U.S. patent application number 16/984971 was filed with the patent office on 2021-04-22 for sustained drug delivery implant.
The applicant listed for this patent is Allergan, Inc.. Invention is credited to Chetan Pujara, Jane-Guo Shiah.
Application Number | 20210113458 16/984971 |
Document ID | / |
Family ID | 1000005312724 |
Filed Date | 2021-04-22 |
United States Patent
Application |
20210113458 |
Kind Code |
A1 |
Shiah; Jane-Guo ; et
al. |
April 22, 2021 |
SUSTAINED DRUG DELIVERY IMPLANT
Abstract
Biocompatible intraocular implants may include a brimonidine
free base and a biodegradable polymer associated with the
brimonidine free base to facilitate the release of the brimonidine
free base into an eye with the polymer matrix lasts a period of
time of not more than twice the drug release duration, but more
than the drug release duration.
Inventors: |
Shiah; Jane-Guo; (Irvine,
CA) ; Pujara; Chetan; (Irvine, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Allergan, Inc. |
Irvine |
CA |
US |
|
|
Family ID: |
1000005312724 |
Appl. No.: |
16/984971 |
Filed: |
August 4, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16354692 |
Mar 15, 2019 |
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16984971 |
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15350577 |
Nov 14, 2016 |
10231926 |
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16354692 |
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14218324 |
Mar 18, 2014 |
9610246 |
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15350577 |
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14181250 |
Feb 14, 2014 |
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14218324 |
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61765554 |
Feb 15, 2013 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61F 9/0017 20130101;
Y10S 514/953 20130101; A61K 47/32 20130101; Y10S 514/956 20130101;
A61F 2210/0004 20130101; Y10S 514/954 20130101; A61K 9/0051
20130101; Y10S 514/912 20130101; Y10S 514/913 20130101; A61K 31/498
20130101 |
International
Class: |
A61K 9/00 20060101
A61K009/00; A61F 9/00 20060101 A61F009/00; A61K 31/498 20060101
A61K031/498; A61K 47/32 20060101 A61K047/32 |
Claims
1. A solid intraocular implant for the treatment of a posterior
ocular condition in a human patient, the solid intraocular implant
comprising: a brimonidine free base in an amount of about 40% by
weight to about 60% by weight of the implant, based on the total
weight of the implant; and a biodegradable polymer matrix
comprising an acid end-capped poly (D, L-lactide) polymer and a
75:25 poly (D,L-lactide-co-glycolide) polymer; wherein the weight
ratio of the acid end-capped poly (D, L-lactide) polymer to the
75:25 poly (D,L-lactide-co-glycolide) polymer is 1:1; and wherein
the implant has a polymer matrix degradation time in the range of
about three months to about six months when placed in the eye of a
human.
2. The implant of claim 1, wherein the brimonidine free base is
present in an amount of about 50% by weight of the implant, based
on the total weight of the implant.
3. The implant of claim 2, wherein the implant has a brimonidine
free base delivery duration of two months to four months when
placed in the eye of a human.
4. The implant of claim 1, wherein the acid end-capped poly (D,
L-lactide) polymer is present in an about of about 25% by
weight.
5. The implant of claim 1, wherein the 75:25 poly
(D,L-lactide-co-glycolide) polymer is present in an about of about
25% by weight.
6. The implant of claim 5, wherein the total weight of the implant
is about 800 .mu.g.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 16/354,692, filed Mar. 15, 2019, which is a
continuation of U.S. patent application Ser. No. 15/350,577 filed
Nov. 14, 2016, now U.S. Pat. No. 10,231,926, issued Mar. 19, 2019,
which is a continuation of U.S. patent application Ser. No.
14/218,324 filed Mar. 18, 2014, now issued as U.S. Pat. No.
9,610,246, which is a continuation of U.S. patent application Ser.
No. 14/181,250 filed Feb. 14, 2014, now abandoned, which claims the
benefit of U.S. Provisional Application No. 61/765,554 filed Feb.
15, 2013, the entire content of each application is incorporated
herein by reference.
BACKGROUND
Field
[0002] The disclosure of the present application generally relates
to drug delivery implants, and more specifically, drug delivery
implants used to treat ocular conditions.
Description of the Related Art
[0003] Diabetic retinopathy is the leading cause of blindness among
adults aged 20 to 74 years. It is estimated that 75,000 new cases
of macular edema, 65,000 cases of proliferative retinopathy, and
12,000 to 24,000 new cases of blindness arise each year. Retinitis
pigmentosa (RP) is a heterogeneous group of inherited
neurodegenerative retinal diseases that cause the death of
photoreceptor cells (rods and cones) that eventually leads to
blindness. Glaucoma is a multifactorial optic neuropathy resulting
from loss of retinal ganglion cells, corresponding atrophy of the
optic nerve, and loss of visual function, which is manifested
predominantly by visual field loss and decreased visual acuity and
color vision. Geographic atrophy ("GA") is one of 2 forms of the
advanced stage of Age-Related Macular Degeneration ("AMD"). The
advanced stage of AMD refers to that stage in which visual acuity
loss can occur from AMD. Retinal detachments are a significant
cause of ocular morbidity. There are 3 types of retinal detachment:
rhegmatogenous, tractional, and exudative.
