US20230097309A1 - Solid dispersions of a erb2 (her2) inhibitor - Google Patents
Solid dispersions of a erb2 (her2) inhibitor Download PDFInfo
- Publication number
- US20230097309A1 US20230097309A1 US17/895,951 US202217895951A US2023097309A1 US 20230097309 A1 US20230097309 A1 US 20230097309A1 US 202217895951 A US202217895951 A US 202217895951A US 2023097309 A1 US2023097309 A1 US 2023097309A1
- Authority
- US
- United States
- Prior art keywords
- dispersion
- triazolo
- yloxy
- pyridin
- methylphenyl
- 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
- 239000007962 solid dispersion Substances 0.000 title claims abstract description 164
- 239000003112 inhibitor Substances 0.000 title description 2
- 101100314454 Caenorhabditis elegans tra-1 gene Proteins 0.000 title 1
- SDEAXTCZPQIFQM-UHFFFAOYSA-N 6-n-(4,4-dimethyl-5h-1,3-oxazol-2-yl)-4-n-[3-methyl-4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)phenyl]quinazoline-4,6-diamine Chemical compound C=1C=C(OC2=CC3=NC=NN3C=C2)C(C)=CC=1NC(C1=C2)=NC=NC1=CC=C2NC1=NC(C)(C)CO1 SDEAXTCZPQIFQM-UHFFFAOYSA-N 0.000 claims abstract description 114
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 69
- 238000000034 method Methods 0.000 claims abstract description 28
- 239000004815 dispersion polymer Substances 0.000 claims description 63
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical group [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 44
- 239000000203 mixture Substances 0.000 claims description 37
- 206010028980 Neoplasm Diseases 0.000 claims description 35
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 32
- 201000011510 cancer Diseases 0.000 claims description 31
- 239000007884 disintegrant Substances 0.000 claims description 27
- 239000006185 dispersion Substances 0.000 claims description 27
- 201000010099 disease Diseases 0.000 claims description 22
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 22
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 20
- 229920001577 copolymer Polymers 0.000 claims description 14
- 229920003139 Eudragit® L 100 Polymers 0.000 claims description 13
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 11
- 208000035475 disorder Diseases 0.000 claims description 10
- 229920000642 polymer Polymers 0.000 claims description 9
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 8
- 210000004072 lung Anatomy 0.000 claims description 7
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical group C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 5
- 229960000913 crospovidone Drugs 0.000 claims description 4
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 4
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 4
- 230000007935 neutral effect Effects 0.000 claims description 3
- 230000008569 process Effects 0.000 abstract description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 87
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 64
- 239000002904 solvent Substances 0.000 description 54
- 239000007921 spray Substances 0.000 description 36
- 239000003814 drug Substances 0.000 description 27
- 238000001035 drying Methods 0.000 description 27
- FYUWIEKAVLOHSE-UHFFFAOYSA-N ethenyl acetate;1-ethenylpyrrolidin-2-one Chemical compound CC(=O)OC=C.C=CN1CCCC1=O FYUWIEKAVLOHSE-UHFFFAOYSA-N 0.000 description 26
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 25
- 229940079593 drug Drugs 0.000 description 24
- 229920008347 Cellulose acetate propionate Polymers 0.000 description 23
- 238000004090 dissolution Methods 0.000 description 23
- 239000007789 gas Substances 0.000 description 23
- 241000894007 species Species 0.000 description 21
- 238000001694 spray drying Methods 0.000 description 21
- 239000000314 lubricant Substances 0.000 description 20
- 239000003826 tablet Substances 0.000 description 18
- ZUAAPNNKRHMPKG-UHFFFAOYSA-N acetic acid;butanedioic acid;methanol;propane-1,2-diol Chemical compound OC.CC(O)=O.CC(O)CO.OC(=O)CCC(O)=O ZUAAPNNKRHMPKG-UHFFFAOYSA-N 0.000 description 16
- 238000000634 powder X-ray diffraction Methods 0.000 description 16
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 15
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical group [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 14
- 239000003085 diluting agent Substances 0.000 description 13
- 239000007787 solid Substances 0.000 description 13
- 239000000725 suspension Substances 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 12
- 239000011230 binding agent Substances 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- 238000004458 analytical method Methods 0.000 description 11
- 239000007853 buffer solution Substances 0.000 description 11
- 150000001875 compounds Chemical class 0.000 description 11
- 238000009506 drug dissolution testing Methods 0.000 description 11
- 239000008363 phosphate buffer Substances 0.000 description 11
- 241000124008 Mammalia Species 0.000 description 10
- 239000000945 filler Substances 0.000 description 8
- 230000002496 gastric effect Effects 0.000 description 8
- -1 Eudragit®) Chemical compound 0.000 description 7
- 206010033128 Ovarian cancer Diseases 0.000 description 7
- 206010061535 Ovarian neoplasm Diseases 0.000 description 7
- 210000000481 breast Anatomy 0.000 description 7
- 230000003463 hyperproliferative effect Effects 0.000 description 7
- 235000019359 magnesium stearate Nutrition 0.000 description 7
- 108010079943 Pentagastrin Proteins 0.000 description 6
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 6
- 239000008186 active pharmaceutical agent Substances 0.000 description 6
- 239000003937 drug carrier Substances 0.000 description 6
- XUFQPHANEAPEMJ-UHFFFAOYSA-N famotidine Chemical compound NC(N)=NC1=NC(CSCCC(N)=NS(N)(=O)=O)=CS1 XUFQPHANEAPEMJ-UHFFFAOYSA-N 0.000 description 6
- 229960001596 famotidine Drugs 0.000 description 6
- ANRIQLNBZQLTFV-DZUOILHNSA-N pentagastrin Chemical compound C([C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1[C]2C=CC=CC2=NC=1)NC(=O)CCNC(=O)OC(C)(C)C)CCSC)C(N)=O)C1=CC=CC=C1 ANRIQLNBZQLTFV-DZUOILHNSA-N 0.000 description 6
- 229960000444 pentagastrin Drugs 0.000 description 6
- 239000001103 potassium chloride Substances 0.000 description 6
- 229910052710 silicon Inorganic materials 0.000 description 6
- 239000010703 silicon Substances 0.000 description 6
- 239000011780 sodium chloride Substances 0.000 description 6
- 206010006187 Breast cancer Diseases 0.000 description 5
- 208000026310 Breast neoplasm Diseases 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
- 208000005718 Stomach Neoplasms Diseases 0.000 description 5
- 239000012527 feed solution Substances 0.000 description 5
- 206010017758 gastric cancer Diseases 0.000 description 5
- 208000014829 head and neck neoplasm Diseases 0.000 description 5
- 239000013557 residual solvent Substances 0.000 description 5
- 201000011549 stomach cancer Diseases 0.000 description 5
- 206010046766 uterine cancer Diseases 0.000 description 5
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 206010009944 Colon cancer Diseases 0.000 description 4
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 4
- 229920003134 Eudragit® polymer Polymers 0.000 description 4
- 208000002495 Uterine Neoplasms Diseases 0.000 description 4
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 4
- 239000004615 ingredient Substances 0.000 description 4
- 208000020816 lung neoplasm Diseases 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 206010041823 squamous cell carcinoma Diseases 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 3
- 201000009030 Carcinoma Diseases 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 3
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 3
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 3
- 206010038389 Renal cancer Diseases 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 201000010536 head and neck cancer Diseases 0.000 description 3
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 3
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N lactose group Chemical group OC1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@@H](O)[C@H](O2)CO)[C@H](O1)CO GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- 201000005202 lung cancer Diseases 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 229940016286 microcrystalline cellulose Drugs 0.000 description 3
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 3
- 239000008108 microcrystalline cellulose Substances 0.000 description 3
- 230000002611 ovarian Effects 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 229920002451 polyvinyl alcohol Polymers 0.000 description 3
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 238000009492 tablet coating Methods 0.000 description 3
- 239000002700 tablet coating Substances 0.000 description 3
- HZCZAJGNAXZBTF-UHFFFAOYSA-N 1-(1-hydroxy-2-methylpropan-2-yl)-3-[4-[3-methyl-4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)anilino]quinazolin-6-yl]thiourea Chemical compound C1=CN2N=CN=C2C=C1OC1=CC=C(NC=2C3=CC(NC(=S)NC(C)(C)CO)=CC=C3N=CN=2)C=C1C HZCZAJGNAXZBTF-UHFFFAOYSA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- 206010005003 Bladder cancer Diseases 0.000 description 2
- 208000003174 Brain Neoplasms Diseases 0.000 description 2
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 2
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 208000008839 Kidney Neoplasms Diseases 0.000 description 2
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 239000004372 Polyvinyl alcohol Substances 0.000 description 2
- 206010039491 Sarcoma Diseases 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 229920002301 cellulose acetate Polymers 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 229940088679 drug related substance Drugs 0.000 description 2
- 238000002036 drum drying Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- JBKVHLHDHHXQEQ-UHFFFAOYSA-N epsilon-caprolactam Chemical compound O=C1CCCCCN1 JBKVHLHDHHXQEQ-UHFFFAOYSA-N 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 238000001125 extrusion Methods 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- 208000005017 glioblastoma Diseases 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 201000010982 kidney cancer Diseases 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 208000032839 leukemia Diseases 0.000 description 2
- 208000014018 liver neoplasm Diseases 0.000 description 2
- 201000005249 lung adenocarcinoma Diseases 0.000 description 2
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 2
- 208000026037 malignant tumor of neck Diseases 0.000 description 2
- 201000001441 melanoma Diseases 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000003002 pH adjusting agent Substances 0.000 description 2
- 201000002528 pancreatic cancer Diseases 0.000 description 2
- 208000008443 pancreatic carcinoma Diseases 0.000 description 2
- 210000003800 pharynx Anatomy 0.000 description 2
- 229920002689 polyvinyl acetate Polymers 0.000 description 2
- 239000011118 polyvinyl acetate Substances 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 238000002390 rotary evaporation Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 208000017572 squamous cell neoplasm Diseases 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 229920002554 vinyl polymer Polymers 0.000 description 2
- UOCLXMDMGBRAIB-UHFFFAOYSA-N 1,1,1-trichloroethane Chemical compound CC(Cl)(Cl)Cl UOCLXMDMGBRAIB-UHFFFAOYSA-N 0.000 description 1
- VNKYLVIITITJCY-UHFFFAOYSA-N 1-[3-cyano-4-(dimethylaminomethylideneamino)phenyl]-3-(1-hydroxy-2-methylpropan-2-yl)thiourea Chemical compound CN(C)C=NC1=CC=C(NC(=S)NC(C)(C)CO)C=C1C#N VNKYLVIITITJCY-UHFFFAOYSA-N 0.000 description 1
- DFMSLMUVJUMZPA-UHFFFAOYSA-N 3-methyl-4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)aniline Chemical compound CC1=CC(N)=CC=C1OC1=CC2=NC=NN2C=C1 DFMSLMUVJUMZPA-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 1
- 208000010507 Adenocarcinoma of Lung Diseases 0.000 description 1
- 208000003200 Adenoma Diseases 0.000 description 1
- 206010001233 Adenoma benign Diseases 0.000 description 1
- 206010061424 Anal cancer Diseases 0.000 description 1
- 206010004593 Bile duct cancer Diseases 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 208000010667 Carcinoma of liver and intrahepatic biliary tract Diseases 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- 241000699800 Cricetinae Species 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- 206010014733 Endometrial cancer Diseases 0.000 description 1
- 206010014759 Endometrial neoplasm Diseases 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 206010017993 Gastrointestinal neoplasms Diseases 0.000 description 1
- 229940125497 HER2 kinase inhibitor Drugs 0.000 description 1
- 206010073069 Hepatic cancer Diseases 0.000 description 1
- 208000017604 Hodgkin disease Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 1
- 229920001479 Hydroxyethyl methyl cellulose Polymers 0.000 description 1
- 206010023347 Keratoacanthoma Diseases 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 1
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 206010029260 Neuroblastoma Diseases 0.000 description 1
- 239000006057 Non-nutritive feed additive Substances 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 description 1
- 208000015634 Rectal Neoplasms Diseases 0.000 description 1
- 206010061934 Salivary gland cancer Diseases 0.000 description 1
- 201000010208 Seminoma Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical group O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 208000000453 Skin Neoplasms Diseases 0.000 description 1
- 206010041067 Small cell lung cancer Diseases 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 206010047741 Vulval cancer Diseases 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- IYKJEILNJZQJPU-UHFFFAOYSA-N acetic acid;butanedioic acid Chemical compound CC(O)=O.OC(=O)CCC(O)=O IYKJEILNJZQJPU-UHFFFAOYSA-N 0.000 description 1
- UGZICOVULPINFH-UHFFFAOYSA-N acetic acid;butanoic acid Chemical compound CC(O)=O.CCCC(O)=O UGZICOVULPINFH-UHFFFAOYSA-N 0.000 description 1
- GAMPNQJDUFQVQO-UHFFFAOYSA-N acetic acid;phthalic acid Chemical compound CC(O)=O.OC(=O)C1=CC=CC=C1C(O)=O GAMPNQJDUFQVQO-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 208000009956 adenocarcinoma Diseases 0.000 description 1
- 239000003570 air Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 201000007538 anal carcinoma Diseases 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 238000000889 atomisation Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 201000001531 bladder carcinoma Diseases 0.000 description 1
- 201000000053 blastoma Diseases 0.000 description 1
- 229920001400 block copolymer Polymers 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 210000000133 brain stem Anatomy 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000007894 caplet Substances 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229940081734 cellulose acetate phthalate Drugs 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 210000003679 cervix uteri Anatomy 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 239000008380 degradant Substances 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000000113 differential scanning calorimetry Methods 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 208000037765 diseases and disorders Diseases 0.000 description 1
- 238000007922 dissolution test Methods 0.000 description 1
- 238000011833 dog model Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 201000008184 embryoma Diseases 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 201000003914 endometrial carcinoma Diseases 0.000 description 1
- 230000002357 endometrial effect Effects 0.000 description 1
- 210000003238 esophagus Anatomy 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229920000578 graft copolymer Polymers 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 229920013819 hydroxyethyl ethylcellulose Polymers 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 description 1
- 229920000639 hydroxypropylmethylcellulose acetate succinate Polymers 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 208000003849 large cell carcinoma Diseases 0.000 description 1
- 210000002429 large intestine Anatomy 0.000 description 1
- 210000000867 larynx Anatomy 0.000 description 1
- 210000000088 lip Anatomy 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 201000002250 liver carcinoma Diseases 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 210000000214 mouth Anatomy 0.000 description 1
- YKYONYBAUNKHLG-UHFFFAOYSA-N n-Propyl acetate Natural products CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 201000010198 papillary carcinoma Diseases 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 208000030940 penile carcinoma Diseases 0.000 description 1
- 201000008174 penis carcinoma Diseases 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 201000002628 peritoneum cancer Diseases 0.000 description 1
- 235000020030 perry Nutrition 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 238000001907 polarising light microscopy Methods 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920002503 polyoxyethylene-polyoxypropylene Polymers 0.000 description 1
- 229920006316 polyvinylpyrrolidine Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 229940090181 propyl acetate Drugs 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 206010038038 rectal cancer Diseases 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 201000001275 rectum cancer Diseases 0.000 description 1
- 201000010174 renal carcinoma Diseases 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 201000003804 salivary gland carcinoma Diseases 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 208000000649 small cell carcinoma Diseases 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 238000010922 spray-dried dispersion Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 210000001550 testis Anatomy 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- 208000030901 thyroid gland follicular carcinoma Diseases 0.000 description 1
- 210000002105 tongue Anatomy 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 125000005591 trimellitate group Chemical group 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 208000010576 undifferentiated carcinoma Diseases 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 208000010570 urinary bladder carcinoma Diseases 0.000 description 1
- 208000012991 uterine carcinoma Diseases 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 229920006163 vinyl copolymer Polymers 0.000 description 1
- 201000005102 vulva cancer Diseases 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Images
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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
-
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
-
- 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
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
-
- 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
- A61K9/10—Dispersions; Emulsions
-
- 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
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- 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
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2009—Inorganic compounds
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
-
- 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
-
- 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
Definitions
- a solid dispersion of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine is provided herein.
