U.S. patent application number 15/900583 was filed with the patent office on 2018-08-23 for method of treatment of eyelid laxity.
The applicant listed for this patent is QUEENSLAND EYE INSTITUTE FOUNDATION. Invention is credited to Traian Vasile CHIRILA, Brendan Gerard CRONIN, Tai Mountford SMITH, Shuko SUZUKI.
Application Number | 20180236261 15/900583 |
Document ID | / |
Family ID | 63166316 |
Filed Date | 2018-08-23 |
United States Patent
Application |
20180236261 |
Kind Code |
A1 |
SMITH; Tai Mountford ; et
al. |
August 23, 2018 |
METHOD OF TREATMENT OF EYELID LAXITY
Abstract
A method of treating eyelid laxity in a subject comprising
exposing a tarsal plate of an eye, and applying to at least part of
the exposed tarsal plate a photosensitizer that initiates
crosslinking in response to photo-activating radiation; and
irradiating the exposed tarsal plate with photo-activating
radiation to initiate crosslinking in the tarsal plate tissue.
Inventors: |
SMITH; Tai Mountford;
(Kalinga, AU) ; CRONIN; Brendan Gerard;
(Clayfield, AU) ; SUZUKI; Shuko; (Ormeau, AU)
; CHIRILA; Traian Vasile; (Robertson, AU) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
QUEENSLAND EYE INSTITUTE FOUNDATION |
South Brisbane |
|
AU |
|
|
Family ID: |
63166316 |
Appl. No.: |
15/900583 |
Filed: |
February 20, 2018 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61N 2005/0661 20130101;
A61N 5/062 20130101; A61N 5/0616 20130101; A61N 5/1017
20130101 |
International
Class: |
A61N 5/06 20060101
A61N005/06 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 21, 2017 |
AU |
2017900561 |
Claims
1. A method of treating eyelid laxity in a subject comprising:
exposing a tarsal plate of an eye; applying to at least part of the
exposed tarsal plate a photosensitizer that initiates crosslinking
in response to photo-activating radiation; and irradiating the
exposed tarsal plate with photo-activating radiation to initiate
crosslinking in the tarsal plate tissue.
2. The method according to claim 1 wherein the photosensitizer is
in solubilized form.
3. The method according to claim 1 wherein the photosensitizer is
riboflavin or a pharmaceutically acceptable salt, derivative or
solvate thereof.
4. The method according to claim 1 wherein the photosensitizer is
riboflavin 5'-phosphate or a pharmaceutically acceptable salt or
solvate thereof.
5. The method according to claim 1 wherein the photo-activating
radiation is UV-A radiation.
6. The method according to claim 1 wherein the method comprises:
exposing a tarsal plate of an eye by making an incision; applying
to at least part of the exposed tarsal plate riboflavin or a
pharmaceutically acceptable salt, derivative or solvate thereof in
solubilized form; irradiating the exposed tarsal plate with UV-A
radiation to initiate crosslinking in the tarsal plate tissue; and
closing the incision.
7. The method according to claim 1 wherein the method further
includes delivery of O.sub.2 gas at a site of irradiation.
8. The method according to claim 1 performed either simultaneously
or sequentially in combination with an additional tightening
procedure.
9. A system configured to crosslink tarsal plate tissue comprising:
an applicator configured to apply a photosensitizer solution to an
exposed tarsal plate of an eye; and a radiation source configured
to provide photo-activating radiation to the tarsal plate wherein
the radiation source provides a beam profile of greater than 12 mm
at 10 mm from a surface of the tarsal plate.
10. The system of claim 9 further comprising a means for delivering
O.sub.2 to the tarsal plate.
11. A method of crosslinking tarsal plate tissue comprising topical
application to the tarsal plate of a photosensitizer that initiates
crosslinking in response to photo-activating radiation and,
simultaneously or subsequently, treating the tarsal plate with
photo-activating radiation.
12. The method according to claim 11, wherein the photosensitizer
is a pharmaceutical composition comprising riboflavin or a
pharmaceutically acceptable derivative, salt or solvate
thereof.
13. The method according to claim 12, wherein the pharmaceutical
composition comprises an aqueous solution of riboflavin
5'-phosphate or a pharmaceutically acceptable salt or solvate
thereof.
14. The method according to claim 11, wherein the radiation is UV-A
radiation.
15. A kit for performing the method of claim 1 comprising a
pharmaceutical composition comprising a photosensitizer that
initiates crosslinking in response to photo-activating radiation
together with an applicator adapted to apply the photosensitizer to
a tarsal plate.
16. A kit according to claim 15 wherein the photosensitizer is
riboflavin or a pharmaceutically acceptable salt, derivative or
solvate thereof.
17. A kit according to claim 16 wherein the riboflavin
pharmaceutical composition is an aqueous solution.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to Australian Provisional
Application No. 2017900561 entitled "METHOD OF TREATMENT" filed on
21 Feb. 2017, the entire content of which is incorporated herein by
reference.
FIELD
[0002] The methods, apparatuses and compositions herein relate
generally to a method of treatment of eyelid laxity, and in
particular to a method comprising exposure of the tarsal plate
followed by irradiation in the presence of a photosensitizer to
enhance the rigidity or strength of the tarsal plate and inhibit
the progression of the disorder.
BACKGROUND
[0003] The reference in this specification to any prior publication
(or information derived from it), or to any matter which is known,
is not, and should not be taken as an acknowledgment or admission
or any form of suggestion that that prior publication (or
information derived from it) or known matter forms part of the
common general knowledge in the field of endeavor to which this
specification relates.
[0004] The condition known as eyelid laxity (or lax eyelid), also
known as floppy eyelid syndrome (FES), is regarded as a subset of
the conditions generated by the laxity of the eyelid [see A. M.
Fowler, J. J. Dutton: "Floppy eyelid syndrome as a subset of lax
eyelid conditions: Relationships and clinical relevance (an ASOPRS
thesis)", Ophthal. Plast. Reconstr. Surg., 26 (2010) 195-204].
Eyelid laxity can be defined as an acquired hyperelasticity
disorder where the inherent rigidity of the lids is lost. It can
affect both upper and lower eyelids. Due to corneal complications
and associations with other eyelid disorders, a floppy eyelid can
lead to blindness. Eyelid laxity is commonly associated with other
conditions including obesity, cardiovascular disease, obstructive
sleep apnea, and eye rubbing.
[0005] The main clinical feature of a floppy eyelid is the extreme
laxity of the upper or lower tarsus (or tarsal plate), which
becomes pliant and rubbery. In normal conditions, the upper or
lower tarsal plate is a specialized dense fibrous tissue that is
able to display significant rigidity and provide structural
integrity, shape and firmness to the entire eyelid. Tarsal plate
tissue can be regarded as a unique tissue with transient character
possessing features common to both cartilage and fibers [see a
description of fibrocartilage tissues in M. Benjamin, J. R. Ralphs:
"Biology of fibrocartilage cells", Int. Rev. Cytol., 233 (2004)
1-45]. The tarsal tissue consists mainly of fibrillar collagens
type I, III and, to a lesser extent, type VI, as well as elastic
networks of fibrillin and elastin fibers [see: S. Milz, J. Neufang,
I. Higashiyama, R. Putz, M. Benjamin: "An immunohistochemical study
of the extracellular matrix of the tarsal plate in the upper lid in
human beings", J. Anat., 206 (2005) 37-45; D. G. Ezra, M.
Beaconsfield, R. Collin: "Surgical anatomy of the upper eyelid: old
controversies, new concepts", Expert Rev. Ophthalmol., 4 (2009)
47-57]. In the tarsal plates of the lax eyelids, the collagen
expression, structure and distribution remains the same as in
normal tarsus, as was reported for instance in: R. Goldberg, S.
Seiff, J. McFarland, K. Simons, N. Shorr: "Floppy eyelid syndrome
and blefarochalasis", Am. J. Ophthalmol., 102 (1986) 376-381; and
E. Arrocker-Mettinger, R. Haddad, K. Konrad, F. J. Steinkogler:
"Floppy eyelid syndrome: Investigations by light and electron
microscopies" (Ger.), Klin. Mbl. Augenheilk., 188 (1986) 596-598.
However, the decrease in the amount of elastin and mature elastic
fibers observed histopathologically in the tarsal plate of a lax
eyelid [as reported for instance in: P. A. Netland, S. P. Sugrue,
D. M. Albert, J. W. Shore: "Histopathologic features of the floppy
eyelid syndrome. Involvement of tarsal elastin", Ophthalmology, 101
(1994) 174-181; U. Schlotzer-Schrehardt, M. Stojkovic, C.