[0004] Brimonidine (5-bromo-6-(2-imidazolidinylideneamino)
quinoxaline) is an alpha-2-selective adrenergic receptor agonist
effective for treating open-angle glaucoma by decreasing aqueous
humor production and increasing uveoscleral outflow. Brimonidine
tartrate ophthalmic solution 0.2% (marketed as ALPHAGAN.RTM.) was
approved by the US Food and Drug Administration (FDA) in September
1996 and in Europe in March 1997 (United Kingdom). Brimonidine
tartrate ophthalmic solution with Purite.RTM. 0.15% and 0.1%
(marketed as ALPHAGAN.RTM. P) was approved by the FDA in March 2001
and August 2005, respectively. These formulations are currently
indicated for lowering IOP in patients with open-angle glaucoma
(OAG) and ocular hypertension (OHT).
[0005] A neuroprotective effect of brimonidine tartrate has been
shown in animal models of optic nerve crush, moderate ocular
hypertension, pressure-induced ischemia, and vascular ischemia. The
neuroprotective effect of topical applications of brimonidine
tartrate has also been explored clinically in patients with
glaucoma, age-related macular degeneration, retinitis pigmentosa,
diabetic retinopathy, and acute non-arteritic anterior ischemic
optic neuropathy. However, certain limitations exist with the use
of brimonidine tartrate in intraocular implants. For example,
because of the size of the brimonidine tartrate molecule, the
amount of drug that can be loaded into an implant may be limited.
Also, the hydrophilic nature of brimonidine tartrate may limit the
ability of the drug's use in sustained release formulations.
SUMMARY
[0006] Accordingly, an embodiment provides an intraocular implant
for the treatment of a posterior ocular condition in a human
patient including a biodegradable polymer matrix including at least
one biodegradable polymer and a brimonidine free base agent,
wherein the implant can be configured to deliver the brimonidine
free base agent to the vitreous of an eye of a patient suffering
from a posterior ocular condition for a brimonidine free base agent
delivery duration of up to six months and wherein the biodegradable
polymer matrix is configured to completely or almost completely
degrade, once placed into the vitreous of the eye, within a period
of time of about two times the brimonidine free base agent delivery
duration or less. In some embodiments, the brimonidine free base
agent is present in the implant in an amount of about 50% by weight
of the implant, based on the total weight of the implant. In some
embodiments, the implant can have a rod shape, and the rod shape
can have a rod diameter of about 350 .mu.m and a rod length of
about 6 mm. According to other embodiments, the brimonidine free
base agent is dispersed within the biodegradable polymer matrix. In
some embodiments, the at least one biodegradable polymer includes
poly(D,L-lactide-co-glycolide) and poly(D,L-lactide). In some
embodiments, the biodegradable polymer matrix includes at least one
polymer selected from the group consisting of acid-end capped
poly(D,L-lactide-co-glycolide) and acid-end capped
poly(D,L-lactide). In some embodiments, the brimonidine free base
agent delivery duration is in the range of about 1 month to about 6
months.
[0007] These and other embodiments are described in greater detail
below.
BRIEF DESCRIPTION OF THE FIGURES
[0008] These and other features will now be described with
reference to the drawings summarized below. These drawings and the
associated description are provided to illustrate one or more
embodiments and not to limit the scope of the invention.
[0009] FIG. 1 illustrates brimonidine tartrate implant formulation
drug release profiles in 0.01 M PBS with a pH of 7.4 at 37.degree.
C., according to comparative example formulations.
[0010] FIG. 2 shows brimonidine free base implant formulation drug
release profiles in 0.01 M PBS with a pH of 7.4 at 37.degree. C.,
according to example formulations.
[0011] FIG. 3 shows brimonidine tartrate implant formulation drug
release profiles in Albino rabbits, according to comparative
example formulations.
[0012] FIG. 4 shows brimonidine tartrate implant formulation drug
release profiles in Cyno monkeys, according to comparative example
formulations.
[0013] FIG. 5 illustrates brimonidine free base implant formulation
drug release profiles in Albino rabbits, according to example
formulations.
[0014] FIG. 6 illustrates brimonidine free base implant formulation
drug release profiles in Cyno monkeys, according to example
formulations.
[0015] FIG. 7 shows the drug concentration of brimonidine tartrate
implant formulations in the retina (optic nerve) of Albino rabbits
over time according to comparative example formulations. The dotted
line indicates the human .alpha.2A EC90 concentration.
[0016] FIG. 8 shows the drug concentration of brimonidine free base
implant formulations in the retina (optic nerve) of Albino rabbits
over time according to example formulations. The dotted line
indicates the human .alpha.2A EC90 concentration.
[0017] FIG. 9 illustrates the drug concentration of brimonidine
free base implant formulations in the retina (macula) of Cyno
monkeys over time according to example formulations. The dotted
line indicates the human .alpha.2A EC90 concentration. For
comparison, the CE1 brimonidine formulation is included.
[0018] FIG. 10 illustrates the polymer matrix degradation of
brimonidine tartrate implant formulations in Cyno monkeys over
time, according to comparative example formulations.
