U.S. patent application number 16/109127 was filed with the patent office on 2018-12-20 for ophthalmic composition for treatment of dry eye disease.
The applicant listed for this patent is NOVALIQ GMBH. Invention is credited to Markus BEIER, Bernhard GUNTHER, Jorg HAISSER, Sonja KROSSER, Frank LOSCHER, Alice MEIDES, Hartmut VOSS.
Application Number | 20180360908 16/109127 |
Document ID | / |
Family ID | 61002978 |
Filed Date | 2018-12-20 |
United States Patent
Application |
20180360908 |
Kind Code |
A1 |
BEIER; Markus ; et
al. |
December 20, 2018 |
OPHTHALMIC COMPOSITION FOR TREATMENT OF DRY EYE DISEASE
Abstract
The invention provides pharmaceutical compositions comprising
about 0.05 to 0.1% (w/v) cyclosporine dissolved in
1-perfluorobutyl-pentane for use in the topical treatment of dry
eye disease and provides for dosing and treatment methods thereof.
The invention further provides kits comprising such
compositions.
Inventors: |
BEIER; Markus; (Weinheim,
DE) ; HAISSER; Jorg; (Siegelsbach, DE) ;
MEIDES; Alice; (Heidelberg, DE) ; KROSSER; Sonja;
(Heidelberg, DE) ; VOSS; Hartmut; (Schriesheim,
DE) ; LOSCHER; Frank; (Schriesheim, DE) ;
GUNTHER; Bernhard; (Dossenheim, DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
NOVALIQ GMBH |
Heidelberg |
|
DE |
|
|
Family ID: |
61002978 |
Appl. No.: |
16/109127 |
Filed: |
August 22, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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PCT/EP2017/083770 |
Dec 20, 2017 |
|
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16109127 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/08 20130101; A61P
27/02 20180101; A61J 1/00 20130101; A61K 9/0048 20130101; A61K
31/00 20130101; A61K 47/06 20130101; A61J 1/067 20130101; A61K
47/10 20130101; A61K 38/13 20130101 |
International
Class: |
A61K 38/13 20060101
A61K038/13; A61K 9/00 20060101 A61K009/00; A61K 47/10 20060101
A61K047/10; A61K 9/08 20060101 A61K009/08; A61P 27/02 20060101
A61P027/02 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 23, 2016 |
EP |
16206735.9 |
Apr 7, 2017 |
EP |
17165578.0 |
Claims
1-15. (canceled)
16. A method of treating dry eye disease, the method comprising
topically administering twice daily to an eye of a human with dry
eye disease a composition comprising about 0.1% (w/v) cyclosporine
dissolved in 1-perfluorobutyl-pentane, wherein said composition is
substantially free of water and is substantially free of a
preservative, wherein the amount of cyclosporine administered in a
single dose per eye is about 10 .mu.g cyclosporine.
17. The method according to claim 16, wherein the composition
comprises up to about 1% (w/w) ethanol.
18. The method according to claim 16, wherein the composition
comprises about 0.1% (w/v) cyclosporine dissolved in
1-perfluorobutyl-pentane and about 1.0% (w/w) of ethanol.
19. The method according to claim 18, wherein the composition
consists of about 0.1% (w/v) cyclosporine dissolved in
1-perfluorobutyl-pentane and about 1.0% (w/w) of ethanol.
20. The method according to claim 18, wherein i. a reduction in
corneal staining, ii. an early onset of action, iii. a reduction of
visual impairment associated with dry eye disease, or iv. a
reduction of ocular surface damage associated with dry eye disease
is achieved.
21. The method according to claim 16, wherein the dry eye disease
is moderate to severe dry eye disease, and optionally wherein the
subject is not responsive to treatment with artificial tears.
22. The method according to claim 16, wherein the subject suffering
from dry eye disease experiences symptoms such as blurring, pain,
irritation or corneal surface damage.
23. The method according to claim 16, wherein the composition
further comprises up to about 2% (w/w)
2-perfluorobutyl-pentane.
24. A method of reducing reading impairment associated with dry eye
disease, the method comprising topically administering twice daily
to an eye of a human with dry eye disease a composition comprising
about 0.1% (w/v) cyclosporine dissolved in
1-perfluorobutyl-pentane, wherein said composition is substantially
free of water and is substantially free of a preservative, wherein
the amount of cyclosporine administered in a single dose per eye is
about 10 .mu.g cyclosporine.
25. The method according to any of the claim 24, wherein the
composition further comprises up to about 1% (w/w) ethanol.
26. The method according to claim 24, wherein the composition
comprises about 0.1% (w/v) cyclosporine dissolved in
1-perfluorobutyl-pentane and about 1.0% (w/w) of ethanol.
27. The method according to claim 26 wherein the composition
consists about 0.1% (w/v) cyclosporine dissolved in
1-perfluorobutyl-pentane and about 1.0% (w/w) of ethanol.
28. The method according to claim 26, wherein i. a reduction in
corneal staining, ii. an early onset of action, or iii. a reduction
of ocular surface damage associated with dry eye disease is
achieved.
29. The method according to claim 24, wherein the composition
further comprises up to about 2% (w/w)
2-perfluorobutyl-pentane.
30. A method of reducing ocular surface damage associated with dry
eye disease, the method comprising topically administering twice
daily to an eye of a human with dry eye disease a composition
comprising about 0.1% (w/v) cyclosporine dissolved in
1-perfluorobutyl-pentane, wherein said composition is substantially
free of water and is substantially free of a preservative, wherein
the amount of cyclosporine administered in a single dose per eye is
about 10 .mu.g cyclosporine.
31. The method according to any of the claim 30, wherein the
composition comprises up to about 1% (w/w) ethanol.
32. The method according to claim 30, wherein the composition
comprises about 0.1% (w/v) cyclosporine dissolved in
1-perfluorobutyl-pentane and about 1.0% (w/w) of ethanol.
33. The method according to claim 32, wherein the composition
consists of about 0.1% (w/v) cyclosporine dissolved in
1-perfluorobutyl-pentane and about 1.0% (w/w) of ethanol.
34. The method according to claim 32, wherein i. a reduction in
corneal staining, ii. an early onset of action, or iii. a reduction
of visual impairment associated with dry eye disease is
achieved.
35. The method according to claim 30, wherein the composition
further comprises up to about 2% (w/w)
2-perfluorobutyl-pentane.
36. A pharmaceutical composition for (a) treating dry eye disease
or (b) reducing ocular surface damage associated with dry eye
disease, the composition comprising about 0.1% (w/v) cyclosporine
dissolved in 1-perfluorobutyl-pentane, wherein said composition is
substantially free of water and is substantially free of a
preservative, and wherein said composition is topically
administered twice daily in a single dose per eye of about 10 .mu.g
cyclosporine.
37. The composition according to claim 36, wherein the composition
comprises up to about 1% (w/w) ethanol.
38. The composition according to claim 36, wherein the composition
comprises about 0.1% (w/v) cyclosporine dissolved in
1-perfluorobutyl-pentane and about 1.0% (w/w) of ethanol.
39. The composition according to claim 38, wherein the composition
consists about 0.1% (w/v) cyclosporine dissolved in
1-perfluorobutyl-pentane and about 1.0% (w/w) of ethanol.
40. The composition according to claim 36, wherein said composition
is safe, well tolerated and comfortable to the eye of the
human.
41. The composition according to claim 36, wherein the composition
further comprises up to about 2% (w/w)
2-perfluorobutyl-pentane.
42. The composition according to claim 36, wherein the composition
is essentially free of ethanol.
43. A kit comprising the pharmaceutical composition according to
claim 36, wherein the kit comprises a container for holding the
composition and a drop dispenser adapted for administering about 10
.mu.L volume of the composition per drop.
44. The kit according to claim 43, wherein the ratio of the volume
of the pharmaceutical composition in the container to the total
volume of the container is between 0.4 to 0.7, or wherein the ratio
of the volume of the head space of the container to the volume of
the pharmaceutical composition is between 0.5 to 1.5.
45. The kit according to claim 43, wherein the container and/or
drop dispenser is manufactured from a thermoplastic material,
optionally selected from polyethylene or polypropylene.
Description
BACKGROUND OF THE INVENTION
[0001] Keratoconjunctivitis sicca, also known as dry eye disease or
dysfunctional tear syndrome, is today understood as a
multifunctional disorder of the tear film and of the ocular surface
which results in discomfort, visual disturbance, and often even in
ocular surface damage caused by tear film instability. Estimates of
the prevalence of dry eye vary considerably, depending on the
criteria used to define the disease, but in the U.S., it has been
estimated that as many as 3.2 million women and 1.7 million men
over the age of 50 have dry eye, with a projected 40% increase in
number of patients affected by 2030.
[0002] A pharmacological treatment option for dry eye disease is
cyclosporine. Cyclosporine is available, at least in the US as an
approved medicine in the form of an ophthalmic (o/w) emulsion
(Restasis.RTM.). This product is indicated to increase tear
production in patients whose tear production is presumed to be
suppressed due to ocular inflammation associated with
keratoconjunctivis sicca.
[0003] WO2011/073134 A1 discloses pharmaceutical compositions in
the form of solutions comprising cyclosporine and a semifluorinated
alkane as a liquid vehicle which may be administered to the eye of
a patient, such as for the treatment of keratoconjunctivitis sicca,
for instance compositions comprising cyclosporine in
semifluorinated alkane 1-perfluorobutyl-pentane (F4H5) in the
presence of ethanol as a co-solvent. WO2011/073134 A1 however does
not describe dosing and treatment regimen for the treatment of dry
eye disease, in particular moderate to severe dry eye disease and
associated conditions.
[0004] Gehlsen et al. (Investigative Ophthalmology & Visual
Science June 2015, Vol. 56, 319) describes a study to test the use
of CsA in SFA (F4H5) as a carrier for topical therapy in a mouse
model of experimental dry eye disease. Gehlsen et al describes that
in the study, topical therapy was performed on mice with induced
experimental dry eye disease 3.times./day (5 L/eye). Gehlsen et al.
however does not disclose a treatment or dosing regimen for the
treatment of dry eye disease in human subjects, in particular
subjects with moderate to severe dry eye disease and associated
conditions.
[0005] It is thus an object of the present invention to provide
pharmaceutical compositions for use in the treatment of dry eye
disease, in particular moderate to severe dry eye disease and
associated conditions comprising cyclosporine and
1-perfluorobutyl-pentane. Further objects of the invention will be
clear on the basis of the following description of the invention,
examples and claims.
SUMMARY OF THE INVENTION
[0006] In a first aspect, the invention relates to a pharmaceutical
composition for use in the topical treatment of dry eye disease,
wherein the composition comprises about 0.05 to 0.1% (w/v)
cyclosporine dissolved in 1-perfluorobutyl-pentane and wherein the
amount of cyclosporine administered in a single dose per eye is
about 4 to 12 g.
[0007] In a further aspect, the present invention provides
pharmaceutical compositions for use in the treatment of ocular
surface damage in subjects suffering from dry eye disease, and/or
for use in the treatment of reading impairment in subjects
suffering from dry eye disease, preferably wherein the
pharmaceutical compositions are topically administered to provide
an amount of about 4 to 12 .mu.g of cyclosporine per single dose
per eye. In particular, the subjects may have moderate to severe
dry eye disease,
[0008] In yet a further aspect, the invention provides for a kit
comprising a pharmaceutical compositions for such uses, wherein the
kit comprises a container for holding the pharmaceutical
composition and a drop dispenser adapted for administering about 8
to 12 .mu.l volume of the composition per drop.
DETAILED DESCRIPTION OF THE INVENTION
[0009] The present invention relates to, in a first aspect, a
pharmaceutical composition for use in the topical treatment of dry
eye disease, wherein the composition comprises about 0.05 to 0.1%
(w/v) cyclosporine dissolved in 1-perfluorobutyl-pentane and
wherein the amount of cyclosporine administered in a single dose
per eye is about 4 to 12 .mu.g.
[0010] Dry eye disease (also abbreviated as DED, and which also may
be known as keratoconjunctivitis sicca, dysfunctional tear syndrome
or dry eye syndrome) is a complex disease that results in symptoms
of discomfort, visual disturbance, and tear film instability, and
which creates potential for damage of the ocular surface. It may be
accompanied by increased osmolarity of the tear film and
inflammation of the ocular surface. A patient having
keratoconjunctivitis sicca may experience any one of, or a
combination of tear hyperosmolarity, tear film instability or
abnormalities in the lipid layer composition of the tear film.
[0011] Two major categories of keratoconjunctivitis sicca or dry
eye disease (DED) are distinguished today, which are
aqueous-deficient DED and evaporative DED. Within the class of
aqueous-deficient forms of DED, two major subtypes may be
differentiated, Sjogren and non-Sjogren.
[0012] Sjogren syndrome patients suffer from autoimmune disorders
in which the lacrimal glands are invaded by activated T-cells,
which leads not only to dry eye disease but also to a dry mouth
condition. The Sjogren syndrome can be a primary disease or result
from other autoimmune diseases such as systemic lupus
erythrematosus or rheumathroid arthritis. Non-Sjogren patients
suffering from an aqueous-deficient DED usually have a lacrimal
gland insufficiency, lacrimal duct obstruction or reflex
hyposecretion.
[0013] The second major class, evaporative dry eye disease, is also
somewhat heterogeneous and can develop as a result of diverse root
causes. One of the major causes is meibomian gland disease or
dysfunction, eyelid aperture disorders, blink disorders (as in
Parkinson disease) or ocular surface disorders (as in allergic
conjunctivitis).
[0014] Symptoms of dry eye disease may include, but are not limited
to any one, or combination of the following: a dry, scratchy,
gritty, or sandy feeling in the eye; foreign body sensation; pain
or soreness; stinging or burning; itching; increased blinking; eye
fatigue; photophobia; blurry vision; redness; mucus discharge;
contact lens intolerance; and excessive reflex tearing. It is
understood that not all patients suffering from dry eye disease may
exhibit all of these symptoms simultaneously.
[0015] As understood herein, the term "dry eye disease"
individually may refer to any one or combination of the subtypes or
categories, or root causes as described herein and that any symptom
or aspect or pathophysiological consequences of dry eye disease may
be addressed.
[0016] Cyclosporine is a pharmacological treatment option for dry
eye disease, which is available as a prescription medication, for
example in the US in the form of an 0.05% ophthalmic (o/w) emulsion
(Restasis.RTM.). This product is indicated to increase tear
production in patients whose tear production is presumed to be
suppressed due to ocular inflammation associated with
keratoconjunctivis sicca. Restasis.RTM. is administered twice a day
in each eye approximately 12 hours apart. It is packaged in
single-vials. (Prescribing Information, Restasis.RTM.).
[0017] Cyclosporine (synonyms include cyclosporin A, CsA, or
ciclosporin) is a cyclic nonribosomal peptide comprising 11 amino
acids with the empirical formula C.sub.62H.sub.111N.sub.11O.sub.12
and molecular weight of 1202.61. It is an immunosuppressant drug
that is widely used in post-allergenic organ transplant, to reduce
the activity of the patient's immune system and thereby, the risk
of organ rejection. Cyclosporine is typically provided as a
colourless or white powder. Cyclosporine is thought to bind to the
cytosolic protein cyclophilin (immunophilin) of immunocompetent
lymphocytes, especially T-lymphocytes. This complex of cyclosporin
and cyclophilin inhibits calcineurin, which, under normal
circumstances, is responsible for activating the transcription of
interleukin 2. It also inhibits lymphokine production and
interleukin release and, therefore, leads to a reduced function of
effector T-cells.
