WO2012053011A2 - Ophthalmic compositions comprising brinzolamide - Google Patents

Abstract

Disclosed herein is a novel process for preparation of ophthalmic suspensions of Carbonic anhydrase inhibitor such as Brinzolamide. Said process is characterized in that it does not involve autoclaving of the active ingredient Brinzolamide. The invention further discloses ophthalmic suspensions comprising Brinzolamide and combination of Brinzolamide and beta-blocker prepared by the novel process.

Description

"Ophthalmic compositions comprising Brinzolamide" Related application:

This application claims the benefit of Indian Provisional Application No.

2894/MUM/2010 filed on 18 October 2010.

Technical field of the invention:

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.

Background of the invention:

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.

Although there are various known ways to sterilize ophthalmic suspensions, preparation of sterile suspension of Brinzolamide is not industrially feasible. Aseptic addition of Brinzolamide to sterile vehicle is not a feasible process for large scale preparation. Sterilization using ethylene oxide or irradiation would degrade the product. 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.

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.

Thus, prior art discloses autoclaving of the slurry of Brinzolamide and surfactant and further ball milling the slurry. However, 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.

Object of Invention:

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.

Summary of Invention:

The present invention provides a novel process for preparation of sterile, ophthalmic suspensions of carbonic anhydrase inhibitor, such as Brinzolamide.

According to one aspect of the present invention there is provided a process for preparing sterile ophthalmic suspension, the process comprising the steps of:

(a) aseptically preparing a milled slurry comprising Brinzolamide and surfactant;

(b) preparing sterile suspension vehicle comprising polymer, tonicity agent and preservative;

(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. Preferably, said process is characterized in that it does not involve autoclaving of the active ingredient Brinzolamide.

According to another aspect of the present invention there is provided a process for preparing sterile ophthalmic suspension, the process comprising the steps of:

(a) preparing an aqueous solution of Brinzolamide;

(b) adding a surfactant solution to said aqueous solution of Brinzolamide;

(c) aseptically filtering said Brinzolamide solution containing surfactant;

(d) precipitating Brinzolamide from the solution of step (c) to form a slurry comprising Brinzolamide and surfactant;

(e) ball milling or jet milling said slurry comprising Brinzolamide and surfactant;

(f) preparing a viscous polymer solution comprising an ophthalmically acceptable polymer;

(g) preparing an aqueous solution comprising tonicity agent and preservative;

(h) mixing said polymer solution of step (f) and said aqueous solution of step (g) to form suspension vehicle and autoclaving said suspension vehicle;

(i) aseptically adding said suspension vehicle to Brinzolamide slurry of step (e) to obtain a suspension; and

(j) homogenizing said suspension of step (i) under vacuum.

According to another aspect of the present invention there is provided a process for preparing sterile ophthalmic suspension, the process comprising the steps of:

(a) preparing an aqueous solution of Brinzolamide;

(b) aseptically filtering said Brinzolamide solution;

(c) adding a sterile surfactant to said Brinzolamide solution;

(d) precipitating Brinzolamide from said solution of step (c) to form a slurry comprising Brinzolamide and surfactant;

(e) ball milling or jet milling said slurry comprising Brinzolamide and surfactant;

(f) preparing a viscous polymer solution comprising an ophthalmically acceptable polymer;

(g) preparing an aqueous solution comprising tonicity agent and preservative;

(h) mixing said polymer solution of step (f) and said aqueous solution of step(g) to form suspension vehicle and autoclaving said suspension vehicle;

(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.