[0019] FIG. 11 shows the polymer matrix degradation of brimonidine
free base implant formulations in Cyno monkeys over time, according
to example formulations.
[0020] FIG. 12 shows the implant image when incubating in PBS (pH
7.4, 0.01N) at 37.degree. C.
DETAILED DESCRIPTION
[0021] In general terms, an embodiment relates to brimonidine free
base sustained delivery for back-of-the-eye therapeutic
applications. In some embodiments, the brimonidine free base is
formulated into an implant with one or more polymers in a polymer
matrix, the polymers selected in order to give a target sustained
delivery of the brimonidine free base and/or a target degradation
of the one or more polymers. According to some embodiments,
formulations of brimonidine free base and biodegradable polymer or
polymers are created such that the polymer matrix will be degraded
within a period of not more than twice the brimonidine free base
release duration, but more than the brimonidine free base release
duration. According to some embodiments, the brimonidine free base
drug delivery system exhibits a target drug delivery duration of
one to six months and a target matrix degradation time of two to
twelve months.
[0022] Embodiments herein disclose 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 can be in
the form of implants or implant elements that can be placed in an
eye. The systems and methods disclosed in some embodiments herein
can provide for extended release time of one or more therapeutic
agent or agents. Thus, for example, a patient who has received such
an implant in their eye can receive a therapeutic amount of an
agent for a long or extended time period without requiring
additional administrations of the agent. According to some
embodiments an implant may also only remain within the eye of a
patient for a targeted or limited amount of time before it degrades
completely or nearly completely. By limiting the amount of time a
foreign object, such as an implant is in a patient's eye or
vitreous, a patient's comfort is optimized and their risk for
infection or other complications is minimized. Also, complications
that may arise from an implant colliding with the cornea or other
part of the eye in the dynamic fluid of the vitreous can be
avoided.
[0023] As used herein, an "intraocular implant" refers to a device
or elements that is structured, sized, or otherwise configured to
be placed in an eye. Intraocular implants are generally
biocompatible with physiological conditions of an eye. Intraocular
implants may be placed in an eye without disrupting vision of the
eye.
[0024] As used herein, "therapeutic component" refers to 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
the eye.
[0025] As used herein, an "ocular condition" is a disease ailment
or condition which affects or involves the eye or one of the parts
or regions of the eye. The eye can include the eyeball and the
tissues and fluids that 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 the eyeball.
[0026] 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 can affect or involve the conjunctiva,
the cornea, the anterior chamber, the iris, the posterior chamber
(located 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.
[0027] 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 or optic disc, and
blood vessels and nerves that vascularize or innervate a posterior
ocular region or site.
[0028] Thus a posterior ocular condition can include a disease,
ailment or condition such as, but not limited to, acute macular
neuroretinopathy; Behcet's disease; geographic atrophy; choroidal
neovascularization; diabetic uveitis; histoplasmosis; infections,
such as fungal, bacterial, 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, cystoids 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; or posterior ocular conditions caused by or
influenced by a photodynamic therapy, photocoagulation, radiation
retinotherapy, 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 (e.g. neuroprotection).
[0029] The terms "biodegradable polymer" or "bioerodible polymer"
refer to a polymer or polymers which degrade in vivo, and wherein
erosion of the polymer or polymers over time occurs concurrent with
and/or subsequent to the release of a therapeutic agent. A
biodegradable polymer may be a homopolymer, a copolymer, or a
polymer comprising more than two polymeric units. In some
embodiments, a "biodegradable polymer" may include a mixture of two
or more homopolymers or copolymers.
[0030] The terms "treat", "treating", or "treatment" as used
herein, refer to reduction or resolution or prevention of an ocular
condition, ocular injury or damage, or to promote healing of
injured or damaged ocular tissue.
[0031] The term "therapeutically effective amount" as used herein,
refers to the level or amount of therapeutic agent needed to treat
an ocular condition, or reduce or prevent ocular injury or
damage.
[0032] Those skilled in the art will appreciate the meaning of
various terms of degree used herein. For example, as used herein in
the context of referring to an amount (e.g., "about 6%"), the term
"about" represents an amount close to and including the stated
amount that still performs a desired function or achieves a desired
result, e.g. "about 6%" can include 6% and amounts close to 6% that
still perform a desired function or achieve a desired result. For
example, the term "about" can refer to an amount that is within
less than 10% of, within less than 5% of, within less than 0.1% of,
or within less than 0.01% of the stated amount.
[0033] Intraocular implants can include a therapeutic component and
a drug release control component or components. The therapeutic
agent can comprise, or consist essentially 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, such as conditions associated
with the eye of a human patient.
[0034] The alpha-2 adrenergic receptor agonist of the implant is
typically an agent that selectively activates alpha-2 adrenergic
receptors relative to alpha-2 adrenergic receptors. In certain
implants, the alpha-2 adrenergic receptor agonist 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.
[0035] According to some embodiments, the alpha-2 receptor
antagonist used is brimonidine. Brimonidine is a quinoxaline
derivative having the structure:
##STR00001##
[0036] Brimonidine, an organic base, is publicly available as
brimonidine free base. Brimonidine free base is generally
hydrophobic.
