U.S. patent application number 11/739540 was filed with the patent office on 2007-08-16 for ocular therapeutic agent delivery devices and methods for making and using such devices.
This patent application is currently assigned to Govemment of the U.S.A, represented by the Secretary, Department. of Health and Human. Invention is credited to Karl G. Csaky, Matthew P. Fronheiser, Hyuncheol Kim, Robert B. Nussenblatt, Michael R. Robinson, Janine A. Smith, Cynthia Sung, Peng Yuan.
Application Number | 20070190111 11/739540 |
Document ID | / |
Family ID | 25198008 |
Filed Date | 2007-08-16 |
United States Patent
Application |
20070190111 |
Kind Code |
A1 |
Robinson; Michael R. ; et
al. |
August 16, 2007 |
OCULAR THERAPEUTIC AGENT DELIVERY DEVICES AND METHODS FOR MAKING
AND USING SUCH DEVICES
Abstract
Ocular implant devices (10, 20, 121) for the delivery of a
therapeutic agent to an eye (101, 301) in a controlled and
sustained manner. Dual mode and single mode drug delivery devices
(10, 20, 121) are illustrated and described. Implants (10, 20)
suitable for subconjunctival placement are described. Implants
(121, 10, 20) suitable for intravitreal placement also are
described. The invention also includes fabrication and
implementation techniques associated with the unique ocular implant
devices (10, 20, 121) that are presented herein.
Inventors: |
Robinson; Michael R.;
(Irvine, CA) ; Csaky; Karl G.; (Kensington,
MD) ; Nussenblatt; Robert B.; (Bethesda, MD) ;
Smith; Janine A.; (Potomac, MD) ; Yuan; Peng;
(Rockville, MD) ; Sung; Cynthia; (Silver Spring,
MD) ; Fronheiser; Matthew P.; (Durham, NC) ;
Kim; Hyuncheol; (North Bethesda, MD) |
Correspondence
Address: |
LEYDIG VOIT & MAYER, LTD
TWO PRUDENTIAL PLAZA, SUITE 4900
180 NORTH STETSON AVENUE
CHICAGO
IL
60601-6731
US
|
Assignee: |
Govemment of the U.S.A, represented
by the Secretary, Department. of Health and Human
Rockville
MD
20852
|
Family ID: |
25198008 |
Appl. No.: |
11/739540 |
Filed: |
April 24, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10471468 |
May 3, 2004 |
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PCT/US02/07836 |
Mar 14, 2002 |
|
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11739540 |
Apr 24, 2007 |
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09808149 |
Mar 15, 2001 |
6713081 |
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10471468 |
May 3, 2004 |
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Current U.S.
Class: |
424/427 |
Current CPC
Class: |
A61K 9/5047 20130101;
A61P 27/02 20180101; Y10S 425/808 20130101; A61K 38/13 20130101;
A61K 9/0051 20130101; A61F 9/00781 20130101; B29K 2827/18 20130101;
A61F 9/0017 20130101; A61K 31/58 20130101; A61K 9/5031 20130101;
A61K 31/565 20130101; A61K 9/5089 20130101; B29D 11/023 20130101;
B29K 2083/00 20130101; A61K 9/5026 20130101 |
Class at
Publication: |
424/427 |
International
Class: |
A61F 2/02 20060101
A61F002/02 |
Claims
1. A method of preventing or reducing graft rejection in a
mammalian eye following corneal transplantation, the method
comprising the step of: implanting at a subconjunctival location, a
sustained release implant comprising an immune system modifying
agent dispersed within a nonbiodegradable polymer, such that the
implant releases the agent continuously to the eye at a
substantially constant release rate for at least three months to
prevent or reduce graft rejection in the eye.
2. The method according to claim 1, wherein the agent is
cyclosporine A.
3. The method according to claim 1, wherein the implant further
comprises a discrete solid core containing the immune system
modifying agent or a second therapeutic agent.
4. The method according to claim 1, wherein the polymer is
silicone.
5. The method according to claim 2, wherein the polymer is
silicone.
6. The method according to claim 3, wherein the polymer is
silicone.
7. The method according to claim 1, wherein the polymer is
poly(ethylene vinyl) acetate (EVA).
8. The method according to claim 2, wherein the polymer is
poly(ethylene vinyl) acetate (EVA).
9. The method according to claim 3, wherein the polymer is
poly(ethylene vinyl) acetate (EVA).
10. The method according to claim 1, wherein the polymer is
biologically inert.
11. The method according to claim 1, wherein the implant releases
the agent continuously to the eye at a substantially constant rate
for at least six months.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This patent application is a continuation of copending U.S.
patent application Ser. No. 10/471,468, filed Sep. 12, 2003
[pending], which is a PCT national phase application of
PCT/US0207836 filed Mar. 14, 2002, which is a continuation-in-part
of U.S. patent application Ser. No. 09/808,149, filed Mar. 15, 2001
[issued Mar. 30, 2004 as U.S. Pat. No. 6,713,081].
FIELD OF THE INVENTION
[0002] The present invention generally relates to local therapies
for the eye and, more particularly, to controlled-release ocular
implant devices, including methods for making and using such
devices, for delivery of therapeutic agents to the eye.
BACKGROUND OF THE INVENTION
[0003] In the treatment of many diseases and disorders of the eye,
and especially in the case of degenerative or persistent
conditions, implantable sustained-release delivery devices have
been desired that would continuously administer a therapeutic agent
to the eye for a prolonged period of time.
[0004] Local ocular implants of a wide variety of constructions and
placements have been proposed heretofore for dispensing a
therapeutic drug to the eye.
[0005] For instance, U.S. Pat. No. 4,014,335 describes an ocular
drug delivery device placed in the cul-de-sac between the sclera
and lower eyelid for administering the drug and acting as a
reservoir. The ocular device is characterized therein as
administering drug to the eye in a controlled, continuous dosage
rate over a prolonged time. To accomplish this, the ocular device
comprises a three-layered laminate of polymeric materials holding
the drug in a central reservoir region of the laminate. The drug
diffuses from the reservoir through at least on of the polymeric
layers of the laminate.
[0006] U.S. Pat. No. 5,773,021 describes bioadhesive ophthalmic
inserts that are placed in the conjunctival sac, in which the
inserts are prepared by extrusion, thermoforming, or heat
compression of a polymeric material matrix and the drug to be
delivered. The polymeric matrix comprises a water-soluble
biocompatible polymer, such as hydroxyalkyl celluloses,
maltodextrins, chitosans, modified starches or polyvinyl alcohols;
a water-soluble biocompatible polymer such as an alkyl cellulose;
and where applicable a bioadhesive polymer such as polyvinyl
carboxlic acid type polymers or certain bioadhesive polysaccharides
or derivates thereof. The ophthalmic inserts are characterized
therein as intended for the prolonged and controlled release of a
medicinal substance.
[0007] U.S. Pat. No. 5,773,019 describes a continuous release drug
delivery implant which, among other mentioned places, can be
mounted either on the outer surface of the eye or within the eye. A
drug core is covered by a polymer coating layer that is permeable
to the low solubility agent without being release rate limiting.
Descriptions include a coating of cyclosporine A (CsA) drug cores
with one or multiple coatings of polyvinyl alcohol solution,
followed by heating to 110, 104 or 120.degree. C., presumable to
cross link and harden the coating(s) in place around the core. Also
described is a implant prepared by fixing a pellet directly over a
smaller hole formed in a silicone film, followed by a suture being
placed around the pellet in a gapped relationship thereto, and then
the entire assembly is coated again with silicone to form the
implant. The ocular device is characterized therein as giving a
continuous release to an affected area, once implanted, and
producing long-term sustained tissue and vitreous levels at
relatively low concentrations.
[0008] U.S. Pat. No. 5,378,475 describes a sustained-release
implant for insertion into the vitreous of the eye. The implant has
a first impermeable coating, such as ethylene vinyl acetate,
surrounding most, but not all, of a drug reservoir and a second
permeable coating, such as a permeable crosslinked polyvinyl
alcohol, disposed over the first coating including the region where
the first coating does not cover the drug reservoir, to provide a
location through which the drug can diffuse out of the implant. The
implant also has a tab, which can be used to suture the device in
place in the eye. The implant devices are prepared by applying
coating solutions, such as by dipping, spraying or brushing, of the
various coating layers around the drug reservoir.
[0009] U.S. Pat. No. 5,725,493 describes an ocular implant device
for providing drugs to the vitreous cavity over a period of time.
The drug reservoir is attached to the outside of the eye with a
passageway permitting medicament to enter the vitreous cavity of
the eye. The above-listing of publications describing prior ocular
implant systems is intended to be only illustrative in nature, and
not exhaustive.
[0010] Local ocular implants avoid the shortcomings and
complications that can arise from systemic therapies of eye
disorders. For instance, oral therapies for the eye fail to provide
sustained-release of the drug into the eye. Instead, oral therapies
often only result in negligible actual absorption of the drug in
the ocular tissues due to low bioavailability of the drug. Ocular
drug levels following systemic administration of the drugs is
usually limited by blood/ocular barriers (i.e., tight junctions
between the endothelial cells of the capillaries) limit drugs
entering the eye via systemic circulation. In addition, variable
gastrointestinal drug absorption and/or liver metabolism of the
medications can lead to dose to dose and inter-individual
variations in vitreous drug levels. Moreover, adverse side effects
have been associated with systemic administration of certain drugs
to the eyes.
[0011] For instance, systemic treatments of the eye using the
immune response modifier cyclosporine A (CsA) have the potential to
cause nephrotoxicity or increase the risk of opportunistic
infections, among other concerns. This is unfortunate since CsA is
a recognized effective active agent for treatment of a wide variety
of eye diseased and indications, such as endogenous or anterior
uveitis, corneal transplantation, Behcet's disease, vernal or
ligneous keratoconjunctivitis, dry eye syndrome, and so forth. In
addition, rejection of corneal allografts and stem cell grafts
occurs in up to 90% of patients when associated with risk factors
such as corneal neovascularization. CsA has been identified as a
possible useful drug for reducing the failure rate of such surgical
procedures for those patients. Thus, other feasible delivery routes
for such drugs that can avoid such drawbacks associated with
systemic delivery are in demand.
[0012] Apart from implant therapies, other local administration
routes for the eye have included topical delivery, such as
ophthalmic drops and topical ointments containing the medicament.
Tight junctions between corneal epithelial cells limit the
intraocular penetration of eye drops and ointments. Topical
delivery to the eye surface via solutions or ointments can in
certain cases achieve limited, variable penetration for the
anterior chamber of the eye. However, therapeutic levels of the
drug are not achieved and sustained in the middle or back portions
of the eye. This is a major drawback, as the back (posterior)
chamber of the eye is a frequent site of inflammation or otherwise
the site of action where, ideally, ocular drug therapy should be
targeted for many indications.
[0013] Age-related macular degeneration (AMD) is a common disease
associated with aging that gradually impairs sharp, central vision.
There are two common forms of AMD: dry AMD and wet AMD. About
ninety percent of the cases of AMD are the dry form, caused by
aging and thinning of the tissues of the macula; a region in the
center of the retina that allows people to see straight ahead and
to make out fine details. Although only about ten percent of people
with AMD have the wet form, it poses a much greater threat to
vision. With the wet form of the disease, rapidly growing abnormal
blood vessels known as choroidal neovascular membranes (CNVM)
develop beneath the macula, leaking fluid and blood that destroy
light sensing cells and causing a blinding scar tissue, with
resultant sever loss of central vision. Wet AMD is the leading
cause of legal blindness in the United States for people aged
sixty-five or more with approximately 25,000 new cases diagnosed
each year in the United States. Ideally, treatments of the
indication would include inducing an inhibitory effect on the
choroidal neovascularization (CNV) associated with AMD. However, in
that the macula is located at the back of the eye, treatment of
CNVM by topical delivery of pharmacological agents to the macula
tissues is not possible. Laser photocoagulation, photodynamic
therapy, and surgical removal is currently used to treat CNVM.
Unfortunately, the recurrence rate using such methods exceeds 50%
within a year of therapy.
[0014] As an approach for circumventing the barriers encountered by
local topical delivery, local therapy route for the eye has
involved direct intravitreal injection of a treatment drug through
the sclera (i.e., the spherical, collagen-rich outer covering of
the eye). However, the intravitreal injection delivery route tends
to result in a short half life and rapid clearance, without
sustained release capability being attained. Consequently, daily
injections are frequently required to maintain therapeutic ocular
drug levels, with is not practical for many patients.
[0015] Given these drawbacks, the use of implant devices placed in
or adjacent to the eye tissues to delivery therapeutic drugs
thereto should offer a great many advantages and opportunities over
the rival therapy routes. Despite the variety of ocular implant
devices which have been described and used in the past, the full
potential of the therapy route has not been realized. Among other
things, prior ocular implant devices deliver the drug to the eye
tissues via a single mode of administration for a given treatment,
such as via slow constant rate infusion at low dosage. However, in
many different clinical situations, such as with CNVM in AMD, this
mode of drug administration might be a sub-optimal ocular therapy
regimen.
[0016] Another problem exists with previous ocular implants, from a
construction standpoint, insofar as preparation techniques thereof
have relied on covering the drug pellet or core with a permeable
polymer by multi-wet coating and drying approaches. Such wet
coating approaches can raise product quality control issues such as
an increased risk of delamination of the thinly applied coatings
during subsequent dippings, as well as thickness variability of the
polymer around the drug pellets obtained during hardening.
Additionally, increased production costs and time from higher
rejection rates and labor and increased potential for device
contamination from additional handling are known problems with
present implant technology.
[0017] Accordingly, this invention provides local treatment of a
variety of eye diseases. The present invention also provides a
method for the delivery of pharmaceuticals to the eye to
effectively treat eye disease, while reducing or eliminating the
systemic side effects of these drugs. This invention also provides
sustained-release ocular implants for administration of therapeutic
agents to the eye for prolonged periods of time. Additionally, this
invention provides multi-modal sustained-release ocular implants.
The invention also provides methods for making ocular implants with
reduced product variability. The invention also provides methods
for making ocular implants well-suited for ocular treatment trials
using animal models. Other advantages and benefits of the present
invention will be apparent from consideration of the present
specification.
SUMMARY OF THE INVENTION
[0018] The present invention provides ocular implant devices for
the delivery of a therapeutic agent to an eye in a controlled
manner. The invention also includes fabrication and implementation
techniques associated with the unique ocular implant devices that
are presented therein.
[0019] In one embodiment of this invention, ocular implants are
provided which administer a therapeutic drug to the eye according
to dual mode release kinetics during a single treatment regimen.
For instance, an ocular implant under this embodiment of this
invention delivers drug continuously to the eye by initial delivery
at a high release rate to eye tissues soon after placement of the
implant in or near the eye, as a first administration mode,
followed by drug delivery via a continuous, sustained lower release
rate thereafter, as a second administration mode, and within the
same treatment regimen using the same implant device. The delivery
of drug is never interrupted during the regimen, as a smooth
transition occurs in the changeover from the high to low release
rate modes of drug delivery during the regimen. In this manner, the
delivery of drug by the implant is dual mode or dual action in
nature. Animal model studies have been performed, which are
described elsewhere herein, that confirm this dual mode performance
capability in local eye therapies for several embodiments of
implants of this invention. As a consequence, no intervention is
needed between initiation of the treatment, i.e., installing the
ocular implant, and discontinuation of the treatment regimen, i.e.,
exhaustion of the drug reservoir after a prolonged period of
time.
