U.S. patent application number 14/473419 was filed with the patent office on 2014-12-18 for ophthalmic solution.
This patent application is currently assigned to SUCAMPO AG. The applicant listed for this patent is Sucampo AG. Invention is credited to Ryuji UENO.
Application Number | 20140371309 14/473419 |
Document ID | / |
Family ID | 46304405 |
Filed Date | 2014-12-18 |
United States Patent
Application |
20140371309 |
Kind Code |
A1 |
UENO; Ryuji |
December 18, 2014 |
OPHTHALMIC SOLUTION
Abstract
The present invention relates to an ophthalmic solution
comprising a prostaglandin compound and viscosity-increasing
compound. The ophthalmic solution of the invention is excellent in
stability and can provide long lasting and increased effect when
administrated topically to the eyes of a patient.
Inventors: |
UENO; Ryuji; (Potomac,
MD) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Sucampo AG |
Zug |
|
CH |
|
|
Assignee: |
SUCAMPO AG
Zug
CH
|
Family ID: |
46304405 |
Appl. No.: |
14/473419 |
Filed: |
August 29, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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14048250 |
Oct 8, 2013 |
8853268 |
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14473419 |
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11110698 |
Apr 21, 2005 |
8580851 |
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14048250 |
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PCT/JP2004/003288 |
Mar 12, 2004 |
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11110698 |
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10644870 |
Aug 21, 2003 |
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PCT/JP2004/003288 |
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60404779 |
Aug 21, 2002 |
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Current U.S.
Class: |
514/530 |
Current CPC
Class: |
Y10S 514/912 20130101;
A61K 47/32 20130101; A61K 47/36 20130101; A61K 47/38 20130101; A61K
31/5575 20130101; A61K 9/0014 20130101; A61K 9/0048 20130101; A61K
31/557 20130101; A61K 47/10 20130101 |
Class at
Publication: |
514/530 |
International
Class: |
A61K 47/38 20060101
A61K047/38; A61K 9/00 20060101 A61K009/00; A61K 31/5575 20060101
A61K031/5575 |
Claims
1. A method for improving the duration and/or potency of the effect
of an ophthalmic solution comprising
13,14-dihydro-15-keto-20-ethyl-prostaglandin F2.alpha. isopropyl
ester when administered to the eyes of a subject, comprising:
adding methyl cellulose in an amount of about 0.01-10 w/v % to the
ophthalmic solution.
2. The method of claim 1, wherein the ophthalmic solution comprises
13,14-dihydro-15-keto-20-ethyl-prostaglandin F2.alpha. isopropyl
ester in an amount of about 0.001-1 w/v %.
3. The method of claim 2, wherein the ophthalmic solution comprises
13,14-dihydro-15-keto-20-ethyl-prostaglandin F2.alpha. isopropyl
ester in an amount of about 0.12 w/v %.
4. The method of claim 1, wherein the method improves the duration
of the intraocular pressure lowering effect of the ophthalmic
solution to longer than 4 hours.
5. The method of claim 1, wherein the ophthalmic solution is
administered to a patient in need thereof only once a day.
6. The method of claim 1, further comprising a dissolving agent.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of application Ser. No.
14/048,250 filed Oct. 8, 2013, which is a continuation of
application Ser. No. 11/110,698 filed Apr. 21, 2005, now U.S. Pat.
No. 8,580,851 issued Nov. 12, 2013, which is a continuation-in-part
application of application Ser. No. 10/644,870 filed on Aug. 21,
2003 claiming the benefit under 35 U.S.C. 119(e) of U.S.
Provisional Application No. 60/404,779 filed on Aug. 21, 2002 and
International Patent Application No. PCT/JP2004/003288 filed on
Mar. 12, 2004, designating U.S.
FIELD OF THE INVENTION
[0002] The present invention relates to an ophthalmic solution or
an eye drop composition comprising a prostaglandin compound and a
viscosity-increasing compound.
[0003] The present invention also relates to a method for treating
glaucoma and/or ocular hypertension.
BACKGROUND ART
[0004] Prostaglandins (hereinafter, referred to as PGs) are members
of class of organic carboxylic acids, which are contained in
tissues or organs of human and other mammals, and exhibit a wide
range of physiological activities. PGs found in nature (primary
PGs) have, as a general structural property thereof, a prostanoic
acid skeleton as shown in the formula (A):
##STR00001##
[0005] On the other hand, some synthetic analogues have modified
skeletons. The primary PGs are classified into PGAs, PGBs, PGCs,
PGDs, PGEs, PGFs, PGGs, PGHs, PGIs and PGJs on the basis of the
structural property of the five membered ring moiety, and further
classified into the following three types by the number and
position of the unsaturated bond in the carbon chain moiety.
Type 1 (subscript 1): 13,14-unsaturated-15-OH Type 2 (subscript 2):
5,6- and 13,14-diunsaturated-15-OH Type 3 (subscript 3): 5,6-,
13,14-, and 17,18-triunsaturated-15-OH.
