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WO2012053011A2 - Compositions ophthalmiques comprenant de la brinzolamide - Google Patents

Compositions ophthalmiques comprenant de la brinzolamide Download PDF

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Publication number
WO2012053011A2
WO2012053011A2 PCT/IN2011/000720 IN2011000720W WO2012053011A2 WO 2012053011 A2 WO2012053011 A2 WO 2012053011A2 IN 2011000720 W IN2011000720 W IN 2011000720W WO 2012053011 A2 WO2012053011 A2 WO 2012053011A2
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WIPO (PCT)
Prior art keywords
brinzolamide
solution
suspension
preparing
slurry
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PCT/IN2011/000720
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English (en)
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WO2012053011A3 (fr
Inventor
Ashok Omray
Varsha Shashank Choudhary
Yogesh Sharad Bhide
Dinesh Yashawant Parsai
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Usv Limited
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Publication of WO2012053011A2 publication Critical patent/WO2012053011A2/fr
Publication of WO2012053011A3 publication Critical patent/WO2012053011A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems

Definitions

  • the present invention relates to a novel process for preparation of ophthalmic suspensions of carbonic anhydrase inhibitor such as Brinzolamide.
  • the invention further relates to suspensions comprising Brinzolamide and combination of Brinzolamide and a beta-blocker prepared by the novel process.
  • Carbonic anhydrase inhibitors inhibit the aqueous humor formation and thereby reduces elevated intraocular pressure (IOP).
  • Brinzolamide is an inhibitor of carbonic anhydrase II (CA-II). Brinzolamide on ocular administration inhibits aqueous humor formation and reduces elevated intraocular pressure.
  • Brinzolamide is chemically (R)-(+)-4-Ethylamino-2-(3-methoxypropyl)-3,4- dihydro-2H-thieno [3, 2-e]-l,2-thiazine-6-sulfonamide- 1,1 -dioxide and has the empirical formula C12H21N3O5S3 Brinzolamide has a molecular weight of 383.5 and a melting point of about 131°C.
  • Brinzolamide is disclosed in US5378703.
  • Brinzolamide ophthalmic suspension is developed and marketed by Alcon Laboratories Inc. in United States under the brand name Azopt ® (Brinzolamide ophthalmic suspension 1%).
  • Brinzolamide is indicated for lowering elevated intra-ocular pressure (IOP) in patients with open- angle glaucoma or ocular hypertension (OHT). Glaucoma is characterized by a progressive loss of visual field due to irreversible damage to the optic nerve. Glaucoma if not treated would lead to total blindness.
  • US5240923 discloses methods for lowering and controlling Intra ocular pressure (IOP) by administration of the Brinzolamide compositions.
  • EP0941094 discloses a process for making Brinzolamide suspension by autoclaving of a concentrated slurry of Brinzolamide in milling bottle, ball milling of the hot slurry, and then adding the slurry to the rest of the ingredients.
  • prior art discloses autoclaving of the slurry of Brinzolamide and surfactant and further ball milling the slurry.
  • the drawback associated with this method is that it requires a milling bottle in which the slurry of Brinzolamide could initially be autoclaved and then ball milled for further size reduction of needle shaped crystals of Brinzolamide that are formed during autoclaving.
  • the inventors of the present invention have developed a novel process for preparation of sterile ophthalmic suspension of Brinzolamide. This process ameliorates the drawbacks associated with prior art methods for preparation of Brinzolamide ophthalmic suspension. The process does not require the use of any specific equipments such as milling bottle.
  • An object of the present invention is to provide a novel process for preparation of sterile, ophthalmic suspensions of carbonic anhydrase inhibitor, such as Brinzolamide. Said ophthalmic suspensions are useful in the treatment of elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma.
  • Another object of the invention is to provide a novel process for preparation of sterile, ophthalmic suspension of Brinzolamide and a beta-blocker.
  • Another object of the invention is to provide a process for preparation of Brinzolamide ophthalmic suspension, the process being efficient, economic, feasible for commercial scale preparation and which does not involve the use of any special equipments.
  • Another object of the invention is to provide a process for preparation of Brinzolamide ophthalmic suspension which ameliorates one or more drawbacks of the prior art processes.
  • the present invention provides a novel process for preparation of sterile, ophthalmic suspensions of carbonic anhydrase inhibitor, such as Brinzolamide.
  • a process for preparing sterile ophthalmic suspension comprising the steps of:
  • step (c) aseptically adding said suspension vehicle of step (b) to said milled slurry of step (a) to obtain a suspension and making up the volume with water;
  • step (d) homogenizing said suspension of step (c) under vacuum.
