U.S. patent application number 09/734692 was filed with the patent office on 2002-03-21 for treatment of ocular hypertension.
Invention is credited to Ueno, Ryuji.
Application Number | 20020035148 09/734692 |
Document ID | / |
Family ID | 27088716 |
Filed Date | 2002-03-21 |
United States Patent
Application |
20020035148 |
Kind Code |
A1 |
Ueno, Ryuji |
March 21, 2002 |
Treatment of ocular hypertension
Abstract
15-keto latanoprost and other 15-keto prostaglandin analogs are
used as ocularly applied intraocular pressure reducing agents.
Inventors: |
Ueno, Ryuji; (Potomac,
MD) |
Correspondence
Address: |
SUGHRUE, MION, ZINN,
MACPEAK & SEAS, PLLC
2100 PENNSYLVANIA AVENUE, N.W.
WASHINGTON
DC
20037-3213
US
|
Family ID: |
27088716 |
Appl. No.: |
09/734692 |
Filed: |
December 13, 2000 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
09734692 |
Dec 13, 2000 |
|
|
|
09620416 |
Jul 20, 2000 |
|
|
|
Current U.S.
Class: |
514/530 |
Current CPC
Class: |
A61P 27/06 20180101;
A61P 27/02 20180101; A61K 31/5575 20130101 |
Class at
Publication: |
514/530 |
International
Class: |
A61K 031/5575 |
Claims
We claim:
1. A method for reducing intraocular pressure which comprises
topically applying to a mammal as an ocular eye drop a compound
selected from the group consisting of 15-oxo-16-(3-trifluoromethyl
phenoxy)-17,18,19,20-tet- ranor PGF.sub.2.alpha. isopropyl ester,
13,14-dihydro-15-oxo-16-(3-trifluo- romethyl
phenoxy)-17,18,19,20-tetranor PGF.sub.2.alpha. isopropyl ester and
13,14-dihydro-15-oxo-17-phenyl-18,19,20-trinor PGF.sub.2.alpha.
isopropyl ester in a dose below the known dose for the
corresponding 15-OH compound.
2. The method of claim 1 wherein the compound administered is
13,14-dihydro-15-oxo-17-phenyl-18,19,20-trinor PGF.sub.2.alpha.
isopropyl ester.
3. The method of claim 1 wherein the dose is about 0.05 to 0.750
.mu.g per eye.
4. The method of claim 3 wherein the dose is about 0.075 to 0.250
.mu.g per eye.
5. The method of claim 4 wherein the dose is about 0-100 to below
0.175 .mu.g per eye.
6. A method for reducing intraocular pressure which comprising
topically applying to a mammal as an ocular eye drop a compound
selected from the group consisting of 15-oxo-16-(3-trifluoromethyl
phenoxy)-17,18,19,20-tet- ranor PGF.sub.2.alpha. isopropyl ester,
13,14-dihydro-15-oxo-16-(3-trifluo- romethyl
phenoxy)-17,18,19,20-tetranor PGF.sub.2.alpha. isopropyl ester and
13,14-dihydro-15-oxo-17-phenyl-18,19,20-trinor PGF.sub.2.alpha.
isopropyl ester in a dose of about 0.050 to below 5.0 .mu.g per
eye.
7. The method of claim 6 wherein the compound administered is
13,14-dihydro-15-oxo-17-phenyl-18,19,20-trinor PGF.sub.2.alpha.
isopropyl ester.
8. The method of claim 6 wherein the dose is about 0.10 to 4.5
.mu.g per eye.
9. The method of claim 8 wherein the dose is about 0.50 to 2.5
.mu.g per eye.
10. The method of claim 9 wherein the dose is about 1.0 to 2.0
.mu.g per eye.
11. The method of claim 1 or claim 6 wherein the compound is
applied one or two times a day.
12. The method of claim 1 or claim 6 wherein the dose is about
one-tenth the usual dose of the corresponding 15-OH compound.
13. The method of claim 2 or claim 7 wherein the dose is about
one-tenth the usual dose of latanoprost.
14. The method of claim 1 or claim 6 wherein the mammal is a
human.
15. The method for maintaining a reduced intraocular pressure by
periodic administration to a mammal as a topically applied ocular
eye drop, an effective amount of a compound selected from the group
consisting of 15-oxo-16-(3-trifluofomethyl
phenoxy)-17,18,19,20-tetranor PGF.sub.2.alpha. isopropyl ester,
13,14-dihydro-15-oxo-16-(3-trifluoromet- hyl
phenoxy)-17,18,19,20-tetranor PGF.sub.2.alpha. isopropyl ester and
13,14-dihydro-15-oxo-17-phenyl-18,19,20-trinor PGF.sub.2.alpha.
isopropyl ester.
