Note: Descriptions are shown in the official language in which they were submitted.
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DESCRIPTION
METHOD AND COMPOSITION FOR TREATMENT OF
OCULAR HYPERTENSION AND GLAUCOMA
TECHNICAL FIELD
The present invention relates to a method for treating
ocular hypertension and glaucoma, which causes reduced or
substantially no ocular irritation such as conjunctival
hyperemia. The present invention also provides a composition
useful for treatment of the present invention.
BACKGROUND ART
Prostaglandins (hereinafter referred to as PG(s)) are
the members of class of organic carboxylic acids that are
contained in the tissues or organs of humans or other mammals
and exhibit a wide range of physiological activity. PGs found
in nature (primary PGs) generally have a prostanoic acid
skeleton as shown in the formula (A):
( cx chain)
,' 7 5 3 1 C~~H
10 8 6 4 2
.12 14 16 18 2~ CH
3
11
13 15 17 19
( w chain)
On the other hand, some of synthetic analogues of primary
PGs have modified skeletons. The primary PGs are classified
to PGAs, PGBs, PGCs, PGDs, PGEs, PGFs, PGGs, PGHs, PGIs and PGJs
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according to the structure of the five-membered ring moiety,
and further classified into the following three types by the
number and position of the unsaturated bond at the carbon chain
moiety:
Subscript ~.: 13,14-unsaturated-15-OH
Subscript 2: 5,6- and 13,14-diunsaturated-15-OH
Subscript 3: 5,6-, 13,14-, and 17,18-triunsaturated-15-OH.
Further, the PGFs are classified, according to the
configuration of the hydroxyl group at the 9-position, into ex
type (the hydroxyl group is of an a-configuration) and (3 type
(the hydroxyl group is of a ~3-configuration).
PGE1, PGE2 and PGE3 are known to have vasodilation,
hypotension, gastric secretion decreasing, intestinal tract
movement enhancement, uterine contraction, diuretic,
bronchodilation and anti ulcer activities . PGF1«, PGFz« and PGF3«
have been known to have hypertension, vasoconstriction,
intestinal tract movement enhancement, uterine contraction,
lutein body atrophy and bronchoconstriction activities.
Some 15-keto ( i . a . , having oxo at the Z 5-position instead
of hydroxy) -PGs and 13, 14-dihydro-15-keto-PGs are known as the
substances naturally produced by the action of enzymes during
the metabolism of primary PGs. It is also known that some
15-keto-PG compounds have intraocular pressure reducing
effects and are effective for the treatment of ocular
hypertension and glaucoma (U. S. Patent Nos. 5,001,153,
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5,151,444, 5,166,178 and 5,212,200, all of which are
incorporated herein by reference).
Meanwhile, "Xalatan~" that has been launched as an eye
drops for ocular hypertension and glaucoma contains, as an
active ingredient thereof, latanoprost, i.e., 13,14
dihydro-17-phenyl-18,19,20-trinor-PGFZ a isopropyl ester,
which is a prostaglandin derivative having a ring structure at
the end of the w chain and having hydroxy at the 15-position.
The clinical concentration of latanoprost in the "Xalatan~" eye
drops is 0.005% and, estimating from about 30-35u1 of one drop
volume of "Xalatan~" eye drops, the clinical dose of latanoprost
is about 1.5~g-1.75~g per eye per administration. Problematic
side effects of this eye drops in clinically applied dose,
including iris pigmentation, ocular irritation such as
conjunctival hyperemia and chemosis of conjunctiva have been
reported (American Journal of Ophthalmology 2001;131:631-
635, Survey of Ophthalmology 1997; 41:5105-5110, the cited
references are herein incorporated by reference).
It is known that a 15-keto-prostaglandin compound having
a ring structure at the end of the ~ chain has intraocular
pressure reducing effects. U.S. Patent No. 5,321,128
describes that administration of 13,14-dihydro-15-keto- 17-
phenyl-18, 19, 20-trinor-PGFza isopropyl ester to healthy human
eyes and monkey eyes in a dose of 5ug and 3ug, respectively,
showed intraocular pressure reducing effects, and showed no
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side effect such as conjunctival hyperemia, ocular irritation
and foreign body sensation in the human. There is another
document reporting that administration of 13,14-dihydro-15-
keto-17-phenyl-18,19,20-trinor-PGFza isopropyl ester to
monkey eyes (50ug per eye) showed intraocular pressure reducing
effects (Clinical Report Vol. 28, No. 11, pages 3505-3509,
1994).
