CA2864643A1 - Novel pharmaceutical formulations - Google Patents
Novel pharmaceutical formulations Download PDFInfo
- Publication number
- CA2864643A1 CA2864643A1 CA 2864643 CA2864643A CA2864643A1 CA 2864643 A1 CA2864643 A1 CA 2864643A1 CA 2864643 CA2864643 CA 2864643 CA 2864643 A CA2864643 A CA 2864643A CA 2864643 A1 CA2864643 A1 CA 2864643A1
- Authority
- CA
- Canada
- Prior art keywords
- compound
- formula
- pharmaceutical formulation
- lactose
- magnesium stearate
- Prior art date
- Legal status (The legal status 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 status listed.)
- Abandoned
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 78
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims abstract description 120
- 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 abstract description 77
- 239000008101 lactose Substances 0.000 claims abstract description 77
- 150000003839 salts Chemical class 0.000 claims abstract description 68
- 229910052751 metal Inorganic materials 0.000 claims abstract description 65
- 239000002184 metal Substances 0.000 claims abstract description 65
- 235000019359 magnesium stearate Nutrition 0.000 claims abstract description 60
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims abstract description 49
- 235000021355 Stearic acid Nutrition 0.000 claims abstract description 43
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims abstract description 43
- 239000008117 stearic acid Substances 0.000 claims abstract description 43
- 239000000843 powder Substances 0.000 claims abstract description 36
- 239000004480 active ingredient Substances 0.000 claims abstract description 31
- MHQJUHSHQGQVTM-HNENSFHCSA-N Octadecyl fumarate Chemical class CCCCCCCCCCCCCCCCCCOC(=O)\C=C/C(O)=O MHQJUHSHQGQVTM-HNENSFHCSA-N 0.000 claims abstract description 23
- 239000003381 stabilizer Substances 0.000 claims abstract description 23
- 229940071138 stearyl fumarate Drugs 0.000 claims abstract description 23
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical class [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000012453 solvate Substances 0.000 claims abstract description 9
- 230000000155 isotopic effect Effects 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 141
- 229960001375 lactose Drugs 0.000 claims description 77
- 239000000203 mixture Substances 0.000 claims description 60
- 239000007787 solid Substances 0.000 claims description 40
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 30
- 238000000034 method Methods 0.000 claims description 29
- 238000009472 formulation Methods 0.000 claims description 28
- 239000003814 drug Substances 0.000 claims description 27
- 238000011282 treatment Methods 0.000 claims description 20
- 208000006673 asthma Diseases 0.000 claims description 17
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 15
- 238000002144 chemical decomposition reaction Methods 0.000 claims description 8
- 239000012458 free base Substances 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 206010006458 Bronchitis chronic Diseases 0.000 claims description 5
- 206010006451 bronchitis Diseases 0.000 claims description 5
- 208000007451 chronic bronchitis Diseases 0.000 claims description 5
- -1 6-(2-((4-amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl) methyl)-3-(2-chlorobenzyl)-4-oxo-3,4-dihydroquinazolin-5-yl)-N,N-bis(2-methoxyethyl)hex-ynamide Chemical group 0.000 claims description 4
- 201000003883 Cystic fibrosis Diseases 0.000 claims description 4
- 206010014561 Emphysema Diseases 0.000 claims description 4
- 201000009794 Idiopathic Pulmonary Fibrosis Diseases 0.000 claims description 4
- 208000036971 interstitial lung disease 2 Diseases 0.000 claims description 4
- 230000002265 prevention Effects 0.000 claims description 4
- 201000000306 sarcoidosis Diseases 0.000 claims description 4
- 230000000087 stabilizing effect Effects 0.000 claims description 2
- 206010006895 Cachexia Diseases 0.000 claims 3
- 206010027476 Metastases Diseases 0.000 claims 3
- 230000005764 inhibitory process Effects 0.000 claims 3
- 208000037841 lung tumor Diseases 0.000 claims 3
- 230000009401 metastasis Effects 0.000 claims 3
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims 3
- JYMKTJSCJHGOMJ-UHFFFAOYSA-N 5-(hydroxymethyl)-6-[4,5,6-trihydroxy-2-(hydroxymethyl)oxan-3-yl]oxyoxane-2,3,4-triol Chemical group OCC1OC(O)C(O)C(O)C1OC1C(CO)C(O)C(O)C(O)O1 JYMKTJSCJHGOMJ-UHFFFAOYSA-N 0.000 claims 1
- UBLOHCIYTDRGJH-UHFFFAOYSA-N 6-[2-[[4-amino-3-(3-hydroxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]-3-[(2-chlorophenyl)methyl]-4-oxoquinazolin-5-yl]-n,n-bis(2-methoxyethyl)hex-5-ynamide Chemical compound C=1C=CC=C(Cl)C=1CN1C(=O)C=2C(C#CCCCC(=O)N(CCOC)CCOC)=CC=CC=2N=C1CN(C1=NC=NC(N)=C11)N=C1C1=CC=CC(O)=C1 UBLOHCIYTDRGJH-UHFFFAOYSA-N 0.000 abstract 1
- 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 description 74
- 239000000126 substance Substances 0.000 description 30
- 229940079593 drug Drugs 0.000 description 24
- 239000002245 particle Substances 0.000 description 21
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 18
- 210000004072 lung Anatomy 0.000 description 17
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 16
- 102000003993 Phosphatidylinositol 3-kinases Human genes 0.000 description 15
- 108090000430 Phosphatidylinositol 3-kinases Proteins 0.000 description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 238000004128 high performance liquid chromatography Methods 0.000 description 15
- 238000003860 storage Methods 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- 238000004458 analytical method Methods 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- 238000009826 distribution Methods 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 238000002425 crystallisation Methods 0.000 description 9
