Note: Descriptions are shown in the official language in which they were submitted.
CA 02830555 2013-10-18
INTRAOCULAR DRUG DELIVERY DEVICE AND ASSOCIATED METHODS
RELATED APPLICATIONS
None.
FIELD OF THE INVENTION
The present invention relates to systems, methods, and devices for the
sustained and
targeted (local) delivery of a pharmaceutical active agent into an eye of a
subject.
Accordingly, the present invention involves the fields of polymer chemistry,
material science,
polymer science, drug delivery, formulation science, pharmaceutical sciences,
and medicine,
particularly ophthalmology.
BACKGROUND
Age-related macular degeneration (AMD) and glaucoma are two of the leading
causes
of blindness in the United States and across the world. Present glaucoma
therapies generally
require polypharmacy, where subjects are often prescribed several topical
agents that must be
applied to the eye with varying frequencies, in some cases up to 3 or 4 times
a day. These
=
dosing regimens are often difficult for subjects to consistently follow, and
many individuals
progress to needing surgical treatments such as intraocular shunts or
trabeculectomies, which
have significant attendant complications.
Subjects having macular degeneration are often required to have monthly
intravitreal
injections. Such injections are painful and may lead to retinal detachment,
endophthalmitis,
and other complications. Furthermore, these injections are generally performed
only by
retinal surgeons, a small fraction of the ophthalmic community, producing a
bottleneck in eye
care delivery and increased expense.
Postoperative surgery inflammation is associated with raised intraocular
pressure
(lOP), and increases the likelihood of cystoid macular edema (CME), synechial
formation,
posterior capsule opacification (PCO), and secondary glaucoma. Patient
compliance is of
concern in the management of postoperative inflammation because multiple eye
drops must
be taken multiple times per day at regular intervals over the course of weeks.
Poor
compliance compromises the efficacy of topical drugs, which are further
limited by corneal
absorption and have highly variable intraocular concentrations during the
therapeutic course.
Uveitis specifically refers to inflammation of the middle layer of the eye,
termed the "uvea"
but in common usage may refer to any inflammatory process involving the
interior of the eye.
CA 02830555 2013-10-18
Uveitis is estimated to be responsible for approximately 10% of the blindness
in the United
States.
Postoperative cataract surgery inflammation can be well controlled by
improving
patient compliance. Available literature and experience shows penetration of
the drug after
topical administration is poor and higher systemic concentration means
frequent systemic
adverse events. All of these factors highlight the need for sustained
intraocular delivery for
pharmaceutical active agents to effectively control inflammation.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a top view of an active agent delivery device in the shape of a
disc.
FIG. 2 is a side view of an active agent delivery device in the shape of a
disc.
FIG. 3 is a graphical representation of the amount of an active agent present
in various
eye tissues following implantation of an intraocular device in accordance with
a further
aspect of the present invention.
FIG. 4 is a photograph showing a bioerodible dexamethasone implant (BDI).
FIG. 5 is a graph of in-vitro release kinetics of the BDI-1 implant. Data are
presented
as mean SD (n=3).
FIG. 6 is a time vs. concentration profile of BDI-1 implant with 120 to 160
lig of
dexamethasone (DXM) in aqueous and vitreous humor of New Zealand White (NZW)
rabbits.
FIG. 7 is a time vs. concentration profile of BDI-1 implant with 120 to 160
lig of
DXM in iris/ciliary body and retina/choroid of NZW rabbits.
FIG. 8 is a graph of in vitro release kinetics of dexamethasone from BDI-2
implants
(containing 300 1.ig of DXM). Data are presented as Mean SD (n=3) [Form. A:
PLGA
50:50, M.W. 7,000-17000; Form. B: PLGA 65:35, M.W. 17000-32000; Form. C: PLGA
50:50, M.W. 7,000-17000 (50%), PLGA 65:35, M.W. 17000-32000 (50%); Form. D:
PLGA
50:50, M.W. 7,000-17000 with 10% hydroxypropyl methylcellulose (HPMC)].
FIG. 9 is a graph of time vs. concentration profile of BDI-2 implant and
topical drops
in aqueous humor of New Zealand white rabbits.
FIG. 10 is a graph of time vs. concentration profile of BDI-2 implant and
topical
drops in vitreous humor of New Zealand white rabbits.
FIG. 11 is a graph of time vs. concentration profile of BDI-2 implant and
topical
drops in retina/choroid of New Zealand white rabbits.
FIG. 12 is a graph of time vs. retinal thickness of New Zealand white rabbits
in four
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CA 02830555 2013-10-18
groups: standard control, topical drops, BDI, and normal control.
These drawings merely depict exemplary embodiments of the present invention
and
they are, therefore, not to be considered limiting of its scope. It will be
readily appreciated
that the components of the present invention, as generally described and
illustrated in the
figures herein, could be arranged, sized, and designed in a wide variety of
different
configurations.