[0006] Further, PGFs are classified on the basis of the
configuration of the hydroxyl group at the 9-position into .alpha.
type (wherein the hydroxyl group is of the .alpha.-configuration)
and .beta. type (wherein the hydroxyl group is of the
.beta.-configuration).
[0007] In addition, some 15-keto-PGs (PGs having an oxo group at
position 15 in place of the hydroxy group) and
13,14-dihydro-15-keto-PGs have been known as substances naturally
produced by enzymatic actions during metabolism of the primary PGs.
15-keto-PGs have been disclosed in U.S. Pat. Nos. 5,073,569,
5,534,547, 5,225,439, 5,166,174, 5,428,062 5,380,709 5,886,034
6,265,440, 5,106,869, 5,221,763, 5,591,887, 5,770,759 and
5,739,161. The contents of these publications are herein
incorporated by reference.
[0008] Some prostaglandin compounds have been known to be useful as
pharmaceutical agents in the ophthalmic area, namely as an ocular
hypotensive agent or an agent for treatment of glaucoma. For
example, latanoprost, that is
13,14-dihydro-17-phenyl-18,19,20-trior-PGF.sub.2.alpha. isopropyl
ester, travoprost, that is 16-(3-trifluoromethyl
phenoxy)-17,18,19,20-tetranor PGF.sub.2.alpha. isopropyl ester and
bimatoprost, that is 17-phenyl-18,19,20-trinor-PGF.sub.2.alpha.
N-ethylamide have already been placed on the market under the name
of Xalatan.TM., Travatan.TM. and Lumigan.TM. eye drops for the
treatment of glaucoma and ocular hypertension.
[0009] Further, 15-keto-prostaglandin compounds have been known to
be useful as pharmaceutical agents in the ophthalmic area, namely
as an ocular hypotensive agent or an agent for treatment of
glaucoma, see U.S. Pat. Nos. 5,001,153; 5,151,444, 5,166,178,
5,194,429 and 5,236,907, for treatment of cataract, see U.S. Pat.
Nos. 5,212,324 and 5,686,487, for increasing the choroidal blood
flow, see U.S. Pat. No. 5,221,690 and for treatment of optic nerve
disorders, see U.S. Pat. No. 5,773,471. The contents of these USPs
are herein incorporated by reference. Especially, isopropyl ester
of 13,14-dihydro-15-keto-20-ethyl-PGF2.alpha. has already been
placed on the market under the name of Rescula.TM. (common name:
isopropyl unoprostone) ophthalmic solution for treatment of
glaucoma and ocular hypertension. Rescula.TM. ophthalmic solution
provides sufficient ocular hypotensive effect by administrating
twice a day.
SUMMARY OF THE INVENTION
[0010] An object of the present invention is to provide an
ophthalmic solution, which is excellent in stability, potency or
duration of the activity.
[0011] This inventor found that an ophthalmic solution comprising a
PG compound and a specific viscosity-increasing compound is
excellent in stability and provides long-lasting and increased
effects and therefore, said ophthalmic solution shows great
advantages.
[0012] Accordingly, the present invention provides an ophthalmic
solution comprising a prostaglandin compound of formula (I) shown
below and at least one viscosity-increasing compound selected from
the group consisting of acrylate polymers, polyols, cellulose
polymers, polysaccharides and polyl-lactams.
[0013] The present invention also provides a method for improving
the duration of the effect of an ophthalmic solution comprising a
prostaglandin compound of formula (I) shown below when
administrated to the eyes of a subject, comprising: adding at least
one viscosity-increasing compound selected from the group
consisting of acrylate polymers, polyols, cellulose polymers,
polysaccharides and polyl-lactams to the ophthalmic solution.
[0014] The present invention further provides a method for treating
ocular hypertension and/or glaucoma, which comprises administrating
an ophthalmic solution comprising as an active ingredient thereof a
prostaglandin compound of formula (I) shown below and at least one
viscosity-increasing compound selected from the group consisting of
acrylate polymers, polyols, cellulose polymers, polysaccharides and
polyl-lactams.
DETAILED DESCRIPTION
[0015] The nomenclature of the PG compounds used herein is based on
the numbering system of prostanoic acid represented in the above
formula (A).
[0016] The formula (A) shows a basic skeleton of the C-20 PG
compound, but the present invention is not limited to those having
the same number of carbon atoms. In the formula (A), the numbering
of the carbon atoms which constitute the basic skeleton of the PG
compounds starts at the carboxylic acid (numbered 1), and carbon
atoms in the .alpha.-chain are numbered 2 to 7 towards the
five-membered ring, those in the ring are 8 to 12, and those in the
.omega.-chain are 13 to 20. When the number of carbon atoms is
decreased in the .alpha.-chain, the number is deleted in the order
starting from position 2; and when the number of carbon atoms is
increased in the .alpha.-chain, compounds are named as substitution
compounds having respective substituents at position 2 in place of
carboxy group (C-1). Similarly, when the number of carbon atoms is
decreased in the .omega.-chain, the number is deleted in the order
starting from position 20; and when the number of carbon atoms is
increased in the .omega.-chain, compounds are named as substitution
compounds having respective substituents at position 20.