  • said process is characterized in that it does not involve autoclaving of the active ingredient Brinzolamide.
  • step (d) precipitating Brinzolamide from the solution of step (c) to form a slurry comprising Brinzolamide and surfactant;
  • step (h) mixing said polymer solution of step (f) and said aqueous solution of step (g) to form suspension vehicle and autoclaving said suspension vehicle;
  • step (i) aseptically adding said suspension vehicle to Brinzolamide slurry of step (e) to obtain a suspension
  • step (j) homogenizing said suspension of step (i) under vacuum.
  • step (d) precipitating Brinzolamide from said solution of step (c) to form a slurry comprising Brinzolamide and surfactant;
  • step (h) mixing said polymer solution of step (f) and said aqueous solution of step(g) to form suspension vehicle and autoclaving said suspension vehicle;
  • step (j) homogenizing said suspension of step (i) under vacuum.
  • step (d) precipitating Brinzolamide from the solution of step (c) to form a slurry comprising Brinzolamide and surfactant;
  • step (h) mixing said polymer solution of step (f) and said aqueous solution of step(g) to form suspension vehicle and autoclaving said suspension vehicle;
  • step (i) aseptically adding said suspension vehicle of step (h) to Brinzolamide slurry of step (e) to obtain a suspension; and (j) homogenizing said suspension of step (i) under vacuum.
  • step (d) precipitating Brinzolamide from the solution of step (c) to form a slurry comprising Brinzolamide and surfactant;
  • step (h) mixing said polymer solution of step (f) and said aqueous solution of step(g) to form suspension vehicle and autoclaving said suspension vehicle;
  • step (i) aseptically adding said suspension vehicle of step (h) to Brinzolamide slurry of step (e);
  • step (j) homogenizing said suspension of step (i) under vacuum.
  • said ball milling or jet milling is carried out to achieve size reduction of the active ingredient Brinzolamide such that the average particle size of Brinzolamide is less than about 5 microns; preferably less than about 2 microns.
  • said ball milling is carried out using Zirconia-Yttria beads, glass beads or alumina as milling media and jet milling is carried out using microjet reactor.
  • a sterile ophthalmic suspension prepared by the process as described herein comprising Brinzolamide in an amount from 0.001% to 5.0% by weight, surfactant and optionally a beta-blocker.
  • Fig.l Flow chart showing the process for making Brinzolamide Ophthalmic suspension, wherein the Brinzolamide solution is first aseptically filtered and into it the sterile solution of surfactant is added.
  • Fig.2 Flow chart showing the process for making Brinzolamide Ophthalmic suspension, wherein the surfactant solution is first added to the Brinzolamide solution and then aseptically filtered .(Process II).
  • the present invention provides a novel process for preparation of sterile ophthalmic suspensions of carbonic anhydrase inhibitor such as Brinzolamide. More particularly, the invention provides suspensions comprising Brinzolamide or pharmaceutically acceptable salts thereof. The invention further provides ophthalmic suspensions comprising combination of Brinzolamide and a beta- blocker prepared by the novel process as disclosed herein.
  • a slurry of Brinzolamide on autoclaving yields needle like crystals of the active ingredient Brinzolamide, which would further necessitate its size reduction for preparation of ophthalmic suspension.
  • Prior art has over come this problem by autoclaving the slurry of Brinzolamide in a milling bottle and then ball milling the slurry.
  • this process necessitates the use of a milling bottle in which the Brinzolamide could be autoclaved and then size reduced by ball milling technique.
  • the inventors of the present invention have conducted extensive studies and have found a method by which Brinzolamide can initially be solubilized and the solution can be aseptically filtered to get a filtrate which can further be precipitated to get a slurry of Brinzolamide.
  • the slurry of Brinzolamide may further be ball milled or jet milled along with surfactants and further processed with suitable excipients.
  • a process for preparing sterile ophthalmic suspension comprising the steps of:
  • step (c) aseptically adding said suspension vehicle of step (b) to said milled slurry of step (a) to obtain a suspension and making up the volume with water;
  • step (d) homogenizing said suspension of step (c) under vacuum.
  • said said process is characterized in that it does not involve autoclaving of the active ingredient Brinzolamide.
  • a process for preparing sterile ophthalmic suspension comprising the steps of:
  • step (c) aseptically adding said suspension vehicle of step (b) to said milled slurry of step (a) to obtain a suspension and making up the volume with water; (d) homogenizing said suspension of step (c) under vacuum;
  • step (d) precipitating Brinzolamide from the solution of step (c) to form a slurry comprising Brinzolamide and surfactant;
  • step (h) mixing said polymer solution of step (f) and said aqueous solution of step (g) to form suspension vehicle and autoclaving said suspension vehicle;
  • step (i) aseptically adding said suspension vehicle to Brinzolamide slurry of step (e) to obtain a suspension
  • step (j) homogenizing said suspension of step (i) under vacuum.
