U.S. patent application number 13/842288 was filed with the patent office on 2013-09-19 for apparatus and formulations for suprachoridal drug delivery.
This patent application is currently assigned to ISCIENCE INTERVENTIONAL CORPORATION. The applicant listed for this patent is ISCIENCE INTERVENTIONAL CORPORATION. Invention is credited to Stanley R. Conston, David Sierra, Ronald Yamamoto.
Application Number | 20130245600 13/842288 |
Document ID | / |
Family ID | 38444302 |
Filed Date | 2013-09-19 |
United States Patent
Application |
20130245600 |
Kind Code |
A1 |
Yamamoto; Ronald ; et
al. |
September 19, 2013 |
APPARATUS AND FORMULATIONS FOR SUPRACHORIDAL DRUG DELIVERY
Abstract
Drug formulations, devices and methods are provided to deliver
biologically active substances to the eye. The formulations are
delivered into scleral tissues adjacent to or into the
suprachoroidal space without damage to the underlying choroid. One
class of formulations is provided wherein the formulation is
localized in the suprachoroidal space near the region into which it
is administered. Another class of formulations is provided wherein
the formulation can migrate to another region of the suprachoroidal
space, thus allowing an injection in the anterior region of the eye
in order to treat the posterior region.
Inventors: |
Yamamoto; Ronald; (San
Francisco, CA) ; Conston; Stanley R.; (San Carlos,
CA) ; Sierra; David; (Aptos, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
ISCIENCE INTERVENTIONAL CORPORATION |
Menlo Park |
CA |
US |
|
|
Assignee: |
ISCIENCE INTERVENTIONAL
CORPORATION
Menlo Park
CA
|
Family ID: |
38444302 |
Appl. No.: |
13/842288 |
Filed: |
March 15, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
11709941 |
Feb 21, 2007 |
|
|
|
13842288 |
|
|
|
|
60776903 |
Feb 22, 2006 |
|
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Current U.S.
Class: |
604/506 |
Current CPC
Class: |
A61K 31/722 20130101;
A61F 9/007 20130101; A61K 9/0048 20130101; A61K 31/728 20130101;
A61K 31/718 20130101; A61F 9/0026 20130101; A61K 9/1635 20130101;
A61K 31/717 20130101; A61F 9/0017 20130101; A61K 9/14 20130101;
A61K 9/0051 20130101; A61K 47/36 20130101; A61K 31/737
20130101 |
Class at
Publication: |
604/506 |
International
Class: |
A61F 9/00 20060101
A61F009/00 |
Claims
1. A method of administering drugs in the suprachoroidal space of
the eye comprising the steps of placing a needle in scleral tissues
toward the suprachoroidal space at a depth of at least half of the
scleral thickness, and injecting a drug formulation through said
needle into the sclera in close proximity to the inner boundary of
the sclera such that said formulation dissects the scleral tissues
adjacent to said suprachoroidal space and enters said
suprachoroidal space.
2. A method of administering drugs in the suprachoroidal space of
the eye comprising the steps of placing a needle in scleral tissues
toward the suprachoroidal space at a depth of at least half of the
scleral thickness, and injecting a drug formulation through said
needle into the sclera such that said formulation dissects the
scleral tissues adjacent to said suprachoroidal space to enter said
suprachoroidal space and flows toward the posterior region of said
suprachoroidal space.
3. A method for administering drugs to an eye comprising: injection
of a drug formulation into the suprachoroidal space, said drug
formulation comprising a biologically active substance and a
polymer excipient, wherein the drug formulation forms a layer
between the choroid and sclera in the area of administration.
4. The method according to claim 3, wherein said injection
comprises injection through a needle.
5. The method according to claim 3, wherein said biologically
active substance comprises a steroid or non-steroidal
anti-inflammatory agent to treat inflammation and edema.
6. The method according to claim 3 wherein said polymer excipient
comprises a water soluble polymer.
7. The method according to any one of claim 1, 2, or 4 wherein the
placing of the needle tip is guided by imaging surrounding
tissues.
8. The method according to any one of claim 1, 2, or 4 wherein said
needle comprises a sensor to guide the placement of the needle
tip.
9. A method for administering drugs to an eye comprising: injection
of a drug formulation into the suprachoroidal space, said drug
formulation comprising microspheres or microparticles with an outer
diameter in the range of about 1 to 33 microns, and a polymer
excipient, wherein said microspheres or microparticles comprising a
biologically active substance, wherein said polymer excipient acts
to uniformly distribute the microspheres or microparticles
administered to the suprachoroidal space.
10. A method for administering drugs to an eye comprising:
injection of a drug formulation into the suprachoroidal space, said
drug formulation comprising microspheres or microparticles with an
outer diameter in the range of about 1 to 33 microns; wherein said
microspheres or microparticles comprise a biologically active
substance, wherein said microspheres or microparticles subsequently
migrate posteriorly to treat a posterior region distant from the
injection site.
11. The method according to 10 wherein said drug formulation
additionally comprises a polymer excipient.
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This is a continuation of U.S. Ser. No. 11/709,941, filed
Feb. 21, 2007, which, in turn, claims the priority of provisional
U.S. Ser. No. 60/776,903, filed Feb. 22, 2006, pursuant to 35 USC
119(e). The prior applications are incorporated herein by reference
in their entirety for all purposes.
FIELD OF THE INVENTION
[0002] The invention relates to the field of drug delivery into the
eye.
BACKGROUND OF INVENTION
[0003] The eye is a complex organ with a variety of specialized
tissues that provide the optical and neurological processes for
vision. Accessing the eye for medical treatment is hindered by the
small size and delicate nature of the tissues. The posterior region
of the eye, including the retina, macula and optic nerve, is
especially difficult to access due to the recessed position of the
eye within the orbital cavity. In addition, topical eye drops
penetrate poorly into the posterior region, further restricting
treatment options.
