Note: Descriptions are shown in the official language in which they were submitted.
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COMPOSITIONS FOR USE IN TREATING EYE DISORDERS USING DIPYRIDAMOLE
TECHNICAL FIELD
[0001] The present invention relates to compositions for use in treating
eye disorders
using dipyridamole.
BACKGROUND ART
[0002] As known in the art, the medical condition referred to as "dry eye"
is a disorder
of the tear film due to tear deficiency or excessive tear evaporation which
causes damage to
the interpalpebral ocular surface associated with symptoms of ocular
discomfort. Currently,
dry eye includes two major classes: (i) aqueous tear deficient dry eye (ADDE),
and
(ii) evaporative dry eye (EDE). ADDE refers mainly to a failure of sufficient
tear secretion
due to lacrimal dysfunction. ADDE has two major subclasses: (i) Sjogren's
Syndrome dry
eye (SSDE), and (ii) non-SS dry eye (such as in Graft-versus-Host Disease
(GvHD) or in
diabetes mellitus). EDE may be: (i) intrinsic, due to diseases affecting lid
structures or
dynamics, or (ii) extrinsic, in which ocular surface disease occurs due to
some extrinsic
exposure, such as topical drug preservatives, contact lens wear, pterygium, or
vitamin A
deficiency.
[0003] The term "corneal ulcer" usually refers to the medical condition in
which the
corneal epithelium, stroma, or both are lysed and deleted by the activation
and
hypersecretion of collagenolytic enzyme. The collagenolytic enzyme causing
corneal ulcer,
bacterial collagenase, and matrix metalloproteases (MMPs) are known to be
involved in the
ulcerative process.
[0004] The changes in the extracellular environment caused by the
degradation of
stromal collagen promote ulcers. Such conditions produce a vicious circle of
activation of
corneal stromal cells and degradation of corneal stroma. When the bacteria are
killed by
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antibiotics, secretion of bacterial collagenase is suppressed, and direct
corneal stroma
degradation due to the bacteria is suppressed. However, since most antibiotics
cannot
suppress activation of corneal stromal cell caused by the biological signals
once transmitted
from bacteria to corneal stromal cells, progression of ulcer is clinically
observed from time to
time.
[0005] The corneal/conjunctival diseases, including a repeated erosion of
the cornea
and a prolonged corneal epithelial deficiency, are associated with such
disorders. The
repairing process of the corneal/conjunctival epithelial disorders involves
the coverage of the
epithelial deficiency by the migration of corneal epithelial cells, followed
by a subsequent cell
division and differentiation, resulting in reconstitution of normal cornea and
conjunctiva.
Corneal anesthesia and congenital corneal anesthesia usually develop into
neurotrophic
keratopathy. Neurotrophic keratopathy is a degenerative corneal disease
induced by an
impairment of the trigeminal nerve. Impairment or loss of corneal sensory
innervation is
responsible for corneal epithelial defects, ulcers, and perforations.
[0006] A pterygium is a non-cancerous growth that starts in the clear, thin
tissue
(conjunctiva) of the eye. This growth covers the white part of the eye
(sclera), and extends
onto the cornea. It is often slightly raised, and contains visible blood
vessels. The problem
may occur in one or both eyes. Pterygium may become inflamed and cause
burning,
irritation, or a feeling like there's something foreign in the eye. Vision may
be affected if the
grows extends far enough onto the cornea. There is at present no known
curative treatment
for pterygium other than surgery.
[0007] A pinguecula is a yellowish, slightly-raised thickening of the
conjunctiva on the
sclera, close to the edge of the cornea. Pingueculae typically occur on the
part of the sclera
that is between the eyelids, and therefore is exposed to the sun. In some
cases,
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pingueculae become swollen and inflamed, a condition called pingueculitis.
Frequently,
pingueculae can lead to the formation of pterygia. There is at present no
known curative
treatment for pinguecula other than surgery.
[0008] Uveitis is inflammation of the middle layer of the eye, called the
uvea or uveal
tract. The uvea consists of the middle, pigmented, vascular structures of the
eye, and
includes the iris, ciliary body, and choroid. In western countries, anterior
uveitis accounts for
between 50% and 90% of uveitis cases, while in Asian countries the proportion
drops to be
between 28% and 50%. Uveitis is estimated to be responsible for approximately
10-20% of
the cases of blindness in the United States. The cause is generally infectious
(bacterial or
viral infection) or autoimmune. Genetic factors act as a predisposing factor
for this difficult-
to-treat condition.
