U.S. patent application number 13/397466 was filed with the patent office on 2012-09-20 for method and apparatus for the delivery of photo-chemical (cross-linking) treatment to corneal tissue.
This patent application is currently assigned to Seros Medical, LLC. Invention is credited to Donald J. EATON, Satish V. HEREKAR, Edward E. MANCHE.
Application Number | 20120238938 13/397466 |
Document ID | / |
Family ID | 46637397 |
Filed Date | 2012-09-20 |
United States Patent
Application |
20120238938 |
Kind Code |
A1 |
HEREKAR; Satish V. ; et
al. |
September 20, 2012 |
METHOD AND APPARATUS FOR THE DELIVERY OF PHOTO-CHEMICAL
(CROSS-LINKING) TREATMENT TO CORNEAL TISSUE
Abstract
Systems and methods for delivering and infusing formulations
containing riboflavin or its analogues, or other ophthalmic
formulations, into corneal tissue are disclosed. Systems and
methods are further disclosed to cross-link the corneal tissue
through exposure to UVA irradiation. The systems and methods for
formulation delivery employ micro-needle array delivery
devices.
Inventors: |
HEREKAR; Satish V.; (Palo
ALto, CA) ; MANCHE; Edward E.; (Los Altos, CA)
; EATON; Donald J.; (Los Altos, CA) |
Assignee: |
Seros Medical, LLC
Palo Alto
CA
|
Family ID: |
46637397 |
Appl. No.: |
13/397466 |
Filed: |
February 15, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61443191 |
Feb 15, 2011 |
|
|
|
Current U.S.
Class: |
604/20 ; 514/251;
604/173; 604/506 |
Current CPC
Class: |
A61K 41/0057 20130101;
A61N 5/062 20130101; A61K 41/0038 20130101; A61F 9/0079 20130101;
A61K 9/0051 20130101; A61P 27/02 20180101; A61F 9/0017 20130101;
A61K 31/525 20130101 |
Class at
Publication: |
604/20 ; 514/251;
604/506; 604/173 |
International
Class: |
A61M 37/00 20060101
A61M037/00; A61P 27/02 20060101 A61P027/02; A61M 5/00 20060101
A61M005/00; A61K 31/525 20060101 A61K031/525 |
Claims
1. A method of treating ocular tissue comprising: providing a
treatment apparatus comprising micro-needles; and delivering a drug
formulation to corneal ocular tissue through penetration of
micro-needles into the corneal ocular tissue, and wherein the drug
formulation comprises riboflavin, wherein the delivered formulation
is capable of inducing crosslinking of corneal collagen tissue upon
exposure to irradiation.
2. The method of claim 1, wherein the riboflavin is delivered
through the corneal ocular tissue trans-epithelially and beneath
the Bowmans layer into the mid-stroma.
3. The method of claim 1, wherein an auto-injector associated with
the micro-needles provides a spring actuated force to press the
micro-needles into corneal tissue.
4. The method of claim 3, wherein a suction ring is placed on a
surface of the cornea to center the auto-injector on a pupil and
stretches and flattens the corneal surface to facilitate
penetration of the micro-needles.
5. The method of claim 1, wherein the micro-needles comprise solid
micro-needles, hollow micro-needles, dissolvable micro-needles, or
a combination thereof.
6. The method of claim 1, wherein the micro-needles deliver at
least 10 to 50 .mu.L into the corneal ocular tissue in less than 60
seconds and the formulation diffuses through the stromal region of
the cornea in 10 to 20 minutes.
7. The method of claim 1, further comprising delivery of UVA to the
corneal ocular tissue to crosslink corneal collagen tissue exposed
to the delivered formulation.
8. A method of treating ocular tissue comprising: providing a UVA
applicator; and delivering UVA irradiation from the UVA applicator
to corneal ocular tissue exposed to a formulation comprising
riboflavin, wherein the UVA irradiation crosslinks corneal collagen
tissue exposed to the formulation.
9. The method of claim 8, wherein the UVA applicator delivers a UVA
irradiance of 25 to 35 mw/cm2 with a beam of about 8 to 9 mm in
diameter.
10. The method of claim 8, further comprising positioning a contact
lens assembly over a cornea comprising the UVA applicator.