[0004] The suprachoroidal space is a potential space in the eye
that is located between the choroid, which is the inner vascular
tunic, and the sclera, the outer layer of the eye. The
suprachoroidal space extends from the anterior portion of the eye
near the ciliary body to the posterior end of the eye near the
optic nerve. Normally the suprachoroidal space is not evident due
to the close apposition of the choroid to the sclera from the
intraocular pressure of the eye. Since there is no substantial
attachment of the choroid to the sclera, the tissues separate to
form the suprachoroidal space when fluid accumulation or other
conditions occur. The suprachoroidal space provides a potential
route of access from the anterior region of the eye to treat the
posterior region.
[0005] The present invention is directed to drug formulations for
administration to the suprachoroidal space and an apparatus to
deliver drugs and other substances in minimally invasive fashion to
the suprachoroidal space.
SUMMARY
[0006] Drug formulations are provided characterized by a zero shear
viscosity of at least 300,000 mPas. A subclass of the drug
formulations is further characterized by a viscosity of not more
than about 400 mPas at 1000 s.sup.-1 shear rate.
[0007] For injection into the suprachoroidal space of an eye
comprising a biologically active substance and a thixotropic
polymeric excipient that acts as a gel-like material to spread
after injection and uniformly distribute and localize the drug in a
region of the suprachoroidal space. In one embodiment, gel-like
material crosslinks after injection into the suprachoroidal space.
The biologically active substance may comprise microparticles or
microspheres. The polymeric excipient may comprise hyaluronic acid,
chondroitin sulfate, gelatin, polyhydroxyethylmethacrylate,
dermatin sulfate, polyethylene oxide, polyethylene glycol,
polypropylene oxide, polypropylene glycol, alginate, starch
derivatives, a water soluble chitin derivative, a water soluble
cellulose derivative or polyvinylpyrollidone.
[0008] In another embodiment, a drug formulation is provided for
delivery to the suprachoroidal space of an eye comprising a
biologically active substance and microspheres with an outer
diameter in the range of about 1 to 33 microns. The microparticles
or microspheres additionally may comprise a controlled release
coating and/or a tissue affinity surface.
[0009] The biologically active substance preferably comprises an
antibiotic, a steroid, a non-steroidal anti-inflammatory agent, a
neuroprotectant, an anti-VEGF agent, or a neovascularization
suppressant.
[0010] Devices are also provided for minimally invasive delivery of
a drug formulation into the suprachoroidal space of the eye
comprising a needle having a leading tip shaped to allow passage
through scleral tissues without damage to the underlying choroidal
tissues, and a sensor to guide placement of the tip to deliver the
formulation adjacent to or within the suprachoroidal space.
[0011] The sensor may provide an image of the scleral tissues. The
sensor preferably responds to ultrasound, light, or differential
pressure.
[0012] In another embodiment, devices are provided for minimally
invasive delivery of a drug formulation into the suprachoroidal
space of the eye comprising a needle having a leading tip shaped to
allow passage through scleral tissues, and an inner tip that
provides an inward distending action to the choroid upon contacting
the choroid to prevent trauma thereto.
[0013] Methods are provided for administering drugs to the eye
comprising placing a formulation comprising a biologically active
substance and a polymer excipient in the suprachoroidal space such
that the excipient gels after delivery to localize said
biologically active substance. The formulation may be placed in a
posterior or anterior region of the suprachoroidal space.
[0014] In another embodiment, method are provided for administering
drugs to a posterior region of the eye comprising placing a
formulation comprising a biologically active substance comprising
microspheres or microparticles with an outer diameter in the range
of about 1 to 33 microns in an anterior region of the
suprachoroidal space such that the microspheres or microparticles
subsequently migrate to the posterior region. The formulation
preferably comprises a polymer excipient to uniformly disperse the
microparticles or microspheres in the suprachoroidal space.
[0015] In another embodiment, a method is provided of administering
drugs in the suprachoroidal space of the eye comprising the steps
of placing a needle in scleral tissues toward the suprachoroidal
space at a depth of at least half of the scleral thickness, and
injecting a drug formulation through the needle into the sclera
such that the formulation dissects the scleral tissues adjacent to
the suprachoroidal space and enters the suprachoroidal space.
[0016] In the methods disclosed herein, the formulation preferably
comprises a thixotropic polymer.
BRIEF DESCRIPTION OF THE DRAWINGS
[0017] FIG. 1 is an ultrasound image of a portion of the eye after
injection by needle into the sclera of a hyaluronic acid surgical
viscoelastic material according to Example 9.
[0018] FIG. 2 is an ultrasonic image of a portion of the eye during
injection by needle into the sclera of a 1:1 by volume mixture of
the viscoelastic material and 1% solution of polystyrene
microspheres according to Example 9.
[0019] FIGS. 3a and 3b are diagrams of an embodiment of a delivery
device according to the invention having a distending and cutting
or ablative tip.
[0020] FIG. 4 is a diagram showing the location of a delivery
device according to the invention relative to the target sclera,
suprachoroidal space and choroid.
[0021] FIG. 5 is a diagram of an embodiment of a delivery device
according to the invention having a stop plate to set the depth and
angle of penetration of the needle into the eye.
[0022] FIG. 6 is a diagram of an embodiment of a delivery device
according to the invention that accommodates a microendoscope and
camera to monitor the location of the cannula tip during
surgery.
[0023] FIG. 7 is a diagram of an embodiment of a delivery device
having a lumen for delivery of drugs through a catheter into the
eye and a fiber optic line connected to an illumination source to
illuminate the tip if the cannula.
[0024] FIG. 8 is a diagram of an embodiment of the use of a device
according to the invention in conjunction with a high resolution
imaging device to monitor the location of the tip of the
cannula.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0025] The present invention comprises drug formulations, devices
and related methods to access the suprachoroidal space of an eye
for the purpose of delivering drugs to treat the eye. Specifically,
the invention relates to drug formulations designed for
suprachoroidal space administration to treat the eye, including
specific regions of the eye by localization of the delivered drug.
