WO2013179253A1

WO2013179253A1 - Dose combination comprising nsaid and steroidal anti-inflammatory agent for treating post operative ocular inflammation

Info

Publication number: WO2013179253A1
Application number: PCT/IB2013/054468
Authority: WO
Inventors: Shivanand Dhanure; Rajesh Kshirsagar
Original assignee: Micro Labs Limited
Priority date: 2012-06-02
Filing date: 2013-05-30
Publication date: 2013-12-05
Also published as: WO2013179253A8

Abstract

The present invention relates to use of fixed dose combination comprising Ketorolac or its pharmaceutically acceptable salts thereof and Difluprednate for the treatment of post operative ocular inflammation. The present invention further relates to a pharmaceutical composition comprising fixed dose combination comprising Ketorolac or its pharmaceutically acceptable salts thereof and Difluprednate for the treatment of post operative ocular inflammation.

Description

DOSE COMBINATION COMPRISING NSAID AND STEROIDAL ANTI¬

INFLAMMATORY AGENT FOR TREATING POST OPERATIVE OCULAR

INFLAMMATION

FIELD OF THE INVENTION

The present invention relates to a fixed dose combination comprising one or more NSAIDs and one or more steroidal anti-inflammatory agents for the treatment of post operative ocular inflammation.

BACKGROUND OF THE INVENTION

In ocular tissue, arachidonic acid is metabolized by cyclooxygenase (COX) to prostaglandins which are the most important lipid-derived mediators of inflammation. Ocular inflammation is characterized by redness, swelling, and/or pain associated with irritation or trauma to the eye. Surgical trauma causes a trigger of the arachidonic acid cascade which in turn generates prostaglandins (PG) by activation of COX-1 and COX-2. Phospholipids in the cell membrane are the substrate for phospholipase A to generate arachidonic acid from which a family of chemically distinct prostaglandins and leukotrienes are produced. Clinical symptoms of prostaglandin production include hyperemia, miosis, impaired vision, pain, and diminished visual acuity secondary to cystoid macular edema (CME). Ocular actions of prostaglandins are manifested in three ways. Firstly, they act on intraocular pressure (IOP). Prostaglandin El (PGE1) and prostaglandin E2 (PGE2) increase the IOP by local vasodilation and increased permeability of the blood-aqueous barrier. Conversely, prostaglandin F2-a (PGF2-a) lowers the IOP which is attributed to increased uveoscleral outflow. Secondly, they act on iris smooth muscle to cause miosis. Thirdly, prostaglandins cause vasodilation and increase the vascular permeability resulting in increased aqueous humor protein concentration.

Prostaglandin synthesis can be reduced by inhibiting phospholipase A2, which inhibits the release of arachidonic acid from cell membrane phospholipids, or by inhibiting the conversion of arachidonic acid to prostaglandins via the COX pathway. Different classes of anti-inflammatory medications may block different portions of this pathway. Corticosteroids interfere with the activity of phospholipase A2, thereby inhibiting the release of arachidonic acid and the production of all arachidonic acid metabolites, including prostaglandins.

NSAIDs inhibit the cyclo-oxygenase enzyme essential for biosynthesis of prostaglandins. However literature survey revealed that till date the fixed dose combination of NSAID and steroidal anti-inflammatory agent for treating post operative ocular inflammation has not been reported.

Thus, there is an unmet need in the art for effective treatment of post operative ocular inflammation. The present inventors have found that fixed dose combination of NSAID and steroidal anti-inflammatory agents are effective for treatment of post operative ocular inflammation.

SUMMARY OF THE INVENTION

The present invention is directed to a method of treating post operative ocular inflammation, comprising administration of a fixed dose combination comprising one or more non-steroidal anti-inflammatory agent/s (NSAIDs) and one or more steroidal anti-inflammatory agent/s.

In one aspect, the present invention provides a fixed dose combination comprising one or more NSAIDs and one or more steroidal anti-inflammatory agents for the treatment of post operative ocular inflammation.

In yet another aspect, the present invention provides a pharmaceutical composition comprising a fixed dose combination comprising one or more NSAIDs and one or more steroidal antiinflammatory agents for the treatment of post operative ocular inflammation.