[0037] In some embodiments, the alpha-2 adrenergic receptor
antagonist may be a pharmaceutically acceptable acid addition salt
of brimonidine. One such salt can be brimonidine tartrate (AGN
190342-F, 5-bromo-6-(2-imidazolidinylideneamino) quinoxaline
tartrate). Both brimonidine free base and brimonidine tartrate are
chemically stable and have melting points higher than 200.degree.
C.
[0038] Thus, an intraocular implant can comprise, consist of, or
consist essentially of a therapeutic agent such as an alpha-2
adrenergic receptor agonist such as a brimonidine salt alone (such
as brimonidine tartrate), a brimonidine free base alone, or
mixtures thereof.
[0039] The use of brimonidine free base in solid implant
formulations has several advantages over brimonidine tartrate, such
as the lower solubility of brimonidine free base lowers potential
drug burst effect, and the free base drug equivalent dose per
implant can be higher under the same weight. Thus, according to
some embodiments, no brimonidine tartrate is included in an
intraocular implant. According to some embodiment, the only
therapeutic agent used in an intraocular implant is brimonidine
free base.
[0040] The alpha-2 adrenergic receptor agonist may be in a
particulate or powder form and entrapped by the biodegradable
polymer matrix. According to an embodiment, the alpha-2 adrenergic
receptor agonist is a brimonidine free base having a D90 particle
size of less than about 20 .mu.m. According to another embodiment,
the alpha-2 adrenergic receptor agonist is a brimonidine free base
having a D90 particle size of less than about 10 .mu.m. According
to another embodiment, the alpha-2 adrenergic receptor agonist is a
brimonidine free base having a D90 particle size in the range of
about 10 .mu.m to about 20 .mu.m.
[0041] According to some embodiments, implants can be formulated
with particles of the brimonidine free base agent dispersed within
the bioerodible polymer matrix. According to some embodiments, the
implants can be monolithic, having the therapeutic agent
homogenously distributed through the biodegradable polymer matrix,
or encapsulated, where a reservoir of active agent is encapsulated
by the polymeric matrix. In some embodiments, the therapeutic agent
may be distributed in a non-homogeneous pattern in the
biodegradable polymer matrix. For example, in an embodiment, an
implant may include a first portion that has a greater
concentration of the therapeutic agent (such as brimonidine free
base) relative to a second portion of the implant.
[0042] The alpha-2 adrenergic receptor agonist can be present in an
implant in an amount in the range of about 20% to about 70% by
weight of the implant, based on the total weight of the implant. In
some embodiments, the alpha-2 adrenergic receptor agonist can be
present in an implant in an amount in the range of about 40% to
about 60% by weight of the implant, based on the total weight of
the implant. In an embodiment, the alpha-2 adrenergic receptor
agonist can be present in an implant in an amount of about 40% by
weight of the implant, based on the total weight of the implant. In
another embodiment, the alpha-2 adrenergic receptor agonist can be
present in an implant in an amount of about 50% by weight of the
implant, based on the total weight of the implant. In an example
embodiment, brimonidine free base can be present in an implant in
an amount of about 50% by weight of the implant, about 55% by
weight of the implant, about 60% by weight of the implant, or about
70% by weight of the implant, based on the total weight of the
implant.
[0043] Suitable polymeric materials or compositions for use in the
implant can include those materials which are compatible with the
eye so as to cause no substantial interference with the functioning
or physiology of the eye. Such materials can be at least partially
or fully biodegradable.
[0044] Examples of suitable polymeric materials for the polymer
matrix include polyesters. For example, polymers of D-lactic acid,
L-lactic acid, racemic lactic acid, glycolic acid,
polycaprolactone, and combinations thereof may be used for the
polymer matrix. In some embodiments, a polyester, if used, may be a
homopolymer, a copolymer, or a mixture thereof.
[0045] In some implants, copolymers of glycolic acid and lactic
acid are used, where the rate of biodegradation can be controlled,
in part, by the ratio of glycolic acid to lactic acid. The mol
percentage (% mol) of polylactic acid in the polylactic acid
polyglycolic acid (PLGA) copolymer can be between 15 mol % and
about 85 mol %. In some embodiments, the mol percentage of
polylactic acid in the (PLGA) copolymer is between about 35 mol %
and about 65 mol %. In some embodiments, a PLGA copolymer with 50
mol % polylactic acid and 50 mol % polyglycolic acid can be used in
the polymer matrix.
[0046] The polymers making up the polymer matrix may also be
selected based on their molecular weight. Different molecular
weights of the same or different polymeric compositions may be
included in the implant to modulate the release profile. In some
embodiments, the release profile of the therapeutic agent and the
degradation of the polymer may be affected by the molecular weight
of one or more polymers in the polymer matrix. In some embodiments,
the molecular weight of one or more poly (D,L-lactide) components
may be advantageously selected to control the release of the
therapeutic agent and the degradation of the polymer. According to
some embodiments, the average molecular weight of a polymer, such
as poly (D,L-lactide), may be "low." According to some embodiments,
the average molecular weight of a polymer, such as poly
(D,L-lactide), may be "medium." According to some embodiments, only
low molecular weight poly(D,L-lactide) is included in a polymer
matrix in an intraocular implant. According to some embodiments,
high molecular weight (Mw) poly(D,L-lactide)s are not present in
the biodegradable polymer matrix or they are only present in a
negligible amount (about 0.1% by weight of an implant, based on the
total weight of the implant). By limiting the amount of high
molecular weight poly(D,L-lactide) present in an implant, the
matrix degradation duration may be shortened.