However, in the treatment of ocular hypertension and
glaucoma, nobody has known the extent of ocular irritation such
as conjunctival hyperemia shown in the administration of a
15-keto-prostaglandin compound having a ring structure at the
end of the e~ chain to mammal eyes in a high dose.
DISCLOSURE OF THE INVENTION
The present inventor has conducted intensive studies on
the biological activity of a 15-keto-prostaglandin compound
having a ring structure at the end of the e~ chain, and found
that administration of said compound topically to mammal eyes
effectively lowered the intraocular pressure while causes
substantially no or reduced ocular irritation such as
conjunctival hyperemia, even in a high dose.
Namely, the present invention relates to a method for
treatment of ocular hypertension and glaucoma, which comprises
administrating a 15-keto-prostaglandin compound having a ring
structure at the end of the c~ chain topically to the eyes of
a mammalian subject in need of such treatment more than 5ug and
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less than 50~g per eye per administration. According to the
present invention, intro ocular pressure of the subject is
effectively lowered while substantially no or reduced ocular
irritation, such as conjunctival hyperemia, is observed despite
5 of the high dose.
The present invention further relates to an ophthalmic
composition for treating ocular hypertension and glaucoma of
a mammalian subject, which comprises a 15-keto-prostaglandin
compound having a ring structure at the end of the cu chain in
an amount to provide a dose of more than 5~ag and less than 50ug
per eye per administration.
The present invention further relates to use of a
15-keto-prostaglandin compound having a ring structure at the
end of the ~ chain for manufacturing an ophthalmic composition
for treating ocular hypertension and glaucoma of a mammalian
subject, wherein said composition comprises the 15-keto-
prostaglandin compound in an amount to provide a dose of more
than 5~g and less than 50ug per eye per administration.
In the present invention, the "15-keto-prostaglandin
compound" (hereinafter, referred to as "15-keto-PG compound")
may include any of derivatives or analogs (including
substituted derivatives) of a compound having an oxo group at
15-position of the prostanoic acid skeleton instead of the
hydroxy group, irrespective of the configuration of the
five-membered ring, the number of double bonds, presence or
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absence of a substituent, or any other modification in the a
or c~ chain .
The nomenclature of the 15-keto-PG compounds used herein
is based on the numbering system of the prostanoic acid
represented in the above formula (A).
A preferred compound used in the present invention is
represented by the formula (I):
L
W~ R~ A
1 o N.,,,"~W~ ( I )
W3 B- C- Ra
~~
0
[wherein W~, W? and W3 are carbon atom or oxygen atom,
Z, M and N are hydrogen, hydroxy, halogen, lower alkyl,
hydroxy(lower)alkyl or oxo (wherein at least one of L and M is
a group other than hydrogen, and the five-membered ring may have
at least one double bond);
A is -CH~OH, -COCHZOH, -CObH or a functional derivative
thereof;
B is -CHI-CHz-, -CH=CH- or -C---C-;
Rl is a saturated or unsaturated bivalent .lower or medium
aliphatic hydrocarbon residue, which is unsubstituted or
substituted by halogen, alkyl, hydroxy, oxo, aryl or
heterocyclic groups and
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Ra is a saturated or unsaturated lower or medium aliphatic
hydrocarbon residue, which is substituted at the end by
cyclo(lower)alkyl, cyclo(lower)alkyloxy, aryl, aryloxy,
heterocyclic group or hetrocyclic-oxy group.]