Hofmann-Rummelt, C. Cursiefen, F. E. Kruse, L. M. Holbach: "The
pathogenesis of floppy eyelid syndrome. Involvement of matrix
metalloproteinases in elastic fiber degradation", Ophthalmology,
112 (2005) 694-704] is not consistent with an enhanced elasticity
and reduced mechanical strength that have been evidenced
clinically. A more recent study [D. G. Ezra, J. S. Ellis, C.
Gaughan, M. Beaconsfield, R. Collin, C. Bunce, M. Bailly, P.
Luthert: "Changes in tarsal plate fibrillar collagens and elastic
fiber phenotype in floppy eyelid syndrome", Clin. Exp. Ophthalmol.,
39 (2011) 564-571] has demonstrated that instead of a reduction of
elastic fibers in the tarsal plates belonging to lax eyelids, the
main process consists rather of a change in the phenotype of these
fibers. The same study also confirmed that the expression and
periodicity of the main fibrillar collagens remain normal.
[0006] Current treatment methods for eyelid laxity include
nocturnal lid shielding, taping or lubrication. These treatment
methods generally only provide temporary benefit. Surgical methods
may be used to tighten the lid. These surgical methods include
full-thickness wedge excision; lateral tarsal strip; lateral
canthal tendon plication; or lateral tarsorrhaphy (D. G. Ezra, M.
Beaconsfield, R. Collin: "Floppy eyelid syndrome: Stretching the
limits", Surv. Ophthalmol., 55 (2010) 35-46).
[0007] These surgical horizontal tightening procedures usually only
provide temporary benefit as the eyelid tissue continues to stretch
with time and the eyelid laxity returns. Furthermore, these
surgical procedures are usually performed under general anesthesia.
This is a particular problem as many patients with floppy eye
syndrome are commonly also afflicted by cardiovascular disease,
obesity and sleep apnea: conditions that require particular
considerations with respect to administration of general
anesthesia.
[0008] There is a need for improved methods for treating or
inhibiting the progression of eyelid laxity that overcome one or
more drawbacks of the present therapies.
SUMMARY
[0009] The methods, compositions and apparatuses herein are
predicated in part on the surprising discovery that exposure of a
tarsal plate to radiation in the presence of a photosensitizer
initiates crosslinking within the tissue, and particularly
crosslinking of collagen in the tarsal plate tissue. This
crosslinking has been found to improve or restore strength or
rigidity to the tarsal plate resulting in arresting or slowing the
progression of eyelid laxity.
[0010] Accordingly, in one aspect the methods herein advantageously
provide a method of treating eyelid laxity in a subject
comprising:
exposing a tarsal plate of an eye; [0011] applying to at least part
of the exposed tarsal plate a photosensitizer that initiates
crosslinking in response to photo-activating radiation; and [0012]
irradiating the exposed tarsal plate with photo-activating
radiation to initiate crosslinking activity in the tarsal plate
tissue.
[0013] The method suitably further comprises making an incision to
expose the tarsal plate and subsequent closure of the incision
after irradiation with the photo-activating radiation.
[0014] The inventors have discovered that it is desirable that the
photosensitizer is in solubilized form, suitably in the form of an
aqueous composition. The method may advantageously include delivery
of O.sub.2 at the site of crosslinking.
[0015] The methods herein may be applied to one or both eyes of a
subject, individually, simultaneously or sequentially; or to the
upper and/or lower tarsal plates of an eye, individually,
simultaneously or sequentially. A method may be performed
simultaneously or sequentially in combination with an additional
surgical tightening procedure.
[0016] In another aspect, there is provided a system for
crosslinking tarsal plate tissue comprising:
[0017] an applicator that applies or delivers a photosensitizer to
an exposed tarsal plate of an eye; and [0018] a radiation source
that provides photo-activating radiation to the tarsal plate with a
beam profile of greater than 12 mm at a distance of about 10 mm
from a surface of the tarsal plate.
[0019] In another aspect, there is provided a kit or commercial
package for crosslinking tarsal plate tissue comprising:
an applicator that applies or delivers a photosensitizer to an
exposed tarsal plate of an eye; and a radiation source for
providing photo-activating radiation to the tarsal plate; together
with instructions to treat eyelid laxity or crosslink a tarsal
plate or tarsal plate tissue.
[0020] The system, kit or commercial package may further include a
means of delivering O.sub.2 to the site of crosslinking.
[0021] In a yet further aspect, there is advantageously provided
herein a photosensitizer that initiates crosslinking in response to
photo-activating radiation for use in treatment or prevention of
eyelid laxity.
[0022] In a yet further aspect, the methods herein advantageously
provide use of a photosensitizer that initiates crosslinking in
response to photo-activating radiation for crosslinking of tarsal
plate tissue.
[0023] In another aspect, there is provided the use of a
photosensitizer that initiates crosslinking in response to
photo-activating radiation for the manufacture of a medicament for
treatment of eyelid laxity.
[0024] In another aspect, there is provided a use of a
photosensitizer that initiates crosslinking in response to
photo-activating radiation for inhibiting the progression or
development of eyelid laxity in a subject.
[0025] The inventors have found it desirable to use riboflavin or a
pharmaceutically acceptable salt, derivative and/or solvate thereof
as a photosensitizer in combination with UV-A photo-activating
radiation. In preferred embodiments the riboflavin is in a water
soluble form, for example a water soluble salt, derivative and/or
solvate thereof.
[0026] In a further aspect, there is advantageously provided a
pharmaceutical composition comprising a photosensitizer, for
example riboflavin or a pharmaceutically acceptable salt,
derivative or solvate thereof, for use in combination with
photo-activating radiation for treatment or prevention of eyelid
laxity.
[0027] In another aspect, the apparatuses herein also provide a kit
or commercial package comprising a pharmaceutical composition
comprising a photosensitizer that initiates crosslinking in
response to photo-activating radiation; together with instructions
for use in combination with photo-activating radiation to treat
eyelid laxity, or to effect crosslinking in a tarsal plate or
tarsal plate tissue. In some embodiments the photosensitizer is
riboflavin or a pharmaceutically acceptable salt, derivative or
solvate thereof. In some embodiments the pharmaceutical composition
is an aqueous composition. In some embodiments the photosensitizer
is in solubilized form.
BRIEF DESCRIPTION OF THE DRAWINGS
[0028] FIG. 1 is a representation of a horizontal skin incision on
an upper eyelid.
[0029] FIG. 2 shows cauterization made with a Bovie hot-temperature
cautery machine through the underlying orbicularis oculi muscle
down to the orbital septum.
[0030] FIG. 3 shows the creation of a pretarsal pocket in the
central upper eyelid using the Bovie cautery machine.
[0031] FIG. 4 shows the insertion of a neurosurgical patty, soaked
in a photosensitizer solution, into the pretarsal pocket.
[0032] FIG. 5 shows the insertion of a corneal protector against
the eye globe.
[0033] FIG. 6 shows the exposure of the anterior aspect of the
tarsal plate of the upper eyelid, where irradiation is
delivered.
[0034] FIG. 7 shows the closure of the incision using sutures.
[0035] FIG. 8 shows the stress-strain plots for untreated and
UV-crosslinked (365 nm, 6 mW/cm.sup.2) sheep tarsal plates.
[0036] FIG. 9 shows comparative bar graphs of the experimentally
measured Young's moduli, prior and after crosslinking with UV-A
radiation at high irradiances of the sheep tarsal tissue from upper
and lower eyelids. The asterisk indicates statistical
significance.
[0037] FIG. 10 shows comparative bar graphs of the experimentally
measured stress at 20% strain, prior and after crosslinking with
UV-A radiation at high irradiances of the sheep tarsal tissue from
upper and lower eyelids. An asterisk indicates statistical
significance.
[0038] FIG. 11 shows comparative bar graphs of the experimentally
measured Young's moduli, prior and after crosslinking of the sheep
tarsal tissue from upper and lower eyelids with UV-A radiation at
an irradiance of 45 mW/cm.sup.2, with the photosensitizer solution
being applied either by direct immersion or through contact with
fluid-saturated surgical patties. An asterisk indicates statistical
significance.
[0039] FIG. 12 shows comparative bar graphs of the experimentally
measured stress at 20% strain, prior and after crosslinking of the
sheep tarsal tissue from upper and lower eyelids with UV-A
radiation at an irradiance of 45 mW/cm.sup.2, with the
photosensitizer solution being applied either by direct immersion
or through contact with fluid-saturated surgical patties. An
asterisk indicates statistical significance.
DETAILED DESCRIPTION
1. Definitions
[0040] Unless defined otherwise, all technical and scientific terms
used herein have the same meaning as commonly understood by those
of ordinary skill in the art to which the methods, compositions and
apparatuses herein belong. Although any methods and materials
similar or equivalent to those described herein can be used in the
practice or testing of the present methods, compositions and
apparatuses, preferred methods and materials are described. For the
purposes of the methods, compositions and apparatuses herein, the
following terms are defined below.
