Description:FIELD OF THE INVENTION

The present invention relates to a stable pharmaceutical composition comprising lifitegrast and one or more pharmaceutical excipients, wherein said composition is free of antioxidant and/or preservative and is useful to treat dry eye disease. It further relates to a method of preparing such compositions.

BACKGROUND OF THE INVENTION

Lifitegrast, is chemically known as (S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4­tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl) propanoic acid. It acts as a lymphocyte function-associated antigen-1 (LFA-1) antagonist. It is marketed under the brand name of Xiidra® in USA and is indicated to treat signs and symptoms of dry eye disease. Xiidra® contains 50 mg/mL i.e. 5% lifitegrast as active ingredient and sodium chloride, sodium phosphate dibasic anhydrous, sodium thiosulfate pentahydrate, sodium hydroxide and/or hydrochloric acid (to adjust pH) and water for injection. Xiidra® is supplied as a sterile, clear, colorless to slightly brownish-yellow colored, isotonic solution of lifitegrast with a pH of 7.0–8.0 and an osmolality range of 200–330 mOsmol/kg. It is supplied in a foil pouch containing low density polyethylene 0.2 mL single-use containers.

U.S. Patent No. 7,314,938; 7,745,460; 7,790,743 and 7,928,122 disclose lifitegrast generically. However, lifitegrast is specifically disclosed in U.S. Patent No. 8,084,047; 8,168,655 and 8,592,450. Polymorphic forms of lifitegrast are disclosed in U.S. Patent No. 8,367,701 and 9,447,077.

U.S. Patent No. 9, 216,174 discloses a topical composition of lifitegrast. U.S. Patent No. 8,927,574 discloses a composition of lifitegrast having a lower level of residual palladium. U.S. Patent No. 9,353,088 discloses a composition of lifitegrast wherein said composition is essentially free of a chemical catalyst. Further, U.S. Patent No. 9,085,553 discloses a composition of lifitegrast which is prepared by such a process that the compound has an optical purity of >98%.

U.S. Patent Publication No. US 2015/0320737 discloses a topical pharmaceutical composition of lifitegrast which is stabilized using thiosulfate salt as an antioxidant. Further, the composition is buffered to a pH of about 7.5.

Therefore, ophthalmic compositions in the prior published references suggest the use of antioxidants such as sodium thiosulfate and use of preservatives to stabilize the compositions. In view of all the prior art references, there exists an unmet need to develop an alternate stable pharmaceutical composition of lifitegrast which either does not use antioxidant or use any other antioxidant which is better and cheaper as compared to sodium thiosulfate. The present inventors have further developed a pharmaceutical composition which is free of preservative and still maintains the product stability. Further, the present invention also provides a multi-dose pharmaceutical composition which will avoid wastage of medication, as the medication needs not to be discarded once used and can be used for multiple times. The pharmaceutical composition of lifitegrast as per the present invention have similar stability as compared to Xiidra®.

SUMMARY OF THE INVENTION

The present inventors have developed a stable pharmaceutical composition comprising lifitegrast which is free of antioxidant and/or preservative and is supplied as multi-dose or single-dose vials.

According to one aspect, the present invention provides a stable pharmaceutical composition comprising lifitegrast and one or more pharmaceutical excipients, wherein the pharmaceutical composition is free of antioxidant and/or preservative.

According to one embodiment, the pharmaceutical composition has less than about 0.5 % of total impurities when stored at 40°C for a period of at least one month.
According to one embodiment, the present invention provides a stable pharmaceutical composition comprising lifitegrast and one or more pharmaceutical excipients, wherein the pharmaceutical composition is free of antioxidant.

According to another embodiment, the present invention provides a stable pharmaceutical composition comprising lifitegrast and one or more pharmaceutical excipients, wherein the pharmaceutical composition is free of sodium thiosulfate.

According to another embodiment, the present invention provides a stable pharmaceutical composition comprising lifitegrast and one or more pharmaceutical excipients, wherein the pharmaceutical composition is free of preservative and sodium thiosulfate.

According to another embodiment, the present invention provides a stable pharmaceutical composition comprising lifitegrast and one or more pharmaceutical excipients, wherein the pharmaceutical excipients are selected from the group comprising buffering agent, tonicity adjusting agent, pH adjusting agent, vehicle/diluent/solvent, surfactant, antioxidant, preservative and/or combinations thereof.