The invention also relates to the design and methods of use for a
minimally invasive device to inject drug formulations and drug
containing materials directly into the suprachoroidal space through
a small needle.
[0026] A biologically active substance or material is a drug or
other substance that affects living organisms or biological
processes, including use in the diagnosis, cure, mitigation,
treatment, or prevention of disease or use to affect the structure
or any function of the body. A drug formulation contains a
biologically active substance.
[0027] As used herein, the anterior region of the eye is that
region of the eye that is generally readily accessible from the
exposed front surface of the eye in its socket. The posterior
region of the eye is generally the remaining region of the eye that
is primarily surgically accessed through a surface of the eye that
is unexposed, thus often requiring temporary retraction of the eye
to gain access to that surface.
[0028] Formulations:
[0029] The drug formulations of the invention provide compatibility
with the suprachoroidal space environment and may be formulated to
control the distribution of the biologically active substance by
migration of the formulation as well as provide for sustained
release over time. The drug formulation comprises one or more
biologically active substances formulated with physiologically
compatible excipients that are administered, typically by
injection, into the suprachoroidal space of an eye. Suitable
biologically active substances include antibiotics to treat
infection, steroids and non-steroidal anti-inflammatory compounds
to treat inflammation and edema, neuroprotectant agents such as
calcium channel blockers to treat the optic nerve and retinal
agents such as anti-VEGF compounds or neo-vascular suppressants to
treat macular degeneration.
[0030] Formulations for Localized Treatment:
[0031] For treatment of a localized region of the eye, for example,
to treat a macular lesion, the posterior retina, or the optic
nerve, the drug may be prepared in a formulation to limit migration
after delivery and delivered to the region of the lesion. While not
intending to be bound by a particular theory, we observe that drug
microparticles typically travel toward the posterior region of the
suprachoroidal space under physiological conditions, presumably due
to uveal-scleral fluid flow within the space. Such drug
microparticles may be fabricated with sufficient size and
optionally with tissue surface affinity to limit drug migration.
Tissue surface affinity may be modified by the addition of
polymeric or lipid surface coatings to the microparticles, or by
the addition of chemical or biological moieties to the
microparticle surface. Tissue affinity is thereby obtained from
surface charge, hydrophobicity, or biological targeting agents such
as antibodies or integrins that may be incorporated to the surface
of the microparticles to provide a binding property with the
tissues to limit drug migration. Alternatively or in combination,
the drug may be formulated with one or more polymeric excipients to
limit drug migration. A polymeric excipient may be selected and
formulated to act as a viscous gel-like material in-situ and
thereby spread into a region of the suprachoroidal space and
uniformly distribute and retain the drug. The polymer excipient may
be selected and formulated to provide the appropriate viscosity,
flow and dissolution properties. For example,
carboxymethylcellulose is a weakly thixotropic water soluble
polymer that may be formulated to an appropriate viscosity at zero
shear rate to form a gel-like material in the suprachoroidal space.
The thixotropic effect of the polymer may be enhanced by
appropriate chemical modification to the polymer to increase
associative properties such as the addition of hydrophobic
moieties, the selection of higher molecular weight polymer or by
formulation with appropriate surfactants. Preferred is the use of
highly associative polymeric excipients with strong thixotropic
properties such as hyaluronic acid to maximize the localization and
drug retaining properties of the drug formulation while allowing
the formulation to be injected through a small gauge needle. The
dissolution properties of the drug formulation may be adjusted by
tailoring of the water solubility, molecular weight, and
concentration of the polymeric excipient in the range of
appropriate thixotropic properties to allow both delivery through a
small gauge needle and localization in the suprachoroidal space.
The polymeric excipient may be formulated to increase in viscosity
or to cross-link after delivery to further limit migration or
dissolution of the material and incorporated drug. For example, a
highly thixotropic drug formulation will have a low viscosity
during injection through a small gauge needle, but dramatically
increases in effective viscosity once in the suprachoroidal space
at zero shear conditions. Hyaluronic acid, a strongly thixotropic
natural polymer, when formulated at concentrations of 1 to 2 weight
percent demonstrates a viscosity of approximately 300,000 to
7,000,000 mPas at zero shear and viscosity of 150 to 400 mPas at a
shear rate of 1000 s.sup.-1, typical of injection though a small
gauge needle, with the exact viscosity depending of the molecular
weight. Chemical methods to increase the molecular weight or degree
of crosslinking of the polymer excipient may also be used to
increase localization of the drug formulation in-situ, for example
the formulation of hyaluronic acid with bisepoxide or
divinylsulfone crosslinking agents. The environment in the
suprachoroidal space may also be used to initiate an increase in
viscosity or cross-linking of the polymer excipient, for example
from the physiologic temperature, pH or ions associated with the
suprachoroidal space. The gel-like material may also be formulated
with surface charge, hydrophobicity or specific tissue affinity to
limit migration within the suprachoroidal space.
[0032] Water soluble polymers that are physiologically compatible
are suitable for use as polymeric excipients according to the
invention include synthetic polymers such as polyvinylalcohol,
polyvinylpyrollidone, polyethylene glycol, polyethylene oxide,
polyhydroxyethylmethacrylate, polypropylene glycol and propylene
oxide, and biological polymers such as cellulose derivatives,
chitin derivatives, alginate, gelatin, starch derivatives,
hyaluronic acid, chondroiten sulfate, dermatin sulfate, and other
glycosoaminoglycans, and mixtures or copolymers of such polymers.
The polymeric excipient is selected to allow dissolution over time,
with the rate controlled by the concentration, molecular weight,
water solubility, crosslinking, enzyme lability and tissue adhesive
properties of the polymer. Especially advantageous are polymer
excipients that confer the formulation strong thixotropic
properties to enable the drug formulation to exhibit a low
viscosity at high shear rates typical of delivery through a small
gauge needle to facilitate administration, but exhibit a high
viscosity at zero shear to localize the drug in-situ.