According to another aspect of the present invention there is provided a process for preparing sterile ophthalmic suspension, the process comprising the steps of:

(a) preparing an aqueous solution of Brinzolamide;

(b) adding a surfactant solution to said aqueous solution of Brinzolamide;

(c) aseptically filtering said Brinzolamide solution containing surfactant;

(d) precipitating Brinzolamide from the solution of step (c) to form a slurry comprising Brinzolamide and surfactant;

(e) ball milling or jet milling said slurry comprising Brinzolamide and surfactant;

(f) preparing a viscous polymer solution comprising an ophthalmically acceptable polymer;

(g) preparing an aqueous solution comprising a beta-blocker, tonicity agent and preservative;

(h) mixing said polymer solution of step (f) and said aqueous solution of step(g) to form suspension vehicle and autoclaving said suspension vehicle;

(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.

According to another aspect of the present invention there is provided a process for preparing sterile ophthalmic suspension, the process comprising the steps of:

(a) preparing an aqueous solution of Brinzolamide;

(b) aseptically filtering said Brinzolamide solution;

(c) adding a sterile surfactant to said Brinzolamide solution;

(d) precipitating Brinzolamide from the solution of step (c) to form a slurry comprising Brinzolamide and surfactant;

(e) ball milling or jet milling said slurry comprising Brinzolamide and surfactant;

(f) preparing a viscous solution comprising an ophthalmically acceptable polymer;

(g) preparing an aqueous solution comprising a beta-blocker, tonicity agent and preservative;

(h) mixing said polymer solution of step (f) and said aqueous solution of step(g) to form suspension vehicle and autoclaving said suspension vehicle;

(i) aseptically adding said suspension vehicle of step (h) to Brinzolamide slurry of step (e); and

(j) homogenizing said suspension of step (i) under vacuum.

Preferably, 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.

Preferably, 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.

According to yet another aspect of the present invention there is provided 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.

Additional aspects and/or advantages of the present invention will be evident from the description that follows.

Brief description of the drawings:

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. (Process I)

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).

Description of the invention:

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. However, 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.

According to one embodiment of the present invention there is provided a process for preparing sterile ophthalmic suspension, the process comprising the steps of:

(a) aseptically preparing a milled slurry comprising Brinzolamide and surfactant;

(b) preparing sterile suspension vehicle comprising polymer, tonicity agent and preservative;

(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.

According to a preferred embodiment said said process is characterized in that it does not involve autoclaving of the active ingredient Brinzolamide.

According to a more preferred embodiment there is provided a process for preparing sterile ophthalmic suspension, the process comprising the steps of:

(a) aseptically preparing a milled slurry comprising Brinzolamide and surfactant;

(b) preparing sterile suspension vehicle comprising polymer, tonicity agent and preservative;

(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;

wherein said process is characterized in that it does not involve autoclaving of the active ingredient Brinzolamide.

According to another embodiment of the present invention there is provided a process for preparing sterile ophthalmic suspension, the process comprising the steps of:

(a) preparing an aqueous solution of Brinzolamide;

(b) adding a surfactant solution to said aqueous solution of Brinzolamide;

(c) aseptically filtering said Brinzolamide solution containing surfactant;

(d) precipitating Brinzolamide from the solution of step (c) to form a slurry comprising Brinzolamide and surfactant;

(e) ball milling or jet milling said slurry comprising Brinzolamide and surfactant;

(f) preparing a viscous polymer solution comprising an ophthalmically acceptable polymer;

(g) preparing an aqueous solution comprising tonicity agent and preservative;

(h) mixing said polymer solution of step (f) and said aqueous solution of step (g) to form suspension vehicle and autoclaving said suspension vehicle;

(i) aseptically adding said suspension vehicle to Brinzolamide slurry of step (e) to obtain a suspension; and

(j) homogenizing said suspension of step (i) under vacuum.