- a pharmaceutical composition comprising a solid dispersion of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine is provided herein.
- N4-(4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine also called “ARRY-380”
- N4-(4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine has been tested in human clinical trials for hyperproliferative diseases, particularly cancer (see Koch, Kevin. “ARRY-380: A Selective, Oral HER2 Inhibitor for the Treatment of Solid Tumors.” American Association of Cancer Research 102 nd Annual Meeting, Apr. 3, 2011; which may also be found at: http://www.arraybiopharma.com/_documents/Publication/PubAttachment462.pdf).
- a powder-in-capsule (“PIC”) composition of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine was prepared and administered to patients with cancer, and the overall inter-patient variability for area under the plasma concentration-time curve (“AUC”) and maximum concentration (“Cmax”) was moderate to high.
- AUC plasma concentration-time curve
- Cmax maximum concentration
- a solid dispersion comprising N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine is described herein.
- a pharmaceutical composition comprising N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine is described herein.
- a pharmaceutical composition comprising a solid dispersion of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine is described herein.
- a pharmaceutical composition comprising a solid dispersion of spray dried N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine is described herein.
- FIG. 1 shows a comparison of XRPD scans of amorphous 30% solid dispersions and crystalline N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine, with a close up of the amorphous solid dispersions.
- FIG. 2 shows a dissolution profile of a 30% solid dispersion of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine.
- FIG. 3 shows a dissolution profile of a 30% solid dispersion of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine.
- FIG. 4 shows a dissolution profile of a 30% solid dispersion of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine.
- FIG. 5 shows a dissolution profile of a 30% solid dispersion of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine.
- FIG. 6 shows a dissolution profile of a 30% solid dispersion of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine.
- FIG. 7 shows a comparison of XRPD scans of amorphous 60% solid dispersions and crystalline N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine, with a close up of the amorphous solid dispersions.
- FIG. 8 shows a dissolution profile of a 60% solid dispersion of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine.
- FIG. 9 shows a dissolution profile of a 60% solid dispersion of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine.
- FIG. 10 shows a dissolution profile of a 60% solid dispersion of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine.
- FIG. 11 shows a dissolution profile of a 60% solid dispersion of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine.
- FIG. 12 shows a dissolution profile of a 60% solid dispersion of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine.
- FIG. 13 shows a dissolution comparison of a solid dispersion tablet and a crystalline PIC composition.
- variable can be equal to any integer value of the numerical range, including the end-points of the range.
- variable can be equal to any real value of the numerical range, including the end-points of the range.
- a variable that is described as having values between 0 and 2 can be 0, 1 or 2 for variables that are inherently discrete, and can be 0.0, 0.1, 0.01, 0.001, or any other real value for variables that are inherently continuous.
- amorphous means a solid in a solid state that is a non-crystalline state.
- Amorphous solids generally possess crystal-like short range molecular arrangement, but no long range order of molecular packing as found in crystalline solids.
- the solid state form of a solid may be determined by polarized light microscopy, x-ray powder diffraction (“XRPD”), differential scanning calorimetry (“DSC”), or other standard techniques known to those of skill in the art.
- amorphous solid dispersion means a solid comprising a drug substance and a dispersion polymer.
- the amorphous solid dispersion discussed herein comprises amorphous N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine and a dispersion polymer, wherein the amorphous solid dispersion contains N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine in a substantially amorphous solid state form.
- the substantially amorphous solid state form means that the N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine component in the amorphous solid dispersion is at least 80% amorphous N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine.
- the substantially amorphous solid state form means that the N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine component in the amorphous solid dispersion is at least 85% amorphous N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine.
- the substantially amorphous solid state form means that the N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine component in the amorphous solid dispersion is at least 90% amorphous N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine.
- the substantially amorphous solid state form means that the N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine component in the amorphous solid dispersion is at least 95% amorphous N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine.
- cancer and “cancerous” refer to or describe the physiological condition in mammals that is typically characterized by abnormal or unregulated cell growth.
- a “tumor” comprises one or more cancerous cells. Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies.
- squamous cell cancer e.g., epithelial squamous cell cancer
- lung cancer including small cell lung cancer, non-small cell lung cancer (“NSCLC”), adenocarcinoma of the lung and squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer including gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, brain, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, skin cancer, including melanoma, as well as head and neck cancer.
- NSCLC non-small cell lung cancer
- adenocarcinoma of the lung and squamous carcinoma of the lung cancer of the peritoneum, hepatocellular
- dispenser polymer means a polymer that allows for N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine to be dispersed throughout such that a solid dispersion may form.
- the dispersion polymer is preferably neutral or basic.
- the dispersion polymer may contain a mixture of two or more polymers.
- dispersion polymers include, but are not limited to, vinyl polymers and copolymers, vinylpyrrolidine vinylacetate copolymer (“PVP-VA”), polyvinyl alcohols, polyvinyl alcohol polyvinyl acetate copolymers, polyvinyl pyrrolidine (“PVP”), acrylate and methacrylate copolymers, methylacrylic acid methyl methacrylate copolymer (such as Eudragit®), polyethylene polyvinyl alcohol copolymers, polyoxyethylene-polyoxypropylene block copolymers (also referred to as poloxamers), graft copolymer comprised of polyethylene glycol, polyvinyl caprolactam and polyvinyl acetate (such as Soluplus®), cellulosic polymers, such as hydroxypropyl methyl cellulose acetate (“HPMCA”), hydroxypropyl methyl cellulose (“HPMC”), hydroxypropyl cellulose (“HPC”), methyl cellulose, hydroxyethy
- mammal means a warm-blooded animal that has or is at risk of developing a disease described herein and includes, but is not limited to, guinea pigs, dogs, cats, rats, mice, hamsters, and primates, including humans.
- phrases “pharmaceutically acceptable” indicates that the substance or composition is compatible chemically and/or toxicologically, with the other ingredients comprising a composition, and/or the mammal being treated therewith.
- phrases “pharmaceutically acceptable salt,” as used herein, refers to pharmaceutically acceptable organic or inorganic salts of a compound described herein.
- solid dispersion means a system in a solid state comprising at least two components, wherein one component is dispersed throughout the other component.
- the solid dispersion discussed herein comprises one component of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine dispersed throughout another component, particularly a dispersion polymer.
- spray drying means processes involved in breaking up liquid mixtures into small droplets (atomization) and rapidly removing solvent from the mixture in a spray drying apparatus where there is a strong driving force for evaporation of solvent from the droplets.
- spray drying is used conventionally and broadly. Spray drying processes and spray drying equipment are described generally in Perry, Robert H., and Don W. Green (eds.). Perry's Chemical Engineers' Handbook . New York: McGraw-Hill, 2007 (8 th edition).
- terapéuticaally effective amount or “effective amount” mean an amount of a compound described herein that, when administered to a mammal in need of such treatment, sufficient to (i) treat or prevent the particular disease, condition, or disorder, (ii) attenuate, ameliorate, or eliminate one or more symptoms of the particular disease, condition, or disorder, or (iii) prevent or delay the onset of one or more symptoms of the particular disease, condition, or disorder described herein.
- the amount of a compound that will correspond to such an amount will vary depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight) of the mammal in need of treatment, but can nevertheless be routinely determined by one skilled in the art.
- treat refers to therapeutic, prophylactic, palliative or preventative measures.
- Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable.
- Treatment can also mean prolonging survival as compared to expected survival if not receiving treatment.
- Those in need of treatment include those already with the condition or disorder, as well as those prone to have the condition or disorder or those in which the condition or disorder is to be prevented.
- Solid dispersion comprising N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine.
- the solid dispersions are generally prepared by dissolving the drug substance and the dispersion polymer in a suitable solvent to form a feed solution, and then the feed solution may be spray dried to form the solid dispersion (and remove the solvent).
- Spray drying is a known process. Spray drying is generally performed by dissolving N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine and the dispersion polymer in a suitable solvent to prepare a feed solution.
- the feed solution may be pumped through an atomizer into a drying chamber.
- the feed solution can be atomized by conventional means known in the art, such as a two-fluid sonicating nozzle, a pressure nozzle, a rotating nozzle and a two-fluid non-sonicating nozzle. Then, the solvent is removed in the drying chamber to form the solid dispersion.
- a typical drying chamber uses hot gases, such as forced air, nitrogen, nitrogen-enriched air, or argon to dry particles. The size of the drying chamber may be adjusted to achieve particle properties or throughput.
- solid dispersion are preferably prepared by conventional spray drying techniques, other techniques known in the art may be used, such as melt extrusion, freeze drying, rotary evaporation, drum drying or other solvent removal processes.
- a process of preparing a solid dispersion comprising:
- the evaporation of the solvent in step (b) is performed by spray drying, melt extrusion, freeze drying, rotary evaporation, drum drying or other solvent removal processes.
- the dispersion polymer is selected from PVP-VA, methylacrylic acid methyl methacrylate copolymer, HPMCP, CAP, HPMCAS and HPMC and mixtures thereof. In certain embodiments, the dispersion polymer is selected from PVP-VA, methylacrylic acid methyl methacrylate copolymer, HPMCP, CAP, HPMCAS and HPMC. In certain embodiments, the dispersion polymer is selected from PVP-VA, Eudragit® L100, HPMCP H-55, CAP, HPMCAS Grade M, HPMC and mixtures thereof. In certain embodiments, the dispersion polymer is selected from PVP-VA, Eudragit® L100, HPMCP H-55, CAP, HPMCAS Grade M and HPMC.
- the dispersion polymer is selected from PVP-VA, methylacrylic acid methyl methacrylate copolymer, HPMCP, CAP and HPMCAS, and mixtures thereof. In certain embodiments, the dispersion polymer is selected from PVP-VA, methylacrylic acid methyl methacrylate copolymer, HPMCP, CAP and HPMCAS. In certain embodiments, the dispersion polymer is selected from PVP-VA, Eudragit® L100, HPMCP H-55, CAP and HPMCAS Grade M, and mixtures thereof. In certain embodiments, the dispersion polymer is selected from PVP-VA, Eudragit® L100, HPMCP H-55, CAP and HPMCAS Grade M.
- the dispersion polymer is selected from PVP-VA, methylacrylic acid methyl methacrylate copolymer, HPMCP, CAP and HPMC, and mixtures thereof. In certain embodiments, the dispersion polymer is selected from PVP-VA, methylacrylic acid methyl methacrylate copolymer, HPMCP, CAP and HPMC. In certain embodiments, the dispersion polymer is selected from PVP-VA, Eudragit® L100, HPMCP H-55, CAP and HPMC, and mixtures thereof. In certain embodiments, the dispersion polymer is selected from PVP-VA, Eudragit® L100, HPMCP H-55, CAP and HPMC.
- the dispersion polymer is selected from PVP-VA, methylacrylic acid methyl methacrylate copolymer, HPMCP and CAP, and mixtures thereof. In certain embodiments, the dispersion polymer is selected from PVP-VA, methylacrylic acid methyl methacrylate copolymer, HPMCP and CAP. In certain embodiments, the dispersion polymer is selected from PVP-VA, Eudragit® L100, HPMCP H-55 and CAP, and mixtures thereof. In certain embodiments, the dispersion polymer is selected from PVP-VA, Eudragit® L100, HPMCP H-55 and CAP.
- the dispersion polymer is PVP-VA.
- the dispersion polymer is methylacrylic acid methyl methacrylate copolymer. In certain embodiments, the dispersion polymer is Eudragit®. In certain embodiments, the dispersion polymer is Eudragit® L100.
- the dispersion polymer is HPMCP. In certain embodiments, the dispersion polymer is HPMCP H-55.
- the dispersion polymer is CAP.
- the dispersion polymer is HPMCAS. In certain embodiments, the dispersion polymer is HPMCAS Grade M.
- the dispersion polymer is preferably neutral or basic. In certain embodiments, the dispersion polymer is selected from PVP-VA and HPMC. In certain embodiments, the dispersion polymer is HPMC.
- Suitable solvents are a solvent or mixture of solvents in which both N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine and the dispersion polymer have adequate solubility (solubility greater than 1 mg/mL).
- a mixture of solvents may be used if each component of the solid dispersion (i.e., N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine and dispersion polymer) require different solvents to obtain the desired solubility.
- the solvent may be volatile with a boiling point of 150° C. or less.
- the solvent should have relatively low toxicity and be removed from the dispersion to a level that is acceptable to The International Committee on Harmonization (“ICH”) guidelines.
- solvents include, but are not limited to, alcohols, such as methanol (“MeOH”), ethanol (“EtOH”), n-propanol, isopropanol (“IPA”) and butanol; ketones, such as acetone, methyl ethyl ketone (“MEK”) and methyl isobutyl ketone; esters, such as ethyl acetate (“EA”) and propyl acetate; and various other solvents, such as tetrahydrofuran (“THF”), acetonitrile (“ACN”), methylene chloride, toluene and 1,1,1-trichloroethane.
- alcohols such as methanol (“MeOH”), ethanol (“EtOH”), n-propanol, isopropanol (“IPA”) and butanol
- ketones such as acetone, methyl ethyl ketone (“MEK”) and methyl isobutyl ketone
- Lower volatility solvents such as dimethyl acetate or dimethylsulfoxide (“DMSO”)
- DMSO dimethylsulfoxide
- Mixtures of solvents with water may also be used, so long as the polymer and N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine are sufficiently soluble to make the spray drying process practicable.
- non-aqueous solvents may be used, meaning the solvent comprises less than about 10 weight % water.
- the suitable solvent is selected from MeOH and THF, and mixtures thereof. In certain embodiments, the suitable solvent is MeOH:THF solvent system of about 1:3. In certain embodiments, the suitable solvent is a 1:3 MeOH:THF solvent system.
- the suitable solvent is selected from MeOH, THF and water, and mixtures thereof. In certain embodiments, the suitable solvent is selected from MeOH, THF and water. In certain embodiments, the suitable solvent is a THF:MeOH:water solvent system of about 80:10:10. In certain embodiments, the suitable solvent is a 80:10:10 THF:MeOH:water solvent system. In certain embodiments, the suitable solvent is a THF:MeOH:water solvent system of about 82:8:10. In certain embodiments, the suitable solvent is a 82:8:10 THF:MeOH:water solvent system. In certain embodiments, the suitable solvent is a THF:MeOH:water solvent system of about 82.2:8.2:9.6. In certain embodiments, the suitable solvent is a 82.2:8.2:9.6 THF:MeOH:water solvent system.
- the amount of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine in the solid dispersion ranges from about 0.1% to about 70% by weight relative to the dispersion polymer.
- the amount of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine in the solid dispersion ranges from 0.1% to 70% by weight relative to the dispersion polymer.
- the amount of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine in the solid dispersion ranges from about 1% to about 60% by weight relative to the dispersion polymer.
- the amount of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine in the solid dispersion ranges from 1% to 60% by weight relative to the dispersion polymer.
- the amount of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine in the solid dispersion ranges from about 5% to about 60% by weight relative to the dispersion polymer.
- the amount of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine in the solid dispersion ranges from 5% to 60% by weight relative to the dispersion polymer.
- the amount of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine in the solid dispersion ranges from about 55% to about 65% by weight relative to the dispersion polymer.
- the amount of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine in the solid dispersion ranges from 55% to 65% by weight relative to the dispersion polymer.
- the amount of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine in the solid dispersion is about 60% by weight relative to the dispersion polymer.
- the amount of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine in the solid dispersion is 60% by weight relative to the dispersion polymer.
- the amount of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine in the solid dispersion ranges from about 25% to about 35% by weight relative to the dispersion polymer.
- the amount of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine in the solid dispersion ranges from 25% to 35% by weight relative to the dispersion polymer.
- the amount of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine in the solid dispersion is about 30% by weight relative to the dispersion polymer.
- the amount of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine in the solid dispersion is 30% by weight relative to the dispersion polymer.
- the amount of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine in the solid dispersion ranges from about 45% to about 55% by weight relative to the dispersion polymer.