In yet another aspect, the present invention provides a process of preparing a pharmaceutical composition comprising fixed dose combination comprising one or more NSAIDs and one or more steroidal anti-inflammatory agents for the treatment of post operative ocular inflammation. In yet preferred aspect, the present invention provides a method of treating a post operative ocular inflammation, comprising administering to an eye of patient a combination of effective amount Ketorolac or its pharmaceutically acceptable salts thereof and Difluprednate, optionally together with pharmaceutically acceptable excipients.

In yet another preferred aspect, the present invention provides a fixed dose combination of Ketorolac or its pharmaceutically acceptable salts thereof and Difluprednate for the treatment of post operative ocular inflammation.

In yet another preferred aspect, the present invention provides a stable pharmaceutical composition comprising an effective amount of Ketorolac or its pharmaceutically acceptable salts thereof, an effective amount of Difluprednate and pharmaceutically acceptable excipients. In yet another preferred aspect, the present invention provides a process for preparation of a pharmaceutical composition comprising Ketorolac tromethamine, Difluprednate and pharmaceutically acceptable excipients. DETAILED DESCRIPTION OF INVENTION

The invention includes the combinational use of one or more NSAIDs and one or more steroidal anti-inflammatory agent/s for the treatment of post operative ocular inflammation. More specifically present invention includes the combinational use of Ketorolac or its pharmaceutically acceptable salts thereof and Difluprednate for the treatment of post operative ocular inflammation.

As used herein, the term "non-steroidal anti-inflammatory agent" or "NSAIDs" refers to the drugs that inhibit the cyclo-oxygenase enzyme essential for biosynthesis of prostaglandins.

As used herein, the term "anti-inflammatory steroids" refers to the drugs that block the synthesis of new histamine release by mast cells, inactivate available histamine, inhibit mast cell degranulation, decrease capillary permeability, and inhibit phospholipase A synthesis, which is used in the production of arachidonic acid and thereby prevent inflammation.

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

In one advantageous embodiment, the active components of present invention are present in the form of a fixed dose combination, owing to which the administration is simpler for the patients, since both active compounds are contained in one and the same container.

In yet another embodiment, the present invention provides a fixed dose combination of Ketorolac or its pharmaceutically acceptable salts thereof and Difluprednate.

In yet another preferred embodiment, the present invention provides a stable pharmaceutical composition for ophthalmic or topical use comprising a fixed dose combination of NSAIDs and steroidal anti-inflammatory agent/s.

In yet another preferred embodiment, the present invention provides a stable pharmaceutical composition for ophthalmic or topical use comprising a fixed dose combination of Ketorolac or its pharmaceutically acceptable salts thereof and Difluprednate.

In yet another preferred embodiment, the present invention provides a stable pharmaceutical composition for ophthalmic use in the form of a liquid.

In yet another preferred embodiment, the present invention provides a liquid ophthalmic composition in the form of emulsion, more preferably in the form of o/w emulsion.

In specific embodiment, the ophthalmic emulsion comprising a fixed dose combination of Ketorolac or its pharmaceutically acceptable salts thereof and Difluprednate for ophthalmic or topical use. In yet another specific embodiment, the ophthalmic emulsion comprising a fixed dose combination of Ketorolac or its pharmaceutically acceptable salts thereof and Difluprednate for the treatment of post operative ocular inflammation.

In yet another embodiment, the NSAIDs (e.g. Ketorolac tromethamine) is present in a composition or formulation described herein in an amount of about 0.1 to about 1 wt%, more preferably 0.25 wt % to 0.75 wt %.

In yet another embodiment, the steroidal anti-inflammatory agent (e.g. Difluprednate) is present in the composition or formulation described herein in an amount of about 0.01 wt % to about 0.1 wt %, more preferably 0.025 wt% to 0.075 wt%.

In yet other embodiment, the ophthalmic composition of present invention have a pH from 4.0 to 9.0, preferably from 5 to 8, more preferably from 5.5 to 7.5.

In yet another embodiment, the ophthalmic composition of present invention has an osmolarity from 200 to 500 milliosmoles/liter (mOsm/L), preferably from 250 to 450 mOsm/L, and more preferably from 275 to 425 mOsm/L.

