U.S. patent application number 15/714831 was filed with the patent office on 2018-08-16 for compositions & methods for lowering intraocular pressure.
The applicant listed for this patent is ALLERGAN, INC.. Invention is credited to Chetan P. Pujara.
Application Number | 20180228814 15/714831 |
Document ID | / |
Family ID | 50547845 |
Filed Date | 2018-08-16 |
United States Patent
Application |
20180228814 |
Kind Code |
A1 |
Pujara; Chetan P. |
August 16, 2018 |
COMPOSITIONS & METHODS FOR LOWERING INTRAOCULAR PRESSURE
Abstract
Disclosed herein are compositions for lowering intraocular
pressure (IOP) of an eye comprising a combination IOP-lowering
agents bimatoprost, brimonidine, and timolol. Further disclosed are
methods for reducing IOP in the eye of a subject.
Inventors: |
Pujara; Chetan P.; (Irvine,
CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
ALLERGAN, INC. |
Irvine |
CA |
US |
|
|
Family ID: |
50547845 |
Appl. No.: |
15/714831 |
Filed: |
September 25, 2017 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
15347532 |
Nov 9, 2016 |
9801891 |
|
|
15714831 |
|
|
|
|
14147302 |
Jan 3, 2014 |
9522153 |
|
|
15347532 |
|
|
|
|
13698182 |
Nov 15, 2012 |
|
|
|
PCT/US10/61563 |
Dec 21, 2010 |
|
|
|
14147302 |
|
|
|
|
61361749 |
Jul 6, 2010 |
|
|
|
61288936 |
Dec 22, 2009 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/0048 20130101;
A61K 9/08 20130101; A61K 47/12 20130101; A61K 31/498 20130101; A61K
31/5575 20130101; A61K 47/186 20130101; A61K 31/5377 20130101; A61K
47/02 20130101; A61K 31/498 20130101; A61K 2300/00 20130101; A61K
31/5377 20130101; A61K 2300/00 20130101; A61K 31/5575 20130101;
A61K 2300/00 20130101 |
International
Class: |
A61K 31/5575 20060101
A61K031/5575; A61K 47/02 20060101 A61K047/02; A61K 47/12 20060101
A61K047/12; A61K 47/18 20060101 A61K047/18; A61K 9/08 20060101
A61K009/08; A61K 31/498 20060101 A61K031/498; A61K 31/5377 20060101
A61K031/5377; A61K 9/00 20060101 A61K009/00 |
Claims
1) A pharmaceutical composition for lowering intraocular pressure
in a patient suffering from elevated intraocular pressure
comprising bimatoprost, brimonidine, and timolol.
2) The pharmaceutical composition of claim 1 wherein the
pharmaceutical composition is effective in lowering intraocular
pressure in patients who do not have adequate IOP control with mono
or dual combination therapy.
3) The pharmaceutical composition of claim 1 wherein the
brimonidine is brimonidine tartrate and the timolol is timolol
maleate.
4) The pharmaceutical composition of claim 2 wherein the
composition is applied topically and further comprising sodium
phosphate dibasic heptahydrate, citric acid monohydrate, sodium
chloride, and sodium hydroxide in an aqueous carrier.
5) The pharmaceutical composition of claim 3 further comprising
benzalkonium chloride.
6) The pharmaceutical composition of claim 1 comprising about 0.01%
w/v bimatoprost, about 0.15% w/v brimonidine tartrate and about
0.68% w/v timolol maleate.
7) The pharmaceutical composition of claim 5 further comprising
about 0.005% w/v benzalkonium chloride.
8) A pharmaceutical composition for lowering IOP in patients
suffering from elevated IOP who do not have adequate IOP control
with mono or dual combination therapy consisting essentially of
bimatoprost, brimonidine tartrate, timolol maleate, sodium
phosphate dibasic heptahydrate, citric acid monohydrate, sodium
chloride, and sodium hydroxide in an aqueous carrier.
9) The pharmaceutical composition of claim 8 further consisting
essentially of benzalkonium chloride.
10) The pharmaceutical composition of claim 8 consisting
essentially of about 0.01% w/v bimatoprost, about 0.15% w/v
brimonidine tartrate, about 0.68% w/v timolol maleate, about 1.5%
w/v sodium phosphate dibasic heptahydrate, about 0.025% w/v citric
acid monohydrate and about 0.35% w/v sodium chloride.
11) The pharmaceutical composition of claim 10 consisting
essentially of about 0.005% w/v benzalkonium chloride.
12) The pharmaceutical composition of claim 8 wherein said
composition consists of bimatoprost, brimonidine tartrate, timolol
maleate, sodium phosphate dibasic heptahydrate, citric acid
monohydrate, sodium chloride, and sodium hydroxide in an aqueous
carrier.
13) The pharmaceutical composition of claim 12 further consisting
of benzalkonium chloride.
14) A method of reducing intraocular pressure (IOP) in a patient
suffering from elevated IOP in patients who do not have adequate
IOP control with mono or dual combination therapy comprising
administering a topical pharmaceutical composition comprising
bimatoprost, brimonidine, and timolol to the eye of a subject in
need thereof.
15) The method of claim 14 wherein the pharmaceutical composition
further comprises sodium phosphate dibasic heptahydrate, citric
acid monohydrate, sodium chloride, and sodium hydroxide in an
aqueous carrier.
16) The method of claim 15 wherein the pharmaceutical composition
further comprises benzalkonium chloride and is applied to the eye
at least once a day.
17) The method of claim 15 wherein said composition consists
essentially of bimatoprost, brimonidine tartrate, timolol maleate,
sodium phosphate dibasic heptahydrate, citric acid monohydrate,
sodium chloride, and sodium hydroxide in an aqueous carrier.
18) The method of claim 16 wherein said composition is applied
twice a day.
19) The method of claim 17 wherein said composition consists
essentially of 0.01% w/v bimatoprost, 0.15% w/v brimonidine
tartrate, 0.68% w/v timolol maleate, 1.5% w/v sodium phosphate
dibasic heptahydrate, 0.025% w/v citric acid monohydrate and 0.35%
w/v sodium chloride.
20) The method of claim 18 wherein said composition consists
essentially of 0.005% w/v benzalkonium chloride.
Description
CROSS REFERENCE TO RELATED APPLICATION
[0001] This application is a continuation of U.S. patent
application Ser. No. 15/347,532, filed Nov. 9, 2016, which is a
continuation of U.S. patent application Ser. No. 14/147,302, filed
Jan. 3, 2014, now U.S. Pat. No. 9,522,153, issued Dec. 20, 2016,
which is a continuation-in-part of U.S. patent application Ser. No.
13/698,182, filed Nov. 15, 2012, and now abandoned, which is a U.S.
National Stage Application under 35 U.S.C. .sctn. 371 of PCT
Application No. PCT/US10/61563, filed Dec. 21, 2010, which claims
priority to U.S. Provisional Application No. 61/361,749, filed Jul.
6, 2010 and U.S. Provisional Application No. 61/288,936, filed Dec.
22, 2009, the disclosures of which are hereby incorporated by
reference in their entireties and serve as the basis of a priority
and/or benefit claim for the present application.
FIELD
[0002] Embodiments disclosed herein provide compositions and
methods that lower intraocular pressure. The compositions and
methods disclosed herein include bimatoprost, brimonidine and
timolol and combinations thereof and are particularly suited for
patients who require maximum medical therapy for lowering
intraocular pressure and for treatment of glaucoma.
BACKGROUND
[0003] Numerous disturbances or disorders of the eye lead to an
increase in intraocular pressure (IOP). For example, post-surgical
or post-laser trabeculectomy, ocular hypertensive episodes and
glaucoma all can result in increased IOP.
[0004] On the basis of its etiology, glaucoma has been classified
as primary or secondary. Primary glaucoma, also known as congenital
glaucoma, can occur in the absence of other ocular conditions. The
underlying causes of primary glaucoma are not known. It is known,
however, that the increased IOP observed in primary glaucoma is due
to the obstruction of aqueous humor flow out of the eye. In chronic
open-angle primary glaucoma, the anterior chamber and its anatomic
structures appear normal, but drainage of the aqueous humor is
impeded. In acute or chronic angle-closure primary glaucoma, the
anterior chamber is shallow, the filtration angle is narrowed, and
the iris may obstruct the trabecular meshwork at the entrance of
the canal of Schlemm. Dilation of the pupil may also push the root
of the iris forward against the angle to produce pupillary block
precipitating an acute attack. Additionally, eyes with narrow
anterior chamber angles are predisposed to acute angle-closure
glaucoma attacks of various degrees of severity.
[0005] Secondary glaucoma results from another pre-existing ocular
disease such as, without limitation, uveitis, intraocular tumor,
enlarged cataract, central retinal vein occlusion, trauma to the
eye, operative procedures and intraocular hemorrhage. Accordingly,
any interference with the outward flow of aqueous humor from the
posterior chamber into the anterior chamber and subsequently, into
the canal of Schlemm can lead to secondary glaucoma.
[0006] Considering all types of glaucoma together, this ocular
disorder occurs in about 2% of all persons over the age of 40.
Unfortunately, glaucoma can be asymptomatic for years before
progressing to a rapid loss of vision.
[0007] In cases where surgery is not indicated, topical
.beta.-adrenoreceptor antagonists have traditionally been the drugs
of choice for treating glaucoma. Certain eicosanoids and their
derivatives have also been reported to possess ocular hypotensive
activity, and have been recommended for use in glaucoma management.
Eicosanoids and their derivatives include numerous biologically
important compounds such as prostaglandins and their derivatives.
While prostaglandins were earlier regarded as potent ocular
hypertensives, evidence has accumulated that some prostaglandins
are highly effective ocular hypotensive agents ideally suited for
long-term medical management of glaucoma.
[0008] Prostaglandins can be described as derivatives of prostanoic
acid which have the structural formula:
##STR00001##
[0009] Particularly useful hypotensive prostaglandins include
PGF.sub.2.alpha., PGF.sub.1.alpha., PGE.sub.2.alpha., and certain
lipid-soluble esters, such as C.sub.1 to C.sub.5 alkyl esters, e.g.
1-isopropyl ester, of such compounds. Many patients needing to
lower their intraocular pressure are on fixed combination therapies
such as COMBIGAN.RTM. and GANFORT.RTM.. However, for some patients,
combination therapies are not enough to lower intraocular pressure
and Triple Combination therapy is required. The combined effect is
expected to result potentially in additional IOP reduction in
patients with chronic open-angle glaucoma or ocular hypertension
who are not well controlled on 2 IOP-lowering agents.
SUMMARY
[0010] Embodiments disclosed herein relate to enhanced medical
therapy for patients with increased intraocular pressure (IOP)
using a combination of IOP-lowering agents. Particularly,
embodiments disclosed herein contain a Triple Combination of
IOP-lowering agents for use by patients with increased IOP
providing superior efficacy while maintaining safety and
tolerability. In certain embodiments, the patient or subject is
human.
[0011] Bimatoprost is a potent ocular hypotensive agent (Cantor,
2001; Sherwood et al, 2001). It is a synthetic prostamide,
structurally related to prostaglandin F2.alpha. (PGF2.alpha.), that
selectively mimics the effects of biosynthesized substances called
prostamides.
[0012] Bimatoprost reduces IOP in humans by increasing aqueous
humor outflow through the trabecular meshwork and enhancing
uveoscleral outflow (Brubaker et al, 2001). Brimonidine tartrate is
an alpha-2 adrenergic receptor agonist that is 1000-fold more
selective for the alpha-2 adrenoceptor than the alpha-1
adrenoreceptor
(Munk et al, 1994). It is thought that brimonidine tartrate lowers
IOP by enhancing uveoscleral outflow and reducing aqueous humor
formation (Report BIO-94-012; Serle et al, 1991). Timolol is a
beta-1 and beta-2 non-selective adrenergic receptor blocking agent.
Timolol lowers IOP by reducing aqueous humor formation
(Coakes and Brubaker, 1978; Yablonski et al, 1978).
[0013] According to the various example embodiments, the
compositions contain bimatoprost, brimonidine, and timolol. In
another embodiment, the brimonidine is a salt thereof, such as
brimonidine tartrate, and the timolol is a salt thereof, such as
timolol maleate. In another embodiment, the compositions further
contain sodium phosphate dibasic heptahydrate, citric acid
monohydrate, sodium chloride, and sodium hydroxide in an aqueous
carrier. In yet another embodiment, the compositions further
contain benzalkonium chloride.
[0014] In another embodiment, the compositions contain 0.01% w/v
bimatoprost, 0.15% w/v brimonidine tartrate, and 0.683% w/v timolol
maleate. In this combination, both brimonidine tartrate and timolol
maleate are at concentrations and regimens that are approved for
the individual components. Bimatoprost in this combination,
however, is at 0.01%, which is lower than the 0.03% concentration
approved.
[0015] In yet another embodiment, the compositions further contain
1.5% w/v sodium phosphate dibasic heptahydrate, 0.025% w/v citric
acid monohydrate, and 0.35% w/v sodium chloride. In yet another
embodiment, the compositions further contain 0.005% w/v
benzalkonium chloride.
[0016] In another embodiment, the compositions consist essentially
of bimatoprost, brimonidine, and timolol. In another embodiment,
the brimonidine is a salt thereof, such as brimonidine tartrate,
and the timolol is a salt thereof, such as timolol maleate. In yet
another embodiment, the compositions further consist essentially of
sodium phosphate dibasic heptahydrate, citric acid monohydrate,
sodium chloride, and sodium hydroxide in an aqueous carrier. In yet
another embodiment, the compositions further consist essentially of
benzalkonium chloride.
[0017] In another embodiment, the compositions consist essentially
of 0.01% w/v bimatoprost, 0.15% w/v brimonidine tartrate, and 0.68%
w/v timolol maleate. In another embodiment, the compositions
further consist essentially of 1.5% w/v sodium phosphate dibasic
heptahydrate, 0.025% w/v citric acid monohydrate, 0.35% w/v sodium
chloride, sodium hydroxide, in an aqueous carrier. In yet another
embodiment, the compositions further consists essentially of 0.005%
w/v benzalkonium chloride.
[0018] In another embodiment, the compositions consist of
bimatoprost, brimonidine, timolol, sodium phosphate dibasic
heptahydrate, citric acid monohydrate, sodium chloride, and sodium
hydroxide in an aqueous carrier. In another embodiment, the
brimonidine is a salt thereof, brimonidine tartrate, and the
timolol is a salt thereof, timolol maleate. In yet another
embodiment, the compositions further consist of benzalkonium
chloride.
[0019] In another embodiment, the compositions consist of 0.01% w/v
bimatoprost, 0.15% w/v brimonidine tartrate, and 0.68% w/v timolol
maleate, 1.5% w/v sodium phosphate dibasic heptahydrate, 0.025% w/v
citric acid monohydrate, 0.35% w/v sodium chloride, sodium
hydroxide, and water. In yet another embodiment, the compositions
further consist of 0.005% w/v benzalkonium chloride.
[0020] In certain embodiments disclosed herein, the compositions do
not contain, consist of, or consist essentially of components other
than bimatoprost, brimonidine, timolol, sodium phosphate dibasic
heptahydrate, citric acid monohydrate, sodium chloride,
benzalkonium chloride, and sodium hydroxide in an aqueous
carrier.
[0021] Embodiments disclosed herein also include methods of
reducing IOP through the administration of compositions containing
bimatoprost, brimonidine, and timolol. In another embodiment the
brimonidine is a salt thereof, such as brimonidine tartrate, and
the timolol is a salt thereof, such as timolol maleate. In yet
another embodiment the administered compositions further contain
sodium phosphate dibasic heptahydrate, citric acid monohydrate,
sodium chloride, and sodium hydroxide in an aqueous carrier. In yet
another embodiment the administered compositions further contain
benzalkonium chloride.
[0022] In another embodiment the method of lowering IOP includes
administering compositions containing 0.01% w/v bimatoprost, 0.15%
w/v brimonidine tartrate, and 0.68% w/v timolol maleate. In yet
another embodiment, the administered compositions further contain
1.5% w/v sodium phosphate dibasic heptahydrate, 0.025% w/v citric
acid monohydrate, 0.35% w/v sodium chloride, sodium hydroxide, in
an aqueous carrier. In yet another embodiment, the administered
compositions further contain 0.005% w/v benzalkonium chloride.
[0023] Embodiments disclosed herein also include methods of
reducing IOP through the administration of compositions described
herein to subjects or patients. In certain embodiments the
compositions described herein are administered to human
subjects.
[0024] Embodiments disclosed herein also include methods of
reducing IOP through the administration of compositions that
consist essentially of bimatoprost, brimonidine, and timolol. In
another embodiment the brimonidine is a salt thereof, such as
brimonidine tartrate, and the timolol is a salt thereof, such as
timolol maleate. In yet another embodiment the administered
compositions further consist essentially of sodium phosphate
dibasic heptahydrate, citric acid monohydrate, sodium chloride, and
sodium hydroxide in an aqueous carrier. In yet another embodiment
the administered compositions further consist essentially of
benzalkonium chloride.
[0025] In another embodiment the method of lowering IOP includes
administering compositions consisting essentially of 0.01% w/v
bimatoprost, 0.15% w/v brimonidine tartrate, and 0.68% w/v timolol
maleate. In yet another embodiment, the administered compositions
further consist essentially of 1.5% w/v sodium phosphate dibasic
heptahydrate, 0.025% w/v citric acid monohydrate, 0.35% w/v sodium
chloride, and sodium hydroxide in an aqueous carrier. In yet
another embodiment, the administered compositions further consist
essentially of 0.005% w/v benzalkonium chloride.
[0026] Embodiments disclosed herein also include methods of
reducing IOP through the administration of compositions that
consist of bimatoprost, brimonidine, timolol, sodium phosphate
dibasic heptahydrate, citric acid monohydrate, sodium chloride, and
sodium hydroxide in an aqueous carrier. In another embodiment the
brimonidine is the salt, brimonidine tartrate, and the timolol is
the salt, timolol maleate. In yet another embodiment the
administered compositions further consist of benzalkonium
chloride.
[0027] In another embodiment the method of lowering IOP includes
administering compositions consisting of 0.01% w/v bimatoprost,
0.15% w/v brimonidine tartrate, 0.68% w/v timolol maleate, 1.5% w/v
sodium phosphate dibasic heptahydrate, 0.025% w/v citric acid
monohydrate, 0.35% w/v sodium chloride, and sodium hydroxide in an
aqueous carrier. In yet another embodiment, the administered
compositions further consist of 0.005% w/v benzalkonium
chloride.
[0028] Some embodiments of the present invention are included in
the following paragraphs:
[0029] 1) A pharmaceutical composition for lowering intraocular
pressure in a patient suffering from elevated intraocular pressure
comprising bimatoprost, brimonidine, and timolol.
[0030] 2) The pharmaceutical composition of paragraph 1 wherein the
pharmaceutical composition is effective in lowering intraocular
pressure in patients who do not have adequate IOP control with mono
or dual combination therapy.
[0031] 3) The pharmaceutical composition of paragraph 1 wherein the
brimonidine is brimonidine tartrate and the timolol is timolol
maleate.
[0032] 4) The pharmaceutical composition of paragraph 2 wherein the
composition is applied topically and further comprising sodium
phosphate dibasic heptahydrate, citric acid monohydrate, sodium
chloride, and sodium hydroxide in an aqueous carrier.
[0033] 5) The pharmaceutical composition of paragraph 3 further
comprising benzalkonium chloride.
[0034] 6) The pharmaceutical composition of paragraph 1 comprising
about 0.01% w/v bimatoprost, about 0.15% w/v brimonidine tartrate
and about 0.68% w/v timolol maleate.
[0035] 7) The pharmaceutical composition of paragraph 5 further
comprising about 0.005% w/v benzalkonium chloride.
[0036] 8) A pharmaceutical composition for lowering IOP in patients
suffering from elevated IOP who do not have adequate IOP control
with mono or dual combination therapy consisting essentially of
bimatoprost, brimonidine tartrate, timolol maleate, sodium
phosphate dibasic heptahydrate, citric acid monohydrate, sodium
chloride, and sodium hydroxide in an aqueous carrier.
[0037] 9) The pharmaceutical composition of paragraph 8 further
consisting essentially of benzalkonium chloride.
[0038] 10) The pharmaceutical composition of paragraph 8 consisting
essentially of about 0.01% w/v bimatoprost, about 0.15% w/v
brimonidine tartrate, about 0.68% w/v timolol maleate, about 1.5%
w/v sodium phosphate dibasic heptahydrate, about 0.025% w/v citric
acid monohydrate and about 0.35% w/v sodium chloride.
[0039] 11) The pharmaceutical composition of paragraph 10
consisting essentially of about 0.005% w/v benzalkonium
chloride.
[0040] 12) The pharmaceutical composition of paragraph 8 wherein
said composition consists of bimatoprost, brimonidine tartrate,
timolol maleate, sodium phosphate dibasic heptahydrate, citric acid
monohydrate, sodium chloride, and sodium hydroxide in an aqueous
carrier.
[0041] 13) The pharmaceutical composition of paragraph 12 further
consisting of benzalkonium chloride.
[0042] 14) A method of reducing intraocular pressure (IOP) in a
patient suffering from elevated IOP in patients who do not have
adequate IOP control with mono or dual combination therapy
comprising administering a topical pharmaceutical composition
comprising bimatoprost, brimonidine, and timolol to the eye of a
subject in need thereof.
[0043] 15) The method of paragraph 14 wherein the pharmaceutical
composition further comprises sodium phosphate dibasic
heptahydrate, citric acid monohydrate, sodium chloride, and sodium
hydroxide in an aqueous carrier.
[0044] 16) The method of paragraph 15 wherein the pharmaceutical
composition further comprises benzalkonium chloride and is applied
to the eye at least once a day.
[0045] 17) The method of paragraph 15 wherein said composition
consists essentially of bimatoprost, brimonidine tartrate, timolol
maleate, sodium phosphate dibasic heptahydrate, citric acid
monohydrate, sodium chloride, and sodium hydroxide in an aqueous
carrier.
[0046] 18) The method of paragraph 16 wherein said composition is
applied twice a day.
[0047] 19) The method of paragraph 17 wherein said composition
consists essentially of 0.01% w/v bimatoprost, 0.15% w/v
brimonidine tartrate, 0.68% w/v timolol maleate, 1.5% w/v sodium
phosphate dibasic heptahydrate, 0.025% w/v citric acid monohydrate
and 0.35% w/v sodium chloride.
[0048] 20) The method of paragraph 18 wherein said composition
consists essentially of 0.005% w/v benzalkonium chloride.
Definition of Terms
[0049] For the purposes of this disclosure, "treat," "treating,"
"treatment," or "therapy" refer to the use of a compound,
composition, therapeutically active agent, or drug in the
diagnosis, cure, mitigation, or treatment of the disease or
underlying condition.
[0050] A "pharmaceutically acceptable salt" is any salt that
retains the activity of the parent compound and does not impart any
additional deleterious or untoward effects on the subject to which
it is administered and in the context in which it is administered
compared to the parent compound. A pharmaceutically acceptable salt
also refers to any salt which can form in vivo as a result of
administration of an acid, another salt, or a prodrug which is
converted into an acid or salt.
[0051] Pharmaceutically acceptable salts of acidic functional
groups can be derived from organic or inorganic bases. The salt can
comprise a mono or polyvalent ion. Of particular interest are the
inorganic ions lithium, sodium, potassium, calcium, and magnesium.
Organic salts can be made with amines, particularly ammonium salts
such as mono-, di- and trialkyl amines or ethanol amines. Salts can
also be formed with caffeine, tromethamine and similar molecules.
Hydrochloric acid or some other pharmaceutically acceptable acid
can form a salt with a compound that includes a basic group, such
as an amine or a pyridine ring.
[0052] A "prodrug" is a compound which is converted to a
therapeutically active compound after administration, and the term
should be interpreted as broadly herein as is generally understood
by one of ordinary skill in the art. While not intending to limit
the scope of this disclosure, conversion can occur by hydrolysis of
an ester group or some other biologically labile group. Generally,
but not necessarily, a prodrug is inactive or less active than the
therapeutically active compound to which it is converted. Ester
prodrugs of the compounds disclosed herein are specifically
contemplated. An ester can be derived from a carboxylic acid of Cl
(i.e. the terminal carboxylic acid of a natural prostaglandin), or
an ester can be derived from a carboxylic acid functional group on
another part of the molecule, such as on a phenyl ring. While not
intending to be limiting, an ester can be an alkyl ester, an aryl
ester, or a heteroaryl ester. The term alkyl has the meaning
generally understood by those of ordinary skill in the art and
refers to linear, branched, or cyclic alkyl moieties. C.sub.1-6
alkyl esters are particularly useful, where alkyl part of the ester
has from 1 to 6 carbon atoms and includes, but is not limited to,
methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl,
t-butyl, pentyl isomers, hexyl isomers, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, and combinations thereof having from 1-6
carbon atoms, etc.
DESCRIPTION
[0053] In a series of United States patent applications assigned to
Allergan, Inc., prostaglandin esters with increased ocular
hypotensive activity accompanied with substantially reduced
side-effects are disclosed. U.S. patent application Ser. No.
386,835 (filed Jul. 27, 1989), relates to certain
11-acyl-prostaglandins, such as 11-pivaloyl, 11-acetyl,
11-isobutyryl, 11-valeryl, and 11-isovaleryl PGF.sub.2.alpha.
useful for lowering intraocular pressure (IOP). Intraocular
pressure-reducing 15-acyl prostaglandins are disclosed in U.S.
patent application Ser. No. 357,394 (filed May 25, 1989).
Similarly, 11,15-9,15- and 9,11-diesters of prostaglandins, for
example 11,15-dipivaloyl PGF.sub.2.alpha. have ocular hypotensive
activity. See U.S. patent application Ser. No. 385,645 (filed Jul.
27, 1990), now U.S. Pat. No. 4,994,274; U.S. patent application
Ser. No. 584,370 (filed Sep. 18, 1990), now U.S. Pat. No.
5,028,624, which is a continuation of U.S. patent application Ser.
No. 386,312 (filed Jul. 27, 1989), and U.S. patent application Ser.
No. 585,284 (filed Sep. 18, 1990), now U.S. Pat. No. 5,034,413
which is a continuation of U.S. patent application Ser. No. 385,834
(filed Jul. 27, 1989). Each of these references is incorporated by
reference herein in its entirety for its teachings regarding
prostaglandin esters with ocular hypotensive activity.
[0054] Disclosed herein are compositions and methods for lowering
IOP using a combination of at least three IOP-lowering agents, or
pharmaceutical salts or prodrugs thereof including bimatoprost,
brimonidine, and timolol. In certain embodiments, additional
ingredients are added to the Triple Combination of bimatoprost,
brimonidine, and timolol to make the composition more
ophthalmically acceptable, including, without limitation,
preservatives, buffers, tonicity adjusters, and surfactants.
Additionally, various vehicles can be used in the disclosed
embodiments. These compositions are useful in reducing IOP in
patients with increased IOP, thus, for example, preventing or
delaying glaucoma in those with ocular hypertension, and preventing
or delaying further vision loss in those with glaucoma.
[0055] Without wishing to be bound by any particular theory, it is
thought that the prostamide analog, bimatoprost (sold by Allergan,
Inc. under the name LUMIGAN.RTM.) reduces IOP by increasing the
aqueous humor outflow of an eye. Bimatoprost's chemical name is
(Z)-7-[(1R,2R,3R,5S)-3,5-Dihydroxy-2-[1E,3S)-3-hydroxy-5-phenyl-1-penteny-
l]cyclopentyl]-5-N-ethylheptenamide, and it has a molecular weight
of 415.58.
[0056] Brimonidine, an .alpha.2-andrenergic agonist receptor,
reduces the body's production of aqueous humor and increases the
flow of aqueous humor out of the eye, resulting in a decrease in
IOP. Brimonidine is available from Allergan, Inc. as ALPHAGAN.RTM..
The chemical name of brimonidine tartrate, a salt of brimonidine,
is 5-bromo-6-(2-imidazolidinylideneamino) quinoxaline L-tartrate.
Brimonidine has a molecular weight of 442.24 as the tartrate
salt.
[0057] Timolol, a non-selective .beta.-adrenergic receptor blocking
agent, reduces the body's aqueous humor production through the
blockage of the .beta. receptors on the ciliary epithelium. In one
embodiment, the timolol component contains an acid salt of timolol
and in another embodiment contains timolol maleate. The chemical
name of timolol maleate, is
(-)-1-tert-butylamino)-3-[(4-morpholino-1,2,5-thiodiazol-3-yl)oxy]-2-prop-
anol maleate (1:1) (salt). Timolol maleate has a molecular weight
of 432.50. Timolol is commercially available from Merck as
TIMOPTIC.RTM..
[0058] Preservatives that can be used in the pharmaceutical
compositions of the present embodiments include, but are not
limited to, benzalkonium chloride, chlorobutanol, thimerosal,
phenylmercuric acetate and phenylmercuric nitrate.
Preservative-free compositions can be considered, in one
non-limiting embodiment for patients experiencing hypersensitivity
reactions with the above listed preservatives or other
preservatives not listed.
[0059] Various buffers and means for adjusting pH can be used so
long as the resulting preparation is ophthalmically acceptable.
Accordingly, buffers include acetate buffers, citrate buffers,
phosphate buffers and borate buffers. Acids or bases can also be
used to adjust the pH of these formulations as needed. The pH of
the disclosed compositions should preferably be maintained between
6.5 and 7.2 with an appropriate buffer system.
[0060] Tonicity adjustors can be added as needed and include,
without limitation, glycerin, sorbitol, sodium chloride, potassium
chloride, and mannitol, or any other suitable ophthalmically
acceptable tonicity adjustor. In one embodiment the tonicity
adjustor is sodium chloride.
[0061] In certain embodiments, a surfactant such as a polysorbate,
for example, a TWEEN.RTM. by Sigma, can be added. Further, any
other suitable surfactants can be used as well.
[0062] Various vehicles can also be used in the ophthalmic
preparations of the present embodiments. These vehicles include,
but are not limited to, polyvinyl alcohol, povidone, hydroxypropyl
methyl cellulose, poloxamers, carboxymethyl cellulose, hydroxyethyl
cellulose, physiological saline solution, water, purified water,
and combinations thereof.
[0063] Additionally, ophthalmically acceptable antioxidants can be
included in the disclosed compositions. Suitable antioxidants
include, but are not limited to, sodium metabisulfite, sodium
thiosulfate, acetylcysteine, butylated hydroxyanisole and butylated
hydroxytoluene and the like and mixtures thereof.
[0064] Another excipient component that can be included in the
ophthalmic preparations are chelating agents. A useful chelating
agent is edetate disodium, although other chelating agents can also
be used in place of or in conjunction edetate disodium.
[0065] Compositions and methods disclosed herein can also be used
in combination with the following classes of drugs,
pharmaceutically acceptable salts or prodrugs thereof:
.beta.-Blockers (or .beta.-adrenergic antagonists) including,
without limitation, carteolol, levobunolol, metiparnolol, timolol
hemihydrate, .beta.1-selective antagonists such as betaxolol, and
the like; Adrenergic Agonists including, without limitation,
non-selective adrenergic agonists such as epinephrine borate,
epinephrine hydrochloride, and dipivefrin, and the like; and
.alpha..sub.2-selective adrenergic agonists such as apraclonidine
and the like; Carbonic Anhydrase Inhibitors including, without
limitation, acetazolamide, dichlorphenamide, methazolamide,
brinzolamide, dorzolamide, and the like; Cholinergic Agonists
including, without limitation, direct acting cholinergic agonists
such as carbachol, pilocarpine hydrochloride, pilocarpine nitrate,
pilocarpine, and the like; Cholinesterase inhibitors such as
demecarium, echothiophate, physostigmine, and the like; Glutamate
Antagonists and other neuroprotective agents such as Ca.sup.2+
channel blockers such as memantine, amantadine, rimantadine,
nitroglycerin, dextrorphan, dextromethorphan, CGS-19755,
dihydropyridines, verapamil, emopamil, benzothiazepines, bepridil,
diphenylbutylpiperidines, diphenylpiperazines, HOE 166 and related
drugs, fluspirilene, eliprodil, ifenprodil, CP-101,606, tibalosine,
2309BT, and 840S, flunarizine, nicardipine, nifedipine, nimodipine,
barnidipine, verapamil, lidoflazine, prenylamine lactate,
amiloride, and the like; Additional prostamides or pharmaceutically
acceptable salts or prodrugs thereof; Prostaglandins including
travoprost, UFO-21, cloprostenol, fluprostenol,
13,14-dihydro-cloprostenol, isopropyl unoprostone, latanoprost and
the like; and Cannabinoids including CB1 agonists such as
WIN-55212-2 and CP-55940 and the like.
[0066] For treatment of diseases affecting the eye, the disclosed
compositions can be administered topically or as ocular
implants.
[0067] Pharmaceutical compositions can be prepared by combining a
therapeutically effective amount of bimatoprost, brimonidine and
timolol according to the present disclosure, or pharmaceutically
acceptable acid addition salts thereof, as active ingredients, with
conventional ophthalmically acceptable pharmaceutical excipients,
and by preparation of unit dosage forms suitable for ocular use.
The therapeutically efficient amount will vary with the activity of
the active ingredients; however, typically in combination will be
between 0.0001 and 20% (w/v), between 0.0001 and 10% (w/v), between
0.0001 and 5% (w/v), between 0.0005 and 3% (w/v), between 0.00075
and 2% (w/v), between 0.001 and 1.0% (w/v), between 0.2 and 1.0%
(w/v), between 0.5 and 1.0% (w/v), 0.85% (w/v) or 0.843% (w/v) of
the composition. The compositions can be prepared as follows:
[0068] 1. Add quantity of water i.e. approximately 70% of the batch
size in a chosen stainless steel vessel. [0069] 2. Add Sodium
Phosphate Dibasic Heptahydrate to step 1 under mechanical stirring
and mix until dissolved. [0070] 3. Add Citric Acid Monohydrate to
step 2 under stirring and mix until dissolved. [0071] 4. Add Sodium
Chloride to step 3 under stirring and mix until dissolved. [0072]
5. Add bimatoprost to step 4 under stirring and mix until a clear
solution is obtained. [0073] 6. Add timolol maleate to step 5 under
stirring and mix until dissolved. [0074] 7. Add brimonidine
tartrate to step 6 under stirring and mix until dissolved. [0075]
8. Add benzalkonium chloride to step 7 as a stock solution under
stirring. [0076] 9. Check pH of the solution, adjust if necessary
to pH 7.1 [0077] 10. Make up the volume to 100% of the batch size
with water and stir for 5-10 minutes.
[0078] Bimatoprost can be included in compositions of the
embodiments disclosed herein in an amount of between 0.0001 and 15%
(w/v), between 0.0001 and 10% (w/v), between 0.0001 and 5% (w/v),
between 0.0005 and 3% (w/v), between 0.00075 and 2% (w/v), between
0.001 and 1.0% (w/v), between 0.001 and 0.1 (w/v), between 0.005
and 0.05% (w/v), or 0.01% (w/v) of the composition.
[0079] Brimonidine can be included in compositions of the
embodiments disclosed herein in an amount of between 0.0001 and 15%
(w/v), between 0.0001 and 10% (w/v), between 0.0001 and 5% (w/v),
between 0.0005 and 3% (w/v), between 0.00075 and 2% (w/v), between
0.001 and 1.0% (w/v), between 0.001 and 0.2 (w/v), between 0.005
and 0.05% (w/v), or 0.15% (w/v) of the composition. In one
embodiment brimonidine is provided as brimonidine tartrate in an
amount of 0.15% (w/v) of the composition.
[0080] Timolol can be included in compositions of the embodiments
disclosed herein in an amount of between 0.0001 and 15% (w/v),
between 0.0001 and 10% (w/v), between 0.0001 and 5% (w/v), between
0.0005 and 3% (w/v), between 0.01 and 2% (w/v), between 0.1 and
1.0% (w/v), between 0.1 and 0.9 (w/v), between 0.3 and 0.8% (w/v),
0.5%, 0.6% (w/v), 0.68% (w/v/) or 0.683% (w/v) of the composition.
In one embodiment timolol is provided as timolol maleate in an
amount of 0.6%, 0.68% or 0.683% (w/v) of the composition.
[0081] The amount of the presently useful compositions administered
is dependent on the therapeutic effect or effects desired, on the
specific patient being treated, on the severity and nature of the
patient's condition, on the manner of administration, on the
potency and pharmacodynamics of the particular compound or
compounds employed, and on the judgment of the prescribing
physician. The therapeutically effective dosage of the presently
useful compositions can be in the range of 0.01 to 200 mg/kg/day.
In certain embodiments, the therapeutically effective dosage can be
0.1, 0.5, 1, 2.5, 5, 15, 20, 25, 50, 60, 70, 75, 80, 85, 90 or 100
mg/kg/day. The dosage can be provided in a single daily dosage or
in a number of doses from 2 to 24 over the course of day. In
certain embodiments, dosages can be administered every other day,
every third day, once a week, once a month, etc . . . .
[0082] In preferred embodiments, the comfort of formulations
disclosed herein is maximized as much as possible, although
sometimes formulation considerations (e.g. drug stability) can
necessitate less than optimal comfort. In the case that comfort
cannot be maximized, the compositions should be formulated such
that the compositions are tolerable to the patient for ophthalmic
use.
[0083] The ophthalmic formulations of the present disclosure are
conveniently packaged in forms suitable for metered application,
such as in containers equipped with a dropper, to facilitate
application to the eye. Containers suitable for dropwise
application are usually made of suitable inert, non-toxic plastic
material, and generally contain between 0.5 and 15 ml solution. One
package can contain one or more unit doses.
[0084] Preservative-free solutions (e.g., Table 7) can be
formulated in non-resealable containers containing up to 1, 2, 5,
10, 50, or 100 unit doses, where a typical unit dose is from 1 to 8
drops. The volume of one drop generally will be from 20 to 35
.mu.l.
[0085] Various exemplary embodiments can be formulated as shown in
the Tables follows:
TABLE-US-00001 TABLE 1 Ingredients Amount (% w/v) Active
Ingredients 0.001-5 Preservative 0-0.10 Vehicle 0-40 Tonicity
Adjuster 1-10 Buffer 0.01-10 pH Adjuster q.s. pH 4.5-7.5
Antioxidant As needed Surfactant As needed Purified Water As needed
to make 100%
TABLE-US-00002 TABLE 2 Ingredient Function % w/v Bimatoprost Active
0.003-0.03 Brimonidine Active 0.005-0.2 Timolol Active 0.2-0.5
Sodium Phosphate Buffering Agent As needed to make Dibasic
Heptahydrate ophthalmically acceptable Citric Acid Monohydrate
Buffering Agent As needed to make ophthalmically acceptable Sodium
Chloride Tonicity Agent As needed to make ophthalmically acceptable
Sodium Hydroxide pH Adjuster q.s. Water Vehicle q.s.
TABLE-US-00003 TABLE 3 Ingredient Function % w/v Bimatoprost Active
0.003-0.03 Brimonidine Tartrate Active 0.005-0.3 Timolol Maleate
Active 0.2-0.8 Sodium Phosphate Buffering Agent 1.0-2.0 Dibasic
Heptahydrate Citric Acid Monohydrate Buffering Agent 0.01-0.05
Sodium Chloride Tonicity Agent 0.10-0.30 Sodium Hydroxide pH
Adjuster q.s. Water Vehicle q.s.
TABLE-US-00004 TABLE 4 Ingredient Function % w/v Bimatoprost Active
0.003-0.03 Brimonidine Active 0.005-0.2 Timolol Active 0.2-0.5
Sodium Phosphate Buffering Agent As needed to make Dibasic
Heptahydrate ophthalmically acceptable Citric Acid Monohydrate
Buffering Agent As needed to make ophthalmically acceptable Sodium
Chloride Tonicity Agent As needed to make ophthalmically acceptable
Benzalkonium Chloride Preservative As needed to make ophthalmically
acceptable Sodium Hydroxide pH Adjuster q.s. Water Vehicle q.s.
TABLE-US-00005 TABLE 5 Ingredient Function % w/v Bimatoprost Active
0.01 Brimonidine Tartrate Active 0.1 Timolol Maleate Active 0.6
Sodium Phosphate Buffering Agent 1.5 Dibasic Heptahydrate Citric
Acid Monohydrate Buffering Agent 0.025 Sodium Chloride Tonicity
Agent 0.35 Sodium Hydroxide pH Adjuster q.s. Water Vehicle q.s.
TABLE-US-00006 TABLE 6 Ingredient Function % w/v Bimatoprost Active
0.01 Brimonidine Tartrate Active 0.1 Timolol Maleate Active 0.6
Sodium Phosphate Buffering Agent 1.5 Dibasic Heptahydrate Citric
Acid Monohydrate Buffering Agent 0.025 Sodium Chloride Tonicity
Agent 0.35 Benzalkonium Chloride Preservative 0.005 Sodium
Hydroxide pH Adjuster q.s. Water Vehicle q.s.
TABLE-US-00007 TABLE 7 Ingredient Function % w/v Bimatoprost Active
0.01 Brimonidine Tartrate Active 0.15 Timolol Maleate Active 0.68
Sodium Phosphate Buffering Agent 1.5 Dibasic Heptahydrate Citric
Acid Monohydrate Buffering Agent 0.025 Sodium Chloride Tonicity
Agent 0.35 Sodium Hydroxide pH Adjuster q.s. Water Vehicle q.s.
TABLE-US-00008 TABLE 8 Ingredient Function % w/v Bimatoprost Active
0.01 Brimonidine Tartrate Active 0.15 Timolol Maleate Active 0.68
Sodium Phosphate Buffering Agent 1.5 Dibasic Heptahydrate Citric
Acid Monohydrate Buffering Agent 0.025 Sodium Chloride Tonicity
Agent 0.35 Benzalkonium Chloride Preservative 0.005 Sodium
Hydroxide pH Adjuster q.s. Water Vehicle q.s.
TABLE-US-00009 TABLE 9 Ingredient Function % w/v Bimatoprost Active
0.01 Brimonidine Tartrate Active 0.15 Timolol Maleate Active 0.683
(equivalent to 0.5 timolol) Sodium Phosphate Buffering Agent 1.5
Dibasic Heptahydrate Citric Acid Monohydrate Buffering Agent 0.025
Sodium Chloride Tonicity Agent 0.35 Sodium Hydroxide pH Adjuster
q.s. Water Vehicle q.s.
TABLE-US-00010 TABLE 10 Ingredient Function % w/v Bimatoprost
Active About 0.01 Brimonidine Tartrate Active About 0.15 Timolol
Maleate Active About 0.683 Sodium Phosphate Buffering Agent About
1.5 Dibasic Heptahydrate Citric Acid Monohydrate Buffering Agent
About 0.025 Sodium Chloride Tonicity Agent About 0.35 Benzalkonium
Chloride Preservative About 0.005 Sodium Hydroxide pH Adjuster q.s.
Water Vehicle q.s. *"About" refers to variations in the
concentrations which would be considered bioequivalent by a
regulatory agency
[0086] Unless otherwise indicated, all numbers expressing
quantities of ingredients, properties such as molecular weight,
reaction conditions, and so forth used in the specification and
claims are to be understood as being modified in all instances by
the term "about." Accordingly, unless indicated to the contrary,
the numerical parameters set forth in the specification and
attached claims are approximations that may vary depending upon the
desired properties sought to be obtained by the present invention.
At the very least, and not as an attempt to limit the application
of the doctrine of equivalents to the scope of the claims, each
numerical parameter should at least be construed in light of the
number of reported significant digits and by applying ordinary
rounding techniques.
Example I--Triple Combination of Bimatoprost, Brimonidine and
Timolol
[0087] Thirty-six female New Zealand White rabbits, obtained from
Charles River Laboratories, Wilmington, Mass., 4 months old, and
weighing from 2.96 to 3.54 kilograms at the start of dosing, were
used for the study. One drop (.about.30 .mu.L/drop) of the
formulation of Table 11 was administered directly onto the superior
corneal surface of the left eye using a dropper bottle 2 or 4 times
daily (2 or 6 hour intervals) for 1 month.
TABLE-US-00011 TABLE 11 Ingredient Function % w/v Bimatoprost
Active 0.01 Brimonidine Tartrate Active 0.15 Timolol Maleate Active
0.683* Sodium Phosphate Buffering Agent 1.5 Dibasic Heptahydrate
Citric Acid Monohydrate Buffering Agent 0.025 Sodium Chloride
Tonicity Agent 0.35 Benzalkonium Chloride Preservative 0.005 Sodium
Hydroxide pH adjuster q.s. Water Vehicle q.s. *Equivalent to 0.5%
w/v timolol
[0088] The contralateral right eye served as an untreated control.
Dose administration and time of dosing are manually recorded onto
raw data sheets, and the worksheets serve as the official record of
dosing.
[0089] The intraocular pressure (IOP) in both eyes of all rabbits
was measured prior to initiation of dosing and at the end of the
1-month interim period. Future examinations will occur at the end
of the 3-month treatment period and following the 1-month recovery
period. IOP measurements are performed at approximately the same
time each examination day. An ophthalmic topical anesthetic (eg,
proparacaine HCl), is administered to the eye prior to
measurements. If deemed necessary, the eye is rinsed with sterile
saline at the completion of the measurement. IOP measurements are
manually recorded on raw data sheets.
[0090] In conclusion, female NZW rabbits (12/group) were
administered one topical ocular drop (.about.30 .mu.L/drop) of
Triple Combination or Triple Combination Placebo two or four times
daily in the left eye for 1 month. No drug-related effects were
observed in ophthalmology, gross ocular observations, body weight,
clinical observations, or food consumption. Expected, acceptable
drug-related decreases in intraocular pressure were observed in
rabbits given Triple Combination Ophthalmic Solution. Triple
Combination Ophthalmic Solution was well-tolerated.
TABLE-US-00012 TABLE 12 OS - Triple Combination Ophthalmic
Solution, 50 ppm BAK, (1 drop ~30 .mu.L, 4X/day) OD - Untreated OS
OD Study Animal Number Baseline Day 27 Baseline Day 27 350 9 9 9 9
351 13 8 12 8 352 11 8 11 9 353 9 8 9 10 354 10 8 11 9 355 12 9 11
9 356 11 9 13 9 357 10 7 11 8 358 12 9 11 9 359 11 9 10 10 360 10 9
11 10 361 12 9 12 10 Mean (n = 12) 10.8 8.5 10.9 9.2 SD 1.3 0.7 1.2
0.7 % Change from -- -21.5 -- -16.0 Baseline % Change from OD -0.8
-7.3 -- -- % Change from 0.8 -19.0 -5.8 -19.1 Placebo OS = Left
eye; OD = Right eye; Baseline = Day -6; "--" = Not applicable %
change from baseline = [(mean - baseline mean) / baseline mean]
.times. 100 % change from OD = [( mean OS - mean OD) / mean OD]
.times. 100.
Example II--IOP Lowering Effect of the Triple Combination Product
of Table 11
[0091] A 71 year old Caucasian male is suffering from open angle
glaucoma and elevated intraocular pressure which is threatening to
worsen his vision if left untreated. After three months on
combination therapy, the patient's IOP was not lowered to the
satisfaction of his physician. The 71 year old Caucasian begins
daily dosing in both eyes of the Triple Combination of Table 11 and
the patient is expected to experience adequate lowering of IOP that
was not achievable.
Example III--IOP Lowering of the Triple Combination Product of
Table 11 in a 64 Year African American Female
[0092] A 64 year old African American female suffering from
glaucoma is having difficulty lowering her IOP adequately with
combination therapy product of brimonidine and timolol. After four
months of combination therapy of the brimonidine and timolol
product, her physician switches her to the Triple Combination
therapy product in Table 11. After three weeks on the Triple
Combination therapy product, the patient's IOP in both eyes is
expected to be at acceptable levels.
Example IV--Treatment of Glaucoma of a 57 Year Old Caucasian
Female
[0093] A 57 year old Caucasian female suffering from open-angle
glaucoma has been largely non-responsive to first monotherapy and
then combination therapy for lowering IOP. She switches to twice
daily dosing of the composition in Table 11 and her IOP is expected
to return to normal levels. After 30 days of dosing both eyes with
the formulation of Table 11, the 57 year old Caucasian female's IOP
returns to normal levels as long as she continues dosing with the
formulation of Table 11.
Example V--Treatment of Elevated Intraocular Pressure in a 61 Year
Old Asian Male
[0094] A 61 year old Asian male IOP was measured with a tonometer
as being between 21.3 mmHg and 23.7 mmHg. Both monotherapy and
combination therapy with various therapeutic agents known to lower
IOP failed to bring the patient's IOP to acceptable levels. The
patient began taking twice a day administration of the formulation
of Table 11, with a single drop per eye in the morning and a single
drop per eye 12 hours later in the evening. After 31 days, the
patient's IOP is expected to lower to between 16.1-18.2 mmHg which
is considered acceptable. After 90 days, the patient's IOP is
expected to lower to between 15.5-16.8 mmHg.
Example VI--a Multicenter, Open-Label Study to Evaluate the Safety
and Efficacy of Twice-Daily 0.01% Bimatoprost/0.15%
Brimonidine/0.5% Timolol Ophthalmic Solution (Triple Combination)
in Patients in India, in Who have Glaucoma or Ocular Hypertension
with Elevated IOP, and are on Twice-Daily 0.2% Brimonidine/0.5%
Timolol Ophthalmic Solution (Dual Combination) Therapy
Phase: 3
Name of Investigational Product: 0.01% Bimatoprost/0.15%
Brimonidine/0.5% Timolol Ophthalmic Solution
Brief Description: Multicenter, Open-label, Phase 3 Study
[0095] Objectives: To evaluate the efficacy, safety and
tolerability of twice-daily dosed Triple Combination ophthalmic
solution administered for 12 weeks in patients, who have glaucoma
or ocular hypertension with elevated intraocular pressure (IOP),
and were on twice-daily 0.2% brimonidine/0.5% timolol ophthalmic
solution (either as COMBIGAN or as individual monotherapies,
hereafter referred to as Dual Combination) therapy.
Methodology:
[0096] This was a 12-week, multicenter, open label study of Triple
Combination. Patients administered study medications twice-daily in
each eye for 12 weeks. Prior to study entry, patients received Dual
Combination for at least 1 month. At baseline, patients
transitioned to open-label Triple Combination and were followed
post-baseline for 12 weeks. There were 5 scheduled visits
(prestudy, baseline [day 0], week 4, week 8, and week 12).
[0097] Triple Combination is a fixed combination ophthalmic
solution containing bimatoprost 0.01%, timolol 0.5%, and
brimonidine 0.15%. Each of these active drug substances is
available as individual monotherapies or as fixed-combinations of 2
of the 3 components. The inactive ingredients are: BAK (50 ppm) as
preservative, sodium chloride, sodium phosphate dibasic, citric
acid, and purified water.
[0098] Triple Combination ophthalmic solution was instilled twice
daily, at approximately 12 hour intervals for 12 weeks. As the
individual components have different dosing frequencies
(bimatoprost is dosed once daily, timolol once or twice daily, and
brimonidine is dosed twice daily), Triple Combination is dosed
twice daily. The concentrations of the active drug substances in
Triple Combination are at or less than when given concurrently, and
expose a patient too less BAK per dose. The overall daily exposure
to BAK with Triple Combination is less than that of the concurrent
use of the individual components. Bimatoprost 0.01% once daily,
timolol twice daily and ALPHAGAN P twice daily exposes a patient to
400 ppm BAK daily (LUMIGAN 0.01% has 200 ppm BAK, timolol 0.5% has
100 ppm BAK, and brimonidine 0.15% [ALPHAGAN P] has 0 ppm BAK),
whereas Triple Combination exposes a patient to 100 ppm daily [50
ppm per dose]).
[0099] This was a multicenter, open-label study to evaluate the
safety, tolerability, and efficacy of Triple Combination ophthalmic
solution administered twice daily in each eye for 12 weeks in
Indian patients with glaucoma or ocular hypertension with elevated
IOP on Dual Combination. This study represents the first
administration of this Triple Combination ophthalmic solution to
human subjects.
[0100] Triple Combination was prescribed to patients who did not
have adequate IOP control with dual combination. Thus, patients
with glaucoma or ocular hypertension while on Dual Combination
(brimonidine plus timolol) during the run-in period were an
appropriate population in which to assess the effects of Triple
Combination.
[0101] The primary efficacy measure, IOP, was assessed using the
"gold standard" instrument to measure IOP, the Goldmann applanation
tonometer (GAT). The primary efficacy variable was change from
baseline in the study eye mean diurnal IOP at week 12, an accepted
variable for studies evaluating IOP. Safety assessments were
adverse events (ocular and non-ocular), pulse rate, blood pressure,
visual acuity, biomicroscopy, ophthalmoscopy, cup/disc ratio,
visual fields (VFs), and pregnancy tests (for females of
childbearing potential).
Number of Patients (Planned and Enrolled):
Planned:
[0102] A total of 120 patients were planned to be enrolled.
Enrolled:
[0103] A total of 126 patients were enrolled in the study.
Diagnosis and Main Criteria for Eligibility:
[0104] Male or female patients 18 years of age or older, with a
diagnosis of glaucoma or ocular hypertension in each eye and who
had elevated IOP requiring bilateral administration of IOP-lowering
treatment.
Test Product, Dose and Mode of Administration:
[0105] 0.01% bimatoprost/0.15% brimonidine/0.5% timolol ophthalmic
solution. Duration of Treatment: 12 weeks.
Safety Measures:
[0106] The safety measures in this study included: adverse events,
pulse rate, blood pressure, visual acuity, biomicroscopy,
ophthalmoscopy and cup/disc ratio, visual field examinations, and
pregnancy testing for females of childbearing potential.
Adverse Events:
[0107] An adverse event was defined as any untoward medical
occurrence in a patient or clinical investigation patient
administered a pharmaceutical product and that does not necessarily
have a causal relationship with this treatment. An adverse event
could therefore be any unfavorable and unintended sign (including
an abnormal laboratory finding), symptom, or disease temporally
associated with the use of a medicinal (investigational) product,
whether or not related to the medicinal (investigational)
product.
Adverse events were monitored throughout the study.
Serious Adverse Events:
[0108] A serious adverse event was defined as any adverse event
occurring at any dose that resulted in any of the following
outcomes: death, a life-threatening adverse event, inpatient
hospitalization or prolongation of existing hospitalization, a
persistent or significant disability/incapacity, or a congenital
anomaly/birth defect. Important medical events that may not result
in death, be life-threatening, or require hospitalization could
have been considered a serious adverse event when, based upon
appropriate medical judgment, they could have jeopardized the
patient or subject and could have required medical or surgical
intervention to prevent one of the outcomes listed in this
definition.
Serious Medical Event:
[0109] A serious medical event was defined as a medical event
satisfying the same criteria as a serious adverse event, but the
event occurred between the obtaining of informed consent and entry
into the study.
Severity:
[0110] A clinical determination of the intensity of an adverse
event, serious adverse event, or serious medical event was
completed using the following definitions as guidelines:
Mild: Awareness of sign or symptom, but easily tolerated; Moderate:
Discomfort enough to cause interference with usual activity;
Severe: Incapacitating with inability to work or do usual activity;
and, Not applicable: In some cases, an adverse event could be an
`all or nothing` finding which could not be graded.
Relationship to Study Drug:
[0111] A determination was made regarding the relationship (if any)
between an adverse event and the study drug. A causal relationship
was present if a determination was made that there was a reasonable
possibility that the adverse event may have been caused by the
drug.
Pulse Rate:
[0112] Pulse rate was recorded as beats per minute and measured
with patients in a resting state (seated) for at least 5
minutes.
Systolic and Diastolic Blood Pressure:
[0113] Systolic and diastolic blood pressures were measured by
sphygmomanometer with patients in a resting state (seated upright)
for at least 5 minutes and recorded in mm Hg, using the same arm
each time.
Visual Acuity:
[0114] Best corrected visual acuity was measured for each eye using
a logarithmic visual acuity chart for testing at 10 feet
(approximately 3 meters). Snellen equivalent units were entered on
the appropriate CRF (eg, 20/20).
Biomicroscopy:
[0115] Biomicroscopy was performed without pupil dilation using
slit lamp examination. The examinations included evaluation of the
conditions of the lids, lid margins, conjunctiva, anterior chamber,
and cornea.
Ophthalmoscopy and Cup/Disc Ratio:
[0116] Lens, vitreous, and fundus pathology observations were made
through a dilated pupil. In addition, cup/disc ratio was measured
using direct and indirect ophthalmoscopy, and the Allergan Armaly
chart. Evaluations were performed after the IOP examination of the
relevant visits.
Visual Field Examinations:
[0117] Visual field examinations (including historical tests for
the prestudy visit) were performed using either Humphrey or Octopus
automated perimetry. Acceptable test methods were Humphrey 24-2
(full threshold or Swedish Interactive Thresholding Algorithm
Standard) and Octopus G1 or 24-2 programs and Dynamic or Normal
strategies. Visual fields were reported as normal or abnormal and
the mean deviation/mean defect/mean loss was also recorded in
decibels.
Efficacy and Safety Measures:
[0118] Efficacy: IOP as measured by Goldmann applanation tonometry.
Safety: Adverse events, pulse rate, systolic and diastolic blood
pressure, visual acuity, biomicroscopy, ophthalmoscopy and cup/disc
ratio, visual field examinations, and pregnancy testing.
Statistical Methods:
[0119] There were three analysis populations: a safety population,
a modified intent-to-treat (mITT) population, and a per-protocol
(PP) population. One study site was identified as having major Good
Clinical Practice (GCP) violations. The data for this site were not
included in any of the three analysis populations. Sensitivity
analyses were performed for efficacy and safety to confirm that the
removal of this site did not impact the results. With the exception
of the patients from this site, the safety population included all
treated patients; the mITT population included all enrolled
patients with a baseline and at least one postbaseline efficacy
evaluation; the PP population included all patients who had no
major protocol violations, received study medication, and had
at-least one follow-up visit. The mITT and PP populations were used
for the efficacy analyses and the safety population was used for
all safety analyses.
[0120] In general, continuous variables were summarized by
descriptive statistics including sample size, mean, standard
deviation (SD), median, and minimum and maximum. Categorical
variables were summarized by frequency and percentage.
[0121] The primary efficacy variable was change from baseline (on
Dual Combination) in the study eye mean diurnal IOP at week 12 (on
Triple Combination) in the mITT population. The null hypothesis was
that there was no difference between the week 12 and baseline
visits in study eye mean diurnal IOP. The alternative hypothesis
was that Triple Combination will decrease (from baseline) study eye
mean diurnal IOP at week 12. This hypothesis was tested using a
2-sided 1-sample t-test. Adverse events were coded using the
Medical Dictionary for Regulatory Activities nomenclature. The
preferred terms were summarized by primary system organ class and
maximum severity for all events (regardless of causality),
treatment-related adverse events, serious adverse events, and
adverse events that lead to study withdrawal.
Data Conventions:
[0122] The following data conventions were applied to all
analyses.
[0123] For efficacy analyses in the mITT population, unless
otherwise specified or implied, the missing values were imputed
using the method of last-observation-carried-forward (LOCF) from
the most recent preceding scheduled visit with nonmissing data and
corresponding hour. For example, if hour 8, week 12 IOP was
missing, the value at hour 8, week 8 (if nonmissing) was used for
imputation. If necessary, baseline values were carried forward.
[0124] Descriptive statistics (number of observations (n),
arithmetic mean (mean), SD, median, minimum and maximum [range])
were presented in the summary tables for continuous data. For
categorical data, frequency counts (n) and percentages (%) were
presented. The percentages were based on the population under
consideration.
[0125] Patient-wise data listings were generated. The listings were
sorted by site number followed by the patient number. The age, sex,
and race of patients were included in each listing.
Day 0 was the baseline visit. No data imputation for missing
baseline values was performed. Days from baseline (day 0) were
calculated as: [0126] Treatment days=visit date--day 0 visit date+1
[0127] Study days=visit date--day 0 visit date
[0128] The change from baseline value was computed as the value for
a given visit minus the baseline value, unless otherwise
indicated.
[0129] Partial dates were treated as missing in computations, but
were listed in the data listings as they appeared on the CRFs
unless otherwise specified. No imputation of missing values was
performed unless otherwise specified.
Primary Efficacy Analysis:
[0130] The primary efficacy variable was derived from the IOP
measurements. Each IOP assessment consisted of 2 consecutive
measurements in each eye. If these 2 measurements differed by >2
mm Hg, a third measurement was performed. If 2 measurements were
obtained, the IOP value for a given eye was the average of the 2
measurements. If the first 2 measurements differed by >2 mm Hg,
the IOP value for the given eye was the median of the 3
measurements. The study eye was defined as the eye that met the
enrollment criteria. If both eyes met the enrollment criteria, then
the eye with the higher IOP was considered the study eye. If both
eyes met all criteria and had the same IOP, then the right eye was
deemed the study eye.
[0131] The primary efficacy variable was the change from baseline
(day 0) in study eye mean diurnal IOP at the week 12 visit in the
mITT population. The mean diurnal IOP is calculated as the mean of
the IOP values (mean of hour 0, hour 2 and hour 8 IOPs) at each
visit. The null hypothesis was that there was no difference between
the week 12 and baseline visits in study eye mean diurnal IOP. The
alternative hypothesis was that Triple Combination would decrease
(from baseline) study eye mean diurnal IOP at week 12.
[0132] Descriptive statistics were provided for baseline and change
from baseline in mean diurnal IOP at week 12. The null hypothesis
was tested using a 1-sample t-test. A point estimate of the mean
change from baseline and the corresponding 95% confidence interval
was provided. The null hypothesis was rejected and Triple
Combination was considered superior to Dual Combination if the
two-sided p-value was <0.05 and the point estimate of the mean
change from baseline was negative.
Other Efficacy Analysis:
[0133] Analysis on the change from baseline in mean diurnal IOP was
performed for all scheduled postbaseline visits through week 12, in
the study eye using the mITT and PP populations.
Safety Analysis:
[0134] All the safety analyses were performed on patients in the
safety population.
[0135] For all safety data collected from ophthalmic examination,
the analysis for each visit was based on the examination of the eye
with the worst outcome as compared with the baseline.
[0136] No imputation for missing data was performed for the safety
population.
[0137] Adverse events were listed. The number and percent of
patients experiencing an event were tabulated for each system organ
class (SOC) and preferred term (PT). Adverse events were also
tabulated according to severity and causality. All aforementioned
analyses were performed for ocular adverse events separately.
Ocular adverse events are determined based on the investigator
indicating that the adverse event was related to the eye on the
adverse event data collection form and thus were not limited to
adverse events in the `eye disorders` SOC. Serious adverse events
were listed separately.
[0138] Individual data listings of vital signs (observed and change
from baseline) were presented for each patient. Individual
clinically significant vital sign findings that were considered
adverse events by the investigator were presented in the adverse
event listings. Observed values as well as change from baseline
data were summarized descriptively in tabular format by treatment
group.
Other Safety Analysis:
[0139] The BCVA (change from baseline in the number of lines read
at the final visit) was calculated for each eye. The data was
tabulated by the number and percentage of patients for the eye with
the worse line change.
[0140] The number and percent of patients experiencing clinically
significant biomicroscopy/ophthalmoscopy findings were tabulated by
PT. Clinically significant biomicroscopy/ophthalmoscopy findings
were also tabulated according to mean severity grade and the
frequency distribution of severity scores.
[0141] Cup/disc ratio (change from baseline) was calculated and
tabulated data was presented by the number and percentage of
patients for the eye with the worse change.
Determination of Sample Size:
[0142] Sample size was calculated based on the primary efficacy
variable and combined data from GANFORT pivotal studies in which
the SD for change from baseline (based on the study eye defined in
this protocol) in mean diurnal IOP at month 3 was 3.22 mm Hg for
GANFORT-treated patients. It was expected that with Triple
Combination the IOP-lowering effect would be at least 1 mm Hg
greater than with the Dual Combination (ie, the change from
baseline in mean diurnal IOP would be at least 1 mm Hg). With a
sample size of 112, a single group t-test with a 0.025 1-sided
significance level had 90% power to detect a mean decrease in IOP
of 1.0 mm Hg between Dual and Triple Combination, assuming that the
SD was 3.22. In the GANFORT pivotal studies, the discontinuation
rate was approximately 7% at month 3. Allowing for a similar
discontinuation rate, 120 patients were planned to be enrolled into
this study to provide approximately 112 completed patients.
Primary Efficacy: Change from Baseline in Mean Diurnal IOP at Week
12 in the Modified Intent-to-Treat Population:
[0143] At week 12, the mean change from baseline in study eye mean
diurnal IOP was -3.98 mm Hg (p<0.001) demonstrating that Triple
Combination provided a clinically meaningful and statistically
significant additional IOP reduction from the Dual
Combination-treated baseline. A summary of study eye mean diurnal
IOP and change from baseline in mean diurnal IOP by visit for the
mITT population is provided in Table 13.
TABLE-US-00013 TABLE 13 Summary of Study Eye Mean Diurnal IOP by
Visit (Modified Intent-to-treat Population) TRIPLE COMBINATION
GROUP Visit Statistics (N = 121) Baseline N 121 Mean (SD) 22.35
(3.417) Median; Range (Min, Max) 21.50; (16.5, 35.7) Week 4 N 121
Mean (SD) 17.87 (3.621) Median; Range (Min, Max) 17.33; (11.0,
33.3) Change from N 121 Baseline to Mean (SD) -4.49 (3.018) Week 4
Median; Range (Min, Max) -4.00; (-13.0, 3.0) 95% CI.sup.a (-5.0,
-3.9) p-value.sup.a <0.001 Week 8 N 121 Mean (SD) 18.13 (3.669)
Median; Range (Min, Max) 17.83; (11.2, 34.0) Change from N 121
Baseline to Mean (SD) -4.22 (2.795) Week 8 Median; Range (Min, Max)
-4.20; (-15.0, 1.8) 95% CI.sup.a (-4.7, -3.7) p-value.sup.a
<0.001 Week 12 N 121 Mean (SD) 18.37 (3.732) Median; Range (Min,
Max) 18.00; (10.7, 34.0) Change from N 121 Baseline to Mean (SD)
-3.98 (2.856) Week 12 Median -4.00 Range (Min, Max) -12.7, 3.0 95%
CI.sup.a (-4.5, -3.5) p-value.sup.a <0.001 Min = minimum; max =
maximum; SD = standard deviation Note: Study eye is the eye that
met the IOP inclusion criteria at baseline hour 0 (>18 and
<34 mm Hg); it is the eye with the higher IOP values if both
eyes met the criteria; it is the right eye if both eyes had the
same IOP values or neither eye met the inclusion criteria. The mean
diurnal IOP at each visit is the mean IOP of hour 0, hour 2, and
hour 8. Missing value at each visit is imputed by Last Observation
Carried Forward before mean diurnal at the visit is calculated.
.sup.aconfidence interval (CI) and p-value are obtained by using 1
sample t-test.
Other Efficacy:
[0144] The other efficacy analyses included change from baseline
(day 0) in study eye mean diurnal IOP at the week 12 visit using
the PP population and at weeks 4, and 8 using the mITT and PP
populations.
[0145] In the mITT population, at weeks 4 and 8, the mean change
from baseline in study eye mean diurnal IOP were -4.49 and -4.22,
respectively (p<0.001) demonstrating that Triple Combination
provided a clinically meaningful and statistically significant
additional IOP reduction from the Dual Combination-treated baseline
at both visits.
[0146] In the PP population, at weeks 4, 8, and 12, the mean
changes from baseline in study eye mean diurnal IOP were -4.64,
-4.14, and -4.22, respectively. The changes were clinically and
statistically significant and similar to those of the mITT
population.
Sub-Group Analysis of Efficacy Variables:
[0147] Results similar to those seen in the overall mITT population
were also observed for each age subgroup (.ltoreq.65 years and
>65 years) for the primary efficacy variable, demonstrating that
Triple Combination provided a clinically meaningful and
statistically significant additional IOP reduction from the Dual
Combination-treated baseline in both subgroups.
[0148] In the subgroup of patients that were .ltoreq.65 years of
age in the mITT population, at weeks 4, 8, and 12, the mean changes
from baseline in study eye mean diurnal IOP were -4.67, -4.41, and
-4.04, respectively (p<0.001).
[0149] In the subgroup of patients that were >65 years of age in
the mITT population, at weeks 4, 8, and 12, the mean change from
baseline in study eye mean diurnal IOP were -3.94, -3.66, and
-3.80, respectively (p<0.001).
Efficacy Conclusions:
[0150] At week 12, Triple Combination provided a clinically
meaningful and statistically significant additional IOP-lowering
effect from the Dual Combination-treated baseline. The mean changes
from baseline at week 12 in the study eye mean diurnal IOP were
-3.98 and -4.22 mm Hg in the mITT and PP populations, respectively
(p<0.001). [0151] The changes from baseline in the study eye
mean diurnal IOP at weeks 4 and 8 were also clinically meaningful
and statistically significant, ranging from -4.49 to -4.22 mm Hg
for the mITT and from -4.64 to -4.14 mm Hg for the PP population,
respectively. [0152] Results similar to those seen in the overall
mITT population were also observed for each age subgroup
(.ltoreq.65 years and >65 years) for the primary efficacy
variable. [0153] Sensitivity analyses demonstrated no meaningful
differences in efficacy with or without patients from the excluded
study site.
Brief Summary of Adverse Events:
[0154] A summary of patients with adverse events is provided in
Table 14. A total of 54/121 (44.6%) patients experienced 1 or more
adverse events. Of the 121 patients, 39 (32.2%) patients
experienced treatment-related adverse events. The vast majority of
patients who experienced adverse events had adverse events that
were ocular in nature.
[0155] The maximum severity of adverse events was mild in 39/121
(32.2%) patients, moderate in 14/121 (11.6%) patients, and severe
in 1/121 (0.8%) patient (adverse event of glaucoma, which was not
considered treatment-related). A total of 7/121 (5.8%) patients
were discontinued from the study due to adverse events (all of
which were ocular in nature). The most commonly reported adverse
events leading to discontinuation were conjunctival hyperaemia (3
patients), conjunctival disorder (2 patients), conjunctivitis
allergic (2 patients), and eye pain (2 patients). No serious
adverse events were reported.
TABLE-US-00014 TABLE 14 Summary of Patients with Adverse Events
(Safety Population) TRIPLE COMBINATION GROUP (N = 121) n (%) All
adverse events 54 (44.6) All ocular adverse events 49 (40.5) All
serious adverse events 0 Treatment-related adverse events 39 (32.2)
Treatment-related ocular adverse 38 (31.4) events Treatment-related
serious adverse 0 events All adverse events by severity Missing 0
Mild 39 (32.2) Moderate 14 (11.6) Severe.sup.a 1 (0.8) N/A 0
Adverse events leading to death 0 Adverse events leading to 7 (5.8)
discontinuation from study Ocular adverse events leading 7 (5.8) to
discontinuation from study Note: For adverse event severity
category, a patient is counted only once based on maximum severity
of all adverse events. .sup.aSevere adverse event was reported as
`glaucoma` (preferred term) and was described clinically as
`worsening of glaucoma`. This worsening of glaucoma was not
considered treatment-related.
[0156] A total of 49/121 (40.5%) patients experienced ocular
adverse events. Of the 121 patients, 38 (31.4%) patients
experienced treatment-related ocular adverse events. The maximum
severity of ocular adverse events was mild in 35/121 (28.9%)
patients, moderate in 13/121 (10.7%) patients, and severe in 1/121
(0.8%) patient. A total of 7/121 (5.8%) patients were discontinued
from the study due to ocular adverse events.
All Adverse Events:
[0157] Except for headache (4/121 [3.3%]), the most frequently
reported adverse events (in 3 or more patients), were ocular in
nature: conjunctival hyperaemia (20/121 [16.5%] patients), dry eye
(6/121 [5.0%] patients), conjunctivitis (5/121 [4.1%] patients),
conjunctival follicles (4/121 [3.3%] patients), eye pain (4/121
[3.3%] patients), lacrimation increased (4/121 [3.3%] patients),
growth of eyelashes (3/121 [2.5%] patients), meibomian gland
dysfunction (3/121 [2.5%] patients), and skin hyperpigmentation
(3/121 [2.5%] patients).
Treatment-Related Adverse Events:
[0158] A summary of patients with treatment-related adverse events
s by SOC and PT is provided in Table 15. A total of 39/121 (32.2%)
patients experienced treatment-related adverse events and 38/121
(31.4%) patients experienced treatment-related ocular adverse
events. Headache was the only non-ocular treatment-related adverse
event.
TABLE-US-00015 TABLE 15 Summary of Patients with Treatment-related
Adverse Events by System Organ Class and Preferred Term (Safety
Population) TRIPLE COMBINATION GROUP System organ class (N = 121)
Preferred term n (%) Treatment-related adverse events 39 (32.2) Eye
disorders 36 (29.8) Conjunctival hyperaemia 17 (14.0) Dry eye 5
(4.1) Conjunctival follicles 4 (3.3) Eye pain 4 (3.3) Lacrimation
increased 4 (3.3) Growth of eyelashes 3 (2.5) Conjunctival disorder
2 (1.7) Conjunctivitis 2 (1.7) Conjunctivitis allergic 2 (1.7) Eye
irritation 2 (1.7) Eye pruritus 2 (1.7) Meibomianitis 2 (1.7)
Eyelid irritation 1 (0.8) Eyelids pruritus 1 (0.8) Keratitis 1
(0.8) Vision blurred 1 (0.8) Visual impairment 1 (0.8) Skin and
subcutaneous tissue 2 (1.7) disorders Skin hyperpigmentation 2
(1.7) Nervous system disorders 1 (0.8) Headache 1 (0.8) Note:
System organ class (SOC) and preferred terms (PT) are coded using
the MedDRA version 15.0 dictionary. Preferred terms are sorted by
descending frequencies. Within each combination of PT and SOC, a
patient is counted at most once.
[0159] The most frequently reported treatment-related adverse
events (in 3 or more patients) were conjunctival hyperaemia (17/121
[14.0%] patients), dry eye (5/121 [4.1%] patients), conjunctival
follicles (4/121 [3.3%] patients), eye pain (4/121 [3.3%]
patients), lacrimation increased (4/121 [3.3%] patients), and
growth of eyelashes (3/121 [2.5%] patients).
Summary of Results:
[0160] Overall, 126 patients were enrolled in the study. A total of
121 patients were included in the mITT and safety populations; 5
patients (from study site 13001) were excluded from all analysis
populations due to site termination for GCP violations. Of the 121
patients, 109 (90.1%) patients completed the study and 12 (9.9%)
patients were discontinued from the study. In the mITT and safety
populations, the mean (SD) age was 58.6 (11.44) years. The majority
of patients (80/121 [66.1%]) were between .gtoreq.45 to .ltoreq.65
years of age. The majority of patients were male (76/121 [62.8%]).
All patients had dark irides. All of the enrolled patients had a
history of eye disorders. The most common eye disorder diagnosis
was glaucoma. The specific glaucoma diagnoses were open angle
glaucoma (62/121 [51.2%]) and angle closure glaucoma (44/121
[36.4%]). Sixteen (16/121 [13.2%]) patients had a diagnosis of
ocular hypertension. Patient disposition and demographics of the PP
population was similar to that of the mITT and safety
populations.
Efficacy:
[0161] At week 12, TRIPLE COMBINATION provided a clinically
meaningful and statistically significant additional IOP-lowering
effect from the DUAL COMBINATION-treated baseline. The mean changes
from baseline at week 12 in the study eye mean diurnal IOP were
-3.98 and -4.22 mm Hg in the mITT and PP populations, respectively
(p<0.001). [0162] The changes from baseline in the study eye
mean diurnal IOP at weeks 4 and 8 were also clinically meaningful
and statistically significant, ranging from -4.49 to -4.22 mm Hg
for the mITT and from -4.64 to -4.14 mm Hg for the PP population,
respectively. [0163] Results similar to those seen in the overall
mITT population were also observed for each age subgroup
(.ltoreq.65 years and >65 years) for the primary efficacy
variable. [0164] Sensitivity analyses demonstrated no meaningful
differences in efficacy with or without patients from the excluded
study site.
Safety:
[0164] [0165] A total of 54/121 (44.6%) patients experienced 1 or
more adverse events. Of the 121 patients included in the safety
population, 39 (32.2%) experienced treatment-related adverse
events. A total of 38/121 (31.4%) patients experienced
treatment-related ocular adverse events, the majority of which were
mild or moderate in intensity. [0166] The most frequently reported
treatment-related adverse events (in 3 or more patients) were
conjunctival hyperaemia (14.0%), dry eye (4.1%), conjunctival
follicles (3.3%), eye pain (3.3%), lacrimation increased (3.3%),
and growth of eyelashes (2.5%). [0167] No deaths or other serious
adverse events were reported during the study. [0168] A total of
7/121 (5.8%) patients discontinued due to adverse events (all were
ocular). The most common adverse events (reported in >1 patient)
leading to discontinuation were conjunctival hyperaemia,
conjunctival disorder, conjunctivitis allergic, and eye pain.
[0169] In general, no clinically significant change was observed in
vital signs, cup/disc ratio, and visual acuity. Few patients were
reported to have clinically significant findings (defined as
.gtoreq.2 full severity grade increase from baseline in either eye
during treatment) on slit-lamp biomicroscopy, with hyperaemia being
the most frequently reported finding (7/121 [5.8%] patients).
[0170] The adverse events profile in each age subgroup (.ltoreq.65
years and >65 years) was similar to that of the overall safety
population. [0171] Sensitivity analyses demonstrated no meaningful
differences in safety with or without patients from the excluded
study site.
[0172] Conclusion:
[0173] Triple Combination provides a clinically meaningful and
statistically significant additional IOP-lowering effect from a
Dual Combination-treated baseline and has an acceptable safety and
tolerability profile in Indian patients with glaucoma or ocular
hypertension with elevated IOP.
[0174] Notwithstanding that the numerical ranges and parameters
setting forth the broad scope of the invention are approximations,
the numerical values set forth in the specific examples are
reported as precisely as possible. Any numerical value, however,
inherently contains certain errors necessarily resulting from the
standard deviation found in their respective testing
measurements.
[0175] The terms "a," "an," "the" and similar referents used in the
context of describing the invention (especially in the context of
the following claims) are to be construed to cover both the
singular and the plural, unless otherwise indicated herein or
clearly contradicted by context. "About" refers to variations in
the concentrations of excipients and active agents which would be
considered bioequivalent by a regulatory agency.
[0176] Recitation of ranges of values herein is merely intended to
serve as a shorthand method of referring individually to each
separate value falling within the range. Unless otherwise indicated
herein, each individual value is incorporated into the
specification as if it were individually recited herein. All
methods disclosed herein can be performed in any suitable order
unless otherwise indicated herein or otherwise clearly contradicted
by context. The use of any and all examples, or exemplary language
(e.g., "such as") provided herein is intended merely to better
illuminate the invention and does not pose a limitation on the
scope of the invention otherwise claimed. No language in the
specification should be construed as indicating any non-claimed
element essential to the practice of the invention.
[0177] Groupings of alternative elements or embodiments of the
invention disclosed herein are not to be construed as limitations.
Each group member may be referred to and claimed individually or in
any combination with other members of the group or other elements
found herein. It is anticipated that one or more members of a group
may be included in, or deleted from, a group for reasons of
convenience and/or patentability. When any such inclusion or
deletion occurs, the specification is deemed to contain the group
as modified thus fulfilling the written description of all Markush
groups used in the appended claims.
[0178] Certain embodiments of this invention are disclosed herein,
including the best mode known to the inventors for carrying out the
invention. Of course, variations on these described embodiments
will become apparent to those of ordinary skill in the art upon
reading the foregoing description. The inventor expects one of
ordinary skill in the art to employ such variations as appropriate,
and the inventors intend for the invention to be practiced
otherwise than specifically disclosed herein. Accordingly, this
invention includes all modifications and equivalents of the subject
matter recited in the claims appended hereto as permitted by
applicable law. Moreover, any combination of the above-described
elements in all possible variations thereof is encompassed by the
invention unless otherwise indicated herein or otherwise clearly
contradicted by context.
[0179] Specific embodiments disclosed herein may be further limited
in the claims using consisting of and/or consisting essentially of
language. When used in the claims, whether as filed or added per
amendment, the transition term "consisting of" excludes any
element, step, or ingredient not specified in the claims. The
transition term "consisting essentially of" limits the scope of a
claim to the specified materials or steps and those that do not
materially affect the basic and novel characteristic(s).
Embodiments of the invention so claimed are inherently or expressly
described and enabled herein.
[0180] It is to be understood that the embodiments of the invention
disclosed herein are illustrative of the principles of the present
invention. Other modifications that may be employed are within the
scope of the invention. Thus, by way of example, but not of
limitation, alternative configurations of the present invention may
be utilized in accordance with the teachings herein. Accordingly,
the present invention is not limited to that precisely as shown and
described.
* * * * *