MXPA99001755A - Process for manufacturing ophthalmic suspensions - Google Patents

Abstract

Ophthalmic suspensions containing brinzolamide or brinzolamide and a beta-blocker and processes for manufacturing the suspensions are disclosed. The use of Tyloxapol or Triton X-100 avoids chrystallization of brinzolamide after autoclaving.

Description

PROCESS FOR THE MANUFACTURE OF OPHTHALMIC SUSPENSIONS Field of the Invention This invention relates to sterile topical ophthalmic suspensions containing a carbonic anhydrase inhibitor or a carbonic anhydrase inhibitor and a beta-blocker and to processes for making the suspensions. Suspensions are useful for controlling elevated intraocular pressure in people suffering from ocular hypertension or primary open-angle glaucoma.

Background of the Invention Ophthalmic, topical, sterile suspensions have typically been manufactured in the past in one of three ways: by volumetric sterilization of a ground suspension, by aseptic addition of sterile micronized raw materials in a vehicle, or by the aseptic addition of a raw material Sterile to sterile menstruum followed by treatment in a ball mill and aseptic addition of the sterile concentrate in a sterile vehicle. R? F.029527 The present suspensions, which contain a carbonic anhydrase inhibitor, (CAI) or a CAI and a beta-blocker, can not be made by these routes. Due to the solubility of the CAI at autoclave treatment temperatures, large needle-like crystals are formed during the gradual cooling of the final formulation. The treatment of an aseptic ball mill of this final formulation is not practical. The aseptic addition of the CAI to a sterile vehicle is also impractical because the CAI can not be sterilized by conventional means. Heat sterilization, dry, causes the material to melt. CAI sterilization by ethylene oxide introduces unacceptable degradation products and residues, and gamma sterilization of the micronized material produces degradation products unacceptable to regulatory protocols.

The present process provides a method for making a CAI or a blocking CAI / beta suspension on a processing scale without the problems described above.

BRIEF DESCRIPTION OF THE INVENTION The present invention is directed to a CAI and a CAI / beta blocking suspension, methods for making them and a "package" for use in the process. In accordance with one aspect of the present invention, there is provided a method of making an ophthalmic, sterile suspension, wherein the method comprises the steps of: to. autoclave a slurry for grinding or milling comprising brinzolamide, beads for grinding and a surfactant selected from the group consisting of a polymer Tiloxapol (4-1,1,3,3-tetraethylbutyl) phenol with formaldehyde and oxirane and Triton X -100 (a- [4- (1, 1, 3, 3-tetramethylbutyl) phenyl] -? - hydroxypropyloxy-1, 2-ethanediyl); b. grind in a ball mill the suspension for; crushing or grinding; c. preparing a suspension of a polymer of ophthalmically acceptable thickness comprising the polymer and water; d. preparing a solution comprising tonicity and preservative agents. and. mix the suspension of the polymer and the solution to form a concentrated vehicle; F. sterilize the mixture of stage β using steam; g. aseptically add the suspension for grinding or milling through a protection to the mixture of stage f.

The suspension of the polymer of step c may comprise, for example, carbomer. The solution of step d preferably comprises mannitol, sodium chloride, disodium edetate and benzalkonium chloride. The solution of step d may further comprise a beta blocker, for example, and step e may include the step of pH adjustment.

Alternatively, between step f and step g of the method of the invention, a solution of timolol maleate can be added aseptically to the mixture of step f, and the pH can be adjusted aseptically. The step of steam sterilization can for example be done by being autoclaved. In a further aspect, the present invention provides topical, sterile ophthalmic suspensions comprising a pharmaceutically effective amount of brinzolamide and 0.001 to 5.0 weight percent of a polymer of Tyloxapol (4- (1,1,3,3-tetramethylbutyl) ) phenol with formaldehyde and oxirane). The concentration of the polymer Tyloxapol (4- (1,1,3,3-tetramethylbutyl) phenol with formaldehyde and oxirane) is from about 0.01 to 0.10 weight percent, for example. The suspension may include betaxolol or timolol maleate.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a flowchart showing the procedure for making an ophthalmic brinzolamide suspension. Figure 2 is a flow chart showing the process for making an ophthalmic suspension of brinzolamide / timolol.

Figure 3 is an enlarged side view of a grinding container that can be used in the present invention.

DETAILED DESCRIPTION OF THE PREFERRED MODALITIES.