According to another embodiment, the present invention provides a stable pharmaceutical composition which is administered topically into an eye.

According to yet another embodiment, the present invention provides a stable pharmaceutical composition which is in the form of solution or drops.

According to another aspect, the present invention provides a process for preparing a stable pharmaceutical composition comprising lifitegrast and one or more pharmaceutical excipients, wherein the pharmaceutical composition is free of antioxidant and/or preservative and, wherein said process comprises the step of:
(a) preparing a solution comprising tonicity adjusting agent and buffering agent in water for injection;
(b) adding lifitegrast or a pharmaceutically acceptable salt thereof to the solution of step (a) and stirring to form a clear solution;
(c) optionally adding preservative and/or antioxidant to the solution of step (b);
(d) making the final volume of the solution using water for injection,
(e) adjusting the pH of the solution of step (d) if required;
(f) optionally filtering the final solution of step (e), and
(g) filling the solution into a suitable container.

According to another embodiment, the present invention provides a stable pharmaceutical composition comprising lifitegrast and one or more pharmaceutical excipients, wherein the pharmaceutical composition is free of antioxidant and/or preservative and wherein said pharmaceutical composition is filled into a single-dose container.

According to another embodiment, the present invention provides a stable pharmaceutical composition comprising lifitegrast and one or more pharmaceutical excipients, wherein the pharmaceutical composition is free of antioxidant and/or preservative and wherein said pharmaceutical composition is filled into a multi-dose container.

According to another embodiment, the present invention provides a stable pharmaceutical composition comprising lifitegrast and one or more pharmaceutical excipients, wherein said pharmaceutical composition is filled into a multi-dose container and is free of preservative.

According to another embodiment, the present invention provides a stable pharmaceutical composition comprising lifitegrast and one or more pharmaceutical excipients, wherein said pharmaceutical composition is filled into a multi-dose container and is free of preservative and sodium thiosulfate.

According to yet another embodiment, the multi-dose container comprises a non-return valve system.

According to another aspect, the present invention provides a pharmaceutical composition which is useful for treating dry eye disease.

DETAILED DESCRIPTION OF THE INVENTION

While selected embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the appended claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference.

The term “single dose container(s)/single use container” as used herein refers to those containers which contain composition which is intended for a single use. Examples of single-dose containers include: pre-filled syringes, cartridges, fusion-sealed containers, closure-sealed containers, opened or needle-punctured single-dose containers such as ampoules, bags, bottles, syringes, BFS, and vials.

The term “multi-dose container(s)/multi-use container” as used herein refers to those containers which are designed for removal of portions of composition on multiple occasions such as multi-dose vials or bottle.

The container used in the present invention is based on a non-return valve system used in conjunction with a silicone membrane to filter the returning air. The one-way valve ensures that no contaminated liquid can be re-introduced to the container after the drop has been dispensed, completely removing the need to filter the liquid.

Lifitegrast as used herein include any pharmaceutically acceptable salts, esters, hydrates, solvates and polymorphs thereof. The compositions of the invention may comprise the amorphous form of lifitegrast or any of its crystalline form or a combination thereof. The present invention contains lifitegrast in an amount of about 0.5% w/v to about 50% w/v of the composition. Preferably, of about 1.0 % w/v to about 10% w/v of the composition. Most preferably, about 5% w/v of the composition.

Suitable buffering agents include, but are not limited to, phosphates, such as sodium phosphate monobasic, sodium phosphate dibasic, citrates, acetates such as sodium acetate, borates, boric acid, tartrates, succinates, amino acids and/or combinations thereof. Preferably, the buffering agent is sodium phosphate dibasic.

The compositions of the present invention include a tonicity adjusting agent to render the solution isotonic and more compatible. The preferred agents include sodium chloride, glycerol, mannitol, sucrose, sorbitol and mixtures thereof. The most preferred agent is sodium chloride.

Suitable pH adjusting agent as used in the present invention includes acids and bases. Suitable acids to adjust the pH of the composition include, but are not limited to, hydrochloric acid, citric acid, sulfuric acid, nitric acid, and other organic or inorganic acids and/or combinations thereof. Preferably, hydrochloric acid is used to adjust pH.

