FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
PROVISIONAL/COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
AN IMPROVED PROCESS FOR THE PREPARATION OF AN AQUEOUS
OPHTHALMIC SOLUTION OF DIFLUPREDNATE
2. APPLICANT(S)
a) Name: Sun Pharma Advanced Research Company Limited
b) Nationality: A company incorporated under the laws of India
c) Address: 17/B, Mahal Industrial Estate, Mahakali Caves Road, Andheri
(E), Mumbai - 400093, Maharashtra, India
The following specification particularly describes the invention and the manner
in which it is to be performed.
2
FIELD OF THE INVENTION
The present invention relates an improved process for the preparation of an aqueous
ophthalmic solution of difluprednate or pharmaceutically acceptable salts thereof. The
present invention further relates to an aqueous ophthalmic solution of difluprednate or
pharmaceutically acceptable salts thereof, prepared 5 by the improved process of the present
invention.
BACKGROUND OF THE INVENTION
Difluprednate is an anti-inflammatory corticosteroid drug represented by formula I
below:
10
Formula I
Difluprednate, a steroidal drug is practically insoluble in aqueous vehicle. The
currently approved formulation of difluprednate in the United States is marketed under the
brand name of DUREZOL®, which is an emulsion dosage form and not an aqueous solution.
15 Durezol® comprises 0.05 % w/v difluprednate emulsified between castor oil and water.
Durezol® emulsion formulation is indicated for the treatment of inflammation and pain
associated with ocular surgery and endogenous anterior uveitis when administered four
times a day. As the emulsion needs to be instilled four times-a-day, there are high chances
of patient non-compliance and missing a dose.
20 United States Patent Number 6,114,319 (herein after referred to as the ‘319 patent)
describes an oil-in-water emulsion formulation of difluprednate, which contains a fatty acid
ester of glycerol as an oil and non-ionic surfactant as emulsifier. The process according to
the ‘319 patent comprises: preparation of an oil phase comprising difluprednate and an
aqueous phase comprising the surfactant followed by addition of an oil phase to the aqueous
25 phase.
United States Patent Number 5,556,848 (herein after referred to as the ‘848 patent)
describes an aqueous suspension formulation of difluprednate and a non-ionic surfactant as
3
dispersion stabilizer. The process according to the ‘848 patent comprises suspending
difluprednate in an aqueous solution comprising the non-ionic surfactant.
United States Patent Number 11,000,475 (herein after referred to as the ‘475 patent)
describes an ophthalmic solution of difluprednate comprising a crystal growth inhibitor. The
ophthalmic solution of difluprednate according 5 to the ‘475 was prepared by the process as
described in the examples 1-4 therein.
While scaling up the process for the preparation of the aqueous solution of
difluprednate, the inventors of the present invention observed excessive foaming. Due to
the foaming, the inventors faced critical issues in terms of unpredictable and inaccurate
10 volume measurement. Further, when the solution was filtered or allowed to settle-down the
foam, it resulted to high yield loss, increased batch processing time and thus increased
operational cost.
SUMMARY OF THE INVENTION
The inventors have surprisingly identified an improved process which avoids
15 excessive foaming during the commercial manufacturing of the aqueous ophthalmic
solution of difluprednate.
In the first aspect, the present invention relates to a process for the preparation of an
aqueous ophthalmic solution of difluprednate having a pH of 4.5 to 5.5 and an osmolality
from about 95 to about 150 mOsm/kg, comprising:
20 a. preparation of a non-aqueous drug phase by dissolving difluprednate and
benzalkonium chloride in polyoxyl 35 castor oil;
b. preparation of an aqueous phase comprising:
i. preparing a polymer phase by dissolving polyvinyl alcohol in water
for injection;
25 ii. preparing a buffer phase by dissolving glacial acetic acid, glycerin,
boric acid, disodium edetate, sodium acetate and N-lauryl sarcosine
sodium in water for injection at a stirring rate of about 200 to about
400 rotations per minute; and
iii. addition of buffer phase to the polymer phase, wherein the addition
30 is done at a stirring rate of about 200 to about 600 rotations per
minute;
4
c. preparation of a bulk solution by addition of the non-aqueous drug phase to
the aqueous phase; and
d. addition of polyhexamethylene biguanide to the bulk solution to achieve the
aqueous ophthalmic solution of difluprednate.
In a second aspect, the present invention 5 relates to an aqueous ophthalmic solution
of difluprednate having a pH of 4.5 to 5.5 and an osmolality from about 95 to about 150
mOsm/kg, comprising:
i. about 0.03% w/v to about 0.04% w/v difluprednate;
ii. about 0.5% w/v to about 3.0% w/v polyvinyl alcohol or a derivative
10 thereof;
iii. about 0.01% w/v to about 0.05% w/v benzalkonium chloride; and
iv. about 1.5% w/v to about 6.0% w/v polyoxyl 35 castor oil;
wherein the said aqueous ophthalmic solution is prepared by the process comprising:
a. preparation of a non-aqueous drug phase by dissolving difluprednate and
15 benzalkonium chloride in polyoxyl 35 castor oil;
b. preparation of an aqueous phase comprising:
i. preparing a polymer phase by dissolving polyvinyl alcohol in water
for injection;
ii. preparing a buffer phase by dissolving glacial acetic acid, glycerin,
20 boric acid, disodium edetate, sodium acetate and N-lauryl sarcosine
sodium in water for injection at a stirring rate of about 200 to about
400 rotations per minute; and
iii. addition of the buffer phase to the polymer phase, wherein the addition
is done at a stirring rate of about 200 to about 600 rotations per minute;
25 c. preparation of a bulk solution by addition of non-aqueous drug phase to
aqueous phase; and
d. addition of polyhexamethylene biguanide to the bulk solution to achieve the
aqueous ophthalmic solution of difluprednate.
DETAILED DESCRIPTION OF THE INVENTION
5
The “aqueous ophthalmic solution” as stated herein, is a solution of difluprednate
in an aqueous vehicle, wherein difluprednate is in the solubilized form and not in particulate
form, either microparticulate or nanoparticulate or in micellar form.
The word ‘difluprednate’ as used herein includes prodrugs of difluprednate wherein
the hydroxyl group 5 in difluprednate is converted to a labile ester or an amide.
In a first aspect, the present invention relates to a process for the preparation of an
aqueous ophthalmic solution of difluprednate having a pH of 4.5 to 5.5 and an osmolality
from about 95 to about 150 mOsm/kg, comprising:
a. preparation of a non-aqueous drug phase by dissolving difluprednate and
10 benzalkonium chloride in polyoxyl 35 castor oil;
b. preparation of an aqueous phase comprising:
i. preparing a polymer phase by dissolving polyvinyl alcohol in water
for injection;
ii. preparing a buffer phase by dissolving glacial acetic acid, glycerin,
15 boric acid, disodium edetate, sodium acetate and N-lauryl sarcosine
sodium in water for injection at a stirring rate of about 200 to about
400 rotations per minute; and
iii. addition of the buffer phase to the polymer phase, wherein the
addition is done at a stirring rate of about 200 to about 600 rotations
20 per minute;
c. preparation of a bulk solution by addition of the non-aqueous drug phase to
the aqueous phase; and
d. addition of polyhexamethylene biguanide to the bulk solution to achieve the
aqueous ophthalmic solution of difluprednate.
25 In one embodiment of the present disclosure, the process further comprises addition
of water for injection in order to make up the volume according to the batch size.
In another embodiment of the present disclosure, the process further comprises
filtration through a sterile 0.2 micron filter. In a preferred embodiment, the solution is
6
filtered through a hydrophilic modified polyvinylidene fluoride (PVDF) filter, available
under the brand name Fluorodyne® II DFL capsule filters having pore size 0.2 micron.
Upon considerable efforts and evaluating various process parameters, the inventors
believe that stirring rate is an important parameter to avoid foaming. It was further identified
that by controlling the stirring rate during preparation 5 of an aqueous phase, any foaming
issue is prevented. Particularly during the preparation of the buffer phase, when N-lauryl
sarcosine sodium is added, uncontrolled stirring causes excessive foaming, which is then
carried forward and increases upon addition of the buffer phase to the polymer phase and
further to the final bulk phase and finished aqueous solution of difluprednate. Thus, it is
10 important to prevent foaming during the preparation of the aqueous phase, specifically
during the preparation of the buffer phase and addition thereof to the polymer phase.
In one embodiment of the present disclosure, the buffer phase is prepared at a stirring
rate not more than 400 rotations per minute. In a preferred embodiment, the buffer phase is
prepared at a stirring rate of about 200 to about 400 rotations per minute.
15 In one preferred embodiment, the addition of N-lauryl sarcosine sodium in the buffer
phase preparation is done at a stirring rate not more than 400 rotations per minute. In a
preferred embodiment, said addition of N-lauryl sarcosine sodium is done at a stirring rate
of about 200 to about 400 rotations per minute.
In another embodiment of the present disclosure, the addition of the buffer phase to
20 the polymer phase is done at a stirring rate not more than 600 rotations per minute. In a
preferred embodiment, said addition is done at a stirring rate of about 200 to about 600
rotations per minute.
In one preferred embodiment of the present disclosure, the aqueous ophthalmic
solution of difluprednate comprises:
25 i. about 0.03% w/v to about 0.04% w/v difluprednate;
ii. about 0.5% w/v to about 3.0% w/v polyvinyl alcohol or derivative thereof;
iii. about 0.01% w/v to about 0.05% w/v benzalkonium chloride; and
iv. about 1.5% w/v to about 6.0% w/v polyoxyl 35 castor oil;
In another embodiment of the present disclosure, wherein the aqueous ophthalmic
30 solution of difluprednate further comprises:
7
v. about 0.002% w/v to about 0.02% w/v polyhexamethylene biguanide;
vi. about 0.02 % w/v to about 0.05 % w/v N-lauroyl sarcosine sodium;
vii. about 0.05 % w/v to about 1.5 % w/v boric acid;
viii. about 0.01 % w/v to about 0.1 % w/v disodium edetate; and
5 ix. about 1.0 % w/v to about 3.0 % w/v glycerine.
In a second aspect, the present invention relates to an aqueous ophthalmic solution
of difluprednate having a pH of 4.5 to 5.5 and an osmolality from about 95 to about 150
mOsm/kg, comprising:
i. about 0.03% w/v to about 0.04% w/v difluprednate;
10 ii. about 0.5% w/v to about 3.0% w/v polyvinyl alcohol or derivative thereof;
iii. about 0.01% w/v to about 0.05% w/v benzalkonium chloride; and
iv. about 1.5% w/v to about 6.0% w/v polyoxyl 35 castor oil;
wherein the said aqueous ophthalmic solution is prepared by the process comprising:
a. preparation of a non-aqueous drug phase by dissolving difluprednate and
15 benzalkonium chloride in polyoxyl 35 castor oil;
b. preparation of an aqueous phase comprising:
i. preparing a polymer phase by dissolving polyvinyl alcohol in water
for injection;
ii. preparing a buffer phase by dissolving glacial acetic acid, glycerin,
20 boric acid, disodium edetate, sodium acetate and N-lauryl sarcosine
sodium in water for injection at a stirring rate of about 200 to about
400 rotations per minute; and
iii. addition of the buffer phase to the polymer phase, wherein the
addition is done at a stirring rate of about 200 to about 600 rotations
25 per minute;
c. preparation of a bulk solution by addition of the non-aqueous drug phase to
the aqueous phase; and
d. addition of polyhexamethylene biguanide to the bulk solution to achieve the
aqueous ophthalmic solution of difluprednate.
8
In one embodiment of the present disclosure, the concentration (% weight by volume
or % w/v) of difluprednate is expressed in terms of difluprednate base, and is present at a
concentration that ranges from about 0.005 % w/v to about 0.07 % w/v, preferably from
about 0.02 % w/v to about 0.045 % w/v, more preferably from about 0.03 % w/v to about
5 0.04 % w/v.
In another embodiment of the present disclosure, the aqueous ophthalmic solution
comprises a mixture of a quaternary ammonium compound and polyethoxylated castor oil
as a solubilizer.
In one embodiment of the present disclosure, the quaternary ammonium compound
10 that is used in the mixture as a solubilizer is preferably benzalkonium chloride. According
to another embodiment, the benzalkonium chloride is present in an amount ranging from
about 0.0002 % w/v to about 0.08 % w/v, preferably from about 0.01 % w/v to about 0.05
% w/v.
In one embodiment, the polyethoxylated castor oil that is used in the mixture as a
15 solubilizer is preferably polyoxyl 35 castor oil, marketed under the tradename Cremophor®
EL by BASF Corp. According to another embodiment, the polyoxyl 35 castor oil is present
in an amount ranging from about 1.9 % w/v to about 10 % w/v, preferably from about 1.5
% w/v to about 6.0 % w/v.
In one particularly preferred embodiment, the aqueous ophthalmic solution
20 comprises a mixture of benzalkonium chloride and polyoxyl 35 castor oil as solubilizer.
In another embodiment of the present disclosure, the aqueous ophthalmic solution
comprises polyvinyl alcohol or its derivatives as a crystal growth inhibitor. In one specific
embodiment, polyvinyl alcohol is present in the range from about 0.1 % w/v to about 5.0 %
w/v, preferably from about 0.5 % w/v to about 3.0 % w/v.
25 The aqueous solution of the present invention may further include, other
conventional excipients such as preservatives, chelating agents, co-solvents, buffers and so
on.
In one preferred embodiment, the aqueous ophthalmic solution comprises one or
more preservatives selected from a polyhexamethylene biguanide, boric acid, N-lauroyl
30 sarcosine sodium or mixtures thereof. In one particularly preferred embodiment, the
aqueous ophthalmic solution of difluprednate comprises a mixture of polyhexamethylene
biguanide, boric acid and N-lauroyl sarcosine sodium as preservative.
9
In one preferred embodiment, the aqueous ophthalmic solution comprises
polyhexamethylene biguanide in an amount ranging from about 0.001% w/v to about 0.04%
w/v, preferably from about 0.002 % w/v to about 0.02 % w/v, more preferably for example
0.005 % w/v.
In another preferred embodiment, 5 the aqueous ophthalmic solution comprises boric
acid in an amount ranging from about 0.05 % w/v to about 1.5 % w/v, preferably for
example, 0.6 % w/v.
In another preferred embodiment, the aqueous ophthalmic solution comprises Nlauroyl
sarcosine sodium in an amount ranging from about 0.001 % w/v to about 0.5 % w/v,
10 preferably from about 0.02 w/v to about 0.05 % w/v, more preferably for example 0.03 %
w/v.
In one preferred embodiment, the aqueous ophthalmic solution comprises disodium
edetate as a chelating agent present in an amount ranging from about 0.001 % w/v to about
0.5 % w/v, preferably from about 0.01 % w/v to about 0.1 % w/v, more preferably for
15 example 0.05 % w/v.
In one preferred embodiment, the aqueous ophthalmic solution comprises glycerine
as a co-solvent present in an amount ranging from about 0.5 % w/v to about 5.0 % w/v,
preferably from about 1.0 % w/v to about 3.0 % w/v, preferably for example 1.6 % w/v of
the solution.
20 In one preferred embodiment, the aqueous ophthalmic solution comprises acetic
acid, sodium acetate or mixtures thereof as a pH adjusting agent and/or buffer. In another
preferred embodiment, the pH adjusting agent and/or buffer are added in quantities
sufficient to achieve a pH of the aqueous ophthalmic solution from about 4.5 to about 5.5.
The said aqueous solution has an osmolality from about 95 to about 150 mOsm/kg,
25 preferably from about 100 to about 130 mOsm/kg, more preferably from about 115 to about
125 mOsm/kg.
In one embodiment, the present invention relates to an aqueous ophthalmic solution
of difluprednate having a pH of 4.5 to 5.5 and an osmolality from about 95 to about 150
mOsm/kg.
30 In one preferred embodiment of the present disclosure, the aqueous ophthalmic
solution of difluprednate comprises:
10
i. about 0.03% w/v to about 0.04% w/v difluprednate;
ii. about 0.5% w/v to about 3.0% w/v polyvinyl alcohol or derivative thereof;
iii. about 0.01% w/v to about 0.05% w/v benzalkonium chloride; and
iv. about 1.5% w/v to about 6.0% w/v polyoxyl 35 castor oil;
In another embodiment of the present 5 disclosure, wherein the aqueous ophthalmic
solution of difluprednate further comprises:
v. about 0.002% w/v to about 0.02% w/v polyhexamethylene biguanide;
vi. about 0.02 % w/v to about 0.05 % w/v N-lauroyl sarcosine sodium;
vii. about 0.05 % w/v to about 1.5 % w/v boric acid;
10 viii. about 0.01 % w/v to about 0.1 % w/v disodium edetate; and
ix. about 1.0 % w/v to about 3.0 % w/v glycerine.
In another embodiment, the present invention relates to an aqueous ophthalmic
solution of difluprednate of above embodiments, prepared by the process according to the
first aspect.
15 While the present invention is disclosed generally as above, additional aspects are
further discussed and illustrated with reference to the example below. However, the example
is presented merely to illustrate the invention and should not be considered as a limitation
thereto.
EXAMPLE
20 The example describes an improved process for the preparation of an aqueous ophthalmic
solution of difluprednate according to the present invention.
Table 1: Aqueous ophthalmic solution of difluprednate:
Ingredients Example 1
Difluprednate 20 g
Benzalkonium chloride 12.5 g
N-lauroyl sarcosine sodium 15 g
Polyoxyl 35 castor oil (Cremophor® EL) 2500 g
Polyvinyl alcohol 700 g
Glycerine 750 g
Boric acid 300 g
Poly hexa methylene biguanide 2.5 g
11
Disodium edetate 25 g
Sodium acetate trihydrate 5 g
Glacial acetic acid 2.5 g
Water for Injection q.s to 50 L
Stage A: Preparation of a non-aqueous drug phase:
Polyoxyl 35 castor oil (500 mL) was added to difluprednate (20 g) followed by
addition of benzalkonium chloride (12.5 g as 50% solution). The mixture was further added
to additional polyoxyl 35 castor oil (500 mL) 5 and stirred until the difluprednate was
completely dissolved.
Stage B: Preparation of an aqueous phase:
i. Preparation of a polymer phase: Polyvinyl alcohol (700 g) was dissolved in
water for injection (21 L) under stirring at 70-80°C. The resulting solution was then cooled
10 at 40-45°C and eventually at 20-25°C.
ii. Preparation of a buffer phase: Sodium acetate trihydrate (5 g), Glacial acetic
acid (2.5 g), glycerine (750 g), boric acid (300 g) and disodium edetate (25 g) were dissolved
in water for injection (13 L). The resulting solution was slowly added to N-lauryl sarcosine
sodium (15 g as 30% solution) and stirred under controlled stirring at about 200 to about
15 400 rotations per minute to obtain the buffer phase.
iii. The buffer phase was then added to the polymer phase, again under
controlled stirring at about 200 to about 600 rotations per minute, followed by addition of
water for injection (2 L) to obtain the aqueous phase.
Stage C: Preparation of a bulk solution:
20 The non-aqueous drug phase of Stage A was added to the aqueous phase of Stage B
followed by the addition of water for injection (3 L). The resulting bulk solution was stirred
until a uniform mixture was formed.
Stage D: Preparation of final aqueous solution:
Polyhexamethylene biguanide (2.5 g as 20% solution) was added to the bulk solution
25 of Stage C. Subsequently, volume make up was carried out using water for injection up to
50 L. The resulting solution was filtered through a sterile 0.2μm PVDF capsule filter to
obtain the final aqueous ophthalmic solution of difluprednate.
12
The resulting aqueous ophthalmic solution had a pH of about 4.5 to 5.5 and an
osmolality of about 117 mOsm/kg.
Measurement of Osmolality – Transfer 2ml of sample into 5ml volumetric flask and
add mili-Q water up to mark. Mix well and measure osmolality of sample using Osmometer
(Advanced Instruments, Model 3250) with the 5 working principle of freezing point
depression; ensure that there are no air bubble during analysis.
The physicochemical stability of the aqueous ophthalmic solution obtained by the
improved process was tested upon storage at room temperature (25°C / 40% relative
humidity), at 2 - 8oC for 24 months and under accelerated storage conditions (40°C / 25%
10 relative humidity) for 6 months. Surprisingly, it was found that the aqueous solution
remained clear and free from particles, crystals or precipitate upon storage. The assay of
difluprednate remained in the range of 95% - 105% w/v, the known and unknown impurities
did not increase substantially upon storage and the content of impurities remained below the
desired specified limit.
15
13
I / We Claim(s):
1. A process for the preparation of an aqueous ophthalmic solution of difluprednate
having a pH of 4.5 to 5.5 and an osmolality from about 95 to about 150 mOsm/kg,
comprising:
a. preparation of a non-aqueous drug 5 phase by dissolving difluprednate and
benzalkonium chloride in polyoxyl 35 castor oil;
b. preparation of an aqueous phase comprising:
i. preparing a polymer phase by dissolving polyvinyl alcohol in water
for injection;
10 ii. preparing a buffer phase by dissolving glacial acetic acid, glycerin,
boric acid, disodium edetate, sodium acetate and N-lauryl sarcosine
sodium in water for injection at a stirring rate of about 200 to about
400 rotations per minute; and
iii. addition of the buffer phase to the polymer phase, wherein the
15 addition is done at a stirring rate of about 200 to about 600 rotations
per minute;
c. preparation of a bulk solution by addition of the non-aqueous drug phase to
the aqueous phase; and
d. addition of polyhexamethylene biguanide to the bulk solution to achieve the
20 aqueous ophthalmic solution of difluprednate.
2. The process according to claim 1, wherein the process further comprises filtration of
the aqueous ophthalmic solution of difluprednate through a sterile 0.2 micron filter.
25 3. The process according to claim 1, wherein the addition of N-lauryl sarcosine sodium
in the buffer phase preparation is done at a stirring rate of about 200 to about 400
rotations per minute.
4. The process according to claim 1, wherein the aqueous ophthalmic solution of
30 difluprednate comprises:
i. about 0.03% w/v to about 0.04% w/v difluprednate;
ii. about 0.5% w/v to about 3.0% w/v polyvinyl alcohol or derivative thereof;
iii. about 0.01% w/v to about 0.05% w/v benzalkonium chloride; and
iv. about 1.5% w/v to about 6.0% w/v polyoxyl 35 castor oil.
35
5. An aqueous ophthalmic solution of difluprednate having a pH of 4.5 to 5.5 and an
osmolality from about 95 to about 150 mOsm/kg, comprising:
i. about 0.03% w/v to about 0.04% w/v difluprednate;
ii. about 0.5% w/v to about 3.0% w/v polyvinyl alcohol or derivative thereof;
40 iii. about 0.01% w/v to about 0.05% w/v benzalkonium chloride; and
14
iv. about 1.5% w/v to about 6.0% w/v polyoxyl 35 castor oil;
wherein said aqueous ophthalmic solution is prepared by the process comprising:
a. preparation of a non-aqueous drug phase by dissolving difluprednate and
benzalkonium chloride in polyoxyl 35 castor oil;
b. 5 preparation of an aqueous phase comprising:
i. preparing a polymer phase by dissolving polyvinyl alcohol in water
for injection;
ii. preparing a buffer phase by dissolving glacial acetic acid, glycerin,
boric acid, disodium edetate, sodium acetate and N-lauryl sarcosine
10 sodium in water for injection at a stirring rate of about 200 to about
400 rotations per minute; and
iii. addition of the buffer phase to the polymer phase, wherein the
addition is done at a stirring rate of about 200 to about 600 rotations
per minute;
15 c. preparation of a bulk solution by addition of the non-aqueous drug phase to
the aqueous phase; and
d. addition of polyhexamethylene biguanide to the bulk solution to achieve the
aqueous ophthalmic solution of difluprednate.
20 6. An aqueous ophthalmic solution of difluprednate having a pH of 4.5 to 5.5 and an
osmolality from about 95 to about 150 mOsm/kg.
7. The aqueous ophthalmic solution of difluprednate according to claim 6 comprises:
i. about 0.03% w/v to about 0.04% w/v difluprednate;
25 ii. about 0.5% w/v to about 3.0% w/v polyvinyl alcohol or derivative thereof;
iii. about 0.01% w/v to about 0.05% w/v benzalkonium chloride; and
iv. about 1.5% w/v to about 6.0% w/v polyoxyl 35 castor oil.
8. The aqueous ophthalmic solution of difluprednate according to claim 7 further
30 comprises:
v. about 0.002% w/v to about 0.02% w/v polyhexamethylene biguanide;
vi. about 0.02 % w/v to about 0.05 % w/v N-lauroyl sarcosine sodium;
vii. about 0.05 % w/v to about 1.5 % w/v boric acid;
viii. about 0.01 % w/v to about 0.1 % w/v disodium edetate; and
35 ix. about 1.0 % w/v to about 3.0 % w/v glycerine.
9. The aqueous ophthalmic solution of difluprednate according to any of claims 6-8,
prepared by the process comprising:
15
a. preparation of a non-aqueous drug phase by dissolving difluprednate and
benzalkonium chloride in polyoxyl 35 castor oil;
b. preparation of an aqueous phase comprising:
iv. preparing a polymer phase by dissolving polyvinyl alcohol in water
5 for injection;
v. preparing a buffer phase by dissolving glacial acetic acid, glycerin,
boric acid, disodium edetate, sodium acetate and N-lauryl sarcosine
sodium in water for injection at a stirring rate of about 200 to about
400 rotations per minute; and
10 vi. addition of the buffer phase to the polymer phase, wherein the
addition is done at a stirring rate of about 200 to about 600 rotations
per minute;
c. preparation of a bulk solution by addition of the non-aqueous drug phase to
the aqueous phase; and
15 d. addition of polyhexamethylene biguanide to the bulk solution to achieve the
aqueous ophthalmic solution of difluprednate.