[0009] In the prior art, dipyridamole
{2,6-bis(diethanolamino)-4,8-dipiperidinopyrimido[5,4-d]pyrimidinel,
closely related substituted pyrimido-pyrimidines, and their preparation are
taught by Fischer
in U.S. Patent No. 3,031,450 (hereinafter referred to as Fischer '450).
Dipyridamole was
introduced as a coronary vasodilator in the early 1960s, and is well known to
have platelet
aggregation inhibitor properties due to the inhibition of adenosine uptake.
Subsequently,
dipyridamole was shown to reduce thrombus formation in a study of arterial
circulation of the
brain in a rabbit model. These investigations led to its use as an anti-
thrombotic agent.
Dipyridamole soon became the therapy of choice for such applications as stroke
prevention,
maintaining the patency of coronary bypass and valve-replacement, as well as
for treatment
prior to coronary angioplasty.
[0010] In Patent Publication No. EP 0234854 B1 by Gilbard et al.
(hereinafter referred
to as Gilbard '854), it is suggested that cyclic cAMP functions as a second
messenger for
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exocytosis in the lacrimal gland, and acts to increase tear secretion. cAMP is
degraded by
phosphodiesterases. It is therefore thought that suppressing
phosphodiesterases can result
in increased intracellular cAMP levels, and thus enhance tear secretion.
Dipyridamole is
believed to act as a phosphodiesterase inhibitor, and is thought to exert some
of its
cardiovascular benefits via this mechanism.
[0011] However, on page 19 of Patent Publication No. WO 2007/1 401 81 by
Leung
(hereinafter referred to as Leung '181), it is disclosed that there was a
negligible effect on
cAMP after the addition of dipyridamole in comparison to a control. Only a
combination of
caffeine and dipyridamole yielded the desired effect of decreasing cAMP in-
vitro, which is
assumed to indicate increased cellular levels of cAMP.
[0012] It would be desirable to have compositions for use in treating eye
disorders
using dipyridamole. Such compositions and treatment indications would, inter
alia, overcome
the problems mentioned above associated with such ailments.
DISCLOSURE OF THE INVENTION
[0013] It is the purpose of the present invention to provide compositions
and treatment
indications for use in treating eye disorders using dipyridamole.
MODES FOR CARRYING OUT THE INVENTION
[0014] In the interest of clarity, the term "eye disorder" is specifically
defined for use
herein to include, but not be limited to, any ailment of Scleritis, Graft-
versus-Host Disease
(GvHD), keratitis, corneal ulcer, corneal abrasion, snow blindness, Thygeson's
superficial
punctuate keratopathy, corneal neovascularization, Fuchs dystrophy,
keratoconus,
keratoconjunctivitis sicca (dry eye), iritis, corneal anesthesia, neurotrophic
keratopathy, red
eye, pink eye, keratomycosis, xeropthalmia, retinoblastoma, uveitis,
pterygium, keratopathy,
and pingueculae.
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[0015] Furthermore, it is noted that the term "exemplary is used herein to
refer to
examples of embodiments and/or implementations, and is not meant to
necessarily convey a
more-desirable use-case. Similarly, the term "preferred" is used herein to
refer to an
example out of an assortment of contemplated embodiments and/or
implementations, and is
not meant to necessarily convey a more-desirable use-case. Therefore, it is
understood
from the above that "exemplary' and "preferred" may be applied herein to
multiple
embodiments and/or implementations.
[0016] Dipyridamole is readily absorbed from the gastrointestinal tract,
reaching peak
plasma levels in humans 1-3 hours following oral administration. Peak plasma
levels are
dose dependent and range from about 0.5 g/mL after a 25mg dose to 1.6 g/mL
after a
75mg dose. Blood levels are quite variable, possibly depending on food intake
and
gastrointestinal peristalsis. Ingestion on an empty stomach may result in
higher blood levels.
Following intravenous (IV) administration, the distribution half-life in
humans is about 25
minutes, and after oral administration, is about 3 hours. When plasma levels
of drug are
followed for up to 60 hours after IV or oral administration of 20-50mg, plasma
levels decline
tri-exponentially with half-lives of 5 minutes (IV only), 53 minutes, and
about 10-12 hours.
The volume of distribution is about 140L with about 92 to 99% binding to
plasma proteins,
primarily alpha1-acid glycoprotein. Typical daily oral doses of dipyridamole
range from 100-
400mg.
