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WO2019171260A1 - Composition pharmaceutique de lifitégrast - Google Patents

Composition pharmaceutique de lifitégrast Download PDF

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Publication number
WO2019171260A1
WO2019171260A1 PCT/IB2019/051752 IB2019051752W WO2019171260A1 WO 2019171260 A1 WO2019171260 A1 WO 2019171260A1 IB 2019051752 W IB2019051752 W IB 2019051752W WO 2019171260 A1 WO2019171260 A1 WO 2019171260A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
composition
solution
lifitegrast
antioxidant
Prior art date
Application number
PCT/IB2019/051752
Other languages
English (en)
Inventor
Manish Kumar Sharma
Raghuveera H.G.
Satish Chandra Upadhyay
Nehate Chetan NARAYAN
P.V.S Narasimham
Anil Kumar
Original Assignee
Mankind Pharma Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Mankind Pharma Ltd. filed Critical Mankind Pharma Ltd.
Publication of WO2019171260A1 publication Critical patent/WO2019171260A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears

Definitions

  • 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.
  • Lifitegrast is chemically known as (S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro- l,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl) propanoic acid. It acts as a lymphocyte function-associated antigen- 1 (LFA-l) 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.
  • 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.
  • 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.
  • ophthalmic compositions in the prior published references suggest the use of antioxidants such as sodium thiosulfate and use of preservatives to stabilize the compositions.
  • antioxidants such as sodium thiosulfate
  • preservatives to stabilize the compositions.
  • the present inventors have further developed a pharmaceutical composition which is free of preservative and still maintains the product stability.
  • 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 ® .
  • 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.
  • 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.
  • 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.
  • the present invention provides a stable pharmaceutical composition comprising lifitegrast and one or more pharmaceutical excipients, wherein the pharmaceutical composition is free of antioxidant.
  • 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.
  • 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.
  • the present invention provides a stable pharmaceutical composition
  • 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.
  • the present invention provides a stable pharmaceutical composition which is administered topically into an eye.
  • the present invention provides a stable pharmaceutical composition which is in the form of solution or drops.
  • 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:
  • step (b) adding lifitegrast or a pharmaceutically acceptable salt thereof to the solution of step (a) and stirring to form a clear solution;
  • step (c) optionally adding preservative and/or antioxidant to the solution of step (b);
  • step (e) adjusting the pH of the solution of step (d) if required;
  • step (f) optionally filtering the final solution of step (e), and
  • 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.
  • 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.
  • 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.
  • 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.
  • the multi-dose container comprises a non return valve system.
  • the present invention provides a pharmaceutical composition which is useful for treating dry eye disease.
  • single dose container(s)/single use container refers to those containers which contain composition which is intended for a single use.
  • 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.
  • 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.
  • the buffering agent is sodium phosphate dibasic.
  • 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.
  • 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.
  • 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.
  • thickeners/suspending agent 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, hydroxy ethyl cellulose, carboxymethyl cellulose, hydroxy propyl cellulose, sodium alginate, gum tragacanth and/or combinations thereof.
  • 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 pyrrol
  • the solubility of the components of the present compositions may be enhanced by a surfactant or other appropriate co-solvent in the composition.
  • a surfactant or other appropriate co-solvent in the composition 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.
  • 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.
  • 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,
  • 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- hydro xyethy lene- 1 ,1 ,-diphosphonic acid.
  • the pharmaceutical compositions as per the present invention may be delivered as topical, intravenous, oral, aerosolized, and nebulized compositions.
  • 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.
  • the pharmaceutical composition is in the form of solution.
  • compositions as per the present invention is meant for topical administration into eye or ear of a human or animal.
  • 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%.
  • 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, phaco anaphylactic 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 l00-500m0smol/kg.
  • compositions optionally further comprise one or more additional therapeutic agents.
  • 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.
  • 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-l.
  • the compositions of the present invention can also be provided as kits.
  • Example 1 The following examples will illustrate in more detail the various aspects of the present invention.
  • step (c) optionally adding preservative and/or antioxidant to the solution of step (b);
  • step (e) adjusting the pH of the solution of step (d) if required;
  • step (f) filtering the final solution of step (e);
  • 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.
  • the impurities preferably measured include
  • Impurity A 2(lH)-Isoquinolinecarboxylic acid, 5,7-dichloro-3,4-dihydro-6-[[[(lS)- l-[[3-(methylsulfonyI)phenyl]methyl]-2-oxo-2-(phenylmethoxy)ethyl]
  • Impurity B 3-(methylsulfonyl)- phenylmethyl ester, hydrochloride (1:1) D- Phenyl alanine;
  • Impurity C N-[(5,7-dichloro-l,2,3,4-tetrahydro-6-isoquinolinyl)carbonyl]-3- (methylsulfonyl)- phenylmethyl ester, hydrochloride (1:1) L- Phenylalanine; Impurity D: 5,7-dichloro-l,2,3,4-tetrahydro-, hydrochloride (1:1) 6-
  • Impurity E N-[[2-(6-benzofuranylcarbonyl)-5,7-dichloro-l,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.
  • 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%.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Ophthalmology & Optometry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une composition pharmaceutique stable comprenant du lifitégrast et un ou plusieurs excipients pharmaceutiques, où la composition pharmaceutique est exempte d'antioxydants et/ou de conservateurs. Un procédé de préparation desdites compositions, leur conditionnement dans un flacon à dose unique ou à doses multiples approprié et leur utilisation dans le traitement de la sécheresse oculaire sont en outre décrits.
PCT/IB2019/051752 2018-03-09 2019-03-05 Composition pharmaceutique de lifitégrast WO2019171260A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN201811008714 2018-03-09
IN201811008714 2018-03-09

Publications (1)

Publication Number Publication Date
WO2019171260A1 true WO2019171260A1 (fr) 2019-09-12

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3842032A1 (fr) 2019-12-24 2021-06-30 Warszawskie Zaklady Farmaceutyczne Polfa S.A. Formulation pharmaceutique
CN115813853A (zh) * 2022-12-18 2023-03-21 山东济坤生物制药有限公司 一种立他司特滴眼液及其制备方法
CN116211796A (zh) * 2022-12-30 2023-06-06 新领先(重庆)医药科技有限公司 一种立他司特滴眼液及其制备方法
WO2024042550A1 (fr) * 2022-08-25 2024-02-29 Sentiss Pharma Private Limited Composition de combinaison ophtalmique

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150320737A1 (en) * 2012-12-19 2015-11-12 Sarcode Bioscience Inc. Lfa-1 inhibitor formulations

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150320737A1 (en) * 2012-12-19 2015-11-12 Sarcode Bioscience Inc. Lfa-1 inhibitor formulations

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3842032A1 (fr) 2019-12-24 2021-06-30 Warszawskie Zaklady Farmaceutyczne Polfa S.A. Formulation pharmaceutique
WO2021130168A1 (fr) 2019-12-24 2021-07-01 Warszawskie Zaklady Farmaceutyczne Polfa Sa Formulation pharmaceutique
WO2024042550A1 (fr) * 2022-08-25 2024-02-29 Sentiss Pharma Private Limited Composition de combinaison ophtalmique
CN115813853A (zh) * 2022-12-18 2023-03-21 山东济坤生物制药有限公司 一种立他司特滴眼液及其制备方法
CN116211796A (zh) * 2022-12-30 2023-06-06 新领先(重庆)医药科技有限公司 一种立他司特滴眼液及其制备方法

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