[0047] Some example polymers that may be used alone or in
combination to form the polymer matrix include those listed in
TABLE A below, the data sheets of the commercially available
polymers are incorporated by reference, in their entirety:
TABLE-US-00001 TABLE A Trade Name of Molecular Commercially Weight
Available Intrinsic (low, Polymer (From Viscosity medium, EVONIK)
Polymer (dL/g) high) RG502S 50:50 poly (D, L- 0.16-0.24 low
lactide-co-glycolide) RG502H 50:50 poly (D, L- 0.16-0.24 low
lactide-co-glycolide), acid end capped RG504 50:50 poly (D, L-
0.45-0.60 medium lactide-co-glycolide) RG505 50:50 poly (D, L-
0.61-0.74 medium lactide-co-glycolide) RG752S 75:25 poly (D, L-
0.16-0.24 low lactide-co-glycolide) RG755 75:25 poly (D, L-
0.50-0.70 medium lactide-co-glycolide) RG858S 85:15 poly (D, L-
1.3-1.7 medium lactide-co-glycolide) R202H poly (D, L-lactide),
0.16-0.24 low acid end capped R203S poly (D, L-lactide) 0.25-0.35
medium R208 poly (D, L-lactide) 1.8-2.2 high
[0048] The biodegradable polymer matrix of the intraocular implant
can comprise a mixture of two or more biodegradable polymers. In
some embodiments, only one biodegradable polymer listed above is
used in the biodegradable polymer matrix. In some embodiments, any
one of the biodegradable polymers listed in the above chart can be
used in an amount in the range of 12.5% w/w to 70% w/w each in a
drug delivery system or implant. In some embodiments, any one of
the biodegradable polymers listed in the above chart can be used in
an amount in the range of 25% w/w to 50% w/w each in a drug
delivery system or implant. In some embodiments, any one of the
biodegradable polymers listed in the above chart can be used in an
amount in the range of 20% w/w to 40% w/w each in a drug delivery
system or implant. In some embodiments, any one of the
biodegradable polymers listed in the above chart can be used in an
amount of about 15% w/w, about 25% w/w, about 12.5% w/w, about
37.5% w/w, about 40% w/w, about 50% w/w, or about 60% w/w each in a
drug delivery system or implant. 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.
[0049] In some embodiments, release of a therapeutic agent from a
biodegradable polymer matrix in an intraocular implant can be the
consequence of various mechanisms and considerations. Release of
the agent can be achieved by erosion of the biodegradable polymer
matrix followed by exposure of previously embedded drug particles
to the vitreous of an eye receiving the implant, and subsequent
dissolution and release of the therapeutic agent. The release
kinetics by this form of drug release are different than that
through formulations which release agent by polymer swelling alone,
such as with hydrogel or methylcellulose. The parameters which may
determine the release kinetics include the size of the drug
particles, the water solubility of the drug, the ratio of drug to
polymer, and the erosion rate of the polymers.
[0050] According to some embodiments, compositions and methods
extend the brimonidine free base delivery in the vitreous with
concomitantly moderate matrix degradation duration. The sustained
ocular drug delivery can be achieved by formulating brimonidine
free base with properly selected blend of bioerodible
poly(D,L-lactide) and/or poly(D,L-lactide-co-glycolide).
[0051] According to some example embodiments, a drug delivery
system or implant can contain a polymer matrix with an acid-capped
poly (D,L-lactide) in an amount in the range of 25% w/w to about
50% w/w. According to some example embodiments, a drug delivery
system or implant can contain a polymer matrix with an acid-capped
50:50 poly (D,L-lactide-co-glycolide) in an amount in the range of
about 25% w/w to about 50% w/w or about 37.5% to about 50% w/w of
the implant. According to some example embodiments, a drug delivery
system or implant can contain a polymer matrix with an acid-capped
75:25 poly (D,L-lactide-co-glycolide) in an amount in the range of
about 25% w/w to about 50% w/w or about 15% w/w to about 50% w/w of
the implant. According to some example embodiments, a drug delivery
system or implant can contain a polymer matrix with an acid-capped
85:15 poly (D,L-lactide-co-glycolide) in an amount in the range of
about 25% w/w to about 50% w/w or about 30% to about 60% w/w of the
implant.