Stereochemistry of the compounds is the same as that of the above
formula (A) unless otherwise specified.
[0017] In general, each of PGD, PGE and PGF represents a PG
compound having hydroxy groups at positions 9 and/or 11, but in the
present specification they also include those having substituents
other than the hydroxyl groups at positions 9 and/or 11. Such
compounds are referred to as 9-dehydroxy-9-substituted-PG compounds
or 11-dehydroxy-11-substituted-PG compounds. A PG compound having
hydrogen in place of the hydroxy group is simply named as 9- or
11-dehydroxy compound.
[0018] As stated above, the nomenclature of PG compounds is based
on the prostanoic acid skeleton. However, in case the compound has
a similar partial construction as a prostaglandin, the abbreviation
of "PG" may be used. Thus, a PG compound of which .alpha.-chain is
extended by two carbon atoms, that is, having 9 carbon atoms in the
.alpha.-chain is named as 2-decarboxy-2-(2-carboxyethyl)-PG
compound. Similarly, a PG compound having 11 carbon atoms in the
.alpha.-chain is named as 2-decarboxy-2-(4-carboxybutyl)-PG
compound. Further, a PG compound of which .omega.-chain is extended
by two carbon atoms, that is, having 10 carbon atoms in the w-chain
is named as 20-ethyl-PG compound. These compounds, however, may
also be named according to the IUPAC nomenclatures.
[0019] According to the IUPAC naming system, for example,
13,14-dihydro-15-keto-16R,S-fluoro-PGE.sub.2 is
(Z)-7-((1R,2R,3R)-3-hydroxy-2-[(4R,
S)-fluoro-3-oxo-1-octyl]-5-oxocyclopentyl)-hept-5-enoic acid;
13,14-dihydro-15-keto-20-ethyl-11-dehydroxy-11R-methyl-PGE.sub.2
methyl ester is methyl
7-{(1R,2S,3S)-3-methyl-2-[3-oxo-1-decyl]-5-oxocyclopentyl}-hept-5-enoate;
and 13,14-dihydro-6,15-diketo-19-methyl-PGE.sub.2 ethyl ester is
ethyl
7-{(1R,2S,3S)-3-hydroxy-2-(7-methyl-3-oxo-1-octyl)-5-oxocyclopentyl}-6-ox-
o-heptanoate. 13,14-dihydro-15-keto-20-ethyl-PGF.sub.2.alpha.
isopropyl ester is isopropyl
(Z)-7-[(1R,2R,3R,5S)-3,5-dihydro-2-{3-oxo-1-decyl)-cyclopentyl]-hept-5-en-
oate; and 13,14-dihydro-15-keto-20-methyl-PGF.sub.2.alpha. methyl
ester is methyl
(Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-{3-oxo-1-nonyl}-cyclopentyl]--
hept-5-enoate.
[0020] The 15-keto-PG compound used in the present invention may be
any derivative of a PG insofar as having an oxo group at position
15 in place of the hydroxy group, and may further include a
compound having one double bond between positions 13 and 14
(15-keto-PG type 1 compound), two double bonds between positions 13
and 14, and positions 5 and 6 (15-keto-PG type 2 compound), and
three double bonds between positions 5 and 6, positions 13 and 14,
and positions 17 and 18(15-keto-PG type 3 compound), and a
derivative thereof wherein the bond between the positions 13 and 14
is single bond, in place of the double bond
(13,14-dihydro-15-keto-PG compound).
[0021] Typical examples of the PG compounds used in the present
invention include 15-keto-PG type 1, 15-keto-PG type 2, 15-keto-PG
type 3,13,14-dihydro-15-keto-PG type 1, 13,14-dihydro-15-keto-PG
type 2,13,14-dihydro-15-keto-PG type 3 and the derivatives
thereof.
[0022] Examples of the substitution compounds or derivatives
include a PG compound of which the carboxy group at the end of the
alpha chain is esterified; physiologically acceptable salt thereof;
an unsaturated derivative having a double bond between positions 2
and 3 or a triple bond between positions 5 and 6; PG compounds
having substituent(s) on carbon atom(s) at position(s) 3, 5, 6, 16,
17, 18, 19 and/or 20; and PG compounds having lower alkyl or a
hydroxy (lower) alkyl group at position 9 and/or 11 in place of the
hydroxy group.