[0041] The articles "a" and "an" are used herein to refer to one or
to more than one (i.e. to at least one) of the grammatical object
of the article. By way of example, "an element" means one element
or more than one element.
[0042] By "about" is meant a quantity, level, value, number,
frequency, percentage, dimension, size, amount, weight or length
that varies by as much 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3,
2 or 1% to a reference quantity, level, value, number, frequency,
percentage, dimension, size, amount, weight or length.
[0043] As used herein, the term "and/or" refers to and encompasses
any and all possible combinations of one or more of the associated
listed items, as well as the lack of combinations when interpreted
in the alternative (or).
[0044] The phrase "aqueous carrier" is used herein to refer to a
liquid aqueous diluent, wherein the aqueous carrier includes, but
is not limited to, water, saline, aqueous buffer and aqueous
solutions comprising water soluble or water miscible additives such
as glucose or glycerol. The aqueous carrier may also be in the form
of an oil-in-water emulsion.
[0045] Throughout this specification and the claims which follow,
unless the context requires otherwise, the word "comprise", and
variations such as "comprises" and "comprising", will be understood
to imply the inclusion of a stated integer or step or group of
integers or steps but not the exclusion of any other integer or
step or group of integers or steps. Thus, the use of the term
"comprising" and the like indicates that the listed integers are
required or mandatory, but that other integers are optional and may
or may not be present. By "consisting of" is meant including, and
limited to, whatever follows the phrase "consisting of". Thus, the
phrase "consisting of" indicates that the listed elements are
required or mandatory, and that no other elements may be present.
By "consisting essentially of" is meant including any elements
listed after the phrase, and limited to other elements that do not
interfere with or contribute to the activity or action specified in
the disclosure for the listed elements. Thus, the phrase
"consisting essentially of" indicates that the listed elements are
required or mandatory, but that other elements are optional and may
or may not be present depending upon whether or not they affect the
activity or action of the listed elements.
[0046] As used herein, the terms "condition" or "disease" refers to
an abnormality in the physical state of the body as a whole or one
of its parts.
[0047] As used herein, the term "salts", "derivative" and "solvate"
include any pharmaceutically acceptable salt, derivative, or
solvate or any other compound which, upon administration to the
recipient, is capable of providing (directly or indirectly) a
desired photosensitizer. Suitable pharmaceutically acceptable
derivatives include esters, such as phosphate esters. Suitable
pharmaceutically acceptable salts include salts of pharmaceutically
acceptable inorganic acids such as hydrochloric, sulfuric,
phosphoric, nitric, carbonic, boric, sulfamic and hydrobromic
acids, or salts of pharmaceutically acceptable organic acids such
as acetic, propionic, butyric, tartaric, maleic, hydroxymaleic,
fumaric, citric, lactic, mucic, gluconic, benzoic, succinic,
oxalic, phenylacetic, methanesulfonic, toluenesulfonic,
benzenesulfonic, salicylic, sulfanilic, aspartic, glutamic, edetic,
stearic, palmitic, oleic, lauric, pantothenic, tannic, ascorbic and
valeric acids. Base salts include, but are not limited to, those
formed with pharmaceutically acceptable cations, such as sodium,
potassium, lithium, calcium, magnesium, ammonium and alkylammonium,
particularly sodium. Also, basic nitrogen-containing groups may be
quaternized with such agents as lower alkyl halides, such as
methyl, ethyl, propyl and butyl chlorides, bromides and iodides;
dialkyl sulfates such as dimethyl and diethyl sulfate; and others.
Pharmacologically acceptable solvates are known in the art, and
include hydrates and alcoholates. Suitably, pharmaceutically
acceptable solvates include hydrates, for example monohydrates,
dihydrates and trihydrates. The skilled person will understand that
a photosensitizer may be in the form of a pharmaceutically
acceptable salt, and/or a solvate and/or a derivative, for example
riboflavin 5'-phosphate monosodium salt dihydrate and the like. The
preparation of salts, derivatives and solvates can be carried out
by methods well known in the art.
[0048] As used herein, the phrase "solubilized form" refers to a
form where a compound, such as a photosensitizer, is dissolved in a
liquid such that a solution comprising a uniform distribution of
the compound is obtained which is substantially free of solid
compound. In some embodiments, the liquid is an aqueous carrier as
described herein.
[0049] As used herein "water soluble form" refers to a chemical
and/or physical form of a compound, such as a photosensitizer,
where the compound or a salt and/or derivative and/or solvate
and/or polymorph thereof has sufficient solubility in water at
ambient temperature to achieve a concentration of from 0.1% to 20%
w/v, 0.1% to 10% w/v, 0.1% to 5% w/v, 0.1% to 3%, 0.1% to 2.5%,
0.1% to 1%, 0.1% to 0.5%, or 0.1% to 0.25%. Solubility can be
determined using methods well known in the art.
[0050] The term "subject" or "individual" as used herein refers to
a vertebrate subject, particularly a mammalian subject, for whom
therapy or prophylaxis is desired. Suitable subjects include, but
are not limited to, primates; livestock animals such as sheep,
cows, horses, deer, donkeys and pigs; laboratory test animals such
as rabbits, mice, rats, guinea pigs and hamsters; companion animals
such as cats and dogs; and captive wild animals such as foxes, deer
and dingoes. In particular embodiments, the subject is a human.
However, it will be understood that the aforementioned terms do not
imply that symptoms are present.
[0051] The term "eyelid laxity" or "floppy eyelid syndrome" when
used herein refers to conditions where an acquired hyperelasticity
disorder in an eyelid has resulted in the inherent rigidity of the
eyelid being lost.
[0052] When used herein, the term "photosensitizer" refers to a
molecule that, on irradiation by photo-activating irradiation,
produces a chemical change in another molecule through a
photochemical process. Examples of "another molecule" include, for
example, a crosslinker or crosslinking agent such as O.sub.2. A
photosensitizer may convert O.sub.2 molecules from the normal
O.sub.2 triplet state to a more energetic singlet state that can
initiate crosslinking, for example in tissue molecules or
macromolecules. Further examples of "another molecule" include
tissue molecules or macromolecules, including collagen
macromolecules. A photosensitizer, after exposure to radiation and
transition to a more energetic state, may also produce a chemical
change in collagen and/or other tissue molecules and initiate or
generate crosslinking in the tissue. The skilled person will
appreciate that optimum results will be achieved when the selected
photosensitizer absorbs radiation at a wavelength of the
photo-activating radiation. The absorption wavelength(s) of a
photosensitizer can be determined by Ultraviolet/Visible (UV/VIS)
Spectrophotometry using a commercially available UV/VIS
spectrophotometer in accordance with well known procedures. A
photosensitizer will preferably be pharmaceutically acceptable,
non-irritant and non-toxic.
[0053] When used herein, the term "crosslinker" or "crosslinking
agent" refers to a chemical moiety that can chemically join two or
more molecules, for example by covalent bonding or ionic bonding,
preferably by covalent bonding. An example of a crosslinking agent
is O.sub.2 which acts as a crosslinking agent when in the form of
its high energy singlet state. A crosslinker or crosslinking agent
will preferably be pharmaceutically acceptable. A molecule may be a
macromolecule. Preferably a crosslinker or crosslinking agent will
be substantially non-irritant and non-toxic.
[0054] The term "photo-activating radiation" when used herein
refers to radiation that can activate a photosensitizer to produce
a chemical change in another molecule. Suitably the photosensitizer
absorbs radiation at a wavelength of the photo-activating
radiation. In some embodiments the radiation is UV-A radiation.
[0055] The terms "treat", "treating" or "treatment" as used herein
cover the treatment of eyelid laxity, and includes: inhibiting the
disease or condition, i.e., arresting its development; relieving
the disease or condition, i.e., causing regression of the disease
or condition; or relieving the symptoms resulting from the disease
or condition, i.e., relieving pain or inflammation without
addressing the underlying disease or condition.
[0056] Each embodiment described herein is to be applied mutatis
mutandis to each and every embodiment unless specifically stated
otherwise.
2. Methods
[0057] The present methods are based, in part, on the
identification that irradiation of tarsal plate tissue in the
presence of a photosensitizer can significantly enhance the
mechanical rigidity and strength of the tarsal plate. Thus, the
inventors conceived that treatment of eyelid laxity or inhibition
of the development of eyelid laxity may be achieved by irradiating
an exposed tarsal plate with photo-activating radiation in the
presence of a photosensitizer.
