WO2022215045A1 - Lyophilized composition comprising selexipag - Google Patents
Lyophilized composition comprising selexipag Download PDFInfo
- Publication number
- WO2022215045A1 WO2022215045A1 PCT/IB2022/053312 IB2022053312W WO2022215045A1 WO 2022215045 A1 WO2022215045 A1 WO 2022215045A1 IB 2022053312 W IB2022053312 W IB 2022053312W WO 2022215045 A1 WO2022215045 A1 WO 2022215045A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- pharmaceutical composition
- lyophilized pharmaceutical
- selexipag
- lyophilized
- pharmaceutically acceptable
- Prior art date
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- QXWZQTURMXZVHJ-UHFFFAOYSA-N selexipag Chemical compound C=1C=CC=CC=1C1=NC(N(CCCCOCC(=O)NS(C)(=O)=O)C(C)C)=CN=C1C1=CC=CC=C1 QXWZQTURMXZVHJ-UHFFFAOYSA-N 0.000 title claims abstract description 60
- 229960003841 selexipag Drugs 0.000 title claims abstract description 59
- 239000000203 mixture Substances 0.000 title claims abstract description 20
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 74
- 150000003839 salts Chemical class 0.000 claims abstract description 32
- 239000000872 buffer Substances 0.000 claims abstract description 16
- 238000000034 method Methods 0.000 claims abstract description 13
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 10
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 40
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 39
- 235000002639 sodium chloride Nutrition 0.000 claims description 39
- 239000000243 solution Substances 0.000 claims description 36
- 229920001213 Polysorbate 20 Polymers 0.000 claims description 21
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 claims description 21
- 239000004471 Glycine Substances 0.000 claims description 20
- 239000003002 pH adjusting agent Substances 0.000 claims description 20
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 claims description 20
- 229940068977 polysorbate 20 Drugs 0.000 claims description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 18
- 239000004067 bulking agent Substances 0.000 claims description 15
- 238000003756 stirring Methods 0.000 claims description 15
- 239000004094 surface-active agent Substances 0.000 claims description 15
- 239000001509 sodium citrate Substances 0.000 claims description 13
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 12
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 claims description 12
- 229940038773 trisodium citrate Drugs 0.000 claims description 12
- 239000007972 injectable composition Substances 0.000 claims description 11
- 239000000194 fatty acid Substances 0.000 claims description 10
- DNIAPMSPPWPWGF-UHFFFAOYSA-N monopropylene glycol Natural products CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 8
- -1 propylene glycol diesters Chemical class 0.000 claims description 8
- 239000011780 sodium chloride Substances 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 6
- 229960002449 glycine Drugs 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical group OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 4
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 4
- 229930195725 Mannitol Natural products 0.000 claims description 4
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 4
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 4
- 239000008121 dextrose Substances 0.000 claims description 4
- 239000000594 mannitol Substances 0.000 claims description 4
- 235000010355 mannitol Nutrition 0.000 claims description 4
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 3
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 3
- 229930006000 Sucrose Natural products 0.000 claims description 3
- 239000008101 lactose Substances 0.000 claims description 3
- 239000005720 sucrose Substances 0.000 claims description 3
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 claims description 2
- 229920000858 Cyclodextrin Polymers 0.000 claims description 2
- 229920001612 Hydroxyethyl starch Polymers 0.000 claims description 2
- 229920002472 Starch Polymers 0.000 claims description 2
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 claims description 2
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims description 2
- 239000001913 cellulose Substances 0.000 claims description 2
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- 229940097362 cyclodextrins Drugs 0.000 claims description 2
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- 150000007524 organic acids Chemical class 0.000 claims description 2
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 14
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- 208000035475 disorder Diseases 0.000 abstract description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- 229910052757 nitrogen Inorganic materials 0.000 description 15
- 239000008215 water for injection Substances 0.000 description 11
- 208000002815 pulmonary hypertension Diseases 0.000 description 10
- 235000011121 sodium hydroxide Nutrition 0.000 description 9
- 238000001035 drying Methods 0.000 description 8
- 235000019263 trisodium citrate Nutrition 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 238000004519 manufacturing process Methods 0.000 description 7
- 208000010228 Erectile Dysfunction Diseases 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 239000006184 cosolvent Substances 0.000 description 6
- 201000001881 impotence Diseases 0.000 description 6
- 201000000306 sarcoidosis Diseases 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 5
- 239000008364 bulk solution Substances 0.000 description 5
- 238000011049 filling Methods 0.000 description 5
- 238000011010 flushing procedure Methods 0.000 description 5
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 5
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 4
- 108091006335 Prostaglandin I receptors Proteins 0.000 description 4
- 206010064911 Pulmonary arterial hypertension Diseases 0.000 description 4
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- 210000000056 organ Anatomy 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
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- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
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- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
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- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 2
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- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
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- BSVBQGMMJUBVOD-UHFFFAOYSA-N trisodium borate Chemical compound [Na+].[Na+].[Na+].[O-]B([O-])[O-] BSVBQGMMJUBVOD-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- KKTNQJMZBPLVKM-UHFFFAOYSA-K trisodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxymethyl)amino]acetate;hydrate Chemical compound O.[Na+].[Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O KKTNQJMZBPLVKM-UHFFFAOYSA-K 0.000 description 1
- DRTQHJPVMGBUCF-UHFFFAOYSA-N uracil arabinoside Natural products OC1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-UHFFFAOYSA-N 0.000 description 1
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- NWONKYPBYAMBJT-UHFFFAOYSA-L zinc sulfate Chemical compound [Zn+2].[O-]S([O-])(=O)=O NWONKYPBYAMBJT-UHFFFAOYSA-L 0.000 description 1
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Classifications
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- 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
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
Definitions
- the present invention relates to a lyophilized pharmaceutical composition
- a lyophilized pharmaceutical composition comprising Selexipag or pharmaceutically acceptable salt thereof and process for preparing the said composition.
- Selexipag is a selective non-prostanoid IP prostacyclin receptor agonist. Prostacyclin agonists have an established use in pulmonary arterial hypertension. Selexipag is a newer compound in this class and is structurally distinct from prostacyclin. Selexipag is hydrolyzed by carboxylesterase 1 to yield its active metabolite, which is approximately 37-fold as potent as Selexipag. Selexipag and the active metabolite are selective for the prostacyclin receptor. US 7,205,302 discloses Selexipag compound and its use in pulmonary hypertension.
- Selexipag is currently available in the US as tablets in multiple strengths of 200 meg, 400 meg, 600 meg, 800 meg, 1000 meg, 1200 meg, 1400 meg, and 1600 meg.
- the dose needs to be uptitrated starting from the smallest dose due to tolerability issues. This is particularly of inconvenience in situations where oral administration is not possible to patients or in case of emergency, where there might not be enough time for up-titration process.
- Selexipag is effective at low doses starting from micrograms, and hence present a challenge in dose delivery in injectable dosage form, as adsorption to the container parts might pose a difficulty in effective doses being delivered in a reproducible manner. Further, physical and chemical stability of Selexipag in aqueous or non-aqueous solvents needs to be monitored.