[0023] According to the present invention, preferred substituents
on the carbon atom at position(s) 3, 17, 18 and/or 19 include alkyl
having 1-4 carbon atoms, especially methyl and ethyl. Preferred
substituents on the carbon atom at position 16 include lower alkyl
such as methyl and ethyl, hydroxy, halogen atom such as chlorine
and fluorine, and aryloxy such as trifluoromethylphenoxy. Preferred
substituents on the carbon atom at position 17 include halogen atom
such as chlorine and fluorine. Preferred substituents on the carbon
atom at position 20 include saturated or unsaturated lower alkyl
such as C.sub.1-4 alkyl, lower alkoxy such as C.sub.1-4 alkoxy, and
lower alkoxy alkyl such as C.sub.1-4 alkoxy-C.sub.1-4 alkyl.
Preferred substituents on the carbon atom at position 5 include
halogen atoms such as chlorine and fluorine. Preferred substituents
on the carbon atom at position 6 include an oxo group forming a
carbonyl group. Stereochemistry of PGs having hydroxy, lower alkyl
or hydroxy(lower)alkyl substituent on the carbon atom at positions
9 and 11 may be .alpha., .beta. or a mixture thereof.
[0024] Further, the above described derivatives may have a .omega.
chain shorter than that of the primary PGs and a substituent such
as alkoxy, cyclohexyl, cyclohexyloxy, phenoxy and phenyl at the end
of the truncated .omega.-chain.
[0025] Especially preferred compounds include a
13,14-dihydro-15-keto-PG compound that has a single bond between
positions 13 and 14; a 15-keto-20-lower alkyl (especially ethyl) PG
compound that has a lower alkyl, especially ethyl, at carbon atom
of position 20; a 15-keto-PGF compound that has hydroxy groups at
positions 9 and position 11 of the five membered ring.
[0026] A preferred prostaglandin compound used in the present
invention is represented by the formula (I):
##STR00002##
[0027] wherein L, M and N are hydrogen, hydroxy, halogen, lower
alkyl, hydroxy(lower)alkyl, lower alkanoyloxy 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;
[0028] A is --CH.sub.3, or --CH.sub.2OH, --COCH.sub.2OH, --COOH or
a functional derivative thereof;
[0029] B is --CH.sub.2--CH.sub.2--, --CH.dbd.CH--, --C.ident.C--,
--CH.sub.2--CH.sub.2--CH.sub.2--, --CH.dbd.CH--CH.sub.2--,
--CH.sub.2--CH.dbd.CH--, --C.ident.C--CH.sub.2-- or
--CH.sub.2--C.ident.C--;
[0030] Z is
##STR00003##
[0031] wherein R.sub.4 and R.sub.5 are hydrogen, hydroxy, halogen,
lower alkyl, lower alkoxy or hydroxy(lower)alkyl, wherein R.sub.4
and R.sub.5 are not hydroxy and lower alkoxy at the same time;
[0032] R.sub.1 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, and at least one carbon atom in the aliphatic hydrocarbon is
optionally substituted by oxygen, nitrogen or sulfur; and
[0033] Ra is a saturated or unsaturated lower or medium aliphatic
hydrocarbon residue, which is unsubstituted or substituted with
halogen, oxo, hydroxy, lower alkoxy, lower alkanoyloxy,
cyclo(lower)alkyl, cyclo(lower)alkyloxy, aryl, aryloxy,
heterocyclic group or hetrocyclic-oxy group, and at least one
carbon atom in the aliphatic hydrocarbon is optionally substituted
by oxygen, nitrogen or sulfur; lower alkoxy; lower alkanoyloxy;
cyclo(lower)alkyl; cyclo(lower)alkyloxy; aryl; aryloxy;
heterocyclic group; heterocyclic-oxy group.
[0034] A more preferred prostaglandin compound used in the present
invention is represented by the formula (II):
##STR00004##
[0035] wherein L and M are hydrogen, hydroxy, halogen, lower alkyl,
hydroxy(lower)alkyl, lower alkanoyloxy or oxo, wherein at least one
of L and M is a group other than hydrogen, and the five-membered
ring may have one or more double bonds;
[0036] A is --CH.sub.3, or --CH.sub.2OH, --COCH.sub.2OH, --COOH or
a functional derivative thereof;
[0037] B is --CH.sub.2--CH.sub.2--, --CH.dbd.CH--, --C.ident.C--,
--CH.sub.2--CH.sub.2--CH.sub.2--, --CH.dbd.CH--CH.sub.2--,
--CH.sub.2--CH.dbd.CH--, --C.ident.C--CH.sub.2-- or
--CH.sub.2--C.ident.C--;
[0038] Z is
##STR00005##
[0039] wherein R.sub.4 and R.sub.5 are hydrogen, hydroxy, halogen,
lower alkyl, lower alkoxy or hydroxy(lower)alkyl, wherein R.sub.4
and R.sub.5 are not hydroxy and lower alkoxy at the same time;
[0040] X.sub.1 and X.sub.2 are hydrogen, lower alkyl, or
halogen;
[0041] R.sub.1 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, and at least one carbon atom in the aliphatic hydrocarbon is
optionally substituted by oxygen, nitrogen or sulfur;
[0042] R.sub.2 is a single bond or lower alkylene, and at least one
carbon atom in the lower alkylene is optionally substituted by
oxygen, nitrogen or sulfur; and
[0043] R.sub.3 is lower alkyl, lower alkoxy, lower alkanoyloxy,
cyclo(lower)alkyl, cyclo(lower)alkyloxy, aryl, aryloxy,
heterocyclic group or heterocyclic-oxy group.