[0020] Although not desiring to be bound to any particular theory,
a large initial dosage is delivered at a relatively high release
rate to the eye tissues via an ocular implant according to one
embodiment of the present invention in a manner effective to
substantially saturate the eye compartments, permitting an ensuing
lower release rate, maintenance dosage delivered over a period of
time by the same implant to more effectively reach the target site
of treatment, even if located in posterior chamber of the eye. A
dual mode implant according to the embodiment of this invention
provides the sustained-release of the therapeutic agent for a
prolonged period of time after the period of high release
kinetics.
[0021] For purposes of this application, the term "loading dose"
refers to a rapid release phase of a pharmacological drug in a
mammalian organism in which an initial high release rate of the
drug is observed followed by exponential or nearly exponential
decline or decay in the release rate as a function of time. The
terminology "sustained dose" refers to the phase during which
release rates are substantially constant over a prolonged period of
time, and consequently concentration of the therapeutic agent in
the eye tissues achieves a substantially steady state value over
that period of time. The terms "loading dose" and "sustained dose"
are used in connection with drug treatments of the eye, unless
indicated otherwise. Moreover, from a pharmacological standpoint,
the initial dosage delivered at a relatively high release rate
constitutes a loading dose, and the sustained lower release rate
dose constitutes a maintenance dosage, suitable for the effective
treatment of an eye disease, disorder, ailment or condition. The
terms "dose" and "dosage" are used interchangeably therein.
[0022] The present invention embodies implants that can provide
such dual mode ("dual action") performance, or optionally other
modes of therapy via modified configurations thereof which are also
described therein.
[0023] One aspect of the invention relates to "matrix" type
implants, so referenced occasionally herein for convenience sake as
every embodiment of implant under this category at least includes a
composite matrix of polymer and therapeutic agent dispersed
therein.
[0024] In one embodiment of this aspect of the invention, an
implant provides therapeutic agent to the eye, in which the implant
includes: [0025] (a) a composite material matrix layer including:
[0026] (i) a therapeutic agent, and [0027] (ii) a polymeric matrix
material into which the therapeutic agent is dispersed, including
(1) a polymer permeable to the therapeutic agent and present as a
bioerodible solid matrix structure, and (2) a water-soluble polymer
having greater water solubility than the permeable polymer, and
[0028] (b) optionally, a discrete solid core containing additional
therapeutic agent, which is surrounded and covered by the composite
material matrix layer.
[0029] This matrix type implant configuration is particularly
well-suited for subconjunctival or intravitreal placement, but is
not limited thereto and could be installed on or in other eye
regions where convenient and useful.
[0030] In a more specific embodiment, the composite material matrix
layer component of the matrix type implant comprises about 5 to
about 50 wt % permeable polymer, about 0.05 to about 90 wt %
water-soluble polymer, and about 1 to about 50 wt % therapeutic
agent. Preferable, the composite material matrix layer component
comprises about 5 to about 20 wt % permeable polymer, about 0.05 to
about 20 wt % water-soluble polymer, and about 1 to about 50 wt %
therapeutic agent. As fabricated, the implant is a solid
structure.
[0031] In one preferred embodiment of the matrix type implant, the
permeable polymer is a superhydrolyzed polyvinyl alcohol (PVA),
which permits diffusion of the therapeutic agent therethrough, and
forms a slowly bioerodible solid structure, and the water-soluble
polymer is a pharmaceutical grade cellulose ether. Uncrosslinked
superhydrolyzed PVA releases the drug by surface erosion of the PVA
and by diffusion of the drug through the superhydrolyzed PVA. The
rate of erosion of the superhydrolyzed PVA is sufficiently slow
that the polymer material in the implant will dissolve so that the
therapeutic agent pellet ("drug pellet"), when included, will
disintegrate only after an extended period of time, such as months
or even years, in order to provide a slow sustained delivery of
drug.
[0032] In addition, the superhydrolyzed PVA is water permeable and
permeable to the therapeutic agent in a predictable manner upon
saturation with body fluids, yet offers the advantage of undergoing
very limited expansion when the implant is installed. The low wet
expansion behavior of superhydrolyzed PVA prevents the implant from
being extruded, and also permits more predictable pharmacokinetic
behavior of the device. Also, the superhydrolyzed polyvinyl alcohol
used in the polymer matrix material is essentially noncrosslinked
through its secondary hydroxyl functionality, i.e., it is not
heated to temperatures during preparation of the implant sufficient
to induce a level of crosslinking which impairs its permeability to
the therapeutic agent present in either the inner core of the
composite material matrix layer. The superhydrolyzed PVA is slowly
bioerodible and not rapidly water-soluble in body fluids, so that
the inner core does not disintegrate soon after installation of the
implant. For purposes of this invention, a superhydrolyzed
polyvinyl alcohol is a polyvinyl alcohol having at least 98.8 wt %
hydrolysis, preferably at least 99.0 wt % hydrolysis, and most
preferably at least 99.3 wt % or more hydrolysis. Generally, the
superhydrolyzed polyvinyl alcohol for use in this invention
generally have a weight average molecular weight of about 85,000 to
about 150,000, and preferably about 100,000 to about 145,000.
[0033] On the other hand, the separate water-soluble polymer
included in the polymeric matrix material provided in the matrix
type implant preferably is a nonionic cellulose ether polymer. The
cellulose ether polymer used generally has a weight average
molecule weight of about 70,000 to about 100,000, and preferable
about 80,000 to about 90,000. The water-soluble polymer is used as
a processing aid during preparation of the composite material
matrix layer. Namely, it acts as a suspension and dispersion aid
for introducing the therapeutic agent into an aqueous medium, and
before admixture with the superhydrolyzed PVA ingredient, in a
premix step involved with fabricating the implant (discussed in
more detail below). Examples of such cellulose ether compounds
include hydroxyalkyl cellulose materials, such as hydroxypropyl
methyl cellulose (HPMC), hydroxypropyl cellulose (HPC), and
hydroxyethyl cellulose (HEC). In general, the higher the proportion
of cellulose ether present in the polymeric matrix part of the
matrix implant relative to the proportion of superhydrolyzed PVA,
the more rapid the release of the therapeutic agent.
[0034] In one preferred embodiment of the matrix implant, a
therapeutic agent is included in both the inner core or pellet and
the exterior composite material matrix layer or cladding. This
results in a dual mode release of the therapeutic agent or drug
into the eye during a treatment regimen. That is, a loading dose is
initially delivered to the eye by the matrix implant followed by a
transition in the release rate, continuing uninterrupted drug
delivery by the implant, down to a relatively steady maintenance
dosage that is sustained over a prolonged period. Initially, the
therapeutic agent is released both from the polymer matrix and the
inner core or pellet of this embodiment of implant, creating the
rapid release rate of the loading dose. Once the concentration of
drug initially preloaded into the composite drug/polymer matrix
cladding material diffuses into the eye, the maintenance dosage of
drug is derived at a relatively constant rate from the remainder of
the drug diffusing from the inner core or pellet through the
composite material matrix layer which surrounds the core.
[0035] Moreover, an added advantage of this embodiment is that this
dual mode therapy can be achieved via subconjunctival implant for
some eye treatments. Thus, a less invasive and simpler procedure
that does not require piercing of the vitreous body is provided.
Used as a subconjunctival implant, it can be placed behind the
surface epithelium within the subconjunctival space. It also is
possible to install these implants at or near other specific sites
on or within the eye, such as intravitreal, if desired or
useful.
[0036] This matrix implant embodiment of the invention also can be
deployed for single mode or single action therapy in the eye by
omitting the solid core or pellet of therapeutic agent, and using
the composite material matrix layer alone, which is the same
general construction as that used in the dual mode device. The
single mode matrix implant releases a loading dose for a short
period of time (e.g., up to about 30 days), but does not provide a
sustained maintenance dosage over a prolonged period
thereafter.
[0037] In an optional configuration, a portion of the outer
surfaces of the matrix implant, such as one side of the composite
material matrix layer, has a top coat provided that is a polymeric
material that is impermeable to the therapeutic agent, such as
polymethyl methacrylate (PMMA). In this way, the release rate of
the matrix implant can be reduced in a managed manner, if
desired.
[0038] As another alternative embodiment of matrix implant
according to this invention, poly(ethylene vinyl) acetate (EVA)
control can be used in the polymeric matrix material in lieu of the
superhydrolyzed PVA. EVA is a nonbiodegradable and permeable to
water. In the same general manner as the PVA-based matrix implants,
the EVA-based matrix implants can provide dual mode or single mode
drug release depending on whether the drug pellet is included (dual
mode, i.e., loading plus slow constant rate release) or not (single
mode, i.e. slow constant rate release only).
[0039] Both the dual mode and single mode variants f the matrix
implants of this invention are well-tolerated and non-toxic to the
patient or recipient (i.e., a mammalian host-human or veterinary).
In addition, the matrix implant design of this invention can be
prepared by unique methodologies and selections of materials
leading to and imparting the unique pharmacological performance
properties present in the finished devices.
[0040] Among other eye therapies, the matrix implant of the present
invention, such as when used in a subconjunctival placement,
provides an effective treatment in corneal transplantation
procedures to reduce rejection rates. For example, an immune system
modifier agent such as cyclosporine can be delivered
non-systemically to the eye, in order to reduce rejection rates of
corneal allografts. Alternatively, this implant can be installed in
the vitreous humor to deliver 2-methoxyestradiol (occasionally
abbreviated herein as "2ME2") for treatment of CNVM. Also, other
drugs or drug cocktails can be delivered as desired and
appropriate.
[0041] Another aspect of the invention relates to "reservoir" type
implants which include a silicone-encapsulated reservoir containing
therapeutic agent. The reservoir type implants of this invention
are intraocular, and preferable intravitreous implants. The
intraocular reservoir implants are sustained-release devices which
deliver therapeutic agent to the eye over a prolonged period of
time.
[0042] The intraocular reservoir implant generally includes an
inner core comprising a therapeutic agent for the eye covered by,
and radially centered within, a polymeric layer comprising a
nondegradable material permeable to the therapeutic agent, as a
subassembly, and an ocular attachment means affixed to an exterior
surface of the polymeric layer of the subassembly. In a preferred
embodiment of the invention, the nondegradable material is
silicone.
[0043] Methodologies are used in this intraocular reservoir implant
configuration which ensure that the silicone or other suitable
polymer is degassed and that the inner core is well-centered, at
least radially, within a polymer comprising silicone or other
suitable polymer. This results in unhindered diffusion of the drug
from the reservoir through the silicone, as air bubbles or pockets
are eliminated which otherwise would not permit such diffusion. As
a result, a controlled and predictable drug release rate can be
obtained. In particular, polytetrafluoroethylene molds are used to
produce one-piece implants for intraocular use. Excellent centering
of a drug pellet within the encapsulating polymer with high
reproducibility is achieved.
[0044] In one embodiment of using a polytetrafluorethylene mold in
manufacturing intraocular implants of this invention, there is a
method of providing a mold comprising an upper surface including at
least one impression provided therein including lateral and depth
dimensions sufficient to receive a drug pellet and an upright rigid
post fixed in location at a side of the impression. The upper
surface of the mold comprises polytetrafluoroethylene release
material that well-tolerates heating temperatures to be used for
silicone curing. Flowable silicone fluid is introduced into the
impression. This silicone fluid can optionally contain a dispersion
of therapeutic drug to form a composite implant together with an
embedded drug pellet. The drug pellet is submerged in the silicone
fluid. It is centered such that all exposed peripheral sides and
the top surface of the drug pellet are surrounded by the silicone
fluid. The mold can be placed in a centrifuge tube and centrifuged
as necessary sufficient to degas the silicone fluid. A polyester
mesh optionally can be pushed down the post until submerged in the
flowable silicone fluid. The silicone fluid is hardened via curing
to form an integral silicone/pellet subassembly, which can be
easily separated from the upper surface of the mold. The mold can
then be re-used.
[0045] In another embodiment of using a polytetrafluoroethylene
mold in manufacturing intraocular implants of this invention,
centrifugation is used in conjunction with a temporary thin walled
tubular mold made of low adhesion plastic in a multi-step process
effective to degas the silicone encapsulating material and radially
center the drug core within a polymeric material before the
polymeric material is fully hardened. In this aspect of preparing
the intraocular reservoir implant, the steps of the method
generally include positioning a thin walled tube made of low
adhesion (releasable) plastic, such as a polytetrafluoroethylene
tube, in a temporarily fixed upright position within a centrifuge
tube. A base made of hardened silicone, or a polymeric material
having similar permeability, is then formed at the bottom section
of the plastic tube, such as by introducing a curable silicone
fluid in the bottom of the microcentrifuge tube, positioning a
bottom section of plastic tube below the surface of the curable
silicone fluid. This is done in a manner such that the silicone
fluid infiltrates and fills a lower section of the plastic tube,
and also fills the space between the outer surface of the lower
section of the plastic tube and the inner facing wall of the
centrifuge tube, followed by curing or hardening the silicone fluid
to hold the plastic tube in an upright position within the
microcentrifuge tube. Thereafter, a drug pellet, as the drug core,
is introduced into the plastic tube followed by addition of
additional wet silicone into the plastic tube. The microcentrifuge
tube is centrifuged as needed to degas the additional silicone and
place, if necessary, the pellet on the silicone base positioned at
the bottom of the plastic tubing. The additional curable silicone
fluid added inside the plastic tube is sufficient to completely
immerse the exposed surfaces of the pellet as it rests on the
hardened silicone base. As needed, the drug pellet can be manually
or mechanically centered on the silicone base using an
insertable/retractable device or probe to move and center the
pellet as needed. The added silicone fluid is then cured inside the
plastic tube. After the silicone is cured, the plastic tube is
separated from the centrifuge tube, and the resulting
silicone-coated pellet reservoir type implant is in turn removed
from the releasable plastic tube, as an implant subassembly. The
reservoir implant subassembly is joined to a means for attaching
the implant subassembly to intraocular tissues of the eye, such as
a suture stub.
[0046] As an alternative to the suture stub, a silk mesh fabric can
be embedded in the silicone at one end of the reservoir type
implant. This allows a suture to pass through the mesh embedded at
the one end and the suture will not scissor through the soft
silicone since it is caught by the mesh. The suture then passes
through the edges of the scleral wound and is tied down.
[0047] The implant subassembly of the intraocular reservoir
implants of the invention provide a sustained, substantially
constant delivery rate of drug over a prolonged period. The
intraocular reservoir implants also can be modified to form dual
mode release devices. For instance, in a dual mode configuration,
additional therapeutic agent could be dispersed in the silicone
fluid before being used to encapsulate the drug core to create an
initial higher release rate, or loading dose; alternatively,
additional amounts of the drug could be dispersed in or attached as
a discrete inlay member onto a separate silicone adhesive used to
attach a surface of the reservoir implant subassembly to a suture
stub or the like. Alternatively, multi-drug therapy could be
provided by including a drug different from the drug core in the
silicone surrounding the pellet or, in or on the silicone adhesive
used to affix the implant reservoir subassembly, each comprising an
encapsulated drug core, can be attached to a common suture stub to
provide concurrent delivery of different drugs or additive
introduction of a common drug.