According to a preferred embodiment, the invention provides a process for preparing Brinzolamide ophthalmic suspension comprising the steps of:

(a) preparing an aqueous solution of Brinzolamide;

(b) adding the solution of Tyloxapol^® into said Brinzolamide solution;

(c) aseptically filtering said Brinzolamide solution containing Tyloxapol^®; (d) precipitating Brinzolamide from the solution of step (c) to form a slurry comprising Brinzolamide and Tyloxapol^®;

(e) ball milling or jet milling of Brinzolamide slurry and Tyloxapol^®;

(f) preparing a viscous solution comprising Carbopol^® 974 P;

(g) preparing an aqueous solution comprising mannitol, sodium chloride, Edetate disodium and benzalkonium chloride;

(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;

(i) aseptically adding the suspension vehicle to Brinzolamide slurry of step (e) to obtain a suspension; and

(j) homogemzing said suspension of step (i) under vacuum to get the bulk sample.

According to another embodiment of the present invention there is provided a process for preparing sterile ophthalmic suspension, the process comprising the steps of:

(a) preparing an aqueous solution of Brinzolamide;

(b) aseptically filtering said Brinzolamide solution;

(c) adding a sterile surfactant to said Brinzolamide solution;

(d) precipitating Brinzolamide from said solution of step (c) to form a slurry comprising Brinzolamide and surfactant;

(e) ball milling or jet milling said slurry comprising Brinzolamide and surfactant;

(f) preparing a viscous polymer solution comprising an ophthalmically acceptable polymer;

(g) preparing an aqueous solution comprising tonicity agent and preservative;

(h) mixing said polymer solution of step (f) and said aqueous solution of step(g) to form suspension vehicle and autoclaving said suspension vehicle;

(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.

According to another preferred embodiment, the invention provides a process for preparing Brinzolamide ophthalmic suspension comprising the steps of:

(a) preparing an aqueous solution of Brinzolamide;

(b) aseptically filtering said Brinzolamide solution;

(c) adding a sterile solution of Tyloxapol^® into said Brinzolamide solution ;

(d) precipitating Brinzolamide from said solution of step (c) to form a slurry comprising Brinzolamide and Tyloxapol^® ;

(e) ball milling or jet milling said slurry comprising Brinzolamide and Tyloxapol®;

(f) preparing a viscous solution comprising Carbopol^® 974 P;

(g) preparing an aqueous solution comprising mannitol, sodium chloride, Edetate disodium and benzalkonium chloride;

(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;

(i) aseptically adding the 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 to get the bulk sample.

According to a preferred embodiment, the invention provides a process for preparing Brinzolamide ophthalmic suspension comprising the steps of:

(a) preparing an aqueous solution of Brinzolamide;

(b) adding the solution of Tyloxapol^® into said Brinzolamide solution;

(c) aseptically filtering said Brinzolamide solution containing Tyloxapol^®; (d) precipitating Brinzolamide from the solution of step (c) to form a slurry comprising Brinzolamide and Tyloxapol^®;

(e) ball milling or jet milling of Brinzolamide slurry and Tyloxapol^®;

(f) preparing a viscous solution comprising Carbopol^® 974 P;

(g) preparing an aqueous solution comprising a beta blocker such as timolol or betaxolol; mannitol, sodium chloride, Edetate disodium and benzalkonium chloride;

(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;

(i) aseptically adding the suspension vehicle to Brinzolamide slurry of step (e) to obtain a suspension; and

(j) homogenizing said suspension of step (i) under vacuum to get the bulk sample.

According to one embodiment, 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.

According to one embodiment, 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.

Preferably, 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. According to another embodiment of the present invention there is provided a process for preparing sterile ophthalmic suspension, the process comprising the steps of:

(a) preparing an aqueous solution of Brinzolamide;

(b) adding a surfactant solution to said aqueous solution of Brinzolamide;

(c) aseptically filtering said Brinzolamide solution containing surfactant;

(d) precipitating Brinzolamide from the solution of step (c) to form a slurry comprising Brinzolamide and surfactant;

(e) ball milling or jet milling said slurry comprising Brinzolamide and surfactant;

(f) preparing a viscous polymer solution comprising an ophthalmically acceptable polymer;

(g) preparing an aqueous solution comprising a beta-blocker, tonicity agent and preservative;

(h) mixing said polymer solution of step (f) and said aqueous solution of step(g) to form suspension vehicle and autoclaving said suspension vehicle;

(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.

