegradable intraocular implant made by the process of
claim 12, wherein the brimonidine free base is homogenously
distributed throughout the implant.
14. A method for treating an ocular condition selected from the
group consisting of: macular degeneration, age related macular
degeneration, non-exudative age related macular degeneration,
exudative age related macular degeneration, choroidal
neovascularization, retinopathy, diabetic retinopathy, acute and
chronic macular neuroretinopathy, central serous chorioretinopathy,
macular edema, cystoid macular edema, and diabetic macular edema,
acute multifocal placoid pigment epitheliopathy, Behcet's disease,
birdshot retinochoroidopathy, syphilis, lyme disease, tuberculosis,
toxoplasmosis, uveitis, intermediate uveitis, pars planitis, and
anterior uveitis, multifocal choroiditis, multiple evanescent white
dot syndrome, ocular sarcoidosis, posterior scleritis, serpignous
choroiditis, subretinal fibrosis, uveitis syndrome,
Vogt-Koyanagi-Harada syndrome, retinal arterial occlusive disease,
central retinal vein occlusion, disseminated intravascular
coagulopathy, branch retinal vein occlusion, hypertensive fundus
changes, ocular ischemic syndrome, retinal arterial microaneurysms,
Coat's disease, parafoveal telangiectasis, hemi-retinal vein
occlusion, papillophlebitis, central retinal artery occlusion,
branch retinal artery occlusion, carotid artery disease, frosted
branch angitis, sickle cell retinopathy and other
hemoglobinopathies, angioid streaks, familial exudative
vitreoretinopathy, Eales disease, sympathetic ophthalmia, uveitic
retinal disease, retinal detachment, eye trauma, laser induced eye
damage, photocoagulation, eye hypoperfusion during surgery,
radiation retinopathy, bone marrow transplant retinopathy,
proliferative vitreal retinopathy, appearance of epiretinal
membranes, proliferative diabetic retinopathy, ocular
histoplasmosis, ocular toxocariasis, presumed ocular histoplasmosis
syndrome, endophthalmitis, toxoplasmosis, retinal diseases
associated with HIV infection, choroidal disease associated with
HIV infection, uveitic disease associated with HIV Infection, viral
retinitis, acute retinal necrosis, progressive outer retinal
necrosis, fungal retinal diseases, ocular syphilis, ocular
tuberculosis, diffuse unilateral subacute neuroretinitis, myiasis,
retinitis pigmentosa, systemic disorders with associated retinal
dystrophies, congenital stationary night blindness, cone
dystrophies, Stargardt's disease and fundus flavimaculatus, Bests
disease, pattern dystrophy of the retinal pigmented epithelium,
X-linked retinoschisis, Sorsby's fundus dystrophy, benign
concentric maculopathy, Bietti's crystalline dystrophy,
pseudoxanthoma elasticum, retinal detachment, macular hole, giant
retinal tear, retinal disease associated with tumors, congenital
hypertrophy of the RPE, posterior uveal melanoma, choroidal
hemangioma, choroidal osteoma, choroidal metastasis, combined
hamartoma of the retina and retinal pigmented epithelium,
retinoblastoma, vasoproliferative tumors of the ocular fundus,
retinal astrocytoma, intraocular lymphoid tumors, punctate inner
choroidopathy, acute posterior multifocal placoid pigment
epitheliopathy, myopic retinal degeneration, acute retinal pigment
epithelitis, the method comprising the step of intraocular
administration of a biodegradable intraocular implant comprising
brimonidine free base and a biodegradable polymer, wherein the
biodegradable polymer comprises an ester end-capped biodegradable
polymer and an acid end-capped biodegradable polymer.
Description
CROSS REFERENCE
[0001] This application is a continuation of copending application
Ser. No. 11/394,765, filed Mar. 31, 2006, which is a continuation
in part of application Ser. No. 11/119,021, filed Apr. 29, 2005,
now issued as U.S. Pat. No. 8,293,741, which is continuation in
part of application Ser. No. 10/836,911 filed Apr. 30, 2004, now
abandoned. The entire contents of these applications are
incorporated herein by reference.
BACKGROUND
[0002] The present invention generally relates to devices and
methods to treat an eye of a patient, and more specifically to
intraocular implants that provide extended release of a therapeutic
agent to an eye in which the implant is placed, and to methods of
making and using such implants, for example, to treat ocular
vasculopathies, or to generally improve vision.
[0003] Brimonidine, 5-bromo-6-(2-imidazolidinylideneamino)
quinoxaline, is an alpha-2-selective adrenergic receptor agonist
that is effective in the treatment of open-angle glaucoma by
decreasing aqueous humor production and increasing uveoscleral
outflow. Brimonidine is available in two chemical forms,
brimonidine tartrate and brimonidine free base. Brimonidine
tartrate (Alphagan P.RTM.) is commercially available from Allergan
for treating glaucoma. Topical ocular brimonidine formulation,
0.15% Alphagan P.RTM. (Allergan, Irvine, Calif.), is currently
commercially available for treatment of open-angle glaucoma. The
solubility of brimonidine tartrate in water is 34 mg/mL, while the
solubility of brimonidine freebase is negligible in water.
[0004] Recent studies have suggested that brimonidine can promote
survival of injured retinal ganglion nerve cells by activation of
the alpha-2-adrenoceptor in the retina and/or optic nerve. For
example, brimonidine can protect injured neurons from further
damage in several models of ischemia and glaucoma. See e.g. U.S.
Pat. Nos. 5,856,329; 6,194,415; 6,248,741, and; 6,465,464.
[0005] Glaucoma-induced ganglion cell degeneration is one of the
leading causes of blindness. This indicates that brimonidine can be
utilized in a new therapeutic approach to glaucoma management in
which neuroprotection and intraocular pressure reduction are valued
outcomes of the therapeutic regimen. For brimonidine to protect the
optic nerve, however, it must have access to the posterior segment
of the eye at therapeutic levels. Currently available techniques
for administering brimonidine to the posterior chamber of the eye
are not sufficient to address this issue. It has been reported that
intravitreal injection of brimonidine may have a neuroprotective
effect. Gao H., et al., Up-regulation of brain-derived neurotrophic
factor expression by brimonidine in rat retinal ganglion cells,
Arch Opthal 2002 June; 120(6): 797-803.
[0006] Biocompatible implants for placement in the eye have been
disclosed in a number of patents, such as U.S. Pat. Nos. 4,521,210;
4,853,224; 4,997,652; 5,164,188; 5,443,505; 5,501,856; 5,766,242;
5,824,072; 5,869,079; 6,074,661; 6,331,313; 6,369,116; and
6,699,493.
[0007] It would be advantageous to provide eye implantable drug
delivery systems, such as intraocular implants, and methods of
using such systems, that are capable of releasing a therapeutic
agent at a sustained or controlled rate for extended periods of
time and in amounts with few or no negative side effects.
SUMMARY
[0008] The present invention provides new drug delivery systems,
and methods of making and using such systems, for extended or
sustained drug release into an eye, for example, to achieve one or
more desired therapeutic effects. The drug delivery systems are in
the form of implants or implant elements that may be placed in an
eye. The present systems and methods advantageously provide for
extended release times of one or more therapeutic agents. Thus, the
patient in whose eye the implant has been placed receives a
therapeutic amount of an agent for a long or extended time period
without requiring additional administrations of the agent. For
example, the patient has a substantially consistent level of
therapeutically active agent available for consistent treatment of
the eye over a relatively long period of time, for example, on the
order of at least about one week, such as between about two and
about six months after receiving an implant. Such extended release
times facilitate obtaining successful treatment results.
[0009] Intraocular implants in accordance with the disclosure
herein comprise a therapeutic component and a drug release
sustaining component associated with the therapeutic component. In
accordance with the present invention, the therapeutic component
comprises, consists essentially of, or consists of, an alpha-2
adrenergic receptor agonist. The alpha-2 adrenergic receptor
agonist may be an agonist or agent that selectively activates
alpha-2 adrenergic receptors, for example by binding to an alpha-2
adrenergic receptor, relative to other types of adrenergic
receptors, such as alpha-1 adrenergic receptors. The selective
activation can be achieved under different conditions, but
preferably, the selective activation is determined under
physiological conditions, such as conditions associated with an eye
of a human or animal patient. The drug release sustaining component
is associated with the therapeutic component to sustain release of
an amount of the alpha-2 adrenergic receptor agonist into an eye in
which the implant is placed. The amount of the alpha-2 adrenergic
receptor agonist is released into the eye for a period of time
greater than about one week after the implant is placed in the eye
and is effective in preventing or reducing ocular vasculopathies,
such as vascular occlusions.
[0010] In one embodiment, the intraocular implants comprise an
alpha-2 adrenergic receptor agonist and a biodegradable polymer
matrix. The alpha-2 adrenergic receptor agonist is associated with
a biodegradable polymer matrix that degrades at a rate effective to
sustain release of an amount of the agonist from the implant for a
time sufficient to reduce or prevent an ocular vascular occlusion.
The intraocular implant is biodegradable or bioerodible and
provides a sustained release of the alpha-2 adrenergic receptor
agonist in an eye for extended periods of time, such as for more
than one week, for example for about three months or more and up to
about six months or more. In certain implants, the alpha-2
adrenergic receptor agonist is released for about 30-35 days or
less. In other implants, the alpha-2 adrenergic receptor agonist is
released for 40 days or more.
[0011] The biodegradable polymer component of the foregoing
implants may be a mixture of biodegradable polymers, wherein at
least one of the biodegradable polymers is a polylactic acid
polymer having a molecular weight less than 64 kiloDaltons (kD).
Additionally or alternatively, the foregoing implants may comprise
a first biodegradable polymer of a polylactic acid, and a different
second biodegradable polymer of a polylactic acid. Furthermore, the
foregoing implants may comprise a mixture of different
biodegradable polymers, each biodegradable polymer having an
inherent viscosity in a range of about 0.3 deciliters/gram (dl/g)
to about 1.0 dl/g.
[0012] The alpha-2 adrenergic receptor agonist of the implants
disclosed herein may include quinoxaline derivatives, or other
agonists that are effective in treating ocular conditions. One
example of a suitable quinoxaline derivative is brimonidine or
brimonidine tartrate. In addition, the therapeutic component of the
present implants may include one or more additional and different
therapeutic agents that may be effective in treating an ocular
condition.
[0013] A method of making the present implants involves combining
or mixing the alpha-2 adrenergic receptor agonist with a
biodegradable polymer or polymers. The mixture may then be extruded
or compressed to form a single composition. The single composition
may then be processed to form individual implants suitable for
placement in an eye of a patient.
[0014] The implants may be placed in an ocular region to treat a
variety of ocular conditions, including conditions such as ocular
vasculopathies that affect an anterior region or posterior region
of an eye. For example, the implants may be used to treat many
conditions of the eye, including, without limitation, conditions
associated with vascular occlusion.
[0015] Kits in accordance with the present invention may comprise
one or more of the present implants, and instructions for using the
implants. For example, the instructions may explain how to
administer the implants to a patient, and types of conditions that
may be treated with the implants.
[0016] The present invention also encompasses a biodegradable
intraocular implant for improving vision. The implant can comprise
an alpha-2 adrenergic receptor agonist and a biodegradable polymer.
The implant releases the alpha-2 adrenergic receptor agonist from
the polymer, upon intravitreal placement of the implant, in an
amount effective to improve the vision of the eye in which the
implant is placed. The alpha-2 adrenergic receptor agonist can be a
quinoxaline, such as a (2-imidazolin-2-ylamino) quinoxaline, a
5-bromo-6-(2-imidazolin-2-ylamino) quinoxaline, and derivatives
thereof and mixtures thereof. Thus, the alpha-2 adrenergic receptor
agonist can be a brimonidine or salts thereof or mixtures thereof.
For example, the alpha-2 adrenergic receptor agonist can be
brimonidine tartrate.
[0017] The alpha-2 adrenergic receptor agonist can be dispersed
within the biodegradable polymer of the implant. The biodegradable
polymer can comprise a mixture of a first biodegradable polymer of
polylactic acid, and a different second biodegradable polymer of
polylactic acid. The polymer can release drug at a rate effective
to sustain release of an amount of the alpha-2 adrenergic receptor
agonist from the implant for more than one month or for more that
forty days or for less than thirty five days from the time the
implant is placed in the vitreous of the eye.
[0018] An embodiment of the present invention is a method of making
a biodegradable intraocular implant by extruding a mixture of an
alpha-2 adrenergic receptor agonist and a biodegradable polymer
component to form a biodegradable material that releases drug at a
rate effective to sustain release of an amount of the alpha-2
adrenergic receptor agonist from the implant for a time effective
to improve vision in an eye in which the implant is placed.
[0019] A further embodiment of the present invention is a method
for improving or for maintaining vision by placing in the vitreous
of an eye a biodegradable intraocular implant comprising an alpha-2
adrenergic receptor agonist associated with a biodegradable
polymer, thereby improving or maintaining vision. This method can
be used to treat an ocular condition such as: macular degeneration,
macular edema, retinal arterial occlusive disease, central retinal
vein occlusion, disseminated intravascular coagulopathy, branch
retinal vein occlusion, hypertensive fundus changes, ocular
ischemic syndrome, retinal arterial microaneurysms, hemi-retinal
vein occlusion, central retinal artery occlusion, branch retinal
artery occlusion, carotid artery disease (cad), eales disease,
vasculopathies associated with diabetes, Non-Exudative Age Related
Macular Degeneration, Exudative Age Related Macular Degeneration,
Choroidal Neovascularization, Diabetic Retinopathy, Acute Macular
Neuroretinopathy, Central Serous Chorioretinopathy, Cystoid Macular
Edema, Diabetic Macular Edema, Acute Multifocal Placoid Pigment
Epitheliopathy, Behcet's Disease, Birdshot Retinochoroidopathy,
Syphilis, Lyme, Tuberculosis, Toxoplasmosis, Intermediate Uveitis,
Multifocal Choroiditis, Multiple Evanescent White Dot Syndrome,
Ocular Sarcoidosis, Posterior Scleritis, Serpiginous Choroiditis,
Subretinal Fibrosis and Uveitis Syndrome, Vogt-Koyanagi-Harada
Syndrome, Coat's Disease, Parafoveal Telangiectasia,
Papillophlebitis, Frosted Branch Angiitis, Sickle Cell Retinopathy
and other Hemoglobinopathies, Angioid Streaks, Familial Exudative
Vitreoretinopathy, Sympathetic Ophthalmia, Uveitic Retinal Disease,
Retinal Detachment, Trauma, Laser, photodynamic therapy,
Photocoagulation, Hypoperfusion During Surgery, Radiation
Retinopathy, Bone Marrow Transplant Retinopathy, Proliferative
Vitreal Retinopathy and Epiretinal Membranes, Proliferative
Diabetic Retinopathy, Ocular Histoplasmosis, Ocular Toxocariasis,
Presumed Ocular Histoplasmosis Syndrome, Endophthalmitis,
Toxoplasmosis, Retinal Diseases Associated with HIV Infection,
Choroidal Disease Associated with HIV Infection, Uveitic Disease
Associated with HIV Infection, Viral Retinitis, Acute Retinal
Necrosis, Progressive Outer Retinal Necrosis, Fungal Retinal
Diseases, Ocular Syphilis, Ocular Tuberculosis, Diffuse Unilateral
Subacute Neuroretinitis, Myiasis, Retinitis Pigmentosa, Systemic
Disorders with Associated Retinal Dystrophies, Congenital
Stationary Night Blindness, Cone Dystrophies, Stargardt's Disease
and Fundus Flavimaculatus, Best's Disease, Pattern Dystrophy of the
Retinal Pigmented Epithelium, X-Linked Retinoschisis, Sorsby's
Fundus Dystrophy, Benign Concentric Maculopathy, Bietti's
Crystalline Dystrophy, pseudoxanthoma elasticum, Retinal
Detachment, Macular Hole, Giant Retinal Tear, Retinal Disease
Associated with Tumors, Congenital Hypertrophy of the RPE,
Posterior Uveal Melanoma, Choroidal Hemangioma, Choroidal Osteoma,
Choroidal Metastasis, Combined Hamartoma of the Retina and Retinal
Pigmented Epithelium, Retinoblastoma, Vasoproliferative Tumors of
the Ocular Fundus, Retinal Astrocytoma, Intraocular Lymphoid
Tumors, Punctate Inner Choroidopathy, Acute Posterior Multifocal
Placoid Pigment Epitheliopathy, Myopic Retinal Degeneration, and
Acute Retinal Pigment Epithelitis.
[0020] Notably, the method can improve vision in a normal eye. A
normal eye is an eye which is not diseased or damaged. For example,
the method can improve vision (as by improving visual acuity) in a
normal eye by up to about 56%. The method can also improve vision
in an eye with an ocular condition. For example, the method can
improve vision in an eye with an ocular condition by up to about
23%. The ocular condition can be a vasculopathy. Alternately, the
ocular condition can be due to an elevated intraocular pressure
and/or the ocular condition can be a retinal ischemic injury.
[0021] The implant can release the alpha-2 adrenergic receptor
agonist from the polymer, upon intravitreal placement of the
implant, for a period of about ninety days. Significantly, the
alpha-2 adrenergic receptor agonist can be retained in the retina
for a period of time longer than it is retained in the vitreous. An
embodiment of the present invention is a method for improving,
maintaining, restoring or repairing vision, the method comprising
the step of placing in the vitreous of an eye a biodegradable
intraocular implant comprising a brimonidine associated with a
biodegradable polymer, thereby improving, maintaining, restoring or
repairing vision.