16. A method of claim 15 wherein the compound administerd is
13,14-dihydro-15-oxo-17-phenyl-18,19,20-trinor PGF.sub.2.alpha.
isopropyl ester
17. The method of claim 15 wherein the dose is about 0.050 to 0.750
.mu.g per eye.
18. The method of claim 17 wherein the dose is about 0.075 to 0.250
.mu.g per eye.
19. The method of claim 18 wherein the dose is about 0.100 to 0.175
.mu.g per eye.
20. The method of claim 15 wherein the dose is about 0.050 to below
5.0 .mu.g per eye.
21. The method of claim 20 wherein the dose is about 0.10 to 4.50
.mu.g per eye.
22. The method of claim 21 wherein the dose is about 0.50 to 2.5
.mu.g per eye.
23. The method of claim 22 wherein the dose is about 1.0 to 2.0
.mu.g per eye.
24. The method of claim 15 wherein the compound is applied one or
two times a day.
25. The method of claim 15 wherein intraocular pressure is
initially reduced by application of a 15-OH compound.
26. The method of claim 25 wherein intraocular pressure is
initially reduced by application of latanoprost.
27. The method of claim 15 wherein the mammal is a human.
Description
[0001] This application is a Continuation-In-Part of U.S.
application Ser. No. 09/620,416, filed Jul. 20, 2000.
BACKGROUND OF THE INVENTION
[0002] The prior art describes the use of prostaglandin analogs
containing a ring structure in the omega chain for reducing
intraocular pressure. A representative patent in this area is U.S.
Pat. No. 5,321,128 to Stjernschantz. These compounds contain a
hydroxy group or keto group as a substituent at the 15-position.
Also, one subset of these compounds contains an unsubstituted
phenyl group substituted on carbon atom number 17 of the omega
chain and the absence of carbons 18-20. These types of structures,
where the conventional prostaglandin carbons 18-20 and their
equivalent are absent are named by Stjemschantz as 18, 19,20-trinor
prostaglandins.
[0003] One of the above-described type of compounds, latanoprost,
is now sold commercially as an IOP (intraocular pressure) reducing
eye drop. The clinical dosage is 1.5 .mu.g per dose as an eye drop.
This is the U.S. FDA approved dosage. The provided liquid
composition product can contain 0.005% latanoprost used at a dosage
of one drop, or about 30 .mu.l, providing 1.5 .mu.g per dose.
Latanoprost is named by Stjernschantz as 13,
14-dihydro-17-phenyl-18, 19,20-trinor-PGF.sub.2.alpha. isopropyl
ester.
[0004] Another compound of this family known to date is
13,14-dihydro-15-oxo-17-phenyl-18,19,20-trinor PGF.sub.2.alpha.
isopropyl ester, hereinafter referred to as 15-keto
latanoprost.
[0005] The above noted patent describes a wide potential dosage
range as therapeutically active. For example, see column 5, lines
33-66 of the '128 patent ("The composition contains about 0.1-30
.mu.g, especially 1-10 .mu.g, per application of the active
substance . . . ") Even so, the lowest dosage used in the '128
patent for any test compound for evaluating IOP reduction in humans
or monkeys is 1.0 .mu.g per eye. For 15-keto latanoprost in the
'128 patent, the tested dosage in healthy human volunteers is 5
.mu.g per eye and is 3 .mu.g in the monkey eye. Latanoprost is
tested in the '128 patent at a dosage of 1.0 .mu.g per eye in
healthy human volunteers and at a dosage of 10.4 .mu.g in the
monkey eye.
[0006] Latanoprost at its clinical concentration can cause
pigmentation of the iris, a mild IOP spike and/or mild
hyperemia.
SUMMARY OF THE INVENTION
[0007] It has been discovered that 15-keto latanoprost can be used
in an unusually low dosage for reduction of IOP. Another embodiment
of the present invention is the use of 15-keto latanoprost at a
dosage up to about the clinical dosage of latanoprost. 15-keto
latanoprost does not cause iridic pigmentation, an initial IOP
spike nor any hyperemia at the dosages described herein. Still
another embodiment of the present invention is the use of 15-keto
latanoprost for maintaining IOP reduction over an extended time
following an initial rapid IOP reduction bought about by another
IOP reducing agent, such as latanoprost.