Suitable bases to adjust the pH of the composition include, but are not limited to, sodium hydroxide, potassium hydroxide, barium hydroxide, and/or combinations thereof. Preferably, sodium hydroxide is used to adjust pH.

Suitable vehicles/diluents/solvents include, but are not limited to, water for injection, Ringer's solution, normal saline solution. Other vehicles may be chosen, as is known in the art, including but not limited to: water soluble polyethers such as polyethyene glycol, glycerin, polyvinyls such as polyvinyl alcohol and povidone, cellulose derivatives such as methylcellulose and hydroxypropyl methylcellulose, petroleum derivatives such as mineral oil and white petrolatum, animal fats such as lanolin, polymers of acrylic acid such as carboxypolymethylene gel, vegetable fats such as peanut oil and polysaccharides such as dextrans, and glycosaminoglycans such as sodium hyaluronate and/or combinations thereof. More preferably, water for injection is used to prepare pharmaceutical compositions of the present invention.

The product is developed under controlled conditions w.r.t. humidity, atmosphere and light. Water for injection is sparged with nitrogen till the dissolved oxygen level reaches to not more than 10 ppm, preferably not more than 5 ppm and more preferably not more than 2 ppm.

Suitable antioxidants include, but are not limited to, sodium thiosulfate, sodium bisulfite, acetone sodium bisulfite, gentisic acid, gentisic acid ethanolamide, sodium formaldehyde sulfoxylate, thiourea, butylated hydroxyanisole, butylated hydroxy toluene, esters of gallic acid, ascorbic acid, salts of ascorbic acids such as ascorbyl palmitate, sodium ascorbate, retinoids and derivatives of vitamin A, acetylcysteine, thioglycerol, Vitamin E and its derivatives e.g. Vitamin E TPGS and/or combinations thereof.

Suitable preservatives include, but are not limited to, peroxides, benzalkonium chloride, purite, benzethonium chloride, methyl paraben, propyl paraben, ethyl paraben, butyl paraben, perborates, phenol and its derivatives such as m-cresol and chlorocresol, benzyl alcohol, chlorobutanol, polyquad and/or combinations thereof.

Other additives can also be included in the present compositions, such as thickeners/suspending agent, complexing agent, surfactant, co-solvents and stabilizers. Suitable thickeners/suspending agents include, but are not limited to, saccharide such as lactose, mannitol, maltose; hyaluronic acid or its salt such as sodium hyaluronate, potassium hyaluronate; chondroitin sulfate, carboxyvinyl polymer, crosslinked polyacrylate, polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose, hydroxy propyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, hydroxy propyl cellulose, sodium alginate, gum tragacanth and/or combinations thereof.

The solubility of the components of the present compositions may be enhanced by a surfactant or other appropriate co-solvent in the composition. Such cosolvents include polysorbate 20, 60, and 80, PluronicTM, cyclodextrin, tyloxapol or other agents known to those skilled in the art. Suitable surfactant which can be used to form pharmaceutical compositions and dosage forms of the invention include, but are not limited to, hydrophilic surfactants, lipophilic surfactants, and mixtures thereof. The compositions can contain surface-active agents conventionally employed in topical compositions, such as oleic acid, lecithin, sorbitan trioleate, cetylpyridinium chloride, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan mono-oleate, polyoxypropylene/polyoxyethylene block copolymers, polyoxypropylene/ polyoxyethylene/ethylene diamine block copolymers, ethoxylated castor oil and/or combinations thereof.

Suitable chelating agents include, but are not limited to, ethylene diaminetetraacetic acid (EDTA), EDTA disodium, calcium disodium edetate, EDTA trisodium, EDTA tetrasodium and/or combinations thereof.

Suitable stabilizers include, but are not limited to caffeine, creatine, sodium iodide, sodium sulfate, peroxy compounds including phosphonates, phosphates, stannates, and mixtures thereof. Physiologically compatible salts of phosphonic acids may also be used, such as diethylene triamine penta(methylene-phosphonic acid and 1-hydroxyethylene-1 ,1 ,-diphosphonic acid.