According to another embodiment of the present invention there is provided a process for preparing sterile ophthalmic suspension, the process comprising the steps of:

(a) preparing an aqueous solution of Brinzolamide;

(b) aseptically filtering said Brinzolamide solution;

(c) adding a sterile surfactant to said Brinzolamide solution;

(d) precipitating Brinzolamide from the solution of step (c) to form a slurry comprising Brinzolamide and surfactant;

(e) ball milling or jet milling said slurry comprising Brinzolamide and surfactant;

(f) preparing a viscous solution comprising an ophthalmically acceptable polymer;

(g) preparing an aqueous solution comprising a beta-blocker, tonicity agent and preservative;

(h) mixing said polymer solution of step (f) and said aqueous solution of step(g) to form suspension vehicle and autoclaving said suspension vehicle;

(i) aseptically adding said suspension vehicle of step (h) to Brinzolamide slurry of step (e); and

(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.

The process for preparation of Brinzolamide ophthalmic suspension developed by the inventors of the present invention has the following advantages:

(1) The process as disclosed herein does not require the use of any specific equipments such as milling bottle.

(2) In the present process of preparation of ophthalmic suspension, the active ingredient Brinzolamide is not subjected to heat.

(3) The process as disclosed herein is less time consuming than the prior art processes.

(4) The process as disclosed herein is simple and feasible.

(5) The cold process of sterilization of active ingredient Brinzolamide prevents the generation of undue impurities in the formulation.

According to one embodiment of the present invention there is provided 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.

According to a preferred embodiment, 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.

In the practice of the present invention 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.

Examples of polymers that may be used according to the invention 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%.

Examples of preservatives that may be used according to the invention 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%.

Examples of surfactants that may be used according to the invention 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)

Examples of tonicity agents that may be used according to the invention 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%.

In the practice of the present invention, the 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.

Autoclaving of the suspension vehicle may be done using any conventional steam sterilizer dedicated for ophthalmic preparations.

In the practice of the present invention, 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.

In one embodiment of the present invention, Brinzolamide API used in the preparation of pharmaceutical composition can be obtained by the process comprising the steps of,

a) subjecting 3-bromoacetyl-5-chloro-2-thiophenesulfonamide to asymmetric reduction in a polar aprotic solvent such as diethyl ether, tetrahydrofuran or t-butyl methyl ether to provide (S)-bromohydrin and then treating the obtained (S)-bromohydrin with an aqueous base to form (S)-3,4-dihydro- 6-chloro-4-hydroxy-2H-thieno[3,2-e]- 1 ,2-thiazine- 1 , 1 -dioxide;

b) alkylating compound of step a) using 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;

c) reacting (S)-3,4-dihydro-6-chloro-4-hydroxy-2-(3-methoxypropyl)-2H- thieno[3,2-e]-l,2-thiazine-l,l-dioxide with alkyl lithium, then reacting the resultant anion with sulfur dioxide to form lithium sulfinate, and then reacting the lithium sulfinate with hydroxylamine-O-sulfonic acid to form (S)-3,4-dihydro-4-hydroxy-2-(3-methoxypropyl)-2H-thieno[3,2-e]-l,2- thiazine-6-sulfonamide- 1 , 1 -dioxide; and

d) converting (S)-3,4-dihydro-4-hydroxy-2-(3-methoxypropyl)-2H- thieno[3,2-e]-l,2-thiazine-6-sulfonamide-l,l-dioxide to Brinzolamide.