  • the invention provides a process for preparing Brinzolamide ophthalmic suspension comprising the steps of:
  • step (c) aseptically filtering said Brinzolamide solution containing Tyloxapol ® ;
  • step (d) precipitating Brinzolamide from the solution of step (c) to form a slurry comprising Brinzolamide and Tyloxapol ® ;
  • step (h) mixing the viscous polymer solution of Carbopol ® 974 P and the aqueous solution of step (g) to form suspension vehicle and autoclaving said suspension vehicle;
  • step (i) aseptically adding the suspension vehicle to Brinzolamide slurry of step (e) to obtain a suspension
  • step (j) homogemzing said suspension of step (i) under vacuum to get the bulk sample.
  • step (d) precipitating Brinzolamide from said solution of step (c) to form a slurry comprising Brinzolamide and surfactant;
  • step (h) mixing said polymer solution of step (f) and said aqueous solution of step(g) to form suspension vehicle and autoclaving said suspension vehicle;
  • step (j) homogenizing said suspension of step (i) under vacuum.
  • the invention provides a process for preparing Brinzolamide ophthalmic suspension comprising the steps of:
  • step (d) precipitating Brinzolamide from said solution of step (c) to form a slurry comprising Brinzolamide and Tyloxapol ® ;
  • step (h) mixing the viscous polymer solution of Carbopol ® 974 P and aqueous solution of step (g) to form suspension vehicle and autoclaving said suspension vehicle;
  • step (i) aseptically adding the suspension vehicle of step (h) to Brinzolamide slurry of step (e) to obtain a suspension
  • step (j) homogenizing said suspension of step (i) under vacuum to get the bulk sample.
  • the invention provides a process for preparing Brinzolamide ophthalmic suspension comprising the steps of:
  • step (c) aseptically filtering said Brinzolamide solution containing Tyloxapol ® ;
  • step (d) precipitating Brinzolamide from the solution of step (c) to form a slurry comprising Brinzolamide and Tyloxapol ® ;
  • aqueous solution comprising a beta blocker such as timolol or betaxolol; mannitol, sodium chloride, Edetate disodium and benzalkonium chloride;
  • step (h) mixing the viscous polymer solution of Carbopol ® 974 P and the aqueous solution of step (g) to form suspension vehicle and autoclaving said suspension vehicle;
  • step (i) aseptically adding the suspension vehicle to Brinzolamide slurry of step (e) to obtain a suspension
  • step (j) homogenizing said suspension of step (i) under vacuum to get the bulk sample.
  • the process for preparation of ophthalmic suspension of Brinzolamide as disclosed herein does not involve the autoclaving of Brinzolamide slurry and thus application of heat onto the active ingredient Brinzolamide is avoided.
  • the process of ball milling of Brinzolamide slurry and surfactant can be performed for about 2 to 12 hours at 50-55 revolutions per minute using 3mm Zirconia-Yttria beads.
  • Ball milling is carried out using Zirconia-Yttria beads, glass beads or alumina as milling media and jet milling is carried out using microjet reactor.
  • said ball milling or jet milling is carried out to achieve size reduction of the active ingredient Brinzolamide such that the average particle size of Brinzolamide is less than about 5 microns; preferably less than about 2 microns.
  • a process for preparing sterile ophthalmic suspension comprising the steps of:
  • step (d) precipitating Brinzolamide from the solution of step (c) to form a slurry comprising Brinzolamide and surfactant;
  • step (h) mixing said polymer solution of step (f) and said aqueous solution of step(g) to form suspension vehicle and autoclaving said suspension vehicle;
  • step (j) homogenizing said suspension of step (i) under vacuum.
  • step (d) precipitating Brinzolamide from the solution of step (c) to form a slurry comprising Brinzolamide and surfactant;
  • step (h) mixing said polymer solution of step (f) and said aqueous solution of step(g) to form suspension vehicle and autoclaving said suspension vehicle;
  • step (i) aseptically adding said suspension vehicle of step (h) to Brinzolamide slurry of step (e);
  • step (j) homogenizing said suspension of step (i) under vacuum.
  • the inventors of the present invention have developed a novel process for preparation of sterile ophthalmic suspension of Brinzolamide. This process is advantageous over the prior art methods for preparation of Brinzolamide ophthalmic suspension.