11. The method of claim 8, wherein the irradiation comprises a UVA
beam from the UVA applicator that matches a convex profile of the
cornea so that the irradiation is over 80% uniform over its
illumination region.
12. A device for treating ocular tissue comprising: a micro-needle
array disposed on a concave disk sized to fit over a corneal
surface, wherein the micro-needles are configured to deliver
formulation into a cornea upon penetration of the micro-needles
into the corneal surface.
13. The device of claim 12, further comprising a reservoir
connected to the micro-needle array for providing formulation to
hollow micro-needles of the micro-needle array.
14. The device of claim 13, further comprising an actuator which
forces the formulation from the reservoir into the micro-needle
array for delivery into the cornea.
15. The device of claim 12, wherein the micro-needle array
comprises micro-needles coated with the formulation which comprises
riboflavin.
16. The device of claim 12, further comprising an auto-injector
associated with the micro-needles that provides a spring actuated
force to press the micro-needle array into corneal tissue.
17. The device of claim 16, further comprising a suction ring for
centering the auto-injector on a corneal surface configured to
stretch the corneal surface so as to facilitate penetration of the
micro-needle array.
18. A device for treating ocular tissue comprising: a contact lens
assembly comprising a contact lens that conforms to a corneal
surface; a skirt around the contact lens configured to sit on a
region of the sclera surrounding the cornea; and a UVA applicator
associated with the contact lens assembly for providing UVA
irradiation through the contact lens into the cornea.
19. The device of claim 18, wherein the UVA applicator is connected
to a UVA source external to the contact lens assembly.
20. The device of claim 18, wherein the skirt comprises rubber.
Description
[0001] This application claims the benefit of U.S. Provisional
Patent Application No. 61/443,191 filed on Feb. 15, 2011 and is
incorporated by reference herein.
BACKGROUND OF THE INVENTION
[0002] This invention is directed to designs and methods for
delivering and infusing dosage forms containing riboflavin or its
analogues, or other ophthalmic formulations, into ocular tissue
(such as the cornea) using rapid and minimally invasive methods. In
general, the devices created to perform these tasks have
capabilities that provide a micro-needle array drug delivery method
combined with a high intensity photonic excitation of ocular
tissue. As a result, such devices provide effective crosslinking of
collagen ocular tissue. Additionally, the embodiments of the
present invention herein described are directed at the treatment of
refractive myopia and other conditions (such as presbyopia) wherein
re-shaping of the cornea is required to obtain normal vision. The
corneal reshaping is done with a thermal subsurface continuous wave
infrared laser device as described in US Patent Pub. No.
20110282333 of U.S. patent application Ser. No. 13/068,126 filed
May 2, 2011, which is incorporated herein by reference. Following
such reshaping, CXL is performed to provide rigidity
(stabilization) and prevent regression of the reshaped corneal
tissue.
[0003] Collagen cross-linking (herein CXL) in the cornea is now a
widespread method used to stiffen and stabilize corneal tissue. It
is approved in the European Union as a medical device application
for the treatment of keratoconus, a degenerative collagenous
disease. CXL has been shown to prevent the progression of
keratonconus by collagen stiffening. There are other conditions and
diseases of the cornea where CXL treatment has been shown to be
safe and effective, for example: corneal ectasia, corneal
ulceration, and bullous keratopathy.
[0004] CXL is a two-step process intended to enhance tissue
rigidity and shape stability. The first step involves the
application of a photo-sensitizer, such as riboflavin (Vitamin
B-2--herein referred to as "R/F"), which is infused into the
collagen tissue in the stroma layer of the cornea. In order to
create this infusion of R/F, the current prior art technique for
CXL is to place a speculum onto the patient's eye to hold open the
eye lid. The physician then surgically debrides (removes) the outer
layer of the cornea, which is the protective epithelium layer. This
debridement permits the R/F, which is typically placed directly on
the corneal tissue with an eye dropper, to soak and be absorbed
into the corneal tissue. This delivery and absorption process takes
approximately 30 to 45 minutes, and the R/F solution is
administered manually every few minutes with the eye dropper. Step
two is performed after the R/F saturates the corneal stroma. Step
two involves the delivery of ultraviolet light (herein "UVA") into
the riboflavin soaked corneal tissue. This UVA activation of the
riboflavin results in increased biomechanical rigidity or stiffness
to the treated corneal tissue. The mechanism of action for the
creation of such rigidity is attributed to the generation of
radical oxygen species which trigger the formation of covalent
bonds between and within collagen strands as well as, it is
hypothesized, bridging bonds between collagen fibrils and the local
extracellular matrix (ECM).
[0005] The current prior art CXL process has several significant
limitations. The two most critical are: 1) the debridement of the
protective epithelium tissue; and, 2) the extended time period
required for the absorption of R/F into the collagen tissue.
Debridement is painful to the patient, but more importantly, over
70% of the adverse events reported from CXL can be traced to
debridement. CXL takes, on average, one hour per eye, which is not
considered a patient-friendly procedure, especially with a speculum
remaining in the patient's eye during the entire procedure.
[0006] As previously indicated, cross-linking of corneal tissue
using prior art methods has become a standard of care in the
European Union (EU), primarily for the treatment of keratoconus.
CXL stabilizes and thereby prevents the progressive elongation of
the corneal tissue in a keratoconic patient, which if gone unabated
can lead to blindness. However, following CXL treatment by such
prior art methods, the keratoconic patient continues to have an
irregular myopically shaped cornea. Therefore, for the treatment of
refractive myopia, as well as the treatment for keratoconus, there
is a need to provide safe, rapid, and effective devices and
techniques for cross-linking of corneal tissue with an outcome that
affords patient comfort, stability, reliable, uniformity and
corneal shape retention.
[0007] Refractive myopia (i.e. <0.5 diopters) is a major eye
condition throughout the world. It has increased annually over the
past 20 years and is now estimated at nearly 30% prevalence in
Europe and USA, at over 40% in Japan, and over 60% in many Asian
countries, such as Singapore. The etiology of nearsightedness
(myopia formation) is caused by a steepening of the corneal
curvature which results in light being focused to a sub-optimal
location in the posterior segment of the eye, instead of directly
on the optic nerve (fovea) in the back of the eye.
SUMMARY OF THE INVENTIONS
[0008] Various embodiments of the present invention include a
method of treating ocular tissue comprising: providing a treatment
apparatus comprising micro-needles; and delivering a drug
formulation to corneal ocular tissue through penetration of
micro-needles into the corneal ocular tissue, and wherein the drug
formulation comprises riboflavin, wherein the delivered formulation
is capable of inducing crosslinking of corneal collagen tissue upon
exposure to irradiation.
[0009] Further embodiments of the present invention include a
method of treating ocular tissue comprising: providing a UVA
applicator; and delivering UVA irradiation from the UVA applicator
to corneal ocular tissue exposed to a formulation comprising
riboflavin, wherein the UVA irradiation crosslinks corneal collagen
tissue exposed to the formulation.
[0010] Additional embodiments of the present invention include a
device for treating ocular tissue comprising: a micro-needle array
disposed on a concave disk sized to fit over a corneal surface,
wherein the micro-needles are configured to deliver formulation
into a cornea upon penetration of the micro-needles into the
corneal surface.
[0011] Other embodiments of the present invention include a A
device for treating ocular tissue comprising: a contact lens
assembly comprising a contact lens that conforms to a corneal
surface; a skirt around the contact lens configured to sit on a
region of the sclera surrounding the cornea; and a UVA applicator
associated with the contact lens assembly for providing UVA
irradiation through the contact lens into the cornea.
BRIEF DESCRIPTION OF THE DRAWINGS
[0012] The inventions herein have other advantages and features
which will be more readily apparent from the following detailed
descriptions, when taken in conjunction with the accompanying
drawings, in which:
[0013] FIG. 1 depicts an in-use corneal infuser of R/F using a
hollow MNA.
[0014] FIG. 2 depicts an in-use corneal injector of R/F using a MNA
which has individual R/F coated micro-needles.
[0015] FIG. 3 depicts the side view of a typical single hollow
micro-needle.
[0016] FIG. 4 depicts the bottom view of a typical hollow
micro-needle array.
[0017] FIG. 5 depicts the side view of a typical solid micro-needle
coated with R/F.
[0018] FIG. 6 depicts the bottom view of a typical solid
micro-needle array.
[0019] FIG. 7 depicts an in-use UVA delivery system for the
cornea.
[0020] FIG. 8a depicts a UVA applicator assembly.
[0021] FIG. 8b depicts the two parts of the UVA applicator
assembly.
DETAILED DESCRIPTIONS OF THE INVENTIONS
[0022] The present inventions generally relate to various methods
and embodiments to rapidly dose ocular tissue with photo-chemical
exposures. Specifically, this involves a trans-epithelial drug
transfusion, such as riboflavin (R/F) formulations, into the
collagen tissue in the corneal mid-stroma region. Additionally,
these methods and embodiments also provide for photonic (typically
UVA) delivery to the cornea. The R/F so delivered to corneal
collagen tissue (by micro-injection) is then rapidly activated with
UVA irradiation thereby inducing cross-linking of the collagen
tissue.
[0023] The embodiments providing treatment for the cornea as
described herein include various applications of micro-needle array
(MNA) technology to provide rapid, sub-surface delivery of R/F into
the corneal ocular tissue. In such methods of treatment, the MNA's
may be inserted into corneal tissue through penetration of MNA's
into the cornea. A R/F formulation can be delivered into the tissue
through the application of MNA's. These MNAs can be solid with R/F
coatings, or hollow, or dissolvable, or even a combination of solid
MNAs with dissolvable tips. The MNAs used in this invention can
have a diameter ranging from 40 microns to 400 microns, and a
length of 100 microns to 1200 microns. They can be made from a
variety of materials, such as polymeric or sucrose compounds,
plastics and metals. The MNAs are produced with a base line
curvature that has the flexibility to easily conform to ocular
tissue upon applanation on ocular tissue.
[0024] For application of the MNAs into the cornea, the invention
may include an auto-injector associated with the MNAs that provides
a spring driven force (similar to an insulin injector) that ensures
instant penetration of the MNAs into the ocular tissue. An
"auto-injector" generally refers to a medical device designed to
deliver a specific or selected amount (dose) of a formulation, such
as a drug. In vitro studies have shown that the use of such an
auto-injector for MNAs provides a uniform delivery of R/F at a
therapeutically viable dose (which is in the range of 10 uL-50 uL
to deliver 0.1% or higher R/F concentration) into the targeted
ocular tissue in less than 1 minute or about one minute. An
integral addition to the auto-injector includes the placement of a
suction ring on the corneal surface in order to center the
auto-injector on the pupil and protect the limbal region. This
suction ring also stretches (flattens) the corneal surface so as to
facilitate the MNA penetration.
[0025] Once the R/F is delivered into the stromal region of the
cornea, the R/F will then diffuse in a targeted area of the stroma
in 10 to 20 minutes. Clinical studies have shown that the
application of MNAs, because of their microscopic size penetration,
do not damage the protective (epithelial & Bowmans) layers of
the cornea. The transient micro-porations in the ocular tissue,
which are caused by MNA penetration, will effectively close or seal
within approximately one hour following MNA removal. Importantly,
the length of the MNA is designed to deliver R/F at a depth in the
corneal stroma that does not impinge upon the corneal endothelium
and, as a result of this design, the endothelium remains safe from
cellular destruction during treatment.
[0026] Several manufacturers of MNA technology are known in the
art. However, the use of MNA for riboflavin (R/F) photo-sensitizer
transport for ocular cross-linking has not been reported to the
inventors' knowledge. The R/F formulation used for cross-linking
with hollow micro-needles may contain R/F (concentration ranging
from 0.1%-0.5%) combined with deuterated water (D2O) (up to 99.9%+
concentration). The R/F formulation used for cross-linking with R/F
coated micro-needles may have a coating thickness of up to 25 um of
rapidly dissolvable R/F. Formulations as disclosed in WO
2011/019940 A3 (publication of PCT/US2010/045356 filed Aug. 12,
2010), which is incorporated herein by reference, may also be
used.
[0027] Embodiments of the present invention involve the
simultaneous use of two contact lenses, one on the sclera in the
shape of a skirt, and the second on the cornea in an elongated
configuration. The sclera contact lens provides stability for the
corneal contact lens during UVA delivery. Because the sclera lens
is translucent, it facilitates adequate visualization. The cornea
contact lens delivers a homogeneous, high irradiance, targeted
diameter UVA beam. This cornea contact lens also enables the UVA to
maintain precise alignment throughout the delivery process. Both
the cornea and sclera contact lenses are held in place by a head
band on the patient.
[0028] UVA may be delivered into the corneal tissue through
fractionation and pulsation techniques and protocols as disclosed
in WO2009/073600, which is incorporated by reference herein,
thereby maximizing the use of dissolved oxygen in the ocular
tissue. The combination of the R/F soak methods provide the end
result that the time needed to cross-link collagen fibers can be
significantly shortened while at the same time the cross-link
densities will be higher than prior art treatments. It should be
noted that the UVA beam profile matches the profile of the (convex)
cornea so that the UVA is uniform over its illumination region.
[0029] The inventions set forth herein will be better understood by
reference to the following detailed descriptions in connection with
the accompanying drawings. Although the detailed descriptions of
the inventions herein contain many specifics, these should not be
construed as limiting the scope of the inventions but merely as
illustrating different examples and aspects of the inventions. It
should be appreciated that the scope of the inventions includes
other embodiments not discussed in detail below. Various other
modifications, changes and variations which will be apparent to
those skilled in the art may be made in the arrangement, operation
and details of the method and apparatus of the present inventions
disclosed herein without departing from the spirit and scope of the
inventions as described herein below.
[0030] Although the detailed descriptions of the inventions herein
contain many specifics, these should not be construed as limiting
the scope of the inventions but merely as illustrating different
examples and aspects of the inventions. It should be appreciated
that the scope of the inventions includes other embodiments not
discussed in detail below. Various other modifications, changes and
variations which will be apparent to those skilled in the art may
be made in the arrangement, operation and details of the method and
apparatus of the present inventions disclosed herein without
departing from the spirit and scope of the inventions as described
hereinbelow.
[0031] FIG. 1 depicts an exemplary corneal R/F hollow MNA injector
which provides a mid-stromal (8) trans-epithelial (50) deposition
of up to 50 uL of R/F. More specifically, the R/F is delivered at a
targeted depth starting at 100 um below the corneal surface (51)
and extends to a depth of 400 um. To position the injector
accurately on the cornea, a suction ring (52) is placed around the
cornea, on scleral tissue near the limbus (9). The suction ring
(52) is vacuum actuated through a tube 11 with a spring loaded
syringe (10), which produces a gentle vacuum (.about.300 mbar-400
mbar range), thereby affixing the suction ring (52) at the desired
position on the cornea. The purpose of the suction ring (52) is
also to help stretch and provide tension to the cornea. This
minimal reshaping facilitates penetration of the MNA. After the MNA
injector has been properly positioned, the device utilizes a spring
loaded actuator (4) to automatically pierce the cornea. This
actuator is triggered by a switch (1). To deliver the R/F contained
in the reservoir (3), a second spring actuator (2) is triggered
which forces the R/F through a tube (53) to the micro-needle array
(5) for delivery to the mid-stroma. Micro-needle array (5) includes
a plurality of needles (7) set in a concave disk (6). There is an
interlocking mechanism (not shown) which connects the MNA injector
to the suction ring, ensuring the MNA's are positioned accurately
and securely throughout delivery of the R/F. The hollow MNA
injector delivers an R/F dose of up to 50 uL in less than 60
seconds. After depositing this R/F dose in the cornea, there is a
waiting period of approximately 5 to 20 minutes to allow for
uniform corneal diffusion of the R/F.
[0032] FIG. 2 depicts an exemplary corneal R/F coated MNA injector
which provides a mid-stromal (18) trans-epithelial (54) deposition
of up to 15 ug of R/F. More specifically, the R/F is delivered at a
targeted depth starting at 100 um below the corneal surface (55)
and extends to a depth of 400 um. R/F coated MNA (14) includes a
plurality of needles (16) set in a concave disk (15). To position
the injector accurately on the cornea, a suction ring (56) is
placed around the cornea, on scleral tissue near the limbus (19).
The suction ring (56) is vacuum actuated through a tube (20) with a
spring loaded syringe (17), which produces a gentle vacuum
(.about.300 mbar-400 mbar range), thereby affixing the suction ring
(56) at the desired position on the cornea. The purpose of the
suction ring (56) is also to help stretch and provide tension to
the cornea. This transient reshaping facilitates penetration of the
MNA. After the MNA injector has been properly positioned, the
device utilizes a spring loaded actuator (13) to automatically
pierce the cornea. This actuator is triggered by a switch (12).