[0044] In the above formula, the term "unsaturated" in the
definitions for R.sub.1 and 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.
[0045] 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 1 to 8 carbon atoms.
[0046] The term "halogen atom" covers fluorine, chlorine, bromine
and iodine.
[0047] The term "lower" throughout the specification is intended to
include a group having 1 to 6 carbon atoms unless otherwise
specified.
[0048] 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, butyl,
isobutyl, t-butyl, pentyl and hexyl.
[0049] The term "lower alkylene" refers to a straight or branched
chain bivalent saturated hydrocarbon group containing 1 to 6 carbon
atoms and includes, for example, methylene, ethylene, propylene,
isopropylene, butylene, isobutylene, t-butylene, pentylene and
hexylene.
[0050] The term "lower alkoxy" refers to a group of lower
alkyl-O--, wherein lower alkyl is as defined above.
[0051] 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.
[0052] The term "lower alkanoyloxy" refers to a group represented
by the formula RCO--O--, wherein RCO-- is an acyl group formed by
oxidation of a lower alkyl group as defined above, such as
acetyl.
[0053] 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 example, cyclopropyl,
cyclobutyl, cyclopentyl and cyclohexyl.
[0054] The term "cyclo(lower)alkyloxy" refers to the group of
cyclo(lower)alkyl-O--, wherein cyclo(lower)alkyl is as defined
above.
[0055] The term "aryl" may include unsubstituted or substituted
aromatic hydrocarbon rings (preferably monocyclic groups), for
example, phenyl, tolyl, xylyl. Examples of the substituents are
halogen atom and halo(lower)alkyl, wherein halogen atom and lower
alkyl are as defined above.
[0056] The term "aryloxy" refers to a group represented by the
formula ArO--, wherein Ar is aryl as defined above.
[0057] 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 atom and 1 to 4, preferably 1 to 3 of 1 or 2 type of hetero
atoms selected from nitrogen atom, oxygen atom and sulfur atom.
Examples of the heterocyclic group include furyl, thienyl,
pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,
imidazolyl, pyrazolyl, furazanyl, pyranyl, pyridyl, pyridazinyl,
pyrimidyl, pyrazinyl, 2-pyrrolinyl, 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.
[0058] The term "heterocyclic-oxy group" means a group represented
by the formula HcO--, wherein Hc is a heterocyclic group as
described above.
[0059] The term "functional derivative" of A includes salts,
preferably pharmaceutically acceptable salts, ethers, esters and
amides.
[0060] Suitable "pharmaceutically acceptable salts" include salts
formed with non-toxic bases conventionally used in pharmaceutical
field, for example a salt with 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 including 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, 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.
[0061] 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 ether; 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 ether; lower
alkynyl ethers such as ethynyl ether and propynyl ether;
hydroxy(lower)alkyl ethers such as hydroxyethyl ether and
hydroxyisopropyl ether; lower alkoxy (lower)alkyl ethers such as
methoxymethyl ether and 1-methoxyethyl ether; optionally
substituted aryl ethers such 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.
[0062] 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, pentyl ester and 1-cyclopropylethyl ester; lower alkenyl
esters such as vinyl ester and allyl ester; lower alkynyl esters
such as ethynyl ester and propynyl ester; hydroxy(lower)alkyl ester
such as hydroxyethyl ester; 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.
[0063] The amide of A means a group represented by the formula
--CONR'R'', wherein each of R' and R'' is hydrogen, 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.
[0064] Preferred examples of L and M include hydrogen, hydroxy and
oxo, and especially, a compound wherein both of L and M are hydroxy
which has a 5-membered ring structure of, so called, PGF type, or a
compound wherein L is hydroxy and M is oxo which has a 5-membered
ring structure of, so called, PGE type. PGF type is more
preferable.
[0065] Preferred example of A is --COOH, its pharmaceutically
acceptable salt, ester or amide thereof.
[0066] Preferred example of B is --CH.sub.2--CH.sub.2--, which
provides a compound so called 13,14-dihydro type PG.
[0067] Preferred examples of X.sub.1 and X.sub.2 comprise hydrogen
and halogen and preferably, both are hydrogen atom or at least one
of them is a halogen. The compound wherein both of X.sub.1 and
X.sub.2 are fluorine, which provides a compound so called
16,16-difluoro type PG, is also preferable.