[0022] An embodiment of our invention is a biodegradable
intraocular implant comprising an alpha-2 adrenergic receptor
agonist and a biodegradable polymer, wherein the biodegradable
polymer comprises an ester end-capped biodegradable polymer and an
acid end-capped biodegradable polymer. The implant can comprise
from about 10% to about 91% ester end-capped biodegradable polymer,
from about 5 wt % to about 40 wt % acid end-capped biodegradable
polymer, and from about 4 wt % to about 50 wt % alpha-2 adrenergic
receptor agonist. Preferably, the implant can comprise from about
45% to about 80% ester end-capped biodegradable polymer, from about
10 wt % to about 40 wt % acid end-capped biodegradable polymer, and
about 10 wt % to about 15 wt % alpha-2 adrenergic receptor agonist.
More preferably, the implant can comprise about 88 wt % ester
end-capped biodegradable polymer, about 10 wt % acid end-capped
biodegradable polymer, and about 12 wt % alpha-2 adrenergic
receptor agonist. Most preferably, the implant can comprise from
about 53 wt % to about 73% ester end-capped biodegradable polymer,
from about 15 wt % to about 35 wt % acid end-capped biodegradable
polymer, and from about 9 wt % to about 12 wt % alpha-2 adrenergic
receptor agonist.
[0023] The biodegradable polymer of the implant can comprise more
than one ester end-capped biodegradable polymer. Alternately, the
biodegradable polymer of the implant can comprise more than one
acid end-capped biodegradable polymer. The implant can have no or a
nominal lag time after ocular implantation or insertion of the
implant before release of a therapeutically effective amount of the
alpha-2 adrenergic receptor agonist from the implant occurs. The
implant comprise greater than or equal to 4 weight percent (wt %)
of a biologically active alpha-2 adrenergic receptor agonist and
the implant preferably does not include any pore forming additives,
release rate modulators or release rate modifiers. The implant can
exhibit a sustained release of the alpha-2 adrenergic receptor
agonist from the biodegradable polymeric matrix over a period of at
least 115 days. Additionally, the implant can exhibit a
substantially linear release of the alpha-2 adrenergic receptor
agonist from the biodegradable polymeric matrix of the implant over
a period of time of from about 20 days to about 50 days.
[0024] A preferred embodiment of a biodegradable intraocular
implant within the scope of our invention can comprise an alpha-2
adrenergic receptor agonist, and a biodegradable polymer, wherein
the biodegradable polymer comprises an ester end-capped
biodegradable polymer and an acid end-capped biodegradable polymer,
wherein the implant comprises from about 40% to about 91% of at
least two different ester end-capped biodegradable polymers, from
about 5 wt % to about 40 wt % acid end-capped biodegradable
polymer, and from about 4 wt % to about 20 wt % alpha-2 adrenergic
receptor agonist.
[0025] Our invention also includes a process for making a
biodegradable intraocular implant by mixing an alpha-2 adrenergic
receptor agonist and a biodegradable polymer, wherein the
biodegradable polymer comprises an ester end-capped biodegradable
polymer and an acid end-capped biodegradable polymer; heating the
mixture, and; extruding the heated mixture, to thereby make a
biodegradable intraocular implant.
[0026] An implant within the scope of our invention can be an
extruded filament with a diameter of about 0.5 mm, a length of
about 6 mm and a weight of about 1 mg. The alpha-2 adrenergic
receptor agonist can be homogenously distributed throughout the
implant.
[0027] Our implants can be used to treat ocular conditions by
intraocular administration of a biodegradable intraocular implant
comprising an alpha-2 adrenergic receptor agonist and a
biodegradable polymer, wherein the biodegradable polymer comprises
an ester end-capped biodegradable polymer and an acid end-capped
biodegradable polymer. The alpha-2 adrenergic receptor agonist can
be selected from the group consisting of brimonidine, salts
thereof, and mixtures thereof.
[0028] In another embodiment of our invention a biodegradable
intraocular implant can comprise a plurality of forms of an alpha-2
adrenergic receptor agonist and a biodegradable polymer. The
alpha-2 adrenergic receptor agonist can be a brimonidine and the
brimonidine can be present in two forms in the implant. The two
forms of brimonidine present in the implant can be brimonidine free
base and brimonidine tartrate. Such and implant can comprises from
about 50 wt % to about 70% ester end-capped biodegradable polymer,
from about 1 wt % to about 49 wt % brimonidine free base and from
about 1 wt % to about 49 wt % brimonidine tartrate. Alternately,
the implant can comprises from about 50 wt % to about 60% ester
end-capped biodegradable polymer, from about 1 wt % to about 49 wt
% brimonidine free base and from about 1 wt % to about 49 wt %
brimonidine tartrate. More preferably, the implant can comprise
from about 50 wt % to about 70% ester end-capped biodegradable
polymer, from about 10 wt % to about 30 wt % brimonidine free base
and from about 10 wt % to about 30 wt % brimonidine tartrate. In
most preferred embodiment the implant can comprise from about 55 wt
% to about 65% ester end-capped biodegradable polymer, from about
15 wt % to about 20 wt % brimonidine free base and from about 15 wt
% to about 20 wt % brimonidine tartrate, for example the implant
can comprise about 65 wt % ester end-capped biodegradable polymer,
about 18 wt % brimonidine free base and about 18 wt % brimonidine
tartrate. The implant of claim 21, wherein the biodegradable
polymer comprises more than one ester end-capped biodegradable
polymer. And the implant can have no burst effect and no or a
nominal lag time after ocular implantation or insertion of the
implant before release of a therapeutically effective amount of the
alpha-2 adrenergic receptor agonist from the implant occurs.
Additionally, the implant can exhibit a sustained release of the
alpha-2 adrenergic receptor agonist from the biodegradable
polymeric matrix over a period of at least 60 days. Furthermore,
the implant can exhibits a substantially linear release of the
alpha-2 adrenergic receptor agonist from the biodegradable
polymeric matrix of the implant over a period of time of from about
20 days to about 50 days.
[0029] A preferred embodiment of our invention can comprise a
brimonidine free base; a brimonidine tartrate, and an ester
end-capped biodegradable polymer, wherein the implant comprises
from about 50 wt % to about 70% of the ester end-capped
biodegradable polymer, from about 1 wt % to about 49 wt % of the
brimonidine free base and from about 1 wt % to about 49 wt % of the
brimonidine tartrate.
[0030] Our invention encompasses a process for making a
biodegradable intraocular implant comprising (a) mixing a plurality
of forms of alpha-2 adrenergic receptor agonist and a biodegradable
polymer; (b) heating the mixture, and; (c) extruding the heated
mixture, to thereby make a biodegradable intraocular implant. The
implant can be extruded as a filament with a diameter of about 0.5
mm, a length of about 6 mm and a weight of about 1 mg. The implant
can also be made by a direct compression or solvent extraction
method. The shape of the implant can also be as a tablet, pellet or
rod.
[0031] Finally, our invention encompasses a method of treating a
symptom of glaucoma by placing a biodegradable intraocular implant
comprising an alpha-2 adrenergic receptor agonist associated with a
biodegradable polymer into the vitreous of an eye, thereby treating
a symptom of the glaucoma. The symptom of the glaucoma can be
reduced for at least about 35 days after intravitreal placement of
the implant. The symptom of the glaucoma treated can be an elevated
intraocular pressure.
[0032] Additional aspects and advantages of the present invention
are set forth in the following description and claims, particularly
when considered in conjunction with the accompanying drawings.
DRAWINGS
[0033] FIG. 1 is a graph showing the cumulative release profiles
for biodegradable brimonidine tartrate containing implants as
determined in 0.9% phosphate buffered saline at 37 degrees
Celsius.
[0034] FIG. 2 is a graph similar to FIG. 1 showing the cumulative
release profiles for biodegradable brimonidine free base containing
implants with different combinations of biodegradable polymers.
[0035] FIG. 3 is a graph similar to FIG. 1 showing the cumulative
release profiles for biodegradable brimonidine tartrate containing
implants having different concentrations of brimonidine
tartrate.
[0036] FIG. 4 is a graph similar to FIG. 3 showing the cumulative
release profiles for biodegradable brimonidine tartrate containing
implants having different concentrations of brimonidine tartrate
and polymeric blends.
[0037] FIG. 5 is a graph similar to FIG. 4 showing the cumulative
release profiles for biodegradable brimonidine free base containing
implants having different concentrations of brimonidine tartrate
and polymeric blends.
[0038] FIG. 6 is a graph showing the cumulative release profiles
for brimonidine tartrate containing implants (wafers) having
different concentrations of brimonidine tartrate and polymeric
combinations.
[0039] FIG. 7 is a graph similar to FIG. 6 showing the cumulative
release profiles for biodegradable brimonidine free base containing
implants having a different concentration of brimonidine tartrate
and polymeric blends.
[0040] FIG. 8 is a graph similar to FIG. 4 showing the cumulative
release profiles for biodegradable brimonidine free base containing
implants having a different concentration of brimonidine tartrate
and polymeric blends.
[0041] FIG. 9 is a graph similar to FIG. 5 showing the cumulative
release profiles for biodegradable brimonidine free base containing
wafer implants.
[0042] FIG. 10 is a graph showing the delay in filling of sodium
fluorescein during angiography following branch retinal vein
occlusion (BRVO) versus time in monkeys that have received
brimonidine tartrate containing biodegradable implants or placebo
implants.
[0043] FIG. 11 is a graph of foveal thickness as a function of time
in monkeys that have received brimonidine tartrate containing
biodegradable implants or placebo implants and experienced
BRVO.
[0044] FIG. 12 is a graph of intraocular pressure as a function of
time in monkeys that have received brimonidine tartrate containing
biodegradable implants or placebo implants and experienced
BRVO.
[0045] FIG. 13 is a graph of the superior/inferior percent response
to a multifocal ERG as a function of time in monkeys that have
received brimonidine tartrate containing biodegradable implants or
placebo implants and experienced BRVO.
[0046] FIG. 14 is a graph of blood flow as a function of time in
monkeys that have received brimonidine tartrate containing
biodegradable implants or placebo implants and experienced
BRVO.
[0047] FIG. 15 is a bar graph showing the effect upon visual acuity
(as a percent of the visual acuity of the untreated [control] left
eye) (Y-axis) in normal rabbit right eyes two weeks after
intravitreal administration of either a brimonidine implant or a
placebo implant (X-axis).
[0048] FIG. 16 is a bar graph showing the effect upon visual acuity
(as a percent of the visual acuity of the untreated [control] left
eye) (Y-axis) three weeks after intravitreal administration of
either a brimonidine implant or of a placebo implant in the right
eyes and one week after VEGF induced injury of the same right eyes
(X-axis).
[0049] FIG. 17 is a bar graph showing the effect upon visual acuity
(as a percent of the visual acuity of the untreated [control] right
eye) (Y-axis) twelve weeks after intravitreal administration of
either a brimonidine implant or of a placebo implant in the right
eyes and eleven months after induced ischemic injury of the same
right eyes X-axis).
[0050] FIG. 18 is a graph which illustrates three different
possible release profiles for the release of an active agent from
an implant. Amount of an active agent released is shown on the
Y-axis while the X-axis represents time after intraocular placement
of the implant.
[0051] FIG. 19 is a graph showing the percent of the total amount
of brimonidine released (Y-axis) versus time (X-axis) in days for a
period of 21 days in vitro for the three Table 4 implants.
[0052] FIG. 20 is a graph showing the percent of the total amount
of brimonidine released (Y-axis) versus time in days (X-axis) for a
period of 151 days in vitro for the Table 4 implant 7746-073.
[0053] FIG. 21 is a graph showing the percent of the total amount
of brimonidine released (Y-axis) versus time (X-axis) in days for a
period of 14-26 days in vitro for the seven the Table 5
implants.
[0054] FIG. 22 is a graph showing the percent of the total amount
of brimonidine released (Y-axis) versus time (X-axis) in days over
a period of 60 days in vitro for the six Table 6 implants.
[0055] FIG. 23 is a graph showing intraocular pressure (in mm Hg)
on the Y-axis and time in weeks on the X-axis after intravitreal
placement of the Example 10 brimonidine implant in hypertensive
rabbit eyes.
DESCRIPTION
[0056] As described herein, controlled and sustained administration
of a therapeutic agent through the use of one or more intraocular
implants may improve treatment of undesirable ocular conditions.
The implants comprise a pharmaceutically acceptable polymeric
composition and are formulated to release one or more
pharmaceutically active agents, such as alpha-2 adrenergic receptor
agonists, over an extended period of time. The implants are
effective to provide a therapeutically effective dosage of the
agent or agents directly to a region of the eye to treat or prevent
one or more undesirable ocular conditions. Thus, with a single
administration, therapeutic agents will be made available at the
site where they are needed and will be maintained for an extended
period of time, rather than subjecting the patient to repeated
injections or, in the case of self-administered drops, ineffective
treatment with only limited bursts of exposure to the active agent
or agents.
[0057] An intraocular implant in accordance with the disclosure
herein comprises a therapeutic component and a drug release
sustaining component associated with the therapeutic component. In
accordance with the present invention, the therapeutic component
comprises, consists essentially of, or consists of, an alpha-2
adrenergic receptor agonist. The drug release sustaining component
is associated with the therapeutic component to sustain release of
a therapeutically effective amount of the alpha-2 adrenergic
receptor agonist into an eye in which the implant is placed. The
therapeutic amount of the alpha-2 adrenergic receptor agonist is
released into the eye for a period of time greater than about one
week after the implant is placed in the eye.
DEFINITIONS
[0058] For the purposes of this description, we use the following
terms as defined in this section, unless the context of the word
indicates a different meaning.
[0059] "About" means plus or minus ten percent of the value so
qualified.
[0060] "Biocompatible" means that there is an insignificant
inflammatory response upon contact of the biocompatible material
with an ocular tissue.
[0061] "Effective amount" as applied to an active agent means that
amount of the compound which is generally sufficient to effect a
desired change in the subject.
[0062] "Intraocular implant" means a device or element that is
structured, sized, or otherwise configured to be placed in an eye.
Intraocular implants are generally biocompatible with physiological
conditions of an eye and do not cause adverse side effects.
Intraocular implants may be placed in an eye without disrupting
vision of the eye.
[0063] "Therapeutic component" means a portion of an intraocular
implant comprising one or more therapeutic agents or substances
used to treat a medical condition of the eye. The therapeutic
component may be a discrete region of an intraocular implant, or it
may be homogenously distributed throughout the implant. The
therapeutic agents of the therapeutic component are typically
ophthalmically acceptable, and are provided in a form that does not
cause adverse reactions when the implant is placed in an eye.
[0064] "Drug release sustaining component" means a portion of the
intraocular implant that is effective to provide a sustained
release of the therapeutic agents of the implant. A drug release
sustaining component may be a biodegradable polymer matrix, or it
may be a coating covering a core region of the implant that
comprises a therapeutic component.
[0065] "Associated with" means mixed with, dispersed within,
coupled to, covering, or surrounding.
[0066] "Ocular region" or "ocular site" means any area of the
eyeball, including the anterior and posterior segment of the eye,
and which generally includes, but is not limited to, any functional
(e.g., for vision) or structural tissues found in the eyeball, or
tissues or cellular layers that partly or completely line the
interior or exterior of the eyeball. Specific examples of areas of
the eyeball in an ocular region include the anterior chamber, the
posterior chamber, the vitreous cavity, the choroid, the
suprachoroidal space, the conjunctiva, the subconjunctival space,
the episcleral space, the intracorneal space, the epicorneal space,
the sclera, the pars plana, surgically-induced avascular regions,
the macula, and the retina.
[0067] "Ocular condition" means a disease, ailment or condition
which affects or involves the eye or one of the parts or regions of
the eye. Broadly speaking the eye includes the eyeball and the
tissues and fluids which constitute the eyeball, the periocular
muscles (such as the oblique and rectus muscles) and the portion of
the optic nerve which is within or adjacent to the eyeball.
[0068] An anterior ocular condition is a disease, ailment or
condition which affects or which involves an anterior (i.e. front
of the eye) ocular region or site, such as a periocular muscle, an
eye lid or an eye ball tissue or fluid which is located anterior to
the posterior wall of the lens capsule or ciliary muscles. Thus, an
anterior ocular condition primarily affects or involves the
conjunctiva, the cornea, the anterior chamber, the iris, the
posterior chamber (behind the retina but in front of the posterior
wall of the lens capsule), the lens or the lens capsule and blood
vessels and nerve which vascularize or innervate an anterior ocular
region or site.
[0069] Thus, an anterior ocular condition can include a disease,
ailment or condition, such as for example, aphakia; pseudophakia;
astigmatism; blepharospasm; cataract; conjunctival diseases;
conjunctivitis; corneal diseases; corneal ulcer; dry eye syndromes;
eyelid diseases; lacrimal apparatus diseases; lacrimal duct
obstruction; myopia; presbyopia; pupil disorders; refractive
disorders and strabismus. Glaucoma can also be considered to be an
anterior ocular condition because a clinical goal of glaucoma
treatment can be to reduce a hypertension of aqueous fluid in the
anterior chamber of the eye (i.e. reduce intraocular pressure).
[0070] A posterior ocular condition is a disease, ailment or
condition which primarily affects or involves a posterior ocular
region or site such as choroid or sclera (in a position posterior
to a plane through the posterior wall of the lens capsule),
vitreous, vitreous chamber, retina, optic nerve (i.e. the optic
disc), and blood vessels and nerves which vascularize or innervate
a posterior ocular region or site.