There is an interlocking mechanism that connects the MNA injector
to the suction ring (56), ensuring the MNA's are positioned
accurately and securely throughout delivery of the R/F. The coated
MNA injector delivers an R/F dose of up to 15 ug in less than 60
seconds. After depositing this R/F dose in the cornea, there is a
waiting period of approximately 5 to 20 minutes to allow for
uniform corneal diffusion of the R/F.
[0033] FIG. 3 illustrates an exemplary single hollow micro-needle,
which contains channels (23) for transporting R/F and dual exit
ports (22) for depositing R/F in the stroma. In addition, the
single hollow micro-needle has a sharp non-coring tip (21) for
rapid and minimally destructive penetration. The single hollow
micro-needle has a length in the range of 100 um to 600 um.
[0034] FIG. 4 depicts an exemplary hollow MNA on a concave disk
(24) with a diameter of 6 mm to 9 mm. The hollow micro-needles (25,
26) on the disk are spaced at about 0.5 mm apart. The disk contains
two ports (27, 28) for suction on the outer perimeter of the
concave disk (24). The needles in the hollow MNA may be fabricated
with polymeric materials or metals that permit sterilization and
have tips (21) having requisite sharpness. The hollow MNA needle
tips (21) have a .about.10 um-20 um radius of curvature that
enables rapid, pain free, reliable and uniform penetration into the
cornea.
[0035] FIG. 5 illustrates an exemplary single R/F coated
micro-needle. The coating (30) thickness may be in the range of 20
um. The coated micro-needle has a sharp non-coring tip (29) for
rapid and minimally destructive penetration, and it has a length in
the range of 100 um to 600 um.
[0036] FIG. 6 depicts an exemplary coated MNA on a concave disk
(32) with a diameter of 6 mm to 9 mm. The coated micro-needles (33,
34) on the disk are spaced at about 1 mm apart. The disk contains
two ports (35, 36) for suction on the outer perimeter. The needles
in the coated MNA may be fabricated with polymeric materials or
metals that permit sterilization and have tips (29) having
requisitesharpness. The coated MNA needle tips have a .about.10
um-20 um radius of curvature that enables rapid, pain free,
reliable and uniform penetration into the cornea.
[0037] FIG. 7 illustrates an in-use UVA delivery system for
activating R/F in corneal tissue and thereby causing cross-linking
of such collagen tissue. This system includes a UVA source box (37)
coupled to a fiber (38) that has a dual contact lens assembly (41)
on the distal end. This contact lens assembly rests directly on the
cornea. This fiber is stabilized by a guide (39) which is connected
to a head band (40) on the patient. The contact lens assembly (41)
can be adjusted to achieve proper alignment on the cornea. The UVA
source box can provide UVA irradiance up to 100 mw/cm2, or more
narrowly 15 to 75 mw/cm2, 15 to 30 mw/cm2, 20 to 50 mw/cm2, 25 to
35 mw/cm2, or about 30 mw/cm2 and delivers a uniform beam with
about 8 mm, or about 9 mm or 8 to 9 mm in diameter. The beam
irradiance is over 80% uniform or homogeneous over the region of
delivery of irradiation.
[0038] FIGS. 8a and 8b depict the contact lens assembly (41) in
detail. FIG. 8a shows a scleral skirt (44) attached to a UVA
applicator (43). The scleral skirt (44) surrounds the cornea and
sits on the sclera near the limbus. The skirt (44) provides a
stabilizing base for the UVA applicator (43) during UVA
irradiation. The skirt (44) is made from natural pellethane rubber,
or an equivalent material, and is translucent. The skirt (44) is
disposable.
[0039] FIG. 8b shows the two separate parts of the contact lens
assembly (41), the scleral skirt (44) and the UVA applicator (43).
The UVA applicator has a custom molded plastic (non-brittle)
contact lens (45) made with Zeonor 1020R, or equivalent material,
that provides for over 80% uniformity or homogeneity of UVA
transmission over the irradiated region, and can be ETO
sterilized.
* * * * *