[0017] Dipyridamole is practically insoluble in water (water solubility is
8.17mg/L
(Meylan, WM ET AL. (1996))), and very soluble in methanol. This creates a
challenge for
finding a suitable method for ocular application in which an aqueous solution
delivered via
single drops is preferred. Embodiments of the present invention provide
compositions and
treatment indications for use in treating eye disorders using dipyridamole. It
was determined
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that by adjusting the pH of the aqueous solution to -6.6 (6.5-6.7),
dipyridamole fully
dissolves in the aqueous solution. The natural pH of tear fluid is 7.4;
however, discomfort for
the user will not be felt as long as the pH of the administered medication
stays in the range
of 6.6-7.8 (Sampath Kumar et al Recent Challenges and Advances in Ophthalmic
Drug
Delivery System," in The Pharma Innovation, Vol. 1, No. 4 (2012)).
[0018] Other methods may be used to achieve water solubility such as
ultrasonic
mixing, or dissolving dipyridamole in methanol, chloroform, acetic acid, DMSO,
or other
carriers in which the dipyridamole is soluble, followed by adding water or
saline, and then
removing all or part of the carrier. Another method may involve grinding the
compound to a
nano-particle size prior to mixing in water/saline. It should be noted that
when preparing the
more dilute Exemplary Formulations C and D described below, less acidification
was
required. While aqueous solutions tend to be preferred for ocular
instillation, preparing the
dipyridamole in an oil or cream base is another method to overcome the aqueous
solubility
challenge.
[0019] In accordance with aspects of the present invention, dipyridamole
was found to
be effective in treating ocular medical conditions when applied topically in
physiological
saline formulations. Topical application of dipyridamole may serve to treat
dry eye caused
by, for example, Graft-versus-Host Disease (GvHD), diabetes, allergic
conjunctivitis, contact
lens-related dry eye, and Sjorgen's syndrome.
[0020] In an exemplary embodiment of the present invention, topical
dipyridamole may
also be used to treat corneal ulcers resulting from, for example: viral
infection, bacterial
infection, fungal infection, injury resulting from wearing contact lenses,
traumatic injury, and
parasite infection. Moreover, topical dipyridamole may also be used for the
treatment of
pterygium, corneal anesthesia, and corneal neovascularization.
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[0021] Therefore, according to the present invention, there is provided for
the first time
a composition for use in treating eye disorders, the composition including:
(a) an effective
amount of a topically-administered dipyridamole. Preferably, the topically-
administered
dipyridamole is formulated as a solution. Preferably, the topically-
administered dipyridamole
is at least one agent selected from the group consisting of: dipyridamole and
a
pharmaceuticallyacceptable salt thereof. Preferably, the effective amount
corresponds to a
concentration of at least about 10-5 molarity. Preferably, the effective
amount is based on a
treatment administration of at least once every other day. These and further
embodiments
will be apparent from the detailed description and examples that follow.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0022] The present invention relates to compositions for use in treating
eye disorders
using dipyridamole. The aspects, uses, and advantages for such compositions,
according to
the present invention, may be better understood with reference to the
accompanying
description. The description is not to be taken in a limiting sense, but is
made merely for the
purpose of illustrating the general principles of the invention, since the
scope of the present
invention is best defined by the appended claims. Exemplary embodiments of the
present
invention are detailed below in the following exemplary formulations.
EXEMPLARY FORMULATON A:
[0023] Dipyridamole eye drops were prepared as follows. 1g of citric acid
was mixed in
100mL saline (0.9% w/v sodium chloride in sterile water) to obtain a pH of
6.7. 8.5mg of
dipyridamole was weighed, irradiated by UVB for 30 minutes for sterility, and
diluted in the
100mL saline. This solution was then filtered through a 0.22 micron filter for
sterilization,
resulting in a solution containing 85mcg of dipyridamole per mL. Using a
dropper, one drop
(equivalent to approximately 0.05mL) was applied to the eye.
EXEMPLARY FORMULATON B:
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[0024] Dipyridamole eye drops were prepared as follows. lg of citric acid
was mixed in
100mL saline (0.9% w/v sodium chloride in sterile water) to obtain a pH of
6.7. 4.25mg of
dipyridamole was weighed, irradiated by UVB for 30 minutes for sterility, and
diluted in the
100mL saline. This solution was then filtered through a 0.22 micron filter for
sterilization,
resulting in a solution containing 42.5mcg of dipyridamole per mL. Using a
dropper, one
drop (equivalent to approximately 0.05mL) was applied to the eye.
EXEMPLARY FORMULATON C:
[0025] Dipyridamole eye drops were prepared as follows. 1g of citric acid
was mixed in
100mL saline (0.9% w/v sodium chloride in sterile water) to obtain a pH of
6.7. 2.125mg of
dipyridamole was weighed, irradiated by UVB for 30 minutes for sterility, and
diluted in the
100mL saline. This solution was then filtered through a 0.22 micron filter for
sterilization,
resulting in a solution containing 21.25mcg of dipyridamole per mL. Using a
dropper, one
drop (equivalent to approximately 0.05mL) was applied to the eye.