- the amount of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine in the solid dispersion ranges from 45% to 55% by weight relative to the dispersion polymer.
- the amount of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine in the solid dispersion is about 50% by weight relative to the dispersion polymer.
- the amount of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine in the solid dispersion is 50% by weight relative to the dispersion polymer.
- the solid dispersion is an amorphous solid dispersion.
- Another embodiment provides a pharmaceutical composition
- a pharmaceutical composition comprising a solid dispersion of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine and a dispersion polymer, and a carrier or excipient.
- Suitable carriers and excipients are well known to those skilled in the art and are described in detail in, e.g., Ansel, Howard C., et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems . Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy . Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients . Chicago, Pharmaceutical Press, 2005.
- the pharmaceutical compositions may also include one or more additional components, such as buffers, dispersion agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug, i.e., a compound described herein or pharmaceutical composition thereof, or aid in the manufacturing of the pharmaceutical product, i.e., medicament (see Ansel; Gennaro; and Rowe above).
- the components of the pharmaceutical composition should be pharmaceutically acceptable.
- the pharmaceutical composition comprises:
- the pharmaceutical composition comprises:
- the pharmaceutical composition comprises:
- the pharmaceutical composition comprises:
- the pharmaceutical composition comprises:
- the pharmaceutical composition comprises:
- the osmogen is selected from NaCl and KCl, and mixtures thereof.
- the lubricant is magnesium stearate.
- the glidant is colloidal silicon dioxide.
- the binder/diluent is microcrystalline cellulose. In certain embodiments, the binder/diluent acts as both a binder and a diluent.
- the binder is microcrystalline cellulose.
- the diluent is microcrystalline cellulose.
- the filler is lactose.
- the disintegrant is selected from crospovidone and sodium bicarbonate (NaHCO 3 ), and mixtures thereof. In certain embodiments, the disintegrant is selected from crospovidone and sodium bicarbonate. In certain embodiments, the disintegrant is sodium bicarbonate. In certain embodiments, the disintegrant is crospovidone.
- the composition contains sodium bicarbonate.
- N4-(4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine may slowly degrade, through hydrolysis or other means, to a carbamate impurity:
- Sodium bicarbonate helps to slow the degradation to the carbamate impurity. Sodium bicarbonate also helps to provide consistent tablet disintegration when the tablets are exposed to different humidities.
- the pharmaceutical composition comprises:
- the pharmaceutical composition comprises:
- the pharmaceutical composition comprises:
- the pharmaceutical composition comprises:
- the pharmaceutical composition comprises:
- the pharmaceutical composition comprises:
- the pharmaceutical composition preferably contains a therapeutically effective amount of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine.
- each individual dose contains a portion of a therapeutically effective amount of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine, such that multiple doses of the composition may be required (for example, two or more tablets are required for a therapeutically effective amount).
- the pharmaceutical composition contains a therapeutically effective amount it means that the composition may be one dose (for example, one tablet) or multiple doses (for example, two tablets).
- the pharmaceutical composition contains between 1 and 500 mg of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine.
- the pharmaceutical composition contains between 25 and 400 mg of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine.
- the pharmaceutical composition contains between 100 and 300 mg of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine.
- compositions described herein may be administered by any convenient route appropriate to the condition to be treated. Suitable routes include oral, parenteral (including subcutaneous, intramuscular, intravenous, intraarterial, intradermal, intrathecal and epidural), transdermal, rectal, nasal, topical (including buccal and sublingual), ocular, vaginal, intraperitoneal, intrapulmonary and intranasal. If parenteral administration is desired, the compositions will be sterile and in a solution or suspension form suitable for injection or infusion.
- the compounds may be administered in any convenient administrative form, e.g., tablets, powders, capsules, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc.
- compositions described herein are typically administered orally.
- the pharmaceutical compositions described herein are typically administered as a tablet, caplet, hard or soft gelatin capsule, pill, granules or a suspension.
- a human patient is treated with a pharmaceutical composition described herein in an amount to inhibit ErbB2 activity. In one embodiment, a human patient is treated with a pharmaceutical composition described herein in an amount to detectably inhibit ErbB2 activity.
- a method of treating a hyperproliferative disease in a mammal comprising administering the pharmaceutical composition described herein, to the mammal is provided.
- the hyperproliferative disease is cancer.
- a method of treating or preventing cancer in a mammal in need of such treatment comprises administering to said mammal a pharmaceutical composition described herein.
- the cancer is selected from breast, ovary, cervix, prostate, testis, genitourinary tract, esophagus, larynx, glioblastoma, neuroblastoma, stomach, skin, keratoacanthoma, lung, epidermoid carcinoma, large cell carcinoma, NSCLC, small cell carcinoma, lung adenocarcinoma, bone, colon, adenoma, pancreas, adenocarcinoma, thyroid, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder carcinoma, liver carcinoma and biliary passages, kidney carcinoma, myeloid disorders, lymphoid disorders, hairy cells, buccal cavity and pharynx (oral), lip, tongue, mouth, pharynx (oral), lip
- the cancer is ErbB2 positive.
- the cancer is selected from breast, gastric, biliary, colorectal, lung, NSCLC, pancreatic, head and neck, ovarian, uterine and brain cancer.
- the cancer is selected from breast, gastric, biliary, colorectal, lung, NSCLC, pancreatic, head and neck, ovarian and uterine cancer.
- the cancer is selected from breast, gastric, colorectal, lung and ovarian cancer.
- the cancer is selected from breast, ovarian, gastric and uterine cancer.
- the cancer is selected from breast, gastric, colorectal, NSCLC and ovarian cancer.
- the cancer is selected from breast, lung, pancreatic, colorectal and head and neck cancers.
- the cancer is breast cancer.
- the cancer is gastric cancer.
- the cancer is biliary cancer.
- the cancer is colorectal cancer.
- the cancer is lung cancer.
- the cancer is NSCLC.
- the cancer is pancreatic cancer.
- the cancer is head and neck cancer.
- the cancer is ovarian cancer.
- the cancer is uterine cancer.
- the cancer is brain cancer.
- a method of treating or preventing a disease or disorder modulated by ErbB2 comprising administering to a mammal in need of such treatment an effective amount of a pharmaceutical composition described herein.
- diseases and disorders include, but are not limited to, cancer.
- Another embodiment provides the use of a pharmaceutical composition described herein, in the manufacture of a medicament for the treatment of cancer.
- Another embodiment provides the solid dispersions described herein for the treatment of disease.
- the disease is a hyperproliferative disease.
- the hyperproliferative disease is cancer.
- the disease is a hyperproliferative disease.
- the hyperproliferative disease is cancer.
- a solid dispersion was prepared containing 30 weight percent N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine and PVP-VA using a Buchi B-290 mini spray drier.
- the solid dispersion was spray dried from a MeOH:THF (1:3) solvent system, a 5% spray solution concentration, an inlet temperature of 100° C.
- Dissolution testing was performed at a pH of 6.5 in phosphate buffer.
- the solid dispersion was suspended in H 2 O and added directly to the buffer solution at 37° C.
- the dissolution profile was collected over a period of about 240 minutes.
- the results are in FIG. 2 .
- the Cmax and AUC for the total drug species (colloidal+free) was 63.46 ⁇ g/mL and 245.05 ⁇ g/mL*hr, respectively.
- the Cmax and AUC for the free drug species was 52.50 ⁇ g/mL and 204.12 ⁇ g/mL*hr, respectively.
- a solid dispersion was prepared containing 30 weight percent N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine and Eudragit L100 using a Buchi B-290 mini spray drier.
- the solid dispersion was spray dried from a MeOH:THF (1:3) solvent system, a 5% spray solution concentration, an inlet temperature of 100° C.
- Dissolution testing was performed at a pH of 6.5 in phosphate buffer.
- the solid dispersion was suspended in H 2 O and added directly to the buffer solution at 37° C.
- the dissolution profile was collected over a period of about 240 minutes.
- the results are in FIG. 3 .
- the Cmax and AUC for the total drug species (colloidal+free) was 22.70 ⁇ g/mL and 71.06 ⁇ g/mL*hr, respectively.
- the Cmax and AUC for the free drug species was 9.26 ⁇ g/mL and 35.49 ⁇ g/mL*hr, respectively.
- a solid dispersion was prepared containing 30 weight percent N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine and HPMCP H-55 using a Buchi B-290 mini spray drier.
- the solid dispersion was spray dried from a MeOH:THF (1:3) solvent system, a 5% spray solution concentration, an inlet temperature of 100° C.
- Dissolution testing was performed at a pH of 6.5 in phosphate buffer.
- the solid dispersion was suspended in H 2 O and added directly to the buffer solution at 37° C.
- the dissolution profile was collected over a period of about 240 minutes.
- the results are in FIG. 4 .
- the Cmax and AUC for the total drug species (colloidal+free) was 25.00 ⁇ g/mL and 96.66 ⁇ g/mL*hr, respectively.
- the Cmax and AUC for the free drug species was 16.15 ⁇ g/mL and 56.81 ⁇ g/mL*hr, respectively.
- a solid dispersion was prepared containing 30 weight percent N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine and CAP using a Buchi B-290 mini spray drier.
- the solid dispersion was spray dried from a MeOH:THF (1:3) solvent system, a 5% spray solution concentration, an inlet temperature of 100° C.
- Dissolution testing was performed at a pH of 6.5 in phosphate buffer.
- the solid dispersion was suspended in H 2 O and added directly to the buffer solution at 37° C.
- the dissolution profile was collected over a period of about 240 minutes.
- the results are in FIG. 5 .
- the Cmax and AUC for the total drug species (colloidal+free) was 11.62 ⁇ g/mL and 36.69 ⁇ g/mL*hr, respectively.
- the Cmax and AUC for the free drug species was 5.64 ⁇ g/mL and 20.58 ⁇ g/mL*hr, respectively.
- a solid dispersion was prepared containing 30 weight percent N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine and HPMCAS Grade M using a Buchi B-290 mini spray drier.
- the solid dispersion was spray dried from a MeOH:THF (1:3) solvent system, a 5% spray solution concentration, an inlet temperature of 80° C.
- Dissolution testing was performed at a pH of 6.5 in phosphate buffer.
- the solid dispersion was suspended in H 2 O and added directly to the buffer solution at 37° C.
- the dissolution profile was collected over a period of about 240 minutes.
- the results are in FIG. 6 .
- the Cmax and AUC for the total drug species (colloidal+free) was 19.04 ⁇ g/mL and 68.09 ⁇ g/mL*hr, respectively.
- the Cmax and AUC for the free drug species was 13.50 ⁇ g/mL and 51.74 ⁇ g/mL*hr, respectively.
- a solid dispersion was prepared containing 60 weight percent N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine and PVP-VA using a Buchi B-290 mini spray drier.
- the solid dispersion was spray dried from a MeOH:THF (1:3) solvent system, a 5% spray solution concentration, an inlet temperature of 80° C.
- Dissolution testing was performed at a pH of 6.5 in phosphate buffer.
- the solid dispersion was suspended in H 2 O and added directly to the buffer solution at 37° C.
- the dissolution profile was collected over a period of about 240 minutes.
- the results are in FIG. 8 .
- the Cmax and AUC for the total drug species (colloidal+free) was 34.80 ⁇ g/mL and 133.76 ⁇ g/mL*hr, respectively.
- the Cmax and AUC for the free drug species was 21.88 ⁇ g/mL and 84.43 ⁇ g/mL*hr, respectively.
- a solid dispersion was prepared containing 60 weight percent N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine and Eudragit L100 using a Buchi B-290 mini spray drier.
- the solid dispersion was spray dried from a MeOH:THF (1:3) solvent system, a 5% spray solution concentration, an inlet temperature of 80° C.
- Dissolution testing was performed at a pH of 6.5 in phosphate buffer.
- the solid dispersion was suspended in H 2 O and added directly to the buffer solution at 37° C.
- the dissolution profile was collected over a period of about 240 minutes.
- the results are in FIG. 9 .
- the Cmax and AUC for the total drug species (colloidal+free) was 26.82 ⁇ g/mL and 84.49 ⁇ g/mL*hr, respectively.
- the Cmax and AUC for the free drug species was 9.85 ⁇ g/mL and 34.89 ⁇ g/mL*hr, respectively.
- a solid dispersion was prepared containing 60 weight percent N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine and HPMCP H-55 using a Buchi B-290 mini spray drier.
- the solid dispersion was spray dried from a MeOH:THF (1:3) solvent system, a 5% spray solution concentration, an inlet temperature of 80° C.
- Dissolution testing was performed at a pH of 6.5 in phosphate buffer.
- the solid dispersion was suspended in H 2 O and added directly to the buffer solution at 37° C.
- the dissolution profile was collected over a period of about 240 minutes.
- the results are in FIG. 10 .
- the Cmax and AUC for the total drug species (colloidal+free) was 32.21 ⁇ g/mL and 38.28 ⁇ g/mL*hr, respectively.
- the Cmax and AUC for the free drug species was 9.96 ⁇ g/mL and 38.28 ⁇ g/mL*hr, respectively.
- a solid dispersion was prepared containing 60 weight percent N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine and CAP using a Buchi B-290 mini spray drier.
- the solid dispersion was spray dried from a MeOH:THF (1:3) solvent system, a 5% spray solution concentration, an inlet temperature of 80° C.
- Dissolution testing was performed at a pH of 6.5 in phosphate buffer.
- the solid dispersion was suspended in H 2 O and added directly to the buffer solution at 37° C.
- the dissolution profile was collected over a period of about 240 minutes.
- the results are in FIG. 11 .
- the Cmax and AUC for the total drug species (colloidal+free) was 51.98 ⁇ g/mL and 144.91 ⁇ g/mL*hr, respectively.
- the Cmax and AUC for the free drug species was 15.07 ⁇ g/mL and 59.69 ⁇ g/mL*hr, respectively.
- a solid dispersion was prepared containing 60 weight percent N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine and HPMCAS Grade M using a Buchi B-290 mini spray drier.
- the solid dispersion was spray dried from a MeOH:THF (1:3) solvent system, a 5% spray solution concentration, an inlet temperature of 80° C.
- Dissolution testing was performed at a pH of 6.5 in phosphate buffer.
- the solid dispersion was suspended in H 2 O and added directly to the buffer solution at 37° C.
- the dissolution profile was collected over a period of about 240 minutes.
- the results are in FIG. 12 .
- the Cmax and AUC for the total drug species (colloidal+free) was 26.45 ⁇ g/mL and 96.21 ⁇ g/mL*hr, respectively.
- the Cmax and AUC for the free drug species was 10.96 ⁇ g/mL and 42.83 ⁇ g/mL*hr, respectively.
- a solid dispersion was prepared containing 50 weight percent N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine and PVP-VA using a Buchi B-290 mini spray drier.
- the solid dispersion was spray dried from a MeOH:THF (1:3) solvent system, a 3.9% spray solution concentration, an inlet temperature of 100° C.
- Step 1 (E)-N′-(2-Cyano-4-(3-(1-hydroxy-2-methylpropan-2-yl)thioureido) phenyl)-N,N-dimethylformimidamide was coupled with 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylaniline in isopropyl acetate:acetic acid (65:35 v/v) at 45° C.
- Step 2 1-(4-((4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl) amino)quinazolin-6-yl)-3-(1-hydroxy-2-methylpropan-2-yl)thiourea was agitated in tetrahydrofuran under basic conditions (2.5N NaOH), followed by the addition of p-toluenesulfonyl chloride.
- Step 3 N4-(4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine from Step 2 was triturated in ethanol at greater than 65° C. to provide N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine Form B Ethanol (89%).
- Dissolution testing was performed at a pH of 6.5 in phosphate buffer.
- the crystals (particles) were suspended in H 2 O and added directly to the buffer solution at 37° C.
- the dissolution profile was collected over a period of about 240 minutes.
- the Cmax and AUC for the free drug species was 0.44 ⁇ g/mL and 5.49 ⁇ g/mL*hr, respectively.