[0058] These surprising findings have enabled the development of a
method of treating eyelid laxity comprising subjecting an exposed
tarsal plate to photo-activating radiation in the presence of a
photosensitizer to crosslink tarsal tissue and thus strengthen the
tarsal plate. This leads to slowing or arresting of the progression
of eyelid laxity. This provides a simple and effective procedure
for treatment of eyelid laxity. The method addresses a major
drawback of known surgical interventions where the benefit is
temporary as the eyelid continues to stretch and the laxity
returns. The method impacts on the underlying pathology in that it
prevents or arrests tarsal stretching. Furthermore, the method can
provide sustained benefit from surgery when combined with
additional tightening procedures, such as surgical tightening
procedures including full-thickness wedge excision; lateral tarsal
strip; lateral canthal tendon plication; or lateral tarsorrhaphy.
The method can also be used as a prophylactic treatment in at-risk
patients before the symptoms arise. Furthermore, the method does
not significantly alter the macroscopic eyelid anatomy, so it can
be performed prior to, in combination with, or subsequent to other
eyelid operations. Another advantage of the method is that it can
be performed under local anesthesia, making it more acceptable to
patient affected by the often associated conditions of
cardiovascular disease, obesity and sleep apnea.
[0059] Without being bound by theory or mode of operation, it is
believed that the photosensitizer initiates crosslinking within the
tarsal plate tissue, particularly crosslinking of collagen
macromolecules, when exposed to photo-activating radiation. This
results in increased rigidity and strength of the tarsal plate. It
is believed that the photosensitizer absorbs radiation and is
raised to an energetically excited state, which further initiates
reactions within the tarsal plate tissue, particularly in
constitutive collagen (Type I reactions) and with O.sub.2 (Type II
reactions). Both types of reaction are thought to be able to
generate covalent crosslinkages between the macromolecules in the
tarsal tissue, particularly crosslinkages between collagen
macromolecules.
[0060] It is believed that the collagen expression, structure and
distribution remains the same in the tarsal plates of the lax
eyelids as that found in the normal tarsus. However, the decrease
in the amount of elastin and mature elastic fibers observed
histopathologically in the tarsal plate of a lax eyelid is not
consistent with an enhanced elasticity and reduced mechanical
strength that is evidenced clinically. Instead of a reduction of
elastic fibers in the tarsal plates of lax eyelids, the main
process appears to involve a change in the phenotype of these
fibers. The expression and periodicity of the main fibrillar
collagens remain normal. Since an unaltered integration of the
elastic fiber networks (imparting compliance and elasticity) with
the collagen fibers (imparting tensile strength and rigidity) is
critical for ensuring and maintaining the normal mechanical
properties of the tarsal plate, it is believed that the stiffening
of the collagen fibrils in the tarsal plate of a lax eyelid can
compensate for the loss of strength and restore the rigidity of the
entire plate, leading to the arrest or slowing of eyelid
laxity.
[0061] Accordingly, in view of the surprising finding that
irradiation of tarsal plate tissue in the presence of a
photosensitizer can significantly enhance the mechanical rigidity
and strength of the tarsal plate, the methods herein advantageously
provides a method of treating eyelid laxity in an individual
comprising the steps of: [0062] exposing a tarsal plate of an eye;
[0063] applying to at least part of the exposed tarsal plate a
photosensitizer that generates crosslinking in the tarsal plate
tissue in response to photo-activating radiation; and [0064]
irradiating the exposed tarsal plate with photo-activating
radiation to initiate crosslinking in the tarsal plate tissue.
[0065] Suitably the methods may be applied to a tarsal plate of an
upper eyelid, a lower eyelid, or to both eyelids, subsequently or
simultaneously. A method may be applied to eyelids of one or both
eyes of a subject, individually, subsequently or
simultaneously.
[0066] The skilled person, such as an oculoplastic surgeon, will be
familiar with methods and procedures for exposing a tarsal plate of
an eye, particularly the anterior aspect of the tarsal plate.
Suitably the tarsal plate may be exposed by making an incision line
horizontally within the eyelid crease (for an upper eyelid), or
approximately 3 to 5 mm, for example 4 mm, from the margin in the
lower eyelid. The incision is then deepened through the underlying
orbicularis oculi muscle down to the orbital septum and creating a
pretarsal pocket in the central eyelid area by extending medially
and laterally using, for example, a hot temperature cautery
instrument, to expose the anterior aspect of the tarsal plate.
Suitably the area of the tarsal plate exposed is an area between 25
mm by 10 mm and 15 mm by 5 mm, for example approximately 20 mm by 8
mm, on the upper eyelid; or an area between 25 mm by 6 mm and 15 mm
by 2 mm, for example 20 mm by 3 mm, on the lower eyelid.
[0067] A photosensitizer is suitably pharmaceutically acceptable,
substantially non-toxic and substantially non-irritant. The skilled
person will readily understand that different photosensitizers will
absorb photosensitizing radiation of specific wavelengths according
to the chemical structure of the chromophore, and will be able to
match the photosensitizer to the appropriate wavelength of
photosensitizing radiation. In some embodiments the photosensitizer
absorbs radiation in the ultraviolet region of the electromagnetic
spectrum, preferably long wavelength ultraviolet radiation (UV-A
radiation, wavelength from 320 to 400 nm). In some other
embodiments, the photosensitizer absorbs radiation at a wavelength
of 495-570 nm (green light). Preferably the photosensitizer is
pharmaceutically acceptable, non-toxic and non-irritant. Preferably
the photosensitizer has regulatory approval for food and/or drug
use. In some embodiments the photosensitizer may comprise one or
more chemical entities. In some embodiments there may be a single
photosensitizer molecule type present.
[0068] In some embodiments the photosensitizer comprises riboflavin
or a pharmaceutically acceptable salt, derivative or solvate
thereof. Riboflavin is also known as vitamin B2, and has the IUPAC
name
7,8-dimethyl-10-[(2S,3S,4R)-2,3,4,5-tetrahydroxypentyl]benzo[g]pteridine--
2,4-dione. Preferably riboflavin is in a water soluble form, for
example as a water soluble derivative, salt or solvate, such as an
alkali metal salt, of riboflavin 5'-phosphate. Preferably the
riboflavin derivative, solvate or salt is non-toxic and
non-irritant. In some embodiments the photosensitizer comprises a
sodium salt of riboflavin 5'-phosphate or a pharmaceutically
acceptable solvate thereof, such as riboflavin 5'-phosphate
monosodium salt. Preferably a solvate is a hydrate.
[0069] In some embodiments the photosensitizer is rose Bengal
(4,5,6,7-tetrachloro-2',4',5',7'-tetraiodofluorescein disodium
salt). Preferably rose Bengal is used in conjunction with
irradiation by green light, i.e. radiation wavelength 495-470
nm.
[0070] In some embodiments the photosensitizer is selected from
lucigenin, acridine orange, Quantacure QTX, Lissamine green B,
fluorescein, Brilliant blue G, triamcinolone, or trypan blue. In
some embodiments the photosensitizer is selected from lucigenin,
acridine orange, and Quantacure QTX
(2-hydroxy-3-(3,4-dimethyl-9-oxo-9H-thioxanthen-2-yloxy)-N,N,N-trimethyl--
1-propanaminium chloride) and the irradiation has a wavelength
greater than 300 nm (UV-A/visible).
[0071] In some embodiments, the photosensitizer is applied to at
least part of the exposed tarsal plate. Suitably the
photosensitizer is applied to at least 25%, at least 50%, at least
75%, at least 80%, or at least 90% of the surface of the exposed
tarsal plate. Preferably the photosensitizer is applied to
substantially the entire surface of the exposed tarsal plate.
[0072] In some embodiments the photosensitizer is in solubilized
form. Preferably the sensitizer is water soluble. Preferably the
sensitizer is in aqueous solution. In preferred embodiments, the
photosensitizer is formulated in an aqueous carrier. For example,
the aqueous carrier may be selected from, but is not limited to,
saline, water, aqueous buffer, an aqueous solution comprising water
and a miscible solvent, and combinations thereof. In some
embodiments, the aqueous carrier is saline. In preferred
embodiments the photosensitizer and aqueous carrier form a sterile
solution.
[0073] In some embodiments, the photosensitizer is formulated as an
aqueous formulation, for example an aqueous solution, an aqueous
gel, or an oil in water emulsion, preferably as an aqueous
solution. In some embodiments the photosensitizer is present in an
amount of 0.1 to 20% w/v. Suitable water soluble photosensitizers
are readily available from commercial sources, for example
riboflavin 5'-phosphate sodium salt, riboflavin 5'-phosphate sodium
salt hydrate and riboflavin 5'-phosphate sodium salt dihydrate are
available from Sigma Aldrich Co. LLC. Photosensitizers formulated
as a solution are commercially available, for example ParaCel.TM.