The present CAI suspension contains the pharmaceutically active CAI, R of 4-ethylamino-3,4-dihydro-2- (3-methoxy) propyl-2H-thieno [3, 2-e] -l, 2-dioxide. -thiazine-6-sulfonamide, which is known as brinzolamide. This compound is described in common in assigned U.S. Patent No. 5,378,703 (Dean, et al.). The present suspension and the process for its preparation are not described in Dean, et al. The process for making the suspension of binzolamide is used when autoclaving a concentrated brinzolamide suspension in a crushing or milling container 19, in the ball mill of the hot suspension, and then adding the suspension to the rest of the ingredients as described. shown in Figure 1. Referring now to Figure 1, first the grinding or grinding solvent containing either the polymer Tiloxapol (4, (1, 1, 3, 3-tetramethylbutyl) phenol with formaldehyde and oxirane), available from Sterling CO. Or Triton X-100, (a [4- (1,1,3,3-tetramethylbutyl) phenyl] -? - hydroxypropyloxy-1,1-ethanediyl), available from Rohm and Hass Corp. is prepared. The solvent for trituration- or milling is critical to the manufacture of this suspension. The use of surfactant-containing solvents instead of Tyloxapol or Triton X-100, such as Polysorbate 80, (derivatives of sorbitan mono-9-octadecenoate of poly (oxy-l, 2-ethanediyl), a common wetting agent for its use in ophthalmic suspensions, leads to a demeaning or grinding inadequate large crystals of brinzolamide which are formed during gradual cooling after autoclaving. The use of Tyloxapol or Triton X-100 at concentrations of about 0.001 to 5 weight percent (% by weight) in the menstruum for grinding, unexpectedly minimizes foaming and allows for proper grinding or crushing of the crystals. Although, the use of either Tyloxapol or Triton X-100 in the menstruum for grinding is acceptable, Tyloxapol at concentrations of 0.01 to 0.10% by weight in the final suspension is the preferred agent because the Triton X-100 is not used. commonly in ophthalmic preparations. Once the vehicle for grinding is prepared, it is filtered and then mixed with pearls or globules for grinding, such as alumina, glass, or zirconia, preferably beads or globules of 3 mm Y-zirconia and added to the crushing or comminution bottle 10. The mixture is then treated with an autoclave in a crushing bottle 10 at normal temperatures and pressures known to those skilled in the art, for example, 121-129 ° C, preferably 123-127 ° C. , for 30-45 minutes. After autoclaving and while the suspension is above 80 ° C, the mixture is treated in a ball mill under conditions to achieve an average particle size of 0.2-10 μm, preferably 1-5 μm, preferably 18- 19 hours at 50-55 RPM. After grinding, the shredded suspension is added aseptically through a mesh with openings smaller than the size of the beads or globules for grinding, to the rest of the ingredients that include, 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, thimerosol or EDTA; and at least one polymer, including, but not limited to, carbomer, hydroxypropylmethylcellulose (HPMC), hydroxyethyl cellulose (HEC), or polyvinyl alcohol (PVA) which are mixed, filtered, adjusted in pH, and sterilized prior to their combination with the ground mixture. Preferred ingredients are mannitol, NaCl, EDTA, BAC, carbomer, such as Carbopol 934P or 974P. Purified, sterile water is used to rinse the beads or globules and then added to the mixture and the batch is brought to the final volume. The ingredients are mixed until they become homogeneous.