- Tablets containing the solid dispersions of any of Examples 1 to 11 may be prepared in a conventional manner comprising:
- Blend API Solid dispersion as 50 prepared in Example 11 Disintegrant Crospovidone- 6 Polyplasdone ® Osmogen NaCl 5 Osmogen KCl 5 Glidant Colloidal Silicon 0.5 Dioxide Lubricant Magnesium Stearate 0.25 Extragranular Binder/Diluent Microcrystalline 19.25 cellulose-Avicel ® Osmogen NaCl 4.625 Osmogen KCl 4.625 Disintegrant Polyplasdone 4 Glidant Colloidal Silicon 0.5 Dioxide Lubricant Magnesium Stearate 0.25
- tablets were made using OPADRY II 85F92727 at 3% by weight as a tablet coating.
- the tablets contained 150 mg of API.
- Tablets containing the solid dispersions of any of Examples 1 to 11 may be prepared in a conventional manner comprising:
- Blend API Solid dispersion as 50 prepared in Example 11 Disintegrant Crospovidone- 6 Polyplasdone ® Disintegrant NaHCO 3 3 Osmogen NaCl 5 Osmogen KCl 5 Glidant Colloidal Silicon 0.5 Dioxide Lubricant Magnesium Stearate 0.25 Extragranular Binder/Diluent Microcrystalline 16.25 cellulose-Avicel ® Osmogen NaCl 4.625 Osmogen KCl 4.625 Disintegrant Polyplasdone 4 Glidant Colloidal Silicon 0.5 Dioxide Lubricant Magnesium Stearate 0.25
- tablets were made using OPADRY II 85F92727 at 3% by weight as a tablet coating.
- the tablets contained 150 mg of API.
- Tablets containing the solid dispersions of any of Examples 1 to 11 may be prepared in a conventional manner comprising:
- Blend API Solid dispersion as 50 prepared in Example 11 Disintegrant Crospovidone- 6 Polyplasdone ® Osmogen NaCl 10.625 Osmogen KCl 10.625 Filler Lactose 21.25 Glidant Colloidal Silicon 0.5 Dioxide Lubricant Magnesium Stearate 0.25 Extragranular Glidant Colloidal Silicon 0.5 Dioxide Lubricant Magnesium Stearate 0.25
- tablets were made using OPADRY II 85F92727 at 3% by weight as a tablet coating.
- the tablets contained 150 mg of API.
- a PIC composition was prepared containing 25 mg or 100 mg of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine as prepared in Example 12.
- the PIC composition was prepared in size 00 white opaque hard gelatin capsules.
- Example 11 A dissolution test comparison was performed comparing the crystalline hemi-ethanolate PIC composition of Example 16 and the 50% PVP-VA solid dispersion (Example 11) tablet of Example 13 in 900 mL of 10 mM citrate buffer at 37° C. and a pH of 4.5, using USP Apparatus II at 75 rpm. The results are shown in FIG. 13 .
- a stability screen of the spray dried dispersions was completed at 40° C., 75% relative humidity under open conditions, in glass vials, over a period of 8 days. Results are shown in TABLE 2.
- Example 2 TABLE 2 HPLC Area % Time Example 1
- Example 3 Example 4 Standard 99.39 99.39 99.39 99.39 As 99.45 98.63 97.30 95.45 received 4 days 99.21 96.10 93.03 90.89 8 days 99.35 93.16 86.63 87.15
- the solid dispersion of Example 1 was prepared as a suspension in water and administered orally.
- the micronized suspension of Example 12 was prepared as a suspension with SyrSpend® SF Dry reconstituted with water and administered orally. To reduce variability, beagles were crossed over from pentagastrin to famotidine after a 5 day washout period.
- Pentagastrin is a pH modifier to modify gastric pH to about 2 to 3
- famotidine is a pH modifier to modify gastric pH to about 5 to 7.5
- Group A received pentagastrin pretreatment, the micronized suspension of Example 12, followed by a 5 day washout period, then famotidine pretreatment, and finally the micronized suspension of Example 12.
- Group B received pentagastrin pretreatment, the solid dispersion of Example 1, followed by a 5 day washout period, then famotidine pretreatment, and finally the solid dispersion of Example 1.
- Group C received the micronized suspension of Example 12, followed by a 5 day washout period, and finally the solid dispersion of Example 1. Results are shown in TABLE 3.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Inorganic Chemistry (AREA)
- Dispersion Chemistry (AREA)
- Nutrition Science (AREA)
- Physiology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Glass Compositions (AREA)
- Inorganic Insulating Materials (AREA)
- Optical Communication System (AREA)
Abstract
A solid dispersion of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine and processes for preparing the solid dispersion are provided herein. Also, a pharmaceutical composition comprising a solid dispersion of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine and uses thereof are provided herein.
Description
- This application a Continuation of U.S. patent application Ser. No. 17/133,094, filed Dec. 23, 2020, which is a Continuation of U.S. patent application Ser. No. 16/353,951, filed Mar. 14, 2019, which is a Continuation of U.S. patent application Ser. No. 15/275,163, filed Sep. 23, 2016, which is a Continuation of U.S. patent application Ser. No. 14/351,840, filed Apr. 14, 2014, now U.S. Pat. No. 9,457,093, which is a 35 U.S.C § 371 application of International Patent Application No. PCT/US2012/060044, filed Oct. 12, 2012, which claims the benefit of U.S. Provisional Application No. 61/606,207, filed Mar. 2, 2012 and which also claims the benefit of U.S. Provisional Application No. 61/547,620, filed Oct. 14, 2011. The entire content of the applications referenced above are hereby incorporated by reference herein.
- A solid dispersion of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine is provided herein. Also, a pharmaceutical composition comprising a solid dispersion of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine is provided herein.
- N4-(4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine (also called “ARRY-380”), which has the structure:
- is a selective ErbB2 (HER2) inhibitor described in WO 2007/059257, which is incorporated by reference in its entirety. N4-(4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine has been tested in human clinical trials for hyperproliferative diseases, particularly cancer (see Koch, Kevin. “ARRY-380: A Selective, Oral HER2 Inhibitor for the Treatment of Solid Tumors.” American Association of Cancer Research 102nd Annual Meeting, Apr. 3, 2011; which may also be found at: http://www.arraybiopharma.com/_documents/Publication/PubAttachment462.pdf).
- A powder-in-capsule (“PIC”) composition of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine was prepared and administered to patients with cancer, and the overall inter-patient variability for area under the plasma concentration-time curve (“AUC”) and maximum concentration (“Cmax”) was moderate to high.
- There remains a need to prepare a pharmaceutical composition containing N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine that minimizes inter-patient variability of pharmacokinetics.
- A solid dispersion comprising N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine is described herein.
- A pharmaceutical composition comprising N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine is described herein.
- A pharmaceutical composition comprising a solid dispersion of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine is described herein.
- A pharmaceutical composition comprising a solid dispersion of spray dried N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine is described herein.
- Processes for preparing the solid dispersion and pharmaceutical composition and methods of using the pharmaceutical composition are also described herein.
-
FIG. 1 shows a comparison of XRPD scans of amorphous 30% solid dispersions and crystalline N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine, with a close up of the amorphous solid dispersions. -
FIG. 2 shows a dissolution profile of a 30% solid dispersion of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine. -
FIG. 3 shows a dissolution profile of a 30% solid dispersion of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine. -
FIG. 4 shows a dissolution profile of a 30% solid dispersion of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine. -
FIG. 5 shows a dissolution profile of a 30% solid dispersion of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine. -
FIG. 6 shows a dissolution profile of a 30% solid dispersion of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine. -
FIG. 7 shows a comparison of XRPD scans of amorphous 60% solid dispersions and crystalline N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine, with a close up of the amorphous solid dispersions. -
FIG. 8 shows a dissolution profile of a 60% solid dispersion of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine. -
FIG. 9 shows a dissolution profile of a 60% solid dispersion of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine. -
FIG. 10 shows a dissolution profile of a 60% solid dispersion of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine. -
FIG. 11 shows a dissolution profile of a 60% solid dispersion of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine. -
FIG. 12 shows a dissolution profile of a 60% solid dispersion of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine. -
FIG. 13 shows a dissolution comparison of a solid dispersion tablet and a crystalline PIC composition. - Reference will now be made in detail to certain embodiments, examples of which are illustrated herein. While enumerated embodiments will be described, it will be understood that they are not intended to limit the invention to those embodiments. On the contrary, the invention is intended to cover all alternatives, modifications, and equivalents, which may be included within the scope of the present invention as defined by the claims. One skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described. In the event that one or more of the incorporated literature and similar materials differs from or contradicts this application, including but not limited to defined terms, term usage, described techniques, or the like, this application controls.
- The term “about” is used herein to mean approximately, in the region of, roughly, or around. When the term “about” is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term “about” is used herein to modify a numerical value above and below the stated value by a variance of 20%.
- As used herein, the recitation of a numerical range for a variable is intended to convey that the invention may be practiced with the variable equal to any of the values within that range. Thus, for a variable that is inherently discrete, the variable can be equal to any integer value of the numerical range, including the end-points of the range. Similarly, for a variable that is inherently continuous, the variable can be equal to any real value of the numerical range, including the end-points of the range. As an example, a variable that is described as having values between 0 and 2, can be 0, 1 or 2 for variables that are inherently discrete, and can be 0.0, 0.1, 0.01, 0.001, or any other real value for variables that are inherently continuous.
- The term “amorphous” means a solid in a solid state that is a non-crystalline state. Amorphous solids generally possess crystal-like short range molecular arrangement, but no long range order of molecular packing as found in crystalline solids. The solid state form of a solid may be determined by polarized light microscopy, x-ray powder diffraction (“XRPD”), differential scanning calorimetry (“DSC”), or other standard techniques known to those of skill in the art.
- The phrase “amorphous solid dispersion” means a solid comprising a drug substance and a dispersion polymer. The amorphous solid dispersion discussed herein comprises amorphous N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine and a dispersion polymer, wherein the amorphous solid dispersion contains N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine in a substantially amorphous solid state form. In certain embodiments, the substantially amorphous solid state form means that the N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine component in the amorphous solid dispersion is at least 80% amorphous N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine. In certain embodiments, the substantially amorphous solid state form means that the N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine component in the amorphous solid dispersion is at least 85% amorphous N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine. In certain embodiments, the substantially amorphous solid state form means that the N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine component in the amorphous solid dispersion is at least 90% amorphous N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine. In certain embodiments, the substantially amorphous solid state form means that the N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine component in the amorphous solid dispersion is at least 95% amorphous N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine.
- The terms “cancer” and “cancerous” refer to or describe the physiological condition in mammals that is typically characterized by abnormal or unregulated cell growth. A “tumor” comprises one or more cancerous cells. Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies. More particular examples of such cancers include squamous cell cancer (e.g., epithelial squamous cell cancer), lung cancer including small cell lung cancer, non-small cell lung cancer (“NSCLC”), adenocarcinoma of the lung and squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer including gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, brain, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, skin cancer, including melanoma, as well as head and neck cancer.
- The phrase “dispersion polymer” means a polymer that allows for N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine to be dispersed throughout such that a solid dispersion may form. The dispersion polymer is preferably neutral or basic. The dispersion polymer may contain a mixture of two or more polymers. Examples of dispersion polymers include, but are not limited to, vinyl polymers and copolymers, vinylpyrrolidine vinylacetate copolymer (“PVP-VA”), polyvinyl alcohols, polyvinyl alcohol polyvinyl acetate copolymers, polyvinyl pyrrolidine (“PVP”), acrylate and methacrylate copolymers, methylacrylic acid methyl methacrylate copolymer (such as Eudragit®), polyethylene polyvinyl alcohol copolymers, polyoxyethylene-polyoxypropylene block copolymers (also referred to as poloxamers), graft copolymer comprised of polyethylene glycol, polyvinyl caprolactam and polyvinyl acetate (such as Soluplus®), cellulosic polymers, such as hydroxypropyl methyl cellulose acetate (“HPMCA”), hydroxypropyl methyl cellulose (“HPMC”), hydroxypropyl cellulose (“HPC”), methyl cellulose, hydroxyethyl methyl cellulose, hydroxyethyl cellulose, hydroxyethyl cellulose acetate, and hydroxyethyl ethyl cellulose, hydroxypropyl methyl cellulose acetate succinate (“HPMCAS”), hydroxypropyl methyl cellulose phthalate (“HPMCP”), carboxymethylethyl cellulose (“CMEC”), cellulose acetate phthalate (“CAP”), cellulose acetate succinate (“CAS”), hydroxypropyl methyl cellulose acetate phthalate (“HPMCAP”), cellulose acetate trimellitate (“CAT”), hydroxypropyl methyl cellulose acetate trimellitate (“HPMCAT”), and carboxymethylcellulose acetate butyrate (“CMCAB”), and the like.
- The term “mammal” means a warm-blooded animal that has or is at risk of developing a disease described herein and includes, but is not limited to, guinea pigs, dogs, cats, rats, mice, hamsters, and primates, including humans.
- The phrase “pharmaceutically acceptable” indicates that the substance or composition is compatible chemically and/or toxicologically, with the other ingredients comprising a composition, and/or the mammal being treated therewith.
- The phrase “pharmaceutically acceptable salt,” as used herein, refers to pharmaceutically acceptable organic or inorganic salts of a compound described herein.
- The phrase “solid dispersion” means a system in a solid state comprising at least two components, wherein one component is dispersed throughout the other component. The solid dispersion discussed herein comprises one component of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine dispersed throughout another component, particularly a dispersion polymer.
- The phrase “spray drying” means processes involved in breaking up liquid mixtures into small droplets (atomization) and rapidly removing solvent from the mixture in a spray drying apparatus where there is a strong driving force for evaporation of solvent from the droplets. The phrase spray drying is used conventionally and broadly. Spray drying processes and spray drying equipment are described generally in Perry, Robert H., and Don W. Green (eds.). Perry's Chemical Engineers' Handbook. New York: McGraw-Hill, 2007 (8th edition).
- The phrases “therapeutically effective amount” or “effective amount” mean an amount of a compound described herein that, when administered to a mammal in need of such treatment, sufficient to (i) treat or prevent the particular disease, condition, or disorder, (ii) attenuate, ameliorate, or eliminate one or more symptoms of the particular disease, condition, or disorder, or (iii) prevent or delay the onset of one or more symptoms of the particular disease, condition, or disorder described herein. The amount of a compound that will correspond to such an amount will vary depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight) of the mammal in need of treatment, but can nevertheless be routinely determined by one skilled in the art.
- The terms “treat” or “treatment” refer to therapeutic, prophylactic, palliative or preventative measures. Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment. Those in need of treatment include those already with the condition or disorder, as well as those prone to have the condition or disorder or those in which the condition or disorder is to be prevented.
- Provided herein is a solid dispersion comprising N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine.
- The solid dispersions are generally prepared by dissolving the drug substance and the dispersion polymer in a suitable solvent to form a feed solution, and then the feed solution may be spray dried to form the solid dispersion (and remove the solvent). Spray drying is a known process. Spray drying is generally performed by dissolving N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine and the dispersion polymer in a suitable solvent to prepare a feed solution. The feed solution may be pumped through an atomizer into a drying chamber. The feed solution can be atomized by conventional means known in the art, such as a two-fluid sonicating nozzle, a pressure nozzle, a rotating nozzle and a two-fluid non-sonicating nozzle. Then, the solvent is removed in the drying chamber to form the solid dispersion. A typical drying chamber uses hot gases, such as forced air, nitrogen, nitrogen-enriched air, or argon to dry particles. The size of the drying chamber may be adjusted to achieve particle properties or throughput.
- Although the solid dispersion are preferably prepared by conventional spray drying techniques, other techniques known in the art may be used, such as melt extrusion, freeze drying, rotary evaporation, drum drying or other solvent removal processes.
- In one embodiment, a process of preparing a solid dispersion is provided, comprising:
- (a) dissolving N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine and a dispersion polymer in a suitable solvent; and
- (b) evaporating the solvent to form the solid dispersion.