EXEMPLARY FORMULATON D:
[0026] Dipyridamole eye drops were prepared as follows. 1g of citric acid
was mixed in
100mL saline (0.9% w/v sodium chloride in sterile water) to obtain a pH of
6.7. 1.0625mg of
dipyridamole was weighed, irradiated by UVB for 30 minutes for sterility, and
diluted in the
100mL saline. This solution was then filtered through a 0.22 micron filter for
sterilization,
resulting in a solution containing 10.625mcg of dipyridamole per mL. Using a
dropper, one
drop (equivalent to approximately 0.05mL) was applied to the eye.
RESULTS:
[0027] Five human males suffering from GvHD-related dry eye were treated
with one
drop of Formulation A bilaterally twice daily. Subjective relief from the dry-
eye symptoms
was attained within half an hour. The patients required subsequent application
twice daily.
After 3 days of use, redness in the eye (or pink eye) disappeared.
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[0028] Two human females suffering from diabetes-related dry eye were
treated with
one drop of Formulation C bilaterally twice daily. Relief from the dry-eye
symptoms was
attained within an hour. The patients required subsequent application twice
daily. After 5
days of use, redness in the eye (or pink eye) disappeared.
[0029] A human female suffering from diabetes-related dry eye was treated
with one
drop of Formulation B bilaterally once every other day. Relief from the dry-
eye symptoms
was attained within twenty minutes. The patient required subsequent
application once every
other day. After 10 days of use, redness in the eye (or pink eye) disappeared.
Maintenance
continued with administration once every other day.
[0030] A human male suffering from a viral eye infection with corneal ulcer
was treated
with one drop of Formulation B bilaterally twice daily. Exudation ceased
within 8 hours. The
patient required subsequent application twice daily. After 4 days of use,
redness in the eye
(or pink eye) disappeared, and the eye was completely healed within 5 days.
[0031] A human male suffering in one eye from pterygium, with related dry
eye and
pink eye, was treated with one drop of Formulation B twice daily. Relief from
the dry-eye
symptoms was attained within one day. The patient required subsequent
application twice
daily. After 10 days of use, redness in the eye (or pink eye) disappeared.
After 6 weeks of
use, the ptyregium shrank by about half its size, and continued to decrease in
size with
ongoing use.
[0032] A human female suffering in one eye from pterygium, with related dry
eye and
inflammation, was treated with one drop of Formulation C twice daily. Relief
from the dry-
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eye symptoms was attained within two days. The patient required subsequent
application
twice daily. After 8 weeks of use, the ptyregium shrank by about half its
size, and continued
to decrease in size with ongoing use.
[0033] A human male suffering from a deep corneal ulcer with stromal
involvement in
one eye was treated with one drop of Formulation A three times daily. Relief
from pain and
irritation was attained within 24 hours. The patient required subsequent
application twice
daily. After 7 days of use, the cornea had completely reepithelialized.
[0034] Three females suffering from diabetes-related corneal anesthesia
(neurotrophic
keratopathy) were treated with one drop of Formulation C daily. Symptoms of
corneal
anesthesia began improving within 2-3 days. The patients required subsequent
application
twice daily. After about 3 weeks of use, the patients reported complete relief
of symptoms.
[0035] One male suffering from diabetes-related neovascularization was
treated with
one drop of Formulation A twice daily. When examined after 4 weeks of use, the
abnormal
vessels were no longer visible by slit-lamp examination.
[0036] Two human males suffering from a viral eye infection with corneal
abrasion (i.e.,
the onset of a corneal ulcer) were treated with one drop of Formulation A
bilaterally twice
daily. Exudation ceased within 5 hours. The patients required subsequent
application twice
daily. After 2-3 days of use, redness in the eye (or pink eye) disappeared,
and the eyes
were completely healed within 5-6 days.
[0037] A human female suffering from a corneal ulcer in one eye was treated
with one
drop of Formulation A twice daily. Relief from pain and irritation was
attained within one day.
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The patients required subsequent application twice daily. After 7 days of use,
the ulcer had
healed completely.
[0038] Four human males suffering from diabetes-related dry eye were
treated with one
drop of Formulation A bilaterally twice daily. Relief from the dry-eye
symptoms was attained
on average within half an hour. The patients required subsequent application
twice daily.
After an average of one week of use, redness in the eye (or pink eye)
completely
disappeared.
[0039] Two females suffering from diabetes-related corneal anesthesia were
treated
with one drop of Formulation A daily. Symptoms of corneal anesthesia started
improving
within 2 days. After approximately one week of use, the patients reported
complete relief of
symptoms.