[0008] The embodiments of the present invention involve treatment
of glaucoma where IOP reduction is needed and the lowering of IOP
for purposes other than treatment of glaucoma.
DESCRIPTION OF THE DRAWING
[0009] FIGS. 1 and 2 set forth the results of Example 1 comparing
the employment of a dose of 0.175 .mu.g latanoprost (FIG. 1) and
the same dose of 15-keto latanoprost (FIG. 2) in the monkey
eye.
[0010] FIG. 3 is a graph depicting a comparison of the results for
the active ingredients of Example 1 without the controls, as
depicted in FIGS. 1 and 2.
[0011] FIG. 4 depicts the results of Example 2 where an additional
instillation of a small amount of latanoprost or 15-keto
lantanoprost is administered 12 hours after instillation of a
clinical dose of latanoprost in the monkey eye.
DETAILED DESCRIPTION OF THE INVENTION
[0012] The present invention relates to the employment of varying,
including small, ocular dosages of 15-keto latanoprost, and related
15-keto compounds, as an IOP reducing agent, administered topically
to the eye in the treatment of glaucoma or ocular hypertension. The
active agent is administered as a topically applied ocular
composition, most usually in the form of a liquid eye drop.
[0013] The dose of 15-keto latanoprost is selected so that any side
effects caused by the ocular application of prostaglandin analogs,
including those which contain a ring such as latanoprost, are
substantially completely eliminated. The effective dose exemplified
herein can be as low as about one-tenth the clinical dose of
latanoprost.
[0014] The ophthalmic vehicle employed in the practice of the
present invention is that now know in the art for IOP reducing
agents, such as the a-fore-mentioned latanoprost and Rescula.RTM.,
the latter which has an extended omega chain providing a docosanoid
classification. Additional information on ophthalmic vehicles is
found in the patent noted in the background section of this patent
application. Although 15-keto latanoprost is an isopropyl ester, it
is contemplated that the free acid as well as pharmaceutically
acceptable salts, ethers and other esters are potentially useful in
the practice of the present invention, such as those described in
the above-noted patent.
[0015] As noted above, the clinical dose for latanoprost is about
1.5 .mu.g per eye. At one-tenth the clinical dose, latanoprost is
essentially inactive. Quite surprisingly, 15-keto latanoprost is an
effective IOP reducing agent when used at about one tenth the
clinical dose of latanoprost. It is contemplated in one embodiment
of the present invention that the dosage range for 15-keto
latanoprost as a topically applied ocular IOP reducing agent is
about 0.100 to 0.750 .mu.g/eye, preferably about 0.125 to 0.250
.mu.g/eye, more preferably about 0.150 to 0.175 .mu.g/eye. In
another embodiment of the present invention, the dosage range for
15-keto latanoprost as a topically applied ocular IOP reducing
agent is about 0.050 to below 5.0 .mu.g/eye, or about 0.10 to 4.5
.mu.g/eye, or about 0.50 to 2.5 .mu.g/eye, or about 1.0 to 2.0
.mu.g/eye.
EXAMPLE 1
[0016] This Example is an IOP test using the monkey eye in which
about one tenth the clinical dose of latanoprost is compared in IOP
reduction with the same dose of 15-keto latanoprost.
Summary
[0017] The intraocular pressure lowering effects of the 0.0005%
solution of
13,14-dihydro-15-keto-17-phenyl-18,19,20-trinor-PGF.sub.2.alpha.-isopr-
opyl ester (15-keto-latanoprost) and the 0.0005% solution of
13,14-dihydro-17-phenyl-18,19,20-trinor-PGF.sub.2.alpha.-isopropyl
ester (latanoprost) were compared following a single, topical
ocular instillation in monkeys.
[0018] No intraocular pressure lowering effect was noted following
the instillation of 0.0005% latanoprost. On the other hand, the
instillation of 0.0005% 15-keto-latanoprost lowered the intraocular
pressure by 2.4 mmHg 8 hours after the administration as compared
with the pre-treatment value. The reduction in the intraocular
pressure by the instillation of 15-keto-latanoprost was
statistically significant as compared with that by the instillation
of the vehicle (contralateral eye) or of 0.0005% latanoprost.
[0019] These results indicate that 15-keto-latanoprost exerts a
potent intraocular pressure lowering effect with a minute dose, and
suggest that
13,14-dihydro-15-keto-17-phenyl-18,19,20-trinor-PGF.sub.2.alpha.
