U.S. patent application number 11/222167 was filed with the patent office on 2006-01-12 for corneal epithelial migration promoter.
Invention is credited to Tsutomu Fujihara, Hiromi Fujita, Masatsugu Nakamura, Katsuhiko Nakata.
Application Number | 20060009415 11/222167 |
Document ID | / |
Family ID | 18664160 |
Filed Date | 2006-01-12 |
United States Patent
Application |
20060009415 |
Kind Code |
A1 |
Nakata; Katsuhiko ; et
al. |
January 12, 2006 |
Corneal epithelial migration promoter
Abstract
Based on research for compounds that can display a corneal
epithelial migration promoting effect in ophthalmology, the present
invention provides P2Y receptor agonist corneal epithelial
migration promoters, such as phosphoric acid compounds having an
adenosyl group, uridyl group, xanthosyl group, guanosyl group, or
thymidyl group, or their salts, with excellent corneal epithelial
migration promoting effects.
Inventors: |
Nakata; Katsuhiko;
(Sakurai-shi, JP) ; Nakamura; Masatsugu;
(Nara-shi, JP) ; Fujihara; Tsutomu; (Osaka,
JP) ; Fujita; Hiromi; (Osaka, JP) |
Correspondence
Address: |
HOWERY LLP
C/O IP DOCKETING DEPARTMENT
2941 FAIRVIEW PARK DRIVE SUITE 200
FALLS CHURCH
VA
22042
US
|
Family ID: |
18664160 |
Appl. No.: |
11/222167 |
Filed: |
September 7, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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10297233 |
May 20, 2003 |
|
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PCT/JP01/04520 |
May 30, 2001 |
|
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11222167 |
Sep 7, 2005 |
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Current U.S.
Class: |
514/45 ; 514/47;
514/50 |
Current CPC
Class: |
A61K 31/7084 20130101;
A61K 31/00 20130101; Y10S 514/912 20130101; A61K 31/7076 20130101;
A61K 31/7072 20130101; A61P 27/02 20180101 |
Class at
Publication: |
514/045 ;
514/047; 514/050 |
International
Class: |
A61K 31/7076 20060101
A61K031/7076; A61K 31/7072 20060101 A61K031/7072 |
Foreign Application Data
Date |
Code |
Application Number |
May 30, 2000 |
JP |
2000-159889 |
Claims
1. A method of promoting epithelial migration in the cornea or
conjunctiva, said method comprising: administering to the eye of a
subject an epithelial migration promoter formulation comprising a
P2Y receptor agonist in an amount effective to promote epithelial
migration in the cornea or conjunctiva, wherein said P2Y receptor
agonist is a compound of formula I or its pharmacologically
tolerated salts: ##STR5## wherein n is an integer of 1-4; X is
hydrogen, and R.sub.1 is a uracil group, thymine group, adenine
group, hypoxanthine group, or guanine group.
2. The method according to claim 1, wherein said promoting
epithelial migration is to repair epithelial defects.
3. The method according to claim 1, wherein said promoting
epithelial migration to repair epithelial defects is such that the
epithelium extends to cover a damaged portion of the cornea or
conjunctiva.
4. The method according to claim 3, wherein said damaged portion of
the cornea or conjunctiva results from corneal disease.
5. The method according to claim 4, wherein said corneal disease is
selected from the group consisting of corneal ulcers, exfoliation
of corneal epithelium, and keratitis.
6. The method according to claim 1, wherein said epithelial
migration promoter formulation contains an effective amount of said
P2Y receptor agonist or its pharmacologically tolerated salt
together with a pharmacologically tolerated additive.
7. The method according to claim 16, wherein said uracil group,
thymine group, adenine group, hypoxanthine group, or guanine group
is a substituted uracil, thymine, adenine, hypoxanthine, or guanine
group.