[0048] As another dual mode embodiment of the reservoir implant, a
circular wafer shaped pellet or table of therapeutic agent having a
larger radial diameter than thickness can be fixed to a suture stub
with silicone adhesive; and a temperature-curable type silicone
adhesive is then used to form a coating bead around the periphery
of the wafer-shaped pellet or tablet. Curing the bead of silicone
coating around the tablet periphery can be delayed (preferably for
about 18 to 30 hours, more preferably approximately 24 hours), by
keeping the coated assembly at room temperature (e.g.,
20-30.degree. C.); thereafter peripheral bead coating of silicone
ultimately becomes fully cured. The silicone adhesive is in a
constant state of curing but the process is not complete for 18-30
hours. The top surface of the table is coated separately with
silicone before or after this "delay in cure" procedure, and cured.
During the interim delay in cure period, some, but not all, of the
therapeutic agent diffuses into the surrounding nonfully cured
silicone coating polymer at its periphery, which creates a high
release rate or loading dose with the implant is initially
installed, followed by slow, lower dosage sustained release of the
therapeutic agent.
[0049] Among other eye therapies, the intraocular reservoir
implants of the present invention provide an effective treatment
for sight-threatening eye diseases that include but are not limited
to uveitis, age-related macular degeneration, and glaucoma.
Therapeutic agents useful in this implant design include, for
example, 2-methoxyestradiol (2ME2) or angiogenesis compounds such
as VEGF antagonists for treating CNVM; or corticosteroids for
treating uveitis, to name just a few examples.
[0050] The therapeutic agents and drugs deliverable by the implants
of this invention generally are low solubility substances relative
to the various polymeric matrices described herein, such that the
agents diffuse from the drug core into and through the polymer
material, when saturated with body fluids, in continuous,
controlled manner.
[0051] The therapeutic agents and drugs that can be delivered by
the implants of this invention include, for example, antibiotic
agents, antibacterial agents, antiviral agents, anti-glaucoma
agents, antiallergenic agents, anti-inflammatory agents,
anti-angiogenesis compounds, antiproliferative agents, immune
system modifying agents, anti-cancer agents, antisense agents,
antimycotic agents, miotic agents, anticholinesterase agents,
mydriatic agents, differentiation modulator agents, sympathomimetic
agents, anaesthetic agents, vasoconstructive agents, vasodilatory
agents, decongestants, cell transport/mobility impending agents,
polypeptides and protein agents, polycations, polyanions, steroidal
agents, carbonic anhydride inhibitor agents, and lubricating
agents, and the like singly or in combinations thereof.
[0052] In these and other ways described below, the inventive
implants offer a myriad of advantages, improvements, benefits, and
therapeutic opportunities. The inventive implants are highly
versatile and can be tailored to enhance the delivery regimen both
in terms of administration mode(s) and type(s) of drugs delivered.
The implants of this invention permit continuous release of
therapeutic agents into the eye over a specified period of time,
which can be weeks, months, or even years as desired. A another
advantage, the inventive implant systems of this invention require
intervention only of initiation and termination of the therapy
(i.e., removal of the implant). Patient compliance issues during a
regimen are eliminated. The time-dependent delivery of one or more
drugs to the eye by this invention makes it possible to maximize
the pharmacological and physiological effects of the eye treatment.
The inventive implants have human and veterinary applicability.
BRIEF DESCRIPTION OF THE DRAWINGS
[0053] Other features, benefits, and advantages of the present
invention will become apparent from the following detail
description of preferred embodiments of the invention with
reference to the drawings.
[0054] FIG. 1 is enlarged view of a sustained release,
subconjunctival matrix single mode implant device according to the
embodiment of the invention.
[0055] FIG. 2A is enlarged view of a sustained release,
subconjunctival matrix dual mode implant device according to an
embodiment of the invention, in which a drug pellet is surrounded
by a composite material matrix layer including polymeric material
and a dispersion therein of additional drug.
[0056] FIG. 2B is a view of the sustained release, subconjunctival
matrix dual mode implant device similar to the one sown in FIG. 2A,
including a view of the drug pellet surrounded by the polymeric
material and dispersed additional drug, and an optional eye
attachment (suture stub). The cross-section shows the relationship
of the drug pellet to the surrounding polymer coating.
[0057] FIG. 3A schematically illustrates the delivery of a loading
dose by a subconjunctival matrix dual mode implant of this
invention into the surrounding tissues and vitreous cavity.
[0058] FIG. 3B schematically illustrates delivery of a maintenance
dosage by the subconjunctival matrix dual mode implant shown in
FIG. 3A, subsequent to delivery of the loading dose.
[0059] FIG. 4A graphically illustrates the delivery of a delivery
of a loading dosage according to a subconjunctival matrix single
mode implant of this invention described in Example 4 herein.
[0060] FIG. 4B graphically illustrates delivery of a loading and
maintenance dosage according to a subconjunctival matrix dual mode
implant of this invention described in Example 4 herein.
[0061] FIG. 5 graphically illustrates the effect of surface area
and drug concentration on release rates for a subconjunctival
matrix single mode implant of this invention.
[0062] FIG. 6 schematically illustrates the placement in the eye of
an intraocular matrix implant according to another embodiment of
this invention.
[0063] FIG. 7 is enlarged view, in cross-section, of a sustained
release intraocular implant device according to another embodiment
of the invention a drug pellet surrounded by a permeable polymeric
material including optional additional drug, and an eye attachment
means.
[0064] FIGS. 8A-I schematically depicts an enlarged view of process
steps associated with making a reservoir implant subassembly
according to another embodiment of this invention.
[0065] FIGS. 9A-C depicts top, perspective, and front views,
respectively, of a reservoir implant (subassembly) according to a
reservoir type implant of this invention.
[0066] FIGS. 10A-D schematically depict an enlarged view of
diffusion of therapeutic agent into an uncured silicone head
surrounding a drug pellet at different time intervals (0 min., 30
min., 2 hr., and 24 hr., respectively) in a step associated with
the making of a reservoir implant according to a "delay in cure"
technique of yet another embodiment of this invention.
[0067] FIG. 10E is a graphical illustration of in vitro loading
doses in PBS achieved with 2ME2 reservoir implants of the type
described in connection with FIGS. 10A-H herein, as a function of
the delay in cure time.
[0068] FIG. 11A schematically illustrates the delivery of a loading
dose by an intravitreal reservoir dual-mode implant of this
invention, which has been placed in an eye as shown in FIG.
11C.
[0069] FIG. 11B schematically illustrates delivery of a maintenance
dosage by the intravitreal reservoir dual mode implant shown in
FIG. 11A, subsequent to delivery of the loading dose.
[0070] FIG. 12A schematically illustrates an intravitreal reservoir
single mode implant according to an embodiment of the
invention.
[0071] FIG. 12B schematically illustrates a dual mode intravitreal
reservoir implant according to an embodiment of the invention,
including therapeutic agent in the silicone surrounding the drug
pellet.
[0072] FIG. 12C schematically illustrates an intravitreal reservoir
dual mode implant according to an embodiment of the invention,
including therapeutic agent in a silicone adhesive used to attach
the reservoir implant subassembly to the suture stub.
[0073] FIG. 12D schematically illustrates an intravitreal reservoir
dual mode implant according to an embodiment of the invention,
including therapeutic agent in an inlay attached to a silicone
adhesive used to attach the reservoir implant subassembly to the
suture stub.
[0074] FIG. 12E schematically illustrates a double-barreled
intravitreal reservoir implant configuration according to an
embodiment of the invention.
[0075] FIG. 13 graphically shows ocular tissue levels of a drug
(CsA) at different locations as delivered by a dual mode matrix
implant of this invention implanted in the subconjunctival space,
as described in Example 4.
[0076] FIG. 14 graphically shows the average in vitro release rate
of a drug (2ME2) over time as delivered by a matrix implant of this
invention suitable for placement in the vitreous, as described in
Example 5.
[0077] FIG. 15 graphically illustrates the in vitro release rates
of a drug (2ME2) according to reservoir implants of this invention
that varies the polymer thickness surrounding the drug pellet, as
described in Example 6 herein.
[0078] FIG. 16 is a table of the 2ME2 in vitro release rates
observed for the intravitreal reservoir dual mode implant studies
described in Example 6 herein.
[0079] FIG. 17 graphically illustrates the levels of 2ME2 in the
aqueous humor, vitreous humor and blood in rabbits at one and three
months after receiving an intravitreal reservoir dual mode implant
according to the invention, as described in Example 7.
[0080] FIG. 18 graphically illustrates the release rates of
triamcinolone acetonide (TAAC) according to an embodiment of the
invention and a comparison implant in a rat model of induced CNVM,
as described in Example 8.
[0081] FIGS. 19A-19H schematically depicts an enlarged view of
process steps associated with making a reservoir implant
subassembly according to yet another embodiment of this
invention.
[0082] FIG. 20 graphically illustrates the release rates of 2ME2
according to an embodiment of the invention in which an implant is
manufactured using the release mold described in FIGS. 19A-19H.
[0083] FIG. 21 graphically illustrates the release rates of 2ME2 at
different concentrations according to an embodiment of the
invention in which composite implants are manufactured using the
release mold described in FIGS. 19A-19H.
[0084] Skilled artisans will appreciate that elements in the
figures are illustrated for simplicity and clarity and have not
necessarily been drawn to scale. For example, the dimensions of
some of the features shown in the figures may be enlarged relative
to other elements to better illustrate and/or facilitate the
discussion herein of the embodiments of the invention. Features in
the various figures identified with the same reference numerals
represent like features unless indicated otherwise.
DETAILED DESCRIPTION OF THE INVENTION
[0085] Matrix Implants:
[0086] Referring now to the figures, and in particular to FIG. 1, a
sustained release, matrix single mode implant device 10 of the
invention is shown comprised of a single composite material matrix
layer containing a dispersion of a therapeutic agent, seen as white
particles 12 in the figure, and a polymeric matrix includes a
polymer permeable to the therapeutic agent and present as a
bioerodible solid matrix structure, and a water-soluble polymer
having greater water solubility than the permeable polymer.
[0087] The implant configuration provides a single-mode, single
action therapy in the eye in which a loading dose of drug is
released.
[0088] Referring now to FIG. 2A, a modified variant of the matrix
implant shown in FIG. 1, is illustrated, which provides dual mode
(dual action) drug delivery to an eye. In this implant 20, a drug
core or pellet embedded and encapsulated within a composite
material matrix layer 22, 21 having the composition described above
for implant 10. The composite material matrix layer includes a flat
base portion 22 upon which the bottom of the drug pellet rests, and
an upraised portion 24, which conformably makes intimate physical
contact with the top and side surfaces of the drug pellet. The drug
pellet 26 is not visible in FIG. 2A. FIG. 2B illustrates the
embedded drug pellet 26, and an optional suture stub 28 that can be
used to attach the implant 20 to eye or other nearby tissue if
desired or useful.
[0089] In this way, and as illustrated in FIGS. 3A and 3B,
therapeutic agent is included in both an inner core or drug
reservoir and as dispersed in the exterior composite material
matrix layer or cladding of implant 20. This results in a dual mode
or bimodal release of the therapeutic agent into the eye 301 during
a treatment regimen. That is, a loading dosage is initially
delivered by the conjunctival implant (FIG. 3A), followed by a
transition in the release rate, during continuing uninterrupted
drug delivery by the implant, down to a relatively steady lower
maintenance dosage 32 that is sustained over a prolonged period
(FIG. 3B).
[0090] FIGS. 4A-B, based on data developed in the studies described
in Example 4 infra, graphically show the difference in the single
mode matrix implant (FIG. 1) performance as compared to that of the
dual mode matrix implant (FIG. 2A) which further includes a drug
pellet core.
[0091] For the dual mode matrix implant, the therapeutic agent
initially is released both from the polymer matrix and the inner
core reservoir of this embodiment of the subconjunctival implant,
creating the loading dosage. Once the concentration of drug
initially preloaded into the composite cladding material diffuses
out into the eye, the maintenance dosage of drug is derived at a
relatively constant rate from the remainder of the drug diffusing
from the inner core through the composite material.
[0092] As to the materials used in constructing the matrix
implants, the following considerations are important. The composite
material matrix layer or member (22, 24) includes at least, and
preferable predominantly or exclusively, the following three
ingredients: (1) a drug permeable polymer, (2) a water soluble
polymer, and (3) a dispersed therapeutic agent.
[0093] The permeable polymer preferably is superhydrolyzed
polyvinyl alcohol. The permeable polymer is imperforate; i.e., it
is not microporous. Thus, the drug or therapeutic agent passes
through it by diffusion process. For purposes of this invention, a
superhydrolyzed polyvinyl alcohol means a polyvinyl alcohol of at
least 98.8 wt % hydrolysis, preferably at least 99.0 wt %
hydrolysis, and more preferably 99.3 wt % or more hydrolysis.
Superhydrolyzed PVA is obtained in granular powder form from Air
Products and Chemicals, Inc., Allentown, Pa., U.S.A., as Airvol
125. Airvol 125 has at least 99.3 wt % hydrolysis, and intermediate
viscosities of 28-32 cps and a pH of 5.5-7.5. The superhydrolyzed
PVA that can be used in the invention generally has a weight
average molecular weight of about 85,000-150,000, and preferable
about 100,000 to about 145,000. Additional information on
superhydrolyzed PVA is provided at CAS No. 900289-5. Other suitable
superhydrolyzed PVA products, include Airvol 165, also available
from Air Products and Chemicals, Inc., Allentown, Pa., U.S.A.
[0094] Superhydrolyzed PVA provides the requisite functionalities
of permitting diffusion of the therapeutic agent while forming a
slowly bioerodible structure in the composite material matrix layer
or member (22, 24) of the implant. The rate of erosion of the
superhydrolyzed PVA is sufficiently slow that a slow sustained
delivery of drug, such as many months or even years, can be
obtained as desired.
[0095] In addition, the low wet expansion behavior or
superhydrolyzed PVA prevents the implant from being extruded from
its position within or near the eye, and also permits more
predictable pharmacokinetic modeling behavior of the device. For
example, once the subconjunctival matrix implants of this invention
are implanted in the subconjunctival space (e.g., in a rabbit),
after 3-4 weeks, the edges of the matrix implants constructed with
superhydrolyzed PVA have been observed to soften as the surface of
the polymer hydrates which decreases the risk that it will extrude
(i.e., a sharp edge under the conjunctiva tends to catch the lid
when it blinds, and this would undesirably move the implant
anteriorly and increase the risk it will extrude at the corneal
limbus). Also, the superhydrolyzed PVA totally conforms to the
globe of the eye and is adherent to the sclera after 3-4 weeks.
[0096] For bulkier implants (e.g. dual mode implants with large
drug pellets) that are at higher risk of extrusion, one or two
sutures can be placed through the edges of the implant to secure
the implant to the sclera.
[0097] Also, the superhydrolyzed polyvinyl alcohol used in the
polymeric matrix is essentially noncrosslinked through its
secondary hydroxyl functionality, i.e., it is not heated to
temperatures during preparation of the implant sufficient to induce
a level of crosslinking which impairs its permeability to the
therapeutic agent present in either the inner core of the composite
matrix material.
[0098] Heating the matrix implants at temperatures >100.degree.
C. for 3-8 hours will encourage PVA crosslinking and this may be
desirable when attempting to reduce drug release rates from a
particular implant.
[0099] The separate water-soluble polymer included in the polymeric
matrix material is a nonionic cellulose ether. Among other things,
acts as a suspension and dispersion aid for the therapeutic agent
in premix step involved with fabricating the implant. Examples of
such cellulose ether include hydroxyalkyl cellulose materials, such
as hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose
(HPC), and methylcellulose (MC). HPMC can be obtained as METHOCEL
from Dow Chemical (e.g., METHOCEL E4M). METHOCEL is cellulosic in
nature. It is dissolve in the same temperature ranges as
superhydrolyzed PVA. The preferred hydroxypropyl methyl cellulose
has a weight average molecular weight of about 70,000 to about
100,000, preferably about 80,000 to about 90,000, and more
preferably about 85,000.
[0100] In that many useful therapeutic agents for ocular treatments
are hydrophobic or lipophilic in nature, the present invention
provides a processing strategy effective to uniformly disperse and
maintain a suspension of such active agents and compounds in an
aqueous medium in the preparation of the matrix implants. To
accomplish this, the method for preparing the composite material
matrix layer component of the matrix implants includes a step of
separately mixing and dispersing the therapeutic agent to be
incorporated in the composite (cladding) material first with
cellulose ether and the like, which acts as a dispersing or
emulsifying aid to permit an emulsion-like suspension of
therapeutic agent in an aqueous fluid. Generally, this premixture
will involve preparing an aqueous emulsion or suspension containing
a mixture of drug and an amount of cellulose ether effective to
provide the above-mentioned processing aid effects needed. This
preliminary dispersion and suspension of the therapeutic agent
using the cellulose ether is done in the absence of the
superhydrolyzed PVA and without heating. The premixture generally
comprises the drug in a range amount of about 1.5% to about 80% and
the cellulose ether in a range amount of about 0.05% to about 95%,
on a dry weight basis.
[0101] In general, the premixture is not heated. An occasional drug
needs 70-110.degree. C. to help the dispersion of the drug in the
premixture.
[0102] Thereafter, the separately prepared emulsion or suspension
of drug and dispersing aid polymer then is combined and mixed
effectively and thoroughly with an aqueous solution of the
superhydrolyzed PVA ingredient. The superhydrolyzed PVA solution
generally contains about 5 to about 50 wt % of the superhydrolyzed
PVA. Higher concentration solutions of superhydrolyzed PVA are more
difficult to work with due to increased viscosities. To optimize
the drug suspension when using high concentrations of PVA,
preferably small volumes are prepared of the PVA solution with
frequent stirring under mild (noncrosslinking) heat.
[0103] The superhydrolyzed PVA solution can be combined with the
cellulose ether/drug mixture with a spatula or other suitable
manual mixing instruments. However, for more highly viscous
suspensions, a blender may be desirable. As such a blender, a
MiniContainer is adapted to the blender to hold small volumes,
where the blender is a Laboratory Blender (Model 51BL30), operated
at speeds of 18,000 RPM (low) or 22,000 RPM (high) as needed. The
MiniContainer (MMGC1) was stainless steel and held 12-37 ml, and
was obtained from Waring Factory Service Center, Torrington, Conn.
To add the materials to a blender, a bottom of the assay tube
containing the PVA/METHOCEL/drug mixture is cut with a razor blade
and the contents poured into the blender. In one method, the
mixture is blended at high speed (22K RPM) for up to 5 minutes, and
the blended contents are then poured into a 50 ml assay tube and
centrifuge for 2 minutes at 1-4 k RPM to degas it.
[0104] In this way, an overall homogenous premixture can be
provided for the composite material matrix layer that includes the
three above-mentioned ingredients.
[0105] When describing the components of the PVA/cellulose
ether/drug mixture, the amount of PVA is expresses as a wt % of the
PVA/water solution, e.g., 50 grams of PVA in 100 ml of water is a
50% PVA solution. However, the other components, i.e., the drug and
cellulose ether, weights are expressed as the % of the total dry
weight of the PVA/cellulose ether/drug mixture. The combined
drug/cellulose ether premixture and PVA solution generally has a
composition of about 5 wt % superhydrolyzed PVA, about 0.05 wt % to
about 90 wt % cellulose ether, about 1 to about 50 wt % drug. More
preferably, the composite material matrix layer comprises about 5
to about 20 wt % superhydrolyzed PVA, about 0.05 to about 20 wt %
cellulose ether, and about 1 to 50 wt % therapeutic agent.
[0106] The homogeneous premixture including the three
above-mentioned ingredients, then is formed into a sheet-like
coating on a flat releasable surface, or is injected between two
releasable plates (e.g., glass) to provide a uniform desired
thickness, and dried at room temperature and without application of
heat (i.e., preferable at less than about 30.degree. C.). Pieces of
the dried uncrosslinked material are cut after drying from the
sheet in the profiles desired for the matrix implant. At this
point, a single-mode version of the implant (FIG. 1) has been
manufactured. Other implant shapes, such as a curvilinear design,
can be easily fabricated to conform to the curvature of the cornea,
which may be helpful for corneal or stem-cell graft transplantation
and ocular inflammatory diseases. The dried matrix implant is
uncrosslinked so that it is bioerodible.
[0107] For lower concentrations of PVA in the composition of matrix
implants, such as less than about 15 wt %, the homogeneous
drug/cellulose ether/PVA mixture can be poured out onto a glass
plate and this will flatten out on its own upon drying without the
need for compression via a top plate. Alternatively, the mixture
can be compressed between two glass plates to further ensure
uniform thickness. The top glass plate can be removed without
damaging the drug/cellulose ether/PVA composite by cooling the
lay-up before its removal. One glass plate (top one) is removed
after cooling, and the other is left so that the PVA has a place to
dry. The surface tension of the PVA generally keeps it adhered to
the bottom glass plate so that it dries as a flat sheet. If both
glass plates are removed simultaneously after the cooling step, the
PVA curls up and is not usable. Where PVA concentrations higher
than about 15% are used in making a matrix implant, such as about
50 wt % PVA, the sandwich or double glass plate technique
preferable is used to help flatten out the surface of the coating
before it dries.
[0108] For preparation of dual mode matrix implants (FIG. 2A), a
modified process is required to introduce and embed the inner drug
core. The drug core is a self-supporting solid or semi-solid part
containing the drug, and has any convenient shape conducive for the
making of sealing coverage thereon by the composite material. For
instance, the core can be formed as a cylindrical-shaped pellet of
the drug alone, or in combination with a pharmaceutically
acceptable carrier. In any event, the dual-mode implant is
assembled by depositing the drug core, such as drug pellet or
table, on the surface of a freshly prepared and coated layer of the
composite material while still semi-floatable; the pellet is then
tapped or pushed with light force on its upper surface, such by use
of an elongated tipped surgical device (e.g., a triple-0 Bowman
probe), so as to submerge and embed it completely within and in
contact with the polymeric room temperature) to fix it in position.
The polymeric coating layer thickness is selected to adequate to
permit complete encapsulation of the drug pellet. The submerging of
the drug pellets into the wet, non-fully dried PVA slabs according
to this invention avoids tendencies of alternate approaches
involving multiple dip and dry coat applications that tend to
delaminate in use, thereby dramatically altering the drug release
rates. Also, when drug pellets are embedded in a matrix with high
PVA concentrations to make dual mode implants, this preferably is
done by embedding them at the edges where the two glass plates come
together and the polymer is exposed.
[0109] As seen in FIG. 2A, when a drug pellet having a rounded
tablet shape is used, the matrix implant resulting from drying the
above-mentioned matrix coating layer containing the pellet has a
saucer like shape with a flat surface on one side, and a hat shape
on the opposite side, where the drug core is completely and
physically intimately covered by a polymer coating including
dispersed drug, without an entrapped air pockets or air spaces
inside the implant. Depending on the type of mammal intended for
treatment with this implant, the purpose of the ocular treatment,
and the type of drug and polymer coating material, the drug pellet
cores generally range in diameter from about 1 mm to about 5 mm and
about 1.0 to about 2.5 mm in thickness, and the thickness of the
polymeric coating can range from about 0.01 mm to 1.0 mm (as
measured form a pellet surface to the outer surface of the
polymeric layer). In the case of the single-mode matrix implants,
the thickness of the homogenous wafer-shaped polymeric material
generally ranges from about 0.1 mm to 2 mm, and the wafer has
opposite flat surfaces.
[0110] Adjusting the loading in the matrix implant generally can be
done by changing the relative proportions of superhydrolyzed PVA,
cellulose ether, and drug in the matrix component. The maintenance
dose delivered by the dual mode matrix implants can be adjusted by
changing the surface area of release (i.e., generally by altering
the geometry and mass of the compressed drug pellet).
[0111] For instance, for a more rapid release rate in the matrix
implant, a higher portion of the cellulose ether can be used
relative to the proportion of superhydrolyzed PVA. If the mixture
is predominately cellulose ether, however, the loading dose
generally lasts for only 24 hours maximum. In that situation,
during fabrication of the implant, the pellet is precoated with 15%
uncrosslinked PVA (e.g., Airvol 125) and dried, before the coated
pellet is embedded within the wet polymeric coating slab. In this
way, when the cellulose ether rapidly dissolves, the pellet still
holds together.
[0112] Other than the mixing proportions of the ingredients,
factors affecting the release rate in the matrix implants include:
the permeability of the drug in the matrix polymers; the drug
concentration in the laminate layer and in the embedded pellet; the
surface area of the pellet; the amount of surface of the matrix
polymeric layer disposed on the eye. The effect of the surface area
and drug concentration on the release rates of single mode matrix
implants can be seen in FIG. 5.
[0113] Also, a slightly modified superhydrolyzed PVA polymer can be
used to modify the quantity and duration of the loading dose. For
example, using progressively higher amounts of gamma radiation
and/or heat exposure, can crosslink the PVA and reduce the implant
release rate. Chemical curing agents or catalysts are generally not
employed since the extent of crosslinking becomes to extensive and
the loading dose drug release capability can be lost. If radiation,
thermal or chemical crosslinking is too extensive, the PVA will
have inadequate permeability to the drug for the implant to
function effectively.
[0114] In another embodiment of the matrix implant, high (about 40
to about 50%) superhydrolyzed PVA concentration polymeric matrices
are provided. Small volumes (e.g., 3 ml or less) are advantageous
when working with high concentrations of PVA to optimize the drug
suspension in the matrix. After these matrices are made into dried
sheets, 1.times.1.times.2 mm rectangular pieces can be cut from the
sheet, each representing a microimplant, for placement into animal
eyes with smaller vitreous volumes (e.g., mouse, rat, or rabbit).
Each microimplant has drug dispersed as in the single mode matrix
implant described above. The advantage of high concentrations of
superhydrolyzed PVA is there is negligible expansion of the implant
if superhydrolyzed PVA (such as Airvol 125) is used. This lack of
expansion is critical when placing these microimplants in small
eyes since they are less likely to damage the lens and retina.
These microimplants are useful for releasing drugs in the vitreous
cavity to assess their efficacy in animal models of disease. These
microimplants can also be employed as inlays that attach to
reservoir implants, as described elsewhere herein. These inlays
attached to the reservoir implants can be employed for animal
models as well as in humans that require an intravitreal
implant.
[0115] As mentioned above, where PVA concentrations higher than
about 10 to about 15 wt % are used in making a matrix implant, such
as about 50 wt % PVA, the sandwich glass plate technique is
preferably used to help flatten out this highly viscous matrix.
Subsequent cooling and removal of the top plate, enable the matrix
to have uniform thickness upon drying.
[0116] In another embodiment, the matrix implant can be assembled
with a suture stub to which the implant is attached. Suture stubs
are used primarily for holding implants, whether of the matrix type
or reservoir type described elsewhere herein, in the vitreous
cavity or beneath the sclera. Thus, the stubs generally are not
biodegradable.
[0117] The suture stub can be formed of a biocompatible,
aqueous-insoluble polymer, such as crosslinked PVA. The suture
stubs can be made, for example, using non-super hydrolyzed, high
viscosity (62-72 cPs) polyvinyl alcohol (hydrolysis <99%) to
increase bonding to hydrophobic surfaces. A suitable non-super
hydrolyzed, high viscosity polyvinyl alcohol for use in making the
suture stubs includes, for example, Airvol 350 obtainable from Air
Products and Chemicals, Inc., Allentown, Pa., U.S.A. The polyvinyl
alcohol is thermally crosslinked. The act of heating with or
without radiation generally crosslinks the PVA sufficiently that
the addition of a chemical crosslinker is not necessary.
Optionally, a chemical crosslinker can be used while the PVA is
dissolving in solution, i.e., before it is dried into a sheet, when
a more rigid suture stub is required, for example, when larger
implants need to be secured in the vitreous cavity. In this
situation, the PVA is cured into the desired suture stub dimensions
including previously added conventional chemical crosslinking
agents for that purpose, and preferably those that are
non-formaldehyde based crosslinking agent are used. These optional
chemical crosslinkers include certain aldehydes such as glyoxal,
glutaraldehyde, hydroxyadipaldehyde, and salts of multivalent
anions such as zirconium ammonium carbonates. For the purpose of
reducing the potential for ocular toxicity, a non-formaldehyde
based crosslinking agent is preferred. Examples of suitable
crosslinkers in this regard include Polycup 172 (1-4% d/d;
Hercules, Inc.), which is a water-soluble
polyamide-epiclorohydrin-type resin, and Bacote-20 (2-10$ d/d;
Magneium Elektron, Ltd.), a zirconium ammonium carbonate salt. To
prevent dissolution, the stubs are heated about 130 to about
150.degree. C. for about 5 to 10 hours before use in the presence
of a dispersed crosslinker. A silicone adhesive, such as MED1-4213
silicone adhesive (NuSil, Carpinteria, Calif.) can be used to bond
the implants to the suture stub.
[0118] In another configuration, a portion of the outer surfaces of
the implant, such as one side of the composite material matrix
layer, has a polymer top coat that is impermeable to the
therapeutic agent, such as polymethyl methacrylate (PMMA). PMMA,
such as obtained from Sigma, can be prepared by dissolution of 1 g
PMMA/10 ml acetone with stirring for about 12 hours. One side or a
portion of the implant can be immersed in the resulting PMMA (e.g.,
three times over 30 minutes) and then dried (without heating). In
this way, the release of the implant can be modified (viz.,
reduced) as desired.
[0119] As another alternative embodiment of the invention,
poly(ethylene vinyl) acetate (EVA) is used in the polymeric matrix
material in lieu of the superhydrolyzed PVA, all other things
essentially the same in the construction. This provides an optional
dual mode implant structure giving a loading dose followed by
sustained slow release of drug. The EVA is non-bioerodible.
[0120] These single mode and dual mode implant configurations are
particularly well-suited for subconjunctival placement, but are not
limited thereto and could be installed on or in other eye regions
where convenient and useful, such as intravitreal placement using a
suture stub. For instance, FIG. 6 is a schematic representation of
a 2ME2-containing intraocular matrix implant 61 in an eye 63. Other
features of the eye 63 are also illustrated, including the cornea
601, lens 602, iris 603, conjunctiva 604, sclera 605, choroids 606,
retina 607, optic nerve 608, and vitreous humor 609.
[0121] In administration, the subconjunctival matrix implant
preferably is placed behind the surface epithelium within the
subconjunctival space. This is done by a surgical procedure that
can be performed in an out-patient setting. A lid speculum is
placed and a conjunctival radial incision is made through the
conjunctiva over the area where the implant is to be placed.
Wescott scissors are used to dissect posterior to tenon's fascia
and the implant is inserted. The conjunctiva is reapproximated
using a running 10-0 vicryl suture. The eye has many barriers that
do not permit easy penetration of drugs. These include the surface
epithelium on the front of the eye and the blood/retinal barrier
behind the eye that both have tight junctions. Thus, in one
administration strategy of the invention, the dual mode or single
mode matrix implant described herein is placed behind the surface
epithelium in the subconjunctival space. These subconjunctival
implants are generally about 1-2 mm in diameter for small rodent
(i.e., mouse and rat) eyes, 3-4 mm in diameter for rabbit and human
eyes and 6-8 mm in diameter for equine eyes.
[0122] Additionally, when the subconjunctival matrix implant is
placed near the limbus (i.e., the area where the conjunctiva
attaches anteriorly on the eye) to encourage the drug diffusion to
enter the cornea, it is preferable to fixate the matrix implant
with one or two absorbable sutures (e.g. 10-0 absorable vicryl
sutures). This is done by malting holes with a 30 gauge needle in
the peripheral portion of the implant, approximately 250-500 .mu.m
away from the peripheral edge of the implant. The holes are made
180 degrees from each other. This is done because subconjunctival
matrix implants of this invention, when placed near the cornea, are
at higher risk to extrude because of the action of the upper eye
lid when blinking. When subconjunctival matrix implants of this
invention are placed about 4 mm or more away from the limbus, the
sutures are optional.
[0123] This matrix implant can deliver therapeutic levels of
different pharmaceuticals agents to the eye to treat a variety of
diseases. Using a rabbit model, drug released from the implant
placed in the eye produces negligible levels of the drug in the
blood. This significantly reduces changes of systemic drug
side-effects.
[0124] In either case, whether the dual mode or single mode
variants, this embodiment of implant of this invention is
well-tolerated and non-toxic to the patient or recipient, viz., a
mammalian host-human or veterinary. In addition, this implant
design of this invention is prepared by unique methodologies and
selections of materials leading to and impairing the unique
pharmacological performance properties present in the finished
devices.
[0125] Among other eye therapies, the subconjunctival matrix
implants of the present invention provide an effective treatment
for corneal transplantation procedures, where it is desirable to
delivery an immune system modulator agent such as cyclosporine A
non-systemically to the eye, in order to reduce rejection rates of
corneal allografts. The matrix implants containing 2ME2 can be
attached to suture stubs and placed in the vitreous humor for used
in treatment of CNVM. 2ME2 is a drug manufactured by EntreMed,
Inc., Rockville, Md., U.S.A., and is currently referred to as
"Panzem". The matrix implant also has potential for replacing the
need for topical eye drops to treat certain eye diseases like
glaucoma and uveitis and the implant has the potential to treat eye
diseases in the back of the eye that are potentially
sight-threatening (e.g. retinal disease).
[0126] Also, for either the matrix implant, or the reservoir
implant described infra, the drug released for the loading dose can
be different than the drug that is released for the long-term
maintenance dose. For example, it may be advantageous to have a
loading dose of corticosteroid from the dual mode implant for about
a month postoperatively to reduce the inflammatory response
resulting from surgery and have a continuous release of different
drug to effect the disease that is being treated.
[0127] The drug pellets or tablets used for either the dual mode
matrix implants, or the intraocular reservoir implants described
elsewhere herein, are made by compressing a free-flowing powdered
form of the drug in any suitable compression or molding machine,
such as a pellet press. Pellet presses can be obtained, for
example, from Parr Instrument Company, Moline, Ill. A force
transducer can be used in ways one skilled in the art will
appreciate to closely manage the compressive force applied. In the
pellet press, the powdered form of the drug is enclosed within an
open-mouthed cylindrical receptacle having a solid base and a
continuous inner wall defining the radial diameter and length
(thickness) of the pellet to be formed. A ram applies a controlled
uniform amount of pressure across the exposed surface of the powder
for a given period of time sufficient to consolidate the powder
into a free-standing solid pellet form.
[0128] Depending on the drug, binders and excipients for
pellet-making optionally can be used. For example, magnesium
stearate or hydroxypropylmethyl cellulose could be used. For
example, for CsA pellets (suing 0.04% magnesium stearate as a
binder) to be used in corneal transplantation treatments, a
compressive pressure of about 110 lb-force is used (for a round
pellet, 3 mm diameter, 2 mm length). For 2ME2 pellets for use in
treatment of CNVM, a micronized preparation of 2ME2 (size of drug
particle is <5 micrometers) is used without binders, and a
pressure of about 190 lb-force is used (for a round pellet, 2 mm
diameter, 3 mm length). The pressure consolidates the powder into
an integral, discrete solid pellet or tablet.
[0129] Reservoir Implants:
[0130] FIGS. 8A-I and 10A-D show methods for fabricating
intraocular reservoir implants according to this invention. The
reservoir implants are sustained-release devices, which deliver
therapeutic agent to the eye over a prolonged period of time. With
some modifications described herein, a loading dose or dual mode
release capability also can be added to the reservoir implants.
[0131] The reservoir implants generally include an implant
reservoir subassembly, a suture stub or other attachment means, and
a means to adhere those two features together.
[0132] In general, the suture stub attachment means and adhering
means include the same respective materials described supra in
connection with suture stubs optionally usable with intravitreal
matrix implants, and reference is made thereto.
[0133] As an alternative to the suture stub, a silk mesh fabric can
be embedded in one end of the reservoir type implant. This allows a
suture to pass through the one end and the suture will not scissor
through the soft silicone since it is caught by the mesh. The
suture then passes through the edges of the scleral wound and is
tied down.
[0134] The discussion turns now to a method of making reservoir
implant subassemblies according to an embodiment of the reservoir
implants of the invention.
[0135] Referring to FIG. 8A, a microcentrifuge tube 84 is provided
of plastic construction, such as polyurethane, polypropylene or
high density polyethylene construction, of suitable dimensions
(e.g., ID of about 10 mm and a length of about 40 mm), which can be
obtained from Peninsula Laboratories Inc., Belmont, Calif. As shown
in FIG. 8A, the microcentrifuge tubes have a tapered conical-shaped
bottom and cylindrical upper portion having an open end.
[0136] As en in FIG. 8B, a curable (wet) silicone 86 fluid is
poured into the lower section of the microcentrifuge tube 84 (e.g.
about 10 mm depth).
[0137] The silicone used in making the reservoir implants is a
medical grade silicone, and generally is a polydimethylsiloxane
(PDMS)-based compound. The silicone used is biologically
(physiologically) inert and is well tolerated by body tissues.
Suitable silicones for use in the practice of this embodiment
include MED-6810 silicone, MED1-4213, MED2-4213 silicone, which can
be obtained from NuSil, Carpinteria, Calif. Both of these silicones
are two-part which silicones including a metal curing system (e.g.,
Pt). The time and temperature needed to cure the silicone will
depend on the silicone used and the drug release profile desired.
These silicones, if left to cure at room temperature (e.g.,
20-30.degree. C.), will require about 24 hours or more to cure. The
cure rate will increase with increasing cure temperatures. For
instance, MED2-4213 silicone will cure in about 30 minutes at about
100.degree. C. As will be discussed in more detail below, the more
quickly the silicone is cured, the less opportunity for therapeutic
agent to leach out into the surrounding silicone. Thus, the more
rapid the curing, the less likely any burst or loading dose will be
yielded by the device along with the slow steady state release
action.
[0138] Referring to FIG. 8C, to provide a low adhesion, thin walled
plastic tube 82 shown, thin walled coiled polytetrafluoroethylene
tubing, viz., Teflon.RTM. tubing or the like releasable plastics,
is heated at about 110.degree. C. for about 30 seconds and then
straightened, and thereafter cooled and set in the straightened
orientation. The straightened low adhesion plastic was then cut
into about 1.0 inch (2.54 cm) long tubes. The Teflon.RTM. tubing is
selected so as to have an outer diameter less than the inner
diameter of the microcentrifuge tube, and the inner diameter of
this low adhesion plastic tube must be larger than the radial
diameter of a pellet to be encapsulated therein with silicone, as
discussed below.
[0139] Referring still to FIG. 8C, soon after the wet silicone is
introduced into the microcentrifuge tube 84, one of the cut low
adhesion plastic tubes 82 is placed within the microcentrifuge
tube. The low adhesion plastic tube 82 is spun vertically down a
distance within the centrifuge tube such that the lower end of the
plastic tube 82 is submerged a distance "d" (e.g., about 3 mm)
below the surface of the silicone 86 already in the microcentrifuge
tube 84 (distance "d" is best seen in FIG. 8E). The centrifuge
device used can be a TOMY MTX-150 centrifuge, obtained from
Peninsula Laboratories, Inc., Belmont, Calif. The submerged portion
82a of the plastic tube 82 is indicated in FIG. 8C. A portion 86a
of the silicone 86 fills the lower 3 mm of the plastic tube 82, but
another portion 86b fills space between the outside surface of the
tube 82 and the inner wall of the tube 84 in the lower section of
the tube 84.
[0140] Soon after introducing the tube 82 into microcentrifuge tube
84 in this manner, the microcentrifuge tube 84 is centrifuged to
degas the wet silicone 86 and to radially center the tube 82 inside
the outer tube 84.
[0141] At this juncture, the microcentrifuge tubes and contents are
held at room temperature (or optionally higher temperatures) until
the silicone 86 cures and solidifies, generally about 24-72 hours
for room temperature cure. This hardens the portion of silicone 86a
located inside the lower end of the plastic tube 82, providing a
solid silicone base 86a inside tube 82, and a hardened silicone 86b
outside tube 82 which serves to retain it in an upright
position.
[0142] Then, and as shown in FIG. 8D, a drug pellet 88 is
introduced into the plastic tube 82 followed by adding additional
uncured silicone fluid 86c into the tube 82. The microcentrifuge
tube 84 is then centrifuged as needed to degas the additional
silicone 86c and place, if necessary the pellet 88 on the silicone
base 86a positioned at the bottom portion 82a of the plastic tube
82. The additional uncured silicone 86c added inside the plastic
tube is sufficient to completely immerse the exposed surfaces of
the pellet 88 as it rests on the pre-hardened silicone base 86a. As
needed, the drug pellet 88 can be manually or mechanically centered
on the silicone base 86a before curing silicone 86c using an
insertable/retractable device or probe (such as a triple-0 Bowman
probe) to move and center the pellet 88. The added silicone fluid
86c is then cured inside the top portion 82b of the plastic tube
82.
[0143] As shown in FIG. 8E, the microcentrifuge tube 84 is then
removed by sharp dissection thereof with care taken not to disrupt
the plastic tube 82 or its contents. All of the silicone portions
86a, 86b and 86c remain with the tube 82 at this juncture. Then as
illustrated in FIG. 8F, the silicone portion 86b is manually
separated form the exterior of the tube 82 leaving tub 82
containing silicone portion 86a and 86c sandwiched over the pellet
88. Nex, as shown in FIG. 8G, plastic tube 82 is removed by sharp
dissection in which the plastic tube 82 has a transverse cut made
at the lower end thereof with a blade, and the tube 82 is then
split away from the internal silicone/pellet complex subassembly
89. FIG. 8H shows the internal silicone/pellet complex subassembly
89 after removal of the low adhesion plastic tube 82. As shown in
FIG. 8I, the top and bottom ends of the reservoir implant
subassembly are trimmed closer to the top and bottom ends of the
drug pellet 88 to provide a finished reservoir implant subassembly
89. FIGS. 9A-C show various enlarged views of the resulting
reservoir implant subassembly 89 comprised of the silicone-encased
drug pellet.
[0144] Referring now to FIG. 7, a reservoir implant subassembly 71
made in this manner is attached to a suture stub 73, such as one
constructed of processed Airvol 650 as described above, using a
silicone adhesive 75, such as Nusil MED1-4213. The suture stub can
be used to fasten the implant reservoir in the eye such that it
cannot drift or move about.
[0145] Reservoir implant subassemblies 121 made in this manner with
various drugs in the reservoir, e.g., leflunomide (lef) or
2-methoxyestradiol (2ME2), have been adhered to Airvol 350 suture
stubs using silicon adhesive (see FIG. 12A) in order to examiner
the release properties. For each drug, 3 different diameters
(inner) of Teflon7 tubing were used to make implants with a polymer
thicknesses (i.e., 0.20, 0.36, and 0.70 mm), as described in
Example 8 infra, to provide a thin-walled "mold" for the radial
dimensions of the silicone encasement to be formed around the
pellet. As seen in FIGS. 13 and 14, the reservoir implants has
lower release rates with increasing polymer thickness, radial
and/or top/bottom, surrounding the drug pellet.
[0146] By varying the sizes of pellets and Teflon.RTM. tubing it is
possible to create many thicknesses of polymer surrounding the
implant, as shown in Table A below. Table A reports such polymer
thicknesses for various pellet sizes and various tube gauges (i.e.,
8, 9, and 10 gauge). A typical releasable tubing used is PTFE
tubing (Texloc, Ltd., Fort Worth, Tex.). The release rate of a
reservoir implant according to this invention is strongly dependent
upon the thickness of the polymer coating. For a cylindrical
reservoir implant device containing a cylindrical drug pellet
radially centered within the silicone cladding, this relationship
is described by the following formula:
DM.sub.t/d.sub.t=2.pi.DKC.sub.s/(Inr.sub.o/r.sub.i)
[0147] where dM.sub.t/d.sub.t is the release rate, r.sub.o is the
outside radius of the implant, r.sub.i is the radius of the drug
pellet, h is the height of the cylinder, D is the diffusion
coefficient of the drug through the polymer, K is the distribution
coefficient and C.sub.s is the solubility of the drug in the fluid.
TABLE-US-00001 TABLE A Thickness of Polymer Coating (mm) Pellet
Diam. Tubing Sizes (gauge) (mm) 8 9 10 0.5 1.45 1.26 1.11 1.0 1.20
1.01 0.86 1.5 0.92 0.76 0.31 2.0 0.70 0.51 0.36 2.5 0.45 0.26 0.11
3.0 0.20 0.01 0
[0148] This method for preparing the intraocular reservoir implant
of this invention provides an implant having a controlled radial
thickness of degassed silicone cladding around the drug pellet with
no significant variability in the cladding thickness from one
coated pellet to the next. Also, rigorous post-production quality
control inspections (including measuring individual implant release
rates before vivo use) of the implant products are not necessary,
which reduces the chances for contamination of the device from
additional handling as well as the cost of malting the devices.
Drug pellets of the medicament can be made using a Parr pellet
press, as described earlier.
[0149] Modifications available to adjust the drug administration of
the reservoir implants include:
[0150] an intravitreal reservoir dual mode implant further
including therapeutic agent 127 dispersed in the silicone 121'
surrounding the drug pellet 121'' of the reservoir implant
subassembly 121 (FIG. 12B);
[0151] an intravitreal reservoir dual mode implant including
therapeutic agent 127 dispersed in a silicone adhesive 125 used to
attach the reservoir implant subassembly 121 to the suture stub 123
(FIG. 12C);
[0152] an intravitreal reservoir dual mode implant including
therapeutic agent provided in an inlay 129 attached to a silicone
adhesive 125 used to attach the reservoir implant subassembly 121
to the suture stub 123 (FIG. 12D);
[0153] a double-barreled intravitreal reservoir implant
configuration including two reservoir implant subassemblies 121A
and 21B attached to a common suture stub 123 (FIG. 12E). This
configuration effectively increases the surface area of drug
release from the central pellet to correspondingly increase the
maintenance release rates.
[0154] The drug delivery behavior of the intraocular reservoir
implants (121, 123), as mounted on a suture stub as described
above, is schematically shown in FIGS. 11A (initial loading dose
103) and 11B (long term sustained or maintenance does 105), for an
implant placed in an eye 101 as shown in FIG. 11C.
[0155] As another dual mode embodiment of the reservoir implant,
and as shown in FIGS. 10A-D, a circular wafer shaped pellet 107 of
the therapeutic agent, which has a tablet shape by having a larger
radial diameter than thickness, is fixed at its lower surface to a
suture stub 109 with silicone adhesive (not shown), such as the
above-mentioned Nusil MED1-4213 silicone adhesive. The dimensions
of the wafer-shaped pellet or tablet could be, for example, 1-2 mm
in height and 3 mm in radial diameter. A temperature-curable
silicone adhesive, such as the same type above (e.g. NuSil
MED1-4213 silicone adhesive), is then used to form a bed or ribbon
of wet silicone 111 around the periphery of the tablet 107 (i.e.,
coating the side edge surfaces of the tablet and contacting the
adjoining surface of the suture stub). Then, the cure of the
silicone bead coating is slowed or delayed preferably for about 18
to 30 hours, more preferably approximately 24 hours, by keeping the
coated assembly at room temperature (e.g., 20-30.degree. C.). The
upper flat surface of the tablet is covered with thin silicone
coating 113, such as MED1-4213 or Nusil MED-6810 (a two-part
silicone) that is cured with (radiant) heat before or after the
"delay in cure" procedure is conducted on the peripheral silicone
bead coating. During the interim delay in cure period when the
silicone adhesive is gradually and slowly curing, some, but not
all, of the therapeutic agent diffuses into the surrounding unfully
cured bead of silicone polymer, which creates a significant burst
or loading dose when the implant is installed, followed by slow,
lower dosage sustained release of the therapeutic agent. This
effect is shown by FIG. 10E, which relates to in vitro tests
performed on this class of reservoir implants where the tested
implants included 2ME2 tablets of about 1.5 mm height and 3 mm in
diameter, the bottom and peripheral bead silicone adhesive was
NuSil-4213 silicone adhesive, and the top surface silicone coating
was Nusil MED-6810 applied and cured after the "delay in cure"
procedure.
[0156] Certain silicones, such as MED1-4213, that contact the drug
pellet in a wet phase for a long period of time, yield more
substantial loading dosages. By using this drug leaching to
advantage, and using silicones that can quick cure (MED2-4123 or
the 6810), it is possible to control the degree of drug loading by
curing at different times.
[0157] The reservoir implants of this invention can be used to
treat a number of eye diseases and indications including, for
example, age-related macular degeneration, glaucoma, diabetic
retinopathy, uveitis, retinopathy of prematurity in newborns,
choroidal melanoma, chorodial metastasis, and retinal capillary
hermagioma. For these indications, a suitable therapeutic agent
includes, for example, 2-methoxyestradiol. For example, the
reservoir implant provides for a sustained release of drugs, such
as 2-methoxyestradiol for the treatment of undesirable angiogenesis
involved in the degeneration of the macula.
[0158] The loading dose from the reservoir implant can be estimated
when the target drug concentrations in the vitreous and drug
clearance from the eye is known. Assuming a one-compartment model
with no partitioning, the steady-state concentration (Css) is the
release rate time bioavailability (F) divided by the clearance
(CL). Benet, L., et al., Pharmokinetics In: Goodman and Gilman's:
The Pharmacological Basis of Therapeutics. New York: McGraw-Hill;
1996: 3-27. This relationship is expressed by the following
formula: (Css)=steady-state implant release.times.F/CL (1).
[0159] The fractional bioavailability of the dose (F) can be
assumed to be 1 for the intravitreal implants and <1 for
subconjunctival implants (since some drug is lost in route to the
vitreous cavity through the conjunctival, episcleral, and choroidal
vasculature). Classic pharmacokinetics teach that steady state
concentrations can be obtained after approximately four half-times.
For example, the CL of an antimetabolite from the vitreous cavity,
when scaled to humans, is 0.38 ml/hr and the half life is 10.4
hours. Velez, G., et al., Intravitreal Chemotherapy for Primary
Intraocular Lymphoma. Arch Ophthalmol (in press). 2001.
[0160] If the target concentration in the vitreous is 1 .mu.g/ml, a
release rate of 0.38 .mu.g/hr will be required to achieve Css in
the vitreous after approximately 4 half times or 41.6 hours. For
comparison, if the drug is being released by a subconjunctival
matrix implant according to this invention, with a bioavailability
of 0.5, the release rate from the implant would need to be doubled
(i.e., 0.76 .mu.g/hr).
[0161] For conditions, such as CNVM associated with AMD, long
delays (i.e., 41.6 hours) are not desirable. Loading doses from the
implant can shorten the length of time required to reach Css. For
example, using the equation: V.sub.d*(dC/dt)=I(t)-CL*C(t)
[0162] where V.sub.d is the volume of distribution, C is the
concentration of distribution, dC/dt is the rate of change of
concentration in the vitreous, I(t) is the release rate fro the
implant. The notation with parentheses (t) indicates that the rate
may change with time, for example, a rapid release on and then
settling to a lower rate for a prolonged period of time.
[0163] A doubling of the release rate of an intravitreal implant
for a period equal to the half-life of the drug allows Css to be
reached in one half-time (10.4 hours) instead of four half-lives
(41.6 hr). To further increase the speed at which the Css is
reached, for example, in 2 hrs (20% of a half-life) after the
implant is placed, the drug release rate should be approximately 8
times higher during that period.
[0164] The reservoir implants have been designed to release a
loading dose of drug within the first few hours after implant
placement. For example, using the "cure time delay" technique,
periods of delay in the curing the silicone around the drug pellet
can change the drug burst from the implant; however, the reservoir
implants continue to release a steady state concentration after the
loading dose.
[0165] Referring now to FIGS. 19A-19H, a polytetrafluoroethylene
mold is used in another embodiment of the invention. FIG. 19A shows
a polytetrafluoroethylene (e.g., Teflon.RTM.) mold 1900. The
purpose of the Teflon mold is that it is durable with the
temperatures required for curing the silicone, which is generally
150.degree. C., and after curing, the implant complex can be peeled
off of the mold completely and be reused. Although the depicted
mold shows one implant impression 1901, a plurality of implant
impressions, such as four, of any desired size can be made for each
mold, size permitting. The Teflon mold can fit tightly in a
standard 60 mL centrifuge tube for periodic degassing of the
silicone before curing. A stainless steel rigid bar or post 1902
projects from and is fixed at its bottom end in the mold 1900. Bar
1902 produces a hole in the suture platform to pass a suture. A
polyester mesh is embedded in the suture platform before curing and
increases the durability to reduce the "scissoring" effect of
suture material through silicone. The preferred mesh is a 100%
polyester 20/1 weave, such as fabricated at Mohawk Fabrics,
Amsterdam, N.Y., USA. The preferred silicone products are available
through NuSil Technology, Carpinteria, Calif.
[0166] FIG. 19B shows silicone poured into the impression in the
Teflon mold. The mold is placed in a centrifuge tube (not shown)
and degassed.
[0167] FIG. 19C shows a compressed drug pellet 1904 being placed
and centered in the Teflon mold 1900. Alternatively, when making a
silicone composite implant (i.e., without a compressed drug
pellet), the silicone is mixed with a dry drug powder until uniform
and placed in the implant impression. Degassing is done as
necessary. Related FIG. 19H shows the impression 1901 via a
cross-sectional view of mold 1900.
[0168] FIG. 19D shows a segment of polyester mesh 1905 passed down
the steel bar 1902 and submerged in the silicone. Care should be
taken that cut segments of the mesh will not project outside of the
confines of the silicone.
[0169] FIG. 19E shows the pellet 1904 and mesh 1905 in position and
this is placed in heat for curing or left overnight for silicones
that cure at room temperature.
[0170] FIG. 19F shows the implant after completion of curing, and
the edge of the silicone is peeled up and the entire complex is
lifted away from the mold 1900.
[0171] FIG. 19G shows the final implant product with the silicone
flashing dissected away.
[0172] FIG. 20 shows release rates obtained from intraocular
implants made using the mold technique of FIGS. 19A-19H, with a
central compressed pellet. An initial burst release was followed by
steady state release. At a steady state release of 2 .mu.g/day,
this design of implant with a 5 mg compressed pellet would last a
minimum of three years.
[0173] FIG. 21 shows release rates obtained using different
concentrations of 2-methoxyestradiol composite implants made using
the mold technique of FIGS. 19A-19H. A bolus is seen initially
followed by steady state release.
[0174] The one-piece intraocular implants manufactured according to
the methodology generally described in FIGS. 19A-19H avoid
variability in the amount of polymer surrounding a central
compressed drug pellet. This mold technique enables a precise
coating of encapsulating polymer around the drug pellets with high
reproducibility. It is cost-effective and straight-forward and can
be easily scaled up for mass production scenarios. Close
predictions can be made of the release rate of the implant knowing
the dimensions of the implant and the diffusivity of the drug
through the surrounding polymer. This expedites the production of
implants when a target release rate is known. Also, the
incorporation of the suture platform in the one-piece system avoids
delamination problems in the pellet/polymer complex from the suture
stub.
[0175] In addition, these molds can be used to make composite
silicone/drug complexes that deliver drug at higher release rates
following a steady state release rate (zero-order kinetics). By
altering the concentrations of the drug in the silicone, and also
changing the size of the implant by using different size
impressions in the Teflon mold, this composite technique permits
great flexibility in changing release rates. Fabricating different
implant geometries (i.e., curvilinear implants) are also fabricated
using these molds. The composite technique described herein does
not require drug pellet compression using conventional pellet press
and can increase the efficiency of the large-scale production of
the implants.
[0176] The therapeutic agents and drags that can be delivered by
the various matrix and reservoir implants of this invention
include, for example:
[0177] antibiotic agents such as fumagillin analogs, minocycline,
fluoroquinolone, cephalosporin antibiotics, herbimycon A,
tetracycline, chlortetracycline, bacitracin, neomycin, polymyxin,
gramicidin, oxytetracycline, chloramphenicol, gentamicin and
erythromycin;
[0178] antibacterial agents such as sulfonamides, sulfacetamide,
sulfamethizole, sulfoxazole, nitrofurazone, and sodium
propionate;
[0179] antiviral agents such as idoxuridine, famvir, ttisodium
phosphonoformate, trifluorothymidine, acyclovir, ganciclovir, DDI
and AZT, protease and integrase inhibitors;
[0180] anti-glaucoma agents such as beta blockers (timolol,
betaxolol, atenolol), prostaglandin analogues, hypotensive lipids,
and carbonic anhydrase inhibitors;
[0181] antiallergenic agents such as antazoline, methapyriline,
chlolpheniramine, pyrilamine and prophenpyridamine;
[0182] antiinflammatory agents such as hydrocortisone, leflunomide,
dexamethasone phosphate, fluocinolone acetonide, medrysone,
methylprednisolone, prednisolone phosphate, prednisolone acetate,
fluoromethalone, betamethasone, triamcinolone acetonide,
adrenalcortical steroids and their synthetic analogues, and
6-mannose phosphate;
[0183] antifungal agents such as fluconazole, amphotericin B,
lipsomal amphotericin B, voriconazole, imidazole-based antifungals,
triazole antifungals, echinocandin-like lipopeptide antibiotics,
lipid formulations of antifungals;
[0184] polycations and polyanions such as suramine and
protamine;
[0185] decongestants such as phenylephrine, naphazoline, and
tetrahydrazoline;
[0186] anti-angiogenesis compounds including those that can be
potential anti-choroidal neovascularization agents such as
2-methoxyestradiol and its analogues (e.g., 2-propenyl-estradiol,
2-propenyl-estradiol, 2-ethoxy-6-oxime-estradiol, 2-hydroxyestrone,
4-methoxyestradiol), VEGF antagonists such as VEGF antibodies and
VEGF antisense, angiostatic steroids (e.g., anecortave acetate and
its analogues, 17-ethynylestradiol, norethynodrel,
medroxyprogesterone, mestranol, androgens with angiostatic activity
such as ethisterone);
[0187] adrenocortical steroids and their synthetic analogues
including fluocinolone acetonide and triamcinolone acetonide and
all angiostatic steroids;
[0188] immunological response modifying agents such as cyclosporine
A, Prograf (tacrolimus), macrolide immunosuppressants,
mycophenolate mofetil, rapamycin, and muramyl dipeptide, and
vaccines;
[0189] anti-cancer agents such as 5-fluoroucil, platinum
coordination complexes such as cisplatin and carboplatin,
adriamycin, antimetabolites such as methotrexate, anthracycline
antibiotics, antimitotic drugs such as paclitaxel and docetaxel,
epipdophylltoxins such as etoposide, nitrosoureas including
carmustine, alkylating agents including cyclophosphamide; arsenic
trioxide; anastrozole; tamoxifen citrate; triptorelin pamoate;
gemtuzumab ozogamicin; irinotecan hydrochloride; leuprolide
acetate; bexarotene; exemestrane; epirubicin hydrochloride;
ondansetron; temozolomide; topoteanhydrochloride; tamoxifen
citrate; irinotecan hydrochlorise; trastuzumab; valrubicin;
gemcitabine HCL; goserelin acetate; capecitabine; aldesleukin;
rituximab; oprelvekin; interferon alfa-2a; letrozole; toremifene
citrate; mitoxantrone hydrochloride; irinotecan HCL; topotecan HCL;
etoposide phosphate; gemcitabine HCL; and amifostine;
[0190] antisense agents;
[0191] antimycotic agents;
[0192] miotic and anticholinesterase agents such as pilocarpine,
eserine salicylate, carbachol, diisopropyl fluorophosphate,
phospholine iodine, and demecarium bromide;
[0193] mydriatic agents such as atropine sulfate, cyclopentane,
homatropine, scopolamine, tropicamide, eucatropine, and
hydroxyamphetamine;
[0194] differentiation modulator agents;
[0195] sympathomimetic agents such as epinephrine;
[0196] anesthetic agents such as lidocaine and benzodiazepam;
[0197] vasoconstrictive agents;
[0198] vasodilatory agents;
[0199] polypeptides and protein agents such as angiostatin,
endostatin, matrix metalloproteinase inhibitors, platelet factor 4,
interferon-gamma, insulin, growth hormones, insulin related growth
factor, heat shock proteins, humanized anti-IL-2 receptor mAb
(Daclizumab), etanercept, mono and polyclonal antibodies,
cytokines, antibody to cytokines;
[0200] neuroprotective agents such as calcium channel antagonists
including nimodipine and diltiazem, neuroimmunophilin ligands,
neurotropins, memantine and other NMDA antagonists,
acetylcholinesterase inhibitors, estradiol and ananlogues, vitamin
B12 analogues, alpha-tocopherol, NOS inhibitors, antioxidants (e.g.
glutathione, superoxide dismutase), metals like cobalt and copper,
neurotrophic receptors (Akt Kinase), growth factors, nicotinamide
(vitamin B3), alpha-tocopherol (vitamin E), succinic acid,
dihydroxylipoic, acid, fusidic acid;
[0201] cell transport/mobility impending agents such as colchicine,
vincristine, cytochalasin B;
[0202] carbonic anhydrase inhibitor agents;
[0203] integrin antagonists; and lubricating agents, singly or in
combinations thereof.
[0204] This listing of therapeutic agents is illustrative, and not
exhaustive. Other drugs that could be delivered by the ocular
implant include, for example, thalidomide.