The CAI / beta-blocker suspension contains brinzolamide, but also includes a beta-blocker, such as (Z) 2-butanedioate salt of (S) -l- [(1,1-dimethylethyl) amino] -3 - [[4- (4-morpholinyl) -1,2,5-thiadiazol-3-yl] oxy] -2-propanol (1: 1), which is known as timolol maleate or (+) hydrochloride - [p- [2- (cyclopropylmethoxy) ethyl] phenoxy] -3- (isopropylamino) -Z-propanol, which is known as betaxolol hydrochloride. Different isomers, for example, S-betaxolol, and salts, can be used. A sterile ophthalmic solution containing timolol maleate (Timoptic®) is available from Merck and Co., Inc. It is useful for the treatment of elevated intraocular pressure with ocular hypertension or open-angle glaucoma. A sterile ophthalmic solution containing betaxolol hydrochloride (Betoptic®) is available from Alcon Laboratories, Inc. It is also useful for the treatment of ocular hypertension and open-angle glaucoma. The process for manufacturing the suspension of CAI / beta-blocker is similar to that for making the brinzolamide suspension described above. The process for making a suspension of CAI / beta-blocker in which the beta-blocker is sensitive to heating and should be filtered aseptically (eg timolol maleate) is shown in Figure 2. If the beta-blocker is going to to be used can be treated in an autoclave (for example betaxolol), it can be added with mannitol and the other ingredients listed to manufacture the concentrate of the vehicle. Referring to Figure 2, the process for handling brinzolamide is the same as shown in Figure 1. The process for making the combination differs in that timolol maleate is incorporated by sterile filtration into the concentrate of the sterilized vehicle which it is adjusted in the pH aseptically to 6.0-8.0, preferably 6.5-7.6, and more preferably 7.0-7.4. The concentrate is then combined with the brinzolamide composition and mixed until it becomes homogeneous. As shown in Figure 3, the grinding bottle 10 includes the demijohn 11 and the filter 12. The demijohn 11 is preferably made of a material that can withstand autoclaving, such as polypropylene, and is large enough to contain the slurry and suspension for milling, for example, ten liters. The filter 12 is preferably a hydrophobic filter having a pore size of 0.2 to 10 μm, preferably 1-5 μm, and made of any hydrophobic material of sufficient mechanical strength which is sterilizable with steam. A filter 12 suitable for use in the present invention is commercially available from Millipore under the trade name DURAPEL of 2 μm. The filter 12 prevents the slurry and pulp for grinding from expanding out of the demijohn 11 during autoclaving, but allows the equalization of the pressure during heating and cooling. The excess pressure in the jug or demijohn 11 is vented through the steam extraction valve 22 and the air is allowed to be aseptically introduced to the demijohn 11 through the vent or vent filter 20 which is connected to the steam extraction valve 22 by pipe 24. The vent or vent filter 20 is preferably a hydrophobic filter having a pore size of 0.2 μm. The steam extraction valve 22 is connected to the demijohn 11 by the connector 16 and the complete assembly is sealed by means of gaskets 14 and 18. The formulations of the present invention are described in the following examples.

Example 1 Ingredients Concentration (% weight) Brinzolamide 1.0% plus 5% excess Tyloxapol 0.025 Carbomer 974P 0.40 Edetate Disodium 0.01 BAC 0.01 plus 5% excess Mannitol 3.30 10 Sodium Chloride 0.25 Purified Water c. s. 100% Example 2 Ingredients Concentration (% weight) Brinzolamide 1.0% plus 5% excess Triton X-100 0.025 Carbomer 974P 0.40 Edetate Disodium 0.01 20 BAC 0.01 plus 5% excess Mannitol 3.30 Sodium Chloride 0.25 Purified Water c. s. 100% Example 3 The formulation in Example 1 was made as follows: A. Preparation of the Aguada Paste for Grinding 1. In a container of suitable composition containing a stir bar, approximately 2300 g of hot purified water (50-70 ° C) were added. 15.0 g of tyloxapol was added to the container • and the ingredients were mixed until they became homogeneous. 2. The tyloxapol solution was brought to 2700 g using hot purified water (50-70 ° C). 3. The tyloxapol solution was filtered through a 10 μm polishing filter and retained for use in the slurry for milling. 4. The following materials were combined in the jug or demijohn 11: 3mm Zirconia-Itria Beads 22kg Tyloxapol Grinding Solution 2700g (Step 3) Brinzolamide 640g . The filter 12, the gaskets 14 and 18, the connector 16, the steam extraction valve 22, the venting or venting filter 20 and the pipe 24 are placed securely on the demijohn 11. 6. The grinding bottle 10 and its ingredients were subjected to autoclave treatment in a standard rapid cooling cycle. 7. The grinding bottle 10 was removed immediately after the treatment cycle was completed in the autoclave and treated in a ball mill at 50-55 RPM for 18-19 hours. 8. The paste for grinding was then retained for use in an aseptic addition.

B. Preparation of Carbomer Wash Paste 1. 84 kg of hot purified water (50-70 ° C) are transferred to a container of suitable composition with an agitator. 2. 1380 g of Carbomer 974P were added to the water and dispersed with agitation at high speed until they become homogeneous. 3. The slurry of Carbomer was brought to 86.25 kg with purified water and mixed until they become homogeneous.

C. Preparation of Vehicle Concentrate 1. Approximately 100 kg of warm purified water (50-70 ° C) are added to a vessel of suitable composition with a stirrer. 2. The following ingredients were added in the order listed using moderate agitation: Mannitol 10.56 kg Sodium Chloride 800 g Disodium Edetate 32 g Benzalkonium Chloride 10% solution 336 g 3. The solution is filtered through a polishing filter and added to a 300 liter reactor. The composition vessel and the filter are rinsed with approximately 15 liters of warm purified water (50-70 ° C) which is added to the reactor. 4. 80 kg of the suspension of Carbomer 974P (Section B) are added to the solution with mixing.

. The mixture of 4 is stirred and the pH is adjusted to 7.5 +/- 0.2 using IN sodium hydroxide (and 1 N hydrochloric acid if necessary). Approximately 16 liters of IN NaOH are required. 6. The vehicle concentrate is adjusted to 230.4 kg and sterilized using steam at 121-128 ° C for 35 minutes. 7. The vehicle concentrate is cooled to approximately room temperature (less than 30 ° C) and retained for use in aseptic processing. 8. 43 kg of the vehicle concentrate were transferred aseptically to a sterile mixing tank in a clean room or space.

E. Aseptic Addition of Suspension for Grinding 1. 15 kg of purified water are sterilized in glass jugs in an autoclave. 2. A transfer assembly that includes stainless steel tubing, silicone tubing, and stainless steel sieves is autoclaved and transferred to the clean room. 3. The milling suspension is transferred through sieves and the pipeline to the vehicle concentrate. 4. The beads or globules, the pipe, the sieves, and the jug 11 were rinsed with the purified water that is necessary to transfer the suspension for grinding as completely as possible.

. The sterile purified water was used to bring the weight of the batch to 61 kg. The batch was mixed until it becomes homogeneous.

Example 4 Ingredients Concentration (% weight) Brinzolamide, NOC 1.0% plus 5% excess Timolol Maleate 0.68 * Carbomer 974P 0.4 Sodium Chloride 0.10 Mannitol 3.3 Tyloxapol 0.025 Disodium Edetate 0.01 Benzalkonium Chloride 0.01 plus 5% excess Sodium Hydroxide or Hydrochloric Acid Adjust pH 7.2 + 0.2 Purified Water c. s. 100% Equivalent to 0.5% of Timolol as the free base Example 5 The formulation in Example 4 was made as follows: A. Preparation of the Aguada Paste for Grinding 1. In a vessel of suitable composition containing a stir bar, approximately 200 g of warm purified water (50-70 ° C) were added. 1.25 g of tyloxapol was added to the container and the ingredients were mixed until they became homogeneous. 2. The tyloxapol solution was brought to 300 g using hot purified water (50-70 ° C). 3. The tyloxapol solution was filtered through a polishing filter and retained for use in the slurry for milling. 4. The following materials were combined in a bottle for grinding: 3mm Zirconia-Itria Beads 2180kg Tyloxapol Grinding Solution 300g (Step 3) Brinzolamide 52.6g . The grinding bottle and its ingredients were subjected to autoclave treatment in a standard rapid cooling cycle. 6. The milling bottle was removed immediately after the treatment cycle in the autoclave was completed and treated in a ball mill at 50-55 RPM for 18-19 hours. 7. The slurry paste for grinding was then retained for use in an aseptic addition.

B. Preparation of 2% Carbomer Aguada Paste 1. 4000 kg of warm purified water (50-70 ° C) are transferred to a container of suitable composition with a top mixer. 2. 80.0 g of Carbomer 974P were added to the water and dispersed with high speed agitation until they become homogeneous. 3. The Carbomer paste was brought to 5000 g with purified water and mixed until they become homogeneous. 4. 1250 g of the suspension are added to a vessel through a polishing filter (40 μm) and covered.

C. Preparation of Vehicle Concentrate 1. Approximately 1000 kg of hot purified water (50-70 ° C) are added to a vessel of suitable composition with an agitator. 2. The following ingredients were added in the order listed using moderate agitation: Mannitol 165 kg Sodium Chloride 5.00 g Disodium Sodium 0.500 g Benzalkonium Chloride 10% solution 5.25 g 3. The dispersion is filtered through a polishing filter and added to a medium bottle with 2 screw cap, 5 liters. The composition vessel and the filter are rinsed with approximately 300 ml of warm purified water (50-70 ° C) and added to the glass medium bottle. 4. The suspension of Carbomer 974P (Section B) is added to the dispersion with mixing. Its container is rinsed with 250 ml of purified water which is added to the bottle with the glass medium.

. The vehicle concentrate is brought to 2750 kg with purified water. 6. 200 ml of 6N NaOH are prepared in a laboratory beaker. 7. 51.0 g of timolol maleate are dissolved in 1074 g of purified water.

D. Preparation for aseptic addition 1. Approximately 1000 ml of purified water were added to each of two bottles of the medium with a screw cap of two liters, with 2.0 μm breathing filters. 2. The following materials were subjected to autoclave treatment: Miscellaneous glassware and utensils Concentrate of the vehicle which includes the suspension of the Carbomer (Section C) Purified water (Step 1) Stainless steel pipe with sieve and silicone tubing 13-liter jug with stir bar 500 ml medium bottle Containing 1N HCl 500 ml medium bottle with 0.2 μm filter for 6N NaOH 3. The vehicle concentrate was cooled to approximately ambient temperature (less than 30 ° C) and is retained for use in aseptic processing.

E. Aseptic Addition of Suspension for Crushing or Grinding 1. All the materials needed for the aseptic composition, including the grinding suspension (Section A), the vehicle concentrate (Section C), the water, the magnetic mixer, the rest of the substances, the tubes, and the sieve, are taken to the clean room. 2. 6N NaOH is sterile filtered in a sterile laboratory vessel. 3. The timolol maleate solution is sterile filtered in a sterile bottle and 750 g is added to the vehicle concentrate. 4. The pH is aseptically adjusted to 7.2 + 0.2 with 6N NaOH. Approximately 52 g are required.

. The suspension for grinding or milling is transferred through the tube and sieve into the vehicle concentrate. 6. The beads or globules, the pipe, and the milling bottle were rinsed with the purified water that is necessary to transfer the milling suspension as completely as possible. 7. Purified water was used to bring the batch weight to (5094 g). The batch was miuntil it became homogeneous (not less than 15 minutes).

It is noted that in relation to this date • the best method known by the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Having described the invention as above, property is claimed as contained in the following

Claims (11)

1. A method of making an ophthalmic suspension, sterile, characterized in that the method comprises the steps of: to. autoclaving a slurry for grinding or milling comprising brinzolamide, grinding beads and a surfactant selected from the group consisting of a polymer (4-1,1,3,3-tetramethylbutyl) phenol with formaldehyde and oxirane and (a- [ 4- (1, 1,3,3-tetramethylbutyl) phenyl] -? - hydroxypropyloxy-1, 2-ethanediyl); * b. milling in a ball mill the suspension for grinding or grinding; c. preparing a suspension of an ophthalmically acceptable thick polymer comprising the. polymer and water; d. preparing a solution comprising tonicity and preservative agents. and. mix the suspension of the polymer and the solution to form a concentrated vehicle; F. sterilize the mixture of stage e using steam; g. Aseptically add the suspension for grinding or milling through a protection to the mixture of step £.

2 . A method according to claim 1, characterized in that the surfactant is the polymer 4- (1,1,3,3-tetramethylbutyl) phenol with formaldehyde and oxirane.

3. A method according to claim 1 or 2, characterized in that the suspension of the polymer comprises carbomer.

. A method in accordance with the claim 1 or 2, characterized in that the solution of step d comprises mannitol, sodium chloride, disodium edetate f and benzalkonium chloride.

5. A method according to any of claims 1 to 4, characterized in that the solution of step d comprises a beta blocker.

6. A method according to any of the preceding claims, characterized in that step e includes the step of pH adjustment.

7. A method according to any of claims 1 to 4, characterized in that it includes between step f and step g the step of aseptically adding a solution of timolol maleate to the mixture of step f, and aseptically adjusting pH.

8. A method according to any of the preceding claims, characterized in that the steam esterization of step f is done by treating it in an autoclave.

9. An ophthalmic, topical, sterile suspension characterized in that it comprises a pharmaceutically effective amount of brinzolamide and 0.001 to 5.0 weight percent of the polymer of 4- (1,1,3,3-tetramethylbutyl) phenol with formaldehyde and oxirane.

10. A suspension of compliance with claim 9, characterized in that the polymer of 4- (1,1,3,3-tetramethylbutyl) phenol with a concentration of formaldehyde and oxirane is 0.01 to 0.10 weight percent.

11. A suspension of conformity with claim 9 or 10, characterized in that the ophthalmic suspension includes betaxolol or thiomolol maleate.