  • a sterile ophthalmic suspension prepared by the process as described herein comprising Brinzolamide in an amount from 0.001% to 5.0% by weight, surfactant and optionally a beta-blocker.
  • the present invention provides Brinzolamide ophthalmic suspensions comprising: the active ingredient Brinzolamide, Tyloxapol®; Carbopol® 974 P; mannitol, sodium chloride, Edetate disodium, benzalkonium chloride; sodium Hydroxide and/or Hydrochloric acid (to adjust the pH) wherein the said ophthalmic suspension is prepared by the process as described herein.
  • Brinzolamide may be present in an amount of from about 0.001% to 5.0% by weight.
  • Beta-blockers that may be used according to the invention include timolol, betaxolol and the like.
  • polymers examples include, but are not limited to Carbopol® such as Carbopol® 974 P, povidone, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose and mixtures thereof. Polymers may be used in amount from 0.1% to 5.0%, preferably 0.3% to 1.0%.
  • preservatives examples include but are not limited to benzethonium chloride, phenyl ethanol, phenyl propanol, phenyl mercuric acetate, phenyl mercuric nitrate, phenyl mercuric borate, chlorhexidine acetate or gluconate, cetrimide, chlorocresol, sodium methyl paraben, sodiumpropyl paraben, thimerosal, benzalkonium chloride and mixtures thereof and may be used in an amount from 0.001% to 0.5%, preferably 0.005% to 0.05%.
  • surfactants examples include but are not limited to Tyloxapol®, Triton X-100®, polysorbates, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 40 stearates, sorbitan monolaureates, poloxamer and mixtures thereof and may be used in amount from 0.001% to 15 %, preferably 0.01% to 0.5%.
  • Tyloxapol® is chemically known as 4-(l,l,3,3-Tetramethylbutyl)phenol polymer with formaldehyde and oxirane.
  • Triton X-100® is chemically known as (a-[4-(l,l,3,3-tetramethylbutyl)phenyl]- co-hydroxypolyoxy-l,2-ethane diyl)
  • tonicity agents examples include but are not limited to mannitol, dextrose, glycerin, potassium chloride, sodium chloride and mixtures thereof. Tonicity agents may be used in amount from about l% to 5%.
  • composition of the present invention may be aseptically sterilized using membrane filters such as PES (Polyethersulphone), PVDF (Polyvinylidene Fluoride) having pore size of about 0.45 microns to 0.22 microns.
  • membrane filters such as PES (Polyethersulphone), PVDF (Polyvinylidene Fluoride) having pore size of about 0.45 microns to 0.22 microns.
  • Autoclaving of the suspension vehicle may be done using any conventional steam sterilizer dedicated for ophthalmic preparations.
  • the homogenized ophthalmic suspension of Brinzolamide prepared according to the process as described herein may be filled in LDPE vials of suitable capacity in volumes of 2.5ml, 5ml, 10ml and 15ml.
  • Sterile ophthalmic compositions prepared by the process as described herein is stable when stored at 4 -30 deg C.
  • Brinzolamide API used in the preparation of pharmaceutical composition of the present invention can be obtained by the processes known in the art or by the process disclosed in WO2008062463.
  • Brinzolamide API used in the preparation of pharmaceutical composition can be obtained by the process comprising the steps of,
  • an alkylating agent preferably 1- halo-3-methoxy propane in presence of base preferably potassium carbonate and polar aprotic solvent, preferably ketone such as acetone to provide (S)-3,4-dihydro-6-chloro-4-hydroxy-2-(3-methoxypropyl)-2H- thieno [3 ,2-e]- 1 ,2-thiazine- 1 , 1 -dioxide;
  • the conversion of (S)-3,4-dihydro-4-hydroxy-2-(3- methoxypropyl)-2H-thieno[3,2-e]- 1 ,2-thiazine-6-sulfonamide- 1 , 1 -dioxide to Brinzolamide comprises the steps of,
  • NSAID non-steroidal anti-inflammatory drug
  • Nepafenac e.g. Nepafenac and the like.
  • the invention provides a process for preparing Nepafenac ophthalmic suspension comprising the steps of:
  • the invention provides a process for preparing Nepafenac ophthalmic suspension comprising the steps of:
  • ophthalmically acceptable refers to ingredients that are suitable for use in mammalian eye and does not cause any irritation, allergic conditions or any other complicated side effects.
  • the term “solubilized” or “solubilizing”, refers to ingredient is solubilized in the aqueous solution and that there will substantially be no traces of particles that may be present.
  • excipient refers to a pharmaceutically acceptable ingredients that are commonly used in the pharmaceutical technology for preparing ophthalmic preparations.