- In a further embodiment, the evaporation of the solvent in step (b) is performed by spray drying, melt extrusion, freeze drying, rotary evaporation, drum drying or other solvent removal processes.
- In certain embodiments, the dispersion polymer is selected from PVP-VA, methylacrylic acid methyl methacrylate copolymer, HPMCP, CAP, HPMCAS and HPMC and mixtures thereof. In certain embodiments, the dispersion polymer is selected from PVP-VA, methylacrylic acid methyl methacrylate copolymer, HPMCP, CAP, HPMCAS and HPMC. In certain embodiments, the dispersion polymer is selected from PVP-VA, Eudragit® L100, HPMCP H-55, CAP, HPMCAS Grade M, HPMC and mixtures thereof. In certain embodiments, the dispersion polymer is selected from PVP-VA, Eudragit® L100, HPMCP H-55, CAP, HPMCAS Grade M and HPMC.
- In certain embodiments, the dispersion polymer is selected from PVP-VA, methylacrylic acid methyl methacrylate copolymer, HPMCP, CAP and HPMCAS, and mixtures thereof. In certain embodiments, the dispersion polymer is selected from PVP-VA, methylacrylic acid methyl methacrylate copolymer, HPMCP, CAP and HPMCAS. In certain embodiments, the dispersion polymer is selected from PVP-VA, Eudragit® L100, HPMCP H-55, CAP and HPMCAS Grade M, and mixtures thereof. In certain embodiments, the dispersion polymer is selected from PVP-VA, Eudragit® L100, HPMCP H-55, CAP and HPMCAS Grade M.
- In certain embodiments, the dispersion polymer is selected from PVP-VA, methylacrylic acid methyl methacrylate copolymer, HPMCP, CAP and HPMC, and mixtures thereof. In certain embodiments, the dispersion polymer is selected from PVP-VA, methylacrylic acid methyl methacrylate copolymer, HPMCP, CAP and HPMC. In certain embodiments, the dispersion polymer is selected from PVP-VA, Eudragit® L100, HPMCP H-55, CAP and HPMC, and mixtures thereof. In certain embodiments, the dispersion polymer is selected from PVP-VA, Eudragit® L100, HPMCP H-55, CAP and HPMC.
- In certain embodiments, the dispersion polymer is selected from PVP-VA, methylacrylic acid methyl methacrylate copolymer, HPMCP and CAP, and mixtures thereof. In certain embodiments, the dispersion polymer is selected from PVP-VA, methylacrylic acid methyl methacrylate copolymer, HPMCP and CAP. In certain embodiments, the dispersion polymer is selected from PVP-VA, Eudragit® L100, HPMCP H-55 and CAP, and mixtures thereof. In certain embodiments, the dispersion polymer is selected from PVP-VA, Eudragit® L100, HPMCP H-55 and CAP.
- In certain embodiments, the dispersion polymer is PVP-VA.
- In certain embodiments, the dispersion polymer is methylacrylic acid methyl methacrylate copolymer. In certain embodiments, the dispersion polymer is Eudragit®. In certain embodiments, the dispersion polymer is Eudragit® L100.
- In certain embodiments, the dispersion polymer is HPMCP. In certain embodiments, the dispersion polymer is HPMCP H-55.
- In certain embodiments, the dispersion polymer is CAP.
- In certain embodiments, the dispersion polymer is HPMCAS. In certain embodiments, the dispersion polymer is HPMCAS Grade M.
- In certain embodiments, the dispersion polymer is preferably neutral or basic. In certain embodiments, the dispersion polymer is selected from PVP-VA and HPMC. In certain embodiments, the dispersion polymer is HPMC.
- Suitable solvents are a solvent or mixture of solvents in which both N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine and the dispersion polymer have adequate solubility (solubility greater than 1 mg/mL). A mixture of solvents may be used if each component of the solid dispersion (i.e., N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine and dispersion polymer) require different solvents to obtain the desired solubility. The solvent may be volatile with a boiling point of 150° C. or less. In addition, the solvent should have relatively low toxicity and be removed from the dispersion to a level that is acceptable to The International Committee on Harmonization (“ICH”) guidelines. Removal of solvent to this level may require a subsequent processing step, such as tray drying. Examples of suitable solvents include, but are not limited to, alcohols, such as methanol (“MeOH”), ethanol (“EtOH”), n-propanol, isopropanol (“IPA”) and butanol; ketones, such as acetone, methyl ethyl ketone (“MEK”) and methyl isobutyl ketone; esters, such as ethyl acetate (“EA”) and propyl acetate; and various other solvents, such as tetrahydrofuran (“THF”), acetonitrile (“ACN”), methylene chloride, toluene and 1,1,1-trichloroethane. Lower volatility solvents, such as dimethyl acetate or dimethylsulfoxide (“DMSO”), may be used. Mixtures of solvents with water may also be used, so long as the polymer and N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine are sufficiently soluble to make the spray drying process practicable. Generally, due to the hydrophobic nature of low solubility drugs, non-aqueous solvents may be used, meaning the solvent comprises less than about 10 weight % water.
- In certain embodiments, the suitable solvent is selected from MeOH and THF, and mixtures thereof. In certain embodiments, the suitable solvent is MeOH:THF solvent system of about 1:3. In certain embodiments, the suitable solvent is a 1:3 MeOH:THF solvent system.
- In certain embodiments, the suitable solvent is selected from MeOH, THF and water, and mixtures thereof. In certain embodiments, the suitable solvent is selected from MeOH, THF and water. In certain embodiments, the suitable solvent is a THF:MeOH:water solvent system of about 80:10:10. In certain embodiments, the suitable solvent is a 80:10:10 THF:MeOH:water solvent system. In certain embodiments, the suitable solvent is a THF:MeOH:water solvent system of about 82:8:10. In certain embodiments, the suitable solvent is a 82:8:10 THF:MeOH:water solvent system. In certain embodiments, the suitable solvent is a THF:MeOH:water solvent system of about 82.2:8.2:9.6. In certain embodiments, the suitable solvent is a 82.2:8.2:9.6 THF:MeOH:water solvent system.
- In certain embodiments, the amount of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine in the solid dispersion ranges from about 0.1% to about 70% by weight relative to the dispersion polymer. In certain embodiments, the amount of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine in the solid dispersion ranges from 0.1% to 70% by weight relative to the dispersion polymer.
- In certain embodiments, the amount of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine in the solid dispersion ranges from about 1% to about 60% by weight relative to the dispersion polymer. In certain embodiments, the amount of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine in the solid dispersion ranges from 1% to 60% by weight relative to the dispersion polymer.
- In certain embodiments, the amount of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine in the solid dispersion ranges from about 5% to about 60% by weight relative to the dispersion polymer. In certain embodiments, the amount of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine in the solid dispersion ranges from 5% to 60% by weight relative to the dispersion polymer.
- In certain embodiments, the amount of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine in the solid dispersion ranges from about 55% to about 65% by weight relative to the dispersion polymer. In certain embodiments, the amount of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine in the solid dispersion ranges from 55% to 65% by weight relative to the dispersion polymer. In certain embodiments, the amount of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine in the solid dispersion is about 60% by weight relative to the dispersion polymer. In certain embodiments, the amount of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine in the solid dispersion is 60% by weight relative to the dispersion polymer.
- In certain embodiments, the amount of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine in the solid dispersion ranges from about 25% to about 35% by weight relative to the dispersion polymer. In certain embodiments, the amount of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine in the solid dispersion ranges from 25% to 35% by weight relative to the dispersion polymer. In certain embodiments, the amount of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine in the solid dispersion is about 30% by weight relative to the dispersion polymer. In certain embodiments, the amount of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine in the solid dispersion is 30% by weight relative to the dispersion polymer.
- In certain embodiments, the amount of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine in the solid dispersion ranges from about 45% to about 55% by weight relative to the dispersion polymer. In certain embodiments, the amount of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine in the solid dispersion ranges from 45% to 55% by weight relative to the dispersion polymer. In certain embodiments, the amount of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine in the solid dispersion is about 50% by weight relative to the dispersion polymer. In certain embodiments, the amount of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine in the solid dispersion is 50% by weight relative to the dispersion polymer.
- In certain embodiments, the solid dispersion is an amorphous solid dispersion.
- Another embodiment provides a pharmaceutical composition comprising a solid dispersion of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine and a dispersion polymer, and a carrier or excipient.
- Suitable carriers and excipients are well known to those skilled in the art and are described in detail in, e.g., Ansel, Howard C., et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005.
- The pharmaceutical compositions may also include one or more additional components, such as buffers, dispersion agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug, i.e., a compound described herein or pharmaceutical composition thereof, or aid in the manufacturing of the pharmaceutical product, i.e., medicament (see Ansel; Gennaro; and Rowe above). The components of the pharmaceutical composition should be pharmaceutically acceptable.
- Certain embodiments provide a pharmaceutical composition comprising:
- (a) about 1 to about 70 weight % of a solid dispersion of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine;
- (b) about 0.1 to about 20 weight % of a disintegrant;
- (c) about 0.1 to about 25 weight % of an osmogen;
- (d) about 0.1 to about 10 weight % of a glidant;
- (e) about 0.1 to about 10 weight % of a lubricant; and
- (f) about 0.1 to about 25 weight % of a binder/diluent.
- In a further embodiment, the pharmaceutical composition comprises:
- (a) 1 to 70 weight % of a solid dispersion of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine;
- (b) 0.1 to 20 weight % of a disintegrant;
- (c) 0.1 to 25 weight % of an osmogen;
- (d) 0.1 to 10 weight % of a glidant;
- (e) 0.1 to 10 weight % of a lubricant; and
- (f) 0.1 to 25 weight % of a binder/diluent.
- Certain embodiments provide a pharmaceutical composition comprising:
- (a) about 25 to about 60 weight % of a solid dispersion of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine;
- (b) about 5 to about 15 weight % of a disintegrant;
- (c) about 15 to about 25 weight % of an osmogen;
- (d) about 0.1 to about 3 weight % of a glidant;
- (e) about 0.1 to about 3 weight % of a lubricant; and
- (f) about 10 to about 25 weight % of a binder/diluent.
- In a further embodiment, the pharmaceutical composition comprises:
- (a) 25 to 60 weight % of a solid dispersion of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine;
- (b) 5 to 15 weight % of a disintegrant;
- (c) 15 to 25 weight % of an osmogen;
- (d) 0.1 to 3 weight % of a glidant;
- (e) 0.1 to 3 weight % of a lubricant; and
- (f) 10 to 25 weight % of a binder/diluent.
- Certain embodiments provide a pharmaceutical composition comprising:
- (a) about 40 to about 60 weight % of a solid dispersion of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine;
- (b) about 5 to about 15 weight % of a disintegrant;
- (c) about 15 to about 25 weight % of an osmogen;
- (d) about 0.1 to about 3 weight % of a glidant;
- (e) about 0.1 to about 3 weight % of a lubricant; and
- (f) about 10 to about 25 weight % of a binder/diluent.
- In a further embodiment, the pharmaceutical composition comprises:
- (a) 40 to 60 weight % of a solid dispersion of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine;
- (b) 5 to 15 weight % of a disintegrant;
- (c) 15 to 25 weight % of an osmogen;
- (d) 0.1 to 3 weight % of a glidant;
- (e) 0.1 to 3 weight % of a lubricant; and
- (f) 10 to 25 weight % of a binder/diluent.
- Certain embodiments provide a pharmaceutical composition comprising:
- (a) about 1 to about 70 weight % of a solid dispersion of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine;
- (b) about 0.1 to about 20 weight % of a disintegrant;
- (c) about 0.1 to about 25 weight % of an osmogen;
- (d) about 0.1 to about 10 weight % of a glidant;
- (e) about 0.1 to about 10 weight % of a lubricant; and
- (f) about 0.1 to about 25 weight % of a filler.
- In a further embodiment, the pharmaceutical composition comprises:
- (a) 1 to 70 weight % of a solid dispersion of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine;
- (b) 0.1 to 20 weight % of a disintegrant;
- (c) 0.1 to 25 weight % of an osmogen;
- (d) 0.1 to 10 weight % of a glidant;
- (e) 0.1 to 10 weight % of a lubricant; and
- (f) 0.1 to 25 weight % of a filler.
- Certain embodiments provide a pharmaceutical composition comprising:
- (a) about 25 to about 60 weight % of a solid dispersion of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine;
- (b) about 1 to about 10 weight % of a disintegrant;
- (c) about 15 to about 25 weight % of an osmogen;
- (d) about 0.1 to about 3 weight % of a glidant;
- (e) about 0.1 to about 3 weight % of a lubricant; and
- (f) about 10 to about 25 weight % of a filler.
- In a further embodiment, the pharmaceutical composition comprises:
- (a) 25 to 60 weight % of a solid dispersion of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine;
- (b) 1 to 10 weight % of a disintegrant;
- (c) 15 to 25 weight % of an osmogen;
- (d) 0.1 to 3 weight % of a glidant;
- (e) 0.1 to 3 weight % of a lubricant; and
- (f) 10 to 25 weight % of a filler.
- Certain embodiments provide a pharmaceutical composition comprising:
- (a) about 40 to about 60 weight % of a solid dispersion of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine;
- (b) about 1 to about 10 weight % of a disintegrant;
- (c) about 15 to about 25 weight % of an osmogen;
- (d) about 0.1 to about 3 weight % of a glidant;
- (e) about 0.1 to about 3 weight % of a lubricant; and
- (f) about 10 to about 25 weight % of a filler.
- In a further embodiment, the pharmaceutical composition comprises:
- (a) 40 to 60 weight % of a solid dispersion of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine;
- (b) 1 to 10 weight % of a disintegrant;
- (c) 15 to 25 weight % of an osmogen;
- (d) 0.1 to 3 weight % of a glidant;
- (e) 0.1 to 3 weight % of a lubricant; and
- (f) 10 to 25 weight % of a filler.
- In certain embodiments, the osmogen is selected from NaCl and KCl, and mixtures thereof.
- In certain embodiments, the lubricant is magnesium stearate.
- In certain embodiments, the glidant is colloidal silicon dioxide.
- In certain embodiments, the binder/diluent is microcrystalline cellulose. In certain embodiments, the binder/diluent acts as both a binder and a diluent.
- In certain embodiments, the binder is microcrystalline cellulose.
- In certain embodiments, the diluent is microcrystalline cellulose.
- In certain embodiments, the filler is lactose.
- In certain embodiments, the disintegrant is selected from crospovidone and sodium bicarbonate (NaHCO3), and mixtures thereof. In certain embodiments, the disintegrant is selected from crospovidone and sodium bicarbonate. In certain embodiments, the disintegrant is sodium bicarbonate. In certain embodiments, the disintegrant is crospovidone.
- In certain embodiments, the composition contains sodium bicarbonate. N4-(4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine may slowly degrade, through hydrolysis or other means, to a carbamate impurity:
- Sodium bicarbonate helps to slow the degradation to the carbamate impurity. Sodium bicarbonate also helps to provide consistent tablet disintegration when the tablets are exposed to different humidities.
- Certain embodiments provide a pharmaceutical composition comprising:
- (a) N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine; and
- (b) sodium bicarbonate.
- Certain embodiments provide a pharmaceutical composition comprising:
- (a) about 1 to about 70 weight % of a solid dispersion of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine; and
- (b) about 0.1 to about 30 weight % sodium bicarbonate.
- In a further embodiment, the pharmaceutical composition comprises:
- (a) 1 to 70 weight % of a solid dispersion of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine; and
- (b) 0.1 to 30 weight % sodium bicarbonate.
- Certain embodiments provide a pharmaceutical composition comprising:
- (a) about 1 to about 70 weight % of a solid dispersion of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine;
- (b) about 0.1 to about 30 weight % sodium bicarbonate; and
- (c) the remaining weight is other pharmaceutically acceptable excipients and carriers.
- In a further embodiment, the pharmaceutical composition comprises:
- (a) 1 to 70 weight % of a solid dispersion of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine;
- (b) 0.1 to 30 weight % sodium bicarbonate; and
- (c) the remaining weight is other pharmaceutically acceptable excipients and carriers.