[0052] The drug delivery systems are designed to release
brimonidine free base at therapeutic levels to the vitreous for a
sustained period of time (the brimonidine free base delivery
duration), then degrade over period of time in the range of half
the brimonidine free base delivery duration to a time equivalent to
the brimonidine free base delivery duration. According to other
embodiments, the drug delivery system including the polymer matrix
can degrade over a period of time of about one quarter the
brimonidine free base delivery duration to about one half the
brimonidine free base delivery duration. According to other
embodiments, the drug delivery system including the polymer matrix
can degrade over a period of time of about one third the
brimonidine free base delivery duration to about one half the
brimonidine free base delivery duration. According to other
embodiments, the drug delivery system including the polymer matrix
can degrade over a period of time equivalent to about the
brimonidine free base delivery duration to about twice the
brimonidine free base delivery duration. For example, in an
embodiment, an intraocular implant may include a mixture of
brimonidine free base and a biodegradable polymer matrix that
releases brimonidine free base over a period of time of three
months, then the polymer matrix degrades for a period of an
additional 2 months until the implant is completely degraded or
almost completely degraded. According to some embodiments, the
brimonidine free base delivery duration is a period of time in the
range of about 1 month to about 6 months, about 1 month to about 5
months, about 1 month to about 3 months, about 1 month to about 4
months, about 2 months to about 4 months, or about 3 months to
about 6 months. According to some embodiments, the polymer matrix
degradation time for the total drug delivery system is in the range
of about 1 month to about 7 months, about 1 month to about 6
months, about 3 months to about 7 months, about 1 month to about 4
months, about 3 months to about 4 months, about 4 months to about 5
months, about 5 months to about 7 months, or about 3 months to
about 6 months. According to some embodiments, the polymer matrix
degradation time for the drug delivery system is fewer than 10
weeks, fewer than 8 weeks, fewer than 6 weeks, or fewer than 4
weeks.
[0053] According to one example embodiment, a biodegradable
intraocular implant comprises brimonidine free base associated with
a biodegradable polymer matrix, which comprises a mixture of
different biodegradable polymers. The brimonidine free base is
present in the implant in an amount of 50% by weight, based on the
total weight of the implant. A first biodegradable polymer is an
acid end capped poly (D,L-lactide) having an inherent viscosity of
between 0.16 dL/g and 0.24 dL/g, and comprising 25% by weight of
the implant, based on the total weight of the implant. A second
biodegradable polymer is a PLGA copolymer having 75 mol %
polylactic acid and 25 mol % polyglycolic acid. The PLGA copolymer
has an inherent viscosity of between 0.16 dL/g and 0.24 dL/g, and
the PLGA copolymer comprises 25% of weight of the implant, based on
the total weight of the implant. Such a mixture is effective in
releasing an effective amount of the brimonidine free base over a
delivery duration of about three months, then degrading the polymer
matrix over the span of one-two additional months, less than twice
the brimonidine free base delivery duration.
[0054] According to another example embodiment, a biodegradable
intraocular implant comprises brimonidine free base associated with
a biodegradable polymer matrix, which comprises a single type of
biodegradable polymer. The brimonidine free base is present in the
implant in an amount of 50% by weight, based on the total weight of
the implant. In this embodiment, the biodegradable polymer matrix
is made of a PLGA copolymer having 85 mol % polylactic acid and 15
mol % polyglycolic acid. The PLGA copolymer has an inherent
viscosity of between 1.3 dL/g and 1.7 dL/g, and the PLGA copolymer
comprises 50% of weight of the implant, based on the total weight
of the implant. Such a mixture is effective in releasing an
effective amount of the brimonidine free base over a delivery
duration of about three or four months, then degrading the polymer
matrix over the span of one-two additional months, less than twice
the brimonidine free base delivery duration.
Manufacture of Implants
[0055] According to some embodiments, intraocular implants can be
formed through suitable polymer processing methods. In an
embodiment, a mixture of a therapeutic agent (such as brimonidine
free base) may be blended with PLA and/or PLGA polymers in a mixer,
such as a Turbula mixer. In an embodiment, the intraocular implants
are formed by extrusion. Extrusion can be performed by a suitable
extruder, such as a Haake extruder. After the therapeutic agent and
the polymer matrix have been blended together, they can then be
force fed into an extruder and extruded into filaments. The
extruded filaments may then be cut into implants with a target
weight. In some embodiments, a 800 .mu.g implant may be cut to
deliver about 300 .mu.g, 400 .mu.g, or 500 .mu.g of drug over the
brimonidine free base delivery duration. Implants can then be
loaded into an injection device, such as a 25 G applicator and
sterilized. According to some embodiments, the extruded filaments
are cut to a weight of less than 1000 .mu.g, less than 800 .mu.g,
or less than 600 .mu.g. In some embodiments, the implants can be
gamma sterilized. The implants can be gamma sterilized at doses
such as 20 kGy to 60 kGy, 25 kGy to 50 kGy, 25 kGy to 40 kGy, and
the like.
Methods for Treatment
[0056] According to an embodiment, a method for treating a
posterior ocular condition includes administering an implant, such
as the implants disclosed herein, to a posterior segment of an eye
of a human or animal patient, and preferably a living human or
animal. In some embodiments, a method of treating a patient may
include placing the implant directly into the posterior chamber of
the eye. In some embodiments, a method of treating a patient may
comprise administering an implant to the patient by at least one of
intravitreal injection, subconjunctival injection, subtenon
injections, retrobulbar injection, and suprachoroidal
injection.
[0057] In at least one embodiment, a method of treating retinitis
pigmentosa, glaucoma, macular degeneration, and/or geographic
atrophy in a patient comprises administering one or more implants
containing brimonidine free base, 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.
According to some embodiments, no more than one injection is
administered to the patient to treat the condition. According to
other embodiments, more than one injection is administered to the
patient to treat the condition.
Examples
[0058] Example intraocular implants containing brimonidine tartrate
or brimonidine free base and a biodegradable polymer matrix were
created and tested for their release and degradation properties.
The brimonidine tartrate or brimonidine free base was first weighed
and blended with PLA and/or PLGA polymers in a Turbula mixer for 30
minutes. The resulting powder blend was then fed to the Haake
extruder by a force feeder. The extruded filaments were cut to
implants with a target weight, e.g., 857 .mu.g or 800 .mu.g to
deliver 300 .mu.g brimonidine tartrate or 400 .mu.g brimonidine
free base per implant. Implants were loaded into 25 G applicators
and gamma-sterilized at 25 to 40 kGy dose. The potency per implant
was confirmed by a HPLC assay.
[0059] Examples and Comparative Examples of formulation
compositions using brimonidine tartrate (as Comparative Examples
1-4) and brimonidine free base (Examples 1-4) as the drug are shown
in Tables B and C, and their drug release profiles are shown in
FIGS. 1 and 2, respectively. In FIGS. 1 and 2, they axis is number
of days and they axis is the percentage (%) of total release. For
in vitro drug release testing, four implants per each formulation
were randomly cut from extruded filaments, gamma sterilized, and
incubated in 10 mL of 0.01M PBS pH 7.4 in a shaking water bath set
at 37.degree. C. and 50 rpm. The drug release was sampled at
designated time point, and the drug content was analyzed by a HPLC
assay. The release medium was completely replaced with fresh medium
during each sampling time point. The polymer Mw degradation rate
constant k, as determined by incubating implant samples in 0.01M
PBS pH 7.4 at 25.degree. C. and their Mw determined by size
exclusion chromatography, is included in Tables B and C as
well.
TABLE-US-00002 TABLE B Brimonidine tartrate formulation comparative
example composition, dimension and degradation kinetic parameters
Brimonidine Polymer Excipient, % w/w Implant Implant Implant k at
37 C. Tartrate, R R R RG RG Diameter Length Weight (1/day), in
Formulation % w/w 202H 203S 208 752S 858S (.mu.m) (mm) (.mu.g)
vitro CE 1 35 40 25 356 ~6 857 0.0041 CE2 35 65 356 ~6 857 0.0033
CE3 35 48 17 356 ~6 857 0.0073 CE4 35 15 40 10 356 ~6 857
0.0064
TABLE-US-00003 TABLE C Brimonidine free base example formulation
composition, dimension and degradation kinetic parameter
Brimonidine Polymer Excipient, % w/w Implant Implant Implant k at
37 C. free base, R RG RG RG RG Diameter Length Weight (1/day), in
Formulation % w/w 202H 502H 502S 752S 858S (.mu.m) (mm) (.mu.g)
vitro EX 1 50 50 356 ~6 800 0.02 EX 2 50 50 356 ~6 800 0.012 EX 3
50 25 25 356 ~6 800 0.012 EX 4 50 37.5 12.5 356 ~6 800 0.057
[0060] The polymer matrix degradation was then analyzed both in
vitro and in vivo. For in vitro study, the polymer Mw degradation
rate constant k as described above was used to calculate the
degradation time for the polymer Mw degraded to 1000 Da t(1000) by
assuming the degradation follows first order kinetics. For in vivo
study, the polymer matrix degradation was determined by harvesting
the implant samples that were injected to the vitreous of New
Zealand rabbit. The results are summarized in Table D.
TABLE-US-00004 TABLE D Brimonidine formulation in vitro and in vivo
drug release and polymer matrix degradation time In Vitro Rabbit
Calc. Matrix Drug Drug Degradation Drug Matrix Substance
Formulation Release t(1000) Release Degradation Brimo CE 1 6 months
~30 months >6 months >>6 months Tartrate CE 2 4 months ~28
months 5 months >>6 months CE 3 4 months ~15 months 4.5
months >>6 months CE 4 3 months ~14 months 3 months >6
month Brimo EX 1 3 months ~3 months ~2 months 2 months Free EX 2 4
months ~7 months ~3 months 4 months Base EX 3 3 months ~5 months ~3
months 3 months EX 4 1 month ~1 months ~1 month 1 month
In Vitro Testing of Intraocular Implants Containing Brimonidine and
a Biodegradable Polymer Matrix
Weight Loss Study
[0061] For the implant weight loss study, each implant was first
weighed, moved to a plastic micromesh cassette, and incubated in a
glass jar filled with PBS (pH 7.4, 0.01M) before placed in a
shaking water bath set at 37.degree. C. and 50 rpm. The implants
were harvested at designated time points and dried under vacuum.