(Avedro, Inc, Waltham, Mass., USA) is a commercially available
aqueous solution comprising 0.25% riboflavin in the form of
riboflavin 5'-phosphate sodium salt, and VibeX Rapid.TM. (Avedro,
Inc) is a commercially available solution comprising 0.1%
riboflavin 5'-phosphate sodium salt. In some embodiments the
photosensitizer is commercially available as a sterile formulation
in a dispenser, for example as a sterile aqueous sodium riboflavin
5'-phosphate solution packaged in a syringe, ampoule, vial or
dropper, for example a single use syringe.
[0074] The skilled person will understand that the amount of
photosensitizer required will depend on the identity of the
photosensitizer. In some embodiments the amount of photosensitizer
applied to the exposed tarsal plate is from 1 to 5 mL of a solution
comprising from 0.1 to 0.5% w/v of photosensitizer, suitably 0.1 to
0.25% w/v. In some embodiments the amount of riboflavin applied to
an exposed tarsal plate is 1.8 mL of 0.25% riboflavin (as
riboflavin 5'-phosphate) in aqueous carrier; or 2 mL of 0.22%
riboflavin (as riboflavin 5'-phosphate) in aqueous carrier; or 3 mL
of 0.146% riboflavin (as riboflavin 5'-phosphate) in aqueous
carrier or 2 mL of 0.1% riboflavin (as riboflavin 5'-phosphate) in
aqueous carrier.
[0075] The photosensitizer is applied to the exposed tarsal plate
using any suitable means known to the skilled person. In some
embodiments the photosensitizer is applied using an applicator. In
some embodiments the photosensitiser is applied dissolved in an
aqueous carrier, preferably as an aqueous solution. In some
embodiments, the photosensitizer is instilled directly onto the
surface of the exposed tarsal plate. In some embodiments the
photosensitizer is instilled onto the tarsal plate or pretarsal
pocket using, a suitable applicator such as a syringe, pipette or
dropper. In some embodiments, a pretarsal pocket is formed
surgically and the photosensitiser solution is instilled into the
pretarsal pocket. In some embodiments, excess photosensitizer is
removed from the tarsal plate or pretarsal pocket prior to
irradiation. In some embodiments excess photosensitizer solution is
removed from the tarsal plate using absorbent material, such as
surgical sponge. In some embodiments, photosensitizer solution is
first absorbed onto an absorbent material, preferably a disposable
textile pad, for example a surgical sponge or neurosurgical patty,
prior to application to the exposed tarsal plate or insertion into
the tarsal pocket. In some embodiments the photosensitizer is
applied to substantially the entire exposed surface of the tarsal
plate.
[0076] In some embodiments the photosensitizer, preferably in the
form of an aqueous solution, is allowed to remain in contact with
the exposed tarsal plate for a period of from 6 to 60 minutes, for
example 6 to 30 minutes, 30 to 60 minutes, 10 to 30 minutes, 10 to
40 minutes, 6 to 15 minutes, 6 to 20 minutes or 10 to 20 minutes.
The exact timing will depend on the amount and concentration of the
photosensitizer, and can be easily determined by the skilled person
based on the concentration of the photosensitizer solution. In some
embodiments the photosensitizer instilled in the pretarsal pocket
is 0.1% riboflavin (as riboflavin 5'-phosphate, sodium salt) in
aqueous solution which is allowed to contact the tarsal plate for
approximately 30 minutes. In some embodiments the photosensitizer
instilled in the pretarsal pocket is 0.25% riboflavin (as
riboflavin 5'-phosphate, sodium salt) in aqueous solution which is
allowed to contact the tarsal plate for approximately 30
minutes.
[0077] After the photosensitizer has contacted the tarsal plate for
the required length of time, the absorbent material, or excess
solution, is removed and the exposed tarsal tissue is exposed to
radiation of appropriate wavelength for the photosensitizer used.
In some embodiments the photosensitizer is a sodium salt of
riboflavin 5'-phosphate and the radiation is UV-A radiation of
wavelength of about 320 nm to about 400 nm. In some embodiments the
UV-A radiation wavelength is approximately 365 nm.
[0078] Treatment of the tarsal plate with photo-activating
radiation may be simultaneous and/or subsequent to treatment with a
photosensitizer. In some embodiments additional photosensitizer may
be applied to the tarsal plate during irradiation.
[0079] The skilled person will understand that the irradiation time
necessary to induce sufficient crosslinking in the tarsal plate
tissue will be dependent on several factors including the
irradiance intensity delivered by the radiation source
(mW/cm.sup.2), and the beam width. Preferably, use of an irradiance
of about 3 mW/cm.sup.2 up to about 150 mW/cm.sup.2 is envisaged. It
will also be appreciated that the radiant exposure should not be
detrimental to the health of the tissue. A radiant exposure, or
fluence, of about 4 to about 27 J/cm.sup.2 is considered
appropriate. In some embodiments, the radiant exposure of the
tarsal tissue, or fluence, is from about 5 to about 8 J/cm.sup.2.
In some embodiments, the fluence is about 27 J/cm.sup.2. The
skilled person will be able to determine the duration of the
exposure required based on the power of the radiation.
[0080] Suitably, the tarsal tissue is exposed to UV-A radiation
(320 nm to 400 nm, for example 365 nm) at an irradiance of about 3
to about 6 mW/cm.sup.2, for example about 3 mW/cm.sup.2 or about 6
mW/cm.sup.2. In some embodiments, irradiation of the
photosensitizer treated tarsal plate with UV-A radiation is
maintained for a duration between about 6 minutes and about one
hour, for example 6 to 40 minutes, 6 to 30 minutes, 6 to 20 minutes
or 6 to 10 minutes.
[0081] In some embodiments, the irradiation may be carried out at
high irradiance, for example at 30-45 mW/cm.sup.2 for 1 to 4
minutes, for example 2 to 3 minutes. In some embodiments the
radiant exposure, or fluence, is from about 5 to 8 J/cm.sup.2, for
example from about 5.4 to 7.2 J/cm.sup.2.
[0082] The skilled person will appreciate that there will be an
upper limit to the amount of irradiation that is considered useful.
It is considered that irradiation levels of up to and including 150
mW/cm.sup.2, for example 150 mW/cm.sup.2, may be used safely.
Irradiation at a level of 150 mW/cm.sup.2 should be carried out for
up to 4 minutes, or up to 3 minutes; for example 1 to 4 minutes, 1
to 3 minutes, 2 to 3 minutes, 1 to 2 minutes, or approximately 1
minute. Irradiances exceeding 150 mW/cm.sup.2 are considered to be
less effective in improving the stiffness or strength of tarsal
tissue. This is thought to be due to the presence of competing
photodegradative processes which may prevail over the beneficial
crosslinking reactions.
[0083] In some embodiments, the delivery of the irradiation is
continuous. In some embodiments, the delivery of irradiation is
pulsed. In some embodiments, the radiation is applied using a beam
profile of greater than 12 mm at 10 mm from a surface of the tarsal
plate. In some embodiments, a narrower radiation beam of, for
example, about 11 mm, may be used if it is repositioned at time
intervals, for example to ensure that the entire surface of the
tarsal plate is irradiated.
[0084] In some embodiments, the tarsal plate is irradiated over its
entire exposed surface. In some embodiments the tarsal plate is
irradiated substantially where the photosensitizer has been
applied.
[0085] In some preferred embodiments, an eye shield or protector,
such as a metallic eye protector, is placed under the eyelid and
against the anterior aspect of the eye globe prior to irradiation
to protect the eye globe from radiation.
[0086] In some embodiments of the methods herein, irradiation is
carried out in the presence of one or more crosslinking agents. A
crosslinking agent will preferably be pharmaceutically acceptable.
The skilled person will understand that a crosslinking agent will
be preferably substantially non-irritant and non-toxic. In some
embodiments irradiation is carried out in the presence of O.sub.2
gas. In some embodiments a method is carried out in the presence of
additional O.sub.2 gas to provide O.sub.2 concentrations greater
than those present in the normal atmospheric conditions or in the
tarsal tissue. In some embodiments, the additional O.sub.2 is
provided at the site of crosslinking during irradiation. In some
embodiments O.sub.2 gas is delivered to the surface of the tarsal
plate in the proximity of the irradiation site, for example using a
delivery device such as an applicator. In some embodiments, the
O.sub.2 gas is humidified prior to use. Methods of generating
humidified O.sub.2 gas are known to the skilled person, and include
passing the gas flow through a humidifier prior to delivery to the
required site.