- Certain embodiments provide a pharmaceutical composition comprising:
- (a) about 25 to about 60 weight % of a solid dispersion of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine; and
- (b) about 1 to about 15 weight % of sodium bicarbonate.
- In a further embodiment, the pharmaceutical composition comprises:
- (a) 25 to 60 weight % of a solid dispersion of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine; and
- (b) 1 to 15 weight % of sodium bicarbonate.
- Certain embodiments provide a pharmaceutical composition comprising:
- (a) about 25 to about 60 weight % of a solid dispersion of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine;
- (b) about 1 to about 15 weight % of sodium bicarbonate; and
- (c) the remaining weight is other pharmaceutically acceptable excipients and carriers.
- In a further embodiment, the pharmaceutical composition comprises:
- (a) 25 to 60 weight % of a solid dispersion of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine;
- (b) 1 to 15 weight % of sodium bicarbonate; and
- (c) the remaining weight is other pharmaceutically acceptable excipients and carriers.
- Certain embodiments provide a pharmaceutical composition comprising:
- (a) about 40 to about 60 weight % of a solid dispersion of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine; and
- (b) about 1 to about 15 weight % of sodium bicarbonate.
- In a further embodiment, the pharmaceutical composition comprises:
- (a) 40 to 60 weight % of a solid dispersion of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine; and
- (b) 1 to 15 weight % of sodium bicarbonate.
- Certain embodiments provide a pharmaceutical composition comprising:
- (a) about 40 to about 60 weight % of a solid dispersion of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine;
- (b) about 1 to about 15 weight % of sodium bicarbonate;
- (c) the remaining weight is other pharmaceutically acceptable excipients and carriers.
- In a further embodiment, the pharmaceutical composition comprises:
- (a) 40 to 60 weight % of a solid dispersion of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine;
- (b) 1 to 15 weight % of sodium bicarbonate;
- (c) the remaining weight is other pharmaceutically acceptable excipients and carriers.
- The pharmaceutical composition preferably contains a therapeutically effective amount of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine. However, in some embodiments, each individual dose contains a portion of a therapeutically effective amount of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine, such that multiple doses of the composition may be required (for example, two or more tablets are required for a therapeutically effective amount). Thus, in this application when it states that the pharmaceutical composition contains a therapeutically effective amount it means that the composition may be one dose (for example, one tablet) or multiple doses (for example, two tablets). In certain embodiments, the pharmaceutical composition contains between 1 and 500 mg of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine.
- In certain embodiments, the pharmaceutical composition contains between 25 and 400 mg of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine.
- In certain embodiments, the pharmaceutical composition contains between 100 and 300 mg of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine.
- The pharmaceutical compositions described herein may be administered by any convenient route appropriate to the condition to be treated. Suitable routes include oral, parenteral (including subcutaneous, intramuscular, intravenous, intraarterial, intradermal, intrathecal and epidural), transdermal, rectal, nasal, topical (including buccal and sublingual), ocular, vaginal, intraperitoneal, intrapulmonary and intranasal. If parenteral administration is desired, the compositions will be sterile and in a solution or suspension form suitable for injection or infusion.
- The compounds may be administered in any convenient administrative form, e.g., tablets, powders, capsules, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc.
- The pharmaceutical compositions described herein are typically administered orally. The pharmaceutical compositions described herein are typically administered as a tablet, caplet, hard or soft gelatin capsule, pill, granules or a suspension.
- Methods of Treatment with Compounds of the Invention
- Also provided are methods of treating or preventing disease or condition by administering the pharmaceutical composition described herein. In one embodiment, a human patient is treated with a pharmaceutical composition described herein in an amount to inhibit ErbB2 activity. In one embodiment, a human patient is treated with a pharmaceutical composition described herein in an amount to detectably inhibit ErbB2 activity.
- In another embodiment, a method of treating a hyperproliferative disease in a mammal comprising administering the pharmaceutical composition described herein, to the mammal is provided.
- In certain embodiments, the hyperproliferative disease is cancer.
- In another embodiment, a method of treating or preventing cancer in a mammal in need of such treatment, wherein the method comprises administering to said mammal a pharmaceutical composition described herein. The cancer is selected from breast, ovary, cervix, prostate, testis, genitourinary tract, esophagus, larynx, glioblastoma, neuroblastoma, stomach, skin, keratoacanthoma, lung, epidermoid carcinoma, large cell carcinoma, NSCLC, small cell carcinoma, lung adenocarcinoma, bone, colon, adenoma, pancreas, adenocarcinoma, thyroid, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder carcinoma, liver carcinoma and biliary passages, kidney carcinoma, myeloid disorders, lymphoid disorders, hairy cells, buccal cavity and pharynx (oral), lip, tongue, mouth, pharynx, small intestine, colon-rectum, large intestine, rectum, brain and central nervous system, Hodgkin's and leukemia. Another embodiment provides the use of a pharmaceutical composition described herein, in the manufacture of a medicament for the treatment of cancer.
- In another embodiment, the cancer is ErbB2 positive.
- In another embodiment, the cancer is selected from breast, gastric, biliary, colorectal, lung, NSCLC, pancreatic, head and neck, ovarian, uterine and brain cancer.
- In another embodiment, the cancer is selected from breast, gastric, biliary, colorectal, lung, NSCLC, pancreatic, head and neck, ovarian and uterine cancer.
- In another embodiment, the cancer is selected from breast, gastric, colorectal, lung and ovarian cancer.
- In another embodiment, the cancer is selected from breast, ovarian, gastric and uterine cancer.
- In another embodiment, the cancer is selected from breast, gastric, colorectal, NSCLC and ovarian cancer.
- In another embodiment, the cancer is selected from breast, lung, pancreatic, colorectal and head and neck cancers.
- In another embodiment, the cancer is breast cancer.
- In another embodiment, the cancer is gastric cancer.
- In another embodiment, the cancer is biliary cancer.
- In another embodiment, the cancer is colorectal cancer.
- In another embodiment, the cancer is lung cancer.
- In another embodiment, the cancer is NSCLC.
- In another embodiment, the cancer is pancreatic cancer.
- In another embodiment, the cancer is head and neck cancer.
- In another embodiment, the cancer is ovarian cancer.
- In another embodiment, the cancer is uterine cancer.
- In another embodiment, the cancer is brain cancer.
- In another embodiment, a method of treating or preventing a disease or disorder modulated by ErbB2, comprising administering to a mammal in need of such treatment an effective amount of a pharmaceutical composition described herein. Examples of such diseases and disorders include, but are not limited to, cancer.
- Another embodiment provides the use of a pharmaceutical composition described herein, in the manufacture of a medicament for the treatment of cancer.
- Another embodiment provides the solid dispersions described herein for the treatment of disease. In a further embodiment, the disease is a hyperproliferative disease. In a further embodiment, the hyperproliferative disease is cancer.
- Another embodiment provides the pharmaceutical compositions described herein for the treatment of disease. In a further embodiment, the disease is a hyperproliferative disease. In a further embodiment, the hyperproliferative disease is cancer.
- For illustrative purposes, the following Examples are included. However, it is to be understood that these Examples do not limit the invention and are only meant to suggest a method of practicing the invention. Persons skilled in the art will recognize that the chemical reactions described may be readily adapted to prepare the compounds described herein, and alternative methods for preparing the compounds are deemed to be within the scope of this invention. For example, the synthesis of the compounds described herein may be successfully performed by modifications apparent to those skilled in the art, e.g., by appropriately protecting interfering groups, by utilizing other suitable reagents known in the art other than those described, and/or by making routine modifications of reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be recognized as having applicability for preparing the compounds described herein. Persons skilled in the art will also recognize that the solid dispersions and compositions described may be readily adapted to prepare other dispersions and compositions, and alternative methods for preparing the dispersions and compositions, as well as alternative compositions are deemed to be within the scope of this invention.
- A solid dispersion was prepared containing 30 weight percent N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine and PVP-VA using a Buchi B-290 mini spray drier. The solid dispersion was spray dried from a MeOH:THF (1:3) solvent system, a 5% spray solution concentration, an inlet temperature of 100° C. at a flow rate of 22 mL/minute, drying gas flow rate of 35 m3/hour, nozzle pressure of 80 psig, nozzle gas flow of 0.66 m3/hour, and a 1.5 mm nozzle type. Secondary drying of the dispersion was done at 40° C. under vacuum for about 16 hours. The spray drying yielded 19.6 g (87.7% yield) of the solid dispersion. Physicochemical analysis results are in Table 1. The XRPD scan is shown in
FIG. 1 . Residual solvent analysis showed that the dispersion had less than 0.5% THF and no detectable MeOH. - Dissolution testing was performed at a pH of 6.5 in phosphate buffer. The solid dispersion was suspended in H2O and added directly to the buffer solution at 37° C. The dissolution profile was collected over a period of about 240 minutes. The results are in
FIG. 2 . The Cmax and AUC for the total drug species (colloidal+free) was 63.46 μg/mL and 245.05 μg/mL*hr, respectively. The Cmax and AUC for the free drug species was 52.50 μg/mL and 204.12 μg/mL*hr, respectively. - A solid dispersion was prepared containing 30 weight percent N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine and Eudragit L100 using a Buchi B-290 mini spray drier. The solid dispersion was spray dried from a MeOH:THF (1:3) solvent system, a 5% spray solution concentration, an inlet temperature of 100° C. at a flow rate of 22 mL/minute, drying gas flow rate of 35 m3/hour, nozzle pressure of 80 psig, nozzle gas flow of 0.66 m3/hour, and a 1.5 mm nozzle type. Secondary drying of the dispersion was done at 40° C. under vacuum for about 16 hours. The spray drying yielded 18.6 g (82.7% yield) of the solid dispersion. Physicochemical analysis results are in Table 1. The XRPD scan is shown in
FIG. 1 . Residual solvent analysis showed that the dispersion had about 4.5% THF and no detectable MeOH. - Dissolution testing was performed at a pH of 6.5 in phosphate buffer. The solid dispersion was suspended in H2O and added directly to the buffer solution at 37° C. The dissolution profile was collected over a period of about 240 minutes. The results are in
FIG. 3 . The Cmax and AUC for the total drug species (colloidal+free) was 22.70 μg/mL and 71.06 μg/mL*hr, respectively. The Cmax and AUC for the free drug species was 9.26 μg/mL and 35.49 μg/mL*hr, respectively. - A solid dispersion was prepared containing 30 weight percent N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine and HPMCP H-55 using a Buchi B-290 mini spray drier. The solid dispersion was spray dried from a MeOH:THF (1:3) solvent system, a 5% spray solution concentration, an inlet temperature of 100° C. at a flow rate of 22 mL/minute, drying gas flow rate of 35 m3/hour, nozzle pressure of 80 psig, nozzle gas flow of 0.66 m3/hour, and a 1.5 mm nozzle type. Secondary drying of the dispersion was done at 40° C. under vacuum for about 16 hours. The spray drying yielded 20.3 g (90.3% yield) of the solid dispersion. Physicochemical analysis results are in Table 1. The XRPD scan is shown in
FIG. 1 . Residual solvent analysis showed that the dispersion had less than 0.5% THF and no detectable MeOH. - Dissolution testing was performed at a pH of 6.5 in phosphate buffer. The solid dispersion was suspended in H2O and added directly to the buffer solution at 37° C. The dissolution profile was collected over a period of about 240 minutes. The results are in
FIG. 4 . The Cmax and AUC for the total drug species (colloidal+free) was 25.00 μg/mL and 96.66 μg/mL*hr, respectively. The Cmax and AUC for the free drug species was 16.15 μg/mL and 56.81 μg/mL*hr, respectively. - A solid dispersion was prepared containing 30 weight percent N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine and CAP using a Buchi B-290 mini spray drier. The solid dispersion was spray dried from a MeOH:THF (1:3) solvent system, a 5% spray solution concentration, an inlet temperature of 100° C. at a flow rate of 22 mL/minute, drying gas flow rate of 35 m3/hour, nozzle pressure of 80 psig, nozzle gas flow of 0.66 m3/hour, and a 1.5 mm nozzle type. Secondary drying of the dispersion was done at 40° C. under vacuum for about 16 hours. The spray drying yielded 20.0 g (90.4% yield) of the solid dispersion. Physicochemical analysis results are in Table 1. The XRPD scan is shown in
FIG. 1 . Residual solvent analysis showed that the dispersion had less than 0.5% THF and no detectable MeOH. - Dissolution testing was performed at a pH of 6.5 in phosphate buffer. The solid dispersion was suspended in H2O and added directly to the buffer solution at 37° C. The dissolution profile was collected over a period of about 240 minutes. The results are in
FIG. 5 . The Cmax and AUC for the total drug species (colloidal+free) was 11.62 μg/mL and 36.69 μg/mL*hr, respectively. The Cmax and AUC for the free drug species was 5.64 μg/mL and 20.58 μg/mL*hr, respectively. - A solid dispersion was prepared containing 30 weight percent N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine and HPMCAS Grade M using a Buchi B-290 mini spray drier. The solid dispersion was spray dried from a MeOH:THF (1:3) solvent system, a 5% spray solution concentration, an inlet temperature of 80° C. at a flow rate of 35 mL/minute, drying gas flow rate of 40 m3/hour, nozzle pressure of 80 psig, nozzle gas flow of 0.66 m3/hour, and a 1.5 mm nozzle type. Secondary drying of the dispersion was done at 40° C. under vacuum for about 16 hours. The spray drying yielded 163.19 mg (48.3% yield) of the solid dispersion. Physicochemical analysis results are in Table 1. The XRPD scan is shown in
FIG. 1 . Residual solvent analysis showed that the dispersion had less than 0.5% THF and no detectable MeOH. - Dissolution testing was performed at a pH of 6.5 in phosphate buffer. The solid dispersion was suspended in H2O and added directly to the buffer solution at 37° C. The dissolution profile was collected over a period of about 240 minutes. The results are in
FIG. 6 . The Cmax and AUC for the total drug species (colloidal+free) was 19.04 μg/mL and 68.09 μg/mL*hr, respectively. The Cmax and AUC for the free drug species was 13.50 μg/mL and 51.74 μg/mL*hr, respectively. -