In a preferred embodiment, 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,

a) activation of C-4 hydroxyl group of (S)-3,4-dihydro-4-hydroxy-2-(3- methoxypropyl)-2H-thieno[3,2-e]- 1 ,2-thiazine-6-sulfonamide- 1 , 1 -dioxide with an activated sulfonic acid derivative preferably p- toluenesulfonyl chloride or methanesulfonyl chloride in the presence of a base preferably triethylamine and polar aprotic solvent preferably tetrahydrofuran; and b) displacement of the activated hydroxyl group using ethylamine to provide Brinzolamide.

The features of the present invention can be extended to other therapeutic categories of drugs such as non-steroidal anti-inflammatory drug (NSAID), e.g. Nepafenac and the like.

According to one embodiment, the invention provides a process for preparing Nepafenac ophthalmic suspension comprising the steps of:

(a) preparing a milled slurry of Nepafenac and surfactant;

(b) preparing sterile suspension vehicle comprising polymer, tonicity agent and preservative;

(c) adding the milled slurry to the suspension vehicle and homogenizing it to get Nepafenac Ophthalmic suspension.

According to one embodiment, the invention provides a process for preparing Nepafenac ophthalmic suspension comprising the steps of:

(a) aseptically preparing a milled slurry of Nepafenac and surfactant;

(b) preparing sterile suspension vehicle comprising polymer, tonicity agent and preservative;

(c) adding the milled slurry to the suspension vehicle and homogenizing it to get Nepafenac Ophthalmic suspension;

wherein said process is characterized in that it does not involve the autoclaving of the active ingredient Nepafenac.

As used herein, the term "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.

As used herein, 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.

As used herein, the term "excipient" refers to a pharmaceutically acceptable ingredients that are commonly used in the pharmaceutical technology for preparing ophthalmic preparations.

The present invention is further illustrated by reference to the following examples which is for illustrative purpose only and does not limit the scope of the invention in any way.

Examples:

Example 1

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 0.22μ 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.

Example 2

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 0.22μ 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.

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 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.

Example 3

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 0.22μ 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.

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 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.

Example 4

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 0.22μ 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.

Step II: Preparation of suspension vehicle:

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.

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.

Example 5

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 0.22μ 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.

It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative examples and that the present invention may be embodied in other specific forms without departing from the essential attributes thereof, and it is therefore desired that the present embodiments and examples be considered in all respects as illustrative and not restrictive, reference being made to the appended claims, rather than to the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.

Claims

We claim,

1. A process for preparing sterile ophthalmic suspension, the process comprising the steps of:

(a) aseptically preparing a milled slurry comprising Brinzolamide and surfactant;

(b) preparing sterile suspension vehicle comprising polymer, tonicity agent and preservative;

(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.

2. The process as claimed in claim 1, wherein said process is characterized in that it does not involve autoclaving of the active ingredient Brinzolamide.

3. A process for preparing sterile ophthalmic suspension, the process comprising the steps of:

(a) preparing an aqueous solution of Brinzolamide;

(b) adding a surfactant solution to said aqueous solution of Brinzolamide;

(c) aseptically filtering said Brinzolamide solution containing surfactant;

(d) precipitating Brinzolamide from the solution of step (c) to form a slurry comprising Brinzolamide and surfactant;

(e) ball milling or jet milling said slurry comprising Brinzolamide and surfactant;

(f) preparing a viscous polymer solution comprising an ophthalmically acceptable polymer;

(g) preparing an aqueous solution comprising tonicity agent and preservative;

(h) mixing said polymer solution of step (f) and said aqueous solution of step (g) to form suspension vehicle and autoclaving said suspension vehicle;

(i) aseptically adding said suspension vehicle to Brinzolamide slurry of step (e) to obtain a suspension; and

(j) homogenizing said suspension of step (i) under vacuum.

