BACKGROUND OF THE INVENTION

Sterility is one of main criteria for ophthalmic compositions. If the ophthalmic compositions are in the form of eye drops solutions the filtration sterilization is preferred method of sterilization. However if the ophthalmic compositions are in the form of ophthalmic suspensions then filtration sterilization can not be used hence the alternate ways for sterilizing ophthalmic suspensions can be: by bulk sterilization of a milled suspension, by aseptic addition of sterile micronized raw material into a sterile vehicle, or by aseptic addition of a sterile raw material to a sterile menstruum followed by ball milling and aseptic addition of the sterile concentrate into a sterile vehicle.

The US patent No. 6,071,904 discloses that the suspensions, containing a brinzolamide sterilized using autoclaving as brinzolamide gets solubilized at autoclaving temperatures and form large needle-like crystals upon cooling of the final formulation. Also other option, ball milling of this final formulation is not practically feasible. Aseptic addition of the brinzolamide to a sterile vehicle is also not practical, as the brinzolamide cannot be sterilized by conventional means. Dry heat sterilization causes melting of the material. Further sterilization of the brinzolamide by ethylene oxide introduces unacceptable degradation products and residues, and sterilization by gamma irradiation of micronized material produces degradation products unacceptable for regulatory filing.

However present inventors have surprisingly found against the teachings of prior art that ethylene oxide (EtO) sterilization gives stable brinzolamide suspension with acceptable impurity profile and do not increase impurities. Thus present invention provides a process for preparing a stable brinzolamide suspension on a manufacturing scale with acceptable impurity levels using EtO sterilization.

SUMMARY OF THE INVENTION:

The present invention is directed to brinzolamide ophthalmic suspension, processes for making them, process of sterilizing ophthalmic suspension containing brinzolamide.

DETAILED DESCRIPTION OF THE INVENTION:

The term "brinzolamide" as used in the invention is meant to cover brinzolamide in the form of freebase or its pharmaceutically acceptable salt(s), hydrate(s), solvate(s) thereof. The term also includes all polymorphic forms, whether crystalline or amorphous.

The ophthalmic suspension of present invention comprises one or more following ingredients.

Examples of buffering agents include but are not limited to phosphate, borate, citrate, acetate, carbonate, borate-polyol complexes, boric acid and the like.
Examples of preservatives include but are not limited to benzalkonium chloride, benzethonium chloride and other quaternary amines and the like, p- oxybenzoates such as methyl p-oxybenzoate or ethyl p-oxybenzoate, benzyl alcohol, phenethyl alcohol, chlorobutanol, sorbic acid or its salt, thimerosal, chlorhexidine gluconate and the like.

Examples of tonicity-adjusting agents include but are not limited to mannitol, xylitol, sodium chloride and the like.

Examples of antioxidants include, but are not limited to ascorbic acid, malic acid, citric acid, sodium citrate, butylated hydroxyanisole, butylated hydroxytoluene, propyl gallate, sodium ascorbate, sodium metabisulfite and the like and mixtures thereof.

Examples of the alkaline agents that may be used as pH adjusting agents, include, but are not limited to sodium hydroxide (NaOH), potassium hydroxide (KOH), sodium bicarbonate (NaHCO3) tromethamine, monoethanolamine and other organic and inorganic bases.

Examples of the acidic agents that may be used as pH adjusting agents include, but are not limited to hydrochloric acid, citric acid, tartaric acid, lactic acid and other organic and mineral acids and the like and mixtures thereof.

Examples of chelating agents include but are not limited to EDTA, sodium edetate, sodium citrate, condensed sodium phosphate and the like.

The various embodiments of the present invention can be assembled in several different ways.

In one embodiment, the present invention provides a process of sterilization of ophthalmic suspension comprising brinzolamide using ethylene oxide.

In yet another embodiment the present invention provides a process of sterilization of ophthalmic suspension comprising brinzolamide using ethylene oxide wherein the impurity levels of brinzolamide are below 1%.

In yet another embodiment the present invention provides a process for preparing a stable brinzolamide suspension wherein the process comprises step of ethylene oxide sterilization of brinzolamide and aseptic addition of the brinzolamide to a sterile vehicle.

