U.S. patent application number 11/552835 was filed with the patent office on 2008-04-24 for ocular implant delivery assemblies.
This patent application is currently assigned to ALLERGAN, INC.. Invention is credited to James N. Chang, Robert T. Lyons, Michael R. Robinson, John T. Trogden.
Application Number | 20080097335 11/552835 |
Document ID | / |
Family ID | 38668682 |
Filed Date | 2008-04-24 |
United States Patent
Application |
20080097335 |
Kind Code |
A1 |
Trogden; John T. ; et
al. |
April 24, 2008 |
OCULAR IMPLANT DELIVERY ASSEMBLIES
Abstract
Ocular implant delivery assemblies are provided which include a
cannula having a lumen extending therethrough, a proximal end, a
proximal end opening, a distal end, a distal end opening, and a
lumen extending through the cannula. A removable distal closure
element is provided for closing the distal end opening, and a
removable proximal closure element is provided for closing the
proximal end opening. An ocular implant is located in the lumen.
The implant may be sealed in the cannula without the addition of a
liquid carrier or it may be contained in a liquid carrier medium in
the cannula. The implant may be made up of a number of
microparticles having different compositions or different forms.
The assembly also includes a sleeve located on the proximal end of
the cannula and suitable for coupling the assembly to a syringe
containing a pushing gel.
Inventors: |
Trogden; John T.; (Anaheim,
CA) ; Lyons; Robert T.; (Laguna Hills, CA) ;
Chang; James N.; (Newport Beach, CA) ; Robinson;
Michael R.; (Irvine, CA) |
Correspondence
Address: |
ALLERGAN, INC.
2525 DUPONT DRIVE, T2-7H
IRVINE
CA
92612-1599
US
|
Assignee: |
ALLERGAN, INC.
Irvine
CA
|
Family ID: |
38668682 |
Appl. No.: |
11/552835 |
Filed: |
October 25, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60835488 |
Aug 4, 2006 |
|
|
|
Current U.S.
Class: |
604/192 ;
604/59 |
Current CPC
Class: |
A61F 9/0017 20130101;
A61K 9/0051 20130101 |
Class at
Publication: |
604/192 ;
604/59 |
International
Class: |
A61M 5/178 20060101
A61M005/178 |
Claims
1. An ocular implant delivery assembly comprising: a cannula having
a proximal end, a proximal end opening, a distal end, a distal end
opening, and a lumen extending through the cannula; a removable
distal closure element positioned relative to the cannula to close
the distal end; a removable proximal closure element positioned
relative to the cannula to close the proximal end; and an ocular
implant sized and adapted for implantation in an eye, the ocular
implant being located in the cannula.
2. The assembly of claim 1 wherein the cannula has an outside
diameter no larger than a 25 gauge syringe needle.
3. The assembly of claim 1 wherein the lumen has a diameter of less
than about 350 microns.
4. The assembly of claim 1 further comprising a carrier medium
located in the cannula.
5. The assembly of claim 4 wherein the ocular implant comprises
particles suspended in the carrier medium.
6. The assembly of claim 4 wherein the carrier medium comprises an
aqueous component and a viscosity inducing component.
7. The assembly of claim 1 wherein the ocular implant comprises a
corticosteroid component.
8. The assembly of claim 1 wherein substantially no liquid material
is present in the lumen with the ocular implant.
9. The assembly of claim 1 wherein the distal closure element
covers the distal end and the distal end opening.
10. The assembly of claim 1 wherein the distal closure element
comprises a polymeric material.
11. The assembly of claim 1 wherein the distal closure element
composes a silicone polymeric material.
12. The assembly of claim 1 wherein the proximal closure element is
positioned in or substantially directly adjacent the proximal end
opening of the cannula.
13. The assembly of claim 1 wherein the proximal closure element is
positioned to seal the proximal end opening of the cannula.
14. The assembly of claim 1 wherein the proximal closure element
comprises a polymeric material.
15. The assembly of claim 1 which further comprises an enlarged
sleeve coupled to the cannula and extending proximally of the
cannula, the sleeve being structured and positioned to facilitate
coupling the cannula to a syringe.
16. The assembly of claim 1 wherein the ocular implant comprises a
plurality of particles.
17. The assembly of claim 1 wherein the ocular implant comprises a
plurality of particles in a one-by-one array along the length of
the lumen.
18. The assembly of claim 1 wherein the ocular implant comprises a
plurality of particles selected from the group consisting of
spheres, rods, filaments, plaques and combinations thereof.
19. The assembly of claim 1 wherein the ocular implant comprises a
plurality substantially uniformly sized microspheres.
20. The assembly of claim 16 wherein the plurality of particles
includes a number of particles in a range of about 10 to about
200.
21. The assembly of claim 16 wherein the plurality of particles
includes at least one of particles having different compositions
and particles having different release rates.
22. The assembly of claim 1, further comprising a force applying
assembly coupled to the cannula and being structured, when
activated to provide a force effective to urge the implant to exit
the distal end of the cannula.
23. An ocular implant delivery assembly comprising: a cannula
having a proximal end, a proximal end opening, a distal end, a
distal end opening, and a lumen extending through the cannula; a
removable distal closure element sealing the distal end opening; a
removable proximal closure element sealing the proximal end
opening; an ocular implant sized and adapted for implantation in an
eye, the ocular implant being located in the cannula; and a carrier
medium located in the lumen.
24. The assembly of claim 23 wherein the carrier medium comprises a
viscosity inducing component.
25. The assembly of claim 23 wherein the implant is substantially
insoluble in the carrier medium.
26. The assembly of claim 23 wherein the implant comprises a
plurality of particles in the carrier medium.
27. The assembly of claim 23 wherein the implant comprises a
therapeutic component and a polymer component.
28. The assembly of claim 23 wherein the implant comprises a
corticosteroid.
29. The assembly of claim 23 wherein the distal closure element
comprises a polymeric material.
30. The assembly of claim 23 wherein the proximal closure element
comprises a polymeric material.
31. An ocular implant delivery assembly comprising: (a) a cannula
having a proximal end, a proximal end opening, a distal end, a
distal end opening, and a lumen extending through the cannula; (b)
an ocular implant sized and adapted for implantation in an eye, the
ocular implant being located in the cannula, and; (c) a distal plug
positioned relative to the cannula to reduce the size of or close
the distal end opening.
32. The assembly of claim 31, wherein the lumen is the lumen of a
25 gauge or higher syringe needle.
33. The assembly of claim 31, wherein the distal plug comprises a
bioerodible polymeric material.
34. The assembly of claim 31, further comprising a force applying
assembly coupled to the cannula and being structured, when
activated, to provide a force effective to urge the implant to exit
the distal end of the cannula.
35. The assembly of claim 34, wherein the distal plug is removable
or can be pierced so as to permit passage of the implant out
through the distal opening of the cannula.
36. The assembly of claim 31, which further comprises (d) a
proximal plug positioned relative to the cannula to reduce the size
of or close the proximal end opening.
37. An ocular implant delivery assembly comprising: (a) a cannula
having a proximal end, a proximal end opening, a distal end, a
distal end opening, and a lumen extending through the cannula; (b)
an ocular implant sized and adapted for implantation in an eye, the
ocular implant being located in the cannula, and; (c) a proximal
plug positioned relative to the cannula to reduce the size of or
close the proximal end opening.
38. The assembly of claim 36, wherein the lumen is the lumen of a
25 gauge or higher syringe needle.
39. The assembly of claim 36, wherein the distal plug comprises a
bioerodible polymeric material.
40. The assembly of claim 36, further comprising a force applying
assembly coupled to the cannula and being structured, when
activated, to provide a force effective to urge the implant to exit
the distal end of the cannula.
Description
RELATED APPLICATION
[0001] This application claims the benefit of Application Ser. No.
60/835,488, filed Aug. 4, 2006, the disclosure of which is
incorporated in its entirety herein by reference.
BACKGROUND
[0002] The present invention generally relates to apparatus useful
in implanting ocular implants in eyes. More particularly, the
invention relates to pre-loaded ocular implant delivery assemblies
for delivering, placing, positioning and the like, ocular implants
in an eye, for example, at one or more of various locations in an
eye, for example, a mammalian eye.
[0003] The mammalian eye is a complex organ comprising an outer
covering including the sclera (the tough white portion of the
exterior of the eye) and the cornea (the clear outer portion
covering the pupil and iris). In a medial cross section, from
anterior to posterior, the eye comprises features including,
without limitation: the cornea, the anterior chamber (a hollow
feature filled with a watery, clear fluid called the aqueous humor
and bounded by the cornea in the front and the lens in the
posterior direction), the iris (a curtain-like feature that can
open and close in response to ambient light), the lens, the
posterior chamber (filled with a viscous fluid called the vitreous
humor), the retina (the innermost coating of the back of the eye
and comprising light-sensitive neurons), the choroid (an
intermediate layer providing blood vessels to the cells of the
eye), and the sclera. The posterior chamber comprises approximately
2/3 of the inner volume of the eye, while the anterior chamber and
its associated features (lens, iris etc.) comprise about 1/3 of the
eye's inner volume.
[0004] Ocular implants containing one or more therapeutic
components combined with matrix components, such as polymeric
components, have been proposed for use, for example, to treat
conditions/diseases of the eye. Such implants have been suggested
for use at various locations in the eye, for example, in the
vitreous, subconjunctivally, anterior chamber and posterior chamber
of the eye.
[0005] Although such prior art implants have taken on various
shapes, forms and configurations, one very useful implant form is a
plurality of variously sized microparticles. For example,
intravitreal injection of conventional microparticles, which
average about 1-100 microns in size, is known and has been
previously practiced. This injection of such microparticles is
usually conducted using the microparticles suspended in a liquid
aqueous medium.
[0006] Another type of implant that has been found to be very
useful is in the form of a rod shape. Dry delivery in the eye of
extruded, rod shaped implants, for example having diameters of
about 450 microns and maximum lengths of 3-6 millimeters, has been
successfully accomplished. However, it would be highly desirable to
reduce the diameter of the implant in order to allow the use of a
narrower gauge needle for injection. Reducing the diameter of such
rod shaped implants often reduces the strength of the implant so
that it breaks up during handling. Moreover, as such a rod shaped
implant is reduced in diameter, the length of the implant gets much
longer (so as to deliver an equal amount of therapeutic component
to the eye) making the implant impractical for use.
[0007] It would be beneficial to provide assemblies including
ocular implants that are useful in delivering ocular implants to
eyes which are pre-packaged and allow for safe, long-term storage
of the ocular implant. It would also be beneficial to provide
assemblies containing ocular implants effective in conveniently
treating an eye in a single procedure and using a delivery needle
that is as narrow as possible.
SUMMARY
[0008] New ocular implant delivery assemblies have been discovered.
The present assemblies are useful in conveniently and controllably
placing ocular implants, for example, substantially biodegradeable
drug delivery ocular implants containing pharmaceutical
compositions, into an eye in a single, relatively straightforward
procedure without causing any substantial breakage or other damage
to the implant. Further, the apparatus enables injection of such
implants, for example but not limited to such implants in the form
of one or more thin filaments or microparticles, into an eye by
means of an exceptionally small cannula or needle, thereby reducing
invasiveness of the injection procedure and accelerating healing
relative to injection of implants by means of more conventionally
sized needles.
Definitions
[0009] For the purposes of this description, the words or terms set
forth herein have the following definitions, unless the context of
the word indicates a different meaning.
[0010] As used herein, an "ocular implant" or "intraocular implant"
refers to a device, element, or elements, that is structured,
sized, or otherwise configured to be placed "in an eye", including
the subconjunctival space. Ocular or intraocular implants are
generally biocompatible with physiological conditions of an eye and
do not cause adverse side effects. Ocular or intraocular implants
may be placed in an eye without disrupting vision of the eye.
[0011] As used herein, "implant" refers to an ocular or intraocular
implant or a drug delivery device which can be inserted into any
number of locations in the eye, and which is designed such that a
controlled amount of desired drug or therapeutic can be released
over time. Such implants, which can be solid or semi-solid, are
biocompatible, and in many but not all cases are formed of a
bioerodible substance, such as a bioerodible polymer.
"Microimplants" refers to such implants having a sufficiently small
cross-sectional area that they can be delivered by assemblies
according to the invention that result in self-sealing of the eye
at the puncture site associated with the delivery. In particular,
such microimplants have dimensions such that they are deliverable
through 21 gauge or 22 gauge or preferably smaller gauge cannulas.
Thin wall versions of 21 gauge needles can be manufactured having
inner or lumen diameters of up to 0.028 inches (711 microns), thus
cylindrical microimplants deliverable through such sized cannulas
will have outer diameters of less than 0.028 inches (711 microns).
Thin wall versions of 22 gauge needles can have inner diameters of
up to 0.023 inches (585 microns), and thus cylindrical
microimplants with diameters of less than 0.023 inches (585
microns) will be deliverable through such sized cannulas. Thin wall
versions of 25 gauge cannulas or needles allow implants having
diameters of about 0.015 inch (about 381 microns) or less, for
example, in a range of about 0.014 inch (about 355 microns) to
about 0.015 inch (about 380 microns) to be delivered through such
cannulas. Microimplants can also have non-circular cross-sectional
geometries for delivery through cannulas having corresponding
cross-sectional geometries. Where the micro-implant has
non-circular cross-section, the cross-sectional area may be up to
0.00025 square inches (0.16 square millimeters) or more, depending
on the particular cross-sectional geometry.
[0012] As used herein, "self sealing" methods of delivering
microimplants into the eye refers to methods of introducing
microimplants through a cannula and into desired locations of a
patient's eye without the need for a suture, or other like closure
means, at the cannula puncture site. Such "self sealing" methods do
not require that the puncture site completely seal immediately upon
withdrawal of the cannula, but rather that any initial leakage is
minimum and dissipates in short order such that a surgeon or
another equally skilled in the art, in his or her good clinical
judgment, would not be compelled to suture or otherwise provide
other like closure means to the puncture site.
[0013] As used herein, a "therapeutic component" refers to a
portion of an ocular or intraocular implant comprising one or more
therapeutic agents or substances used to treat a medical condition
of the eye. The therapeutic component may be a discrete region of
an ocular or intraocular implant, or it may be homogenously
distributed throughout the implant. The therapeutic agents of the
therapeutic component are typically ophthalmically acceptable, and
are provided in a form that does not cause adverse reactions when
the implant is placed in an eye.
[0014] As used herein, a "pharmaceutical composition" is a
formulation which contains at least one active ingredient (for
example a corticosteroid) as well as, for example, one or more
excipients, buffers, carriers, stabilizers, preservatives and/or
bulking agents, and is suitable for administration to a patient to
achieve a desired effect or result. The pharmaceutical compositions
disclosed herein can have diagnostic, therapeutic, cosmetic and/or
research utility in various species, such as for example in human
patients or subjects.
[0015] As used herein, a "drug release sustaining component" refers
to a portion of the ocular or intraocular implant that is effective
to provide a sustained release of the therapeutic agents of the
implant. A drug release sustaining component may be a biodegradable
polymer matrix, or it may be a coating covering a core region of
the implant that comprises a therapeutic component.
[0016] As used herein, "associated with" means mixed with,
dispersed within, coupled to, covering, or surrounding.
