FORM-2
THE PATENTS ACT, 1970
(39 OF 1970)
&
The Patent Rules, 2003
COMPLETE SPECIFICATION
Sec 10-Rule 13
"A Stable Aqueous Suspension of Loteprednol Etabonate."
INDOCO REMEDIES LIMITED
Indian
R-92-93, T.T.C Industrial Area, Thane Belapur Road, Rabale MIDC
Navi Mumbai - 400701
The following specification describes the invention

Technical Field:
The present invention relates to a stable aqueous suspension of Loteprednol etabonate. Particularly, the present invention relates to an aqueous suspension of Loteprednol etabonate using acetate buffer system to prevent pH drift under storage condition. The present invention further relates to method of preparing an aqueous suspension of Loteprednol etabonate.
Background & Prior Art:
Loteprednol etabonate is a white to off-white powder. The empirical formula is C24H31CIO7. Its molecular weight is 466.96 and its chemical structure is represented below.

Chemical Name: Chloromethyl 17a-[(ethoxycarbonyl)oxy]-lip-hydroxy-3-oxoandrosta-1,4-diene-l 7p-carboxylate.
Loteprednol etabonate is structurally similar to other corticosteroids. However, the number 20 position ketone group is absent. It is highly lipid soluble which enhances its penetration into cells. Loteprednol etabonate is synthesized through structural modifications of prednisolone related compounds so that it will undergo a predictable transformation to an inactive metabolite.

Loteprednol is indicated for the treatment of steroid responsive inflammatory conditions of the palpebral and bulbar conjunctiva, cornea and anterior segment of the globe such as allergic conjunctivitis, acne rosacea, superficial punctuate keratitis, herpes zoster keratitis, iritis, cyclitis, selected infective conjuctivitides, when the inherent hazard of steroid use is accepted to obtain an advisable diminution in edema and inflammation. It is also indicated for the treatment of post-operative inflammation following ocular surgery.
US 4996335 and US 4710495 disclose Loteprednol etabonate as a known soft corticosteroid based on the known inactive metabolite prednisolone acetate of the active drug prednisolone.
US 5916550 discloses therapeutic suspension of Loteprednol etabonate using aliphatic amino acid containing 2-7 carbon atoms to prevent pH depression even on prolonged
storage.
CN 101416940 discloses ophthalmic sterile suspension prepared by adopting different sterilization methods for Loteprednol etabonate and the other components. Apart from the components, the ophthalmic sterile suspension also contains 0.3 percent of
tobramycin.
US 5747061 discloses a composition comprising a) Loteprednol, b) a nonionic polymer in aqueous medium, c) a nonionic tonicity agent and d) a non ionic surface active agent along with preservative.
A major cause of non-compliance of patients to ophthalmic preparations is the discomfort associated with instilling them into the eye. Discomfort in the form of irritation or pain may be caused due to various reasons, which includes compositions having unfavorable osmotic pressure or pH or due to formulations containing an irritating component, which could be the drug, preservative, surfactant or any other excipient that may be used as a carrier.

Major problems related to ophthalmic composition are crystallization and agglomeration of active ingredients during preparation as well as during storage. Agglomeration of active leads to non-uniformity of dose, difficulty of administration, irritation to eye due to large drug particles and/or any ocular adverse effect due to high drug concentration or failure of treatment due to low drug concentration.
One of the reasons for agglomeration of active ingredient could be change in pH of composition. This may lead to problems related to redispersibility of suspension. Generally ophthalmic preparations are prepared in the pH range of 4.0 to 7.5. The pH value is generally targeted to provide a specific level or range which provides the least amount of discomfort to the end user. Below pH 4.0, the suspension is too acidic and could cause stinging sensation. Marketed products of Loteprednol etabonate shows drift in pH over a period of time.
In the light of the prior art and problem of pH drift during prolonged storage, the inventors of the present invention seek to provide a stable aqueous suspension of Loteprednol etabonate wherein a stable pH is maintained with use of suitable amounts of buffering agents,
Object of the Invention:
The main object of the present invention is to provide a stable aqueous suspension comprising of Loteprednol etabonate, acetate buffer system to prevent pH drift under storage conditions along with pharmaceutically acceptable ingredients.
Another object of the present invention is to provide a stable aqueous suspension of Loteprednol etabonate, which is devoid of agglomeration throughout shelf-life and is readily re-dispersed into a uniform composition.
Yet another object of the present invention is to provide an aqueous suspension of Loteprednol etabonate with stable pH throughout the shelf life.