TABLE 1 TGA Hygroscopicity API: HPLC Tg wt loss % THF (% wt change Example Polymer Polymer (area %) (° C.) (%) (w/w) at 80% RH) REF 99.39 4.9 <1% 1 PVP-VA 3:7 99.45 117 2.3 0.5 14.4 2 Eudragit L100 3:7 98.63 116 5.9 4.5 7.5 3 HPMCP H-55 3:7 97.30 149 1.7 0.3 7.5 4 CAP 3:7 95.45 179 1.9 0.5 7.8 5 HPMCAS 3:7 113 NA NA NA - A solid dispersion was prepared containing 60 weight percent N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine and PVP-VA using a Buchi B-290 mini spray drier. The solid dispersion was spray dried from a MeOH:THF (1:3) solvent system, a 5% spray solution concentration, an inlet temperature of 80° C. at a flow rate of 35 mL/minute, drying gas flow rate of 40 m3/hour, nozzle pressure of 80 psig, nozzle gas flow of 0.66 m3/hour, and a 1.5 mm nozzle type. Secondary drying of the dispersion was done at 40° C. under vacuum for about 16 hours. The spray drying yielded 135.0 mg (88.2% yield) of the solid dispersion. The XRPD scan is shown in
FIG. 7 . - Dissolution testing was performed at a pH of 6.5 in phosphate buffer. The solid dispersion was suspended in H2O and added directly to the buffer solution at 37° C. The dissolution profile was collected over a period of about 240 minutes. The results are in
FIG. 8 . The Cmax and AUC for the total drug species (colloidal+free) was 34.80 μg/mL and 133.76 μg/mL*hr, respectively. The Cmax and AUC for the free drug species was 21.88 μg/mL and 84.43 μg/mL*hr, respectively. - A solid dispersion was prepared containing 60 weight percent N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine and Eudragit L100 using a Buchi B-290 mini spray drier. The solid dispersion was spray dried from a MeOH:THF (1:3) solvent system, a 5% spray solution concentration, an inlet temperature of 80° C. at a flow rate of 35 mL/minute, drying gas flow rate of 40 m3/hour, nozzle pressure of 80 psig, nozzle gas flow of 0.66 m3/hour, and a 1.5 mm nozzle type. Secondary drying of the dispersion was done at 40° C. under vacuum for about 16 hours. The spray drying yielded 88.1 mg (52.4% yield) of the solid dispersion. The XRPD scan is shown in
FIG. 7 . - Dissolution testing was performed at a pH of 6.5 in phosphate buffer. The solid dispersion was suspended in H2O and added directly to the buffer solution at 37° C. The dissolution profile was collected over a period of about 240 minutes. The results are in
FIG. 9 . The Cmax and AUC for the total drug species (colloidal+free) was 26.82 μg/mL and 84.49 μg/mL*hr, respectively. The Cmax and AUC for the free drug species was 9.85 μg/mL and 34.89 μg/mL*hr, respectively. - A solid dispersion was prepared containing 60 weight percent N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine and HPMCP H-55 using a Buchi B-290 mini spray drier. The solid dispersion was spray dried from a MeOH:THF (1:3) solvent system, a 5% spray solution concentration, an inlet temperature of 80° C. at a flow rate of 35 mL/minute, drying gas flow rate of 40 m3/hour, nozzle pressure of 80 psig, nozzle gas flow of 0.66 m3/hour, and a 1.5 mm nozzle type. Secondary drying of the dispersion was done at 40° C. under vacuum for about 16 hours. The spray drying yielded 98.0 mg (58.0% yield) of the solid dispersion. The XRPD scan is shown in
FIG. 7 . - Dissolution testing was performed at a pH of 6.5 in phosphate buffer. The solid dispersion was suspended in H2O and added directly to the buffer solution at 37° C. The dissolution profile was collected over a period of about 240 minutes. The results are in
FIG. 10 . The Cmax and AUC for the total drug species (colloidal+free) was 32.21 μg/mL and 38.28 μg/mL*hr, respectively. The Cmax and AUC for the free drug species was 9.96 μg/mL and 38.28 μg/mL*hr, respectively. - A solid dispersion was prepared containing 60 weight percent N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine and CAP using a Buchi B-290 mini spray drier. The solid dispersion was spray dried from a MeOH:THF (1:3) solvent system, a 5% spray solution concentration, an inlet temperature of 80° C. at a flow rate of 35 mL/minute, drying gas flow rate of 40 m3/hour, nozzle pressure of 80 psig, nozzle gas flow of 0.66 m3/hour, and a 1.5 mm nozzle type. Secondary drying of the dispersion was done at 40° C. under vacuum for about 16 hours. The spray drying yielded 74.9 mg (44.6% yield) of the solid dispersion. The XRPD scan is shown in
FIG. 7 . - Dissolution testing was performed at a pH of 6.5 in phosphate buffer. The solid dispersion was suspended in H2O and added directly to the buffer solution at 37° C. The dissolution profile was collected over a period of about 240 minutes. The results are in
FIG. 11 . The Cmax and AUC for the total drug species (colloidal+free) was 51.98 μg/mL and 144.91 μg/mL*hr, respectively. The Cmax and AUC for the free drug species was 15.07 μg/mL and 59.69 μg/mL*hr, respectively. - A solid dispersion was prepared containing 60 weight percent N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine and HPMCAS Grade M using a Buchi B-290 mini spray drier. The solid dispersion was spray dried from a MeOH:THF (1:3) solvent system, a 5% spray solution concentration, an inlet temperature of 80° C. at a flow rate of 35 mL/minute, drying gas flow rate of 40 m3/hour, nozzle pressure of 80 psig, nozzle gas flow of 0.66 m3/hour, and a 1.5 mm nozzle type. Secondary drying of the dispersion was done at 40° C. under vacuum for about 16 hours. The spray drying yielded 113.3 mg (67.2% yield) of the solid dispersion. The XRPD scan is shown in
FIG. 7 . - Dissolution testing was performed at a pH of 6.5 in phosphate buffer. The solid dispersion was suspended in H2O and added directly to the buffer solution at 37° C. The dissolution profile was collected over a period of about 240 minutes. The results are in
FIG. 12 . The Cmax and AUC for the total drug species (colloidal+free) was 26.45 μg/mL and 96.21 μg/mL*hr, respectively. The Cmax and AUC for the free drug species was 10.96 μg/mL and 42.83 μg/mL*hr, respectively. - A solid dispersion was prepared containing 50 weight percent N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine and PVP-VA using a Buchi B-290 mini spray drier. The solid dispersion was spray dried from a MeOH:THF (1:3) solvent system, a 3.9% spray solution concentration, an inlet temperature of 100° C. at a flow rate of 30 mL/minute, drying gas flow rate of 40 m3/hour, nozzle pressure of 80 psig, nozzle gas flow of 0.66 m3/hour, and a 1.5 mm nozzle type. Secondary drying of the dispersion was done at 50° C. under vacuum for about 72 hours. The spray drying yielded 28.7 g (72.7% yield) of the solid dispersion.
- Step 1: (E)-N′-(2-Cyano-4-(3-(1-hydroxy-2-methylpropan-2-yl)thioureido) phenyl)-N,N-dimethylformimidamide was coupled with 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylaniline in isopropyl acetate:acetic acid (65:35 v/v) at 45° C. to yield 1-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)-3-(1-hydroxy-2-methylpropan-2-yl)thiourea (91%).
- Step 2: 1-(4-((4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl) amino)quinazolin-6-yl)-3-(1-hydroxy-2-methylpropan-2-yl)thiourea was agitated in tetrahydrofuran under basic conditions (2.5N NaOH), followed by the addition of p-toluenesulfonyl chloride. Water was charged to yield N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine (96%) as a mixture of polymorphs (generally a mixture containing one or more of Form C, Form G hemi-THF, Form G mono-THF, Form M or Form P).
- Step 3: N4-(4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine from
Step 2 was triturated in ethanol at greater than 65° C. to provide N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine Form B Ethanol (89%). - The crystalline hemi-ethanolate (Form B Ethanol) XRPD scans are shown in
FIGS. 1 and 7 . - Dissolution testing was performed at a pH of 6.5 in phosphate buffer. The crystals (particles) were suspended in H2O and added directly to the buffer solution at 37° C. The dissolution profile was collected over a period of about 240 minutes. The Cmax and AUC for the free drug species was 0.44 μg/mL and 5.49 μg/mL*hr, respectively.
- Tablets containing the solid dispersions of any of Examples 1 to 11 may be prepared in a conventional manner comprising:
-
Function Ingredient % of Blend API Solid dispersion as 50 prepared in Example 11 Disintegrant Crospovidone- 6 Polyplasdone ® Osmogen NaCl 5 Osmogen KCl 5 Glidant Colloidal Silicon 0.5 Dioxide Lubricant Magnesium Stearate 0.25 Extragranular Binder/Diluent Microcrystalline 19.25 cellulose-Avicel ® Osmogen NaCl 4.625 Osmogen KCl 4.625 Disintegrant Polyplasdone 4 Glidant Colloidal Silicon 0.5 Dioxide Lubricant Magnesium Stearate 0.25 - In one preparation, tablets were made using OPADRY II 85F92727 at 3% by weight as a tablet coating. The tablets contained 150 mg of API.
- Tablets containing the solid dispersions of any of Examples 1 to 11 may be prepared in a conventional manner comprising:
-
Function Ingredient % of Blend API Solid dispersion as 50 prepared in Example 11 Disintegrant Crospovidone- 6 Polyplasdone ® Disintegrant NaHCO 3 3 Osmogen NaCl 5 Osmogen KCl 5 Glidant Colloidal Silicon 0.5 Dioxide Lubricant Magnesium Stearate 0.25 Extragranular Binder/Diluent Microcrystalline 16.25 cellulose-Avicel ® Osmogen NaCl 4.625 Osmogen KCl 4.625 Disintegrant Polyplasdone 4 Glidant Colloidal Silicon 0.5 Dioxide Lubricant Magnesium Stearate 0.25 - In one preparation, tablets were made using OPADRY II 85F92727 at 3% by weight as a tablet coating. The tablets contained 150 mg of API.
- Tablets containing the solid dispersions of any of Examples 1 to 11 may be prepared in a conventional manner comprising:
-
Function Ingredient % of Blend API Solid dispersion as 50 prepared in Example 11 Disintegrant Crospovidone- 6 Polyplasdone ® Osmogen NaCl 10.625 Osmogen KCl 10.625 Filler Lactose 21.25 Glidant Colloidal Silicon 0.5 Dioxide Lubricant Magnesium Stearate 0.25 Extragranular Glidant Colloidal Silicon 0.5 Dioxide Lubricant Magnesium Stearate 0.25 - In one preparation, tablets were made using OPADRY II 85F92727 at 3% by weight as a tablet coating. The tablets contained 150 mg of API.
- A PIC composition was prepared containing 25 mg or 100 mg of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine as prepared in Example 12. The PIC composition was prepared in size 00 white opaque hard gelatin capsules.
- A dissolution test comparison was performed comparing the crystalline hemi-ethanolate PIC composition of Example 16 and the 50% PVP-VA solid dispersion (Example 11) tablet of Example 13 in 900 mL of 10 mM citrate buffer at 37° C. and a pH of 4.5, using USP Apparatus II at 75 rpm. The results are shown in
FIG. 13 . - A stability screen of the spray dried dispersions was completed at 40° C., 75% relative humidity under open conditions, in glass vials, over a period of 8 days. Results are shown in TABLE 2.
-
TABLE 2 HPLC Area % Time Example 1 Example 2 Example 3 Example 4 Standard 99.39 99.39 99.39 99.39 As 99.45 98.63 97.30 95.45 received 4 days 99.21 96.10 93.03 90.89 8 days 99.35 93.16 86.63 87.15 - The main degradant observed was the carbamate impurity, likely due to the acidic nature of some of these polymers. XRPD analysis over the course of the study showed no evidence of crystallization for any solid dispersion of Examples 1-4.
- The solid dispersion of Example 1 was tested against a crystalline, micronized suspension formulation (d(v, 0.9)=3.0 μm) of Example 12 under normal fasted conditions, as well as with pretreatment using pentagastrin or famotidine. The solid dispersion of Example 1 was prepared as a suspension in water and administered orally. The micronized suspension of Example 12 was prepared as a suspension with SyrSpend® SF Dry reconstituted with water and administered orally. To reduce variability, beagles were crossed over from pentagastrin to famotidine after a 5 day washout period. Pentagastrin is a pH modifier to modify gastric pH to about 2 to 3, and famotidine is a pH modifier to modify gastric pH to about 5 to 7.5 (Zhou, Rong, et al. “pH-Dependent Dissolution in Vitro and Absorption in Vivo of Weakly Basic Drugs: Development of a Canine Model.” Pharm. Res. Vol. 22, No. 2 (February 2005): pp. 188-192). There were four beagles per group. Group A received pentagastrin pretreatment, the micronized suspension of Example 12, followed by a 5 day washout period, then famotidine pretreatment, and finally the micronized suspension of Example 12. Group B received pentagastrin pretreatment, the solid dispersion of Example 1, followed by a 5 day washout period, then famotidine pretreatment, and finally the solid dispersion of Example 1. Group C received the micronized suspension of Example 12, followed by a 5 day washout period, and finally the solid dispersion of Example 1. Results are shown in TABLE 3.
-
TABLE 3 Pre- AUCinf Cmax treatment Dosing Formulation (μg*hr/mL) (μg/mL) None Micronized Suspension 7.43 ± 1.77 1.88 ± 0.35 of Example 12 Solid Dispersion of 10.0 ± 2.7 2.29 ± 0.54 Example 1 6 μg/kg Micronized Suspension 17.2 ± 2.7 3.29 ± 0.13 Pentagastrin of Example 12 Solid Dispersion of 13.0 ± 3.6 3.12 ± 0.62 Example 1 40 mg/kg Micronized Suspension 1.74 ± 0.39 0.514 ± 0.092 Famotidine of Example 12 Solid Dispersion 6.32 ± 2.88 1.45 ± 0.54 of Example 1 - It will be understood that the enumerated embodiments are not intended to limit the invention to those embodiments. On the contrary, the invention is intended to cover all alternatives, modifications and equivalents, which may be included within the scope of the present invention as defined by the claims. Thus, the foregoing description is considered as illustrative only of the principles of the invention.
- The words “comprise,” “comprising,” “include,” “including,” and “includes” when used in this specification and in the following claims are intended to specify the presence of stated features, integers, components, or steps, but they do not preclude the presence or addition of one or more other features, integers, components, steps, or groups thereof.
Claims (17)
1. A solid dispersion comprising N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine and a dispersion polymer, wherein the dispersion polymer is a methacrylate copolymer or a cellulosic polymer or cellulosic copolymer.
2. The dispersion of claim 1 , wherein the N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine is amorphous.
3. The dispersion of claim 1 , wherein the N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine is present in an amount of from about 0.1% to about 60% by weight relative to the dispersion polymer.
4. The dispersion of claim 1 , wherein the dispersion polymer is Eudragit L100.
5. The dispersion of claim 1 , wherein the dispersion polymer is neutral or basic.
6. The dispersion of claim 1 , wherein at least 95% the N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine is in amorphous form.
7. A pharmaceutical composition comprising the solid dispersion of claim 1 and one or more pharmaceutically acceptable excipients.
8. The pharmaceutical composition of claim 7 , wherein a disintegrant is a pharmaceutically acceptable excipient of the composition.
9. The pharmaceutical composition of claim 7 , wherein the solid dispersion ranges from about 25% to about 60% by weight.
10. The pharmaceutical composition of claim 8 , wherein the disintegrant ranges from about 0.1 to about 20 weight %.
11. The pharmaceutical composition of claim 8 , wherein the disintegrant is Crospovidone.
12. The pharmaceutical composition of claim 8 , wherein the disintegrant is sodium bicarbonate.
13. The pharmaceutical composition of claim 8 , wherein the disintegrant is Polyplasdone.
14. A method for the treatment of ErbB2 positive non-small cell lung (NSCLC) cancer comprising administering to a patient in need thereof a therapeutically effective amount of the pharmaceutical composition of claim 7 .
15. The method of claim 14 , wherein the pharmaceutical composition is administered orally.
16. The method of claim 14 , wherein the pharmaceutical composition is administered in the form of a tablet.
17. A method of treating or preventing a disease or disorder modulated by ErbB2, comprising administering to a subject in need of such treatment an effective amount of the pharmaceutical composition of claim 7 .