(15-keto acid of latanoprost) itself produced as a metabolite from
latanoprost in the eyes participates in the reduction in the
intraocular pressure after the instillation of latanoprost.
Materials and Methods
[0020] 1. Test Substance
[0021]
13,14-dihydro-15-keto-17-phenyl-18,19,20-trinor-PGF.sub.2.alpha.-is-
opropyl ester (15-keto-latanoprost).
[0022]
13,14-dihydro-17-phenyl-18,19,20-trinor-PGF.sub.2.alpha.-isopropyl
ester (latanoprost,).
[0023] 2. Preparation of Dosing Solutions
[0024] The solution containing 15-keto-latanoprost or latanoprost
at 0.0005% was prepared with the following vehicle. Composition of
the vehicle.sup.1) (/mL): NaCl (4.1 mg), NaH.sub.2PO.sub.4-H.sub.2O
(4.6 mg), Na.sub.2HPO.sub.4--2H.sub.2O (5.94 mg), Benzalkonium
Chloride (0.2 mg) and water for injection
[0025] 3. Animals
[0026] Five male cynomolgus monkeys purchased from Kasyo Co., Ltd.
were used. These monkeys were housed individually in cages for
monkeys in a room which was maintained at room temperature of
24.+-.1.degree. C., relative humidity of 55.+-.10%, ventilation
rate of about 12 times/hour and 12-hour light-dark cycle
(fluorescent lighting: 8:00 a.m. to 8:00 p.m.). The animals were
given food pellets for monkeys (PS, Oriental Yeast Co., Ltd.),
vegetables and fruits, and allowed free access to tap water from an
automatic dispenser. The healthy animals without abnormalities in
the anterior segment of the eye were used in this study.
[0027] 4. Test Groups and Administration Method
1 Administration Volume of Group method administration n
15-keto-latanoprost Instillation 35 .mu.L/eye 5 0.0005% Latanoprost
Instillation 35 .mu.L/eye 5 0.0005%
[0028] Five monkeys were divided into 2 groups of the group 1 (3
monkeys) and group 2 (2 monkeys). The 0.0005% 15-keto-latanoprost
and 0.0005% latanoprost were instilled into the right eye of
monkeys in the group 1 and 2, respectively. One week later, 0.0005%
latanoprost and 0.0005% 15-keto-latanoprost were instilled into the
right eye of monkeys in the group 1 and 2, respectively, in a
crossover way. Thirty-five .mu.L of each test solution was
administered by use of a micropipet (Pipetman P 100, Gilson). To
the left eye the same volume of the vehicle was administered. The
intraocular pressure in each group before the instillation was as
follows (in mmHg, mean .+-.S.E.): the group receiving
15-keto-latanoprost; the right eye: 16.6.+-.0.5, the left eye:
16.6.+-.0.2, the group receiving latanoprost; the right eye:
15.8.+-.0.7, the left eye: 17.0.+-.0.3. There were no statistically
significant differences between the values of the intraocular
pressure before the instillation (Student's t-test).
[0029] 5. Measurement of Intraocular Pressure
[0030] The animals were systemically anesthetized by an
intramuscular injection of 5 mg/kg of ketamine hydrochloride
(Ketalar.RTM.50, Sankyo Co., Ltd.), and the anterior segment of
both eyes was anesthetized by a instillation of 0.4% oxybuprocaine
hydrochloride (Benoxil.RTM. 0.4% solution, Santen Pharmaceutical
Co., Ltd.). The animals were fixed in a sitting position, and the
intraocular pressure was measured by use of an applanation
pneumatonograph (Alcon Japan Ltd.) before, and 2, 4, 8, 12 and 24
hours after the instillation. The animals were kept in cages
excepting the time of measurement of the intraocular pressure.
[0031] 6. Statistical Analysis
[0032] The data were statistically analyzed with Student's t-test.
P values less than 0.05 were considered to be statistically
significant.
Results
[0033] The instillation of 0.0005% latanoprost did not lower the
intraocular pressure (FIG. 1). On the contrary, the intraocular
pressure in 0.0005% 15-keto-latanoprost-treated eye was lowered by
2.4 mmHg 8 hours after the instillation as compared with the
pre-treatment value, and the reduction in the intraocular pressure
was statistically significant as compared with that in the
vehicle-treated contralateral eye (FIG. 2). In addition, as shown
in FIG. 3, the reduction in the intraocular pressure with 0.0005%
15-keto-latanoprost was also statistically significant as compared
with 0.0005% latanoprost.