The pharmaceutical compositions as per the present invention may be delivered as topical, intravenous, oral, aerosolized, and nebulized compositions. Preferably, the pharmaceutical composition as per the present invention is delivered by topical route.
The present invention provides a pharmaceutical composition wherein the pharmaceutical composition is in the form of a solution, suspension, emulsion, ointment, paste, cream, lotion, gel, powder, spray, inhalant, patch, oil, plaster or liposome. Preferably, the pharmaceutical composition is in the form of solution.
The pharmaceutical compositions as per the present invention is meant for topical administration into eye or ear of a human or animal. Preferably, the pharmaceutical composition is in the form of ophthalmic drops.
The pharmaceutical compositions of the invention may be administered one to ten times per day per eye, more preferably one to four times a day, most preferably once a day. The pharmaceutical compositions of the invention may be administered one to four drops per time, preferably one to three drops, more preferably one to two drops, and most preferably one drop per day.
The frequency of administration and the amount of the presently useful composition to use during each administration varies depending upon the therapeutic effect to be obtained, the severity of the condition being treated and the like factors. Such administration may occur on an as needed basis, for example, in treating or managing dry eye syndrome, on a one time basis or on a repeated or periodic basis once, twice, thrice or more times daily depending on the needs of the human or animal being treated and other factors involved in the application at hand.
The pharmaceutical composition as per the present invention contains less than about 1 % of total impurities when stored at 40°C for a period of at least one month. Preferably, less than about 0.5%.
The pharmaceutical compositions as per the present invention can be sterilized using any of the known methods of sterilization, such as filtration, moist heat, dry heat, gas sterilization or irradiation (gamma and electron beam). The container in which composition is filled can be sterilized using gamma irradiation or ethylene oxide or pre-acetic acid or any other conventional method of sterilization.
The present invention provides a pharmaceutical composition which is useful in treating any condition which is therapeutically sensitive to or treatable with lifitegrast. Such conditions preferably are ophthalmic or ocular conditions that is relating to or having to do with one or more parts of an eye of a human or animal. Included among such conditions are, without limitation, dry eye syndrome, phacoanaphylactic endophthalmitis, uveitis, macular edema, vernal conjunctivitis, atopic keratoconjunctivitis, corneal graft rejection and the like conditions. The present invention is particularly effective in treating dry eye syndrome also known as keratoconjunctivitis sicca.
The pharmaceutical compositions of the present invention have pH within the physiological range of about 6 to about 10, preferably in a range of about 7.0 to about 8.0. The pharmaceutical compositions of the present invention have osmolality within range of 100-500mOsmol/kg.
The present compositions optionally further comprise one or more additional therapeutic agents. Alternatively, a compound of this invention may be administered to a patient in need thereof in combination with the administration of one or more other therapeutic agents. For example, additional therapeutic agents for conjoint administration or inclusion in a pharmaceutical composition with a compound of this invention may be an approved anti-inflammatory agent, analgesic, anaesthetic or it may be any one of a number of agents undergoing approval in the Food and Drug Administration that ultimately obtain approval for the treatment of any disorder mediated by LFA-1. The compositions of the present invention can also be provided as kits.
The following examples will illustrate in more detail the various aspects of the present invention.
Example 1
Ingredient % (w/v)
Lifitegrast 5.00
Sodium chloride 0.001-10
Sodium phosphate dibasic 0.001-10
Sodium hydroxide q.s
Hydrochloric acid q.s
Water for injection q.s

Manufacturing process:
(a) preparing a solution comprising tonicity adjusting agent and buffering agent in water for injection sparged with nitrogen;
(b) adding lifitegrast or a pharmaceutically acceptable salt thereof to the solution of step (a) and stirring to form a clear solution;
(c) optionally adding preservative and/or antioxidant to the solution of step (b);
(d) making the final volume using water for injection;
(e) adjusting the pH of the solution of step (d) if required;
(f) filtering the final solution of step (e); and
(f) filling the solution into a suitable container under aseptic conditions.