[0068] Preferred R.sub.1 is a hydrocarbon residue containing 1-10
carbon atoms, preferably 6-10 carbon atoms. Further, at least one
carbon atom in the aliphatic hydrocarbon is optionally substituted
by oxygen, nitrogen or sulfur.
[0069] Examples of R.sub.1 include, for example, the following
groups:
[0070]
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--,
[0071] --CH.sub.2--CH.dbd.CH--CH.sub.2--CH.sub.2--CH.sub.2--,
[0072] --CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.dbd.CH--,
[0073] --CH.sub.2--C.ident.C--CH.sub.2--CH.sub.2--CH.sub.2--,
[0074] --CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--O--CH.sub.2--,
[0075] --CH.sub.2--CH.dbd.CH--CH.sub.2--O--CH.sub.2--,
[0076] --CH.sub.2--C.ident.C--CH.sub.2--O--CH.sub.2--,
[0077]
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.su-
b.2--,
[0078]
--CH.sub.2--CH.dbd.CH--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--,
[0079]
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.dbd.CH--,
[0080]
--CH.sub.2--C.ident.C--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--,
[0081]
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH(CH.sub.3)--C-
H.sub.2--,
[0082]
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH(CH.sub.3)--CH.sub.2--,
[0083]
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.su-
b.2--CH.sub.2--,
[0084]
--CH.sub.2--CH.dbd.CH--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.s-
ub.2--,
[0085]
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.db-
d.CH--,
[0086]
--CH.sub.2--C.ident.C--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.s-
ub.2--, and
[0087]
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH(CH-
.sub.3)--CH.sub.2--.
[0088] Preferred Ra is a hydrocarbon containing 1-10 carbon atoms,
more preferably, 1-8 carbon atoms. Ra may have one or two side
chains having one carbon atom.
[0089] The configuration of the ring and the .alpha.- and/or
.omega. 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.
[0090] The typical example of the present compounds are
13,14-dihydro-15-keto-20-ethyl-PGF compound or
13,14-dihydro-15-keto-17-phenyl-18,19,20-trinor-prostaglandin F
compound and its derivative or analogue, or
13,14-dihydro-17-phenyl-18,19,20-trior-PGF.sub.2.alpha. isopropyl
ester, 16-(3-trifluoromethyl phenoxy)-17,18,19,20-tetranor
PGF.sub.2.alpha. isopropyl ester or
17-phenyl-18,19,20-trinor-PGF.sub.2.alpha. N-ethylamide.
[0091] In the present invention, the PG compound which is dihydro
between 13 and 14, and keto(.dbd.O) at 15 position may be in the
keto-acetal equilibrium by formation of a hemiacetal between
hydroxy at position 11 and keto at position 15.
[0092] For example, it has been revealed that when both of X.sub.1
and X.sub.2 are halogen atoms, especially, fluorine atoms, the
compound contains a tautomeric isomer, bicyclic compound.
[0093] 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 present
invention includes both isomers.
[0094] Further, the 15-keto-PG compounds used in the invention
include the bicyclic compound and analogs or derivatives
thereof.
[0095] The bicyclic compound is represented by the formula
(III)
##STR00006##
[0096] wherein, A is --CH.sub.3, or --CH.sub.2OH, --COCH.sub.2OH,
--COOH or a functional derivative thereof;
[0097] X.sub.1' and X.sub.2' are hydrogen, lower alkyl, or
halogen;
[0098] X is
##STR00007##
[0099] wherein R.sub.4' and R.sub.5' are hydrogen, hydroxy,
halogen, lower alkyl, lower alkoxy or hydroxy(lower)alkyl, wherein
R.sub.4' and R.sub.5' are not hydroxy and lower alkoxy at the same
time.
[0100] R.sub.1 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, and at least one carbon atom in the aliphatic hydrocarbon is
optionally substituted by oxygen, nitrogen or sulfur; and
[0101] R.sub.2' is a saturated or unsaturated lower or medium
aliphatic hydrocarbon residue, which is unsubstituted or
substituted with halogen, oxo, hydroxy, lower alkoxy, lower
alkanoyloxy, cyclo(lower)alkyl, cyclo(lower)alkyloxy, aryl,
aryloxy, heterocyclic group or hetrocyclic-oxy group; lower alkoxy;
lower alkanoyloxy; cyclo(lower)alkyl; cyclo(lower)alkyloxy; aryl;
aryloxy; heterocyclic group; heterocyclic-oxy group.
[0102] R.sub.3' is hydrogen, lower alkyl, cyclo(lower)alkyl, aryl
or heterocyclic group.
[0103] Furthermore, while the compounds used in the invention may
be represented by a 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 acetal type
compound.
[0104] 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.
[0105] Some of the compounds used in the present invention may be
prepared by the method disclosed in U.S. Pat. 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.
[0106] The PG compounds described as above are useful as agent for
treating various symptoms in the ophthalmic area. For example, it
is useful for treating glaucoma and/or ocular hypertension,
cataract and optic nerve disorders and for increasing the choroidal
blood flow.
[0107] The term "ophthalmic solution" used herein refers any form
of liquid composition suitable for topical eye administration and
the liquid composition may be in the form of solution, emulsion or
suspension.
[0108] The term "treatment" or "treating" used herein refers to any
means of control of a condition including prevention, cure, relief
of the condition, and arrestation or relief of development of the
condition.
[0109] In the ophthalmic solution of the present invention, the PG
compound, the active ingredient, may be any of the above described
compounds.
[0110] The amount of the PG compound in the ophthalmic, solution is
not limited as long as it is sufficient to provide the expected
therapeutic effects. In general, the amount of the PG compound in
the solution may be from about 0.00001 to about 10 w/v %,
preferably, about 0.0001 to about 5 w/v %, more preferably about
0.001 to about 1 w/v % of the solution.
[0111] In this specification and claims, "viscosity-increasing
compound" represents a polymer compound which can increase
viscosity of an aqueous medium when it is dissolved or dispersed in
the medium. The combination of the viscosity-increasing compound
and PG compound is excellent in stability and provides long-lasting
and increased effects. Viscosity-increasing compound may preferably
be selected from the group consisting of acrylate polymers,
polyols, cellulose polymers, polysaccharides and polyl-lactams.
Examples of the viscosity-increasing compounds include acrylate
polymers, or also called as carboxyvinyl polymers, such as
carbomer, for example CARBOPOL.TM. 941, 934, 940, 971, 974, 980 and
981, and polycarbophil, for example NOVEON.TM. AA-1, CA-1 and CA-2;
polyols such as polyvinyl alcohols, glycerin, polyethyleneglycols;
cellulose polymers such as methylcellulose, methylethylcellulose,
hydroxypropylmethylcellulose, hydroxyethylcellulose, and
carboxymethylcellulose; polysaccharides such as carrageenan, gellan
gum, xanthan gum, dextran and locust bean gum; poly-lactams such as
polyvinyl pyrrolidone.
[0112] Based on the necessity or purpose of the treatment, the
viscosity-increasing compound may optionally be a combination of
two or more above-described compounds. Further, if it is required,
the other viscosity-increasing compounds such as gelatins may be
admixed with the above described viscosity-increasing compounds of
the present invention.
[0113] The amount of the viscosity-increasing compound in the
present ophthalmic solution may vary depending on the amount of the
PG compound, or the kind or the molecular weight of the
viscosity-increasing compound employed. Generally, the amount of
about 0.001-30 w/v %, preferably about 0.01-10 w/v % of the whole
solution is enough to provide the expected effect.
[0114] The ophthalmic solution of the present invention may be
manufactured by a conventional manner, for example, by adding a PG
compound and a viscosity-increasing compound to an aqueous solution
such as physiological saline or buffering solution, etc., and
dissolving or mixing them or by combining powder composition with
the aqueous solution as above or water before use. Further, in
order to improve the solubility of the PG compound to water, esters
of polyoxyethylene sorbitane mono higher fatty acid such as
polysorbate 80, may be added to the purified water. Alternatively,
by mixing a PG compound with an ester of polyoxyethylene sorbitane
mono higher fatty acid and then adding the mixture to purified
water. The concentration of the esters of polyoxyethylene sorbitane
mono higher fatty acid may vary depending on the amount of the PG,
and in general, may be 0.01-10 w/w %, preferably, 0.05-5 w/w % of
whole solution.
[0115] In addition, the ophthalmic solution of the present
invention may contain other active ingredients in so far as it does
not act adverse to the purpose of the present invention.
[0116] The ophthalmic solution of the present invention may further
contain additives which have been employed in conventional
ophthalmic solutions. For example, buffers or isotonic agents such
as salts like phosphates (e.g. sodium monohydrogen phosphate and
sodium dihydrogen phosphate), borates, sodium chloride or mannitol;
dissolving agent such as polysorbate 80 or polyoxyethylene
hydrogenated caster oil such as polyethylene hydrogenated caster
oil 60; preservatives such as benzalkonium chloride, benzethonium
chloride, chloro butanol or paraben.
[0117] The present composition may be formulated as a sterile unit
dose type product comprising no preservatives.
[0118] The ophthalmic solution of the invention is useful for
treating glaucoma, cataract or optic nerve disorders, or for
lowering the intraocular pressure or for increasing the choroidal
blood flow. The ophthalmic solution of the present invention can
provide enough therapeutic effect, since it is excellent in
stability and the duration and potency of the effect of the PG
compound is elongated. Further, the ophthalmic solution of the
present invention can provide an improved compliance for the
patients due to the reduced administration frequency (e.g. once a
day) of the PG compound, which may be expected the reduced side
effect such as corneal disorder. Accordingly, the ophthalmic
solution of the present invention may be useful for treatment of a
various symptoms in the ophthalmic area.