A group of particularly preferable compounds among the
above-described compounds are represented by the formula
(II)
L
~ X~ (II)
M B- i -C-R2 . R3
O
[wherein L and M are hydrogen, hydroxy, halogen, lower
alkyl, hydroxy(lower)alkyl or oxo (wherein.at least one of L
and M is a group other than hydrogen, and the five-membered ring
may have at least one double bond);
A is -CH20H, -COCHZOH, -COOH or a functional derivative
thereof;
B is -CHZ-CH~-, -CH=CH-, -C=C-;
X1 and Xz are hydrogen, lower alkyl, or halogen;
R1 is a saturated or unsaturated bivalent lower or medium
aliphatic hydrocarbon residue, which is unsubstituted or
substituted with halogen, alkyl, hydroxy, oxo, aryl or
heterocyclic group;
~5 Rz is a single bond or lower alkylene; and
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R3 is cyclo(lower)alkyl, cyclo(lower)alkyloxy, aryl,
aryloxy, heterocyclic group or heterocyclic-oxy group.]
In the above formula, the term "unsaturated" in the
definitions for Rland Ra is intended to include at least one
or more double bonds and/or triple bonds that are isolatedly,
separately or serially present between carbon atoms of the main
and/or side chains. According.to the usual nomenclature, an
unsaturated bond between two serial positions is represented
by denoting the lower number of the two positions, and an
unsaturated bond between two distal positions is represented
by denoting both of the positions.
The term "lower or medium aliphatic hydrocarbon" refers
to a straight or branched chain hydrocarbon group having 1 to
14 carbon atoms (for a side chain, 1 to 3 carbon atoms are
preferable) and preferably 1 to 10, especially 6 to 10 carbon
atoms for R1 and 1 to 10, especially 1 to 8 carbon atoms for
Ra.
The term "halogen atom" covers fluorine, chlorine,
bromine and iodine.
The term "lower" throughout the specification is
intended to include a group having 1 to 6 carbon atoms unless
otherwise specified.
The term "lower alkyl" refers to a straight or branched
chain saturated hydrocarbon group containing 1 to 6 carbon atoms
and includes, for example, methyl, ethyl, propyl, isopropyl,
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butyl, isobutyl, t-butyl, pentyl and hexyl.
The term "lower alkoxy" refers to a group of lower
alkyl-O-, wherein lower alkyl is as defined above.
The term "hydroxy (lower) alkyl" refers to a lower alkyl
as defined above which is substituted with at least one hydroxy
group such as hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl
and 1-methyl-1-hydroxyethyl.
The term "lower alkanoyloxy" refers to a group
represented by the formula RCO-0-, wherein RCO- is an acyl group
formed by oxidation of a lower alkyl group as defined above,
such as acetyl.
The term "cyclo(lower)alkyl" refers to a cyclic group
formed by cyclization of a lower alkyl group as defined above
but contains three or more carbon atoms, and includes, for
25 example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
The term "cyclo (lower) alkyloxy" refers to the group of
cyclo (lower) alkyl-O-, wherein cyclo (lower) alkyl is as defined
alcove .
The term "aryl" may include unsubstituted or substituted
aromatic hydrocarbon rings (preferably monocyclic groups), for
example, phenyl, tolyl, xylyl. Examples of the substituent
include halogen atom and halo substituted (lower) alkyl, wherein
halogen atom and lower alkyl are as defined above.
The term "aryloxy" refers to a group represented by the
formula Ar0-, wherein Ar is aryl as defined above.
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The term "heterocyclic group" may include mono- to
tri-cyclic, preferably monocyclic heterocyclic group which is
5 to 14, preferably 5 to 10 membered ring having optionally
substituted carbon atoms) and 1 to 4, preferably 1 to 3 of
5 1 or 2 type of hetero atoms selected from nitrogen atom, oxygen
atom and sulfer atom. Examples of the heterocyclic group include
furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl,
isothiazolyl, imidazolyl, pyrazolyl, furazanyl, pyranyl,
pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, 2-pyrrolinyl,
10 pyrrolidinyl, 2-imidazolinyl, imidazolidinyl, 2-pyrazolinyl,
pyrazolidinyl, piperidino, piperazinyl, morpholino, indolyl,
benzothienyl, quinolyl; isoquinolyl, purinyl, quinazolinyl,
carbazolyl, acridinyl, phenanthridinyl, benzimidazolyl,
benzimidazolinyl, benzothiazolyl, phenothiazinyl. Examples of
the substituent in this case include halogen, and halogen
substituted lower alkyl group, wherein halogen atom and lower
alkyl group are as described above.