[0205] Reference can be made to Remington's Pharmaceutical
Sciences, Mack Publishing Press, Easton, Pa., U.S.A., to identify
other possible therapeutic agents for the eye. Any pharmaceutically
acceptable form of the agents can be used, such as the free base
form or a pharmaceutically acceptable salt or ester thereof.
[0206] Among other things, this invention includes dual mode
implants and related treatments effective to saturate all
compartments of the eye via large initial loading dose release and
then provide a sustained maintenance dosage to the target area of
the eye thereafter over an extended period of time. Because the
ocular tissues are not homogenous, and also because many drugs to
be used in the eye are lipophilic, ideally a large loading dose
should be initially delivered by an ocular implant, and once all
the tissues of the eye are saturated, then uniform lower yet
maintenance levels of the drug need to be released over an extended
period of time by the implant which can more easily gravitate to
the target areas of the eye for treatment.
[0207] The Examples that follow are intended to illustrate, and not
to limit, the invention. All percentages used herein-are by weight,
unless otherwise indicated.
EXAMPLE 1
[0208] This example illustrates the preparation of a matrix,
implant of the invention useful for subconjunctival implants.
[0209] 4.5 g of superhydrolyzed polyvinyl alcohol (Airvol 125, Air
Products and Chemicals, Inc., Allentown, Pa., U.S.A.) was added to
30 ml of molecular biology grade water in an assay tube that was
then tightly closed. The tightly closed assay tube was placed in a
beaker of boiling water until the density becomes uniform
(generally about 3-7 hrs). Since the assay tube was tightly closed,
the contents could not evaporate. Water was periodically replaced
in the beaker to keep the water height near the height of water in
the assay tube. The assay tube was centrifuged for 1 minute at
1000-4000 rpm to degass the mixture. This formed a 15 wt % solution
of superhydrolyzed polyvinyl alcohol.
[0210] Separate premixtures were prepared using each of
cyclosporine A and 2ME2 as the therapeutic agent. Each therapeutic
agent was separately premixed in a solution of hydroxypropyl
methylcellulose (HPMC), obtained as METHOCEL E4M from Dow Chemical,
Midland Mich., in amount of 0.05 wt % about (on a dry basis; drug
plus HPMC). In this regard, 500 mg of drug was combined and mixed
with 2.25 g HPMC. For instance, the cyclosporine A (or 2ME2) powder
was placed in microbiology grade water (i.e., endotoxin free water)
with the HPMC and mixed with a stir bar, no heat, for up to 24
hours. The superhydrolyzed PVA solution was then combined with the
HPMC/drug mixture with a spatula. For more highly viscous
suspensions, a blender may be desirable. As such a blender, a
MiniContainer is adapted to the blender to hold small volumes,
where the blender is a Laboratory Blender (Model 51BL30), operated
at speeds of 18,000 rpm (low) or 22,000 rpm (high) as needed. The
Mini Container (MMGC1) was stainless steel and held 12-37 ml, and
was obtained from Waring Factory Service Center, Torrington, Conn.
To add the materials to a blender, a bottom of the assay tube
containing the PVA/METHOCEL/drug mixture is cut with a razor blade
and the contents poured into the blender. In one method, the
mixture is blended at high speed (22K RPM) for up to 5 minutes, and
the blended contents are then poured into a 50 ml assay tube and
centrifuged for 2 minutes at 1000-4000 rpm to degas it.
[0211] The resulting highly viscous superhydrolyzed PVA/HPMC/drug
mixtures were injected with a large volume syringe between 2 glass
plates (6.times.6 inches). Spacers (1-5 mm thick) were placed
between the glass plates. This allowed a measured thickness of
mixture to be applied to the glass plate. This complex was the
placed at 0.degree. C. for up to 30 minutes. Chilling the glass
plates sufficient that the top glass plate could be removed without
impairing the matrix layer. The top plate was removed in this
manner. The mixture was then left attached to the other bottom
glass plate and allowed to air dry at room temperature for
approximately 15 hours. To make dual mode subconjunctival matrix
implants, compressed drug pellets were formed to the desired
dimensions using a Parr pellet press (Parr Instrument Co., Moline
EL, USA). Also, before the above-mentioned chilling step performed
on the glass plates, the top glass plate was temporarily moved
sufficient to permit access to the surface of the wet coating so
that the pellet could be lightly pushed or tapped on its upper
surface, such as using a Bowman's probe, into the wet coating layer
deep enough that the pellet is completely immersed and embedded
within the coating layer. At least one mm coating is provided on
each side of the pellet in this example, although smaller uniform
thicknesses could be used. The top glass plate was replaced again
over the surface of the coating layer (now containing the embedded
pellet), and the glass plates were chilled as described above.
Then, the top glass plate was removed.
[0212] After the slab had dried for about 15 hours, trephines (skin
Biopsy Punches) (Acuderm Inc., Ft. Lauderdale, Fla.) of varying
diameters were used to make the implants. A trephine of dimensions
of at least 1 mm greater than pellet diameter was used to punch out
pellets. The punched pieces were permitted to sit for 48 additional
hours and then irradiated with a low dosage of (e.g., about 3
megarads of gamma radiation) for sterilization purposes only, such
that significant levels of crosslinking does not occur.
EXAMPLE 2
[0213] This example illustrates the preparation of another matrix
implant of the invention, which is useful as an intravitreal
implant. Alternatively, this matrix implant can be used for an
inlay used in combination with reservoir implants of the invention
described elsewhere herein.
[0214] Preparation of 50% Superhydrolyzed PVA, 6% 2ME2, 0.05% HPMC
Matrix Implant:
[0215] The polymer drug mixture was prepared in a 3 cc syringe (the
tip sealed with a Luer lok and a HPLC septum). The plunger was
removed. A drug emulsion was prepared by adding 63.8 mg 2ME2 and
0.5 mg hydroxypropyl methylcellulose (E4M, Dow Chemical) to 2 ml
molecular grade biological water. The emulsion was mixed with a
magnetic stirrer over night, and then it was added to 1 g
superhydrolyzed PVA (Airvol 125; Air Products and Chemicals, Inc.,
Allentown, Pa., U.S.A.) in the syringe. The mixture was stirred
until uniform and then placed into a water bath at about
100.degree. C. for 60 minutes. The sample with the syringe was then
spun down for 2 minutes at 2000 rpm to dislodge air bubbles. It was
then returned to the 100.degree. C. water bath for 15 minutes to
make it pliable. The original plunger was inserted into the syringe
and a small hole was made just above the drug/polymer sample to
prevent reintroduction of air into the sample. The tip of the
syringe was then cut off and the sample ejected onto a glass plate.
Using spacers, another plate is used to sandwich the sample the
resulting sandwich is then cooled at 5.degree. C. for 30 minutes.
The glass plates were separated and the sample dried under ambient
conditions for 24 hours and then under vacuum for 48 hours. The
implants were then cut to size using a razor blade. For dual mode
implants made from this slab, 0.5 mm drug pellets (generally 0.3 to
1.0 mm long and about 100 .mu.g to 500 .mu.g) were inserted into
the space between the glass plates before refrigerating. This was
done by placing the pellets in the coating layer at the edges
thereof where the two glass plates come together and the coaling
layer is exposed. Once the PVA slab was desiccated, the dual action
implants were cut in the desired shape (e.g., circular) leaving the
desired amount of drug loaded PVA around the drug pellet.
EXAMPLE 3
[0216] A 1.times.1.times.2 mm matrix implant was prepared using
poly(ethylene vinyl) acetate (EVA) in place of superhydrolyzed PVA
in the subconjunctival implant.
[0217] Preparation of 30% EVA, 6% 2ME2, 0.05% HPMC Matrix
Implants:
[0218] The polymer drug mixture was prepared in a 3 cc syringe (the
tip sealed with a Luer lok and a HPLC septum). The plunger is
removed. A drug emulsion is prepared by adding 38.3 mg 2ME2 and 0.3
mg HPMC (E4M, Dow Chemical) to 2 ml methylene chloride. The
emulsion is mixed over night with a magnetic stirrer and then
transferred to a 10 ml vial containing 0.6 g EVA (Elvax 40W,
Dupont). The mixture was stirred with a magnetic stirrer until it
becomes too viscous. The magnetic stirrer was then removed and the
mixture was left overnight. The sample was centrifuged as needed to
degas the specimen. The specimen was poured onto a glass plate and
permitted to dry for 48 hours under vacuum. The implants were then
cut to size using a razor blade, e.g., multiple 1.times.1.times.2
mm slabs or wafers. For dual mode implants, 0.5 mm drag pellets
that are generally 0.3 to 1.0 mm long and about 200 .mu.g) are
inserted until fully embedded in a centered manner in the wet
EVA/drug mixture after it was poured out on the glass. Once the
slab was desiccated, the dual action implants were cut leaving a
desired amount of drug loaded EVA around the drug pellet.
EXAMPLE 4
[0219] Matrix implants of this invention were used in a study to
document the in vitro release rates of single and dual mode CsA
implants to evaluate their usefulness for the treatment of eye
diseases, such as high risk corneal transplantation. In addition,
to evaluate the feasibility of using these implants in humans,
rabbit studies were performed to assay the ocular drug levels
following the insertion of these implants in the subconjunctival
space. The ocular toxicity of these implants were evaluated by
electroretinography (a test of retinal function) and
histopathology.
[0220] Methods:
[0221] In Vitro Studies
[0222] Two matrix implant designs were studied, i.e. single and
dual mode CsA implants, designated Matrix Implant (1) and (2),
respectively.
[0223] A Matrix Implant (1) was made generally according to the
protocol described in Example 1 except without adding the drug
pellet. That is, a superhydrolyzed PVA solution made using 4.5
grams of Airvol 125 (Air Products and Chemicals, Inc., Allentown,
Pa., U.S.A.), in solution, was combined with 5 ml of an emulsion of
CsA. The CsA emulsion was separately previously prepared as a
premixture of 0.5 g powdered CsA, (USP-23, Xenos Bioresources,
Inc., Santa Barbara, Calif.) and 0.0023 g HPMC (METHOCEL E4M,
obtained from Dow Chemical, Midland, Mont.) in 5 ml of microbiology
grade water. The combined PVA and CsA/HPMC solutions gave a 10% CsA
concentration by weight. The PVA/HPMC/CsA aqueous mixture was mixed
at 70.degree. C. for 30 minutes. The PVA/HPMC/drag suspension was
placed between glass plates. Upon drying, a uniform film of 0.5-mm
thickness was produced in the manner described in Example 1. A 3-mm
trephine was used to cut circular implant discs from the resulting
film.
[0224] Matrix Implant (2) was made using the same procedure as
above except a 1.5 mg compressed CsA drug pellet of a thickness of
2.0 mm was embedded within the center of the circular disc. To
embed the pellet, the pellet was embedded within the coating layer
in the manner described in Example 1.
[0225] In-vitro release rates were determined by placing the
implants in PBS (pH 7.4) at 37.degree. C. and assaying drug levels
over time by HPLC.
[0226] In Vivo Studies:
[0227] Ocular Drug Levels:
[0228] Eight New Zealand White rabbits (16 eyes) of either sex
weighing 2-3 kg were used in this study and the procedures adhered
to the guidelines from the Association for Research in Vision and
Ophthalmology for animal use in research. Animals were anesthetized
with ketamine hydrochloride (Fort Dodge, Inc., Fort Dodge, Ind.)
(35 mg/kg) IM, xylazine (Phoenix Scientific, Inc., St. Joseph, Mo.)
(5 mg/kg) IM, and proparacaine 1% ophthalmic drops (Allergan
America, Hormigueros, Puerto Rico) were used topically on the eye.
A lid speculum was placed and a 4 mm conjunctival radial incision
was made through the conjunctiva 1 mm from the limbus and 3 mm
nasal to the superior rectos muscle. Wescott scissors were used to
dissect posterior to Tenon's fascia and the implant was inserted
with its anterior edge 3 mm from the limbus and secured to the
episclera using a single interrupted 10-0 suture. The conjunctiva
was reapproximated using a running 10-0 suture. In vivo studies
were performed using the dual mode CsA implant because of its
potential to release CsA for an extended period of time to treat
eye diseases. The right eye of each rabbit received a dual mode CsA
implant. Postoperatively, bacitracin-neomycin-polyrayxin ophthalmic
ointment (Pharmaderm, Melville, N.Y.) was placed in both eyes twice
daily (2.times./day) for 3 days. The animals were examined
regularly and euthanized with a pentobarbital overdose (B
euthanasia-D Special, Scheming-Plough Animal Health Corp.,
Kemilworth, N.J.) 2 months post-implantation. Both eyes were
enucleated. Eyes from 5 rabbits had a 5.times.5 mm section of
conjunctiva both over the implant and 180.degree. away isolated for
drug extraction. The implants were firmly attached to the episclera
and they were gently peeled away from the underlying tissues. The
globes were immediately frozen at -70.degree. C. for later
dissection and drug extraction. The time from enucleation to
freezing was rapid (<10 seconds) which limited postmortem drug
redistribution. The eyes were dissected while frozen and a
5.times.5 mm section of full thickness sclera beneath the implant
and 180.degree. away was isolated. Other tissues (cornea, aqueous
humor, lens, and vitreous humor) were isolated for separate drug
analysis. The CsA was extracted from the tissues by the addition of
an equivalent weight of HPLC grade Acetonitrile (Burdick &
Jackson, Inc., Muskegon, Mich.), sonicated for 45-90 seconds with a
model GEX 600 Ultrasonic processor (Thomas Scientific, Swedesboro,
N.J.) and incubated for 24 hours at room temperature. The samples
were spun down in a TOMY MTX-150 centrifuge (Peninsula Laboratories
Inc., Belmont, Calif.) for 30 minutes at 10,000 rpm and the
supernatants were submitted for HPLC analysis. The CsA
concentrations in the tissues were expressed as .mu.g/g wet weight
(mean) for the solid tissues and .mu.g/ml (mean) for the aqueous
and vitreous humor.
[0229] Eyes from 3 rabbits were placed in formalin 10% (Biochemical
Science, Inc., Swedesboro, N.J.) for at least 7 days, embedded in
paraffin, and sectioned for histopathology.
[0230] Ocular Toxicity Testing (Electroretinography):
[0231] The rabbits were anesthetized using the same procedures
detailed above and the pupils were dilated with 1 drop of
phenylephrine hydrochloride 2.5% (Alcorn, Inc., Decatur, Ill.) and
tropicamide 1% (Alcon, Inc., Humacao, Puerto Rico). ERGs were
recorded from each eye separately after 30 minutes of dark
adaptation. A monopolar contact lens electrode (ERG-jet, La Chaux
des Fonds, Switzerland) was placed on the cornea and served as a
positive electrode. Subdermal needle electrodes inserted in the
forehead area and near the outer canthus served as the ground and
negative electrodes, respectively. ERGs were elicited by flash
stimuli delivered with a Grass PS22 photostimulator (Grass
Instruments, Quincy, Mass.) at 0.33 Hz. Responses were amplified,
filtered and averaged with a Nicolet Spirit signal averager
(Nicolet Instruments Corp., Madison, Wis.). Averages of 20
responses were measured to obtain amplitude and implicit time
values of a-waves and b-waves. Recordings were performed at
baseline, and 1 and 2 months post-implantation. A permutation test
of mean amplitude differences and analysis of variance of the
logarithmic transform of amplitudes were performed to determine
statistically significant changes between readings.
