United States Patent [19J
`Ali et al.
`
`[54] PROCESS FOR MANUFACTURING
`OPHTHALMIC SUSPENSIONS
`
`[75]
`
`Inventors: Yusuf Ali; Robert E. Beck, both of
`Fort Worth; Rex C. Sport, Grapevine,
`all of Tex.
`
`[73] Assignee: Alcon Laboratories, Inc., Fort Worth,
`Tex.
`
`[21] Appl. No.: 08/886,933
`
`[22] Filed:
`
`Jul. 2, 1997
`
`Related U.S. Application Data
`[ 60] Provisional application No. 60/032,820, Dec. 11, 1996.
`
`Int. Cl? ..................................................... A61K 31/54
`[51]
`[52] U.S. Cl. ......................................... 514/222.8; 514/912
`[58] Field of Search .................................. 514/222.8, 912
`
`[56]
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`111111
`
`1111111111111111111111111111111111111111111111111111111111111
`US006071904A
`[11] Patent Number:
`[45] Date of Patent:
`
`6,071,904
`Jun.6,2000
`
`5,378,703
`
`1!1995 Dean eta!. .......................... 514/222.8
`
`FOREIGN PATENT DOCUMENTS
`
`0601619A2
`0602702A1
`0509752A2
`wo 93/16701
`
`5/1993 European Pat. Off ..
`6/1994 European Pat. Off ..
`7/1994 European Pat. Off ..
`8/1993 WIPO .
`
`OTHER PUBLICATIONS
`
`Martin, F. et al. "Sterilisation par la Chaleur des Solutions de
`Sulfamides", Journal de Pharmacie de Belgique, vol. 25, No.
`4, pp. 317-329, Jul.-Aug. 1970.
`
`Primary Examiner-Zohreh Fay
`Attorney, Agent, or Firm-Sally Yeager
`
`[57]
`
`ABSTRACT
`
`Ophthalmic suspensions containing brinzolamide or brin(cid:173)
`zolamide and a beta-blocker and processes for manufactur(cid:173)
`ing the suspensions are disclosed.
`
`5,362,758 11/1994 Ahmed .................................... 514/777
`
`12 Claims, 3 Drawing Sheets
`
`Metrics EX1052, Page 1
`
`

`
`U.S. Patent
`
`Jun.6,2000
`
`Sheet 1 of 3
`
`6,071,904
`
`Mannitol
`Sodium Chloride
`Edetote Disodium
`BAC
`Purified Water
`
`Corbomer
`Purified
`Water
`
`Polish
`Filter
`,,
`t
`Polish ~
`H20
`Reactor ~ Rinse
`Filter
`
`Tyloxopol or
`Triton X-1 00
`Purified
`Water
`
`Polish Filter
`
`Brinzolamide
`Milling
`Beads
`
`~ Milling ~
`Bottle
`
`10
`
`Autoclave
`
`Ball
`Mill
`
`pH
`Adjust
`~
`Bulk
`Sterilize
`
`FIG. 1
`
`Aseptically
`Pump
`through
`Screen to
`Reactor
`
`QS to 100%
`Batch Volume
`~
`Mix to
`Homogeneity
`~
`Bulk
`Sample
`
`Metrics EX1052, Page 2
`
`

`
`U.S. Patent
`
`Jun.6,2000
`
`Sheet 2 of 3
`
`6,071,904
`
`Carbo mer
`Purified
`Water
`
`Polish Filter
`
`Bulk
`
`Sterilize -....
`
`Reactor
`
`Mannitol
`Sodium Chloride
`Edetate Disodium
`BAC
`Purified Water
`
`t
`I Polish Filter I
`t
`I
`H20
`Rinse
`
`Brinzolamide
`Milling
`Beads
`
`H20
`Rinse
`
`....
`.......