[0017] As used herein, "liquid carrier medium" or liquid medium"
means material that is substantially flowable when at room
temperature (i.e. about 20 to about 25 degrees Celsius), and
includes gels and other viscous flowable materials that are useful
to facilitate delivery of solid or semi-solid implants through a
cannula of the inventive assemblies.
[0018] As used herein, an "ocular region" or "ocular site" refers
generally to any area of the eyeball, including the anterior and
posterior segment of the eye, and which generally includes, but is
not limited to, any functional (e.g., for vision) or structural
tissues found in the eyeball, or tissues or cellular layers that
partly or completely line the interior or exterior of the eyeball.
Specific examples of areas of the eyeball in an ocular region
include the anterior chamber, the posterior chamber, the vitreous
cavity, the choroid, the suprachoroidal space, the conjunctiva, the
subconjunctival space, the episcleral space, the intracorneal
space, the epicorneal space, the sclera, the pars plana,
surgically-induced avascular regions, the macula, and the
retina.
[0019] As used herein, an "ocular condition" is a disease, ailment
or condition which affects or involves the eye or one of the parts
or regions of the eye. Broadly speaking the eye includes the
eyeball and the tissues and fluids which constitute the eyeball,
the periocular muscles (such as the oblique and rectus muscles) and
the portion of the optic nerve which is within or adjacent to the
eyeball.
[0020] An "anterior ocular condition" is a disease, ailment or
condition which affects or which involves an anterior (i.e. front
of the eye) ocular region or site, such as a periocular structure,
for example, a periocular muscle, an extraocular structure, an
orbital structure, an eye lid or an eye ball tissue or fluid which
is located anterior to the posterior wall of the lens capsule or
ciliary muscles. Thus, an anterior ocular condition primarily
affects or involves the conjunctiva, the cornea, the anterior
chamber, the iris, the posterior chamber (behind the retina but in
front of the posterior wall of the lens capsule), the lens or the
lens capsule and blood vessels and nerve which vascularize or
innervate an anterior ocular region or site.
[0021] Thus, an anterior ocular condition can include a disease,
ailment or condition, such as for example, aphakia; pseudophakia;
astigmatism; blepharospasm; cataract; conjunctival diseases;
conjunctivitis; corneal diseases; corneal ulcer; dry eye syndromes;
eyelid diseases; lacrimal apparatus diseases; lacrimal duct
obstruction; myopia; presbyopia; pupil disorders; refractive
disorders and strabismus. Glaucoma can also be considered to be an
anterior ocular condition because a clinical goal of glaucoma
treatment can be to reduce a hypertension of aqueous fluid in the
anterior chamber of the eye (i.e. reduce intraocular pressure).
[0022] A "posterior ocular condition" is a disease, ailment or
condition which primarily affects or involves a posterior ocular
region or site such as choroid or sclera (in a position posterior
to a plane through the posterior wall of the lens capsule),
vitreous, vitreous chamber, retina, optic nerve (i.e. the optic
disc), and blood vessels and nerves which vascularize or innervate
a posterior ocular region or site.
[0023] Thus, a posterior ocular condition can include a disease,
ailment or condition, such as for example, acute macular
neuroretinopathy; Behcet's disease; choroidal neovascularization;
diabetic uveitis; histoplasmosis; infections, such as fungal or
viral-caused infections; macular degeneration, such as acute
macular degeneration, non-exudative age related macular
degeneration and exudative age related macular degeneration; edema,
such as macular edema, cystoid macular edema and diabetic macular
edema; multifocal choroiditis; ocular trauma which affects a
posterior ocular site or location; ocular tumors; retinal
disorders, such as central retinal vein occlusion, diabetic
retinopathy (including proliferative diabetic retinopathy),
proliferative vitreoretinopathy (PVR), retinal arterial occlusive
disease, retinal detachment, uveitic retinal disease; sympathetic
ophthalmia; Vogt Koyanagi-Harada (VKH) syndrome; uveal diffusion; a
posterior ocular condition caused by or influenced by an ocular
laser treatment; posterior ocular conditions caused by or
influenced by a photodynamic therapy, photocoagulation, radiation
retinopathy, epiretinal membrane disorders, branch retinal vein
occlusion, anterior ischemic optic neuropathy, non-retinopathy
diabetic retinal dysfunction, retinitis pigmentosa, and glaucoma.
Glaucoma can be considered a posterior ocular condition because the
therapeutic goal is to prevent the loss of or reduce the occurrence
of loss of vision due to damage to or loss of retinal cells or
optic nerve cells (i.e. neuroprotection).
[0024] The term "biodegradable polymer" refers to a polymer or
polymers which degrade in vivo, and wherein erosion of the polymer
or polymers over time is required to achieve release of the
therapeutic agent. Specifically, hydrogels such as methylcellulose
which act to release drug through polymer swelling are specifically
excluded from the term "biodegradable polymer". The terms
"biodegradable" and "bioerodible" are equivalent and are used
interchangeably herein. A biodegradable polymer may be a
homopolymer, a copolymer, or a polymer comprising more than two
different polymeric units.
[0025] The term "treat", "treating", or "treatment" as used herein,
refers to reduction or resolution or prevention of an ocular
condition, ocular injury or damage, or to promote healing of
injured or damaged ocular tissue.
[0026] The term "therapeutically effective amount" as used herein,
refers to the level or amount of agent needed to treat an ocular
condition, or reduce or prevent ocular injury or damage without
causing significant negative or adverse side effects to the eye or
a region of the eye.
[0027] In a broad aspect of the invention, ocular implant delivery
assemblies are provided, the assemblies generally comprising a
cannula having a proximal end, a proximal end opening, a distal
end, a distal end opening, and a lumen extending through the
cannula. The assemblies further comprise a removable distal closure
element positioned relative to the cannula to close the distal end,
and a removable proximal closure element positioned relative to the
cannula to close the proximal end. Advantageously, the assemblies
further include an ocular implant located in the cannula and sized
and adapted for implantation in an eye. The assemblies are designed
to be coupled to a syringe, for example, a gel containing syringe,
or other device, for example and without limitation, a push-rod
device and the like, effective to deliver the implant from the
cannula and into a target region of an eye.
[0028] In another aspect of the present invention, ocular implant
delivery assemblies are provided which generally comprise a cannula
having a proximal end, a proximal end opening, a distal end, a
distal end opening, and a lumen extending through the cannula; an
ocular implant sized and structured for implantation in an eye
located in the lumen of the cannula; and a distal plug, for example
and without limitation, a bioerodible polymeric distal plug, that
is a distal plug comprising a bioerodible polymeric material,
positioned relative to the cannula to reduce the size of or close
the distal end opening of the cannula. In one embodiment, the
distal plug is located in or substantially directly adjacent the
lumen of the cannula. The distal plug may be located distal of the
ocular implant in the lumen and/or at or near the distal end of the
cannula. The distal plug is structured, when in place relative to
the cannula, to prevent the ocular implant from passing out of the
distal end opening of the cannula. In addition, the distal plug may
be effective in closing, for example and without limitation, in
sealing, the distal end opening of the cannula. The lumen can be
the lumen of a 25 gauge or higher gauge syringe needle. The plug
can comprise, for example and without limitation, a hydroxypropyl
methyl cellulose (HPMC). The plug is removable or can be pierced so
as to permit passage of the implant out through the distal opening
of the cannula by applying a distally extending force, for example
and without limitation, by advancing a plunger, in the lumen of the
cannula.
[0029] In one embodiment, a proximal plug, for example and without
limitation, a bioerodible polymeric proximal plug, that is a distal
plug comprising a bioerodible polymeric material, is positioned
relative to the cannula to reduce the size of or close the proximal
end opening of the cannula. In one embodiment, the proximal plug is
located in or substantially directly adjacent the lumen of the
cannula. The proximal plug may be located proximal of the ocular
implant in the lumen and/or at or near the proximal end of the
cannula. The proximal plug is structured, when in place relative to
the cannula, to prevent the ocular implant from passing out of the
proximal end opening of the cannula. In addition, the proximal plug
may be effective in closing, for example and without limitation, in
sealing the proximal end opening of the cannula.
[0030] When it is desired to pass the ocular implant into an eye
through the distal end opening of the cannula, the distal plug
and/or the proximal plug may be removed prior to coupling the
cannula to a force applying device, e.g., syringe, push-rod device
and the like, to urge the ocular implant into an eye. Alternately,
the distal plug and/or proximal plug may be maintained in place as
the cannula is coupled to a force applying device. In this
embodiment, when the force applying device is activated, for
example and without limitation, manually activated, the proximal
plug and/or the distal plug are urged distally by the force
generated. Thus, the distal plug and/or the proximal plug pass into
the eye along with the ocular implant. In this embodiment, it is
advantageous that the distal plug and/or proximal plug be
compatible with the region of the eye in which the ocular implant
is placed. In one embodiment, the distal plug and/or proximal plug
are soluble in the environment of the eye region in which the
ocular implant is placed.
[0031] In another broad aspect of the invention, ocular implant
delivery assemblies are provided which generally comprise a cannula
having an outer wall, a proximal end, a proximal end opening, a
distal end, a distal end opening, and a lumen extending through the
cannula; an ocular implant sized and structured for implantation in
an eye located in the lumen of the cannula; and a cap having a
closed distal end. The cap is in contact with the outer wall of the
cannula, and covers the distal end and distal end opening of the
cannula. The cap is structured to allow the distal end and distal
end opening of the cannula to pass through the cap, for example and
without limitation, to pierce and pass through the cap, as the
cannula is passed into an eye. The embodiments of the present
assemblies which include a cap, may also include a removable
proximal closure element positioned relative to the cannula to
close the proximal end opening of the cannula.
[0032] Assemblies which include any of a removable distal closure
element, distal plug and cap, as described herein, may include
either or both of a removable proximal closure element and a
proximal plug. Moreover, any of a distal closure element, distal
plug, cap, proximal closure element or proximal plug may be used
alone. Assemblies which include any one of such elements and any
two or more of such elements are included within the scope of the
present invention.
[0033] The present assemblies may include, for example, may be
coupled to, a syringe, for example, a gel containing syringe, or
other device, for example and without limitation, a push-rod device
effective to at least assist in delivering the implant from the
cannula into an eye, for example, into a target region of an
eye.
[0034] In one aspect of the invention, the assemblies are
structured to preserve structural and/or chemical integrity of the
implant during an extended period of time, for example, during a
period of time extending from when the assembly is produced or
manufactured to when the assembly is used to deliver the ocular
implant into an eye.
[0035] For example, the assembly may be structured to prevent
light, moisture and air from entering the cannula prior to use of
the assembly. For example, the cannula may be substantially opaque
to light to substantially prevent degradation, more specifically,
photodegradation, of the implant. Further, the proximal closure
element and the proximal plug, and the distal closure element, the
distal plug and the cap, may be effective to seal the cannula so as
to prevent air and/or moisture from entering the cannula.
[0036] In some embodiments, the cannula comprises a rigid,
preferably metallic, needle preferably having a substantially
circular cross section. The distal end is sharpened or otherwise
suitable for being introduced into an eye.
[0037] In one embodiment, the cannula has sufficient sharpness to
be passed into an eye. In embodiments in which a cap is provided
covering the distal end and distal end opening of the cannula. The
cap is structured, for example, has sufficient softness, to be
pierced by the cannula in passing the cannula into an eye,
advantageously without substantially detrimentally affecting the
cannula or the eye into which the cannula is passed. For example,
the cap may be structured to allow the distal end and distal end
opening to pierce and pass through the cap without substantially
detrimentally affecting the sharpness of the distal end of the
cannula. Thus, the cap can remain on the cannula and cover the
distal end and distal end opening of the cannula until the cannula
is passed into an eye. This feature of the present invention
facilitates maintaining the ocular implant in the cannula until it
is to be delivered into an eye. In other words, the cap prevents
the ocular implant from leaving the lumen of the cannula until it
is desired that the implant pass from the lumen into the eye. This
is highly advantageous in that the risk of losing the implant or
portion of the implant from the cannula prior to delivery into an
eye is reduced or even substantially eliminated.
[0038] Advantageously, the cap may be structured, for example, have
sufficient softness, to move proximally along the cannula as the
cannula is passed into an eye. This is a very useful feature of the
present invention. For example, the position of the cap, for
example, the pierced cap, on the cannula as the distal portion of
the cannula is passed into an eye provides a direct visual
indication of the extent to which the cannula is in the eye. In
other words, the operator, for example and without limitation, the
physician, surgeon and the like, placing the implant into the eye
is provided a direct visual indication, for example, by observing
the distance between the cap and the proximal end region of the
cannula, of the length of the cannula that has been passed into the
eye. Although passing the cannula into an eye is often done using
x-ray and/or other imaging methodologies, the direct visual
indication of how much of the cannula has been passed into an eye
provided by the present invention is an at least added control
and/or safety feature for use by the operator, and provides for
added control/safety of the procedure for implanting ocular
implants.
[0039] The cannula may be configured to contain and deliver an
ocular implant having very small dimensions, for example, a
microimplant. For example, the cannula may have an outer diameter
of 0.032 inches (813 microns) or less. In further embodiments, the
cannula is configured to have an outer diameter of 0.028 inches
(711 microns) or less or 0.025 inches (635 microns) or less.
Alternatively, the cannula has a non-circular transverse
cross-section. In these embodiments, the cannula can have a
transverse cross-sectional area of up to about 0.0008 square inches
(0.52 square millimeters) or greater, depending on the particular
cannula geometry. Cannulas having such configurations are able to
receive and deliver very small ocular implants, i.e., so-called
"microimplants" and effectively allow for self-sealing of the
delivery site.
[0040] The assemblies are suitable to deliver ocular implants to a
target location of the eye where the implant will be most
therapeutically effective. Various sites exist in the eye for
implantation of a drug delivery device or implant, such as the
vitreous of the eye, anterior or posterior chambers of the eye, or
other areas of the eye including intraretinal, subretinal,
intrachoroidal, suprachoroidal, intrascleral, episcleral,
subconjunctival, intracorneal or epicorneal spaces or sub-tenon's
space.
[0041] Advantageously, in some embodiments of the invention, the
cannula has an outside diameter no larger than a 22 gauge syringe
needle. For example, the cannula may have an outside diameter no
larger than a 25 gauge syringe needle, or about equal to the
outside diameter of a 27 gauge syringe needle or about equal to the
outside diameter of a 30 gauge syringe needle.
[0042] In some embodiments the lumen has a diameter of less than
about 350 microns, or less than about 300 microns, or even less
than about 250 microns. In a specific embodiment, the cannula is a
25 gauge needle having a lumen with a diameter of 262 microns or
312 microns. In another specific embodiment, the cannula is a 27
gauge needle having a lumen with a diameter of 210 microns or 287
microns.
[0043] In some embodiments, substantially no liquid material is
present in the lumen with the ocular implant. As will be explained
in greater detail hereinafter, in these embodiments, the implant is
stored in the cannula in a substantially dry state, more
specifically, without the inclusion of a liquid carrier. Dry
storage of the implant in some instances is effective to prolong
the shelf life of the drug or drugs, particularly drugs which are
soluble or partially soluble in aqueous based carriers.