[0071] Thus, a posterior ocular condition can include a disease,
ailment or condition, such as for example, acute macular
neuroretinopathy; Behcet's disease; choroidal neovascularization;
diabetic uveitis; histoplasmosis; infections, such as fungal or
viral-caused infections; macular degeneration, such as acute
macular degeneration, non-exudative age related macular
degeneration and exudative age related macular degeneration; edema,
such as macular edema, cystoid macular edema and diabetic macular
edema; multifocal choroiditis; ocular trauma which affects a
posterior ocular site or location; ocular tumors; retinal
disorders, such as central retinal vein occlusion, diabetic
retinopathy (including proliferative diabetic retinopathy),
proliferative vitreoretinopathy (PVR), retinal arterial occlusive
disease, retinal detachment, uveitic retinal disease; sympathetic
ophthalmia; Vogt Koyanagi-Harada (VKH) syndrome; uveal diffusion; a
posterior ocular condition caused by or influenced by an ocular
laser treatment; posterior ocular conditions caused by or
influenced by a photodynamic therapy, photocoagulation, radiation
retinopathy, epiretinal membrane disorders, branch retinal vein
occlusion, anterior ischemic optic neuropathy, non-retinopathy
diabetic retinal dysfunction, retinitis pigmentosa, and glaucoma.
Glaucoma can be considered a posterior ocular condition because the
therapeutic goal is to prevent the loss of or reduce the occurrence
of loss of vision due to damage to or loss of retinal cells or
optic nerve cells (i.e. neuroprotection).
[0072] "Biodegradable polymer" means a polymer or polymers which
degrade in vivo, and wherein erosion of the polymer or polymers
over time is occurs concurrent with or subsequent to release of the
therapeutic agent. Specifically, hydrogels such as methylcellulose
which act to release drug through polymer swelling are specifically
excluded from the term "biodegradable polymer". The terms
"biodegradable" and "bioerodible" are equivalent and are used
interchangeably herein. A biodegradable polymer may be a
homopolymer, a copolymer, or a polymer comprising more than two
different polymeric units.
[0073] "Treat", "treating", or "treatment" means a reduction or
resolution or prevention of an ocular condition, ocular injury or
damage, or to promote healing of injured or damaged ocular
tissue.
[0074] "Therapeutically effective amount" means the level or amount
of agent needed to treat an ocular condition, or reduce or prevent
ocular injury or damage without causing significant negative or
adverse side effects to the eye or a region of the eye.
[0075] Intraocular implants have been developed which can release
drug loads over various' time periods. These implants, which when
inserted into an eye, such as the vitreous of an eye, provide
therapeutic levels of an alpha-2 adrenergic receptor agonist for
extended periods of time (e.g., for about 1 week or more). The
implants disclosed are effective in treating ocular conditions,
such as posterior ocular conditions.
[0076] In one embodiment of the present invention, an intraocular
implant comprises a biodegradable polymer matrix. The biodegradable
polymer matrix is one type of a drug release sustaining component.
The biodegradable polymer matrix is effective in forming a
biodegradable intraocular implant. The biodegradable intraocular
implant comprises an alpha-2 adrenergic receptor agonist associated
with the biodegradable polymer matrix. The matrix degrades at a
rate effective to sustain release of an amount of the alpha-2
adrenergic receptor agonist for a time greater than about one week
from the time in which the implant is placed in ocular region or
ocular site, such as the vitreous of an eye.
[0077] The alpha-2 adrenergic receptor agonist of the implant is
typically an agent that selectively activates alpha-2 adrenergic
receptors relative to alpha-1 adrenergic receptors. In certain
implants, the alpha-2 adrenergic receptor agonist is selectively
activates a subtype of the alpha-2 adrenergic receptors. For
example, the agonist may selectively activate one or more of the
alpha-2a, the alpha-2b, or the alpha-2c receptors, under certain
conditions, such as physiological conditions. Under other
conditions, the agonist of the implant may not be selective for
alpha-2 adrenergic receptor subtypes. The agonist may activate the
receptors by binding to the receptors, or by any other
mechanism.
[0078] In certain implants, the alpha-2 adrenergic receptor agonist
is a quinoxaline derivative. The quinoxaline derivatives useful in
the present implants are those quinoxaline derivatives having the
formula,
##STR00001##
[0079] pharmaceutically acceptable acid addition salts thereof, and
mixtures thereof. R.sub.1 and R.sub.2 each is independently
selected from the group consisting of H, alkyl radicals containing
1 to 4 carbon atoms and alkoxy radicals containing 1 to 4 carbon
atoms. R.sub.2 is preferably a methyl radical. The
2-imidazolin-2-ylamino group may be in any of the 5-, 6-, 7- and
8-positions, preferably in the 6-position, of the quinoxaline
nucleus. R.sub.3, R.sub.4 and R.sub.5 each is located in one of the
remaining 5-, 6-, 7- or 8-positions of the quinoxaline nucleus and
is independently selected from the group consisting of Cl, Br, H
and alkyl radicals containing 1 to 3 carbon atoms. R.sub.3 is
preferably in the 5-position of the quinoxaline nucleus, and
R.sub.4 and R.sub.5 are preferably both H. In a particularly useful
embodiment R.sub.3 is Br.
[0080] In at least one implant, R.sub.1 is H and R.sub.2 is
selected from alkyl radicals containing 1 to 4 carbon atoms.
R.sub.3 may advantageously be in the 5-position of the quinoxaline
nucleus and be selected from H and alkyl radicals containing 1 to 3
carbon atoms. All stereoisomers, tautomers and mixtures thereof
which comply with the constraints of one or more of the presently
useful compounds are included within the scope of the present
invention.
[0081] Pharmaceutically acceptable acid addition salts of the
compounds of the invention are those formed from acids which form
non-toxic addition salts containing pharmaceutically acceptable
anions, such as the hydrochloride, hydrobromide, hydroiodide,
sulfate, or bisulfate, phosphate or acid phosphate, acetate,
maleate, fumarate, oxalate, lactate, tartrate, citrate, gluconate,
saccharate and p-toluene sulphonate salts.
[0082] In more specific implants, the quinoxaline derivative has
the formula
##STR00002##
[0083] In additional implants, the alpha-2 adrenergic receptor
agonist is provided as a salt having the formula
##STR00003##
[0084] The foregoing salt is known as brimonidine tartrate (AGN
190342-F, 5-bromo-6-(2-imidazolidinylideneamino) quinoxaline
tartrate), and is publicly available from Allergan, Inc. under the
tradename Alphagan-P.RTM.. Brimonidine, an organic base, is
publicly available as either brimonidine tartrate salt or as
brimonidine freebase. The tartrate salt is more soluble than the
freebase in various aqueous media. Since both the tartrate salt and
the freebase are chemically stable and have melting points higher
than 200.degree. C., both forms are suitable in forming the present
implants.
[0085] Thus, the implant may comprise a therapeutic component which
comprises, consists essentially of, or consists of a brimonidine
salt, such as brimonidine tartrate, a brimonidine free base, or
mixtures thereof.
[0086] The alpha-2 adrenergic receptor agonist may be in a
particulate or powder form and entrapped by the biodegradable
polymer matrix. Usually, alpha-2 adrenergic receptor agonist
particles will have an effective average size less than about 3000
nanometers. In certain implants, the particles may have an
effective average particle size about an order of magnitude smaller
than 3000 nanometers. For example, the particles may have an
effective average particle size of less than about 500 nanometers.
In additional implants, the particles may have an effective average
particle size of less than about 400 nanometers, and in still
further embodiments, a size less than about 200 nanometers.
[0087] The alpha-2 adrenergic receptor agonist of the implant is
preferably from about 10% to 90% by weight of the implant. More
preferably, the alpha-2 adrenergic receptor agonist is from about
20% to about 80% by weight of the implant. In a preferred
embodiment, the alpha-2 adrenergic receptor agonist comprises about
20% by weight of the implant (e.g., 15%-25%). In another
embodiment, the alpha-2 adrenergic receptor agonist comprises about
50% by weight of the implant.
[0088] Suitable polymeric materials or compositions for use in the
implant include those materials which are compatible, that is
biocompatible, with the eye so as to cause no substantial
interference with the functioning or physiology of the eye. Such
materials preferably are at least partially and more preferably
substantially completely biodegradable or bioerodible.
[0089] Examples of useful polymeric materials include, without
limitation, such materials derived from and/or including organic
esters and organic ethers, which when degraded result in
physiologically acceptable degradation products, including the
monomers. Also, polymeric materials derived from and/or including,
anhydrides, amides, orthoesters and the like, by themselves or in
combination with other monomers, may also find use. The polymeric
materials may be addition or condensation polymers, advantageously
condensation polymers. The polymeric materials may be cross-linked
or non-cross-linked, for example not more than lightly
cross-linked, such as less than about 5%, or less than about 1% of
the polymeric material being cross-linked. For the most part,
besides carbon and hydrogen, the polymers will include at least one
of oxygen and nitrogen, advantageously oxygen. The oxygen may be
present as oxy, e.g. hydroxy or ether, carbonyl, e.g.
non-oxo-carbonyl, such as carboxylic acid ester, and the like. The
nitrogen may be present as amide, cyano and amino. The polymers set
forth in Heller, Biodegradable Polymers in Controlled Drug
Delivery, In: CRC Critical Reviews in Therapeutic Drug Carrier
Systems, Vol. 1, CRC Press, Boca Raton, Fla. 1987, pp 39-90, which
describes encapsulation for controlled drug delivery, may find use
in the present implants.
[0090] Of additional interest are polymers of hydroxyaliphatic
carboxylic acids, either homopolymers or copolymers, and
polysaccharides. Polyesters of interest include polymers of
D-lactic acid, L-lactic acid, racemic lactic acid, glycolic acid,
polycaprolactone, and combinations thereof. Generally, by employing
the L-lactate or D-lactate, a slowly eroding polymer or polymeric
material is achieved, while erosion is substantially enhanced with
the lactate racemate.
[0091] Among the useful polysaccharides are, without limitation,
calcium alginate, and functionalized celluloses, particularly
carboxymethylcellulose esters characterized by being water
insoluble, a molecular weight of about 5 kD to 500 kD, for
example.
[0092] Other polymers of interest include, without limitation,
polyvinyl alcohol, polyesters, polyethers and combinations thereof
which are biocompatible and may be biodegradable and/or
bioerodible.
[0093] Some preferred characteristics of the polymers or polymeric
materials for use in the present invention may include
biocompatibility, compatibility with the therapeutic component,
ease of use of the polymer in making the drug delivery systems of
the present invention, a half-life in the physiological environment
of at least about 6 hours, preferably greater than about one day,
not significantly increasing the viscosity of the vitreous, and
water insolubility.
[0094] The biodegradable polymeric materials which are included to
form the matrix are desirably subject to enzymatic or hydrolytic
instability. Water soluble polymers may be cross-linked with
hydrolytic or biodegradable unstable cross-links to provide useful
water insoluble polymers. The degree of stability can be varied
widely, depending upon the choice of monomer, whether a homopolymer
or copolymer is employed, employing mixtures of polymers, and
whether the polymer includes terminal acid groups.
[0095] Equally important to controlling the biodegradation of the
polymer and hence the extended release profile of the implant is
the relative average molecular weight of the polymeric composition
employed in the implant. Different molecular weights of the same or
different polymeric compositions may be included in the implant to
modulate the release profile. In certain implants, the relative
average molecular weight of the polymer will range from about 9 to
about 64 kD, usually from about 10 to about 54 kD, and more usually
from about 12 to about 45 kD.
[0096] In some implants, copolymers of glycolic acid and lactic
acid are used, where the rate of biodegradation is controlled by
the ratio of glycolic acid to lactic acid. The most rapidly
degraded copolymer has roughly equal amounts of glycolic acid and
lactic acid. Homopolymers, or copolymers having ratios other than
equal, are more resistant to degradation. The ratio of glycolic
acid to lactic acid will also affect the brittleness of the
implant, where a more flexible implant is desirable for larger
geometries. The % of polylactic acid in the polylactic acid
polyglycolic acid (PLGA) copolymer can be 0-100%, preferably about
15-85%, more preferably about 35-65%. In some implants, a 50/50
PLGA copolymer is used.
[0097] The biodegradable polymer matrix of the intraocular implant
may comprise a mixture of two or more biodegradable polymers. For
example, the implant may comprise a mixture of a first
biodegradable polymer and a different second biodegradable polymer.
One or more of the biodegradable polymers may have terminal acid
groups.
[0098] Release of a drug from an erodible polymer is the
consequence of several mechanisms or combinations of mechanisms.
Some of these mechanisms include desorption from the implants
surface, dissolution, diffusion through porous channels of the
hydrated polymer and erosion. Erosion can be bulk or surface or
combination of both. As discussed herein, the matrix of the
intraocular implant may release drug at a rate effective to sustain
release of an amount of the alpha-2 adrenergic receptor agonist for
more than one week after implantation into an eye. In certain
implants, therapeutic amounts of the alpha-2 adrenergic receptor
agonist are released for no more than about 30-35 days after
implantation. For example, an implant may comprise brimonidine
tartrate, and the matrix of the implant degrades at a rate
effective to sustain release of a therapeutically effective amount
of brimonidine tartrate for about one month after being placed in
an eye. As another example, the implant may comprise brimonidine
tartrate, and the matrix releases drug at a rate effective to
sustain release of a therapeutically effective amount of
brimonidine tartrate for more than forty days, such as for about
six months.
[0099] One example of the biodegradable intraocular implant
comprises an alpha-2 adrenergic receptor agonist associated with a
biodegradable polymer matrix, which comprises a mixture of
different biodegradable polymers. At least one of the biodegradable
polymers is a polylactide having a molecular weight of about 63.3
kD. A second biodegradable polymer is a polylactide having a
molecular weight of about 14 kD. Such a mixture is effective in
sustaining release of a therapeutically effective amount of the
alpha-2 adrenergic receptor agonist for a time period greater than
about one month from the time the implant is placed in an eye.
[0100] Another example of a biodegradable intraocular implant
comprises an alpha-2 adrenergic receptor agonist associated with a
biodegradable polymer matrix, which comprises a mixture of
different biodegradable polymers, each biodegradable polymer having
an inherent viscosity from about 0.16 dl/g to about 1.0 dl/g. For
example, one of the biodegradable polymers may have an inherent
viscosity of about 0.3 dl/g. A second biodegradable polymer may
have an inherent viscosity of about 1.0 dl/g. The inherent
viscosities identified above may be determined in 0.1% chloroform
at 25.degree. C.
[0101] One particular implant comprises brimonidine tartrate
associated with a combination of two different polylactide
polymers. The brimonidine tartrate is present in about 20% by
weight of the implant. One polylactide polymer has a molecular
weight of about 14 kD and an inherent viscosity of about 0.3 dl/g,
and the other polylactide polymer has a molecular weight of about
63.3 kD and an inherent viscosity of about 1.0 dl/g. The two
polylactide polymers are present in the implant in a 1:1 ratio.
Such an implant provides for release of the brimonidine for more
than two months in vitro, as described herein. The implant is
provided in the form of a rod or a filament produced by an
extrusion process.
[0102] The release of the alpha-2 adrenergic receptor agonist from
the intraocular implant comprising a biodegradable polymer matrix
may include an initial burst of release followed by a gradual
increase in the amount of the alpha-2 adrenergic receptor agonist
released, or the release may include an initial delay in release of
the alpha-2 adrenergic receptor agonist followed by an increase in
release. When the implant is substantially completely degraded, the
percent of the alpha-2 adrenergic receptor agonist that has been
released is about one hundred. Compared to existing implants, the
implants disclosed herein do not completely release, or release
about 100% of the alpha-2 adrenergic receptor agonist, until after
about one week of being placed in an eye.
[0103] It may be desirable to provide a relatively constant rate of
release of the alpha-2 adrenergic receptor agonist from the implant
over the life of the implant. For example, it may be desirable for
the alpha-2 adrenergic receptor agonist to be released in amounts
from about 0.01 .mu.g to about 2 .mu.g per day for the life of the
implant. However, the release rate may change to either increase or
decrease depending on the formulation of the biodegradable polymer
matrix. In addition, the release profile of the alpha-2 adrenergic
receptor agonist may include one or more linear portions and/or one
or more non-linear portions. Preferably, the release rate is
greater than zero once the implant has begun to degrade or
erode.
[0104] The implants may be monolithic, i.e. having the active agent
or agents homogenously distributed through the polymeric matrix, or
encapsulated, where a reservoir of active agent is encapsulated by
the polymeric matrix or as a core-shell type of implant. Due to
ease of manufacture, monolithic implants are usually preferred over
encapsulated forms. However, the greater control afforded by the
encapsulated, reservoir-type implant may be of benefit in some
circumstances, where the therapeutic level of the drug falls within
a narrow window. In addition, the therapeutic component, including
the alpha-2 adrenergic receptor agonist, may be distributed in a
non-homogenous pattern in the matrix. For example, the implant may
include a portion that has a greater concentration of the alpha-2
adrenergic receptor agonist relative to a second portion of the
implant.
[0105] The intraocular implants disclosed herein may have a size of
between about 5 .mu.m and about 2 mm, or between about 10 .mu.m and
about 1 mm for administration with a needle, greater than 1 mm, or
greater than 2 mm, such as 3 mm or up to 10 mm, for administration
by surgical implantation. The vitreous chamber in humans is able to
accommodate relatively large implants of varying geometries, having
lengths of, for example, 1 to 10 mm. The implant may be a
cylindrical pellet (e.g., rod) with dimensions of about 2
mm.times.0.75 mm diameter. Or the implant may be a cylindrical
pellet with a length of about 7 mm to about 10 mm, and a diameter
of about 0.75 mm to about 1.5 mm.
[0106] The implants may also be at least somewhat flexible so as to
facilitate both insertion of the implant in the eye, such as in the
vitreous, and accommodation of the implant. The total weight of the
implant is usually about 250-5000 .mu.g, more preferably about
500-1000 .mu.g. For example, an implant may be about 500 .mu.g, or
about 1000 .mu.g. For non-human individuals, the dimensions and
total weight of the implant(s) may be larger or smaller, depending
on the type of individual. For example, humans have a vitreous
volume of approximately 3.8 ml, compared with approximately 30 ml
for horses, and approximately 60-100 ml for elephants. An implant
sized for use in a human may be scaled up or down accordingly for
other animals, for example, about 8 times larger for an implant for
a horse, or about, for example, 26 times larger for an implant for
an elephant.
[0107] Thus, implants can be prepared where the center may be of
one material and the surface may have one or more layers of the
same or a different composition, where the layers may be
cross-linked, or of a different molecular weight, different density
or porosity, or the like. For example, where it is desirable to
quickly release an initial bolus of drug, the center may be a
polylactate coated with a polylactate-polyglycolate copolymer, so
as to enhance the rate of initial degradation. Alternatively, the
center may be polyvinyl alcohol coated with polylactate, so that
upon degradation of the polylactate exterior the center would
dissolve and be rapidly washed out of the eye.
[0108] The implants may be of any geometry including fibers,
sheets, films, microspheres, spheres, circular discs, plaques and
the like. The upper limit for the implant size will be determined
by factors such as toleration for the implant, size limitations on
insertion, ease of handling, etc. Where sheets or films are
employed, the sheets or films will be in the range of at least
about 0.5 mm.times.0.5 mm, usually about 3-10 mm.times.5-10 mm with
a thickness of about 0.1-1.0 mm for ease of handling. Where fibers
are employed, the fiber diameter will generally be in the range of
about 0.05 to 3 mm and the fiber length will generally be in the
range of about 0.5-10 mm. Spheres may be in the range of 0.5 .mu.m
to 4 mm in diameter, with comparable volumes for other shaped
particles.
[0109] The size and form of the implant can also be used to control
the rate of release, period of treatment, and drug concentration at
the site of implantation. Larger implants will deliver a
proportionately larger dose, but depending on the surface to mass
ratio, may have a slower release rate. The particular size and
geometry of the implant are chosen to suit the site of
implantation.
[0110] The proportions of alpha-2 adrenergic receptor agonist,
polymer, and any other modifiers may be empirically determined by
formulating several implants with varying proportions. A USP
approved method for dissolution or release test can be used to
measure the rate of release (USP 23; NF 18 (1995) pp. 1790-1798).
For example, using the infinite sink method, a weighed sample of
the implant is added to a measured volume of a solution containing
0.9% NaCl in water, where the solution volume will be such that the
drug concentration is after release is less than 5% of saturation.
The mixture is maintained at 37.degree. C. and stirred slowly to
maintain the implants in suspension. The appearance of the
dissolved drug as a function of time may be followed by various
methods known in the art, such as spectrophotometrically, HPLC,
mass spectroscopy, etc. until the absorbance becomes constant or
until greater than 90% of the drug has been released.
[0111] In addition to the alpha-2 adrenergic receptor agonist or
alpha-2 adrenergic receptor agonists included in the intraocular
implants disclosed herein, the intraocular implants may also
include one or more additional ophthalmically acceptable
therapeutic agents. For example, the implant may include one or
more antihistamines, one or more antibiotics, one or more beta
blockers, one or more steroids, one or more antineoplastic agents,
one or more immunosuppressive agents, one or more antiviral agents,
one or more antioxidant agents, and mixtures thereof.
[0112] Pharmacologic or therapeutic agents which may find use in
the present systems, include, without limitation, those disclosed
in U.S. Pat. Nos. 4,474,451, columns 4-6 and 4,327,725, columns
7-8.
[0113] Examples of antihistamines include, and are not limited to,
loratadine, hydroxyzine, diphenhydramine, chlorpheniramine,
brompheniramine, cyproheptadine, terfenadine, clemastine,
triprolidine, carbinoxamine, diphenylpyraline, phenindamine,
azatadine, tripelennamine, dexchlorpheniramine, dexbrompheniramine,
methdilazine, and trimeprazine doxylamine, pheniramine, pyrilamine,
chlorcyclizine, thonzylamine, and derivatives thereof.
[0114] Examples of antibiotics include without limitation,
cefazolin, cephradine, cefaclor, cephapirin, ceftizoxime,
cefoperazone, cefotetan, cefutoxime, cefotaxime, cefadroxil,
ceftazidime, cephalexin, cephalothin, cefamandole, cefoxitin,
cefonicid, ceforanide, ceftriaxone, cefadroxil, cephradine,
cefuroxime, ampicillin, amoxicillin, cyclacillin, ampicillin,
penicillin G, penicillin V potassium, piperacillin, oxacillin,
bacampicillin, cloxacillin, ticarcillin, azlocillin, carbenicillin,
methicillin, nafcillin, erythromycin, tetracycline, doxycycline,
minocycline, aztreonam, chloramphenicol, ciprofloxacin
hydrochloride, clindamycin, metronidazole, gentamicin, lincomycin,
tobramycin, vancomycin, polymyxin B sulfate, colistimethate,
colistin, azithromycin, augmentin, sulfamethoxazole, trimethoprim,
and derivatives thereof.
[0115] Examples of beta blockers include acebutolol, atenolol,
labetalol, metoprolol, propranolol, timolol, and derivatives
thereof.
[0116] Examples of steroids include corticosteroids, such as
cortisone, prednisolone, fluorometholone, dexamethasone, medrysone,
loteprednol, fluazacort, hydrocortisone, prednisone, betamethasone,
prednisone, methylprednisolone, triamcinolone hexacetonide,
paramethasone acetate, diflorasone, fluocinonide, fluocinolone,
triamcinolone, derivatives thereof, and mixtures thereof.
[0117] Examples of antineoplastic agents include adriamycin,
cyclophosphamide, actinomycin, bleomycin, daunorubicin,
doxorubicin, epirubicin, mitomycin, methotrexate, fluorouracil,
carboplatin, carmustine (BCNU), methyl-CCNU, cisplatin, etoposide,
interferons, camptothecin and derivatives thereof, phenesterine,
taxol and derivatives thereof, taxotere and derivatives thereof,
vinblastine, vincristine, tamoxifen, etoposide, piposulfan,
cyclophosphamide, and flutamide, and derivatives thereof.
[0118] Examples of immunosuppressive agents include cyclosporine,
azathioprine, tacrolimus, and derivatives thereof.
[0119] Examples of antiviral agents include interferon gamma,
zidovudine, amantadine hydrochloride, ribavirin, acyclovir,
valaciclovir, dideoxycytidine, phosphonoformic acid, ganciclovir,
and derivatives thereof.
[0120] Examples of antioxidant agents include ascorbate,
alpha-tocopherol, mannitol, reduced glutathione, various
carotenoids, cysteine, uric acid, taurine, tyrosine, superoxide
dismutase, lutein, zeaxanthin, cryptpxanthin, astaxanthin,
lycopene, N-acetyl-cysteine, carnosine, gamma-glutamylcysteine,
quercetin, lactoferrin, dihydrolipoic acid, citrate, Ginkgo Biloba
extract, tea catechins, bilberry extract, vitamins E or esters of
vitamin E, retinyl palmitate, and derivatives thereof.
[0121] Other therapeutic agents include squalamine, carbonic
anhydrase inhibitors, alpha agonists, prostamides, prostaglandins,
antiparasitics, antifungals, and derivatives thereof.
[0122] The amount of active agent or agents employed in the
implant, individually or in combination, will vary widely depending
on the effective dosage required and the desired rate of release
from the implant. Usually the agent will be at least about 1, more
usually at least about 10 weight percent of the implant, and
usually not more than about 80, more usually not more than about 40
weight percent of the implant.
[0123] In addition to the therapeutic component, the intraocular
implants disclosed herein may include effective amounts of
buffering agents, preservatives and the like. Suitable water
soluble buffering agents include, without limitation, alkali and
alkaline earth carbonates, phosphates, bicarbonates, citrates,
borates, acetates, succinates and the like, such as sodium
phosphate, citrate, borate, acetate, bicarbonate, carbonate and the
like. These agents advantageously present in amounts sufficient to
maintain a pH of the system of between about 2 to about 9 and more
preferably about 4 to about 8. As such the buffering agent may be
as much as about 5% by weight of the total implant. Suitable water
soluble preservatives include sodium bisulfite, sodium bisulfate,
sodium thiosulfate, ascorbate, benzalkonium chloride,
chlorobutanol, thimerosal, phenylmercuric acetate, phenylmercuric
borate, phenylmercuric nitrate, parabens, methylparaben, polyvinyl
alcohol, benzyl alcohol, phenylethanol and the like and mixtures
thereof. These agents may be present in amounts of from 0.001 to
about 5% by weight and preferably 0.01 to about 2% by weight. In at
least one of the present implants, a purite preservative is
provided in the implant, such as when the alpha-2 adrenergic
receptor agonist is brimonidine. Thus, these implants may contain a
therapeutically effective amount of Alphagan-P.RTM..
[0124] In some situations mixtures of implants may be utilized
employing the same or different pharmacological agents. In this
way, a cocktail of release profiles, giving a biphasic or triphasic
release with a single administration is achieved, where the pattern
of release may be greatly varied.
[0125] Additionally, release modulators such as those described in
U.S. Pat. No. 5,869,079 may be included in the implants. The amount
of release modulator employed will be dependent on the desired
release profile, the activity of the modulator, and on the release
profile of the alpha-2 adrenergic receptor agonist in the absence
of modulator. Electrolytes such as sodium chloride and potassium
chloride may also be included in the implant. Where the buffering
agent or enhancer is hydrophilic, it may also act as a release
accelerator. Hydrophilic additives act to increase the release
rates through faster dissolution of the material surrounding the
drug particles, which increases the surface area of the drug
exposed, thereby increasing the rate of drug bioerosion. Similarly,
a hydrophobic buffering agent or enhancer dissolve more slowly,
slowing the exposure of drug particles, and thereby slowing the
rate of drug bioerosion.
[0126] In certain implants, an implant comprising brimonidine or
brimonidine tartrate and a biodegradable polymer matrix is able to
release or deliver an amount of brimonidine between about 0.1 mg to
about 0.5 mg for about 3-6 months after implantation into the eye.
The implant may be configured as a rod or a wafer. A rod-shaped
implant may be derived from filaments extruded from a 720 .mu.m
nozzle and cut into 1 mg size. A wafer-shaped implant may be a
circular disc having a diameter of about 2.5 mm, a thickness of
about 0.127 mm, and a weight of about 1 mg.
[0127] The proposed 3-month release formulations may be sterile,
and bioerodible in the form of a rod, a wafer or a microsphere
containing brimonidine tartrate within a PLA matrix or POE matrix.
The implants are designed to delay the clearance of the drug and
reduce the need for repeated implantation over 3-month period,
thereby lowering the risk of complications.
[0128] Various techniques may be employed to produce the implants
described herein. Useful techniques include, but are not
necessarily limited to, solvent evaporation methods, phase
separation methods, interfacial methods, molding methods, injection
molding methods, extrusion methods, co-extrusion methods, carver
press method, die cutting methods, heat compression, combinations
thereof and the like.
[0129] Specific methods are discussed in U.S. Pat. No. 4,997,652.
Extrusion methods may be used to avoid the need for solvents in
manufacturing. When using extrusion methods, the polymer and drug
are chosen so as to be stable at the temperatures required for
manufacturing, usually at least about 85 degrees Celsius. Extrusion
methods use temperatures of about 25 degrees C. to about 150
degrees C., more preferably about 65 degrees C. to about 130
degrees C. An implant may be produced by bringing the temperature
to about 60 degrees C. to about 150 degrees C. for drug/polymer
mixing, such as about 130 degrees C., for a time period of about 0
to 1 hour, 0 to 30 minutes, or 5-15 minutes. For example, a time
period may be about 10 minutes, preferably about 0 to 5 min. The
implants are then extruded at a temperature of about 60 degrees C.
to about 130 degrees C., such as about 75 degrees C.
[0130] In addition, the implant may be coextruded so that a coating
is formed over a core region during the manufacture of the
implant.
[0131] Compression methods may be used to make the implants, and
typically yield implants with faster release rates than extrusion
methods. Compression methods may use pressures of about 50-150 psi,
more preferably about 70-80 psi, even more preferably about 76 psi,
and use temperatures of about 0 degrees C. to about 115 degrees C.,
more preferably about 25 degrees C.
[0132] The implants of the present invention may be inserted into
the eye, for example the vitreous chamber of the eye, by a variety
of methods, including placement by forceps or by trocar following
making a 2-3 mm incision in the sclera. One example of a device
that may be used to insert the implants into an eye is disclosed in
U.S. Patent Publication No. 2004/0054374. The method of placement
may influence the therapeutic component or drug release kinetics.
For example, delivering the implant with a trocar may result in
placement of the implant deeper within the vitreous than placement
by forceps, which may result in the implant being closer to the
edge of the vitreous. The location of the implant may influence the
concentration gradients of therapeutic component or drug
surrounding the element, and thus influence the release rates
(e.g., an element placed closer to the edge of the vitreous may
result in a slower release rate).
[0133] The present implants are configured to release an amount of
alpha-2 adrenergic receptor agonist in an eye for a period of time
to minimize an ocular vascular occlusion, such as a retinal
vascular occlusion. Retinal vascular occlusion may result from a
variety of diseases such as retinal arterial occlusive disease,
central retinal vein occlusion, disseminated intravascular
coagulopathy, branch retinal vein occlusion, hypertensive fundus
changes, ocular ischemic syndrome, retinal arterial microaneurysms,
hemi-retinal vein occlusion, central retinal artery occlusion,
branch retinal artery occlusion, carotid artery disease (cad),
eales disease and vasculopathies associated with diabetes. By
implanting the alpha-2 adrenergic receptor agonist-containing
implants into the vitreous of an eye, it is believed that the
agonist is effective to reduce occlusion within blood vessels
located in the eye.
[0134] In addition, the present implants may be configured to
release an alpha-2 adrenergic receptor agonist in a therapeutically
effective amount for a period of time effective to treat glaucoma
of a patient.
[0135] The implants disclosed herein may also be configured to
release additional therapeutic agents, as described above, which
may be effective in treating diseases or conditions, such as the
following:
[0136] Maculopathies/retinal degeneration: macular degeneration,
including age related macular degeneration (ARMD), such as
non-exudative age related macular degeneration and exudative age
related macular degeneration, choroidal neovascularization,
retinopathy, including diabetic retinopathy, acute and chronic
macular neuroretinopathy, central serous chorioretinopathy, and
macular edema, including cystoid macular edema, and diabetic
macular edema. Uveitis/retinitis/choroiditis: acute multifocal
placoid pigment epitheliopathy, Behcet's disease, birdshot
retinochoroidopathy, infectious (syphilis, lyme, tuberculosis,
toxoplasmosis), uveitis, including intermediate uveitis (pars
planitis) and anterior uveitis, multifocal choroiditis, multiple
evanescent white dot syndrome (MEWDS), ocular sarcoidosis,
posterior scleritis, serpiginous choroiditis, subretinal fibrosis,
uveitis syndrome, and Vogt-Koyanagi-Harada syndrome. Vascular
diseases/exudative diseases: retinal arterial occlusive disease,
central retinal vein occlusion, disseminated intravascular
coagulopathy, branch retinal vein occlusion, hypertensive fundus
changes, ocular ischemic syndrome, retinal arterial microaneurysms,
Coat's disease, parafoveal telangiectasia, hemi-retinal vein
occlusion, papillophlebitis, central retinal artery occlusion,
branch retinal artery occlusion, carotid artery disease (CAD),
frosted branch angiitis, sickle cell retinopathy and other
hemoglobinopathies, angioid streaks, familial exudative
vitreoretinopathy, Eales disease. Traumatic/surgical: sympathetic
ophthalmia, uveitic retinal disease, retinal detachment, trauma,
laser, PDT, photocoagulation, hypoperfusion during surgery,
radiation retinopathy, bone marrow transplant retinopathy.
Proliferative disorders: proliferative vitreal retinopathy and
epiretinal membranes, proliferative diabetic retinopathy.
Infectious disorders: ocular histoplasmosis, ocular toxocariasis,
presumed ocular histoplasmosis syndrome (PONS), endophthalmitis,
toxoplasmosis, retinal diseases associated with HIV infection,
choroidal disease associated with HIV infection, uveitic disease
associated with HIV Infection, viral retinitis, acute retinal
necrosis, progressive outer retinal necrosis, fungal retinal
diseases, ocular syphilis, ocular tuberculosis, diffuse unilateral
subacute neuroretinitis, and myiasis. Genetic disorders: retinitis
pigmentosa, systemic disorders with associated retinal dystrophies,
congenital stationary night blindness, cone dystrophies,
Stargardt's disease and fundus flavimaculatus, Bests disease,
pattern dystrophy of the retinal pigmented epithelium, X-linked
retinoschisis, Sorsby's fundus dystrophy, benign concentric
maculopathy, Bietti's crystalline dystrophy, pseudoxanthoma
elasticum. Retinal tears/holes: retinal detachment, macular hole,
giant retinal tear. Tumors: retinal disease associated with tumors,
congenital hypertrophy of the RPE, posterior uveal melanoma,
choroidal hemangioma, choroidal osteoma, choroidal metastasis,
combined hamartoma of the retina and retinal pigmented epithelium,
retinoblastoma, vasoproliferative tumors of the ocular fundus,
retinal astrocytoma, intraocular lymphoid tumors. Miscellaneous:
punctate inner choroidopathy, acute posterior multifocal placoid
pigment epitheliopathy, myopic retinal degeneration, acute retinal
pigment epithelitis and the like.
[0137] In one embodiment, an implant, such as the implants
disclosed herein, is administered to a posterior segment of an eye
of a human or animal patient, and preferably, a living human or
animal. In at least one embodiment, an implant is administered
without accessing the subretinal space of the eye. For example, a
method of treating a patient may include placing the implant
directly into the posterior chamber of the eye. In other
embodiments, a method of treating a patient may comprise
administering an implant to the patient by at least one of
intravitreal injection, subconjunctival injection, sub-tenon
injections, retrobulbar injection, and suprachoroidal
injection.
[0138] In at least one embodiment, a method of reducing retinal
vascular occlusion in a patient comprises administering one or more
implants containing one or more alpha-2 adrenergic receptor
agonists, as disclosed herein to a patient by at least one of
intravitreal injection, subconjunctival injection, sub-tenon
injection, retrobulbar injection, and suprachoroidal injection. A
syringe apparatus including an appropriately sized needle, for
example, a 27 gauge needle or a 30 gauge needle, can be effectively
used to inject the composition with the posterior segment of an eye
of a human or animal. Repeat injections are often not necessary due
to the extended release of the alpha-2 adrenergic receptor agonists
from the implants.
[0139] In another aspect of the invention, kits for treating an
ocular condition of the eye are provided, comprising: a) a
container comprising an extended release implant comprising a
therapeutic component including an alpha-2 adrenergic receptor
agonist, such as brimonidine free base or brimonidine tartrate
(e.g., Alphagan-P.RTM.), and a drug release sustaining component;
and b) instructions for use. Instructions may include steps of how
to handle the implants, how to insert the implants into an ocular
region, and what to expect from using the implants.
Example 1
Manufacture and Testing of Implants Containing Brimonidine and a
Biodegradable Polymer Matrix
[0140] Biodegradable implants were made by combining brimonidine
tartrate or brimonidine freebase with a biodegradable polymer
composition in a stainless steel mortar. The combination was mixed
via a Turbula shaker set at 96 RPM for 15 minutes. The powder blend
was scraped off the wall of the mortar and then remixed for an
additional 15 minutes. The mixed powder blend was heated to a
semi-molten state at specified temperature for a total of 30
minutes, forming a polymer/drug melt.
[0141] Rods were manufactured by pelletizing the polymer/drug melt
using a 9 gauge polytetrafluoroethylene (PTFE) tubing, loading the
pellet into the barrel and extruding the material at the specified
core extrusion temperature into filaments. The filaments were then
cut into about 1 mg size implants or drug delivery systems. The
rods had dimensions of about 2 mm long.times.0.72 mm diameter. The
rod implants weighed between about 900 .mu.g and 1100 .mu.g.
[0142] Wafers were formed by flattening the polymer melt with a
Carver press at a specified temperature and cutting the flattened
material into wafers, each weighing about 1 mg. The wafers had a
diameter of about 2.5 mm and a thickness of about 0.13 mm. The
wafer implants weighed between about 900 .mu.g and 1100 .mu.g.
[0143] The in-vitro release testing was performed on each lot of
implant (rod or wafer) in six replicates initially, and later in
four replicates. Each implant was placed into a 24 mL screw cap
vial with 10 mL of Phosphate Buffered Saline solution at 37.degree.
C. and 1 mL aliquots were removed and replaced with equal volume of
fresh medium on day 1, 4, 7, 14, 28, and every two weeks
thereafter.
[0144] The drug assays were performed by HPLC, which consists of a
Waters 2690 Separation Module (or 2696), and a Waters 2996
Photodiode Array Detector. An Ultrasphere, C-18 (2), 5 .mu.m;
4.6.times.150 mm column heated at 30.degree. C. was used for
separation and the detector was set at 264 nm. The mobile phase was
(10:90) MeOH-buffered mobile phase with a flow rate of 1 mL/min and
a total run time of 12 min per sample. The buffered mobile phase
comprised of (68:0.75:0.25:31) 13 mM 1-Heptane Sulfonic Acid,
sodium salt-glacial acetic acid-triethylamine-Methanol. The release
rates were determined by calculating the amount of drug being
released in a given volume of medium over time in .mu.g/day.
[0145] The polymers chosen for the implants are were obtained from
Boehringer Ingelheim. The polymers were: RG502, RG752, R202H, R203
and R206, and Purac PDLG (50/50). RG502 is (50:50)
poly(D,L-lactide-co-glycolide), RG752 is (75:25)
poly(D,L-lactide-co-glycolide), R202H is 100% poly(D, L-lactide)
with acid end group or terminal acid groups, R203 and R206 are both
100% poly(D, L-lactide). Purac PDLG (50/50) is (50:50)
poly(D,L-lactide-co-glycolide). The inherent viscosity of RG502,
RG752, R202H, R203, R206, and Purac PDLG are 0.2, 0.2, 0.2, 0.3,
1.0, and 0.2 dL/g, respectively. The average molecular weight of
RG502, RG752, R202H, R203, R206, and Purac PDLG are, 11700, 11200,
6500, 14000, 63300, and 9700 Daltons, respectively.
[0146] A total of 53 formulations were prepared, 31 rods and 22
wafers. Of the rod formulations, 4 had release periods longer than
3 months and 3 had release periods longer than 6 months. Of the
wafer formulations, 7 had release periods longer than 3 months and
4 had release periods longer than 4 months.
[0147] A list of the rod formulations is shown in Table 1, and a
list of wafer formulations is shown in Table 2.
TABLE-US-00001 TABLE 1 Brimonidine Rod Formulations Formulation Lot
BT (w/w) BFB (w/w) Polymer I.V. (dL/g) Core Extr T 1 295-123 50%
RG752 0.2 104.degree. C. 2 295-124 50% RG752 0.2 105.degree. C. 3
295-126 50% RG502 0.2 108.degree. C. 4 295-127 50% RG502 0.2
112.degree. C. 5 295-167 50% R203 0.3 98.degree. C. 6 295-168 50%
R203 0.3 101.degree. C. 7 295-169 50% R206 1.0 118.degree. C. 8
295-170 50% R206 1.0 104.degree. C. 9 295-171 25% R206 1.0
98.degree. C. 10 295-172 25% R203 0.3 96.degree. C. 11 453-3 10%
40% R203 0.3 98.degree. C. 12 453-4 5% 20% R203 0.3 96.degree. C.
13 453-6 10% 40% R206 1.0 105.degree. C. 14 453-7 5% 20% R206 1.0
104.degree. C. 15 453-8 5% 45% R206 1.0 102.degree. C. 16 453-9 15%
R206 1.0 102.degree. C. 17 453-10 20% (1:1) R203/R206 N/A
98.degree. C. 18 453-11 20% (3:1) R203/R206 N/A 96.degree. C. 19
453-12 10% 40% RG752 0.2 108.degree. C. 20 453-13 5% 20% RG752 0.2
104.degree. C. 24 453-50 20% R206 1.0 100.degree. C. 25 453-51 17%
(1:1) R203/R206 N/A 98.degree. C. 26 453-52 40% (1:1) RG752/RG502
N/A 105.degree. C. 27 453-53 40% (3:1) RG752/RG502 N/A 103.degree.
C. 28 453-54 40% (1:1) R203/RG502 N/A 103.degree. C. 29 453-55 50%
R202H 0.2 96.degree. C. 30 453-56 50% R202H 0.2 98.degree. C. 31
453-73 20% RG752 0.2 98.degree. C. 32 453-74 20% Purac (Mw 9700)
N/A 95.degree. C. 33 453-75 20% Purac (Mw 9700) N/A 92.degree. C.
53 453-95 20% (2:1) R203/R206 N/A 97.degree. C. BT = Brimonidine
Tartrate BFB = Brimonidine Free Base I.V. = Inherent Viscosity
TABLE-US-00002 TABLE 2 Brimonidine wafer Formulations BT BFB I.V.
Formulation Lot (w/w) (w/w) Polymer (dL/g) 21 453-47 25% R206 1.0
22 453-48 20% (1:1) R203/R206 N/A 23 453-49 20% (3:1) R203/R206 N/A
34 453-76 20% (1:1) R203/R206 N/A 35 453-77 25% R206 1.0 36 453-78
20% (3:1) R203/R206 N/A 37 453-79 25% R203 0.3 38 453-80 50% R203
0.3 39 453-81 50% R206 1.0 40 453-82 15% R206 1.0 41 453-83 40%
(1:1) RG752/RG502 N/A 42 453-84 40% (2:1) RG752/RG502 N/A 43 453-85
40% (1:1) R203/RG502 N/A 44 453-86 50% R202H 0.2 45 453-87 50%
(1:1) RG752/RG502 N/A 46 453-88 10% (1:1) R203/R206 N/A 47 453-89
15% (1:1) R203/R206 N/A 48 453-90 10% (3:1) R203/R206 N/A 49 453-91
15% (3:1) R203/R206 N/A 50 453-92 10% R206 1.0 51 453-93 10% (2:1)
R203/R206 N/A 52 453-94 15% (2:1) R203/R206 N/A
BT=Brimonidine Tartrate BFB=Brimonidine Free Base I.V.=Inherent
Viscosity
Rod Formulations
[0148] The first 10 formulations were prepared with the five
different polymers, RG752, RG502, R203, R206, and R202H each at 50%
w/w drug load for both brimonidine tartrate and brimonidine free
base. The release profiles are shown in FIG. 1 for brimonidine
tartrate and FIG. 2 for brimonidine free base.
[0149] In most cases, formulations prepared with brimonidine
tartrate had a faster initial burst than those prepared from
brimonidine freebase using the same polymer, except for RG502. The
data also show that brimonidine freebase had a lag time of
approximately 30 days when formulated in poly(D, L-lactide) matrix
(R203, R206, and R202H), while brimonidine tartrate was released
completely on the first day (F5 and F7). This may be due to the
quick dissolution of brimonidine tartrate on the surface of the
implant.
[0150] Several formulations using R203 and R206 with drug doses
lower than 50% were prepared, and the release profiles are shown in
FIG. 3. Dramatic effects were observed when the drug load was
lowered from 50% down to 25%. For example, formulation #9 was
prepared with 25% brimonidine tartrate in R206 and it gave a total
release of 89% after 105 days before leveling off. Comparing this
to formulation #7, which was 50% brimonidine tartrate in R206, and
it released 100% in one day. Similarly, formulation #10 was
prepared with 25% brimonidine tartrate in R203 and it gave a total
release of 90% after 105 days before it leveled off. Comparing this
to formulation #5, which released 74% on day one.
[0151] With 20% brimonidine tartrate in R206 (F24), a 14 day lag
time is present before it started releasing and eventually reaching
89.5% release after 134 days. At 15% brimonidine tartrate in R206
(F16), the lag time increased to 28 days before it started
releasing and eventually reaching 97.6% after 175 days.
[0152] The release profiles of formulation #9 and #10 behaved in an
opposite but complementary way, in that one polymer exhibits early
release while the other exhibits a delayed release, but both
reached the same end point at the same time. When both polymers
were combined with a lower drug load, a more linear and longer
release profile would be obtained, as shown in FIG. 4.
[0153] The data show that formulation #17, 20% brimonidine
tartrate/(1:1) R203/R206, has a desirable in-vitro release profile
for a six month release implant. It released approximately 90% of
the brimonidine tartrate after 175 days. It was also shown that by
varying the proportion of R203 and R206, even with the same drug
load (Formulation #17, #18, and #53), different release profiles
would result.
[0154] Brimonidine freebase formulations with polymer blends were
also prepared to see if a more linear release profile could be
obtained. Knowing its low solubility in aqueous media and its
release characteristics in each polymer, different combinations of
RG502-RG752, and RG502-R203 were prepared, and the release profiles
are shown in FIG. 5.
[0155] The duration of release for all three formulations was
approximately 2 months, but all three exhibited a lag time between
1 to 2 weeks. Two formulations (F32 and F33) were prepared with
Purac polymer, PDLG (50/50)-Mw 9700, one with brimonidine tartrate
and the one with brimonidine freebase. Both formulations had fast
release with high standard of deviation; therefore, the release
tests were stopped after 7 days.
Wafer Formulations
[0156] The first set of wafer formulations was prepared from 3
existing rod formulations. Specifically, formulations #9, #17 and
#18, with release reaching 89.4% after 105 days, 89.2% after 175
days, and 102% after 175 days, respectively. The release profiles
of the first three wafer formulations are shown in FIG. 6.
[0157] These three formulations had release periods lasting only
two to three weeks, while their rod counterparts had release
periods lasting three to four months. This may be due to the
increased surface area of the wafer compared to that of a rod. In
the wafer configuration, drug load also determines the duration of
drug release. Therefore, drug load was reduced from 20-25% down to
15% and 10% and the release profiles are shown in FIGS. 7 and
8.
[0158] At 15% drug load, formulation #7 had a cumulative release
51.4% after 35 days, while formulation #47, 49, and 52 had
cumulative releases of 93.2%, 92.8% and 88.5%, respectively, after
99 days. The latter three formulations may be effective as a
4-month drug delivery system.
[0159] At 10% drug load, formulations #46, #48, #50, and #51 had
cumulative releases of 83.8%, 98.0%, 92.7% and 89.2%, respectively,
after 133 days. These four formulations may be effective as 5-month
drug delivery systems. Both FIGS. 7 and 8 demonstrate that lowering
the drug load yielded not only a longer duration of release but
also more linear release profiles for all formulations. The figures
also show that using a polymer blend instead of just a single
polymer, such as R206, should yield a more linear release profile
with lower standard of deviations.
[0160] Three wafer formulations were prepared from three previous
rod formulations #26, #27, and #28, and the release profiles are
shown in FIG. 9. The three wafer formulations released slightly
faster than their rod counterparts at day 28 and they were expected
to complete their release between days 31 to 55.
Conclusions
[0161] Of the 15 rod formulations prepared from brimonidine
tartrate, three formulations had release periods longer than 3
months (F9, F10, and F53), two formulations had release periods
longer than 4 months (F24 and F25), and three formulations had
release periods close to 6 months (F16, F17, and F18). Of the 8 rod
formulations prepared from brimonidine freebase, 3 had release
periods longer than 2 months (F26, F27, and F28).
[0162] Of the 22 wafer formulations, 11 were prepared from
brimonidine tartrate and 11 were prepared from brimonidine
freebase. Of the 11 wafer formulations prepared from brimonidine
tartrate, 3 had release periods of about 4 months (F47, F49, and
F52), and 4 had release periods between 4 and 5 months (F46, F48,
F50, and F51). Of the 11 wafer formulations prepared from
brimonidine freebase, 4 had release periods between 3 and 4 months
(F35, F36, F38, and F39), and 5 had release periods between one to
two months (F34, F37, F41, F42, and F43).
[0163] In general, the wafer formulations prepared from brimonidine
tartrate or brimonidine freebase have faster release than their rod
counterparts.
Example 2
In Vivo Testing of Intraocular Implants Containing Brimonidine and
a Biodegradable Polymer Matrix
[0164] Cynomolgous monkeys were randomly assigned to receive either
placebo (n=2) or brimonidine (n=2) formulated intravitreal
implants. Baseline measures were performed 3 days prior to
implantation and 10 days following implantation with intraocular
pressure (IOP), mfERG, laser Doppler scanning topography/flowmetry
(HRT/HRF), optical coherence tomography (OCT), indocyanine green
angiography (ICG) and fluorescein angiography (FA).
[0165] Three implants (Formulation #17 described in Example 1),
each formulated with 200 .mu.g brimonidine or placebo were
implanted intravitreally into an eye through a port made with an
MVR blade (OS), the port was closed with sutures. Wide angle
contact lens fundus photography verified implant count and
localization.
[0166] Branch retinal vein occlusion (BRVO) was achieved by
injecting 1 ml of 20 mg/kg Rose Bengal intravenously followed by
thermal irradiation using Omni Coherent Diode laser at 532 nm, 600
mW, 50 um spot size, 0.01 sec pulse mode with a 1.6.times.
inversion contact lens. Laser pulses were delivered until the vein
segment was closed. One brimonidine treated monkey received 235
pulses and the other received 78 pulses. One placebo treated monkey
received 43 pulses and the other received 31 pulses. Vascular
occlusion of a vein was induced in the superior arcade
approximately one disc diameter from the optic nerve head.
Occlusion was verified post-laser by fundus photography.
[0167] Funduscopic observations at day 1 following BRVO showed
dramatic retinopathy and vasculopathy in both monkeys with placebo
implant--marked retinal edema and dot blot hemorrhages, vessel
tortuosity, cotton wool spots. Fluorescein angiography verified
vein occlusion and stagnate blood flow upstream from the lasered
region and elucidated late phase fluorescein leak and pooling from
retina capillaries. Monkeys with brimonidine implants had less than
5 small dot blot hemorrhages, some retinal edema localized to the
superior retina. Fluorescein angiography in brimonidine monkeys
showed reperfusion of the once occluded vein with minimal stagnate
blood flow.
[0168] The brimonidine containing implants decreased the duration
of vascular occlusion as shown in FIG. 10. Delay in fluorescein
filling of the occluded vein was quantified using Metamorph 6.0
software. Intensity measurements were made with pre-defined regions
of interest for early and late phases of fluorescein angiography to
quantify delay in filling and the observed delay in fluorescein
clearance. The delay in early phase filling of fluorescein
(seconds) in the occluded vein from baseline fluorescein
angiography filling is illustrated in FIG. 10.
[0169] Fovea thickness measurements from OCT single line scans (6
mm) show an increase in retinal edema as a result of vascular
occlusion in the placebo group. Brimonidine containing implants
decreased the magnitude of retinal edema associated with vascular
occlusion. A series of line scans (covering 3 mm.sup.2) directly
compare changes in retinal thickness in the superior region
surrounding the occluded vein with thickness changes in the
inferior retina. Retinal edema in placebo monkeys was so profound
that fluid accumulation occurred in the inferior region of the
retina. In contrast, the brimonidine group did not have a
significant change in inferior retina edema compared to baseline,
as shown in FIG. 11.
[0170] Intraocular pressure (IOP) was recorded (OD and OS) in each
group in triplicate post implantation and prior to all follow-up
electrophysiology and retinal imaging procedures. The brimonidine
implants did not significantly lower IOP in eyes prior to or during
BRVO, as shown in FIG. 12
[0171] Multi-focal ERG was performed using a VERIS 5.0 system. A
stimulus field of 241 hexagons was positioned to record superior
retina and central retina foveal response. In the placebo group,
foveal responses were absent through 3-4 weeks post BRVO induction,
whereas, the foveal response in the brimonidine group was slightly
lower but pronounced at day 1 following BRVO, with recovery and/or
higher foveal response for the remainder of the study. The graph in
FIG. 13 shows the superior/inferior % response for both groups.
BRVO in monkeys treated with placebo have less responsive retinal
function with a trend toward recovery late in the study versus
relatively consistent retinal function with brimonidine
implants.
[0172] Laser Doppler Flowmetry (HRF) was used to measure blood flow
in the fovea, superior and inferior retina regions. The graph of
FIG. 14 shows the results from blood flow measurements acquired
with a 10-20 degree zone, centered at the fovea. Blood flow in the
fovea appears to be unchanged in the brimonidine group following
BRVO, but is sharply elevated at day 1 post BRVO in the placebo
group.
[0173] Intravitreal application of three brimonidine intraocular
implants has lessened the magnitude and duration of localized
vascular occlusion and associated vasculopathy and retinopathy in
monkeys.
[0174] In addition, the amount of laser burns needed to close the
veins was higher in the brimonidine group compared to placebo
(brimonidine: 157.+-.79, n=2; placebo: 37.+-.6, n=2). Together,
these data show that the presence of brimonidine increases the
difficulty of occluding retinal vasculature and decreases the
duration of that occlusion.
Example 3
Treatment of Glaucoma with an Intraocular Implant Containing
Brimonidine Associated with a Biodegradable Polymer Matrix
[0175] A 68 year old female complains to her physician that it is
becoming difficult to see. The physician determines that she has
elevated intraocular pressure levels, and diagnoses her with
glaucoma. An implant containing 200 .mu.g of brimonidine tartrate
and 800 .mu.g of a combination of biodegradable polymers (R203 and
R206 at a 1:1 ratio, as described above in Example 1) is placed in
the vitreous of both of the woman's eyes using a trocar. After
about 2 days, the woman begins to notice a change in her eyes,
presumably due to a decrease in intraocular pressure. The loss of
vision is prevented for about five months after the implant
procedure.
Example 4
Treatment of Ocular Conditions with Various Active Agents
[0176] An implant can be formulated with various active agents,
including the agents described herein, following the procedures in
the Examples above. These implants can provide an extended
therapeutic treatment of an ocular condition, that is a therapeutic
effect during a period of time during release of the active agent
or after release of all of the active agent from the implant and
during which there is no longer a therapeutic amount of the active
agent present at the ocular site at which the implant was placed.
Thus, an implant can be prepared containing an alpha-2 adrenergic
receptor agonist, such as clonidine, apraclonidine, or brimonidine
(available from Allergan, Irvine, Calif. as brimonidine tartrate
ophthalmic solution, under the tradename Alphagan-P.RTM.). Thus,
for example, a brimonidine extended therapeutic treatment implant
can be implanted into an ocular site (i.e. into the vitreous) of a
patient with an ocular condition for a desired extended therapeutic
effect. The implant may contain from about 50 .mu.g to about 500
.mu.g of Alphagan or Alphagan-P depending on the size of the
implant. The brimonidine extended therapeutic treatment implant can
be implanted into an ocular region or site (i.e. into the vitreous)
of a patient with an ocular condition for a desired therapeutic
effect. The ocular condition can be an inflammatory condition such
as uveitis or the patient can be afflicted with one or more of the
following afflictions: macular degeneration (including
non-exudative age related macular degeneration and exudative age
related macular degeneration); choroidal neovascularization; acute
macular neuroretinopathy; macular edema (including cystoid macular
edema and diabetic macular edema); Behcet's disease, diabetic
retinopathy (including proliferative diabetic retinopathy); retinal
arterial occlusive disease; central retinal vein occlusion; uveitic
retinal disease; retinal detachment; retinopathy; an epiretinal
membrane disorder; branch retinal vein occlusion; anterior ischemic
optic neuropathy; non-retinopathy diabetic retinal dysfunction,
retinitis pigmentosa and glaucoma. The implant(s) can be inserted
into the vitreous using the procedure such as trocar implantation.
The implant can release a therapeutic amount of the active agent to
provide and retain a therapeutic effect for an extended period of
time to thereby treat a symptom of an ocular condition. For
example, the implant may be effective to improve visual acuity,
visual contract sensitivity, or both.
Example 5
Use of Intraocular Alpha-2 Adrenergic Receptor Agonists Implants to
Enhance, Restore and/or Improve Visual Acuity
[0177] Experiments were carried out with intraocular implants in
mammalian eyes. Thus, degradable polymer implants containing as
active agent an intraocular alpha-2 adrenergic receptor agonist
were placed in the vitreous of both normal and damaged or diseased
(model system) rabbit eyes. The results of the experiments showed
that an intraocular alpha-2 adrenergic receptor agonist implant
can: (1) enhance visual acuity in normal eyes, and; (2) restore
visual acuity in diseased or damaged eyes.
[0178] Formulation #17 of Example 1 was used in these Example 5
experiments. Thus, the implants used comprised the alpha-2 agonist
brimonidine tartrate formulated as a solid, biodegradable rod
(weighing about 1 mg) to form a sustained release drug delivery
device (i.e. an implant). The implant consisted of 200 .mu.g
brimonidine tartrate and 800 .mu.g of a poly-lactide co-polymer
mixture of resomers R203 and R206 in a 1:1 weight ratio. The
placebo implant was a 1 mg rod implant made of a poly-lactide
co-polymer mixture of resomers R203 and R206 in a 1:1 weight
ratio.
[0179] When the implant was administered intravitreally in rabbits
we found that enhanced or normalized visual acuity resulted. Visual
acuity was measured as a sweep visual evoked potential threshold.
Improved visual acuity was measured in each of three different
ocular conditions:
[0180] 1) in normal rabbit eyes;
[0181] 2) in VEGF damaged rabbit eyes. These rabbit eyes were
treated intravitreally with 500 ng of VEGF to induce optic nerve
head swelling, retinal vessel leak, dilation and tortuosity, to
thereby simulate disease aspects common to ocular conditions such
as macular edema, optic nerve head edema, diabetic retinopathy, and
neovascularization, and;
[0182] 3) in rabbit eyes with outer retina injury induced by a
transient ischemic event with elevated IOP 8 months prior to use of
the implant.
[0183] Significantly: (a) in ocular condition 2) above, the implant
improved visual acuity without reducing the vasculopathy
(tortuosity, leak, dilation) associated with the VEGF treatment,
and; (b) in ocular condition 3) above, the implant improved visual
acuity without changing the clinical appearance of the retina in
these ischemic damage eyes, as assessed by color fundus
photography. This indicates that the alpha 2 agonist active agent
released by the implant caused an augmentation of the tonic
activity of the functioning retinal neuronal cells that remained
following the induced injury or disease state in ocular conditions
2) and 3). It can be hypothesized that the remaining normal cells
functioned better to compensate for and to improve vision even
though the disease state was still present.
Procedure for Inducing Retinal Ischemic Injury
[0184] Rabbits were anesthetized with isofluorane, and prepared for
unilateral acute retinal ischemia by raising IOP in the OD eye by
120 mm Hg for 45 minutes. To accomplish this, a reservoir with PBS
was suspended 65 inches above the eye and connected to a 30 gauge
needle inserted through the cornea into the anterior chamber. A
drop of topical anesthetic (proparacaine) was placed upon the
cornea prior to needle insertion. And, a drop of anti-inflammatory
agent (Pred-G) was placed onto the cornea immediately following
needle removal.
Procedure for Measuring Visual Acuity
[0185] Visual acuity was measured in conscious rabbits using sweep
visual evoked potential (swVEP). swVEP is an electrophysiological
technique for assessing visual acuity typically used young children
who can not read the Snellen eye charts. Pattern reversal images of
increasing spatial frequency are projected onto the macula while
simultaneously recording electrical activity (VEP) from the scalp.
Images with lower spatial frequency generate large signals which
get smaller as the spatial frequency increases, until signal=noise;
this threshold is the visual acuity. The procedure in rabbits
requires first implanting permanent electrodes on the scalp to
enhance signal strength and allow recording for the same position
from follow-up visits. After two-weeks to allow for healing, the
visual acuity measurements can be made.
[0186] Rabbits were anesthetized with ketamine and xylazine for the
implantation procedure. The scalp was aseptically prepared and
implanted with four stainless steel screws (#0-80.times.3/8). Two
active electrodes were placed at 6 mm on either side of the
midline, 6 mm above bregma; 1 ground electrode was placed at
midline, 6 mm above the active electrodes; and, 1 reference
electrode was placed at midline, 6 mm above the grounding
electrode.
[0187] For the acuity test, eyes were fully dilated with 1%
tropicamide and 10% phenylephrine. The rabbits were placed in
stainless steel restrainers that allowed projection of the
pattern-reversal images onto the visual streak. The rabbits were
fully-conscious. Images were projected via a specially-designed
fundus camera stimulator under control of the PowerDiva software
version 1.8.5. Each rabbit was placed so that its eye was located
at 50 mm in front of camera which is equivalent to 50 cm from a 21
in CRT monitor. Recording electrodes were connected to Grass
Neurodata Acquisition System (Model 12CA) with the following
specifications:
[0188] Channel 1 for OD eye and Channel 2 for OS eye.
[0189] Filter range between 3 to 100 Hz.
[0190] Amplification: 50K
[0191] Line frequency filter=OFF.
[0192] Vertical steady-state pattern-reversal sweep stimulus at
spatial frequency range of 0.1 to 5 cycles per degree at a temporal
frequency of 7.5 Hz were applied to the eye at mean luminance of
600 cd/m2 and contrast of 80%. Five to 40 trials, 10 secs each,
were collected from each eye. The number of trials was based on the
signal-to-noise ratio. Trials were averaged and the threshold
(visual acuity) was determined by software or manual fitting at
signal-to-noise ration no less than 2.5. Threshold values were then
normalized by expressing as a percent of the contralateral eye.
[0193] The effect on visual acuity of the brimonidine implant vs
placebo was studied in three different conditions on six different
group of rabbit eyes, as explained below. For each of the three
groups of rabbits the implants were placed in the vitreous using
The implants are inserted into the vitreous using the applicator
(with a 22 gauge needle) set forth in U.S. patent application Ser.
No. 11/021,947, filed Dec. 23, 2004.
[0194] (A) In the first study two groups of rabbits with normal
(untreated) eyes were used. One brimonidine implant was
intravitreally implanted into each left eye of each rabbit of group
1 (N=7). One placebo implant was intravitreally implant into the
left eye of each rabbit of group 2 (N=7) using the same procedure.
The right eye of each rabbit in both groups 1 and 2 was not treated
and served as controls to normalize the data obtained. Visual
acuity was measured in both eyes of the rabbits in both groups and
is set forth in FIG. 15 as a percent of the visual acuity of the
contralateral (right) normal eye.
[0195] FIG. 15 shows the effect of the brimonidine implant and of
the placebo implant on visual acuity in normal eyes of rabbits. The
FIG. 15 results were recorded two weeks after implantation of
either the brimonidine implant or the placebo implant and show that
the placebo implant did not cause a significant visual acuity
change. Thus, the placebo implant caused visual acuity to change
only by 1.5%.+-.6%. However, use of the brimonidine implant clearly
caused a significant enhancement of visual acuity in normal rabbit
eyes. Thus, the brimonidine implant caused visual acuity to improve
by 44%.+-.12% (up to a 56% vision improvement in a normal eye). A
comparison of the responses to the placebo implant and to the
brimonidine implant with an unpaired Student's `T` test show
statistical difference with a p value of 0.003.
[0196] (B) In the second study two groups of rabbits eyes were
used. One brimonidine implant was intravitreally implanted into
each left eye of each rabbit of group 1 (N=7). One placebo implant
was intravitreally implant into the left eye of each rabbit of
group 2 (N=7) using the same pars plana insertion procedure. The
right eye of each rabbit in both groups 1 and 2 was not treated and
served as controls to normalize the data obtained. Two weeks after
implantation each implanted eye was intravitreally administered 500
ng of vascular endothelial factor (VEGF) (obtained from R&D
Systems as product number 293-VE-50) as a 50 .mu.l bolus. Visual
acuity was measured in both eyes of the rabbits in both groups and
is set forth in FIG. 16 as a percent of the visual acuity of the
contralateral (right) eye.
[0197] FIG. 16 shows the effect of the brimonidine implant and of
the placebo implant on visual acuity in the VEGF treated rabbit
eyes. The FIG. 16 results were recorded three weeks after
implantation of either the brimonidine implant or the placebo
implant and one week after VEGF administration. The FIG. 16 results
show that the placebo implant, VEGF treated eyes had a visual
acuity deficit of about 25%.+-.4%. The FIG. 16 results also show
that the brimonidine implant, VEGF treated eyes had a visual acuity
improvement of about 14%.+-.8% (up to 22% vision improvement in an
eye with a vasculopathy). Thus, use of the brimonidine implant
normalized visual acuity in eyes treated with VEGF despite the
presence of vasculopathy. The brimonidine implant did not reduce
the vasculopathy induced by VEGF, but did reduce the neurosensory
retina deficit induced by the VEGF treatment. A comparison of the
responses to the placebo implant and to the brimonidine implant
with an unpaired Student's `T` test showed statistical difference
with a p value of 0.0007.
[0198] (C) In the third study two groups of rabbits' eyes were
used. One brimonidine implant was intravitreally implanted into
each left eye of each rabbit of group 1 (N=5). One placebo implant
was intravitreally implant into the left eye of each rabbit of
group 2 (N=5) using the same procedure. The right eye of each
rabbit in both groups 1 and 2 was not treated and served as
controls to normalize the data obtained. At day zero ischemic
injury was induced in the left eye of each rabbit in both groups.
Thirty two weeks later each ischemic injury left eye of each rabbit
in group 1 was implanted with the placebo implant and each left eye
of each ischemic injury left eye of each rabbit in group 2 was
implanted with the brimonidine implant. At week forty four visual
acuity was measured in both eyes of the rabbits in both groups and
is set forth in FIG. 17 as a percent of the of the visual acuity of
the contralateral normal or untreated (right) eye.
[0199] FIG. 17 shows the effect of the brimonidine implant and of
the placebo implant on visual acuity in eyes of rabbits with
existing injury from an ischemic event. Histology shows that this
procedure results in outer retina injury to photoreceptors, the RPE
and associated tissues. Rabbits with a visual acuity deficit in the
left resulting from the transient ischemic procedure were
randomized into two groups. Data are expressed as a percent of the
contralateral normal eye. The FIG. 17 results were recorded twelve
weeks after implantation with either the brimonidine implant or the
placebo implant and eleven months after the induced ischemic event
to each implanted eye. The FIG. 17 results show that the placebo
implant, ischemic injury eyes has a visual acuity decrease of
37%.+-.8%. The FIG. 17 results also show that the brimonidine
implant, ischemic injury eye had a visual acuity improvement of
14%.+-.9%. Thus, use of the brimonidine implant restored or
improved visual acuity in rabbit eyes with an outer retina (induced
ischemic) injury. A comparison of the responses to the placebo
implant and the brimonidine implant with an unpaired Student's `T`
test showed a statistical difference with a p value of 0.001
[0200] These experiments showed that a locally (i.e.
intravitreally) administered alpha-2 adrenergic receptor agonist
can be used to improve vision (enhance visual acuity) in normal
eyes. These experiments also showed that a locally (i.e.
intravitreally) administered alpha-2 adrenergic receptor agonist
can be used to improve, repair or restore vision in eyes with an
ocular condition such as an inflammatory, neovascular, tumor,
vascular occlusive, and/or optic nerve disease or condition,
including glaucoma.
[0201] A separate group of rabbits were studied to obtain
pharmacokinetic data. In these rabbits the implants were inserted
using a surgical intravitreal implantation procedure performed as
follows: a conjunctival incision was made, and a sclerotomy was
performed with a 20-gauge MVR blade. The sclerotomy was 3 mm from
the limbus and lateral to the dorsal rectus muscle between the 10
and 12 o'clock positions on the right eye, and between the 12 and 2
o'clock positions on the left eye. Using a sterile forceps, the
test article was inserted through the sclerotomy. The sclerotomy
was closed with 9-0 Prolene suture material. A sterile ocular
lubricant was applied to the eye following the implantation
procedure. Blood was collected from rabbits prior to
euthanasia/necropsy on Days 8, 31, 58, 91, 136, or 184. The aqueous
humor, vitreous humor, lens, retina and plasma samples from the
rabbits were analyzed by using liquid chromatography-mass
spectrometry/mass spectrometry (LC-MS/MS) methods.
[0202] Table 3 shows the data obtained in this pharmacokinetic
study. Intraocular brimonidine concentrations in the aqueous humor,
iris-ciliary body, lens, retina, vitreous humor and plasma
concentrations at various times ("Days" in the left hand side
column of Table 3) after intravitreal (into the midvitreous)
implantation of the 200 .mu.g brimonidine implant (Formulation #17)
in albino rabbit eyes was measured. As shown by Table 3, after
intravitreal implantation of the Formulation #17 brimonidine
implant:
[0203] 1. brimonidine was not detectable at any time point in the
aqueous humor of the rabbit eyes implanted with the brimonidine
implant;
[0204] 2. the brimonidine had a posterior clearance as opposed to
an anterior clearance after release from the intravitreal implant,
as shown by the higher retinal concentration;
[0205] 3. detectable levels of brimonidine were released from the
implant into the vitreous over at least a ninety day period;
[0206] 4. therapeutic levels of the brimonidine existed in the
retina for about twice as long at the implant released brimonidine
from the implant: brimonidine was present in the retina for at
least 84 days, although all the brimonidine had been released from
the implant after about 91 to about 120 days;
[0207] 5. the implant allowed an intra-retinal depot of brimonidine
to be formed.
TABLE-US-00003 TABLE 3 Intraocular brimonidine concentrations
Aqueous Iris-ciliary Lens Retina Vitreous Plasma Day humor (ng/mL)
body (ng/g) (ng/g) (ng/g) humor (ng/mL) (ng/mL) 8 NC 942
(3010).sup.d 45.1 .+-. 13.4 3630 .+-. 47.2 .+-. 13.1 0.092 (0,
0.184) 31 NC 25.9 .+-. 9.11 17.0 .+-. 3.92 35.3 .+-. 15.5 9.35 .+-.
6.25.sup.b 0.0575 (0, 0.115) 58 NC 69.4 .+-. 55.3 17.9 .+-.
12.5.sup.b 122 .+-. 57.3.sup.a 5.6 .+-. 3.24.sup.b 0.255 (0.208,
0.302) 91 NC 42.9 .+-. 18.7.sup.c 50.1 .+-. 14.8 488 .+-. 471.sup.b
59.3 .+-. 43.2 NC 136 NC 107 .+-. 41.5 16.2 .+-. 12.3.sup.a 22.6
.+-. 5.9 NC NC 184 NC NC 1.18 .+-. 0.71.sup.b 59.8 .+-. 35.0.sup.b
NC NC NC, not calculable because >50% of concentrations
contributing to mean were BLQ (below limit of quantification). Data
expressed as mean .+-. SEM (N = 4 eyes and N = 2 plasma per
sampling time). BLQ = Below limit of quantitation (aqueous and
vitreous humor: <10 ng/mL; lens, retina and iris-ciliary body:
<0.5 ng; plasma: <0.05 ng/mL). .sup.aN = 4. One sample was
BLQ (included in the mean calculation as zero). .sup.bN = 4. Two
samples were BLQ (included in the mean calculation as zero).
.sup.cN = 3. One sample was not determined (not included in the
mean calculation). .sup.dN = 2. Two samples were ALQ (above limit
of quantification) (estimated mean value in parentheses). indicates
data missing or illegible when filed
[0208] To conclude, our results show that an alpha-2 agonist
(non-selective or receptor subtype selective) intravitreal implant
can be used to enhance, repair, restore or improve visual acuity in
mammalian eyes.
[0209] Significantly, our experiments showed that an intravitreal
brimonidine implant can be used to improve visual acuity in both
normal eyes and in diseased eyes. The results presented herein show
that in VEGF treated eyes show that the implant can be used as a
prophylactic to prevent a future vision loss. The results presented
herein in damaged/diseased (i.e. ischemic) eyes show that an
implant can be used to improve visual acuity in an eye without
remission or disappearance of the eye damage/disease. That is, the
implant appears to cause the remaining normal retinal cells to
function better to compensate and improve vision, even though the
eye damage/disease has not been reduced as to it's' physical extent
in the retina.
[0210] Implants within the scope of our invention can be used:
[0211] 1. as a prophylaxis to mitigate against impending retinal
neurosensory dysfunction in a variety of ocular conditions,
including retinal disorders in patients that have a predisposition
to or risk factors associated with a retinal disorder.
[0212] 2. as a therapeutic (alone or in combination with one or
more additional active agents) to treat posterior ocular
conditions, such as retinal diseases associated with degeneration
of the retina, such as a macula degeneration (such as an age
related macular degeneration), an ocular edema, such as a macular
edema, a vascular occlusive condition, an optic or retinal
neuropathy, and/or a retinal tumor. For example, an implant can be
made comprising an alpha 2 agonist to lower IOP and/or to improve
visual acuity and a steroid (such as dexamethasone or
triamcinolone) to reduce inflammation.
[0213] 3. as a therapeutic (alone or in combination with one or
more additional active agents) useful in retinal diseases and
disorders with detachment of the retina.
[0214] 4. as a therapeutic (alone or in combination with one or
more additional active agents) useful in surgical retinal
procedures that require vitrectomies and manipulation that can have
a negative impact of the retina.
[0215] 5. as a therapeutic (alone or in combination with one or
more additional active agents) to treat retinal diseases that have
a nutritional deficiency, such as a vitamin A deficiency
[0216] 6. as a therapeutic (alone or in combination with one or
more additional active agents) to treat retinal injury from
accidental light exposure, such an operating microscope light or
industrial lasers.
[0217] 7. as an adjunct with steroids for treating retinal
diseases, where steroids are used to reduce ocular inflammation and
macular or optic nerve edema.
[0218] 8. as an adjunct to photodynamic therapy (PDT) where PDT is
used to treat retinal conditions associated with leakage from
retinal and related tissue vessels.
[0219] 9. as an adjunct to other types of electromagnetic radiation
such as laser photocoagulation used to treat macula edema or
neovascularization, and transpupillary thermal therapy (TTT) that
is used to treat choroidal neovascularization (CNV).
[0220] 10. as an adjunct to radiation therapy or chemical therapy
that causes maculopathy and papillopathy when used to treat ocular
tumors such as macular retinoblastoma and choroidal osteoma.
[0221] 11. as an adjunct to electromagnetic radiation and steroids
used to treat edema and neovascular abnormalities of the eye.
Example 6
Use of Two Different Intravitreal Brimonidine Implants to Treat
Acute Rhegmatogenous Macular-Off Retinal Detachment
[0222] Patients are implanted with either a 50 .mu.g and 200 .mu.g
brimonidine posterior segment (i.e. intravitreal) implant to treat
acute rhegmatogenous macular-off retinal detachment. The patients
experience at least a 15-letter increase from baseline in the study
eye using the Early Treatment Diabetic Retinopathy Study (ETDRS)
method). The 200 .mu.g brimonidine posterior segment implant is
more effective than the 50 .mu.g brimonidine posterior segment
implant in achieving an improvement in best-corrected visual acuity
(BCVA) (as measured by the proportion of patients experiencing at
least a 15-letter increase from baseline in the study eye using the
Early Treatment Diabetic Retinopathy Study (ETDRS) method). The 50
.mu.g and 200 .mu.g brimonidine posterior segment implants have
acceptable safety profiles
[0223] The patients are seen for a baseline and randomization visit
on day (O), and at months 1, 3, 6, 9, 12 (masked phase) and 15, 18,
and 24 months (extension phase). Additional visits on day 1 and day
7 following any re-treatments are designated as safety visits.
Fifty five patients are enrolled. At least one eye of each patient
has acute rhegmatogenous macular-off retinal detachment eligible
for repair by scleral buckle and laser photocoagulation
[0224] The Inclusion criteria for the patients include: eighteen
years of age or older; best corrected E-ETDRS visual acuity score
of >=20 letters (i.e., approximately 20/400 or better) and
<=65 letters (i.e., approximately 20/50 and worse); diagnosis of
acute rhegmatogenous macular-off retinal detachment in one eye. The
detachment has occurred within twelve hours of presentation, and in
the opinion of the investigator, can be repaired by scleral buckle
placement and external laser photocoagulation of the retinal break
without the anticipated need for vitrectomy or pneumatic
retinopexy. The surgical repair is planned within 48 hrs of the
detachment; media clarity; pupillary dilation, and; patient
cooperation sufficient for adequate fundus photographs.
[0225] The study formulations are: (1) Formulation #17 of Example 1
(a solid, biodegradable rod (weighing about 1 mg implant consisted
of 200 .mu.g brimonidine tartrate and 800 .mu.g of a poly-lactide
co-polymer mixture of resomers R203 and R206 in a 1:1 weight ratio,
and; (2) a solid, biodegradable rod (weighing about 1 mg implant
consisted of 50 .mu.g brimonidine tartrate and 950 .mu.g of a
poly-lactide co-polymer mixture of resomers R203 and R206 in a 1:1
weight ratio.
[0226] A significant number of the patients show an increase of 15
letters or more from baseline of BCVA using the ETDRS method at 6
months in the study eye. Hence, an intravitreal brimonidine implant
can be used to treat acute rhegmatogenous macular-off retinal
detachment.
Example 7
Use of Two Different Intravitreal Brimonidine Implants to Treat
Chronic Retinal Injury
[0227] Patients are implanted with either a 50 .mu.g and 200 .mu.g
brimonidine posterior segment (i.e. intravitreal) implant to treat
chronic retinal injury. The patients experience an improvement in
best-corrected visual acuity (BCVA) (as measured by the proportion
of patients experiencing at least a 15-letter increase from
baseline in the study eye using the Early Treatment Diabetic
Retinopathy Study (ETDRS) method). The 200 .mu.g brimonidine
posterior segment implant is more effective than the 50 .mu.g
brimonidine posterior segment implant in achieving an improvement
in best-corrected visual acuity (BCVA) (as measured by the
proportion of patients experiencing at least a 15-letter increase
from baseline in the study eye using the Early Treatment Diabetic
Retinopathy Study (ETDRS) method). The 50 .mu.g and 200 .mu.g
brimonidine posterior segment implants have acceptable safety
profiles.
[0228] The patients are seen for a baseline and randomization visit
on day (0), and at months 1, 3, 6, 9, 12 (masked phase) and 15, 18,
and 24 months (open label). Additional visits on day 1 and day 7
following any re-treatments are designated as safety visits. At
least one eye of each patient has retinal injury at baseline of one
or more of the following types: tapetoretinal degeneration, macular
ischemia due to diabetic maculopathy or prior rhegmatogenous
macular-off retinal detachment.
[0229] The inclusion criteria for the patients include: a least
eighteen years of age; diagnosis of chronic retinal injury related
to tapetoretinal degeneration, macular ischemia due to diabetic
maculopathy or macular-off retinal detachment in at least one eye
(the study eye); for patients with tapetoretinal degeneration the
diagnosis is based on both clinical, visual field and
electroretinographic findings and the visual field loss is within
the central 10 degrees; for patients with macular ischemia due to
diabetic maculopathy the best corrected E-ETDRS visual acuity score
is >=35 letters (i.e., approximately 20/200 or better) and
<=65 letters (i.e., approximately 20/50 or worse), and the
decreased visual is directly related to the ischemia and not due to
macular edema or previous laser photocoagulation; for patients with
macular-off detachment: the macula detachment has not been present
longer than 48 hours prior to repair, the repair of the detachment
has occurred at least 6 months before the baseline visit, the best
corrected E-ETDRS visual acuity score is >=35 letters (i.e.,
approximately 20/200 or better and <=65 letters (i.e., worse
than approximately 20/50), the visual acuity is stable (is within
one line of Snellen acuity) for at least 3 months, the repair of
the detachment has been deemed an anatomic success; media clarity;
pupillary dilation, and; patient cooperation sufficient for
adequate fundus photographs.
[0230] The study formulations are: (1) Formulation #17 of Example 1
(a solid, biodegradable rod (weighing about 1 mg implant consisted
of 200 .mu.g brimonidine tartrate and 800 .mu.g of a poly-lactide
co-polymer mixture of resomers R203 and R206 in a 1:1 weight ratio,
and; (2) a solid, biodegradable rod (weighing about 1 mg implant
consisted of 50 .mu.g brimonidine tartrate and 950 .mu.g of a
poly-lactide co-polymer mixture of resomers R203 and R206 in a 1:1
weight ratio.
[0231] A significant number of the patients show an increase of 15
letters or more from baseline of BCVA using the ETDRS method at 12
months in the study eye. Hence, an intravitreal brimonidine implant
can be used to treat chronic retinal injury.
Example 8
Manufacture and In Vitro Testing of Drug Delivery Systems
Containing an Alpha-2 Adrenergic Receptor Agonist and a
Biodegradable Polymeric Matrix Comprising Ester End and Acid End
Polymers
[0232] Introduction
[0233] It is known to prepare biodegradable polymer implants
capable of releasing an active agent. See for example Lewis, D.,
Controlled Release of Bioactive Agents from Lactide/Glycolide
Polymers in Drugs and Pharmaceutical Sciences, Vol. 45,
"Biodegradable Polymers as Drug Delivery Systems", edited by Chasin
M., et al., pages 1-35 (1990), and; de Jong S., et al., New
insights into the hydrolytic degradation of poly (lactic acid):
participation of the alcohol terminus, Polymer 42 (2001);
2795-2802.
[0234] An implant (synonymously a drug delivery system) can have
undesirable release characteristics. Indeed, one of the most
difficult and problematic aspects of implant technology is the
discovery and development of an implant with desirable and
consistent active agent release characteristics. Implant release
characteristics (the release profile) depends upon a multitude of
factors including the chosen active agent (including it's
solubility, reactivity and labiality), the selection of a
particular polymer or polymers from the near infinite number of
different polymers and polymer combinations available, and the
manufacturing process by which the implant is made.
[0235] Undesirable implant release characteristics can include an
initial burst release of the active agent and/or a lag time in the
release of the active agent, both illustrated by FIG. 18. Such
undesirable implant release characteristics can cause overdosing or
underdosing of the patient with the active agent with resulting
reduced therapeutic efficacy of the implant. Although an implant
with a burst release or with a lag time may have utility in some
circumstances, generally a desirable implant release characteristic
is a linear rate of release of the active agent, thereby providing
a constant or relatively constant dosing of the therapeutic agent
to the patient.
[0236] Thus, an implant intended for intraocular administration
which comprises an alpha-2 adrenergic receptor agonist (as the
active agent) and a biodegradable polymeric matrix can exhibit a
burst effect or a significant lag time after ocular implantation or
insertion of the implant before release of a therapeutically
effective amount of the alpha-2 adrenergic receptor agonist from
the polymeric matrix of the implant (for example into the vitreous)
takes place. A burst can be due to having too much active drug
incorporated at or near the surface of an implant, and a lag time
to having too little of the active agent incorporated at or near
the surface of the implant. For example, for a biodegradable
implant, having more than about 25% of the active agent within the
polymeric matrix which comprises up to about the top 15% as
measured from the exterior to the center of the implant) of the
volume of the implant can result in a burst effect. Concomitantly,
for a biodegradable implant, having less than about 15% of the
active agent within the polymeric matrix which comprises up to
about the top 25% (as measured from the exterior to the center of
the implant) of the volume of the implant can result in a lag
time.
[0237] Additionally, a burst effect or a lag time before release of
a therapeutically effective amount of the alpha-2 adrenergic
receptor agonist from the polymeric matrix of the implant (for
example into the vitreous) can be due to a selection of polymer or
polymers for constituting the polymeric matrix of the implant which
polymer or polymers have characteristics which do not permit the
active agent to be released with a linear or substantially linear
release profile. Although broad or general polymer characteristics
are known (see eg example Lewis (1990) and de Jong S. (2001) supra)
there is a near infinite variety of different polymer or polymer
combinations (each with their own degradation rates, pore forming
characteristics, reactivities, degradation pathways, intermediates,
by products, active agent-polymer association characteristics, etc)
which can be used to constitute the polymeric matrix of the
implant.
[0238] The size and weight of implants intended for intraocular
administration is significantly limited by the dimensions of
intraocular spaces and potential intraocular spaces. Additionally,
even when it may be physically possible to insert, implant or
inject an implant to or into a particular intraocular site,
considerations such as a desire to reduce injury to sensitive
ocular tissues at the site of and adjacent to the site of
administration site, and to not interfere with vision can require
the implant to be less than it's maximum pp size and weight. Ocular
tissue injury can result in inflammation, pain, increased healing
time and reduced visual acuity. In light of these considerations,
an implant intended for example for intravitreal administration
preferably has no dimension greater than about 20 mm and weighs
less than about 5 mg. For our purposes, the weight of the implant
is the weight of the active agent incorporated into the implant
plus the weight of the polymers or polymers which comprise the
polymeric matrix of the implant. Having too little of the active
agent incorporated into the implant can result in having too little
implant surface active agent (that is having only a minute absolute
weight amount of the active agent present within a few microns of
the exterior surface of the implant). Implant surface active agent
is available for immediate or rapid (i.e. within the first day or
two after implantation) release from the polymeric matrix.
Additionally, having a low amount of implant surface soluble active
agent can delay implant surface pore formation which thereby slows
the release of the active agent from deeper within the implant. To
address this problem pore forming additives have been used to
improve the initial release of an active agent from a biodegradable
implant, but unfortunately use of pore forming additives can result
in a significant decrease in the duration of the time over which a
therapeutically effective amount of the active agent is released
from the implant.
Summary
[0239] With an awareness of these problems and deficiencies of
prior implants and in light of the considerations above, we have
developed implants intended for the treatment of ocular conditions
comprising an alpha-2 adrenergic receptor agonist (as the active
agent) and a biodegradable polymeric matrix with the following
desirable characteristics:
[0240] 1. No burst effect and as well no or a nominal lag time
after ocular implantation or insertion of the implant before
release of a therapeutically effective amount of the alpha-2
adrenergic receptor agonist from the implant occurs. Generally, we
found that a suitable initial release of the active agent from the
implant as well as a long-term sustained release of the active
agent from the implant could be achieved by particular novel
selections of hydrophobic poly (D,L,-lactide) polymers and/or
hydrophilic poly (D,L,-lactide-co-glycolide) polymers to comprise
the polymeric matrix of the implant.
[0241] 2. high dose implants, that is implants which comprise more
than 4 weight percent (wt %) of a biologically active alpha-2
adrenergic receptor agonist. The remaining 96 wt % or less of the
implant will typically comprise one or more biocompatible and
biodegradable polymers.
[0242] 3. absence of pore forming additives or other release rate
modulators or modifiers.
[0243] 4. sustained release of a therapeutic amount of an alpha-2
adrenergic receptor agonist from the biodegradable polymeric matrix
over a period of at least 115 days (about 4 months).
[0244] 5. substantially linear (i.e. first order release rate
kinetics) release of an alpha-2 adrenergic receptor agonist from
the biodegradable polymeric matrix of the implant over a period of
time of from about 20 days to about 50 days. "Substantially linear
release" means that the measured amount of the rate of alpha-2
adrenergic receptor agonist release from the biodegradable
polymeric matrix of the implant does not vary by more than 50% over
a three day period, preferably does not vary by more than 30% over
a seven day period and most preferably does not vary by more than
20% over a ten day period.
[0245] Thus, we made brimonidine tartrate containing sustained
release polymer implants with exhibited desirable in vitro release
profile of the brimonidine tartrate.sup.1. Generally the release
profiles showed no or a reduced initial drug burst and as well
sustained release profile of the active agent over a period of at
least about 115 days. Our novel implant formulations contained
hydrophobic ester end-capped poly (D,L-lactide) homopolymers, ester
end-capped poly (lactide-co-glycolide) copolymers, and a minor
amount of acid end-capped poly (D,L,-lactide-co-glycolide) polymer.
An uncapped polymer (such as a PLGA polymer) has a free carboxyl
group at the polymer terminus. Without wishing to be bound by
theory we believe that these desirable implant release
characteristics were obtained because the polylactide component of
the polymers used can provide an implant polymeric matrix with a
relatively long hydrolysis half-life as well as a durable polymeric
matrix capable of retaining the active agent within the implant
polymer matrix for an extended period of time. Additionally, the
acid-end capped lactide-glycolide polymer can act to speed initial
active agent drug release from the implant by enhancing early water
penetration into the implant by raising the surface energy of the
implant. The acid-end capped lactide-glycolide polymer can also
create a more porous implant as it swells and is eroded from the
implant because its hydrolysis rate is much faster than that of the
polylactide. .sup.1Brimonidine tartrate is a relatively selective
alpha-2 adrenergic agonist approved for ophthalmic use. The
chemical name of brimonidine tartrate is
5-bromo-6-(2-imidazolidinylideneamino)quinoxaline L-tartrate. It is
an off-white, pale yellow to pale pink powder. In solution,
brimonidine tartrate has a clear, greenish-yellow color.
Brimonidine tartrate has a molecular weight of 442.24 as the
tartrate salt and is water soluble (34 mg/ml). The molecular
formula is C.sub.11H.sub.10BrN.sub.5.C.sub.4H.sub.6O.sub.6.
Experiments
[0246] We carried out experiments to make and to test our
particular drug delivery systems comprising an alpha-2 adrenergic
receptor agonist and a biodegradable polymeric matrix comprising
both ester end capped and acid end capped polymers. In particular
we made and tested in vitro brimonidine tartrate containing
sustained release polymer implants intended for intravitreal
administration to treat an ocular condition.
[0247] Examples of three implants formulation we made comprising an
alpha-2 adrenergic receptor agonist and a biodegradable polymeric
matrix are shown in Table 4. The in vitro release rates of the
three Table 4 implants over a 21 day period (in phosphate buffered
saline ("PBS") at pH 7.4 and 37.degree. C. is shown by FIG. 19.
[0248] As shown in Table 4 and in FIG. 19, a particularly
advantageous implant formulation made was formulation number
7746-073. Implant formulation 7746-073 comprised 12 wt %
brimonidine tartrate, 53 wt % R2035 (an ester end-capped poly
(D,L,-lactide) polymer), 25 wt % R208 (also an ester end-capped
poly (D,L,-lactide) polymer), and 10% RG502H (an acid end-capped
poly(D,L-lactide-co-glycolide) polymer). Resomers RG502H, R208 and
R2035 can be obtained from Boehringer Ingelheim. RG502H comprises
48-52 mol % D,L-lactide and 48-52 mol % glycolide (as determined by
NMR spectroscopy) and has an inherent viscosity at 25.degree. C. of
0.16 to 0.24 dl/g. R208 has an inherent viscosity at 25.degree. C.
of 1.8 to 2.2 dl/g. R2035 has an inherent viscosity at 25.degree.
C. of 0.25 to 0.35 dl/g.
TABLE-US-00004 TABLE 4 Formulations of Three Brimonidine Tartrate
Implants w/w, % Brimonidine Resomer Resomer Resomer Formulation No
Tartrate R203S R208 RG502H 7746-073 12 53 25 10 7702-020 15 60 25 0
7702-022 18 65 17 0
[0249] As shown by FIG. 19, in distinction to the implant
formulations which contained only ester end-capped biodegradable
polymers (formulations 7702-020 and 7702-022), the implant
formulation which contained a mixture of ester end-capped and acid
end-capped polymers (formulation 7746-073) showed an essentially
linear rate of release of the brimonidine tartrate active agent in
vitro over the two week period of days 7-21.
[0250] Additionally, as shown by FIG. 20, when the release of the
active agent from formulation 7746-073 was observed over a longer
period of time (in PBS at pH 7.4 and 37.degree. C.), linear rates
of release of the brimonidine tartrate active agent in vitro were
observed during the time periods from about day 30 to about day 45
(15 day period), from about day 50 to about day 90 (40 day period)
and from about day 100 to about day 115 (15 day period).
[0251] We then made seven additional implant formulations each
comprising an alpha-2 adrenergic receptor agonist and various
ratios of ester end-capped and acid-end capped biodegradable
polymers as shown in Table 5. In Table 5 R2035 and R208 are ester
end-capped poly (D,L,-lactide) polymer resomer supplied by
Boehringer-Ingelheim (Resomer), RG502H is an acid end-capped poly
(D,L-lactide-co-glycolide) polymer and RG752 is another ester end
capped poly (D,L,-lactide-co-glycolide) polymer. APO40 is an ester
end-capped poly (D,L,-lactide) polymer with an inherent viscosity
at 30.degree. C. of 0.34-0.40 dl/g, available from Durect
Corporation (Lactel). All inherent viscosities for all resomers set
forth herein were measured using CHCl.sub.3 as solvent.
[0252] The in vitro release rates of the seven Table 5 implant
formulations over a 14-26 day period (in PBS at pH 7.4 and
37.degree. C.) is shown by FIG. 21. Significantly, FIG. 20 shows
linear release profiles of the Table 5 Formulations, all of which
contained acid end-capped polymer in combination with poly
(D,L,-lactide) and poly (lactide-co-glycolide) polymers.
[0253] Thus, FIG. 21 shows that a linear release profile of the
active agent can be obtained with different combinations of ester
end-capped and acid end-capped polymers, even when: (1) the active
agent loading in the polymeric matrix is varied between about 9 wt
% and about 12 wt %, and; (2) the wt % of acid end-capped polymer
compositions is varied from about 15 wt % to about 35 wt %, the
remainder of the implant being a combination of two or three
different ester end-capped polymers.
TABLE-US-00005 TABLE 5 Linear Release Brimonidine Tartrate
Containing Formulations w/w, % Brimonidine Resomer Resomer Resomer
Resomer Formulation No Tartrate APO40 R203S R208 RG502H RG752
7746-061A 12 25 0 25 15 23 7702-068A 10.9 31.8 0 22.7 16.4 18.2
7702-065A 12 35 0 35 18 0 7702-070A 12 25 0 25 18 20 7702-058A 12
23 0 40 25 0 7702-62A 12 20 0 20 25 23 7702-054A 9 0 6 50 35 0
[0254] The polymeric implants in this study were made by melt
extrusion in a Daca instruments microcompounder/extruder, but they
can also be made by direct compression. The implants made were
rod-shaped, but they can be made into any geometric shape by
changing the extrusion or compression die.
[0255] Polymers were used as received from Boehringer Ingelheim
(Resomer) or Durect (APO40) and the brimonidine tartrate was used
as the salt. The polymers and brimonidine tartrate were combined in
a Retsch ball-mill capsule with a 1/4'' stainless steel ball; then
the capsule was placed in the Retsch mill (Type MM200) for 5 min at
20-cycles/min. The capsule was removed from the mill and the powder
blend was stirred with a spatula. The capsule with the powder blend
was mixed for 5 minutes on a Turbula mixer. The powder blend is
inspected for homogeneity and the mixing procedure is repeated if
necessary.
[0256] The Daca microcompounder/extruder was setup according to the
manufacture's instructions. The output of the Daca is fitted with a
laser micrometer and a custom built puller to control the diameter
of the extruded rod. The Daca was allowed to equilibrate to the
extrusion temperature; then the powder blend was manually fed into
the extrusion screws at a rate that maintained a constant load and
torque. All the Example 8 and Example 9 implant filaments were made
at extrusion temperatures between 95.degree. C. and 115.degree. C.
The filaments made were cut into one-milligram rods approximately 6
mm long and each with a diameter of about 0.018 (about 0.46 mm).
Extruded filament active agent release was monitored by HPLC in
phosphate buffered saline pH 7.4 at 37.degree. C.
Example 9
Manufacture and In Vitro Testing of Drug Delivery Systems
Containing Two Forms of an Alpha-2 Adrenergic Receptor Agonist and
an Ester End-Capped Biodegradable Polymeric Matrix
[0257] In Example 1 above filament shaped implants containing
brimonidine free base and brimonidine tartrate were made using the
single polymer resomers R203, R206 or RG752. See Formulations 11-15
and 19-20 in Table 1. These Example 1 implants were made using a
process with mixing, melting, pelletizing and melt extrusion
steps.
[0258] In this Example 9 experiment we made implants containing
brimonidine free base and brimonidine tartrate using a combination
of two different polymer resomers and a different and improved
manufacturing process, as compared to Example 1. The Example 9
sustained release implants having improved release profiles were
made using the Example 8 process, that is by combining a
brimonidine free base and a brimonidine tartrate followed by
stirring, mixing, and melt extrusion of implant filaments. The
filaments made were cut into one-milligram rods, approximately 6 mm
long and each with a diameter of about 0.018 (about 0.46 mm).
[0259] In this Example 9, the polymer matrix consisted of two
poly(D,L-lactide) PLA polymers, although many different types of
polymers can be used. The improvement in the release kinetics is
primarily a function of the physicochemical properties of the
brimonidine free base and the brimonidine tartrate. Therefore the
substantially linear active agent release kinetics can be obtained
with a variety of other polymers, beyond the two poly(D,L-lactide)
PLA polymers used in this experiment. Because brimonidine tartrate
is more water soluble than is brimonidine free base, implants made
with the tartrate can show a burst release due to the availability
of implant surface brimonidine tartrate. On the other hand,
brimonidine free base is not water soluble, thereby making the
implant more hydrophobic and delaying initial water permeation into
the implant and consequently therefore also the release of
brimonidine, resulting in an observed lag before a therapeutic
amount of the brimonidine free base is released from the
implant.
[0260] Based on the known solubility difference between brimonidine
free base and a brimonidine tartrate, the expected release rate of
brimonidine from an implant which comprises both brimonidine free
base and a brimonidine tartrate would be proportional to the amount
of brimonidine tartrate in the formulation. Surprisingly, we
discovered that an implant which comprises a combination of a
brimonidine free base and a brimonidine tartrate has a synergistic
release profile, that is the release of brimonidine from the
combination implant is faster than the release rate of brimonidine
from an implant which comprises only a brimonidine tartrate, with
no brimonidine free base. FIG. 22 (in vitro release in PBS at pH
7.4 and 37.degree. C.) shows that an implant which comprises a
combination of the two forms (brimonidine free base and brimonidine
tartrate) shows a faster release than for either individual form of
brimonidine in an implant by itself.
[0261] An embodiment of our new formulation can comprise
brimonidine free base, brimonidine tartrate, and a biodegradable
polymer, such as a hydrophobic biodegradable polymer. The
hydrophobic biodegradable polymer can be an ester end-capped
polymer. The hydrophobic biodegradable polymer can be an ester
end-capped polymer, such as a hydrophobic, ester end-capped poly
(D, L-lactide) homopolymer. Another embodiment of our invention can
comprise two hydrophobic, ester end-capped poly (D, L-lactide)
homopolymers, as shown by the six Table 6 formulations. The
polylactides can have a relatively long hydrolysis half life and
can provide a more durable matrix to retain the active agent within
the implant for an extended period.
[0262] As shown by FIG. 22 our implant formulation 7746-146 which
comprised 17.5% brimonidine free base, 17.5% brimonidine tartrate,
40% of the ester end-capped poly (D,L,-lactide) polymer R203S, and
25% of the ester end-capped poly (D,L,-lactide) polymer R208 had a
release profile which was faster than the formulations which
contained only a brimonidine free base or only a brimonidine
tartrate (formulations 7746-118, 7746-141, 7746-092A and 7746-142
in Table 5). Significantly, the 7746-146 formulation had a first 20
day linear release profile followed by a second, different 40 day
linear release profile. Notably, formulation 7746-147 which also
comprised a combination of brimonidine free base and brimonidine
tartrate, showed an analogous active agent release profile but with
a different polymer ratio. All the formulations are summarized in
Table 6.
TABLE-US-00006 TABLE 6 Brimonidine Tartrate Containing Formulations
w/w, % Brimonidine Brimonidine Resomer Resomer Formulation No Free
Base Tartrate R203S R208 7746-146 17.5 17.5 40 25 7746-118 0 35 40
25 7746-141 35 0 40 25 7746-147 17.5 17.5 55 10 .sup. 7746-092A 0
35 55 10 7746-142 35 0 55 10
Example 10
Treatment of Elevated Intraocular Pressure with an Intravitreal
Biodegradable Polymeric, Brimonidine Containing Implant
[0263] In Example 2 above it was disclosed that surgical placement
into the vitreous of normotensive monkey eyes of a brimonidine
containing biodegradable polymeric implant did not lower IOP in the
monkeys as compared to placebo. See e.g. FIG. 12.
[0264] In this Example 10 we surprisingly show that surgical
placement into the vitreous of hypertensive monkey eyes of a
brimonidine containing biodegradable polymeric implant does lower
IOP in the monkeys as hypertensive compared to placebo hypertensive
monkey eyes. See eg FIG. 23. Example 10 can therefore be viewed as
a further rendition of, supplement or extension of Example 3.
[0265] In this experiment we observed the effect on intraocular
pressure (IOP) of brimonidine containing drug delivery system
inserted into the vitreous of rabbit eyes (Dutch Belted rabbits).
Elevated IOP was induced in the rabbits by intracameral injection
of Carbopol 934P, an ocular hypertensive (OHT) drug. IOP was
measured using a hand held pneumatonmeter.
[0266] Just as in Example 2, the extruded rod shaped Formulation 17
implant of Example 1 was used as the brimonidine containing implant
in this Example 10 experiment. Thus, the active agent implant used
weighed about 1 mg and comprised 20 wt % brimonidine tartrate (200
.mu.g), 40 wt % resomer R203, and 40 wt % resomer R206 (800 .mu.g
polylactide polymer). The Formulation 17 placebo 1 mg implant used
comprised 50 wt % resomer R203 and 50 wt % resomer R206 (1 mg
polylactide polymer).
[0267] An implant was placed in the right eye only of twelve Dutch
Belted rabbits as follows. The rabbits were sedated by intravenous
syringe injection of Ketamine given in a dose of 15 mg per kg of
rabbit weight (mg/kg) combined with acepromazine maleate 1 mg/kg.
Next 1-2 drops of ocular Betadine was applied to the right eye as a
topical disinfectant followed by 1-2 drops of Proparacaine applied
to the right eye as a topical anesthetic.
[0268] The brimonidine containing implant was placed in the
vitreous of six right eyes and the placebo implant was placed in
the vitreous of the other six eyes. The implants were placed by
making an incision 4 mm from the limbus into the vitreous. In six
right eyes an extruded rod brimonidine implant was so placed. After
implantation topical antibiotic ointment was applied to each right
eye.
[0269] On the day after implantation, ocular hypertension was
induced as follows. The rabbits were sedated with sedated by
intravenous syringe injection of Ketamine 15 mg/kg combined with
acepromazine maleate 1 mg/kg. Next 1-2 drops of ocular Betadine was
applied to the right eye as a topical disinfectant followed by 1-2
drops of Proparacaine applied to the right eye as a topical
anesthetic. Next 50 .mu.l of 0.3% Carbopol 934P solution at pH 4
was administered to each right eye by intracameral injection,
followed by application of topical antibiotic ointment to the right
eye.
[0270] As shown by FIG. 23, as compared to placebo the brimonidine
containing implant lowered IOP in the hypertensive right eyes of
the subject rabbits for up to six weeks after DDS implantation.
[0271] All references, articles, publications and patents and
patent applications cited herein are incorporated by reference in
their entireties.
[0272] While this invention has been described with respect to
various specific examples and embodiments, it is to be understood
that the invention is not limited thereto and that it can be
variously practiced within the scope of the following claims.
* * * * *