Example 2
Ingredient % (w/v)
Lifitegrast 5.00
Sodium chloride 0.001-10
Sodium phosphate dibasic 0.001-10
Benzalkonium chloride 0.001-10
Sodium hydroxide q.s
Hydrochloric acid q.s
Water for injection q.s

Example 3
Ingredient % (w/v)
Lifitegrast 5.00
Sodium chloride 0.001-10
Sodium phosphate dibasic 0.001-10
Gentisic acid ethanolamide 0.001-10
Sodium hydroxide q.s
Hydrochloric acid q.s
Water for injection q.s

Example 4
Ingredient % (w/v)
Lifitegrast 5.00
Sodium chloride 0.001-10
Sodium phosphate dibasic 0.001-10
Sodium formaldehyde sulfoxylate 0.001-10
Sodium hydroxide q.s
Hydrochloric acid q.s
Water for injection q.s

Example 5
Ingredient % (w/v)
Lifitegrast 5.00
Sodium chloride 0.001-10
Sodium phosphate dibasic 0.001-10
Acetone sodium bisulfite 0.001-10
Benzalkonium chloride 0.001-10
Sodium hydroxide q.s
Hydrochloric acid q.s
Water for injection q.s

Example 6
Ingredient % (w/v)
Lifitegrast 5.00
Sodium chloride 0.001-10
Sodium phosphate dibasic 0.001-10
Gentisic acid 0.001-10
Chlorobutanol 0.001-10
Sodium hydroxide q.s
Hydrochloric acid q.s
Water for injection q.s

Example 7
Ingredient % (w/v)
Lifitegrast 5.00
Sodium chloride 0.001-10
Sodium phosphate dibasic 0.001-10
Thiourea 0.001-10
Methylparaben 0.001-10
Sodium hydroxide q.s
Hydrochloric acid q.s
Water for injection q.s

Example 8
Ingredient % (w/v)
Lifitegrast 5.00
Sodium chloride 0.001-10
Sodium phosphate dibasic 0.001-10
Thiourea 0.001-10
Sodium hydroxide q.s
Hydrochloric acid q.s
Water for injection q.s

Example 9
Ingredient % (w/v)
Lifitegrast 5.00
Sodium chloride 0.25
Sodium phosphate dibasic anhydrous 0.36
Sodium ascorbate 0.30
Sodium hydroxide q.s
Hydrochloric acid q.s
Water for injection q.s

Example 10
Ingredient % (w/v)
Lifitegrast 5.00
Sodium chloride 0.30
Sodium phosphate dibasic anhydrous 0.36
Sodium formaldehyde sulfoxylate 0.3
Sodium hydroxide q.s
Hydrochloric acid q.s
Water for injection q.s

Example 11
Ingredient % (w/v)
Lifitegrast 5.00
Sodium chloride 0.30
Sodium phosphate dibasic anhydrous 0.36
Acetone sodium bisulfite 0.35
Sodium hydroxide q.s
Hydrochloric acid q.s
Water for injection q.s

The above examples 2-11 were prepared by the same process as mentioned in example 1
Stability studies:
A sterile, ophthalmic pharmaceutical composition of the present invention is prepared according to examples 3 & 4 and are tested for stability for 1 month at 40°C. The results of the same are provided in table 1 & 2.

As understood by those of skill in the art, when the drug comprises lifitegrast, the impurities preferably measured include
Impurity A: 2(1H)-Isoquinolinecarboxylic acid, 5,7-dichloro-3,4-dihydro-6-[[[(1S)-1-[[3-(methylsulfonyl)phenyl]methyl]-2-oxo-2-(phenylmethoxy)ethyl] amino]carbonyl]-, 1,1-dimethylethyl ester;
Impurity B: 3-(methylsulfonyl)- phenylmethyl ester, hydrochloride (1:1) D-Phenylalanine;
Impurity C: N-[(5,7-dichloro-1,2,3,4-tetrahydro-6-isoquinolinyl)carbonyl]-3-(methylsulfonyl)- phenylmethyl ester, hydrochloride (1:1) L-Phenylalanine;
Impurity D: 5,7-dichloro-1,2,3,4-tetrahydro-, hydrochloride (1:1) 6-Isoquinolinecarboxylic acid;
Impurity E: N-[[2-(6-benzofuranylcarbonyl)-5,7-dichloro-1,2,3,4-tetrahydro-6-isoquinolinyl]carbonyl]-3-(methylsulfonyl)- phenylmethyl ester L-Phenylalanine;
Impurity F: 6-Benzofurancarboxylic acid, ethyl ester
and total impurities, as well as identification of the amount of any independent unspecified impurity.
Table 1:

Parameter Initial 1Month/40°C
Assay of Lifitegrast 100.01% 99.99%
Impurity A ND ND
Impurity B ND ND
Impurity C ND ND
Impurity D 0.08% 0.09%
Impurity E ND ND
Impurity F 0.07% 0.10%
Any single unspecified Impurity 0.05% 0.06%
Total impurity 0.20% 0.25%

Table 2:

Parameter Initial 1Month/40°C
Assay of Lifitegrast 100.01% 99.99%
Impurity A ND ND
Impurity B ND ND
Impurity C ND ND
Impurity D 0.06% 0.08%
Impurity E ND ND
Impurity F 0.07% 0.07%
Any single unspecified Impurity 0.06% 0.07%
Total impurity 0.19% 0.22%

Results:
The lifitegrast content is measured to be 99.99% and 99.98% for compositions of example 3 and 4 respectively, which is in acceptable limits range (Limit 90.0-110.0%). Total impurities is measured to be 0.25% and 0.22% for compositions of example 3 and 4 respectively which are also within the acceptable limit of NMT 2%.
Hence, it is concluded from the above stability data that the composition as per examples 3 & 4 provide an unexpected enhanced stability.
, C , Claims:WE CLAIM:

1. A stable pharmaceutical composition comprising lifitegrast and one or more pharmaceutical excipients in multi-dose vials, wherein said composition is free of preservative.

2. The pharmaceutical composition as claimed in claim 1, wherein said composition has less than about 0.5 % of total impurities when stored at 40°C for a period of at least one month.

3. The pharmaceutical composition as claimed in claim 1, wherein said composition is free of antioxidant.

4. The pharmaceutical composition as claimed in claim 3, wherein said composition is free of sodium thiosulfate.

5. The pharmaceutical composition as claimed in claim 1, wherein the pharmaceutical excipients are selected from the group comprising buffering agent, tonicity adjusting agent, pH adjusting agent, chelating agents, vehicle/diluent/solvent, surfactant, antioxidant, or combinations thereof.

6. The pharmaceutical composition as claimed in claim 5, wherein:
- the buffering agent is selected from sodium phosphate monobasic, sodium phosphate dibasic, citrates, sodium acetate, borates, boric acid, tartrates, succinates, amino acids or a combination thereof.
- the tonicity adjusting agent is selected from sodium chloride, glycerol, mannitol, sucrose, sorbitol and or a combination thereof,
- the pH adjusting agent is selected from acids such as hydrochloric acid, phosphoric acid, citric acid, sulfuric acid, nitric acid, bases selected from sodium hydroxide, potassium hydroxide, barium hydroxide, or combinations thereof, and
- the antioxidant is selected from sodium thiosulfate, sodium bisulfite, acetone sodium bisulfite, gentisic acid, gentisic acid ethanolamide, sodium formaldehyde sulfoxylate, thiourea, butylated hydroxyanisole, butylated hydroxy toluene, esters of gallic acid, ascorbic acid, salts of ascorbic acids such as ascorbyl palmitate, sodium ascorbate, retinoids and derivatives of vitamin A, acetylcysteine, thioglycerol, Vitamin E and its derivatives e.g. Vitamin E TPGS, or combinations thereof.

7. The pharmaceutical composition as claimed in claim 6, wherein:
- the buffering agent is sodium phosphate monobasic, sodium phosphate dibasic, or a combination thereof,
- the tonicity adjusting agent is sodium chloride, and
- pH adjusting agent is hydrochloric acid, sodium hydroxide, or a combination thereof.

8. The pharmaceutical composition as claimed in claim 1, wherein said multi-dose vial comprises a non-return valve system.

9. The pharmaceutical composition as claimed in claim 1, wherein said pharmaceutical composition is useful for treating dry eye disease.

10. A process for preparing a stable pharmaceutical composition comprising lifitegrast and one or more pharmaceutical excipients, wherein the pharmaceutical composition is free of preservative, and wherein said process comprises the step of:
(a) preparing a solution comprising tonicity adjusting agent and buffering agent in water for injection;
(b) adding lifitegrast or a pharmaceutically acceptable salt thereof to the solution of step (a) and stirring to form a clear solution;
(c) optionally adding antioxidant to the solution of step (b);
(d) making the final volume of the solution using water for injection,
(e) adjusting the pH of the solution of step (d) if required;
(f) optionally filtering the final solution of step (e), and
(g) filling the solution into multi-dose vials.