[0044] In other embodiments, the assembly further comprises a
carrier medium comprising, for example, an aqueous component and a
viscosity inducing component, the liquid carrier medium being
located in the cannula with the ocular implant. In these
embodiments, the ocular implant may be of a make-up such that the
implant is insoluble in the carrier medium, for example, when
stored in the cannula at room temperature, but is soluble when
placed in the environment of the eye, for example, the vitreous of
the eye. In some embodiments, the ocular implant comprises a
plurality of particles suspended in a suitable carrier medium.
[0045] The distal closure element covers the distal end and the
distal end opening of the cannula. The distal closure element
preferably comprises a polymeric material, for example, a silicone
polymeric material. The distal closure element may be self secured
to the cannula, for example, by being press fit to the cannula. In
some embodiments, the distal closure element is adhesively secured
to the cannula. Preferably, the distal closure element is manually
removable from the cannula.
[0046] The distal plug and the proximal plug, when employed, may be
fitted and/or otherwise placed into the distal opening and proximal
opening, respectively, of the cannula. In one embodiment, the
distal plug and proximal plug are provided in a liquid or flowable
form, for example and without limitation, as a liquid, a liquid
solution, a liquid-containing suspension, a liquid-containing
emulsion and the like. This liquid or flowable form is coated onto
the distal end or proximal end of the cannula, and is allowed to
pass into the lumen of the cannula through the distal end opening
or the proximal end opening, respectively, to a limited extent. The
cannula is then subjected to conditions effective to cause a solid
distal plug or a solid proximal plug to form. Such plug or plugs
remain in place relative to the cannula until the ocular implant in
the cannula is to be placed into an eye, as described elsewhere
herein.
[0047] With regard to the embodiments in which a cap is employed,
the cap is preferably self-secured to the cannula, for example, by
being friction fitted to the cannula. Advantageously, the cap is
not adhesively secured to the cannula. Although the cap may be
manually removable from the cannula, it is preferred that the cap
remain on the cannula as the cannula is passed into an eye. Thus,
the securement between the cap and the cannula advantageously is
such that the cap moves proximally along the cannula as the distal
portion of the cannula is passed into an eye. In other words, the
cap is advantageously secured to the cannula sufficiently strongly
to reduce or substantially eliminate the risk of an unintended
removal of the implant from the cannula prior to placing the
implant in an eye while, at the same time, being such as to allow
the cap to move proximally on the cannula as the distal portion of
the cannula is passed into an eye.
[0048] Advantageously, the distal end of the cannula is structured
to facilitate entry of a distal portion of the cannula into an eye.
For example, the distal end of the cannula may be beveled or
sharpened.
[0049] The proximal closure element is positioned in or directly
adjacent the proximal end opening of the cannula and is preferably
structured to sealingly close the proximal end opening of the
cannula. In some embodiments, the proximal closure element
comprises a polymeric material, for example, a silicone polymeric
material. Preferably, the proximal closure element is structured to
be manually removable from the cannula.
[0050] In some embodiments, the assembly further comprises a
sleeve, for example, an enlarged sleeve, coupled to the cannula and
extending proximally thereof. The sleeve is structured and
positioned to facilitate coupling of the cannula to a syringe or
other activating device. The proximal closure element may be
structured to be coupled to, for example, received by, the sleeve.
Furthermore, the sleeve may be structured to facilitate the sealing
of the proximal end opening with the proximal closure element.
[0051] Generally, the plurality of particles located in the lumen
includes a number of particles in a range of about 5 or about 10 or
about 25 to about 75 or about 100 or about 150 or about 200
particles.
[0052] In some embodiments, the implant comprises a plurality of
particles having the same or different compositions, for example,
in the same or different proportions relative to one another. In
another aspect of the invention, the implant comprises a plurality
of particles comprising different compositions. The compositions
may include at least one therapeutic component effective to provide
a therapeutic effect when released into an eye, and at least one of
a biodegradable component, a non-biodegradable component, and
combinations thereof. For example, the plurality of particles
comprises a biodegradable polymer in combination with the at least
one therapeutic component. In some situations, the implant
comprises a plurality of different particles having the same or
different release rates and/or delayed release rates.
[0053] Further, the plurality of particles making up the ocular
implant may be in one or more different forms, for example,
different shapes and/or sizes. For example, the particles may be in
the form of particles selected from the group consisting of
spheres, rods, filaments, plaques and the like and combinations
thereof.
[0054] In a more specific embodiment of the invention, the
particles making up the implant comprise microspheres, for example,
a plurality of microspheres, for example, a plurality of
substantially uniformly sized microspheres. For example, the
plurality of substantially uniformly sized microspheres includes a
smallest particle and a largest particle. The largest particle has
a maximum diameter within about 20%, preferably about 10%, more
preferably about 5%, of the maximum diameter of the smallest
particle. In other embodiments, the implant comprises a plurality
of microspheres having different sizes.
[0055] In one aspect of the invention, the implant comprises a
plurality of particles including at least one particle having a
first form and at least one particle having a second form that is
different from the first form. In some embodiments, the implant
comprises at least one rod-shaped particle and at least one
microsphere. As a more specific example, the implant may comprise a
plurality of rods comprising a first therapeutic component, and a
plurality of microspheres comprising a second therapeutic component
that is different than the first therapeutic component.
[0056] In a broad aspect of the invention, the ocular implant
comprises a therapeutic component and a polymer component. For
example, the implant may comprise particles of active, therapeutic
agents contained in a bioerodible polymer. In some embodiments, the
implant comprises a first particle including a therapeutic
component and a polymer component having a first release rate, and
the at least one different particle including the same or a
different therapeutic component and a polymer component having a
second release rate that is different than the first release
rate.
[0057] Many combinations and/or forms of particles making up a
single ocular implant useful in the present assemblies are
possible, and are considered to be included within the scope of the
present invention.
[0058] Preferably, the maximum transverse dimension, for example
diameter, of each particle of the plurality of particles is at
least about 70% of the diameter of the lumen, for example, is at
least about 80% of the diameter of the lumen, for example, is at
least about 90% of the diameter of the lumen.
[0059] The present assemblies are structured to be coupled or
attached to an injector mechanism, for example, a hand-held syringe
or a push-rod device or similar instrument or device. For example,
the assemblies are structured to be coupleable to a conventional or
standard medical syringe including a barrel for containing a fluid,
a hub on a distal end of the barrel and capable of being connected
to the sleeve of the present assemblies, and a plunger or other
actuating element. In a more specific embodiment, the syringe is a
0.5 to 1.0 ml syringe. The syringe is suitable for containing a
fluid, more specifically a liquid medium, which is used to carry
the implant located in the assemblies of the invention into an eye
upon injection from the distal end of the cannula, for example,
upon actuation of the plunger. The liquid medium may be, for
example, a substantially inert or substantially inactive material,
or, alternatively, the liquid medium may comprise an active
component, for example, a therapeutic component, intended to be
introduced into an eye along with the ocular implant.
[0060] In other embodiments, the cannula may be coupled to a
push-rod device, for example, such as disclosed in Weber et al U.S.
Pat. No. 6,899,717. Briefly, such push-rod devices include a
longitudinally extending rod which is positioned relative to the
cannula so that the distal end of the rod is in contact with the
implant in the lumen of the cannula. Upon the application of a
force, for example, a manual force, to the rod, the rod moves
distally. Such distal movement of the rod, urges or pushes the
implant out of the distal end opening of the cannula and into an
eye.
[0061] Advantageously, the present assemblies can be practiced or
provided to treat an anterior ocular condition and/or a posterior
ocular condition. For example, in an especially advantageous
embodiment, the assemblies can be practiced or provided to treat a
condition of the posterior segment of a mammalian eye, such as a
condition selected from the group consisting of macular edema, dry
and wet macular degeneration, choroidal neovascularization,
diabetic retinopathy, acute macular neuroretinopathy, central
serous chorioretinopathy, cystoid macular edema, and diabetic
macular edema, uveitis, retinitis, choroiditis, acute multifocal
placoid pigment epitheliopathy, Behcet's disease, birdshot
retinochoroidopathy, syphilis, lyme, tuberculosis, toxoplasmosis,
intermediate uveitis (pars planitis), multifocal choroiditis,
multiple evanescent white dot syndrome (mewds), ocular sarcoidosis,
posterior scleritis, serpiginous choroiditis, subretinal fibrosis
and uveitis syndrome, Vogt-Koyanagi-and Harada syndrome; retinal
arterial occlusive disease, anterior uveitis, retinal vein
occlusion, central retinal vein occlusion, disseminated
intravascular coagulopathy, branch retinal vein occlusion,
hypertensive fundus changes, ocular ischemic syndrome, retinal
arterial microaneurysms, Coat's disease, parafoveal telangiectasis,
hemiretinal vein occlusion, papillophlebitis, central retinal
artery occlusion, branch retinal artery occlusion, carotid artery
disease (CAD), frosted branch angiitis, sickle cell retinopathy,
angioid streaks, familial exudative vitreoretinopathy, and Eales
disease; traumatic/surgical conditions such as sympathetic
ophthalmia, uveitic retinal disease, retinal detachment, trauma,
photocoagulation, hypoperfusion during surgery, radiation
retinopathy, and bone marrow transplant retinopathy; proliferative
vitreal retinopathy and epiretinal membranes, and proliferative
diabetic retinopathy; infectious disorders such as ocular
histoplasmosis, ocular toxocariasis, presumed ocular histoplasmosis
syndrome (POHS), endophthalmitis, toxoplasmosis, retinal diseases
associated with HIV infection, choroidal disease associated with
HIV infection, uveitic disease associated with HIV infection, viral
retinitis, acute retinal necrosis, progressive outer retinal
necrosis, fungal retinal diseases, ocular syphilis, ocular
tuberculosis, diffuse unilateral subacute neuroretinitis, and
myiasis; genetic disorders such as retinitis pigmentosa, systemic
disorders with associated retinal dystrophies, congenital
stationary night blindness, cone dystrophies, Stargardt's disease
and fundus flavimaculatus, Best's disease, pattern dystrophy of the
retinal pigmented epithelium, X-linked retinoschisis, Sorsby's
fundus dystrophy, benign concentric maculopathy, Bietti's
crystalline dystrophy, and pseudoxanthoma elasticum; retinal
tears/holes such as retinal detachment, macular hole, and giant
retinal tear; tumors such as retinal disease associated with
tumors, congenital hypertrophy of the retinal pigmented epithelium,
posterior uveal melanoma, choroidal hemangioma, choroidal osteoma,
choroidal metastasis, combined hamartoma of the retina and retinal
pigmented epithelium, retinoblastoma, vasoproliferative tumors of
the ocular fundus, retinal astrocytoma, and intraocular lymphoid
tumors; punctate inner choroidopathy, acute posterior multifocal
placoid pigment epitheliopathy, myopic retinal degeneration, acute
retinal pigment epithelitis, retinitis pigmentosa, proliferative
vitreal retinopathy (PVR), age-related macular degeneration (ARMD),
diabetic retinopathy, diabetic macular edema, retinal detachment,
retinal tear, uveitus, cytomegalovirus retinitis and glaucoma and
conditions involving ocular degeneration, such as neurodegeneration
of retinal ganglion cells.
[0062] Incorporated herein by this specific reference is the entire
disclosure of each of the following documents: U.S. patent
application for APPARATUS AND METHODS FOR IMPLANTING PARTICULATE
OCULAR IMPLANTS, having Ser. No. 11/455,392, filed on Jun. 19, 2006
(attorney docket no. 18045 OCU), commonly assigned herewith; U.S.
patent application Ser. No. 10/917,909, filed on Aug. 13, 2004;
U.S. patent application Ser. No. 11/303,462, filed on Dec. 15,
2005; and U.S. patent application Ser. No. 11/091,977, filed on
Mar. 28, 2005.
[0063] Each and every feature described herein, and each and every
combination of two or more of such features, is included within the
scope of the present invention provided that the features included
in such a combination are not mutually inconsistent. In addition,
any feature or combination of features may be specifically excluded
from any embodiment of the present invention.
[0064] Additional aspects and advantages of the present invention
are set forth in the following description and claims, particularly
when considered in conjunction with the accompanying drawings.
DRAWINGS
[0065] The following Drawings illustrate some but not all of the
aspects and advantages of the present invention.
[0066] FIG. 1 is a cross-sectional view of an assembly in
accordance with the invention, the apparatus including a cannula
for implanting an ocular implant in a region of a mammalian eye, a
removable distal closure element, a removable proximal closure
element, and an ocular implant located in the cannula.
[0067] FIG. 2 is a cross-sectional view of the assembly shown in
FIG. 1 having both the removable distal closure element and the
removable proximal closure element disengaged or removed from the
cannula, prior to use of the assembly for injecting the implant
into an eye.
[0068] FIG. 3 is a partially cross-sectional view of the assembly
shown in FIG. 1 in which the cannula is coupled to a syringe
containing a carrier fluid.
[0069] FIG. 4 is an enlarged cross-sectional view of a distal
portion of the cannula shown in FIG. 1, showing the ocular implant
comprising a plurality of substantially uniformly sized
microspheres.
[0070] FIG. 5 is an enlarged cross sectional view of a distal
portion of a cannula containing another form of an ocular implant
useful as a component of the assemblies of the present
invention.
[0071] FIG. 6 is an enlarged cross sectional view of a distal
portion of a cannula containing yet another form of an ocular
implant useful as a component of the assemblies of the present
invention.
[0072] FIG. 7 is a partial cross-sectional view of a further
assembly in accordance with the present invention.
[0073] FIG. 8 is a partial cross-sectional view of an additional
assembly in accordance with the present invention.
[0074] FIG. 9 is a cross-sectional view of an alternate assembly in
accordance with the present invention.
[0075] FIG. 10 is a somewhat schematic view of the capped cannula
of the assembly of FIG. 9 shown coupled to a syringe device.
[0076] FIG. 11 is a somewhat schematic view of another assembly in
accordance with the present invention shown coupled to a push-rod
device.
[0077] FIG. 12 is a cross-sectional view of a portion of the capped
cannula of the assembly of FIG. 11 shown with the cannula ready to
be passed into an eye.
[0078] FIG. 13 is a cross-sectional view of a portion of the capped
cannula of the assembly of FIG. 11 shown with a small portion of
the cannula located inside an eye.
[0079] FIG. 14 is a cross-sectional view of a portion of the
cannula of the assembly of FIG. 11 shown with a larger portion of
the cannula located inside an eye.
DESCRIPTION
[0080] As described herein, assemblies for facilitating
administration of therapeutic agents through the use of one or more
ocular or intraocular implants are provided, and are useful for
improving treatment of a variety of ocular conditions.
[0081] With reference to FIGS. 1 and 2, an assembly in accordance
with the invention for implanting an ocular implant in an eye is
shown generally at 10. The assembly 10 comprises a cannula 12
having a lumen 14 extending therethrough. The cannula 12 has a
proximal end 16, a proximal end opening 18, a distal end 22, and a
distal end opening 24. As shown, the assembly 10 further comprises
a removable distal closure element 32 positioned relative to the
cannula 12 to close, for example, to be sealingly coupled to, the
distal end 22. The assembly further comprises a removable proximal
closure element 36 positioned relative to the cannula 12 to close,
for example, to be sealingly coupled to, the proximal end 16 of the
cannula 12. In addition, the assembly 10 comprises an ocular
implant 40 located in the cannula 12. The ocular implant 40 is
sized and adapted for implantation in an eye.