8. The method according to claim 7, wherein said substituted
uracil, thymine, adenine, hypoxanthine, or guanine group is
substituted with a group selected from the group consisting of:
halogens, C.sub.1-6 straight-chain or branched lower alkyl groups,
C.sub.1-6 straight-chain or branched lower alkoxy groups, aryl
groups, aryloxy groups, aralkyl groups, hydroxyl group, amino
groups, and protecting groups.
9. The method according to claim 8, wherein said protecting groups
are selected from the groups consisting of C.sub.2-6 lower alkanoyl
groups and arylcarbonyl groups.
10. The method according to claim 1, wherein said pharmacologically
tolerated salts are selected from the group consisting of alkali
metal salts, alkaline earth metal salts, ammonia salts, organic
amine salts, hydrochloric acid salts, sulfuric acid salts,
phosphoric acid salts, lactic acid salts, maleic acid salts,
fumaric acid salts, oxalic acid salts, methanesulfonic acid salts,
and para-toluenesulfonic acid salts.
11. The method according to claim 10, wherein said
pharmacologically tolerated salts are selected from the group
consisting of sodium, potassium, calcium, ammonia, diethylamine,
triethanolamine, hydrochloric acid, sulfuric acid, phosphoric acid,
lactic acid, maleic acid, fumaric acid, oxalic acid,
methanesulfonic acid, and para-toluenesulfonic acid salts.
12. The method according to claim 1, wherein said amount of the P2Y
receptor agonist effective to promote epithelial migration in the
cornea or conjunctiva is in the range of 0.0001% to 15%.
13. The method according to claim 1, wherein said epithelial
migration promoter formulation is in the form selected from the
group consisting of eye drops and eye ointments.
14. The method according to claim 1, wherein said formulation
comprises at least one additive selected from the group consisting
of isotonic agents, buffers, stabilizers, preservatives, pH
adjustors, and base agents.
15. The method according to claim 14, wherein said additive is
selected from the group consisting of: sodium chloride, potassium
chloride, sodium phosphate, sodium hydrogen phosphate, sodium
dihydrogen phosphate, sodium edetate, benzalconium chloride, sorbic
acid, sodium hydroxide, dilute hydrochloric acid, white Vaseline,
and fluidic paraffin.
16. The method according to claim 1, wherein said P2Y receptor
agonist uridine 5'-diphosphoric acid, adenosine 5'-diphosphoric
acid, uridine 5'-triphosphoric acid, adenosine 5'-triphosphoric
acid, or the salts thereof.
Description
[0001] This application is a continuation of U.S. application Ser.
No. 10/297,233, filed May 20, 2003, which is National Stage of
International Application PCT/JP01/04520, filed May 30, 2001; which
claims the priority of JP 2000-159889, filed May 30, 2000. The
contents of the above applications are incorporated herein by
reference in their entirety.
TECHNICAL FIELD
[0002] The present invention pertains to a type of corneal
epithelial migration promoter that contains P2Y receptor agonist as
the effective component.
BACKGROUND
[0003] The cornea is transparent tissue with no blood vessels, a
diameter of about 1 cm and a thickness of about 1 mm. The
transparency of a cornea has an important influence on visual
function. Various physiological and biochemical phenomena of the
cornea mainly function to maintain this transparency.
[0004] Corneal epithelial defects caused by corneal ulcers,
exfoliation of corneal epithelium, keratitis, dry eyes, and various
other diseases can be repaired naturally if no mixed infection
occurs. However, if repair is delayed or not made for certain
reasons, corneal epithelial migration takes place, such that the
normal epithelium construction is adversely affected, and the
structure and function of the parenchyma and endothelium are also
harmed. In prior art, the principal therapy was the so-called
passive method, in which the surface of the cornea is protected
from external stimulation so that the epithelium again extends
naturally to cover the damaged portion. In recent years, with
developments in cell biology, factors pertaining to split,
movement, fusion, migration, etc., have been clarified, and it has
been reported that compounds that can promote corneal epithelial
migration play an important role (Ringan, 46, 738-743 (1992); Ganka
Shujutsu, 5, 719-727 (1992)).