- WO 2018162527 discloses an aqueous pharmaceutical composition comprising Selexipag. There still exists a need for a lyophilized pharmaceutical composition of Selexipag.
- the present invention relates to a lyophilized pharmaceutical composition comprising selexipag or pharmaceutically acceptable salt thereof and process of preparing the same.
- the lyophilized pharmaceutical composition comprises selexipag or its pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients selected from bulking agent, surfactant, buffer, one or more pH adjusting agents.
- the lyophilized pharmaceutical composition comprises selexipag or its pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients selected from bulking agent, surfactant, one or more pH adjusting agent and buffer wherein buffer is tri sodium citrate.
- the lyophilized pharmaceutical composition comprises selexipag or its pharmaceutically acceptable salt thereof, glycine, Polysorbate 20, Trisodium Citrate, and one or more pH adjusting agents.
- the lyophilized pharmaceutical composition comprises selexipag or its pharmaceutically acceptable salt thereof, glycine, Polysorbate 20, Trisodium Citrate, and one or more pH adjusting agents selected from sodium hydroxide and hydrochloric acid.
- the lyophilized pharmaceutical composition comprises selexipag or its pharmaceutically acceptable salt thereof, bulking agent, surfactant one or more pH adjusting agents.
- the lyophilized pharmaceutical composition comprises selexipag or its pharmaceutically acceptable salt thereof, glycine, Polysorbate 20, one or more pH adjusting agents.
- the lyophilized pharmaceutical composition comprises selexipag or its pharmaceutically acceptable salt thereof, glycine, Polysorbate 20, one or more pH adjusting agents selected from sodium hydroxide and hydrochloric acid.
- the lyophilized pharmaceutical composition comprising selexipag or its pharmaceutically acceptable salt thereof is a lyophilized composition for reconstitution.
- a further embodiment relates to a process for the preparation of lyophilized injectable composition; said process comprising the steps of: a) loading the solution at a temperature of 20°C b) freezing the solution at a temperature of -50°C to -3°C to -50°C over a time period of 10 hours 5 mins c) primary drying process of the frozen solution of step (b) at a temperature of -10°C to 0°C over a time period of 29 hours d) secondary drying process of step (c) at 40°C over a time period of 6 hours
- Another embodiment relates to a process for the preparation of the lyophilized injectable composition; said process comprising the steps of: a) loading the solution at a temperature of 5°C and holding over a time period of 30 min; b) freezing the solution at a temperature of -45°C to -3°C to -45°C over a time period of 14.5 hours c) primary drying process of the frozen solution of step (b) at a temperature of -10°C to 0°C over a time period of 70.67 hours d) secondary drying process of step (c) at 40°C over a time period of 10.33 hours.
- the lyophilized pharmaceutical composition of the present invention has residual water content of less than about 2 w/w%
- the reconstituted injectable composition wherein the lyophilized pharmaceutical composition is reconstituted using, as diluent, physiologically acceptable solution, preferably, water for injection or saline; wherein the total volume of said reconstituted pharmaceutical composition is between about 2 and 10 mL
- the reconstituted lyophilized composition is reconstituted in a reconstitution time of less than about 2 minutes, preferably in about 1 minute or less.
- the reconstituted pharmaceutical composition wherein said reconstituted pharmaceutical composition, or a part of said reconstituted pharmaceutical composition, is further diluted; wherein said reconstituted and further diluted pharmaceutical composition contains an amount of about 2.25 pg/mL, 4.5 pg/mL, 9 pg/mL, 13.5 pg/mL, 18 pg/mL, 22.5 pg/mL, 27 pg/mL, 31 .5 pg/mL, or 36 pg/mL of the compound 2- ⁇ 4-[N-(5,6- diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy ⁇ -N-(methylsulfonyl)acetamide.
- the lyophilized pharmaceutical compositions of the present invention is chemically stable as a function of time i.e. contains not more than 00.1 to 2 weight percent of total impurities of selexipag after storage for 1, 3, 6, 12, 18, or 24 months at 2-8°C or at about 25 °C and about 60% relative humidity (RH).
- the lyophilized injectable compositions of the present invention described herein has a pH between about 6 and about 8, preferably between about 6.5 to about 7.5.
- the lyophilized pharmaceutical compositions of the present invention described herein has osmolality between about 200 and about 1000 mOsm/ Kg
- the lyophilized pharmaceutical composition may be used for treatment of ulcer, digital ulcer, diabetic gangrene, diabetic foot ulcer, pulmonary hypertension, pulmonary arterial hypertension, Fontan disease and pulmonary hypertension associated with Fontan disease, sarcoidosis and pulmonary hypertension associated with sarcoidosis, peripheral circulatory disturbance (e.g. intermittent claudication, Raynaud's disease), connective tissue disease (e.g. systemic lupus erythematosus, scleroderma), chronic kidney diseases including glomerulonephritis and diabetic nephropathy at any stage, diseases in which fibrosis of organs or tissues is involved.
- peripheral circulatory disturbance e.g. intermittent claudication, Raynaud's disease
- connective tissue disease e.g. systemic lupus erythematosus,
- the present invention relates to a lyophilized pharmaceutical composition comprising selexipag or pharmaceutically acceptable salt therof and process for preparing the said composition.
- Selexipag is an oral prostacyclin receptor (IP receptor) agonist that is structurally distinct from prostacyclin.
- Selexipag is hydrolyzed by carboxylesterase 1 to yield its active metabolite, which is approximately 37-fold as potent as selexipag.
- the chemical name of selexipag is 2- [ 4-[(5,6-di phenyl pyrazi n-2-yl)(i sopropyl )ami nojbutoxy ⁇ -A-( ' m ethyl sulfonyl ) acetamide. It has a molecular formula of C26H32N404S and a molecular weight of 496.62.
- Selexipag has the following structural formula:
- a lyophilized pharmaceutical composition comprising selexipag or its pharmaceutically acceptable salts thereof is in a lyophilized form for reconstitution.
- the composition may also be as a spray dried form.
- the lyophilized pharmaceutical composition may contain about 0.1 mg to about 5 mg selexipag or its pharmaceutically acceptable salt.
- a lyophilized composition may contain selexipag or its pharmaceutically acceptable salt in an amount of about 0.1 mg, about 0.2 mg, about 0.4 mg, about 0.6 mg, about 0.8 mg, about 1 mg, about 1.2 mg, about 1.4 mg, about 1.6 mg, about 1.8 mg, about 1.9 mg, about 2.0 mg, about 3 mg, about 4 mg, and about 5 mg.
- the lyophilized pharmaceutical composition comprises selexipag or its pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients selected from bulking agent, and surfactant.
- the lyophilized pharmaceutical composition comprises selexipag or its pharmaceutically acceptable salt thereof, bulking agent, surfactant, one or more pH adjusting agents.