The term "heterocyclic-oxy group" means a group
represented by the formula Hc0-, wherein He is a ,heterocyclic
group as described above.
The term "functional derivative" of A includes salts
(preferably pharmaceutically acceptable salts), ethers,
esters and amides.
Suitable "pharmaceutically acceptable salts" include
conventionally used non-toxic salts, for example a salt with
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an inorganic base such as an alkali metal salt ( such as sodium
salt and potassium salt), an alkaline earth metal salt (such
as calcium salt and magnesium salt ) , an ammonium salt; or a salt
with an organic base, for example, an amine salt (such as
methylamine salt, dimethylamine salt, cyclohexylamine salt,
benzylamine salt, piperidine salt, ethylenediamine salt,
ethanolamine salt, diethanolamine salt, triethanolamine salt,
tris(hydroxymethylamino)ethane salt, monomethyl-
monoethanolamine salt, lysine salt, procaine salt and caffeine
salt) , a basic amino acid salt (such as arginine salt and lysine
salt), tetraalkyl ammonium salt and the like. These salts may
be prepared by a conventional process, for example from the
corresponding acid and base or by salt interchange.
Examples of the ethers include alkyl ethers, for example,
lower alkyl ethers such as methyl ether, ethyl ether, propyl
ether, isopropyl ether, butyl ether, isobutyl ether, t-butyl
ether, pentyl ether and 1-cyclopropyl ethyl ethers and medium
or higher alkyl ethers such as octyl ether, diethylhexyl ether,
lauryl ether and cetyl ether; unsaturated ethers such as oleyl
ether and linolenyl ether; lower alkenyl ethers such as vinyl
ether, allyl ethers lower alkynyl ethers such as ethynyl ether
and propynyl ether; hydroxy (lower) alKy1 ~~i1~1~ ~u~:u a~
hydroxyethyl ether and hydroxyisopropyl ether; lower alkoxy
(lower)alkyl ethers such as methoxymethyl ether and 1-
methoxyethyl ether; optionally substituted aryl ethers such
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as phenyl ether, tosyl ether, t-butylphenyl ether, salicyl
ether, 3,4-di-methoxyphenyl ether and benzamidophenyl ether;
and aryl (lower) alkyl ethers such as benzyl ether, trityl ether
and benzhydryl ether.
Examples of the esters include aliphatic esters, for
example, lower alkyl esters such as methyl ester, ethyl ester,
propyl ester, isopropyl ester, butyl ester, isobutyl ester,
t-butyl ester, pentylester andl-cyclopropylethylester~ lower
alkenyl esters such as vinyl ester and allyl esters lower
alkynyl esters such as ethynyl ester and propynyl ester;
hydroxy(lower)alkyl ester such as hydroxyethyl esters lower
alkoxy (lower) alkyl esters such as methoxymethyl ester and
1-methoxyethyl ester; and optionally substituted aryl esters
such as, for example, phenyl ester, tolyl ester, t-butylphenyl
ester, salicyl ester, 3,4-di-methoxyphenyl ester and
benzamidophenyl ester; and aryl(lower)alkyl ester such as
benzyl ester, trityl ester and benzhydryl ester.
The amide of A means a group represented by the formula
-CONR' R", wherein each of R' and R" is hydrogen atom, lower alkyl,
aryl, alkyl- or aryl-sulfonyl, lower alkenyl and lower alkynyl,
and include for example lower alkyl amides such as methylamide,
ethylamide, dimethylamide and diethylamide; arylamides such as
anilide and toluidide~ and alkyl- or aryl-sulfonylamides such
as methylsulfonylamide, ethylsulfonyl-amide and
tolylsulfonylamide.
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Preferred examples of L and M include hydroxy which
provides a 5-membered ring structure of, so called, PGF type.
Preferred A is -C00H, its pharmaceutically acceptable
salt, ester or amide thereof.
Preferred B is -CHZ-CHI-, which provide the structure of
so-called, 13,14-dihydro type.