DETAILED DESCRIPTION OF THE INVENTION
The following detailed description of exemplary embodiments of the invention
makes
reference to the accompanying drawings, which form a part hereof and in which
are shown,
by way of illustration, exemplary embodiments in which the invention may be
practiced.
While these exemplary embodiments are described in sufficient detail to enable
those skilled
in the art to practice the invention, it should be understood that other
embodiments may be
realized and that various changes to the invention may be made without
departing from the
spirit and scope of the present invention. Thus, the following more detailed
description of the
embodiments of the present invention is not intended to limit the scope of the
invention, as
claimed, but is presented for purposes of illustration only and not limitation
to describe the
features and characteristics of the present invention, to set forth the best
mode of operation of
the invention, and to sufficiently enable one skilled in the art to practice
the invention.
Accordingly, the scope of the present invention is to be defmed solely by the
appended
claims.
It must be noted that, as used in this specification and the appended claims,
the
singular forms "a," "an," and "the" include plural referents unless the
context clearly dictates
otherwise. Thus, for example, reference to "a drug" includes reference to one
or more of
such drugs, "an excipient" includes reference to one or more of such
excipients, and
"loading" refers to one or more of such steps.
Definitions
In describing and claiming the present invention, the following terminology
will be
used in accordance with the definitions set forth below.
As used herein, "active agent," "bioactive agent," "pharmaceutically active
agent,"
and "drug," may be used interchangeably to refer to an agent or substance that
has
measurable specified or selected physiologic activity when administered to a
subject in a
significant or effective amount. These terms of art are well-known in the
pharmaceutical and
medicinal arts.
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CA 02830555 2013-10-18
As used herein, "bioerodible" and "biodegradable" may be used interchangeably
to
refer to materials that can be broken down over time in the body of a subject
organism,
especially in a lens capsule or a ciliary sulcus of an eye of a subject. A
bioerodible material
can be a solid matrix that dissolves slowly, releasing any active agents that
have been
incorporated into the bioerodible material. A bioerodible implant can
eventually dissolve
completely so that the implant does not need to be removed from the subject.
As used herein, "formulation" and "composition" may be used interchangeably
herein, and refer to a combination of two or more elements, or substances. In
some
embodiments a composition can include an active agent, an excipient, or a
carrier to enhance
delivery, depot formation, etc.
As used herein, "subject" refers to a mammal that may benefit from the
administration
of a composition or method as recited herein. Examples of subjects include
humans, and can
also include other animals such as horses, pigs, cattle, dogs, cats, rabbits,
aquatic mammals,
etc.
As used herein, the terms "reservoir" and "active agent reservoir" may be used
interchangeably, and refer to a body, a mass, or a cavity that can contain an
active agent. As
such, a reservoir can include any structure that may contain a liquid, a
gelatin, a sponge, a
semi-solid, a solid or any other form of active agent known to one of ordinary
skill in the art.
In some aspects a reservoir can also contain an active agent matrix. Such
matrixes are well
known in the art. A reservoir is not necessarily a physical structure that
encloses another
material inside itself. In some cases a reservoir can simply be a specific
volume of an active
agent matrix without any external containing structure.
As used herein, the term "intraocular lens" refers to a lens that is utilized
to replace a
lens in the eye of a subject. Such intraocular lenses can be synthetic or
biological in nature.
Furthermore, in some aspects the term "intraocular lens" can also refer to the
original natural
lens that is associated with the eye.
As used herein, the term "ciliary sulcus" refers to the space between the
posterior root
of the iris and the ciliary body of the eye.
As used herein, the term "substantially" refers to the complete or nearly
complete
extent or degree of an action, characteristic, property, state, structure,
item, or result. For
example, an object that is "substantially" enclosed would mean that the object
is either
completely enclosed or nearly completely enclosed. The exact allowable degree
of deviation
from absolute completeness may in some cases depend on the specific context.
However,
generally speaking the nearness of completion will be so as to have the same
overall result as
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CA 02830555 2013-10-18
if absolute and total completion were obtained. The use of "substantially" is
equally
applicable when used in a negative connotation to refer to the complete or
near complete lack
of an action, characteristic, property, state, structure, item, or result. For
example, a
composition that is "substantially free of' particles would either completely
lack particles, or
so nearly completely lack particles that the relevant effect would be the same
as if it
completely lacked particles. In other words, a composition that is
"substantially free of' an
ingredient or element may still actually contain such item as long as there is
no measurable
effect thereof.
As used herein, the term "about" is used to provide flexibility to a numerical
range
endpoint by providing that a given value may be "a little above" or "a little
below" the
endpoint.