In yet another embodiment, the pharmaceutical composition is prepared by first dissolving the lipophilic active ingredient completely in the oil (previously heated at 70 °C) by stirring to produce oil phase. Further, aqueous phase is prepared by completely dissolving buffer, water soluble active ingredient, tonicity-adjusting agent, surfactant and preservative successively in water for injection by stirring. Further, the aqueous phase and oil phase are individually heated to 70 °C and then oil phase is added to aqueous phase using homogenizer to obtain a coarse emulsion. The coarse emulsion is then cooled to room temperature, and then adjusted at pH up to 6.3 to 6.5 by 1 N sodium hydroxide (NaOH) solution or 0.1 N hydrochloric acid (HC1) solution and then the volume is made up to a fixed volume of desired batch size by water for injection. The coarse emulsion is then processed through high pressure emulsifier to obtain micronized emulsion. The micronized emulsion is then cooled using running water having a temperature of 40°C which is circulated through the metal coil around the high pressure emulsifier; this dissipate the heat produced during the emulsification process. After emulsification process micronized emulsion is cooled to room temperature (25°C). Further micronized emulsion is passed through 1.2 μ filter (as a pre-filter) followed by 0.22 μ filter (as a final filter) to obtain a sterile micronized emulsion. Finally sterile micronized emulsion is filled into a suitable ophthalmic container.

In yet another embodiment, the compositions, formulations and active pharmaceutical agent described herein are thermally stable at room temperature, at 25 °C with relative humidity 40% or at 40 °C with relative humidity NMT 25% for at least 6 months. Examples of NSAIDs, according to the present invention include, but are not limited to, aminoarylcarboxylic acid derivatives (e.g., enfenamic acid, etofenamate, flufenamic acid, isonixin, meclofenamic acid, mefenamic acid, niflumic acid, talniflumate, terofenamate, tolfenamic acid), arylcarboxylic acids (e.g., clidanac, Ketorolac, tinoridine), arylpropionic acid derivatives (e.g., alminoprofen, benoxaprofen, bermoprofen, bucloxic acid, carprofen, fenoprofen, flunoxaprofen, flurbiprofen, ibuprofen, ibuproxam, indoprofen, ketoprofen, loxoprofen, naproxen, oxaprozin, piketoprolen, pirprofen, pranoprofen, protizinic acid, suprofen, tiaprofenic acid, ximoprofen, zaltoprofen), or its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, pro-drugs, or mixtures thereof and the like.

Examples of steroidal anti-inflammatory agents according to the present invention include, but are not limited to, Loteprednol etabonate, Prednisolone sulfacetamide, Hydrocortisone, Dif uprednate, Fluorometholone acetate, Dexamethasone, Prednisolone phosphate or its physiologically acceptable salts thereof, prodrugs thereof, combinations thereof, mixtures thereof and the like.

A pharmaceutical composition according to the present invention may include one or more pharmaceutically acceptable buffering agents, preservatives, tonicity-adjusting agents, surfactants, solubilizing agents, antioxidants, pH-adjusting agents, chelating agents or combinations thereof.

Examples of buffering agents include, but are not limited to phosphate, borate, citrate, acetate, carbonate, borate-polyol complexes, boric acid, sodium acetate, combinations thereof and the like

Examples of preservatives include, but are not limited to benzalkonium chloride, benzethonium chloride, p- oxybenzoates such as methyl p-oxybenzoate or ethyl p- oxybenzoate, benzyl alcohol, phenethyl alcohol, sorbic acid or its salt, thimerosal, chlorobutanol, other quaternary amines and the like, chlorhexidine gluconate combinations thereof and the like.

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

Examples of surfactants include, but are not limited to poloxamers, tyloxapol, polysorbate such as polysorbate 80, polysorbate 20, polyoxyethylene castor oil derivatives, sorbitan esters, combinations thereof and the like.

Examples of solubilizing agents include, but are not limited to castor oil, polyoxyl stearate 40 polyvinylpyrrolidone, polyethylene glycol, propylene glycol, combinations thereof 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), tromethamine, monoethanolamine, sodium bicarbonate (NaHC0₃) 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(HCl), citric acid, tartaric acid, lactic acid and other organic and inorganic 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, combinations thereof and the like.

Examples

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: Ophthalmic Emulsion containing Ketorolac tromethamine (0.5% w/v) and Difluprednate (0.05% w/v)

Manufacturing process:

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

1. Castor oil was weighed in beaker and heated at 60-70 °C. Accurately weighed quantity of Difluprednate was added to castor oil to produce the oil phase. The oil phase was then stirred at 250 ± 10 RPM using magnetic stirrer until the oil phase become clear solution.