[0005] On the other hand, many authors have reported research on
P2Y receptor agonists which are the effective component in the
present invention. For example, U.S. Pat. No. 5,292,498 described
use of uridine 5'-triphosphate (UTP), adenosine triphosphate (ATP),
etc., in maintaining secretion of mucus as a characteristic feature
in treating lung diseases. WO 97/29756 stated that UTP or other
phosphoric acid nucleoside P2Y receptor agonists are effective in
treating tympanitis. WO 98/34593 stated that UTP or other P2Y
receptor agonists have a tear secreting function, and can be used
in treating dry eyes and diseases of the nasolacrimal duct.
However, no research yet exists on the corneal epithelial migration
effect of P2Y receptor agonists.
[0006] Discovery of new applications of said P2Y receptor agonists
is of great interest. Also, in ophthalmology, searching for
compounds that can display a corneal epithelial migration promoting
effect is a very important topic.
DISCLOSURE OF THE INVENTION
[0007] The present inventors have searched for various compounds
and performed tests on their pharmacological functions, and have
found that P2Y receptor agonists have a corneal epithelial
migration promoting effect. As a result, the present invention was
reached.
[0008] The present invention provides a type of corneal epithelial
migration promoter which contains as its effective component a P2Y
receptor agonist; that is, a compound represented by following
formula [I] (hereinafter referred to as "these compounds" if not
specified otherwise).
[0009] The present invention also provides a corneal epithelial
migration promoting method characterized by the fact that the
patient is administered a composition containing an effective
amount of a P2Y receptor agonist or a pharmacologically tolerated
salt of it together with pharmacologically tolerated additives.
[0010] The present invention also pertains to the use of P2Y
receptor agonists for manufacturing a corneal epithelial migration
promoter. ##STR1## where, n represents an integer of 1-4; X
represents a hydrogen atom or the following group represented by
formula [II]: ##STR2## where R.sub.1 and R.sub.2, which may be
identical or different from each other, represent a uracil group,
thymine group, adenine group, hypoxanthine group, or guanine
group).
[0011] In these compounds, the uracil group, thymine group, adenine
group, hypoxanthine group, and guanine group are optionally
substituted with the following groups: a halogen atom such as
fluorine, chlorine, and bromine, methyl group, ethyl group, propyl
group, hexyl group, and C.sub.1-6 straight-chain or branched lower
alkyl groups, methoxy group, ethoxy group, propyloxy group,
hexyloxy group, and other C.sub.1-6 straight-chain or branched
lower alkoxy groups, phenyl group, tolyl group, and other aryl
groups, phenoxy group, and other aryloxy groups, benzyl group,
phenethyl group, and other aralkyl groups, hydroxyl group, etc.
Also, amino groups in the adenine group or guanidine group may be
protected with generally used protecting groups. Examples of
protecting groups include an acetyl group, pivaloyl group, and
other C.sub.2-6 lower alkanoyl groups, a benzoyl group, and other
arylcarbonyl groups. Examples of preferable groups of R.sub.1 and
R.sub.2 include the adenine group and uracil group.
[0012] There is no special limitation on the salts of these
compounds, as long as they are tolerated pharmaceutically. Examples
of salts that may be used include salts of sodium, potassium,
calcium, and other alkali metals or alkaline earth metals; salts of
ammonia or diethylamine, triethanolamine, and other organic amines;
salts of hydrochloric acid, sulfuric acid, phosphoric acid, and
other inorganic acids; salts of lactic acid, maleic acid, fumaric
acid, oxalic acid, methanesulfonic acid, para-toluenesulfonic acid,
and other organic acids; etc.
[0013] Among these compounds, there are optical isomers and
diastereo isomers. These isomers are also included in the present
invention. Also, these compounds may be in the form of a hydrate or
other solvates.