[0033] To treat an anterior region of the eye, a polymeric
excipient to limit drug migration may be combined with a drug and
injected into the desired anterior region of the suprachoroidal
space.
[0034] One method for treating the posterior region of the eye
comprises administration of a drug formulation with localizing
properties directly to the posterior region of the suprachoroidal
space. Drug formulations may be delivered to the posterior region
of the suprachoroidal space by using a flexible microcannula placed
in an anterior region of the suprachoroidal space with subsequent
advancement of the distal tip to the posterior region prior to
delivery of the drug and a localizing excipient. Similarly, a
flexible microcannula may be advanced to the center of a desired
treatment area such as a macular lesion prior to delivery of a drug
formulation with properties to localize the administered drug.
[0035] Treatment of a localized region of the eye, especially the
posterior region, is facilitated by the use of drug preparations of
the present invention in combination with administration devices to
deliver the preparation locally to various regions of the
suprachoroidal space with a flexible device as described in U.S.
patent application 60/566,776 by the common inventors, incorporated
by reference herein in its entirety.
[0036] Formulations for Migration to a Posterior Region:
[0037] For treatment of the posterior region of the eye, for
example, to treat the entire macula, choroid or the optic nerve,
the drug may be prepared in a form to allow migration after
delivery and delivered to an anterior region of the suprachoroidal
space. The drug may be formulated in soluble form, with a rapid
dissoluting polymeric excipient or as small microparticles or
microspheres to allow drug migration after administration. If a
polymeric excipient is used, a low viscosity, rapidly absorbed
formulation may be selected to distribute the drug uniformly in the
region of administration to minimize areas of overly high drug
concentration, and subsequently dissolution of the excipient to
allow drug migration to the posterior region of the suprachoroidal
space. Of particular utility is the use of such a polymeric
excipient in combination with drug microparticles or microspheres.
Such use of drug migration is advantageous as the drug may be
injected into an anterior region of the eye easily accessible by
the physician, and used to treat a posterior region distant from
the injection site such as, the posterior choroid and macula.
Preferred microparticles or microspheres are those with an outer
diameter in the range of about 1 to 33 microns.
[0038] Sustained Release:
[0039] The use of drug microparticles, one or more polymeric
excipients or a combination of both, may also be applied to confer
sustained release properties to the drug formulation. The drug
release rate from the microparticles may be tailored by adjusting
drug solubility or application of a controlled release coating. The
polymeric excipient may also provide sustained release from
incorporated drugs. The polymeric excipient may, for example, be
selected to limit drug diffusion or provide drug affinity to slow
drug release. The dissolution rate of the polymeric excipient may
also be adjusted to control the kinetics of its effect on sustained
release properties.
[0040] Delivery Devices:
[0041] A device for minimally invasive delivery of drugs to the
suprachoroidal space may comprise a needle for injection of drugs
or drug containing materials directly to the suprachoroidal space.
The device may also comprise elements to advance the needle through
the conjunctiva and sclera tissues to or just adjacent to the
suprachoroidal space without perforation or trauma to the inner
choroid layer. The position of the leading tip of the delivery
device may be confirmed by non-invasive imaging such as ultrasound
or optical coherence tomography, external depth markers or stops on
the tissue-contacting portion of the device, depth or location
sensors incorporated into the device or a combination of such
sensors. For example, the delivery device may incorporate a sensor
at the leading tip such as a light pipe or ultrasound sensor to
determining depth and the location of the choroid or a pressure
transducer to determine a change in local fluid pressure from
entering the suprachoroidal space.
[0042] The leading tip of the delivery device is preferably shaped
to facilitate penetration of the sclera, either by cutting, blunt
dissection or a combination of cutting and blunt dissection.
Features of the device may include energy delivery elements to aid
tissue penetration such as ultrasound, high fluid pressure, or
tissue ablative energy at the distal tip. The outer diameter of the
tissue contacting portion of the device is preferably about the
size of a 20 to 25 gauge needle (nominal 0.0358 to 0.0203 inch
outer diameter) to allow minimally invasive use without requiring
additional features for tissue dissection or wound closure.
Suitable materials for the delivery device include high modulus
materials such as metals including stainless steel, tungsten and
nickel titanium alloys, and structural polymers such as nylon,
polyethylene, polypropylene, polyimide and polyetheretherketone,
and ceramics. The tissue contacting portions of the device may also
comprise surface treatments such as lubricious coatings to assist
in tissue penetration or energy reflective or absorptive coatings
to aid in location and guidance during medical imaging.
[0043] The needle may be mounted or slidably disposed at a shallow
angle to a plate or fixation mechanism to provide for localization
and control of the angle and depth of insertion. The plate, such as
shown in FIG. 4, may contain an injection port to allow advancement
of the needle through the plate that has been pre-positioned on the
surface of the globe (eye surface). The plate may further comprise
a vacuum assist seal 12 to provide stabilization of the plate to
the target site on the ocular surface. An external vacuum source
such as a syringe or vacuum pump is connected by line 13 to the
plate to provide suction. The plate should preferably have a bottom
side or bottom flanges which are curved suitably to curvature of
the globe. The needle 11 is advanced through the sclera 1 until
entering the suprachoroidal space 2 but not into choroid 3.
[0044] Elements to seal the needle tract during injection such as a
flexible flange or vacuum seal along the tract may also be
incorporated to aid delivery. Referring to FIG. 4, the location of
the delivery device 11 is shown with respect to the target sclera
1, suprachoroidal space 2, and choroid 3 by positioning with a
vacuum interfacial seal 12 attached to a suction line 13.