As used herein, a plurality of items, structural elements, compositional
elements,
and/or materials may be presented in a common list for convenience. However,
these lists
should be construed as though each member of the list is individually
identified as a separate
and unique member. Thus, no individual member of such list should be construed
as a de
facto equivalent of any other member of the same list solely based on their
presentation in a
common group without indications to the contrary.
Concentrations, amounts, and other numerical data may be expressed or
presented
herein in a range format. It is to be understood that such a range format is
used merely for
convenience and brevity and thus should be interpreted flexibly to include not
only the
numerical values explicitly recited as the limits of the range, but also to
include all the
individual numerical values or sub-ranges encompassed within that range as if
each
numerical value and sub-range is explicitly recited. As an illustration, a
numerical range of
"about 1 to about 5" should be interpreted to include not only the explicitly
recited values of
about 1 to about 5, but also include individual values and sub-ranges within
the indicated
range. Thus, included in this numerical range are individual values such as 2,
3, and 4 and
sub-ranges such as from 1-3, from 2-4, and from 3-5, etc. This same principle
applies to
ranges reciting only one numerical value. Furthermore, such an interpretation
should apply
regardless of the breadth of the range or the characteristics being described.
Any steps recited in any method or process claims may be executed in any order
and
are not limited to the order presented in the claims unless otherwise stated.
Means-plus-
function or step-plus-function limitations will only be employed where for a
specific claim
limitation all of the following conditions are present in that limitation: a)
"means for" or "step
for" is expressly recited; and b) a corresponding function is expressly
recited. The structure,
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CA 02830555 2013-10-18
material or acts that support the means-plus function are expressly recited in
the description
herein. Accordingly, the scope of the invention should be determined solely by
the appended
claims and their legal equivalents, rather than by the descriptions and
examples given herein.
Intraocular Drug Delivery Device
An intraocular drug delivery device can provide improved ophthalmic drug
delivery
by alleviating the need for multiple injections or complex eyedrop regimens by
providing an
intra-capsular reservoir which is implantable and biodegrades such that
subsequent surgery is
often unnecessary. Further, the device can deliver a variety or combination of
different
medicines.
A novel intraocular drug delivery device, system, and associated methods for
providing sustained release of ocular active agents for extended periods of
time are disclosed
and described. One problem with many eye diseases such as Age-related Macular
Degeneration (AMD) is the constant need for a subject to receive painful
ocular injections,
which have significant risks of retinal detachment, vitreous hemorrhage, and
endophthalmitis.
The intraocular drug delivery device allows for sustained release of an active
agent over time,
thus eliminating the need for frequent ocular injections.
In some aspects, the device can be implantable during cataract surgery,
essentially
"piggybacking" on the cataract extraction, and thus eliminating the need for
additional
surgical procedures. One benefit to "piggybacking" on the cataract extraction
is the ability to
deliver steroids, antibiotics, and various non-steroidal agents directly to
the eye after surgery,
thus helping to minimize complications such as cystoid macular edema. In other
aspects, the
device can be implanted in a surgery that is separate from a cataract
procedure, e.g.,
subsequent to a previous cataract extraction with reopening of the lens
capsule.
It should be noted that neovascularization is a key pathobiological process in
a variety
of eye diseases, such as AMD, proliferative diabetic retinopathy, vascular
occlusive disease,
and radiation retinopathy. Additionally, the incidence of glaucoma is
increasing worldwide.
Many other disorders, including severe uveitis and geographic atrophy in AMD,
can be
treated using such an intraocular drug delivery device. Such an anterior
segment drug
delivery device thus has great potential to improve the quality of life for
subjects.
The drug delivery device can continuously deliver dexamethasone or other anti-
inflammatory agents with near zero order kinetics for up to two weeks.
Treatment of uveitis
needs long term (6-8 weeks) sustained delivery of anti-inflammatory agents.
The biggest
disadvantage with topical drops is negligible concentrations of drugs will
reach the posterior
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CA 02830555 2013-10-18
segment of the eye and especially the retina/choroid. The designed and
disclosed drug
delivery device can deliver dexamethasone continuously with near zero order
kinetics both to
the anterior and posterior chamber thus effectively controlling the
inflammation.
Therefore, the opportunity exists to improve management of AMD, postoperative
surgery inflammation and uveitis patients undergoing cataract surgery by
sustained release of
pharmaceutical active agent(s). Accordingly, the present invention provides
systems, devices,
and associated methods for the delivery of active agents into the eye of a
subject. In one
aspect, as is shown in FIG. 1, an ocular active agent delivery device 100 can
include a
biodegradable active agent matrix 110. The ocular active agent delivery device
can be sized
and designed to fit inside of a lens capsule. In one aspect, the device can be
sutureless. A
sutureless device can be defined as a device or structure that can be inserted
and retained
within a lens capsule without the need for a suture to hold the device in
place. The device can
stay in place without obstructing a line of sight of the eye.