[0119] The present invention will be explained in more detail by
means of the following examples, which are illustrated by way of
example only and never intended to limit the scope of the present
invention.
Test Example
[0120] Test ophthalmic solutions comprising 0.12 w/v % of
13,14-dihydro-15-keto-20-ethyl-PGF.sub.2.alpha. isopropyl ester
(test compound 1) were prepared.
Test solution 1: Rescula.TM. ophthalmic solution (0.12%)(R-tech
UENO, Ltd. Tokyo, Japan) Test solution 2: prepared by adding 1 w/v
% methyl cellulose 400 cP to the test solution 1. Test solution 3:
prepared by replacing sodium chloride contained in the test
solution 1 as isotonic agent with 3.5 w/v % mannitol and adding 0.3
w/v % gellan gum to the solution.
[0121] Normal white rabbits were used. Test solution (30 .mu.L/eye)
was administered to one eye and vehicle of the test solution, i.e.
the same solution as the test solution except for comprising test
compound 1, was administrated to the other eye of the rabbit (30
.mu.L/eye). The intraocular pressure (IOP) of the animals were
measured with an applanation tonometer immediately before and 2, 4
and 6 hours after the administration. Change of IOP (.DELTA.IOP) at
each measurement time from that measured just before the
administration (time 0) was calculated.
[0122] Results are shown in tables 1, 2 and 3. Test solution 2 and
3, which comprising certain viscosity-increasing compound,
exhibited significantly longer lasting and increased IOP lowering
effect than test solution 1 containing no viscosity increasing
compound.
TABLE-US-00001 TABLE 1 Change of IOP in normal white rabbits after
administration of test solution 1 change of IOP (mean .+-. SE,
mmHg) time after administration (hr) Test Solution n 0 2 4 6
Vehicle for test 8 0.0 .+-. 0.0 2.8 .+-. 0.7 1.4 .+-. 0.9 1.1 .+-.
0.6 solution 1 Test Solution 1 8 0.0 .+-. 0.0 -2.9 .+-. 0.7** -2.0
.+-. 1.0* -0.1 .+-. 1.4 **P < 0.01, *p < 0.05 Compared with
the other eye received the vehicle (paired Student's t -test)
TABLE-US-00002 TABLE 2 Change of IOP in normal white rabbits after
administration of test solution 2 change of IOP (mean .+-. SE,
mmHg) time after administration (hr) Test Solution n 0 2 4 6
Vehicle for test 8 0.0 .+-. 0.0 2.3 .+-. 0.5 2.0 .+-. 0.7 2.0 .+-.
0.8 solution 2 Test Solution 2 8 0.0 .+-. 0.0 -3.9 .+-. 0.7** -3.3
.+-. 1.3** -1.0 .+-. l.1* **P < 0.01, *p < 0.05 Compared with
the other eye received the vehicle (paired Student's t-test)
TABLE-US-00003 TABLE 3 Change of IOP in normal white rabbits after
administration of test solution 3 change of IOP (mean .+-. SE,
mmHg) time after administration (hr) Test Solution n 0 2 4 6
Vehicle for test 8 0.0 .+-. 0.0 1.1 .+-. 1.0 0.1 .+-. 0.8 1.3 .+-.
0.8 solution 3 Test Solution 3 8 0.0 .+-. 0.0 -3.4 .+-. 0.5** -3.6
.+-. 0.5** -2.0 .+-. 1.0** **P < 0.01, *p < 0.05 Compared
with the other eye received the vehicle (paired Student's t
-test)
Formulation Example 1
[0123] Twelve (12) mg of isopropyl unoprostone, 50 mg of
CARBOPOL.TM. 940 and 90 mg of polysorbate 80 were admixed with 50
ml of purified water, more purified water was added to make the
total volume 100 ml, and dissolved the mixture to provide
Ophthalmic solution 1.
Formulation Example 2
[0124] Ophthalmic solution 2 was prepared by the same manner as
Example 1 except for 200 mg of polyvinyl alcohol was added in place
of CARBOPOL 940.
Formulation Example 3
[0125] Ophthalmic solution 3 was prepared by the same manner as
Example 1 except for 150 mg of glycerin was added in place of
CARBOPOL 940.
Formulation Example 4
[0126] Ophthalmic solution 4 was prepared by the same manner as
Example 1 except for 20 mg of hydroxymethyl cellulose was added in
place of CARBOPOL 940.
Formulation Example 5
[0127] Ophthalmic solution 5 was prepared by the same manner as
Example 1 except for 100 mg of polyvinyl pyrrolidone was added in
place of CARBOPOL 940.
* * * * *