- the lyophilized pharmaceutical composition comprises selexipag or its pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients selected from bulking agent, surfactant, one or more pH adjusting agent and buffer wherein buffer is tri sodium citrate.
- the lyophilized pharmaceutical composition comprises selexipag or its pharmaceutically acceptable salt thereof, glycine, Polysorbate 20, one or more pH adjusting agents.
- the lyophilized pharmaceutical composition comprises selexipag or its pharmaceutically acceptable salt thereof, glycine, Polysorbate 20, one or more pH adjusting agents wherein pH adjusting agent selected from alkali metal hydroxide and hydrochloric acid or combination thereof.
- the lyophilized pharmaceutical composition comprises selexipag or its pharmaceutically acceptable salt thereof, glycine, polysorbate 20, one or more pH adjusting agents selected from sodium hydroxide and hydrochloric acid.
- the lyophilized pharmaceutical composition comprises selexipag or its pharmaceutically acceptable salt thereof, bulking agent, surfactant, and buffer.
- the lyophilized pharmaceutical composition comprises selexipag or its pharmaceutically acceptable salt thereof, bulking agent, surfactant, buffer, and water.
- the lyophilized pharmaceutical composition comprises selexipag or its pharmaceutically acceptable salt thereof, glycine, polysorbate 20, trisodium citrate.
- the lyophilized pharmaceutical composition comprises selexipag or its pharmaceutically acceptable salt thereof, bulking agent, surfactant, buffer, one or more pH adjusting agent.
- the lyophilized pharmaceutical composition comprises selexipag or its pharmaceutically acceptable salt thereof, glycine, polysorbate 20, trisodium citrate, and sodium hydroxide.
- the lyophilized pharmaceutical composition comprising selexipag or pharmaceutically acceptable salt thereof is the lyophilized injectable composition.
- a further embodiment relates to a process for the preparation of the lyophilized pharmaceutical composition; said process comprising the steps of: a) loading the solution at a temperature of 20°C b) freezing the solution at a temperature of -50°C to -3°C to -50°C over a time period of 10 hours 5 min c) primary drying process of the frozen solution of step (b) at a temperature of -10°C to 0°C over a time period of 29 hours d) secondary drying process of step (c) at 40°C over a time period of 6 hours
- Another embodiment relates to a process for the preparation of the lyophilized pharmaceutical composition; said process comprising the steps of : a) loading the solution at a temperature of 5°C and holding over a time period of 30 min; b) freezing the solution at a temperature of -45°C to -3°C to -45°C over a time period of 14.5 hours c) primary drying process of the frozen solution of step (b) at a temperature of -10°C to 0°C over a time period of 70.67 hours d) secondary drying process of step (c) at 40°C over a time period of 10.33 hours
- the lyophilized pharmaceutical composition of the present invention has a residual water content of less than about 2 w/w%.
- the lyophilized pharmaceutical composition of the present invention wherein said reconstituted lyophilized pharmaceutical composition is reconstituted in a reconstitution time of less than about 2 minutes, preferably in about 1 minute or less.
- an injectable composition made by directly reconstituting the lyophilized pharmaceutical composition in a physiologically acceptable solution.
- the reconstituted injectable composition wherein the lyophilized pharmaceutical composition is reconstituted using, as diluent, physiologically acceptable solution, preferably, water for injection or saline; wherein the total volume of said reconstituted pharmaceutical composition is between about 2 and 10 mL
- the lyophilized pharmaceutical composition is reconstituted using suitable solvent before administration.
- the reconstituted injectable composition prepared by combining the lyophilized composition with suitable solvent selected from an aqueous solution or water for injection or saline.
- the reconstituted pharmaceutical composition wherein said reconstituted pharmaceutical composition, or a part of said reconstituted pharmaceutical composition, is further diluted; wherein said reconstituted and further diluted pharmaceutical composition contains an amount of about 2.25 pg/mL, 4.5 pg/mL, 9 pg/mL, 13.5 pg/mL, 18 pg/mL, 22.5 pg/mL, 27 pg/mL, 31 .5 pg/mL, or 36 pg/mL of the compound 2- ⁇ 4-[N-(5,6- diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy ⁇ -N(methylsulfonyl) acetamide.
- the lyophilized pharmaceutical composition of the present invention is chemically stable as a function of time i.e. contains not more than 00.1 to 2 weight percent of total impurities of selexipag after storage for 1, 3, 6, 12, 18, or 24 months at about 2- 8°C or at about 25 °C and about 60% relative humidity (RH).
- the lyophilized pharmaceutical composition of the present invention described herein has a pH between about 6 and about 8, preferably between about 6.5 to about 7.5.
- the lyophilized pharmaceutical compositions of the present invention described herein has osmolality between about 200 and about 1000 mOsm/ Kg.
- the lyophilized pharmaceutical composition may additionally comprise one or more pharmaceutically acceptable excipients.
- suitable pharmaceutically acceptable excipients include, but are not limited to, bulking agents, pH adjusting agents, buffering agents, isotonicity agents, pharmaceutically acceptable co-solvents, suspending agents, optionally chelating agents, surfactants, anti-oxidants, preservatives and pharmaceutically acceptable vehicles.
- bulking agent refers to a substance or component that is chemically compatible with the active pharmaceutical ingredient and with further excipients of a composition, and that adds mass to a lyophilized composition
- Bulking agents include but not limited to mannitol, lactose, sucrose, sodium chloride, trehalose, dextrose, starch, hydroxyethyl starch, cellulose, cyclodextrins, glycine, and mixtures thereof.
- the pH may be adjusted by the addition of one or more pharmaceutically acceptable acids or base.
- suitable pharmaceutically acceptable acids include inorganic acids, such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, and phosphoric acid, and any combination of any of the foregoing.
- suitable pharmacologically acceptable acids include organic acids, such as ascorbic acid, citric acid, malic acid, maleic acid, tartaric acid, succinic acid, fumaric acid, acetic acid, formic acid, propionic acid, and any combination of any of the foregoing and bases such as diethanolamine, triethanolamine and alkali metal hydroxides such as sodium hydroxide, and any combination of the foregoing.
- the pharmaceutically acceptable vehicle in the injectable pharmaceutical composition includes water and optionally a co-solvent.
- Any co-solvent that is suitable for inhalation and capable of dissolving or solubilizing the glycopyrronium and beta2 agonist in the mixture of co-solvent and water can be used.
- suitable co-solvents include, for example, alcohols, ethers, hydrocarbons, and perfluorocarbons.
- the co-solvent is a short chain polar alcohol. More preferably, the co-solvent is an aliphatic alcohol having from one to six carbon atoms, such as ethanol or isopropanol.
- a preferred co-solvent is ethanol.
- suitable hydrocarbons include n-butane, isobutane, pentane, neopentane and isopentanes.
- Suitable surfactants include, but are not limited to, Cs- 2 o-fatty alcohols, Cs- 20 -fatty acids, C 5-2 o-fatty acid esters, lecithin, glycerides, propylene glycol esters, polyoxyethylenes, polysorbates, sorbitan esters, carbohydrates, and any combination of any of the foregoing.