The active agent delivery device can optionally contain one or more
additional/separated reservoirs for the delivery of additional active agents
or other desired
therapeutically beneficial substances. In one aspect, for example, the device
can include a
primary active agent reservoir comprising a bioerodible active agent matrix
containing a
primary active agent, and secondary active agent reservoir comprising a
bioerodible active
agent matrix containing a secondary active agent. The secondary active agent
reservoir can
occupy a region within the device, such as a layer of bioerodible matrix
material disposed
within the primary active agent reservoir. It should be noted that the
secondary active agent
reservoir can contain an active agent that is the same or different from the
active agent
contained in the primary active agent reservoir. Secondary active agent
reservoirs can also
comprise different matrix materials from the primary active agent reservoir.
For example, a
matrix material with a different dissolution rate can be used to control the
rate of drug
delivery from the primary and secondary reservoirs. Individual reservoirs can
be segregated
by impermeable walls or merely by providing an adjacent drug matrix.
In one aspect, as shown in FIG. 1 and FIG. 2, the active agent delivery device
100 can
have an optional secondary active agent reservoir 120 within the device. In
this particular
embodiment, the device is a disc shape with secondary reservoir comprising a
secondary
active agent matrix in the center surrounded by the primary active agent
matrix on the
outside. This configuration can be manufactured by coextruding the primary and
secondary
matrix materials to form a core of the secondary matrix material surrounded by
the primary
matrix material. In other embodiments, an active agent delivery device can be
disc-shaped as
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CA 02830555 2013-10-18
shown in FIG. 1 and FIG. 2, but without a secondary reservoir in the center.
Therefore the
entire active agent delivery device can be one homogeneous matrix material.
Bioerodible matrices can include a variety of polymeric and non-polymeric
materials.
Specific non-limiting examples of suitable matrix materials include
biodegradable polymers
(e.g. PLGA, albumin), colloidal suspensions, nanoparticles, microparticles,
microspheres,
nanospheres, hydrogels, purites, polycarbophil, solid matrix, and the like.
Although numerous active agents are known for the treatment of various eye
conditions, a few examples used in the treatment or prophylaxis of eye
diseases such as AMD
(neovascular form or atrophic form), glaucoma, diabetic retinopathy,
Retinopathy of
Prematurity, uveitis, corneal transplant rejection, capsular fibrosis,
posterior capsule
opacification, retinal vein occlusions, infections, and the like, can be
treated with non-
limiting active agents such as dexamethasone, bevacizumab (Avastin0), Timolol,
Latanoprost, Brimonidine, Nepafenac, and ranibizumab (LucentisS). Other non-
limiting
examples of active agents include antibiotics, prednisolone, fluocinolide, and
the like.
Treatment regimens can additionally include anti-VEGF aptamers such as
pegaptanib
(Macugen0), anti-VEGF Fab fragments such as ranibizumab (Lucentis 0), integrin
antagonists, various photodynamic therapies, and the like.
Yet another aspect of the present invention provides a method of delivering an
active
agent into an eye of a subject. Such a method can include performing a
cataract removal
surgery on the eye of the subject, further including removing an existing lens
from the eye of
the subject, inserting an intraocular lens into the eye of the subject, and
associating a device
as described herein with the intraocular lens. The delivery device may be
attached or
detached from the intraocular lens. The delivery device can be associated by
actual contact or
sufficient proximity to allow effective diffusion of active agent to target
areas of the eye. The
delivery device can itself be a biodegradable matrix or a reservoir system. A
biodegradable
system would have value in routine cataract surgery to enable short-term/time-
limited
delivery of postoperative medicines which would otherwise require eyedrop
usage by the
patient. The lens that is removed can be the original natural lens of the eye,
or it can be a
lens that was previously inserted into the eye as a result of a prior
procedure.
Numerous methods of associating the device into the eye are contemplated. For
example, in one aspect, the device can be associated with the intraocular lens
prior to
inserting the intraocular lens into the eye. In such cases it would be
necessary to configure
the device to comply with any requirements of the surgical procedure. For
example, cataract
surgeries are often performed through a small incision. One standard size
incision is about
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CA 02830555 2013-10-18
2.75 mm; although this device can be compatible with smaller or larger
incision sizes as well.
As such, the intraocular lens assembly can be shaped to allow insertion
through this small
opening. Thus the active agent delivery device must also be configured to be
inserted with
the intraocular lens assembly, e.g. by shape and choice of resilient and
flexible material for
the device. Additionally, the active agent delivery device can also be
physically coupled or
decoupled to the intraocular lens assembly prior to insertion of the assembly
into the eye. In
another aspect, the device can be associated with the intraocular lens
assembly following
insertion of the lens into the eye. The capsular bag can be readily reopened
for a patient
having prior cataract surgery. Thus, the insertion of the delivery device can
be performed
immediately prior to insertion of an intraocular lens or later in time as a
separate procedure.