Discussion
[0034] In the present study, the intraocular pressure lowering
effects of latanoprost and 15-keto-latanoprost in monkeys were
compared following a single instillation at 0.0005%, for about
one-tenth the amount of clinically used latanoprost. While no
reduction in the intraocular pressure was noted following the
instillation of 0.0005% latanoprost, the instillation of 0.0005%
15-keto-latanoprost significantly lowered the intraocular
pressure.
[0035] Above results clearly indicate that the potency of
intraocular pressure lowering effect of 15-keto-latanoprost is
significantly greater than that of latanoprost. Furthermore, the
fact that 15-keto-latanoprost exerted a significant intraocular
pressure lowering effect at such a low concentration, at which
latanoprost had no effect, strongly suggests that 15-keto acid of
latanoprost, a 13,14-dihydro-15-keto-type metabolite produced from
latanoprost in the eyes, participates in the intraocular pressure
lowering effect after the instillation of latanoprost.
REFERENCES
[0036] 1) Sjoquist B., et al.: Drug metabolism and disposition 26
(8): 745-754, 1998
EXAMPLE 2
[0037] This Example illustrates the employment of a low dose of
15-keto latanoprost for maintaining a low IOP level following
single administration of another IOP reducing agent for obtaining a
rapid drop in IOP.
Summary
[0038] The intraocular pressure in monkeys after single
instillation of 0.005% latanoprost (clinical concentration) showed
the maximum reduction at 12 hours after the instillation and
thereafter the intraocular pressure recovered gradually and
returned to the predosing level at 24 hours after the instillation.
No difference was found between changes in intraocular pressure
after additional instillation of 0.0005% latanoprost (the
concentration: 1/10 of latanoprost 0.005%) at 12 hours after
instillation of 0.005% latanoprost and those after single
instillation of 0.005% latanoprost. On the other hand, when 0.0005%
15-keto-latanoprost was additionally instilled at 12 hours after
instillation of 0.005% latanoprost, the intraocular pressure was
significantly maintained continuously at low levels as compared
with that when 0.005% latanoprost alone was instilled or that when
0.0005% latanoprost was instilled additionally at 12 hours after
instillation of 0.005% latanoprost. These results suggest that
15-keto acid of latanoprost, a 13,14-dihydro-15-keto type
metabolite, produced from latanoprost in the eye after instillation
of latanoprost participates in the maintenance of the intraocular
pressure lowering effect after instillation of latanoprost.
I. Introduction
[0039] In the present study, the animals were treated by the
instillation with latanoprost at the clinical concentration alone,
or additional instillation of a small amount of latanoprost or
15-keto-latanoprost 12 hours after instillation of latanoprost when
the IOP showed the maximum reduction after instillation of
latanoprost. The changes of IOP in 3 different treatment groups
were compared to investigate the significance of the presence of
15-keto acid of latanoprost, a 13,14-dihydro-15-keto type
metabolite, in maintaining the IOP lowering effect observed after
instillation of latanoprost.
II. Materials and Methods
[0040] 1. Test Substance
[0041] 15-keto-latanoprost and latanoprost which were synthesized
in Ueno Institute for Medical Science were used.
[0042] 2. Animals
[0043] Six male cynomolgus monkeys (body weight: 3.2-3.8 kg) were
used. These monkeys were housed individually in cages for monkeys
in a monkey rearing room which was maintained at room temperature
of 24.+-.1.degree. C., relative humidity of 55.+-.10%, and
ventilation of about 12 times/hour and a 12-hour light-dark cycle
(fluorescent lighting: 8:00 a.m. to 8:00 p.m.). The animals were
given solid food for monkeys (PS, Oriental Yeast Co., Ltd.),
vegetables and fruits, and allowed free access to tap water from an
automatic dispenser. The healthy animals without abnormalities in
the anterior segment were used in this study.
[0044] 3. Preparation of Dosing Solution
[0045] 0.0005% and 0.005% latanoprost eye drops and 0.0005%
15-keto-latanoprost eye drops were prepared with a vehicle
consisting of the following composition. The composition of the
vehicles in 1 mL was as follows: sodium chloride (4.1 mg), sodium
hydrogenphosphate-1H.sub.2O (4.6 mg), disodium
hydrogenphosphate-2H.sub.2O (5.94 mg), benzalkonium chloride (0.200
mg) and water for injection (1 mL).