2. Sufficient quantity of water for injection was placed into a second beaker. Accurately weighed quantity of Boric acid, Sodium acetate, Ketorolac tromethamine, Polysorbate 80, Glycerin, Sorbic acid were added and dissolved successively to water for injection with stirring at 250 ± 10 RPM using magnetic stirrer to obtain a clear aqueous phase.

3. The aqueous phase and the oil phase were individually heated up to 70 ± 5 °C. The oil phase was then added to the previously heated aqueous phase and emulsified using homogenizer at 8000 rpm for 1 hr. This produced a coarse emulsion. The coarse emulsion was then cooled to room temperature, and then adjusted at pH 6.3 to 6.5 by 1 N sodium hydroxide solution or 0.1 N Hydrochloric acid solution and then the volume was made up to a fixed volume of desired batch size by water for injection.

4. The coarse emulsion of step-3 was processed through high pressure emulsifier. To cool the emulsion, running water having a temperature of 40°C was circulated through the metal coil around the high pressure emulsifier; this dissipated the heat produced during the emulsification process. After emulsification process, the emulsion was cooled to room temperature (25°C), labeled as micronized emulsion.

5. The micronized emulsion of step-4 was passed through 1.2 μ filter (as a pre-filter) followed by 0.22 μ filter (as a final filter) to obtain a sterile micronized emulsion.

6. Finally sterile micronized emulsion was filled into a suitable ophthalmic container. The formulation of example 1 was further subjected to stability studies at 40°C/NMT25%RH, was analyzed at an intervals of 3M & 6M and at 25°C/40%RH, was analyzed at an intervals of 6M, the results obtained are presented in Table No. 7. Example No. 2

Table No. 2: Ophthalmic Emulsion containing Ketorolac tromethamine (0.45% w/v) and Difluprednate (0.05% w/v)

Manufacturing process:

A formulation as shown in table 2 was prepared according to the process described in Example 1.

The formulation of example 2 was further subjected to stability studies at 40°C/NMT25%RH, was analyzed at an intervals of 3M & 6M and at 25°C/40%RH, was analyzed at an intervals of 6M, the results obtained are presented in Table No.8 .

Example No. 3

Table No. 3: Ophthalmic Emulsion containing Ketorolac tromethamine (0.4% w/v) and Difluprednate (0.05% w/v)

4 Castor oil 50.0

5 Polysorbate 80 40.0

6 Glycerin 22.0

7 Sodium acetate 0.5

8 Boric acid 1.0

9 Sodium Hydroxide/Hydrochloric acid q.s to adjust pH

10 Water for injection q.s to 1 mL

Manufacturing process:

A formulation as shown in table 3 was prepared according to the process described in Example 1.

The formulation of example 3 was further subjected to stability studies at 40°C/NMT25%RH, was analyzed at an intervals of 3M & 6M and at 25°C/40%RH, was analyzed at an intervals of 6M, the results obtained are presented in Table No. 9.

Example No. 4

Table No. 4: Ophthalmic Emulsion containing Ketorolac tromethamine (0.5% w/v) and Difluprednate (0.05% w/v)

Manufacturing process:

A formulation as shown in table 4 was prepared according to the process described in Example 1.

Example No. 5

Table No. 5: Ophthalmic Emulsion containing Ketorolac tromethamine (0.45% w/v) and Difluprednate (0.05% w/v)

Manufacturing process:

A formulation as shown in table 5 was prepared according to the process described in Example 1.

Example No. 6

Table No. 6: Ophthalmic Emulsion containing Ketorolac tromethamine (0.4% w/v) and Difluprednate (0.05% w/v)

3 Sorbic acid 1.0

4 Castor oil 50.0

5 Polysorbate 80 30.0

6 Glycerin 20.0

7 Sodium acetate 0.5

8 Boric acid 1.0

9 Sodium Hydroxide/Hydrochloric acid q.s to adjust pH

10 Water for injection q.s to 1 mL

Manufacturing process:

A formulation as shown in table 6 was prepared according to the process described in Example 1.