[0082] The assembly 10 is structured to provide convenient, safe
packaging of ocular implants prior to placement of such implants in
an eye. In use, the assembly provides for sterile containment of an
ocular implant in a manner such that the implant will not be
subject to significant degradation or other significant chemical or
structural changes when stored in the cannula over an extended
period of time. By "extended period of time" is generally meant
herein as a period of time of at least about 1 month, at least
about 3 months, at least about 6 months, at least about one year,
at least about two years, or even greater or longer.
[0083] For example, the cannula 12 may be made of made of metal,
such as stainless steel, or other suitable material. In order to
allow the cannula to easily pass into an eye, the cannula is
preferably made of a generally rigid material. To prevent
photo-initiated degradation of the implant, the cannula, and in one
or more embodiments one or more other components of the assembly,
are preferably made of materials that are substantially opaque to
light, for example, light which can cause such degradation.
[0084] As shown, the cannula 12 includes a distal tip 22a
structured to facilitate entry of the distal end 22 of the cannula
12 into an eye. For example, the distal tip 22a may be beveled,
sharpened, or otherwise shaped or structured to facilitate
insertion of the cannula 12 into an eye without slippage or undue
force.
[0085] It is desirable, although not necessary, that the cannula 12
corresponds in dimensions to a 21 or 22 gauge needle, and more
preferably, an even smaller gauge needle. In one aspect of the
invention, the cannula 12 has an outside diameter no larger than a
22 gauge needle. For example, the cannula may have a diameter equal
to a 27 gauge needle. For example, the cannula 12 may have an outer
diameter equal to or smaller than that of a thin-walled or ultra
thin-walled 25 or 27 gauge needle.
[0086] In some embodiments the cannula lumen has a diameter of less
than about 350 microns, or less than about 300 microns, or less
than about 250 microns. In a specific embodiment, the cannula is a
25 gauge needle having a lumen with a diameter of 262 microns or
312 microns. In another specific embodiment, the cannula is a 27
gauge needle having a lumen with a diameter of 210 microns or 287
microns.
[0087] Such a small gauge cannula has the important advantage that
punctures made by such small gauge cannula according to techniques
described herein are self-sealing. A 21 gauge or 22 gauge needle is
currently considered state of the art, and insertion of an implant
using such a needle size does not always result in a wound that is
self-sealing. The present invention preferably comprises a cannula
or needle that has a smaller gauge or a smaller outer diameter than
the 21 gauge or 22 gauge needle, such that implant delivery into
the eye using the present invention is usually self sealing and can
be accomplished without the need for suturing the puncture site. By
using a cannula that has a gauge or an outer diameter smaller than
a 21 gauge or 22 gauge cannula or needle, the implant can be placed
and the cannula withdrawn without excessive fluid leakage from the
eye, despite the normal fluid pressures within the eye, and
stitching of the puncture site can be avoided. 21 gauge needles
have outer diameters of about 0.032 inches (about 813 microns).
Thin wall or extra or ultra thin wall versions of 21 gauge needles
can have lumen diameters of about 0.023 inches (about 585 microns)
to about 0.026 inches (about 610 microns). 22 gauge needles have
outer diameters of about 0.028 inches (about 711 microns), and thin
wall or extra or ultra thin wall versions of 22 gauge needles have
lumen diameters of about 0.019 inches (about 483 microns) to about
0.023 inches (about 585 microns). Preferably, the cannula of the
present assemblies has dimensions no larger than the dimensions of
22 gauge or 23 gauge, thin wall needle. Even more preferably, the
cannula of the present assemblies has dimensions corresponding to
those of a 25 gauge or 27 gauge, thin wall or extra or ultra thin
wall needle.
[0088] Further, the ocular or intraocular implant 40 located in the
cannula 12 is preferably structured with sufficient tolerance to be
readily pushed through the lumen 14. For example, and without being
so limited, the ocular implant in a cannula having dimensions
corresponding to a lumen of a 22 gauge thin wall needle may
comprise a plurality of a implants or particles having diameters of
about 0.018 inches (about 460 microns). As another example, an
implant having a diameter of 0.015 inches (about 380 microns) is
suitable for delivery through a cannula having dimensions
corresponding to 23 gauge thin wall needle. Implants sized for
delivery through a cannula having dimensions corresponding to a 25
or 27 gauge thin wall or extra or ultra thin wall needle may also
be employed.
[0089] The invention further contemplates that the cannula 12 may
have a circular cross-section or a non-circular cross-section,
including for example and without limitation, an oval or elliptical
cross-section. For such a non-circular cross-sectional cannula, it
is desirable that the cross-sectional area correspond to that of a
circular cannula having up to about a 0.032 inch (813 microns)
outer diameter, that is, a cross-sectional area up to about 0.0008
square inches (0.52 square millimeters) or more, depending on the
particular cross-sectional geometry being employed.
[0090] In addition to cannula dimensions, additional modifications
to both the cannula distal tip 22a and/or methods of insertion can
further aid successful self-sealing methods of implantation. A
typical problem when inserting a cannula into any tissue is the
phenomena of "coring" of the tissue, where the insertion actually
cuts a cylindrical section of tissue that enters the cannula lumen.
Such coring when it occurs in the eye can exacerbate leakage of eye
fluid through the injection site. By approaching the eye tissue at
more of an angle relative to normal, there is a better opportunity
for the cannula distal tip to penetrate and separate through the
tissue layers and reduce coring of the tissue.
[0091] The cannula distal tip 22a itself also can be configured to
reduce the coring phenomena, for instance, by providing that the
tip is beveled, and/or by sharpening certain portions of the tip
and dulling others. One skilled in the art will appreciate that the
particular site of entry and the distance the cannula 12 is
inserted will depend on the particular application and the desired
final location of the implant. As can also be appreciated, the
ability provided herein to provide for a self-sealing method for
delivering implants has enormous impact on the ability of
physicians and healthcare workers to treat diseases of the eye,
because it obviates in most situations the necessity of surgery
facilities, and accompanying surgical support, currently required
by conventional apparatus and methods.
[0092] In one aspect of the invention, the diameter of the lumen 14
is in a range of about 200 microns or less to about 500 microns or
more. The diameter of the lumen 14 may be about 350 microns or
less, and may be in a range of about 250 microns to about 300
microns.
[0093] Referring now specifically to FIG. 1, the distal closure
element 32 covers the distal end 22 and the distal end opening 24
of the cannula 12. For example, the distal closure element 22 may
be of any suitable composition, shape or form that enables the
distal closure element 22 to be removably engaged to the distal end
22 of the cannula 12.
[0094] The distal closure element 22 may be self secured to the
cannula 12. For example, the distal closure element 22 may comprise
a flexible polymeric material, for example, selected from flexible
silicone polymeric materials, other flexible, for example,
thermoplastic, polymeric materials and the like and combinations
thereof, that enables the distal closure element 22 to be
frictionally engaged to or secured to the distal end of the
cannula. Alternatively, the distal closure element 22 may be
adhesively secured to the cannula 12. In any event, it is
preferable that the distal closure element 22 is structured to be
effective in sealing the distal opening 24 of the cannula 12, for
example, in a fluid tight manner.
[0095] Still referring to FIG. 1, the proximal closure element 36
is positioned in or substantially directly adjacent the proximal
end opening of the cannula 12 and is preferably positioned to
sealingly close, meaning, for example, in a fluid tight manner, the
proximal end opening 18 of the cannula. Like the distal closure
element 32, the proximal closure element 22 may comprise a
polymeric material, for example, a flexible polymeric material,
such as a material selected from flexible silicone polymeric
materials, other flexible, for example, thermoplastic, polymeric
materials and the like and combinations thereof. Preferably, the
proximal closure element 36 is structured to be manually removable
from the cannula 12, for example, prior to using the cannula in
delivering the contained implant into an eye.
[0096] In an especially advantageous embodiment, the assembly 10
further comprises an enlarged sleeve 48 coupled to the cannula 12
and extending proximally thereof. The sleeve 48 is structured and
positioned to facilitate coupling of the cannula 12 to a syringe
(not shown in FIGS. 1 and 2) or other mechanism useful for
injecting the implant 40 from the cannula 12 and into a region of
an eye.
[0097] As shown in FIGS. 1 and 2, the sleeve 48 is structured and
positioned to facilitate the sealing of the proximal end opening 18
of the cannula 12 by the proximal closure element 36. For example,
referring now to FIG. 2, the proximal closure element 36 includes a
distal region 36a that is shaped and sized to be received into, for
example, press fit into, a corresponding channel or cavity 48a of
sleeve 48. When the proximal closure element 36 is properly engaged
with the sleeve, such as shown in FIG. 1, a sealing surface 36b of
the proximal closure element 36 substantially entirely covers and
seals, preferably in a fluid tight manner, the proximal end opening
18 of the cannula 12.
[0098] Turning now to FIG. 3, the assembly 10 is shown having the
proximal closure element 36 (shown in FIGS. 1 and 2) removed
therefrom, and the sleeve 48 of assembly 10 being used to
facilitate coupling of the cannula 12 to a syringe 50 which will be
used to inject the implant 40 into a region of an eye. In this
example, the syringe 50 is a standard syringe 50 having a barrel 52
having a hub 54, and a plunger 56.
[0099] To use the assembly 10 to place the implant 40 into a region
of an eye, the following procedure may be followed. An appropriate
amount of sterile carrier fluid 62 is drawn into the barrel 52 of
syringe 50, for example, using the plunger 56. Air trapped in the
barrel between the plunger and a distal opening of the hub is
removed in a conventional manner. The proximal closure element 36
is removed from the cannula 12. The hub 52 of the syringe 50 is
press fit, threaded, or otherwise engaged to the sleeve 48 of the
assembly 10. The distal closure element 32 is removed from the
cannula 12 to expose the distal tip 22a. The syringe 50 and
assembly 10 are then used to place the implant 40 into a region of
an eye by accessing the target area within the ocular region with
the distal end 22 of the cannula 12. Once the distal end 22 of the
cannula 12 is within the target area, e.g., the vitreous cavity,
the plunger 56 can be depressed to drive or force the fluid and the
implant distally. As the plunger is moved distally or forward, it
pushes the implant 40 into the target area (i.e. the vitreous) of
the eye.
[0100] As a specific example, for placement e.g. in the vitreous
cavity of the eye, useful implantation methods include advancing
the cannula through the pars plana at a location about 3.5 to about
4 mm from the limbus of the eye. For smaller diameter cannulas,
e.g., 25 gauge or smaller, the cannula can be inserted from any
angle relative to the eye and still produce acceptable self-sealing
results. For larger gauge cannulas, e.g., 23 gauge and larger,
self-sealing results can be enhanced by inserting the cannula or
needle at an angle, for example, other than perpendicular, relative
to the eye surface. For example, good results are achieved by
inserting the cannula or needle at an angle of about 45.degree. or
less relative to the eye surface. Also, slightly improved results
can be seen in some cases by orienting the bevel of the needle
downward with respect to the eye surface. Another advantageous
method involves a so-called "tunnel technique" approach. In this
technique, the patient's eye is restrained from moving e.g. using a
cotton swab or forceps, and the needle is advanced into the sclera
at an angle approaching parallel relative to the eye surface. In
this technique, the bevel will usually be oriented upward with
respect to the eye surface. Once the tip is advanced sufficiently
far enough into the scleral layer, usually such that the bevel
portion is at least disposed within the scleral layer, the angle of
the needle is adjusted to a more downward angle into the eye, and
the needle is further advanced. Using such methods, with the
shallower angle of insertion, yields wound edges that close up and
seal more readily. Without being bound by theory, it is believed
that insertion of the needle by this technique creates a scleral
"flap" that, under intraocular pressure of the eye, is forced
upward and pressed against the wound path to more effectively close
up the wound.
[0101] In addition, the direction of insertion of the needle
relative to the limbus of eye can have further implications upon
the deposition of the implant in the vitreous cavity. For example,
advancement of the cannula posteriorally of the limbus or even
circumferentially relative to the limbus usually provides for a
suitable and acceptable location for deposition of the implant.
[0102] The implants may have a size in a range of about 5 .mu.m to
about 10 mm or greater, or about 10 .mu.m to about 1 mm or about 3
mm per particle. The implants may have any appropriate length so
long as the diameter of the implant permits the implant to move
through the needle or cannula, and the length of the implant does
not exceed the length of the cannula.
[0103] The implants located in the cannula may have various forms.
Turning now to FIGS. 4-6, several different implant forms, in
accordance with the invention, are shown. FIG. 4 illustrates a
magnified view of implant 40 located in the cannula 12, the implant
40 being comprised of a plurality of substantially uniformly sized
microspheres 64. For example, the plurality of particles includes a
smallest particle and a largest particle having a maximum
transverse dimension within about 20%, preferably within about 10%,
and more preferably within about 5%, of the maximum transverse
dimension of the smallest particle.
[0104] Production of uniformly sized particles may be achieved by
conventional techniques, such as sieving and the like, that are
effective to separate, from a large number of non-uniformly sized
particles, a plurality of particles of substantially uniform size.
In one embodiment, and preferably, the production of uniformly
sized microspheres is accomplished using microfluidic techniques
for producing "precision" microparticles. Examples of such
techniques are described in Barrow et al., United States Patent
Application Publication No. 2006/0108012, published on May 25,
2006.
[0105] The plurality of particles located in the lumen 14 may
include any suitable number of particles, for example and without
limitation, in a range of about 5 or less or about 10 or about 25
to about 75 or about 100 or about 150 or about 200 or more
particles.
[0106] FIG. 5 shows another type of ocular or intraocular implant,
identified generally as 140, located in cannula 12 and useful in
the present assemblies. Implant 140 comprises at least one
cylindrical pellet (e.g., rod-shaped particle or rod 66) and a
plurality of substantially uniformly sized microspheres 64 on
either side of cylindrical pellet 66.
[0107] FIG. 6 shows yet another type of ocular or intraocular
implant, identified generally as 240, located in cannula 12 and
useful in the present assemblies. Implant 240 comprises a plurality
of microspheres 68 which have different diameters.
[0108] With reference now to FIG. 7, a further embodiment of an
assembly in accordance with the present invention is shown. Except
as expressly described herein, this further embodiment, shown as
assembly 310, is structured and functions similarly to assembly 10.
Components of further assembly 310 which correspond to components
of assembly 10 are identified by the same reference numeral
increased by 300.
[0109] The primary difference between further embodiment 310 and
embodiment 10 is the presence of distal seal plug 70, which may be
used with or without the removable distal closure element 32. In
one very useful embodiment the distal seal plug 70 is used instead
of the removable distal closure element. The distal seal plug 70
functions to seal the distal end opening 324 of cannula 312 of
assembly 310 to prevent the implant 340 from passing through the
distal opening 324 unintentionally. In addition, the distal seal
plug 70 advantageously seals the distal end opening 324 so that no
fluid can enter or exit the lumen 314 of cannula 312 through distal
end opening 324 when the distal seal plug is in place sealing the
distal end opening, as shown in FIG. 7.
[0110] The distal seal plug 70 may be made of any suitable
material, for example and without limitation, a polymeric material.
The plug material is preferably anhydrous so that it does not
impart or transfer any water (moisture) to the implant.