Preferred example of X1 and X2 is that at least one of -
them is halogen, more preferably, both of them are halogen,
especially, fluorine that provides a structure of, so called
16, 16-difluoro type.
Preferred R1 is a hydrocarbon containing 1-10 carbon
atoms, preferably, 6-10 carbon atoms.
Examples of R1 include, for example, the following
groups:
-CHZ-CHZ-CHZ-CHZ-CHz-CHI-,
-CHZ-CH=CH-CH~-CHz-CH~-,
-CH2-CHZ-CH2-CHZ-CH=CH-,
-CHz-C=C-CHI-CHZ-CH~-,
-CHI-CHI-CHZ-CHI-CH ( CH3 ) -CHZ-
2 0 -CHZ-CH2-CHz-CHz-CHz-CHZ-CHZ-CHZ-,
-CHI-CH=CH-CHI-CHZ-CHZ-CHI-CHI-,
-CHZ-CHI-CHI-CHZ-CHZ-CHI-CH=CH-,
-CHZ-C=C-CHZ-CHI-CHZ-CHI-CHz-,
-CHI-CHZ-CHZ-CHZ-CHz-CHI-CHI ( CH3 ) -CH~-
Preferred Ra~is a hydrocarbon containing 1-10 carbon
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atoms, more preferably, 1-8 carbon atoms which is substituted
by aryl or aryloxy at the end.
The configuration of the ring and the et- and/or c~ chains
in the above formula (I) and (II) may be the same as or different
from that of the primary PGs . However, the present invention
also includes a mixture of a compound having a primary type
configuration and a compound of a non-primary type
configuration.
The typical example of the compound used in the invention
is a 13,14-dihydro-15-keto-17-phenyl-18,19,20-trinor-
prostaglandin F compound and its derivative or analogue.
The 15-keto-PG compound of the present invention may be
in the keto-hemiacetal equilibrium by formation of a hemiacetal
between hydroxy at position 11 and oxo at position 15.
If such tautomeric isomers as above are present, the
proportion of both tautomeric isomers varies with the structure
of the rest of the molecule or the kind of the substituent present,.
Sometimes one isomer may predominantly be present in comparison
with the other. However, it is to be appreciated that the
15-keto-PG compounds used in the invention include both isomers.
Further, while the compounds used in the invention may be
represented by a structure formula or name based on keto-type
regardless of the presence or absence of the isomers, it is to
be noted that such structure or name does not intend to exclude
the hemiacetal type compound.
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In the present invention, any of isomers such as the
individual tautomeric isomers, the mixture thereof, or optical
isomers, the mixture thereof, a racemic mixture, and other
steric isomers may be used in the same purpose.
5 Some of the compounds used in the present invention may
be prepared by the method disclosed in USP Nos. 5,073,569,
5,166,174, 5,221,763, 5,212,324, 5,739,161 and 6,242,485
(these cited references are herein incorporated by reference) .
The term "treatment", "treat" or "treating" used herein
10 includes any means of control such as prevention, care, relief
of the condition, attenuation of the condition, arrest of
progression of the condition.
The term "a subject in need of such treatment" means a
subject who is suffering from a disease in which a reduction
l5 in his/her intraocular pressure is desirable, for example,
glaucoma and ocular hypertension, or a subject who is
susceptible to suffering from such disease as discussed above.
The subj ect may be any mammalian subj ect including human beings .
According to the present invention, the 15-keto-PG
compound described as above may be formulated as an ophthalmic
composition and applied topically to the eyes of a mammalian
subject. The ophthalmic composition of the present invention
may be any form for local eye administration used in the
ophthalmic field such as eye drops and eye ointment. The
ophthalmic composition may be prepared in a conventional manner
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known to the art. The eye drops may be prepared by dissolving
the active ingredients in a sterile aqueous solution such as
saline and buffering solution, or the eye drop composition may
be provided as a combined powder composition comprising the
active ingredient to be dissolved in the aqueous solution before
use.
Eye drops such as the ones as described in EP-A-0406791
are preferably used in the present invention (the cited
reference is herein incorporated by reference). If desired,
additives ordinarily used in conventional eye drops may be added.