[0014] Examples of compounds having particularly excellent effects
include uracil 5'-diphosphoric acid, adenosine 5'-diphosphoric
acid, uridine 5'-triphosphoric acid, adenosine 5'-triphosphoric
acid, and P.sup.1, P.sup.4-di(uridine-5')tetraphosphoric acid
represented by formula [III], or their salts. ##STR3##
[0015] Among these compounds, the sodium salt represented by
formula [IV] in particular, displays an excellent corneal
epithelial migration promoting effect. ##STR4##
[0016] As pointed out in the prior art section, repair of a cornea
that was damaged for various reasons is closely related to corneal
epithelial migration. As proved in the pharmacological tests to be
described later, P2Y receptor agonists of the present invention
display excellent corneal epithelial migration promoting effects.
Consequently, they may be used in treating various corneal
diseases. Examples of corneal diseases include corneal ulcers,
exfoliation of corneal epithelium, keratitis, etc. Also, since no
substantial difference has been observed between corneas and
conjunctiva, P2Y receptor agonists can display repair effects not
only for corneas, but also for diseases of conjunctiva. In summary,
P2Y receptor agonists are useful in treating diseases of corneas
and conjunctiva.
[0017] Among the several sub-types of P2Y receptors, P2Y.sub.2
receptors are particularly good. Typical compounds of P2Y.sub.2
receptor agonists are disclosed in U.S. Pat. No. 5,292,498, WO
97/29756, etc.
[0018] There is no special limitation on the method of
administration of a P2Y receptor agonist in the present invention.
However, it is preferred that a P2Y receptor agonist be
administered by local administration; in particular, as eye
drops.
[0019] The concentration of P2Y receptor agonist in eye drops is
selected corresponding to symptoms, age, etc., and there is no
special limitation on it. Usually, however, the concentration
should be in the range of 0.0001%-15%, or preferably in the range
of 0.01%-10%. The dose of eye drops is in the range of one
drop--several drops for each round of administration, and
one--several rounds a day. In addition to conventional eye drops,
the form of preparation of the eye drops may also be such that the
agonist is dissolved just before use. Also, the form of preparation
may be an eye ointment.
[0020] When the formulation is prepared it is possible to add
various additives, as needed, such as sodium chloride, potassium
chloride, or other isotonic agents, sodium phosphate, sodium
hydrogen phosphate, sodium dihydrogen phosphate, or other buffers,
sodium edetate or other stabilizers, benzalconium chloride, sorbic
acid, or other preservatives, sodium hydroxide, dilute hydrochloric
acid, or other pH adjustors, white Vaseline, fluidic paraffin, or
other base agents for eye ointments. The formulation is prepared
using a conventional method.
[0021] In the following, the present invention will be explained in
detail with reference to application examples. However, these
examples are only to help understand the present invention. They do
not limit the range of the present invention.
OPTIMUM EMBODIMENT OF THE PRESENT INVENTION
Pharmacological Tests
[0022] Using cornea specimen s collected from male Japanese white
rabbits, the corneal epithelial migration length was used as an
index in studying the cornea tissue culturing system according to
the method of Nishida, et al. (J. Cell Biol., 97, 1653-1657
(1983)).
Experimental method
[0023] Cornea blocks (6 specimens for each group) cut from rabbit
cornea pieces were cultured in a culture solution (TCM-199)
containing an invention compound at 37.5.degree. C. and 5% CO.sub.2
for 24 h. After culturing, the cornea blocks were fixed in an
ethanol/glacial acetic acid (95:5 by volume) mixture solution,
followed by embedding with paraffin to form slices. After removal
of the paraffin, the slices were subjected to hematoxylin-eosin
staining, and the length of migration of the corneal epithelial
layer was observed using a microscope. As a control, culturing was
also performed using a culture solution not containing an invention
compound.