- C 5 - 20 -fatty acids, propylene glycol diesters of the Cs- 20 -fatty acids, triglycerides of the Cs- 20 -fatty acids, and sorbitans of the Cs- 2 o-fatty acids are preferred.
- the surfactant is selected from Polysorbate 20, Polyoxyethylene (20) sorbitan monolaurate, oleic acid, sorbitan mono-, di- or trioleates, and any combination of any of the foregoing.
- the osmolality of the composition may be from about 200-1000 mOsm/kg.
- Suitable tonicity adjusting agents include, but are not limited to, ammonium carbonate, ammonium chloride, ammonium lactate, ammonium nitrate, ammonium phosphate, amonium sulfate, ascorbic acid, bismuth sodium tartrate, boric acid, calcium chloride, calcium disodium edetate, calcium gluconate, calcium lactate, citric acid, dextrose, diethanolamine, dimethyl sulfoxide, edetate disodium, edetate trisodium monohydrate, fluorescein sodium, fructose, galactose, glycerin, lactic acid, lactose, magnesium chloride, magnesium sulfate, mannitol, polyethylene glycol, potassium acetate, potassium chlorate, potassium chloride, potassium iodide, potassium nitrate, potassium phosphate, potassium sulfate
- Suitable osmotic adjusting agents include, but are not limited to, sodium chloride, potassium chloride, zinc chloride, calcium chloride and any combination of any of the foregoing.
- Other osmotic adjusting agents include, but are not limited to, mannitol, glycerol, dextrose and any combination of any of the foregoing.
- the lyophilized pharmaceutical composition may be contained in a suitable container like vials, or syringes.
- the container may also be amber color container or transparent container completely covered to avoid contact of light with composition.
- the lyophilized pharmaceutical composition provided herein have a long shelf life, i.e., it is stable during long term storage.
- the composition may contain greater than about 80%, such as greater than about 85%, greater than about 90%, greater than about 95% or greater than about 98% of the initial amount of selexipag (or its salt) after being stored for 1, 3 or 6 months at 2-8 0 C or 25° C/60%RH when stored in a suitable container.
- the lyophilized pharmaceutical composition of the present invention may be used for the treatment of ulcer, digital ulcer, diabetic gangrene, diabetic foot ulcer, pressure ulcer (bedsore), hypertension, pulmonary hypertension, pulmonary arterial hypertension, Fontan disease and pulmonary hypertension associated with Fontan disease, sarcoidosis and pulmonary hypertension associated with sarcoidosis, peripheral circulatory disturbance (e.g., chronic arterial occlusion, intermittent claudication, peripheral embolism, vibration syndrome, Raynaud's disease), connective tissue disease (e.g., systemic lupus erythematosus, scleroderma, mixed connective tissue disease, vasculitic syndrome), reocclusion/restenosis after percutaneous transluminal coronary angioplasty (PTCA), arteriosclerosis, thrombosis (e.g., acute-phase cerebral thrombosis, pulmonary embolism), transient ischemic attack (TIA), diabetic neuropathy, ischemic disorder (e
- hepatocirrhosis hepatocirrhosis, viral hepatitis, chronic pancreatitis and scirrhous stomachic cancer
- cardiovascular diseases e.g, myocardial fibrosis
- bone and articular diseases e.g, bone marrow fibrosis and rheumatoid arthritis
- skin diseases e.g, cicatrix after operation, scalded cicatrix, keloid, and hypertrophic cicatrix
- obstetric diseases e.g., hysteromyoma
- urinary diseases e.g., prostatic hypertrophy
- other diseases e.g., alzheimer's disease, sclerosing peritonitis, type I diabetes and organ adhesion after operation
- erectile dysfunction e.g., y diabetic erectile dysfunction, psychogenic erectile dysfunction, psychotic erectile dysfunction, erectile dysfunction associated with chronic renal
- the lyophilized pharmaceutical composition of the present invention maybe used for the treatment of ulcer, digital ulcer, diabetic gangrene, diabetic foot ulcer, pulmonary hypertension, pulmonary arterial hypertension, Fontan disease and pulmonary hypertension associated with Fontan disease, sarcoidosis and pulmonary hypertension associated with sarcoidosis, peripheral circulatory disturbance (e.g. intermittent claudication, Raynaud's disease), connective tissue disease (e.g. systemic lupus erythematosus, scleroderma), chronic kidney diseases including glomerulonephritis and diabetic nephropathy at any stage, diseases in which fibrosis of organs or tissues is involved.
- peripheral circulatory disturbance e.g. intermittent claudication, Raynaud's disease
- connective tissue disease e.g. systemic lupus erythematosus, scleroderma
- chronic kidney diseases including glomerulonephritis and diabetic nephropathy at any stage, diseases in
- pH is measured of the bulk solution and adjusted to 7.5 ⁇ 0.5 with 0.1 N HC1 and/ or 0.1 NNaOH;
- pH is measured of the bulk solution and adjusted to 7.0 ⁇ 0.5 with 0.1 N NaOH, if required.
- pH is measured of the bulk solution and adjusted to 7.0 ⁇ 0.5 with 0.1 N NaOH, if required.
- volume is made up with pre nitrogen purged water for injection
- volume is then made up with nitrogen purged water for injection;
- volume is made up with nitrogen purged water for inj ection.
Abstract
The invention relates to a lyophilized pharmaceutical composition comprising Selexipag or pharmaceutically acceptable salt thereof. The composition of the present invention further comprises pharmaceutically acceptable excipients and optionally contains buffer. The invention further relates to a process of preparing the said composition which may be used for the treatment of various diseases or disorders.
Description
LYOPHILIZED COMPOSITION COMPRISING SELEXIPAG
RELATED APPLICATIONS
This application claims the benefit of Indian Provisional Application No. 202121016614 filed on April 8, 2021; which is hereby incorporated by reference in its entirety.
FIELD OF THE INVENTION
The present invention relates to a lyophilized pharmaceutical composition comprising Selexipag or pharmaceutically acceptable salt thereof and process for preparing the said composition.
BACKGROUND OF THE INVENTION
Selexipag is a selective non-prostanoid IP prostacyclin receptor agonist. Prostacyclin agonists have an established use in pulmonary arterial hypertension. Selexipag is a newer compound in this class and is structurally distinct from prostacyclin. Selexipag is hydrolyzed by carboxylesterase 1 to yield its active metabolite, which is approximately 37-fold as potent as Selexipag. Selexipag and the active metabolite are selective for the prostacyclin receptor. US 7,205,302 discloses Selexipag compound and its use in pulmonary hypertension.
Selexipag is currently available in the US as tablets in multiple strengths of 200 meg, 400 meg, 600 meg, 800 meg, 1000 meg, 1200 meg, 1400 meg, and 1600 meg. The dose needs to be uptitrated starting from the smallest dose due to tolerability issues. This is particularly of inconvenience in situations where oral administration is not possible to patients or in case of emergency, where there might not be enough time for up-titration process. There is a need for injectable composition of Selexipag for ease and convenience of administration.