[0045] The device may also comprise elements to mechanically open
the suprachoroidal space, in order to allow injection of
microparticulate drugs or drug delivery implants which are larger
than can be delivered with a small bore needle. In one embodiment,
such a delivery device may comprise a first element provided to
penetrate the scleral tissue to a specified depth, and a second
element, which can advance, and atraumatically distend the choroid
inwards, maintaining a pathway to the suprachoroidal space. The
second element may be disposed within or placed adjacent to the
first element. An embodiment of a device having such elements is
shown in FIGS. 3a and 3b.
[0046] Referring to FIG. 3a a delivery device with a distending tip
is shown. The delivery device comprises a cutting or ablative tip 4
a choroidal distention tip 8 at the distal end of the device, and
an ultrasonic sensor 6 used to guide the device through the
tissues. A luer connector 7 is provided at the proximal end (away
from the cutting tip) of the device. The knob 5 is connected to the
mechanism for activating the distention tip 8. The device is placed
facing the sclera 1 to address the suprachoroidal space 2 adjacent
to the choroid 3. The device is then advanced in scleral tissues
using the depth sensor for guidance. When the depth sensor
indicates that the tip 4 is to or just adjacent to the
suprachoroidal space 2, the distension tip 8 is activated to
prevent damage to the choroid. Referring to FIG. 3b, the knob 5 has
been activated to advance the distention tip to its activated
position 9 which results in a distended choroid 10. A pathway to
the suprachoroidal space 2 is thereby attained without trauma to
the choroid from the ablative tip 4.
[0047] In another embodiment, the delivery device comprises a thin
walled needle fabricated with a short, high angle bevel at the
leading tip to allow the bevel to be advanced into or through
scleral tissues. Maintaining the beveled section with the opening
directed inward prevents the drug from being expressed away from
the suprachoroidal space. Various types of access and delivery may
be achieved through the precise placement of the needle tip into or
through the scleral tissues. If the needle is advanced through the
sclera and into the suprachoroidal space, the needle may then be
used for direct injections into the space or to serve as an
introducer for the placement of other devices such as a
microcannula. If the needle is placed in close proximity to the
inner boundary of the sclera, injection of drug formulations
through the needle will allow fluid dissection or flow through any
remaining interposing scleral tissue and delivery to the
suprachoroidal space. An embodiment of a device useful in such
manner is shown in FIG. 8.
[0048] In FIG. 8, a system to inject a substance into the
suprachoroidal space 2 comprises an access cannula 26 and a high
resolution imaging device 27. The access cannula may accommodate a
hypodermic type needle (not shown) or introducer sheath with a
trocar (not shown). Furthermore, the access means may comprise a
plate as shown in FIG. 4 or FIG. 5. The access cannula incorporates
a beveled sharp distal tip suitably shaped for penetration of the
tissues. The imaging device may comprise real-time modalities such
as ultrasound, optical coherence tomography (OCT) or micro-computed
tomography (MicroCT). The advancement of the access needle or
introducer through the sclera is monitored using the imaging
device. The access cannula 26 is advanced until the leading tip is
in close proximity to the inner boundary of the sclera 28, at which
point the injection of the drug is made. Injection of drug
formulations through the needle will allow fluid dissection or flow
through any remaining interposing scleral tissue and delivery to
the suprachoroidal space 29.
[0049] In one embodiment, the delivery device may allow a specific
angle of entry into the tissues in order to provide a tissue
pathway that will maintain the tract within the sclera, or
penetrate to the suprachoroidal space without contacting the
choroid. Referring to FIG. 5, an embodiment of the device is shown
with a luer connector 7 at the proximal end and a bevel needle tip
14 at the distal end. The needle is affixed to an angled stop plate
15 to set the depth and angle of penetration of the needle tip 14.
The assembly is advanced until the stop plate encounters the
surface of the globe, placing the needle tip at the target depth.
The mounting plate may also contain sensors for indicating or
directing the position of the needle tip.
[0050] In one embodiment, a system for obtaining minimally invasive
access to the suprachoroidal space comprises an access cannula and
an optical device used to determine the location of the access
cannula distal tip in the tissue tract providing direct feedback
upon entry to the suprachoroidal space. The color differential
between the sclera (white) and the choroid (brown) may be used to
provide location information or OCT methods may be used to
determine the distance to the choroid interface from the sclera.
The optical device may be incorporated within a microcannula, or
may be an independent device such as a microendoscope or a
fiber-optic sensor and transducer capable of detecting the tissue
properties. The optical signal may be sent to a camera and monitor
for direct visualization, as in the case of an endoscope, or to an
optical signal processing system, which will indicate depth by
signaling the change in tissue properties at the tip of the optical
fiber. The access microcannula may be a needle or introducer-type
device made of metal or plastic. The distal end of the access
cannula is suitable to pierce ocular tissue. If independent, the
optical device will be removed from the access microcannula after
cannulation to allow access to the space for other devices or for
an injectate to administer treatment. An embodiment of such a
system is shown in FIG. 6. The optical device comprises a flexible
microendoscope 18, coupled to a CCD camera 16 with the image viewed
on a monitor 19. The endoscope is sized to fit slidably in an
access cannula 17 that is preferably less than 1 mm in outer
diameter. The access cannula 17 comprises a beveled sharp distal
tip for tissue access. The distal tip of the endoscope is
positioned at the proximal end of the cannula bevel to provide an
image of the cannula tip. The cannula is advanced against the
ocular surface at the region of the pars plana at a low angle,
piercing the sclera 1, and advancing until the endoscope image
shows access into the suprachoridal space 2.
[0051] In another embodiment, the optical device of the system
comprises a focal illumination source at the distal tip. The amount
of light scatter and the intensity of the light will vary depending
upon the type of tissues and depth of a small light spot traversing
the tissues. The change may be seen from the surface by the
observing physician or measured with a sensor. The focal spot may
be incorporated as an illuminated beacon tip on a microcannula.
