This application claims priority to Provisional Indian Patent Application No.
3626/DEL/2013, filed 12 December 2013, the contents of which are incorporated herein in their
entirety.
FIELD OF THE INVENTION
The present invention is directed to stable, aqueous solution comprising a non-steroidal
anti-inflammatory drug (NSAID) such as bromfenac or a pharmacologically acceptable salt or a
hydrate thereof and/or pharmaceutically acceptable excipients which does not comprises an alkyl
aryl polyether alcohol type polymer such as tyloxapol, or a polyethylene glycol fatty acid ester
such as polyethylene glycol monostearate for the treatment of ocular inflammation and pain after
cataract surgery. More particularly the present invention is directed to reduce the level of
degradation of bromfenac with the addition of pharmaceutically acceptable solubilizers other
than an alkyl aryl polyether alcohol type polymer such as tyloxapol, or a polyethylene glycol
fatty acid ester such as polyethylene glycol monostearate.
BACKGROUND
Bromfenac (chemical name 2-amino-3-(4-bromobenzoyl)phenylacetic acid), a nonsteroidal
anti-inflammatory agent, is disclosed in JP-A-23052/1977 and its corresponding US
patent No. 4,045,576, as well as in Japanese patent no. 2683676 corresponding to US patent no.
4,910,225. The sodium salt of bromfenac has been used ophthamologically, e.g., in the form of
eye drops. Bromfenac is effective against inflammatory diseases (e.g. blepharitis, conjunctivitis,
scleritis, postoperative inflammation) of the extraocular segment or the anterior ocular segment
in the field of ophthalmology, and in particular, its efficacy for treating uveitis is equal to
nonsteroidal anti-inflammatory agents which have previously been used in the field of
ophthalmology, and its sodium salt has been practically used in the form of eye drops. The eye
drop as mentioned above is designed to stabilize 2-amino-3-(4-bromobenzoyl)phenylacetic acid
by means of addition of a water-soluble polymer (e.g. polyvinylpyrrolidone, polyvinyl alcohol,
etc.) and a sulfite (e.g. sodium sulfite, potassium sulfite, etc.) (Japanese patent No. 2,683,676 and
its corresponding US patent No. 4,910,225).
In addition, as an eye drop other than the above-mentioned one, Japanese patent No.
2,954,356 (corresponding to US patents Nos. 5,603,929 and 5,653,972) discloses a stable
3
ophthalmic composition which comprises incorporating an antibacterial quaternary ammonium
polymer and boric acid into an acidic ophthalmic agent. The acidic agent described therein
includes, for example, 2-amino-3-(4-bromobenzoyl)phenylacetic acid.
US8129431, US2012115957, US2013090384, US2007287749 and WO2013055856
disclose an aqueous liquid preparation containing 2-amino-3-(4-bromobenzoyl)phenylacetic acid
or its pharmacologically acceptable salt or a hydrate thereof, an alkyl aryl polyether alcohol type
polymer such as tyloxapol, or a polyethylene glycol fatty acid ester such as polyethylene glycol
monostearate.
The present invention provides a stable, aqueous solution comprising bromfenac or its
pharmacologically acceptable salt or hydrate thereof and/or pharmaceutically acceptable
excipients wherein the solution does not comprise an alkyl aryl polyether alcohol type polymer
such as tyloxapol, and/or a polyethylene glycol fatty acid ester such as polyethylene glycol
monostearate.
Additionally the stable, aqueous solution of the present invention does not comprise
antioxidants such as sulfite(s) but not limited to sodium sulfite, potassium sulfite and the like.
Sodium sulfite is irritating to the eyes. Symptoms of irritation may include redness, itching or
tearing as disclosed and mentioned in various companies Material Safety Data Sheet (MSDS)
such as Santa Cruz Biotechnology, Inc.; LabChem, Inc., New Jersey department of health and
senior services and the like.
The inventors of the present invention with expenditure of intellectual effort and careful
experimentation have prepared a stable, aqueous solution comprising a non-steroidal antiinflammatory
drug (NSAID) and/or pharmaceutically acceptable excipients for the treatment of
ocular inflammation and pain after cataract surgery wherein more specifically, the present
invention is directed to reduce the level of degradation of bromfenac with the addition of
pharmaceutically acceptable solubilizers such as an polyoxyethylene sorbitan fatty acid esters
such as polysorbate 80 or a non-ionic solubilizer such as polyoxyl-15-hydroxystearate.
There is a need for a method for treating ocular inflammation and pain after cataract
surgery wherein the method comprises a once a day or twice a day topical application to the eye
of the patient in need of a stable, aqueous solution comprising bromfenac or a pharmacologically
acceptable salt or a hydrate thereof and/or pharmaceutically acceptable excipients.
4
OBJECT OF THE INVENTION
The main object of the present invention is to develop a stable, aqueous solution
comprising bromfenac or a pharmacologically acceptable salt or a hydrate thereof, for the
treatment of ocular inflammation and pain after cataract surgery.
Yet another object of the present invention is to develop a stable solution within a pH
range giving no irritation to eyes.
Yet another object of the present invention is to remove the anti-oxidants/stabilizer,
sodium sulfite from the formulation of the control formulation (PROLENSA) as sodium sulfite is
a known irritant to the eye. In the process, inventors of this formulation stabilized it more than
that of the control formulation, with respect to the formation of Impurity B.
Yet another object of the present invention is directed to reduce the level of degradation
of bromfenac with the addition of pharmaceutically acceptable solubilizers other than an alkyl
aryl polyether alcohol type polymer such as tyloxapol, or a polyethylene glycol fatty acid ester
such as polyethylene glycol monostearate.
Yet another object of the present invention is to develop a method to prepare a stable,
aqueous solution comprising bromfenac or its pharmacologically acceptable salt or hydrate
thereof and/or pharmaceutically acceptable excipients wherein the invention does not comprise
an alkyl aryl polyether alcohol type polymer such as tyloxapol, and/or a polyethylene glycol fatty
acid ester such as polyethylene glycol monostearate.
Yet another object of the present invention provides a method for treating ocular
inflammation and pain after cataract surgery wherein the method comprises a once a day or twice
a day topical application to the eye of the patient in need of a stable, aqueous solution comprising
bromfenac or a pharmacologically acceptable salt or a hydrate thereof and/or pharmaceutically
acceptable excipients.
SUMMARY OF THE INVENTION
The present invention is directed to a stable, aqueous solution comprising bromfenac or a
pharmacologically acceptable salt or a hydrate thereof, for the treatment of ocular inflammation
and pain after cataract surgery wherein the solution is stable within a pH range giving no
irritation to eyes.
5
The present invention is directed to stable, aqueous solution which does not comprise an
alkyl aryl polyether alcohol type polymer such as tyloxapol, and/or a polyethylene glycol fatty
acid ester such as polyethylene glycol monostearate for the treatment of ocular inflammation and
pain after cataract surgery.
More particularly the present invention is directed to reduce the level of degradation of
bromfenac with the addition of pharmaceutically acceptable solubilizers other than an alkyl aryl
polyether alcohol type polymer such as tyloxapol, or a polyethylene glycol fatty acid ester such
as polyethylene glycol monostearate.
More specifically the invention provides a method for stabilizing an aqueous solution of
bromfenac or a pharmacologically acceptable salt or a hydrate thereof by adding a solubilizer
such as a polyoxyethylene sorbitan fatty acid esters such as polysorbate 80 or a non-ionic
solubilizer such as polyoxyl-15-hydroxystearate to an aqueous solution of bromfenac, wherein
the aqueous solution becomes stable within acceptable pH range giving no irritation to eyes, and
unexpectedly reduces the level of degradation of bromfenac.
Additionally the solution of the present invention does not comprise an antioxidant such
as sulfite(s) preferably sodium sulfite and potassium sulfite and can be formulated both as multidose
as well as unit-dose composition.
The present invention provides a method to prepare a stable, aqueous solution comprising
bromfenac or its pharmacologically acceptable salt or hydrate thereof and/or pharmaceutically
acceptable excipients wherein the invention does not comprise an alkyl aryl polyether alcohol
type polymer such as tyloxapol, and/or a polyethylene glycol fatty acid ester such as
polyethylene glycol monostearate.
The present invention provides a method for treating ocular inflammation and pain after
cataract surgery wherein the method comprises a once a day or twice a day topical application to
the eye of the patient in need of a stable, aqueous solution comprising bromfenac or a
pharmacologically acceptable salt or a hydrate thereof and/or pharmaceutically acceptable
excipients wherein more specifically, the present invention does not comprise an alkyl aryl
polyether alcohol type polymer such as tyloxapol, and/or a polyethylene glycol fatty acid ester
such as polyethylene glycol monostearate.
6
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. I shows the comparative leukocyte counts between Group I (Negative control),
Group II (Present Invention formulation - 036A) & Group III (Innovator product –
PROLENSA™).
FIG. II shows the comparative vasodilation reduction between Group I (Negative
control), Group II (Present Invention formulation - 036A) & Group III (Innovator product -
PROLENSA™).
FIG. III shows the levels of “Impurity B” in Control formulation - PROLENSA™ and
present invention formulation (batch 35B & 35C) at accelerated stability condition (40°C/ NMT
25% RH).
DETAILED DESCRIPTION OF THE INVENTION
As used herein, an “antioxidant” is a substance that when present in a mixture containing
an oxidizable substrate biological molecule significantly delays or prevents oxidation of the
substrate biological molecule. In the context of this invention, antioxidants include, but are not
limited to, antioxidants that are irritating to the eyes. Such antioxidants include sodium sulfite,
potassium sulfite, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated
hydroxyanisole, butylated hydroxytoluene and the like, and mixtures thereof.
As used herein, the term “°C” wherever appears is an abbreviation for “Degree Celsius”.
As used herein, the term “BKC” wherever appears is an abbreviation for “benzalkonium
chloride”.
As used herein, the term “Control” wherever appears is a marketed product
“PROLENSA™”.
As used herein, the “bromfenac sodium” wherever appears is an abbreviation for
“bromfenac sodium salt or hydrate thereof, wherein the hydrate is at least one selected from a 1/2
hydrate, 1 hydrate and 3/2 hydrate”.
As used herein, the “NMT” wherever appears is an abbreviation for “not more than”.
Unless indicated otherwise, all ingredient amounts are presented in units of %
weight/volume (% w/v).
As used herein, the “CGYS” wherever appears is an abbreviation for “Clear greenish
yellow solution”.
7
One embodiment of the present invention, is to develop a stable, aqueous solution
comprising bromfenac or a pharmacologically acceptable salt thereof or a hydrate thereof, for the
treatment of ocular inflammation and pain after cataract surgery wherein which is stable within a
pH range giving no irritation to eyes.
Other embodiment of the invention is to provide a method for stabilizing an aqueous
solution of bromfenac or a pharmacologically acceptable salt thereof or a hydrate thereof
wherein more specifically, the present invention does not comprise an alkyl aryl polyether
alcohol type polymer such as tyloxapol, and/or a polyethylene glycol fatty acid ester such as
polyethylene glycol monostearate.
In yet other embodiment of the present invention, citrate buffer is used instead of borate
buffer but when benzalkonium chloride (BKC) was added in the citrate formulation it causes
haziness of the formulation. It is an object of the present invention to stabilize the aqueous
solution, in which, when a preservative such as benzalkonium chloride is incorporated therein,
does not result in haziness, preferably for the shelf-life of the solution.
The inventors of the present invention extensively studied how to overcome the haziness
occurred during the addition of BKC. Surprisingly it was found that surfactants such as
polyoxyethylene sorbitan fatty acid esters such as polysorbate 80 or a non-ionic solubilizer such
as polyoxyl-15-hydroxystearate (Kolliphor® HS 15 or Solutol® HS 15) remove the haziness. In
addition several other surfactants such as Kolliphor® TPGS (Vitamin E Polyethylene Glycol
Succinate USP/NF, Tocophersolan (CAS number 9002-96-4)) and Brij™ C20 also removed
haziness. However, different surfactants affected stability of bromfenac in a different manner and
surprisingly it was found that polysorbate 80 or polyoxyl-15-hydroxystearate (Kolliphor® HS 15
or Solutol® HS 15) has the least amount of degradation of the present solution.
So the inventors of the present invention after careful experimentation have identified
surfactants that clarify the solution (remove or avoid haziness) and also reduce the level of
degradation of bromfenac.
In another embodiment, the invention provides a method for stabilizing an aqueous
solution of bromfenac or a pharmacologically acceptable salt or a hydrate thereof by adding a
solubilizer such as a polyoxyethylene sorbitan fatty acid ester such as polysorbate 80 or a nonionic
solubilizer such as polyoxyl-15-hydroxystearate to an aqueous solution of bromfenac, the
8
aqueous solution becomes stable within a pH range giving no irritation to eyes, and unexpectedly
reduces the level of degradation of bromfenac.
As a result of various studies, the inventors of the present invention have found that, by
adding one or more solubilizers to an aqueous solution of bromfenac or a pharmacologically
acceptable salt or a hydrate thereof, the aqueous solution becomes stable within a pH range
giving no irritation to eyes, and unexpectedly reduces the level of degradation of bromfenac.
Some preferred solubilizers in context to the present invention includes but not limited to, for
example, a polyoxyethylene sorbitan fatty acid ester such as polysorbate 80 or a non-ionic
solubilizer such as polyoxyl-15-hydroxystearate such as Kolliphor® HS 15.
One embodiment of the present invention, is to develop a stable, aqueous solution
comprising bromfenac or a pharmacologically acceptable salt thereof or a hydrate thereof and a
solubilizer such as an polyoxyethylene sorbitan fatty acid esters such as polysorbate 80 and/or
pharmaceutically acceptable excipients, for the treatment of ocular inflammation and pain after
cataract surgery wherein which is stable within a pH range giving no irritation to eyes.
Another embodiment of the present invention, is to develop a stable, aqueous solution
comprising bromfenac or a pharmacologically acceptable salt thereof or a hydrate thereof and a
non-ionic solubilizer such as polyoxyl-15-hydroxystearate and/or pharmaceutically acceptable
excipients, for the treatment of ocular inflammation and pain after cataract surgery wherein
which is stable within a pH range giving no irritation to eyes.
Yet another embodiment of the invention is to provide a method for stabilizing an
aqueous solution of bromfenac or a pharmacologically acceptable salt or a hydrate thereof by
adding a solubilizer, preferably polsorbate 80 or Polyoxyl-15-Hydroxystearate.
In a preferred embodiment, the present invention provides a method to prepare a stable,
aqueous solution comprising bromfenac or its pharmacologically acceptable salt or hydrate
thereof and/or pharmaceutically acceptable excipients wherein the invention does not comprise
an alkyl aryl polyether alcohol type polymer such as tyloxapol and a polyethylene glycol fatty
acid ester such as polyethylene glycol monostearate.
In another preferred embodiment, the present invention provides a method to prepare a
stable, aqueous solution comprising bromfenac or its pharmacologically acceptable salt or a
hydrate thereof and/or pharmaceutically acceptable excipients and a solubilizer. Preferred
solubilizers in context to the present invention includes but not limited to, for example, a
9
polyoxyethylene sorbitan fatty acid ester such as polysorbate 80 or a non-ionic solubilizer such
as polyoxyl-15-hydroxystearate such as Kolliphor® HS 15.
In yet another preferred embodiment of the present invention, the stable, aqueous solution
of the present invention is also devoid of antioxidants, preferably devoid of sulfites, more
preferably devoid of sodium sulfite, potassium sulfite and the like which causes irritation to the
eyes wherein symptoms of irritation may include redness, itching or tearing. So, the absence of
sodium sulfite adds to the benefit for better patient compliance.
In another preferred embodiment of the present invention, citrate buffer is used,
preferably instead of borate buffer.
Furthermore in another preferred embodiment, the present invention provides a method
for treating ocular inflammation and pain after cataract surgery wherein the method comprises
application to the eye of the patient in need of a stable, aqueous solution comprising bromfenac
and a solubilizer such as an polyoxyethylene sorbitan fatty acid esters such as polysorbate 80 or a
non-ionic solubilizer such as polyoxyl-15-hydroxystearate. Application is preferably once a day,
but may be more than once per day, e.g., two times a day.
Furthermore in another preferred embodiment, the present invention provides a method
of using the inventive compositions.
Furthermore in yet another preferred embodiment, the present invention provides a clear,
isotonic, sterile bromfenac ophthalmic aqueous solution, useful for the treatment of ocular
inflammation and pain after cataract surgery wherein the solution is contained in a unit dose kit
form and is applied once a day to each eye.
In another embodiment, aqueous solution of the present invention may also be packaged
in a single-use container and/or multi-use container.
In another preferred embodiment the stable, ophthalmic compositions can also be
prepared as one of the embodiments of the present invention to make the composition
pharmaceutically acceptable for used as a single or multi-unit dose.
Any concentration of NSAID that is effective can be used, and can be determined by one
of ordinary skill in the art using the present disclosure as guidance. When the NSAID comprises
bromfenac, bromfenac is preferably present in a concentration of 0.01%w/v – 0.1%w/v (based on
bromfenac free base). Some preferred concentrations include 0.02, 0.04, 0.05, 0.06, 0.07, 0.08,
10
and 0.09%w/v bromfenac and ranges formed from these values. These bromfenac
concentrations may be used with the excipients and amounts thereof listed in Table 1.
In an embodiment, the present invention provides a stable, aqueous solution of bromfenac
or a pharmacologically acceptable salt or a hydrate thereof, wherein the pharmacologically
acceptable salt of bromfenac includes, but not limited to, for example, sodium salt; potassium
salt; calcium salt and magnesium salt, wherein sodium salt is especially preferable.
In another embodiment, the present invention provides a stable, aqueous solution of
bromfenac or a pharmacologically acceptable salt or a hydrate thereof, wherein the hydrate is at
least one selected from a 1/2 hydrate, 1 hydrate and 3/2 hydrate.
The aqueous solution of the present invention is stable at 50°C for four weeks wherein
the stability result clearly demonstrates that the assay of bromfenac and related substance are
well within specification ranges. The bromfenac content in the formulation of present invention
(containing polysorbate 80 as a solubilizer) is 101.5%, compared to 99.3% of the label in control
formulation and the bromfenac content in the formulation of present invention (containing
Polyoxyl-15-Hydroxystearate as a solubilizer) is 100.7%, compared to 99.3% of the label in
control formulation respectively at 50°C for four (4) weeks. Also the related substance (total
impurities) in the formulation of present invention (containing polysorbate 80 as a solubilizer) is
0.30%, compared to 0.33% of the label in control formulation and the related substance (total
impurities) in the formulation of present invention (containing Polyoxyl-15-Hydroxystearate as a
solubilizer) is 0.32%, compared to 0.33% of the label in control formulation respectively at 50°C
for four (4) weeks. Hence, one can conclude that the formulation of present invention is
unexpectedly as stable as that of the control at pH 7.8, without the need for, or use of,
antioxidants such as sulfite(s) such as sodium sulfite, potassium sulfite, and the like, and/or with
the addition of pharmaceutically acceptable solubilizers such as either an polyoxyethylene
sorbitan fatty acid esters such as polysorbate 80 or a non-ionic solubilizer such as polyoxyl-15-
hydroxystearate.
“Stable” refers to low bromfenac degradation and/or low formation of degradation
products (or “related substance”) after aging. Stable formulations preferably include those in
which bromfenac assay is greater than or equal to 97%, more preferably 98%, 99% or 99.5%
after aging. Stable formulations preferably include those in which the related substance assay is
less than 3%, more preferably less than 2.5, 2.0, and 1.0% after aging. Aging may be accelerated
11
or non-accelerated, preferably accelerated. Accelerated aging preferably comprises storage at
50° C for two (2) weeks, preferably in a closed container in the dark. As is known in the art,
“related substances” preferably include substances regulated by regulatory authorities, e.g., the
U.S. FDA. Related substances preferably include Impurity A as well as the highest unknown
impurity, and more preferably includes all bromfenac degradation products. These impurities
can be determined and assayed by one of ordinary skill in the art. As is known in the art,
Impurity A is 7-(4-bromobenzoyl)-1,3-dihydro-2H-indol-2-one.
In one of the preferred embodiments, excipients used are ophthalmically acceptable
which includes, without limitation, solubilizers, buffering agents, chelating agents, tonicity
agents, permeation enhancers, surfactants, pH adjusting agents, preservatives and the like.
In another preferred embodiment, compositions of the present invention may include one
or more buffering agent. Preferred buffering agents include, but are not limited to, acetate
buffers, citrate buffers, phosphate buffers, sodium dihydrogen phosphate dihydrate, dibasic
sodium phosphate heptahydrate, monobasic sodium phosphate, citric acid, citric acid
monohydrate or ε-aminocaproic acid and the like. Preferred buffers include citrate buffers.
In another preferred embodiment, compositions of the present invention may comprise
one or more chelating agents. Preferred chelating agents include, but are not limited to,
disodium edetate or ethylenediamine tetraacetic acid ("EDTA"), diammonium EDTA,
dipotassium EDTA, calcium disodium EDTA, hydroxyethylethylenediaminetriacetic acid
("HEDTA"), ethylenediaminetetraacetic acid, mono(triethanolamine) salt ("TEA-EDTA"),
tetrasodium EDTA, tripotassium EDTA, trisodium phosphate, diammonium citrate, galactaric
acid, galacturonic acid, gluconic acid, glucuronic acid, cyclodextrin, potassium citrate, the
potassium salt of ethylenediamine-tetra (methylene phosphonic acid) ("EDTMP"), sodium
citrate, sodium EDTMP, and the like.
When a preservative is used, any ophthalmically acceptable preservative may be used.
When used, preferred preservatives include, but are not limited to, one or more of quaternary
ammonium salts (e.g. benzalkonium chloride, benzethonium chloride, etc.), chlorhexidine
gluconate, benzethonium chloride, benzododecinium bromide, quaternary ammonium
compounds such as but not limited to benzethonium chloride, methylbenzethonium chloride,
cetalkonium chloride, cetylpyridinium chloride, cetrimonium, cetrimide, dofanium chloride,
tetraethylammonium bromide, didecyldimethylammonium chloride, domiphen bromide and the
12
like; Polyquaternium-1 (Polyquad®), 1phenyl ethanol, phenyl propanol, phenyl mercuric acetate,
phenyl mercuric nitrate, phenyl mercuric borate, chlorhexidine acetate or gluconate,
chlorocresol, benzoic acid, benzyl alcohol, butylparaben, propylparaben, methylparaben,
chlorobutanol, phenoxyethanol, sodium methyl paraben, sodiumpropyl paraben, thimerosal, and
mixtures thereof. Any effective amount may be used, preferably from 0.005% to 0.5% (w/w).
In yet another preferred embodiment of the present invention, tonicity adjusting agents
may be added. Preferred tonicity agents include, without limitation, glycerin, sorbitol, sodium
hydroxide, sodium chloride, potassium chloride, mannitol, dextrose, and propylene glycol, as
well as combinations thereof, or any other suitable ophthalmically acceptable tonicity adjusting
agents.
In other preferred embodiments of the present invention, vehicles can also be used in the
ophthalmic compositions of the present embodiments. These vehicles include, but are not limited
to, methylcellulose, hydroxypropyl methylcellulose, poloxamers, carboxymethyl cellulose,
hydroxyethyl cellulose, polyethylene glycol, hyaluronic acid, polygalacturonic acid, xyloglucan,
carbopol, polycarbophil, gellan gum, physiological saline solution, water, purified water, and
combinations thereof.
Aqueous compositions may comprise any suitable amount of water. Preferred aqueous
compositions comprise more than 90% water by weight, more preferably more than 95% water,
or more than 98% water by weight.
The present invention is preferably devoid of any kind of antioxidants such as sodium
sulfite, potassium sulfite, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated
hydroxyanisole, butylated hydroxytoluene and the like and mixtures thereof which causes
irritation to the eyes.
In another preferred embodiment, surfactants, when used, may be selected from the group
consisted of, but are not limited to sodium lauryl sulfate, docusate sodium, polyoxyalkyl ethers,
polyoxylalkyl phenyl ethers, polyoxyl 40 hydrogenated castor oil (Cremophor RH 40), polyoxy
hydrogenated castor oil, polyoxy sorbitan esters, sorbitan esters, polysorbates, an
polyoxyethylene sorbitan fatty acid esters such as Polysorbate 20; Polysorbate 21; Polysorbate
40; Polysorbate 60; Polysorbate 61; Polysorbate 65; Polysorbate 80; Polysorbate 81; Polysorbate
85; Polysorbate 120, polyoxyl 35 castor oil, sorbitan monolaureates, poloxamer and non-ionic
surfactant such as Kolliphor® TPGS (Vitamin E Polyethylene Glycol Succinate USP/NF,
13
Tocophersolan (CAS number 9002-96-4)); non-ionic solubilizer such as Kolliphor® HS 15 or
Solutol® HS 15 (polyoxyl-15-hydroxystearate) and mixtures thereof.
Any ophthamically acceptable pH adjusting agent may be used. Preferred pH adjusting
agents include hydrochloric acid, sodium hydroxide, phosphoric acid, acetic acid and the like.
The excipients used in the present invention are preferably selected to be non-toxic and
have no substantial detrimental effect (preferably, in the amount used) on the present ophthalmic
compositions, on the use of the compositions or on the human or animal to which the ophthalmic
compositions are to be administered.
In preferred embodiments, the present invention provides ophthalmic compositions in the
form of aqueous liquids, solutions, emulsion, dispersion, suspension, reverse emulsion and
microemulsion, nanoemulsion, nano reservoir system, in-situ gel drops, nanoparticulate system,
liposomal drops, bioadhesive gel drops, drops and the like.
In another preferred embodiment, the present invention provides ophthalmic
compositions for topical ophthalmic delivery comprising administering said composition in the
eyes. Other preferred embodiments include otic and/or nasal formulations for administration to
the ear and/or nose of a human or animal.
In a preferred embodiment, the stable, solution is an aqueous solution having a pH value
within the range of from about 6.5 to about 9, especially from about 6.8 to about 8.0 and
preferably from about 7.0 to about 7.8. In another preferred embodiment, the inventive
composition has osmolality in range of at least about 250 mOsmol/kg and/or less than or equal to
about 350 mOsmol/kg.
In an especially preferred embodiment, the osmolality or tonicity of the carrier
component substantially corresponds to the tonicity of the fluids of the eye, in particular the
human eye. The pH of the aqueous solution of the present invention is closer to ocular or
lacrimal fluid as compared to the marketed product.
In a yet further preferred embodiment, the present invention provides a process of
preparing a stable, aqueous solution comprising bromfenac and/or pharmaceutically acceptable
excipients.
Still further, the present invention may also preferably be presented as a kit comprising a
stable, aqueous solution comprising bromfenac and/or pharmaceutically acceptable excipients,
14
the aqueous solution being contained within a container prepared from a pharmaceutically
acceptable packaging material.
Any pharmaceutically acceptable packaging material may be use, preferably packaging
material that is suitable for containing ophthalmic aqueous solution, more preferably bromfenac
ophthalmic aqueous solution. Pharmaceutically acceptable packaging materials include but are
not limited to low density polyethylene ("LDPE"), high density polyethylene ("HDPE"),
polypropylene, polystyrene, polycarbonate, polyesters (such as polyethylene terephthalate and
polyethylene naphthalate), nylon, polyvinyl chloride), poly(vinylidine chloride),
poly(tetrafluoroethylene) and other materials known to those of ordinary skill in the art. Flexible
bottles prepared from, or comprising, LDPE, HDPE or polypropylene are particularly preferred.
Preferred containers include bottles, preferably a dropper (e.g., a bottle or ampule suitable
for dropwise application of the composition), more preferably, a single-use bottle or dropper.
The containers are preferably sterilized, preferably prior to filling. Any suitable method can be
used to sterilize the containers, and can be determined by the person of ordinary skill in the art.
Some preferred methods include exposure to gamma irradiation and/or exposure to ethylene
oxide gas.
The aqueous solution is preferably sterile. An article comprising the aqueous solution
filled in a container is preferably sterile, preferably at the time the container is filled. The
aqueous solution is preferably filled into sterile multi-use or single-use containers.
The present invention provides a method for treating ocular inflammation and pain after
cataract surgery wherein the method comprises a once a day or twice a day topical application to
the eye of the patient in need of a stable, aqueous solution comprising bromfenac or a
pharmacologically acceptable salt or a hydrate thereof and/or pharmaceutically acceptable
excipients and a solubilizer (preferably an polyoxyethylene sorbitan fatty acid esters such as
polysorbate 80 or a non-ionic solubilizer such as polyoxyl-15-hydroxystearate).
In some of the main embodiments, the present invention provides the following:
1. A stable pharmaceutical composition comprising bromfenac, or a pharmaceutically
acceptable salt or hydrate thereof, wherein the composition is a solution, wherein the
solution has a pH of from about 6.5 to about 8.
2. The composition according to the above 1, further comprising a polyoxyethylene sorbitan
fatty acid esters comprising polysorbate 80.
15
3. The composition according to the above 2, wherein the polyoxyethylene sorbitan fatty
acid ester is polysorbate 80.
4. The composition according to the above 1, further comprising a non-ionic solubilizer
such as polyoxyl-15-hydroxystearate.
5. A stable pharmaceutical composition comprising bromfenac or a pharmacologically
acceptable salt or hydrate thereof, wherein the composition is a solution, is stable, and
comprises at least one of:
a. an polyoxyethylene sorbitan fatty acid esters such as polysorbate 80 or;
b. a non-ionic solubilizer such as polyoxyl-15-hydroxystearate and wherein the
composition does not comprise any of the following;
c. an alkyl aryl polyether alcohol type polymer;
d. a polyethylene glycol fatty acid ester or;
e. an antioxidant.
6. The bromfenac composition according to the above 1 to 5 that does not comprise an alkyl
aryl polyether alcohol type polymer, a polyethylene glycol fatty acid ester, and an
antioxidant.
7. The bromfenac composition according to the above 1 to 5 that does not comprise
tyloxapol or polyethylene glycol monostearate such as polyoxyl 40 stearate.
8. The bromfenac composition of claim 7, that does not comprise an alkyl aryl polyether
alcohol type polymer, a polyethylene glycol fatty acid ester, and an antioxidant.
9. The bromfenac composition according to the above 1 to 5 that does not comprise a sulfite
anti-oxidant.
10. The bromfenac solution according to the above 1 to 5 does not comprise a borate buffer.
11. The bromfenac solution according to the above 1 to 5, wherein the solution is aqueous
and comprises citrate buffer.
12. The bromfenac solution according to the above 1 to 5 that has a pH from about 6.5 to
about 8.
13. The bromfenac solution according to the above 12 that has a pH from about 7.2 to about
7.8.
14. A bromfenac solution according to the above 1 to 5, wherein the solution is contained in
a unit dose kit form.
16
15. A bromfenac solution according to the above 1 to 5, wherein the solution is contained in
a multi dose kit form.
16. An aqueous solution according to the above 1 to 5, which is an aqueous solution
comprising bromfenac sodium salt or a hydrate thereof, wherein the concentration of the
bromfenac sodium salt or the hydrate thereof is from about 0.01 to about 0.1 w/v%.
17. The bromfenac composition according to the above 1 to 5 wherein benzalkonium
chloride is contained as a preservative.
18. The bromfenac composition according to the above 1, 5 and 16 wherein the hydrate is at
least one selected from a 1/2 hydrate, 1 hydrate and 3/2 hydrate.
19. A bromfenac composition according to the above 1 to 5 wherein the composition is a
solution and is applied once a day to each eye in need thereof.
20. A bromfenac composition according to the above 1 to 5 wherein the composition is a
solution and is applied twice a day to each eye in need thereof.
21. A method for stabilizing an aqueous solution of bromfenac or its pharmacologically
acceptable salt or a hydrate thereof, comprising combining bromfenac or a
pharmacologically acceptable salt or hydrate thereof, water, and a solubilizer, wherein the
solubilizer is selected from a group consist of either a polyoxyethylene sorbitan fatty acid
esters such as polysorbate 80 or a non-ionic soulbilizer such as polyoxyl-15-
hydroxystearate according to any of the above 1 to 19.
22. A process of preparing a stable, aqueous solution according to the above 1 to 5 and 20.
23. The aqueous solution prepared by the method according to the above 22.
24. The aqueous solution according to the above 22, which exhibits stability when stored at
stress conditions at 50°C for 4 weeks, when stored at accelerated conditions at 40°C for 6
months, or when stored at long term conditions.
25. The aqueous solution according to the above 24, wherein said stability includes one or
more of the following:
a) at least 90% remaining bromfenac;
b) not more than 3.0% total impurity;
c) not more than 0.8% impurity A;
d) not more than 0.8% impurity B.
17
26. A method of treating ocular inflammation or pain in a patient in need thereof, comprising
administering to an eye of the patient an effective amount of an aqueous solution
according to any of the above 25.
27. The bromfenac solution according to the above 25, which upon storage for 6 months at
accelerated conditions at 40°C at no more than 25% relative humidity, comprises less
than 0.8% of impurity B {(7-(4-bromobenzoyl) indoline-2, 3-dione} of active ingredient.
28. A method of treating ocular inflammation or pain in a patient in need thereof, comprising
administering to an eye of the patient an effective amount of a stable pharmaceutical
aqueous solution comprising bromfenac, or a pharmaceutically acceptable salt or hydrate
thereof; further comprising a polyoxyethylene sorbitan fatty acid ester and/or a polyoxyl-
15-hydroxystearate; wherein the solution has a pH of from about 6.5 to about 8; and
wherein the solution does not comprise any of an alkyl aryl polyether alcohol type
polymer, a polyethylene glycol fatty acid ester, and an antioxidant.
29. Use of a composition for treating ocular inflammation or pain in a patient in need thereof,
comprising administering to an eye of the patient an effective amount of an aqueous
solution according to any of the above 25.
30. Use of a composition for treating ocular inflammation or pain in a patient in need thereof,
comprising administering to an eye of the patient an effective amount of a stable
pharmaceutical aqueous solution comprising bromfenac, or a pharmaceutically
acceptable salt or hydrate thereof; further comprising a polyoxyethylene sorbitan fatty
acid ester and/or a polyoxyl-15-hydroxystearate; wherein the solution has a pH of from
about 6.5 to about 8; and wherein the solution does not comprise any of an alkyl aryl
polyether alcohol type polymer, a polyethylene glycol fatty acid ester, and an antioxidant.
The present invention provides a method of using the inventive compositions for treating ocular
inflammation and pain after cataract surgery.
In a preferred embodiment, the present invention provides a process of preparing a stable,
aqueous solution wherein the composition is prepared by a process comprising:
1. Add quantity of purified water approximately 80% of the batch size in a
container, e.g., a stainless steel vessel.
18
2. Add one component of a buffer system (e.g., Sodium citrate dihyrate) to step 1
under stirring and mix until dissolved.
3. Add mannitol to step 2 under stirring and mix until dissolved.
4. Add sodium chloride to step 3 under stirring and mix until dissolved.
5. Add chelating agent (e.g., disodium edetate) to step 4 under stirring and mix until
dissolved.
6. Add surfactant (e.g., a polyoxyethylene sorbitan fatty acid esters such as
polysorbate 80 or a non-ionic solubilizer such as polyoxyl-15-hydroxystearate) to step 5 under
stirring and mix until dissolved.
7. Add preservative (e.g., BKC) to step 6 under stirring and mix until dissolved.
8. Add NSAID (e.g., bromfenac sodium) to step 7 under stirring and mix until
dissolved.
9. Check pH of the solution; adjust if necessary to pH 7.8.
10. Make up the volume to 100% of the batch size with purified water and stir for 5
minutes.
11. Finally the solution is filtered through 0.22micron filter.
As can be determined by one of skill in the art using the present disclosure as a guide, the
order of the above steps can be changed, and two or more steps may be combined.
STABILITY STUDIES:
The stable, aqueous formulations (batch numbers 35B & 35C) of Bromfenac are prepared
with ranges of ingredients as shown in Table 1, and are exposed to stress conditions at 50°C for
initial (0 days), 2 to 4 weeks; at accelerated conditions at 40°C for 1, 2, 3 & 6 months and finally
exposed to long term conditions at 25°C for 3 months and 6 months to determine the stability of
the proposed formulations of the present invention.
One more formulation (Formulation 2) of the present invention is exposed to stress
conditions at 50°C for initial (0 days), 2 weeks and 4 weeks for stress stability at 50°C in the
dark.
A comparative study is initiated to determine the stability of present invention
formulations with a marketed product PROLENSA™ herein defined as “Control”.
19
A non-accelerated or accelerated study method may be used to test stability. A preferred
stress (or accelerated) study comprises placing the composition/solution is filled in Opaque
LDPE vial with LDPE nozzle and HDPE cap, packing in secondary packaging material, and
maintaining at 50°C in the dark. Impurities are measured by HPLC for initial (0 days), 2 weeks
and 4 weeks.
As understood by those of skill in the art, when the NSAID comprises bromfenac, the
impurities preferably measured include “Impurity A” as (7-(4-Bromobenzoyl)-1,3-dihydro-2Hindol-
2-one), “Impurity B” as (7-(4-bromobenzoyl) indoline-2, 3-dione) and the total impurities,
as well as identification of the amount of the highest unknown impurity.
Table 1
Ingredients
Ranges varied in %w/v
(batch numbers 35B &
35C)
Ranges varied in %w/v
(Formulation 2)
Bromfenac Sodium 0.0805 0.0805
Edetate Disodium 0.02 – 0.15 0.02 – 0.15
Sodium citrate dihydrate 0.05 – 0.4 0.05 – 0.4
Mannitol 0.2 – 4.0 0.2 – 4.0
Sodium chloride 0.05 – 0.6 0.05 – 0.6
Benzalkonium chloride 0.0005 – 0.5 0.0005 – 0.5
Polysorbate 80 0.005 – 0.2 -----
Polyoxyl-15-Hydroxystearate ----- 0.005 – 0.2
Sodium hydroxide QS QS
MilliQ water QS QS
pH 7.8 7.8
RESULTS AND OBSERVATIONS:
The control formulation (PROLENSA™) is evaluated for bromfenac content and related
substances at initial (0 days), 2 weeks and 4 weeks for stress stability at 50°C; at accelerated
conditions at 40°C for 1, 2, 3 & 6 months in the dark. Results are shown in Table 2.
The formulations (batch numbers 35B & 35C) of the present invention are evaluated for
bromfenac content and related substances at initial (0 days), 2 weeks and 4 weeks for stress
20
stability at 50°C; at accelerated conditions at 40°C for 1, 2, 3 & 6 months and finally exposed to
long term conditions at 25°C for 3 months and 6 months in the dark. Results are shown in Table
3 for batch numbers 35B and Table 4 for batch numbers 35C.
One more formulation (Formulation 2) of the present invention is evaluated for
bromfenac content and related substances at initial (0 days), 2 weeks and 4 weeks for stress
stability at 50°C in the dark. Results are shown in Table 5 for formulation 2.
Table 2 {Control formulation (PROLENSA™)}
Parameters
Proposed
Shelf life
Specs.
Limits
Initial
Stress conditions Accelerated conditions
2
Weeks/
50°C
4
Weeks/
50°C
1
Month/
40°C
2
Month/
40°C
3
Month/
40°C
6
Month/
40°C
Appearance CGYS CGYS CGYS CGYS CGYS CGYS CGYS CGYS
pH 7.2-8.0 7.78 NA 7.83 NA NA 7.80 7.78
Osmolality
(mOsmol/kg) 280-340 310 NA 328 NA NA 320 335
Related Substances
Impurity A* NMT 0.8 0.02 0.01 ND ND ND ND BQL
Impurity B $ NMT 0.8 BDL 0.14 0.16 0.07 0.25 0.49 1.47
Highest
unknown
impurity
NMT 0.8 ND ND 0.12 0.06 0.08 0.12 0.42
Total
impurities NMT 3.0 0.02 0.15 0.33 0.13 0.40 0.77 2.89
Assay of
bromfenac
free acid
90.0-
110.0 99.1 NA 99.3 NA NA 97.0 92.7
Content of
BKC 75-120 NA NA NA NA NA NA NA
Content of
EDTA 70-115 NA NA NA NA NA NA NA
*7-(4-Bromobenzoyl)-1, 3-dihydro-2H-indol-2-one
$ 7-(4-bromobenzoyl) indoline-2, 3-dione
ND: Not Detected
NA: Not Analyzed
BDL: Below Disregard Limit
BQL: Below Quantification Limit
21
Table 3 (Batch no. PR3F048-35B)
Parameters
Proposed
Shelf life
Specs.
Limits
Initial
Stress
conditions Accelerated conditions Long term
conditions
2
Weeks/
50°C
4
Weeks/
50°C
1
Month/
40°C
2
Month/
40°C
3
Month/
40°C
6
Month/
40°C
3
Month/
25°C
6
Month/
25°C
Appearance CGYS CGYS CGYS CGYS CGYS CGYS CGYS CGYS CGYS CGYS
pH 7.2-8.0 7.59 7.52 7.59 7.58 7.57 7.47 7.47 7.35 7.39
Osmolality
(mOsmol/kg) 280-340 304 309 321 310 313 320 324 310 312
Related Substances
Impurity A* NMT 0.8 0.01 0.04 0.06 0.06 0.09 0.11 0.12 0.13 0.17
Impurity B $ NMT 0.8 0.08 0.08 0.08 0.09 0.08 0.08 0.50 0.08 0.07
Highest
unknown
impurity
NMT 0.8 ND ND 0.07 ND BDL 0.09 0.12 BDL 0.08
Total
impurities NMT 3.0 0.09 0.12 0.19 0.15 0.17 0.28 0.74 0.21 0.32
Assay of
bromfenac
free acid
90.0-
110.0 98.8 102.3 103.1 99. 100.4 100.7 104.1 99.2 101.0
Content of
BKC 75-120 96.6 104.0 107.0 100.0 104.4 103.6 104.0 100.4 101.2
Content of
EDTA 70-115 100.6 102.0 104.1 101.6 104.0 104.4 106.9 102.0 102.2
*7-(4-Bromobenzoyl)-1, 3-dihydro-2H-indol-2-one
$ 7-(4-bromobenzoyl) indoline-2, 3-dione
ND: Not Detected
BDL: Below Disregard Limit
NA: Not Analyzed
CGYS: Clear, greenish yellow solution
Table 4 (Batch no. PR3F048-35C)
Parameters
Propos
ed
Shelf
life
Specs.
Limits
Initial
Stress
conditions Accelerated conditions Long term
conditions
2
Week/
50°C
4
Week/
50°C
1
Month/
40°C
2
Month/
40°C
3
Month/
40°C
6
Month/
40°C
3
Month/
25°C
6
Month/
25°C
Appearance CGYS CGYS CGYS CGYS CGYS CGYS CGYS CGYS CGYS CGYS
pH 7.2-8.0 7.88 7.63 7.59 7.58 7.56 7.48 7.49 7.47 7.47
Osmolality
(mOsmol/k
g)
280-
340 304 307 317 310 313 317 331 310 317
22
Related Substances
Impurity
A*
NMT
0.8 0.03 0.04 0.04 0.05 0.07 0.09 0.11 0.12 0.13
Impurity B
$
NMT
0.8 0.08 0.08 0.08 0.09 0.08 0.07 0.43 0.08 0.06
Highest
unknown
impurity
NMT
0.8 ND ND 0.05 ND BDL 0.09 0.11 BDL 0.08
Total
impurities
NMT
3.0 0.11 0.12 0.17 0.14 0.15 0.25 0.65 0.20 0.27
Assay of
bromfenac
free acid
90.0-
110.0 98.8 101.4 101.8 98.5 100.1 101.4 103.4 99.2 101.0
Content of
BKC 7-120 102.2 102.8 103.2 101.9 103.4 103.4 103.4 100.8 101.4
Content of
EDTA 70-115 101.0 100.1 102.7 100.4 102.4 104.1 107.2 102.3 100.9
*7-(4-Bromobenzoyl)-1, 3-dihydro-2H-indol-2-one
$ 7-(4-bromobenzoyl) indoline-2, 3-dione
ND: Not Detected
BDL: Below Disregard Limit
CGYS: Clear, greenish yellow solution
Table 5 (Formulation 2)
Parameters (Formulation 2) Initial sample
results
2 weeks, 50°C 4 weeks, 50°C
Description CGYS CGYS CGYS
pH 7.43 7.43 7.35
Osmolality (mOsmol/kg) 305 307 314
Related Substance
Impurity A 0.02% 0.07% 0.10%
Highest unknown impurity 0.08% 0.10% 0.22%
Total impurities 0.17% 0.17% 0.32%
Specified unidentified impurity at
RRT ~ 0.30 Not detected Not detected Not detected
Assay (bromfenac free acid) 101.50% 102.00% 100.70%
23
RESULTS OF CONTROL FORMULATION (PROLENSA™) (BATCH – 178392):
The results of stress stability at 50°C for 4 weeks for “Control” formulation:
The Bromfenac content is measured and found to be 99.3% (Limit: 90.0 -110.0%) which
is in the acceptable limit range, the highest unknown impurity is measured and found to be
0.12% (Limit: NMT 0.8%) which is in the acceptable limit range and total impurity is measured
and found to be 0.33% (Limit: NMT 3.0%) which is in the acceptable limit range.
The results of accelerated stability at 40°C for 6 months for “Control” formulation:
The Bromfenac content is measured and found to be 92.7% (Limit: 90.0 -110.0%) which
is in the acceptable limit range, the highest unknown impurity is measured and found to be
0.42% (Limit: NMT 0.8%) which is in the acceptable limit range and total impurity is measured
and found to be 2.89% (Limit: NMT 3.0%) which is in the acceptable limit range.
RESULTS OF PRESENT INVENTION FORMULATION (BATCH – 35B):
The results of stress stability at 50°C for 4 weeks for present invention formulation (batch –
35B):
The Bromfenac content is measured and found to be 103.1% (Limit: 90.0 -110.0%)
which is in the acceptable limit range, the highest unknown impurity is measured and found to be
0.07% (Limit: NMT 0.8%) which is in the acceptable limit range and total impurity is measured
and found to be 0.19% (Limit: NMT 3.0%) which is in the acceptable limit range.
The results of accelerated stability at 40°C for 6 months for present invention formulation
(batch – 35B):
The Bromfenac content is measured and found to be 104.1% (Limit: 90.0 -110.0%)
which is in the acceptable limit range, the highest unknown impurity is measured and found to be
0.12% (Limit: NMT 0.8%) which is in the acceptable limit range and total impurity is measured
and found to be 0.74% (Limit: NMT 3.0%) which is in the acceptable limit range.
The results of long term stability at 25°C for 6 months for present invention formulation
(batch – 35B):
The Bromfenac content is measured and found to be 101.0% (Limit: 90.0 -110.0%)
which is in the acceptable limit range, the highest unknown impurity is measured and found to be
24
0.08% (Limit: NMT 0.8%) which is in the acceptable limit range and total impurity is measured
and found to be 0.32% (Limit: NMT 3.0%) which is in the acceptable limit range.
RESULTS OF PRESENT INVENTION FORMULATION (BATCH – 35C):
The results of stress stability at 50°C for 4 weeks for present invention formulation (batch –
35C):
The Bromfenac content is measured and found to be 101.8% (Limit: 90.0 -110.0%)
which is in the acceptable limit range, the highest unknown impurity is measured and found to be
0.05% (Limit: NMT 0.8%) which is in the acceptable limit range and total impurity is measured
and found to be 0.17% (Limit: NMT 3.0%) which is in the acceptable limit range.
The results of accelerated stability at 40°C for 6 months for present invention formulation
(batch – 35C):
The Bromfenac content is measured and found to be 103.4% (Limit: 90.0 -110.0%)
which is in the acceptable limit range, the highest unknown impurity is measured and found to be
0.11% (Limit: NMT 0.8%) which is in the acceptable limit range and total impurity is measured
and found to be 0.65% (Limit: NMT 3.0%) which is in the acceptable limit range.
The results of long term stability at 25°C for 6 months for present invention formulation
(batch – 35C):
The Bromfenac content is measured and found to be 101.0% (Limit: 90.0 -110.0%)
which is in the acceptable limit range, the highest unknown impurity is measured and found to be
0.08% (Limit: NMT 0.8%) which is in the acceptable limit range and total impurity is measured
and found to be 0.27% (Limit: NMT 3.0%) which is in the acceptable limit range.
RESULTS OF PRESENT INVENTION FORMULATION (FORMULATION 2):
The results of stress stability at 50°C for 4 weeks for polyoxyl 15 hydroxy stearate
(Formulation 2):
The Bromfenac content is measured to be 100.7% (Limit: 90.0 -110.0%) which is in the
acceptable limit range, the highest unknown impurity is measured to be 0.22% (Limit: NMT
25
0.8%) which is in the acceptable limit range and total impurity is measured to be 0.32% (Limit:
NMT 3.0%) which is in the acceptable limit range.
All the following formulations (batch numbers 35B; 35C & formulation 2) were found to
be stable at all stability conditions.
Based on the stability studies conducted on control formulation (PROLENSA™)
(BATCH – 178392) and formulations (batch numbers 35B; 35C) of the present invention, it was
observed that level of Impurity B in present invention formulations is approximately 1/3rd of the
level in Control formulation at 6 month accelerated condition (Levels of Impurity B level as
shown in Figure 3 - 0.43% (batch 35C) & 0.50% (batch 35B) of present invention formulation
verses 1.47% of Control formulation - PROLENSA™).
Subsequently, the levels of total impurities are also less in present invention formulations
in comparison to Control formulation at 6M accelerated condition (0.65% (batch 35C) in Sentiss
formulation verses 2.89% in Control formulation). All other parameters were well within the
specifications.
ANIMAL EFFICACY STUDIES:
The objective of the study was to evaluate and compare ocular anti-inflammatory activity
of different formulations in Wistar rats following ocular installation. The summary of Animal
efficacy studies is in table 6.
Table 6: Summary of Animal Studies
Clinical signs All animals were normal, except diarrhoea in few animals due to
endotoxin and recovered during next observation.
Mortality All animals survived throughout the experiment
Ophthalmoscopic examinations
26
Vasodilatation
(% of the mean of negative
control)
Dilatation of blood vessels was assessed on the basis of the
hyperaemia developed. The ophthalmoscopic observation data
have been reported in table 8 and same has been plotted in figure
2.
Group I – Negative control (Normal saline - 10 μL/eye)
Group II (036A) - Present Invention formulation (10 μL/eye)
Group III (178392) - Innovator’s product (PROLENSA™) (10
μL/eye)
• Groups II vs Group III:
Comparable (p< 1.000 @ 24hrs & 0.794 @ 48hrs)
Presence of flare & corneal
observations
Scored zero (0) as no flare observed and no corneal damage in
any of the dose groups
Others No abnormalities detected in any of the dose groups
Leukocyte counts (from aqueous humor)
Counts
(% of the mean of negative
control)
Leucocyte count: The leukocyte count data have been
reported in table 7 and same has been plotted in figure 1.
 Group I: 86.40±16.71 (100%)
 Group II: 48.20±6.29 (55.79%)
 Group III: 49.35±4.86 (57.12%)
Groups II (55.79%) vs Group I:
Significant reduction in Group II (p < 0.039 @ 48
hrs)
Groups III (57.12%) vs Group I:
Significant reduction in Group III (p < 0.040 @ 48
hrs)
Groups II vs Group III: Comparable (p < 0.886 @ 48 hrs)
27
Table 7: Comparative leukocyte counts between Group I (Negative control), Group II
(Present Invention formulation - 036A) & Group III (Innovator product – PROLENSA™).
Table 8: Comparative vasodilation reduction between Group I (Negative control), Group II
(Present Invention formulation - 036A) & Group III (Innovator product - PROLENSA™).
Groups
Parameters Time points
Average Pre-dose 24 hrs 48 hrs
Group I
% inflammation
(Dilatation score)
0.00 % (0.00) 100.00 % (2.70) 100.00 % (2.80)
Group II
% inflammation
(Dilatation score)
0.00 % (0.00) 87.04 % (2.35) 76.79 % (2.15)
Group
III
% inflammation
(Dilatation score)
0.00 % (0.00) 87.04 % (2.35) 78.57 % (2.20)
CONCLUSION: Based on the observations obtained from this study, it is concluded that both
the formulations {batch numbered Group II (Present Invention formulation) 036A & & Group III
(Innovator product – PROLENSA™ -178392} have shown statistically significant efficacy on
ocular inflammation when administered to Wistar rats by ocular route and this effect of Group II
(036A) was statistically comparable to the efficacy of Group III (178392).
Groups Parameters Time point: 48 hrs
Group I % leukocytes (leukocytes count) 100 % (86.4/mm2)
Group II % leukocytes (leukocytes count) 55.79 % (48.20/mm2)
Group III % leukocytes (leukocytes count) 57.12 % (49.35/mm2)
28
EXAMPLES:
The scope of the present invention is illustrated by the following examples which are not
meant to restrict the scope of the invention in any manner whatsoever.
The term 'q.s.' wherever appears in the examples is an abbreviation for 'quantity
sufficient' which is the amount of the excipient in such quantities that is just sufficient for its use
in the composition of the present invention.
The term '°C' wherever appears is an abbreviation for “Degree Celsius” and the term
“NMT” wherever appears is an abbreviation for “Not More Than”.
Formulas I exhibit good stability following the stress stability test at 50°C for initial (0
days), 2 weeks and 4 weeks; at accelerated conditions at 40°C for 1, 2, 3 & 6 months and finally
exposed to long term conditions at 25°C for 3 months and 6 months.
Formulas II exhibit good stability following the stress stability test at 50°C for initial (0
days), 2 weeks and 4 weeks.
FORMULA I:
Ingredients %w/v
Bromfenac Sodium 0.0805
Edetate disodium 0.1
Polysorbate 80 0.01
Sodium citrate dihyrate 0.292
Mannitol 2.0
Sodium chloride 0.45
BKC 0.005
Sodium hydroxide q.s.
MilliQ water q.s.
pH 7.8
METHOD:
1. Add quantity of purified water approximately 80% of the batch size in a
container, e.g., a stainless steel vessel.
29
2. Add one component of a buffer system (e.g., Sodium citrate dihyrate) to step 1
under stirring and mix until dissolved.
3. Add mannitol to step 2 under stirring and mix until dissolved.
4. Add sodium chloride to step 3 under stirring and mix until dissolved.
5. Add chelating agent (e.g., disodium edetate) to step 4 under stirring and mix until
dissolved.
6. Add surfactant (e.g., Polysorbate 80) to step 5 under stirring and mix until
dissolved.
7. Add preservative (e.g., BKC) to step 6 under stirring and mix until dissolved.
8. Add NSAID (e.g., bromfenac sodium) to step 7 under stirring and mix until
dissolved.
9. Check pH of the solution; adjust if necessary to pH 7.8.
10. Make up the volume to 100% of the batch size with purified water and stir for 5
minutes.
11. Finally the solution is filtered through 0.22micron filter.
FORMULA II:
Ingredients %w/v
Bromfenac Sodium 0.0805
Edetate disodium 0.1
Kolliphore HS 15 (Polyoxyl 15
hydroxy stearate) 0.01
Sodium citrate dihyrate 0.292
Mannitol 2.0
Sodium chloride 0.45
BKC 0.005
Sodium hydroxide q.s.
MilliQ water q.s.
pH 7.8
30
METHOD:
1. Add quantity of purified water approximately 80% of the batch size in a
container, e.g., a stainless steel vessel.
2. Add one component of a buffer system (e.g., Sodium citrate dihyrate) to step 1
under stirring and mix until dissolved.