[0018] The pharmaceutical composition according to the present
invention employs, as a liquid vehicle for the cyclosporine, the
compound 1-perfluorobutyl-pentane. 1-perfluorobutyl-pentane is a
semifluorinated alkane with the chemical formula
F(CF.sub.2).sub.4(CH.sub.2).sub.5H. It is an inert, water-insoluble
liquid, with a density of 1.284 g/cm.sup.3 at 25.degree. C. and
refractive index of 1.3204 at 20.degree. C. Alternative
nomenclature for this compound includes F4H5, wherein F denotes a
linear perfluorinated alkane segment comprising 4 carbon atoms and
wherein H denotes a linear and non-fluorinated alkane hydrocarbon
segment of 5 carbon atoms. Preferably, the 1-perfluorobutyl-pentane
is substantially free of water.
[0019] In one embodiment, the pharmaceutical composition for use
according to the present invention may comprise or consist, further
to the cyclosporine featured in any one the preferred
concentrations of the invention, of at least about 97% (w/w) or
more preferably, of at least about 98% (w/w), or of at least about
99% (w/w) of 1-perfluorobutyl-pentane, based on the total weight of
the final pharmaceutical composition (final dosage form). In
another embodiment, the pharmaceutical composition for use
according to the present invention may consist of, in addition to
the cyclosporine in an amount or concentration as defined herein,
from about 95.0 to about 99.99% (w/w), or about 96.0 to about
99.99% (w/w), or from about 98.0 to 99.99% (w/w), or from about
99.999 to about 99.9999% (w/w) of 1-perfluorobutyl-pentane, based
on the total weight of the final composition.
[0020] In another embodiment, the pharmaceutical composition of the
present invention may optionally further comprise
2-perfluorobutyl-pentane. Preferably the composition, in addition
to 1-perfluorobutyl-pentane, may optionally comprise minor amounts
of 2-perfluorobutyl-pentane of up to 2% (w/w), or up to 1% (w/w),
or most preferably, of up to 0.5% (w/w).
[0021] The concentration of cyclosporine in the pharmaceutical
compositions for use according to the invention are in the range of
about 0.05 to 0.1% (w/v) of the composition. Preferably, the
concentration of cyclosporine in the composition is about 0.05%
(w/v) or about 0.1% (w/v).
[0022] Unless otherwise indicated, the term "% (w/v)" denotes the
amount of a component of a composition as a weight percentage in
relation to the total volume of the composition (with `w` denoting
the weight and `v` denoting volume). For example 0.05% (w/v) may be
understood as relating to 0.5 mg of a component in 1 mL of the
composition, and 0.1% (w/v) would correspond to 1.0 mg of a
component in 1 mL of the composition. Unless otherwise indicated,
the term "% (w/w)" refers to the amount of a component of a
composition as a weight percentage in relation to the total weight
of the composition (with `w` denoting weight).
[0023] The term `about` as used herein and in reference or
connection to a parameter, for example such as the concentration of
cyclosporine dissolved in the composition or the amount of
cyclosporine featured in a single dose of the composition includes
the precise value as defined, as well as any value falling within
the degree of variability usually observed in measuring or
determining these parameters using the standard techniques and
equipment known in the art and field.
[0024] In respect of the amount of cyclosporine administered for
the topical treatment of dry eye disease, the preferred dosage of
the pharmaceutical composition is about 4 to 12 .mu.g of
cyclosporine per single dose per eye. In another embodiment, the
topically administered single dose per eye may be about 5 to 10
.mu.g, or more preferably, about .mu.g or about 10 .mu.g.
[0025] Preferably, the total daily dosage of cyclosporine
administered per eye of a pharmaceutical composition according to
the invention is about 8 to 24 .mu.g per day, or more preferably,
about 10 to 20 .mu.g per day, or even more preferably, about 10
.mu.g or 20 .mu.g per day.
[0026] In a preferred embodiment of the invention in respect of
treatment of dry eye disease, about 5 .mu.g of cyclosporine is
administered per single dose per eye, of a pharmaceutical
composition comprising 0.05% (w/v) of cyclosporine dissolved in
1-perfluorobutyl-pentane, and optionally up to about 1.0% (w/w)
ethanol.
[0027] In a further preferred embodiment of the invention in
respect of topical treatment of dry eye disease, about 10 .mu.g of
cyclosporine is administered per single dose per eye, of a
pharmaceutical composition comprising 0.1% (w/v) of cyclosporine
dissolved in 1-perfluorobutyl-pentane, and optionally up to about
1.0% (w/w) ethanol.
[0028] In yet a further embodiment, the total daily administered
dose per eye of the pharmaceutical composition for use as described
in any of the embodiments according to the invention is less than
about 28 .mu.g. Preferably, the total daily administered dose per
eye does not exceed about 24 .mu.g. Even more preferably, the total
daily administered dose per eye does not exceed about 20 .mu.g, or
about 10 .mu.g.
[0029] It is further preferred, that the amount of a single dose
per eye of cyclosporine of the pharmaceutical composition for use
in the topical treatment of dry eye disease, comprising about 0.05
to 0.1% (w/v) cyclosporine dissolved in 1-perfluorobutyl-pentane,
optionally up to about 1.0% (w/w) ethanol, is administered in a
volume of about 8-12 .mu.l, preferably in a volume of about 10
.mu.l.
[0030] It is even further preferred that the amount of a single
dose per eye of cyclosporine of the pharmaceutical composition for
use in the topical treatment of dry eye disease comprising about
0.05% (w/v) cyclosporine dissolved in 1-perfluorobutyl-pentane, and
optionally, up to about 1.0% (w/w) ethanol, is administered in a
volume of about 8-12 .mu.l, preferably in a volume of about 10
.mu.l.
[0031] It is even further preferred that the amount of a single
dose per eye of cyclosporine of the pharmaceutical composition for
use in the topical treatment of dry eye disease comprising about
0.1% (w/v) cyclosporine dissolved in 1-perfluorobutyl-pentane and
optionally, up to about 1.0% (w/w) ethanol, is administered in a
volume of about 8-12 .mu.l, preferably in a volume of about 10
.mu.l.
[0032] It has been found that treatment of subjects with dry eye
disease with the pharmaceutical compositions according to the
invention and at the defined doses surprisingly provided a
reduction in dry eye disease indicators such as corneal and
conjunctival staining and patient questionnaire (See Example, FIG.
2-4), at improved levels over the comparator product, which was
administered at its prescribed dose. Subjects receiving and treated
with a pharmaceutical composition according to the invention were
exposed to a daily dose of cyclosporine per eye that approximately
30-65% less than the comparator cyclosporine product. An earlier
onset of effect, already in the first 2 to 4 weeks of treatment was
also observed. It was also shown that CyclASol 0.05% and CyclASol
0.1% (ref. Example) have excellent safety profiles, with high
tolerability and patient acceptance.
[0033] The reduction in required dosing may be advantageous in that
less of the active ingredient is required to reach the treatment
objective. This may potentially also be beneficial in lessening
adverse effect or reactions associated with cyclosporine in
subjects such as for those who may require longer term
treatment.
[0034] It was found that treatment of subjects with dry eye disease
with the pharmaceutical compositions according to the invention and
at the defined doses surprisingly did result not only in a
reduction of the total adverse effects (also referred to as adverse
events), but also in particular to a reduction of ocular adverse
effects, namely a reduction of eye irritation, blurred vision,
conjunctival haemorrhage, conjunctivitis and a reduction in
instillation site pain, especially a reduction of eye irritation,
blurred vision and a reduction in instillation site pain, when
compared to the 0.05% cyclosporine aqueous (o/w) emulsion
(Restasis). With the reduction in occurrence of adverse events, in
particular ocular adverse effects as noted above, the
pharmaceutical compositions are found to be safe, well tolerated
and comfortable to the eye of the human and suitable for use in the
methods of treatment as described herein.
[0035] The pharmaceutical compositions as defined herein are not
only preferably used for the treatment of subjects with dry eye
disease, but also for specific conditions associated there with,
and also in particular for subjects with moderate to severe dry eye
disease.
[0036] A further aspect of the present invention relates to a
pharmaceutical composition for use in the treatment of reading
impairment in a subject suffering from dry eye disease, wherein the
composition comprises about 0.05 to 0.1% (w/v) cyclosporine
dissolved in 1-perfluorobutyl-pentane. The treatment involves
topical administration of said composition to an eye or eyes of a
subject suffering from dry eye disease and who as a result has
difficulties in reading.
[0037] Subjects suffering from dry eye disease may experience
symptoms which individually, or collectively, such as blurring,
pain, irritation or corneal surface damage such as to the central
cornea, which may contribute to visual impairment or difficulties
which can be reflected by a negative effect on the subject's
performance in functional tasks where visual performance and acuity
may be essential. In particular, subjects suffering from dry eye
disease may experience symptoms which individually or collectively
may contribute to poorer quality of vision or ocular comfort which
results or contributes to difficulties in reading and overall
reduction in reading performance. Reading impairment may be caused
by increased ocular discomfort during, or as a consequent to the
task of reading (for example heightened symptoms of any one of the
dry eye disease symptoms referenced herein), and/or difficulty in
visualizing or perceiving characters while reading, for instance
due to blurred vision or a high frequency of blinking.
[0038] Dry eye disease patients with a reading impairment may have
a score of at least equal to, or greater than about 1.0 on the OSDI
question relating to reading. Question 6 of the OSDI questionnaire
assesses a subject's problems with their eyes during the week
preceding the assessment in terms of their reading ability with a
scoring of 0 to 4 (0 for none of the time, 1 for some of the time,
2 for half of the time, 3 for most of the time and 4 for all of the
time). Reading impairment may also be assessed by parameters such
as a subject's reading speed or acuity (e.g. with silent or reading
out loud) of a standard text.
[0039] In a preferred embodiment, the invention relates to a
pharmaceutical composition for use in the treatment of reading
impairment in a subject suffering from dry eye disease, wherein the
composition comprises about 0.05 to 0.1% (w/v) cyclosporine
dissolved in 1-perfluorobutyl-pentane and optionally up to about
1.0% (w/w) of ethanol; and wherein the amount of cyclosporine
administered in a single dose per eye is about 4 to 12 .mu.g.
[0040] In a further preferred embodiment, such pharmaceutical
composition may be used in the treatment of reading impairment in a
subject suffering from moderate to severe dry eye disease, and
preferably wherein the composition is administered twice daily, or
wherein the total daily administered dose is less than about 28
.mu.g per eye, or preferably, wherein the daily administered dose
is does not exceed about 24 .mu.g. Even more preferably, the total
daily administered dose per eye is below about 20 .mu.g, or below
about 10 .mu.g.
[0041] In another embodiment, the topically administered single
dose per eye used in the treatment of reading impairment in
subjects suffering from dry eye disease may be about 5 to 10 .mu.g,
or more preferably, about 5 .mu.g or about 10 .mu.g.
[0042] In a further preferred embodiment of the invention in
respect of the treatment of reading impairment in subjects
suffering from dry eye disease, about 5 .mu.g of cyclosporine is
administered per single dose per eye, of a pharmaceutical
composition comprising 0.05% (w/v) of cyclosporine dissolved in
1-perfluorobutyl-pentane, and optionally up to about 1.0% (w/w)
ethanol.
[0043] In yet a further preferred embodiment of the invention in
respect of the treatment of reading impairment in subjects
suffering from dry eye disease, about 10 .mu.g of cyclosporine is
administered per single dose per eye, of a pharmaceutical
composition comprising 0.1% (w/v) of cyclosporine dissolved in
1-perfluorobutyl-pentane, and optionally up to about 1.0% (w/w)
ethanol.
[0044] A reading impairment can introduce difficulties in many
tasks in daily life and employment where such function is
important, and may lead to reduction in work productivity and
performance. It has been found unexpectedly that topical ophthalmic
treatment, utilizing the compositions of the present invention, of
patients suffering from dry eye disease, preferably moderate to
severe category may lead to improvement in scoring for reading
impairment (such as from the OSDI ref. FIG. 4).
[0045] In particular, it has been found that reading impairment in
patients suffering from (moderate to severe) dry eye disease
treated via topical administration of a pharmaceutical composition
as described herein in the described amounts and dosing methods,
may lead to a reduction in the scoring of the reading impairment
(such as OSDI) by at least about 15%, or at least about 25%, or at
least about 30%.
[0046] In another aspect, the invention relates to a pharmaceutical
composition for use in the treatment of ocular surface damage in a
subject suffering from dry eye disease, wherein the composition
comprises about 0.05 to 0.1% (w/v) cyclosporine dissolved in
1-perfluorobutyl-pentane and wherein the amount of cyclosporine
administered in a single dose per eye is about 4 to 12 .mu.g.
[0047] In further aspect, the invention relates to a pharmaceutical
composition for use in the treatment of ocular surface damage
selected from corneal and/or conjunctival damage in a subject
suffering from dry eye disease, wherein the composition comprises
about 0.05 to 0.1% (w/v) cyclosporine dissolved in
1-perfluorobutyl-pentane, and wherein the amount of cyclosporine
administered in a single dose per eye is about 4 to 12 .mu.g.
[0048] Damage to the cornea and associated tissues is prevalent in
patients with dry eye disease, in particular those with moderate to
severe, or severe dry eye disease. The tear film, with its lipid,
aqueous and mucin layers normally provides a protective barrier to
corneal tissue and corneal epithelium and has a wetting function
i.e. prevents drying/desiccation. It acts as a conduit for the
provision of oxygen and nutrients to the corneal epithelial cells,
as well as removal of any potential pathogens, debris and waste
products. In patients with dry eye disease, the tear film is
typically unstable or disrupted (for example, as a result of
reduced aqueous secretion or increased evaporation of the tear
film, or reduced secretion of mucin or lipids) and consequently,
the corneal tissue, and conjunctiva may become less protected and
vulnerable and/or prone to damage and deterioration.
[0049] The severity of ocular surface damage (which may be
characterized by, for example punctate disruption of the corneal
epithelium or surface disruption of the bulbar conjunctiva) may be
assessed by corneal and conjunctival staining measurements, for
example such as described herein, i.e. fluorescein staining (NEI
scale) and lissamine green staining (Oxford scale), which highlight
and stain in particular, dead or damaged corneal and conjunctival
cells. Particularly, central corneal fluorescein staining (NEI
scale), which assays the central corneal area (as compared to the
peripheral corneal area including inferior, superior, nasal, and
temporal regions of the cornea), reflects ocular surface damage
that impacts visual function impairment.
[0050] As used herein, the term `corneal staining` or `total
corneal staining`, optionally in conjunction with the mention of
fluorescein, or a dye that is suitable or adapted for staining of
the cornea, refers to staining observed as a sum in respect of all
regions of the cornea, i.e. the inferior, superior, central,
temporal, and nasal regions of the cornea. The term `central
corneal staining` or the like (i.e. with specific corneal region
prefacing) and optionally in conjunction with the dye used for
staining, such as fluorescein, refers specifically to staining
observed only in the specified anatomical region.
[0051] As used herein, the term `conjunctival staining` or `total
conjunctival staining`, optionally in conjunction with the mention
of fluorescein or a dye suitable or adapted for staining of the
cornea, refers to staining observed as a sum in respect of all
regions of the conjunctivis, i.e. the temporal and nasal regions of
the conjunctivis. Where the term is used specifying the specific
conjunctival region (e.g. nasal conjunctiva staining), optionally
in conjunction with mention of the dye used for staining, such as
lissamine green, it is to be understood that this refers
specifically to staining observed in said region.
[0052] In one embodiment, the pharmaceutical composition for use
according to the invention may be used to treat ocular surface
damage, such as corneal damage and/or conjunctival damage, in a
subject suffering from dry eye disease, preferably said subject
having a total corneal fluorescein staining score of at least equal
to, or greater than 6 (.gtoreq.6), the score being the sum of
scores obtained for inferior, superior, central, nasal, and
temporal regions of the cornea, based on the NEI grading scale of
0-3. In another embodiment, the pharmaceutical composition for use
according to the invention may be used to treat ocular surface
damage, such as corneal damage and/or conjunctival damage, in a
subject suffering from dry eye disease, preferably said subject
having a central corneal fluorescein staining score of at least
equal to, or greater than 1 (.gtoreq.1), based on the NEI grading
scale of 0-3. In another embodiment, said subject may in addition
also have a total lissamine green conjunctival staining score (sum
of temporal and nasal regions), based on the Oxford scale, of at
least equal to, or greater than 2 (i.e. .gtoreq.2).