[0087] In some embodiments, the methods herein comprise making an
incision to expose the tarsal plate and subsequent closure of the
incision after irradiation with the photo-activating radiation.
Techniques for making incisions are well known in the art and
include, for example, use of a scalpel or a laser. Techniques and
materials for effecting closure of incisions are well known in the
art, and include sutures, for example silk, catgut or synthetic
sutures; adhesives, for example 2-octyl cyanoacrylate; adhesive
tapes or strips; or staples.
[0088] In some embodiments, a method may be performed
simultaneously or sequentially in combination with an additional
tightening procedure, such as a surgical tightening procedure.
Suitable surgical tightening procedures are well known in the art,
and include for example full-thickness wedge excision; lateral
tarsal strip; lateral canthal tendon plication; or lateral
tarsorrhaphy.
[0089] In some embodiments there is provided a method of treating
eyelid laxity in an individual comprising the steps of: [0090] (a)
making an incision line within an eyelid crease in an upper eyelid,
and/or about 4 mm from the margin in a lower eyelid; [0091] (b)
anesthetizing the eyelid; [0092] (c) sterilizing the eyelid; [0093]
(d) performing a horizontal skin incision on the eyelid on the
marked incision line; [0094] (e) deepening the incision through the
underlying orbicularis oculi muscle down to the orbital septum;
[0095] (f) creating a pretarsal pocket in the central eyelid,
extending medially and laterally; [0096] (g) exposing the anterior
aspect of the tarsal plate; [0097] and either: [0098] (h)
instilling a photosensitizer solution into the pretarsal pocket;
and [0099] (i) removing the excess of solution after from 6-60
minutes; [0100] or: [0101] (j) as an alternative to step (h),
inserting an absorbent material soaked in an aqueous solution of
photosensitizer into the pretarsal pocket; and [0102] (k)
maintaining the absorbent material in the pretarsal pocket for from
6-60 minutes; and removing the absorbent material; [0103] and then:
[0104] (l) inserting an eye protector under the eyelid and against
the anterior aspect of the eye globe; [0105] (m) applying directly
to the exposed tarsal tissue a UV-A radiation beam, optionally in
the presence of O.sub.2 gas delivered close to the irradiation site
to effect crosslinking, for example for 1 to 60 minutes or 6 to 60
minutes, or 1 to 6 minutes, or 1 to 4 minutes, depending on the
irradiance level; [0106] (n) removing the corneal protector; and
[0107] (o) closing the skin incision on the eyelid.
[0108] In some embodiments there is provided a method of treating
eyelid laxity in an individual comprising the steps of: [0109] (a)
making an incision line, suitably with an indelible skin marker,
within an eyelid crease in an upper eyelid, and/or 4 mm from the
margin in a lower eyelid; [0110] (b) anaesthetizing the eyelid, for
example by injecting local anesthetic into the eyelid via
transcutaneous or transconjunctival delivery; [0111] (c)
sterilizing the eyelid skin, for example with Betadine, and placing
a sterile drape to expose the individual's face; [0112] (d)
performing a horizontal skin incision on the eyelid on the marked
line, for example using a scalpel; [0113] (e) deepening the
incision through the underlying orbicularis oculi muscle down to
the orbital septum, for example using a hand-held hot-temperature
cautery machine; [0114] (f) creating with the hot-temperature
cautery machine a pretarsal pocket in the central eyelid, extending
medially and laterally; [0115] (g) exposing the anterior aspect of
the tarsal plate, preferably approximately 20.times.8 mm on the
upper eyelid, or 20.times.3 mm on the lower eyelid, avoiding breach
of the eyelid margin at the gray line, and dehiscence of the
levator aponeurosis; [0116] (h) placing a traction suture in the
pretarsal skin, close to the incision line; and either: [0117] (i)
instilling a photosensitizer, for example an aqueous solution of
riboflavin 5'-phosphate monosodium salt into the pretarsal pocket;
and [0118] (j) removing the excess of solution after, for example
6-60 minutes, using for example an absorbent material, such as a
sponge; [0119] or: [0120] (k) as an alternative to step (i),
inserting an absorbent material, such as a neurosurgical patty,
soaked in an aqueous solution of photosensitizer, such as
riboflavin 5'-phosphate monosodium salt, into the pretarsal pocket;
and [0121] (l) maintaining the absorbent material in the pretarsal
pocket, for example for 6-60 minutes and removing the absorbent
material; [0122] and then: [0123] (m) inserting a metallic eye
protector under the eyelid and against the anterior aspect of the
eye globe; [0124] (n) exposing the tarsal plate, for example by
clamping the traction suture to the drape, for example using an
artery forcep; [0125] (o) applying directly to the exposed tarsal
tissue a radiation beam, for example UV-A, optionally in the
presence of O.sub.2 gas delivered close to the irradiation site,
for example for 1 to 60 minutes, or 6 to 60 minutes or 1 to 6
minutes, or 1 to 4 minutes, depending on the irradiance level;
[0126] (p) removing the corneal protector and the traction suture;
[0127] (q) checking the eyelid position, both open and closed, to
ensure the elevator palpebri or lower eyelid retractors are
functioning normally; [0128] (r) closing the incision on the
eyelid, for example with a suture.
[0129] An exemplary procedure in accordance with the methods herein
is carried out in accordance with the method as illustrated in
FIGS. 1 to 8. FIG. 1 depicts the upper eyelid 11 and the incision
12 on the upper eyelid. FIG. 2 depicts cauterization through the
muscles made with a hand-held hot-temperature cautery machine, for
example a Bovie cautery instrument 21 (Bovie Medical Corporation,
Purchase, N.Y., 10577, USA). FIG. 3 depicts the creation of a
pretarsal pocket 31 using the Bovie cautery tool 21. FIG. 4 depicts
the insertion into the pretarsal pocket 31 of a neurosurgical patty
41 soaked in a photosensitizer solution. FIG. 5 depicts the
insertion of a metallic eye protector 51 under the eyelid and
against the anterior aspect of the eye globe. FIG. 6 depicts the
clamping of a traction suture 62 to the drape 61 in order to expose
the anterior aspect of the upper tarsal plate, where the
irradiation is applied. FIG. 7 depicts the final closure of the
incision 12 with suture 71.
[0130] In one embodiment the method for the treatment of an eye
affected by eyelid laxity is performed as follows. Local anesthetic
(e.g. Alcaine) is applied to the patient's eye. An incision line is
marked with indelible skin marker, within the eyelid crease in the
upper eyelid, or 4 mm from the margin in the lower eyelid. Local
anesthetic (2.5-3 mL) is injected into the eyelid either
transcutaneously or transconjuctivally. The skin is sterilized with
a suitable preparation (e.g. half-strength Betadine.TM.), and
sterile drape is placed around surgical field, exposing the
patient's face. A horizontal skin incision 12 is performed on the
eyelid 11 on the marked line, using a blade #15 scalpel, as shown
in FIG. 1. As indicated in FIG. 2, the incision is extended through
the underlying orbicularis oculi muscle down to the orbital septum
using a hand-held hot-temperature cautery machine, e.g. a Bovie
cautery tool 21. A pretarsal pocket 31 is created in the central
eyelid, extending medially and laterally, as shown in FIG. 3. The
anterior aspect of the tarsal plate is exposed, approximately
20.times.8 mm on the upper eyelid, or 20.times.3 mm on the lower
eyelid. Care is taken not to breach the eyelid margin at the grey
line, and to avoid dehiscence of the levator aponeurosis. A
traction suture (for example using 6-0 Vicryl) is placed in the
pretarsal skin, close to the incision line. Aqueous solution of the
photosensitizer riboflavin 5'-phosphate monosodium salt (1 to 5 mL
of 0.1 to 0.5% by weight) is instilled into the tarsal plate where
it remains for from 6 to 60 minutes. Excess solution is removed by
using a sponge device, e.g. a Weck-Cell.TM. cellulose eye spear
sponge. Alternatively, as depicted in FIG. 4, a neurosurgical patty
(25.times.12 mm) 41 trimmed to an appropriate size, is soaked for
about 5 minutes in the aqueous solution of the photosensitizer, and
then inserted into the pretarsal pocket 31, where it remains for
from 6 to 60 minutes prior to removal. A metallic eye protector 51
is inserted under the eyelid 11 and against the anterior aspect of
the eye globe, as shown in FIG. 5. The traction suture 62 is
clamped to drape 61 with an artery forcep, as shown in FIG. 6, in
order to expose the tarsal plate and allow direct irradiation of
the tarsal tissue by a UV-A radiation beam. The UV-A radiation may
be provided by a commercially available UV corneal crosslinking
machine. The duration of the irradiation will depend on the
wavelength and power of the radiation beam, and can be readily
determined by the skilled person. Typical irradiation times at an
irradiance of 3 mW/cm.sup.2 are 6 to 60 minutes, suitably from 10
to 50 minutes, 15 to 45 minutes, 20 to 40 minutes, 30 to 40
minutes, 20 to 30 minutes or approximately 30 minutes. Typical
irradiation times at an irradiance of 6 mW/cm.sup.2 are 6 to 60
minutes, suitably from 10 to 40 minutes, 15 to 45 minutes, 20 to 40
minutes, 20 to 30 minutes, 15 to 20 minutes or approximately 30
minutes. Humidified O.sub.2 gas can be delivered at the site of
crosslinking if desired. After the radiation treatment, the corneal
protector and traction suture are removed. The eyelid position is
checked, in both opened and closed situations, to ensure that the
elevator palpebri or lower eyelid retractors are functioning
normally. If necessary, reattachment is performed surgically. The
skin incision 12 on the eyelid 11 is then closed with the suture 71
(e.g. 6-0 Vicryl, Ethicon Inc.), as shown in FIG. 7.