Selexipag is effective at low doses starting from micrograms, and hence present a challenge in dose delivery in injectable dosage form, as adsorption to the container parts might pose a difficulty in effective doses being delivered in a reproducible manner. Further, physical and chemical stability of Selexipag in aqueous or non-aqueous solvents needs to be monitored.
WO 2018162527 discloses an aqueous pharmaceutical composition comprising Selexipag. There still exists a need for a lyophilized pharmaceutical composition of Selexipag.
SUMMARY OF THE INVENTION
The present invention relates to a lyophilized pharmaceutical composition comprising selexipag or pharmaceutically acceptable salt thereof and process of preparing the same.
In one embodiment, the lyophilized pharmaceutical composition comprises selexipag or its pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients selected from bulking agent, surfactant, buffer, one or more pH adjusting agents.
In other embodiment, the lyophilized pharmaceutical composition comprises selexipag or its pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients selected from bulking agent, surfactant, one or more pH adjusting agent and buffer wherein buffer is tri sodium citrate.
In another embodiment, the lyophilized pharmaceutical composition comprises selexipag or its pharmaceutically acceptable salt thereof, glycine, Polysorbate 20, Trisodium Citrate, and one or more pH adjusting agents.
In another embodiment, the lyophilized pharmaceutical composition comprises selexipag or its pharmaceutically acceptable salt thereof, glycine, Polysorbate 20, Trisodium Citrate, and one or more pH adjusting agents selected from sodium hydroxide and hydrochloric acid.
In one embodiment, the lyophilized pharmaceutical composition comprises selexipag or its pharmaceutically acceptable salt thereof, bulking agent, surfactant one or more pH adjusting agents.
In one embodiment, the lyophilized pharmaceutical composition comprises selexipag or its pharmaceutically acceptable salt thereof, glycine, Polysorbate 20, one or more pH adjusting agents.
In one embodiment, the lyophilized pharmaceutical composition comprises selexipag or its pharmaceutically acceptable salt thereof, glycine, Polysorbate 20, one or more pH adjusting agents selected from sodium hydroxide and hydrochloric acid.
In another embodiment, the lyophilized pharmaceutical composition comprising selexipag or its pharmaceutically acceptable salt thereof is a lyophilized composition for reconstitution.
A further embodiment relates to a process for the preparation of lyophilized injectable composition; said process comprising the steps of: a) loading the solution at a temperature of 20°C b) freezing the solution at a temperature of -50°C to -3°C to -50°C over a time period of 10 hours 5 mins
c) primary drying process of the frozen solution of step (b) at a temperature of -10°C to 0°C over a time period of 29 hours d) secondary drying process of step (c) at 40°C over a time period of 6 hours
Another embodiment relates to a process for the preparation of the lyophilized injectable composition; said process comprising the steps of: a) loading the solution at a temperature of 5°C and holding over a time period of 30 min; b) freezing the solution at a temperature of -45°C to -3°C to -45°C over a time period of 14.5 hours c) primary drying process of the frozen solution of step (b) at a temperature of -10°C to 0°C over a time period of 70.67 hours d) secondary drying process of step (c) at 40°C over a time period of 10.33 hours.
In another embodiment, the lyophilized pharmaceutical composition of the present invention has residual water content of less than about 2 w/w%
In another embodiment, the reconstituted injectable composition; wherein the lyophilized pharmaceutical composition is reconstituted using, as diluent, physiologically acceptable solution, preferably, water for injection or saline; wherein the total volume of said reconstituted pharmaceutical composition is between about 2 and 10 mL
In another embodiment, the reconstituted lyophilized composition is reconstituted in a reconstitution time of less than about 2 minutes, preferably in about 1 minute or less.
In another embodiment, the reconstituted pharmaceutical composition; wherein said reconstituted pharmaceutical composition, or a part of said reconstituted pharmaceutical composition, is further diluted; wherein said reconstituted and further diluted pharmaceutical composition contains an amount of about 2.25 pg/mL, 4.5 pg/mL, 9 pg/mL, 13.5 pg/mL, 18 pg/mL, 22.5 pg/mL, 27 pg/mL, 31 .5 pg/mL, or 36 pg/mL of the compound 2-{4-[N-(5,6- diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide.
In one embodiment, the lyophilized pharmaceutical compositions of the present invention is chemically stable as a function of time i.e. contains not more than 00.1 to 2 weight percent of total impurities of selexipag after storage for 1, 3, 6, 12, 18, or 24 months at 2-8°C or at about 25 °C and about 60% relative humidity (RH).
In another embodiment, the lyophilized injectable compositions of the present invention described herein has a pH between about 6 and about 8, preferably between about 6.5 to about 7.5.
In another embodiment, the lyophilized pharmaceutical compositions of the present invention described herein has osmolality between about 200 and about 1000 mOsm/ Kg
In other embodiment, the lyophilized pharmaceutical composition may be used for treatment of ulcer, digital ulcer, diabetic gangrene, diabetic foot ulcer, pulmonary hypertension, pulmonary arterial hypertension, Fontan disease and pulmonary hypertension associated with Fontan disease, sarcoidosis and pulmonary hypertension associated with sarcoidosis, peripheral circulatory disturbance (e.g. intermittent claudication, Raynaud's disease), connective tissue disease (e.g. systemic lupus erythematosus, scleroderma), chronic kidney diseases including glomerulonephritis and diabetic nephropathy at any stage, diseases in which fibrosis of organs or tissues is involved.
Other objects, features and advantages of the present invention will be apparent to those of ordinary skill in the art in view of the following detailed description of the invention.
DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a lyophilized pharmaceutical composition comprising selexipag or pharmaceutically acceptable salt therof and process for preparing the said composition.
Selexipag is an oral prostacyclin receptor (IP receptor) agonist that is structurally distinct from prostacyclin. Selexipag is hydrolyzed by carboxylesterase 1 to yield its active metabolite, which is approximately 37-fold as potent as selexipag. The chemical name of selexipag is 2- [ 4-[(5,6-di phenyl pyrazi n-2-yl)(i sopropyl )ami nojbutoxy } -A-('m ethyl sulfonyl ) acetamide. It has a molecular formula of C26H32N404S and a molecular weight of 496.62. Selexipag has the following structural formula:
A lyophilized pharmaceutical composition comprising selexipag or its pharmaceutically acceptable salts thereof is in a lyophilized form for reconstitution. Alternatively, the composition may also be as a spray dried form.
The lyophilized pharmaceutical composition may contain about 0.1 mg to about 5 mg selexipag or its pharmaceutically acceptable salt. Preferably, a lyophilized composition may contain selexipag or its pharmaceutically acceptable salt in an amount of about 0.1 mg, about 0.2 mg, about 0.4 mg, about 0.6 mg, about 0.8 mg, about 1 mg, about 1.2 mg, about 1.4 mg,
about 1.6 mg, about 1.8 mg, about 1.9 mg, about 2.0 mg, about 3 mg, about 4 mg, and about 5 mg.