[0053] In a preferred embodiment, the invention relates to a
pharmaceutical composition for use in the treatment of ocular
surface damage in a subject suffering from dry eye disease, wherein
the composition comprises about 0.05 to 0.1% (w/v) cyclosporine
dissolved in 1-perfluorobutyl-pentane, and optionally up to about
1.0% (w/w) of ethanol; and wherein the amount of cyclosporine
administered in a single dose per eye is about 4 to 12 .mu.g. In a
specific embodiment, such use may be for the treatment of corneal
damage.
[0054] In a further preferred embodiment, such pharmaceutical
composition may be used in the treatment of ocular surface damage
in a subject suffering from moderate to severe dry eye disease,
preferably wherein the composition is administered twice daily, or
wherein the total daily administered dose is less than about 28
.mu.g per eye, or wherein preferably the daily administered dose
does not exceed about 24 .mu.g. Even more preferably, the total
daily administered dose per eye is below about 20 .mu.g, or below
about 10 .mu.g.
[0055] In another embodiment, the topically administered single
dose per eye used in the treatment of ocular surface damage may be
about 5 to 10 .mu.g, or more preferably, about 5 .mu.g or about 10
.mu.g. In yet another embodiment, the topically administered single
dose per eye used in the treatment of ocular surface damage,
wherein the ocular surface damage is corneal damage, may be about 5
to 10 .mu.g, or more preferably, about 5 .mu.g or about 10
.mu.g.
[0056] In yet a further preferred embodiment of the invention in
respect of treatment of ocular surface damage in subjects suffering
from dry eye disease, about 5 .mu.g of cyclosporine is administered
per single dose per eye, of a pharmaceutical composition comprising
0.05% (w/v) of cyclosporine dissolved in 1-perfluorobutyl-pentane,
and optionally up to about 1.0% (w/w) ethanol.
[0057] In another preferred embodiment of the invention in respect
of treatment of ocular surface damage in subjects suffering from
dry eye disease, about 10 .mu.g of cyclosporine is administered per
single dose per eye, of a pharmaceutical composition comprising
0.1% (w/v) of cyclosporine dissolved in 1-perfluorobutyl-pentane,
and optionally up to about 1.0% (w/w) ethanol.
[0058] In particular, it has been found that ocular surface damage
such as corneal or conjunctival damage is effectively treated and
reduced, as observed in patients undergoing treatment with the
compositions as defined and as administered according to the
invention (ref. FIGS. 2 and 3), as evidenced by a distinct
reduction, compared to that observed in subjects prior to
treatment, of corneal and conjunctival staining. Moreover, compared
to the comparator product and the vehicle, an earlier onset of
efficacy in the treatment of corneal damage was observed, i.e.
already within two to four weeks of treatment time.
[0059] Preferably, the pharmaceutical compositions and dosages
thereof as described herein may be used for the treatment of a
subject with moderate to severe dry eye disease, optionally wherein
the subject is not responsive to treatment with artificial
tears.
[0060] The severity of dry eye disease in subjects or patients can
be classified and scored using one or more, or a combination of
standard tests. For example, the severity of dry eye disease may be
determined using tests based on the assessment of patient
perception of ocular symptoms and their effect on vision, based on
questionnaires such as the Ocular Surface Disease Index (OSDI)
questionnaire which is a 12-item question focussed on symptoms of
ocular irritation associated with dry eye disease and their impact
on daily activities and lifestyle, or the dry eye symptom visual
analogue scale (VAS), where subjects are asked to rate their ocular
symptoms (both eyes simultaneously) due to ocular dryness by
placing a vertical mark on the horizontal line to indicate the
level of discomfort (0 corresponds to "no dryness" and 100%
corresponds to "maximal dryness") and about the severity of dry eye
symptoms, dryness, sticky feeling, burning/stinging, foreign body
sensation, itching, blurred vision, sensitivity to light, and pain,
as well as frequency in occurrence of dryness.
[0061] Dry eye disease may also be evaluated and determined using
any combination of objective clinical measures such as the Schirmer
test type 1, fluorescein staining and/or lissamine green staining
of the cornea and conjunctiva, and tear-film break up time (TBUT)
as a measurement of tear quality.
[0062] Within the context of the present invention, it is
understood that any one of these measures of determining the
severity of dry eye disease, or combination thereof may be
applied.
[0063] Preferably, a subject or patient with moderate to severe dry
eye, prior to treatment with the compositions defined herein, may
have at least one or a combination of the following: a total
corneal fluorescein staining score of .gtoreq.6 according to NEI
grading (i.e. equal to or greater than 6 of the sum of scoring for
the inferior, superior, central, nasal, and temporal cornea
regions); being symptomatic (i.e. a score of .gtoreq.40 (equal to
or greater than 40) on the dryness visual scale (VAS); or a score
.gtoreq.20 on the Ocular Surface Disease Index (OSDI)); or a
Schirmer's Test I score of between .gtoreq.2 mm and 8 mm (i.e.
equal to or greater than 2 mm, but equal to or less than 8 mm);
[0064] In a further embodiment, the pharmaceutical compositions for
use according to the invention may also be used for the treatment
of subjects with dry eye disease who are not responsive to
treatment with artificial tears.
[0065] Artificial tears, also known as lubricating eye drops or
tear substitutes are used for relief and treatment of the symptoms
of dry eye disease, and which normally may be obtained over the
counter (OTC). These are normally aqueous-based compositions, in
the form of solutions, but also in the form of gels or ointments
which function by adding moisture to the eyes, and usually may
comprise lubricating agents (e.g. hydroxypropyl methyl cellulose
(HPMC), carbomethylcellulose (CMC), polyvinyl alcohol, liquid
polyols such as propylene glycol, polyethylene glycol) and may
contain additives which promote healing (e.g. hyaluronic acid) or
mimic electrolyte composition of natural tear film, or which
promote retention (e.g. gelling agents such as carbomers) of the
composition on the eye surface.
[0066] Preferably, the pharmaceutical compositions for use
according to the invention may be used to treat subjects suffering
from dry eye disease, in particular subjects with moderate to
severe dry eye disease, with persisting dry eye disease symptoms,
and associated conditions even following a treatment period with
only artificial tears over a period of at least 2 weeks, or at
least 1 month, or at least about 6 months.
[0067] A dose of a composition for use according to the present
invention and as described in any one of the embodiments herein is
preferably topically administered in the form of a (i.e. one)
single drop to an eye of a subject. The drop may be administered to
the surface of the eye, preferably to any surface region or tissue
of the eye that is accessible to topical administration or
instillation, for example to the cornea or conjunctiva. The single
drop of the composition may be instilled directly onto a surface of
the eye, such as the corneal surface of the eye, or alternatively
into a space i.e. sac or pocket formed by gently pulling down of
the lower eyelid of an eye.
[0068] As used herein, the term `administration to an eye` or `per
eye` refers to the administration of a given dose, e.g. a single
dose, of a pharmaceutical composition according to the invention to
an individual eye of a subject. The therapy of the dry eye disease
and dry eye disease associated conditions as described herein
however, should be understood as being not limited to the treatment
of a single eye in a subject, but as being also inclusive of a
therapy involving the administration of compositions according to
the present invention to each i.e. both eyes of a subject which are
affected by the dry eye condition.
[0069] Preferably, the pharmaceutical compositions for any of the
uses described herein are administered at a dose of a single drop
four times a day per eye. In a more preferred embodiment, the
compositions are administered to the eye as a single drop twice per
day per eye. Thus, a patient undergoing treatment for both eyes in
accordance with such dosing scheme would receive a total of two
drops for each eye on each day of a given treatment period.
[0070] Where the pharmaceutical composition is administered more
than once per day to each eye, for example four times daily, or two
times daily per eye it is preferred, in a further embodiment, that
the time interval between topical administration of the composition
to the eye or eye surface is at least 4 hours, or at least 6 hours,
or at least 12 hours.
[0071] In a further embodiment, the pharmaceutical compositions for
use according to the invention are administered over a treatment
period of at least 1 month (four weeks), and more preferably at
least 4 months (16 weeks). In another embodiment, the
pharmaceutical compositions for use in the treatment of the dry eye
disease conditions and disorders as described herein may be
administered on a continuous basis while dry eye disease symptoms
and indicators persist.
[0072] Preferably, the pharmaceutical compositions for use in
accordance with the invention may comprise up to about 1.0% (w/w)
of ethanol.
[0073] As used herein, the term "up to about" or "up to" used in
context of a parameter, such as presently in relation to the amount
of ethanol in the composition, refers to any value of the parameter
greater than zero and up to, and inclusive of, the defined
parameter. For example, an amount of "up to about 1.0% (w/w) of
ethanol" should be understood as including any value greater than
zero ranging up to and including the value of 1.0% (w/w) of
ethanol, and would include, for example, values such as 0.01%,
0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5% 0.6%, 0.7, 0.8, 0.9, 0.95%,
0.99% (w/w) of ethanol, taking into account any degree of
variability usually observed in measuring or determining this
parameter, using the standard techniques and equipment known in the
relevant field.
[0074] In one embodiment of the invention, the compositions for the
therapeutic uses as described herein may consist essentially of
about 0.05% or 0.1% (w/v) cyclosporine dissolved in
1-perfluorobutyl-pentane, and optionally about 1.0% (w/w) of
ethanol.
[0075] In another embodiment, the compositions as described herein
are essentially free of ethanol, in which the composition consists
essentially only of cyclosporine in an amount as described in any
of the embodiments described herein dissolved in
1-perfluorobutyl-pentane.
[0076] The absence of an organic co-solvent such as ethanol may
offer the advantages of a simpler two component formulation
compared to a three component formulation additionally comprising a
co-solvent such as ethanol. The further inclusion, of even one
additional composition component may add complexity in terms of
factors such as cost, manufacturing, handling, packaging, and also
patient compliance.
[0077] In preferred embodiments of the invention, the compositions
for use as described herein may preferably comprise, or consist of:
[0078] 0.05 to 0.1% (w/v) of cyclosporine dissolved in
1-perfluorobutyl-pentane and 0.5% (w/w) ethanol, or [0079] 0.05 to
0.1% (w/v) of cyclosporine dissolved in 1-perfluorobutyl-pentane
and 1.0% (w/w) ethanol, or [0080] 0.05% (w/v) cyclosporine
dissolved in 1-perfluorobutyl-pentane and 0.5% (w/w) ethanol, or
[0081] 0.1% (w/v) of cyclosporine dissolved in
1-perfluorobutyl-pentane and 0.5% (w/w) ethanol, or [0082] 0.1%
(w/v) cyclosporine dissolved in 1-perfluorobutyl-pentane and 1.0%
(w/w) ethanol, or [0083] 0.05% (w/v) cyclosporine dissolved in
1-perfluorobutyl-pentane and 1.0% (w/w) ethanol, or [0084] 0.05 to
0.1% (w/v) of cyclosporine dissolved in 1-perfluorobutyl-pentane,
or [0085] 0.1% (w/v) cyclosporine dissolved in
1-perfluorobutyl-pentane, or [0086] 0.05% (w/v) cyclosporine
dissolved in 1-perfluorobutyl-pentane.
[0087] The compositions of the invention are preferably provided as
a clear solution, wherein the cyclosporine is fully dissolved and
in solution in the 1-perfluorobutyl-pentane (at room temperature
conditions i.e. between 15 to 25.degree. C.). If ethanol is
included, said compositions are also provided as a clear solution
of cyclosporine dissolved and in solution in
1-perfluorobutyl-pentane and the ethanol. In a preferred
embodiment, the compositions are provided in sterile form.
[0088] In another preferred embodiment, the pharmaceutical
compositions for use according to the present invention are
substantially free of water and/or substantially free of a
preservative. As understood herein, the term `substantially free`,
or alternatively `essentially free` in reference to a composition
constituent refers to the presence of said constituent in no more
than trace amounts and that if present in trace amounts the
constituent provides no technical contribution to the
composition.
[0089] Preferably, the pharmaceutical compositions for use
according to the present invention are substantially free of water,
substantially free of a preservative and are effective in
inhibiting microbal growth.
[0090] In another preferred embodiment, the pharmaceutical
compositions for use according to the present invention are
characterized by a remarkable wetting and spreading behaviour by
which they can rapidly and effectively spread over the surface of
the eye, such as the corneal and/or the conjunctival surface. Thus,
a droplet (drop) of the pharmaceutical compositions for use
according to the present invention when administered to the surface
of the eye leads to rapid spreading of the compositions over the
corneal and/or the conjunctival surface.
[0091] Preferably, the pharmaceutical compositions for use
according to the present invention form small droplets (drops), in
the range of about 8-12 .mu.l, more preferably about 9-11 .mu.l,
most preferably about 10 .mu.l, when administered from a drop
dispenser. This distinguishes the compositions of the present
invention from the 0.05% cyclosporine aqueous (o/w) emulsions, that
are characterized by droplet sizes of about 28.5 .mu.l.
[0092] In another preferred embodiment, the pharmaceutical
compositions for use according to the present invention are
characterized by the comparable low amount of cyclosporine
administered in a single dose per eye, such as about 4-12 .mu.g of
cyclosporine, preferably 5-10 g cyclosporine administered in a
single dose per eye.
[0093] This distinguishes the compositions of the present invention
from the 0.05% cyclosporine aqueous (o/w) emulsions, that are
characterized by droplet sizes of about 28.5 .mu.l and allows for
reduction of about 30 to 65% of the total daily dose when utilizing
the pharmaceutical compositions for use according to the present
invention.
[0094] As used herein, the term "consists" and related terms
"consisting" or "consist" is to be understood as meaning that no
other features, other than those prefaced by the term are present.
In the context of pharmaceutical compositions, if any other
constituent or component is present in the composition other than
those prefaced by such term, then it is present only in trace or
residual amounts such as to confer no technical advantage or
relevance in respect of the object of the invention, such as may be
further understood by the term `essentially" or "substantially"
used in conjunction with these terms (e.g. `essentially consisting
of").
[0095] The use of a pharmaceutical composition as described in any
one of the above embodiments in the manufacture or preparation of a
medicament or a medicine for the treatment of a subject in need
thereof in relation to any one of preferred dry eye disease
conditions described herein are also provided for in the context of
the present invention. Further provided for within the context of
the present invention, are also methods of treating subjects
diagnosed with, and/or suffering from said dry eye disease
conditions as described herein, wherein the methods may comprise
the topical administration, such as by direct topical instillation
to the eye, of any one of the defined compositions, preferably in
any one of the described doses or amounts, and/or over any one of
the defined periods for therapy.
[0096] Said treatment methods and compositions for therapeutic use
are moreover preferably targeted towards human subjects diagnosed
and/or suffering dry eye disease.
[0097] In yet a further aspect, the invention provides also a kit
comprising a pharmaceutical composition for use according to the
invention and any of the embodiments described above, wherein the
kit comprises a container for holding the pharmaceutical
composition and a drop dispenser adapted for administering about 8
to 12 .mu.l volume of the composition per drop.
[0098] In a further embodiment, the drop dispenser is adapted for
administering about 10 .mu.l of the composition per drop.
[0099] As understood herein, the drop dispenser may be a dispenser
or applicator means which may be mounted, fixed or connected to the
container for holding the pharmaceutical composition. Preferably,
the drop dispenser is adapted for dispensing a single dose in the
form of a single drop of the composition. More preferably, the drop
dispenser is adapted for dispensing a single dose of 8- to 12-.mu.l
volume, or is adapted for dispensing a single dose of about
10-.mu.l volume.