In yet another embodiment the present invention provides a process for preparing a stable brinzolamide suspension wherein the micronized brinzolamide API is taken and sterilized using ethylene oxide at a concentration and for a time sufficient to achieve sterility; and this brinzolamide is further used in preparing stable brinzolamide suspension with aseptic addition of the brinzolamide to a sterile vehicle.

In yet another embodiment the present invention provides a process for preparing stable brinzolamide suspension comprising the steps of:

a) sterilizing a micronized brinzolamide, with ethylene oxide (EtO) at a concentration and for a time sufficient to achieve sterility;
b) preparing suspension of EtO sterilized brinzolamide under aseptic condition;
c) transferring brinzolamide suspension under aseptic conditions into sterilized LDPE container.

In yet another embodiment the present invention provides a process for preparing stable brinzolamide suspension wherein the process comprises step of ethylene oxide sterilization of brinzolamide and aseptic addition of the brinzolamide to a sterile vehicle and filling into LDPE containers.

In yet another embodiment the present invention provides a process for preparing stable brinzolamide suspension wherein the process comprises step of ethylene oxide sterilization of brinzolamide wherein the process do not comprise step of autoclaving and aseptic ball milling of the suspension.

In yet another embodiment the present invention provides a process for preparing stable brinzolamide suspension wherein the process comprises step of ethylene oxide sterilization of micronized brinzolamide and aseptic addition of the brinzolamide to a sterile vehicle and filling into LDPE containers.

The invention will be further illustrated by the following examples, which are intended to be illustrative but not limiting.

Example No. 1
Table No. 1

Manufacturing process:
A formulation as shown in table 1 was prepared as follows:

A) In a clean beaker (50°C to 70°C) some quantity of water for injection was taken and tyloxapol was added, dissolved and resulting solution was filtered through 0.22u PVDF membrane filter. Ethylene oxide sterilized micronized brinzolamide was added to this solution and was homogenized for 2-3 hours.

B) In another beaker (50°C to 70°C), some quantity of water for injection was taken to which carbomer 974P was added, dissolved and the resulting solution was autoclaved for121°C for 30 min.

C) In another beaker remaining quantity of water for injection was taken to this EDTA, Mannitol, NaCI and BKC one by one added and dissolved with continuous stirring until clear solution is obtained and this solution was further filtered through 0.22u PVDF membrane filter.

D) The solution of step B and C were mixed and the pH was adjusted to 7.5 using
NaOH.

E) The suspension of step A was added to solution of step D and pH was adjusted to 7.5 using NaOH and volume was adjusted using water for injection.

Using the formula of Table No. 1 different batches were manufactured using Gamma sterilized brinzolamide or Ethylene oxide sterilized brinzolamide or non-sterile brinzolamide. The obtained formulations were filled in suitable containers and were kept on stability at different stability conditions. The formulations were subjected to for impurities and related substances analysis. Also the Gamma sterilized brinzolamide API or Ethylene oxide sterilized brinzolamide API or non sterile brinzolamide API was also analyzed for impurities and related substances. All the results obtained are presented in Table No. 2.

The formulation was further subjected to stability studies at 40°C/NMT25%RH, was analyzed at an intervals of 1M, 2M, 3M & 6M and at 25°C/40%RH, was analyzed at an intervals of 3M and 6M, the results obtained are presented in Table No. 3.

Table No. 2
ND: Not Detected.

Table No. 3

WE CLAIM :

1. A process of sterilization of ophthalmic suspension comprising Brinzolamide using ethylene oxide.

2. A process according to claim 1, wherein the impurity levels of Brinzolamide are below 1%.

3. A process according to claim 1, wherein the ophthalmic suspension is filled in LDPE container.

4. A process for preparing stable Brinzolamide suspension comprising the steps of:

a) sterilizing a micronized Brinzolamide, with ethylene oxide (EtO) at a concentration and for a time sufficient to achieve sterility;
b) preparing suspension of EtO sterilized Brinzolamide under aseptic condition.
c) transferring Brinzolamide suspension under aseptic conditions into sterilized LDPE container.

5. A process according to claim 4, wherein the impurity levels of Brinzolamide are below 1%.

6. A process for preparing stable brinzolamide suspension wherein the process comprises step of ethylene oxide sterilization of brinzolamide wherein the process do not comprise step of autoclaving and aseptic ball milling of the suspension.

7. A process according to claim 6, wherein the impurity levels of Brinzolamide are below 1%.