In one more embodiment, the lyophilized pharmaceutical composition comprises selexipag or its pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients selected from bulking agent, and surfactant.
In one embodiment, the lyophilized pharmaceutical composition comprises selexipag or its pharmaceutically acceptable salt thereof, bulking agent, surfactant, one or more pH adjusting agents.
In other embodiment, the lyophilized pharmaceutical composition comprises selexipag or its pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients selected from bulking agent, surfactant, one or more pH adjusting agent and buffer wherein buffer is tri sodium citrate.
In one embodiment, the lyophilized pharmaceutical composition comprises selexipag or its pharmaceutically acceptable salt thereof, glycine, Polysorbate 20, one or more pH adjusting agents.
In one embodiment, the lyophilized pharmaceutical composition comprises selexipag or its pharmaceutically acceptable salt thereof, glycine, Polysorbate 20, one or more pH adjusting agents wherein pH adjusting agent selected from alkali metal hydroxide and hydrochloric acid or combination thereof.
In one embodiment, the lyophilized pharmaceutical composition comprises selexipag or its pharmaceutically acceptable salt thereof, glycine, polysorbate 20, one or more pH adjusting agents selected from sodium hydroxide and hydrochloric acid.
In one more embodiment, the lyophilized pharmaceutical composition comprises selexipag or its pharmaceutically acceptable salt thereof, bulking agent, surfactant, and buffer.
In one more embodiment, the lyophilized pharmaceutical composition comprises selexipag or its pharmaceutically acceptable salt thereof, bulking agent, surfactant, buffer, and water.
In another embodiment, the lyophilized pharmaceutical composition comprises selexipag or its pharmaceutically acceptable salt thereof, glycine, polysorbate 20, trisodium citrate.
In one embodiment, the lyophilized pharmaceutical composition comprises selexipag or its pharmaceutically acceptable salt thereof, bulking agent, surfactant, buffer, one or more pH adjusting agent.
In another embodiment, the lyophilized pharmaceutical composition comprises selexipag or its pharmaceutically acceptable salt thereof, glycine, polysorbate 20, trisodium citrate, and sodium hydroxide.
In another embodiment, the lyophilized pharmaceutical composition comprising selexipag or pharmaceutically acceptable salt thereof is the lyophilized injectable composition.
A further embodiment relates to a process for the preparation of the lyophilized pharmaceutical composition; said process comprising the steps of: a) loading the solution at a temperature of 20°C b) freezing the solution at a temperature of -50°C to -3°C to -50°C over a time period of 10 hours 5 min c) primary drying process of the frozen solution of step (b) at a temperature of -10°C to 0°C over a time period of 29 hours d) secondary drying process of step (c) at 40°C over a time period of 6 hours
Another embodiment relates to a process for the preparation of the lyophilized pharmaceutical composition; said process comprising the steps of : a) loading the solution at a temperature of 5°C and holding over a time period of 30 min; b) freezing the solution at a temperature of -45°C to -3°C to -45°C over a time period of 14.5 hours c) primary drying process of the frozen solution of step (b) at a temperature of -10°C to 0°C over a time period of 70.67 hours d) secondary drying process of step (c) at 40°C over a time period of 10.33 hours
In another embodiment, the lyophilized pharmaceutical composition of the present invention has a residual water content of less than about 2 w/w%.
In another embodiment, the lyophilized pharmaceutical composition of the present invention wherein said reconstituted lyophilized pharmaceutical composition is reconstituted in a reconstitution time of less than about 2 minutes, preferably in about 1 minute or less.
In another embodiment, an injectable composition made by directly reconstituting the lyophilized pharmaceutical composition in a physiologically acceptable solution.
In another embodiment, the reconstituted injectable composition; wherein the lyophilized pharmaceutical composition is reconstituted using, as diluent, physiologically acceptable solution, preferably, water for injection or saline; wherein the total volume of said reconstituted pharmaceutical composition is between about 2 and 10 mL
In another embodiment, the lyophilized pharmaceutical composition is reconstituted using suitable solvent before administration.
In another embodiment, the reconstituted injectable composition prepared by combining the lyophilized composition with suitable solvent selected from an aqueous solution or water for injection or saline.
In another embodiments, the reconstituted pharmaceutical composition; wherein said reconstituted pharmaceutical composition, or a part of said reconstituted pharmaceutical composition, is further diluted; wherein said reconstituted and further diluted pharmaceutical composition contains an amount of about 2.25 pg/mL, 4.5 pg/mL, 9 pg/mL, 13.5 pg/mL, 18 pg/mL, 22.5 pg/mL, 27 pg/mL, 31 .5 pg/mL, or 36 pg/mL of the compound 2-{4-[N-(5,6- diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N(methylsulfonyl) acetamide.
In one embodiment, the lyophilized pharmaceutical composition of the present invention is chemically stable as a function of time i.e. contains not more than 00.1 to 2 weight percent of total impurities of selexipag after storage for 1, 3, 6, 12, 18, or 24 months at about 2- 8°C or at about 25 °C and about 60% relative humidity (RH).
In another embodiment, the lyophilized pharmaceutical composition of the present invention described herein has a pH between about 6 and about 8, preferably between about 6.5 to about 7.5.
In another embodiment, the lyophilized pharmaceutical compositions of the present invention described herein has osmolality between about 200 and about 1000 mOsm/ Kg.
The lyophilized pharmaceutical composition may additionally comprise one or more pharmaceutically acceptable excipients. Suitable pharmaceutically acceptable excipients include, but are not limited to, bulking agents, pH adjusting agents, buffering agents, isotonicity agents, pharmaceutically acceptable co-solvents, suspending agents, optionally chelating agents, surfactants, anti-oxidants, preservatives and pharmaceutically acceptable vehicles.
The term "bulking agent" refers to a substance or component that is chemically compatible with the active pharmaceutical ingredient and with further excipients of a composition, and that adds mass to a lyophilized composition Bulking agents include but not limited to mannitol, lactose, sucrose, sodium chloride, trehalose, dextrose, starch, hydroxyethyl starch, cellulose, cyclodextrins, glycine, and mixtures thereof.
The pH may be adjusted by the addition of one or more pharmaceutically acceptable acids or base. Non-limiting examples of suitable pharmaceutically acceptable acids include inorganic acids, such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, and phosphoric acid, and any combination of any of the foregoing. Non-limiting examples of other suitable pharmacologically acceptable acids include organic acids, such as ascorbic acid, citric acid, malic acid, maleic acid, tartaric acid, succinic acid, fumaric acid, acetic acid, formic acid,
propionic acid, and any combination of any of the foregoing and bases such as diethanolamine, triethanolamine and alkali metal hydroxides such as sodium hydroxide, and any combination of the foregoing.