The weights of the dried implants were recorded and the implant
weight loss was calculated. The results are summarized in Table E
and show that the brimonidine free base implants lose weight more
quickly than those of brimonidine tartrate, implying and
illustrating the difference in matrix degradation rate.
TABLE-US-00005 TABLE E Implant weight loss in PBS (pH 7.4, 0.01M)
at 37.degree. C. Remaining Weight Time (wk) CE 1 CE 2 CE 3 CE 4 EX
1 EX 2 EX 3 EX 4 1 99.7% 99.7% 99.7% 99.5% 99.4% 99.5% 99.7% 99.3%
2 98.8% 99.4% 98.9% 91.7% 94.2% 100.7% 99.0% 0.0% 4 98.5% 95.5%
95.7% 78.7% 0.0% 95.0% 72.2% 6 97.9% 93.8% 93.0% 63.2% 81.0% 0.0% 8
98.8% 96.6% 89.3% 67.0% 0.0% 10 93.1% 85.7% 81.5% 57.3% 12 84.9%
74.3% 72.6% 61.9% 14 84.3% 40.4% 72.7% 67.0% 16 81.2% 66.9% 70.2%
51.5% 18 78.6% 71.9% 65.5% 53.9%
Implant Swelling
[0062] To investigate the implant swelling, each implant was
incubated in 20 mL of PBS (pH 7.4, 0.01M) in a glass scintillation
vial and placed in a shaking water bath set at 37.degree. C. and 50
rpm. The implant images were recorded and summarized in FIG. 12.
The results show that brimonidine free base implants swelled and
degraded much faster than those of brimonidine tartrate.
[0063] The drug releases of brimonidine tartrate formulations in
rabbit and monkey eyes are shown in FIGS. 3 and 4, respectively.
The drug releases of brimonidine free base formulations in rabbit
and monkey eyes are shown in FIGS. 5 and 6.
[0064] The in vivo drug release profiles were determined by
retrieving the implants from the vitreous humor at designated time
points. The implant mass was recorded before and after in vivo
implantation to determine the quantity of residual polymer matrix.
The drug release rates in both animal models showed that Example 4
had the highest release rate, followed by Example 1, then Example
3, then Example 2 demonstrated the slowest drug release rate.
[0065] The drug concentration of brimonidine tartrate formulations
in the retina (optic nerve) of Albino rabbit eyes are shown in FIG.
7. All formulations maintained the brimonidine concentration above
the human .alpha.2A EC90 (88 nM, 25.7 ng/mL) for more than 3
months. For brimonidine free base formulations, the drug
concentrations in retina (optic nerve in rabbit and macula in
monkey) were determined, and the results are shown in FIGS. 8 and 9
for rabbit and monkey, respectively. The period for brimonidine
concentration above the human .alpha.2A EC90 in the rabbit optic
nerve was <3 months for all formulations. In a contrast, the
time of brimonidine concentration above the human .alpha.2A EC90 in
the monkey macula was >4 months for all formulations except
Example 4 that lasted about one month.
[0066] The polymer matrix degradation of brimonidine tartrate and
free base formulations in monkey eyes are shown in FIGS. 10 and 11,
respectively. For brimonidine tartrate formulations, less than 50%
of matrix was degraded for Comparative Example 1 and Comparative
Example 2 formulations in one year, while that for Comparative
Example 3 and Comparative Example 4 reached more than 90%. For
brimonidine free base formulations, all formulations became small
and hard to handle after one month, except Example 2, that the
polymer matrix was expected to last for about six months. The in
vitro matrix degradation observation matches the in vivo
results.
[0067] The polymer matrix degradation of brimonidine tartrate and
free base formulations in rabbit eyes were analyzed by photo
images, and the matrix degradation time is longer than 6 months for
brimonidine tartrate formulations and shorter than 4 months for
brimonidine free base formulations.
[0068] The polymers used in the formulations include, but not
limited to, poly(D,L-lactide) and poly(D,L-lactide-co-glycolide).
They are summarized in Table A.
[0069] The four brimonidine free base formulations demonstrated
implants with controlled drug release from one to four months and
polymer matrixes lasting for less than two times the drug release
duration. In contrast, the brimonidine tartrate formulations
delivered the drug for a comparable duration as the brimonidine
free base formulations, but the polymer matrix lasted more than two
times of the drug release duration.
[0070] Although this invention has been disclosed in the context of
certain preferred embodiments and examples, it will be understood
by those skilled in the art that the present invention extends
beyond the specifically disclosed embodiments to other alternative
embodiments and/or uses of the invention and obvious modifications
and equivalents thereof. In addition while the number of variations
of the invention have been shown and described in detail, other
modifications, which are within the scope of this invention, will
be readily apparent to those of skill in the art based on this
disclosure. It is also contemplated that various combinations or
subcombinations of the specific features and aspects of the
embodiments can be made and still fall within the scope of the
invention. Accordingly, it should be understood that various
features and aspects of the disclosed embodiments can be combined
with, or substituted for, one another in order to perform varying
modes of the disclosed invention. Thus, it is intended that the
scope of the present invention herein disclosed should not be
limited by the particular disclosed embodiments described above,
but should be determined only by a fair reading of the claims.
* * * * *