3. Add mannitol to step 2 under stirring and mix until dissolved.
4. Add sodium chloride to step 3 under stirring and mix until dissolved.
5. Add chelating agent (e.g., disodium edetate) to step 4 under stirring and mix until
dissolved.
6. Add surfactant (e.g., Kolliphore HS 15 (Polyoxyl 15 hydroxy stearate)) to step 5
under stirring and mix until dissolved.
7. Add preservative (e.g., BKC) to step 6 under stirring and mix until dissolved.
8. Add NSAID (e.g., bromfenac sodium) to step 7 under stirring and mix until
dissolved.
9. Check pH of the solution; adjust if necessary to pH 7.8.
10. Make up the volume to 100% of the batch size with purified water and stir for 5
minutes.
11. Finally the solution is filtered through 0.22micron filter.
COMPARATIVE EXAMPLE:
Polysorbate 80 concentrations at or above 0.15%w/v may be unstable during stress
stability at 50°C for four weeks as shown in table 5.
Ingredients %w/v
Bromfenac Sodium 0.0805
Edetate disodium 0.1
Polysorbate 80 0.15
Sodium citrate dihyrate 0.292
Mannitol 2.0
Sodium chloride 0.45
Sodium hydroxide q.s.
BKC 0.005
Purified water (MilliQ water) q.s.
pH 7.8
31
Table 5
Parameters (Polysorbate 80) 4 weeks, 50°C
Description Yellow colored solution
pH 7.14
Osmolality (mOsmol/kg) 337
Related Substance
Impurity A 0.23%
Highest unknown impurity 2.54%
Total impurities 6.64%
Assay (bromfenac free acid) 75.80%
After four weeks of the stress test, Bromfenac content is measured to be 75.80% (Limit:
90.0 -110.0%), which is below the acceptable limit range, the highest unknown impurity is
measured to be 2.54% (Limit: NMT 1.0%), which is above the acceptable limit range and total
impurity is measured to be 6.64% (Limit: NMT 3.0%), which is above the acceptable limit
range.
The comparative Stability studies between control and present inventions show that the
ingredients used in the formulations have varied effects on the stability of the formulations
investigated when measured at different time periods (at initial (0 days), 2 weeks and 4 weeks) at
50°C; at accelerated conditions at 40°C for 1, 2, 3 & 6 months and finally exposed to long term
conditions at 25°C for 3 months and 6 months..
The inventors of the present invention with expenditure of intellectual effort and careful
experimentation have identified unique concentration of solubilizers such as Polysorbate 80 that
resolves the hazinesss of the formulations of the present invention but does not affect
degradation of bromfenac, in spite of not using antioxidants.
Formulations of the present invention are unexpectedly as stable as that of control at a
pH 7.8, without the need for, or use of, antioxidants such as sulfite(s) such as sodium sulfite,
potassium sulfite, and the like, and/or with the addition of pharmaceutically acceptable
solubilizers such as either an polyoxyethylene sorbitan fatty acid esters such as polysorbate 80 or
a non-ionic solubilizer such as polyoxyl-15-hydroxystearate.
Even based on the stability studies conducted on control formulation (PROLENSA™)
(BATCH – 178392) and formulations (batch numbers 35B; 35C) of the present invention, it was
observed that level of Impurity B in present invention formulations is approximately 1/3rd of the
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level in Control formulation at 6 month accelerated condition (Levels of Impurity B level as
shown in Figure 3 - 0.43% (batch 35C) & 0.50% (batch 35B) of present invention formulation
verses 1.47% of Control formulation - PROLENSA™). This demonstrates that the present
invention formulations are unexpectedly as stable as and even more stable than that of control
formulation (PROLENSA™) as shown in Figure III.
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We Claim:
1. A stable pharmaceutical composition comprising bromfenac, or a pharmaceutically
acceptable salt or hydrate thereof, wherein the composition is a solution; and wherein the
solution has a pH of from about 6.5 to about 8.
2. The composition of claim 1, further comprising a polyoxyethylene sorbitan fatty acid
ester comprising polysorbate 80.
3. The composition of claim 2, wherein the polyoxyethylene sorbitan fatty acid ester is
polysorbate 80.
4. The composition of claim 1, further comprising a non-ionic solubilizer such as polyoxyl-
15-hydroxystearate.
5. A stable pharmaceutical composition comprising bromfenac or a pharmacologically
acceptable salt or hydrate thereof, wherein the composition is a solution, is stable, and
comprises at least one of:
a. an polyoxyethylene sorbitan fatty acid esters such as polysorbate 80 or;
b. a non-ionic solubilizer such as polyoxyl-15-hydroxystearate; and wherein the
composition does not comprise any of the following;
c. an alkyl aryl polyether alcohol type polymer;
d. a polyethylene glycol fatty acid ester or;
e. an antioxidant.
6. The bromfenac composition of any of claims 1 to 5 that does not comprise an alkyl aryl
polyether alcohol type polymer, a polyethylene glycol fatty acid ester, and an antioxidant.
7. The bromfenac composition of any of claims 1 to 5 that does not comprise tyloxapol or
polyethylene glycol monostearate such as polyoxyl 40 stearate.
8. The bromfenac composition of claim 7, that does not comprise an alkyl aryl polyether
alcohol type polymer, a polyethylene glycol fatty acid ester, and an antioxidant.
9. The bromfenac composition of any of claims 1 to 5, that does not comprise a sulfite antioxidant.
10. The bromfenac solution of any of claims 1 to 5, that does not comprise a borate buffer.
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11. The bromfenac solution of any of claims 1 to 5, wherein the solution is aqueous and
comprises citrate buffer.
12. The bromfenac solution of any of claims 1 to 5 that has a pH from about 6.5 to about 8.
13. The bromfenac solution of claim 12 that has a pH from about 7.2 to about 7.8.
14. The bromfenac solution of any of claims 1 to 5, wherein the solution is contained in a
unit dose kit form.
15. The bromfenac solution of any of claims 1 to 5, wherein the solution is contained in a
multi dose kit form.
16. The bromfenac solution of any of claims 1 to 5, which is an aqueous solution comprising
bromfenac sodium salt or a hydrate thereof, wherein the concentration of the bromfenac
sodium salt or the hydrate thereof is from about 0.01 to about 0.1 w/v%.
17. The bromfenac composition of any of the claims 1 to 5 wherein benzalkonium chloride is
contained as a preservative.
18. The bromfenac composition of any of claims 1, 5 and 16 wherein the hydrate is at least
one selected from a 1/2 hydrate, 1 hydrate and 3/2 hydrate.
19. The bromfenac composition of any of claims 1 to 5 wherein the composition is a solution
and is applied once a day to each eye in need thereof.
20. The bromfenac composition of any of the claims 1 to 5 wherein the composition is a
solution and is applied twice a day to each eye in need thereof.
21. A method for stabilizing an aqueous solution of bromfenac or its pharmacologically
acceptable salt or a hydrate thereof, comprising combining bromfenac or a
pharmacologically acceptable salt or hydrate thereof, water, and a solubilizer, wherein the
solubilizer is selected from a group consist of either a polyoxyethylene sorbitan fatty acid
esters such as polysorbate 80 or a non-ionic soulbilizer such as polyoxyl-15-
hydroxystearate.
22. A process of preparing a stable, aqueous solution of any of claims 1 to 5 and 20.
23. The aqueous solution prepared by the method of claim 22.
24. The aqueous solution of claim 22, which exhibits stability when stored at stress
conditions at 50°C for 4 weeks, when stored at accelerated conditions at 40°C for 6
months, or when stored at long term conditions.
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25. The aqueous solution of claim 24, wherein said stability includes one or more of the
following:
a) at least 90% remaining bromfenac;
b) not more than 3.0% total impurity;
c) not more than 0.8% impurity A;
d) not more than 0.8% impurity B.
26. The bromfenac solution of claim 25, which upon storage for 6 months at accelerated
conditions at 40°C at no more than 25% relative humidity, comprises less than 0.8% of
Impurity B {(7-(4-bromobenzoyl) indoline-2, 3-dione} of active ingredient.