Consistent with the principles set forth above, another optional configuration
includes
the use of a homogeneous delivery device formed of an active agent matrix and
the active
agent. The ocular active agent delivery device can be configured to fit within
a lens capsule
or ciliary sulcus of an eye. The delivery device can be shaped in any geometry
which allows
for insertion into the lens capsule or ciliary sulcus. Although dimensions can
vary, typical
dimensions can range from about 0.5 mm to about 4 mm width and about 0.2 mm to
about 1
mm thickness. Although the total mass of the delivery device can vary, most
often the total
mass can be from 0.2 mg to 4 mg. For example, about 2 mg total mass can
provide effective
active agent volume, while also balancing overall size to fit within the
target tissue areas.
An active agent delivery device comprising a biodegradable polymer matrix can
contain one or several excipients depending on the duration of active agent
delivery. The
device can be in the following dimensions as shown in FIG. 4, e.g. 2 to 2.5 mm
in diameter
and 1.0-1.5 mm in thickness. Placement of the device can be inferior to the
intraocular lens
(TOL) and implanted during cataract surgery. The ocular active agent delivery
device can be
configured to fit within a lens capsule or ciliary sulcus of an eye. The
delivery device can be
shaped in any geometry which allows for insertion into the lens capsule or
ciliary sulcus. The
device can be in the shape of a disc, pellet, rod, square shape, crescent,
donut shape, or other
shapes. Depending on the dosage requirement one or two devices can be
implanted per eye.
Suitable active agent matrices can include dexamethasone or those listed
previously
as active agent carriers. Non-limiting examples of active agent matrix
materials can include
polymeric and non-polymeric materials. Specific non-limiting examples of
suitable matrix
materials include biodegradable polymers such as PLGA (different ratios of
lactic to
glycolide content and end groups such as acid or ester termination), PVA, PEG,
PLA, PGA,
HPMC, hydroxypropylcellulose, sodium carboxymethylcellulose, croscarmellose
sodium,
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polycaprolactone, hyaluronic acid, albumin, sodium chloride block copolymers
thereof, and
the like. Specific copolymers such as polylactic-polyglycolic acid block
copolymers (PLGA),
polyglycolic acid-polyvinyl alcohol block copolymers (PGA/PVA),
hydroxypropylmethylcellulose (HPMC), polycaprolactone-polyethylene glycol
block
copolymers, croscarmellose, and the like can be particularly effective. In one
aspect, the
active agent matrix can be a PLGA having about 45-80% PLA and 55-20% PGA such
as
about 65% PLA and 35% PGA. In another alternative embodiment, the ratios of
PLGA,
dexamethasone and Croscarmellose sodium can be 60-90/5-25/5-25 or 50-75/10-
40/10-40
ratios.
Homogeneous delivery devices can be formed, for example, by mixing a polymer
material with a loading amount of active agent to form a matrix dispersion.
The loading
amount can be chosen to correspond to the desired dosage during diffusion.
Loading amount
can take into account diffusion characteristics of the polymer and active
agent, residual active
agent, delivery time, and the like. The matrix dispersion can then be formed
into the device
shape using any suitable technique. For example, the matrix dispersion can be
cast, sprayed
and dried, extruded, stamped or the like. Such configurations will most often
be formed using
a biodegradable matrix, although non-biodegradable materials can also be used.
For example,
in one embodiment the matrix dispersion can be extruded through a die with a
circular cross
section, and then the extruded matrix dispersion can be sliced to create disc-
shaped implants.
In one alternative formulation, the device can be formed in situ from a
suspension of the
active agent within a biodegradable polymer matrix precursor. Upon delivery
into the target
site, the biodegradable polymer matrix precursor can form (via precipitation
and/or
polymerization) the biodegradable active agent matrix in situ.
With the above homogeneous delivery device, particular efficacy can be
provided for
treatment of uveitis and post-operative cataract surgery inflammation. For
example,
dexamethasone can be dispersed within a biodegradable active agent matrix.
Although
dexamethasone dosage amounts can vary, generally from about 100 mcg to about
400 mcg
can be effective for these indications. More specifically, some patients can
be categorized as
low risk while others can be categorized as high risk due to various factors
such as age,
secondary complications, pre-existing conditions, etc. Most often, a low risk
patient can
benefit from a low dosage of about 100 mcg to about 150 mcg. In contrast, a
high risk
individual can be administered a high dosage of about 250 mcg to about 350
mcg. One
particular embodiment of an active agent delivery device, the "BDI-1 implant,"
has been
specifically designed and tested for the treatment of postoperative surgery
inflammation and
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can deliver pharmaceutical active agent up to 2 weeks. The "BDI-2 implant" is
designed and
tested for the treatment of postoperative surgery inflammation and uveitis and
can deliver
active agent up to 6-8 weeks. Depending on the severity of the inflammation
one or two
implants can be implanted during surgery per eye.