Such additives may include isotonizing agents (e. g., sodium
chloride), buffering agent (e. g., boric acid, sodium
monohydrogen phosphate, sodium dihydrogen phosphate),
preservatives (e. g., benzalkonium chloride, benzethonium
chloride, chlorobutanol), thickeners (e.g., saccharide such as
lactose, mannitol, maltose; hyaluronic acid or its salt such
as sodium hyaluronate, potassium hyaluronate;
mucopolysaccharide such as chondroitin sulfate; sodium .
polyacrylate, carboxyvinyl polymer, crosslinked
polyacrylate.)
The eye drops may be formulated as a sterile unit dose
type eye drops containing no preservatives.
Eye ointment may also be prepared in a conventional
manner known to the art. For example, it may be prepared by
mixing the active ingredient into a base component
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conventionally used for known eye ointments under a sterile
condition. Examples of the base components for the eye ointment
include petrolatum, selen 50, Plastibase and macrogol, but not
limited thereto. Further, in order to increase the
hydrophilicity, a surface-active agent can be added to the
composition. The eye ointment may also contain the above-
mentioned additives such as the preservatives and the like, if
desired.
According to the present invention, more than 5ug and
less than 50ug per eye of the above-defined I5-keto-compound
is topically administered to the subject per administration.
The dose of the 15-keto-compound is preferably less than 30ug,
more preferably less than 20ug, further more preferably less
than l5ug and still further preferably less than l2ug per eye
per administration. The lower limit of the dose may be more
than 7~g or more than lO~Zg per eye per administration.
The dose of the above-defined 15-keto-compound may vary
within the range defined as above depending on the compound to
be used, the type of subj ect such as animals or human, age, weight,
symptom to be treated, desirable therapeutic effect, period for
treatment and the like.
According to the invention, the frequency of the
administration of the above-defined 15-keto-prostaglandin
compound may vary depending on the compound to be used, the type
of subject such as animals or human, age, weight, symptom to
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be treated, desirable therapeutic effect, period for treatment
and the like. The frequency of administration may be at least
once a day and preferably, one to six times, more preferably,
one to four times a day.
Since the 15-keto-prostaglandin compound used in the
invention causes substantially no or reduced ocular irritation
even in a high dose, the treatment of the instant invention may
be carried out for a long period of time.
The ophthalmic composition of the invention may contain
a single active ingredient or a combination of two or more active
ingredients. In a combination of plural active ingredients,
their respective contents may be suitably increased or
decreased in consideration of their therapeutic effects and
safety.
The concentration of the 15-keto-prostaglandin compound
in the ophthalmic composition of the present invention is
adjusted so that the amount of the compound to be administrated
is within the range of more than 5~g and less than 50ug,
preferably less than 30ug, more preferably less than 20~g,
further more preferably less than 15 ug and still further
preferably less than 12~g per eye per administration. The lower
limit of the amount may be more than lug or more than l0ug per
eye per administration.
Further, the ophthalmic composition of the present
invention may contain any other pharmaceutically active
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ingredients as far as they are not contrary to the obj acts of
the present invention.
Despite the high dose of the 15-keto-prostaglandin
compound, a safe and comfortable treatment of ocular
hypertension and glaucoma can be conducted for a long period
of time according to the present invention. Besides, the
present ophthalmic composition may be administered safely to
subjects with ocular hypertension and glaucoma having some
disorders on their cornea or conjunctiva such as allergic
disease and dry eye.
The present invention will be described in more detail
with reference to the following example, which is not intended
to limit the present invention.
EXAMPLE 1
The incidence rate of conjunctival hyperemia was
compared between the present compound 13,14-dihydro-15-keto-
17-phenyl-18,19,20-trinor-PGFZa isopropyl ester and 13,14-
dihydro-17-phenyl-18,19,30-trinor-PGFZa isopropyl ester.
1 ) Method
Either 13,14-dihydro-15-keto-17-phenyl-18,19,20-
trinor-PGFZa isopropyl ester or 13,14-dihydro-17-phenyl-
18,19,20-trinor-PGFZa isopropyl ester was ocularly
administered once to one eye of white rabbits (three cases each,
total of 12 cases) in a dose of 1.75ug or 50~g.