Additionally the plug material is preferably rapidly bioerodible or
biodegradable and can therefore be a suitable material, for example
and without limitation, selected from poly(esters) based on
polylactide (PLA), polyglycolide (PGA), polycaprolactone (PCL), and
their copolymers, as well as poly(hydroxyalkanoates) of the PHB-PHV
class, additional poly(esters), other synthetic polymers and
natural polymers, particularly, modified so as to be rapidly
biodegradable. In one embodiment, poly(saccharides), e.g., starch,
cellulose, cellulose or cellulosic derivatives, such as HPMC and
the like materials compatible with the eye and chitosan can form
the plug material.
[0111] Although the distal seal plug 70 can be removed from the
cannula 312 prior to the assembly 310 being used to implant ocular
implant 340 in an eye, in one useful embodiment, the distal seal
plug is structured to be passed into the eye with the implant. In
this latter embodiment, the distal seal plug 70 advantageously
comprises a biodegradable or bioerodible polymeric component. Thus,
as the implant 340 is being urged distally in the cannula 312, for
example, by a syringe or push-rod device, the urging force also
urges the distal seal plug distally. With the distal end 322 of
cannula 312 in the eye, the distal seal plug 324, as well as the
implant 340, are deposited in the eye.
[0112] In one embodiment the distal seal plug 70 is formed by
coating the distal end opening 324 of cannula 312 with a fluid
polymeric component, for example, a molten polymeric component, a
polymeric component in an aqueous solution and the like. After such
coating, the polymeric component is allowed to solidify, forming
the distal seal plug 70. The polymeric component and the structure
of the distal seal plug may be selected to provide a distal seal
plug which functions as described herein and can be urged into an
eye by the force generated by a syringe or push-rod device coupled
to assembly 310.
[0113] In one useful embodiment, the polymeric component employed
in the distal seal plug 70 may be, for example and without
limitation, cellulosic polymers, such as HPMC, polyesters, such as
PLGA, and the like and combinations thereof.
[0114] Now, with reference to FIG. 8, an additional embodiment of
an assembly in accordance with the present invention is shown.
Except as expressly described herein, this additional embodiment,
shown as assembly 410, is structured and functions similarly to
assembly 10. Components of additional assembly 410 which correspond
to the embodiments of assembly 10 are identified by the same
reference numeral increased by 400.
[0115] The primary difference between further between additional
embodiment 410 and embodiment 10 is the presence of a proximal seal
plug 72 which may be used with or without the removable proximal
closure element 36 and with or without the removable distal closure
element 32 and/or the distal seal plug 70. In one very useful
embodiment, the proximal seal plug 72 is used instead of the
removable proximal closure element 36.
[0116] The proximal seal plug 72 functions to seal the proximal end
opening 418 of cannula 412 of assembly 410 to prevent the implant
440 from passing through the proximal opening 418 unintentionally.
In additional, the proximal seal plug 72 advantageously seals the
proximal end opening 418 so that no fluid can enter or exit the
lumen 414 of cannula 412 through proximal end opening 418 while the
proximal seal plug is in place sealing the proximal end opening, as
shown in FIG. 8. The proximal seal plug 72 may be made of any
suitable material, for example and without limitation, a polymeric
material. Examples of suitable materials for use in proximal seal
plug 72 include, without limitation, the materials from which
distal seal plug 70 can be made, as described elsewhere herein.
[0117] Although the proximal seal plug 72 can be removed from the
cannula 412 prior to the assembly 410 being used to implant the
ocular implant 440 in an eye, in one useful embodiment, the
proximal seal plug is structured to be passed into the eye with the
implant. In this latter embodiment, the proximal seal plug 72
advantageously comprises a biodegradable or bioerodible component,
for example and without limitation, a biodegradable or bioerodible
polymeric component. Thus, as the implant 440 is being urged
distally in the cannula, for example, by a syringe or push-rod
device, the urging force also urges the proximal seal plug 72
distally through the distal end opening of cannula 412 in the eye.
Thus the proximal seal plug 72, as well as the implant 440 are
deposited in the eye.
[0118] In one embodiment, the proximal seal plug 72 is formed by
coating the proximal end opening 418 of cannula 412 with a fluid
polymeric component, for example a molten polymeric component, a
polymeric component in an aqueous solution and the like. After such
coating, the polymeric component is allowed to solidify forming the
proximal seal plug 72. The polymeric component and the structure of
the proximal seal plug 72 may be selected to provide a distal seal
plug or a proximal seal plug 72 which functions as described herein
and can be urged into the eye by the force generated by a syringe
or push-rod device coupled to assembly 410. The polymeric component
employed in the proximal seal plug 72 may be, for example and
without limitation, selected from a cellulosic polymers, such as
HPMC, polyesters such as PLGA, and the like and combinations
thereof.
[0119] With reference now to FIGS. 9 to 14, an alternate embodiment
of an assembly in accordance with the present invention is shown.
Except as expressly described herein, this further embodiment,
shown as assembly 510, is structured and functions similarly to
assembly 10. Components of alternate assembly 510 which correspond
to components of assembly 10 are identified by the same reference
numeral increased by 500.
[0120] The primary difference between alternate embodiment 512 and
embodiment 10 is the presence of a distal cap 74 to cover the
distal end 522 and distal opening 520 of cannula 512 of assembly
510. In addition, the distal cap 74 advantageously seals the distal
end opening 524 so that no fluid can enter or exit the lumen 514 of
cannula 512 through distal end opening 524 when the distal cap is
in place sealing the distal end opening, as shown in FIG. 9.
[0121] This distal cap 74 may be made of any suitable material, for
example and without limitation, a polymeric material, effective to
provide a cap which is structured and functions as described
herein. In one embodiment, the distal cap is made of flexible, for
example and without limitation, thermoplastic, polymeric material.
In a very useful embodiment, the distal cap comprises a flexible,
silicone polymeric material. The distal cap can be a single solid
piece of silicone polymeric material. In one embodiment, the distal
cap may be opaque or substantially translucent or substantially
transparent, for example, clear or optically clear. Using a
substantially transparent or clear distal cap may allow the
operator to visualize the cannula so as to at least assist in
determining where the cannula tip is located as it is being placed
in the eye. The distal cap may, and advantageously does, have
sufficient softness to be pierced by the cannula 512 of the
assembly 510 in passing the cannula into an eye without
significantly detrimentally effecting the cannula or the eye into
which the cannula is passed. The distal cap 74 advantageously has a
durometer in a range of about 30 to about 75. Such a relatively
soft distal cap 74 is effective in receiving the distal end 522 and
distal end opening 524 of the cannula 512 of alternate assembly 510
without requiring the provision of a separate bore in the distal
cap. The distal cap 74 is advantageously configured or structured
and formulated to remain securely in place covering the distal end
522 and distal opening 524 of cannula 512 which the assembly 510 is
being shipped and stored; to be pierced by the distal end 522 of
the cannula 512 as the cannula is moved distally toward an eye, for
example, without significantly detrimentally affecting the
sharpness of the cannula and/or its ability to pass into an eye;
and/or to move proximally on the cannula 512 as the distal end 522
is inserted in the eye.
[0122] In one useful embodiment, the distal cap 74 has a generally
disc-like shape, for example, a generally circular disc-like shape.
In this embodiment, the distal cap has a diameter, for example, and
without limitation, in a range of about 4 mm or about 5 mm to about
8 mm or about 10 mm, and a thickness, for example and without
limitation, in a range of about 1 mm to about 2 mm or about 3
mm.
[0123] One advantage of having a distal cap 74 with an 8 mm
diameter is that the operator, by positioning the edge of the cap
towards the limbus of the eye, is provided with a quick 4 mm
measurement from the limbus. That is, with the edge of the cap
toward the limbus of the eye, the distal end of the cannula is 4 mm
or about 4 mm from the limbus. The operator does not have to use a
caliper to pre-measure the distance to the limbus. At 4 mm from the
limbus, the operator can safely and effectively insert the implant
through the pars plana into the vitreous cavity. With a thickness
in a range of about 1 mm to about 2 mm, the distal cap 74 can be
securely placed over the distal end of a cannula, for example, a 25
gauge, ultra thin walled.times.5/8 inch.
[0124] In one embodiment, the cap may be provided with markings or
graduations at different radial distances from the cannula
indicating the distance of the individual marking or graduation
from the cannula. For example, the markings or graduations can be
on a millimeter scale or smaller distance increments so that the
operator can measure the distance between a given point on the eye,
for example the limbus of the eye, and the cannula tip so as to
insert the cannula tip at a desired point into the eye. This
embodiment is useful, for example, if the cap has an 8 mm diameter
and the surgeon chooses to go 3 mm from the limbus for a pars plana
injection. Thus, by placing the 3 mm marking or graduation of the
cap on or in proximity to the limbus, the operator has also placed
the cannula tip at the desired injection region. Using a cap with
such markings or graduations also allows the operator to avoid
using a caliper to pre-measure the 3 mm distance from the
limbus.
[0125] Advantageously, the distal cap 74 remains associated with
the cannula 512 as the implant 540 is implanted into an eye.
[0126] It should also be noted that a proximal closure element 536
is used to close an preferably seal the proximal end opening 518 of
assembly 510. A proximal seal plug, such as proximal seal plug 72,
may be used in combination with or in place of proximal closure
element 536, as described herein.
[0127] FIG. 10 shows cannula 512 with cap 74, located on the distal
end of the cannula joined to a syringe device 80.
[0128] FIG. 11 shows an assembly 510 without a sleeve joined
directly to a conventional push-rod device 82.
[0129] Both the syringe device 80 and push-rod device 82 are of
conventional design and structure and are used to provide or apply
a force to the lumen of cannula 512 to urge the implant 540 into
the eye.
[0130] FIGS. 12, 13 and 14 illustrate more clearly the interaction
between the cannula 512, the cap 74 and the surface 84 of an eye
into which the implant 540 is to be placed. With specific reference
to FIG. 12, the assembly 510, attached to either a syringe 80 or a
push-rod device 82 (not shown in FIGS. 12, 13 or 14) is placed
against the surface 84 of the eye. The assembly 510 is urged
distally. Such urging causes the distal end 522 and distal end
opening 524 of the assembly 510 to pass distally through the distal
cap 74 through the surface 84 and into the eye. The position of the
cannula 512 after the distal end 522 and distal end opening 524 are
in the eye is shown in FIG. 13. One important aspect of the present
invention is that the cap 78 moves proximally along the outer
surface 511 of the cannula 512 so that the further the cannula is
passed into the eye, the cap moves more proximal on the
cannula.
[0131] FIG. 14 shows the position of the cap 74 as the distal end
522 of the cannula 512 is moved further into the eye. The cap 74
has moved further proximally on the cannula 512.
[0132] The position of the cap 74 on the cannula provides the
operator with a direct visualization of how much of the cannula is
placed in the eye. This gives the operator an additional control
for judging the progress of the procedure.
[0133] Once the cannula is in the proper position in the eye, the
syringe or push-rod assembly is activated to urge the implant 540
into the eye. After the implant 540 has been delivered in the eye,
the cannula is removed from the eye.
[0134] Generally, the particles or microparticles making up the
ocular or intraocular implants 40, 140, 240, 340, 440 and 540
should have a diameter that is less than the diameter of the lumen
14 of the cannula 12. In one embodiment, the maximum transverse
dimension of each particle of the plurality of particles is about
70% of the diameter of the lumen, for example, is about 80% of the
diameter of the lumen, for example, is about 90% of the diameter of
the lumen. Smaller particles, for example in combination with
relatively larger particles, may also be employed.
[0135] In certain implants, the particle diameter is less than
about 500 .mu.m, for example, is less than about 350 .mu.m. The
vitreous chamber in humans is able to accommodate relatively large
implants of varying geometries, having lengths of, for example,
about 1 to about 10 mm. Rod shaped particles 64 may have dimensions
of about 2 mm length or about 7 mm to about 10 mm length by about
0.75 mm to about 1.5 mm. diameter.
[0136] Advantageously, because the implants 40, 140, 240, 340, 440
or 540 are made up of separate particles, such implants are
generally more flexible than implants made up of a single uniform
structure. This feature of the invention greatly facilitates both
insertion of the implant in the eye, such as in the vitreous, and
accommodation of the implant. As shown, each of implants 40 and 140
may comprise a plurality of particles disposed in a one-by-one
(synonymously, in a single file manner) array along the length of
the lumen.
[0137] The total weight of the implant is often in a range of about
250 to about 5000 .mu.g, for example, about 500 to about 1000
.mu.g. An implant may be about 500 .mu.g, or about 1000 .mu.g. For
non-human individuals, the dimensions and total weight of the
implant(s) may be larger or smaller, depending on the type and size
of the individual. For example, humans have a vitreous volume of
approximately 3.8 ml, compared with approximately 30 ml for horses,
and approximately 60-100 ml for elephants. An implant sized for use
in a human may be scaled up or down accordingly for other animals,
for example, about 8 times larger for an implant for a horse, or
for example, about 26 times larger for an implant for an
elephant.
[0138] Implants 40, 140, 240, 340, 440 and 540 can be prepared
where all or some of the particles are made of one material having
a single outer surface and/or may have one or more layers of the
same composition or different compositions, where the layers may be
of cross-linked and/or uncross-linked polymeric materials, or of
materials having different molecular weights, different densities,
different porosities, and the like. Such particles may be
structured and/or formulated to alter, and preferably control, the
release rate or profile of a drug from the implant. For example,
where it is desirable to quickly release an initial bolus of drug,
the center of a particle may include a polylactate coated with a
polylactate-polyglycolate copolymer, so as to enhance the rate of
initial degradation. Alternatively, the center may include a water
soluble polymer, such as polyvinyl alcohol and the like, coated
with a polylactate, so that upon degradation of the polylactate
exterior the center would dissolve and be rapidly washed out of the
eye.
[0139] Although not shown, it is to be appreciated that the
implants suitable for use in the present assemblies may be of
particles having geometries or forms other than rods and spheres.
Such other geometries or forms include, but are not limited to
fibers, sheets, films, cubes, ellipsoids, discs, plaques and the
like.
[0140] The upper limit for the particle size will be determined by
factors such as toleration for the particle, the size of the target
area of the eye, size limitations on insertion, ease of handling,
etc. Where sheets or films are employed, the sheets or films may be
at least about 0.5 mm by about 0.5 mm, usually in a range of about
3 to about 10 mm by about 5 to about 10 mm, with a thickness in a
range of about 0.1 to about 1.0 mm for ease of handling. Where
fibers are employed, the fiber diameter will generally be in the
range of about 0.05 to about 3 mm and the fiber length will
generally be in the range of about 0.5 to about 10 mm. Ellipsoids
may be in the range of about 0.5 .mu.m to 4 mm along the major and
minor axes thereof, with comparable volumes for other shaped
particles.
[0141] The present assemblies may include substantially no liquid
material in the lumen with the implant. For many types of implants
having certain compositions, by maintaining the implant in a dry
state the implant will have an extended storage life.
[0142] In other embodiments of the invention, the assemblies
further comprise a carrier medium, more specifically, a flowable
carrier medium, located in the lumen with the implant, for example,
sealed in the lumen with the implant.