3. Systems and Apparatus
[0131] There is further advantageously provided a system for
crosslinking tarsal plate tissue comprising:
an applicator that applies or delivers a photosensitizer to an
exposed tarsal plate of an eye; and
[0132] a radiation source for providing photo-activating radiation
to the tarsal plate.
[0133] In another aspect there is provided a kit or commercial
package for crosslinking tarsal plate tissue comprising:
an applicator that applies or delivers a photosensitizer to an
exposed tarsal plate of an eye; and a radiation source for
providing photo-activating radiation to the tarsal plate; together
with instructions to treat eyelid laxity or crosslink a tarsal
plate.
[0134] In yet another aspect there is provided a kit or commercial
package for crosslinking tarsal plate tissue comprising:
an applicator that applies or delivers a photosensitizer to an
exposed tarsal plate of an eye; and a radiation source for
providing photo-activating radiation to the tarsal plate wherein
the beam width is greater than 12 mm at 10 mm from a surface of the
tarsal plate; and, optionally, instructions to treat eyelid laxity
or crosslink a tarsal plate.
[0135] In preferred embodiments, the radiation source provides a
beam profile of greater than 12 mm at a distance of 10 mm from a
surface of the tarsal plate, preferably the beam profile is from 13
mm to 15 mm at a distance of 10 mm from a surface of the tarsal
plate.
[0136] Radiation sources are known in the art, and suitable sources
are commercially available. In some embodiments the radiation is
UV-A with a wavelength of from 320 to 400 nm. Radiation sources
include those suitable for or intended for corneal crosslinking
procedures such as, for example, XLink.TM. (Optos, Dunfermline,
Scotland); CBM Vega XLink Crosslinking System (Carleton Optical,
Chesham, UK); LightLink CXL.TM. (LightMed, San Clemente, Calif.,
USA); UV-X.TM. 2000 Crosslinking System (IROC Innocross, Zurich,
Switzerland) and KXL.TM. CrossLinking System (Avedro Waltham,
Mass., USA). These radiation sources typically have a beam width of
approximately 10 to 12 mm, or about 11 mm. The skilled person would
understand that repositioning of such a radiation beam would be
necessary to effect radiation of the entire surface of an exposed
tarsal plate. Alternatively, the radiation source instrument may be
modified to produce a greater beamwidth to irradiate substantially
all of the tarsal plate surface at the same time.
[0137] Applicators for delivering or applying a photosensitizer to
an exposed tarsal plate of an eye include syringes, droppers,
vials, ampoules, pipettes, and absorbent materials such as surgical
sponges and neurosurgical patties. In some embodiments a preferred
applicator is an absorbent material, such as a neurosurgical patty.
The skilled person will appreciate that absorbent materials may be
cut or folded to size where necessary.
[0138] A system, kit or commercial package as defined herein may
also comprise a photosensitizer or a photosensitizer composition as
defined herein.
[0139] The system, kit or commercial package may also comprise a
delivery device that delivers O.sub.2 gas to the exposed tarsal
plate. In some embodiments the O.sub.2 gas may be delivered using a
nozzle, syringe, diffuser, or the like. Suitable methods of
delivering O.sub.2 to the exposed tarsal tissue and/or the site of
irradiation or site of crosslinking are disclosed in, for example,
U.S. Pat. No. 8,574,277.
4. Compositions
[0140] Photosensitizers suitable for use in the methods described
herein are molecules having a chemical structure which includes a
chromophore that absorbs radiation at a wavelength of the
photo-activating radiation. The photosensitizer, on irradiation by
photo-activating irradiation, produces a chemical change in another
molecule, for example, O.sub.2 and/or one or more tissue molecules,
for example collagen molecules. This can initiate crosslinking thus
producing chemical change in the tissue. In some embodiments the
methods defined herein generate crosslinking in collagen.
Preferably the photosensitizers are non-irritant, and
pharmaceutically acceptable. A photosensitizer may be in the form
of a pharmaceutically acceptable salt, derivative or solvate
thereof. Preferably a photosensitizer is soluble to a sufficient
extent in an aqueous carrier to provide a concentration of from
0.1% to 10% w/v, preferably 0.1% to 5% w/v, 0.1% to 2% w/v, 0.1% to
1% w/v, 0.1% to 0.5% w/v, or 0.1% to 0.3% w/v. Suitable
photosensitizers are known in the art, and are commercially
available from, for example Sigma Aldrich Co. LLC. A preferred
photosensitizer is riboflavin as an aqueous soluble form, for
example a sodium salt of riboflavin 5'-phosphate, or a
pharmaceutically acceptable solvate thereof. Suitable
photosensitizers are known in the art, and are commercially
available from, for example Sigma Aldrich Co. LLC).
[0141] Photosensitizer compositions used in the methods and systems
defined herein are preferably pharmaceutical compositions and may
be formulated and administered using methods known in the art.
Techniques for formulation and administration may be found in, for
example, Remington: The Science and Practice of Pharmacy, Loyd V.
Allen, Jr (Ed), The Pharmaceutical Press, London, 22.sup.nd
Edition, September 2012.
[0142] A photosensitizer composition is preferably in a form
suitable for topical administration to the tarsal plate. In some
embodiments, the photosensitizer composition is formulated for
example as an emulsion, cream, lotion, gel, jelly, paste, ointment,
solution, salve, or solution, especially as a gel, oil in water
emulsion or solution, as described in, for example, the United
States Food and Drug Administration Monograph No. C-DRG-00201
entitled CDER Data Standards Manual Definitions for Topical Dosage
Forms. In some embodiments, the composition is a solution.
[0143] Preferably the photosensitizer is in a solubilized form.
Suitably, a photosensitizer pharmaceutical composition is in a
sterile aqueous solution. In some embodiments the sensitizer is
formulated in a sterile ophthalmic solution. Suitably a sterile
aqueous photosensitizer solution is packaged in a vial, ampoule,
syringe, for example as a single use syringe.
[0144] Aqueous compositions, such as solutions, of a
photosensitizer, for example a water soluble form of riboflavin,
are commercially available or may be prepared using known methods.
For example, a water soluble salt, derivative or solvate of
riboflavin may be dissolved in an aqueous pharmaceutically
acceptable carrier selected from, but not limited to, saline,
water, aqueous buffer, an aqueous solution comprising water and a
miscible solvent, and combinations thereof. An aqueous composition
may additionally include pharmaceutically acceptable excipients
selected from viscosity modifiers such as dextran, buffers,
rheology modifiers, surfactants, and chelating agents.
[0145] Commercially available riboflavin solutions include VibeX
Xtra.TM., [0.22% riboflavin, saline isotonic]; MedioCROSS TE [0.25%
riboflavin 5'-phosphate, 1.2% HPMC (hydroxypropylmethylcellulose),
0.01% BAC (benzalkonium chloride)]; MedioCROSS M [0.1% riboflavin
5'-phosphate, 1.1% HPMC]; VibeX Rapid.TM., [0.1% riboflavin
5'-phosphate, saline, HPMC]; ParaCel.TM. [0.25% riboflavin
5'-phosphate, HPMC, BAC], Photrexa [0.146% riboflavin 5'-phosphate
ophthalmic solution] or Photrexa viscous [0.146% riboflavin
5'-phosphate in 20% dextran ophthalmic solution], all available
from Avedro Inc, USA. Riboflavin is typically in the form of
riboflavin 5'-phosphate sodium salt.