[0100] The container for holding the pharmaceutical composition as
understood herein is preferably of a volume which may hold a single
dose, but more preferably of a volume which may hold multiple or a
plurality of doses of the composition. In an embodiment of the
invention, the container of the kit may hold up to 160 doses of the
pharmaceutical composition for use according to the present
invention.
[0101] The container and/or the drop dispenser preferably may be
manufactured from a thermoplastic material or polymer. In a one
embodiment, the container and/or drop dispenser is manufactured
from a thermoplastic material selected from polyethylene and
polypropylene.
[0102] In one particular embodiment, the drop dispenser is
manufactured from a polyethylene material, preferably selected from
low density polyethylene and high density polyethylene, and more
preferably is manufactured from a high-density polyethylene. In
another embodiment, the container is manufactured from a
polypropylene or polyethylene material, and more preferably is
manufactured from polypropylene.
[0103] In yet a further embodiment, the invention relates to a kit
comprising a pharmaceutical composition for use according to the
invention, the kit comprising a container for holding the
pharmaceutical composition and a drop dispenser adapted for
administering about 8 to 12 .mu.l per drop wherein the container is
manufactured from polypropylene and wherein the drop dispenser is
manufactured from a polyethylene selected from a low density
polyethylene and a high density polyethylene, preferably a high
density polyethylene.
[0104] Preferably, the container has a volume, or an interior space
which is at least partially filled with a pharmaceutical
composition for use according to the invention. In a further
embodiment, the ratio of the volume of the pharmaceutical
composition in the container to the total volume of the container
is between 0.4 and 0.7. The total volume of the container, as
understood herein refers to the total interior volume formed by the
interior dimensions of the container. The volume of the
pharmaceutical composition in the container refers to the fill
volume, i.e. the volume of the pharmaceutical composition held in
the container. For example, in a kit comprising a container with a
total volume of 3.0 mL, it is preferred that the container holds a
volume of 2.0 mL of a pharmaceutical composition according to the
invention. Here, the ratio of the volume of the pharmaceutical
composition in the container to the total volume of the container
would be about 0.7.
[0105] Particularly preferred are kits comprising a pharmaceutical
composition for use in accordance with the present invention,
wherein the kit comprises, in addition to a drop dispenser adapted
for administering about 8 to 12 .mu.l per drop, any one of the
following:
about 2.0 mL of the pharmaceutical composition filled in a 3.0 mL
volume container (i.e. a respective ratio of about 0.7); or about
2.0 mL of a pharmaceutical composition filled in a 5.0 mL volume
container (i.e. a respective ratio of about 0.4); or about 2.5 mL
of a pharmaceutical composition filled in a 5.0 mL volume container
(i.e. a respective ratio of about 0.5).
[0106] Also preferred is a kit comprising a pharmaceutical
composition for use in accordance with the present invention,
wherein the kit comprises a container for holding the
pharmaceutical composition and a drop dispenser adapted for
administering about 8 to 12 .mu.l per drop and wherein the ratio of
the volume of head space in the container to the volume of the
pharmaceutical composition is between 0.5 to 1.5. As understood
herein, the volume of head space (or head space volume) in the
container refers to the interior volume of the container, formed by
the interior dimensions of the container which is not filled or
occupied by the liquid pharmaceutical composition but which may
contain atmosphere or inert gas.
[0107] For example, in a kit comprising a container holding a fill
volume of 2.5 mL of a pharmaceutical composition for use according
to the present invention, it is preferred that the head space
volume available in the container is about 2.5 mL, wherein the
ratio of the head space to pharmaceutical composition fill volume
is about 1.0.
[0108] Particularly preferred are kits comprising a pharmaceutical
composition for use in accordance with the present invention,
wherein the kit comprises, in addition to a drop dispenser adapted
for administering about 8 to 12 .mu.l per drop, or preferably about
10 .mu.l per drop, any one of the following:
a container holding about 2.0 mL of the pharmaceutical composition,
wherein the container has about 1.0 mL volume of head space (i.e. a
head space to fill volume ratio of about 0.5); or a container
holding about 2.0 mL of the pharmaceutical composition, wherein the
container has about 3.0 mL volume of head space (i.e. a head space
to fill volume ratio of about 1.5); or a container holding about
2.4 mL of the pharmaceutical composition, wherein the container has
about 2.6 mL volume of head space (i.e. a head space to fill volume
ratio of about 1.1).
[0109] Such kits as provided in accordance with these embodiments
may improve storage and dispensability (i.e., ease and consistency
in dispensing) of the pharmaceutical compositions.
[0110] Further, the present invention comprises the following items
1 to 37, relating to a method for treating dry eye disease: [0111]
1. A method of treating dry eye disease, the method comprising
topically administering twice daily to an eye of a human with dry
eye disease a composition comprising about 0.05 to 0.1% (w/v)
cyclosporine dissolved in 1-perfluorobutyl-pentane, wherein the
amount of cyclosporine administered in a single dose per eye is
about 4 to 12 .mu.g cyclosporine, and wherein said method is
therapeutically effective in treating dry eye in said human. [0112]
2. A method of treating dry eye disease according to Item 1,
wherein said composition further comprises up to about 1% (w/w)
ethanol. [0113] 3. A method of treating dry eye disease according
to Item 1, wherein said composition consists of cyclosporine
dissolved in a solution of about 99% (w/w) 1-perfluorobutyl-pentane
and about 1% (w/w) ethanol. [0114] 4. A method of treating dry eye
disease according to Item 1, wherein said composition consists of
cyclosporine dissolved in a solution of at about least 99% (w/w)
1-perfluorobutyl-pentane and up to about 1% (w/w) ethanol. [0115]
5. A method of treating dry eye disease according to Item 1,
wherein said composition further comprises up to about 0.5% (w/w)
ethanol. [0116] 6. A method of treating dry eye disease according
to Item 1, wherein said composition consists of cyclosporine
dissolved in a solution of about 99.5% (w/w)
1-perfluorobutyl-pentane and about 0.5% (w/w) ethanol. [0117] 7. A
method of treating dry eye disease according to Item 1, wherein
said composition consists of the cyclosporine dissolved in a
solution of at least about 99.5% (w/w) 1-perfluorobutyl-pentane and
up to about 0.5% (w/w) ethanol. [0118] 8. A method of treating dry
eye disease, the method comprising topically administering twice
daily to an eye of a human with dry eye disease a composition
comprising about 0.05% (w/v) cyclosporine dissolved in
1-perfluorobutyl-pentane, wherein said composition is substantially
free of water and is substantially free of a preservative, wherein
the amount of cyclosporine administered in a single dose per eye is
about 5 .mu.g cyclosporine, and wherein said method is
therapeutically effective in treating dry eye in said human. [0119]
9. A method of treating dry eye disease according to Item 8,
wherein said composition further comprises up to about 1% (w/w)
ethanol. [0120] 10. A method of treating dry eye disease according
to Item 8, wherein said composition consists of the cyclosporine
dissolved in a solution of about 99% (w/w) 1-perfluorobutyl-pentane
and about 1% (w/w) ethanol. [0121] 11. A method of treating dry eye
disease according to Item 8, wherein said composition consists of
the cyclosporine dissolved in a solution of at least about 99%
(w/w) 1-perfluorobutyl-pentane and up to about 1% (w/w) ethanol.
[0122] 12. A method of treating dry eye disease according to Item
8, wherein said composition further comprises up to about 0.5%
(w/w) ethanol. [0123] 13. A method of treating dry eye disease
according to Item 8, wherein said composition consists of the
cyclosporine dissolved in a solution of about 99.5% (w/w)
1-perfluorobutyl-pentane and about 0.5% (w/w) ethanol. [0124] 14. A
method of treating dry eye disease according to Item 8, wherein
said composition consists of the cyclosporine dissolved in a
solution of at least about 99.5% (w/w) 1-perfluorobutyl-pentane and
up to about 0.5% (w/w) ethanol. [0125] 15. A method of treating dry
eye disease according to any of the Items 8 to 14, wherein a
reduction in corneal staining is achieved. [0126] 16. A method of
treating dry eye disease according to Item 15, wherein a reduction
in corneal staining is achieved over a four month treatment period.
[0127] 17. A method of treating dry eye disease according to any of
the Items 8 to 14, wherein a reduction in central corneal staining,
and/or any one or combination of inferior, superior, nasal, or
temporal corneal staining is achieved. [0128] 18. A method of
treating dry eye disease according to any of the items 8 to 14,
wherein an early onset of action is achieved. [0129] 19. A method
of treating dry eye disease according to Item 18, wherein said
early onset of action is measured by reduction in corneal and
conjunctival staining and is achieved in about 2 to 4 weeks. [0130]
20. A method of treating dry eye disease according to any of the
items 8 to 14, wherein visual impairment associated with dry eye
disease is reduced. [0131] 21. A method of treating dry eye disease
according to any of the items 8 to 14, wherein ocular surface
damage associated with dry eye disease is reduced. [0132] 22. A
method of treating dry eye disease according to any of the items 8
to 14, wherein said composition is safe, well tolerated and
comfortable to the eye of the human. [0133] 23. A method of
treating dry eye disease, the method comprising topically
administering twice daily to an eye of a human with dry eye disease
a composition comprising about 0.1% (w/v) cyclosporine dissolved in
1-perfluorobutyl-pentane, wherein said composition is substantially
free of water and is substantially free of a preservative, wherein
the amount of cyclosporine administered in a single dose per eye is
about 10 .mu.g cyclosporine, and wherein said method is
therapeutically effective in treating dry eye in said human. [0134]
24. A method of treating dry eye disease according to Item 23,
wherein said composition further comprises up to about 1% (w/w)
ethanol. [0135] 25. A method of treating dry eye disease according
to Item 23, wherein said composition consists of the cyclosporine
dissolved in a solution of about 99% (w/w) 1-perfluorobutyl-pentane
and about 1% (w/w) ethanol. [0136] 26. A method of treating dry eye
disease according to Item 23, wherein said composition consists of
cyclosporine dissolved in a solution of at least about 99% (w/w)
1-perfluorobutyl-pentane and up to about 1% (w/w) ethanol. [0137]
27. A method of treating dry eye disease according to Item 23,
wherein said composition further comprises up to about 0.5% (w/w)
ethanol. [0138] 28. A method of treating dry eye disease according
to Item 23, wherein said composition consists of the cyclosporine
dissolved in a solution of about 99.5% (w/w)
1-perfluorobutyl-pentane and about 0.5% (w/w) ethanol. [0139] 29. A
method of treating dry eye disease according to Item 23, wherein
said composition consists of the cyclosporine dissolved in a
solution of at least about 99.5% (w/w) 1-perfluorobutyl-pentane and
up to about 0.5% (w/w) ethanol. [0140] 30. A method of treating dry
eye disease according to any of the items 23 to 29, wherein a
reduction in corneal staining is achieved. [0141] 31. A method of
treating dry eye disease according to Item 30, wherein a reduction
in corneal staining is achieved over a four month treatment period.
[0142] 32. A method of treating dry eye disease according to any of
the items 23 to 29, wherein a reduction in central corneal staining
and/or any one or combination of inferior, superior, nasal, or
temporal corneal staining is achieved. [0143] 33. A method of
treating dry eye disease according to any of the items 23 to 29
wherein an early onset of action is achieved. [0144] 34. A method
of treating dry eye disease according to Item 33, wherein said
early onset of action is measured by reduction in corneal and
conjunctival staining and is achieved in about 2 to 4 weeks. [0145]
35. A method of treating dry eye disease according to any of the
items 23 to 29, wherein visual impairment associated with dry eye
disease is reduced. [0146] 36. A method of treating dry eye disease
according to any of the items 23 to 29, wherein ocular surface
damage associated with dry eye disease is reduced. [0147] 37. A
method of treating dry eye disease according to any of the items 23
to 29, wherein said composition is safe, well tolerated and
comfortable to the eye of the human.
[0148] Further, the present invention comprises the following items
38 to 72 relating to a method for reducing reading impairment
associated with dry eye disease: [0149] 38. A method of reducing
reading impairment associated with dry eye disease, the method
comprising topically administering twice daily to an eye of a human
with dry eye disease a composition comprising about 0.05 to 0.1%
(w/v) cyclosporine dissolved in 1-perfluorobutyl-pentane, wherein
the amount of cyclosporine administered in a single dose per eye is
about 4 to 12 .mu.g cyclosporine, and wherein said method is
effective in reducing reading impairment in said human. [0150] 39.
A method of reducing reading impairment according to Item 38,
wherein said composition further comprises up to about 1% (w/w)
ethanol. [0151] 40. A method of reducing reading impairment
according to Item 38, wherein said composition consists of the
cyclosporine dissolved in a solution of about 99% (w/w)
1-perfluorobutyl-pentane and about 1% (w/w) ethanol. [0152] 41. A
method of reducing reading impairment according to Item 38, wherein
said composition consists of the cyclosporine dissolved in a
solution of at least about 99% (w/w) 1-perfluorobutyl-pentane and
up to about 1% (w/w) ethanol. [0153] 42. A method of reducing
reading impairment according to Item 38, wherein said composition
further comprises up to about 0.5% (w/w) ethanol. [0154] 43. A
method of reducing reading impairment according to Item 38, wherein
said composition consists of the cyclosporine dissolved in a
solution of about 99.5% (w/w) 1-perfluorobutyl-pentane and about
0.5% (w/w) ethanol. [0155] 44. A method of reducing reading
impairment according to Item 38, wherein said composition consists
of the cyclosporine dissolved in a solution of at least about 99.5%
(w/w) 1-perfluorobutyl-pentane and up to about 0.5% (w/w) ethanol.
[0156] 45. A method of reducing reading impairment associated with
dry eye disease, the method comprising topically administering
twice daily to an eye of a human with dry eye disease a composition
comprising about 0.05% (w/v) cyclosporine dissolved in
1-perfluorobutyl-pentane, wherein said composition is substantially
free of water and is substantially free of a preservative, wherein
the amount of cyclosporine administered in a single dose per eye is
about 5 .mu.g cyclosporine, and wherein said method is effective in
reducing reading impairment in said human. [0157] 46. A method of
reducing reading impairment according to Item 45, wherein said
composition further comprises up to about 1% (w/w) ethanol. [0158]
47. A method of reducing reading impairment according to Item 45
wherein said composition consists of the cyclosporine dissolved in
a solution of about 99% (w/w) 1-perfluorobutyl-pentane and about 1%
(w/w) ethanol. [0159] 48. A method of reducing reading impairment
according to Item 45 wherein said composition consists of the
cyclosporine dissolved in a solution of at least about 99% (w/w)
1-perfluorobutyl-pentane and up to about 1% (w/w) ethanol. [0160]
49. A method of reducing reading impairment according to Item 45,
wherein said composition further comprises up to about 0.5% (w/w)
ethanol. [0161] 50. A method of reducing reading impairment
according to Item 45, wherein said composition consists of the
cyclosporine dissolved in a solution of about 99.5% (w/w)
1-perfluorobutyl-pentane and about 0.5% (w/w) ethanol. [0162] 51. A
method of reducing reading impairment according to Item 45, wherein
said composition consists of the cyclosporine dissolved in a
solution at least about 99.5% (w/w) 1-perfluorobutyl-pentane and up
to about 0.5% (w/w) ethanol. [0163] 52. A method of reducing
reading impairment according to any of the items 45 to 51, wherein
a reduction in corneal staining is achieved. [0164] 53. A method of
reducing reading impairment according to Item 52, wherein a
reduction in corneal staining is achieved over a four month
treatment period. [0165] 54. A method of reducing reading
impairment according to any of the items 45 to 51, wherein a
reduction in central corneal staining and/or any one or combination
of inferior, superior, nasal, or temporal corneal staining is
achieved. [0166] 55. A method of reducing reading impairment
according to any of the items 45 to 51, wherein an early onset of
action is achieved. [0167] 56. A method of reducing reading
impairment according to Item 55, wherein said early onset of action
is measured by reduction in corneal and conjunctival staining and
is achieved in about 2 to 4 weeks. [0168] 57. A method of reducing
reading impairment according to any of the items 45 to 51, wherein
ocular surface damage associated with dry eye disease is reduced.