[0232] Results:
[0233] The single mode Matrix Implant (1) produced an initial
loading dose of CsA (12.54+/-1.47 .mu.g/day) with a logarithmic
decline to <0.5 .mu.g/day by day 31 (see FIG. 4A), while Matrix
Implant (2) produced an initial loading dose of CsA (39.9+/-10
.mu.g/day) with a logarithmic decline in release rate to
7.67+/-1.79 .mu.g/day by day 38 (FIG. 4B). Daily release rates
reached a steady state release of 6 .mu.g/day after day 40 and the
release rates were predicted to be stable for 18 months.
[0234] CsA Levels in Tissues:
[0235] Five rabbits had the eye with the dual mode CsA implant
processed to determine CsA concentrations. The distribution of the
CsA in the eye is shown in FIG. 13. Corneal levels of 2.25 .mu.g/g
(mean) were present which are potentially therapeutic for the
treatment of graft rejection. Unexpectedly, an unusually high
concentration of CsA was present in the vitreous (21.78 .mu.g/ml
(mean)) which can potentially be therapeutic for the treatment of
posterior segment inflammatory diseases.
[0236] Ocular Toxicity Testing:
[0237] Electroretinography showed no signs of retinal toxicity from
the CsA implants. Histopathologic examination of eyes from 3
rabbits with the dual mode implant was performed by light
microscopy. The conjunctiva overlying the implant and the sclera
beneath was intact. All ocular structures appeared intact with a
mild chronic inflammatory infiltrate present in the substantia
propia of the conjunctiva overlying the implants in all eyes. The
peripheral retina anterior to the equator showed some vacuolated
spaces predominantly in the photoreceptor layer in both eyes but
the photoreceptor layer in the posterior segment of the eye along
the medullary rays was normal.
[0238] Conclusions:
[0239] These results demonstrated that single mode Matrix Implant
(1) subconjunctival implant can deliver potentially therapeutic
levels of CsA to the eye for approximately a month. The dual mode
Matrix Implant (2) subconjunctival implant could deliver an initial
loading dose of CsA lasting 1 month followed by a steady state
sustained-release delivery of CsA as a maintenance dose for at
least 1 year. The implants were determined to be reasonably safe by
Mstopathological examination and by electroretinography.
[0240] The implant was initially designed to release CsA into the
cornea for prevention of graft rejection in patients with high risk
corneal allografts. To this end, the implants delivered potentially
therapeutic levels of CsA to the cornea. This study revealed an
unexpected finding that the dual mode implant representing an
embodiment of this invention delivered high levels of CsA in the
vitreous cavity. Since the vitreous cavity is in direct contact
with the retina and the other important tissues of the eye, the
subconjunctival implant (which is installed outside the eye) has
the potential to treat many intraocular diseases.
EXAMPLE 5
[0241] A study was performed to investigate the use of
2-methoxyestradiol in intravitreal matrix implants of this
invention in a rat model of choroidal neovascularization (CNV).
[0242] Methods:
[0243] Implant Design:
[0244] 2ME2 dry powder was premixed in a solution containing 0.05%
HPMC then mixed with a 50% polyvinyl alcohol (PVA) solution to
produce a 6% (by dry weight) 2ME2 matrix suspension (see example 2
for details). The suspension was poured onto a glass plate
producing a thin firm, dried at room temperature, and cut into
1.0.times.1.0.times.2.0 mm sections, each section representing one
implant. Sham implants (PVA without drug) were made in a similar
fashion. In-vitro release rates were determined by placing the
implants in PBS and assaying drug concentrations over time with
HPLC.
[0245] CNV Model:
[0246] Fifteen Brown-Norway rats were used. An El-deleted
adenoviral vector encoding human VEGF165 was injected
(2.5.times.10.sup.4 pfu/.mu.L) into the subretinal space nasal to
the disc of one eye using a 32 gauge needle. In the same eye, a 2
mm full-thickness scleral incision was made temporally and 2ME2
implants were placed in the vitreous cavity of 9 eyes and sham
implants placed in 8 eyes. The sclerotomy was closed using a 10-0
nylon suture. Five rats (3 with 2ME2 and 2 with sham implants) were
euthanized at 1 week. Five rats (2 with 2ME2 and 3 with sham
implants) were euthanized at 2 weeks. Five rats (2 with 2ME2 and 3
with sham implants) were euthanized at 3 weeks. The implant eyes
were enucleated, fixed in formalin and embedded in
methacrylate-JB4. The eyes were sectioned in the area of injection
(75 total, 3 .mu.m sections), counterstained with H&E and
examined with a light microscope for choroidal neovascularization.
The maximal axial length of the CNV was recorded in
micrometers.
[0247] Results:
[0248] In Vitro Release Rates of 3 Implants:
[0249] The mean in-vitro release rates (graph below) followed first
order kinetics, typical of matrix implants. The implants released
2ME2>1 (.mu.g/day over 30 days, as shown in FIG. 15.
[0250] CNV Model:
[0251] CNV was present in 1/9 eyes with the 2ME2 implant: the axial
length of the one membrane=46.5 .mu.m. A proliferation of RPE cells
in a bi or tri-layer was present in all 3 eyes at 1 week. CNV was
present in 5/8 eyes with the sham implant: mean axial length=347.4
.mu.m.
[0252] Results:
[0253] These results demonstrated that the sustained-release 2ME2
microimplants representing this invention can successfully suppress
choroidal neovascularization in a rat model.
EXAMPLE 6
[0254] The dual mode reservoir implants were made and tested in
vitro for release rate behavior.
[0255] Methods:
[0256] Three designs were constructed using 2ME2 compressed in a
customized Parr pellet press to 190 lb force.
[0257] Design Summary:
[0258] Design A: A 2ME2 pellet (3 mm, mean weight 23.0 mg) was
coated with 0.20 mm silicone (using 8 gauge, 3.28 mm internal
diameter PTEE (Teflon) tubing from Texloc, LTD. Fort Worth,
Tex.);
[0259] Design B: A 2ME2 pellet (2 mm, mean weight 10.5 mg) was
coated with 0.36 mm silicone (using 10 gauge, 2.59 mm internal
diameter PTFE tubing);
[0260] Design C: A 2ME2 pellet (2 mm, mean weight 10.5 mg) was
coated with 0.70 mm silicone (using 8 gauge, 3.28 mm internal
diameter PTFE tubing)
[0261] A microcentrifuge having an ID of about 10 mm and a length
of about 40 mm, was obtained from Peninsula Laboratories Inc.,
Belmont, Calif. U.S.A. The microcentrifuge tube was filled with
MED-6810 about 10 mm in depth.
[0262] To make uniform silicone coatings of 0.20 mm, 0.36 mm and
0.70 mm around the drug pellets, thin walled plastic tube (PTFE
Teflon tubing from Texloc, LTD., Fort Worth, Tex.) was used. The
PTFE tubing was heated at 110 degrees celcius for 30 seconds and
then straightened, cut into 1.0 inch (2.54 cm) long tubes, and
thereafter cooled and set in the straightened orientation in the
microcentrifuge tube. The microcentrifuge tube was centrifuged to
degas the wet silicone and to radially center the PTFE tube. The
silicone was then cured with heat (100.degree. C. for 30 minutes).
The pellet sizes and PTFE tubing diameters used for the 3 designs
are detailed supra.
[0263] The 2ME2 drug pellet was introduced into the PTFE tubing
followed by adding additional fresh MED-6810 silicone sufficient to
immerse the pellet. The microcentrifuge tube was then centrifuged
as needed to degas the additional silicone. As needed, the drug
pellet was manually or mechanically centered on the silicone base
before curing the added silicone using a Bowman probe. Drug loading
was performed using the "delay in cure" technique. That is, the
pellets were left in the wet silicone for a total of 1 hour and
then cured for 1 hour at 100.degree. C.
[0264] In vitro release rates were determined by placing the
implants in 20 mL of phosphate buffered saline pH 7.4 maintained at
37.degree. C. for 3 hours. The concentration of 2ME2 in the vial
was determined by HPLC and the release rates of drug from the
implants were recorded as .mu.g/day (microgram/day).
[0265] Results:
[0266] The release rates for the different implant designs are
shown in FIG. 15. FIG. 16 tabulates the results. As was
demonstrated, dual mode reservoir implants representing this
invention can be manufactured to release predictable loading and
maintenance doses. Using the delay in cure technique effectively
loads the surrounding silicone for the burst effect and changing
the thickness of the silicone coating surrounding a 2ME2 drug
pellet can alters the maintenance release rate of the implant.
Design B was chosen for the rabbit studies, described in Example 7
infra, because of its superior durability, optimal release rate,
and desirable life span.
EXAMPLE 7
[0267] To evaluate the feasibility of using the implants of this
invention for human diseases, such as choroidal neovascularization,
rabbit studies were performed using 2ME2 intravitreal implants.
Drug extraction techniques were done to assay the ocular drug
levels following the insertion of these implants in the vitreous
cavity. The ocular toxicity of these implants were evaluated by
electroretinography (a test of retinal function) and
histopathology.
[0268] 2ME2 powder was obtained from EntreMed Inc., Rockville Md.
For this study, we chose a dual mode reservoir implant of Design B
releasing 2ME2 as described in Example 6.
[0269] Ocular Drug Levels:
[0270] Seven rabbits had 2ME2 implants (Design B) surgically placed
in the vitreous cavity of the right eye as follows: All procedures
on animals were performed in accordance with protocols approved by
the Animal Care and Use Committee. Male and female New Zealand
white rabbits, weighing 2-3 kg were anesthetized with intramuscular
ketamine (35 mg/kg) and xylazine (5 mg/cg). One drop of
proparicaine (1%) was placed in the inferior fornix for topical
anesthesia, and the pupils were dilated with 1 drop of
phenylephrine hydrochloride (2.5%) and topicamide (1%). Using
sterile procedures, a lid speculum was placed in the right eye, and
a fornix-based conjunctiva! flap was made in the superotemporal
quadrant. A 4 mm sclerostomy was made 3 mm posterior to the
surgical limbus. The drug implant was inserted through the incision
into the vitreal cavity. Prolapsed vitreous was excised as needed
using a week cell vitrectomy technique. The sclerostomy was closed
using 8-0 nylon and the conjunctiva was reapproximated to the
limbus using 10-0 vicryl. The eye was injected with balanced salt
solution as necessary to normalize the intraocular pressure.
Indirect ophmalmoscopy was done to confirm placement of the implant
in the vitreal cavity. Bacitracin ophthalmic ointment was applied
twice daily for three days.
[0271] Four rabbits were sacrificed at 1 month post-implantation
and 3 rabbits at 3 months. The right eye of each rabbit was removed
and the tissues processed for 2ME2 drug levels. Following
enucleation the eyes were frozen at -80.degree. C. in order to
prevent drug redistribution. The drug extraction procedure was as
follows: the eyes were dissected while frozen and an equal weight
of acetonitrile was added to extract the drug from the aqueous
humor, vitreous humor, and blood. The specimens were sonicated,
centrifuged, and the drug levels in the supernatant determined by
HPLC.
[0272] Ocular Toxicity Testing:
[0273] The details of the electroretinography procedure in rabbit
is described in Example 4. Six NZW rabbits had 2ME2 implants
(Design B) surgically placed in the vitreous cavity of the right
eye (OD) and a sham implant in the left eye (OS). The rabbits had
their eyes examined clinically and serial electroretinography (ERG)
performed to assess for drug toxicity over a 6 month period. The
rabbits were sacrificed at 6 months post-implantation and their
eyes were processed for histopathology. The results are summarized
below.
[0274] Ocular and Blood Drug Levels:
[0275] The 2ME2 levels in the vitreous humor, the tissue that has
ultimate contact with the retina, were in the therapeutic range for
the control of angiogenesis (see FIG. 17). There was no detectable
level of 2ME2 in the blood.
[0276] Ocular Toxicity:
[0277] The electroretinograms showed no abnormalities over the 6
month period. The clinical examinations and histopathology showed
no signs of ocular toxicity.
[0278] Results:
[0279] The 2ME2 levels in the vitreous treated with implants
representing this embodiment of the invention are potentially
therapeutic levels to treat choroidal neovascularization. Since
there were no detectable drug levels in the blood of these rabbits,
the risk of systemic toxicity from drug released by the ocular
implant are negligible.
EXAMPLE 8
[0280] A study was performed to compare the efficacy in a rat model
of choroidal neovascularization (CNV) of triamcinolone acetonide
(TAAC) in intravitreal matrix implants of this invention to a
comparison implant.
[0281] Methods:
[0282] Implant Design:
[0283] Design A1: (Comparison Reservoir Design):
[0284] A compressed TAAC pellet (0.5 nun diameter at 120 lb-force)
was coated with medical grade silicone (final implant dimensions
1.times.2.5 mm).
[0285] Design B1: (Single Mode Matrix Design According to this
Invention):
[0286] TAAC dry powder was premised with 0.05% HPMC then mixed with
a 20% polyvinyl alcohol (PVA) solution to produce a 5% (by dry
weight) TAAC matrix suspension (see example 2 for details). The
suspension was poured onto a glass plate producing a thin film,
dried at room temperature, and cut into 1.times.1.times.2.5 mm
sections, each section representing one matrix implant.
[0287] In-vitro release rates were determined by placing the
implants in PBS and assaying drug concentrations over time with
HPLC.
[0288] CNV Model:
[0289] To induce experimental CNVM formation, a series of 8 laser
photocoagulation sites were concentrically placed around the optic
disk (of 1 eye) followed by surgical placement of either a Design
A1, Design B1, or sham implant (3 animals minimum in each group).
The surgical procedure for implant insertion was similar to that in
Example 5. At 35 days, the eyes were enucleated, fixed in formalin
and embedded in methacrylate-JB4. The eyes were sectioned in the
area of injection, counterstained with H&E and examined with a
light microscope for choroidal neovascularization. The CNVM at each
laser burn was quantified by measuring the thickness and the mean
value for each eye was recorded.
[0290] Results:
[0291] In Vitro Release Rates:
[0292] Design A1 followed constant release kinetics and the release
was 1.96.+-.1.73 .mu.g/day over a 28 day period.
[0293] Design B1 followed first-order kinetics with an initial
release rate 42.8.+-.1.73 .mu.g/day over the initial 48 hours;
decreasing to 1.94.+-.1.46 .mu.g/day by day 28. These results are
graphically shown in FIG. 18.
[0294] CNV Model:
[0295] In the eyes with the sham implants, CNV development was very
rapid and occurred at 3-7 days after lesion induction and was
sustained over 4 weeks. The mean CNVM thickness at 35 days with the
sham implant (no drug) was 55.+-.10 .mu.m. The mean values for eyes
with Design A implant was 35-50 .mu.m; Design B implant, 15-20
.mu.m.
[0296] Results:
[0297] These results demonstrate that Design B1, a single mode
matrix design representing an embodiment of this invention, was
more effective in suppressing CNV in a rat laser model compared
with a comparative reservoir device representing the prior art.
Design B1 implants delivered a large loading dose of drug that may
be more effective for the treatment of CNV that the low dose
delivery of implant represent the prior art. Most effective for
human may be a loading dose of an angiostatic steroid followed by a
low dose maintenance delivery to promote dormancy of the lesion
over time. However, rat models of CNV only last 4-5 weeks and these
dual mode implants cannot currently be assessed adequately.
[0298] While the invention has been described in terms of preferred
embodiments, those skilled in the art will recognize that the
invention can be practiced with modification within the spirit and
scope of the appended claims.
* * * * *