[0040] A human male suffering from diabetes-related neovascularization was
treated
with one drop of Formulation C twice daily. The patient required subsequent
application
twice daily. When examined after 16 days of use, the abnormal vessels were no
longer
visible by slit-lamp photography examination.
[0041] Six human patients suffering from GvHD-related dry eye were treated
with one
drop of Formulation C bilaterally twice daily. Relief from the dry-eye
symptoms was attained
within one hour. The patients required subsequent application twice daily.
After an average
of one week of use, redness in the eye (or pink eye) disappeared.
[0042] A human male suffering from anterior uveitis in both eyes was
treated with one
drop of Formulation C three times daily. Relief from pain was attained within
three days.
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Blurred vision was resolved within 7 days. Inflammation appeared to be
completely resolved
within 14 days. The patient continued subsequent application twice daily to
maintain
remission.
[0043] A human male suffering from anterior uveitis in both eyes was
treated with one
drop of Formulation B three times daily. Relief from pain was attained within
two days.
Blurred vision was resolved within 14 days. Inflammation appeared to be
completely
resolved within 18 days. The patient continued subsequent application twice
daily to
maintain remission.
[0044] Three human patients suffering from GvHD-related dry eye were
treated with
one drop of Formulation D bilaterally twice daily. Relief from the dry-eye
symptoms was
attained within one hour. The patients required subsequent application twice
daily. After an
average of one week of use, redness in the eye (or pink eye) disappeared.
ADDITIONAL PREFERRED EMBODIMENTS AND EXPERIMENTS
[0045] Dipyridamole eye drops were prepared by dissolving dipyridamole in
sterile
water. pH was adjusted, as needed, to achieve solubility. Several
concentrations were
prepared, ranging from 5mcg/m1to 200mcg/ml. Sterile procedures were followed.
[0046] Dipyridamole eye ointment was prepared by mixing dipyridamole in a
base of
yellow soft paraffin, liquid paraffin and wool fat at a ratio of (8:1:1).
Several concentrations
were prepared, ranging from 5mcg/m1to 200mcg/ml. Sterile procedures were
followed.
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[0047] Either the dipyridamole eye drops (one drop [approximately 0.05m1]
once to three
times daily) or the dipyridamole eye ointment (approximately 0.1 ¨ 0.3m1 [once
to twice daily])
was administered to the eyes of subjects suffering from Sjorgen's related dry
eye, non-specific
keratitis, keratoconus or allergic conjunctivitis. The concentrations used
were gradually
increased as tolerated.
RESULTS
[0048] Sjorgen's related dry eye: A slight transient stinging sensation was
experienced
upon application of the drops/ointment. Partial relief of dry eye symptoms set
in within one
hour of application. The relief became complete after about seven days of
continuous use and
continues with daily administration in some patients and period (every 3 ¨ 4
days)
administration in others.
[0049] Non-specific keratitis: A slight transient stinging sensation was
experienced upon
application of the drops/ointment. A lowered intensity of pain was experienced
within 1 ¨2
hours of application. The relief of pain became complete after 3 ¨4 periodic
applications
(spaced several hours apart) of the drops/ointment. Complete resolution of
keratitis was
achieved within 2 ¨ 7 days of ongoing application.
[0050] Keratoconus: Daily administration (once to twice daily) for three
months led to an
improvement in astigmatism enabling lowering of cylinder by a quarter to half
a number in two
subjects.
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[0051] Conjunctivitis (non-specific): A slight transient stinging sensation
was experienced
upon application of the drops/ointment. Partial relief of conjunctivitis
symptoms (itchiness,
burning or excessive tearing) set in within one hour of application.
Application continued once
to twice daily. After two to four days of use all symptoms including exudation
had relieved.
[0052] While the present invention has been described with respect to a
limited number
of embodiments, it will be appreciated that many variations, modifications,
and other
applications of the present invention may be made.
[0053] All of the eye disorders listed in this description such as in
paragraphs [0002], [0003],
[0004], [0005], [0006], [0007], [0008], [0014], [0019], [0020], [0027],
[0028], [0029], [0030], [0031],
[0032], [0033], [0034], [0035], [0036], [0038], [0039], [0040], [0041],
[0042], [0043], [0044], [0047],
[0048], [0049], [0050] and [0051] are known to affect the anterior segment of
the eye (including
conjunctiva) and/or lacrimal system.
INDUSTRIAL APPLICABILITY
[0054] Compositions using dipyridamole are applied in the treatment of eye
disorders,
an innovation which overcomes problems associated with such ailments.