Table No. 7: Ketorolac Tromethamine & Difluprednate Ophthalmic Emulsion (0. 5% w/v & 0.05% w/v) finished product analysis data-initial and on stability

H (5.5-7.5) 6.62 6.50 6.30 6.70

Osmolality (mOsmol/kg) 364 360 370 365

(304-411)

Viscosity (1-3 cps) 2.40 2.43 2.44 2.49

Table No. 8: Ketorolac Tromethamine & Difluprednate Ophthalmic Emulsion (0.45% w/v & 0.05% w/v) finished product analysis data-initial and on stability

Description (Product) White to pale yellow emulsion

Stability Condition 40°C / NMT 25 % RH 25°C / 40 % RH

Test parameters Initial 3M 6M 6M

Description White Pale Pale yellow Pale yellow emulsion yellow emulsion emulsion

emulsion

Ketorolac Tromethamine in % 101.5 99.5 98.0 98.5

Difluprednate in % 101.2 100.2 97.2 97.9

Preservative content in % 99.4 97.1 94.5 95.2 pH (5.5-7.5) 6.60 6.50 6.70 6.94

Osmolality (mOsmol/kg) 352 365 370 360

(304-411)

Viscosity (1-3 cps) 2.39 2.44 2.46 2.52 Table No. 9: Ketorolac Tromethamine & Difluprednate Ophthalmic Emulsion (0. 4% w/v & 0.05% w/v) finished product analysis data-initial and on stability

Claims

We claim:

1 . A stable pharmaceutical composition comprising an effective amount of Ketorolac or its pharmaceutically acceptable salts thereof, an effective amount of Difluprednate and pharmaceutically acceptable excipients.

2. The composition of claim 1, wherein the composition comprises from about 0.1 to about 1 % (w/v) of Ketorolac tromethamine.

3. The composition of claim 1, wherein the composition comprises from about 0.01 to about 0.1 % (w/v) of Difluprednate.

4. The composition of claim 1, wherein said composition is intended for ocular use.

5. The composition of claim 1, wherein said composition is in the form of an emulsion.

6. The composition of claim 1, wherein the pharmaceutically acceptable excipients are selected from the group comprising buffering agents, preservatives, tonicity-adjusting agents, surfactants, solubilizing agents, pH-adjusting agents or combination thereof.

7. The pharmaceutical composition of claim 1, wherein the composition has a pH in the range from 5.5 to 7.5.

8. The pharmaceutical composition of claim 1, wherein the composition has an Osmolality in the range from 275 to 425 mOsml/kg.

9. A stable pharmaceutical composition comprising an effective amount of Ketorolac or its pharmaceutically acceptable salts thereof, an effective amount of Difluprednate and pharmaceutically acceptable excipients, wherein the process for preparation of the stable pharmaceutical composition comprising the steps of:

(a) mixing castor oil and Difluprednate to obtain clear oil phase mixture;

(b) mixing Ketorolac or its pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients in a water for injection to obtain clear water phase mixture;

(c) adding the oil phase mixture of step (a) which is preheated into the water phase mixture of step(b) which is preheated and homogenize the mixture to obtain coarse emulsion and adjusting the pH of said coarse emulsion in the range of 5.5 to 7.5;

(d) treating coarse emulsion obtained in step (c) through high speed homogenizer to obtain micronized emulsion and

(e) filtering the micronized emulsion to obtain a final sterile emulsion comprising Ketorolac and Difluprednate.

10. The stable pharmaceutical composition of claim 9, wherein the pharmaceutically acceptable excipient comprises one or more buffering agent, preservative, tonicity-adjusting agent and surfactant.

1 1 . The stable pharmaceutical composition of claim 10, wherein the buffering agent is selected from a group comprising boric acid, sodium acetate, borate-polyol complexes or combination thereof.

12. The stable pharmaceutical composition of claim 10, wherein the preservative is selected from a group comprising sorbic acid or its salt, benzalkonium chloride, benzyl alcohol or combination thereof.

13. The stable pharmaceutical composition of claim 10, wherein the tonicity-adjusting agent is selected from a group comprising glycerin, sodium chloride, mannitol or combination thereof.

14. The stable pharmaceutical composition of claim 10, wherein surfactant is selected from a group comprising polysorbate 80, polysorbate 20, poloxamers, tyloxapol or combination thereof.

15. A method of treating post operative ocular inflammation comprising administering to an eye of patient, a combination of effective amount of Ketorolac or its pharmaceutically acceptable salts thereof and Difluprednate optionally together with pharmaceutically acceptable excipients.