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- 239000002253 acid Substances 0.000 description 8
- 239000003246 corticosteroid Substances 0.000 description 8
- 239000008380 degradant Substances 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 7
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 7
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.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 WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 238000004566 IR spectroscopy Methods 0.000 description 7
- 230000015556 catabolic process Effects 0.000 description 7
- 238000006731 degradation reaction Methods 0.000 description 7
- 229940112141 dry powder inhaler Drugs 0.000 description 7
- 238000002329 infrared spectrum Methods 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 229910021645 metal ion Inorganic materials 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- VTGOHKSTWXHQJK-UHFFFAOYSA-N pyrimidin-2-ol Chemical group OC1=NC=CC=N1 VTGOHKSTWXHQJK-UHFFFAOYSA-N 0.000 description 6
- 239000002516 radical scavenger Substances 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 5
- 206010061218 Inflammation Diseases 0.000 description 5
- 108010029485 Protein Isoforms Proteins 0.000 description 5
- 102000001708 Protein Isoforms Human genes 0.000 description 5
- 125000002355 alkine group Chemical group 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 239000007857 degradation product Substances 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 230000004054 inflammatory process Effects 0.000 description 5
- 239000003112 inhibitor Substances 0.000 description 5
- 238000011200 topical administration Methods 0.000 description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- 108091007960 PI3Ks Proteins 0.000 description 4
- GIIZNNXWQWCKIB-UHFFFAOYSA-N Serevent Chemical compound C1=C(O)C(CO)=CC(C(O)CNCCCCCCOCCCCC=2C=CC=CC=2)=C1 GIIZNNXWQWCKIB-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 150000007513 acids Chemical class 0.000 description 4
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 4
- 239000008116 calcium stearate Substances 0.000 description 4
- 235000013539 calcium stearate Nutrition 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 239000010419 fine particle Substances 0.000 description 4
- 229960000289 fluticasone propionate Drugs 0.000 description 4
- WMWTYOKRWGGJOA-CENSZEJFSA-N fluticasone propionate Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@@H](C)[C@@](C(=O)SCF)(OC(=O)CC)[C@@]2(C)C[C@@H]1O WMWTYOKRWGGJOA-CENSZEJFSA-N 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 230000003993 interaction Effects 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 239000002935 phosphatidylinositol 3 kinase inhibitor Substances 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 4
- 238000012430 stability testing Methods 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- HQAIUXZORKJOJY-UHFFFAOYSA-N 3-iodo-2h-pyrazolo[3,4-d]pyrimidin-4-amine Chemical compound NC1=NC=NC2=NNC(I)=C12 HQAIUXZORKJOJY-UHFFFAOYSA-N 0.000 description 3
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 3
- 239000005695 Ammonium acetate Substances 0.000 description 3
- VOVIALXJUBGFJZ-KWVAZRHASA-N Budesonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H]3OC(CCC)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O VOVIALXJUBGFJZ-KWVAZRHASA-N 0.000 description 3
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
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- 102000038030 PI3Ks Human genes 0.000 description 3
- 102000013530 TOR Serine-Threonine Kinases Human genes 0.000 description 3
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- 150000001345 alkine derivatives Chemical class 0.000 description 3
- 235000019257 ammonium acetate Nutrition 0.000 description 3
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- BPZSYCZIITTYBL-UHFFFAOYSA-N formoterol Chemical compound C1=CC(OC)=CC=C1CC(C)NCC(O)C1=CC=C(O)C(NC=O)=C1 BPZSYCZIITTYBL-UHFFFAOYSA-N 0.000 description 3
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- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
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- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 3
- 238000000825 ultraviolet detection Methods 0.000 description 3
- PHHVQWRVIMNMHB-UHFFFAOYSA-N 3-(4-amino-2h-pyrazolo[3,4-d]pyrimidin-3-yl)phenol Chemical compound C=12C(N)=NC=NC2=NNC=1C1=CC=CC(O)=C1 PHHVQWRVIMNMHB-UHFFFAOYSA-N 0.000 description 2
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 2
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- KUAYRUSMQNNVPY-UHFFFAOYSA-N n,n-bis(2-methoxyethyl)hex-5-ynamide Chemical compound COCCN(CCOC)C(=O)CCCC#C KUAYRUSMQNNVPY-UHFFFAOYSA-N 0.000 description 2
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Landscapes
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| NZ628072A (en) | 2012-03-13 | 2015-08-28 | Respivert Ltd | Crystalline pi3 kinase inhibitors |
| US8940742B2 (en) | 2012-04-10 | 2015-01-27 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
| US9737521B2 (en) | 2012-11-08 | 2017-08-22 | Rhizen Pharmaceuticals Sa | Pharmaceutical compositions containing a PDE4 inhibitor and a PI3 delta or dual PI3 delta-gamma kinase inhibitor |
| US9227977B2 (en) | 2013-03-15 | 2016-01-05 | Respivert Ltd. | Phosphoinositide 3-kinase inhibitors |
| JO3279B1 (ar) | 2013-03-15 | 2018-09-16 | Respivert Ltd | مشتقات 2-((4- امينو -3- (3- فلورو-5- هيدروكسي فينيل)-h1- بيرازولو [d-3,4] بيرمدين-1-يل )ميثيل )- 3- (2- تراي فلورو ميثيل ) بينزيل ) كوينازولين -4 (h3)- واحد واستخدامها كمثبطات فوسفواينوسيتايد 3- كاينيز |
| WO2015051241A1 (en) | 2013-10-04 | 2015-04-09 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
| MX2021012208A (es) | 2013-10-04 | 2023-01-19 | Infinity Pharmaceuticals Inc | Compuestos heterocíclicos y usos de los mismos. |
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