[0143] It is to be appreciated that the suitable carrier media
described herein are, in many instances, suitable for use as
pushing fluids, or pushing gels, as described elsewhere herein, for
example, with such pushing fluids or gels being contained in a
syringe to be coupled to the present cannulas containing the
implants. For example, in some assemblies of the invention in which
the cannula contains an implant in dry form and the cannula is
structured to be coupled to a syringe containing a pushing fluid,
the pushing fluid may be made of the same or a similar material as
the carrier medium as will now be described.
[0144] The carrier medium preferably is a composition that causes
substantially no chemical or physical degradation or erosion of the
implant for the period of time in which the implant is intended to
be stored in the cannula. Preferably, the carrier medium functions
at least in part as a lubricant to facilitate delivery of the
implant from the lumen and into the eye. Depending on the
composition of the implant and other factors such as
biocompatibility, the carrier medium may be a saline solution,
other aqueous based or alcohol based media, including, without
limitation, flowable gels.
[0145] In a more specific embodiment, the carrier medium comprises
an aqueous component and a viscosity inducing component. The
viscosity inducing component is present in an amount effective in
increasing the viscosity of the medium. Any suitable, preferably
ophthalmically acceptable, viscosity inducing component may be
employed in the assemblies of the present invention. Many such
viscosity inducing components have been proposed and/or used in
ophthalmic compositions used on or in the eye. Advantageously, the
viscosity inducing component is present in an amount in a range of
about 0.05% to about 20% (w/v) of the liquid medium. In one
particularly useful embodiment, the viscosity inducing component is
a hyaluronic acid component, such as sodium hyaluronate, other
alkali metal hyaluronates and the like and mixtures thereof.
[0146] In one embodiment, the carrier medium has a viscosity of at
least about 10 cps or at least about 100 cps, preferably at least
about 1,000 cps, more preferably at least about 10,000 cps and
still more preferably at least about 70,000 cps, for example, up to
about 250,000 cps, or about 300,000 cps, at a shear rate of
0.1/second. It is to be appreciated that these measurements of
viscosity refer to the viscosity of the medium generally at room
temperature, which is in a range from about 20 degrees Celsius to
about 25 degrees Celsius. The carrier media preferably have
make-ups so as to be effectively, for example, manually, injected
into a posterior segment of an eye of a human or animal, preferably
through a 25 gauge needle, a 27 gauge needle, a 29 gauge needle or
even a 30 gauge needle.
[0147] Any suitable viscosity inducing component, for example,
ophthalmically acceptable viscosity inducing component, may be
employed in accordance with the present invention. Many such
viscosity inducing components have been proposed and/or used in
ophthalmic compositions used on or in the eye. The viscosity
inducing component is present in an amount effective in providing
the desired viscosity to the composition. Advantageously, the
viscosity inducing component may be present in an amount in a range
of about 0.05% or about 0.5% or about 1.0% to about 5% or about 10%
or about 20% (w/v) of the medium. The specific amount of the
viscosity inducing component employed depends upon a number of
factors including, for example and without limitation, the specific
viscosity inducing component being employed, the molecular weight
of the viscosity inducing component being employed, the viscosity
desired for delivering the implants, including for example, factors
such as shear thinning.
[0148] The viscosity inducing component preferably comprises a
polymeric component and/or at least one viscoelastic agent, such as
those materials which are useful in ophthalmic surgical
procedures.
[0149] Examples of useful viscosity inducing components include,
but are not limited to, hyaluronic acid (such as a polymeric
hyaluronic acid), carbomers, polyacrylic acid, cellulosic
derivatives, polycarbophil, polyvinylpyrrolidone, gelatin, dextrin,
polysaccharides, polyacrylamide, polyvinyl alcohol, polyvinyl
acetate, derivatives thereof and mixtures and copolymers
thereof.
[0150] The molecular weight of the presently useful viscosity
inducing components may be in a range of about 10,000 Daltons or
less to about 2 million Daltons or more. In one particularly useful
embodiment, the molecular weight of the viscosity inducing
component is in a range of about 100,000 Daltons or about 200,000
Daltons to about 1 million Daltons or about 1.5 million Daltons.
Again, the molecular weight of the viscosity inducing component
useful in accordance with the present invention may vary over a
substantial range based on the type of viscosity inducing component
employed, and the desired final viscosity of the medium in
question, as well as, possibly one or more other factors.
[0151] In one embodiment, a viscosity inducing component is a
hyaluronate component, for example, a metal hyaluronate component,
preferably selected from alkali metal hyaluronates, alkaline earth
metal hyaluronates and mixtures thereof, and still more preferably
selected from sodium hyaluronates and mixtures thereof. The
molecular weight of such hyaluronate component preferably is in a
range of about 50,000 Daltons or about 100,000 Daltons to about 1.3
million Daltons or about 2 million Daltons. In one embodiment, the
medium may include a hyaluronate component in an amount in a range
about 0.05% to about 0.5% (w/v).
[0152] In a more preferred embodiment, the hyaluronate component is
present in an amount in a range of about 1% to about 4% (w/v) of
the medium. In this case, the high molecular weight hyaluronate
component forms a gel, for example, an aqueous-based gel, that
slows particle sedimentation rate to the extent that often no
resuspension processing is necessary over the estimated shelf life,
for example, at least about 1 year or at least about 2 years or
longer, of the medium and implant contained in the cannula of the
present assemblies. Such a medium is especially useful in the
present assemblies since the gel cannot be easily removed by a
needle and syringe from a bulk container. Pre-filled cannulas as
described herein have the advantages of convenience for the
injector and the safety which results from less handling.
[0153] The carrier medium is advantageously ophthalmically
acceptable, that is substantially compatible with the eye and/or
causes no undue or significant detrimental effect on the eye, and
may include one or more conventional excipients useful in
ophthalmic compositions. The present carrier media preferably
include a major amount of liquid water. The present carrier media
may be, and are preferably, sterile, for example, prior to being
used in the eye.
[0154] Suitable carrier media may include one or more other
components in amounts effective to provide one or more useful
properties and/or benefits to the present assemblies. For example,
the carrier medium may include effective amounts of a preservative
component, preferably such components which are more compatible
with or friendly to the tissue in the posterior segment of the eye
into which the composition is placed than benzyl alcohol.
Preferably, however, since the implant and carrier medium are
advantageously sterilized and sealed in the cannula of the present
assembly, preservatives are not used in or in conjunction with the
implants or carrier media of the present invention. If
preservatives are to be used, some that may be beneficial include
without limitation, benzalkonium chloride, chlorhexidine, PHMB
(polyhexamethylene biguanide), methyl and ethyl parabens,
hexetidine, chlorite components, such as stabilized chlorine
dioxide, metal chlorites and the like, other ophthalmically
acceptable preservatives and the like and mixtures thereof. The
concentration of the preservative component, if any, is a
concentration effective to preserve the implant and the carrier
medium, and is often in a range of about 0.00001% to about 0.05% or
about 0.1% (w/v) of the carrier medium.
[0155] If suitable, the carrier medium may further include an
effective amount of resuspension component effective to facilitate
the suspension or resuspension of the implant particles in the
present assemblies. Such resuspension components are employed, for
example, to provide an added degree of insurance that the implant
particles remain in suspension, as desired and/or can be relatively
easily resuspended in the carrier medium, if such resuspension is
desired. Advantageously, the resuspension component employed in
accordance with the present invention, if any, is chosen to be more
compatible with or friendly to the tissue in the posterior segment
of the eye into which the composition is placed than polysorbate
80.
[0156] Any suitable resuspension component may be employed in
accordance with the present invention. Examples of such
resuspension components include, without limitation, surfactants
such as poloxanes, for example, sold under the trademark
Pluronic.RTM.; tyloxapol; sarcosinates; polyethoxylated castor
oils, other surfactants and the like and mixtures thereof.
[0157] One very useful class of resuspension components are those
selected from vitamin derivatives. Although such materials have
been previously suggested for use as surfactants in ophthalmic
compositions, they have been found to be effective in the present
invention as resuspension components. Examples of useful vitamin
derivatives include, without limitation, Vitamin E tocopheryl
polyethylene glycol succinates, such as Vitamin E tocopheryl
polyethylene glycol 1000 succinate (Vitamin E TPGS). Other useful
vitamin derivatives include, without limitation, Vitamin E
tocopheryl polyethylene glycol succinamides, such as Vitamin E
tocopheryl polyethylene glycol 1000 succinamide (Vitamin E TPGSA)
wherein the ester bond between polyethylene glycol and succinic
acid is replaced by an amide group.
[0158] The presently useful resuspension components are present, if
at all, in the carrier media in accordance with the present
invention in an amount effective to facilitate suspending the
implant particles in the present carrier media, for example, during
manufacture and thereafter. The specific amount of resuspension
component employed may vary over a wide range depending, for
example, on the specific resuspension component being employed, the
specific implant particles and carrier medium with which the
resuspension component is being employed and the like factors.
Suitable concentrations of the resuspension component, if any, in
the present carrier media are often in a range of about 0.01% to
about 5%, for example, about 0.02% or about 0.05% to about 1.0%
(w/v), of the carrier medium.
[0159] Without wishing to limit the invention to any particular
theory of operation, it is believed that the use of relatively high
viscosity carrier media, as described herein, provides for
effective, and preferably substantially uniform, suspension of
certain particulate implants.
[0160] For example, the implant may comprise a corticosteroid
component present as a plurality of microparticles which are
substantially uniformly suspended in the carrier medium. The
particles may remain substantially uniformly suspended in the
medium for at least about 1 week, preferably at least about 2 weeks
or at least about 1 month, and still more preferably at least about
6 months or at least about 1 year or at least about 2 years,
without requiring resuspension processing, that is, without
requiring being shaken or otherwise agitated to maintain the
corticosteroid component particles substantially uniformly
suspended in the composition.
[0161] Implants comprising particles suspended in a carrier medium
as described elsewhere herein provide such substantially uniform
suspension of the particles, so as to be able to provide a
consistent and accurate dose upon administration to an eye using
the present assemblies. The assemblies thus provide substantial
advantages relative to the prior art. In particular, the assemblies
may be manufactured, shipped and stored for substantial periods of
time without the implant particles precipitating from the carrier
medium. Having the particles maintained substantially uniformly
suspended in the carrier medium allows the assemblies to provide
long term dosing consistency and accuracy per unit dose amount
administered, without any need to resuspend the particles.
[0162] For some types of implants, it may be preferable to place
the implant into a region of an eye without the use of a carrier
fluid or carrier medium. For such purposes, a push-rod type
activator device rather than syringe 50 may be used to drive the
implant, for example, the implant stored in the cannula in a dry
state, from the cannula without the use of a carrier medium.
[0163] It may be desirable to provide a relatively constant rate of
release of the therapeutic component from the implant over the life
of the implant. For example, it may be desirable for the
therapeutic component to be released in amounts from about 0.01
.mu.g to about 2 .mu.g per day for the life of the implant.
However, the release rate may change to either increase or decrease
depending on the structure and/or formulation of the implant, for
example and without limitation, the biodegradable polymer matrix of
the implant. In addition, the release profile of the therapeutic
component, that is the rate of release of the therapeutic component
as a function of time, may include one or more linear portions
and/or one or more non-linear portions. Preferably, the release
rate is greater than zero once the implant has begun to degrade or
erode.
[0164] The particles which make up the implant may be monolithic,
i.e. having the active agent or agents homogenously distributed
through the polymeric matrix, or encapsulated, where a reservoir of
active agent is encapsulated by the polymeric matrix. Due to ease
of manufacture, monolithic implants may be preferable over
encapsulated forms. However, the greater control afforded by the
encapsulated, reservoir-type implant may be of benefit in some
circumstances, where the therapeutic level of the drug falls within
a narrow window. In addition, the therapeutic component may be
distributed in a non-homogenous pattern in the matrix. For example,
the implant may include a portion that has a greater concentration
of the therapeutic component relative to a second portion of the
implant.
[0165] The size and form of the implant can also be used to control
period of treatment and/or drug concentration at the site of
implantation. Larger implants will deliver a proportionately larger
dose, but, for example, depending on the surface to mass ratio, may
have a slower release rate. The particular size and geometry of the
implant are chosen to suit the site of implantation.
[0166] The proportions of the therapeutic component, matrix, and
any other additives and/or modifiers may be empirically determined
by formulating several implants with varying proportions. A USP
approved method for dissolution or release test can be used to
measure the rate of release (USP 23; NF 18 (1995) pp. 1790-1798).
For example, using the infinite sink method, a weighed sample of
the implant is added to a measured volume of a solution containing
0.9% NaCl in water, where the solution volume will be such that the
drug concentration is, after release, less than 5% of saturation.
The mixture is maintained at 37.degree. C. and stirred slowly to
maintain the implants in suspension. The appearance of the
dissolved drug as a function of time may be followed by various
methods known in the art, such as spectrophotometrically, HPLC,
mass spectroscopy, etc. until the absorbance becomes constant or
until greater than 90% of the drug has been released.
[0167] The particles which make up the implants 40, 140, 240, 340,
440 and 540 preferably comprise a composition comprising a
therapeutic component and matrix, for example, a polymeric
component, for controlling release of the therapeutic component
from the particle. Suitable polymeric materials or compositions for
use in the polymeric components of the particles of the present
invention include those materials which are compatible, that is,
biocompatible, with the eye so as to cause no substantial
interference with the functioning or physiology of the eye. Such
materials preferably are at least partially and more preferably
substantially completely biodegradable or bioerodible. Examples of
useful polymeric materials include, without limitation, such
materials derived from and/or including organic esters and organic
ethers, which when degraded result in physiologically acceptable
degradation products, including the monomers. Also, polymeric
materials derived from and/or including, anhydrides, amides,
orthoesters and the like, by themselves or in combination with
other monomers, may also find use. The polymeric materials may be
addition or condensation polymers, advantageously condensation
polymers. The polymeric materials may be cross-linked or
non-cross-linked, for example not more than lightly cross-linked,
such as less than about 5%, or less than about 1% of the polymeric
material being cross-linked. For the most part, besides carbon and
hydrogen, the polymers will include at least one of oxygen and
nitrogen, advantageously oxygen. The oxygen may be present as oxy,
e.g. hydroxy or ether, carbonyl, e.g. non-oxo-carbonyl, such as
carboxylic acid ester, and the like. The nitrogen may be present as
amide, cynao and amino. The polymers set forth in Heller,
Biodegradable Polymers in Controlled Drug Delivery, In:CRC Critical
Reviews in Therapeutic Drug Carrier Systems, Vol. 1, CRC Press,
Boca Raton, Fla. 1987, pp 39-90, which describes encapsulation for
controlled drug delivery, may find use in the present invention,
and that disclosure is specifically incorporated herein by
reference.
[0168] Of additional interest are polymers of hydroxyaliphatic
carboxylic acids, either homopolymers or copolymers, and
polysaccharides. Included among the polyesters of interest are
polymers of D-lactic acid, L-lactic acid, racemic lactic acid,
glycolic acid, polycaprolactone, and combinations thereof.
Generally, by employing the L-lactate, a slowly eroding polymer or
polymeric material is achieved, while erosion is substantially
enhanced with the lactate racemate.
[0169] Among the useful polysaccharides are, without limitation,
calcium alginate, and functionalized celluloses, particularly
carboxymethylecellulose esters characterized by being water
insoluble, a molecular weight of about 5000 Daltons to about
500,000 Daltons, etc.