Referring to FIG. 7, the access device comprises a flexible
microcannula or microcatheter 20, sized suitably for atraumatic
access into the suprachoroidal space 2. The microcatheter comprises
a lumen 22 for the delivery of materials to the space 2 and a fiber
optic 23 to provide for an illuminated distal tip. The fiber optic
is connected to an illumination source 24 such as a laser diode,
superbright LED, incandescent or similar source. The microcatheter
is slidably disposed within the access cannula 21. As the access
cannula is advanced through the tissues, the light 25
transilluminating the tissues will change. Scleral tissues scatter
light from within the sclera tissues to a high degree, however once
inside the suprachoroidal space, the light intensity and
backscatter seen at the surface diminishes significantly,
indicating that the illuminated tip has transited the sclera 1, and
is now in the target location at the suprachoroidal space.
[0052] Of particular utility with a delivery device are drug
formulations as previously described that are compatible with the
delivery device. Drug in microparticulate form are preferred to be
substantially smaller than the lumen diameter to prevent lumen
obstruction during delivery. Microparticles of average outer
dimension of approximately 10 to 20% of the device lumen at maximum
are preferred. A useful formulation includes microspheres or
microparticles with an outer diameter in the range of about 1 to 33
microns. Also preferred is the use of a polymeric excipient in the
drug formulation to enable the formulation to be injected into the
scleral tissues adjacent to the suprachoroidal space, with
subsequent dissection of the tissue between the distal tip and the
suprachoroidal space by the excipient containing fluid to form a
flow path for the drug into the suprachoroidal space. Formulations
with thixotropic properties are advantageous for passage through a
small needle lumen as well as for fluid dissection of scleral
tissue.
[0053] The following examples are provided only for illustrative
purposes and are not intended to limit the invention in any
way.
Example 1
[0054] Fluorescent dyed polystyrene microspheres (Firefli.TM., Duke
Scientific, Inc., Palo Alto, Calif.) suspended in
phosphate-buffered saline were used as model drug to evaluate the
size range in which particulates will migrate in the suprachoroidal
space from the anterior region to the posterior region.
[0055] An enucleated human cadaver eye was radially incised to the
choroid in the pars plana region, which is in the anterior portion
of the eye. Using a syringe terminated with a blunt 27 gauge
needle, 0.15 mL of a 1% by volume microsphere suspension (mean
diameter 6 micron) was delivered into the anterior region of the
suprachoroidal space. The needle was withdrawn and the incision
sealed with cyanoacrylate adhesive.
[0056] The eye was then perfused for 24 hours with phosphate
buffered saline at 10 mm Hg pressure by introducing into the
anterior chamber a 30 gauge needle attached to a reservoir via
infusion tubing. The reservoir was placed on a lab jack and
elevated to provide constant perfusion pressure. Several hours
prior to examination, the eye was placed into a beaker of glycerin
to clarify the scleral tissue by dehydration, allowing direct
visualization of the suprachoroidal space.
[0057] The microspheres were visualized using a stereofluorescence
microscope (Model MZ-16, Leica, Inc.) with fluorescence filters
selected for the microsphere fluorescence. Under low magnification
(7 to 35.times.) the microspheres could be clearly seen in a
stream-like pattern running from the site of instillation back
toward the optic nerve region, collecting primarily in the
posterior region of the suprachoroidal space.
[0058] The experiment was repeated using microsphere suspensions of
1, 6, 10, 15, 24 and 33 micron diameter with the same resulting
pattern of migration and distribution to the posterior region of
the eye.
Example 2
[0059] The experiment of Example 1 was repeated, except that a
mixture of 6 and 33 micron diameter fluorescent microspheres as a
model drug was suspended in a polymeric excipient comprising a
surgical viscoelastic (Healon 5, Advanced Medical Optics, Inc.), a
2.3% concentration of sodium hyaluronic acid of 4,000,000 Daltons
molecular weight, with thixotropic properties of a zero shear
viscosity of 7,000,000 mPas and 400 mPas viscosity at 1000 s.sup.-1
shear rate. The mixture was introduced into the suprachoroidal
space in the manner of Example 1. After 24 hour perfusion, the
microspheres resided solely in the suprachoroidal space at the
anterior instillation site and did not show evidence of migration,
demonstrating the localizing effect of the thixotropic polymeric
excipient.
Example 3
[0060] To demonstrate the effect of polymeric excipient viscosity
on drug localization, the experiment of Example 1 was repeated,
except that bevacizumab (Avastin.TM., Genentech), an anti-VEG
antibody, was adsorbed onto 5 micron diameter carboxylated
fluorescent microspheres and mixed at equal volumes with one of
three hyaluronic acid based surgical viscoelastics (Healon, Healon
GV, Healon 5, Advanced Medical Optics, Inc.), each with a different
viscosity and thixotropic properties. (Healon, 300,000 mPas
viscoscity at zero shear rate, 150 mPas viscosity at 1000 s-1 shear
rate; Healon GV, 3,000,000 mPas viscosity at zero shear rate, 200
mPas at 1000 s-1 shear rate; Healon 5, 7,000,000 mPas viscosity at
zero shear rate, 400 mPas viscosity at 1000 s-1 shear rate.) Each
mixture was introduced into the anterior region of the
suprachoroidal space at the pars plana in the anterior region of
the eye in the manner of Example 1. After 24 hours perfusion, the
microspheres in Healon and Healon GV were found to be in process of
migration to the posterior region of the suprachoroidal space with
the formulation found at both the pars plana site of instillation
and the posterior pole. The microspheres in Healon 5 remained
dispersed in the viscoelastic localized at the original injection
site in the pars plana region of the suprachoroidal space.
Example 4
[0061] The experiment of Example 1 was repeated, except that
bevacizumab (Avastin.TM., Genentech) was covalently crosslinked
using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDAC,
Sigma-Aldrich) onto 5 micron diameter carboxylated fluorescent
microspheres and mixed at equal volumes with one of three surgical
viscoelastics (Healon, Healon GV, Healon 5, Advanced Medical
Optics, Inc.), each with a different viscosity and thixotropic
properties as in Example 3. The mixture was introduced into the
suprachoroidal space at the pars plana in the manner of Example 1.