2) Evaluation Method
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The presence of conjunctival hyperemia was examined at
two hours after the administration and the ratio of cases
showing conj unctival hyperemia was evaluated by percent in each
group.
5 3) Results
Table 1 shows the results.
Table 1
Incidence Rate
of
Groups Conjunctival
Hyperemia
1.75ug eye drop 50~g eye drop
13,14-dihydro-15-keto-17-
phenyl-18,19,20-trinor- Oo 330
PGFZa isopropyl ester
13,14-dihydro-17-phenyl-
18,19,20-trinor-PGFZa 67% 1000
isopropyl ester
In the administration of 13,14-dihydro-17-phenyl-
10 18,19,20-trinor-PGFZa isopropyl ester, 670 of the subjects
receiving a clinical dose of 1.75pg and 1000 of the subjects
receiving 50~zg showed conjunctival hyperemia.
On the other hand, in the administration of the present
compound 13,14-dihydro-15-keto-17-phenyl-18,19,20-trinor-
15 PGFZa isopropyl ester, none of the subjects receiving the dose
of 1.75ug showed conjunctival hyperemia. Even in the
administration of a high dose of 50ug, the percent of the
subj ects showing conj unctival hyperemia was only about half the
percent of the subjects receiving 1.75~g of 13,14-dihydro-
20 17-phenyl-18,19,20-trinor-PGFza isopropyl ester.
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EXAMPLE 2
Method
13, 14-dihydro-15-keto-17-phenyl-18, 19, 20-trinor-PGFz« .
isopropyl ester at a dose of 30 ~.g was ocularly administered
to one eye of Dutch rabbits ( 4 male and 4 female, total 8 cases ) .
The administration was performed 4 times a day with 2-hour
intervals for 13 weeks. The cornea, conjunctiva and iris were
observed about occurrence of irritable response before, and 4,
8, and 13 weeks after the initiation of the administration. The
observation was performed within the time from 0.5 hour to 2
hours after the last administration of the day. The cornea was
observed about a presence of opacity and its area in the cornea.
The conjunctiva was observed about occurrence of hyperemia,
redness and swelling. The iris was observed about occurrence
of hyperemia, congestion, swelling and hemorrhage. The ratio
of cases showing irritable response in the cornea, conjunctiva
or iris was evaluated by percent in the group.
Results
As shown in Table 2, the ocular administration of
13,14-dihydro-15-keto-17-phenyl-18,19,20-trinor-PGF~a
isopropyl ester at a dose of 30 ~,g/eye each 4 times a day for
13 weeks had no effect on the cornea, conjunctiva and iris.
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Table 2
Incidence
rate
of
ocular
irritation
Time
after
the'
initiation
of
Test Compound Dose n
ocular
administration
4 8 13
Pre weeks weeks weeks
13,14-dihydro-15-
keto-17-phenyl- 30 ~g/eye
18, 19, 20-trinor-4 times/day 8 0 % 0 % 0 % 0
PGFZa isopropyl for 13 weeks
ester
These results demonstrate that the present compound causes
substantially no or reduced ocular irritation even in a high
dose.
EXAMPT~E 3
Method
13,14-dihydro-15-keto-17-phenyl-18,19,20-trinor-PGFZ«.
isopropyl ester at a dose of 12 ~g was ocularly administered
to one eye (test eye) of 6 healthy volunteers. The vehicle
solution was ocularly administered to the contralateral eye
(control eye). Intraocular pressure (IOP) was measured by
means of an applanation tonometer before, and 4, &, and 12 hours
after the administration. The TOP lowering effect of the test
compound was evaluated based on difference in IOP between test
eye and the control eye at each time point of TOP measurement .
Results
As shown in Table 3, the ocular administration of
13,14-dihydro-15-keto-17-phenyl-18,19,20-trinor-PGFZ«
isopropyl ester at a dose of 12 ~,g lowered the IOP by 1.0, 0.8
and 1.1 mmHg at 4, c~, and 12 hours after the administration
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23
respectively as compared with the control eye.