`
`1\__10
`
`Tyloxapol
`Purified
`Water
`
`'II
`Polish
`Filter
`
`'~
`Milling
`Bottle
`
`"
`Autoclave
`
`Timolol
`Vehicle
`Maleate
`Concentrate
`Aseptic Transfer Purified Water
`to Sterile Receiving
`Reactor /Vessel
`
`\I;'
`Sterile
`Filtration
`t
`H20
`Rinse
`
`"
`
`Ball
`Mill
`
`"
`Aseptically
`Pump
`through
`Screen to
`Reactor
`
`t
`H20
`Rinse
`
`FIG. 2
`
`-
`
`--""
`
`~
`
`.......
`'V
`Aseptic
`pH
`Adjustment
`-
`as to 100%
`Batch Volume
`t
`Mix to
`Homogeneity
`t
`Bulk
`Sample
`
`Metrics EX1052, Page 3
`
`

`
`U.S. Patent
`
`Jun.6,2000
`
`Sheet 3 of 3
`
`6,071,904
`
`22
`
`18~
`
`~16
`
`14~
`
`~12
`
`1 1
`
`,----10
`
`-------------------------i-------(cid:173)
`
`....
`
`,..-
`
`'
`
`FIG. 3
`
`Metrics EX1052, Page 4
`
`

`
`6,071,904
`
`1
`PROCESS FOR MANUFACTURING
`OPHTHALMIC SUSPENSIONS
`
`Priority is claimed from the provisional application, U.S.
`patent application Ser. No. 60/032820, filed Dec. 11, 1996.
`This invention relates to sterile topical ophthalmic sus(cid:173)
`pensions containing a carbonic anhydrase inhibitor or a
`carbonic anhydrase inhibitor and a beta-blocker and pro(cid:173)
`cesses for making the suspensions. The suspensions are
`useful in controlling the elevated intraocular pressure in
`persons suffering from ocular hypertension or primary open
`angle glaucoma.
`
`BACKGROUND OF THE INVENTION
`
`Sterile, topical, ophthalmic suspensions have typically
`been manufactured in the past in one of three ways: by bulk
`sterilization of a milled suspension, by aseptic addition of
`sterile micronized raw material into a sterile vehicle, or by
`aseptic addition of a sterile raw material to a sterile men(cid:173)
`struum followed by ball milling and aseptic addition of the
`sterile concentrate into a sterile vehicle.
`The present suspensions, containing a carbonic anhydrase
`inhibitor (CAl) or a CAl and a beta-blocker, can not be made
`via these routes. Due to the solubility of the CAl at auto(cid:173)
`claving temperatures, large needle-like crystals form on cool
`down of the final formulation. Aseptic ball milling of this
`final formulation is not practical. Aseptic addition of the CAl
`to a sterile vehicle is also not practical as the CAl cannot be
`sterilized by conventional means. Dry heat sterilization
`causes melting of the material. Sterilization of the CAl by
`ethylene oxide introduces unacceptable degradation prod(cid:173)
`ucts and residues, and sterilization by gamma irradiation of
`micronized material produces degradation products unac(cid:173)
`ceptable for regulatory filing.
`The present process provides a procedure for making a
`CAl or a CAI/beta-blocker suspension on a manufacturing
`scale without the problems described above.
`
`BRIEF DESCRIPTION OF THE DRAWING
`FIG. 1 is a flow diagram showing the process for making
`brinzolamide ophthalmic suspension.
`FIG. 2 is a flow diagram showing the process for making
`brinzolamide/timolol ophthalmic suspension.
`FIG. 3 is an expanded side view of one milling bottle that
`may be used in the present invention.
`
`SUMMARY OF THE INVENTION
`
`The present invention is directed to a CAl and a CAl/ 50
`beta-blocker suspension, processes for making them, and a
`"bottle" for use in the processes.
`
`DETAILED DESCRIPTION OF PREFERRED
`EMBODIMENTS
`
`The present CAl suspension contains the pharmaceuti(cid:173)
`cally active CAl, R 4-ethylamino-3,4-dihydro-2-(3-
`me thoxy)propy l-2H- thieno [3 ,2-e] -1,2- thiazine- 6-
`sulfonamide 1,1 dioxide, which is known as brinzolamide.
`This compound is disclosed in commonly assigned U.S. Pat.
`No. 5,378,703 (Dean, et al.). The present suspension and the
`process for making it are not disclosed in Dean, et al.
`The process for making the brinzolamide suspension uses
`autoclaving of a concentrated slurry of brinzolamide in
`milling bottle 10, ball milling of the hot slurry, and then
`adding the slurry to the rest of the ingredients as shown in
`FIG. 1.
`
`5
`
`10
`
`15
`
`20
`
`2
`Referring now to FIG. 1, first the milling menstruum
`containing either Tyloxapol, ( 4-(1,1,3,3-tetramethylbutyl)
`phenol polymer with formaldehyde and oxirane ), available
`from Sterling Co. or Triton X-100, (a-[4-(1,1,3,3-
`tetramethylbutyl)phenyl]-w-hydroxypolyoxy-1,2-ethane
`diyl), available from Rohm and Haas Corp. is prepared. The
`milling menstruum is critical to the manufacture of this
`suspension. Use of menstrua containing surfactants other
`than Tyloxapol or Triton X-100, such as Polysorbate 80,
`(sorbitan mono-9-octadecenoate poly ( oxy-1,2-ethanediyl)
`derivatives), a common wetting agent for use in ophthalmic
`suspensions, results in inadequate milling of large crystals of
`brinzolamide which form during cool down following auto(cid:173)
`claving. Use of Tyloxapol or Triton X-100 at concentrations
`of about 0.001 to 5 weight percent (wt. %) in the milling
`menstruum unexpectedly minimizes foaming and allows for
`adequate milling of the crystals. Although use of either
`Tyloxapol or Triton X-100 in the milling menstruum is
`acceptable, Tyloxapol at concentrations of 0.01 to 0.10 wt.
`% in the final suspension is the preferred agent as Triton
`X-100 is not commonly used in ophthalmic preparations.
`Once the milling vehicle is prepared it is filtered and then
`mixed with milling beads, such as, alumina, glass, or
`zirconia, preferably 3mm zirconia-Y beads and added to
`25 milling bottle 10. The mixture is then autoclaved in milling
`bottle 10 at normal temperatures and pressures known to
`those skilled in the art, e.g., 121-129° C., preferably
`123-127° C., for 30-45 minutes. After autoclaving and
`while the slurry is above 80° C., the mixture is ball milled
`30 under conditions to achieve an average particle size of
`0.2-10 ,urn, preferably 1-5 ,urn, preferably 18-19 hours at
`50-55 RPM.
`After milling, the milled slurry is aseptically added
`through a screen with smaller openings than the milling bead
`35 size to the rest of the ingredients including, water, one or
`more tonicity agents, such as, but not limited to, mannitol or
`sodium chloride; one or more preservatives, including, but
`not limited to, benzalkonium chloride or one of its
`derivatives, polyquaternium 1, thimerosal or EDTA; and at
`40 least one polymer, including, but not limited to carbomer,
`hydroxypropylmethylcellulose (HPMC), hydroxyethylcel(cid:173)
`lulose (HEC), or polyvinylalcohol (PYA) which are mixed,
`filtered, pH adjusted, and sterilized prior to their combina(cid:173)
`tion with the milled mixture. Preferable ingredients are
`45 mannitol, NaCl, EDTA, BAC, carbomer, such as Carbopol
`934P or 974P.
`Sterile, purified water used to rinse the beads is then
`added to the mixture and the batch is brought to final
`volume. The ingredients are mixed until homogeneous.
`The CAilbeta-blocker suspension contains brinzolamide,
`but also includes a beta-blocker, such as, (S)-1-[(1,1-
`dime thy lethy l)amino ]-3-[[ 4-( 4-morpholiny 1 )-1 ,2,5-
`thiadiazol-3-yl]oxy ]-2-propanol (Z) 2-butenedioate (1:1)
`salt, which is known as timolol maleate or (±) 1-[p-[2-
`ss ( cyclopropylmethoxy)ethy l]phenoxy ]-3-(isopropy lamina)(cid:173)
`Z-propanol hydrochloride, which is known as betaxolol
`hydrochloride. Different isomers, for example, S-betaxolol,
`and salts can be used. A sterile ophthalmic solution contain(cid:173)
`ing timolol maleate (Timoptic®) is available from Merck
`60 and Co., Inc. It is useful for the treatment of elevated
`intraocular pressure in persons with ocular hypertension or
`open angle glaucoma. A sterile ophthalmic solution contain(cid:173)
`ing betaxolol hydrochloride (Betoptic®) is available from
`Alcon Laboratories, Inc. It is also useful for the treatment of
`65 ocular hypertension and open angle glaucoma.
`The process for making the CAI/beta-blocker suspension
`is similar to that for making the brinzolamide suspension
`
`Metrics EX1052, Page 5
`
`

`
`6,071,904
`
`3
`described above. The process for making a CAI/beta(cid:173)
`blocker suspension in which the beta-blocker is sensitive to
`heat and must be aseptically filtered (e.g. timolol maleate) is
`shown in FIG. 2. If the beta-blocker to be used can be
`autoclaved (e.g. betaxolol), it can be added with the man-
`nitol and other listed ingredients to make the vehicle con(cid:173)
`centrate.
`Referring now to FIG. 2, the process for handling brin(cid:173)
`zolamide is the same as shown in FIG. 1. The process for
`making the combination differs in that timolol maleate is 10
`incorporated by sterile filtration into the sterilized vehicle
`concentrate which is then aseptically pH adjusted to 6.0--8.0,
`preferably 6.5-7.6, and most preferably 7.0-7.4. The con(cid:173)
`centrate is then combined with the brinzolamide composi(cid:173)
`tion and mixed until homogeneous.
`As shown in FIG. 3, milling bottle 10 includes carboy 11
`and filter 12. Carboy 11 preferably is made from a material
`that can withstand autoclaving, such as polypropylene, and
`is sufficiently large so as to contain the suspension and the
`milling slurry, for example, ten liters. Filter 12 preferably is 20
`a hydrophobic filter having a pore size of 0.2 to 10 ,urn,
`preferably 1-5 ,urn, and made from any hydrophobic mate(cid:173)
`rial of sufficient mechanical strength which is steam steril(cid:173)
`izable. One filter 12 suitable for use in the present invention
`is commercially available from Millipore under the trade- 25
`name DURAPEL 2 ,urn. Filter 12 prevents the suspension
`and the milling slurry from expanding out of carboy 11
`during autoclaving, but allows for pressure equalization
`during heating and cooling.
`Excess pressure in carboy 11 is vented through bleed
`valve 22 and air is allowed to enter aseptically carboy 11
`through vent filter 20 which is connected to bleed valve 22
`by tubing 24. Vent filter 20 preferably is a hydrophobic filter
`having a pore size of 0.2 ,urn. Bleed valve 22 is connected to
`carboy 11 by connector 16 and the entire assembly is sealed
`by gaskets 14 and 18.
`The formulations of the present invention are set forth in
`the following examples.
`
`4
`EXAMPLE 3
`
`The formulation in Example 1 was made as follows:
`
`A Preparation of Milling Slurry
`
`1. Into a suitable compounding vessel containing a stir-bar
`approximately 2300 g of hot ( 50-70° C.) purified water were
`added. 15.0 g of tyloxapol were added to the vessel and the
`ingredients were mixed until homogeneous.
`2. The tyloxapol solution was brought to 2700 g using hot
`(50-70° C.) purified water.
`3. The tyloxapol solution was filtered through a 10 ,urn
`polishing filter and held for use in the milling slurry.
`4. The following materials were combined in carboy 11:
`
`3 mm Zirconia-Yttria beads
`Tyloxapol milling solution (Step 3)
`Brinzolamide
`
`22 kg
`2700 g
`640 g
`
`5
`
`15
`
`5. Filter 12, gaskets 14 and 18, connector 16, bleed valve
`22, vent filter 20 and tubing 24 were placed securely on
`carboy 11.
`6. Milling bottle 10 and its ingredients were autoclaved on
`standard fast cool cycle.
`7. Milling bottle 10 was removed immediately after
`completion of the autoclave cycle was ball milled at 50-55
`30 RPM for 18-19 hours.
`8. The milling slurry was then held for use in aseptic
`addition.
`
`35
`
`EXAMPLE 1
`
`40
`
`B. Preparation of Carbomer Slurry
`
`1. 84 kg of hot (50-70° C.) purified water were transferred
`to a suitable compounding vessel with an agitator.
`2. 1380 g of Carbomer 974P were added to the water and
`dispersed with high speed agitation until homogeneous.
`3. The Carbomer slurry was brought to 86.25 kg with
`purified water and mixed to homogeneity.
`
`Ingredient
`
`Concentration (wt. %)
`
`Brinzolamide
`Tyloxapol
`Carbo mer 97 4P
`Edetate Disodium
`BAC
`Mannitol
`Sodium Chloride
`Purified Water
`
`1.0% plus 5% excess
`0.025
`0.40
`0.01
`0.01 plus 5% excess
`3.30
`0.25
`q.s. 100%
`
`EXAMPLE 2
`
`Ingredient
`
`Concentration (wt. %)
`
`Brinzolamide
`Triton X-100
`Carbo mer 97 4P
`Edetate Disodium
`BAC
`Mannitol
`Sodium Chloride
`Purified Water
`
`1.0% plus 5% excess
`0.025
`0.40
`0.01
`0.01 plus 5% excess
`3.30
`0.25
`q.s. 100%
`
`C. Preparation of Vehicle Concentrate
`
`1. Approximately 100 kg of hot (50-70° C.) purified water
`45 were added to a suitable compounding vessel with an
`agitator.
`2. The following ingredients were added in the order
`listed using moderate agitation:
`
`50
`
`55
`
`Mannitol
`Sodium Chloride
`Edetate Disodium
`Benzalkonium Chloride,
`10% Solution
`
`10.56 kg
`800 g
`32 g
`336 g
`
`3. The solution was filtered through a polishing filter and
`added to a 300 L reactor. The compounding vessel and filter
`60 were rinsed with approximately 15 L of hot (50-70° C.)
`purified water which was added to the reactor.
`4. 80 kg of Carbomer 974P slurry (Section B) was added
`to the solution with mixing.
`5. The mixture of 4 was agitated and the pH adjusted to
`65 7.5±0.2 using 1N sodium hydroxide (and 1N hydrochloric
`acid if necessary). Approximately 16 L of 1N NaOH were
`required.
`
`Metrics EX1052, Page 6
`
`

`
`6,071,904
`
`5
`6. The vehicle concentrate was adjusted to 230.4 kg and
`sterilized using steam at 121-128° C. for 35 minutes.
`7. The vehicle concentrate was cooled to approximately
`room temperature (less than 30° C.) and held for use in
`aseptic processing.
`8. 43 kg of the vehicle concentrate was aseptically trans(cid:173)
`ferred to a sterile mixing tank in a clean room.
`
`E. Aseptic Addition of Milling Slurry
`
`1. 15 kg of purified water were sterilized in glass carboys
`in an autoclave.
`2. A transfer set up including stainless steel tubing,
`silicone tubing, and stainless steel screens was autoclaved
`and transferred to the clean room.
`3. The milling slurry was transferred through the screens
`and tubing into the vehicle concentrate.
`4. The beads, tubing, screens, and carboy 11 were rinsed
`with purified water as necessary to transfer the milling slurry
`as completely as possible.
`5. Sterile purified water was used to bring the batch
`weight to 61 kg. The batch was mixed until homogeneous.
`
`EXAMPLE 4
`
`Ingredient
`
`Concentration (wt. %)
`
`Brinzolamide, NOC
`Timolol Maleate
`Carbo mer 97 4P
`Sodium Chloride
`Mannitol
`Tyloxapol
`Disodium Edetate
`Benzalkonium Chloride
`Sodium Hydroxide or
`Hydrochloric Acid
`Purified Water
`
`1.0% plus 5% excess
`0.68*
`0.4
`0.10
`3.3
`0.025
`0.01
`0.01 plus 5% excess
`Adjust pH 7.2 ± 0.2
`
`q.s. 100%
`
`*Equivalent to 0.5% Timolol as free base
`
`EXAMPLE 5
`
`The formulation in Example 4 was made as follows:
`
`A Preparation of Milling Slurry
`
`6
`7. The milling slurry was then held for use m aseptic
`addition.
`
`B. Preparation of 2% Carbomer Slurry
`
`5
`
`1. 4000 g of hot (50--70° C.) purified water were trans(cid:173)
`ferred to a suitable compounding vessel with an overhead
`m1xer.
`2. 80.0 g of Carbomer 974P were added to the water and
`10 dispersed with high speed agitation until homogeneous.
`3. The Carbomer slurry was brought to 5000 g with
`purified water and mixed to homogeneity.
`4. 1250 g of the slurry were added to a vessel through a
`polish filter ( 40 ,urn) and covered.
`
`C. Preparation of Vehicle Concentrate
`
`1. Approximately 1000 g of hot (50-70° C.) purified water
`were added to a suitable compounding vessel with an
`agitator.
`2. The following ingredients were added in the order
`listed using moderate agitation:
`
`Mannitol
`Sodium Chloride
`Edetate Disodium
`Benzalkonium Chloride,
`10% Solution
`
`165 g
`5.00 g
`0.500 g
`5.25 g
`
`15
`
`20
`
`25
`
`30
`
`3. The dispersion was filtered through a polishing filter
`and added to a 5 L glass screw cap media bottle. The
`compounding vessel and filter were rinsed with approxi(cid:173)
`mately 300 mL of hot (50--70° C.) purified water and added
`35 to the glass media bottle.
`4. The Carbo mer 974P slurry (Section B) was added to the
`dispersion with mixing. Its vessel was rinsed with 250 mL
`of purified water which was added to the glass media bottle.
`5. The vehicle concentrate was brought to 2750 g with
`purified water.
`6. 200 mL of 6N NaOH were prepared in a beaker.
`7. 51.0 g of timolol maleate were dissolved in 1074 g
`purified water.
`
`40
`
`D. Preparation for Aseptic Addition
`
`1. Approximately 1000 mL of purified water were added
`to each of two 2 L glass screw cap media bottles with 0.2 ,urn
`breather filters.
`2. The following materials were autoclaved:
`Miscellaneous glassware and utensils
`Vehicle concentrate which includes the Carbomer slurry
`(Section C)
`Purified water (Step 1)
`Stainless steel tube with screen and silicone tubing
`13 L carboy with stir bar
`500 mL media bottle containing 1N HCl
`500 mL media bottle with 0.2 ,urn filter for 6N NaOH
`3. The vehicle concentrate was cooled to approximately
`room temperature (less than 30° C.) and held for use in
`aseptic processing.
`
`E. Aseptic Compounding
`1. All materials necessary for aseptic compounding,
`including milling slurry (Section A), vehicle concentrate
`
`45
`
`1. Into a suitable compounding vessel containing a stir-bar
`approximately 200 g of hot (50-70° C.) purified water were
`added. 1.25 g of tyloxapol were added to the vessel and the
`ingredients were mixed until homogeneous.
`2. The tyloxapol solution was brought to 300 g using hot 50
`(50-70° C.) purified water.
`3. The tyloxapol solution was filtered through a polishing
`filter and held for use in the milling slurry.
`4. The following materials were combined in a milling
`bottle:
`
`55
`
`3 mm Zirconia-Yttria beads
`Tyloxapol milling solution (Step 3)
`Brinzolamide
`
`2180 g
`300 g
`52.6 g
`
`60
`
`5. The milling bottle and its ingredients were autoclaved
`on standard fast cool cycle.