[0170] Other polymers of interest include, without limitation,
polyvinyl alcohol, polyesters, polyethers and combinations thereof
which are biocompatible and may be biodegradable and/or
bioerodible.
[0171] Some preferred characteristics of the polymers or polymeric
materials for use in the particles suitable for use in the present
invention may include biocompatibility, compatibility with the
therapeutic component, ease of use of the polymer in making the
implants of the present invention, a half-life in the physiological
environment of at least about 6 hours, preferably greater than
about one day, not significantly increasing the viscosity of the
vitreous, and water insolubility.
[0172] The biodegradable polymeric materials which are included in
the particles are desirably subject to enzymatic or hydrolytic
instability. Water soluble polymers may be cross-linked with
hydrolytic or biodegradable unstable cross-links to provide useful
water insoluble polymers. The degree of stability can be varied
widely, depending upon the choice of monomer, whether a homopolymer
or copolymer is employed, employing mixtures of polymers, where the
polymers may be employed as varying layers or mixed.
[0173] The present implants advantageously are structured to have a
lifetime at least equal to the desired period of therapeutic
component administration in the eye, and may have lifetimes of
about 5 to about 10 times the desired period of administration. The
period of administration may be at least about 3 days, at least
about 7 days, at least about 15 days, at least about 20 days, at
least about 30 days, at least about 2 months, at least about 4
months, at least about 6 months, at least about 8 months, at least
about 10 months, at least about 1 year or longer.
[0174] The therapeutic component useful in the implants may include
any suitable pharmacologically active agent or therapeutic agent
for which sustained release, for example, in the eye, is desirable.
Advantageously, the therapeutic component is sufficiently soluble
in region of the eye in which the implant is to be placed, for
example, in the vitreous of the eye, such that it will be present
at a pharmacologically or therapeutically effective dose. In some
embodiments, the ocular implant may be of a make-up such that the
implant is substantially insoluble in the carrier medium when
contained in the lumen with the implant for example at room
temperature, but is soluble when placed in the environment of the
eye.
[0175] Pharmacological or therapeutic agents of interest include
hydrocortisone (5-20 mcg/l as plasma level), gentamycin (6-10
mcg/ml in serum), 5-fluorouracil (about 0.30 mg/kg body weight in
serum), sorbinil, IL-2, TNF, Phakan-a (a component of glutathione),
thioloa-thiopronin, Bendazac, acetylsalicylic acid,
trifluorothymidine, interferon (alpha., beta. and gamma.), immune
modulators, e.g. lymphokines, monokines, and growth factors, etc.
Pharmacological or therapeutic agents of particular interest
include, without limitation, anti-glaucoma drugs, such as the
beta-blockers, such as timolol maleate, betaxolol and metipranolol;
mitotics, such as pilocarpine, acetylcholine chloride,
isofluorophate, demacarium bromide, echothiophate iodide,
phospholine iodide, carbachol, and physostigimine; epinephrine and
salts, such as dipivefrin hydrochloride; and dichlorphenamide,
acetazolamide and methazolamide; anti-cataract and anti-diabetic
retinopathy drugs, such as aldose reductase inhibitors, such as
tolrestat, lisinopril, enalapril, and statil; thiol cross-linking
drugs other than those considered previously; anti-cancer drugs,
such as retinoic acid, methotrexate, adriamycin, bleomycin,
triamcinoline, mitomycin, cis-platinum, vincristine, vinblastine,
actinomycin-D, ara-c, bisantrene, CCNU, activated cytoxan, DTIC,
HMM, melphalan, mithramycin, procarbazine, VM26, VP16, and
tamoxifen; immune modulators, other than those indicated
previously; anti-clotting agents, such as tissue plasminogen
activator, urokinase, and streptokinase; anti-tissue damage agents,
such as superoxide dismutase; proteins and nucleic acids, such as
mono- and polyclonal antibodies, enzymes, protein hormones and
genes, gene fragments and plasmids; steroids, particularly
anti-inflammatory or anti-fibrous drugs, such as cortisone,
hydrocortisone, prednisolone, prednisome, dexamethasone,
progesterone-like compounds, medrysone (HMS) and fluorometholone;
non-steroidal anti-inflammatory drugs, such as ketrolac
tromethamine, dichlofenac sodium and suprofen; antibiotics, such as
loridine (cephaloridine), chloramphenicol, clindamycin, amikacin,
tobramycin, methicillin, lincomycin, oxycillin, penicillin,
amphotericin B, polymyxin B, cephalosporin family, ampicillin,
bacitracin, carbenicillin, cepholothin, colistin, erythromycin,
streptomycin, neomycin, sulfacetamide, vancomycin, silver nitrate,
sulfisoxazole diolamine, and tetracycline; other antipathogens,
including anti-viral agents, such as idoxuridine, trifluorouridine,
vidarabine (adenine arabinoside), acyclovir (acycloguanosine),
pyrimethamine, trisulfapyrimidine-2, clindamycin, nystatin,
flucytosine, natamycin, miconazole and piperazie derivatives, e.g.
diethylcarbamazine; cycloplegic and mydriatic agents, such as
atropine, cyclogel, scopolamine, homatropine and mydriacyl; and the
like and mixtures thereof.
[0176] Other agents useful in the systems of the present invention
include, without limitation, anticholinergics, anticoagulants,
antifibrinolytic agents, antihistamines, antimalarials, antitoxins,
chelating agents, hormones, immunosuppressives, thrombolytic
agents, vitamins, salts, desensitizing agents, prostaglandins,
amino acids, metabolites, antiallergenics, and the like and
mixtures thereof.
[0177] In some embodiments of the invention, the implants are
suitable for treating inflammation-mediated conditions of the eye.
The term "inflammation-mediated condition of the eye" is meant to
include any condition of the eye which may benefit from treatment
with an anti-inflammatory agent, and is meant to include, but is
not limited to, uveitis, macular edema, acute macular degeneration,
retinal detachment, ocular tumors, fungal or viral infections,
multifocal choroiditis, diabetic uveitis, proliferative
vitreoretinopathy (PVR), sympathetic ophthalmia, Vogt
Koyanagi-Harada (VKH) syndrome, histoplasmosis, and uveal
diffusion.
[0178] For example, the implant may comprise a plurality of
particles comprising a steroidal anti-inflammatory agent, for
example but not limited to, dexamethasone, and a bioerodible
polymer, for example but not limited to, a polylactic acid
polyglycolic acid (PLGA) copolymer. The plurality of particles,
when implanted in an eye, preferably delivers the therapeutic agent
to the eye, for example, to the vitreous of the eye, in an amount
sufficient to reach a concentration equivalent to at least about
0.05 .mu.g/ml dexamethasone within about 48 hours and maintain a
concentration equivalent to at least about 0.03 .mu.g/ml
dexamethasone for at least about three weeks. In another embodiment
of the invention, the implant preferably delivers the agent to the
vitreous in an amount sufficient to reach a concentration
equivalent to at least about 0.2 .mu.g/ml dexamethasone within
about 6 hours and maintains a concentration equivalent to at least
about 0.01 .mu.g/ml dexamethasone for at least about three
weeks.
[0179] "A concentration equivalent to dexamethasone", as used
herein, refers to the concentration of a steroidal
anti-inflammatory agent necessary to have approximately the same
efficacy in vivo as a particular dose of dexamethasone. For
example, hydrocortisone is approximately twenty-five fold less
potent than dexamethasone, and thus a 25 mg dose of hydrocortisone
would be equivalent to a 1 mg dose of dexamethasone. One of
ordinary skill in the art would be able to determine the
concentration equivalent to dexamethasone for a particular
steroidal anti-inflammatory agent from one of several standard
tests known in the art. Relative potencies of selected
corticosteroids may be found, for example, in Gilman, A. G., et
al., eds. (1990). Goodman and Gilman's: The Pharmacological Basis
of Therapeutics. 8th Edition, Pergamon Press: New York, p. 1447,
which is incorporated herein by this specific reference.
[0180] In other embodiments, the implant delivers the agent to the
vitreous in an amount sufficient to reach a concentration
equivalent to at least about 0.3 .mu.g/ml, or at least about 0.5
.mu.g/ml, or at least about 0.75 .mu.g/ml, or at least about 1.0
.mu.g/ml, or at least about 2.0 .mu.g/ml dexamethasone within about
4 hours, or within about 6 hours, or within about 8 hours, or
within about 10 hours, or within about 24 hours.
[0181] A concentration equivalent to at least about 0.01 .mu.g/ml,
or at least about 0.02 .mu.g/ml, or at least about 0.03 .mu.g/ml,
or at least about 0.05 .mu.g/ml, or at least about 0.07 .mu.g/ml
dexamethasone may be maintained for an extended period of time
(e.g., at least about three weeks or longer). The preferred
concentration levels of therapeutic component or drug in the
vitreous may vary according to the inflammatory mediated condition
being treated. For example, for treating uveitis, a concentration
equivalent of at least about 0.01 to 0.1 .mu.g/ml dexamethasone is
preferred.
[0182] In one embodiment, the concentration of therapeutic
component is maintained for least about four weeks. In other
embodiments, the concentration is maintained for at least about
five weeks, or at least about six weeks, or at least about seven
weeks, or at least about eight weeks, or at least about nine weeks,
or at least about 10 weeks, or at least about 12 weeks or longer.
The preferred duration of therapeutic component or drug release may
be determined by the inflammatory mediated condition being treated.
For treating uveitis, a drug release duration of at least about
three weeks is preferable, more preferably at least about four
weeks. In one embodiment, more than one implant 16 may be
sequentially implanted into the vitreous, for example in different
locations in the vitreous, in order to maintain therapeutic
component or drug concentrations for even longer periods.
[0183] The formulation of the implants in accordance with the
present invention may vary according to the desired therapeutic
component release profile, the particular therapeutic component
used, the condition being treated, and the medical history of the
patient.
[0184] Copolymers of glycolic and lactic acid are of particular
interest, where the rate of biodegradation is controlled by the
ratio of glycolic to lactic acid. The % of polylactic acid in the
polylactic acid polyglycolic acid (PLGA) copolymer can be in a
range of about 0% to about 100%, preferably about 15% to about 85%,
and more preferably about 35% to about 65%. In a particularly
preferred embodiment, a 50/50 PLGA copolymer is used. The most
rapidly degraded copolymer has roughly equal amounts of glycolic
and lactic acid, where either homopolymer is more resistant to
degradation. The ratio of glycolic acid to lactic acid will also
affect the brittleness of in the implant, where a more flexible
implant is desirable for larger geometries.
[0185] Moreover, in embodiments in which the implant comprises a
plurality of particles, the particles themselves may be made up of
different compositions, one from the other. For example, a single
implant may comprise one or more particles comprising a first
therapeutic component, and one or more other particles comprising a
second therapeutic component that is different from the first
therapeutic component. Implants made up of various differently
composed particles, in different proportions, can be employed to
treat the eye.
[0186] In some situations, the implant comprises a plurality of
different particles having the same or different therapeutic agent,
and the same or different release rates and/or delayed release
rates. For example, 2, 3, 4 or more different particles can make up
an implant. In this way, in a single administration a course of
drug treatment may be achieved, where the pattern of release may be
greatly varied. For example, a biphasic or triphasic release
profile may be achieved with a single administration of an implant
comprising a plurality of substantially uniformly sized
microparticles having different compositions and/or the same
compositions in different proportions.
[0187] Various techniques may be employed to produce the particles
making up the implants described and shown herein. Useful
techniques include, but are not necessarily limited to, extrusion
methods, co-extrusion methods, carver press method, die cutting
methods, heat compression, combinations thereof and the like.
Techniques for producing the therapeutic component of the particles
include solvent-evaporation methods, phase separation methods,
interfacial methods and the like.
[0188] Generally, implants that are compatible for use in the
present assemblies can be formed by a number of known methods,
including phase separation methods, interfacial methods, extrusion
methods, compression methods, molding methods, injection molding
methods, heat press methods and the like. Particular methods used
can be chosen, and technique parameters varied, based on desired
implant size and drug release characteristics. For implants
described herein which comprise a plurality of substantially
uniformly sized particles, preferably microspheres, which can be
delivered through cannulas corresponding to a 21 gauge needle or
smaller, and which therefore have cross-sectional diameters of
0.026 inches or less, or similar cross-sectional areas,
microfluidic techniques are useful. Extrusion methods, as well as
injection molding, compression molding, and tableting methods, may
also be effective to achieve the small cross-sectional diameters or
areas required of microspheres.
[0189] In manufacturing an assembly according to the invention, the
implant is loaded in the cannula having the sleeve attached
thereto, and the distal closure element and the proximal closure
element are used to close the distal opening and the proximal
opening respectively. The loaded, closed assembly may then be
sterilized using appropriate methods, such as gamma or beta
radiation and the like. Inscriptions or indicia located on the
sleeve or cannula can include the appropriate information relative
to particular implant loaded. Given this interchangeability, unique
apparatus for the delivery of selected implants can be easily
identified and utilized by providing the particular labeled
assembly for the selected implant.
[0190] When the assemblies are assembled, it may be further
desirable that the implant be positioned just proximal of the
opening at the cannula tip. In this fashion, the introduction of
air into the eye can be avoided when the implant is ejected, as
could otherwise occur were the implant located further within the
cannula lumen and an air bubble or air pocket allowed to exist
between the cannula tip and the implant and ejection of the implant
were to force the air bubble or air pocket into the eye. One method
to accomplish this is to load the implant distally into the cannula
followed by a holding element located proximal of the implant. The
holding element may comprise a suitable structure, for example a
detent or berm in the cannula lumen, that maintains the distal
position of the implant while allowing fluid from the syringe to
bypass the holding element and drive the implant forward during an
implant procedure.
[0191] To guard against inadvertent premature release of the
implant, the cannula can have a slight bend incorporated into the
tip such that enough friction exists between the inner wall of the
cannula and the implant to hold the implant in place, but at the
same time, the frictional force is easily overcome by action of the
plunger to eject the implant upon actuation of the apparatus.
[0192] Other cannula designs can likewise achieve the desired
effect of avoiding the introduction of air into the eye upon
ejection of the implant. For example, the implant can be positioned
proximally of the cannula tip but with sufficient tolerance between
the implant and cannula wall to provide for air exhaust past the
implant as it is moved through the cannula. Adequate tolerances are
those that retain air in front of the implant at close to ambient
pressure as the implant is moved along the cannula. Because fluid
pressure within the eye is typically slightly positive relative to
ambient pressure, air at ambient pressure will not enter the
eye.
[0193] As can be appreciated, an apparatus according to the
invention that is provided loaded with the desired implant is of
great benefit to the physician user. Such apparatus can be provided
sterile packaged for a single use application. The user need not
ever handle the implant itself. Further, when the apparatus is
configured to deliver a micro-implant, the apparatus provides a
self-sealing method for delivery, as previously discussed. This has
enormous benefit to the physician and patient in that the entire
implant procedure can safely, easily, and economically be performed
in a physician's office, without the need for more costly surgical
support currently required for implant delivery.
[0194] Thus, in an exemplary embodiment, the present invention
provides a narrow gauge, polymer-based, drug delivery system
suitable for intraocular injection. At approximately 0.015 inches
in diameter, the ocular implants of the assemblies are typically
too brittle and fragile for use in a standard delivery needle or
device. However, these implants can be relatively easily placed
into the cannulas of the present assemblies which often have
dimensions equivalent to a 25 gauge, ultra-thin walled needle or
smaller. When attached to a syringe containing a viscous pushing
fluid, for example, sodium hyaluronate gel, the assemblies can
inject the implants precisely at the required intraocular location.