  • Step I Preparation of milled slurry of Brinzolamide:
  • Brinzolamide (1.0 kg) was added to purified water (10 kg) in a suitable stainless steel vessel and dispersed uniformly by stirring. Sodium hydroxide solution (5% w/v) (2.798 liter) was added to the Brinzolamide dispersion and stirred till a clear solution was obtained. Brinzolamide solution that was obtained was aseptically filtered using 0.22 ⁇ filter under nitrogen pressure. A sterile solution of Tyloxapol ® was prepared by dissolving Tyloxapol ® (25 g) in hot purified water (0.8 kg) and this solution was added to the filtered Brinzolamide solution under stirring. Rinsing was given with 0.5 kg hot purified water and the rinse was added to Brinzolamide solution.
  • Sterile hydrochloric acid solution (20% v/v) (1.498 kg) was prepared and added to the mixture of Brinzolamide solution and Tyloxapol ® solution, till the Brinzolamide precipitated out and a slurry of Brinzolamide was formed.
  • the slurry of Brinzolamide was added to the ball mill and ball milled for about 2 to 12 hours at 50-55 revolutions per minute using 3mm Zirconia-Yttria beads. The milled slurry was transferred aseptically to a jacketed stainless steel vessel equipped with stirring rod.
  • Step II Preparation of suspension vehicle: Carbopol 974P (0.4 kg) was dispersed uniformly in purified water (20 kg). To this dispersion sodium hydroxide solution (5% w/v) was added and the mixture was soaked for about 2 hours to get a dispersion of the polymer. A solution of Disodium EDTA (10 g), mannitol (3300 g), sodium chloride (250 g) and benzalkonium chloride (10 g) in water (20 kg) was prepared in a separate mixing vessel. This solution was added to the polymer dispersion and the pH was adjusted to 7.0 ⁇ 0.2 and stirred for 15 minutes to get the suspension vehicle. The suspension vehicle was sterilized using steam at 121-128°C for 35 minutes and the sterilized suspension vehicle was cooled to room temperature.
  • Step III Addition of suspension vehicle to milled slurry and Homogenization.
  • the suspension vehicle prepared according to step II was added to the jacketed stainless steel vessel containing the milled slurry of Brinzolamide and the total volume was made up to 98 liter using purified water and further homogemzed under vacuum for 10 minutes to get a uniform suspension.
  • the final pH was adjusted to 7.5 ⁇ 0.3 and the final volume was made up using purified water and further homogemzed for 15 minutes under vacuum to get uniform Brinzolamide ophthalmic suspension.
  • Step I Preparation of milled slurry of Brinzolamide:
  • Brinzolamide (1.0 kg) was added to purified water (10 kg) in a suitable stainless steel vessel and dispersed uniformly by stirring. Sodium hydroxide solution (5% w/v) (2.798 liter) was added to the Brinzolamide dispersion and stirred till a clear solution was obtained.
  • a solution of Tyloxapol ® was prepared by dissolving Tyloxapol ® (25 g) in hot purified water (0.8 kg) and this solution was added to Brinzolamide solution under stirring. Rinsing was given with 0.5 kg hot purified water and the rinse was added to Brinzolamide solution. Brinzolamide solution containing the Tyloxapol ® was aseptically filtered using 0.22 ⁇ filter under nitrogen pressure.
  • Sterile hydrochloric acid solution (20% v/v) (1.498 kg) was prepared and added to the mixture of Brinzolamide solution and Tyloxapol ® solution, till the Brinzolamide precipitated out and a slurry of Brinzolamide was formed.
  • the slurry of Brinzolamide was added to the ball mill and ball milled for about 2 to 12 hours at 50-55 revolutions per minute using 3mm Zirconia-Yttria beads. The milled slurry was transferred aseptically to a jacketed stainless steel vessel equipped with stirring rod.
  • Carbopol 974P (0.4 kg) was dispersed uniformly in purified water (20 kg). To this dispersion sodium hydroxide solution (5% w/v) was added and the mixture was soaked for about 2 hours to get a dispersion of the polymer. A solution of Disodium EDTA (10 g), mannitol (3300 g), sodium chloride (250 g) and benzalkonium chloride (10 g) in water (20 kg) was prepared in a separate mixing vessel. This solution was added to the polymer dispersion and the pH was adjusted to 7.0 ⁇ 0.2 and stirred for 15 minutes to get the suspension vehicle. The suspension vehicle was sterilized using steam at 121-128°C for 35 minutes and the sterilized suspension vehicle was cooled to room temperature.
  • Step III Addition of suspension vehicle to milled slurry and Homogenization.