`6. The milling bottle was removed immediately after 65
`completion of the autoclave cycle and ball milling was
`begun at 50-55 RPM for 18-19 hours.
`
`Metrics EX1052, Page 7
`
`

`
`6,071,904
`
`5
`
`7
`(Section C), water, magnetic mixer, balance, tube, and
`screen, were taken to the clean room.
`2. The 6N NaOH was sterile filtered into a sterile beaker.
`3. The timolol maleate solution was sterile filtered into a
`sterile bottle and 750 g added to the vehicle concentrate.
`4. The pH was aseptically adjusted to 7.2±0.2 with 6N
`NaOH. Approximately 52 g are required.
`5. The milling slurry was transferred through the tube and
`screen into the vehicle concentrate.
`6. The beads, tubing, and milling bottle were rinsed with
`purified water as necessary to transfer the milling slurry as
`completely as possible.
`7. Purified water was used to bring the batch weight to
`(5094 g). The batch was mixed until homogeneous (not less 15
`than 15 minutes).
`We claim:
`1. A method for making a sterile ophthalmic suspension,
`which comprises;
`a. autoclaving a milling slurry comprising brinzolamide,
`milling beads, and a surfactant selected from the group
`consisting of tyloxapol and triton X-100;
`b. ball milling the milling slurry;
`c. preparing a polymer slurry comprising polymer and 25
`water;
`d. preparing a solution comprising tonicity and preserva(cid:173)
`tive agents;
`e. mixing the polymer slurry and the solution to form a
`vehicle concentrate and adjusting pH;
`f. autoclaving the mixture of step e; and
`g. aseptically adding the milling slurry through a screen to
`the mixture from step f.
`2. The method of claim 1 wherein the surfactant is 35
`tyloxapol.
`3. The method of claim 1 wherein the polymer slurry
`comprises carbomer.
`4. The method of claim 1 wherein the solution of step d
`comprises mannitol, sodium chloride, edetate disodium, and 40
`benzalkonium chloride.
`5. A method for making a sterile ophthalmic suspension,
`which comprises;
`a. autoclaving a milling slurry comprising brinzolamide,
`milling beads, and a surfactant selected from the group
`consisting of tyloxapol and triton X-100;
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`b. ball milling the milling slurry;
`c. preparing a polymer slurry comprising polymer and
`water;
`d. preparing a solution comprising tonicity and preserva(cid:173)
`tive agents;
`e. mixing the polymer slurry and the solution to form a
`vehicle concentrate;
`f. autoclaving the mixture of step e;
`g. aseptically adding a timolol maleate solution to the
`mixture in step f;
`h. aseptically adjusting pH; and
`i. aseptically adding the milling slurry through a screen to
`the mixture of step g.
`6. The method of claim 1 wherein the surfactant is
`tyloxapol.
`7. The method of claim 1 wherein the polymer slurry
`comprises carbomer.
`8. The method of claim 7 wherein the solution comprises
`20 mannitol, sodium chloride, edetate disodium, and benzalko(cid:173)
`nium chloride.
`9. A method for making a sterile ophthalmic suspension,
`which comprises;
`a. autoclaving a milling slurry comprising brinzolamide,
`milling beads, and a surfactant selected from the group
`consisting of tyloxapol and triton X-100;
`b. ball milling the milling slurry;
`c. preparing a polymer slurry comprising polymer and
`water;
`d. preparing a solution comprising a beta-blocker and
`tonicity and preservative agents;
`e. mixing the polymer slurry and the solution to form a
`vehicle concentrate and adjusting pH;
`f. sterilizing the mixture of step e using steam; and
`g. aseptically adding the milling slurry through a screen to
`the mixture of step f.
`10. The method of claim 9 wherein the surfactant is
`tyloxapol.
`11. The method of claim 9 wherein the polymer slurry
`comprises carbomer.
`12. The method of claim 9 wherein the solution comprises
`mannitol, sodium chloride, edetate disodium, and benzalko(cid:173)
`nium chloride.
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`Metrics EX1052, Page 8