[0146] Materials for use in surgical procedures are well known to
the skilled person and are readily available from commercial
sources. Suitable local anaesthetics for anaesthetizing the eyelid
are well known to the skilled person and include, for example
Alcaine.RTM. (Proparacaine hydrochloride), Naropin.RTM. (Ropivicane
hydrochloride), Marcaine.TM. (Bupivacaine hydrochloride) and
Novesin.RTM. (Benoxinate, Oxybuprocaine hydrochloride). Suitable
antiseptics include Betadine.RTM. (povidone/iodine) and
Betasept.RTM. (chlorhexidine). Wound closure may be effected using
techniques known in the art and include sutures; adhesives;
adhesive tapes; staples and the like.
[0147] In order that the methods, compositions and apparatuses may
be readily understood and put into practical effect, particular
preferred embodiments will now be described by way of the following
non-limiting examples.
EXAMPLES
Materials and Methods
[0148] The experiments described were performed on tarsal plates
excised from sheep, based on the fact that the ovine and human
tarsal plates are structurally and functionally identical, as shown
in: M. J. Boileau, M. A. Gilmour: "Diseases of the eye", in Sheep
and Goat Medicine, 2nd Edn, D. G. Pugh, A. N. Baird (Eds),
Elsevier, Amsterdam, 2012, pp. 406-410; D. A. Samuelson:
"Ophthalmic structures", in Essentials of Veterinary Ophthalmology,
3rd Edn, K. N. Gelatt (Ed.), Wiley, Oxford, U K, 2014, pp.
12-20.
[0149] Riboflavin and its salts, solvates and derivatives are
readily available from commercial sources. For example USP
riboflavin 5'-phosphate monosodium salt is commercially available
from Sigma-Aldrich Co LLC. Aqueous 0.25% riboflavin is commercially
available as ParaCel.TM. from Avedro Inc, USA. Aqueous 0.1%
riboflavin 5'-phosphate (dextran free) is available from Avedro
Inc, USA as VibeX Rapid.TM..
[0150] Commercially available corneal crosslinking systems are
available, for example, Opto XLink.TM. corneal crosslinking system
(Opto Electronica S/A, Sao Carlos,--SP 13563-330, Brazil; Opto USA
Corp, North Miami, Fla.-33181, USA; opto.com.br); or KXL
Accelerated Cross-Linking System (Avedro, Inc, Waltham, Mass.
O.sub.2451, USA; avedro.com). Alternatively, the UV curing system
OmniCure.RTM. 1500 (Excelitas Technologies Corp, Waltham, Mass.,
O.sub.2451; excelitas.com) can be used to provide a large range of
irradiances.
Example 1
Crosslinking of Sheep Tarsal Plates
[0151] Upper and lower eyelids were isolated from cadaveric sheep
eyes (1-2 years old), and the tarsal plates were excised. The
resulting tarsal strips, with a mean thickness of 1.5.+-.0.2 mm for
both upper and lower eyelids, were treated with a commercially
available riboflavin solution (ParaCel.TM.) for 30 min, and then
irradiated in a commercially available corneal crosslinking system
(Opto XLink.TM.) with UV-A radiation (365 nm) at an irradiance of
either 3 mW/cm.sup.2 or 6 mW/cm.sup.2, for various durations.
Humidified O.sub.2 gas was delivered at the site of
crosslinking.
Example 2
Tensile Measurements on Sheep Tarsal Plates
[0152] Tensile measurements on either untreated and crosslinked
tarsal strips were performed in an Instron mechanical microtester
equipped with a 50-N load cell, at a set gauge distance of 6 mm and
a speed of 1.5 mm/min. The stress-strain plots were recorded and
Young's moduli were computed in the linear region. Four to six
measurements for each specimen were performed and recorded. The
results were statistically processed by the one-way analysis of
variance (ANOVA) in conjunction with Tukey-Kramer multiple
comparisons, using the GraphPad.RTM. Prism software (Version
6.0).
Example 3
Stress-Strain Plots of the Sheep Tarsal Plates
[0153] FIG. 8 shows the stress-strain plots of an untreated tarsal
plate and a UV-crosslinked tarsal plate, demonstrating the effect
of the crosslinking process on the mechanical properties of the
tarsal fibrocartilage tissue.
Example 4
Mechanical Properties of Sheep Tarsal Plates
[0154] Table 1 presents the UV-irradiation conditions, and the
values of Young's modulus and stress at 20% strain for the sheep
tarsal strips isolated from the upper and lower eyelids. The
crosslinking process increased the stiffness of the tarsal tissue,
as indicated by the higher values of Young's modulus and
stress.
TABLE-US-00001 TABLE 1 Young's modulus and stress values at 20%
strain measured for the sheep tarsal plates excised from upper and
lower lids UV Increase in Conditions Time Young's Young's Tarsus
Irradiance (min- modulus modulus Stress location (mW/cm.sup.2)
utes) n (MPa) (%) (kPa) Upper Untreated -- 6 3.1 .+-. 1.5 -- 319.6
.+-. 224.6 eyelid 3 30 4 3.9 .+-. 0.6 25.8 449.6 .+-. 104.3 6 30 4
4.8 .+-. 1.1 54.8 480.1 .+-. 121.4 Lower Untreated -- 6 4.2 .+-.
1.8 -- 459.6 .+-. 212.9 eyelid 3 30 4 5.0 .+-. 1.4 19.0 685.6 .+-.
327.2 6 30 4 5.5 .+-. 0.8 31.0 477.6 .+-. 163.2
Example 5
Crosslinking of the Sheep Tarsal Plates at High Irradiance
[0155] Upper and lower eyelid tarsal strips excised from cadaveric
sheep eyes were crosslinked at high irradiance in a KXL Accelerated
Cross-Linking System machine, which delivered a maximum irradiance
of 45 mW/cm.sup.2 at the maximum fluence of 7.2 J/cm.sup.2. The
tarsal specimens were immersed in 0.1% riboflavin solution (VibeX
Rapid.TM.) for 30 min, and then irradiated continuously with
radiation UV-A (365 nm) without delivery of O.sub.2 gas at the site
of crosslinking. The irradiance levels of 150 mW/cm.sup.2 and 250
mW/cm.sup.2, respectively, were generated using the UV curing
system OmniCure.RTM. 1500, equipped with a 365-nm filter.
[0156] Table 2 presents the conditions used for crosslinking at
high irradiances.
TABLE-US-00002 TABLE 2 Conditions for crosslinking at high
irradiances Irradiance Fluence Time Number of samples (n)
(mW/cm.sup.2) (J/cm.sup.2) (s) Upper eyelid Lower eyelid 30 5.4 180
2 2 45 5.4 120 3 3 45 7.2 160 3 3 150 27.0 180 3 5 250 45.0 180 3
5
[0157] FIGS. 9 and 10 show, respectively, the effect of irradiation
at high irradiances on Young's modulus (stiffness) and on tensile
stress (mechanical strength) of the tarsal tissue specimens excised
from upper and lower eyelids of sheep eyes. The process of
crosslinking increased significantly the rigidity of the tarsal
fibrocartilage tissue. However, at irradiance levels exceeding 150
mW/cm.sup.2, the increase in stiffness or strength of the tarsal
tissue appears to cease as an opposite effect, potentially due to
photodegradation, becomes evident leading to the decline of these
properties.
Example 6
Effect of Different Procedures for the Application of
Photosensitizer Solution
[0158] Two different approaches were used for treating with 0.1%
riboflavin solution (VibeX Rapid.TM.) the ovine upper and lower
eyelid tarsal strips prior to their irradiation. In the first
procedure, the strips were soaked in the riboflavin solution for
two different durations (15 min or 30 min), and then irradiated. In
the second procedure, the strips were kept in contact with surgical
patties that were completely soaked in riboflavin solution. The
contact between the tarsal strips and patties was maintained for 15
min or 30 min. Following the riboflavin treatment, the samples were
irradiated using the OmniCure.RTM. 1500 machine, which delivered a
maximum irradiance of 45 mW/cm.sup.2 at the maximum fluence of 7.2
J/cm.sup.2. The results presented in FIGS. 11 and 12 indicate that
the mechanical properties were enhanced when the photosensitizer
solution was applied to the tarsal tissue through an absorbent
material such as a surgical patty.
[0159] The disclosure of every patent, patent application, and
publication cited herein is hereby incorporated herein by reference
in its entirety.
[0160] The citation of any reference herein should not be construed
as an admission that such reference is available as "Prior Art" to
the instant application.
[0161] Throughout the specification the aim has been to describe
the preferred embodiments of the methods, compositions and
apparatuses without limiting to any one embodiment or specific
collection of features. Those of skill in the art will therefore
appreciate that, in light of the instant disclosure, various
modifications and changes can be made in the particular embodiments
exemplified without departing from the scope of the methods,
compositions and apparatuses defined herein. All such modifications
and changes are intended to be included within the scope of the
appended claims.
* * * * *