As previously mentioned, the delivery device herein is targeted for a
relatively short
delivery duration, and in most cases less than eight weeks. In one
alternative, the active agent
has a delivery duration of about two weeks to about six weeks. Delivery
duration can be a
function of the type of polymer used in the matrix, copolymer ratios, and
other factors.
Although other biodegradable polymers can be suitable such as those listed
previously,
particularly suitable polymers can include at least one of poly(lactic-co-
glycolide),
hydroxypropyl methyl cellulose, hydroxyl methyl cellulose, polyglycolide-
polyvinyl alcohol,
croscarmellose, polycaprolactone, eudragit L100, eudragit RS100, poly(ethylene
glycol)
4000, poly(ethylene glycol) 8000 and poly(ethylene glycol) 20,000. The
biodegradable active
agent matrix can comprise poly(lactic-co-glycolide) having a copolymer ratio
from 52/48 to
90/10. In one specific example, the copolymer ratio can be 52-78/48-22 and in
another
specific example from 60-90/40-10. Although degradation rates can be dependent
on such
proportions, additional alternative approaches can also be useful such as
device coatings,
particle encapsulation, and the like.
Examples:
Example 1:
A standard clear-corneal phacoemulsification with intraocular lens (Acrysof
SA6OAT;
Alcon) implantation was performed on 35 rabbits. At the time of each surgery,
an intraocular
device containing an active agent was inserted into a lens capsule of each
rabbit. The rabbits
were divided into 4 groups, depending on the active agent in the intraocular
device. Devices
were loaded with 5-15 mg of either Avastin, Timolol, Brimonidine, or
Latanoprost. Each
group was evaluated to determine the intraocular device and lens stability,
capsular fibrosis,
and healing of cataract wounds and anterior segment. A subgroup of eyes was
evaluated
weekly for 4 weeks for inflammation and harvested at 1 month for
histopathologic evaluation
of capsular and CDR integrity.
Example 2:
The surgery and setup as described in Example 1 was repeated, with the
exception
that aqueous and vitreous taps were performed biweekly and assayed for drag
concentrations
with HPLC and/or ELISA. In each drag group, half of the eyes were harvested at
one month
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and the other half at two months. This was accomplished as follows:
immediately after
sacrificing the rabbit and enucleating the eye, the eye was frozen in liquid
nitrogen to prevent
perturbation and redistribution of drug in eye tissues. The eye was then
dissected into 3 parts
(aqueous humor, vitreous and retina/choroid layer) to evaluate anatomic
toxicity and tissue
drug concentration. The intraocular device was retrieved and assessed for
remaining drug
amounts. The distribution profile of the intraocular device was compared with
the
conventional intravitreal injection of 2.5 mg/0.1 cc Avastin for direct
comparison of the
different delivery methods.
At 2 and 4 months, eyes from the remaining subgroups of rabbits were
enucleated,
fixed by 10% formalin, embedded in paraffin, step sectioned, stained by
hematoxyline and
eosin (H & E), and examined for histological changes.
Example 3:
Three intraocular devices were implanted into eyes of New Zealand white
rabbits
under general anesthesia after lens extraction (phacoemulsification
technique). Two of the
devices were loaded with Avastin and one was loaded with the contrast agent
Galbumin as a
control. Proper intraocular device position was verified by MRI as well as
clinical
examination.
The rabbits were sacrificed and the eyes are removed and assayed after 1 week
post
implantation. Avastin was detected by ELISA in the retina and vitreous at
concentrations of
24-48 mcg/mL, and was not present in the control rabbit eye. FIG. 3 shows the
amount of
Avastin assayed per ocular region at 1 week post implantation.
Example 4:
To confirm that placement of implant in the capsular bag and delivers drugs
both to
the front and back of the eye for short and long term, microparticles were
prepared using
PLGA [poly(d,l-lactide-co-glycolide), MW. 7000-17000, acid terminated],
hydroxypropyl
methyl cellulose (HPMC) and dexamethasone. Dexamethasone loaded PLGA
microspheres
were prepared using standard oil-in-water (o/w) emulsion-solvent extraction
method. An
amount of 160 mg PLGA was dissolved in 4 mL methylene chloride and 1 mL
acetonitrile.
An amount of 40 mg dexamethasone and 10 mg of HPMC was dispersed in the PLGA
solution by vortexing for 5 min. This organic phase was then emulsified in 20
mL of a 2%
(w/v) PVA (MW 90 kDa) solution and homogenized. The resultant emulsion was
poured into
200 mL of a 2.0% (w/v) PVA (MW 90 kDa) solution and stirred in an ice bath for
6 min. The
contents were stirred for 8 hr at room temperature to evaporate the
dichloromethane and
acetonitrile to form a turbid microparticulate suspension. The microparticles
were separated
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CA 02830555 2013-10-18
by centrifugation, washed twice, resuspended in deionized water, and freeze-
dried to obtain
lyophilized particles. The prepared microparticles were characterized and
pelleted using
bench top pellet press with 2 mm die set to form an implant.
These implants were sterilized, implanted in the capsular bag of rabbit's
eyes. Two
dose groups were used (300 and 600 p.g), two rabbits were sacrificed from each
of low and
high dose group at 1, 2, 4, 6 weeks and various tissue samples (aqueous humor,
vitreous
humor, IOL, iris/ciliary body and retina/choroid) were collected and samples
were analyzed
by a validated LC/MS/MS method. Microspheres were in the range of 6 2 }un as
confirmed
by Zetasizer nano and SEM photomicrographs. Drug loading in the microparticles
was >99%
and the final yield was 60% (i.e. encapsulation efficiency). Drug loading was
determined as
percent drug loading = (weight of drug loaded/weight of microspheres) x100.
Dose related
pharmacokinetics with near zero order kinetics was observed in rabbits up to 6
weeks.
Further, dexamethasone flow was bidirectional from the endocapsular space into
both the
anterior and posterior chambers. There were also no cells or formation of
fibrin in the anterior
and posterior chambers of the eye. Histological examinations revealed all the
tissues
examined were normal and showed no signs of inflammation.
All the study animals were acquainted to study room conditions once they are
out of
quarantine and randomized. All the positive control group and implantation
groups
underwent phacoemulsification and insertion of an intraocular lens (IOL) in
both the eyes.
Group III and IV received one and two implants per eye respectively.
Group I: Normal control group; n=6
Group II: Phacoemulsification and inserting IOL; DXM drops (up to 4 weeks with
tapering) and antibiotic drops (up to 2 days); positive control group; n=6
Group-III: Phacoemulsification and inserting IOL; BDI implant low dose (one
implant per eye) and antibiotic drops up to 2 days (b.i.d.) after surgery; n=8
Group-IV: Phacoemulsification and inserting IOL; BDI implant high dose (two
implants per eye) and antibiotic drops up to 2 days (b.i.d.) after surgery,
n=8
Results of in vitro release kinetics are presented in FIG. 8. All the batches
exhibited
biphasic release pattern with initial burst release on day-1 and thereafter
slow and sustained
release. The burst effect was slightly higher with implants containing HPMC.
A total of 16 animals (32 eyes) received the implant. Dexamethasone
concentrations
are presented in FIG. 9 through FIG. 11. The implants degraded slowly over 4
weeks and by
week 6 were completely disappeared. Therapeutic concentrations of DXM was
found up to
week 6 with minimal systemic exposure (<40 ng/mL with high dose), whereas,
with
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CA 02830555 2013-10-18
dexamethasone drops systemic exposure was higher (>150 ng/mL during week 1).
Mean PK
parameters for BDI-2 implant and positive control group in aqueous humor,
vitreous humor,
retina/choroid, and iris/ciliary body are shown in Table 1 and 2.
Table 1: Pharmacokinetics in aqueous humor and vitreous humor
Low dose: 300 jag High dose: 600 p.g Dexamethasone Drops
Parameter Aqueous Vitreous Aqueous Vitreous Aqueous Vitreous
humor humor humor humor humor humor
1570 1379
Cmax (ng/mL) 650 109 892 151 62 24 3 0
113 233
Tmax (day) 19 8 28 0 7 0 28 0 14 0 16 11
AUCo-t 15231 18317 28202 32933 1023
61 5
(day*ng/mL) 361 2435 3369 4027 320
Ciast (ng/mL) 8 3 2 1 52 18 85 23 6 2 2 1
Table 2: Pharmacokinetics in retina/choroid and iris/ciliary body
Low dose: 300 1.1g High dose: 600 j.tg Dexamethasone Drops
Parameter Retina/ Retina/ Retina/
Iris/CB Iris/CB Iris/CB
Choroid Choroid Choroid
Cmax (givi) 21 4 35 5 117 40 209 24 3 1 3
2
Tmax (day) 14 0 7 0 23 8 14 0 14 0 9 4
AUCo-t 2226
455 61 759 132 3913 685 48 16 42 27
(day*Ilm) 1105
Ciast (I.LN) 1.3 0.6 1.5 0.5 12 8 13 10 0.2
0.1 0.5 0.3
Intraocular pressure was normal in all the groups. Further, there were no
signs of
anterior or posterior chamber inflammation as assessed with Slit lamp
biomicroscopy and
confirmed by histological examination. There was a trend in increase in
retinal thickness in
animals treated with dexamethasone drops whereas, implants maintained retinal
thickness.
The PLGA polymer degrades in to lactic and glycolic acid through hydrolysis,
then
further degrades in to carbon dioxide and water before eliminating from the
body. Implants
did not migrate to the center to obstruct the visual field.
BDI-1 implant was manufactured by following partial solvent casting method
with
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CA 02830555 2013-10-18
subsequent evaporation and removing the residual solvent by drying the product
under high
vacuum for 3 days. Various implants were prepared using PLGA [poly(d,l-lactide-
co-
glycolide), MW. 7000-17000, acid terminated], hydroxypropyl methyl cellulose
(HPMC),
croscarmellose sodium (cross linked sodium carboxymethylcellulose),
hydroxypropyl
cellulose and dexamethasone in several different compositions.
The dried particles were directly pelleted using bench top pellet press with a
2 mm die
set to form an implant.
The selected BDI-1 implants (from in-vitro release studies, FIG. 5) were
sterilized,
implanted in the capsular bag of rabbit's eyes. Two implants with different
composition and
dose were tested in-vivo in NZW rabbits to establish pharmacokinetics. Two
rabbits were
sacrificed at 2, 6, 10, 15 days and various tissue samples (aqueous humor,
vitreous humor,
IOL, iris/ciliary body and retina/choroid) were collected and samples were
analyzed by a
validated LC/MS/MS method. Pharmacokinetics with near zero order kinetics was
observed
in rabbits up to 15 days. Further, dexamethasone flow was bidirectional from
the
endocapsular space into both the anterior and posterior chambers. There were
also no cells or
formation of fibrin in the anterior and posterior chambers of the eye.
Histological
examinations revealed all the tissues examined were normal and showed no signs
of
inflammation.
Results of in vitro release kinetics are presented in FIG. 5. All the batches
exhibited
smooth release pattern with initial burst release on day-1 and thereafter slow
and sustained
release. The burst effect was slightly higher with implants containing HPMC.
A total of 8 animals (16 eyes) received the implant containing 120 g of DXM.
DXM
concentrations are presented in FIG. 6 and FIG. 7. The implants eroded slowly
over 10 days
and reaching trough concentrations of DXM by day 15. The implants are degraded
by 80% of
its mass by day 15 and expected to fully degrade by day 20. Therapeutic
concentrations of
DXM was found up to day 15 with minimal systemic exposure (<23 ng/mL),
whereas, with
dexamethasone drops systemic exposure was higher (>150 ng/mL during week 1, in-
house
data).
Example 5:
Microparticles containing DXM were prepared with PLGA [poly(lactide-co-
glycolide)] and hydroxypropyl methylcellulose (HPMC) as reported previously by
our group.
The BDI was placed in the inferior fornix of the capsular bag after
intravitreal injection of
Concanavalin A (Con-A) and subsequent phacoemulsification in New Zealand White
(NZW)
rabbits (n=18). All eyes were assessed clinically using slit lamp
biomicroscopy and graded
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with Draize scoring scale. Retinal thickness measurements were also performed.
The BDI
was effective at preventing retinal thickening. Retinal thickness measurements
were carried
out using SD-OCT (Spectral Domain Optical Coherence Tomography; Heidelberg
Engineering GmbH, Heidelberg, Germany). Rabbits were anesthetized and dilated
as above.
At least 4 measurements were taken from each eye. Readings were reported as
mean SD.
Retinal thickness was defined as the distance between the inner retinal
boundary (vitreous¨
retina interface) and the outer retinal boundary (retina¨retinal pigment
epithelium
interface).23 Baseline mean retinal thickness was 130 5 m in all study
rabbits as measured
by SD-OCT. In the standard control group, retinal edema increased
progressively and
architectural disruption was seen in n=4 eyes by week 4 (Fig. 6). Retinal
thickness in the BDI
group was controlled effectively and was close to normal at all time points.
However, in the
topical drops group, retinal thickness increased significantly (P<0.05) by
week 1 which
persisted up to week 6 in comparison to both normal control and BDI groups.
Results are
presented in FIG. 12.
It should be understood that the above-described arrangements are only
illustrative of
application of the principles of the present invention. Numerous modifications
and
alternative arrangements may be devised by those skilled in the art without
departing from
the spirit and scope of the present invention. Thus, while the present
invention has been
described above with particularity and detail in connection with what is
presently deemed to
be the most practical and preferred embodiments of the invention, it will be
apparent to those
of ordinary skill in the art that numerous modifications, including, but not
limited to,
variations in size, materials, shape, form, function and manner of operation,
assembly and use
may be made without departing from the principles and concepts set forth
herein.
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