Yet another object of the present invention is to provide a process or method of preparing an aqueous suspension of Loteprednol etabonate.
Further object of the present invention is to provide an aqueous suspension of Loteprednol etabonate for treatment of ophthalmic and otorhinolaryngological inflammation.
Still further the object of the present invention is to provide an aqueous suspension of Loteprednol etabonate for topical administration.
Summary of the Invention:
The present invention relates to a stable aqueous suspension comprising of Loteprednol etabonate, acetate buffer solution pH 5.5 and pharmaceutically acceptable excipients, to prevent pH drift under storage condition.
The present invention provides a method for preparation of aqueous suspension
comprises of-
i) Preparation of acetate buffer solution pH 5.5 USP.
ii) Inactive Phase: Dissolve at least one preservative, at least one chelating agent, at
least one tonicity agent and at least one water soluble polymer in said buffer
solution to get a clear solution. iii) Adjust the pH of the said solution using base or acid. iv) Active Phase: Prepare surfactant solution and disperse pre-sterilized Loteprednol
etabonate in said surfactant solution. v) Add active phase to inactive phase under stirring and make up the volume of
suspension.

Description of the Present Invention:
The present invention relates to an ophthalmic composition of Loteprednol etabonate. Particularly, the present invention relates to an aqueous suspension comprising of Loteprednol etabonate, acetate buffer system to prevent pH drift under storage conditions along with pharmaceutically acceptable ingredients.
The present invention also relates to a process or method of preparing an aqueous suspension of Loteprednol etabonate.
In a preferred aspect an aqueous suspension of Loteprednol etabonate is prepared by
following process:
i) Preparation of acetate buffer solution pH 5.5 USP.
ii) Inactive Phase: Dissolve at least one preservative, at least one chelating agent, at
least one tonicity agent and at least one water soluble polymer in said buffer
solution to get a clear solution. iii) Adjust the pH of the said solution using base or acid. iv) Active Phase: Prepare surfactant solution and disperse pre-sterilized Loteprednol
etabonate in said surfactant solution. v) Add active phase to inactive phase under stirring and make up the volume of
suspension.
In accordance with the present invention, an aqueous suspension comprising of Loteprednol etabonate and one or more of surfactants, tonicity agents, buffers, chelating agents, preservatives, water soluble polymers and pH adjusting agents.
Surfactant used in the present invention may be selected from group comprising of polysorbate 80, polysorbate 20, tyloxapol, tween 80, poloxamer, ethoxylated alcohol, propoxylated alcohol and combinations thereof.

Water soluble polymer used in the present invention may be selected from group comprising of polyvinyl pyrrolidone (PVP), polyvinyl alcohol, dextran, cyclodextrins and combinations thereof.
Preservative used in the present invention may be selected from group comprising of benzalkonium chloride, benzyl alcohol, methyl paraben, propyl paraben, thimerosal, chlorobutanol, benzethonium chloride and combinations thereof.
Tonicity agent used in the present invention may be selected from group comprising of mannitol, glycerol, sodium chloride, phosphate buffer and combinations therof.
Buffer used in the present invention may be selected from group comprising of acetic acid, adipic acid, ammonium carbonate, ammonium phosphate, boric acid, citric acid anhydrous, citric acid monohydrate, lactic acid, phosphoric acid, potassium citrate, potassium metaphosphate, potassium phosphate, dibasic potassium phosphate, monobasic sodium acetate, sodium citrate, sodium lactate solution, sodium phosphate, dibasic sodium phosphate, monobasic succinic acid and combinations thereof, preferably sodium acetate and glacial acetic acid.
Disodium edetate is used as chelating agent.
Sodium hydroxide (NaOH) or Hydrochloric acid (HC1) is used as pH adjusting agent.
The particle size of Loteprednol etabonate used is preferably with d (90) 1-10 urn measured by laser diffraction.
Preferred aspect of the present invention is to provide a stable aqueous suspension of Loteprednol etabonate using acetate buffer system, which does not undergo change in pH on long term storage.
In accordance with the present invention, the stable aqueous suspension comprises of 6.25 % to 50 % of acetate buffer solution pH 5.5 USP.

Another aspect of the present invention to provide a stable aqueous suspension of Loteprednol etabonate produced over a varying range of pH values. A pH of about 4.5-7.4 is useful for preparing the stable suspension of Loteprednol etabonate.
Although the invention has been described with reference to specific embodiments, this description is not meant to be construed in a limiting sense. Various modifications of the disclosed embodiments, as well as alternate embodiments of the invention, will become apparent to person skilled in the art upon reference to the description. It is therefore contemplated that such modifications can be made without departing from the spirit or scope of the present invention as defined.
The invention is further exemplified with following examples and is not intended to limit the scope of the invention.