4. A process for preparing sterile ophthalmic suspension, the process comprising the steps of:

(a) preparing an aqueous solution of Brinzolamide;

(b) aseptically filtering said Brinzolamide solution;

(c) adding a sterile surfactant to said Brinzolamide solution;

(d) precipitating Brinzolamide from said solution of step (c) to form a slurry comprising Brinzolamide and surfactant;

(e) ball milling or jet milling said slurry comprising Brinzolamide and surfactant;

(f) preparing a viscous polymer solution comprising an ophthalmically acceptable polymer;

(g) preparing an aqueous solution comprising tonicity agent and preservative;

(h) mixing said polymer solution of step (f) and said aqueous solution of step(g) to form suspension vehicle and autoclaving said suspension vehicle;

(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.

5. A process for preparing sterile ophthalmic suspension, the process comprising the steps of:

(a) preparing an aqueous solution of Brinzolamide;

(b) adding a surfactant solution to said aqueous solution of Brinzolamide;

(c) aseptically filtering said Brinzolamide solution containing surfactant; (d) precipitating Brinzolamide from the solution of step (c) to form a slurry comprising Brinzolamide and surfactant;

(e) ball milling or jet milling said slurry comprising Brinzolamide and surfactant;

(f) preparing a viscous polymer solution comprising an ophthalmically acceptable polymer;

(g) preparing an aqueous solution comprising a beta-blocker, tonicity agent and preservative;

(h) mixing said polymer solution of step (f) and said aqueous solution of step(g) to form suspension vehicle and autoclaving said suspension vehicle;

(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.

6. A process for preparing sterile ophthalmic suspension, the process comprising the steps of:

(a) preparing an aqueous solution of Brinzolamide;

(b) aseptically filtering said Brinzolamide solution;

(c) adding a sterile surfactant to said Brinzolamide solution;

(d) precipitating Brinzolamide from the solution of step (c) to form a slurry comprising Brinzolamide and surfactant;

(e) ball milling or jet milling said slurry comprising Brinzolamide and surfactant;

(f) preparing a viscous solution comprising an ophthalmically acceptable polymer;

(g) preparing an aqueous solution comprising a beta-blocker, tonicity agent and preservative;

(h) mixing said polymer solution of step (f) and said aqueous solution of step(g) to form suspension vehicle and autoclaving said suspension vehicle;

(i) aseptically adding said suspension vehicle of step (h) to Brinzolamide slurry of step (e); and

(j) homogenizing said suspension of step (i) under vacuum.

7. The process as claimed in claim 3, 4, 5 or 6, wherein 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.

8. The process as claimed in claim 3, 4, 5 or 6, wherein said aseptic filtration is carried out using Polyethersulphone or Polyvinylidene Fluoride filters having pore size of about 0.22 microns.

9. The process as claimed in claim 5 or claim 6, wherein said beta-blocker is selected from timolol or betaxolol.

10. The process as claimed in claim 3, 4, 5 or 6, wherein said surfactant is selected from the group consisting of Tyloxapol®, Triton X-100®, polysorbates, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 40 stearates, sorbitan monolaureates, poloxamer and mixture thereof and may be used in amount from 0.001% to 15 %; preferably 0.01% to 0.5%.

11. The process as claimed in claim 3, 4, 5 or 6, wherein the polymer is selected from the group consisting of Carbopol®, povidone, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose and mixture thereof and may be used in amount from 0.1% to 5.0%; preferably 0.3% to 1.0%.

12. The process as claimed in claim 3, 4, 5 or 6, wherein said preservative is selected from the group consisting of 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 mixture thereof and may be used in an amount from 0.001% to 0.5%; preferably 0.005% to 0.05%.

13. The process as claimed in claim 3, 4, 5 or 6, wherein said tonicity agent is selected from the group consisting of mannitol, dextrose, glycerin, potassium chloride, sodium chloride and mixture thereof and may be used in an amount from 1% to 5%.

14. The process as claimed in claim 3, 4, 5 or 6, wherein 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.

15. A sterile ophthalmic suspension prepared by the process as claimed in any of the preceeding claims comprising Brinzolamide in an amount from 0.001% to 5.0% by weight, surfactant and optionally a beta-blocker.