The pharmaceutically acceptable vehicle in the injectable pharmaceutical composition includes water and optionally a co-solvent. Any co-solvent that is suitable for inhalation and capable of dissolving or solubilizing the glycopyrronium and beta2 agonist in the mixture of co-solvent and water can be used. Examples of suitable co-solvents include, for example, alcohols, ethers, hydrocarbons, and perfluorocarbons. Preferably, the co-solvent is a short chain polar alcohol. More preferably, the co-solvent is an aliphatic alcohol having from one to six carbon atoms, such as ethanol or isopropanol. A preferred co-solvent is ethanol. Non-limiting examples of suitable hydrocarbons include n-butane, isobutane, pentane, neopentane and isopentanes.
Suitable surfactants include, but are not limited to, Cs-2o-fatty alcohols, Cs-20-fatty acids, C5-2o-fatty acid esters, lecithin, glycerides, propylene glycol esters, polyoxyethylenes, polysorbates, sorbitan esters, carbohydrates, and any combination of any of the foregoing. C5- 20-fatty acids, propylene glycol diesters of the Cs-20-fatty acids, triglycerides of the Cs-20-fatty acids, and sorbitans of the Cs-2o-fatty acids are preferred. In one preferred embodiment, the surfactant is selected from Polysorbate 20, Polyoxyethylene (20) sorbitan monolaurate, oleic acid, sorbitan mono-, di- or trioleates, and any combination of any of the foregoing.
The osmolality of the composition may be from about 200-1000 mOsm/kg. Suitable tonicity adjusting agents include, but are not limited to, ammonium carbonate, ammonium chloride, ammonium lactate, ammonium nitrate, ammonium phosphate, amonium sulfate, ascorbic acid, bismuth sodium tartrate, boric acid, calcium chloride, calcium disodium edetate, calcium gluconate, calcium lactate, citric acid, dextrose, diethanolamine, dimethyl sulfoxide, edetate disodium, edetate trisodium monohydrate, fluorescein sodium, fructose, galactose, glycerin, lactic acid, lactose, magnesium chloride, magnesium sulfate, mannitol, polyethylene glycol, potassium acetate, potassium chlorate, potassium chloride, potassium iodide, potassium nitrate, potassium phosphate, potassium sulfate, propylene glycol, silver nitrate, sodium acetate, sodium bicarbonate, sodium biphosphate, sodium bisulfite, sodium borate, sodium bromide, sodium cacodylate, sodium carbonate, sodium chloride, sodium citrate, sodium iodide, sodium lactate, sodium metabisulfite, sodium nitrate, sodium nitrite, sodium phosphate, sodium propionate, sodium succinate, sodium sulfate, sodium sulfite, sodium tartrate, sodium thiosulfate, sorbitol, sucrose, tartaric acid, triethanolamine, urea, urethan, uridine, zinc sulfate, and any combination of any of the foregoing. Suitable osmotic adjusting agents include, but are
not limited to, sodium chloride, potassium chloride, zinc chloride, calcium chloride and any combination of any of the foregoing. Other osmotic adjusting agents include, but are not limited to, mannitol, glycerol, dextrose and any combination of any of the foregoing.
The lyophilized pharmaceutical composition may be contained in a suitable container like vials, or syringes. The container may also be amber color container or transparent container completely covered to avoid contact of light with composition.
The lyophilized pharmaceutical composition provided herein have a long shelf life, i.e., it is stable during long term storage. The composition may contain greater than about 80%, such as greater than about 85%, greater than about 90%, greater than about 95% or greater than about 98% of the initial amount of selexipag (or its salt) after being stored for 1, 3 or 6 months at 2-80 C or 25° C/60%RH when stored in a suitable container.
The lyophilized pharmaceutical composition of the present invention may be used for the treatment of ulcer, digital ulcer, diabetic gangrene, diabetic foot ulcer, pressure ulcer (bedsore), hypertension, pulmonary hypertension, pulmonary arterial hypertension, Fontan disease and pulmonary hypertension associated with Fontan disease, sarcoidosis and pulmonary hypertension associated with sarcoidosis, peripheral circulatory disturbance (e.g., chronic arterial occlusion, intermittent claudication, peripheral embolism, vibration syndrome, Raynaud's disease), connective tissue disease (e.g., systemic lupus erythematosus, scleroderma, mixed connective tissue disease, vasculitic syndrome), reocclusion/restenosis after percutaneous transluminal coronary angioplasty (PTCA), arteriosclerosis, thrombosis (e.g., acute-phase cerebral thrombosis, pulmonary embolism), transient ischemic attack (TIA), diabetic neuropathy, ischemic disorder (e.g., cerebral infarction, myocardial infarction), angina (e.g., stable angina, unstable angina), chronic kidney diseases including glomerulonephritis and diabetic nephropathy at any stage, allergy, bronchial asthma, restenosis after coronary intervention such as atherectomy and stent implantation, thrombocytopenia by dialysis, the diseases in which fibrosis of organs or tissues is involved [e.g., renal diseases such as tubulointerstitial nephritis), respiratory diseases (e.g., interstitial pneumonia, (idiopathic) pulmonary fibrosis, chronic obstructive pulmonary disease), digestive diseases (e.g,. hepatocirrhosis, viral hepatitis, chronic pancreatitis and scirrhous stomachic cancer), cardiovascular diseases (e.g, myocardial fibrosis), bone and articular diseases (e.g, bone marrow fibrosis and rheumatoid arthritis), skin diseases (e.g, cicatrix after operation, scalded cicatrix, keloid, and hypertrophic cicatrix), obstetric diseases (e.g., hysteromyoma), urinary diseases (e.g., prostatic hypertrophy), other diseases (e.g., alzheimer's disease, sclerosing peritonitis, type I diabetes and organ adhesion after operation)], erectile dysfunction (e.g., y
diabetic erectile dysfunction, psychogenic erectile dysfunction, psychotic erectile dysfunction, erectile dysfunction associated with chronic renal failure, erectile dysfunction after intrapelvic operation for removing prostata, and vascular erectile dysfunction associated with aging and arteriosclerosis), inflammatory bowel disease (e.g., ulcerative colitis, Crohn's disease, intestinal tuberculosis, ischemic colitis and intestinal ulcer associated with Behcet disease), gastritis, gastric ulcer, ischemic ophthalmopathy (e.g., retinal artery occlusion, retinal vein occlusion, ischemic optic neuropathy), sudden hearing loss, avascular necrosis of bone, intestinal damage caused by administration of a non-steroidal anti-inflammatory agent and symptoms associated with lumbar spinal canal stenosis.
The lyophilized pharmaceutical composition of the present invention maybe used for the treatment of ulcer, digital ulcer, diabetic gangrene, diabetic foot ulcer, pulmonary hypertension, pulmonary arterial hypertension, Fontan disease and pulmonary hypertension associated with Fontan disease, sarcoidosis and pulmonary hypertension associated with sarcoidosis, peripheral circulatory disturbance (e.g. intermittent claudication, Raynaud's disease), connective tissue disease (e.g. systemic lupus erythematosus, scleroderma), chronic kidney diseases including glomerulonephritis and diabetic nephropathy at any stage, diseases in which fibrosis of organs or tissues is involved.
The following examples further illustrate the invention, but are not limiting.