  • the suspension vehicle prepared according to step II was added to the jacketed stainless steel vessel containing the milled slurry of Brinzolamide and the total volume was made up to 98 liter using purified water and further homogenized under vacuum for 10 minutes to get a uniform suspension.
  • the final pH was adjusted to 7.5 ⁇ 0.3 and the final volume was made up using purified water and further homogenized for 15 minutes under vacuum to get uniform Brinzolamide ophthalmic suspension.
  • Step I Preparation of milled slurry of Brinzolamide: Brinzolamide (1.0 kg) was added to purified water (10 kg) in a suitable stainless steel vessel and dispersed uniformly by stirring. Sodium hydroxide solution (5% w/v) (2.798 liter) was added to the Brinzolamide dispersion and stirred till a clear solution was obtained. Brinzolamide solution that was obtained was aseptically filtered using 0.22 ⁇ filter under nitrogen pressure. A solution of Polysorbate 80 was prepared by dissolving Polysorbate 80 (20 g) in hot purified water (0.8 kg) and this solution was added to the filtered Brinzolamide solution under stirring. Rinsing was given with 0.5 kg hot purified water and the rinse was added to Brinzolamide solution.
  • Sterile hydrochloric acid solution (20% v/v) (1.498 kg) was prepared and added to the mixture of Brinzolamide solution and Polysorbate 80 solution, till the Brinzolamide precipitated out and a slurry of Brinzolamide was formed.
  • the slurry of Brinzolamide was added to the ball mill and ball milled for about 2-8 hours at 50-55 revolutions per minute using 3mm Zirconia-Yttria beads. The milled slurry was transferred aseptically to a jacketed stainless steel vessel equipped with stirring rod.
  • Carbopol 974P (0.4 kg) was dispersed uniformly in purified water (20 kg). To this dispersion sodium hydroxide solution (5% w/v) was added and the mixture was soaked for about 2 hours to get a dispersion of the polymer. A solution of Disodium EDTA (10 g), mannitol (3300 g), sodium chloride (250 g) and benzalkonium chloride (10 g) in water (20 kg) was prepared in a separate mixing vessel. This solution was added to the polymer dispersion and the pH was adjusted to 7.0 ⁇ 0.2 and stirred for 15 minutes to get the suspension vehicle. The suspension vehicle was sterilized using steam at 121-128°C for 35 minutes and the sterilized suspension vehicle was cooled to room temperature.
  • Step III Addition of suspension vehicle to milled slurry and Homogenization.
  • the suspension vehicle prepared according to step II was added to the jacketed stainless steel vessel containing the milled slurry of Brinzolamide and the total volume was made up to 98 liter using purified water and further homogenized under vacuum for 10 minutes to get a uniform suspension.
  • the final pH was adjusted to 7.5 + 0.3 and the final volume was made up using purified water and further homogenized for 15 minutes under vacuum to get uniform Brinzolamide ophthalmic suspension.
  • Step I Preparation of milled slurry of Brinzolamide:
  • Brinzolamide (1.0 kg) was added to purified water (10 kg) in a suitable stainless steel vessel and dispersed uniformly by stirring. Sodium hydroxide solution (5% w/v) (2.798 liter) was added to the Brinzolamide dispersion and stirred till a clear solution was obtained. Brinzolamide solution that was obtained was aseptically filtered using 0.22 ⁇ filter under nitrogen pressure. A solution of Tyloxapol ® was prepared by dissolving Tyloxapol ® (25 g) in hot purified water (0.8 kg) and this solution was added to the filtered Brinzolamide solution under stirring. Rinsing was given with 0.5 kg hot purified water and the rinse was added to Brinzolamide solution.
  • Sterile hydrochloric acid solution (20% v/v) (1.498 kg) was prepared and added to the mixture of Brinzolamide solution and Tyloxapol ® solution, till the Brinzolamide precipitated out and a slurry of Brinzolamide was formed.
  • the slurry of Brinzolamide was added to the ball mill and ball milled for about 2-8 hours at 50-55 revolutions per minute using 3mm Zirconia-Yttria beads. The milled slurry was transferred aseptically to a jacketed stainless steel vessel equipped with stirring rod.
  • Hydroxypropylmethyl cellulose (HPMC E3) (0.6 kg) was dispersed uniformly in hot purified water (15 kg). To this dispersion sodium hydroxide solution (5% w/v) was added and the mixture was soaked for about 2 hours to get a dispersion of the polymer. A solution of Disodium EDTA (10 g), mannitol ( 3300 g), sodium chloride ( 250 g) and benzalkonium chloride (10 g) in water (20 kg) was prepared in a separate mixing vessel. This solution was added to the polymer dispersion and the pH was adjusted to 7.0 ⁇ 0.2 and stirred for 15 minutes to get the suspension vehicle. The suspension vehicle was sterilized using steam at 121- 128°C for 35 minutes and the sterilized suspension vehicle was cooled to room temperature.