Table 3
I_ntraocular
pressure
lowerin
effect
Test compound dose n Time after
administration
(hours)
4 6 12
13.14-dihydro-15-keto-17-
phenyl-18,19,20-trinor-PGFZap~ ye 6 - 1.0 - 0.8 - 1.1
mmHg mmHg mmHg
iso ro 1 ester
EXAMPLE 4
Method
Nine male cynomolgus monkeys (body weights of animals
ranged between 3.2 and 5.4 kg) without abnormalities in the
anterior segment of the eye were used.
13,14-dihydro-15-keto-17-phenyl-18,19,20-trinor-PGFZa
isopropyl ester at a dose of 15 ~.g/eye was administered
topically to the right eyes of the animals at an administration
volume of 30 ~,L/eye. The left eye received an equal volume of
the vehicle.
Intraocular pressure (20P) measurements were conducted
by means of an applanation pneumatonometer (Model 30 ClassicTM,
Mentor O & 0, Inc. , USA) immediately before the administration
(0-hour), and at 2, 4, 8, 12, 24, 28, and 32 hours after the
administration.
Eye irritancy Haas scored according to the criteria
presented in Table 4 at the same time points as IOP measurements .
These criteria are based on those of Draize test.
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Table 4: Scale for Scoring Ocular Zesions
1. Cornea
A. Opacity-Degree of Density (area which is most
dense is taken for reading.)
No
opacity..,.....................................................................
...............................0
Scattered or diffuse area-details of iris clearly 1
visible.......................",.."",
Easily discernible translucent areas, details of 2
iris slightly obscured.............
Opalescent areas, no details of iris visible, size 3
of pupil barely discernible...
Opaque, iris
invisible......................................................................
.................'
4
B. Area of Cornea Involved
One quarter (or less) but not
zero............................................1
..
. 2
.....................
Greater than one quarter-Less than one-
half,..................,..,..".""""""""".",
Greater than one-half less than three
quarters............................,..,.""""""""3
Greater than three quarters up to whole area....................,..,..."""q
"""""""""
Score equals A ~C B X 5 Total maximum = 80
2. Iris
A. Values
Normal.........................................................................
............0
.
..
.....................
Folds above normal, congestion, swelling, circumcorneal
injection
(any one or all of these or combination of any
thereof)....,..,.....,.,."""""."""1
Hemorrhage; gross destruction (any one or both of 2
these)...................,..""""
Score equals A X S Total maximum = 80
3. Conjunctivae
A. Redness (refers to palpebral conjunctivae only)
Normal.........................................................................
...0
..
. 1
.......................... .
Vessels definitely injected above normal.................,.,....".."".
""".""."..,_.",.. 2
More diffuse, deeper crimson red, individual vessels
not easily discernible..
3 Diffuse beefy
red............................................................................
.................3
0
B. Chemosis
No
swelling.....................,.................................................
.....0
................ . 1
Any swelling above normal (includes nictitating
membrane)........,............""
Obvious swelling with partial eversion of the
lids................,..,......""""""""2
Swelling with lids about half closed................,...,.,.".,.,.....3
.
.. 4
...""."", "
Swelling with lids about half closed to completely
closed..........,..,...,..".""".
C. Discharge
4 No
discharge......................................................................
........0
0
......................
Any amount different from normal (does not include
small amount
observed in inner canthus of normal
animals)....................,..,.,....."",1
Discharge. with moistening of the lids and hairs 2
just adjacent to the lids........
Discharge with moistening of the lids and considerable3
area around the eye..
4 Score (A + B +C) ~C 2 Total maximum = 20
5
l he maximum total score is the sum of all scores obtained for the cornea,
iris and conjunctivae.
Results
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As shown in Table 5, topical administration of 13,14-
dihydro-15-keto-17-phenyl-18,19,20-trinor-PGF~« isopropyl
ester at a dose of 15 ~,g/eye produced a significant IOP
reduction.
5 As shown in Table 6, no signs or symptoms of ocular
irritation were observed after topical administration of
13,14-dihydro-15-keto-17-phenyl-18,19,20-trinor-PGFz«
isopropyl ester.
These results demonstrate that the compound used in the
10 invention shows I0P-lowering effect while causes substantially
no or reduced ocular irritation even in a high dose.
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26
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