[0169] 58. A method of reducing reading impairment according to any
of the items 45 to 51, wherein said composition is safe, well
tolerated and comfortable to the eye of the human. [0170] 59. A
method of reducing reading impairment associated with dry eye
disease, the method comprising topically administering twice daily
to an eye of a human with dry eye disease a composition comprising
about 0.1% (w/v) cyclosporine dissolved in
1-perfluorobutyl-pentane, wherein said composition is substantially
free of water and is substantially free of a preservative, wherein
the amount of cyclosporine administered in a single dose per eye is
about 10 .mu.g cyclosporine, and wherein said method is effective
in reducing reading impairment in said human. [0171] 60. A method
of reducing reading impairment according to Item 59, wherein said
composition further comprises up to about 1% (w/w) ethanol. [0172]
61. A method of reducing reading impairment according to Item 59,
wherein said composition consists of the cyclosporine dissolved in
a solution of about 99% (w/w) 1-perfluorobutyl-pentane and about 1%
(w/w) ethanol. [0173] 62. A method of reducing reading impairment
according to Item 59, wherein said composition consists of
cyclosporine dissolved in a solution of at least about 99% (w/w)
1-perfluorobutyl-pentane and up to about 1% (w/w) ethanol. [0174]
63. A method of reducing reading impairment according to Item 59,
wherein said composition further comprises up to about 0.5% (w/w)
ethanol. [0175] 64. A method of reducing reading impairment
according to Item 59, wherein said composition consists of the
cyclosporine dissolved in a solution of about 99.5% (w/w)
1-perfluorobutyl-pentane and about 0.5% (w/w) ethanol. [0176] 65. A
method of reducing reading impairment according to Item 59, wherein
said composition consists of the cyclosporine dissolved in a
solution of at least about 99.5% (w/w) 1-perfluorobutyl-pentane and
up to about 0.5% (w/w) ethanol. [0177] 66. A method of reducing
reading impairment according to any of the items 59 to 65, wherein
a reduction in corneal staining is achieved. [0178] 67. A method of
reducing reading impairment according to Item 66, wherein a
reduction in corneal staining is achieved over a four month
treatment period. [0179] 68. A method of reducing reading
impairment according to any of the items 59 to 65, wherein a
reduction in central corneal staining and/or any one or combination
of inferior, superior, nasal, or temporal corneal staining is
achieved. [0180] 69. A method of reducing reading impairment
according to any of the items 59 to 65, wherein an early onset of
action is achieved. [0181] 70. A method of reducing reading
impairment according to Item 69, wherein said early onset of action
is measured by reduction in corneal staining and is achieved in
about 2 to 4 weeks. [0182] 71. A method of reducing reading
impairment according to any of the items 459 to 65 or items 59 to
65, wherein ocular surface damage associated with dry eye disease
is reduced. [0183] 72. A method of reducing reading impairment
according to any of the items 59 to 65, wherein said composition is
safe, well tolerated and comfortable to the eye of the human.
[0184] Further, the present invention comprises the following items
73 to 107 relating to a method of reducing ocular surface damage
associated with dry eye disease: [0185] 73. A method of reducing
ocular surface damage associated with dry eye disease, the method
comprising topically administering twice daily to an eye of a human
with dry eye disease a composition comprising about 0.05 to 0.1%
(w/v) cyclosporine dissolved in 1-perfluorobutyl-pentane, wherein
the amount of cyclosporine administered in a single dose per eye is
about 4 to 12 .mu.g cyclosporine, and wherein said method is
effective in reducing ocular surface damage in said human. [0186]
74. A method of reducing ocular surface damage according to Item
73, wherein said composition further comprises up to about 1% (w/w)
ethanol. [0187] 75. A method of reducing ocular surface damage
according to Item 73, wherein said composition consists of the
cyclosporine dissolved in a solution of about 99% (w/w)
1-perfluorobutyl-pentane and about 1% (w/w) ethanol. [0188] 76. A
method of reducing ocular surface damage according to Item 73,
wherein said composition consists of the cyclosporine dissolved in
a solution of at least about 99% (w/w) 1-perfluorobutyl-pentane and
up to about 1% (w/w) ethanol. [0189] 77. A method of reducing
ocular surface damage according to Item 73, wherein said
composition further comprises up to about 0.5% (w/w) ethanol.
[0190] 78. A method of reducing ocular surface damage according to
Item 73, wherein said composition consists of the cyclosporine
dissolved in a solution of about 99.5% (w/w)
1-perfluorobutyl-pentane and about 0.5% (w/w) ethanol. [0191] 79. A
method of reducing ocular surface damage according to Item 73,
wherein said composition consists of the cyclosporine dissolved in
a solution of at least about 99.5% (w/w) 1-perfluorobutyl-pentane
and up to about 0.5% (w/w) ethanol. [0192] 80. A method of reducing
ocular surface damage associated with dry eye disease, the method
comprising topically administering twice daily to an eye of a human
with dry eye disease a composition comprising about 0.05% (w/v)
cyclosporine dissolved in 1-perfluorobutyl-pentane, wherein said
composition is substantially free of water and is substantially
free of a preservative, wherein the amount of cyclosporine
administered in a single dose per eye is about 5 .mu.g
cyclosporine, and wherein said method is effective in reducing
reducing ocular surface damage in said human. [0193] 81. A method
of reducing ocular surface damage according to Item 80, wherein
said composition further comprises up to about 1% (w/w) ethanol.
[0194] 82. A method of reducing ocular surface damage according to
Item 80, wherein said composition consists of the cyclosporine
dissolved in a solution of about 99% (w/w) 1-perfluorobutyl-pentane
and about 1% (w/w) ethanol. [0195] 83. A method of reducing ocular
surface damage according to Item 80, wherein said composition
consists of the cyclosporine dissolved in a solution of at least
about 99% (w/w) 1-perfluorobutyl-pentane and up to about 1% (w/w)
ethanol. [0196] 84. A method of reducing ocular surface damage
according to Item 80, wherein said composition further comprises up
to about 0.5% (w/w) ethanol. [0197] 85. A method of reducing ocular
surface damage according to Item 80, wherein said composition
consists of the cyclosporine dissolved in a solution of about 99.5%
(w/w) 1-perfluorobutyl-pentane and about 0.5% (w/w) ethanol. [0198]
86. A method of reducing ocular surface damage according to Item
80, wherein said composition consists of the cyclosporine dissolved
in a solution of at least about 99.5% (w/w)
1-perfluorobutyl-pentane and up to about 0.5% (w/w) ethanol. [0199]
87. A method of reducing ocular surface damage according to any of
the items 80 to 86, wherein a reduction in corneal staining is
achieved. [0200] 88. A method of reducing ocular surface damage
according to Item 87, wherein a reduction in corneal staining is
achieved over a four month treatment period. [0201] 89. A method of
reducing ocular surface damage according to any of the items 80 to
86, wherein a reduction in central corneal staining and/or any one
or combination of inferior, superior, nasal, or temporal corneal
staining is achieved. [0202] 90. A method of reducing ocular
surface damage according to any of the items 80 to 86, wherein an
early onset of action is achieved. [0203] 91. A method of reducing
ocular surface damage according to Item 90, wherein said early
onset of action is measured by reduction in corneal and
conjunctival staining and is achieved in about 2 to 4 weeks. [0204]
92. A method of reducing ocular surface damage according to any of
the items 80 to 86, wherein visual impairment associated with dry
eye disease is reduced. [0205] 93. A method of reducing ocular
surface damage according to any of the items 80 to 86, wherein said
composition is safe, well tolerated and comfortable to the eye of
the human. [0206] 94. A method of reducing ocular surface damage
associated with dry eye disease, the method comprising topically
administering twice daily to an eye of a human with dry eye disease
a composition comprising about 0.1% (w/v) cyclosporine dissolved in
1-perfluorobutyl-pentane, wherein said composition is substantially
free of water and is substantially free of a preservative, wherein
the amount of cyclosporine administered in a single dose per eye is
about 10 .mu.g cyclosporine, and wherein said method is effective
in reducing ocular surface damage in said human. [0207] 95. A
method of reducing ocular surface damage according to Item 94,
wherein said composition further comprises up to about 1% (w/w)
ethanol. [0208] 96. A method of reducing ocular surface damage
according to Item 94, wherein said composition consists of the
cyclosporine dissolved in a solution of about 99% (w/w)
1-perfluorobutyl-pentane and about 1% (w/w) ethanol. [0209] 97. A
method of reducing ocular surface damage according to Item 94,
wherein said composition consists of the cyclosporine dissolved in
a solution of at least about 99% (w/w) 1-perfluorobutyl-pentane and
up to about 1% (w/w) ethanol. [0210] 98. A method of reducing
ocular surface damage according to Item 94, wherein said
composition further comprises up to about 0.5% (w/w) ethanol.
[0211] 99. A method of reducing ocular surface damage according to
Item 94 wherein said composition consists of the cyclosporine
dissolved in a solution of about 99.5% (w/w)
1-perfluorobutyl-pentane and about 0.5% (w/w) ethanol. [0212] 100.
A method of reducing ocular surface damage according to Item 94
wherein said composition consists of the cyclosporine dissolved in
a solution of at least about 99.5% (w/w) 1-perfluorobutyl-pentane
and up to about 0.5% (w/w) ethanol. [0213] 101. A method of
reducing ocular surface damage according to any of the items 94 to
100, wherein a reduction in corneal staining is achieved. [0214]
102. A method of reducing ocular surface damage according to Item
101, wherein a reduction in corneal staining is achieved over a
four month treatment period. [0215] 103. A method of reducing
ocular surface damage according to any of the items 94 to 100
wherein a reduction in central corneal staining and/or any one or
combination of inferior, superior, nasal, or temporal corneal
staining is achieved. [0216] 104. A method of reducing ocular
surface damage according to any of the items 94 to 100, wherein an
early onset of action is achieved. [0217] 105. A method of reducing
ocular surface damage according to Item 104, wherein said early
onset of action is measured by reduction in corneal staining and is
achieved in about 2 to 4 weeks. [0218] 106. A method of reducing
ocular surface damage according to any of the items 94 to 100,
wherein visual impairment associated with dry eye disease is
reduced. [0219] 107. A method of reducing ocular surface damage
according to any of the items 94 to 100, wherein said composition
is safe, well tolerated and comfortable to the eye of the
human.
[0220] Further, the present invention comprises the following items
108 to 140, relating to a method of reducing the total daily amount
of cyclosporine administered topically to a human for the treatment
of dry eye disease: [0221] 108. A method of reducing the total
daily amount of cyclosporine administered topically to a human for
the treatment of dry eye disease, the method comprising topically
administering twice daily to an eye of said human a single drop per
eye of a composition comprising about 0.05 to 0.1% (w/v)
cyclosporine dissolved in 1-perfluorobutyl-pentane, wherein the
amount of cyclosporine administered in a single dose per eye is
about 4 to 12 .mu.g cyclosporine and wherein said method reduces
the amount of cyclosporine per total daily dose by about 30 to 65%
and is at least as therapeutically effective in treating dry eye as
compared to twice daily topical administration of a single drop per
eye of a 0.05% (w/v) cyclosporine aqueous (o/w) emulsion; or [0222]
wherein the amount of cyclosporine administered in a single dose
per eye is about 5 to 10 .mu.g cyclosporine and wherein said method
reduces the amount of cyclosporine per total daily dose by about 30
to 65% and is at least as therapeutically effective in treating dry
eye as compared to twice daily topical administration of a single
drop per eye of a 0.05% (w/v) cyclosporine aqueous (o/w) emulsion.
[0223] 109. A method of reducing the total daily amount of
cyclosporine administered topically to a human for the treatment of
dry eye disease according to Item 108, wherein said composition
further comprises up to about 1% (w/w) ethanol. [0224] 110. A
method of reducing the total daily amount of cyclosporine
administered topically to a human for the treatment of dry eye
disease according to Item 108, wherein said composition consists of
the cyclosporine dissolved in a solution of about 99% (w/w)
1-perfluorobutyl-pentane and about 1% (w/w) ethanol. [0225] 111. A
method of reducing the total daily amount of cyclosporine
administered topically to a human for the treatment of dry eye
disease according to Item 108, wherein said composition consists of
the cyclosporine dissolved in a solution of at least about 99%
(w/w) 1-perfluorobutyl-pentane and up to about 1% (w/w) ethanol.
[0226] 112. A method of reducing the total daily amount of
cyclosporine administered topically to a human for the treatment of
dry eye disease according to Item 108, wherein said composition
further comprises up to about 0.5% (w/w) ethanol. [0227] 113. A
method of reducing the total daily amount of cyclosporine
administered topically to a human for the treatment of dry eye
disease according to Item 108, wherein said composition consists of
the cyclosporine dissolved in a solution of about 99.5% (w/w)
1-perfluorobutyl-pentane and about 0.5% (w/w) ethanol. [0228] 114.
A method of reducing the total daily amount of cyclosporine
administered topically to a human for the treatment of dry eye
disease according to Item 108, wherein said composition consists of
the cyclosporine dissolved in a solution of at least about 99.5%
(w/w) 1-perfluorobutyl-pentane and up to about 0.5% (w/w) ethanol.
[0229] 115. A method of reducing the total daily amount of
cyclosporine administered topically to a human for the treatment of
dry eye disease according to Item 108 to 114, wherein the single
drop of said composition has a drop volume of about 10 .mu.l and
the single drop of said emulsion has a drop volume of about 28.5
.mu.l. [0230] 116. A method of reducing the total daily amount of
cyclosporine administered topically to a human for the treatment of
dry eye disease according to Item 108 to 114, wherein the systemic
exposure to cyclosporine is reduced as compared to twice daily
topical administration of a single drop of a 0.05% (w/v)
cyclosporine aqueous (o/w) emulsion. [0231] 117. A method of
reducing the total daily amount of cyclosporine administered
topically to a human for the treatment of dry eye disease according
to Item 108 to 114, wherein one or more adverse effects are reduced
as compared to twice daily topical administration of a single drop
of a 0.05% (w/v) cyclosporine aqueous (o/w) emulsion. [0232] 118. A
method of reducing the total daily amount of cyclosporine
administered topically to a human for the treatment of dry eye
disease according to Item 117, wherein the adverse effects are
selected from the group consisting of visual blurring, eye pain,
and eye irritation. [0233] 119. A method of reducing the total
daily amount of cyclosporine administered topically to a human for
treatment of dry eye disease, the method comprising topically
administering twice daily to an eye of a human with dry eye disease
a single drop of a composition comprising about 0.05% (w/v)
cyclosporine dissolved in 1-perfluorobutyl-pentane, wherein said
composition is substantially free of water and is substantially
free of a preservative, wherein the amount of cyclosporine
administered in a single dose per eye is about 5 g cyclosporine,
and wherein said method reduces the amount of cyclosporine per
total daily dose by about 65% and is at least as therapeutically
effective in treating dry eye as compared to twice daily topical
administration of a single drop per eye of a 0.05% (w/v)
cyclosporine aqueous (o/w) emulsion. [0234] 120. A method of
reducing the total daily amount of cyclosporine administered
topically to a human for the treatment of dry eye disease according
to Item 119, wherein said composition further comprises up to about
1% (w/w) ethanol. [0235] 121. A method of reducing the total daily
amount of cyclosporine administered topically to a human for the
treatment of dry eye disease according to Item 119, wherein said
composition consists of the cyclosporine dissolved in a solution of
about 99% (w/w) 1-perfluorobutyl-pentane and about 1% (w/w)
ethanol. [0236] 122. A method of reducing the total daily amount of
cyclosporine administered topically to a human for the treatment of
dry eye disease according to Item 119, wherein said composition
consists of the cyclosporine dissolved in a solution of at least
about 99% (w/w) 1-perfluorobutyl-pentane and up to about 1% (w/w)
ethanol. [0237] 123. A method of reducing the total daily amount of
cyclosporine administered topically to a human for the treatment of
dry eye disease according to Item 119, wherein said composition
further comprises up to about 0.5% (w/w) ethanol. [0238] 124. A
method of reducing the total daily amount of cyclosporine
administered topically to a human for the treatment of dry eye
disease according to Item 119, wherein said composition consists of
the cyclosporine dissolved in a solution of about 99.5% (w/w)
1-perfluorobutyl-pentane and about 0.5% (w/w) ethanol. [0239] 125.