Results
[0024] Table 1 lists the results of corneal epithelial migration
rates under action of the following compounds, with a control set
at 100%: P.sup.1, P.sup.4-di(uridine-5')tetraphosphate tetrasodium
[DUTP--Na], uridine 5'-diphosphate di-sodium [UDP--Na], adenosine
5'-diphosphate disodium [ADP--Na], uridine 5'-triphosphate
trisodium [UTP--Na], and adenosine 5'-triphosphate trisodium
[ATP--Na]. TABLE-US-00001 TABLE 1 Compound (Concentration) Corneal
Epithelial Migration Rate (%) DUTP-Na (100 .mu.M) 118.9 UDP-Na (100
.mu.M) 115.3 ADP-Na (10 .mu.M) 116.1 UTP-Na (100 .mu.M) 123.1
ATP-Na (10 .mu.M) 119.3 Control 100.0
Example Formulations
[0025] Typical formulations were prepared using P.sup.1,
P.sup.4-di(uridine-5')tetraphosphate tetra-sodium [DUTP--Na],
uridine 5'-triphosphate tri-sodium [UTP--Na], and uridine
5'-diphosphate di-sodium [UDP--Na]. Eye drops were prepared
according to the following examples.
EXAMPLE 1
[0026] In 100 ml:
[0027] DUTP--Na: 10 mg Sodium chloride: 900 mg Sterilized purified
water: appropriate amount [0028] By changing the amount of P.sup.1,
P.sup.4-di(uridine-5')tetraphosphate tetra-sodium [DUTP--Na], eye
drop concentrations of 0.03% (w/v), 0.1% (w/v), 0.3% (w/v), 1.0%
(w/v), and 3.0% (w/v), were obtained.
EXAMPLE 2
[0029] In 100 ml:
[0030] UTP--Na: 100 mg
[0031] Sodium chloride: 800 mg
[0032] Disodium hydrogen phosphate: 100 mg
[0033] Sodium dihydrogen phosphate: appropriate amount
[0034] Sterilized refined water: appropriate amount
[0035] By changing the amount of uridine-5' triphosphate tri-sodium
[UTP--Na], eye drop concentrations of 0.3% (w/v), 0.5% (w/v), 1.5%
(w/v), and 3.0% (w/v), were obtained.
EXAMPLE 3
[0036] In 100 g:
[0037] DUTP--Na: 0.3 g [0038] Fluidic paraffin: 10.0 g [0039] White
Vaseline: appropriate amount [0040] By changing the amount of
P.sup.1, P.sup.4-di(uridine-5')tetraphosphate tetra-sodium
[DUTP--Na], eye ointment concentrations of 1% (w/v) and 3% (w/v)
were obtained.
EXAMPLE 4
[0041] In 100 g:
[0042] UDP--Na: 0.3 g
[0043] Fluidic paraffin: 10.0 g
[0044] White Vaseline: appropriate amount
[0045] By changing the amount of uridine-5 '-diphosphoric acid
disodium [UDP--Na], eye ointment concentrations of 1% (w/v) and 5%
(w/v) were obtained.
[0046] As can be seen in Table 1, in the present invention,
P.sup.1, P.sup.4-di(uridine-5') tetraphosphate tetrasodium
[DUTP--Na], uridine 5'-diphosphate disodium [UDP--Na], adenosine
5'-diphosphate disodium [ADP--Na], uridine 5'-triphosphate
trisodium [UTP--Na], and adenosine 5'-triphosphate acid trisodium
[ATP--Na] all can display significant corneal epithelial migration
promoting effects. From such results of pharmacological tests, it
is found that formulations containing P2Y receptor agonists in the
present invention as the effective component can display an
excellent corneal epithelial migration promoting effect, and can be
used in treating diseases of corneas and conjunctiva.
INDUSTRIAL APPLICATION FIELD
[0047] P2Y receptor agonists can display an excellent corneal
epithelial migration promoting effect, and can be used in treating
diseases of corneas and conjunctiva.
* * * * *