Example %w/w

A B C D E
Loteprednol Etabonate 0.5 0.5 0.5 0.5 0.5
Disodium Edetate 0.01 0.01 0.01 0.01 0.01
Glycerin 2.4 2.1 1.9 1.7 2.4
Benzalkonium Chloride 0.01 0.01 0.01 0.01 0.01
Povidone (Plasdone C-30) 0.6 0.6 0.6 0.6 0.6
Tyloxapol 0.3 0.3 0.3 0.3 0.3
Acetate Buffer Solution pH
5.5 (USP) 6.25 12.5 37.5 50 —
Sodium Hydroxide qs qs qs qs qs
Manufacturing Process:
A) Preparation of Buffer Phase:
1. Dissolve sodium acetate and glacial acetic acid in water to prepare acetate buffer solution of pH 5.5 as per USP.

B) PART -1: Inactive Phase
2. Dissolve disodium EDTA, glycerin, plasdone C-30, benzalkonium chloride in buffer phase to get a clear solution.
3. Adjust the pH of above solution between pH 5,5 to 5.6 using sodium hydroxide solution.
4. Filter the step (3) solution through 0.22μ. filter.
C) PART - II: Active Phase
5. Dissolve tyloxapol in water for injection and filter it through 0.22μ filter.
6. Disperse pre-sterilized Loteprednol etabonate in tyloxapol solution.
D) PART - III: Mixing of Inactive Phase and Active Phase
7. Add Active phase to Inactive phase under stirring.
8. Make up the volume of suspension up to required quantity with water for injection.
Ophthalmic suspensions of Loteprednol etabonate with various concentrations of acetate buffer and without buffer were dispensed in white opaque polyethylene and stored at 40°C/25% RH for 6 months. The pH and particle size of Loteprednol etabonate were evaluated and determined. The results for pH and particle size are presented in table:

Sr.
No. Example Parameter Initial 40C/25% PvH 1M 40C/25% RH 2M 40C/25% RH 3M 40C/25% RH 6M
1 A pH 5.58 5.54 5.36 5.28 5.25

Particle Size d(90) <15μm <15μm < 15μm <15μm <15μm
2 B pH 5.54 5.40 5.37 5.37 5.15

Particle Size d(90) <15μm <15μm <15μm <15μm < 15μm
3 C pH 5.51 5.41 5.35 5.30 5.28

Particle Size d (90) <15μm <15μm <15μm <15μm <15μm
4 D pH 5.56 5.63 5.51 5.40 5.45

Particle Size d (90) <15μm <15μm <15μm <15μm <15μm
5 E. pH 5.60 4.58 4.35 3.92 3.51

Particle Size d (90) <15μm <15μm <15μm <15μm <15μm

We claim:
1. A stable aqueous suspension comprising of Loteprednol etabonate, acetate buffer solution and pharmaceutically acceptable excipients.
2. A stable aqueous suspension of claim 1, wherein the acetate buffer solution comprises of sodium acetate and glacial acetic acid.
3. A stable aqueous suspension of claim 1, wherein the acetate buffer solution is present in an amount of 6.25% to 50%.
4. A stable aqueous suspension of claim 1, wherein the pH of acetate buffer solution is 5.5.
5. A method for preparation of aqueous suspension comprises of
i) Preparation of acetate buffer solution pH 5.5 USP;
ii) Inactive Phase: Dissolve at least one preservative, at least one chelating agent, at
least one tonicity agent and at least one water soluble polymer in said buffer
solution to get a clear solution; iii) Adjust the pH of the said solution using base or acid; iv) Active Phase: Prepare surfactant solution and disperse pre-sterilized
Loteprednol etabonate in said surfactant solution; v) Add active phase to inactive phase under stirring and make up the volume of
suspension.
6. A stable aqueous suspension of claim 1, wherein said pharmaceutically acceptable excipients are selected from group comprising of tonicity agents, preservatives, chelating agents, water soluble polymers, surfactants, buffering agents and combinations thereof.
7. A stable aqueous suspension of claim 1, wherein tonicity agent is selected from group comprising of mannitol, glycerol, sodium chloride, phosphate buffer and combinations thereof.
8. A stable aqueous suspension of claim 1, wherein preservative is selected from group comprising of benzalkonium chloride, benzyl alcohol, methyl paraben,

propyl paraben, thimerosal, chlorobutanol, benzethonium chloride and combinations thereof.
9. A stable aqueous suspension of claim 1, wherein surfactant is selected from group comprising of polysorbate 80, polysorbate 20, tyloxapol, poloxamer, ethoxylated alcohol, propoxylated alcohol and combinations thereof.
10. A stable aqueous suspension of claim 1, wherein water soluble polymer is selected from group comprising of polyvinyl pyrrolidone (PVP), polyvinyl alcohol, dextran, cyclodextrin and combinations thereof.