A method of reducing the total daily amount of cyclosporine
administered topically to a human for the treatment of dry eye
disease according to Item 119, wherein said composition consists of
the cyclosporine dissolved in a solution of at least about 99.5%
(w/w) 1-perfluorobutyl-pentane and up to about 0.5% (w/w) ethanol.
[0240] 126. A method of reducing the total daily amount of
cyclosporine administered topically to a human for the treatment of
dry eye disease according to any of Items 119 to 125, wherein the
single drop of said composition has a drop volume of about 10 .mu.l
and the single drop of said emulsion has a drop volume of about
28.5 .mu.l. [0241] 127. A method of reducing the total daily amount
of cyclosporine administered topically to a human for the treatment
of dry eye disease according to any of Items 119 to 125, wherein
the systemic exposure to cyclosporine is reduced as compared to
twice daily topical administration of a single drop of a 0.05%
(w/v) cyclosporine aqueous (o/w) emulsion. [0242] 128. A method of
reducing the total daily amount of cyclosporine administered
topically to a human for the treatment of dry eye disease according
to any one of Items 119 to 125, wherein one or more adverse effects
are reduced as compared to twice daily topical administration of a
single drop of a 0.05% (w/v) cyclosporine aqueous (o/w) emulsion.
[0243] 129. A method of reducing the total daily amount of
cyclosporine administered topically to a human for the treatment of
dry eye disease according to any of Items 119 to 125, wherein the
adverse effects are selected from the group consisting of visual
blurring, eye pain, and eye irritation. [0244] 130. A method of
reducing the total daily amount of cyclosporine administered
topically to a human for the treatment of dry eye disease, the
method comprising topically administering twice daily to an eye of
a human with dry eye disease a single drop of a composition
comprising about 0.1% (w/v) cyclosporine dissolved in
1-perfluorobutyl-pentane, wherein said composition is substantially
free of water and is substantially free of a preservative, wherein
the amount of cyclosporine administered in a single dose per eye is
about 10 .mu.g cyclosporine, and wherein said method reduces the
amount of cyclosporine per total daily dose by about 30% and is at
least as therapeutically effective in treating dry eye as compared
to twice daily topical administration of a single drop per eye of a
0.05% (w/v) cyclosporine aqueous (o/w) emulsion. [0245] 131. A
method of reducing the total daily amount of cyclosporine
administered topically to a human for the treatment of dry eye
disease according to Item 130, wherein said composition further
comprises up to about 1% (w/w) ethanol. [0246] 132. A method of
reducing the total daily amount of cyclosporine administered
topically to a human for the treatment of dry eye disease according
to Item 130, wherein said composition consists of the cyclosporine
dissolved in a solution of about 99% (w/w) 1-perfluorobutyl-pentane
and about 1% (w/w) ethanol. [0247] 133. A method of reducing the
total daily amount of cyclosporine administered topically to a
human for the treatment of dry eye disease according to Item 130,
wherein said composition consists of the cyclosporine dissolved in
a solution of at least about 99% (w/w) 1-perfluorobutyl-pentane and
up to about 1% (w/w) ethanol. [0248] 134. A method of reducing the
total daily amount of cyclosporine administered topically to a
human for the treatment of dry eye disease according to Item 130,
wherein said composition further comprises up to about 0.5% (w/w)
ethanol. [0249] 135. A method of reducing the total daily amount of
cyclosporine administered topically to a human for the treatment of
dry eye disease according to Item 130, wherein said composition
consists of the cyclosporine dissolved in a solution of about 99.5%
(w/w) 1-perfluorobutyl-pentane and about 0.5% (w/w) ethanol. [0250]
136. A method of reducing the total daily amount of cyclosporine
administered topically to a human for the treatment of dry eye
disease according to Item 130, wherein said composition consists of
the cyclosporine dissolved in a solution of at least about 99.5%
(w/w) 1-perfluorobutyl-pentane and up to about 0.5% (w/w) ethanol.
[0251] 137. A method of reducing the total daily amount of
cyclosporine administered topically to a human for the treatment of
dry eye disease according to any one of Items 130 to 136, wherein
the single drop of said composition has a drop volume of about 10
.mu.l and the single drop of said emulsion has a drop volume of
about 28.5 .mu.l. [0252] 138. A method of reducing the total daily
amount of cyclosporine administered topically to a human for the
treatment of dry eye disease according to any one of Items 130 to
136, wherein the systemic exposure to cyclosporine is reduced as
compared to twice daily topical administration of a single drop of
a 0.05% (w/v) cyclosporine aqueous (o/w) emulsion. [0253] 139. A
method of reducing the total daily amount of cyclosporine
administered topically to a human for the treatment of dry eye
disease according to any one of Items 130 to 136, wherein one or
more adverse effects are reduced as compared to twice daily topical
administration of a single drop of a 0.05% (w/v) cyclosporine
aqueous (o/w) emulsion. [0254] 140. A method of reducing the total
daily amount of cyclosporine administered topically to a human for
the treatment of dry eye disease according to Item 139, wherein the
adverse effects are selected from the group consisting of visual
blurring, eye pain, and eye irritation.
[0255] Further, the present invention comprises the following items
141 to 177 relating to a composition for treating dry eye disease:
[0256] 141. A composition for treating dry eye disease comprising
about 0.05 to 0.1% (w/v) cyclosporine dissolved in
1-perfluorobutyl-pentane, wherein said composition is
therapeutically effective in treating dry eye in a human with dry
eye disease when topically administered twice daily in a single
dose per eye of about 4 to 12 .mu.g cyclosporine. [0257] 142. A
composition according to Item 141, wherein said composition further
comprises up to about 1% (w/w) ethanol. [0258] 143. A composition
according to Item 141, wherein said composition consists of the
cyclosporine dissolved in a solution of about 99% (w/w)
1-perfluorobutyl-pentane and about 1% (w/w) ethanol. [0259] 144. A
composition according to Item 141, wherein said composition
consists of the cyclosporine dissolved in a solution of at least
about 99% (w/w) 1-perfluorobutyl-pentane and up to about 1% (w/w)
ethanol. [0260] 145. A composition according to Item 141, wherein
said composition further comprises up to about 0.5% (w/w) ethanol.
[0261] 146. A composition according to Item 141, wherein said
composition consists of the cyclosporine dissolved in a solution of
about 99.5% (w/w) 1-perfluorobutyl-pentane and about 0.5% (w/w)
ethanol. [0262] 147. A composition according to Item 141, wherein
said composition consists of the cyclosporine dissolved in a
solution of at least about 99.5% (w/w) 1-perfluorobutyl-pentane and
up to about 0.5% (w/w) ethanol. [0263] 148. A composition according
to Item 141, wherein said cyclosporine concentration is about 0.05%
(w/v) cyclosporine and said single dose per eye is about 5 .mu.g
cyclosporine and wherein said composition is substantially free of
water and is substantially free of a preservative. [0264] 149. A
composition according to Item 148, wherein said composition further
comprises up to about 1% (w/w) ethanol. [0265] 150. A composition
according to Item 148, wherein said composition consists of the
cyclosporine dissolved in a solution of about 99% (w/w)
1-perfluorobutyl-pentane and about 1% (w/w) ethanol. [0266] 151. A
composition according to Item 148, wherein said composition
consists of the cyclosporine dissolved in a solution of at least
about 99% (w/w) 1-perfluorobutyl-pentane and up to about 1% (w/w)
ethanol. [0267] 152. A composition according to Item 148, wherein
said composition further comprises up to about 0.5% (w/w) ethanol.
[0268] 153. A composition according to Item 148, wherein said
composition consists of the cyclosporine dissolved in about 99.5%
(w/w) 1-perfluorobutyl-pentane and about 0.5% (w/w) ethanol. [0269]
154. A composition according to Item 148, wherein said composition
consists of the cyclosporine dissolved in at least about 99.5%
(w/w) 1-perfluorobutyl-pentane and up to about 0.5% (w/w) ethanol.
[0270] 155. A composition according to any of the items 148 to 154,
wherein said composition is effective in reducing corneal staining.
[0271] 156. A composition according to Item 155, wherein the
reduction in corneal staining is achieved over a four month
treatment period. [0272] 157. A composition according to any of the
items 148 to 154, wherein said composition is effective in reducing
central corneal staining and/or any one or combination of inferior,
superior, nasal, or temporal corneal staining. [0273] 158. A
composition according to any of the items 148 to 154, wherein said
composition is effective in achieving an early onset of action.
[0274] 159. A composition according to Item 130 or item 158,
wherein said early onset of action is measured by reduction in
corneal and conjunctival staining and is achieved in about 2 to 4
weeks. [0275] 160. A composition according to any of the items 148
to 154, wherein said composition is effective in reducing visual
impairment associated with dry eye disease. [0276] 161. A
composition according to any of the items 148 to 154, wherein said
composition is effective in reducing ocular surface damage
associated with dry eye. [0277] 162. A composition according to any
of the items 148 to 154, wherein said composition is safe, well
tolerated and comfortable to the eye of the human [0278] 163. A
composition according to Item 141, wherein said cyclosporine
concentration is about 0.10% (w/v) cyclosporine and said single
dose per eye is about 10 .mu.g cyclosporine and wherein said
composition is substantially free of water and is substantially
free of a preservative. [0279] 164. A composition according to Item
163, wherein said composition further comprises up to about 1%
(w/w) ethanol. [0280] 165. A composition according to Item 163,
wherein said composition consists of the cyclosporine dissolved in
a solution of about 99% (w/w) 1-perfluorobutyl-pentane and about 1%
(w/w) ethanol. [0281] 166. A composition according to Item 163,
wherein said composition consists of the cyclosporine dissolved in
a solution of at least about 99% (w/w) 1-perfluorobutyl-pentane and
up to about 1% (w/w) ethanol. [0282] 167. A composition according
to Item 163, wherein said composition further comprises up to about
0.5% (w/w) ethanol. [0283] 168. A composition according to Item
163, wherein said composition consists of the cyclosporine
dissolved in a solution of about 99.5% (w/w)
1-perfluorobutyl-pentane and about 0.5% (w/w) ethanol. [0284] 169.
A composition according to Item 163, wherein said composition
consists of cyclosporine dissolved in a solution of at least about
99.5% (w/w) 1-perfluorobutyl-pentane and up to about 0.5% (w/w)
ethanol. [0285] 170. A composition according to any of the items
163 to 169, wherein said composition is effective in reducing
corneal staining. [0286] 171. A composition according to Item 170,
wherein the reduction in corneal staining is achieved over a four
month treatment period. [0287] 172. A composition according to any
of the items 163 to 169, wherein said composition is effective in
reducing central corneal staining and/or any one or combination of
inferior, superior, nasal, or temporal corneal staining. [0288]
173. A composition according to any of the items 163 to 169,
wherein said composition is effective in achieving an early onset
of action. [0289] 174. A composition according to Item 173, wherein
said early onset of action is measured by reduction in corneal and
conjunctival staining and is achieved in about 2 to 4 weeks. [0290]
175. A composition according to any of the items 163 to 169,
wherein said composition is effective in reducing visual impairment
associated with dry eye disease. [0291] 176. A composition
according to any of the items 163 to 169, wherein said composition
is effective in reducing ocular surface damage associated with dry
eye. [0292] 177. A composition according to any of the items 163 to
169, wherein said composition is safe, well tolerated and
comfortable to the eye of the human.
[0293] Further, the present invention comprises the following items
178 to 214, relating to a composition effective in treating dry eye
disease in a human with a reduction in total daily amount of
cyclosporine: [0294] 178. A composition effective in treating dry
eye disease in a human with a reduction in total daily amount of
cyclosporine administered topically to said human, the composition
comprising about 0.05 to 0.1% (w/v) cyclosporine dissolved in
1-perfluorobutyl-pentane, wherein the composition is topically
administered twice daily in a single dose per eye of about 4 to 12
.mu.g cyclosporine and wherein the total daily amount of
cyclosporine is between about 30 to 65% less than a 0.05% (w/v)
cyclosporine aqueous (o/w) emulsion topically administered twice
daily in a single drop per eye. [0295] 179. A composition according
to Item 178, wherein said composition further comprises up to about
1% (w/w) ethanol. [0296] 180. A composition according to Item 178,
wherein said composition consists of the cyclosporine dissolved in
a solution of about 99% (w/w) 1-perfluorobutyl-pentane and about 1%
(w/w) ethanol. [0297] 181. A composition according to Item 178,
wherein said composition consists of the cyclosporine dissolved in
a solution of at least about 99% (w/w) 1-perfluorobutyl-pentane and
up to about 1% (w/w) ethanol. [0298] 182. A composition according
to Item 178, wherein said composition further comprises up to about
0.5% (w/w) ethanol. [0299] 183. A composition according to Item
178, wherein said composition consists of the cyclosporine
dissolved in a solution of about 99.5% (w/w)
1-perfluorobutyl-pentane and about 0.5% (w/w) ethanol. [0300] 184.
A composition according to Item 178, wherein said composition
consists of the cyclosporine dissolved in a solution of at least
about 99.5% (w/w) 1-perfluorobutyl-pentane and up to about 0.5%
(w/w) ethanol. [0301] 185. A composition according to Item 178,
wherein said cyclosporine concentration is about 0.05% (w/v)
cyclosporine, wherein said composition is substantially free of
water and is substantially free of a preservative, wherein said
single dose per eye is about 5 .mu.g cyclosporine with a single
drop volume of about 10 .mu.l, and wherein the total daily amount
of cyclosporine is about 65% less than a 0.05% (w/v) cyclosporine
aqueous (o/w) emulsion topically administered twice daily in a
single drop per eye having a volume of about 28.5 .mu.l. [0302]
186. A composition according to Item 185, wherein said composition
further comprises up to about 1% (w/w) ethanol. [0303] 187. A
composition according to Item 185, wherein said composition
consists of the cyclosporine dissolved in a solution of about 99%
(w/w) 1-perfluorobutyl-pentane and about 1% (w/w) ethanol. [0304]
188. A composition according to Item 185, wherein said composition
consists of the cyclosporine dissolved in a solution of at least
about 99% (w/w) 1-perfluorobutyl-pentane and up to about 1% (w/w)
ethanol. [0305] 189. A composition according to Item 185, wherein
said composition further comprises up to about 0.5% (w/w) ethanol.
[0306] 190. A composition according to Item 185, wherein said
composition consists of the cyclosporine dissolved in a solution of
about 99.5% (w/w) 1-perfluorobutyl-pentane and about 0.5% (w/w)
ethanol. [0307] 191. A composition according to Item 185, wherein
said composition consists of the cyclosporine dissolved in a
solution of at least about 99.5% (w/w) 1-perfluorobutyl-pentane and
up to about 0.5% (w/w) ethanol. [0308] 192. A composition according
to any of the items 185 to 191, wherein said composition is
effective in reducing corneal staining. [0309] 193. A composition
according to Item 192, wherein the reduction in corneal staining is
achieved over a four month treatment period. [0310] 194. A
composition according to any of the items 185 to 191, wherein said
composition is effective in reducing central corneal staining
and/or any one or combination of inferior, superior, nasal, or
temporal corneal staining. [0311] 195. A composition according to
any of the items 185 to 191, wherein said composition is effective
in achieving an early onset of action. [0312] 196. A composition
according to Item 195, wherein said early onset of action is
measured by reduction in corneal and conjunctival staining and is
achieved in about 2 to 4 weeks. [0313] 197. A composition according
to any of the items 185 to 191, wherein said composition is
effective in reducing visual impairment associated with dry eye
disease. [0314] 198. A composition according to any of the items
185 to 191, wherein said composition is effective in reducing
ocular surface damage associated with dry eye. [0315] 199. A
composition according to any of the items 183 to 189 or items 185
to 191, wherein said composition is safe, well tolerated and
comfortable to the eye of the human [0316] 200. A composition
according to Item 178, wherein said cyclosporine concentration is
about 0.10% (w/v) cyclosporine, wherein said composition is
substantially free of water and is substantially free of a
preservative, wherein said single dose per eye is about 10 .mu.g
cyclosporine with a single drop volume of about 10 .mu.l, and
wherein the total daily amount of cyclosporine is about 30% less
than a 0.05% (w/v) cyclosporine aqueous (o/w) emulsion topically
administered twice daily in a single drop per eye having a volume
of about 28.5 .mu.l. [0317] 201. A composition according to Item
200, wherein said composition further comprises up to about 1%
(w/w) ethanol. [0318] 202. A composition according to Item 200,
wherein said composition consists of the cyclosporine dissolved in
a solution of about 99% (w/w) 1-perfluorobutyl-pentane and about 1%
(w/w) ethanol. [0319] 203. A composition according to Item 200,
wherein said composition consists of the cyclosporine dissolved in
a solution of at least about 99% (w/w) 1-perfluorobutyl-pentane and
up to about 1% (w/w) ethanol. [0320] 204. A composition according
to Item 200, wherein said composition further comprises up to about
0.5% (w/w) ethanol. [0321] 205. A composition according to Item
200, wherein said composition consists of the cyclosporine
dissolved in a solution of about 99.5% (w/w)
1-perfluorobutyl-pentane and about 0.5% (w/w) ethanol. [0322] 206.
A composition according to Item 200, wherein said composition
consists of the cyclosporine dissolved in a solution of at least
about 99.5% (w/w) 1-perfluorobutyl-pentane and up to about 0.5%
(w/w) ethanol. [0323] 207. A composition according to any of the
items 200 to 206, wherein said composition is effective in reducing
corneal staining. [0324] 208. A composition according to Item 207,
wherein the reduction in corneal staining is achieved over a four
month treatment period. [0325] 209. A composition according to any
of the items 200 to 206, wherein said composition is effective in
reducing central corneal staining and/or any one or combination of
inferior, superior, nasal, or temporal corneal staining. [0326]
210. A composition according to any of the items 200 to 206,
wherein said composition is effective in achieving an early onset
of action. [0327] 211. A composition according to Item 210, wherein
said early onset of action is measured by reduction in corneal and
conjunctival staining and is achieved in about 2 to 4 weeks. [0328]
212. A composition according to any of the items 200 to 206,
wherein said composition is effective in reducing visual impairment
associated with dry eye disease. [0329] 213. A composition
according to any of the items 200 to 206, wherein said composition
is effective in reducing ocular surface damage associated with dry
eye. [0330] 214. A composition according to to any of the items 200
to 206, wherein said composition is safe, well tolerated and
comfortable to the eye of the human.
[0331] Further, the present invention comprises the following items
215 to 251, relating to a composition for reducing reading
impairment associated with dry eye disease: [0332] 215. A
composition for reducing reading impairment associated with dry eye
disease comprising about 0.05 to 0.1% (w/v) cyclosporine dissolved
in 1-perfluorobutyl-pentane, wherein said composition is effective
in reducing reading impairment in a human with dry eye disease when
topically administered twice daily, in a single dose per eye of
about 4 to 12 .mu.g cyclosporine. [0333] 216. A composition
according to Item 215, wherein said composition further comprises
up to about 1% (w/w) ethanol. [0334] 217. A composition according
to Item 215, wherein said composition consists of the cyclosporine
dissolved in a solution of about 99% (w/w) 1-perfluorobutyl-pentane
and about 1% (w/w) ethanol. [0335] 218. A composition according to
Item 215, wherein said composition consists of the cyclosporine
dissolved in a solution of at least about 99% (w/w)
1-perfluorobutyl-pentane and up to about 1% (w/w) ethanol. [0336]
219. A composition according to Item 215, wherein said composition
further comprises up to about 0.5% (w/w) ethanol. [0337] 220. A
composition according to Item 215, wherein said composition
consists of the cyclosporine dissolved in a solution of about 99.5%
(w/w) 1-perfluorobutyl-pentane and about 0.5% (w/w) ethanol. [0338]
221. A composition according to Item 215, wherein said composition
consists of the cyclosporine dissolved in a solution of at least
about 99.5% (w/w) 1-perfluorobutyl-pentane and up to about 0.5%
(w/w) ethanol. [0339] 222. A composition according to Item 215,
wherein said cyclosporine concentration is about 0.05% (w/v)
cyclosporine and said single dose per eye is about 5 .mu.g
cyclosporine and wherein said composition is substantially free of
water and is substantially free of a preservative. [0340] 223. A
composition according to Item 222, wherein said composition further
comprises up to about 1% (w/w) ethanol. [0341] 224. A composition
according to Item 222, wherein said composition consists of the
cyclosporine dissolved in a solution of about 99% (w/w)
1-perfluorobutyl-pentane and about 1% (w/w) ethanol. [0342] 225. A
composition according to Item 222, wherein said composition
consists of the cyclosporine dissolved in a solution of at least
about 99% (w/w) 1-perfluorobutyl-pentane and up to about 1% (w/w)
ethanol. [0343] 226. A composition according to Item 222, wherein
said composition further comprises up to about 0.5% (w/w) ethanol.
[0344] 227. A composition according to Item 222, wherein said
composition consists of cyclosporine dissolved in a solution of
about 99.5% (w/w) 1-perfluorobutyl-pentane and about 0.5% (w/w)
ethanol. [0345] 228. A composition according to Item 222, wherein
said composition consists of cyclosporine dissolved in a solution
of at least about 99.5% (w/w) 1-perfluorobutyl-pentane and up to
about 0.5% (w/w) ethanol. [0346] 229. A composition according to
any of the items 222 to 228, wherein said composition is effective
in reducing corneal staining. [0347] 230. A composition according
to Item 229, wherein the reduction in corneal staining is achieved
over a four month treatment period. [0348] 231. A composition
according to any of the items 222 to 228, wherein said composition
is effective in reducing central corneal staining and/or any one or
combination of inferior, superior, nasal, or temporal corneal
staining. [0349] 232. A composition according to any of the items
222 to 228, wherein said composition is effective in achieving an
early onset of action. [0350] 233. A composition according to Item
232, wherein said early onset of action is measured by reduction in
corneal and conjunctival staining and is achieved in about 2 to 4
weeks. [0351] 234. A composition according to any of the items 222
to 228, wherein said composition is effective in reducing visual
impairment associated with dry eye disease. [0352] 235. A
composition according to any of the items 222 to 228, wherein said
composition is effective in reducing ocular surface damage
associated with dry eye. [0353] 236. A composition according to any
of the items 222 to 228, wherein said composition is safe, well
tolerated and comfortable to the eye of the human [0354] 237. A
composition according to Item 215, wherein said cyclosporine
concentration is about 0.10% (w/v) cyclosporine and said single
dose per eye is about 10 .mu.g cyclosporine and wherein said
composition is substantially free of water and is substantially
free of a preservative. [0355] 238. A composition according to Item
237, wherein said composition further comprises up to about 1%
(w/w) ethanol. [0356] 239. A composition according to Item 237,
wherein said composition consists of the cyclosporine dissolved in
a solution of about 99% (w/w) 1-perfluorobutyl-pentane and about 1%
(w/w) ethanol. [0357] 240. A composition according to Item 237,
wherein said composition consists of the cyclosporine dissolved in
a solution of at least about 99% (w/w) 1-perfluorobutyl-pentane and
up to about 1% (w/w) ethanol. [0358] 241. A composition according
to Item 237, wherein said composition further comprises up to about
0.5% (w/w) ethanol. [0359] 242. A composition according to Item
237, wherein said composition consists of the cyclosporined
dissolved in a solution of about 99.5% (w/w)
1-perfluorobutyl-pentane and about 0.5% (w/w) ethanol. [0360] 243.
A composition according to Item 237, wherein said composition
consists of the cyclosporined dissolved in a solution of at least
about 99.5% (w/w) 1-perfluorobutyl-pentane and up to about 0.5%
(w/w) ethanol. [0361] 244. A composition according to any of the
items 237 to 243, wherein said composition is effective in reducing
corneal staining. [0362] 245. A composition according to Item 244,
wherein the reduction in corneal staining is achieved over a four
month treatment period. [0363] 246. A composition according to any
of the items 237 to 243, wherein said composition is effective in
reducing central corneal staining and/or any one or combination of
inferior, superior, nasal, or temporal corneal staining. [0364]
247. A composition according to any of the items 237 to 243,
wherein said composition is effective in achieving an early onset
of action. [0365] 248. A composition according to Item 247, wherein
said early onset of action is measured by reduction in corneal and
conjunctival staining and is achieved in about 2 to 4 weeks. [0366]
249. A composition according to any of the items 237 to 243,
wherein said composition is effective in reducing visual impairment
associated with dry eye disease. [0367] 250. A composition
according to any of the items 237 to 243, wherein said composition
is effective in reducing ocular surface damage associated with dry
eye. [0368] 251. A composition according to any of the items 237 to
243, wherein said composition is safe, well tolerated and
comfortable to the eye of the human.
[0369] Further, the present invention comprises the following items
252 to 288 relating to a composition for reducing ocular surface
damage associated with dry eye disease: [0370] 252. A composition
for reducing ocular surface damage associated with dry eye disease
comprising about 0.05 to 0.1% (w/v) cyclosporine dissolved in
1-perfluorobutyl-pentane, wherein said composition is effective in
reducing ocular surface damage in a human with dry eye disease when
topically administered twice daily, in a single dose per eye of
about 4 to 12 .mu.g cyclosporine. [0371] 253. A composition
according to Item 252, wherein said composition further comprises
up to about 1% (w/w) ethanol. [0372] 254. A composition according
to Item 252, wherein said composition consists of the cyclosporine
dissolved in a solution of about 99% (w/w) 1-perfluorobutyl-pentane
and about 1% (w/w) ethanol. [0373] 255. A composition according to
Item 252, wherein said composition consists of the cyclosporine
dissolved in a solution of at least about 99% (w/w)
1-perfluorobutyl-pentane and up to about 1% (w/w) ethanol. [0374]
256. A composition according to Item 252, wherein said composition
further comprises up to about 0.5% (w/w) ethanol. [0375] 257. A
composition according to Item 252, wherein said composition
consists of the cyclosporine dissolved in a solution of about 99.5%
(w/w) 1-perfluorobutyl-pentane and about 0.5% (w/w) ethanol. [0376]
258. A composition according to Item 252, wherein said composition
consists of the cyclosporine dissolved in a solution of at least
about 99.5% (w/w) 1-perfluorobutyl-pentane and up to about 0.5%
(w/w) ethanol. [0377] 259. A composition according to Item 252,
wherein said cyclosporine concentration is about 0.05% (w/v)
cyclosporine and said single dose per eye is about 5 .mu.g
cyclosporine and wherein said composition is substantially free of
water and is substantially free of a preservative. [0378] 260. A
composition according to Item 259, wherein said composition further
comprises up to about 1% (w/w) ethanol. [0379] 261. A composition
according to Item 259, wherein said composition consists of
cyclosporine dissolved in a solution of about 99% (w/w)
1-perfluorobutyl-pentane and about 1% (w/w) ethanol. [0380] 262. A
composition according to Item 259, wherein said composition
consists of the cyclosporine dissolved in a solution of at least
about 99% (w/w) 1-perfluorobutyl-pentane and up to about 1% (w/w)
ethanol. [0381] 263. A composition according to Item 259, wherein
said composition further comprises up to about 0.5% (w/w) ethanol.
[0382] 264. A composition according to Item 259, wherein said
composition consists of the cyclosporine dissolved in a solution of
about 99.5% (w/w) 1-perfluorobutyl-pentane and about 0.5% (w/w)
ethanol. [0383] 265. A composition according to Item 259, wherein
said composition consists of the cyclosporine dissolved in a
solution of at least about 99.5% (w/w) 1-perfluorobutyl-pentane and
up to about 0.5% (w/w) ethanol. [0384] 266. A composition according
to any of the items 259 to 265, wherein said composition is
effective in reducing corneal staining. [0385] 267. A composition
according to Item 266, wherein the reduction in corneal staining is
achieved over a four month treatment period. [0386] 268. A
composition according to any of the items 259 to 265, wherein said
composition is effective in reducing central corneal staining
and/or any one or combination of inferior, superior, nasal, or
temporal corneal staining. [0387] 269. A composition according to
any of the items 259 to 265, wherein said composition is effective
in achieving an early onset of action. [0388] 270. A composition
according to Item 269, wherein said early onset of action is
measured by reduction in corneal and conjunctival staining and is
achieved in about 2 to 4 weeks. [0389] 271. A composition according
to any of the items 259 to 265, wherein said composition is
effective in reducing visual impairment associated with dry eye
disease. [0390] 272. A composition according to any of the items
259 to 265, wherein said composition is effective in reducing
ocular surface damage associated with dry eye. [0391] 273. A
composition according to any of the items 259 to 265, wherein said
composition is safe, well tolerated and comfortable to the eye of
the human. [0392] 274. A composition according to Item 252, wherein
said cyclosporine concentration is about 0.10% (w/v) cyclosporine
and said single dose per eye is about 10 .mu.g cyclosporine and
wherein said composition is substantially free of water and is
substantially free of a preservative. [0393] 275. A composition
according to Item 274, wherein said composition further comprises
up to about 1% (w/w) ethanol. [0394] 276. A composition according
to Item 274, wherein said composition consists of the cyclosporine
dissolved in a solution of about 99% (w/w) 1-perfluorobutyl-pentane
and about 1% (w/w) ethanol. [0395] 277. A composition according to
Item 274, wherein said composition consists of the cyclosporine
dissolved in a solution of at least about 99% (w/w)
1-perfluorobutyl-pentane and up to about 1% (w/w) ethanol. [0396]
278. A composition according to Item 274, wherein said composition
further comprises up to about 0.5% (w/w) ethanol. [0397] 279. A
composition according to Item 274, wherein said composition
consists of the cyclosporine dissolved in a solution of about 99.5%
(w/w) 1-perfluorobutyl-pentane and about 0.5% (w/w) ethanol. [0398]
280. A composition according to Item 274, wherein said composition
consists of the cyclosporine dissolved in a solution of at least
about 99.5% (w/w) 1-perfluorobutyl-pentane and up to about 0.5%
(w/w) ethanol. [0399] 281. A composition according to any of the
items 274 to 280, wherein said composition is effective in reducing
corneal staining. [0400] 282. A composition according to Item 281,
wherein the reduction in corneal staining is achieved over a four
month treatment period. [0401] 283. A composition according to any
of the items 274 to 280, wherein said composition is effective in
reducing central corneal staining and/or any one or combination of
inferior, superior, nasal, or temporal corneal staining. [0402]
284. A composition according to any of the items 274 to 280,
wherein said composition is effective in achieving an early onset
of action. [0403] 285. A composition according to Item 284, wherein
said early onset of action is measured by reduction in corneal and
conjunctival staining and is achieved in about 2 to 4 weeks. [0404]
286. A composition according to any of the items 274 to 280,
wherein said composition is effective in reducing visual impairment
associated with dry eye disease. [0405] 287. A composition
according to any of the items 274 to 280, wherein said composition
is effective in reducing ocular surface damage associated with dry
eye. [0406] 288. A composition according to any of the items 274 to
280, wherein said composition is safe, well tolerated and
comfortable to the eye of the human.
[0407] The invention further also comprises the following items 289
to 303, relating to: [0408] 289. A pharmaceutical composition for
use in the topical treatment of dry eye disease, wherein the
composition comprises about 0.05 to 0.1% (w/v) cyclosporine
dissolved in 1-perfluorobutyl-pentane and wherein the amount of
cyclosporine administered in a single dose per eye is about 4 to 12
.mu.g. [0409] 290. A pharmaceutical composition for use in the
treatment of ocular surface damage in a subject suffering from dry
eye disease, wherein the composition comprises about 0.05 to 0.1%
(w/v) cyclosporine dissolved in 1-perfluorobutyl-pentane and
wherein the amount of cyclosporine administered in a single dose
per eye is about 4 to 12 .mu.g. [0410] 291. A pharmaceutical
composition for use in the treatment of reading impairment in a
subject suffering from dry eye disease, wherein the composition
comprises about 0.05 to 0.1% (w/v) cyclosporine dissolved in
1-perfluorobutyl-pentane. [0411] 292. The pharmaceutical
composition for use according to item 291, wherein the amount of
cyclosporine administered in a single dose per eye is about 4 to 12
.mu.g. [0412] 293. The pharmaceutical composition for use according
to any one of the preceding items 289-292, wherein the total daily
administered dose per eye is less than about 28 .mu.g. [0413] 294.
The pharmaceutical composition for use according to any one of the
preceding items 289-293, wherein the amount of cyclosporine
administered in a single dose per eye is about 5 .mu.g or about 10
.mu.g. [0414] 295. The pharmaceutical composition for use according
to any one of the preceding items 289-294, wherein the dose of the
composition is administered as one single drop to an eye of a
subject. [0415] 296. The pharmaceutical composition for use
according to any one of the preceding items 289-295, wherein the
dry eye disease is moderate to severe dry eye disease, and
optionally wherein the subject is not responsive to treatment with
artificial tears. [0416] 297. The pharmaceutical composition for
use according to any one of the preceding items 289-296, wherein
the composition comprises up to about 1.0% (w/w) ethanol. [0417]
298. The pharmaceutical composition for use according to any one of
the preceding items 289-297, wherein the composition consists
essentially of about 0.05% or 0.1% (w/v) cyclosporine dissolved in
1-perfluorobutyl-pentane, and optionally about 1.0% (w/w) of
ethanol. [0418] 299. The pharmaceutical composition for use
according to any one of the preceding items 289-298, wherein the
composition is administered twice per day. [0419] 300. A kit
comprising a pharmaceutical composition for use according to any
one of items 289 to 299, wherein the kit comprises a container for
holding the pharmaceutical composition and a drop dispenser adapted
for administering about 8 to 12 .mu.l volume of the composition per
drop. [0420] 301. The kit according to item 300, wherein the
container and/or drop dispenser is manufactured from a
thermoplastic material, preferably selected from polyethylene or
polypropylene. [0421] 302. The kit according to item 301, wherein
the container is manufactured from polypropylene and wherein the
drop dispenser is manufactured from a polyethylene selected from
low or high density polyethylene. [0422] 303. The kit according to
any one of items 300-302, wherein the ratio of the volume of the
pharmaceutical composition in the container to the total volume of
the container is between 0.4 to 0.7, or wherein the ratio of the
volume of the head space of the container to the volume of the
pharmaceutical composition is between 0.5 to 1.5.
DESCRIPTION OF THE DRAWINGS
[0423] FIG. 1 depicts the study schedule including the screening
and a 2-week run-in phase (subjects were provided with lubricant
eye drops), followed by a 4-month treatment phase.
[0424] FIG. 2 demonstrates Corneal Fluorescein Staining (the
National Eye Institute (NEI) Scale) of patients suffering from
moderate to severe dry eye disease treated with a) a 0.05% (w/v)
cyclosporine solution in 1-perfluorobutyl-pentane and 1.0% (w/v)
ethanol (CyclASol 0.05%); b) a 0.1% (w/v) cyclosporine solution in
1-perfluorobutyl-pentane and 1.0% (w/v) ethanol (CyclASol 0.1%); c)
Restasis.RTM. (comprising 0.05% (w/v) cyclosporine) and d) the
vehicle (1-perfluorobutyl-pentane and 1.0% (w/w) ethanol) alone.
Depicted is the change over time of the Corneal Fluorescein
Staining Total Score (NEI Scale) as compared to baseline scores
obtained prior to commencement of treatment (V1, day 1) for visits
V2 (2-week follow-up), V3 (4-week follow-up), V4 (12-week
follow-up) and V5 (16-week follow-up). It is observed herein that
both CyclASol 0.05% and CyclASol 0.1% provide an earlier onset of
effect as well as a higher efficacy when compared to the open label
comparator Restasis.RTM.. This is surprising since lower volumes
(10 .mu.l) were administered to the patients as compared to
Restasis.RTM. (28.5 .mu.l), which translates to a 30 to 65%
reduction of daily exposure of cyclosporine A but at the same time
resulting even higher efficacy.
[0425] FIG. 3 features results based on Conjunctival Lissamine
Green Staining (Oxford Scale) following treatment of patients
suffering from moderate to severe dry eye disease with CyclASol
0.05%, CyclASol 0.1%, Restasis.RTM. and the vehicle. Depicted is
the change of the Conjunctival Lissamine Green Staining Total Score
(Oxford Scale) as compared to baseline (V1, day 1) for visits V2
(2-week follow-up), V3 (4-week follow-up), V4 (12-week follow-up)
and V5 (16-week follow-up). It is observed that both CyclASol 0.05%
and CyclASol 0.1% show an earlier onset of effect as well as higher
efficacy when compared to the open label comparator Restasis.RTM..
This is surprising since lower volumes (10 .mu.l) are administered
to the patients as compared to Restasis.RTM. (28.5 .mu.l), which
translates to a 30-65% reduction of daily exposure of cyclosporine
A to the patients resulting in even higher efficacy.
[0426] FIG. 4 demonstrates the effect on the treatment of reading
impairment of patients suffering from moderate to severe dry eye
disease by administration of CyclASol 0.05% and CyclASol 0.1% based
on data derived from assessment of the reading assessment portion
of the OSDI questionnaire (OSDI, Ocular Surface Disease Index)
which relates to a scale of 0 to 4 (with 0 indicating no reading
problems and 4 translating to most severe reading problems). In
FIG. 4, the relative reading impairment (expressed as a percentage
%) observed in patients treated with CyclASol 0.05% and CyclASol
0.1% versus Baseline (V1, day 1) is compared to the vehicle over
visits V2 (2-week follow-up), V3 (4-week follow-up), V4 (12-week
follow-up) and V5 (16-week follow-up). Negative relative values
indicate an improvement of reading impairment. The comparison
demonstrates that reading capability in patients treated with
CyclASol 0.05% and CyclASol 0.1% was improved, compared to vehicle
at visit V5 (16-week follow-up), resulting in a reduction in
reading impairment of 28% and 31% respectively.
[0427] FIG. 5 demonstrates Central Corneal Fluorescein Staining
(the National Eye Institute (NEI) Scale) of patients suffering from
moderate to severe dry eye disease treated with a) a 0.05% (w/v)
cyclosporine solution in 1-perfluorobutyl-pentane and 1.0% (w/v)
ethanol (CyclASol 0.05%); b) a 0.1% (w/v) cyclosporine solution in
1-perfluorobutyl-pentane and 1.0% (w/v) ethanol (CyclASol 0.1%); c)
Restasis.RTM. (comprising 0.05% (w/v) cyclosporine) and d) the
vehicle (1-perfluorobutyl-pentane and 1.0% (w/w) ethanol) alone.
Depicted is the change over time of the Central Corneal Fluorescein
Staining Score (NEI Scale) as compared to baseline scores obtained
prior to commencement of treatment (V1, day 1) for visits V2
(2-week follow-up), V3 (4-week follow-up), V4 (12-week follow-up)
and V5 (16-week follow-up). It is observed herein that both
CyclASol 0.05% and CyclASol 0.1% provide an earlier onset of effect
as well as a higher efficacy when compared to the open label
comparator Restasis.RTM.. This is surprising since lower volumes
(10 .mu.l) were administered to the patients as compared to
Restasis.RTM. (28.5 .mu.l), which translates to a 30 to 65%
reduction of daily exposure of cyclosporine A but at the same time
resulting even higher efficacy.
[0428] The following examples serve to illustrate the invention,
however should not to be understood as restricting the scope of the
invention.
EXAMPLES
Example 1
Study Setup
[0429] A Phase 2, multi-center, randomized, double-masked, placebo
(vehicle)-controlled clinical study with an open label comparator
arm to assess the efficacy, safety and tolerability of topical
CyclASol for treatment of dry eye disease was conducted. This dose
finding trial in moderate to severe dry eye patients not responding
to artificial tears was set up as a 4-arm randomized parallel
double masked vehicle controlled study with 2 doses of CyclASol
(0.05% and 0.1%) and an open label comparator arm.
[0430] CyclASol is a clear ophthalmic solution of Cyclosporine A
dissolved in 1-perfluorobutyl-pentane. 1-perfluorobutyl-pentane,
which is commonly abbreviated F4H5 is used as the vehicle. The only
other component in the formulation is ethanol (1.0% (w/w) as
co-solvent.
[0431] In addition to the masked vehicle control arm, an open-label
treatment arm consisting of Restasis.RTM. was included to allow a
head to head comparison of effects of CyclASol and Restasis.RTM..
Restasis.RTM. is an approved medication for dry eye disease,
comprising 0.05% Cyclosporine A, formulated as an aqueous
emulsion.
Study Plan
TABLE-US-00001 [0432] Study # Arm Medication Subjects Dosage 1
CyclASol 0.05% N = 51 one drop 2 CyclASol 0.1% N = 51 per eye, 3
Vehicle N = 52 twice daily 4 Restasis 0.05% N = 53 (BID), for (open
label comparator) 4 months CyclASol 0.05% = 0.05% (w/v)
cyclosporine A, dissolved in 1-perfluorobutylpentane (F4H5) and 1%
(w/w) ethanol CyclASol 0.1% = 0.1% (w/v) cyclosporine A, dissolved
in 1-perfluorobutylpentane (F4H5) and 1% (w/w) ethanol Vehicle =
solution of 1-perfluorobutylpentane (F4H5) and 1% (w/w) ethanol
Study Population
[0433] In total of 207 (153 female, 54 male) patients with a
subject-reported history of dry eye in both eyes and meeting all
other study eligibility criteria were included, with a similar
distribution of age and sex across the groups. The subjects were
randomized to receive treatment with 0.05% CyclASol, 0.1% CyclASol,
Vehicle, or Restasis.RTM. in a 1:1:1:1 ratio. The study consisted
of two periods: a 14-day run-in period and a 112-day treatment
period.
[0434] Patients included in the study had to fulfill following
criteria: [0435] (a) Be at least 18 years of age; [0436] (b)
Provide written informed consent; [0437] (c) Have a subject
reported history of dry eye disease in both eyes for at least 6
months prior to Visit 0; [0438] (d) Current use (within 30 days
prior to Visit 0) of over-the-counter and/or prescription eye drops
for dry eye symptoms at Visit 0; [0439] (e) Have a score of
.gtoreq.40 on the dryness visual analogue scale at Visit 0 and
Visit 1; [0440] (f) Have a total corneal fluorescein staining score
of .gtoreq.6 (e.g. sum of inferior, superior, central, nasal, and
temporal) according to the NEI grading at Visits 0 and Visit 1;
[0441] (g) Have a total lissamine green conjunctival score (sum of
temporal and nasal) of .gtoreq.2, based on the Oxford grading at
Visits 0 and Visit 1; [0442] (h) Have a Schirmer's Test I score
between .gtoreq.2 mm and .ltoreq.8 mm at Visits 0 and Visit 1;
[0443] (i) Have at least one eye (the same eye) satisfy all
criteria for (f), (g), and (h) above; [0444] (j) Be able and
willing to follow instructions, including participation in all
study assessments and visits.
[0445] The patients were examined during the 112-day treatment
period according to the following schedule:
TABLE-US-00002 Visit Day Purpose V0 Day -14 .+-. 2 Screening V1 Day
1 Baseline/Randomization V2 Day 15 .+-. 1 2-week follow-up V3 Day
29 .+-. 2 4-week follow-up V4 Day 85 .+-. 3 12-week follow-up V5
Day 113 .+-. 3 16-week follow-up/Study
Instructions for Use
[0446] The study subjects were instructed to instill one dose (one
single droplet) in each eye two times daily (in the morning and in
the evening before bed).
[0447] The application volume per single dose (10 .mu.L) of
CyclASol 0.05%, CyclASol 0.1% solution and vehicle and as well as
the amount of active ingredient was significantly lower as compared
to the administered single dose of Restasis.RTM. 0.05% aqueous
(o/w) emulsion (28.5 .mu.L, ref. Restasis NDA 21-023, Clinical
Pharmacology Biopharmaceutics Review(s)).
TABLE-US-00003 CyclASol, CyclASol, Restasis .RTM. 0.05% 0.1% 0.05%
Drop volume (1 droplet) 10 .mu.l 10 .mu.l 28.5 .mu.l Single dose,
per eye 5 .mu.g 10 .mu.g 14.25 .mu.g Daily dose (2.times. per day),
10 .mu.g 20 .mu.g 28.5 .mu.g per eye Dose relative to 35.1% 70.2%
100.0% Restasis .RTM. Total reduction in daily 64.9% 29.8% 0.0%
dose exposure
Study Analysis
[0448] At each visit during the 112-day treatment period, each
subject was assessed in terms of treatment efficacy using tests
including corneal fluorescein staining (NEI Grading); conjunctival
staining (Lissamine, Oxford grading) as well as subject symptom
assessment questionnaires such as Ocular Surface Disease Index
(OSDI, ref. Schiffman R. M. et al 2000; 118:615-621.) questionnaire
(including question 6 relating to reading impairment) and dryness
severity visual analogue scale (VAS).
[0449] For corneal staining (Sook Chun Y et al., Am J Ophthalmol.
2014 May; 157(5):1097-102), 5 .mu.l of 2% preservative-free sodium
fluorescein solution was instilled into the inferior conjunctival
cul-de-sac of each eye. In order to achieve maximum fluorescence,
the fluorescein staining is evaluated only after approximately 3-5
minutes after instillation. A Wratten #12 yellow filter was used to
enhance the ability to grade fluorescein staining.
[0450] The staining was graded with the NEI Grading Scale (The
National Eye Institute grading system), with only the cornea being
graded. Corneal fluorescein staining scores were obtained for each
of the inferior, superior central, temporal, and nasal regions of
the cornea based on a 0-3 scale, where a score of 0 means no
staining is observed. The term "total corneal fluorescein staining
total score" (ref. FIG. 2) refers to a sum of scores from the
inferior, superior, central, temporal, and nasal regions of the
cornea.
[0451] Conjunctival Lissamine Green Staining (Bron A. J. et al,
Cornea. 2003; 22:640-650) was conducted by instillation of 10 .mu.l
of lissamine green solution into the inferior conjunctival
cul-de-sac of a subject. After waiting for approximately 30 seconds
the staining was evaluated. The subject was instructed to blink
several times to distribute the lissamine green. The staining was
graded with the Oxford Grading Scale. Herein, the lissamine
staining is represented by punctate dots on a series of panels
(A-E). Staining ranges from 0-5 for each panel and 0-10 for the
total exposed inter-palpebral conjunctiva. Both nasal and temporal
regions were graded separately. A score of 0 meaning no staining.
Total conjunctival lissamine green staining scores were obtained,
referring to the sum of scores from both temporal and nasal regions
of the conjunctiva.
* * * * *