  • HPMC E3 Hydroxypropylmethyl cellulose
  • Step III Addition of suspension vehicle to milled slurry and Homogenization.
  • the suspension vehicle prepared according to step II was added to the jacketed stainless steel vessel containing the milled slurry of Brinzolamide and the total volume was made up to 98 liter using purified water and further homogenized under vacuum for 10 minutes to get a uniform suspension.
  • the final pH was adjusted to 7.5 ⁇ 0.3 and the final volume was made up using purified water and further homogenized for 15 minutes under vacuum to get uniform Brinzolamide ophthalmic suspension.
  • Step I Preparation of milled slurry of Brinzolamide:
  • Brinzolamide (1.0 kg) was added to purified water (10 kg) in a suitable stainless steel vessel and dispersed uniformly by stirring. Sodium hydroxide solution (5% w/v) (2.798 liter) was added to the Brinzolamide dispersion and stirred till a clear solution was obtained.
  • a solution of Tyloxapol ® was prepared by dissolving Tyloxapol ® (25 g) in hot purified water (0.8 kg) and this solution was added to Brinzolamide solution under stirring. Rinsing was given with 0.5 kg hot purified water and the rinse was added to Brinzolamide solution.
  • Brinzolamide solution containing the Tyloxapol ® was aseptically filtered using 0.22 ⁇ filter under nitrogen pressure. This was then fed into Microjet reactor with an impinging jet of Sterile hydrochloric acid solution (20% v/v) (1.498 kg), wherein the Brinzolamide precipitated out and a fine slurry of Brinzolamide was formed.
  • Step II Preparation of suspension vehicle: Carbopol 974P (0.4 kg) was dispersed uniformly in purified water (20 kg). To this dispersion sodium hydroxide solution (5% w/v) was added and the mixture was soaked for about 2 hours to get a dispersion of the polymer. A solution of Disodium EDTA (10 g), mannitol (3300 g), sodium chloride (250 g) and benzalkonium chloride (10 g) in water (20 kg) was prepared in a separate mixing vessel. This solution was added to the polymer dispersion and the pH was adjusted to 7.0 ⁇ 0.2 and stirred for 1 minutes to get the suspension vehicle. The suspension vehicle was sterilized using steam at 121-128°C for 35 minutes and the sterilized suspension vehicle was cooled to room temperature.
  • Step III Addition of suspension vehicle to milled slurry and Homogenization.
  • the suspension vehicle prepared according to step II was added to the jacketed stainless steel vessel containing the milled slurry of Brinzolamide and the total volume was made up to 98 liter using purified water and further homogenized under vacuum for 10 minutes to get a uniform suspension.
  • the final pH was adjusted to 7.5 ⁇ 0.3 and the final volume was made up using purified water and further homogenized for 15 minutes under vacuum to get uniform Brinzolamide ophthalmic suspension.

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Abstract

L'invention concerne un nouveau procédé de préparation de suspensions ophtalmiques d'un inhibiteur d'anhydrase carbonique tel que la brinzolamide. Le procédé se caractérise en ce qu'il ne nécessite pas l'autoclavage de l'ingrédient actif brinzolamide. L'invention concerne en outre des suspensions ophtalmiques contenant de la brinzolamide seule ou en association avec un bêta-bloquant préparé par ce nouveau procédé.