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US17/895,951 US20230097309A1 (en) | 2011-10-14 | 2022-08-25 | Solid dispersions of a erb2 (her2) inhibitor |
Applications Claiming Priority (8)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201161547620P | 2011-10-14 | 2011-10-14 | |
US201261606207P | 2012-03-02 | 2012-03-02 | |
PCT/US2012/060044 WO2013056108A2 (en) | 2011-10-14 | 2012-10-12 | Solid dispersion |
US201414351840A | 2014-04-14 | 2014-04-14 | |
US15/275,163 US20170136022A1 (en) | 2011-10-14 | 2016-09-23 | Solid dispersions of a erb2 (her2) inhibitor |
US16/353,951 US20190275043A1 (en) | 2011-10-14 | 2019-03-14 | Solid dispersions of a erb2 (her2) inhibitor |
US17/133,094 US20210220361A1 (en) | 2011-10-14 | 2020-12-23 | Solid dispersions of a erb2 (her2) inhibitor |
US17/895,951 US20230097309A1 (en) | 2011-10-14 | 2022-08-25 | Solid dispersions of a erb2 (her2) inhibitor |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US17/133,094 Continuation US20210220361A1 (en) | 2011-10-14 | 2020-12-23 | Solid dispersions of a erb2 (her2) inhibitor |
Publications (1)
Publication Number | Publication Date |
---|---|
US20230097309A1 true US20230097309A1 (en) | 2023-03-30 |
Family
ID=47471981
Family Applications (5)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US14/351,840 Active US9457093B2 (en) | 2011-10-14 | 2012-10-12 | Solid dispersions of a ERB2 (HER2) inhibitor |
US15/275,163 Abandoned US20170136022A1 (en) | 2011-10-14 | 2016-09-23 | Solid dispersions of a erb2 (her2) inhibitor |
US16/353,951 Abandoned US20190275043A1 (en) | 2011-10-14 | 2019-03-14 | Solid dispersions of a erb2 (her2) inhibitor |
US17/133,094 Abandoned US20210220361A1 (en) | 2011-10-14 | 2020-12-23 | Solid dispersions of a erb2 (her2) inhibitor |
US17/895,951 Abandoned US20230097309A1 (en) | 2011-10-14 | 2022-08-25 | Solid dispersions of a erb2 (her2) inhibitor |
Family Applications Before (4)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US14/351,840 Active US9457093B2 (en) | 2011-10-14 | 2012-10-12 | Solid dispersions of a ERB2 (HER2) inhibitor |
US15/275,163 Abandoned US20170136022A1 (en) | 2011-10-14 | 2016-09-23 | Solid dispersions of a erb2 (her2) inhibitor |
US16/353,951 Abandoned US20190275043A1 (en) | 2011-10-14 | 2019-03-14 | Solid dispersions of a erb2 (her2) inhibitor |
US17/133,094 Abandoned US20210220361A1 (en) | 2011-10-14 | 2020-12-23 | Solid dispersions of a erb2 (her2) inhibitor |
Country Status (31)
Country | Link |
---|---|
US (5) | US9457093B2 (en) |
EP (1) | EP2765990B1 (en) |
JP (2) | JP5944514B2 (en) |
KR (1) | KR102000312B1 (en) |
CN (3) | CN103998023B (en) |
AU (3) | AU2012322039C1 (en) |
BR (2) | BR122020010643B1 (en) |
CA (2) | CA2852058C (en) |
CL (1) | CL2014000930A1 (en) |
CO (1) | CO6960547A2 (en) |
CR (1) | CR20140228A (en) |
CY (1) | CY1119837T1 (en) |
DK (1) | DK2765990T3 (en) |
ES (1) | ES2650608T3 (en) |
HR (1) | HRP20171578T1 (en) |
HU (1) | HUE035247T2 (en) |
IL (1) | IL232103B (en) |
LT (1) | LT2765990T (en) |
ME (1) | ME02913B (en) |
MX (1) | MX353970B (en) |
MY (1) | MY169072A (en) |
NO (1) | NO2021029I1 (en) |
PL (1) | PL2765990T3 (en) |
PT (1) | PT2765990T (en) |
RS (1) | RS56608B1 (en) |
RU (1) | RU2648448C2 (en) |
SG (1) | SG11201401459YA (en) |
SI (1) | SI2765990T1 (en) |
TW (3) | TWI594769B (en) |
WO (1) | WO2013056108A2 (en) |
ZA (1) | ZA201606123B (en) |
Families Citing this family (28)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2852060A1 (en) | 2011-10-14 | 2013-04-18 | Array Biopharma Inc. | Polymorphs of arry-380, a selective herb2 inhibitor and pharmaceutical compositions containing them |
SI2765990T1 (en) * | 2011-10-14 | 2017-11-30 | Array Biopharma, Inc. | Solid dispersion |
RS57140B1 (en) * | 2012-03-23 | 2018-07-31 | Array Biopharma Inc | Amorphous solid dispersion for use in the treatment of brain cancer |
CA3128535A1 (en) * | 2013-07-19 | 2015-01-22 | Siga Technologies, Inc. | Amorphous tecovirimat preparation |
WO2015095659A2 (en) * | 2013-12-20 | 2015-06-25 | Phosphorex, Inc. | Indirubin solid dispersion composition |
RU2696578C1 (en) | 2014-02-05 | 2019-08-05 | Мерк Шарп И Доум Корп. | Tablets preparation technology for cgrp-active compounds |
WO2016198983A1 (en) * | 2015-06-09 | 2016-12-15 | Bend Research Inc. | Formulations to achieve rapid dissolution of drug from spray-dried dispersions in capsules |
CN107126419B (en) * | 2016-02-26 | 2020-06-19 | 石药集团中诺药业(石家庄)有限公司 | Obeticholic acid tablet and preparation method thereof |
CN115057861A (en) | 2016-03-01 | 2022-09-16 | 上海医药集团股份有限公司 | Nitrogen-containing heterocyclic compound, preparation method, intermediate, composition and application |
PL3601277T3 (en) * | 2017-03-30 | 2024-07-08 | Merck Patent Gmbh | Pharmaceutical formulation |
AU2018258663B2 (en) | 2017-04-28 | 2022-08-04 | Seagen Inc. | Treatment of HER2 positive cancers |
TWI780270B (en) | 2017-11-28 | 2022-10-11 | 靜岡縣公立大學法人 | Solid dispersion |
SG11202007198WA (en) | 2018-01-31 | 2020-08-28 | Deciphera Pharmaceuticals Llc | Combination therapy for the treatment of gastrointestinal stromal tumors |
EP3773509B1 (en) * | 2018-04-06 | 2023-11-01 | Capsugel Belgium NV | Spray drying process for low aspect ratio particles comprising poly[(methyl methacrylate)-co-(methacrylic acid)] |
CN109942576B (en) * | 2019-03-07 | 2020-09-11 | 上海工程技术大学 | Irbinitinib and preparation method of intermediate |
CN111825604A (en) * | 2019-04-16 | 2020-10-27 | 宁波药腾医药科技有限公司 | Synthesis method of cartinib and intermediate product thereof |
BR112022002609A2 (en) | 2019-08-12 | 2022-08-09 | Deciphera Pharmaceuticals Llc | METHODS OF TREATMENT OF GASTROINTESTINAL STROMAL TUMORS |
WO2021030405A1 (en) | 2019-08-12 | 2021-02-18 | Deciphera Pharmaceuticals, Llc | Ripretinib for treating gastrointestinal stromal tumors |
MX2022003025A (en) * | 2019-09-19 | 2022-04-07 | Forma Therapeutics Inc | Activating pyruvate kinase r. |
US20240092936A1 (en) | 2019-10-21 | 2024-03-21 | Seagen Inc. | Methods of treating her2 positive breast cancer with tucatinib in combination with capecitabine and trastuzumab |
KR20220115566A (en) | 2019-11-15 | 2022-08-17 | 시아겐 인크. | Methods of treating HER2-positive breast cancer with tucatinib in combination with an anti-HER2 antibody-drug conjugate |
KR20220123058A (en) | 2019-12-30 | 2022-09-05 | 데시페라 파마슈티칼스, 엘엘씨. | 1-(4-Bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl ) -3-Phenylurea composition |
DK4084778T3 (en) * | 2019-12-30 | 2023-12-11 | Deciphera Pharmaceuticals Llc | AMORPHOUS KINASE INHIBITOR FORMULATIONS AND METHODS OF USING THEREOF |
AU2021281336A1 (en) | 2020-05-29 | 2022-12-15 | Seagen Inc. | Methods of treating HER2 positive cancer with tucatinib in combination with trastuzumab and an oxaliplatin-based chemotherapy |
JP2023537676A (en) | 2020-07-29 | 2023-09-05 | シージェン インコーポレイテッド | Methods of treating HER2-positive cancer with tucatinib in combination with trastuzumab, taxanes and VEGFR-2 antagonists |
CN115340541B (en) * | 2022-07-01 | 2024-01-30 | 上海艾洋化学科技有限公司 | Preparation method of tocartinib intermediate |
US11779572B1 (en) | 2022-09-02 | 2023-10-10 | Deciphera Pharmaceuticals, Llc | Methods of treating gastrointestinal stromal tumors |
CN115650977A (en) * | 2022-10-09 | 2023-01-31 | 广东润兴生物科技有限公司 | Synthesis method of tocaintinib |
Family Cites Families (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6350786B1 (en) * | 1998-09-22 | 2002-02-26 | Hoffmann-La Roche Inc. | Stable complexes of poorly soluble compounds in ionic polymers |
EP1350793A1 (en) * | 2000-12-11 | 2003-10-08 | Takeda Chemical Industries, Ltd. | Medicinal compositions having improved absorbability |
KR20040025880A (en) * | 2000-12-11 | 2004-03-26 | 다케다 야쿠힌 고교 가부시키가이샤 | Medicinal compositions improved in solubility in water |
US7501427B2 (en) | 2003-08-14 | 2009-03-10 | Array Biopharma, Inc. | Quinazoline analogs as receptor tyrosine kinase inhibitors |
CA2535614C (en) | 2003-08-14 | 2009-12-22 | Array Biopharma Inc. | Quinazoline analogs as receptor tyrosine kinase inhibitors |
GB0321648D0 (en) | 2003-09-16 | 2003-10-15 | Astrazeneca Ab | Quinazoline derivatives |
BRPI0509381A (en) * | 2004-04-08 | 2007-09-18 | Wyeth Corp | solid dispersion, methods of preparing solid dispersion, treating a mammal having a disease or syndrome associated with estrogen deficiency or excess, a disease or disorder associated with abnormal proliferation or development of endometral tissues, treating breast cancer, a mammal, and a postmenopausal woman regarding one or more vasomotor disorders, reducing cholesterol, and inhibiting bone loss in a mammal, composition, dosage form, and, use of a solid dispersion. |
PL1971601T3 (en) * | 2005-11-15 | 2010-03-31 | Array Biopharma Inc | N4-phenyl-quinazoline-4 -amine derivatives and related compounds as erbb type i receptor tyrosine kinase inhibitors for the treatment of hyperproliferative diseases |
US9101617B2 (en) * | 2007-04-20 | 2015-08-11 | Daido Chemical Corporation | Base for dry solid dispersion, solid dispersion containing the base, and composition containing the dispersion |
CN101702878B (en) * | 2007-05-11 | 2012-11-28 | 弗·哈夫曼-拉罗切有限公司 | Pharmaceutical compositions for poorly soluble drugs |
JP2010540460A (en) * | 2007-09-24 | 2010-12-24 | トラガラ ファーマシューティカルズ,インク. | Treatment of cancer using a mixture of a COX-2 inhibitor and an anti-HER2 [ErbB2] antibody or a mixture of a COX-2 inhibitor and a HER2 [ErbB2] receptor tyrosine kinase inhibitor |
ATE551604T1 (en) * | 2008-05-05 | 2012-04-15 | Abbott Gmbh & Co Kg | METHOD FOR ASSESSING THE SOLUBILITY OF A CRYSTALLINE SUBSTANCE IN A POLYMER |
EP2158912A1 (en) * | 2008-08-25 | 2010-03-03 | Ratiopharm GmbH | Pharmaceutical composition comprising N-[3-chhloro-4-[3-fluorophenyl)methoxy)phenyl]6-[5[[[2-(methylsulfonyl)ethyl]amino]methyl]-2-furyl]-4-quinazolinamine |
EP2253306A1 (en) * | 2009-05-18 | 2010-11-24 | Royal College of Surgeons in Ireland | Orodispersible dosage forms containing solid drug dispersions |
SI2765990T1 (en) * | 2011-10-14 | 2017-11-30 | Array Biopharma, Inc. | Solid dispersion |
CA2852060A1 (en) | 2011-10-14 | 2013-04-18 | Array Biopharma Inc. | Polymorphs of arry-380, a selective herb2 inhibitor and pharmaceutical compositions containing them |
RS57140B1 (en) | 2012-03-23 | 2018-07-31 | Array Biopharma Inc | Amorphous solid dispersion for use in the treatment of brain cancer |
-
2012
- 2012-10-12 SI SI201231101T patent/SI2765990T1/en unknown
- 2012-10-12 HU HUE12809373A patent/HUE035247T2/en unknown
- 2012-10-12 PL PL12809373T patent/PL2765990T3/en unknown
- 2012-10-12 KR KR1020147012944A patent/KR102000312B1/en active IP Right Grant
- 2012-10-12 WO PCT/US2012/060044 patent/WO2013056108A2/en active Application Filing
- 2012-10-12 LT LTEP12809373.9T patent/LT2765990T/en unknown
- 2012-10-12 CN CN201280061909.7A patent/CN103998023B/en active Active
- 2012-10-12 BR BR122020010643-3A patent/BR122020010643B1/en active IP Right Grant
- 2012-10-12 MY MYPI2014700908A patent/MY169072A/en unknown
- 2012-10-12 PT PT128093739T patent/PT2765990T/en unknown
- 2012-10-12 CN CN201810490376.3A patent/CN108498465B/en active Active
- 2012-10-12 JP JP2014535944A patent/JP5944514B2/en active Active
- 2012-10-12 SG SG11201401459YA patent/SG11201401459YA/en unknown
- 2012-10-12 AU AU2012322039A patent/AU2012322039C1/en active Active
- 2012-10-12 ES ES12809373.9T patent/ES2650608T3/en active Active
- 2012-10-12 ME MEP-2017-256A patent/ME02913B/en unknown
- 2012-10-12 EP EP12809373.9A patent/EP2765990B1/en active Active
- 2012-10-12 CA CA2852058A patent/CA2852058C/en active Active
- 2012-10-12 US US14/351,840 patent/US9457093B2/en active Active
- 2012-10-12 BR BR112014009092-0A patent/BR112014009092B1/en active IP Right Grant
- 2012-10-12 MX MX2014004551A patent/MX353970B/en active IP Right Grant
- 2012-10-12 RU RU2014119283A patent/RU2648448C2/en active
- 2012-10-12 DK DK12809373.9T patent/DK2765990T3/en active
- 2012-10-12 RS RS20171188A patent/RS56608B1/en unknown
- 2012-10-12 CA CA3114454A patent/CA3114454C/en active Active
- 2012-10-12 CN CN202210434174.3A patent/CN114886853A/en active Pending
- 2012-10-15 TW TW101137971A patent/TWI594769B/en active
- 2012-10-15 TW TW109141025A patent/TWI788733B/en active
- 2012-10-15 TW TW106116008A patent/TWI722189B/en active
-
2014
- 2014-04-11 CL CL2014000930A patent/CL2014000930A1/en unknown
- 2014-04-13 IL IL232103A patent/IL232103B/en active IP Right Grant
- 2014-05-14 CO CO14103943A patent/CO6960547A2/en unknown
- 2014-05-14 CR CR20140228A patent/CR20140228A/en unknown
-
2015
- 2015-11-13 JP JP2015223018A patent/JP2016027062A/en active Pending
-
2016
- 2016-09-05 ZA ZA2016/06123A patent/ZA201606123B/en unknown
- 2016-09-23 US US15/275,163 patent/US20170136022A1/en not_active Abandoned
-
2017
- 2017-07-31 AU AU2017210499A patent/AU2017210499C1/en active Active
- 2017-10-17 HR HRP20171578TT patent/HRP20171578T1/en unknown
- 2017-10-30 CY CY20171101121T patent/CY1119837T1/en unknown
-
2019
- 2019-01-15 AU AU2019200243A patent/AU2019200243C1/en active Active
- 2019-03-14 US US16/353,951 patent/US20190275043A1/en not_active Abandoned
-
2020
- 2020-12-23 US US17/133,094 patent/US20210220361A1/en not_active Abandoned
-
2021
- 2021-07-09 NO NO2021029C patent/NO2021029I1/en unknown
-
2022
- 2022-08-25 US US17/895,951 patent/US20230097309A1/en not_active Abandoned
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20230097309A1 (en) | Solid dispersions of a erb2 (her2) inhibitor | |
US10034854B2 (en) | Pharmaceutical composition with improved bioavailability | |
NZ624942B2 (en) | Solid dispersions of a erb2 (her2) inhibitor |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: ARRAY BIOPHARMA INC., COLORADO Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:LINDEMANN, CHRISTOPHER M.;PREIGH, MICHAEL;FRY, DAVID SHANK;AND OTHERS;SIGNING DATES FROM 20130110 TO 20130306;REEL/FRAME:061537/0237 |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: SENT TO CLASSIFICATION CONTRACTOR |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: DOCKETED NEW CASE - READY FOR EXAMINATION |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: NON FINAL ACTION MAILED |
|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |