CN109152740A - 一种马吲哚即释/缓释多层片剂及其在治疗注意力缺失/多动障碍(adhd)中的用途 - Google Patents
一种马吲哚即释/缓释多层片剂及其在治疗注意力缺失/多动障碍(adhd)中的用途 Download PDFInfo
- Publication number
- CN109152740A CN109152740A CN201780028569.0A CN201780028569A CN109152740A CN 109152740 A CN109152740 A CN 109152740A CN 201780028569 A CN201780028569 A CN 201780028569A CN 109152740 A CN109152740 A CN 109152740A
- Authority
- CN
- China
- Prior art keywords
- dosage forms
- unit dosage
- dihydro
- imadazo
- chlorophenyl
- 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.)
- Pending
Links
- 208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 title claims abstract description 54
- 208000036864 Attention deficit/hyperactivity disease Diseases 0.000 title claims abstract description 54
- 238000011282 treatment Methods 0.000 title claims abstract description 30
- 238000013265 extended release Methods 0.000 title description 2
- 239000007942 layered tablet Substances 0.000 title description 2
- 239000000203 mixture Substances 0.000 claims abstract description 40
- 206010041349 Somnolence Diseases 0.000 claims abstract description 35
- 208000015802 attention deficit-hyperactivity disease Diseases 0.000 claims abstract description 22
- 208000035231 inattentive type attention deficit hyperactivity disease Diseases 0.000 claims abstract description 22
- 208000032140 Sleepiness Diseases 0.000 claims abstract description 15
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 15
- 230000037321 sleepiness Effects 0.000 claims abstract description 15
- 201000010099 disease Diseases 0.000 claims abstract description 13
- 208000007590 Disorders of Excessive Somnolence Diseases 0.000 claims abstract description 11
- 201000003631 narcolepsy Diseases 0.000 claims abstract description 11
- 208000016588 Idiopathic hypersomnia Diseases 0.000 claims abstract description 10
- ZRHANBBTXQZFSP-UHFFFAOYSA-M potassium;4-amino-3,5,6-trichloropyridine-2-carboxylate Chemical compound [K+].NC1=C(Cl)C(Cl)=NC(C([O-])=O)=C1Cl ZRHANBBTXQZFSP-UHFFFAOYSA-M 0.000 claims abstract description 9
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 47
- 239000002552 dosage form Substances 0.000 claims description 42
- 238000002360 preparation method Methods 0.000 claims description 27
- 229910052742 iron Inorganic materials 0.000 claims description 25
- 238000004090 dissolution Methods 0.000 claims description 24
- 238000013268 sustained release Methods 0.000 claims description 24
- 239000012730 sustained-release form Substances 0.000 claims description 24
- 238000000034 method Methods 0.000 claims description 23
- 229920000642 polymer Polymers 0.000 claims description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- 239000001913 cellulose Substances 0.000 claims description 15
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 12
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 12
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 12
- 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 claims description 12
- -1 polyethylene Polymers 0.000 claims description 11
- 239000002671 adjuvant Substances 0.000 claims description 9
- 239000003795 chemical substances by application Substances 0.000 claims description 9
- 239000000463 material Substances 0.000 claims description 9
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 8
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 8
- 229920002125 Sokalan® Polymers 0.000 claims description 8
- 229920002472 Starch Polymers 0.000 claims description 8
- 235000010980 cellulose Nutrition 0.000 claims description 8
- 229920002678 cellulose Polymers 0.000 claims description 8
- 239000008101 lactose Substances 0.000 claims description 8
- 239000008107 starch Substances 0.000 claims description 8
- 235000019698 starch Nutrition 0.000 claims description 8
- 239000011159 matrix material Substances 0.000 claims description 7
- 230000036470 plasma concentration Effects 0.000 claims description 7
- 235000019814 powdered cellulose Nutrition 0.000 claims description 7
- 229920003124 powdered cellulose Polymers 0.000 claims description 7
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 6
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 claims description 6
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 6
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 6
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 6
- 229920000881 Modified starch Polymers 0.000 claims description 5
- 239000001506 calcium phosphate Substances 0.000 claims description 5
- 229910000389 calcium phosphate Inorganic materials 0.000 claims description 5
- 235000011010 calcium phosphates Nutrition 0.000 claims description 5
- 239000013066 combination product Substances 0.000 claims description 5
- 229940127555 combination product Drugs 0.000 claims description 5
- 239000003085 diluting agent Substances 0.000 claims description 5
- 239000000314 lubricant Substances 0.000 claims description 5
- 229940126701 oral medication Drugs 0.000 claims description 5
- 239000003368 psychostimulant agent Substances 0.000 claims description 5
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 claims description 5
- ATVJXMYDOSMEPO-UHFFFAOYSA-N 3-prop-2-enoxyprop-1-ene Chemical compound C=CCOCC=C ATVJXMYDOSMEPO-UHFFFAOYSA-N 0.000 claims description 4
- CPLXHLVBOLITMK-UHFFFAOYSA-N Magnesium oxide Chemical compound [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 claims description 4
- 229940086737 allyl sucrose Drugs 0.000 claims description 4
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 4
- 229960001631 carbomer Drugs 0.000 claims description 4
- 238000001727 in vivo Methods 0.000 claims description 4
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 4
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 4
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 4
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 3
- 229920001353 Dextrin Polymers 0.000 claims description 3
- 239000004375 Dextrin Substances 0.000 claims description 3
- 239000005913 Maltodextrin Substances 0.000 claims description 3
- 229920002774 Maltodextrin Polymers 0.000 claims description 3
- 150000001242 acetic acid derivatives Chemical class 0.000 claims description 3
- 235000010216 calcium carbonate Nutrition 0.000 claims description 3
- 230000007062 hydrolysis Effects 0.000 claims description 3
- 238000006460 hydrolysis reaction Methods 0.000 claims description 3
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 claims description 3
- 239000001095 magnesium carbonate Substances 0.000 claims description 3
- 229910000021 magnesium carbonate Inorganic materials 0.000 claims description 3
- 235000014380 magnesium carbonate Nutrition 0.000 claims description 3
- 229940035034 maltodextrin Drugs 0.000 claims description 3
- 125000005395 methacrylic acid group Chemical group 0.000 claims description 3
- WXZMFSXDPGVJKK-UHFFFAOYSA-N pentaerythritol Chemical compound OCC(CO)(CO)CO WXZMFSXDPGVJKK-UHFFFAOYSA-N 0.000 claims description 3
- 229920002689 polyvinyl acetate Polymers 0.000 claims description 3
- 239000011118 polyvinyl acetate Substances 0.000 claims description 3
- XBBVURRQGJPTHH-UHFFFAOYSA-N 2-hydroxyacetic acid;2-hydroxypropanoic acid Chemical compound OCC(O)=O.CC(O)C(O)=O XBBVURRQGJPTHH-UHFFFAOYSA-N 0.000 claims description 2
- 239000005995 Aluminium silicate Substances 0.000 claims description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 2
- 229930195725 Mannitol Natural products 0.000 claims description 2
- 229930006000 Sucrose Natural products 0.000 claims description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 2
- 235000012211 aluminium silicate Nutrition 0.000 claims description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 2
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 claims description 2
- SMHNUIFHMAGAFL-UHFFFAOYSA-N calcium;2-hydroxypropanoic acid Chemical compound [Ca].CC(O)C(O)=O SMHNUIFHMAGAFL-UHFFFAOYSA-N 0.000 claims description 2
- ZQNPDAVSHFGLIQ-UHFFFAOYSA-N calcium;hydrate Chemical compound O.[Ca] ZQNPDAVSHFGLIQ-UHFFFAOYSA-N 0.000 claims description 2
- 235000019425 dextrin Nutrition 0.000 claims description 2
- 235000019700 dicalcium phosphate Nutrition 0.000 claims description 2
- 229940126534 drug product Drugs 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 claims description 2
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 claims description 2
- 239000000395 magnesium oxide Substances 0.000 claims description 2
- 235000012245 magnesium oxide Nutrition 0.000 claims description 2
- 239000000594 mannitol Substances 0.000 claims description 2
- 235000010355 mannitol Nutrition 0.000 claims description 2
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 2
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 claims description 2
- 239000000843 powder Substances 0.000 claims description 2
- 239000005720 sucrose Substances 0.000 claims description 2
- 239000001993 wax Substances 0.000 claims description 2
- 238000004132 cross linking Methods 0.000 claims 2
- DJOWTWWHMWQATC-KYHIUUMWSA-N Karpoxanthin Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1(O)C(C)(C)CC(O)CC1(C)O)C=CC=C(/C)C=CC2=C(C)CC(O)CC2(C)C DJOWTWWHMWQATC-KYHIUUMWSA-N 0.000 claims 1
- 239000004698 Polyethylene Substances 0.000 claims 1
- 230000005059 dormancy Effects 0.000 claims 1
- 239000008103 glucose Substances 0.000 claims 1
- 235000001727 glucose Nutrition 0.000 claims 1
- 230000001709 ictal effect Effects 0.000 claims 1
- 229920001542 oligosaccharide Polymers 0.000 claims 1
- 150000002482 oligosaccharides Chemical class 0.000 claims 1
- 239000011505 plaster Substances 0.000 claims 1
- 229920000573 polyethylene Polymers 0.000 claims 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims 1
- 239000003826 tablet Substances 0.000 description 42
- 239000010410 layer Substances 0.000 description 39
- 239000003814 drug Substances 0.000 description 23
- 229940079593 drug Drugs 0.000 description 17
- 230000000694 effects Effects 0.000 description 12
- 239000004615 ingredient Substances 0.000 description 11
- 239000000523 sample Substances 0.000 description 9
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
- KWTSXDURSIMDCE-QMMMGPOBSA-N (S)-amphetamine Chemical compound C[C@H](N)CC1=CC=CC=C1 KWTSXDURSIMDCE-QMMMGPOBSA-N 0.000 description 7
- 229940025084 amphetamine Drugs 0.000 description 7
- 230000008859 change Effects 0.000 description 7
- 238000009472 formulation Methods 0.000 description 7
- 210000002381 plasma Anatomy 0.000 description 7
- 102000008857 Ferritin Human genes 0.000 description 6
- 108050000784 Ferritin Proteins 0.000 description 6
- 238000008416 Ferritin Methods 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- 238000010521 absorption reaction Methods 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 208000024891 symptom Diseases 0.000 description 6
- 239000007916 tablet composition Substances 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- YFGHCGITMMYXAQ-UHFFFAOYSA-N 2-[(diphenylmethyl)sulfinyl]acetamide Chemical compound C=1C=CC=CC=1C(S(=O)CC(=O)N)C1=CC=CC=C1 YFGHCGITMMYXAQ-UHFFFAOYSA-N 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 5
- 210000001072 colon Anatomy 0.000 description 5
- 239000000470 constituent Substances 0.000 description 5
- 239000003405 delayed action preparation Substances 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- BAUYGSIQEAFULO-UHFFFAOYSA-L iron(2+) sulfate (anhydrous) Chemical group [Fe+2].[O-]S([O-])(=O)=O BAUYGSIQEAFULO-UHFFFAOYSA-L 0.000 description 5
- 230000000638 stimulation Effects 0.000 description 5
- 210000002784 stomach Anatomy 0.000 description 5
- 239000000758 substrate Substances 0.000 description 5
- 230000002459 sustained effect Effects 0.000 description 5
- CWYNVVGOOAEACU-UHFFFAOYSA-N Fe2+ Chemical compound [Fe+2] CWYNVVGOOAEACU-UHFFFAOYSA-N 0.000 description 4
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 4
- 206010022971 Iron Deficiencies Diseases 0.000 description 4
- DUGOZIWVEXMGBE-UHFFFAOYSA-N Methylphenidate Chemical compound C=1C=CC=CC=1C(C(=O)OC)C1CCCCN1 DUGOZIWVEXMGBE-UHFFFAOYSA-N 0.000 description 4
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 description 4
- VHGCDTVCOLNTBX-QGZVFWFLSA-N atomoxetine Chemical compound O([C@H](CCNC)C=1C=CC=CC=1)C1=CC=CC=C1C VHGCDTVCOLNTBX-QGZVFWFLSA-N 0.000 description 4
- 230000004888 barrier function Effects 0.000 description 4
- 238000013270 controlled release Methods 0.000 description 4
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 4
- 239000011790 ferrous sulphate Substances 0.000 description 4
- 235000003891 ferrous sulphate Nutrition 0.000 description 4
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 4
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 4
- 229940071676 hydroxypropylcellulose Drugs 0.000 description 4
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 4
- 206010022437 insomnia Diseases 0.000 description 4
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 4
- 229910000359 iron(II) sulfate Inorganic materials 0.000 description 4
- 229960001375 lactose Drugs 0.000 description 4
- 235000019359 magnesium stearate Nutrition 0.000 description 4
- 239000008194 pharmaceutical composition Substances 0.000 description 4
- FASDKYOPVNHBLU-ZETCQYMHSA-N pramipexole Chemical compound C1[C@@H](NCCC)CCC2=C1SC(N)=N2 FASDKYOPVNHBLU-ZETCQYMHSA-N 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 210000002966 serum Anatomy 0.000 description 4
- 238000007873 sieving Methods 0.000 description 4
- DPJRMOMPQZCRJU-UHFFFAOYSA-M thiamine hydrochloride Chemical compound Cl.[Cl-].CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N DPJRMOMPQZCRJU-UHFFFAOYSA-M 0.000 description 4
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 description 3
- 206010057315 Daydreaming Diseases 0.000 description 3
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical class CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 3
- 241000282414 Homo sapiens Species 0.000 description 3
- ZPXSCAKFGYXMGA-UHFFFAOYSA-N Mazindol Chemical compound N12CCN=C2C2=CC=CC=C2C1(O)C1=CC=C(Cl)C=C1 ZPXSCAKFGYXMGA-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 102000002070 Transferrins Human genes 0.000 description 3
- 108010015865 Transferrins Proteins 0.000 description 3
- YFGHCGITMMYXAQ-LJQANCHMSA-N armodafinil Chemical compound C=1C=CC=CC=1C([S@](=O)CC(=O)N)C1=CC=CC=C1 YFGHCGITMMYXAQ-LJQANCHMSA-N 0.000 description 3
- 229960002430 atomoxetine Drugs 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 238000007906 compression Methods 0.000 description 3
- 230000000857 drug effect Effects 0.000 description 3
- 230000036541 health Effects 0.000 description 3
- 230000006872 improvement Effects 0.000 description 3
- 229960001021 lactose monohydrate Drugs 0.000 description 3
- 229960001344 methylphenidate Drugs 0.000 description 3
- 229960001165 modafinil Drugs 0.000 description 3
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 3
- 229960003089 pramipexole Drugs 0.000 description 3
- 102000005962 receptors Human genes 0.000 description 3
- 108020003175 receptors Proteins 0.000 description 3
- UHSKFQJFRQCDBE-UHFFFAOYSA-N ropinirole Chemical compound CCCN(CCC)CCC1=CC=CC2=C1CC(=O)N2 UHSKFQJFRQCDBE-UHFFFAOYSA-N 0.000 description 3
- 239000012748 slip agent Substances 0.000 description 3
- 210000000813 small intestine Anatomy 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- CETWSOHVEGTIBR-FORAGAHYSA-N (2s)-2,6-diamino-n-[(2s)-1-phenylpropan-2-yl]hexanamide;methanesulfonic acid Chemical compound CS(O)(=O)=O.CS(O)(=O)=O.NCCCC[C@H](N)C(=O)N[C@@H](C)CC1=CC=CC=C1 CETWSOHVEGTIBR-FORAGAHYSA-N 0.000 description 2
- JVTIXNMXDLQEJE-UHFFFAOYSA-N 2-decanoyloxypropyl decanoate 2-octanoyloxypropyl octanoate Chemical compound C(CCCCCCC)(=O)OCC(C)OC(CCCCCCC)=O.C(=O)(CCCCCCCCC)OCC(C)OC(=O)CCCCCCCCC JVTIXNMXDLQEJE-UHFFFAOYSA-N 0.000 description 2
- 206010000117 Abnormal behaviour Diseases 0.000 description 2
- KORNTPPJEAJQIU-KJXAQDMKSA-N Cabaser Chemical compound C1=CC([C@H]2C[C@H](CN(CC=C)[C@@H]2C2)C(=O)N(CCCN(C)C)C(=O)NCC)=C3C2=CNC3=C1 KORNTPPJEAJQIU-KJXAQDMKSA-N 0.000 description 2
- GJSURZIOUXUGAL-UHFFFAOYSA-N Clonidine Chemical compound ClC1=CC=CC(Cl)=C1NC1=NCCN1 GJSURZIOUXUGAL-UHFFFAOYSA-N 0.000 description 2
- 239000001856 Ethyl cellulose Substances 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 239000004471 Glycine Substances 0.000 description 2
- INJOMKTZOLKMBF-UHFFFAOYSA-N Guanfacine Chemical compound NC(=N)NC(=O)CC1=C(Cl)C=CC=C1Cl INJOMKTZOLKMBF-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N Iron oxide Chemical compound [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 2
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 239000004368 Modified starch Substances 0.000 description 2
- 208000029726 Neurodevelopmental disease Diseases 0.000 description 2
- BKRGVLQUQGGVSM-KBXCAEBGSA-N Revanil Chemical compound C1=CC(C=2[C@H](N(C)C[C@H](C=2)NC(=O)N(CC)CC)C2)=C3C2=CNC3=C1 BKRGVLQUQGGVSM-KBXCAEBGSA-N 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000000853 adhesive Substances 0.000 description 2
- 230000001070 adhesive effect Effects 0.000 description 2
- 230000036626 alertness Effects 0.000 description 2
- 239000002269 analeptic agent Substances 0.000 description 2
- 208000007502 anemia Diseases 0.000 description 2
- 229960004596 cabergoline Drugs 0.000 description 2
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical class [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 2
- 235000011132 calcium sulphate Nutrition 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 229920002301 cellulose acetate Polymers 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 229960002896 clonidine Drugs 0.000 description 2
- 230000006835 compression Effects 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 230000003111 delayed effect Effects 0.000 description 2
- 229960000632 dexamfetamine Drugs 0.000 description 2
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 2
- 229960003638 dopamine Drugs 0.000 description 2
- 238000001647 drug administration Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 229920001249 ethyl cellulose Polymers 0.000 description 2
- 235000019325 ethyl cellulose Nutrition 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 229960002048 guanfacine Drugs 0.000 description 2
- 239000002955 immunomodulating agent Substances 0.000 description 2
- 229940121354 immunomodulator Drugs 0.000 description 2
- 230000002584 immunomodulator Effects 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 230000002045 lasting effect Effects 0.000 description 2
- 229960004502 levodopa Drugs 0.000 description 2
- 229960003587 lisuride Drugs 0.000 description 2
- 235000012054 meals Nutrition 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 230000003340 mental effect Effects 0.000 description 2
- JUMYIBMBTDDLNG-UHFFFAOYSA-N methylphenidate hydrochloride Chemical compound [Cl-].C=1C=CC=CC=1C(C(=O)OC)C1CCCC[NH2+]1 JUMYIBMBTDDLNG-UHFFFAOYSA-N 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 235000019426 modified starch Nutrition 0.000 description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 238000005453 pelletization Methods 0.000 description 2
- 229960004851 pergolide Drugs 0.000 description 2
- YEHCICAEULNIGD-MZMPZRCHSA-N pergolide Chemical compound C1=CC([C@H]2C[C@@H](CSC)CN([C@@H]2C2)CCC)=C3C2=CNC3=C1 YEHCICAEULNIGD-MZMPZRCHSA-N 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 230000007958 sleep Effects 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000008117 stearic acid Substances 0.000 description 2
- 208000011580 syndromic disease Diseases 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 1
- NHOWDZOIZKMVAI-UHFFFAOYSA-N (2-chlorophenyl)(4-chlorophenyl)pyrimidin-5-ylmethanol Chemical compound C=1N=CN=CC=1C(C=1C(=CC=CC=1)Cl)(O)C1=CC=C(Cl)C=C1 NHOWDZOIZKMVAI-UHFFFAOYSA-N 0.000 description 1
- LYYQHISTJJLOEF-JEDNCBNOSA-N (2S)-2,6-diaminohexanoic acid methanesulfonic acid Chemical compound S(C)(=O)(=O)O.N[C@@H](CCCCN)C(=O)O LYYQHISTJJLOEF-JEDNCBNOSA-N 0.000 description 1
- QFLMOYQNYBDXMT-ZCMDIHMWSA-N (2s)-2-amino-3-(3,4-dihydroxyphenyl)propanoic acid;2-amino-3-hydroxy-n'-[(2,3,4-trihydroxyphenyl)methyl]propanehydrazide Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1.OCC(N)C(=O)NNCC1=CC=C(O)C(O)=C1O QFLMOYQNYBDXMT-ZCMDIHMWSA-N 0.000 description 1
- DMBUODUULYCPAK-UHFFFAOYSA-N 1,3-bis(docosanoyloxy)propan-2-yl docosanoate Chemical compound CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCCCCCC DMBUODUULYCPAK-UHFFFAOYSA-N 0.000 description 1
- KWJPTZSGVFKSDH-UHFFFAOYSA-N 1-(3-nitrophenyl)piperazine;dihydrochloride Chemical compound Cl.Cl.[O-][N+](=O)C1=CC=CC(N2CCNCC2)=C1 KWJPTZSGVFKSDH-UHFFFAOYSA-N 0.000 description 1
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 1
- GIPOFCXYHMWROH-UHFFFAOYSA-L 2-aminoacetate;iron(2+) Chemical compound [Fe+2].NCC([O-])=O.NCC([O-])=O GIPOFCXYHMWROH-UHFFFAOYSA-L 0.000 description 1
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 1
- UQSASSBWRKBREL-UHFFFAOYSA-K 2-hydroxyethyl(trimethyl)azanium;iron(3+);2-oxidopropane-1,2,3-tricarboxylate;trihydrate Chemical compound O.O.O.[Fe+3].C[N+](C)(C)CCO.[O-]C(=O)CC([O-])(C([O-])=O)CC([O-])=O UQSASSBWRKBREL-UHFFFAOYSA-K 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical class [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- DQEFEBPAPFSJLV-UHFFFAOYSA-N Cellulose propionate Chemical compound CCC(=O)OCC1OC(OC(=O)CC)C(OC(=O)CC)C(OC(=O)CC)C1OC1C(OC(=O)CC)C(OC(=O)CC)C(OC(=O)CC)C(COC(=O)CC)O1 DQEFEBPAPFSJLV-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 244000131522 Citrus pyriformis Species 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 229920003151 Eudragit® RL polymer Polymers 0.000 description 1
- PMVSDNDAUGGCCE-TYYBGVCCSA-L Ferrous fumarate Chemical compound [Fe+2].[O-]C(=O)\C=C\C([O-])=O PMVSDNDAUGGCCE-TYYBGVCCSA-L 0.000 description 1
- DKKCQDROTDCQOR-UHFFFAOYSA-L Ferrous lactate Chemical compound [Fe+2].CC(O)C([O-])=O.CC(O)C([O-])=O DKKCQDROTDCQOR-UHFFFAOYSA-L 0.000 description 1
- 102000001554 Hemoglobins Human genes 0.000 description 1
- 108010054147 Hemoglobins Proteins 0.000 description 1
- 206010020651 Hyperkinesia Diseases 0.000 description 1
- 208000000269 Hyperkinesis Diseases 0.000 description 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 229940086616 Monoamine oxidase B inhibitor Drugs 0.000 description 1
- RCEAADKTGXTDOA-UHFFFAOYSA-N OS(O)(=O)=O.CCCCCCCCCCCC[Na] Chemical compound OS(O)(=O)=O.CCCCCCCCCCCC[Na] RCEAADKTGXTDOA-UHFFFAOYSA-N 0.000 description 1
- MHQJUHSHQGQVTM-HNENSFHCSA-N Octadecyl fumarate Chemical compound CCCCCCCCCCCCCCCCCCOC(=O)\C=C/C(O)=O MHQJUHSHQGQVTM-HNENSFHCSA-N 0.000 description 1
- 241000920340 Pion Species 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- XDXHAEQXIBQUEZ-UHFFFAOYSA-N Ropinirole hydrochloride Chemical compound Cl.CCCN(CCC)CCC1=CC=CC2=C1CC(=O)N2 XDXHAEQXIBQUEZ-UHFFFAOYSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 102000007238 Transferrin Receptors Human genes 0.000 description 1
- 108010033576 Transferrin Receptors Proteins 0.000 description 1
- 102100026144 Transferrin receptor protein 1 Human genes 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 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
- 239000011149 active material Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000008051 alkyl sulfates Chemical class 0.000 description 1
- 230000001539 anorectic effect Effects 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 230000036528 appetite Effects 0.000 description 1
- 235000019789 appetite Nutrition 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- UMEAURNTRYCPNR-UHFFFAOYSA-N azane;iron(2+) Chemical compound N.[Fe+2] UMEAURNTRYCPNR-UHFFFAOYSA-N 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- 238000005452 bending Methods 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 239000013060 biological fluid Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 230000036765 blood level Effects 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 235000021152 breakfast Nutrition 0.000 description 1
- SNPPWIUOZRMYNY-UHFFFAOYSA-N bupropion Chemical compound CC(C)(C)NC(C)C(=O)C1=CC=CC(Cl)=C1 SNPPWIUOZRMYNY-UHFFFAOYSA-N 0.000 description 1
- 229960001058 bupropion Drugs 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 235000011116 calcium hydroxide Nutrition 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 239000001175 calcium sulphate Substances 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 239000004359 castor oil Chemical class 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 150000003943 catecholamines Chemical class 0.000 description 1
- 229920006217 cellulose acetate butyrate Polymers 0.000 description 1
- 229920006218 cellulose propionate Polymers 0.000 description 1
- 239000007765 cera alba Substances 0.000 description 1
- 239000007766 cera flava Substances 0.000 description 1
- 210000001175 cerebrospinal fluid Anatomy 0.000 description 1
- 239000013522 chelant Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000005253 cladding Methods 0.000 description 1
- 229940112502 concerta Drugs 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 229940099112 cornstarch Drugs 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- GXGAKHNRMVGRPK-UHFFFAOYSA-N dimagnesium;dioxido-bis[[oxido(oxo)silyl]oxy]silane Chemical compound [Mg+2].[Mg+2].[O-][Si](=O)O[Si]([O-])([O-])O[Si]([O-])=O GXGAKHNRMVGRPK-UHFFFAOYSA-N 0.000 description 1
- FWZTTZUKDVJDCM-CEJAUHOTSA-M disodium;(2r,3r,4s,5s,6r)-2-[(2s,3s,4s,5r)-3,4-dihydroxy-2,5-bis(hydroxymethyl)oxolan-2-yl]oxy-6-(hydroxymethyl)oxane-3,4,5-triol;iron(3+);oxygen(2-);hydroxide;trihydrate Chemical compound O.O.O.[OH-].[O-2].[O-2].[O-2].[O-2].[O-2].[O-2].[O-2].[O-2].[Na+].[Na+].[Fe+3].[Fe+3].[Fe+3].[Fe+3].[Fe+3].O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 FWZTTZUKDVJDCM-CEJAUHOTSA-M 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000003136 dopamine receptor stimulating agent Substances 0.000 description 1
- 239000000221 dopamine uptake inhibitor Substances 0.000 description 1
- 230000003291 dopaminomimetic effect Effects 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 239000011706 ferric diphosphate Substances 0.000 description 1
- 235000007144 ferric diphosphate Nutrition 0.000 description 1
- CADNYOZXMIKYPR-UHFFFAOYSA-B ferric pyrophosphate Chemical compound [Fe+3].[Fe+3].[Fe+3].[Fe+3].[O-]P([O-])(=O)OP([O-])([O-])=O.[O-]P([O-])(=O)OP([O-])([O-])=O.[O-]P([O-])(=O)OP([O-])([O-])=O CADNYOZXMIKYPR-UHFFFAOYSA-B 0.000 description 1
- 229940036404 ferric pyrophosphate Drugs 0.000 description 1
- 229950003601 ferrocholinate Drugs 0.000 description 1
- 229960001459 ferrous ascorbate Drugs 0.000 description 1
- 229940086413 ferrous bisglycinate Drugs 0.000 description 1
- 239000011773 ferrous fumarate Substances 0.000 description 1
- 235000002332 ferrous fumarate Nutrition 0.000 description 1
- 229960000225 ferrous fumarate Drugs 0.000 description 1
- 239000004222 ferrous gluconate Substances 0.000 description 1
- 235000013924 ferrous gluconate Nutrition 0.000 description 1
- 229960001645 ferrous gluconate Drugs 0.000 description 1
- 239000004225 ferrous lactate Substances 0.000 description 1
- 235000013925 ferrous lactate Nutrition 0.000 description 1
- 229940037907 ferrous lactate Drugs 0.000 description 1
- 229940062993 ferrous oxalate Drugs 0.000 description 1
- 230000035558 fertility Effects 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 210000005095 gastrointestinal system Anatomy 0.000 description 1
- 231100000734 genotoxic potential Toxicity 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Chemical class CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- FETSQPAGYOVAQU-UHFFFAOYSA-N glyceryl palmitostearate Chemical compound OCC(O)CO.CCCCCCCCCCCCCCCC(O)=O.CCCCCCCCCCCCCCCCCC(O)=O FETSQPAGYOVAQU-UHFFFAOYSA-N 0.000 description 1
- 229940046813 glyceryl palmitostearate Drugs 0.000 description 1
- 239000008240 homogeneous mixture Substances 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- JUMYIBMBTDDLNG-OJERSXHUSA-N hydron;methyl (2r)-2-phenyl-2-[(2r)-piperidin-2-yl]acetate;chloride Chemical compound Cl.C([C@@H]1[C@H](C(=O)OC)C=2C=CC=CC=2)CCCN1 JUMYIBMBTDDLNG-OJERSXHUSA-N 0.000 description 1
- 208000013403 hyperactivity Diseases 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
- 229960003284 iron Drugs 0.000 description 1
- 235000013980 iron oxide Nutrition 0.000 description 1
- 229940032961 iron sucrose Drugs 0.000 description 1
- OWZIYWAUNZMLRT-UHFFFAOYSA-L iron(2+);oxalate Chemical compound [Fe+2].[O-]C(=O)C([O-])=O OWZIYWAUNZMLRT-UHFFFAOYSA-L 0.000 description 1
- VRIVJOXICYMTAG-IYEMJOQQSA-L iron(ii) gluconate Chemical compound [Fe+2].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O VRIVJOXICYMTAG-IYEMJOQQSA-L 0.000 description 1
- 150000002518 isoindoles Chemical class 0.000 description 1
- 239000010977 jade Substances 0.000 description 1
- 229940059904 light mineral oil Drugs 0.000 description 1
- 229920001427 mPEG Polymers 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 235000001055 magnesium Nutrition 0.000 description 1
- 239000000391 magnesium silicate Substances 0.000 description 1
- 235000019793 magnesium trisilicate Nutrition 0.000 description 1
- 229940099273 magnesium trisilicate Drugs 0.000 description 1
- 229910000386 magnesium trisilicate Inorganic materials 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 229940101972 mirapex Drugs 0.000 description 1
- 238000002703 mutagenesis Methods 0.000 description 1
- 231100000350 mutagenesis Toxicity 0.000 description 1
- DNKKLDKIFMDAPT-UHFFFAOYSA-N n,n-dimethylmethanamine;2-methylprop-2-enoic acid Chemical compound CN(C)C.CC(=C)C(O)=O.CC(=C)C(O)=O DNKKLDKIFMDAPT-UHFFFAOYSA-N 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000002767 noradrenalin uptake inhibitor Substances 0.000 description 1
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 1
- 229960002748 norepinephrine Drugs 0.000 description 1
- 229940127221 norepinephrine reuptake inhibitor Drugs 0.000 description 1
- 229940117152 nuvigil Drugs 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 208000014451 palmoplantar keratoderma and congenital alopecia 2 Diseases 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000011458 pharmacological treatment Methods 0.000 description 1
- 238000012503 pharmacopoeial method Methods 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- WSHYKIAQCMIPTB-UHFFFAOYSA-M potassium;2-oxo-3-(3-oxo-1-phenylbutyl)chromen-4-olate Chemical compound [K+].[O-]C=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 WSHYKIAQCMIPTB-UHFFFAOYSA-M 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 229940117394 provigil Drugs 0.000 description 1
- 229940113775 requip Drugs 0.000 description 1
- 229940100486 rice starch Drugs 0.000 description 1
- 229940099204 ritalin Drugs 0.000 description 1
- 229960001879 ropinirole Drugs 0.000 description 1
- MEZLKOACVSPNER-GFCCVEGCSA-N selegiline Chemical compound C#CCN(C)[C@H](C)CC1=CC=CC=C1 MEZLKOACVSPNER-GFCCVEGCSA-N 0.000 description 1
- 229960003946 selegiline Drugs 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229920002545 silicone oil Polymers 0.000 description 1
- 239000002356 single layer Substances 0.000 description 1
- 230000003860 sleep quality Effects 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 229940071138 stearyl fumarate Drugs 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 229940012488 strattera Drugs 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 230000009747 swallowing Effects 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229940015977 teferrol Drugs 0.000 description 1
- 210000001103 thalamus Anatomy 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 238000004879 turbidimetry Methods 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 229940013007 vyvanse Drugs 0.000 description 1
- 235000013618 yogurt Nutrition 0.000 description 1
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—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
- A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
- A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
-
- 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
- A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/26—Iron; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
- A61K8/36—Carboxylic acids; Salts or anhydrides thereof
- A61K8/365—Hydroxycarboxylic acids; Ketocarboxylic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
- A61K8/36—Carboxylic acids; Salts or anhydrides thereof
- A61K8/368—Carboxylic acids; Salts or anhydrides thereof with carboxyl groups directly bound to carbon atoms of aromatic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/67—Vitamins
- A61K8/673—Vitamin B group
- A61K8/675—Vitamin B3 or vitamin B3 active, e.g. nicotinamide, nicotinic acid, nicotinyl aldehyde
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
- A61Q19/08—Anti-ageing preparations
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
- A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
- A61K2800/52—Stabilizers
- A61K2800/522—Antioxidants; Radical scavengers
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Organic Chemistry (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Inorganic Chemistry (AREA)
- Psychiatry (AREA)
- Birds (AREA)
- Emergency Medicine (AREA)
- Physiology (AREA)
- Gerontology & Geriatric Medicine (AREA)
- Dermatology (AREA)
- Nutrition Science (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
本发明涉及马吲哚的调释组合物及其在治疗注意力缺失症(ADD)或注意力缺失/多动障碍(ADHD)或相关的戒心缺失(即难以控制的睡意)或警惕性降低(即日间嗜睡)或过高的日间睡意(例如发作性睡病、特异性过眠症)中的用途,尤其是在治疗患有这些疾病的儿童、青少年和成人中的用途。
Description
本发明根据《美国法典》第35编第119节针对2016年3月9日向位于海牙的欧洲专利局提交的、申请号为PCT/EP2016/055048的PCT申请主张优先权,该PCT申请以引用方式被整体纳入本申请。本发明还根据《美国法典》第35编第119节针对2016年3月9日提交的、临时申请号为62/305,600的美国临时申请主张优先权,该美国临时申请以引用方式被整体纳入本申请。
本发明涉及马吲哚的调释组合物及其在治疗注意力缺失症(ADD)或注意力缺失/多动障碍(ADHD)或相关的戒心缺失(即难以控制的睡意)或警惕性降低(即日间嗜睡)或过高的日间睡意(例如发作性睡病、特异性过眠症)中的用途,尤其是在治疗患有这些疾病的儿童、青少年和成人中的用途。
ADHD是一种行为障碍,其构成了儿童和青少年精神病理学的最常见的模式(pattern)之一。这种行为障碍也出现在成人身上。虽然最近的纵向研究认为出现ADHD症状表象的成人可能不存在儿童期初发神经发育障碍(Moffitt 2015),但大多数可用数据和科学共识显示ADHD在成人和儿童中是同一病症(Kooji 2010)。实际上,ADHD的标准在DSM-V(美国精神医学学会,2013)中有所变化,将ADHD更加准确的定义为一种神经发育障碍,其始发于童年期,但是某些人会持续到成年后。在最近的研究中,ADHD的发病率在学龄儿童中约为7~8%(Barbaresi 2002),在成人中约为4~5%(Kessler 2006)。临床上,该障碍结合了注意力不集中、易冲动和运动机能亢进,对学习/工作、社交和人际功能造成了损害。未经治疗,儿童和成人无法专注于任务,降低了其学习/工作表现。另外,易冲动可能导致工作质量低下以及社交功能失常。
在ADHD药理学治疗中使用并被广泛接受的刺激剂属于数个药理学类别:精神刺激剂(安非他命、哌醋甲酯)、优格瑞格瑞克(eugregorics)类(阿莫达非尼、莫达非尼和阿屈非尼)、非刺激剂(阿托西汀、可乐定、胍法辛)和B型单胺氧化酶抑制剂(司来吉兰)。这些多巴胺能精神刺激剂通常能非常显著的改善注意力不集中、易冲动和多动,但是对许多患者而言却不够。
刺激剂(例如哌醋甲酯或安非他命盐)具有短半衰期,并且对大多数病人而言需要控释给药。即使是控释给药,要在上学(和/或工作)时间保持足够的药效并在集中注意力的同时能够使患者在夜间入眠并保持睡眠也是 很困难的。刺激剂与“开-关”效果的出现是有关联的,关停效果伴随着“症状反弹”效果并且在傍晚(例如需要完成家庭作业的时候)症状会加剧。
虽然刺激剂药物对与ADHD相关的很多症状都是一种有效的治疗手段,但是有人担心这些药物被误用或滥用,并且使用刺激剂药物会发生一些罕见但严重的心血管副作用。已经发现例如阿托西汀、可乐定、胍法辛等非刺激剂对治疗ADHD也有效果,但是这些制剂的药效无法与已观察到的刺激剂的药效相提并论(Faraone 2009)。即使是使用刺激剂治疗,大概四个患有ADHD的孩子中只有一个能获得最佳效果(Greenhill 1996)。虽然我们对于ADHD的理解和治疗已经获得了巨大的进步,但是这种病仍然很难治愈,需要开发其它治疗手段(Antshel 2011)。另外,在治疗ADHD时服用的一些药物不适于儿童服用,尤其是因为药片体积过大或需要一天数次服药。
根据DSM-IV(或DSM-V)标准使用马吲哚治疗注意力缺失/多动障碍(ADHD),包括让需要该治疗的患者服用有效量的马吲哚,该方法已在US8,293,779美国专利中有所描述。马吲哚具有下述的化学式:
5-(4-氯苯基)-2,5-二氢-3H-咪唑并[2,1-a]异吲哚-5-醇。
马吲哚在当代医药分类中被认为是精神刺激和食欲抑制药物。其在阿根廷、墨西哥/中美洲和日本被批准用于治疗肥胖。
在所有已研究的物种中,马吲哚对健康动物和人类的基本药理学作用是作用于下丘脑的调节食欲的多巴胺能中枢(Hadler, 1972)。它被大量代谢,然后大部分代谢物通过尿液排泄出去。马吲哚因具有三环化学结构而属于非安非他命化合物。它能够提供与安非他命非常接近的药代动力学性质,但是滥用倾向更小。实际上,马吲哚无法代谢为安非他命类化合物,但它通过阻碍多巴胺和去甲肾上腺素的再吸收来实现与安非他命类似的作用。
另外,在动物毒性研究中,马吲哚的潜在毒性被证明非常低。具体而言,没有观察到任何致癌作用、致突变作用、生育毒理学作用。
US8,293,779美国专利公开了以下内容:在单次或多次口服后,马吲哚的吸收在2-4小时后达到最大浓度(Tmax)。在健康的志愿者服用即释制剂后马吲哚的半衰期为9.1±1.7h(Kim 2009)。因此,在大约30~55小时后达到稳定状态的浓度。当剂量在1毫克/日和4毫克/日之间时,药代动力学是线性的(不依赖于剂量)。但是该结果与现有的马吲哚即释制剂相关。
马吲哚的即释药物组合物,例如Diminex®、Sanorex®和Teronac®,确保在体外时活性成分在<1h的时期内释放。实际上,已有报告称马吲哚的即释药物组合物处于中等温度时在中性和碱性水溶液包括人类血浆中出现了水解。由于血浆的弱碱性质,通过添加酸性缓冲液使马吲哚在人类血浆中获得更好的稳定性。
此类即释组合物因此需要每日服用两次,这就限制了其在学龄儿童这种特殊情形中的应用,因为第二次服用常常需要在中午完成,即上学时间。即使考虑到即释片在体外时将在1小时内完全溶出,在健康志愿者服用药物后3-4个小时后才会达到最大浓度(Tmax)(Kim 2009)。快速的初始吸收将更早的实现充分的全身接触以获得期望的疗效(例如提前服用并在1-2小时后患者在上学或工作时生效)。
Kidane等人的WO2001/123496号国际公布(2011)公开了一种马吲哚制剂,用于在高pH环境(例如结肠)中吸收马吲哚。这些制剂主要为胶囊包覆的颗粒,其可以用于即释、缓释和迟释。在Kidane文献中所公开的制剂被设计为具有肠溶包衣以在高pH环境中,例如6.8(示例参见实施例2、3、9和12),释放马吲哚,使其延迟至在小肠中溶出和释放,这将可能导致一大部分的药在到达结肠前不会被释放(Fallingborg J.)。由于临床药代动力学研究已经显示马吲哚不太可能在结肠中被吸收并且马吲哚的可溶性也随着pH增高而降低(即胃部的pH时溶解度最高,在结肠里溶解度最低,特别是由于再吸收导致水不够的情况下),这些制剂可能导致可吸收和溶出的马吲哚的利用率大幅降低。
为了获得每日一次的给药方案(需求很高的方案),还需要更好的控释部分来确保从白天到傍晚都能获得足够的血浆浓度,同时让服药者在夜晚入睡并保持睡眠。因此,需要一种包括马吲哚的药物组合物,该组合物具有改善并结合了即释和缓释的活性成分释放性质、对患者更少的要求以及在给药间隔期中稳定状态的马吲哚血浆浓度更小的波动。
发明内容
根据第一个方面,本发明涉及一种马吲哚口服药物单位剂型,该单位剂型为多层基质型片剂,包括:
-至少一个即释(IR)层,所述即释层包括马吲哚和至少一种稀释剂;
-至少一个缓释(SR)层,所述缓释层包括马吲哚和至少一种缓释、非pH依赖并且不溶于水的聚合物,
所包含的马吲哚总量在1至6毫克之间,所述即释层和缓释层的重量比在40:60至80:20之间,优选的为在50:50至70:30之间,更优选的为50:50。
根据本发明的形态为多层基质型片剂的口服药物单位剂型能够快速释放药物以快速获得治疗性血液水平,同时提供缓释部分以持续释放马吲哚供吸收进入患者血流中以获得更长的治疗效果。该组合因此能够使产品可以每日服用一次。该口服药物单位剂型具有以下优点:
-便于吞咽;
-便于生产;
-通过改变各个单层的成分来控制药物释放速率的能力;
-相对于其它剂型如胶囊和水剂极佳的稳定性;
-防止患者篡改剂型;
-在给药间隔期中稳定状态的马吲哚血浆浓度波动更小;
-更好的稳定性;
-1-2小时生效,无需推迟进食;以及
-缓慢加快心率。
根据另一个方面,本发明涉及一种用于制备根据本发明的所述单位剂型的方法,所述方法包括以下步骤:
(a)制备所述即释层的辅剂的混合物;
(a’)制备所述缓释层的辅剂的混合物;
(b)将步骤(a)得到的即释混合物和步骤(a’)得到的缓释混合物加入多层(优选的为双层)片剂的压片机中。
根据另一个方面,本发明涉及根据本发明的单位剂型在作为通过口服途径每日一次重复服用的药物产品的用途。
根据另一个方面,本发明涉及根据本发明的单位剂型在治疗注意力缺失症(ADD)或注意力缺失/多动障碍(ADHD)或相关的戒心缺失(即难以控制的睡意)或警惕性降低(即日间嗜睡)或过高的日间睡意(例如发作性睡病、特异性过眠症)中的用途,尤其是在治疗患有这些疾病的儿童、青少年和成人中的用途。
根据另一个方面,本发明涉及用于治疗注意力缺失症(ADD)或注意力缺失/多动障碍(ADHD)或相关的戒心缺失(即难以控制的睡意)或警惕性降低(即日间嗜睡)或过高的日间睡意(例如发作性睡病、特异性过眠症)的方法,所述方法包括让需要治疗的患者,尤其是需要治疗的儿童、青少年和成人,优选的通过口服途径每日一次重复服用根据本发明的所述单位剂型。
根据本发明的另一个方面,本发明涉及根据本发明的单位剂型,其与铁组合使用作为同时、单独或顺序使用的组合产品,特别是用于治疗注意力缺失症(ADD)或注意力缺失/多动障碍(ADHD)或相关的戒心缺失(即难以控制的睡意)或警惕性降低(即日间嗜睡)或过高的日间睡意(例如发作性睡病、特异性过眠症),尤其是治疗患有这些疾病的儿童、青少年和成人。
根据另一个方面,本发明涉及用于治疗注意力缺失症(ADD)或注意力缺失/多动障碍(ADHD)或相关的戒心缺失(即难以控制的睡意)或警惕性降低(即日间嗜睡)或过高的日间睡意(例如发作性睡病、特异性过眠症)的方法,所述方法包括让需要治疗的患者,尤其是需要治疗的儿童、青少年和成人,优选的通过口服途径每日一次重复服用根据本发明的所述单位剂型和铁。
根据本发明的另一个方面,本发明涉及根据本发明的单位剂型,其与精神刺激剂组合使用作为同时、单独或顺序使用的组合产品,特别是用于治疗注意力缺失症(ADD)或注意力缺失/多动障碍(ADHD)或相关的戒心缺失(即难以控制的睡意)或警惕性降低(即日间嗜睡)或过高的日间睡意(例如发作性睡病、特异性过眠症),尤其是治疗患有这些疾病的儿童、青少年和成人。
根据另一个方面,本发明涉及用于治疗注意力缺失症(ADD)或注意力缺失/多动障碍(ADHD)或相关的戒心缺失(即难以控制的睡意)或警惕性降低(即日间嗜睡)或过高的日间睡意(例如发作性睡病、特异性过眠症)的方法,所述方法包括让需要治疗的患者,尤其是需要治疗的儿童、青少年和成人,优选的通过口服途径每日一次重复服用根据本发明的所述单位剂型和精神刺激剂。
术语定义
术语“基质型片剂”在本发明中用于指代每层的内部结构从每层的中心至边缘都是均匀和相同的片剂。因此,根据本发明的片剂的层由粉末或颗粒状的活性成分和压缩基质的均匀混合物构成。
在本发明中所用的术语“压缩基质”指代参与了片剂凝聚的所有辅剂。所述压缩基质不溶于水,但是具有一定渗透性(亲水基质)或多孔网络(惰性基质),用于活性成分的缓慢释放,其不会随着介质的pH条件发生变化。术语“压缩混合物”在本申请中用于指代在压缩成片剂形态前片剂的所有组分(颗粒或非颗粒的活性成分以及压缩基质的组分)。
在本发明中使用时,术语“Cmax值”是指单次给药后血浆中的最大浓度,Cmax(ss)值是指稳定状态的Cmax值。控释制剂的Cmax值和Cmax(ss)值较低。
在本发明中使用时,术语“稳定状态”是指重复给药后4至7个半衰期后体内的浓度。稳定状态的浓度随着所用的制剂和给药频率而变化。处于稳定状态时,马吲哚的血浆浓度将在Cmax(ss)值和Cmin(ss)值(稳定状态观察到的最小浓度)之间变化。
重复给药的研究不仅提供了通常药代动力学参数(给药间隔稳定状态的曲线下方面积AUC(0-τ)值、Cmax(ss)值、达到Cmax值或Cmax(ss)值的时间Tmax值)的测定,而且显示了稳定状态峰值浓度(Cmax(ss)值)和谷值浓度(Cmin(ss)值)之间波动的剧烈程度。
Tmax是指达到峰值浓度的时间。该值依赖于药学活性材料的吸收速率。药代动力学参数Cmax值、Cmax(ss)值和Tmax值直接由实验图表决定。药物重复给药可涉及药物或其代谢物的一定累积,其大小取决于所用的给药安排。
假设药物M,以剂量D按照给药时间间隔τ口服。由于该药物在前一剂量完全消除前服用,因此服用量添加至之前剂量的未移除量(叠加原则)。在4-7个半衰期后,进入体内的药物吸收量相当于从体内移除的量并达到稳定状态。浓度在谷值浓度Cmin(ss)值和峰值浓度Cmax(ss)值之间变化。在本发明中使用时,“重复口服给药”是指以给药时间间隔τ(20至24小时之间)服用剂量D的根据本发明的制剂。
“波动”和“摆动”参数以“%”表示,根据下列等式计算:
-波动:100*(Cmax(ss)-Cmin(ss))/Cav
其中Cav为“平均稳定状态浓度”,表示AUC(0-τ)除以给药间隔:Cav=AUC(0-τ)/τ。
在本发明中,短语“波动减少”可以指Cmax(ss)值与Cmin(ss)值之间的差或峰值与谷值之间的差减小,或优选地,“波动”参数的值在一个具体实施方式中为25%至75%,在一个具体实施方式中为<60%,在一个具体实施方式中为<50%,并且更优选的小于35%。
-摆动:100*(Cmax(ss)-Cmin(ss))/Cmin(ss)=Δ。
半衰期(t1/2)是指药物在体液或组织中的浓度C达到C/2浓度的时间。
给药间隔稳定状态的曲线下方面积AUC(0-τ)值对应于给定给药间隔期间血浆浓度的积分。AUC(0-τ)值的单位为质量(毫克、纳克)X升(或毫升)-1X小时,并且依赖于药物的生物可用性和清除率。
在本发明中,具有“较小波动”的曲线图是指一个具体实施方式所述的摆动Δ小于50%或一个具体实施方式所述的摆动Δ<60%或一个具体实施方式所述的摆动Δ<35%的曲线图。
在本发明中,具有“较小波动”的曲线图是指血浆曲线图至少12小时维持在Cmax(ss)值的40%以上或优选的50%以上。
“即释(IR)层”是指在约1小时或之内释放重量百分比约80%或以上的马吲哚的层。
“缓释(SR)层”是指马吲哚释放速率慢于即释层的层。
附图说明
图1-6显示了实施例3的原型片剂的溶出曲线图。
图1是所有溶出曲线重叠图;
图2是系列1制剂的曲线重叠图;
图3是系列2制剂的曲线重叠图;
图4是50/50即释/缓释比片剂制剂的溶出曲线重叠图;
图5是60/40即释/缓释比片剂制剂的溶出曲线重叠图;
图6是70/30即释/缓释比片剂制剂的溶出曲线重叠图;
图7是用UV探针(100-15021)和HPLC分析(15021LC)的100-15021批次的片剂的溶出曲线重叠图;
图8是用UV探针(100-15022)和HPLC分析(15022LC)的100-15022批次的片剂的溶出曲线重叠图。
具体实施方式
根据本发明的药物组合物为马吲哚口服药物单位剂型,其形态为多层基质型片剂,所述单位剂型包括:
-至少一个即释(IR)层,所述即释层包括马吲哚和至少一种稀释剂;
-至少一个缓释(SR)层,所述缓释层包括马吲哚和至少一种缓释、非pH依赖并且不溶于水的聚合物,
所包含的马吲哚总量在1至5毫克之间,所述即释层和缓释层的重量比在40:60至80:20之间,优选的为在50:50至70:30之间,更优选的为50:50。优选的,根据本发明的所述单位剂型为双层片剂。
在根据本发明的制剂的具体实施方式中,马吲哚的溶出度可以为1小时60%至80%以及2小时70%至90%,根据美国药典方法2(Pharmacopeia Method 2)用50rpm的转叶法(rotating blade method)测定,溶解介质为500毫升的0.01N(当量浓度)HCl。在另一个具体实施方式中,根据本发明的单位剂型的溶出度为0.5小时50%-65%、1小时55%-85%、2小时65%-95%、4小时不少于75%以及8小时不少于85%。
优选的,根据本发明的单位剂型处于50至200毫克之间,优选的为100毫克。优选的,根据本发明的单位剂型包括2至5毫克的马吲哚,优选的包括1至3毫克的马吲哚,更优选的包括4毫克马吲哚。
优选的,根据本发明的单位剂型在体内获得的马吲哚血浆浓度维持在稳定状态,具有较小波动,至少12小时维持在Cmax(ss)值的40%以上,优选的维持在Cmax(ss)值的50%以上,更优选的维持在Cmax(ss)值的60%以上。
稀释剂的示例包括:乳糖、一水乳糖、无水乳糖、喷雾干燥乳糖、碳酸钙、硫酸钙、无水硫酸钙、三水乳酸钙、一水硫酸氢钙、碳酸钙、磷酸钙、磷酸氢钙、可压缩糖、淀粉水解寡糖、糊精、右旋葡萄糖、磷酸钙、高岭土、碳酸镁、氧化镁、麦芽糖糊精、甘露醇、粉状纤维素、淀粉、改性淀粉、淀粉水解物、预胶凝淀粉、微晶纤维素、粉状纤维素、纤维素及纤维素衍生物、羟基丙基甲基纤维素、羟基丙基甲基纤维素及蔗糖,优选的为乳糖、无水乳糖、喷雾干燥乳糖、微晶纤维素、粉状纤维素、纤维素及纤维素衍生物。
即释层中的稀释剂含量可以在即释层总重量的1%至95%(重量百分比)之间变化,优选的在30%至60%(重量百分比)之间变化,更优选的在45%至55%(重量百分比)之间变化。
优选的,根据本发明的单位剂型每一层都包括润滑剂。
润滑剂和助滑剂可以用在本申请中以防止、减少或禁止组合物中各成分的粘黏或摩擦。它们能够辅助压缩以及被压缩的组合物从期望的模具中脱模。它们与药物组合物的各成分是兼容的并且不会明显降低药物组合物的可溶性、硬度、化学稳定性、物理稳定性或生物活性。用于本申请的药学上可接受的润滑剂和助滑剂选自但并不限于以下物质组成的组:硬脂酸、硬脂酸金属盐、硬脂酸锌、硬脂酸镁、三硅酸镁、氢氧化钙、磷酸钙、碳酸镁、氧化镁、硬脂酸钙、单硬脂酸甘油酯、蜡、甘油酯、山嵛酸甘油酯、棕榈酸硬脂酸甘油酯、硅油、氢化植物油、氢化蓖麻油、轻矿物油、矿物油、聚乙二醇、甲氧基聚乙二醇、乙酸钠、油酸钠、氯化钠、亮氨酸、苯甲酸钠、烷基硫酸盐、十二烷基硫酸钠、硬脂基富马酸钠、滑石粉、硅胶、玉米淀粉、粉状纤维素和/或硼酸。润滑剂/助滑剂的优选范围为层的重量百分比的0%至1%。
根据本发明的片剂中的缓释层的缓释、非pH依赖并且不溶于水的聚合物选自以下物质组成的组:纤维素聚合物、与烯丙基蔗糖或季戊四醇烯丙基醚交联的丙烯酸高分子聚合物(卡波普、卡波姆)、甲基丙烯酸类聚合物、聚乙烯醇衍生物、乳酸-乙醇酸聚合物(PLGA)、淀粉、蜡、聚乙酸乙烯酯衍生物、聚乙烯吡咯烷酮衍生物及其混合物,优选的选自以下物质组成的组:纤维素聚合物、与烯丙基蔗糖或季戊四醇烯丙基醚交联的丙烯酸高分子聚合物(卡波普、卡波姆)。
纤维素聚合物包括羟基丙基甲基纤维素(HPMC)、羟基丙基纤维素(HPC)、羧甲基纤维素钠 (sodium CMC)、乙基纤维素衍生物,例如乙酸纤维素、乙酸丁酸纤维素、乙酸纤维素丙酸纤维素、乙酸琥珀酸羟基丙基甲基纤维素、微晶纤维素(例如商标为Avicel®的微晶纤维素)和乙基纤维素(例如商标为Aqualon®的乙基纤维素)。
甲基丙烯酸类聚合物包括以下等级:Eudragit®RL 12.5、RL PO与RL 100与RS12.5、RS PO与RS 100。淀粉包括天然淀粉(例如玉米淀粉)和改性淀粉(例如预凝胶淀粉)。蜡包括白蜂蜡或黄蜂蜡、聚乙酸乙烯酯衍生物。
缓释层中的缓释、非pH依赖并且不溶于水的聚合物的含量为缓释层总重量的80%~99%(重量百分比),优选的为90%~97%(重量百分比)。
根据本发明的单位剂型可以包括防聚剂。本发明所使用的防聚剂包括滑石粉、二氧化硅及其衍生物、丙烯酸酯、蓖麻油衍生物、纤维素化合物、氧化铁、硬脂酸镁、硬脂酸和/或硬脂酸钠。
根据本发明的片剂的层可以包括粘合剂。根据本发明的粘合剂包括羟基丙基甲基纤维素(HPMC)、羟基丙基纤维素(HPC)、麦芽糖糊精、聚乙烯吡咯烷酮(PVP)和/或微晶纤维素。
压缩基质优选的,除了压缩基质的辅剂外,还包括一个或多个用于促进压缩过程适当进行的辅剂。
马吲哚的代谢物(即2-(2-氨基乙基)-3-(对氯苯基)-3-羟基苯并吡咯酮或2-(对氯苯甲酰基)-N-2-(氨基乙基) 苯甲酰胺))的Cmax值约为马吲哚的1/4,其半衰期比马吲哚长。它可以累积并带来马吲哚的疗效,特别是在稳定状态。可以使用剂量为0.25毫克至12毫克此种代谢物来治疗发作性睡病或ADHD。
本发明还涉及制备根据本发明的单位剂型的方法,所述方法包括以下步骤:
(a)制备所述即释层的辅剂的混合物;
(a’)制备所述缓释层的辅剂的混合物;
(b)将步骤(a)得到的即释混合物和步骤(a’)得到的缓释混合物加入多层(优选的为双层)片剂的压片机中。
马吲哚只要中等温度和极少量的水就会水解。因此去除马吲哚制剂中的水能够提供更好的稳定性。在制备根据本发明的单位剂型时,优选的在过程中不加入水。在本发明的一个方面,提供一种基本不含水的马吲哚制剂,使得含水量的重量比小于1.5%、1%或优选的小于0.5%。由于制备根据本发明的双层或多层片剂的优选方法不使用水,这能够有效的去除湿气并因此为根据本发明的双层或多层片剂制剂提供更好的稳定性。另外,根据本发明的双层或多层设计提供了更好的均匀性以及在片剂一致性方面更小的变化,从而使片剂中以及最终服用时的马吲哚量保持一致。
在本发明的上下文中,注意力缺失/多动障碍(ADHD)的诊断是基于ICD-10(国际疾病分类(ICD),世界健康组织)以及DSM-V(精神障碍诊断统计手册第五版)使用的国际分类所定义的临床特征。
DSM-V的标准包括三个维度(注意力不集中、冲动和多动)、普通智能(IQ>80)并且存在单纯缺铁但不贫血,也就是说具有正常的血红蛋白水平。短语“缺铁”是指缺铁症但是对可溶性转铁蛋白受体的血清浓度没有显著改变。
“ADHD症状”具体指代注意力障碍,例如注意力不集中、冲动、耐心缺失、对立性障碍,还包括日间或夜间运动机能亢进、不安腿综合症以及失眠。
“失眠”指代的是:
a.特征为入睡困难的入睡失眠;
b.特征为夜间运动机能亢进和夜间醒来的持续失眠;
c.一般是慢性的并且与焦虑、压力和抑郁发作相关联的精神病理学失眠。
对通过根据本发明的包括马吲哚的调释药物组合物并任选的与铁和/或精神刺激剂一起在治疗注意力缺失/多动障碍中的疗效进行评估的标准是注意力缺失/多动症状的评定量表严重程度评分AHD-RS降低(>30%)(经过12周的治疗并且康纳父母问卷(CPRS)、康纳教师问卷(CTRS)和CGI(临床总体印象)的严重程度评分有改善)。使用CASS量表(儿童及青少年嗜睡量表)来评估主观嗜睡。通过不安腿综合症严重程度量表来评估入睡质量。
本发明中的患者选自新生儿、儿童、青少年和成人。根据优选的具体实施方式,患者为儿童或青少年或成人,更优选的为大约为5~12岁的儿童。本发明中的患者优选的缺铁但不贫血。铁蛋白缺乏可以通过血清来测定,但也可以通过其它生物液如脑脊液来测定。
铁蛋白缺乏对应于成人患者血清中的铁蛋白含量低于约50微克/升。这种“铁存储缺失”(表现为低铁蛋白水平)可以达到铁蛋白含量低于约40微克/升,或者甚至低于约35微克/升、低于30微克/升、低于20微克/升、低于15微克/升,或者甚至低于约10微克/升。确定血清中的铁蛋白的技术对于本领域的技术人员而言是已知的。可以引用免疫酶方法(IMX铁蛋白试剂盒,雅培实验室)。
本发明中的患者的血清中可溶于转铁蛋白的受体的浓度正常。转铁蛋白涉及生物体细胞对铁的获取。该获取行为由细胞表面存在的转铁蛋白受体的数量控制。这些受体的浓度可以通过本领域技术人员已知的技术来评估,例如比浊法(Ruivard等人,《内科学杂志》(Rev Méd Interne),21:837-843)。可溶于转铁蛋白的受体的浓度的正常范围是男性2.0-4.50毫克/升以及女性1.80-4.70毫克/升(参见罗氏公司的RsTF试剂盒,编号2148315)。
根据本发明的另一个方面,马吲哚与铁组合作为同时、单独或顺序使用的组合产品。
根据该用途的一个优选具体实施方式,铁作为补充剂在患者服用马吲哚之前使用。在本发明中,“铁”是指形态为铁原子、铁盐或有机铁或任何药学上可接受的含有铁的制剂的铁。以下以非穷尽的方式列举,药学上可接受的铁盐选自亚铁盐和铁盐,优选的选自柠檬酸铁铵、焦磷酸铁、铁胆盐、抗坏血酸亚铁、门冬氨酸亚铁、氯化亚铁、硫酸亚铁、酒石酸亚铁、富马酸亚铁、葡萄糖酸亚铁、葡庚糖酸亚铁、硫酸甘氨酸亚铁、乳酸亚铁、草酸亚铁和琥珀酸亚铁。
根据本发明的优选具体实施方式,所述铁盐为硫酸亚铁,优选的为护胃的硫酸亚铁。
或者,所述药学上可接受的铁的形态为右旋糖酐铁、蔗糖铁、聚麦芽糖铁或山梨醇铁。当铁的形态为药学上可接受的有机盐时,其优选的为双甘氨酸铁、甘氨酸铁或蛋白琥珀酸铁。
根据本发明的优选具体实施方式,根据本发明的可以与铁相关联使用的马吲哚可以与至少一种化合物组合实施,以作为同时、单独或顺序使用的组合产品,所述至少一种化合物选自精神刺激剂。
精神刺激剂化合物指代多巴胺和/或去甲肾上腺素再摄取抑制剂和儿茶酚胺激动剂。其中可以非穷尽的引用下列药物:
1)精神刺激剂化合物:哌醋甲酯(特别推荐Ritalin®、Concerta®、Equasym®、Quasym、Medikinet Retard®)、阿莫达非尼(Nuvigil®)、莫达非尼(Sparlon®、Modiodal®、Provigil®)、阿托西汀(Strattera®)、安非他酮以及安非他命,例如d-安非他命、右旋苯丙胺、右旋安非他命和甲磺酸赖氨酸安非他命(Vyvanse®、Elvanse®)。
2)左旋多巴胺:美道普(Modopar)、息宁(Sinemat)。
3)选择性多巴胺受体激动剂:普拉克索(pramipexole)(Sifrol®、Mirapex®)、罗匹尼罗(ropinirole)(Requip®、Adartrel®)、麦角乙脲(lisuride)、培高利特(Pergolide)、卡麦角林(cabergoline)等。
具体而言,当马吲哚与硫酸亚铁关联使用时,患者每日单次或多次服用的硫酸亚铁的量为0.1毫克至10毫克,优选的为每日100毫克至2克,更优选的约为500毫克。
更具体而言,根据本发明,患者持续12周补充铁,特别是硫酸亚铁,并且接受12周的马吲哚治疗。
根据本发明,所述组合物还包括铁或其药学上可接受的盐中的一种和/或精神刺激剂。
在本发明的具体实施方式中,提供马吲哚控释制剂,其在分层片剂中包含即释和缓释层,所述片剂被摄入后一开始会大量释放马吲哚,接下来则是缓慢持续(例如从摄入起6~8小时)的释放,这样就能在其到达结肠前在小肠中被溶出和吸收。马吲哚的初始利用率对ADHD患者很有益处,因为他们在一日之初需要足够水平的精神警觉性和敏锐度从而使他们能够集中精神在例如工作或驾车去工作上。之后,根据本发明的制剂所提供的马吲哚在肠道中缓慢持续的释放和吸收确保了在白天和傍晚(例如用于完成工作日或家庭作业)都能达到足够的血浆浓度,同时允许服药者入睡并在夜间保持睡眠。
使用体外TIM肠胃系统(一种模拟人类胃部和小肠的动态多隔室系统,用于研究各种生物肠胃条件下口服剂型强度的变化)获得的数据显示根据本发明所配制的马吲哚的生物可接受量在进食和禁食条件下是类似的;但是进食状态中Tmax值相对于禁食状态被延迟了一小时或以上,表明食物对马吲哚的影响。如果需要快速起效,根据这些数据应当预期患者可能需要在服用马吲哚后等待约2小时再吃早饭。但是,有利地,如果在体内使用根据本发明的制剂,就可以在进餐前提前少得多的时间(例如30分钟)服用马吲哚,并且仍然能一开始就在胃部大量释放马吲哚,而无需延迟进餐,仍能在不晚于禁食状态的情况下在进食状态达到Tmax值。如上文所述,这对ADHD患者尤其有益,因为所提供的马吲哚初始量提高了患者在一日之初(例如驾车上班和开始上课)的精神警觉性和敏锐度。
Konofal(2014)文献报告了马吲哚Cmax值与其对患有ADHD的儿童的疗效或安全方面无关。出乎我们意料的是,相对于服用例如马吲哚即释制剂,服用本发明的马吲哚制剂后的低Cmax值在不牺牲疗效的情况下导致心率加快得更加缓慢。如果服用根据本发明的制剂后Cmax值比服用马吲哚即释制剂后的Cmax值低20%至40%,那么服用本发明的制剂后与服用马吲哚相关的心率加速令人吃惊和出人意料的减少了4至11跳/分。这是临床方面的重大成果。
实施例
实施例1:溶出曲线图的条件:
溶解介质:0.01N HCl
介质体积:500毫升
美国药典装置2(桨叶)
速度:50rpm
介质温度:37℃±0.5℃
测试6片剂(除非另有说明)
时间点:1、2、4、6、8小时
使用注射器或连接有套管和10微米全流式过滤器的自动采样器从每个容器中取约5毫升样本。
实施例2:生产马吲哚双层片剂的流程
A.缓释(SR)层(2毫克片剂)生产流程
1.对以下成分称重: 含量 W/W%
a.马吲哚 2.0
b.一水乳糖NF/羟基丙基甲基纤维素NF(Retalac®) 97.0
c.卡波普 971P 0.5
d.硬脂酸镁 0.5
总计=100%
2.将来自步骤1的成分a、b、c过筛进入V型混合机并混合20分钟;
3.将步骤2所得成分通过粉碎整粒机(Comil);
4.将步骤3所得成分加入V型混合机中;
5.将来自步骤1的成分d过筛进入混合机并混合5分钟;
6.收取来自步骤5的材料用于片剂生产。
B.即释(IR)层(2毫克)片剂生产流程
1.对以下成分称重: 含量 W/W%
a.马吲哚 2.0
b.一水乳糖NF 97.5
c.硬脂酸镁 0.5
总计=100%
2.将来自步骤1的成分a、b过筛进入V型混合机并混合20分钟;
3.将步骤2所得成分通过粉碎整粒机(Comil);
4.将步骤3所得成分加入V型混合机中;
5.将来自步骤1的成分c过筛进入混合机并混合5分钟;
6.收取来自步骤5的材料用于片剂生产。
C.片剂生产
1.为双层压片机设定正确的重量;
2.将即释混合物加入料斗1;
3.将缓释混合物加入料斗2;
4.将片剂压缩至100毫克的总重量。
实施例3:实施例2的双层片剂的溶出曲线图
制备了6片双层片剂。根据美国药典马吲哚片剂专题进行溶出度测试。
使用Pion公司Rainbow UV探针对每个批次n=3片片剂收集数据。报告的释放百分比数值是每个原型药批次中两片或三片片剂的平均值。
双层片剂制剂基于两种缓释(SR)制剂和一种即释(IR)制剂。
即释制剂与每个缓释制剂以三个不同的质量比(IR/SR=50/50、60/40以及70/30)组合形成六个双层片剂原型。
各个原型片剂的定量配方与其研发批次号一起列在表1和表2中。
表-1的制剂包括利用HPMC和卡波普971P来调节马吲哚溶出度的缓释制剂,其被归类为系列1原型制剂。
表-2的制剂包括含有两种不同分子量级的HPMC来调节马吲哚溶出度的缓释制剂,其被归类为系列2原型制剂。
表-3:各个原型制剂的溶出度测试结果报告。
表-1:系列1原型片剂制剂
表-2:系列2原型片剂制剂
表-3:原型片剂批次的溶出度结果(UV探针分析数据)
所有原型片剂批次都进行了两轮不同的溶出度测试,使用UV探针分析的n=3轮次和使用HPLC分析的n=4轮次。
表-4:对批次100-15021和100-15022以n=3UV探针分析的溶出度测试和n=4 HPLC分析的溶出度测试的结果比对报告。
表4-样本溶出度的UV探针分析和HPLC分析比对
原型片剂的溶出度数据揭示了系列1制剂在早期时间点溶出度曲线的差异最大。
系列2制剂显示了该缓释/即释层重量比范围内这些时间点的差异较小。
引用文献
Kim SS,Lee HW,Lee KT,《通过液相色谱质谱联用法来确定人血浆中马吲哚的有效方法》,生物医学生命科学杂志色谱B分析技术,2009;877: 1011-16。
Barbaresi WJ等人: 《注意力缺失/多动障碍有多常见明尼苏达州罗切斯特基于人口的出生组的发病率》,儿科学与青少年疾病文献集,2002; 156(3):217-224。
Kessler RC等人: 《美国成人ADHD患病率及相关内容:来自国家发病率研究复测的结果》,美国精神病学杂志, 2006, 163(4):716-723。
Faraone SV, Glatt SJ:《使用效果大小荟萃分析对用于注意力缺失/多动障碍的药物的疗效的比对》,临床精神病学杂志,2009;71(6):754-763。
Fallingborg J:《人类胃肠道的管腔内pH值》,丹麦医学公报,1999年6月;46(3):183-96。
Greenhill LL等人: 《MTA研究中的药物治疗策略:与临床人员和研究人员的关联》,美国儿童和青少年精神病学学会杂志,1996;35(10): 1304-1313。
Antshel KM等人: 《对ADHD的理解和治疗的进步》, BMC医药杂志,2011;9:72-84。
Moffitt TE等人:《成人ADHD是否是儿时初发的精神发展性障碍来自持续四十年的纵向同期组群研究的证据》,美国精神病学杂志,2015:appiajp201514101266 (电子版先于纸版)。
Kooij SJ等人:《关于成人ADHD诊断和治疗的欧洲共识声明:欧洲网络成人ADHD》,BMC精神病学杂志,2010;10:67。
Konofal, Eric等人:《对患有注意力缺失/多动障碍的儿童的II期试验研究》. 药物设计、开发及疗法,8 (2014): 2321-2332。
Kidane等人, 国际公布号:WO2001/123496, 公布日:2011年10月6日。
Claims (12)
1.一种马吲哚口服药物单位剂型,所述单位剂型为多层基质型片剂,其特征在于,所述单位剂型包括:
-至少一个即释(IR)层,所述即释层包括马吲哚和至少一种稀释剂;
-至少一个缓释(SR)层,所述缓释层包括马吲哚和至少一种缓释、非pH依赖并且不溶于水的聚合物,
所包含的马吲哚总量在1至6毫克之间,所述即释层和缓释层的重量比在40:60至80:20之间,优选的为在50:50至70:30之间,更优选的为50:50。
2.根据权利要求1所述的单位剂型,其特征在于,所述单位剂型的溶出度为1小时60%至80%、2小时70%至90%,该溶出度根据美国药典方法2用50rpm的转叶法测定,溶解介质为500毫升的0.01NHCl。
3.根据权利要求1或2所述的单位剂型,其特征在于,所述单位剂型的重量为50至200毫克,优选的为100毫克。
4.根据权利要求1至3中任一项所述的单位剂型,其特征在于,所述即释层中的所述稀释剂选自以下物质组成的组:乳糖、无水乳糖、喷雾干燥乳糖、碳酸钙、硫酸钙、无水硫酸钙、三水乳酸钙、一水硫酸氢钙、碳酸钙、磷酸钙、磷酸氢钙、可压缩糖、淀粉水解寡糖、糊精、右旋葡萄糖、磷酸钙、高岭土、碳酸镁、氧化镁、麦芽糖糊精、甘露醇、粉状纤维素、淀粉、改性淀粉、淀粉水解物、预胶凝淀粉、微晶纤维素、粉状纤维素、纤维素及纤维素衍生物、羟基丙基甲基纤维素、羟基丙基甲基纤维素及蔗糖,优选的选自以下物质组成的组:乳糖、无水乳糖、喷雾干燥乳糖、微晶纤维素、粉状纤维素、纤维素及纤维素衍生物。
5.根据权利要求1至4中任一项所述的单位剂型,其特征在于,所述缓释层的缓释、非pH依赖并且不溶于水的聚合物选自以下物质组成的组:纤维素聚合物、与烯丙基蔗糖或季戊四醇烯丙基醚交联的丙烯酸高分子聚合物(卡波普、卡波姆)、甲基丙烯酸类聚合物、聚乙烯醇衍生物、乳酸-乙醇酸聚合物(PLGA)、淀粉、蜡、聚乙酸乙烯酯衍生物、聚乙烯吡咯烷酮衍生物及其混合物,优选的选自以下物质组成的组:纤维素聚合物、与烯丙基蔗糖或季戊四醇烯丙基醚交联的丙烯酸高分子聚合物(卡波普、卡波姆)。
6.根据权利要求1至5中任一项所述的单位剂型,其特征在于,所述单位剂型的每一层都包括润滑剂。
7.根据权利要求1至6中任一项所述的单位剂型,其特征在于,所述单位剂型在体内获得的马吲哚血浆浓度维持在稳定状态,所述马吲哚血浆浓度具有较小波动,至少12小时维持在Cmax(ss)值的40%以上,优选的维持在Cmax(ss)值的60%以上。
8.一种用于制备权利要求1至7所述单位剂型的方法,所述方法包括以下步骤:
(a)制备所述即释层的辅剂的混合物;
(a’)制备所述缓释层的辅剂的混合物;
(b)将步骤(a)得到的即释混合物和步骤(a’)得到的缓释混合物加入多层(优选的为双层)片剂的压片机中。
9.权利要求1至7所述单位剂型作为通过口服途径每日一次重复服用的药物产品的用途。
10.权利要求1至7所述单位剂型在治疗注意力缺失症(ADD)或注意力缺失/多动障碍(ADHD)或相关的戒心缺失(即难以控制的睡意)或警惕性降低(即日间嗜睡)或过高的日间睡意(例如发作性睡病、特异性过眠症),尤其是在治疗患有这些疾病的儿童、青少年和成人中的用途。
11.权利要求1至7所述单位剂型与铁组合使用作为同时、单独或顺序使用的组合产品,特别是用于治疗注意力缺失症(ADD)或注意力缺失/多动障碍(ADHD)或相关的戒心缺失(即难以控制的睡意)或警惕性降低(即日间嗜睡)或过高的日间睡意(例如发作性睡病、特异性过眠症),尤其是治疗患有这些疾病的儿童、青少年和成人的用途。
12.权利要求1至7所述单位剂型与精神刺激剂组合使用作为同时、单独或顺序使用的组合产品,特别是用于治疗注意力缺失症(ADD)或注意力缺失/多动障碍(ADHD)或相关的戒心缺失(即难以控制的睡意)或警惕性降低(即日间嗜睡)或过高的日间睡意(例如发作性睡病、特异性过眠症),尤其是治疗患有这些疾病的儿童、青少年和成人的用途。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202310749459.0A CN116803379A (zh) | 2016-03-09 | 2017-03-08 | 一种马吲哚即释/缓释多层片剂及其在治疗注意力缺失/多动障碍(adhd)中的用途 |
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201662305600P | 2016-03-09 | 2016-03-09 | |
PCT/EP2016/055048 WO2017152974A1 (en) | 2016-03-09 | 2016-03-09 | A mazindol ir/sr multilayer tablet and its use for the treatment of attention deficit/hyperactivity disorder (adhd) |
EPPCT/EP2016/055048 | 2016-03-09 | ||
US62/305,600 | 2016-03-09 | ||
PCT/IB2017/000352 WO2017153846A2 (en) | 2016-03-09 | 2017-03-08 | A mazindol ir/sr multilayer tablet and its use for the treatment of attention deficit/hyperactivity disorder (adhd) |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202310749459.0A Division CN116803379A (zh) | 2016-03-09 | 2017-03-08 | 一种马吲哚即释/缓释多层片剂及其在治疗注意力缺失/多动障碍(adhd)中的用途 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN109152740A true CN109152740A (zh) | 2019-01-04 |
Family
ID=58710015
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201780028569.0A Pending CN109152740A (zh) | 2016-03-09 | 2017-03-08 | 一种马吲哚即释/缓释多层片剂及其在治疗注意力缺失/多动障碍(adhd)中的用途 |
CN202310749459.0A Pending CN116803379A (zh) | 2016-03-09 | 2017-03-08 | 一种马吲哚即释/缓释多层片剂及其在治疗注意力缺失/多动障碍(adhd)中的用途 |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202310749459.0A Pending CN116803379A (zh) | 2016-03-09 | 2017-03-08 | 一种马吲哚即释/缓释多层片剂及其在治疗注意力缺失/多动障碍(adhd)中的用途 |
Country Status (16)
Country | Link |
---|---|
US (3) | US11207271B2 (zh) |
EP (2) | EP3928770A1 (zh) |
JP (2) | JP7127832B2 (zh) |
KR (1) | KR102304743B1 (zh) |
CN (2) | CN109152740A (zh) |
AU (2) | AU2017230974B2 (zh) |
BR (1) | BR112018068143A2 (zh) |
CA (1) | CA3016852C (zh) |
ES (1) | ES2884973T3 (zh) |
IL (2) | IL295519A (zh) |
MA (2) | MA55045A (zh) |
MX (1) | MX2018010864A (zh) |
NZ (1) | NZ745921A (zh) |
PL (1) | PL3426232T3 (zh) |
PT (1) | PT3426232T (zh) |
WO (1) | WO2017153846A2 (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN110946826A (zh) * | 2019-12-12 | 2020-04-03 | 烟台大学 | 一种利奥西呱口服制剂及其制备方法 |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3302442A4 (en) | 2015-06-03 | 2019-02-06 | Triastek, Inc. | PHARMACEUTICAL FORM AND USE THEREOF |
MX2020002560A (es) | 2017-09-07 | 2020-07-13 | Nls 1 Pharma Ag | Tratamiento con mazindol de la dependencia a la heroina y el trastorno de uso de sustancias. |
US11571391B2 (en) | 2018-01-09 | 2023-02-07 | Triastek, Inc. | Oral drug dosage forms compromising a fixed-dose of an ADHD non-stimulant and an ADHD stimulant |
Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1579401A (zh) * | 2003-08-11 | 2005-02-16 | 李亦武 | 一种止咳平喘药物新剂型及制备方法 |
CN1593404A (zh) * | 2004-07-16 | 2005-03-16 | 南京亿华药业有限公司 | 甲硝唑双层叠合缓释片及其制备方法 |
WO2006069030A1 (en) * | 2004-12-20 | 2006-06-29 | Collegium Pharmaceutical, Inc. | Pharmaceutical compositions for sleep disorders |
CN1985823A (zh) * | 2006-11-21 | 2007-06-27 | 北京润德康医药技术有限公司 | 一种含有盐酸二甲双胍罗格列酮的缓释制剂及其制备方法 |
US20070264323A1 (en) * | 2006-05-12 | 2007-11-15 | Shire Llc | Controlled dose drug delivery system |
US20090318520A1 (en) * | 2008-06-20 | 2009-12-24 | Afecta Pharmaceuticals Drive | Use of isoindoles for the treatment of neurobehavioral disorders |
WO2011123496A1 (en) * | 2010-03-31 | 2011-10-06 | Supernus Pharmaceuticals, Inc. | Formulations of mazindol |
CN104013620A (zh) * | 2006-04-11 | 2014-09-03 | 法国公立援助医院 | 在治疗注意力缺陷/多动障碍中联合使用马吲哚 |
Family Cites Families (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4855440A (en) | 1988-02-16 | 1989-08-08 | Sherex Chemical Company, Inc. | Method for producing stabilized imidazoline derivatives |
US20060240105A1 (en) | 1998-11-02 | 2006-10-26 | Elan Corporation, Plc | Multiparticulate modified release composition |
JP2001102172A (ja) | 1999-09-30 | 2001-04-13 | Idemitsu Kosan Co Ltd | 有機エレクトロルミネッセンス素子 |
GB0009522D0 (en) | 2000-04-19 | 2000-06-07 | Smithkline Beecham Plc | Composition |
WO2002038133A2 (en) | 2000-11-10 | 2002-05-16 | F. Hoffman-La Roche Ag | Compositions containing hydrolytically unstable compounds |
US20050226927A1 (en) * | 2004-04-02 | 2005-10-13 | Impax Laboratories, Inc. | Pharmaceutical dosage forms having immediate release and/or controlled release properties that contain a GABAB receptor agonist |
ES2383330T3 (es) * | 2005-11-28 | 2012-06-20 | Orexigen Therapeutics, Inc. | Formulación de liberación sostenida de zonisamida |
KR100752417B1 (ko) | 2006-02-14 | 2007-08-28 | 대원제약주식회사 | 안정성이 증진된, 마진돌을 포함하는 약제학적 조성물 |
EP2240022B1 (en) * | 2008-01-09 | 2016-12-28 | Charleston Laboratories, Inc. | Bilayered tablets comprising oxycodone and promethazine |
US8796338B2 (en) * | 2011-01-07 | 2014-08-05 | Elcelyx Therapeutics, Inc | Biguanide compositions and methods of treating metabolic disorders |
-
2017
- 2017-03-08 US US16/083,131 patent/US11207271B2/en active Active
- 2017-03-08 PL PL17724102T patent/PL3426232T3/pl unknown
- 2017-03-08 KR KR1020187028626A patent/KR102304743B1/ko active IP Right Grant
- 2017-03-08 WO PCT/IB2017/000352 patent/WO2017153846A2/en active Application Filing
- 2017-03-08 IL IL295519A patent/IL295519A/en unknown
- 2017-03-08 NZ NZ745921A patent/NZ745921A/en unknown
- 2017-03-08 PT PT177241023T patent/PT3426232T/pt unknown
- 2017-03-08 IL IL261418A patent/IL261418B/en unknown
- 2017-03-08 ES ES17724102T patent/ES2884973T3/es active Active
- 2017-03-08 CN CN201780028569.0A patent/CN109152740A/zh active Pending
- 2017-03-08 MA MA055045A patent/MA55045A/fr unknown
- 2017-03-08 CN CN202310749459.0A patent/CN116803379A/zh active Pending
- 2017-03-08 BR BR112018068143A patent/BR112018068143A2/pt active Search and Examination
- 2017-03-08 MX MX2018010864A patent/MX2018010864A/es unknown
- 2017-03-08 CA CA3016852A patent/CA3016852C/en active Active
- 2017-03-08 EP EP21177251.2A patent/EP3928770A1/en active Pending
- 2017-03-08 EP EP17724102.3A patent/EP3426232B1/en active Active
- 2017-03-08 JP JP2018546837A patent/JP7127832B2/ja active Active
- 2017-03-08 AU AU2017230974A patent/AU2017230974B2/en active Active
- 2017-03-08 MA MA045840A patent/MA45840A/fr unknown
-
2021
- 2021-11-30 US US17/538,333 patent/US20220160639A1/en not_active Abandoned
-
2022
- 2022-04-27 AU AU2022202771A patent/AU2022202771A1/en active Pending
- 2022-08-10 JP JP2022127603A patent/JP7504488B2/ja active Active
-
2024
- 2024-01-10 US US18/409,041 patent/US20240165034A1/en active Pending
Patent Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1579401A (zh) * | 2003-08-11 | 2005-02-16 | 李亦武 | 一种止咳平喘药物新剂型及制备方法 |
CN1593404A (zh) * | 2004-07-16 | 2005-03-16 | 南京亿华药业有限公司 | 甲硝唑双层叠合缓释片及其制备方法 |
WO2006069030A1 (en) * | 2004-12-20 | 2006-06-29 | Collegium Pharmaceutical, Inc. | Pharmaceutical compositions for sleep disorders |
CN104013620A (zh) * | 2006-04-11 | 2014-09-03 | 法国公立援助医院 | 在治疗注意力缺陷/多动障碍中联合使用马吲哚 |
US20070264323A1 (en) * | 2006-05-12 | 2007-11-15 | Shire Llc | Controlled dose drug delivery system |
CN1985823A (zh) * | 2006-11-21 | 2007-06-27 | 北京润德康医药技术有限公司 | 一种含有盐酸二甲双胍罗格列酮的缓释制剂及其制备方法 |
US20090318520A1 (en) * | 2008-06-20 | 2009-12-24 | Afecta Pharmaceuticals Drive | Use of isoindoles for the treatment of neurobehavioral disorders |
WO2011123496A1 (en) * | 2010-03-31 | 2011-10-06 | Supernus Pharmaceuticals, Inc. | Formulations of mazindol |
Non-Patent Citations (2)
Title |
---|
叶勇等: "《制药工艺学》", 28 February 2014, 华南理工大学出版社 * |
朱盛山: "《药物新剂型》", 31 January 1993, 人民卫生出版社 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN110946826A (zh) * | 2019-12-12 | 2020-04-03 | 烟台大学 | 一种利奥西呱口服制剂及其制备方法 |
Also Published As
Publication number | Publication date |
---|---|
KR20190019044A (ko) | 2019-02-26 |
MA55045A (fr) | 2021-12-29 |
IL261418B (en) | 2022-09-01 |
CA3016852A1 (en) | 2017-09-14 |
US20240165034A1 (en) | 2024-05-23 |
JP7504488B2 (ja) | 2024-06-24 |
WO2017153846A3 (en) | 2017-10-12 |
IL295519A (en) | 2022-10-01 |
JP7127832B2 (ja) | 2022-08-30 |
AU2017230974B2 (en) | 2022-02-03 |
MA45840A (fr) | 2021-05-05 |
PL3426232T3 (pl) | 2022-01-10 |
KR102304743B1 (ko) | 2021-09-24 |
US20220160639A1 (en) | 2022-05-26 |
WO2017153846A2 (en) | 2017-09-14 |
ES2884973T3 (es) | 2021-12-13 |
EP3928770A1 (en) | 2021-12-29 |
CA3016852C (en) | 2021-03-23 |
IL261418A (en) | 2018-10-31 |
NZ745921A (en) | 2021-12-24 |
AU2022202771A1 (en) | 2022-05-19 |
BR112018068143A2 (pt) | 2019-07-30 |
EP3426232B1 (en) | 2021-06-02 |
EP3426232A2 (en) | 2019-01-16 |
US20210038521A1 (en) | 2021-02-11 |
AU2017230974A1 (en) | 2018-09-20 |
MX2018010864A (es) | 2019-03-28 |
US11207271B2 (en) | 2021-12-28 |
JP2022160647A (ja) | 2022-10-19 |
PT3426232T (pt) | 2021-08-31 |
CN116803379A (zh) | 2023-09-26 |
JP2019507771A (ja) | 2019-03-22 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
ES2427628T3 (es) | Nuevas composiciones de 1-[2-(2,4-dimetil-fenilsulfanil)-fenil]piperazina | |
US20220160639A1 (en) | Mazindol ir/sr multilayer tablet and its use for the treatment of attention deficit/hyperactivity disorder (adhd) | |
CN104812378B (zh) | 固体剂型 | |
BRPI0708059A2 (pt) | formulação de niacina de baixo rubor | |
BRPI0609779A2 (pt) | composição farmacêutica oral de liberação controlada, e, método de tratamento da deficiência de hormÈnio da tireóide | |
WO2017152974A1 (en) | A mazindol ir/sr multilayer tablet and its use for the treatment of attention deficit/hyperactivity disorder (adhd) | |
CN113018271B (zh) | 一种坦度螺酮药物组合物及其制备方法和用途 | |
CN100528144C (zh) | 醋氯芬酸缓释片及其制备方法 | |
KR20230008913A (ko) | 알펠리십을 포함하는 제약 조성물 | |
TWI297609B (en) | A new oral dosage containing desloratadine and pseudoephedrine hc1 or h2s04 drugs with immediate-release and controlled-release delivery. | |
EP2478902A1 (en) | Pharmaceutical composition for reducing weight and method for the production thereof | |
PT2848259E (pt) | Formulações farmacêuticas de tiocolquicosido de libertação prolongada |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 40002539 Country of ref document: HK |
|
RJ01 | Rejection of invention patent application after publication | ||
RJ01 | Rejection of invention patent application after publication |
Application publication date: 20190104 |