Example 1
Manufacturing Process:
1. 0.1 M trisodium citrate dihydrate solution prepared with pre nitrogen purged water for injection;
2. Polysorbate 20 added and dissolved in the above solution at stirring;
3. selexipag added under stirring till complete dissolution and clear solution is obtained;
4. Glycine is added and dissolved completely at RT under stirring;
5. Volume made up with nitrogen purged 0.1 M tri sodium citrate buffer;
6. pH is measured of the bulk solution and adjusted to 7.5±0.5 with 0.1 N HC1 and/ or 0.1 NNaOH;
7. after filtration with 0.2 pm filter; filling done with pre and post nitrogen flushing followed by partial stoppering and lyophilized.
Example 2
Manufacturing Process:
1. 0.1 M trisodium citrate dihydrate solution prepared with pre nitrogen purged water for injection
2. Polysorbate 20 added and dissolved in the above solution under stirring.
3. selexipag added under stirring till complete dissolution of selexipag and clear solution is obtained.
4. Glycine added and dissolved completely at RT under stirring.
5. Volume made up with nitrogen purged 0.1 M trisodium citrate buffer.
6. pH is measured of the bulk solution and adjusted to 7.0±0.5 with 0.1 N NaOH, if required.
7. After filtration with 0.2 pm filter; filling done with pre and post nitrogen flushing followed by partial stoppering and lyophilized.
Example 3
Manufacturing Process:
1. 0.1 M trisodium citrate dihydrate solution prepared with pre nitrogen purged water for injection;
2. 0.1 M trisodium citrate dihydrate solution withdrawn in the volume equal to 80% of the batch volume and stirred at RT.
3. Polysorbate 20 added to the above solution and stirred till clear solution is obtained.
4. selexipag added and stirred at 300 rpm till clear solution is obtained.
5. Glycine added and dissolved completely at RT under stirring.
6. pH is measured of the bulk solution and adjusted to 7.0±0.5 with 0.1 N NaOH, if required.
7. Volume is made up with pre nitrogen purged water for injection;
8. After filtration with 0.2 pm filter; filling done with pre and post nitrogen flushing followed by partial stoppering and subjected to lyophilization
Example 4
Manufacturing Process:
1. 0.025 N aqueous Sodium Hydroxide solution prepared with nitrogen purged water for injection;
2. Polysorbate 20 added to the above solution and dissolved under stirring;
3. Selexipag added under stirring till clear solution is obtained;
4. Glycine added and dissolved completely at RT under stirring;
5. Volume is then made up with nitrogen purged water for injection;
6. pH measured of the bulk solution and filtration conducted with 0.2 pm filter.
7. Filling done with pre and post nitrogen flushing followed by partial stoppering and lyophilized.
Example 5
Manufacturing Process:
1. 0.025 N aqueous sodium hydroxide solution prepared with nitrogen purged water for injection.
2. Polysorbate 20 added and dissolved to the above solution under stirring.
3. Selexipag added and stirred till clear solution obtained.
4. Glycine added and dissolved completely at RT under stirring.
5. Volume is made up with nitrogen purged water for inj ection.
6. pH measured of the bulk solution and filtered with 0.2 pm filter.
7. Filling done with pre and post nitrogen flushing followed by partial stoppering and lyophilized.
Throughout this specification it is to be understood that the words "comprise" and "include" and variations such as "comprises", "comprising", "includes", "including" are to be interpreted inclusively, unless the context requires otherwise. That is, the use of these words may imply the inclusion of an element or elements not specifically recited.
Claims
1. A lyophilized pharmaceutical composition comprising selexipag or pharmaceutically acceptable salt thereof, and pharmaceutically acceptable excipients selected from bulking agent, surfactant, pH adjusting agent; and optionally one or more buffer.
2. The lyophilized pharmaceutical composition according to claim 1; wherein the bulking agent is selected from mannitol, lactose, sucrose, sodium chloride, trehalose, dextrose, starch, hydroxyethyl starch, cellulose, cyclodextrins, glycine, or combination thereof.
3. The lyophilized pharmaceutical composition according to claim 1; wherein the surfactant is selected from Cs-2o-fatty acids, propylene glycol diesters of the Cs-2o-fatty acids, triglycerides of the Cs-20-fatty acids, polysorbate 20 and sorbitans of the C5-2o-fatty acids or combination thereof.
4. The lyophilized pharmaceutical composition according to claim 1; wherein the pH adjusting agent is selected from inorganic acids or organic acids to adjust pH between about 6 and about 8.
5. The lyophilized pharmaceutical composition according to claim 1; comprises trisodium citrate buffer.
6. A lyophilized pharmaceutical composition comprising selexipag or pharmaceutically acceptable salt thereof, and pharmaceutically acceptable excipients selected from one or more of bulking agent, surfactant, pH adjusting agent; and buffer, wherein buffer is trisodium citrate.
7. The lyophilized pharmaceutical composition according to claim 6 comprises glycine, polysorbate 20, trisodium citrate, pH adjusting agent selected from alkali metal hydroxide or hydrochloric acid.
8. The lyophilized pharmaceutical composition according to claim 7 comprises sodium hydroxide or hydrochloric acid or combination thereof.
9. A lyophilized pharmaceutical composition comprising selexipag or pharmaceutically acceptable salt thereof, glycine, polysorbate 20, pH adjusting agent selected from alkali metal hydroxide or hydrochloric acid.
10. The lyophilized pharmaceutical composition according to claim 9; comprises glycine, polysorbate 20, sodium hydroxide or hydrochloric acid or combination thereof.
11. A process for the preparation of the lyophilized pharmaceutical composition comprising steps:
1. Addition of polysorbate 20 to the aqueous sodium hydroxide solution under stirring.
2. addition of Selexipag or pharmaceutically acceptable salt thereof at stirring till clear solution is obtained.
3. Addition of glycine under stirring.
4. pH of solution adjusted with sodium hydroxide and lyophilized to obtain lyophilized composition.
12. The process for preparation of the lyophilized pharmaceutical composition according to claim 11, comprises optional step of addition of trisodium citrate buffer.
13. A lyophilized pharmaceutical composition according to claim 1 is reconstituted using suitable solvent before administration.
14. An injectable composition made by directly reconstituting the lyophilized pharmaceutical composition according to claim 1 in a physiologically acceptable solution.
15. An inj ectable composition according to claim 14 prepared by combining the lyophilized composition with an aqueous solution or saline.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018162527A1 (en) * | 2017-03-08 | 2018-09-13 | Actelion Pharmaceuticals Ltd | Pharmaceutical composition comprising selexipag |
| IN201821034315A (en) * | 2018-09-12 | 2020-07-31 | Enaltec Pharma Research Private Limited |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018162527A1 (en) * | 2017-03-08 | 2018-09-13 | Actelion Pharmaceuticals Ltd | Pharmaceutical composition comprising selexipag |
| IN201821034315A (en) * | 2018-09-12 | 2020-07-31 | Enaltec Pharma Research Private Limited |
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