Further, the present assemblies can be safely stored for long
periods of time. The assemblies can be sterilized using
irradiation, for example, beta or gamma irradiation, and require no
additional excipients to seal the implant. While in the assemblies,
the implants are protected from light, moisture and microbial
contamination. Immediately before injection of the implant from the
assembly, the protective closure elements are easily removed from
the cannula and the cannula is attached to a syringe containing the
pushing fluid.
[0195] The following Examples set forth experiments and/or
exemplify features of the present invention and are not intended to
limit the scope of the present invention.
EXAMPLE 1
Dexamethasone-Containing Microspheres in a Pre-Loaded Assembly
[0196] Microspheres are provided comprising 40% by weight of
poly-d, l-lactide-co-glycolide copolymer (Boehringer-Ingleheim
752H) and 60% by weight of dexamethasone, and having uniform
diameters of 280.+-.5 .mu.m. Each microsphere has about 0.0083 mg
dexamethasone. A cannula having the dimensions of a thin-walled 25
gauge needle (i.d.=0.3 mm) is filled with about 85 of these
microspheres, in a side-by-side array, to reach a total drug
content of about 0.7 mg. The total length of loaded microspheres in
the cannula is about 23.8 mm, compared to 15.8 mm of a thermally
extruded rod with a 280 .mu.m diameter and 0.7 mg dexamethasone.
The cannula is sealed with closure elements located covering the
distal and proximal end openings of the needle to form an assembly
that will be later used with a barrel and plunger actuator
mechanism to inject the microspheres into an eye without the use of
a carrier medium.
EXAMPLE 2
Dexamethasone-Containing Microspheres and Rod-Shaped Particles
Having Different Release Rates in a Pre-Loaded Assembly
[0197] In batch 1, microspheres are provided comprising 40% by
weight poly-d, l-lactide-co-glycolide copolymer
(Boehringer-Ingleheim 752H) and 60% by weight dexamethasone, and
having uniform diameters of 280.+-.5 .mu.m. Each microsphere has
about 0.0083 mg dexamethasone. Separately, in batch 2, extruded
rod-shaped particles are provided comprising 40% by weight poly-d,
l-lactide (Boehringer-Ingleheim 203S) and 60% by weight
dexamethasone, each rod-shaped particle having a length of about 2
mm and a diameter of 280.+-.5 .mu.m. Each rod-shaped particle
contains about 0.058 mg dexamethasone. An assembly in accordance
with the invention as described herein is provided including a
cannula having the dimensions of a thin-walled 25-g needle
(i.d.=0.3 mm). The cannula is filled with about 42 microspheres
from batch 1 and 6 rod shaped particles from batch 2 to reach a
total drug content of about 0.7 mg. Total length of loaded
microspheres and rod shaped particles in the cannula is about 23.8
mm, compared to 15.8 mm of a thermally extruded rod with a 280
.mu.m diameter and 0.7 mg dexamethasone. The cannula is sealed with
closure elements located covering the distal and proximal end
openings of the needle to form an assembly that will be later used
with a barrel and plunger actuator mechanism to inject the
microspheres into an eye without the use of a carrier medium.
EXAMPLE 3
Treatment of Glaucoma Using an Implant Made Up of
Bimatoprost-Containing Microspheres and Cyclosporine-Containing
Microspheres
[0198] A 72 year old female suffering from glaucoma in both eyes
receives an intraocular implant in each of both eyes using
assemblies in accordance with the invention. Each assembly includes
a cannula having dimensions equivalent to a 25 gauge needle. The
cannula contains an implant made up of 100 microspheres, each
microsphere having a diameter of about 500 .mu.m. 90 of the
microspheres contain bimatoprost and poly-d, l-lactide-co-glycolide
copolymer, and 10 of the microspheres contain a cyclosporine and
poly-d, l-lactide-co-glycolide copolymer. The proximal and distal
end openings of the cannula are sealed with proximal and distal
closure elements, respectively, as described elsewhere herein.
After removing the proximal and distal closure elements, the
cannula is coupled to a syringe containing a suitable amount of an
aqueous-based pushing gel. Each eye then receives an implant
containing about 500 mg of bimatoprost and about 0.0028 mg of
cyclosporine. The implant is delivered into the vitreous of each
eye using the syringe coupled to the cannula and the pushing
gel.
[0199] In about two days, the patient reports a substantial
reduction in ocular discomfort. Examination reveals that the
intraocular pressure has decreased; the average intraocular
pressure measured at 8:00 AM has decreased from 28 mm Hg to 14.3 mm
Hg. The patient is monitored monthly for about 6 months.
Intraocular pressure levels remain below 15 mm Hg for the next six
months
EXAMPLE 4
Manufacture and Extended Storage of Bimatoprost/Polymer Intraocular
Implant-Containing Assemblies
[0200] Bimatoprost is combined with a biodegradable polymer
composition in a mortar. The combination is mixed with a shaker for
about 15 minutes. The resulting powder blend is scraped off the
wall of the mortar and is then remixed for an additional 15
minutes. The mixed powder blend is then heated to a semi-molten
state at a specified temperature for a total of 30 minutes, forming
a polymer/drug melt.
[0201] The polymer/drug melt is pelletized using a 9 gauge
polytetrafluoroethylene (PTFE) tubing. The pellets are melted and
extruded at a specified core extrusion temperature to form very
thin filaments having maximum diameters of about 0.015 inches. The
filaments are then cut into individual implants, each having a
length of about 6 mm.
[0202] One of the implants is loaded into a 25-gauge cannula having
a sleeve suitable for coupling a distal end of the cannula to a
standard syringe and a needle length of about 15 cm. Silicone
polymer closure elements are coupled to the proximal and distal
ends of the cannula. The assembly made up of the cannula, sleeve,
implant and closure elements is sealed and sterilized by
irradiating the entire assembly with gamma radiation. The
sterilized assembly is then appropriately labeled, packaged and
stored in a cool dry location. When the assembly is opened and
examined a year later, it is observed that the implant has not
eroded, degraded or otherwise chemically or physically changed in
any significant way from when the assembly was originally
produced.
EXAMPLE 5
Bimatoprost/Polymer Implants Used to Treat Glaucoma
[0203] A 72 year old female is suffering from glaucoma in both
eyes. A physician selects two packages, each containing an assembly
containing a bimatoprost/polymer implant, the assembly having been
produced six months earlier as described in Example 4. The
physician treats each eye by opening one of the packages, removing
the closure elements from the proximal and distal ends of the
cannula, coupling the pre-loaded cannula to a syringe containing a
suitable pushing fluid, and injecting the implant into the vitreous
of the eye. In about two days, the patient reports a substantial
relief in ocular comfort. Healing of the injection site appears to
be complete. Further examination reveals that the intraocular
pressure has decreased, the average intraocular pressure measured
at 8:00 AM has decreased from 28 mm Hg to 14.3 mm Hg. The patient
is monitored monthly for about 6 months. Intraocular pressure
levels remain below 15 mm Hg for six months, and the patient
reports reduced ocular discomfort.
EXAMPLE 6
Dexamethasone/PLGA Implants Used to Treat Macular Degeneration
[0204] A 70 year old female patient complains of blind spots in her
vision. Upon examination, the physician diagnoses her with the wet
form of macular degeneration. Upon examination of her eyes, it is
found that blood vessels have grown beneath the retina of each eye
and are leaking blood and fluid which are causing the blind spots.
On the day of scheduled treatment, the physician selects a
pre-filled assembly in accordance with the invention from a supply
of such pre-filled assemblies. Each selected assembly is contained
in a sterile packaging and appropriately labeled as containing an
implant in the form of 80 bioerodible microspheres each containing
dexamethasone (70 percent by weight) distributed in a polylactic
acid polyglycolic acid (PLGA) copolymer (30 percent by weight). The
physician carefully removes the proximal closure element from one
end of the cannula and secures the sleeve of the assembly to a
syringe containing an appropriate amount of sodium hyaluronate gel.
The physician removes the distal closure element from the distal
end of the cannula and positions the distal end of the cannula in
the vitreous of the eye. The physician presses the syringe plunger
to cause the gel to push the microspheres into the eye. After three
days, the patient is examined and there is found a decrease in the
amount of leakage at the back of the eyes. The implants are left to
remain in the patient's eyes in order to provide continuous dosing
of dexamethasone over the next two months. Vision is improved and
further degeneration of vision is prevented.
EXAMPLE 7
Manufacture of Pre-Loaded Assemblies Containing Triamcinolone
Acetonide Suspended in a Sodium Hyaluronate Viscous Medium
[0205] Assemblies in accordance with the invention are manufactured
as follows.
[0206] A concentrated triamcinolone acetonide dispersion is made by
combining triamcinolone acetonide with water, Vitamin E-TPGS and
.gamma.-cyclodextrin. These ingredients are mixed to disperse the
triamcinolone acetonide, and then autoclaved.
[0207] Sodium hyaluronate is purchased as a sterile powder. The
sterile sodium hyaluronate is dissolved in water to make an aqueous
concentrate. The concentrated triamcinolone acetonide dispersion is
mixed and added as a slurry to the sodium hyaluronate concentrate.
Water is added q.s. (quantum sufficit, as much as suffices, in this
case as much as is required, to prepare the suspension) and the
mixture is mixed until homogenous.
[0208] The homogenous mixture is a loose flocculation of
triamcinolone acetonide particles suspended in a viscous sodium
hyaluronate medium. The homogenous mixture is loaded in unit doses
into sterile 25 gauge cannulas which are sealed and packaged as
described in Example 4. The packages are sterilized by beta or
gamma radiation.
[0209] The assemblies are marketed as single dose unit packages
that are therapeutically effective in treating macular edema when
injected intravitreally into human eyes.
EXAMPLE 8
Pre-Loaded Assembly with Plugged, Small Diameter Cannula
[0210] An alternate embodiment of an ocular implant delivery
assembly ("applicator") can comprise a bioerodible polymeric plug
to keep the implant in the needle (that is in the cannula) of the
applicator without any need to secure the implant with a sleeve or
O-ring. This can be accomplished by putting the bioerodible
polymeric plug into the applicator cannula. The cannula is a 25
gauge needle cannula. Thus, the implant is loaded in the cannula
and about 10-30 ul of a suitable lubricant such as HPMC
(hydroxypropyl methyl cellulose) is then applied to just the distal
end of the cannula (that is to block just the lumen at the distal
end of the cannula), or preferably the biodegradable plug material
is applied so as to block both proximal and distal end openings of
the pre-loaded (with the implant) cannula, that is both distal and
proximal to the implant in the lumen of the cannula. A cellulose
lubricant such as HPMC dries over night as a film and acts to
decrease the internal diameter of both end openings of the cannula
thereby preventing the implant from falling out of the cannula. The
bioerodible polymer plug material can be any suitable material
which can act to temporarily plug one or both ends of the lumen
(distal alone or both distal and proximal to the implant in the
lumen of the cannula). The plug serves the temporary purpose of
retaining the implant securely in the lumen until the plunger is
advanced, and the plug is thereby broken (film plug) or advanced
along with the implant into the ocular site of administration of
the implant.
[0211] When ready for use, a needle assembly which comprises the
blocked HPMC blocked cannula is placed onto a syringe filled with
either saline, or a more viscous solution like hyaluronic acid or
HPMC, and the polymeric seals are easily broken when the plunger of
the syringe is advanced. Having a sleeveless needle on the
applicator allows the use of ultra-thin wall needles. 25G Popper
needles which have an internal diameter of 0.015 inch may be used.
This embodiment provides a sleeveless system which permits use of
thin-wall needles to thereby significantly reduce the size of the
hole in the eye upon use of the applicator and still maintain
implants that have reasonable diameters. A sleeveless needle also
allows for deeper entry into the vitreous or sub-Tenon's space
since the somewhat obstructive sleeve is not present.
EXAMPLE 9
Pre-Loaded Assembly with Capped, Small Diameter Cannula
[0212] A further alternate embodiment of an ocular implant delivery
assembly can comprise a polymeric cap to keep the implant in the
needle or cannula of the assembly without any need to secure the
implant with a sleeve or O-ring. This can be accomplished by
putting a polymeric cap, for example and without limitation, a
flexible or soft, substantially clear silicone polymeric cap, onto
the distal end of the cannula. The cannula is a 25 gauge needle.
The cap is substantially as shown in FIGS. 10 to 14, and described
elsewhere herein. The cap, prior to being placed on the distal end
of the cannula, is a substantially solid soft silicone polymeric
disc. Thus, substantially no structure, such as a partial bore, is
included in the cap prior to the cap being placed on the distal end
of the cannula. The cap covers the entire distal end opening of the
cannula. The cap also has markings every 0.25 mm radially outwardly
from the cannula which provides a scale of the distance between
each marking and the cannula.
[0213] After the implant is placed into the lumen of the cannula,
the cap is placed over the distal end opening and distal end of the
cannula so that the distal end opening of the cannula is within the
silicone polymeric disc. In this manner, not only is the implant
prevented from passing through the distal end opening of the
cannula but, in addition, the distal end opening of the cannula is
sealed so that no fluid can enter the lumen of the cannula through
the distal end opening or exit the lumen through the distal end
opening.
[0214] In addition, either a removable proximal closure element
and/or a proximal plug can be placed near the proximal end opening
of the cannula to seal the proximal end opening prior to use of the
assembly.
[0215] In use, the cannula, for example with the proximal plug
and/or removable proximal closure element removed, is secured to a
syringe or push-rod device. The silicone polymeric cap remains in
place. The silicone polymeric cap and exposed portion of the
cannula are dipped in normal saline solution to lubricate the
cannula and cap. The silicone polymeric cap is placed in contact
with a surface of an eye, for example, using the scale noted above
to determine the desired implantation location, such as by placing
the tip of the cannula at a specific distance from the limbus of
the eye, into which the implant is to be placed. Because the cap is
clear, the operator can see the cannula tip through the cap and can
verify that the cannula tip is at the desired implantation
location. The cannula is urged distally so that it passes through
the cap and into the eye. As the cannula passes through the cap,
substantially no silicone polymeric material passes into the lumen
of the cannula or into the eye. The cannula is moved further into
the eye until it is located at the target area within the eye in
which the implant is to be placed. This distal movement of the
cannula into the eye causes the silicone polymeric cap to move
proximally along the cannula toward the syringe device or push-rod
device. The operator performing the procedure is provided with a
visualization of how far the cannula has been placed in the eye
based on the distance between the cap and the syringe device or
push-rod device.
[0216] Once the distal end and distal end opening of the cannula
are at the target location within the eye, the syringe device or
push-rod device is activated to urge the implant in the lumen of
the cannula forward or distally out of the lumen and into the eye.
After implantation of the implant, the cannula is removed from the
eye and the procedure is completed.
[0217] A number of publications and patents have been cited
hereinabove. All of the cited publications and patents are hereby
incorporated by reference in their entireties.
[0218] While this invention has been described with respect to
various specific examples and embodiments, it is to be understood
that the invention is not limited thereto and that it can be
variously practiced within the scope of the following claims.
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