After 24 hour perfusion the microspheres remained exclusively in
the pars plana region of the suprachoroidal space for all
viscoelastic carriers.
Example 5
[0062] To demonstrate the effect of a crosslinking polymeric
excipient on drug localization, the experiment of Example 1 was
repeated, except that 10 micron diameter fluorescent microspheres
were mixed into a 4% alginate solution and introduced into the
suprachoroidal space at the pars plana region. Before sealing the
incision site an equal volume of 1 M CaCl2 solution was instilled
at the site of the microsphere/alginate suspension to initiate
crosslinking of the alginate excipient. The mixture was allowed to
gel for 5 minutes before perfusing as in Example 1. The
microspheres remained exclusively at the site of instillation,
dispersed in the crosslinked polymer excipient.
Example 6
[0063] A drug containing injectate was prepared by suspending 1.5
mg of Triamcinolone acetonide in microparticulate form, in 15
microliters of Healon viscoelastic (Advanced Medical Optics, Irvine
Calif.) with a zero shear viscosity of 300,000 mPas and a viscosity
of 150 mPas at a shear rate of 1000 s-1. Forty porcine subjects
were placed under anesthesia and the right eye prepared and draped
in a sterile manner. A conjunctival peritomy was made near the
superior limbus, exposing and providing surgical access to a region
of sclera. A small radial incision was made in the sclera, exposing
bare choroid. A flexible microcannula with a 360 micron diameter
tip and 325 micron diameter body (iTrack microcannula, iScience
Interventional Corp.) was inserted in to the scleral incision and
advanced in a posterior direction to a target region behind the
macula. The drug suspension was injected into the posterior region
of the suprachoroidal space, and was observed to form a layer
between the choroid and sclera at the target region. The
microcannula was retracted and the scleral and conjunctival
incisions closed with 7-0 Vicryl suture. The subjects were observed
and eyes tissues recovered at 12 hours, 24 hours, 48 hours, 4 days,
7 days, 14 days, 30 days and 90 days. Angiographic, histologic, and
photographic studies of the subjects demonstrated no sign of
posterior segment pathology. Recovered samples of choroid
demonstrated significant concentration of the drug, in the range of
at least 1 mg per gram of tissue at all recovery time periods.
Example 7
[0064] A drug-containing formulation comprising 20 mL Healon 5 and
50 mL (1.5 mg) bevacizumab (Avastin.TM., Genentech) was prepared.
Eighteen porcine subjects were anesthetized and the right eye
prepared and draped in a sterile manner. A conjunctival peritomy
was made near the superior limbus, exposing and providing surgical
access to a region of sclera. A small radial incision was made in
the sclera, exposing bare choroid. A flexible microcannula with a
360 micron diameter tip and 325 micron diameter body (iTrack
microcannula, iScience Interventional Corp.) was inserted in to the
scleral incision and advanced in a posterior direction to a target
region behind the macula. The drug formulation was injected into
the posterior region of the suprachoroidal space, and was observed
to form a layer between the choroid and sclera at the target
region. The microcannula was retracted and the scleral and
conjunctival incisions closed with 7-0 Vicryl suture. Another 18
porcine subjects were anesthetized and each received a 50 mL bolus
of bevacizumab via injection into the vitreous. Both groups of test
subjects were evaluated and sacrificed at 0.5, 7, 30, 60, 90, and
120 days post-injection. Serum samples were taken and tested for
bevacizumab using an enzyme-based immunoassay. Higher plasma levels
of bevacizumab were found in the intravitreally injected subjects
and for longer duration of time than the suprachoroidal delivery
group. The right globes were removed and dissected in order to
quantitate bevacizumab in specific tissues and regions using an
enzyme-based immunoassay. The enzyme immunoassay demonstrated that
bevacizumab delivered via intravitreal injection was distributed
throughout eye, but when delivered suprachoroidally remained
largely in the retina and choroid, with little found in the
vitreous and anterior chamber.
Example 8
[0065] The experiment of Example 1 was repeated, except a drug
formulation 0.2 mL of Healon 5, 0.6 mL of Avastin, and 24 mg of
triamcinolone acetonide was prepared to provide a treatment with
both anti-inflammatory and anti-VEGF properties. An approximately 5
mm long incision was made longitudinally in the pars plana region
transecting the sclera, exposing the choroid of a cadaver globe
that had been clarified by immersion in glycerol for approximately
30 minutes and perfused with saline at 12 mm Hg pressure. The
flexible microcannula of Example 6 was primed with the drug
formulation and the microcannula tip was inserted into the
suprachoroidal space through the scleral incision. With the aid of
the fiber optic beacon at the microcannula tip, the distal end of
the microcannula was steered toward the posterior pole of the
globe, stopping approximately 5 mm short of the optic nerve. Using
a Viscoelastic Injector (iScience Interventional), 70 microliters
of the drug formulation was injected into the posterior region of
the suprachoroidal space. The microcannula was removed by
withdrawing though the pars plana incision. The mixture was visible
though the clarified sclera, and formed a deposit near the optic
nerve with the mixture also following the catheter track. The
incision was sealed with cyanoacrylate (Locktite 4011) and the
globe perfused again with saline at 12 mm Hg for 3 hours. The
sclera was re-cleared by immersion in glycerol to examine the
administered drug formulation. The drug formulation was observed by
microscopy to have formed a layer of dispersed drug within the
polymer excipient in the posterior region of the suprachoroidal
space.
Example 9
[0066] A series of experiments were performed to evaluate minimally
invasive delivery of substances to the suprachoroidal space. The
goal of the experiments was to use non-invasive imaging and fluid
dissection as a means of delivering substances through scleral
tissue and into the suprachoroidal space, without having direct
penetration into the suprachoroidal space.
[0067] Human cadaver eyes were obtained from an eye bank and were
prepared by inflating the eyes to approximately 20 mm Hg pressure
with phosphate buffered saline (PBS). A delivery needle was
fabricated using stainless steel hypodermic tubing, 255 .mu.m
ID.times.355 .mu.m OD. The needle distal tip was ground into a
bi-faceted short bevel point, 400 um in length and at an angle of
50.degree.. The fabricated needle was then silver-soldered into a
standard 25 gauge.times.1 inch hypodermic needle to complete the
assembly.
[0068] The needle was gently advanced into scleral tissue at an
acute angle (<10.degree.) with respect to the surface of the
eye. The needle entry was started in the pars plana region
approximately 4 mm from the limbus, and the needle advanced
posteriorly in scleral tissue to create a tract between 5 and 6 mm
long without penetrating through the sclera into the suprachoroidal
space. A high resolution ultrasound system (iUltrasound, iScience
Surgical Corp.) was used to guide and verify placement of the
needle tip within scleral tissues and to document the
injections.
[0069] In the first set of experiments, a polymeric excipient alone
comprising a hyaluronic acid surgical viscoelastic (Healon 5,
Advanced Medical Optics, Inc) was injected. In a second set of
experiments, the viscoelastic was mixed in a 1:1 ratio with a 1%
aqueous solution of 10 micron diameter polystyrene microspheres
(Duke Scientific, Inc) to represent a model microparticulate drug.
The viscoelastic and the mixture were delivered through the needle
using a screw driven syringe (ViscoInjector, iScience Surgical
Corp.) in order to control delivery volume and injection pressure.
The injections were made with the needle bevel turned inwards
towards the center of the globe. Multiple locations on three
cadaver eyes were used for the experiments.
[0070] In the first experiments, the needle tract was approximately
3 to 4 mm in length and the injectate was observed to flow back out
the tract. With placement of the needle tip in a longer tract,
higher injection pressure was obtained and allowed the injectate to
dissect through the remaining interposing layers of the sclera and
deliver to the suprachoroidal space. Through trials it was found
that needle tip placement in the outer layers of the sclera
(<1/2 scleral thickness) resulted in the delivery of the
viscoelastic into an intra-scleral pocket or sometimes through to
the outer surface of the globe. With the needle tip approaching the
basement of the sclera, the injections dissected through the
remaining interposing scleral tissue, entered the suprachoroidal
space and spread to fill the suprachoroidal space in the region of
the injection. FIG. 1 shows the needle tract 30 clearly visible
(after removal of the needle) and a region 31 of the suprachoroidal
space filled with injectate. The sclera 1 and choroid 3 are shown.
FIG. 2 shows a region 33 of the suprachoroidal space filled with
the microsphere and hyaluronic acid excipient containing injectate,
and the tip of the needle 4 in the sclera and needle shadow 32.
Example 10
[0071] An experiment was performed to use micro-endoscopic imaging
to allow minimally invasive access to the suprachoroidal space in a
human cadaver eye. A custom fabricated, flexible micro-endoscope
(Endoscopy Support Services, Brewster N.Y.) with an outer diameter
of 350 microns containing an imaging bundle with 1200 pixels was
mounted on a micrometer adjusted stage. The stage was mounted on a
vertical stand allowing for controlled up and down travel of the
endoscope. The micro-endoscope was attached to a 1/2'' chip CCD
camera and then to a video monitor. A 20 gauge hypodermic needle
was placed over the endoscope to provide a means for piercing the
tissues for access.
[0072] The camera was turned on and an external light source with a
light pipe (Model MI-150, Dolan Jenner, Boxborough, Mass.) was used
to provide transcleral imaging illumination. The needle was
advanced until the distal tip was in contact with the scleral
surface of a human cadaver whole globe approximately 4 mm posterior
of the limbus. The micro-endoscope was then lowered until the white
scleral surface could be seen through the end of the needle. The
needle was then slowly advanced into the scleral tissue by slight
back-and-forth rotation. As the needle was advanced in this manner,
the endoscope was lowered to follow the tract created by the
needle. At or within the sclera, the endoscopic image was seen as
white or whitish-grey. As the needle pierced the scleral tissues,
the image color changed to dark brown indicating the presence of
the dark choroidal tissues, demonstrating surgical access of the
suprachoroidal space.
Example 11
[0073] An experiment was performed to use fiber-optic illuminated
guidance to allow minimally invasive access to the suprachoroidal
space in a human cadaver eye. A flexible microcannula with an
illuminated distal tip (iTrack-250A, iScience Interventional, Menlo
Park, Calif.) was placed into a 25 gauge hypodermic needle. The
microcannula comprised a plastic optical fiber that allowed for
illumination of the distal tip. The microcatheter fiber connector
was attached to a 635 nm (red) laser diode fiber optic illuminator
(iLumin, iScience Interventional) and the illuminator turned on to
provide a steady red light emanating for the microcannula tip. The
microcannula was fed through the 25 gauge needle up to the distal
bevel of the needle but not beyond.
[0074] The needle was slowly advanced in the pars plana region of a
human cadaver whole globe until the needle tip was sufficiently
embedded in the scleral tissues to allow a slight advancement of
the microcannula. The illumination from the microcannula tip was
seen clearly as the scleral tissues diffused the light to a
significant extent. As the needle was advanced slowly, the
microcannula was pushed forward at the same time. When the
hypodermic needle tip pierced through sufficient scleral tissue to
reach the suprachoroidal space, the red light of the microcannula
tip immediately dimmed as the illuminated tip passed out of the
diffusional scleral tissues and into the space beneath. The
microcannula was advanced while keeping the needle stationary,
thereby placing the microcannula tip into the suprachoroidal space.
Further advancement of the microcannula in a posterior direction in
the suprachoroidal space could be seen transclerally as a focal red
spot without the broad light diffusion seen when the tip was inside
the scleral tissues. Using a high frequency ultrasound system
(iUltraSound, iScience Interventional), the location of the
microcannula in the suprachoroidal space was confirmed.
* * * * *