[0046] 4. Administration Method of Test Substance
[0047] In the present study, changes in IOP after instillation of
0.005% latanoprost alone at the clinical concentration were
compared with those in IOP after additional instillation of 0.0005%
latanoprost or 0.0005% 15-keto-latanoprost 12 hours after
instillation of 0.005% latanoprost to investigate the significance
of the presence of a 13,14-dihydro-15-keto type metabolite in
maintaining the IOP lowering effect observed after instillation of
latanoprost.
[0048] The following 3 treatments were given to the right eye of
monkeys at the intervals of at least 10 days. Namely, (1)
instillation of 0.005% latanoprost alone, (2) additional
instillation of 0.0005% latanoprost at 12 hours after instillation
of 0.005% latanoprost, and (3) additional instillation of 0.0005%
15-keto-latanoprost at 12 hours after instillation of 0.005%
latanoprost. Thirty .mu.L of each test substance was instilled into
the right eye of animals with a Pipetman (Gilson). The same amount
of the vehicle was instilled into the left eye.
[0049] 5. Measurement of IOP
[0050] After the ocular surface of monkeys was anesthetized with
0.4% oxybuprocaine hydrochloride (Benoxil.RTM. 0.4% solution,
Santen Pharmaceutical Co., Ltd.) under i.m. systemic anesthesia
with 5-7.5 mg/kg of ketamine hydrochloride, IOP was measured with
an applanation pneumatonograph (Alcon Japan Ltd.). IOP was measured
before instillation and at 4, 8, 12, 16, 20, 24, 28 and 32 hours
after instillation of 0.005% latanoprost.
III. Results
[0051] As FIG. 4 shows, when 0.005% latanoprost alone was instilled
into the eye of monkeys, IOP decreased with time at 4, 8 and 12
hours after instillation. The IOP returned with time toward the
predosing levels at 16 and 20 hours after instillation of 0.005%
latanoprost. IOP returned toward the predosing levels at 24 hours
after instillation.
[0052] Additional instillation of 0.0005% latanoprost at 12 hours
after instillation of 0.005% latanoprost did not affect IOP as
compared with that after instillation of 0.005% latanoprost
alone.
[0053] On the other hand, the IOP was maintained at significantly
low levels when 0.0005% 15-keto-latanoprost was additionally
instilled at 12 hours after instillation of 0.005% latanoprost as
compared with that when 0.005% latanoprost alone was instilled, or
that when 0.0005% latanoprost was additionally instilled 12 hours
after instillation of 0.005% latanoprost.
[0054] These results indicate that the IOP lowering effect after
instillation of latanoprost is prolonged markedly by additional
instillation of a small amount of 15-keto-latanoprost.
[0055] Other 15-keto prostaglandins which should be useful in the
practice of the present invention are 15-oxo-16-(3-trifluoromethyl
phenoxy)-17,18,19,20-tetranor PGF.sub.2.alpha. and
13,14-dihydro-15-oxo-16-(3-trifluoromethyl
phenoxy)-17,18,19,20-tetranor PGF.sub.2.alpha.. See U.S. Pat. No.
5,510,383 for the corresponding 15-OH compound. The low dosage
contemplated herein for these compounds is below 0.2 .mu.g/eye, to
as low as 0.03 .mu.g/eye. In another embodiment of this invention,
these two compounds are topically applied to the eye in a dosage of
about 0.050 to below 5.0 .mu.g/eye, or about 0.10 to 4.5 .mu.g/eye,
or about 0.50 to 2.5 .mu.g/eye, or about 1.0 to 2.0 .mu.g/eye. In
still another embodiment of this invention, the three compounds
disclosed herein are topically applied in a dosage range of about
0.050 to 0.750 .mu.g/eye, preferably about 0.075 to 0.250
.mu.g/eye, more preferably about 0.100 to 0.175 .mu.g/eye.
[0056] Variations of the present invention will be apparent to the
skilled artisan. For example, when 15-keto latanoprost is used in a
low dose maintenance regimen, the initial rapid IOP reduction can
be obtained with known IOP reducing agents other than latanoprost,
for example, Rescula.RTM., Timolol, Alphagan, Azopt, Cosopt,
Travoprost (isopropyl ester of fluprostenol) and so on can be
employed. Another alternative is to initially use a higher dose of
15-keto latanoprost. The dosages disclosed herein are for human
use.
* * * * *