PCT/IN2011/000720 2010-10-18 2011-10-18 Compositions ophthalmiques comprenant de la brinzolamide WO2012053011A2 (fr)

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013175285A1 (fr) 2012-05-21 2013-11-28 Aurobindo Pharma Limited Procédé de préparation d'une suspension ophtalmique de brinzolamide
WO2014057499A1 (fr) 2012-10-11 2014-04-17 Indoco Remedies Limited Procédé de production d'une suspension ophtalmique stérile à base de la brinzolamide
WO2015068105A1 (fr) * 2013-11-08 2015-05-14 Sentiss Pharma Private Limited Procédé amélioré de fabrication de suspensions pharmaceutiques ophtalmiques stériles
WO2015147665A1 (fr) * 2014-03-28 2015-10-01 Instytut Farmaceutyczny Procédé pour produire une suspension ophtalmique à base de brinzolamide et formulation de collyre
JP2015212231A (ja) * 2014-05-01 2015-11-26 東亜薬品株式会社 ブリンゾラミド懸濁性点眼液組成物の製造方法
US20160175317A1 (en) * 2013-11-08 2016-06-23 Sentiss Pharma Pvt. Ltd. Pharmaceutical composition comprising brinzolamide
US9872910B2 (en) 2014-07-11 2018-01-23 Fujifilm Corporation Aqueous ophthalmic composition
WO2022156372A1 (fr) * 2021-01-22 2022-07-28 成都瑞沐生物医药科技有限公司 Préparation ophtalmique administrée par collyre et utilisée pour la prévention et le traitement de la dégénérescence maculaire sèche et de la détérioration de la lumière rétinienne

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US5240923A (en) 1990-04-09 1993-08-31 Alcon Laboratories, Inc. Sulfonamides useful as carbonic anhydrase inhibitors
US5378703A (en) 1990-04-09 1995-01-03 Alcon Laboratories, Inc. Sulfonamides useful as carbonic anhydrase inhibitors
EP0941094A1 (fr) 1996-12-11 1999-09-15 Alcon Laboratories, Inc. Procede de fabrication de suspensions ophtalmiques
WO2008062463A2 (fr) 2006-10-13 2008-05-29 Usv Limited Procédé perfectionné pour la préparation de (r)-(+)-4-(éthylamino)-3,4-dihydro-2-(3-méthoxypropyl)-2h-thiéno[3,2-e]-1,2-thiazine-6-sulfonamide-1,1-dioxyde

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EP1985618A1 (fr) * 2007-04-27 2008-10-29 Duke Chem, S. A. Procédé de préparation de brinzolamide et intermédiaires correspondants
JP2010037327A (ja) * 2008-07-07 2010-02-18 Wakamoto Pharmaceut Co Ltd ブリンゾラミド水性組成物
EP2414343A1 (fr) * 2009-03-13 2012-02-08 Azad Pharmaceutical Ingredients AG Procédé de préparation de brinzolamide

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5240923A (en) 1990-04-09 1993-08-31 Alcon Laboratories, Inc. Sulfonamides useful as carbonic anhydrase inhibitors
US5378703A (en) 1990-04-09 1995-01-03 Alcon Laboratories, Inc. Sulfonamides useful as carbonic anhydrase inhibitors
EP0941094A1 (fr) 1996-12-11 1999-09-15 Alcon Laboratories, Inc. Procede de fabrication de suspensions ophtalmiques
WO2008062463A2 (fr) 2006-10-13 2008-05-29 Usv Limited Procédé perfectionné pour la préparation de (r)-(+)-4-(éthylamino)-3,4-dihydro-2-(3-méthoxypropyl)-2h-thiéno[3,2-e]-1,2-thiazine-6-sulfonamide-1,1-dioxyde

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013175285A1 (fr) 2012-05-21 2013-11-28 Aurobindo Pharma Limited Procédé de préparation d'une suspension ophtalmique de brinzolamide
WO2014057499A1 (fr) 2012-10-11 2014-04-17 Indoco Remedies Limited Procédé de production d'une suspension ophtalmique stérile à base de la brinzolamide
WO2015068105A1 (fr) * 2013-11-08 2015-05-14 Sentiss Pharma Private Limited Procédé amélioré de fabrication de suspensions pharmaceutiques ophtalmiques stériles
US20160175317A1 (en) * 2013-11-08 2016-06-23 Sentiss Pharma Pvt. Ltd. Pharmaceutical composition comprising brinzolamide
US9820991B2 (en) * 2013-11-08 2017-11-21 Sentiss Pharma Private Limited Pharmaceutical composition comprising brinzolamide
US10463674B2 (en) 2013-11-08 2019-11-05 Sentiss Pharma Private Limited Process for manufacturing sterile ophthalmic pharmaceutical suspensions
WO2015147665A1 (fr) * 2014-03-28 2015-10-01 Instytut Farmaceutyczny Procédé pour produire une suspension ophtalmique à base de brinzolamide et formulation de collyre
JP2015212231A (ja) * 2014-05-01 2015-11-26 東亜薬品株式会社 ブリンゾラミド懸濁性点眼液組成物の製造方法
US9872910B2 (en) 2014-07-11 2018-01-23 Fujifilm Corporation Aqueous ophthalmic composition
WO2022156372A1 (fr) * 2021-01-22 2022-07-28 成都瑞沐生物医药科技有限公司 Préparation ophtalmique administrée par collyre et utilisée pour la prévention et le traitement de la dégénérescence maculaire sèche et de la détérioration de la lumière rétinienne

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